Dermatopathology: Third Edition

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Dermatopathology

Notice Medicine is an ever-changing science. As new research and clinical experience broaden our knowledge, changes in treatment and drug therapy are required. The authors and the publisher of this work have checked with sources believed to be reliable in their efforts to provide information that is complete and generally in accord with the standards accepted at the time of publication. However, in view of the possibility of human error or changes in medical sciences, neither the authors nor the publisher nor any other party who has been involved in the preparation or publication of this work warrants that the information contained herein is in every respect accurate or complete, and they are not responsible for any errors or omissions or for the results obtained from use of such information. Readers are encouraged to confirm the information contained herein with other sources. For example and in particular, readers are advised to check the product information sheet included in the package of each drug they plan to administer to be certain that the information contained in this book is accurate and that changes have not been made in the recommended dose or in the contraindications for administration. This recommendation is of particular importance in connection with new or infrequently used drugs.

Dermatopathology Editor in Chief Raymond L. Barnhill, MD Professor of Dermatology and Pathology Hôpital Saint-Louis Université Paris Diderot Paris, France

Associate Editors Arthur Neil Crowson, MD Clinical Professor of Dermatology, Pathology and Surgery Director of Dermatopathology University of Oklahoma Chairman of Pathology St John Medical Center President Pathology Laboratory Associates Tulsa, Oklahoma

Cynthia M. Magro, MD Professor Division of Dermatopathology Deptartment of Pathology Cornell University Weill Medical College New York, New York

Michael W. Piepkorn, MD Clinical Professor of Dermatology, Department of Medicine, University of Washington School of Medicine, Seattle, Washington

New York Chicago San Francisco Lisbon London Madrid Mexico City Milan New Delhi San Juan Scoul Singapore Sydney Toronto

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To Claire

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CONTENTS

PA RT 2. Predominantly Noninflammatory Conditions 14 Alterations of the Stratum Corneum and Epidermis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .313

CONTENTS

Contributors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ix Foreword . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . xiii Preface to the Third Edition . . . . . . . . . . . . . . . . . . . . . . . . . . xv Preface to the First Edition . . . . . . . . . . . . . . . . . . . . .xvii

Michael W. Piepkorn

PA RT 1. Inflammatory Reactions In the Skin 1 Introduction to Microscopic Interpretation . . . . . .3 Raymond L. Barnhill and Daniel M. Jones

2

Spongiotic Dermatitis . . . . . . . . . . . . . . . . . . . . . .15 Michael Murphy and Jane M. Grant-Kels

3

Interface Dermatitis . . . . . . . . . . . . . . . . . . . . . . .36 Frances I. Ramos-Ceballos and Thomas D. Horn

4

Psoriasiform Dermatitis . . . . . . . . . . . . . . . . . . . .64 Timothy T. Chang and Loren E. Golitz

5 6

Franco Rongioletti and Raymond L. Barnhill

17 Alterations of Collagen and Elastin . . . . . . . . . .387 Kapil Gupta, Laurence Verneuil, Clifton R. White, Jr., and Raymond L. Barnhill

18 Ectopic Tissue . . . . . . . . . . . . . . . . . . . . . . . . . . .408 Jacqueline M. Junkins-Hopkins

PA RT 3. Infections 19 Bacterial Infections . . . . . . . . . . . . . . . . . . . . . . .421

Nodular and Diffuse Cutaneous Infiltrates . . . . .98 Intraepidermal Vesiculopustular Diseases . . . . .136

Subepidermal Blistering Diseases . . . . . . . . . . .156 Mosaad Megahed and Akmal Saad Hassan

9

16 Deposition Disorders . . . . . . . . . . . . . . . . . . . . .362

Superficial and Deep Perivascular Dermatitis . . .81

Terence J. Harrist, Brian Schapiro, Lisa Lerner, Cynthia M. Magro, James Ramirez, and Jenny Cotton

8

A. Neil Crowson, Sarah Zeller, and Raymond L. Barnhill

A. Neil Crowson

Jeff D. Harvell and Raymond L. Barnhill

7

15 Disorders of Pigmentation . . . . . . . . . . . . . . . . .338

Vasculitis and Related Disorders . . . . . . . . . . . .179 Sarah K. Barksdale and Raymond L. Barnhill

10 Disorders of Cutaneous Appendages . . . . . . . .213 David A. Whiting, Douglas C. Parker, Amy K. Reisenauer, and Alvin R. Solomon

11 Panniculitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . .250 Raymond L. Barnhill and Birgitta Schimdt

12 Cutaneous Drug Eruptions . . . . . . . . . . . . . . . . .281 A. Neil Crowson and Cynthia M. Magro

13 Cutaneous Reactions to Exogenous Agents . . .301 Raymond L. Cornelison and A. Neil Crowson

Ronald P. Rapini

20 Treponemal and Rickettsial Diseases . . . . . . . .446 A. Neil Crowson, Cynthia M. Magro, J. Stephen Dumler, Grace F. Kao, and Raymond L. Barnhill

21 Fungal Infections . . . . . . . . . . . . . . . . . . . . . . . . .458 Catherine Lisa Kauffman, Victoria Hobbs Hamet, Steven R. Tahan, Klaus J. Busam, and Raymond L. Barnhill

22 Viral Infections . . . . . . . . . . . . . . . . . . . . . . . . . .495 Clay J. Cockerell and James J. Lyons

23 Protozoal and Algal Infections . . . . . . . . . . . . . .517 Ann Marie Nelson, Paul Hofman, and Freddye Lemons-Estes

24 Helminthic Diseases . . . . . . . . . . . . . . . . . . . . . .530 Kapil Gupta and Franz von Lichtenberg

PA RT 4. Proliferations—Hamartomas, Hyperplasias, and Neoplasias 25 Cutaneous Cysts and Related Lesions . . . . . . . .543 Glynis A. Scott

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26 Tumors of the Epidermis . . . . . . . . . . . . . . . . . .556 Alan S. Boyd

27 Tumors of Melanocytes . . . . . . . . . . . . . . . . . . .615 Raymond L. Barnhill

28 Tumors with Hair Follicle and Sebaceous Differentiation . . . . . . . . . . . . . . . . . . . . . . . . . .689

34 Lymphoid, Leukemic, and Other Cellular Infiltrates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .905 Werner Kempf, Guenter Burg, Lorenzo Cerroni, Helmut Kerl, Stanislaw A. Buechner, and W.P. Daniel Su

35 Cutaneous Metastases . . . . . . . . . . . . . . . . . . . .960 Michael S. Rabkin

Mark R. Wick and Raymond L. Barnhill

29 Sweat Gland Tumors . . . . . . . . . . . . . . . . . . . . .725 Mark R. Wick and Raymond L. Barnhill

30 Fibrous and Fibrohistiocytic Tumors . . . . . . . .766 Stefan Kraft and Scott R. Granter

CONTENTS

31 Vascular Tumors and Vascular Malformations . . . . . . . . . . . . . . . . . . . . . . . . . .802 Michel Wassef, Steven J. Hunt, Daniel J. Santa Cruz, and Raymond L. Barnhill

32 Tumors of Adipose Tissue, Muscle, Cartilage, and Bone . . . . . . . . . . . . . . . . . . . . . . .857 Shady El-Zayaty and Thomas Krausz

33 Neural and Neuroendocrine Tumors . . . . . . . . .883 Zsolt B. Argenyi and Chris H. Jokinen

PA RT 5. Disorders of Nails and the Oral Mucosa 36 Disorders of the Nail Apparatus . . . . . . . . . . . .983 Aldo González-Serva

37 Disorders of the Oral Mucosa . . . . . . . . . . . . .1002 Mark A. Lerman and Sook-Bin Woo

Appendix 1: Stem Cells and the Skin . . . . . . . . . . . .1022 Laurence Verneuil, Anne Janin, and Raymond L. Barnhill

Appendix 2: Laboratory Methods . . . . . . . . . . . . . . .1024 Klaus J. Busam and Raymond L. Barnhill

Appendix 3: Molecular Biologic Techniques for the Diagnosis of Cutaneous Lymphomas . . . . . . .1033 Gary S. Wood

Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1039

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CONTRIBUTORS

Sarah K. Barksdale, MD Dermatopathologist Summit Pathology Greeley, Colorado Chapter 9: Vasculitis and Related Disorders Raymond L. Barnhill, MD Professor of Dermatology and Pathology Hôpital Saint-Louis Universitè Paris VII Paris, France Appendix, Chapters 1, 6, 9, 11, 15, 16, 17, 20, 21, 27, 28, 29, 31 Emmanuelle Bourrat, MD Dermatologist Hôpital Saint-Louis Paris, France Provision of Clinical Photographs Alan S. Boyd, MD Associate Professor Departments of Dermatology and Pathology Vanderbilt University Nashville, Tennessee Chapter 26: Tumors of the Epidermis Stanislaw A. Buechner, MD Professor of Dermatology University of Basel Basel, Switzerland Chapter 34: Lymphoid, Leukemic, and Other cellular Infiltrates (Section 3: Cutaneous Hodgkin Lymphoma)

Guenter Burg, MD Department of Dermatology, University Hospital of Zürich Zürich, Switzerland Chapter 34: Lymphoid, Leukemic, and Other cellular Infiltrates (Section 1: Cutaneous T-Cell Lymphoid Hyperplasia and Cutaneous T-Cell Lymphomas)

Raymond L. Cornelison, Jr. MD Professor and Herzog Chair Department of Dermatology University of Oklahoma College of Medicine Oklahoma City, Oklahoma Chapter 13: Cutaneous Reactions to Exogenous Agents

Klaus J. Busam, MD Professor Department of Pathology Memorial Sloan-Kettering Cancer Center New York, New York Chapter 21: Fungal Infections, Appendix

Jenny Cotton, MD, PhD Dermatopathology Department St. Joseph Mercy Hospital Ann Arbor, Michigan Chapter 7: Intraepidermal Vesiculopustular Diseases

Lorenzo Cerroni, MD Associate Professor, Department of Dermatology Medical University of Graz Graz, Austria Chapter 34: Lymphoid, Leukemic, and Other cellular Infiltrates (Section 2: Cutaneous B-Cell Lymphoid Hyperplasia and Cutaneous B-Cell Lymphomas) Timothy T. Chang, MD Dermatopathology Fellow Department of Pathology University of Colorado Health Sciences Center Denver, Colorado Chapter 4: Psoriasiform Dermatitis Clay J. Cockerell, MD Clinical Professor Director of Dermatopathology Division University of Texas Southwestern Medical Center Medical Director, Cockerell & Associates Dallas, Texas Chapter 22: Viral Infections

CONTRIBUTORS

Zsolt B. Argenyi, MD Professor of Pathology and Dermatology Director of Dermatopathology University of Washington Medical Center Seattle, Washington Chapter 33: Neural and Neuroendocrine Tumors

Arthur Neil Crowson, MD Clinical Professor of Dermatology, Pathology and Surgery Director of Dermatopathology University of Oklahoma Chairman of Pathology St John Medical Center President, Pathology Laboratory Associates Tulsa, Oklahoma Chapter 5: Superficial and Deep Perivascular Dermatitis; Chapter 12: Cutaneous Drug Eruptions; Chapter 15: Disorders of Pigmentation; Chapter 20: Treponemal and Rickettsial Diseases J. Stephen Dumler, MD Professor Division of Medical Microbiology Department of Pathology Johns Hopkins University School of Medicine and Johns Hopkins Hospital Baltimore, Maryland Chapter 20: Treponemal and Rickettsial Diseases

ix

Shady El-Zayaty, MD Fellow Department of Pathology The University of Chicago Chicago, Illinois Chapter 32: Tumors of Adipose Tissue, Muscle, Cartilage, and Bone Loren E. Golitz, MD Clinical Professor of Pathology and Dermatology University of Colorado Health Sciences Center Denver, Colorado Chapter 4: Psoriasiform Dermatitis

CONTRIBUTORS

Aldo González-Serva, MD Dermatophathologist Winchester Hospital and Strata Diagnostics Winchester and Waltham, Massachusetts Chapter 36: Disorders of the Nail Apparatus Scott R. Granter, MD Associate Professor Harvard Medical School Associate Pathologist Department of Pathology Brigham and Women’s Hospital Consultant, Dana-Farber Cancer Institute Boston, Massachusetts Chapter 30: Fibrous and Fibrohistiocytic Tumors Jane M. Grant-Kels, MD Assistant Dean of Clinical Affairs Professor and Chair, Department of Dermatology Director of Dermatopathology Director of the Cutanous Oncology Center and Melanoma Program Director, Dermatology Residency University of Connecticut Health Center Farmington, Connecticut Chapter 2: Spongiotic Dermatitis Kapil Gupta, MD Dermatopathologist Dermatology Group of the Carolinas Concord, North Carolina Chapter 17: Alterations of Collagen and Elastin; Chapter 24: Helminthic Diseases Jeff D. Harvell, MD Bethesda Dermatopathology Silver Spring, Maryland Chapter 6: Nodular and Diffuse Cutaneous Infiltrates

x

Akmal S. Hassan MSc, MD Consultant in Dermatology Faculty of Medicine Cairo University Cairo, Egypt Chapter 8: Subepidermal Blistering Diseases

Victoria Hobbs Hamet, MD Division of Dermatology Georgetown University Washington, DC Chapter 21: Fungal Infections Terence J . Harrist, MD Dermatophathologist Winchester Hospital and Strata Diagnostics Winchester and Waltham, Massachusetts Chapter 7: Intraepidermal Vesiculopustular Diseases Paul Hofman MD, PhD Professor Department of Pathology Pasteur Hospital University of Nice Sophia Antipolis, Nice, France Laboratory of Clinical and Experimental Pathology Pasteur Hospital Nice, France Chapter 23: Protozoal and Algal Infections Thomas D. Horn MD, MBA Dermatopathologist CarisCohenDx Newton, Massachusetts Chapter 3: Interface Dermatitis Steven J. Hunt, MD Northern Pathology Laboratory Iron Mountain, Michigan Chapter 31: Vascular Tumors and Vascular Malformations Anne Janin, MD, PhD Professor of Pathology Universitè Paris Diderot Head of Research Unit 728 Inserm Medical Coordinator Pathology and Biology Departments Hôpital Saint-Louis Paris, France Appendix: Stem cells and the skin Chris H. Jokinen, MD Dermatopathology Fellow Department of Pathology University of Washington Seattle, Washington Chapter 33: Neural and Neuroendocrine Tumors Daniel M. Jones, MD Associate Professor Division of Pathology and Laboratory Medicine University of Texas M.D. Anderson Cancer Center Houston, Texas Chapter 1: Introduction to Microscopic Interpretation

Jacqueline M. Junkins-Hopkins, MD Associate Professor Division of Dermatopathology Departments of Dermatology and Pathology Johns Hopkins University School of Medicine and Johns Hopkins Hospital Baltimore, Maryland Chapter 18: Ectopic Tissue Grace F. Kao, MD Director of Dermapathology Department of Pathology and Laboratory Medicine Maryland Veterans Affairs Medical Center Baltimore, Maryland Professor of Dermatopathology and Dermatology George Washington University School of Medicine Washington, DC Chapter 20: Treponemal and Rickettsial Diseases Catherine Lisa Kauffman MD, FACP Chief, Division of Dermatology Associate Professor of Medicine, Dermatology, and Pathology Georgetown University Washington, DC Chapter 21: Fungal Infections Werner Kempf, MD Lecturer and Consultant Physician Department of Dermatology University Hospital of Zürich Zürich, Switzerland Kempf und Pfaltz Histologische Diagnostik Zürich, Switzerland Chapter 34: Lymphoid, Leukemic, and Other cellular Infiltrates (Section 1: Cutaneous T-Cell Lymphoid Hyperplasia and Cutaneous T-Cell Lymphomas) Helmut Kerl, MD Professor of Dermatology Emeritus Department of Dermatology Medical University of Graz Graz, Austria Chapter 34: Lymphoid, Leukemic, and Other cellular Infiltrates (Section 2: Cutaneous B-Cell Lymphoid Hyperplasia and Cutaneous B-Cell Lymphomas) Stefan Kraft, MD Clinical Fellow Harvard Medical School Resident in Pathology Brigham and Women’s Hospital Boston, Massachusetts Chapter 30: Fibrous and Fibrohistiocytic Tumors

Thomas Krausz, MD, FRCPath Professor Director of Anatomic Pathology Department of Pathology The University of Chicago Chicago, Illinois Chapter 32: Tumors of Adipose Tissue, Muscle, Cartilage, and Bone

Michael J. Murphy, MB, BCh, BAO Associate Professor of Dermatology Director of Immunopathology Dermatopathology Laboratory Department of Dermatology University of Connecticut Health Center Farmington, Connecticut Chapter 2: Spongiotic Dermatitis

Freddye M. Lemons-Estes, MD Quest Diagnostics, Inc. North Florida Anatomic Pathology Tampa, Florida Chapter 23: Protozoal and Algal Infections

Ann Marie Nelson, MD Chairman, Department of Scientific Laboratories Chief, Division of AIDS Pathology Armed Forces Institute of Pathology Washington, DC Chapter 23: Protozoal and Algal Infections

Lisa Lerner, MD Dermatopathologist CarisCohenDx Newton, Massachusetts Chapter 7: Intraepidermal Vesiculopustular Diseases James J. Lyons, MD Dermatopathology Fellow University of Texas Southwestern Medical Center Dallas, Texas Chapter 22: Viral Infections Cynthia M. Magro, MD Professor Dermatopathology Division Department of Pathology Cornell University Weill Medical College New York, New York Chapter 12: Cutaneous Drug Eruptions; Chapter 20: Treponemal and Rickettsial Diseases M. Megahed, MD Professor Department of Dermatology and Allergy University of Aachen Aachen, Germany Chapter 8: Subepidermal Blistering Diseases Patrice Morel, MD Professor Department of Dermatology Hôpital Saint Louis Paris, France Provision of Clinical Photographs

Douglas C. Parker, MD, DDS Assistant Professor of Pathology and Dermatology Emory University School of Medicine Atlanta, Georgia Chapter 10: Disorders of Cutaneous Appendages Michael W. Piepkorn, MD Clinical Professor Division of Dermatology University of Washington School of Medicine Seattle, Washington Dermatopathology Northwest Bellevue, Washington Chapter 14: Alterations of the Stratum Corneum and Epidermis Michael S. Rabkin, MD, PhD Director, Rabkin Dermatopathology Laboratory Pittsburgh, Pennsylvania Chapter 35: Cutaneous Metastases James Ramirez, MD Dermatopathology Department St. Joseph Mercy Hospital Ann Arbor, Michigan Chapter 7: Intraepidermal Vesiculopustular Diseases Frances I. Ramos-Ceballos, MD Department of Dermatology University of Arkansas for Medical Sciences Little Rock, Arkansas Chapter 3: Interface Dermatitis Ronald P. Rapini, MD Professor of Pathology Chair, Department of Dermatology University of Texas Medical School MD Anderson Cancer Center Houston, Texas Chapter 19: Bacterial Infections

Franco Rongioletti, MD Professor of Dermatology Section of Dermatology, DISEM University of Genoa Genoa, Italy Chapter 16: Deposition Disorders Daniel Santa Cruz, MD Cutaneous Pathology Maryland Heights, Missouri Chapter 31: Vascular Tumors and Vascular Malformations Brian Schapiro BSc (Med), MBChB Dermatopathology Department St. Joseph Mercy Hospital Ann Arbor, Michigan Chapter 7: Intraepidermal Vesiculopustular Diseases

CONTRIBUTORS

Mark Lerman, DMD Instructor in Oral Pathology Harvard School of Dental Medicine Attending, Division of Oral Medicine and Dentistry Division of Oral Medicine and Dentistry Brigham and Women’s Hospital Boston, Massachusetts Chapter 37: Disorders of the Oral Mucosa

Amy K. Reisenauer, MD Dermatologist St Kihei, Hawaii Chapter 10: Disorders of Cutaneous Appendages

Birgitta Schmidt, MD Instructor Department of Pathology Children’s Hospital Boston Harvard Medical School Boston, Massachusetts Chapter 11: Panniculitis Glynis A. Scott, MD Associate Professor Departments of Dermatology and Pathology University of Rochester School of Medicine Rochester, New York Chapter 25: Cutaneous Cysts and Related Lesions Alvin R. Solomon, MD Professor of Dermatology and Pathology, Emory University School of Medicine, Chief, Dermatology Service Atlanta Veterans Administration Medical Center Atlanta, Georgia Chapter 10: Disorders of Cutaneous Appendages W. P. Daniel Su Professor in Dermatology Mayo Medical School Consultant in Dermatology Mayo Clinic Rochester Minnesota Chapter 34: Lymphoid, Leukemic, and Other cellular Infiltrates (Section 3: Cutaneous Leukemic infiltrates)

xi

Steven R. Tahan Department of Pathology Beth Israel Deaconess Medical Center Harvard Medical School Boston, Massachusetts Chapter 21: Fungal Infections Laurence Verneuil, MD, PhD Service de Dermatologie CHU Caen Caen, France Appendix; Chapter 17: Alterations of Collagen and Elastin

CONTRIBUTORS

Dominique Vignon-Pennamen, MD Departments of Dermatology and Pathology Hôspital Saint-Louis Paris, France Provision of Clinical Photographs Franz von Lichtenberg Department of Pathology Brigham and Women’s Hospital Harvard Medical School Boston, Massachusetts Chapter 24: Helminthic Diseases

Michel Wassef, MD Associate Professor of Pathology University Paris VII- Denis Diderot Faculty of Medicine Attending Pathologist, Department of Pathology Hôpital Lariboisière Paris, France Chapter 31: Vascular Tumors and Vascular Malformations Clifton R. White, Jr., MD Professor of Dermatology and Pathology Oregon Health Science University Portland, Oregon Chapter 17: Alterations of Collagen and Elastin David A. Whiting, MD University of Texas Southwestern Medical Center Baylor Hair Research and Treatment Center Dallas, Texas Chapter 10: Disorders of Cutaneous Appendages

Mark R. Wick, MD Professor of Pathology University of Virginia Medical Center Charlottesville, Virginia Chapter 28: Tumors with Hair Follicle and Sebaceous Differentiation; Chapter 29: Sweat Gland Tumors Sook-Bin Woo, DMD, MMSc Associate Professor Harvard School of Dental Medicine Division of Oral Medicine and Dentistry Brigham and Women’s Hospital Boston, Massachusetts Staff Pathologist Strata-Pathology Services, Inc. Cambridge, Massachusetts Chapter 37: Disorders of the Oral Mucosa Gary S. Wood, MD Johnson Professor and Chairman Department of Dermatology University of Wisconsin Madison, Wisconsin Appendix: Molecular Biologic Techniques for the Diagnosis of Cutaneous Lymphomas Sarah Zeller, MD, MPH Dermatologist Blue Ridge Dermatology Waynesbore, Virginia Chapter 15: Disorders of Pigmentation

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FOREWORD

Training Program, he has developed the knowledge and skills to interact with pathologists, dermatologists, trainees, and students. The success of his monograph on melanocytic lesions of the skin speaks to the effectiveness of his writing and teaching approaches. For this book, Dr. Barnhill has assembled a stellar roster of authors from various disciplines and has appropriately included both established leaders in the field as well as the cream of our younger generation of dermatopathologists. He himself has coauthored one-third of the chapters of the book, and I know

first hand that he has spent a great deal of effort meticulously editing all chapters for consistency, style, and accuracy. His associate editor, Dr. Neil Crowson, has been instrumental in providing the highquality micrographs for many of the entities in the book, and two young, energetic assistant editors, Drs Klaus Busam and Scott Granter, contributed heavily to the book. I look forward to the publication of this text and wish it the success it truly deserves.

FOREWORD

As senior editor of this new Textbook of Dermatopathology, Dr. Raymond Barnhill brings to the task years of experience as a dermatopathologist, clinical dermatologist, clinical investigator, and author. This has given him an unparalleled understanding of inflammatory and neoplastic diseases of the skin and the ability to teach others. As director of dermatopathology at the Brigham and Women’s Hospital and the Children’s Hospital in Boston, he has had contact with both pediatric and adult dermatologic conditions, and as a member of the Combined Harvard Dermatopathology

Ramzi S. Cotran, MD, 1998

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P R E FA C E T O T H E THIRD EDITION

histopathology and differential diagnosis, critical analysis, balanced perspectives on what is known and what is not, clarity of writing, the use of tables to summarize the key features of major entities, and color photomicrographs” and also to maintain a rather uniform style. In the course of revising the book, a significant effort has been made to improve the overall quality of photographs in the book. The latter has been accomplished by replacing the existing black and white with color images, improving the quality of many existing color images, increasing the overall number of photographs, and finally including new clinical images. All chapters have been superbly revised, and much new information has been included with respect to various inflammatory

conditions, infections, melanocytic, vascular, lymphoid and other neoplastic conditions. Newly described entities have been added to the book where appropriate, and approximately one hundred new color photomicrographs have been incorporated into the third edition. As before, I acknowledge the tremendous efforts of the many people involved in this third edition, without which it would not have been possible. I am especially indebted to all the contributors and to the staff at McGraw-Hill who have made the third edition a reality. I sincerely hope that the information contained in this book may contribute to improved and more enlightened patient care.

PREFACE TO THE THIRD EDITION

The editor and publisher are extremely enthusiastic to offer a third edition of this book to physicians and others in the fields of dermatopathology, dermatology, and allied specialties. It is the express wish of the editors, contributors, and the publisher that the information compiled in this work greatly aides physicians and other health care workers in facilitating the best patient care possible. The editor is deeply appreciative of the prodigious work of the new coeditors Neil Crowson, Cynthia Magro, and Michael Piepkorn and the many eminent contributors in producing an accessible and scholarly book. The third edition has been revised with the same goals as the first and second editions, that is, to provide “descriptive

Raymond L. Barnhill, MD

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P R E FA C E T O T H E FIRST EDITION

pattern recognition as a prologue to algorithms and the description of the major patterns of inflammation of the skin. Christopher French, MD, has, in addition, designed schematic color figures that enhance the recognition of patterns of inflammation of the skin. Another major feature is that associate editor Neil Crowson, MD, has taken high-quality photomicrographs for most of the entities in the book. This is another characteristic that provides a uniform style to the book. I am deeply grateful to Dr. Crowson for this enormous undertaking. Although all major entities have been covered in an erudite fashion in the book, a number of unique features must be mentioned. The chapter on disorders of the skin appendages provides new quantitative information on the alopecias and describes the use of transverse sections in the diagnosis of alopecia. Dr Crowson has written a comprehensive chapter on drug eruptions and included lists of medications implicated in these eruptions. Critical chapters on controversial and difficult topics such as vasculitis, panniculitis, disorders of pigmentation, and melanocytic lesions will provide greater insight and aid to the pathologist dealing with these conditions. Finally, there are more detailed chapters on disorders of the nails and the oral mucosa than are currently available in most other texts. Another modification has been the inclusion of a scholarly section on normal skin histol-

ogy, laboratory methods, immunohistochemistry, and the molecular biology of cutaneous lymphoid infiltrates in an appendix rather than in the text itself. It will become evident to the reader that there is occasionally some overlap or duplication of some conditions among the various chapters, since no method of classification is entirely consistent. My intention has been to allow some duplication since this provides different perspectives on a disease process. Finally and most importantly, I would like to acknowledge the tremendous efforts of many friends and colleagues without whose advice, encouragement, and help this book would not have been possible. First of all, I would like to thank Neil Crowson for his enormous contributions in photography, writing, and for his unflagging encouragement and support throughout the project. I am also indebted to my former fellows Klaus Busam and Scott Granter for their commitment and hard work on the book, and I am most appreciative of my secretaries Robin McCarthy (who has since departed for an undoubtedly easier job!) and Maria Palaima, and the staff at McGraw-Hill for their dedication and efforts in bringing the book to closure. Lastly, I am most grateful to all the contributors who have sacrificed so much of their time and energy to make the book not only possible but a learned work that will have an impact on the field.

PREFACE TO THE FIRST EDITION

The question might be posed, “Why another textbook of dermatopathology?” since a number of books are currently available and would seem to do justice to the subject. Quite simply, I have perceived the need for another book. Following on the success of a monograph on melanocytic lesions of the skin, The Pathology of Melanocytic Nevi and Malignant Melanoma, I believe that there is indeed a need for a general text on dermatopathology emphasizing the same format as the aforementioned monograph: descriptive histopathology and differential diagnosis, critical analysis, balanced perspectives on what is known and what is not, clarity of writing, the use of tables to summarize the key features of major entities, and color photomicrographs. At the same time it must be acknowledged that the scope of such a book goes well beyond that of a monograph on melanocytic lesions. As a result, I have engaged a scholarly group of individuals to help in writing such a book in a timely fashion. Nonetheless, one of my major goals has been to maintain a uniform style in keeping with the philosophy of the book. In recent years I have been impressed with the need to provide some orientation for beginning the process of learning dermatopathology. Thus, the first chapter of this book is devoted to the approach to diagnosis at the microscope. Daniel Jones, MD, PhD, also discusses succinctly the scientific basis of

Raymond L. Barnhill, MD

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1 PART

Inflammatory Reactions In the Skin

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CHAPTER 1 Introduction to Microscopic Interpretation Raymond L. Barnhill Daniel M. Jones

the chapter on a step-by-step approach to microslide review (see Fig. 1-1). Although the correct diagnosis of common skin tumors often can be made by inspection of the microslide with the naked eye or at the lowest scanning magnification, the perceptual processes involved in diagnosis are quite complex. They can be schematized by the simplified algorithm that follows. 1. “Reading” the slide (ie, visual perception/ attention) 2. Processing the acquired visual information

Perhaps in no other area of pathology does one encounter such diverse disease processes and bewildering terminology as in dermatopathology. The classic approach to learning dermatopathology, as in many other areas of medicine, has been disease oriented, a style not easily mastered by beginners or even more advanced students. However, in recent years there has been greater emphasis on using a systematic and logical approach of pattern recognition for diagnosis, particularly for inflammatory conditions in the skin.1-5 The objectives of this chapter are (1) to present an outline of the perceptual principles and pitfalls underlying pathologic diagnoses and (2) to outline a practical step-by-step method for interpreting a microslide and formulating a differential diagnosis using techniques of pattern recognition and algorithms.

Interpretation of the Slide The diagnostic approach of this textbook is to bring a systematic approach to diagnosis of skin lesions. The chapter organization reflects this explicit algorithmic approach, with an emphasis in

4. Testing the preliminary diagnosis with further examination 5. Confirming the diagnosis 6. Attending to secondary features (eg, status of margins, tumor grade) 7. Correlating available clinical information 8. Finalizing the diagnosis

Initial Examination of the Slide with the Naked Eye The histopathologist should first inspect the microslide with the naked eye in order to gain some appreciation of the size, number, and nature of the histologic sections on the slide. Often one can make certain deductions from this gross examination alone. For example, a small specimen is either a curetting, a shave, or a punch biopsy and connotes particular pathologic processes (In contrast, a large specimen generally indicates an excision. Often it is possible to establish the process as epidermal, dermal, or subcutaneous by this examination. The tinctorial properties (histochemical staining) also may provide clues to diagnosis; for example,

Proliferative/ neoplastic

Principally inflammatory

Epidermal alteration

Epidermis normal

Epidermis

 FIGURE 1-1 Algorithmic approach to diagnosis.

Examination of the Microslide at Scanning (2⫻ or 4⫻) Magnification The microslide next should be viewed at scanning magnification, that is, with a 2⫻ or 4⫻ objective. Although a 2⫻ objective may prove optimal for the initial examination of many specimens, particularly large specimens, many microscopes are equipped only with 4⫻ objectives. However, the 4⫻ objective is a reasonable alternative, and additional information generally can be obtained at this magnification. If possible, the specimen always should be studied initially without knowledge of age, gender, or other clinical information in order to gather information objectively and formulate a differential diagnosis. Although the experienced pathologist often does not need to resort to such a method unless a diagnosis is not immediately apparent, the beginner should systematically study a slide with specific goals in mind. 1. First of all, the pathologist should attempt to identify the type of specimen submitted; that is, is it a curettage, punch, shave, or excisional specimen? Determination of the type of specimen is important because it often provides some clue to the type of disease process suspected by the submitting clinician. For example, curettage specimens often are taken for neoplastic processes such as actinic or seborrheic keratoses or basal cell carcinoma. Shave biopsies usually are obtained for diagnosis of keratoses

Noninflammatory

CHAPTER 1 ■ INTRODUCTION TO MICROSCOPIC INTERPRETATION

3. Arriving at a tentative diagnosis (ie, model building)

INTRODUCTION

bluish cellular aggregates or nodules suggest high nuclear-to-cytoplasmic ratios because of basophilic staining of nuclei and, as a result, processes such as basal cell carcinoma, small cell carcinoma, and infiltrates of small lymphocytes or calcium deposition.

“Normal skin”

Dermis and/or subcutis

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PART I ■ INFLAMMATORY REACTIONS IN THE SKIN

or basal or squamous cell carcinoma. In general, punch biopsies are submitted for diagnosis of either neoplastic or inflammatory conditions. In some instances they are used to “excise” a proliferation or tumor, and thus margins may need to be assessed. By and large, skin ellipses (excisions) are submitted for suspected tumors but also on occasion for inflammatory processes such as vasculitis or panniculitis.

4

2. Next, the pathologist should inspect the specimen with the idea of determining in general terms from what anatomic site the tissue was taken. In general, based on characteristics such as prominence of sebaceous follicles, relative paucity of hair follicles, thickness of the reticular dermis, and thickness of the stratum corneum, one can recognize the following general regions of the integument: (a) head and neck, (b) trunk and proximal extremities, and (c) acral (including frictional) surfaces. It is evident that many diseases have characteristic site distributions, and knowledge of the particular localization of the lesion or eruption is useful in formulating one’s differential diagnosis. 3. The entire specimen (ie, epidermis, dermis, or subcutis) should be scanned for the principal site of involvement by a disease process, if any, and the nature of the process, whether inflammatory, proliferative, inflammatory and proliferative, or noninflammatory. Although in most instances the site of involvement is obvious, it is important that the specimen is examined systematically when the process is not so obvious. In general, the specimen should be scrutinized in a sequential fashion, for example, beginning with the stratum corneum and then proceeding to the epidermis, dermis, subcutis, and fascia. At scanning magnification, one should be able to appreciate many aspects of the disease process without going to greater magnification. If an inflammatory process is present, one should attempt to recognize the nature of epidermal involvement, for example, spongiosis, interface vacuolopathy, psoriasiform epidermal hyperplasia, or vesicle, blister, or pustule formation; the pattern of the inflammatory infiltrate, whether bandlike (cell-poor or cell-rich/lichenoid), perivascular, interstitial, periadnexal, nodular, or diffuse (pandermal); the depth of the infiltrate, for example, superficial only or superficial and deep; possibly the presence of vascular damage; the

cellular composition of an infiltrate, that is, whether it is comprised of mononuclear cells, suggesting small lymphocytes or larger cells; and alterations of the dermis, for example, by fibrosis or sclerosis resulting in a “square” punch biopsy versus the typical inverted cone configuration, thickening, or atrophy of the dermis or deposition of material such as calcium. A primary proliferative or neoplastic condition also should be obvious in most instances at scanning magnification. After the completion of this exercise, the pathologist is often able to establish the basic nature and localization of the disease process and possibly to develop a preliminary differential diagnosis if he or she has not already arrived at a specific diagnosis. In many instances, this may not be possible at scanning magnification because the changes are too subtle for diagnosis at this or perhaps any magnification or there has been a sampling error. At this point, the pathologist must go to greater magnification in order to confirm an impression or to gain more information that is only possible at increased magnification.

Examination at Intermediate Magnification It cannot be overemphasized that, in general, most information about a pathologic process is obtained at scanning magnification. The tendency to go to higher magnification too soon should be resisted because one often will overlook a crucial feature, and thus, in effect, one “cannot see the forest for the trees.” The reasons for closer inspection of the specimen (with 10⫻ and 20⫻ objectives) are to confirm particular features of pathologic processes, for example, parakeratosis, spongiosis, fibrinoid necrosis, or mucin deposition, and for identification of specific cell types, such as lymphocytes or granulocytes. However, in some instances, greater magnification may be needed in order to identify a morphologic feature not recognizable at low magnification, such as, hyphal elements in the cornified layer, epidermal basal layer vacuolopathy, amyloid deposits in the papillary dermis, or mucinosis in the reticular dermis.

Examination at High Magnification As mentioned for intermediate magnification, use of the high-power objective also should be reserved for specific indications. Such examination is necessary in

order to study the cytologic details of cells, such as, the nuclear contours of lymphocytes or nuclear atypia in general; to confirm the nature of infectious organisms; and to confirm other findings.

Integration of All Information During the preceding exercise of examining the microslide, the histopathologist should take the perspective that he or she is objectively gathering information that can be integrated with other (clinical and laboratory) information to arrive at some conclusion about the disease process and not necessarily to arrive at a single diagnosis. One should, at all times, try to avoid reaching a conclusion too quickly and failing to observe other pertinent findings in the specimen. The pathologist always should try to think expansively of every potential pathologic process that might explain the histologic findings. One should continuously weigh the various points that argue for or against a particular pathologic condition. After completing the preceding examination and reaching some tentative impression (or lack of conclusion) about the specimen without knowledge of clinical parameters, it is then necessary to consider the clinical context of the specimen. Even if the histopathologic diagnosis appears straightforward, such as, for example, basal cell carcinoma, the pathologist always should have certain clinical information before finalizing the case: age, gender, anatomic site, and clinical diagnosis. Without such information, the pathologist is much more prone to blatant errors, such as mislabeled specimens or misdiagnosis. On the other hand, for many conditions, particularly inflammatory processes, detailed clinical information concerning the onset, evolution, distribution, and specific character of the skin lesions is essential in order to arrive at a diagnosis or to formulate a differential diagnosis. Many inflammatory reaction patterns are not specific and may be secondary to several processes. Thus an accurate clinical history is needed to establish the most likely condition or group of conditions that might explain the histologic findings. Finally the histopathologist must recognize the limitations of histopathological interpretation: in some instances specific diagnosis is not possible since either the histological findings are nonspecific and diagnosis rests in the clinical domain, current knowledge about the disease process is inadequate, the biopsy specimen is inadequate, or sampling error has occurred.

PATTERN RECOGNITION IN DERMATOPATHOLOGY

Features of Benign versus Malignant Tumors Although it may appear intuitive and instantaneous, recognition of cutaneous tumors is a highly complex perceptual process that involves more than simple “wallpaper matching.” However, in the diagnosis of cutaneous tumors, the lowpower pattern (tumor silhouette) often can be at least as important if not definitive for diagnosis as high-power cytologic findings.3 Certain tumor growth patterns appear to be intrinsically more readily recognizable and often are the first to be mastered

 FIGURE 1-2 Distinguishing benign from malignant neoplasms by low-power microscopic features. Characteristic acanthosis, hyperkeratosis, and keratin pseudocyst formation in seborrheic keratosis are easy to detect (left). Similar features are evident in a benign keratosis due to chronic irritation (right).

by the student of dermatopathology. This is supported by a large body of perceptual research demonstrating that some visual targets (termed good patterns) are consistently recognized more rapidly than others. Conversely, there is impaired performance of visual tasks that involve recall of “poor” visual targets. Easy recognition of some benign skin tumors (Fig. 1-2, eg, seborreic keratosis, keratoacanthoma, or cylindroma) in contrast to others (eg, a sclerosing melanocytic nevus or desmoplastic melanoma) is due to the visual impact of their particular growth patterns evident at low magnification. Similarly, the presence of ancillary features such as inflammatory infiltrate can be an instantly recognizable clue to search for evidence of tumor invasion (Fig. 1-3). As a pathologist gains experience with dematopathology tumors, the distinction of the range of benign versus malignant growth patterns becomes easier.

Features of Inflammatory and Reactive Lesions Although it also involves pattern recognition, the diagnosis of inflammatory lesions presents a much different challenge. Instead of rendering a definitive diagnosis, the usual approach is descriptive (ie, what kinds of epidermal alterations and inflammatory cells are present and where they are located). In the absence of adequate clinical information, a range of possible diagnoses usually is provided. This is a different perceptual task where the goal is simply not to match a precise stored visual image but to compare the features of a lesion with the clinical entity to which it is (statistically) most similar. Inflammatory lesions are grouped initially into general categories (see Figs. 1-4 to 1-8), and then specific features are sought to narrow (or prioritize) the diagnoses. For instance, once the pattern of

 FIGURE 1-3 Combining epidermal changes and reaction patterns in diagnosis. Even at low magnification, the regular pattern of acanthosis and hyperkeratosis seen in squamous cell carcinoma in situ (right) is contrasted with the irregular squamous proliferation, abnormal maturation, and robust inflammatory infiltrate associated with invasive squamous cell carcinoma (middle). Examination at higher magnification reveals infiltrating tumor cells (right panel, arrow).

CHAPTER 1 ■ INTRODUCTION TO MICROSCOPIC INTERPRETATION

Accurate perception of the findings on a microslide is obviously the initial step in accurate diagnosis. Many, perhaps most, serious errors in diagnosis are related to a failure to attend to or notice critical histologic findings rather than a misinterpretation of these features. A trivial but common reason for misdiagnosis is simply a failure to examine a relevant tissue fragment or level. Poor tissue preservation and histologic detail or substandard tissue sectioning also can contribute greatly to problems in accurate perception. The visual fatigue and information overload that occur after examining many cases also contributes to perceptual mistakes. As outlined in Fig. 1-1, the initial decision one must make is whether a process is predominantly inflammatory, predominantly proliferative/neoplastic, both inflammatory and proliferative, or noninflammatory/nonproliferative. This is not always possible, but, in general, the vast majority of pathologic processes can be categorized into one of these groups. Thus one is able to proceed along one of the decision trees.

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Vesicle/ blister/ papule

PART I ■ INFLAMMATORY REACTIONS IN THE SKIN

Intraepidermal Chap. 7

Subcorneal substratum granulosum

Spongiotic dermatitis Chap. 2

Subepidermal Chap. 8

Interface dermatitis Chap. 3

Vacuolar type

Junctional

Dermolytic

Intrastratum spinosum

Suprabasilar, intrabasilar

Conventional spongiosis

Eosinophilic spongiosis

Psoriasiform dermatitis Chap. 4

Lichenoid type

Neutrophilic spongiosis

Follicular spongiosis

Miliarial spongiosis

 FIGURE 1-4 Inflammatory conditions with epidermal alteration.

No vascular damage

Perivascular infiltrates Chap. 5

Disorders of skin appendages Chap. 10

Hair follicle, folliculitis, perifolliculitis, alopecia

Nodular infiltrates Chap. 6

Vascular damage

Diffuse infiltrates Chap. 6

Panniculitis fasciitis Chap. 11

Vasculopathy Chap. 9

Sweat glands, milaria, hidradenitis

Vasculitis Chap. 9

 FIGURE 1-5 Inflammatory conditions of the dermis and/or subcutis without epidermal alterations and with and without vascular injury.

Granulomas/granulomatous inflammation Chap. 6

Sarcoidal epithelioid cell

Tuberculoid caseating

Foreign body

 FIGURE 1-6 Inflammatory infiltrates with granulomas/granulomatous inflammation.

6

Suppurative

Elastolytic

provides detailed descriptions of both the histologic features and clinical appearance of each entity. There are also added complexities to diagnosis of inflammatory lesions in the skin that are related to the nature of the immune responses producing these lesions. These include:

Alterations of stratum corneum and epidermis Chap. 14

Hyperkeratosis with parakeratosis focal or diffuse

Hyperorthokeratosis

Alteration of basal layer melanin

Normal granular layer or hypergranulosis

Hypogranulosis

Hypopigmentation, focal or diffuse Chap. 15

Hyperpigmentation, focal or diffuse Chap. 15

 FIGURE 1-7 Noninflammatory disorders with alterations of stratum corneum and epidermis.

Papillary dermal alteration vs Reticular dermal alteration

Atrophy

Deposition of material Chap. 16

Hypertrophy fibrosis Chap. 17

 FIGURE 1-8 Noninflammatory disorders with dermal alteration.

vacuolar interface dermatitis has been identified, visual search for viral inclusions or apoptotic bodies could support the diagnoses of a viral exanthem or erythema multiforme. Combining the available information on the gross appearance and the clinical differential diagnosis with the histologic diagnosis is the vitally important penultimate stage prior to rendering a final diagnosis. The close linkage in training and expertise between dermatologist and dermatopathologist often makes this process easier because the histopathologist becomes more familiar with the clinical appearance of the lesions in the differential diagnosis. This synergistic effect is most obvious in the rare cases where the biopsy specimen is being diagnosed by the person who has actually examined the patient. However, in all cases, the differential diagnosis provided by the submitting dermatologist may force a reexamination of the microscopic features, and as a result, this book

Pigmentary alterations Chap. 15

2. The severity of the reaction. For inflammatory lesions incited by external or internal antigenic reaction, there is a spectrum of responses ranging from mild to severe (Fig. 1-10). 3. The overlap of benign dermatoses and cutaneous T-cell lymphomas. There are a limited number of epidermal reaction patterns seen in response to infiltration by immune cells or neoplastic lymphocytes. Furthermore, cutaneous T-cell lymphomas (CTCL) often evolve from preceding dermatitis. Therefore, there can be overlap in the histologic features seen in CTCL and reactive inflammatory conditions requiring careful attention to lymphocyte atypia at high magnification (Fig. 1-11). Full maturation of expertise in dermatopathology thus requires not only a

 FIGURE 1-9 Spongiotic dermatitis, acute versus chronic changes. Spongiosis and neutrophilic crust are characteristic of a self-limited contact dermatitis (left). In contrast, chronic spongiotic dermatitis results in dermal fibrosis and vascular proliferation (right).

CHAPTER 1 ■ INTRODUCTION TO MICROSCOPIC INTERPRETATION

1. The temporal phase of a lesion. Many dermatitis reactions have acute, subacute, and chronic phases with fairly specific histologic correlates (Fig. 1-9). Therefore, it is important to consider the varying histologic appearances that can occur over the life span of a skin lesion.

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PART I ■ INFLAMMATORY REACTIONS IN THE SKIN

epidermis shows one of the following major reaction patterns or is uninvolved by the inflammatory process.

 FIGURE 1-10 Interface dermatitis, mild to severe. Mild graft-versus-host (GVH) disease shows minimal interface lymphoid infiltrate (left panel, arrow). In comparison, severe GVH shows numerous necrotic keratinocytes and subepidermal cleft formation (right).

Table 1-1 Spongiotic Dermatitis

 FIGURE 1-11 Psoriasiform reaction pattern. Psoriasis shows hyperkeratosis with thinned granular layers and elongation of the rete ridges (left). A case of mycosis fungoides shows similar psoriasiform epidermal hyperplasia, with cytologic atypia of the lymphocytes only appreciated on high magnification (inset).

“library” of stored visual images of inflammatory skin lesions that correlate with clinical syndromes but also knowledge of the time-course and spectrum of changes seen for each particular entity. As discussed below, the stepwise approach to learning to diagnose inflammatory lesions in skin emphasizes the importance of mastering the diagnostic differential for each inflammatory pattern.

Major Inflammatory Reaction Patterns in the Skin 8

INFLAMMATORY REACTION PATTERNS OF THE EPIDERMIS Spongiotic dermatitis Spongiotic dermatitis refers specifically to the presence of spongiosis or intercellular edema that stretches apart keratinocytes and sometimes results in the formation of intraepidermal vesicles. Spongiosis is often variable, multifocal, and accompanied by intracellular edema and exocytosis of inflammatory cells. The disease process is dynamic and in general has been categorized according to morphologic features correlating with the stages of its life history (1) acute, (2) subacute, and (3) chronic (Fig. 1-9). Other alterations such as granulocyte infiltration of the epidermis (eg, eosinophilic or neutrophilic spongiosis) or involvement of skin appendages (eg, follicular spongiosis) may be observed. Spongiosis is a relatively nonspecific morphologic alteration observed in a wide variety of conditions (see Table 1-1). It is

Since the pathogenesis of most inflammatory dermatitides is unknown, one must, of necessity, use morphologic criteria for

classification at present. Although most inflammatory conditions can be categorized into one of the major reaction patterns, there are inevitable dermatitides that show overlapping features and some that defy classification. Some inflammatory conditions may be sampled either too early or too late in their evolution to be diagnostic. Inflammatory diseases are dynamic, and knowledge of the point in time when the dermatitis is sampled is critical to optimal microscopic interpretation. The histopathologist should strive to assess specimens with the “fourth dimension” of time always kept in mind. As mentioned previously, one initially attempts to ascertain whether the

Conventional spongiotic dermatitis Allergic contact dermatitis Irritant contact dermatitis Atopic (endogenous) dermatitis Nummular dermatitis Dyshidrotic eczema (pompholyx) Id reaction Seborrheic dermatitis Stasis dermatitis Spongiotic drug eruption Erythroderma Pityriasis rosea Pityriasis alba Photoallergic contact dermatitis Polymorphous light eruption Arthropod bites Gyrate/figurate erythemas Dermatophyte infection Transient acantholytic dermatosis Pigmented purpuric dermatitis Papular and urticarial eruptions of pregnancy Eosinophilic spongiosis Pemphigus group Bullous pemphigoid Allergic contact dermatitis Spongiotic drug eruptions Infestations Cutaneous larva migrans Arthropod bites Incontinentia pigmenti Eosinophilic folliculitis

Neutrophilic spongiosis Psoriasis Reiter syndrome Seborrheic dermatitis Irritant contact dermatitis Phototoxic dermatitis Pemphigus variants (particularly IgA pemphigus) Follicular spongiosis Atopic dermatitis Pityriasis alba Contact dermatitis Infundibulofolliculitis Eosinophilic folliculitis Follicular mucinosis Fox-Fordyce disease

perhaps most characteristic of the group of conditions referred to as eczematous dermatitis. These disorders include endogenous or atopic dermatitis, contact allergic and irritant dermatitis, and nummular dermatitis. Other common dermatitides showing spongiosis include seborrheic dermatitis, spongiotic drug eruptions, and some primary bullous conditions.

Interface dermatitis Interface dermatitis refers to a morphologic alteration at the junction or interface between the epidermis (or epithelium) and dermis. Specifically, one observes vacuolization (vacuoles or discrete clear spaces) either within basilar keratinocytes or within the basement membrane zone. This reaction pattern is often accompanied by a number of other alterations present to variable extent: individually dyskeratotic keratinocytes (which are probably apoptotic cells), disruption of orderly keratinocytic maturation to the surface, and clefts resulting from coalescence of vacuoles. Interface dermatitides may be further subclassified according to the density and pattern of the inflammatory cell infiltrate in the papillary dermis as (1) the vacuolar or cell-poor type, based on perivascular or patchy infiltrates in the papillary dermis or (2) the lichenoid or cell-rich type, which shows a dense bandlike infiltrate that fills the papillary dermis (Table 1-2). As with all inflammatory processes, interface dermatitides also may be characterized according to their severity (Fig. 1-10, illustrating graft-versus-host reaction) or their stage of evolution as acute or early stage, subacute or developed, or chronic or late stage. Certain diseases are prototypic of the two patterns of interface dermatitis

Table 1-3 Psoriasiform Dermatitis

Vacuolar interface dermatitis Erythema multiforme Fixed drug eruption Drug eruptions Viral xanthems HIV interface dermatitis Connective tissue disease Lupus erythematosus Dermatomyositis Graft-versus-host reaction Pityriasis lichenoides Poikiloderma congenitale Bloom syndrome Vitiligo Pigmented purpuric dermatitis Lichenoid interface dermatitis Lichen planus and variants Lichenoid drug eruption Lichenoid keratosis Lichen striatus Lichen nitidus Lichenoid purpura Porokeratosis Histologic regression of many tumors

Psoriasis Reiter syndrome Subacute to chronic eczematous dermatitis Seborrheic dermatitis Lichen simplex chronicus Pityriasis rubra pilaris Parapsoriasis Mycosis fungoides Psoriasiform drug eruption Erythroderma Candidiasis Secondary syphilis Inflammatory linear verrucous epidermal nevus (ILVEN) Scabies Lamellar ichthyosis Clear cell acanthoma Pellagra Acrodermatitis enteropathica Migratory necrolytic erythema Bazex syndrome

mentioned earlier. Erythema multiforme, many drug eruptions, viral exanthems, and connective tissue diseases result in a vacuolar pattern of interface dermatitis. On the other hand, lichen planus, lichenoid drug eruptions, lichen planus-like keratosis, and “halo” nevus are associated with lichenoid patterns of inflammation.

Psoriasiform dermatitis Psoriasiform dermatitis refers to a characteristic pattern of epidermal hyperplasia typified by elongation of the epidermal rete ridges (Fig. 1-11). In general, the topography of the epidermal surface is unaffected, that is, remains essentially flat-topped. This pattern of epidermal alteration may be further described as either regular or irregular. Regular psoriasiform hyperplasia, as the name suggests, indicates elongated epidermal rete ridges of fairly uniform length and thickness and is typical of psoriasis in a well-developed stage. This morphologic feature is accompanied by a number of other histologic alterations notable in psoriasis: broad zones of parakeratosis, absence of the granular layer, exocytosis of neutrophils, pallor of keratinocytes (intracellular edema), thinning of the epidermis above the dermal papillae, prominent dilated and tortuous papillary dermal microvessels, and papillary dermal edema. Irregular psoriasiform epidermal hyperplasia may

be observed in psoriasis but typifies other processes more commonly, such as chronic eczematous dermatitis, lichen simplex chronicus, or mycosis fungoides (Table 1-3, Fig. 1-11). Other conditions that exhibit this reaction in addition to those already mentioned are psoriasiform drug eruptions, lamellar ichthyosis, and secondary syphilis.

Vesicular and bullous dermatitis This reaction pattern refers to the formation of tissue clefts or spaces that may or may not be accompanied by cellular infiltrates such as eosinophils, neutrophils, or lymphocytes. In general, these disorders are classified according to whether the level of cleavage is (1) intraepidermal or (2) subepidermal (Figs. 1-4, 1-12; see also Tables 1-4 and 1-5). Intraepidermal blisters may include, for example, subcorneal or intragranular layer cleavage or cleavage through the superficial layer or suprabasal layer of the epidermis. Subepidermal blisters may be further delineated as cleavage through the lamina lucida of the basement membrane zone or through the superficial dermis. Blistering dermatitides may then be characterized as predominantly inflammatory or noninflammatory. If inflammatory, the composition of the infiltrate and possibly immunofluorescence and serological studies will further aid classification. Finally, one may be able to recognize the mechanism of vesicle/blister formation as spongiotic, acantholytic,

CHAPTER 1 ■ INTRODUCTION TO MICROSCOPIC INTERPRETATION

Miliarial spongiosis Miliaria

Table 1-2 Interface Dermatitis

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PART I ■ INFLAMMATORY REACTIONS IN THE SKIN

 FIGURE 1-12 Subepidermal bullous dermatitis. Bullous pemphigoid shows numerous lymphocytes and eosinophils with no necrosis of overlying epithelium (left). Erythema multiforme shows nearly fullthickness epidermal necrosis and mild lymphocytic infiltrate in association with the subepidermal blister.

Table 1-4 Intraepidermal Vesicular and Pustular Dermatitis

Intracorneal and subcorneal vesicles and pustules Impetigo Staphylococcal “scalded skin” syndrome Superficial fungal infection Pemphigus foliaceus Pemphigus erythematosus Subcorneal pustular dermatosis Infantile acropustulosis Erythema toxicum Transient neonatal pustular melanosis Miliaria crystallina Intraepidermal vesicles and pustules Spongiotic vesicles Viral vesicles Palmoplantar pustulosis Friction blister Epidermolysis bullosa

ballooning degeneration, or resulting from prominent basal layer vacuolization or subepidermal edema.

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Other epidermal reactions and overlapping patterns Inevitably the procedure of classification is somewhat artificial, and there are always exceptions and entities that defy categorization. Many inflammatory conditions in the skin show two or more of the patterns of epidermal alteration just discussed. The predominant reaction pattern generally should be used as the basis for categorization, if possible. The following morphologic reactions represent additional subsets:

Table 1-5 Subepidermal Vesicular Dermatitis

Subepidermal blisters with little inflammation Epidermolysis bullosa Porphyria Pseudoporphyria Bullous pemphigoid (cell-poor type) Burns Toxic epidermal necrolysis Bullae associated with diabetes Blisters overlying scars Bullous amyloidosis Subepidermal blisters with lymphocytes Erythema multiforme Fixed drug eruption Lichen planus pemphigoides Polymorphous light eruption Bullous mycosis fungoides Bullous fungal infections Subepidermal blisters with eosinophils Bullous pemphigoid Epidermolysis bullosa acquisita Pemphigoid gestationis Arthropod bites Drug reactions Subepidermal blisters with neutrophils Dermatitis herpetiformis Linear IgA bullous dermatosis Cicatricial pemphigoid and localized cicatricial pemphigoid Pustular vasculitis Bullous lupus erythematosus Sweet syndrome Epidermolysis bullosa acquisita Erysipelas Bullous urticaria Subepidermal blisters with mast cells Bullous mastocytosis Miscellaneous blistering diseases Drug-overdose-related bullae PUVA-induced bulla Etretinate-induced bullae

Pityriasiform dermatitis A small but important group of inflammatory dermatitides shows a constellation of epidermal changes that include focal or spotty parakeratosis, slight epidermal hyperplasia, and variable spongiotic and interface alteration. Depending on which of these features might predominate, various dermatitides in this group also might be classified as a subacute spongiotic, psoriasiform, or interface dermatitis (see Overlapping Patterns below). These conditions generally include pityriasis rosea, pityriasis lichenoides, seborrheic dermatitis, eruptive or guttate psoriasis, pre- or early mycosis fungoides lesions (parapsoriasis), some drug eruptions, subacute eczematous dermatitis, pityriasis rubra pilaris, and superficial fungal infections. Overlapping reaction patterns The four patterns listed below emphasize the prominence of two or more morphologic alterations. Particular patterns often correlate with particular disease processes. For example, spongiotic psoriasiform dermatitis is a typical pattern associated with chronic-active eczematous dermatitis. 1. Spongiotic psoriasiform dermatitis 2. Spongiotic interface dermatitis 3. Spongiotic psoriasiform interface dermatitis 4. Psoriasiform interface dermatitis CHARACTERIZATION OF THE INFLAMMATORY PROCESS IN THE DERMIS After one has examined the epidermis for morphologic alteration, one proceeds to evaluate the inflammatory process in the dermis (and subcutis and fascia, as the case may be). An immediate concern is whether recognizable vascular injury is present or absent.

Absence of vascular injury At this point, one proceeds with the assessment of the pattern, depth, density, and composition of the inflammatory cell infiltrate, as well as whether it is granulomatous or not. The patterns of inflammatory infiltrates in the dermis generally are described as lichenoid, perivascular (Fig. 1-13), periadnexal, interstitial (infiltrating collagen bundles), nodular (Fig. 1-14), or diffuse (occupying the entire dermis) (Fig. 1-15 and Table 1-6). The depth of involvement is important to recognize because many dermatitides correlate with depth. For example, drug eruptions and viral exanthems often show superficial perivascular involvement only, whereas conditions such as lupus erythematosus,

Table 1-6 Dermal Inflammatory Infiltrates without Vascular Injury

 FIGURE 1-13 Superficial perivascular dermatitis. Nonspecific features of mild lymphocytic infiltrate with no atypia and perivascular edema are seen in this case of self-limited drug rash. polymorphous light eruption, and secondary syphilis are prone to involvement of the deep dermal vascular plexus (ie, socalled superficial and deep perivascular pattern). Deep infiltrates also may be indicative of a systemic disease process, as in lupus or secondary syphilis. Density of an infiltrate is difficult to assess except in

rather subjective terms, such as sparse, moderate, or dense. However, recognizing the density of an infiltrate has relevance for particular disease processes, such as acute urticaria (which is sparse), figurate erythema (which is moderately dense), and cutaneous lymphoid hyperplasia or lymphoma (which tends to be dense). a

Further classified according to cell types present, such as lymphocytes, eosinophils, neutrophils, and so on.

 FIGURE 1-14 Nodular dermal infiltrates. Multifocal neutrophil-rich dermal infiltrates centered on destroyed follicles likely representing pustular folliculitis.

 FIGURE 1-15 Diffuse dermal infiltrate. Loose lymphoid infiltrate representing cutaneous infiltration by chronic lymphocytic leukemia (CLL).

CHAPTER 1 ■ INTRODUCTION TO MICROSCOPIC INTERPRETATION

Superficial or superficial and deep perivascular infiltrates* Urticaria Urticarial reactions Viral exanthems Drug eruptions Gyrate/figurate erythemas Lupus erythematosus Polymorphous light eruption Photosensitive eruptions Chilblains/perniosis Leprosy (indeterminate) Syphilis Borreliosis Leukemia Urticaria pigmentosa Nodular infiltrates Arthropod bite reactions Cutaneous lymphoid hyperplasia Histiocytic infiltrates Neutrophilic dermatoses Lymphoma Diffuse infiltrates a Reactive infiltrates Leukemia Lymphoma Histiocytic infiltrates Mast cell infiltrates

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PART I ■ INFLAMMATORY REACTIONS IN THE SKIN

The cellular infiltrates in the dermis commonly are composed of lymphocytes, possibly with varying admixtures of other cell types, including monocytes/ macrophages (histiocytes), eosinophils, neutrophils, plasma cells, and mast cells. The particular cellular composition often has diagnostic significance, particularly when integrated with the other features mentioned earlier, such as pattern, depth, and density. Thus a sparse superficial perivascular infiltrate containing lymphocytes and eosinophils (and often neutrophils) would suggest urticaria. Infiltrates with the same cell types but of greater density (moderate) would suggest the broad category of allergic hypersensitivity reactions, and finally, circumscribed superficial and deep perivascular aggregates of epithelioid macrophages would suggest the sarcoidal granulomatous reaction pattern (see Granulomatous Reaction Patterns).

Presence of vascular injury Vascular injury refers to a spectrum of morphologic alterations ranging from endothelial perturbation or activation to frank fibrinoid necrosis and the presence of inflammation for an interpretation of vasculitis (Table 1-7). These changes may be primary or secondary (a distinction not always easily made). In assessing vascular injury, a number of parameters must be considered, and these include caliber and type of vessels involved, degree of vascular injury (as already mentioned), the composition and density of the cellular infiltrate, and the presence or absence of such factors as antineutrophil cytoplasmic antibodies (ANCA). Granulomatous reaction patterns The essential definition of a granuloma is a circumscribed aggregate of macrophages. The cytologic characteristics of such cells vary from mononuclear cells with abundant pale, vacuolated, or lipidized cytoplasm to cells with plentiful pink cytoplasm, resembling epithelial cells and hence the term epithelioid cells (Fig. 1-6). Multinucleated giant cells are commonly present and are generally one of two types: foreign-body

Table 1-7 Vasculitis and Related Disorders

Vasculopathy Small-vessel vasculitis Neutrophilic/leukocytoclastic vasculitis Lymphocytic vasculitis Granulomatous vasculitis Medium-Sized vessel Vasculitis

12

 FIGURE 1-16 Granulomatous reaction pattern. Multifocal histiocytic infiltrates in dermis (arrow) and subcutis caused by bacterial infection (bottom panel shows organisms detected by Fite stain, arrow).

and Langhans giant cells. Granulomas often contain a variable admixture of other cell types, such as lymphocytes, plasma cells, neutrophils, and mast cells. Poorly defined granulomatous infiltrates often are referred to as granulomatous inflammation. Granulomas may be classified in a number of ways, such as infectious (Fig. 1-16) or noninfectious or by morphologic features, acknowledging that there is considerable overlap among many of these entities. A generally accepted scheme is as follows: (1) sarcoidal or epithelioid cell granulomas, (2) tuberculoid or caseating granulomas, (3) foreign-body granulomas, (4) suppurative granulomas, (5) palisading/necrobiotic granulomas, and (6) elastolytic granulomas. In general, these reaction patterns are nonspecific and should prompt a

differential diagnosis and systematic evaluation, as discussed in more detail in Chap. 6 (see Fig. 1-6).

Disorders of skin appendages The skin appendages, principally the hair follicle and the eccrine sweat apparatus, may show primary inflammatory involvement. Disorders of the hair follicle In general, folliculitis is categorized as to whether it is infectious or noninfectious and according to its depth: superficial only or superficial and deep. Acne is an extremely common form of folliculitis that has a multifactorial basis, for example. The hair follicle also may show a peculiar reaction— follicular mucinosis—which may be associated with a number of processes, including mycosis fungoides and inflammatory

panniculitis has been classified as septal or lobular, in fact, in most instances the inflammatory process is both septal and lobular, often spreading from the septae. Particular factors that should be considered when evaluating panniculitis include presence or absence of infection, vascular injury, cold-related injury, factitial disease, or physical injury. Adequate sampling and the stage of disease when the biopsy is taken will influence the morphologic findings observed. The reaction pattern of adipose tissue to injury is rather limited. Initially one observes an influx of neutrophils (erythema nodosum pattern, Fig. 1-17), followed by mononuclear cells (lymphocytes and macrophages), and finally, reparative fibrosis (Fig. 1-18),

depending on the nature and severity of the insult.

Proliferative or Neoplastic Conditions A large category of conditions encompasses hyperplasias, hamartomas, and benign and malignant neoplasms involving the epidermis, melanocytes, skin appendages, dermis, subcutis, and hematopoietic cells in the skin.

Noninflammatory Conditions In the absence of an obvious inflammatory dermatitis or proliferative/neoplastic process, one must proceed along the

Disorders of the sweat apparatus The eccrine duct may be involved primarily in an inflammatory reaction termed miliaria and categorized according to depth of involvement as (superficial) miliaria crystallina, miliaria rubra, and miliaria profunda. Hidradenitis refers to an inflammatory disorder involving the sweat coil as in neutrophilic eccrine hidradenitis, which may be infectious or noninfectious. Panniculitis The primary focus of inflammation may be in the subcutaneous fat, fascia, or both. Although traditionally

 FIGURE 1-17 Panniculitis (erythema nodosum reaction pattern). Dense neutrophil-rich inflammatory infiltrates extending out from the fibrous septae into the fat lobules in a patient undergoing treatment for Hodgkin lymphoma.

 FIGURE 1-18 Panniculitis with fibrous replacement. Histiocyte-rich lobular and septal panniculitis with ischemic fat necrosis and progressive fibrosis and calcification (bottom panel arrow) caused by lipodermatosclerosis (venous insufficiency).

CHAPTER 1 ■ INTRODUCTION TO MICROSCOPIC INTERPRETATION

conditions such as arthropod bites and lupus erythematosus. Alopecia histologically refers to an overall reduction in the number of terminal anagen hair follicles, which may be reversible or irreversible. Operationally (and perhaps simplistically), alopecia may be classified as nonscarring or scarring. Nonscarring alopecias may result from any number of factors interrupting the hair growth cycle, whether inflammatory, as in the case of alopecia areata, or noninflammatory, as in androgenetic alopecia or telogen effluvium. Scarring alopecia follows a wide variety of processes such as infective follicultis, lupus erythematosus, lichen planus, or traumatic injury.

13

Table 1-8 Differential Diagnosis of “Normal Skin”

PART I ■ INFLAMMATORY REACTIONS IN THE SKIN

Superficial fungal infection Dermatophytosis and tinea versicolor Porokeratosis Ichthyosis Hypopigmentation Vitiligo Piebaldism Chemical leukoderma Nevus depigmentosus Hyperpigmentation Café-au-lait macule Freckle Melasma Lentigo Macular amyloidosis Onchocerciasis Dermal melanocytosis Urticaria pigmentosa Argyria

Urticaria Anhidrotic ectodermal dysplasia Anetoderma Cutis laxa Connective tissue nevus Dermal mucinosis Myxedema Scleromyxedema Atrophoderma Lipoatrophy

algorithm now considering noninflammatory conditions. Histologic alterations may suggest “normal skin” and may include the so-called invisible dermatoses (Table 1-8).6,7 As already outlined earlier, one generally must resort to systemic study of the specimen beginning with the stratum corneum or perhaps with the subcutis in the reverse order. It goes without saying that the histopathologist

14

Hyphae and spores in stratum corneum Cornoid lamella Slight hyperkeratosis, diminished or absent granular layer Diminished or absent basal layer melanin, melanocytes

Increased basilar melanin and possibly melanocytes

Pink amorphous globules in papillary dermis Pigment incontinence Microfilaria in superficial dermis Dendritic melanocytes in dermis Increased numbers of mast cells in dermis Deposition of silver granules in basement membranes, particularly surrounding eccrine sweat coils Sparse perivascular infiltrate Edema Absence of eccrine sweat glands Focal or diffuse absence of elastic tissue Inflammation present or absent Absence of elastic fibers Increased or decreased collagen and/or elastin Abnormal connective tissue Increased dermal mucin

Decreased thickness of dermis Fat lobules diminished in size

should have some understanding of the regional microanatomy and age-related variations of skin in order to know what is within normal limits. ALTERATIONS OF STRATUM CORNEUM AND EPIDERMIS The stratum corneum is studied for subtle abnormalities such as parakeratosis, hyperkeratosis, and fungal elements. The epidermis is inspected for

acanthosis, atrophy, subtle alterations suggesting an inflammatory or vesicular reaction, alterations of the granular layer as in ichthyosiform dermatitides, peculiar processes such as epidermolytic hyperkeratosis, and finally, pigmentary alterations associated with hypo- and hyperpigmentation. ALTERATIONS OF PAPILLARY DERMIS The papillary dermis is then studied for alterations such as deposition of amyloid, hyalinization of vessels as in porphyria, and incontinence of melanin (melaninladen macrophages in papillary dermis). ALTERATIONS OF RETICULAR DERMIS The reticular dermis is examined systematically for alterations of collagen as in morphea/scleroderma or scleredema, thickening or atrophy of the reticular dermis, alterations of elastic fibers, and deposition of materials such as mucin or amyloid.

REFERENCES 1. Ackerman A, Boer A, Bennin B, Gottlieb G. Histologic Diagnosis of Inflammatory Skin Diseases: A Method of Pattern Analysis. 3rd ed. Philadelphia, PA: Lea & Febiger; 2005. 2. Ackerman AB. An algorithmic method for histologic diagnosis of inflammatory and neoplastic skin diseases by analysis of their patterns. Am J Dermatopathol. 1985; 7(2):105-107. 3. Ackerman AB. Differentiation of benign from malignant neoplasms by silhouette. Am J Dermatopathol. 1989;11(4):297-300. 4. Murphy BW, Webster RJ, Turlach BA, et al. Toward the discrimination of early melanoma from common and dysplastic nevus using fiber optic diffuse reflectance spectroscopy. J Biomed Opt. 2005;10(6): 064020. 5. Nathwani B, Burke J, Winberg C. Architectural features of normal, neoplastic, and nonneoplastic lymph nodes: a practical diagnostic approach. In: Murphy G, Mihm M, eds. Lymphoproliferative Disorders of the Skin. Boston, MA: Butterworths; 1986. 6. Bernhard JD. Invisible dermatoses versus nonrashes. J Am Acad Dermatol. 1983;9(4): 599-600. 7. Brownstein MH, Rabinowitz AD. The invisible dermatoses. J Am Acad Dermatol. 1983;8(4):579-588.

CHAPTER 2 Spongiotic Dermatitis Michael Murphy Jane M. Grant-Kels

INTRODUCTION

neutrophilic spongiosis, respectively. A PAS stain to exclude dermatophytoses should be performed in all biopsies showing spongiosis, particularly those associated with neutrophil exocytosis (Fig. 2-12).

Secondary Changes Because spongiotic dermatoses are often pruritic, secondary changes are common. The most frequently identified secondary changes seen in association with spongiosis include: (a) superimposed infection; (b) lichenification/lichen simplex chronicus, secondary to chronic rubbing (Fig. 2-13 and 2-14); (c) prurigo nodularis, secondary to chronic picking (Fig. 2-15); and (d) erosions or ulcers secondary to excoriations. Patients chronically rub itchy spongiotic dermatoses. As a result, the skin clinically becomes thickened and papular with accentuation of normal skin markings, hyperpigmentation, and scaliness (Table 2-4). Superimposed infection or secondary impetiginization is not an infrequent complication. This change is secondary to the scratching of these often intensely pruritic eruptions. The resultant bacterial infection overlying the changes of the spongiotic dermatitis results in abundant scale-crust laden with bacteria that can be identified on routine staining and highlighted with a Gram stain. In more severe cases vesiculopustules may be identified.

CHAPTER 2 ■ SPONGIOTIC DERMATITIS

The term spongiotic dermatitis refers to a large group of inflammatory disorders that share the histopathologic finding of spongiosis, characterized by impairment of cohesion between epidermal keratinocytes and intercellular edema (Fig. 2-1 and Table 2-1). Spongiosis is the hallmark of eczematous dermatitides, but can be seen in a variety of other skin conditions (Table 2-2). The mechanisms underlying the pathogenesis of spongiotic changes have only recently begun to be eludicated.1,2 Skin-infiltrating T-cells damage the epidermis by releasing proinflammatory cytokines and induce keratinocyte apoptosis through “killer molecules.”1,2 There is subsequent cleavage of adhesion molecules, including E-cadherin, on keratinocytes.1,2 Accumulation of extracellular fluid results in widening of the spaces between keratinocytes, causing the epidermis to resemble a sponge histologically.1,2 Other terms used to refer to these diseases include eczema, eczematous dermatitis, or simply dermatitis. The clinical appearance of the spongiotic dermatoses can vary significantly, depending on the duration, etiology, and location of the lesions and the presence of superimposed secondary changes such as excoriation. However, the salient clinical finding is that of epidermal alteration. These primary and secondary epidermal changes may include erythema, vesiculation, scaling, crusting, lichenification, hyperpigmentation, excoriation, oozing, erosions, or fissures. Most lesions of spongiotic dermatitis are poorly demarcated clinically, with the notable exceptions of nummular dermatitis (round well-defined, coinshaped plaques) and some lesions of contact dermatitis. Collectively, the spongiotic dermatoses are among the most common cutaneous disorders presenting to dermatologists and primary care providers. Spongiotic dermatitis is conventionally divided into acute, subacute, and chronic stages (Table 2-3). A single lesion may evolve through these three stages;

however, not all lesions do this. The classic example of acute spongiotic dermatitis is acute allergic contact dermatitis, such as that caused by exposure to poison ivy. Acute spongiotic dermatitis is characterized histologically by significant intercellular edema with formation of spongiotic microvesicles or even macrovesicles (that can be seen clinically) (Figs. 2-2 to 2-3). An associated superficial, perivascular inflammatory infiltrate composed of lymphocytes, histiocytes, some eosinophils, and occasionally associated extravasated red blood cells is noted. Subepidermal edema may also be prominent. The stratum corneum may still be normally cornified without parakeratosis. The clinical lesion reflects these histologic features; appearing as edematous, inflamed oozing papules and plaques, often with visible vesicles. A lesion of subacute spongiotic dermatitis usually demonstrates spongiosis with formation of some microvesicles, and overlying parakeratosis (Figs. 2-4 to 2-6). Mild epidermal acanthosis may be a feature. A superficial perivascular inflammatory infiltrate of lymphocytes, histiocytes, with or without eosinophils is present in the dermis, but papillary dermal edema is not a prominent feature. Good examples of subacute spongiotic dermatitis are lesions of atopic dermatitis and nummular dermatitis present for several weeks. Clinically these lesions are scaling pink-to-red papules and plaques, often with secondary changes such as excoriation. Many lesions of subacute spongiotic dermatitis become chronic (such as the atopic dermatitis) (Figs. 2-7 to 2-9). Chronic spongiotic dermatitis describes lesions that have been present for a time and demonstrate changes of repair and/or secondary changes, in addition to spongiosis. Chronic spongiotic dermatitis lesions can show compact hyperkeratosis, acanthosis with hypergranulosis, spongiosis, and sometimes papillary dermal fibrosis due to chronic rubbing (Fig. 2-10). Spongiosis is usually minimal and only focal in chronic lesions. These lesions present as lichenified, firm papules and plaques with accentuation of skin lines and often with postinflammatory pigmentary changes (hyperpigmentation more commonly than hypopigmentation). The most common inflammatory cells identified in the spongiotic epidermis are lymphocytes, often in association with Langerhans cell microvesicles (Fig. 2-11), but as discussed later in this chapter, other cells may predominate, including eosinophils and/or neutrophils, resulting in changes of eosinophilic spongiosis and

Eosinophilic Spongiosis Eosinophilic spongiosis describes a reaction pattern in which there is exocytosis of eosinophils associated with changes of spongiosis (Figs. 2-16 to 2-17).3-6 These changes can be seen in a variety of inflammatory dermatoses, described in other chapters (Table 2-5).

Neutrophilic Spongiosis A heterogeneous group of dermatoses can demonstrate neutrophilic spongiosis (Figs. 2-12, 2-18, and 2-19), described as the presence of neutrophil exocytosis with epidermal spongiosis (Table 2-6).4,7,8 Occasionally, neutrophils can form collections within the epidermis (ie, spongiform pustules).

Contact Dermatitis Contact dermatitis describes an inflammatory skin reaction to an exogenous agent. Two variants have been described: (1) allergic contact dermatitis and (2) irritant contact dermatitis.9-16 Allergic contact

15

Spongiotic Dermatitis

Proliferation of the superficial vascular plexus, thickened vessel walls, variable amount of lymphocytic infiltrate, hemorrhage, and hemosiderin-laden macrophages:

Superficial perivascular lymphoid infiltrates with hemorrhage and/or hemosiderinladen macrophages: Pigmentary purpura (eczematid variant of Doucas and Kapetanakis)

Chronic stasis dermatitis

Superficial and deep perivascular lymphoid infiltrate, tightly cuffed “coat-sleeve” around vessel: Figurate erythemas Dyskeratotic cells: Polymorphous light reaction Photodrug reaction Many dyskeratotic cells and keratinocytic atypia:

Angiodermatitis

Wedge-shaped superficial and deep perivascular lymphoid infiltrates with eosinophils: Hypersensitivity reaction to arthropod assaults

Superficial perivascular lymphoid infiltrate and intraepidermal or intracorneal neutrophils: Seborrheic dermatitis Early or treated psoriasis Sneddon-Wilkinson disease Contact dermatitis (esp. irritant)

Phototoxic reaction

PART I ■ INFLAMMATORY REACTIONS IN THE SKIN

 FIGURE 2-1 Algorithm for spongiotic dermatitis.

Table 2-1 Differential Diagnosis of Spongiotic Dermatoses ENTITY

DISTINGUISHING HISTOLOGIC FINDING

Allergic contact dermatitis

Eosinophilic spongiosis Spongiotic micro- and macrovesiculation Neutrophils Ballooning Necrosis Eosinophilic spongiosis Necrotic keratinocytes Sunburn (necrotic) keratinocytes Pallor of keratinocytes Neutrophils Prominent papillary dermal edema Epidermal acanthosis Prominent vasculature Secondary changes of LSC Follicular infundibular spongiosis None Vesiculopustules Parakeratosis at lips of follicular ostia None None Genital skin Mounds of parakeratosis Extravasated red blood cells Depends on underlying disease Thick-walled venules Extravasated red blood cells Hemosiderin deposition Fibrosis Spongiotic ± interface changes Necrotic keratinocytes Eosinophils Follicular spongiosis Parafollicular parakeratosis Decreased melanization in basal layer Reduction in basal melanocytes Melanophages Spongiotic ± interface changes Lymphocyte exocytosis Papillary dermal edema None Eosinophilic spongiosis Dyskeratotic squamous cells Involvement of eccrine duct

Irritant contact dermatitis

Photoallergic contact dermatitis Phototoxic dermatitis

Dermal/protein contact dermatitis Atopic dermatitis

Fox-Fordyce disease Nummular dermatitis Pompholyx Seborrheic dermatitis Id reaction Asteatotic eczema Sulzberger-Garbe syndrome Pityriasis rosea Exfoliative erythroderma Stasis dermatitis

Spongiotic drug eruptions

Pityriasis alba

Gianotti-Crosti syndrome

PUPPP Incontinentia pigmenti Miliaria

16

Table 2-2 Skin Diseases in which Spongiosis May be Seen Dermatophytosis Erythema neonatorum Grover disease, spongiotic variant Gyrate erythemas Lichen striatus Mycosis fungoides Parapsoriasis Pigmented purpuric dermatoses Pityriasis lichenoides Polymorphous light eruption Primary syphilis Psoriasis, early or treated Reaction to arthropod assault

dermatitis is a type IV delayed hypersensitivity reaction in the skin of a patient who has been previously sensitized to an allergen. Common allergens include nickel, urushiol (poison ivy), and topical medications, including local anesthetics and topical antibiotics. Irritant contact dermatitis is due to exposure to chemical or physical agents that induce direct (non–immunologically mediated) damage to the skin. Common offending agents include detergents, soaps, some sunscreens, acids, and alkalis. Irritant contact dermatitis is the most common mechanism of occupational hand dermatitis. Irritant contact dermatitis occurs more quickly after exposure, tends to resolve more quickly, and is more common than allergic contact dermatitis, but it may be difficult to distinguish allergic and irritant contact dermatitis from each other or from other spongiotic dermatitides on the basis of clinical or histopathologic features. In addition, some agents may act as both an irritant and an allergen.

Superficial perivascular lymphoid infiltrate with or without eosinophils and large, well-formed intraepidermal vesicles:

Superficial perivascular lymphoid infiltrate without eosinophils:

Superficial perivascular lymphoid infiltrate with or without eosinophils

Chronic superficial dermatitis

Atopic dermatitis

Pityriasis lichenoides chronica

Nummular dermatitis

Allergic contact dermatitis

Pruritic urticarial papules and plaques of pregnancy

Pityriasis rosea (especially inflammatory variant)

Dyshidrotic eczema

Gianotti-Crosti syndrome

Pompholyx

Early mycosis fungoides

Grover disease (spongiotic variant)

Impetigo With plasma cells and endothelial cell swelling: Secondary syphilis

Id reaction Hypersensitivity reaction to arthropod assault

A CUTE S P O N G I O T I C DERMATITIS

SUBACUTE SPONGIOTIC DERMATITIS

CHRONIC SPONGIOTIC DERMATITIS

Often normal; sometimes parakeratosis, scale-crust None to minimal

Parakeratosis and scale-crust

Hyperkeratotic orthokeratosis

Mild to moderate

Moderate to marked

Mild to marked Yes ± macrovesicles Lymphocytes and eosinophils

Mild to moderate Yes

Minimal to absent No

Lymphocytes and eosinophils

Lymphocytes and histiocytes

Minimal to marked

Minimal

No

No

No

Yes

(intracellular edema), all three spongiotic (acute, subacute, and chronic) patterns can be seen. Similar to allergic contact dermatitis, skin lesions are typically localized, but may become generalized. Lesions may be prevented if the irritant is identified and avoided, or contact reduced.

Histopathological Features If the irritant is applied in sufficient concentration, the epidermis will show ballooning degeneration of keratinocytes with necrosis, in addition to changes of keratinocyte regeneration. At lower irritant concentrations, acute, subacute, and chronic spongiotic patterns can be seen, depending on the duration of exposure. Histologic clues to distinguishing allergic contact dermatitis from irritant contact dermatitis are:

CHAPTER 2 ■ SPONGIOTIC DERMATITIS

Epidermal acanthosis Spongiosis Intraepidermal microvesicles Dermal perivascular inflammation Papillary dermal edema Papillary dermal thickening

Dermatophytosis With intracorneal gram-positive cocci:

Drug hypersensitivity reaction

Table 2-3 Histopathologic Features in Spongiotic Dermatitis

Stratum corneum

With intracorneal hyphal forms:

1. Variable presence of eosinophils and predominance of spongiosis in allergic contact dermatitis ALLERGIC CONTACT DERMATITIS Clinical Features The skin changes are often localized, with the distribution of the lesions providing clues to the diagnosis and potential etiological agent(s) (Table 2-7). Patients usually have a history of contact with an allergen prior to the cutaneous eruption. Clinical lesions vary depending on the nature and concentration of the allergen and duration of “contact.” Mild skin erythema, erythematous, scaly papules and plaques, vesiculobullous reactions, or any combination of these changes can be seen (Fig. 2-20A). The rash may become generalized if autoeczematization (id reaction) occurs. Long-standing lesions can show skin thickening with scaling and accentuation of skin markings (lichenification). The diagnosis can be confirmed by patch testing, and lesions typically resolve with avoidance of allergens.

Histopathological Features Allergic contact dermatitis is the prototypic spongiotic

reaction pattern. Acute, subacute, and chronic stages of disease can be seen, depending on the duration of contact with the offending allergen, and correlating with the clinical features. The earliest changes are seen in the superficial dermis; with a perivascular lymphohistiocytic and sometimes eosinophilic inflammatory infiltrate, and papillary dermal edema. This is followed by exocytosis of inflammatory cells into the epidermis with varying degrees of intercellular edema, often associated with spongiotic microvesiculation (Figs. 2-20 to 2-21). Parakeratosis with inflammatory cell debris and serum may be present in the stratum corneum. With time, the pathology reflects a progressive reduction in epidermal spongiosis, with irregular (nonpsoriasiform) epidermal hyperplasia, and fibroplasia of the superficial dermis. IRRITANT CONTACT DERMATITIS Clinical Features In addition to “burntype reactions,” necrosis, and ballooning

2. Variable presence of neutrophils and ballooning in irritant contact dermatitis (Fig. 2-19)

PHOTOALLERGIC DERMATITIS Photoallergic eruptions represent either UVA-induced immediate type I or delayed hypersensitivity type IV reactions to either (a) topical agents, such as antihistamines and local anesthetics (contact photoallergy), or (b) systemic medications such as NSAIDs or sulphonamides (systemic photoallergy).17,18

Clinical Features Cutaneous manifestations can include overlapping acute, subacute, and chronic spongiotic and/or lichenoid reactions of sun-protected areas, including the backs of the hands, face, and V-shaped area of the anterior neck. Occasionally, unexposed skin can be affected, in contrast to phototoxic reactions. Generalized erythroderma can also occur.

17

PART I ■ INFLAMMATORY REACTIONS IN THE SKIN

UVB and/or UVA non–immunologically mediated reactions to topical agents (ie, tars and certain plants/phytophotodermatitis) or systemic medications (ie, psoralens, thiazides, tetracyclines, NSAIDs).17,18 Cellular damage is induced by the direct reaction between the drug (sensitizer) and UVlight. Pseudoporphyria is a variant of a phototoxic reaction. Some drugs can produce both phototoxic and photoallergic reactions.

Clinical Features A phototoxic eruption resembles a sunburn reaction, with erythema, edema and vesiculation/blistering, occurring within minutes-to-hours after exposure, and confined to sunexposed areas. This is later followed by desquamation and hyperpigmentary changes. In chronic phototoxic eruptions, epidermal atrophy with telangiectasias may be features.

 FIGURE 2-2 Acute spongiotic dermatitis. Marked epidermal intercellular edema with spongiotic microvesicles and superficial perivascular lymphocytic infiltrate. The stratum corneum shows normal basket weave pattern.

 FIGURE 2-3 Acute spongiotic dermatitis. Marked epidermal intercellular edema, with spongiotic microvesicles and macrovesicles, and superficial perivascular lymphocytic and eosinophilic infiltrate. There is focal parakeratosis.

18

Histopathological Features Photoallergic dermatitis shows histologic features similar to those of typical allergic contact dermatitis, with epidermal spongiosis and often eosinophil exocytosis. Clues to a photoallergic eruption can include papillary dermal edema, vascular dilatation, the presence of eosinophils, extension of the inflammatory infiltrate into the deep dermis, and the presence

of a few necrotic keratinocytes (Fig. 2-22). A lichenoid tissue reaction can be seen in some cases. Variable epidermal spongiosis can also be seen in other lightinduced reactions, including polymorphous light eruption and persistent light reaction. PHOTOTOXIC DERMATITIS Unlike photoallergic dermatoses, phototoxic eruptions are

Histopathological Features The hallmark of an acute phototoxic reaction is the presence of necrotic/apoptotic keratinocytes (sunburn cells) in the epidermis. In addition to epidermal spongiosis, other histologic features including pallor of keratinocytes, neutrophil exocytosis, variable vacuolar alteration along the dermoepidermal junction, possible subepidermal vesiculation, papillary dermal edema, and a superficial dermal inflammatory infiltrate containing variable numbers of neutrophils and eosinophils can be seen. Chronic phototoxic reactions can show epidermal thinning with hyperkeratosis, and intradermal melanin deposition with vascular ectasias. Superficial dermal blood vessels may demonstrate basement membrane reduplication. DERMAL/PROTEIN CONTACT DERMATITIS The term “dermal/protein contact dermatitis” describes an unusual variant of allergic contact dermatitis, characterized by more prominent papillary dermal edema than typically seen in the classic form of allergic contact dermatitis (Fig. 2-23).19,20 It can be associated with exposure to fish, vegetables, fruits, plants, meat proteins, zinc and nickel, and topical neomycin. The differential diagnosis includes other causes of epidermal spongiosis associated with papillary dermal edema, including dermatophytosis and spongiotic drug eruptions. ATOPIC DERMATITIS Atopic dermatitis (AD) is a common chronic, relapsing dermatosis, affecting 1% to 2% of the general population, that is associated with asthma and allergic rhinitis (~50% of cases), a family history of atopy (~75% of cases),

 FIGURE 2-4 Subacute spongiotic dermatitis. Parakeratosis, slight epidermal acanthosis, minimal spongiosis, and occasional lymphocyte exocytosis.

Histopathological Features AD can show the typical histologic spectrum of acute, subacute, and chronic spongiotic dermatitides.21-23 Therefore, the changes seen on skin biopsies in AD patients can be indistinguishable from other spongiotic processes (Figs. 2-5 to 2-10). A number of subtle histologic features have been suggested as favoring a diagnosis of AD. These include an increase in epidermal volume (acanthosis); prominent vasculature in the superficial dermis; and a relative paucity of eosinophils in the inflammatory infiltrate (compared with other spongiotic dermatitides, particularly allergic contact dermatitis). In addition, clinically unaffected skin in patients with AD can show a sparse superficial perivascular infiltrate of lymphocytes, histiocytes, and eosinophils.

CHAPTER 2 ■ SPONGIOTIC DERMATITIS

papulovesicular lesions on the head, neck, diaper area, and extensor surfaces. In childhood, flexural areas are commonly involved by scaly, lichenified plaques (secondary to chronic rubbing). The disease is characterized by a course of remissions and exacerbations, and resolves in up to 50% of cases by adolescence. AD persisting into adulthood tends to show more widespread disease or may be manifested by chronic hand dermatitis. Skin lesions in AD are largely secondary to the scratching and rubbing in response to the intense pruritus patients with AD experience (Fig. 2-23A). AD is commonly associated with dry skin (xerosis), and an increased susceptibility to secondary dermatophyte, bacterial and viral infections.

FOLLICULAR “ECZEMA” (FOLLICULAR ATOPIC DERMATITIS) Clinical Features A minority of patients with AD will develop small follicularbased, pruritic, flesh-colored to erythematous papules, predominantly on the trunk and/or extremities, with or without the typical lesions of AD, as previously described. Follicular AD is more common in skin of color.  FIGURE 2-5 Subacute spongiotic dermatitis. Mounds of parakeratosis, slight epidermal acanthosis, spongiosis with Langerhans microvesicle, and superficial perivascular lymphocytic infiltrate.

marked pruritus, increased serum IgE antibody levels (~90% of cases), and often exacerbations in the winter months (Table 2-8).21-23 Staphylococcal superantigens are postulated to play a role in the pathogenesis of AD. AD is commonly observed with other dermatological disorders, including pityriasis alba, keratosis pilaris, nipple eczema, and white

dermatographism. Patients with AD show an increased incidence of pompholyx and irritant contact dermatitis of the hands. Patients with ichthyosis vulgaris can have AD-like skin changes.

Clinical Features The disease usually begins within the first 6 months of life.21-23 Infantile AD is characterized by eroded

Histopathological Features There is spongiosis of the follicular infundibulum, with or without involvement of the isthmus, with lymphocyte exocytosis (Fig. 2-24). Mild acanthosis, spongiosis, and focal parakeratosis can be seen in the adjacent epidermis. Differential Diagnosis In addition to AD, follicular spongiosis can be seen in infundibulofolliculitis, Fox-Fordyce disease (apocrine miliaria), and pityriasis alba (Table 2-9). A number of clinical

19

PART I ■ INFLAMMATORY REACTIONS IN THE SKIN

Compared to AD, Fox-Fordyce disease can show increased numbers of neutrophils as part of the inflammatory response. Lesions of pityriasis alba can show follicular spongiosis, in addition to other changes such as follicular dilatation with plugging, parafollicular parakeratosis, and atrophic sebaceous glands.

 FIGURE 2-6 Subacute spongiotic dermatitis. Hyperkeratosis, slight epidermal acanthosis, lymphocyte exocytosis, spongiosis with microvesicle formation, and superficial perivascular lymphohistiocytic infiltrate.

Histopathological Features There is an intrafollicular keratotic plug with follicular infundibular spongiosis (adjacent to the opening of the apocrine sweat gland). Subsequently, there is dilatation of the upper region of the apocrine duct with cyst formation. PITYRIASIS ALBA Pityriasis alba is a very common disorder characterized by the presence of scaly, faintly erythematous patches that heal with postinflammatory hypopigmentation.26-28 The disease occurs mainly in children, but adults may be affected. While the etiology is unknown, the disease is exacerbated by cold weather and sun exposure, and patients often have a personal and/or family history of atopic dermatitis.

 FIGURE 2-7 Subacute/chronic spongiotic dermatitis. Compact hyperkeratosis, parakeratosis, slight hypergranulosis, epidermal acanthosis, and spongiosis.

20

FOX-FORDYCE DISEASE Clinical Features Fox-Fordyce disease (apocrine miliaria) is characterized by long-standing, itchy, follicular-based papules in areas with high apocrine gland concentrations, including the axillae, areolae, and anogenital regions.24,25 The disease is rare, but greater than 90% of cases have been described in young women. There is a lack of apocrine sweating with folliculocentric retention cyst formation in the epidermis due to keratotic plugging of the apocrine duct opening.

and/or histologic features may aid in the differential diagnosis of these entities. Similar to AD, infundibulofolliculitis is characterized by a widespread pruritic papular eruption on the truck and/or proximal extremities, but usu-

ally occurs in young black patients without an atopic history. Fox-Fordyce disease is typically limited to the axilla and groin (areas with increased numbers of apocrine glands), with 90% of cases occurring in young women.

Clinical Features Three clinical stages of disease lasting from months to several years are described: (1) papular erythematous; (2) papular hypochromic; and (3) macular and patchy hypochromic. The condition may be pruritic. The disease progresses from erythematous to hypopigmented, round-to-oval, scaly 0.5 to 3 cm patches on the face (>50% of cases), neck, upper chest, and arms. The clinical differential diagnosis includes vitiligo, pityriasis versicolor, progressive macular hypomelanosis, and hypopigmented mycosis fungoides. Frequently, folliculocentric papular lesions are seen. The lesions eventually repigment. Histopathological Features Skin biopsy usually shows mild spongiotic features,

middle-aged and older men and women (Table 2-10).29 There is an association with xerosis, atopy, and/or hypersensitivity to nickel. The condition may be exacerbated by cold weather and certain drugs, including gold. The term nummular dermatitis refers to a particular clinical appearance rather than a specific disease.

 FIGURE 2-8 Subacute/chronic spongiotic dermatitis. Compact hyperkeratosis, parakeratosis, epidermal acanthosis, and spongiosis with microvesicle formation and lymphocyte exocytosis.

Histopathological Features The histologic features of nummular dermatitis are similar to the other spongiotic dermatitides at comparable chronologic stages of evolution, with the pathologic changes varying with the activity and chronicity of the disease (Figs. 2-5 to 2-10). POMPHOLYX (DYSHIDROTIC) “ECZEMA” Pompholyx as an isolated finding is a rare disorder, constituting less than 2% of all hand dermatoses (Table 2-11).30,31 However, chronic hand dermatitis is not uncommon in adult atopics. Like all hand eczemas, the disease has been associated with several putative causal factors, including allergens, irritants, friction, drugs, atopy, foodstuffs, and infections (~15% of patients have dermatophytosis). The disease may be associated with hyperhidrosis. It is because of this rare association with sweat gland dysfunction that the disease has been called by some “dyshidrosis.” Up to 15% of cases are idiopathic.

 FIGURE 2-9 Subacute/chronic spongiotic dermatitis. Marked parakeratosis, epidermal acanthosis, spongiosis with lymphocyte exocytosis, and superficial perivascular and interstitial lymphocytic infiltrate.

including hyperkeratosis, focal parakeratosis, minimal spongiosis with lymphocyte exocytosis, decreased melanization of the basilar layer, a slight reduction in basal melanocytes, and a superficial perivascular lymphocytic infiltrate. Occasional melanophages may be present in the superficial dermis. Folliculocentric lesions

can show follicular spongiosis, follicular dilatation with plugging, parafollicular parakeratosis, and atrophic sebaceous glands. NUMMULAR DERMATITIS Nummular dermatitis is most commonly seen in young women (15-30 years), and in both

CHAPTER 2 ■ SPONGIOTIC DERMATITIS

Clinical Features Nummular dermatitis is characterized by well-demarcated, oval to coin-shaped erythematous pruritic patches and plaques, predominantly on the dorsum of the hands and forearms and anterior aspects of the thighs and legs and upper back (Fig. 2-24A). The disease typically evolves from small confluent papules with scaling into larger annular plaques with central clearing, resembling tinea corporis.

Clinical Features The disease is characterized by recurrent crops of vesicles or bullae (on nonerythematous skin) located on the lateral aspects of the fingers and on the palms and soles.30,31 The vesicles may be pruritic or associated with a burning sensation, persist for 1 to 2 weeks, subsequently desquamate, and then recur at irregular intervals. Histopathological Features Pompholyx shows an intraepidermal microvesicle(s) with serum and often few inflammatory cells, typically lymphocytes (Fig. 2-25). A sparse lymphocytic infiltrate within the superficial dermis is seen. Vesicles can

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PART I ■ INFLAMMATORY REACTIONS IN THE SKIN

(affecting ~3% of the general population), most often distributed to the scalp, ears, nasolabial folds, eyebrows, central chest, and intertriginous areas (“seborrheic” areas) (Table 2-12).32,33 The etiology is unknown, but a causative role for Malassezia spp. (Pityrosporum) has been proposed, and a family history is present in many patients. Exacerbations may be associated with stress. The disease is closely related to infantile SD, and is common in patients with AIDS (20%80% of HIV-infected patients), Parkinson disease, and mood disorders.

 FIGURE 2-10 Chronic spongiotic dermatitis. Marked compact hyperkeratosis and parakeratosis, epidermal acanthosis, minimal spongiosis, and superficial perivascular lymphocytic infiltrate.

 FIGURE 2-11 Langerhans cell microvesicles with adjacent epidermal spongiosis.

22

develop into pustules, with prominent neutrophil exocytosis, and raises the differential diagnosis of pustular psoriasis or pustular dermatophytosis. A PAS stain should be performed in all cases. The disease can mimic acute allergic contact dermatitis. Of note, the presence of epidermal spongiosis adjacent to the

microvesicle and/or the presence of intradermal eosinophils would argue against a diagnosis of pompholyx, and support an interpretation of allergic contact dermatitis. SEBORRHEIC DERMATITIS Seborrheic dermatitis (SD) is a common dermatosis

Clinical Features The condition most commonly occurs within the first 3 months of life and in adults over 30 years old, with males more commonly affected. There is erythema with overlying flaking, yellowbrown, greasy scales in areas of increased sebaceous glands. However, sebaceous gland activity and sebum production do not appear to be altered in SD.32,33 Distribution of lesions is generally symmetrical, and in many patients there is clinical overlap with psoriasis. Dandruff, cradle cap, and some forms of diaper rash are regarded as variants of SD. It is commonly observed with other dermatological disorders, including blepharitis, acne vulgaris, rosacea, and other Malassezia spp.-associated diseases (ie, Pityrosporum folliculitis and tinea versicolor). Histopathological Features The histologic changes vary with the age of the lesion biopsied.32,33 SD can show overlapping histologic features between spongiotic dermatitides (acute, subacute, or chronic spongiotic dermatitis) and psoriasis; including hyperkeratosis, parakeratosis, psoriasiform epidermal hyperplasia, spongiosis, and neutrophilic exocytosis. In SD the parakeratosis is particularly prominent at the margins of follicular ostia (Fig. 2-26). Yeast forms (spores) are common in the stratum corneum, but hyphae are not seen. Early changes of SD may show edema, ectatic blood vessels, and neutrophils within the superficial dermis, reminiscent of early psoriatic lesions. AIDS-associated SD can show increased hyperkeratosis, confluent parakeratosis, follicular plugging, more prominent lymphocyte and neutrophil exocytosis, necrotic and dyskeratotic squamous cells within the epidermis, and greater numbers of plasma cells as a component of the dermal inflammatory infiltrate. Unlike SD in immunocompetent patients, lesional skin of AIDS patients characteristically expresses heat shock proteins (HSP65 and HSP72).

plausible alternative etiology for the secondary inflammatory process.34,35 The pathogenesis of this disorder is a matter of debate, but may be related to activated T-lymphocytes and/or cytokines generated at the primary site.

Histopathological Features The pathologic changes typically mimic those seen in the primary lesions. In addition to spongiotic changes, the secondary (id) lesions often show prominent papillary dermal edema (Fig. 2-27). A combination of these features can also be seen in dermatophytoses, spongiotic drug eruptions, and protein/dermal contact dermatitis.

CHAPTER 2 ■ SPONGIOTIC DERMATITIS

 FIGURE 2-12 Dermatophytosis (PAS stain). Spongiosis with neutrophil exocytosis and fungal hyphae within the stratum corneum.

ASTEATOTIC “ECZEMA” Aseatotic “eczema” (eczema craquelé, winter eczema) is an inflammatory dermatosis with xerosis, which may be associated with decreased surface lipid. The lesions can be produced or exacerbated by cold weather, dry indoor heat or air conditioning, and exposure to soaps and detergents, and are usually seen in elderly adults. The condition shows dry criss-crossing scale (resembling the fine cracks of porcelain) on the hands, arms, and legs, often with associated underlying/adjacent erythema and spongiotic changes. A generalized type of asteatotic “eczema” involving the trunk and extremities may be a marker of a visceral malignancy. SULZBERGER-GARBE SYNDROME SulzbergerGarbe syndrome (exudative discoid and lichenoid dermatosis) is a chronic pruritic eczematous dermatitis typically seen in middle-aged to older Jewish men. The condition is characterized by erythematous, often oozing papules and plaques, in addition to discoid and lichenoid lesions. An urticarial phase has been described. Genital lesions are common and considered to be a hallmark of Sulzberger-Garbe syndrome.

 FIGURE 2-13 Lichen simplex chronicus. Marked compact hyperkeratosis, hypergranulosis, irregular epidermal acanthosis, and fibrosis of the superficial dermis with sparse inflammation.

ID REACTION Clinical Features Id reaction (autoeczematization or autosensitization) describes the diffuse, symmetric spread of a papular acute spongiotic eruption, associated with previously localized spongiotic dermatitis. The entity is characterized by (1) a localized spongiotic eruption of known etiology (including dermatophyte infec-

tion, scabies infestation, acute contact dermatitis, stasis dermatitis, or ionizing radiation); (2) the development of a usually distant (but sometimes contiguous) nonspecific acute spongiotic dermatitis, days to weeks after the initial localized dermatitis; (3) the same morphology and pathologic findings in both primary and secondary skin lesions; and (4) lack of a

PITYRIASIS ROSEA Pityriasis rosea (PR) is a mild, acute, self-limited papulosquamous skin disorder of unknown, but possible viral or bacterial etiology (Table 2-13).36,37 There is an increased incidence in pregnant women and bone marrow transplant recipients. PR-like eruptions have also been associated with certain drugs, including captopril, gold, and barbiturates.

Clinical Features The majority (~75%) of cases of PR are seen in children and young adults.36,37 PR is characterized by the development in 80% of cases of an initial 2- to 10-cm single, salmon-pink, oval herald patch or plaque on the trunk

23

PART I ■ INFLAMMATORY REACTIONS IN THE SKIN

been devised and validated for PR, including essential clinical features: discrete circular or oval lesions; scaling on most lesions; and peripheral collarette scaling with central clearance on at least two lesions.36 Unusual and uncommon locations include the face, scalp, genitalia, palms, soles, and oral cavity. Inverse PR lesions predominate on the extremities rather than the trunk. Localized and unilateral variants have been described. Individual lesions may be clinically atypical, showing urticarial, papular, pustular, vesicular (particularly in children), and/or purpuric morphology. Some authors have suggested a slight seasonal pattern with cases peaking in the spring and fall.  FIGURE 2-14 Lichen simplex chronicus. Marked compact hyperkeratosis, hypergranulosis, irregular epidermal acanthosis, and sparse inflammation in the superficial dermis.

 FIGURE 2-15 Prurigo nodularis. Marked compact hyperkeratosis, parakeratosis, hypergranulosis, papillated epidermal acanthosis, and dermal fibrosis with vascular ectasias and sparse inflammation.

Table 2-4 Secondary Changes in Spongiotic Dermatitis

24

CLINICAL APPEARANCE

HISTOLOGIC FINDING

Thickened skin with exaggerated skin markings Scaling Hyperpigmentation

Marked epidermal hyperplasia and papillary dermal thickening with coarse collagen bundles Compact orthokeratosis and parakeratosis Epidermal acanthosis and occasional melanophages in superficial dermis

or proximal extremity, followed (7-14 days later; range: 2-84 days) by the appearance of a more generalized eruption of approximately 1-cm, salmonpink, scaly plaques usually on the trunk and proximal extremities along Langer

lines of cleavage, resulting in the characteristic “fir-tree” distribution. The rash typically lasts 6 to 8 weeks. A minority (~5%) of patients have prodromal symptoms, including headache, fever, and malaise. A set of diagnostic criteria has

Histopathologic Features The generalized eruption typically shows slight epidermal hyperplasia, focal spongiosis, and mounds of parakeratosis (Fig. 2-28).37 The dermis shows a superficial perivascular infiltrate of lymphocytes, histiocytes, and occasionally eosinophils, with variable papillary dermal edema and extravasated erythrocytes. Often, lymphocyte and erythrocyte exocytosis is observed. Dyskeratotic keratinocytes are a rare feature. The herald patch has similar histologic features, but may show greater epidermal hyperplasia, less spongiosis, and a deeper inflammatory component in the dermis. ERYTHRODERMA/EXFOLIATIVE DERMATITIS Erythroderma (generalized redness) associated with scaling (exfoliative dermatitis) can occur with a wide variety of cutaneous diseases, including spongiotic dermatitides, especially allergic contact dermatitis, stasis dermatitis, atopic dermatitis, and seborrheic dermatitis.38-42 Other nonspongiotic disorders, most commonly psoriasiform disorders (including psoriasis and pityriasis rubra pilaris), and reactions to topical or systemic medications (~16% of cases), scabetic infestation, lichen planus, pemphigus foliaceus, immunodeficiency states, and lymphoproliferative disorders (including mycosis fungoides, Sezary syndrome, and adult T-cell lymphoma/leukemia in ~10% of cases) can produce a similar exfoliative dermatitis.

Clinical Features The clinical features of erythroderma are typically nonspecific, with little clues to the underlying etiology. There is widespread erythema and slight scaling, often associated with pruritus, fever, and lymphadenopathy. A history of a prior, specific, localized dermatitis can be useful in discerning an underlying pathogenesis. However,

Table 2-5 Skin Diseases with Eosinophilic Spongiosisa

a

See Figs. 2-16 and and 2-17.

 FIGURE 2-16 Eosinophilic spongiosis. Intraepidermal microvesicle with eosinophils and mononuclear cells.

 FIGURE 2-17 Eosinophilic spongiosis. Spongiosis with eosinophil exocytosis.

in up to 15% of cases no underlying disorder can be determined by history, pathologic findings, and/or laboratory studies, and are classified as idiopathic.

Histopathological Features Clinicians may submit multiple skin biopsies in patients

with erythroderma. In the case of a spongiotic dermatosis, biopsy of the generalized eruption usually shows a subacute or chronic spongiotic reaction pattern: minimal spongiosis associated with slight epidermal acanthosis and a superficial perivascular predominantly

lymphocytic infiltrate. Other generalized cutaneous diseases usually show some or all of their characteristic pathologic changes that are seen when the conditions are localized. For example, an eosinophil-rich infiltrate would suggest a generalized drug eruption or scabies, particularly if the inflammatory infiltrate extends beyond the superficial vascular plexus and into the mid-to-deep dermis (Fig. 2-29). The presence of neutrophil exocytosis/microabscesses and/ or neutrophils within the stratum corneum may indicate a psoriasiform diathesis. Epidermotropism of atypical mononuclear cells with the formation of Pautrier microabscesses would favor a cutaneous lymphoproliferative disorder. However, a correlation between the pathologic features and clinical features is found in only up to two-third of cases, and therefore multiple and/or serial biopsies may be necessary for a definitive diagnosis and to exclude cutaneous T-cell lymphoma.

CHAPTER 2 ■ SPONGIOTIC DERMATITIS

Allergic contact dermatitis Photoallergic dermatitis Atopic dermatitis Drug reactions Arthropod-bite reactions Urticarial/precursor lesions of pemphigoid group -Bullous pemphigoid, cicatricial pemphigoid, herpes gestationis Urticarial/precursor lesions of pemphigus group PUPPP Incontinentia pigmenti (first stage) Eosinophilic folliculitis Grover disease

STASIS DERMATITIS Stasis dermatitis is a dermatitis of the lower extremities of middle-aged and elderly individuals seen in association with other signs of venous insufficiency, including varicosities and edema (Table 2-14).43-45 This condition is more common in women and believed to be a result of chronic venous insufficiency and venous hypertension. CLINICAL FEATURES The condition most frequently begins on the medial ankle, progressing to involve the lower calf and foot. There are poorly demarcated edematous changes with erythema and

25

PART I ■ INFLAMMATORY REACTIONS IN THE SKIN

Table 2-6 Skin Diseases with Neutrophilic Spongiosisa Psoriasis Reiter syndrome Seborrheic dermatitis Irritant contact dermatitis Phototoxic dermatitis Pemphigus variants (particularly IgA pemphigus) Toxic shock syndrome Dermatophytosis Impetigo Acute generalized exanthematous pustulosis (AGEP) Infantile acropustulosis Transient neonatal pustular melanosis a

See Figs. 2-12, 2-18, and 2-19.

 FIGURE 2-18 Neutrophilic spongiosis. Spongiosis with neutrophil exocytosis.

Table 2-7 Allergic Contact Dermatitis

 FIGURE 2-19 Irritant contact vulvitis. Spongiosis with neutrophil exocytosis.

26

sometimes scaling and/or oozing. The deposition of hemosiderin in the superficial dermis, secondary to red blood extravasation, produces the characteristic reddish-brown discoloration. Ulceration and scarring with atrophic changes can give rise to the classic inverted champagne bottle appearance (lipodermatosclerosis). The condition is frequently associated with increased

incidence of allergic contact dermatitis, id reaction (autoeczematization), and secondary infection, including cellulitis. In long-standing lesions, lichenification may occur as a consequence of chronic scratching and rubbing. Chronic venous ulcers may be complicated by squamous and basal cell carcinomas. Occasionally, patients will develop violaceous plaques and nodules on the dorsal feet and legs,

Clinical Features Delayed hypersensitivity reaction (type IV) All ages affected except below age 5 years and the elderly Rash occurs at the site of exposure in previously sensitized host Morphology of rash is eczematous—acute, subacute, or chronic Histopathologic Features Acute Spongiosis often with formation of clinically evident intraepidermal vesicles, superficial perivascular lymphocytic infiltrate usually rich in eosinophils, migration of inflammatory cells into the epidermis Subacute Epidermal hyperplasia with spongiosis, superficial perivascular lymphocytic and eosinophilic infiltrate with variable exocytosis Chronic Psoriasiform hyperplasia with a superficial perivascular lymphocytic and eosinophilic infiltrate; spongiosis is minimal to absent Differential Diagnosis Many forms of eczematous dermatitis Irritant and photoallergic reactions Scabetic infestation Drug reactions Bullous pemphigoid Parasitic infestations

A

B

atypical endothelial cells, and the promontory sign (a normal blood vessel protruding into an atypical vessel) are not features of acroangiodermatitis.

 FIGURE 2-21 Allergic contact dermatitis. Epidermal acanthosis, spongiosis with microvesicles containing eosinophils, and superficial perivascular and interstitial lymphocytic and eosinophilic infiltrate.

called acroangiodermatitis or pseudo– Kaposi sarcoma. These lesions frequently undergo painful ulceration and can be clinically indistinguishable from classic Kaposi sarcoma or changes seen secondary to arteriovenous malformations.

Histopathologic Features Chronic venous stasis results in lobular proliferations of thick-walled blood vessels, extravasated erythrocytes, hemosiderin deposition with siderophages, and fibrosis within the superficial dermis. The changes eventually involve the deep dermis and superficial

subcutaneous tissue. Typical acute, subacute, and chronic spongiotic features can be seen overlying the dermal changes (Figs. 2-30 to 2-31). Chronic rubbing can result in changes of lichen simplex chronicus. Lipodermatosclerosis shows dermal and subcutaneous septal sclerosis, with variably-sized pseudocysts lined by thickened eosinophilic-hyaline, PASpositive material (lipomembraneous change) in the subcutaneous tissue. A biopsy of acroangiodermatitis shows clusters of capillaries that maintain round-to-oval lumina. In contrast to Kaposi sarcoma, slit-like vascular spaces,

SPONGIOTIC (“ECZEMATOID”) DRUG ERUPTIONS Topical or systemic medications can induce immunologically mediated (delayed hypersensitivity type IV reactions) or non–immunologically mediated (ie, direct toxicity) cutaneous reactions. Allergic contact dermatitis-like, seborrheic dermatitis-like, nummular dermatitis-like, and pityriasis rosealike reactions, in addition to phototoxic and photoallergic eruptions, and generalized erythroderma, are described.46-49 Occasionally, morbilliform drug eruptions can show mild spongiosis. Common offending agents include antibiotics, NSAIDs, carbamazepine, captopril, thiazide diuretics, gold, and topical antihistamines.46-49 Up to 10% of cutaneous drug reactions can show spongiotic changes.49 Laboratory studies may reveal a peripheral eosinophilia.

Histopathological Features Cutaneous drug reactions can produce acute, subacute, and chronic spongiotic reaction patterns. One clue to the diagnosis of a spongiotic drug eruption is the presence of eosinophils as a significant component of the inflammatory infiltrate, often with eosinophil exocytosis (eosinophilic spongiosis). However, these reactions can also occur in the absence of eosinophils. Papillary dermal edema and extravasated erythrocytes are variable findings. Occasionally, a mixed reaction pattern with spongiosis and interface changes (the latter identified by vacuolar alteration along the

CHAPTER 2 ■ SPONGIOTIC DERMATITIS

 FIGURE 2-20 Allergic contact dermatitis. (A) Erythematous moist plaques with scale-crust involve the eyelids. (B) Epidermal acanthosis, spongiosis with focal microvesicle containing eosinophils, and superficial perivascular lymphocytic and eosinophilic infiltrate.

27

PART I ■ INFLAMMATORY REACTIONS IN THE SKIN 28

be associated with lymphadenopathy and acute anicteric hepatitis.53-56 While initially described as a cutaneous response to hepatitis B virus infection, a number of viral (including hepatitis A and C, Epstein-Barr virus, coxsackieviruses, and HIV) and bacterial infections (including group A ␤-hemolytic streptococci, Mycobacterium aviumintracellulare, Mycoplasma pneumoniae, Bartonella henselae, and Borrelia burgdorferi), and immunizations (including polio, diphtheria, influenza, pertussis, and measles) have been implicated as etiologic agents. The condition occurs primarily in children aged 3 months to 15 years, peaking between ages 1 to 6 years.

 FIGURE 2-22 Photoallergic dermatitis. Parakeratosis, minimal spongiosis, occasional necrotic keratinocytes, and superficial perivascular lymphocytic infiltrate.

dermoepidermal junction and/or necrotic keratinocytes) can be seen (lichenoid and/or fixed drug reaction). Unlike typical spongiotic reactions, the inflammatory infiltrate can extend into to the mid-todeep dermis. Occasionally, a “lymphoma-

 FIGURE 2-23A Atopic dermatitis. The patient demonstrates ill-defined, diffuse xerosis (dryness and fine scaling); erythema; and slight edema of the face. There is an accentuation of skin cleavage lines.

toid” reaction in which mononuclear cells are enlarged and atypical is seen, mimicking a cutaneous T-cell lymphoproliferative disorder.50-52 GIANOTTI-CROSTI SYNDROME GianottiCrosti syndrome, also known as papular acrodermatitis of childhood, is a benign, self-limited infectious exanthem that can

Clinical Features The rash which is usually of sudden onset following an acute infectious illness or immunization typically lasts for 2 to 4 weeks. The disease is characterized by multiple 1 to 5 mm mildly pruritic, symmetrical, flesh-colored to erythematous flat-topped edematous (juicy) papules on the face, buttocks, and extensor surfaces of the extremities. The trunk is usually spared. Histopathological Features The pathologic changes can be variable. There is typically a superficial perivascular lymphocytic infiltrate, as seen in classic morbilliform viral exanthems. Slight epidermal acanthosis, mild spongiosis and focal lymphocyte exocytosis can be seen in some cases. In addition, the infiltrate may focally obscure the dermoepidermal junction, producing a spongiotic-interface

 FIGURE 2-23B Dermal/protein contact dermatitis. Spongiotic microvesicles and macrovesicles, marked papillary dermal edema with hemorrhage, and perivascular and interstitial dermal inflammation.

Table 2-8 Atopic Dermatitis

 FIGURE 2-24A Nummular dermatitis. There is a coalescence of coinshaped erythematous papules and plaques on the distal lower extremity. The lesions exhibit scattered erosions, lichenification, and scaling.

CHAPTER 2 ■ SPONGIOTIC DERMATITIS

Clinical Features Common disorder of all ages Associated with allergic rhinitis and/or asthma Family history of atopy common Marked pruritus associated with a variety of lesions Erythematous, scaling areas Edematous, oozing, weepy areas Lichenified areas Dry fissured scaly areas Skin of patients generally lackluster, pruritic, and irritable Abnormalities of vascular and immune responses Histopathologic Features Acute pattern Spongiosis, sometimes spongiotic vesiculation, a usually superficial perivascular lymphocytic and eosinophilic infiltrate, epidermis of normal thickness Subacute pattern Thickened epidermis (usually psoriasiform type), spongiosis, a usually superficial perivascular lymphocytic and eosinophilic infiltrate, variable fibrosis of papillary dermis Chronic pattern Psoriasiform hyperplasia, spongiosis minimal to absent, vascular ectasia, a usually superficial perivascular lymphocytic infiltrate with eosinophils, variable fibrosis of the papillary dermis Differential Diagnosis All other types of eczematous dermatitis Clinicopathologic correlation largely determines the diagnosis Pathologic diagnosis is usually expressed as acute, subacute, or chronic eczematous dermatitis

 FIGURE 2-24B Follicular spongiosis with lymphocyte exocytosis.

overlap (Fig. 2-32). Papillary dermal edema and focal red blood cell extravasation with endothelial cell swelling can be seen, but vasculitis is not a feature. The condition most likely represents a local, type IV, delayed hypersensitivity reaction to a viral or bacterial antigen within the dermis. Direct immunofluorescence studies are negative for immunoreactant deposition, and electron microscopy has not demonstrated virus particles in the skin. PRURITIC AND URTICARIAL PAPULES AND PLAQUES OF PREGNANCY This condition, also known as polymorphic eruption of pregnancy, is characterized by a markedly pruritic eruption that occurs during the last

trimester in a primigravida. The cause and pathogenesis are unknown.57,58 Pruritic and urticarial papules and plaques of pregnancy (PUPPP) need to be distinguished from herpes gestationis (HG). In contrast to PUPPP, HG is associated with a greater prevalence of premature and smallfor-gestational-age babies. In addition, patients with HG have an increased incidence of systemic autoimmune disorders.

Clinical Features Lesions typically begin adjacent to the umbilicus, but with umbilical sparing, and then spread to the remainder of the abdomen, buttocks, and extremities. There are markedly pruritic urticarial papules which coa-

lesce to form plaques, but true bullae are not typical (unlike in HG). Targetoid lesions may be seen. The rash typically resolves within days postpartum.

Histopathologic Features There is variable parakeratosis and epidermal acanthosis, minimal spongiosis with focal lymphocyte exocytosis, edema of the papillary dermis, and a superficial perivascular lymphocytic and sometimes eosinophilic infiltrate with focal exocytosis. The marked pruritus can lead to erosions, with neutrophils as secondary changes. Direct immunofluorescence studies are negative for immunoreactant deposition in peri-lesional PUPPP skin.

29

Table 2-9 Skin Diseases with Follicular Spongiosisa Atopic dermatitis Infundibulofolliculitis Fox-Fordyce disease (apocrine miliaria) Pityriasis alba Infectious folliculitis Eosinophilic folliculitis Follicular mucinosis a

PART I ■ INFLAMMATORY REACTIONS IN THE SKIN

See Fig. 2-24

Table 2-10 Nummular (Discoid) Dermatitis

Clinical Features Coin-shaped, pruritic, erythematous patches on the hands, forearms, and legs Patches may have tiny vesicles or erosions, which can evolve to form annular plaques or dry scaly areas Tends to affect men and women 55 years and older as well as women 15-30 years old Histopathologic Features Varies according to the lesion biopsied: acute, subacute, and chronic eczematous patterns Differential Diagnosis All types of eczematous dermatitis Dermatophytosis Figurate erythemas Seborrheic dermatitis

Table 2-11 Dyshidrotic Dermatitis

30

Clinical Features Itchy tense vesicles on the digits, palms, and soles Histopathologic Features Intraepidermal spongiotic vesicles usually on epidermis of normal or increased thickness Variable amount of superficial perivascular lymphocytic infiltrate Differential Diagnosis Atopic dermatitis Allergic contact dermatitis Dermatophytosis Miliaria Other types of acute vesicular eczematous eruptions

 FIGURE 2-25 Pompholyx. Large intraepidermal microvesicle(s) containing serum and inflammatory cells, with adjacent epidermal spongiosis.

Table 2-12 Seborrheic Dermatitis

Clinical Features Common disorder affecting the scalp, face, upper chest, and back Greasy, scaley, red-brown patches Often pruritic Dandruff is one type of seborrheic dermatitis Histopathologic Features Psoriasiform hyperplasia Hyperkeratosis and parakeratosis, especially parafollicular Spongiosis Neutrophilic exocytosis Superficial perivascular lymphocytic infiltrate Differential Diagnosis Psoriasis Eczematous dermatitis Impetigo Dermatophytosis Secondary syphilis Gyrate erythemas Pityriasis rosea Irritant contact dermatitis Drug reaction

Differential Diagnosis HG is the main clinical differential consideration. Unlike PUPPP, it can present in the first or any subsequent pregnancy, and occur in second or third trimester, or even postpartum.

HG is a polymorphous dermatitis and the typical presence of umbilical involvement by the rash in HG helps to distinguish it from PUPPP. Eosinophils at the dermal-epidermal junction are seen more often in HG than in PUPPP. In addition, direct immunofluorescence studies demonstrate linear C3 and/or IgG deposition along the dermoepidermal junction in skin from patients with HG. INCONTINENTIA PIGMENTI Incontinentia pigmenti (IP) is an uncommon X-linked multisystem disorder that is usually seen in females (97% of cases).59,60 Males with the disorder (3% of cases) most likely have acquired spontaneous mutations, as it is believed that males who inherit the abnormal gene die in utero. The skin lesions typically are distributed along Blaschko lines, which is thought to represent the effects of functional X chromosome mosaicism (ie, these are the areas where the abnormal gene that is not inactivated can express its phenotype). Females with incontinentia pigmenti are thought to exhibit functional X chromosome mosaicism.

Clinical Features Cutaneous lesions of IP occur in three stages that usually follow sequentially, but significant overlap can occur. The first stage usually presents at birth or shortly thereafter and is characterized by small vesicles arising on a background of erythema; the changes

Table 2-13 Pityriasis Rosea

 FIGURE 2-27 Id reaction. Spongiosis with microvesicle formation, slight papillary dermal edema, and perivascular and interstitial dermal inflammation.

are more prominent on the extremities and arranged in a whorled pattern following Blaschko lines. The second stage, which follows several months later, shows linear verrucous lesions also predominantly on the extremities. The third stage, again occurring several months later, consists of areas of hyperpigmentation in an irregularly whorled pattern, usually widespread

on the trunk rather than the extremities, again following Blaschko lines. The pigmentation often but not always resolves within several years. Nail dystrophy, alopecia, and extracutaneous manifestations are common associated features.

Histopathologic Features Skin lesions in the first stage of IP show spongiosis

CHAPTER 2 ■ SPONGIOTIC DERMATITIS

 FIGURE 2-26 Seborrheic dermatitis. Epidermal acanthosis with minimal spongiosis, lymphocyte exocytosis, and perifollicular mounds of parakeratosis, scale-crust, and fungal spores (Pityrosporum).

Clinical Features Duration of disease: less than 10 weeks Herald patch Generalized eruption, usually on trunk Multiple salmon-colored macules with fine scale “Fir tree”pattern Atypical pityriasis rosea may exhibit vesicles, pustules, urticarial lesions, purpura Inverse pityriasis rosea refers to a rash that is distributed on the extremities instead of the trunk Drug eruptions may result in a pityriasis rosea–like eruption Histopathologic Features Mild subacute spongiotic dermatitis often with focal parakeratosis (which may tilt upward) Perivascular lymphocytic infiltrate with variable exocytosis Sometimes a microvesicle containing mononuclear cells in the epidermis Atypical forms tend to show vesicles, dyskeratosis, more parakeratosis and infiammation, hemorrhage, and eosinophils Differential Diagnosis Drug reactions Eczematous dermatitis Chronic superficial dermatitis (parapsoriasis) Pityriasis lichenoides Guttate psoriasis Dermatophytosis

with eosinophil exocytosis, spongiotic vesicles containing mostly eosinophils, and isolated and/or collections of dyskeratotic squamous cells within the epidermis (Fig. 2-33). Spongiosis is typically not a histologic feature of the second and third stages of the disease. The skin lesions of the second stage show epidermal hyperplasia with papillomatosis, dyskeratotic cells, vacuolar alteration along the dermoepidermal junction, and a superficial dermal lymphocytic infiltrate with melanophages. Melanophages become a more prominent feature in the third stage of disease.

Differential Diagnosis Similar to the first stage of IP, erythema toxicum neonatorum (ETN) and eosinophilic pustular folliculitis (EPF) can also show an eosinophilrich pustule within the epidermis. In contrast to IP, these changes are typically folliculocentric and are not associated with spongiosis or necrotic keratinocytes

31

PART I ■ INFLAMMATORY REACTIONS IN THE SKIN

Table 2-14 Stasis Dermatitis

Clinical Features Legs, especially the inner aspects Red, edematous, scaling lesions Variable oozing Evidence of stasis, such as brown pigmentation, ulcers, varicose veins, and atrophic scars Histopathologic Features Acute, subacute, or chronic eczematous pattern with lobular proliferation of capillaries, hemorrhage, hemosiderin deposition, and fibrosis Differential Diagnosis Granulation tissue next to a leg ulcer Kaposi sarcoma

 FIGURE 2-28 Pityriasis rosea. Slight epidermal hyperplasia, spongiosis, mounds of parakeratosis, with lymphocyte and erythrocyte exocytosis.

Staphylococcus spp. may play a role in the pathogenesis of miliaria, as the PASpositive, diastase-resistant material forming within the intraductal keratotic plug is believed to represent staphylococcal extracellular polysaccharide substance. However, the hyperkeratotic plug could be a late change and not the precipitating cause of the sweat blockage. Three types of miliaria are classified according to the level at which obstruction of the sweat duct occurs: (a) miliaria crystallina, (b) miliaria rubra, and (c) miliaria profunda.61 The clinical and histological features of the subtypes of miliaria differ. Miliaria pustulosa are pustular lesions of miliaria rubra. MILIARIA CRYSTALLINA (SUDAMINA) In miliaria crystallina, the obstruction occurs most superficially, within the stratum corneum portion of the duct.

 FIGURE 2-29 Erythroderma. Epidermal acanthosis, spongiosis, rare eosinophil exocytosis, and perivascular lymphocytic and eosinophilic infiltrate.

in ETN. In addition, cutaneous lesions of ETN resolve spontaneously. EPF in children is usually not related to HIV infection, unlike the condition in adults. Similar to ETN, it can start within the first days of life and produce follicularbased eosinophil-rich pustules. However, in contrast to ETN, the condition can persist for 3 months to 5 years. In addition, scalp and palmoplantar involvement is common in EPF. Miliaria, transient neonatal pustular melanosis, and

32

infantile acropustulosis are childhood dermatoses that form pustules which are neutrophil-rich. MILIARIA Miliaria is a common skin disorder caused by the leakage of eccrine sweat into the epidermis or dermis secondary to the blockage of eccrine sweat ducts (Fig 2-34).61 The condition often occurs in areas of increased heat and humidity. Skin occlusion and excessive sweating can be contributing factors.

Clinical Features This form of the disease is found in newborns less than 2 weeks old and adults who are febrile or those who recently moved to a humid climate. It is characterized by mulitple asymptomatic tiny (1-2 mm), fragile, clear vesicles on noninflamed skin, which tend to occur on the head, neck, and upper trunk. Lesions appear in crops and may become confluent, but without any surrounding erythema. Desquamation follows. Histopathologic Features Biopsies of miliaria crytallina demonstrate an intracorneal or subcorneal vesicle overlying an eccrine duct. The vesicles may contain occasional neutrophils. Obstruction of the eccrine duct within the stratum corneum may be seen.

ments. There are numerous small (1-2 mm), intensely pruritic, erythematous, non-folliculocentric papules and rarely vesicules on a background of erythema. A distinctive prickly or stinging sensation is described. The lesions do not tend to confluence. Affected areas include the scalp, neck, upper trunk, axillae, and groin. There is facial sparing. Lesions resolve within days after the patient is removed from the humid climate.

Differential Diagnosis The spongiotic microvesicles in miliaria rubra can resemble those in other forms of acute spongiotic dermatitis. However, the localization of these vesicles to acrosyringia, with normal intervening epidermis, serves to distinguish miliaria rubra.

CHAPTER 2 ■ SPONGIOTIC DERMATITIS

 FIGURE 2-30 Stasis dermatitis. Epidermal acanthosis, spongiosis, and lobular proliferation of blood vessels with fibrosis in the dermis.

Histopathologic Features Lesions of miliaria rubra show spongiosis and spongiotic microvesicles centered on an acrosyringium (the intraepidermal eccrine duct) within the stratum malpighian. There is a predominantly lymphocytic infiltrate around and within the vesicles and in the superficial dermis. Gram-positive bacterial cocci may be seen in the stratum corneum, and a PAS-positive plug may occlude the affected duct lumen.

MILIARIA PROFUNDA Miliaria profunda is caused by occlusion of the eccrine sweat duct at the level of the dermal-epidermal junction. It typically occurs as a complication of repeated episodes of miliaria rubra.

 FIGURE 2-31 Stasis dermatitis. Spongiosis, lymphocyte exocytosis, and lobular proliferation of blood vessels with fibrosis in the dermis.

Differential Diagnosis Subcorneal pustular dermatosis and pustular drug eruptions also demonstrate intracorneal vesicle(s) containing neutrophils. However, the vesicles in miliaria crystallina typically contain more fluid and fewer neutrophils than the vesicles in these latter diseases. Transient neonatal pustular melanosis and infantile acropustulosis are childhood dermatoses that can also

form subcorneal pustules that are neutrophil-rich. MILIARIA RUBRA (PRICKLY HEAT RASH) Obstruction of the sweat duct occurs within the superficial epidermis.

Clinical Features Similar to miliaria crystallina, this form also affects neonates and adults who live in humid environ-

Clinical Features Similar to other variants, miliaria profunda occurs in adults who live in hot, humid climates. Numerous, usually asymptomatic, small (1-3 mm), flesh-colored nonfollicular papules appear on the truck and often extremities. Other features include lymphadenopathy, fever, nausea, and tropical anhidrotic asthenia (the widespread inability to sweat as a result of eccrine ductal rupture). Histopathologic Features There is spongiosis and sometimes vesiculation of the lower portion of the acrosyringium and upper dermal part of the sweat duct. There is a periductal lymphocytic infiltrate, dermal edema, and occasional duct rupture. A PAS-positive, diastaseresistant eosinophilic cast may be seen in the ductal lumen.

33

PART I ■ INFLAMMATORY REACTIONS IN THE SKIN

 FIGURE 2-32 Gianotti-Crosti syndrome. Spongiotic-interface reaction pattern: Spongiosis with microvesicle formation, perivascular and interstitial lymphocytic infiltrate that focally obscures the dermoepidermal junction with lymphocyte exocytosis, and papillary dermal edema.

 FIGURE 2-33 Incontinentia pigmenti. Spongiosis with microvesicle, eosinophil exocytosis, and solitary and aggregated dyskeratotic squamous cells within the epidermis. Miliarial Spongiosis (Spongiosis Involving the Acrosyringium)

34

Subcorneal vesicle filled with fluid and < 50% neutrophils by volume in and around the duct:

Spongiosis involving the upper half of the acrosyringium and lymphocytic infiltrate in and around the duct:

Spongiosis involving the lower half of the acrosyringium and lymphocytic infiltrate:

Inflammatory dermatitis which involves the epidermis and the acrosyringium:

Miliaria crystallina

Miliaria rubra

Miliaria profunda

See relevant pattern

 FIG 2-34 Algorithm for miliarial spongiosis.

REFERENCES

44. Beacham BE. Common dermatoses in the elderly. Am Fam Physician. 1993;47: 1445-1450. 45. Bonnetblanc JM. Stasis dermatitis. Ann Dermatol Venereol. 2002;129(1 Pt 1):98-101. 46. Fitzpatrick JE. New histopathologic findings in drug eruptions. Dermatol Clin. 1992;10:19-36. 47. Crowson AN, Brown TJ, Magro CM. Progress in the understanding of the pathology and pathogenesis of cutaneous drug eruptions: implications for management. Am J Clin Dermatol. 2003;4:407-428. 48. Crowson AN, Magro CM. Recent advances in the pathology of cutaneous drug eruptions. Dermatol Clin. 1999; 17:537-560,viii. 49. Kauppinen K, Stubb S. Drug eruptions: causative agents and clinical types. A series of in-patients during a 10-year period. Acta Derm Venereol. 1984;64:320-324. 50. Magro CM, Crowson AN, Kovatich AJ, et al. Drug-induced reversible lymphoid dyscrasia: a clonal lymphomatoid dermatitis of memory and activated T cells. Hum Pathol. 2003;34:119-129. 51. Wolf R, Kahane E, Sandbank M. Mycosis fungoides-like lesions associated with phenytoin therapy. Arch Dermatol. 1985; 121:1181-1182. 52. Welykyj S, Gradini R, Nakao J, et al. Carbamazepine-induced eruption histologically mimicking mycosis fungoides. J Cutan Pathol. 1990;17:111-116. 53. Baleviciene G, Maciuleviciene R, Schwartz RA. Papular acrodermatitis of childhood: the Gianotti-Crosti syndrome. Cutis. 2001; 67:291-294. 54. Brandt O, Abeck D, Gianotti R, et al. Gianotti-Crosti syndrome. J Am Acad Dermatol. 2006;54:136-145. 55. Caputo R, Gelmetti C, Ermacora E, et al. Gianotti-Crosti syndrome: a retrospective analysis of 308 cases. J Am Acad Dermatol. 1992;26(2 Pt 1):207-210. 56. Taieb A, Plantin P, Du Pasquier P, et al. Gianotti-Crosti syndrome: a study of 26 cases. Br J Dermatol. 1986;115:49-59. 57. Winton GB, Lewis CW. Dermatoses of pregnancy. J Am Acad Dermatol. 1982;6: 977-998. 58. Ambros-Rudolph CM, Müllegger RR, Vaughan-Jones SA, et al. The specific dermatoses of pregnancy revisited and reclassified: results of a retrospective two-center study on 505 pregnant patients. J Am Acad Dermatol. 2006;54:395-404. 59. Ehrenreich M, Tarlow MM, GodlewskaJanusz E, et al. Incontinentia pigmenti (Bloch-Sulzberger syndrome): a systemic disorder. Cutis. 2007;79:355-362. 60. Berlin AL, Paller AS, Chan LS. Incontinentia pigmenti: a review and update on the molecular basis of pathophysiology. J Am Acad Dermatol. 2002;47: 169-187. 61. Feng E, Janniger CK. Miliaria. Cutis. 1995; 55:213-216.

CHAPTER 2 ■ SPONGIOTIC DERMATITIS

1. Trautmann A, Disch R, Bröcker EB, et al. How does eczema arise? J Dtsch Dermatol Ges. 2003;1:8-11. 2. Houck G, Saeed S, Stevens GL, et al. Eczema and the spongiotic dermatoses: a histologic and pathogenic update. Semin Cutan Med Surg. 2004;23:39-45. 3. Ruiz E, Deng JS, Abell EA. Eosinophilic spongiosis: a clinical, histologic, and immunopathologic study. J Am Acad Dermatol. 1994;30:973-976. 4. Machado-Pinto J, McCalmont TH, Golitz LE. Eosinophilic and neutrophilic spongiosis: clues to the diagnosis of immunobullous diseases and other inflammatory disorders. Semin Cutan Med Surg. 1996;15:308-316. 5. Crotty C, Pittelkow M, Muller SA. Eosinophilic spongiosis: a clinicopathologic review of seventy-one cases. J Am Acad Dermatol. 1983;8:337-343. 6. Knight AG, Black MM, Delaney TJ. Eosinophilic spongiosis: a clinical histological and immunofluorescent correlation. Clin Exp Dermatol. June 1976;1: 141-153. 7. Batista G, Santos AN, Sampáio SA. Neutrophilic spongiosis. a new entity? Br J Dermatol. 1986;114:131-134. 8. Hoss DM, Shea CR, Grant-Kels JM. Neutrophilic spongiosis in pemphigus. Arch Dermatol. 1996;132:315-318. 9. Brasch J, Becker D, Aberer W, et al. Contact dermatitis. J Dtsch Dermatol Ges. 2007;5:943-951. 10. Fyhrquist-Vanni N, Alenius H, Lauerma A. Contact dermatitis. Dermatol Clin. 2007;25:613-623. 11. Mark BJ, Slavin RG. Allergic contact dermatitis. Med Clin North Am. 2006;90: 169-185. 12. Saint-Mezard P, Rosieres A, Krasteva M, et al. Allergic contact dermatitis. Eur J Dermatol. 2004;14:284-295. 13. English JS. Current concepts of irritant contact dermatitis. Occup Environ Med. 2004;61:722-726, 674. 14. Mozzanica N. Pathogenetic aspects of allergic and irritant contact dermatitis. Clin Dermatol. 1992;10:115-121. 15. Dahl MV. Chronic, irritant contact dermatitis: mechanisms, variables, and differentiation from other forms of contact dermatitis. Adv Dermatol. 1988;3:261-275. 16. Belsito DV. Occupational contact dermatitis: etiology, prevalence, and resultant impairment/disability. J Am Acad Dermatol. 2005;53:303-313. 17. Stein KR, Scheinfeld NS. Drug-induced photoallergic and phototoxic reactions. Expert Opin Drug Saf. 2007;6:431-443. 18. Lugovi´c L, Situm M, Ozanic-Buli ´ c´ S, et al. Phototoxic and photoallergic skin reactions. Coll Antropol. 2007;31(Suppl 1): 63-67. 19. Janssens V, Morren M, Dooms-Goossens A, et al. Protein contact dermatitis: myth or reality? Br J Dermatol. 1995;132:1-6. 20. Wüthrich B. Protein contact dermatitis. Br J Dermatol. 1996;135:332-333.

21. Lipozencic´ J, Wolf R. Atopic dermatitis: an update and review of the literature. Dermatol Clin. 2007;25:605-612. 22. Guttman-Yassky E. Atopic dermatitis. Curr Probl Dermatol. 2007;35:154-172. 23. Simpson EL, Hanifin JM. Atopic dermatitis. Med Clin North Am. 2006;90:149-167. 24. Boer A. Patterns histopathologic of FoxFordyce disease. Am J Dermatopathol. 2004;26:482-492. 25. Ozcan A, Senol M, Aydin NE, et al. FoxFordyce disease. J Eur Acad Dermatol Venereol. 2003;17:244-245. 26. Lin RL, Janniger CK. Pityriasis alba. Cutis. 2005;76:21-24. 27. Martin RF, Lugo-Somolinos A, Sanchez JL. Clinicopathologic study on pityriasis alba. Bol Asoc Med P R. 1990;82:463-465. 28. Vargas-Ocampo F. Pityriasis alba: a histologic study. Int J Dermatol. 1993;32:870-873. 29. Sirot G. Nummular eczema. Semin Dermatol. 1983;2:68-74. 30. Guillet MH, Wierzbicka E, Guillet S, et al. A 3-year causative study of pompholyx in 120 patients. Arch Dermatol. 2007; 143:1504-1508. 31. Warshaw EM, Ahmed RL, Belsito DV, et al. North American Contact Dermatitis Group. Contact dermatitis of the hands: cross-sectional analyses of North American Contact Dermatitis Group Data, 1994-2004. J Am Acad Dermatol. 2007;57:301-314. 32. Gupta AK, Bluhm R. Seborrheic dermatitis. J Eur Acad Dermatol Venereol. 2004;18: 13-26. 33. Schwartz RA, Janusz CA, Janniger CK. Seborrheic dermatitis: an overview. Am Fam Physician. 2006;74:125-130. 34. Moschella SL, Hurley HJ. Autoeczematization. In: Dermatology. 3rd ed. Philadelphia, PA: WB Saunders; 1992:484-485. 35. Belsito DV. Autosensitization dermatitis. In: Fitzpatrick’s Dermatology in General Medicine. 5th ed. New York, NY: McGraw-Hill; 1999:1462-1464. 36. Chuh A, Lee A, Zawar V, et al. Pityriasis rosea—an update. Indian J Dermatol Venereol Leprol. 2005;71:311-315. 37. González LM, Allen R, Janniger CK, et al. Pityriasis rosea: an important papulosquamous disorder. Int J Dermatol. 2005;44:757-764. 38. Rothe MJ, Bialy TL, Grant-Kels JM. Erythroderma. Dermatol Clin. 2000;18: 405-415. 39. Milavec-Puretic´ V, Zoric´ Z, Zidanic´ M, et al. Exfoliative erythroderma. Acta Dermatovenerol Croat. 2007;15:103-107. 40. Zip C, Murray S, Walsh NM. The specificity of histopathology in erythroderma. J Cutan Pathol. 1993;20:393-398. 41. Walsh NM, Prokopetz R, Tron VA, et al. Histopathology in erythroderma: review of a series of cases by multiple observers. J Cutan Pathol. 1994;21:419-423. 42. Vasconcellos C, Domingues PP, Aoki V, et al. Erythroderma: analysis of 247 cases. Rev Saude Publica. 1995;29:177-182. 43. Yi JU, Lee CW. Acroangiodermatitis. A clinical variant of stasis dermatitis. Int J Dermatol. 1990;29:515-516.

35

CHAPTER 3 Interface Dermatitis

PART I ■ INFLAMMATORY REACTIONS IN THE SKIN

Frances I. Ramos-Ceballos Thomas D. Horn

A large group of skin diseases is characterized by histologic changes categorized as interface dermatitis (Fig. 3-1). At a minimum, a variable combination of leukocyte infiltration of the dermis, vacuolar change of the basilar epidermis, accumulation of melanophages in the upper dermis, and necrosis of keratinocytes must be observed. The term interface dermatitis is therefore apt because these findings occur at the interface between the epidermis and dermis. This common thread binds otherwise disparate entities together. Other terms applied to this group of disorders include vacuolar dermatitis, vacuolar interface dermatitis, and lichenoid tissue reaction. Before considering specific diseases, definition and illustration of the common histologic findings are in order.

LEUKOCYTE INFILTRATION The term leukocyte infiltration of the dermis is cumbersome but more generally accurate than inflammation because, in the case of mycosis fungoides, some portion of the infiltrating lymphocytes is neoplastic and not inflammatory in nature. In all other

disorders considered here, lymphoid infiltration represents inflammation. Some degree of upper dermal perivascular accumulation of leukocytes is observed in interface dermatitides. Extension of cells into surrounding collagen may impart a bandlike appearance (or lichenoid appearance, given the similarity to lichen planus) to the infiltrate. Density, pattern, and composition of the infiltrate are variable elements of interface dermatitis that aid in establishing more specific diagnosis.

VACUOLAR ALTERATION Vacuolar alteration of the basilar epidermis is also termed basal vacuolization. At the junction between the epidermis and dermis, small, often contiguous, discrete vacuoles are observed. The vacuolization imparts a ragged appearance to the base of the epidermis. When there is sufficient vacuolar destructive interface change, subepidermal clefts form, best exemplified by lesions of bullous lichen planus and grade 3 or 4 lesions of graft-versushost disease. Melanin generally resides mostly in keratinocytes and to a lesser degree in melanocytes. Damage to basilar keratinocytes, as part of an interface dermatitis, results in deposition of melanin granules in the upper dermis. The pigment is phagocytosed by macrophages, which become progressively more melanin-laden and are termed melanophages. Recognition of melanophages correlates with stage in evolution of the interface dermatitis and constitutive degree of pigmentation.

The presence of many melanophages suggests that the process is well established. Extension of leukocytes into the epidermis is also termed exocytosis. The definition of exocytosis also encompasses extension of erythrocytes into the epidermis. The small, round nuclei of lymphocytes are seen to intercalate between keratinocytes, admixed with variable but generally little spongiosis in the case of interface dermatitis. This infiltration may be subtle or pronounced and may be confined to the basilar epidermis or may extend throughout the thickness of the epidermis. Direct apposition of lymphocytes to necrotic keratinocytes is termed satellite cell necrosis (ie, lymphocyte satellitosis). A nonviable keratinocyte exhibits an irregularly shrunken, hyperchromatic nucleus positioned adjacent to dense eosinophilic, refractile cytoplasm. The nucleus may not be observed. The cytoplasmic change is most apparent and is progressive as the cell dies. A variety of terms exists to describe a degenerated/ dead keratinocyte. Based solely on histologic observation, there is little validity to the many names. Important and real differences in pathophysiology exist for these terms and are not discernible on routine light microscopic assessment. Among the various terms are keratinocyte necrosis, dyskeratosis (dyskeratotic keratinocyte), apoptosis (apoptotic keratinocyte), Civatte body, and colloid body. For purposes of this discussion we will use the term keratinocyte necrosis. Understanding the individual histopathologic elements of interface dermatitis

Interface dermatitis

Vacuolar interface dermatitis

Vacuolar interface dermatitis Erythema multiforme Fixed drug eruption Drug eruptions Viral xanthems HIV interface dermatitis Connective tissue disease Lupus erythematosus Dermatomyositis Graft-versus-host reaction Pityriasis lichenoides Vitiligo

36

Poikilodermatous interface dermatitis Poikiloderma of Civatte Poikiloderma congenitale Bloom syndrome Dyskeratosis congenita Dermatomyositis Mycosis fungoides Radiation dermatitis

 FIGURE 3-1 Interface dermatitis: diagnostic algorithm.

Lichenoid interface dermatitis

Lichenoid interface dermatitis Lichen planus and variants Lichenoid drug eruption Lichenoid keratosis Lichen striatus Lichen nitidus Lichenoid purpura Porokeratosis Histologic regression of many tumors

A

B

is the framework on which to build a detailed description of the specific entities described in this chapter. Considerable variation exists in histologic expression of specific diseases depending on body site sampled, adequacy of the sample, and most important, stage of evolution of the lesion sampled. This chapter is organized such that diseases with shared histologic features are considered as a group, with the proposed prototype discussed first. The first general categorization to be made lies in the distinction between a lichenoid-interface dermatitis, which is heavily inflamed (cell-rich) relative to a vacuolar-interface dermatitis, which contains few inflammatory cells (cell-poor) (see Fig. 3-2).

LICHENOID-INTERFACE DERMATITIS Lichen planus serves as the prototype for several disorders (Table 3-1). The main findings in samples from fully evolved lesions include a fairly continuous band of lymphoid cells in the upper dermis, overlying interface changes, and further characteristic epidermal changes consisting of acanthosis, pointed rete ridges, an expanded granular layer, and hyperkeratosis.

Lichen Planus and Variants CLINICAL FEATURES Lichen planus, an inflammatory disorder of uncertain cause, consists of variably distributed erythematous to violaceous polygonal papules and plaques, typically well defined in contour and often grouped on flexor surfaces,

Table 3-1 Lichen Planus and Variants

Clinical Features Lichen planus Prominent pruritus Violaceous polygonal papules Flexural surfaces favored Oral and genital involvement frequent Atrophic lichen planus (actinicus) Atrophic erythematous patches Sun-exposed skin Hypertrophic lichen planus Verrucous plaques Extensor surfaces favored Bullous lichen planus Bullae within erythematous patches Histopathologic Features Lichen planus Band of lymphocytes in upper dermis, melanophages Acanthosis, hypergranulosis, “sawtoothing” of rete ridges Basal vacuolization Atrophic lichen planus (actinicus) Lichenoid interface dermatitis Epidermal atrophy Hypertrophic lichen planus Lichenoid interface dermatitis Irregular acanthosis Hyperkeratosis Bullous lichen planus Lichenoid interface dermatitis Subepidermal cleft Differential Diagnosis Lichen planus Lichenoid drug eruption Lichenoid keratosis Lichenoid actinic keratosis Lupus erythematosus

Atrophic lichen planus (actinicus) Lupus erythematosus Lichen sclerosus Hypertrophic lichen planus Lichen simplex chronicus Verrucous lupus erythematosus Bullous lichen planus Paraneoplastic pemphigus Erythema multiforme Toxic epidermal necrolysis Fixed drug eruption

especially the wrists (Fig. 3-2A). The genitalia are frequently involved. Scale is generally absent, but surface change consisting of white lines or grooves known as Wickham striae are often observed. The patient frequently complains of intense pruritus. Oral and nail changes may accompany the cutaneous eruption. Rare cases of esophageal and ocular involvement are reported.1,2 Lacy, white patches commonly involve the buccal mucosa. Dystrophy of the nail plate may develop with ridging and distal splitting. Variants include hypertrophic, atrophic, and bullous forms. Hypertrophic lichen planus commonly occurs on the lower legs and consists of erythematous hyperkeratotic plaques that are quite pruritic. Lichen planus actinicus (actinic lichen planus) is an unusual variant localized to sun-exposed skin. Scarring alopecia in association with lichen planus, known as lichen planopilaris, is discussed in Chap. 10. Associations between lichen planus and hepatitis C infection, as well as vaccination against hepatitis B, occur.3,4

CHAPTER 3 ■ INTERFACE DERMATITIS

 FIGURE 3-2 Lichen planus. (A) Note violaceous flat-topped polygonal papules with slight whitish scale. The papules show characteristic coalescence into plaques. (B) The most notable feature is a bandlike infiltrate of lymphocytes that obscures the dermal-epidermal junction.

37

PART I ■ INFLAMMATORY REACTIONS IN THE SKIN

HISTOPATHOLOGIC FEATURES A fully evolved lesion will display a perivascular and interstitial infiltration of the upper dermis by lymphocytes and histiocytes, forming a band of cells positioned in the papillary and upper reticular dermis (Figs. 3-2 through 3-4). Interspersed melanophages are usually present, and eosinophils may accompany the mononuclear elements of the infiltrate. The inflammatory cells extend up to and

38

infiltrate the lower epidermis. Significant perivascular inflammation of the middle or deep reticular dermis is uncommon. The density of the infiltrate partially or totally obscures the junction between the epidermis and dermis. Exocytosis of lymphocytes is noted, with scattered necrotic keratinocytes generally concentrated in the lower epidermis but possibly arrayed at all epidermal levels (see Fig. 3-4). Necrotic keratinocytes may be observed

 FIGURE 3-3 Lichen planus. This lesion shows hyperkeratosis, hypergranulosis, some acanthosis, and a bandlike infiltrate that fills the papillary dermis and obscures the dermal-epidermal junction.

 FIGURE 3-4 Lichen planus. There is basal layer vacuolization. The epidermis is slightly acanthotic, and there is tendency to a saw-tooth pattern of the lower epidermis.

in the upper dermis and stratum corneum. Direct immunofluorescence studies reveal shaggy deposits of fibrin along the basement membrane zone and complement and immunoglobulin reactivity of eosinophilic globular remnants of necrotic keratinocytes in the superficial dermis 5,6 Destruction of the basilar and parabasilar epidermis results in exposure of the spinous layer to the subjacent dermis defining the concept of “squamotization.” Lymphocyte satellitosis around necrotic keratinocytes is not uncommon. A constellation of additional epidermal changes is also evident. Acanthosis with wedge-shaped hypergranulosis occurs. The rete ridges become pointed with sharply tapering tips, the so-called sawtooth pattern. Hyperkeratosis is seen, but significant parakeratosis is absent. The combination of a band of mononuclear cells confined to the upper dermis, interface changes, and these characteristic epidermal features represent a theme uniting several entities, as discussed later, but should prompt consideration of lichen planus first. Specimens from early lesions display less inflammation and incompletely evolved epidermal changes; melanophages may be absent. Old lesions generally show reparative changes in the papillary dermis and vascular ectasia, contain numerous melanophages with little inflammation, and display variable epidermal alteration. Biopsy specimens from mucosa and nail display similar changes.7 In hypertrophic lichen planus, irregular acanthosis is pronounced but is accompanied by the elements of interface dermatitis and a band of lymphocytes (Fig. 3-5). This combination of findings represents an element of lichen simplex chronicus in addition to lichen planus. Epidermal atrophy typifies actinic lichen planus.8 Inflammation of the deep vascular plexus and adnexae is absent. However a lichenoid interface may involve the acrosyringium, superficial straight eccrine duct, and hair follicle. In bullous lichen planus, the basal vacuolization becomes confluent, leading to separation of the epidermis from the dermis (Fig. 3-6). The clefts, or MaxJoseph spaces, may remain microscopic or become clinically apparent. As mentioned, the infiltrating lymphocytes express CD3, with a majority of cells in the T-helper/inducer phenotype (CD4+). Terminal effector mechanisms are not completely understood. Typical cytokines patterns are found in affected tissue, referable to aberrant keratinocyte and lymphocyte physiology.9 These cytokines may affect epidermal keratin expression, which tends to resemble keratin

Alteration in the structure and distribution of type VII collagen, a6b4 integrin, and kalinin is reported in lichen planus.

 FIGURE 3-6 Bullous lichen planus. There is dermal-epidermal separation leading to formation of a blister cavity. Otherwise, features typical of lichen planus are present.

expression in wound healing.10 Additionally, the pattern of intercellular adhesion molecule 1 (ICAM-1) expression is restricted to basilar keratinocytes in lichen planus, in contrast to lupus erythematosus and erythema multiforme, where

more diffuse staining at upper epidermal levels is attributed to the effects of photosensitivity and herpes simplex virus triggers, respectively.11 The interface change leads to disruption of the normal integrity of epidermal anchoring mechanisms.12

CHAPTER 3 ■ INTERFACE DERMATITIS

 FIGURE 3-5 Hypertrophic lichen planus. The epidermal surface is slightly papillomatous, and there is irregular hyperplasia of the epidermis.

DIFFERENTIAL DIAGNOSIS The fully evolved histopathology of lichen planus generally allows confident diagnosis in the correct clinical setting. Specimens of lichenoid (lichen planus-like) keratosis and lichenoid drug eruption may strongly resemble lichen planus, requiring accompanying clinical information. The lichenoid keratosis is often distinguished from lichen planus by the presence of parakeratosis, delicate laminated hyperkeratosis, a normal granular layer, and in some cases, remnants of a solar lentigo. Most lichenoid keratoses are solitary lesions developing on sun-exposed skin. The anterior chest is a common site. The lesion is often mistaken for basal cell carcinoma, actinic keratosis, or melanocytic nevus clinically. Lichenoid drug eruptions cannot be reliably distinguished from lichen planus but more commonly display the following features: parakeratosis, a normal granular layer, eosinophils, and plasma cells in the inflammatory infiltrate. Inflammation is also more likely to be perivascular and bandlike, in contrast to only bandlike in lichen planus. In general, epidermis involved with lichen planus contains a greater number of Langerhans cells than seen in lichenoid keratosis and lichenoid actinic keratosis.13 Lichenoid actinic keratosis should possess the diagnostic elements of an actinic keratosis, with crowding of keratinocytes and nuclear atypia in addition to the elements of interface dermatitis. Since chronic ulcerating lichen planus of mucosal surfaces is rarely associated with the development of squamous cell carcinoma, epithelial dysplasia in these sites must be sought and noted.14 In lupus erythematosus, the pattern of inflammation is quite variable but in the discoid variant the inflammation often extends to involve the deep vascular plexus and eccrine coil. In general, the degree of upper dermal inflammation and number of necrotic keratinocytes in the systemic and discoid variants of lupus erythematosus is less than in lichen planus; however in subacute cutaneous lupus erythematosus a dense lichenoid pattern may be observed although usually there is variable attenuation and hyperplasia of the epidermis and the granular cell layer is not increased. Epidermal atrophy suggests the diagnosis of lupus erythematosus, keeping in mind that an atrophic form of lichen planus exists and generally lacks inflammation

39

PART I ■ INFLAMMATORY REACTIONS IN THE SKIN

of the deep vessels and adnexa. Basement membrane thickening and increased dermal mucin also suggest connective tissue disease rather than lichen planus. Hypertrophic (verrucous) lupus erythematosus may show many of the same features of hypertrophic lichen planus but is discriminated by foci of cell-poor interface dermatitis, whereby the papillary dermis has an almost hyalin-like appearance, vascular ectasia, basement membrane thickening, dermal mucin, and deep extension of the inflammatory infiltrate. Overlap of lupus erythematosus and lichen planus is possible and must be diagnosed based on clinicopathologic correlation. Erythema multiforme and toxic epidermal necrolysis (see below) are characterized by more keratinocyte necrosis relative to the degree of inflammation than lichen planus. The inflammation in a specimen of fixed drug eruption often involves the deep vascular plexus and may be polymorphous with occasional eosinophils, neutrophils, and plasma cells. At times, confident discrimination among these disorders requires clinicopathologic correlation. Any skin biopsy specimen with an upper dermal interstitial infiltrate of lymphocytes should prompt consideration of mycosis fungoides. Interface changes are variably present in mycosis fungoides, although the destructive epidermal changes of lichen planus generally are absent. Other discriminating features include many hyperconvoluted cerebriform lymphocytes assuming a passive pattern of epidermal colonization typically present in epidermal lacunae. One of the other characteristic hallmarks is a narrow grenz zone of uninvolved papillary dermis, which separates the neoplastic bandlike infiltrate from the overlying epidermis. Significant nuclear atypia of lymphocytes and aggregation of lymphocytes in epidermal lacunae are absent in lichen planus.

Lichenoid Drug Eruption CLINICAL FEATURES Drug eruptions with clinical and histologic features similar to lichen planus have been described15,16 (see also Chap. 12). Various components of drugs of abuse also may cause lichenoid reactions. Photodistribution is observed frequently. Discontinuation of the offending medication results in resolution of the eruption.

40

HISTOPATHOLOGIC FEATURES Lichenoid drug eruptions may resemble lichen planus. Parakeratosis and inflammation around the middle and deep vascular plexus occur regularly. Eosinophils are

variably present. The absence of eosinophils does not preclude the diagnosis of lichenoid drug eruption. Lichenoid drug eruption often displays epidermal atrophy. DIFFERENTIAL DIAGNOSIS Observation of parakeratosis, epidermal atrophy, eosinophils including foci of eosinophilic spongiosis, and deep dermal inflammation suggest the diagnosis of lichenoid drug eruption when lichen planus is also a consideration. Adequate clinical history is imperative for accurate diagnosis.

Lichenoid Keratosis (Lichen Planus-Like Keratosis) and Lichenoid Actinic Keratosis CLINICAL FEATURES Lichenoid keratoses typically occur as solitary lesions on the chest and arms but may develop elsewhere. Women are affected more frequently than men.17 The clinical lesion is not specific, consisting of an erythematous papule or plaque. The clinical impression of basal cell carcinoma is common. Lichenoid actinic keratosis occurs mostly in actinically damaged skin as an erythematous scaling patch or plaque. HISTOPATHOLOGIC FEATURES A lichenoid keratosis may greatly resemble lichen planus.13 As in lichenoid drug eruption, the presence of parakeratosis and middermal inflammation is a subtle clue to help in the differentiation. Because solar lentingines may evolve into lichenoid keratoses, the epidermis of a lichenoid keratosis may show changes of solar lentigo with elongated rete ridges and basilar hypermelanosis. Atrophic, bullous, lupus erythematosus-like, and atypical variants have been described.18 The infiltrating lymphocytes in benign lichenoid keratosis are predominantly CD8+, in contrast to lichen planus.19,20 A lichenoid actinic keratosis should possess the epidermal characteristics of the usual actinic keratosis along with a moderately dense band of lymphocytes in the upper dermis and overlying interface change. In some instances reactive maturational disturbance of the epidermis in lichenoid keratosis may mimic a lichenoid actinic keratosis. DIFFERENTIAL DIAGNOSIS The distinction of lichenoid keratosis from lichen planus and lichenoid drug eruption often relies in large measure on accompanying clinical history (see differential diagnosis of lichen planus). In lichenoid keratosis, the density of the infiltrate and pattern of

epidermal alteration are often not as fully evolved as in lichen planus, but the similarities frequently are striking. It is important to scan the epidermis and dermis for melanocytic proliferation and features of an inflamed or regressing melanocytic nevus or melanoma because the inflammation in such nevi or melanoma may assume an interface pattern and may partially obscure the tumor. Any suspiscion for regressing melanoma should prompt consideration of step sections in an effort to clearly identify residual melanoma. If clear epidermal features of seborrheic keratosis are observed, yet underlying inflammation is present in an interface pattern, the diagnosis of inflamed seborrheic keratosis is preferable because a true lichenoid keratosis bears greater resemblance to lichen planus in its epidermal findings.

VACUOLAR INTERFACE DERMATITIS Compared with lichen planus, the diseases considered under this heading generally display less intense inflammation without the dense, bandlike pattern. Interface change, especially necrosis of keratinocytes, is prominent relative to the degree of inflammation, and this difference, along with the absence of epidermal changes characteristic of lichen planus, helps to distinguish between diseases in these groups.

Erythema Multiforme CLINICAL FEATURES Clinical and histologic subtypes of eruptions identified as erythema multiforme are likely to exist, and the description of target lesions oversimplifies the range of clinical findings.21,22 Erythema multiforme exhibits a fairly nonspecific histologic pattern, hence the wide clinical spectrum. The classic target lesion consists of at least three zones of color change: a peripheral rim of erythema with an inner rim of relative pallor and a central erythematous macule. This concentric pattern imparts a “bull’s eye appearance”(Fig. 3-7A). Variation from this pattern is described with erythematous patches, some with a dusky, violaceous center, but no distinct target appearance. Blisters, when present, form centrally in most cases, but a peripheral pattern also may occur. The distribution of erythema multiforme is frequently acral, with concentration on the palms and soles, but widespread lesions occur commonly.

A

B

The disease is self-limited but often recurrent. Involvement of mucosal and conjunctival surfaces occurs and, if extensive, leads to classification of the disease as “major” (possibly synonymous with the term Stevens-Johnson syndrome) versus the “minor” form with less severe extracutaneous disease. Universally accepted criteria distinguishing major from minor erythema multiforme and major erythema multiforme from toxic epidermal necrolysis do not exist. The most common causes of erythema multiforme include herpes simplex virus infection, medications, and other infectious agents, especially Mycoplasma pneumoniae.23 Typical target lesions were associated more frequently with herpes simplex virus infection and “atypical” lesions with drug etiology in one study.23 The pathophysiology of erythema multiforme is likely one of cytotoxic cellmediated immunity (type IV immune reaction). The relative roles of autoimmune triggers, actual presence of virus in clinical lesions,24 and genetic susceptibility are unclear. In vitro, herpes virus-infected peripheral blood mononuclear cells upregulate ICAM-1 (CD54) and major histocompatability (MHC) class I molecules on dermal microvascular endothelial cells with increased binding avidity.25 HISTOPATHOLOGICAL FEATURES At low magnification, there is a perivascular infiltrate of lymphocytes with some extension between collagen bundles, but a bandlike infiltrate is not observed (Fig. 3-7). Eosinophils are observed in drug-associated cases but should not be the predominant infiltrating leukocyte. In herpes-associated erythema multiforme eosinophils are typically absent. The papillary dermis is often edematous with dilated capillaries. Subepidermal edema may be marked in

some instances, leading to subepidermal blisters. Exocytosis and spongiosis are evident, and variable degrees of epidermal necrosis may be observed. At higher magnification, many elements of interface dermatitis are noted (Fig. 3-8). Necrotic keratinocytes generally are present at all epidermal levels, including the stratum corneum, and may be solitary or grouped. The number of necrotic keratinocytes is variable, depending on the age of the lesion and the lesional site selected for sampling. In early lesions, the stratum corneum will retain its basketweave appearance. One of the characteristic hallmarks is direct lymphocyte satellitosis around necrotic keratinocytes.

Samples from early lesions and from the periphery of established lesions show less keratinocyte necrosis than tissue from the center of fully evolved targets. As the number of necrotic keratinocytes increases, so do the number and size of basal vacuoles. Corresponding to the clinical appearance of blisters are the histologic findings of confluent (or nearly confluent) keratinocyte necrosis and basal vacuolization leading to separation of the epidermis from the dermis. The relative contribution of lymphocytic infiltrate and interface change to the histopathology in a given specimen is quite variable and may relate to underlying cause. For example, drug-induced

 FIGURE 3-8 Erythema multiforme. High magnification shows basal layer vacuolization and scattered necrotic keratinocytes.

CHAPTER 3 ■ INTERFACE DERMATITIS

 FIGURE 3-7 Erythema multiforme. (A) Classic target lesions consist of at least three zones of color change: a peripheral rim of erythema with an inner rim of relative pallor and a central erythematous macule. This concentric pattern imparts a “bull’s eye appearance.” (B) This lesion exhibits an acute interface dermatitis with basal layer vacuolization, subepidermal edema, and a predominantly lymphocytic infiltrate in the superficial dermis.

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erythema multiforme may be associated with a greater number of eosinophils and more pronounced keratinocyte injury and relative lack of dermal perivascular inflammation. In contrast, in herpes simplex-associated erythema multiforme the degree of epithelial injury may be less. There is greater perivascular inflammation and a relative lack of eosinophils.22 Immunophenotypic analysis fails to clearly identify a specific effector lymphocyte population. CD4+ and CD8+ T lymphocytes as well as natural killer (NK) cells are reported. Autoantibodies to desmoplakin I and II may play a role in erythema multiforme major.26 Overexpression of Fas antigen in keratinocytes may be important to the pathogenesis of druginduced erythema multiforme.27 Increased soluble Fas ligand has been observed in the serum and epidemis of herpes simplex virus-induced erythema multiforme.28 DIFFERENTIAL DIAGNOSIS The differential diagnosis of erythema multiforme includes toxic epidermal necrolysis, fixed drug eruption, graft-versus-host reaction, viral exanthem, pityriasis lichenoides, and connective tissue disease (Table 3-2). The relationship between erythema multiforme and toxic epidermal necrolysis is controversial. Some authors consider erythema multiforme and toxic epidermal necrolysis to be distinct entities, whereas others maintain that they are part of the same disease continuum. In general,

typical toxic epidermal necrolysis shows full-thickness necrosis of the epidermis with a scant inflammatory cell infiltrate, although areas of classic erythema multiforme–like interface dermatitis can be seen in some cases. In comparison, erythema multiforme shows less epidermal necrosis (except centrally in a given lesion), usually with single and occasionally clumped necrotic keratinocytes and a denser infiltrate. There are interposed zones of completely viable epidermis. The histologic changes in both disorders constitute a spectrum, and in some instances, discrimination between the two diseases is exceedingly difficult in the absence of clinical information. Superficial samples from central portions of lesions of fixed drug eruption also may strongly resemble erythema multiforme. The presence of a more polymorphous and deep inflammatory cell infiltrate typifies fixed drug eruption. Melanophages accumulate progressively in the upper dermis in both conditions but are somewhat more numerous in a fixed drug eruption. In addition, eosinophils and neutrophils, including foci of intraepidermal eosinophilic spongiosis, are more common in fixed drug eruption. A final discriminating feature is one of chronic epidermal changes including benign epidermal hyperplasia with hyperkeratosis and hypergranulosis. Histologic differentiation of an acute graft-versus-host reaction from erythema multiforme is generally unnecessary

Table 3-2 Comparison of Erythema Multiforme and Toxic Epidermal Necrolysis ERYTHEMA MULTIFORME

TOXIC EPIDERMAL NECROLYSIS

Clinical Features Erythematous patches with dusky centers Target lesions Bullae and erosions Mucosal and conjunctival involvement

Diffuse erythematous patches with diffuse, full-thickness epidermal denudation Mucosal and conjunctival involvement

Histopathologic Features Upper dermal interstitial infiltrate of lymphocytes Basal vacuolization Single and clusters of necrotic keratinocytes Full-thickness epidermal necrosis possible

Toxic Epidermal Necrolysis Little or no inflammation Vacuolar interface dermatitis Full-thickness epidermal necrosis typical Scattered necrotic keratinocytes at periphery

Differential Diagnosis

42

Toxic epidermal necrolysis Fixed drug eruption Graft-versus-host reaction Viral exanthem Pityriasis lichenoides

because these disorders are clinically distinct; the histopathology is quite similar, although a graft-versus-host reaction generally contains fewer lymphocytes and necrotic keratinocytes. Nonspecific viral exanthems may greatly resemble erythema multiforme. The presence of specific viral cytopathic effects, such as multinucleated keratinocytes in herpesvirus infections, allows more specific diagnosis. Erythema multiforme lacks significant inflammation around the deep vascular plexus and around adnexal epithelium, aiding in the differentiation from pityriasis lichenoides et varioliformis acuta (PLEVA) and lupus erythematosus. Erythema multiforme also usually does not exhibit parakeratosis-containing granulocytes, as is typically observed in pityriasis lichenoides. Tissue from pityriasis lichenoides chronica (PLC) typically displays denser upper dermal inflammation and hemorrhage in the dermal papillae with extension of erythrocytes into the epidermis. A haphazard epidermotropic pattern of lymphocyte migration into the epidermis with some degree of lymphoid atypia, including cells with a cerebriform appearance, is seen in the classic lesion of pityriasis lichenoides. Features favoring connective tissue disease over erythema multiforme include hyperkeratosis, follicular plugging, epidermal atrophy, and increased dermal mucin. Correlation with clinical findings is often necessary. Other miscellaneous conditions requiring differentiation from erythema multiforme include coma bulla, in which variable necrosis of eccrine glandular epithelium occurs in association with overlying epidermal keratinocyte necrosis and sparse inflammation. Additionally, many specimens of paraneoplastic pemphigus will only display features of interface dermatitis and will strongly resemble erythema multiforme; tissue from paraneoplastic pemphigus generally is more heavily inflamed.

Erythema multiforme Fixed drug eruption

CLINICAL FEATURES Toxic epidermal necrolysis typically presents as diffuse erythema, becoming dusky over time. The patient often complains of painful skin. Erythema and injection of mucosal surfaces and conjunctivae are common early. As the disease worsens, the eruption becomes generalized, blistering develops, and mucosal surfaces ulcerate. The blisters are occasionally discrete and flaccid, but sheets of sloughing skin, leaving a glistening, occasionally bleeding base, is a common presentation. Toxic epidermal necrolysis is reported in patients with

HISTOPATHOLOGIC FEATURES The essential features include substantial or fullthickness necrosis of the epidermis with little or no inflammation (Figs. 3-9 and 310; see also Table 3-2). A pattern of single-cell necrosis may occur at the periphery of lesional skin. Mild inflammation around the eccrine apparatus is noted, with necrosis of distal elements of the duct a common finding.35 Sparse numbers of eosinophils might be present. Pathologists often are called on to interpret frozen sections from the blister roof in order to obtain rapid laboratory support for the clinical impression. These sections should reveal full-thickness necrosis of epidermis with occasional evidence of individual keratinocyte necrosis, often in aggregates. DIFFERENTIAL DIAGNOSIS The final diagnosis of toxic epidermal necrolysis is made based on clinical examination, with consideration given to erythema multiforme and fixed drug eruption based on histopathology. Specimens

 FIGURE 3-9 Toxic epidermal necrolysis. This lesion shows dermal-epidermal separation, necrosis of the overlying epidermis, and almost no inflammation in the dermis.

CHAPTER 3 ■ INTERFACE DERMATITIS

AIDS, and HIV-1 may be detected in blister fluid. The patient is generally systemically ill. Widespread denudation of the epidermis results in significant risk of sepsis, fluid and electrolyte derangement, and hemodynamic instability. Despite aggressive supportive measures, many patients die. Most cases of toxic epidermal necrolysis are caused by drugs,29 and there is evidence that an inability to detoxify certain drugs is a predisposing factor in the development of toxic epidermal necrolysis.30 Moreover, drug-specific cytotoxicity by T lymphocytes against autologous cells plays a role in mediating tissue damage.31 Compared with serum, blister fluid contains significantly elevated levels of interleukin 6 (IL-6), tumor necrosis factor alpha, and IL-10.32 Apoptosis of keratinocytes appears to be mediated by the interaction of Fas/CD95 with its ligand; a potential beneficial effect from intravenous gammaglobulin (IVIG) may relate to the presence of anti-Fas antibodies in the administered gammaglobulin.33 Serum tumor necrosis factor alpha is also increased. Other soluble mediators such as perforin and granzyme may contribute to the injury. High concentrations of mononuclear cells typically CD8 lymphocytes exhibiting drug-specific MHC classic 1 restricted cytotoxicity toward autologous epidermal keratinocytes have been described. Certain drugs are characteristically implicated and as well there may be an underlying genetic predisposition.34

 FIGURE 3-10 Toxic epidermal necrolysis. There is full-thickness necrosis of the epidermis.

from staphylococcal scalded-skin syndrome reveal subcorneal or granular layer blister formation with minimal necrosis of keratinocytes. Other causes of full-thickness epidermal necrosis include environmental trauma, such as excoriation or thermal injury, and application of a caustic substance to the epidermis (acid). Such injury creates a picture of uniform keratinocyte necrosis without individual cell death. True vasculitis may produce sufficient

ischemic damage to the epidermis to cause full-thickness epidermal necrosis. Toxic epidermal necrolysis lacks vessel destruction as an integral part of its histopathology.

Fixed Drug Eruption CLINICAL FEATURES (See Chap. 12) A fixed drug eruption consists of variable number of well-defined erythematous to violaceous edematous plaques with central

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duskiness and bulla formation. These plaques often recur in the same anatomic site on second ingestion of the causative drug. New plaques may develop on reexposure. As the inflammatory stage resolves, hyperpigmentation, often quite intense, ensues. The plaques may arise at any site but frequently occur on the genitalia and other acral locations. Barbiturates, phenolphthalein, tetracyclines, sulfonamides, and nonsteroidal anti-inflammatory agents are implicated most commonly. Since many of these medications are compounded in overthe-counter formulations, a detailed history of drug ingestion is necessary. HISTOPATHOLOGIC FEATURES All elements of interface dermatitis are evident in a fixed drug eruption. As with erythema multiforme, the degree of epidermal damage varies with the site of sampling within the individual lesion—full-thickness epidermal necrosis may occur in the central bullous zone. Adequate sampling will allow inspection of the reticular dermis, where a moderately intense superficial and deep perivascular and interstitial inflammatory cell infiltrate is generally seen. The composition of this infiltrate is variable. A superficial and deep perivascular lymphocytic infiltrate is common, but inflammation is often polymorphous with lymphocytes, eosinophils, and neutrophils. Neutrophils and eosinophils may predominate, and some karyorrhexis may be evident. Foci of eosinophilic spongiosis may be observed. Chronic epidermal changes are observed including hyperplasia, hyperkeratosis, and hypergranulosis. No vasculitis is seen (Fig. 3-11). Samples from early lesions will display few melanophages in the upper dermis. Over time and with continued damage to the basilar epidermis, melanophages accumulate progressively in the papillary and upper reticular dermis (Figs. 12-5 and 12-6). Specimens from late stages of a fixed drug eruption may only contain melanophages.

DIFFERENTIAL DIAGNOSIS In comparison with erythema multiforme and toxic epidermal necrolysis, fixed drug eruption displays heavier and more polymorphous inflammation. Involvement of the deep vascular plexus also helps distinguish these entities. It is difficult to make confident distinctions based on the degree of melanophage accumulation. While numerous melanophages

44

 FIGURE 3-11 Fixed drug eruption. Interface dermatitis and a superficial and deep perivascular lymphocytic infiltrate.

typify the fixed drug eruption, stage of the lesion sampled and constitutive differences among individuals make this finding a variable component of any interface dermatitis.

Interface Dermatitis of HIV Infection CLINICAL FEATURES Variably distributed but often widespread erythematous patches and plaques characterize this incompletely understood cutaneous eruption associated with HIV-1 infection. The lesions become violaceous over time and result in hyperpigmentation. This hyperpigmentation often involves the face and is of significant cosmetic concern. The eruption is accompanied by pruritus and frequently assumes a photodistribution. The precise cause of the interface dermatitis associated with HIV infection is unknown but may relate to medications, many of which are capable of photosensitization.36 HISTOPATHOLOGIC FEATURES The principal features include basal layer vacuolization, occasional necrotic keratinocytes, and a superficial perivascular and interstitial predominantly lymphocytic infiltrate. The infiltrate may involve the deeper reticular dermis and often is polymorphous with admixed histiocytes, eosinophils, neutrophils, and plasma cells. Vasculitis is usually absent; melanophages may accumulate progressively in the upper dermis.

DIFFERENTIAL DIAGNOSIS The differential diagnosis includes true lichenoid drug eruption, infectious diseases (including viruses), and connective tissue disease. Given adequate clinical information, this combination of findings is reasonably distinct. The occasional presence of plasma cells raises the possibility of syphilis. Cutaneous inflammatory cell infiltrates in the HIV-1–infected person are often polymorphous, making correlation with clinical impression vital for the final diagnosis.

Acute Graft-versus-Host Disease CLINICAL FEATURES Erythematous macules and patches usually develop within the first month after marrow transplant as a manifestation of acute disease. The skin is the earliest and most commonly involved organ in graft-versus-host disease (GVHD), making accurate interpretation of skin biopsy specimens important in patient management. The erythematous patches may remain localized, often acrally, or may generalize to cause erythroderma. Increasing severity is manifested by the formation of blisters and a clinical picture of toxic epidermal necrolysis. Reliable criteria for distinction between a blistering acute cutaneous graft-versushost reaction (GVHR) and toxic epidermal necrolysis do not exist. The clinical features of the acute cutaneous GVHR are similar after allogeneic and autologous marrow transplants, although the clinical severity is greater in the former setting. It is imperative that

 FIGURE 3-12 Acute graft-versus-host reaction. Scanning magnification shows a relatively subtle interface dermatitis. There is a relatively sparse lymphocytic infiltrate in the dermis.

Confluence of the basal vacuoles and separation of epidermis from dermis define grades 3 and 4, respectively. Follicular epithelium is similarly involved. This cytotoxic folliculitis is the earliest manifestation in acute cutaneous GVHR, and it is advisable to study many tissue profiles from a given sample in search of this finding. Loss of polarity of keratinocytes resulting in disordered maturation of the epidermis from small cuboidal keratinocytes

to flattened squamous epithelial cells, is attributable to antineoplastic chemotherapy effect because these drugs disrupt the keratinocyte cell cycle. Individual keratinocyte necrosis accompanies this change, and the diagnosis of a GVHR is best made in unaffected portions of the epidermis, or not at all, if this change is diffusely present. Similarly, within the first 3 weeks after marrow transplant, increased numbers of necrotic keratinocytes are

CHAPTER 3 ■ INTERFACE DERMATITIS

the pathologist be aware of immunologic manipulation of autologous marrow transplants, which results in higher incidences and greater severity of cutaneous disease than in unmanipulated scenarios. For example, administration of moderate doses of cyclosporine increases the incidence and severity of cutaneous eruptions, presumably by promoting autoreactive T-cell clones in the peripheral circulation. This autoimmunity can be enhanced by the addition of interferon-γ, resulting in erythroderma after autologous marrow transplantation, an otherwise uncommon event.37 Accurate identification of histopathologic changes compatible with a GVHR is vital for determining the outcome of clinical trials in the field of autologous marrow transplantation. Apposition of a lymphocyte to a necrotic keratinocyte may be observed in the epidermis, consistent with “satellite cell necrosis.” Despite great effort to identify the effector cell responsible for a GVHR, no clear cell population emerges. Epidermal damage mediated by CD8+ T cells is a widely held concept that lacks mechanistic confirmation. To what extent CD4+ T cells and NK cells play a role is unclear. It is unlikely that one specific lymphocyte population acts as the sole effector cell. The mechanism of cytotoxicity is also unclear. Cytokines elaborated by infiltrating lymphocytes may play a role, as may molecules directly damaging cell membranes, such as perforin. HISTOPATHOLOGIC FEATURES A grading scheme exists (Table 3-3) by which all specimens taken for the diagnosis of acute GVHR may be classified.38 The minimum criteria to establish the diagnosis are codified as grade 2, namely, basal vacuolization, keratinocyte necrosis (at least four necrotic keratinocytes per linear millimeter of epidermis), and a lymphocytic infiltrate in the upper dermis with variable exocytosis39,40 (Figs. 3-12 and 3-13).

Table 3-3 Acute Cutaneous Graft-versus Host Reaction Grade 0 No pathologic change or diagnosis unrelated to GVHR Grade 1 Basal vacuolization Grade 2 Basal vacuolization, necrotic keratinocytes, dermal inflammation Grade 3 Confluence of basal vacuoles Grade 4 Separation of epidermis from dermis

 FIGURE 3-13 Acute graft-versus-host reaction. The epidermis shows some disturbance in the maturation of keratinocytes, slight spongiosis, vacuolization of the basal layer, and a relatively scant superficial perivascular lymphocytic infiltrate.

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referable to ionizing radiation, making quantification helpful41,42. The matter is made simpler by the requirement for significant dermal inflammation because neither chemotherapy artifact nor acute radiation change is accompanied by large numbers of lymphocytes in the dermis. DIFFERENTIAL DIAGNOSIS The diagnostic specificity of the interface dermatitis recognized as the acute cutaneous GVHR is debated (Table 3-4). The effect of potentially confounding variables such as prior marrow ablative chemotherapy and ionizing radiation must be kept in mind when interpreting these skin biopsy specimens. Neither preparative regimen induces significant cutaneous inflammation, whereas inflammation is necessary for the diagnosis of a GVHR. Similarity to erythema multiforme is great, but clinically, the diffuse erythema of a GVHR is rarely confused with the more discrete patches and plaques of erythema multiforme. The development of blisters makes clinical and histologic distinction of a GVHR from toxic epidermal necrolysis nearly impossible—concomitant development of voluminous watery diarrhea and elevated liver transaminase values typify GVHD and are more helpful than histologic examination of the skin. Samples containing grade 1 changes may require further tissue acquisition over time or may reflect the eruption of lymphocyte recovery, not a true GVHR.

Early after marrow infusion, samples from cutaneous eruptions may display eosinophils in the upper dermis. The presence of eosinophils generally is not compatible with the diagnosis of a GVHR and often is interpreted as drug hypersensitivity. This situation requires caution because subsequent marrow engraftment may lead to a switch in histologic findings with a clear diagnosis of GVHR and explosive GVHD, whereas meanwhile the cutaneous eruption has persisted largely unchanged.

Chronic Graft-versus-Host Disease CLINICAL FEATURES Chronic GVHD is divided into lichenoid and sclerodermoid forms. A lichenoid GVHR resembles lichen planus in that the primary lesion is a relatively small, discrete, erythematous to violaceous flat papule without scale. Oral changes identical to lichen planus also occur and often are the predominant manifestation of the disease. The lichenoid GVHR typically arises 60 days or more after marrow transplantation but may occur earlier or later. The development of acute GVHD predisposes to chronic GVHD, but chronic disease may arise de novo. Development of lichenoid GVHD is associated with a lower incidence of tumor relapse. A sclerodermoid GVHR typically begins 100 days or more after marrow transplantation, but again, the time of onset is variable. Progressive cutaneous

Table 3-4 Acute versus Chronic Graft-versus Host Reaction ACUTE GVHR

CHRONIC GVHR

Clinical Features Variably distributed erythematous patches Acral accentuation Blisters rarely

Discrete erythematous to violaceous papules of variable distribution Lacy white patches on buccal mucosa

Histopathologic Features Upper dermal perivascular and interstitial infiltrate of lymphocytes, often mild Basal vacuolization, keratinocyte necrosis Subepidermal bullae rarely

Denser band of lymphocytes in upper dermis Epidermal features of lichen planus Dermal sclerosis, especially involving superficial dermis, in sclerodermoid variant

Differential Diagnosis Erythema multiforme Toxic epidermal necrolysis Viral exanthema

46

Lichen planus Lichenoid drug eruption Lichenoid keratosis Morphea/scleroderma

sclerosis resembles systemic scleroderma. Fasciitis accompanies the skin changes and is a major cause of morbidity leading to joint contractures. Progressive cutaneous sclerosis leads to ischemia and chronic erosion and ulceration of the skin—particularly the scalp and feet. Alopecia is common. Spontaneous resolution of cutaneous sclerosis with completely normal skin examination may occur. In both forms of chronic GVHD, death is usually due to the accompanying smoldering immunoincompetence that predisposes to frequent infectious complications, including sepsis. HISTOPATHOLOGIC FEATURES The fully evolved picture of a lichenoid GVHR resembles lichen planus (Figs. 3-14 and 3-15; see also Table 3-4). The diagnosis rests on (1) the correct clinical setting and (2) epidermal changes of lichen planus, namely, acanthosis with pointed rete ridges, hypergranulosis, and hyperkeratosis. The infiltrate in a lichenoid GVHR is sparse compared with the typical case of lichen planus. As with acute graft-versus-host disease the interface process can show follicular accentuation (Fig. 3-14B and Fig. 3-14C). Oral changes resemble those of oral lichen planus. In addition, it is not uncommon to see areas of epidermal flattening with loss of the rete ridge pattern along with some component of superficial subepidermal fibroplasia. Samples from the oral mucosa are submitted commonly because this site may be the only manifestation of chronic GVHD. The sclerodermoid reaction is characterized by progressive thickening of collagen bundles with loss of the normal interstices. This progression reportedly begins in the papillary dermis and extends toward the subcutis, in contrast to progressive systemic sclerosis and morphea, in which the collagen alteration proceeds upward from a superficial panniculitis. Full histologic expression of the sclerodermoid GVHR includes a thickened dermis with loss of pilosebaceous apparatus and loss of adipose tissue around eccrine glands, so-called entrapment. Invariably, there is evidence of interface damage as well. While active inflammation is sparse, the epidermal-dermal junction will display basal vacuolization with occasional necrotic keratinocytes and upper dermal melanophages. This finding raises the interesting possibility that an epidermal cytokine mediates the pathologic collagen alteration during and after chronic damage to the interface. Fasciitis is characterized by lymphocytic inflammation and thickening of collagen bundles.43 Myositis also may be observed in these samples.

B

A

CHAPTER 3 ■ INTERFACE DERMATITIS

C  FIGURE 3-14 Chronic graft-versus-host reaction. (A) This lesion shows hyperkeratosis, acanthosis, and a sawtooth pattern reminiscent of lichen planus. However, a bandlike infiltrate typical of lichen planus is not present. (B) In this case of chronic graft-versus-host disease there is prominent follicular involvement. A destructive lichenoid process involves the outer root sheath epithelium with resultant thinning of the follicle. (C) Note the adjacent perifollicular epidermis appears attenuated with hypergranulosis and hyperkeratosis. The basal layer has a squamotized appearance reflecting antecedent epidermal injury.

 FIGURE 3-15 Lichenoid graft-versus-host reaction. This biopsy shows hypergranulosis, slight acanthosis, a sawtooth pattern of the epidermis, and prominent interface dermatitis.

DIFFERENTIAL DIAGNOSIS To what extent the lichenoid chronic GVHR is reliably separable from acute disease is uncertain (Horn, unpublished observations). Both conditions are interface dermatitides, with the main difference residing in the extent to which epidermal change resembles lichen planus. This distinction is important because therapy differs depending on whether the process is called acute or chronic. It is the rare biopsy specimen that fulfills all criteria for the diagnosis of a lichenoid chronic GVHR. Therefore, when uncertain, it is advisable to make a diagnosis of “interface dermatitis consistent with graft-versus-host reaction” and allow the clinician to establish the final diagnosis. The differential diagnosis includes lichen planus and lichenoid drug eruption. As noted earlier, the density of the inflammatory cell infiltrate is relatively less in the lichenoid chronic GVHR. In addition, the epidermis is altered be it in the context of

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hyperplasia or attenuation which is not the case in acute GVHD. A biopsy from lesions of chronic GVHD typically involve much of the entire lateral breadth in contradistinction to the more focal nature of the interface process observed in acute graft-versus-host disease. Provided that an adequate sample was submitted, the diagnosis of sclerodermoid disease generally is not difficult. One pitfall resides in a biopsy of skin that appears normal histologically and which represents normal skin overlying fasciitis. Fascial sampling is rarely necessary because the diagnosis is evident clinically, but it should be requested when appropriate. Other causes of increased fibrosis in the dermis and subcutis should be considered, including morphea, progressive systemic sclerosis, and porphyria.

Lupus Erythematosus and Related Entities The entities discussed here share similarities in pattern of inflammation and/or epidermal atrophy, all in association with interface changes, and thus they bear a resemblance to lupus erythematosus (Table 3-5). The epidermal changes typical of lichen planus combined with the dense band of lymphocytes are not the usual features of this group of disorders. Furthermore, inflammatory infiltrates in the conditions considered in this section tend to display more specific and reproducible distribution within the dermis than erythema multiforme and allied entities. The common theme of interface dermatitis persists.

Lupus Erythematosus

48

CLINICAL FEATURES Cutaneous involvement in lupus erythematosus presents several differing clinical pictures. While photodistribution is common, any form of lupus erythematosus may display generalized distribution of lesions. In acute systemic lupus erythematosus (acute cutaneous lupus erythematosus), diffuse erythematous macules and patches are common, often with alopecia. Little surface change is present, and the eruption is evanescent. Photoaccentuation is common, leading to the malar “butterfly” distribution (Fig. 3-16A). Fully evolved systemic disease is common, and serologic tests reveal positive antinuclear antibodies in high titer and antibodies to double-stranded DNA. Patients with systemic lupus erythematosus rarely develop a blistering eruption. The bullous disorder of lupus erythematosus is discussed in Chap. 8.

Table 3-5 Lupus Erythematosus and Variantsa

Clinical Features Systemic lupus erythematosus Diffuse erythematous macules, atrophy possible In general, sun-exposed skin for all variants Subacute lupus erythematosus Psoriasiform lesions Arcuate or serpiginous plaques Ro/La+ Discoid lupus erythematosus Erythematous plaques with atrophy, scarring, alopecia, and dyspigmentation Histopathologic Features Systemic lupus erythematosus Mild upper dermal perivascular and interstitial infiltrate of lymphocytes Mild epidermal atrophy Dermal mucin Thickened basement membrane Subacute lupus erythematosus Denser lymphocytic infiltrate Periadnexal inflammation possible Dermal mucin Moderate regular acanthosis in psoriasiform variant Discoid lupus erythematosus Hyperkeratosis, follicular plugging Epidermal atrophy Features of vacuolar interface dermatitis (above) with dense perivascular interstitial and periadnexal inflammation Thickened basement membrane Dermal mucinosis Loss of adnexae Differential Diagnosis Systemic lupus erythematosus Dermatomyositis Mixed connective tissue disease Viral exanthem Reticular erythematous mucinosis Subacute lupus erythematosus Dermatomyositis Neonatal lupus erythematosus PLEVA Syphilis Lymphocytic infiltrate of Jessner Figurate erythemas Discoid lupus erythematosus Lichen planus Lichen sclerosus Polymorphous light eruption Chilblains Deep gyrate erythema Pityriasis lichenoides Syphilis a At times, dermatomyositis may resemble any variant of lupus erythematosus.

Subacute cutaneous lupus erythematosus may bear similarity to psoriasis clinically or may manifest as arcuate and serpiginous plaques, typically in a photodistribution. These patients typically have antibodies to Ro and La (SSA and SSB). Discoid (chronic) lupus erythematosus is characterized by varying numbers of lesions, usually erythematous plaques, often with atrophy, scale, and dyspigmentation and usually involving the face and scalp. Systemic disease is rare in patients presenting with discoid lupus erythematosus, although patients with systemic disease may develop discoid lesions. While some patients possess reactive antinuclear antibody titers, no serologic test is reliably positive in this subtype. A hypertrophic (or verrucous) variant exists in which the primary lesions have a verrucous surface. Lupus panniculitis (profundus) is usually associated with discoid lupus erythematosus but may evolve in patients with systemic disease. Lupus panniculitis is discussed in Chap. 11. In neonatal lupus erythematosus, the infant is born with or quickly develops variably distributed erythematous scaling macules and patches. Annular erythema is common. The mother may or may not have an established diagnosis of lupus erythematosus prior to birth, but the large majority will have Ro or La autoantibodies. In most instances, the cutaneous eruption resolves over weeks to months in the child. The major complication of neonatal lupus erythematosus is congenital heart block manifested by bradycardia in about 40% of cases. Heart block and the cutaneous eruption occur independently in neonatal lupus erythematosus, with only occasional patients exhibiting both clinical manifestations. The risk for subsequent connective tissue disease later in the life of the affected child is uncertain. Deposition of immunoreactants (immunoglobulin and complement) in the skin of patients with lupus erythematosus is well described but may be of limited value as a diagnostic aid. A granular deposition pattern is observed for IgG, IgA, and/or IgM along with components of complement activation including C3 and C5b9 along the dermal epidermal junction. The most common form of a positive lupus band test is one where there are prominent deposits of IgM within the basement membrane zone unaccompanied by other immunoglobulins. An important caveat is that IgM in isolation from other immunoglobulins can be seen in other settings including

B

 FIGURE 3-16 Acute lupus erythematosus. (A) In acute systemic lupus erythematosus, diffuse erythematous macules and patches with photoaccentuation and a characteristic malar “butterfly” distribution involving the cheeks are observed as in this photograph. Striking facial edema is present. (B) This lesion exhibits hyperkeratosis, atrophy of the epidermis, homogenization of the papillary dermis near the dermal-epidermal junction, and a mononuclear cell infiltrate in the papillary dermis.

CHAPTER 3 ■ INTERFACE DERMATITIS

A

sun-exposed skin of healthy adults. This pattern occurs in most lesional skin of all subtypes as well as in nonlesional, sun-exposed skin from patients with systemic lupus erythematosus (the lupus band test). In systemic lupus erythematosus patients in whom a positive lupus band test is also observed on nonlesional sun-protected skin there is a significant correlation with active renal disease. Improved serologic tests have largely supplanted the diagnostic utility of direct immunofluorescence testing. HISTOPATHOLOGIC FEATURES There is debate whether the clinical subtypes can be reliably distinguished based on histologic criteria44,45 (Figs. 3-16 through 3-20). Although there is sufficient overlap of histologic features such that confident distinction is difficult, typical histologic patterns are recognized in fully evolved clinical lesions from the various subtypes. The descriptions that follow are intended to characterize these findings according to subtype of disease, realizing that clinical practice-specific diagnoses require correlation with the entire clinical picture and with serologic tests. An interface dermatitis is common to all forms of lupus erythematosus.46

 FIGURE 3-17 Acute lupus erythematosus. Higher magnification shows atrophy of the epidermis, basal layer vacuolization, and eosinophilic homogenization of the papillary dermis near the dermalepidermal junction.

ACUTE SYSTEMIC LUPUS ERYTHEMATOSUS Subtle histologic changes often characterize acute disease. A mild upper dermal perivascular and interstitial infiltrate of lymphocytes is present with little or

no epidermal change, imparting a nonspecific picture. Some degree of basal vacuolization and keratinocyte necrosis is present. Atrophy of the epidermis, edema of the upper dermis, and an

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PART I ■ INFLAMMATORY REACTIONS IN THE SKIN 50

 FIGURE 3-18 Subacute lupus erythematosus. The epidermis shows hyperkeratosis and a lymphoid infiltrate that is primarily superficial.

increase in mucin in the upper reticular dermis may be observed (see Figs 3-16 and 3-17). In aggregate, these findings allow the diagnosis of lupus erythematosus in the correct clinical setting. The subtle histologic findings often belie the severity of clinical disease; this disparity should be expected. Marked accumulation of mucin throughout the reticular dermis in the absence of significant inflammation may occur in systemic lupus erythematosus (and occasionally skin-limited disease). Mild overlying interface dermatitis is present. This variant is known as tumid lupus erythematosus. Systemic lupus erythematosus is also reported to display elements of granulomatous dermatitis with neutrophils accompanying the mononuclear inflammation.47 Patients with systemic lupus erythematosus may also exhibit cutaneous lesions resembling Kikuchi disease. The characteristic hallmarks are those of striking periadnexal and perivascular infiltrates of serpentine-like mononuclear cells with concomitant leukocytoclasia. Many of the histiocytes contain engulfed nuclear debris. There is typically supervening mucin deposition and an interface dermatitis. The mononuclear cells show a phenotypic profile

 FIGURE 3-19 Discoid lupus erythematosus. This lesion is notable for hyperkeratosis and rather dense lymphoid infiltrates in the dermis.

 FIGURE 3-20 Discoid lupus erythematosus. There is prominent follicular hyperkeratosis and basement membrane thickening.

compatible with a plasmacytoid dendrocyte exhibiting CD4, myxovirus protein, and CD123 positivity.

SUBACUTE CUTANEOUS LUPUS ERYTHEMATOSUS In contrast to the acute subtype, subacute disease displays more inflammation. A lymphocytic infiltrate is present and primarily surrounds the superficial vascular plexus, with possible extension to deeper dermal levels and the subcutis (see Fig. 3-18). It is not uncommon to see areas of frank lichenoid inflammation although typically with interposed areas of cell-poor interface dermatitis. In general, eosinophils are absent. While lymphocytes extend between collagen bundles in the upper dermis, formation of a dense band of lymphocytes is uncommon. Epidermal interface changes and increased dermal mucin may be observed. The lymphocytic infiltrate extends around pilosebaceous and eccrine epithelium as well but generally is not as dense as in discoid disease. The histopathologic features of neonatal lupus erythematosus resemble those of subacute disease. In the psoriasiform variant, moderate regular acanthosis is present, with a diminished granular layer and parakeratosis, again with interface change at the dermal-epidermal junction. The arcuate form often displays slight epidermal atrophy. Thus, in comparison with acute systemic lupus erythematosus, subacute disease is characterized by a heavier lymphocytic infiltrate with a more distinct superficial perivascular and periadnexal pattern. Subacute cutaneous lupus erythematosus is associated with antibodies

Differential diagnosis Subacute lupus erythematosus shares histologic features with dermatomyositis. Dermatomyositis is generally less heavily inflamed and lacks significant periadnexal inflammation (see Figs. 3-21 and 3-22). Interface dermatitis accompanied by a superficial and deep perivascular lymphocytic infiltrate also characterizes PLEVA and syphilis. Accumulation of mucin and periadnexal patterning of the infiltrate favor the diagnosis of lupus erythematosus. Rarely, mucin deposition may be observed in pityriasis lichenoides. Furthermore, PLEVA and syphilis tend to display heavier exocytosis and more keratinocyte necrosis than any variant of lupus erythematosus. Plasma cells, while typical of syphilis, may occur in lupus erythematosus. Lymphocytic infiltrate of Jessner, a condition of uncertain nosology, is best distinguished from subacute lupus erythematosus by the absence of significant epidermal interface change. Otherwise, the pattern of the lymphocytic infiltrate and increase in mucin greatly resemble subacute lupus erythematosus. Polymorphous light eruption and chilblains are distinguished by the presence of

upper dermal edema with hemorrhage and lack of significant interface dermatitis. Periadnexal inflammation is also not characteristic of either polymorphous light eruption or chilblains. Certain figurate erythemas may mimic the superficial and deep perivascular nature of the infiltrate in subacute lupus erythematosus, but interface changes are absent, and in the case of erythema chronicum migrans, the infiltrate may contain plasma cells and eosinophils. Psoriasis is easily distinguished from the psoriasiform variant of subacute lupus erythematosus by the presence of interface dermatitis and mucin deposition in the latter entity. Occasional photosensitive drug eruptions, such as, those induced by thiazide diuretics and antihistamines, may closely resemble and possibly induce subacute lupus erythematosus. These drug eruptions are discriminated by clinical history and possibly the presence of eosinophils. DISCOID LUPUS ERYTHEMATOSUS Discoid lupus erythematosus is the most common subtype and thus is sampled most frequently. Fully evolved changes include a moderately intense superficial and deep perivascular and interstitial infiltrate of lymphocytes with distinct periadnexal inflammation (Fig. 3-19). The infiltrate extends along the pilosebaceous apparatus, and all elements of interface dermatitis may be found here. Lymphocytes track along eccrine ductal

 FIGURE 3-21 Dermatomyositis. This lesion exhibits atrophy, eosinophilic homogenization of the subjacent papillary dermis, pigment incontinence, and relatively little inflammation.

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Differential diagnosis Distinction between acute systemic lupus erythematosus and dermatomyositis is not possible based solely on histopathology. Mild interface change and scant inflammation may occur in viral exanthems and phototoxic reactions. The observation of increased dermal mucin narrows the focus to connective tissue disease. Tumid forms of lupus erythematosus must be distinguished from reticular erythematous mucinosis, myxedema associated with the treatment of hyperthyroidism, and localized mucinosis. Reticular erythematous mucinosis has both mucin and mononuclear infiltrates in common with lupus erythematosus but lacks interface dermatitis and evidence of a systemic disease. The mucin accumulation in papular mucinosis and scleromyxedema is accompanied by a concomitant increase in fibroblasts; this cellular proliferation is absent in lupus erythematosus. These conditions lack significant interface dermatitis.

directed against Ro/La, SSA/SSB epitopes. Exposure of keratinocytes in tissue culture to ultraviolet B (UVB) radiation results in enhanced expression of these antigens, possibly explaining the photosensitivity in this subtype.48

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A

B

C  FIGURE 3-22 Dermatomyositis. (A and B) The basement membrane zones of A and B). In these two biopsies of dermatomyositis, the vessels of the superficial vascular plexus exhibit ectasia and endothelial the vessels have a thickened appearance, reflecting the sequelae of prior episodes of immunebased microvascular injury. (C) The presumptive basis of the vascular injury in dermatomyositis is one related to antiendothelial cell antibodies. The image is an indirect immunofluorescent assay using human umbilical vein endothelial cells as substrate. A positive reaction following incubation of the patient’s serum tagged with a fluoresceinated human anti-IgG antibody.

52

epithelium and surround glandular epithelium as well. Significant keratinocyte necrosis in eccrine ductal and glandular epithelium generally is absent. Aggregates of lymphoid cells may be sufficiently dense to resemble cutaneous lymphoid hyperplasia, including foci of germinal center formation. Closer inspection reveals the interface nature of the inflammation. Over time, destruction of follicular epithelium ensues, leading to loss of follicles. As a primary manifestation in the scalp, this process leads to the scarring alopecia associated with lupus erythematosus. The perifollicular inflammation primarily targets sebaceous epithelium and follicular epithelium above the entry of sebaceous glands. It is interesting to note that the same pattern is observed in lichen planopilaris and that both lichen planopilaris and lupus erythematosus result in scarring alopecias primarily due to an inflammation directed against the pilosebaceous apparatus. To what extent damage to the follicular bulge and its stem cell population explains this observation is uncertain. Interface change in lupus erythematosus is characterized by basal vacuolization and exocytosis with necrosis of keratinocytes but at lower levels than lichen planus and erythema multiforme. Additional epidermal changes are variable. While atrophy of the epidermis is typical in combination with the interface change, acanthosis also may develop, or the epidermal thickness may be normal. When present, atrophy may be striking, with only two to three layers of keratinocytes evident. Ulceration may develop with crust formation, underlying granulation tissue, and ultimately, dermal fibrosis. With atrophy, orthohyperkeratosis is frequently present, forming a sharp contrast to the thinned stratum spinosum. The hypertrophic variant displays irregular acanthosis with papillomatosis and orthohyperkeratosis; interface change is evident. However, in the hypertropic variants small zones of epidermal attenuation is common. Superficial specimens from the hypertrophic subtype may be mistaken for keratoacanthoma or squamous cell carcinoma.49 Rarely, squamous cell carcinoma arises in long-standing discoid lupus erythematosus. An additional finding at the dermal-epidermal junction is thickening of the basement membrane, seen as a somewhat refractile eosinophilic band hugging basal keratinocytes. Periodic acid–Schiff (PAS) stain highlights this finding. Another variable finding typical of the fully evolved discoid lesion is dilated and keratin-filled epidermal

Differential diagnosis The differential diagnosis includes dermatomyositis, lichen planus, lichen sclerosus, polymorphous light eruption, chilblains, deep gyrate erythemas, pityriasis lichenoides, certain viral exanthems, drug eruption, and syphilis. The fully evolved picture of discoid lupus erythematosus is diagnostic. Dermatomyositis lacks heavy inflammation and significant periadnexal patterning, but in rare instances may greatly resemble discoid lupus erythematosus. As mentioned, the occasional case of lupus erythematosus may contain sufficient lymphoid aggregation to warrant consideration of lymphocytoma. Hypertrophic lupus erythematosus is distinguished from hypertrophic lichen planus by basement membrane thickening, deep dermal and periadnexal inflammation, and dermal mucin deposition.

Dermatomyositis CLINICAL FEATURES Dermatomyositis is a syndrome consisting of variably distributed erythematous macules and plaques with photoaccentuation,50 inflammation of skeletal muscle, and malignant neoplasms.51 Dermatomyositis in association with Lyme disease has been reported.52 The cutaneous manifestations

vary in terms of extent and location, but the typical presentation consists of erythematous infiltrated plaques usually on the face but possibly generalized. The location of the erythema on the face is often periorbital, assuming a violaceous hue, the so-called heliotrope. Atrophic papules with scale on the knuckles are characteristic and are known as Gottron papules. Poikiloderma as a manifestation of dermatomyositis is considered below. Myositis may accompany the skin changes or may precede or follow them. Severe proximal muscle weakness may ensue, and determination of serum levels of muscle-derived enzymes and degradation products aids in diagnosis. Muscle biopsy may be necessary to establish the diagnosis. An electromyogram also may be a useful adjunct. On occasion, cutaneous findings or muscle findings may be absent, prompting the terms polymyositis and dermatomyositis sine myositis, respectively.53 A careful search for visceral malignant neoplasms is necessary if they are not apparent at the time of diagnosis. The neoplasm may predate the onset of the symptoms or may be concomitant or follow the diagnosis of dermatomyositis. A wide range of incidence figures exists for the association between dermatomyositis and malignant neoplasms. The relative risk was 2.4 in men and 3.4 in women in one study.54 While ovarian cancer is overrepresented in comparison with the general population, the proportion of other malignant neoplasms parallels that of age-matched controls. Dermatomyositis occurs in children, unassociated with malignant neoplasms. Vasculitis and severe calcinosis cutis often accompany the juvenile form. Drug-induced dermatomyositis, which has a similar histopathologic appearance to classic dermatomyositis, has been reported in the literature.55 HISTOPATHOLOGIC FEATURES Dermatomyositis is characterized by a variable but often mild degree of lymphocytic inflammation in the upper dermis with overlying epidermal atrophy, interface change, and increased mucin deposition in the dermis, largely indistinguishable from lupus erythematosus (Figs. 3-21 and 3-22). This increased ground substance may be more evident than the inflammatory changes. Massive dermal edema may develop in the heliotrope region. Inflammation around the deep vascular plexus and adnexa may occur. The central portion of a Gottron papule displays atrophy and superficial dermal inflammation

with overlying interface change.56 A septal and lobular panniculitis with lymphoid infiltrates has been described (see Chap. 11). Immunoreactants, including complement components, are identified in lesional skin on direct immunofluorescence testing.57 In particular, vascular deposition of C5b9 appears to confer high sensitivity and specificity for dermatomyositis.58 It has been shown that microvascular injury likely attributable to antiendothelial cell antibodies may play an important role in the pathogenesis of the cutaneous lesions of dermatomyositis. Endothelial cell injury, vascular ectasia, and vascular fibrin deposition were observed in the superficial vascular plexus more frequently in dermatomyositis than in cases of lupus erythematosus59 (Figs.3-22A, 3-22B , and 3-22C). Dermal fibrosis has also been noted in dermatomyositis in the absence of clinical features of scleroderma, correlating with a more severe disease course and possibly implicating TGF-β in the pathogenesis of the sclerosis.60 DIFFERENTIAL DIAGNOSIS As discussed earlier, confident distinction of dermatomyositis from acute lupus erythematosus may be difficult; however the vascular changes along with the immunofluorescent profile may be helpful discriminating features.

CHAPTER 3 ■ INTERFACE DERMATITIS

invaginations associated with follicular orifices. These follicular “plugs” are often identified macroscopically. The associated follicular epithelium is usually thinned, and the dilatation generally extends to the level of the sebaceous gland entry in correctly oriented specimens (Fig. 3-20). Increased dermal mucin generally is present to a variable degree. The dermal vessels may display swelling of endothelium, but true vasculitis usually is absent. If subcutis is included in the specimen, panniculitis is encountered frequently with mixed septal and lobular inflammation composed of lymphocytes, plasma cells, and histiocytes, including lipophages. When panniculitis is the primary histologic manifestation, a specific diagnosis of lupus erythematosus may be difficult to establish without adequate clinical information, especially if the characteristic findings of lupus profundus are not observed. The latter is discussed in detail elsewhere. In brief, there is a necrotizing and eosinophilic hyalinizing lobular lymphocytic panniculitis with numerous admixed plasma cells and germinal center formation. Thickened collagen bundles and increased eosinophilia of collagen bundles of the lower reticular dermis often accompany the panniculitis. Dystrophic calcification may ensue.

Mixed Connective Tissue Disease While many overlap syndromes are recognized among the connective tissue diseases, mixed connective disease is the most common, consisting of features of systemic lupus erythematosus, scleroderma, polymyositis, and rheumatoid arthritis. Facial erythema, heliotrope, acral telangiectases, and scleroderma are the more common cutaneous manifestations. These patients possess high-titer antinuclear antibodies with antibodies to ribonucleoprotein (RNP) as well. HISTOPATHOLOGIC FEATURES There are certain characteristic findings seen in mixed connective tissue disease. The hallmarks include an interface dermatitis which ranges in quality from areas of lichenoid inflammation to zones of cellpoor interface dermatitis in concert with variable dermal sclerosis (Fig. 3-23). The direct immunofluorescence testing will demonstrate characteristic reactivity of epidermal keratinocytes for IgG and C5b9 along with prominent vascular deposits of C5b9.

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 FIGURE 3-23 Mixed connective tissue diseae. In this biopsy of mixed connective tissue diseae there is both an atrophying interface dermatitis along with a scleroderma like-reaction involving the superficial dermis.

Lichen Sclerosus CLINICAL FEATURES Lichen sclerosus (LS) has protean clinical manifestations ranging from localized disease in the perineum to widespread erythematous plaques. The primary lesion in any site is an erythematous patch or plaque, often with an edematous center. This central zone may display pallor and thus impart a white color. Over time, dermal fibrosis may ensue, resulting in the clinical impression of sclerosis resembling scleroderma; rare lesions of LS blister, often with hemorrhagic contents. Most commonly, LS occurs in the genital skin of women, but men and children are also affected.61 On the penis, LS is termed balanitis xerotica obliterans. There is a reported association between squamous cell carcinoma and chronic LS of the vulva, with the incidence estimated at 3% to 4%. Involved vulvar skin displays a higher expression of p53 in association with increased epidermal cell proliferation.62 In North America, tissue from LS lacks evidence of borrelial infection.63 An association is reported between increased severity of disease and presence of specific IL-1 receptor alleles.64 HISTOPATHOLOGIC FEATURES Histologic alterations parallel the age of the lesion. Early, there is an upper dermal perivascular and interstitial lymphocytic infiltrate immediately below the epidermis. Overlying interface change is evident, and the epidermis may be of normal thickness. A fully evolved lesion displays an interstitial band of lymphocytes in the upper to middle reticular dermis

(Figs. 3-24 and 3-25). The epidermis is usually atrophic with hyperkeratosis and dilated and keratin-filled acrotrichial and acrosyringeal ostia. Melanophages are present in a variably edematous dermis. The nature of connective tissue alteration in LS is variable. Initially, the papillary and upper reticular dermis display edema, imparting a light, airy, and indistinct quality to the collagen

bundles. This zone of alteration lies above the band of lymphocytes, is of variable thickness, and usually contains ectatic vascular channels. The edema may lead to subepidermal bulla formation, often with hemorrhage in the blister cavity. Over time, this wispy, edematous collagen gives place to a more dense, homogeneous, and deeply eosinophilic collagen that continues to overlie the zone of inflammation.65 Evidence exists that abnormal fibrillin, elastin, collagen I, and collagen III contribute to the dermal changes observed in LS.66 Older lesions of LS may no longer contain inflammation, or the band of lymphocytes may localize more deeply within the reticular dermis. There is loss of pilosebaceous units and marked atrophy of the epidermis with numerous upper dermal melanophages. The nature of the collagen alteration is often fibrotic rather than edematous. Overlap of histologic features between LS and morphea occurs and generally consists of a combination of the changes described earlier, as well as collagen alteration consistent with morphea in the deep reticular dermis, including superficial panniculitis and entrapped eccrine coils.67 Given the occasional development of squamous cell carcinoma in genital lichen sclerosus, the presence of epidermal

 FIGURE 3-24 Lichen sclerosus. The lesion shows typical features of lichen sclerosis, hyperkeratosis, epidermal atrophy, prominent homogenization of the papillary dermis, and a subjacent, bandlike lymphoid infiltrate.

atypia, exaggerated acanthosis, and loss of the dermal edematous-sclerotic band should be sought because these features are observed more commonly in the vicinity of an associated carcinoma.68 DIFFERENTIAL DIAGNOSIS Lupus erythematosus may mimic LS, but the characteristic collagen alteration is absent, and periadnexal inflammation is more pronounced in the former disease. Otherwise, the epidermal changes are quite similar. Chronic radiation dermatitis may closely resemble LS with fibrotic alteration of the upper dermal collagen, vascular ectasia, and interface change. Radiation fibroblasts and the thickened, waxy blood vessel walls are absent in LS. The interstitial pattern of inflammation typical of LS is absent in radiation dermatitis. Sufficient overlap of histologic features in LS and morphea make confident distinction difficult on occasion. In general, the predominance of upper dermal collagen alteration in association with interface change and dilated keratin-filled follicular ostia distinguishes LS from the predominantly deep dermal alterations of morphea. Both diagnoses may be rendered in certain samples, usually as “lichen sclerosus-morphea overlap.” The nosology of this entity is unclear.

Acrodermatitis Chronica Atrophicans Acrodermatitis chronica atrophicans occurs mostly commonly in Europe, where an association between this disease and

borrelial infection (Borrelia afzellii subspecies of B burgdorferi) exists.69,70 (See Chap, 20.)

Pityriasis PLEVA and Related Diseases PLEVA serves as the histologic prototype for several diseases also characterized by interface dermatitis. One distinguishing feature of this group of disorders is marked exocytosis of lymphocytes into the epidermis as compared with the diseases described thus far. All other elements of interface dermatitis are present in the fully evolved lesion. The pattern of dermal inflammation typically involves the superficial and deep vascular plexuses with interstitial extension in the upper reticular and papillary dermis. Unlike lupus erythematosus, periadnexal inflammation is not a prominent feature, although inflammation involving vessels in the adventitial dermis, especially of the pilosebaceous apparatus, may be noted. Hemorrhage in the papillary dermis accompanies the inflammation in fully evolved lesions. PITYRIASIS LICHENOIDES ET VARIOLIFORMIS ACUTA Clinical features The primary lesion of PLEVA is an erythematous papule that undergoes central vesiculation, pustulation, erosion, and ulceration, forming a crust. PLEVA is abrupt in onset

Histopathologic features At scanning magnification, a pattern of dermal inflammation is seen that involves the superficial and deep vascular plexuses and includes extension of lymphocytes between collagen bundles in the upper reticular and papillary dermis (Fig. 3-26). The degree of inflammation is variable but usually intense in the fully evolved lesion.74 Extension of lymphocytes into the overlying epidermis typically is marked, leading to the impression of equal numbers of keratinocyte and lymphocyte nuclei in the epidermis. A characteristic finding in PLEVA is a confluent parakeratotic scale usually containing degenerated lymphocytes (Fig. 3-26B). Basal vacuolization and necrosis of keratinocytes are evident. A characteristic finding is the presence of cohesive collections of Langerhans cells with a few admixed lymphocytes localized to the upper layers of the epidermis (Figs. 3-26C and 3-26D). The inflammatory infiltrate is composed of T lymphocytes with a predominant CD3+ and CD8+ phenotype, in contrast to pityriasis lichenoides chronica, in which the inflammatory infiltrate has relatively more CD4+ infiltrating T lymphocytes in the dermis and epidermis than CD8+ T lymphocytes.75,76 Reports of clonal T-cell populations, the presence of cells with atypical nuclear forms, and a diminution in the expression of the pan T-cell markers CD7 and CD62L has led to speculation that this condition like PLC is a form of cutaneous

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 FIGURE 3-25 Lichen sclerosus. Higher magnification shows the homogenous eosinophilic hyalinization of the papillary dermis.

with generalized distribution and clustering of lesions in flexural areas. Fever and malaise may accompany the eruption. The papules may enlarge to form nodules, but most lesions remain less than 1 cm in largest diameter. The papules occur in successive crops, with individual lesions resolving with hyperpigmentation and scarring over several weeks’ time. Systemic symptoms may occur.72 The pattern of scarring is randomly scattered, as are the active lesions, imparting similarity to varicella. New papules appear as older papules resolve, resulting in an often polymorphous clinical appearance. PLEVA typically occurs in children and young adults but may develop at any age. The cause is unknown. An infectious agent has been postulated, but no clear pathogen has been clearly implicated, including herpesviruses.73 If untreated, PLEVA may resolve in several months or persists for years. Since the clinical appearance of PLEVA resembles that of lymphomatoid papulosis, periodic skin biopsy specimens are indicated in persistent cases to confirm the diagnosis.

55

C

B

D

PART I ■ INFLAMMATORY REACTIONS IN THE SKIN

A

E

56

 FIGURE 3-26 Pityriasis lichenoides et varioliformis acuta. (A) The lesion displays confluent parakeratosis, basal layer vacuolization, some exocytosis of lymphoid cells, and a perivascular lymphoid infiltrate in the dermis. (B) Classic changes of pityriasis lichenoides. Note the psoriasiform hyperplasia. There are classic changes of pityriasis lichenoides as defined by a psoriasiform pattern of epithelial hyperplasia and striking migration of lymphocytes to involve all layers of the epidermis with preferential localization of lymphocyte migration within the upper layers of the epidermis. As well the epidermis is surmounted by a leukocyte-imbued scale crust. Extensive red cell extravasation is noted amidst a superficial interstitial and perivascular lymphocytic infiltrate. (C) In pityriasis lichenoides the pattern of lymphocyte migration is epidermotropic. In this particular photomicrograph there is passive migration of lymphocytes and histiocytes into the epidermis with lymphoid forms extending into the upper layers of the epidermis. Note the focal red cell extravasation and overlying parakeratotic scale. (D) One of the characteristic hallmarks of pityriasis lichenoides is the presence of pseudo Pautrier-like microabscesses within the superficial layers of the epidermis. As opposed to a true Pautrier microabscess, the composition is one of small lymphocytes and histiocytes closely aggregated in contradistinction to a true Pautrier microabscess which is composed exclusively of atypical lymphoid forms. (E) In this case of pityriasis lichenoides there is a loss of expression of CD7 amidst the lymphocytes.

Differential diagnosis The differential diagnosis includes drug eruptions, viral exanthems, secondary syphilis, papulonecrotic tuberculid, arthropod bite reactions, polymorphous light eruption, connective tissue disease, and erythema multiforme. Drug eruptions and viral exanthems usually do not exhibit the degree of keratinocyte necrosis, parakeratosis with neutrophils, and degree of inflammation encountered in PLEVA. Drug eruptions generally contain eosinophils. Lesions of PLEVA and PLC do not contain eosinophils. Secondary syphilis may closely mimic the pattern of inflammation seen in PLEVA. The presence of numerous plasma cells suggests the diagnosis of syphilis. Correlation with results of serologic examinations and, possibly, tissue silver stains is indicated. Papulonecrotic tuberculid and occasional necrotic arthropod bite reactions may closely simulate PLEVA. Clinicopathologic correlation is helpful. PLEVA lacks the upper dermal edema characteristic of polymorphous light eruption. Polymorphous light eruption also should not display the degree of interface change typical of PLEVA. Both PLEVA and lupus erythematosus have superficial and deep lymphocytic infiltrates. PLEVA lacks the accompanying changes of follicular plugging, epidermal atrophy, basement membrane thickening, periadnexal

Table 3-6 Pityriasis Lichenoides et Varioliformis Acuta versus Pityriasis Lichenoides Chronica PLEVA

PLC

Clinical Features Abrupt onset of erythematous papules Central vesiculation and ulceration Scarring

More gradual onset of erythematous papules with dusky center

Histopathologic Features Superficial and deep perivascular and intersitial infiltrate of lymphocytes; wedge-shaped Upper dermal hemorrhage Features of interface dermatitis with marked exocytosis Parakeratotic scale with neutrophils Central confluent keratinocyte necrosis

Less inflammation, mostly upper dermal Interface dermatitis and hemorrhage persist

Differential Diagnosis Syphilis Drug eruption Viral exanthem Papulonecrotic tuberculid Arthropod bite reaction Polymorphous light eruption Connective tissue disease Erythema multiforme

inflammation, and increased dermal mucin often seen in lupus erythematosus. In contrast to PLEVA, the inflammatory infiltrate of erythema multiforme usually is restricted to the upper dermis and is less dense. Other features more characteristic of erythema multiforme include upper dermal edema and retention of the basketweave stratum corneum. Distinction of PLEVA from pityriasis lichenoides chronica (Table 3-6) is generally based on the degree of inflammation, with pityriasis lichenoides chronica displaying fewer lymphocytes in general, especially in the deep dermis. The pattern of upper dermal inflammation as well as hemorrhage resembles PLEVA. Vesiculation, confluent epidermal necrosis, and ulceration are uncommon in pityriasis lichenoides chronica. PLEVA lacks a significant number of atypical lymphocytes. Lymphomatoid papulosis is characterized by numerous atypical lymphocytes expressing the CD30 antigen (Reed-Sternberg–related antigen and a marker of “activated lymphocytes”). The occasional case of PLEVA will contain a subset of “activated lymphocytes” that possess larger irregular nuclear contours than that usually observed in most cases of PLEVA. These cells may express CD30, but should represent a clear

Erythema multiforme Syphilis Drug eruption Viral exanthem Lichenoid pigmented purpuric dermatitis Pityriasis rosea

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T-cell lymphoid dyscrasia (Fig. 3-26E).77,78,79 One case of PLEVA is noted with enrichment of T cells bearing the g/d receptor.78 Hemorrhage in the upper dermis is typical of fully evolved lesions. Erythrocytes extend into the epidermis along with lymphocytes. Endothelial cells are plump, partially or entirely occluding vessel lumina. This change has prompted consideration of PLEVA as a “lymphocytic vasculitis.” True vessel destruction, with fibrin deposition and loss of integrity of the vessel wall, generally is not seen, and thus categorization of PLEVA in the spectrum of vasculitis is of questionable validity. Rare cases may display histologic changes of vasculitis and are associated with infarction, resulting in more epidermal and dermal necrosis typical of the ulceronecrotic type of PLEVA. As the lesion ages, the keratinocyte necrosis becomes confluent centrally, leading to vesiculation, ulceration with associated crust formation, and granulation tissue. The inflammation becomes progressively less intense. Resolution of the ulceration leaves dermal fibrosis consistent with a scar. The overlying epidermis may be flattened with variable melanin content.

minority of the overall lymphocyte population. Examination of multiple samples, especially over time, may be necessary to clearly distinguish PLEVA from lymphomatoid papulosis. Clonal populations of T cells have been identified by T-cell receptor gene rearrangement studies in tissue samples of PLEVA.79 PITYRIASIS LICHENOIDES CHRONICA Clinical features PLC is more common than PLEVA. The primary lesion of PLC is an erythematous papule, 3 to 10 mm in diameter, that evolves to form a pinpoint dusky center but rarely displays vesiculation or ulceration. The eruption is widely distributed and chronic. Lesions resolve with dyspigmentation over several weeks, but little or no scarring ensues. The nosology of this entity is uncertain, especially its relationship to PLEVA. Because of the somewhat nonspecific clinical appearance of PLC, diagnosis may be difficult. PLC may evolve from PLEVA but also may arise without an antecedent inflammatory condition. PLC may occur at any age and is especially common in children and adolescents. The cause is unknown; however recent studies have suggested that this condition may represent a distinct form of cutaneous T-cell lymphoid dyscrasia. The basis of this categorization includes

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Secondary Syphilis

58

CLINICAL FEATURES A more comprehensive discussion of syphilis is presented in Chap. 20. Secondary syphilis presents with a wide range of clinical findings but most commonly a papulosquamous eruption of variable distribution. Involvement of the palms and soles is typical. Obtaining a skin biopsy specimen in search of the diagnosis of secondary syphilis is less reliable than serologic testing. However, since the diagnosis is occasionally not suspected clinically and often falls within the clinical differential diagnosis of entities that are separable histologically, the pathologist will be asked to identify cutaneous eruptions of secondary syphilis.

 FIGURE 3-27 Pityriasis lichenoides chronica. This lesion exhibits prominent hyperkeratosis, occasional necrotic keratinocytes, and slight basal layer vacuolization.

the persistent waxing and waning nature of the eruption in the absence of an obvious trigger, lymphoid atypia, phenotypic abnormalities including variable losses of CD7 and CD62L, clonality, and occasional cases progressing to mycosis fungoides, especially in the pediatric setting.80

Histopathologic features In contrast to PLEVA, the features of an interface dermatitis are more subtle in PLC (Fig. 3-27). One observes parakeratotic scale, occasional or rare necrotic keratinocytes, slight basal layer vacuolization, and a predominantly superficial perivascular infiltrate of lymphocytes. As with PLEVA, the degree of exocytosis of lymphocytes can be striking. Hemorrhage around capillaries and venules of the upper dermis occurs with extension of erythrocytes into the epidermis. In typical PLC, aggregation of keratinocyte necrosis, vesiculation, and ulceration are uncommon. PLEVA and PLC may form part of a disease spectrum termed pityriasis lichenoides. This concept allows for overlapping histologic and clinical features and subacute variant of pityriasis lichenoides: pityriasis lichenoides subacuta. The dermal and epidermal infiltrating T lymphocytes are predominantly CD4+ and have been shown to exhibit phenotypic abnormalities and clonality.75,76 Differential diagnosis The distinction of PLC from PLEVA was discussed earlier. Epidermal features of lichen planus are absent in PLC. The degree and pattern of inflammation may resemble erythema multiforme, but significant epidermal

necrosis, especially in greater proportion than the degree of inflammation, should not be observed in PLC. As with PLEVA, consideration of secondary syphilis is warranted in the presence of plasma cells. PLC may be classified among the pityriasiform dermatitides (see Chap. 1), and thus the following entities should be considered in the differential diagnosis: pityriasis rosea, certain drug eruptions, superficial gyrate erythema, subacute spongiotic dermatitis, guttate or eruptive psoriasis, pityriasis rubra pilaris (PRP), and early mycosis fungoides. The distinction of PLC from the later stages of pityriasis rosea can be difficult. In general, pityriasis rosea shows greater spongiosis and less interface change with confluent parakeratosis than PLC. This distinction is also true for superficial gyrate erythema and subacute spongiotic dermatitis. The typical drug eruption will contain eosinophils. PRP may be quite nonspecific but often displays follicular plugging, alternating ortho- and parakeratosis, and little inflammation. Guttate and early psoriasis may show parakeratosis, as is the case with PLC, but often exhibit exocytosis of neutrophils, papillary dermal edema, dilated upper dermal vessels, and no significant interface change. PLC may enter the differential diagnosis of circumscribed hypopigmentation. Consideration of tinea versicolor, vitiligo, leprosy, and mycosis fungoides may be necessary (see Chaps. 15, 19, and 34). Clonal T-cell populations are identified frequently in tissue from PLC.81 Whether PLC represents a form of cutaneous T-cell lymphoma remains unproven.

HISTOPATHOLOGIC FEATURES Any cutaneous infiltrate that contains significant numbers of plasma cells warrants consideration of syphilis. The typical pattern of secondary syphilis is that of an interface dermatitis with a superficial and deep perivascular and to some extent interstitial infiltrate of lymphocytes, including plasma cells.82,83 The absence of plasma cells does not definitively exclude the diagnosis of syphilis. Psoriasiform epidermal hyperplasia with marked exocytosis of lymphocytes is observed commonly. Endothelial cells are enlarged and partially or totally obliterate vessels. In older lesions of secondary syphilis, histiocytes accumulate, often leading to the formation of granulomas. These granulomas generally are not well formed when compared with the granulomas of sarcoidosis; rather, they consist of a variable admixture of histiocytes, multinucleated giant cells, lymphocytes, and plasma cells in a loose and somewhat poorly circumscribed aggregate. DIFFERENTIAL DIAGNOSIS The similarities between secondary syphilis and PLEVA and PLC were noted earlier. Occasional skin biopsies specimens will contain heavy infiltration by plasma cells. Consideration should be given to plasmacytoma, especially if some degree of atypia is observed. Determination of monoclonality by demonstration of lightchain restriction or immunoglobulin gene rearrangement should be sought.

DISEASES CHARACTERIZED BY POIKILODERMA The term poikiloderma does not imply a specific diagnosis. Poikiloderma is a clinical and histologic finding with many causes. Clinically, poikiloderma consists

Poikiloderma of Civatte Poikiloderma of Civatte occurs as patches of wrinkled skin with mottled pigmentation and telangiectases in sun-exposed sites, frequently on the necks of women. Samples from poikiloderma of Civatte show solar elastosis and lack significant inflammation. This form of poikiloderma is poorly understood but most likely is due to chronic sun exposure.

Poikiloderma Congenitale (Rothmund-Thomson Syndrome) Childhood onset of poikiloderma, photosensitivity, osteosarcoma, short stature, juvenile cataracts, skeletal defects, nail dystrophy, and hypogonadism combine to characterize poikiloderma congenitale. The poikilodermatous changes typically are photodistributed and, viewed histologically, lack significant inflammation.84 Rothmund-Thomson syndrome is inherited in an autosomal recessive manner and is associated with mutations in the DNA helicase gene RECQL4.85

Congenital Telangiectatic Erythema (Bloom Syndrome) Facial telangiectasia beginning in infancy or early childhood with photosensitivity and progression to a poikilodermatous appearance characterizes the cutaneous

manifestations of congenital telangiectatic erythema. Skin biopsy specimens reveal interface dermatitis with some features of poikiloderma as noted earlier. Other features include short stature, genomic instability, development of malignant neoplasms, variable immunoglobulin deficiencies, and mutations in the gene-encoding DNA helicase RECQL3.85 Bloom syndrome is inherited in an autosomal recessive manner and is associated with sister-chromatid exchange.86

Dyskeratosis Congenita A retiform erythema with mottled pigmentation is characteristic of dyskeratosis congenita. Recognition of this syndrome is crucial because there is a high incidence of squamous cell carcinoma arising in dysplastic oral and anal mucosal epithelium. The oral changes consist of white plaques that display variable keratinocyte atypia progressing to full-thickness dysplasia and invasive carcinoma. Skin biopsy specimens of the poikiloderma show the typical findings. Additional features of this syndrome include nail dystrophy bone marrow failure, lacrimal duct atresia, and mutation in the gene encoding dyskerin (DKC 1).85,87 Dyskeratosis congenita is inherited in an X-linked recessive manner.85

Poikiloderma Accompanying Dermatomyositis Poikiloderma may represent a prominent clinical finding in patients with dermatomyositis. The poikiloderma generally arises in long-standing plaques of erythema. The histopathology of poikiloderma in the setting of dermatomyositis is often remarkable for other changes typical of the connective tissue disorder, namely, more pronounced interface change and increased dermal mucin deposition.

Poikiloderma Accompanying Mycosis Fungoides Poikiloderma as the primary clinical manifestation of cutaneous T-cell lymphoma is rare. Many observers consider this finding to be an involutionary or regressive phase of the disease process. With any clinical description of poikiloderma, it behooves the pathologist to consider the diagnosis of cutaneous T-cell lymphoma. In addition to the constellation of findings typical of poikiloderma, the diagnosis rests mainly on identification of a band of atypical lymphocytes in the upper dermis with variable epidermotropism including the formation

of Pautrier microabscesses. The epidermal changes typical of fully evolved cutaneous T-cell lymphoma are generally less pronounced in poikilodermatous forms of the disease, an argument for the resolving-lesion theory. Nonetheless, a diagnosis of cutaneous T-cell lymphoma must rest on recognition of a neoplastic T-cell population in the skin regardless of specific pattern or density of the infiltrate (see Chap. 34).

MISCELLANEOUS DISEASES WITH FEATURES OF INTERFACE DERMATITIS Some of the entities considered in this section are covered more extensively elsewhere in this text but display interface change as an integral part of their histopathology. No specific pathophysiology unifies these diseases.

Lichen Nitidus CLINICAL FEATURES Lichen nitidus consists of discrete 1- to 2-mm, skin-colored to minimally erythematous papules of variable distribution and extent but often grouped and located on the genital and acral skin. Lichen nitidus occurs commonly in children and is seen often on the penis. Cases of generalized lichen nitidus have been reported.88,89,90 The disease is self-limited. Overlap with lichen planus occurs, and both conditions may be recognized in a given patient. HISTOPATHOLOGIC FEATURES A discrete interstitial aggregate of mononuclear cells expands one dermal papilla to form the typical lesion of lichen nitidus (Fig. 3-28). This expansion causes the adjacent epidermal rete ridges to bow outward and give the appearance of extension underneath the inflammatory cell aggregate as a collarette (so-called ball-and-claw effect). This discrete anatomic localization corresponds to the clinical picture of pinpoint papules and is distinct from the histopathology of lichen planus.91 The infiltrate filling two adjacent dermal papillae may fuse to form a larger lesion on occasion. Initially, the infiltrate is composed almost entirely of lymphocytes, whereas established lesions exhibit an admixture of lymphocytes and histiocytes with occasional multinucleated giant cells and melanophages. The overlying epidermis is slightly thinned and flattened with basal vacuolization and rare necrotic keratinocytes. Parakeratotic scale often overlies these epidermal changes. Lichen nitidus represents one of the classic

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of patches of skin with variable melanin content, imparting a mottled hyper- and hypopigmented appearance. The epidermis is thin and may be shiny with fine wrinkles. Ectatic papillary dermal vessels are responsible for a faint erythema or distinct telangiectasis. The minimum criteria for the histologic diagnosis of poikiloderma include epidermal atrophy with loss of the normal pattern of rete ridges, variable epidermal melanin content, dilated upper dermal vessels, and melanophages with some element of interface change. Determining hyper- and hypopigmentation in a given skin biopsy specimen generally is not possible unless the clinician includes or identifies skin with normal pigmentation for comparison. Mild papillary dermal fibrosis often accompanies these changes. The degree of inflammation is highly variable and depends, in part, on the stage of evolution of the lesion sampled. This section will discuss entities characterized by poikiloderma. The clinical and pathologic features making these diseases distinctive will be emphasized together because the histopathology alone often is not specific.

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HISTOPATHOLOGIC FEATURES The histopathologic features of lichen striatus are variable. Findings of a lichenoid dermatitis indistinguishable from lichen planus, lichen nitidus, or a combination may occur (Fig. 3-29). Para-keratosis may be seen. Lichen striatus also may present as a spongiotic dermatitis that typically exhibits prominent necrosis of keratinocytes. Another typical feature of lichen striatus is involvement of the eccrine coil by the infiltrate of lymphocytes (Fig 3-30). Occasional cases are reported with involvement of the deep vascular plexus.92

 FIGURE 3-28 Lichen nitidus. There is a circumscribed nodular lymphoid infiltrate filling the papillary dermis. The infiltrate contains some multinucleate giant cells.

idiopathic eruptions associated with a lichenoid and granulomatous form of inflammation.93 DIFFERENTIAL DIAGNOSIS The fully evolved lesion is quite characteristic. Serial sectioning of a sample submitted for the diagnosis of lichen nitidus may be necessary because the diagnostic area may be missed in initial cuts. Some lesions of lichen striatus may resemble lichen nitidus (Table 3-7) but are distinguished by additional features similar to lichen planus, some spongiosis with necrotic keratinocytes, and eccrine coil involvement. The clinical appearance of lichen striatus is as a linear patch.

Lichen Striatus CLINICAL FEATURES Lichen striatus may affect individuals of any age but most commonly occurs in children as a linear array of closely set skin-colored to erythematous papules with little or no scale. Almost any skin site may be affected; however, a common presentation is a progressively lengthening collection of erythematous papules beginning on the proximal portion of an extremity with progressive growth over several months to acral skin, commonly a digit. No associated systemic abnormalities occur. As mysteriously as lichen striatus begins, it involutes, leaving variable dyspigmentation.

Table 3-7 Lichen Nitidus versus Lichen Striatus LICHEN NITIDUS

LICHEN STRIATUS

Clinical Features 1-2-mm flesh-colored papules, often genital and acral

Grouped erythematous papules in linear array

Histopathologic Features Discrete aggregate of lymphocytes, histiocytes, and occasional multinucleated giant cells expanding a dermal papilla Epidermal collarette

Variable findings resembling lichen planus with deep perivascular and perieccrine inflammation at times May resemble lichen nitidus May display spongiosis and dyskeratosis

Differential Diagnosis

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Lichen planus

ILVEN Lichen planus

DIFFERENTIAL DIAGNOSIS While many cutaneous diseases assume a linear patterning, lichen striatus most closely resembles linear lichen planus and inflammatory linear verrucous epidermal nevus (ILVEN). Linear lichen planus displays the same histopathology as conventional lichen planus with its typical epidermal change and band of lymphocytes in the upper dermis. Lichen striatus may show fully evolved features of lichen planus but often also demonstrates parakeratosis, features of lichen nitidus, and deep dermal extension of the infiltrate. Another manifestation of lichen striatus is spongiotic dermatitis, as mentioned earlier. The epidermal changes in ILVEN usually more closely resemble psoriasis than interface dermatitis. The significant acanthosis and hyperkeratosis that impart the verrucous appearance to ILVEN are absent in lichen striatus.

Lichenoid Pigmented Purpuric Eruption of Gougerot and Blum As a group, pigmented purpuric dermatitis is discussed in more detail in Chap. 9. The lichenoid variant displays the typical erythematous/hemorrhagic patches and bronze discoloration characteristic of pigmented purpuric dermatitis. Skin samples reveal a perivascular and interstitial infiltrate of lymphocytes in the upper dermis with overlying interface change. This interstitial inflammation and the accompanying epidermal findings separate lichenoid pigmented purpuric eruption from other forms of pigmented purpuric dermatitis. Pericapillary hemorrhage is similar to that in pityriasis lichenoides chronica. In fact, these two entities are best distinguished on clinical grounds. Vasculitis with fibrin deposition and thrombosis are uncommon. Idiopathic pigmented purpuric dermatosis especially the lichenoid variant is held to represent a form of cutaneous lymphoid dyscrasia, hence lymphoid atypia, some loss of CD7, and clonality may be observed.93,94

erythematous rim show a mild-to-moderately dense perivascular and interstitial infiltrate of lymphocytes with lymphocyte apposition to degenerating melanocytes. The local cytokine milieu, such as the elaboration of soluble cytotoxic mediators, may result in the keratinocyte being injured as an innocent bystander.

Morbilliform Drug Eruption (See also Chap. 12)

Morbilliform Viral Exanthem (See also Chap. 22) Viral exanthems manifest as variably distributed erythematous macules often concentrated on the trunk. Skin biopsy samples display an upper dermal perivascular and interstitial infiltrate of lymphocytes with overlying basal vacuolization and variable numbers of necrotic keratinocytes. Typically only a few necrotic keratinocytes are noted. It is common to see erythrocyte extravasation and mild papillary dermal edema. Spongiosis and parakeratosis may be present.

 FIGURE 3-30 Lichen striatus. There is inflammation of the eccrine coils.

Macular and Lichen Amyloidosus (See also Chap. 16) Macular amyloidosus typically presents as hyperpigmented macules, often on the upper back, whereas the clinical appearance of lichen amyloidosus consists of verrucous plaques that are quite pruritic, usually on the shins. In both entities there is an accumulation of amorphous eosinophilic material to variable extent in the upper dermis. In general, greater amounts of amyloid are present in lichen amyloidosus than in macular amyloidosus. In both instances, the amyloid is derived from keratin. This fact explains the frequent finding of damage to the epidermal-dermal interface with basal

vacuolization, scattered necrotic keratinocytes, and melanophages in the upper dermis admixed with the amyloid. Acanthosis, hyperkeratosis, and papillomatosis further characterize lichen amyloidosus. These changes may reflect the sequela of chronic rubbing of the skin.

Vitiligo (See also Chap. 15) Progressive hypopigmentation leading to depigmentation of the skin correlates with the histologic findings of progressive loss of melanin content and melanocytes from the epidermis. Sampling of a chronic lesion reveals minimal inflammation with mild interface changes consisting mainly of basal vacuolization. Samples of the

CHAPTER 3 ■ INTERFACE DERMATITIS

 FIGURE 3-29 Lichen striatus. The lesion exhibits a bandlike infiltrate expanding the papillary dermis in a pattern resembling both lichen planus and lichen nitidus.

Exanthematous drug eruptions present as variably distributed pruritic erythematous macules and papules, often with a generalized distribution. The histopathology is not specific, consisting of an upper dermal perivascular and interstitial infiltrate of lymphocytes and eosinophils. Typically, these eruptions have basal vacuolization as the primary manifestation of interface change. At times, this finding may become pronounced, with rare necrotic keratinocytes. Any significant number of necrotic keratinocytes should prompt consideration of erythema multiforme.

Paraneoplastic Pemphigus (See also Chap. 7) The clinical and histologic features in paraneoplastic pemphigus (PNP) are protean. Marked mucositis is a nearly constant finding, whereas skin lesions range from erythema multiforme–like to overt blisters. The most characteristic skin biopsy specimens demonstrate interface dermatitis and suprabasal acantholysis. Many, possibly most, specimens will show only interface change. Such lesions exhibit a moderately dense upper dermal infiltrate of lymphocytes and features closely resembling erythema multiforme. Occasional eosinophils may be observed. As a rule, the degree of inflammation is heavier in PNP than in typical erythema multiforme.95 Acantholysis may be entirely absent or minimal in these specimens. Confirmation of the diagnosis through direct and indirect immunofluorescence is necessary.95

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MISCELLANEOUS DISEASES WITH SOME FEATURES OF INTERFACE DERMATITIS Although many diseases of the skin display some elements of interface dermatitis as part of the overall histopathology, such as, for example, spongiotic dermatitis, a few entities deserve special mention. The patch and plaques stages of mycosis fungoides often are characterized by basal vacuolization and migration of lymphocytes into the epidermis. Necrotic keratinocytes may be observed, but not in significant numbers. Even in that scenario one invariably sees areas of passive lymphocyte migration into the epidermis unaccompanied by significant destructive epithelial alterations. Other clues include the narrow grenz zone separating areas of band-like infiltration in the superficial dermis from the overlying epidermis and the extent of lymphocyte atypia. Under oil examination (1000×) excessive gyrate nuclear convolutions oftentimes transecting the nucleus is characteristic. Ultimately, the extent and degree of atypia, the architectural disposition of the lymphocytes in both the epidermis and dermis, and the epithelial and dermal response discriminate mycosis fungoides from other interface dermatitides. Lichenoid contact dermatitis is characterized by a perivascular and interstitial infiltrate composed of lymphocytes and eosinophils with variable overlying spongiosis and features of interface dermatitis. Most cases of contact dermatitis lack the features of interface dermatitis. Occasional immunologic reactions to the foreign materials in a tattoo will exhibit features of interface dermatitis, with the moderately heavy inflammatory infiltrate admixed among the exogenous pigments. This pattern is more common in response to mercury implantation.

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of cutaneous lesions of dermatomyositis. Hum Pathol. 1996;27:15-19. Magro CM, Dyrsen M, Kerns MJ. Cutaneous lesions of dermatomyositis with supervening fibrosis. J Cutan Pathol. 2008;35:31-39. Hinchliffe SA, Ciftci AO, Khine MM, et al. Composition of the inflammatory infiltrate in pediatric penile lichen sclerosus et atrophicus (balanitis xerotica obliterans): a prospective, comparative immunophenotyping study. Pediatr Pathol. 1994;14: 223-233. Tan SH, Derrick E, McKee PH, et al. Altered p53 expression and epidermal cell proliferation is seen in vulval lichen sclerosus. J Cutan Pathol. 1994;21: 316-323. Dillon WI, Saed GM, Fivenson DP. Borrelia burgdorferi DNA is undetectable by polymerase chain reaction in skin lesions of morphea, scleroderma, or lichen sclerosus et atrophicus of patients from North America. J Am Acad Dermatol. 1995;33:617-620. Clay FE, Cork MJ, Tarlow JK, et al. Interleukin 1 receptor antagonist gene polymorphism association with lichen sclerosus. Hum Genet. 1994;94:407-410. Mihara Y, Mihara M, Hagani Y, Shimao S. Lichen sclerosus et atrophicus: a histological, immunohistochemical, and electron microscopic study. Arch Dermatol Res. 1994;286:434-442. Farrell AM, Dean D, Millard PR, et al. Alterations in fibirillin as well as collagens I and III and elastin occur in vulva lichen sclerosus. J Eur Acad Dermatol Venereol. 2001;15(3):212-217. Glockenberg A, Cohen-Sobel E, Caselli M, Chico G. Rare case of lichen sclerosus et atrophicus associated with morphea. J Am Podiatr Med Assoc. 1994;84:622-624. Scurry J, Whitehead J, Healey M. Histology of lichen sclerosus varies according to site and proximity to carcinoma. Am J Dermatopathol. 2001;23(5): 413-418. Lubbe J, Schlupen EM, Fierz W, et al. Identification of Borrelia afzelii in a juxtaarticular fibroid nodule from a human immunodeficiency virus-positive patient with acrodermatitis chronica atrophicans. Arch Dermatol. 1995;131:1341-1342. Balmelli T, Piffaretti JC. Association between different clinical manifestations of Lyme disease and different species of Borrelia burgdorferi sensu lato. Res Microbiol. 1995;146:329-340. deKoning J, Tazelaar DJ, HoogkampKorstanje JA, Elema JD. Acrodermatitis chronica atrophicans: a light and electron microscopic study. J Cutan Pathol. 1995; 22:23-32. Fink-Puches R, Soyer HP, Kerl H. Febrile ulceronecrotic pityriasis lichenoides et varioliformis acuta. J Am Acad Dermatol. 1994;30: 261-263. Magro CM, Crowson AN, Morrison C, Li J. Pityriasis lichenoides chronica: stratification by molecular and phenotypic profile. Hum Pathol. 2007 Mar;38(3):479490. Epub 2007 Jan 19. PMID: 17239929 [PubMed—Indexed for MEDLINE]. Black MM. Lymphomatoid papulosis and pityriasis lichenoides: are they related? Br J Dermatol. 1982;106:717-721. Muhlbauer JE, Bhan AK, Harrist TJ, et al. Immunopathology of pityriasis lichenoides

76.

77. 78.

79. 80. 81.

82. 83. 84.

85. 86.

87. 88. 89. 90. 91.

92.

93.

94.

95.

acuta. J Am Acad Dermatol. 1984;10:783795. Wood GS, Strickler JG, Abel EA. Immunohistology of pityriasis lichenoides et varioliformis acuta and pityriasis lichenoides chronia. Evidence for their interrelationship with lymphomatoid papulosis. J Am Acad Dermatol. 1987;16: 559-570. Terhune MH, Cooper KD. Gene rearrangements and T-cell lymphomas. Arch Dermatol. 1993;129:1484-1490. Alaibac M, Morris J, Yu R, Chu AC. T-lymphocytes bearing the gamma delta T-cell receptor: a study in normal human skin and pathologic skin conditions. Br J Dermatol. 1992;127:458-462. Weinberg JM, Kristal L, Chooback L, et al. The clonal nature of pityriasis lichenoides. Arch Dermatol. 2002;138:1063-1067. Takahashi K, Atsumi M. Pityriasis lichenoides chronica resolving after tonsillectomy. Br J Dermatol. 1993;129:353-354. Magro C, Crowson AN, Kovatich A, Burns F. Pityriasis lichenoides: a clonal T-cell lymphoproliferative disorder. Hum Pathol. 2002;33(8):788-795. Abell E, Marks R, Wilson-Jones E. Secondary syphilis: a clinicopathological review. Br J Dermatol. 1975;93:53-61. Jeerapaet P, Ackerman AB. Histologic patterns of secondary syphilis. Arch Dermatol. 1973;107:373-377. Vennos EN, Collins M, James WD. Rothmund-Thomson syndrome: review of the world literature. J Am Acad Dermatol. 1992;27:750-762. Online Medelian Inheritance in Man. http://www.ncb.inlm.nih.gov/sites/entrex? db=omn. Weksberg R. Low-sister-chromatidexchange Bloom syndrome cell lines: an important new tool for mapping the basic genetic defect in Bloom syndrome and for unraveling the biology of human tumor development. Am J Hum Genet. 1995;57:994-997. Drachtman RA, Alter BP. Dyskeratosis congenita. Dermatol Clin. 1995;13:33-39. Laxmisha C, Thappa DM. Generalized lichen nitidus with Down syndrome. J Eur Acad Dermatol Venereol. 2006;20:1156-1157. AL-Mutairi N, Hassanein A, Nour-Eldin O, et al. Generalized lichen nitidus. Pediatr Dermatol. 2005;22:158-160. Arizaga AT, Gaughan MD, Bang RH. Generalized lichen nitidus. Clin Exp Dermatol. 2002;27:115-117. Smoller BR, Flynn TC. Immunohistochemical examination of lichen nitidus suggests that it is not a localized papular variant of lichen planus. J Am Acad Dermatol. 1992;27:232-236. Gianotti R, Restano L, Grimalt R, et al. Lichen striatus—a chameleon: an histopathological and immunohistological study of forty-one cases. J Cutan Pathol. 1995;22: 18-22. Guitart J, Magro C. Cutaneous T-cell lymphoid dyscrasia: a unifying term for idiopathic chronic dermatoses with persistent T-cell clones. Arch Dermatol. 2007 Jul;143(7):921-932. Magro CM, Schaefer JT, Crowson AN, Li J, Morrison C. Pigmented purpuric dermatosis: classification by phenotypic and molecular profiles. Am J Clin Pathol. 2007 Aug;128(2):218-229. Horn TD, Anhalt GJ. Histologic features of paraneoplastic pemphigus. Arch Dermatol 1991;128:1091-1095.

CHAPTER 3 ■ INTERFACE DERMATITIS

46.

and histopathologic indicators of the development of progressive acute graftversus-host disease. J Invest Dermatol. 1992;99:397-402. LeBoit PE. Subacute radiation dermatitis: a histologic imitator of acute cutaneous graft-versus-host disease. J Am Acad Dermatol. 1989;20:236-241. Janin A, Socie G, Devergie A, et al. Fasciitis in chronic graft-versus-host disease: a clincopathologic study of 14 cases. Ann Intern Med. 1994;120:993-998. Bielsa I, Herrero C, Collado A, et al. Histopathologic findings in cutaneous lupus erythematosus. Arch Dermatol. 1994;130:54-58. Jerdan MS, Hood AF, Moore GW, et al. Histologic comparisons of subsets of lupus erythmatosus. Arch Dermatol. 1990;126:52-55. Crowson AN, Magro C. The cutaneous pathology of lupus erythematosus: a review. J Cutan Pathol. 2001;28(1):1-23. Chu P, Connolly MK, LeBoit PE. The histopathologic spectrum of palisaded neutrophilic and granulomatous dermatitis in patients with collagen vascular disease. Arch Dermatol. 1994;130:1278-1283. Kawashima T, Zappi EG, Lieu TS, Sontheimer RD. Impact of ultraviolet radiation on expression of SSA/Ro autoantigenic polypeptides in transformed human epidermal keratinocytes. Lupus. 1994;3:493-500. Perniciario C, Randle HW, Perry HO. Hypertrophic discoid lupus erythematosus resembling squamous cell carcinoma. Dermatol Surg. 1995;21:255-257.. Cheong WK, Hughes GR, Norris PG, Hawk JL. Cutaneous photosensitivity in dermatomyositis. Br J Dermatol. 1994;131: 205-208. Whitmore SE, Rosenschein NB, Provost TT. Ovarian cancer in patients with dermatomyositis. Medicine. 1994;73:153-160. Horowitz HW, Sanghera K, Goldberg N, et al. Dermatomyositis associated with Lyme disease: case report and review of Lyme myositis. Clin Infec Dis. 1994;18: 166-171. Cosnes A, Amaudric F, Gherardi R, et al. Dermatomyositis without muscle weakness: long-term follow-up of 12 patients without systemic corticosteroids. Arch Dermatol. 1995;131:1381-1385. Sigurgeirsson B, Lindelof B, Edhag O, et al. Risk of cancer in patients with dermatomyositis or polymositis: a populationbased study. New Engl J Med. 1992;326: 363-367. Magro CM, Schaefer JT, Waldman J, et al. Terbinafine-induced dermatomyositis: a case report and review of drug-induced dermatomyositis. J Cutan Pathol. 2007;35: 74-81. Hanno R, Callen JP. Histopathology of Gottron’s papules. J Cutan Pathol. 1985; 12:389-394. Mascaro JM, Jr, Hausman G, Herrero C, et al. Membrane attack complex deposits in cutaneous lesions of dermatomyositis. Arch Dermatol. 1995;131:1386-1392. Magro CM, Crowson AN. The immunoflourescent profile of dermatomyositis: a comparative study with lupus erythematosus. J Cutan Pathol. 1997;24(9): 543-552. Crowson AN, Magro CM. The role of microvascular injury in the pathogenesis

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CHAPTER 4 Psoriasiform Dermatitis

PART I ■ INFLAMMATORY REACTIONS IN THE SKIN

Timothy T. Chang Loren E. Golitz

Inflammatory dermatoses may be categorized based on the pattern of inflammation1 and epidermal changes.2 With psoriasis as the prototype, the psoriasiform dermatitides are characterized by regular elongation of rete ridges.3 This may result from increased keratinocyte proliferation due to more rapid turnover of stem cells or an increased pool of proliferating cells. Epidermal thickening may affect any or all of the layers of the epidermis. The stratum corneum may be thickened (hyperkeratosis) and may retain nuclear remnants (parakeratosis). Thickening of the granular layer or spinous layer is termed hypergranulosis or acanthosis, respectively. In psoriasis, there is prominent parakeratosis associated with a thin to absent granular layer. Rete ridges show clubbing, are uniformly elongated, expanded at the tips, and fused. The epidermis shows thinning of the suprapapillary plates. Neutrophils migrate from dilated capillaries in the papillary dermis and extend into the stratum corneum to form Munro microabscesses. A number of inflammatory dermatoses share these features, including psoriasis, Reiter syndrome, pityriasis rubra pilaris, and neurodermatitis (lichen simplex chronicus).4 However, just as there are differences in the clinical appearance and pathogenesis, there are histologic differences in quality of scale and distribution or composition of inflammation that allow these dermatoses to be distinguished from each other.

MAJOR PSORIASIFORM DERMATOSES

Psoriasis

64

Psoriasis is a chronic papulosquamous disease affecting about 1% to 2% of the US population. There is considerable geographic and ethnic variation in incidence. For example, psoriasis is rare in native Americans. The onset is typically in the third decade, with a second peak in

the sixth.5 Certain areas of the skin are preferentially involved, including the scalp, groin, elbows, knees, umbilicus, and lumbar spine.6 The disease follows a chronic relapsing course characterized by remission and exacerbation. Psoriasis is characterized by an increased epidermal turnover rate7 leading to thickening of the epidermis and accumulation of scale. There is evidence for an inherited component in psoriasis. There is high concordance for disease in monozygotic twins8 and a linkage disequilibrium with certain human lymphocyte antigen (HLA) types, especially HLA-Cw6.9 There is evidence for genomic imprinting in the inheritance of psoriasis, in that children of males with psoriasis are more often affected than children of females with psoriasis. This and other genetic phenomena in psoriasis can be explained by the “allelic instability in mitosis” model of dominantly inherited disease, the subject of recent reviews.10,11 Evidence supporting a genetic susceptibility locus (PSORS1) within the major histocompatability (MHC) complex is presented by Capon and colleagues.12 A total of nine chromosomal loci (PSORS1-PSORS9) have now been linked to psoriasis susceptibility, with PSORS1 being the most important genetic determinant for heritability.13 An elegant experiment has demonstrated that psoriasis is not a primary defect of keratinocytes. Human psoriatic skin was grafted onto mice with severe combined immunodeficiency. Over time, mouse epidermis grew over the human dermis, but the epidermis retained psoriasiform architecture, indicating that the defect more likely lay in the dermis.14 The pathogenesis of psoriasis involves the interaction between inflammatory cells and keratinocytes. T-cell activation and cytokines are involved in epidermal proliferation,15 and cytokines produced by activated keratinocytes are thought to induce keratinocyte proliferation and lymphocyte migration.16 Psoriasis has been classified as a Th1 disease characterized by an increased production of cytokines of the Th1 pathway (IL-2, IFN-γ, and IL-12/23).17 One hypothesis is that genetic susceptibility coupled with an inflammatory process that may be triggered by activation of T cells by bacterial superantigens leads to the development of psoriasis.18,19 CLINICAL FEATURES The most common clinical presentation is chronic stationary psoriasis (psoriasis vulgaris). Individual lesions are sharply demarcated, erythematous, and covered with a thick,

silvery scale (Fig. 4-1A) (Table 4-1). They may show the Auspitz sign, in which forcible removal of scale produces pinpoint areas of bleeding. The tendency to involve the extensors has been attributed to the Koebner (isomorphic) phenomenon, in which typical lesions arise at sites of trauma. Inverse psoriasis is characterized by involvement of the flexures. Here, lesions may show less scale and exhibit a shiny erythema. Fingernails are involved in 50% and toenails in 35% of patients with psoriasis.20 Involvement of the proximal nail fold overlying the nail matrix produces pitting of the nail plate. Psoriasis of the nail bed produces yellow-brown discoloration under the nail plate (“oil spots”). Inflammation of the nail matrix causes a deformed, thickened nail plate termed onychodystrophy that can result in distal onycholysis and subungual hyperkeratosis. Mucosal lesions are rare, except on the glans penis, especially in uncircumcised men. Abrupt onset of small (guttate) lesions, especially on the trunk and proximal extremities, may follow a streptococcal infection.21,22 This phenomenon is more common in children. It may be related to cross-reactive antibodies between streptococcal M protein and human skin.23 Psoriasis may be pustular. A generalized form of pustular psoriasis with systemic symptoms is termed pustular psoriasis of von Zumbusch, which may be precipitated by systemic corticosteroids.24 When pustules are localized to the palms and soles, the process is termed pustular psoriasis of Barber. Erythrodermic psoriasis is characterized by generalized erythema and shedding of large amounts of scale. In this setting, marked dilatation of cutaneous blood vessels adversely affects body temperature regulation. Verrucous psoriasis is a recent variant of psoriasis that has been described by Khalil et al.25 Patients present with flesh-toned to white mammilated plaques and coalesced plaques primarily on the extensor surfaces of the upper and lower extremities. HISTOPATHOLOGIC FEATURES Just as the clinical picture varies with the age of the lesions, so do the histopathologic findings.26 Biopsies of fully developed plaques reflect the hyperproliferative and intermittent nature of psoriasis, showing extensive hyperkeratosis with horizontally confluent but vertically intermittent parakeratosis (Figs. 4-1 through 4-5). In areas of parakeratosis, the granular layer is thinned or absent. Parakeratosis may alternate with orthokeratosis, reflecting the episodic nature

B

 FIGURE 4-1 Psoriasis. (A) Individual lesions are sharply demarcated, erythematous, and covered with a thick, silvery scale. (B) The epidermis shows regular elongation of the epidermal rete ridges.

of the disease. Mitoses are more frequent than in uninvolved skin and may appear one or two layers above the basal layer. There is uniform elongation of rete ridges with thinning of the suprapapillary epidermis. The tips of the rete ridges are often clubbed or fused with adjacent ones. The dermal papillae are

Table 4-1 Psoriasis

Clinical Features Sharply circumscribed plaques with silvery scale Auspitz sign, Koebner phenomenon Predilection for scalp, groin, extensor surfaces (especially elbows and knees), nails Inherited component Histopathologic Features Hyperkeratosis with confluent parakeratosis Uniform elongation of rete ridges Papillary dermal edema with dilated tortuous capillaries Thinned suprapapillary plates Neutrophils within the stratum corneum (Munro microabscesses) Neutrophils within the spinous layer (spongiform pustule of Kogoj) Superficial perivascular lymphocytic infiltrate Differential Diagnosis Chronic spongiotic (eczematous) dermatitis Superficial cutaneous fungal infections Secondary syphilis Reiter syndrome Lichen simplex chronicus

edematous and contain dilated, tortuous capillaries. Despite the dermal edema, spongiosis is mild or absent. The granular and spinous layers are thinned over the edematous dermal papillae, and exocytosis of neutrophils frequently occurs in these areas. It is the thinned suprapapillary plates and the proximity of dilated dermal capillaries to the skin surface that produce the Auspitz sign. Collections of neutrophils with pyknotic nuclei in the parakeratotic stratum corneum, Munro microabscesses, are

found in approximately 75% of cases.27 Neutrophils are found less commonly in the spinous layer, where they may aggregate to form spongiform pustules of Kogoj. The underlying dermis is characterized by a superficial perivascular infiltrate of lymphocytes. Eosinophils generally are absent, and plasma cells are unusual except in mucosal biopsies or in association with HIV infection. This classic picture is seen in only a small percentage of lesions.28 Earlier or eruptive lesions may show initially a

 FIGURE 4-2 Psoriasis. The cornified layer shows horizontally confluent parakeratosis with exocytosis of neutrophils.

CHAPTER 4 ■ PSORIASIFORM DERMATITIS

A

65

PART I ■ INFLAMMATORY REACTIONS IN THE SKIN

(see Fig. 4-4). The migration of neutrophils from dermal papillae into the overlying epidermis has been referred to as squirting papillae.30 Neutrophils are more numerous in eruptive psoriasis than in psoriasis vulgaris31 (see Fig. 4-5). Verrucous psoriasis shows many of the classical features of psoriasis including regular psoriasiform epidermal hyperplasia, hyperkeratosis, Munro microabscesses, and spongiform pustules. However, there is prominent papillomatosis and pointing of the rete ridges toward the center of the lesion that is suggestive of a verruca vulgaris. Importantly, hypergranulosis and koilocytic change are not identifed in these lesions.25

 FIGURE 4-3 Psoriasis. The granular layer is absent, and there is prominent exocytosis of neutrophils.

DIFFERENTIAL DIAGNOSIS Seborrheic dermatitis may show neutrophils within parakeratotic scale but typically situated about follicular ostia rather than diffuse and confluent. The presence of marked spongiosis within the rete ridges suggests the diagnosis of a spongiotic (eczematous) process such as nummular dermatitis or contact dermatitis. Lichen simplex chronicus shows papillary dermal fibrosis, whereas psoriasis shows papillary dermal edema and dilated, tortuous capillaries. Neutrophils in the stratum corneum may be seen in candidiasis or dermatophytosis. In these conditions, a fungal stain, such as a periodic acidSchiff (PAS) stain with diastase predigestion, may reveal hyphae, pseudohyphae, or budding yeast. Secondary syphilis may show psoriasiform epidermal hyperplasia, but may have a deeper dermal infiltrate containing plasma cells. Psoriasiform drug eruptions often show features of both psoriasis vulgaris and lichen simplex chronicus, but can be histologically identical to psoriasis. Some medications, such as lithium, induce psoriasis while other medications, such as betablockers and nonsteroidal anti-inflammatory drugs (NSAIDs), either exacerbate psoriasis or induce psoriasiform eruptions.32

Pustular Psoriasis  FIGURE 4-4 Guttate psoriasis. Note prominent focal parakeratotic scale.

66

nonspecific pattern of changes confined to the dermis.29 There is a superficial perivascular lymphocytic infiltrate with extravasation of erythrocytes associated with papillary dermal edema and dilated,

tortuous capillaries. Only later are the suprapapillary plates thinned in association with elongation of rete ridges. In early lesions, parakeratosis is typically mounded or spotty rather than confluent

Pustules in psoriasis may occur in several settings. Occasionally, pustules may be found at the periphery of typical plaquetype lesions. Sterile pustules may be localized to the palms and soles (Barber), to the paronychial tissues (acrodermatitis continua of Hallopeau), or may be generalized with associated constitutional symptoms (von Zumbusch). Impetigo herpetiformis is pustular psoriasis in association with pregnancy. Patients

Other changes are the same as those in psoriasis vulgaris, namely, diffuse parakeratosis, hypogranulosis, regular elongation of rete ridges, papillary dermal edema, and capillary dilatation in association with a superficial perivascular infiltrate of lymphocytes and neutrophils. These findings are less well developed in eruptive lesions. On acral skin, as in palmoplantar pustular psoriasis of Barber or acrodermatitis continua of Hallopeau, pustules are large and unilocular, with the typical spongiform pattern seen primarily at the periphery of the pustule (Fig. 4-9).

with impetigo herpetiformis usually have typical lesions of psoriasis elsewhere. CLINICAL FEATURES Pustular psoriasis of von Zumbusch33 presents as a sudden eruption of 2- to 3-mm sterile pustules tending toward confluence and a distribution over the trunk and extremities. The underlying skin shows a fiery erythema. The face is usually spared, but oral lesions are common.34 This process is episodic and may be accompanied by fever, leukocytosis, and arthralgias lasting several days. Nails may be shed. The average age of onset is 50 years, with males and females affected equally.35 Hypocalcemia may be present,24 possibly related to hypoalbuminemia. Pustular psoriasis of von Zumbusch has been precipitated by numerous medications, including systemic corticosteroids, iodides, salicylates, and progesterone.36 The clinical differential diagnosis includes acute generalized exanthematous pustulosis. Palmoplantar pustulosis describes psoriasis in which lesions are confined to the palms and soles. Some authors separate clinical variants, such as pustular psoriasis of Barber, acrodermatitis continua of Hallopeau, and pustular bacterid of Andrews. We will consider these entities together because they show identical histopathologic features, although the clinical presentation and/or clinical associations may allow their discrimination. HISTOPATHOLOGIC FEATURES The constant histologic feature of pustular psoriasis

is the spongiform pustule of Kogoj. Neutrophils migrate from dilated, tortuous papillary dermal capillaries and collect between residual plasma membranes, accompanied by intercellular edema, producing a spongelike appearance within the Malpighian layer37 (Figs. 4-6 through 4-9). Keratinocytes in the center of the spongiotic areas degenerate, leaving large unilocular pustules. With time, neutrophils arrive in the parakeratotic stratum corneum as Munro microabscesses.

 FIGURE 4-6 Pustular psoriasis. This lesion shows prominent parakeratotic scale, an intraepidermal neutrophilic pustule, and prominent subepidermal edema.

CHAPTER 4 ■ PSORIASIFORM DERMATITIS

 FIGURE 4-5 Guttate psoriasis. There is focal exocytosis of neutrophils.

DIFFERENTIAL DIAGNOSIS A number of processes can present with spongiform or subcorneal pustules. Identification of the primary pathologic process is important in differentiating these disorders. Dyshidrotic eczema may show intraepidermal pustules but is more spongiotic and often has eosinophils in the dermal infiltrate. Eosinophils also may indicate a pustular drug eruption.38 Superficial fungal infections such as candidiasis and dermatophytosis may show pustules in the stratum corneum. Fungal elements cannot be reliably excluded without the use of special stains. Impetigo, pustular drug eruptions, and subcorneal pustular dermatosis of Sneddon-Wilkinson all may show subcorneal pustules. In these conditions, parakeratosis and epidermal hyperplasia are less developed. Pustular miliaria, pustular lupus erythematosus, pustular syphillis, pemphigus foliaceus, IgA pemphigus, and necrolytic migratory

67

PART I ■ INFLAMMATORY REACTIONS IN THE SKIN

Approximately 80% of patients have mucocutaneous lesions.40 There is a wellestablished genetic component demonstrated by the strong association with HLA B27.41 In addition to genitourinary infections, enteric infections may trigger the reactive disease in genetically predisposed individuals. There is evidence that microbial antigens persist in patients with reactive arthritis.42 Although organisms are rarely cultured, nucleic acid sequences of Chlamydia subspecies have been found in the synovium of affected patients.43 Comprehensive reviews of the pathogenesis of reactive arthritis (Reiter syndrome) are available.44,45

 FIGURE 4-7 Pustular psoriasis. Higher magnification showing intraepidermal neutrophilic pustule.

HISTOPATHOLOGIC FEATURES The histopathologic features of keratoderma blenorrhagicum and balanitis circinata are essentially identical to those of pustular psoriasis (Fig. 4-10). Broad hyperkeratosis and parakeratosis with a thinned granular layer and elongated rete ridges are seen. Within the parakeratotic stratum corneum are collections of neutrophils with pyknotic nuclei (Munro microabscesses). Geographic tongue shows prominent spongiform pustules with less hyperkeratosis than in cutaneous lesions.47

 FIGURE 4-8 Pustular psoriasis. There are spongiform pustules in the upper part of the Malpighian layer of the epidermis.

erythema can all show spongiform or subcorneal pusutles.

Reactive Arthritis (Reiter Syndrome) 68

CLINICAL FEATURES Patients with reactive arthritis tend to be young males in whom arthritis follows urethritis and conjunctivitis by several days or weeks. Urethral cultures are usually negative. One-third of patients manifest the complete triad, and 40% have arthritis only.46 Mucocutaneous lesions include a psoriasiform eruption of the palms and soles (keratoderma blenorrhagicum), a pustular or psoriasiform eruption on the glans penis (balanitis circinata), erosive or ulcerative oral lesions (geographic tongue), and subungual pustules associated with onycholysis.

Reactive arthritis is characterized by the triad of urethritis, arthritis, and conjunc-

tivitis (Table 4-2). However, only onethird of patients manifest the classic triad. A more recent definition by the American Rheumatism Association requires “an episode of peripheral arthritis of more than 1 month’s duration occurring in association with urethritis and/or cervicitis.”39

DIFFERENTIAL DIAGNOSIS Both the keratoderma of reactive arthritis and pustular psoriasis have large, unilocular spongiform pustules. Striking hyperkeratosis favors reactive arthritis, as does a more intense perivascular inflammatory infiltrate, especially if neutrophils are prominent. Mucosal lesions are more common in Reiter syndrome. Clinical correlation may be necessary to distinguish Reiter syndrome from pustular psoriasis because the histologic changes may be identical.

Pityriasis Rubra Pilaris Pitryriasis rubra pilaris (PRP) is a rare, idiopathic, chronic papulosquamous disease with a bimodal age of onset.48

 FIGURE 4-9 Palmoplantar pustulosis. Note large intraepidermal pustule.

There is an equal sex ratio. Some cases are familial and are transmitted as an autosomal dominant trait49 with expression of keratins not normally found in

epidermis.50 As in psoriasis, the epidermal turnover rate is increased.51 CLINICAL FEATURES PRP usually begins as asymptomatic scaling and erythema of the scalp resembling seborrheic dermatitis.49 Later, truncal lesions develop as small,

HISTOPATHOLOGIC FEATURES In PRP, discrete foci of lamellar hyperkeratosis and parakeratosis alternate with orthokeratosis both perpendicular to and parallel to the skin surface (Figs. 4-11 through 4-13). Parakeratotic mounds at the edges of follicular ostia are termed shoulder parakeratosis. Keratotic plugs fill the follicular ostia and extend above the level of the adjacent epidermis. The epidermis, including the suprapapillary plates, shows hyperplasia and hypergranulosis55 and occasional acantholysis.56 Rete ridges are irregularly elongated and thickened but less so than in psoriasis. There is a mild

CHAPTER 4 ■ PSORIASIFORM DERMATITIS

orange-red, accuminate follicular papules with perifollicular erythema (Table 4-3). These coalesce into large plaques with fine scale and distinct borders, expanding to leave islands of uninvolved skin. The disease may progress to generalized erythroderma. There is a yellow-red keratoderma of the palms and soles (Fig. 4-11A). Follicular papules on the dorsa of fingers are said to resemble a “nutmeg grater.” Nail changes include thickening of the nail plate and subungual hyperkeratosis.52 Oral lesions are infrequent. In the classic adult form (type I) the disease may undergo spontaneous remission within 3 years in approximately 80% of the cases, but the childhood form (type II) tends to be chronic.48,53 HIV-associated PRP may have coexisting acne conglobata or hidradenitis suppurativa.54

Table 4-2 Reiter Syndrome

Clinical Features Triad of urethritis (negative urethral cultures), arthritis, and conjunctivitis Predominantly young males, HLA-B27 Palms and soles (keratoderma blenorrhagicum) Penile lesions (balanitis circinata) Histopathologic Features (identical to psoriasis) Hyperkeratosis with confluent parakeratosis Uniform elongation of rete ridges Papillary dermal edema with dilated tortuous capillaries Thinned suprapapillary plates Neutrophils within the stratum corneum (Munro microabscesses) Neutrophils within the spinous layer (spongiform pustule of Kogoj) Superficial perivascular lymphocytic infiltrate Differential Diagnosis Psoriasis Chronic spongiotic (eczematous) dermatitis Superficial cutaneous fungal infections Secondary syphilis

 FIGURE 4-10 Reiter syndrome. This lesion shows a parakeratotic stratum corneum containing neutrophils that overlies psoriasiform epidermal hyperplasia.

69

PART I ■ INFLAMMATORY REACTIONS IN THE SKIN

Table 4-3 Pityriasis Rubra Pilaris

Clinical Features Inherited (autosomal dominant) and sporadic forms Scalp involvement resembling seborrheic dermatitis Accuminate follicular papules Erythroderma with islands of sparing Palmoplantar keratoderma Histopathologic Features Vertical and horizontal foci of orthokeratosis alternate with parakeratosis Parakeratotic mounds at follicular ostia (shoulder parakeratosis) Follicular plugging Rete ridges irregularly elongated and thickened Thickened suprapapillary plates Superficial perivascular lymphocytic inflammation Differential Diagnosis Psoriasis Seborrheic dermatitis Keratosis pilaris

A

B superficial perivascular lymphocytic infiltrate, sometimes containing eosinophils or plasma cells.56 The neutrophils and Munro microabscesses of psoriasis are usually absent. Spongiosis is minimal.

 FIGURE 4-11 Pityriasis rubra pilaris. (A) There is a yellow-red keratoderma of the palms with diffuse scaling. (B) The epidermis shows psoriasiform epidermal hyperplasia with a hyperkeratotic stratum corneum.

DIFFERENTIAL DIAGNOSIS An objective histologic diagnosis of PRP can be made in about 50% of cases. The most distinctive features are follicular hyperkeratosis, hypergranulosis, and shoulder parakeratosis. In psoriasis the hyperkeratosis and parakeratosis tend to be confluent, whereas in PRP the changes are focal. The presence of neutrophils and spongiform pustules in association with dilated, tortuous capillaries argues against the diagnosis of PRP. Chronic eczematous dermatitis usually shows some degree of spongiosis. Follicular plugging may be seen in discoid lupus erythematosus, keratosis pilaris, and lesions of vitamin A deficiency (phrynoderma). In discoid lupus, the pattern of inflammation is lichenoid or deep and periappendageal. Keratosis pilaris and phrynoderma do not show significant epidermal hyperplasia.

Lichen Simplex Chronicus

70

Lichen simplex chronicus (LSC) is produced by repetitive mechanical trauma to the skin. A number of stimuli produce pruritus and provoke scratching. When

 FIGURE 4-12 Pityriasis rubra pilaris. High magnification showing alternating ortho- and parakeratosis.

DIFFERENTIAL DIAGNOSIS LSC may show residual intercellular edema and hypergranulosis, which are mild or absent in psoriasis. Both conditions show vascular ectasia, but vessels are more tortuous in psoriasis. Seborrheic dermatitis, psoriasis, and chronic fungal infections are more likely to show neutrophils within the stratum corneum. Psoriasis shows more prominent parakeratosis and an edematous rather than fibrotic papillary dermis. Benign keratoses and other epidermal neoplasms tend to be more sharply circumscribed. Chronic lesions of spongiotic dermatitis may show a superimposed pattern of LSC.

 FIGURE 4-13 Pityriasis rubra pilaris. There is follicular hyperkeratosis with parakeratosis involving the shoulders of the follicular infundibulum.

the sensation and scratching are localized, papular and nodular lesions are produced (prurigo nodularis, “picker’s nodule”). Psychogenic factors may be involved. Over time, the behavior may become subconscious. Identical lesions can be induced in normal skin by a minimum of 140,000 scratches.57 Any pruritic or eczematous dermatosis can develop secondary lichenification. We reserve the term LSC (localized neurodermatitis) for those cases in which a primary dermatosis is not apparent. CLINICAL FEATURES Lesions of LSC are always pruritic and often solitary. They are chronic and most commonly involve the lower lateral legs, dorsal feet, extensor forearms, genital region, and posterior neck. Lesions of LSC are thickened, well-demarcated, scaly papules, nodules, or plaques with excoriation and lichenification. Hyperpigmentation is common and persistent. The prurigo nodularis pattern is usually multiple and symmetrically distributed on the extremities with evidence of chronicity including dyschromia and scarring. HISTOPATHOLOGIC FEATURES A biopsy of LSC shows thickening of all layers of the skin above the reticular dermis, imparting some resemblance to acral skin (Table 4-4 and Figs. 4-14 and 4-15). Hyperkeratosis, hypergranulosis, and acanthosis are seen. When present, parakeratosis is discontinuous. The rete ridges are irregularly elongated and thickened. The epidermis may

Table 4-4 Lichen Simplex Chronicus

Clinical Features Prominent pruritus Changes produced by repetitive scratching Chronic well-demarcated plaques Lichenification/excoriation/hyperpigmentation Lateral legs, posterior neck, flexures Histopathologic Features Thickening of all layers of the skin above the reticular dermis Hyperkeratosis/hypergranulosis/acanthosis Papillary dermal fibroplasia Stellate/multinucleated fibroblasts Superficial perivascular lymphocytic infiltrate Pointed rete ridges rather than club shaped Differential Diagnosis Psoriasis Chronic spongiotic (eczematous) dermatitis Superficial cutaneous fungal infections

be papillomatous, and the superficial Malpighian layer may be pale as the result of glycogen accumulation.58 There is usually some spongiosis in the acute stage, but vesicles are rare. The papillary dermis shows thickened collagen fibers oriented perpendicular to the skin surface. There may be stellate or multinucleated fibroblasts in the superficial dermis. The superficial dermis shows vascular ectasia and a perivascular lymphocytic infiltrate with minimal exocytosis.

Parapsoriasis is not a disease but a group of diseases that includes pityriasis lichenoides, large-plaque parapsoriasis (LPP), and small-plaque parapsoriasis (SPP). This group of diseases was first proposed by Brocq in an attempt to organize the inflammatory dermatoses.59 The diseases are essentially unrelated, except that all are idiopathic, asymptomatic (although pruritus can be a variable feature), chronic, and relatively unresponsive to therapy. A review of the nosology of these diseases is available.60 In addition to a confusing nomenclature and to difficulties in defining parapsoriasis in a reproducible fashion, considerable controversy surrounds the relationship between LPP and mycosis fungoides. Many authors consider LPP to be an inflammatory process that may progress to mycosis fungoides.61 Others consider LPP to be part of the spectrum of cutaneous T-cell lymphoma or mycosis fungoides from the outset,62,63 a low-grade malignancy that smolders in the majority of cases and follows a more aggressive course in a few. In either case, both processes may show similar abnormalities of T-cell antigen expression64 and monoclonal T-cell proliferation.65,66 CLINICAL FEATURES Large-plaque parapsoriasis (LPP) is a chronic disease of middle age. It is characterized by large (>10 cm), slightly scaly, erythematous patches and plaques with irregular outlines (Table 4-5). The eruption is asymmetrical and affects predominantly the buttocks, flexures, and female breasts. Mucosal disease, nail changes, and acral involvement are rare. Lesions are usually asymptomatic but may be pruritic. Plaques often show epidermal atrophy manifested as fine wrinkling of the skin. The skin lesions may resemble poikiloderma atrophicans

CHAPTER 4 ■ PSORIASIFORM DERMATITIS

Parapsoriasis (Parapsoriasis en Plaques)

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PART I ■ INFLAMMATORY REACTIONS IN THE SKIN

Table 4-5 Parapsoriasis en Plaques

Clinical Features Chronic disease of middle age Scaly erythematous patches and plaques Predilection for buttocks, flexures, and breasts Unresponsive to treatment Histopathologic Features Mild irregular acanthosis Mounding parakeratosis Papillary dermal fibrosis Focal vacuolar change Superficial perivascular lymphocytic infiltrate Differential Diagnosis Guttate (eruptive) psoriasis Mild chronic dermatitis Mycosis fungoides (see text)  FIGURE 4-14 Lichen simplex chronicus. There is prominent irregular psoriasiform epidermal hyperplasia with pointed rete ridges. is unusual. With chronicity, the infiltrate may become more dense and bandlike with associated papillary dermal fibrosis. Lymphocytes may be seen along the basal layer in association with vacuolar change and pigment incontinence. DIFFERENTIAL DIAGNOSIS In early lesions, the differential diagnosis includes a mild chronic dermatitis or superficial perivascular dermatitis. Clinically, the eruption may be unresponsive to standard therapy. When lymphocytes infiltrate the deeper layers of the epidermis, the histologic features resemble those seen in the earliest or patch stage of mycosis fungoides.67 Lymphocyte atypia, epidermal lymphocytes larger than dermal lymphocytes, and halos around papillary dermal lymphocytes favor mycosis fungoides. Other reactive inflammatory dermatoses usually do not show monoclonal T-cell proliferation.65,66

OTHER PSORIASIFORM DERMATOSES

Subacute and Chronic Spongiotic Dermatitides  FIGURE 4-15 Prurigo nodularis. Note the irregular psoriasiform epidermal hyperplasia as in lichen simplex chronicus.

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vasculare, which is characterized by epidermal atrophy, dyschromia, and telangiectasia. Progression to overt mycosis fungoides may be heralded by thickening of the plaques.

HISTOPATHOLOGIC FEATURES The earliest lesions show only a superficial perivascular lymphocytic infiltrate. The epidermis initially shows mild, irregular acanthosis and mounding parakeratosis. Spongiosis

Spongiotic dermatitis represents a cutaneous reaction to a variety of endogenous or exogenous stimuli. This pattern clinically has been termed eczema or eczematous dermatitis. However, some authors have argued that the term eczema lacks a specific meaning and should be avoided.68 The acute phase of this reaction pattern is considered in detail in Chap. 2. The chronic phase is included

here because it may show psoriasiform epidermal hyperplasia.

HISTOPATHOLOGIC FEATURES The histologic picture of chronic and subacute spongiotic dermatitis is dominated by the changes produced by chronic rubbing and scratching, as seen in lichen simplex chronicus. All layers of the epidermis and papillary dermis are thickened, manifesting as compact hyperkeratosis, parakeratosis, hypergranulosis, acanthosis, and papillary dermal fibrosis. These changes correspond to the clinical finding of lichenification. The prominent spongiosis and exocytosis of lymphocytes of acute lesions are diminished in chronic ones. Dried plasma is present as crust, and there may be superficial ulceration due to excoriation. DIFFERENTIAL DIAGNOSIS Different clinical forms of spongiotic dermatitis may show distinctive histologic features. Stasis dermatitis shows clusters of tortuous capillaries and siderophages within a fibrotic papillary dermis. Nummular dermatitis shows focal, mounding parakeratosis and spongiosis associated with a superficial perivascular infiltrate of lymphocytes and a variable number of eosinophils.

Erythroderma Erythroderma is a clinical term referring to generalized redness of the skin. Exfoliative dermatitis refers to those cases with extensive scaling. This reaction pattern may result from a number of mechanisms.69 Generalization of preexisting papulosquamous disease or spongiotic dermatitis accounts for 25% to 62.5% of cases. Psoriasis, pityriasis rubra pilaris, atopic dermatitis, and seborrheic dermatitis are common causes. Drugs are another major cause of erythroderma (14%-42%). Lymphoma, especially Sézary syndrome, accounts for 8% to 21% of cases. Many cases are idiopathic. CLINICAL FEATURES Erythema, scaling, and desquamation may involve the entire body. High blood flow to the skin may disrupt temperature regulation or lead to high-output cardiac failure. Nails or hair may be shed. There may be a history of a drug eruption or a preexisting dermatosis. A careful examination may reveal typical lesions of psoriasis, stigmata of atopy, or “islands of sparing,” as seen in pityriasis rubra pilaris. Many cases show no distinguishing features. HISTOPATHOLOGIC FEATURES The histologic pattern varies with the underlying etiology. In those cases resulting from chronic or subacute spongiotic dermatitis, the histologic picture is nonspecific. A biopsy may show intercellular and

intracellular edema with exocytosis of mononuclear cells. Crusting may be present. The superficial dermis contains perivascular lymphocytic iniltrates and edema. Chronic changes are inversely related to the preceding. They consist of hyperkeratosis, parakeratosis, acanthosis, and papillary dermal fibrosis. In cases related to a primary inflammatory dermatosis, such as psoriasis or pityriasis rubra pilaris, the histologic pattern may still be recognizable70 but is usually less typical than in the primary disease. Cases of Sézary syndrome may show atypical, cerebriform lymphocytes in the epidermis with minimal associated spongiosis; however, fully developed Pautrier microabscesses are less common than in the plaque stage of mycosis fungoides. Drug eruptions may show atypical lymphocytes along the interface and within the epidermis, leading to confusion with mycosis fungoides. In a blinded retrospective study of erythrodermic patients, histologic impression correlated with final diagnosis in up to 66% of cases. The authors suggest that multiple biopsies taken simultaneously may improve diagnostic accuracy.71

Pityriasis Rosea Pityriasis rosea (PR) is a self-limited exanthematous eruption of unknown etiology. However, there is some evidence that it is infectious. Recent work has shown an association with human herpesvirus (HHV)-7 and to a lesser extent, HHV-6 infection.72 There is a seasonal variation, with an increased incidence in the fall.73 Cases are often clustered,74 recurrence is unusual, and passive transfer of immunity has been demonstrated.75 Patients are usually in the first to fourth decades of life, and there is a slight female preponderance. Drugs may induce a similar eruption, particularly captopril76 and gold.77 Although PR is clinically a papulosquamous eruption, the histologic appearance is fundamentally that of spongiotic dermatitis, reviewed in Chap. 2. CLINICAL FEATURES The classic presentation is that of a single larger initial lesion known as the herald patch or mother patch. There may be a prodrome consisting of coryza, fever, and malaise. A secondary, more diffuse eruption appears 1 to 3 weeks after the initial lesion. Both the primary and the secondary lesions are oval orange-brown- or salmon-colored patches distributed on the upper trunk and proximal extremities. Individual lesions show a collarette of trailing scale. The long axis of lesions follows the lines of skin cleavage

CHAPTER 4 ■ PSORIASIFORM DERMATITIS

CLINICAL FEATURES Lesions of the spongiotic reaction pattern have a similar clinical appearance regardless of etiology. Acute lesions show poorly defined pruitic, erythematous, edematous patches studded with vesicles. Subacute lesions show secondary changes of excoriation and crust formation, often with impetiginization. In chronic lesions, the edema and vesiculation are replaced by lichenification, scaling, and dyschromia. The clinical distribution of spongiotic dermatitis may offer clues to the specific etiology. Briefly, allergic contact dermatitis occurs at the site of antigen contact and may be patterned. It is uncommon on the thick skin of the palms and soles but may affect the dorsa of the hands and feet. Atopic dermatitis typically involves the flexures and occurs in people with a personal or family history of asthma or allergic rhinitis. Spongiotic systemic drug eruptions are unusual, but when they do occur, they are typically diffuse or photodistributed. Seborrheic dermatitis involves the central face, scalp, ears, upper chest, axillae, and groin. Lesions of nummular dermatitis are symmetrically distributed on the extremities as small, round plaques. Dyshidrotic dermatitis is characterized by vesicles along the margins of the digits and on the palms and soles.

In chronic atopic dermatitis, one sees a pattern indistinguishable from lichen simplex chronicus except that eosinophils are more common in the former. Dyshidrotic dermatitis shows spongiotic vesicles on acral skin. Neutrophils may be present in older vesicles. Allergic contact dermatitis may show intraepidermal spongiotic vesicles containing Langerhans cells and lymphocytes. Eosinophils are uncommon in allergic contact dermatitis. Seborrheic dermatitis shows follicular plugging, focal spongiosis, hemorrhage, and neutrophils within perifollicular parakeratotic scale/ crust. Vesicular dermatophyte infections show small collections of neutrophils within the stratum corneum. Hyphae may be recognized in hematoxylin and eosin (H&E)-stained sections as small holes in the stratum corneum. Fungal stains confirm the diagnosis. Dyshidrotic dermatitis may be pustular but can be distinguished from pustular psoriasis of the palms and soles by the presence of more extensive spongiosis and the absence of intracorneal collections of neutrophils (Munro microabscesses) in the former.

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PART I ■ INFLAMMATORY REACTIONS IN THE SKIN

(Langer lines) such that the pattern on the back has been compared with a Christmas tree. Less common patterns include flexural (inverse), papular, and purpuric PR. The clinical differential diagnosis includes secondary syphilis, nummular eczema, dermatophytosis, guttate psoriasis, and drug eruptions.

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HISTOPATHOLOGIC FEATURES Lesional skin shows mounding parakeratosis with underlying hypogranulosis, spongiosis, lymphocytic exocytosis, and extravasation of erythrocytes, sometimes extending into the epidermis (Fig. 4-16). There may be spongiotic microvesicles and irregular acanthosis. The superficial dermis contains a patchy, predominantly lymphocytic infiltrate, and the epidermis may contain dyskeratotic cells.78 DIFFERENTIAL DIAGNOSIS In PR, dermal papillae are not as elongated as in psoriasis, and neutrophils are not usually present. Spongiosis and lymphocytic exocytosis are more focal than in chronic spongiotic dermatitis, sometimes resembling Pautrier microabscesses. The eosinophils found in nummular dermatitis are usually absent in PR. Large-plaque parapsoriasis shows less spongiosis and a tendency for lymphocytes to line the dermal-epidermal junction. Plasma cells and endothelial swelling suggest syphilis. The superficial form of erythema annulare centrifugum is indistinguishable from PR.

Chronic Candidiasis and Dermatophytosis Dermatophytosis and candidiasis represent superficial fungal infections of the skin and its appendages. Infection is limited to the nonviable cornified components, including the hair, nails, and stratum corneum. Host factors are important in the development of clinical infection and the subsequent course of disease. Atopic patients,79 in whom IgE-mediated type I hypersensitivity response may inhibit delayed-type hypersensitivity, are susceptible to dermatophytosis. These infections are considered in greater detail in Chap. 21. CLINICAL FEATURES Chronic dermatophytosis may involve the glabrous skin (tinea corporis), palms and soles (tinea manuum and pedis), or nails (tinea unguium, onychomycosis). Tinea corporis is characterized by annular, scaly, erythematous plaques with central clearing. Lesions may be psoriasiform with abundant scale. On the feet or hands, chronic infection presents as thick, hyperkeratotic scale with minimal inflammation. Involvement of the thick stratum corneum of the hands or feet produces a glove- or moccasin-like pattern. Some patients may have involvement of both feet and one hand. Although candidiasis in otherwise healthy individuals is restricted to the intertriginous areas,

 FIGURE 4-16 Pityriasis rosea. The lesion exhibits focal parakeratosis and psoriasiform epidermal hyperplasia.

chronic mucocutaneous candidiasis may be more extensive, involving the scalp and acral skin. Lesions are often hyperkeratotic or granulomatous rather than the more typical erosive, erythematous, or pustular lesions seen in acute infection. Patients with chronic mucocutaneous candidiasis have an immune deficiency. HISTOPATHOLOGIC FEATURES In acute infections with dermatophytes or Candida species, the epidermis is spongiotic with focal parakeratosis. With chronicity, the epidermis becomes acanthotic with elongation of rete ridges. There may be aggregates of neutrophils within the parakeratotic scale or in subcorneal pustules resembling the spongiform pustules of Kogoj. Demonstration of organisms within the stratum corneum is diagnostic. The organisms are found in the nonviable, cornified components of the epidermis and its appendages, but they are sparse and may not be visible on routinely stained sections. Fungi may be visualized better in sections stained with PAS stain following diastase predigestion or with the methenamine silver stain. Typically, organisms may be found between an orthokeratotic layer and a parakeratotic layer (“sandwich sign”).80

Mycosis Fungoides (Cutaneous T-Cell Lymphoma) Mycosis fungoides (MF) is a T-cell lymphoma that primarily affects the skin.81 It is considered in detail in Chap. 34 but is included here because it may mimic nearly all patterns of inflammatory dermatoses, including psoriasiform dermatitis.82,83 CLINICAL FEATURES Classically, mycosis fungoides evolves through several stages. The patch stage is characterized by large, erythematous, scaly patches usually located on the trunk and proximal extremities. Lesions tend to be chronic, asymptomatic, and unresponsive to treatment. There may be dyschromia, epidermal atrophy, and telangiectasia (poikiloderma). The patch stage may persist for years, with an average of 6.1 years between the onset of disease and the ultimate diagnosis.84 Thickened plaques may develop from existing lesions or arise on previously unaffected skin. Plaques may be arcuate or annular as the result of coalescence or central clearing. They may have abundant scale resembling psoriasis. The development of cutaneous tumors is correlated with a poor prognosis, with a mean survival of 2.5 years.84 Plaques and tumors have a tendency to ulcerate and may become secondarily infected.

Sézary syndrome represents the leukemic phase of the disease, presenting as erythroderma with constitutional symptoms. Sézary syndrome must be distinguished clinically from other causes of erythroderma, such as pityriasis rubra pilaris, psoriasis, drug eruptions, and widespread spongiotic dermatitis.

DIFFERENTIAL DIAGNOSIS Because the earliest changes of MF are subtle and may mimic inflammatory dermatoses, multiple specimens taken over time may be necessary to establish the diagnosis. MF and psoriasis both show epidermal

A

Scabies Scabies infestation is a pruritic communicable disease caused by infestation by the human scabies mite, Sarcoptes scabiei var. hominis. The itch results from sensitization to the mite or its products and subsequent cell-mediated immune response. The mite is usually transmitted by direct contact with infested individuals or, less commonly, by fomites. Mites may survive away from the human host for several days.89 After mating, the female mite burrows into the superficial layers of the skin and lays her eggs. The female dies after about 5 weeks; the eggs hatch, and the cycle repeats.90 Typically, a patient is infested with only 10 to 15 adult mites,91 making demonstration and diagnosis occasionally difficult. In crusted scabies, however, mites are much more numerous.92 This clinical pattern is seen

in incapacitated, immunosuppressed, or institutionalized patients. CLINICAL FEATURES Scabies infestation is pruritic, particularly at night. Sites of predilection include the web spaces of fingers and toes, wrists, flexures, elbows, and male genitals. The diagnostic lesion is a linear burrow with a tiny vesicle at the blind end. Although there are typically few mites, intense pruritus and scratching may produce widespread secondary lesions. Areas of excoriation, irritant dermatitis, lichenification, or secondary infection are common.93 In crusted scabies, one sees hyperkeratotic or psoriasiform papules and plaques. The eruption may be diffuse, presenting as erythroderma. Because mites are numerous, these patients are highly contagious. Testing for human immunodeficiency virus (HIV) may be appropriate in patients with crusted scabies.94 Nodular scabies represents a persistent hypersensitivity response, as seen in other arthropod assaults (Fig. 4-17 A). HISTOPATHOLOGIC FEATURES The epidermis shows irregular acanthosis and focal spongiosis (Fig. 4-17). There may be a space within or just underneath the stratum corneum corresponding to the clinical burrow. The end of the burrow extends into the superficial stratum malpighii.95 Step sections may reveal the female mite or its products, including eggs or fecal material (scabala). The dermis contains a superficial and deep perivascular or nodular infiltrate composed of lymphocytes and variable numbers of eosinophils (sometimes producing flame figures). The infiltrate in

CHAPTER 4 ■ PSORIASIFORM DERMATITIS

HISTOPATHOLOGIC FEATURES The histologic findings of mycosis fungoides vary with the clinical stage of the disease. Biopsies of infiltrated plaques show epidermal hyperplasia with elongation of the rete ridges resembling psoriasis. However, there are atypical lymphocytes in both the epidermis and the dermis. The epidermotropic lymphocytes may be single, in small aggregates (Pautrier microabscesses), or in a diffuse pattern resembling Paget disease. Adnexal epithelium may be similarly involved,62 and the pattern of epidermotropism may be limited to follicular epithelium85 or eccrine glands.86 These lymphocytes may show hyperchromatic, cerebriform nuclei and may be surrounded by clear halos. Similar cells may line the dermal-epidermal junction with vacuolar change of basal keratinocytes, the so-called “sentinel sign.” The papillary dermis shows random irregular fibrosis. Lymphocytes in the superficial dermis are also surrounded by clear halos.

hyperplasia and a superficial infiltrate composed of lymphocytes. Features favoring MF include irregular papillary dermal fibrosis and epidermotropism of atypical lymphocytes. Features favoring psoriasis include papillary dermal edema with dilated, tortuous capillaries and neutrophils within the stratum corneum. MF also may resemble chronic dermatitis. Inflammatory dermatoses may show some atypical cells, but the irregularity of nuclear contour, as determined by image analysis, is not as great as in MF.87 Although spongiosis may be seen in MF, it is mild compared with the number of lymphocytes within the epidermis. Drug eruptions, particularly those due to anticonvulsants, may simulate MF.88

B

 FIGURE 4-17 Scabies. (A) Nodular scabies. Erythematous firm nodules indistinguishable from chronic arthropod bite reactions. (B) Crusted scabies. The epidermis shows psoriasiform epidermal hyperplasia. The exoskeleton of two mites can be observed in the lower stratum corneum.

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nodular lesions may have the picture of lymphocytoma cutis and may contain atypical lymphocytes suggesting lymphoma.96 In crusted (Norwegian) scabies, mites are usually numerous and easily identified within a greatly thickened stratum corneum.97 Mites or their products are diagnostic. A nodular dermal infiltrate with eosinophils is not seen in other psoriasiform dermatitides.

PART I ■ INFLAMMATORY REACTIONS IN THE SKIN

Inflammatory Linear Verrucose (Verrucous) Epidermal Nevus Epidermal nevi are hamartomas of the epidermis or its appendages and are considered in detail in Chap. 26. Briefly, epidermal nevi may represent a mosaic state of disorders of cornification. For example, the acantholytic dyskeratotic variant may represent a localized form of Darier disease (keratosis follicularis), and the epidermolytic variant may represent localized epidermolytic hyperkeratosis, a disorder of keratins 1 or 10.98 Inflammatory linear verrucose epidermal nevus (ILVEN) was described as a distinct entity in 1971.99 Most cases are sporadic, but familial cases have been described.100 CLINICAL FEATURES ILVEN consists of grouped or coalescent lichenoid, psoriasiform, or verrucous papules in a linear arrangement, most commonly on the lower extremities. Fifty percent are

present by 6 months of age and seventyfive percent by 5 years of age.99 Lesions follow the lines of Blaschko,98 are pruritic, and may wax and wane in intensity. Associated skeletal malformations occur in some cases.101 HISTOPATHOLOGIC FEATURES The classic histopathologic finding of ILVEN consists of broad columns of parakeratosis without an underlying granular layer, alternating in the horizontal direction with columns of compact hyperkeratosis with underlying hypergranulosis102 (Fig. 4-18). Rete ridges are thickened and elongated with occasional slight spongiosis.99 Exocytosis of neutrophils as in psoriasis may occur. The superficial dermis contains a predominantly perivascular lymphocytic infiltrate. DIFFERENTIAL DIAGNOSIS The clinical differential diagnosis includes other linear papulosquamous lesions, such as linear psoriasis, linear Darier disease, linear porokeratosis, lichen striatus, and noninflammatory linear epidermal nevi. At the histological level, suprapapillary plates are thickened in ILVEN, whereas they are usually thinned in psoriasis. Parakeratosis in psoriasis is diffuse rather than arrayed in the broad columns of ILVEN. Linear Darier disease shows acantholysis and dyskeratosis. Porokeratosis is characterized by cornoid lamellae. Ordinary epidermal nevi show papillomatosis and are not inflammatory.

Bazex Syndrome Bazex syndrome (acrokeratosis neoplastica) is a paraneoplastic syndrome characterized by psoriasiform skin lesions in association with internal malignancy. Bullous lesions are also reported.103 A review of 113 cases found the most common neoplasm to be squamous cell carcinoma of the upper aerodigestive tract. Patients had a mean age of 61 years with a striking male predominance (108 of 113 patients).104 The pathogenesis may be related to a shared antigen between the neoplasm and normal skin or to tumor production of keratinocyte growth factors. An unrelated X-linked disorder showing follicular atrophoderma on the dorsal hands and feet, hypotrichosis, hypohidrosis, and basal cell carcinomas also carries the eponym Bazex syndrome (Bazex-Dupre-Christol syndrome).105 CLINICAL FEATURES Acrokeratosis neoplastica is a symmetrical psoriasiform eruption affecting acral areas, including hands and feet, ears, and nose. Nail involvement is common, with periungual and subungual hyperkeratosis and shedding of the nail plate. Lesions are distinctly violaceous and often resistant to treatment. Commonly the skin changes precede the diagnosis of internal malignancy. Treatment of the underlying malignancy reverses the skin changes but not the nail changes. Relapse of skin lesions may herald tumor recurrence.104 HISTOPATHOLOGIC FEATURES The histopathologic pattern is nonspecific. In addition to psoriasiform epidermal hyperplasia, keratinocytes may show vacuolar change and nuclear pyknosis.106

Pellagra

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 FIGURE 4-18 Inflammatory linear verrucose epidermal nevus. The epidermis shows psoriasiform epidermal hyperplasia with alternating hyperkeratosis and parakeratosis.

Pellagra results from a systemic deficiency of niacin (nicotinic acid) or its precursor, the essential amino acid tryptophan. The disease is characterized by the three D’s—diarrhea, dementia, and dermatitis. It was thought to be infectious until the remarkable work of Joseph Golberger.107 One hypothesis holds that the clinical manifestations may be caused by increased extracellular matrix viscosity.108 In this model, cutaneous lesions are localized to areas of sun exposure and trauma because “mediators” cannot diffuse from the site. Increased viscosity in the gastrointestinal tract may limit absorption leading to diarrhea.

Niacin deficiency also may occur in the carcinoid syndrome, where tryptophan is converted in quantity into serotonin (5-OH tryptophan). Hartnup disease is an autosomal recessive disorder characterized by an impairment of neutral amino acid transport. Tryptophan is not absorbed from the diet and is lost in the urine, leading to a deficiency of niacin.109 Regardless of the cause of niacin deficiency, the signs and symptoms respond promptly to replacement therapy.

HISTOPATHOLOGIC FEATURES The histopathologic features of pellagra are essentially identical to those seen in acrodermatitis enteropathica, necrolytic migratory erythema, essential fatty acid deficiency, and various nutritional disorders. They consist of extensive parakeratosis with underlying irregular epidermal hyperplasia. There is a pallor of the upper epidermis representing diffuse superficial keratinocyte necrosis. There may be a superficial perivascular lymphocytic infiltrate. A rash produced by a topical anesthetic demonstrated similar histology.110

CLINICAL FEATURES The hereditary form of zinc deficiency (ie, acrodermatitis enteropathica) develops earlier in bottlefed as opposed to breast-fed infants. As the name implies, the eruption typically starts as eczematous, scaly plaques on acral skin, including the scalp, paronychial folds, and perineum. Lesions may be erosive, pustular, or bullous, and secondary infection with Candida or bacteria is common. There may be failure to thrive. There may be alopecia or alternating light and dark banding of hair, which may be observed with polarizing light microscopy.114 HISTOPATHOLOGIC FEATURES Early lesions show continuous parakeratotic scale overlying a zone of normal stratum corneum. The epidermis is verrucous with pallor of the superficial malpighian layer and extensive necrosis of individual keratinocytes. Chronic lesions show psoriasiform epidermal hyperplasia with overlying hyperkeratosis and parakeratosis (Fig. 4-19). The superficial dermis contains a mild perivascular lymphocytic infiltrate. Bullous lesions show intraepidermal vacuolar change and ballooning degeneration associated with

extensive epidermal necrosis without acantholysis.115

Glucagonoma Syndrome Glucagon-producing islet cell (alpha cell) tumors of the pancreas are associated with necrolytic migratory erythema.116 The cutaneous manifestations may be related to a hypoaminoacidemia or to the high levels of glucagon itself. Diagnosis is made by demonstrating increased levels of glucagon in patients with the typical syndrome. Removal of the pancreatic tumor is curative. Necrolytic migratory erythema also may occur without glucagonoma117 in association with hepatocellular dysfunction and hypoalbuminemia.118 CLINICAL FEATURES The eruption is periorificial, acral, and flexural, often with severe glossitis. Lesions begin as erythematous papules. Later there are superficial vesicular lesions, erosions, crusting, and fissuring. Older lesions may be psoriasiform.119 Secondary infection with Candida and bacteria is common. Noncutaneous findings include stomatitis, weight loss, glucose intolerance, and diarrhea. HISTOPATHOLOGIC FEATURES Specimens are characterized by psoriasiform epidermal hyperplasia with confluent parakeratosis. There is pallor of the superficial epidermis with dyskeratotic keratinocytes. The pallor may result from intracellular edema.120 In more acute lesions, necrosis may be extensive, producing an intraepidermal

CHAPTER 4 ■ PSORIASIFORM DERMATITIS

CLINICAL FEATURES In addition to the gastrointestinal symptoms (diarrhea) and neurologic disease, there is a characteristic skin eruption. Lesions are symmetrical and involve sun-exposed skin and areas of pressure. There are first erythema and burning or itching. Early lesions may be bullous. Later the eruption is characterized by hyperpigmentation, scaling, and fissuring. Facial involvement may simulate the “butterfly” eruption of lupus erythematosus. The limitation to sun-exposed sites may be striking, with extremity involvement showing a glove or stocking distribution. Involvement of the neck by a sharply demarcated photoinduced rash has been termed Casal necklace.

infants.111 As with the inherited form, dietary deficiency is quickly and completely reversed by supplementation with oral or parenteral zinc salts. The defective gene, SLC39A4, which encodes a zinc transporter named Zip4 has recently been described.112,113

Acrodermatitis Enteropathica Acrodermatitis enteropathica is an autosomal recessive disease caused by a defect in dietary zinc absorption. The defect is not complete, in that the disease may be reversed by zinc supplementation. Identical symptoms also may be produced by a diet deficient in zinc. Causes of noninherited zinc deficiency are numerous and include chronic diarrhea of any etiology, inadequate dietary content as in alcoholism or crash dieting, or renal loss as in dialysis. Also, chronic diseases with an increased catabolic rate may lead to zinc deficiency. Breast milk may have a low concentration of zinc, leading to zinc deficiency in breast-fed

 FIGURE 4-19 Acrodermatitis enteropathica.This well-developed lesion displays confluent parakeratosis, absence of the granular layer, and psoriasiform epidermal hyperplasia.

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bulla. Subcorneal pustules have been noted either in association with epidermal necrosis or as an isolated finding.121 There is a superficial perivascular lymphocytic infiltrate with papillary dermal edema. This condition also has been reported to show extensive suprabasilar acantholysis.122

PART I ■ INFLAMMATORY REACTIONS IN THE SKIN

Secondary Syphilis Syphilis is a venereal disease caused by Treponema pallidum. This and other treponemal infections are considered in detail in Chap. 20. Secondary syphilis is reviewed briefly here because it may present as generalized psoriasiform lesions. As in psoriasis, the palms and soles may be involved. Mucosal lesions include condylomata lata, which are mamillated or papillomatous whitish papules or plaques. The clinical differential diagnosis of secondary syphilis includes guttate psoriasis, pityriasis rosea, tinea corporis, tinea versicolor, and nummular eczema. HISTOPATHOLOGIC FEATURES The papulosquamous lesions of secondary syphilis may show psoriasiform hyperplasia and hyperkeratosis, associated with exocytosis of neutrophils that accumulate in the scale-crust. The dermis shows a superficial and deep perivascular123 infiltrate composed of lymphocytes and plasma cells. Endothelial cells may be swollen, protruding into vascular lumina. The lichenoid pattern is more common than the psoriasiform pattern in secondary syphilis. DIFFERENTIAL DIAGNOSIS The inflammatory infiltrate of psoriasis, chronic dermatitis, and dermatophytosis is uniformly superficial rather than deep and does not contain plasma cells. Mycosis fungoides may have a superficial and deep infiltrate as well as a lichenoid pattern. However, the presence of atypical lymphocytes,124 Pautrier microabscesses, and a variable number of eosinophils distinguishes it from syphilis. Serological testing allows definitive diagnosis in syphilis.

Bowen Disease

78

Bowen disease, originally described in 1912,125 is a squamous cell carcinoma in situ. Although not a dermatitis, Bowen disease is included here because it may show psoriasiform epidermal thickening. Lesions arise more commonly on sun-exposed than covered skin, usually in patients older than 60 years of age.126 Bowen disease presents as a long-standing, fairly well-circumscribed, scaly, erythematous plaque. Lesions are usually solitary but may be multiple. Thus, Bowen

disease clinically may resemble papulosquamous dermatoses. HISTOPATHOLOGIC FEATURES Overall, the neoplasm is poorly circumscribed and asymmetrical. The epidermis is thickened with elongated rete ridges and may be papillomatous, resembling seborrheic keratosis in silhouette. The granular layer is absent with broad, thick overlying parakeratosis, which may form a cutaneous horn. Keratinocytes show marked atypia, lack of maturation, and individual cell dyskeratosis. Large, atypical cells with ample glycogen-containing cytoplasm may be distributed singly in a pagetoid pattern or in clusters among normal keratinocytes. This pattern may involve adnexal epithelium, particularly follicular infundibula.127 The superficial dermis often shows extensive solar elastosis and a perivascular lymphocytic infiltrate. At low power, the presence of parakeratosis, a thickened epidermis, and superficial dermal inflammation may suggest psoriasis. However, the presence of full-thickness keratinocyte atypia and lack of maturation define Bowen disease as a neoplasm and exclude inflammatory causes of psoriasiform epidermal changes.

Clear Cell Acanthoma Clear cell acanthoma (CCA, Degos acanthoma, pale cell acanthoma) is included here because it may show psoriasiform epidermal changes. A study of keratin expression found a pattern similar to that seen in inflammatory dermatoses such as psoriasis, and the authors speculate that CCA is an inflammatory dermatosis rather than a neoplasm.128 Another recent study lends support to CCA being a psoriasiform reaction pattern often occuring in the setting of chronic inflammation such as stasis dermatitis or a scar.129 The process is uncommon and most often occurs in adults. CCA is usually solitary but may be multiple.130 It is located most commonly on the extensor aspect of the leg. The typical presentation is a redbrown papule with a somewhat eroded surface. Lesions share clinical features with irritated seborrheic keratoses and pyogenic granuloma.131 HISTOPATHOLOGIC FEATURES CCA has the silhouette of a benign epidermal neoplasm in that it is well circumscribed, symmetrical, and sharply demarcated from the surrounding uninvolved skin. The granular layer is absent, and the surface may show hyperkeratosis, parakeratosis, or erosion. Rete ridges are elongated and interconnected in an anastomosing pattern.

Keratinocytes contain ample pale-staining cytoplasm, except for the basal layer, acrosyringia, and acrotrichia, which are spared. The pale-staining pattern represents accumulation of glycogen, which is PAS-positive and diastase-labile. Throughout the lesion are numerous neutrophils in association with spongiosis. Neutrophils may extend into the stratum corneum, forming microabscesses132 resembling psoriasis. The papillary dermis between elongated, interconnected rete ridges often is edematous with dilated capillaries and a perivascular lymphocytic infiltrate.

Lamellar Ichthyosis Lamellar ichthyosis (LI) is an autosomal recessive disorder of cornification distinct from nonbullous congenital ichthyosiform erythroderma.133 Affected individuals may be born encased in a colloidion membrane that is shed in the first 2 weeks of life. There is a lifelong thick scale over the entire body. This represents a retention hyperkeratosis rather than a hyperproliferative process. Palms and soles are hyperkeratotic, and the eyelids and lips are often everted (ectropion and eclabium). The disease has been attributed to a mutation in the gene for transglutaminase 1134 leading to defective cross-links required for normal cell envelope production with resulting permeability barrier abnormality.135 HISTOPATHOLOGIC FEATURES The histologic pattern of lamellar ichthyosis is nonspecific. In addition to irregular acanthosis, there is striking compact hyperkeratosis without parakeratosis.136 This pattern reflects the fact that LI is a retention hyperkeratosis rather than a hyperproliferative disorder. The granular layer may be thickened or thinned.137 Because LI is a genodermatosis rather than an inflammatory dermatosis, it is usually noninflammatory.

REFERENCES 1. Ackerman AB. Histologic Diagnosis of Inflammatory Skin Diseases. Philadelphia, PA: Lea and Febiger; 1978. 2. Farmer ER, Hood AF. Pathology of the Skin. East Norwalk, CT: Appleton and Lange; 1990. 3. Pinkus H. Psoriasiform tissue reactions. Aust J Dermatol. 1965;3:31-35. 4. Pinkus H, Mehregen AH. A Guide to Dermatohistopathology. East Norwalk, CT: Appleton Lange; 1976. 5. Henseler T, Christophers E. Psoriasis of early and late onset: characterization of two types of psoriasis vulgaris. J Acad Dermatol. 1985;13:450-458.

27. Gordon M, Johnson WC. Histopathology and histochemistry of psoriasis: I. The active lesion and clinically normal skin. Arch Dermatol. 1967;95:402. 28. Cox AJ, Watson W. Histologic variation in lesions of psoriasis. Arch Dermatol. 1972;106:503. 29. Ragaz A, Ackerman AB. Evolution, maturation, and regression of lesions of psoriasis. Am J Dermatopathol. 1979;1:199-214. 30. Pinkus H, Mehregan AH. The primary histologic lesion of seborrheic dermatitis and psoriasis. J Invest Dermatol. 1966;46:109–116. 31. Braun-Falco O, Christophers E. Structural aspects of initial psoriatic lesions. Arch Dermatol Res. 1974;251:95. 32. Tsankov N, Angelova I, Kazandjieva J. Drug-induced psoriasis. recognition and management. Am J Clin Dermatol. 2000;1:159-165. 33. Baker H, Ryan TJ. Generalized pustular psoriasis: a clinical and epidemiological study of 104 cases. Br J Dermatol. 1968;80:771. 34. Wagner G, Luckasen JR, Goltz RW. Mucous membrane involvement in generalized psoriasis. Arch Dermatol. 1976;112:1010-1014. 35. Zelickson B, Muller S. Generalized pustular psoriasis: a review of 63 cases. Arch Dermatol. 1991;127:1339-1345. 36. Shelly WB. Generalized Pustular Psoriasis: Consultations in Dermatology. Philadelphia, PA; Saunders: 1972. 37. Rupec M. Zur ultrastruktur der spongiformen pustel. Arch Klin Exp Dermatol. 1970;239:30-49. 38. Spencer J, Silvers D, Grossman M. Pustular eruption after drug exposure: is it pustular psoriasis or a pustular drug eruption? Br J Dermatol. 1994;130:514-519. 39. Wilkins RF. Reiter’s syndrome: evaluation of preliminary criteria for definite diagnosis. Arthritis Rheum. 1981;24:844. 40. Engelman EP, Weber HM. Reiter’s syndrome. Clin Orthop. 1968;57:19. 41. Brewerton DA. Reiter’s disease and HLA 27. Lancet. 1973;2:996. 42. Granfors K. Yersinia antigens in synovial fluid cells from patients with reactive arthritis. New Engl J Med. 1989;320:216. 43. Beutler A, Whittum-Hudson J, Nanagara R, et al. Intracellular location of inapparently infecting Chlamydia in synovial tissue from patients with Reiter’s syndrome. Immunol Res. 1994;13:163-171. 44. Keat A. Reactive arthritis (review). Adv Exp Med Biol. 1999;455:201-206. 45. Petersel DL, Sigal LH. Reactive arthritis. Infect Dis Clin North Am. 2005;19:863-883. 46. Arnett FC. Incomplete Reiter’s syndrome: clinical comparison with the classical triad. Ann Rheumatol Dis. 1979;38:73. 47. Kulka JP. The lesions of Reiter’s syndrome. Arthritis Rheum. 1962;5:195. 48. Griffiths WAD. Pityriasis rubra pilaris. Clin Exp Dermatol. 1980;5:105. 49. Gross DA, Landau JW, Newcomer VD. Pityriasis rubra pilaris: report of a case and analysis of the literature. Arch Dermatol. 1969;99:710. 50. Vanderhooft SL, Francis JS, Holbrook KA, et al. Familial pityriasis rubra pilaris. Arch Dermatol. 1995;131:448-453. 51. Porter D, Shuster S. Epidermal renewal and amino acids in psoriasis and pityriasis rubra pilaris. Arch Dermatol. 1968; 98:339.

52. Sonex TS. Nail changes in adult type I pityriasis rubra pilaris. J Am Acad Dermatol. 1986;15:956. 53. Albert MR, Mackool BT. Pityriasis rubra pilaris. Int J Dermatol. 1999;38:1-11. 54. Gonzalez-Lopez A, Velasco E, Pozo T, Del Villar A. HIV-associated pityriasis rubra pilaris responsive to triple antiretroviral therapy. Br J Dermatol. 1999;140: 931-934. 55. Soeprono FF. Histologic criteria for the diagnosis of pityriasis rubra pilaris. Am J Dermatopathol. 1986;8:277-283. 56. Magro CM, Crowson AN. The clinical and histomorphological features of pityriasis rubra pilaris: a comparative analysis with psoriasis. Cutan Pathol. 1997;24:416-424. 57. Goldblum RW, Piper WN. Artificial lichenification produced by a scratching machine. J Invest Dermatol. 1957;22: 405-415. 58. Neumann E, Winter V. The character of cells with “alteration cavitaire” (Leloir). Acta Dermatol Venereol. 1965;45:272-274. 59. Brocq L. Les parapsoriasis. Ann Dermatol Syphiligr. 1902;3:433. 60. Lambert WC, Everett MA. The nosology of parapsoriasis. J Am Acad Dermatol. 1981;5:373. 61. Samman PD. The natural history of parapsoriasis en plaque (chronic superficial dermatitis) and prereticulotic poikiloderma. Br J Dermatol. 1972;87:405. 62. Sanchez JL, Ackerman AB. The patch stage of mycosis fungoides. Am J Dermatopathol. 1979;1:5-26. 63. Simon M, Flaig MJ, Kind P, et al. Large plaque parapsoriasis: clinical and genotypic correlations. J Cutan Pathol. 2000; 27:57-60. 64. Lindae ML. Poikilodermatous mycosis fungoides and atrophic large plaque psoriasis exhibit similar abnormalities of T-cell antigen expression. Arch Dermatol. 1988;124:366. 65. Staib G, Sterry W. Use of polymerase chain reaction in the detection of clones in lymphoproliferative diseases of the skin. Recent Results Cancer Res. 1995;139: 239-247. 66. Klemke CD, Dippel E, Dembinski A, et al. Clonal T cell receptor gammachain gene rearrangement by PCRbased GeneScan analysis in the skin and blood of patients with parapsoriasis and early-stage mycosis fungoides. J Pathol. 2002;197:348-354. 67. Kikuchi A, Naka W, Harada T, et al. Parapsoriasis en plaques: its potential for progression to malignant lymphoma. J Am Acad Dermatol. 1993;29: 419-422. 68. Ackerman AB, Ragaz A. A plea to expunge the word “eczema” from the lexicon of dermatology and dermatopathology. Am J Dermatopathol. 1982;4:315-326. 69. Botella-Estrada R, Sanmartin O, Oliver V, et al. Erythroderma: a clinicopathological study of 56 cases. Arch Dermatol. 1994;130:1503-1507. 70. Zip C, Murray S, Walsh NM. The specificity of histopathology in erythroderma. J Cutan Pathol. 1993;20:393-398. 71. Walsh N, Prokopetz R, Tron V, et al. Histopathology in erythroderma: review of a series of cases by multiple observers. J Cutan Pathol. 1994;21:419-423. 72. Broccolo F, Drago F, Careddu AM, et al. Additional evidence that pityriasis rosea is associated with reactivation of

CHAPTER 4 ■ PSORIASIFORM DERMATITIS

6. Cram DL. Psoriasis: current advances in etiology and treatment. J Am Acad Dermatol. 1981;4:1-14. 7. Weinstein GD. Autoradiographic analysis of turnover times of normal and psoriatic epidermis. J Invest Dermatol. 1968;45:257. 8. Farber EM, Nall ML, Watson W. Natural history of psoriasis in 61 twin pairs. Arch Dermatol. 1974;109:207. 9. Henseler T, Christophers E. Psoriasis of early and late onset: characterization of two types of psoriasis vulgaris. J Am Acad Dermatol. 1985;13:450-456. 10. Theeuwes M, Morhenn V. Allelic instability in the mitosis model and the inheritance of psoriasis (review). Am Acad Dermatol. 1995;32:44-52. 11. Zheng G, Thomson G, Pen Y. Allelic instability in mitosis can explain “genome imprinting” and other genetic phenomena in psoriasis. J Med Genet. 1994;51: 163-164. 12. Capon F, Munro M, Barker J, Trembath R. Searching for the major histocompatibility complex psoriasis susceptibility gene. J Invest Dermatol. 2002;118: 745-751. 13. Capon F, Trembath RC, Barker JN. An update on the genetics of psoriasis. Dermatol Clin. 2004;22:339-347. 14. Boehncke W, Sterry W, Hainzl A, et al. Psoriasiform architecture of murine epidermis overlying human psoriatic dermis transplanted onto SCID mice. Arch Dermatol Res. 1994;286:325-330. 15. Bata-Csorgo Z, Hammerberg C, Voorhees J, Cooper K. Intralesional Tlymphocyte activation as a mediator of psoriatic epidermal hyperplasia (review). J Invest Dermatol. 1995;105:89s-94s. 16. Creamer J, Barker J. Vascular proliferation and angiogenic factors in psoriasis. Clin Exp Dermatol. 1995;20:6-9. 17. Griffiths CE, Barker JN. Pathogenesis and clinical features of psoriasis. Lancet. 2007;370:263-271. 18. Leung D, Walsh P, Giorno R, Norris D. A potential role for superantigens in the pathogenesis of psoriasis. J Invest Dermatol. 1993;100:225-228. 19. Valdimarsson H, Baker B, Jonsdottir I, et al. Psoriasis: a T-cell-mediated autoimmune disease induced by streptococcal superantigens? (review). Immunol Today. 1995;16:145-149. 20. Farber EM, Nall ML. The natural history of psoriasis in 5600 patients. Dermatologica. 1974;148:1. 21. Whyte HJ, Baughmann RD. Acute guttate psoriasis and streptococcal infection. Arch Dermatol. 1964;89:350. 22. Telfer N, Chalmers R, Whale K, Colman G. The role of streptococcal infection in the initiation of guttate psoriasis. Arch Dermatol. 1992;128:39-42. 23. McFadden J, Valdimarsson H, Fry L. Cross-reactivity between streptococcal M surface antigen and human skin. Br J Dermatol. 1991;125:443-447. 24. Braverman JM, Cohen I, Black MM. Metabolic and ultrastructural studies in a patient with pustular psoriasis. Br J Dermatol. 1972;105:189. 25. Khalil FK, Keehn CA, Saeed S, et al. Verrucous psoriasis: a distinctive clinicopathologic variant of psoriasis. Am J Dermatopathol. 2005;27:204-207. 26. Ackerman AB, Ragaz A. The Lives of Lesions: Chronology in Dermatopathology. New York: Masson; 1984.

79

73.

74

75.

76.

PART I ■ INFLAMMATORY REACTIONS IN THE SKIN

77.

78.

79. 80. 81. 82.

83. 84.

85. 86.

87.

88.

89.

90. 91. 92.

80

human herpesvirus-6 and -7. J Invest Dermatol. 2005;124:1234-1240. Chuang T. Pityriasis rosea in Rochester, Minnesota, 1969 to 1978: a 10-year epidemiologic study. J Am Acad Dermatol. 1982;7:80. Bjornberg A, Hellgren L. Pityriasis rosea: a statistical, clinical, and laboratory investigation of 826 patients and matched healthy controls. Acta Dermatol Venereol. 1962;42(suppl 50):1. Salin RW. The treatment of pityriasis rosea with convalescent plasma, gamma globulin, and pooled plasma. Arch Dermatol. 1957;76:659. Wilkin JK, Kirkendall WM. Pityriasis rosea-like rash from Captopril. Arch Dermatol. 1982;118:186. Wilkinson SM, Smith AG, Davis MJ, et al. Pityriasis rosea and discoid eczema: doserelated reactions to treatment with gold. Ann Rheumatol Dis. 1992;51:881-884. Okamato H, Imamura S, Aoskima T. Dyskeratotic degeneration of epidermal cells in pityriasis rosea. Br J Dermatol. 1982;107:189-194. Jones HE. The atopic-chronic-dermatophytosis syndrome. Acta Dermatol Venereol. 1980;92(suppl):81. Gottlieb GJ, Ackerman AB. The “sandwich sign” of dermatophytosis. Am J Dermatopathol. 1986;8:347-350. Willemze R, Jaffe ES, Burg G, et al. WHOEORTC classification for cutaneous lymphomas. Blood. 2005;105:3768-3785. Shapiro P, Pinto F. The histologic spectrum of mycosis fungoides/Sezary syndrome (cutaneous T-cell lymphoma): a review of 222 biopsies, including newly described patterns and the earliest pathologic changes. Am J Surg Pathol. 1994;18:645-667. Reddy K, Bhawan J. Histologic mimickers of mycosis fungoides: a review. J Cutan Pathol. 2007;34:519-525. Epstein EHJ. Mycosis fungoides: survival, prognostic factors, response to therapy, and autopsy findings. Medicine. 1972;51:61. Goldenhersh M, Zlotogorski A, Rosenmann E. Follicular mycosis fungoides. Am J Dermatopathol. 1994;16:52-55. Zelger B, Sepp N, Weyrer K, et al. Syringotropic cutaneous T-cell lymphoma: a variant of mycosis fungoides? Br J Dermatol. 1994;130:756-769. McNutt NS, Crain WR. Quantitative electron microscopic comparison of lymphocyte nuclear contours in mycosis fungoides and benign infiltrates in the skin. Cancer. 1981;47:698. Rijlaarsdam U, Scheffer E, Meijer CJ, et al. Mycosis fungoides-like lesions associated with phenytoin and carbamazepine therapy. J Am Acad Dermatol. 1991;24:216-220. Arlian LG. Prevalence of Sarcoptes scabiei in the homes and nursing homes of scabietic patients. J Am Acad Dermatol. 1988;19:806. Molinaro MJ, Schwartz RA, Janniger CK. Scabies. Cutis. 1995;56:317-321. Commons CA. We can get rid of scabies: new treatment available soon. Med J Aust. 1994;160:317-318. Sierra G, Ruis F, Romeu J. Hospital outbreak of scabies stemming from two AIDS patients with Norwegian scabies. Lancet. 1990;335:1227.

93. O’Donnell BF, O’Loughlin S, Powell FC. Management of crusted scabies. Int J Dermatol 1990;29:258-266. 94. Schlesinger I, Oelrich DM, Tyring SK. Crusted (Norwegian) scabies in patients with AIDS: the range of clinical presentations. South Med J. 1994;87:352-356. 95. Hejazi N, Mehregen AH. Histologic study of inflammatory lesions. Arch Dermatol. 1975;111:37-39. 96. Thomson J, Cochrane T, Cochran R. Histology simulating reticulosis in nodular scabies. Br J Dermatol. 1974;90: 421-429. 97. Fernandez N, Torres A, Ackerman AB. Pathological findings in human scabies. Arch Dermatol. 1977;113:320-324. 98. Bolognia JL, Orlow SJ, Glick SA. Lines of Blaschko. J Am Acad Dermatol. 1994; 31:157-190. 99. Altman L, Mehregan AH. Inflammatory linear verrucose epidermal nevus. Arch Dermatol. 1971;104:385-389. 100. Goldman K, Don PC. Adult onset of inflammatory linear verrucous epidermal nevus in a mother and her daughter. Dermatology. 1994;189:170-172. 101. Golitz LE, Weston WL. Inflammatory linear verrucose epidermal nevus. Arch Dermatol. 1979;115:1208-1212. 102. Dupre A, Christol B. Inflammatory linear verrucose epidermal nevus. Arch Dermatol. 1977;113:767-769. 103. Mutasim DF, Meiri G. Bazex syndrome mimicking a primary autoimmune bullous disorder. J Am Acad Dermatol. 1999;40:822-825. 104. Bolognia JL. Bazex syndrome: acrokeratosis paraneoplastica. Semin Dermatol. 1995;14:84-89. 105. Plosila M, Kustala R, Niemi KM. Bazex syndrome: follicular atrophoderma with multiple basal cell carcinomas, hypotrichosis, and hypohidrosis. Clin Exp Dermatol. 1981;6:31. 106. Pecora AL, Landsman L, Imgrund SP. Acrokeratosis neoplastica (Bazex syndrome). Arch Dermatol. 1983;120: 820-826. 107. Elmore JG, Feinstein AR. Joseph Goldberger: an unsung hero of American clinical epidemiology. Ann Intern Med. 1994;121:372-375. 108. Stone OJ. Pellagra: increased viscosity of extracellular matrix. Med Hypoth. 1993;40:355-359. 109. Halvorsen K, Halvorsen S. Hartnup disease. Pediatrics. 1963;31:565. 110. Dong H, Kerl H, Cerroni L. EMLA cream-induced irritant contact dermatitis. J Cutan Pathol. 2002;29:190-192. 111. Lee MG. Transient symptomatic zinc deficiency in a full term breast fed infant. J Am Acad Dermatol. 1990;23:375-379. 112. Kury S, Dreno B, Bezieau S, et al. Identification of SLC39A4, a gene involved in acrodermatitis enteropathica. Nature Genet. 2002;31:239-240. 113. Maverakis E, Fung MA, Lynch PJ, et al. Acrodermatitis enteropathica and an overview of zinc metabolism. J Am Acad Dermatol. 2007;56:116-124. 114. Traupe H. Polarizing microscopy of hair in AE. Pediatr Dermatol. 1986;3:300. 115. Borroni G, Brazzelli V, Vignati G, et al. Bullous lesions in acrodermatitis enteropathica: histopathologic findings regarding two patients. Am J Dermatopathol. 1992;14:304-309.

116. Mallinson CN, Bloom SR, Warin AP, et al. A glucagonoma syndrome. Lancet. 1974; 2:1-5. 117. Thivolet J. Necrolytic migratory erythema without glucagonoma. Arch Dermatol. 1981;117:4. 118. Marinkovich MP, Botella R, Datloff J, Sangueza OP. Necrolytic migratory erythema without glucagonoma in patients with liver disease. J Am Acad Dermatol. 1995;32:604-609. 119. Kahan RS, Perez-Figaredo RA, Neimanis A. Necrolytic migratory erythema. Arch Dermatol. 1977;113:792-797. 120. Sweet R. A dermatosis specifically associated with a tumor of pancreatic alpha cells. Br J Dermatol. 1974;90:301-308. 121. Kheir SM, Omura EF, Grizzle WE, et al. Histologic variation in the skin lesions of the glucagonoma syndrome. Am J Surg Pathol. 1986;10:445-453. 122. Long CC, Laidler P, Holt P. Suprabasal acantholysis: an unusual feature of necrolytic migratory erythema. Clin Exp Dermatol. 1993;18:464-467. 123. Jeerapeet P, Ackerman A. Histologic patterns of secondary syphilis. Arch Dermatol. 1973;107:373-377. 124. Cochran R, Thomson J, Flemming K. Histology simulating reticulosis in secondary syphilis. Br J Dermatol. 1976;95: 251-254. 125. Bowen JT. Precancerous dermatosis. J Cutan Dis. 1912;30:241-255. 126. Thestrup-Pedersen K. Morbus Bowen: a description of the disease in 617 patients. Acta Dermatol Venereol. 1988; 68:236. 127. Brownstein MH, Raboniwitz AD. The precursors of cutaneous squamous cell carcinoma (review). Int J Dermatol. 1979; 18:1-16. 128. Ohnishi T, Watanabe S. Immunohistochemical characterization of keratin expression in clear cell acanthoma. Br J Dermatol. 1995;133:186-193. 129. Zedek DC, Langel DJ, White WL. Clear cell acanthoma acanthosis: a psoriasiform reaction pattern lacking tricholemmal differentiation. Am J Dermatopathol. 2007;29:378-384. 130. Baden TJ. Multiple clear cell acanthomas. J Am Acad Dermatol. 1987; 16:1075. 131. Fine RM, Chernosky ME. Clinical recognition of clear-cell acanthoma (Degos). Arch Dermatol. 1969;100: 559-563. 132. Jones EW, Wells GC. Dego’s acanthoma (acantome a cellules claires). Arch Dermatol. 1966;94:286-294. 133. Williams ML, Elias PM. Heterogeneity in autosomal recessive ichthyosis: clinical and biochemical differentiation of lamellar ichthyosis and non-bullous congenital ichthyosiform erythroderma. Arch Dermatol. 1985;121:477. 134. Russell LJ, DiGiovanna JJ, Rogers GR, et al. Mutations in the gene for transglutaminase 1 in autosomal recessive lamellar ichthyosis. Nature Genet. 1995;9:279-283. 135. Elias PM, Schmuth M, Uchida Y, et al. Basis for the permeability barrier abnormality in lamellar ichthyosis. Exp Dermatol. 2002;11:248-256. 136. Williams ML, Elias PM. Heterogeneity in autosomal recessive ichthyosis. Arch Dermatol. 1985;121:477-488. 137. Vandersteen PR, Muller SA. Lamellar ichthyosis. Arch Dermatol. 1972;106: 694-701.

CHAPTER 5 Superficial and Deep Perivascular Dermatitis A. Neil Crowson

SUPERFICIAL PERIVASCULAR DERMATITIS

SUPERFICIAL AND DEEP PERIVASCULAR DERMATITIS

Urticaria Perivascular lymphocytic dermatitis Toxic erythema of pregnancy Gyrate erythemas Pityriasis lichenoides Perniosis Rickettsial and viral infections Polymorphous light eruption (superficial variant)

Urticaria Superficial and deep perivascular dermatitis lymphocytic Toxic erythema of pregnancy Gyrate erythemas Pityriasis lichenoides Perniosis Rickettsial and viral infections Polymorphous light eruption (superficial and deep variant) Photosensitive eruptions Connective tissue disease Discoid lupus erythematosus

Connective tissue disease Systemic lupus erythematosus Subacute cutaneous lupus erythematosus Mixed connective tissue disease Dermatomyositis

Urticaria pigmentosa

Leprosy (indeterminate) Syphilis Borreliosis Leukemia and leukemids Urticaria pigmentosa

URTICARIA CLINICAL FEATURES The urticarias are common, transient eruptions that affect roughly 15% of the population at some time in life.1 They comprise palpable erythematous papules or wheals that lack surface alteration and wax and wane without a clinical residuum (Fig. 5-1A). Lesions of urticaria are typically “here today and gone tomorrow,” unlike urticarial rashes induced by drugs or urticarial vasculitis, in which the individual lesions superficially may resemble urticaria but last several days.2 Urticarias may be acute or chronic, the latter defined as those that last longer than 6 weeks, and may be either idiopathic or of physical, IgE-, immune-complex-, or histamine-releasing agent-mediated types (Table 5-2). The term chronic urticaria embraces idiopathic urticaria, urticarial vasculitis, and physical urticaria.3 Roughly one-third of all cases of chronic urticaria represent physical urticarias, defined by specific triggering stimuli and subclassified as adrenergic, aquagenic, cholinergic, cold, delayed pressure, localized heat, and solar urticarias; vibratory angioedema; dermographism; and exercise-induced anaphylaxis.2 The physical urticarias typically manifest within 10 minutes of exposure to the triggering stimulus and resolve within a day. The exception is delayed pressure urticaria, which often

arises several hours after an episode of sustained pressure and may last over a day. Contact urticaria often manifests 10 to 20 minutes after the stimulus and disappears within a few hours. Various forms of physical urticaria may overlap with idiopathic urticaria, and some patients manifest multiple different types of physical urticaria.4,5 Physical triggers are held to be the most common precipitating factors in children.6 It is important to attempt to separate the various triggers and forms of urticaria, as both the pathogenesis and therapy may be different. Acute urticarias, for example, typically reflect a hypersensitivity response, while chronic urticarias have a more complex pathogenesis.7 The clinical appearance of individual lesions results from vasodilation, enhanced vascular permeability, and extravasation of proteins into the dermis. There is often a surrounding flare due to an axonal reflex.2 Lesions may progress to form confluent plaques with an annular or arcuate morphology. Angioedema is an analogous physiologic process that extends to the subcutis and subjacent soft tissues and sometimes to the upper airways with potentially fatal consequences; it may relate to an absolute or relative C1 esterase-inhibitor deficiency that may be familial. The main mediators include histamine, prostaglandins, and interleukin 1 (IL-1), the liberation of

CHAPTER 5 ■ SUPERFICIAL AND DEEP PERIVASCULAR DERMATITIS

When approaching a skin biopsy showing a dermal inflammatory cell infiltrate, one must take note of the presence and type of epidermal alteration, vascular changes, stromal response, and the character of the infiltrate itself. With respect to the former, the presence or absence of parakeratosis and orthohyperkeratosis and concomitant acanthosis or atrophy is a clue to the chronicity of the process and the type of injury pattern; eg, a spongiotic versus a cell-poor vacuolopathic interface dermatitis, respectively, points toward a delayed-type hypersensitivity reaction versus a humorally mediated or autoimmune disease. The infiltrate may be lymphohistiocytic or may contain an admixture of granulocytes, the former usually a sign of delayed-type hypersensitivity and the latter often a clue to an immune-complex (type III) or an anaphylactic (type I) hypersensitivity reaction. Histiocyte-predominant infiltrates may be a clue to a drug, viral, or idiopathic granulomatous process. The disposition of the infiltrate, either tightly “cuffed” around the vasculature or both perivascular and interstitial in distribution, may be a clue to a gyrate erythema, on the one hand, or to urticaria, on the other. The stromal response, in the context of either a fibrosing reaction or collagen necrobiosis, may be a clue to a chronic process or a systemic disease. The presence or absence of vascular fibrin deposition is essential to definition of a vasculitis, and the presence or absence of endothelial cell necrosis, telangiectasia, and diminished vascular density of the superficial plexus, features indicative of certain of the connective tissue diseases, must be addressed, as must the type of inflammatory cells in vessel walls and lumina. Although by no means comprehensive, Table 5-1 provides a differential diagnostic approach to the superficial and the superficial and deep perivascular dermatitides. The reader is referred to other sections of this book for an in-depth consideration of many of these entities.

Table 5-1 Perivascular Inflammatory Cell Infiltrates with Minimal or No Epidermal Alteration

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A

B

 FIGURE 5-1 Urticaria. (A) Erythematous papules and plaques without surface alteration show expansion, coalescence, and central clearing. Such lesions wax and wane and usually disappear in a matter of hours without any clinical residuum. (B) The reticular dermis shows edema, consisting of separation of collagen bundles, accompanied by an interstitial granulocytic infiltrate.

Table 5-2 The Common Forms of Chronic Urticarias TYPE OF URTICARIA

PRINCIPAL CLINICAL FEATURES

HISTOPATHOLOGICAL FEATURES

Acute and chronic idiopathic

Profuse or sparse edematous papules or wheals, often annular with itching

Symptomatic dermatographism

Itchy, linear wheals with a surrounding bright red flare at sites of scratching or rubbing

Absence of epidermal alteration Dermal edema Sparse perivascular infiltrate composed of lymphocytes, eosinophils, neutrophils (variable) As above

Other physical urticarias Cold

Itchy pale or red swelling at sites of contact with cold surfaces or fluids Large painful or itchy red swelling at sites of pressure lasting 24 hours or more

As above but neutrophils may be more prominent

Solar

Itchy pale or red swelling at site of exposure to ultraviolet or visible light

As above but neutrophils may be more prominent

Cholinergic

Itchy wheals on trunk, neck, and limbs

As above but neutrophils may be more prominent

Pressure

As above but neutrophils may be more prominent

DIAGNOSTIC TEST

Light stroking of skin causes an immediate wheal with itching 10-minute application of an ice pack causes a wheal within 5 minutes of the removal of ice Application of pressure produces persisent red swelling after a latent period of 1-4 hours Irradiation by a 2.5 kW 290-690 nm source for 30-120 seconds causes wheals in 30 minutes Exercise or a hot shower elicits eruption

SOURCE: After Greaves.1

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which is provoked by type I and III immune reactions (see Chap. 22) and nonimmunologic mechanisms causing mast cell or basophil degranulation. The latter are exemplified by opiates and foods such as strawberries and shellfish.

The IgE-mediated urticarias constitute antigen-specific reactions to certain foods, drugs, pollens, insect bites, and stings. Roughly 35% of urticarias have an autoimmune basis2 and are associated with autoimmune thyroid disease,

insulin-dependent diabetes, vitiligo, pernicious anemia, and rheumatoid arthritis.8 Patients with autoantibodies tend to have more severe disease.8 There is evidence that delayed-type hypersensitivity mechanisms may play a role in cases of

urticaria, typically of acute type, implying that acute urticaria may be a risk factor for anaphylactic reactions.19 HISTOPATHOLOGIC FEATURES The histology reflects the age of the lesion biopsied and the type of provocative stimulus. One constant is edema, characterized by separation of collagen bundles (Fig. 5-1 B). Blood vessels and lymphatics usually are dilated and show endothelial swelling. The upper dermis is preferentially involved, except in angioedema, which prominently involves the deep reticular dermis and subcutis. A sparse perivascular inflammatory infiltrate consisting of a variable admixture of lymphocytes, eosinophils, and neutrophils characterizes the lesions. Mast cells and granulocytes are seen within the interstitium and granulocytes within blood vessels. Degranulated mast cells resemble lymphocytes and, when present, may suggest a mononuclear cell-predominant vascular reaction. The neutrophilic urticarias tend to have a more cellular infiltrate, often with neutrophilic packing of blood vessels (Fig. 5-2). This neutrophil-rich histology may be seen in an incipient lesion of physical urticaria, which is, in its chronic state, more likely to manifest the cell-poor morphology previously described. The autoimmune and nonautoimmune urticarias have a similar histomorphology.20 DIFFERENTIAL DIAGNOSIS The differential diagnosis of urticaria includes persistent dermal hypersensitivity reactions to drugs,

insect bite reactions, dermal contact hypersensitivity, viral exanthems, gyrate erythemas, and small-vessel vasculitides. Most of these can be distinguished from urticaria by epidermal changes such as parakeratosis, acanthosis, spongiosis, and basal layer vacuolization, by lymphocytic infiltrates that usually are heavier and manifest a more pronounced perivascular distribution, and by the absence of interstitial granulocytes or prominent reticular dermal edema. With respect to gyrate erythemas, these can be either superficial, associated with the aforementioned epidermal changes, or deep; the latter show striking perivascular cuffing of lymphocytes, accompanied in some cases by eosinophils. The absence of vascular fibrin deposition, leukocytoclastic debris, or extravasation of fragmented red blood cells enables distinction from leukocytoclastic vasculitis. More challenging is the distinction from urticarial vasculitis, which characteristically manifests only mild vascular injury, but should be suspected when urticaria-like lesions resolve clinically after more than 24 hours with a residuum of pigmentation. The histopathology of urticarial vasculitis is typified by a mild form of leukocytoclastic vasculitis comprising erythrocyte extravasation, slight leukocytoclasia, and neutrophilic infiltration of venular endothelia with minimal fibrin deposition. It is important to make this distinction, and when urticarial vasculitis is present, to explore for manifestations of systemic disease including renal involvement.3

 FIGURE 5-2 Urticaria. A sparse superficial and deep perivascular mixed-cell infiltrate is seen, including lymphocytes, neutrophils, and eosinophils. Neutrophils are present in blood vessels, and a sparse interstitial infiltrate of granulocytes is present.

CHAPTER 5 ■ SUPERFICIAL AND DEEP PERIVASCULAR DERMATITIS

urticaria, particularly those due to food additives and chronic infections.9 Roughly one in eight children with physical urticaria will develop respiratory symptoms and two-thirds will manifest angioedema.5 Long-term follow-up indicates that less than half will manifest complete remissions over time.5 Novel cellular basophil activation tests, including the measurement of CD203c and/or CD63 as activation markers on human basophils when incubated with patient serum, are developing as an effective screening measure,3,10 and may ultimately bear fruit from the standpoint of elucidating specific drug and other antigenic triggers in the individual patient. Physical urticarias tend to respond to H1 antihistamines, save for the exceptions of solar and delayed pressure urticaria.11 The neutrophilic urticarias usually represent the sequelae of complement activation, causes of which include C1q esterase deficiency and circulating immune complexes containing antigens of endogenous or exogenous origin, the latter often comprising drug or microbial antigens such as Epstein-Barr virus or the hepatitis viruses.12 Characteristic endogenous causes include connective tissue diseases, neoplasms, and mixed cryoglobulinemia. Neutrophilic urticaria also may characterize the physical urticarias. Chronic urticarias relate in some patients to IgG autoantibodies that crosslink the alpha subunit of the high-affinity IgE receptor (FceRIa) on basophils and mast cells, causing their degranulation with subsequent upregulation of endothelial adhesion molecules.13,14 Some patients with chronic urticaria exhibit allergies to food, acetylsalicylic acid, or other common antigens. A link to Helicobacter pylori colonization of gastric mucosa has been suggested but must be considered unproven in the absence of a controlled eradication trial.15,16 Cholinergic urticaria is caused by a rise in core temperature following exercise, overheating, or stress2; enhancement of sympathetic activity is postulated to lead to acetylcholine release at nerve endings, triggering degranulation of apposed mast cells. Schnitzler syndrome is a rare form of chronic urticaria associated with IgM-k paraproteinemia, bone pain, hyperostosis, and pyrexia.17 Even more rare are cases of autosomal dominantly inherited familial cold urticaria characterized by recurrent inflammatory crises commencing in childhood and associated with fever, arthralgia, and urticaria in response to cold exposure.18 One study of patients with idiopathic anaphylaxis showed that some 58% had a prior history of idiopathic

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Other extracutaneous manifestations include involvement of synovia, and of ophthalmologic, respiratory, central nervous, and gastrointestinal systems.9,21 The same underlying systemic diseases are as implicated in conventional leukocytoclastic vasculitis, such as malignancy or systemic connective tissue diseases.

PART I ■ INFLAMMATORY REACTIONS IN THE SKIN

TOXIC ERYTHEMA OF PREGNANCY (POLYMORPHIC ERUPTION OF PREGNANCY/ PRURITIC URTICARIAL PAPULES AND PLAQUES OF PREGNANCY) CLINICAL FEATURES The most common dermatosis of the gravid state, pruritic urticarial papules and plaques of pregnancy (PUPPP), has an incidence of 1 in 20 pregnancies and manifests as pruritic papules and urticarial plaques, sometimes with superimposed vesicles, in and near striae of the abdomen and proximal thighs22 (Table 5-3). While the initial lesions are as described above, roughly half of the patients show changing morphology over time,23 developing polymorphous features including erythema, vesicles, and targetoid eczematous lesions.23 Lesions usually develop in the last few weeks of pregnancy and may spread to the extremities or become generalized. Periumbilical sparing and spontaneous resolution are characteristic. The association of this eruption with large babies, twin and triplet pregnancies, and increased

maternal weight gain raises the possibility that it relates somehow to excessive abdominal distension.24 It occurs in late pregnancy in 85% of cases and in the immediate postpartum period in 15% of cases.23 HISTOPATHOLOGIC FEATURES Superficial perivascular lymphocytic or lymphocytic and eosinophilic infiltrates with a nondescript appearance, accompanied in one-third of cases by exocytosis and spongiosis, are characteristic (Fig. 5-3). Fibroblast proliferation is an infrequent concomitant.22 Leukocyte debris may be present, but there is no vascular fibrin deposition to suggest a leukocytoclastic vasculitis. Although usually nonreactive by direct immunofluorescent testing, lesions of PUPPP may show granular IgM, IgA, or C3 deposition at the dermalepidermal junction and/or in blood vessels,25,26 suggesting a delayed-type hypersensitivity reaction or possibly an immune-complex contribution to the pathogenesis.22,25,26 Analysis of serum hormone levels in one series showed a significant drop in cortisol levels in patients with PUPPP versus normal pregnant control patients27; enhanced progesterone receptor expression in lesional as opposed to nonlesional keratinocytes also suggests the possibility that the action of hormones may play a role.28 DIFFERENTIAL DIAGNOSIS The differential diagnosis of PUPPP includes atopic dermatitis; dermal hypersensitivity reactions

to drugs, contactants, and insect bites; and herpes gestationis. Most of the hypersensitivity reactions cannot be reliably distinguished from PUPPP because of its nondescript histomorphology. Herpes gestationis can occur at any time during pregnancy and often is raised as a clinical consideration. Lesions of herpes gestationis often show subepidermal blisters accompanied by eosinophils in the epidermis, at tips of dermal papillae, and in a perivascular disposition associated with focal necrosis of basal layer keratinocytes and colloid body formation. Tissue eosinophilia is quantitatively greater in herpes gestationis than in PUPPP.29 Circulating anti-basement membrane IgG is demonstrable by indirect immunofluorescence in 25% of herpes gestationis patients, associated invariably with linear C3 deposition along the dermal-epidermal junction and, in 50% of cases, a similar pattern of IgG deposition.22,30 The linear dermal-epidermal junction deposition of C3 and IgG that characterizes herpes gestationis is not seen in PUPPP. Direct immunofluorescence testing is thus a valuable adjunct to light microscopy in making this important distinction. Herpes gestationis is associated with increased fetal morbidity and may require systemic steroid therapy, whereas PUPPP is a selflimited eruption with no associated fetal morbidity.22,30,31 A less problematic concern is that of pruritic folliculitis of pregnancy that manifests a follicular-based eruption characterized histologically by a neutrophilic folliculitis.32

Table 5-3 Pruritic Urticarial Papules and Plaques of Pregnancy

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Clinical Features Pruritic erythematous urticarial papules, vesicles, and plaques in and near abdominal striae Most common dermatosis of pregnancy Occurs classically in week 35+ Histopathologic Features Superficial perivascular lymphocytic or lymphocytic and eosinophilic dermal infiltrate Exocytosis and spongiosis in one-third of cases Differential Diagnosis Delayed-type hypersensitivity reactions of diverse causes: Drugs Contactants Insect bite reactions (including papular urticaria) Atopic dermatitis Herpes gestationis

 FIGURE 5-3 Pruritic urticarial papules and plaques of pregnancy. A nondescript superficial perivascular infiltrate of lymphocytes and eosinophils is present.

GYRATE ERYTHEMAS CLINICAL FEATURES The gyrate erythemas are characterized by annular, polycyclic, often migratory erythematous macular eruptions. Erythema annulare centrifugum (EAC) (Table 5-4) consists of one or more annular fixed or migratory large (>1 cm), erythematous, scaly, indurated plaques, often with a fine peripheral scale at the advancing edge, involving the trunk and proximal extremities (Fig. 5-4 A). A number of triggers are implicated33 (Table 5-5). Although A

Clinical Features Erythematous infiltrated papules which slowly enlarge to form annular or arciform arrays Histopathologic Features Superficial EAC Superficial perivascular lymphocytic or lymphocytic and eosinophilic dermal infiltrate Exocytosis and spongiosis with focal parakeratosis Superficial and deep EAC Superficial and deep perivascular lymphocytic or lymphocytic and eosinophilic dermal infiltrate with prominent “cuffing” around blood vessels Differential Diagnosis Superficial EAC Delayed-type hypersensitivity reactions including: Allergic contact reactions Atopy Pityriasis rosea Pityriasiform and other drug eruptions Polymorphous light eruption and other photoallergic conditions Insect bite reactions Connective tissue diseases including: Discoid lupus erythematosus Subacute lupus erythematosus Relapsing polychondritis Sjögren syndrome Mixed connective tissue disease Superficial and deep EAC Jessner lymphocytic infiltrate Connective tissue diseases including: Discoid and tumid lupus erythematosus Relapsing polychondritis Sjogren syndrome Mixed connective tissue disease Delayed-type hypersensitivity reactions including: Dermal contact hypersensitivity reactions (to nickel) Polymorphous light eruption, deep variant Insect bite reactions and papular urticaria

B  FIGURE 5-4 Erythema annulare centrifugum, superficial type. (A) Large annular erythematous, indurated plaques with central clearing involving the shoulder and trunk. A fine peripheral scale is present at the advancing edges of the plaques. (B) There is a moderately heavy superficial perivascular infiltrate of lymphocytes and eosinophils associated with exocytosis of inflammatory cells, concomitant spongiosis, and often an adherent plasma-containing scale-crust.

lesions may be seen in the neonatal period, in which they may be a sign of maternal systemic lupus erythematosus, onset is most often in early adulthood or middle age.34 The initial lesion, a pink infiltrated papule, slowly enlarges to form a ring as its center fades; some lesions reach a diameter of 8.0 cm over a 2- to 3-week period. Eccentric expansion may yield an irregular arciform pattern. Lesions may last from days to months and may be associated with purpuric or pigmented residua. The clinical differential diagnosis includes granuloma annulare (which more often has a beaded edge), fungal infections, parapsoriasis, sarcoidosis, urticaria, urticarial bullous pemphigoid, connective tissue disease, atypical forms of pityriasis rosea (particularly the pityriasis marginatum et circinatum of Vidal variant), and necrolytic migratory erythema associated with pancreatic islet cell neoplasms. The nature of the factors that trigger EAC implicate delayed-type hypersensitivity

as the pathogenetic basis; internal disease and superficial fungal infection are thought to be highly associated.35 Lymphoma, chronic lymphocytic leukemia, autoimmune disease, sarcoidosis, drug intake, and bacterial and viral infections have been reported variably in association with EAC.35-46 The disorder tends to be a chronic and recurrent one despite treatment. Erythema gyratum repens manifests as broad polycyclic patches that resemble the rings on the cut surface of a tree. This eruption is associated in over 80% of cases with malignancies of parenchymal organs such as lung or kidney,47-49 tuberculosis, ichthyotic states, pityriasis rubra pilaris, hematologic dyscrasias including hypereosinophilic syndrome,50 and CREST syndrome.51 Clinical mimics include atypical cases of autoimmune bullous dermatoses, such as bullous pemphigoid or linear IgA disease, and subacute cutaneous lupus erythematosus.51 The pathophysiologic

CHAPTER 5 ■ SUPERFICIAL AND DEEP PERIVASCULAR DERMATITIS

Table 5-4 Erythema Annulare Centrifugum

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Table 5-5 Possible Trigger Factors for Erythema Annulare Centrifugum

86

Infective and Nondrug Hypersensitivity States Tinea Candida infection Ascaris infection Viral infection Ingested molds Autoimmune Diseases Sjögren syndrome Hyperthyroidism Liver disease Immunologic disturbances Drug-Related Cimetidine Salicylates Diazides Antimalarials Neoplastic Liver disease Carcinoma Dysproteinemia Blood dyscrasias

basis is held to reflect an autoimmune basis, although the antigen is not well characterized.52,53 Erythema marginatum is associated with rheumatic fever in less than 10% of cases and consists of erythematous macules with a raised edge and a pale center. Rheumatic fever is a multisystem inflammatory disease associated with group A streptococcal pharyngitis. By consensus, one establishes the diagnosis clinically through the system described by T. Duckett Jones, requiring the expression of two major or one major and two minor criteria. The major criteria are carditis, migratory large joint polyarthritis, chorea, erythema marginatum, and subcutaneous nodules, whereas the minor criteria include fever, arthralgia, an elevated erythrocyte sedimentation rate or C-reactive protein level, and an elongated P-R interval on an electrocardiogram.54,55 None of 44 patients with rheumatic fever in one study manifested erythema marginatum.56 Erythema chronicum migrans, the distinctive cutaneous manifestation of stage I Lyme disease, is discussed in Chap. 20. HISTOPATHOLOGIC FEATURES There are two discrete forms of gyrate or figurate erythema. The superficial variant (the most common form, usually termed erythema annulare centrifugum) shows epidermal spongiosis and parakeratosis with papillary dermal edema, which may be considerable (Fig. 5-4 B). There are superficial

 FIGURE 5-5 Erythema annulare centrifugum, superficial and deep type. A moderately heavy superficial and deep perivascular lymphocyte-predominant infiltrate manifests “cuffing” around blood vessels without exocytosis of inflammatory cells into the epidermis, which shows no appreciable pathology.

perivascular lymphocytic infiltrates that typically exhibit some degree of cuffing about blood vessels in addition to a loose scattering of lymphocytes in the papillary dermis. The second form is a superficial and deep one in which a sharply demarcated perivascular lymphoid infiltrate spares the overlying epidermis57 (Fig. 5-5). In one series, 80% of patients had superficial EAC, and 20% had the deep form.34 Endothelial swelling may be seen in both types and may be accompanied by hemorrhage, but fibrin deposition is absent. Eosinophils are seen in roughly 10% to 20% of cases (personal observation) (Fig. 5-6). The histopathology of erythema gyratum repens comprises spongiosis with parakeratosis, focal mild perivascular lymphoid infiltrates, and variable edema or eosinophilia of the dermis. Skin biopsies in erythema marginatum show perivascular neutrophilic, lymphocytic, and eosinophilic infiltrates with perivascular debris but absent vascular fibrin deposition.

DIFFERENTIAL DIAGNOSIS The differential diagnosis of the superficial variant of gyrate erythema (erythema annulare centrifugum) includes allergic contact reactions, atopy, pityriasis rosea and pityriasiform drug eruptions, polymorphous light eruption and other photoallergic conditions, insect bite reactions, and occasional cases of lupus erythematosus. With respect to the superficial

and deep forms of gyrate erythema, differential diagnostic considerations include Jessner lymphocytic infiltrate, connective tissue diseases such as discoid and tumid lupus erythematosus, relapsing polychondritis, Sjögren syndrome, and lesions of mixed connective tissue disease and subacute cutaneous lupus erythematosus that have been treated with topical steroids, all of which may manifest perivascular lymphocytic infiltrates without epidermal alterations, and those hypersensitivity reactions whose expression is principally confined to the dermis. With respect to Jessner lymphocytic infiltrate and the aforementioned connective tissue diseases, eosinophils are most unusual, whereas in tumid lupus erythematosus, massive mucin deposition is characteristic, and the lymphocytic infiltrate usually is sparse. The dermal contact hypersensitivity reactions, such as those owing to nickel, manifest perivascular lymphocytic and eosinophilic infiltrates in the absence of epidermal changes. With respect to erythema marginatum, other conditions that combine perivascular lymphocytic infiltrates with a neutrophilic and eosinophilic component in the presence of perivascular leukocytoclasia but absent or minimal fibrin deposition include urticaria, urticarial vasculitis, rheumatoid neutrophilic dermatosis, and some cases of Henoch-Schönlein purpura.58 With respect to the latter, although a mononuclear cellpredominant vascular injury pattern may be seen, most cases manifest a distinctive pustular vasculitis.58,59

Table 5-6 Pityriasis Lichenoides

PITYRIASIS LICHENOIDES CLINICAL FEATURES Pityriasis lichenoides is a self-limited dermatosis that usually presents in the first to third decades of life and shows a predilection for males60 (Table 5-6). The onset ranges from an acute eruption termed pityriasis lichenoides et varioliformis acuta (PLEVA), consisting of hemorrhagic papules (thus pityriasis lichenoides), pustules or vesicles that heal with scars mimicking smallpox (thus varioliformis), and a chronic eruption termed pityriasis lichenoides chronica. The latter may heal with postinflammatory hyperpigmentation. Lesions number from dozens to hundreds and frequently affect the anterior trunk and flexor aspects of the proximal extremities preferentially.61 Although occasional cases of pityriasis lichenoides are seen in patients with autoimmune diseases such as autoimmune hepatitis,62 the etiologic basis has long been postulated to be viral in nature, based in part on the clinical behavior, in part on phenotypic studies that show a characteristic infiltrate comprising CD8+ lymphocytes admixed with a minor populace of Langerhans cells or indeterminate cells, and in light of case reports of the detection of Cytomegalovirus in

endothelia in cases of PLEVA.63 However, larger series in the modern era have shown clonal restriction of T-cell populations in lesions of PLEVA64-69 and PLC.64-69 T-cell populations in both forms of pityriasis lichenoides show deletion of pan-Tcell markers indicating that the process represents a true lymphoid dyscrasia.67 Recently, defects in activity of the CD4+/CD25+ T-regulatory cell population have been described.65 HISTOPATHOLOGIC FEATURES In PLEVA, the dermal-epidermal junction often is obscured by a pure population of lymphocytes associated with basal layer vacuolopathy, colloid body formation, and variable but sometimes confluent epidermal necrosis (see Chap. 3). As a reflection of the underlying T-cell dyscrasia, small lymphoid forms percolate the epidermis in a fashion that often mimics patch or early plaque stage mycosis fungoides. Intraepidermal hemorrhage, endothelial swelling, papillary dermal edema, bleeding, and wedge-shaped superficial and deep dermal lymphoid infiltrates are classical.60 The parakeratotic scale often contains neutrophils. A rare extreme expression of the disease is the ulceronecrotic variant, in which necrotizing

lymphocytic vasculitis produces confluent epidermal necrosis.70 Parakeratosis is often confluent and epidermal injury less striking in pityriasis lichenoides chronica.71 The epidermis may show superficial pallor, and melanophages often are present in the papillary dermis, reflecting basal layer injury. Since PLEVA and pityriasis lichenoides chronica represent opposite poles of a spectrum of injury, not all cases can be reliably classified as one or the other; some authorities sign out most cases simply as pityriasis lichenoides without further qualification. Incidental IgM and C3 deposition may be seen along the basement membrane zone and in blood vessels by direct immunofluorescence. DIFFERENTIAL DIAGNOSIS The differential diagnosis includes pityriasis rosea, in which discrete mounds of parakeratin overlie foci of epidermal spongiosis, and small-plaque parapsoriasis, where the

CHAPTER 5 ■ SUPERFICIAL AND DEEP PERIVASCULAR DERMATITIS

 FIGURE 5-6 Erythema annulare centrifugum, superficial and deep type. The dermal lymphocyte-predominant infiltrate is associated with scattered eosinophils and mural and endothelial swelling but no fibrin deposition within blood vessel walls or lumina.

Clinical Features Self-limited dermatosis comprising 10s to 100s of hemorrhagic papules, pustules, or vesicles that heal with scars Onset in first to third decades with male predominance Spectrum ranging from acute (pityriasis lichenoides et varioliformis acuta, or PLEVA) to chronic (pityriasis lichenoides chronica, or PLC) eruptions Histopathologic Features PLEVA Lymphocytic infiltrate obscures dermoepidermal junction Erythrocyte extravasation into degenerating epidermis Papillary dermal edema Wedge-shaped superficial and deep, purely lymphocytic dermal infiltrate Sometimes atypical transformed lymphocytes PLC Confluent parakeratotic scale, often containing neutrophils More sparse lymphocytic interface injury pattern Less conspicuous epidermal injury and hemorrhage Melanophages in papillary dermis Differential Diagnosis Pityriasis rosea Small plaque parapsoriasis Viral exanthemata Lymphomatoid papulosis Secondary syphilis Connective tissue disease

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degree of epithelial injury generally is less and the infiltrate more sparse.71 The common viral exanthem pattern may mimic PLEVA by virtue of a perivascular and interface lymphocytic infiltrate accompanied by basilar vacuolopathy with scattered cytoid bodies and streak dyskeratosis, but the epidermis usually is surmounted by a basket-weave pattern of orthokeratinization, and the lymphocytic infiltrate is usually superficial only. Similar features also typify evolving lesions of erythema multiforme, which may show scattered eosinophils in the dermal inflammatory populace, enabling distinction. Secondary syphilis merits consideration but usually has a significant plasma cell component, at variance with the pure lymphoid populace of pityriasis lichenoides. Connective tissue diseases with pronounced keratinocyte degeneration, such as subacute cutaneous lupus erythematosus, can be problematic if a superfical shave biopsy is submitted, and the deep infiltrates of pityriasis lichenoides, which would enable distinction, cannot be assessed. The atypical pigmentary purpuras and purpuric forms of mycosis fungoides merit consideration but generally show little or no epidermal necrosis despite epidermotropism of transformed lymphocytes and intraepithelial hemorrhage.72 These lesions also show horizontal wiry sclerosis of collagen in the fashion of lesions of large-plaque parapsoriasis, a finding typically absent in lesions of PLEVA but common in lesions of PLC.

Table 5-7 Perniosis (Chilblains)

Clinical Features Cold-induced purplish macules, papules, and nodules involving acral, thigh, or buttock skin Occurs in humid climates Histopathologic Features Dense superficial and deep lymphocytic infiltrates with preferential migration to epidermal retia and acrosyringia Occasional fibrin thrombi in dermal papillae capillaries Transmural lymphocytic migration through blood vessel walls Marked papillary dermal edema Mucinosis around eccrine coil Differential Diagnosis Connective tissue diseases, especially: Chilblains lupus erythematosus Mixed connective tissue disease Behçet disease Erythema multiforme Viral exanthems

resulting ischemia of vessel walls is the proposed etiology, with humidity playing a role through enhanced air conductivity of temperature. Lesions clear dramatically

with warming.73-75 An association with anorexia nervosa has been reported; it appears that anxiety states and the ingestion of antidepressant medications with immune dysregulating properties may play a role.76,77 HISTOPATHOLOGIC FEATURES Biopsies show a dense superficial or superficial and deep perivascular lymphocytic infiltrate with exocytosis to retia and acrosyringia (Fig. 5-7). Epithelial necrosis is observed occasionally. Edema of blood vessel walls accompanied by transmural lymphocytic infiltrates is characteristic (the so-called fluffy edema of microvessels), and thrombi may be observed in dermal papillae capillaries. Pronounced papillary dermal edema is often present.74 Mucinosis around the eccrine coil and luminal fibrin thrombi localized to dermal papillae capillaries may be seen, but pandermal mucin deposition or reticular dermal vascular thrombosis is unusual.75 DIFFERENTIAL DIAGNOSIS Other causes of acral purpuric papulonodular lesions include rare childhood lesions of leukemiacutis,76 of zoophilic mycoses in farm workers,77 celiac disease,78 hyperviscosity and procoagulant states, namely,

PIGMENTED PURPURIC DERMATOSES The pigmented purpuric dermatoses, a group of idiopathic disorders having in common a lymphocytic vascular reaction associated with endothelial swelling and perivascular hemorrhage, are discussed in detail in Chap. 9.

PERNIOSIS

88

CLINICAL FEATURES Perniosis (chilblains) is a form of cold-induced injury that manifests as inflammatory red to purple macules, nodules, papules, or plaques, at times accompanied by overlying blisters, erosions, or ulcers characteristically distributed symmetrically on acral skin, thighs, or buttocks (Table 5-7). It is common in the humid climate of northwest Europe but is decreasing in frequency with modern home heating methods.73-75 A vasospastic response to cold with

 FIGURE 5-7 Perniosis (chilblains). There is a dense superficial and deep perivascular lymphocytic infiltrate associated with marked papillary dermal edema and migration of lymphocytes into retia and acrosyringia.

RICKETTSIAL AND VIRAL INFECTIONS Rickettsial and viral infections produce a lymphocytic interface injury pattern mimicking the common viral exanthem pattern, often in concert with vascular injury, and are discussed in detail in Chap. 20.

Table 5-8 Polymorphous Light Eruption

Clinical Features Erythematous, pruritic papules or papulovesicles and urticarial plaques Eruption occurs 30 minutes to 3 days after sun exposure, and resolves in 7-10 days Predilection for sun-exposed sites: hands, forearms, head, and neck area Histopathologic Features Perivascular infiltrates of lymphocytes, eosinophils, and neutrophils Exocytosis, spongiosis, vesiculation, acanthosis, and focal parakeratosis common Some cases show vacuolopathic interface injury pattern or no epidermal changes Marked papillary dermal edema classically Blood vessels show ectasia and endothelial swelling which preferentially affects superficial vasculature Differential Diagnosis Delayed-type hypersensitivity reactions including: Allergic contact reactions Rosacea Other photoallergic/phototoxic eruptions Insect bite reactions Connective tissue diseases including: Discoid lupus erythematosus Subacute cutaneous lupus erythematosus Jessner lymphocytic infiltrate

3 days after UV exposure and characteristically resolve in 7 to 10 days.90 Lesions may appear eczematous or may resemble pemphigus, prurigo nodularis, erythema multiforme, or insect bite reactions. There is a predilection for the hands, forearms, upper arms, and the head and neck region. Females are preferentially affected and there is a small statistical predilection for African Americans91; onset is classically in the third to fourth decade of life.92 Roughly 50% of patients show decreasing photosensitivity over time. Polymorphous light eruption can be a clue to underlying seropositivity for antibodies to Ro.93 HISTOPATHOLOGIC FEATURES Characteristic findings include papillary dermal edema accompanied in early lesions by a superficial perivascular lymphoid infiltrate (Fig. 5-8) and in late lesions by a moderate-to-intense superficial and deep lymphocytic infiltrate, which often manifests perivascular “cuffing.” Eosinophils, neutrophils, hemorrhage, and vesiculation owing to marked papillary dermal edema may be seen (Fig. 5-9). The epidermis may be normal or may show basal layer vacuolization, acanthosis, parakeratosis, spongiosis, vesiculation, and uncommonly, necrosis.94 Vascular changes consisting of mural and endothelial swelling and edema diminish in the depths of the biopsy. By direct immunofluorescence examination, perivascular IgM and C3 deposition is seen in the setting of a negative lupus band test. On occasion, patients with apparently robust clinical findings may manifest only minimal histologic changes.95

POLYMORPHOUS LIGHT ERUPTION CLINICAL FEATURES AND PATHOGENESIS Polymorphous light eruption is an idiopathic photoinduced eruption (Table 5-8). It likely represents the combined effects of phototoxicity and a delayed-type hypersensitivity reaction to ultraviolet (UV) light of both UVA and UVB spectra.88 Early lesions are dominated by CD4+ lymphocytes, whereas late lesions manifest a predominant CD8+ populace. Patients with polymorphous light eruption fail to manifest the UV-induced downregulation of function of epidermal CD1a+ Langerhans cells seen in normal individuals; this deviant response may be a clue to pathogenesis as well as to diagnosis.89 Lesions manifest as pruritic erythematous papules, papulovesicles, or urticarial plaques that erupt 30 minutes to

 FIGURE 5-8 Polymorphous light eruption. A superficial perivascular lymphocytic infiltrate is associated with papillary dermal edema in the absence of an interface dermatitis or eczematous epithelial alterations.

CHAPTER 5 ■ SUPERFICIAL AND DEEP PERIVASCULAR DERMATITIS

hypergammaglobulinemia, essential cryofibrinogenemia, antiphospholipid antibody syndrome, rheumatoid arthritis, Crohn disease, Behçet disease, and systemic lupus erythematosus.81-83 The latter lesions are termed chilblains lupus erythematosus and resemble Behçet disease by virtue of the distribution of the infiltrate and the presence of a vacuolopathic lymphocytic interface dermatitis.83,84 All the aforementioned differential diagnostic considerations are associated with reticular dermal endovascular thrombi. The perniosis-like lesions in Crohn disease characteristically manifest an interstitial histiocytopathy mimicking granuloma annulare and accompanied at times by granulomatous vasculitis.85,86 When seen in concert with pulp atrophy and “parrotbeaked” clawing of the nails, perniosis constitutes a component of a pseudo sclerodermatous triad that may indicate chronic crack cocaine use.87 Pandermal mucinosis should prompt consideration of a systemic connective tissue disease.75,83 Erythema multiforme merits consideration but rarely shows vasculopathy. Polymorphous light eruption demonstrates many of the same findings but is usually more photodistributed.

89

Table 5-9 Causes of a Cell-Poor Interface Dermatitis

PART I ■ INFLAMMATORY REACTIONS IN THE SKIN

Connective tissue disease syndromes Systemic lupus erythematosus Subacute cutaneous lupus erythematosus Dermatomyositis Mixed connective tissue disease Hypersensitivity reactions Erythema multiforme Drug reaction Viral exanthem Graft-versus-host disease

90

 FIGURE 5-9 Polymorphous light eruption. In addition to a superficial perivascular mononuclear cell infiltrate there is often, but not invariably, striking papillary dermal edema.

DIFFERENTIAL DIAGNOSIS The differential diagnosis of polymorphous light eruption includes the other photoallergic and phototoxic dermatoses (including those that are drug-related; see Chap. 22), lupus erythematosus, Jessner lymphocytic infiltrate, the gyrate erythemas (particularly superficial erythema annulare centrifugum), granuloma faciale, and other delayed-type hypersensitivity reactions such as rosacea, atopy, insect bite, and contact reactions. Whereas distinction from photoallergic eruptions may be impossible, epidermal changes tend to be more pronounced than in polymorphous light eruption. Purely phototoxic eruptions show a greater degree of epidermal necrosis. The pattern of epithelial injury in lupus erythematosus is one of vacuolopathic basal layer degeneration usually associated with atrophy, whereas Jessner lymphocytic infiltrate typically spares the epidermis altogether. The superficial gyrate erythemas show eczematous epithelial changes such as may be seen in polymorphous light eruption, accompanied by a similar pattern of dermal inflammation, but generally lack a neutrophilic component. Granuloma faciale manifests a dermal inflammatory infiltrate of a similarly polymorphous composition, but the infiltrate usually is much more dense, is associated with a grenz zone of papillary dermal sparing, and is accompanied by vasculitic alterations and eosinophilic dermal trabeculation, features not seen in polymorphous light eruption. Acne rosacea frequently manifests eczematous alterations, but demodectic mites

commonly are present in hair follicles, and the dermal infiltrate usually is folliculocentric. The dermal neutrophilia seen in some examples of polymorphous light eruption would not be a feature of most other types of hypersensitivity reaction. Patients with polymorphous light eruption may have an increased incidence of underlying autoimmune diseases, including lupus erythematosus and autoimmune thyroid disorders.96,97 Two other forms of photodermatosis deserve mention: actinic prurigo and hydroa vacciniforme. The former is a form of chronic photosensitivity dermatitis that combines phototoxic, photoadaptive, and photoallergic features to produce a chronic, typically psoriasiform dermatitis that is more prevalent in native Americans.98 Hydroa vacciniforme consists of crops of discrete erythematous macules that evolve into blisters within a few days of sun exposure.99

CONNECTIVE TISSUE DISEASES The manifestations of connective tissue disease in the skin encompass vasculopathy and vasculitis of leukocytoclastic, granulomatous, and lymphocytic subtypes; panniculitis; and dermal and epidermal infiltrates. The vasculitides and panniculitides are addressed elsewhere. With respect to the epidermal and dermal findings, the characteristic morphology seen in most skin lesions of lupus erythematosus, dermatomyositis, relapsing polychondritis (personal observation), Sjögren syndrome, and mixed connective tissue disease consists of a

variable superficial or superficial and deep lymphocytic infiltrate in concert with a lymphocytic interface dermatitis ranging from a subtle cell-poor vacuolopathic injury pattern to a lichenoid infiltrate (see Chap. 3).83,100-103 The hallmark of the cell-poor interface dermatitis, the causes of which are listed in Table 5-9, is a sparse number of lymphocytes scattered along the dermal-epidermal junction with concomitant degenerative epithelial changes manifested by basilar vacuolopathy and dyskeratosis.104 Relatively specific to the connective tissue diseases are hyperkeratosis with follicular and acrosyringeal plugging, epidermal atrophy, basement membrane zone thickening, and prominent dermal mucinosis. In cases of cell-poor interface dermatitis owing to hypersensitivity reactions, where the insult is acute, no alteration of the stratum corneum or of the basement membrane zone is seen, nor is dermal mucinosis conspicuous. With respect to the subclassification of connective tissue disease, a skin biopsy processed for both routine microscopy and immunofluorescence analysis can provide information of essential value in support of the clinical diagnosis. However, knowledge of the clinical findings, including in the context of extracutaneous disease and serology (Table 5-10), must be integrated carefully to arrive at a correct diagnosis. The pathologist is in a powerful position to positively influence this process.

Lupus Erythematosus CLINICAL FEATURES Lupus erythematosus (LE) is an autoimmune disorder affecting skin, hematopoietic and lymphoreticular organs, joints, kidneys, lungs, serosa, and cardiovascular structures in concert or in isolation (see Chap. 3). Lupus erythematosus is subdivided clinically into systemic (SLE), subacute cutaneous (SCLE),

Table 5-10 Seropositivitya by Connective Tissue Disease Classification ANA SLE SCLE DLE CRST PSS MCTD

C

95-100 70 20-30 90 70 95-100

0-10 0 90 10 0

ss-DNA 70 10-20 10-20 0 10-20 30

ds-DNA 70 0 10-20 0 0 0

Sm b

90% Active disease 90% Inactive disease 30%

60% 30%

90% 0-10%

Abbreviations: SLE, systemic lupus erythematosus; SCLE, subacute cutaneous lupus erythematosus; DLE, discoid lupus erythematosus, ACR, America College of Rheumatology SOURCE: After Crowson and Magro.83

of the basement membrane zone or follicular plugging, and no significant deep perivascular or periadnexal infiltrate. Atrophy is variable but usually is present in lesions of SLE and SCLE. Lesions of DLE generally manifest a heavier superficial and deep perivascular and periappendageal lymphocytic infiltrate, basement membrane zone thickening, keratotic follicular plugging, and variable acanthosis and atrophy.83,100 DIFFERENTIAL DIAGNOSIS The differential diagnosis is that of lymphocytic interface dermatitis and embraces dermatomyositis, Sjögren syndrome, drug-related lupus erythematosus-like eruptions, polymorphous light eruption, Jessner lymphocytic infiltrate, and certain delayed-type hypersensitivity reactions and viral exanthemata.101,102,108,110,111 Kikuchi necrotizing lymphadenitis can produce skin lesions with a lymphocytic vasculopathy and cell-poor interface dermatitis identical to that seen in SLE.112 The idiopathic lichenoid eruptions lichen planus, lichen nitidus, and lichen striatus can be problematic if parakeratosis and atrophy are seen.113 Another pitfall is the distinction of lichen planus-like keratoses and lichenoid actinic keratoses from lesions of DLE in sun-damaged skin. Correlation with clinical, serologic, and immunofluorescence findings is imperative.

CHAPTER 5 ■ SUPERFICIAL AND DEEP PERIVASCULAR DERMATITIS

Abbreviations: ANA, antinuclear antibody; C, centromere; CRST, CREST syndrome; DLE, discoid lupus erythematosus; ds-DNA, double-stranded DNA; MCTD, mixed connective tissue disease; nRNP, nuclear ribonucleoprotein; PSS, progressive systemic sclerosis/scleroderma; SCLE, subacute cutaneous lupus erythematosus; SLE, systemic lupus erythematosus; Sm, Smith; ss-DNA, single-stranded DNA. a Expressed as percentage of cases. b Dependent on ethnicity. SOURCE: After Crowson and Magro.83

Direct Immunofluorescence: The Lupus Band Test and Its Implications for Pathogenesis of Connective Tissue Diseases The examination by fluorescence microscopy of frozen sections cut from lesional or nonlesional sun-exposed or nonsun-exposed skin received fresh, in saline

91

Table 5-12 Revised Criteria of the American College of Rheumatology for the Classification of Systemic Lupus Erythematosus

PART I ■ INFLAMMATORY REACTIONS IN THE SKIN

1. 2. 3. 4. 5. 6. 7. 8. 9.

Malar rash Discoid rash Photosensitivity Oral ulcers Arthritis Serositis: (a) pleuritis or (b) pericarditis Renal disorder: (a) proteinuria >0.5 g/24 h or 3+ , persistently, or (b) cellular casts Neurological disorder: (a) seizures or (b) psychosis (having excluded other causes, eg, drugs) Hematologic disorders: Hemolytic anemia Leukopenia 10 mast cells per 40 × field)

bullous pemphigoid, and pemphigoid gestationis.141 CLINICAL FEATURES Wells syndrome presents as arcuate, erythematous, indurated plaques typically on the upper back, extremities, or buttocks. As the lesions evolve, they may become indurated, and complete resolution usually occurs within months.140 HISTOPATHOLOGIC FEATURES Histology reveals a diffuse and, early on, massive infiltrate of eosinophils with few lymphocytes

CHAPTER 6 ■ NODULAR AND DIFFUSE CUTANEOUS INFILTRATES

Histopathologic Features Perivascular or diffuse mast cells within upper dermis

Rare progression to systemic mastocytosis

Table 6-20 Parasitic Causes of Diffuse Eosinophilic Infiltrates DISEASE

ORGANISM

Schistosomiasis

Schistosoma haematobium S japonicum S mansoni Taenia solium Spirometra sp. Onchocerca volvulus Dirofilaria immitis Ancylostoma braziliense Strongyloides stercoralis Gnathostoma spinigerum Trichinella spiralis Paragonimus skrjabini P westermani T canis T cati Dracunculus medinensis

Cysticercosis Sparganosis Onchocerciasis Dirofilariasis Larva migrans Strongyloidiasis Gnathostomiasis Trichinosis Paragonimiasis Toxocariasis Dracunculosis

131

PART I ■ INFLAMMATORY REACTIONS IN THE SKIN 132

A

B

 FIGURE 6-30 Wells syndrome. ( A ). A superficial and deep perivascular mixed inflammatory cell infiltrate containing numerous eosinophils and flame figures. ( B ) Flame figures are formed by degranulation of eosinophils upon collagen bundles.

(Fig. 6-30A). In areas where eosinophils have degranulated, so-called flame figures are created (see Fig. 6-30B). These represent dermal collagen fibers that become coated with bright red eosinophilic granules containing major basic protein surrounded by macrophages, sometimes with giant cells. Early lesions may result in subepidermal or intraepidermal vesicle/bulla formation. In later stages, macrophages with giant cells may predominate.140,141 The panniculus occasionally may be involved, one cause of eosinophilic panniculitis.59 In the proper clinical setting, flame figures are very suggestive of Wells syndrome, but isolated lesions of common dermatoses with numerous eosinophils may exhibit flame figures.141 A search to rule out associated conditions (especially internal malignancy, parasite infestation, and drug hypersensitivity) is warranted in patients with Wells syndrome (Table 6-21). DIFFERENTIAL DIAGNOSIS Cutaneous arthropod assaults owing to insects (tungiasis, myiasis, pediculosis), scabies, ticks, and spiders demonstrate dense superficial and deep perivascular and interstitial mixed-cell infiltrates with numerous eosinophils and are the most common demonstrable cause of clinical papular urticaria. Fortuitous sections may demonstrate embedded mouth or body parts, eggs, or excreta. Lesions of chronic urticaria or of physical urticaria demonstrate a perivascular lymphocytic infiltrate with scattered interstitial mixed-cell infiltrates composed of lymphocytes, neutrophils, and eosinophils. Papular dermatitis (subacute prurigo) features a relatively sparse superficial and deep perivas-

cular lymphocytic infiltrate with scattered interstitial eosinophils and, at times, overlying epidermal spongiosis.142 Virtually identical appearances are seen in papular dermatitis of HIV.130 Changes to the side of eosinophilic folliculitis may resemble Wells syndrome. Eosinophilic folliculitis may occur as an idiopathic condition in otherwise healthy individuals (Ofuji disease) or in the setting of HIV infection. Often cutting deeper into the tissue blocks of tangential samples

Table 6-21 Wells Syndrome

Clinical Features Most cases idiopathic, but Associations with: Drug hypersensitivity Parasites Internal malignancy Dermatophytes Arcuate, erythematous, indurated plaques Upper back, extremities, buttocks Histopathologic Features Diffuse eosinophils Flame figures Eosinophilic panniculitis, sometimes Granulomas, especially in late lesions Differential Diagnosis Hypereosinophilic syndrome Arthropod assault Allergic contact dermatitis Bullous pemphigoid Herpes gestationis Pruritic urticarial papules and plaques of pregnancy (PUPPP) Urticaria

reveals a folliculocentric infiltrate of eosinophils and lymphocytes that both surround and infiltrate the follicular epithelium, sometimes producing eosinophilic pustules.143 Urticarial lesions of bullous pemphigoid may feature slight psoriasiform hyperplasia, variable spongiosis with eosinophils in the epidermis (so-called eosinophilic spongiosis), and eosinophils in number in a slightly edematous papillary dermis. Both pemphigoid gestationis and pruritic urticarial papules and plaques of pregnancy (PUPPP) (or the polymorphous eruption of pregnancy) are pregnancy-associated dermatoses that feature superficial perivascular lymphocytic infiltrates with interstitial eosinophils. Spongiosis with eosinophils is common in pemphigoid gestationis but absent in PUPPP.144 Additionally, the density of eosinophils is much greater in pemphigoid gestationis and bullous pemphigoid, and in PUPPP they tend to involve the reticular dermis more than the papillary dermis.144 Angiolymphoid hyperplasia with eosinophilia (aka epithelioid hemangioma) is a vascular lesion that occurs most commonly on the head and neck. As its name implies, histology features a vascular proliferation with prominent endothelial cells, numerous eosinophils, and lymphoid aggregates, sometimes with germinal center formation. It is unclear as to whether this represents a reactive or neoplastic condition. The differential diagnosis of panniculitis with eosinophils includes erythema nodosum, vasculitis, Wells syndrome, drug reaction, atopic dermatitis, contact dermatitis, streptococcal infection, parasitic infection

(Gnathostoma or Toxocara canis), atheromatous emboli, foreign-body, malignancy, or lupus erythematosus panniculitis.145

Hypereosinophilic Syndrome

CLINICAL FEATURES The cutaneous lesions are pruritic, erythematous papules, plaques, or nodules and/or lesions of urticaria, angioedema, or dermatographism. They are distributed on trunk, extremities, or face.146 HISTOPATHOLOGIC FEATURES Histology demonstrates a superficial and deep perivascular mixed inflammatory cell infiltrate of eosinophils and lymphocytes. In some cases neutrophils and plasma cells may be present. Flame figures typically are not seen, but cutaneous microthrombi may be present.148 Cutaneous microthrombi most likely result from the large amounts of plateletactivating factor released by eosinophils. Similar microthrombi are seen in other involved organs, and their presence portends a bad prognosis.148 DIFFERENTIAL DIAGNOSIS Histologic diagnosis of this rare disorder requires clinicopathologic correlation because similar histologic appearances may be seen in many of the entities discussed in the differential diagnosis of Wells syndrome. Evidence of systemic involve-

20.

21.

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CHAPTER 6 ■ NODULAR AND DIFFUSE CUTANEOUS INFILTRATES

The hypereosinophilic syndrome is a systemic disorder featuring peripheral eosinophilia and eosinophilic infiltration of numerous organs, including heart, lungs, skin, kidneys, liver, gastrointestinal tract, and nervous system. The skin is the second most common organ to be involved, preceded only by the heart.146 Patients usually succumb to eosinophilic cardiomyopathy. According to the WHO classification of hematopoietic and lymphoid diseases, the hypereosinophilic syndrome is defined as persistent peripheral eosinophilia (≥1.5 × 109/L), for which no underlying cause can be found, and which is associated with signs and symptoms of organ system involvement. Also, there is no evidence of either clonality or cytogenetic abnormalities that would indicate a myeloproliferative/myelodysplastic syndrome or leukemia.147 It is a diagnosis of exclusion. Specifically, it requires exclusion of other known causes of peripheral eosinophilia, such as atopy, parasite infestation, drug hypersensitivity, Löeffler syndrome, chronic eosinophilic leukemia, and secondary eosinophilia due to lymphomas, myelodysplastic and myeloproliferative syndromes.

ment is suggestive of hypereosinophilic syndrome, but it is a diagnosis of exclusion (see NIH inclusion criteria above). Cutaneous microthrombi may provide a valuable clue to the diagnosis.148

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83. 84. 85.

86.

87.

88.

89.

90.

91. 92. 93. 94.

95.

96.

unusual presentation of sinus histiocytosis with massive lymphadenopathy (Rosai-Dorfman disease). Arch Dermatol. 1988;124:1246. Sangueza OP, Salmon JK, White CR, Beckstead JH. Juvenile xanthogranuloma: a clinical, histopatholgic, and immunohistochemical study. J Cutan Pathol. 1995;22:327. Zelger G, Cerio R, Orchard G, WilsonJones E. Juvenile and adult xanthogranuloma: a histological and immunohistochemical comparison. Am J Surg Pathol. 1994;18:126. Janney CG, Hurt MA, Santa Cruz DJ. Deep juvenile xanthogranuloma: aubcutaneous and intramuscular forms. Am J Surg Pathol. 1991;15:150. Gianotti R, Alessi E, Caputo R. Benign cephalic histiocytosis: a distinct entity or a part of a wide spectrum of histiocytic proliferative disorders of children? A histopathological study. Am J Dermatopathol. 1993;15:315. Umbert IJ, Winkelmann RK. Eruptive histiocytoma. J Am Acad Dermatol. 1989;20:958. Gibbs NF, O’Grady TC. Progressive eruptive histiocytoma. J Am Acad Dermatol. 1996;35:323. Caputo R, Marzano AV, Passoni E, et al. Unusual variants of non-Langerhans cell histiocytoses. J Am Acad Dermatol. 2007;57:1031. Oliver GF, Umbert I, Winkelmann RK. Reticulohistiocytoma cutis: review of 15 cases and an association with systemic vasculitis in two cases. Clin Exp Dermatol. 1990;15:1. Zelger B, Cerio R, Soyer HP, et al. Reticulohistiocytoma and multicentric reticulohistiocytosis: histopathologic and immunophenotypic distinct entities. Am J Dermatopathol. 1994; 16:577. LeBoit PE, Barr RJ, Burall S, et al. Primitive polypoid granular cell tumor and other cutaneous granular cell neoplasms of apparent nonneural origin. Am J Surg Pathol. 1991;15:48. Mentzel T, Wadden C, Fletcher CDM. Granular cell change in smooth muscle tumors of skin and soft tissue. Histopathology. 1994;24:223. Motley RJ, Jasani B, Ford AM, et al. Regressing atypical histiocytosis, a regressing cutaneous phase of Ki-1 positive anaplastic large cell lymphoma. Cancer. 1992;70:476. LeBoit PE. Lymphomatoid papulosis and cutaneous CD30+ lymphoma. Am J Dermatopathol. 1996;18:221. Taunton OD, Yeshurun D, Jarratt M. Progressive nodular histiocytoma. Arch Dermatol. 1978;114:1505. Burgdorf WHC, Kusch SL, Nix TE, Pitta J. Progressive nodular histiocytoma. Arch Dermatol. 1981;117:644. Bork K, Hoede N. Hereditary progressive mucinous histiocytosis in women: report of three members in a family. Arch Dermatol. 1988;124:1225. Schroder K, Hettmannsperger U, Schmuth M, et al. Hereditary progressive mucinous histiocytosis. J Am Acad Dermatol. 1996;35:298. Shapiro PE, Nova MP, Rosmarin LA, Halperin AJ. Multinucleate cell angiohistiocytoma: a distinct entity diagnosable

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99. 100.

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104. 105. 106. 107.

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110.

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112.

113.

114.

115.

116. 117.

118. 119.

120. 121.

122.

123. 124. 125. 126.

127.

128. 129.

130. 131.

132.

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tion with rheumatoid vasculitis. Arch Dermatol. 1989;125:1101. Scherbenske JM, Benson PM, Lupton GP, Samlaska CP. Rheumatoid neutrophilic dermatitis. Arch Dermatol. 1989;125:1105. Lowe L, Kornfeld B, Clayman J, Golitz LE. Rheumatoid neutrophilic dermatitis. J Cutan Pathol. 1992;19:48. Caughman W, Stern R, Haynes H. Neutrophilic dermatosis of myeloproliferative disorders. J Am Acad Dermatol. 1983;9:751. O’Loughlin S, Perry HO. A diffuse pustular eruption associated with ulcerative colitis. Arch Dermatol. 1978;114:1061. Jorizzo JL, Apisarntharnarax P, Subrt P, et al. Bowel-bypass syndrome without bowel bypass: bowel-associated dermatosis arthritis syndrome. Arch Intern Med. 1983;143:457. International Study Group Criteria in Behçet’s Disease. Criteria for diagnosis of Behçet’s disease. Lancet. 1990;335:1078. Jorizzo JL, Abernethy JL, White WL, et al. Mucocutaneous criteria for the diagnosis of Behçet’s disease: an analysis of clinicopathologic data from multiple international centers. J Am Acad Dermatol. 1995;32:968. Ergun T, Gurbuz O, Harvell J, et al. The histopathology of pathergy: a chronological study of skin hyperreactivity in Behçet’s disease. Int J Dermatol. 1998;37:929. Peters MS, Argenyi Z, Cerio R, et al. Friday evening slide symposium. J Cutan Pathol. 1993;20:465. Berger TG, Dhar A, McCalmont TH. Neutrophilic dermatoses in HIV infection. J Am Acad Dermatol. 1994;31:1045. Fitzpatrick JE. The cutaneous histopathology of chemotherapeutic reactions. J Cutan Pathol. 1993;20:1. Stahr BJ, Cooper PH, Caputo RV. Idiopathic plantar hidradenitis: a neutrophilic eccrine hidradenitis occurring primarily in children. J Cutan Pathol. 1994;21:289. Rabinowitz LG, Cintra ML, Hood AF, Esterly NB. Recurrent palmoplantar hidradenitis in children. Arch Dermatol. 1995;131:817. Nishimura M, Matsuda T, Muto M, Hori Y. Balanitis of Zoon. Int J Dermatol. 1990;29:421. Wong KF, Chan JKC, Li LPK, et al. Primary cutaneous plasmacytoma: report of 2 cases and review of the literature. Am J Dermatopathol. 1994;16:392. LeBoit PE. Dermatopathologic findings in patients infected with HIV. Dermatol Clin. 1992;10:59. McGovern TW, Erickson AR, Fitzpatrick JE. Sjögren’s syndrome plasma cell panniculitis and hidradenitis. J Cutan Pathol. 1996;23:170. Hurt MA, Santa Cruz DJ. Cutaneous inflammatory pseudotumor: lesions resembling “inflammatory pseudotumors” or “plasma cell granulomas” of extracutaneous sites. Am J Surg Pathol. 1990;14:764. Kodama A, Tani M, Hori K, et al. Systemic and cutaneous plasmacytosis with multiple skin lesions and poly-

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135.

136.

137.

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139. 140.

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142.

143.

144.

145.

146.

147.

148.

clonal hypergammaglobulinaemia: significant serum interleukin-6 levels. Br J Dermatol. 1992;127:49. Carey WP, Rico MJ, Nierodzik M, Sidhu G. Systemic plasmacytosis with cutaneous manifestations in a white man: successful therapy with cyclophosphamide/prednisone. J Am Acad Dermatol. 1998;38:629. Watanabe T, Tada Y, Nakamura K, et al. Failure to detect human herpesvirus type 8-DNA sequences in systemic plasmacytosis from HIV-uninfected Japanese patients. Br J Dermatol. 1999; 141:350. Kubota Y, Noto S, Takakuwa T. Skin involvement in giant lymph node hyperplasia (Castleman’s disease). J Am Acad Dermatol. 1993;29:778. Valent P, Horny H-P, Escribano L, et al. Diagnostic criteria and classification of mastocytosis: a consensus proposal. Leukemia Res. 2001;25:603. Kasper CS, Freeman RG, Tharp MD. Diagnosis of mastocytosis subsets using a morphometric point counting technique. Arch Dermatol. 1987;123:1017. Sweet WL, Smoller BR. Perivascular mast cells in urticaria pigmentosa. J Cutan Pathol. 1996;23:247. Aberer W, Konrad K, Wolff K. Wells’ syndrome is a distinctive disease entity and not a histologic diagnosis. J Am Acad Dermatol. 1988;18:105. Wood C, Miller AC, Jacobs A, et al. Eosinophilic infiltration with flame figures: a distinctive tissue reaction seen in Well’s syndrome and other diseases. Am J Dermatopathol. 1986;8:186. Sherertz EF, Jorizzo JL, White WL, et al. Papular dermatitis in adults: subacute prurigo, American style? J Am Acad Dermatol. 1991;24:697. McCalmont TH, Altemus D, Maurer T, Berger TG. Eosinophilic folliculitis: the histologic spectrum. Am J Dermatopathol. 1995;17:439. Pruritic urticarial papules and plaques of pregnancy vs. herpes gestationis, urticarial stage. In: Ackerman AB, White W, Guo Y, Umbert I (eds.) Differential Diagnosis in Dermatopathology IV. Philadelphia, PA: Lea & Febiger; 1994:26. Adame J, Cohen PR. Eosinophilic panniculitis: diagnostic considerations and evaluation. J Am Acad Dermatol. 1996; 34:229. Kazmierowski JA, Chusid MJ, Parrillo JE, et al. Dermatologic manifestations of the hypereosinophilic syndrome. Arch Dermatol. 1978;114:531. Bain B, Pierre R, Imbert M, et al. Chronic eosinophilic leukemia and the hypereosinophilic syndrome. In: Jaffe ES, Harris NL, Stein H, Vardiman JW (eds.) Tumours of Haematopoietic and Lymphoid Tissues. Lyon: IARC Press; 2001:29. Fitzpatrick JE, Johnson C, Simon P, Owenby J. Cutaneous microthrombi: a histologic clue to the diagnosis of hypereosinophilic syndrome. Am J Dermatopathol. 1987;9:419.

CHAPTER 6 ■ NODULAR AND DIFFUSE CUTANEOUS INFILTRATES

102.

by clinical and histologic features. J Am Acad Dermatol. 1994;30:417. Sass U, Noel JC, Andre J. Multinucleate cell angiohistiocytoma: report of two cases with no evidence of human herpesvirus-8 infection. J Cutan Pathol. 2000;27:258. Chang SN, Kim HS, Kim S-C, Yang WI. Generalized multinucleate cell angiohistiocytoma. J Am Acad Dermatol. 1996;35:320. Annessi G, Girolomoni G, Giannetti A. Multinucleate cell angiohistiocytoma. Am J Dermatopathol. 1992;14:340. Palazzo JP, Ellison DJ, Garcia IE, et al. Cutaneous malakoplakia simulating malignant lymphoma. J Cutan Pathol. 1990;17:171. Horn TD, Burke PJ, Karp JE, Hood AF. Intravenous administration of recombinant human granulocyte-macrophage colony-stimulating factor causes a cutaneous eruption. Arch Dermatol. 1991;127:49. Mehregan DR, Fransway AF, Edmonson JH, Leiferman KM. Cutaneous reaction to granulocyte-monocyte colony-stimulating factor. Arch Dermatol. 1992;128:1055. Scott GA. Report of three cases of cutaneous reactions to granulocytemacrophage colony-stimulating factor and a review of the literature. Am J Dermatopathol. 1995;17:107. Fitzpatrick JE. New histopathologic findings in drug eruptions. Dermatol Clin. 1992;10:19. Wood C, Severin GL. Unusual histiocytic reaction to Monsel’s solution. Am J Dermatopathol. 1980;2:261. Hanau D, Grosshans E. Monsel’s solution and histological lesions. Am J Dermatopathol. 1981;3:418. Elston DM, Bergfeld WF, McMahon JT. Aluminum tattoo: a phenomenon that can resemble parasitized histiocytes. J Cutan Pathol. 1993;20:326. Jorizzo JL, Solomon AR, Zanolli MD, Leshin B. Neutrophilic vascular reactions. J Am Acad Dermatol. 1988;19:983. Jordaan HF. Acute febrile neutrophilic dermatosis: a histopathological study of 37 patients and a review of the literature. Am J Dermatopathol. 1989;11:99. Malone JC, Slone SP, Wills-Frank LA, et al. Vascular inflammation (vasculitis) in Sweet syndrome. Arch Dermatol. 2002;138:345. Requena L, Kutzner H, Palmedo G, et al. Histiocytoid Sweet syndrome: a dermal infiltration of immature neutrophilic granulocytes. Arch Dermatol. 2005;141:834. Chow S, Pasternak S, Green P, et al. Histiocytoid neutrophilic dermatoses and panniculitides: variations on a theme. Am J Dermatopathol. 2007;29:334. Carlson JA, LeBoit PE. Localized chronic fibrosing vasculitis of the skin: an inflammatory reaction that occurs in settings other than erythema elevatum diutinum and granuloma faciale. Am J Surg Pathol. 1997;21:698. Delaporte E, Graveau DJ, Piette FA, Bergoënd HA. Acute febrile neutrophilic dermatosis (Sweet’s syndrome): associa-

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PART I ■ INFLAMMATORY REACTIONS IN THE SKIN

Intraepidermal Vesiculopustular Diseases Terence J. Harrist Brian Schapiro Lisa Lerner Cynthia M. Magro James Ramirez Jenny Cotton

Distinct diseases may have similar or even identical pathologic features. In addition, the histopathologic findings in each disease evolve over time. Thus the algorithmic approach to diagnosis in this group is, of necessity, complex but facilitates the diagnosis in this complex group of disorders (Figs 7-1 through 7-3, Table 7-1). Correlation of the clinical findings and historical data with the microscopic findings is often essential to derive a definitive diagnosis. The algorithm narrows the differential diagnosis to a few entities or a specific diagnosis through evaluation of the blister-cleft separation plane, the principal pathologic process, and if present, the inflammatory cell complement.

DEFINITIONS A wide variety of disorders may produce intraepidermal vesicles and pustules.

A blister is a fluid-filled cavity within or beneath the epidermis containing tissue

Level of vesicle/pustule

Subcorneal/intragranular layer of epidermis

Spongiosis Miliaria crystallina

Spinous layer Fig. 7-3

Pustule Fig. 7-2

Acantholysis

Focal transient acantholytic dermatosis (pemphigus foliaceus type)

Few acantholytic granular layer keratinocytes

+ DIF Pemphigus foliaceus

136

fluid, plasma, and a variable complement of inflammatory cells. Vesicles are blisters less than 0.5 cm in diameter, and bullae are blisters greater than 0.5 cm in diameter. A vesicopustule is a vesicle in which there is a prominent component of neutrophils. Some diseases produce microscopic slit-like spaces within the epidermis that are known as clefts. Clefts characteristically occur in the group of diseases that have focal acantholytic dyskeratosis as their histologic reaction pattern and do not, as a rule, have clinically apparent blisters. A pustule is a dense aggregate of neutrophils or eosinophils, viable or degenerated, with a small component of tissue fluid. A pustule is yellow-white clinically and resides intracorneally, within the stratum spinosum or at the dermalepidermal junction. A microabscess is a small aggregate of neutrophils or eosinophils

Diffuse

Dyskeratosis pemphigus foliaceus

– DIF SSSS

 FIGURE 7-1 Intraepidermal blistering and pustular diseases.

Suprabasal layer

Cytolysis Friction blister Epidermolytic hyperkeratosis Irritant contact dermatitis (rare)

Focal acantholytic dyskeratosis

Few rete Transient acantholytic dermatosis (Darier type)

Acantholysis

Pure acantholysis

Interface dermatitis Apoptosis Paraneoplastic pemphigus

Several rete Darier disease

Spinous layer Hailey-Hailey disease

Suprabasal only P vulgaris

Subcorneal/intragranular pustule

Neutrophils predominate

Vesiculopustule

Pustule

Infective organisms Impetigo Dermatophyte Candidiasis

Sterile

Epidermis Eosinophilic pustulosis (folliculitis)

Hair follicle Erythema toxicum neonatorum Eosinophilic folliculitis

Sterile

+ DIF

+ IgA IgA pemphigus

+ IgG Pemphigus foliaceus

– DIF Subcorneal pustular dermatosis Acropustulosis Transient neonatal pustular melanosis

Dermal plasma cells Secondary syphilis

Dermal eosinophils Drug eruption Scabies

Dermal neutrophils IgA pemphigus

 FIGURE 7-2 Intraepidermal blistering and pustular diseases.

observed histologically. At times a microabscess may be predominated by mononuclear cells usually Langerhans cells and/or lymphocytes. The separation plane is relatively constant in each vesiculobullous disease. Each process tends to reliably produce blisters in either the subcorneal/granular, spinous, or suprabasal zones in the epidermis. Occasionally, blisters may extend from one plane to another. Pustules tend to form in the subcorneal or intracorneal zone but are not limited to those locations. Spongiosis is the accumulation of extracellular fluid within the epidermis causing separation between adjacent keratinocytes. The keratinocytes often appear stellate with clear spaces separating them from their neighbors, producing a “spongy” appearance. As the degree of spongiosis increases, microscopic vesicles develop and may progress to macroscopic vesicles or bullae. In cases of

severe spongiosis, ballooning degeneration (intracellular edema) with subsequent rupture of the cell membranes (a form of cytolysis) may lead to a lacelike appearance (reticular degeneration). Spongiosis develops primarily due to transudation of serum from damaged or inflamed vessels within the superficial plexus. Ballooning degeneration occurs when the keratinocytes lose osmotic control. Acantholysis is the result of loss of appropriate keratinocyte-keratinocyte adherence. This adherence is mediated by tight junctions, adherens junctions, gap junctions, and desmosomes. The role of desmosomes in keratinocytic adhesion is paramount, and they are the last structures to split when acantholysis occurs. Acantholytic disorders that have been well characterized develop as sequelae of desmosomal dysfunction or disruption of the desmosomal connections with the intracellular keratin struc-

tural matrix. Keratinocyte-keratinocyte adhesion is a dynamic process because the relationship of one keratinocyte to another must change during epidermal maturation. Thus acantholysis may be viewed as a loss of equilibrium between the formation and dissolution of junctions. This dysequilibrium may occur primarily when the adhesion junctions are impaired directly or secondarily when keratinocytic viability is affected. Acantholytic keratinocytes are rounded with condensed eosinophilic cytoplasm, large nuclei, peripherally marginated chromatin, and prominent nucleoli. Cytolysis of keratinocytes, as well as apoptosis, may lead to blister formation. Cytolysis may occur in the normal epidermis when the structural matrix of the keratinocytes is overwhelmed by high levels of deleterious physical agents such as mechanical forces or heat. Mechanical energy applied parallel to the epidermis (friction) may lead to shearing between

CHAPTER 7 ■ INTRAEPIDERMAL VESICULOPUSTULAR DISEASES

Infective organisms Bullous impetigo (S aureus) Bullous dermatophyte Candida

Eosinophils predominate

137

Spinous layer blister/pustule

Cytolysis Herpes virus Friction blister

PART I ■ INFLAMMATORY REACTIONS IN THE SKIN

Spongiosis

Lymphocytes predominate

Eosinophils predominate

Neutrophils predominate

Miliaria rubra Spongiotic/eczematous dermatitis Transient acantholytic dermatitis (spongiotic foci) Pemphigus (very early) Miliaria rubra Pityriasis rosea Eczematous drug eruption

Incontinentia pigmenti Pemphigus (eosinophilic spongiosis; early lesions) Allergic contact dermatitis Spongiotic drug eruption

Spongiotic dermatitis irritant type impetiginized Seborrheic dermatitis Dermatophytosis Pustular drug eruption Pemphigus vulgaris (rare) Kawasaki disease Perifolliculitis, epidermal changes

Variable inflammation Hailey-Hailey disease Pemphigus foliaceus P vulgaris

Little inflammation

Focal Transient acantholytic dermatosis (Hailey-Hailey type)

Diffuse Hailey-Hailey disease

 FIGURE 7-3 Pemphigus vulgaris.Relatively discreet flaccid blisters, erosions and vegetating crusted lesions are present on nonerythematous skin of the upper and mid back.

keratinocytes and within keratinocytes themselves, that is, cytolysis. Minimal friction may lead to cytolysis when keratinocytes do not have a normal structural matrix, as in epidermolysis bullosa simplex. Immune-mediated cell necrosis in the context of antibody-dependent cellmediated immunity or a delayed-type hypersensitivity reaction may lead to blister formation, which most typically is subepidermal in nature. The morphologic hallmark of this pattern of necrosis is karyolysis producing colloid bodies. This is not to be confused with apoptosis, which is a unique form of cell death whereby individual, scattered single cells die without release of cellular contents. Such a pattern of programmed cell death usually does not lead to epidermal disruption.

SPONGIOTIC DERMATITIS 138

Acantholysis

The spongiotic disorders are covered in detail in Chapter 2.

ACANTHOLYTIC DERMATITIS (See Figs 7-1 through 7-3, Tables 7-1 and 7-2)

Pemphigus Vulgaris and Variants CLINICAL FEATURES Large and flaccid bullae develop on the oral mucosa, face, scalp, central chest, and intertriginous zones in older individuals (Table 7-3). Oral lesions are the first manifestation in 10% to 15% of patients and almost invariably develop during the course of the disease.1 Since the blisters are fragile, they collapse rather quickly giving place to erosions with the most common lesions in pemphigus. Vegetative lesions with prominent crusting and granulation tissue are also characteristic of pemphigus. The surrounding skin is typically nonerythematous. The ability to extend blisters by external pressure has been referred to as Nikolsky sign.

In 1% to 2% of cases of pemphigus vulgaris, vegetative plaques containing pustules may develop principally in the intertriginous areas.2 Referred to as pemphigus vegetans, it is thought by many to be a “reactive state” in pemphigus.2,3 Polyclonal IgG develops against the pemphigus vulgaris antigen, desmoglein 3, a desmosomal cadherin that mediates cell binding.4,5 Desmoglein 3 appears to be in greater concentration in the lower epidermis, the location of the suprabasal acantholytic blister of pemphigus vulgaris. The antigen-antibody union results in desmosomal dysfunction and potentiates dyshesion by causing production of a cytoplasmic proteinase, plasminogen activator, that is released into the squamous intercellular substance. Complement fixation may potentiate the acantholysis. In pemphigus vulgaris with cutaneous involvement there are antibodies to both desmoglein 3 and desmoglein 1.6 About 80% to 90% of patients have circulating

Table 7-1 Intraepidermal Blistering And Pustular Diseases PATHOLOGIC PROCESS

INFLAMMATORY CELLS

DISEASE

Subcorneal/ intragranular

Spongiosis Acantholysis

Lymphocytes —

Pustules

Neutrophils

Miliaria crystallina Staphylococcal scalded skin syndrome Pemphigus foliaceus Transient acantholytic dermatosis (Pemphigus foliaceus–like foci) Impetigo Bullous impetigo Subcorneal pustular dermatosis IgA pemphigus Dermatophytosis Candidiasis Pustular secondary lues Pustular drug eruption Acropustulosis of infancy Transient neonatal pustular melanosis Pustular Id reaction Pemphigus vulgaris (rare) Pustular psoriasis Scabies Erythema toxicum neonatorum Miliaria rubra Spongiotic/eczematous dermatitis Transient acantholytic dermatitis (spongiotic foci) Pemphigus (very early) Miliaria rubra Pityriasis rosea Eczematous drug eruption Incontinentia pigmenti Pemphigus (eosinophilic spongiosis; early lesions) Allergic contact dermatitis Spongiotic drug eruption Spongiotic dermatitis irritant type impetiginized Seborrheic dermatitis Dermatophytosis Pustular drug eruption Pemphigus vulgaris (rare) Kawasaki disease Perifolliculitis, epidermal changes Hailey-Hailey disease Transient acantholytic dermatosis (Hailey-Hailey-like foci) Hailey-Hailey disease Pemphigus foliaceus and variants (extension from subcorneal plane) Pemphigus vulgaris and variants (extension from suprabasal plane) Irritant contact dermatitis (rare) Herpes virus infection Friction blister Friction blister Epidermolytic hyperkeratosis Irritant contact dermatitis (rare) Pemphigus vulgaris and variants Darier disease Transient acantholytic disease (Pemphigus vulgaris–like foci) .

Eosinophils Spinous

Spongiosis

Lymphocytes

Eosinophils

Neutrophils

Acantholysis

Little inflammation

Variable inflammation

Cytolysis Suprabasal

Cytolysis

Acantholysis

Marked inflammation Little inflammation

CHAPTER 7 ■ INTRAEPIDERMAL VESICULOPUSTULAR DISEASES

SEPARATION PLANE

SOURCE: Data from Elder D, Elenitsas R, Jaworsky C, Johnson B. Lever’s Histopathology of the Skin: Algorithmic Classification of Skin Diseases for Differential Diagnosis. 8th ed. Philadelphia: Lippincott-Raven; 1997:61-116.

139

PART I ■ INFLAMMATORY REACTIONS IN THE SKIN

Table 7-2 Important Differential Diagnostic Features of Acantholytic Dermatoses

Subcorneal cleavage Intraspinous cleavage Suprabasal cleavage Cleft Blister Dyskeratosis Villi Tombstone basal keratinocyte Follicular involvement Epidermal hyperplasia Spongiotic early change Eosinophilic spongiosis

PEMPHIGUS FOLIACEUS

SSSS

+++

+++

−

−

−

−

−

0/+

−

+++

0/+

−

−

−

−

−

0/+

+++

+++

+++

+ (small)

− + + (some) − −

− + − − −

− + − + −

− + − +/+++ +++

− + − +++ +

++ − ++ +/+++ −

++ − + (some lesions) + −

+

−

−

++

+

+

−

−

−

+/++

0/+

+++

+

−

+

−

−

+

+

−

+

0/+

−

−

0/+ (some)

+++ (abscesses)

−

−

PEMPHIGUS VULGARIS

PEMPHIGUS VEGETANS

DARIER DISEASE

GROVER DISEASE

Legend: 0 = none; + = present; ++ = moderate change; +++ = marked change.

Table 7-3 Pemphigus Vulgaris and Variants

Clinical Features Flaccid bullae on skin; face, scalp, chest, and intertriginous areas (especially pemphigus vegetans) Oral mucosa involved in 100% cases Older individuals Histopathologic Features Suprabasal acantholysis with blister formation Involvement of hair follicles by acantholysis Spongiosis early Superficial perivascular mononuclear cell infiltrate Direct immunofluorescence: squamous epithelial intercellular deposition of lgG and possibly C3 Differential Diagnosis Other forms of pemphigus Benign familial pemphigus (Hailey-Hailey disease) Transient acantholytic dermatosis (Grover disease) Focal acantholytic dyskeratosis Acantholytic variants of actinic keratosis Herpesvirus infection

140

HAILEY-HAILEY DISEASE

IgG antibodies detectable by indirect immunfluorescence that show a general (but imperfect) correlation with disease activity. The IgG consists predominantly of the IgG4 subclass.7 HISTOPATHOLOGIC FEATURES The earliest stage is most often a paucicellular spongiotic dermatitis with edema most prominent in the lower epidermis. Less commonly the early phase is eosinophilic spongiosis. Later, acantholysis supervenes, leading first to the formation of clefts and then to clinically apparent blisters that arise in suprabasal location (Fig. 7-4). They frequently extend into follicular external root sheaths. The basal keratinocytes separate from one another but remain attached to the basal lumina, reminiscent of a “row of tombstones.”8 The acantholytic blister may be limited to the suprabasal plane or may extend higher within the epidermis. The acantholysis extends into appendages (Fig. 7-4E). The acantholytic keratinocytes are of relatively large size with prominent eosinophilic glassy cytoplasm, prominent nuclei with large nucleoli, and perinuclear clearing. There is a superficial perivascular lymphohistiocytic infiltrate with dermal

edema. As the lesions erode and ulcerate, a mixed infiltrate composed principally of neutrophils may develop. Older blisters may exhibit necrosis of the blister roof, with several keratinocytic layers lining the blister cavity on its lowermost aspect, due to keratinocyte migration and proliferation. As well, epidermal reti may elongate, giving rise to the so-called villi. A neutrophilic spongiotic dermatitis may be present in some cases of pemphigus vulgaris. In these, spongiosis is a much more prominent feature than acantholysis. There is a variant designated as pemphigus herpetiformis owing to the fact that the clinical lesions are small vesicles and resemble dermatitis herpetiformis. The histopathology resembles pemphigus vulgaris; however the segment of acantholysis is a fairly confined narrow zone corresponding to a clinical vesicle (Fig 7-4C,D). All patients with active pemphigus have IgG autoantibodies against the cell surface of keratinocytes detectable by direct and often indirect immunofluorescence (see also Appendix: Laboratory Methods). The pattern of intercellular space deposition of IgG may be identical in pemphigus vulgaris, pemphigus foliaceus (and their closely related variants

B

C

D

E

F

CHAPTER 7 ■ INTRAEPIDERMAL VESICULOPUSTULAR DISEASES

A

 FIGURE 7-4 Pemphigus vulgaris (A ) Relatively discreet flaccid blisters, erosions and vegetating crusted lesions are present on non-erythematous skin of the upper and mid back. (B ) Blister in suprabasilar location. In this well-developed lesion there is a suprabasalar cleft with acantholytic cells present in the blister cavity. (C ) Also seen are elongated epidermal rete below a single row of basal keratinocytes. (D,E ) In this case of pemphigus herpetiformis the lesions clinically are in the context of small vesicles which is captured histomorphologically. Note the small zone of suprabasilar acantholysis with intraepidermal tissue eosinophilia. (F,G ) In this biopsy of pemphigus there is prominent acantholysis which is most conpicuous in the lower third of the epidermis. There is prominent involvement of the follicle. Using an immunohistochemical methodology, intercellular deposits of C3d can be observed within the epidermis, hence corroborative of the diagnosis of pemphigus. (H,I,J ) There are cases whereby a mixed pemhigus pemphigoid pattern is seen despite no underlying malignancy (ie, mimicking paraneoplastic pemphigus). This particular patient was 17 years old, otherwise healthy, in whom a pemphigus-like eruption developed clinically. Histologically, a combined pemhigoid and pemphigus pattern was seen. While the direct immunofluroescent studies showed only linear deposits of IgG along the dermal epidermal junction without any supervening intercellular pattern, the C3d assay showed intercellular deposits while the C4d demonstrated a sharp linear staining pattern. ELISA studies conducted on the patient’s peripheral blood confirmed the diagnosis of a hybrid circulating antibody profile with specificity to both pemphigus and pemphigoid antigens.

141

H

I

J

PART I ■ INFLAMMATORY REACTIONS IN THE SKIN

G

 FIGURE 7-4 (Continued )

142

pemphigus vegetans and erythematosus, respectively), and the majority of patients with drug-induced pemphigus. The immunohistochemical demonstation of C3d on formalin-fixed paraffin-embedded tissue is a new technique that can be applied to highlight this pattern of diagnostic intercellular staining (Figure 7-4F).9 However, the site of predominant immunoreactivity may correspond to the location of intra-epidermal cleavage, that is, the suprabasal epidermis in pemphigus vulgaris and the superficial spinous layer in pemphigus foliaceus. The latter patterns of immunofluorescence provide evidence of pemphigus vulgaris versus pemphigus foliaceus, but final diagnosis should be based on the level of cleavage observed by light microscopy and the clinical context. In addition to IgG, C3 and other complement components are often (up to 50% of cases) found on direct immunofluorescence and exhibit a similar intercellular pattern of immunore-

activity as with IgG. Pemphigus should not be diagnosed if only C3 is present. About 30% of patients exhibit deposition of IgM and IgA. In pemphigus vegetans, the initial lesions are identical to those of pemphigus vulgaris. As the lesions age, verrucous epidermal hyperplasia develops (Fig 7-5) with prominent eosinophilic spongiosis and eosinophilic pustules. Neutrophilrich intraepidermal pustules may be present as well. Acantholysis is often focal and may be difficult to identify. DIFFERENTIAL DIAGNOSIS Although the clinical and histopathologic features of pemphigus vulgaris are often distinctive, other acantholytic disorders such as pemphigus foliaceus and variants, druginduced pemphigus, IgA pemphigus, paraneoplastic pemphigus, familial benign pemphigus, transient acantholytic dermatosis, herpesvirus infection, and acantholytic variants of actinic keratosis

may enter into the differential diagnosis. Pemphigus vulgaris is distinguished from pemphigus foliaceus and variants only by the suprabasal location of cleavage in pemphigus vulgaris versus the superficial cleavage in pemphigus foliaceus, that is, a subcorneal/granular blister with or without dyskeratosis. Pemphigus erythematosus in addition may show basal layer vacuolopathy of the epidermis and a supervening positive lupus band test, the latter being defined by a granular deposits of immunoglobulin and complement along the dermal epidermal junction. A clear association with a drug may be necessary to separate drug-induced pemphigus from pemphigus vulgaris; however, some cases with drug-induced pemphigus do not have detectable antibodies by immunofluorescence. IgA pemphigus differs from pemphigus vulgaris by demonstrating subcorneal or intraepidermal neutrophilic pustules with mininimal or no acantholysis and

crowding and atypia of the basilar keratinocytes, and the clinical presentation as a solitary lesion. The presentation of pemphigus as eosinophilic spongiosis without vesicles raises a rather extensive differential diagnosis, the principal entities of which are mentioned in Fig. 7-6 (also see Chap. 2). Clinical information and immunofluorescence studies are needed for definitive diagnosis in most instances.

Pemphigus Foliaceus and Variants

B  FIGURE 7-5 (A) Pemphigus vegetans. In this early lesion there is irregular epidermal hyperplasia with hyperkeratosis and hypergranulosis. In the suprabasal zone and lower stratum spinosum, there is acantholysis and accumulation of eosinophils, which may progress to eosinophilic pustules. (B ) In this particular case of herpes while there are features reminiscent of pemphigus, there are striking cytopathic changes that one associates with herpetic cytopathic effect, including an effaced heterochromatin, beading of the nuclear membrane, and multinucleation.

positive immunoreactivity for IgA in an intercellular pattern in the epidermis in the absence of concomitant IgG or with lesser degrees of IgG. Paraneoplastic pemphigus is distinctive because of a close relationship with cancer, the usual widespread nature of the eruption and striking mucocutaneous involvement, histologically the presence of interface alterations and dyskeratosis resembling erythema multiforme, and both intercellular and BMZ patterns of immunofluorescence in addition to acantholysis. Familial benign pemphigus (HaileyHailey disease) is discriminated from pemphigus by the usual presence of acanthosis, acantholysis involving at least half of the epidermis in a diffuse pattern, possibly some dyskeratosis, the lack of appendageal involvement, and finally, negative immunofluorescence results. Pemphigus differs from transient acantholytic dermatosis (ie, Darier and Grover diseases) by exhibiting greater

breadth of involvement of the epidermis and involvement of appendages by the acantholysis versus only focal epidermal involvement in focal acantholytic dyskeratosis and the usual absence of dykeratosis. On occasion, pemphigus may mimic herpesvirus infection by showing, in addition to acantholysis, alterations suggesting viral cytopathic changes of herpes, that is, the “ground glass” nuclear changes, rounded appearing hypereosinophilic cytoplasms, and multinucleation. Paraneoplastic pemphigus affecting the oral mucosa may be difficult to distinguish from oral herpes, both occurring in the immunosuppressed individuals. Regenerative epithelial changes encountered in paraneoplastic pemphigus can be associated with multinucleation although the characteristic nuclear changes of herpes are not seen. Acantholytic variants of actinic keratosis are usually distinguished from pemphigus by the presence of parakeratosis,

FOGO SELVAGEM Fogo selvagem is similar clinically but develops in people who live adjacent to rivers and streams in Brazil.10,11 An arthropod (Simulium sp.) vector may mediate this disorder. It has been hypothesized that a component of the saliva within the arthropod vector triggers antibody development to desmoglein 1. In both pemphigus foliaceus and fogo selvagem, polyclonal IgG in the serum is directed against desmoglein 1, a desmosomal cadherin.4,12 Desmoglein 1 may be of a greater concentration in the upper epidermis. This distribution likely explains the subcorneal-granular layer cleavage plane of the blisters and lack of intraoral lesions. As with pemphigus vulgaris the IgG is of the IgG4 subclass.6

CHAPTER 7 ■ INTRAEPIDERMAL VESICULOPUSTULAR DISEASES

CLINICAL FEATURES Flaccid, fragile bullae rupture to leave shallow crusted erosions and crusted patches and plaques on the trunk, intertriginous areas, proximal extremities, and head and neck of middle-aged and older individuals (Table 7-4). Most patients experience a chronic generalized course, although some patients present with an exfoliative dermatitis. The mucous membranes are almost never involved.

A

PEMPHIGUS ERYTHEMATOSUS This is a variant of pemphigus foliaceus that has features of both pemphigus and lupus erythematosus. It usually presents with erythematous plaques of the nose and malar areas. HISTOPATHOLOGIC FEATURES Three characteristic histopathologic patterns occur: eosinophilic spongiosis and abscesses,13,14 subcorneal/granular blisters with few acantholytic keratinocytes, and subcorneal/ granular blisters with dyskeratotic granular cells (see Table 7-4). The latter pattern is diagnostic of this disorder (Fig. 7-6). As in pemphigus vulgaris, the cleavage plane is not exact and may extend to the suprabasal zone, on occasion rendering histologic distinction of the two principal pemphigus variants difficult.15 There is an associated superficial perivascular dermatitis with

143

and cultures and negative immunofluorescence findings. Pemphigus foliaceus is separated from the other disorders by IgG or lack of any positivity on immunofluorescence studies. Both pemphigus erythematosus and paraneoplastic pemphigus usually demonstrate deposition of immunoreactants, that is, IgG in intercellular and BMZ patterns, and must be discriminated by other findings (clinical, histopathologic, and laboratory).

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A

144

Drug-Induced Pemphigus

B  FIGURE 7-6 (A,B) Pemphigus foliaceus. There is acantholysis of the granular layer with loss of the stratum corneum. Accumulation of neutrophils in the acantholytic blister may lead to confusion with bullous impetigo. The acantholytic granular cells are seen in Fig. 7-3B.

Table 7-4 Pemphigus Foliaceus and Variants

Clinical Features Crusted erosions and patches Very fragile flaccid bullae Middle-aged and elderly Trunk, head and neck, intertriginous areas, and proximal extremities “Butterfly rash” mimicking lupus erythematosus seen in pemphigus erythematosus Histopathologic Features Subcorneal/granular blister with acantholytic keratinocytes or dyskeratotic granular cells Variable eosinophilic spongiosis Direct immunofluorescence: squamous epithelial intercellular deposition of IgG and possibly C3 Possible accentuation in superficial epidermis Pemphigus erythematosus usually shows linear or granular IgG and possibly C3 at the epidermal basement membrane zone Differential Diagnosis Other forms of pemphigus Impetigo Staphylococcal scalded skin syndrome Subcorneal pustular dermatosis

edema. As the lesions erode and age, a mixed infiltrate may appear. Bacterial suprainfection may lead to a picture identical to that of impetigo. The histologic features of pemphigus erythematosus are identical to those of pemphigus foliaceus; however, in rare cases, an interface dermatitis similar to that of lupus erythematosus has been present. As discussed above for pemphigus vulgaris, all patients with active pemphigus foliaceus have positive direct immunofluorescence for IgG and to a lesser degree C3 in a typical intercellular pattern that is indistinguishable from other forms of pemphigus or concentrated in the superficial epidermis. In the vast majority of cases, indirect immunofluorescence is also positive. Pemphigus erythematosus, as already mentioned, usually exhibits BMZ deposition of immunoglobulin and occasionally C3 in addition to the intercellular immunoreactivity. The most common immunoreactant is one of IgM. DIFFERENTIAL DIAGNOSIS See “Differential Diagnosis” above for pemphigus vulgaris. Other considerations not already mentioned include bacterial and fungal infections, especially impetigo and bullous impetigo; pustular drug eruption; IgA pemphigus; and subcorneal pustular dermatosis. Impetigo is distinguished from pemphigus foliaceus by a positive Gram stain (not present in bullous impetigo)

CLINICAL FINDINGS Drug-induced pemphigus usually begins as a nonspecific eruption of morbilliform, annular, or urticarial plaques without blisters (Table 7-5). Patients with penicillamine-induced pemphigus have a characteristic generalized toxic erythema that has been labeled “a toxic pre-pemphigus rash.”15,16 After a variable period of time, blisters develop on scaly crusted patches, similar to those of pemphigus foliaceus in most cases. The most common causative drugs include penicillamine and captopril.17 Drug-induced pemphigus can be separated into two subsets. In the first group, representing 10% of cases, pemphigus antibodies are produced and cause

Table 7-5 Drug-Induced Pemphigus

Clinical Features Morbilliform, annular, or urticarial plaques progress to blisters Scaly crusted plaques Penicillamine and captopril are common causative agents Histopathologic Features Plane of blister separation may occur in either subcorneal or suprabasal plane Subacute eczematous dermatitis seen in early lesions Direct immunofluorescence study: intercellular deposition of IgG and possibly C3 in epidermis in almost all active cases Differential Diagnosis Other forms of pemphigus Benign familial pemphigus (Hailey-Hailey disease) Transient acantholytic dermatosis (Grover disease) Focal acantholytic dyskeratosis Acantholytic variants of actinic keratosis Herpesvirus infection Impetigo Staphylococcal scalded skin syndrome Subcorneal pustular dermatosis

acantholysis identical to that of idiopathic pemphigus.8 Direct binding of the drugs to the pemphigus antigens may render the antigens immunogenic in such cases. In the second group, the drugs or metabolites, rich in sulfhydryl groups, accumulate within the epidermis. They may cleave the disulfide bonds of keratin and incorporate into the keratin molecule itself because of their similarity to cystine, leading to dyshesion which is nonimmunologically mediated. Another possible mechanism is the direct binding of the drugs to the pemphigus vulgaris and foliaceus antigens, disrupting their interchain disulfide bonds.

DIFFERENTIAL DIAGNOSIS See the discussions under “Pemphigus Vulgaris and Variants” and “Pemphigus Foliaceus and Variants” above.

Clinical Features Flaccid vesicles, pustules, and bullae arise on an erythematous base Middle-aged to elderly patients Histopathologic Features Subcorneal or intraepidermal pustules Direct immunofluorescence: intercellular IgA in epidermis Differential Diagnosis Other forms of pemphigus Impetigo Staphylococcal scalded skin syndrome Subcorneal pustular dermatosis

Circulating IgA is directed against adhesion molecules within the epidermis. The antigens against which the antibodies are directed are neither the pemphigus foliaceus nor vulgaris antigen but rather desmocollins and/or desmogleins.18,19 The differing clinical presentation likely relates to the fact that the antibodies are directed against desmocollins in particular Dsc1 (subcorneal pustular type) and desmogleins (intraepidermal pustular type) that have differing distributions within the epidermis.20 HISTOPATHOLOGIC FEATURES Two histologic patterns, a subcorneal pustular pattern and an intraepidermal pustular pattern, are observed18,21,22 (see Table 7-6). In the former there are subcorneal vesi-

copustules with minimal acantholysis. In the latter there are intraepidermal pustules containing small to moderate numbers of neutrophils throughout the breadth of the epidermis (Fig. 7-7). Suprabasal separation is not apparent. Minimal acantholysis is apparent such that the histologic reaction pattern is best considered an intraepidermal pustular dermatosis. In one case no neutrophil infiltration was present.23 IgA pemphigus is defined by the presence of IgA intercellular deposition on immunofluorescence. DIFFERENTIAL DIAGNOSIS The major entities to be considered include pemphigus foliaceus, subcorneal pustular dermatosis, bacterial and fungal infection (particularly impetigo), pustular psoriasis, pustular drug eruption, and nutritional deficiency such as migratory necrolytic erythema and, on occasion, Hailey-Hailey disease. Systematic evaluation with clinical history for evidence of psoriasis, drug ingestion, and so on; special stains and cultures for infective organisms; and immunofluorescence studies should facilitate making a specific diagnosis.

Paraneoplastic Pemphigus CLINICAL FEATURES Paraneoplastic pemphigus was first recognized by Anhalt et al.20,24 It is characterized by a generalized polymorphous eruption of blisters and lichenoid papules23,25 (Table 7-7). Painful oral ulcerations are a prominent

IgA Pemphigus Synonyms: IgA pemphigus foliaceus, IgA herpetiform pemphigus, intercellular IgA vesiculopustulardermatosis, intercellular IgA dermatosis, intraepidermal IgA pustulosis. CLINICAL FEATURES IgA pemphigus is a pruritic vesiculopustular eruption that develops in middle-aged to older individuals, often involving the axilla, trunk, and extremities (see Table 7-6). Many cases of subcorneal pustular dermatosis, in which immunologic investigation was not undertaken, may represent IgA pemphigus. Flaccid vesicles, pustules, or bullae arise on erythematous bases similar to the lesions of pemphigus foliaceus. The pustules tend to coalesce and form an annular pattern. Mucous membrane involvement is very rare. Patients have been segregated into two groups, one with a subcorneal pustular dermatosis and one with an intraepidermal pustular eruption.

 FIGURE 7-7 IgA pemphigus, subcorneal pustular variant. There is a large subcorneal pustule with spongiform pustulation. This picture is similar to Sneddon-Wilkinson disease, pustular psoriasis, and a pustular drug eruption.

CHAPTER 7 ■ INTRAEPIDERMAL VESICULOPUSTULAR DISEASES

HISTOPATHOLOGIC FEATURES In the early eruption there is an acute to subacute eczematous dermatitis (see Table 7-2). Eosinophils may be present, on occasion giving rise to eosinophilic spongiosis. The blister separation plane may either be in the subcorneal or suprabasal zones such that in well-developed lesions the histologic features are identical to pemphigus foliaceus or vulgaris. The immunofluorescence findings also may be indistinguishable from other forms of pemphigus; however in those cases of drug-induced pemphigus where the acantholysis is not immunologically triggered the direct immunofluorescence is characteristically negative.

Table 7-6 IgA Pemphigus

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Table 7-7 Paraneoplastic Pemphigus

146

Clinical Features Polymorphous eruption of blisters and lichenoid papules Painful oral ulcerations Remission may be seen following successful treatment of underlying malignancy Histopathologic Features Suprabasal acantholysis Interface dermatitis; either vacuolar or lichenoid type Direct immunofluorescence: squamous epithelial intercellular deposition of IgG, or IgM, and possibly C3 usually shows linear or granular IgG, or IgM, and possibly C3 in epidermal basement membrane zone Differential Diagnosis Other forms of pemphigus Benign familial pemphigus (Hailey-Hailey disease) Transient acantholytic dermatosis (Grover disease) Focal acantholytic dyskeratosis Acantholytic variants of actinic keratosis Lichen planus Erythema multiforme

feature and have been present in all cases. The ulcerations are often extensive over the lower lips, mimicking those of Stevens-Johnson syndrome. Any mucosal surface may be involved and pseudomembraneous conjunctivitis is a common occurence. Cutaneous involvement is characterized by lichenoid papules often involving the palms and the soles (which helps differentiate the disorder from pemphigus vulgaris). With one possible exception, all patients have had known or occult malignancies,26 including Hodgkin disease, thymoma, chronic lymphocytic leukemia, and other hematopoietic malignancies, as well as bronchogenic carcinoma and retroperitoneal sarcoma.27 The disorder is aggressive and generally refractory to treatment. Successful treatment of the underlying malignancy may induce a remission of the pemphigus. A panoply of autoantibodies is directed against a number of epidermal antigens and bind to simple, columnar, and transitional epithelia in addition to epidermis. Initial studies identified four proteins with molecular weights 250, 230, 210, and 190 kd. Since this discovery the antigens have been further characterized and new antigens have been described.20 A 170-kd antigen is present in nealy all PNP sera

and represents a novel transmembrane glycoprotein.20 The 210-kd protein is a doublet consisting of envoplakin and periplakin. The 250-kd protein is desmoplakin 1 and the 230-kd protein is bullous pemphigoid antigen 1; desmoplakin is structurally homologous to the bullous pemphigoid antigen and hence the antibodies to the bullous pemphigoid antigen 1 may really reflect molecular mimickry rather than being indicative of a true overlap with bullous pemphigoid. Perhaps corroborative of this theory is the fact that patients with paraneoplastic pemphigus do not demonstrate antibodies to bullous pemphigoid antigen II. In addition, antibodies to desmoglein 1 and 3 have been reported.20. HISTOPATHOLOGIC FEATURES The hallmarks include suprabasal acantholysis with principally basal layer keratinocyte apoptosis and an interface dermatitis that resembles erythema multiforme or lichen planus28

(Fig. 7-8; see also Table 7-7). Some cases may appear identical to pemphigus vulgaris without interface dermatitis and apoptosis. It is important to note that acantholysis may be focal or not present at all in a single lesion. Thus the lesions may appear as either a purely erythema multiforme-like interface dermatitis or a cell-rich lichenoid interface dermatitis.29 Thus biopsies of more than one lesion or level sections of a biopsy specimen may be necessary to make the diagnosis. One of the authors has encountered a patient assumed to have severe refractory graftversus-host disease based on the extent of interface change with epithelial destruction. The patient was subsequently established to have the classic serologic profile that one associates with paraneoplastic pemphigus. The light microscopic findings in this particular case are illustrated (Figure 7-8A,B). Direct immunofluorescence studies usually reveal (1) intercellular IgG and

A

B  FIGURE 7-8 (A ) Paraneoplastic pemphigus. There is an interface dermatitis with necrotic keratinocytes (left) in association with a suprabasalar acantholytic blister (right). (B ) In this case of paraneoplastic pemphigus, the dominant reaction pattern is a destructive interface dermatitis resembling accelerated chronic lichenoid graft-versus-host disease. From a clinical perspective, the patient had a severe erythematous scaly rash reminiscent of severe graft-versus-host disease.

atosis and only a few acantholytic keratinocytes. Few inflammatory cells are present initially, but later, neutrophilic infiltration may be striking, producing a histopathologic picture identical to that of impetigo.

DIFFERENTIAL DIAGNOSIS See the discussion for differential diagnosis under “Pemphigus Vulgaris and Variants”. One recent study revealed intercellular staining of the rat bladder incubating serum with fluoresceinated IgG. These contained circulating aAbs to a 190-kDa protein corresponding to periplakin, suggesting a role of these antibodies in the pathogenesis of TEN. There are indeed cases of paraneoplastic pemphigus which clinically and even histologicaly resemble toxic epidermal necrolysis.30 Antidesmoplakin antibodies have been identified in rare cases of pemphigus foliaceus and pemphigus vulgaris. Another study identified intercellular staining within rat bladder epithelium in 21% of sera from patients with classic pemphigus vulgaris; the majority of these patients had antibodies to both DP I (250 kDa) and DP II (210 kDa).31

Synonym: Keratosis follularis.

Generalized Staphylococcal Scalded Skin Syndrome (Ritter Disease) CLINICAL FEATURES Affected infants develop painful, tender, orange-tinged erythematous rash associated with a purulent conjunctivitis, otitis media, occult nasopharyngeal infection, or umbilical stump infection.32 The disease begins with fever and malaise followed by an erythematous rash. Within 2 days, large, flaccid bullae develop in the axillae and groin and around body orifices and become generalized. The mucous membranes are not involved. Healing usually is complete within 5 to 7 days. The associated infection is usually caused by staphylococci of group II phage type 71. They produce two epidermolysins (Exfoliative Toxins A and B) that enter the circulation and deposit in the skin, producing a subcorneal-granular layer separation plane.33 Exfoliative toxin A exerts specific protease activity on desmoglein 1.6 In adults, these epidermolysins usually are cleared rapidly due to the presence of neutralizing antibodies. Neonates do not have these neutralizing antibodies and have a decreased renal clearance of the epidermolysin. HISTOPATHOLOGIC FEATURES There is a subcorneal separation without dysker-

Darier Disease CLINICAL FEATURES Darier disease is an autosomal dominant genodermatosis presenting in the first two decades of life (Table 7-8).34 Reddish-brown papules covered by a tenacious scale coalesce into large plaques that involve the chest, back, head, and groin (Fig. 7-9A). Cobblestone papules are present on the oral mucosa. Warty papules are present acrally. Several variants have been described, including a hyperkeratotic form involving the intertriginous zones, a vesiculobullous form in which true clinical blisters may develop, and a linear pattern that likely represents an epidermal nevus with the histopathologic features of focal acantholytic dyskeratosis. The Darier disease gene has been localized to chromosome 12q23-q24.1. Mutations in the ATP2A2 gene that encodes the sarco/endoplasmic reticulum Ca2+-ATPase isoform 2 are found in patient’s with the disease.35 This is one of the proteins that catalyses the transport of calcium from the cytosol into the lumen of the endoplasmic reticulum,36 and is a critical determinant in resulting in enhanced apoptosis. Not surprisingly therefore Bcl-2 expression is diminished in the lesional epidermis of patients

Table 7-8 Darier Disease

Clinical Features Scaly papules and plaques of the head, back, chest, and groin Autosomal dominant Histopathologic Features Acantholytic dyskeratosis with suprabasal split Corps ronds and corps grains Acanthosis and parakeratosis Direct immunofluorescence: nonspecific pattern of granular C3 at the epidermal basement membrane zone Differential Diagnosis Hailey-Hailey disease Transient acantholytic dermatosis (Grover disease) Pemphigus vulgaris

with Darier disease.37 Similar genetic defects have been discovered in patients with Hailey-Hailey disease, a point which will be alluded to presently. HISTOPATHOLOGIC FEATURES Darier disease is the prototype of focal acantholytic dyskeratosis38 (Fig. 7-9; see also Table 7-8). Over a broad zone within the epidermis there is an acantholytic suprabasal cleft, beneath which the basal cell layer is intact. The rete may be elongated, giving rise to so-called villi. Within the cleft (lacuna) are occasional acantholytic keratinocytes. Above the acantholytic cleft, the compact, enlarged keratinocytes of the stratum granulosum are surmounted by parakeratotic keratinocytes within the hyperkeratotic stratum corneum. Dyskeratosis may be apparent in the acantholytic cells or above or lateral to the acantholytic cleft. Large keratinocytes contain clumped keratohyalin granules in an eosinophilic cytoplasm and have large nuclei with perinuclear chromatin clumping and halos about prominent nucleoli. At the other end of the spectrum are small, seed-shaped cells with pyknotic, elongated nuclei and dense, eosinophilic, often elongated cytoplasm. The dyskeratotic acantholytic granular cells are referred to as corp ronds, and the dyskeratotic parakeratotic cells are referred to as corp grains. Intermediate forms may be observed. The focal acantholytic dyskeratosis occurs in the background of a papillary epidermal hyperplasia, with the dells between the papillae formed by keratotic debris. In other zones of papillary epidermal hyperplasia there may be small foci of ill-defined focal acantholytic dyskeratosis. Immunofluorescence studies do not detect any immunoreactants in Darier disease. Expectedly C3d and C4d studies conducted on paraffinembedded tissue are negative.9 DIFFERENTIAL DIAGNOSIS The principal conditions to be considered include transient acantholytic dermatosis (TAD; Grover disease), Hailey-Hailey disease, and on occasion, other acantholytic processes such as herpesvirus infection and pemphigus. TAD may be indistinguishable from Darier disease but usually shows additional histologic patterns resembling pemphigus, Hailey-Hailey disease, and spongiotic dermatitis (see below). Hailey-Hailey disease differs from Darier disease by demonstrating more diffuse or full-thickness acantholysis and less dyskeratosis. There is dyskeratosis, however it is very distinctive. Many of the cells

CHAPTER 7 ■ INTRAEPIDERMAL VESICULOPUSTULAR DISEASES

possibly C3 and (2) BMZ IgG, C3, and occasionally IgM (in both granular and linear patterns). Indirect immunofluorescence demonstrates intercellular IgG in all cases studied. When using rat bladder as substrate, the demonstration of an intercellular staining pattern is held to be diagnostic.

147

B

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A

C  FIGURE 7-9 Darier disease. (A ) Brown papules with adherent scale show coalescence into a plaque involving the midline of the chest and upper abdomen. (B ) There is an epidermal invagination filled with ortho- and parakeratotic debris. A suprabasalar lacuna with dyskeratotic acantholytic cells is present. (C) At higher power, the typical large keratinocytes with perinuclear halos and clumped keratohyalin granules in eosinophilic cytoplasm (corps ronds) and the small seed-shaped cells with pyknotic nuclei and dense eosinophilic cytoplasm (corps grains) are noted.

throughout the spinous layer demonstrate perinuclear eosinophilic globules (ie, dyskeratosis), although without any alterations of the nucleus. In fact the nucleus may have a somewhat activated appearance with a finely dispersed chromatin and conspicuous nucleoli. Pemphigus shows more diffuse suprabasilar acantholysis with involvement of appendages, usually no dyskeratosis (except for pemphigus foliaceus), and positive immunofluorescence as compared with none in Darier disease. Herpesvirus is discriminated by clear-cut viral cytopathic changes, that is, multinucleate keratinocyte giant cells with molding of nuclei and “ground glass” chromatin. Perhaps one of the cardinal hallmarks that is rarely emphasized is the characteristic beading of the nuclear membrane, the sequelae of virions exiting the cells with segments of the nuclear membrane.

Hailey-Hailey Disease 148

Synonym: Familial benign pemphigus.

CLINICAL FEATURES This autosomal dominant genodermatosis presents in adolescence or adulthood with localized, recurrent vesicles arising on erythematous bases (Table 7-9). The vesicles often become eroded and develop scale crust. The plaques expand serpiginously, with healing or ensuing vegetation (Fig. 7-10A). Lesions are usually limited to the intertriginous areas, sides of the neck, and less commonly, the antecubital, perianal, and inframammary zones. Lesions may extend elsewhere and in rare cases become widespread. Maceration and fissuring may be prominent, particularly in intertriginous areas. The Hailey-Hailey disease gene has been mapped to chromosome 3q.39 Recent studies have shown mutations in the ATP2C1 gene that codes for a P-type Ca2+ transport ATPase is the cause of the disease.40 It is unclear how the gene products result in keratinocyte dyshesion but they may be involved in assembly of the desmosomes.36 Cell cultures of keratinocytes derived from patients with Hailey-Hailey disease will result in epi-

dermal monolayers associated with acantholysis. Friction or superinfection may augment the acantholysis. HISTOPATHOLOGIC FEATURES Full-thickness acantholysis of the stratum spinosum develops in a hyperplastic epidermis, resulting in an appearance resembling a “dilapidated brick wall” without a discrete suprabasal cleft (Fig. 7-10; see also Table 7-9). The acantholysis does not extend down follicles. Basal layer budding and villi are usually less prominent than those observed in Darier disease. Dyskeratosis is usually minimal. The roof of the blister consists of intact upper stratum spinosum or stratum granulosum. In the later lesions, the upper portion of the epidermis degenerates into a parakeratotic crust, above the residual acantholytic epidermis. In some cases a subacute to chronic eczematous dermatitis may be present. Immunofluorescence studies are also negative, as in Darier disease. DIFFERENTIAL DIAGNOSIS One must primarily consider pemphigus and Darier

Table 7-9 Hailey-Hailey Disease

(Fig. 7-11; Fig 7-11A see also Table 7-10): focal acantholytic dyskeratosis resembling Darier disease, full-thickness acantholysis mimicking Hailey-Hailey disease, small suprabasalar clefts as observed in pemphigus vulgaris, and a spongiotic dermatitis. Any or all of these histologic patterns may be present in an individual biopsy from an individual patient.43 The most common pattern is pemphigus

A

Table 7-10 Transient Acantholytic Dermatosis (Grover Disease) B  FIGURE 7-10 Hailey-Hailey disease. (A ) Erythematous vegetative and scaling plaque in axilla. (B ) There is extensive acantholysis of the stratum spinosum in a hyperplastic epidermis. The degree of acantholysis is much greater than that seen in Pemphigus vulgaris.

disease (see preceding discussions for the differential diagnosis for each respective condition).

Transient Acantholytic Dermatosis Synonym: Grover disease. CLINICAL FEATURES Also known as Grover disease, transient acantholytic dermatosis (TAD) is characterized by pruritic discrete papulovesicles on the chest, back, and thighs, usually in middle-

aged or elderly men (Table 7-10), often following sun exposure.41 The appellation transient is appropriate in some cases; however, in others, the process may persist for several years. The pathogenesis is unknown. Some recent work suggests an association with miliaria.42 In some studies a loss of desmosomal proteins has been reported. HISTOPATHOLOGIC FEATURES Any of four histologic patterns may be observed in small foci, often only several rete wide

CHAPTER 7 ■ INTRAEPIDERMAL VESICULOPUSTULAR DISEASES

Clinical Features Fragile flaccid blisters give rise to scale crust Intertriginous areas, neck, perianal, inframammary, and antecubital regions Autosomal dominant Histopathologic Fearures Acantholysis giving rise to dilapidated brick wall appearance in at least half of epidermis Acanthosis Often slight dyskeratosis Direct immunofluorescence: nonspecific pattern Differential Diagnosis Darier disease Transient acantholytic dermatosis (Grover disease) Pemphigus vulgaris

Clinical Features Pruritic papulovesicles on chest, back, and thighs Middle-aged or elderly men Histopathologic Features Acantholytic dyskeratosis in small foci Four histological patterns: Focal acantholytic dyskeratosis as in Darier disease Hailey-Hailey disease pattern Pemphigus vulgaris or foliaceus pattern Spongiotic dermatitis pattern Any or all four patterns may be present in a single biopsy Direct immunofluorescence: nonspecific pattern Differential Diagnosis Darier disease Hailey-Hailey disease Pemphigus vulgaris or foliaceus Spongiotic dermatitis

149

sites of the keratin 1 gene and keratin 10 gene complexes.44 It is thought that the abnormal keratins cannot form a normal cytoskeleton and result in the aggregated tonofilaments that have been observed on electron microscopic evaluation.

PART I ■ INFLAMMATORY REACTIONS IN THE SKIN

A

B  FIGURE 7-11 (A ) Grover disease, Darier pattern.There are two well-developed foci of acantholytic dyskeratosis. In the dermis, a superficial perivascular lymphocytic infiltrate is present. Eosinophils may be seen in the infiltrate. (B ) Grover disease. The biopsy shows small foci of suprabasilar acantholytic dyskeratosis associated with an area of bandlike lymphocytic infiltration. Typically the foci of acantholysis are very small in this setting and there may be an accompanying prominent inflammatory cell infiltrate.

vulgaris-like, with Darier-like the second most common.43 DIFFERENTIAL DIAGNOSIS Because the four histologic patterns just described may occur in TAD, the differential diagnosis includes Darier disease, Hailey-Hailey disease, pemphigus, and a spongiotic dermatitis. TAD is distinguished from the latter entities based on the presence of two or more histologic patterns and their limitation to small foci, often only several rete wide. On occasion, these foci may be larger, rendering it difficult to make a specific diagnosis without clinical information.

also occur, including localized annular hyperkeratotic plaques and palmoplantar keratoderma. Recent studies have shown mutations on chromosomes 12 and 17, the respective

HISTOPATHOLOGIC FEATURES Beneath compact hyperorthokeratosis, there is striking keratinocytic cytoplasmic vacuolization extending from the granular layer to the suprabasal zone (Fig. 7-12). At the periphery of the vacuoles there is condensation of cytoplasmic elements, including markedly enlarged keratohyalin granules and dense eosinophilic granules that resemble trichohyalin. The irregularly shaped shrunken nuclei are preserved. The blisters occur in irregular fashion throughout the stratum malpighii due to coalescence of the vacuoles. The background epidermis exhibits irregular psoriasiform hyperplasia, but this feature may not be present in early lesions. It should be remembered that these exact histologic events can occur as a part of congenital ichthyosiform bullous erythroderma, as the principal histologic findings of epidermal nevi, and as incidental small foci within the epidermis, analogous to focal acantholytic dyskeratosis. DIFFERENTIAL DIAGNOSIS Although the clinical and histopathologic features are distinctive, one might consider verruca, a viral vesicle, or a spongiotic dermatitis as other diagnostic possibilities.

Friction Blisters CLINICAL FEATURES These blisters develop mainly on the soles and palms as a result of repetitive actions producing mechanical forces applied parallel to the cutaneous

CYTOLYTIC DERMATITIS

Epidermolytic Hyperkeratosis

150

CLINICAL FEATURES Epidermolytic hyperkeratosis is an autosomal dominantly inherited genodermatosis that presents at birth with widespread blistering followed by a generalized icthyosis (see Chap. 14). Other milder phenotypes

 FIGURE 7-12 Epidermolytic hyperkeratosis. Beneath diffuse hyperorthokeratosis there is vacuolization of the suprabasalar keratinocytes. The vacuolated keratinocytes have a characteristic appearance with large keratohyalin granules. Trichohyalin granules are often present as well.

Table 7-11 Friction Blister

Clinical Features Palms and soles most common sites affected History of mechanical injury at site affected Histopathologic Features Blister with intraepidermal cleavage Individual necrotic keratinocytes Hemorrhage is common Differential Diagnosis Epidermolysis bullosa simplex superficialis

HISTOPATHOLOGIC FEATURES The intraepidermal cleavage, a result of cytolysis of keratinocytes, may be present in the superficial or lower stratum spinosum46 (see Fig 7-13 and Table 7-11). There are individual necrotic keratinocytes with cytoplasmic strands of disrupted keratinocytes. Pale degenerated keratinocytes, which have been sheared, are located on the superior and inferior aspects of the blister.45-47 The blister fluid is usually clear due to transudation. When the shearing force extends into the dermis, hemorrhage into the blister cavity is common. DIFFERENTIAL DIAGNOSIS The differential diagnosis includes epidermolysis bullosa simplex superficialis (see Chap. 14).

Thermal Burns First-degree burns are those in which the lower epidermis is intact and only the upper epidermis is necrotic. The nuclei appear pyknotic and the cytoplasm pale, giving the upper epidermis a mummified, ghostlike appearance. Extensive dermal edema leads to transudation of fluid above the intact lower superficial vessels and forming a purulent layer beneath the necrotic epidermis.48 Second- and thirddegree burns are not discussed because they do not give rise to intraepidermal blisters or pustules.

 FIGURE 7-13 Friction blister. In this biopsy from an acral site, there is intraepidermal cleavage in the stratum spinosum with a minimal inflammatory cell infiltrate.

VESICULOPUSTULAR DISEASES

Impetigo and Bullous Impetigo CLINICAL FEATURES In impetigo, red papules that transform into vesicles and pustules develop at sites where abrasions, insect bites, or excoriations disrupt the cutaneous barrier. Honey-colored crusts develop rapidly. Secondary, impetigo may develop in all varieties of eczematous dermatitis, particularly atopic eczema. Ordinary impetigo is caused by infection by group A streptococci.49 Bullous impetigo is almost entirely due to infections by S aureus, primarily phage group 2, type 71, which produces an epidermolysin identical to that implicated in staphococcal scalded skin syndrome. The exfoliatin targets desmoglein 3 resulting in a picture that closely resembles pemphigus foliaceus. In bullous impetigo, vesicles, bullae, and vesicopustules form on erythematous macules and plaques. HISTOPATHOLOGIC FEATURES In ordinary nonbullous impetigo, neutrophils migrate throughout the epidermis to form subcorneal pustules. The exocytosis of neutrophils as single cells and clusters into the hyperplastic and spongiotic epidermis resembles psoriasis. There is usually prominent edema in the upper

dermis and diapedesis of neutrophils from the superficial vessels. In contrast, bullous impetigo begins as a fluid-filled acantholytic blister in a subcorneal location. Few acantholytic keratinocytes are present, and neutrophils may be sparse. As the vesicopustule ages, it usually becomes filled with neutrophils (Figure 7-14 A,B). Otherwise, the features are similar to those of nonbullous impetigo, although the inflammatory infiltrate and reactive epidermal changes are usually less intense. Bacterial cocci, often few in number, may be noted within the stratum corneum, pustules, or vesicopustules and are best demonstrated by a tissue Gram stain (Figure 7-14 C,D). DIFFERENTIAL DIAGNOSIS The major entities to be considered include other infective processes such as dermatophytosis, Candida infection, syphilis, pemphigus foliaceus, IgA pemphigus, subcorneal pustular dermatosis, pustular psoriasis, pustular drug eruption, pustular bite reaction, pustular vasculitis, a neutrophilic dermatosis such as pyoderma gangrenosum, and a nutritional deficiency such as that due to zinc or an amino acid, resulting in an eruption such as migratory necrolytic erythema. Systematic evaluation with clinical history for evidence of

CHAPTER 7 ■ INTRAEPIDERMAL VESICULOPUSTULAR DISEASES

surface in normal individuals (Table 7-11). In the mechanobullous diseases, only minimal friction will produce blisters due to a lack of appropriate structural integrity of the epidermis and dermis. Friction blisters are caused by shearing forces within the epidermis. They tend to occur where the epidermis is thick and firmly attached to the underlying tissues.45

151

PART I ■ INFLAMMATORY REACTIONS IN THE SKIN

A

B

C

D

 FIGURE 7-14 (A,B,C, and D). In this case of bullous impetigo there is a rather striking superficial acantholysis resulting in a picture that closely resembles pemphigus foliaceus. However a Gram stain shows numerous gram-positive cocci within the blister cavity.

psoriasis, drug ingestation, and so on; special stains and cultures for infective organisms; and immunofluorescence studies should facilitate making a specific diagnosis.

Candidiasis

152

CLINICAL FEATURES Red papules and plaques develop, most frequently in the intertriginous areas. Pustules may develop at the surface, often at the edges. Satellite pustules also may develop around the spreading plaque. Candida albicans is the most frequent infectious agent. It is a dimorphic fungus that produces both yeasts (2-5 μm) and pseudohyphae. Local disruption of the integrity of the upper epidermis, such as maceration and abrasion, facilitates infection. While other mechanisms are at play, mannin in the fungal cell walls fixes complement, which then leads to neutrophilic infiltration.

HISTOPATHOLOGIC FEATURES There is neutrophilic permeation of the parakeratotic stratum corneum.50 Beneath the stratum corneum, micropustules coalesce into larger pustules. Neutrophils, as single cells and small clusters, permeate the underlying stratum spinosum, which is spongiotic. The underlying dermis is edematous, with a perivascular and interstitial infiltrate composed principally of neutrophils. Although the yeasts and branching pseudohyphae, which are 2 to 5 μm in diameter, may be demonstrable on routine H&E stain, PAS stain is more reliable in revealing the organisms. It may be difficult to specifically identify the agent as C albicans, leading to the need for culture in selected cases. DIFFERENTIAL DIAGNOSIS See “Impetigo and Bullous Impetigo” above.

Pustular Secondary Lues CLINICAL FEATURES Approximately 3 to 6 weeks after the chancre, secondary lesions may develop. Macules and papules (mimicking pityriasis rosea) develop on the trunk, extremities, and palms and soles. Mucous patches are common. Pustules are usually a later development. Dissemination of Treponema pallidum to distant sites is the etiology. They are spiral bacteria that range from 7 to 15 μm in length and 0.25 μm in width. Intact spirochetes are demonstrated in histopathologic sections in up to 30% of secondary lesions using Warthin-Starry silver stain or Dieterle stain. HISTOPATHOLOGIC FEATURES Subcorneal pustules surmount a variably platelike acanthotic or psoriasiform epidermis. Numerous neutrophils transverse the stratum spinosum. In the dermis there is a

variable perivascular and lichenoid lymphohistiocytic infiltrate often rich in plasma cells. In fact, plasma cells are observed in up to 75% of these late-stage lesions. This is in contrast to early lesions of secondary syphilis, in which only a perivascular lymphohistiocytic infiltrate may be observed. The infiltration extends into the interstitium in some lesions with numerous macrophages. DIFFERENTIAL DIAGNOSIS See “Impetigo and Bullous Impetigo” above.

CLINICAL FEATURES Pustules and vesicopustules develop on erythematous skin (Table 7-12). The lesions may be annular or serpiginous and have a predilection for flexural surfaces as well as axillary and inguinal folds. Subcorneal pustular dermatosis may occur in association with IgA gammopathy, multiple myeloma, or other neutrophilic dermatoses. It also has been described in association with rheumatoid arthritis and inflammatory bowel disease.51-54 It is presumed that the neutrophils are responding to chemotactic factors present in the subcorneal zone, in particular tumor necrosis factor alpha, which has been identified in the blister fluid (Fig. 7-4). Those cases of subcorneal pustular dermatosis with squamous intercellular deposits of IgA are best classifed as IgA pemphigus.52

Table 7-12 Subcorneal Pustular Dermatosis (Sneddon-Wilkinson)

Clinical Features Pustules develop in erythematous skin Predilection for flexural skin, axillary and inguinal folds Histopathologic Features Subcorneal neutrophil-rich pustules Superficial and deep perivascular mononuclear cell infiltrates Direct immunofluorescence: negative Differential Diagnosis Impetigo Candida Dermatophytosis Staphylococcal scalded skin syndrome Psoriasis Keratoderma blenorrhagicum (Reiter disease) IgA pemphigus Pemphigus foliaceus Pustular drug eruption

 FIGURE 7-15 Subcorneal pustular dermatosis (Sneddon-Wilkinson disease). There is a florid subcorneal pustule containing neutrophils. This tense pustule is distinct from the flaccid pustule of bullous impetigo.

HISTOPATHOLOGIC FEATURES Subcorneal neutrophil-rich pustules and scale crust are present (Fig. 7-15 ; see also Table 7-13). The pustules tend to be tense rather than flaccid (see Fig. 7-4 ). In most cases the underlying edematous spongiotic stratum malphigii contains only few neutrophils, and eosinophils are absent or rare. Occasional acantholytic keratinocytes may be present at the lower edge of the pustule, primarily in older lesions. These changes surmount a psoriasiform epidermis with little change or, in older lesions, a psoriasiform eruption with exocytosis of lymphocytes as well. There is a superficial and deep perivascular infiltrate of lymphocytes and histiocytes that on occasion may give rise to a bandlike pattern. DIFFERENTIAL DIAGNOSIS See “IgA Pemphigus” and “Impetigo and Bullous Impetigo” above.

Table 7-13 Erythema Toxicum Neonatorum

Clinical Features Pustules and macules arise in the first few days of life Face, torso, and extremities Histopathologic Features Intraepidermal and subcorneal eosinophilic pustules in hair follicles Differential Diagnosis Scabies Incontinentia pigmenti Eosinophilic folliculitis

Pustular Drug Reaction CLINICAL FEATURES Drug-induced pustular eruptions have been reported infrequently. Drugs implicated include antibiotics (including streptomycin, cotrimoxazole, and oxytetracycline) and other drugs, including chloramphenicol, pyrimethamine, diltiazem, furosemide, and carbamazepine. Patients usually present 3 to 10 days after initiation of therapy with diffuse macular erythema and multiple non-follicular-based pustules. In addition, malaise, chills, and low-grade fever may be present. The term acute generalized exanthematous pustulosis describes a pustular drug reaction characterized by fever, leukocytoclasis, and a rapidly evolving pustular eruption on an erythematous base.55 The dermatitis rapidly resolves after withdrawal of the offending drug.

CHAPTER 7 ■ INTRAEPIDERMAL VESICULOPUSTULAR DISEASES

Subcorneal Pustular Dermatosis/ Sneddon-Wilkinson Disease

HISTOPATHOLOGIC FEATURES Foci of neutrophilic spongiosis with or without subcorneal or intraepidermal pustules are seen. The process may be based around the acrosyringium or follicle. There is underlying papillary dermal edema and a perivascular infiltrate usually containing eosinophils. DIFFERENTIAL DIAGNOSIS See “IgA Pemphigus” and “Impetigo and Bullous Impetigo” above. The differential diagnosis includes pustular psoriasis,56 Reiter disease, subcorneal pustular dermatosis, impetigo, pemphigus foliaceus, and a pustular id reaction. The presence of eosinophils excludes pustular psoriasis, Reiter disease, subcorneal pustular

153

dermatosis, and impetigo. In Reiter disease, vasculitis is usually present. In pustular psoriasis, a background of conventional psoriasis may or may not be present. Pemphigus foliaceus shows acantholysis. In difficult cases, immunofluorescence will help distinguish neutrophil-rich pemphigus foliaceus from a pustular drug reaction.

PART I ■ INFLAMMATORY REACTIONS IN THE SKIN

Infantile Acropustulosis CLINICAL FEATURES Recurrent crops of intensely pruritic vesicles or pustules develop most commonly in black infants at birth or during the first year of life.57,58 The lesions involve predominantly the distal extremities, particularly the palms and soles, dorsa of the hands and feet, and the sides of the fingers and toes. Individual lesions heal with hyperpigmentation, and the process resolves within 2 years in most cases. Some patients have a history of atopic dermatitis, and in several patients there has been associated scabetic infestation. The etiology is unknown. HISTOPATHOLOGIC FEATURES Early lesions reveal spongiosis and small foci of epidermal necrosis, apoptosis, and exocytosis of neutrophils and eosinophils. Later lesions reveal subcorneal and intraepidermal vesicopustules59,60 containing numerous neutrophils and admixed eosinophils (Fig. 7-16 ). A few cases have shown a predominance of eosinophils. There is minimal papillary dermal edema and a sparse mixed-cell perivascular infiltration. As in all intraepidermal pustular disorders, PAS stain and tissue Gram stain should be performed in order to exclude infection. DIFFERENTIAL DIAGNOSIS See “IgA Pemphigus” and “Impetigo and Bullous Impetigo” above.

Transient Neonatal Pustular Melanosis CLINICAL FEATURES Flaccid vesicopustules on the trunk and diaper area are present at birth.61 The vesicopustules rupture after 1 to 2 days, leaving hyperpigmented macules with collarettes of scale. The pathogenesis is unknown.

154

HISTOPATHOLOGIC FEATURES Vesicopustules in the intracorneal or subcorneal zones contain neutrophils with an admixture of eosinophils. There is slight spongiosis. The papillary dermis is edematous with an infiltrate of neutrophils and eosinophils around superficial vessels. Later lesions consist only of basal hypermelanosis.

 FIGURE 7-16 Infantile acropusulosis. There is a vesicopustule involving the follicular epithelium. The vesicle is composed of neutrophils admixed with eosinophils.

DIFFERENTIAL DIAGNOSIS See “Impetigo and Bullous Impetigo” above. Some have suggested that erythema toxicum neonatorum and neonatal pustular melanosis are related disorders.

Erythema Toxicum Neonatorum CLINICAL FEATURES Erythema toxicum neonatorum is characterized by pustules that develop on macules, papules, or wheals distributed on the face, torso, and proximal extremities (Table 7-13). The pustules arise within the first 2 days of life, being occasionally present at birth. On occasion, vesicles precede the development of the pustules. The pathogenesis is unknown. HISTOPATHOLOGIC FEATURES In macular lesions, a sparse perivascular infiltrate is associated with mild papillary dermal edema. The papules reveal numerous eosinophils and some neutrophils in the outer root sheath of hair follicles, giving rise to eosinophilic pustules overlying follicular orifice (see Table 7-13). Intraepidermal subcorneal pustules consisting predominantly of eosinophils are also present.62 DIFFERENTIAL DIAGNOSIS See “Neonatal Pustular Melanosis” above. One also might consider eosinophilic pustular folliculitis/ pustulosis in the differential diagnosis.

REFERENCES 1. Younus J, Ahmed AR. The relationship of pemphigus to neoplasia. J Am Acad Dermatol. 1990;23:498.

2. Korman N. Pemphigus. J Am Acad Dermatol. 1988;18:1219. 3. Korman NJ. Pemphigus. Dermatol Clin. 1990;8:689. 4. Stanley JR, Koulu L, Thivolet C. Pemphigus vulgaris and pemphigus foliaceus autoantibodies bind different molecules (abstract). J Invest Dermatol. 1984; 82:439. 5. Thivolet J. Pemphigus: past, present and future. Dermatology. 1994;189(suppl 2):26. 6. Devries DT, Warren SJ. Recent advances in intraepidermal blistering diseases. Adv Dermatol. 2002;18:203. 7. Sitaru C, Mihai S, Zillikens D. The relevance of the IgG subclass of autoantibodies for blister induction in autoimmune bullous skin diseases. Arch Dermatol Res. 2007 April;299(1):1-8. 8. Korman NJ, Eyre RW, Zone J, et al. Drug-induced pemphigus: autoantibodies directed against the pemphigus antigen complexes are present in penicillamine and captopril-induced pemphigus. J Invest Dermatol. 1991;96:273. 9. Magro C, Dyrsen M. The Use of C3d and C4d as a diagnostic adjunct in the evaluation of inflammatory skin disease Journal of the American Academy of Dermatology. In press 10. Crosby DL, Diaz LA. Endemic pemphigus foliaceus. Fogo selvagem. Dermatol Clin. 1993;11:453. 11. Warren SJ, Lin MS, Giudice GJ, et al. The prevalence of antibodies against desmoglein 1 in endemic pemphigus foliaceus in Brazil. Cooperative Group on Fogo Selvagem Research. N Engl J Med. 2000;343:23. 12. Koulu L, Kusumi A, Steinberg MS, et al. Human autoantibodies against a desmosomal core protein in pemphigus foliaceus. J Exp Med. 1984;160:1509. 13. Emerson RW, Wilson Jones E. Eosinophilic spongiosis in pemphigus. Arch Dermatol. 1968;97:252. 14. Jablonska S, Chorzelski TP, Beutner EH, et al. Herpetiform pemphigus, a variable pattern of pemphigus. Int J Dermatol. 1975;14:353.

31. 32. 33.

34. 35.

36.

37.

38. 39.

40.

41. 42.

43. 44.

contain autoantibodies to periplakin. Br J Dermatol. 2006;155:337-343. Cozzani E, Dal Bello MG, Mastrogiacomo A. Antidesmoplain antibodies in pemphigus vulgaris. Br J Dermatol. 2006;154:634-638. Resnick SD. Staphylococcal toxin-mediated syndromes in childhood. Semin Dermatol. 1992;11:11. Florman AL, Holzman RS. Nosocomial scalded skin syndrome. Ritter’s disease caused by phage group 3 Staphylococcus aureus. Am J Dis Child. 1980;134:1043. Burge SM, Wilkinson JD. Darier-White disease: a review of the clinical features in 163 patients. J Am Acad Dermatol. 1992;27:40. Sakuntabhai A, Ruiz-Perez V, Carter S, et al. Mutations in ATP2A2, encoding a Ca2+ pump, cause Darier disease. Nat Genet. 1999;21:271,. Dhitavat J, Fairclough RJ, Hovnanian A, et al. Calcium pumps and keratinocytes: lessons from Darier’s disease and HaileyHailey disease. Br J Dermatol. 2004;150:821. Pasmatzi E, Badavanis G, Monastiri LA, Tsambaos D. Reduced expression of the antiapoptotic proteins of the BCL-2 genfamily in the lesional epidermis of patients with Darier’s disease. J Cutan Pathol. 2007;34:234-238. Pani B, Singh BB. Darier’s disease: a calcium-signaling perspective. Cell Mol Life Sci. 2008;65:205. Ikeda S, Welsh EA, Peluso AM, et al. Localization of the gene whose mutations underlie Hailey-Hailey disease to chromosome 3q. Hum Mol Genet. 1994;3:1147. Dobson-Stone C, Fairclough R, Dunne E, et al. Hailey-Hailey disease: molecular and clinical characterization of novel mutations in the ATP2C1 gene. J Invest Dermatol. 2002;118:338. Grover RW. Transient acantholytic dermatosis. Arch Dermatol. 1970;101:426. Hu CH, Michel B, Farber EM. Transient acantholytic dermatosis (Grover’s disease). A skin disorder related to heat and sweating. Arch Dermatol. 1985; 121:1439. Davis MD, Dinneen AM, Landa N, et al. Grover’s disease: clinicopathologic review of 72 cases. Mayo Clin Proc. 1999;74:229. Syder AJ, Yu QC, Paller AS, et al. Genetic mutations in the K1 and K10 genes of patients with epidermolytic hyperkeratosis. Correlation between location and disease severity. J Clin Invest. 1994;93:1533.

45. Sulzberger MB, Cortese TA, Fishman L, et al. Studies on blisters produced by friction. I. Results of linear rubbing and twisting technics. J Invest Dermatol. 1966; 47:456. 46. Naylor PF. Experimental friction blisters. Br J Dermatol. 1955;67:327. 47. Brehmer-Andersson E, Goransson K. Friction blisters as a manifestation of pathomimia. Acta Derm Venereol. 1975;55:65. 48. Sevitt S. Histological changes in burned skin. In: Sevitt S (eds.) Burns: Pathology and Therapeutic Application. London: Butterworth & Co; 1957:18. 49. Dajani AS, Ferrieri P, Wannamaker LW. Natural history of impetigo. II. Etiologic agents and bacterial interactions. J Clin Invest. 1972;51:2863. 50. Lever W, Schaumburg-Lever G. Histopathology of the Skin. 7th ed. Philadelphia, PA: Lippincott: 1990:368. 51. Burns RE, Fine G. Subcorneal pustular dermatosis. AMA Arch Derm. 1959;80:72. 52. Cheng S, Edmonds E, Ben-Gashir M, et al. Subcorneal pustular dermatosis: 50 years on. Clin Exp Dermatol. 2008;33:229. 53. Dal Tio R, Di Vito F, Salvi F. Subcorneal pustular dermatosis and IgA myeloma. Dermatologica. 1985;170:240. 54. Wilkinson DS. Subcorneal pustular dematosis. Bull Soc Fr Dermatol Syphiligr. 1962;69:674. 55. Sidoroff A, Halevy S, Bavinck JN, et al. Acute generalized exanthematous pustulosis (AGEP)—a clinical reaction pattern. J Cutan Pathol. 2001;28:113. 56. Spencer JM, Silvers DN, Grossman ME. Pustular eruption after drug exposure: is it pustular psoriasis or a pustular drug eruption? Br J Dermatol. 1994;130:514. 57. Jarratt M, Ramsdell W. Infantile acropustulosis. Arch Dermatol. 1979;115:834. 58. Newton JA, Salisbury J, Marsden A, et al. Acropustulosis of infancy. Br J Dermatol. 1986;115:735. 59. Bundino S, Zina AM, Ubertalli S. Infantile acropustulosis. Dermatologica. 1982; 165:615. 60. Palungwachira P. Infantile acropustulosis. Australas J Dermatol. 1989;30:97. 61. Ramamurthy RS, Reveri M, Esterly NB, et al. Transient neonatal pustular melanosis. J Pediatr. 1976;88:831. 62. Freeman RG, Spiller R, Knox JM. Histopathology of erythema toxicum neonatorum. Arch Dermatol. 1960;82:586.

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15. Perry HO. Pemphigus foliaceus. Arch Dermatol. 1961;83:52. 16. Pisani M, Ruocco V. Drug-induced pemphigus. Clin Dermatol. 1986;4:118. 17. Ruocco V, Sacerdoti G. Pemphigus and bullous pemphigoid due to drugs. Int J Dermatol. 1991;30:307. 18. Ebihara T, Hashimoto T, Iwatsuki K, et al. Autoantigens for IgA anti-intercellular antibodies of intercellular IgA vesiculopustular dermatosis. J Invest Dermatol. 1991;97:742. 19. Hashimoto T, Yasumoto S, Nagata Y, et al. Clinical, histopathological and immunological distinction in two cases of IgA pemphigus. Clin Exp Dermatol. 2002;27:636. 20. Robinson ND, Hashimoto T, Amagai M, et al. The new pemphigus variants. J Am Acad Dermatol. 1999;40:649. 21. Hodak E, David M, Ingber A, et al. The clinical and histopathological spectrum of IgA-pemphigus—report of two cases. Clin Exp Dermatol. 1990;15:433. 22. Teraki Y, Amagai N, Hashimoto T, et al. Intercellular IgA dermatosis of childhood. Selective deposition of monomer IgA1 in the intercellular space of the epidermis. Arch Dermatol. 1991;127:221. 23. Neumann E, Dmochowski M, Bowszyc J, et al. The occurrence of IgA pemphigus foliaceus without neutrophilic infiltration. Clin Exp Dermatol. 1994;19:56. 24. Anhalt GJ, Kim SC, Stanley JR, et al. Paraneoplastic pemphigus. An autoimmune mucocutaneous disease associated with neoplasia. N Engl J Med. 1990; 323:1729. 25. Mutasim DF, Pelc NJ, Anhalt GJ. Paraneoplastic pemphigus. Dermatol Clin. 1993;11:473. 26. Ostezan LB, Fabre VC, Caughman SW, et al. Paraneoplastic pemphigus in the absence of a known neoplasm. J Am Acad Dermatol. 1995;33:312. 27. Camisa C, Helm TN, Valenzuela R, et al. Paraneoplastic pemphigus: Three new cases (abstract). J Invest Dermatol. 1992;98:590. 28. Horn TD, Anhalt GJ. Histologic features of paraneoplastic pemphigus. Arch Dermatol. 1992;128:1091. 29. Stevens SR, Griffiths CE, Anhalt GJ, et al. Paraneoplastic pemphigus presenting as a lichen planus pemphigoides-like eruption. Arch Dermatol. 1993;129:866. 30. Park GT, Quan G, Lee JB. Sera from patients with toxic epidermal necrolysis

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CHAPTER 8 Subepidermal Blistering Diseases

PART I ■ INFLAMMATORY REACTIONS IN THE SKIN

Mosaad Megahed Akmal Saad Hassan

The epidermis binds to the dermis through the basement membrane (BM) zone which is a complex network of interconnecting proteins located at the dermo-epidermal junction (DEJ).1,2 Perturbing the functions of these proteins, for example due to mutation3 or circulating autoantibodies,4 leads to loss of tissue adhesion at the DEJ causing subepidermal blistering diseases. These diseases can be classified into three main groups (Fig. 8-1). These are as follows: I. Autoimmune subepidermal blistering diseases

The cutaneous BM zone is located between the epidermis and the dermis and was originally defined as a 0.5- to 1.0μm-thick, bandlike structure that is positively stained by periodic acid-Schiff (PAS).5 Subsequently, ultrastructural, biochemical, and molecular biological studies have shown that this zone is an extraordinarily complex network of interconnecting proteins that provide integrity and mechanical stability to the skin.1,2 They are also involved in signal transduction and many other important functions. Ultrastructurally the cutaneous BM zone consists of three regions6,7(Fig. 8-2). 1. Hemidesmomes into which the keratin intermediate filaments (KIF) insert 2. Lamina lucida, an electron-lucent region, which is traversed by anchoring filaments 3. Lamina densa, an electron-dense area from which anchoring fibrils extend into the papillary dermis

1. Bullous pemphigoid

Hemidesmosomes

2. Herpes gestationis

Hemidesmosomes (HDs) appear as electron-dense condensations of less than 50 nm that reside at intervals on the plasma membrane of the basal keratinocyte (Fig.8-2). They are highly complicated adhesion structures that are implicated in signal transduction, influencing cytoskeletal architecture, cell differentiation, and cell growth.8-10 Hemidesmosomal proteins known to play a role in subepidermal blistering diseases are: bullous pemphigoid antigen 1,11,4,12 plectin,13,14 bullous pemphigoid antigen 2,15,16 and α6β4 integrin.17,18

3. Lichen planus pemphigoidis 4. Cicatricial pemphigoid 5. Dermatitis herpetiformis 6. Linear IgA disease (LAD) 7. Epidermolysis bullosa acquisita (EBA) 8. Bullous systemic lupus erythematosus II. Subepidermal blistering diseases due to mutations of proteins of the BM zone 1. Junctional epidermolysis bullosa 2. Dystrophic epidermolysis bullosa 3. Kindler syndrome III. Miscellaneous subepidermal blistering diseases 1. Toxic epidermal necrolysis (TEN) 2. Porphyria cutanea tarda (PCT) 3. Pseudoporphyria 4. Coma blister 5. Bullosis diabeticorum

156

ULTRASTRUCTURE AND MOLECULAR ANATOMY OF THE CUTANEOUS BM ZONE

To be able to comprehend subepidermal blistering diseases, their histopathology, and diagnostics we need first to understand the ultrastructure and the protein constituents of the BM zone. Therefore, the latter will be discussed first in this chapter followed by the histopathology.

Bullous Pemphigoid Antigen 1 Bullous pemphigoid antigen 1 (BPAG1) is a 230-kDa glycoprotein19 that represents the major antigenic determinant of bullous pemphigoid, with greater than 90% of patients having circulating autoantibodies targeting the protein.19,20 BPAG1 represents also one of the target autoantigens of paraneoplastic pemphigus21 and cicatricial pemphigoid,22 and is reportedly the autoantigen in some cases of lichen planus pemphigoides (LPP)23 and herpes gestationis.24

Plectin Plectin is a 300-kDa protein. The plectin gene is mutated in patients suffering from

the recessive form of epidermolysis bullosa simplex associated with muscle dystrophy,14,25,26 a disease characterized by skin blistering and late-onset progressive muscle dystrophy. Circulating autoantibodies against plectin occur in patients with bullous pemphigoid27,28 and paraneoplastic pemphigus.29

Bullous Pemphigoid Antigen 2 Bullous pemphigoid antigen 2 (BPAG2, COL17A1) is a transmembrane glycoprotein of 180 kDa. BPAG2 is mutated in patients with junctional epidermolysis bullosa.30 BPAG2 also serves as autoantigen for immunobullous skin diseases, such that about 50% of bullous pemphigoid sera and most sera from patients with herpes gestationis and lichen planus pemphigoides react with it.20,31,32,33,34 BPAG2 is also one of the autoantigens of cicatricial pemphigoid.35

α6β4 Integrin α6β4 Integrin is a transmembrane hemidesmosomal protein serving as an autoantigen in ocular and oral cicatricial pemphigoid.36,37 Furthermore, it is mutated in junctional epidermolysis bullosa with pyloric atresia,38,39 a disease characterized by intra-lamina lucida skin blistering and congenital pyloric atresia.40

Lamina Lucida and Anchoring Filaments Lamina lucida (LL) is an electron-lucent zone situated between the plasma membrane of the basal keratinocyte and the lamina densa6,7 (Fig. 8-2). In the areas beneath HDs, the LL is traversed by fine threadlike structures called anchoring filaments. Anchoring filaments are composed mainly of laminin 5.41,42-45

Laminin 5 Laminin 5 consists of the chains α3,46 β3,47 and γ2,48 which assemble into a cross-like structure. Laminin 5, which serves as target autoantigen in a subset of patients with cicatricial pemphigoid26 is mutated in patients with junctional epidermolysis bullosa.3,49

Lamina Densa and Anchoring Fibrils The lamina densa (LD) is a continuous electron-dense layer that runs parallel to the plasma membrane of basal

Site of blister

Intraepidermal (Chap.7)

Minimally inflammatory

Subepidermal

Lymphocytes predominate

Epidermal necrosis

Necrotic keratinocytes

No necrotic keratinocytes

Epidermolysis bullosa acquista Epidermolysis bullosa Bullosis diabeticorum Pseudoporphyria Porphyria cutanea tarda Bullous pemphigoid (cell poor)

Toxic epidermal necrolysis Thermal injury

Lichen planus pemphigoides Fixed drug eruption Erythema multiforme

Polymorphous light eruption Lichen sclerosus et atrophicus

Neutrophils predominate

Bullous drug reaction Arthropod bite reaction Herpes gestationis Bullous pemphigoid

Epidermolysis bullosa acquisita Sweet syndrome Bullous lupus erythematosus Bullous vasculitis Cicatricial pemphigoid Linear IgA bullous dermatosis Dermatitis herpetiformis

 FIGURE 8-1 Subepidermal blistering diseases algorithm.

keratinocytes (Fig. 8-2). It consists mainly of type IV collagen.50,51 Antibodies to type IV collagen can therefore be used to define the LD. This helps to localize

the site of blister formation in subepidermal blistering diseases, providing a useful diagnostic tool for the differentiation of those diseases.

Anchoring fibrils are cross-banded fibrillar structures that are mainly composed of type VII collagen and extend from the lamina densa into the papillary dermis, where they loop back into the lamina densa or insert into anchoring plaques.52,53 Anchoring plaques are small electron-dense islands present in the papillary dermis and composed mainly of type IV collagen.

CHAPTER 8 ■ SUBEPIDERMAL BLISTERING DISEASES

No epidermal necrosis

Eosinophils predominate

Type VII Collagen Type VII collagen is a 290-kDa protein of three α1(VII) chains.54 It is the autoantigen in epidermolysis bullosa acquisita,55,56 bullous systemic lupus erythematosus,57 and a subset of linear IgA bullous disease.58 Mutations in type VII collagen gene have been identified in patients with dystrophic epidermolysis bullosa.59,60 Figure 8-3 displays a simplified diagrammatic presentation of the proteins of the cutaneous BM zone.

HISTOPATHOLOGY OF SUBEPIDERMAL BLISTERING DISEASES

 FIGURE 8-2 Ultrastructure of the BMZ of the skin. AF = anchoring filaments, Afb = anchoring fibrils, C = collagen fibers, Pd = papillary dermis, HD = hemidesmosome, LL = lamina lucida, LD = lamina densa, Pm = plasma membrane of basal keratinocyte, Ap = anchoring plaque.

Autoimmune Subepidermal Blistering Diseases BULLOUS PEMPHIGOID Bullous pemphigoid (BP) is an acquired autoimmune subepidermal blistering disease characterized

157

Keratin intermediate filaments

Plectin

Pm

BPAG1

Hemidesmosome

BPAG2

Lamina lucida

α6β4 integrin

PART I ■ INFLAMMATORY REACTIONS IN THE SKIN

Laminin 5

158

Laminadensa (Type IV collagen) Anchoring fibrils (Type VII collagen) Anchoring plaque (Type IV collagen)

 FIGURE 8-3 Diagrammatic presentation of the protein constituents of the BMZ of the skin. Pm = plasma membrane of the basal keratinocyte.

by in vivo deposition of IgG autoantibodies along the cutaneous basement membrane zone.61-63 BP is considered the most common autoimmune blistering disease, with a reported incidence of 10 cases per 1 million population.63 It affects mainly elderly people61-63 but can also occur in any age, including infants6 and children.64 No ethnic or gender predominance has been found.61 Patients with BP have circulating IgG autoantibodies against BPAG113,17 and BPAG2.29,65 BPAG1 is considered the major antigenic determinant of BP, such that greater than 90% of sera from BP patients immunoprecipitate it. About 50% of bullous pemphigoid sera react with BPAG2. CLINICAL FEATURES BP is clinically characterized by large serous or hemorrhagic, tense blisters that arise on normal or erythematous skin (Table 8-1) (Fig. 8-4 A).66 The sites of predilection are the inner and anterior thighs, groin, flexor surfaces of the upper extremities, and lower abdomen.61,62 Any skin region may, however, be involved. Erosions and crusts as a consequence of the blisters’ rupture are usually present,61 and the lesions characteristically heal without scar formation. In the early stage of the disease, there are urticarial papules and plaques.61,62 Occasionally, pruritus is present and may range from mild to severe.67

Table 8-1 Bullous Pemphigoid

Clinical Features Usually elderly patients Tense blisters on erythematous base Blisters remain intact Predilection for extremities Mucosal surfaces can be involved Histopathologic Features Subepidermal blister Scarce or moderate to dense infiltrate of lymphocytes, eosinophils, and/or neutrophils, or perivascular and interstitial infiltrate of lymphocytes, eosinophils, and sometimes neutrophils No necrosis of overlying epidermis Laboratory Evaluation Blister mapping using antibodies against type IV collagen Intra-lamina lucida blister DIF examination Perilesional intact human skin: Linear deposits of IgG and C3 along the BM zone Perilesional salt-split skin: IgG deposits, along the epidermal, dermal, or both sides of the split IIF examination Linear deposits of IgG along the BM zone in most cases ELISA test Circulating IgG antibodies to BPAG1 and/or BPAG2

Western blot Circulating IgG antibodies to 180- and/or 230-kDa protein bands Differential Diagnosis Cell-poor bullous pemphigoid Classical epidermolysis bullosa acquisita Toxic epidermal necrolysis Junctional epidermolysis bullosa Dystrophic epidermolysis bullosa Porphyria cutanea tarda Pseudoporphyria Cell-rich bullous pemphigoid with numerous eosinophils Inflammatory epidermolysis bullosa acquisita Linear IgA disease Herpes gestationis Cicatricial pemphigoid Bullous drug eruption Cell-rich bullous pemphigoid with numerous neutrophils Inflammatory epidermolysis bullosa acquisita Linear IgA disease Dermatitis herpetiformis Bullous systemic lupus erythematosus Bullous pemphigoid, urticarial stage Urticarial stage of intraepidermal autoimmune bullous disease Urticarial stage of inflammatory EBA Linear IgA disease Herpes gestationis Drug reaction Insect bite

HISTOPATHOLOGICAL FEATURES A fully developed lesion of BP is characterized histopathologically by formation of a subepidermal blister66 (Table 8-1). The blisters are usually accompanied by moderate to dense infiltrates of lymphocytes, numerous eosinophils, and a few neutrophils (cell rich BP) (Fig. 8-4B). Occasionally, the accompanying infiltrate is very sparse (cell poor BP) (Fig. 8-5). Plasma, fibrin, and inflammatory cells, for example, lymphocytes, eosinophils, and sometimes neutrophils, are usually present within the blister. The epidermis above the blister is flattened along its base and may be necrotic. In cell-rich BP, the infiltrate is usually present at the base and at the sides of the blister (Fig. 8-4). Sometimes the infiltrate extends to the deep dermis. In some cases of cell-rich BP, neutrophils may dominate in the infiltrate and can be located along the dermoepidermal junction, which usually shows vacuolar degeneration. The neutrophils may also collect in the dermal papillae resulting in papillary neutrophilic abscesses

B

 FIGURE 8-4 Bullous pemphigoid. (A) Tense bullae are characteristically present on erythematous skin. (B) Histopathology of cell-rich bullous pemphigoid, showing a subepidermal blister containing fibrin and inflammatory cells. At the sides and base of the blister, there is a lymphocytic infiltrate with numerous eosinophils and some neutrophils.

similar to those seen in dermatitis herpetiformis. Early urticarial lesions of BP are characterized by a superficial perivascular and interstitial infiltrate of lymphocytes, numerous eosinophils, and variable

neutrophils (Fig. 8-6). Eosinophils and neutrophils may be observed in the epidermis and at the dermo-epidermal junction, which usually shows vacuolar degeneration. Eosinophilic or neutrophilic

spongiosis, or a combination of both, also may be present. On immunomapping using antibodies to type IV collagen, the blister in BP is located within the lamina lucida (Fig. 8-7). OTHER DIAGNOSTIC TESTS Direct immunofluorescence (DIF) on clinically normalappearing, perilesional skin shows, in almost all cases of BP,62 linear deposits of IgG along the BM zone (Fig. 8-8). With salt-split, clinically normal-appearing, perilesional skin, the deposits of IgG usually reside along the epidermal side of the split66,68 (Fig. 8-9). However, the IgG deposits may be also detected on the dermal side or even on the dermal and epidermal sides of the split.66,68 Indirect immunofluorescence (IIF) examination with patients’ sera applied to normal human skin as substrate demonstrates circulating IgG antibodies to proteins of the BM zone in 65% to 80% of the cases with active disease.67 By Western blot and ELISA, the antibodies recognize BPAG1 and/or BPAG2.20,31

 FIGURE 8-5 Histopathology of cell-poor bullous pemphigoid, displaying a subepidermal blister containing fibrin and inflammatory cells. In the dermis, there is a sparse lymphocytic infiltrate with few eosinophils and neutrophils.

DIFFERENTIAL DIAGNOSIS Epidermolysis bullosa acquisita may be indistinguishable from bullous pemphigoid on clinical and histologic grounds and on routine direct immunofluorescence (Table 8-1).66 In the routine laboratory setting, the differential diagnosis hinges on direct immunofluorescence studies performed on salt spit skin. IgG is deposited on the

CHAPTER 8 ■ SUBEPIDERMAL BLISTERING DISEASES

A

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PART I ■ INFLAMMATORY REACTIONS IN THE SKIN 160

 FIGURE 8-6 Urticarial lesion of bullous pemphigoid showing perivascular and interstitial lymphocytic infiltrates with numerous eosinophils. Eosinophils are aligned along the basement membrane zone, accompanied by vacuolar degeneration.

floor of the blister in epidermolysis bullosa acquisita and localizes almost exclusively to the roof of the blister in bullous pemphigoid. The more specialized techniques that differentiate between the two entities, such as immunoblotting, immunoprecipitation, and immunoelectron microscopy are limited to few facilities. The histopathologic alterations and direct immunofluorescence findings in cicatricial pemphigoid are the same as those seen in bullous pemphigoid. Clinical features usually differentiate the two diseases. The usual variant of cicatricial pemphigoid affects almost exclusively the mucous membranes as opposed to

bullous pemphigoid that mainly involves the skin. Direct immunofluorescence performed on salt-split skin is of little help as cicatricial pemphigoid is a heterogeneous disease on the molecular level and the majority of antigens targeted by the autoantibody localize to the roof of the blister as in bullous pemphigoid. The histologic differential diagnosis also includes herpes gestationis. This entity is best distinguished by the clinical presentation. Direct immunofluorescence may be of some help: C3 is deposited in a linear fashion along the dermalepidermal junction in nearly 100% of

 FIGURE 8-7 Epitope mapping (using antibodies against type IV collagen) in a bullous lesion of bullous pemphigoid. The blister is located in the lamina lucida region.

cases of herpes gestationis and bullous pemphigoid. IgG, in contrast, can be seen in 60% to 80% of cases of bullous pemphigoid but only in 30% to 50% of patients with herpes gestations. On histology, the presence of necrotic basal keratinocytes may also favor a diagnosis of herpes gestationis over bullous pemphigoid. Occasional cases of dermatitis herpetiformis and linear IgA dermatosis may have increased numbers of eosinophils. Conversely, occasional cases of bullous pemphigoid may display increased numbers of neutrophils. In these situations, direct immunofluorescence is probably the easiest way to distinguish these entities. Other conditions which may give rise to a subepidermal blister with abundant eosinophils include bullous arthropod bite reaction and bullous drug eruption. Bullous arthropod bite reactions tend to have an inflammatory infiltrate which is more intense, extends deeper into the reticular dermis and subcutaneous fat, and may have eosinophils individually dispersed between collagen bundles. Bullous drug eruptions may also have a deeper infiltrate, but can be histologically indistinguishable from bullous pemphigoid. Bullous arthropod bite reactions and bullous drug eruptions will be negative, or demonstrate only nonspecific features of vascular leakage on direct immunofluorescence examination. Lesions of cell-poor bullous pemphigoid must be distinguished from each of the entities described as subepidermal blisters with minimal inflammation. These distinctions are best made on the basis of clinical and immunologic methods.

 FIGURE 8-8 DIF on perilesional clinically normal-appearing skin from a patient with bullous pemphigoid. There are linear IgG deposits along the basement membrane zone.

Cell-rich bullous pemphigoid with numerous eosinophils Inflammatory epidermolysis bullosa acquisita Linear IgA disease Cicatricial pemphigoid Bullous drug reaction Bullous arthropod bite reaction Urticarial lesion of herpes gestationis Urticarial stage of intraepidermal autoimmune bullous diseases Urticarial stage of inflammatory EBA, linear IgA disease, BP Pruritic urticarial papules and plaques of pregnancy Drug reaction Arthropod bite reaction

Herpes Gestationis (Pemphigoid Gestationis) Herpes gestationis (HG) is an acquired, autoimmune, subepidermal blistering disease that develops in association with pregnancy. It is estimated to occur in 1 of 3000 to 1 of 10000 pregnancies70 and usually begins in the second or third trimester. However, it may occur at any time during pregnancy70-74 or even in the postpartum period. In rare cases HG may develop with the trophoblastic tumours, hydratiform mole, and chorioncarcinoma. CLINICAL FEATURES HG presents as severe pruritic, erythematous, urticarial papules and plaques (Table 8-2).66,70-75 Occasionally, blisters develop and are usually arranged in a herpetiform pattern. Lesions of HG usually begin on the abdomen, with a predilection for the periumbilical region. As the disease evolves, the blisters spread peripherally and may become generalized. The lesions resolve within weeks or months and subside at the end of pregnancy; however, many patients may experience exacerbation of skin lesions immediately or shortly after delivery. Recurrence of HG may occur with resumption of menstruation, on administration of oral contraceptives, or within subsequent pregnancies. HISTOPATHOLOGICAL FEATURES The histopathology of HG is similar to that of cellrich BP66 and shows subepidermal blisters with infiltration of lymphocytes, numerous eosinophils, and a few neutrophils (Table 8-2). The blister usually contains plasma, fibrin, and inflammatory

Table 8-2 Herpes Gestationis

Clinical Features Uncommon Usually in second or third trimesters of pregnancy Recurs with subsequent pregnancies Most lesions on trunk and extremities Newborn may have blisters Mucosal lesions uncommon Histopathologic Features Subepidermal blister with sparce or moderate to dense infiltrate of lymphocytes, eosinophils, and/or neutrophils or Perivascular and interstitial infiltrate of lymphocytes, eosinophils, and sometimes neutrophils Papillary dermal edema Rare necrotic keratinocytes Laboratory Evaluation Blister mapping using antibodies against type IV collagen Intra-lamina lucida blister DIF examination Perilesional intact human skin: Linear deposits of C3, IgG along the BM zone Perilesional salt-split skin: C3, IgG deposits on the epidermal sides of the split Complement fixation assay Detection of HG factor ELISA test Circulating IgG antibodies to BPAG1 or BPAG2 Western blot Circulating IgG antibodies to 180- or 230-kDa protein bands Differential Diagnosis Blistering lesion of herpes gestationis

cells (lymphocytes, eosinophils, and sometimes also neutrophils). Urticarial lesions of HG are also histopathologically similar to those of BP. On immunomapping with antibodies to type IV collagen, the blister in HG is located within the lamina lucida. OTHER DIAGNOSTIC TESTS DIF with perilesional, clinically normal-appearing skin shows deposits of C3 (in 100% of the cases) and IgG (in 27% of the cases) along the BM zone.76 Patients with HG have circulating antibodies mainly directed against BPAG2 and, in rare cases, against BPAG1.24,33,77,78 These circulating autoantibodies can be detected by IIF testing in about 21% of the patients with normal human skin as a substrate.76 The circulating IgG antibodies in HG are of IgG1 and IgG3 classes and have the ability to fix normal human complement to the BM zone of normal human skin.79,80 These circulating IgG antibodies are called HG factor and can be detected by the complement fixation assay.73,79,80 Complement fixation assay is more sensitive than conventional IIF and is performed by incubating the test serum with normal human skin, followed by normal human complement, and then a fluorescein-conjugated antibody specific for the complement.80 By complement fixation assay, circulating IgG antibodies are detected in 91% of HG patients.76 The circulating IgG antibodies in HG can also be detected by ELISA using recombinant proteins of BPAG1 and BPAG2.78,82 DIFFERENTIAL DIAGNOSIS The histologic differential diagnosis includes bullous pemphigoid, bullous arthropod bite, bullous drug eruption, and pruritic urticarial

CHAPTER 8 ■ SUBEPIDERMAL BLISTERING DISEASES

 FIGURE 8-9 DIF using salt-split, perilesional, clinically normal-appearing skin from a patient with bullous pemphigoid. There are linear IgG deposits along the epidermal side of the split.

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papules and plaques of pregnancy (Table 8-2). On histologic sections, the presence of individually necrotic keratinocytes would favor herpes gestationis over bullous pemphigoid, but in most cases these two entities can most easily be distinguished by the clinical setting as well as differences in immunologic findings. Bullous arthropod bite reactions usually have a more dense infiltrate which extends deeper into the dermis. Direct immunofluorescence examinations are invariably negative for immune complexes in arthropod bite reactions and bullous drug eruptions. Subepidermal blisters are not seen in pruritic urticarial papules and plaques of pregnancy, but in some cases of pemphigoid gestationis, eosinophilic spongiosis without fully formed blisters may be present. In these cases, the histologic features of these two entities may be identical. The clinical features are most often different, and pruritic urticarial papules and plaques of pregnancy are always negative on direct immunofluorescence examination.

Lichen Planus Pemphigoides LPP is a rare, acquired, autoimmune subepidermal blistering disease characterized by the simultaneous occurrence of lichen planus lesions and blisters.83 Circulating autoantibodies in sera from patients with LPP recognize in most instances BPAG2 and in few cases a 200-kDa protein that remains uncharacterized.84-87 Epitope mapping using BPAG2 fusion proteins show that LPP sera and BP sera react with different epitopes of BPAG2.87 These results suggest that LPP is a distinct disease and not a coexistence of BP and lichen planus, as previously suggested.

Table 8-3 Lichen Planus Pemphigoides

Clinical Features Adults, rarely in children Lesions indistinguishable from lichen planus, ie, flat-topped violaceous papules with whitish scale Tense blisters on normal-appearing skin or surmounting preexistent lesions of lichen planus Histopathologic Features Subepidermal blister with sparse or moderate to dense infiltrate of lymphocytes, eosinophils, and/or neutrophils or Subepidermal as well as typical histopathological changes of lichen planus Laboratory Evaluation Blister mapping using antibodies against type IV collagen Intra-lamina lucida blister DIF examination Perilesional intact human skin: Linear deposits of IgG along the BM zone Perilesional salt-split skin: IgG deposits on the epidermal side of the split ELISA test Circulating IgG antibodies to BPAG2 Western blot Circulating IgG antibodies to 180-kDa protein band Differential Diagnosis Lichenoid lesion Lichen planus Lichenoid drug eruption Bullous lesion Inflammatory epidermolysis bullosa acquisita Linear IgA disease Herpes gestationis Cicatricial pemphigoid Bullous drug eruption

CLINICAL FEATURES Clinically, there are typical lesions of lichen planus as well as tense blisters that surmount lesions of lichen planus or develop in clinically normal skin (Table 8-3).83 Extremities, trunk, and oral mucosa are the sites of predilection. The age of onset ranges between 9 and 85 years, with a mean age of 46 years. There is no race predominance.

planus lesions will display a subepidermal vesicle as well as typical histopathological changes of lichen planus, namely compact stratum corneum, acanthosis, hypergranulosis, and a bandlike infiltrate of lymphocytes. Using antibodies to type IV collagen, the blister of LPP (with or without concurrent changes of lichen planus) is located within the lamina lucida.

HISTOPATHOLOGICAL FEATURES The histopathological findings in LPP are lesion dependent.66 Blisters on clinically normal skin will display a subepidermal blister with perivascular and interstitial infiltrate of lymphocytes and eosinophils (Table 8-3). Occasionally, the accompanying infiltrate is sparse, as in cases of cell-poor BP. A blister forming on lichen

OTHER DIAGNOSTIC TESTS DIF on perilesional skin shows in all patients with LPP linear IgG deposits along the BM zone.83 On NaCl-split perilesional skin, the deposits are located on the epidermal side of the split. IIF with sera of LPP using human skin (intact or NaCl split) as a substrate shows, in about 64% of the reported cases, circulating IgG autoanti-

bodies to proteins of the BM zone.83 Via ELISA testing these autoantibodies predominantly recognize BPAG2.88 DIFFERENTIAL DIAGNOSIS The histologic differential diagnosis of lichen planus pemphigoides is dependent upon the type of lesion biopsied (Table 8-3).66 A biopsy from a lichenoid lesion will be difficult to distinguish from lichen planus, and one from a blister, indistinguishable from bullous pemphigoid. Clinical history in conjunction with direct immunofluorescence studies should enable accurate distinction.

Cicatricial Pemphigoid Cicatricial pemphigoid (CP) is a rare, heterogeneous, acquired, autoimmune, subepithelial blistering disease of mucous membranes and/or the skin (Tables 8-4 and 8-5). 66,89-91 It affects mainly elderly persons and occurs in females more than in males. No ethnical or geographic predominance is evident.89,90 CLINICAL FEATURES The clinical spectrum of CP varies widely89-91 (Table 8-4). It affects squamous mucosa, especially that of the oral cavity (85%), conjunctiva (65%), nasopharynx (20%), genitalia (20%), larynx (8%), esophagus (4%), and anus (3%).89,90 The skin is reportedly involved in 25% of the cases. The primary lesion of CP is a tense blister that on rupture heals slowly and usually with scar formation. HISTOPATHOLOGICAL FEATURES In CP, three histological patterns can be defined.66 (Table 8-4). In the first pattern, there is a subepidermal blister and a lymphocytic infiltrate at its base and sides. Eosinophils and occasionally neutrophils may be present. In oral and genital lesions, plasma cells are also present. In the second pattern, there is a subepidermal blister, fibrosis, and lymphocytic infiltrates with eosinophils and sometimes also neutrophils (Fig. 8-10). In the third pattern, the changes of the epithelium are similar to that seen in lichen planus. This histological pattern is observed only in oral and genital lesions. On immunomapping using antibodies to type IV collagen, the blister in CP localizes within the lamina lucida. OTHER DIAGNOSTIC TESTS DIF examination using perilesional clinically normalappearing skin or mucosa shows, in 80% to 100% of the cases of CP, linear IgG and/or C3 deposits along the basement membrane zone.91 IIF examination with

Table 8-4 Cicatricial Pemphigoid

Table 8-5 Antigenic Targets in Cicatricial Pemphigoid The antigen (its molecular weight) 1. BPAG1 (230 kDa) 2. BPAG2 (180 kDa) 3. α3 chain of laminin 5 and laminin 6 (145 kDa) 4. β integrin subunit (205 kDa) 5. α integrin subunit (130 kDa)

 FIGURE 8-10 Cicatricial pemphigoid. The subepidermal blister is associated with fibrosis and a mixed infiltrate of lymphocytes, eosinophils, and neutrophils.

CP patients’ sera demonstrates circulating IgG antibodies to the BM zone. These antibodies are usually present in a very low titer. The sensitivity of IIF on using conventional substrates (monkey esophagus, normal human skin) is reportedly 10% to 36%.92 On using 1 M NaCl-split normal human skin, the sensitivity of IIF in CP is markedly improved.91 The deposition of IgG in CP may be limited to the epidermal or dermal side of the split92 or even to both sides. Western blot or immunoprecipitation examinations as well as ELISA-testing using recombinant fusion proteins of the BM zone identify the target autoantigen in CP (Table 8-5). DIFFERENTIAL DIAGNOSIS The histologic differential diagnosis depends upon the degree of dermal inflammatory infiltrate. In lesions which are intensely inflammatory, the differential diagnosis would include Sweet syndrome and linear IgA bullous dermatosis, neither of which is associated with dermal scarring. Dermatitis herpetiformis could also be in the differential diagnosis, but usually has neutrophils which are more localized to dermal papillae than is seen in cicatricial

pemphigoid. Bullous lupus could appear quite similar to cicatricial pemphigoid on routine histology. The differences in direct immunofluorescence staining patterns are helpful in discriminating between these diseases. Epidermolysis bullosa acquisita would also be in the differential diagnosis and can also produce dermal scarring. Direct immunofluorescence on salt-split skin probably offers the most reliable method for distinguishing between these two entities.

CHAPTER 8 ■ SUBEPIDERMAL BLISTERING DISEASES

Clinical Features Elderly patients More common in women Vesiculobullous eruption primarily involves mucous membranes Extensive scarring Skin involvement in only 25% of cases Histopathologic Features Subepidermal blister Moderate to dense infiltrate of lymphocytes, eosinophils, and/or neutrophils With or without fibrosis or Subepidermal blister Bandlike infiltrate of lymphocytes and eosinophils (occasionally also neutrophils and plasma cells) Lichen planus–like changes of the epithelium Fibrosis Laboratory Evaluation Epitope mapping using antibodies against type IV collagen Intra-lamina lucida blister DIF examination Perilesional intact human skin: Linear deposits of IgG, C3 along the BM zone Perilesional salt-split skin: IgG deposits, along the epidermal, dermal, or both sides of the split ELISA test Circulating IgG antibodies to BPAG1 and/or BPAG2; at present ELISA test for other proteins of the BMZ is not available Western blot Circulating IgG antibodies to 180-, 230-, 145-, 205-, or 130-kDa protein bands Differential Diagnosis Bullous pemphigoid Linear IgA disease Epidermolysis bullosa acquisita Dystrophic epidermolysis bullosa Bullous drug eruption Dermatitis herpetiformis Bullous lupus erythematosus Epidermolysis bullosa acquisita Sweet syndrome

Dermatitis Herpetiformis Dermatitis herpetiformis (DH) is an acquired, pruritic, autoimmune, subepidermal blistering disease characterized by IgA deposits in the dermal papillae.93,94 It occurs in males more than in females3 and usually begins in the second to fourth decade.2 It can, however, commence at any age. DH affects mainly Caucasians and is rarely seen in blacks or Asians.3,7 CLINICAL FEATURES The condition is characterized by erythematous papules, urticarial plaques, papulovesicles, vesicles,

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and rarely bullae, either isolated or in herpetiform grouping (Table 8-6 and Fig. 8-11A). 94,95 The lesions are intensely pruritic and often heal with scarring. The lesions are symmetrically distributed and appear mainly on elbows, knees, nape, scapular region, sacral region, and buttocks. All patients with DH have glutensensitive enteropathy indistinguishable from celiac disease. However, only 10% have clinical manifestations of intestinal disease.95

164

HISTOPATHOLOGICAL FEATURES In early lesions of DH, infiltrates of lymphocytes and neutrophils are arrayed about the superficial plexus and within the edematous papillary dermis (Table 8-6). 66,97-100 The neutrophils are also present in the epidermis and at the dermoepidermal junction, which usually shows vacuolar degeneration. With evolution of the

A

Table 8-6 Dermatitis Herpetiformis

Clinical Features Intensely pruritic Usual onset in early adulthood Symmetrical vesicles on extensor surfaces of extremities Mucous membrane involvement uncommon Gluten-sensitive enteropathy associated with HLA-A1, HLA-B8, HLA-DR3 Histopathologic Features Depends on the stage of the lesions Subepidermal blister Neutrophilic microabscesses in papillary dermal tips Lymphocytic infiltrate around superficial vascular plexus Laboratory Evaluation Epitope mapping using antibodies against type IV collagen Intra-lamina lucida blister DIF examination (using perilesional, normal-appearing skin) Granular IgA, C3 deposits in the dermal papillae or Linear IgA deposits along the basement membrane zone, as well as granular IgA deposits in the dermal papillae ELISA test Circulating IgA antibodies to tissue transglutaminase Differential Diagnosis Linear IgA bullous dermatosis Epidermolysis bullosa acquisita Bullous lupus erythematosus Cicatricial pemphigoid Bullous pemphigoid Pustular drug eruption

B  FIGURE 8-11 Dermatitis herpetiformis. (A) Grouped papules and vesicles on elbows and flanks with extensive excoriations. (B) There is a subepidermal blister, which contains neutrophils, eosinophils, and fibrin. At the sides of the blister, there are papillary neutrophilic abscesses and subepidermal clefts. The dermis contains perivascular and interstitial infiltrates of lymphocytes, neutrophils, and eosinophils.

lesions, neutrophils collect in some of the dermal papillae, and fibrin often appears at their tips. Eosinophils may also be present in the dermal infiltrate and in the papillary abscesses. With further lesional evolution, a subepidermal blister develops. The blister usually contains serum, fibrin, neutrophils, and eosinophils (Fig. 8-11B). The dermis displays perivascular and interstitial infiltrates of lymphocytes, neutrophils, and eosinophils, the latter often numerous. The infiltrate may be dense and deep. At the sides of the blister, neutrophilic

abscesses in the dermal papillae and subepidermal clefts are usually present (Fig. 8-12). On immunomapping using antibodies to type IV collagen, the blister of DH is located in the lamina lucida. OTHER DIAGNOSTIC TESTS DIF examination shows granular IgA deposits in the dermal papillae (Fig. 8-13).66,93,94 In some patients, linear IgA deposits occur concomitantly along the basement membrane zone.66,101 In DH by IIF examination, there is no evidence for circulating autoantibodies against proteins of

 FIGURE 8-12 Dermatitis herpetiformis. Neutrophilic abscesses and subepidermal clefts are present in the dermal papillae.

keratinocytes or the basement membrane zone.94 However, patients with DH have IgA antibodies to gliadin102 (a component of gluten) and endomysium103 (connective tissue surrounding smooth muscles). The anti-endomysial antibodies target tissue transglutaminase, which was recently identified as the autoantigen of celiac disease. IgA antibodies to tissue transglutaminase

(detected via ELISA) serve nowadays as the serological diagnostic marker for DH and celiac disease.104,105 DIFFERENTIAL DIAGNOSIS The histologic differential diagnosis of dermatitis herpetiformis includes linear IgA bullous dermatosis, epidermolysis bullosa acquisita, bullous lupus erythematosus, cicatricial pemphigoid, pustular drug

 FIGURE 8-13 DIF using perilesional, normal-appearing skin in DH. There is granular IgA deposition in the dermal papillae.

Linear IgA Disease LAD is an acquired, autoimmune, subepithelial blistering disease of the skin and/or mucous membranes characterized by the presence of linear IgA deposits along the BM zone.106,107 LAD may affect adults,13 children,108 or even neonates.109 CLINICAL FEATURES The clinical picture of LAD is heterogenous.13,106-111 The disease may simulate clinically BP, DH, erythema multiforme, erythema annulare centrifugum, or Lyell syndrome (Table 8-7).17,18,106,107,112,113,114 However in its classical form there are annular, tense, large blisters on normal or erythematous skin.13,106-110 The individual blisters may be elliptical in shape, and the new blisters usually appear around those resolving, forming rosette or jewellike clusters. Occasionally, the blisters will lie within an erythematous area in a linear distribution (“string of pearls”). Itching is often an accompanying complaint and may be mild to severe. Urticarial patches and plaques may be present, especially in the early stage of the disease. The sites of predilection are the trunk, limbs, face, groin, and perineum. Involvement of the mucous membranes, especially that of the oral cavity and conjunctiva, is not uncommon and may be the only presenting manifestations.115,116 HISTOPATHOLOGICAL FEATURES Like the clinical picture, the histology of LAD is

CHAPTER 8 ■ SUBEPIDERMAL BLISTERING DISEASES

eruptions, and occasional cases of bullous pemphigoid. Dermatitis herpetiformis is the only one of these entities in which the neutrophils tend to aggregate within papillary dermal tips. The blister spaces tend to be smaller in dermatitis herpetiformis than in the other entities. Epidermolysis bullosa acquisita is less inflammatory in many cases, and bullous pemphigoid demonstrates a predominantly eosinophilic infiltrate in most cases. Pustular drug eruptions may exhibit papillary dermal collections of neutrophils similar to dermatitis herpetiformis, but in contrast to dermatitis herpetiformis also show evidence of leukocytoclastic vasculitis with fibrinoid necrosis of vessel walls.52 The serological detection of antiendomysial antibodies should allow distinction of DH from the other entities and direct immunofluorescence staining patterns will be different for each of the disorders in this differential diagnosis and probably represent the most reliable method of distinguishing between them.

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PART I ■ INFLAMMATORY REACTIONS IN THE SKIN

Table 8-7 Linear IgA Bullous Dermatosis

166

Clinical Features Childhood disease has onset within 5-6 years of birth Adult onset in sixth to eighth decades Often antecedent infection Annular erythematous patches with tense blisters at edges Trunk and extremities most commonly affected sites Histopathologic Features Subepidermal blister Neutrophils linearly aligned along dermal-epidermal junction Papillary dermal edema Occasional eosinophils present Laboratory Evaluation Epitope mapping using antibodies against type IV collagen Intra-lamina lucida blister (rarely sub-lamina densa blister) DIF examination Perilesional intact human skin: Linear deposits of IgA along the BM zone Perilesional salt-split skin: IgA deposits, along the epidermal, dermal, or both sides of the split ELISA test Circulating IgG antibodies to BPAG1 and/or BPAG2 Western blot Circulating IgA antibodies to different protein bands Differential Diagnosis Cell-rich bullous pemphigoid Inflammatory variant of epidermolysis bullosa acquisita Herpes gestationis Bullous drug eruption Cicatricial pemphigoid Dermatitis herpetiformis Bullous systemic lupus erythematosus Bullous arthropod bite reaction Sweet syndrome

heterogenous (Table 8-7). 66 Fully developed lesions show subepidermal blisters, accompanied by infiltrates of lymphocytes, eosinophils, and neutrophils (Fig. 8-14). The infiltrate is superficially situated at the sides and base of the blister. In most of the cases, neutrophils predominate over eosinophils in the infiltrate. They are usually present along the BM zone, which shows vacuolar degeneration. The neutrophils also accumulate in some of the dermal papillae as abscesses resembling those of DH. The histopathology of fully developed oral lesions of LAD is similar to that of the

 FIGURE 8-14 Histopathology of linear IgA disease, displaying a subepidermal blister and lymphocytic infiltrates of numerous neutrophils and a few eosinophils. The blister contains neutrophils, eosinophils, and fibrin.

cutaneous lesions, but in the former there are many plasma cells. The ocular lesions of LAD are not distinguishable from those of CP. Early urticarial lesions of LAD show perivascular and interstitial lymphocytic infiltrates of neutrophils and eosinophils. Eosinophilic or neutrophilic spongiosis, or a combination of both, may also be present. The site of the blister formation in LAD patients is within the lamina lucida. However, in LAD

patients with circulating autoantibodies to type VII collagen, the blister is located beneath the lamina densa. OTHER DIAGNOSTIC TESTS DIF examination of perilesional skin or mucosa displays linear IgA deposits along the BM zone (Fig. 8-15). IIF examination with patients’ sera demonstrates circulating IgA antibodies to proteins of the BM zone. The sensitivity of IIF is 62% with normal

 FIGURE 8-15 DIF using perilesional, normal-appearing skin from a patient with linear IgA disease. IgA is deposited in a linear fashion along the basement membrane zone.

human intact skin as substrate and 73% with NaCl-split normal human skin.117 With NaCl-split skin, the antibodies bind to the epidermal side of the split in most cases.117 In a few cases they bind to the dermal side,118 or both, of the split.117 Western blot or immunoprecipitation examinations, as well as ELISA-testing using recombinant fusion proteins of the BM zone, may define the target autoantigen in LAD (Table 8-8).

Table 8-8 Autoantigens of Linear IgA Disease ANTIGEN

MOLECULAR WEIGHT

1. BPAG1 2. BPAG2 3. LAD1 (LABD 97) (cleaved ectodomin of BPAG2) 4. Ladinin 5. LAD225 (still not characterized) 6. LAD285 (still not characterized) 7. Type VII collagen

230 kDa 180 kDa 120/97 kDa

95 kDa 255 kDa 285 kDa 290 kDa

Epidermolysis Bullosa Acquisita Epidermolysis bullosa acquisita (EBA) is an acquired subepidermal autoimmune blistering disease of the skin and/or mucous membranes which is characterized by the presence of IgG deposits along the BM zone and circulating IgG autoantibodies targeting type VII collagen.55,56,66,119,120 It affects mainly adults but can also occur in children and even infants. The mean age at onset is 47 years. EBA affects all races and is reported to be slightly more common in females. CLINICAL FEATURES Clinically, EBA can be divided in three variants66: Classical variant of EBA, where there are trauma-induced blisters and erosions on the extensor surface of the limbs (Table 8-9). The blisters arise on normal-appearing skin, are tense, clear, or hemorrhagic, and heal with scarring and milia formation. The inflammatory variant of EBA, displays widespread eruptions with tense blisters spontaneously forming on erythematous or nonerythematous skin. These lesions occur on flexural and/or intertriginous areas and tend to heal with less scarring and milia formation. And mucosal EBA, where the lesions are limited to the mucous membranes of the mouth, nose, pharynx, larynx, esophagus, eye, and genitourinary tract.

Table 8-9 Epidermolysis Bullosa Acquisita

Clinical Features Usually affects middle-aged to elderly adults Blisters on noninflammatory skin Scarring and milia Predilection for trauma-prone sites Nail dystrophy may be present Histopathologic Features Subepidermal blister Sparce or moderate to dense infiltrates of lymphocytes, eosinophils, and/or neutrophils or Eosinophilic and/or neutrophilic spongiosis No keratinocyte necrosis Dermal scarring may be present Laboratory Evaluation Epitope mapping using antibodies against type IV collagen Sub-lamina densa blister DIF examination Perilesional intact human skin: Linear deposits of IgG,C3 along the BM zone Perilesional salt-split skin: IgG deposits, along the dermal side of the split ELISA test Circulating IgG antibodies to collagen type VII Western blot Circulating IgG antibodies to a 290-kDa protein band Differential Diagnosis Classical epidermolysis bullosa acquisita Cell-poor bullous pemphigoid Bullous systemic lupus erythematosus Toxic epidermal necrolysis Junctional epidermolysis bullosa Dystrophic epidermolysis bullosa Porphyria cutanea tarda Pseudoporphyria Inflammatory epidermolysis bullosa acquisita Cell-rich bullous pemphigoid Linear IgA disease Herpes gestationis Cicatricial pemphigoid Dermatitis herpetiformis Bullous systemic lupus erythematosus Bullous drug reaction Epidermolysis bullosa acquisita (urticarial stage) Urticarial stage of intraepidermal autoimmune bullous diseases Urticarial stage of cell-rich bullous pemphigoid Linear IgA disease Herpes gestationis Drug reaction Arthropod bite reaction

CHAPTER 8 ■ SUBEPIDERMAL BLISTERING DISEASES

DIFFERENTIAL DIAGNOSIS The major histologic differential diagnosis is dermatitis herpetiformis. In the classic situation, dermatitis herpetiformis has a less diffuse and more abscess-like distribution of neutrophils, confined to papillary dermal tips, whereas linear IgA dermatosis and chronic bullous disease of childhood display neutrophils in a more evenly distributed pattern along the dermalepidermal junction. However, there is great overlap in these cases, and frequently, direct immunofluorescence demonstrating a linear or granular staining pattern with IgA is the only way to distinguish these entities. Clinical parameters such as HLA-B8/DR3 haplotype and small bowel abnormalities in dermatitis herpetiformis may further aid in the differential diagnosis. Occasional arthropod bite reactions can display neutrophil-predominant infiltrates, and these cases resemble linear IgA dermatosis. The presence of a punctum, or a deep component to the inflammatory infiltrate, as well as a negative or nonspecific direct immunofluorescence study would favor a bite reaction. The neutrophilic infiltrate in Sweet syndrome is usually far more florid and diffuse than that seen in linear IgA dermatosis or chronic bullous disease of childhood. In addition, Sweet syndrome

is characterized by much more papillary dermal edema. Bullous lupus erythematosus can present with a histologic picture similar to linear IgA disease. Patients with bullous lupus erythematosus have serologic findings of systemic lupus. On direct immunofluorescence, the staining pattern of lupus is granular and bandlike and is usually observed with several immunoglobulins and not just IgA. Epidermolysis bullosa acquisita, cicatricial pemphigoid, and bullous pemphigoid may have histologic features similar to linear IgA disease but can be discerned by direct immunofluorescence. Cases with neutrophilic blisters and with linear deposition of IgA and IgG along the dermal-epidermal junction are more problematic. One approach is to classify the disease according to the stronger staining immunoglobulin, that is, as linear IgA disease if IgA is the predominant immunoglobulin or as bullous pemphigoid when IgG predominates. Some authors accept as linear IgA disease only cases with exclusive staining with IgA and classify all others as bullous pemphigoid or epidermolysis bullosa acquisita.

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PART I ■ INFLAMMATORY REACTIONS IN THE SKIN

HISTOPATHOLOGICAL FEATURES Histopathologically, lesions of EBA are characterized by formation of subepidermal blisters associated with no or sparse perivascular and interstitial infiltrates of lymphocytes in the upper dermis (classic variant of EBA) (Table 8-9) (Fig. 8-16).66 On occasion, a few eosinophils and/or neutrophils are present. In the inflammatory variant of EBA, the blister is associated with moderately dense lymphocytic infiltrates with eosinophils and neutrophils. Early urticarial lesions of the inflammatory variant are histopathologically not distinguishable from urticarial lesions of other autoimmune blistering diseases, showing perivascular and interstitial infiltrates of lymphocytes, neutrophils, and eosinophils. The eosinophils or the neutrophils may dominate the infiltrate and are present along the dermal-epidermal junction, which displays vacuolar degeneration. Eosinophilic and/or neutrophilic spongiosis may be present. Fibrosis, with or without milia, may occur in relapsing lesions of EBA. Mucosal EBA has findings similar to those of the inflammatory variant of EBA, although usually the infiltrate is denser and contains plasma cells. The blisters in all variants of EBA localize to the sublamina densa region. OTHER DIAGNOSTIC TESTS DIF using perilesional skin or perilesional mucosa displays in all active cases linear deposits of IgG along the BM zone. Using NaClsplit perilesional skin or mucosa, the deposits segregate to the dermal side of the split (Fig. 8-17).66 Circulating IgG antibodies to proteins of the BM zone occur by IIF testing in about 25% to 50% of the patients with normal human skin or monkey esophagus as substrate.119 The sensitivity increases markedly with NaCl-split normal skin.121 The circulating antibodies react by Western blot or

 FIGURE 8-17 DIF of salt-split, perilesional, normal-appearing skin from a patient with epidermolysis bullosa acquisita. IgG is deposited in linear array along the dermal side of the split.

immunoprecipitation assay with a 290-kDa protein band which represents type VII collagen.119 These antibodies also react positively with recombinant fusion protein of type VII collagen by ELISA.122 DIFFERENTIAL DIAGNOSIS The histologic differential diagnosis is dependent upon the histologic subtype of epidermolysis bullosa acquisita. In relatively noninflammatory lesions, the differential diagnosis includes porphyria cutanea tarda and cellpoor bullous pemphigoid. These two conditions can be distinguished from epidermolysis bullosa acquisita on the basis of immunofluorescence staining patterns (requiring salt-split skin to differentiate bullous pemphigoid and epidermolysis bullosa acquisita). Porphyria cutanea tarda can be further distinguished with urine, fecal, and blood porphyrin studies.

In more inflammatory cases of epidermolysis bullosa acquisita with abundant dermal neutrophils, bullous lupus erythematosus is the major differential diagnostic possibility. Bullous lupus erythematosus may display other histologic features of lupus, such as a superficial and deep perivascular and periappendageal lymphocytic infiltrate, but these features are often absent. In fact, the histologic features of epidermolysis acquisita and bullous lupus erythematosus may be indistinguishable. Patients with the latter disease meet the criteria of the American, Rheumatologic Association for systemic lupus erythematosus. Further, the granular nature of the immunoglobulin deposits seen in lupus erythematosus on direct immunofluorescence often differentiates this entity from the linear deposits seen in epidermolysis bullosa acquisita.

Bullous Systemic Lupus Erythematosis Bullous SLE is an acquired autoimmune disease characterized by the occurrence of vesiculobullous eruptions, often in a herpetiform arrangement, in patients diagnosed as having SLE by criteria of the American Rheumatism Association (ARA).123-125 It affects mainly adults but may also occur in children.

168

 FIGURE 8-16 A classical lesion of epidermolysis bullosa acquisita illustrates a subepidermal blister and sparse perivascular and interstitial lymphocytic infiltrates.

CLINICAL FEATURES Clinically, there are tense blisters on normal or erythematous skin (Table 8-10). The blisters are usually herpetiform, with a predilection to the trunk and flexural surfaces.123-125

Table 8-10 Bullous Systemic Lupus Erythematosus63

Oral lesions have been frequently observed, and pruritus, which may be severe, has also been reported. HISTOPATHOLOGICAL FEATURES The histopathology of bullous SLE is similar to that of dermatitis herpetiformis, with subepidermal blisters and infiltrate of lymphocytes and numerous neutrophils (Table 8-10) (Fig. 8-18). 66 In contrast to dermatitis

 FIGURE 8-18 Bullous SLE. The subepidermal blister is associated with lymphocytic infiltrates and many neutrophils. The neutrophils also distribute to the basement membrane zone and the dermal papillae.

herpetiformis, the infiltrate in bullous SLE is also present around the hair follicles. Moreover, in bullous SLE there are interstitial mucin deposits. Also in contrast to dermatitis herpetiformis, the blister in bullous SLE localizes to the sublamina densa region. OTHER DIAGNOSTIC TESTS DIF of perilesional skin of patients with bullous SLE displays linear and/or granular deposits of IgG and/or IgA, IgM, and C3 at the BM zone.124,125 With NaCl-split perilesional skin, the deposits are located on the dermal side of the split. Patients’ sera contain circulating IgG autoantibodies to the BM zone by IIF assay.125 These circulating IgG autoantibodies recognize in Western blot or by immunoprecipitation a 290-kDa protein band which represents type VII collagen.57 DIFFERENTIAL DIAGNOSIS The histologic differential diagnosis of bullous lupus erythematosus includes dermatitis herpetiformis, linear IgA bullous dermatosis, Sweet syndrome, epidermolysis bullosa acquisita, and cicatricial pemphigoid. The presence of leukocytoclastic changes favors the diagnosis of lupus over the other entities listed. The most compelling diagnostic information is found on direct immunofluorescence examination, which separates out each of these entities.

SUBEPIDERMAL BLISTERING DISEASES DUE TO MUTATIONS OF PROTEINS OF THE BASEMENT MEMBRANE ZONE

Junctional Epidermolysis Bullosa Junctional epidermolysis bullosa (JEB) is a group of congenital disorders characterized by trauma-induced bullae and caused by mutations of the genes coding for BPAG2,126,127 the α3, the β3, and the χ2 polypeptide chains of laminin 5,3,128-132 and the α639 and the β438,133 integrin subunits.

CHAPTER 8 ■ SUBEPIDERMAL BLISTERING DISEASES

Clinical Features Young adults, women > men, particularly African American women Widespread vesicles and bullae often on an erythematous base or plaques Trunk and flexural surfaces most commonly involved Predominately sun-exposed skin or any site Four or more ARA criteria Histopathologic Features Subepidermal blister Often numerous neutrophils in papillary dermis, often dermal papillae or in a more diffuse pattern Usually prominent papillary dermal edema Superficial and mid-dermal perivascular lymphoid infiltrates with occasional neutrophils and eosinophils Uncommonly microvascular injury, rarely leukocytoclastic vasculitis Extravasation of erythrocytes on occasion Rarely typical features of lupus erythematosus: basal layer vascuolopathy, epidermal atrophy, thickened basement membrane, thickening Laboratory Evaluation Epitope mapping using antibodies against type IV collagen Sub-lamina densa blister DIF examination Perilesional intact human skin: Linear deposits of IgG along the BM zone Perilesional salt-split skin: IgG deposits along the dermal side of the split ELISA test Circulating IgG antibodies to collagen type VII Western blot Circulating IgG antibodies to a 290-kDa protein band Differential Diagnosis Dermatitis herpetiformis Linear IgA bullous dermatosis Epidermolysis bullosa acquisita Cicatricial pemphigoid Drug eruption Neutrophilic dermatoses such as Sweet syndrome

CLINICAL FEATURES JEB can be classified into three main subgroups distinguished by their clinical characteristics: junctional epidermolysis bullosa of the Herlitz type, junctional epidermolysis bullosa of the non-Herlitz type, and junctional epidermolysis bullosa with pyloric atresia. Tables 8-11 to 8-13 display the clinical features and molecular defects of JEB variants.66 HISTOPATHOLOGICAL FEATURES Histologically, all variants of JEB are characterized by the formation of subepidermal blisters associated with sparse infiltrates in the dermis (Fig. 8-19).66 On immunomapping using antibodies to type IV collagen, the split localizes to the lamina lucida.

169

Table 8-11 Variants of Junctional Epidermolysis Bullosa and Their Molecular Defects66

Junctional epidermolysis bullosa of Herlitz type (JEB-H)

PART I ■ INFLAMMATORY REACTIONS IN THE SKIN

Junctional epidermolysis bullosa of the non-Herlitz type (JEB-nH)

Junctional epidermolysis bullosa with pyloricatresia (JEB-PA)

MOLECULAR DEFECT

MODE OF INHERITANCE

ONSET

BLISTERS

OTHER CHANGES

Mutations of the genes coding for the α3, the β3, and the χ2 polypeptide chains of laminin 5 Mutations of the genes encoding for BPAG2 or any of the three polypeptide chains of laminin 5 Mutations of the genes encoding for α6 or the β4 integrin subunits

Autosomal recessive

Birth or shortly thereafter

Generalized

Autosomal recessive

Birth, shortly thereafter or in early childhood Birth or shortly thereafter

Localized or generalized

Dystrophic nails, dysplastic teeth, growth retardation, anemia, mucous membrane lesions There may be pigmentary changes, dystrophic nails, and dysplastic teeth

OTHER DIAGNOSTIC MEASURES DIF and IF examinations are negative.66 Mutation analysis demonstrating the gene defect confirms the diagnosis. DIFFERENTIAL DIAGNOSIS The histology of JEB is not diagnostic and can be seen in such other diseases as cell-poor BP, EBA, PCT, pseudoporphyria, and dystrophic EB.66 Therefore, it should be correlated with the clinical picture, immunofluorescence findings, and immunomapping to establish the diagnosis. Table 8-12 displays the diagnostic criteria of JEB.66

Table 8-12 Diagnostic Criteria of Junctional Epidermolysis Bullosa 1. Histology: Subepidermal blister with sparse infiltrates in the dermis 2. Epitope mapping using antibodies against type IV collagen: Intra-lamina lucida split 3. Mutation analysis: • Mutations of the genes coding for the α3, β3, or χ2 polypeptide chains of laminin 5 • Mutations of the gene encoding for the α6 or the β4 integrin subunits • Mutations of the gene encoding for BPAG2

170

Autosomal recessive

Dystrophic Epidermolysis Bullosa Dystrophic epidermolysis bullosa (DEB) is a group of congenital disorders caused by mutations of the gene encoding type VII collagen and is characterized by trauma-induced blisters that heal with scarring and milia.134-136 CLINICAL FEATURES DEB may be autosomal dominant or autosomal recessive. Autosomal dominant DEB comprises four subtypes: (1) epidermolysis bullosa and congenital, localized absence of the skin (Bart syndrome)137; (2) dystrophic epidermolysis bullosa—CockayneTouraine134,136,138,139; (3) albopapuloid dystrophic epidermolysis bullosa, or dystrophic epidermolysis bullosa, Pasini type134; (4) and transient bullous dermatolysis of new-born.140,141 Autosomal recessive DEB encompasses two subtypes: (1) dystrophic epidermolysis bullosa—Hallopeau-Siemens type, (2) dystrophic epidermolysis bullosa—nonHallopeau-Siemens type. Table 8-13 lists the clinical features and molecular defects of DEB variants.66 HISTOPATHOLOGICAL FINDINGS Histopathologically, all variants of DEB are characterized by the formation of a subepidermal blister with sparse lymphocytic infiltration in the upper dermis.66 In recurrent lesions, fibrosis and/or milia may be present. On immunomapping using antibodies to type IV collagen, the blister localizes to the sublamina densa region.

Generalized

Congenital esophageal, pyloric or duodenal atresia, aplasia cutis congenita, renal abnormalities

OTHER DIAGNOSTIC TESTS DIF and IF examinations are negative.66 Mutation analysis confirms the diagnosis by showing the gene defect. DIFFERENTIAL DIAGNOSIS The histology of DEB is not diagnostic and can be seen in such other diseases as cell-poor BP, EBA, PCT, pseudoporphyria, and JEB.66 It should therefore be correlated with the clinical findings, the results of IF, and immunomapping with antibodies to type IV collagen. Table 8-14 displays the diagnostic criteria of DEB.66

Kindler Syndrome Kindler syndrome is a rare autosomal recessive disorder caused by mutation of the KIND1 gene.142,143 That gene codes the kindlin1 protein, which is a human homolog of the Caenorhabditis elegans protein UNC-112, a membrane associated structural/signaling protein that has been implicated in linking the actin cytoskeleton to the extracellular matrix. CLINICAL FEATURES Clinically, blisters, poikiloderma-like changes, photosensitivity, and marked cutaneous atrophy may involve a large area of the skin (Table 8-15). 144,145 Often, nail dystrophy and syndactyly of fingers and toes are present. The blisters are trauma induced, heal with scarring, and occur mainly on the hands and feet. The blisters appear at birth, persist usually through infancy and childhood, and

Table 8-13 Variants of Dystrophic Epidermolysis Bullosa. Features and Molecular Defects66 MOLECULAR DEFECT

MODE OF INHERITANCE

ONSET

BLISTERS

OTHER CHANGES

1. Bart syndrome

Mutations of the gene coding for type VII collagen

Autosomal dominant

Birth

2. Dystrophic epidermolysis Cockayne-Touraine (DEB-CT) 3. Dystrophic epidermolysis bullosa, albopapulodea

Mutations of the gene coding for type VII collagen Mutations of the gene coding for type VII collagen

Autosomal dominant Autosomal dominant

Congenital absence the skin, dystrophic or absent nails Dystrophic nails

4. Transient bullous dermatolysis of newborn

Mutations of the gene coding for type VII collagen

Autosomal dominant

Birth, infancy, early childhood Blisters: birth, infancy, early childhood: adolescence Birth

Affects skin and mucous membranes Localized mainly to extremities Localized mainly to extremities

-

5. Dystrophic epidermolysis bullosa-Hallopeau-Siemens

Mutations of the gene coding for type VII collagen

Autosomal recessive

Birth or shortly thereafter

Generalized, disappear spontaneously in the first few months of life Generalized and heal with marked scarring

6. Dystrophic epidermolysis bullosa-non-HallopeauSiemens

Mutations of the gene coding for Type VII

Autosomal recessive

Birth or shortly thereafter

HISTOPATHOLOGICAL FINDINGS Examination of blistering lesions of patients with Kindler syndrome show histopathologically a subepidermal blister with fibrosis and perivascular and interstitial infiltrate in the upper and mid-dermis.66 On immunomapping using antibodies to type IV collagen, the blister of Kindler syndrome is located in the lamina lucida.

and can be seen in other diseases such as EBA, CP, JEB, and DEB. Correlations of the histopathology with the clinical picture, the results of the immunomapping, IF, and/or electron microscopy are necessary for diagnosis of Kindler syndrome.66

CHAPTER 8 ■ SUBEPIDERMAL BLISTERING DISEASES

tend to decrease with age. The poikiloderma-like changes usually occur on the face and neck. Like the blisters, the photosensitivity abates with age.

Albopapuloid papules, dystrophic nails

 FIGURE 8-19 Junctional epidermolysis bullosa. The subepidermal blister is associated with sparse perivascular and interstitial infiltration by lymphocytes in the dermis.

171

findings in Kindler syndrome are characteristic and show branching and duplication of the lamina densa.66 DIFFERENTIAL DIAGNOSIS The histopathology of Kindler syndrome is not diagnostic

Generalized

Contracture, mittenlike deformities, scarring alopecia, ,dysplastic teeth, dystrophic nails, mucosal strictures ocular involvement Dysplastic teeth, dystrophic nails

OTHER DIAGNOSTIC TESTS DIF and IIF examinations are negative. Ultrastructural

Table 8-14 Diagnostic Criteria of Dystrophic Epidermolysis Bullosa Histology: Subepidermal blister with sparse infiltrates in the dermis Epitope mapping using antibodies against type IV collagen: Sublamina densa blister Mutation analysis: Mutations of the gene coding for type VII collagen

PART I ■ INFLAMMATORY REACTIONS IN THE SKIN

Table 8-15 Kindler Syndrome

Table 8-16 Toxic Epidermal Necrolysis

Clinical Features Rare autosomal recessive Blisters present at birth Poikiloderma-like changes Photosensitivity Marked cutaneous atrophy Nail dystrophy and syndactyly Histopathologic Features Subepidermal blister with basketweave stratum corneum Minimal inflammation with lymphocytes Fibrosis Laboratory Evaluation Epitope mapping using antibodies against type IV collagen Intra-lamina lucida split DIF and IIF examinations Negative Electron microscopy Branching and duplication of the lamina densa Mutation analysis Mutation within the KIND1 gene Differential Diagnosis Junctional and dystrophic epidermolysis bullosa Epidermolysis bullosa acquisita Cicatricial pemphigoid

Clinical Features Rapid onset Fever, malaise Frequent drug history 30% mortality Histopathologic Features Subepidermal blister with basketweave stratum corneum Full-thickness epidermal necrosis Extensive basal vacuolization Minimal inflammation with lymphocytes and occasionally a few neutrophils Laboratory Evaluation Negative direct immunofluorescence Epitope mapping using antibodies against type IV collagen Intra-lamina lucida blister Differential Diagnosis Thermal injury Erythema multiforme Graft vs host disease Staphylococcal scalded skin syndrome

MISCELLANEOUS SUBEPIDERMAL BLISTERING DISEASES

Toxic Epidermal Necrolysis (Lyell Syndrome) Toxic epidermal necrolysis (TEN) is a severe life-threatening drug reaction, in which necrosis of keratinocytes is widespread, affecting large areas of the epidermis. By definition, more than 30% of the body surface is affected by separation of the epidermis from the dermis through the level of the dermal-epidermal junction, producing a scalded skin appearance.146-149 It occurs in all age groups, including children, infants, and neonates.150-154 TEN is a rare disorder, occurring at an estimated incidence of 0.4 to 1.2 cases per million population.146

172

CLINICAL FEATURES Clinically, the cutaneous and mucous membrane lesions147,150-155 are usually preceded by a prodrome that may last for 2 to 3 days and that resembles an upper respiratory tract infection (Table 8-16). The cutaneous lesions begin most often on the

face or the trunk and consist of a morbilliform exanthem, with discrete areas of macular erythema or targetoid lesions (Fig. 8-20A). The lesions coalesce rapidly and spread quickly to other areas of the body. The epidermis in the affected areas becomes necrotic and is raised by flaccid, large blisters. The necrotic epidermis may adhere over the dermis, resulting in a characteristic wrinkled appearance or sheetlike desquamation. About 97% of TEN patients have mucosal lesions.153,155 These usually occur shortly before the onset of the cutaneous lesions. StevensJohnson syndrome (SJS) is a milder form of TEN, where the epidermal necrosis involves less than 10% the body’s surface area.148,156 Patients whose disease involves 10% to 30% of their body surface area have SJS/TEN overlap. HISTOPATHOLOGICAL FINDINGS TEN is characterized histologically by formation of a subepidermal blister.66 The epidermis forming the blister roof shows full thickness necrosis and has a basket weave stratum corneum (Fig. 8-20B). In the dermis is a sparse perivascular and interstitial infiltrate of lymphocytes and occasional eosinophils neutrophils. Erythrocytes may have extravasated. Epidermal necrosis and the subepidermal blister usually affect the entire width of the biopsy. The subepidermal blisters of TEN are located in the lamina lucida region. On immunomapping using

antibodies to type IV collagen, the split localizes to the lamina lucida. OTHER DIAGNOSTIC TESTS DIF is negative. DIFFERENTIAL DIAGNOSIS The histologic differential diagnosis of toxic epidermal necrolysis includes severe thermal injury, in which full-thickness epidermal necrosis is seen. However, in the thermally damaged skin, there is an elongation of keratinocyte nuclei not seen in toxic epidermal necrolysis and the dermal homogenization characteristic of thermal injury is not present. Severe erythema multiforme also enters the histologic differential diagnosis for those who believe it to be a separate entity. There is generally slightly more of a lymphocytic infiltrate within the papillary dermis accompanied by exocytosis in erythema multiforme than is seen in toxic epidermal necrolysis. In the earliest lesions of toxic epidermal necrolysis, distinction from erythema multiforme may be impossible. Graft versus host disease, grade III also has a subepidermal blister with abundant necrotic keratinocytes, but in most cases has a more prominent inflammatory infiltrate. The presence of necrotic keratinocytes within eccrine structures is also more commonly seen in graft versus host disease than in toxic epidermal necrolysis. Another entity which enters into the clinical differential diagnosis and must be distinguished from toxic epidermal necrolysis is staphylococcal scalded skin syndrome. Clinically, toxic epidermal necrolysis and staphylococcal scalded skin syndrome may present in a very similar manner with extensive blistering and denudation. Both entities constitute potentially life-threatening diseases but require different lines of therapy. Frozen section diagnosis is therefore often required for rapid therapeutic intervention. Full-thickness epidermal necrosis is characteristic for toxic epidermal necrolysis and differentiates this disorder from staphylococcal scalded skin syndrome, which shows an intraepidermal blister with a cleavage plane in the uppermost epidermis. Also, paraneoplastic pemphigus and linear IgA disease may clinically resemble TEN.157,158 These diseases can, however, be distinguished from TEN by microscopic findings and IF.

Porphyria Cutanea Tarda The porphyrias comprise a group of disorders characterized by excessive accumulation of porphyrins or their precursors

A

B

in tissues due to inherited or acquired deficiencies in any one of the enzymes that synthesize heme (Table 8-17).159,160 There are several types of porphyrias. Porphyria cutanea tarda is the most common of them.159 It has an estimated incidence of 1:1000 to 1:30000. About 60% of the affected patients are males.159 PCT is due to reduced activity of the enzyme uroporphyrinogen decarboxylase (UROD), which catalyzes several steps in heme synthesis.161-163 CLINICAL FEATURES Clinically, blisters develop on the dorsal surfaces of the hands, in association with increased fragility of sun-exposed skin and hypertrichosis of the periorbital area (Table 8-17). There is mottled pigmentation of sunexposed areas and sometimes morphealike changes.159,160,164 The blisters are usually induced by minor trauma and heal with atrophic scars and milia. HISTOPATHOLOGICAL FINDINGS Bullous lesions of PCT are characterized histopathologically by the formation of subepidermal blisters (Table 8-17 and Figs. 8-21 and 8-22).66,165 The bullae may contain fibrin and a few inflammatory cells. The epidermis forming the blister roof is usually effaced and may be necrotic.66 In the dermis, there is actinic elastosis and a sparse superficial perivascular and interstitial infiltration by lymphocytes. The blood vessels of the superficial dermal plexus usually have thickened walls that can be best demonstrated by PAS stain. On immunomapping with antibodies to type IV collagen, the blister in PCT is located in the lamina lucida.66 OTHER DIAGNOSTIC TESTS IIF examinations in patients with PCT are negative.66,166 DIF usually reveals C3 depositis

around the upper dermal vascular plexus and/or at the DEJ.165,167 Sometimes linear deposits of IgG and/or IgA may be seen at the DEJ.

Table 8-17 Porphyria Cutanea Tarda

Clinical Features Sporadic or familial Blisters at sites of sun exposure and trauma Scarring and milia Facial hypertrichosis Hyperpigmentation Often associated with liver disease Histopathologic Features Subepidermal blister Sparse perivascular and interstitial lymphoid infiltrates Usually solar elastosis Thick-walled blood vessels Caterpillar bodies—basement membrane material (segment eosinophilic structures) Laboratory Evaluation Direct immunofluorescence Linear dermal-epidermal and perivascular C3, and sometimes IgG, IgM, IgA Epitope mapping using antibodies against type IV collagen Intra-lamina lucida blister Porphyrin laboratory tests Elevated total porphyrin levels in urine Isocoproporphyrin is demonstrable in feces Differential Diagnosis Cell-poor bullous pemphigoid Epidermolysis bullosa (hereditary and acquired) Thermal injury Toxic epidermal necrolysis Bullosis diabeticorum Pseudoporphyria Traumatic blisters

Confirmation of the diagnosis of PCT requires porphyrin laboratory tests.159,160 In PCT, total porphyrin levels in urine are elevated (10 to 100 times than normal), with a predominence of uroporphyrin and heptacarboxyporphyrin. Isocoproporphyrin is demonstrable in feces. DIFFERENTIAL DIAGNOSIS The histologic differential diagnosis is that of the minimally inflammatory subepidermal blistering disorders and includes hereditary and acquired epidermolysis bullosa, pseudoporphyria, penicillamine dermopathy, cell-poor bullous pemphigoid, traumatic blisters, bullosis diabeticorum, and blisters overlying recent scars. The markedly thickened papillary dermal vessel walls and the prominent dermal elastosis are helpful in making a diagnosis of porphyria. Direct immunofluorescence demonstrating linear deposits of IgG and C3 around the papillary dermal vessels and less frequently along the dermal epidermal junction is also helpful in confirming the diagnosis and ruling out epidermolysis bullosa acquisita and cell-poor bullous pemphigoid. The histologic and immunologic findings in pseudoporphyria are identical to those of porphyria. The distinction between the two entities hinges on porphyrin studies, which are negative in pseudoporphyria.

CHAPTER 8 ■ SUBEPIDERMAL BLISTERING DISEASES

 FIGURE 8-20 Toxic epidermal necrolysis. (A) The patient demonstrates striking facial edema and hemorragic crusting of lips. (B) The epidermis is necrotic, generating a subepidermal blister. In the dermis is a sparse lymphocytic infiltrate, with few neutrophils.

Pseudoporphyria Pseudoporphyria is a bullous disorder that is clinically and histopathologically similar to PCT, but with normal UROD activity.159,168 CLINICAL FEATURES The clinical findings in pseudoporphyria are similar to those

173

Cell-poor bullous pemphigoid Epidermolysis bullosa (hereditary and acquired) Thermal injury Toxic epidermal necrolysis Bullosis diabeticorum Traumatic blisters

PART I ■ INFLAMMATORY REACTIONS IN THE SKIN

Coma Blisters Coma blisters are bullae that appear at pressure sites in patients with druginduced and non-drug-induced coma.169,170

 FIGURE 8-21 Porphyria cutanea tarda. The subepidermal blister contains fibrin and few inflammatory cells. The epidermis is effaced. In the upper dermis are found actinic elastosis and a scant infiltrate of lymphocytes.

of PCT (Table 8-18). Pseudoporphyria may occur in patients undergoing hemodialysis for chronic renal insufficiency (dialysis-induced pseudoporphyria) or in those taking drugs such as naproxen, furosemide, nalidixic acid, and tetracycline (drug-induced pseudoporphyria)159,168. Pseudoporphyria has also been attributed to PUVA therapy, excessive sun exposure, and tanning bed use (UVA-induced pseudoporphyria).168 HISTOPATHOLOGICAL FINDINGS Blisters of pseudoporphyria are histopathologically indistinguishable from those of PCT (Table 8-18). 66 Similarly, the splits in the two disorders localize to the lamina lucida on immunomapping. OTHER DIAGNOSTIC TESTS Results of IIF and DIF in pseudoporphyria are similar to those of PCT.20 Porphyrin levels in drug-induced pseudoporphyria and UVA drug-induced pseudoporphyria are normal. In dialysis-induced pseudoporphyria, serum porphyrins are increased, although UROD activity is normal.

174

DIFFERENTIAL DIAGNOSIS The histology of pseudoporphyria is not diagnostic and can be seen in such other diseases as PCT, EBA, DEB, JEB, and cell-poor BP.66 It should therefore be correlated with porphyrin assay, IF, and immunomapping. Table 8-18 shows the diagnostic criteria of pseudoporphyria.66

Table 8-18 Pseudoporphyria

Clinical Features Features often identical to porphyria cutanea tarda Chronic renal failure with hemodialysis common Secondary to particular medications: Furosemide Nalidixic acid Tetracycline Naproxen Tense bullae in sun-exposed skin Histopathologic Features Subepidermal blister In the dermis: Sparse perivascular and interstitial infiltration by lymphocytes Actinic elastosis and thick-walled blood vessels Laboratory Evaluation Blister mapping using antibodies against type IV collagen Intra-lamina lucida split Porphyrin laboratory tests Dialysis-induced pseudoporphyria: elevated serum porphyrin levels, normal UROD activity Drug-induced and UVA-induced pseudoporphyrias: normal UROD activity and serum porphyrin levels Differential Diagnosis Porphyria cutanea tarda

CLINICAL FEATURES Coma blisters are tense, usually clear, and occur at sites subjected to pressure, such as the hands, wrists, scapulae, sacrum, knees, legs, ankles, and heels (Table 8-19). 169-171 They appear on normal or erythematous skin, often in a linear distribution, and may reach substantial size. HISTOPATHOLOGICAL FEATURES Histopathologically, subepidermal blisters occur in association with necrosis of the eccrine

Table 8-19 Coma Blisters

Clinical Features Blisters at sites of pressure in comatose patients: hands, wrists, scapulae, sacrum, knees, legs, ankles, heels Often linear distribution Tense clear blisters on normal-appearing or erythematous skin Often quite large in size Histopathologic Features Subepidermal blister Necrosis of eccrine sweat glands and ducts and less commonly pilosebaceous units Sparse inflammation Laboratory Evaluation Direct immunofluorescence Negative Epitope mapping using antibodies against type IV collagen Intra-lamina lucida blister Differential Diagnosis Cell-poor bullous pemphigoid Epidermolysis bullosa (hereditary and acquired) Thermal injury Bullosis diabeticorum Pseudoporphyria Traumatic blisters

sweat glands and ducts (Table 8-19).66,171-173 Necrosis of pilosebaceous units may also be present. On immunomapping with antibodies against type IV collagen, the split localizes within the lamina lucida. OTHER DIAGNOSTIC TESTS DIF and IIF examinations in coma blisters are negative.66 DIFFERENTIAL DIAGNOSIS The histology of coma blisters is diagnostic based on the necrosis of appendageal structures and in combination with the clinical picture allows definitive diagnosis.66 Table 8-19 shows the diagnostic criteria of coma blisters.66

Cutaneous manifestations of diabetes mellitus occur in about 30% of diabetic patients.174 One of these is blister formation, known as bullosis diabeticorum or bullous diabeticorum (BD). BD usually affects patients with long-standing DM; however, it has been reported in newly diagnosed cases.175-178 CLINICAL FEATURES Clinically, clear painless blisters of several millimetres to many centimeters appear abruptly and spontaneously and are mainly located on the feet and lower legs and occasionally on the hands and forearms. They heal spontaneously in 2 to 5 weeks, without scarring, although the lesion(s) may relapse (Table 8-20). HISTOPATHOLOGICAL FEATURES BD is characterized histopathologically by formation of a subepidermal blister that may contain fibrin and a few inflammatory cells (Table 8-20). 66,177-178 The epidermis forming the blister roof is usually necrotic. In the dermis, there is sparse, superficial perivascular, and interstitial infiltration by lymphocytes. The blood vessels may have thickened walls. On immunomapping using antibodies against type IV collagen, the split is located in the lamina lucida.176,178 OTHER DIAGNOSTIC TESTS DIF and IIF examinations in BD are negative.66,176-179 Laboratory tests reveal the presence of diabetes mellitus. DIFFERENTIAL DIAGNOSIS The histology of BD is not diagnostic, and similar changes can be seen in such other diseases as PCT, EBA, DEB, JEB, and cellpoor BP.66 Interpretation requires correlation with the clinical presentation, laboratory test for diabetes mellitus, IF, and immunomapping.180

Clinical Features Patients with long-standing diabetes and other conditions Feet, lower legs, hands, forearms most affected Spontaneous healing without scarring in 2-5 weeks Painless clear blisters on normal-appearing or erythematous skin Several millimeters to several centimeters in size Histopathologic Features Subepidermal blister often with necrotic blister roof Fibrin Sparse perivascular and interstitial lymphocytic infiltrate Thickened walls of blood vessels Laboratory Evaluation Direct immunofluorescence Negative Epitope mapping using antibodies against type IV collagen Intra-lamina lucida blister Differential Diagnosis Cell-poor bullous pemphigoid Epidermolysis bullosa (hereditary and acquired) Porphyria cutanea tarda Pseudoporphyria Traumatic blisters

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Bullosis Diabeticorum

Table 8-20 Bullosis Diabeticorum

175

PART I ■ INFLAMMATORY REACTIONS IN THE SKIN 176

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CHAPTER 8 ■ SUBEPIDERMAL BLISTERING DISEASES

75. Jenkins RE, Hern S, Black MM. Clinical features and management of 87 patients with pemphigoid gestationis. Clin Exp Dermatol. 1999 Jul;24(4):255-259. 76. Holmes RC, Black MM, Dann J, James DC, Bhogal B. A comparative study of toxic erythema of pregnancy and herpes gestationis. Br J Dermatol. 1982 May; 106(5):499-510. 77. Matsumura K, Amagai M, Nishikawa T, Hashimoto T. The majority of bullous pemphigoid and herpes gestationis serum samples react with the NC16a domain of the 180-kDa bullous pemphigoid antigen. Arch Dermatol Res. 1996;288:507-509. 78. Murakami H, Amagai M, Higashiyama M, et al. Analysis of antigens recognized by autoantibodies in herpes gestationis. Usefulness of immunoblotting using a fusion protein representing an extracellular domain of the 180 kD bullous pemphigoid antigen. J Dermatol Sci. 1996 Nov;13(2):112-117. 79. Kelly SE, Cerio R, Bhogal BS, Black MM. The distribution of IgG subclasses in pemphigoid gestationis: PG factor is an IgG1 autoantibody. J Invest Dermatol. 1989;92:695-698. 80. Chimanovitch I, Schmidt E, Messer G, et al. IgG1 and IgG3 are the major immunoglobulin subclasses targeting epitopes within BP180 NC16A in pemphigoid gestationis. J Invest Dermatol. 1999;113:140-142. 81. Bhogal B, Black MM. Diagnosis, diagnostic and research techniques. In: Wojnarowska F, Briggaman RA, eds. Management of Blistering Diseases. New York: Raven Press; 1990:15-34. 82. Giudice GJ, Wilske KC, Anhalt GJ, et al. Development of an ELISA to detect antiBP180 autoantibodies in bullous pemphigoid and herpes gestationis. J Invest Dermatol. 1994 Jun;102(6):878-881. 83. Demircay Z, Baykal C, Demirkesen C. Lichen planus pemphigoides: report of two cases. Int J Dermatol. 2001 Dec; 40(12):757-759. 84. Yoon KH, Kim SC, Kang DS, Lee IJ. Lichen planus pemphigoides with circulating autoantibodies against 200 and 180 kDa epidermal antigens. Eur J Dermatol. 2000 Apr-May;10(3):212-214. 85. Hsu S, Ghohestani RF, Uitto J. Lichen planus pemphigoides with IgG autoantibodies to the 180 kd bullous pemphigoid antigen (type XVII collagen). J Am Acad Dermatol. 2000 Jan;42(1 Pt 1): 136-141. 86. Skaria M, Salomon D, Jaunin F, Friedli A, Saurat JH, Borradori L. IgG autoantibodies from a lichen planus pemphigoides patient recognize the NC16A domain of the bullous pemphigoid antigen 180. Dermatology. 1999;199(3):253-255. 87. Zillikens D, Caux F, Mascaro JM, et al. Autoantibodies in lichen planus pemphigoides react with a novel epitope within the C-terminal NC16A domain of BP 180. J Invest Dermatol. 1999;113:117-121. 88. Zillikens D, Mascaro JM, Rose PM, et al. A highly sensitive enzyme-linked immunosorbent assay for the detection of circulating anti-BP180 autoantibodies in patients with bullous pemphigoid. J Invest Dermatol. 1997;109:679-683. 89. Ahmed AR, Kurgis BS, Rogers RS. Cicatricial pemphigoid. J Am Acad Dermatol. 1991 Jun;24(6 Pt 1):987-1001.

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CHAPTER 9 Vasculitis and Related Disorders Sarah K. Barksdale Raymond L. Barnhill

CLINICAL AND HISTOLOGIC DEFINITIONS The clinical manifestations of vascular damage include edema, livedo reticularis, and various manifestations of subcutaneous hemorrhage or purpura. Hemorrhagic lesions less than 3 mm in diameter are called petechiae. If they are larger, they are called ecchymoses. Raised or palpable purpura generally indicate the presence of an inflammatory cell infiltrate. If vascular damage is severe, vascular occlusion may lead to ischemic injury resulting in necrosis, gangrene, and/or ulceration. Vascular injury can occur in forms limited to the skin. However, in many instances vascular injury occurs in the context of a systemic disease. Vascular damage may be the principal event of a disease process, such as in polyarteritis nodosa (PAN); a significant component of a complex disease, as in connective tissue disease; or simply a secondary effect to a localized injury, such as an arthropod bite or traumatic ulcer. Histologically, vascular injury may occur with or without inflammation. The composition and cellularity of the associated inflammatory cell infiltrate, as well as the extent of vascular damage, may also vary (Table 9-1). Vasculitis is defined as an inflammatory process resulting in clear-cut vascular damage. Histologic recognition of vasculitis relies on the recognition of two components: an inflammatory cell infiltrate and evidence of vascular injury (see Table 9-1; Fig. 9-1). If vasculitis is defined as an inflammatory process, the absence of inflammation, even if vascular damage is present, precludes the diagnosis. The composition and cellularity of the

Primary Vascular Injury Vasculitis Inflammatory cell infiltrate Clear-cut vascular damage (eg, fibrinoid necrosis of vessel wall) Inflammatory vascular reaction Inflammatory cell infiltrate Limited vascular damage (insufficient for vasculitis) Vasculopathy Lack of inflammation Vascular damage of any degree Secondary Vascular Injury May present as vasculitis, inflammatory vascular reaction, or vasculopathy Secondary to another insult such as external trauma, ulceration Variable vascular alterations with sparing of some vessels Peripheral perivascular fibrinoid deposition

inflammatory infiltrate of a vasculitis may correlate with the chronology of the process, but not always. Early on, neutrophils and/or eosinophils may predominate. In the late healing stage, the inflammatory cell infiltration may be minimal with an excess of lymphocytes and macrophages. The histologic criteria for recognizing microvascular injury are somewhat arbitrary, and the minimal criteria for vasculitis remain controversial. Various histologic

Table 9-2 Histological Manifestations of Vascular Damage Necrosis of vessel wall with deposition of fibrinoid materiala Leukocytoclasis Extravasation of erythrocytes Endothelial cell swelling Luminal thrombosis Edema a

Generally required for a diagnosis of vasculitis.

features are considered to be indicative of vascular injury (Table 9-2). Certain changes, including edema, extravasation of erythrocytes, infiltration of vessel walls by inflammatory cells, leukocytoclasis, and thrombosis, may occur without actual damage to the structural integrity of the vessel. Vessels become leaky for physiologic reasons, leading to edema or even extravasation of erythrocytes and leukocytes. Leukocytoclasis may result from the breakdown of a perivascular neutrophilic infiltrate during the resolution of an inflammatory process unrelated to vasculitis. Similarly, fibrin thrombi may be present in essentially uninjured vessels in the setting of a hypercoagulable state. Unequivocal injury to the vascular wall is manifested by deposition of fibrinoid material and/or necrosis. In other words, a diagnosis of vasculitis is established histologically if vascular inflammation is

 FIGURE 9-1 Fibrinoid degeneration. Fibrinoid material is deposited within a vessel. There is also a polymorphonuclear infiltrate.

CHAPTER 9 ■ VASCULITIS AND RELATED DISORDERS

This chapter discusses a group of conditions whose common denominator is damage to cutaneous blood vessels. Emphasized is the concept that vascular injury is a dynamic process with a limited spectrum of clinical and histologic reaction patterns.

Table 9-1 Definitions of Vascular Injury

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accompanied by fibrinoid alterations of the vessel wall. Is the presence of fibrinoid necrosis an absolute prerequisite for the pathologist to render a diagnosis of vasculitis? For didactic purposes, it is tempting to answer the question with an unambiguous “yes.” Yet in some cases other features of vascular damage, such as leukocytoclasis or intraluminal thrombi, are developed to such a degree that the constellation of findings favors vasculitis despite the lack of clear-cut fibrinoid necrosis. As a general rule, however, we advise the application of strict criteria for the diagnosis of vasculitis and caution in diagnosing vasculitis in the absence of fibrinoid necrosis. The term vasculopathy or pseudovasculitis is used to describe evidence of vascular damage in the absence of inflammation. The degree of vascular damage is variable. The spectrum of clinical settings in which noninflammatory vascular injury commonly occurs includes mainly coagulopathies and other vascular occlusive conditions. Hemmorrhage, intraluminal thrombi, or emboli are histologic findings in these disorders (Fig. 9-2). There is a third group of reactions in which inflammation is present, but the extent of vascular injury usually is limited and appears insufficient for vasculitis. This group of disorders encompasses a great number of heterogeneous inflammatory conditions, which may regularly or occasionally manifest vascular injury. Accordingly, including these entities in a chapter on vasculitis is a somewhat arbitrary decision. We have included those diseases whose histologic or clinical presentation warrants distinction from “true” vasculitis. Since the only common denominator for these disorders is the presence of an inflammatory infiltrate and some limited vascular damage, we designate them inflammatory vascular reactions (Fig. 9-3). This term is an adaptation and generalization of the more established term neutrophilic vascular reactions, which was coined to define a group of inflammatory disorders that showed histologic overlap with neutrophilic smallvessel vasculitis.1 An important step in evaluating vascular injury is to determine whether the vascular damage is a primary or secondary process. Primary vascular injury implies that the vascular insult is the predominant disease process. Secondary vascular injury indicates that another disease process outside the vessels is the primary pathologic process. An example of the latter would be vessels engulfed by the necrotizing inflammation around an ulceration initiated by external insult

 FIGURE 9-2 Vasculopathic reaction. Fibrin thrombi in small dermal vessels are seen with a minimal inflammatory cell infiltrate.

 FIGURE 9-3 Inflammatory vascular reaction. Occasional perivascular karyorrhectic debris and endothelial cell swelling are noted. However, no fibrinoid necrosis is present.

or infection. Usually, the primary disease process is evident microscopically. However, occasionally, secondary vascular changes can be misleading when noted on evaluation of shallow tissue sections before the primary process becomes visible. Secondary vascular injury often is variable, with sparing of

some vessels in the zone of tissue injury. Other indications of secondary vascular injury include deposition of fibrinoid material at the periphery of the vessel wall, focal thrombosis without significant infiltration by inflammatory cells, and extensive inflammation or granulation tissue between blood vessels.

VASCULITIS

CONDITION Giant cell (temporal) arteritis

Takayasu arteritis

Polyarteritis nodosa (classic polyarteritis nodosa) Kawasaki disease

Wegener granulomatosisc,d

Churg-Strauss syndromec,d

Microscopic polyangiitis (microscopic polyarteritis)c,d

Henoch-Schönlein purpurad

Essential cryoglobulinemic vasculitisd

Cutaneous leukocytoclastic angiitis

DEFINITION

Large-Vessel Vasculitisb (>10 mm in diameter) Granulomatous arteritis of the aorta and its major branches, with a predilection for the extracranial branches of the carotid artery; often involves the temporal artery; usually occurs in patients older than 50 years and often is associated with polymyalgia rheumatica Granulomatous inflammation of the aorta and its major branches; usually occurs in patients younger than 50 years Medium-Sized Vessel Vasculitisb (about 0.3-10 mm) Necrotizing inflammation of medium-sized or small arteries without glomerulonephritis or vasculitis in arterioles, capillaries, or venules Arteritis involving large, medium-sized, and small arteries, and associated with mucocutaneous lymph node syndrome; coronary arteries are often involved; aorta and veins may be involved; usually occurs in children Small-Vessel Vasculitisb (10-20 um to 300 um) Granulomatous inflammation involving the respiratory tract, and necrotizing vasculitis affecting small-to medium-sized vessels, eg, capillaries, venules, arterioles, and arteries; necrotizing glomerulonephritis is common Eosinophil-rich and granulomatous inflammation involving the respiratory tract and necrotizing vasculitis affecting small- to medium-sized vessels, and associated with asthma and blood eosinophilia Necrotizing vasculitis with few or no immune deposits affecting small vessels, ie, capillaries, venules, or arterioles; necrotizing arteritis involving small- and medium-sized arteries may be present; necrotizing glomerulonephritis is very common; pulmonary capillaritis often occurs Vasculitis with IgA-dominant immune deposits affecting small vessels, ie, capillaries, venules, or arterioles; typically involves skin, gut, and glomeruli, and is associated with arthralgias or arthritis Vasculitis with cryoglobulin immune deposits affecting small vessels, ie, capillaries, venules, or arterioles, and associated with cryoglobulins in serum; skin and glomeruli are often involved Isolated cutaneous leukocytoclastic angiitis without systemic vasculitis or glomerulonephritis

CHAPTER 9 ■ VASCULITIS AND RELATED DISORDERS

The classification of vasculitis is difficult for a number of reasons.2-5 The various vasculitic disease entities do not have specific histologic features, and the same disease process may show a spectrum of histologic changes depending on the stage of the disease, the level of activity, and treatment that might have modified its course. Moreover, advances in research have redefined or expanded the definitions of certain disease processes with subsequent loss of histologic criteria previously thought to be specific. Considerable, overlap between vasculitis syndromes exists with many case reports describing patients with hybrid disease states. In an attempt to standardize nomenclature for the vasculitides, an international conference has proposed a system based primarily on the size of the involved vessels4 (Table 9-3). A second international conference has proposed a similar classification tailored to the childhood vasculitides.5 Classification based on vessel size is helpful because there is some correlation with the clinical presentation. Purpura, palpable purpura, urticaria, vesicles and bullae, and splinter hemorrhages typically reflect small-vessel injury. Cutaneous nodules, ulcers, livedo reticularis, and racemosa and digital gangrene suggest the involvement of medium-sized arteries. However, classification based on vessel size alone is of limited value in dermatopathology because most cutaneous vasculitides affect primarily small dermal vessels. In addition, medium-sized-vessel vasculitis frequently will show some degree of small-vessel involvement and vice versa. Classification by etiology or pathogenetic mechanism is difficult because much remains to be learned about the causes of vasculitis. A practical approach (Table 9-4) to evaluating inflammed blood vessels is first to decide whether or not clear-cut vascular damage is present and is sufficient for a designation as vasculitis and then to assess the composition of the inflammatory infiltrate (neutrophilic/leukocytoclastic versus lymphocytic versus granulomatous) and its distribution (superficial, superficial and deep, or deep only) and to look for associated findings, such as microorganisms, that might narrow the differential diagnosis. The context of the histologic findings is important. Are the vasculitic changes merely secondary events in the setting of a herpetic ulcer? Lesions have a life span, and for example, a lesion that shows a leukocytoclastic vasculitis (LCV) at one

Table 9-3 Names and Definitions of Vasculitis Adopted by the Chapel Hill (NC) Consensus Conference on the Nomenclature of Systemic Vasculitisa

a

Modified from Jennette et al.4 Larger artery refers to the aorta and the largest branches directed toward major body regions (eg, to the extremities and the head and neck); medium-sized artery refers to the main visceral arteries (eg, renal, hepatic, coronary, and mesenteric arteries), and small artery refers to the distal arterial radicals that connect with arterioles (eg, renal arcuate and interlobular arteries). Note that some small- and large-vessel vasculitides may involve medium-sized arteries; but large- and medium-sized vessel vasculitides do not involve vessels smaller than arteries. c Strongly associated with antineutrophil cytoplasmic autoantibodies. d May be accompanied by glomerulonephritis and can manifest as nephritis or pulmonary-renal vasculitis syndrome.

b

point may show a predominantly lymphocytic or even granulomatous infiltrate at another point in time. The following sections discuss the histologic features and differential diagnoses

of vasculitides affecting the skin with emphasis on the small-vessel vasculitides. As suggested, classification of these disease entities into discrete categories is somewhat arbitrary because significant

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Table 9-4 Approach to Vasculitis

PART I ■ INFLAMMATORY REACTIONS IN THE SKIN

Determine if vasculitis or vasculopathy is present or absent Determine if primary or secondary vascular injury, if possible Size of vessel and type Large Medium Small Composition of infiltrate Neutrophilic/leukocytoclastic Lymphocytic Histiocytic/granulomatous Evaluation for infection (special stains for microorganisms and cultures) Additional histologic clues: Intravascular PAS-positive bright red material (suspicious for cryoprecipitates) Viral cytopathic changes (eg, HSVaassociated vascular damage) Plasma cells (spirochetes) Presence of eosinophils (r/o drug, hypersensitivity reaction) Changes suggestive of connective tissue disease (eg, interface dermatitis; dermal mucin) Edema (urticarial reaction) Serologic and immunopathologic evaluation ANCA, ANA, rheumatoid factor, cryoglobulins immunofluorescence, and other studies for the detection of immune complexes, eg, IgA fibronectin aggregates Clinical context Cutaneous involvement only Extent of systemic involvement a

HSV: Herpes simplex virus.

overlap of features exists. A key concept is that some of the histologic entities discussed are not actual diseases per se but are reaction patterns to a wide variety of etiologic stimuli. As an organizing principle for discussing small-vessel vasculitides, we follow mainly morphologic criteria, that is, the composition of the inflammatory cell infiltrate (neutrophilic versus lymphocytic versus granulomatous). After reviewing small-vessel vasculitides and other inflammatory vascular reactions that need to be distinguished from vasculitis, we discuss systemic ANCA-associated vasculitides and vasculitides of mediumand large-sized vessels separately.

SMALL-VESSEL NEUTROPHILIC/ LEUKOCYTOCLASTIC VASCULITIS

182

A large number of different disease processes can be accompanied by smallvessel vasculitis with predominantly

Table 9-5 Differential Diagnosis of Cutaneous Neutrophilic Small Vessel Vasculitis Infection associated Bacterial Gram-positive/-negative organisms, mycobacteria, spirochetes Rickettsial Rocky Mountain spotted fever Scrub typhus Fungal Viral Immunologic-injury associated Immune-complex mediated Henoch-Schoenlein purpura Urticarial vasculitis Cryoglobulinemia Serum sickness Connective tissue diseases Autoimmune diseases Infection-induced immunologic injury (eg, hepatitis B or C, streptococcal) Drug-induced Paraneoplastic processes Behçet disease Erythema elevatum diutinum Antineutrophil-antibody associated Wegener granulomatosis Microscopic polyangiitis Churg-Strauss syndrome Some drug-induced vasculitis No known association Polyarteritis nodosa

neutrophilic infiltrates. The main diseases to be considered are listed in Table 9-5.6 CLINICAL FEATURES The clinical manifestations are related to the depth of vascular involvement and degree of vascular injury. Vasculitis confined to the superficial dermis may exhibit lesions ranging from urticarial lesions to erythematous and purpuric macules, papules, and pustules (Fig. 9-4A). Involvement of the deep reticular dermal vascular plexus and subcutaneous fat by small-vessel vasculitis may result in hemorrhagic bullae, livedo reticularis, erythematous nodules, and cutaneous infarcts and necrosis. The single most common manifestation of this form of vasculitis is palpable purpura, that is, small papules associated with purpura (Fig. 9-4A). The distal lower extremities are the most common location, although any site may be involved. HISTOPATHOLOGIC FEATURES Neutrophilic small-vessel vasculitis is a reaction pattern of small dermal vessels, almost exclusively postcapillary venules, characterized by a combination of vascular

damage and an infiltrate composed largely of neutrophils (Fig. 9-4). Since there is often fragmentation of nuclei (karyorrhexis or leukocytoclasis), the term leukocytoclastic vasculitis (LCV) is used frequently. Depending on its severity, this process can be subtle and limited to the superficial dermis or pandermal and florid and associated with necrosis and ulceration. If edema is prominent, a subepidermal blister may form. In a typical case of LCV, the dermal vessels show swelling of the endothelial cells and deposits of strongly eosinophilic strands of fibrin within and around their walls. The deposits of fibrin and the marked edema together give the walls of the vessels a “smudgy” appearance referred to as fibrinoid degeneration (see Fig. 9-1). Actual necrosis of the perivascular collagen, however, is seen primarily in conjunction with lesions of vasculitis showing ulceration. Luminal occlusion of vessels by an expanded, inflamed, edematous vessel wall or by microthrombi may be observed. The cellular infiltrate is present predominantly around or within dermal blood vessels, blurring the vascular outlines. Neutrophils and varying numbers of eosinophils and mononuclear cells are found in the infiltrate. Karyorrhectic nuclear debris, or nuclear dust, gives these infiltrates a dirty appearance. If neutrophils are numerous and densely packed, micropustules are formed. If large pustules are found, the process can be termed pustular vasculitis (Fig. 9-5). Inflammatory cells also may be scattered throughout the upper dermis in association with fibrin deposits between and within collagen bundles. Extravasation of erythrocytes is almost invariably present. As with any inflammatory process, the appearance of the reaction pattern depends on the stage at which the biopsy is taken. In older lesions, the number of neutrophils may be decreased and the number of mononuclear cells increased so that mononuclear cells may predominate, and a designation of a lymphocytic or even granulomatous vasculitis or vascular reaction might be made. Many infectious and immunologically mediated processes are associated with vasculitis (see Table 9-5). In many cases the pathogenesis is unknown. The final common pathway typically involves neutrophils and monocyte activation with adherence to endothelial cells, infiltration of the vessel wall, and release of lytic enzymes and toxic radicals. The cascade leading to vascular injury may be initiated by (1) the deposition of immune complexes, (2) direct binding of antibodies to antigens in vessel walls, and (3) activation

B

 FIGURE 9-4 Leukocytoclastic vasculitis. (A) Erythematous and violaceous purpuric macules and papules (“palpable purpura”) characertistically involving the distal lower extremities. In addition necrotic, eroded, and ulcerated lesions are present. (B) Vascular damage with fibrinoid necrosis (red material at arrow head) and a perivascular neutrophilic infiltrate and nuclear debris are seen.

of leukocytes by antibodies with specificity for leukocyte antigens (ANCAs).

Diagnostic Approach to Neutrophilic Small-Vessel Vasculitis The cutaneous and histologic manifestations are largely nonspecific for the small-vessel vasculitides. Palpable purpura

may be the clinical appearance of dermal leukocytoclastic small-vessel vasculitis secondary to any of the entities listed in Table 9-5. Therefore, to reach an appropriate diagnosis, additional histologic clues (see Table 9-4) must be sought, and the histologic findings should only be interpreted in the context of clinical information. Often additional

 FIGURE 9-5 Pustular vasculitis. Intraepidermal pustule formation with many polymorphonuclear cells and vascular damage are present.

laboratory data, such as from microbiologic cultures, special stains for organisms, immunofluorescence, or serologic studies, are needed. One of the most important diagnostic steps in the evaluation of a vasculitis is to rule out an infectious process. If noninfectious vasculitis is suspected, evidence for systemic vasculitis must be sought. Clinical findings, such as hematuria, arthritis, and myalgia, and laboratory findings, such as enzymatic assays for muscle or liver enzymes, serologic analysis for ANCAs, antinuclear antibodies, cryoglobulins, hepatitis B and C antibodies, IgAfibronectin aggregates, and complement levels, are important to further delineate the disease process. Exposure to a potential allergen, such as a drug, that might have elicited a hypersensitivity reaction should be sought. Evidence of an allergic pathogenesis reassuringly suggests that the vasculitic process may be self-limited and not associated with systemic vasculitis. As mentioned previously, the possibility that the vasculitislike histologic findings are a secondary phenomenon should be excluded. The following paragraphs discuss the main clinical settings in which LCV occurs. INFECTIOUS VASCULITIS An infectious process needs to be ruled out early in the evaluation of an LCV.2,4 Clinically, the spectrum of findings ranges from small macules to papules, pustules, and purpura. Histologically, infection-related vasculitis probably shows a greater frequency of the following changes: subcorneal, intraepidermal, and subepidermal neutrophilic pustules and abscesses, that is, pustular vasculitis; dermal infiltrates with more

CHAPTER 9 ■ VASCULITIS AND RELATED DISORDERS

A

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PART I ■ INFLAMMATORY REACTIONS IN THE SKIN 184

neutrophils relative to other cell types, such as eosinophils and lymphocytes; and intravascular fibrin thrombi, some of which will contain microorganisms on occasion. On the other hand, infectionrelated vasculitis may show a lesser degree of vascular damage compared with noninfectious vasculitides. Microorganisms may invade vessels directly or damage them by an immune-mediated mechanism. Neisseria meningitidis is a common cause of infectious cutaneous leukocytoclastic vasculitis. Meningococci may be found within endothelial cells and neutrophils at sites of vascular inflammation. However, other gram-positive or gramnegative bacteria and fungi also may cause cutaneous small-vessel vasculitis. Staphylococcal sepsis can lead to neutrophilic vasculitis with purpura or nodular lesions that may contain microabscesses (Fig. 9-6). Acid-fast organisms also cause vasculitis. Lucio phenomenon (erythema necroticans) and erythema nodosum leprosum (ENL) are syndromes that may arise during the course of lepromatous leprosy. These entities are discussed in Chap. 19. In both cases, biopsies show vascular damage, including LCV. Histologically, Lucio phenomenon shows necrotizing small-vessel vasculitis, and Fite-Faraco staining reveals large

aggregates of acid-fast bacilli within the vascular walls and endothelium and throughout the dermis. Ischemia and necrosis of the epidermis, dermis, and adnexal structures often with ulceration are seen. Some researchers have suggested that the massive endothelial mycobacterial burden in Lucio phenomenon may lead directly to vascular damage.7 Rickettsial infections, such as Rocky Mountain spotted fever (RMSF), are characterized by invasion of endothelial cells by organisms causing vascular damage. Inflammation, however, often is minimal in RMSF. The Brown-Hopp stain and direct immunofluorescence microscopy may demonstrate the organism. Many viral organisms such as hepatitis C, herpesvirus, and parvovirus B198 may result in LCV on occasion. ANCA-ASSOCIATED VASCULITIDES Microscopic polyarteritis (MPA) nodosa, Wegener granulomatosis (WG), and Churg-Strauss syndrome (CSS) may be associated with LCV and are discussed at length under ANCA-associated vasculitides. HENOCH-SCHÖNLEIN PURPURA HenochSchönlein purpura (HSP) is characterized clinically by palpable purpura of the buttocks and lower extremities, abdominal

 FIGURE 9-6 Septic vasculitis. Small dermal vessel filled with coccal forms and surrounded by a neutrophilic infiltrate.

pain, and hematuria. Retiform or patterned purpura is considered characteristic of HSP. Occasionally, hemorrhagic bullae may be seen.9 Typically, but not exclusively, children are affected after a streptococcal upper respiratory tract or other infection. However, the clinical picture of HSP is often incomplete. A diagnostic skin biopsy can clarify such cases before significant renal injury occurs. In adults, HSP is less common and histologic confirmation is also important to exclude mimics including serious underlying illnesses such as malignancy.10 Acute infantile hemorrhagic edema (AHE) is an uncommon benign form of cutaneous vasculitis occurring in children less than 2 years of age and is considered by some to be a variant of HSP. AHE often presents with striking inflammatory edema and ecchymotic purpura with a targetoid or cockade appearance. Recently rotavirus infection has been implicated in one case.11 Theoretically, abnormalities in the production of IgA follow stimulation of the mucosal immune system. A selflimited syndrome results and usually resolves within 6 to 16 weeks after onset. Complications generally arise from renal involvement that may even necessitate kidney transplantation. Various genetic polymorphisms may lead to a predisposition to or protection from these complications.12 IgA myeloma also has resulted in HSP-like manifestations.13 Familial Mediterranean fever is also associated with HSP, and occult cases of this genetic disease may be uncovered in patients presenting with HSP.14 HSP cannot be distinguished histologically from other forms of LCV, although the vascular damage in HSP often is more subtle. The limited extent of vascular damage is similar to that observed in some cases of infectious vasculitis or urticarial vasculitis (see the following section). However, in HSP, immunofluorescence studies typically demonstrate deposition of IgA in capillaries. IgA-associated vasculitis may occur outside the symptom complex of HSP.15 However, serologic detection of IgA-fibronectin aggregates may be associated with greater likelihood of renal or systemic disease in patients with cutaneous LCV.16 URTICARIAL VASCULITIS Urticarial vasculitis is not a specific disease but is a pattern of often minimal vasculitis associated with increased vascular permeability. Persistent wheals (lasting more than 24 hours by convention) with faint purpura are a typical clinical finding. Often,

CRYOGLOBULINEMIAS AND OTHER SMALLVESSEL VASCULITIDES ASSOCIATED WITH PARAPROTEINS Small-vessel vasculitis may be associated with paraproteins, that is, abnormal serum proteins, including cryoglobulins, cryofibrinogens, macroglobulins, and gamma heavy chains.2,19 Type I cryoglobulinemia most commonly leads to an occlusive vasculopathy, as discussed later in this chapter, but also can be associated with LCV. Examples include the hyperglobulinemic purpura of Waldenström hyperglobulinemia and Schnitzler syndrome, which manifests as chronic urticaria with macroglobulinemia (usually monoclonal IgM) and other paraproteinemias. Types II and III or mixed cryoglobulinemia frequently are associated with connective tissue disorders or infection, in particular, hepatitis C (HCV) infection. Idiopathic cases are referred to as essential cryoglobulinemia. The cryoprecipitates in mixed cryoglobulinemias are typically a composite of polyclonal IgG and an IgM rheumatoid factor that may be monoclonal. Clonal expansion of the rheumatoid factor-synthesizing B lymphocytes is fundamental to the development of mixed cryoglobulinemia. In the case of cryoglobulinemia associated with HCV, HCV particles and nonenveloped nucleocapsid protein participate in the formation of immune complexes.20 The rheumatoid factor Bcell clonal expansion primarily takes place in the liver and correlates directly with

 FIGURE 9-7 Urticarial vasculitis.There is dermal edema and a sparse predominantly polymorphonuclear vascular reaction.

intrahepatic HCV viral load, indicating the critical role of HCV the pathogenesis of such B-cell clonality. In any case, mixed cryopercipitates commonly trigger a cutaneous LCV but occasionally form periodic

acid-Schiff (PAS)-positive intramural and intravascular deposits (Fig. 9-8). SERUM SICKNESS This self-limited syndrome is typified by a morbilliform

 FIGURE 9-8 Cryoglobulinemia. PAS-positive bright red cryoprecipitates (arrow) are seen in small superficial dermal vessels.

CHAPTER 9 ■ VASCULITIS AND RELATED DISORDERS

residual purpura are seen after resolution of the urticarial lesions.17 The clinical course generally is benign and episodic, lasting several months. However, urticarial vasculitis occurs with some frequency in lupus erythematosus and may be the initial clinical manifestation of the disease. The histology of urticarial vasculitis ranges from mild vascular damage with swollen endothelial cells and a sparse infiltrate composed of neutrophils, eosinophils, and lymphocytes to fully developed LCV (Fig. 9-7). The minimal essential criteria for UV include nuclear debris or fibrinoid alteration of microvessels, with or without extravasation of erythrocytes. Approximately one-third of patients with vasculitic urticaria have decreased complement levels (hypocomplementemic vasculitis). These patients may have systemic findings, such as arthralgias and adenopathy, and may be more likely to have underlying systemic lupus erythematosus.18 Low complement levels and positive anti-C1q antibodies may indicate greater likelihood of more severe systemic disease.

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Table 9-6 Drugs and Sera Associated with SerumSickness Reactionsa

Table 9-7 Common Examples of Drugs Associated with Vasculitisa

Cefaclor Minocycline Penicillins Propranolol Streptokinase Horse serum diphtheria antitoxin Horse serum antithymocyte globulins Human diploid cell rabies vaccine

Allopurinol Penicillin and aminopenicillins Sulphonamides Thiazide diuretics Pyrazolones Hydantoins Propylthiouracil a

Data from Wollenstein and Revuf, 1995.23

PART I ■ INFLAMMATORY REACTIONS IN THE SKIN

a

urticarial eruption, fever, arthralgias-myalgias, and lymphadenopathy occurring 7 to 10 days after a primary antigen exposure or 2 to 4 days after a repeat exposure. The offending antigen may be a drug, an arthropod sting, an antecedent infection, or therapeutic serum globulins.21 The LCV of serum sickness is not distinctive. Drugs and sera commonly associated with serum sickness are listed in Table 9-6. CONNECTIVE TISSUE DISEASE Rheumatoid arthritis, lupus erythematosus, dermatomyositis, and other diseases in the spectrum of connective tissue disease may develop LCV. Leukocytoclastic vasculitis may also occur in patients with antiphospholipid antibody syndrome.22 Clinical and serologic information is critical to arrive at the correct interpretation of the cutaneous findings in these clinical settings. AUTOIMMUNE DISEASES Primary Sjögren syndrome not associated with connective tissue disease may present with purpura in addition to ocular and glandular involvement.2 Skin biopsy commonly shows an LCV or lymphocytic vasculitis.

186

DRUG-INDUCED VASCULITIS A hypersensitivity reaction to a drug or immunotherapeutic agent may result in an LCV or even a pustular vasculitis.2,6,23,24 Penicillin, thiazides, and sulfonamides are the most common drugs to induce LCV (Table 9-7). Increased tissue eosinophil counts (5.2 vs 1.05 per 10 high-power fields) have recently been shown to correlate with drug-induced versus non-drug-induced LCV.25 Vasculitic hypersensitivity may also result from the ingestion of nondrug chemicals, such as food additives, or allergenic foodstuffs.

Data from Wollenstein and Revuf, 1995.23

PARANEOPLASTIC VASCULITIS A wide spectrum of vasculitic processes has been associated with neoplastic disorders.26 The most common associations include polyarteritis nodosa with hairy cell leukemia and cutaneous smallvessel vasculitis with lympho or myelo proliferative disorders. Solid tumors are less commonly implicated. Occasional cases of Wegener granulomatosis, microscopic polyarteritis nodosum, and HenochSchönlein purpura have been reported.27,28 VASCULITIS INDUCED BY PHYSICAL FACTORS Leukocytoclastic vasculitis and urticarial vasculitis are not uncommon, occur in long-distance runners, and/or in females after long walks, especially in hot weather. The skin compressed by socks may be spared. No clear relation with chronic venous disease or underlying medical conditions has been established.29,30 Occasional reports of solar induced urticaria with leukocytoclastic vasculitis have been reported.31

Behçet Disease CLINICAL FEATURES Behçet disease is a multisystem disease characterized by oral aphthous lesions and at least two of the following criteria: genital aphthae, synovitis, posterior uveitis, superficial thrombophlebitis (STP), cutaneous pustular vasculitis, and meningoencephalitis (Table 9-8). Exacerbations and remissions are unpredictable. The skin pathergy reaction, a nonspecific hyperreactive lesion in response to a needle-prick, has been used in the diagnosis of Behçet disease. This reaction is similar to the erythematous papules or pustules that appear spontaneously in these patients. Behçet disease is most common from the Middle East through Asia, but is rare in northern Europe and the United States. An association with HLA-B51 has been reported. The clinical presentation is

Table 9-8 Behçet Syndrome

Clinical Features Oral and genital aphthae Synovitis Posterior uveitis Meningoencephalitis Vascular lesions: cutaneous pustular vasculitis, aneurysms, arterial or venous occlusions, varices Middle East and Japan, rare in Northern Europe and the United States HLA-B51 associated Histopathologic Features Early: neutrophilic, fully developed necrotizing leukocytoclastic vasculitis or pustular vasculitis Late: lymphocytic and granulomatous vascular reactions Differential Diagnosis Infection and infectious vasculitis Vasculitis in connective tissue disease Paraneoplastic vasculitis Neutrophilic vascular reactions Sweet syndrome Pyoderma gangrenosum Inflammatory bowel disease Other pustular vasculitides Bowel bypass–associated process

extremely variable and so is the vascular involvement. Vascular lesions include not only active inflammatory lesions but also aneurysms, arterial or venous occlusions, and varices.32 The etiology of Behçet disease remains unknown. Enhanced inflammatory response to minor stimuli and the possibility of a genetic susceptibility suggest that Behçet disease may be an autoinflammatory disorder, similar to familial Mediterranean fever.33 HISTOPATHOLOGIC FEATURES The histopathologic spectrum of mucocutaneous inflammatory vascular lesions, depending on the stage and activity of the lesion, includes neutrophilic, lymphocytic, and granulomatous vascular reactions. Biopsy specimens of early lesions typically show a neutrophilic vascular reaction, and Behçet disease is sometimes classified as a neutrophilic dermatosis/neutrophilic vascular reaction. However, unlike in the neutrophilic dermatoses, fully developed necrotizing leukocytoclastic vasculitis, pustular vasculitis, or lymphocytic vasculitis may develop (see Figs. 9-4, 9-5, 9-12).

LOCALIZED FIBROSING SMALL-VESSEL VASCULITIS Erythema elevatum diutinum (EED) and granuloma faciale (GF) and some examples of cutaneous inflammatory pseudotumor are very similar chronic fibrosing conditions that show evidence of vascular damage. Sometimes, these entities are classified with the neutrophilic dermatoses. All are hypothesized to be reactions to localized persistent immune-complex deposition or hypersensitivities to a persistent antigen. EED- and GF-like reactions may be seen occasionally in clinical settings atypical for either entity.34

EED probably is not a distinct disease entity but rather a clinicopathologic reaction pattern most often developing in association with either a monoclonal or polyclonal gammopathy and in particular IgA hyperglobulinemia. Inflammatory bowel disease, rheumatoid arthritis, and systemic lupus erythematosus also may be associated with EED. HIV-infected patients also develop EED, which can mimic Kaposi sarcoma clinically.36 HISTOPATHOLOGIC FEATURES In the early stage of EED, LCV is observed. In later stages, granulation tissue and fibrosis

develop with a diffuse mixed-cell infiltrate showing a predominance of neutrophils (Fig. 9-9). The capillaries may still show deposits of fibrinoid material or merely fibrous thickening. Vertically oriented vessels, as noted in scars, suggest EED. In the late fibrotic stage, lipid material also may be present as cholesterol clefts. Serial sections may be required to demonstrate vascular damage in late lesions. DIFFERENTIAL DIAGNOSIS Early lesions of EED show nonspecific LCV. Fully developed lesions of EED may be indistinguishable from Sweet syndrome,

CHAPTER 9 ■ VASCULITIS AND RELATED DISORDERS

Erythema Elevatum Diutinum CLINICAL FEATURES This rare condition is characterized by persistent, initially redto-violaceous and later brown-to-yellow papules, nodules, and plaques.35 The lesions, typically distributed symmetrically on the extensor surfaces of the extremities, initially are soft and then evolve into fibrous nodules (Table 9-9).

Table 9-9 Erythema Elevatum Diutinum

Clinical Features Red to violaceous, soft papules Nodules and plaques evolving into brown to yellow fibrous nodules primarily on the extensor surfaces of the extremities Histopathologic Features Early: LCV Mature: Granulation tissue Fibrosis with vertical vessels A diffuse mixed-cell infiltrate with neutrophils Capillaries with fibrinoid necrosis or fibrous thickening Late: Fibrosis Lipid material may also be present as cholesterol clefts Active vasculitis may still be observed Differential Diagnosis Early: Sweet syndrome Other causes of LCV Rheumatoid neutrophilic dermatitis Bowel bypass–associated dermatosis Neutrophilic drug reaction Behçet syndrome Mature: Granuloma faciale Late: Kaposi sarcoma Dermatofibroma Granuloma annulare

A

B  FIGURE 9-9 Erythema elevatum diutinum. (A) A mixed infiltrate is noted in the dermis with a Grenz zone (arrow). (B) Higher magnification shows neutrophilic infiltrates and fibroplasia.

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PART I ■ INFLAMMATORY REACTIONS IN THE SKIN

rhe-umatoid neutrophilic dermatitis, bowel bypass-associated dermatosis, neutrophilic drug reaction, and Behçet syndrome. GF also may resemble EED but is distinguished by clinical localization to the face, sparing of the superficial papillary dermis (a grenz zone), and prominence of eosinophils and plasma cells in addition to neutrophils. Occasional cases show neutrophilic microabscesses in the tips of dermal papillae that might suggest dermatitis herpetiformis.37 Older lesions of EED must be differentiated from Kaposi sarcoma, dermatofibroma, or granuloma annulare. In old, fibrotic lesions of EED there is an orderly array of spindle cells and collagen bundles often parallel to the skin surface with vertically arranged capillaries similar to a scar. Many of the spindle cells have the immunohistochemical and electron microscopic features of macrophages. Neutrophils, nuclear dust, and fibrin owing to persistent vascular damage may be present, helping to distinguish these lesions from dermatofibromas or scars. The irregularly arranged, jagged vascular spaces of Kaposi sarcoma are absent. Focal areas of basophilic collagen caused by nuclear dust in EED can resemble the mucin seen in granuloma annulare but do not stain with alcian blue.

Granuloma Faciale CLINICAL FEATURES Clinically, GF presents as one or several asymptomatic, soft, brown-red, slowly enlarging papules or plaques, almost always on the face of older individuals (Table 9-10).

A

188

Table 9-10 Granuloma Faciale

Clinical Features Asymptomatic, soft, brown-red, slowly enlarging papules or plaques usually on the face Histopathologic Features Dense polymorphous dermal infiltrate primarily of neutrophils but also eosinophils, plasma cells Grenz-zone beneath epidermis and around pilosebaceous appendages Intact pilosebaceous structures Subtle evidence of vascular damage Nuclear dust Fibrinoid material within and around vessels Foam cells and fibrosis in older lesions Differential Diagnosis Infections Erythema elevatum diutinum Acne vulgaris or rosacea Acute folliculitis Other neutrophilic dermatoses Sweet syndrome

Rare upper respiratory tract forms have been described.38 HISTOPATHOLOGIC FEATURES A dense polymorphous infiltrate is present (see Table 9-10) mainly in the upper half of the dermis, but it may extend into the lower dermis and occasionally even into the subcutaneous tissue. Quite characteristically, the infiltrate does not

invade the epidermis or the pilosebaceous appendages but is separated from them by a narrow grenz zone of normal collagen (Fig. 9-10A). The pilosebaceous structures tend to remain intact. The polymorphous infiltrate consists primarily of neutrophils and eosinophils, but mononuclear cells, plasma cells, and mast cells also are present. Vascular damage in GF is seen but often is limited, and thus perhaps GF is best termed a neutrophilic vascular reaction39 (see Fig. 9-10B). However, vascular damage may be important to the pathogenesis of this lesion because direct immunofluorescence data suggest an immune complex–mediated event with deposition of mainly IgG in and around vessels. Frequently, the nuclei of some of the neutrophils are fragmented, especially in the vicinity of the capillaries, thus forming nuclear dust. Often there is some evidence of vasculitis with deposition of fibrinoid material within and around vessel walls. Occasionally, some hemorrhage is noted. Foam cells and fibrosis are observed frequently in older lesions. DIFFERENTIAL DIAGNOSIS GF can appear similar to EED, although a grenz zone and prevalence of eosinophils and plasma cells favor GF. Other neutrophilic dermatoses can be distinguished from GF by the lack of a grenz zone and clinical features. Frank leukocytoclastic vasculitis should not be seen in GF. In acneiform lesions and folliculitides, pilosebaceous units are invaded by inflammatory cells and may be destroyed or disrupted.

B

 FIGURE 9-10 Granuloma faciale. (A) There is a small grenz zone between the epidermis and the dermal mixed inflammatory cell infiltrate. (B) The infiltrate is composed of neutrophils, eosinophils, lymphocytes, and histiocytes.

NEUTROPHILIC VASCULAR REACTIONS

Acute Febrile Neutrophilic Dermatosis (Classic Sweet Syndrome) CLINICAL FEATURES In 1964, Sweet described a disease process that he termed acute febrile neutrophilic dermatosis that was characterized by acute onset of fever, leukocytosis, and erythematous plaques infiltrated by neutrophils.42-43 This condition classically occurs in middle-aged women after a nonspecific infection of the respiratory or gastrointestinal

 FIGURE 9-11 Bowel-associated dermatosis arthritis syndrome. In addition to a dense superficial dermal infiltrate composed of neutrophils and mild vascular damage, there is an intraepidermal pustule.

Table 9-11 Differential Diagnosis of Neutrophilic Dermatoses Neutrophilic dermatoses Granuloma faciale Sweet syndrome Inherited autoinflammatory syndromes Bowel-associated neutrophilic dermatosis Pyoderma gangrenosum Infection Neutrophilic vesicular dermatoses Linear IgA disease Dermatitis herpetiformis Leukocytoclastic vasculitis Leukemia cutis Neutrophilic drug reaction

tract (Table 9-12). Abrupt onset of painful or tender erythematous plaques, nodules, vesicles, and pustules on the face, extremities, and rarely, the trunk is characteristic. Occasional cases are limited to the hands.44,45 Involvement of noncutaneous sites, such as the eyes, joints, and oral mucosa, as well as visceral sites (eg, lung, liver, brain, and kidney), has been reported. A number of disorders have been associated with neutrophilic dermatoses similar to those seen in Sweet syndrome, as listed in Table 9-12. About 20% of cases are associated with malignancy. The etiology of Sweet syndrome is unknown. Current hypotheses include altered T-cell activation and altered function of neutrophils. The neutrophils within the lesions may be clonal whether or not associated with myelodysplasia. The vascular alterations seen in Sweet syndrome may be secondary to the massive extravasation of activated neutrophils. Direct immunofluorescence studies generally are negative in Sweet syndrome.46 HISTOPATHOLOGIC FEATURES A dense, bandlike, and perivascular infiltrate composed largely of neutrophils occupies the superficial dermis (Fig 9-12B). Some of the neutrophils may show leukocytoclasis. Lymphocytes, histiocytes, and occasionally eosinophils may be included in the infiltrate. The density of the infiltrate varies and may be limited in a small proportion of patients. Although extensive vascular damage is not a feature of Sweet syndrome, common vascular alterations include vasodilation, swelling of endothelium, erythrocyte extravasation, and occasional karyorrhectic debris. Frank fibrinoid

CHAPTER 9 ■ VASCULITIS AND RELATED DISORDERS

In many clinical conditions there are reactions characterized by a neutrophilic infiltrate with variable leukocytoclasis and some vascular damage1 (Fig. 9-11). However, the extent of vascular damage is insufficient for necrotizing vasculitis; that is, fibrinoid necrosis is lacking. This histologic pattern needs to be distinguished from necrotizing vasculitis. However, occasionally a neutrophilic vascular reaction may be a precursor to or associated with full-blown necrotizing vasculitis. Conditions with a neutrophilic vascular reaction that rarely develop necrotizing vasculitis generally are categorized as neutrophilic dermatoses. The term neutrophilic dermatosis includes a number of conditions characterized (1) histologically by a neutrophilic infiltrate, which may be clonal even if unassociated with myelodysplasia,40 (2) by the lack of microorganisms on special stains and cultures, and (3) by clinical improvement on systemic steroid treatment. The lesions are most commonly associated with hematologic, gastrointestinal, or rheumatologic diseases. A relationship

between these entities is suggested by their occasional co-occurrence in patients with predisposing conditions. The differential diagnosis of these lesions is outlined in Table 9-11. The stimulus for the aggregation of neutrophils is unclear. However, as more is understood about the inherited disorders associated with neutrophilic aggregates, termed autoinflammatory disorders, revelations regarding the etiology of acquired neutrophilic dermatoses may be around the corner. Vascular damage has been observed in these conditions, but is likely secondary to the dense neutrophilic infiltrate.41

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Table 9-12 Sweet Syndrome

Clinical Features Women greater than men Adults, but patients of any size Fever Leukocytosis Elevated erythrocyte sedimentation rate Erythematous plaques Vesicles and pustules of the face or extremities, rarely trunk Response to systemic steroids or potassium iodide Involvement of noncutaneous sites: eye, joints, oral mucosa, visceral sites Associations: Gastrointestinal or upper respiratory tract infection (classic Sweet syndrome) Malignancy, especially myeloproliferative disorders Sjögren syndrome Pustular psoriasis Rheumatoid arthritis Subacute lupus erythematous Subacute thyroiditis Pregnancy Histopathologic Features Superficial dermal neutrophilic infiltrate with some leukocytoclasis Vascular alterations, including vasodilation and swelling of endothelium Erythrocyte extravasation Prominent edema with subepidermal blister formation Differential Diagnosis Infection Vasculitis Other neutrophilic dermatoses Dermatitis herpetiformis or linear IgA disease Neutrophilic drug reaction Leukemia cutis Suppurative panniculitides Neutrophilic arthropod bite Secondary syphilis

necrosis may occur but is rare.46 Prominent edema of the upper dermis may result in subepidermal blister formation (Fig. 9-12A). As expected, the histologic appearance varies depending on the stage of the process. In later stages, lymphocytes and histiocytes may predominate.

190

DIFFERENTIAL DIAGNOSIS Infection (bacterial or fungal especially) must be excluded by special stains and tissue cultures. Vasculitis should be considered, but necrotizing vasculitis, that is, fibrinoid

A

B  FIGURE 9-12 Sweet Syndrome. (A) Prominent subepidermal edema is noted above a dense infiltrate. (B) The infiltrate is mostly neutrophilic.

necrosis, should not be observed in Sweet or Sweet-like lesions. The findings overlap with other neutrophilic dermatoses such as early or bullous pyoderma gangrenosum, bowel-associated dermatosisarthritis, periodic fever syndromes, and EED. Clinical features should distinguish these entities. A neutrophilic vesicular disease such as dermatitis herpetiformis or linear IgA disease may be suspected in cases of Sweet syndrome with vesicle formation. In addition, some cases of lupus erythematosus or polymorphous light eruption with an unusual neutrophilic component may resemble Sweet syndrome. Clinicopathologic and immunofluorescence studies should distinguish these entities. Secondary syphilis also may mimic Sweet syndrome. Other considerations include a neutrophilic drug reaction. Leukemia cutis must be excluded in the appropriate clinical setting.

Inherited Autoinflammatory Syndromes Synonyms: Hereditary periodic fever syndromes. The inherited autoinflammatory syndromes are characterized by bouts of inflammation, unprovoked by infection or autoimmunity. Many are characterized by mutations in genes involved in the system of innate immunity that provides rapid host defense against microbes and rapid response to cellular injury. The end result of many of these molecular lesions is deregulated production of proinflammatory cytokines.47 Cutaneous neutrophilic eruptions which resemble the neutrophilic dermatoses or frank vasculitis may occur. The familial fever syndromes, such as familial Mediterranean fever (FMF), hyperimmunoglobulinemia D and periodic fever syndrome (HIDS),

Bowel-Associated DermatosisArthritis Syndrome CLINICAL FEATURES Initially described in patients after jejunoileal bypass surgery, this syndrome has been expanded to include neutrophilic cutaneous lesions associated with many bowel diseases.1 Patients may have inflammatory bowel disease or a blind loop after peptic ulcer surgery (Table 9-14). The cutaneous

Table 9-14 Bowel-Associated Dermatosis-Arthritis Syndrome

Clinical Features Status post-jejunoileal bypass Inflammatory bowel disease Blind loop syndrome Associated fever, myalgias, and arthralgias Episodic, recurrent crops of cutaneous lesions on upper body, especially arms Initial small macules developing into papules, then pustules on a purpuric base Histopathologic Features Neutrophilic dermal infiltrate with minimal or no vascular injury Occasional frank necrotizing small vessel vasculitis Papillary dermal edema with subepidermal pustule formation Differential Diagnosis As for Sweet-like neutrophilic dermatoses

lesions are characterized by initial small macules that develop through a papular phase into pustules on a purpuric base. This evolution usually occurs within a 2-day period. The lesions commonly reach a size of 0.5 to 1.5 cm. They are typically distributed on the upper part of the body, especially the arms, rather than the dependent sites of the legs and often occur in episodic, recurrent crops. Fever, myalgias, and arthralgias may accompany the disease process. An immune complex–mediated reaction triggered by intestinal bacteria-derived antigens may lead to the initiating vascular insult. HISTOPATHOLOGIC FEATURES The histopathologic changes are usually those of a neutrophilic vascular reaction with minimal or no vascular damage, as seen in Sweet syndrome and the other neutrophilic dermatoses (see Fig. 9-11, 9-12). However, frank, necrotizing, small-vessel vasculitis may be noted occasionally. In fully developed lesions, the neutrophilic infiltrate and papillary dermal edema may be florid, and subepidermal pustules form. If vascular damage is observed in such a context, the term pustular vasculitis is applied.

Pyoderma Gangrenosum Pyoderma gangrenosum (PG) is included in this chapter because in these and other authors’ opinions it falls within the spectrum of neutrophilic dermatoses.1 As with other neutrophilic dermatoses, an infection must be excluded to arrive at the correct diagnosis.

CLINICAL FEATURES Several clinical types have been described: ulcerative PG with an undermined border; pustular PG with discrete, painful pustules; painful bullae with progression to a superficial ulceration; and vegetative PG with a painless ulcer and a nonundermined exophytic border.50 Classically, lesions begin as tender papulopustules or folliculitis that eventually may ulcerate. Again, as with other neutrophilic dermatoses, pyoderma gangrenosum, especially the vegetative form, may occur as an isolated cutaneous phenomenon or may be a cutaneous manifestation associated with a number of systemic disease processes, such as inflammatory bowel disease, connective tissue disease, or a lymphoproliferative disorder (Table 9-13). Bullous PG, when associated with leukemia, is an indicator of poor prognosis.50

Table 9-13 Pyoderma Gangrenosum

Clinical Features Tender papulopustules or folliculitis Ulcerated lesions with bluish borders Vegetating lesions Associated diseases: Inflammatory bowel disease Malignancy (especially leukemia) Connective tissue disease Immunologic abnormalities Monoclonal gammopathy (hypogammaglobulinemia, hyperimmunoglobulin E, iatrogenic immunosuppression) Histopathologic Evaluation Possible lymphocytic infiltrates early Extensive neutrophilic infiltrates often involving follicular structures Neutrophilic vascular reaction with variable vascular damage Pustular vasculitis Ulceration Necrosis Occasional granulomatous inflammation Differential Diagnosis Deep fungal infection Mycobacterial lesions Traumatic deep ulceration (factitial diseases) Sweet and Sweet-like dermatosis Subcorneal pustular dermatosis Erythema elevatum diutinum Bowel-associated dermatosis Spider bite Pustular drug reactions Blastomycosis-like pyoderma (from vegetative PG)

CHAPTER 9 ■ VASCULITIS AND RELATED DISORDERS

and tumor necrosis factor receptor superfamily 1A-associated periodic syndrome (TRAPS), and the rare cryopyrin-associated familial cold autoinflammatory syndrome (CAFCA, subsuming Muckle-Wells syndrome, familial cold urticaria, and chronic infantile neurological cutaneous articular syndrome), are a subset of the inherited autoinflammatory syndromes.48 The skin lesions of FMF typically have an erysipelas-like appearance and occur on the shins or feet. Neutrophilic infiltration is seen histologically. Leukocytoclastic vasculitis, including polyarteritis nodosa and Henoch-Schönlein purpura, has been reported. Amyloid deposits are a major complication of the disease. In HIDS, erythematous macules and papules, and even petechiae and purpura, may occur. Aphthous ulcers can be seen in the oral mucosa. Neutrophilic infiltrates and leukocytoclastic vasculitis have been reported. TRAPS was first described in a large Irish family and had been called familial Hibernian fever. Recurrent fevers associated with myalgia and painful erythema are common. During febrile attacks, painless erythematous macules and plaques may develop on the trunk and extremities and may migrate distally. Leukocytoclastic vasculitis of small vessels, nonspecific, perivascular, and interstitial mononuclear cell infiltrates and panniculitis have been reported. Amyloidosis is also a complication in some patients. CAFCA is associated with an urticarial rash and sometimes with amyloidosis.49 Other rare hereditary diseases with neutrophilic or granulomatous inflammation, such as pyogenic sterile arthritis, pyoderma gangrenosum and acne syndrome, Blau syndrome (early-onset sarcoidosis), and chronic recurrent multifocal osteomyelitis have also been grouped under the umbrella of autoinflammatory disease. Idiopathic diseases with a genetic predisposition and symptoms suggesting dysregulated innate inflammation such as Behçet disease, Crohn disease, sarcoidosis and psoriatic arthritis may be placed in this category, depending on future research.

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HISTOPATHOLOGIC FEATURES The histologic findings are nonspecific and depend on the type of lesion and timing of the biopsy. The diagnosis primarily is clinical. Most authors studying early lesions have reported a primarily neutrophilic infiltrate that frequently involves follicular structures. Other authors, however, have stated that the lesions begin with a lymphocytic reaction. Degrees of vessel involvement range from none to fibrinoid necrosis. In the majority of biopsied lesions, a neutrophilic vascular reaction is present with limited vascular damage. The infiltrate tends to be deeper and more extensive than in classic Sweet syndrome. The pattern of pustular vasculitis may be present. Fully developed lesions show ulceration, necrosis, and a mixed inflammatory cell infiltrate. Involvement of the deep reticular dermis and subcutis may exhibit primarily mononuclear cell and granulomatous inflammatory reactions.

LYMPHOCYTIC VASCULITIDES AND VASCULAR REACTIONS A histologic diagnosis of a lymphocytic vasculitis may be made if there is sufficient evidence of vascular damage and the inflammatory infiltrate is predominantly lymphocytic (Fig. 9-13). Often the vascular damage is subtle, and in many cases there may be disagreement among

dermatopathologists on whether the term vasculitis is warranted or not.51 Clear-cut evidence of vasculitis again is indisputable if an inflammatory infiltrate is present together with fibrinoid necrosis of the vascular wall. A diagnosis of lymphocytic vasculitis may still be rendered in the absence of fibrinoid necrosis if the constellation of findings suggests clear-cut vascular damage. Features indicative of vascular damage include lamination of the adventitia of venules by concentrically arranged pericytes and basement membrane material, lymphocytic nuclear fragmentation, and subendothelial or intramural infiltration of arterioles by lymphocytes. Lymphocytic vasculitis, if rigidly defined as here, is rare. However, in the majority of conditions to manifest lymphocytic vasculitis, “true vasculitis” is the exception rather than the rule. In instances one might use the term lymphocytic vascular reaction to indicate that a lymphocytic infiltrate is accompanied by some, albeit limited, vascular injury. The disease processes in which lymphocytic vasculitis is seen commonly include a variety of hypersensitivities and reactive processes, autoimmune and connective tissue diseases, infections, and idiopathic conditions as listed in Table 9-15. The histologic picture of lymphocytic vasculitis or lymphocytic vascular reaction

Table 9-15 Differential Diagnosis of Lymphocytic Vasculitis and Lymphocytic Vascular Reactions Pernio (chilblains) Arthropod bites Drug-induced or other hypersensitivity reactions Infection-associated reactions (eg, viral) Connective tissue diseases Behçet disease Pigmented purpuric dermatitides Pityriasis lichenoides (acute and chronic) Lymphomatoid papulosis Cutaneous lymphoma Autoimmune diseases Polymorphous light eruption Atrophie blanche Malignant atrophic papulosis (Degos disease) Infestations (eg, scabies)

also may occur in other situations. Leukocytoclastic vasculitides (eg, drug reactions), neutrophilic vascular reactions (eg, pyoderma gangrenosum), or usually noninflammatory vasculopathies (eg, atrophie blanche) may show a lymphocytic vasculitis-like picture at some stages. Clinical information and other histologic features are needed to determine the significance of lymphocytic vasculitis. Most of these entities are discussed at greater length elsewhere in this text.

Perniosis Pernio (chilblains) is perhaps the most commonly biopsied condition in which lymphocytic vasculitis is observed. Most patients are young or middle-aged women. The acral surfaces and less commonly the thighs and buttocks are involved. Erythematous to purpuric lesions develop in response to cold damp air or cold water.52 Histologically, a biopsy typically shows a superficial and possibly deep dermal perivascular and perieccrine lymphocytic infiltrate accompanied by variable degrees of vascular damage, most commonly in the form of fibrin in the walls of venules. There may be associated papillary dermal edema or interface dermatitis (Fig. 9-14).

192

 FIGURE 9-13 Lymphocytic vasculitis. A dermal vessel infiltrated by lymphocytes with red cell extravasation.

DIFFERENTIAL DIAGNOSIS Acral erythematous and violaceous papular and nodular lesions can be associated with a number of systemic disease states, most importantly systemic lupus erythematosus but also chronic viral infection and clotting abnormalities.53 Significant histologic

B

 FIGURE 9-14 Pernio. (A) A superficial and deep, mostly perivascular lymphocytic infiltrate is present with (B) superficial edema.

overlap can occur, and clinical information, direct immunofluorescence, and serologic studies may be needed to differentiate these entities.

Pigmented Purpuric Dermatitis Synonyms: Purpura pigmentosa chronica, pigmented purpura, capillaritis, pigmented purpuric dermatitis, chronic purpuric dermatitis, or purpura pigmentosa chronica. Four clinical presentations of these entities have been described and named: purpura annularis telangiectoides of Majocchi (Majocchi disease), progressive pigmentary dermatosis of Schamberg (Schamberg disease), pigmented purpuric dermatitis of Gougerot and Blum, and eczematid-like purpura of Doucas and Kapetanakis (Table 9-16).54 However, they are closely related and often cannot be reliably distinguished on clinical and histologic grounds.55 Precise subclassification may not be necessary in dermatopathologic practice, but some knowledge of the spectrum of their various appearances is helpful. Lichen aureus is a closely related entity because the clinical lesion has a purpuric component and the histologic findings are similar to the other four variants of pigmented purpuric dermatitis (PPD).56 The etiology of PPD is essentially unknown, and there are probably a number of different factors involved. Some degree of venous insufficiency or stasis is present in most or many patients with PPD. In some instances PPD also may be related to drug or contact hypersensitivity. Eruptions with the clinical and histologic appearance of a PPD also have been associated

with subsequent development of a T-cell lymphoproliferative disorder. Thus it is possible that some PPD may be the initial manifestation of T-cell lymphoproliferative disease.55 CLINICAL FEATURES Clinically, the primary lesion consists of discrete puncta and pigmentation. Telangiectatic puncta may appear as a result of capillary dilatation and pigmentation as a result of hemosiderin deposits. In some cases, telangiectasia predominates (Majocchi disease), and in others, pigmentation (Schamberg disease). In Majocchi disease, the lesions usually are irregular in shape and occur predominantly on the lower legs. In some cases the findings may mimic those of stasis. Frequently, clinical signs of inflammation are present, such as erythema, papules, and scaling (Gougerot-Blum disease) or papules, scaling, and lichenification (eczematid-like purpura). The disorder often is limited to the lower extremities, but it may be extensive. Mild pruritus may be present, but usually there are no systemic symptoms. Lichen aureus, a localized, persistent variant of PPD, most commonly involves the lower extremities but may occur anywhere.57 One or a few patches are composed of closely set, flat papules of rust, copper, or orange color. In some cases petechiae are present within the patches. Lichen aureus shows a male predilection, and its peak incidence is in the fourth decade. HISTOPATHOLOGIC FEATURES The principal histologic finding is a lymphocytic perivascular infiltrate limited to the papillary dermis (Fig. 9-15). The pattern of

the infiltrate often is not strictly confined to the perivascular area and may infiltrate the adjacent papillary dermis between vessels. In some instances the infiltrate may assume a bandlike or lichenoid pattern (Fig. 9-16), particularly in the lichenoid variant of Gougerot-Blum, and may involve the reticular dermis in a perivascular distribution. Epidermal alterations are variable and include parakeratosis, slight acanthosis, spongiosis, exocytosis, and basal layer vacuolopathy. Evidence of vascular damage may be present, and the reaction pattern then may be termed lymphocytic vasculopathy or vasculitis. However, the extent of vascular injury usually is mild and often insufficient to justify the term vasculitis. Vascular damage commonly consists only of endothelial cell swelling and dermal hemorrhage. Extravasated red blood cells and often subtle hemosiderin deposits usually are found in the vicinity of the capillaries. However, less commonly one may observe deposition of fibrinoid material in vessel walls. This may be observed particularly in pigmented purpuric lichenoid dermatitis of Gougerot and Blum and eczematid-like purpura of Doucas and Kapetanakis. In older lesions the capillaries often show dilatation of their lumen and proliferation of their endothelium. Extravasated red blood cells may no longer be present, but one frequently finds hemosiderin deposition. An iron stain may aid in the diagnosis in these cases. The inflammatory infiltrate is less pronounced than in the early stage. Lichen aureus is characterized by a dense mononuclear cell infiltrate in the papillary dermis, typically distributed in

CHAPTER 9 ■ VASCULITIS AND RELATED DISORDERS

A

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Table 9-16 Pigmented Purpuric Dermatoses

Clinical Features Orange/brown pigmentation Interspersed pinpoint (cayenne pepper-like) purpura Histological Features Superficial dermal perivascular lymphocytic infiltrate Vascular damage (usually limited, eg, endothelial cell swelling, focal karyorrhectic debris) Extravasation of red blood cells Hemosiderin Occasional epidermal changes: Spongiosis Basal layer vasculopathy Clinicopathological Patterns Schamberg disease Clinical: Male predominance Ill-defined lesions, pinhead-sized reddish purpura Predilection for lower leg Histological: usually moderately dense perivascular lymphocytic infiltrate and hemorrhage Majocchi disease Clinical: Discrete annular lesions Associated telangiectasia Often symmetric involvement beginning on lower extremities Histological: telangiectasia may be prominent Lichenoid dermatitis of Gougerot and Blum Clinical: Male predominance Purpuric lesions with lichenoid papules, erythema Predilection for legs Histological: lichenoid, more densely cellular infiltrate Eczematid-like purpura of Doucas and Kapetanakis Clinical: papules, scale, lichenification Histological: spongiosis, parakeratosis more prominent Lichen aureus Clinical: Male predominance Younger individuals Discrete confluent macules and papules (golden yellow, dark brown, or bruise-like) Variable purpura Persistent clinical course Predilection for lower legs Usually unilateral * Histological: Band-like lymphocytic infiltrate Increase in vascularity Prominent hemosiderin-laden macrophages Usually no or minimal vascular damage Differential Diagnosis Stasis dermatitis Eczematous dermatitis Drug eruptions Cutaneous T-cell lymphoproliferative disorders

a bandlike fashion. Scattered within the infiltrate are hemosiderin-laden macrophages. The epidermal changes are variable, as in the other forms of PPD.

194

DIFFERENTIAL DIAGNOSIS PPD may resemble stasis dermatitis because inflammation,

dilatation of capillaries, extravasation of erythrocytes, and deposits of hemosiderin occur in both. However, stasis dermatitis usually extends much deeper into the dermis and exhibits more pronounced epidermal changes and fibrosis of the dermis than PPD. In addition,

intravascular sludging of erythrocytes and fibrin is indicative of stasis. PPD also may resemble an atypical T-cell process. Careful evaluation of the lesion for epidermotropism and lymphoid atypia and clinicopathologic correlation are needed to arrive at the correct diagnosis. Patients with suspicious or equivocal lesions require monitoring and possibly further evaluation to exclude a cutaneous T-cell lymphoproliferative disorder. However, evidence of T-cell clonality may even be demonstrated in some examples of PPD that otherwise lack sufficient criteria for T-cell lymphoma. The scarcity of Civatte bodies or basal layer vacuolopathy facilitates the differential diagnosis of lichen aureus from lichenoid dermatitides, such as lichen planus or lichen striatus.

Lymphomatoid Vasculitis and Vascular Reactions The terms lymphomatoid vasculitis and lymphomatoid vascular reaction may be used if there is a lymphocytic vasculitis or lymphocytic vascular reaction with significant cytologic atypia of the lymphoid cells. Although lymphoid nuclear irregularities of some degree may be present in many lymphocytic vascular reactions, probably as a reflection of an activated state of the lymphocytes, lymphoid atypia tends to be particularly well developed in lymphomatoid papulosis (LYP) and some viral processes (Table 9-17). The differential diagnosis includes vascular damage in the context of cutaneous or systemic lymphoma, such as angiocentric T-cell lymphoma.57 Marked lymphocytic hyperchromasia, nuclear atypia, and exaggerated nuclear fragmentation are clues to lymphomatous destruction of blood vessels.

Vasculitis with Granulomatosis In the life span of many inflammatory reactions involving blood vessels, histiocytes may predominate at a certain stage and form granulomas58 (Fig. 9-17). At that point, little or no vascular wall damage or associated fibrinoid degeneration of the vessel wall may be observed. In the latter situation, a granulomatous vasculitis is present. Granulomatous vasculitis is seen only rarely in a cutaneous biopsy. Some cases of leukocytoclastic vasculitis, such as that associated with rheumatoid papules can show necrobiotic change in the surrounding collagen or associated palisading granulomas, but granulomatous destruction of vessel walls is not seen.59 In several diseases (eg, Takayasu arteritis, Wegener granulomatosis, Churg-Strauss

Table 9-17 Differential Diagnosis of Lymphomatoid Vasculitis and Vascular Reaction

 FIGURE 9-15 Pigmented purpuric dermatitis. There is a papillary dermal lymphocytic perivascular infiltrate and extravasation of red blood cells.

syndrome), a granulomatous vasculitis can be found in large visceral vessels, whereas cutaneous biopsies show extravascular granulomas, leukocytoclastic vasculitis, or ulcerative lesions. Adequate clinical information is essential to an accurate assessment of the skin biopsy in such situations. The main disease processes that need to be considered in the differential diagnosis of a granulomatous vascular reaction are listed in Table 9-18.

NCA-ASSOCIATED SYSTEMIC VASCULITIDES

A

B  FIGURE 9-16 Pigmented purpuric dermatitis. (A) A lichenoid infiltrate of lymphocytes and hemorrhage are seen. (B) Iron stain shows positivity (blue) in the superficial dermis.

Antineutrophil cytoplasmic antibodies (ANCAs) are important serologic markers of certain vasculitides.58,60,61 ANCAs may be demonstrated by a combination of indirect immunofluorescence of normal peripheral blood neutrophils followed by enzyme-linked immunosorbent assay (ELISA) to detect specific autoantibodies. Indirect immunofluorescence assays reveal two staining patterns: cytoplasmic (c-ANCAs) and perinuclear (p-ANCAs). ELISAs show that the majority of cANCAs are autoantibodies to proteinase 3, and most p-ANCAs are specific for myeloperoxidase (MPO). These antibodies are especially helpful, in combination with clinical features, in the differential diagnosis of three primarily small-vessel vasculitides: Wegener granulomatosis, Churg-Strauss syndrome, and microscopic polyarteritis. WG is usually associated with c-ANCAs, MPA with either p- or c-ANCAs, and CSS with p-ANCAs (Table 9-19). However, these syndromes cannot be discriminated by ANCA subtype alone as exceptional cases and population differences are seen.62

CHAPTER 9 ■ VASCULITIS AND RELATED DISORDERS

T-cell lymphoproliferative disorders Peripheral T-cell lymphoma Angiocentric T-cell lymphoma Lymphomatoid papulosis Lymphomatoid granulomatosis Angioimmunoblastic lymphadenopathy Pigmented purpuric dermatitis-like eruptions Lymphomatoid drug eruptions Lymphomatoid contact dermatitis Connective tissue disease Viral processes Florid hypersensitivity reactions Arthropod bite Scabies infestation

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 FIGURE 9-17 Granulomatous vasculitis. There is a perivascular histiocytic/granulomatous infiltrate and focal vascular damage.

These three syndromes are termed pauci-immune vasculitides because vascular injury is not associated with immunoglobulin deposition in vessel walls, in contrast to the immune-complex-mediated

Table 9-18 Differential Diagnosis of Vasculitides Associated with Granulomatous Inflammation Temporal arteritis Infection Wegener granulomatosis Churg-Strauss syndrome Polyarteritis nodosa Cutaneous Crohn disease Drug reaction Connective tissue disease Granuloma annulare Necrobiosis lipoidica Paraneoplastic phenomena Angiocentric T-cell lymphoma (lymphomatoid granulomatosis) Erythema nodosum and erythema nodosumlike reactions

small-vessel injury seen in entities such as Henoch-Schönlein purpura. The pathogenesis of the vascular injury and the role of ANCAs in these disease processes are still unclear although there is evidence for a direct role.63,64 ANCAs may play a role in inducing vasculitis by activating circulating neutrophils and monocytes, causing them to adhere to vessels, degranulate, and release toxic metabolites, thereby causing vascular injury. Another possibility is that immune deposits are present at an early stage of vasculitis but are degraded rapidly, resulting in pauci-immune lesions.65 Both environmental insult and genetic predisposition have been implicated in the pathogenesis of WG. A recessive genetic defect completely unrelated to ANCAs has been shown to lead to a vasculitis/granulomatosis syndrome similar to WG. This inherited syndrome differs from WG, though, showing familial clustering and not responding to immunosuppression. Recurrent bacterial infection is also a feature. A mutation in the transporter associated with antigen processing (TAP) leads to a decreased cell surface

Table 9-19 ANCA-Positive Vasculitides

196

DISEASE PROCESS

ANTI-MYELOPEROXIDASE (PANCA)

ANTI-SERINE PROTEINASE (CANCA)

Wegener granulomatosis Microscopic polyarteritis Churg-Strauss syndrome

Rare (5%) Common (50%-60%) Common (70%)

Common (80%) Common (45%) Rare (7%)

expression of HLA class I molecules and possibly increased self-reactivity.66 Novel immunologic defects may await detection in patients with systemic vasculitis. A number of cases of ANCA-associated vasculitis have been reported in patients with Grave disease receiving treatment, most commonly with propylthiouracil.67 CSS and WG most often are classified as granulomatous vasculitides in textbooks. However, the most common cutaneous histologic finding in both diseases is leukocytoclastic vasculitis. The granulomatous inflammation seen in the skin usually is not angiodestructive. Although MPA does not have a significant granulomatous component, it is discussed here because there is significant overlap, histologically and clinically, with WG and CSS patients who show an extensive vasculitic diathesis. In fact, significant overlap between these three syndromes as well as polyarteritis nodosum is well recognized. Over time, particular patients may shift from one disease category to another.

Churg-Strauss Syndrome Synonym: Allergic granulomatosis. The classic clinicopathologic syndrome of Churg-Strauss is characterized by asthma, fever, hypereosinophilia, eosinophilic tissue infiltrates, necrotizing vasculitis, and extravascular granuloma formation (Table 9-20). Short of an autopsy, the classic pathologic triad of necrotizing vasculitis, eosinophilic tissue

Table 9-20 Churg Strauss Syndrome

Clinical Features Men and women equally affected 20-40 years of age Asthma Allergic rhinitis Eosinophilia Petechiae, extensive ecchymoses Necrotic ulcers Cutaneous-subcutaneous nodules Histopathologic Features Leukocytoclastic vasculitis Tissue eosinophilia Churg-Strauss granulomata (extravascular granulomas with numerous eosinophils) Differential Diagnosis Infection Connective tissue disease Wegener granulomatous Microscopic polyarteritis nodosa

infiltration, and extravascular granulomas is extremely difficult to demonstrate because of the focality of the process.68 A broader definition of CSS requiring asthma, hypereosinophilia greater than 1.5 × 109/L, and systemic vasculitis involving two or more extrapulmonary organs has been suggested. Considerable overlap with other systemic vasculitides and with other inflammatory disorders associated with eosinophils, such as eosinophilic pneumonitis, has brought the legitimacy of the CSS into question.

bundles with eosinophilic granules (flame figures).73,74 DIFFERENTIAL DIAGNOSIS CSS is a clinicopathologic entity whose diagnosis depends on the presence of respiratory disease, in particular a history of asthma, p-ANCA positivity, and particular histologic features such as extravascular granulomas described earlier, necrotizing vasculitis, and eosinophilia. The differential diagnosis includes all varieties of smallvessel LCV but in particular, PAN, MPA, and WG, and the conditions mentioned earlier that may show extravascular necrotizing granulomas. Although Churg and Strauss initially characterized allergic granulomatosis as a “strikingly uniform clinical picture,” there is less clarity today about its distinction from other vasculitic processes, particularly WG and PAN.75

Wegener Granulomatosis WG was first recognized as a distinct clinicopathologic disease process in 1936, when Wegener reported three patients with a “peculiar rhinogenic granulomatosis.”76 Godman and Churg summarized postmortem studies in 1954, from which the classic triad of this clinicopathologic complex evolved: (1) necrotizing and granulomatous inflammation of the upper and lower respiratory tracts, (2) glomerulonephritis, and (3) systemic vasculitis.77 Limited variants of the disease involving the respiratory tract only have been described. In the protracted superficial variant, ulcerated, necrotizing lesions remain localized to the mucosa and skin for many years,

 FIGURE 9-18 Palisading necrotizing granuloma. A blue-tinted area of fibrinoid dermal necrosis is surrounded by epithelioid histiocytes.

CHAPTER 9 ■ VASCULITIS AND RELATED DISORDERS

CLINICAL FEATURES Despite multiple reports, CSS appears to be rare. Between 1950 and 1995, only 120 cases were identified at the Mayo Clinic.69 The incidence of CSS is similar in males and females. It typically presents in the third and fourth decades of life. Patients tend to move through several phases of disease development from nonspecific signs and symptoms such as asthma and allergic rhinitis (prodromal phase), to a phase of hypereosinophilia with eosinophilic pneumonitis or gastroenteritis (second phase), and finally, to systemic vasculitis (third phase). The three disease phases are not always sequential and on occasion may occur simultaneously. The internal organs most commonly involved are the lungs, the gastrointestinal tract, and less commonly, the peripheral nerves and heart. In contrast to polyarteritis nodosa, renal failure is rare. A limited form of allergic granulomatosis is characterized by preexisting asthma and lesions confined to the conjunctiva, skin, and subcutaneous tissue. Two types of cutaneous lesions occur in about two-thirds of patients: (1) hemorrhagic lesions varying from petechiae to palpable purpura to extensive ecchymoses, sometimes accompanied by necrotic ulcers and often associated with areas of erythema (similar to HenochSchönlein purpura), and (2) cutaneoussubcutaneous nodules. The most common sites of skin lesions are the extremities, followed by the trunk. In some instances the petechiae and ecchymoses are generalized. Other skin manifestations include urticaria, erythematous macules, and livedo reticularis. Diagnostically helpful laboratory findings include an elevated peripheral eosinophil count. Patients with active CSS have anti-MPOs (p-ANCAs) in most cases (see Table 9-19). The levels of antiMPOs have been found to correlate with disease activity. Anti-MPOs are found less often in patients with limited forms of the disease. Anti-serine proteinase antibodies (c-ANCAs) are uncommon in patients with CSS (see Table 9-19).

HISTOPATHOLOGIC FEATURES The areas of cutaneous hemorrhage typically show small-vessel LCV often with numerous eosinophils. Granulomatous arteritis may also be occasionally observed.70 In some instances the dermis shows a distinctive granuloma typified by radially arranged histiocytes and multinucleated giant cells centered around degenerated collagen fibers (Fig. 9-18). The central portion of these so-called “red” palisading granuloma contains not only degenerated collagen fibers but also disintegrated cells, particularly eosinophils, in great numbers.71 These granulomas initially were thought to be characteristic and were referred to as Churg-Strauss granulomas. However, they are not always present and are not a prerequisite for the diagnosis. The “Churg-Strauss granuloma” can also can be observed in other disease processes, such as connective tissue disease (rheumatoid arthritis and lupus erythematosus), WG, PAN, lymphoproliferative disorders, subacute bacterial endocarditis, chronic active hepatitis, and inflammatory bowel disease (Crohn disease and ulcerative colitis).72 The extravascular granulomas may involve subcutaneous fat, where they may attain considerable size through expansion and confluence, thus giving rise to the clinically apparent cutaneoussubcutaneous nodules. These palisading granulomas are embedded in a diffuse inflammatory exudate rich in eosinophils. Erythematous plaques, sometimes annular or bullous lesions can show the histopathology of eosinophilic cellulitis or Wells syndrome with an intense dermal eosinophilic infiltrate encrusting collagen

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with pulmonary and renal involvement eventually developing in some of these patients. With the recognition of an association between ANCAs and WG, the concept of WG has been modified, and the need for demonstrating granulomatous inflammation as a prerequisite for the diagnosis of WG has been challenged. A less restrictive definition has been proposed; Wegener vasculitis.4 Subsumed under this less restrictive category are ANCA-positive patients with clinical presentations of WG, such as sinusitis, pulmonary infiltrates, and nephritis, and documented necrotizing vasculitis but without biopsyproven granulomatous inflammation. Wegener syndrome, a more generic term can include both classic WG and Wegener vasculitis. CLINICAL FEATURES Two-thirds of patients with WG are male, and the mean age of diagnosis is 35 to 54 years.78 The vast majority of patients are Caucasians. The clinical presentation is extremely variable, ranging from an insidious course with a prolonged period of nonspecific constitutional symptoms and upper respiratory tract findings to abrupt onset of severe pulmonary and renal disease (Table 9-21).

Table 9-21 Wegener Granulomatosis

Clinical Features Sinusitis Recurrent pneumonitis Glomerulonephritis Myalgia, arthralgia, fever Palpable purpura, nodules, and ulcers Histopathologic Features LCV Granulomatous inflammation with suppuration and necrosis Cutaneous extravascular necrotizing granuloma Erythema elevatum diutinum, granuloma annulare, or erythema nodosum Nonspecific acute or chronic inflammatory lesions and ulcerations Differential Diagnosis Vasculitic component MPA, CSS, other causes of LCV Metastatic Crohn disease Granulomatous component Granulomatous infections CSS Sarcoidosis Granulomatous rosacea Foreign body reactions Ruptured cysts

The most commonly involved anatomic sites include the upper respiratory tract, lower respiratory tract, and kidney. Other organ systems that are commonly affected include the joints and skin. Migratory polyarticular arthralgia of large and small joints is found in up to 85% of patients with WG. Cutaneous involvement is extremely variable in different series, ranging from less than 20% to over 50% of patients. The most common presentation is palpable purpura. Other cutaneous manifestations include macular erythematous eruptions, papulonecrotic lesions, subcutaneous nodules with and without ulceration, and pyoderma gangrenosum. Occasionally, cutaneous lesions are the first indication of WG. However, because of their nonspecific appearance, they are infrequently recognized as presentations of WG. HISTOPATHOLOGIC FEATURES The majority of skin biopsies in patients with WG are nonspecific, such as, perivascular lymphocytic infiltrates.79 However, in about 25% to 50% of patients the histopathologic findings are fairly characteristic. The most frequent reaction patterns that are distinctive include necrotizing/leukocytoclastic small-vessel vasculitis and granulomatous inflammation. The small-vessel vasculitis is characterized by neutrophilic infiltrates and is indistinguishable from LCV secondary to many other processes (Fig. 9-19). Eosinophils can be as numerous

in LCV lesions from patients with WG, as in those with CSS. The granulomatous reactions contain histiocytes, lymphocytes, and giant cells and show suppurative necrosis. Microgranulomas, minute foci of tissue necrosis surrounded by histiocytes, are characteristic and are similar to lesions described in open lung biopsies from WG patients. True granulomatous vasculitis (see Fig. 9-17), acneiform perifollicular granulomatous inflammation, EED, and erythema nodosum-like reaction patterns have been described.80 The palisading granulomas of WG resemble those of CSS, except that the center of the WG granuloma contains necrobiotic collagen and basophilic fibrillar necrotic debris admixed with neutrophils, the so-called “blue” pallisading granuloma (Fig. 9-18).81 Tissue eosinophilia and eosinophilic debris are observed less frequently in the granulomata of WG. These lesions, also referred to as cutaneous extravascular necrotizing granuloma, are not specific for WG and may be associated with systemic vasculitis, connective tissue disease, or lymphoproliferative disease.72 Cutaneous ulcerations in WG may show granulomatous inflammation and necrotizing vasculitis and also secondary nonspecific vascular damage. DIFFERENTIAL DIAGNOSIS The histologic differential diagnosis of WG includes numerous entities causing LCV and palisading granulomas. Infective processes

 FIGURE 9-19 Wegener granulomatosis. A subcutaneous small artery shows fibrinoid necrosis and a florid inflammatory cell infiltrate.

Microscopic Polyarteritis Nodosum Synonyms: Microscopic polyangiitis, ANCA-positive leukocytoclastic angiitis, MPA. Microscopic polyarteritis nodosa is a systemic small-vessel vasculitis that is typically associated with focal necrotizing glomerulonephritis with crescents and serum myeloperoxidase-antineutrophil cytoplasmic autoantibodies. Involvement of the small vessels of the kidneys, lungs, and skin gives MPA a particular clinical picture and separates MPA from “classic” polyarteritis nodosum, which is to a greater degree a disease of medium-sized vessels. CLINICAL FEATURES Most patients with MPA are male and over 50 years of age (Table 9-22). Prodromal symptoms include fever, myalgias, arthralgias, and sore throat. The most common clinical feature is renal disease, manifesting as microhematuria, proteinuria, or acute oliguric renal failure. Although cutaneous involvement is rare in classic PAN, at least 30% to 40% of patients with MPA have skin changes. These include erythematous macules (100% in one study), livedo reticularis, palpable purpura, splinter hemorrhages, and ulcerations. Tender erythematous nodules typical of classic PAN are exceedingly rare in MPA. Pulmonary involvement without granulomatous tissue reaction occurs in approximately one-third of patients. Other organ systems (eg, gastrointestinal tract, central nervous system, serosal and articular surfaces) also may be affected, but this is less common. Serious clinical

Table 9-22 Microscopic Polyarteritis Nodosa (MPA)

Clinical Features Males over 50 years of age Viral-like prodrome Renal disease: Microhematuria, proteinuria, or acute oliguric renal failure Cutaneous symptoms: Palpable purpura, splinter hemorrhages, and ulcerations Pulmonary involvement without granulomas Histopathologic Features LCV Differential Diagnosis Wegener granulomatosus Churg-Strauss syndrome PAN Other causes of LCV

complications usually arise from renal and pulmonary disease. HISTOPATHOLOGIC FEATURES A leukocytoclastic vasculitis primarily affecting arterioles, venules, and capillaries is observed (see Fig. 9-20). Necrotizing vasculitis of medium-sized arteries typical of classic PAN is present on occasion (see Fig. 9-21). Cutaneous granulomatous inflammation is only rarely seen in MPA.

DIFFERENTIAL DIAGNOSIS MPA and classic PAN may not be distinguishable in every case, practically speaking. Glomerulonephritis, typical skin signs, ANCA positivity, and lack of arteriographic findings (aneurysms and stenoses reflecting medium-sized vessel involvement) favor MPA over classic PAN.82 MPA also tends not to be associated with viral hepatitis in contradistinction to some cases of classic PAN. Biopsy findings are less useful in distinguishing between these two syndromes because the size of diseased vessels detected is highly dependent on biopsy site, size of specimens, and number of tissue samples. Thus lack of medium-sized vessel involvement by no means excludes classic PAN. Detection of small-vessel involvement also does not exclude classic PAN, which may show small-vessel disease. A number of cases of vasculitis show overlapping features, leading to introduction of the term overlapping syndrome of vasculitis to encompass vasculitis affecting both small- and medium-sized arteries.83 The differential diagnosis also includes Wegener vasculitis and other small-vessel vasculitides that are occasionally ANCA-positive, such as certain drug reactions. The granulomatous inflammation of WG should be lacking in MPA; however, these two entities share many features, and some are of the opinion that the distinction between MPA and WG is largely artificial.84

 FIGURE 9-20 Microscopic polyarteritis nodosum. Florid inflammation and fibrinoid necrosis of a microvessel in the dermis.

CHAPTER 9 ■ VASCULITIS AND RELATED DISORDERS

causing granulomatous inflammation and possibly vasculitis should be excluded; the list of such agents is large and includes mycobacteria, deep fungi, viruses, and syphilis, among others. Other conditions causing LCV and granulomatous reactions include CSS, metastatic Crohn disease, rheumatoid arthritis, and sarcoidosis. Granulomatous vascular reactions also may be a manifestation of Tcell lymphomas such as angiocentric T-cell lymphoma or panniculitic T-cell lymphoma. Tightly packed, nonnecrotizing granulomas characteristic of sarcoid are not typical of WG. The distinction between WG and these other diseases relies primarily on clinical findings. In contrast to WG, CSS is associated with asthma, lacks lesions in the upper respiratory tract, rarely shows severe renal involvement, and typically is accompanied by eosinophilia or eosinophilic infiltrates and p-ANCA positivity.

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A

B

 FIGURE 9-21 Polyarteritis nodosum. (A) Erythematous papules and nodules are associated with a subtle pattern of livedo reticularis on the foot. (B) Fibrinoid necrosis and inflammation of a medium-sized vessel in the deep dermis.

VASCULITIS OF MEDIUM AND LARGE-SIZED VESSELS This section on vasculitides concludes with a brief review of conditions that preferentially affect medium- and largesized vessels. WG and CSS can affect medium-sized arteries, but they have been discussed previously as ANCAassociated vasculitis. The remaining entities to be discussed include PAN and processes that characteristically affect visceral vessels or large veins with rather nonspecific cutaneous findings.

Polyarteritis Nodosa

200

Synonyms: Periarteritis nodosa, PAN, classic polyarteritis nodosa. The first report of PAN in 1885 describes a 27-year-old man with fever, abdominal pain, muscle weakness, peripheral neuropathy, and renal disease.85 The fatal illness was termed periarteritis nodosa, referring to nodular protuberances along the course of medium-sized muscular arteries. Ferrari in 1903 emphasized the characteristic presence of inflammatory cells within all levels of the affected vessels (panarteritis) and suggested the term polyarteritis instead of periarteritis.86 The term PAN now subsumes three entities: (1) classic systemic PAN, (2) cutaneous PAN, and (3) microscopic polyarteritis.87,88 Classic PAN is a multisystem disorder characterized by inflammatory vasculitis involving arterioles and small and medium-sized arteries. Cutaneous PAN according to some authors is the only variety of PAN consistently involving the deep dermis and

subcutaneous fat with diagnostic features of arteritis. Some authors maintain that if there is no evidence of systemic involvement by (skin-limited) PAN at the time of initial diagnosis, then the condition will remain confined to the skin despite a potentially prolonged clinical course with multiple recurrences. MPA was discussed earlier in the chapter. The pathogenesis of PAN is poorly understood. Direct immunofluorescence testing of skin lesions of PAN shows some immune deposits in dermal vessels. However, these deposits may reflect a secondary event after vascular injury from another cause. As discussed earlier, there is some clinical overlap with microscopic PAN, although ANCAs generally are absent in patients with only medium-sized vessel involvement and thus not involved in the pathogenesis of these cases of PAN. CLINICAL FEATURES PAN is more common in men than in women, usually occurring between the ages of 20 and 60 years. Clinical manifestations may be dramatic and protean. Fever, malaise, weight loss, weakness, myalgias, arthralgias, and anorexia are common symptoms reflecting the systemic nature of the disease. Other findings may reflect infarction of specific organs (Table 9-23). Renal involvement, present in about 75% of patients, is the most common cause of death. Hematuria, proteinuria, hypertension, and azotemia may result from both infarction owing to disease of renal arteries or focal, segmental necrotizing glomerular lesions suggesting involvement of small vessels. Acute abdominal crises, strokes, myocardial

infarction, and mononeuritis multiplex result from involvement of the relevant arteries. Arteriography of visceral arteries often shows multiple aneurysms that are highly suggestive of PAN. Symptoms such as asthma, Löffler syndrome, and rashes may be related to the hypereosinophilia sometimes seen in these patients. Cutaneous manifestations

Table 9-23 Polyarteritis Nodosa

Clinical Features Fever, malaise, weight loss, weakness myalgias, arthralgias, and anorexia Hematuria, proteinuria, hypertension, and azotemia Acute abdominal crises, strokes, myocardial infarction, and mononeuritis multiplex Subcutaneous nodules which may pulsate or ulcerate Ecchymoses and gangrene of fingers and toes Livedo reticularis, bullae, papules, scarlatiniform lesions, and urticaria Histopathologic Features Early: leukocytoclastic vasculitis of small to medium-sized arteries Late: intimal proliferation and thrombosis, chronic inflammatory infiltrate, fibrosis Differential Diagnosis Infection (bacterial, eg, pseudomonas; viral, eg, hepatitis B or HIV) Connective tissue disease (lupus erythematosus, rheumatoid arthritis) Vasculitides with granulomatosis Wegener granulomatosis Churg-Strauss syndrome

include subcutaneous nodules that may pulsate or ulcerate, ecchymoses, and gangrene of fingers and toes. Livedo reticularis, bullae, papules, scarlatiniform lesions, and urticaria occur in some patients (Fig. 9-21A). A limited form of PAN without visceral involvement may exist, but this concept is controversial.87 So-called cutaneous PAN actually may show skin, muscle, peripheral nerve, and joint involvement. The course of disease is benign but protracted and shows steroid dependence.89

DIFFERENTIAL DIAGNOSIS Vasculitides indistinguishable from idiopathic PAN may be observed in infection (bacterial, eg, Streptococcus and Pseudomonas; viral, eg, hepatitis B or HIV), connective tissue disease (lupus erythematosus, rheumatoid arthritis), WG, CSS, and other settings without explanation, for example, acute myelogenous leukemia. Some cases of erythema induratum with limited septolobular panniculitis can mimic PAN histologically.90 In general, any panniculitis accompanying PAN should be limited to the area directly adjacent to the affected vessel. Widespread inflammation of the fat suggests panniculitis is the primary disease category. As with all vasculitides, the disease process should be defined by ruling out

occur in other processes, including nonspecific thrombosis and inflammation of intermediate-sized arteries and veins. Peripheral vascular disease from arteriosclerosis must be excluded.

Buerger Disease Synonym: Thromboangiitis obliterans. CLINICAL AND HISTOPATHOLOGIC FEATURES This distinctive but rare condition is observed most frequently in men ranging in age from 20 to 40 years of age who are tobacco smokers (Table 9-24). A similar condition effecting canabis smokers has also been reported.91 Painful segmental, thrombosis and inflammation effects intermediate- and small-sized arteries and sometimes veins, primarily of the upper and lower extremities. The clinical findings are manifestations of ischemic injury and include claudication, cyanosis, painful ulcers, and gangrene. Cessation of smoking is the most important therapeutic intervention. However, the ischemic injury often is so extreme that amputation is needed to control the process. Active lesions show luminal thrombotic occlusion, a mixed inflammatory cell infiltrate of the vessel wall, and luminal microabscesses that are thought to be characteristic. A granulomatous reaction may be present as well. Later, the thrombus is organized and its lumen may be recanalized. DIFFERENTIAL DIAGNOSIS The histologic findings in Buerger disease have been thought to be unique; however, they are likely to be nonspecific and probably

Table 9-24 Buerger Disease, Thromboangiitis Obliterans

Clinical Features Men greater than women, 20-40 years of age Smokers Lower extremities more than upper extremities Painful ulcers, gangrene Histopathologic Features Mixed inflammatory cell infiltrates of intermediate and small vessel walls with micro-abscesses +/– a granulomatous reaction Luminal thrombi Differential Diagnosis Infection

Superficial Thrombophlebitides Synonyms: Mondor disease, nonsclerosing lymphangitis of the penis. CLINICAL FEATURES Superficial thrombophlebitis of small- to medium-sized veins may be seen at many anatomic sites but especially the lower extremities. The usual presentation is a tender, erythematous cordlike structure or nodule. Affected individuals often have predisposing factors such as varicose veins, a hypercoagulable state, ingestion of oral contraceptives, or an underlying malignancy. Superficial septic thrombophlebitis is usually secondary to peripheral venous infusion. Mondor disease is a thrombophlebitis of the subcutaneous veins of the chest region and often is manifested clinically by a cordlike induration.92 It usually is not accompanied by general symptoms and tends to resolve within weeks. In most cases the etiology remains unknown; however, local interference with venous flow may be a factor as associations include trauma and surgical procedures. A variety of other conditions including connective tissue disease and, rarely, breast carcinoma have also occurred with Mondor disease. Nonvenereal sclerosing lymphangitis of the penis arises acutely and has features similar to Mondor disease. Despite the name, the involved vessel is most likely a vein, and some refer to this condition as Mondor phlebitis of the penis.93 Clinically, a firm, tender, wormlike cord lying just behind the corona of the glans penis in the coronary sulcus appears suddenly. Resolution usually occurs in 4 to 6 weeks regardless of therapy. Proposed etiologic factors include trauma during coitus and infectious agents such as viruses or chlamydiae. HISTOPATHOLOGIC FEATURES In early lesions, small and medium-sized veins of the lower dermis demonstrate dense inflammatory infiltrates, primarily composed of neutrophils, within the vessel wall. The venous wall is significantly thickened by this influx of leukocytes and edema. In later stages, the infiltrate is composed of lymphocytes, histiocytes, and multinucleate giant cells. However, most biopsied lesions show subcutaneous veins with organizing thrombi and

CHAPTER 9 ■ VASCULITIS AND RELATED DISORDERS

HISTOPATHOLOGIC FEATURES Although affected skin often shows only a smallvessel necrotizing vasculitis, the characteristic lesion of classic PAN is a panarteritis involving medium-sized and small arteries in visceral sites (Fig. 9-21B). A panarteritis of the larger arteries in deeper dermis or panniculus is observed most commonly in patients presenting with cutaneous nodules. Lesions typically are in different stages of development. Early lesions show degeneration of the arterial wall with deposition of fibrinoid material. There is partial to complete destruction of the external and internal elastic laminae. An infiltrate present within and around the arterial wall is composed largely of neutrophils showing evidence of leukocytoclasis, although eosinophils often are admixed. At a later stage, intimal proliferation and thrombosis lead to complete occlusion of the lumen with subsequent ischemia and possibly ulceration. The subacute infiltrate often contains lymphocytes, histiocytes, and some plasma cells. The healing stage is distinguished by a fibroblastic proliferation extending into the perivascular area. The small vessels of the middle and upper dermis often show a nonspecific lymphocytic perivascular infiltrate.

infection, searching for underlying systemic diseases, and then documenting the extent of systemic involvement and associated findings.

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fibrous, thickened walls, giving them a cordlike appearance at scanning magnification. Recanalization of the affected veins ultimately occurs with resolution of the process. A Gram stain is indicated for the assessment of septic STP. DIFFERENTIAL DIAGNOSIS Polyarteritis nodosa is the principal entity to be distinguished. PAN affects medium-sized arteries rather than veins, is more inflammatory and less thrombogenic than STP, that is, thrombi are usually absent in PAN, and finally PAN shows conspicuous fibrinoid necrosis whereas STP usually does not. An elastic tissue stain to demonstrate the presence of an internal elastic lamina in an arterial vessel versus its usual absence (not always) in a vein may facilitate the differentiation of PAN and STP.

Kawasaki Syndrome

Clinical Features Young Asian women Upper extremity claudication Visual symptoms and Raynaud phenomenon Arterial bruits and diminished arterial pulses Cutaneous findings: Erythema nodosum–like nodules Ulcers with features of pyoderma gangrenosum and papular lesions Histopathologic Features Necrotizing vasculitis of both small and large vessels Granulomatous vasculitis Sarcoidal noncaseating tuberculoid granulomas Acute panniculitis “Cutaneous extravascular granulomas” Differential Diagnosis Infection similar to that described under Wegener granulomatosis

Synonym: Mucocutaneous lymph node syndrome. CLINICAL FEATURES Kawasaki syndrome is a necrotizing arteritis that usually affects young children, with a peak age incidence at 1 year.94 The disease is most common in Japan and shows seasonal variations, hinting at an interplay between an infectious precipitant and a genetically predisposed host. Mucocutaneous findings are common and include a polymorphous exanthematous macular rash, conjunctival congestion, dry reddened lips, “strawberry tongue,” oropharyngeal reddening, and swelling of the hands and feet, especially the palms and soles. There is typically an associated nonpurulent cervical lymphadenopathy. Desquamation of the skin of the fingers typically occurs after 1 to 2 weeks, often followed by thrombocytosis. The most serious clinical complications are related to arteritis and thrombosis of coronary arteries. HISTOPATHOLOGIC FEATURES Cutaneous vasculitis is rare. The macular rash usually is accompanied by nonspecific histologic changes, such as a perivascular infiltrate of lymphocytes and histiocytes. Characteristic arteritis typically is seen in visceral sites, such as the coronary arteries.

Takayasu Arteritis Synonym: Pulseless disease.

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Table 9-25 Takayasu Arteritis

CLINICAL FINDINGS Takayasu arteritis primarily affects the aorta and has its

main branches in young Asian women (Table 9-25). Chronic granulomatous vascular inflammation with fibrosis and thickening of the vessel walls is the predominant pathologic feature. The resulting vascular stenosis leads to symptoms such as upper extremity claudication, visual symptoms, and Raynaud phenomenon. Arterial bruits and diminished arterial pulses are found. Cutaneous findings include erythema nodosum-like nodules and ulcers with features of pyoderma gangrenosum. HISTOPATHOLOGIC FEATURES Nodular cutaneous lesions potentially related to Takayasu arteritis have shown necrotizing vasculitis of both small and large vessels, granulomatous vasculitis, septal and lobular panniculitis, and sarcoidal noncaseating tuberculoid granulomas.95 The cutaneous extravascular granuloma discussed earlier in the section on WG also may be seen. DIFFERENTIAL DIAGNOSIS None of the pathologic findings in the skin are specific for Takayasu arteritis. A number of vasculitic or granulomatous diseases are included in the differential diagnosis of the lesions described earlier. Infection must be excluded. Sarcoidosis occasionally may be complicated by large-vessel vasculitis mimicking Takayasu arteritis.96 Clinically, Cogan syndrome may show a Takayasu-like arteritis, but interstitial keratitis and Meniere-like episodes are also features. Angiography and the

appropriate clinical context should differentiate Takayasu arteritis from other entities.

Temporal Arteritis Synonyms: Giant cell arteritis, giant cell arteritis of the elderly, cranial arteritis, Horton disease. CLINICAL FEATURES Temporal arteritis affects primarily large- or medium-sized arteries in the temporal region of elderly people. Other arteries of the head and neck, particularly retinal arteries, may be involved, and patients with generalized arterial involvement have been described. The clinical presentation may include pain and tenderness of the forehead or scalp and possibly sudden visual impairment. There may be systemic symptoms, such as fever and malaise. Erythema and edema of the skin overlying the involved arteries may be noted, and occasionally, ulcerations of the scalp occur.97 The involved artery may be palpable. Clinical laboratory findings include a significantly elevated erythrocyte sedimentation rate (ESR) and sometimes a normochromic, microcytic, or normocytic anemia. Although the clinical presentation strongly suggests the diagnosis, a biopsy often is performed for confirmation prior to initiation of systemic steroid therapy. Long segments of the artery, preferably nodular or tender areas, should be biopsied because skip lesions are common. Although the etiology of temporal arteritis is unknown, in some cases actinic degeneration of the internal elastic lamina may provoke the granulomatous inflammation in a reaction similar to actinic granuloma. HISTOPATHOLOGIC FEATURES Involved arteries show partial destruction by an inflammatory infiltrate composed mainly of lymphocytes and macrophages (Fig. 9-22). In some instances neutrophils may be present, but this finding should not dissuade one from the diagnosis. The inflammatory infiltrate may extend throughout the entire arterial wall but is unevenly distributed, and step sections often are needed for identification. Some of the macrophages are multinucleated and intimately associated with the internal elastic lamina. Fragmentation of the elastic lamina and elastophagocytosis by the multinucleated giant cells even may be observed. An elastica-van Gieson stain greatly facilitates evaluation of elastic fibers. Some find the CD68 marker for histiocytes helpful in the evaluation of the inflammatory infiltrate. Depending

 FIGURE 9-22 Giant cell arteritis. A biopsy of the temporal artery shows a panmural predominantly mononuclear infiltrate with giant cells and fragmentation of elastic fibers (arrow).

on the stage of the disease process or corticosteroid treatment history, giant cells may not be present.98 In late stages, there only may be thickening of the intima by deposits of fibrin-like material and myofibroblastic proliferation with subsequent luminal narrowing or obliteration. DIFFERENTIAL DIAGNOSIS Not all cases of arteritis involving the temporal artery represent examples of temporal arteritis. Biopsy of the temporal artery may show necrotizing vasculitis, such as PAN, hypersensitivity angiitis, or vasculitis associated with infection or connective tissue disease. However, the biopsy findings may not always discriminate between TA and other systemic vasculitities.99 Serologic studies, the exclusion of infection, and the appropriate clinical findings along with the histopathologic requisite features lead to the correct diagnosis.

VASCULOPATHIC REACTIONS AND PSEUDOVASCULITIS A vasculopathic reaction as defined in Table 9-1 refers to vascular damage without inflammation. As already mentioned, the term pseudovasculitis has been used to describe a closely related group of conditions that mimic or exhibit some attributes of vasculitis. Vasculopathies or pseudovasculitis may

be associated with vascular occlusive phenomena, including thrombi or emboli, pathologic alterations of the vessel wall or structural deficiencies of the perivascular connective tissue, and miscellaneous other disease processes including drug-induced vasospasm and repetitive vascular injury.

Vascular Occlusive Conditions In these conditions, thrombi are present in blood vessels of dermis and subcutis. Extensive infarctions and necrosis may be associated and are more characteristic of some coagulopathies, cryoglobulinemias, early livedoid vasculitis (atrophie blanche), cholesterol emboli, and calciphylaxis. Livedo reticularis and late atrophie blanche present a more fibrotic chronic picture. Usually, the various conditions can be distinguished by other distinctive pathologic findings, such as calcification in calciphylaxis, needleshaped crystals in cholesterol emboli, or the wedge-shaped dermal alteration of Degos syndrome. Characteristic clinical findings or serologic tests (eg, cryoglobulinemia, cryofibrinogenemia, coagulopathy) further narrow the differential diagnosis. A differential diagnosis is provided in Table 9-26A and 9-26B.

Coagulopathies Any coagulopathy may be accompanied by vasculopathic changes, although the

CLINICAL FEATURES In mild forms, the clinical manifestations may be subtle and limited to petechiae. Severe forms of coagulopathy may show palpable purpura or large areas of ecchymoses, often on the extremities. Large hemorrhagic bullae may overlie the ecchymoses, and in some instances, necrosis may supervene. Retiform purpura (a livedoid pattern of cutaneous hemorrhage) in palpable plaques is characteristic of antiphospholipid antibody syndrome, heparin-induced skin necrosis, coumadin/ warfarin-induced skin necrosis, and calciphylaxis.101 HISTOPATHOLOGIC FEATURES The histologic findings are nonspecific. In mild forms of coagulopathy, dermal hemorrhage with extravasation of red blood cells into perivascular connective tissue may be the only histologic manifestation. With increasing severity of the coagulopathic process, intravascular fibrin thrombi may be found (see Fig. 9-2). In the severe coagulopathies (eg, thrombotic thrombocytopenic purpura, coumarin necrosis, or purpura fulminans), thrombotic vascular occlusion may lead to hemorrhagic infarcts, epidermal and dermal necroses, or subepidermal bullae formation. Systemic intravascular coagulation with widespread thrombosis of the small vessels of internal organs leading to hemorrhagic necrosis also may develop.

CHAPTER 9 ■ VASCULITIS AND RELATED DISORDERS

extent of vascular damage is variable. Vascular damage may occur in the setting of altered platelet counts, such as in idiopathic thrombocytopenic purpura, in coagulation factor deficiencies (eg, inherited or acquired protein C and S deficiencies), coagulopathies associated with connective tissue disease (eg, lupus anticoagulant, antiphospholipid antibody syndrome), and platelet thrombosis in heparin-induced skin necrosis. Extensive vascular damage with luminal occlusion by thrombotic material may develop in coumarin/warfarin-induced skin necrosis, thrombotic thrombocytopenic purpura, and disseminated intravascular coagulation, in particular in the setting of purpura fulminans.100

Cryoglobulinemia Cryoglobulins are serum immunoglobulins that precipitate when the serum is cooled and redissolve with rewarming. There are three major types of cryoglobulinemia (Tables 9-27A and 9-27B). In type I cryoglobulinemia, monoclonal IgG or IgM cryoglobulins are found. This type of cryoglobulinemia may be idiopathic but often is associated with lymphoma,

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Table 9-26A Vasculopathic Reactions and Pseudovasculitis MECHANISM

CONDITION

Coagulopathies

Idiopathic thrombocytopenic purpura Coagulation factor deficiencies (eg, protein C and S deficiencies) Antiphospholipid antibody syndrome Thrombotic thrombocytopenic purpura Coumadin/warfarin-induced skin necrosis Heparin-induced skin necrosis Calciphylaxis Purpura fulminans Disseminated intravascular coagulation Monoclonal gammopathy Sickle cell disease Livedo vasculopathy Calciphylaxis Primary hyperoxaluria Diabetes mellitus Amyloidosis Porphyria Radiation vasculopathy Cholesterol embolism Atrial myxoma Solar/senile purpura Scurvy Ergot derivatives Cocaine Methamphetamines Hypothenar hammer syndrome

Pathological alterations of the vessel wall

Embolic phenomena Structural deficiencies of the perivascular connective tissue Vasospasm

Repetitive vascular trauma

leukemia, Waldenström macroglobulinemia, or multiple myeloma. Types II and III cryoglobulinemia were discussed in detail earlier in the chapter. CLINICAL FEATURES Cutaneous lesions in patients with cryoglobulinemia may manifest as chronic palpable purpura, urticarialike lesions, livedo reticularis, Raynaud phenomenon, acrocyanosis, digital gangrene, and leg ulcers (see Table 9-27A). Systemic manifestations may include arthralgia, hepatosplenomegaly, lymphadenopathy, and glomerulonephritis.

Table 9-26B The Differential Diagnosis of Cutaneous Vascular Occlusive Conditions

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Coagulopathy Cryoglobulinemia Cholesterol embolism Livedo reticularis Atrophie blanche Degos syndrome Calciphylaxis Oxalosis Secondary vasculopathy

HISTOPATHOLOGIC FEATURES In type I cryoglobulinemia, amorphous material (precipitated cryoglobulins) is deposited subjacent to endothelium, throughout the vessel wall, and within the vessel lumen, resulting in a thrombus-like appearance. These precipitates stain pink with hematoxylin and eosin and bright red with PAS stain, as opposed to less intense staining of fibrinoid material (see Fig. 9-8). Cracking of the precipitate may be a prominent feature. Some capillaries are filled with red blood cells, and extensive extravasation of erythrocytes may be present. An inflammatory infiltrate usually is lacking, in contrast to the vascular injury seen in mixed cryoglobulinemias, which typically show a vasculitis, as previously discussed. PAS-positive intramural and intravascular cryoprecipitate also may be found in mixed cryoglobulinemia (see Fig. 9-8), but less frequently than in type I cryoglobulinemia.15

Cutaneous Cholesterol Embolism Synonym: Atheroembolism. Cholesterol crystal embolization is usually a disease of the elderly with significant atherosclerosis102 (Table 9-28).

Table 9-27A Type I Cryoglobulinemia

Clinical Features Cutaneous: Palpable purpura Urticaria-like lesions Livedo reticularis Acrocyanosis Digital gangrene Leg ulcers Raynaud phenomenon Systemic: Arthralgia Hepatosplenomegaly Lymphadenopathy Glomerulonephritis Histopathologic Evaluation Amorphous, PAS-positive thrombi Cracking of thrombi Extensive extravasation of erythrocytes Differential Diagnosis Coagulopathies

Atheromatous plaque material may detach spontaneously or, more commonly, may follow an invasive procedure, such as arterial catheterization. Microemboli, composed of cholesterol crystals and/or other components of atheromatous plaque, often result in ischemic changes, most commonly involving the lower extremities. The cutaneous manifestations include livedo reticularis; purple discoloration; gangrene of toes; small, painful ulcerations; and on occasion, nodules or indurated plaques. The latter findings often closely mimic vasculitis, cryoglobulinemia, and chilblains. A helpful feature is the presence of intact arterial pulses on examination of the affected extremity, indicating that the ischemia is secondary to smallvessel involvement rather than major arteries. HISTOPATHOLOGIC FEATURES Cholesterol emboli may be found as needle-shaped clefts within the lumina of small vessels (Fig. 9-23). The intravascular clefts that are in effect dissolved crystals may be single or multiple and commonly are associated with amorphous eosinophilic material, macrophages, or a foreign body-giant cell reaction. Vascular walls exhibit intimal fibrosis and often obliteration of lumina in older lesions. In many instances only fibrin thrombi are observed. Often a deep biopsy is needed to reveal such emboli, which are distributed focally and therefore difficult to find.

Table 9-27B Clinical-Pathologic Associations of Cryoglobulinemias IMMUNOGLOBULIN

ASSOCIATIONS

SITE

CLINICAL FINDINGS HISTOPATHOLOGY

CHARACTERISTIC

Type I

Monoclonal IgG or IgM

Head, neck, oral, or nasal mucosa

Hemorrhagic crusts, skin ulcerations

Noninflammatory hyaline thrombosis Cutaneous infarction

Type II

Monoclonal and polyclonal immune complexes

Lymphoma, leukemia, Waldenström macroglobulinemia, or multiple myeloma Connective tissue disorders idiopathic (essential) Infection Autoimmune diseases

Legs

Erythematous to purpuric macules or papules

Leukocytoclastic vasculitis

Data from Cohen et al.19

CLINICAL FEATURES Livedo reticularis is red-blue mottling of the skin in a netlike pattern. This nonspecific physical sign indicates sluggish blood flow, which may result from a number of causes (Table 9-29). Physiologic livedo (cutis marmorata), commonly seen in young women, is mottling of the skin that subsides with warming. An idiopathic form, that is persistent and does not respond to warming, is limited to the lower extremities, may be associated with subtle coagulation abnormalities, and autoimmune phenomena.103 Druginduced livedo has been seen with interferon-alpha therapy for melanoma and amantadine therapy for Parkinson disease.104

HISTOPATHOLOGIC FEATURES Histopathologic changes may only be detected in punch biopsies sampling the dermis-subcutis boundry. Multiple areas from different areas of the livedo may need to be sampled, especially the seemingly uninvolved white skin at the center. Initially, blood vessels may show attachment of lymphohistiocytic cells and detachment of endothelial cells (endothelitis). Later, partial or complete occlusion of the lumen by a plug of lymphohistiocytic cells and fibrin may be seen, which is replaced by proliferating subendothelial cells accompanied by dilated capillaries in the adventitia of the occluded vessel. Late-stage vessels may show fibrosis and shrinkage. Intravascular aggregates of red blood cells suggest a low-flow state.

CHAPTER 9 ■ VASCULITIS AND RELATED DISORDERS

Livedo Reticularis

 FIGURE 9-23 Cholesterol emboli. Needle-shaped clefts (arrow) are present within the lumen of a small vessel.

205

Livedo racemosa is also a violaceous mottling of the skin similar to livedo reticularis, but more generalized and widespread, and showing irregularities and breaks in the network patterning. Persistent livedo reticularis and livedo racemosa may be associated with vasoocclusive disorders, vasculitides, or connective tissue diseases including the antiphospholidid antibody syndrome. Lupus patients with livedo reticularis are more likely to suffer cerebral vascular accidents.105 Generalized livedo reticularis and livedo racemosa are also part of a potentially severe arterio-occlusive syndrome (Sneddon syndrome) that often is complicated by cerebrovascular disease.106,107

Table 9-28 Cutaneous Cholesterol Embolism

Clinical Features Elderly patient with significant atherosclerosis Often status post-arterial catheterization Often lower extremities effected Extremity with adequate pulsation Livedo reticularis, purple discoloration, gangrene of toes, and small, painful ulcerations on the legs, nodules, or indurated plaques Histopathologic Features Emboli with needle-shaped clefts in the lumina of small vessels associated with amorphous eosinophilic material Macrophages Foreign body giant cell reaction Intimal fibrosis Obliteration of lumina Fibrin thrombi

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Table 9-29 Livedo Reticularis

Table 9-30 Atrophie Blanche

Clinical Features Persistent red-blue mottling of the skin in a netlike pattern Histopathologic Features Erythematous areas: no distinct findings White areas: thick vessel walls, thrombi, arterioles obliteration, red blood cell slugging Associations Vasculitis or a vasculopathies due to infection Atrophie blanche Cholesterol emboli Connective tissue disease Calciphylaxis and oxalosis Idiopathic Sneddon syndrome

Clinical Features Seasonal Middle-aged or elderly females Lower portions of the legs ankles and the dorsa of the feet Purpuric macules and papules developing into small, painful ulcers then irregularly outlined with peripheral hyperpigmentation and telangiectasia Histopathologic Features Early: Fibrinoid material in vessel walls or lumina Infarction with hemorrhage and an inflammatory infiltrate Late: Thinning of epithelium Dermal sclerosis with little cellular thickening and intimal hyalinization of dermal vessel walls Occlusion of vessel lumina by intimal proliferation and/or fibrinoid recanalized vessels Differential Diagnosis Stasis Coagulopathy Lymphocytic vasculitis, not otherwise specified

Atrophie Blanche Synonyms: Livedoid vasculitis, segmental hyalinizing vasculitis, livedo reticularis with seasonal ulceration. CLINICAL FEATURES Atrophie blanche is a common condition that may be seasonal, with greatest disease activity in the summer and winter months. Usually middleaged or elderly females are affected.108 Initially, purpuric macules and papules develop into small, painful ulcers with a tendency to recur. Healing of the ulcers results in the white atrophic areas that have given the disease its name. Typically lesions are located on the lower portions of the legs, particularly on the ankles and the dorsa of the feet. In the fully developed state, there are irregularly outlined, whitish atrophic areas with peripheral hyperpigmentation and telangiectasia. Many of the patients have associated livedo reticularis. The etiology of atrophie blanche is unknown. Immune-complex deposits that have been observed in late lesions are likely secondary changes. A primary disturbance of fibrinolysis in the endothelium of affected microvessels has been postulated. HISTOPATHOLOGIC FEATURES The histologic findings are nonspecific and vary with the stage of the lesion (Table 9-30). However, in all stages, vascular changes are present. In early lesions, fibrinoid material may be noted in vessel walls or vessel lumina (Fig. 9-24A). Infarction with hemorrhage and an inflammatory infiltrate may be present as well. In late atrophic lesions, the epithelium is

thinned, and the dermis is sclerotic with little, if any, cellular infiltrate. The walls of the dermal vessels may show thickening and intimal hyalinization. Occlusion of vessel lumina by intimal proliferation and/or fibrinoid material and sometimes recanalized thrombotic vessels may be seen (Fig. 9-24B). In some cases the vessels in the superficial dermis are predominantly affected; in others, the vessels in the middle and even deep dermis are mostly affected. Cutaneous polyarteritis nodosum can show atrophie blanche-like histology in superficial biopsies and can look similar to atrophie blanche clinically. A deep biopsy may aid in distinguishing these two conditions.109

Degos Syndrome Synonyms: Malignant atrophic papulosis (MAP), Degos disease. Degos initially described a cutaneointestinal syndrome in which distinct skin findings (“drops of porcelain”) were associated with recurrent attacks of abdominal pain that often ended in death from intestinal perforations.110 He chose the name malignant atrophic papulosis to emphasize the serious clinical course of

the disease. Originally, the cutaneous lesions were thought to be specific and pathognomonic for a unique disease entity (Degos disease). Currently, MAP is considered to be a clinicopathologic reaction pattern that can be associated with a number of conditions other than the cutaneointestinal syndrome described by Degos and others.110 Lesions similar, if not identical, to MAP have been noted in particular in connective tissue diseases such as lupus erythematosus, dermatomyositis, and progressive systemic sclerosis; in atrophie blanche; and in CreutzfeldtJakob disease. A “benign” form, involving only the skin, has been reported.112,113 The etiology of Degos syndrome is unclear. The findings have been ascribed to a coagulopathy, vasculitis, or mucinosis. However, convincing evidence to support any single causal factor is lacking. CLINICAL FEATURES The cutaneous manifestations of Degos syndrome include crops of asymptomatic, slightly raised, yellowish red or pale rose papules (Table 9-31). Gradually the papules become umbilicated and develop an atrophic porcelain white center with a livid red, telangiectatic margin. These papules tend to affect the trunk and proximal extremities. Symptoms of an acute abdomen or, less commonly, of a cerebral infarction may supervene. HISTOPATHOLOGIC FEATURES The histopathology observed varies with the evolution of the lesions.113 Early papular lesions may show a superficial and deep perivascular, periadnexal, and perineural chronic inflammatory cell infiltrate associated with interstitial mucin deposition and an overlying mild vacuolar interface reaction mimicking tumid lupus. More evolved lesions with the porcelain white scale show a wedge-shaped area of altered dermis covered by atrophic epidermis with slight hyperkeratosis. Dermal alterations may include frank necrosis. However, more commonly, edema, extensive mucin deposition (which may mimic tumid lupus), and slight sclerosis or a lichen sclerosis-like appearance is seen (Fig. 9-25A). Typically, vascular damage is noted in the vessels at the base of the “cone of necrobiosis.” Vascular alterations may be subtle and manifest as endothelial swelling only. However, more characteristically, intravascular fibrin thrombi may be noted (see Fig. 9-25B). Their presence suggests that the dermal and epidermal changes result from ischemia. Altered vessels usually lack an inflammatory infiltrate.

B

 FIGURE 9-24 Atrophie blanche. (A) The microvessels show deposition of fibrinoid material in their walls (arrow) and an associated lymphoid infiltrate. (B) Fibrin thrombi (arrow) may be found in other vessels. (Courtesy of Dr. Charles Palmer.)

Calciphylaxis Synonyms: Widespread calcification with vascular thrombosis, calcific uremic arteriolopathy (CUA), calcifying panniculitis, vascular calcification-cutaneous necrosis syndrome. CLINICAL FEATURES Calciphylaxis is an uncommon complication of renal failure

Table 9-31 Degos Syndrome

Clinical Features Crops of asymptomatic, slightly raised, yellowish-red or pale rose papules which umbilicate and develop an atrophic porcelain-white center with a livid red, telangiectatic surrounding Trunk and proximal extremities commonly affected Acute abdominal crisis Cerebral infarction Histopathologic Features Atrophic epidermis with hyperkeratosis Wedge-shaped area of altered dermis Necrosis or edema Mucin deposition and slight sclerosis Vascular damage at the base of the wedge Fibrin thrombi common Differential Diagnosis Coagulopathies Cryoglobulinemia Atrophie blanche Pityriasis lichenoides

(Table 9-32). Usually secondary or tertiary hyperparathyroidism is found in these patients. Obesity, female gender, alcoholic cirrhosis, and poor nutritional status are some putative risk factors.114 Retiform purpura in plaques, palpable purpura in a livedoid, reticulate, or arciform pattern develop on the trunk and extremities (Fig. 9-26A). These dramatic painful lesions reflect occlusion of dermal and subcutaneous vasculature and can progress rapidly to form bullae, ulcers, eschars, and gangrene. The clinical differential diagnosis includes calciphylaxis, antiphospholipid antibody syndrome, warfarin-induced skin necrosis, and heparin-induced skin necrosis.101 The prognosis for calcifylaxis is extremely poor, especially for proximal disease, even with aggressive treatment by parathyroidectomy.115 Fulminant sepsis may develop from infection of necrotic or gangrenous tissue. The relationships amongst the calcification, thrombosis, and ischemic necrosis in calciphylaxis are unclear. Although vascular calcification is common in uremic patients, calciphylaxis is rare. Elevation of the calcium and phosphorous products, along with a poorly defined precipitating or challenging event or agent, is hypothesized to be necessary for calcium deposition in cutaneous tissues. However, the list of putative sensitizing agents is long, and the calcium and phosphorus products may be within normal limits. The development of a hypercoagulable state may be an additional important element in the pathogenesis of this entity but is not present in all cases.116

HISTOPATHOLOGIC FEATURES The principal histologic findings include (1) calcification of soft tissue and small vessels2 (Fig. 9-26), (2) nonspecific intimal proliferation of small vessels, often resulting in luminal narrowing, (3) variable fibrin thrombi, and (4) frequent ischemic necrosis of skin and subcutis (see Chap. 11). The small vessels involved by this process cannot be identified as either arterial or venous. Often one observes foreign body-giant cell reaction to calcium and mixed inflammatory cell infiltrates that are neutrophil-rich. Pseudoxanthoma elasticum-like changes and the changes of nephrogenic fibrosing dermopathy, also associated with chronic renal failure, can rarely be seen in association with calciphylaxis.117,118 DIFFERENTIAL DIAGNOSIS Cutaneous calcium deposits may be seen in a number of other conditions, especially cutaneous calcinosis and metastatic calcifications. In contrast to calciphylaxis (see Chap. 16), calcinosis usually lacks prominent vascular involvement. Occasionally, incidental medial calcification of blood vessels is seen as part of a mild atherosclerosis called Monckeberg medial calcific sclerosis. This change may be seen in patients without renal disease who have been biopsied for an unrelated condition. Other crystal-induced inflammatory diseases such as gout, pseudogout, or oxalosis that are associated with a giant cell reaction to crystal deposits and surrounding fibrosis may resemble calciphylaxis. Histopathologically, pancreatic

CHAPTER 9 ■ VASCULITIS AND RELATED DISORDERS

A

207

PART I ■ INFLAMMATORY REACTIONS IN THE SKIN

A

 FIGURE 9-25 Degos lesion. Atrophic epidermis overlies a wedge-shaped area of dermis with mucin deposition (A) and a thrombosed vessel at the base (B). This Degos lesion was seen in a patient with dermatomyositis.

panniculitis may suggest calciphylaxis. However, the polymorphous infiltrate and ghostlike cells are absent in calciphylaxis, in contrast to pancreatic panniculitis.119 If the sampling lacks significant

Table 9-32 Calciphylaxis

208

B

Clinical Features Renal failure with secondary hyperparathyroidism Primary hyperparathyroidism Hypercalcemia of malignancy Livedo reticularis Firm, indurated, painful, violaceous lesions Progression to bullae, ulcers, eschars, and gangrene Trunk and extremities involved Histopathologic Features Calcium deposition in soft tissue and small blood vessels Intimal proliferation and luminal occlusion Thrombi in uncalcified, noninflamed small vessels of the subcutis Full-thickness ischemic necrosis of skin Differential Diagnosis Coagulopathies Calcinosis cutis Panniculitis with calcification

calcium deposits, the biopsy may mimic ischemic damage or a coagulopathy.

Oxalosis CLINICAL FINDINGS Oxalosis is characterized by the deposition of calcium oxalate crystals in multiple organs, most frequently the kidneys and myocardium. The disease may be primary, owing to inborn errors of metabolism, or secondary. The most common cause of secondary oxalosis is hyperabsorption of dietary oxalate secondary to intestinal disease or ileal resection or excessive intake of oxalates or oxalate precursors, such as ethylene glycol. Deposition of calcium oxalate in small vessels of the dermis and subcutis may result in livedo reticularis, whereas involvement of larger peripheral blood vessels may lead to peripheral gangrene.120,121 HISTOPATHOLOGIC FEATURES Calcium oxalate is a light yellow-brown birefringent crystal exhibiting a number of shapes, including rosettes, ellipses, prisms, and radial patterns. The latter crystals may be deposited in the walls or occlude the lumina of small vessels with or without fibrin thrombi or localize to the media of larger vessels. There may

be infiltration of vessel walls by neutrophils. Varying degrees of ischemic necrosis of skin may result. DIFFERENTIAL DIAGNOSIS The histopathologic findings may resemble calciphylaxis. However, the calcium oxalate crystal morphology and birefringence allow discrimination from calcium phosphate. Although both oxalosis and calciphylaxis patients exhibit renal failure, the cutaneous clinical findings are distinct. Other crystal deposition syndromes, such as gout, may resemble oxalosis. However, urate crystals are dissolved during routine processing, unlike oxalate crystals, and are not deposited in vascular walls with associated thrombi. Oxalate thrombi may be confused with a cholesterol embolus; however, cholesterol is removed by routine processing and is not birefringent. Calcium oxalate can be identified histochemically by the method of Johnson and Pani.122

Conditions Leading to Alteration of the Vessel Wall Metabolic disorders may lead to the deposition of endogenously produced material within the walls of the small vessels supplying the skin. These metabolic

B

 FIGURE 9-26 Calciphylaxis. (A) Hyperpigmented and purpuric plaques with vaguely livedoid, reticulate, and arciform patterns showing coalescence on the lower extremity. (B) Vascular calcification of a small blood vessel in the panniculus. (Figure 9-26B is Courtesy of Dr Charles Palmer.)

vasculopathies may result in ischemic damage. Examples of such disorders include diabetes mellitus, amyloidosis, or porphyria, which are discussed in more detail in Chaps. 8 and 16. The salient histologic vascular alteration in the abovementioned disorders is the deposition of amorphous material in the walls of dermal capillaries. Atherosclerosis is by far the most common type of metabolic vasculopathy. However, atherosclerosis is primarily a disease of large vessels supplying visceral organs and is not a usual finding in skin biopsies. Cutaneous changes, usually secondary manifestations of peripheral ischemia, are more common in the amputation specimens seen in general surgical pathology. Luminal occlusion may result from intimal thickening and lipid deposition, superimposed thrombosis, or less frequently, cholesterol emboli (discussed earlier).

HISTOPATHOLOGIC FEATURES In senile purpura, extravasation of red blood cells occurs in atrophic skin with severe solar elastosis and normal-appearing capillaries (Fig. 9-27). Such lesions may simulate melanoma or angiosarcoma clinically.

Scurvy is characterized by dermal hemorrhage predominantly in the vicinity of hair follicles without evidence of vascular damage. Hemosiderin-laden macrophages, follicular keratotic plugs, and coiled hair are also seen.123

CHAPTER 9 ■ VASCULITIS AND RELATED DISORDERS

A

Vasculopathies Owing to Deficiencies of Connective Tissue Last, structural deficiencies of the perivascular connective tissue may contribute to vascular fragility and the attendant extravasation of erythrocytes. Such alterations underlie the hemorrhage in senile purpura and scurvy. This group of conditions can be described as noninflammatory purpura.

 FIGURE 9-27 Senile purpura. Extravasated red cells within elastotic dermis.

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75. Churg J, Strauss L. Allergic granulomatosis, allergic angiitis, and periarteritis nodosa. Am J Pathol. 1951;27:277-301. 76. Wegener F. Ueber generalisierte, septische Gefaesserkrankungen. Verh Dtsch Ges Pathol. 1936;29:202-210. 77. Godman GC, Churg J. Wegener’s granulomatosis: pathology and review of the literature. Arch Pathol. 1954;58:533-553. 78. Fauci AS, Wolff SM. Wegener’s granulomatosis: studies in 18 patients and a review of the literature. Medicine. 1973;52:535-561. 79. Barksdale SK, Hallahan CW, Kerr GS, et al. Cutaneous pathology in Wegener’s granulomatosis. Am J Surg Pathol. 1995; 19:161-172. 80. Comfere NI, Macaron NC, Gibson LE. Cutaneous manifestations of Wegener’s granulomatosis: a clinicopathologic study of 17 patients and correlation to antineutrophil cytoplasmic antibody status. J Cutan Pathol. 2007;34(10):739-747. 81. Lynch JM, Barrett TL. Collagenolytic (necrobiotic) granulomas: part 1—the ‘blue’ granulomas. J Cutan Pathol. 2004; 31(5):353-361. 82. Guillevin L, Lhote F, Amouroux J, et al. Antineutrophil cytoplasmic antibodies, abnormal angiograms, and pathological findings in polyarteritits nodosa and Churg-Strauss syndrome: Indications for the classification of vasculitides of the polyarteritits nodosa group. Br J Rheumatol. 1996;35:958-964. 83. deShazo RD, Levinson AI, Lawless OJ, Weisbaum G. Systemic vasculitis with coexistent large and small-vessel involvement: a classification dilemma. JAMA. 1977;238:1940-1942. 84. Modesto A, Keriven O, DupreGoudable C, et al. There is no real difference beween Wegener’s granulomatosis and micropolyarteritis. Contrib Nephrol. 1991;94:191-194. 85. Kussmaul A, Maier K. Ueber eine bisher nicht beschriebene eigentuemliche Arterien veraenderung (periarteritis nodosa), die mit Morbus Briggti und rapide fortschreitender all gemeiner Muskellaehmung einhergeht. Dtsch Akad Klin Med. 1885;1:484-517. 86. Ferrari E. Veber Polylarteritis acuta nodosa (sogerannte Periarteritis nodosa) undihre Beziehurgen zur polylmyositis and polyneuritis acuta. Beitr Pathol Anat. 1903;34:350-386. 87. Diaz-Perez JL, Winkelman RK. Cutaneous periarteritis nodosa. Arch Dermatol. 1974; 110:407-414. 88. Díaz-Pérez JL, De Lagrán ZM, DíazRamón JL, Winkelmann RK. Cutaneous polyarteritis nodosa. Semin Cutan Med Surg. 2007 Jun;26(2):77-86. 89. Rogalski C, Sticherling M. Panarteritis cutanea benigna—an entity limited to the skin or cutaneous presentation of a systemic necrotizing vasculitis? Report of seven cases and review of the literature. Int J Dermatol. 2007;46(8):817-821. 90. Schneider JW, Jordaan HF. The histologic spectrum of erythema induratum of Bazin. Am J Dermatopathol. 1997;19(4): 323-333. 91. Peyrot I, Garsaud AM, Saint-Cyr I, Quitman O, Sanchez B, Quist D. Cannabis arteritis: a new case report and a review of literature. J Eur Acad Dermatol Venereol. 2007;21(3):388-391.

92. Johnson WC, Wallrich R, Helwig EB. Superficial thrombophlebitis of the chest wall. JAMA. 1962;180:103-108. 93. Kumar B, Narang T, Radotra BD, Gupta S. Mondor’s disease of penis: a forgotten disease. Sex Transm Infect. 2005;81(6): 480-482. 94. Landing BH, Larson EJ. Pathologic features of Kawasaki disease (mucocutaneous lymph node syndrome). Am J Cardiovasc Pathol. 1987;4:75-84. 95. Perniciaro CV, Winkelmann RK, Hunder GG. Cutaneous manifestations of Takayasu’s arteritis. J Am Acad Dermatol. 1987;17:998-1005. 96. Fernandes SRM, Singsen BH, Hoffman GS. Sarcoidosis and systemic vasculitits. Semin Arthitis Rheum. 2000;30:33-46. 97. Baum EW, Sams WM, Jr, Payne RR. Giant cell arteritis: a systemic disease with rare cutaneous manifestations. J Am Acad Dermatol. 1982;6:1081-1088. 98. Font RL, Prabhakaran VC. Histological parameters helpful in recognising steroidtreated temporal arteritis: an analysis of 35 cases. Br J Ophthalmol. 2007;91(2):204209. 99. Hamidou MA, Moreau A, Toquet C, El Kouri D, de Faucal P, Grolleau JY. Temporal arteritis associated with systemic necrotizing vasculitis. J Rheumatol. 2003;30(10):2165-2169. 100. Robboy SJ, Mihm MC, Colman RC, et al. The skin in disseminated intravascular coagulation. Br J Dermatol. 1973;88: 221-229. 101. Jones A, Walling H. Retiform purpura in plaques: a morphological approach to diagnosis. Clin Exp Dermatol. 2007; 32(5):596-602. 102. Falanga V, Fine MJ, Kapoor WN. The cutaneous manifestations of cholesterol crystal embolization. Arch Dermatol. 1986;122:1194-1198. 103. Faclieru D, Bergman R, Lanir N, et al. A study of coagulation and anti-endothelial antibodies in idiopathic livedo reticularis. Acta Derm Venereol (Stockh). 1997; 77:181-183. 104. Ruiz-Genao D, García-F-Villalta MJ, Hernández-Núñez A, Ríos-Buceta L, Fernández-Herrera J, García-Díez A. Livedo reticularis associated with interferon-a therapy in two melanoma patients. J Eur Acad Dermatol Venereol. 2005;19(2):252-254. 105. Francès C, Niang S, Laffitte E, le Pelletier F, Costedoat N, Piette JC. Dermatologic manifestations of the antiphospholipid syndrome: two hundred consecutive cases. Arthr Rheumat. 2005;52(6):1785-1793. 106. Sneddon IB. Cerebro-vascular lesions and livedos reticularis. Br J Dermatol. 1975;77:180-185. 107. Uthman IW, Khamashta MA. Livedo racemosa: a striking dermatological sign for the antiphospholipid syndrome. J Rheumatol. 2006;33(12):2379-2382. 108. Stiefler RE, Bergfeld WF. Atrophie blanche (review). Int J Dermatol. 1982;21:1-7. 109. Mimouni D, Ng PP, Rencic A, Nikolskaia OV, Bernstein BD, Nousari HC. Cutaneous polyarteritis nodosa in patients presenting with atrophie blanche. Brit J Dermatol. 2003;148(4):789-794. 110. Degos R, Delort J, Tricot R. Dermatite papulo-squameuse atrophiante. Bull Soc Fr Dermatol Syph. 1942;49:148-150.

CHAPTER 9 ■ VASCULITIS AND RELATED DISORDERS

65.

of the early stage of rheumatoid vasculitis. Eur J Dermatol. 1999;4:313-316. Jennette JC, Falk RJ. Diagnostic classification of antineutrophil cytoplasmic autoantibody-associated vasculitides. Am J Kidney Dis. 1991;16:184-187. Hoffman GS, Specks U. Antineutrophil cytoplasmic antibodies. Arthritis Rheum. 1998;41:1521-1537. Chen M, Yu F, Zhang Y, et al. Characteristics of Chinese patients with Wegener’s granulomatosis with anti-myeloperoxidase autoantibodies. Kid Int. 2005;68(5):2225-2229. Brons RH, de Jong MC, de Boer NK, et al. Detection of immune deposits in skin lesions of patients with Wegener’s granulomatosis. Ann Rheum Dis. 2001;60: 1097-1102. Xiao H, Heeringa P, Hu P, et al. Antineutrophil cytoplasmic autoantibodies specific for myeloperoxidase cause glomerulonephritis and vasculitis in mice. J Clin Invest. 2002;110:955963. Bansal PJ, Tobin MC. Neonatal microscopic polyangiitis secondary to transfer of maternal myeloperoxidase-antineutrophil cytoplasmic antibody resulting in neonatal pulmonary hemorrhage and renal involvement. Ann Allergy Asthma Immunol. 2004;93:398-401. Teisserenc H, Schmit W, Blake N, et al. A case of primary immunodeficiency due to a defect of the major histocompatibility gene complex class I processing and presentation pathway. Immunol Lett. 1997;57:183-187. Bonaci-Nikolic B, Nikolic MM, Andrejevic S, Zoric S, Bukilica M. Antineutrophil cytoplasmic antibody (ANCA)-associated autoimmune diseases induced by antithyroid drugs: comparison with idiopathic ANCA vasculitides. Arthritis Res Ther. 2005;7(5): R1072-R1081. Lanham JG, Elhon KB, Pusey CD, Hughes GR. Systemic vasculitis with asthma and eosinophilia: a clinical approach to Churg-Strauss syndrome. Medicine. 1984;63:65-81. Davis MD, Daoud MS, McEvoy MT, Su WP. Cutaneous manifestations of ChurgStrauss syndrome: a clinicopathologic correlation. J Am Acad Dermatol. 1997;37: 199-203. Chen KR, Sakamoto M, Ikemoto K, Abe R, Shimizu H. Granulomatous arteritis in cutaneous lesions of Churg-Strauss syndrome. J Cutan Pathol. 2007;34(4): 330-337. Lynch JM, Barrett TL. Collagenolytic (necrobiotic) granulomas: part II—the ‘red’ granulomas. J Cutan Pathol. 2004; 31(6):409-418. Finan MC, Winkelman RK. The cutaneous extravascular necrotizing granuloma (Churg-Strauss granuloma) and systemic disease: a review of 27 cases. Medicine. 1983;62:142-158. Schuttelaar ML Jonkman MF. Bullous eosinophilic cellulitis (Wells’ syndrome) associated with Churg-Strauss syndrome. J Eur Acad Dermatol Venereol. 2003;17(1):91-93. Caputo R, Marzano AV, Vezzoli P, Lunardon L. Wells syndrome in adults and children: a report of 19 cases. Arch Dermatol. 2006;142(9):1157-1161.

211

PART I ■ INFLAMMATORY REACTIONS IN THE SKIN

111. Doutre MS, Beylot C, Bioulac P, et al. Skin lesion resembling malignant atrophic papulosis in lupus erythematosus. Dermatologica. 1987;175:45-46. 112. Wilson J, Walling H, Stone M. Benign cutaneous degos disease in a 16-year-old girl. Pediat Dermatol. 2007;24(1):18-24. 113. Harvell JD, Williford PL, White WL. Benign cutaneous Degos’ disease: a case report with emphasis on histopathology as papules chronologically evolve. Am J Dermatopathol. 2001;23:116-123. 114. Ferreres JR, Marcoval J, Bordas X, et al. Calciphylaxis associated with alcoholic cirrhosis. J Eur Acad Dermatol Venereol. 2006;20(5):599-601. 115. Fischer AH, Morris DJ. Pathogenesis of calciphylaxis: study of 3 cases with

212

116.

117.

118.

119.

literature review. Hum Pathol. 1995;26: 1055-1064. Mehta RL, Scott G, Sloand JA, Francis CW. Skin necrosis associated with acquired protein C deficiency in patients with renal failure and calciphylaxis. Am J Med. 1990;88:252-257. Nikko AP, Dunningan M, Cockerell CJ. Calciphylaxis with histologic changes of pseudoxanthoma elasticum. Am J Dermatopathol. 1996;18(4):396-399. Edsall L, English III, JC, Patterson JW. Calciphylaxis and metastatic calcification associated with nephrogenic fibrosing dermopathy. J Cutan Pathol. 2004; 31(3):247-253. Lugo-Somolinos A, Sanchez JL, MenedezColl J, Joglar F. Calcifying panniculitis

120.

121. 122. 123.

associated with polycystic kidney disease and chronic renal failure. J Am Acad Dermatol. 1990;22:743-747. Greer KE, Cooper PH, Campbell R, Westervelt FB. Primary oxalosis with livedo reticularis. Arch Dermatol. 1980; 116:213-214. Arbus GS, Sniderman S. Oxalosis with peripheral gangrene. Arch Pathol. 1974;97:107-110. Johnson FB, Pani K. Histochemical identification of calcium oxalate. Arch Pathol Lab Med. 1962;74:347-351. Walker A. Chronic scurvy. Br J Dermatol. 1968;80:625-630.

CHAPTER 10 Disorders of Cutaneous Appendages David A. Whiting Douglas C. Parker Amy K. Reisenauer Alvin R. Solomon

tissue and therefore hair bulbs. For additional information, two 4-mm punch biopsies are taken from comparable sites. One biopsy is bisected vertically parallel to the direction of any hairs, and both halves are placed in a cassette for formalin fixation and standard staining with hematoxylin and eosin (H&E). If necessary, one-half of the vertical biopsy can be reserved for immunofluorescence or any other purpose that requires different processing. The other 4-mm punch is carefully bisected horizontally (transversely) parallel to the epidermis and 1 to 1.5 mm below it.4 Both segments are embedded in paraffin side by side with the cut surfaces face down in the block.5 Sectioning will progress down toward the subcutaneous tissue in one half and up toward the epidermis in the other. The pathologist who uses this technique and is familiar with the transverse anatomy of the hair follicle can then count the hair bulbs; terminal anagen, catagen, and telogen hairs; telogen germinal units; and stelae (fibrous tracts or streamers) in sections through reticular dermis6,7 (Tables 10-2 and 10-3). Terminal hairs, vellus hairs (which include true vellus hairs and miniaturized or velluslike hairs), and follicular units can be counted in sections of the papillary dermis (Tables 10-3 and 10-4). From these data, total follicular counts are derived with anagen-telogen ratios, terminal-vellus hair ratios, and follicular concentration per square millimeter. Comparative data for controls versus androgenetic alopecia, chronic telogen effluvium, alopecia areata, and trichotillomania are shown in Table 10-4.8-10 For pathologists who rely only on vertical sections, multiple sections may be required to estimate the total follicular counts and the terminalvellus and anagen-telogen ratios, which are helpful in the diagnosis of nonscarring alopecia. The presence or absence of inflammatory changes and fibrosis is also important in establishing the diagnosis.

CHAPTER 10 ■ DISORDERS OF CUTANEOUS APPENDAGES

The interpretation of scalp biopsies from patients with hair loss can be difficult (Fig. 10-1). The pathologist depends on accurate clinical information when assessing scalp biopsies. The most common causes of hair loss or shedding are nonscarring and include androgenetic alopecia, diffuse alopecia, alopecia areata, trichotillomania, and other types of traumatic alopecia1 (Table 10-1). A basic understanding of the hair follicle and the hair cycle is needed to interpret scalp biopsies.1-3 The human hair follicle consists of a permanent upper segment, comprised of infundibulum and isthmus, and an impermanent lower segment, comprised of lower follicle and hair root. The infundibulum is lined with keratinized skin surface epithelium and ends at the entry of the sebaceous duct into the follicle. The isthmus extends down from the sebaceous duct and ends at the bulge where the arrector pili muscle inserts into the follicle. It is lined by trichilemma (external root sheath) and trichilemmal keratin. The lower segment surrounds a growing hair with internal and external root sheaths, hyaline membrane, and fibrous sheath. The bulb consists of the dermal papilla surrounded by hair matrix cells. It generates the growing hair. The dermal papilla and fibrous sheath are continuous. Human scalp hair follicles cycle continuously through periods of growth and rest. Asynchronous follicular growth produces an ever-changing mosaic pattern of growing follicles on the scalp. The growth or anagen phase lasts 2 to 7 years, 1000 days on average, and the resting or telogen phase lasts 2 to 4 months, an average of 100 days. The end of telogen is signaled by the appearance of a new anagen hair and the shedding of the telogen hair. Assuming an average of 100,000 hairs on the human scalp, with 5% to 10% in telogen at any one time, then up

to 10,000 hairs are shed every 100 days, an average loss of 100 hairs per day. Large hairs with a diameter exceeding 0.03 mm, growing more than 1 cm in length, often pigmented and medullated, are classified as terminal hairs. Small hairs with a diameter of less than 0.03 mm, growing less than 1 cm in length, and with no pigment or medullary cavity, are classified as vellus (downy) hairs. Depigmented hairs less than 0.03 mm in diameter that have been miniaturized by androgenetic alopecia, alopecia areata, or any other cause can be classified as vellus-like hairs. The designation vellus hairs used in this chapter includes true vellus hairs and vellus-like hairs. Terminal hairs are rooted in the subcutaneous tissue, but vellus hairs are rooted in the dermis. Terminal-to-vellus ratios therefore denote the proportions of large hairs to small hairs, and a normal scalp averages seven terminal hairs per vellus hair. Less than four terminal hairs to one vellus hair denotes a relative increase in vellus hairs, perhaps indicating a miniaturization process. The termination of anagen is signaled by the onset of catagen. Catagen is the short, 10- to 14-day intermediate phase between anagen and telogen that indicates the onset of telogen, since it irrevocably commits the growing follicle to a resting phase. In catagen, the hair shaft retracts upward, the hyaline basement membrane thickens and corrugates, and individual cell necrosis or apoptosis occurs in the outer root sheath or trichilemma. The hair displacement and volumetric reduction of root sheath lead to the progressive disappearance of the lower or impermanent part of the hair follicle so that in telogen the resting hair root is seen near the insertion of the arrector pili muscle, where the permanent follicle begins. A telogen bulb lacks pigment and internal and external root sheaths and is surrounded by trichilemmal keratin. An angiofibrotic strand extending down from the permanent follicle, known variously as a fibrous tract, streamer, or stela, indicates the former position of the retracted follicle. Histopathologic examination is helpful for diagnostic purposes and for evaluating the capacity for future hair regrowth. If possible, the biopsy should be taken from an area of active alopecia. For predictive purposes, an area of maximal hair loss can be sampled. Punch biopsies of the scalp are adequate substitutes for excisional biopsies. A sharp trephine of at least 4 mm diameter is used. The biopsy is angled in the direction of any emerging hairs and taken deep enough to include subcutaneous

TRANSVERSE VERSUS VERTICAL SECTION TECHNIQUES The advantages of transverse sections in evaluating alopecia are many (Table 10-5). Familiarity with follicular microanatomy is essential when evaluating transverse sections (see Tables 10-2 and 10-3), and several recent reviews describe this in detail.2-4,6-8 Transverse sections allow for rapid detection of pathologic alteration of this normal follicular microanatomy, especially follicular density.

213

Alopecia

Nonscarring alopecia

PART I ■ INFLAMMATORY REACTIONS IN THE SKIN

No follicular loss Normal terminal:vellus ratio Diffuse alopecia (telogen effluvium) Trichotillomania Traction alopecia

Slight decrease anagen:telogen ratio Diffuse alopecia Androgenetic alopecia

Mild follicular loss Decreased terminal: vellus ratio Androgenetic alopecia Alopecia areata

Moderate follicular loss Congenital hypotrichosis Congenital triangular alopecia

Peribulbar lymphocytic infiltrates absent Perifollicular lymphocytic infiltrates: 70% Androgenetic alopecia

Large decrease anagen:telogen ratio Trichotillomania

Trichomalacia often absent Traction alopecia

Scarring alopecia

Peribulbar lymphocytic infiltrates present Moderate decrease anagen: telogen ratio Alopecia areata

Trichomalacia often present Trichotillomania

Scarring alopecia

Primary scarring alopecia

Lymphocyte-associated scarring alopecia Discoid lupus erythematosus Lichen planopilaris Pseudopelade/follicular degeneration syndrome Alopecia mucinosa

Interface alteration Lupus erythematosus Lichen planopilaris

Vacuolar interface alteration Superficial and deep infiltrates Discoid lupus erythematosus

Lichenoid interface alteration Perifollicular infiltrates mainly Lichen planopilaris

Secondary scarring alopecia

Neutrophil-associated (pustulo-follicular) scarring alopecia Dissecting cellulitis Folliculitis decalvans Acne keloidalis Tinea kerion and favus

No interface alteration Pseudopelade Follicular mucinosis

No follicular mucin Perifollicular fibrosis Pseudopelade

Follicular mucin No perifollicular fibrosis Follicular mucinosis

Sclerosing disorders

Tumors

Physical/ chemical agents

Granulomatous infiltrates

Dermal infiltrative processes

Amyloidosis

 FIGURE 10-1 An algorithm for the histopathologic diagnosis of alopecia.

214

Transverse sectioning provides for either quantitative or semiquantitative evaluation of numerous follicles and follicular units in one section, thus allowing for a rapid, accurate assessment of whether the specimen represents a scarring or

nonscarring alopecia. By definition, scarring alopecias show diminished follicular density (complete follicular atrophy) and disruption of follicular unit morphology. Evaluation of follicular density is more difficult using traditional vertical sections

because multiple serial sections must be examined. Furthermore, follicular unit morphology cannot be assessed accurately with vertical sections. The dermalepidermal junction is evaluated more easily in vertical sections but also can be

Table 10-1 Common Causes of Alopecia NO

DISEASE Male androgenetic alopecia Diffuse alopecia Female pattern alopecia Alopecia areata Cicatricial alopecia Trichotillomania Other

NONSCARRING VERSUS SCARRING ALOPECIA Determining whether a patient clinically has scarring or nonscarring alopecia can be challenging, and in these cases, scalp biopsy is a very useful tool for specific diagnosis and prognosis for possible regrowth. The terms scarring and nonscarring are firmly entrenched in the dermatologic lexicon and are helpful for classification and prognosis in many cases of alopecia. However, some of the traditionally designated nonscarring alopecias may eventuate in permanent follicular atrophy and hair loss. Androgenetic alopecia, alopecia areata, traction alopecia, and trichotillomania are examples of nonscarring alopecia that may progress to complete, permanent hair loss. Thus the terms scarring

2447 1719 1848 1155 658 142 1123 9092

27.0 18.9 20.3 12.7 7.2 1.6 12.3 100

and nonscarring as they have been used historically do not always correlate with prognosis for hair regrowth. Some of the histopathologic differences in the common forms of nonscarring alopecia are set out in Table 10-6.

NONSCARRING ALOPECIA

Androgenetic Alopecia Androgenetic alopecia, or common baldness, affects at least 50% of the population by age 50 years in males11 and a decade later in females. The familiar pattern of frontoparietal hair loss is due to a genetically determined end-organ sensitivity of the hairs on the crown to androgens. The affected terminal hairs are replaced progressively by finer and shorter hairs.12 CLINICAL FEATURES Androgenetic alopecia predominantly affects the top of the scalp in both sexes, with relative sparing

HISTOPATHOLOGIC FEATURES The histopathologic changes in androgenetic alopecia are similar in males and females and reflect the pathogenesis of the condition17,18 (see Table 10-7). With shorter hair cycles, terminal hairs become vellus-like. The hair roots retreat upward toward the epidermis so that many of the miniaturized hair bulbs are found in mid- or papillary dermis. Residual follicular stelae (fibrous tracts or streamers) extending from the subcutaneous tissue up the old follicular tract to the miniaturized hair mark the former position of the original terminal follicle (Fig. 10-2). Thus the expected findings in androgenetic alopecia are decreased terminal hairs, increased follicular stelae, and increased vellus hairs17-24 (Fig. 10-3). A varying

CHAPTER 10 ■ DISORDERS OF CUTANEOUS APPENDAGES

viewed in transverse sections, although in tangential orientation.7

% OF PATIENTS

of the back and sides (Table 10-7). It is of dominant inheritance with variable penetrance.13 Hair thinning occurs in males at any time after puberty. It often begins with bitemporal hair recession followed by a circular patch of hair loss over the vertex and then thinning of the frontal hairline.11 In females, hair thinning also can begin after puberty, but an onset at between 25 and 35 years of age is more common, and many patients only present around menopause. Female-pattern alopecia causes diffuse thinning over the top of the scalp with an intact frontal hair margin14,15 and without total baldness. In females, severe bitemporal recession, vertex baldness, acne, hirsutism, and abnormal menses reflect significant hyperandrogenism, which needs investigation.16

Table 10-2 Description of Follicular Structures Terminal (big hair) Vellus (small)

Hair bulb Anagen hairs Telogen hairs

Follicular stelae

Follicular units

SOURCE: After Whiting32

Shaft diameter exceeds 0.03 mm and is thicker than its inner root sheath. A medullary cavity and/or pigment may be present. This definition includes “intermediate” hair shafts of diameter 0.03-0.06 mm. Shaft diameter equals 0.03 mm or less and is thinner than its inner root sheath. Shaft lacks pigment and medullary cavity, and arrector pili muscle is usually not found. All hairs of this size are counted as vellus hairs, whether true vellus hairs or vellus-like hairs secondary to miniaturization from any cause. The hair bulb consists of root sheath, hair matrix, and dermal papilla. Hair bulbs or hair shafts surrounded by inner and outer root sheaths. Only identifiable in lower follicle below bulge area. Catagen hairs with trichilemmal apoptosis and thickened, corrugated, vitreous membrane, telogen hairs containing trichilemmal keratin, and telogen germinal units (resting telogen follicles containing basaloid cells). Only identifiable in lower follicle below bulge area. Residual fibrous tracts or streamers representing the impermanent lower third of the hair follicle below the bulge area. Not counted as extra hair-forming structures because they are either downward prolongations of follicular structures that are counted in horizontal sections of the papillary dermis anyway or are permanently fibrosed follicles. Hexagonal areas seen in horizontal sections at sebaceous duct level, surrounded by collagen and containing terminal and vellus hairs, sebaceous glands and ducts, and arrector pili muscles. Not counted as follicular structures, but if fibrosed, represent severe cicatricial alopecia.

215

trichotillomania. Hair miniaturization does not occur in diffuse alopecia or in trichotillomania but is present in alopecia areata, often with a peribulbar lymphocytic infiltrate. Increased catagen hairs are present in trichotillomania and alopecia areata. Trichomalacia is characteristic of traction alopecia, notably trichotillomania, but can occur in alopecia areata.

Table 10-3 Normal Transverse Section Microanatomy: 4-mm Punch Biopsy Follicular unita composition

2-4 terminal follicles 2-4 vellus follicles Sebaceous lobules Arrector pili muscles 10-14 follicular units 20-40 terminal follicles 90%± 10%±

Follicular unit density Hair folliclea density Anagen follicles Telogen follicles

Diffuse Alopecia

a

PART I ■ INFLAMMATORY REACTIONS IN THE SKIN

Follicular units include terminal and vellus hairs, sebaceous glands and ducts, and arrector pili muscles; hair follicle refers to terminal follicular units.

number of intermediate hairs, with a shaft diameter less than the average 0.06-mm terminal hair diameter but more than the 0.03-mm vellus hair diameter, may be present25; for simplicity, these intermediate hairs are classified as terminal hairs in follicular counts quoted in this chapter. The progressive reduction in duration of anagen, but not telogen, causes a relative increase in telogen hairs. The average follicular counts in horizontal sections of a 4-mm punch biopsy of male pattern alopecia are 20.9 terminal hairs + 14.7 vellus hairs + 35.6 total hairs, with a terminalvellus ratio of 1.4:1 and a ratio of 80% anagen to 20% telogen (see Table 10-4). The follicular counts in female pattern alopecia are 21.6 terminal hairs + 11.1 vellus hairs = 32.6 total hairs, with a terminal-vellus ratio of 1.9:1, and 86% anagen hairs and 14% telogen hairs. These counts contrast with those in normal controls, which are 35 terminal hairs + 5 vellus hairs + 40 total hairs, with a terminal-vellus ratio of 7:1 and a ratio of 93.5% anagen to 6.5% telogen17,18 (see Table 10-4). A terminal-vellus ratio of less than 4:1 indicates increased follicular miniaturization. A significant

reduction in the total follicular count is seen in 10% of cases of androgenetic alopecia, indicating a decreased capacity for follicular regrowth in these cases.17 A mild perifollicular lymphohistiocytic infiltrate, usually around upper follicles, is present in one-third of cases of androgenetic alopecia, as it is in one-third of normal controls. A moderate perifollicular lymphohistiocytic infiltrate, perhaps with concentric layers of collagen deposition, is present in 40% of cases of androgenetic alopecia but only in 10% of normal controls.17 Occasional mast cells and even eosinophils are seen. Despite the inflammatory changes, sebaceous glands remain intact in androgenetic alopecia. Routine stains are adequate to evaluate androgenetic alopecia, but periodic acid–Schiff (PAS) stains apoptotic cells and vitreous layer to highlight catagen, and elastic stains show up Arao-Perkins bodies (ie, elastin aggregates at the site of an antecedent follicular papilla) in follicular stelae. DIFFERENTIAL DIAGNOSIS Androgenetic alopecia must be distinguished from diffuse alopecia, alopecia areata, and

Diffuse alopecia implies generalized hair loss or shedding involving the back, sides, and top of the scalp. Common causes are listed in Table 10-8.26 The underlying mechanism is often a telogen effluvium.27 Headington has described five functional types of telogen effluvium based on changes occurring in different phases of the hair cycle.28 These consist of immediate anagen release (postfebrile), delayed anagen release (postpartum), short anagen cycle (inability to grow long hair), immediate telogen release (minoxidil), and delayed telogen release (molting). Basically, an abnormal number of hairs go into the telogen phase and only fall out 1 to 3 months later when new anagen hairs grow in.29 Classic acute telogen effluvium occurs after childbirth, severe illness, operations, stress, crash diets, or various drugs29 (Table 10-9). In chronic telogen effluvium, the trigger factor may be obscure, and any one of Headington’s functional types can be implicated, although short anagen cycle may be the most common. Anagen effluvium is a severe condition, often resulting from antimitotic drugs, in which large amounts of hair fall out within a few weeks of impaired DNA synthesis.30,31

Table 10-4 Horizontal Sections of 4-mm Scalp Biopsies Mean Follicular Counts in Differential Diagnosis of Alopecia: 1987-2007 DIAGNOSIS Controls Male pattern alopecia Female pattern alopecia Diffuse alopecia Alopecia areata Trichotillomania

216

NO. OF PATIENTS

AGE, YEARS

SEX (M:F)

TERMINAL (T) HAIRS

+

VELLUS (V) HAIRS

=

TOTAL HAIRS

T:V RATIO

ANAG: TELO %

22 305

43 34.4

1.4:1 M

35 20.9

+ +

5 14.7

= =

40 35.6

7:1 1.4:1

93.5:6.5 80:20

1338

46.2

F

21.6

+

11.1

=

32.6

1.9:1

86:14

1061 834 85

48.4 31.9 20.2

1:36 1:2 1:5.5

32.8 16.4 27.5

+ + +

4.4 12.9 6.6

= = =

37.2 29.3 34.1

7.4:1 1.3:1 4.2:1

89:11 56:44 65:35

Table 10-5 Advantages and Disadvantages of Transverse Sections

SOURCE: Adapted with permission from Templeton SF, Santa Cruz DJ, Solomon AR. Alopecia: histologic diagnosis by transverse section. Semin Diagn Pathol. 1996;13:2-18.

women, and usually does not cause severe baldness (see Fig. 10-3 and Table 10-10).

CLINICAL FEATURES In an acute phase of diffuse alopecia, hair pull tests are positive from all over the scalp (Table 10-10). In telogen effluvium, the extracted hairs show depigmented club roots and no root sheaths.29 In anagen effluvium, extracted hairs show a proximal taper with a fracture30; when the antimitotic influence is removed, hairs grow back promptly with a distal taper due to reversal of the pencilpointing process. Classic acute telogen effluvium affecting any age group has an abrupt onset and a short course of 3 to 6 months.29 Chronic telogen effluvium can last from 6 months to 7 years or more, with an abrupt or gradual onset and a cyclic course.32,33 It is often idiopathic,34 usually affects middle-aged

HISTOPATHOLOGIC FEATURES The histopathology of telogen effluvium is often similar to that seen in a normal scalp, except for the definite increase in telogen hairs seen during an active phase of hair loss35,36 (see Table 10-10). In vertical sections, many terminal hairs are present, few vellus hairs are seen, and follicular stelae are uncommon (Fig. 10-4). Follicular counts in horizontal sections of a 4-mm punch biopsy of the crown in chronic telogen effluvium average 32.8 terminal hairs + 4.4 vellus hairs = 37.2 total hairs, with a terminal-vellus ratio of 7:1 and a ratio of 89% anagen to 11%

DIFFERENTIAL DIAGNOSIS Diffuse alopecia usually can be diagnosed on clinical grounds but sometimes is confused with female androgenetic alopecia, diffuse alopecia areata,38 or congenital hypotrichosis, and biopsies may be necessary. There is no reduction in terminal hair numbers in diffuse alopecia, but there is a definite reduction in terminal hairs, with increased vellus hairs, in androgenetic alopecia, diffuse alopecia areata, and congenital hypotrichosis.

CHAPTER 10 ■ DISORDERS OF CUTANEOUS APPENDAGES

Advantages More follicles per section Rapid, accurate assessment of follicle density, the number of terminal follicles, and the preservation or loss of normal follicular unit morphology Easy assessment of follicle and shaft diameters Most accurate anagen-telogen ratios Disadvantages Must be familiar with scalp microanatomy in a different plane of sectioning Gross tissue specimen processing requires a different protocol The epidermis and dermal-epidermal interface is more easily evaluated in vertical sections Limitations of Both Methods The 4- to 6-mm scalp biopsy is a small sample compared with the total scalp area Biopsy site selection is critical The specificity of the histopathologic diagnosis decreases with the duration and extent of follicular destruction

telogen37 (see Table 10-4). These findings are the same as in normal controls, except that the 11% telogen hairs exceeds the 6.5% telogen hairs found in normal individuals (Figs. 10-5 and 10-6). The telogen count can increase to 20% to 30% or higher in active phases of telogen effluvium. Inflammatory changes are similar to controls in that mild perifollicular lymphohistiocytic infiltration occurs in one-third and moderate infiltration in 10% of cases of telogen effluvium. Normal numbers of follicular stelae are found.32 The diffuse alopecia caused by hypothyroidism, other systemic diseases, and many drugs and chemicals results from a telogen effluvium and shows a similar histology. Anagen effluvium involves 90% of scalp hairs in anagen.37 The diagnosis is usually simple, since there is a clear history of the drug or influence that interferes with DNA synthesis. Examination of plucked hairs is diagnostic, so biopsies are usually not indicated, except in cases of persistent hairloss following chemotherapy. The proximal tapering of a plucked hair in anagen effluvium is shown in Fig. 10-7.

Table 10-6 Histopathologic Features of Nonscarring Alopecias

Congenital hypotrichosis Congenital triangular alopecia Androgenetic alopecia Alopecia areata Diffuse alopecia (telogen effluvium) Trichotillomania Traction alopecia

FOLLICULAR LOSS

TERMINALVELLUS RATIO

ANAGEN-TELOGEN RATIO

PERIFOLLICULAR LYMPHOID INFILTRATES

PERIBULBAR LYMPHOID INFILTRATES

TRICHOMALACIA

Moderate

NA

Large decrease

Usually absent

Absent

Absent

Moderate

Decreased

Large decrease

Usually absent

Absent

Absent

Mild

Decreased

Slight decrease

70%a

Absent

Absent

Mild None

Decreased Normal

Moderate decrease Slight decrease

Usually absent 40%a

Present Absent

Absent Absent

None None

Normal Normal

Large decrease Large decrease

Usually absent Usually absent

Absent Absent

Often present Often absent

NA = Not applicable. a Percentage of patients with mild to moderate infiltrates; 40% of normal controls have mild to moderate infiltrates.

217

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Table 10-7 Androgenetic Alopecia

218

Clinical Features Progressive miniaturization of hairs on crown, with relative sparing of hair on back and sides of scalp Male: onset from puberty to 50 years; marked bitemporal recession with balding of vertex Female: onset often one decade later than males; intact frontal hairline with diffuse thinning over crown Histopathologic Features Increased miniaturized, vellus hairs Increased follicular stelae Decreased terminal hairs Increased telogen hairs Mild to moderate perifollicular lymphohistiocytic inflammation in 70% of cases Intact sebaceous glands Differential Diagnosis Diffuse alopecia, especially telogen effluvium Diffuse alopecia areata Diffuse trichotillomania

Peribulbar lymphocytes often are present in alopecia areata.

Alopecia Areata Alopecia areata presents with patchy hair loss.39,40 It is not uncommon and may affect 1.7% of Americans by age 50. The etiology of alopecia areata is unknown, and many believe it to be an autoimmune disease. Helper T cells are consistently found in the predominately lymphocytic infiltrate around affected hair bulbs. A family history is present in 20% of cases. Recent studies have shown the importance of the HLA class II antigen DQ3, DR4, and DR11 genes in susceptibility to alopecia areata and of DRW52A in resistance to the condition.41 Longstanding alopecia totalis or universalis patients have unique associations with HLA antigens DR4, DR11, and DQ7.42 Trigger factors include seasonal variation, emotional stress, and infections. CLINICAL FEATURES The initial patch of alopecia areata on the scalp is often barely noticeable,43 but it may enlarge, and further patches may appear (Fig. 10-8A) (Table 10-11). Disease activity is indicated by “exclamation point” hairs at the spreading margin of lesions. Specific forms of alopecia areata include ophiasis, a persistent bandlike loss of hair; diffuse alopecia areata including an acute form

 FIGURE 10-2 Female androgenetic alopecia. Vertical section: Two terminal hairs and five follicular stelae (streamers or fibrous tracts) project down into the subcutaneous tissue; four vellus (vellus-like or miniaturized) hairs are seen in the upper dermis, two of which are connected to follicular stelae extending down to subcutaneous tissue. There is no inflammation and no fibrosis.

labeled alopecia areata incognito; and reticular alopecia areata with multiple patches of hair loss.39 In some cases the alopecia primarily involves beard, eyebrow, eyelash, and rarely, body hair. In the most severe cases all scalp (alopecia totalis) and body (alopecia universalis) hair is lost. Alopecia areata is more common in females, except in children. Its course is unpredictable. HISTOPATHOLOGIC FEATURES In the active stage of alopecia areata there is a characteristic cluster of mononuclear cells around follicular bulbs that has been likened to a swarm of bees39 (see Table 10-11 and Figs. 10-9 and 10-10). The infiltrate in alopecia areata consists primarily of CD4 lymphocytes and Langerhans cells, but some eosinophils and plasma cells may be seen.44,45 This lymphocytic infiltrate can invade the hair bulb and cause pigment incontinence.46 The infiltrate also can surround the adjacent suprabulbar portion of the hair shaft. Inflammatory cells invading bulbar epithelium can cause inter- and intracellular edema; nuclear pyknosis; apoptosis of matrix and outer sheath keratinocytes,

melanocytes, Langerhans cells, and dermal dendrocytes; and necrosis and microvesicle formation in the upper bulb above the dermal papilla.47 In the initial stages the disease usually involves terminal hairs, but later on miniaturized, velluslike hairs also are involved.48 As the disease progresses, follicular stelae infiltrated with lymphocytes (see Fig. 10-8) and containing melanin pigment are common. The inflammatory process involves anagen hairs that either become tapered and dystrophic, sometimes progressing to trichomalacia,25 or more commonly are projected through catagen into premature telogen (Fig. 10-10). The increased number of catagen hairs that results (Figs. 10-11 and 10-12) is equaled or exceeded only by the number of catagen hairs found in trichotillomania. Persistent disease results in miniaturization of hairs with decreased terminal hairs and increased vellus hairs and follicular stelae. The average follicular count found in horizontal sections of a 4-mm punch biopsy consists of 16.4 terminal hairs + 12.9 vellus hairs = 29.3 total hairs, a terminal-vellus ratio of 1.3:1, and 56% of terminal hairs in anagen and 44% in telogen (see Table 10-4). The reduction

and loose anagen syndrome and in familial focal alopecia, in which a marked increase of telogen germinal units with no scarring indicates telogen arrest; terminal hairs are reduced in congenital triangular alopecia but not in loose anagen syndrome. Plasma cells may be sparse or plentiful in the diffuse inflammation of secondary syphilis. Cicatricial alopecia is characterized by permanent destruction of hair follicles with replacement by fibrosis. Follicles are undamaged in tick-bite alopecia, which is a localized telogen effluvium caused by an anticoagulant in tick saliva.

 FIGURE 10-3 Male androgenetic alopecia. Horizontal section, papillary dermis: Relatively few terminal hairs and many vellus hairs are visible. A mild lymphohistiocytic infiltrate is present around a few follicular infundibula, and no fibrosis is seen.

in total hairs and the increase in vellus and telogen hairs contrast with normal controls.49 Contrary to general belief, there is a definite follicular dropout with fibrosis in about 10% of patients with a long history of attacks of alopecia areata.9 Peribulbar lymphocytic infiltration may not be prominent between acute attacks. In such cases, the reduced anagen-telogen and terminal-vellus ratios and the possible presence of catagen hairs may be useful indicators of alopecia areata.9 Melanin incontinence, trichomalacia, and foreign-body tissue reaction may be further diagnostic pointers.39 It is surprising, however, that in some chronic and apparently inactive cases of alopecia areata, perifollicular mononuclear cell infiltrates are still found, often around miniaturized hairs.25

DIFFERENTIAL DIAGNOSIS Causes of patchy alopecia that may be confused with alopecia areata include tinea capitis, trichotillomania, traction alopecia, pressure alopecia, congenital triangular alopecia, loose anagen syndrome, familial focal alopecia,50 secondary syphilis,25 tick-bite alopecia, and scarring alopecia such as aplasia cutis and pseudopelade. These usually can be distinguished by the history and clinical appearance, but biopsies may be necessary. Tinea capitis shows chronic folliculitis, often granulomatous, with intrafollicular neutrophils; fungal spores and hyphae may still be present. Inflammation and miniaturized hairs are lacking in trichotillomania and other forms of traumatic alopecia, but catagen hairs occur. Inflammation is absent in congenital triangular alopecia

Table 10-8 Causes of Diffuse Alopecia Classic acute telogen effluvium Chronic telogen effluvium Anagen effluvium Drugs Other chemicals Thyroid disorders Iron deficiency

Nutritional causes Malabsorption Renal failure Hepatic failure Systemic disease Miscellaneous causes Idiopathic

SOURCE: Data from Simpson NB: Diffuse alopecia: endocrine, metabolic, and chemical influences on the follicular cycle. In: Rook A, Dawber R, eds: Diseases of the Hair and Scalp. 2nd ed. Oxford: Blackwell Scientific; 1991: Chap 5, 136-166.

Trichotillomania is an abnormal compulsion to pull out hair. It affects more children than adults and after age 6 years is more common in females. Two polar forms of trichotillomania occur: The juvenile type peaks between 2 and 6 years of age, and the adult type peaks between 11 and 17 years of age.51 In children, the habit may develop subconsciously and replace thumb sucking or represent an effort to gain attention. Mental retardation or severe psychological disturbances are more common in adults. CLINICAL FEATURES Trichotillomania presents with one or more patches of hair thinning52 (Table 10-12). The patches are characterized by an irregular stubble due to hair breakage at different times.53 In severe patches, only newly growing anagen hairs remain.54 The underlying scalp is usually normal. Trichotillomania can involve eyebrows and lashes. The onset is often sudden, and the course is fluctuating and prolonged. HISTOPATHOLOGIC FEATURES Normal numbers of hair follicles are present (Fig. 10-13), although some may be distorted by hair shaft avulsion and show perifollicular shearing and hemorrhages (see Table 10-12). Follicular plugging and pigment casts are common, but true trichomalacia, or softened, twisted hair, is less frequent. Hair plucking induces telogen via catagen, accounting for the high catagen and telogen counts seen in trichotillomania55 (Figs. 10-14 and 10-15). Miniaturized hairs are not typically seen, although true vellus hairs persist, because they are too small to grasp, thereby reducing the terminalvellus ratio.56 Inflammatory changes are not a feature of trichotillomania, unless excoriations are complicated by secondary bacterial infection with infiltration of neutrophils, lymphocytes, and

CHAPTER 10 ■ DISORDERS OF CUTANEOUS APPENDAGES

Trichotillomania

219

PART I ■ INFLAMMATORY REACTIONS IN THE SKIN

Table 10-9 Drugs Causing Diffuse Alopecia Allopurinol Amoxapine ACE inhibitorsa,TE AnticonvulsantsTE AspirinTE Beta blockersTE Boric acidAE Carbamazepine Clomiphene DanazolTE Ethionamide GoldAE LevodopaTE Methyldopa NitrofurantoinTE Para amino salicylic acid Probenecid RetinolTE Terfenadine

Alpha receptor blockers AmphetamineTE Anticancer drugsAE Antithyroid drugsTE Azathioprine Birth control drugsTE BromocriptineTE Cholesterol reducersTE Clonidine Estrogen Fluoxetine Haloperidol LithiumTE MethysergideTE NSAIDsb,TE Penicillamine Pyridostigimine bromidetTE SalicylatesTE Thallium saltsAE

a

Angiotensin-converting enzyme inhibitors. Nonsteroidal anti-inflammatory drugs. AE Cause of anagen effluvium. TE Cause of telogen effluvium. b

histiocytes.25 The average follicular count in horizontal sections of a 4-mm punch biopsy of trichotillomania consists of 27.5 terminal hairs + 6.6 vellus hairs = 34.1 total hairs, with a terminal-vellus ratio of 4.2:1, just within normal limits; however, a ratio of 65% anagen to 35%

Table 10-10 Diffuse Alopecia

Clinical Features Diffuse shedding, all over scalp, often abrupt Classic acute telogen effluvium: moderate hair thinning, within months of childbirth, severe illness, accident or operation, crash diets, drugs, etc. Chronic telogen effluvium: mild-tomoderate hair thinning, often idiopathic Anagen effluvium: severe hair thinning within weeks of cytostatic drugs, etc. Histopathologic Features Normal numbers of terminal hairs Normal numbers of vellus hairs Normal numbers of follicular stelae Increased numbers of telogen hairs in active phases of telogen effluvium Differential Diagnosis Female pattern androgenetic alopecia Diffuse alopecia areata Congenital hypotrichosis

220

Amiodarone Androgens AnticoagulantsTE ArsenicalsTE Azulfidine BismuthAE Calcium channel blockersTE CimetidineTE ColchicineAE Ethambutol Gentamycin Histamine 2 blockers Mercury MethyraponeTE Omerprazole Prazosin RetinoidsTE Sulfasalazine Tricyclic antidepressants

telogen and an average of 5 catagen hairs are strikingly abnormal9 (see Table 10-4). Catagen hairs are rare in normal controls. DIFFERENTIAL DIAGNOSIS Other causes of patchy alopecia must be excluded. Trichotillomania is often misdiagnosed as tinea capitis, alopecia areata, or even loose anagen syndrome. Other conditions to be excluded include other forms of traction alopecia, pressure alopecia, secondary syphilis, congenital triangular alopecia, tick-bite alopecia, and subtle forms of scarring alopecia such as pseudopelade and congenital aplasia cutis. The history and appearance are often diagnostic, but in some cases scalp biopsies are necessary. The lack of inflammation, fungal elements, and scarring and the presence of terminal hairs, catagen hairs, and trichomalacia exclude most other conditions (see discussion of differential diagnosis of alopecia areata). Differentiation from other forms of traction alopecia may depend on clinical history.

results from hair weaves, other hair additions glued or clipped in place,57,58 excessive brushing, backcombing, braiding, or tight ponytails (see Figs. 10-4 and 10-5). Prolonged pressure on the scalp from prolonged immobility can cause alopecia. CLINICAL FEATURES Bandlike traction alopecia involving frontal, temporal, and occipital scalp hair margins is usually due to ponytails with the maximum pull on peripheral hairs (Table 10-13). Traction alopecia from hair weaves and other hair additions occurs at the point of attachment.59 Traction alopecia can occur between tight braids and in areas where hair is wound too tightly on rollers.60 Sustained traction usually induces telogen in affected hairs, which eventually fall out. Pressure alopecia can occur in the newborn and in patients of any age who are severely injured, very ill, or anesthetized or who have sustained blunt trauma to the scalp. It usually results from prolonged immobilization of the patient on a hard operating table, bed, or floor.61 The soft-tissue compression over underlying skull causes ischemia.62 A patch of alopecia develops over the compressed scalp within 2 to 4 weeks but regrows within a few months, unless permanent scarring has resulted from necrosis and ulceration.60

Traction and Pressure Alopecia

HISTOPATHOLOGIC FEATURES The histopathology of traction alopecia is similar to trichotillomania. Due to the sustained traction, many catagen and telogen hairs are seen, which reduces the anagen-telogen ratio (see Table 10-13 and Figs. 10-16 and 10-17). There is usually a lack of inflammation. Total follicular counts on horizontal section are identical to normal controls. Pigment casts and trichomalacia are rare25 (Fig. 10-18). In chronic traction alopecia affecting hair margins, dense fibrosis may be present around upper and lower follicles. In the early stages of pressure alopecia, vascular thrombosis and tissue necrosis, with a mild lymphohistiocytic infiltrate, may be present. Most of the terminal hairs are then projected into a catagen or telogen phase. Fat necrosis with foamy macrophages and varied degrees of dermal fibrosis may eventuate.18

There are many other causes of traction alopecia besides trichotillomania.55 Acute traction alopecia results from sudden, painful avulsion in accidental or intentional hair pulling or domestic or industrial accidents. Chronic traction alopecia is more common and insidious and

DIFFERENTIAL DIAGNOSIS The diagnosis of an acute traction or avulsion alopecia is usually easy from the history and physical appearance. Marginal alopecia must be distinguished from ophiasis and tinea capitis and frontal fibrosing alopecia (FFA). Other forms of patchy hair loss

Miscellaneous Causes of Nonscarring Alopecia

 FIGURE 10-4 Diffuse alopecia, chronic telogen effluvium. Vertical section: Five terminal hairs and no follicular stelae are seen projecting into the subcutaneous tissue. A mild lymphohistiocytic infiltrate is present around a few upper follicles. The epidermis is normal.

 FIGURE 10-5 Diffuse alopecia, chronic telogen effluvium. Horizontal section, reticular dermis: Many terminal hairs are seen with relatively few vellus hairs; one telogen hair and four telogen germinal units are present. There is no inflammation of note.

Rarer causes of nonscarring alopecia include alopecia due to infections and infestations, alopecia due to hair shaft abnormalities, alopecia due to hereditary and congenital conditions such as ectodermal dysplasias, and alopecia due to various dermatoses involving the scalp that are sometimes accompanied by hair loss. Some of these conditions are discussed elsewhere, and others are beyond the scope of this chapter. CLINICAL FEATURES A common cause of patchy alopecia in small children is tinea capitis.63 This produces circumscribed areas of hair loss with inflammation, scaling, crusting, and broken-off hairs. Black dots from hairs broken off flush with the skin indicate endothrix ringworm due to Trichophyton tonsurans in the United States. Whitish gray hairs broken off a few millimeters away from the scalp and fluorescent to Wood light are caused by an ectothrix infection such as Microsporum canis or M audouini. Most cases of tinea capitis occur in children, peaking at 5 to 6 years of age, but endothrix ringworm caused by T tonsurans and favus caused by T schoenleinii can occur in adults. The diagnosis usually can be confirmed by a potassium hydroxide preparation or by culture, and a biopsy is rarely necessary. Bacterial infections such as syphilis and viral infections such as herpes zoster, which are capable of causing alopecia, will not be discussed here.63,64 Broken-off hairs can result from hair shaft abnormalities. Only the histopathology of loose anagen syndrome will be discussed in this chapter. The reader is referred to other source material for a discussion of hair shaft anomalies.65-68

CHAPTER 10 ■ DISORDERS OF CUTANEOUS APPENDAGES

such as loose anagen syndrome, secondary syphilis, alopecia from chemical trauma, congenital triangular alopecia, tick-bite alopecia, and subtle forms of scarring such as pseudopelade and congenital aplasia cutis also may have to be excluded (see Table 10-13 and Figs. 10-16, 10-17, and 10-18). This usually can be done on clinical grounds, but in some cases scalp biopsies are helpful. The frequent presence of scarring with increased catagen and telogen hairs in chronic cases and the lack of inflammation and fungal elements should exclude alopecia areata and tinea capitis. For discussion of other causes of patchy hair loss, see discussion of the differential diagnosis of alopecia areata.

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PART I ■ INFLAMMATORY REACTIONS IN THE SKIN

 FIGURE 10-6 Diffuse alopecia, chronic telogen effluvium. Horizontal section, reticular dermis: Two terminal hairs, one telogen germinal unit (left lower margin), and one telogen hair (right lower margin) are visible.

 FIGURE 10-7 Anagen effluvium. The broken-off hair shaft shows proximal tapering adjacent to the fracture.

A

222

There are many different forms of congenital or inherited hair loss.69,70 These include congenital hypotrichosis with or without associated defects, congenital triangular alopecia,71 and a large variety of ectodermal dysplasias affecting the hair, teeth, nails, and sweat glands. There are also major congenital hypotrichoses that occur in hereditary syndromes such as the hereditary hypotrichosis of Marie Unna,72 Hallerman-Streiff syndrome, and atrichia with papular lesions. Major congenital hypotrichosis also occurs in premature aging syndromes and with skeletal abnormalities. Minor hypotrichosis can occur in other hereditary syndromes and in chromosomal abnormalities. In general, the diseases causing congenital or inherited hypotrichosis are associated with hair loss due to a reduction in hair follicles that may be patchy or patterned or generalized. Various dermatoses that do not directly cause alopecia may lead to pruritus, erythema, scaling, crusting, and excoriations. A secondary alopecia may result that usually is reversed by treating the underlying cause. Such dermatoses include seborrheic dermatitis, psoriasis, tinea amiantacea, and prurigo and lichen simplex.63,25 HISTOPATHOLOGIC FEATURES If the alopecia is produced by an infection, the histopathology should reflect the pathology of that particular infection. Sometimes unsuspected fungal infections are seen on histopathologic examination and confirmed with a PAS stain. Secondary syphilis can be difficult to diagnose.64,25 Hair shaft abnormalities usually are diagnosed by microscopic examination

B

 FIGURE 10-8 Alopecia areata. (A) Confluent well-demarcated patch of alopecia. (B) Vertical section: Four hair bulbs are seen surrounded by lymphocytes, with follicular stelae beneath them, also infiltrated by lymphocytes. A lymphocytic infiltration is also present around lower hair follicles.

Table 10-11 Alopecia Areata

of the hair shaft. In loose anagen syndrome, the hair shafts may show absent inner and outer root sheaths, a ruffled cuticle, and longitudinal grooving73-75; in biopsies, loss of adhesion

 FIGURE 10-10 Alopecia areata. Horizontal section, reticular dermis: One catagen hair (left lateral margin), one follicular stela infiltrated by lymphocytes (right lateral margin), and two telogen germinal units are visible.

between follicular sheaths may be seen only with transmission electron microscopy. However, splits between follicular sheaths sometimes are seen with light microscopy and may represent real changes due to loose anagen syndrome rather than to fixation and sectioning artifacts (Fig. 10-19); inflammation is absent, but premature keratinization of the inner root sheath may be seen.76

Congenital triangular alopecia is distinguished by a normal follicular count with a reduction in the total number of terminal anagen hairs, although many vellus hairs are seen.25 However, a frequent feature of these cases is the presence of many telogen hairs. This arrested state of hair cycling also appears to be common in various types of congenital hypotrichoses (Figs. 10-20 and 10-21) and ectodermal dysplasia (Fig. 10-22). Associated dermatoses, such as seborrheic dermatitis, psoriasis, or lichen simplex, may be diagnosed by their specific pathologic appearance.

CHAPTER 10 ■ DISORDERS OF CUTANEOUS APPENDAGES

Clinical Features Periodic attacks of circumscribed patches of hair loss Unpredictable course: patches may regrow or progress to confluent patches, alopecia totalis or alopecia universalis Histopathologic Features Peribulbar and intrabulbar mononuclear cell infiltrate Degenerative changes in hair matrix Decreased numbers of terminal anagen hairs Increased numbers of terminal catagen and telogen hairs Increased numbers of follicular stelae Increased numbers of miniaturized vellus hairs Pigment incontinence of hair bulbs and follicular stelae Differential Diagnosis Other causes of patchy alopecia include tinea capitis, trichotillomania, traction and pressure alopecia, loose anagen syndrome, secondary syphilis, congenital triangular alopecia, familial focal alopecia, aplasia cutis, pseudopelade, tick bite alopecia, etc.

DIFFERENTIAL DIAGNOSIS The differential diagnosis of infections, congenital and inherited causes of alopecia, hair shaft abnormalities, and miscellaneous dermatoses includes most of the conditions discussed in this chapter. The diagnosis usually can be made on clinical grounds or by examination of hair shafts, but scalp biopsies may be necessary to clarify diagnoses.

SCARRING (CICATRICIAL) ALOPECIA

 FIGURE 10-9 Alopecia areata. Horizontal section, reticular dermis: Two hair bulbs surrounded by lymphocytes and three follicular stelae infiltrated by lymphocytes are visible.

Clinically, scarring, or cicatricial, alopecia is characterized by loss of follicular orifices. Distinguishing characteristics that aid in diagnosis include the pattern of alopecia, pigmentary alteration, follicular prominence, keratinous plugs, follicular pustules, and any other associated

223

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Table 10-12 Trichotillomania

Clinical Features Recurrent attacks of patchy hair loss— chronic course Affected hairs broken off at different lengths Underlying scalp usually normal Histopathologic Features Normal follicular counts with normal terminal:vellus ratio Marked increase in catagen and telogen hairs Follicular damage may be present Follicles may contain pigmented casts Trichomalacia can occur Inflammatory changes usually absent Differential Diagnosis Other causes of patchy alopecia include alopecia areata, tinea capitis, loose anagen syndrome, traction and pressure alopecia, secondary syphilis, tick bite alopecia, aplasia cutis, congenital triangular alopecia, familial focal alopecia, pseudopelade, etc.  FIGURE 10-11 Alopecia areata. Vertical section: Two catagen hairs are present showing a thickened vitreous membrane and central apoptotic cells.

nonscalp cutaneous findings. 6,77-83 Histologic evaluation of progressive, “active” alopecia is often very helpful for diagnosis of specific scarring alopecias. However, biopsies from patients with

inactive, “burned out” scarring alopecia infrequently yield a specific diagnosis, but these specimens still may be useful in assessment of the extent of follicular destruction and regrowth potential.

As noted earlier, the traditional separation of alopecia into either scarring or nonscarring is not very helpful from a patient’s perspective because he or she is concerned with only one issue—whether or not the hair loss is potentially reversible or permanent.84,85 If a patch of alopecia areata never regrows, the patient will not be comforted by the fact that he or she has a nonscarring alopecia. Nevertheless, histopathologic differentiation of scarring from nonscarring alopecia remains of value because the former usually will progress to permanent hair loss unless therapeutic intervention is successful, whereas the latter is less predictable.

Scarring Alopecia Is Either Primary or Secondary

224

 FIGURE 10-12 Alopecia areata. Horizontal section, reticular dermis: Several hair bulbs surrounded by lymphocytes, a large number of catagen hairs surrounded by thickened vitreous membranes and lymphocytes, several telogen germinal units, and some follicular stelae infiltrated by lymphocytes are visible.

Many classification systems of scarring alopecia have been proposed according to clinical, histologic, and pathogenic factors. We endorse the concept of primary and secondary scarring alopecia based on the pattern of follicular destruction.6,80,81 Primary scarring alopecia occurs as the result of preferential destruction of follicular epithelium and/or its associated adventitial dermis, with relative sparing of the intervening reticular dermis. In primary scarring alopecia, the hair follicle is the primary target of destruction. The interfollicular epidermis may be affected as in lupus erythematosus and lichen planopilaris

impinge on and eventually destroy the follicle. Follicular destruction and subsequent permanent scarring alopecia are not the primary pathologic process, but they occur secondarily due to the close anatomic location of follicles to the primary pathologic event, eg, dermal sclerosis in coup de sabre linear morphea.

LYMPHOCYTE-ASSOCIATED PRIMARY SCARRING ALOPECIA

 FIGURE 10-13 Trichotillomania. Vertical section: One terminal hair, one telogen hair, and two follicular stelae are seen projecting into the subcutaneous tissue. Another telogen hair is seen in the middle dermis; one follicular infundibulum shows trichomalacia.

(LPP), but the epidermal changes in and of themselves do not result in follicular destruction. Primary scarring alopecias are a diverse group of diseases with differing or uncertain etiologies. The unifying feature of these varied disorders is destruction of sufficient follicles to yield permanent alopecia. Microscopically, primary

scarring alopecia can be further categorized into two groups according to the predominant inflammatory cell type: (1) lymphocyte-associated scarring alopecia and (2) neutrophil-associated (pustulofollicular) scarring alopecia.6,80,82 Secondary scarring alopecia occurs as the result of nonfollicular events that

 FIGURE 10-14 Trichotillomania. Horizontal section, reticular dermis: One hair bulb, some terminal hairs, many catagen hairs, a telogen hair, and a telogen germinal unit are visible.

Discoid Lupus Erythematosus CLINICAL FEATURES Scalp involvement in DLE is common, and 30% to 50% of patients develop scarring alopecia. DLE typically occurs in young to middle-aged females (2:1 female predominance), and lesions occur on sun-exposed sites, especially the face, scalp, and conchal bowl of the ear. Early lesions are scaly erythematous papules, whereas late lesions are sclerotic plaques with follicular plugging, telangiectasia, and pigmentary alteration.86 Patients with DLE uncommonly progress to systemic lupus erythematosus.87 Diffuse, nonscarring alopecia may occur in patients with systemic lupus erythematosus but is best categorized as inflammatory telogen effluvium. HISTOPATHOLOGIC FEATURES Vacuolar interface alteration at the level of the epidermis and hair follicle is the primary feature of DLE88,89 (see Table 10-14). Epidermal and follicular dyskeratosis are also present but less so than in LPP. The epidermis is often atrophic with overlying orthokeratotic hyperkeratosis, but the hypertrophic variant of DLE is characterized by marked acanthosis and hyperkeratosis. Focal parakeratosis may be seen in some lesions. Laminated keratin fills dilated follicular ostia corresponding to the clinical follicular plugs. The basement membrane zone of the epidermis and/or follicle may be thickened with a corrugated appearance. This finding is best seen with the PAS stain and ultrastructurally represents a multilayered basal lamina. Superficial and deep, perivascular and periadnexal lymphocytic infiltrates of

CHAPTER 10 ■ DISORDERS OF CUTANEOUS APPENDAGES

Discoid lupus erythematosus (DLE), lichen planopilaris, central centrifugal scarring alopecia/follicular degeneration syndrome (CCSA/FDS), and alopecia mucinosa (AM) are lymphocyte-associated scarring alopecias that may be distinguished by the presence and type of interface alteration, pattern and density of lymphocytic infiltrates, and intrafollicular mucin deposits (Table 10-14).

225

as in LPP.88 The superficial and deep infiltrates are both perivascular and periadnexal in DLE as opposed to tightly perifollicular in LPP. FDS lacks interface alteration around follicles. The presence of increased dermal mucin is an important finding that points toward DLE rather than LPP or FDS.

PART I ■ INFLAMMATORY REACTIONS IN THE SKIN

Lichen Planopilaris Including Frontal Fibrosing Alopecia

226

 FIGURE 10-15 Trichotillomania. Horizontal section, papillary dermis: Terminal hairs, telogen hairs, telogen germinal units, and vellus hairs are visible. Several follicular infundibula show pigment casts or trichomalacia. There is no inflammation.

Table 10-13 Traction and Pressure Alopecia

Clinical Features Acute traction alopecia from avulsion: easily diagnosable from history and clinical findings Obvious linear alopecia at scalp hair margins, caused by chronic traction from ponytails Chronic traction alopecia under points of attachment of hair weaves or other hair additions more subtle Pressure alopecia: localized to the area of pressure and usually transient Histopathologic Features Normal follicular counts with normal terminal:vellus ratio Marked increase in catagen and telogen hairs Occasional pigmented casts; trichomalacia uncommon Inflammatory changes usually absent In late cases of marginal alopecia, terminal hairs decreased due to follicular fibrosis Catagen and telogen hairs increased from pressure alopecia Differential Diagnosis Common causes of patchy alopecia to be differentiated from traumatic alopecia include trichotillomania, alopecia areata—especially ophiasis, tinea capitis, loose anagen syndrome, and other causes of localized alopecia

variable density are present (Figs. 10-23 and 10-24). Occasional admixed plasma cells can be found. Lymphocyte exocytosis into the epidermis and follicular epithelium may be present but usually is not prominent. Pigment incontinence with melanophagocytosis is seen commonly in the papillary dermis. Increased dermal mucin (hyaluronic acid) is present both superficially and deep and is best detected in colloidal iron—or alcian blue—stained sections. Dermal sclerosis and complete follicular dropout occurs in advanced lesions and is similar to end-stage microscopic findings of other primary scarring alopecias (see section on CCSA below). Biopsies of well-established clinical lesions for immunofluorescence usually show granular immunoglobulin and complement at the dermal-epidermal junction. IgM deposits are more common but less specific for DLE than IgG deposits.90,91 The incidence of lesional immunoglobulin deposition in DLE is about 75%, with older, sun-exposed lesions more likely to be positive. DIFFERENTIAL DIAGNOSIS LPP and FDS are the primary differential diagnostic considerations, as described below (see Table 10-14). Both are also lymphocyteassociated scarring alopecias, and endstage biopsies from all these entities can be identical. However, in “active” clinical lesions, interface alteration in DLE is primarily vacuolar rather than lichenoid,

CLINICAL FEATURES LPP is an uncommon scarring alopecia. First described in 1895 by Pringle, LPP presents as acuminate, spinous, and hyperkeratotic follicular papules with perifollicular erythema (see Table 10-14). LPP is more common in women, and onset ranges from young adulthood to elderly age. As follicles are destroyed, smooth, atrophic, polygonalshaped patches of complete alopecia result. Typical lichen planus papules and plaques are present elsewhere on the body in 50% to 70% of patients. The clinical triad of typical lichen planus, spinous or accuminate lesions, and alopecia of the scalp or other nonglabrous skin is known as the Graham-Little syndrome. In 1994, Kossard described a distinctive form of cicatricial alopecia that he termed postmenopausal frontal fibrosing alopecia.92,93 The patients presented with a bandlike progressive zone of alopecia that ultimately spanned the entire frontal hairline from temple to temple. The frontal alopecia is usually accompanied by alopecia of the eyebrows and perifollicular erythema.94 FFA has subsequently been reported to also occur in premenopausal women and men.95,96 FFA may develop in association with other findings of the Graham-Little syndrome (follicular papules and alopecia in sites remote from the scalp).97 HISTOPATHOLOGIC FEATURES Lichenoid interface alteration of follicular epithelium is the primary microscopic feature of LPP (see Table 10-14).98 Although not always completely distinct from vacuolar interface alteration, lichenoid interface alteration of the follicle is characterized by disruption of the epithelial-adventitial dermal junction with angular, glassy, basal keratinocytes and a tight perifollicular lymphocytic infiltrate that is largely confined to the follicular adventitial dermis (Figs. 10-25 and 10-26). Exocytosis into the follicular epithelium and dyskeratosis are more prominent in LPP than DLE. Artifactual clefting similar to that seen at the dermal-epidermal junction in lichen planus (Max Joseph space) also can occur around hair follicles in LPP.88,89 In a

 FIGURE 10-16 Traction alopecia. Vertical section: One terminal catagen hair and one terminal telogen hair are seen. A mild lymphohistiocytic infiltrate is present around one follicular infundibulum.

minority of cases, lichenoid interface alteration typical of lichen planus may affect the intervening epidermis. Superficial and deep perivascular lymphocytic infiltrates and dermal mucin typical of DLE are lacking in LPP.

Complete follicular dropout with scattered unsheathed hair shafts surrounded by sparse histiocytic and granulomatous infiltrates occurs in late lesions. These end-stage features are not specific for LPP but may occur in all

 FIGURE 10-17 Traction alopecia. Horizontal section, reticular dermis: Three terminal hairs, three vellus hairs, and seven telogen germinal units are visible. There is no inflammation.

Central Centrifugal Scarring Alopecia/Follicular Degeneration Syndrome

CHAPTER 10 ■ DISORDERS OF CUTANEOUS APPENDAGES

scarring alopecias (see section on CCSA below). Lesional biopsy for direct immunofluorescence reveals globular IgM deposits on cytoid bodies and fibrin at the dermalepidermal junction and infundibularadventitial dermal junction.90 However these immunofluorescent findings are not specific for LPP and may be seen in other dermatoses with interface dermatitis. The histopathologic findings in FFA are reported to be similar if not identical to those of LPP.92,93 Abbas and coauthors reported a greater number of apoptotic (dyskeratotic) cells and less dense lymphocytic infiltrates in FFA along with complete sparring of the interfollicular epidermis, although these findings may be difficult to apply to individual cases.97

A century after it was coined, controversy still surrounds the term pseudopelade.6,79,80,82,83,88,99-104 Brocq first described this form of alopecia in 1885 as a clinically noninflammatory, progressive, idiopathic scarring alopecia.105 Since then, conflicting opinions have arisen as to whether pseudopelade of Brocq (PPOB) is a disease sui generis or the end-stage lesion of various types of scarring alopecia. Support for the concept of pseudopelade as a unique clinicopathologic entity appears to be continually dwindling, given the substantial overlap in the clinical and histopathologic features with other forms of scarring alopecia.80,99 The main argument for elimination of the term pseudopelade is that it has never been defined as a unique clinicopathologic entity. In other words, if defined clinically, there is no specific histopathology. If defined microscopically, there is no specific clinical presentation. To address the pseudopelade issue and the problem of overlap in the clinical and histopathologic findings of

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DIFFERENTIAL DIAGNOSIS DLE and FDS are the primary entities considered in the differential diagnosis (see Table 10-14). Please see the discussions of these topics for details. In practice, it can be very difficult to distinguish between vacuolar and lichenoid interface change at the level of infundibulum, so that the presence or absence of other findings is extremely helpful, for example, increased dermal mucin in DLE. Another common cause of confusion is artifactual clefting that simulates true interface change between remnants of the infundibulum and the encompassing lymphocytes in advanced lesions of FDS.

PART I ■ INFLAMMATORY REACTIONS IN THE SKIN 228

 FIGURE 10-18 Traction alopecia. Horizontal section, papillary dermis: Terminal and vellus hairs are seen. Several follicular infundibula are empty. No trichomalacia is present. There is a mild lymphohistiocytic infiltrate around a few follicular infundibula.

several types of scarring alopecia, Sperling and coauthors80 introduced the concept of central centrifugal scarring alopecia. As described, this term is meant to be a unifying concept with the goal of more rational clinical and microscopic diagnosis and eventually better therapeutic approaches.80 Central centrifugal scarring alopecia denotes alopecia with the following common

clinical features: (1) primary involvement of the crown and vertex, (2) relentless progression to broad areas of scalp devoid of follicular orifices, and (3) symmetric expansion with an active, inflammatory border. These clinical features are common to several subtypes of scarring alopecia, such as the follicular degeneration syndrome, follicullitis decalvans, and

 FIGURE 10-19 Loose anagen syndrome. Horizontal section, reticular dermis: In many follicles, clefts are present between the hair shaft and the internal root sheath, within the layers of the internal root sheath, between the internal root sheath and the external root sheath, or between the external root sheath and the surrounding connective tissue layer. One hair bulb shows a cleft between the matrix of the bulb and the surrounding connective tissue sheath.

tufted folliculitis. Other well-defined types of scarring alopecia, including LPP and DLE, also may present as CCSA. These subtypes of scarring alopecia usually can be defined by the clinical presentation and histopathologic features, but there may be significant overlap in both, especially in chronic lesions with extensive follicular destruction. The concept of CCSA is most useful in addressing the late-stage lesions because attempts to make a specific clinicopathologic diagnosis are frequently futile.106 It should be noted that pseudopelade was included in the construct for conceptual reasons, but the authors conclude that it could be abolished “if we had the courage to eliminate the redundant nomenclature of the past century.” We agree. In this section FDS will be discussed as a discrete entity within CCSA in order to highlight the earlier important diagnostic findings. CLINICAL FEATURES The FDS, described by Sperling and Sau, usually can be recognized both clinically and microscopically in early-stage lesions.107,108 The central scalp (crown) is by far the most frequent location. The alopecia progressively expands centrifugally to involve the entire crown and vertex, leaving a smooth skin surface devoid of follicular orifices. Variable perifollicular erythema and scale are present. Only isolated hair fibers remain in the alopecic regions. Polytrichia may be present. It is the most common form of scarring alopecia in African American women. It occurs occasionally in Caucasian women and African American men as well. HISTOPATHOLOGIC FEATURES The earliest findings are perifollicular lymphocytic infiltrates and perifollicular fibroplasia without interface alteration (see Table 10-14). The infiltrate is more dense in these early lesions and present from the level of the follicular infundibulum to the midsegment of the follicle.107,108 Sparse adjacent perivascular lymphocytic infiltrates also may be present. Follicular density is diminished, and follicular unit morphology is disrupted. Scattered residual fibrous tracks indicating the site of destroyed follicles are present (Fig. 10-27). In more advanced areas, the predominant finding is concentric lamellar fibroplasia and follicular epithelial atrophy (Fig. 10-28). Frequently, the follicular canal is eccentrically located, and premature disintegration of the inner root sheath is emphasized in FDS.107,108 Finally, the residual follicular epithelium

decalvans are indistinguishable from each other, forming the basis for the concept of CCSA.

Alopecia Mucinosa

ruptures, and a foreign-body giant cell reaction ensues. In end-stage FDS, only rare, viable though somewhat miniaturized follicles and numerous residual fibrous tracts are present (Fig. 10-29). Direct immunofluorescence usually is negative, but occasional, minimal, nonspecific IgM deposits may be seen around the follicular infundibulum.

DIFFERENTIAL DIAGNOSIS DLE, LPP, and end-stage folliculitis decalvans (FD) may be considered (see Table 10-14). The lack of interface dermatitis in FDS is the primary distinguishing microscopic feature from DLE and LPP. The neutrophil is the predominant inflammatory cell in active folliculitis decalvans. End-stage lesions of FDS, DLE, LPP, and folliculitis

 FIGURE 10-21 Congenital hypotrichosis. Horizontal section, middle dermis: One terminal hair, two telogen hairs, two telogen germinal units, and one vellus are visible.

HISTOPATHOLOGIC FEATURES Mucin (hyaluronic acid) deposition in hair follicle epithelium is the cardinal microscopic feature of AM and is termed follicular mucinosis (see Table 10-14). Follicular keratinocytes are stellate shaped and splayed apart by extracellular mucin.110,111 The mucin is deposited initially in the infundibulum but involves the entire follicle in advanced lesions with intrafollicular mucin-filled cystic spaces (Fig. 10-30). The mucin can be identified in H&E–stained sections but is best appreciated with colloidal iron or alcian blue stains. Variably dense perifollicular lymphocytic infiltrates with admixed eosinophils are present. Folliculotropism of lymphocytes can be seen in both lymphoma-associated and benign AM. Although it is difficult to distinguish the banal form from the lymphoma-associated form, lymphocytes surrounded by clear spaces, pronounced epidermotropism, cellular atypia, lymphocytes that line up along the basal layer, and confluent papillary dermal infiltrates are suspicious for coexisting cutaneous T-cell lymphoma.112 DIFFERENTIAL DIAGNOSIS Follicular mucinosis is considered by some to be a synonym of AM, but this term is best used as a microscopic description of intrafollicular mucin deposits and not the clinical pathologic entity AM.113 Focal, limited follicular mucinosis outside the setting of AM occurs and likely represents a reactive follicular process. Follicular spongiosis in follicular eczema and seborrheic dermatitis may mimic early AM, and mucin stains help to differentiate follicular mucin from follicular

CHAPTER 10 ■ DISORDERS OF CUTANEOUS APPENDAGES

 FIGURE 10-20 Congenital hypotrichosis. Vertical section: Two terminal hairs and four follicular stelae are seen in the subcutaneous tissue; one telogen hair is seen in the dermis. There is no inflammation.

CLINICAL FEATURES Alopecia mucinosa most commonly involves the head and neck, but involvement of the trunk and extremities may occur (see Table 10-14). Lesions are erythematous, infiltrated plaques devoid of hair. When AM affects children and young adults, it is usually self-limited without permanent alopecia; however, follicular destruction by extensive mucin deposits occasionally can lead to permanent alopecia in some patients.109 An associated lymphoproliferative disorder, most commonly cutaneous T-cell lymphoma (CTCL), occurs in approximately 30% of cases, especially older patients with numerous lesions on the trunk and extremities.110,111

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surrounds the sinus tracts, and the follicles are destroyed by the fibroinflammatory process. The infiltrate in older, more scarred lesions is primarily lymphoplasmacytic and histiocytic with few neutrophils. DIFFERENTIAL DIAGNOSIS Other pustulofollicular scarring alopecias need to be considered (see Table 10-15). The microscopic features of DCS are very similar to those in hidradenitis suppurativa. PAS and Gram stains should be done to rule out fungal and bacterial infection.

PART I ■ INFLAMMATORY REACTIONS IN THE SKIN

Folliculitis Decalvans

 FIGURE 10-22 Anhidrotic ectodermal dysplasia. Vertical section: Only one terminal hair is present and no mature eccrine glands are seen. Primordial eccrine glands are present at the inferior margin of the specimen.

spongiosis. If an epidermotropic lymphocytic infiltrate is also present, CTCL must be considered, especially in lesions not located on the scalp.

PUSTULOFOLLICULAR, NEUTROPHIL-ASSOCIATED PRIMARY SCARRING ALOPECIA The pustulofollicular, neutrophil-associated primary scarring alopecias are dissecting cellulitis of the scalp (DCS), folliculitis decalvans, acne keloidalis (AK), erosive pustular dermatosis of the scalp (EPDS), and tinea capitis (TC) (Table 10-15). Common features include early follicular dilatation and predominately neutrophilic infiltrates within and around the affected follicles. Early lesions have overlapping clinical and microscopic features, but welldeveloped cases usually are distinct both clinically and microscopically.

Dissecting Cellulitis of the Scalp (Perifolliculitis Capitis Abscedens et Suffodiens) 230

CLINICAL FEATURES In 1908, Hoffman described perifolliculitis capitis abscedens

et suffodiens.114 It was later renamed dissecting cellulitis of the scalp, and synonyms include dissecting perifolliculitis and dissecting folliculitis of the scalp. It is most common in young black men and begins as fluctuant scalp nodules that coalesce progressively to form complex, interconnected, crusted abscesses and sinus tracts that drain spontaneously or with slight pressure. Well-developed lesions are painful and result in extensive scarring of the scalp. Some patients with DCS also have acne conglobata and hidradenitis suppurativa and are said to have the follicular occlusion triad. HISTOPATHOLOGIC FEATURES The initial finding is acneiform dilatation with neutrophilic infiltrates (see Table 10-15). Biopsies from fluctuant nodules and sinuses reveal large dermal and subcutaneous abscesses.6,82,115 Well-developed lesions are abscesses and sinus tracts partially lined with squamous epithelium derived from the overlying epidermis or follicular epithelium (Fig. 10-31). Bacteria may be seen superficially in follicular infundibula but not in abscesses, and the pathogenic significance is unclear. Dense dermal and subcutaneous fibrosis eventually

CLINICAL FEATURES FD is a rare pustulofollicular alopecia that presents as round to irregular-shaped patches of alopecia with follicular pustules at the peripheral, advancing edge116 (see Table 10-15). Tufts of hair shafts may occur.117 FD occurs in both sexes and primarily affects the scalp, but involvement of the beard, axillae, pubic area, arms, and legs also may occur.118 End-stage FD without pustules is included within CCSA by some, but not all, authors.80,119 HISTOPATHOLOGIC FEATURES The initial finding is comedonal dilatation with intra- and perifollicular neutrophilic infiltrates (see Table 10-15 and Fig. 10-32). Follicular rupture ensues with resulting perifollicular fibrosis and eventual permanent follicular destruction.6,82 Localized perifollicular dermal abscesses are often present but are not as extensive or deep as seen in DCS. Sinus tracts are not seen in FD. In later stages, the infiltrate is mixed with lymphocytes, plasma cells, and neutrophils. Unsheathed hair shafts surrounded by foreign-body giant cells are present after the follicular epithelium has been destroyed, and as in all primary scarring alopecias, numerous residual fibrous tracts mark sites of destroyed follicles. DIFFERENTIAL DIAGNOSIS Special stains are necessary to rule out fungal and bacterial folliculitis (see Table 10-15).

Acne Keloidalis CLINICAL FEATURES AK is a destructive pustulofollicular process that primarily affects the occipital scalp and neck of young black men (see Table 10-15). Lesions begin as discrete follicular papules or pustules and may progress to large exophytic keloidal plaques devoid of hair.120,121 Similar lesions may occur in the beard region in patients with pseudofolliculitis barbae. HISTOPATHOLOGIC FEATURES Early lesions display comedonal dilatation and pustular

Table 10-14 Lymphocyte-Associated Primary Scarring Alopecia DISCOID LUPUS ERYTHEMATOSUS

LICHEN PLANOPILARIS

CENTRAL CENTRIFUGAL SCARRING ALOPECIA/FOLLICULAR DEGENERATION SYNDROME

FOLLICULAR MUCINOSIS

Clinical Features Young to middle-aged Women > men Erythematous papules to sclerotic plaques Follicular plugging, telangiectasia, dyspigmentation

Perifollicular infiltrates Perieccrine infiltrates Intrafollicular mucin Dermal mucin Concentric lamellar fibrosis Pigment incontinence

Primarily vacuolar Primarily vacuolar Minimal to moderate Lymphocytic Superficial and deep

Present, prominent Present Minimal Moderate to prominent End-stage finding Yes

Primarily lichenoid if present Primarily lichenoid Moderate to prominent Lymphocytic Minimal superficial perivascular, primarily perifollicular Present, prominent Absent Absent Absent Yes in advanced lesions Yes

Young to middle-aged African American Women >> men Slowly progressive, irregularly shaped alopecic patches (“footprints in the snow”) Confluence of patches Noninflammatory

All ages Head and neck > trunk, extremities Erythematous infiltrate Sometimes boggy plaques with scaling, expression of mucin Adults have lymphoproliferative disorder in about 30% of cases

Absent Absent Absent Lymphocytic Mostly superficial

Absent Absent Absent Lymphocytic May be superficial and deep in lymphoma

Present, sparse Absent Absent Absent Prominent

Present, variable Absent Prominent Minimal No

Minimal

No

*Source: Data from Templeton SF, Solomon AR. Scarring alopecia: a classification based on microscopic criteria. J Cutan Pathol 1994:21:97–109.81

folliculitis as in other pustulofollicular alopecias (see Table 10-15). Follicular rupture with subsequent mixed neutrophilic infiltrates occurs. Well-developed lesions are characterized by dense dermal scar with many entrapped unsheathed hair shafts surrounded by lymphohistiocytic infiltrates with admixed neutrophils and abundant plasma cells (Fig. 10-33). Variable numbers of broad eosinophilic hyalinized keloidal collagen bundles may be present but are not essential for diagnosis.6,82,120-123 DIFFERENTIAL DIAGNOSIS Special stains are necessary to rule out bacterial and fungal infections (see Table 10-15). The extensive dermal fibrosis typical of keloidal scar is the most distinctive microscopic feature of AK.

Tinea Capitis/Kerion/Favus CLINICAL FEATURES Kerion and favus subtypes of tinea capitis (TC) can result in

permanent alopecia and are seen most commonly in children. Kerion is inflammatory TC caused by a zoophilic or geophilic follicular dermatophyte infection and presents as boggy, erythematous, scaling, crusted, partially alopecic plaques with regional adenopathy. Favus is an uncommon follicular dermatophyte infection of the scalp seen in rural regions and associated with poor nutrition and poor hygiene. Yellow, cup-shaped crusts termed scutula are present on the scalp and often result in permanent alopecia. The causative organism is T schoenleinii. In adults, noninflammatory endothrix dermatophyte infections, usually T tonsurans, occasionally can cause a more diffuse alopecia mimicking female-pattern androgenetic alopecia or FDS. HISTOPATHOLOGIC FEATURES The follicular infundibula generally are dilated and often hyperkeratotic. Pustular folliculitis with incipient or complete rupture is seen

CHAPTER 10 ■ DISORDERS OF CUTANEOUS APPENDAGES

Histopathological Features Interface alteration at DEJ at follicle Dyskeratosis Inflammation type Perivascular pattern

Adults Women > men Acuminate, spinous hyperkeratotic follicular papules Perifollicular erythema Smooth atrophic polygonal patches of alopecia

commonly in kerion. Dense, mixed inflammatory infiltrates including many neutrophils surround the affected follicles. Endothrix (hyphae within hair shafts) and ectothrix (hyphae around hair shafts) patterns of follicular dermatophytosis may be seen and are best appreciated in PAS-stained or silver-impregnated sections (Fig. 10-34). Hyphae usually are not seen in the overlying epidermis. Some endothrix infections do not illicit a brisk inflammatory response but result in a relatively noninflammatory diffuse alopecia with broken shafts and perifollicular fibroplasia. Thick parakeratotic and orthokeratotic hyperkeratosis overlying an atrophic dermis with lymphoplasmacytic and granulomatous dermal infiltrates and follicular dermatophytosis are seen in favus.8.82,124 DIFFERENTIAL DIAGNOSIS Definitive diagnosis requires demonstration of the fungal organisms in either routine or special stains.

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morphea, lichen sclerosus et atrophicus, and external trauma (Table 10-16).

FORMS OF ALOPECIA THAT ARE DIFFICULT TO CLASSIFY

PART I ■ INFLAMMATORY REACTIONS IN THE SKIN

Erosive Pustular Dermatosis of the Scalp CLINICAL FEATURES Erosive pustular dermatosis of the scalp is an uncommon erosive and pustular process that may lead to permanent alopecia.125,126 It generally begins on the crown as a localized area of crusted erosion with occasional pustules, and it occurs most commonly in elderly Caucasian women. HISTOPATHOLOGIC FEATURES The histology is not specific and consists of neutrophilfilled pustules, ulcers, and erosions with subjacent-mixed inflammatory infiltrates and abscesses.127,128

Lipedematous Alopecia  FIGURE 10-23 Discoid lupus erythematosus. Vertical sections: Superficial and deep perifollicular and perivascular lymphocytic infiltrates with vacuolar interface alteration of follicular epithelium.

 FIGURE 10-24 Discoid lupus erythematosus. Horizontal sections: Perifollicular lymphocytic infiltrate with vacuolar inerface alteration of the follicular epithelium.

Secondary Scarring Alopecia

232

Hair loss in secondary scarring alopecias is the result of nonfolliculocentric skin disease.74-76,116-120 The pilosebaceous apparatus is not the focus of disease but is only involved secondarily. The clinical

and microscopic features of secondary scarring alopecia are characteristic for the specific disease involved. Some examples include hair loss produced by neoplasms, sarcoidal granulomas, sclerodermoid porphyria cutanea tarda, necrobiosis lipoidica, and dermal sclerosis from

CLINICAL FEATURES Lipedematous alopecia (LA) is the term used to describe alopecia associated with boggy thickening of the subcutaneous adipose tissue of the scalp.129 This rare form of alopecia has been described primarily in African American females, but has also been reported in Caucasian women and a Japanese man.130.131 The defining clinical feature is the compressible bogginess of the thickened scalp. The latter may occur without associated alopecia (lipedematous scalp). When present, the associated alopecia ranges from extensive and diffuse to limited and patchy. Some patients with this condition state their hair will not grow beyond a short length. HISTOPATHOLOGIC FEATURES Histopathologic studies have found the primary abnormality to be an increase in the thickness of the subcutaneous adipose tissue of the scalp.132,133 In some cases the latter structure is nearly 1 cm thick, as opposed to the reported 3 mm in normal scalp.131 In addition, the thickened adipose tissue shows other abnormalities including edema and dilated lymphatics, but neither inflammation nor mucin is increased.131,134 Peculiarly, characteristic and reproducible follicular changes in alopecic scalp have not yet been documented.

Follicular Hyperkeratosis Synonyms: Keratosis pilaris (KP), lichen spinulosus, phyronoderma, scarring follicular keratosis.

CLINICAL FEATURES Keratosis pilaris is a common follicular dermatosis often associated with ichthyosis and atopic dermatitis.135 Onset occurs in the first and second decades of life with persistence into

adulthood. Lesions consist of patches of follicular hyperkeratosis with variable perifollicular erythema commonly affecting the upper outer arm, thighs, and buttocks. Lichen spinulosus (LS) is a closely related

HISTOPATHOLOGIC FEATURES Follicular dilatation with compact follicular hyperkeratosis, at times tightly adherent to the hair shaft, is present in KP and LS (Fig. 10-35). Follicular infundibular atrophy with slight perifollicular lymphocytic infiltrates is also present. Follicular rupture with subsequent inflammatory folliculitis may occur.135,136,137 Similar findings are seen in the scarring follicular keratosis. Early lesions display typical KP features but may have more prominent infundibular hypergranulosis. Inflammatory and pustular lesions show follicular rupture and folliculitis. Late lesions are no different from other end-stage scarring alopecias, with complete follicular dropout, numerous residual fibrous tracts, and scattered “naked” hair shafts.

CHAPTER 10 ■ DISORDERS OF CUTANEOUS APPENDAGES

 FIGURE 10-25 Lichen planopilaris. Vertical sections: Infundibular keratinocytes are glassy with lichenoid interface alteration and perifollicular lymphocytic infiltrate. The epidermis is largely spared.

follicular hyperkeratotic condition presenting in children as patches of minute horny follicular spines. Patients with vitamin A deficiency develop numerous follicular hyperkeratotic lesions termed phrynoderma that begin on the thighs and posterolateral arms with subsequent involvement of extensor surfaces. Night blindness, xerophthalmia, keratomalacia, diarrhea, weakness, and generalized wasting may occur in hypovitaminosis A. Several genetically determined syndromes characterized by KP, follicular destruction, and typical clinical findings have been described.136,137 This group of disorders is often termed scarring follicular keratosis. Three major variants include keratosis pilaris spinulosa decalvans (KPSD), keratosis pilaris atrophicans (KPA; also known as ulerythema oophryogenes), and atrophoderma vermiculata (AV, also known as acne vermiculata and folliculitis ulerythematosa reticulata). Scarring alopecia with KP-like lesions occurs in KPSD with onset during the teenage years. Loss of eyebrow hair with atrophy and follicular hyperkeratosis is characteristic of KPA. AV is characterized by reticulate, ice-pick scarring of the cheeks with follicular hyperkeratosis. Overlapping clinical findings may be seen in these three clinical subtypes of scarring follicular keratosis.

FOLLICULITIS

 FIGURE 10-26 Lichen planopilaris. Horizontal sections: Dense perifollicular lichenoid infiltrates with artifactual clefting.

Folliculitis is characterized by inflammation within and adjacent to hair follicles. The folliculitides comprise a group of diseases that share the histopathologic findings of folliculitis and/or perifolliculitis and can be broadly characterized as infectious, acneiform, eosinophilic, and miscellaneous (Table 10-17).

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PART I ■ INFLAMMATORY REACTIONS IN THE SKIN

Gram-negative folliculitis may occur as a complication of long-term oral antibiotic treatment for acne and presents clinically as worsening acneiform papules and pustules around the nose, mouth, and cheeks. Culture of these lesions usually grows a species of Enterobacter, Klebsiella, or Escherichia coli.138 Hot-tub folliculitis is a less common gram-negative folliculitis usually caused by Pseudomonas aeruginosa and acquired through exposure to inadequately chlorinated water in swimming pools and hot tubs.139 Lesions generally are distributed over areas covered by the bathing suit. Mud-wrestling folliculitis caused by soil bacteria, Enterobacteriaceae, also occurs on covered skin in individuals participating in this activity.140  FIGURE 10-27 Follicular degeneration syndrome. Vertical sections: Diminished follicular density with vertically oriented residual fibrous tracts and sparse lymphocytic infiltrates.

INFECTIOUS FOLLICULITIS Bacterial, fungal, parasitic, viral, and mycobacterial follicular infections comprise the infectious folliculitides (see Table 10-17).

Bacterial Folliculitis CLINICAL FEATURES Bacterial folliculitis may affect the superficial portion of the hair follicle and present clinically as a pustule or the deep portion of the hair follicle and present as indurated,

erythematous nodules or plaques. Superficial bacterial folliculitis, also known as Bockhart impetigo, is usually caused by Staphylococcus aureus. Furuncles, or deep folliculitis, are larger, tender, warm, erythematous nodules and plaques with central pustules, generally caused by S aureus. Furuncles may occur on any nonglabrous skin but are more common on the legs, buttocks, posterior neck, and axillae. Carbuncles, composed of two or more coalescing furuncles, are more common in diabetics.

Fungal Folliculitis CLINICAL FEATURES Fungal folliculitis is typically caused by Malassezia furfur, formerly termed Pityrosporum ovale (Pityrosporum folliculitis) or dermatophytes (Majocchi granuloma and tinea capitis). Pityrosporum folliculitis occurs on the trunk as pruritic acneiform papules and pustules most commonly in young adults.141 Majocchi granuloma is a form of follicular dermatophytosis that occurs on nonglabrous skin, most commonly on extremities.142 The lesions present as grouped, somewhat annular inflammatory papulopustules or as deep furuncle-like nodules. Topical corticosteroid usage prior to a correct diagnosis is common in Majocchi granuloma and may allow for more extensive infection of hair shafts. HISTOPATHOLOGIC FEATURES Bacterial and fungal folliculitis share similar microscopic features and show intra- and perifollicular, predominantly neutrophilic inflammatory infiltrates. Follicular rupture with adjacent dense, mixed inflammatory infiltrates, abscess formation, and granulation tissue is common. Bacterial organisms may be present in the infundibular region in bacterial folliculitis and at a deeper follicular level in furuncles and carbuncles (Fig. 10-36). Acneiform dilatation with budding yeast and follicular hyperkeratosis is seen in Pityrosporum folliculitis (Fig. 10-37). The histology of Majocchi granuloma is similar to tinea capitis/kerion with follicular rupture, abscess, and dermatophyteinfected hair shafts (Fig. 10-38).

Demodex Folliculitis 234

 FIGURE 10-28 Follicular degeneration syndrome. Horizontal sections: Concentric lamellar fibroplasia surrounds a follicle with eccentric thinning of follicular epithelium. Only sparse lymphocytes are seen.

CLINICAL FEATURES The ectoparasites Demodex folliculorum and D brevis are hair

HISTOPATHOLOGIC FEATURES Demodex mites are elongate eosinophilic ectoparasites and are more numerous on the head and neck.145 One or more mites may be found in normal follicular infundibula. Mites also may be seen within the sebaceous duct. Follicular spongiosis with perifollicular lymphohistiocytic infiltrates can occur in rosacea-like lesions, especially on the face (Fig. 10-39).

Viral Folliculitis

follicle mites found frequently in normal adult skin. The pathogenicity of the mites in folliculitis, especially acne rosacea, is controversial.143 However, in some cases, facial rosacea-like papules and pustules respond to topical acaricidal therapy,

suggesting that Demodex mites may play a role in some instances. In addition, the mean mite count in a facial biopsy was significantly higher in patients with rosacea than in matched control patients in one study.144

HISTOPATHOLOGIC FEATURES In herpes folliculitis, viral cytopathic changes of herpesvirus infection may be seen initially in the follicular infundibulum. These changes include keratinocyte pallor with chromatin margination, nuclear molding, acantholysis, dyskeratosis, and multinucleation. In papular chronic herpesvirus infections, typical viral cytopathic changes are seen in the epidermis and hair follicles with prominent overlying hyperkeratosis.147 Early herpes folliculitis lesions may show a lymphocytic folliculitis without diagnostic cytopathic changes.146 Extensive necrosis occurs in some cases. The adjacent dermis shows moderate to dense, perivascular and occasionally perineural lymphocytic inflammatory infiltrates. In addition, dense, atypical, but reactive lymphocytic infiltrates-simulating lymphoma can occur in herpesvirus folliculitis.150 Molluscum contagiosum folliculitis is characterized by multiple molluscum bodies within the epithelium of the hair follicle.148,149

CHAPTER 10 ■ DISORDERS OF CUTANEOUS APPENDAGES

 FIGURE 10-29 End-stage scarring alopecia. Horizontal sections: Complete follicular dropout with numerous residual fibrous tracts. These end-stage features occur in many primary scarring alopecias and are not diagnostic of a specific entity.

CLINICAL FEATURES Although not typically a follicular process, herpesvirus infections (herpes simplex and herpes zoster) can involve hair follicles, especially in early lesions. A recent study showed herpes zoster more commonly affects hair follicles than herpes simplex virus.146 In addition, chronic cutaneous herpesvirus infections can involve follicles and present as persistent hyperkeratotic papules in an acneiform distribution on the trunk in immunocompromised patients.147-149 Cases of herpetic sycosis, with widespread vesiculopustular eruptions in the beard area, have been reported in immunocompetent men.148 A case of molluscum contagiosum folliculitis in an HIV-positive man presented with asymptomatic, numerous, nonumbilicated, flesh-colored papules in the beard area.148

Atypical Mycobacterial Folliculitis  FIGURE 10-30 Alopecia mucinosa. Vertical sections: Extensive mucin deposits are present, including mucin-filled cystic spaces.

CLINICAL FEATURES Cutaneous nontuberculous mycobacterial infections are rare and can present clinically as papules, pustules, nodules, abscesses, plaques, ulcers, or cellulitis. A linear (sporotrichoid) spread of

235

Table 10-15 Pustulofollicular, Neutrophil-Associated Primary Scarring Alopecia DISSECTING CELLULITIS

FOLLICULITIS DECALVANS

ACNE KELOIDALIS

TINEA KERION AND FAVUS

African American men Fluctuant scalp nodules Progression to extensive interconnected abscesses, sinus tracts Spontaneous drainage Painful, prominent scarring Associated follicular occlusion triad

Adults of either sex Round or irregularly shaped patches of alopecia with follicular pustules Other sites may be affected

African American men Occipital scalp, neck Follicular papules, pustules progress to large, exophytic, keloidal alopecic plaques

Children, adolescents Boggy, erythematous, crusted, scaling nodules and plaques with variable alopecia Zoophilic and geophilic forms of dermatophyte Yellow, cup-shaped crusts (scutula) with favus

Early finding, persists

Early finding, persists

Early finding, persists

Present Present in dermis

Present Less prominent in dermis

Present Variable, may be prominent

Absent

Largely absent

Absent

Less dense perifollicular fibrosis in dermis

Dense dermal hypertrophic scar and/or keloid

Perifollicular dermal scar, may be extensive in favus

Occasional staph within follicular infundibulum Neutrophilic initially, later mixed

Occasional propionibacteria acnes Neutrophilic initially, later mixed with lymphocytes and prominent plasma cells Primarily peri-infundibular, may extend to involve entire follicle

Endothrix and ectothrix

PART I ■ INFLAMMATORY REACTIONS IN THE SKIN

Clinical Features

Histopathologic Features Acneiform follicular Early finding, persists dilatation Follicular rupture Present Abscess formation Extensive dermal and subcutaneous Sinus tract formation Yes, partially squamous-lined Location of fibrosis Dense fibrotic scar around sinus tracts in dermis and subcutis Infectious agents Occasional staph within follicular infundibulum Inflammation type Neutrophilic initially, later mixed granulomatous with plasma cells Location Initially peri-infundibular, progresses to involve entire follicle and subcutis

Primarily peri-infundibular, may extend to involve entire follicle

*SOURCE: Data from Templeton SF, Solomon AR. Scarring alopecia: a classification based on microscopic criteria. J Cutan Pathol 1994:21:97–109.81

lesions along lymphatic drainage lines may be observed, especially in Mycobacterium marinum infections.151 HISTOPATHOLOGIC FEATURES Acute suppurative folliculitis has been demonstrated in M chelonae infections.151 The histopathologic features of nontuberculous mycobacterial infection range from diffuse granulomatous dermatitis with tuberculoid, sarcoidal, or palisading patterns of inflammation to cutaneous abscesses, suppurative granulomas, and necrotizing folliculitis. Therefore, folliculitis generally is not an isolated histopathologic finding in the biopsy specimen.

ACNEIFORM FOLLICULITIS

236

Primarily peri-infundibular, may extend to involve entire follicle

Neutrophilic initially, later mixed granulomatous

Acne vulgaris (Table 10-18), other acne subtypes, pseudofolliculitis barbae, hidradenitis suppurativa (Table 10-19), and pustulofollicular scarring alopecias are all acneiform folliculitides. Some forms

of rosacea are also included in this group of diseases (Table 10-20).

Acne Variants CLINICAL FEATURES Acne can be comedonal, papular, pustular, nodular, or cystic. The face, chest, and back are involved, and this disorder primarily affects adolescents and young adults152,153 (see Table 10-18). Comedonal, papular, and pustular acnes are the most common variants and are termed acne vulgaris. Comedones are either open (blackheads) or closed (whiteheads). Acne conglobata is a severe form of nodulocystic acne that usually involves the back, chest, and posterior neck and consists of numerous coalescing large comedones, acne cysts, and nodules. Extensive irregularly shaped scars and epidermoid cysts occur in the later stages, and association with the follicular occlusion triad is common. Chloracne is a rare acne variant occurring after exposure to halogenated aromatic

compounds, especially dioxin.154 Patients using systemic and topical corticosteroids may develop a monomorphic acneiform follicular eruption termed steroid acne.155 A number of other drugs, including anticonvulsants, anabolic steroids, lithium, isoniazid, azathioprine, cyclosporine A, etretinate, and epidermal growth factor inhibitors also may cause acneiform eruptions.138,156,157 Acne cosmetica (pomade acne) is more common in women and occurs on the face as the result of persistent follicular occlusion by cosmetics and applied hair oils.152 Noninflammatory comedones and cysts associated with nodular solar elastosis is termed the Favre-Racouchot syndrome and generally occurs on the upper to lateral cheeks and temples near the eyes.158 HISTOPATHOLOGIC FEATURES The follicular infundibulum is thinned, dilated, and filled with compact hyperkeratosis in acne comedones (see Table 10-18 and

may occur in old, scarred acne lesions. Extensive solar elastosis, open comedones, and small epidermoid cysts are seen in the Favre-Racouchot syndrome.

Pseudofolliculitis Barbae CLINICAL FEATURES Pseudofolliculitis barbae is an acneiform eruption of the bearded area most common in men with thick, tightly curled hair. Concomitant acne keloidalis often occurs in these patients.159-162

 FIGURE 10-31 Dissecting cellulitis of the scalp. Vertical sections: Partially squamous-lined abscess with unsheathed hair shaft. Follicles are destroyed by the fibroinflammatory process.

Fig. 10-40). Inflammatory comedones, papules, and pustules show mixed infiltrates of increasing density within and around dilated follicles.138 Follicular rupture with dermal abscess is seen in nodu-

locystic acne lesions, and subsequent scarring is common. Extensive abscesses and partially squamous-lined sinuses with prominent scarring are seen in acne conglobata. Focal dystrophic calcification

Hidradenitis Suppurativa CLINICAL FEATURES Hidradenitis suppurativa is a painful, deep, scarring folliculitis of the axillae and groin often associated with nodulocystic acne and dissecting cellulitis of the scalp (see Table 10-19). HISTOPATHOLOGIC FEATURES The histopathology of hidradenitis is very similar to that of dissecting cellulitis of the scalp and consists of extensive scarring of the dermis and subcutis with deep dermal and subcutaneous abscesses and sinuses partially lined with squamous epithelium163 (see Table 10-19 and Fig. 10-41). Follicular occlusion occurs initially with subsequent superficial and deep folliculitis and abscess formation. A persistent fibro-inflammatory response occurs as the result of continuous keratin production by ruptured squamous-lined sinuses. Abundant granulation tissue is seen in some patients. Suppurative inflammation of apocrine glands occurs secondarily and only in a minority of patients.164,165 In one study, secondary apocrine gland involvement was found in 12% of specimens, and secondary involvement of eccrine glands was found in 25%.163

CHAPTER 10 ■ DISORDERS OF CUTANEOUS APPENDAGES

HISTOPATHOLOGIC FEATURES Pseudofolliculitis barbae results from close shaving in individuals with thick, tightly curled hair. The hair shafts either penetrate their own follicular infundibulum or curl back and penetrate the adjacent epidermis after exiting the acrotrichium. The histopathologic features show a follicular and perifollicular mixed inflammatory infiltrate with an associated foreign-body histiocytic giant cell response and variable fibrosis.159-162

Rosacea and Perioral Dermatitis

 FIGURE 10-32 Folliculitis decalvans. Horizontal sections: Pustular folliculitis with incipient rupture and adjacent mixed dermal infiltrates.

CLINICAL FEATURES Rosacea is an acneiform disorder that most commonly affects the middle-aged and elderly (see Table 10-20). Telangiectatic, papulopustular, granulomatous, and rhinophyma variants occur.166

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Table 10-16 Secondary Scarring Alopecia

238

 FIGURE 10-33 Acne keloidalis. Vertical sections: Chronic lesion with dense dermal scar, recent follicular rupture, unsheathed hair shafts, and mixed infiltrates including neutrophils and numerous plasma cells.

The nose, cheeks, and chin typically are affected, but extrafacial involvement can occur rarely. Transient and persistent flushing of the face is common and may be aggravated by external and psycho-

logical factors. Inflammatory papular and granulomatous lesions can mimic basal cell carcinoma clinically and therefore often are biopsied. Although once considered a tuberculid, lupus miliaris

 FIGURE 10-34 Tinea capitis. Horizontal sections: Dermatophyte hyphae extensively permeate (endothrix) and surround (ectothrix) hair shafts in this patient treated with topical steroids. Numerous neutrophils are seen.

Sclerosing disorders Morphea Sclerodermoid porphyria cutanea tarda Lichen sclerosus et atrophicus Parry-Romberg syndrome Physical/chemical agents Mechanical trauma, laceration Thermal burns Chemical burns Radiation dermatitis Dermal infiltrative processes Tumors Basal cell carcinoma Squamous cell carcinoma Metastatic carcinoma Lymphoma Adnexal tumors Dermatofibrosarcoma protuberans Others Granulomatous conditions Sarcoidosis Necrobiosis lipoidica Miecher granuloma Actinic granuloma Infections Syphilis (tertiary) Tuberculosis Viral infections Protozoal infections Other Amyloidosis SOURCE: Data from Templeton SF, Solomon AR. Scarring alopecia: a classification based on microscopic criteria. J Cutan Pathol 1994:21: 97–109.81

disseminata facei is now considered a variant of granulomatous rosacea and consists of discrete red-brown papules distributed over the face and eyelids.167,168 Rhinophyma is an end-stage variant of rosacea that results in enlargement of the nose, especially the nasal tip, due to sebaceous gland hypertrophy.169 On occasion, other areas of the face or ears may be involved by rhinophyma. The pathogenesis is poorly understood, but the vascular flushing reaction is one of the earliest stages in the development of rosacea and recent evidence suggests angiogenesis is an important factor in the pathogenesis of rosacea.170 Aggravating factors include hot, spicy foods and liquids, alcohol, certain vasodilatory drugs, and sunlight.166 Ocular rosacea is relatively common, with symptoms of stinging, burning, tearing, photophobia, scratchiness, and feelings of foreign material in the eye.167

Perioral dermatitis is a relatively common facial eruption consisting of acneiform papules and pustules distributed around the mouth of young women.171 Use of topical fluorinated corticosteroids on the face is often the inciting cause, but idiopathic cases occur. Clinically, perioral dermatitis has features of acne rosacea

and seborrheic dermatitis. Granulomatous variants of perioral dermatitis occur, especially in children, and in these cases involvement of the eyelids and neck is common.

CHAPTER 10 ■ DISORDERS OF CUTANEOUS APPENDAGES

 FIGURE 10-35 Keratosis pilaris. Follicular hyperkeratosis with slight perifollicular fibroplasia and sparse lymphocytic infiltrates are seen.

HISTOPATHOLOGIC FEATURES Histopathologic features vary according to clinical subtype172-174 (see Table 10-20). In telangiectatic rosacea, increased numbers of ectatic venules with sparse perivascular lymphocytic infiltrates are seen. Solar elastosis is common. Papular rosacea lesions have perivascular and perifollicular lymphohistiocytic infiltrates involving the superficial to middle dermis (Fig. 10-42). Admixed multinucleate histiocytes and loose granulomas are seen in papular and granulomatous rosacea (Fig. 10-43). Nonfollicular epithelioid granulomas that occasionally exhibit caseation necrosis occur less frequently. The inflammatory infiltrate in papular rosacea may have a perivascular to nodular pattern rather than a strictly perifollicular distribution. Suppurative folliculitis with admixed lymphohistiocytic infiltrates, including foreign-body giant cells, is characteristic of pustular rosacea. Extensive hypertrophy of mature sebaceous glands, follicular dilatation, and hyperkeratosis with variable inflammation are seen in rhinophyma. In contrast to discrete lesions of sebaceous hyperplasia, in which sebaceous lobules radiate around a central dilated sebaceous duct, rhinophyma exhibits more extensive and diffuse sebaceous gland hypertrophy, fibroplasia, fibrovascular hypertrophy (fibroplasia with prominent vascular ectasia), and nodular accumulation of solar elastotic material. The histopathology of perioral dermatitis is similar to that of papular,

Table 10-17 Folliculitis Subtypes Infectious folliculitis Bacterial—Staphylococcus, Pseudomonas, other Fungal folliculitis—Majocchi granuloma, Pityrosporum folliculitis Demodex folliculitis Herpesvirus folliculitis Acneiform folliculitis Acne variants Hidradenitis suppurativa Pseudofolliculitis barbae Pustulofollicular scarring alopecias Rosacea Perioral dermatitis Eosinophilic folliculitis Neonatal and adult HIV associated

 FIGURE 10-36 Bacterial folliculitis. Numerous intrafollicular gram-positive bacteria are seen as well as early follicular rupture.

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PART I ■ INFLAMMATORY REACTIONS IN THE SKIN

 FIGURE 10-37 Pityrosporum folliculitis. Numerous oval to round M furfur organisms are present within an inflamed follicle.

pustular, and granulomatous variants of rosacea.171

Perforating Folliculitis CLINICAL FEATURES Perforating folliculitis was defined as a clinicopathologic entity

240

in 1968 by Mehregan and Coskey.175 The primary lesion was described as a follicular centered erythematous papule perforated by a central hair shaft. The papules typically are located on the thighs and buttocks of young adults, anatomic sites where chronic friction,

 FIGURE 10-38 Majocchi granuloma. A disintegrating hair shaft with numerous endothrix dermatophyte hyphae is present in a dermal abscess.

presumably secondary to tight-fitting clothing on hair-bearing surfaces, could induce the lesion. The perforating hair shaft may be encompassed by a keratotic plug. Other than the postulated role of chronic rubbing and friction, no pathogenesis is known. In addition to the discrete clinicopathologic entity described above, the microscopic finding of infundibular perforation is common to several types of folliculitis, including bacterial and fungal folliculitis, acne vulgaris, keratosis pilaris, and pustulofollicular forms of alopecia such as folliculitis decalvans and acne keloidalis.176-178 Perforating folliculitis also may occur in patients with chronic renal failure on hemodialysis, and in this clinical setting, the disease can be considered part of the spectrum of acquired perforating dermatoses previously termed Kyrle disease.179-181 Perforating folliculitis is also associated with TNF-alpha inhibitor therapy.182 Therefore, infundibular perforation appears to be a nonspecific event occurring in the course of inflammatory follicular destruction. The microscopic finding of perforating folliculitis should not be considered indicative of the specific entity bearing the same name without appropriate clinicopathologic correlation. HISTOPATHOLOGIC FEATURES The diagnostic microscopic change of the specific clinicopathologic entity known as perforating folliculitis is an eccentric infundibular perforation.176,177,179 A plug of hyperkeratotic stratum corneum usually is present within the acrotrichium. The infundibular epithelium is variably hyperplastic, but attenuation of the epithelium usually is evident adjacent to the site of rupture. The dilated infundibulum is filled with necrotic basophilic debris, sebaceous material, keratin, and inflammatory cells. Intact and karyorrhectic neutrophils predominate. A hair shaft may be present within the follicular canal at or near the site of perforation, but it is not invariably present. A mixed inflammatory infiltrate composed of neutrophils, lymphocytes, and plasma cells is found in the dermis adjacent to the ruptured infundibular epithelium. Granulomatous inflammation may be present in older lesions. The reticular dermal collagen near the site of perforation frequently is basophilic and granular. DIFFERENTIAL DIAGNOSIS Perforating folliculitis must be distinguished from elastosis perforans serpiginosa (EPS) and reactive perforating collagenosis (RPC). EPS contains altered perifollicular elastic fibers not seen in perforating folliculitis.

Table 10-20 Rosacea and Rhinophyma

Table 10-18 Acne Vulgaris

Table 10-19 Hidradenitis Suppurativa

Clinical Features Adolescence, early adulthood Men ≥ women Face >> back, chest, shoulder Comedones Erythematous papules, pustules, nodules, cysts Occasional scarring Association with hidradenitis suppurativa and dissecting cellulitis Histopathologic Features Comedone: dilated follicular infundibulum with keratinous plug, open to surface or closed Follicular pustule with or without rupture into surrounding dermis Neutrophilic and foreign-body granulomatous reaction to keratin and follicular contents in dermis Epithelial cyst and sinus tract formation Dermal scarring Differential Diagnosis Keratosis, pilaris, and related conditions Other forms of folliculitis, eg, bacterial, fungal, viral

Clinical Features Onset after puberty Axillae, inguinal, and perineal areas, other sites Erythematous nodules followed by draining abscesses, sinus tracts, prominent scarring Association with severe acne, dissecting cellulitis of scalp Histopathologic Features Early lesions Follicular plugging, folliculitis Chronic lesions Features of chronic folliculitis Abscesses within apocrine glands and in the dermis and subcutis Prominent foreign body granulomatous reaction Dermal scarring often extensive Sinus tract and cyst formation Differential Diagnosis Other chronic active deep folliculitides, infectious and noninfectious Pyoderma gangrenosum Crohn disease

CHAPTER 10 ■ DISORDERS OF CUTANEOUS APPENDAGES

 FIGURE 10-39 Demodex folliculitis. Elongated D folliculorum mites are present in the follicular infundibulum with perifollicular infiltrates.

Clinical Features Age 20-50 years common Women > men Fair-skinned individuals Central face: nose, cheek, chin, glabella, forehead; rarely neck, upper trunk Blushing, flushing Erythema, telangiectasia, edema Papules, pustules Rhinophyma, other phymas involving forehead, chin Histopathologic Features Variable degrees of the following: Vascular ectasia Perivascular and perifollicular lymphoid infiltrates Folliculitis Solar elastosis Edema Granulomatous inflammation Epithelioid granulomas, especially perifollicular Sebaceous hyperplasia Rhinophyma and other phymas show variable degrees of the following: Florid sebaceous gland hyperplasia Diffuse fibroplasia Ectatic venular vessels Nodular solar elastosis Differential Diagnosis Lupus erythematosus Perioral dermatitis Acne vulgaris Sarcoidosis Other granulomatous dermatitides

In RPC, the epidermis is the site of perforation rather than the follicular infundibulum.

Eosinophilic Folliculitis (Eosinophilic Pustular Folliculitis) CLINICAL FEATURES Eosinophilic folliculitis (EF) is a histopathologically distinct group of diseases that occur in several patient populations: (1) adult males, usually Japanese (classic form), (2) neonates and young children, (3) HIV-infected and other immunocompromised patients, and (4) a miscellaneous group of patients, including those with atopic dermatitis. The etiology of EF has not been determined. Classic EF was first described in Japanese men by Ofuji and colleagues in 1970 but has been reported in non-Japanese patients.183-186 Clinically, patients present with erythematous follicular papules and pustules that coalesce to form polycyclic plaques with

241

PART I ■ INFLAMMATORY REACTIONS IN THE SKIN 242

 FIGURE 10-40 Comedone. A large comedone displays a keratin-filled dilated follicle with atrophy of infundibular epithelium. Inflammation is variable.

centrifugal extension and central clearing. Postinflammatory hyperpigmentation occurs frequently. The lesions typically affect the face, trunk, and proximal extremities and can be pruritic. Peripheral leukocytosis and eosinophilia are often present.183,184

The pediatric variant occurs predominately in males younger than 1 year of age and generally affects the scalp and forehead as pruritic indurated erythematous plaques with pustules.187-189 Lesions also can occur on the face, trunk, and extremities.190,191 The lesions typically

 FIGURE 10-41 Hidradenitis suppurativa: Extensive dermal scarring is present with a partially squamous-lined sinus tract and associated suppurative infiltrates.

lack the polycyclic morphology and centifugal extension seen in the adult form. Peripheral leukocytosis and eosinophilia are often present. HIV-associated EF was described initially by Soeprono and authors in 1986.192 In contrast to classic EF, HIV-associated EF is associated with severe pruritus, rare pustules, and the absence of polycyclic plaques. Discrete follicular urticarial papules, which are often excoriated, occur on the head, neck, and trunk with sparing of the lower extremities.193,194 Females may show predominantly facial involvement.195 CD4 counts typically are below 200 cells/mm3, and the presence of EF suggests more advanced disease. Serum IgE levels frequently are elevated. Follicular mucinosis has been coexistent in two reported cases.196 EF has also been reported in patients immunosuppressed secondary to bone marrow transplantation.197 A necrotizing variant of EF has been described in nine patients with an atopic diathesis.198 The cases in atopic patients differed from the presentation of classic EF clinically by ulceration and nodule formation and microscopically by follicular necrosis and eosinophilic vasculitis. HISTOPATHOLOGIC FEATURES The various subtypes of EF share similar microscopic features. Intra- and perifollicular mixed inflammatory infiltrates with numerous eosinophils and associated follicular spongiosis are characteristic of EF199 (Table 10-21 and Fig. 10-44). Spongiosis of the sebaceous lobules is commonly present. Subcorneal eosinophilic pustules also may be seen. In many cases, variably dense, perivascular and interstitial lymphocytic infiltrates are present in both the superficial and deep reticular dermis. Flame figures are rare. In the variant reported in atopic patients, follicular necrosis and eosinophilic vasculitis are present in addition to follicular inflammation. DIFFERENTIAL DIAGNOSIS Lesions that may present with a similar eosinophilic infiltrate include papular urticaria, arthropod bite reactions, papular eruption of HIV, scabies infestation, dermatophyte infection, drug reactions, and erythema toxicum neonatorum. A PAS and/or silver stain should be performed to exclude an infectious etiology. The inflammatory infiltrate in papular urticaria, arthropod bite reactions, and drug reactions generally lacks the folliculocentric distribution of EF. The neonatal presentation and rapid resolution of erythema toxicum neonatorum should allow clinical distinction from EF.

Table 10-21 Eosinophilic Folliculitis

MISCELLANEOUS DISORDERS OF CUTANEOUS APPENDAGES

Fox-Fordyce Disease (Apocrine Miliaria) CLINICAL FEATURES Fox-Fordyce disease is a rare, chronic, pruritic, follicular-based

papular eruption that affects skin containing apocrine glands.200,201 It occurs almost exclusively in adolescent and adult females, although rare cases in males and prepubertal females have been reported.202,203 It typically affects the axilla, but lesions can be present in other

 FIGURE 10-43 Granulomatous rosacea. Loose to well-formed granulomas comprised of histiocytes and multinucleate giant cells are seen. Granulomas may or may not be perifollicular.

apocrine gland–bearing sites, including the pubis, labia, perineum, areola, intramammary region, umbilicus, and proximal thigh. Severe paroxysmal pruritus initiated by emotional stimuli, physical activity, and sexual activity is common.204 The pathogenesis remains unknown, although keratotic plugging of the apocrine duct is a consistent finding. HISTOPATHOLOGIC FEATURES The microscopic presentation usually is not specific and can show significant variation, requiring examination of multiple serial sections.205 Transverse sections have been reported to be more effective in demonstrating the histopathologic features.206 The most reproducible findings are hyperkeratosis and spongiosis of the follicular infundibulum. Hyperkeratotic plugging of the follicle at the level of apocrine duct entry is often present but may be difficult to demonstrate in conventional sections. Spongiosis and apocrine sweat retention are observed occasionally in the distal apocrine duct.207 A sparse, predominantly lymphocytic inflammatory infiltrate often is present in a perivascular, perifollicular, and periductal distribution. Xanthoma cells may also be present.205,208 The overlying epidermis may exhibit acanthosis and spongiosis.

CHAPTER 10 ■ DISORDERS OF CUTANEOUS APPENDAGES

 FIGURE 10-42 Rosacea. Papular lesion: Perifollicular and perivascular lymphohistiocytic infiltrates are characteristic of papular rosacea.

Clinical Features Adult young to middle-aged men, mainly Japanese Neonates and young children HIV-infected patients Face, trunk, upper extremities Erythematous follicular pustules Polycyclic plaques often with centripetal extension, central clearing Urticarial follicular papules often in HIV patients Low CD4 counts (usually < 200 cells/mm3) Histopathologic Features Peri and intrafollicular eosinophilic infiltration Occasional subcorneal eosinophilic pustules Follicular spongiosis often Perivascular and interstitial lymphocytic infiltrates Flame figures rare Differential Diagnosis Other folliculitides, especially infectious Arthropod bite reaction Papular urticaria Papular eruption of HIV

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leukemia.214 It has since been reported in association with other chemotherapeutic agents, particularly bleomycin, nonmyeloid malignancies, and granulocyte colony-stimulating factor.215-219 It also has occurred in HIV-infected patients and in patients with myeloid leukemia prior to induction chemotherapy.220,221 NEH is a polymorphous cutaneous eruption affecting the neck, trunk, and extremities. Lesions consist of tender erythematous macules, papules, and plaques. Spontaneous resolution of the lesions may occur.

 FIGURE 10-44 Eosinophilic folliculitis. Both intrafollicular and perifollicular eosinophils are seen in this case of eosinophilic folliculitis.

DIFFERENTIAL DIAGNOSIS Keratosis pilaris, lichen spinulosis, pityriasis rubra pilaris, ichthyosis, and some eczematous lesions have prominent follicular hyperkeratosis and may mimic Fox-Fordyce disease microscopically. The clinical distribution of lesions should allow distinction of these entities from Fox-Fordyce disease. Infundibulofolliculitis (disseminate and recurrent infundibulofolliculitis) is a microscopic consideration but generally has less prominent follicular hyperkeratosis and occurs predominantly in black males.

Chromhidrosis (Apocrine Chromhidrosis) CLINICAL FEATURES Chromhidrosis is a rare disorder that is characterized by the production of colored perspiration by apocrine or eccrine glands.209-211 The face and axilla are the most common sites, although involvement of the areola has been reported.212 Secretion of brown or black perspiration occurs in response to emotional or mechanical stimulation. Less commonly, the secretions may be colored blue, green, yellow, or red. The common coloring of perspiration by exogenous

244

HISTOPATHOLOGIC FEATURES The predominant microscopic finding in classic NEH is a sparse to dense neutrophilic infiltrate surrounding eccrine units214,217 (Table 10-22 and Fig. 10-45). Secretory coils in the superficial subcutis generally show more extensive involvement by the neutrophilic infiltrate, and eccrine epithelial vacuolization and necrosis are commonly present. Focal degenerative mucinous changes often are evident in the adjacent subcutis. Squamous metaplasia and variable dyskeratosis can affect part or all of the eccrine unit in chemotherapy and has been termed eccrine squamous syringometaplasia. In association with chemotherapy, it is considered in the histopathologic spectrum of NEH.218

pigments or chromogenic microorganisms is known as pseudochromhidrosis.213 HISTOPATHOLOGIC FEATURES Apocrine secretory cells exhibit increased basophilia and contain variably sized yellow-brown granules. The granules show a positive Schmorl reaction and are autofluorescent with fluorescent microscopy. The difference in the clinical color of perspiration has been suggested to reflect varying amounts of lipofuscin in different states of oxidation. DIFFERENTIAL DIAGNOSIS Given the distinctive clinical presentation, the diagnosis should be straightforward. Since exogenous pigments and chromogenic microorganisms can show similar changes in the color of perspiration, those entities should be excluded by clinical history and special stains.

Neutrophilic Eccrine Hidradenitis CLINICAL FEATURES Neutrophilic eccrine hidradenitis (NEH) was described initially by Harrist and colleagues in 1982 as a complication of cytarabine chemotherapy in patients with acute myelogenous

Table 10-22 Neutrophilic Eccrine Hidradenitis

Clinical Features Onset a few days after administration of chemotherapeutic agents such as cytarabine, bleomycin Neck, trunk, extremities Tenderness Erythematous macules, papules, plaques Spontaneous resolution Histopathologic Features Neutrophilic infiltrates associated with eccrine sweat coil Eccrine epithelial cells show vacuolar degeneration and necrosis Mucin deposition in peri-eccrine adipose tissue Dermal edema Sparse dermal infiltrates composed of lymphocytes and neutrophils Differential Diagnosis Infectious hidradenitis and pyoderma Other neutrophilic dermatitides

an abrupt onset of tender, erythematous papules and nodules on the plantar and less commonly palmar surfaces.222-224 The lesions resolve spontaneously in most cases. The disease affects children and young adults of both sexes. There is no disease or chemotherapy association, and no specific etiology has been identified.222-224

 FIGURE 10-45 Neutrophilic eccrine hidradenitis. An eccrine sweat coil is infiltrated by neutrophils. The epithelial tubular structures show slight degenerative changes.

DIFFERENTIAL DIAGNOSIS The differential diagnosis is identical to that of NEH. The clinical distribution and presentation in healthy patients should allow distinction from NEH.

Sweat Gland Necrosis DIFFERENTIAL DIAGNOSIS The microscopic differential diagnosis includes infectious hidradenitis, neutrophilic dermatoses, leukocytoclastic vasculitis, and coma or pressure-induced eccrine necrosis. Special stains and/or tissue culture should be used to exclude an infectious hidradenitis. NEH has been hypothesized to be in the spectrum of neutrophilic dermatoses; however, in contrast to Sweet syndrome, the neutrophilic infiltrate is confined to the

eccrine unit. Although the pattern of the infiltrate in NEH may mimic vasculitis at low magnification, vessels typically are not affected.

Palmoplantar Eccrine Hidradenitis (Idiopathic Palmoplantar Hidradenitis) CLINICAL FEATURES Palmoplantar eccrine hidradenitis shares clinical and microscopic features with NEH. It presents as

 FIGURE 10-46 Sweat gland necrosis. Extensive noninflammatory necrosis of eccrine units is seen in coma-associated sweat gland necrosis.

CLINICAL FEATURES Patients in a comatose state due to carbon monoxide poisoning, drug overdose (especially barbiturates), severe illness, or trauma may develop bullae with sweat gland necrosis at pressure sites.225-227 The cause of these blisters is thought to be related to pressureinduced ischemia and possible toxic effect of offending drugs. HISTOPATHOLOGIC FEATURES Intra- and subepidermal vesiculation with variable dyskeratosis and necrosis is present in the epidermis. Eosinophilic coagulative necrosis of the eccrine secretory coils with minimal inflammation is the most characteristic finding in this entity (Fig. 10-46). Similar necrotic changes can be observed in adjacent hair follicles and sebaceous lobules. The dermis may be acellular or contain degenerating fibroblasts. Generally, the inflammatory infiltrate is minimal, but sparse neutrophils can be present around necrotic adnexal structures. DIFFERENTIAL DIAGNOSIS Other causes of cutaneous necrosis, such as coumarin necrosis, purpura fulminans, and vascular insufficiency–induced necrosis should be considered, but occlusion of vessels by fibrin, thrombi, or embolic material is identified in these cases. Chemotherapy-associated squamous metaplasia and necrosis also can be considered but lack the homogenized eosinophilic necrosis is seen in comaassociated sweat gland necrosis.

CHAPTER 10 ■ DISORDERS OF CUTANEOUS APPENDAGES

HISTOPATHOLOGIC FEATURES The microscopic findings are similar to NEH. There is a moderate to dense neutrophilic infiltrate involving the eccrine unit. Superficial and deep perivascular neutrophilic inflammatory infiltrates may be present.224

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125. Caputo R, Veraldi S. Erosive pustular dermatosis of the scalp. J Am Acad Dermatol. 1993;28:96-98. 126. Pye RJ, Peachey RD, Burton JL. Erosive pustular dermatosis of the scalp. Br J Dermatol. 1979;100:559-566. 127. Van Exel CE, English JC III. Erosive pustular dermatosis of the scalp and nonscalp. J Am Acad Dermatol. 2007;57:S11-S14. 128. Patton D, Lynch PJ, Fung MA, et al. Chronic atrophic erosive dermatosis of the scalp and extremities: a recharacterization of erosive pustular dermatosis. J Am Acad Dermatol. 2007;57:421-427. 129. Bridges A, von Kuster L, Estes S. Lipedematous alopecia. Cutis. 2000;65: 199-202. 130. Ikejima A, Yamashita M, Ikeda S, et al. A case of lipedematous alopecia occurring in a male patient. Dermatol. 2000; 201:168-170. 131. Martin JM, Monteagudo C, Montesinos E, et al. Lipedematous scalp and lipedematous alopecia: a clinical and histologic analysis of 3 cases. J Am Acad Dermatol. 2005;52:152-156. 132. Yasar S, Mansur AT, Goktay F, et al. Lipedematous scalp and lipedematous alopecia: report of three cases in white adults. J Dermatol. 2007;34:124-130. 133. Scheufler O, Kania NM, Heinrichs CM, et al. Hyperplasia of the subcutaneous adipose tissue is the primary histopathologic abnormality in lipedematous scalp. Am J Dermatopathol. 2003; 25:248-252. 134. Fair K, Knoell KA, Patterson J, et al. Lipedematous alopecia: a clinicopathologic, histologic and ultrastructural study. J Cutan Pathol. 2000;27:49-53. 135. Poskitt L, Wilkinson JD. Natural history of keratosis pilaris. Br J Dermatol. 1994; 130:711-713. 136. Baden H, Byers H. Clinical findings, cutaneous pathology, and response to therapy in 21 patients with keratosis pilaris atrophicans. Arch Dermatol. 1994;130:469-475. 137. Oranje AP, van Osch LD, Oosterwijk JC. Keratosis pilaris atrophicans. One heterogeneous disease or a symptom in different clinical entities? Arch Dermatol. 1994;130:500-502. 138. Plewig G, Jansen T. Acneiform dermatoses. Dermatol. 1998;196:102-107. 139. Yu Y, Cheng AS, Wang L, et al. Hot tub folliculitis or hot hand-foot syndrome caused by Pseudomonas aeruginosa. J Am Acad Dermatol. 2007;57:596-600. 140. Adler A, Altman J. An outbreak of mudwrestling-induced pustular dermatitis in college students. Dermatitis palaestrae limosae. JAMA. 1993;269:502-504. 141. Back O, Faergemann J, Hornqvist R. Pityrosporum folliculitis: a common disease of the young and middle-aged. J Am Acad Dermatol. 1985;12:56-61. 142. Smith KJ, Neafie R, Skelton H, et al. Majocchi’s granuloma. J Cutan Pathol. 1991;18:28-35. 143. Bonnar E, Eustace P, Powell F. The Demodex mite population in rosacea. J Am Acad Dermatol. 1993;28:443-448. 144. Erbagci Z, Ozgoztasi O. The significance of Demodex folliculorum density in rosacea. Int J Dermatol. 1998;37:421-425. 145. Aylesworth R, Vance J. Demodex folliculorum and Demodex brevis in cutaneous biopsies. J Am Acad Dermatol. 1982;7:583-589.

146. Boer A, Herder N, Winter K, et al. Herpes folliculitis: clinical, histopathological, and molecular pathologic observations. Br J Dermatol. 2006;154:743-746. 147. Smith K, Skelton H, Frissman D, et al. Verrucous lesions secondary to DNA viruses in patients infected with the human immunodeficiency virus in association with increased factor XIIIa-positive dermal dendritic cells. J Am Acad Dermatol. 1992;27:943-950. 148. Weinberg JM, Mysliwiec A, Turiansky GW, et al. Viral folliculitis. Atypical presentations of herpes simplex, herpes zoster, and molluscum contagiosum. Arch Dermatol. 1997;133:983-986. 149. Weinberg JM, Turiansky GW, James WD. Viral folliculitis. AIDS Patient Care Stds. 1999;13:513-516. 150. Sexton M. Occult herpesvirus folliculitis clinically simulating pseudolymphoma. Am J Dermatopathol. 1991;13:234-240. 151. Bartralot R, Pujol RM, Garcia-Patos V, et al. Cutaneous infections due to nontuberculous mycobacteria: histopathological review of 28 cases. Comparative study between lesions observed in immunosuppressed patients and normal hosts. J Cutan Pathol. 2000;27:124-129. 152. Kaminer M, Gilchrest B. The many faces of acne. J Am Acad Dermatol. 1995;32:S6-S14. 153. Leyden J. New understandings of the pathogenesis of acne. J Am Acad Dermatol. 1995;32:S15-S25. 154. Tindall J. Chloracne and chloracnegens. J Am Acad Dermatol. 1985;13:539-558. 155. Kligman A, Frosch P. Steroid addiction. Int J Dermatol. 1979;18:23-31. 156. DeWitt CA, Siroy AE, Stone SP. Acneiform eruptions associated with epidermal growth factor receptor-targeted chemotherapy.[see comment]. J Am Acad Dermatol. 2007;56:500-505. 157. Eames T, Landthaler M, Karrer S. Severe acneiform skin reaction during therapy with erlotinib (Tarceva), an epidermal growth factor receptor (EGFR) inhibitor. Eur J Dermatol. 2007;17:552-553. 158. Goeteyn M, Mestdagh M, Aelbrecht M. Elastoidosis with cysts and comedones (Favre and Racouchot). Dermatologica. 1990;180:194. 159. Brown L. Pathogenesis and treatment of pseudofolliculitis barbae. Cutis. 1983;32: 373-375. 160. Crutchfield C. The causes and treatment of pseudofolliculitis barbae. Cutis. 1998;61:351-356. 161. Halder RM. Pseudofolliculitis barbae and related disorders. Dermatol Clin. 1988;6:407-412. 162. Perry P, Cook-Bolden F, Rahman Z, et al. Defining pseudofolliculitis barbae in 2001: a review of the literature and current trends. J Am Acad Dermatol. 2002;46:S113-S119. 163. Jemec G, Hansen U. Histology of hidradenitis suppurativa. J Am Acad Dermatol. 1996;34:994-999. 164. Attanoos R, Appleton M, Douglas-Jones A. The pathogenesis of hidradenitis suppurativa: a closer look at apocrine and apoeccrine glands. Br J Dermatol. 1995;133:254-258. 165. Attanoos R, Appleton M, Hughes L, et al. Granulomatous hidradenitis suppurativa and cutaneous Crohn’s disease. Histopathol. 1993;23:111-115.

166. Jansen T, Plewig G. Rosacea: classification and treatment. J R Soc Med. 1997; 90:144-150. 167. Kligman A. Ocular rosacea. Current concepts and therapy. Arch Dermatol. 1997;133:89-90. 168. Snapp RH, Lewandowsky A. Rosacealike eruption: a clinical study. J Invest Dermatol. 1949;13:175-189. 169. Tope W, Sangueza O. Rhinophyma’s fibrous variant. Histopathology and immuno histochemistry. Am J Dermatopathol. 1994;16:307-310. 170. Aroni K, Tsagroni E, Kavantzas N, et al. A study of the pathogenesis of rosacea: how angiogenesis and mast cells may participate in a complex multifactorial process. Arch Dermatol Res. 2008;300: 125-131. 171. Hogan D. Perioral dermatitis. Curr Probl Dermatol. 1995;22:98-104. 172. Helm K, Menz J, Gibson L, et al. A clinical and histopathologic study of granulomatous rosacea. J Am Acad Dermatol. 1991;25:1038-1043. 173. Marks R, Harcourt-Webster JN. Histopathology of rosacea. Arch Dermatol. 1969;100:683-691. 174. Sahn E, Sheridan D. Demodicidosis in a child with leukemia. J Am Acad Dermatol. 1992;27:799-801. 175. Mehregan A, Coskey R. Perforating folliculitis. Arch Dermatol. 1968;97:394-399. 176. Golitz L. Follicular and perforating disorders. J Cutan Pathol. 1985;12:282-288. 177. Patterson J. The perforating disorders. J Am Acad Dermatol. 1984;10:561-581. 178. Sehgal V, Jain S, Thappa D, et al. Perforating dermatoses: a review and report of four cases. J Dermatol. 1993; 20:329-340. 179. Hurwitz R. The evolution of perforating folliculitis in patients with chronic renal failure. Am J Dermatopathol. 1985;7:231239. 180. Hurwitz R, Melton M, Creech F, et al. Perforating folliculitis in association with hemodialysis. Am J Dermatopathol. 1982;4:101-108. 181. Moss HV. Kyrle’s disease. Cutis. 1979;23:463-466. 182. Gilaberte Y, Coscojuela C, Vazquez C, et al. Perforating folliculitis associated with tumour necrosis factor-alpha inhibitors administered for rheumatoid arthritis. Br J Dermatol. 2007;156:368-371. 183. Blume-Peytavi U, Chen W, Djemadji N, et al. Eosinophilic pustular folliculitis (Ofuji’s disease). J Am Acad Dermatol. 1997;37:259-262. 184. Dinehart S, Noppakun N, Solomon A, et al. Eosinophilic pustular folliculitis. J Am Acad Dermatol. 1986;14:475-479. 185. Jaliman H, Phelps R, Fleischmajer R. Eosinophilic pustular folliculitis. J Am Acad Dermatol. 1986;14:479-482. 186. Ofuji S, Ogino A, Horio T, et al. Eosinophilic pustular folliculitis. Acta Derm Venereol. 1970;50:195-203. 187. Giard F, Marcoux D, McCuaig C, et al. Eosinophilic pustular folliculitis (Ofuji disease) in childhood: a review of four cases. Pediatr Dermatol. 1991;8:189-193. 188. Lucky A, Esterly N, Heskel N, et al. Eosinophilic pustular folliculitis in infancy. Pediatr Dermatol. 1984;1:202206. 189. Taieb A, Bassan-Andrieu L, Maleville J. Eosinophilic pustulosis of the scalp in

190.

191.

192.

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195.

196.

197.

198.

199.

200. 201.

202. Effendy I, Ossowski B, Happle R. FoxFordyce disease in a male patient– response to oral retinoid treatment. Clin Exp Dermatol. 1994;19:67-69. 203. Ranalletta M, Rositto A, Drut R. FoxFordyce disease in two prepubertal girls: histopathologic demonstration of eccrine sweat gland involvement. Pediatr Dermatol. 1996;13:294-297. 204. Miller ML, Harford RR, Yeager JK. FoxFordyce disease treated with topical clindamycin solution. Arch Dermatol. 1995;131:1112-1113. 205. Boer A. Patterns histopathologic of FoxFordyce disease. Am J Dermatopathol. 2004;26:482-492. 206. Stashower M, Krivda S, Turiansky G. Fox-Fordyce disease: diagnosis with transverse histologic sections. J Am Acad Dermatol. 2000;42:89-91. 207. Shelley WB, Levy EJ. Apocrine sweat retention in man. Arch Dermatol. 1956; 73:38-49. 208. Kossard S, Dwyer P. Axillary perifollicular xanthomatosis resembling Fox-Fordyce disease.[see comment]. Aust J Dermatol. 2004;45:146-148. 209. Cilliers J, de Beer C. The case of the red lingerie—chromhidrosis revisited. Dermatol. 1999;199:149-152. 210. Mali-Gerrits M, van de Kerkhof P, Mier P, et al. Axillary apocrine chromhidrosis. Arch Dermatol. 1988;124:494-496. 211. Shelley WB, Hurley HJ. Localized chromhidrosis: a survey. Arch Dermatol Syphilol. 1954;69:449-471. 212. Saff D, Owens R, Kahn T. Apocrine chromhidrosis involving the areolae in a 15-year-old amateur figure skater. Pediatr Dermatol. 1995;12:48-50. 213. Thami GP, Kanwar AJ. Red facial pseudochromhidrosis. Br J Dermatol. 2000;142:1219-1220. 214. Harrist TJ, Fine JD, Berman RS, et al. Neutrophilic eccrine hidradenitis. A distinctive type of neutrophilic dermatosis associated with myelogenous leukemia and chemotherapy. Arch Dermatol. 1982;118:263-266. 215. Bachmeyer C, Aractingi S. Neutrophilic eccrine hidradenitis. Clin Dermatol. 2000; 18:319-330.

216. Bachmeyer C, Chaibi P, Aractingi S. Neutrophilic eccrine hidradenitis induced by granulocyte colony-stimulating factor. Br J Dermatol. 1998; 139: 354-355. 217. Fitzpatrick JE, Bennion SD, Reed OM, et al. Neutrophilic eccrine hidradenitis associated with induction chemotherapy. J Cutan Pathol. 1987;14:272-278. 218. Hurt MA, Halvorson RD, Petr FC, Jr., et al. Eccrine squamous syringometaplasia. A cutaneous sweat gland reaction in the histologic spectrum of ‘chemotherapy-associated eccrine hidradenitis’ and ‘neutrophilic eccrine hidradenitis’. Arch Dermatol. 1990;126:73-77. 219. Templeton SF, Solomon AR, Swerlick RA. Intradermal bleomycin injections into normal human skin. A histopathologic and immunopathologic study. Arch Dermatol. 1994;130:577-583. 220. Bachmeyer C, Reygagne P, Aractingi S. Recurrent neutrophilic eccrine hidradenitis in an HIV-1-infected patient. Dermatol. 2000;200:328-330. 221. Roustan G, Salas C, Cabrera R, et al. Neutrophilic eccrine hidradenitis unassociated with chemotherapy in a patient with acute myelogenous leukemia. Int J Dermatol. 2001;40:144-147. 222. Landau M, Metzker A, Gat A, et al. Palmoplantar eccrine hidradenitis: three new cases and review. Pediatr Dermatol. 1998;15:97-102. 223. Simon M, Jr., Cremer H, von den Driesch P. Idiopathic recurrent palmoplantar hidradenitis in children. Report of 22 cases. Arch Dermatol. 1998;134:76-79. 224. Stahr BJ, Cooper PH, Caputo RV. Idiopathic plantar hidradenitis: a neutrophilic eccrine hidradenitis occurring primarily in children. J Cutan Pathol. 1994;21:289-296. 225. Leavell UW. Sweat gland necrosis in barbituate poisoning. Arch Dermatol. 1969;100:218-221. 226. Leavell UW, Farley CH, McIntire JS. Cutaneous changes in a patient with carbon monoxide poisoning. Arch Dermatol. 1969;99:429-433. 227. Mandy S, Ackerman A. Characteristic traumatic skin lesions in drug-induced coma. JAMA. 1970;213:253-256.

CHAPTER 10 ■ DISORDERS OF CUTANEOUS APPENDAGES

194.

childhood. J Am Acad Dermatol. 1992; 27:55-60. Dupond A, Aubin F, Bourezane Y, et al. Eosinophilic pustular folliculitis in infancy: report of two affected brothers. Br J Dermatol. 1995;132:296-299. Larralde M, Morales S, Santos Munoz A, et al. Eosinophilic pustular folliculitis in infancy: report of two new cases. Pediatr Dermatol. 1999;16:118-120. Soeprono F, Schinella R. Eosinophilic pustular folliculitis in patients with acquired immunodeficiency syndrome. Report of three cases. J Am Acad Dermatol. 1986;14:1020-1022. Blauvelt A, Plott R, Spooner K, et al. Eosinophilic folliculitis associated with the acquired immunodeficiency syndrome responds well to permethrin. Arch Dermatol. 1995;131:360-361. Rosenthal D, LeBoit PE, Klumpp L, et al. Human immunodeficiency virus-associated eosinophilic folliculitis. A unique dermatosis associated with advanced human immunodeficiency virus infection. Arch Dermatol. 1991;127:206-209. Parker SRS, Parker DC, McCall CO. Eosinophilic folliculitis in HIV-infected women: case series and review. Am J Clin Dermatol. 2006;7:193-200. Buezo G, Fraga J, Abajo P, et al. HIVassociated eosinophilic folliculitis and follicular mucinosis. Dermatol. 1998; 197:178-180. Goiriz R, Guhl-Millán G, Peñas P, et al. Eosinophilic folliculitis following allogeneic peripheral blood stem cell transplantation: case report and review. J Cutan Pathol. 2007;34:33-36. Magro C, Crowson A. Necrotizing eosinophilic folliculitis as a manifestation of the atopic diathesis. Int J Dermatol. 2000;39:672-677. McCalmont T, Altemus D, Maurer T, et al. Eosinophilic folliculitis. The histologic spectrum. Am J Dermatopathol. 1995; 17:439-446. Macmillan DC, Vickers HR. FoxFordyce disease. Br J Dermatol. 1971; 84:181. Winkelmann RK, Montgomery H. FoxFordyce disease: a histopathologic and histochemical investigation. Arch Dermatol. 1956;74:63.

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CHAPTER 11 Panniculitis

PART I ■ INFLAMMATORY REACTIONS IN THE SKIN

Raymond L. Barnhill Birgitta Schimdt

One of the more difficult subjects in all of dermatopathology is the study and classification of inflammatory processes that involve the subcutaneous fat.1-6 Why does panniculitis pose such a challenge to dermatopathologists? On the whole, many of these conditions have not been studied at the molecular level in detail, and thus inadequate information is available to date concerning their pathogenesis. Some of the reasons for this lack of data include the following: (1) in general, panniculitis is relatively uncommon, (2) dermatologists and other physicians often are reluctant to biopsy subcutaneous nodules because poor wound healing is commonly expected, (3) biopsies often are too small and do not sample the affected area adequately (Table 11-1), (4) the clinical findings for

Table 11-1 Evaluation of Panniculitis 1. Excisional wedge biopsy is necessary for adequate sampling. 2. Punch biopsies are to be discouraged and may be misleading. 3. Biopsy an active rather than a late-stage lesion. 4. Special stains for infectious organisms include Gram, acid-fast, fungal,WarthinStarry, Fite-Faraco. 5. Examine specimen under polarized light for foreign material. 6. Laboratory investigation includes cultures and other techniques, such as immunostaining and polymerase chain reaction, for infection; serologic testing for syphilis, borreliosis, connective tissue disease, vasculitis, alpha-l-antitrypsin deficiency, calcium, phosphorus, oxalate, coagulopathy, lipase, amylase. 7. Directed clinical history for isolated lesion (eg, ruptured cyst), trauma, factitial causes, psychiatric illness, drug abuse, cold exposure, recent medications, systemic disease, eg, vasculitis, connective tissue disease, sarcoidosis, infections, malignancy.

250

many panniculitides are fairly similar, (5) the response of adipose tissue to injury is limited, and (6) the histopathologic findings depend on when the biopsy is obtained during the time course of the disease process. Based on these points, skin pathologists often have tended to ascribe too much specificity to morphologic observations made on limited samplings taken from limited numbers of patients, often without considering when the specimen(s) were obtained in the natural history of the panniculitis. To gain a better understanding of the nature of pathologic processes in subcutaneous tissue, it is necessary to review briefly (1) the microanatomy of adipose tissue and (2) the reactions of subcutaneous fat to injury. In this chapter, we provide an overview and update of the findings of interest to the dermatopathogist in the diagnosis of panniculitis and fasciitis.

MICROANATOMY OF SUBCUTANEOUS FAT The subcutaneous tissue consists of depot fat sandwiched between the reticular dermis above and the superficial fascia beneath.1,2 Adipose tissue is organized into two compartments: (1) discrete round or ovoid lobules composed of confluent aggregates of the clearappearing fat cells and (2) fibrous trabeculae (or septa) that form a meshwork separating the individual fat lobules. The fibrous septa are continuous with collagen of the reticular dermis and the superficial fascia and contain all the blood vessels, lymphatics, and nerves of the subcutaneous fat. In one sense, the fibrous septa simply serve as scaffolding for vascular and nerve plexi traversing the subcutis from deeper tissue to supply the skin. Thus, inflammatory conditions affecting the fat often involve the reticular dermis and fascia, and vice versa. Arterial vessels in the fat are small to medium in size and are categorized as muscular arteries. Thus it is not possible to develop large-vessel arteritis in the subcutaneous fat but rather an arteritis affecting vessels of the caliber noted in polyarteritis nodosa. Each fat lobule is vascularized by a single arteriole and, in effect, is an end organ with no collateral blood supply.1,2 There are no lymphatics within the lobules. Any interruption to this arterial supply will eventuate in ischemia or infarction of the fat lobule depending on the speed with which vascular compromise develops. The individual fat cells

are supplied by arterial capillaries with drainage to venous capillaries and venules at the peripheries of the fat lobules. Based on these vascular patterns, in very general terms pathologic processes affecting arterial vessels may result in a “lobular” pattern of panniculitis versus a “septal” pattern associated with venular or venous inflammatory disorders.

REACTIONS OF SUBCUTANEOUS FAT TO INJURY Many of the morphologic changes observed in panniculitis are simply nonspecific reparative reactions of the fat tissues (ie, adipocytes ) and surrounding tissue to local injury, often irrespective of the particular etiologic agent1-5 (Table 11-2). For sometime it has been recognized that injury to the fat cells result in the release of lipid that becomes a foreign body or irritant. Also, recent results indicate that activation of adipocytes leads to the release of local mediators, such as eicosanoids and adipokines, that serve similar functions as chemokines and thus can elicit a local leukocytic infiltrates via chemotaxis.7 The ensuing host response is thus involved in removing this “foreign” substance or chemoattractants to restore the tissue to normal homeostasis. The initial reaction within seconds to minutes is the influx of neutrophils (acute inflammation) and then the local proliferation of blood vessels. The next phase of the tissue reaction is characterized by the arrival of mononuclear cells, that is, lymphocytes and monocytes/macrophages. The latter cells are concerned primarily with the phagocytosis

Table 11-2 Manifestations of Fat Necrosis Lipophages—macrophages containing phagocytosed lipid following necrosis of adipocytes Microcysts—coalesced tissue spaces in fat following fat necrosis Liquefactive alterations—granular cellular debris Hyalinizing (sclerosing) alterations— intact mummified lipocytes with a grainy and, at late stages, glassy amorphous appearance Membranous (lipomembranous) microcyst formation—microcysts lined by feathery, almost ciliated membranes Ischemic alterations—pallor of adipocytes with loss of nuclei and microvessels, hemorrhage, hemosiderin deposits, karyorrhexis

of the damaged adipocyte-released lipids and other debris which can often result in the formation of lipidized macrophages (foamy histiocytes) and multinucleate giant cells. The final histologic stage in this response to local injury of adipose tissue is fibroplasia and the eventual reconstitution of tissue integrity. The ultimate outcome in many instances is a scarring process. These three stages of the host reaction—acute inflammation, chronic inflammation, and fibrosis—are fairly constant but obviously may vary depending on the intensity and nature of the insult to the local fat tissues.

Major problems with traditional classification of panniculitis include the tendency to place too much emphasis on categorizing a process as either a septal or lobular panniculitis and the application of often arcane terminology, such as Weber-Christian disease or erythema induratum, to the condition rather than investigation for a specific cause. Indeed, many panniculitides may be either septal or lobular, and probably most are both septal and lobular; thus this pattern approach often adds little additional

SEPTAL PANNICULITIS As stated above, the goals of the histopathologist are to systematically evaluate a mainly septal process (see Fig. 11-3) for histopathologic findings or clues leading to a specific diagnosis if at all possible1-9 (see Tables 11-3 and 11-5). Such alterations include vasculitis; prominent sclerosis of septa as in morphea, scleroderma, and eosinophilic fasciitis; lymphoid infiltrates or nodules, as in connective tissue disease; lymphoid infiltrates and hyalinization, as in lupus panniculitis; infectious agents; foreign bodies; and palisading granulomas. If no characteristic features are observed, one is often left with a nonspecific panniculitis. Based on the cellular composition and degree of fibrosis, the septal panniculitis may be categorized as (1) an acute process, that is, neutrophils, eosinophils, edema, little or no septal thickening, (2) a subacute panniculitis (predominantly mononuclear cells), that is, presence of lymphocytes, monocytes/macrophages, some septal thickening, and fibrosis, or (3) a chronic or late-stage septal panniculitis with clear septal thickening and marked fibrosis. Many processes may produce a nonspecific predominantly septal panniculitis, particularly in the early stages (see Table 11-4).

CHAPTER 11 ■ PANNICULITIS

PANNICULITIS: APPROACH TO THE INTERPRETATION

information to the diagnostic evaluation when, in fact, it is not so important as looking for a cause of the panniculitis (Figs 11-1 and 11-2 and Table 11-3). The overall objective of this chapter is to emphasize the systematic evaluation of panniculitis for a specific etiology and to discourage the use of outdated terminology. The use of outdated terms can, if anything, obfuscate the rational investigation of disorders of adipose tissue. The objectives of the histopathologist when confronted with a disease process in subcutaneous fat are (1) to identify the predominant pattern as septal or lobular, or both septal and lobular, without placing too much emphasis on this exercise (Table 11-4), (2) to identify whether there is any alteration of the epidermis, dermis, or fascia; and (3) to look for particular histologic findings that would indicate or suggest a specific diagnosis (see Table 11-3). The histopathologic findings must then be correlated with clinical history and laboratory studies. The evaluation of panniculitis will be approached using the major categories of septal panniculitis and lobular panniculitis, realizing that this categorization is often of limited value because many processes may be septal or lobular or show varying degrees of both septal and lobular involvement.

Panniculitis

Fasciitis: eosinophilic fasciitis and related disorders; borreliosis; nonborrelial

Neutrophils, edema: infection; neutrophilic dermatosis

Epidermal and/or dermal alterations

Interface changes, dermal mucin: lupus panniculitis

Dermal sclerosis: morphea, scleroderma

Panniculitis only (see Fig. 11-2)

Vasculitis

Small-vessel vasculitis (see Chap. 9)

Medium-sized vessel (see Chap. 9)

Artertis Polyarteritis nodosa Arteritis, not otherwise specified

Superficial migratory  FIGURE 11-1 Algorithmic Approach to Diagnosis of Panniculitis.

Thrombophlebitis

Venous insufficiency

251

Panniculitis only

Septal

PART I ■ INFLAMMATORY REACTIONS IN THE SKIN

Erythema nodosum reactions

Short duration reactions

Other, early

Septal, lobular

Lymphoplasma cellular infiltrates: connective tissue disease

Chronic reactions

Crystals

Cytophagocytosis: Cytophagocytosis: cytophagic cytophagichistiocytic histiocytic panniculitis; panniculitis; immunosuppression: infection; infection;malignancy malignancy

Inflammation; crystals in macrophages; lipocytes: subcutaneous fat; necrosis; poststeroid panniculitis

Septal sclerosis: morphea; scleroderma

Granulomatous inflammation: infection; physical panniculitis; metastatic Crohn disease; pyoderma gangrenosum

Neutrophilicinfiltrates: infiltrates: Neutrophilic EN EN reactions; reactions; infection; infection; neutrophilic neutrophilicdermatosis; dermatosis; pyoderma pyodermagangrenosum; gangrenosum; physicalpanniculitis panniculitis physical

Little or no inflammation; crystals in lipocytes: sclerema neonatorum

 FIGURE 11-2 Algorithmic Approach to Diagnosis of Panniculitis.

In many cases, based on thorough evaluation of the patient and clinical history and follow-up, it is possible to identify a cause or presumed cause.

Erythema Nodosum

252

Ghost cells saponification: pancreatic panniculitis

Lobular

Thought by many clinicians to be a rather distinctive clinicopathologic entity,2-4,6-11 erythema nodosum (EN) is in fact a relatively nonspecific hypersensitivity reaction associated with a wide variety of causes (see Table 11-5) eventuating in fairly short-lived tender red nodules and raised plaques most often located on the extensor aspects of the legs.8-17 Streptococcal infections are the most common etiology in children, whereas sarcoidosis, drugs, and inflammatory bowel disease are among the most common causes in adults.18 In a recent review of the literature, upper respiratory tract infection was the most frequent cause of EN in adults, and in many parts of the world tuberculosis is still a common underlying condition. EN has now been shown to be the most prevalent cutaneous manifestation of inflammatory bowel disease, and about

15% of Crohn disease patients exhibit EN reactions.19 Of interest, EN may be the first manifestation of inflammatory bowel disease.20 EN may be thought of as a nonspecific clinical finding, perhaps analogous to urticaria or a maculopapular erythematous eruption. A major problem is that the clinical lesions are thought to be distinctive, almost regardless of the histopathologic findings. Histologic examination of the red nodules most commonly discloses a (predominately) septal panniculitis, but in some instances lobular infiltrates are observed. Thus the histologic spectrum associated with EN has expanded and now includes neutrophilic,9 eosinophilic,21 and granulomatous lobular infiltrates.10 Furthermore, the clinical spectrum of EN has been extended to encompass long-standing or chronic forms of panniculitis, termed chronic EN, EN migrans, or subacute nodular migratory panniculitis of Villanova and Piñol.18,22-26 However, some authors believe that chronic EN and EN migrans are related but have clinical and histopathologic differences.26 The term EN probably should be reserved for panniculitides that have been

thoroughly investigated and monitored for a specific etiology and show the appropriate clinical and pathologic features. CLINICAL FEATURES Typical EN is strictly defined as a rapid onset of symmetric crops of tender, bright-red nodules lasting usually 3 to 6 weeks and often resolving with a bruiselike appearance (erythema contusiformis) but always without ulceration, scarring, or atrophy3,4,8-13,18 (Fig. 11-3A) (Table 11-6). Recurrence is not uncommon.18 The bruiselike progression and appearance is very characteristic of EN.18 The lesions may occur anywhere but characteristically involve the ankles, knees, and anterior shins. Women are afflicted three to six times more often than men.18 The age typically ranges between 20 and 50 years, with the peak incidence between 20 and 30 years of age.18 However, EN can occur at any age.18 Often the lesions are accompanied by abdominal pain, arthralgias, cough, diarrhea, fever, headache, malaise, and vomiting.11,18 Chronic EN and EN migrans appear to represent hypersensitivity reactions of longer duration, often 1 to 4 years or

Table 11-4 Predominant Patterns of the Panniculitides

Vasculitis Small-vessel vasculitis Thrombophlebitis Polyarteritis and other arteritides Calcification of vessels Calciphylaxis Thrombotic occlusion of vessels Coagulopathy Cryoprecipitate Septal sclerosis Morphea profunda Scleroderma Eosinophilic fasciitis Lymphoplasma cellular infiltrates Connective tissue disease Lupus panniculitis Dermatomyositis Connective tissue panniculitis Lipoatrophy Necrobiosis lipoidica Hyalinization and lymphoplasmacellular infiltrates Lupus panniculitis Infectious organisms Palisading granulomas Granuloma annulare Rheumatoid nodule Necrobiosis lipoidica Panniculitis with crystal formation Subcutaneous fat necrosis Sclerema neonatorum Poststeroid panniculitis Oxalosis Gout Ghost cells, saponification Pancreatic (enzymic) panniculitis Cytophagocytosis Cytophagic histiocytic panniculitis Infection Lymphoma Sclerosing lipogranuloma Injected or implanted lipids Foreign bodies Chemical and factitial panniculitis Atypical cellular infiltrates Lymphoma Leukemia

Hypersensitivity reactions Short duration (erythema nodosum reactions) Longer duration (chronic EN) Vasculitis Small-vessel vasculitis Medium- to large-vessel vasculitis Lipodermatosclerosis

more.22-26 Some authors maintain that chronic EN is characterized by fairly discrete, persistent nodules that are symmetric and not migratory, whereas EN migrans tends to show nodules that coalesce into spreading plaques that are commonly unilateral.26 HISTOPATHOLOGIC FEATURES Although erythema nodosum may be thought of

PATTERN OF PANNICULITIS

CONDITION

Septal → lobular Septal → lobular

Calciphylaxis Oxalosis Morphea profunda, scleroderma, eosinophilic fasciitis Palisading granulomas Alpha-l-antitrypsin deficiency Cytophagic histiocytic panniculitis Pancreatic panniculitis Subcutaneous fat necrosis Sclerema neonatorum Poststeroid panniculitis Infection-related panniculitis Physical panniculitis Cold panniculitis Trauma-related Chemical and factitial Connective tissue disease Lupus panniculitis Dermatomyositis Connective tissue panniculitis Eosinophilic panniculitis Noninfectious granulomatous panniculitis Sarcoidosis Metastatic Crohn disease Lymphoma and leukemia

as a nonspecific reaction resulting from a wide variety of agents, the histopathologic findings may be categorized as principally early, intermediate/established, or late stage8-13 (Figs. 11-3B and 11-4; see also Table 11-4). Early or acute lesions commonly show changes primarily confined to the fibrous trabeculae: edema, hemorrhage, and variable inflammatory cell infiltrates composed primarily of neutrophils, possibly with some admixture of lymphocytes and eosinophils (Table 11-6) (Fig. 11-3 and 11-4f). This infiltrate often extends into the peripheries of the fat lobules. Otherwise, the fat lobules are largely unaffected. Older lesions often exhibit some thickening of the septa and a predominance of mononuclear cells, lymphocytes in particular (see Fig. 11-4). There may be greater encroachment into the fat lobules by the inflammatory cell infiltrates. Often at this stage one

Septal → lobular Septal and lobular Septal and lobular Septal early Septal and lobular Septal and lobular Septal → lobular Septal early Septal → lobular Septal and lobular Lobular → septal Lobular → septal Lobular → septal Lobular → septal Lobular → septal Septal and lobular Septal and lobular Lobular → septal Lobular → septal

CHAPTER 11 ■ PANNICULITIS

Table 11-3 Histopathologic Findings Suggesting a Particular Category or Type of Panniculitis

Septal and lobular Septal and lobular Septal and lobular Septal and lobular

Septal and lobular Septal and lobular Lobular → septal

begins to encounter mononuclear cells arranged in a radial array and somewhat later multinucleate histiocytic giant cells in the thickened fibrotic septa, the so-called Miescher granulomas27 (see Figs. 11-4E). The latter feature is considered by some authors to be diagnostic or supportive of EN. It appears as a radially shaped granuloma with well-delineated, small collections of histiocytes surrounding a staror crescent-shaped fissure.18 However, this granulomatous reaction involving the fibrous trabeculae is likely to be a nonspecific reparative response associated with phagocytosis of collagen and other materials. With evolution of lesions, there is greater thickening and fibrosis of the septa. The infiltrate becomes more granulomatous, and there is a general tendency to greater involvement of the lobules.4,8,10 With time, there is gradual obliteration of fat lobules by the septal fibrosis.

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B

A

C  FIGURE 11-3 Erythema nodosum. (A) Erythematous plaques involving the lateral aspects of lower extremities below the knees and near the ankle. (B) Erythema nodosum reaction pattern. Acute erythema nodosum: Scanning magnification shows inflammation and extravasation of erythrocytes involving the fibrous trabeculae and peripheries of the fat lobules. The fat lobules are virtually uninvolved. (B and C) Acute erythema nodosum: Note that the fibrous septae are not significantly thickened at this stage.

Although some fat necrosis is observed occasionally, this is not a prominent feature in EN. To the extent that fat necrosis does occur, lipophages and granulomatous inflammation are present. Two additional reaction patterns observed in this setting of EN include (1) acute (neutrophilic) panniculitis9 (see Fig. 11-4F) and (2) eosinophilic panniculitis21 (see the heading later in the chapter). Both present as predominately lobular infiltrates of neutrophils and

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eosinophils, respectively. The inclusion of panniculitides with the preceding histologic features speaks to the nonspecific nature of EN. By definition, vasculitis is not a major feature of EN. However, low-grade vascular injury and thrombophlebitis have been emphasized as findings commonly encountered in the EN reaction pattern.8 One must determine whether septal panniculitis or thrombophlebitis is the predominant finding and also consider

the clinical features in order to arrive at a final interpretation of their significance. Chronic EN and EN migrans have been reported to have histopathologic as well as clinical differences.26 Chronic EN has been described as showing discrete perivascular lymphocytic infiltrates and very little fibrosis and thickening of fibrous trabeculae. Characteristic findings of chronic EN also include extravasated erythrocytes and phlebitis.18 On the other hand, EN migrans may have septal thickening and

Table 11-5 Causes of Septal Panniculitis (Erythema Nodosum Reactions)

fibrosis, epithelioid granulomas with multinucleated giant cells, and vascular proliferation resembling granulation tissue.18 EN migrans does not have phlebitis or extravasated erythrocytes.18 These differences may represent a spectrum of the same pathologic process (EN) rather than two other distinct entities.18 DIFFERENTIAL DIAGNOSIS As already discussed, this reaction pattern is nonspecific,

Clinical Features Women > men Age 20-50 years Tender reddish nodules 3-6-week duration No ulceration or scarring—anterior shins most often Fever Malaise Arthralgias Bilateral hilar lymphadenopathy (Löfgren syndrome) Histopathologic Features Septal panniculitis Neutrophils, occasional eosinophils, followed by lymphocytes, mononuclear cells Edema, hemorrhage Thickening of septa Peripheral involvement of fat lobules Usually no fat necrosis Thrombophlebitis on occasion Lobular panniculitis Acute neutrophilic panniculitis Granulomatous panniculitis Usually minimal fat necrosis Differential Diagnosis Septal panniculitis Sclerosing panniculitis Connective tissue disease Many conditions early Lobular panniculitis Infection Neutrophilic dermatosis Sweet syndrome Pyoderma gangrenosum Vasculitis Calciphylaxis Physical and factitial panniculitis Alpha-l-antitrypsin deficiency Subcutaneous fat necrosis of newborn

since a number of processes may begin or present as a septal panniculitis. Thus one must consider connective tissue disease, infection, neutrophilic dermatoses (Sweet syndrome and pyoderma gangrenosum),16,28 physical insults, fibrosing panniculitides, and palisading granulomas in this differential diagnosis. Recently, a case of nephrogenic systemic fibrosis, seen in patient with end-stage renal disease, demonstrated histologic findings consistent with EN with several Miescher radial granulomas.29 Careful scrutiny of the specimen for histologic findings leading to one of the latter diagnoses, special stains for organisms,

evaluation with polarized light, serologic evaluation, and clinical history are needed to exclude specific causes of the panniculitis.

Vasculitis, Vasculopathy, and Ischemic Necrosis of Subcutaneous Fat As discussed previously, vascular injury is a common component and cause of panniculitis. Vessels ranging from capillaries to medium-sized arteries or veins may be involved.1-4,8 Thus the subcutis should be examined for leukocytoclastic venulitis, arteritis, as in polyarteritis nodosa, or thrombophlebitis. Vasculitis is discussed in detail in Chap. 9 and is beyond the scope of this chapter. In general, vasculitis should be assessed with respect to the caliber of the vessel involved; the type of vessel, that is, venule, arteriole, vein, or medium-sized artery; and the composition of the infiltrate, that is, the presence of neutrophils, eosinophils, lymphocytes, or granulomatous elements. The vasculitis must be correlated with the extent of systemic involvement, that is, other organs involved. The patient must be evaluated for infection, connective tissue disease, inflammatory bowel disease, or other systemic disease. Terms such as nodular vasculitis should be discouraged because they may impede thorough investigation of the patient for a specific etiology and may be confused with other entities (specifically, nodular vasculitis is also called erythema induratum of Bazin).30 A vasculitis or arteritis without obvious cause is best designated as such and the patient followed with the goal of eventually identifying a cause of the process. Ischemic fat necrosis is the end result of interruption of the vascular supply to fat lobules from any cause. Potentially any type of vasculitis or intravascular occlusive process can result in ischemic necrosis of fat. The latter entities, which include hypercoagulable states and other occlusive vasculopathies, are discussed in Chap. 9. However, three distinctive forms of ischemic fat necrosis will be discussed in this chapter: sclerosing panniculitis, calciphylaxis, and oxalosis.

CHAPTER 11 ■ PANNICULITIS

Sarcoidosis Streptococcal infection Mycobacteria Tuberculosis Leprosy Gastrointestinal infections and infestations Yersiniosis Salmonellosis Campylobacter colitis Shigellosis Deep fungal infections Coccidioidomycosis Histoplasmosis Blastomycosis (North American) Deep trichophytosis Other infections Ornithosis Cat-scratch disease Syphilis Gonorrhea Lymphogranuloma inguinale Other chlamydial infections Infectious mononucleosis Inflammatory bowel disease Crohn disease Ulcerative colitis Hormonal causes Pregnancy Contraceptive pills Malignancies Leukemias Carcinomas Sarcomas Hodgkin disease Drugs Iodine Bromine Sulphathiazole Penicillin Phenacetin Pyritinol Other causes Periarteritis nodosa Sweet syndrome Behçet disease

Table 11-6 Erythema Nodosum

Lipodermatosclerosis CLINICAL FEATURES Lipodermatosclerosis is a distinctive clinicopathologic entity associated with striking induration of the distal third of the lower extremity and ischemic fat necrosis.31-33 The condition is observed most commonly in

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A

B

C

D

E

F

 FIGURE 11-4 Erythema nodosum reaction pattern. (A-C) Well-developed erythema nodosum. The fibrous trabeculae are thickened by fibroplasia. (D) Higher magnification showing thickened fibrous trabeculum. (E) Inflammatory cell infiltrates are present at the periphery of fat lobules. (F) A thickened fibrous septum contains Miescher granulomas. (G) Acute neutrophilic lobular panniculitis associated with clinical presentation of erythema nodosum.

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 FIGURE 11-4 (Continued.)

adult women with a history of venous insufficiency and stasis of one or both of the lower extremities, often resulting from superficial or deep thromboses, thrombophlebitis, arterial ischemia, or varicosities 30-34 (Table 11-7). The stasis causes decreased flow in the capillaries of the lobules, leading to ischemia and centrolobular necrosis of the fat. 30 Characteristically, the distal

Table 11-7 Lipodermatosclerosis

Clinical Features Adult women > men Venous insufficiency Stasis Thromboses Erythematous, edematous indurated plaques with “inverted bottle” appearance, distal lower extremities above ankles Histopathologic Features Stasis dermatitis Septal and lobular involvement Perivascular lymphocytic infiltrates Ischemic fat necrosis Pallor of adipocytes, loss of nuclei Karyorrhexis, hemorrhage, hemosiderin deposition Progressive fibrosis, obliteration of fat lobules and vessels Lipomembranous fat necrosis Fat microcysts Differential Diagnosis Septal panniculitides (erythema nodosum) Other fibrosing panniculitides Lupus panniculitis Morphea profunda, fasciitis Physical panniculitis

third of the lower extremities is affected by circumferential, erythematous, edematous, telangiectatic woodlike plaques that give place to hyperpigmented, indurated, depressed lesions that have a characteristic “inverted bottle” appearance resulting from atrophy of the subcutaneum secondary to deep fibrosis.30 Vascular damage early in this process causes blood vessel fragility and hemorrhage into the dermis, which causes the skin to appear a red-brown color.35 Lipodermatosclerosis has been recognized clinically for many years under a variety of terms, including hypodermitis sclerodermiformis, membranous lipodystrophy, lipomembranous fat necrosis, lipomembranous change in chronic panniculitis, stasis-associated lipomembranous panniculitis (SALP), and stasis-related (or associated) sclerosing panniculitis.33-38 HISTOPATHOLOGIC FEATURES The epidermis and dermis commonly show stasis dermatitis with variable acanthosis, spongiosis, lobular vascular proliferation, fibroplasia, dermal atrophy, and hemosiderin deposition.30-32 The panniculitis is septal and lobular, and the histopathologic findings are related to the age of the lesion (see Table 11-7). At any age, however, the superficial dermis will show stasis dermatitis, and the papillary dermis will show increased numbers of capillaries and venules.30 Early lesions show perivascular lymphocytic infiltrates involving the fibrous trabeculae and the peripheries of fat lobules. At this stage, ischemic fat necrosis is typified by pallor of and loss of nuclei in adipocytes in the central part of the fat lobule; loss of lobular vessels; and variable karyorrhexis, extravasation and degeneration of erythrocytes, and hemosiderin

DIFFERENTIAL DIAGNOSIS Early lesions may be confused histologically with almost any septal panniculitis; however, the clinical features with evidence of venous insufficiency and stasis should provide evidence in favor of lipodermatosclerosis and the exclusion of other conditions. More developed lesions may be difficult to distinguish from lupus profundus and other fibrosing panniculitides. Lipodermatosclerosis shows ischemic fat necrosis, whereas lupus profundus is notable for prominent lymphoplasmacytic

CHAPTER 11 ■ PANNICULITIS

G

deposits within and outside of the macrophages.33,34 The endothelium of the vessel walls is thicker in the early stages.39 The presence of pericapillary fibrin cuffs has been shown not to act as a barrier to oxygen flow between capillaries and tissues, as was supposed originally.39 With time, there is progressive fibrosis and sclerosis of septa and gradual obliteration of fat lobules (Fig. 11-5A). The inflammatory infiltrates show an admixture of lymphocytes, macrophages, some lipidized, and plasma cells. Lipophagic granulomas are not uncommon around the fat lobules.30 Necrosis of fat with microcysts is also observed with evolution of the process. Later stages of these lesions show sclerosis of the septa as the main finding with little or no inflammation.30 A finding commonly observed in this context but not specific for this entity is membranous (pseudomembranous, lipomembranous, or membranocystic) fat necrosis33,36,37,40,41 (Fig. 11-5B). The latter change refers to cystic spaces in areas of fat necrosis that are lined by eosinophilic, feathery, crenulated membranous structures suggesting the cuticle of a parasite. These membranes stain with periodic acid–Schiff (PAS)-diastase and the lipid stains Sudan black and Luxol fast blue. Ultrastructurally, the membranes are composed of tubular structures containing neutral fat corresponding to the breakdown and collapse of lipocytes. Although membranous fat necrosis is perhaps observed most commonly in ischemia, it also has been reported in a variety of other settings, including traumatic injury and connective tissue disease.37,40 Elevated expression of urokinase-type plasminogen activator and its receptor CD87 has been reported as a possible early step in lipodermatosclerosis and other venous stasis disorders through activation of matrix metalloproteinase-2 (MMP2).42 MMP2 is an interstitial collagenase thought to contribute to the development of the ulcers found in advanced lipodermatosclerosis.42-44

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A

B

 FIGURE 11-5 Lipodermatosclerosis. (A) There is obliteration of fat lobules by hyalinized fibrous tissue. There is relatively little inflammation at this late stage. (B) There is prominent lipomembranous alteration resulting in a feathery membrane in this fat lobule. The latter changes are nonspecific.

infiltrates and hyalinizing fat necrosis. Morphea and related conditions should not show stasis changes, dermal atrophy, and ischemic necrosis to the degree observed in lipodermatosclerosis. The clinical manifestations should easily allow distinction of even late-stage sclerosing panniculitis from collagen-vascular disease.

Calciphylaxis A rare syndrome of vascular calcification and ischemic necrosis has been recognized for almost a hundred years, yet its pathophysiology remains poorly understood.46-55 Patients presenting with this dramatic condition often have a systemic disease commonly associated with perturbation of calcium and/or phosphorus metabolism, such as chronic renal failure and/or renal transplant, primary or secondary hyperparathyroidism, idiopathic hypercalcemia, or hypervitaminosis D.30,47-51,54,55 However, rare patients without any of the latter conditions or abnormal calcium or phosphorus levels have been reported.54 Although Selye described many features of the syndrome in an animal model, the mechanisms responsible for triggering ischemia and necrosis have yet to be fully elucidated.46,54 Possible etiologic factors include (1) endovascular fibrosis and calcification of small vessels, (2) a hypercoagulable state, and (3) luminal narrowing by calcification. Risk factors include AIDS, arterial hypertension, calcium/phosphate imbalance, Caucasian race, chronic dialysis, corticosteroid use, Crohn disease, diabetes mellitus type 1, female gender, hypotension, liver disease (including hypoalbuminemia),

malnutrition (including morbid obesity) and overload of iron, peripheral vascular disease, polycythemia, posthemodialysis metabolic alkalosis, protein C or protein S deficiency, recent weight loss, localized trauma, and/or warfarin use.30,52,,56-58 Controversy exists about the name calciphylaxis, but until a consensus can be reached on another name, it will continue to be used. It is also known as azotemic or uremic calcific arteriolopathy, calcifying panniculitis, uremic gangrene syndrome, and vascular calcification—cutaneous necrosis syndrome.56,58 CLINICAL FEATURES The clinical manifestations of calciphylaxis are distinctive.47-55 Patients usually develop painful erythematous to dusky lesions that undergo necrosis in a background of livedo reticularis (Table 11-8). Bullae have been reported occasionally.30 The lesions are often bilateral and may involve the trunk and extremities. Radiographic examination commonly reveals vascular calcification of large vessels, the so-called pipe-stem pattern of calcific medial stenosis, which is nonspecific. Small-vessel ( mononuclear cells/lipophages > granulomas > fibrosis (Figs. 11-8). As will be outlined in the following sections, over

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A

B

C

D

E

F

 FIGURE 11-8 Lobular panniculitis. (A) Acute lobular panniculitis. The fat lobule shows prominent infiltration by neutrophils. These changes are nonspecific and may be associated with a wide variety of etiologies. (B) Acute lobular panniculitis. The adipocytes are separated by sheets of neutrophils. (C) Lobular panniculitis at a later stage of evolution and characterized by predominence of mononuclear cells infiltrating fat lobule. These changes represent the typical sequence of inflammation irrespective of etiology. (D) Lipidized macrophages diffusely infiltrate fat lobule. (E) Granulomatous inflammation involving fat lobules. (F) Later fibrosing stage of lobular panniculitis. Mononuclear and granulomatous infiltrates progressively subside and the fat lobule gradually undergoes fibrosis. (G) Endstage lobular panniculitis. The fat lobules are obliterated by fibrosis.

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adipocytes. In some instances, particularly early in the disease, the clinical picture is similar to cellulitis.30 Patients may have other manifestations of the protease inhibitor deficiency such as emphysema, hepatitis, and acquired angioedema. Laboratory evaluation usually discloses a reduction in level of the serum alpha-1antitrypsin activity, although too few cases have been reported to make a definitive correlation.96 Resolution of the lesions results in atrophic scarring.30

 FIGURE 11-8 (Continued.)

the years, specific causes of WCD have been recognized and probably will continue to be identified. For example, when revisited, cases of WCD have been reclassified as alpha-1-antitrypsin deficiency panniculitis, cytophagic histiocytic panniculitis (CHP), erythema induratum of Bazin/nodular vasculitis, erythema nodosum, factitial panniculitis, pancreatic panniculitis, subcutaneous panniculitic lymphoma, superficial thrombophlebitis, and traumatic panniculitis.30,91 Recently WCD-like symptomes and findings were found in patients with detected mutations in the TNFRSF 1A gene, coding for the p55 TNF receptor. Mutations in this gene are the cause of tumor necrosis factor (TNF) receptor–associated periodic syndrome (TRAPS), with an unbalanced TNF alfa action.92 Beyond acknowledging WCD as a historical entity, the term should probably be abandoned. If no cause of a particular panniculitis can be established, the process should be designated lobular panniculitis of unknown etiology, and the patient should continue to be evaluated and monitored. In the following section, specific causes of predominately lobular panniculitis (or mixed septal and lobular panniculitis) will be detailed. As mentioned below, many of these conditions may show septal panniculitis as the predominant finding.

Alpha-1-Antitrypsin Deficiency Severe homozygous deficiency of the protease inhibitor alpha-1-antitrypsin may result in a recurrent ulcerating lobular panniculitis thought in the past to be WCD.93-95 Alpha-1-antitrypsin, which is synthesized in the liver, is the major inhibitor of serine proteases circulating

in the blood. The deficiency of alpha-1antitrypsin is thought to result in unopposed proteolytic activity and the promotion of inflammatory reactions. CLINICAL FEATURES There is often a history of tender, recurrent, erythematous, subcutaneous nodules associated with ulceration that involves the face, trunk, buttocks, and proximal extremities30,35,92-94 (Table 11-10). The nodules commonly follow trauma and exhibit drainage of clear or serosanguineous material. There also may be an exudate similar to necrotic

Table 11-10 Alpha-1-Antitrypsin Deficiency

Clinical Features Tender recurrent erythematous nodules Ulceration Drainage Cellulitis-like presentation Trunk, buttocks, proximal extremities Emphysema Hepatitis Acquired angioedema Histopathologic Features Lobular panniculitis Fat necrosis Neutrophilic infiltrates Septal panniculitis Liquefactive necrosis of septa, dermis Neutrophilic and macrophage infiltrates Laboratory Evaluation Reduced serum alpha-l-antitrypsin activity Differential Diagnosis Infection Physical and factitial panniculitis

CHAPTER 11 ■ PANNICULITIS

G

HISTOPATHOLOGIC FEATURES Two patterns of panniculitis have been described: (1) a lobular panniculitis with fat necrosis and (2) a septal panniculitis with proteolysis of collagen and necrosis of the fibrous trabeculae94 (see Table 11-10). The first pattern is commonly characterized by neutrophilic infiltration of fat lobules that may be focal but often is indistinguishable from other forms of lobular panniculitis. The entire fat lobule may be destroyed. The septal pattern of panniculitis also shows neutrophilic infiltration of fibrous septa of the reticular dermis but usually is accompanied by prominent numbers of macrophages.30 Concomitant lobular involvement with fat necrosis may or may not be present. An important feature is the presence of liquefactive necrosis of the dermis, which, along with a similar pattern in the fibrous septa, is thought to be characteristic of alpha-1antitrypsin deficiency panniculitis. As the necrosis progresses and scar formation ensues, the number of neutrophils and macrophages found on biopsy decreases.96 Having well-demarcated edges and being well localized are other unique features of alpha-1-antitrypsin deficiency.30 Vasculitis usually is not present on biopsy except in the necrotic areas surrounding the panniculitis.30 DIFFERENTIAL DIAGNOSIS The lobular form of alpha-1-antitrypsin deficiency may be indistinguishable from other lobular panniculitides, particularly those associated with infection and physical or factitial agents. Cultures, special stains, polaroscopy, clinical history, and laboratory evaluation of serum alpha-1-antitrypsin activity are needed to sort out these possibilities. Marshall syndrome is considered part of the clinical spectrum of alpha1-antitrypsin deficiency.30

Cytophagic Histiocytic Panniculitis and Subcutaneous Panniculitic Lymphoma For years these disorders have been poorly understood and classified. Until

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recently, it was believed that CHP was an early finding in a spectrum of diseases that eventuated in a subcutaneous lymphoma. However, cytophagic panniculitides presently are classified into two separate conditions.30 One is a genuine panniculitis, which retains the original name cytophagic histiocytic panniculitis.30 It is a prolonged systemic disease state that lasts from months to years.30 Complications may include recurrent ulcerating subcutaneous nodules, fever, generalized lymphadenopathy, hepatosplenomegaly, pancytopenia, liver dysfunction, a hemorrhagic diathesis, and purpura.30,97-105 Generally, these patients do not have evidence of active or dormant Epstein-Barr virus (EBV), and they respond well to prednisone or cyclosporine.30 The second condition is called subcutaneous panniculitic lymphoma.30 Patients with subcutaneous panniculitic lymphoma do not suffer from an actual panniculitis, although the clinical findings suggest panniculitis.30 This rare form of peripheral T-cell lymphoma presents as subcutaneous nodules mimicking conventional panniculitis in both children and adults.106-110 There is a slight predominance among females (1.4:1) but no major difference in the median age between genders.111 Patients usually experience a rapidly progressive clinical course often ending in death from a hemophagocytosis syndrome, but it may be protracted with multiple recurrences.30 Treatment with radiation or chemotherapy is usually not effective in altering the course.30 There is also a common association with EBV infection, whether active or latent.30 Subcutaneous panniculitic lymphoma is also known as subcutaneous panniculitic (or panniculitislike) T-cell lymphoma, panniculitis-like subcutaneous lymphoma with cytophagocytosis, and subcutaneous T-cell lymphoma.30,112-114 The Revised European-American Classification of Lymphoid Neoplasms (REAL) in the year 1997 classified subcutaneous panniculitic T-cell lymphoma as a “peripheral or mature T-cell neoplasm.”114 Patients with this lymphoma have less than 3-year median survival.114

Table 11-11 Cytophagic Histiocytic Panniculitis

Clinical Features Hemophagocytic syndrome often Immunosuppression, immune dysregulation Recurrent subcutaneous nodules—extremities commonly involved Fever Lymphadenopathy Hepatosplenomegaly Pancytopenia Liver dysfunction Hemorrhagic diathesis Often fatal Associated diseases Infections, particularly viral Lymphoproliferative disorders, usually T-cell Connective tissue disease Histopathologic Features Lobular panniculitis Monocyte-macrophage infiltration Phagocytosis of erythrocytes, platelets, lymphocytes by macrophages (“beanbag” cells) Extravasation of erythrocytes Infiltration by other cell types Septal panniculitis Atypical infiltrates in lymphoproliferative disorders Differential Diagnosis Infection Connective tissue diseases Lymphoproliferative disorder

and T-lymphocyte inflammatory infiltrates with “beanbag cells” (macrophages with erythrocytes and leukocytes within their cytoplasm) surrounding fat lobules in a mostly lobular panniculitis.30 The epidermis and dermis usually are uninvolved. In most cases of either CHP or subcutaneous panniculitic lymphoma, the principal finding is a lobular infiltration of the subcutaneous fat by T-lymphocytes and benign monocytes/macrophages (histiocytes) (Fig. 11-9). On occasion, the panniculitis shows a mainly septal pattern. This infiltrate shows phagocytosis of other cellular elements, for example, erythrocytes, platelets, lymphocytes, and neutrophils, and may extend to bone marrow30,97105,115,116 (see also Table 11-11). Histologically, the lymphoid cells most commonly infiltrate the fat lobules in a lacelike pattern or in sheets. This cellular population is cytologically banal in CHP but represents malignant T-lymphocytes in subcutaneous panniculitic lymphoma, which may originate from delta or gamma T cells.30,114 These atypical lymphocytes may be found forming a halo around necrotic adipocytes and express CD3, CD8, and other cytotoxic proteins but lack CD4.30 A cytokine phagocytosisinducing factor (PIF) secreted by other Tlymphocytes, which are CD4-positive, may be responsible for the prominent phagocytic properties of monocytes/ macrophages in this syndrome.116 These changes usually are accompanied by prominent extravasation of erythrocytes in the fat lobules, karyorrhectic debris,

CLINICAL FEATURES Patients with either CHP or subcutaneous panniculitic lymphoma usually present with recurrent large erythematous nodules involving the extremities but also occasionally the face and trunk (Table 11-11). The nodules may ulcerate and show ecchymoses.

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HISTOPATHOLOGIC FEATURES The original description of CHP included the following, which still applies today: histiocytic

 FIGURE 11-9 Cytophagic histiocytic panniculitis. High magnification shows phagocytosis of erythrocytes and leukocytes by macrophages in a fat lobule.

variable infiltration by other cells (such as lymphocytes, lipophages, plasma cells, and granulocytes), and possibly some fat necrosis. Hemophagocytosis occurring in association with other malignancies, such as acute leukemia, is usually minimal.115-119

Pancreatic Panniculitis A syndrome including pancreatic disease, subcutaneous fat necrosis, arthritis, lytic bone lesions, eosinophilia, and polyserositis has been recognized for over a century.120-128 This syndrome is associated most commonly with alcoholrelated acute pancreatitis but also has been associated with chronic pancreatitis, cholelithiasis, traumatic panniculitis, pancreatic cysts and pseudocysts, calculi of the pancreatic duct, acinar cell carcinoma, pancreatic adenocarcinoma, pancreatic divisum, unusual pancreatic infections (including a syphilitic gumma and tuberculosis), vasculopancreatic fistulas, and ingestion of sulindac.30 Pancreatic panniculitis has also been described in a child with nephrotic syndrome, caused by hypertriglyceridemia.127 The clinical lesions occurring in various organs are secondary to widespread or metastatic fat necrosis. The pathogenesis of these lesions, including those in the panniculus, is poorly understood but thought secondary to lipolytic enzymes released into the systemic circulation from the diseased pancreas.122 In particular, elevations of serum lipase and, to a lesser extent, amylase and other enzymes have been reported. Support for this etiology is twofold: First, pancreatic lipase has been found in areas of subcutaneous necrosis in these patients, and second, antilipase antibodies in these necrotic areas are reactive.30 Yet in vitro experimentation did not replicate panniculitis when serum high in pancreatic enzymes was incubated with subcutaneous fat.30 Since pancreatic panniculitis does not

CLINICAL FEATURES In contrast to other forms of panniculitis, pancreatic panniculitis is more common in men than in women (3:1) and generally presents as a tender, erythematous nodule or nodules on the lower extremities resembling or indistinguishable from EN4,120-125 (Table 11-12). The nodules often measure about 1 to 2 cm and commonly involve the anterior shins. The distribution of lesions, however, is often more wide-

Table 11-12 Pancreatic Panniculitis

Clinical Features Men > women Age 30-50 years Alcohol-related pancreatitis Pancreatic carcinoma Traumatic pancreatitis Fluctuant tender erythematous nodules Extremities, especially pretibial Buttocks Arthritis Polyserositis Histopathologic Features Early septal panniculitis with perivascular lymphocytic infiltrates Fat necrosis with ghost cells Basophilic alteration (saponification) Calcification Neutrophilic infiltration of fat lobules Mononuclear cells later Laboratory Evaluation Elevated lipase, amylase levels Differential Diagnosis Early septal panniculitides Infection

spread than typical EN. These lesions also may break down and drain a creamy, oily substance resulting from liquefactive necrosis.30 The ages of patients most commonly afflicted are in the range of 30 to 50 years. Patients commonly exhibit systemic involvement with fever, arthralgias, arthritis, and occasionally, widespread necrosis of fat, including the bone marrow. HISTOPATHOLOGIC FEATURES In the fully developed state, the histologic findings in pancreatic panniculitis are diagnostic4,120-125 (see Table 11-12). The fat lobules show a characteristic form of necrosis with formation of “ghost cells” (Fig. 11-10). The latter finding refers to necrotic adipocytes with intact but thickened eosinophilic cell walls and absence of nuclei. At the peripheries of necrotic foci with ghost cells, there is variable calcification, resulting in a basophilic lamellation that constitutes saponification, that is, formation of calcium soaps from the reaction of free fatty acids with ionizable calcium. Neutrophilic infiltration of fat lobules accompanies the fat necrosis and later gives place to mononuclear cells and granulomatous inflammation. The earliest lesions have been reported to show perivascular lymphocytic infiltrates without evidence of fat necrosis in a pattern resembling EN.121 Still other early lesions show what appears to be a mostly septal panniculitis thought to be initiated by vascular damage from pancreatic enzymes.30 Once damaged, endothelial leakage of these enzymes into the perivascular space allows enzymatic attack of adjacent fat lobules, causing the lobular pattern.30

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DIFFERENTIAL DIAGNOSIS Although the histologic findings of cytophagocytosis are distinctive, it is important that the patient and such lesions are assessed carefully for infection, connective tissue disease, lymphoproliferative disease, and other systemic disorders. It is important to differentiate between CHP and subcutaneous panniculitic lymphoma through cell surface protein markers and the specific histologic differences mentioned earlier. The presence of infection does not necessarily rule out malignancy.30 Patient follow-up is also important to determine the course of disease and modifications to treatment.

occur in every patient with pancreatitis, an additional underlying cause or causes for the panniculitis possibly await elucidation.30 The resemblance of the syndrome to connective tissue disease has prompted studies to identify an immune mechanism for tissue injury.123 The deposition of immunoglobulin and complement in the pleura and a reduced complement level in one patient provided some evidence for possible immune injury. The cutaneous lesions usually resolve simultaneously with cases of pancreatic inflammation.30 Subcutaneous lesions associated with cancer tend to be more chronic, recurrent, and ulcerative and may spread beyond the usual location of the lower extremities.30,128 Skin manifestations may precede the diagnosis of a pancreatic disease by several months, and with correction of the underlying pancreatic disorder the skin lesions fade away.127

DIFFERENTIAL DIAGNOSIS As mentioned earlier, early lesions may show nonspecific change suggesting a broad differential diagnosis, including vasculitides and EN.129 However, typical lesions showing fat necrosis with ghost cells and saponification are pathognomonic and should not be confused with other forms of panniculitis.129

CRYSTAL-RELATED PANNICULITIS (PANNICULITIS IN NEONATES AND CHILDREN ASSOCIATED WITH CRYSTAL FORMATION) Subcutaneous fat necrosis of the newborn (SFN),130-138 sclerema neonatorum (SN),120,133,135,139,140 and poststeroid panniculitis (PSP)141,142 are three forms of

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A

 FIGURE 11-10 Pancreatic panniculitis. (A) Lobular panniculitis. (B) The outlines of necrotic adipocytes are still maintained as so-called ghost cells.

panniculitis occurring in either neonates or children and showing crystallization of subcutaneous fat. The pathogenesis of this crystal formation remains poorly understood, but certain factors may contribute to its development. At least with respect to SFN and SN, the composition of the subcutaneous fat in infants differs from that in older individuals. In this age group, hydrolases that break down unsaturated fatty acids are released in unusual events, such as mild trauma.30 The large ratio of body surface area to weight combined with a higher ratio of saturated to unsaturated fatty acids compared with adults favors this release.30 Since saturated fatty acids have a higher melting point than unsaturated fatty acids, solidification (or crystallization) of fat may occur at lower temperatures. Additional factors that have some bearing on this phenomenon include prematurity, trauma, infection, fetal asphyxia, hypothermia, and other stresses. It should be pointed out that none of the latter factors have been consistently implicated in precipitating these diseases.

Subcutaneous Fat Necrosis of the Newborn CLINICAL FEATURES Full-term or postmature infants develop variably sized red to violaceous indurated nodules that are reasonably well circumscribed and not bound down to deep tissue (Table 11-13). The lesions are localized primarily to the

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B

cheeks, shoulders, back, buttocks, and thighs. The lesions usually develop in the first few days or weeks of life and generally resolve over 3 to 5 months with an excellent outcome in most newborns. Occasional infants develop an associated hypercalcemia that potentially can result in extensive calcification. This hypercalcemia has been suggested to be caused from increased prostaglandin E, parathormone, or extrarenal 1,25-dihydroxyvitamin D.143 It may be preceded by hypocalcemia in the first day of life and has been

reported up to 7 weeks after the onset of SFN.143 HISTOPATHOLOGIC FEATURES The epidermis and dermis generally are uninvolved. The most characteristic findings are patchy fat necrosis with crystallization of fat (Fig. 11-11; see also Table 11-13). Typically, macrophages and, to a lesser extent, lipocytes contain radially oriented needle-shaped clefts that correspond to triglyceride crystals dissolved during processing (Fig. 11-11). In addition to

Table 11-13 Crystal-Related Panniculitis SUBCUTANEOUS FAT NECROSIS (SFN) OF THE NEWBORN Clinical Features Full- or post-term Healthy Onset first few days or weeks

Reddish indurated nodules Cheeks, shoulder, back, buttocks Good prognosis Histopathologic Features Inflammation Needle-shaped clefts in macrophages and lipocytes Variable fat necrosis

SCLEREMA NEONATORUM

POSTSTEROID PANNICULITIS

Often premature Seriously ill Onset within 1 week of birth Widespread board-like induration Often fatal

Young children Healthy Onset days after stopping high-dose steroids

Little or no inflammation Crystals mainly in adipocytes

Similar to SFN

B

 FIGURE 11-11 Subcutaneous fat necrosis of the newborn. (A) There is a prominent lobular panniculitis. (B) The characteristic stellate clefting from triglyceride crystals is evident in the center of the field.

macrophages and foreign-body giant cells, other inflammatory cells, including neutrophils, lymphocytes, and plasma cells, may be observed. Early lesions may exhibit prominent neutrophilic infiltrates. The panniculitis is often septal and lobular, and it is important to emphasize that one may not detect the needle-shaped clefts in all cases of SFN. Furthermore, there may be prominent calcification of the fibrous trabeculae in some specimens. Frozen specimens or those not yet subjected to paraffin embedding show positive staining with lipid stains such as oil red O, and birefringent crystals may be observed when examined with polarized light. Later stages of SFN show septal fibrosis and calcification in fat lobules.30 DIFFERENTIAL DIAGNOSIS Poststeroid panniculitis is histologically indistinguishable from SFN, and thus one is dependent on clinical history to differentiate the two conditions. SN characteristically shows crystal formation in lipocytes and lacks inflammation. If crystals are not detected in SFN, one must exclude other forms of panniculitis, particularly infection or cold panniculitis. However, the clinical features of SFN should enable one to make the diagnosis without too much difficulty.

Sclerema Neonatorum CLINICAL FEATURES Neonates developing SN are often premature and develop the process within 1 week of birth (see Table 11-13). These newborns are usually seriously ill at the onset of SN, and many are dehydrated or undernour-

ished. In general, a widespread yellowwhite boardlike induration involves the entire cutaneous surface except the palms, soles, and scrotum.30 The process commonly begins on the lower extremities and progresses upward, causing immobility of limbs.30 There is a high mortality rate, often resulting from sepsis. Patients who recover from SN in the first week of life have no lasting complications or residual cutaneous manifestations of their illness.30 HISTOPATHOLOGIC FEATURES The findings in SN are fairly distinctive although there may be considerable histologic overlap with SFN. On gross examination, the subcutaneous fat is greatly thickened and has a firm, lardlike consistency. The expanded fat lobules are separated by thickened fibrous trabeculae. Histologically, the expanded fat lobules show lipocytes containing the characteristic needle-shaped clefts with a radial or starburst pattern, as described earlier for SFN. In general, there is little or no associated inflammation. However, occasional neutrophils, lymphocytes, eosinophils, macrophages, and multinucleated giant cells, some containing the needle-shaped clefts, are observed. Older lesions may show thickening of fibrous trabeculae and rarely calcification. DIFFERENTIAL DIAGNOSIS As discussed earlier, SFN differs from SN by showing radial clefts predominately in macrophages, greater inflammation, and fat necrosis in contrast to SN, which shows crystals primarily in lipocytes and little or no inflammation or fat necrosis.

Poststeroid Panniculitis This is an extremely rare form of panniculitis, thus far only observed in young children 1 to 13 days after the rapid discontinuation of high doses of oral corticosteroids141,142 (see Table 11-13). Subcutaneous nodules develop particularly in areas of fat accumulation, especially the cheeks, secondary to steroid therapy. The lesions generally are asymptomatic and resolve without scarring over a period of weeks to months, unless they ulcerate, in which case they heal with atrophic scarring.30 The histologic findings are similar to SFN, with needle-shaped clefts occurring within both macrophages and adipocytes.

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Infection-Related Panniculitis Infection is a relatively frequent cause of panniculitis.144,145 Bacterial organisms are probably the most common agents, including Staphylococcus, Streptococcus, and both conventional and atypical mycobacteria.30 They are followed in incidence by fungi, Nocardia, and recently, Acanthamoeba. A particularly important predisposing factor to infection-related panniculitis is immunosuppression. Many such patients have undergone organ transplantation and have received immunosuppressive agents such as systemic corticosteroids and other cytotoxic drugs. Other conditions associated with this form of panniculitis include diabetes mellitus, AIDS, cancer, and connective tissue disease. CLINICAL FEATURES Most patients are adults, but individuals of any age may be

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Table 11-14 Infection-Related Panniculitis

Clinical Features Immunosuppression Organ transplantation Corticosteroid and cytotoxic therapy Cancer Connective tissue disease Diabetes mellitus Inflammatory nodules—lower extremities most common Histopathologic Features Epidermal and dermal changes common Neutrophil-rich infiltrate Edema Septal and lobular panniculitis often Septal changes frequent with bacterial infection Neutrophilic infiltrates Abscess formation Basophilic necrosis Hemorrhage Granulomatous inflammation in nonbacterial panniculitis Vascular damage and vasculitis Differential Diagnosis Acute neutrophilic panniculitis (erythema nodosum syndromes) Neutrophilic dermatoses Sweet syndrome Pyoderma gangrenosum Inflammatory bowel disease—metastatic Crohn disease Physical and factitial panniculitis

affected. Patients present most commonly with inflammatory subcutaneous nodules involving the lower extremities, but any site may be affected (Table 11-14). Lesions may be primary (sites of inoculation) or secondary (sites of direct or hematogenous spread).30 The most common route of infectious entry is via the respiratory tract.30 HISTOPATHOLOGIC FEATURES Epidermal and dermal changes are more frequent in infection-related panniculitis than in the other panniculitides (Table 11-14). Often there is parakeratosis, acanthosis, and spongiosis. In addition, dermal edema and a neutrophil-rich inflammatory infiltrate are encountered commonly in the dermis. In general, the panniculitis is both septal and lobular. A predominantly septal panniculitis with infiltration of fibrous trabeculae and the peripheries of fat lobules may be noted with bacterial infection. Other notable features include a prominent neutrophilic infiltrate with occasional abscess formation, hemorrhage, basophilic necro-

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sis (Fig. 11-12A and B), and associated necrosis of sweat glands. Bacterial panniculitis as a general rule does not exhibit granulomatous inflammation. However, granulomatous inflammation is a common finding in other forms of infectionrelated panniculitis, particularly those with mycobacterial infection (Fig. 11-12C). Both small and medium-sized vessel vasculitis may be observed. In the case of atypical mycobacteria, suppurative granulomas inside the fat lobules contain histiocytes surrounding groups of neutrophils.30 In primary lesions, the superficial dermis is the center of the inflammation, whereas secondary lesions are deeper and involve the reticular dermis and subcutaneum.30 Blood vessels are thrombosed and are expanded with large numbers of the infective organism.30 DIFFERENTIAL DIAGNOSIS The differential diagnosis includes causes of acute neutrophilic panniculitis such as might be associated with short-lived hypersensitivity reactions (the EN reaction pattern), vasculitis, a primary neutrophilic dermatosis (as in Sweet syndrome and pyoderma gangrenosum), inflammatory bowel disease, and physical and factitial forms of panniculitis. One recent case report demonstrates a neutrophilic panniculitis in an infant as a manifestation of juvenile rheumatoid arthritis.146 Infection can be confirmed by special stains, cultures, and possibly special techniques, including immunostaining and the polymerase chain reaction (PCR).

Erythema Induratum and Nodular Vasculitis (Bazin Disease) Erythema induratum of Bazin and nodular vasculitis should be used interchangeably when discussing this most frequent form of lobular panniculitis associated with vasculitis.30 Since the description of this entity by Bazin in 1861,148 there has been continued controversy as to its relationship to tuberculosis as a “tuberculide,” the relationship to and the nature of the vasculitis described in many cases (“nodular” vasculitis), and its very legitimacy. Nonetheless, many clinicians maintain that erythema induratum/ nodular vasculitis is a distinctive clinical entity characterized by tender, dusky, bluish nodules, principally localized to the posterior calves of obese adult women.30 These nodules seem to have some relationship to cold exposure, as does ulceration of the nodules.30 When ulceration occurs, healing is slow and

usually results in atrophic scars. Other features and possible predisposing factors are cutis marmorata, erythocyanosis, and column-like, weighty calves.30 Variants that are clearly related to cold exposure have been termed erythema induratum of Whitfield and are likely to a form of perniosis (Whiting DA, personal communication, 1996). A pattern of livedo reticularis has been described in many cases. Recurrence can last decades.30 An atypical variant occurs in men, in whom the lesions are unilateral involving the shins and thighs most commonly.30 The relationship of erythema induratum/nodular vasculitis to Mycobacterium tuberculosis (MTB) has remained controversial over the past century.148-152 Some authors have provided convincing evidence for a relationship to MTB based on documentation of tuberculosis at other sites, positive Mantoux (tuberculin-purified protein derivative) tests, and response to antituberculous therapy. Others have disavowed any relationship, and Montgomery et al emphasized the presence of vasculitis in these lesions and proposed the term nodular vasculitis to describe nodules not having any clear association with MTB.64 A relationship to perniosis was suggested for some lesions. Nonetheless, recent studies using molecular diagnostic techniques (PCR) have isolated MTB DNA from 25% to 77% of lesions considered to be erythema induratum.30,153 Using newly developed primers for PCR, bacille Calmette-Guérin was ruled out as a source of false-positive results, as reported in one study.153 Furthermore, patients with these lesions have responded to treatment for MTB. HISTOPATHOLOGIC FEATURES The histopathologic features described in these lesions are entirely nonspecific and often are related to the age of the lesion biopsied. In early lesions, small collections of mostly neutrophils are interspersed throughout the fat lobules, where extensive ischemic necrosis may be found.30 Foamy macrophages are likely to be present depending on the stage of the lesion.30 The fat lobules are affected by extensive inflammatory infiltrates consisting of lymphocytes, multinucleated giant cells, and epithelioid histiocytes contributing to granulomatous inflammation and caseation necrosis.30 The caseous process may extend to the dermis and epidermis, causing ulceration and exudation of the necrotic, liquefied fat.30 Vasculitis is not always identified but is accepted as one of the histopathologic criteria.30 Still, controversy exists as to

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B

C  FIGURE 11-12 Infection-related panniculitis. (A and B) Bacterial panniculitis. There is granular basophilic necrosis of fat. (C) Septal and lobular panniculitis with caseation necrosis. These changes are nonspecific but may be associated with infectious agents such as mycobacteria.

whether the involved vessels are small and medium-sized arteries or veins since both have been observed.30 A prevailing belief is that venous vessels are involved primarily, and the arteries are affected as they become trapped within the areas of caseation.30 Some authors have concluded that venous structures are involved almost exclusively and that those vessels labeled as arteries in past years were largely misclassified.154 Montgomery et al reported features similar to polyarteritis nodosum in some lesions.64 Recently, lesions have been categorized histopathologically into two types.155 Type I, also called focal panniculitis, is distinguished by only one artery or nonspecific blood vessel involved with a neutrophilic vasculitis in the fat lobule.155 Type II, also called diffuse panniculitis, differs in that more than one vessel is involved with the neutrophilic

vasculitis, and both the septa and fat lobule are affected.155 Also, type II has more pronounced inflammation.155 However, since vasculitis is not an absolute finding in every case of erythema induratum/ nodular vasculitis, this classification scheme is not always used.30 Taken together, there is increasing evidence that many cases of erythema induratum are likely to be a form of infection-related panniculitis in which a florid hypersensitivity reaction probably has resulted in the death of MTB organisms, since they cannot be cultured from such lesions. Nonetheless, the structure of some organisms remains intact because they can be detected by PCR amplification. Since MTB has been reported to also be associated with EN and possibly cutaneous periarteritis nodosa, further studies are needed to confirm the infectious etiology of erythema induratum.156,157

The author recommends that the terms erythema induratum and nodular vasculitis be abandoned in favor of more objective morphologic descriptions. For example, such panniculitides are best designated as granulomatous panniculitis associated with MTB detection, granulomatous panniculitis without specific cause (failure to detect an infective agent), or panniculitis associated with small or medium-sized vessel vasculitis. Patients should have a thorough evaluation for a local or systemic cause of their panniculitis.

Erythema Nodosum Leprosum CLINICAL FEATURES Erythema nodosum leprosum (ENL) is characterized by multiple, tender, violacious, erythematous papules or nodules on the extremities of patients with lepromatous or borderline

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lepromatous leprosy.30 It usually begins after initiating treatment for leprosy, although it has been reported as the presenting complaint.158 Sometimes referred to as a type 2 leprosy reaction, ENL is a serious complication of patients with multibacillary leprosy.159 Regional—not worldwide—prevalence has been established within various populations of leprosy patients and varies from population to population.159 It is more common with dapsone monotherapy and less common in patients undergoing multidrug therapy, especially the regimens that include clofazimine.160 ENL is also associated with bacterial or viral infections.161 Pregnancy has been reported as a precipitant to ENL, with no resolution of lesions after delivery, continuing through lactation.162 Risk factors include bacterial index greater than 4+ and age over 40 years, according to one study.160 HIV has been reported as a risk factor in another study.159 Recurrence has been reported in 45% to 60% of patients.159,160 Patients who have a diffuse form of lepromatous leprosy can develop a necrotizing vasculitis called Lucio phenomenon.30 This is an infarctive, hemorrhagic, ulcerative process that is painful.30 The course involves serious systemic symptoms and has an associated mortality.30 HISTOPATHOLOGIC FEATURES A small-vessel vasculitis with fibrinoid necrosis and associated neutrophilic infiltrates usually involves the dermis and/or subcutis.30 The panniculitis is often septal and lobular with variable fat necrosis. Although macrophages generally contain lepra bacilli, the vasculitis appears to be Arthus-type, immune-complex related.158 Direct immunofluorescence demonstrates complement and IgG deposits in the wall of the associated blood vessels.30 Fine-needle aspiration cytology shows neutrophils, foamy macrophages, and Ziehl-Neelsen staining for acid-fast bacilli.158 A current theory is that immune-complex formation leads to vasculitis and secretion of tumor necrosis factor alpha (TNF-α) from macrophages.160 Whether or not T cells augment the secretion of TNF-α is still being defined.160 Patients with a polymorphism in the TNF-α gene are at a higher risk of lepromatous leprosy and possibly increased risk for ENL.160 The vasculitis of Lucio phenomenon is usually confined to the upper and middle dermis with subsequent epidermal ulceration, but it also may extend into the subcutaneous fat involving the small vessels.30 There is also a slight perivascular inflammation comprised of

foamy histiocytes.30 The latter histiocytes, as well as the endothelial cells of the involved vessels, contain acid-fast bacilli.30 The inflammation is not as pronounced as in ENL lesions.30

PHYSICAL AND FACTITIAL PANNICULITIS This category of panniculitis refers to injury to fat secondary to various physical insults, such as cold, pressure, external trauma, chemical agents, and selfinduced injury.

Cold Panniculitis Cold-related panniculitis was first described in 1902 by Hochsinger in children 4 to 10 years of age, primarily involving the face.106-110,163,164 The propensity to develop cold panniculitis is inversely correlated with age. Thus, as with crystal-associated panniculitis, cold panniculitis has been attributed to a higher ratio of saturated to unsaturated fatty acids and generally presents in infants and young children. Because of a higher melting point, saturated fatty acids will crystallize more rapidly when exposed to cold temperature than unsaturated fatty acids.165 These crystals disrupt the normal architecture of the fat and cause the panniculitis.165 CLINICAL FEATURES The exposed skin, especially the cheeks and submental area of the chin, of neonates and young children is affected most commonly (see Table 11-15). Individuals wearing thin, tight clothing particularly on the buttocks in cold weather are also susceptible.30 Typically patients develop tender, often indurated, erythematous plaques and nodules without well-defined margins about 2 to 3 days after cold exposure from cold air, ice cubes, cold fluids, ice packs, or “popsicles.”30 The lesions will soften and then heal without scarring in a few days to 2 weeks if maintained at a warm temperature.30,165 HISTOPATHOLOGIC FEATURES In general, the epidermis and dermis are unaffected. The most prominent findings often are perivascular lymphocytic infiltrates at the dermal-subcutaneous interface with features observed in chilblains, that is, the “fluffy” edema involving the walls of blood vessels (see Table 11-15). However, as with many other insults to the fat, the panniculitis is nonspecific, with variable fat necrosis and inflammatory cell infiltrates, including neutrophils,

Table 11-15 Cold Panniculitis

Clinical Features Infants and young children Young women Exposed skin, cheeks Tender, indurated plaques, nodules Onset 2-3 days after cold exposure Histopathologic Features Perivascular lymphoid infiltrates Histologic features of chilblains Dermal-subcutis interface “Fluffy” edema of vessels Lobular and septal panniculitis Fat necrosis Mixed infiltrates Differential Diagnosis Other physical panniculitides

lymphocytes, macrophages, and other inflammatory cells involving fat lobules and, to a lesser extent, fibrous trabeculae. Cryoglobulins and cold agglutinins have not been shown to be a factor in cold panniculitis.165

Trauma-Related Panniculitis Physical trauma, whether self-inflicted (factitial) or otherwise, is a major cause of injury to fat (Fig. 11-13A).1-5,166,167 Common locations include the breasts of women and accessible sites, such as the extremities. Purpura and scarring may be important clinical features. Secrétan syndrome and l’oedeme bleu are forms of factitial panniculitis resulting from blunt trauma to the dorsal hand and forearm and upper arm, respectively, or any site. Clinically, one observes traumatic edema and hemorrhage, often resulting in brawny, discolored, indurated plaques or nodules that may have a peau d’orange appearance, especially when located on the breast.30 Healing of trauma-related panniculitis to the breast usually occurs, but it may resolve with lipoatrophy.30 Lipoatrophia semicircularis is possibly a variant of trauma-related panniculitis that occurs when individuals, particularly women, bump one of their thighs on a hard object.30 It manifests as a semicircular ring of atrophic subcutaneous fat around half the anterolateral thigh.30 Nodularcystic fat necrosis, also known as encapsulated fat necrosis or encapsulated lipoma, is also a possible variant of trauma-related panniculitis.30 These subcutaneous, wellcircumscribed, movable nodules are induced by trauma and are located on the elbows, lower extremities, and hips.30

B

 FIGURE 11-13 Traumatic fat necrosis. (A) These changes are nonspecific and may follow a number of insults. (B) Encapsulated fat necrosis. Small nodule of adipose tissue compartmentalized by fibrous tissue “capsule.”

Histologically, the subcutaneous nodules show organizing hematoma, granulation tissue, fibrosis and hemosiderin often in the late stage, and focal fat necrosis and prominent hemorrhage surrounding cyst-filled fat lobules.30 These cysts are of various shapes and sizes.30 They are bordered by foamy histiocytes and lymphocytes.30 Mobile encapsulated lipomas differ from normal lipomas in that they are bordered by nucleated, necrotic adipocytes.30 Their thin, fibrous capsule completely or almost completely surrounds normal-appearing adipocytes (Fig. 11-13B).30 They are likely formed in association with vascular insufficiency or trauma.30

Chemical and Factitial Panniculitis Injection of various foreign or organic substances and medications is also a common cause of panniculitis.166-172 Sclerosing lipogranuloma is a term used to describe the reaction of adipose tissue to various mineral, animal, and vegetable oils, silicone, and other hydrocarbons injected into the subcutaneous fat for cosmetic and other reasons. Almost every conceivable substance, including milk, feces, and blood, has been injected into the subcutis. Many medications have been associated with panniculitis, including meperidine, pentazocine, povidone-iodine, morphine, corticosteroids, vitamin K, tetanus toxoid, and augmentation substances such as paraffin, silicone, PMMA microspheres, and polymethylsiloxane.30,34 A recent case report demonstrates a patient with several years history of recurrent areas of panniculitis and hospital admissions

that was self-induced and an expression of Munchausen syndrome.173 CLINICAL FEATURES The injection or implantation of various oils, paraffin, and other hydrocarbons may involve any site (Table 11-16). However, particularly common locations include the male genitalia, face and scalp, female breasts, and hands (“greasegun granuloma”). Such lesions are often indurated and

Table 11-16 Chemical and Factitial Panniculitis

Clinical Features Injection of foreign or organic substances, oils, paraffin, silicone, medications Psychiatric history Health care professionals Unusual or bizarre manifestations Indurated lesions—drainage Histopathologic Features Sclerosing lipogranuloma Variable-size vacuoles (“Swiss cheese” pattern) Foreign body reaction Dense hyalinized fibrous tissue Variable inflammation Fat necrosis Microcyst formation Mixed and granulomatous inflammation Fibrosis Calcification Birefringent material, often Differential Diagnosis Infection Alpha-l-antitrypsin deficiency Pancreatic panniculitis

may break down with drainage of oily material. The clinical manifestations associated with injections of other substances, for example, feces, or medications are related to the properties of the particular substance. Many such patients have health profession backgrounds and psychiatric histories and exhibit unusual or bizarre manifestations. There may be systemic signs, such as fever and, in some instance, a liquefying panniculitis. HISTOPATHOLOGIC FEATURES Sclerosing lipogranuloma shows a rather characteristic constellation of findings involving fat lobules: the so-called Swiss cheese pattern, with variably sized vacuoles corresponding to lipid removed with tissue processing, variable foreign-body giant cell reaction associated with vacuolated spaces, dense hyalinized fibrous tissue, and variable inflammatory cell infiltrates (see Table 11-16). The histologic features associated with injection or implantation of other substances is in general nonspecific but varies with the particular agent (Fig. 11-13A). Commonly, there is patchy, sometimes focal fat necrosis accompanied by microcyst formation and inflammatory infiltrates composed of neutrophils, especially early lesions; mononuclear cells; and granulomatous elements, more specifically in late-stage lesions.30 Birefringent material may be demonstrated with polarized light. Some agents such as meperidine may result in exuberant fibrotic reactions. Various methods can be used to identify the offending material, such as slide polarization or special staining techniques.20

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DIFFERENTIAL DIAGNOSIS In many instances the cause of physical panniculitis is obvious. However, factitial panniculitis may present considerable difficulties in diagnosis. Unusual forms of panniculitis, particularly persistent or recurrent, should raise suspicion for factitial etiologies. The differential diagnosis includes infection, alpha-1-antitrypsin deficiency, pancreatic panniculitis, and superficial thrombophlebitis. Evaluation for birefringent material and calcification may provide evidence for self-administered local injections.

Lupus Panniculitis (Lupus Profundus) The first recorded observation of subcutaneous nodules in lupus erythematosus (LE) was by Kaposi in 1883.174-181 Reports over the past half century have confirmed the rarity of lupus profundus (incidence about 1%-30% of patients with LE).30,182 Lupus panniculitis occassionally occurs without evidence of systemic lupus erythematous (SLE).30 Patients with systemic involvement seem to have a milder course, often exhibiting only arthralgias, polyserositis, and Raynaud phenomenon. Trauma to the subcutaneum often occurs to sites where lesions later arise, for example, injection, biopsy, or excision sites.30 Recent evidence suggests a close relationship of lupus panniculitis to subcutaneous lymphoma, an observation that requires further study and clarification.30 CLINICAL FEATURES In general, lupus panniculitis is a chronic disease of adults aged 20 to 60 years, but children as young as 3 years may be affected183 (Table 11-17). Women are afflicted two to four times as often as men.183 Patients commonly present with multiple indurated, deep-seated subcutaneous nodules or plaques involving the proximal extremities, particularly the upper extremities, as well as the shoulders, breasts (lupus mastitis), buttocks, trunk, or face.30,182 There also have been reports of lupus profundus associated with the subcutaneum of the orbit and periparotid area.30 Ulceration may develop, and the lesions often heal with lipoatrophy and depressed scars. Cutaneous manifestations overlying the panniculitis may include discoid LE (DLE), poikiloderma, atrophy, telangiectasia, and dyspigmentation. HISTOPATHOLOGIC FEATURES The epidermis and dermis may or may not show features typical of LE, such as hyperkeratosis,

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Table 11-17 Lupus Panniculitis

Clinical Features Women > men Age 20-60 years Multiple indurated subcutaneous nodules or plaques—proximal extremities, buttocks, breasts, trunk, or face Ulceration Overlying discoid lupus erythematosus, poikiloderma Lipoatrophy, depressed scars late Histopathologic Features Epidermis and dermis may or may not show features of lupus erythematosus Septal and lobular panniculitis Hyaline necrosis of fat lobules Hyalinization of adipocytes, connective tissue, blood vessels (“onion-skin” pattern) Karyorrhectic material Lymphocytic infiltrates and nodules at peripheries of fat lobules Plasma cells often Lymphocytic vasculopathy and vasculitis Occasional fibrin thrombi Mucin deposition Variable fibrous thickening of septa Differential Diagnosis Septal panniculitis Panniculitis in connective tissue disease Morphea/scleroderma Eosinophilic fasciitis Dermatomyositis Lipoatrophy, not otherwise specified Borreliosis Necrobiosis lipoidica

follicular plugging, epidermal atrophy, basal layer vacuolization, basement membrane thickening, perivascular and periadnexal lymphoid infiltrates, and dermal mucin. Most cases show changes consistent with DLE, including epidermal atrophy, increased thickness of the basement membrane, vacuolar change within the junction of the dermis and epidermis, mucin among bundles of collagen in the dermis, and a lymphocytic perivascular dermal inflammatory infiltrate that may be superficial and/or deep.30 The remainder of the cases are characterized by changes confined to the subcutaneous fat only.30 In general, lupus panniculitis shows distinctive changes involving septal and lobular areas (Fig. 11-14; see Table 11-17). The principal findings include (1) hyaline necrosis (Fig. 11-14C involving primarily

fat lobules but extending to the fibrous trabeculae in many instances, (2) lymphocytic infiltrates often forming nodules and occasionally containing germinal centers looking very much like lymphoid follicles (Figs. 11-14A, B), and (3) nuclear dust within the infiltrates, which is not seen in most other forms of panniculitis.30 The presence of such lymphoid follicles in the subcutaneum is highly suggestive of lupus profundus but not diagnostic because of their presence in other panniculitides such as erythema induratum of Bazin, panniculitis in dermatomyositis, deep morphea, and EN.30 The hyaline necrosis refers to the degeneration of fat lobules and connective tissue with development of a progressive glassy eosinophilic appearance. This alteration is often accompanied by karyorrhectic debris and mucin deposition. The fat lobules are commonly characterized by the formation of hyalinized microcysts (Fig. 11-14C), and involved blood vessels exhibit a characteristic onion skin-like concentric layering of eosinophilic fibrils. The lymphocytic infiltrates are variable and primarily localized to the peripheries of fat lobules or septal-lobular interface but rarely may involve the entire lobule. The lymphocytic infiltrates often are present between vessels, as well as having a perivascular disposition. Almost without exception, plasma cells are an integral part of the infiltrate, often surrounding it.30 Lesions in later stages likely will reveal membranocystic changes.30 Immunohistochemistry reveals IgM and C3 linear deposition at the dermal-epidermal junction.30 Some studies have shown atypical lymphocytes with clonal proliferation within the infiltrate as well.184 Variable degrees of vascular injury are observed commonly, with lymphocytic vasculitis the most frequent finding. Fibrinoid necrosis and fibrin thrombi are noted on occasion. Other more variable features include fibrous thickening of septa, deposition of elastic fibers in the septa, calcification that may be extensive, mucin deposition, granulomas involving septa, and occasional eosinophils in the infiltrate. On occasion, the histopathologic findings are nonspecific. DIFFERENTIAL DIAGNOSIS Early lesions of lupus panniculitis may be confused with septal patterns of panniculitis (the EN reaction pattern). However, the major entities to be considered include connective tissue disease-related panniculitis, that is, morphea, eosinophilic fasciitis, and allied conditions; dermatomyositis;

B

CHAPTER 11 ■ PANNICULITIS

A

C  FIGURE 11-14 Lupus panniculitis. (A) A septal and lobular panniculitis is present. There is some hyalinization of the fibrous septa and fat lobules. Fat lobules also exhibit infiltration by rather dense mononuclear cell infiltrates. (B) Lupus panniculitis. Higher magnification shows hyalinizing necrosis of fat with mononuclear infiltrates. (C) Lupus panniculitis. There is hyalinization of the fat lobule accompanied by lymphocytic infiltrates.

necrobiosis lipoidica; lipoatrophy; and borreliosis. The greatest difficulty may be distinguishing lupus panniculitis from morphea profunda/eosinophilic fasciitis. Both may present as clinically indurated plaques or nodules, and both exhibit prominent lymphoplasmacellular infiltrates, thickening of fibrous septa, lymphocytic vasculitis, mucinosis, and occasional eosinophilic infiltrates. As discussed earlier (see “Morphea Profunda, Scleroderma, Eosinophilic Fasciitis”), lupus panniculitis is distinguished from morphea by the frequent presence of the epidermal changes of hyperkeratosis, atrophy, basal layer vacuolopathy, basement membrane thickening, prominent dermal mucin, hyalinizing necrosis of adipose tissue, and less prominent sclerosis of the subcutis and dermis compared with morphea profunda (and eosinophilic fasciitis). Subcutaneous T-cell lymphoma must be excluded

because of commonly found peripheral rimming of atypical lymphocytes around the fat lobules and the evidence of clonality.184

Panniculitis in Dermatomyositis and Polymyositis Pure panniculitis is rarely observed in both children and adults with dermatomyositis.30,179-181,185-187 In fact, since 1924, only 10 adults and 2 children have been reported in the literature.188 It is more common for these patients to have an association with deep tissue and muscle calcification.30 Regardless of how pure the panniculitis is, these patients may present with painful, erythematous, indurated nodules or plaques on the buttocks, thighs, and arms, or the panniculitis may be asymptomatic and diagnosed coincidentally with skin or muscle biopsy.189

CLINICAL AND HISTOPATHOLOGIC FEATURES Histologically, one often observes features noted in the other connective tissue diseases, especially lupus panniculitis.30 A mostly lobular panniculitis with lymphoplasmacytic infiltrates of variable density affecting the fat lobules is commonly found.30 The pannicular septa exhibit hyaline sclerosis, and fibrous tissue replaces the adipose tissue.30 Other features noted less commonly include hyaline necrosis of fat, mucinosis, thickening of the vessels supplying the fat lobules, neutrophilic or lymphocytic vasculitis, and calcification.30 Vacuolar change may be found, and as the lesion progresses, membranocystic changes may occur.30 There may be overlying features of dermatomyositis affecting the epidermis and dermis. Immunofluorescence studies have been inconclusive thus far.30 Patients generally have a good prognosis

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and a decreased incidence of cancer versus patients with only dermatomyositis.30

Connective Tissue Panniculitis

PART I ■ INFLAMMATORY REACTIONS IN THE SKIN

Winkelmann and Padilha-Goncalves reported an unusual form of panniculitis that they considered to be closely related to lupus panniculitis and morphea.189,190 However, connective tissue panniculitis was distinguished from the latter conditions by florid lymphocytic infiltration and extensive caseation necrosis of fat lobules. There was no hyaline necrosis or vasculitis according to these authors, and the lesions resolved with lipoatrophy.

LIPOATROPHY AND LIPODYSTROPHY This category includes a highly heterogeneous and confusing group of conditions perhaps only related by the clinical finding of loss of subcutaneous fat. 2,179,190-198 This atrophy or disappearance of fat may be localized, partial, or generalized (total) (Table 11-18). Specifically, lipoatrophy is the loss of a previously inflamed subcutaneum, whereas lipodystrophy is a similar condition but lacks a preceding inflammatory episode of the panniculus.30 Much more work is needed to characterize the pathogenesis of these various disorders. Various classifications have been proposed, but until a more definitive nosology is devised, this text will continue with the current classification: localized, partial, and generalized or total lipoatrophy.30,199 Recent studies in this area have

shown mutations in several genes in patients with inherited lipodystrophies. In patients with partial lipodystrophies, mutations in LMNA, PPARG, and ZMPSTE24 and in total lipodystrophy BSCL2 and AGPAT2 have been noticed.200 The localized lipoatrophies probably encompass the most heterogeneous grouping of conditions. One well-recognized outcome of panniculitis occurring in connective tissue disease, for example, lupus panniculitis and morphea profunda, is localized lipoatrophy, which has been designated atrophic connective tissue panniculitis. However, other autoimmune diseases such as diabetes mellitus, Hashimoto thyroiditis, and juvenile rheumatoid arthritis may result in localized lipoatrophic panniculitis. Localized lipoatrophy may be secondary to a variety of local insults to fat, such as injections of depot corticosteroids, antibiotics, vasopressin, human growth hormone, and insulin, and factitial disease.30 Other unusual and poorly understood variants include centrifugal lipodystrophy and the annular and semicircular lipoatrophies. Centrifugal lipodystrophy is characterized by round, depressed lesions having a raised erythematous border, often involving the trunk and groin areas of children. The annular and semicircular variants show circumscribed bands of lipoatrophy involving the upper extremities and thighs, respectively, of adult patients. Annular lipoatrophy of the ankles is typified by a broad (~10 cm) annulus of lipoatrophy involving the distal leg above the ankle. It is often induced secondarily by compression of tightly fitted clothing on the

abdomen, sacrum, and extremities, especially the thighs and ankles.30 The partial lipodystrophies most commonly show progressive loss of facial fat that may extend gradually to the upper trunk and arms (cephalothoracobrachial lipodystrophy). They are more common in female than male children.199 Many patients have reduced serum complement (C3) levels, a circulating immunoglobulin that activates C3 (the C3 nephritic factor), membranoproliferative glomerulonephritis, SLE, scleroderma, Sjögren syndrome, sicca syndrome, dermatomyositis, recurrent infections, high thyroid autoantibody titers, hypertriglyceridemia, insulin resistance, and diabetes.30 The generalized or total lipodystrophies may present at birth or develop later in life. They are more common in females and show a number of cutaneous signs, including acanthosis nigricans, hypertrichosis, and hyperpigmentation. Endocrine abnormalities, including diabetes and hypothalamic dysfunction, often are present. Patients with human immunodeficiency virus 1 (HIV-1) infection have been reported with lipodystrophy while undergoing combination antiretroviral therapy that has specifically included protease inhibitors.199 The most commonly areas affected are the gluteal region, face, and extremities.199 HISTOPATHOLOGIC FEATURES All forms of lipoatrophy are characterized by loss of subcutaneous fat in their established or fully developed stages; that is, fat lobules are greatly diminished in size and

Table 11-18 Lipoatrophies And Lipodystrophies CONDITION Localized lipoatrophies Atrophic connective tissue panniculitis; lipoatrophic panniculitis Secondary localized lipoatrophies Centrifugal lipodystrophy (lipodystrophia centrifugalis, abdominalis infantilis) Annular lipoatrophy, semicircular lipoatrophy, annular lipoatrophy of the ankle Localized lipoatrophy Partial lipoatrophies, dystrophies; cephalothoracic lipodystrophy

Generalized lipodystrophies

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CLINICAL FEATURES Children or adults with connective tissue and autoimmune diseases Localized lipoatrophy secondary to local processes such as injections, factitial disease Annular erythematous lesions involving abdomen and other sites of children, possibly related to Kawasaki disease Circumferential band of lipoatrophy affecting circumscribed areas of the extremities Localized lipoatrophy without evidence of inflammation Progressive loss of fat from the face and upper trunk; relationship to hypocomplementemia, C3 nephritic factor, glomerulonephritis, and diabetes; often inherited Congenital or acquired; generalized loss of fat; diabetes and other endocrine abnormalities; often inherited

Table 11-19 Eosinophilic Panniculitis

 FIGURE 11-15 Lipoatrophy. Note prominence of microvessels associtated with diminished overall size of fat lobule.

associated with prominent microvessels and myxoid alteration (Fig. 11-15). Mostly, small fat lobules are surrounded by lipophagic granulomas and perilobular fibrosis.30 Early lesions, particularly those associated with inflammation and autoimmune or connective tissue disease in localized lipoatrophy, have been reported to show infiltration of fat lobules by lymphocytes, plasma cells, and macrophages with little change to the surrounding adipocytes or blood vessels. Direct immunofluorescence highlights the walls of blood vessels or the basement membrane at the junction of the dermis and epidermis.30 An involutional phase of localized lipoatrophy has been described and may or may not have a relationship to antecedent inflammation. This stage is characterized by diminished sizes of fat lobules, variation in the sizes of adipocytes, prominent vascularity, and a hyaline or myxoid stromal alteration. The latter findings greatly resemble fetal adipose tissue. Part of the clinical differential diagnosis consists of SHORT syndrome (short height, hyperextensability of limbs, ocular depression, Reiger anomaly, and teething delay), Werner syndrome, Wiedemann Rautenstrauch syndrome, leprechaunism, and Cushing syndrome.199

Eosinophilic Panniculitis Eosinophilic panniculitis is the improperly used term to describe a distinctive but nonspecific histopathologic reaction pattern associated with a wide variety of processes that may be localized or systemic.21,30,201-203 Reviews of many patients with eosinophilic panniculitis have included the following associations: asthma, atopy, bacterial infections, cancer (particularly leukemia and T- and B-cell lymphomas), deep insect bites, deep morphea, drug dependency with injection granuloma, EN, glomerulonephiritis, leukocytoclastic and systemic vasculitides, local injections, lupus panniculitis, parasitic infection (eg, Toxocara canis and Gnathostoma), parotitis, psychiatric diseases, radiotherapy, sarcoidosis, Sjögren syndrome, thyroid disease, and Wells syndrome (eosinophilic cellulitis, a closely related nonspecific reaction).30,204 With so many disorders in which eosinophilic panniculitis may be found, patients with this pattern should be evaluated for associated systemic processes.30 CLINICAL AND HISTOPATHOLOGIC FEATURES Eosinophilic panniculitis may show a lobular or septal panniculitic pattern, but

CHAPTER 11 ■ PANNICULITIS

Clinical Features Many etiologies Atopy Local injections Cancer (especially lymphoma) Vasculitis Borrelial infection Inflammatory subcutaneous nodules Vesicles, pustules, urticarias Histopathologic Features Infiltration of fat lobules by eosinophils Other inflammatory cells to variable extent Occasional “flame figures” Occasional eosinophilic cellulitis and fasciitis Laboratory Evaluation Special stains and serologic evaluation for Borrelial infection Differential Diagnosis Lymphoma

it is not a true panniculitis.30 In general, adults are affected and present with inflammatory nodules, occasionally associated with other cutaneous findings, including vesicles, pustules, and urticaria (Table 11-19). The panniculitis is characterized by prominent infiltration of fat lobules by eosinophils, possibly with an admixture of other inflammatory cells, including lymphocytes, neutrophils, plasma cells, and macrophages. Vasculitis, “flame figures” (deposition of eosinophilic granules on connective tissue), and palisading granulomas may be seen in some instances. Associated eosinophilic cellulitis and fasciitis also may be present. If relevant, silver stains (eg, Warthin-Starry) and serologic evaluation may be considered to rule out borrelial infection.

Neutrophilic Dermatitides and Vascular Reactions The neutrophilic dermatitides, including Sweet syndrome and pyoderma gangrenosum, may involve the panniculus.16,28 These conditions often show varying degrees of septal and/or lobular infiltration by neutrophils and possibly microvascular injury. There may be some admixture of other inflammatory cells.

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Infections must be excluded by special stains and culture. These disorders are discussed in more detail in Chap. 9.

PART I ■ INFLAMMATORY REACTIONS IN THE SKIN

Noninfectious Granulomatous Panniculitis A number of (presumed) noninfectious processes may involve the subcutaneous fat, eventuating in varying degrees of septal and/or lobular panniculitis, in addition to the palisading/necrobiotic granulomatous disorders.2,4 These conditions include metastatic Crohn disease, sarcoidosis, granulomatous reactions secondary to arthropod bites, rupture of pilosebaceous units, granulomatous angiopanniculitis (GAP), and epithelial cysts.205 In Crohn disease, the lesions may resemble EN clinically and usually are located on the lower extremities.30 Histologically, they may show noncaseating granulomas in the subcutaneous septa or within the fat lobules accompanied by a lymphocytic vasculitis in the medium-sized vessels at the dermalpannicular junction.30 In sarcoidosis, deep subcutaneous nodules are present on the lower extremities, but there are usually no visible indications of an inflammatory process except for pink to tan coloration.30,34 Microscopically, these small noncaseating granulomas are associated with the subcutaneous septa and fat lobules but show only a few lymphocytes around their perimeter (“naked” granulomas).30,34 Occasionally, these sarcoid granulomas will undergo necrosis in their centers, and calcification may develop.30 GAP may appear microscopically similar to carcinoma, as in GAP of the breast, but close inspection will reveal granulomas lacking involvement of breast lobules and ducts.205 Because a possible infectious etiology still exists in patients with panniculitis and Crohn disease or sarcoidosis, noninfectious granulomatous panniculitis must be a diagnosis of exclusion.30

panniculitis.14 The number of leukemic cells in such infiltrates varies from none to many. It has recently been shown that drug-associated lymphomatoid hypersensitivity reactions can show cytologic atypia, clonality, and an immunophenotypic profile that can simulate CTCL. This may of course cause diagnostic difficulties. Performing TCR-beta gene rearrangement on these cases showed that monoclonality on TCR was a reliable finding in CTCL and that polyclonality indicated a benign process.206

FASCIITIS Fasciitis needs to be differentiated from panniculitis and eosinophilic fasciitis, which is a specific clinical entity. Fasciitis, on histologic grounds, is a marked inflammation and thickening of the deep fasciitis. The term, fasciitis panniculitis syndrome (FPS) as previously discussed in this chapter (see Morphea Profunda, Scleroderma, Eosinophilic Fasciitis (Shulman Syndrome)), has recently been proposed as a new category of fasciitis and includes eosinophilic fasciitis (EP).207 EP (Shulman syndrome) has been described to have a consistent eosinophilia, with eosinophilic infiltrate of the lesion. FPS on the other hand does not show consistent findings of eosinophilia. The major histologic findings are dermal thickening, inflammation and thickening of the panniculus, fibrosis and thickening of the fascia, and inflammation of the muscle. Often FPS patient are resistant to corticosteroid treatment and the treatment of choice has been shown to be cyclophosphamide together with prednisolone.207 Necrotizing fasciitis (NF) is a serious and potential life-threatening bacterial infection associated with progressive necrosis of the superficial fascia. The overall mortality ranges from 25% to 73%. (This entity is discussed in greater detail in Chapter 19.)

Lymphoma and Leukemia Cutaneous lymphoid infiltrates, lymphoma, and leukemia may involve the subcutaneous fat. These entities are discussed in more detail in Chap. 34. Nonetheless, because of its importance in differential diagnosis, subcutaneous T-cell lymphoma was discussed earlier. Patients with leukemia on occasion may develop erythematous subcutaneous nodules (resembling EN) that histologically suggest an inflammatory septal

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CHAPTER 12 Cutaneous Drug Eruptions A. Neil Crowson Cynthia M. Magro

IMMUNOLOGIC DRUG REACTIONS Allergic reactions to drugs encompass immediate hypersensitivity (type I) reactions, type II reactions in which antibodies are directed against cell surface antigens, immune-complex-mediated (type III) reactions, and delayed-type hypersensitivity (type IV) reactions. Since the histomorphology of each pattern is distinctive, the pathogenetic basis of the reaction often can be inferred. The first step in the evolution of the cutaneous drug reaction is primary sensitization, often via topical exposure to contactants that cross-react with an offending oral agent. Following primary sensitization, a reaction may occur within seconds to hours after subsequent antigenic rechallenge. Factors that influence the development of hypersensitivity include the nature of the allergen (ie, lipid versus water solubility), the antigenic load (ie, drug dose), individual genetic variations in absorption or metabolism of the drug, immunomodulatory effects of concurrently administered drugs or systemic diseases, environmental factors such as sun exposure, and route of administration.

Immediate Hypersensitivity (Type I) Reactions Most dramatic are the drug reactions of immediate hypersensitivity type (type I),

mediated by the in vivo cross-linkage by polyvalent drug-protein complexes of IgE molecules on the surface of sensitized mast cells or basophils, provoking the release of histamine, leukotrienes, and other proinflammatory molecules that result in vasodilatation, increased vascular permeability, angioedema, pruritus, urticaria, bronchospasm, laryngeal edema, and in some cases, death. The prototype is that due to penicillin.16

Antibody-Mediated (Type II) Reactions Antibody binding to cells leads to damage through complement-mediated lysis. One example is hemolytic anemia associated with methyldopa, mediated by the induction of autoantibodies directed against red blood cell antigens; another is autoimmune thrombocytopenic purpura, mediated through antibodies against platelets and provoked by pyrazolone derivatives (ie, phenylbutazone and allopurinol), sulfonamides, penicillin, salicylates, thiazides, diuretics, and chloramphenicol.

Immune-Complex-Mediated (Type III) Reactions Immune-complex-mediated reactions encompass urticaria; the Arthus reaction, a localized form of immune-complexmediated leukocytoclastic vasculitis (LCV); urticarial vasculitis; Henoch-Schonlein purpura; and serum sickness.

CHAPTER 12 ■ CUTANEOUS DRUG ERUPTIONS

In consequence of polypharmacy in an aging population and the continuous stream of novel drugs being brought to market in the modern era, systemic drug reactions are increasing in frequency and complexity and are thus a constant challenge to clinicians and pathologists.1,2 Adverse clinical manifestations resulting from administration of medicinal agents account for 2% of hospital admissions,3 affect 1% to 2% of the population, and are said to generate roughly $3 billion of annual expense in the United States.4 Although many organ systems may be involved, cutaneous manifestations are frequent and offer a window for diagnosis. Drug reactions may be immunologic or nonimmunologic, the latter consisting of overdosage, intolerance, teratogenicity, facultative effects that result from disruption of bacterial flora in mucous membranes and skin, and toxicity, the latter either delayed (ie, carcinogenic) or cumulative (ie, pigmentary disturbances due to deposition of gold or silver). Other nonimmunologic mechanisms of drug toxicity include anaphylactic reactions due to agents that degranulate mast cells (ie, opiates) or impair arachidonic acid metabolism (ie, cyclooxygenase inhibitors such as acetylsalicylic acid or other nonsteroidal anti-inflammatory agents). Recent advances in our understanding of perturbational effects of drugs on the immune system indicate that classes of drugs that alter immune function may dramatically modify the cutaneous response to exogenous antigens, including drugs of alternate classes.5 Cutaneous drug reactions also can be exacerbated in the setting of immune dysregulation caused by infection with agents such as human immunodeficiency virus (HIV),6,7 cytomegalovirus (CMV),8,9 and human herpesvirus 6 (HHV-6) in the context of the idiopathic drug hypersensitivity syndrome consisting of erythroderma, facial edema, lymphadenopathy, hepatopathy with circulating atypical lymphocytes, and a rash with a mycosis fungoides (MF)like histology.9-11 Drug interactions reflect pharmacokinetic and pharmacodynamic factors, the

former operative when one drug alters the effective serum concentration of another by interfering with its absorption, secretion, or metabolism and the latter reflecting changes induced in one drug by another without alteration of its serum concentration.1,12 Synergistic and cumulative effects of different agents may exacerbate the cutaneous manifestations of a drug reaction, often making it difficult to implicate one agent in isolation. The diagnosis of a cutaneous drug reaction is thus challenging and requires a thorough history, often aided by clinical algorithms. In particular, it is essential to know whether the drug in question has an established adverse effect, whether an alternative explanation for an eruption is possible, whether the timing of the eruption plausibly can be attributed to drug ingestion, whether the eruption resolves after drug therapy is stopped, and whether the rash recurs following rechallenge.3,4,13-15 Confirmatory drug rechallenge is not without risk; patch testing is generally better tolerated than is a systemic (ie, oral or parenteral) challenge.15

Delayed-Type Hypersensitivity (Type IV) Reactions The initial event in the delayed-type hypersensitivity (DTH) or cell-mediated immune response, endocytosis by Langerhans cells of an exogenous antigen (hapten) of drug, viral, or other derivation, is followed by complexing with tissue proteins. The latter leads to the recruitment of a subset of skin-seeking T lymphocytes that attach to high endothelial venules via interaction between lymphocyte function antigens and their respective endothelial receptors.17,18 These T cells, in turn, migrate into the perivascular dermis, where they may encounter antigen-presenting Langerhans cells. The sensitized lymphocytes then migrate to the peripheral lymph nodes, where proliferation of memory and effector cells occurs. The circulating effector lymphocytes return to sites of cutaneous sensitization via homing receptors for

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tissue-specific endothelial ligands. The expression of these ligands is upregulated, as is that of corresponding endothelial adhesion markers, in sites of DTH reactions19; memory or previously activated lymphocytes return to the tissue or lymphatic bed in which they were first activated. Drug reactions in which this mechanism is likely to be operative include erythema multiforme and morbilliform, fixed, eczematous, pustular, lichenoid, lymphomatoid, and pigmentary purpura-like drug reactions.

282

CLINICAL FORMS OF DRUG REACTIONS AND THEIR HISTOPATHOLOGIC EXPRESSION The types of clinical drug reactions are listed in Table 12-1.1-3,20,21

Exanthematous (Morbilliform) Drug Eruptions CLINICAL FEATURES Accounting for up to 95% of all cutaneous drug eruptions, the exanthematous or morbilliform eruptions are characterized by red to salmoncolored macular or papular eruptions that may form polycyclic, gyrate, or reticular patterns resembling a viral exanthem (Fig.12-1 A)1,22 (Table 12-2). Lesions often appear first on the trunk and spread peripherally in a symmetric fashion with dependent areas such as the lower extremities manifesting purpura. Lesions clear with withdrawal of the causative agent but may progress to a generalized exfoliative dermatitis if the drug is continued. Pruritus and fever may be present. Lesions may fade following drug cessation or resolve with a residuum of postinflammatory hyperpigmentation. The commonly implicated agents are listed in Table 12-3. One unusual cause is the lymphocyte recovery state in patients receiving chemotherapeutic drugs for leukemia and lymphoma following the nadir of their peripheral lymphocyte counts.23 HISTOPATHOLOGIC FEATURES Findings include a cell-poor lymphocytic interface dermatitis with basilar and suprabasilar vacuolopathy in an epidermis of normal thickness surmounted by a basketweave pattern of orthokeratinization (Fig. 12-1B). Scattered cytoid bodies may be seen along the lower layers of the epithelium with patchy parakeratosis and slight acanthosis in lesions of several days’ duration. Scattered eosinophils, histiocytes, and plasma cells are seen

Table 12-1 Clinical Forms of Drug Reactions

Table 12-2 Exanthematous Drug Reactions

Exanthematous (maculopapular) Lichenoid Fixed Photosensitivity Pustular Eczematous Bullous Porphyria and pseudoporphyria Drug-induced pemphigoid Drug-induced pemphigus Erythema multiforme and Stevens-Johnson syndrome Toxic epidermal necrolysis Psoriasiform Pityriasiform Lymphomatoid Drug-induced lupus erythematosus Collagen and elastic tissue alterations Elastosis perforans serpiginosa Sclerodermoid Alopecia Ichthyosiform Purpuric Annular erythema Erythrodermic/exfoliative Urticarial or anaphylactic Pigmentary abnormalities Vasculitis Serum sickness Halogenoderma Eosinophilia-myalgia syndrome Erythema nodosum Erythromelalgia Drug-induced hypertrichosis Drug-induced nail abnormalities Drug-induced oral abnormalities Acanthosis nigricans Hidradenitis Panniculitis Dermatomyositis

Clinical Features Salmon-colored macular or papular eruption Often polycyclic, gyrate, or reticular patterns Trunk → acral areas in symmetric distribution Dependent areas may manifest purpura Clear following drug withdrawal May progress to exfoliative erythroderma if drug continued Histopathologic Features Cell-poor lymphocytic interface dermatitis with basilar vacuolopathy Basket-weave orthokeratosis overlying epidermis of normal thickness Mixed lymphohistiocytic, eosinophilic, and/or plasmacellular dermal infiltrate Papillary dermal edema Differential Diagnosis Viral exanthemata Erythema multiforme

it should be easily excluded by clinical history, may be indistinguishable histologically from a drug eruption or viral exanthem. Acute graft-versus-host disease typically manifests a sparse perivascular lymphocytic infiltrate lacking eosinophils. Rashes of systemic connective tissue disease typically produce perivascular and periadnexal lymphoid infiltrates in concert with epidermal atrophy and dermal mucinosis.24

Table 12-3 Drugs Causing Exanthematous (Morbilliform) Eruptions

around the superficial vascular plexus (Fig. 12-2), often accompanied by papillary dermal edema. Some examples, particularly the scarlatiniform eruptions, may show no epithelial alterations. DIFFERENTIAL DIAGNOSIS Viral exanthemata and erythema multiforme reactions closely mimic exanthematous drug eruptions. Tissue eosinophilia is unusual in the former two entities, except in the context of erythema multiforme-like drug reactions. The presence of individually necrotic keratinocytes would point toward an erythema multiforme reaction. Acute graft-versus-host disease, although

Penicillin and synthetic derivatives Phenylbutazone Sulfonamide Phenytoin and carbamazepine Gold Amphotericin B Oral hypoglycemic agents Thiazides Barbiturates Benzodiazepines Phenothiazines Allopurinol Quinidine Captopril Nonsteroidal anti-inflammatory agents Gentamicin Lithium

A

B

 FIGURE 12-1 Morbilliform drug eruption. (A) Characteristic diffuse erythematous macular and papular eruption. (B) A basket-weave pattern of orthokeratinization surmounts a slightly acanthotic epidermis showing a cell-poor lymphocytic interface dermatitis.

CLINICAL FEATURES Lichenoid drug eruptions (Table 12-4) resemble lichen planus by virtue of a violaceous papular eruption with or without oral involvement. Eruptions develop in weeks to months, tend to be extensive, and often develop a psoriasiform appearance. Resolution following cessation of therapy is slow, with postinflammatory pigmentation being more pronounced than in idiopathic lichen planus. Implicated drugs are listed in Table 12-5.1,3,25-27 Lichenoid dermatitis also may be caused by ingestion of gold-containing liquor.28

HISTOPATHOLOGIC FEATURES A bandlike lymphocytic infiltrate along the dermalepidermal junction associated with vacuolopathic basal layer keratinocyte degeneration and colloid body formation is cognate to lichen planus (Fig. 12-3). Eosinophils and plasma cells frequently are present. DIFFERENTIAL DIAGNOSIS Compared with lichen planus, acanthosis is often less striking in the lichenoid drug eruption, and the wedge-shaped hypergranulosis of lichen planus, although present in some cases (see Fig. 12-3), is uncommon. Eosinophils and parakeratosis, common

 FIGURE 12-2 Morbilliform drug eruption due to fluvoxamine, an antidepressant. A vacuolar lymphocytic interface dermatitis is associated with a superficial, perivascular, lymphohistiocytic, and eosinophilic infiltrate.

in lichenoid drug eruptions, are rare in lichen planus, as is middle or deep dermal perivascular extension of the infiltrate. Lichenoid inflammation may be seen in

Table 12-4 Lichenoid Drug Reactions

Clinical Features Extensive violaceous papular eruption, sometimes with psoriasiform appearance Individual lesions resemble lichen planus Postinflammatory hyperpigmentation more pronounced than lichen planus Clear following drug withdrawal Histopathologic Features Bandlike lymphocytic infiltrate hugs dermal-epidermal junction Basilar vacuolopathy of keratinocytes and colloid body formation Patchy parakeratosis often seen Mixed lymphohistiocytic, eosinophilic, and/or plasmacellular dermal infiltrate Middermal perivascular extension Differential Diagnosis Lichen planus Connective tissue diseases with lichenoid infiltrates Subacute cutaneous lupus erythematosus Discoid lupus erythematosus Systemic lupus erythematosus in the setting of anti-Ro antibodies Mixed connective tissue disease Postherpetic eruptions Other lichenoid hypersensitivity reactions, including: Some insect bite reactions Lichenoid contact reactions (ie, color photodeveloper fluids) Erythema multiforme

CHAPTER 12 ■ CUTANEOUS DRUG ERUPTIONS

Lichenoid Drug Eruptions

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Table 12-5 Causes of Lichenoid Drug Eruptions Beta blockers Captopril Methyldopa Thiazides Lasix Gold Antimalarials Quinidine Oral hypoglycemic agents Phenytoin and carbamazepine Antituberculous agents Phenylbutazone Antipsychotics (including phenothiazines) Bismuth p-Aminosalicylic acid Lithium

 FIGURE 12-3 Lichenoid drug eruption due to a beta blocker. Wedge-shaped hypergranulosis overlying an acanthotic epidermis with a lichenoid lymphocytic infiltrate. the setting of hepatobiliary disease such as that induced by hepatitis C infection29 and with connective tissue diseases including mixed connective tissue disease, some cases of discoid and subacute cutaneous lupus erythematosus (SCLE), and cases of systemic lupus erythematosus (SLE) in the setting of anti-Ro antibodies.24,30 However, such cases typically manifest at least focal epidermal atrophy and only exhibit tissue eosinophilia when seen in the context of drug-induced lupus erythematosus (DIL)24,25. A novel form of lichenoid drug reaction consisting of a lichenoid and granulomatous dermatitis may be seen in patients receiving sulfa drugs and other antibiotics, angiotensinconverting enzyme inhibitors, lipid-lowering agents, antihistamines, and beta blockers.31

Fixed Drug Eruption

284

CLINICAL FEATURES Fixed drug eruptions (Table 12-6) are associated with the drugs listed in Table 12-7.1-3,20,21,25,27,31-35 Over-the-counter preparations such as pseudoephedrine may go unreported to the clinician and so obscure the diagnosis.36,37 The eruptions characteristically recur in the same locations following antigenic rechallenge, with areas of involvement often increasing in size and distribution with each recurrence. The mechanism appears to reflect upregulated keratinocyte expression of intercellular adhesion molecule (ICAM)-1 and endothelial expression of E-selectin and vascular adhesion molecule-1.38 Lesions occur more often on acral and anogenital sites than on the trunk. The acute lesion, a sharply circumscribed round or oval

patch of violaceous or dusky erythema, generally arises within 30 minutes to several hours following drug administration. Vesiculation or blistering may ensue.33

Table 12-6 Fixed Drug Eruption

Clinical Features Oval or round, sharply demarcated violaceous or dusky macule Arises 30 minutes to several hours after drug ingestion Anogenital areas, especially glans penis, and acral sites most common Vesiculation and blistering may ensue Areas of involvement tend to expand and multiply with drug rechallenge Postinflammatory hyperpigmentation Clear following drug withdrawal Histopathologic Features Variably bandlike lymphocytic interface infiltrate Basilar vacuolopathy of keratinocytes and colloid body formation, often accentuated at tips of retia Acanthosis more pronounced than erythema multiforme Patchy parakeratosis often seen Mixed lymphohistiocytic, eosinophilic, plasmacellular, and neutrophilic dermal infiltrate, often superficial and deep Differential Diagnosis Erythema multiforme Viral exanthema Connective tissue disease Graft-versus-host disease

Multifocal and extensive eruptions may resemble erythema multiforme and toxic epidermal necrolysis, respectively. Lesions may progress to scaling and resolve with striking postinflammatory pigmentary alteration. HISTOPATHOLOGIC FEATURES The fixed drug eruption manifests a lymphocytic

Table 12-7 Drugs Associated with Fixed Drug Eruptions Antibiotic agents Sulfonamides Tetracycline Penicillin and synthetic penicillins Trimethoprim Antifungal agents Dapsone Arsenicals p-Aminosalicylic acid Antimalarials Flagyl Sedatives Barbiturates Opiates Benzodiazepines Anticonvulsants Dextromethorphan Nonsteroidal anti-inflammatory agents Acetylsalicylic acid Phenylbutazone Ibuprofen Miscellaneous agents

eosinophilic, neutrophilic, and plasma cellular infiltrates, inclusive of intraepithelial eosinophilic microabscesses. The cytoid bodies in erythema multiforme tend to be scattered across the breadth of a 3- or 4-mm punch biopsy as opposed to clustered around rete ridges, as seen in the fixed drug eruption. Graftversus-host disease and viral exanthemata are usually pauci-inflammatory and lack granulocytes.

Photosensitivity Drug Eruptions

 FIGURE 12-4 Fixed drug eruption. A lymphocytic interface dermatitis is present showing focal accentuation at tips of retia associated with striking colloid body formation and a dermal, perivascular, and bandlike lymphocytic and eosinophilic infiltrate.

interface dermatitis with rete ridge accentuation associated with marked colloid body formation, often with a superficial and deep dermal perivascular lymphocytic and eosinophilic infiltrate (Fig. 12-4). Clusters of colloid bodies are seen in the damaged retia. There may be an admixture of neutrophils or plasma cells or both. Later in lesional evolution, more pronounced epithelial necrosis

and pigment incontinence may be seen (Fig. 12-5). Neutrophilic fixed drug eruptions occur rarely.39 DIFFERENTIAL DIAGNOSIS Fixed drug eruptions can be distinguished from erythema multiforme by virtue of relatively greater epithelial hyperplasia, pigment incontinence, deeper extension of lymphoid infiltration, and more frequent

 FIGURE 12-5 Fixed drug eruption in a patient on Premarin. More pronounced epidermal necrosis and colloid body formation are seen, and a bandlike dermal lymphocytic and eosinophilic infiltrate are associated with pigment incontinence.

Table 12-8 Photosensitivity Drug Reactions

Clinical Features Erythematous macular, papular, or vesicular eruptions in a photodistribution, sparing submental and retroauricular areas Phototoxic: occur 5-20 hours after exposure to drug and light Photoallergic: occur within 24 hours of repeat antigenic challenge with drug and sunlight and may occur on non-sun-exposed skin Combined phototoxic/photoallergic eruptions common Histopathologic Features Phototoxic Keratinocyte injury (apoptosis or reticular degeneration) at all levels with architectural disarray and dysmaturation Neutrophilic epidermotropism at sites of injury Perivascular lymphocytic infiltrate in dermis Superficial vasculature ectatic with endothelial swelling Photoadaptive: hypergranulosis, hyperkeratosis, and melanocytic hyperplasia Photoallergic Spongiosis and vesiculation with adherent scale-crust Mixed lymphohistiocytic and eosinophilic dermal infiltrate Papillary dermal edema Differential Diagnosis Phototoxic Viral exanthemata Erythema multiforme Graft-versus-host disease Photoallergic: delayed-type hypersensitivity reactions of diverse cause

CHAPTER 12 ■ CUTANEOUS DRUG ERUPTIONS

CLINICAL FEATURES Drugs that induce photosensitivity absorb electromagnetic radiation in the ultraviolet (UV) and visible ranges, the former mainly consisting of UVA (320-400 nm) and UVB (290-320 nm) (Table 12-8). In phototoxic

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reactions, the drug absorbs radiation and enters an excited state, producing species that react with other cellular constituents, including reactive oxygen species. In photoallergic reactions, the drug is converted into an immunologically active compound. Interactions between drugs and UV light produce eruptions in a photodistribution, sparing the submental and retroauricular areas and upper eyelids. Phototoxic eruptions characteristically occur within 5 to 20 hours of first exposure to a drug and resemble an exaggerated sunburn reaction, being characterized by erythema with blistering, vesiculation, desquamation, and hyperpigmentation of sun-exposed skin. Photoallergic eruptions require a latent period for sensitization and characteristically appear within 24 hours of repeat antigenic challenge with both drug and UV light. Unlike purely phototoxic reactions, photoallergic eruptions also may be seen on non-sun-exposed sites. Most drugs associated with photoallergy, if given in sufficient quantities, can induce

a phototoxic reaction. Combined photallergic-phototoxic eruptions are common. Implicated drugs are listed in Table 12-9.1-3,20,21,40,41 HISTOPATHOLOGIC FEATURES The phototoxic eruption manifests keratinocyte injury at all levels of the epidermis with architectural disarray and dysmaturation (Fig. 12-6). Parakeratosis may surmount areas of epithelial injury, the patterns of which include apoptosis and reticular degeneration. Neutrophils may infiltrate the epidermis at sites of injury. There is a variable perivascular mononuclear cellpredominant infiltrate that is accentuated around the superficial vascular plexus and manifests exocytosis. Blood vessels usually are dilated and show endothelial swelling or necrosis that diminishes in the depths of the biopsy and is accompanied by hemorrhage. The photoadaptive reaction (Fig. 12-7) shows hypergranulosis, hyperkeratosis, melanocytic hyperplasia, suprabasilar melanization, and transepidermal elimination of melanin. Photoallergic features consist of epidermal spongiosis and vesiculation, which frequently eventuates in an adherent

plasma-rich scale crust. Eosinophils are a frequent component of the infiltrate. In eruptions of combined phototoxicphotoallergic type, variable expressions of these two prototypic morphologies are seen. Some patients develop persistent photosensitivity at exposed and nonexposed skin sites. If accompanied by skin infiltration by transformed lymphocytes, the designation chronic photosensitivity dermatitis may be appropriate. Histologically, the presence of intraepithelial cerebriform lymphocytes arranged into groups surrounded by a clear halo reminiscent of Pautrier microabscesses results in a histologic pattern mimicking mycosis fungoides. DIFFERENTIAL DIAGNOSIS Subacute and chronic dermatitides of diverse causes mimic photoallergic eruptions but generally lack the scattered epidermal cytoid bodies and vascular alterations of phototoxic states and the photoadaptive changes in melanocytes. The nodular perivascular distribution of the infiltrates, psoriasiform hyperplasia, multinucleated stromal giant cells, and perivascular elastolysis, in concert with the clinical history,

Table 12-9 Drugs Associated with Photosensitivity Eruptions Common Amiodarone (PA) Phenothiazines (PA, PT, pigmentation) Psoralens (PT) Sulfonamides Tetracyclines (PT) Thiazide diuretics (lichenoid, LE-like) Nonsteroidal anti-inflammatory agents (PA, PT, PCT-like) Nalidixic acid (PA, PT, PCT-like) Coal tar Quinidine (lichenoid, eczematous) Uncommon Antihistamines (PA) Synthetic penicillins Antidepressants (PA, PT) Antifungal agents (PA) Beta blockers Anticonvulsants (PA) Benzodiazepines (PA) Methyldopa Oral contraceptives (PA) Antimalarials (PA, PT) Retinoids (PA, PT) Sun screens (PA) Oral hypoglycemics (PA) PA = predominately photoallergic. PT = predominately phototoxic. PCT = porphyria cutanea tarda. LE = lupus erythematosus.

 FIGURE 12-6 Phototoxic drug eruption. Cytoid bodies are present along the basal layer, in suprabasilar epidermis, and in the cornified layer. Ectasia of superficial blood vessels, associated with endothelial swelling, is characteristic.

neutrophilic dermal infiltrate unaccompanied by leukocytoclastic vasculitis.52-56

Eczematous Drug Reactions enable distinction of the chronic photosensitivity dermatitides from mycosis fungoides.

With respect to drug-induced pustular Sweet-like eruption, biopsies show massive papillary dermal edema and a diffuse

CLINICAL FEATURES Oral ingestion, inhalation, or transcutaneous application of a drug to which a person has been previously sensitized via contact exposure may

Pustular Eruptions CLINICAL FEATURES Acute generalized exanthematous pustulosis (AGEP) is a distinctive generalized toxic pustular erythema associated with reactions to drugs, including calcium channel blockers, nonsteroidal anti-inflammatory agents, anticonvulsants, b-lactam and macrolide antimicrobials, and antifungal agents.42-50 Less common associations are with antiarrhythmic agents, including quinidine, and contact with mercury. Typically, patients present with a generalized scarlatiniform eruption of sudden onset that is studded with sterile pustules, is associated with fever, and follows a self-limited course of 4 to 17 days.51 A drug-induced eruption mimicking Sweet syndrome has been described in the setting of therapy with diltiazem, sulfamethoxasole-trimethoprim, minocycline, oral contraceptives, and nonsteroidal anti-inflammatory agents and in patients receiving colony-stimulating factors for therapy of leukemic or congenital neutropenic states.52-56 HISTOPATHOLOGIC FEATURES Biopsies of AGEP lesions show spongiform pustulation of the epidermis typically with follicular and acrosyringeal accentuation (Fig. 12-8). An accompanying leukocytoclastic vasculitis may be seen but is not typical in our experience.

 FIGURE 12-8 Pustular drug eruption. Spongiform pustulation involving a hair follicle is accompanied by a subcorneal pustule in the adjacent interfollicular epidermis and a perivascular and diffuse dermal infiltrate of lymphocytes and eosinophils.

CHAPTER 12 ■ CUTANEOUS DRUG ERUPTIONS

 FIGURE 12-7 Photoallergic drug eruption in a patient on amiodarone. Hypergranulosis, hyperkeratosis, and acanthosis are seen, and a plump photoactivated melanocyte is present in the basal layer.

DIFFERENTIAL DIAGNOSIS The main considerations include variants of pustular psoriasis, infection, and neutrophilic dermatoses, including Sweet syndrome. A leukocytoclastic vasculitis is not seen in lesions of psoriasis, except in the setting of concomitant hypersensitivity reactions, such as due to drugs. When a psoriasiform diathesis is seen in concert with a leukocytoclastic vasculitis, Reiter disease merits strong consideration.57 It has been suggested that some patients with AGEP have latent psoriasis58 or underlying immune dysregulation, such as that due to HIV infection.51,59 Pustular IgA vasculitis is also seen in patients with mucosal infections.60 Other pustular eruptions such as Sneddon-Wilkinson syndrome or impetigo show broad subcorneal pustulation or admixed bacteria, respectively; both lack acrosyringeal centricity.

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Table 12-10 Eczematous Drug Reactions

Clinical Features Erythematous, papular, or vesicular eruption in patients exposed to an agent to which they were previously sensitized Sites often correspond to those previously affected Histopathologic Features Spongiosis and intraepidermal vesiculation Moderately dense dermal lymphocytic and eosinophilic infiltrate with variable exocytosis Differential Diagnosis Other delayed-type hypersensitivity reactions of diverse cause

elicit an eczematous drug reaction61 (Table 12-10). Affected sites frequently correspond to those involved in a prior contact dermatitis, with symptoms arising 2 to 24 hours after an oral dose. The term baboon syndrome has been used to describe bright-red, well-demarcated anogenital lesions associated with a symmetric eczematous eruption involving elbow flexures, axillae, eyelids, and the sides of the neck. Drugs commonly associated with eczematous reactions include antibiotics and ethylenediaminecontaining antihistaminic and aminophylline preparations.1,2,20,21 HISTOPATHOLOGIC FEATURES Biopsies show spongiosis with intraepidermal vesiculation and a moderately dense lymphoeosinophilic infiltrate with variable exocytosis of lymphocytes and eosinophils.61 DIFFERENTIAL DIAGNOSIS Hypersensitivity reactions to a variety of antigenic triggers will look similar.

Blistering Drug Eruptions The blistering drug eruptions include pseudoporphyria cutanea tarda, bullous erythema multiforme, bullous fixed drug eruption, and drug-induced pemphigus, pemphigoid, and linear IgA dermatosis.62-64

Drug-Induced Pseudoporphyria Cutanea Tarda

288

Pseudoporphyria cutanea tarda is a blistering disorder reminiscent of porphyria cutanea tarda by virtue of clinical, histologic, and immunofluorescent findings64 but in which porphyrin metabolism is normal. Patients often have an underlying

connective tissue disease.63 This process is discussed in Chap. 7.

Drug-Induced Pemphigus CLINICAL FEATURES AND PATHOGENESIS In idiopathic pemphigus, autoantibodies are directed at antigenic targets that include a 130-kDa glycoprotein complexed to an 85-kDa cytoplasmic plaque protein called plakoglobin to form the adhesion molecule desmoglein III in pemphigus vulgaris and a 165-kDa cell adhesion molecule termed desmoglein I in pemphigus foliaceus.64,65 The distribution of desmoglein I in buccal mucosa, scalp, and lower torso correlates with lesional distribution. Drug-induced blistering eruptions may present as a superficial pemphigus state, as grouped annular plaques mimicking pemphigus herpetiformis, or with a picture cognate to pemphigus vulgaris. A preblistering prodrome, either a morbilliform or an urticarial eruption similar to a morbilliform or urticarial drug rash, helps to distinguish drug-induced from idiopathic pemphigus. The main agents implicated include those which contain a thiol (sulfhydryl) group, such as angiotensinconverting enzyme inhibitors, penicillamine, and gold sodium thiomalate, and nonthiol drugs such as penicillin and its derivatives, cephalosporins, pyrazolone derivatives such as phenylbutazone, and miscellaneous drugs. It is postulated that sulfhydryl groups of offending drugs bind to the disulfide bond-rich intercellular junctions and so render them antigenic. The drug-induced autoantibodies have similar specificities to those seen in idiopathic pemphigus.66 Thiols also can induce a superficial IgA pemphigus state mimicking idiopathic subcorneal pustular dermatosis of Sneddon-Wilkinson.67 In some patients in whom antibodies are not demonstrable, the blisters may reflect a direct toxic chemical effect on intercellular junctions. HISTOPATHOLOGIC FEATURES Early lesions may exhibit nondiagnostic parakeratosis, spongiosis, and a lymphoeosinophilic dermal infiltrate. The fully-evolved blistering lesions are identical to their idiopathic counterparts (ie, superficial pemphigus, pemphigus vulgaris, or subcorneal pustular dermatosis). Direct immunofluorescence (DIF) microscopy reveals pericellular deposition of immunoreactants in the perilesional epidermis in 90% of cases64 in a distribution that does not reliably correlate with antibody specificity or pemphigus subtype. Some 70% of patients have circulating antibodies by indirect immunofluorescence testing.

Drug-Induced Pemphigoid CLINICAL FEATURES AND PATHOGENESIS Bullous pemphigoid (BP) is an autoimmune blistering dermatosis typically seen in elderly patients who manifest tense blisters on an erythematous or urticarial base involving the trunk, extremities, and intertriginous areas. Typical are IgG antibodies directed at antigenic targets of 230 and 180 kDa localized to the lamina lucida of the basement membrane zone (BMZ) that are components of the hemidesmosome.64,68 Circulating antibodies usually are detectable in sera. A drug-induced BP syndrome is seen in patients receiving furosemide, penicillamine, penicillins, salicylazosulfapyridine, sulfasalazine, and phenacetin. Case-control studies show enhanced relative risk with diuretic and neuroleptic agents.68 Clinical presentations range from classical BP-like lesions to scarring plaques affecting mucosal sites in the fashion of cicatricial pemphigoid,69 an erythema multiforme-like picture, and a pemphigus-like morphology. HISTOPATHOLOGIC FEATURES Skin biopsies show a subepidermal eosinophilrich blister reminiscent of that seen in BP, and DIF testing shows linear IgG and C3 in the BMZ of the dermal-epidermal junction in a fashion indistinguishable from idiopathic BP.

Drug-Induced Linear IgA Disease CLINICAL FEATURES AND PATHOGENESIS Classic linear IgA disease presents as a vesiculobullous eruption of the trunk, inner thighs, and pelvic region that may resemble dermatitis herpetiformis and/or BP but is never symmetric, is inconstantly pruritic, and exhibits mucosal involvement in up to 50% of patients. Some patients manifest mucosal scarring, as seen in cicatricial pemphigoid, typically in the setting of IgA antibodies directed at type VII collagen.70,71 Linear IgA disease has been associated with such drugs as antibiotics (vancomycin, penicillins, cetriaxone, metronidazole, Septra, and rifampicin), lithium, Dilantin, lipid-lowering agents, furosemide, angiotensin-converting enzyme inhibitors, granulocyte colony-stimulating factor, piroxicam, and diclophenac.72-83 While drug-associated linear IgA disease clears with drug cessation, a rechallenge may generate a more severe eruption with a shorter latent period.72-75 HISTOPATHOLOGIC FEATURES Characteristic is a neutrophil-rich interface dermatitis with effacement of the epidermal

Table 12-11 Drug Classes Associated with Drug-Induced Lupus Erythematosus Antihypertensive Antipsychotic Anticonvulsant Anti-inflammatory Antimicrobial Immunosuppressive Antihormonal Recombinant cytokines

vary somewhat with drugs from different classes, skin disease in general is less frequent and pulmonary manifestations more common than in idiopathic LE. A systemic LE-like syndrome is characteristic, although some cases resemble discoid LE clinically. A form of drug-induced SCLE is seen in the setting of therapy with calcium channel blockers and antihistaminic preparations.25,92 The prototypical drugs associated with DIL generate two distinctive serologic profiles; chlorpromazine and hydralazine are associated with antihistone antibodies, and procainamide and quinidine generate anti–H2a-H2b-DNA antibodies, the latter directed at a histone-DNA complex. Predisposition to the development of DIL tends to be in part genetically determined; patients are often slow acetylators and thus metabolize hydralazine and

procainamide slowly. Although the mechanisms by which these agents provoke DIL are not fully elucidated, we know that procainamide and hydralazine inhibit T-cell DNA methylation, provoking autoreactivity in cloned T-helper (Th) lymphocytes, and perhaps share the capacity to induce autologous B-cell differentiation. Passive transfer of Th cells treated with procainamide or other DNA methyltransferase inhibitors causes a lupus-like illness in syngeneic mice. Agents most closely associated with DIL, including methyldopa, procainamide, chlorpromazine, and hydralazine, are known to disturb a variety of lymphocyte functions, as do calcium channel blockers and antihistaminics. This may create an immunologic milieu permissive of the development of autoantibodies against ribonucleoproteins.92 With respect to the SCLE-like eruptions, most patients are women with photoinduced annular papulosquamous lesions in whom serologic studies demonstrate a positive ANA assay with or without anti-Ro, anti-La, and anticentromere antibodies.92 HISTOPATHOLOGIC FEATURES Light microscopic and DIF studies tend to show features typical for LE,24,93 namely, SLE in the case of methyldopa, procainamide, chlorpromazine, and hydralazine and SCLE in patients receiving calcium channel blockers92 or antihistaminics25 (Fig. 12-9). The histologic features of LE

CHAPTER 12 ■ CUTANEOUS DRUG ERUPTIONS

architecture, variable tissue eosinophilia, and subepidermal blisters containing granulocytes and fibrin. It is postulated that IgA binding to specific antigenic components of the BMZ may cause hemidesmosomes to function as a ligand for neutrophil adherence and activation. Routine DIF studies show a thin, linear band of homogeneous IgA decoration along the dermal-epidermal junction. Immuno-ultrastructural localization shows the IgA deposition to be variably in the lamina lucida or hemidesmosomal plaques and adjacent lamina lucida, below the lamina densa, or on both sides of the lamina densa.84 A 97-kDa/120-kDa antigen and a 285-kDa dermal antigen are the target antigens,85 with antibodies to the former targeting the anchoring filament protein ladinin (LAD-1) synthesized and secreted by keratinocytes.86 LAD-1 is sandwiched between the NC-16A and the carboxylterminal domains of BPAg2, a localization that also encompasses the collagenous domain of BPAg2.87,88 The NC-16A domain of BPAg2 is found within the plasma membrane of the hemidesmosomal complex, whereas the carboxyl terminus of BPAg2 is in the lower lamina lucida; thus LAD-1 and the extracellular portion of BPAg2 co-localize in the lamina lucida.89 Since the 285-kDa antigen represents the NC-1 domain of collagen type VII, there is clinical overlap with epidermolysis bullosa aquisita.85 Most patients with idiopathic or drug-induced linear IgA disease manifest antibodies of IgA and IgG classes directed against BPAg2, particularly the carboxyl-terminal portion,90 also the major target region of antibodies in cases of cicatriceal pemphigoid. The latter finding may explain the clinical overlap between the two conditions from the standpoint of cicatricial mucosal involvement. Immunoblotting techniques demonstrate antibodies to type VII collagen, LAD-1, and BPAg1 in cases of drug-associated linear IgA disease.73,91

Drug-Associated Lupus Erythematosus-Like Eruptions CLINICAL FEATURES Drug-induced lupus erythematosus (DIL) occurs with a variety of medication classes (Table 12-11) and should be suspected in patients who, in the absence of underlying lupus erythematosus (LE), develop antinuclear antibodies (ANAs) and at least one clinical manifestation of LE while ingesting a drug and in whom symptoms abate after its discontinuance.1,2,24 Although the clinical stigmata of DIL

 FIGURE 12-9 Drug-induced subacute lupus erythematosus in a patient on diltiazem. A lymphocytic interface dermatitis is associated with epidermal atrophy, vacuolar basal layer degeneration, cytoid body formation, and suprabasilar lymphocytic satellitosis around degenerating keratinocytes.

289

are discussed elsewhere24 (see Chaps. 3 and 5).

Table 12-13 Histologic Features of the Lymphomatoid Hypersensitivity Reaction

DIFFERENTIAL DIAGNOSIS Concomitant features typically associated with delayed-type hypersensitivity reactions, namely, tissue eosinophilia and epithelioid histiocytic granulomata, may be seen and are distinguishing features from idiopathic LE.

PART I ■ INFLAMMATORY REACTIONS IN THE SKIN

Lymphomatoid Drug Eruptions CLINICAL FEATURES Lymphomatoid drug reactions are a type of lymphomatoid hypersensitivity reaction,5 a spectrum that also encompasses aberrant and excessive immune reactions to other antigenic stimuli inclusive of insect bites,94 viruses, bacteria, contactants, and light.95 The most frequently encountered drugs are listed in Table 12-12.5,96-100 Patients often receive two or more such drugs, suggesting a synergistic or cumulative effect on lymphoid function. Although the iatrogenic causes of immune dysregulation usually reflect the ingestion of one or more drugs with immune-dysregulating properties,100 patients often have underlying systemic immune-perturbing conditions such as malignant lymphoma, HIV infection, or connective tissue disease.5 Lesions present as one or more plaques resembling mycosis fungoides, as multiple papules, or as a solitary nodule. Long-term clinical follow-up is necessary because distinction from lymphoma can be difficult and because progression from pseudolymphoma to malignant

MYCOSIS FUNGOIDES-LIKE PATTERN OF LYMPHOMATOID HYPERSENSITIVITY

FEATURES COMMON TO MYCOSIS FUNGOIDES AND LYMPHOMATOID HYPERSENSITIVITY

Infiltration of the epidermis by mildly atypical lymphocytes or by cells with a comparable cytomorphology to the small and intermediate-sized atypical dermal lymphocytes Sézary cells Directed pattern of epidermal infiltration with maximal involvement of suprapapillary plates/adnexaea Vesiculationa Papillary dermal edemaa No Pautrier’s microabscesses Vascular fibrin depositiona

Dermal Sézary cells

Atrophy Vascular ectasia Dermal fibrosis, either vertical or laminated

a

Histologic features characteristic of delayed-type hypersensitivity reactions.

lymphoma can occur.5 Immune dysregulation may persist for weeks after a drug is discontinued; failure of an eruption to resolve within several weeks should not be held to indicate a diagnosis of malignant lymphoma, although lesional persistence several months after appropriate drug modulation should prompt that consideration.5 HISTOPATHOLOGIC FEATURES Distinctive patterns seen in the context of the lymphomatoid drug reaction (Table 12-13) include the MF-like pattern (Fig. 12-10),

the lymphomatoid vascular reaction (Fig. 12-11), follicular mucinosis, and lymphocytoma cutis. The MF-like pattern combines features of epidermotropic cutaneous T-cell lymphoma (CTCL) with histologic hallmarks of delayedtype hypersensitivity,5,96,97 including basilar vacuolopathy, spongiosis, vesiculation, keratinocyte nec-rosis, and papillary dermal edema. Epithelial infiltration is frequently only mild and is of maximal intensity in suprapapillary plates and adnexae, sites of preferential antigenic processing.5 The lymphomatoid

Table 12-12 Drugs Implicated in Pseudolymphomata ACE inhibitors Alpha antagonists Anticonvulsants Antidepressants Benzodiazepines Beta blockers Calcium channel blockers H1 antagonists H2 antagonists Lithium Lipid-lowering agents Nonsteroidal anti-inflammatory agents Phenothiazines Sex steroids

290

ACE = angiotensin-converting enzyme. H1 = histamine receptor, type 1. H2 = histamine receptor, type 2.

 FIGURE 12-10 Lymphomatoid hypersensitivity reaction (mycosis fungoides-like) in a patient on amitriptyline. A bandlike dermal lymphocytic infiltrate is present and shows haphazard epidermotropism with minimal spongiosis; in other areas not shown, the epidermis was spared, unlike mycosis fungoides, where epidermal involvement is continuous in shave biopsy specimens.

drugs that can induce cutaneous sclerosis are bromocriptine, lithium, valproic acid, hydantoins, b-interferon, hydroxyurea, and L-tryptophan.1,2,106 Sclerodermoid tissue reactions localized to injection sites are associated with corticosteroids, heparin, vitamin K1, pentazocine, and prior radiotherapy. With respect to pathobiology, the ergot derivatives provoke peripheral vasoconstriction that damages capillary endothelium. A reduction in cyclic AMP levels promotes collagen synthesis and is the proposed mechanism of fibrosis in patients receiving beta blockers. Trytophan-associated eosinophilic fasciitis is addressed elsewhere.

vascular reaction manifests an angiocentric infiltrate of atypical lymphocytes that obscures the vessel architecture, usually without fibrinoid necrosis (see Fig. 12-11). DIFFERENTIAL DIAGNOSIS The mycosis fungoides-like lymphomatoid hypersensitivity reaction pattern is distinguished from MF by virtue of the architecture of the lymphoid infiltrate, the lack of intraepidermal Sézary cells, infrequent apoptosis of lymphocytes, low mitotic rates, tingible body macrophages, and often by lymphocyte polyphenotypy and polygenotypy. Recent studies have demonstrated both clonal restriction and aberrantly diminished expression of CD5 and CD7 in some cases, suggesting that a form of reversible drug-induced cutaneous T-cell dyscrasia at times may be operative.101,102 The lymphomatoid vascular reaction pattern may be seen in a variety of neoplastic and nonneoplastic lesions, including angioimmunoproliferative lesions (AILs) ranging from lowgrade lymphomatoid granulomatosis to angiocentric T-cell lymphoma, adult T-cell leukemia/lymphoma, lymphomatoid papulosis, angioimmunoblastic lymphadenopathy, delayed-type hypersensitivity reactions, and lymphomatoid connective tissue disease.103,104

Drug-Associated Alopecia Drugs-induced alopecia occurs primarily through two mechanisms: induction of

telogen effluvium or mitotic arrest of anagen hair (anagen effluvium) (see Chap. 10). Causes of the former include anticoagulants, lithium, and boric acid, whereas chemotherapeutic agents cause the latter. Although virtually any drug may induce alopecia, only a few are associated routinely with hair loss. Exacerbation of hair loss with reexposure and hair recovery following withdrawal are the best evidence to incriminate a specific drug. Other drugs associated with diffuse hair loss through unclear mechanisms include naproxen, colchicine, thiamphenicol, amiodarone, levodopa, anticonvulsants, and estrogen therapy following withdrawal.21,105 HISTOPATHOLOGIC FEATURES Drugs associated with a lichenoid reaction, the prototype being quinidine, can produce a scarring alopecia (see Chap. 10). DIFFERENTIAL DIAGNOSIS Distinction of drug-induced alopecia from idiopathic anagen and telogen effluvium may be impossible. The lichenoid infiltrate provoked by quinidine mimics lichen planopilaris but lacks hypergranulosis of the interfollicular epidermis and may manifest eosinophilic infiltrates.

Sclerodermoid Tissue Reactions Drugs implicated in the pathogenesis of fibrosing disorders include serotonin, methysergide and other ergot alkaloids, practolol, and hydralazine. Among the

DIFFERENTIAL DIAGNOSIS The morphology is indistinguishable from idiopathic morphea and from sclerodermoid alterations associated with connective tissue disease and Borrelia infection.

Other Alterations of Collagen and Elastic Fibers Associated With Drug Therapy Cutis laxa, anetoderma, elastosis perforans serpiginosa, and pseudoxanthoma elasticum, the clinical and histopathologic features and differential diagnosis of which are considered elsewhere, can be provoked by drugs1,2 (Table 12-14).

CHAPTER 12 ■ CUTANEOUS DRUG ERUPTIONS

 FIGURE 12-11 Lymphomatoid vascular reaction in a patient on diazepam. A perivascular and transmural infiltrate of mature and transformed lymphocytes is present and is unaccompanied by vascular fibrin deposition.

HISTOPATHOLOGIC FEATURES Scleroder-moid tissue reactions demonstrate widened collagen fibers with diminished fibrillar striations and interstitial infiltrates of lymphocytes and plasma cells.

Side Effects of Chemotherapeutic Agents CLINICAL FEATURES Chemotherapyinduced reactions include acral erythema characterized by erythema and swelling

Table 12-14 Alterations of Collagen and Elastic Fibers by Drugs Elastosis perforans serpiginosa Tiopronine D-Penicillamine Cutis laxa/pseudoxanthoma elasticum-like Penicillin Isoniazid L-Tryptophan D-Penicillamine Anetoderma Penicillamine

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PART I ■ INFLAMMATORY REACTIONS IN THE SKIN 292

of the hands after administration of fluorouracil, Taxol, doxorubicin, methotrexate, and arabinoside1,107,108; neutrophilic hidradenitis109; and radiation recall dermatitis provoked by doxorubicin, oxaliplatin, and methotrexate, in which an eruption occurs in a previously quiescent radiation field.110,111 As mentioned earlier, a fibrosing dermopathy can be induced by hydroxyurea, as can the erosion of psoriatic plaques in patients treated for psoriasis over long time periods.112

tration of other drugs, such as lithium,114 or of id reactions to microbial pathogens.

HISTOPATHOLOGIC FEATURES Acral erythema manifests as basilar vacuolopathy accompanied by focal dyskeratosis107 (Fig 12-12). In radiation-recall dermatitis, an atrophying interface dermatitis characterized by basilar vacuolopathy and superficial vascular ectasia is observed (personal observation). Neutrophilic eccrine hidradenitis manifests neutrophilic infiltrates surrounding and permeating the eccrine apparatus with epithelial cell degeneration and necrosis.109 Eccrine ducts may exhibit squamous syringometaplasia, manifesting comma-shaped structures showing mat-ure squamous epithelium113 in response to a variety of chemotherapeutic agents.

HISTOPATHOLOGIC FEATURES The prototypical drug-induced vasculitis is a leukocytoclastic vasculitis confined to the superficial vascular plexus and sometimes accompanied by significant tissue eosinophilia115; the histopathology and differential diagnosis are discussed elsewhere. Older lesions of drug-associated vasculitis may be predominated by mononuclear cells. A pandermal severe LCV such as typifies systemic vasculitic syndromes is not a feature of druginduced vasculitis; granulomatous vasculitis is uncommon. A lymphocytic vascular reaction with hemorrhage can be observed in drug-induced vasculitides, but the presence of tissue eosinophilia and absence of luminal thrombosis are unlike the prototypical lymphocytic vasculitides of connective tissue disease.115 A pustular hypersensitivity vasculitis associated with vascular IgA deposition is seen in the setting of therapy with drugs including carbamazepine.116 The pigmented purpuric dermatoses, for

DIFFERENTIAL DIAGNOSIS Connective tissue diseases, erythema multiforme, and viral exanthemata mimic acral erythema lesions; the incipient lesion is often indistinguishable from acute graft-versus-host disease. Neutrophilic eccrine hidradenitis may be a manifestation of the adminis-

Drug-Associated Vasculitis Including Serum Sickness CLINICAL FEATURES Drug-associated vasculitis in the skin is expressed as palpable purpura or a maculopapular rash. Some implicated drugs and their associated vascular injury patterns are listed in Table 12-15.1,2

 FIGURE 12-12 Taxotere-induced acral erythema. There are scattered cytoid bodies within the epidermis that appear concentrated in the acrosyringia as confirmed in deeper levels.

which a lymphocyte-mediated vascular injury state is the pathophysiologic basis, are associated in some cases with the intake of sedatives, nonsteroidal anti-inflammatory drugs, and antibacterial and antifungal agents such as itraconozole.116,117 An IgA-mediated pigmented purpura has been described in the setting of therapy with captopril.118 Drug-associated atypical pigmentary purpura is a form of lymphocytic vasculopathy that represents roughly 50% of all cases of pigmentary purpura showing lymphoid atypia and epitheliotropism and so mimicking purpuric mycosis fungoides.119 The implicated drugs fall in the

Table 12-15 Drug-Associated Vasculitis Leukocytoclastic vasculitis, not otherwise specified Phenylbutazone Indomethacin Allopurinol Penicillins Erythromycin Sulfonamides Thiazide diuretics Hydantoins Henoch-Schonlein purpura Acetylsalicylic acid Penicillins Quinine Thiouracil Gold Pustular vasculitis Naproxen Penicillins Ampicillin Amoxicillin Furosemide Diltiazem Carbamazepine Mercury Pigmentary purpuras Bromhexine Carbromal Bromisoval Captopril Polyarteritis nodosa-like Acetylsalicylic acid Sulfasalazine Allopurinol Sulfamethoxazole Sulfonamides Quinidine Phenytoin Meprobamate Thiouracil Potassium

immune-dysregulating classes considered to be causal of pseudolymphomata.

Psoriasiform Drug Reactions A variety of drugs can be associated with a psoriasiform eruption and/or with the induction or exacerbation of psoriasis1,2,21 (Table 12-16).

DIFFERENTIAL DIAGNOSIS The hallmark of the psoriasiform diathesis, namely, tortuous dermal papillae capillaries in apposition to thinned suprapapillary plates, is not seen except in the context of drugs that induce or aggravate underlying psoriasis, whereby the histomorphology is indistinguishable from psoriasis, save for the presence of tissue eosinophilia.

Pityriasiform Eruptions CLINICAL FEATURES Drugs associated with eruptions resembling pityriasis rosea are listed in Table 12-17.1,2

Table 12-16 Drugs that Induce or Aggravate Psoriasiform Eruptions ACE inhibitors Acetylsalicylic acid Morphine Ibuprofen Codeine Ampicillin Chloroquin Quinidine Beta blockers Propanolol Pindolol Practolol Lithium Cyclosporine Gold Arsenic Iodine Penicillamine Interleukins Interferon Etretinate Methoxsalen

 FIGURE 12-13 Psoriasiform drug eruption in a patient of African origin. Psoriasiform hyperplasia of epidermis is present with a nodular perivascular dermal lymphocyte-predominant infiltrate; unlike true psoriasis, tortuous dermal papillae capillaries in apposition to thinned suprapapillary plates are not seen.

HISTOPATHOLOGIC FEATURES These reactions are morphologically indistinguishable from pityriasis rosea, the hallmarks of which are a subacute dermatitis with focal parakeratosis, superficial erythrocyte extravasation, dyskeratosis, and tissue eosinophilia. DIFFERENTIAL DIAGNOSIS The histopathology of pityriasis lichenoides chronica can look similar to the pityriasiform drug eruption but is usually separable by the presence of eosinophils in the latter. The epithelial injury of pityriasis lichenoides et varioliformis acuta is usually greater, and the dermal infiltrate, as in pityriasis lichenoides chronica, is usually purely lymphocytic.

Drug-Associated Ichthyosiform Dermatoses CLINICAL FEATURES Certain classes of drugs may provoke ichthyosiform reactions (Table 12-18).

HISTOPATHOLOGIC FEATURES The histopathology resembles ichthyosis vulgaris by virtue of laminated orthohyperkeratosis, a diminished or absent granular cell layer, and in some cases, attenuation of the epidermis. DIFFERENTIAL DIAGNOSIS Distinction from ichthyosis vulgaris under the microscope can be impossible, although the presence of eosinophils tends to point toward a drug-based etiology. Most other heritable ichthyosis states manifest a normal or increased granular cell layer, as discussed elsewhere (see Chap. 14).

CHAPTER 12 ■ CUTANEOUS DRUG ERUPTIONS

HISTOPATHOLOGIC FEATURES Psoriasiform epidermal hyperplasia, granular cell layer diminution, and foci of neutrophil-imbued parakeratosis are variably accompanied by an interface dermatitis, spongiotic epithelial changes, eosinophilia, and focal dyskeratosis (Fig. 12-13). Some patients also manifest a lichenoid infiltrate, particularly those taking beta blockers.

Erythema Multiforme, Including Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis Drugs implicated in erythema multiforme and toxic epidermal necrolysis are listed in Tables 12-19 and 12-20.1,2 The clinical and histologic features are

Table 12-17 Drugs Associated with Pityriasiform Reactions

Table 12-18 Drugs Inducing Ichthyosiform Dermatoses

Acetylsalicylic acid Griseofulvin Metronidazole Captopril Clonidine Gold Arsenic

Allopurinol Clofazimine Hydrochlorothiazide Nicotinic acid (niacin) Dyrazine Ergocalciferol Lipid-lowering agents

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PART I ■ INFLAMMATORY REACTIONS IN THE SKIN

Table 12-19 Erythema Multiforme and StevensJohnson Syndrome Pyrazolone derivatives including phenylbutazone and oxyphenbutazone Penicillins Slowly excreted sulfonamides Ampicillin Salicylates Salazopyrin Barbiturates Phenobarbital Hydantoins Carbamazepine Phenothiazine derivatives D-Penicillamine

Table 12-20 Toxic Epidermal Necrolysis Sulfonamides Trimethoprim and sulfadoxine Trimethoprim and sulfamethoxazole Pyrazalones including phenybutazone and allopurinol Barbiturates Anti-inflammatory drugs Tetracycline Nitrofurantoin Antituberculous drugs Hydantoins Carbamazepine

Genetic factors may predispose patients to SJS in specific populations.124 There are rare reports of erythema multiforme following allergic contact dermatitis with nickel and poison ivy (ie, Rhus dermatitis). The epidermal necrosis in erythema multiforme is mediated by cytotoxic T cells of the Tc1/Tc2 subsets 125 through provocation of apoptosis via interaction between circulating soluble Fas and its receptor, FasL.126 Therapeutic application of intravenous immunoglobulin (IVIG), which binds soluble Fas, has thus been thought to have a potential role in the treatment of TEN.122,127 Synergistic action with helper T cells, including those of the Th2 subset, is implied by demonstration of the thymus- and activation-regulated chemokine (TARC).128 Antibodies directed against desmosomal plaque proteins desmoplakin I and II have been described in a subset of patients with severe erythema multiforme and suggest a humoral mechanism in the propagation of lesions in these patients. The epitope, localized at the carboxy terminal domain of desmoplakin, is responsible for the assembly of keratin filaments and desmosomes. Purified human antibody directed against the carboxy terminus of desmoplakin I and II, when injected into newborn mice, produces lesions that resemble erythema multiforme, suggesting a role for these antibodies in a subset of patients with erythema multiforme.129

Halogenodermas

294

discussed in Chap. 3. Erythema multiforme has long been considered to reflect a type 4 cellular cytotoxic reaction.120 Provocation of lesions often relates to the ingestion of drugs or to infection by microbial pathogens such as Mycoplasma sp.121 or herpes virus, including in the context of recurrent herpes labialis, in which the classical targetoid lesions are more common and disease is typically self-limited. In contrast, drug-induced erythema multiforme can be quite severe; when the eruption is extensive, there may be severe oral mucosal involvement which defines Stevens-Johnson syndrome (SJS). In SJS, greater than 10% of the body surface is affected by epidermal necrosis and detachment, in a fashion reminiscent of, but less marked than, toxic epidermal necrolysis (TEN), in which more than 30% of the skin surface is so affected.122 Case fatality rates are 1% to 5% in the former instance and 25% to 35% in the latter, where management in a dedicated burn unit is advised.123

CLINICAL FEATURES Iodides, bromides, and fluorine can induce vegetative, fungating, papulopustular, and ulcerating lesions130 (Table 12-21). Iododermas tend to manifest as a pustular facial eruption, often with ulceration. Bromodermas present as nodules or plaques with a verrucous or granulating surface, most commonly on the lower extremities; some patients manifest panniculitis.131

Table 12-21 Halogenodermas Iodides Amiodarone Potassium iodide Iodized radiographic contrast media Iodized salt Iodine in seaweed and other food Bromides Fluorides

The pathophysiology of the halogenodermas is not well understood, although underlying systemic diseases may predispose to their development.132 HISTOPATHOLOGIC FEATURES The epidermis shows pseudoepitheliomatous hyperplasia with neutrophilic intraepidermal and dermal microabscesses and superficial dermal edema.132 In lesions of iododerma, epithelial proliferation is less prominent, but vascular alterations may be more conspicuous and likely account for the ulceration that may be observed. DIFFERENTIAL DIAGNOSIS Other causes of pseudoepitheliomatous hyperplasia associated with tissue neutrophilia and intraepidermal pustulation include infections with atypical mycobacteria or fungi, which may be distinguished from halogenodermas by special stains and culture; pyostomatitis vegetans of Crohn disease, separable by clinical history and by proximity to a mucosal orifice133; and blastomycosis-like pyoderma of the immunocompromised, a bacterial infection.134

Erythroderma CLINICAL FEATURES Erythroderma due to drugs must be distinguished from other causes such as pityriasis rubra pilaris, psoriasis, seborrheic dermatitis, and cutaneous T-cell lymphoma. The common drugs associated with erythroderma are listed in Table 12-22.1,2

Table 12-22 Drugs Associated with Erythroderma Acetylsalicylic acid Sulfasalazine Fenbufen Oxytetracycline Gentamicin Nystatin Ketoconazole Sulfonamides Cotrimoxazole Clofazimine Quinidine Captopril Timolol Minoxidil Phenobarbital Methotrexate Granulocyte-macrophage colony-stimulating factor Etretinate

HISTOPATHOLOGIC FEATURES Characteristic is psoriasiform hyperplasia with granular cell layer diminution, variable spongiosis, and a diffuse parakeratotic scale that may contain neutrophils. Additional features include a vacuolopathic interface dermatitis, focal dyskeratosis, and a mixed inflammatory cell infiltrate often containing lymphocytes, eosinophils, and neutrophils.

Dilantin Hypersensitivity Syndrome CLINICAL FEATURES In addition to its perturbative effects on lymphocyte function, namely, enhancement of blast transformation and abrogation of T-suppressor function, phenytoin and its analogues also may function as antigens in some patients. In concert, these two processes promote a variety of clinical consequences, including the Dilantin hypersensitivity syndrome, which is seen in 2% to 20% of patients who consume the drug.135 The manifestations of Dilantin hypersensitivity syndrome include fever, lymphadenopathy, hepatosplenomegaly, mucositis, a rash that characteristically manifests as patchy erythema that may progress to generalized erythroderma, a folliculocentric pustular eruption, erythema multiforme, and toxic epidermal necrolysis. Lymphoma may supervene rarely. Dilantin also perturbs collagen synthesis, resulting in gingival hyperplasia in roughly 50% of patients receiving the drug. The types of phenytoin-induced exanthems are listed in Table 12-23. HISTOPATHOLOGIC FEATURES Histologic features reflect the type of eruption biopsied. The pustular lesions exhibit intraepidermal neutrophilic vesiculopustules, often accentuated in hair follicles, whereas the erythema multiforme-like eruptions manifest lymphocytic interface inflammation with keratinocyte necrosis, and the maculopapular eruptions demonstrate a mild perivascular lymphocytic infiltrate with variable interface injury.

Acneiform eruptions Exfoliative dermatitis Hyper- and hypopigmentation Maculopapular eruptions Erythema multiforme Toxic epidermal necrolysis Vasculitis Pseudolymphoma

annular array involving inner aspects of the arms, medial thighs, and intertriginous areas, prompting differential diagnoses including cutaneous T-cell lymphoma, erythema annulare centrifigum, GA, and LE. Lesions tend to resolve gradually over a 6- to 12-week period following discontinuation of the implicated drug.

DIFFERENTIAL DIAGNOSIS Depending on the type of lesion biopsied, Dilantininduced eruptions may mimic mycosis fungoides and other mycosis fungoidelike pseudolymphomata, other pustular drug eruptions and pustular bacterid, and other causes of erythema multiforme and vasculitis.

HISTOPATHOLOGIC FEATURES Characteristic is diffuse infiltration of the interstitium by lymphocytes and histiocytes (Fig. 12-14) with fragmentation of collagen and elastic fibers in concert with a vacuolar interface dermatitis. Some patients show superimposed atypical lymphoid infiltrates. This lesion is distinctive from the granulomatous drug eruption seen in erythema nodosum, namely, a granulomatous septal panniculitis in patients receiving sulfonamides, penicillin, minocycline, or oral contraceptives.

Interstitial Granulomatous Drug Reaction

Cutaneous Reactions to Targeted Biological Therapy: The Cytokines

CLINICAL FEATURES An interstitial granulomatous inflammatory process mimicking granuloma annulare (GA) at the light microscopic and sometimes at the clinical level has been associated with therapy with angiotensin-converting enzyme inhibitors, lipid-lowering agents, calcium channel blockers, beta blockers, antihistamines, anticonvulsants, and antidepressants.136 Classic lesions are asymptomatic erythematous to violaceous plaques in an

The clinical application of cytokines produced through recombinant DNA technology has been associated with cutaneous reactions in patients undergoing therapy for cancer and autoimmune disease. The most frequently reported reactions are those to injection of granulocyte-macrophage colonystimulating factor (GM-CSF), granulocyte colony-stimulating factor (G-CSF), and interferons (IFNs).

 FIGURE 12-14 Interstitial palisading granulomatous drug reaction. The interstitium shows columns of histiocytes infiltrating between collagen bundles.

CHAPTER 12 ■ CUTANEOUS DRUG ERUPTIONS

DIFFERENTIAL DIAGNOSIS The constellation of findings diagnostic of a true psoriasiform diathesis, namely, the direct apposition of ectatic capillaries to thinned suprapapillary plates, is not seen. Tissue eosinophilia may be observed in pityriasis rubra pilaris, erythrodermic psoriasis, and cutaneous T-cell lymphoma and is not in isolation a discriminating feature. Mycosis fungoides usually can be distinguished by continuous epidermotropism of atypical lymphoid forms accompanied by epidermal atrophy.

Table 12-23 Phenytoin-Induced Exanthems

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GM-CSF and G-CSF GM-CSF and G-CSF are used to counter neutropenia in patients with HIV infection, aplastic anemia, myelodysplasia, and congenital neutropenic states. Skin reactions reported with GM-CSF and G-CSF tend to be expressed as forms of neutrophilic dermatosis: pyoderma gangrenosum, Sweet syndrome, neutrophilic folliculitis, and vasculitis.137,138 A widespread annular papular eruption described in patients receiving G-CSF after bone marrow transplantation manifests histologically as a purely mononuclear cell or mixed mononuclear cell and granulocyte dermal infiltrate.128 The pathogenesis of such lesions involves the enhanced proliferation of myelomonocytic and granulocytic precursors and possibly stimulation of dermal dendrocytes to increase in size and number and to produce cytokines such as interleukin-1 (IL-1) and tumor necrosis factor a (TNF-a).139 Upregulation of endothelial adhesion molecule expression may contribute to the propogation of vasculitis. G-CSF promotes differentiation and chemotaxis of neutrophils and prolongation of their survival and so may promote the Sweet syndrome reactions seen in neutropenic patients.138,139

Interferon-β1b Interferon-β1b (IFN-β1b), an immunomodulatory agent used in the treatment of multiple sclerosis, has been associated with the generation of sclerotic or erythematous dermal plaques and ulcers at injection sites along with a sclerodermalike syndrome consisting of sclerodactyly and digital infarction (personal observation). Lesions manifest dermal fibrosis and a pandermal pauci-inflammatory thrombogenic vasculopathy; overt vasculitis has not, to our knowledge, been documented. The pathogenesis of IFNβ–related ischemic dermopathy may reflect platelet activation and aggregation. Pustular psoriasis flares as well as otherwise typical delayed-type hypersensitivity reactions are also reported.

keratinocytes and so provoke lichenoid reactions and epidermolytic hyperkeratosis; IFN also may promote the migration of T-lymphocytes into the epidermis. The latter may cause upregulation of IL-2 production by keratinocytes and promote TNF-α production by dermal dendrocytes, which, in turn, upregulates adhesion molecule expression on keratinocytes and triggers keratinocyte proliferation.140

Cutaneous Reactions to Targeted Biological Therapy: Cytokine Receptor Blockers Epidermal Growth Factor Inhibition CLINICAL FEATURES In recent years, novel biologically targeted therapies designed to interfere with the molecular pathways of carcinogenesis have been brought forward as therapeutic options in patients who have failed other, more conventional therapies, either because those therapies have proven ineffective or because the patients were intolerant to the former chemotherapeutic regimes. New targeted therapies approved by the Food and Drug Administration141 include monoclonal antibodies and small molecular inhibitors which have significantly changed the character of cancer therapy for a small subgroup of patients.142 Such targeted therapies are frequently better tolerated than traditional chemotherapy but are associated with specific adverse effects,

including acneiform rashes, cardiac dysfunction, thrombosis, proteinuria, and hypertension.142 Furthermore, the small molecule inhibitors are frequently metabolized by the hepatic cytochrome P450 enzyme system and therefore provoke, and are subject to, multiple drug interactions. With respect to dermatologic side effects associated with epidermal growth factor receptor (EGFR) inhibitors, the majority of patients receiving such agents experience some form of cutaneous toxicity.143 Most frequently, these mucocutaneous side effects include papulopustular rashes, hair and nail changes, xerosis, pruritus, telangiectasias, hyperpigmentation, mucositis,144-149 psoriatic eruptions, erythema nodosum, and nummular eczema. Typically, blockade of the EGFR is done through the use of monoclonal antibodies of which examples include panitumumab (Vectibix), cetuximab, gefitinib, and erlotinib. In addition to specific blockade of epidermal growth factor, most of the oncogenes that impact cell cycle activities and are aberrantly regulated or mutated in malignant neoplasia function through tyrosine receptor kinase activity. Specific agents can inhibit tyrosine kinases, including sorafenib,150 have provoked a similar variety of skin erruptions in addition to localized pulmoplantar epidermal hyperplasia.150 The reactions seen in patients receiving these agents appear to act as a surrogate marker for the clinical response to drug therapy; those patients in whom skin toxicity develops have a higher response rate,151 and survivorship

Interferon-α2

296

Interferon-α2 (IFN-α2) plays a key role in the therapy of hepatitis C virus (HCV) infection. Variably reported to initiate, clear, and exacerbate lesions of lichen planus, IFN-α2b has an association with the development of oral erosive lichen planus and psoriasiform hyperplasia with epidermolytic hyperkeratosis in the setting of HCV infection. From a pathogenetic standpoint, IFN may induce expression of hidden surface antigens on

 FIGURE 12-15 Drug-induced psoriasiform eruption. A patient taking the epidermal growth factor receptor blocker erlotinib (Tarceva) developed a diffuse pustular rash with an acneiform follicular component. The biopsy shows spongioform pustulation of the epidermis with a pyodermatous dermal component.

B

 FIGURE 12-16 (A) A mycosis fungoides-like and subacute lupus erythematosus-like morphology in a patient receiving adalimumab (Humira) for rheumatoid arthritits. The epidermis is percolated in a haphazard fashion by small lymphoid forms with associated keratinocyte necrosis. (B) The same patient illustrated in Fig. 12-16(A) had infiltrative plaques which showed a granuloma annulare-like interstitial histiocytic infiltrate. Still other foci had a lichen planus-like histology. This overlap of morphologies cognate to disparate idiopathic dermatoses is an important clue, in our estimation, to a drug-based etiology.

appears to be increased.152 In consequence of the foregoing, it has been advised that agents be used at the maximum-tolerated dose to maximize the subsequent clinical benefit.151,152 HISTOPATHOLOGIC FEATURES Histopathologic studies of the papular-pustular rash show an acneiform eruption centered upon the superficial aspects of the hair folicle where intense neutrophilic inflamation is seen (Fig. 12-15); there is a rupture of the epithelial lining of the hair folicle with adjacent dermal changes. The exact mechanisms of this eruption are not known but there appears to be inhibition of epithelial cell proliferation of the follicular lining.

Bortezomib (Velcad) Bortezomib is a proteasome inhibitor developed and principally used for the treatment of myeloma.153 It inhibits the degradation of wild type p53; preservation of wild type p53 helps to down regulate the cell cycle and slows tumor growth in patients with myeloma. Among the various rashes reported with the ingestion of bortezomib include plaque-like urticarial, erythematous, and edematous eruptions.

Tumor Necrosis Factor α Tumor Necrosis Factor α (TNF-α) is a cytokine implicated in the pathogenesis of several idiopathic and/or autoimmune inflammatory disorders. Accordingly, pharmaceutical firms have developed

specific blockers of the TNF-α receptor in an attempt to modulate the activity of the immune system. Inhibitors of TNF-α include specific blockers of the receptors, such as infliximab (Remicade), etanercept (Enbrel), adalimumab (Humira), and thalidomide. These agents have been employed successfully in mediation of psoriasis, rheumatoid arthritis, and inflammatory bowel disease, and also have a role in the treatment of lymphoproliferative disorders.154 Patients may develop complications from the use of TNF-α receptor inhibitors, such as infection and dermatological reactions. Recently described are annular plaques on the trunk and extremities which show an interstitial granulomatous dermatitis in skin biopsies.154 Other cutaneous eruptions documented in the setting of TNF-α receptor blocker therapy include leukocytoclastic vasculitis, lichenoid tissue reactions, urticaria, lupus erythematosus-like eruptions, chilblains, folliculitis, and necrotizing fasciitis.155,156 The histopathology of the tissue reactions to TNF-α blockade include, in the setting of the folliculitis lesions, pustular follicular reactions, lymphocytic interface dermatitis with papillary dermal edema in the setting of chilblains eruptions, variably intense interface dermatitis in lupus erythematosus-like eruptions (Fig. 12-16A), classical features of psoriasis with superimposed tissue eosinophilia in the case of the psoriasiform eruptions,157 and lymphocytic and histiocytic interstitial infiltrates mimicking granuloma annulare in the case of the interstitial granulomatous dermatitides (Fig. 12-16B).

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134. Rongioletti F, Semino M, Drago F, et al. Blastomycosislike pyoderma (pyoderma vegetans) responding to antibiotics and topical disodium chromoglycate. Int J Dermatol. 1996;35:828-830. 135. Silverman AK, Fairley J, Wong RC. Cutaneous and immunologic reactions to phenytoin. J Am Acad Dermatol. 1988; 18:721-741. 136. Magro CM, Crowson AN, Schapiro BL. Interstitial and palisading granulomatous drug reaction: a distinctive clinical and pathological entity. J Cutan Pathol. 1998;25:72-78. 137. Prevost-Blank PL, Shwayder TA. Sweet’s syndrome secondary to granulocyte colony-stimulating factor. J Am Acad Dermatol. 1996;35:995-997. 138. Richard MA, Grob JJ, Laurans R, et al. Sweet’s syndrome induced by granulocyte colony-stimulating factor in a woman with congential neutropenia. J Am Acad Dermatol. 1996;35:629-631. 139. Glass LF, Fotopoulos T, Messina JL. A generalized cutaneous reaction induced by granulocyte colony-stimulating factor. J Am Acad Dermatol. 1996;34:455-459. 140. Elgart GW, Sheremata W, Ahn YS. Cutaneous reactions to recombinant human interferon beta-1b: the clinical and histologic spectrum. J Am Acad Dermatol. 1997;37:553-558. 141. Ross JS, Schenkein DP, Pietrusko R, et al. Targeted therapies for cancer 2004. Am J Clin Pathol. 2004;122(4):598-609. 142. Gerber de. Targeted therapies: a new generation of cancer treatments. Am Fam Physician. 2008;77(3):294-296. 143. Boone SL, Rademaker A, Liu D, Pfeiffer C, Mauro DJ, Lacouture ME. Impact and management of skin toxicity associated with anti-epidermal growth factor receptor therapy: survey results. Oncology. 2007;72(3-4):152-159. 144. Mitchell EP, Perez-Soler R, Van Cutsem E, Lacouture ME. Clinical presentation and pathophysiology of EGFRI dermatologic toxicities. Oncology. (Williston Park) 2007:21(Suppl 5):4-9. 145. Perez-Soler R, Van Cutsem E. Clinical research of EGFR inhibitors and related dermatologic toxicities. Oncology. (Williston Park) 2007;21(1 Suppl 5):10-16. 146. Yamazaki N, Muro K. Clinical management of EGFRI dermatologic toxicities: the Japanese perspective. Oncology. (Williston Park). 2007;21(11 Suppl 5):27-28.

147. Agero AL, Dusza SW, BenvenutoAndrade C, Busam KJ, Myskowski P, Halpern AC. Dermatologic side effects associated with the epidermal growth factor receptor inhibitors. J Am Acad Dermatol. 2006;55(4):657-670. 148. Schalock PC, Zug KA. Acneiform reaction to erlotinib. Dermatitis. 2007;18(4): 230-231. 149. Delle Sedie A, Bazzichi L, Bombardieri S, Riente L. Psoriasis, erythema nodosum, and nummular eczema onset in an ankylosing spondylitis patient treated with infliximab. Scand J Rheumatol. 2007;36(5): 403-404. 150. Beldner M, Jacobson M, Burges GE, Dewaay D, Maize JC Jr, Chaudhary UB. Localized palmar-plantar epidermal hyperplasia: a previously undefined dermatologic toxicity to sorafenib. Oncologist. 2007;12(10):1178-1182. 151. Cunningham D, Humblet Y, Siena S, et al. Cetuximab monotherapy and cetuximab plus irinotecan in irinotecanrefractory metastatic colorectal cancer. N Engl J Med. 2004;351(4):337-345. 152. Saltz LB, Meropol NJ, Loehrer PJ Sr, Needle MN, Kopit J, Mayer RJ. Phase II trial of cetuximab in patients with refractory colorectal cancer that expresses the epidermal growth factor receptor. J Clin Oncol. 2004;22(7):1201-1208. 153. Sanchez-Politta S, Favet L, Kerl K, Dietrich PY, Piguet V. Bortezomibinduced skin eruption. Dermatology. 2008; 216(2):156-158. 154. Deng A, Harvey V, Sina B, Strobel D, et al. Interstitial granulomatous dermatitis associated with the use of tumor necrosis factor α inhibitors. Arch Dermatol. 2006;142:198-202. 155. Devos SA, Van Den Bossche N, De Vos M, Naeyaert JM. Adverse skin reactions of anti-TNF-α monoclonal antibody. Dermatology. 2003;206:388-390. 156. Chan ATY, Cleeve V, Daymond TJ. Necrotising fasciitis in a patient receiving infliximab for rheumatoid arthritis. Postgrad Med J. 2002;78:47-48. 157. Seneschal J, Lepreux S, Milpied B, Schaeverbeke T, Taieb A. Psorasiform eruptions during anti TNF-alpha treatment: psoriasis or not? Arch Dermatol. 2007;143(2):223-231.

CHAPTER 13 Cutaneous Reactions to Exogenous Agents Raymond L. Cornelison A. Neil Crowson

REACTIONS TO TRAUMA AND IRRITATION

HISTOPATHOLOGIC FEATURES The histology associated with trauma and irritation follows the continuum observed clinically. Minimal trauma may result in parak eratosis, crust, mild spongiosis, superficial vasodilatation, and mild papillary dermal inflammation. More severe changes

DIFFERENTIAL DIAGNOSIS Most of the pathologic features associated with external trauma and irritation require clinical correlation because the histologic patterns are not diagnostic in isolation. Certain clinical and histologic features such as a deep decubitus ulcer on the sacrum of an elderly person may favor a more precise diagnosis.

 FIGURE 13-1 Decubitus ulcer. Ulcerated epidermis with impetiginized neutrophilic scale-crust, underlying acute and chronic inflammation, and granulation tissue formation.

REACTIONS TO RADIATION Ionizing radiation can affect the skin. For the purposes of this text, radiation dermatitis is subclassified as acute, subacute, and chronic radiation dermatitis (Table 13-1). Rarely, a form of fibrosing dermopathy can be seen after diagnostic radiation. Termed radiation-induced morphea, it has a variable time of onset ranging from 1 month to 30 years after fluoroscopy, does not appear to be dose-dependent, and unlike radiation fibrosis, does not always remain confined to the radiation port.2 CLINICAL FEATURES Acute radiation dermatitis follows exposure to a threshold dose of ionizing radiation. The multiphasic response is dose- and timedependent and is characterized initially by transient redness, hair loss, and sometimes by vesiculation. In the second phase, redness develops 7 to 9 days following radiation exposure. Redness and pigmentary changes may recur weeks after radiation exposure. Intense exposure may produce ulceration that

Table 13-1 Radiation Dermatitis

Clinical Features Acute Erythema Hair loss Vesicle formation Chronic Atrophy Telangiectasia Pigmentary changes Histopathologic Features Acute Spongiosis Epidermal necrosis Dermal edema Vascular ectasia and thrombosis Chronic Epidermal hypoplasia and/or hyperplasia Squamous epithelial atypia Dermal sclerosis/hyalinization Deeply located elastotic material in dermis Loss of adnexae Bizarre “radiation fibroblasts” Hyalinization of vessel walls and thrombosis Differential Diagnosis Scar Thermal burn Lichen sclerosus Morphea/scleroderma Chronic graft-versus-host reaction

CHAPTER 13 ■ CUTANEOUS REACTIONS TO EXOGENOUS AGENTS

CLINICAL FEATURES The skin interfaces with and protects from an array of external irritants and other stimuli that range from minimal to severe, with objective results that follow the same continuum. Minimal stimuli may result in redness, mild scale, and symptoms such as pruritus and burning. More severe irritation can lead to vesicles, eczematous changes, ulceration, and necrosis. Artifactual dermatitis, ulceration, friction blisters, and calcaneal petechiae are examples of clinical patterns seen in response to trauma and irritation.

include prominent intracellular edema, spongiosis with vesicle formation and overlying parakeratotic scale-crust, ulceration, and polymorphous dermal inflammation with hemorrhage. The histopathology of ulceration is not specific as to etiology and consists of a polymorphous inflammatory infiltrate, varying degrees of vascular damage, hemorrhage, dermal necrosis, scale-crust formation, and fibrin deposition (Fig. 13-1). Nodular primary localized cutaneous amyloidosis has been reported after blunt trauma to the skin.1 If foreign material is part of the process, it may be detected within the necrotic mass or in the adjacent dermis. Foreign material may be detected through the use of special stains and by polarized light microscopy. Location may be helpful in arriving at a clinicopathologic cor-relation; for example, transepidermal elimination of hemorrhage with intracorneal collections in a biopsy specimen from a plantar site would be compatible with the shear injury that produces calcaneal petechiae.

301

typically occurs after several weeks. The National Cancer Institute common toxicity criteria version 3.0 is the standard for evaluation of acute radiation dermatitis.3

changes (Fig.13-2A). Late radiation necrosis can occur over bony prominences, generally beginning 1 or more years after exposure and often precipitated by trauma.

Grade:

HISTOPATHOLOGIC FEATURES The location of the pathologic change in radiationinduced cutaneous injury will depend on the radiation penetration. In acute radiation dermatitis, keratinocytes show intracellular edema, variation in nuclear size and tinctorial qualities, and individual cell necrosis in an epidermis that manifests spongiosis and vacuolar change. Dermal injury is variable and includes degenerative effects in the adnexae, dermal edema, ectasia of vessels, and scattered endovascular fibrin thrombi. Variably intense mononuclear and/or granulocytic inflammatory infiltrates may be seen. In subacute radiation dermatitis, epidermal changes include vacuolar alteration with necrosis and focal atypia of keratinocytes, hypergranulosis, and compact hyperkeratosis. Dermal changes may contain a variably dense infiltrate of lymphocytes and histiocytes in the papillary dermis, telangiectatic vessels, and reparative changes.4 Chronic radiation dermatitis manifests epidermal changes that range from slight

• 0—None • 1—Faint erythema or dry desquamation

PART I ■ INFLAMMATORY REACTIONS IN THE SKIN

• 2—Moderate to brisk erythema or patchy moist desquamation, mostly confined to skin folds and creases; moderate edema • 3—Confluent moist desquamation, equal to 1.5 cm diameter, not confined to skin folds; pitting edema • 4—Skin necrosis or ulceration of fullthickness dermis; may include bleeding not induced by minor trauma or abrasion Healing in the acute phase occurs with scaling and pigmentary changes. Subacute radiation dermatitis develops several months following exposure and produces scaling with postinflammatory alterations.4 Chronic radiation dermatitis develops months to years following exposure and is associated with induration, atrophy, telangiectasia, and pigmentary

A

302

alterations in the stratum corneum, edema, atrophy and/or acanthosis, and vacuolar basal layer alteration to ulceration (Fig. 13-2B). There may be cytologic atypia of keratinocytes, dyskeratosis, and loss of the rete-ridge pattern. The dermis may be hyalinized and sclerotic. Dermal fibroblasts may exhibit variation in the size and tinctorial qualities of their nuclei (Fig. 13-3). Blood vessels manifest variable ectasia, proliferative change, hyalinization of media, and thrombosis. Adnexal structures may be diminished or absent. Radiation-induced fibrosis extends deep into subcutaneous fat, fascia, and muscle.2 Inflammatory infiltrates are variable and may be associated with dermal pigmentary alteration. DIFFERENTIAL DIAGNOSIS The histology of radiation dermatitis provokes a number of differential diagnostic considerations depending on the specific findings in a given biopsy. An interface injury, if present, raises consideration to cytotoxic effects from chemotherapy, burn injury, lupus erythematosus, lichen sclerosus, erythema multiforme, fixed drug eruption, acute graft-versus-host disease, and dermatomyositis. Dermal changes mimic cicatrices, scleroderma, morphea, and lichen sclerosus. The dermal changes in

B

 FIGURE 13-2 Chronic radiation dermatitis. (A) Well-defined indurated plaque demonstrating atrophy, telangiectasia, both hypo- and hyperpigmentation, and scaling. (B) Hyperkeratotic and parakeratotic epidermal hyperplasia with vacuolar interface change. Full-thickness dermal sclerosis with lymphatic dilation and loss of adnexa is characteristic.

Table 13-2 Thermal Burns

 FIGURE 13-3 Chronic radiation dermatitis. Bizarre-appearing “stellate” fibroblast with features of radiation effect: pleomorphic hypochromatic nuclei, abundant cytoplasm, and intranuclear and intracytoplasmic vacuoles.

the late stages of burns may be indistinguishable from those in chronic radiation dermatitis, except that “radiation fibroblasts” are present in the latter. Markedly atypical nucleolated dermal fibroblasts may raise the possibility of neoplasia. The array of histologic findings seen with radiation change usually enables accurate diagnosis.

(Fig. 13-5). Lesions result from coldinduced spasm of dermal arterioles. Subsequent upregulation of endothelial adhesion molecules is felt to be associated with an efflux of mononuclear cells

at reperfusion. The diagnosis is suggested by the temporal relationship between symptom onset and cool weather or immersion in cold liquids5,6 in patients without occlusive peripheral arterial disease. Spontaneous resolution follows removal of the cold insult. The association with wet climates and with cold fluids is held to be a physical one, in

REACTIONS TO HEAT AND COLD Thermal stress and electrical injury can produce tissue damage. These external stresses have been studied in animal systems, and the histologic changes associated with the degree of damage have been identified. CLINICAL FEATURES The clinical appearance of thermal burns ranges from faint erythema to vesiculation and necrosis (Table 13-2). Electrical injury produces three zones: a central zone of carbonization, a pale ischemic intermediate zone, and an erythematous peripheral zone. Cold injury presents in a similar fashion to thermal injury, the clinical lesion ranging from mild redness to vesiculation and necrosis (Fig. 13-4). Chilblains (perniosis) are itchy, burning, red vesicular, or ulcerative patches or plaques that occur symmetrically in acral locations, particularly toes, following exposure to cold, especially in a wet environment5

 FIGURE 13-4 Frostbite. Coagulative necrosis of epidermis and dermis to the deep reticular dermal compartment with an inflamed scale-crust. These changes are identical to those seen with full-thickness burns.

CHAPTER 13 ■ CUTANEOUS REACTIONS TO EXOGENOUS AGENTS

Clinical Features Erythema Vesiculation Necrosis Histopathologic Features Degree and thickness of injury are highly variable Epidermal necrosis Necrosis and “mummification” of dermis Reepithelialization of epidermis in less severe burns Differential Diagnosis Cicatrix resulting from trauma or iatrogenic injury Lichen sclerosus Morphea/scleroderma Radiation dermatitis

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PART I ■ INFLAMMATORY REACTIONS IN THE SKIN

limited differential diagnosis of perivascular lymphoid infiltrates; the presence of deep vascular thrombosis should provoke consideration of a systemic connective tissue disease, of procoagulant states such as those seen with antiphospholipid antibody syndrome or cryoprecipitates,14 or of (Hutchinson) chilblains lupus erythematosus.15 In the latter condition, a cellpoor lymphocytic interface inflammatory infiltrate is also present, and deep involvement of the eccrine coil is unusual.5,8,15,16 Some chilblains lupus erythematosus patients are seropositive for antibodies to Ro/SSA.17,18

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REACTIONS TO LIGHT

 FIGURE 13-5 Perniosis (chilblains). There is marked papillary dermal edema in this biopsy of acral skin. A lymphocytic perivascular infiltrate shows directed migration into the epidermis, unlike the haphazard infiltration of cutaneous T-cell lymphoma or the vacuolar interface injury of lupus erythematosus. There is dilatation of dermal papillae capillaries, in which platelet-fibrin thrombi are seen.

that moisture serves to augment heat extraction from the skin surface. Females are affected more commonly than males. There is an association with the intake of certain immune-perturbing drugs such as fluoxetine. HISTOPATHOLOGIC FEATURES Mild thermal and cold injuries produce epidermal and dermal edema, vacuolated keratinocytes, and vascular dilatation.7 More severe injury leads to necrosis of keratinocytes, vesiculation, dermal thrombosis, and hemorrhage. The severity of cutaneous injury following a burn correlates with depth and traditionally has been categorized as first degree (epidermal damage only), second degree (both epidermal and partial dermal injury), or third degree (full-thickness necrosis of the epidermis and dermis). The histopathologic features of burns correlate with the severity of the thermal insult and thus vary from focal epidermal cell necrosis, vascular ectasia, and dermal edema to full-thickness necrosis of the dermis. Second-degree burns are characterized by subepidermal bulla formation. In thirddegree burns, extensive necrosis of the dermis is present. Some lesions show carbonized debris. Severe burns may be associated with a “mummified” appearance of the dermis; dermal collagen fibers are swollen and eosinophilic, and stromal cell nuclei are absent. In concert with

necrosis of the overlying epidermis, these changes constitute evidence of thermal injury. In lesions with significant inflammation, superinfection should be considered, and special stains and/or cultures for microbial pathogens should be preformed. Frostbite produces a histology identical to a burn, with the level and extent of tissue destruction correlating with the degree of thermal tissue injury (see Fig. 13-4). Electrical burns produce vascular thrombosis in the intermediate and peripheral zones and necrosis in the central area that varies in degree and depth depending on the severity of the injury. Perniosis manifests perivascular and periadnexal lymphoid infiltrates with striking extension around the deep eccrine coils,5,8 edema and thickening of blood vessel walls, marked subepidermal edema, and vascular thrombosis accentuated in the superficial vascular plexus5,9,10 (see Fig. 13-5). Sometimes present is a lymphocytic vasculitis,11 endothelial proliferation with necrosis,12 and leukocytoclastic vasculitis.13 DIFFERENTIAL DIAGNOSIS The overlapping histologic features of thermal, electrical, and cold injury are similar and raise consideration to external trauma; the latter is suggested in limited injuries by necrosis of keratinocytes limited to the upper stratum spinosum. The histologic picture of perniosis provokes consideration of a

Light-related eruptions offer a spectrum of clinical morphologies and histologic patterns, often augmented by drug intake or a coexisting connective tissue disease diatheses. Recognized syndromes related to light exposure include phototoxic reactions, photoallergic reactions,19 and entities where the precise etiologic basis is unknown. Drugs that induce photosensitivity reactions absorb electromagnetic radia in the ultraviolet (UV) and visible ranges to produce an excited state that is injurious to the skin. Light-induced eruptions have a characteristic photodistribution that spares the submental and retroauricular areas and upper eyelids. Phototoxic eruptions typically occur within 5 to 20 hours of first exposure to a drug and resemble an exaggerated sunburn with erythema, blistering, vesiculation, desquamation, and hyperpigmentation of sun-exposed skin. Photoallergic eruptions require a latent period for sensitization and appear within 24 hours of repeat antigenic challenge. Unlike the purely phototoxic reactions, photoallergic eruptions also may occur in non-sun-exposed sites. Combinations of phototoxic, photoallergic, and photoadaptive change are common. The common thread for the photodermatoses is that light exposure provokes lesional development in all of hydroa vacciniforme, polymorphous light eruption, actinic prurigo, chronic photodermatoses, persistent light reactions, photosensitive eczema, and actinic reticuloid.19 The use of sunscreens will produce variable benefit in the photodermatoses. The addition of topically applied antioxidants in patients with polymorphous light eruption has shown beneficial effects that imply a pathogenic role for oxidant injury in pathogenesis.20 CLINICAL FEATURES Clinical features of these light-related eruptions are listed in

Table 13-3 Reactions to Light CLINICAL FINDINGS

HISTOPATHOLOGIC FEATURES

Polymorphous light eruption

Acquired; recurrent; worse in spring and early summer; in sun-exposed areas hours to days after exposure; burning or pruritus; lesions vary from papules to plaques and vesicles

Photoallergic dermatitis

Acute or chronic papular and/or vesicular eruption following exposure to photosensitive agent and light; pruritic

Hydroa vacciniforme

A chronic eruption with redness, vesicles, necrosis, and varicelliform scars generally in children; absence of laboratory abnormalities; eye involvement has been reported; resolves in adolescence Nonimmunologic; can be elicited in majority of persons exposed; redness, burning, edema in affected areas, possibly with vesiculation Familial in Native Americans; acute and chronic phases; eczematous; cheilitis and pruritus are common

Spectrum of changes; epidermal changes ranging from minimal to spongiotic; dermal changes range from superficial and deep perivascular cuffed lymphocytoid patterns to polymorphous infiltrates with neutrophils and other cell types; prominent papillary dermal edema may be present Variable epidermal changes including edema and spongiosis; a superficial polymorphous infiltrate including lymphocytes, eosinophils, neutrophils, and edema Intraepidermal reticular degeneration and cellular necrosis; spongiosis and epidermal necrosis with dense lymphohistiocytic infiltrates with hemorrhage and thrombosis of small vessels

Phototoxic eruption

Actinic prurigo

Chronic photodermatoses

Present for 3 months or longer; decreased MED to UVA, UVB, or both

Persistent light reaction

May be a form of photoallergic contact dermatitis; musk ambrette and oxybenzone are frequently implicated; the MED is shortened Severe variant of chronic actinic dermatitis; persistent infiltrated papules and plaques, often extending to covered areas; broadbanded photosensitivity; usually, a prominent component of lichen simplex chronicus is present

Photosensitive eczema Actinic reticuloid

Table 13-3. Photoaccentuation in exposed skin areas is typical. Polymorphous light eruption is a common, acquired. nonscarring photodermatosis with an incidence of at least 10% that is held to reflect a delayed-type hypersensitivity reaction to UV-altered cutaneous antigens.21 Both UVA and UVB and visible light play a role in photoprovocation of lesions.22 Lesions are polymorphous from patient to patient but monomorphous in any individual patient. The eruption frequently is recurrent, may resolve spontaneously, and often shows reduced activity from spring to summer. Hydroa vacciniforme primarily affects children, can be induced by UVA,23-25 and heals with scarring. Actinic prurigo is an idiopathic familial photodermatosis classically seen in Amerindians that uncommonly affects Caucasians and Asians26,27 (Fig. 13-6). The face is affected most commonly, and in chronic cases it

Variable epidermal changes including edema and spongiosis; there is minimal inflammatory infiltrate; neutrophils may be present Epidermal spongiosis with a superficial and deep lymphocytic perivascular infiltrate and dermal edema; chronic forms show hyperkeratosis, acanthosis, and signs of tissue repair and/or photoadaptations A dermal infiltrate of lymphocytes and macrophages, with or without epidermal spongiosis and atypical mononuclear cells in the dermis and epidermis The histology is that of a spongiotic dermatitis and similar to that seen in photoallergic and allergic contact dermatitis Usually, a prominent component of lichen simplex chronicus; dermal lymphoid infiltrate with atypical cells; CD8+ lymphoid cells dominate in the infiltrate; reversed CD4+ to CD8+ ratio in peripheral blood

manifests leonine or swarthy coarsening of features. A coexisting cheilitis occurs commonly. The latter has been termed follicular cheilitis or actinic prurigo cheilitis.28 Chronic photodermatosis or chronic actinic dermatitis is a poorly defined group in which there is a persistent eczematous eruption in sun-exposed sites; cases are defined by the following: (1) presence for greater than 3 months, (2) decreased minimal erythema dose to either UVA and/or UVB, and (3) histologic changes, including an infiltrate of lymphocytes and macrophages, with or without epidermal spongiosis and atypical mononuclear cells in the dermis and epidermis.29 Actinic reticuloid is the most severe variant of chronic actinic dermatitis.30 There may be multiple etiologies, including chronic contact dermatitis, photoallergic contact dermatitis, and phototoxic, immunologic, and other factors.

CHAPTER 13 ■ CUTANEOUS REACTIONS TO EXOGENOUS AGENTS

DISORDER

A clinical diagnosis of actinic reticuloid should be made in patients who manifest photo-induced plaques and infiltrated papules that may extend to sun-protected areas, sometimes with erythroderma,31 a broad spectrum of photosensitivity, and an infiltrate that contains atypical lymphoid cells. HISTOPATHOLOGIC FEATURES There is an overlapping spectrum of histopathologic findings in light-related eruptions that makes subclassification challenging (see Table 13-3; see also Chap. 5). Our approach is to specifically identify phototoxic, photoallergic, and photoadaptive effects. Phototoxic eruptions are characterized by keratinocyte injury at all levels of the epidermis but particularly the cornified layer. These so-called sunburn cells differ from the apoptotic keratinocytes

305

PART I ■ INFLAMMATORY REACTIONS IN THE SKIN 306

 FIGURE 13-6 Actinic prurigo in an Amerindian. There are overlapping features of phototoxic injury (the necrotic keratinocytes in the superficial statum spinosum, unaccompanied by lymphocyte satellitosis), photoadaptive changes (the psoriasiform hyperplasia and hypergranulosis), and photoallergy (the nodular superficial perivascular lymphocytic infiltrates).

of connective tissue disease or graft-versus-host diseases by virtue of absent lymphocyte satellitosis in apposition to their cellular debris. Often present is architectural disarray, keratinocyte dysmaturation, and parakeratosis (see Fig. 13-6). Neutrophils may infiltrate the epidermis at sites of injury in response to cytokine release by injured keratinocytes. A variable perivascular mononuclear cell-predominant infiltrate is accompanied by dilatation, edema, and mural swelling of the superficial vascular plexus, whose endothelia may show cytoplasmic vacuolation. This vascular injury diminishes in the depths of the biopsy. The photoallergic response consists of epidermal spongiosis and vesiculation that frequently eventuates in an adherent plasma-rich scale-crust. Eosinophils are often a component of the infiltrate. Features of the photoadaptive response consist of hypergranulosis, hyperkeratosis, melanocytic hyperplasia, suprabasilar melanization, and transepidermal elimination of melanin. Some patients develop persistent photosensitivity at exposed and nonexposed skin sites that, if accompanied by skin infiltration by transformed lymphocytes, defines chronic photosensitivity dermatitis or actinic reticuloid. The presence of intraepithelial

cerebriform lymphocytes arranged as groups surrounded by a clear halo reminiscent of Pautrier microabscesses results in a histology that mimicks mycosis fungoides. Recently described in an actinic reticuloid patient receiving methotrexate was a neutrophilic eccrine hidradenititis;32 the eccrine inflammation was most likely a secondary effect of chemotherapy, but the case serves to illustrate the issue of overlapping pathophysiologic effects complicating interpretation of biopsies in patients with photo-induced eruptions. Eruptions of combined phototoxic, photoallergic, and photadaptive types are common and manifest as variable expressions of the above-described prototypic morphologies (see Fig. 13-6). Hydroa vacciniforme is an accelerated phototoxic/photoallergic reaction that consists of keratinocytic edema, spongiosis, and necrosis that may progress to panepidermal necrosis. There is a variable infiltrate of lymphocytes and mononuclear phagocytes that occasionally is associated with hemorrhage and vascular thrombosis. The histology of actinic prurigo includes spongiotic epidermal changes and a lymphohistiocytic nodular perivascular infiltrate in the superficial dermis; the acute form is indistinguishable from polymorphous

light eruption. Chronic lesions of actinic prurigo exhibit hyperkeratosis, acanthosis, and signs of photoadaptation.33,34 Lymphocyte function and adhesion molecule studies in actinic prurigo indicate that it is a form of delayed-type hypersensitivity reaction in a genetically predisposed host, with different HLA associations in distinct populations.35,36 The resistance of Langerhans cells to UVinduced suppression may play a role.37 In consequence of dominant T-helper lymphocyte type 1 (Th1) function,38 therapies targeted at down-regulating Th1 tone, such as thalidomide, have proven successful in isolated cases.39 Lesions of actinic prurigo are reputed to heal with atrophic scars, perhaps reflecting anomalous fibroblast responses to UVA.40 Chronic actinic dermatitis has a nonspecific pattern including a dermal perivascular and sometimes bandlike infiltrate of lymphocytes and macrophages, with or without epidermal spongiosis and atypical mononuclear cells in the dermis and epidermis.29 Actinic reticuloid may have a pattern similar to chronic actinic dermatitis and, by definition, must have atypical lymphoid cells within the infiltrate. There is usually a prominent component of lichen simplex chronicus. Multinucleated giant cells often are noted in the papillary dermis and may be associated with perivascular elastolysis; immunophenotyping of the infiltrate shows dominance of CD8+ cells.30 DIFFERENTIAL DIAGNOSIS The differential diagnosis for this group lies mainly in the spectrum of either spongiotic or superficial dermal inflammatory processes. The spongiotic forms of light-related eruptions are not distinguishable histologically from other forms of spongiotic dermatitis. Photo-induced eruptions characterized by minimal epidermal changes and welldefined cuff-like perivascular lymphoid infiltrates need to be differentiated from gyrate erythemas, dermal contact reactions, and connective tissue disease. The severe phototoxic reactions may show significant epidermal necrosis and so raise consideration to erythema multiforme and pityriasis lichenoides, whereas the release of chemokines from the damaged epidermis may provoke tissue neutrophilia and so bring to mind the neutrophilic dermatoses. The dermal components of phototoxic and photoallergic dermatitis may dominantly consist of perivascular infiltrates of mononuclear cells and so be similar; an eosinophilic component would implicate photoallergy. The differential diagnosis of the latter would include insect bite reactions, dermal

contact reactions, and other hypersensitivity states.

REACTIONS TO MARINE AGENTS The array of potential interactions between the marine environment and skin includes granulomatous reactions to foreign materials such as sea urchin

spines (Fig. 13-7), envenomations, toxic exposures following discharge of nematocysts (Portuguese man-of-war stings), contact allergic dermatitis to many agents such as coral and infections. The clinical and histologic pictures vary depending on the inciting agent. CLINICAL FEATURES The clinical features of the most common marine reactions are presented in Table 13-4. Seabather’s

HISTOPATHOLOGIC FEATURES Histopathologic changes of seabather’s eruption include a dermal infiltrate around superficial and deep vessels composed of lymphocytes, neutrophils, and eosinophils. The histopathology of sea urchin spine penetration is that of a polymorphous inflammatory infiltrate consisting of neutrophils, eosinophils, and mononuclear cells, including plasma cells with occasional foreign-body giant cells and foreign material (see Fig. 13-7). Prominent edema and hemorrhage may be present.

Table 13-4 Reactions to Marine Agents DISORDER

ETIOLOGY

CLINICAL FEATURES

HISTOPATHOLOGIC FEATURES

Seabather’s eruption

Cnidarian larvae of the thimble jellyfish, Linuche unguiculata

Sea urchin spines

Penetration by the spines of the sea urchin (Echinoidea)

Portuguese man-of-war

Physalia physalis

Confined to bathing suit areas; chills and fever may be present; erythema, macules, and papules may be present There is immediate burning pain and bleeding, variable swelling, and tender red swollen papules and nodules at site of penetration; delayed reactions can follow 2-4 months after injury At points of contact, there is burning, pain, redness, and whealing; systemic signs also may be present

Swimmer’s itch

Cercariae of avian and mammalian forms of Trichobilharzia

There is a superficial and deep perivascular infiltrate of lymphocytes, neutrophils, and eosinophils Polymorphous inflammation with foreign-body granuloma; foreign material may be identified; a wide spectrum of pathologies, including sarcoidal granulomas Nematocysts may be present in the stratum corneum; superficial vascular dilatation, focal hemorrhage, and lymphocytoid infiltrate Dermal edema with a polymorphous infiltrate containing eosinophils

Itching as water evaporates; urticarial reaction progresses to itchy papules

CHAPTER 13 ■ CUTANEOUS REACTIONS TO EXOGENOUS AGENTS

 FIGURE 13-7 Granulomatous tissue reaction to sea urchin spine. There is a nodular granulomatous infiltrate consisting of lymphocytes admixed with histiocytes, including multinucleated foreign body giant cells. Some cases show a polarizable spine in the middle dermis, which this biopsy does not demonstrate.

eruption is a highly pruritic eruption under swimwear that occurs after bathing in the ocean.41 The average duration of the eruption and pruritus is 10 days. Tiny larvae of the thimble jellyfish Linuche unguiculata appear to be the cause in Floridian and Caribbean waters, where sporadic epidemics are seen. Reaction to the coelenterate Physalia physalis reflects the extrusion of nematocysts from tentacles that adhere to the skin and inject toxin.42 Acute lesions are painful, red, and edematous, with a linear array marking the path of the tentacle. The lesions may resolve with hyperpigmentation. In contrast to seabather’s eruption, swimmer’s itch affects only exposed parts and is produced by cutaneous penetration by shistosomal cercariae.43 Transient urticarial lesions evolve into pruritic papules. A wide array of additional potential reactions can follow exposure to venomous marine agents; however, histologies of these reactions have been poorly documented.

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PART I ■ INFLAMMATORY REACTIONS IN THE SKIN

Portuguese man-of-war stings exhibit vascular dilatation, hemorrhage, and a lymphoid infiltrate. Nematocysts are found rarely in the stratum corneum. The pathologic changes of swimmer’s itch include dermal edema and a polymorphous infiltrate containing eosinophils.43 DIFFERENTIAL DIAGNOSIS While seabather’s eruption, swimmer’s itch, and envenomation can produce nonspecific histologic features characterized by polymorphous inflammatory infiltrates, the presence of exogenous material, such as a portion of nematocyst or sea urchin spine, coupled with the appropriate history, leads to the specific diagnosis. In these cases, the history is most important. The histopathologic features of contact allergic dermatitis such as from coral exposure are nonspecific and include a spongiotic dermatitis with dermal, perivascular, lymphocytic, and eosinophilic infiltrates (see Chap. 2).

REACTIONS TO ARACHNIDS Three orders of arachnids produce cutaneous reactions: spiders, scorpions, and ticks and mites. The arachnids are distinct from insects in that they do not

have wings or antennae, and the body is not divided into distinct segments. CLINICAL FEATURES The constellation of signs and symptoms that follows a spider bite is called arachnidism. In the United States, arachnidism most often follows the bite of either the black widow spider (Latrodectus mactans) or the brown recluse spider (Loxosceles reclusa) (Fig. 13-8). In general, pain and redness develop rapidly at the site of a spider bite, although the patient may not recall the inciting event, particularly in the setting of nocturnal brown recluse spider envenomation. Tissue injury is usually trivial but can progress to induration and necrosis.44-48 Systemic signs such as nausea, fever, and vomiting may be present. Scorpions carry a venom apparatus in their tails. There is rapid onset of burning pain and induration and sometimes tissue necrosis at the site of the sting. Systemic signs and symptoms include diaphoresis, vomiting, and nausea. Tick bite reactions follow implantation of an ectoparasite of the Ixodoidea superfamily.45,46 There are two family groups: soft-bodied ticks and hard-bodied ticks. The species of tick will vary based on geographic and exposure characteristics.

The tissue reaction to implantation represents a response to salivary antigens secreted by the tick after implantation. In the saliva is an adhesive that cements the mouthpart to the tissue. Attachment sites manifest edematous, erythematous, and sometimes persistent inflammatory reactions. Mites from a variety of families are capable of producing dermatitis by biting and sensitizing their targets. Baker’s itch, grocer’s itch, copra itch, and other colorful names have been applied to the clinical syndrome that follows the bite of a mite.49 Diagnosis is made by recognition of the occupational exposure that explains the distribution. Cheyletiella dermatitis is an infrequently reported eruption caused by an ectoparasite, Cheyletiella, whose normal hosts are household pets.50,51 Because the mites do not remain on human skin, support for the diagnosis is obtained by identification of mites on the patient’s pet. Trombiculid mites, known as chiggers, feed on humans only in their larval stage. The larvae, which are very small, attach to a host and seek a soft area, constricted by clothing in humans. The lesion is a macule that evolves into a pruritic red papule that may vesiculate. HISTOPATHOLOGIC FEATURES The histopathologic changes that follow a spider bite are those of infarctive and liquefactive tissue necrosis with thrombosis, vascular injury, hemorrhage, and inflammation consisting of a pan-dermal infiltrate of lymphocytes and neutrophils with variable numbers of eosinophils. The histopathology of a tick attachment site may include sections through the attached ectoparasite (Figs. 13-9 and 13-10). There are varying degrees of spongiosis, dermal edema, and an intense polymorphous superficial and deep lymphohistiocytic and eosinophilic infiltrate with hemorrhage. Mast cells may be increased.46 Epidermal hyperplasia and dense lymphoid infiltrates may persist at the attachment site. DIFFERENTIAL DIAGNOSIS Spider bites need to be separated from the large spectrum of causes associated with focal necrosis, including infections, pyoderma gangrenosum,52 vasculitis, trauma, and thrombotic or embolic infarction.

REACTIONS TO INSECTS

308

 FIGURE 13-8 Brown recluse spider bite. There is focal full-thickness necrosis of the epidermis. The dermal vasculature shows a mixed lymphohistiocytic and leukocytoclastic vasculitis with thrombosis, and there is lysis of the collagen table.

Although the outcome of an insect bite is usually trivial, occasionally bites result in clinically significant reactions. The mosquito bite is the most common clinical

 FIGURE 13-9 Tick bite reaction. Dense superficial and deep perivascular and periadnexal lymphohistiocytic infiltrate with scattered eosinophils.

lesion. It follows contact with a female mosquito whose mouth-parts have penetrated the dermis, where a complex array of salivary antigens is deposited. Depending on the species of insect, a

number of biochemical reactions may ensue, including local anticoagulation, protease release, and cellular infiltration. The type and degree of tissue reaction depend on the immunologic state of the

 FIGURE 13-10 Tick mouthpart. Refractile mouthparts are embedded in the superficial dermis. There is an associated marked lymphoeosinophilic infiltrate and reactive fibrosis.

CLINICAL FEATURES Infestation with either the head or body louse produces pruritus with excoriations. There may be matting of hair and secondary infection. Diagnosis of head lice is made by identifying the oval egg capsules attached to hair shafts. Mobile head lice are seen frequently. The bite site of the body louse is macular and red. Persistent wheals and papules may develop. Eggs are laid in clothing, and infestation is transmitted by clothing and bedding. Diagnosis is made by identifying lice and their eggs in the seams of clothing. Pubic lice produce blue-gray macular lesions on the lower abdomen and upper thighs, often with bacterial superinfection. Cutaneous myiasis occurs on exposed skin, with lesions consisting of either a furuncular or a tortuous red line of papules and vesicles if clinical lesions represent a creeping eruption. Flea bites in a sensitized person produce pruritic papules that may be clustered and sometimes are bullous. The sand flea, T penetrans, generally penetrates the skin on the toes or between the toes. The flea appears initially as a black dot; eventually, inflammation and pustules develop. HISTOPATHOLOGIC FEATURES The histopathology of these lesions almost always consists of edema with superficial and middle-to-deep dermal inflammation in a perivascular and wedge-shaped distribution. The components of the infiltrate may vary; however, the presence of eosinophils, particularly in an interstitial pattern, is a helpful feature. If the biopsy is taken from the vicinity of mouthpart penetration, there will be a vertical area

CHAPTER 13 ■ CUTANEOUS REACTIONS TO EXOGENOUS AGENTS

individual. Particularly florid reactions occur, for example, in patients with chronic lymphocytic leukemia. Pediculosis is produced by infestation with either of two species, Phthirus pubis or Pediculus humanus. Pediculus humanus exists as either the body louse or the head louse. Bed bugs are members of the family Cimicidae and are blood-sucking insects about 3 to 4 mm in size. The bed bug emerges from crevices in floors, walls, and furniture to feed in darkness. They are attracted to the body temperature of the host, feed for several minutes, and then depart. A number of species of Cimicidae will attack humans. Myiasis is the infestation by larvae of Diptera. There are numerous genera capable of producing myiasis in humans, including Dermatobia, Callitroga, Chrysomyia, Cordylobia, and Wohlfahrtia. Tungiasis is caused by infestation of the skin by a fertilized female sand flea, Tunga penetrans.

309

PART I ■ INFLAMMATORY REACTIONS IN THE SKIN 310

of amphophilic tissue necrosis extending vertically from the cornified layer for a variable distance into the dermis, sometimes with attendant hemorrhage. Epidermal changes vary from mild acanthosis through intraepidermal vesicle formation to pustulonecrotic lesions seen with flea, gnat, and mosquito bite puncta. Most reactions have some degree of epidermal spongiosis, occasionally with exocytosis of eosinophils (eg, eosinophilic spongiosis). Rarely, there will be both intraepidermal and subepidermal vesicle formation simultaneously in the same section; this is a strongly supportive finding for an insect bite reaction. The histology of tungiasis may contain portions of the ectoparasite surrounded by a dense polymorphous host response with epidermal spongiosis and acanthosis. DIFFERENTIAL DIAGNOSIS Because these reactions represent a response to a potpourri of toxic and immunologic stimuli, the possible histologic diagnoses are legion. Generally, a superficial and deep infiltrate coupled with the presence of eosinophils suggests an insect bite reaction but does not exclude other forms of hypersensitivity reactions.

REFERENCES 1. Kalajian AH, Waldman M, Knable AL. Nodular primary localized cutaneous amyloidosis after trauma: a case report and discussion of the rate of progression to systemic amyloidosis. J Am Acad Dermatol. 2007 Aug; 57(2 suppl):S26-S29. 2. McClelland M, VanLock JS, Patterson JW, Greer KE. Radiation-induced morphea occurring after fluoroscopy. J Am Acad Dermatol. 2002;47:962-964. 3. From National Cancer Institute Common Terminology Criteria for Adverse Events. Version 3. 4. LeBoit PE. Subacute radiation dermatitis: a histologic imitator of acute cutaneous graft-versus-host disease. J Am Acad Dermatol. 1989;20:236-241. 5. Crowson AN, Magro CM. Idiopathic perniosis and its mimics: a clinical and histological study of 38 cases. Hum Pathol. 1997;28:474-484. 6. Price RD, Murdoch DR. Perniosis (chilblains) of the thigh: report of five cases, including four following river crossings. High Alt Med Biol. 2001;2:535538. 7. Schoning P. Frozen cadaver: antemortem versus postmortem. Am J Forens Med Pathol. 1992;13:18-20. 8. Cribier B, Djeridi N, Peltre B, Grosshans E. A histologic and immunohistochemical study of chilblains. J Am Acad Dermatol. 2001;45:924-929. 9. Vayssairat M. Chilblains. J Mal Vasc. 1992; 17:229-231. 10. Wall LM, Smith NP. Perniosis: a histopathologic review. Clin Exp Dermatol. 1981;6: 263-271.

11. Herman EW, Kezis JS, Silvers DN. A distinctive variant of pernio. Arch Dermatol. 1981;117:26-28. 12. McGovern T, Wright IS, Kruger E. Pernio: a vascular disease. Am Heart J. 1941;22: 583-606. 13. Klapman MH, Johnston WH. Localized recurrent postoperative pernio associated with leukocytoclastic vasculitis. J Am Acad Dermatol. 1991;24:811-813. 14. Weston WL, Morelli JG. Childhood pernio and cryoglobulins. Pediatr Dermatol. 2000;17:97-99. 15. Crowson AN, Magro CM. The cutaneous pathology of lupus erythematosus. J Cutan Pathol. 2001;28:1-23. 16. Crowson AN, Mihm MC Jr, Magro CM. The cutaneous vasculitides: a review. J Cutan Pathol. 2003;30:161-173. 17. Francheschini F, Calzavara-Pinton P, Quinzanini M, et al. Chilblain lupus erythematosus is associated with antibodies to SSA/Ro. Lupus. 1999;8:215-219. 18. Magro CM, Crowson AN. The cutaneous pathology associated with seropositivity for antibodies to Ro/SSA: a clinicopathological study of 23 adult patients without subacute cutaneous lupus erythematosus. Am J Dermatopathol. 1999;21:129-137. 19. Millard TP, Hawk JL. Photosensitivity disorders: cause, effect and management. Am J Clin Dermatol. 2002;3:239-246. 20. Rippke F, Wendt G, Bohnsack K, et al. Results of photoprovocation and field studies on the efficacy of a novel topically applied antioxidant in polymorphous light eruption. J Dermatol Treat. 2001;12:3-8. 21. Stratigos AJ, Antoniou C, Katsambas AD. Polymorphous light eruption. J Eur Acad Dermatol Venereol. 2001;16(3):193-206. 22. Boonstra HE, van Weelden H, Toonstra J, van Vloten WA. Polymorphous light eruption: a clinical pathobiologic, and follow-up study of 110 patients. J Am Acad Dermatol. 2000;42:L199-L207. 23. Halasz CLG, Leach EE, Walther RR, et al. Hydroa vacciniforme: induction of lesions with ultraviolet A. J Am Acad Dermatol. 1983;8:171-176. 24. Leenutaphong V. Hydroa vacciniforme: an unusual clinical manifestation. J Am Acad Dermatol. 1991;25:892-895. 25. Goldgeier MH, Nordlund JJ, Lucky AW, et al. Hydroa vacciniforme: diagnosis and therapy. Arch Dermatol. 1982;118:588-591. 26. Lane PR, Hogan DJ, Martel MJ, et al. Actinic prurigo: clinical features and prognosis. J Am Acad Dermatol. 1992;26: 683-692. 27. Crouch R, Foley P, Baker C. Actinic prurigo: a retrospective analysis of 21 cases refereed to an Australian photobiology clinic. Australas J Dermatol. 2002;43:128-132. 28. Vega-Memije ME, Mosqueda-Taylor A, Irigoyen-Camcho ME, et al. Actinic prurigo cheilitis: clinicopathologic analysis and therapeutic results in 116 cases. Oral Med Oral Surg Med Oral Pathol Oral Radiol Endod. 2002;94:83-91. 29. Lim HW, Morison WL, Kamide R, et al. Chronic actinic dermatitis: an analysis of 51 patients evaluated in the United States and Japan. Arch Dermatol. 1994;130:1284-1289. 30. Toonstra J. Actinic reticuloid. Semin Diagn Pathol. 1991;8:109-116. 31. Healy E, Rogers S. Photosensitivity dermatitis/actinic reticuloid syndrome in an Irish population: a review and some

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46. 47.

48. 49. 50. 51. 52.

unusual features. Acta Derm Venereol (Stockh). 1995;75:72-74. Tojo M, Iwatsuki K, Furukawa H, et al. Neutrophilic eccrine hidradenitis in actinic reticuloid syndrome. Eur J Dermatol. 2002; 12:198-200. Lane PR, Murphy F, Hogan DJ, et al. Histopathology of actinic prurigo. Am J Dermatopathol. 1993;15:326-331. Wiseman M, Magro CM, Toole JWP, Crowson AN. Actinic prurigo: a clinical and dermatopathological study of 7 Inuit and 7 Cree Indian patients (abstract). Lab Invest. 1998;78:54A. Umana A, Gomez A, Duran MM, Porras L. Lymphocyte subtypes and adhesion molecules in actinic prurigo: observations with cyclosporin A. Int J Dermatol. 2002;41:139-145. Grabczynska SA, McGregor JM, Kondeatis E, et al. Actinic prurigo and polymorphous light eruption: common pathogenesis and the importance of HLA-DR4/DRB*0407. Br J Dermatol. 1999;140:232-236. Torres-Alvarez B, Baranda L, Fuentes C, et al. An inmmunohistochemical study of UV-induced skin lesions in actinic prurigo: resistance of Langerhans’ cells to UV light. Eur J Dermatol. 1998;8:24-28. Arrese JE, Dominguez-Soto L, HojyoTomoka MT, et al. Effectors of inflammation in actinic prurigo. J Am Acad Dermatol. 2001;44:957-961. Ng JC, Foley PA, Crouch RB, Baker CS. A case of severe actinic prurigo treated with thalidomide. Australas J Dermatol. 2001; 42:192-195. Kuno Y, Sato K, Hasegawa K, Tsuji T. A case of actinic prurigo showing hypersensitivity of skin fibroblasts to ultraviolet A (UVA). Photodermatol Photoimmunol Photomed. 2000;16:38-41. Wong DE, Meinking TL, Rosen LB, et al. Seabather’s eruption: clinical, histologic and immunologic features. J Am Acad Dermatol. 1994;30:399-406. Ioannides G, Davis JH. Portuguese man-ofwar stings. Arch Dermatol. 1965;91:488-451. Brackett S. Pathology of schistosome dermatitis. Arch Dermatol Syphilol. 1940;42: 410-418. Norment BR, Foil LD. Histopathology and physiological action of venom from the brown recluse spider, Loxosceles reclusa. Toxicon. 1979;17(suppl 1):131. Pucevich MV, McChesney T. Histopathologic analysis of human bites by the brown recluse spider. Arch Dermatol. 1983;119:851. Winer LH, Strakosch EA. Tick bites: Dermacentor variabilis (Say). J Invest Dermatol. 1941;4:249. Sams HH, Hearth SB, Long LL, et al. Nineteen documented cases of Loxososceles reculsa envenomation. J Am Acad Dermatol. 2001;44:603-608. Sams HH, Dunnick CA, Smith ML, King LE. Necrotic arachnidism. J Am Acad Dermatol. 2001;44:561-573. Krinsky W. Dermatoses associated with the bites of mites and ticks (Arthroposi: Acari). Int J Dermatol. 1983;22:75-91. Rivers JK, Martin J, Pukay B. Walking dandruff and Cheyletiella dermatitis. J Am Acad Dermatol. 1986;15:1130-1133. Lee BW. Cheyletiella dermatitis. Arch Dermatol. 1981;117:677-678. Crowson AN, Mihm MC, Jr, Magro CM. Pyoderma gangrenosum: a review. J Cutan Pathol. 2003;28:1-13.

2 PART Predominantly Noninflammatory Conditions

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CHAPTER 14 Alterations of the Stratum Corneum and Epidermis Michael W. Piepkorn

INTRODUCTION

HYPERKERATOSIS WITHOUT EPIDERMOLYTIC CHANGE: THE NONBULLOUS ICHTHYOSES AND RELATED DISORDERS The designation ichthyosis is fundamentally a descriptive term covering a variety of keratinization disorders that are usually genetic in nature. Although their

genetic bases are heterogeneous, all of them share the common feature of scaling skin, which is usually generalized, but as in the instances of the palmoplantar keratodermas and the erythrokeratodermas, they may also be localized. This section covers disorders with significant hyperkeratosis due to defective keratinization but with no cytolytic (epidermolytic) alterations. The organization of these hyperkeratotic disorders, which has been adapted from the work of Traupe,1 follows the diagnostic algorithm presented in Fig. 14-1. This scheme focuses initial attention on whether the predominant mode of keratinization is ortho- or parakeratotic and secondarily on the morphologic status of the stratum granulosum. The features that assist with the differential diagnosis of the entities are summarized in Table 14-1.

DISORDERS WITH HYPERORTHOKERATOSIS AND REDUCED TO ABSENT STRATUM GRANULOSUM The following entities share the common features of hyperorthokeratosis and a general thinning or absence of the stratum granulosum.

Ichthyosis Vulgaris Ichthyosis vulgaris was first discriminated from X-linked recessive ichthyosis,

Mode of hyperkeratosis

Hyperorthokeratosis

Reduced stratum granulosum

Prominent stratum granulosum

Ichthyosis vulgaris acquired ichthyosis Refsum syndrome Tay syndrome X-linked dominant ichthyosis Harlequin ichthyosis

X-linked recessive ichthyosis Lamellar ichthyosis, autosomal recessive Lamellar ichthyosis, autosomal dominant Neutral lipid storage disease KID syndrome Sjögren-Larsson syndrome Palmoplantar keratoderma Erythrokeratoderma variabilis Acanthosis nigricans IFAP inherited pityriasis rubra pilaris Refsum syndrome, some

Parakeratosis

CHAPTER 14 ■ ALTERATIONS OF THE STRATUM CORNEUM AND EPIDERMIS

An exceptionally diverse group of disorders that are both heterogeneous in their genetic bases and pleiotropic in their phenotypic expression can be assembled under the general category of alterations of the stratum corneum and epidermis. These disorders reflect a wide range of acquired and hereditary pathologic processes. Two distinct themes, however, unite many of the entities described here. One common pathophysiologic feature reflects defects in the keratinization process that manifest clinicopathologically as ichthyoses; the other involves molecular defects in keratin genes and other genes yet to be determined that confer defective epidermal integrity and that present clinically as the mechanobullous disorders. Many of the disorders collated here, particularly the ichthyoses, have similar

microscopic features, complicating the histopathologic differential diagnosis and highlighting the importance of clinical correlation. Accurate diagnosis may also involve special procedures, including immunocytochemistry. Indeed, for the hereditary cytolytic (mechanobullous) disorders, immunolabeling of basement membrane components or electron microscopy to delineate the level of the separation within the tissue is necessary for adequate diagnosis. The histopathologic algorithms offered here, therefore, only serve in many situations to resolve the differential diagnosis to a limited level, beyond which one must resort to supplemental strategies. The organization of this chapter follows the two major schema of defects in the process of keratinization and defective epidermal integrity often due to mutations in keratin genes. Pathways for differential diagnosis of the nonbullous ichthyoses are discussed first followed by disorders with epidermolytic changes.

Ichthyosis vulgaris, some lamellar ichthyosis, some Comèl-Netherton CHILD syndrome porokeratosis

 FIGURE 14-1 Hyperkeratosis without epidermolytic change: diagnostic algorithm for the nonbullous ichthyoses and related disorders. The pathway for differential diagnosis is dichotomized on the preponderant mode of hyperkeratosis, whether ortho- or parakeratotic, and if the former, whether the stratum granulosum is reduced or retained. CHILD = congenital hemidysplasia, ichthyosiform erythroderma, limb defects; IFAP = ichthyosis follicularis with atrichia and photophobia; KID = keratitis, ichthyosis-like hyperkeratosis, and deafness.

313

Table 14-1 Differential Diagnosis of Nonbullous Ichthyoses and Related Disorders HISTOLOGIC FEATURE DISORDER

HYPERKERATOSIS

ACANTHOSIS

PART II ■ PREDOMINANTLY NONINFLAMMATORY CONDITIONS

Disorders with Hyperorthokeratosis and a Reduced Granular Layer Ichthyosis vulgaris + to ++ 0 Refsum syndrome + 0 to + Tay syndrome + to ++ + X-linked dominant ichthyosis + to ++ + to ++ Harlequin ichthyosis +++ +

314

FOLLICULAR KERATOSIS

SPONGIOSIS

PERIVASCULAR INFILTRATES

+ 0 0 + to ++ +

0 0 0 + 0

0 to + 0 + + to ++ +

0 0 + 0 + 0 Variable 0

+ to ++ + + Variable + + + to ++ + +

0 +

0 to + ++

Disorders with Hyperorthokeratosis and a Normal to Thickened Granular Layer X-linked recessive ichthyosis + to ++ + 0 to + Lamellar ichthyosis + + + Dorfman syndrome + + + KID syndrome + to ++ Variable + to ++ Sjögren-Larsson syndrome + to ++ 0 to + + Palmoplantar keratoderma ++ + − Erythrokeratoderma variabilis + ++ − IFAP syndrome ++ 0 ++ Pityriasis rubra pilaris ++ to +++ ++ ++ Disorders with Hyperparakeratosis CHILD syndrome + to ++ + 0 Comèl-Netherton syndrome ++ to +++ + to ++ 0

OTHER

Vacuolized keratinocytes Follicular atrophoderma (late) Parakeratosis (some cases)

Foamy keratinocytes

Keratolysis in some cases Follicular atrophy Alternating parakeratosis

PAS-positive debris and neutrophils in corneum

CHILD = congenital hemidysplasia, ichthyosiform erythroderma, limb defects; IFAP = ichthyosis follicularis with atrichia and photophobia; KID = keratitis, ichthyosis-like hyperkeratosis, and deafness; PAS = period acid Schiff.

the other common form of ichthyosis, in the 1960s by Wells and Kerr2 on the basis of inheritance and clinical appearance. The disorder is the most common ichthyosis, with an estimated prevalence of between 1 in 250 and 1 in 5300. 2 Ichthyosis vulgaris is a retention hyperkeratosis disorder inherited as an autosomal dominant trait. Granular layer abnormalities by microscopic examination have led to investigations of the role of profilaggrin, the predominant keratohyalin protein in the human epidermis, in ichthyosis vulgaris. Profilaggrin expression in the affected epidermis is decreased or absent, depending on the disease severity. A subset of individuals with the clinical findings of ichthyosis vulgaris and with no granular layer has been identified; keratinocytes cultured from such individuals have very little detectable profilaggrin protein, and the profilaggrin mRNA level is reduced by approximately 50% in these cells.3 A mouse model, known as flaky tail, presents a clinical phenotype resembling that of the human condition, and at the histologic level, keratohyalin granules are absent from the epidermis; molecular analysis has suggested a defect in the processing of profilaggrin to filaggrin as the potential basis for the phenotype.4 Following from the animal models and

genetic linkage analyses, subsequent mutational analyses have identified specific mutations in the profilaggrin gene that cause ichthyosis vulgaris and predispose individuals to atopic dermatitis, presumably mediated by defects in barrier function.5 CLINICAL FEATURES The disorder presents early in life, usually within the first year, but is rarely present at birth (Table 14-2). Fine, white scales are found on the trunk and extensor surfaces of the extremities in association with superficial fissuring in severe cases (Fig. 14-2A). The central face and cheeks may be involved, but the sides of the neck are almost always spared. The condition is associated with atopy and keratosis pilaris. Hyperlinearity and chafing of the palms and soles are often present, but whether this is linked to the atopy or the ichthyosis is disputed. Because of the overlap in clinical phenotype, ichthyosis vulgaris and X-linked recessive ichthyosis are often confused clinically; the usual mistake in diagnosis is labeling X-linked recessive ichthyosis as ichthyosis vulgaris.6 Assay for reduced levels of steroid sulfatase activity, however, can be used to confirm the diagnosis of X-linked recessive ichthyosis.

HISTOPATHOLOGY Microscopic examination of the stratum corneum in patients with ichthyosis vulgaris reveals compact hyperorthokeratosis.1 The degree of hyperkeratosis varies from mild to moderate. This alteration is associated with a uniformly reduced granular layer that is absent in at least some foci (Fig. 14-2B). Parakeratosis is generally not observed. Follicular dilatation and hyperkeratosis are regularly present. The epidermis is usually of normal thickness,7 but on occasion, acanthosis or even atrophy may be present. The rete ridge pattern is not accentuated. The sebaceous glands are atrophic. No or slight perivascular inflammation is found in the papillary dermis. DIFFERENTIAL DIAGNOSIS The differential diagnosis may include lamellar ichthyosis and X-linked recessive ichthyosis in cases in which the granular layer is not especially thinned. However, the usual patient manifests an absent (or at least a clearly thinned) granular layer. Keratohyalin granules appear crumbly or degenerated by electron microscopy, allowing distinction from the other ichthyoses in which the granular layer is thinned. In the differential diagnosis of nonbullous

Table 14-2 Ichthyosis Vulgaris

ichthyosis with a reduced granular layer, many of the remaining disorders, such as Refsum disease and X-linked dominant ichthyosis,1 are syndromes in which the ichthyotic change is one component associated with other signs and symptoms in a recognizable pattern that collectively allows assignment of the diagnosis. The diagnostic consideration of an acquired ichthyosis is discussed in the next section.

Acquired Ichthyosis Acquired ichthyosis, with onset usually beyond the childhood years, has been

A

CLINICAL FEATURES The clinical findings are reported to resemble those of ichthyosis vulgaris, although large platelike or hyperpigmented scales are sometimes observed. Hyperlinearity of the palms and soles is not a feature, but palmar–plantar keratoderma has been described. HISTOPATHOLOGY The histologic pattern also resembles that of ichthyosis vulgaris with hyperorthokeratosis, compaction of the stratum corneum, and thinning of the granular layer in some cases.10 No cases of a totally absent granular layer have been reported, and staining with antiprofilaggrin or filaggrin antibody demonstrates the presence of profilaggrin or filaggrin. DIFFERENTIAL DIAGNOSIS Clinicopathologic overlap exists between ichthyosis vulgaris, acquired ichthyosis, and dry skin (xerosis). A distinction between ichthyosis vulgaris and acquired ichthyosis is essentially founded on the clinical history and physical examination findings. Xerosis is

poorly understood and loosely defined; other than an association with winter weather and aging, few distinguishing features are present. The distinction of the dry skin seen in atopic eczema from ichthyosis vulgaris has been made on the basis of other clinical findings associated with the two disorders and appears distinct histologically.

Refsum Syndrome (Heredopathia Atactica Polyneuritiformis) Refsum syndrome is an uncommon disorder associated with peroxisomal dysfunction. It affects the eyes, nervous system, and skin.11 The condition is inherited as an autosomal recessive trait. Accumulation of phytanic acid from phytol present in chlorophyll results in altered epidermal metabolism, with an increased thymidine labeling index, increased incorporation of precursors into DNA and protein, and altered lipid metabolism.12,13 It is unclear how accumulation of the long-chain, branched fatty acid effects such changes. The underlying defect lies in the alphaoxidation of phytanic acid, the basis for which is genetically heterogeneous; mutations in one of two AAA ATPases, PEX1 or PEX614 or in phytanoyl-CoA hydroxylase may be etiologic15 in selected kindreds. CLINICAL FEATURES Patients with Refsum syndrome initially present with night blindness caused by retinitis pigmentosa. Sequential involvement with relapsing sensory neuropathy, cerebellar ataxia, cataracts, and nerve deafness is associated with phytanic acidemia.16 Skin changes occur after the eye and neurologic changes and vary from mild scaling of the palms and soles to a presentation

CHAPTER 14 ■ ALTERATIONS OF THE STRATUM CORNEUM AND EPIDERMIS

Clinical Features Onset within the first year of life Fine, white scales on the trunk and extensor extremities, sparing the sides of the neck Hyperlinearity and chafing of the palms and soles Associated with atopy and keratosis pilaris Histopathology Mild to moderated compact hyperorthokeratosis Generally no parakeratosis Diminished to absent stratum granulosum Follicular dilatation and hyperkeratosis Epidermis usually of normal thickness Differential Diagnosis Acquired ichthyosis Xerosis Syndromes with associated ichthyosis: Refsum syndrome, ichthyosis, and trichothiodystrophy, X-linked dominant ichthyosis with chondrodysplasia punctata

described in association with a number of systemic disorders (including thyroid disease, sarcoidosis, systemic lupus erythematosus, graft-versus-host disease after bone marrow transplantation, malnutrition, HIV), drugs, and malignancies.8-10 Nearly half of people with insulin-dependent diabetes clinically show ichthyosiform changes. Although solid tumors have occasionally been found, lymphoproliferative disorders, particularly Hodgkin disease, prevail. Speculation regarding the possible role of vitamin A deficiency caused by liver involvement or malabsorption has not been substantiated. Thus, the cause of the disorder is unknown.

B

 FIGURE 14-2 Ichthyosis vulgaris. (A) Diffuse fine white scale on the extremity. (B) A moderately hyperorthokeratotic stratum corneum overlies a mildly acanthotic spinous layer without an intervening stratum granulosum.

315

resembling ichthyosis vulgaris and occasionally to widespread, severe scaling resembling lamellar ichthyosis.1

PART II ■ PREDOMINANTLY NONINFLAMMATORY CONDITIONS

HISTOPATHOLOGY The stratum corneum exhibits slight hyperorthokeratosis, which is associated with a thinned to normal granular layer. Slight acanthosis may be present. Vacuolization of basal and suprabasal keratinocytes due to lipid accumulation with phytanic acid may not be evident by routine histologic examination, but is shown with histochemical lipid stains such as Sudan red.

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DIFFERENTIAL DIAGNOSIS The routine histopathologic findings resemble those of ichthyosis vulgaris and related disorders. The accumulation of phytanic acid within keratinocytes and other cutaneous cells such as melanocytes, however, is the hallmark of the disorder and can be demonstrated by lipid staining. Its presence serves to discriminate Refsum disease from most other ichthyoses with similar histologic features, although neutral lipid storage disease shows similar lipid accumulations.

Syndromes of Ichthyosis and Trichothiodystrophy The syndromes of ichthyosis and trichothiodystrophy are a heterogeneous group of overlapping phenotypes with no firm criteria allowing for absolute categorization.1 These conditions include Tay syndrome, BIDS (brittle hair, intellectual impairment, decreased fertility, and short stature), IBIDS (ichthyosis, brittle hair, intellectual impairment, decreased fertility, and short stature), and PIBI(D)S (photosensitivity, brittle hair, intellectual impairment, decreased fertility, and short stature). All of these disorders are thought to be inherited as autosomal recessive traits. The nucleotide excision repair defect in PIBI(D)S, which is associated with photosensitivity, may fall into the same complementation group as xeroderma pigmentosum group D, with a mutation in the repair gene XPD that encodes helicase subunits of the repair factor transcription factor II H (TFIIH).17,18 At the biochemical level, the cystine content of the hair is decreased. CLINICAL FEATURES The syndromes have in common the features of ichthyosis, brittle hair, and short stature. The ichthyosis varies from mild to severe congenital erythroderma with a collodion membrane, which evolves to more platelike scaling with little erythema, similar to lamellar ichthyosis. The hair is often

fractured, with varied microscopic findings and characteristic banding when viewed with polarized light; cystine and proline content are reduced. Additional findings include psychomotor and mental retardation and unusual sociability. Photosensitivity with abnormal DNA excision repair and retarded sexual development with decreased fertility are variable findings. HISTOPATHOLOGY Microscopic sections of skin show moderate hyperorthokeratosis and thinning of the granular layer.1 The spinous layer is moderately acanthotic and mildly papillomatous. Slight perivascular lymphocytic inflammation is present within the papillary dermis. DIFFERENTIAL DIAGNOSIS The histopathologic findings are nonspecific and similar to those of autosomal dominant ichthyosis vulgaris and related conditions. Although the differential diagnosis may not be resolvable by the cutaneous histopathology, microscopic examination of the hair shows trichoschisis (transverse breaks), and polarized light reveals alternating (tigertail) light and dark bands.19

X-linked Dominant Ichthyosis with Chondrodysplasia Punctata (Conradi-Hunermann Syndrome) This uncommon disorder is inherited as an X-linked dominant trait that is presumed to be lethal in male embryos and largely restricted in its expression to females. Maternal gonadal mosaicism is postulated in rare reports of seemingly sporadic cases.20 The disease has been linked with deficiency of 3 beta-hydroxysteroiddelta8-delta7-isomerase (emopamil binding protein), which catalyzes a step in the conversion of lanosterol to cholesterol.21,22 CLINICAL FEATURES The disorder may present with generalized ichthyosiform erythroderma and linear areas of thickened hyperkeratosis. The erythema resolves within weeks to months, leaving atrophic follicular involvement, ichthyosis, and hyperpigmentation following the lines of Blaschko. Patchy areas of cicatricial alopecia with nonspecific microscopic hair shaft abnormalities, sparse eyebrows and eyelashes, and nail dystrophy are also seen. Cataracts, short stature, and skeletal defects (chondrodysplasia punctata) are additional components of Conradi-Hunermann syndrome. HISTOPATHOLOGY In this disorder, moderate hyperorthokeratosis is associated with a thinned granular layer and slight

acanthosis.23 A mild perivascular lymphocytic infiltrate may be present in the papillary dermis. Prominent follicular hyperkeratosis associated with dyskeratotic cells occurs in young patients, with late follicular atrophoderma in adults. Some reports have suggested the presence of a variable neutrophilic reaction in the epidermis. DIFFERENTIAL DIAGNOSIS The findings are those of disorders sharing the histologic phenotype of autosomal dominant ichthyosis vulgaris. The differential diagnosis in suspected cases can be resolved by identification of the other components of the syndrome, particularly chondrodysplasia punctata supplemented by von Kossa stain to demonstrate the deposition of calcium salts within lesional epidermis. A reduced density of epidermal Langerhans cells may also be shown by immunostaining with CD1a. A vacuolated granular layer may also occur, along with spicules by electron microscopic examination. All of these findings, however, are seen early in the course of the disease and may resolve over time, leaving the residual, linear areas of pigmentary change, follicular atrophoderma, and cicatricial alopecia with no characteristic histologic features.

Harlequin Ichthyosis Harlequin ichthyosis is a rare, severe keratinizing disorder thought to be inherited as an autosomal recessive trait or a new dominant mutation.24 The disorder is phenotypically heterogeneous.25 Abnormal or absent lamellar granules within keratinocytes are observed by electron microscopy in all forms. Lamellar granules function in lipid transport. A member of the ATP-binding cassette transporter family designated ABCA12 ultrastructurally localizes to lamellar granules and functions in lipid secretion in and out of the cells via these granules.26 Mutational analyses of ABCA12 as a candidate gene for Harlequin ichthyosis and complementary single nucleotide polymorphism mapping strategies have shown that missense and nonsense mutations in highly conserved regions of the gene are etiologic for the condition; the phenotype is thus mediated by deleterious effects on skin barrier function resulting from defective lipid transport.26,27 CLINICAL FEATURES The condition is the most severe of the congenital ichthyoses. Newborns are incarcerated in a massively thick, platelike scale affecting the entire integument, which produces

ectropion and eclabium; restricts respiration and feeding; and alters development of the ears, nose, eyes, and mouth. The cuirass cracks soon after birth, resulting in deep fissures in geometric patterns. Death usually ensues. If the affected infant survives beyond the newborn period, the phenotype evolves into that of a severe nonbullous congenital erythroderma.

DISORDERS WITH HYPERORTHOKERATOSIS AND PROMINENT STRATUM GRANULOSUM A separate pathway of differential diagnosis is suggested when histologic examination indicates a normal to expanded stratum granulosum (Fig. 14-1). The prototypes for these disorders are X-linked recessive ichthyosis and the lamellar ichthyoses. These and most of the other entities included here look alike histologically. In addition, a number of multisystem syndromes enter the

differential diagnosis in which the specific diagnosis is made by the corresponding clinical context.

X-Linked Recessive Ichthyosis X-linked recessive ichthyosis is the second “common” ichthyosis (ichthyosis vulgaris is the other). Distinction between the two was clarified by Wells and Kerr2 on the basis of inheritance, clinical findings, and histology. However, definitive diagnosis is dependent on steroid sulfatase determination because the two disorders may be confused clinically in 10% to 15% of cases. The disorder occurs in between 1 in 4152 and 1 in 9500 individuals. Mutations (most commonly complete gene deletions) in the steroid sulfatase gene, a locus that maps to the telomeric short arm of the X chromosome (Xp22.3), are responsible for the defect.28 The resulting accumulation of cholesterol sulfate in keratinocytes (as well as in other tissues such as leukocytes) is thought to result in retention hyperkeratosis and scaling, and the increased cholesterol sulfate in combination with decreased cholesterol within the stratum corneum contributes to a deficiency in barrier function.29 Due to presumptive contiguous gene defects, some cases are associated with Kallmann syndrome, mental retardation, chondrodysplasia punctata, and short stature.30 CLINICAL FEATURES Affected individuals present at birth or soon thereafter (Table 14-3). A collodion membrane is seen infrequently, but affected infants more commonly manifest fine, relatively mild scaling at birth. The scaling worsens or generalizes in the first two to six months as larger, pigmented scales appear on the trunk, extremities, axillae, sides of the

CHAPTER 14 ■ ALTERATIONS OF THE STRATUM CORNEUM AND EPIDERMIS

HISTOPATHOLOGY The histologic pattern in Harlequin ichthyosis varies between reports.24,25 Across all categories, however, there is massive compact hyperorthokeratosis, creating a stratum corneum that is much thicker than the spinous layer (Fig. 14-3). Changes in the granular layer are variable. This zone is usually thinned, with keratohyalin granules either reduced in density or totally absent, but it may be normal. The follicles are dilated and hyperkeratotic. Inconstant and less striking changes include mild acanthosis and papillomatosis. Pronounced parakeratosis may be observed in patients who completely lack keratohyalin granules. A superficial perivascular lymphocytic infiltrate is an inconstant feature.

DIFFERENTIAL DIAGNOSIS The massive hyperorthokeratosis is distinctive and not simulated as a rule by any of the other ichthyoses. In questionable cases, electron microscopy may be used to establish reduced or absent lamellar granules or genetic testing can now be used. Clinical correlation usually resolves most of the differential diagnostic ambiguities, if any, because of the distinctive clinical phenotype.

Table 14-3 X-linked Recessive Ichthyosis

 FIGURE 14-3 Harlequin ichthyosis. Massive orthokeratotic thickening of the stratum corneum is seen in association with a thinned stratum granulosum and a spinous layer that is mildly acanthotic and papillomatous. The follicular ostia are dilated and plugged with keratin.

Clinical Features Present at birth or shortly thereafter Generalized fine scaling, especially at flexural sites Progresses over the first 6 months to large, pigmented, platelike scales Histopathologic Features Marked hyperorthokeratosis with occasional parakeratotic foci Granular layer usually thickened Variable acanthosis and papillomatosis Differential Diagnosis Ichthyosis vulgaris Autosomal recessive lamellar ichthyosis

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neck, and the popliteal and antecubital fossae, although the volar epidermis is spared. The brownish scales tend to be large polygonal plates that are adherent. Associated findings may include cryptorchidism and asymptomatic corneal opacities. Obstetric complications, such as a late-for-dates pregnancy, weak labor, and prolonged delivery, occur in as many as 30% of affected pregnancies because of blocked placental estrogen synthesis. HISTOPATHOLOGY Patients have marked hyperorthokeratosis with occasional foci of parakeratosis. The granular layer is usually thickened (Fig. 14-4), although this can vary, and it may be thinned in some sections. The spinous layer is variably acanthotic and papillomatous. Perivascular lymphoid infiltrates within the papillary dermis range from mild to marked. Follicular dilatation and plugging are usually absent but may occasionally be observed. DIFFERENTIAL DIAGNOSIS Although in contrast to autosomal dominant ichthyosis vulgaris, the granular layer is thickened, every patient does not have this feature, and in patients with a reduced stratum granulosum, distinction from ichthyosis vulgaris may not be possible from histologic criteria alone. Cases with thickening of the granular layer resemble autosomal recessive lamellar ichthyosis. Biochemical analysis for steroid sulfatase activity may be necessary to resolve the differential diagnosis.31

Lamellar Ichthyosis CLINICAL FEATURES Lamellar ichthyosis is a genetically heterogeneous disease. Most cases are transmitted as an autosomal recessive trait, but cases with dominant transmission have also been described.1 The recessively inherited form is a severe and often generalized dermatosis, usually presenting at birth and accounting for the majority of cases of collodion baby syndrome (Table 14-4). There are erythrodermic and nonerythrodermic clinical variants. Patients with the most severe phenotype show large, brown, platelike scales and pronounced ectropion. Those with milder phenotypes may have involvement of only the flexural sites and the palms and soles. Mutations in keratinocyte (type I) transglutaminase on chromosome 14qll, which cross-links the cornified envelopes of terminally differentiating keratinocytes, are associated with many cases of lamellar ichthyosis, with other cases mapping to a region on chromosome 2 and linked to mutations in the ABCA12 gene that is the major gene for Harlequin ichthyosis.26,32,33 Defective transglutaminase activity results in incomplete cross-linking of substrates such as loricrin and involucrin, disrupted assembly of cornified envelopes, and defective barrier function.34 HISTOPATHOLOGY The histologic patterns are indistinguishable across all erythrodermic and nonerythrodermic clinical variants of lamellar ichthyosis of autosomal

Table 14-4 Autosomal Recessive Lamellar Ichthyosis

Clinical Features Present at birth with generalized involvement, often with a collodion membrane Erythrodermic and nonerythrodermic variants Large platelike scales, ectropion Histopathology Mild to marked compact hyperorthokeratosis Normal to widened stratum granulosum Often acanthosis and papillomatosis Differential Diagnosis X-linked recessive ichthyosis

recessive type, as well as cases with autosomal dominant transmission. Mild to marked compact hyperorthokeratosis and a normal to increased stratum granulosum are observed in these patients (Fig. 14-5). Often acanthosis and occasionally papillomatosis are seen. Parakeratotic foci associated with a focally thinned granular layer are less commonly observed, but parakeratosis with a thickened granular layer is seen in the autosomal dominant variant. The papillary dermis may contain a perivascular lymphocytic infiltrate of variable intensity. DIFFERENTIAL DIAGNOSIS The histopathology is nonspecific, mimicking that of X-linked recessive ichthyosis, but serves to exclude clinical look-alikes, especially disorders with epidermolytic hyperkeratosis (bullous ichthyosiform erythrodermas). Distinction from the Comèl-Netherton syndrome, which clinically resembles erythrodermic autosomal recessive lamellar ichthyosis, is resolved by the presence of marked inflammation, with spongiosis, lymphocytic exocytosis, parakeratosis, and a thinned to absent granular cell layer.

Neutral Lipid Storage Disease with Ichthyotic (Ichthyosiform) Erythroderma (Dorfman Syndrome and Dorfman-Chanarin Syndrome)

318

 FIGURE 14-4 X-linked recessive ichthyosis. A continuous granular layer of normal to slightly increased thickness separates the densely compact orthokeratotic corneum from the histologically unremarkable stratum spinosum.

CLINICAL FEATURES Neutral lipid storage disease has been reported in fewer than 20 cases, primarily in individuals of Arabic background. The disorder is inherited as an autosomal recessive trait and results in the accumulation of neutral lipids in different tissues. Increased cellular triacylglycerol is thought to result from defective recycling of triacylglycerolderived diacylglycerol to phospholipids.35

HISTOPATHOLOGY Microscopic examination shows nonspecific findings of hyperorthokeratosis and acanthosis, although the hyperkeratosis may be marked. The granular layer is generally thickened. Prominent follicular plugging may also be present.7

 FIGURE 14-5 Lamellar ichthyosis. The compact and mildly thickened orthokeratotic corneum is separated from the slightly acanthotic stratum spinosum by a continuous granular layer of normal thickness.

Mutations in the gene for adipose triglyceride lipase (PNPLA2) are etiologic in some cases.36 Neutral lipid storage disease presents in the skin as diffuse nonbullous ichthyosiform erythroderma, which is indistinguishable from other ichthyoses of that phenotype. Hepatomegaly with abnormal liver function test results, myopathy, cataracts, and lipid vacuolization of leukocytes (Jordan anomaly) and keratinocytes are other components of the syndrome. HISTOPATHOLOGY The routine histologic findings are nonspecific, with acanthosis and hyperorthokeratosis present. Variable parakeratotic foci are also present. The stratum granulosum may be thickened or thinned. A slight perivascular infiltrate may be observed in the papillary dermis. The most distinctive feature is the presence of foamy cytoplasm (vacuoles containing lipid) within keratinocytes of the basal and granular layers; by histochemical staining, this is shown to be lipid accumulation. Lipid droplets may also be observed in fibroblasts, Schwann cells, smooth muscle, and eccrine gland epithelium.37 DIFFERENTIAL DIAGNOSIS The microscopic features are indistinguishable from other nonbullous congenital ichthyoses, but the observation of lipid droplets in the keratinocytes by microscopic examination of H&E-stained permanent sections or frozen sections if necessary with confirmation by histochemical lipid staining may allow discrimination from lamellar ichthyosis.

The Ichthyosis and Deafness Syndromes Although similar in name, the two ectodermal dysplasias are distinct clinically and histologically. Cases of HID (hystrix-like ichthyosis with deafness) have appeared to be sporadic. Although X-linked recessive inheritance has been excluded, autosomal dominant or recessive transmission is possible. Most cases of KID (keratitis, ichthyosis-like hyperkeratosis, and deafness) have also appeared to be sporadic, but some evidence supports an autosomal dominant inheritance. The underlying defects are largely unknown, although evidence indicates that both KID and HID may be caused by specific mutations in connexin 26.38 CLINICAL FEATURES Patients with HID present with patches of erythema soon after birth that progress to generalized, dark gray, scaly skin resembling ichthyosis hystrix. The palms and soles may be mildly affected, and alopecia and nail dystrophy may be seen. In patients with KID, erythroderma at birth disappears within a few days; erythematous, sharply marginated, keratotic plaques develop at about age 1 year and increase until puberty. The face, elbows and knees, palms and soles are involved, but the trunk is spared. In both syndromes, sensorineural hearing loss, frequent bacterial and fungal infections, and scarring alopecia are seen.39 Severe palmar–plantar involvement and vascularizing keratopathy are observed in KID; in HID, palmar–plantar involvement is mild, and only punctate keratitis is seen.

Sjögren-Larsson Syndrome CLINICAL FEATURES Sjögren-Larsson syndrome is a severe, autosomal recessive, neurocutaneous disease consisting of mental retardation, spasticity, and ichthyosis. The disorder is genetically homogeneous, with affected individuals exhibiting an enzymatic deficiency in fatty aldehyde dehydrogenase due to a wide range of deletions and point mutations in the encoding gene ALDH3A2.40,41 The generalized, yellow-brown, lichenified ichthyosis associated with SjögrenLarsson syndrome is of early onset and not specifically distinguishable from other widespread ichthyoses of the lamellar type. Erythema is mild and fades with age. HISTOPATHOLOGY Histologic sections exhibit acanthosis and some papillomatosis. Moderate compact hyperorthokeratosis characterizes the stratum corneum, but scattered foci of parakeratosis may be present. The granular layer is retained and may be thickened. Follicular hyperkeratosis is variably observed.1,7

CHAPTER 14 ■ ALTERATIONS OF THE STRATUM CORNEUM AND EPIDERMIS

DIFFERENTIAL DIAGNOSIS The diagnosis is made by the clinical recognition of the other components of the syndrome. In some reports of HID syndrome, vacuolated keratinocytes occur in the granular layer, with the nucleus surrounded by an empty halo and ringed by keratohyalin granules; that finding, along with the characteristic differences in clinical presentation, is helpful in distinguishing between the two disorders.

DIFFERENTIAL DIAGNOSIS Sjögren-Larsson syndrome cannot be discriminated histologically from autosomal recessive lamellar ichthyosis. The diagnosis is made by identification of the other components of the syndrome.

Palmoplantar Keratoderma As the isolated phenotype or an associated component of a syndrome, the palmoplantar keratodermas comprise a heterogeneous group of inherited diseases sharing the common feature of aberrant volar keratinization, occasionally in the setting of other ectodermal dysplasias.42

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The common forms are dominantly inherited; some less prevalent cases represent recessive transmission. The autosomal dominant palmoplantar keratoderma of Unna-Thost syndrome is considered the most common form of this group, but the nomenclature has been clouded by the discovery that the family originally described by Thost in the past century exhibits epidermolytic hyperkeratosis on microscopic examination, indicating overlap with the phenotype of palmoplantar keratoderma type Voerner.43 Palmoplantar keratodermas of the Meleda type and of the Papillon-Lefevre syndrome, which are often the most severe phenotypes, are recessive traits. Mutation in the cathepsin C gene is etiologic in Papillon-Lefevre syndrome. Some affected kindreds with nonepidermolytic palmoplantar keratoderma link genetically to the type I or II keratin gene clusters on chromosomes 17q and 12q.44 Most instances of epidermolytic palmoplantar keratoderma are caused by mutations in the gene for the palmand sole-specific keratin 9.45 In some instances, palmoplantar keratoderma is an acquired condition associated with underlying systemic disorders that predispose to its expression.46 Examples include lymphomas such as mycosis fungoides, myeloma and other internal cancers, acanthosis nigricans, and myxedema. Exposure to toxins such as dioxin and arsenic or to chemotherapeutic agents (eg, fluorouracil) may sometimes be etiologic. Keratoderma climactericum is the designation for the association with the postmenopausal or post-oophorectomy state. CLINICAL FEATURES Patients exhibit localized or diffuse and often marked hyperkeratosis of the palms and soles.47 The epidermolytic and nonepidermolytic variants are clinically indistinguishable. The onset may occur from birth to the fourth decade of life, although early onset is more common. The callouslike lesions are often well demarcated. The borders of the hyperkeratotic plaques may be erythematous. Spread onto the extensor surfaces may occur, especially in those with the Meleda type, and there may be hyperhidrosis, constricting bands with gangrene and autoamputation (as seen in Vohwinkel syndrome), thickening of the nails, and psoriatic-like lesions on other parts of the body. Keratoderma in patients with PapillonLefevre syndrome is associated with periodontosis, resulting in shedding of the permanent dentition. Maceration

due to hyperhidrosis is a feature of mal de Meleda. The Howel-Evans syndrome of palmoplantar keratoderma, which is genetically linked to 17q, is associated with squamous cell carcinoma of the esophagus later in life. Sclerodactyly, nail dystrophy, and squamous cell carcinoma of the affected skin are attributes of the autosomal dominant Huriez syndrome. Punctate keratoderma is a limited variant of varying age of onset characterized by firm, well-demarcated plugs of keratotic material located on normal volar skin, sometimes with a predilection for the skin creases. Rare associations of palmoplantar keratoderma include oculocutaneous tyrosinosis (corneal ulcers, painful volar punctate or more diffuse keratotic lesions, mental retardation), acrokeratoelastoidosis of Costa (with punctate lesions), hidrotic ectodermal dysplasia, and pachyonychia congenita. HISTOPATHOLOGY In all clinical varieties of palmoplantar keratodermas, marked hyperorthokeratosis of the corneum is present in association with thickening of the stratum granulosum. Additionally, acanthosis and some papillomatous changes are seen. Mild perivascular chronic inflammation occurs in the papillary dermis. Some patients display epidermolytic hyperkeratosis of the upper spinous and granular cell layers and scattered dyskeratotic cells (as found in, but apparently not limited to, Voerner syndrome). A pluglike compact column of parakeratosis within the stratum corneum is observed in the subtype of keratosis palmoplantaris punctata. A surface pit may overly the columnar focus. DIFFERENTIAL DIAGNOSIS Whereas the histologic pattern of nonepidermolytic cases is similar to that of the nonbullous lamellar ichthyoses, epidermolytic hyperkeratosis can be distinguished from the bullous ichthyosiform erythrodermas by correlation with the clinical features. Distinction from pityriasis rubra pilaris rests with the associated clinical findings.

Erythrokeratoderma Variabilis and Progressive Symmetric Erythrokeratoderma Erythrokeratoderma variabilis and progressive symmetric erythrokeratoderma are probably closely related variants of the same malady.48 Erythrokeratoderma variabilis is a rare, usually autosomal dominant disease that presents from birth

to early adulthood. The disorder is linked to mutations in the connexin genes.48 CLINICAL FEATURES Erythrokeratoderma variabilis manifests transient, polycyclic or circinate, bright patches of erythema that change in size, shape, and distribution over hours to days. The areas are bounded by a trailing scale and may be ringed by a thin, white line. They are commonly found on the extremities and buttocks, but the trunk and abdomen may also be involved. Affected areas are exacerbated by temperature extremes and stress. More stable, fixed, erythematous, hyperkeratotic plaques develop on the extensor surface of the extremities. Mild palmoplantar keratoderma may be seen in up to 50% of cases, and central nervous system abnormalities have been reported in some families. The lesions of progressive symmetric erythrokeratoderma resemble those of erythrokeratoderma variabilis, but their distribution is strikingly symmetric and limited to the extremities and buttocks, and they remain fixed after they appear. Although the two disorders are usually distinct, the occurrence of both—one each in sisters— suggests that they represent variants of the same process. HISTOPATHOLOGY Erythrokeratoderma variabilis is characterized by a normal granular cell layer underlying a hyperorthokeratotic stratum corneum. The epidermis is acanthotic and shows papillomatosis. The suprapapillary zones of the stratum spinosum may be thinned. The papillary dermis contains a perivascular lymphocytic dermatitis of variable intensity. Progressive symmetric erythrokeratoderma histologically shows hyperkeratosis with focal parakeratosis. The granular cell layer is normal to thickened. Perinuclear granular cell vacuolization may be seen. The spinous layer is acanthotic. DIFFERENTIAL DIAGNOSIS The histologic patterns of erythrokeratoderma variabilis and progressive symmetric erythrokeratoderma are nonspecific, resembling many of the nonbullous ichthyoses. The diagnosis rests with the clinicopathologic correlation.

Acanthosis Nigricans A relatively prevalent mucocutaneous disorder, acanthosis nigricans occurs in several clinically defined types, but most often it is found in association with obesity and insulin resistance and less commonly in an exuberant, paraneoplastic

form.49 The eruption is probably caused in most instances by circulating insulin and insulinlike growth factors acting on keratinocytes and other cutaneous cells that express the cognate growth factor receptor(s).

HISTOPATHOLOGY Despite the impression created by its name, there is usually little acanthosis; the epidermis is more often somewhat thinned and rather moderately to markedly papillomatous (Fig. 14-6). The papillomatosis has a blunted hill-anddale silhouette. The hyperkeratotic stratum corneum often retains the normal basket-weave architecture. Little, if any, perivascular lymphocytic infiltration of the papillary dermis is seen. DIFFERENTIAL DIAGNOSIS Distinction from seborrheic keratosis and hamartomatous epidermal nevi may occasionally be

Ichthyosis Follicularis (Follicular Ichthyosis) with Atrichia and Photophobia Syndrome CLINICAL FEATURES The essential phenotypic components of this syndrome are follicular ichthyosis often accentuated over the head and neck, generalized congenital nonscarring alopecia, and photophobia. Other common findings include mild generalized scaling with erythema, psychomotor and growth retardation, susceptibility to pyodermas, dentition abnormalities, and nail dystrophy.50 The strong gender predilection for males suggests an X-linked recessive inheritance. The expression of a contiguous gene defect may underlie the clinical variability of the disorder. HISTOPATHOLOGY Microscopic examination discloses moderate hyperorthokeratosis with follicular dilatation and plugging. The granular layer is preserved and

 FIGURE 14-6 Acanthosis nigricans. Pronounced hyperorthokeratosis in a basket-weave pattern overlies the papillomatous epidermis, but little acanthosis is seen.

may be thickened. Specimens of scalp skin reveal atrophy of the folliculosebaceous units and thinning of the dermis. DIFFERENTIAL DIAGNOSIS The retention of the granular layer allows distinction from autosomal dominant ichthyosis vulgaris and related disorders. The absence of epidermolytic hyperkeratosis excludes bullous ichthyosiform erythrodermas. Clinical features allow distinction from the keratosis pilaris syndromes.

Inherited Pityriasis Rubra Pilaris CLINICAL FEATURES Whereas most instances of the uncommon disease pityriasis rubra pilaris are sporadic, an inherited form exists and is observed most often juveniles.51 Inheritance is autosomal dominant. The underlying defect is unknown. The clinical lesions of pityriasis rubra pilaris are thick, erythematous, salmoncolored plaques that are localized to sites of predilection, such as the scalp, volar surfaces, and elbows and knees, or more generalized, eventuating into an exfoliative erythroderma. HISTOPATHOLOGY The epidermis is acanthotic and papillomatous, with elongation of the rete ridges that may create a psoriasiform pattern of hyperplasia.52 There may be widening of the intercellular spaces within the spinous layer. The stratum corneum is remarkable for marked hyperkeratosis, which in some foci exhibits horizontally alternating zones of ortho- and parakeratosis. The stratum granulosum is usually hypergranular. Dilatation and keratotic plugging of the follicular infundibulae are often reliably prominent features of pityriasis rubra pilaris and should be sought in additional recuts if the diagnosis is unclear from the original sections. The stratum corneum adjacent to the follicular ostia may show parakeratosis (shoulder parakeratosis). A slight perivascular lymphocytic infiltrate is observed in the papillary dermis. DIFFERENTIAL DIAGNOSIS The psoriasiform hyperplasia of pityriasis rubra pilaris may make distinction from psoriasis difficult or in some instances not possible, especially considering that alternating parakeratotic foci and variably thickened or absent stratum granulosum may be observed in the latter. However, the presence of neutrophilic foci within the corneum (Munro abscesses) and dermal papillae with lymphocytic infiltrates and dilated capillaries favor the interpretation of psoriasis, and there should be few, if any, dilated and keratotic follicular

CHAPTER 14 ■ ALTERATIONS OF THE STRATUM CORNEUM AND EPIDERMIS

CLINICAL FEATURES Although acanthosis nigricans may occur anywhere on the skin, the characteristic velvety hyperpigmented plaques of this disorder exhibit a predilection for the flexural sites of the axillae, nape, groin, and popliteal and antecubital fossae. Associated palmoplantar keratoderma (tylosis) may rarely occur in cases induced by internal malignancy. Occasionally, papillomatous epithelial hyperplasia may affect the conjunctiva and the stratified squamous mucosae of the oropharynx and anal canal.

necessary when the papillomatosis is pronounced; the usual absence of significant acanthosis helps rule out these considerations. Confluent and reticulate papillomatosis of Gougerot and Carteaud is generally not distinguishable histologically, but the flexural distribution of lesions of acanthosis nigricans compared with the more generalized distribution of confluent and reticulate papillomatosis permits clinical distinction of the two.

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infundibulae in the latter. Follicular plugging, although not an invariable feature, is helpful in resolving the differential diagnosis of other papulosquamous diseases when present. Discrimination from cases of nonbullous ichthyosiform erythrodermas may not be possible on histologic grounds alone.

PART II ■ PREDOMINANTLY NONINFLAMMATORY CONDITIONS

DISORDERS WITH HYPERPARAKERATOSIS There are few entities in which prominent parakeratosis is a clue to the diagnosis. More often, parakeratosis is found as a transient or inconstant feature in a disorder with hyperkeratosis developing in an orthokeratotic fashion. Among these are some cases of autosomal dominant ichthyosis vulgaris, lamellar ichthyoses, and Harlequin ichthyosis. Those entities are discussed under the sections reflecting their more constant histopathologic patterns.

Granular Parakeratosis Synonyms: Granular axillary parakeratosis Granular parakeratosis is a rare acquired condition thought to be a disorder of keratinization.53 Although an irritant contact reaction appears operative, other forms of mechanical irritation may also figure into the pathogenesis of these lesions. Recent studies on this entity suggest a basic defect in the processing of profilaggrin to filaggrin, resulting in a failure to degrade keratohyalin granules and to aggregate keratin filaments during cornification. Associated abnormalities of the cell surface structures and dysregulation of cornified envelope components may account for the retention hyperkeratosis.54 CLINICAL FEATURES Individuals of all ages ranging from younger than 1 year of age to the elderly present with intertriginous (most commonly axillary), erythematous, brown or red, scaly or keratotic papules and plaques that are often pruritic. Other sites, including the face, trunk, and buttocks, may also be involved. HISTOPATHOLOGY Characteristic histologic features include a conspicuously thickened stratum corneum with compact parakeratosis, slight epidermal hyperplasia (psoriasiform, papillomatous, or both), and a sparse perivascular lymphohistiocytic infiltrate (Fig. 14-7). Keratohyalin granules are diffusely present within the parakeratotic stratum corneum, and the retained granular layer manifests focal vacuolization.

322

 FIGURE 14-7 Granular parakeratosis. The stratum corneum is dramatically thickened with compact parakeratosis, psoriasiform epidermal hyperplasias, slight papillomatosis, and a perivascular lymphocytic infiltrate. Keratohyalin granules are diffusely present within the parakeratotic stratum corneum, and the retained granular layer manifests focal vacuolization.

DIFFERENTIAL DIAGNOSIS Granular parakeratosis must be distinguished from a number of inflammatory and noninflammatory conditions. Various psoriasiform dermatitides to be considered are psoriasis, pityriasis rubra pilaris, seborrheic dermatitis, allergic or irritant contact dermatitis, atopic dermatitis, nummular dermatitis, dyshidrotic eczema, nodules secondary to infestation, and dermatophyte and candidal infection. Psoriasis usually demonstrates a diminished granular layer and fairly regular psoriasiform hyperplasia. Pityriasis rubra pilaris shows alternating ortho- and parakeratosis. Seborrheic dermatitis frequently displays spongiosis and parafollicular parakeratosis. The various other dermatitides usually exhibit a spongiotic reaction pattern. The fungal infections are easily ruled out by stains for fungi. Noninflammatory processes, such as acanthosis nigricans, confluent and reticulated papillomatosis, seborrheic keratoses, and epidermal nevi, are excluded by the absence of basophilic granules within the parakeratotic layer.

Congenital Hemidysplasia, Ichthyosiform Erythroderma, Limb Defects Syndrome CLINICAL FEATURES This rare, congenital dermatosis, also known as CHILD

syndrome, is defined by unilateral nevoid skin lesions with features of ichthyosiform erythroderma and ipsilateral limb underdevelopment. The nevoid lesions, which may occur in the absence of the other components of the syndrome,55 may develop later in childhood and manifest as linear or diffuse erythematous plaques with waxy yellowbrown scales. The lesions may expand or resolve spontaneously. Because nearly all affected individuals are girls, inheritance is hypothesized to be X-linked dominant and lethal in hemizygous boys.56 Point mutations in NADPH (nicotinamide adenine dinucleotide phosphate) steroid dehyrogenase-like protein are etiologic in some cases.57 HISTOPATHOLOGY Histologic sections show epidermal acanthosis associated with papillomatous hyperplasia. Prominent foci of parakeratosis are found within a compact, hyperkeratotic stratum corneum.58 The granular layer is normal to thinned. Foamy histiocytes may be found in the dermal papillae, simulating verruciform xanthoma. DIFFERENTIAL DIAGNOSIS The histopathologic features are nonspecific. Pityriasis rubra pilaris, epidermal nevi, and erythrodermic psoriasis require consideration. Whereas the presence of alternating

zones of para- and orthokeratosis within the stratum corneum and follicular plugging and minimal inflammatory infiltrates permit the diagnosis of pityriasis rubra pilaris, Munro abscesses within the corneum and inflammatory infiltrates and capillary ectasia within the dermal papillae suggest a diagnosis of psoriasis.

Comèl-Netherton Syndrome with Ichthyosis Linearis Circumflexa or Congenital Ichthyosiform Erythroderma

HISTOPATHOLOGY The microscopic findings in skin specimens are similar across the variable clinical phenotype of either ichthyosis linearis circumflexa (most often) or ichthyotic (ichthyosiform) erythroderma.1 Accumulation of eosinophilic periodic acid Schiff (PAS)–positive material within the stratum corneum is the most characteristic criterion. Parakeratotic hyperkeratosis is marked, and the corneal layer often contains masses of pyknotic neutrophils. Although disputed in some reports, the granular layer is usually thinned and may be focally absent. A subcorneal cleft created by separation of much of the stratum corneum is frequently observed. The spinous layer is acanthotic, and papillomatosis is well developed (Fig. 14-8).7 The papillary dermis contains a marked perivascular lymphocytic infiltrate, which may be associated with spongiosis of the overlying epidermis and lymphocytic exocytosis. Electron microscopy reveals cytoplasmic inclusion bodies, probably lysosomes, in spinous and granular cells that are not seen in other ichthyoses. DIFFERENTIAL DIAGNOSIS The psoriasiform epidermal hyperplasia of ichthyosis

 FIGURE 14-8 Comèl-Netherton syndrome. A moderately thickened stratum corneum with parakeratotic foci is associated with a hyperplastic epidermis and a brisk superficial perivascular lymphocytic infiltrate.

linearis circumflexa may resemble psoriasis. The PAS-positive stratum granulosum, irregular elongation of the rete ridges, subcorneal clefting, when present, and lack of moundlike parakeratosis serve to distinguish between the two disorders. Nodose swelling of hair shafts due to trichorrhexis invaginata taken in context with the combined clinicopathologic phenotype of ichthyosis linearis circumflexa or ichthyotic erythroderma should permit reliable diagnosis in questionable cases.

Porokeratosis CLINICAL FEATURES Whereas the clinical spectrum of porokeratosis is diverse, the defining feature of all types, except for punctate porokeratosis, is the distinctive fine, threadlike rings corresponding to the histologic cornoid lamella at the perimeter of the clinical lesions, which are often gyrate or annular but may also be linear. These rings are numerous or sparse (even solitary) and may be situated at glabrous, volar, genital, and mucocutaneous sites. The clinically recognized varieties consist of the isolated, plaque-type lesions with central atrophy in porokeratosis of Mibelli (Fig. 14-9A); the common disseminated superficial porokeratosis consisting of small annular lesions sited on sunexposed extremities and determined to be linked to a susceptibility locus on chromosome 12q (Fig. 14-9 B); linear porokeratosis; porokeratosis plantaris,

palmaris, et disseminata; and a punctate form restricted to the palms and soles. Point mutations in the SART3 gene on chromosome 12q have been identified in kindreds affected with disseminated superficial actinic porokeratosis (DSAP).62 It has been suggested that the cornoid lamella is formed by atypical keratinocytes that are hyperproliferative and defective in keratinization, resulting in aberrant desquamation.63 Porokeratosis is associated with immunosuppression, and malignancies such as Bowen disease arise within these lesions, but the relative risk of malignant degeneration is unknown.64 Porokeratosis is also found incidentally as a nonspecific reaction pattern in a broad spectrum of other neoplastic and inflammatory disorders.

CHAPTER 14 ■ ALTERATIONS OF THE STRATUM CORNEUM AND EPIDERMIS

CLINICAL FEATURES A rare autosomal recessive disorder of unknown etiology, Comèl-Netherton syndrome presents clinically with a distinctive hair abnormality designated trichorrhexis invaginata (“bamboo hair”) and cutaneous signs of exfoliative ichthyosiform erythroderma, ichthyosis linearis circumflexa, or both, which consists of migratory or evanescent, erythematous patches fringed by a double-edged scale. The other clinical manifestations are variable but often include an associated atopic diathesis, recurrent infections, failure to thrive in infancy, enteropathy, and mild palmoplantar keratoderma.59 Mutations in the serine protease inhibitor SPINK5 are found in affected families.60,61

HISTOPATHOLOGY The histologic hallmark of all clinical varieties of porokeratosis is the cornoid lamella, which is sometimes distributed to both sides of a biopsy sample, delimiting a central zone of either acanthokeratosis or atrophy. It consists of a thin, layered column within the corneum created by parakeratotic corneocytes. This tier of cells is often obliquely oriented to the epidermal surface and appears to arise from a dell in the upper viable layers of the epidermis in association with a focal absence of the stratum granulosum (Fig. 14-9). Dyskeratotic cells are frequently observed in the subjacent upper spinous layer. Edema and patchy, bandlike infiltrates with scattered apoptotic

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A

B

C  FIGURE 14-9 Porokeratosis. (A) Porokeratosis of Mibelli. Coalescent erythematous papules and plaques with distinctive raised, fine, threadlike annulus at the periphery of each lesion corresponding to histologic cornoid lamella. (B) Disseminated actinic porokeratosis. Scattered small individual macules and papules are present, each with a subtle threadlike annulus on the chronically sun-exposed skin of an extremity. (C) The obliquely oriented cornoid lamella containing parakeratotic corneocytes has arisen from a superficial dell, the base of which contains several dyskeratotic cells.

bodies may be a feature within the papillary dermis subjacent to the inner zone of a porokeratotic lesion, particularly in the DSAP variant, in which the pattern may be lichenoid in quality.

324

DIFFERENTIAL DIAGNOSIS The cornoid lamella is a distinctive structure that is not usually confused with other processes, although its presence in tissue sections may be subtle and easily overlooked. Although it is the characteristic finding in porokeratosis, it is not completely specific to the diagnosis. A cornoid lamella may occasionally be found in variety of other

conditions, such as warts, solar keratosis, seborrheic keratosis, squamous cell carcinoma, and basal cell carcinoma. Clinicopathologic correlations or observation of other pathologic processes in the tissues are necessary to resolve the differential diagnosis in instances associated with incidental cornoid lamellae.

EPIDERMOLYTIC DISORDERS The unifying feature in the disorders assembled under this section is epidermal separation due to shearing through various levels of the basement membrane

zone or to vesiculation resulting from cytolysis or acantholysis of epidermal keratinocytes. The basal or suprabasal spinous cells are most often affected in the cytolytic and acantholytic diseases. These usually genetic disorders range from bullous variants of certain ichthyoses to the mechanobullous diseases associated with mutations in genes for keratins and other structural proteins. The diagnostic algorithm (Fig. 14-10) principally exploits the level of the separation within the epidermal layers and, secondarily, associated histologic changes of defective keratinization, if any. Table 14-5 summarizes

Level of separation

Basal cell/sub-basal lysis

Spinous layer separation

Epidermolysis bullosa simplex Dowling-Meara Koebner Weber-Cockayne Epidermolysis bullosa, junctional Epidermolysis bullosa dystrophica

Mode of separation

Cytolysis

Acantholysis

Yes

No

BCIE BCIE-Siemens Ichthyosis Hystrix Palmoplantar keratoderma (Voerner) Pachyonychia congenita (some) Peeling skin syndrome (some)

EBS-W/C

Yes

No

Darier disease Grover disease Hailey-Hailey (most)

Hailey-Hailey (some)

 FIGURE 14-10 Diagnostic algorithm for the epidermolytic disorders. The hierarchy for differential diagnosis follows primarily from the level of separation within the epidermis or basement membrane zone and secondarily from the mode of separation, whether cytolysis or acantholysis. BCIE = bullous congenital ichthyosiform erythroderma; EBS = epidermolysis bullosa simplex; W/C = Weber Cockayne.

Table 14-5 Differential Diagnosis of Epidermolytic Disorders HISTOLOGIC FEATURE DISORDER

LEVEL OF SEPARATION

MECHANISM OF SEPARATION

HYPERKERATOSIS

STATUS OF GRANULAR LAYER

ACANTHOSIS

OTHER

Epidermolysis bullosa simplex Epidermolysis bullosa junctional Epidermolysis bullosa dystrophica Bullous ichthyosiform erythroderma

Basal or spinous layer (or both) Basement membrane zone Beneath basement membrane Spinous and granular layers

Cytolysis

+ (occasional)

Normal to +

0

Focal dyskeratotic cells

Shearing through lamina lucida Shearing through anchoring fibril zone Epidermolytic hyperkeratosis

0

Normal

0

0

Normal

0

++ to +++

+ to ++

+ to ++

Palmoplantar keratoderma (Voerner type) Pachyonychia congenita Darier disease

Spinous and granular layers

Epidermolytic hyperkeratosis

++

+

+

Upper spinous layer

Cytolysis

++ to +++

++

+ to ++

Suprabasal layer

Acantholysis

+ to ++

+ to ++

+

Hailey-Hailey disease

Spinous layers

Acantholysis

0 to +

Normal to +

+-+

Grover disease Peeling skin syndrome

Suprabasal layer Subcorneal

Acantholysis Inter- or intracellular cleavage

+ +

+ Normal or thinned

0 to + + to ++

CHAPTER 14 ■ ALTERATIONS OF THE STRATUM CORNEUM AND EPIDERMIS

Hyperkeratosis?

Perivascular lymphocytic infiltrates Perivascular lymphocytic infiltrates Follicular plugging in some cases Corp ronds and grains “Dilapidated brick wall” appearance Perivascular lymphocytic infiltrates

325

the salient histologic features that may be used to facilitate the differential diagnosis of the epidermolytic diseases.

DISORDERS WITH BASAL LAYER OR BASEMENT MEMBRANE ZONE LYSIS

PART II ■ PREDOMINANTLY NONINFLAMMATORY CONDITIONS

The entities described here are limited to the clinicopathologic varieties of epidermolysis bullosa, which are mechanobullous diseases that have in common heritable lesions in genes coding for structural proteins of basal keratinocytes or for components of the basement membrane zone.

Epidermolysis Bullosa Simplex The genetically heterogeneous diseases grouped under epidermolysis bullosa simplex share an autosomal dominant inheritance, pathophysiologic changes of minor trauma–induced cytolysis within the basal or suprabasal keratinocytes, and the tendency for lesions to heal without scarring. Tonofilament clumps within basal and suprabasal keratinocytes are observed by electron microscopy in the Dowling-Meara variant; these structures contain the keratin pair 5 and 14 by immunolabeling. Point mutations occur in either gene (K5 or K14) in all clinical variants of epidermolysis bullosa simplex.65 The clinical severity is evidently determined in each affected kindred by the extent to which the specific mutation disrupts the functional properties of the gene product.66 Unusual variants of the disorder may result from mutations in other structural genes, such as the cell-linker protein plectin.67

A

326

CLINICAL FEATURES The phenotypes include the generalized Koebner variant; the Dowling-Meara variant, which is characterized by herpetiform clustering of blisters; and the localized (usually acral) Weber-Cockayne variant.68 The Weber-Cockayne variant may represent a mild variant of the Koebner variant. Whereas the Dowling-Meara and Koebner variants usually present early in infancy with blisters and erosions induced by minor trauma, the onset of the Weber-Cockayne variant is often delayed. Mucosal lesions, minor scarring, nail shedding, and widespread erosions with a risk of secondary pyogenic infection occur in severely affected patients. Spontaneous improvement is sometimes seen in later childhood and adulthood. HISTOPATHOLOGY In all variants of epidermolysis bullosa simplex, vesicles form by cytolysis within the basal or lower spinous cell layers (Fig. 14-11).69 Histologic sections thus show focal dissolution of the basal or spinous keratinocytes, resulting in epidermal separation through that layer. Dyskeratotic changes may manifest histologically within the cells, especially in the DowlingMeara variant. On occasion, the DowlingMeara and Koebner variants have been associated with palmoplantar keratoderma in which the histologic sections exhibit compact hyperorthokeratosis and a variably thickened granular layer in addition to the cytolytic changes within the keratinocytes. DIFFERENTIAL DIAGNOSIS In the DowlingMeara subtype, the separation may occur deep in the basal layer such that by

light microscopy it appears that the entire epidermis has formed the roof of the blister; this may simulate the findings in junctional epidermolysis bullosa and may require electron microscopy or immunomapping of basement membrane components for resolution of the level of the separation. The DowlingMeara variant is distinguished from the other two varieties by herpetiform clustering of the clinical lesions and by keratin filament clumping on electron microscopy of lesional skin samples.

Epidermolysis Bullosa, Junctional (Letalis) Junctional epidermolysis bullosa includes several genetically heterogeneous diseases70 that, although phenotypically variable, share autosomal recessive transmission and subepidermal separation through the lamina lucida of the basement membrane zone due to reduced numbers of hemidesmosomes.71 Mutations in the peptide subunits of laminin 5 (epiligrin) and, occasionally, the 180-kDa bullous pemphigoid antigen, both of which are lamina lucida components, are etiologic in most cases.72 More severe phenotypes are linked to premature termination codon mutations in both alleles of one of the three laminin 5 subunit genes, LAMB3, but the less severe variants are associated with slice junction or missense mutations of one allele in trans to a premature termination codon mutation of the other.73 CLINICAL FEATURES The most severe clinical presentation occurs in the Herlitz syndrome (epidermolysis bullosa letalis), which exhibits widespread cutaneous and

B

 FIGURE 14-11 Epidermolysis bullosa, Dowling-Meara variant. (A) Basal and suprabasal keratinocytes display prominent cytolytic degeneration. (B) The more superficial epidermal layers appear normal.

mucosal blisters and erosions soon after birth, usually proving fatal within the first one to two years of life. Less severe (nonHerlitz) forms of junctional epidermolysis bullosa exhibit qualitatively similar changes but differ in the extent of the cutaneous and mucosal blisters and erosions, allowing a normal lifespan, albeit with lifelong blistering. Many of the latter forms display abnormal dental enamel development, which imparts a cobblestone appearance to the teeth.

DIFFERENTIAL DIAGNOSIS By light microscopy, junctional epidermolysis bullosa may be simulated by dystrophic variants of that disease spectrum or by subepidermal autoimmune vesiculobullous disorders such as bullous pemphigoid. The clinical context will direct the histopathologic interpretations along the appropriate pathways. Resolution of the differential diagnosis for the mechanobullous disorders is usually obtained by immunolabeling for markers of basement membrane components, such as type IV collagen and laminin, to localize the plane of separation or by electron microscopy. The autoimmune disorders are confirmed

Epidermolysis Bullosa Dystrophica Epidermolysis bullosa dystrophica is genetically heterogeneous, with either autosomal dominant or recessive inheritance. Cases of dystrophic epidermolysis bullosa have long been known to demonstrate morphologic abnormalities of the anchoring fibrils, which are structures distributed below the basal lamina.74 Type VII collagen was an early candidate for the etiologic molecular defect because it is a major collagenous component of the anchoring fibrils. Immunolabeling for type VII collagen demonstrates either reduced content or disarrayed organization of this component. Genetic studies confirmed linkage between markers for the collagen VII locus on chromosome 3 and both the dominantly and recessively inherited clinical phenotype; mutational analyses subsequently confirmed mutations in the COL7A1 gene.75,76 CLINICAL FEATURES As a reflection of genetic heterogeneity, the clinical severity of epidermolysis bullosa dystrophica varies widely. On one hand, the recessive form (Hallopeau-Siemens syndrome) presents in infancy with extensive blistering and scarring of the entire cutaneous and squamous mucosal surfaces of the oropharynx, anus, and esophagus, eventuating in mutilating deformities, shedding

 FIGURE 14-12 Epidermolysis bullosa, junctional. Separation has occurred beneath the basal keratinocyte layer but superficial to the eosinophilic basement membrane.

of nails, joint contractures, pseudosyndactylies, enteric strictures, and increased risk of squamous cell carcinoma, which may be clinically aggressive.75,77 The phenotype of the dominant form, although also exhibiting mechanically induced blisters and secondary scarring, is much less severe. HISTOPATHOLOGY Due to molecular defects in the subepidermal anchoring fibrils, histologic sections show separation of the entire epidermis from the dermis, with the PAS-positive basement membrane segregating to the epidermal roof of the blister cavity. DIFFERENTIAL DIAGNOSIS Ambiguities in the differential diagnosis are resolved by immunostaining for type IV collagen or electron microscopy to localize the plane of separation below the lamina densa, confirming that the basal lamina remains attached to the epidermis. Immunostaining also demonstrates reduced labeling for collagen type VII in the anchoring fibril zone.

DISORDERS WITH SPINOUS LAYER VESICULATION DUE TO CYTOLYSIS OR ACANTHOLYSIS The entities grouped under this category range from hereditary ichthyoses featuring the distinctive histologic change of epidermolytic hyperkeratosis to vesiculobullous disorders displaying the common feature of spinous layer acantholysis (eg, acantholytic dyskeratosis). Epidermolytic hyperkeratosis is a morphologic manifestation of congenital or acquired disorders of keratinocytic maturation that may be focal or diffuse. It is defined by hyperkeratosis and suprabasilar vacuolar and reticular degeneration (cytolysis) of the strata spinosum and granulosum. Epidermolytic hyperkeratosis is the hallmark feature of generalized ichthyosis known as bullous congenital ichthyosiform erythroderma and of related but more anatomically restricted disorders of either the glabrous or volar skin, such as ichthyosis bullosa of Siemens, ichthyosis hystrix of Curth and Macklin, some epidermal nevi (hamartomas), and palmoplantar keratosis of Voerner. Epidermolytic hyperkeratosis is also found rather commonly as a focal histologic phenomenon in unrelated lesions, including melanocytic nevi, seborrheic keratoses, actinic keratoses, acrochordons, and inflammatory dermatoses, or in morphologically normal skin. A solitary lesion of epidermolytic

CHAPTER 14 ■ ALTERATIONS OF THE STRATUM CORNEUM AND EPIDERMIS

HISTOPATHOLOGY Separation occurs beneath the basal cell layer but above the lamina densa (Fig. 14-12) due to dissolution of the lamina lucida, as shown by electron microscopy. Histologic sections reveal a plane of separation formed between the epidermis and the basement membrane zone. By PAS staining, the basement membrane remains on the dermal side of the split.

diagnostically by the characteristic patterns of autoantibody deposition as shown by direct immunofluorescence methods.

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PART II ■ PREDOMINANTLY NONINFLAMMATORY CONDITIONS 328

hyperkeratosis presenting as a wartlike papule is designated epidermolytic acanthoma. The histologic pattern of suprabasilar vesiculation accompanied by acantholysis and dyskeratotic cells defines acantholytic dyskeratosis. The blistering is usually apparent only at the histologic, not clinical, level. The clinical phenotype of acantholytic dyskeratosis ranges broadly from the focal and incidental acantholytic dyskeratoma on the skin or squamous mucosa and warty dyskeratoma to an uncommon linear form in zosteriform epidermal nevi and to more generalized entities that are acquired and often transient (Grover disease) or are of genetic etiology and persistent (Darier disease). The more generalized entities manifesting acantholytic dyskeratosis are described after descriptions of the epidermolytic, hyperkeratotic disorders. The uncommon, localized disorders that are incidental clinical curiosities (eg, acantholytic dyskeratoma, warty dyskeratoma) are not discussed further in this chapter except as differential diagnostic considerations.

Bullous Congenital Ichthyosiform Erythroderma (Epidermolytic Hyperkeratosis and Bullous Ichthyosis) This dominantly inherited, uncommon dermatosis presents with generalized erythroderma, severe scaling, and blistering. Cornrowlike scaling accumulates in the antecubital fossae, axillae, and over the knees and dorsal ankles. Original ultrastructural studies of ichthyosiform erythroderma indicated clumping and aggregation of suprabasal keratin filaments (tonofilaments) at the cell periphery,78 suggesting molecular defects in keratin genes. Genetic linkage studies demonstrated cosegregation of the trait and markers for the type I and II keratin loci on chromosomes 17q and 12q, and mutational analyses showed that point mutations in the critical rod domains of both suprabasal keratins 1 and 10 associated with the phenotype.79 The etiologic role of the keratin mutations has been established experimentally by expression of mutant keratin alleles in transgenic mice that reproduce the phenotype.80 In some families, somatic mutations with associated epidermal nevi exhibiting the histologic changes of epidermolytic hyperkeratosis have resulted in generalized bullous congenital ichthyosiform erythroderma in subsequent generations as a result of gonadal mosaicism.

Table 14-6 Bullous Congenital Ichthyosiform Erythroderma

Clinical Features Onset at birth or early childhood Erythema, blistering, and verrucous plaques, usually widespread Flexural accentuation Abatement of blistering with age Histopathologic Features Massive hyperorthokeratosis Thickened granular layer with coarse keratohyalin granules Acanthotic spinous layer with epidermolytic changes Differential Diagnosis Ichthyosis bullosa of Siemens Palmoplantar keratoderma, Voerner type Incidental finding in hyperproliferative epidermal disorders

CLINICAL FEATURES Epidermolytic hyperkeratosis is clinically heterogeneous, but the phenotype is relatively uniform within affected kindreds81,82 (Table 14-6). In most cases, widespread erythema, blistering, and hyperkeratotic verrucous plaques are noted at birth or during childhood, frequently with accentuation in the flexures. Clinical blistering often abates after the first few years of life. The presence or absence of palmoplantar keratoderma distinguishes some pedigrees.

HISTOPATHOLOGY Microscopically, all cases exhibit massive hyperorthokeratosis, in either a compact, or more often, a basketweave pattern.1,7 The granular layer is thickened and contains coarse keratohyalin granules. The acanthotic epidermis is distinctive for cytoplasmic edema and perinuclear vacuolization affecting the keratinocytes of the granular and spinous cell layers. The basal and, occasionally, the suprabasal keratinocytes appear normal. The hydropic changes create indistinct boundaries between the epidermolytic cells and a reticular pattern of degeneration, referred to as epidermolytic hyperkeratosis or acanthokeratolysis (Fig. 14-13). When fully evolved in the pattern of epidermolytic hyperkeratosis, vesiculation occurs through the upper spinous to granular layers, the roof of which is formed by thickened stratum corneum and the floor by edematous keratinocytes. A slight to moderate perivascular lymphoid infiltrate is contained in the superficial dermis. DIFFERENTIAL DIAGNOSIS Bullous congenital ichthyosiform erythroderma is distinguished from ichthyosis bullosa of Siemens by clinical differences and by involvement of the entire suprabasal epidermal compartment; the cytolytic changes in the latter disorder are restricted to the upper spinous and granular layers. Epidermolytic hyperkeratosis is not specific to these bullous ichthyoses because it is commonly observed as an incidental

 FIGURE 14-13 Bullous ichthyosiform erythroderma. The markedly acanthotic and hyperkeratotic epidermis exhibits prominent epidermolysis at the levels of the mid- to upper spinous and granular cell layers. The widened stratum granulosum contains coarsely clumped keratohyalin granules.

finding contiguous to melanocytic nevi and hyperproliferative disorders of the epidermis, including linear epidermal nevus, verrucae, actinic keratosis, squamous cell carcinoma, seborrheic keratosis, solitary epidermolytic acanthoma, sundry inflammatory conditions, and some (Voerner-type) palmoplantar keratodermas. Diagnosis in those situations is contingent on recognition of the associated findings that are distinctive for each disorder. The epidermolytic palmoplantar keratodermas are diagnosed from the corresponding clinical presentation.

Ichthyosis Bullosa of Siemens

CLINICAL FEATURES Dark gray, hyperkeratotic lesions are restricted to certain sites of predilection, which include the shins, para-articular (flexural) areas, and periumbilical areas. Characteristic superficial blistering with subsequent shedding of the affected skin (“molting”) and erosions may occur after mild trauma and with sweating.86 HISTOPATHOLOGY The principal histologic change is that of epidermolytic hyperkeratosis, which is limited to the upper strata of the epidermis and is generally less well developed and less extensive than in bullous congenital ichthyosiform erythroderma.87 Tonofilaments forming perinuclear aggregates are seen on electron microscopy. Mild acanthosis may also be a feature. DIFFERENTIAL DIAGNOSIS The histologic differential diagnosis is similar to that for bullous congenital ichthyosiform erythroderma. Ichthyosis bullosa of Siemens is discriminated clinically from the former by the absence of erythroderma, by the more limited distribution of the keratotic lesions, and by the characteristic formation of superficial blisters.

This rare ichthyotic disease is inherited as an autosomal dominant trait. Ultrastructurally, the hyperkeratotic lesions show disruption of the keratin filament network of the suprabasal keratinocytes. Immunolabeling studies for keratin expression have shown that both normal-appearing and lesional skin persistently express fetal keratins.87 Frameshift mutations in the variable tail domain of keratin gene KRT1 underlie the disorder.88 CLINICAL FEATURES The clinical onset of ichthyosis hystrix is usually in childhood. The hyperkeratotic and papillomatous, coalescent papules and verrucous, linear plaques may be localized or distributed extensively and bilaterally in whorled or arborizing arrays of thickened, darkened (hystrixlike) scales anywhere on the skin surface. A palmoplantar involvement is variable. HISTOPATHOLOGY The distinctive pattern of epidermolytic hyperkeratosis is found against the backdrop of mild hyperorthokeratosis, acanthosis, papillomatosis, and elongation of the rete ridges. In the epidermolytic areas, perinuclear vacuolization occurs within the granular and upper spinous layer keratinocytes, with irregularity of cell borders progressing to reticular degeneration. Hypertrophy of the granular layer, which contains coarse keratohyalin granules, is seen. A slight to moderate perivascular lymphoid infiltrate is present in the superficial dermis.

which the designation Voerner is eponymously assigned. The condition has been linked to mutations in the 1A domain of the keratin 9 gene, the expression of which is restricted to the suprabasal zone of the palms and soles.45,78,89,90 Some kindreds with mild epidermolytic palmoplantar keratodermas harbor mutations in keratin 1.91 CLINICAL FEATURES The clinical presentation of diffuse palmoplantar keratoderma does not allow distinction of the epidermolytic variant of Voerner from the ostensibly nonepidermolytic variety described by Unna and Thost. The volar lesions typically are sharply demarcated with erythematous borders. The lesions may be associated with knuckle-pad– like changes and nail clubbing.92 HISTOPATHOLOGY Changes of epidermolytic hyperkeratosis in the upper spinous and granular cell layers are associated with mild orthohyperkeratosis, acanthosis, and papillomatosis.93 A slight to moderate perivascular lymphoid infiltrate is present in the superficial dermis. Clumping of suprabasal keratins is found by electron microscopy. DIFFERENTIAL DIAGNOSIS The differential diagnosis is that discussed under bullous congenital ichthyosiform erythroderma. The clinical presentation, however, appropriately focuses the diagnostic considerations to the palmoplantar keratodermas.

Pachyonychia Congenita

Palmoplantar Keratoderma of Voerner (Epidermolytic Palmoplantar Keratoderma)

Heterogeneous dyskeratotic and dysplastic alterations of ectodermal tissues are characteristic of pachyonychia congenita, a rare, genetically heterogeneous trait that is transmitted in an autosomal dominant manner with variable expressivity.94 Genetic linkage analyses have established that the loci for the more common Jadassohn-Lewandowsky variant and the rarer Jackson-Lawler subtype map to chromosome 17q in close proximity to the type I keratin gene cluster; mutations in keratin 6a account for some cases of the former variant,95 and defective alleles for keratins 16 and 17 are etiologic for the latter subtype.96,97 The seemingly pleiotropic phenotypes reflect the tissue-specific distributions of the variously defective keratin gene products.98

Some kindreds with the autosomal dominant form of diffuse palmoplantar keratoderma show epidermolytic hyperkeratosis on biopsy of the affected skin, to

CLINICAL FEATURES Onset of pachyonychia congenita is usually in early infancy, but tardive presentation into the teenage

DIFFERENTIAL DIAGNOSIS Ichthyosis hystrix (Curth-Macklin type) is distinguished by a discrete dark shell around the nuclei of spinous cells and by the presence of binucleate cells.1 By electron microscopy, a continuous shell of intermediate filaments is seen separating the perinuclear compartment, which often contains vacuoles, from an outer, cytoplasmic compartment. Otherwise, the differential diagnosis is that discussed under bullous ichthyosiform erythroderma.

CHAPTER 14 ■ ALTERATIONS OF THE STRATUM CORNEUM AND EPIDERMIS

This mechanobullous condition is an autosomal dominant disease characterized by a mild, nonerythrodermic clinical phenotype with microscopic changes of epidermolytic hyperkeratosis limited to the granular layer and upper stratum corneum in lesional skin.83 There is clinical and histologic overlap with bullous congenital ichthyosiform erythroderma. Ichthyosis bullosa links genetically to the type II keratin gene cluster on chromosome 12q,83 and most cases are caused by point mutations in the differentiation specific keratin, 2e, which is expressed in the upper spinous and granular layers.84,85

Ichthyosis Hystrix of Curth and Macklin

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years may occur. In the hallmark manifestation of the disorder, symmetrically thickened nails are present in all patients, but the other components of the clinical syndrome are variable.99 The nail involvement, termed pachyonychia, consists of subungual hyperkeratosis in which keratinous material sequentially lifts the nail plate from the bed in a proximal to distal gradient, resembling a ski jump in profile. The more common JadassohnLewandowsky variant exhibits pachyonychia; palmoplantar keratoderma with tender blisters; pedal callosities; hyperhidrosis; and erosions, follicular hyperkeratosis, and leukokeratotic changes of the oral mucosa (resembling white sponge nevus). Multiple epidermoid inclusion cysts, natal teeth, and hair abnormalities (including alopecia) characterize the rarer Jackson-Lawler subtype. HISTOPATHOLOGY The principal histologic changes of involved, thickened skin are marked hyperorthokeratosis, papillomatosis, acanthosis, and moderate hypergranulosis; focal parakeratosis and follicular plugging may also be present. Sections may display an upper spinous layer vesicle created by prominent intracellular edema. The papillary dermis contains a sparse perivascular lymphocytic infiltrate. DIFFERENTIAL DIAGNOSIS In cases without intraspinous vesiculation, the histologic pattern may be indistinguishable from lamellar and X-linked recessive ichthyoses. However, the clinical presentation, especially the pachyonychia, is distinctive.

established as the locus for Darier disease.101 Spontaneous mutations account for some cases. CLINICAL FEATURES The clinical onset of Darier disease ranges from childhood to the early adult years. The lesions are hyperkeratotic, crusted, erythematous papules coalescing as plaques, often with a follicular localization, that are predisposed to seborrheic areas, especially the presternal skin; however, flexural, volar, and oral mucosal lesions also occur occasionally.102 Clinical variants include hypertrophic, vesicular, and linear lesions. Distinctive nail changes are present in most patients and are often associated with palmar pits and keratoses.103 Neuropsychiatric disorders, including mental retardation, cosegregate in some families. Darier disease confers an infection-prone diathesis to a range of fungal, bacterial, and viral pathogens, which in turn exacerbate the clinical condition. The disorder typically has an unremitting course. HISTOPATHOLOGY The characteristic pattern of acantholytic dyskeratosis in Darier disease occurs in association with epidermal papillomatosis, acanthosis, and hyperkeratosis. Acantholytic changes giving rise to microscopic lacunae and dyskeratosis develop in the immediate suprabasal zone (Fig. 14-14). Villus structures lined by single cell layers of basal keratinocytes are created by the apparent

upward proliferation of the dermal papillae into these lacunae. Lying free within the lacunae are dyskeratotic spinous keratinocytes, which have lost their intercellular bridges and may have prematurely keratinized. In the upper epidermis, the acantholytic cells take the morphologic forms of corp ronds and grains. Corp ronds reside in the upper spinous and granular layers and consist of acantholytic cells with homogeneously pyknotic nuclei; a clear pericellular halo; and refractile, eosinophilic cytoplasms. Grains are smaller counterparts within the stratum granulosum or higher, displaying pericellular halos and sparse cytoplasms and resembling (but more plump than) parakeratotic corneocytes. The folliculosebaceous elements may have infundibular dilatation and plugging. A perivascular mixed lymphocytic infiltrate occurs in the superficial dermis. Variants of Darier disease include vesiculobullous lesions, created by large lacunae, and hypertrophic lesions, with accentuation of downward proliferation by the rete. DIFFERENTIAL DIAGNOSIS The pattern of acantholytic dyskeratosis is not specific to Darier disease because it is often found in warty dyskeratoma, Grover disease, and focal acantholytic dyskeratoma and may reside as an incidental finding in diverse lesions, such as verrucae, basal cell carcinoma, keratoacanthoma, psoriasis, and angiomata. Although also

Darier Disease (Darier-White Disease and Keratosis Follicularis)

330

An uncommon dominantly inherited dermatosis, Darier disease manifests as focal keratinocyte defects in intercellular adhesions that are restricted to the sites of the clinical lesions. Fine structure studies have suggested that the initial event in the lesions is separation of the paired desmosomal plaques, followed by retraction of the tonofilaments from their attachment sites in the plaques and redistribution to a perinuclear pattern; dyskeratosis occurs after the initiating acantholytic event. The mutant genetic locus responsible for Darier disease is highly penetrant100 and has been mapped to chromosome 12q, but genes for keratins and other known epidermal proteins were excluded as candidate loci. The gene ATP2A2, which encodes the endosarcoplasmic reticulum calcium ATPase isoform 2, is now

 FIGURE 14-14 Darier disease. Prominent suprabasal acantholysis is present in association with dyskeratotic cells (corp ronds and grains), hypergranulosis, and hyperkeratosis.

evident on occasion in Hailey-Hailey disease, the latter disorder usually exhibits few corp ronds or grains and more widespread acantholysis; this differential diagnosis is further discussed under Hailey-Hailey disease.

Hailey-Hailey Disease

CLINICAL FEATURES The disease often presents in the second to fourth decades of life with vesicles, bullae, and chronic erosive plaques on the neck and in flexural sites, especially the axillae, inframammary folds, and groin, that are well demarcated, often arcuate, and spread centrifugally. They are subject to exacerbation by perspiration, secondary infection, friction, and heat105 (Table 14-7) and confer a burning sensation or mild itch. Uncommon morphologic variants include dermatitic, verrucoid, and papular lesions. Although the condition is chronic, remissions occur, and spontaneous improvement may occur later in

HISTOPATHOLOGY The most typical finding in patients with Hailey-Hailey disease is widespread acantholysis of the spinous layer, which characteristically involves at least half the thickness of the epidermis. Acanthosis is usually present. Whereas numerous completely acantholytic cells may be situated free within the resulting intraspinous vesicles, other regions of contiguously affected cells are not completely separated but rather remain partially tethered to each other (Fig. 14-15). When fully developed, this suprabasal change gives an appearance that has been aptly likened to a “dilapidated brick wall.” As in Darier disease, villus projections of elongated papillae lined by a single row of basal cells often project into the lacunae and bullae. The acantholytic cells generally retain an otherwise normal appearance without morphologically apparent dyskeratosis, but focally, the latter may develop and may resemble the corp ronds and grains of Darier disease. DIFFERENTIAL DIAGNOSIS Hailey-Hailey and Darier diseases share common features of suprabasal acantholysis and formation of villus structures that protrude into separations created by acantholytic

keratinocytes. In Darier disease, however, the separations take the form of small lacunae, contrasted with larger vesicles and bullae resulting from more widespread acantholysis in HaileyHailey disease. Moreover, dyskeratosis is typically a feature of Darier disease and is associated with the development of corp ronds and grains. The discrimination of Hailey-Hailey disease from pemphigus vulgaris may be difficult because the initial pathologic process in each disorder is suprabasal acantholysis. In pemphigus, however, less acantholysis is present overall, and the separations are often strikingly restricted to the cell layer immediately superficial to the basal keratinocytes, lacking the “dilapidated brick wall” effect of Hailey-Hailey disease. When present, the finding of intralesional eosinophils supports the diagnosis of pemphigus vulgaris. Definitive resolution of the differential diagnosis requires direct immunofluorescence assay for display of the characteristic intercellular autoantibody deposition in pemphigus but not in Hailey-Hailey disease.

Grover Disease (Transient Acantholytic Dermatosis) A common, acquired abnormality, Grover disease is a non–immune-mediated acantholytic disorder of the epidermis that affects middle-aged or elderly men most often.106,107 The onset is often acute, and the duration may be transient or persistent

Table 14-7 Hailey-Hailey Disease

Clinical Features Onset in the second to fourth decades of life Bullae and erosions at flexural sites that are exacerbated by friction and heat Dermatitic, verrucoid, and papular variants Histopathologic Features Widespread acantholysis affecting more than half of the spinous layer “Dilapidated brick wall” appearance Infrequent dyskeratotic cells Villi projecting into lacunae Acanthosis Differential Diagnosis Grover disease Darier disease Pemphigus vulgaris

 FIGURE 14-15 Hailey-Hailey disease. Acantholysis affects the suprabasal to mid-spinous layers in an incomplete fashion that has resulted in keratinocytes remaining partially tethered to one another, giving the impression of a “dilapidated brick wall.”

CHAPTER 14 ■ ALTERATIONS OF THE STRATUM CORNEUM AND EPIDERMIS

Hailey-Hailey disease represents a widespread subclinical abnormality of cell adhesion mediated by dissolution of desmosomal plaques.103 Its clinical manifestations, however, are usually restricted to intertriginous anatomic regions that are subject to friction, maceration, and opportunistic infection. This uncommon disorder is genetic, segregating as an autosomal dominant trait linked to chromosome 3q21, and the responsible locus is ATP2C1, which encodes a calcium transport ATPase; regulation of cytoplasmic calcium is defective in cultured keratinocytes from patients with the disease.104

the adult years. With rare exceptions, the mucous membranes are unaffected. The erosions are often secondarily infected. Longitudinal white bands may be found in the nail beds.

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for several years. Structural alterations and dysfunction of keratinocyte adhesion molecules are characteristic of the lesions. Fine structure studies have described dissolution of the components of the desmosomal attachment plaque.103 Although resembling Darier disease, Grover disease does not share an abnormality in the ATP2A2 gene.108 CLINICAL FEATURES Intensely pruritic papules, and occasionally papulovesicles, occur predominantly on the trunk and less often on the buttocks and thighs. A history of fever, excessive perspiration, or occlusion of the affected skin (such as from enforced bed rest) are variable features. Other inflammatory dermatoses, such as eczemas, psoriasis, and Sweet syndrome, may coexist, and some cases are apparently initiated by ultraviolet radiation or chemotherapeutic pharmaceuticals. HISTOPATHOLOGY The principal microscopic finding consists of small foci of spinous layer acantholysis (Fig. 14-16). The spectrum of acantholysis in Grover disease includes both superficial and deep variants, which respectively mimic pemphigus foliaceus and vulgaris. Most often, however, the acantholytic change takes the form of that found in either pemphigus vulgaris or Darier disease, with acantholytic dyskeratosis. On occasion, the histologic image of Hailey-Hailey disease is simulated, or uncommonly, the predominant feature is spongiosis but with

little acantholysis. In some individuals, the histologic pattern may be mixed. The acantholytic focus is usually subtended by a mixed lymphoid reaction arrayed about the vessels of the superficial plexus, with a variable eosinophil component, which, when present, assists with the diagnostic exclusion of Darier disease. DIFFERENTIAL DIAGNOSIS The histopathologic pattern found in Grover disease differs from that of each disease it simulates by the multifocal presentation of small microscopic foci of acantholysis. In dubious instances, the differential diagnosis may be resolved by reference to the clinical presentation, which is generally distinctive for each of the entities simulated histologically by Grover disease.

Peeling Skin Syndrome Several rare syndromes have been described that share the cardinal feature of peeling of the skin.1,109,110 Two distinct phenotypes, A and B, have been described. In type A, no associated abnormalities are described; in type B, variable findings include decreased plasma tryptophan levels, elevated serum copper and iron levels, aminoaciduria, and elevated serum IgE levels. The presentation is frequently congenital, and inheritance patterns have suggested autosomal recessive transmission, often with a history of parental consanguinity. Autoreactive antibodies do not mediate the disorders. A missense mutation in the transglutaminase gene TGM5 is

etiologic in the localized acral variant of the syndrome but apparently not in the more generalized condition.111 The protein product of TGM5 localizes to the stratum granulosum, where it cross-links structural proteins, forming the cornified envelope in the terminal differentiation of the epidermis; defective function of the transglutaminase compromises cell–cell adhesion in the outermost strata of the epidermis. CLINICAL FEATURES Patients with type A peeling skin syndrome display generalized, asymptomatic, noninflammatory skin peeling. In contrast, patients with type B present clinically with generalized patches of peeling skin in association with inflammation and pruritus. A localized, acral variant affecting the dorsal surfaces has also been defined.112 The palms and soles may exhibit keratoderma, and dystrophic nail changes and easily plucked hair are commonly associations. HISTOPATHOLOGY The stratum corneum is hyperkeratotic. The upper epidermis characteristically separates, with the histologic split forming between the stratum corneum and stratum granulosum or in the lower stratum corneum. One report documents splitting within keratinocytes in a patient with type A, but the split appears to be intercellular in patients with type B. In patients with type B, psoriasiform epidermal hyperplasia with both hyperkeratosis and parakeratosis may be present. The granular layer may be either retained or lacking, the keratohyalin granules may appear abnormal, and considerable acanthosis with elongated rete ridges and an underlying chronic perivascular lymphocytic dermatitis in the papillary dermis may be present. DIFFERENTIAL DIAGNOSIS In histologic sections not displaying the subcorneal separation, the differential diagnosis for disorders histologically resembling autosomal dominant ichthyosis vulgaris requires resolution. Epidermal separation at or near that found in peeling skin syndrome may be observed in staphylococcal-scalded skin syndrome and pemphigus foliaceus, but acantholytic cells occur focally in the latter disorders.

THE PERFORATING DERMATOSES

332

 FIGURE 14-16 Grover disease. This microscopic lacuna, which has been created by acantholysis restricted to the suprabasal keratinocytes, contains dyskeratotic cells and is lined at the base by cells anchored to the basement membrane. Corp ronds and grains are situated in the upper epidermal strata.

Four primary perforating dermatoses— Kyrle disease, perforating folliculitis, reactive perforating collagenosis, and elastosis perforans serpiginosa—have traditionally been defined among the conditions

tance patterns in some kindreds diagnosed with reactive perforating collagenosis have raised the possibility of a genetic diathesis in those instances.121 CLINICAL FEATURES The florid (Kyrle disease–like) presentation is rare, but the milder phenotype is rather common in the setting of chronic renal failure, diabetes, or (less commonly) liver disease (Table 14-8).119,120,122 At clinical presentation, which may occur at any age, there may be few to many lesions, which are often localized to the legs, or the onset may be more generalized to all extremities and the torso, with a predilection for the extensor surfaces. The mucous membranes and volar surfaces are spared. The condition is characteristically pruritic but not invariably so. The early lesions are pinhead-sized follicular and extrafollicular papules that resemble keratosis pilaris.115 With progression, the lesions evolve into larger, red-brown or purplish papules and nodules or occasionally plaques and tend to remain nonconfluent. Mature lesions display a central cuplike depression containing a conical, keratinaceous plug. An isomorphic (Koebner) response is frequent. It is uncommon for the condition to remit spontaneously, but improvement may occur after renal transplantation.

Table 14-8 Acquired Perforating Dermatosis

Clinical Features Onset at any age, with few to many lesions and a predilection for the extensor surfaces Commonly associated with chronic renal failure and diabetes mellitus Koebnerization Pruritic, nonconfluent follicular or extrafollicular papules Central, conical keratinaceous plug Histopathologic Features Keratotic plug within epidermal invagination over focus of the perforation Bordered by acanthotic, hyperkeratotic epidermis Inflammatory debris in the channel, with basophilic collagen or eosinophilic elastin Granulomatous reaction at the base Differential Diagnosis Elastosis perforans serpiginosa Acneiform eruptions Keratosis pilaris

neutrophils in the subjacent dermis, and (variably) tinctorial changes in the connective tissue fibers. Some foci are clearly follicular (Fig. 14-17), and others are perifollicular (Fig. 14-18).120 The central cuplike keratotic plug within the epidermal invagination overlies the locus of epithelial perforation, with its apex oriented downward.123 Some reports describe vacuolar changes in the keratinocytes at the

Acquired Perforating Dermatosis

HISTOPATHOLOGY Early lesions are associated with variable acanthosis, follicular and perifollicular hyperkeratosis,

Acquired perforating dermatosis (including Kyrle disease, perforating folliculitis, and reactive perforating collagenosis) is commonly associated with chronic renal failure, hemodialysis, and diabetes mellitus.117-119 Its pathogenesis is poorly understood and has been the subject of wide-ranging conjecture, which includes theories of alterations in vitamin A metabolism, accumulation of nondialyzable metabolic products recognized as foreign by the skin, disordered keratinocyte maturation (eg, keratinization occurring at the expense of proliferation), and an unusual effect of humoral and cell-mediated immunity. The pathophysiologic mechanism may not be the same for all cases of acquired perforating dermatosis; rather, the mechanism may represent a common response pathway to a variety of epidermal and dermal alterations acting alone or in combination. The common association with uremia during the early phases of hemodialysis120 tends to support the theory of dermal deposition of a nondialyzable toxic metabolite. Autosomal recessive inheri-

 FIGURE 14-17 Acquired perforating dermatosis. The perforation in this follicular lesion has occurred through the infundibulum. Brightly eosinophilic elastin fibers are seen within the basophilic collagenous debris filling the transepithelial channel. The adjacent stroma contains a sparse, mixed mononuclear infiltrate.

CHAPTER 14 ■ ALTERATIONS OF THE STRATUM CORNEUM AND EPIDERMIS

displaying transepidermal elimination of stromal elements.113,114 In addition, numerous reports have discussed secondary transepidermal elimination in association with a clearly identifiable primary cutaneous process.113 The prototype for the primary perforating diseases is Kyrle disease, as described early in the early 1900s.115 With further studies, however, it became evident that there are more clinicopathologic similarities than there are differences between Kyrle disease and the other entities, which has obscured the criteria that were originally advanced for their recognition.116 Kyrle disease itself may not be a distinct entity but rather the extreme phenotype of a more common pathophysiologic process.113,117 Perforating folliculitis and reactive perforating collagenosis, according to the current trend for unification, may be phenotypic variants of a disease spectrum or merely different stages in lesional development. Given these considerations and in view of their common clinical association with renal disease and diabetes mellitus, Kyrle disease, reactive perforating collagenosis, and perforating folliculitis have been incorporated for the present purposes under the general designation acquired perforating dermatosis, as recommended by others.117,118 Elastosis perforans serpiginosa is, however, segregated on the basis of its association with disorders of connective tissues and its rather distinctive clinical presentation.

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pattern of inheritance, indicating a genetic substrate.127 The frequent association in approximately 25% of patients with either Down syndrome or an inborn disorder of connective tissue metabolism, such as Ehlers-Danlos syndrome, osteogenesis imperfecta, pseudoxanthoma elasticum, or Marfan syndrome,126 suggests that the pathophysiology is based on a molecular defect in the connective tissues. Some cases have been coincident with penicillamine therapy. From these associations, hyperplastic connective tissue fibers may act as local irritants, provoking epidermal hyperplasia that envelops the altered material, which is then carried upward by the process of keratinocyte differentiation for transepidermal elimination.126

 FIGURE 14-18 Acquired perforating dermatosis. The perforation is situated at an extrafollicular site.

base of the plug and breaks in the basement membrane before channelization. The basophilic material undergoing transepidermal elimination is composed of a mixture of inflammatory cells and leukocytic debris, a parakeratotic column of keratinaceous material, and fragments of basophilic collagen or eosinophilic elastin.117,123,124 At the base may be a foreign-body granulomatous reaction, with or without a suppurative component, occurring after the epithelium has been breached.125 The walls of the channels are bordered by flattened, anucleate, and variably glycogenated keratinocytes, which suggests premature keratinization; these altered keratinocytes follow the outflow of material through the epidermis.115 Extracellular lysosomal enzymes derived from the neutrophils may play an initiating role by altering elastin and collagen (with its basophilic degeneration) and possibly opening up the channel125; under this model, however, the mechanism initiating the chemoattraction of the neutrophils is undefined.

tion may occur in each. The locus of the elimination may be follicular, extrafollicular, or both. Moreover, each condition may be associated with chronic renal failure or diabetes mellitus. Observation of an infundibular locus with hair material destined for transepidermal elimination, as defined for perforating folliculitis,122 may depend on the stage of disease or the extent of the histologic sampling of the biopsy specimen.117 For these reasons, it seems arbitrary to separate them. Elastosis perforans serpiginosa also exhibits histologic similarities, but this condition is distinctive clinically, and it exhibits microscopically a definite increase in the number and thickness of the papillary dermal elastic fibers on elastin stains.126 A cuplike invagination plugged with keratinaceous material is a feature of keratosis pilaris, but there should be no epithelial breach nor elimination of degenerated collagen or elastin in the condition.

DIFFERENTIAL DIAGNOSIS No absolute criteria discriminate the classic perforating dermatoses of Kyrle disease, perforating folliculitis, and reactive perforating collagenosis because transepidermal elimination of altered collagen, elastin, or both via a central, cuplike invagina-

An uncommon but clinically distinctive disorder recognized since the early 1950s, elastosis perforans serpiginosa has as its hallmark the transepidermal elimination of altered elastic fibers. Its pathogenesis remains unclear, but some cases are familial, with an autosomal dominant

Elastosis Perforans Serpiginosa

CLINICAL FEATURES The lesions of elastosis perforans serpiginosa, which are often asymptomatic, occur in arcuate to annular arrays that are characteristically localized to one region of the body, most often the nape but on occasion the face or upper extremities (Table 14-9). The lesions are coalescent flesh-colored or erythematous, keratotic papules with central invaginations. There may be clinical resemblance to granuloma annulare or porokeratosis of Mibelli. Spontaneous remissions occur. HISTOPATHOLOGY The lesions, which may be either follicular or extrafollicular, are associated with hyperplasia and hyperkeratosis of the contiguous epidermis. Transepidermal elimination of altered elastin occurs through a central, narrow channel with a funnel-like or corkscrew

Table 14-9 Elastosis Perforans Serpiginosa

Clinical Features Typically solitary or few lesions, with a predilection for the nape Common association with Down syndrome and disorders of connective tissue Arcuate lesions formed by coalescence of keratotic papules with central plugs Histopathologic Features Increased number and sizes of elastin fibers at the base Narrow transepithelial channel delimited by acanthotic, hyperkeratotic epidermis Brightly eosinophilic elastin among basophilic debris in the channel Granulomatous reaction at the base Differential Diagnosis Acquired perorating dermatosis

configuration, which is delimited by a collarette formed from the acanthotic epidermis. Within the channel there is basophilic necrotic material composed of parakeratotic keratin, degenerated keratinocytes, inflammatory cells, and (most distinctively) brightly eosinophilic elastic fibers126 (Fig. 14-19). At the base of the perforation is a chronic inflammatory infiltrate containing multinucleate macrophages. With specific elastin stains of early and fully evolved lesions, increased numbers and sizes of elastic fibers are situated in the subjacent dermis, from which a stream of fibers enters the perforating channel, losing their normal staining quality as they do so. DIFFERENTIAL DIAGNOSIS The differential diagnosis of the primary perforating dermatoses is most reliably resolved by the differences in their clinical presentations and disease associations because the elimination of altered, eosinophilic elastic fibers via a central keratotic channel may be observed in patients with any of the four classic perforating diseases. The finding of increased numbers and sizes of elastic fibers in the subjacent papillary dermis in elastosis perforans serpiginosa by special staining, however, may offer a criterion for its histologic discrimination.119 The clinical differential diagnosis of elastosis perforans serpiginosa versus granuloma annulare and porokeratosis of Mibelli is discriminated histologically by the absence of transepidermal elimination

and by the presence of necrobiotic dermal changes and the cornoid lamella, respectively, in the latter two diseases.

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 FIGURE 14-19 Elastosis perforans serpiginosa. A channel breaches the acanthotic, hyperkeratotic epidermis and is covered by a wedge-shaped, parakeratotic plug containing aggregates of leukocytic debris. The stroma subjacent to the perforation contains a neutrophil-rich inflammatory infiltrate, within which are several eosinophilic elastic fibers.

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drogenase deficiency. Mol Genet Metab. 2007;90:1-9. Lucker GP, Van de Kerkhof PC, Steijlen PM: The hereditary palmoplantar keratoses: an updated review and classification. Br J Dermatol. 1994;131:1-14. Kuster W, Becker A: Indication for the identity of palmoplantar keratoderma type Unna-Thost with type Vorner. Thost’s family revisited 110 years later. Acta Derm Venereol. 1992;72:120-122. Kelsell DP, Stevens HP, Ratnavel R, et al: Genetic linkage studies in non-epidermolytic palmoplantar keratoderma: evidence for heterogeneity. Hum Mol Genet. 1995;4:1021-1025. Rugg EL, Common JE, Wilgoss A, et al: Diagnosis and confirmation of epidermolytic palmoplantar keratoderma by the identification of mutations in keratin 9 using denaturing high-performance liquid chromatography. Br J Dermatol. 2002;146:952-957. Patel S, Zirwas M, English JC 3rd: Acquired palmoplantar keratoderma. Am J Clin Dermatol. 2007;8:1-11. Itin PH, Lautenschlager S: Palmoplantar keratoderma and associated syndromes. Semin Dermatol. 1995;14:152-161. Common JE, O’Toole EA, Leigh IM, et al: Clinical and genetic heterogeneity of erythrokeratoderma variabilis. J Invest Dermatol. 2005;125:920-927. Torley D, Bellus GA, Munro CS: Genes, growth factors and acanthosis nigricans. Br J Dermatol. 2002;147:1096-1101. Hamm H, Meinecke P, Traupe H: Further delineation of the ichthyosis follicularis, atrichia, and photophobia syndrome. Eur J Pediatr. 1991;150: 627-629. Chan H, Liu FT, Naguwa S: A review of pityriasis rubra pilaris and rheumatologic associations. Clin Dev Immunol. 2004;11:57-60. Vanderhooft SL, Francis JS, Holbrook KA, et al: Familial pityriasis rubra pilaris. Arch Dermatol. 1995;131:448-453. Scheinfeld NS, Mones J. Granular parakeratosis: pathologic and clinical correlation of 18 cases of granular parakeratosis. J Am Acad Dermatol. 2005;52(5): 863-867. Metze D, Rutten A. Granular parakeratosis: a unique acquired disorder of keratinization. J Cutan Pathol. 1999;26: 339-352. Happle R, Mittag H, Kuster W: The CHILD nevus: a distinct skin disorder. Dermatology. 1995;191:210-216. Bittar M, Happle R, Grzeschik KH, et al: CHILD syndrome in 3 generations: the importance of mild or minimal skin lesions. Arch Dermatol. 2006;142:348-351. Konig A, Happle R, Fink-Puches R, et al: A novel missense mutation of NSDHL in an unusual case of CHILD syndrome showing bilateral, almost symmetric involvement. J Am Acad Dermatol. 2002;46:594-596. Hashimoto K, Topper S, Sharata H, et al: CHILD syndrome: analysis of abnormal keratinization and ultrastructure. Pediatr Dermatol. 1995;12:116-129. Judge MR, Morgan G, Harper JI: A clinical and immunological study of Netherton’s syndrome. Br J Dermatol. 1994;131:615-621. Chavanas S, Bodemer C, Rochat A, et al: Mutations in SPINK5, encoding a serine

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protease inhibitor, cause Netherton syndrome. Nat Genet. 2000;25:141-142. Komatsu N, Saijoh K, Jayakumar A, et al: Correlation between SPINK5 gene mutations and clinical manifestations in Netherton syndrome patients. J Invest Dermatol. 2007;128(5):1148-1159. Zhang ZH, Niu ZM, Yuan WT, et al: A mutation in SART3 gene in a Chinese pedigree with disseminated superficial actinic porokeratosis. Br J Dermatol. 2005;152:658-663. Ito M, Fujiwara H, Maruyama T, et al: Morphogenesis of the cornoid lamella: histochemical, immunohistochemical, and ultrastructural study of porokeratosis. J Cutan Pathol. 1991;18:247-256. Schamroth JM, Zlotogorski A, Gilead L: Porokeratosis of Mibelli. Overview and review of the literature. Acta Derm Venereol. 1997;77:207-213. Fuchs E, Coulombe P, Cheng J, et al: Genetic bases of epidermolysis bullosa simplex and epidermolytic hyperkeratosis. J Invest Dermatol. 1994;103(suppl): 25S-30S. Rugg EL, Horn HM, Smith FJ, et al: Epidermolysis bullosa simplex in Scotland caused by a spectrum of keratin mutations. J Invest Dermatol. 2007;127: 574-580. Koss-Harnes D, Hoyheim B, AntonLamprecht I, et al: A site-specific plectin mutation causes dominant epidermolysis bullosa simplex Ogna: two identical de novo mutations. J Invest Dermatol. 2002;118:87-93. Horn HM, Tidman MJ: The clinical spectrum of epidermolysis bullosa simplex. Br J Dermatol. 2000;142:468-472. Smith LT: Ultrastructural findings in epidermolysis bullosa. Arch Dermatol. 1993;129:1578-1584. Varki R, Sadowski S, Pfendner E, et al: Epidermolysis bullosa. I. Molecular genetics of the junctional and hemidesmosomal variants. J Med Genet 2006;43:641-652. Brown TA, Gil SG, Sybert VP, et al: Defective integrin alpha 6 beta 4 expression in the skin of patients with junctional epidermolysis bullosa and pyloric atresia. J Invest Dermatol. 1996;107:384-391. Vidal F, Baudoin C, Miquel C, et al: Cloning of the laminin alpha 3 chain gene (LAMA3) and identification of a homozygous deletion in a patient with Herlitz junctional epidermolysis bullosa. Genomics. 1995;30:273-280. Nakano A, Chao SC, Pulkkinen L, et al: Laminin 5 mutations in junctional epidermolysis bullosa: molecular basis of Herlitz vs. non-Herlitz phenotypes. Hum Genet. 2002;110:41-51. Varki R, Sadowski S, Uitto J, et al: Epidermolysis bullosa. II. Type VII collagen mutations and phenotype-genotype correlations in the dystrophic subtypes. J Med Genet. 2007;44:181-192. Jarvikallio A, Pulkkinen L, Uitto J: Molecular basis of dystrophic epidermolysis bullosa: mutations in the type VII collagen gene (COL7A1). Hum Mutat. 1997;10:338-347. Christiano AM, Suga Y, Greenspan DS, et al: Premature termination codons on both alleles of the type VII collagen gene (COL7A1) in three brothers with recessive dystrophic epidermolysis bullosa. J Clin Invest. 1995;95:1328-1334.

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1 underlies mild epidermolytic palmoplantar keratoderma in three kindreds. J Invest Dermatol. 2001;116:606-609. Kuster W, Zehender D, Mensing H, et al: [Vorner keratosis palmoplantaris diffusa. Clinical, formal genetic and molecular biology studies of 22 families]. Hautarzt. 1995;46:705-710. Requena L, Schoendorff C, Sanchez Yus E: Hereditary epidermolytic palmoplantar keratoderma (Vorner type)— report of a family and review of the literature. Clin Exp Dermatol. 1991;16: 383-388. Dahl PR, Daoud MS, Su WP: JadassohnLewandowski syndrome (pachyonychia congenita). Semin Dermatol. 1995; 14:129-134. Bowden PE, Haley JL, Kansky A, et al: Mutation of a type II keratin gene (K6a) in pachyonychia congenita. Nat Genet. 1995;10:363-365. McLean WH, Rugg EL, Lunny DP, et al: Keratin 16 and keratin 17 mutations cause pachyonychia congenita. Nat Genet. 1995;9:273-278. Smith FJ, Liao H, Cassidy AJ, et al: The genetic basis of pachyonychia congenita. J Investig Dermatol Symp Proc. 2005;10:21-30. McLean WH, Smith FJ, Cassidy AJ: Insights into genotype-phenotype correlation in pachyonychia congenita from the human intermediate filament mutation database. J Investig Dermatol Symp Proc. 2005;10:31-36. Leachman SA, Kaspar RL, Fleckman P, et al: Clinical and pathological features of pachyonychia congenita. J Investig Dermatol Symp Proc. 2005;10:3-17. Munro CS: The phenotype of Darier’s disease: penetrance and expressivity in adults and children. Br J Dermatol. 1992; 127:126-130. Sakuntabhai A, Dhitavat J, Burge S, et al: Mosaicism for ATP2A2 mutations causes segmental Darier’s disease. J Invest Dermatol. 2000;115:1144-1147. Burge SM, Wilkinson JD: Darier-White disease: a review of the clinical features in 163 patients. J Am Acad Dermatol. 1992;27:40-50. Hashimoto K, Fujiwara K, Harada M, et al: Junctional proteins of keratinocytes in Grover’s disease, Hailey-Hailey’s disease and Darier’s disease. J Dermatol. 1995;22:159-170. Hu Z, Bonifas JM, Beech J, et al: Mutations in ATP2C1, encoding a calcium pump, cause Hailey-Hailey disease. Nat Genet. 2000;24:61-65. Burge SM: Hailey-Hailey disease: the clinical features, response to treatment and prognosis. Br J Dermatol. 1992;126: 275-282. Grover RW: Transient acantholytic dermatosis. Arch Dermatol. 1970;101:426-434. Quirk CJ, Heenan PJ: Grover’s disease: 34 years on. Australas J Dermatol. 2004; 45:83-86; quiz 87-88. Powell J, Sakuntabhai A, James M, et al: Grover’s disease, despite histological similarity to Darier’s disease, does not share an abnormality in the ATP2A2 gene. Br J Dermatol. 2000;143:658.

109. Levy SB, Goldsmith LA: The peeling skin syndrome. J Am Acad Dermatol. 1982;7:606-613. 110. Al-Ghamdi F, Al-Raddadi A, Satti M: Peeling skin syndrome: 11 cases from Saudi Arabia. Ann Saudi Med. 2006;26: 352-357. 111. Cassidy AJ, van Steensel MA, Steijlen PM, et al: A homozygous missense mutation in TGM5 abolishes epidermal transglutaminase 5 activity and causes acral peeling skin syndrome. Am J Hum Genet. 2005;77:909-917. 112. Hashimoto K, Hamzavi I, Tanaka K, et al: Acral peeling skin syndrome. J Am Acad Dermatol. 2000;43:1112-1119. 113. Mehregan AH: Perforating dermatoses: a clinicopathologic review. Int J Dermatol. 1977;16:19-27. 114. Sehgal VN, Jain S, Thappa DM, et al: Perforating dermatoses: a review and report of four cases. J Dermatol. 1993;20: 329-340. 115. Kyrle J: Hykeratosis follicularis et parafollicularis in cutem penetrans. Arch Dermatol Syphilol (Berlin) 1916;123:466-493. 116. Saray Y, Seckin D, Bilezikci B: Acquired perforating dermatosis: clinicopathological features in twenty-two cases. J Eur Acad Dermatol Venereol. 2006;20:679-688. 117. Rapini RP, Herbert AA, Drucker CR: Acquired perforating dermatosis. Evidence for combined transepidermal elimination of both collagen and elastic fibers. Arch Dermatol. 1989;125:10741078. 118. Patterson JW, Brown PC: Ultrastructural changes in acquired perforating dermatosis. Int J Dermatol. 1992;31:201-205. 119. Hood AF, Hardegen GL, Zarate AR, et al: Kyrle’s disease in patients with chronic renal failure. Arch Dermatol. 1982;118:85-88. 120. Garcia-Bravo B, Rodriguez-Pichardo A, Camacho F: Uraemic follicular hyperkeratosis. Clin Exp Dermatol. 1985;10: 448-454. 121. Ramesh V, Sood N, Kubba A, et al: Familial reactive perforating collagenosis: a clinical, histopathological study of 10 cases. J Eur Acad Dermatol Venereol 2007;21:766-770. 122. Mehregan AH, Coskey RJ: Perforating folliculitis. Arch Dermatol. 1968;97:394-399. 123. Constantine VS, Carter VH: Kyrle’s disease. II. Histopathologic findings in five cases and review of the literature. Arch Dermatol. 1968;97:633-639. 124. Mehregan AH, Schwartz OD, Livingood CS: Reactive perforating collagenosis. Arch Dermatol. 1967;96:277-282. 125. Zelger B, Hintner H, Aubock J, et al: Acquired perforating dermatosis. Transepidermal elimination of DNA material and possible role of leukocytes in pathogenesis. Arch Dermatol. 1991;127: 695-700. 126. Mehregan AH: Elastosis perforans serpiginosa: a review of the literature and report of 11 cases. Arch Dermatol. 1968;97: 381-393. 127. Langeveld-Wildschut EG, Toonstra J, van Vloten WA, et al: Familial elastosis perforans serpiginosa. Arch Dermatol. 1993;129:205-207.

CHAPTER 14 ■ ALTERATIONS OF THE STRATUM CORNEUM AND EPIDERMIS

77. Horn HM, Tidman MJ: The clinical spectrum of dystrophic epidermolysis bullosa. Br J Dermatol. 2002;146:267-274. 78. Anton-Lamprecht I: Ultrastructural identification of basic abnormalities as clues to genetic disorders of the epidermis. J Invest Dermatol. 1994;103(suppl): 6S-12S. 79. Rothnagel JA, Dominey AM, Dempsey LD, et al: Mutations in the rod domains of keratins 1 and 10 in epidermolytic hyperkeratosis. Science. 1992;257:1128-1130. 80. Fuchs E, Esteves RA, Coulombe PA: Transgenic mice expressing a mutant keratin 10 gene reveal the likely genetic basis for epidermolytic hyperkeratosis. Proc Natl Acad Sci U S A. 1992;89:69066910. 81. DiGiovanna JJ, Bale SJ: Clinical heterogeneity in epidermolytic hyperkeratosis. Arch Dermatol. 1994;130:1026-1035. 82. Nomura K, Umeki K, Hatayama I, et al: Phenotypic heterogeneity in bullous congenital ichthyosiform erythroderma: possible somatic mosaicism for keratin gene mutation in the mildly affected mother of the proband. Arch Dermatol. 2001;137:1192-1195. 83. Steijlen PM, Kremer H, Vakilzadeh F, et al: Genetic linkage of the keratin type II gene cluster with ichthyosis bullosa of Siemens and with autosomal dominant ichthyosis exfoliativa. J Invest Dermatol. 1994;103:282-285. 84. Rothnagel JA, Traupe H, Wojcik S, et al: Mutations in the rod domain of keratin 2e in patients with ichthyosis bullosa of Siemens. Nat Genet. 1994;7:485-490. 85. Smith FJ, Maingi C, Covello SP, et al: Genomic organization and fine mapping of the keratin 2e gene (KRT2E): K2e V1 domain polymorphism and novel mutations in ichthyosis bullosa of Siemens. J Invest Dermatol. 1998;111: 817-821. 86. Steijlen PM, Perret CM, Schuurmans Stekhoven JH, et al: Ichthyosis bullosa of Siemens: further delineation of the phenotype. Arch Dermatol Res. 1990; 282:1-5. 87. Niemi KM, Virtanen I, Kanerva L, et al: Altered keratin expression in ichthyosis hystrix Curth-Macklin. A light and electron microscopic study. Arch Dermatol Res. 1990;282:227-233. 88. Sprecher E, Yosipovitch G, Bergman R, et al: Epidermolytic hyperkeratosis and epidermolysis bullosa simplex caused by frameshift mutations altering the v2 tail domains of keratin 1 and keratin 5. J Invest Dermatol. 2003;120:623-626. 89. Navsaria HA, Swensson O, Ratnavel RC, et al: Ultrastructural changes resulting from keratin-9 gene mutations in two families with epidermolytic palmoplantar keratoderma. J Invest Dermatol. 1995;104:425-429. 90. Terrinoni A, Cocuroccia B, Gubinelli E, et al: Identification of the keratin K9 R162W mutation in patients of Italian origin with epidermolytic palmoplantar keratoderma. Eur J Dermatol. 2004;14: 375-378. 91. Hatsell SJ, Eady RA, Wennerstrand L, et al: Novel splice site mutation in keratin

337

CHAPTER 15 Disorders of Pigmentation

PART II ■ PREDOMINANTLY NONINFLAMMATORY CONDITIONS

A. Neil Crowson Sarah Zeller Raymond L. Barnhill

338

The source of pigment that causes hyperpigmentation of the skin ranges from endogenous products such as melanin and hemosiderin to exogenous agents such as dyes for tattoos, ingested metals, and drugs. In some instances, these agents are combined to produce hyperpigmentation. For example, in argyria- and chlorpromazine-related hyperpigmentation, silver particles plus melanin and drug metabolites plus melanin, respectively, contribute to dyschromasia. Ultraviolet (UV) rays often enhance these pigmentations, so sun-exposed skin shows more intense discoloration. When the epidermis is heavily melanized, pigment incontinence may result in upper dermal melanization as well. Disorders of hypopigmentation and depigmentation are caused mainly by damage to and dysfunction of epidermal melanocytes (Figs. 15-1 and 15-2). In some congenital diseases (eg, piebaldism), melanocytes are absent. The circulation of blood through the superficial capillary plexus may influence the skin color, as evidenced by nevus anemicus. Both hyper- and hypopigmentations may be congenital or hereditary, postinflammatory, or induced by chemicals and foreign materials. Melanocytes from all sites (skin, hair bulb, eyes) produce melanosomes that in the normal process mature into electrondense stage IV melanosomes in darkskinned individuals. The maturation is arrested at stage I or II in fair-skinned whites (Fig. 15-3). In leukodermic conditions, various dysfunctions of tyrosinase or damage to melanocytes produce fewer pigmented melanosomes or a decrease in their number (Figs. 15-4 and 15-5), changes that are more visible in dark skin. Hyperactivity of melanocytes results in various hyperpigmented conditions, and in such disorders, lesions are again more striking in dark than in light skin. In some conditions, the transfer of melanosomes from normal melanocytes to the surrounding basal keratinocytes is disturbed, causing an uneven light color of the lesion

Disorders of pigmentation

Hypomelanosis

Markedly reduced or absent epidermal melanocytes and melanin Established vitiligo Piebaldism Physical leukoderma Chemical exposure Traumatic injury Burns Radiation Onchocerciasis Pinta Scleroderma Halo nevus Melanoma-associated leukoderma

Hyperpigmentation

Normal numbers or slightly reduced numbers of epidermal melanocytes; markedly reduced epidermal melanin Albinism Postinflammatory hypomelanosis Trichrome or evolving vitiligo Pityriasis alba Tinea versicolor Tuberous sclerosis Hypomelanosis of Ito Nevus depigmentosus Malnutrition

 FIGURE 15-1 Disorders of pigmentation.

(eg, nevus depigmentosus) or hyperpigmentation in some instances (eg, PeutzJeghers syndrome). In many hyperpigmented conditions (eg, lentigo simplex and senilis), the rete ridges are elongated, and an aggregation of melanocytes and pigment occurs (Fig. 15-6). The DOPA stain has long been the standard method to demonstrate melaninsynthesizing melanocytes (Table 15-1). Silver stains such as the Fontana-Masson stain have been used to demonstrate melanin granules (aggregated melanosomes) (see Fig. 15-4). It is now much more convenient to use melanocytespecific monoclonal antibodies such as MEL-5, Melan-A, or HMB-45, which are applicable to formalin-fixed, paraffinembedded tissues through immunoperoxidase methodologies.

HYPOPIGMENTATION DISORDERS In these disorders, the histopathology is mostly nonspecific (see Fig. 15-1 and Table 15-2). Epidermal melanocytes are either absent or inactive; accordingly, the epidermis is hypomelanized or totally depigmented.

Piebaldism (Patterned Leukoderma) CLINICAL FEATURES Piebaldism manifests congenital patches of depigmentation (leukoderma), a white forelock, or poliosis (white hairs) in 85% of patients.1-3 Both mice and humans with a null

mutation at either the endothelin 3 or the endothelin receptor b locus show major deficiencies in both melanocytes and enteric ganglion cells, resulting in congenital white spotting and aganglionic megacolon.4 Hyperpigmented macules may occur in the depigmented lesions or in normal skin. The disease has an autosomal dominant inheritance pattern. Unlike vitiligo, the leukoderma is mostly permanent because melanocytes are largely absent in the lesion. Occasionally, repigmentation may occur at the periphery of a lesion or within the depigmented macule. In a similar disorder of mice, socalled “dominant white spotting,” a mutation or deletion of c-kit (a gene encoding a cell surface receptor tyrosine kinase) has been detected. The c-kit protooncogene, originally found in HZ4feline sarcoma virus (hence the name kit), is important for the production of cell surface receptors for embryonic growth factors (eg, stem cell factor, mast cell growth factor) and seems to promote development, migration, and survival of melanocytes. The human piebaldism gene locus has been mapped to chromosome 4q12, a site near the human KIT gene locus. Multiple KIT point mutations, including missense, nonsense, and splice-site nucleoside substitutions, may result in the piebald phenotype.5,6 A novel C-KIT mutation (Val62OAla) has been detected in a family with piebaldism that resulted in progressive depigmentation.7 Some humans and mice with the piebald

Disorders of hyperpigmentation

Predominantly increased epidermal melanin (some pigment incontinence)

Both epidermal and dermal melanin increased Postinflammatory hypermelanosis Melasma

Patterned or circumscribed hypermelanosis Freckle CALM Melanotic macule of Albright Lentigo Melasma (epidermal) Becker’s melanosis

Increased melanin, epidermal and/or dermal, and other pigments Tattoo Hemochromatosis Argyria Chrysiasis Mercury Arsenic Lead Bismuth Minocycline Antimalarials Amiodarone Chlofazamine Phenothiazine

 FIGURE 15-2 Disorders of hyperpigmentation. CALM = café-au-lait macule.

phenotype who lack apparent C-KIT mutations have been found to harbor deletions in the zinc-finger neural crest transcription, although the function of

SLUG in the development of melanocytes remains unclear.8 Other diseases that have been noted to be associated with piebaldism are congen-

ital dyserythropoietic anemia type II (HEMPAS),9 neurofibromatosis type 1 (NF1),10 Grover disease,11 and sensorineural deafness. The occurrence of sensorineural deafness in a patient with genotypically confirmed piebaldism extends the phenotypic range of piebaldism due to C-KIT gene mutation in humans and strengthens the clinical similarity between piebaldism and the various forms of Waardenburg syndrome.12 In Klein-Waardenburg syndrome,13 which is also dominantly inherited, a white forelock is present in 50% of affected individuals, and congenital patches of leukoderma are associated with hypertelorism and heterochromia of the irides as well as deafness.

CHAPTER 15 ■ DISORDERS OF PIGMENTATION

Diffuse hypermelanosis Addison disease Myxedema Grave disease Malnutrition Hemochromatosis, early Chemotherapeutic agents

Predominantly increased dermal melanin (pigment incontinence) Postinflammatory hypermelanosis Melasma (dermal) Incontinentia pigmenti Prurigo pigmentosa

HISTOPATHOLOGIC FEATURES By DOPA reaction and immunohistochemistry, melanocytes are absent in the leukoderma and white hair of the forelock, and electron microscopy reveals no melanocytes with melanosomes. In contrast, the hyperpigmented macules contain normal numbers of melanocytes.

 FIGURE 15-3 An epidermal melanocyte is actively synthesizing melanosomes. Stage 1 melanosome contains amorphous, nebulous material. In stage 2, cristae are formed, and melanin begins to deposit on them. In stage 3, melanin polymers become denser, and in stage 4, the increased density masks the underlying structure of cristae.

DIFFERENTIAL DIAGNOSIS Without clinical information, the depigmented macules in patients with piebaldism cannot be distinguished histologically from established lesions of vitiligo and leukodermas resulting from chemicals, trauma, or burns that show loss of all epidermal melanocytes. Most other leukodermas are distinguished from piebaldism by the presence of melanocytes.

339

PART II ■ PREDOMINANTLY NONINFLAMMATORY CONDITIONS

A

 FIGURE 15-4 Vitiligo. (A) Depigmentation involving the neck in a characteristic periorificial distribution. (B) A Melan-A immunostain at the edge of a vitiligo lesion. Depigmented skin shows progressive loss of melanocyte density.

Vitiligo and Vogt-Koyanagi-Harada Syndrome

 FIGURE 15-5 Oculocutaneous albinism.

340

B

Vitiligo is an acquired patchy pigment loss of the skin and rarely the hairs that may develop at any age; rarely, it may be congenital (Table 15-3). Up to 30% of cases have a familial basis. Individuals with vitiligo may present with focal lesions, that is, one or more isolated macules; segmental lesions, which are unilateral and often show a dermatomal pattern; generalized symmetric lesions that are commonly periorificial; or universal involvement (Fig. 15-4A). Individual macules of established vitiligo often measure several millimeters in diameter; are completely depigmented with a milk white color; and have well-defined, often scalloped borders. Trichrome vitiligo refers to three types of lesions: white (established vitiligo), light tan (transitional areas that will become depigmented), and normal brown areas. When serum IgG from vitiligo patients is injected into nude mice to which normal human skin has been grafted, melanocytes of the grafted skin are damaged and significantly decreased, suggesting an autoimmune mechanism in the etiology.14 A similar occurrence has

gastritis, autoimmune thyroid disease,23 ankylosing spondyloarthritis,24 idiopathic CD44 +ve T-cell lymphocytopenia,25 and lepromatous leprosy.26 These associations strengthen the hypothesis of a role for autoimmunity in vitiligo.

been seen in humans after bone marrow transplantation, as in the case of a patient who developed generalized vitiligo 3 months after receiving an allogeneic bone marrow transplant from an HLA-matched sister with vitiligo.15,16

Table 15-1 Evaluation of Disorders of Pigmentation 1. Hematoxylin and eosin–stained sections of lesional and uninvolved skin for basilar melanocytes, melanin, and other changes such as inflammation, granulomas 2. Silver stains such as Fontana-Masson for melanin, dendritic melanocytes 3. Other stains, such as PAS, acid-fast bacillus, Fite-Faraco for infectious organisms; Prussian blue for iron, hemosiderin 4. DOPA reaction to demonstrate melanocytes (specific for tyrosinase), not practical since special fixation and development required 5. Antibodies to tyrosinase pathway–related or melanosomal matrix–related antibodies (e.g., Melan-A, Mel-5, Mitf or HMB-45) to demonstrate melanocytes by immunohistochemistry 6. Electron microscopy to demonstrate quantitative and qualitative aspects of melanosomes 7. Clinical information, such as congenital or acquired onset, diffuse or circumscribed nature of process, distribution of disorder, history of trauma, chemical exposure, other dermatosis, infectious disease

Autoantibodies are formed against the melanocyte or melanosome and destroy them via antibody-mediated cytotoxicity and complement-mediated cytolysis, either as a primary pathogenic mechanism or as a secondary response to the damage caused by autoreactive T lymphocytes.17 Target antigens demonstrated in the sera of vitiligo patients include those against the tyrosinase antigen gp 100/pmel17 and tyrosinase-related proteins trp-1 and trp-2, 18 Pmel17, the transcription factor SOX10, and the melanin-concentrating hormone receptor 1 (MCHR1).19 The titers of autoantibody, as well as the frequency of A103specific CD8 +ve T cells among the total T-cell pool,20 seem to correlate with disease activity. There is also evidence of modification of epidermal cytokine expression in patients with vitiligo. Granulocyte-macrophage colony-stimulating factor, fibroblast growth factor β, and stem cell factor are decreased, and interleukin-6 and tumor necrosis factor (TNF)–α are increased in vitiliginous skin compared with perilesional, nonlesional, and healthy skin.21 In Vogt-Koyanagi-Harada syndrome, the skin and other melanocyte-bearing tissues, such as the leptomeninges, uveal tract, and stria vascularis of the ear, are attacked by autoantibodies to produce meningitis, uveitis, and dysacousia, respectively.22 Vitiligo is polygenic in nature and has been associated with various other autoimmune diseases. These diseases include diabetes mellitus, atrophic

DIFFERENTIAL DIAGNOSIS The clinical differential diagnosis of vitiligo depends on the distribution and extent of hypopigmentation, as well as on other factors, and includes leukoderma from chemicals, trauma, and burns; halo nevi and melanoma; piebaldism; and Waardenburg syndrome, all of which may show an absence of epidermal melanocytes and melanin and thus be histologically indistinguishable from established vitiligo. Other entities that may be confused clinically with vitiligo include lupus erythematosus, hypochromic mycosis fungoides, postinflammatory hypopigmention, tuberous sclerosis (TS), pityriasis alba, tinea versicolor, leprosy, idiopathic guttate hypomelanosis, and nevus depigmentosus. In general, the latter processes show basilar melanocytes, diminished epidermal melanin, and distinctive features in some patients. The presence of some basilar melanocytes and epidermal melanin does not necessarily rule out vitiligo because they may be seen in the skin adjacent to vitiligo, in trichrome vitiligo, and in repigmenting vitiligo.

CHAPTER 15 ■ DISORDERS OF PIGMENTATION

 FIGURE 15-6 Lentigo simplex. A heavy melanization of rete ridges, particularly around the tip, is seen.

HISTOPATHOLOGIC FEATURES In wellestablished lesions, neither melanocytes nor melanin can be detected in the epidermis with hematoxylin and eosin (H&E) or immunohistochemical stains or electron microscopy. At the periphery of the lesion, large melanocytes with long dendritic processes and many melanosomes are present (see Fig. 15-4B), as if they are trying to cover the depigmented areas. Lymphocytic infiltration and basal cell vacuolization may be seen at the advancing border of vitiligo. The light-tan areas in patients with trichrome vitiligo show both basilar melanocytes and melanin.

Oculocutaneous Albinism CLINICAL FEATURES Oculocutaneous albinism manifests as total loss of pigment from the skin and hair with associated blue irides and red fundi of the eyes27 (Fig. 15-5A). It is congenital and inherited recessively. The two subtypes are tyrosinase positive and tyrosinase negative. In the former, a plucked hair bulb becomes dark after incubation in

341

PART II ■ PREDOMINANTLY NONINFLAMMATORY CONDITIONS

Table 15-2 Disorders of Hypopigmentation: Principal Histopathologic Features

342

DISORDER

BASILAR MELANOCYTES

MELANIN IN BASAL LAYER

Established vitiligo Vitiligo margin

Absent Present, enlarged

Absent Present, reduced

Trichrome vitiligo (light tan skin) Piebaldism, Waardenberg syndrome, Woolf syndrome Albinism

Present Absent

Present Absent Greatly reduced or absent

Chédiak-Higashi syndrome

Normal number, morphology Present

Greatly reduced or absent

Tuberous sclerosis (ash-leaf macules)

Present

Reduced

Hypomelanosis of Ito

Normal or decreased in number Normal numbers

Decreased

Postinflammatory hypomelanosis

Normal or slightly reduced numbers

Decreased

Pityriasis alba

Reduced

Decreased

Tinea versicolor

Normal

Decreased

Idiopathic guttate hypomelanosis

Slightly decreased

Decreased

Physical, chemical depigmentation

Absent

Absent

Nevus depigmentosus

DOPA solution. These patients may develop freckles and pigmented nevi. In the latter, the hair bulb does not become dark after incubation in DOPA solution, and patients never become pigmented. However, the degree of skin pigmentation, such as the ability to tan, is variable among both types depending on the mutant alleles. Due to a lack of melanin pigment in the developing eye,28 optical findings, such as foveal hypoplasia, misrouting of optic nerve to the brain, and reduced visual acuity, are universal for all types of albinism. The tyrosinase-negative type is now further subclassified into OCA-1A, in which there is no tyrosinase activity; OCA-lB (yellow OCA) and OCA-1MP (minimal pigment OCA), in which some tyrosinase activity is present; and OCA2TS, which is temperature sensitive. Various mutations of the tyrosinase gene on chromosome 11q14-21 are responsible for these different clinical phenotypes. The tyrosinase-positive subtypes are OCA2, caused by a mutation in the OCA2 gene (formerly P-gene)

Decreased

responsible for melanosome biogenesis and transport of tyrosinase; OCA3, in which mutated tyrosinase-related protein (TYRP 1) leads to early degradation of tyrosinase; and OCA4, which is characterized by mutations of the membraneassociated transporter protein gene (MATP, also known as SLC45A2).29,30 Albinism is one of the symptoms of Vici syndrome,31 which consists of delayed development, agenesis of the corpus callosum, hypotonia, cardiomyopathy, cataracts, and recurrent infections and has been seen as well in a patient with primary melanoma of the lung.32 HISTOPATHOLOGIC FEATURES In all disease subtypes, basal melanocytes are observed, but the epidermal melanin content is greatly diminished or absent. Electron microscopy proves the presence of normal melanocytes. In the tyrosinasepositive type, some melanosomes mature to stages III and IV, but in the tyrosinase-negative type, the melanosomes are not pigmented even after incubation with DOPA.

OTHER FINDINGS Basal layer vacuolization, lymphocytic infiltrates

Large pigment granules (giant melanosomes) Reduced number, size, and melanization of melanosomes Underdeveloped dendrites Poorly developed dendrites, decreased melanosomes Block in transfer of melanosomes to keratinocytes Fewer and smaller melanosomes Defective melanosome maturation and transfer block Atrophic epidermis, melanocytes with stubby dendrites; immature melanosomes, stages I and II Possible scarring

Hermansky-Pudlak Syndrome CLINICAL FEATURES Hermansky-Pudlak syndrome (HPS) includes a group of genetically distinct disorders characterized by tyrosinase-positive oculocutaneous albinism, a platelet storage pool deficiency that results in a bleeding diathesis, and impaired formation or trafficking of intracellular vesicles. It is an autosomal recessive disorder that affects mainly persons of Puerto Rican origin, although there have been several reported cases in Turkish, Pakistani, and Ashkenazi Jewish kindreds.33,34 There are eight human HPS subtypes, each associated with specific defects in protein trafficking that lead to dysfunction of intracellular lysosome-related organelles.35 The disease complex is subclassified as HPS1 (HPS1 gene abnormality), HPS2 (ADTB3A gene abnormality), and HPS3 (HPS3 gene abnormality). A mutation in the AP3 complex results in abnormal intracellular vesicle formation.36 HISTOPATHOLOGIC FEATURES Melanocytes manifest shortened dendritic processes,

Table 15-3 Vitiligo

Table 15-4 Albinism

Clinical Features Abnormalities of optic system Nystagmus, photophobia, decreased visual acuity Blue and translucent iris (blue eyes) Hair white to yellow White skin Often greatly increased risk for skin cancer Autosomal recessive: Numerous variants Histopathologic Features Melanocytes normal in number and structure Greatly reduced or absent epidermal melanin Differential Diagnosis Rare genetic disorders with hypopigmentation Universal vitiligo

Chédiak-Higashi syndrome CLINICAL FEATURES Chédiak-Higashi syndrome is an autosomal recessive disorder that resembles oculocutaneous albinism because of the fair color of the skin, hair, and irides; nystagmus; and photophobia.37,38 The skin is creamy white, but the degree of depigmentation is not very striking. The hair is light blond to brown and has a silver-green sheen. In addition to reduced pigmentation, affected individuals also have severe immunologic defects (eg, impaired chemotaxis and abnormal natural killer cell function), bleeding tendencies, and progressive neurologic dysfunction.39 Patients rarely survive beyond childhood because of an increased susceptibility to bacterial infection. They may also succumb to an “accelerated phase” during which a nonmalignant lymphohistiocytic infiltration of multiple organs resembling lymphoma occurs. The current treatment is a bone marrow transplant, which aborts the accelerated phase and the immune problems but does not prevent the neurologic disorders, which continue to develop with age.40,41 Although the function of the large protein which the LYST gene encodes is unknown, Chédiak-Higashi syndrome appears to be a disorder of vesicle trafficking.42 This protein may insert itself between other proteins that mediate intracellular fusion or fission reactions.43-45 HISTOPATHOLOGIC FEATURES As with oculocutaneous albinism, basilar melanocytes are present, but epidermal melanin is diminished. Silver stains detect large melanin granules throughout the epidermis and in melanophages in the upper dermis; ultrastructurally, these granules are localized to membrane-bound giant melanosomes in skin and hair. The classic diagnostic feature of Chédiak-Higashi syndrome is the presence of huge cytoplasmic granules and lysosomes within cells.46 Giemsa stains of peripheral blood smears show numerous large granules in leukocytes. These granules are formed by the fusion of abnormal phagosomes incapable of normal bacterial killing.

Ash Leaf Spots of Tuberous Sclerosis Tuberous sclerosis (TS) is an autosomal dominant disease in which find ash leaf–shaped hypopigmented spots (ie, ash

leaf spots) are seen in 50% to 98% of patients.47 Hypopigmented macules are the most frequent skin finding in patients with TS and are considered a tertiary diagnostic feature.48 These spots are scattered over the trunk and extremities from birth or early childhood and thus are a significant early sign of the disease, similar to the axillary freckling of neurofibromatosis. Poliosis and depigmented spots on the iris and retina are also seen. Multiple organ systems may have hamartomatous involvement, including the central nervous system (CNS) (with epilepsy being the most common feature), kidneys, heart, and other viscera. When there is pulmonary involvement, the condition is known as pulmonary lymphangioleiomyomatosis (LAM).49 The skin, kidney, and brain lesions of individuals with TS express CD31 and vascular endothelial growth factor (VEGF).50 The combination of congenital hypopigmented lesions with seizures and mental retardation strongly suggests a diagnosis of TS. The gene for TS has been mapped to chromosomes 9q(33-) 34.3 (tuberous sclerosis-1 or TS1) and l6p13.3 (TS2). The gene product is hamartin for TS1 and is tuberin for TS2; hamartin and tuberin bind together to form a tumor suppressor heterodimer. This complex inhibits the mammalian target of rapamycin (mTOR)51, which results in abnormal cell differentiation and proliferation.49 Mutations in TS2 are seen in the majority of de novo cases and 50% of familial cases and usually portend a more severe clinical phenotype.52,53

CHAPTER 15 ■ DISORDERS OF PIGMENTATION

Clinical Features Onset any age, especially in adolescents, young adults Patterns: Generalized—periorificial, bony prominences, extensor surfaces. Segmental—dermatomal Localized Milk-white macular lesions, well-defined, scalloped borders Trichrome lesions, light-tan Associations: Thyroid disease, diabetes mellitus, Addison disease, pernicious anemia Histopathologic Features Established (depigmented) lesions: Absence of epidermal melanocytes and melanin Marginal (normal) skin Epidermal melanocytes and melanin present Basal layer vacuolization often Sparse lymphocytic infiltrates Trichrome vitiligo: Epidermal melanocytes and melanin present but usually reduced Differential Diagnosis Piebaldism Chemical, physical depigmentation Post-inflammatory hypopigmentation Lupus erythematosus Pityriasis alba Tinea versicolor Tuberous sclerosis Leprosy Melanoma-associated leukoderma Idiopathic guttate hypomelanosis Nevus depigmentosus

and there is a reduced number of melanosomes in both melanocytes and keratinocytes; these melanosomes mature only to stages I to III.37

HISTOPATHOLOGIC FEATURES A normal to reduced density of melanocytes is present, but the DOPA reaction is weak compared with the surrounding normal skin. By electron microscopy, the size of melanosomes and degree of melanization are less than the normal counterparts, and their dendrites are less well developed. DIFFERENTIAL DIAGNOSIS The principal entities to be considered are piebaldism, vitiligo, nevus depigmentosus, hypomelanosis of Ito, and postinflammatory hypopigmentation. The ash leaf macules are discriminated from piebaldism and vitiligo by the presence of melanocytes in the former. Nevus depigmentosus may be difficult to distinguish from ash leaf macules because both lesions are usually congenital and show basilar melanocytes in hypopigmented skin. However, the clinical findings of seizures and mental retardation are indicative of TS. The lesions of postinflammatory hypopigmentation are acquired and more variable clinically.

343

Idiopathic Guttate Hypomelanosis

PART II ■ PREDOMINANTLY NONINFLAMMATORY CONDITIONS

Relatively common among older (>50 years) African American men and women (Table 15-5), idiopathic guttate hypomelanosis may be equally frequent in whites but is not as noticeable. Numerous well-demarcated depigmented and hypopigmented (porcelain white) macules 2 to 10 mm in diameter are seen on the shins and, less frequently, on the extensor aspects of the arms. The pathogenesis is uncertain, but given the distribution, a link to chronic UV exposure has been proposed.54-56 HISTOPATHOLOGIC FEATURES The epidermis is atrophic with flattened rete ridges and shows decreased melanin content; biopsies taken at the interface between normal and hypopigmented skin show an abrupt loss of basal layer melanization (Fig. 15-7). Basilar melanocytes are observed but are reduced in number, as confirmed by immunoperoxidase studies using monoclonal antibodies against the KIT receptor and melanocyte differentiation antigens (Tyrp-1, tyrosinase, and gp100/pmel17).56 Ultrastructurally, most melanosomes are immature (stages I and II), and their dendrites are underdeveloped; normal melanocytes may be intermingled with these less active ones. DIFFERENTIAL DIAGNOSIS Vitiligo, chemical and traumatic depigmentation, postinflammatory hypopigmentation, tuberous sclerosis, and tinea versicolor enter into the differential diagnosis.

Table 15-5 Idiopathic Guttate Hypomelanosis

344

Clinical Features Older individual (especially >50 years) Sun-exposed surfaces of the extremities Discrete, usually round, white macules ~5 mm in diameter, multiple, often numerous Histopathologic Features Hyperkeratosis Effacement of epidermis Reduction in number of melanocytes Poorly developed dendrites Significant reduction in epidermal melanin Electron microscopy: Stage I and II melanosomes Differential Diagnosis Vitiligo Physical leukoderma Post-inflammatory hypopigmentation Tinea versicolor

 FIGURE 15-7 Idiopathic guttate hypomelanosis. An abrupt loss of basal layer melanization is seen in this biopsy taken at the interface between normal and hypopigmented skin.

Idiopathic guttate hypomelanosis differs from vitiligo and chemical and traumatic depigmentation by the presence of melanocytes and is discriminated from other leukodermas by its distinctive clinical features and distribution.

Hypomelanosis of Ito or Incontinentia Pigmenti Achromians Hypopigmented bands or streaks following Blaschko lines on the trunk at birth or during the first year of life characterize hypomelanosis of Ito. Repigmentation may occur in some cases. Structural hair shaft abnormalities are often associated.57 Mental retardation or seizure disorders may be present in addition to various other congenital anomalies. Karyotyping of blood lymphocytes, skin fibroblasts, or keratinocytes reveals nonuniform chromosomal abnormalities, including mosaicism for tetrasomy l2p and for trisomy 18, suggesting that somatic cell line mosaicism is responsible for the hypopigmentation. Diploidy/triploidy 45, X/46, X, r(X) or 45, X/46, X_1_mar and chimerism of 46, XX/46, and XY are also relatively frequent. Single-gene inheritance has not been proven in this disease. Due to the nonspecific manifestation of different chromosomal mosaicisms, it has been suggested that the term hypomelanosis of Ito be discarded for more pathogenically or clinically descriptive terminology such as pigmentary dysplasia, pigmentary mosaicism of the Ito type, pigmentary mosaicism, or hypopigmentation along the lines of Blaschko.58-60

HISTOPATHOLOGIC FEATURES The hypopigmented area has fewer and smaller melanocytes than the normal skin; electron microscopy demonstrates decreased numbers of melanosomes in the melanocytes and basal keratinocytes,61 with some melanocytes showing degenerative changes and containing no melanosomes. DIFFERENTIAL DIAGNOSIS The major conditions to be considered are nevus depigmentosus and postinflammatory hypopigmentation. The clinical findings of symmetric swirled lesions in patients with seizures, mental retardation, and other developmental abnormalities should facilitate this discrimination because the histology may be similar.

Nevus Depigmentosus Nevus depigmentosus manifests as a solitary congenital patch of hypopigmentation on the trunk, neck, and other locations.62 Such a lesion may be localized, segmental, or less often systematized. Lesions may be circumscribed, irregular, oval or round, or a unilateral band or streak that may be arranged along one or more lines of Blaschko. When systematized, the lesion is indistinguishable from hypomelanosis of Ito.63 In contrast to vitiligo or piebaldism, depigmentation is not complete, and the contour is usually not smooth as in vitiligo but is rather ragged. Nevus depigmentosus may be associated with

either ispilateral or contralateral segmental lentiginosis or with the acquired onset of multiple pigmented nevi within the hypopigmented region.64-66

vitiligo, and leprosy. In general, the clinical features and identification of microorganisms should allow discrimination of pityriasis alba from other leukodermas.

HISTOPATHOLOGIC FEATURES The number of basilar melanocytes is normal or decreased,67 and the amount of epidermal melanin is decreased in special stains; electron microscopy reveals poorly developed, less dendritic melanocytes with a greatly reduced number of otherwise normal melanosomes. In addition, some membrane bound aggregated melanosomes may be seen in keratinocytes.68

Postinflammatory Leukoderma or Hypomelanosis

Pityriasis Alba Pityriasis alba causes hypopigmented patchy macules around the nose, cheeks, and eyebrow areas of children, particularly in blacks, and is often misdiagnosed as tinea faciae because fine scales may cover the lesion.69 The condition may be as common but is less noticeable in white children and is probably a variant of seborrheic dermatitis or atopic dermatitis, with Pityrosporum infection a contributing factor.70-72 The prevalence of pityriasis alba in patients with atopic dermatitis of Middle Eastern or Asian origin ranges from 12% to 25%.71 HISTOPATHOLOGIC FEATURES The main findings are hyperkeratosis with patchy parakeratosis, slight acanthosis with spongiosis, and a superficial perivascular lymphocytic infiltrate. The lack of pigmentation is due to decreased basal layer melanin; the number of basilar melanocytes is normal or decreased, and these cells produce fewer and smaller melanosomes. Transfer of melanosomes to the keratinocytes is normal. The clinical depigmentation may reflect postinflammatory alterations, but it is possible that Pityrosporum species are involved in the etiology because the tyrosinase inhibitor azelaic acid is produced by these lipophilic yeasts. DIFFERENTIAL DIAGNOSIS The major conditions to be considered are postinflammatory hypopigmentation, tinea versicolor,

HISTOPATHOLOGIC FEATURES In general, reversible forms of leukoderma show basilar melanocytes often in normal

Table 15-6 Postinflammatory Hypopigmentation

Clinical Features Widespread or localized Usually follows dermatitis, such as eczematous dermatitis, psoriasis, pityriasis lichenoides, lichen planus, lupus erythematosus, seborrheic dermatitis, mycosis fungoides Off-white (not fully depigmented) macular lesions with ill-defined margins Repigmentation occurs Histopathologic Features Basilar melanocytes present Reduced melanin in epidermis (blocked transfer to keratinocytes often) Evidence of antecedent inflammatory process may be present in early lesions Differential Diagnosis Vitiligo Chemical, physical depigmentation Tinea versicolor Pityriasis alba Leprosy

Clinical Features Physical injury Thermal injury Radiation Chemical exposure Phenols Catechols Sulfhydryl compounds Depigmented macular lesions of sites of exposure/injury Histopathologic Features Absence of melanocytes and melanin Reparative changes (depending on agent) Differential Diagnosis Vitiligo Scleroderma Onchocercosis Pinta Melanoma-associated leukoderma

numbers but in some instances reduced in number or damaged in concert with reduced epidermal melanin. Some pigment incontinence may be present as well as features of the antecedent dermatitis, such as, for example, lupus erythematosus. The melanocytes may or may not be detected with special stains depending on the degree of melanocyte damage. Permanent forms of leukoderma are characterized by an absence of intraepidermal melanocytes and melanin. In old scars, the melanocytes may have recovered, but fibrosis and the relative paucity of blood vessels contribute to the white color; examples include atrophie blanche, lichen sclerosis et atrophicus, and nevus anemicus.

CHAPTER 15 ■ DISORDERS OF PIGMENTATION

DIFFERENTIAL DIAGNOSIS Conditions to be excluded include piebaldism, segmental vitiligo, tuberous sclerosis, postinflammatory hypopigmentation, and hypomelanosis of Ito. Nevus depigmentosus is congenital and differs from the first two disorders histologically by virtue of having normal numbers of intraepidermal melanocytes and from the latter three entities based mainly on clinical features because the histology may be quite similar.

Hypomelanotic macular lesions may follow a diverse group of inflammatory dermatitides such as eczematous dermatitis, seborrheic dermatitis, psoriasis, drug eruptions, pityriasis lichenoides chronica, lupus erythematosus, lichen planus, alopecia mucinosa, sarcoidosis, and mycosis fungoides (Table 15-6). The clinical lesions are usually off-white (not fully depigmented), often have indistinct margins, and show gradual repigmentation. Melanocytes may also be severely damaged by various physical, chemical, thermal, and other pathologic injuries (Table 15-7). Hypopigmentation may be temporary or permanent. Repigmentation may occur rapidly on sun-exposed sites and in less severely damaged areas. The repigmentation is irregular and often shows a mottled pattern. Total destruction of melanocytes in burns, exposure to certain chemicals, infectious diseases such as pinta or onchocerciasis, discoid lupus erythematosus, scleroderma, halo nevi, and so on may leave a permanent leukoderma.

Table 15-7 Physical Leukoderma (Depigmentation)

DIFFERENTIAL DIAGNOSIS The differential diagnosis includes conditions with detectable basilar melanocytes and those with absence of epidermal melanocytes. The former include early or trichrome vitiligo, tuberous sclerosis, hypomelanosis of Ito, nevus depigmentosis, leukoderma secondary to infectious processes (tinea versicolor, leprosy, syphilis), and pityriasis alba. The latter include established vitiligo, piebaldism, and other forms of secondary depigmentation. Diagnosis is predicated on confirming a relationship to an antecedent dermatosis, chemical exposure, or trauma; exclusion of an infectious agent; and clinical features.

Nevus Anemicus Nevus anemicus is characterized by a congenital white patch with an irregular

345

PART II ■ PREDOMINANTLY NONINFLAMMATORY CONDITIONS

border and is found most commonly on the trunk, particularly the chest.72,73 Familial cases have been reported.74 Rubbing the border makes the normal skin erythematous while the lesion remains white. It is a vascular malformation in which the abnormality of the involved vessels is functional rather than anatomic.75 The abnormality seems to be a focal hypersensitivity of blood vessels to catecholamines, possibly mediated by an abnormality in endothelial adhesion molecule induction (E selectin expression),76 resulting in vasoconstriction. The intralesional injection of an α-adrenergic blocker, unlike the intralesional injection of vasodilators such as histamine and acetylcholine,76 may induce erythema. Nevus anemicus may be linked with certain genodermatoses, including neurofibromatosis and phakomatosis pigmentovascularis.77 HISTOPATHOLOGIC FEATURES Epidermal melanocytes and dermal blood vessels are normal in number and size. Other dermal components are likewise normal.

HYPERPIGMENTATION DISORDERS In this group of diseases, the epidermal melanocytes manifest an increase in function, in number, or both; accordingly, the epidermis is hypermelanized, and excess pigment is present in the upper dermis either in an extracellular locale or, after phagocytosis, in the cytoplasms of macrophages (melanophages). Vacuolar degeneration of basal cells releases melanin granules into the upper dermis to cause hyperpigmentation, particularly in darkskinned individuals (Fig. 15-8). Disorders of hyperpigmentation thus may be classified histologically according to the predominant pattern as epidermal, dermal (pigment incontinence), or mixed epidermal and dermal. The predominant location of the excess melanin correlates with the color of the hyperpigmentation: brown (epidermal), blue-gray (dermal), and brown-gray (mixed epidermal and dermal). Attempting to classify these disorders is often of limited use because many patients have varying degrees of both epidermal and dermal hyperpigmentation. These disorders are also classified by clinical distribution as generalized or diffuse and patterned or circumscribed.

Generalized or Diffuse Hyperpigmentations 346

Although the patient is diffusely hyperpigmented in the following conditions,

 FIGURE 15-8 Lupus erythematosus. Vacuolization of the basal cells and incontinence of the released melanin into upper dermis are seen. These melanin granules are tattooed in the dermis semipermanently. A thin epidermis makes these pigment granules more readily visible.

disease-specific, preferential areas of hyperpigmentation may be seen (see Fig. 15-2). Sun-exposed areas are affected more frequently in many of these conditions.

Addison Disease Addison disease is a primary disorder of adrenocortical insufficiency and is recognized in the modern era to be predominantly of autoimmune etiology.78 Patients present with hyperpigmentation that is most pronounced in the sun-exposed areas that normally exhibit dark skin such as the axillae, nipples, genitalia and other skin folds, and oral mucosa (including the tongue). Also present are fatigue; nausea; loss of appetite and weight; low blood sugar and sodium; low blood pressure; and decreased levels of plasma cortisol, adrenocorticotropic hormone (ACTH), urinary 17-hydroxy-corticosteroids (OHCS), and 17-ketosteroids (KS). Formerly, blunted or absent responses of plasma cortisol levels to ACTH stimulation were a mainstay of diagnosis, but autoantibodies targeting steroid 21-hydroxylase causing adrenocortical atrophy or hypofunction79 are now detectable clinically and enable the accurate diagnosis of Addison disease of autoimmune type.80 The infrequent nonautoimmune causes reflect metastatic tumors; bilateral adrenal hemorrhage due to anticoagulant therapy; adrenal gland infarction due to coagulation defects such as seen

in the setting of antiphospholipid antibody syndrome81 or factor V Leiden82 infections such as histoplasmosis, tuberculosis, or cytomegalovirus infections83; and infiltrative disorders such as sarcoidosis or amyloidosis.84 The mechanism of hyperpigmentation is thought to be related to the elevated ACTH secretion, which is accompanied by the byproducts α- and β-melanocyte-stimulating hormone (MSH), which stimulate melanin synthesis.85,86 HISTOPATHOLOGIC FEATURES The number of melanocytes is normal, but their activity is increased, resulting in heavily melanized cells in the basal layer and stratum spinosum, often associated with pigment incontinence. DIFFERENTIAL DIAGNOSIS This pattern of increased epidermal melanin with some degree of pigment incontinence is entirely nonspecific and may be associated with a wide variety of etiologies. Some examples include Graves disease, malnutrition, hemochromatosis (especially early), argyria, arsenic ingestion, use of drugs with photosensitizing characteristics such as amiodarone and minocyclin, and use of psychotropic and chemotherapeutic agents.87

Nelson Syndrome CLINICAL FEATURES Nelson syndrome reflects an ACTH-producing pituitary

without incontinence of melanin to the upper dermis is responsible for the pigmentation: porphyria cutanea tarda, dermatomyositis, progressive systemic sclerosis, Whipple intestinal lipodystrophy, primary biliary cirrhosis, vitamin B12 deficiency, and folate deficiency.

HISTOPATHOLOGIC FEATURES Increased melanin production by a normal population of basal melanocytes is observed.

1. Dyschromatosis symmetrica (DohiKoyama), acropigmentatio symmetrica (Dohi), leucopathia punctaa ta et reticularis symmetrica (Matsumoto).100 The dorsal hands, feet, and extensor surfaces of the forearms and lower legs manifest punctate or reticulated hyper- and hypopigmentation. Distal lesions are more prominent than proximal ones, and the face is freckled. Because some patients manifest photosensitivity, some authors believe that these are forme frustes of xeroderma pigmentosum. Inheritance is autosomal dominant. Dyschromatosis symmetrica is characterized by mutations of either the double-stranded RNA-specific adenosine deaminase gene (ADAR1 or DSRAD) on chromosome 1q21.3 or an as yet uncharacterized locus on chromosome 6.101

POEMS or Crow-Fukase Syndrome CLINICAL FEATURES POEMS is an acronym for polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes. In this syndrome, an M protein–producing plasma cell dyscrasia is present. The clinical picture is more broad and more pleomorphic than the acronym suggests.93 For example, patients may manifest sclerotic bone lesions, Castleman disease, papilledema,94 or high-output cardiac failure, perhaps related to high levels of VEGF in the serum.95,96 The skin manifests pigmentation that is diffuse or more prominent on the extensor surfaces of the arms, neck, and back. The hyperpigmentation may be the result of the deposition of neoplastic plasma cell products in the skin; findings of a superficial and deep lymphoplasmacytic perivascular infiltrate without demonstrable kappa or lambda light chain restriction have been reported.94 Also seen are vasculitis,97 scleroderma-like fibrosing dermopathy,98 plethora, leukonychia94 and Raynaud phenomenon.98,99 In addition to the pigmentary anomaly and scleroderma-like skin thickening, hypertrichosis and glomeruloid or cherry-type angiomas are nearly constant, albeit not pathognomonic, findings.91,98,99 Treatment of the plasmacytoma may decrease the hyperpigmentation.

OTHER CONDITIONS Generalized or diffuse hypermelanosis may occur in individuals with the disorders listed below and in those with other conditions. In the following disorders, hypermelanosis of the epidermis with or

Acromelanosis A number of different names are applied to similar dyschromic conditions that are rare or variable in their presentations and are characterized by a hyper- or hypopigmented epidermis showing increased or decreased melanocyte activity with variable basal layer melanization and pigment incontinence.105

universalis 2. Dyschromatosis hereditaria (Toyama-IchikawaHiraga). 100,102,103 In this variant, the lesions are generalized. Sharply demarcated brown macules occur on hypopigmented skin. It has been suggested that this entity is clinically and genetically distinct from dyschromatosis symmetrica. In contrast to dyschromatosis symmetrica, dyschromatosis universalis hereditaria demonstrates normal numbers of activated melanocytes containing decreased amounts of fully melanized melanosomes and may be autosomally recessively inherited.104 3. Diffuse acromelanosis.100,102,103 Diffuse and not reticular pigmentation of the fingers is seen in children from deeply pigmented ethnic groups. Pigmentation may extend proximally as the patient ages. 4. ANOTHER syndrome. This acronym designates alopecia, nail dystrophy,

ophthalmic complications, thyroid dysfunction, hypohidrosis, ephelides and enteropathy, and respiratory tract infection.106,107 Reticulated hyperpigmentation appears during infancy, often on the trunk and the hands and feet, including the palms and soles. Mild basal cell hyperpigmentation and pigment incontinence in the upper dermis are seen.

Circumscribed or Patterned Hypermelanosis In this group of hyperpigmentation disorders, patterned or special regional increases in skin pigmentation occur (Table 15-8). The pigmentation is often reticulated, punctate, or spotty. 1. Zosteriform hyperpigmentation. Lentiginous, cribriform, or macular hyperpigmented lesions are present at birth or develop in the second to fourth decades of life. The pattern of pigmentation is dermatomal or zosteriform on various parts of the body. Histopathologic features range from increased basal layer pigmentation with absent melanocytic hyperplasia to a morphology in which variable keratinocytic pigmentation is accompanied by collections of nevus cells at the tips of rete ridges. Dermal melanophages may be present.108-110 Recently, it has been suggested that zosteriform hyperpigmentation exists on the same spectrum of disease as linear and whorled nevoid hypermelanosis.111

CHAPTER 15 ■ DISORDERS OF PIGMENTATION

adenoma, as is seen in 10% to 47% of patients with Cushing syndrome who have undergone adrenalectomies.88,89 By the same feedback inhibition mechanism as the one that is in play in Addison disease, β-MSH and ACTH are increased concomitant to pituitary hyperplasia or the development of an adenoma. Because the pituitary neoplasm may be slow growing and because tumor volume and plasma ACTH levels correlate, it may take decades for symptoms to occur after adrenalectomy.90,91 Hyperpigmentation is similar to that in Addison disease and consists of generalized darkening of the skin and hair. In addition, multiple lentigines and pigmented bands involving the nails may be seen.92

2. Inherited patterned lentiginosis. Multiple small, pigmented spots are scattered mainly on sun-exposed areas such as the face and outer arms but also on the buttocks and sometimes the palmoplantar surfaces of persons of African origin.112 The onset is in infancy or early childhood, and transmission is in an autosomal dominant fashion. Lightcolored siblings tend to develop this anomaly. Prominent hyperpigmentation of the lower epidermis, particularly the basal layer, and effaced rete ridges are observed. 3. LEOPARD, Moynahan’s, or multiple lentigines syndrome. This is an autosomal dominant disease typified by multiple lentigines affecting any part of the body from the scalp to the feet. Most cases are associated with mutations of protein-tyrosine phosphatase, nonreceptor type 11 (PTPN11).113-115 In addition to

347

Table 15-8 Circumscribed Hypermelanosis

Sunlight responsive, 1–3-mm macules Light to medium brown

Normal

Reduced, normal, increased

Persistent 1–5-mm macule. Light to dark brown Sun-exposed skin, 5–15-mm macules Medium to brown 2–5-cm oval macule, uniform tan to dark brown

Elongated, club-shaped epidermal rete ridges Elongated, club-shaped rete ridges, often anastomosing Normal

Increased

Patterned macular pigmentation on face Macular or raised lesion, a few to several cm Tan to dark brown, often hairy

Normal

Freckle

Lentigo

Café-au-lait macule

PART II ■ PREDOMINANTLY NONINFLAMMATORY CONDITIONS

BASILAR MELANOCYTES

CLINICAL FEATURES

Solar lentigo

348

EPIDERMAL CONFIGURATION

DISORDER

Melasma Becker melanosis

lentigines, electrocardiographic abnormalities, ocular hypertelorism, pulmonic stenosis, abnormal genitalia, growth retardation, and deafness are present; because of these associated abnormalities, the disorder is also called LEOPARD syndrome.116,117 Elongation of rete ridges, increased melanocytes, and increased melanization of the epidermis are noted. On electron microscopy, giant melanosomes and complex melanosomes are seen. 4. Peutz-Jeghers syndrome. In this autosomal dominant disorder associated with mutations of the serine threonine kinase gene STK11/ LKB1,118,119 patients have small, irregularly contoured macules localized to the oral mucosa, lips, perioral skin, and dorsal skin of the fingers.120-122 In the majority of cases, multiple polyps develop in the small intestines that may become malignant in 2% to 3% of patients. The basal cells are heavily pigmented, but there is no increase in the number of melanocytes with special stains. There may be some disturbance of pigment transfer to basal keratinocytes. 5. Dowling-Degos disease or reticulate pigmented dermatosis of the flexures. This is a dominantly inherited condition that manifests slowly spreading areas of reticular hyperpigmentation involving flexural or frictional surfaces such as the axillae;

Elongated rete ridges to papillomatous

OTHER FEATURES Melanocytes larger with increased development of dendrites

Normal or increased

Normal or slightly increased Normal or slightly increased Normal or slightly increased

neck; groin; and in women, inframammary folds.123,124 Rare generalized forms have been reported.125 Perioral comedo-like follicular keratosis and pitted scars may be present. The distribution of hyperpigmentation is similar to that in acanthosis nigricans, but the lesions manifest a velvety texture. The age of onset is usually in the third and fourth decades of life. Haber syndrome consists of rosacea-like facial erythema and telangiectasia associated with black keratotic papules of the axillae, neck, and occasionally trunk; it may be the same as Dowling-Degos disease.126 Dowling-Degos disease and Haber syndrome both manifest elongated, tapered, heavily melanized retia with small horn cysts or follicular plugs (Fig. 15-9), generating an appearance similar to adenoid seborrheic keratosis. 6. Naegli-Franceschetti-Jadassohn syndrome. This is a rare autosomal dominant disease of childhood onset in which punctate pigmentation involves the axillae, neck, and trunk.100 Mutations of KRT14 may render keratinocytes more susceptible to TNF-α–induced apoptosis.127 Hypohidrosis, palmoplantar hyperkeratosis, and abnormalities of the teeth and nails may be present. Increased epidermal melanization and melanophages in the upper dermis may be detected.

Association with neurofibromatosis, melanin macroglobules Pigment incontinence may be prominent Smooth muscle hamartoma in dermis often

7. Dermatopathia pigmentosa reticularis. This is a heterogeneous autosomal dominant disease. A constant finding is reticulated pigmentation over the trunk and extremities. Loss of the fingernails and toenails; hypohidrosis; and atrophy of the skin of the elbows, knees, and extremities may occur.128 8. Cantu syndrome. This is an autosomal dominant disorder characterized by hypertrichosis, osteodysplasia, and cardiomegaly with onset in adolescence. Small punctate, hyperpigmented macules that often have a reticular pattern involve the face, forearms, and feet. Hyperkeratosis of the palms and soles may be associated with the disorder.129,130 neurodysraphic 9. Centrofacial lentiginosis. This is also an autosomal dominant disease characterized by centrofacial lentigines without mucous membrane involvement.131 No lentigines are present in areas other than the face. Associated abnormalities include seizures, mental retardation, psychiatric disorders, endocrine disorders, and bone abnormalities. Lentigines regress over time. 10. Carney syndrome. This is also called lentiginosis with cardiocutaneous myxomas or NAME (nevi, atrial myxoma, myxoid neuroma, and ephelides) syndrome. This autosomal dominant syndrome is caused by inactivating mutations in

 FIGURE 15-9 Dowling-Degos disease. Irregularly elongated, slender rete ridges are heavily pigmented. A few keratin cysts and keratin plugs are present.

the PRKAR1A gene coding for the cyclic AMP–dependent protein kinase A regulatory subunit type 1A.132,133 Mucous membrane lentiginosis and associated cardiac (classically with cardiac myxomas) and endocrine abnormalities may be present.134,135 11. Generalized lentiginosis. In this disorder, patients have many lentigines that appear at birth in a generalized dense distribution yet sparing mucous membranes and without associated abnormalities.136

Incontinentia Pigmenti (Bloch-Sulzberger Syndrome) Incontinentia pigmenti is a multisystem polydysplasia with prominent cutaneous findings accompanied by variable anomalies of dental, CNS, and eye development.137 This is mainly an X-linked dominant disorder that is usually lethal in hemizygous males. Survival of affected males has been attributed to the presence of hypomorphic alleles, postzygotic somatic mosaicism of the NEMO gene, or the 47 XXY karyotype (Klinefelter syndrome).138,139 Mutations in the NF-κB essential modulator (NEMO/IKKγ) gene mapped to chromosome Xq28 account for 85% of cases.140 Mutations of the NEMO gene are also responsible for an allelic X-linked disorder, hypohidrotic ectodermal dysplasia with severe immunodeficiency syndrome. 141,142 When

activated, NF-κB controls the expression of multiple genes, including a variety of cytokines, and protects against apoptosis.137 It is postulated that NF-κB stimulation in IKKγ-positive cells results in the elaboration of cytokines inclusive of RANTES and eotaxin that provoke tissue and peripheral blood eosinophilia. Recent studies have shown that the expression of eotaxin in the epidermis parallels the accumulation of eosinophils.143 The variable expressions and severity of disease are explained by X inactivation (Lyon hypothesis) in females. For example, if the affected allele is inactivated, amelioration of the disease may occur and produce subtle cutaneous and dental findings. The alternate extreme generates debilitating CNS and ophthalmologic anomalies.137 In consequence of mosaicism, some affected patients may manifest involvement of one or a few limbs only.137 There are four stages of cutaneous disease, each of which may overlap or be skipped: vesicular, verrucous, hyperpigmented, and atrophic. The vesicular stage is seen in 90% of patients and manifests between birth and 2 weeks of age as erythematous lesions that occur in groups, often distributed along Blaschko lines on the trunk and extremities in 65% of patients and on the extremities alone in 33% of patients.137 These lesions resolve in a few weeks and are followed at age 2 to 6 weeks in about 70% of patients by the second stage of verrucous lesions that

HISTOPATHOLOGIC FEATURES In vesicular lesions, intraepidermal eosinophilic spongiosis with vesicle formation, intraepidermal eosinophilic microabscesses, and dyskeratosis are seen. In the verrucous stage, skin biopsies show hyperkeratosis and acanthosis with papillomatosis and cytoid bodies. In the lesions of whorled or linear hyperpigmentation, the most prominent alterations are vacuolar basilar keratinocytic degeneration and pigment incontinence. The atrophic latestage lesions manifest epidermal atrophy with attenuation of the retiform pattern and atrophy of adnexal structures with loss of the eccrine straight ducts and secretory coil. Basilar melanocytes are functionally normal but markedly reduced in number. DIFFERENTIAL DIAGNOSIS Clinicopathologic correlation greatly augments the diagnosis of incontinentia pigmenti, with no other pathologic condition showing the classic constellation of lesions and their characteristic progression through the aforementioned recognizable stages. With respect to the early stage, immunobullous diseases such as bullous pemphigoid or dermatitis herpetiformis may generate eosinophilic spongiosis and dyskeratosis but are easily separable based on direct immunofluorescence findings. The hyperpigmented lesions show nonspecific pigment incontinence indistinguishable histologically from other forms of predominantly dermal postinflammatory hyperpigmentation. However, on occasion, the concomitant features of eosinophilic spongiosis or a whorled pattern of dyskeratosis may be observed. Linear and whorled nevoid hypermelanosis may be similar clinically but lacks

CHAPTER 15 ■ DISORDERS OF PIGMENTATION

follow the previous vesicular lesions and particularly affect the extremities. These verrucous lesions subside in 80% of affected patients by 6 months of age, and as they subside, they yield whorled hyperpigmentation in areas that correspond to the previous verrucous lesions (ie, in Blaschko pattern). The late stage is seen in teens and young adults who exhibit atrophic lesions with hypo- or depigmentation on the extremities. These stages may coexist at any given time in any given patient or, alternatively, may not occur at all. Alopecia of the vertex, sometimes accompanied by agenesis of eyebrows and eyelashes, nail dystrophy (≤40% of patients), dental defects (≤80% of patients), eye findings (cataracts, blindness), and CNS abnormalities (seizures, mental retardation) are common disease manifestations.137

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pigment incontinence, the clinical hyperpigmentation reflecting basilar keratinocyte pigmentation.137

PART II ■ PREDOMINANTLY NONINFLAMMATORY CONDITIONS

Dyskeratosis Congenita Dyskeratosis congenita is a heredofamilial bone marrow failure syndrome associated with increased cancer susceptibility.144,145 Most often transmitted as an X-linked recessive trait affecting males, dyskeratosis congenita is caused by mutations of the DKC1 gene that maps to Xq28 and encodes for dyskerin, a protein held to play a role in ribosomal biogenesis. Cell lines with this mutation manifest markedly increased apoptosis with increasing cell division, thus explaining the worsening severity of disease expression after age 10 years.146 Other mutations associated with telomerase enzyme deficiency and progressive telomerase shortening have been described in TERC, TERT, NOP10, and TINF2 telomerase enzyme deficiency and progressive telomere shortening.147 Occasionally, an autosomal dominant mode of inheritance has been observed, with females also being affected. The clinical triad is pterygium-like nail dystrophy, leukoplakia of the oral and occasionally the anal mucosa, and extensive reticulated hyperpigmentation. Leukoplakia may degenerate into squamous cell carcinoma. The hair is thin and lusterless in approximately 50% of patients. The same genetic anomaly is implicated in some cases of idiopathic pulmonary fibrosis. HISTOPATHOLOGIC FEATURES Patients have increased basal layer melanization with slightly increased melanocytes and pigment incontinence. Oral leukoplakia may show in situ or invasive squamous cell carcinoma.

Melasma or Chloasma

350

Melasma is observed most commonly on the faces of dark-skinned women living in tropical or subtropical locations where UV irradiation is intense. Increased estrogen and progesterone levels seem to be causative in susceptible women; pregnancy, contraceptive use, estrogen replacement therapy, and ovarian tumors are often linked to the onset. The face is symmetrically involved in one of three patterns: a centrofacial pattern involving the forehead, nose, cheeks, upper lip, and chin; a malar pattern; and a mandibular pattern. The hyperpigmentation may be predominantly epidermal and consequently brown, dermal and therefore bluish, or both epidermal and dermal and thus both brown and blue.148

HISTOPATHOLOGIC FEATURES Epidermal melanocytes are usually slightly increased in number and activity. Corresponding to the clinical patterns, increased melanin may be localized primarily to the epidermis, upper dermis, or both. Immunostains highlight enlarged, intensely stained melanocytes with prominent dendritic processes. Melanocytes may demonstrate increased numbers of melanosomes on electron microscopy.149 DIFFERENTIAL DIAGNOSIS The major entities to be considered include postinflammatory hyperpigmentation, café-au-lait macules (CALMs), and lentigo. Melasma may be histologically indistinguishable from postinflammatory hyperpigmentation, but the clinical presentation should readily allow its discrimination.

Ephelides or Freckles Freckles, or ephelides, are light-brown macules that predominantly affect lightskinned individuals and occur on sunexposed areas, particularly the face, upper back, shoulders, and dorsa of the hands and forearms. Fair-skinned individuals are more often affected; in northern Sweden, the prevalence among children of ages 12 to 16 years is 18.4%.150 Only occasionally are freckles seen in persons with dark complexions. Lesions are typically less than 2 mm in diameter and almost always smaller than 4 mm in diameter. The borders may be irregular, but pigmentation is uniform, becoming more obvious after sun exposure and less conspicuous during the winter months.151 Lesions often first appear during childhood and tend to persist into adulthood. Freckles may manifest an autosomal dominant pattern of inheritance, appearing in sequential generations.152 Freckles may become clinically inapparent in elderly individuals but even then are be identifiable under Wood’s lamp examination.153 HISTOPATHOLOGIC FEATURES A freckle reflects increased melanization of the epidermis attributed to increased melanin production that manifests as hyperpigmentation of basal layer keratinocytes unaccompanied by elongated retia, adnexal involvement, or increased numbers of melanocytes. Indeed, melanocytes may even be decreased in number relative to uninvolved skin.152 With silver preparations, dendritic melanocytes may be identified, a finding associated with photoadaptive effects. Melanization of the basal layer occurs because of larger and more active melanocytes that produce stage IV

melanosomes, even in fair-skinned individuals. Melanophages may be present in the papillary dermis. DIFFERENTIAL DIAGNOSIS The differential diagnosis includes café-au-lait spots, melanotic macules of Albright, lentigo simplex, and actinic lentigo. In contrast to freckles, the café-au-lait spots manifest giant melanosomes and a normal or slightly increased number of melanocytes. Melanotic macules of Albright and lesions of melasma may be indistinguishable from freckles.153 Lentigo simplex shows elongated retia with variable melanocytic hyperplasia. Other conditions may produce a histomorphology indistinguishable from that of freckles but are associated with a distinctly different clinical appearance, namely, reticulate pigmentation of the neck,154 reticulate pigmentary anomaly of the flexures (Dowling-Degos disease),155 and reticulate acropigmentation of Kitamura,156 with which it overlaps,157 and the Naegli-FranschettiJaddasohn syndrome, which combines reticulate pigmentation of the trunk and limbs with anomalies of eccrine and nail structures.154,158 Solar lentigo differs from freckles by also showing elongated and hypermelanotic club-shaped retia; melanocytes may be normal in number or may present in up to twice the density of non–sun-exposed skin.

Café-Au-Lait Spots and Axillary Freckling Café-au-lait macules (CALMs) are one of the hallmarks of NF1 or von Recklinghausen multiple neurofibromatosis, being seen in 90% of patients.159,160 NF1 is associated with mutation in the NF1 gene, resulting in abnormal expression of neurofibromin, an inhibitor of the Ras growth-promoting pathway.161 The light tan color of CALMs is only apparent in light skin; in individuals with dark complexions, the color is much darker. CALMs are not influenced by UV rays and are most common on the covered areas of the body. If an individual has six CALMs of 1.5 cm or larger, the development or presence of NFl is 100% certain. Axillary, inguinal, and inframammary freckles are not darkened by sun exposure and are different from facial freckles both clinically and histologically. Axillary or inguinal freckles are observed in 8l% of affected children younger than age 6 years and often precede the appearance of neurofibromas. HISTOPATHOLOGIC FEATURES The epidermis is of normal thickness and exhibits basal layer hyperpigmentation. Although the

number of basilar melanocytes appears normal, an increased number and activity of melanocytes can be demonstrated with special stains. By light or electron microscopy, giant melanosomes up to 5 μm in diameter are seen in these melanocytes but are said to be absent in the lesions of children and are also found in melanotic macules of McCuneAlbright syndrome, lentigo simplex, melanocytic nevi, multiple lentiginosis, Chediak-Higashi syndrome, and other conditions.

Macules of McCune-Albright Syndrome Albright syndrome manifests as polyostotic fibrous dysplasia, melanotic macules, and hyperfunctional endocrinopathies that typically eventuate in precocious puberty. It mainly occurs in females. The clinical expression of the syndrome is attributed to sporadic postzygotic mutations of the GNAS1 gene that encodes the α subunit of a signal-transducing guanine nucleotidebinding (G) protein and the mosaic distribution of cells that express the mutant allele.162-164 The G proteins couple hormone receptors to the enzyme adenylate cyclase, the distribution of which includes renal proximal tubules, to generate parathyroid hormone resistance. Mutations in the paternal allele are only rarely expressed clinically.165,166 Patients harbor a sporadic mutation that also results in activation of the tyrosinase gene that is the pathophysiologic basis of skin pigmentation.164 Due to mosaicism, the pigment distribution follows Blaschko lines,167,168 occasionally resulting in a pigmented rectangular pattern. Lesions are usually unilateral and typically involve the head and neck region, buttocks, sacrum, and nuchal area, manifesting irregular borders that have been compared with the coastline of Maine. In contrast, the CALMs of neurofibromatosis are more generalized and generally have smooth or rounded borders reminiscent of the coastline of California, although they too can have a “shaggy” contour, and in fact, this criterion is not reliable.169 Solitary or multiple CALMs are seen in roughly two-thirds of patients with Albright syndrome.169,170 The pigmentation in lesions of Albright syndrome is usually darker, and the lesions are

HISTOPATHOLOGIC FEATURES The basal layer of the epidermis is hyperpigmented. The melanocytes are not increased in number but contain giant or macromelanosomes. DIFFERENTIAL DIAGNOSIS The considerations are similar to those of CALMs.

Becker Pigmented Hairy Nevus or Melanosis CLINICAL FEATURES Becker nevus is an acquired lesion that appears in childhood or early adolescence and is believed by most authorities to be a cutaneous hamartoma.171-178 Becker nevus is also termed pigmented hairy epidermal nevus because the presence in some examples of epidermal hyperplasia can make distinction from an epidermal nevus problematic. The term Becker nevus syndrome is applied to the combination of a Becker nevus with developmental defects such as ipsilateral hypoplasia of the breast or limb or skeletal anomalies such as scoliosis, limb asymmetry, or spina bifida occulta.173,179 Becker nevus has a predilection for males and rarely may be familial, with a presumed autosomal dominant pattern of inheritance, although loss of heterozygosity resulting in mosaicim has also been proposed.173,179 Becker nevus

presents as an area of pigmentation up to 20 cm in diameter, sometimes with hypertrichosis that may be associated with a smooth muscle hamartoma; follicular papules, slight induration, and occasionally pain are then observed. A lymphangioma174 or a connective tissue nevus175 may rarely coexist. Because it is not a primary proliferative disorder of melanocytes,176 individuals with Becker nevus are not at increased risk for the development of melanoma. HISTOPATHOLOGIC FEATURES The epidermal changes vary from almost normal to showing acanthosis, papillomatosis, elongation of rete ridges, and hyperpigmentation of the basal layer. Melanocytes may be slightly increased in number in the epidermis. Becker pigmented hairy nevus therefore refers to the hamartomatous combination of hair follicles, increased melanocytes, and smooth muscle. Dermal melanophages are often present. Hair follicles are usually normal but on occasion may be increased in number and enlarged. Increased bundles of smooth muscle are usually present in the reticular dermis177 (Fig. 15-10). Sebaceous gland hyperplasia and thickening of dermal connective tissue may occur. DIFFERENTIAL DIAGNOSIS Becker nevus must be distinguished from an epidermal nevus; a large or congenital lentigo; and other papillomatous lesions, such as confluent and reticulated papillomatosis (of Gougerot-Carteaud) on occasion.

 FIGURE 15-10 Becker nevus. Hypermelanosis of the basal layer and an increased number of arrector pili muscles are seen. Often, as in this case, there is epidermal acanthosis with a papillomatous or mammilated surface cognate to an epidermal nevus.

CHAPTER 15 ■ DISORDERS OF PIGMENTATION

DIFFERENTIAL DIAGNOSIS CALMs cannot be discriminated histologically from melanotic macules of Albright syndrome and may mimic freckles or melasmas. CALMs do not exhibit the elongated epidermal rete ridges and increased numbers of melanocytes observed in simple lentigo.

often larger.167 Distribution along Blaschko lines is not said to be a feature of neurofibromatosis.167

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The clinical finding of a unilateral hyperpigmented and often a hairy patch or plaque and of a smooth muscle hamartoma histologically should facilitate discrimination from the other entities.

PART II ■ PREDOMINANTLY NONINFLAMMATORY CONDITIONS

Prurigo Pigmentosa Prurigo pigmentosa is a rare idiopathic dermatosis consisting of recurrent erythematous papules and reticulate hyperpigmentation most commonly seen in Japanese women in the second and third decades of life.180,181 Cases have been reported in Turkish, Iranian, and Sicilian women as well.182,183 The eruption begins acutely with erythematous papules that become confluent to form intensely pruritic linear or anastomosing elevated lesions; vesicular or exudative papular lesions are described in the initial acute stage. The upper back, shoulders, neck, and chest are common sites of involvement. A familial basis has been reported. Potential etiologic factors include diabetes mellitus, bacterial infection,184 friction with underwear, and contact with cosmetic and antiseptic agents.185 Treatment with minocycline has produced good results.186,187 HISTOPATHOLOGIC FEATURES The early inflammatory stage manifests an interface dermatitis with vacuolization of basal cells, cytoid body formation, exocytosis of lymphocytes, and spongiosis. Pigment incontinence is noted in the older pigmented lesions. DIFFERENTIAL DIAGNOSIS The histologic findings are nonspecific and indistinguishable from other forms of postinflammatory hyperpigmentation that follow an interface dermatitis.

Postinflammatory Hyperpigmentation

352

Damage to basal keratinocytes from multiple sources may result in pigment incontinence in the upper dermis. Interface injury may be a stimulus for melanocytes to produce melanin and to thus generate epidermal hypermelanization (Table 15-9). Another theoretical mechanism is the result of the epidermal inflammatory response producing proinflammatory mediators that stimulate melanosome transfer from their dendrites into dermal melanophages. 188 Melanin polymers may act as an antioxidant; it is possible that epidermal melanocytes may actively transfer melanosomes to the dermal foci of

Table 15-9 Postinflammatory Hypermelanosis

Clinical Features Usually follows inflammatory process Localized or widespread Common dermatoses include lichen planus, lupus erythematosus, eczematous dermatitis, psoriasis, phytophotodermatitis, drug eruptions Gradual loss of pigmentation but may be permanent Histopathologic Features Variable degrees of 1. Epidermal hypermelanosis 2. Pigment incontinence Differential Diagnosis Melasma Endocrine dysfunction Addison disease Malnutrition

inflammation. Dark-skinned individuals are prone to more florid changes because their melanocytes are easily stimulated to produce more melanin granules; the discoloration may be permanent. Causative dermatoses include lichen planus, lichenoid drug eruption, discoid lupus erythematosus (see Fig. 15-8), dermatomyositis, Riehl melanosis, notalgia paresthetica, and mycosis fungoides. In fixed drug eruption and erythema dyschromicum perstans (“ashy dermatosis”), repeated episodes of interface dermatitis eventuate in a gray-blue dyspigmentation as the incontinent melanin accumulates in large amounts in a deeper location in the dermis. Trauma or chronic irritation may also cause postinflammatory hyperpigmentation. HISTOPATHOLOGIC FEATURES Variable epidermal inflammatory changes, such as interface dermatitis, are often visible in early lesions together with melanin deposition in the upper dermis, either free or in melanophages. Epidermal melaninization may be increased. Long-standing lesions typically show pigment incontinence without active inflammation. DIFFERENTIAL DIAGNOSIS The pigmentary alteration alone is entirely nonspecific; an etiologic diagnosis depends on identification of the antecedent inciting injury. Clinical correlation should exclude other causes such as regression of a pigmented lesion.

Friction Melanosis (Nylon Towel Melanosis) Ill-defined, light-brown hyperpigmentation may occur over the bony prominences such as the clavicle, shoulder blades, frontal neck, Adam’s apple, and shins due to repeated rubbing by nylon towels or scrub brushes189,190 or from vigorous rubbing with nonsynthetic fabrics.191 Over the nonbony areas, pigmentation occurs in a rippled pattern similar to that of macular amyloidosis. Early reports described patients who used more durable nylon towels or brushes for a long time that replaced traditional cotton towels or plant-fiber brushes in postwar Japan; similar changes have been described subsequently in Italian patients using horse-hair brushes and cotton towels.190 It is believed that chronic frictional trauma of thin skin over the hard bony structures causes epidermal damage and subsequent pigment incontinence. The mechanism seems to be similar to that involved in lichen amyloidosis, in which tonofilaments of damaged keratinocytes are transformed into amyloid filaments.192,193 HISTOPATHOLOGIC FEATURES Skin biopsies show epidermal atrophy, pigment incontinence, and basal cell vacuolization leading to dermal–epidermal cleavage in severe cases. Amyloid deposits are rarely demonstrated.190,191

Generalized Melanosis in Metastatic Melanoma Widespread metastasis of melanoma may produce generalized melanosis and melaninuria; slate-blue diffuse discoloration of the skin, mucous membranes, and conjunctivae may occur.194 The exact pathogenesis of generalized melanosis remains unclear; tumor-derived factors seem to drive the hyperproliferation of normal melanocytes.195 Neutrophils and monocytes in the circulation may contain melanin, and the intima of arteries and many visceral organs are black. HISTOPATHOLOGIC FEATURES Perivascular melanophages contain melanin granules that are often DOPA positive, indicating that melanin synthesis is still active in the phagocytosed melanosomes, which most likely are derived from bloodborne melanoma cells carried to the skin. The dermal blood vessels may be occluded with DOPA-positive pigment granules. In some cases, only melanophages are present; in other cases, both melanoma cells and melanophages are admixed in the dermis.

Table 15-10 Metal Deposition and Dyspigmentation DISORDER

EPIDERMAL HYPERMELANOSIS

DERMAL ALTERATION

Hemochromatosis Argyria (silver deposition) Chrysiasis (gold deposition) Mercury

Present Present, sun-exposed skin May be present

Arsenic Lead Bismuth

Present

Hemosiderin Silver particles, basement membranes of sweat glands, elastic fibers Gold particles in macrophages and endothelium Brown-black mercury granules either free or in macrophages Arsenic particles Lead particles Bismuth granules in papillary and reticular dermis

May be present

Miscellaneous pigmented substances may deposit in the skin and produce various discolorations (Tables 15-10 and 15-11).

Ochronosis Endogenous ochronosis is an autosomal recessive disease of homogentisic acid oxidase deficiency.196-198 A slow accumulation of homogentisic acid, which is an intermediate product of metabolism of phenylalanine to tyrosine, causes pigmentation of cartilages and eventually the skin. An affected child’s urine, if

exposed to the air or an alkylizing agent for a few hours, turns pink to brown (alkaptonuria), and staining of the diaper is the first sign of the disease in 50% of cases.199-202 Cutaneous signs usually do not develop until 30 years of age.199 This is a rare disease in the United States (one in 250,000) but is more frequent in the Dominican and the Czech Republics (one in 25,000). Because the cartilage of the ear is covered with thin skin, a bluish gray to dark brown color is readily noticed. A butterfly pattern of pigmentation of the face, including the nose, may suggest photosensitivity. Axillary sweat may be variously colored from greenish blue to greenish yellow-

Refractile granules on dark-field examination Refractile granules on dark-field microscopy

brown. The sclera and teeth may also be pigmented. Alkaptonuria is diagnosed by gas chromatography–mass spectrometry analysis or a colorimetric assay of a 24-hour urine specimen.199 Exogenous ochronosis or pseudoochronosis is caused by the chronic topical use of high-concentration (6%–8%) hydroquinone, resorcinol, phenol, quinine injection, systemic antimalarial therapy, or exposure to benzene.198 In hydroquinone-induced ochronosis, blue-black pigmentation is seen most obviously on prominent parts of the face (ie, the cheeks, forehead, nose, and in some cases, the chin), suggesting photoinduction. The discoloration is usually permanent

CHAPTER 15 ■ DISORDERS OF PIGMENTATION

Pigment Deposits Other Than Melanin

OTHER FINDINGS

Table 15-11 Drug-Related Dyspigmentation DRUG Minocycline 1. Facial, blue-black pigmentation 2. Extremities, bluegray pigmentation

EPIDERMAL HYPERMELANOSIS Usually not present Usually not present

3. Sun-exposed skin, brown pigmentation Antimalarials Chloroquine Quinacrine Amiodarone

Present

Chlofazamine Psychotropic drugs

Present Present

Chemotherapeutic drugs

Present

DERMAL ALTERATION

OTHER FINDINGS

Drug metabolite-protein complex in macrophages that stains for iron but not melanin Drug metabolite-protein complex that stains for iron and is positive by the Fontana reaction but fails to bleach (and thus is not melanin) Melanin, negative iron stain

Drug-melanin complex, hemosiderin Quinacrine Drug metabolite in endothelium, macrophages

Drug metabolite pigment granules in phagolysomes

Melanin, ceroid-like material Drug-metabolite melanin in macrophages, endothelial cells Melanin

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PART II ■ PREDOMINANTLY NONINFLAMMATORY CONDITIONS

despite discontinuation of hydroquinone. Annular lesions similar to actinic granuloma may occur.200 It has been proposed that the inhibition of the enzyme homogentisic oxidase is a pathogeneic mechanism shared by both endogenous and exogenous ochronosis.203

tattoos are clinically evident. The usual histologic appearance for the common carbon tattoo is that of a jet-black material rather than the granular brown character of melanin in dermal melanocytic lesions.

HISTOPATHOLOGIC FEATURES The pigment in the dermis is a yellow-brown or ochre color with the H&E stain, hence the designation ochronosis. A blue-gray-brown color is produced by scattering of light from deep-seated ochre-colored pigment (Tindall effect). The pigment is also observed in the endothelial cells of the blood vessels, basement membranes, secretory cells of eccrine glands, and dermal macrophages. However, the most diagnostic form of deposition is the banana-shaped dermal collagen fibers that become swollen, rigid, and fragmented with jagged ends. The same pigment is deposited on elastic fibers, which also degenerate. The epidermis is normally pigmented. Sarcoidal granulomata may occur, as may transepidermal elimination of degenerated collagen.200

Hereditary hemochromatosis is a spectrum of autosomal recessive diseases characterized by hyperabsorption of dietary iron.202,204-207 The five predominant designations are HFE-related or type 1 hemochromatosis, type 2 hemochromatosis (juvenile hemochromatosis), type 3 hemochromatosis (transferrin receptor 2 hemochromatosis), type 4 hemochromatosis (ferroportin disease), and hypoceruloplasminemia.208 The causative gene in type 1 hereditary hemochromatosis is designated HFE; most patients of European origin are homozygous for a cystein to tyrosine residue subsitution204 that likely renders the gene’s protein product incapable of binding to the transferrin receptor, dysregulating the threshold for iron absorption by enterocytes. Clinical penetration is seen in 4% to 25% of homozygotes.205,207 Skin pigmentation, liver cirrhosis, cardiac failure, and diabetes mellitus make up the clinical tetrad.202,204-207 In white skin, discoloration varies from bronze (bronze diabetes) to blue-gray; in pigmented skin, the discoloration is brown to black. Pigmentation is most pronounced in the sun-exposed areas, skin creases and folds, and nipples and often

Tattoos Tattoos may occur secondary to accidental introduction of pigments into the skin, such as the graphite of lead pencils or of carbon in coal miners, but are more commonly a reflection of the deliberate cosmetic injection of dye substances.201 Common dyes injected in professional tattoo parlors are cinnabar or mercuric sulfide (red), chromic oxide (green), cobaltous albuminate (light blue), cadmium sulfide (yellow), and iron oxide or ochre (brown).

Idiopathic Hemochromatosis

precedes other symptoms; this is an important sign because early treatment with phlebotomy and chelating agents improves the prognosis significantly as long as serum ferritin levels are kept at 100 ng/mL or lower. Systemic symptoms in patients with type 1 disease appear only after sufficient iron storage (20 to 60 g), usually between 35 and 60 years of age; in type 2 hemochromatosis, clinical signs of hypogonadism and cardiomyopathy develop before age 30 years.207 HISTOPATHOLOGIC FEATURES In early cases without systemic symptoms, epidermal atrophy and basilar hypermelanosis (but no deposition of hemosiderin) are observed. Hemosiderin deposition is seen later in the cytoplasm of eccrine secretory cells, periglandular connective tissue, and perivascular macrophages. DIFFERENTIAL DIAGNOSIS The golden refractile appearance of hemosiderin and a Prussian blue stain permit separation from melanin and other pigments.

Hemosiderin from Other Sources Any hemorrhage leaves erythrocytes in tissue, and their degradation causes temporary or long-term hemosiderosis. Yellow-brown discoloration follows chronic, repeated bleeding such as in stasis dermatitis, vasculitis, and pigmented purpuric dermatoses. Histopathology is related to the individual conditions. Hemosiderin is seen

HISTOPATHOLOGIC FEATURES After an acute inflammatory reaction, these inert pigments elicit little or no tissue reaction in most cases. Pigments are found scattered in the upper dermis, particularly around blood vessels. Late-stage reactions include dermal contact dermatitis, lichenoid dermatitis, foreign-body reaction with giant cells, and sarcoidal granulomatous reactions (Fig. 15-11). Several patients have developed hilar lymphadenopathy together with sarcoidal reactions at tattoo sites; patients with underlying sarcoidosis manifest exaggerated reactions to injected dyes. Lymphomatoid reactions may be seen with cinnabar tattoos.

354

DIFFERENTIAL DIAGNOSIS The major conditions to be considered include blue nevi and other dermal melanocytoses as well as iron and other metal depositions. Most

 FIGURE 15-11 Tattoo with graphite (pencil). Black pigment particles are scattered from the main body of accidentally inoculated graphite. A granulomatous reaction is seen.

most often in perivascular spaces and is demonstrable with iron stains.

Gold Deposition (Chrysiasis) or Chrysoderma

“Bronze Baby” Syndrome

Prolonged injection of gold salts induces slate-gray to blue discoloration of exposed skin. In such patients, laser treatment of skin conditions may elicit chrysiasis in normal-colored skin.215,216

HISTOPATHOLOGIC FEATURES The nature of the pigment causing skin discoloration has not been elucidated. It may be a photoisomer of bilirubin or photoproducts of copper-bound porphyrins that have been elevated in the serum of some patients.

Silver Deposition (Argyria) Slate-gray pigmentation, particularly on sun-exposed sites and the azure lunula of nails, develops after a prolonged ingestion or application to mucous membranes of silver salts. Absorption from mucous membranes may cause local as well as systemic argyria. Visceral organs accumulate silver and show blue discoloration. Localized argyria may occur as a result of wearing earrings with silver backs, the application of silver sulfadiazine cream for the treatment of burns, after acupuncture, with the use of silver wire for sutures, and after traumatic implantation of silver.211-213 HISTOPATHOLOGIC FEATURES Silver particles that have a dark brown to black granular appearance are scattered extracellularly in the dermis and are concentrated in the basement membranes of eccrine sweat glands, perifollicular sheath, nerves, capillary walls, and elastic fibers. Silver particles are best demonstrated by polarized light microscopy as refractile particles; silver sulfide deposits may be evident by electron microscopy.214 Silver particles are absent in the epidermis, but hypermelanosis of the epidermis, particularly in exposed areas, is evident. Actinic elastosis of sun-exposed skin also attracts silver particles.

HISTOPATHOLOGIC FEATURES In contrast to silver, gold particles are found in vascular endothelia and dermal phagocytes; polarized light microscopy demonstrates large, refractile particles in those locations. Light seems to intensify the color by making the gold particles larger.

Mercury Mercury-containing cream (ammoniated mercury) was once used extensively by dermatologists to treat bacterial and fungal infections and to bleach hyperpigmented skin.217 The chronic use of such cream caused slate-gray pigmentation that is most pronounced in skin folds of the eyelids, neck, and nasolabial folds. Filling teeth with silver-mercury amalgam also causes tattooing of mercury in the gingiva. Amalgam pigmentation occurs locally near the tooth or at some distance from it. HISTOPATHOLOGIC FEATURES The upper dermis contains small, refractile, brownblack mercury granules, either free or in macrophages. Epidermal melanization is either normal or slightly increased.

HISTOPATHOLOGIC FEATURES Small granules are found in the papillary and reticular dermis.

Titanium A topical cream containing 13.5% titanium dioxide has been applied to erosive herpes simplex lesions of the glans, sulcus, and prepuce, resulting in the development of yellowish lesions at the sites of cream application.220 Titanium dioxide is currently used as a light-scattering agent in some facial moisturizing and sunscreen creams sold over the counter. Pigmentation from these agents has not been reported. HISTOPATHOLOGIC FEATURES Many brown granules are found in the dermis that are brightly refractile by dark-field microscopy and correlate ultrastructurally with granular electron-dense bodies in dermal macrophages and also free in the connective tissue. Energydispersive analysis with x-rays of these dense granules has demonstrated a peak corresponding to the titanium spectrum.

Drug Deposits and Pigmentation

HISTOPATHOLOGIC FEATURES Dermal deposition of arsenic stimulates epidermal melanocytes, and the clinical hyperpigmentation is mainly due to hypermelanosis.

Many systemic and topical medications deposit in the skin and cause discoloration by themselves or by their metabolites and photoproducts.221 Many of these agents simultaneously stimulate melanocytes, and the discolorations observed are thus a combined effect of hypermelanosis and deposition of drugs or drug metabolites. Many of these drugs are photosensitizers or photostimulators, and the hyperpigmentation is a nonspecific postinflammatory phenomenon. In this section, only selected drugs are discussed. Readers are referred to Chapter 12 and to general reviews for a more comprehensive consideration.

Lead

Minocycline

A lead line at the gingival margin and nail pigmentation are associated with lead poisoning.218

Minocycline is notorious for generating skin discoloration, most often a blueblack pigmentation at sites of old acne scars or inflammation, because the antibiotic is used routinely for acne; a typical patient has taken the medication for 1 to 3 years in doses of 100 to 200 mg/day. Bluish macules also develop on previously normal skin of the anterior lower legs, around the eyes, or anywhere else and

Arsenic Diffuse bronze discoloration of the skin, which is prominent on the trunk, may be one of the sequelae of chronic ingestion of inorganic arsenics.217 In less pigmented areas, these pigment spots are described as “raindrops on a dusty road.”

HISTOPATHOLOGIC FEATURES The lead line is caused by submucosal deposition of lead.

Bismuth Generalized blue-gray discoloration resembling argyria has been reported

CHAPTER 15 ■ DISORDERS OF PIGMENTATION

Because blue light effectively oxidizes bilirubin, infants with hyperbilirubinemia (>15 mg/dL) due to various causes, including extrahepatic biliary atresia, are treated with blue light. Within 3 to 4 days after the phototherapy, the patient’s serum, urine, and skin become graybrown-black, and this disappears in about 6 weeks after the discontinuation of treatment. It has been assumed that photodegradation products of bilirubin that are not metabolized properly due to hepatic dysfunction are retained in the skin, leading to the characteristic bronze discoloration. Newer reports indicate that photochemical alterations of high levels of copper porphyrins may be causative.209,210

after prolonged use of oral bismuth.219 A gingival pigment line and oral, conjunctival, and vaginal pigmentations have been reported.

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are accentuated by sun exposure. Generalized gray-brown discoloration (ie, “muddy skin syndrome”) may occur, particularly in exposed areas, the gingiva, the hard palate, the teeth, and the nails. These manifestations occur individually or in combination. HISTOPATHOLOGIC FEATURES Acne scar–associated lesions contain pigmented macrophages that are Prussian blue positive and negative for melanin by the Fontana-Masson stain. Macular lesions on the legs contain pigmented macrophages that are positive for iron and Fontana-Masson stains but fail to bleach with potassium permanganate, indicating that melanin is not present. The generalized muddy skin shows an increased epidermal basal layer melanization and melanophages in the upper dermis but is negative on staining for iron.222,223 A recent case report found pigmented lipomembranous changes in the subcutis of two patients with pretibial minocycline pigmentation.224

Antimalarials Quinacrine produces a diffuse lemonyellow color if taken for a long period, particularly in fair-skinned patients. The yellow color is probably the direct stain of quinacrine itself. Hydroxychloroquine has been reported to cause widespread slate-grey or bluish-grey macular hyperpigmentation.225,226 Chloroquine may cause irregular grayish macules on the shins and diffuse pigmentation of the face. Hard palate and nail discoloration may occur after chronic ingestion. The pigment is found in the dermis as a drug–melanin complex. Hemosiderin is deposited around capillaries.227-229

of continuous medication totaling about 250 g seems to be necessary to cause this discoloration.231 HISTOPATHOLOGIC FEATURES In addition to basilar melanization and melanocyte photoactivation, illustrated in Chapter 12 (see Fig. 12-7), endothelia and dermal macrophages may accumulate pigment demonstrable ultrastructurally in phagolysosomes in the form of lipid membranous structures, likely undigested drug metabolites stored as residual bodies.

Clofazamine Used in the treatment of atypical mycobacterial infection and leprosy, clofazamine may induce a reddish discoloration that represents the color of the drug and occurs in the conjunctivae and skin within four weeks of beginning the medication in 49% to 65% of patients. After two to three months of therapy, the infective lesions and occasionally even normal skin turn a brown or violaceous hue. This color may be due to a combination of epidermal and dermal melanin and a ceroidlike substance in the dermis.232

Psychotropic Drugs Prolonged use of phenothiazine and the tricyclic antidepressant imipramine may cause blue-gray to slate-gray discoloration, mainly in sun-exposed locations. HISTOPATHOLOGIC FEATURES The dark granules associated with chlorpromazine discoloration and scattered golden pigments in imipramine pigmentation are noted in the upper dermis and perivascular spaces (Fig. 15-12). Both melanosomes and electron-dense substances representing drug metabolites are found in dermal macrophages, fibroblasts, vascular endothelial cells, and dermal dendrocytes. The epidermis is hyperpigmented.233,234

Chemotherapeutic Drugs The ingestion of agents such as bleomycin, busulfan, cyclophosphamide, doxorubicin, and 5-fluorouracil or topical application of nitrogen mustard (mechlorethamine) and carmustine (BCNU) may result in diffuse hypermelanosis or, in the case of bleomycin, so-called “flagellate streaks” after long-term ingestion. Sunitinib, a multikinase inhibitor,

Carotinoids Oranges, apricots, carrots, and green vegetables contain carotinoids. Excessive intake of carotinoids causes yellowish discoloration of the palms, soles, and postauricular skin. Synthetic β-carotene is used commonly for photoprotection, as a cancer-preventive drug, and as a “tanning” agent. This tan is not sun protective. Synthetic β-carotene does not produce the same degree of discoloration as natural carotinoids. The pigment is deposited in the subcutaneous fat, skin, and retina.230

Amiodarone

356

Chronic use of amiodarone, an antiarrhythmia drug, may cause a blue-gray discoloration in sun-exposed areas such as the face and hands; at least 20 months

 FIGURE 15-12 Imipramine pigmentation. Yellow granules are scattered in the upper and mid-dermis

has been reported to cause transient yellow discoloration of the skin. Capecitabine is a prodrug of 5-fluorouracil that causes marked hyperpigmentation.235 HISTOPATHOLOGIC FEATURES The epidermis shows increased melanin, usually with some pigment incontinence (see Table 15-11).

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causes Naegeli-Franceschetti-Jadassohn syndrome. J Invest Dermatol. 2008;128(6): 1517-1524. 128. Gablen W: Dermatopathia pigmentosa reticulosa hypohidrotica et atrophica. Dermatol Wochenschr. 1964;34:193. 129. Grange DK, Lorch SM, Cole PL, et al: Cantu syndrome in a woman and her two daughters: further confirmation of autosomal dominant inheritance and review of the cardiac manifestations. Am J Med Genet A. 2006;140(15):16731680. 130. Cantu JM, Sanchez-Corona J, Fragoso R: A new autosomal-dominant genodermatosis characterized by hyperpigmented spots and palmoplantar hyperkeratosis. Clin Genet. 1978;14: 165-168. 131. Touraine A: Une nouvelle neuroectodermose congeniale: La lentiginose centrofaciale et les dysplasie associée. Ann Dermatol Syphiligre (Paris). 1941;8:453. 132. Kirschner LS, Carney JA, Pack SD, et al: Mutations of the gene encoding the protein kinase A type I- regulatory subunit in patients with the Carney complex. Nat Genet. 2000;26:89-92. 133. Horvath A, Bossis I, Giatzakis C, et al: Large deletions of the PRKAR1A gene in Carney complex. Clin Cancer Res. 2008;14(2):388-395. 134. Rees JR, Ross FGM, Keen G: Lentiginosis and left atrial myxoma. Br Heart J. 1973;35:874-876. 135. Atherton DJ, Pitcher DW, Wells RS, MacDonald DM: A syndrome of various cutaneous pigmented lesions, myxoid neurofibromata and atrial myxoma: the NAME syndrome. Br J Dermatol. 1980; 103:421-429. 136.Uhle P, Norvell SS: Generalized lentiginosis. J Am Acad Dermatol. 1988;18:444-447. 137. Berlin AL, Paller AS, Chan LS: Incontinetia pigmenti: a review and update on the molecular basis of pathophysiology. J Am Acad Dermatol. 2002;47:169-187. 138. Fusco F, Fimiani G, Tadini G, et al: Clinical diagnosis of incontinentia pigmenti in a cohort of male patients. J Am Acad Dermatol. 2007;56(2):264-267. 139. Ardelean D, Pope E: Incontinentia pigmenti in boys: a series and review of the literature. Ped Dermatol. 2006;23(6):523527. 140.Smahi A, Courtois G, Rabia SH, et al: The NF-κB signaling pathway in human diseases: From incontinentia pigmenti to ectodermal dysplasia and immunodeficiency syndromes. Hum Mol Genet. 2002;11:2371-2375. 141. Fusco F, Bardaro T, Fimiani G, et al: Molecular analysis of the genetic defect in a large cohort of IP patients and identification of novel NEMO mutations interfering with NF-kappaB activation. Hum Mol Genet. 2004;13(16):1763-1773. 142. Mancini AJ, Lawley LP, Uzel G: Xlinked ectodermal dysplasia with immunodeficiency caused by NEMO mutation: early recognition and diagnosis. Arch Dermatol. 2008;144(3):342-346. 143. Jean-Baptiste S, O’Toole EA, Chen M, et al: Expression of eotaxin, an eosinophilselective chemokine, parallels eosinophil accumulation in the vesiculobullous stage of incontinentia pigmenti. Clin Exp Immunol. 2002;127:470-478.

144. Connor JM, Gatherer D, Gray FC, et al: Assignment of the gene for dyskeratosis congenita to Xq28. Hum Genet. 1986;72:348-351. 145. He J, Navarrete S, Jasinski M, et al: Targeted disruption of Dkc1, the gene mutated in X-linked dyskeratosis congenita, causes embryonic lethality in mice. Oncogene. 2002;21:7740-7744. 146. Montanaro L, Chilla A, Trere D, et al: Increased mortality rate and not impaired ribosomal biogenesis is responsible for proliferative defect in dyskeratosis congenital. J Invest Dermatol. 2002;118:193-198. 147. Savage SA, Giri N, Baerlocher GM, et al: TINF2, a component of the shelterin telomere protection complex, is mutated in dyskeratosis congenita. Am J Hum Genet. 2008;82(2):501-509. 148. Smith AG, Shuster S, Thoday AJ, Peberdy M: Chloasma, oral contraceptives, and plasma immunoreactive βmelanocyte-stimulating hormone. J Invest Dermatol. 1977;68:169-170. 149. Grimes P, Yamada N, Bhawan J, et al: Light microscopic, immunohistochemical, and ultrastructural alterations in patients with melasma. Am J Dermatopathol. 2005; 27(2):96. 150. Larsson P, Lidén S: Prevalence of skin diseases among adolescents 12 to 16 years of age. Acta Derm Venereol (Stockh). 1980;60:415-423. 151. Rhodes AR, Albert LS, Barnhill RL, Weinstock MA: Sun-induced freckles in children and young adults: a correlation of clinical and histopathologic features. Cancer. 1991;67:1990-2001. 152. Crowson AN, Magro CM, Mihm MC Jr: The freckles and lentigines, in Crowson AN, Magro CM, Mihm MC Jr (eds): The Melanocytic Proliferations: A Comprehensive Textbook of Pigmented Lesions. New York: Wiley 200l;49-72. 153. Barnhill RL: Pathology of Melanocytic Nevi and Malignant Melanoma. Boston: Butterworth-Heinemann; 1995. 154. Itin PH, Lautenschlager S, Meyer R, et al: Natural history of the NaegeliFranceschetti-Jadassohn syndrome and further delineation of its clinical manifestations. J Am Acad Dermatol. 1993;28:942-950. 155. Oriba HA, Lo JS, Dijkstra JWE, Bergfeld WF: Reticulate nonmelanocytic hyperpigmentation anomaly: a probable variant of Dowling-Degos disease. Int J Dermatol. 1991;30:39-42. 156. Erel A, Gurer MA, Edali N: Reticulate acropigmentation of Kitamura: two case reports. Int J Dermatol. 1993;32: 726-727. 157. Berth-Jones J, Graham-Brown RAC: A family with Dowling-Degos disease showing features of Kitamura’s reticulate acropigmentation. Br J Dermatol. 1989;120:463-466. 158. Kudo Y, Fujiwari S, Takayasu S, et al: Reticulate pigmentary dermatosis associated with hypohidrosis and short stature: a variant of NaegeliFranceschetti-Jadassohn syndrome? Int J Dermatol. 1995;34:30-31. 159. Riccardi VM: Neurofibromatosis: past, present, and future. New Engl J Med. 1991;324:1283-1285. 160. Obringer AC, Meadows AT, Zackai EH: The diagnosis of neurofibromatosis I in

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179. Danarti R, König A, Salhi A, et al: Becker's nevus syndrome revisited. J Am Acad Dermatol. 2004;51(6):965-969. 180. Nagashima J: Prurigo pigmentosa: clinical observations of our 14 cases. J Dermatol. 1978;5:61-67. 181. Shimizu H, Yamasaki Y, Harada T, Nishkawa T: Prurigo pigmentosa. J Am Acad Dermatol. 1985;12:165-169. 182. Asgari M, Daneshpazhooh M, Chams Davatchi C, Böer A: Prurigo pigmentosa: an underdiagnosed disease in patients of Iranian descent? J Am Acad Dermatol. 2006;55(1):131-136. 183. Gur-Toy G, Gungor E, Artuz F, et al: Prurigo pigmentosa. Int J Dermatol. 2002;41:288-291. 184. Erbagci Z: Prurigo pigmentosa in association with Helicobacter pylori infection in a Caucasian Turkish woman [letter]. Acta Derm Venereol (Stockh). 2002;82:302303. 185. Kim MH, Choi YW, Choi HY, Myung KB: Prurigo pigmentosa from contact allergy to chrome in detergent. Contact Dermatitis. 2001;44:289-292. 186. Chiam L, Lim K, Goh B: Prurigo pigmentosa: a report of 2 cases which responded to minocycline. J Am Acad Dermatol. 2008;58(suppl 2):AB118. 187.Matsumoto C, Kinoshita M, Baba S, et al: Vesicular prurigo pigmentosa cured by minocycline. J Eur Acad Dermatol Venereol. 2001;15:354-356. 188. Lacz NL, Vafaie J, Kihiczak NI, et al: Postinflammatory hyperpigmentation: a common but troubling condition. Int J Dermatol. 2004;43(5):362-365. 189. Tanigaki T, Hata S, Kitano Y, el al: Unusual pigmentation on the skin over trunk bones and extremities. Dermatologica. 1985;170: 235-239. 190. Siragusa M, Ferri R, Cavallari V, Schepis C: Friction melanosis, friction amyloidosis, macular amyloidosis, towel melanosis: many names for the same clinical entity. Eur J Dermatol. 2001;11: 545-548. 191. Sharquie KE, AL-Dorky MK: Frictional dermal melanosis (lifa disease) over bony prominences. J Dermatol. 2001;28: 12-15. 192. Al-Aboosi M, Abalkhail A, Kasim O, et al: Friction melanosis: a clinical, histologic, and ultrastructural study in Jordanian patients. Int J Dermatol. 2004;43(4):261-264. 193. Jambrosic J, From L, Hanna W: Lichen amyloidosus: ultrastructure and pathogenesis. Am J Dermatopathol. 1984;6:151158. 194. Konrad K, Woolf K: Pathogenesis of diffuse melanosis secondary to malignant melanoma. Br J Dermatol. 1974;91: 635-655. 195. Alexander A, Harris RM, Grossman D, et al: Vulvar melanoma: diffuse melanosis and metastasis to the placenta. J Am Acad Dermatol. 2004;50(2): 293-298. 196. Touart DM, Sau P: Cutaneous deposition diseases, part II. J Am Acad Dermatol. 1998;39:527-544. 197. Wyre HW: Alkaptonuria with extensive ochronosis. Arch Dermatol. 1979;115: 461-463. 198. Lawrence N, Bligard CA, Reed R, Perret WJ: Exogenous ochronosis in the United States. J Am Acad Dermatol. 1988;18: 1207-1211.

199. Spenny ML, Suwannarat P, Gahl WA, et al: Blue pigmentation and arthritis in an elderly man. J Am Acad Dermatol. 2005; 52(1):122-124. 200. Jacyk WK: Annular granulomatous lesions in exogenous ochronosis are manifestations of sarcoidosis. Am J Dermatopathol. 1995;17:18-22. 201. Goldstein N: IV. Complications from tatoos. J Dermatol Surg Oncol. 1979;5: 869-878. 202. Ajoka RS, Kushner JP: Hereditary hemochromatosis. Semin Hematol. 2002; 39:235-241. 203. Charlín R, Barcaui CB, Kac BK, et al: Hydroquinone-induced exogenous ochronosis: a report of four cases and usefulness of dermoscopy. Int J Dermatol. 2008;47(1):19-23. 204. Moalem S, Percy M, Kruck T, Gelbart R: Epidemic pathogenic selection: an explanation for hereditary hemochromatosis? Med Hypotheses. 2002;59:325-329. 205. De Gobbi M, Roetto A, Piperno A, et al: Natural history of juvenile hemochromatosis. Br J Hematol. 2002;117:973-979. 206. Moodie SJ, Ang L, Stenner JM, et al: Testing for haemochromatosis in a liver clinic population: relationship between ethnic origin, HFH gene mutations, liver histology, and serum iron markers. Eur J Gastroenterol Hepatol. 2002;14:223-229. 207. Camaschella C, Roetto A, De Gobbi M: Juvenile hemochromatosis. Semin Hematol. 2002;39:242-248. 208. Brissot P, Troadec MB, Bardou-Jacquet E, et al: Current approach to hemochromatosis. Blood Rev. 2008;22(4):195-210. 209. Bertini G, Dani C, Fonda C, et al: Bronze baby syndrome and the risk of kernicterus. Acta Paediatr. 2005;94(7):968-971. 210. Ashley JR, Littler CM, Burgdorf WHC, Brann BS: Bronze baby syndrome. J Am Acad Dermatol. 1985;12:325-328. 211. Kaplan BS: Azure lunulae due to argyria. Arch Dermatol. 1966;94:333-334. 212. Prose PH: An electron microscopic study of human generalized argyria. Am J Pathol. 1963;42:293-297. 213. Espinal MC, Ferrando L: Asymptomatic blue nevus-like macule. Arch Dermatol. 1996;132:461, 464. 214. Jonas L, Bloch C, Zimmermann R, et al: Detection of silver sulfide deposits in the skin of patients with argyria after long-term use of silver-containing drugs. Ultrastruct Pathol. 2007;31(6):379-384. 215. Trotter MJ, Tron VA, Hollingdale J, Rivers JK: Localized chrysiasis induced by laser therapy. Arch Dermatol. 1995; 131:1411-1414. 216. Geist DE, Phillips TJ: Development of chrysiasis after Q-switched ruby laser treatment of solar lentigines. J Am Acad Dermatol. 2006;55(suppl 2):S59-S60. 217. Granstein RD, Sober AJ: Drug- and heavy metal-induced hyperpigmentation. J Am Acad Dermatol. 1981;5:1-18. 218. Zhu WY, Xia MY, Huang SD, Du D: Hyperpigmentation of the nail from lead deposition [letter]. Int J Dermatol. 1989;28:273-275. 219. Leuth HC, Sutton DC, McMullen CJ, Meuhlberger CW: Generalized discoloration of skin resembling argyria following prolonged oral use of bismuth: a case of “bismuthia.” Arch Intern Med. 1936;57:1115. 220. Dupre A, Touron P, Daste J, et al: Titanium pigmentation: an electron

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therapy with hydroxychloroquine. J Clin Rheumatol. 2007;13(2):113. Millar TP, Kirk A, Ratnavel R: Cutaneous hyperpigmentation during therapy with hydroxychloroquine. Clin Exp Dermatol. 2004;29:92-93. Lutterloh CC, Shallenberger PL: Unusual pigmentation developing after prolonged suppressive therapy with quinacrine hydrochloride. Arch Dermatol Venereol. 1946;53:349-354. Tuffanelli D, Abraham RK, Dubois EL: Pigmentation from antimalarial therapy: its possible relation to the ocular lesions. Arch Dermatol. 1963;88:419-426. Levantine A, Almeyda J: Drug-induced changes in pigmentation. Br J Dermatol. 1973;89:105-112. Gupta AK, Haberman JF, Pawlowski D, et al: Canthaxanthine. Int J Dermatol. 1985;24:528-532. Waitzer S, Butany J, From L, et al: Cutaneous ultrastructural changes and

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probe microanalysis study. Arch Dermatol. 1985;121: 656-658. Kang S, Lerner EA, Sober AI, Levine N: Pigmentary disorders from exogenous causes, in Levine N (ed): Pigmentation and Pigmentary Disorders. Boca Raton, FL: CRC Press; 1993:417. Gordon B, Sparano BM, Iatropoulos MJ: Hyperpigmentation of the skin associated with minocycline therapy. Arch Dermatol. 1985;121:618-623. Argenyi ZB, Finelli L, Bergfeld WF, et al: Minocycline-related cutaneous hyperpigmentation as demonstrated by light microscopy, electron microscopy, and xray energy spectroscopy. J Cutan Pathol. 1987;14:176-180. Bowen AR, McCalmont TH: The histopathology of subcutaneous minocycline pigmentation. J Am Acad Dermatol. 2007;57(5):836-839. Amichai B, Gat A, Grunwald MH: Cutaneous hyperpigmentation during

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CHAPTER 16 Deposition Disorders

PART II ■ PREDOMINANTLY NONINFLAMMATORY CONDITIONS

Franco Rongioletti Raymond L. Barnhill

Various substances may form deposits in the skin. They may be classified as endogenous and exogenous. Endogenous substances are the topic of this chapter. They include substances that are normal constituents of the skin but are abnormally deposited (eg, increased deposition of mucin) and substances that are not normal constituents of the skin (eg, amyloid). Exogenous materials, such as tattoos and heavy metals, and the special category of endogenous deposition, such as melanin depositions, are discussed in Chapter 15. Abnormal deposition of endogenous substances exhibits particular histochemical staining properties. However, different substances may show similar staining by the hematoxylin and eosin

CUTANEOUS MUCINOSES Mucin or protein–hyaluronic acid complex is a normal component of the dermal connective tissue produced by fibroblasts

and mast cells. In disease conditions, it is increased, and because hyaluronic acid holds water (hygroscopic), the dermal connective tissue is swollen (myxedema). If this condition persists, the dermis and sometimes the subcutaneous connective tissues react with production of excessive collagen, leading to scleroderma-like fibrosis (scleromyxedema). Mucin is usually present in early lesions and may diminish or even disappear in late stages. Also, during tissue processing, mucin may largely be washed out. If one suspects mucin deposition because of light blue staining between widely separated collagen bundles or empty spaces, special stains should be used such as Alcian blue at a pH of 2.5 (negative at 0.5), toluidine blue with metachromasia at a pH of 4.0 and 7.0 (negative below 2), and colloidal iron. Furthermore, mucin is hyaluronidase sensitive and periodic acid Schiff (PAS) negative. Fixation in absolute alcohol may improve detection.1,2 Monoclonal antibodies to hyaluronan, although not routinely indicated, have been used.3 The cutaneous mucinoses are a heterogeneous group of disorders in which an

Abnormal dermal depositions (H&E stain)

Pink-gray, amorphous PAS +

Hyaline EM: amorphous PAS + + +

Amyloid EM: filaments Congo red (+ + +) Greenish birefringence of Congo red stain

Pale blue, grayish blue, edematous

Colloid EM: amorphous Amyloid P (+) Adult colloid milium

Colloid EM: filaments Antikeratin (+ +) Congo red (+)

Colloidal iron (+) Alcian blue (+), pH 2.5 (–), pH 0.5 Toluidine blue metachromasia (+), >pH 2.0 PAS (–), hyaluronidase +

Hyalinosis cutis et mucosae

Various amyloidoses

Juvenile colloid milium

Mucin

Ig λ or κ chain

Potassium permanganate treatment Congo red (–)

Antikeratin antibody (+)

See Table 16-1

AL amyloid Primary systemic, nodular or Waldenstrom macroglobulinemia

Amyloid K AA amyloid

Secondary systemic amyloidosis

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(H&E) stain (Fig. 16-1). These deposits with similar staining properties are often grouped together and were once considered to be the same chemical substances. Examples are mucin, hyalin, and colloid. When a dermatopathologist examines H&E-stained tissue sections, he or she notices the color characteristics and common texture of a substance in one of these three groups. The dermatopathologist then focuses on the subset of conditions that manifests these particular characteristics. Special stains, immunostains, electron microscopy, and clinical information provide further aid in the differential diagnosis. In many instances, clinical knowledge is essential in the final synthesis of all data to reach a reasonable conclusion. This process is always at work in the experienced pathologist’s mind. An algorithmic approach to differential diagnosis is presented in Fig. 16-1. Tables 16-1 to 16-6 will assist in this analytical process.

 FIGURE 16-1 Abnormal dermal depositions.

Lichenoid macular or concha amyloidosis

Epithelial tumor amyloidoses (eg, BCC, AK, SK, Bowen)

Juvenile colloid milium

Pale blue-gray

Multicolor birefringence

Gouty tophi

Table 16-1 The Cutaneous Mucinoses DERMAL AND FOLLICULAR DEGENERATIVE/INFLAMMATORY MUCINOSES

ASSOCIATED DISORDERS

HISTOPATHOLOGIC FEATURES

Generalized waxiness, nonpitting, waxy facial edema

Hypothyroidism

Pretibial myxedema

Shin, dorsal feet

Thyrotoxicosis, treated

Scant mucin, upper dermis around blood vessels, hair follicles Prominent mucin lower two-thirds of dermis, hyperkeratosis, follicular plugging, mast cells

Generalized papules, including face, sclerodermoid features

Monoclonal gammopathy, systemic involvement

Diffuse mucin, upper dermis, increased collagen and fibroblasts

Papules on trunk and extremities

Sometimes HIV

Focal or diffuse mucin, upper dermis, variable increased numbers of fibroblasts Focal mucin, upper dermis, grenz zone, normal fibroblast number Mucin, upper dermis, increased fibroblasts, mast cells

Lichen myxedematosus (papular mucinosis) Scleromyxedema

Localized forms Discrete type

Acral persistent papular mucinosis

Papules on dorsa of hands and forearms

Self-healing juvenile mucinosis

Children, linear infiltrated plaques, head, trunk, thighs; deep periarticular nodules

Cutaneous mucinosis of infancy Scleredema

Focal mucinosis Digital mucous cyst Mucocele of the lip Oral mucous cyst Papular and nodular mucinosis associated with lupus erythematosus Follicular mucinosis

Sometimes rheumatologic symptoms

Firm papules on extremities Induration of upper back, nape

Solitary papulo-nodule Distal interphalangeal joint, posterior nail fold Mucosal side of lower lip

Diabetes, acute infection, monoclonal gammopathy

Arthrosis

Lumpy papulonodules, trunk and extremities

LE (mainly SLE)

Tumid plaques with follicular papules, alopecia, face and scalp

Mycosis fungoides

abnormal amount of mucin deposits in the skin. The cutaneous mucinoses are categorized into two groups: primary cutaneous mucinoses, in which the mucin deposit is the main histologic feature resulting in clinically distinctive lesions (Table 16-1), and secondary mucinoses, in which the mucin deposition is only an additional histologic finding. A typical example of secondary mucinosis is granuloma annulare, in which mucin deposition is associated with a necrobiotic palisaded granuloma, which is the diagnostic hallmark. Secondary mucinoses are not discussed in this chapter.1,2

Primary cutaneous mucinoses are further categorized into degenerative and inflammatory forms, which may be dermal or follicular (see Table 16-1), and hamartomatous and neoplastic forms.

DERMAL DEGENERATIVE AND INFLAMMATORY PRIMARY CUTANEOUS MUCINOSES These are the most frequent cutaneous mucinoses. Diagnosing a primary dermal mucinosis on histologic grounds alone is a difficult task and always requires

Focal mucin, papillary dermis Thickened dermis, fenestrated collagen, mucin may be absent on H&E stain, normal fibroblast number Focal mucin in dermis, clefts Focal mucin in dermis, collagen pseudocapsule Sialomucin (PAS+) with inflammatory reaction Diffuse mucin in reticular dermis, normal epidermis, lymphocytic infiltrate Mucin within pilosebaceous units, lymphocytes, eosinophils

CHAPTER 16 ■ DEPOSITION DISORDERS

DISTRIBUTION, CHARACTERIZATION

Generalized myxedema

clinicopathologic correlation. Three histologic clues should be considered: the pattern of mucin distribution, the level of mucin deposition in the dermis, and some additional findings (see Table 16-1). The pattern of mucin distribution may be diffuse or focal. In the latter, mucin is localized and well circumscribed (Fig. 16-2); in the former, it is interstitial and poorly circumscribed (Fig. 16-3).

Generalized Myxedema This condition is associated with a severe form of chronic hypothyroidism.1,2,4

363

fibrosis in the deep dermis and subcutis may simulate scleroderma. The diagnosis is mainly clinical, and histopathologic findings are only confirmatory.

PART II ■ PREDOMINANTLY NONINFLAMMATORY CONDITIONS

Pretibial (Localized) Myxedema

364

 FIGURE 16-2 Pattern of focal dermal deposition of mucin in acral persistent papular mucinosis. Alcian blue stain; pH, 2.5.

CLINICAL FEATURES The face, particularly the eyelids and lips, are prominently swollen, and the entire skin is dry, pale, waxy, and edematous but not pitted with pressure. HISTOPATHOLOGIC FEATURES Histologic features include hyperkeratosis, occasional keratinous cysts, and only slight edema (mucinosis) of the dermis in most cases, usually requiring mucin stains for

confirmation. The mucin is frequently deposited around the blood vessels and hair follicles of the upper and mid-dermis only. In some instances, there is massive accumulation of mucin, resulting in the disruption of collagen bundles and accompanied by perivascular mononuclear cell infiltrates. Usually, fibroblasts are not increased. Elastic fibers are fragmented and reduced. In the late stages,

This is most commonly observed in patients with established hyperthyroidism (usually due to Graves disease) who have been treated.1,2,4 These patients are usually euthyroid by the time they develop this condition, although they may still exhibit exophthalmos. With regard to pathophysiology, a serum factor (unrelated to longacting thyroid-stimulating factor or hormone) seems to stimulate fibroblasts to produce mucin. Fibroblasts from the dermis of the lower extremities have been found to be more sensitive to this factor than are fibroblasts from other areas of the body. An insulinlike growth factor, trauma, and lymphatic obstruction due to mucin may be involved. CLINICAL FEATURES The anterior shins and occasionally dorsal feet demonstrate elevated, knobby plaques or dome-shaped nodules. The cutaneous surface is shiny or waxy, and peau d’orange follicular openings with follicular plugging are noted in new lesions. In severe cases, marked edema and verrucoid surface changes, possibly resembling elephantiasis nostras verrucosa, may be seen. Rarely, the condition affects the shoulder, arms, and abdomen. After biopsy, transparent, viscous fluid continues to ooze. HISTOPATHOLOGIC FEATURES The typical features consist of conspicuous, diffuse deposition of mucin (glycosaminoglycans) throughout the reticular dermis with attenuation of collagen fibers (Fig. 16-4). With extensive deposition of mucin, the collagen fibers are frayed, fragmented, and widely separated. Spindle-shaped and large stellate fibroblasts appear to float in the edematous areas, but the number of fibroblasts is not increased. Lymphatic dilated vessels can be seen. In chronic lesions, increased collagen production occurs in the deep dermis and subcutaneous fat, resulting in the replacement of fat lobules by fibrosis. Alcian blue stain is strongly positive and differentiates mucin from conventional lymphedema.4 Hyperkeratosis and follicular plugging, the presence of mast cells, and sparse lymphoid infiltrates with occasional eosinophils are additional findings.2

 FIGURE 16-3 Pattern of diffuse dermal deposition of mucin in pretibial myxedema. Alcian blue stain; pH, 2.5.

DIFFERENTIAL DIAGNOSIS Pretibial myxedema should be distinguished from lymphoedematous mucinosis associated with chronic obesity without thyroid

 FIGURE 16-4 Pretibial myxedema. In the reticular dermis, collagen bundles are widely separated by mucin. The epidermis is hyperkeratotic and acanthotic.

disease. In the latter, vesicles and bullae, semitranslucent papules, or woody plaques are found on the shins in the setting of morbid obesity and bilateral pitting edema of the distal lower extremities. Histologically, epidermal atrophy with effacement of the rete ridge pattern, mucin deposition within the superficial papillary dermis, perivascular glomeruloid neovascularization, and hemosiderin deposition are seen.5 (For other differential diagnoses, see Table 16-1.)

CLINICAL FEATURES In scleromyxedema, a widespread symmetric eruption of closely set papules, often arranged in a linear array and accompanied by skin thickening,

HISTOPATHOLOGIC FEATURES In scleromyxedema, patients have a characteristic triad that includes diffuse mucin deposition in the upper and mid-reticular dermis, increased collagen deposition, and a marked proliferation of irregularly arranged fibroblasts (Figs. 16-5 and 16-6).2,6 The epidermis is usually normal, but in old lesions, it may be thinned by the pressure of the underlying mucin and fibrosis; the follicles may be atrophic; and a slight perivascular, superficial lymphoplasmocytic infiltrate is often present. Rarely, eosinophils are found. The elastic fibers are fragmented and decreased in number. Reactive

CHAPTER 16 ■ DEPOSITION DISORDERS

involves the face, upper trunk, and peripheral extremities. Involvement of the glabella gives rise to leonine facies. The localized form, in which the papules are confined to only a few sites (usually the limbs and trunk) in the absence of paraproteinemia and systemic features, include four subtypes: a discrete papular form, acral persistent papular mucinosis, cutaneous mucinosis of infancy, and nodular lichen myxedematosus. An association of discrete lichen myxedematosus with HIV infection, toxic oil syndrome, eosinophilia myalgia syndrome, and hepatitis C virus (HCV) infection has been reported.1 Selfhealing papular mucinosis, both of the juvenile and adult types, previously considered as a subtype of localized lichen myxedematosus, is probably a mucinosis suis generis.1

Lichen Myxedematosus (Papular Mucinosis) and Scleromyxedema (Papular Mucinosis) Lichen myxedematosus is a chronic idiopathic disorder characterized by lichenoid papules, nodules, or plaques in the absence of thyroid disease, which includes two clinicopathologic subsets: a generalized and sclerodermoid form (also called scleromyxedema) with a monoclonal gammopathy and systemic, even lethal, manifestations and a localized form that does not run a disabling course.6 Occasional patients have overlapping or atypical features and fall between having scleromyxedema and localized lichen myxedematosus.

 FIGURE 16-5 Scleromyxedema. The characteristic triad of mucin deposition, fibroblast proliferation, and fibrosis in the upper and mid-dermis.

365

PART II ■ PREDOMINANTLY NONINFLAMMATORY CONDITIONS 366

 FIGURE 16-6 Scleromyxedema. Colloidal iron stain confirms increased mucin deposition in the upper dermis.

sweat gland proliferation is an occasional finding. The changes in the localized form are not as characteristic as in scleromyxedema but are still recognizable. The pattern of mucin distribution may be diffuse or focal, involving the upper and mid-reticular dermis. Fibroblast proliferation is variable. Fibrosis is not marked and may even be absent (Fig. 16-7). In acral persistent papular mucinosis, a large, focal, well-circumscribed amount of mucin sparing a subepidermal zone is seen (see Fig. 16-2). Fibroblast prolifera-

tion is lacking. In cutaneous mucinosis of infancy, sometimes the mucin deposition in the papillary dermis is pronounced as to appear “hugged” by the epidermis. DIFFERENTIAL DIAGNOSIS Nephrogenic systemic fibrosis (nephrogenic fibrosing dermopathy) is observed in patients with renal disease and more recently liver failure and a history of exposure to gadolinium-containing contrast agents. The latter entity is microscopically similar to scleromyxedema (see Chapter 17). Although the initial manifestations of this disorder

 FIGURE 16-7 Localized lichen myxedematosus (papular mucinosis) of the discrete type. Increased mucin deposition splitting collagen fibers in the upper dermis with slight fibroblast proliferation and absence of fibrosis.

may be cutaneous, this fibrosing reaction may involve extracutaneous sites, including the lungs, heart, and muscle, hence the more recent and preferred name nephrogenic systemic fibrosis. Infection at the time of gadolinium administration and the nature of the gadolinium used (ie, ionic versus nonionic preparations and linear versus macrocyclic chelates) define potential risk factors associated with the development of nephrogenic systemic fibrosis. Fibrosis and mucin deposition of the deep dermis and septa of the subcutis in concert with an increase of CD34+ stromal spindle cells that coexpress procollagen-I and CD45RO are more typical of the former (see Chapter 17).7 Scleromyxedema can only be distinguished from other mucinoses by clinical features and dermal fibrosis, which is not observed in the other mucinoses until the late stages. Granuloma annulare may resemble early papular mucinosis; however, in the former, the cells accompanying the deposit of mucin are histiocytes arranged in palisaded or interstitial pattern.

Reticular Erythematous Mucinosis CLINICAL FEATURES Mostly women are affected by reticulated erythematous macules in the central chest and upper back.1-3 The arms and face may be involved. More infiltrated papular lesions are called plaquelike cutaneous mucinosis. HISTOPATHOLOGIC FEATURES The epidermis is normal. Diffuse interstitial deposits of mucin in the upper dermis are associated with a superficial and mid-dermal perivascular and sometimes perifollicular mild to moderate mononuclear infiltrate, mainly composed of T lymphocytes with vascular dilation (Fig. 16-8).2,3 An increased number of FXIIIa-positive cells has been reported with co-localization of type II hyalaronan to these cells, suggesting that the accumulation of mucin in reticular erythematosus mucinosis is derived from dermal dendrocytes. Direct immunofluorescence results are usually negative, but sometimes granular deposits of IgM, IgA, and C3 are found at the dermal–epidermal junction, making the distinction from lupus erythematosus difficult. DIFFERENTIAL DIAGNOSIS In lupus erythematosus, patients have an involvement of the epidermis by an interface dermatitis. In lupus erythematosus tumidus, the lymphocytic infiltrate is heavier, and mucin deposits are more diffuse and deep throughout the reticular dermis. However, it is unclear if reticular erythematous

it often begins on the upper back with subsequent extension to the neck and occipital scalp. In advanced cases, nonpitting indurated edema elevates the skin of the shoulder blade area with deep associated vertebral folds. Such patients are usually obese, and the mobility of the neck and head may be severely restricted. The skin is shiny and often uneven. The course is usually chronic. Scleredema after a respiratory infection is typically acute and resolves rapidly. Very rarely, the tongue, skeletal muscle, pleura, or pericardium is involved.

mucinosis, Jessner lymphocytic infiltration, and lupus tumidus are distinctive entities or different expressions of cutaneous lupus erythematosus.

associated conditions are monoclonal gammopathies and acute streptococcal respiratory infections.1,9 The onset of the type related to diabetes is insidious, and

CHAPTER 16 ■ DEPOSITION DISORDERS

 FIGURE 16-8 Reticular erythematous mucinosis. An interstitial mucin deposition between the collagen bundles associated with a moderate perivascular lynphocytic infiltrate in the upper dermis and vascular dilation under a normal epidermis.

HISTOPATHOLOGIC FEATURES The dermis is significantly thickened, sometimes up to two to three times normal, by increased collagen, which sometimes replaces subcutaneous fat.2,9 In general, the patient has thick, hyalinized collagen bundles that are widely separated (resulting in socalled “fenestrations”) by abundant interstitial deposits of mucin (Figs. 16-9 and 16-10). After the early stage of disease, mucin stains may become negative. However, frozen sections may be stained with Alcian blue at a pH of 2.5 or toluidine blue at a pH of 7.0. Sometimes multiple biopsies and cetylpyridinium chloride fixation are needed to demonstrate mucin in the dermis.10 No increase in the number of fibroblasts and no prominent

Cutaneous Lupus Mucinosis (Papular and Nodular Mucinosis in Lupus Erythematosus) This is a specific eruption seen in patients with lupus erythematosus (usually systemic lupus erythematosus), consisting of skin-colored and sometimes centrally depressed papules and nodules imparting a lumpy appearance to the skin or, more rarely, of plaquelike lesions on the upper extremities and trunk and independent from specific lesions of lupus.8 HISTOPATHOLOGIC FEATURES Mucin abounds in the upper and mid-dermis but may involve the subcutis as well. No inflammation is usually found, but sometimes a slight perivascular lymphocytic infiltrate is seen. The epidermal changes of lupus erythematosus are absent; however, granular deposits of immunoglobulins, C3, or both are detected at the dermal– epidermal junction on direct immunofluorescence.2,8

Scleredema Adultorum The most common cause of this disorder is chronic adult-onset diabetes. Other

 FIGURE 16-9 Scleredema. A thickened reticular dermis with sclerotic collagen bundles that are separated (fenestration).

367

PART II ■ PREDOMINANTLY NONINFLAMMATORY CONDITIONS

forms on the dorsal skin on or near the distal interphalangeal joint of the finger. 1 It may present near the nail. Subungual and eruptive variants have been reported.13 There are two principal variants. One subtype is derived from synovial cells (ganglion) and is almost always localized to the surfaces of the interphalangeal joints, and the other major variant is derived from dermal-based fibroblasts is usually present between the interphalangeal joints. Puncture or biopsy results in the drainage of viscous, stringy mucin from the cyst.

Digital Mucous (Myxoid) Cyst

HISTOPATHOLOGIC FEATURES The lesion is not a true cyst. The variety that originates in the dermis shows a large deposit of mucin-containing stellate fibroblasts, some vascular spaces, and multiple clefts (Fig. 16-12). The less frequent variant of synovial origin is characterized by a large dermal cavity surrounded by a collagenous pseudocapsule. The overlying epidermis may be acanthotic at the peripheries of the cyst, sometimes forming a “collarette,” and effaced over the central part of the cyst (see Fig. 16-12). Transepidermal elimination of mucinous material may be seen.

A dome-shaped elevation with or without visible semitransparent contents

DIFFERENTIAL DIAGNOSIS See Table 16-1.

 FIGURE 16-10 Scleredema. Fenestration of collagen bundles that are widely separated by abundant interstitial mucin deposits, recognizable even with hematoxylin and eosin staining.

inflammatory infiltrates are present, and the elastic fibers are reduced in number. DIFFERENTIAL DIAGNOSIS Scleredema differs from other forms of mucinosis by showing marked thickening of the dermis, hypertrophied collagen bundles, and the fenestrations between collagen bundles filled with mucin. Scleromyxedema is distinguished by more superficial deposits of mucin in the dermis and fibroblastic proliferation. In contrast to scleredema, morphea and scleroderma tend to exhibit tightly packed hypertrophied collagen bundles without fenestrations or abundant mucin deposition and the presence of a superficial and deep perivascular lymphoplasmocytic infiltrate. However, an important caveat is that significant interstitial mucin deposition can be observed in very early biopsies of morphea and even in established lesions of morphea on occasion.

partially CD34 positive is also found. The elastic and reticulum fibers are absent in the mucinous area, and the capillaries are normal in number. DIFFERENTIAL DIAGNOSIS The major entity to be discriminated is cutaneous (angio)myxoma.

Cutaneous Focal Mucinosis This localized form of mucinosis is characterized by a benign, solitary, symptomless, skin-colored papule or nodule occurring anywhere on the body, except on the skin overlying the joints of the hands and feet, in adults and more rarely in children.11,12

368

HISTOPATHOLOGIC FEATURES Mucin deposition replaces the dermal collagen focally and spares the subcutaneous fat (Fig. 16-11). Spindle-shaped or stellate, vimentin-positive fibroblasts are noted in such mucinous materials.2,11 Cleftlike spaces, but no cysts, are seen. A minor population of dermal dendrocytes that are partially factor XIIIa positive and

 FIGURE 16-11 Cutaneous focal mucinosis. Large, focal deposit of mucin in the dermis with some fibroblasts floating in the mucinous material.

nent follicular openings or as a large indurated plaque in which coalesced follicular and nonfollicular papules are present. Follicular mucinosis may heal spontaneously after a few months to a few years or may have a chronic but benign course.1,2 Very recently, follicular mucinosis of Pinkus has been suggested to be a form of localized, “indolent” cutaneous T-cell dyscrasia rather than an idiopathic benign cutaneous mucinosis.16

Oral Mucous Cyst and Superficial Mucocele of the Lip The ordinary oral mucous cyst develops on areas prone to traumatic insult such as the lower lip, tongue, and bottom of the oral cavity. The superficial variant (called superficial mucocele) usually develops on the soft palate and buccal mucosa14 (also see Chapter 37). HISTOPATHOLOGIC FEATURES The oral mucous cyst forms below the basal membrane or in connective tissue and clinically appears as a submucosal nodule. The superficial mucocele forms in the mucous epithelium or immediately below the subepithelium and appears clinically as a vesicle or bulla. The mucin deposits are composed of sialomucin (neutral glycosaminoglycans) rather than acid glycosaminoglycans. HISTOPATHOLOGIC FEATURES Sialomucin is an epithelial-derived mucin (secreted by salivary glands) that is PAS positive and diastase resistant. Alcian blue stain is also positive, but hyaluronidase does not abolish this staining.14 In ordinary oral mucous cysts, multiple edematous pockets of sialomucin are present in the submucosa. An inflammatory cell reaction surrounds these foci. In an old lesion, one large cavity filled with faintly eosinophilic material is observed. In superficial mucocele of the lip, a blister containing sialomucin, neutrophils, and erythrocytes is present in the mucous epithelium. Also, a dermal infiltrate composed of neutrophils, mononuclear

lymphocytic cells, and eosinophils is present.

FOLLICULAR DEGENERATIVE AND INFLAMMATORY PRIMARY CUTANEOUS MUCINOSES Follicular mucinosis is arguably the most easily recognized histologic pattern of mucin deposition because the mucinous deposits are confined to the hair follicles (see Chapters 10 and 34). Why dermal mucin is deposited selectively in an epithelial structure, however, is unclear. Although follicular keratinocytes have been considered the source of mucin,15 an etiologic role for cell-mediated immune mechanisms has been proposed. Follicular mucinosis of Pinkus and urticaria-like follicular mucinosis are two disorders in which follicular mucinosis is the main histologic feature, resulting in clinically distinctive lesions (primary follicular mucinosis). Otherwise, secondary follicular mucinosis is a histologic epiphenomenon seen in many disorders, particularly the cutaneous lymphomas.

Follicular Mucinosis of Pinkus This condition predominantly affects the face and head and neck region of children and middle-aged adults.1,2,16 If terminal hairs of the beard or head are affected, a localized hair loss is noticed, hence the original term alopecia mucinosa. Vellus hairs may be lost but are not noticeable. These lesions may present as a group of individual follicular papules with promi-

DIFFERENTIAL DIAGNOSIS There are some clinicopathologic criteria for distinguishing Pinkus follicular mucinosis from lymphoma-associated follicular mucinosis. Classic follicular mycosis fungoides associated with follicular mucinosis presents as destructive infiltrative nodules, often with a cystic acneiform appearance and alopecia. The demographics are similar to classic mycosis fungoides, presenting in middle-aged and older adults. Although lymphoid atypia and even clonality may be seen in primary alopecia mucinosa or Pinkus follicular mucinosis, suggesting its categorization as a cutaneous T-cell dyscrasia, the degree of atypia is not as developed as that observed in true follicular mycosis fungoides.16 Although the infiltrate in some cases of alopecia mucinosa in young children may be very prominent, the young age of the patient and the localized nature of the process are helpful in discriminating the features from those of follicular mycosis fungoides.1 Secondary follicular mucinosis occurs in a wide variety of folliculocentric inflammatory lesions such as discoid lupus erythematosus, eosinophilic folliculitis, insect bite reactions, drug reactions associated with antidepressant therapy, follicular eczema, and staphylococcal folliculitis.

CHAPTER 16 ■ DEPOSITION DISORDERS

 FIGURE 16-12 Digital mucous cyst. This is a pseudocyst with a large pool of mucin in the dermis and some vascular spaces and clefts. The epidermis is laterally acanthotic, forming a peripheral “collarette,” and centrally more atrophic.

HISTOPATHOLOGIC FEATURES Early changes consist of intra- and intercellular edema of follicular epithelium due to accumulation of mucin. The intercellular edema produces a reticular network pattern from the cell walls of the outer root sheath keratinocytes. The increased mucin eventually destroys cell walls and inventuates in a pool of mucin within the hair follicle and sebaceous gland (Fig. 16-13).2 The mucin in this condition can be stained with colloidal iron, Alcian blue, and Giemsa but is usually PAS negative. Hyaluronidase digestion abolishes all staining. In severe cases, the accumulated mucin extravasates to form perifollicular mucinosis. The perifollicular inflammatory reaction is variable and consists of lymphocytes, histiocytes, and eosinophils.

369

may be hyperplastic with elongation of the rete ridges and hyperkeratosis, as in an epidermal nevus. In the latter case, a mucinous nevus may be considered a combined hamartoma.

PART II ■ PREDOMINANTLY NONINFLAMMATORY CONDITIONS

Cutaneous Myxoma A cutaneous myxoma is a benign acquired neoplasm. It may be solitary without systemic abnormalities or multiple. In the latter scenario, myxomas may represent a manifestation of Carney complex (cutaneous myxomas, cardiac myxoma, spotty pigmentation, and endocrine overactivity). Cardiac myxoma is fatal, and cutaneous myxoma may be an important first indication of this serious condition.2 Cutaneous myxomas and superficial angiomyxomas are very similar clinically and histomorphologically.

 FIGURE 16-13 Follicular mucinosis. The increased mucin accumulates within the hair follicle and sebaceous gland, forming intercellular edema and large cystic spaces. There is a slight perifollicular lymphocytic infiltrate. Mucin consists of hyaluronic acid.

HAMARTOMATOUS AND NEOPLASTIC CUTANEOUS MUCINOSES Although stromal mucin deposition may be found in a large number of cutaneous tumors (eg, basal cell carcinoma, neurofibroma) as an incidental finding, the mucin deposition is a distinctive histologic feature in mucinous nevus and cutaneous myxoma.

A

370

Mucinous Nevus A mucinous nevus is a benign hamartoma that may be either congenital or acquired. It consists of a cobblestoned plaque, usually in a unilateral nevoid pattern.1,2 HISTOPATHOLOGIC FEATURES A diffuse deposition of mucin is seen in the upper dermis, and collagen and elastic fibers are diminished or absent in the mucinous area.2 The epidermis may be normal or

HISTOPATHOLOGIC FEATURES Cutaneous myxoma is a lobulated lesion characterized by a mucinous matrix involving the dermis and subcutis, with variably shaped fibroblasts, mast cells, and a few collagen and reticulin fibers1,17 (Fig. 16-14A and 16-14B). Bizarre multinucleated cells and regular mitotic figures can be seen. Prominent dilated capillaries are a typical finding. An epithelial component consisting of keratinous cysts or epithelial strands with trichoblastic features is often entrapped in the lesion. Stromal cells are vimentin positive and smooth muscle α-actin positive, supporting myofibroblastic differentiation. DIFFERENTIAL DIAGNOSIS The major process to be distinguished is focal cutaneous mucinosis in which mucin involves only the dermis and spares the

B

 FIGURE 16-14 Cutaneous myxoma. (A and B) In this biopsy of a cutaneous myxoma, there is striking mucin deposition, resulting in a nodular distortion of the dermis with focal epidermal attenuation. There is increased vascularity, hence the alternative name, superficial angiomyxoma.

subcutis in the absence of increased vascularity.1 The differentiation is important because myxoma is a true neoplasm, although benign, which may recur after incomplete excision. Moreover, cutaneous myxoma may be a marker of Carney complex. Acral fibromyxoma is a distinct acral-based neoplasm that has many overlapping features with superficial acral angiomyxoma. The discriminating features include greater collagen deposition, and the stromal fibroblasts are typically CD34 and CD99 positive.

HYALINE DEPOSITIONS

Amyloid was once considered to be a single substance regardless of the differences in clinical presentations. It is now known that the origin and chemical nature of amyloid are quite diverse (see Table 16-2). Why then do we still use the term amyloid? The answer is that so-called “amyloid” defined by Virchow as a starchlike, iodine-stainable substance shares several common characteristics, including an eosinophilic amorphous appearance with the H&E stain (see Table 16-3); Congo red staining resulting in a doubly refractile green color under polariscopy; thioflavine T fluorescence; and straight, nonbranching filaments (6–10 nm in diameter) seen on electron microscopy.18 Keratin, immunoglobulin, insulin, thyrocalcitonin, and other chemical substances can produce β-pleated antiparallel polypeptide sheets and therefore are amyloidogenic. All amyloid deposits, irrespective of their chemical nature and the clinical type of amyloidosis, have a common component, amyloid P component, which is a nonfib-

rillar protein derived from a serum precursor, known as serum amyloid P (SAP). Amyloid can be detected by immunohistochemical stains on paraffin-embedded sections using antibodies against human component P (anti-SAP); however, the specificity of this reaction is limited because amyloid P is also present in elastic tissue. The current classification of amyloidoses is based on the chemical nature of the amyloids with significant consideration of the conventional clinical subclassification (see Table 16-2).

Systemic Amyloid Light Chain Amyloidosis Systemic amyloidosis is classified into a primary (idiopathic) type caused by an occult plasma cell dyscrasia and a myeloma-associated type.18 The precursor of amyloid light chain (AL) amyloidosis is a monoclonal immunoglobulin light chain, more frequently of the lambda type. This form of amyloidosis is mainly a systemic deposition disease (kidney, liver, heart), but cutaneous lesions

Table 16-2 Amyloid-Hyaline-Colloid Deposition DISORDER Amyloidoses Systemic AL amyloidosis

Systemic AA amyloidosis (secondary systemic amyloidosis) Familial amyloidotic neuropathy b2-microglobulin amyloid Colloid milium Hyalinosis cutis et mucosae

Porphyria

DISTRIBUTION AND CHARACTERIZATION Perioral papules and ecchymosis, macroglossia, pinch hemorrhage Subcutaneous fat, rectal submucosa

ASSOCIATED DISORDERS

SPECIAL STAINS

Kidney, liver, heart, muscle deposition

Congo red (green birefringence), crystal violet, thioflavine T fluorescence Same (Congo red – after permanganate) Same

Kidney, liver, spleen

Leg ulcers, atrophic scars, pinch hemorrhage Lichenoid papules on arms and trunk Face, hands, neck

Peripheral nerves kidney, pancreas, testes Long-term hemodialysis

Oral mucous membrane edges of eyelids and nostrils (string of beads), over joints Sun-exposed areas (face, dorsum of hands, arms)

Epilepsy

Gout (tophi)

Auricle, finger, elbow

Waldenstrom macroglobulinemia (storage papule)

Semitranslucent papules

None

Hepatitis C in PCT, hepatic fibrosis and gallstones in EPP, neuropathy in variegated and hereditary coproporphyria Arthritis (big toe), kidney stones, neuropathy IgM gammopathy

CHAPTER 16 ■ DEPOSITION DISORDERS

“Hyaline” is not a single substance. Traditionally, this term has included a variety of skin deposits that appeared eosinophilic and somewhat glassy because of the refraction of light. Therefore, the recognition of hyaline invokes the differential diagnosis of a limited yet diverse group of conditions (Tables 16-2 and 16-3). All hyalines described below are PAS positive, Congo red positive, and thioflavine T positive.

SYSTEMIC AMYLOIDOSES

Adult type: amyloid P component Juvenile type: antikeratin Ab PAS (diastase-resistant)

PAS (diastase-resistant)

Birefringence in alcohol-fixed tissue Anti-IgM stain

371

Table 16-3 Summary of Special Stains for Pink Amorphous Deposits AMYLOID

PART II ■ PREDOMINANTLY NONINFLAMMATORY CONDITIONS

Congo red Apple green birefringence Thioflavin T Yellow-green birefringence Crystal violet metachromasia Methyl violet (red) Pagoda red no. 9 (Dylon) Scarlet red no. 5 (RIT) PAS + diastase Amyloid P-component antibody Keratin antibody IgM antibody Colloidal iron (pH, 2.5) Alcian blue Sudan black (frozen sections) Oil red O

+ − +

+ + + − + + Cutaneous + − − − − −

+ − − − + + Juvenile + − − − − −

HISTOPATHOLOGIC FEATURES Amyloid deposition begins in the perivascular and periappendageal areas (surrounding the sweat glands and hair follicles) and adipose tissue with the formation of “amyloid rings” (about the fat cells). Amyloid eventually fills the papillary dermis and diffusely involves the entire dermis, often associated with hemorrhages due to blood vessel involvement by amyloid

A

372

+ + +

are observed in 30% to 40% of patients. Pinch hemorrhages, periorbital waxy papules and plaques with hemorrhage, enlargement of the tongue (macroglossia), and hardening of the oral mucous membranes are the most common signs.

LIPOID PROTEINOSIS

COLLOID

PORPHYRIA

WALDENSTROM MACROGLOBULINEMIA

+ Weak + Weak + Weak − + + − −

− − −

− − −

− − − − + − −

− − − _ +

− + + + +

− − − − −

+ − − − −

infiltration (Fig. 16-15A). In extensive infiltrates, diffuse or nodular eosinophilic deposits often have a fissured or cracked appearance, rendering smaller aggregates with facets. Fibroblasts are often attached to the fissured edges. The deposits are not usually associated with an inflammatory infiltrate. Congo red stain is strongly positive in dermal amyloid (Fig. 16-15B). Amyloid deposits are reactive with the antibodies against immunoglobulin light chains (Fig. 16-16). In a rare subtype called amyloid elastosis,19 which is seen in the setting of systemic amyloidosis, the amyloid deposits surround individual elastic fibers. These elastic fibers appear shortened and fragmented

−

and show no evidence of elastorrhexis and calcification. Abdominal subcutaneous fat and gingival biopsies may be useful in the absence of specific mucocutaneous lesions. DIFFERENTIAL DIAGNOSIS See Tables 16-2 to 16-5.

Systemic Amyloid A Amyloidosis or Secondary Systemic Amyloidosis This disorder occurs in association with a variety of chronic inflammatory and infectious diseases such as rheumatoid arthritis, familial Mediterranean fever,

B

 FIGURE 16-15 Systemic amyloid light chain amyloidosis. (A) A hyaline substance (ie, amyloid) occupies the entire dermis. There are some fissures and hemorrhages with vascular ectasia (B) Congo red stain is strongly positive in dermal amyloid.

lepromatous leprosy, hidradenitis suppurativa, and generalized arthropathic psoriasis. Visible skin lesions are rare, except in Muckle-Wells syndrome, in which geographic skin lesions are seen (probably not containing amyloid). The major sites of amyloid A (AA) deposition are not the skin but rather the parenchymatous organs such as the kidneys, liver (speckled or wax liver), and spleen (sago spleen). AA is not immunoglobulin but instead is derived from α-globulin called serum amyloid A (SAA), which is split into AA amyloid in chronic febrile conditions.

Table 16-4 Skin-Limited Amyloidoses CLINICAL FEATURES

Keratin-Derived Amyloidoses Macular amyloidosis

Lichen amyloidosis

Biphasic amyloidosis (macular and lichen amyloidosis) Friction amyloidosis (see macular amyloidosis) Epithelioma-associated keratin amyloidosis

Actinic amyloidosis Juvenile colloid milium Insulin-Derived Amyloidosis Insulin amyloidosis

Immunoglobulin-Derived Amyloidosis Nodular amyloidosis

HISTOPATHOLOGIC FEATURES

Rippled pigmentation on the upper back, scapular areas, often middle-aged women of color, often with pruritus Hyperkeratotic papules or plaques on the shins, extensor surfaces, pruritis

Scant eosinophilic globules in the papillary dermis, pigment incontinence, occasional dyskeratotic cells Hyperkeratosis, papillomatous epidermal hyperplasia, aggregates of eosinophilic globules in the papillary dermis

Various cutaneous neoplasms: basal cell carcinoma, Bowen disease, actinic keratosis, seborrheic keratosis Waxy or pearly papules or, nodules on sun-exposed skin

Deposition of eosinophilic globules in both the parenchyma and stroma

Sites of repeated insulin injection

Eosinophilic globules, reparative changes

Single or multiple nodules on the face, scalp, and legs of middle-aged women

Massive accumulation of pink amorphous material in the dermis and occasionally the subcutis, plasmocytes

CHAPTER 16 ■ DEPOSITION DISORDERS

 FIGURE 16-16 Systemic amyloid light chain amyloidosis. Amyloid deposits are reactive with the antibodies against immunoglobulin light chains.

HISTOPATHOLOGIC FEATURES Deep-needle biopsy of the lower abdomen shows amyloid deposition around the subcutaneous fat cells (amyloid rings) and eccrine glands in about 66% of cases. As the amount of amyloid increases, the dermis may be diffusely infiltrated. Rectal biopsy shows amyloid deposition

DIFFERENTIAL DIAGNOSIS Postinflammatory hypermelanosis

Colloid milium, lipoid proteinosis

Large aggregates of pink eosinophilic material

Primary amyloidosis Waldenstrom macroglobulinemia

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PART II ■ PREDOMINANTLY NONINFLAMMATORY CONDITIONS

Table 16-5 Comparison of Lichen Amyloidosis and Colloid Milium of Adults LICHEN AMYLOIDOSIS

COLLOID MILIUM OF THE ADULT

Small deposits within broadened dermal papillae Amyloid in small globules Amyloid is amphophilic or eosinophilic in sections stained with H&E Stellate fibroblasts and melanophages intimately associated with globules of amyloid No clefts within the globules of amyloid Vascular proliferation associated with amyloid Papillary epidermal hyperplasia usually with hyperkeratosis overlies amyloid Solar elastosis not usually seen

Large deposits within the upper half of the dermis Colloid in large, nodular accumulations Colloid is amphophilic or basophilic in sections stained with H&E A few fibroblasts associated with colloid, but no macrophages

in the submucosa. After treatment with potassium permanganate, AA amyloid becomes nonreactive for alkaline Congo red stain; amyloid L is not affected by this treatment.18 DIFFERENTIAL DIAGNOSIS See Tables 16-2 to 16-5.

Familial Amyloidotic Polyneuropathy The familial amyloidoses constitute a group of autosomal dominant diseases in which a mutant protein forms amyloid fibrils.18 The most common form is caused by mutant transthyretin. Skin changes consist of trophic leg ulcers and atrophic scars due to the accumulation of transthyretin-derived amyloid in peripheral nerves. This variety has long been confused with leprosy because of nerve involvement and the deformity of the joints. There are Portuguese, Japanese, and Swedish subtypes. HISTOPATHOLOGIC FEATURES In the skin, blood vessels, arrector pili muscles, and elastic fibers are infiltrated by amyloid in addition to cutaneous nerves. The pancreas and testes may be affected, but the liver and spleen are usually spared.

β2-Microglobulin Amyloid Small, shiny lichenoid papules develop on the arms and trunk of patients who have had long-term hemodialysis. Dermal deposition of amyloid is similar to that in patients with AL amyloidosis.

SKIN-LIMITED AMYLOIDOSES

374

All skin-limited amyloid depositions are of the keratin type, except nodular amyloidosis, which is derived from the light chain of immunoglobulins18 (see

Clefts within the nodules of colloid No vascular proliferation associated with colloid Thin epidermis with loss of the rete pattern and grenz zone overlies colloid Solar elastosis always present

Table 16-4). The source of keratins is either epidermal or from tumors of epidermal or hair follicle origin. Individuals of colo, such as African Americans, Asians, Latin Americans, and those of Middle Eastern origin, are more frequently affected than whites. Macular, lichenoid, and biphasic amyloidosis are the three most common variants. Rare variants include a poikilodermatous type called amyloidosis cutis dyschromica, an anosacral variant, a thermosensitive variant, and a familial primary cutaneous form.20

Macular Amyloidosis The upper back and scapular areas of middle-aged, dark-skinned women are most commonly affected by pruritic macules showing irregular pigmentation with a “rippled” pattern. The constant use of a nylon brush or towel is sometimes involved as a causal factor (frictional amyloidosis).

Lichen Amyloidosis Typical lesions are hyperkeratotic papules and plaques involving the shins and, in severe cases, the extensor surface of the arms, including the shoulders. Severe pruritus is a characteristic feature, and some authors have proposed that lichen amyloidosis is almost always a consequence of scratching in the setting of an underlying pruritic condition. Familial cases of lichen amyloidosus and cases associated with genetic diseases (eg, multiple endocrine neoplasia syndrome type 2A) have been reported.

Biphasic Amyloidosis Both lichenoid and macular amyloidoses are present in the same area or separate

locations in the same patient. The lichenoid lesions are commonly pruritic. HISTOPATHOLOGIC FEATURES Small numbers of eosinophilic globular deposits of amyloid, barely distinguishable from collagen, accumulate initially in the papillary dermis in macular amyloidosis, resembling the cytoid bodies of lichen planus. Although cytoid bodies or other evidence of keratinocyte degeneration are not routinely observed in the epidermis, a careful search may identify such cells. These epidermal cytoid bodies are considered to be the source of amyloid in these varieties of amyloidoses, breaking through the basement membrane and dropping into the dermis. In lichen amyloidosis, large clumps of amyloid expand dermal papillae, pressing the rete ridges into thin septae.20 Lichen amyloidosis may be distinguished from the macular form by hyperkeratosis, acanthosis with hyperpigmentation of the basal layer, and larger deposits of amyloid (Fig. 16-17). In the later stages, diffuse homogeneous eosinophilic amyloid fills the papillary dermis and infiltrates the upper reticular dermis. Adnexal structures and blood vessels are not involved. Some degree of pigment incontinence and hemorrhage is usually present in both forms of cutaneous amyloidosis. A characteristic feature of familial lichen amyloidosus is the transepidermal elimination of amyloid. Keratin amyloids (amyloid K) are strongly stained with polyclonal antikeratin antibodies that contain combinations of antibodies against basal cell keratins (K5, K14) and upper epidermal keratins (K1, K10). Amyloid P component is always positive. Maturation of degenerated keratin proteins into amyloid may require a digestion process in the lysosomes of dermal macrophages.

A

B

Routine Congo red, Dylon, thioflavine T (Fig. 16-18), toluidine blue, and crystal violet stains are positive, but they are not always reliable in formalin or alcohol fixed-tissue sections. These stains are more reliable in fresh-frozen sections. Electron microscopic demonstration of 6to 10-nm straight filaments is the most specific and reliable diagnostic method (Fig. 16-19). DIFFERENTIAL DIAGNOSIS A major condition confused with macular amyloidosis is postinflammatory hypermelanosis. However, postinflammatory hypermelanosis does not exhibit amyloid and is clinically distinctive. The differential diagnosis of lichen amyloidosis includes nodular amyloidosis, colloid milium and colloid degeneration, lipoid proteinosis, and Waldenstrom macroglobulinemia (see Tables 16-2 to 16-4). Nodular amyloidosis usually shows much more extensive amyloid accumulation in the dermis (and possibly the subcutis) and waxy or translucent nodules of the head and neck compared with lichen amyloidosis. In addition, immunoglobulin light chains can be demonstrated in nodular amyloidosis. Juvenile colloid milium may be histologically indistinguishable from lichen amyloidosis except by distribution and clinical features. Adult colloid milium differs from lichen amyloidosis by the features outlined in Table 16-5. Lipoid proteinosis (and erythropoetic porphyria) shows a perivascular pattern of accumulation of amorphous pink material that is PAS+D and weakly Congo red positive. The storage papules of Waldenstrom macroglobulinemia may closely resemble adult colloid milium and lichen amyloidosis

because of the presence of clefts and fissures. The hyaline material in such storage papules is PAS+D positive and Congo red negative and reacts with antibodies against IgM.

Epithelioma-Associated Keratin Amyloidosis Skin tumors derived from the epidermis or hair follicle produce keratin amyloid. Clinically, there is no definitive way to differentiate the amyloid contained in such tumors from other forms of keratin-derived amyloid. The same keratin proteins that are found in lichenoid and

macular amyloidoses (K1, K5, K10, K14) are also found in these tumors, both in the parenchyma and stroma. Common tumors that produce amyloid are basal cell carcinoma, Bowen disease, actinic keratosis, and seborrheic keratosis. It is believed that the growth control of the tumor cell population by apoptosis induces filamentous degeneration of keratin intermediate filaments, resulting in the formation of cytoid bodies, which become amyloidogenic. It is probably necessary for such cytoid bodies to persist without perturbation such as from an inflammatory reaction; similar keratin cytoid bodies occurring in the lichenoid

 FIGURE 16-18 Lichen amyloidosus. Thioflavine T fluorescence is seen in amyloid deposition in the papillary dermis.

CHAPTER 16 ■ DEPOSITION DISORDERS

 FIGURE 16-17 Lichen amyloidosus. (A) Hyperketotic papules present on the extremities. (B) Under the hyperkeratotic epidermis, pale pink hyaline material (ie, amyloid), barely distinguishable from the collagen, is deposited mainly in the papillary dermis.

375

HISTOPATHOLOGIC FEATURES In juvenile colloid milium subepidermal, eosinophilic, fissured colloid masses abut the epidermis without a grenz zone (Fig. 16-20). Colloidlike material appears to develop in basal keratinocytes and drop off into the papillary dermis. Histiocytes and melanophages are noted within the colloid material. Epidermal cytoid bodies and dermal amyloid can be stained with polyclonal antikeratin antibodies in addition to standard amyloid stains. The filaments derived from these cytoid bodies meet the ultrastructural criteria for amyloid filaments.

PART II ■ PREDOMINANTLY NONINFLAMMATORY CONDITIONS

Insulin Amyloidosis It is known that insulin can be converted into amyloid in insulinoma or pancreatic islets in individuals with diabetes. Such amyloid is designated islet amyloid polypeptide. In the skin, insulin amyloid is formed at the sites of repeated insulin injection.

Nodular Amyloidosis  FIGURE 16-19 Filamentous degeneration (f ) of keratinocytes is observed in the lower epidermis. Normal tonofilaments (t ) lose their electron density (*) and become wavy (curved arrow ). Some cellular organelles (arrowheads ) are intact (x2000).

dermatoses, such as lupus erythematosus, do not transform into amyloid. When apoptotic cells are eliminated from the epidermis or tumor parenchyma to the dermis or stroma, the components of the basement membrane become entangled in the amyloidogenic filament mass and can be demonstrated within the mature amyloid; thus, PAS-positive substances and laminin and type IV and VII collagens can be stained in mature keratin amyloid.

sis of the inner auricle or helix of the ear is clinically an aggregation of cobblestonelike waxy or pearly papulonodules.22 Severe keratinocyte degeneration into cytoid bodies is present in the epidermis.

Single and sometimes multiple nodules may occur anywhere on the cutaneous surface, but the face, scalp, and leg of middle-aged women are the most common sites.18 Individual nodules are firm, waxy and tumorlike, or appear semitransparent, amber colored, or hemorrhagic (Fig. 16-21B). About 7% of these patients develop multiple myeloma. Nodular amyloidosis may be associated with Sjögren syndrome and subacute cutaneous lupus erythematosus. In such cases, serum autoantibodies Sjogren

Actinic Amyloidosis

376

These conditions include juvenile colloid milium and amyloidosis of the auricular concha.21,22 Ultraviolet rays have a severe injurious effect on keratinocytes, as evidenced by sunburn cells. Chronic sun exposure of the skin leads to the amyloidal degeneration of the epidermal keratinocytes. For example, actinic keratosis is often associated with the deposition of keratin amyloid. Whereas the “colloid” substance in juvenile colloid milium is actually keratin amyloid, adult-type colloid milium contains severely degenerated elastic fibers. An association of juvenile colloid milium with ligneous conjunctivitis has been identified.1 Concha amyloido-

 FIGURE 16-20 Juvenile colloid milium. Pink-stained hyaline substance (ie, amyloid) occupies widened dermal papillae. Round cytoid body–like amyloid globules can be recognized at the periphery.

B

 FIGURE 16-21 Nodular amyloidosis. (A) Characteristic infiltrative firm, waxy nodules on the face. (B) A massive deposition of amorphous amyloid substance throughout the entire dermis. There are many fissures and cracks caused by processing artefact due to the lack of elasticity in amyloid.

syndrome antigen A/Sjogren syndrome antigen B (SSA/SSB) are positive. HISTOPATHOLOGIC FEATURES A massive deposition of weakly eosinophilic amorphous amyloid substance is noted throughout the entire dermis, often extending into the subcutis (see Fig. 16-21A) and around the blood vessels and the dermal appendages.18,23 Greenish birefringence of Congo red stain makes contrast with white birefringence of collagen fibers (Fig. 16-22). Numerous plasma cells, some with large Russell bodies, are often seen, but they are sparse or absent in nodular lesions of systemic primary and myeloma-associated amyloidosis. Monoclonality of infiltrating plasma cells by polymerase chain reaction has been detected. Giant cells and focal calcification may be found. Contrary to the other localized cutaneous amyloidoses, the amyloid deposits are AL type, derived from immunoglobulin light chains. In all types of amyloid, immunoglobulins are present, probably passively trapped in the meshwork of amyloid filaments. These immunoglobulins can be eluted in acidic buffer without disrupting the filamentous nature of

amyloid or altering the standard amyloid stains. In nodular amyloidosis, the same elution procedure abolishes amyloid staining, suggesting that this amyloid is immunoglobulin itself. However, the

CHAPTER 16 ■ DEPOSITION DISORDERS

A

origin of immunoglobulin is not always elucidated. DIFFERENTIAL DIAGNOSIS See Tables 16-4 and 16-5.

 FIGURE 16-22 Nodular amyloidosis. Congo red stain observed under polarized light. Greenish birefringence of Congo red–stained amyloid makes contrast with white birefringence of collagen fibers.

377

Soft Tissue Amyloidoma (Tumoral Amyloidosis)

PART II ■ PREDOMINANTLY NONINFLAMMATORY CONDITIONS

Amyloidoma is defined as a solitary, localized, tumorlike deposit of amyloid in the absence of systemic amyloidosis. Amyloid deposition may be of the AL or AA type.24 It has been reported in many anatomic sites, including the soft tissues and the skin, mainly on the extremities. Some cases have been associated with local trauma, surgery, infection, peripheral vascular disease, and diabetes.

378

HISTOPATHOLOGIC FEATURES Amyloid deposition fills the dermis and subcutis and is sometimes associated with a giant cell granulomatous reaction, a patchy lymphocytic infiltrate, and focal microcalcification. Plasma cells are not a prominent component; however, in some cases of localized amyloidosis, a light chain–restricted plasma cell infiltrate has been identified, suggesting its classification as a form of low-grade B-cell lymphoproliferative disease. The persistence or absence of congophilia after pretreatment with permanganate is useful in differentiating the type of amyloid. AL amyloid remains positive with Congo red stain after pretreatment.

Hyalinosis Cutis et Mucosae (Lipoid Proteinosis) This is a rare autosomal recessive (OMIM 247100) or sporadic (new mutation) disease.25 In the hereditary form, which is caused by mutations in the extracellular matrix protein 1 gene, the initial symptom is hoarseness due to hyaline infiltration of the vocal cords. A diffuse infiltration of the pharynx, larynx, and oral mucosa (including the tongue) produces extensive induration of the mouth. Early lesions consist of bullae and varicelliform scars on the face and arms, which are similar to those of erythropoietic protoporphyria. The free edges of the eyelids and nostrils show small, waxy, semitransparent papulonodules resembling a “string of beads.” Large plaque-type infiltration may occur on the face and over the joints. The nonfamilial type occurs in an older age group and is typified by similar lesions except bullae and scars on the face are present. HISTOPATHOLOGIC FEATURES Hyalin deposition begins around the dermal blood vessels and eccrine glands where PASpositive diastase-resistant hyaline is demonstrated in concentric rings (onionskin pattern). This material, which also stains with Alcian blue at a pH of 2.5 and

stains only very weakly or negatively with Congo red, may be seen around pilosebaceous units and in arrector pili muscles.25 Hyaline deposits oriented perpendicularly to the dermoepidermal junction gradually fill the entire dermis (Figs. 16-23 and 16-24). Small lipid droplets may be demonstrated with the scarlet red stain, particularly around the blood vessels in late lesions. The epidermis may show hyperkeratosis and papillomatosis in verrucous lesions. Calcified foci and a failure of mucocutaneous lymphangiogenesis have also been described.26 Electron microscopy demonstrates multiplication of lamina densa (basal lamina) in perivascular and periglandular spaces. The hyaline substance is mainly homogeneous, but some filament components are also admixed. Significant degeneration of collagen fibers are seen as longitudinal splitting or fragmentation of fibers. The dermal deposits contain type IV collagen, laminin, neutral muchopolysacchrides, hyaluronic acid, and ceramide or more complex lipids, but the precise pathogenesis of the disease remains unknown. DIFFERENTIAL DIAGNOSIS PAS-positive material in lipoid proteinosis is differentiated from amyloid by its negative or weak staining on Congo red stain. In erythropoetic protoporphyria, the deposits are more limited in distribution, being perivascular only, and the sweat glands are not involved.

Colloid Milium Colloid milium is divided into three clinical types: colloid milium of the adult,

juvenile colloid milium (see earlier in the chapter in Actinic Amyloidosis), and nodular colloid degeneration. A fourth variant, pigmented colloid milium associated with hydroquinone use, is also seen.27

Colloid Milium of the Adult Yellowish semitransparent papules and plaques occur on the face and dorsum of the hands. Interestingly, the left side of the face and left hand are more frequently and severely affected because of more sun exposure on that side while driving. The condition usually occurs in older men with fair skin, particularly farmers and other outdoor workers, sportsmen, and truck drivers. A verrucous variant after exposure to mineral oil and a unilateral variant have been described. The lesions are soft, and a small incision and pressure allow the expression of the gelatinous substance. Hemorrhage is common in large lesions. HISTOPATHOLOGIC FEATURES Colloid in colloid milium of the adult type is the final degeneration product of elastic fibers. H&E-stained sections show a hyaline substance in large sheets occupying the papillary and upper reticular dermis (Fig. 16-25).28 Many cracks and fissures within the colloid material and fibroblasts are commonly seen along the lines of fissuring. Inflammation is lacking. Solar elastosis is always present. A narrow grenz zone of normal collagen separates the atrophic epidermis from the colloid substance. Histochemical studies have shown that the material is PAS positive and only weakly positive

 FIGURE 16-23 Hyalinosis cutis et mucosae. A widened dermal papilla is entirely occupied by vertically oriented hyaline material. Several dilated blood vessels are seen. The tissue reaction against this massive deposition is minimal. (Courtesy of A. Amantea, MD, and P. Donati, MD.)

the two conditions. A good clinicopathologic correlation and electron microscopy are helpful29 (see Table 16-5).

Nodular Colloid Degeneration Single or multiple large nodules occur on the face or head and neck region. The sun-protected skin of the trunk may be involved.

or negative with Congo red or thioflavine T. The disparity in the results of Congo red stain could be due to the different technical procedures performed. An elastic fiber stain is largely negative in the main body of colloid and positive in the grenz zone and at the periphery of the colloid deposition (actinic elastosis). Amyloid P component, which is present in normal elastic fibers, is strongly stained in the lesion with the immunoperoxidase method. On electron microscopy the colloid substance is a moderately electron-dense

amorphous substance with some granules and fine filaments. These findings in contrast to the colloid of juvenile colloid milium despite the clinical and histologic similarity of the juvenile and adult types. As already discussed, juvenile colloid milium contains typical keratin-derived amyloid filaments. DIFFERENTIAL DIAGNOSIS Adult colloid milium may be confused with lichen amyloidosis because both conditions show fissured, homogeneous eosinophilic material and special stains are sometimes similar in

WALDENSTROM MACROGLOBULINEMIA In this condition, extramedullary lymphatic tissues are involved by a B-cell lymphoma that produces monoclonal IgM. The lymph nodes, liver, and spleen are enlarged, and the skin may show purpura. Large plaques and nodules develop in the skin. In some patients, small semitransparent “storage papules” are seen.

CHAPTER 16 ■ DEPOSITION DISORDERS

 FIGURE 16-24 Hyalinosis cutis et mucosae. Periodic acid Schiff stain is strongly positive in the hyaline deposition in the upper dermis.

HISTOPATHOLOGIC FEATURES Colloid material occupies the entire dermis, extending more deeply than in individuals with colloid milium. Scattered fibroblasts, dilated blood vessels, clefts, and fissures are present. These features are similar to amyloid deposition of the dermis. However, on electron microscopy, a predominantly amorphous substance is admixed with fine filaments (3–4 nm in diameter) that are smaller than amyloid filaments (6–10 nm). The amorphous masses stain positively with Verhoeff-Van Gieson stain for elastin.30

HISTOPATHOLOGIC FEATURES The storage papules in this condition are similar to the amyloid deposition in lichen amyloidosus and the colloid in adult colloid milium because the substance contained in these papules is eosinophilic and amorphous with H&E stain and occupies the papillary and upper reticular dermis.31 Furthermore, large deposits show clefts and fissures. The material is PAS positive and strongly reactive with antihuman IgM antibody. The large plaques or nodules show involvement by lymphoma. DIFFERENTIAL DIAGNOSIS See Tables 16-2 and 16-3.

PORPHYRIA

 FIGURE 16-25 Adult colloid milium. Hyaline substance (ie, colloid) occupies dilated dermal papillae. There are many fissures in these masses.

These diseases are caused by defective enzymes involved in heme synthesis. Seven of eight subtypes, except the acute intermittent type, exhibit a variety of photosensitivity and related skin changes. The most common subtype is porphyria

379

PART II ■ PREDOMINANTLY NONINFLAMMATORY CONDITIONS

cutanea tarda (PCT) in which serum uroporphyrin is elevated due to a deficiency of uroporphyringogen decarboxylase. Vesicles and blisters occur on the face and dorsum of the hands. Hypertrichosis of the face may be pronounced and may account for the appearance suggesting a “wolfman.” (see Chapter 8 for more detailed discussion). HCV infection may be a major factor in the etiology of PCT. Hepatitis B virus and HIV infection have also been frequently associated. Patients with erythropoietic protoporphyria show blisters and thickening of the facial skin and the dorsum of the hands. The condition appears to be caused mainly by an autosomal dominant mutation of heme synthase gene located on chromosome 18q21.3. HISTOPATHOLOGIC FEATURES The histopathologic features are similar among all photosensitive subtypes. The primary change in all types of porphyrias is a perivascular deposit of hyaline material stainable with PAS; this staining is resistant to diastase digestion (neutral polysaccharides). 32,33 In mild cases, the hyaline deposition is limited to the capillaries of the upper dermis, and in severe cases, it fills the papillary dermis and extends into the lower dermis. Subepidermal blisters develop. The dermal papillae are hardened by this deposition, and when subepidermal blistering occurs, the stiff dermal papillae remain in place instead of collapsing; this has been termed festooning of dermal papillae (Fig. 16-26). Sometimes peculiar, elongated eosinophilic structures in a linear array in the roof of PCT and EPP bullae are seen and have been termed caterpillar bodies. Scleroderma-like diffuse thickening of the dermal collagen may occur in chronic lesions.

A

B

DIFFERENTIAL DIAGNOSIS See Tables 16-2 and 16-3.

HYALINE ANGIOPATHY This histologic change has been described in the oral cavity and the skin. It is characterized by eosinophilic amorphous material within and around dermal vessels. This material differentially stains for light chain products or collagen. The process has been considered both a reaction associated with acute and chronic inflammation and an unusual form of microvasculopathy.34,35

GOUT 380

This dominantly inherited abnormality of purine metabolism produces a high

C  FIGURE 16-26 Porphyria cutanea tarda. (A) In this patient with porphyria cutaneous tarda, foci of subepidermal bulla formation are seen. (B and C) The dermal papillae capillaries exhibit basement membrane zone reduplication, resulting in a hyaline-like appearance to the vessels. The basis of the microvascular injury is one of complement activation via irradiated porphyrins with c5b-9 as the effector mechanism of microvascular injury. (From Vasil KE, Magro CM: Cutaneous vascular deposition of C5b-9 and its role as a diagnostic adjunct in the setting of diabetes mellitus and porphyria cutanea tarda. J Am Acad Dermatol. 2007;56:96-104.)

collagen bundles and are surrounded by a variable histiocytic response. Without any clinical history, such deposition is puzzling. The material may be weakly PAS positive and negative for mucin stains.

HISTOPATHOLOGIC FEATURES Grayish amorphous material with needlelike clefts in the dermis is surrounded by palisading granulomas37 (Fig. 16-27A). The nuclei in macrophages may be altered by crystals and appear atypical. If fixed in alcohol, uric acid crystals are preserved and yield characteristic multicolor birefringence under polarized light (Fig. 16-27B). Upon examination with a red condenser, these crystals assume a yellow color when parallel to the condenser and blue when perpendicular to the plane of projected light. In formalinfixed tissues, the crystals are less obvious, and no birefringence is observed. With the De Galantha stain, the crystals appear brown to black. Secondary calcification or even ossification is common. Late-stage tophi are surrounded by a fibrous pseudocapsule and contain mucopolysaccharides.

Calcium deposition in the skin occurs in variety of clinical situations (Table 16-6). Four subsets occur: metastatic calcinosis (including calciphylaxis), dystrophic calcinosis, idiopathic calcinosis, and iatrogenic calcinosis.36,38

CORTICOSTEROID INJECTION SITES The cutaneous injection sites of corticosteroids often show multiple pools of eosinophilic hyaline material between

A

CALCIUM, BONE, AND CARTILAGE

Calcinosis Cutis

Metastatic Calcinosis Cutis Metastatic calcification occurs when the final metabolic defects give rise to elevated serum calcium or phosphate levels. This may result from hypercalcemia due to hyperparathyroidism secondary to an adenoma or malignant neoplasms secreting parathyroid-like hormones, hypervitaminosis D, milk alkali syndrome, or hyperphosphatemia caused by renal failure or renal dialysis in which excretion of phosphorus is diminished (see Table 16-6). Because the product of serum calcium and phosphorus levels is physiologically constant, this hyperphosphatemia results in a compensatory decline in serum calcium ion levels and the resulting stimulation of parathyroid secretion to mobilize calcium from bone. The direct destruction of bone and the release of calcium may occur in individuals with sarcoidosis, osteomyelitis,

bone metastases in cancer, and multiple myeloma. The clinical appearance of metastatic calcification in the skin ranges from hard papules and nodules to subcutaneous diffuse hardening. When these lesions are ulcerated, chalky white material may be discharged. When blood vessels are calcified, hard, linear, clinically palpable cords may ensue. In calciphylaxis (calcific uremic arteriolopathy)39 (see Chapters 9 and 11), patients affected by hyperparathyroidism secondary to chronic renal failure present with violaceous, painful, necrotic, and ulcerated lesions with a livedoid pattern on the buttocks and extremities. In patients with normal calcium and phosphate levels, it has been suggested that parathyroid hormone (PTH) sensitizes the vessels of the tissue, and subsequent exposure to various triggering agents (ie, metallic salts, albumin, trauma) results in calcification. HISTOPATHOLOGIC FEATURES Calcium stains deep blue to violet in H&Estained tissue sections, black with the von Kossa stain, and red with Alizarin red. Calcium deposition in the skin may be massive in the deep dermis to subcutaneous tissue and in small foci in the upper dermis. Exclusive involvement of the sweat ducts has been reported. A foreign body reaction with fibrosis may develop around larger calcium deposits. In calciphylaxis, intramural calcium deposition occurs in the media of subcutaneous arteries and arterioles in addition to epidermal ulceration and dermal necrosis. Less commonly, vessels are not involved, and calcium is seen in

CHAPTER 16 ■ DEPOSITION DISORDERS

level of serum uric acid, which deposits as monosodium urate crystals in small joints, typically those of the great toe.36 Increased serum purine levels may be secondary to decreased renal function, diuretic therapy, or an increased purine synthesis in myeloproliferative diseases. Skin deposition of uric acid (called gouty tophi) occurs most frequently on the auricle. The elbow and finger joints are also commonly affected.

B

 FIGURE 16-27 Gouty tophus. (A) The deposition of urate is surrounded with foreign body giant cells. (B) Under polarized light, urate crystals give rise to multicolored birefringence. (Figure 16-27B is courtesy of Min W. Lee, MD.)

381

Table 16-6 Calcium and Bone Deposits DISORDER Calcinosis cutis Metastatic

Dystrophic

PART II ■ PREDOMINANTLY NONINFLAMMATORY CONDITIONS

Idiopathic

Calciphylaxis

Ossification of the skin Primary

Secondary Albright hereditary osteodystrophy

Subungual exostosis

CLINICAL FEATURES

ASSOCIATED DISORDERS

HISTOPATHOLOGY

Papules, nodules Any location

Hypercalcemia due to hyperparathyroidism hyperphosphatemia, hypervitaminosis D, milk alkali syndrome Normal serum calcium Collagen-vascular diseases None

Massive deposition in subcutis Small foci in dermis

Any location preceding tissue damage, skin tumors and cysts Subepidermal calcified nodule, idiopathic calcinosis (genital), tumoral calcinosis, milia-like calcinosis Abdomen, buttocks, thighs, livedoid pattern

Plaque type, nodular Multiple miliary type on the face Other types anywhere Any location depending on preceding condition Any location

Distal toe and finger

the septa of the subcutaneous tissue (calcifying septal panniculitis).

Dystrophic Type

382

Dystropic calcification is characterized by normal serum calcium and phosphorus levels and the internal organs are spared; that is, this is strictly a cutaneous phenomenon secondary to local tissue disruption, necrosis, or “dystrophy.” Widespread cutaneous calcification (calcinosis universalis) may occur in collagen vascular diseases, such as childhood dermatomyositis, progressive systemic sclerosis (particularly CREST [calcinosis, Raynaud syndrome, esophageal dysmotility, sclerodactyly, and telangiectasia] syndrome), and systemic lupus erythematosus. Localized forms (calcinosis circumscripta) may also occur in patients with these diseases, particularly in the digits of patients with acrosclerosis and in acne and stasis ulcers. Inherited diseases such as pseudoxanthoma elasticum and Ehlers-Danlos syndrome (gravis

Individual condition determines the calcification pattern Papillary dermis, acanthosis Well-demarcated areas Massive subcutaneous calcification Intramural deposition in subcutaneous vessels

Down syndrome Renal failure Sensitizer: hyperparathyroidism Challengers: albumin, metallic salts, vitamin D, parathyroid hormone None Acne, scars

Lamellar bone in dermis or fat

Skin appendage tumors, collagen-vascular disease Short stature, round face, absence of some knuckles Mental retardation, hypercalcemia (pseudohypoparathyroidism) or normocalcemia (pseudopseudohypoparathyroidism) None

Metaplastic ossification and calcification Lamellar bone

type), may be associated with calcinosis cutis. Subcutaneous fat necrosis of the newborn, frostbite or trauma of the auricle, old lesions of nodular amyloidosis, and repeated venipuncture of the heels of infants for blood tests are followed by localized calcification. Many appendage tumors of the skin with hair follicle differentiation, notably calcifying epithelioma or pilomatricoma, trichilemmal (pilar) cysts, basal cell carcinoma, and trichoepithelioma, often show calcium deposition. HISTOPATHOLOGIC FEATURES Calcium deposition is usually slight in the upper dermis with localized granular deposits. The deposition in the deep dermis and subcutaneous tissue is usually substantial or massive. Vascular involvement is not a feature. Each of the individual preceding conditions usually determine the pattern of calcification. For example, necrotic fat cells are primarily calcified in subcutaneous fat necrosis of the newborn, and tumor parenchyma is initially calcified in pilar tumors. Leakage of calcium

Enchondral bone

into the connective tissue elicits various degrees of foreign body reactions.

Idiopathic Type TUMORAL CALCINOSIS Calcification of the skin may occur without apparent cause or antecedent tissue injury. “Tumoral calcinosis” is usually a familial condition in which numerous subcutaneous calcified nodules can be palpated in otherwise healthy patients (Fig. 16-28). Hyperphosphatemia may be present. This condition resembles clinically dystrophic calcinosis universalis of dermatomyositis and tends to affect the bony prominences. It is more common in Africa and Papua-New Guinea than North America and Europe. SUBEPIDERMAL CALCIFIED Localized, solitary nodular calcification (subepidermal calcified nodule or cutaneous calculus) is found in infants as a congenital tumor (Fig. 16-28). The face, particularly the ear, or limbs are common sites.

B

 FIGURE 16-28 Tumoral calcinosis. (A) There are nodular foci of calcification with associated fibrosis and foreign body reaction compatible with tumoral calcinosis. (B) In this child, a biopsy of a hard cheek nodule revealed nodular collections of calcium in the dermis with associated transepidermal elimination of calcium through the epidermis.

In rare instances, multiple lesions occur. Adults may be affected. Idiopathic calcinosis of normal skin has been reported to involve the scrotum, penis, and vulva and in patients with Down syndrome (milialike calcinosis).

of the subcutaneous fat, in the spaces between adipocytes, in connective tissue septa (Fig. 16-29), and in the media of small arteries.40

HISTOPATHOLOGIC FEATURES As the dystrophic type, massive calcification is present in the subcutaneous tissue in tumoral calcinosis with multiloculated cystlike structure containing a milky fluid with calcium granules. In subepidermal calcified nodules, multiple granules and islands of calcification are seen just beneath a hyperkeratotic and acanthotic epidermis (Fig. 16-28B). Transepidermal elimination through the hair canals and eccrine sweat ducts may be observed ( Fig. 16-28B). Idiopathic calcinosis of the genital areas and milia-like calcinosis display homogeneous discrete areas of calcification with well-demarcated contours.

Cutaneous ossification is an unusual event that may be primary or secondary to either inflammatory or neoplastic processes41 or systemic conditions with a genetic basis (Albright hereditary osteody-

CUTANEOUS OSSIFICATION

strophy, progressive osseous heteroplasia, fibrodyslasia ossificans progressive) (see Table 16-6).42 The osteoblast, a modified fibroblast, produces type I collagen in a similar fashion to dermal fibroblasts. However, posttranslational alterations of osteoblast-derived type I collagen probably make it more suitable for phosphorylation to initiate ossification. Activators of bone formation, such as osteonectin and transforming growth factor β, are produced by osteoblasts.

CHAPTER 16 ■ DEPOSITION DISORDERS

A

Iatrogenic Calcinosis Iatrogenic calcinosis has been described at the sites of extravasation of calcium associated with the administration of intravenous calcium solutions, at the sites of subcutaneous injection of lowmolecular-weight heparins such as nadroparin,40 and even in patients after liver transplantation. HISTOPATHOLOGIC FEATURES An extensive, widespread calcification with a characteristic “feathery” alteration of collagen and elastic fibers is observed in the dermis. Multiple foci of microcalcification may develop within the lobules

 FIGURE 16-29 Primary cutaneous osteoma cutis. Well-circumscribed nodule of mature lamellar bone with trabecular projections and stromal component of fat cells.

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PART II ■ PREDOMINANTLY NONINFLAMMATORY CONDITIONS

Primary Cutaneous Ossification (Osteoma Cutis) This condition may occur in early life or in adults as widespread multiple nodules or as a single, large plaquelike osteoma. The late onset varieties occur as a single small nodule anywhere in the skin or as “multiple miliary osteoma of the face.” The latter lesions are most commonly encountered in older woman, but the condition has recently been reported in elderly men as well. The face, particularly the forehead, is involved by multiple hard, tiny papules of normal to blue color occurring in acne lesions and scars. Small, pebbly bone chips can be extracted from these papules. HISTOPATHOLOGIC FEATURES Fragments of bone that vary in size and shape are present in the deep dermis or subcutaneous tissue (see Fig. 16-29). This type of bone develops by membranous ossification without the presence of a cartilage precursor and is called lamellar bone. It exhibits a laminated fibrous structure (cement lines) indicating underlying collagen bundles. Osteoblasts are embedded within the bone and are also noted at the peripheries where nonmineralized, condensed collagen islands (osteoid) are still present. Connective tissue and mature fat cells accompanied by blood vessels are enclosed in the bone and form Haversian canals. However, osteoclasts, which are multinucleated giant cells resembling foreign body giant cells, are only rarely observed. Hematopoiesis may occasionally be seen in the marrow spaces. Ulceration and epidermal elimination may occur.

and blood vessels are present. In chondroid syringoma, ossification occurs by the replacement of preformed cartilage (ie, enchondral bone formation).

Subungual Exostosis (Osteochondroma) This is a solitary tender nodule under the distal end of the nail, most commonly at the free edge of the great toe. The lesion is composed of mature trabecular bone with an overlying cap of mature cartilage as the osteogenesis occurs by enchondral ossification.

Albright Hereditary Osteodystrophy This dominantly inherited disorder of bone, caused by mutations in the GNAS1 gene, is also termed pseudohypoparathyroidism or pseudopseudohypoparathyroidism, depending on whether abnormal or normal calcium metabolism is present. The former is characterized by hypocalcemia that does not respond to PTH; in the latter condition, the response is unaltered. These patients show characteristic round facies, diminished stature, and shortened metacarpal bones. Ossifications of any size may occur anywhere in the skin and subcutaneous tissue. Bone may be extruded through cutaneous ulcerations. HISTOPATHOLOGIC FEATURES The bone formation is of the lamellar type, that is, developing by the ossification of

compacted collagen (osteoid) in which lamellar sheets are still visible.

ENDOGENOUS PIGMENT DEPOSITS

Alkaptonuria and Ochronosis Alkaptonuria is a rare autosomal recessive disorder of homogentisic acid catabolism due to loss-of-function mutations in the homogentisate 1,2-dioxygenase gene (HGO). Because of the enzymatic block, homogentisic acid deposits on collagen, especially in the skin and cartilage, and is then oxidized and polymerized to ochronotic pigment. Alkaptonuria is characterized by the triad of homogentisic acid present in the urine, ochronosis, and ochronotic arthropathy.43 Ochronosis refers to the deposition of ochre-colored pigment in the skin and other tissues, giving rise to a blue-black appearance. The ear cartilage is usually the first site affected; the axillae and groin are also commonly involved. HISTOPATHOLOGIC FEATURES Yellowbrown, ochre-colored masses with bizarre (sausage- or banana-shaped structures) and irregular shapes are deposited in the mid-dermis, often in association with solar elastosis (Fig. 16-30).36,43 Degenerated collagen appears as amorphous, fragmented clumps, sometimes associated with a granulomatous reaction. Transepidermal elimination of

Secondary (Metaplastic) Cutaneous Ossification Many conditions in which calcium deposition occur (eg, calcinosis cutis) are prone to ossification. Some examples are skin appendage tumors, notably calcifying epithelioma (pilomatricoma) and chondroid syringoma, melanocytic nevi (osteonevus of Nanta), collagen vascular diseases (particularly CREST syndrome), and childhood dermatomyositis. The chronic stage of fibrosis (eg, scars and scleroderma) seems to induce ossification.

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HISTOPATHOLOGIC FEATURES The laminated layers of eosinophilic bone are the result of mineralization of type I and, to a lesser extent, type III and V collagens. Osteoblasts are found within and along the periphery of the bone. In larger lesions, Haversian canals with collagen

 FIGURE 16-30 Alkaptonuric ochronosis. Yellow-brown, ochre-colored, bizarre (banana-shaped) masses deposited in the upper dermis with solar elastosis and a granulomatous reaction.

ochronotic fibers has been seen. Fine granular pigment may lie free in the dermis or in the endothelial cells and sweat glands. The pigment stains black with crystal violet or methylene blue stains.

MUCOPOLYSACCHARIDOSES

HISTOPATHOLOGIC FEATURES In the thickened skin or in the grouped papular areas (pebbling) of patients with Hunter and Hurler syndromes, an increased amount of mucin-containing sulfated glycosaminoglycans in the reticular dermis and plump fibroblasts containing vacuoles and granules stained with colloidal iron and Alcian blue (both at a pH of 4.0 and a pH 1 mitosis per 10 hpf, necrosis, focal spindling of cells (more than 6 mitoses per 10 hpf better correlates with poor prognosis) Differential Diagnosis Metastatic carcinoma Malignant melanoma Epithelioid sarcoma Epithelioid angiosarcoma Angiolymphoid hyperplasia with eosinophilia Cutaneous mixed tumor

The prognosis of EHE is variable. Patients with EHE of the lung and liver have a higher mortality than do those with EHE of soft tissue. Mortality rates of 65%, 35%, and 13%, respectively, have been reported. Local recurrence and metastatic disease to regional lymph nodes or to lung may occur, yet fewer than 50% of patients with metastases succumb to their disease. Histologically benign-appearing forms of EHE generally have a better prognosis than do those that appear malignant, but histologically bland-appearing lesions have occasionally been associated with metastasis and death. Whether the relatively indolent tumors previously described as cutaneous epithelioid angiosarcoma belong to the spectrum of EHE is unclear. Some of these patients experienced slow, protracted disease

associated with numerous local recurrences and regional lymph node metastases.191 Although the prognosis for primary cutaneous EHE without underlying bone involvement and treated by local excision appears good, the length of follow-up for reported cases is quite limited. HISTOPATHOLOGIC FEATURES EHE displays epithelioid-appearing or “histiocytoid” endothelial cells that may be angiocentric and, in at least half of soft tissue cases, arise from and expand the wall of a medium- to large-size vein.188-191 (see Table 31-13 and Fig. 31-31). A hyaline, myxoid or myxochondroid-appearing stroma is common. The endothelial cells appear as cords or solid nests of rounded or slightly spindled epithelioid cells. Small intracytoplasmic lumina appear as vacuoles; occasionally, these vacuoles are large and may distort the cell, mimicking the mucin-containing (“signet ring”) cells of an adenocarcinoma. Red blood cells may be present within the intracytoplasmic lumina. In contrast to the angiocentric pattern that may be seen with EHE in soft tissue, the vascularity in cutaneous EHE is relatively inconspicuous and, when present, generally consists of small vascular channels that may be lined by cuboidal endothelial cells. Cutaneous EHE is often associated with an acanthotic epidermis that may be accompanied by marked acrosyringeal proliferation reminiscent of eccrine syringofibroadenoma.195

“Benign”-appearing EHE is cytologically bland without appreciable mitotic activity. In contrast, the features of “malignant”-appearing, clinically more aggressive cases of EHE in the past have included significant cytologic atypia, more than 1 mitotic figure per 10 hpf, necrosis, and focal spindling of cells. However, a recent review has emphasized the difficulty of correlating histologic features with prognosis. Only a mitotic rate of more than 6 per 10 hpf clearly correlated with an adverse prognosis.194 Such aggressive forms of EHE may merit designation as “malignant” EHE.199 A reticulin stain will reveal a network of reticulin fibers outlining individual cells and groups of cells. Immunohistochemically, EHE usually marks with CD31, CD34, and von Willebrand factor and less consistently with Ulex europaeus lectin. The staining for von Willebrand factor is accentuated about intracytoplasmic lumina, and varies in distribution and with the degree of tissue preservation. EHE endothelial cells may express simple epithelial keratins, especially K18 and also K7; epithelial membrane antigen is focally present in a minority of cases.194,200 By electron microscopy, EHE shows features of endothelial cells such as Weibel-Palade bodies, pinocytotic vacuoles, and welldeveloped basal lamina. Abundant cytoplasmic intermediate filaments are present. By cytogenetic study, an identical chromosomal translocation t(1;3)(p36.3;q25)

 FIGURE 31-31 Epithelioid hemangioendothelioma. Cords of epithelioid cells in a fibrous stroma. Note the similarities to an infiltrative carcinoma.

was recently detected in two cases of EHE.201

MALIGNANT VASCULAR LESIONS

Angiosarcoma Synonyms: malignant hemangioendothelioma, lymphangiosarcoma Angiosarcoma is a rare, malignant endothelial tumor that arises in skin, soft tissue, breast, bones, liver, and other viscera.142,202-205 Cutaneous angiosarcoma is the most common form of angiosarcoma.

CLINICAL FEATURES In the skin, angiosarcoma most commonly arises in the scalp and face of elderly individuals, with men affected more frequently than women (Table 31-14). Angiosarcoma may also occur in the setting of chronic lymphedema, often developing in a lymphedematous upper extremity as a late sequela of radical mastectomy as described by Stewart and Treves.142 Other causes of lymphedema (idiopathic, filarial, traumatic), congenital hereditary lymphedema (Milroy disease),202 and morbid obesity have also been implicated. Ionizing radiation has been linked to the development of angiosarcoma, with cases developing in the breast after radiation for breast cancer, in the abdominal region after irradiation of pelvic tumors, and on the face after irradiation of a congenital hemangioma.206 Rarely, angiosarcoma arises in association with foreign material (bullets, shrapnel, retained surgical sponges, gouty tophus) and with arteriovenous fistulae and vascular grafts.207,208 Angiosarcoma metastatic to the skin is exceedingly rare but can herald the presence of an occult tumor of an internal site such as the heart and the aorta.209,210 Angiosarcoma generally appears as ill-defined, asymptomatic, red to violaceous patches, plaques, or nodules.203,204 Satellite lesions are frequent. Angiosarcoma frequently presents with multifocal disease, and there is a tendency toward both local recurrence and distant metastasis. The clinical appearance of angiosarcoma varies somewhat according to the degree of histologic differentiation. Histologically more undifferentiated angiosarcoma lesions may grow rapidly, with fungating and ulcerative appearances. Undifferentiated angiosarcoma lesions may appear epithelioid and are high-grade neoplasms that generally affect deep, usually intramuscular, soft tissue and rapidly develop metastases. Cutaneous occurrence has been reported, although a few of the described cases had a distinctly better prognosis than other undifferentiated angiosarcoma. Such cutaneous tumors perhaps may fall into the spectrum of EHE. HISTOPATHOLOGIC FEATURES Cutaneous angiosarcoma extensively infiltrates the dermis, with microscopic involvement extending well beyond

Table 31-14 Angiosarcoma

Clinical Features Clinical settings for cutaneous angiosarcoma Scalp and face of the elderly—men more affected than women Postmastectomy (Stewart-Treves syndrome) and other causes of chronic lymphedema Postradiation therapy Foreign bodies Arteriovenous fistulas and vascular grafts Metastatic from an occult tumor of heart or aorta Ill-defined, red to violaceous patches, plaques, and nodules Extension well into adjacent, normalappearing skin Satellite lesions Local recurrence and distant metastases Histopathologic Features Angiomatous Individual or widely anastamosing vessels in dissection of collagen bundles Variably atypical endothelial cell lining, one or more layers Mixed inflammation, often with plasma cells Hemosiderin, variable extent Lymphangiomatous-appearing areas, minimal cytologic atypia Spindled Bundles of spindled cells Cleftlike spaces containing erythrocytes Syncytium of cells with insignificant blood vessel formation Undifferentiated or epithelioid Circumscribed nodules Sheets of epithelioid-appearing cells Intracytoplasmic lumen formation Cytologic atypia Prominent mitotic activity Starry-sky pattern in a subgroup of epithelioid angiosarcoma Differential Diagnosis Kaposi sarcoma Lymphangioma-like Kaposi sarcoma Hemangiopericytoma Epithelioid angiosarcoma Poorly differentiated carcinoma Malignant melanoma Epithelioid hemangioendothelioma Composite hemangioendothelioma

the clinically apparent boundaries (see Table 31-14).142,202-204 The epidermis may be normal, atrophic, or ulcerated. Direct epidermal invasion or involvement of the papillary dermis does not usually occur. Three distinct patterns of proliferation have been described: angiomatous, spindled, and undifferentiated (Figs. 31-32 to 31-34). Individual tumors

CHAPTER 31 ■ VASCULAR TUMORS AND VASCULAR MALFORMATIONS

DIFFERENTIAL DIAGNOSIS EHE is similar to a variety of tumors that exhibit epithelioid histologic patterns. Among these are metastatic carcinoma, malignant melanoma, epithelioid sarcoma, EH, and epithelioid angiosarcoma. Carcinomas, malignant melanoma, and epithelioid angiosarcoma generally show significant cytologic atypia and mitotic activity that distinguish them from most cases of EHE. Mucin stains mark the vacuoles and signet ring cells of adenocarcinoma but are negative in EHE. Melanomas lack the intracytoplasmic vacuoles of EHE and often show evidence of melanin pigment. EH may show intracytoplasmic vacuoles; however, EH characteristically shows welldeveloped vascularity lined by tombstone-like epithelioid endothelial cells and has a prominent inflammatory infiltrate of lymphoid follicles and eosinophils. Epithelioid sarcoma perhaps has the closest similarity to EHE, but epithelioid sarcoma generally displays a nodular arrangement of cells with central cores of necrotic debris and collagen. EHE exhibiting a well-developed chondromyxoid matrix must be distinguished from chondrosarcoma and chordoma. Cutaneous mixed tumor may also enter the differential diagnosis but can be distinguished by its broader epithelial differentiation, including follicular and sweat gland differentiation, squamous metaplasia, and ducts. Immunohistochemistry is often important in the diagnosis of EHE. A panel of antibodies should be used, and the pattern of reactivity will help in differentiating EHE from its various mimickers. In particular, EHE reacts with endothelial markers, contrary to carcinomas and epithelioid sarcoma, but may express simple epithelia keratins. It is negative for the S-100 protein staining of cutaneous mixed tumor and malignant melanoma and for the other conventional markers of melanoma.

The prognosis for angiosarcoma is poor. In one series of 72 patients with angiosarcoma of the face and scalp, 36 died within 15 months of presentation.

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 FIGURE 31-33 Angiosarcoma. Epithelioid endothelial cells in multilayered patterns fill vascular spaces and infiltrate the dermis.

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are composed of varying proportions of each pattern. In angiomatous areas, vascular spaces that are distinctly individual or widely anastomosing are dispersed between dermal collagen bundles in a dissecting fashion (see Fig. 31-32). The endothelium may be one to several cell layers in thickness and shows variable degrees of cytologic atypia. A mixed inflammatory response often containing plasma cells is usual. Hemosiderin deposition is variable. Some

 FIGURE 31-32 Angiosarcoma, well-differentiated type. Irregular, thin-walled anastomosing vascular spaces dissect collagen throughout the dermis.

lymphedema-associated tumors have a lymphangiomatous appearance with irregular vascular channels devoid of erythrocytes dissecting dermal collagen bundles. The endothelium in these areas may be attenuated and show only subtle cytologic atypia. These foci are usually interspersed with more classic angiosarcomatous areas. In spindle cell areas, spindled tumor cells are arranged in bundles that traverse the dermis in multiple directions, often enveloping adnexal str-uctures.

Cleftlike spaces and cracks containing erythrocytes are formed. The tumor may appear as a syncytium of cells without significant blood vessel formation. Undifferentiated areas are usually encountered as circumscribed nodules within more characteristic areas of angiosarcoma. Solid sheets of “epithelioid” tumor cells with abundant acidophilic cytoplasm and large, atypical nuclei expand the dermis (see Figs. 31-33 and 31-34). Lumen formation is usually only evident at the intracytoplasmic level. Intralesional hemorrhage may be prominent; this may not only obscure the diagnosis of angiosarcoma, but with the addition of endothelial papillary hyperplasia, may appear as an organizing hematoma. A starry-sky histologic pattern has been noted in a subgroup of epithelioid angiosarcomas.211 Recently, risk stratification of cutaneous angiosarcoma has been proposed based on the presence of necrosis, epithelioid features, and patient age older than 70 years. Tumor depth also has been correlated with the risk of local recurrence.212 Angiosarcoma may show considerable heterogeneity, as evidenced by variants suggesting EHE; spindle cell hemangioma; cavernous and capillary hemangioma; granular cell neoplasms; and lymphoproliferative, inflammatory, and infective disorders.213-215 Studies of angiosarcoma have indicated variable blood vascular or lymphatic differentiation; consequently, the histogenesis of angiosarcoma has remained controversial. Ultrastructurally, angiosarcoma generally shows features of endothelial cells, and cases often suggest blood vessel differentiation. Angiosarcoma may react with Ulex europaeus lectin 1, vimentin, and laminin (a constituent of basal lamina). von Willebrand factor, the most sensitive marker in one study,213 is variable, often stains only focally, and is absent in some tumors. CD31 and CD34 may react weakly and favor areas with greater vascular differentiation. Markers of lymphatic endothelial cells (VEGFR-3, Podoplanin/D2-40, LYVE-1) are expressed in a subset of angiosarcoma, representing approximately half of the cases.147-149,164,216 LYVE-1 seems to be more frequently expressed than other lymphatic markers.149 Furthermore, the immunohistochemical pattern of angiosarcoma may vary within tumors, suggesting mixed differentiation of both blood vascular and lymphatic endothelium. Further clarification of the histogenesis must await the development of additional endothelial markers or progress in molecular biology.

DIFFERENTIAL DIAGNOSIS KS displays dissection of dermal collagen by newly formed vascular channels similar to that of angiomatous- and lymphangiomatous-appearing areas of angiosarcoma. An important feature distinguishing angiosarcoma from KS are endothelial “layering” and cytologic atypia. In contrast, the endothelial lining of KS is usually inconspicuous and almost always one cell layer in thickness. Particular confusion, however, may still arise between the lymphangiomatous pattern of angiosarcoma and the lymphangiomatous variant of KS. The clinical setting associated with each entity is very helpful as are areas of more typical angiosarcoma identified in lymphedemaassociated angiosarcoma. In general, angiosarcoma displays more intralesional variation than KS. In contrast to KS and despite some contradictory data, HHV-8 is not closely linked to angiosarcoma,217 except perhaps in patients with AIDS.219 Angiosarcoma with a predominant spindle cell pattern may mimic plaques and nodules of KS. Features of distinction include the identification of angiomatous areas in angiosarcoma and cytologic atypia exceeding that observed in even florid nodules of KS. The clinical presentation is also helpful because angiosarcoma is usually confined to the head and neck of elderly individuals or unilaterally to a lymphedematous upper extremity versus the clinical localization of KS.

In contrast to angiosarcoma, hemangiopericytomas contain dilated sinusoidal spaces with a characteristic antlerlike or staghorn configuration lined by a single layer of flattened endothelial cells. A reticulin stain will further highlight differences between these two entities. Whereas in angiosarcoma, the delicate reticulin sheath is present peripheral to the inner lining of atypical endothelial cells, the tumor cells lie outside this reticulin sheath in hemangiopericytoma. Epithelioid angiosarcoma may be mistaken for poorly differentiated carcinoma or melanoma. Compounding the difficulty in distinction from carcinoma is the coexpression of cytokeratin and endothelial markers by epithelioid angiosarcoma.204 Thus, a broad panel of antibodies is required when such epithelioid tumors are being evaluated. Finally, some squamous cell carcinomas have an intense acantholytic pattern closely resembling the histology of well-differentiated AS. The demonstration of keratins and the absence of endothelial markers by immunohistochemistry are diagnostic.

VASCULAR MALFORMATIONS Vascular malformations are rare lesions representing inborn localized errors in vascular morphogenesis. Their diagnosis and classification have been historically hampered by a confusing nomenclature. For many years, they have been grouped with other vascular tumors as

CHAPTER 31 ■ VASCULAR TUMORS AND VASCULAR MALFORMATIONS

 FIGURE 31-34 Angiosarcoma. Large atypical epithelioid endothelial cells protrude into vascular spaces.

hemangiomas. Their pathogenesis (when known), natural history, and treatment are completely different from those of vascular tumors, from which they merit distinction.3,6,8,220 In 1996, the ISSVA recommended an updated classification scheme based on the distinction between proliferative lesions (vascular tumors and reactive proliferative lesions) and vascular malformations (Table 31-1). Vascular malformations may be further classified as to the type or caliber of main vascular channels present25,220,221 and as their truncal or tissular nature (Table 31-15).8 Truncal vascular malformations are anomalies of caliber, length, course, or number of individual vessels and are generally of large size. Apart from rare lesions, such as caliber persistent labial artery, truncal vascular malformations are not cutaneous lesions and are not dealt with in this chapter. In rare instances, vascular malformations may be associated with nonvascular anomalies; in various, often eponymous, syndromes; and with vascular tumors, especially IH in PHACE (the association of posterior fossa brain malformations, infantile hemangiomas, arterial anomalies, coarctation of the aorta and cardiac defects, and eye abnormalities) syndrome,222 PELVIS (perineal IH, external genitalia malformations, lipomyelomenin-gocele, vesicorenal abnormalities, imperforate anus, and skin tag) syndrome, and SACRAL (spinal dysraphism, anogenital anomalies, cutaneous anomalies, renal and urologic anomalies, associated with angioma of lumbosacral localization) syndrome.223,224 VMs, spindle cell hemangiomas, and enchondromas are associated in Maffucci syndrome. LMs may be associated with kaposiform hemangioendothelioma and endovascular papillary angioendothelioma.225 Most vascular malformations are sporadic, affecting 0.3% to 0.5% of the population.226 However, several types of familial cutaneous vascular malformations have been recently described, and several causative mutations have been identified, providing new insight into the pathogenesis of these lesions.227,228

Capillary Malformations Capillary malformations (CMs) are the more common vascular malformation. They are due to congenital dilatation of the capillary network of the skin and mucosa. They may also affect deeper structures, especially in the face. They are composed mainly of common CMs, also known as a PWSs or nevus flammeus, and other telangiectasias.

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of thin-walled vascular channels with lumina that vary in size or sometimes exhibit thicker walls, histologically simulating acral AVM (Fig. 31-37). In hypertrophic PWS, nodular aggregates of venous-like channels may be found in the deep dermis and subcutis.

Table 31-15 Classification of Vascular Malformations A. Truncal Vascular Malformations Affect arteries, veins, or lymphatics Anomalies of length, diameter, course, number Atresia, aneurysms Persistence of embryonal vessels Direct arteriovenous fistulaa

PART IV ■ PROLIFERATIONS—HAMARTOMAS, HYPERPLASIAS, AND NEOPLASIAS

B. Tissular (Nontruncal) Malformations

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Capillary malformations Port wine stain Other telangiectasia Angiokeratomas Venous malformations Common Nodular With glomus cells (glomangioma) Angiomatosis of soft tissue Lymphatic malformations Capillary type (“acquired progressive lymphangioma”) Micro or macrocystic Arteriovenous malformationsa

DIFFERENTIAL DIAGNOSIS Other vascular ectasias, such as generalized essential telangiectasia, hereditary benign telangiectasia, hereditary hemorrhagic telangiectasia (HHT), unilateral nevoid telangiectasia, and spider angioma, enter into the differential diagnosis. PWS differs from the other conditions based on congenital onset, rather distinctive macular to papular clinical lesions, and fairly discrete dilated capillaries or venules in the upper reticular dermis. Clinically, PWS must be differentiated from the pink macule that may precede the development of an IH, and more importantly, from a quiescent AVM.

C. Combined Vascular Malformations Vascular malformations associating items of A, B, or both Veno-lymphatic malformations Capillary or arteriovenous malformation (RASA1) Arteriovenolymphatic malformations D. Vascular Malformations Associated with Other Anomalies Items of A, B, or C may be associated with nonvascular anomalies of bones, soft tissues or viscera, in complex eponymous syndromes, including Sturge-Weber, Klippel-Trenaunay, Parkes Weber, and Proteus syndromes a

High-flow or “hemodynamically active” malformations Adapted with permission from Wassef, 2006#8.

Common Capillary Malformations (Port Wine Stain) Synonym: Nevus flammeus PWS mainly involves the head and neck with often a unilateral distribution, but they may occur anywhere.2-4,7,229 They are present at birth and generally persist throughout life. However, some variants that affect the midline of the head, such as the forehead, eyelids, and glabella (the so-called salmon patch), or nape (stork bite), may lighten and disappear in the postnatal period or generally before 5 years of age (Table 31-16). There may be an association with other vascular malformations and with syndromes involving other organs. CLINICAL FEATURES The initial lesions present at birth are pink to reddish macules that are often irregular in configuration. The lesions grow proportionately with the child, and their color tends to

darken in adulthood. PG may develop on PWS, usually more frequently than on normal skin. Some PWSs become papular, keratotic, and thickened with time, and nodules may develop. Such papulonodular lesions are most common on the head and neck, especially in the area of the second and third branches of the trigeminal nerve.230 In the head region and especially the mandibular area, PWS may be associated with underlying soft tissue and bone hypertrophy (hypertropic PWS). HISTOPATHOLOGIC FEATURES The essential findings are widely dilated, thin-walled capillaries or venules scattered throughout the upper dermis (Fig. 31-35) or the entire reticular dermis (Fig. 31-36).2,3,8,25,229 A decrease in the number of capillaryassociated small nerves has been suggested to explain the vascular dilation.231 Papular or nodular lesions developing in PWS are composed of a proliferation

SYNDROMIC CAPILLARY MALFORMATIONS CMs may be associated with numerous syndromes that in general have been termed congenital dysplastic angiopathies by Bean. Their clinical presentation are highly variable.229,232 The main syndromes commonly associated with port wine stains are: Sturge-Weber syndrome (encephalotrigeminal angiomatosis): This syndrome is characterized by a unilateral CM in the distribution of the ophthalmic branch of the fifth (trigeminal) cranial nerve; seizures and hemiplegia or hemiparesis related to a vascular malformation involving the leptomeninges; possible choroidal vascular malformations; mental retardation; and glaucoma.229,232 Klippel-Trenaunay-Weber syndrome (hemihemangiectatic hypertrophy, congenital dysplastic angiopathies, angioosteohypertrophy): In addition to a CM in the affected limb, the primary defining feature is the unilateral hypertrophy of a limb, most commonly the lower extremity, often with associated varicosities.229,232 In most instances, there is overgrowth of both bone and soft tissue. Commonly, there is an underlying VM, but LM and angiokeratomas circumscriptum (capillary–LM) are also seen. Klippel-Trenaunay syndrome must be differentiated from Servelle-Martorelle syndrome, in which the CM and varicosities are associated with limb undergrowth. Parkes Weber syndrome: This syndrome is characterized by CM associated with

Capillary Malformation–Arteriovenous Malformation

Table 31-16 Capillary Malformations

limb overgrowth and multiple arteriovenous fistulas or AVM and sometimes LM. At least some cases of Parkes Weber syndrome are due to a RASA1 gene mutation.233

Cobb syndrome: Individuals with this syndrome have an AVM involving the spinal cord and a port wine stain–like lesion in the distribution of the corresponding dermatome of the skin.234

This recently described hereditary disease, reported in six families,233 is caused by an inactivating mutation of the RASA1 gene situated on chromosome 5. It is characterized by multiple, small, round to oval, pale pink to red CMs in patients with AVMs or fistulas in the soft tissues, bone, or brain. HISTOPATHOLOGIC FEATURES AND DIFFERENTIAL DIAGNOSIS The lesions of CM–AVM have not been described histologically. The diagnosis is based on the peculiar clinical features of CM lesions and, when present, the association with AVM or arteriovenous fistula.

Hereditary Benign Telangiectasia Affected individuals exhibit widespread telangiectasias without evidence of visceral organ involvement or systemic disease.235 Several familial cases showing autosomal dominant inheritance have been reported, with one family demonstrating linkage to the CMC1 locus, which is also the site of the RASA1 gene for CM–AVM.236 CLINICAL FEATURES Clinical lesions may involve the face, trunk, and extremities and are often polymorphic, presenting as discrete reddish papules resembling cherry angiomas, plaques, and lesions with erythematous or arborizing appearances.235,237 An underlying AVM (or more probably an arteriovenous fistula) identified by image analysis was recently reported for a group of patients with hereditary benign telangiectasia.238 It was, however, suggested that these cases may be actually cases of CM–AVM.239

CHAPTER 31 ■ VASCULAR TUMORS AND VASCULAR MALFORMATIONS

Clinical Features Onset at birth Often involves head and neck but may occur anywhere Pink macular lesions but may become papular and keratotic Some lesions regress “Stork bite” on nape of neck “Salmon patch” on eyelids Some persistent lesions, such as the port wine stain, are associated with particular syndromes Cobb syndrome: arteriovenous malformation in spinal cord and port wine stain in corresponding dermatome Sturge-Weber syndrome: unilateral port wine stain involving the ophthalmic branch of trigeminal cranial nerve; seizures, hemiparesis, hemiplegia from vascular malformation of contralateral leptomeninges; occasional vascular malformations in other sites such as the choroid; mental retardation; glaucoma Klippel-Trenaunay-Weber syndrome: unilateral hypertrophy of a limb (bone and soft tissue overgrowth); varicosities; venous malformation, lymphatic malformation on occasion; arteriovenous malformation often present; other vascular malformations on occasion Parkes-Weber syndrome: unilateral limb hypertrophy; multiple arteriovenous fistula or arteriovenous malformation; lymphatic malformation on occasion Capillary malformation arteriovenous malformation syndrome: small patchy port wine stains associated with arteriovenous fistulas or arteriovenous malformations, hereditary, caused by mutations in the RASA1 gene Histopathologic Features Widely dilated thin-walled venules in upper dermis or throughout reticular dermis Differential Diagnosis Ateriovenous malformation, when in quiescent stage Telangiectases Spider angioma

HISTOPATHOLOGIC FEATURES The principal findings are widely dilated capillaries or venules in the superficial dermis.235,237 DIFFERENTIAL DIAGNOSIS This condition must be distinguished from other telangiectasias.

Hereditary Hemorrhagic Telangiectasia

 FIGURE 31-35 Nevus flammeus. Dilated, thin-walled microvessels are seen in the superficial dermis.

Synonyms: Osler disease, Osler-WeberRendu disease HHT is a rare autosomal dominant disorder. Several genes are implicated in the pathogenesis of HHT. These gene loci include endoglin (HHT1), which is involved in the TGFβ signaling pathway;

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PART IV ■ PROLIFERATIONS—HAMARTOMAS, HYPERPLASIAS, AND NEOPLASIAS

Table 31-17 Hereditary Hemorrhagic Telangiectasia

 FIGURE 31-36 Nevus flammeus. Note the dilated, thin-walled microvessels throughout the entire dermis.

symptomatic, may be associated with high-output heart failure, portal hypertension, ascites, variceal bleeding, and biliary disease.242 Recurrent nosebleeds beginning in childhood may herald the presence of the disorder, but the characteristic mucocutaneous telangiectasias are usually not seen before puberty. GI hemorrhages may produce recurrent episodes of melena. The clinical severity of HHT depends on the location and frequency of hemorrhage.  FIGURE 31-37 Arteriovenous hemangioma. Note thick-walled vessels in the dermis.

ALK1 (HHT2), which encodes a type 1 serine-threonine kinase receptor in endothelial cells; and a third locus (HHT3), which maps to 5q31.5-32. HHT typically presents with recurrent epistaxis in childhood and mucocutaneous telangiectasias by the third and fourth decades of life. Visceral involvement by telangiectasias and arteriovenous fistulas (so-called AVMs) may result in variable hemorrhage, cerebral abscesses, and even death.

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Clinical Features Autosomal dominant Telangiectases involving mucocutaneous sites, developing at puberty Face, lips, ears, fingers, nail beds, palms, soles, nasopharynx, oral mucosa involved Nonpulsatile, punctate or linear vascular lesions Recurrent epistasis Vascular anomalies and arteriovenous malformations sometimes involving viscera, especially the brain and lungs Melena from gastrointestinal hemorrhage Anemia Histopathologic Features Dilated, thin-walled irregular capillaries and venules beneath epithelial layers Differential Diagnosis Telangiectases in many other conditions Hereditary benign telangiectasia Ataxia-telangiectasia Generalized essential telangiectasia Unilateral nevoid telangiectasia

CLINICAL FEATURES Telangiectasias occur as nonpulsatile, punctate, or linear

lesions that may involve any cutaneous site. However, there is a predilection for the face, ears, lips, fingers, nail beds, palms, and soles (Table 31-17). Capillary microscopy of the nail, which may assist in diagnosis, often reveals one or more giant loops of tortuous capillaries situated between normal capillaries.240 Any mucous membrane site may be affected from the nasopharynx and oral mucosa to the GI tract.241 Vascular aneurysms and arteriovenous fistulas may develop in organs such as the brain, lungs, and liver and potentially manifest clinically as brain abscesses. Liver disease, when

HISTOPATHOLOGIC FEATURES Dilated, thinwalled, irregular capillaries and venules occur directly beneath the surface of mucocutaneous epithelia (Fig. 31-38). Anomalies of endothelial cells, endothelial cell junctions, and perivascular connective tissue have been described.241 DIFFERENTIAL DIAGNOSIS Telangiectasias may be seen as primary cutaneous lesions in patients with other disorders such as ataxia telangiectasia, generalized essential telangiectasia, hereditary benign telangiectasia, and unilateral nevoid telangiectasia syndrome, as well as secondary to many other conditions or insults. The extensive mucocutaneous telangiectasias with recurrent mucosal hemorrhages and systemic visceral involvement serve to distinguish HHT from other telangiectasias.

including capillaries and venous channels. There may be atrophy and ulceration of the overlying skin. Men and women are equally affected by CMTC, and unilateral involvement of an extremity is the most common presentation.250 The vascular abnormalities tend to improve with age. The disorder may be inherited as autosomal dominant. Other abnormalities reported include enlargement or hypoplasia of an affected limb, skeletal anomalies, glaucoma, and mental retardation. Recently, concurrent hypospadia was identified in four of 111 cases of CMTC.251

Ataxia-Telangiectasia (Louis-Bar Syndrome) CLINICAL FEATURES Patients present with telangiectasias, cutaneous atrophy, and mottled hyper- and hypopigmentation involving the head and neck and commencing in childhood.243 Patchy, segmental pigmentary anomalies, reminiscent of Blaschko lines, were found on one child.244 Patients may also have ectasia of bulbar conjunctival vessels and premature graying of the hair. Other important components of this autosomal recessive syndrome, which is due to mutations in the ATM gene on chromosome 11q22-23, include progressive cerebellar ataxia from cerebellar cortical atrophy; a combined immunodeficiency involving cellular and humoral immunity; recurrent infections; chromosomal instability from a striking sensitivity to ionizing radiation; and a markedly increased incidence of neoplasia, particularly lymphoma and leukemia. HISTOPATHOLOGIC FEATURES There is ectasia of venules in the superficial vascular plexus.243 DIFFERENTIAL DIAGNOSIS Ataxia-telangiectasia must be distinguished from other genodermatoses associated with chromosomal instability and telangiectasia such as Bloom syndrome, RothmundThomson syndrome, and xeroderma pigmentosum.

Unilateral Nevoid Telangiectasia CLINICAL FEATURES In this condition, delicate telangiectasias with a unilateral and often dermatomal distribution are noted at birth or later in life.245 This condition most frequently involves the face followed by the neck, chest, and arms. Its presentation may relate to relatively increased levels of circulating estrogen such as occurs with pregnancy, puberty, and the altered liver metabolism associated with both alcoholic cirrhosis and hepatitis C.246 However, the occurrence of unilateral nevoid telangiectasia in a healthy 33-year-old man suggests that the pathogenesis of this disorder may not necessarily have a hormonal basis.247 HISTOPATHOLOGIC FEATURES Dilated capillaries are observed in the superficial and middle dermis.245

Cutis Marmorata Telangiectatica Congenita Synonym: Congenital generalized phlebectasia CLINICAL FEATURES Neonates with cutis marmorata telangiectatica congenita (CMTC) present with a localized or generalized reticular or netlike vascular mottling of the skin that suggests livedo reticularis but is persistent rather than transient.248,249 The mottling is explained by ectasia of a range of vessel types,

DIFFERENTIAL DIAGNOSIS The clinical findings are usually distinctive. Livedo reticularis is a transient mottling that is related to sluggish blood flow from many causes rather than a vascular structural abnormality.

Angioma Serpiginosum Angioma serpiginosum is an unusual benign vascular lesion that was first described by Hutchinson in 1889 as a peculiar form of serpiginous and infective nevoid disease. It was more specifically characterized by Crocker in 1894, and additional reports over time have clarified its clinicopathologic features. CLINICAL FEATURES Angioma serpiginosum typically occurs during the first two decades of life, is more common in women, and occurs at any site.253,254 The lower extremities are most commonly involved, and the palms and soles are typically spared. Extensive involvement of the trunk and extremities occurs infrequently.253 Minute violaceous-red puncta, at times requiring magnification for adequate visualization, occur in gyrate or serpiginous configurations. Groups of puncta may coalesce into patches. Peripheral extension occurs through the formation of satellite puncta. Angioma serpiginosum usually occurs sporadically in individuals, but familial transmission has been reported. Autosomal dominant inheritance with variable penetrance favoring women has been suggested, but recessive inheritance cannot be excluded.254 Angioma serpiginosum may spontaneously regress but is usually slowly progressive. However, there

CHAPTER 31 ■ VASCULAR TUMORS AND VASCULAR MALFORMATIONS

 FIGURE 31-38 Hereditary hemorrhagic telangiectasia. Dilated venules are present in the papillary dermis.

HISTOPATHOLOGIC FEATURES One observes dilated capillaries, venules, and venous vessels throughout the dermis and possibly the subcutis. In rare cases, there may be a proliferation of vascular channels in the reticular dermis.247,252

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may be periods of relative quiescence or prolonged stability.

PART IV ■ PROLIFERATIONS—HAMARTOMAS, HYPERPLASIAS, AND NEOPLASIAS

HISTOPATHOLOGIC FEATURES Angioma serpiginosum is characterized by increased numbers of dilated capillaries in the superficial dermis. The overlying epidermis is normal, and there is no significant inflammation. Red cell extravasation and hemosiderin are absent. The dilated capillaries are relatively thick walled.

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DIFFERENTIAL DIAGNOSIS The absence of red cell extravasation and hemosiderin differentiate angioma serpiginosum from pigmented purpuric dermatoses and Henoch-Schönlein purpura. Clinical similarities to angiokeratoma circumscriptum exist, but the latter condition differs from angioma serpiginosum because of a verrucous, hyperkeratotic surface.

Angiokeratoma Angiokeratomas traditionally occur as five clinical variants.61,255,256 (Table 31-18): 1. Mibelli type, characterized by hyperkeratotic lesions on the dorsal fingers and toes 2. Fordyce type, characterized by involvement of the scrotum and vulva 3. Angiokeratoma corporis diffusum (ACD), a lysosomal storage disease inherited as an X-linked recessive disorder in Fabry disease (α-galactosidase A deficiency) but also seen with the autosomal recessive disorder, fucosidosis (α-L-fucosidase deficiency), and rarely with β-galactosidase deficiency, alone or in combination with neuraminidase deficiency. 4. The solitary or multiple type, which may involve any site but favors the lower extremities 5. Angiokeratoma circumscriptum, characterized by lesions in groups or bands usually on an extremity In contrast to the fundamental telangiectatic nature of the other variants of angiokeratoma, the fifth type of angiokeratoma—angiokeratoma circumscriptum—may demonstrate a deep component composed of a variable admixture of dilated capillaries, lymphatics, and veins. These lesions are best classified as hyperkeratotic capillary, lymphatic, venous, or combined vascular malformations.6,62,246,257 The existence of a sixth type of angiokeratoma, angiokeratoma serpiginosum, clinically simulating angioma serpiginosum, has been suggested.

Table 31-18 Angiokeratoma

Clinical Features Onset in first two decades of life common, but also in older individuals Solitary or multiple Sites vary (see below) Hyperkeratotic lesions that may be pink-red, purple, brown, blue, or black Melanoma often a clinical concern Five clinical types: Mibelli type: lesions on dorsal fingers and toes Fordyce type: lesions on scrotum and vulva Angiokeratoma corporis diffusum: Fabry disease (α-galactosidase A deficiency) Fucosidosis (α-L-fucosidase deficiency) β-Galactosidase deficiency Solitary or multiple type–common on lower extremities but may occur anywhere Angiokeratoma circumscriptum (hyperkeratotic capillary–lymphatic or venolymphatic malformation), usually on the extremities Histopathologic Features Ectatic thin-walled vascular channels in the papillary dermis Vascular spaces intimately associated with or encased by epidermis Intraluminal thrombosis and organization common Differential Diagnosis Telangiectases Targetoid hemosiderotic hemangioma Verrucous hemangioma Vascular malformation with angiokeratoma-like features

CLINICAL FEATURES Most forms of angiokeratoma present during the first two decades of life (see Table 31-18). Angiokeratoma circumscriptum, in contrast, may be visible at birth. Angiokeratomas of the ACD type usually present in late childhood, and angiokeratoma scroti and the solitary or multiple types of angiokeratoma generally arise during the second to fourth decades of life. Vulvar angiokeratomas usually occur in the third and fourth decades and are identical to angiokeratoma scroti because of their anatomic location and pathogenesis related to conditions of increased venous pressure. Angiokeratomas occur as variably hyperkeratotic lesions that may be pink, red, purple, brown, blue, or black. Clinically, the differential diagnosis includes hemangioma, verruca, nevus, and (when thrombosed and deeply

pigmented) malignant melanoma. The latter occurrence has been emphasized in individual case reports. Angiokeratomas usually manifest no symptoms; however, with local trauma, they may become irritated and can bleed, given their highly vascular nature. HISTOPATHOLOGIC FEATURES Angiokeratomas are telangiectasias, and all angiokeratomas are histologically similar except for the addition of certain features in ACD and angiokeratoma circumscriptum (see Table 31-18).61,255 Ectatic, thin-walled vascular spaces occur in the papillary dermis and are intimately associated with and variably encased by a hyperplastic epidermis. The epidermis shows elongated rete ridges and hyperkeratosis that is often slight but usually accentuated on acral sites (Fig. 31-39). Fibrin thrombi in various degrees of organization may be present. Dilated veins often drain the vascular lacunae of angiokeratoma scroti and vulvar angiokeratoma. Angiokeratomas of ACD may show subtle vacuolization of the endothelium, arrector pili muscle, and vascular smooth muscle cells. The latter vacuoles may be highlighted by lipid stains such as Sudan black B or PAS staining of the glycolipid. The lipid is doubly refractile and can be visualized in frozen tissue sections examined by polarized light. Ultrastructural examination reveals characteristic electron-dense lamellar inclusion bodies. DIFFERENTIAL DIAGNOSIS The diagnosis of angiokeratoma is seldom difficult, and the clinical setting allows for appropriate subclassification. It is important to recognize angiokeratomas with enzyme deficiencies because of the obvious systemic implications. Because of their superficial component, VHs may mimic angiokeratomas, and when small, they may enter into the differential diagnosis. However, because angiokeratomas are telangiectasias, they lack the “proliferative” vascular component of VH and the even more extensive deep involvement, possibly including muscle or bone of hyperkeratotic capillary–LMs.

Verrucous Hemangioma Synonyms: Keratotic hemangioma, unilateral verrucous hemangioma, angiokeratoma circumscriptum naeviforme, nevus keratoangiomatosus, nevus vascularis unius lateralis VH is an uncommon vascular lesion that tends to arise at or near birth or in childhood.258 In 1967, Imperial and

reported. The linearity of VH has been theorized to reflect genetic mosaicism.260 VH enlarge proportionately with body growth and tend to recur after surgical excision. Accordingly, they are best removed early in life when they are still small. In contrast to angiokeratomas, which respond to various superficial means of therapy, removal of VH requires a deep and relatively wide surgical excision. Otherwise, the lesions are apt to recur.

Helwig, at the Armed Forces Institute of Pathology, defined the clinicopathologic features of 21 VHs in a retrospective review of 1175 cases that had been previously classified as angiokeratoma or various types of hemangioma.258 CLINICAL FEATURES In Imperial and Helwig’s series, approximately half of VHs developed in the perinatal period, and six others presented by the age of 17 years (Table 31-19).258The most

common site is the lower extremity, particularly distally. VH typically occurs as unilateral, grouped, sometimes linear or serpiginous, discrete to confluent, hyperkeratotic angiomatous papules.259 Early lesions are bluish-red, well demarcated, soft, and compressible. Over time, VHs gradually enlarge, satellite nodules may arise, and ultimately a verrucous hyperkeratotic appearance develops. An unusual case of a young girl with multiple eruptive VH papules developing and progressing since birth, and suggesting infantile hemangiomatosis, has been

Table 31-19 Verrucous Hemangioma

Clinical Features Origin in infancy and childhood Distal lower extremity Hyperkeratotic angiomatous papules Grouped, discrete to confluent, sometimes linear or serpiginous Verrucous appearance developing over time Histopathologic Features Capillary to venous vascular proliferation Pandermal involvement with extension into the subcutis Lateral extension into clinically normalappearing skin Reactive acanthosis, papillomatosis, and hyperkeratosis Occasional inflammatory crusting or ulceration Differential Diagnosis Angiokeratomas Angiokeratoma circumscriptum Angioma serpiginosa Cutaneous keratotic hemangioma

 FIGURE 31-40 Verrucous hemangioma. The epidermis shows papillomatous hyperplasia and is intimately associated with ectatic vascular channels containing erythrocytes. The features are indistinguishable from angiokeratoma. However, a deep vascular component is present.

CHAPTER 31 ■ VASCULAR TUMORS AND VASCULAR MALFORMATIONS

 FIGURE 31-39 Angiokeratoma. A thin-walled ectatic vascular channel is surrounded by epidermis.

HISTOPATHOLOGIC FEATURES VH is mostly composed of small vessels 10 to 50 μmin diameter with multilaminated basement membranes in the dermis and subcutis that are compartmentalized by fibrous or adipose tissue. These vessels are sometimes grouped in vague lobules. Larger, dilated, thin-walled vessels are observed in the papillary dermis and occasionally in the subcutis.62 The vascular component is associated with secondary reactive epidermal changes such as acanthosis, papillomatosis, and hyperkeratosis (Table 31-19 and Fig. 31-40).6,62,246 Although the superficial portion of VH may bear resemblance to angiokeratoma, the VH is distinct since a vascular component extends deeply into the reticular dermis and underlying subcutaneous tissue. Often the vascularity extends laterally into adjacent clinically normalappearing skin. The upper dermis may show fibrosis, hemosiderin, and inflammation. The surface may manifest inflammatory and hemorrhagic crusts and occasional ulceration.

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PART IV ■ PROLIFERATIONS—HAMARTOMAS, HYPERPLASIAS, AND NEOPLASIAS 838

DIFFERENTIAL DIAGNOSIS Clinically, the differential diagnosis includes angiokeratoma, Cobb syndrome, angioma serpiginosum, LM (angiokeratoma circumscriptum), verrucae, and occasionally pigmented lesions. ACD, scrotal angiokeratomas, and angiokeratoma of Mibelli occurring on the fingers and toes are clinically distinct. Except for angiokeratoma circumscriptum, angiokeratomas are telangiectasias and can be differentiated from VH by the absence of a deep angiomatous component. Angiokeratoma circumscriptum may actually represent localized hyperkeratotic capillary-lymphatic or capillary–lymphatic– venous combined malformations composed of dilated, thin-walled vessels.6,257 Angioma serpiginosum, which often involves the legs, does not have a verrucous, hyperkeratotic surface and typically presents as minute violaceous-red puncta in gyrate or serpiginous configurations. Cobb syndrome is a rare congenital vascular nevus with dermatomal distribution on the trunk, the appearance of angiokeratoma circumscriptum or nevus flammeus, and an associated meningospinal vascular malformation. Finally, cutaneous keratotic hemangioma is histologically similar to VH but is clinically distinct because it is an acquired vascular tumor occurring on the volar aspect of the fingers.

Venous Malformation Synonyms: Cavernous hemangioma, cavernous malformation This rather characteristic type of vascular proliferation usually presents at birth or in childhood but may also appear in older individuals and may be associated with a number of syndromes, such as blue rubber bleb nevus syndrome (BRBNS) and Maffucci syndrome.2,3,229,261-263 The term cavernous refers to widely dilated vascular channels that resemble those in corpus cavernosum. This term is misleading because it has been used for number of different lesions with dilated vessels, including fully developed IH, and thus should not be used as a diagnostic term. CLINICAL FEATURES VM usually presents as soft, blue to purple nodules or plaques that have a compressible quality and increase in size with venous pressure or when dependent (Table 31-20). The most common sites include the head and neck; however, lesions may occur anywhere. The onset may be at birth, in the first few weeks of life, or later. VMs may rarely be familial.264 Familial mucocutaneous VMs

Table 31-20 Venous Malformation

Clinical Features Onset commonly at birth or in childhood Involve head and neck most commonly, but may occur anywhere Soft, blue to purple nodules, masses, or plaques Compressible and rubbery, inflate when dependent Sometimes associated with lymphatic malformation (venolymphatic malformation) Rarely familial (mucocutaneous venous malformation) Associated with particular syndromes: Blue rubber bleb nevus syndrome: autosomal dominant; venous malformations involving the skin, gastrointestinal tract, liver, spleen, and central nervous system; pain and hyperhidrosis; melena and anemia Maffucci syndrome: venous malformations, rarely lymphatic malformations, and phlebectasias; spindle cell hemangioma; multiple enchondromas and bony deformities from nonossifying cartilage; high risk of chondrosarcoma and increased risk of angiosarcoma Klippel-Trenaunay syndrome (see Table 31-16) Histopathologic Features Location usually in deep dermis or subcutis Generally diffuse; rarely circumscribed Vascular channels are dilated and often encased in fibrous tissue Vessels contain single layer of endothelium surrounded by fibrous tissue in vessel wall Smooth muscle may be observed in the vessel wall but is often inconspicuous Differential Diagnosis Lymphatic malformation Glomuvenous malformation (glomangioma) Port wine stain Arteriovenous and other malformations Involuting juvenile capillary hemangioma

are related to a mutation of Tie2 gene, which is located on chromosome 9.265 Individuals with BRBNS present at birth with numerous VMs involving the skin, GI tract, central nervous system, liver, and spleen.229,261,262 Patients may exhibit pain and hyperhidrosis from the cutaneous lesions and melena and anemia from those situated in the GI tract. An autosomal dominant inheritance pattern has been suggested for some BRBNS, but these cases seem to correspond to familial mucocutaneous VMs. Two cases of unilateral dermatomal cavernous

hemangiomatosis have been reported; the VMs are similar to those of BRBNS, but they occur only in the skin without the systemic involvement of BRBNS and without the enchondromas and malignant tumors of Maffucci syndrome.266 The principal findings typifying Maffucci syndrome include four varieties of vascular lesions: VMs, LMs, phlebectasias, and spindle cell hemangioma. Nonvascular lesions include multiple enchondromas and bony deformities resulting from nonossifying cartilage in the metaphyses of growing bones, frequent fractures of bone from the latter defects, and the frequent development of chondrosarcoma and angiosarcoma in up to 50% of affected individuals.229,263 HISTOPATHOLOGIC FEATURES VMs are usually situated in the dermis and subcutis and are generally diffuse (Table 31-20 and Fig. 31-41).8,267 The vascular channels form a complex network of slitlike, stellate, or open vessels dissecting the tissues and encasing normal structures such as hair follicles, nerves, arterioles, and cutaneous smooth muscle bundles (Fig. 31-42). In some cases, some fibrosis may be found. The vessels exhibit a single layer of endothelium surrounded by a thin or relatively thickened layer of fibrous tissue. Various amounts of smooth muscle elements may be observed in the fibrous lining of the vessels; this smooth muscle component may be focal or extensive. VMs frequently contain organized thrombi, which manifest either as concentrically hyalinized structures and calcified round phleboliths or as intravascular papillary hyperplasia of Masson. A subset of VM, nodular venous malformations,267 are composed of well-defined nodules containing dilated vascular lumina engorged with erythrocytes. The vascular structures are separated by regular fibrous septa in a honeycomb pattern without intervening normal elements. Generally, the vascular nature of these lesions is not recognized clinically, and they are considered to be “cysts” or nonvascular tumors. Another type of VM, sinusoidal hemangioma,268 demonstrates dilated, interconnecting, thin-walled vascular channels with pseudopapillary features; a generally lobular architecture; and an ill-defined infiltrative pattern in areas. It must be emphasized that VMs may occur as a component of many complex or combined VMs or as part of many of the syndromes described above. Thus, for example, one may observe capillary–venous, lymphatico– VMs, or even more complex combinations of channels.

similar to nodular VM. However, in contrast to nodular VM, spindle cell hemangiomas are distinguished by a solid cellular spindle cell component.

Glomus Tumor and Glomuvenous Malformation

DIFFERENTIAL DIAGNOSIS VM must be distinguished from LMs, glomuvenous malformations (glomangioma), AVMs, CMs, and spindle cell hemangioma. An LM may have a very similar and sometimes identical architecture as a VM, and histologic distinction of the two may not be possible without additional information. LMs may contain blood due to intralesional hemorrhage before or during surgery. Distinction is possible only if the lumina contain numerous lymphocytes or if lymphocytic aggregates are present in the vicinity of the malformed vessels. Encasing of normal elements within the vascular lumina is a feature more commonly noted in VM than

A

in LM. Glomuvenous malformations (GVMs; glomangioma) are also structurally similar to VM but harbor cuboidal glomus cells at least focally in their vessel walls. AVMs differ from VMs by exhibiting arterial-type channels, some with a well-developed internal elastic lamina, and fewer thin-walled vessels. CMs are generally situated in the superficial dermis and are composed of regular round dilated capillaries or venules. They do not display the slitlike vascular channels, the uneven thicknesses of vascular walls, or the anastomosing patterns of VM. Spindle cell hemangiomas may show a honeycomb pattern and organizing thrombi and phleboliths

CLINICAL FEATURES The typical solitary glomus tumor occurs in an adult as a small, blue-red nodule, less than 1 cm in diameter in the deep dermis or subcutis of the extremities. The most common site is the subungual region of the finger, where glomus tumors typically produce a triad of symptoms, including pain that may be paroxysmal, tenderness, and temperature sensitivity. Unusual sites of glomus tumors have included the stomach, rectum, cervix, vagina, mesentery, chest wall, bone, eyelid, and nose. Intravascular or intravenous glomus tumors have been reported.274

CHAPTER 31 ■ VASCULAR TUMORS AND VASCULAR MALFORMATIONS

 FIGURE 31-41 Venous malformation (cavernous hemangioma). A circumscribed aggregate of large vascular channels with walls thickened by smooth muscle and fibrous tissue.

In 1924, Masson described the glomus tumor as a distinct neoplasm with morphologic similarities to the normal neuromyoarterial glomus, an arteriovenous shunt concerned with temperature regulation located in the reticular dermis of the skin of the nail beds, pads of the fingers and toes, volar side of the hands and feet, ears, and center of the face.269-271 Glomus tumors may be classified into solitary and multiple types (Table 31-21). 269-271 The multiple type, which is generally composed of dilated venous-like channels, tends to be considered a vascular malformation termed GVM.220,272,273 In 64% of cases, GVM is an autosomal dominant condition with incomplete penetrance and variable expressivity.227 The mutated gene encodes for glomulin, a protein of unknown function.

B

 FIGURE 31-42 Venous malformation. (A) The vascular channels form a complex network of open vessels dissecting the tissues and encasing normal structures such as hair follicles, nerves, arterioles, and cutaneous smooth muscle bundles. (B) Microvessels encased by malformation (inset).

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PART IV ■ PROLIFERATIONS—HAMARTOMAS, HYPERPLASIAS, AND NEOPLASIAS

Table 31-21 Glomus Tumor and Glomuvenous Malformation

840

Clinical Features Glomus tumor Adults Nail beds, pads of fingers and toes, volar surfaces of hands and feet, ears, center of face Blue-red nodule >distal sites Regional or disseminated Familial in 64% of cases Bluish nodules Often >1 cm Often asymptomatic Histopathologic Features Solitary type Dermal or subcutaneous Well circumscribed Encapsulated usually Nests and sheets of monotonous round or cuboidal cells Glomus cells cuff small vascular channels Round nucleus with amphophilic or eosinophilic cytoplasm Smooth muscle may be present (glomangiomyoma) Nerve fibers present Occasional myxoid stroma Multiple type Large, irregularly shaped vascular channels (glomangioma) Usually fewer layers of glomus cells cuffing vessels Glomus cells may blend with smooth muscle (glomangiomyoma) Immunohistochemistry Positive for vimentin, smooth- or pan-muscle actin, myosin, desmin (variable) Negative for von Willebrand factor–related S-100 protein Differential Diagnosis Adnexal tumor Eccrine acrospiroma Chondroid syringoma (mixed tumor) Mastocytoma Melanocytic nevi (pseudoangiomatous) Cavernous malformation Hemangiopericytoma Angioleiomyoma

In contrast to solitary glomus tumors, GVM are uncommon, often present in childhood, only rarely occur subungually, and may be subdivided anatomically into regional or disseminated variants. In general, GVM tend to be larger than solitary glomus tumors, may reach several centimeters in size, or more rarely present as large plaquelike lesions that may be congenital.270,273,275,276 Widespread GVMs presenting in infancy may mimic BRBNS, and large GVM with their blue hue may mimic venous malformations.277 GVMs differ clinically from VMs because they are pink to purple or dark blue rather than blue with a cobblestone appearance and often hyperkeratosis, especially on the extremities. They are commonly tender, less compressible, less prone to increase in volume when dependent, rarely affect the mucosa, and spare the muscles and viscera.273 Glomangiosarcoma, or malignant glomus tumor, is rare.278,279 These tumors typically exhibit a malignant component superimposed on a preexisting glomus tumor. The initial cases reported as glomangiosarcoma lacked metastases, and thus the prognosis was considered good. Perhaps the latter conclusion was based on the excision of small tumors at an early stage of development. However, cases with widespread metastases have been reported,280,281 a potential de novo malignant variant has been suggested. At present, evidence suggests that superficially situated glomus tumors with malignant-appearing histologic features

show less aggressive behavior than similar-appearing tumors in deep locations. HISTOPATHOLOGIC FEATURES The histology of the glomus tumor is very distinctive (Table 31-21).269-271,283,284 The typical glomus cell is round or cuboidal with a round nucleus in amphophilic to eosinophilic cytoplasm and occurs in monotonous nests and sheets that are interrupted by blood vessels, around which the glomus cells may form collars (Figs. 31-43). Solitary glomus tumors are usually encapsulated, contain numerous small blood vessels, and are associated with ample nerve fibers. Glomangiomyomas are an uncommon variant of glomus tumor and show glomus cells blending with a population of smooth muscle cells. These features are best seen at the periphery of large blood vessels. Solid forms are also seen with a remarkable epithelioid appearance of solid lobules of glomus cells with scant lumen formation. GVM are composed of large, irregularly shaped vascular spaces that may resemble those of a venous malformation (Fig. 31-44). These spaces may be filled with blood or contain organized thrombi. Typically, only a few layers of glomus cells surround these large spaces, and some vessels may lack glomus cells. In contrast to the solitary tumors, nerve fibers about multiple glomus tumors are few. Extensive GVM have been named glomangiomatosis.

 FIGURE 31-43 Glomus tumor, solid variant. Note the similarities to an epithelial tumor. The tumor is composed of uniform cuboidal cells.

of glomus tumors will readily distinguish the two. Glomangiopericytoma, a tumor characterized by branching vessels surrounded by glomoid-appearing cells and thereby having composite features of hemangiopericytoma and glomus tumor, has been described.294 Glomangiosarcomas with a primitive round cell appearance must be differentiated from melanoma and various small round cell tumors such as lymphoma, Merkel cell carcinoma, primitive neuroectodermal tumor, neuroblastoma, Ewing sarcoma, and some sarcomas. Immunohistochemistry and electron microscopy aid in the distinction.

 FIGURE 31-44 Glomus tumor (glomuvenous malformation, glomangioma). Cavernous vascular channels that resemble a venous malformation are present and are lined by several layers of glomus cells, sometimes scant in number.

Glomangiosarcomas are characterized by short spindle cells, disordered arrangements of cells, moderate pleomorphism, single large nucleoli, and numerous mitoses. Recently, criteria for malignant glomus tumor (reserved for lesions with marked risk of metastasis) have been proposed: (1) greater than 2 cm size and a deep location or (2) atypical mitotic figures or (3) moderate to high nuclear grade and greater than or equal to 5 mitotic figures per 50 hpf. Unusual or atypical glomus tumors failing to meet these criteria did not metastasize and were classified as glomus tumor of uncertain malignant potential (high mitotic activity and superficial location, large size, or deep location) and as the two benign groupings symplastic glomus tumor (high nuclear grade) and glomangiomatosis (diffuse or disseminated venous-like lesion and excess glomus cells).281 Immunohistochemically, glomus tumors express vimentin, muscle actins, myosin, pericellular collagen type IV, and variably desmin but are negative for von Willebrand factor, cytokeratin, and S-100 protein. Ultrastructurally, the cells of glomus tumors show characteristics of modified smooth muscle cells such as intracytoplasmic myofilaments with characteristic focal densities, numerous pinocytotic vesicles, and dense attachment plaques on cell membranes. These features suggest that glomus tumors are not derived from capillary pericytes, as was once thought, but instead derive

from smooth muscle cells of the vascular part of the neuromyoarterial glomus. DIFFERENTIAL DIAGNOSIS The histology of benign glomus tumors is so characteristic that it is not readily confused with that of other tumors. An exception is the occasional GVM that exhibits only a subtle, multifocal population of glomus cells. However, careful scrutiny of such GVM for glomus cells will avoid confusion with venous malformations, including those that occur multiply in the setting of BRBNS. Mastocytomas have their own monotonous proliferation of cells, but these unencapsulated tumors lack significant vascularity, and mast cells can be identified by metachromatic stains and immunohistochemistry, if they are not readily recognized by light microscopy and experience. Mast cells express c-kit (CD117) and tryptase. Glomus tumors appearing as cellular sheets of cells may evoke the epithelioid appearance of an adnexal tumor (eccrine acrospiroma or chondroid syringoma); however, the vascularity of glomus tumors combined with their lack of both ductal differentiation and epithelial mucin serve to differentiate these tumors. It should be noted that occasional glomus tumors may exhibit a strikingly myxoid stroma. Pseudoangiomatous melanocytic nevi are usually not confused with glomus tumors, but if there is doubt, the S-100 and melan-A reactivity of nevi and not

Synonyms: Lymphangioma simplex, lymphangioma circumscriptum, cavernous lymphangioma, cystic hygroma LM is composed of variably dilated lymphatic vessels usually present either at birth or within the first few years of life.1-3,6,229 Various clinical types of LM have been reported over the years under a variety of terms, including lymphangioma simplex, lymphangioma circumscriptum, cavernous lymphangioma, and cystic hygroma, the last entity perhaps being a macrocystic (widely dilated lymphatic spaces) variant of LM occurring on typical clinical sites. LM typically have a deep component. Generalized LM (lymphangiomatosis) is exceedingly rare. In general, the features of the above types of LM form a continuum and show considerable overlap, thus making the exact classification of individual cases difficult at times. Moreover, the principal characteristics that determine the prognosis and choice of treatment for an individual lesion are the size of LM cavities (microcystic versus macrocystic LM) and extent of the disease.25,220 CLINICAL FEATURES Microcystic LM have been reported as: Lymphangioma simplex, which appears in infancy as a solitary, rather welldefined, skin-colored dermal, mucosal, or subcutaneous lesion often smaller than a few centimeters in size, usually with a smooth and slightly elevated contour. Lymphangioma circumscriptum, which is clinically characterized by cutaneous vesicles. The localized form is single and of small size. It is present at birth but may be inapparent and may appear in childhood or adulthood. In contrast, the classic form of lymphangioma circumscriptum usually appears at birth or in early childhood, is generally of larger size, and is composed of solitary or multiple

CHAPTER 31 ■ VASCULAR TUMORS AND VASCULAR MALFORMATIONS

Lymphatic Malformations

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patches. Common sites are the proximal extremities, limb girdle, neck, tongue, and buccal mucosa. The degree of involvement may sometimes be quite extensive. Microcystic LM may include vesicles with a variably sanguinous or violaceous appearance due to the presence of admixed red blood cells. Acquired LM-like lesions with features similar to microcystic LM have developed in the setting of lymphedema subsequent to radical mastectomy and radiotherapy. Among such lesions are acquired vulvar microcystic LM, which can be idiopathic but commonly arises secondary to impaired lymphatic drainage from various causes such as congenital lymphedema, infections, Crohn disease, and surgery or radiotherapy of cervical carcinoma. These genital LM-like lesions may present as verrucous papules mimicking condyloma acuminatum.287 Macrocystic LM has been reported as cavernous lymphangioma or cavernous LM and usually presents at birth or in infancy. This large, ill-defined lesion may occur at many sites but favors the head, neck, mouth, and extremities. A particular subtype of macrocystic LM, the cystic hygroma, has extensive, often deforming, cystic dilatations that generally occur on the neck but may also involve the axilla, groin, popliteal fossa, mediastinum, and retroperitoneum. An axillary lesion with a concurrent Becker nevus has been reported.288 HISTOPATHOLOGIC FEATURES Various LMs generally differ based on the size of the lymphatic vessels,1-3,6,229 even if vessels of various sizes occur in some lesions. Lymphangioma simplex is composed of small capillary-sized lymphatic vessels and is similar to the so-called APL or benign lymphangioendothelioma. Microcystic LM is characterized by dilated lymphatic channels occupying the superficial dermis. The overlying epidermis is often elevated and is variably thinned to acanthotic. Papillomatosis and hyperkeratosis may be present, particularly in the classic type of lymphangioma circumscriptum (Fig. 31-45). Also, in contrast to the localized type of lymphangioma circumscriptum, this classic type has deep extension of the lymphatic vessels into the lower dermis and subcutis. Other lesions have widely dilated lymphatic channels occupying and expanding the dermis and subcutis (Fig. 31-46). The wall of the LM vessels may be limited to endothelial cells and a thin fibrous layer but may contain smooth muscle cells in various amounts, sometimes grouped in discontinuous bundles. The intervening stroma may be

 FIGURE 31-45 Lymphatic malformation (lymphangioma circumscriptum). Large lymphatic lumen impinging upon the epidermis. Note the absence of red blood cells.

inapparent or variably fibrotic. The architecture of the lesion is similar to that of venous malformation. “Cystic hygromas” show large unilocular or multilocular cysts with thin or fibrous walls, generally associated with a more conventional macrocystic or microcystic LM component. LMs show homogenous, lightly stained lymph fluid within their lymphatic spaces and may have a variable number of intravascular or stromal lymphocytes. Red blood cells are frequently present, at least

focally, within lymphatic lumina, and macrophages may also be seen. DIFFERENTIAL DIAGNOSIS The diagnosis of LM may have to suffice when clinical correlation is lacking and when vessels of mixed size are present. Moreover, the presence of admixed erythrocytes within a particular LM may generate consideration of a combined lesion (hemolymphatic or venolymphatic malformation). The papillary dermal component of superficial

 FIGURE 31-46 Lymphatic malformation (cavernous lymphatic malformation). Widely dilated lymphatic channels are surrounded by fibrous tissue and lymphocytic infiltrates. The lumina contain proteinaceous material.

LM (lymphangioma circumscriptum) bears similarity to that of an angiokeratoma, and as stated earlier, angiokeratoma circumscriptum is generally a lymphatic or combined hyperkeratotic vascular malformation. The diagnosis of cavernous and cystic lymphangiomas is seldom difficult, and the clinicopathologic features for the cystic hygroma, in particular, are quite unique. Immunohistochemistry using lymphatic endothelial markers as VEGFR-3 and D2-40 may be useful to detect a lymphatic component in lesions that lack intravascular or interstitial lymphocyte aggregates.

Synonyms: Benign lymphangioendothelioma, angioendothelioma (lymphatic type) APL is an entity that has undergone a nosologic evolution over three decades. We prefer the term APL because of the antinomy between benign and lymphangioendothelioma. As with hemangioendothelioma, lymphangioendothelioma should designate lesions with borderline or lowgrade malignant status. APL is a rare entity that may offer diagnostic difficulty with low-grade angiosarcoma and the lymphangioma-like form of KS. CLINICAL FEATURES The incidence of APL is relatively similar in males and females (Table 31-22). Patients range in age from 5 to 90 years. At the point of recognition,

HISTOPATHOLOGIC FEATURES The epidermis is unremarkable. The lesions are

dermal with a tendency to involve the papillary and superficial to mid-reticular dermis (see Table 31-22). Occasional lesions show full-thickness dermal involvement and may involve superficial subcutaneous tissue.292,293 The unifying histologic features identified in all cases are jagged, irregularly shaped vascular channels distributed between dermal collagen bundles (Fig. 31-47). The lumina of these thin-walled vascular spaces may be dilated or collapsed and inconspicuous. The vessels are intimately associated with the dermal collagen, appearing to dissect between the collagen bundles. The thin-walled vessels tend to be arranged in horizontal array, although they may be quite haphazard in distribution. The endothelial lining is one cell layer in thickness. The cytologic features tend to be bland, although occasional plump or hyperchromatic endothelial cells are observed. Pronounced cytologic atypia is not a feature of APL. Exceptionally, a single case report described occasional multinucleated endothelial cells. More recent is a case with aggregated endothelial cells, resembling multinucleate giant cells.289 Occasionally, intraluminal papillary projections may be seen. Rarely, endothelial cells may detach from the vascular wall and appear to float freely within the vessel lumen. Mitotic activity is absent. The vascular spaces are typically empty but may contain a faintly eosinophilic, proteinaceous material. A scant, mononuclear,

Table 31-22 Acquired Progressive Lymphangioma

Clinical Features Men and women equally affected Childhood to elderly Diverse sites Well-demarcated dermal plaques, dull pink to violaceous Variable size (3-30 cm) Slow enlargement over time Histopathologic Features Variable degree of dermal involvement, favoring the upper half Thin-walled, irregular vascular channels “dissecting” collagen Bland endothelial cells Scant or absent mononuclear inflammatory infiltrate Lack of plasma cells, extravasated erythrocytes, and hemosiderin Differential Diagnosis Low-grade angiosarcoma Lymphangioma-like Kaposi sarcoma Lymphatic malformation

 FIGURE 31-47 Acquired progressive lymphangioma (benign lymphangioendothelioma). Thinwalled, infiltrative, staghorn-shaped vessels devoid of red blood cells.

CHAPTER 31 ■ VASCULAR TUMORS AND VASCULAR MALFORMATIONS

Acquired Progressive Lymphangioma

clinical lesions have been present for periods ranging from 2 months to 20 years.289 Sites of involvement are diverse and include the head, neck, oral mucosa, trunk, breast, buttock, shoulder, forearm, thigh, and foot. Multiple sites of involvement, both synchronous and asynchronous, are documented. APL may occur after trauma to the affected area, including a report of APL arising in a traumatized birthmark,290 as well as at the site of a tick bite.291 Clinical lesions are well-demarcated dermal plaques that range in color from dull pink to dusky to violaceous. The lesion borders are usually clearly delineated from the surrounding uninvolved skin.292,293 In general, the lesions have ranged in size from 3 to 30 cm. Presentation as a subcutaneous nodule has been reported. Characteristically, the dermal plaques are painless and nontender. Most lesions tend to pursue a relatively static clinical course, slowly increasing in size over a period of years. There are no reports of malignant transformation. Regression of two asynchronous lesions after oral prednisolone therapy and spontaneous regression of a case of APL have been documented. The significance of lesional regression after steroid therapy is uncertain and requires further investigation. Clinical recurrence after excision has not been reported.

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inflammatory infiltrate is a variable feature. Plasma cells, extravasated erythrocytes, spindle cell proliferation, and hemosiderin are not reported features of APL. There are striking similarities between APL and capillary-type LM, and the nosologic relationship between these lesions has not been resolved. Immunohistochemical studies have been inconsistent, but the endothelial cells of APL most commonly express CD31, CD34, and Ulex europaeus lectin 1. Staining with antibodies to von Willebrand factor is variably reported,289 and smooth muscle cells are found in variable amount and distribution. In any event, the pattern of immunoreactivity is not useful in distinguishing APL from other benign and malignant vascular proliferations. The HHV-8 genome has not been found in the single case of APL studied with PCR.294 In a single case, electron microscopy failed to demonstrate Weibel-Palade bodies. DIFFERENTIAL DIAGNOSIS APL is a histologic mimic of both low-grade or welldifferentiated angiosarcoma and patchstage KS. The clinical setting for each of these entities is distinctive, and an important caveat is that a diagnosis of APL should not be made on a small biopsy in the absence of a clinical history. Considering the relative histologic similarities of APL and angiosarcoma, it seems likely that several early series of cutaneous angiosarcoma may have contained examples of APL, the latter cases constituting the rare cases of angiosarcoma with an indolent course, good prognosis, and odd clinical presentation. Cutaneous angiosarcomas, excluding Stewart-Treves syndrome and postradiation angiosarcomas, are malignant tumors essentially confined to the head and neck of elderly individuals. If an adequate biopsy of angiosarcoma is obtained, the degree of cytologic atypia far exceeds that observed in the spectrum of APL. In addition, APL almost always fails to show extravasated erythrocytes, hemosiderin deposition, and inflammatory infiltration. Patch-stage lesions of KS, in both the classic and epidemic forms, may be clinically subtle. In contrast to APL, however, they tend to be small and multiple and show clinical progression over a relatively short period. Histologic features of KS that are distinct from APL include the tendency for the neovascular channels of KS to aggregate about preexisting dermal structures, erythrocyte extravasation, hemosiderin deposition, and a dermal inflammatory infiltrate that nearly always includes plasma cells.

Immunohistologic detection of HHV-8 in KS will probably be of help, but the HHV-8–negative status of APL has been demonstrated by PCR in only one case and needs confirmation. Lymphangioma circumscriptum demonstrates one or more clusters of vesicles favoring the limb girdles; contains large, dilated lymphatic vessels elevating the epidermis; and lacks the dissection of collagen pattern seen in APL. Hobnail cytomorphology, when present in APL, is only focal and not as prominent a feature as that observed in the typically smaller THH. Giant cell fibroblastoma may, in some rare settings, be confused with APL. The presence of the giant cells and the endothelial marker–negative pseudolumina should facilitate distinction from APL.

Angiomatosis of Soft Tissue This lesion was first definitively described and illustrated in 1992 by Rao and Weiss, who reported a series of 51 cases.295 Unfortunately, the definition they used: “a histologically benign vascular lesion that extensively involves a region of the body or several different tissue types in a contiguous fashion” is rather nonspecific because it may be applied to any type of large vascular malformation. This imprecision in definition may explain why this lesion remains underreported. However, the lesion they described is unique and clearly different from other types of vascular malformations. Because angiomatosis may refer to many types of large or multifocal vascular anomalies with diverse histologies, we suggest that this lesion be described as angiomatosis of soft tissue as a diagnosis or as angiomatosis, Rao and Weiss type. CLINICAL FEATURES AST is a relatively rare and probably underrecognized condition that usually presents in children or young adults with persistent swelling or pain in the soft tissue, muscle, and dermis.295 Nearly two-thirds of the cases involve the extremities, but all body areas may be affected. Occasional lesions extend into bone (Table 31-23). Angiomatosis is associated with a very high rate of recurrence, with up to 90% in one series. Recurrence of AST is probably due to underestimation of the extent of the lesions and incomplete resection. AST often affects several adjacent tissue types but may be confined to one tissue. HISTOPATHOLOGIC FEATURES AST is characterized by infiltration of the dermis and soft tissue by multiple discrete

nodules composed of an admixture of veins, cavernous vascular spaces, and thickwalled vessels with onion-skin concentric appearance (Figs. 31-48 and 31-49).295 The veins demonstrate media of uneven thickness with fissures and muscular pads. Slitlike, tortuous, thin-walled vessels directly branch from their walls of these veins. In addition to such veins, aggregates of open vessels separated by thin fibrous septa in a honeycomb pattern are frequently seen. We have observed as well in many cases a lymphatic component composed of vessels containing lymphocytes and lymphocyte aggregates in the interstitium. As in many vascular lesions affecting skeletal muscles, large amounts of adipose tissue surround intramuscular AST. This feature may cause confusion with adipose tumors. The subtype of angiomatosis characterized by capillary-sized vessels with occasional larger “feeder” vessels described by Rao and Weiss may be a different variety of vascular lesion. DIFFERENTIAL DIAGNOSIS Distinction between AST and other subcutaneous or intramuscular vascular malformations (mainly venous malformation) essentially depends on the presence of the rather characteristic constellation of findings that defines AST. However, due to heterogeneous nature of the lesion, diagnosis may be difficult on small specimens. The small size and discrete nature of angiolipoma preclude confusion with AST.

Arteriovenous Malformations Synonyms: Arteriovenous hemangioma, superficial arteriovenous hemangioma,

Table 31-23 Angiomatosis of Soft Tissue

Clinical Features Usually presents in children and young adults Soft tissue mass, generally tender or painful High recurrence rate Histopathologic Features Ill-defined infiltrating contours Made of veins with uneven walls, honeycomb cavernous spaces, thick onion-bulb vessels, lymphatics and lymphocytes aggregates Rarely capillary-sized vessels Differential Diagnosis Intramuscular hemangioma Venous malformations Lymphatic malformations Soft tissue tumor Angiolipoma

Table 31-24 Acral Arteriovenous Malformation

 FIGURE 31-49 Angiomatosis of soft tissue. Note the thick-walled vascular channels with “onionskin” configuration.

acral arteriovenous tumor, arteriovenous shunt, cirsoid aneurysm Two different types of AVM with different presentations, evolution, and prognosis are described: acral AVM (aAVM) and AVM not otherwise specified.

Acral Arteriovenous Malformation Synonyms: Arteriovenous hemangioma, acral arteriovenous tumor In 1974, Girard and coworkers296 characterized the salient clinical and histologic features of arteriovenous hemangioma.

Subsequent reports have confirmed the benign nature of these vascular lesions and have emphasized their acral distribution as acral arteriovenous tumor.297,298 Their developmental origin has not been clearly established. They have been considered “cirsoid” aneurysmal dilatations of cutaneous arterial structures or vascular channels comparable to the fibromuscular vessels of the Sucquet-Hoyer canal. CLINICAL FEATURES aAVM is a relatively common acquired lesion primarily affecting middle-aged to elderly adults

with a male predominance and a peak incidence in the fourth and fifth decades of life (Table 31-24).296-298 Rare cases have been reported in children, with patients as young as 6 weeks. The lesions present as single red or violaceous papules ranging in size from 1 mm to 3 cm with an average of 4 to 6 mm in the head or neck region and less commonly involve the fingertips and mucosa.299 Most lesions are asymptomatic; however, enlargement, pain, or pruritus may occur. Rarely, aAVM are associated with angiolymphoid hyperplasia with eosinophilia, verruciform xanthoma, and basal cell carcinoma.300-302 HISTOPATHOLOGIC FEATURES aAVM lesions are well circumscribed and unencapsulated (Table 31-24 and Fig. 31-50).295-298 They are composed of an intimate admixture of thick-walled and thinwalled blood vessels distributed within the superficial and middle dermis. The proportion of thick-walled to thinwalled vessels is variable, although the former typically predominates. The vessels may be closely approximated to and dispersed between the cutaneous and mucosal adnexa. The lining endothelium is typically bland. Occasionally, the endothelial cells protrude into the vessel lumen in a “hobnail” fashion. Thrombi,

CHAPTER 31 ■ VASCULAR TUMORS AND VASCULAR MALFORMATIONS

 FIGURE 31-48 Angiomatosis of soft tissue. The dermis and subcutis contain multiple discrete nodules composed of an admixture of veins and cavernous vascular spaces.

Clinical Features Most common in individuals 30 to 50 years of age Affects men more after than women Head and neck, acral sites Red or purple papules Usually solitary, 4-6 mm (≤3 cm) Cutaneous or mucosal Histopathologic Features Well circumscribed, not encapsulated Aggregates of thick-walled and thin-walled vessels Variation in vessel caliber Single layer of bland endothelium in vessels but occasional hobnail features present Vessel walls contain fibrous tissue with occasional small smooth muscle component A true arterial component usually present Differential Diagnosis Cherry angioma Lobular capillary hemangioma Venous lake Angioleiomyoma

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A

846

B

 FIGURE 31-50 Acral arteriovenous malformation (arteriovenous hemangioma). (A) These lesions are well circumscribed and unencapsulated. They are composed of an intimate admixture of thick-walled and thin-walled blood vessels distributed within the superficial and middle dermis. (B) Some of the vessels resemble arteries.

often showing organization and recanalization, are an occasional finding. Girard and colleagues described direct communication between arteries and veins in a subset of their cases. Inflammation is an infrequent feature; when present, it is described as a mixed, chronic inflammatory cell infiltrate associated with accentuation of fibrous changes within vessel walls. Elastin stains typically show vessels with finely fibrillar elastinophilic fibers scattered throughout their walls, alternating with a true arterial component with an internal elastic lamina.

AVM may affect the skin, soft tissue, viscera, bone, and brain.

Arteriovenous Malformation (Not Otherwise Specified)

CLINICAL FEATURES Superficial AVM involves mainly the head and neck; however, it can occur in any location. The lesion is warm and pulsating except in a quiescent stage in children, and a murmur or a thrill may be present. The underlying skin presents variable red discoloration. AVMs may remain stable for years or may show clinical progression with increased erythema, warmth, and a more evident thrill. These changes may be triggered by trauma or hormonal stimuli such as puberty or pregnancy (Table 31-25).305 Capillary steal syndrome may develop with skin atrophy, ulceration, pain, and sudden life-threatening hemorrhage. AVM are staged according to the scheme of Schobinger. Stage I represents the quiescent stage when AVM mimics a CM or an IH; stage II connotes clinical progression to lesions that are warmer, larger, and throbbing with thrills or bruits; stage III indicates progression to a destructive phase as evidenced by the onset of ulceration, hemorrhage, and bony lytic lesions; and stage IV is rare and is composed of all of above plus congestive heart failure owing to increased cardiac output and left ventricle hypertrophy.303,304 In clinical stages II and III, AVM may extend into previously clinically normal contiguous tissues.220

AVM is the rarest and most aggressive type of vascular malformation. It is a high-flow lesion and contains direct arteriovenous communications or fistulas. AVM is present at birth but is often undetected or masquerades as a CM. AVM becomes clinically apparent in childhood or adolescence, and only 20% are detected during adulthood.25,220,303,304

HISTOPATHOLOGIC FEATURES AVM are illdefined lesions comprised of vessels of different calibers and thicknesses evenly distributed throughout the affected tissues and accompanied by variable amounts of fibrosis (Fig. 31-51 and 31-52).8,18,25,267 The thickness of the vessel walls is generally proportionate

DIFFERENTIAL DIAGNOSIS The morphology of aAVM is characteristic, and a limited number of entities enter into the differential diagnosis. Clinically, venous lakes and cherry angiomas are a consideration because of their occurrence in a distribution and age group similar to those of aAVM. The histology of each is characteristic and easily distinguished from AH. The limitation of the lesion and restriction to the dermis separate aAVM from more aggressive AVM. Histologically, vascular leiomyomas are a consideration. The abundance of smooth muscle associated with these lesions is distinct from aAVM, as is the clinical setting.

to the diameter of the lumen but may vary from one segment to another of the same vessel section. Some dilated vessels with thin walls, resembling those of VM, may also occur. The type and structure of the vessels wall is best visualized with elastin stains, which show arteries, veins with thickened walls, and a majority of abnormal unclassified or intermediate vessels with defective elastic architecture. Direct communications between arteries and veins or unclassified vessels

Table 31-25 Arteriovenous Malformation (Not Otherwise Specified)

Clinical Features Present at birth; generally undetected Equally affects both genders Becomes apparent during childhood or adulthood Pulsation, murmur, or both generally present May progress after trauma or hormonal change May be stages according to Schobinger: Stage I: quiescent, asymptomatic Stage II: progression and expansion Stage III: destruction with necrosis and hemorrhage Stage IV: high output cardiac failure Histopathologic Features Ill-defined infiltrative lesion Composed of arteries, veins, arterialized veins, and unclassified vessels Variable capillary component Abnormal vessels evenly distributed, with round or oval contours and relatively thick wall Arteriovenous communications on elastic stains Differential Diagnosis Capillary malformation in AVM quiescent stage Venous malformation

Mitoses, without abnormal figures, may be numerous in the capillary component. Hypervascularization of the subcutaneous fat lobules occurring adjacent to AVM is frequent and may mimic angiolipoma.

ACQUIRED TELANGIECTASIAS

Generalized Essential Telangiectasia  FIGURE 31-51 Arteriovenous malformation. Vessels of different calibers and thicknesses are evenly distributed throughout the affected tissues and are accompanied by variable amounts of fibrosis.

CLINICAL FEATURES This condition most commonly affects adult women and is typified by onset on the lower extremities with subsequent involvement of the trunk, upper extremities, head, and neck.306 Characteristically, there is no evidence of systemic disease or visceral organ involvement. More recently, however, a unique case of generalized essential telangiectasia associated with GI bleeding has been reported.307 HISTOPATHOLOGIC FEATURES The major finding is a dilated capillary vessel in the papillary dermis without inflammation (Fig. 31-53).

CHAPTER 31 ■ VASCULAR TUMORS AND VASCULAR MALFORMATIONS

DIFFERENTIAL DIAGNOSIS Knowledge of the clinical presentation is important in the diagnosis and differential diagnosis of AVM. AVM can be distinguished from more benign acral AVM by the small size and limitation of the latter. Thickness of vessels walls, random distribution in the tissue and, when present, the capillary component allows distinction from VM. Predominance in the superficial dermis and thin walls differentiate CM (PWS) from AVM; however, the nodules that may appear in CM may exhibit thickwalled vessels similar to those in AVM. The differential diagnosis requires the presence of more conventional CM at the periphery of the specimen or knowledge of the clinical presentation.

Secondary Telangiectasias

 FIGURE 31-52 Arteriovenous malformation. The thickness of the vessel walls is generally proportionate to the diameter of the lumen but may vary from one segment to another of the same vessel section.

may be seen, especially on elastin stains. A capillary component is present in some cases, either as ill-defined capillary lobules, especially in the skeletal or

cutaneous muscles, or as sheets of individual or anastomozing capillaries in the dermis. These capillaries may be found even without a history of ulceration.

Secondary causes of telangiectasia are manifold and include conditions such as acne rosacea, varicose veins, trauma, lupus erythematosus, dermatomyositis, scleroderma, CREST (calcinosis, Raynaud phenomenon, esophageal dysmotility, sclerodactyly, and telangiectasia) syndrome, radiation dermatitis, poikiloderma, xeroderma pigmentosum, chronic sun exposure, and mastocytosis.

Venous Lake A venous lake is an acquired venular ectasia that develops on exposed skin of the head and neck in elderly patients probably from lack of support from the surrounding tissue.308

847

HISTOPATHOLOGIC FEATURES The principal finding is a single ectatic vascular structure (usually a venous channel) often containing a thrombus.311 The vascular channel exhibits an unremarkable endothelial lining that is surrounded by a concentric layering of fibrous tissue without smooth muscle or elastic lumina.

PART IV ■ PROLIFERATIONS—HAMARTOMAS, HYPERPLASIAS, AND NEOPLASIAS

DIFFERENTIAL DIAGNOSIS The differential diagnosis includes other ectatic vascular channels with or without thrombosis such as a venous lake, enlarged and torturous arterial and lymphatic channels, and angiokeratoma.

848

Arterial Spider

 FIGURE 31-53 Essential telangiectasia. Telangiectases are present in the superficial dermis.

CLINICAL FEATURES The lesions are often solitary, dark-blue papules 3 to 10 mm in diameter and commonly involve the ears, lips, face, and neck.308 (Table 31-26). PG arising after cryosurgery to a venous lake has been reported.309 HISTOPATHOLOGIC FEATURES The lesion is an ectatic vascular space localized to the superficial to middle dermis and is usually lined by a single layer of endothelium (Fig. 31-54); however, smooth muscle elements may occasionally be associated with the wall of the vessel.308,310 The surrounding dermis usually shows solar elastosis and diminished collagen.

DIFFERENTIAL DIAGNOSIS The lesion is distinctive; however, other vascular ectasias might be considered in the differential diagnosis.

Capillary Aneurysm (or Thrombosed Capillary Aneurysm) CLINICAL FEATURES The lesion usually presents as a solitary bluish papule on the face or trunk, occasionally with itching or tenderness.311 Such lesions may develop slowly or abruptly. Lesions with rapid onset are attributed to occlusion of the vessels by a thrombus. The primary clinical concern in many instances is to rule out melanoma.

Synonyms: Nevus araneus, spider angioma, spider nevus, spider telangiectasis The arterial spider is a common cutaneous lesion often seen as an incidental finding in healthy children.229 Some of these lesions persist into adulthood and may occur as acquired manifestations of pregnancy, hepatic cirrhosis, and thyrotoxicosis.312,313 CLINICAL FEATURES The principal finding is an erythematous central punctum often slightly elevated, pulsatile on diascopy, and the source of an array of peripherally radiating fine vessels. The spider angioma typically blanches with pressure and upon release refills rapidly with blood flow originating from its center. Solitary or multiple arterial spiders occur, and they may be numerous, particularly in chronic liver disease. The most common sites are the face, particularly the upper infraorbital cheeks, neck, trunk, and hands (Table 31-27).

Table 31-26 Venous Lake

Clinical Features Predilection for exposed (“weathered”) skin of elderly individuals—face, ears, lips Dark-blue papule, 3-10 mm, can appear suspicious for melanoma Histopathologic Features Dilated thin-walled vascular channel in dermis Uncommon smooth muscle in wall Occasional intraluminal thrombosis Solar elastosis and lack of supporting dermal collagen Differential Diagnosis Telangiectases Venous malformation

 FIGURE 31-54 Venous lake. A widely dilated, thin-walled vascular channel filled with red blood cells is present in the dermis.

Table 31-27 Arterial Spider

Clinical Features Common in children, young adults, women more than men, individuals with liver disease and thyrotoxicosis Involves face, neck, trunk, and hands Pulsatile red punctum with arborizing channels Blanches with pressure Histopathologic Features Vertically oriented arterial vascular channel in dermis Branching into smaller vessels Differential Diagnosis Telangiectases

DIFFERENTIAL DIAGNOSIS The clinical appearance of the arterial spider, with its pulsatile nature, is distinctive compared with simple telangiectasias. In contrast to the arterial spider, the lesions of HHT, an inherited mucocutaneous disorder that is described above, are numerous and consist of nonpulsatile, punctate, or linear telangiectasias.

Cherry Angioma Synonyms: Senile angioma, Campbell de Morgan spot. The cherry angioma is the most common vascular lesion encountered in the skin in adults. The lesions develop in adults and increase in number with age.229 CLINICAL FEATURES Cherry angiomas often develop in adults beginning in adolescence and are especially common in older adults (Table 31-28).229 They occur at all sites but especially involve the trunk. They present as uniform bright to dull red papules ranging in size from 2 or 3 to 10 mm. Eruptive cherry angiomas have been reported in association with solid organ transplantation; chronic graft-versus-host disease; primary biliary cirrhosis; and exposure to various chemical compounds, including cyclosporine, 2-butoxyethanol (glycol ether solvent), bromides, sulfur mustard gas, and nitrogen mustard.314 HISTOPATHOLOGIC FEATURES Cherry angiomas are usually raised, dome-shaped lesions that exhibit an epidermal collarette.

 FIGURE 31-55 Spider angioma. An arterial vessel is present in the superficial to mid-dermis.

They manifest fairly well-defined lobules composed of thin-walled dilated vascular channels that are largely confined to the papillary dermis (Fig. 31-56). The vascular channels in general are capillary to venular. The vascular lobules

Table 31-28 Cherry Angioma

Clinical Features Prevalent lesion that increases in frequency with age Often multiple involving trunk and extremities Well-defined 2-mm papules Bright red to dusky purple Histopathologic Features Dome shaped Epidermal collarettes Lobular vascular proliferation Lobules containing thin-walled vascular channels, variable cellularity Lobules often separated by fibrous septa Differential Diagnosis Pyogenic granuloma Acral arteriovenous malformation Venous malformation

are separated by fibrous septa that vary in thickness depending on the age of the lesion. DIFFERENTIAL DIAGNOSIS The entities to be considered include PG and BA because of the lobular architecture and epidermal collarettes. Cherry angioma does not show the endothelial proliferation noted in PG or the inflammatory infiltrates of neutrophils, granular debris, and epithelioid endothelium observed in BA.

CHAPTER 31 ■ VASCULAR TUMORS AND VASCULAR MALFORMATIONS

HISTOPATHOLOGIC FEATURES A central arteriole in the superficial dermis (Fig. 31-55) demonstrates branching into smaller anastomosing venules and capillaries.229 Rarely, the wall of the central arterial vessel may contain glomus cells.229

Benign Acquired Vascular Lesions in Irradiated Skin Synonyms: Acquired lymphangiectasies, atypical vascular lesion (proliferation) of the skin, benign lymphangiomatous papules after radiotherapy, lymphangioma circumscriptum, benign lymphangioendothelioma or APL The development of vascular lesions in the irradiated skin of women undergoing radiation therapy for breast or ovarian cancer raises suspicion for high-grade angiosarcoma.315-317 Clinically these lesions appear as solitary or multiple small

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 FIGURE 31-56 Cherry angioma. A dome-shaped lesion contains dilated vascular channels in a vaguely lobular configuration.

papules or reddish to bluish plaques with or without vesicles. Postradiation intervals for the development of such lesions have ranged from 1 to 20 years. A growing body of evidence supports the benign nature of most of these relatively small lesions. However, there is also recent evidence that some of these vascular lesions may be precursors to angiosarcoma. Much more definitive data are needed, however, to clarify the relationship between such atypical vascular lesions and angiosarcoma. HISTOPATHOLOGIC FEATURES These vascular lesions are reasonably circumscribed and confined to the dermis, usually without involvement of the subcutis. However, there are exceptions to the latter characteristics. Two main patterns have been delineated: (1) a pattern composed of dilated lymphatic vessels in the upper dermis, comparable to lymphangioma circumscriptum and designated benign lympangiomatous papule and 2) a pattern characterized by slitlike lymphatic vessels that dissect dermal collagen, reminiscent of APL or THH, and sometimes referred to as atypical vascular proliferation. The abnormal vessels are lined by flat, bland endothelial cells. However, rare lesions exhibit plump endothelial cells with “piling up” of these cells. In addition, thin papillary projections lined by bland endothelial cells or focal micropapillary tufts, reminiscent of Dabska tumor, may often be seen in these peculiar vessels. Inflammatory cells, including rare plasma cells and hemosiderin deposits, may be observed.

DIFFERENTIAL DIAGNOSIS The differential diagnosis includes well-differentiated angiosarcoma and patch-stage or lymphangioma-like KS. Angiosarcoma presents generally as large, often multiple, ill-defined lesions with frequent involvement of the subcutis. In addition, angiosarcoma shows well-developed cytologic atypia and multilayering of endothelium. However, the differential diagnosis may be difficult in some cases, and clinicopathologic correlation and long-term surveillance of patients are essential. The clinical presentation of KS is also different. Moreover, KS histologically usually demonstrates areas with spindle cell cytomorphology, and the immunohistochemical expression of HHV-8 is distinctive.

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CHAPTER 31 ■ VASCULAR TUMORS AND VASCULAR MALFORMATIONS

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histopathology]. Ann Pathol. 1999;19: 253-264. Calonje E, Fletcher CD: Sinusoidal hemangioma. A distinctive benign vascular neoplasm within the group of cavernous hemangiomas. Am J Surg Pathol. 1991;15:1130-1135. Carroll RE, Berman AT: Glomus tumors of the hand: review of the literature and report on twenty-eight cases. J Bone Joint Surg Am. 1972;54:691-703. Landthaler M, Braun-Falco O, Eckert F, et al: Congenital multiple plaquelike glomus tumors. Arch Dermatol. 1990; 126:1203-1207. Gould EW, Manivel JC, Albores-Saavedra J, et al: Locally infiltrative glomus tumors and glomangiosarcomas. A clinical, ultrastructural, and immunohistochemical study. Cancer. 1990;65:310-318. Brouillard P, Boon LM, Mulliken JB, et al: Mutations in a novel factor, glomulin, are responsible for glomuvenous malformations (“glomangiomas”). Am J Hum Genet. 2002;70:866-874. Boon LM, Mulliken JB, Enjolras O, et al: Glomuvenous malformation (glomangioma) and venous malformation: distinct clinicopathologic and genetic entities. Arch Dermatol. 2004;140:971-976. Acebo E, Val-Bernal JF, Arce, F: Giant intravenous glomus tumor. J Cutan Pathol. 1997;24:384-389. Yang JS, Ko JW, Suh KS, et al: Congenital multiple plaque-like glomangiomyoma. Am J Dermatopathol. 1999;21:454-457. Yoon TY, Lee HT, Chang SH: Giant congenital multiple patch-like glomus tumors. J Am Acad Dermatol. 1999;40:826-828. Mounayer C, Wassef M, Enjolras O, et al: Facial “glomangiomas”: large facial venous malformations with glomus cells. J Am Acad Dermatol. 2001;45:239-245. Hiruta N, Kameda N, Tokudome T, et al: Malignant glomus tumor: a case report and review of the literature. Am J Surg Pathol. 1997;21:1096-1103. Lopez-Rios F, Rodriguez-Peralto JL, Castano E, et al: Glomangiosarcoma of the lower limb: a case report with a literature review. J Cutan Pathol. 1997;24:571-574. Brathwaite CD, Poppiti RJ Jr: Malignant glomus tumor. A case report of widespread metastases in a patient with multiple glomus body hamartomas. Am J Surg Pathol. 1996;20:233-238. Folpe AL, Fanburg-Smith JC, Miettinen M et al: Atypical and malignant glomus tumors: analysis of 52 cases, with a proposal for the reclassification of glomus tumors. Am J Surg Pathol. 2001;25:1-12. Watanabe K, Sugino T, Saito A, et al: Glomangiosarcoma of the hip: report of a highly aggressive tumour with widespread distant metastases. Br J Dermatol. 1998;139:1097-1101. Beham A, Fletcher CD: Intravascular glomus tumour: a previously undescribed phenomenon. Virchows Arch A Pathol Anat Histopathol. 1991;418:175-177. Kaye VM, Dehner LP: Cutaneous glomus tumor. A comparative immunohistochemical study with pseudoangiomatous intradermal melanocytic nevi. Am J Dermatopathol. 1991;13:2-6. Granter SR, Badizadegan K, Fletcher CD: Myofibromatosis in adults, glomangiopericytoma, and myopericytoma: a spectrum of tumors showing

CHAPTER 31 ■ VASCULAR TUMORS AND VASCULAR MALFORMATIONS

McGraw-Hill; 1999:1175-1194. 227. Brouillard P, Vikkula M: Vascular malformations: localized defects in vascular morphogenesis. Clin Genet. 2003;63: 340-351. 228. Wang QK: Update on the molecular genetics of vascular anomalies. Lymphat Res Biol. 2005;3:226-233. 229. Bean WB: Vascular Spider and Related Lesions of the Skin. Spingfield, IL: Thomas, CC; 1958. 230. Klapman MH, Yao JF: Thickening and nodules in port-wine stains. J Am Acad Dermatol. 2001;44:300-302. 231. Smoller BR, Rosen S: Port-wine stains. A disease of altered neural modulation of blood vessels? Arch Dermatol. 1986; 122:177-179. 232. Garzon MC, Huang JT, Enjolras O, et al: Vascular malformations. Part II: associated syndromes. J Am Acad Dermatol. 2007; 56:541-564. 233. Eerola I, Boon LM, Mulliken JB, et al: Capillary malformation-arteriovenous malformation, a new clinical and genetic disorder caused by RASA1 mutations. Am J Hum Genet. 2003;73:1240-1249. 234. Jessen RT, Thompson S, Smith EB: Cobb syndrome. Arch Dermatol. 1977;113:15871590. 235. Gold MH, Eramo L, Prendiville JS: Hereditary benign telangiectasia. Pediatr Dermatol. 1989;6:194-197. 236. Brancati F, Valente EM, Tadini G, et al: Autosomal dominant hereditary benign telangiectasia maps to the CMC1 locus for capillary malformation on chromosome 5q14. J Med Genet. 2003;40:849-853. 237. Puppin D Jr, Rybojad M, Morel P: Hereditary benign telangiectasia: two case reports. J Dermatol. 1992;19:384-386. 238. Onishi Y, Ohara K, Shikada Y, et al: Hereditary benign telangiectasia: image analysis of hitherto unknown association with arteriovenous malformation. Br J Dermatol. 2001;145:641-645. 239. Boon LM, Mulliken JB, Vikkula M: RASA1: variable phenotype with capillary and arteriovenous malformations. Curr Opin Genet Dev. 2005;15:265-269. 240. Mager JJ, Westermann CJ: Value of capillary microscopy in the diagnosis of hereditary hemorrhagic telangiectasia. Arch Dermatol. 2000;136:732-734. 241. Peery WH: Clinical spectrum of hereditary hemorrhagic telangiectasia (OslerWeber-Rendu disease). Am J Med. 1987; 82:989-997. 242. Garcia-Tsao G, Korzenik JR, Young L, et al: Liver disease in patients with hereditary hemorrhagic telangiectasia. N Engl J Med. 2000;343:931-936. 243. Smith LL, Conerly SL: Ataxia-telangiectasia or Louis-Bar syndrome. J Am Acad Dermatol. 1985;12:681-696. 244. Khumalo NP, Joss DV, Huson SM, et al: Pigmentary anomalies in ataxia— telangiectasia: a clue to diagnosis and an example of twin spotting. Br J Dermatol. 2001;144:369-371. 245. Wilkin JK, Smith JG Jr, Cullison DA, et al: Unilateral dermatomal superficial telangiectasia. Nine new cases and a review of unilateral dermatomal superficial telangiectasia. J Am Acad Dermatol. 1983;8:468-477. 246. Hynes LR, Shenefelt PD: Unilateral nevoid telangiectasia: occurrence in two

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perivascular myoid differentiation. Am J Surg Pathol. 1998;22:513-525. Dutheil P, Leraillez J, Guillemette J, et al: Generalized lymphangiomatosis with chylothorax and skin lymphangiomas in a neonate. Pediatr Dermatol. 1998;15:296-298. Mu XC, Tran TA, Dupree M, et al: Acquired vulvar lymphangioma mimicking genital warts. A case report and review of the literature. J Cutan Pathol. 1999;26:150-154. Oyler RM, Davis DA, Woosley JT: Lymphangioma associated with Becker’s nevus: a report of coincident hamartomas in a child. Pediatr Dermatol. 1997;14:376379. Guillou L, Fletcher CD: Benign lymphangioendothelioma (acquired progressive lymphangioma): a lesion not to be confused with well-differentiated angiosarcoma and patch stage Kaposi’s sarcoma: clinicopathologic analysis of a series. Am J Surg Pathol. 2000;24:1047-1057. Sevila A, Botella-Estrada R, Sanmartin O, et al: Benign lymphangioendothelioma of the thigh simulating a lowgrade angiosarcoma. Am J Dermatopathol. 2000;22:151-154. Wilmer A, Kaatz M, Mentzel T, et al: Lymphangioendothelioma after a tick bite. J Am Acad Dermatol. 1998;39:126128. Wilson-Jones E, Winkelmann RK, Zachary CB, et al: Benign lymphangioendothelioma. J Am Acad Dermatol. 1990;23:229-235. Mehregan DR, Mehregan AH, Mehregan DA: Benign lymphangioendothelioma: report of 2 cases. J Cutan Pathol. 1992;19:502-505. Kato N, Isu K, Kikuta H: Absence of human herpesvirus 8/Kaposi’s sarcomaassociated herpesvirus in a case of benign lymphangioendothelioma associated with periosteal haemangioma. Br J Dermatol. 2002;146:157-159. Rao VK, Weiss SW: Angiomatosis of soft tissue. An analysis of the histologic fea-

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tures and clinical outcome in 51 cases. Am J Surg Pathol. 1992;16:764-771. Girard C, Graham JH, Johnson WC: Arteriovenous hemangioma (arteriovenous shunt). A clinicopathological and histochemical study. J Cutan Pathol. 1974;1:73-87. Carapeto FJ, Garcia-Perez A, Winkelmann RK: Acral arteriovenous tumor. Acta Derm Venereol. 1977;57:155-158. Connelly MG, Winkelmann RK: Acral arteriovenous tumor. A clinicopathologic review. Am J Surg Pathol. 1985;9:15-21. Kadono T, Kishi A, Onishi Y, et al: Acquired digital arteriovenous malformation: a report of six cases. Br J Dermatol. 2000;142:362-365. Onishi Y, Ohara, K: Angiolymphoid hyperplasia with eosinophilia associated with arteriovenous malformation: a clinicopathological correlation with angiography and serial estimation of serum levels of renin, eosinophil cationic protein and interleukin 5. Br J Dermatol. 1999;140:1153-1156. Kishimoto S, Takenaka H, Shibagaki R, et al: Verruciform xanthoma arising in an arteriovenous haemangioma. Br J Dermatol. 1998;139:546-548. Feinmesser M, Taube E, Badani E, et al: Basal cell carcinomas arising over arteriovenous malformations: some speculations on the theme. Am J Dermatopathol. 1997;19:575-579. Enjolras O, Logeart I, Gelbert F, et al: [Arteriovenous malformations: a study of 200 cases]. Ann Dermatol Venereol. 2000;127:17-22. Kohout MP, Hansen M, Pribaz JJ, et al: Arteriovenous malformations of the head and neck: natural history and management. Plast Reconstr Surg. 1998;102: 643-654. Enjolras O, Mulliken JB: The current management of vascular birthmarks. Pediatr Dermatol. 1993;10:311-333. McGrae, JD, Jr., Winkelmann, RK: Generalized essential telangiectasia:

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report of a clinical and histochemical study of 13 patients with acquired cutaneous lesions. JAMA. 1963;185:909-913. Checketts SR, Burton PS, Bjorkman DJ, et al: Generalized essential telangiectasia in the presence of gastrointestinal bleeding. J Am Acad Dermatol. 1997; 37:321-325. Bean WB, Walsh JR: Venous lakes. AMA Arch Derm. 1956;74:459-463. Cecchi R, Giomi A: Pyogenic granuloma as a complication of cryosurgery for venous lake. Br J Dermatol. 1999;140:373-374. Alcalay J, Sandbank, M: The ultrastructure of cutaneous venous lakes. Int J Dermatol. 1987;26:645-646. Epstein E, Novy FG Jr, Allington HV: Capillary aneurysms of the skin. Arch Dermatol. 1965;91:335-341. Li CP, Lee FY, Hwang SJ, et al: Spider angiomas in patients with liver cirrhosis: role of vascular endothelial growth factor and basic fibroblast growth factor. World J Gastroenterol. 2003;9:2832-2835. Henry F, Quatresooz P, Valverde-Lopez, JC, et al: Blood vessel changes during pregnancy: a review. Am J Clin Dermatol. 20067:65-69. Ma HJ, Zhao G, Shi F et al: Eruptive cherry angiomas associated with vitiligo: provoked by topical nitrogen mustard? J Dermatol. 2006;33:877-879. Diaz-Cascajo C, Borghi S, Weyers W, et al: Benign lymphangiomatous papules of the skin following radiotherapy: a report of five new cases and review of the literature. Histopathology. 1999;35:319-327. Requena L, Kutzner H, Mentzel T, et al: Benign vascular proliferations in irradiated skin. Am J Surg Pathol. 2002;26:328337. Gengler C, Coindre JM, Leroux A, et al: Vascular proliferations of the skin after radiation therapy for breast cancer: clinicopathologic analysis of a series in favor of a benign process: a study from the French Sarcoma Group. Cancer. 2007;109:1584-1598.

CHAPTER 32 Tumors of Adipose Tissue, Muscle, Cartilage, and Bone Shady El-Zayaty Thomas Krausz

superficialis. This is also characterized by mature adipose tissue in the dermis but occurs in adults and is not associated with other defects, and the surrounding collagen is normal.

Nevus Lipomatous Superficialis CLINICAL FEATURES Nevus lipomatous superficialis is a rare lesion of young adults most commonly presenting as unilateral lesions on the lower trunk or gluteal region.4 These are skin-colored papules that may coalesce into plaques with a cerebriform surface up to 10 cm

in diameter. Single and multiple lesions occur; multiple lesions occur in younger patients and often are grouped in a zonal distribution on the buttock. Solitary lesions overlap clinically and histologically with fibroepithelial polyps (skin tags). Only rare recurrences are reported. HISTOPATHOLOGIC FEATURES Histologically, variable amounts of mature adipose tissue are present within the papillary dermis (Fig. 32-1). This often is clustered around blood vessels of the superficial dermal vascular plexus, which may be increased in number. The overlying

Tumors of adipose tissue are common in the skin and subcutaneous tissue (Table 32-1). Although most are lipomas, a number of other lesions have been described with distinct clinical and pathologic features. Several of these have worrisome histologic findings that may lead to confusion with liposarcoma. Although liposarcomas are more common in deep soft tissues, liposarcomas of all types may occur superficially, albeit rarely. The prognosis for these tumors depends not only on grade but also on site and age. Recently, characteristic cytogenetic features have been identified in some of these tumors.

Table 32-1 Generalized Approach to Tumors of Adipose Tissue Mature Adipose Tissue No other features Thrombosed capillaries Spindled cells, collagen, myxoid change Floret cells and spindle cells Chondroblast-like cells and lipoblasts Smooth muscle Brown fat Immature Adipose Tissue Young patient Older patient, presence of lipoblasts

Lipoma Angiolipoma Spindle cell lipoma Pleomorphic lipoma Chondroid lipoma Myolipoma Hibernoma Lipoblastoma Liposarcoma

Hamartomas A hamartoma is a focal malformation that is composed of tissue elements normally found at that site, arranged in a disorganized manner. Hamartomas occur in many different parts of the body, including the skin, and are most often asymptomatic. Although generally benign, they can be a cosmetic issue for patients.

Focal Dermal Hypoplasia CLINICAL AND HISTOPATHOLOGIC FEATURES Focal dermal hypoplasia is an X-linked dominant multisystem birth defect affecting tissues of ectodermal and mesodermal origin, due to a defect in the PORCN signaling in the WNT pathway.1 Clinically, it may be associated with anomalies of the skin, skeleton, eyes, and ears.2 It is more common in women. The lesions may appear anywhere as yellow to red nodules in a reticular pattern. Histologically, the dermis is underdeveloped and replaced by mature adipose tissue.3 The surrounding dermal collagen fibers may be smaller than normal. Focal, total absence of skin may be present. DIFFERENTIAL DIAGNOSIS The differential diagnosis includes nevus lipomatous

 FIGURE 32-1 Nevus lipomatous superficialis. A polypoid lesion containing mature adipose tissue that extends into the papillary dermis.

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epidermis may be normal, acanthotic, or hyperkeratotic. A variable degree of myxoid change is often seen, and the histologic features of nevus lipomatous superficialis overlap significantly with dermal spindle cell lipomas.

PART IV ■ PROLIFERATIONS—HAMARTOMAS, HYPERPLASIAS, AND NEOPLASIAS

DIFFERENTIAL DIAGNOSIS When single, differentiation from a skin tag with herniation of adipose tissue may be impossible but is of little clinical significance. Mature dermal melanocytic nevi occasionally can consist largely of “metaplastic” adipose tissue, obscuring the melanocytes. Distinction from focal dermal hypoplasia is discussed in the preceding text.

Benign Neoplasms Benign adipocytic tumors are the largest group of soft tissue tumors, due largely to the prevalence of lipomas. The World Health Organization’s (WHO’s) classification of benign adipocytic tumors will form the framework of this section (Table 32-2). As with their malignant counterpart, our concept of these tumors has been enhanced by recent advances in molecular studies. Diagnosis of these tumors, however, is still largely based on their morphologic and clinical features, rather than genetic aberrations.

Lipoma CLINICAL FEATURES Lipomas are common, with an annual clinical incidence of at least approximately 0.1% of the population.5 They comprise up to 5% of all benign tumors and 25% to 50% of all soft tissue tumors. They are most common in the fifth and sixth decades of life. They occur anywhere but most are subcutaneous. The head and neck, arm, and upper thorax often are affected; lesions of the lower leg and hand are distinctly uncommon. Up to 7% are multiple; the latter are often more common in younger

Table 32-3 Lipoma

Clinical Features Adults Upper body, but wide distribution Histopathologic Features Mature adipose tissue Encapsulated Differential Diagnosis Angiolipoma Lipomatosis ALT/WDL

men.6 Solitary lesions affect men and women equally. Most are smaller than 5 cm in diameter. Fewer than 1% recur; recurrence suggests incomplete excision or possibly a more aggressive lipomatous lesion that has been misdiagnosed.7, 8 HISTOPATHOLOGIC FEATURES Lipomas are composed of lobules of mature adipose tissue enclosed in a thin fibrous capsule (Table 32-3). The adipocytes are uniform in size and appearance (Fig. 32-2). Fibrous tissue and scattered capillaries may also be present. Several histologic variants are recognized depending on the secondary features, such as myxoid change (myxolipoma) (Fig. 32-3) or fibrosis (fibrolipoma). Occasional cases have metaplastic bone or cartilage. Degenerative changes, including foamy macrophages, lymphocytes, myxoid change, and calcification, may be seen. Multiple karyotypic abnormalities have been described, including rearrangement

of chromosome bands 12q13-15, resulting in deregulation of the HMGA2 gene, loss of material from or rearrangement of chromosome 13, and aberrations of chromosome band 6p21.8 DIFFERENTIAL DIAGNOSIS Adipose tissue hypertrophy is similar but lacks the circumscription of a lipoma or a capsule. However, some cases cannot be distinguished histologically. Nodular–cystic fat necrosis is a rare lesion of uncertain origin that may be confused with lipoma. It occurs in adolescent boys and middleaged women, may be related to trauma, and consists of infarcted adipose tissue with well-preserved cell outlines and no nuclei contained within a thin fibrovascular capsule. It may occasionally show degenerative changes, including hyalinized pseudomembranes, which may resemble amyloid, and dystrophic calcifications.9 The lack of nuclei distinguishes it from lipoma. Distinction from other benign adipose tissue tumors is discussed in the following pages. Well-differentiated liposarcoma (WDL)/atypical lipomatous tumor (ALT) is the most important lesion to exclude. Liposarcomas are discussed in the following text but in general are defined by the presence of enlarged hyperchromatic cells within irregular fibrous septa or lipoblasts, are often greater than 5 cm in size, and commonly are located in the thigh and retroperitoneum.10

Angiolipoma CLINICAL FEATURES Compared with lipomas, angiolipomas are one-fifth as

Table 32-2 WHO Classification of Benign Adipocytic Tumors

858

Lipoma Lipomatosis Lipomatosis of nerve Lipoblastoma or lipoblastomatosis Angiolipoma Myolipoma Chondroid lipoma Extrarenal angiomyolipoma Spindle cell lipoma or pleomorphic lipoma Hibernoma

 FIGURE 32-2 Lipoma. Uniformly sized adipocytes without atypia.

Spindle Cell Lipoma  FIGURE 32-3 Myxolipoma. Abundant myxoid matrix may obscure the lipogenic nature of the tumor.

common, occur at a younger age (17 to 24 years), are more commonly multiple, and often are painful (Table 32-4).5 They occur most commonly in the forearm or on the trunk but also in similar locations as lipomas. Grossly, they may be firmer than lipomas, usually measure less than 2 cm, and are always subcutaneous. Angiolipomas are benign and cured by simple excision.

pericytes. Fibrin microthrombi are present in almost all cases. Examples in which the vascular component comprises the bulk of the lesion are known as cellular angiolipomas.14 DIFFERENTIAL DIAGNOSIS The normal karyotype of subcutaneous angiolipoma as well as its distinct clinical and morphologic features suggests a different

CLINICAL FEATURES Spindle cell lipoma occurs predominantly as a solitary subcutaneous mass in the shoulder and posterior neck of men between the ages of 45 and 70 years (Table 32-5).13 A significant minority of cases arise on the face. They comprise approximately 1.5% of adipo-cyte lesions and are 1/60th as common as lipoma but 10 times as common as pleomorphic lipoma. 14 Local recurrence is rare. Multiple spindle cell lipomas are rare and may mimic Madelung disease (symmetrical lipomatosis). Familial and nonfamilial cases have been reported, with no risk of

HISTOPATHOLOGIC FEATURES The lesion is encapsulated and composed of mature adipose tissue and a variably prominent capillary network that is often denser at the periphery (Fig. 32-4; see also Table 32-3). The vessels may have a complex branching pattern and prominent

CHAPTER 32 ■ TUMORS OF ADIPOSE TISSUE, MUSCLE, CARTILAGE, AND BONE

pathogenesis from pure lipomas.11 In cases with few capillaries, distinction from lipoma may be difficult. The presence of fibrin thrombi may be helpful. Highly vascular lesions may be confused with hemangioma or even Kaposi sarcoma.12 In contrast to angiolipoma, Kaposi sarcoma has more poorly formed vascular spaces, solid aggregates of spindle cells, and hyaline globules and is poorly circumscribed. In hemangiomas, the capillaries radiate out from a central larger vessel, but in angiolipoma, the capillaries are located peripherally and radiate inward. Spindle cell lipomas with prominent vascularity may be similar but present in older individuals, are solitary, and have organized arrays of spindle cells often associated with hyaline collagen bundles.5,10

Table 32-4 Angiolipoma

Clinical Features Young adults Painful, often multiple Upper body Histopathologic Features Mature adipose tissue Capillaries (mainly peripheral) Fibrin thrombi Differential Diagnosis Lipoma Hemangioma Angiomyolipoma

 FIGURE 32-4 Angiolipoma. Numerous vascular channels are present mostly at the periphery of the tumor, some with microthrombi, admixed with adipocytes.

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Table 32-5 Spindle Cell Lipoma

Clinical Features Men Subcutaneous Shoulders, upper back, face Histopathologic Features Mature adipose tissue Bland spindle cells Ropey collagen Mucinous background Mast cells Differential Diagnosis Pleomorphic lipoma Neurofibroma ALT/WDL Solitary fibrous tumor

progression to liposarcoma.15 Both spindle cell and pleomorphic lipomas show karyotypic aberrations of 16q and 13q.14 HISTOPATHOLOGIC FEATURES Grossly, the lesions are circumscribed and average 4 cm in size (range, 1-14 cm). Histologically, they are usually well demarcated and composed of variable amounts of mature adipose tissue, uniform spindle cells in a myxoid matrix, and thick (ropey) bundles of refractile collagen (Fig. 32-5). 16 Cases with little to no

adipose tissue occur and are often mistaken for benign nerve sheath tumors.17 The spindle cells are small, with a single elongated nucleus and slender bipolar cytoplasmic processes. These cells stain positively for CD34 and are often oriented along bundles of collagen or form very short fascicles that are interspersed with the adipocytes. Mitoses are rare. It must be emphasized that otherwise typical spindle cell lipomas may contain lipoblasts. Cases with increased vascular areas and marked pseudoangiomatous degeneration have been described.18 Exceptional cases may contain bone or cartilage. When multiple spindle cell lipomas occur, the tumors become more cellular as the disease progresses, often with features of pleomorphic lipoma.15 Although pleomorphic cells are not present in classic spindle cell lipomas, it is well recognized that spindle cell and pleomorphic lipomas comprise a histologic spectrum of a single biologic entity. As such, hybrid lesions are not uncommonly encountered. DIFFERENTIAL DIAGNOSIS The characteristic age, gender, and site are very helpful in making the diagnosis. Heavily vascular cases may be mistaken for angiolipoma. Classic pleomorphic lipoma is distinguished by the presence of large bizarre cells, cells with multiple nuclei in a floretlike pattern, and occasional lipoblasts.

As mentioned previously, cases with a prominent spindle cell component may be confused with neurofibroma. However, in spindle cell lipoma, the nuclei are not as wavy, and the spindle cells are S-100 protein–negative (the adipocytes can be positive). Cases with a prominent myxoid background may be mistaken for myxoid liposarcoma. However, spindle cell lipoma has very monotonous spindle-shaped cells and abundant thick collagen, lacks the characteristic “chicken wire” vascular pattern, and usually lacks lipoblasts. Cellular cases may be mistaken for well-differentiated or sclerosing liposarcoma. WDL may contain thick bundles of collagen but has a less uniform appearance, with large atypical cells clustered around fibrous septa. Finally, very cellular lesions may resemble solitary fibrous tumor. Solitary fibrous tumors may contain mature adipose tissue and exhibit a similar immunohistochemical profile (so-called lipomatous hemangiopericytoma).19,20 However, spindle cell lipoma lacks the characteristic staghornlike vessels of solitary fibrous tumor. In addition, the spindle cells of solitary fibrous tumor are more often curved rather than straight, do not form discrete fascicles, and are often less associated with either ropey collagen or a myxoid background.

Pleomorphic Lipoma CLINICAL FEATURES Pleomorphic lipoma, similar to spindle cell lipoma, occurs principally in the neck, upper back, and shoulders of men in the fifth to seventh decades of life (Table 32-6).21,22 It is located in the subcutis almost exclusively. Twenty-five percent of cases have areas resembling spindle cell lipoma, and essentially, these lesions form a morphologic

Table 32-6 Pleomorphic Lipoma

860

 FIGURE 32-5 Spindle cell lipoma. Bland spindled cells arranged in short bundles admixed with adipocytes and characteristic ropey collagen.

Clinical Features Men Subcutaneous Shoulders, upper back, face Histopathologic Features Mature adipose tissue Bland spindle cells Floret cells Rare lipoblasts Differential Diagnosis Spindle cell lipoma ALT/WDL Solitary fibrous tumor

continuum. Both spindle cell and pleomorphic lipomas show similar karyotypic aberrations of 16q or 13q.23 Despite the worrisome cytologic features, pleomorphic lipomas are benign.

Chondroid Lipoma CLINICAL FEATURES Chondroid lipoma is a rare and distinctive tumor..24 It occurs more commonly in women over a wide age range and a variety of sites. The tumors are well circumscribed (1-11 cm)

A

and located subcutaneously, within fascia, or intramuscularly. Whether these tumors show true chondroid differentiation is controversial but unlikely. To date, no recurrences or metastases have been reported. HISTOPATHOLOGIC FEATURES A mixture of mature adipose tissue interspersed with nests of round, uni- and multivacuolated cells within a basophilic myxoid background are found (Fig. 32-7). The vacuolated cells often have a prominent cytoplasmic border resembling chondroblasts.5 In some areas, the vacuolated cells form cords superficially resembling myxoid chondrosarcoma. In addition, admixed with these cells are typical multivacuolated lipoblasts. Mitoses are rare. Chondroid lipoma is highly vascular and may exhibit degenerative changes, including hemorrhage, fibrosis, and inflammation. Wellformed cartilage is not seen. Periodic acidSchiff (PAS) stains reveal intracellular glycogen; the tumors are reactive for S-100 protein, CD68, and vimentin. DIFFERENTIAL DIAGNOSIS The pathologic features of chondroid lipoma are unique. Chondromas of soft tissue lack adipose tissue and have mature hyaline cartilage as well as multinucleated giant cells. Mixed tumors may contain fat, but they also contain keratin-positive myoepithelial cells that often form glands and epithelial cords. Myxoid liposarcoma is distinguished by its characteristic vasculature, uniform myxoid background, and lack of vacuolated chondroblast-like cells. Limited cytogenetic data suggest that whereas chondroid lipoma is characterized by t(11;16)(q13;p12-13), myxoid liposarcoma have a typical t(12;16) (q13;p11) translocation.25 Lesions without mature fat may be confused with extraskeletal myxoid chondrosarcoma, but the tumor cells of extraskeletal myxoid chondrosarcoma are smaller, more uniform and round, and lack the extensive cytoplasmic vacuolization. Extraskeletal myxoid chondrosarcomas are also typically large lesions that display prominent hemorrhage. In addition, they display the chromosomal aberration t(9;22), which is not seen in chondroid lipoma.

CHAPTER 32 ■ TUMORS OF ADIPOSE TISSUE, MUSCLE, CARTILAGE, AND BONE

HISTOPATHOLOGIC FEATURES Grossly, the lesions are well circumscribed, range from 1 to 12 cm in diameter (average, 4 cm), and resemble lipomas. Histologically, they are circumscribed and characteristically have a mixture of variably sized fat cells with a varying number of pleomorphic enlarged cells (Fig. 32-6; see also Table 32-5). These cells contain moderate amounts of eosinophilic cytoplasm, are often multinucleated, and often have nuclei arranged in a circumferential pattern that has resulted in the term floret cell. The chromatin can be fine or smudgy and hyperchromatic. Rare lipoblasts, with cytoplasmic vacuoles indenting the nucleus, can also be found. Scarce mitoses may be present, but necrosis is not observed.

DIFFERENTIAL DIAGNOSIS They may be distinguished in general from liposarcoma by their typical location, numerous floret cells greatly outnumbering any lipoblasts, and the absence of necrosis. In addition, in well-differentiated or sclerosing liposarcoma, the atypical cells and lipoblasts are concentrated along fibrous septa and are seen in association with hyperchromatic bizarre stromal cells. Pleomorphic liposarcoma has numerous lipoblasts and lacks floret cells. The atypical cells in pleomorphic liposarcoma are so numerous that they form sheetlike masses rather than being scattered between adipocytes.

Myolipoma B  FIGURE 32-6 Pleomorphic lipoma. Mature adipocytes and multinucleated floret-like giant cells. The background may exhibit abundant ropey collagen and rare mature adipocytes (A), or may be variably myxoid (B).

CLINICAL AND HISTOPATHOLOGIC FEATURES Myolipoma is an uncommon neoplasm occurring in adults but only infrequently arising in subcutaneous tissue.26 Although deep lesions have reached 25 cm in diameter, subcutaneous lesions were

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PART IV ■ PROLIFERATIONS—HAMARTOMAS, HYPERPLASIAS, AND NEOPLASIAS 862

 FIGURE 32-7 Chondroid lipoma. Vacuolated cells simulating lipoblasts arranged in nests admixed with adipocytes within a myxochondroid matrix.

solitary fibrous tumor with mature adipose tissue. The spindle cells of spindle cell lipoma have scant cytoplasm and a myxoid background and are not immunoreactive for actin or desmin. WDLs (atypical lipomatous neoplasms) may have a smooth muscle component (lipoleiomyosarcoma) but these would also exhibit nuclear atypia or lipoblasts.27 Smooth muscle hamartoma may closely resemble this lesion but is usually dermal and congenital. Leiomyomas with fatty infiltration have long, regular fascicles but are unusual outside of the uterus and rarely have such diffuse infiltration with fat. Hemangiopericytoma with adipose tissue does not form fascicles and is desmin negative.20 Lipoblastomatosis exhibits infiltration of adjacent muscle at the periphery. Those that have undergone maturation lack significant lipoblasts and may be composed entirely of mature adipose, mimicking myolipoma. The age of the patient and the presence of an adjacent conventional lipoblastoma are helpful in this instance.

Angiomyolipoma smaller (~5 cm) and well circumscribed. The tumor is an intimate mixture (in varying proportions) of mature adipose tissue interspersed with well-differentiated smooth muscle, resembling a sieve (Fig. 32-8). The muscle cells form only short, irregular fascicles, in contrast to the long fascicles present in leiomyomas.

The smooth muscle is reactive for both actin and desmin. No recurrences have been reported.5 DIFFERENTIAL DIAGNOSIS The differential diagnosis includes spindle cell lipoma, liposarcoma, smooth muscle hamartoma, leiomyomas with fatty infiltration, and

 FIGURE 32-8 Myolipoma. Admixture of mature adipocytes and smooth muscle.

Angiomyolipomas are deeply seated lesions that usually occur in the kidney but rarely may be located in other organs or in deep soft tissue. Approximately half are associated with tuberous sclerosis. The tumor is a member of the PEComa family, which is a group of related mesenchymal neoplasms that include angiomyolipoma, lymphangiomyomatosis, and clear cell “sugar” tumor of the lung. These tumors all share a distinctive cell type—the perivascular epithelioid cell, which has no known normal tissue counterpart.28 Angiomyolipomas exhibit a distinctive triphasic histology, with thickwalled blood vessels, lipid-distended tumor cells (so-called adipocytes), and epithelioid to spindled cells (Fig. 32-9). The epithelioid, spindled, and lipid-distended cells have a distinctive “myomelanocytic” immuno-phenotype with coexpression of smooth muscle actin and melanocytic markers such as HMB-45 or Melan-A. Some early reports of extremity angiomyolipomas in the literature may represent mixed smooth muscle and adipocytic neoplasms, such as myolipoma, rather than PEComas based on provided illustrations and the absence of documented HMB-45 positivity.29-31 Recently, however, several bona fide cases of PEComas involving the extremities have been reported.28,32-34 These occur predominately in the lower extremities of females, with rare incidence of malignant transformation.35

DIFFERENTIAL DIAGNOSIS Although angiomyolipoma is characterized by a triphasic histology, occasionally, one of these components may predominate with exclusion of one ore more other elements. This may give the tumor a biphasic, or rarely monophasic, appearance. Immunohistochemical staining for melanocytic markers can be useful in this instance.

(mean, 10 cm). Occasional examples are intramuscular. These tumors are benign. HISTOPATHOLOGIC FEATURES The tumor usually has a yellow-brown, lobulated cut surface.5 Three cell types are present. Intermediate-sized polygonal cells with

DIFFERENTIAL DIAGNOSIS Diagnosis is usually straightforward. Focal areas of brown fat can be present in an otherwise typical mature lipoma. Hibernomas may be mistaken for liposarcomas, but the uniformity of the lesion, lack of mitoses, lack of atypia, and (most important) lack of true lipoblasts (defined by their indented hyperchromatic nuclei) argue against the diagnosis. Granular cell tumors

Hibernoma CLINICAL FEATURES Hibernomas are tumors of brown fat.36 They arise usually in young to middle-aged adults (average age, 36 years) and are commonly located in the thigh, shoulder, and axilla (Table 32-7). They are most often subcutaneous, well circumscribed, and measure up to 19 cm in diameter

CHAPTER 32 ■ TUMORS OF ADIPOSE TISSUE, MUSCLE, CARTILAGE, AND BONE

 FIGURE 32-9 Angiomyolipoma. Typical triphasic histology exhibiting mature adipocytes, smooth muscle, and thick-walled blood vessels.

abundant granular, eosinophilic cytoplasm, and centrally placed nuclei are often most common (see Table 32-6). Slightly larger cells with multiple cytoplasmic vacuoles that do not indent the centrally placed nucleus are also present. The third cell type resembles a mature adipocyte with a large, solitary vacuole displacing the nucleus off to the side (Fig. 32-10). Four histologic variants are recognized. The typical hibernoma is composed of the aforementioned three cell types in varying proportions. The lipoma-like variant consists of only scattered hibernoma cells among white fat. The spindle cell variant combines the features of hibernoma and spindle cell lipoma. Last, the myxoid variant exhibits hibernoma cells in a myxoid matrix. The importance of these variants lies only in their recognition, not in their clinical behavior.37 The ultrastructural features differ from those of mature adipose tissue and include abundant mitochondria, basal lamina, and micropinocytotic vesicles.

Table 32-7 Hibernoma

Clinical Features Young adults Upper back Histopathologic Features Granular cells Vacuolated cells Mature adipose tissue Differential Diagnosis Lipoma

 FIGURE 32-10 Hibernoma. Mixture of granular eosinophilic cells, multivacuolated cells, and mature adipocytes.

863

and adult rhabdomyomas do not contain adipocytes.

PART IV ■ PROLIFERATIONS—HAMARTOMAS, HYPERPLASIAS, AND NEOPLASIAS

Multiple Symmetric Lipomatosis (Madelung Disease) Multiple symmetric lipomatosis is characterized by unencapsulated masses of adipose tissue symmetrically located in the neck, shoulders, chest, abdomen, groin, or buttocks.38,39 These lesions arise in subcutaneous tissue but spread deeply. Although generally asymptomatic, compression of airways and vital organs has been described. This condition is most common in adult men (20-52 years) and may be familial. Histologically, the adipocytes are said to be smaller than normal and relatively uniform in size. Definitive diagnosis requires clinical correlation.

Lipoblastoma or Lipoblastomatosis CLINICAL FEATURES Lipoblastoma or lipoblastomatosis is rare and occurs almost exclusively in children younger than 7 years old, predominantly in those younger than age 3 years.40 Boys are affected more commonly (2:1). The lesions can be localized or diffuse and usually occur in the extremities. Localized forms are termed lipoblastoma and diffuse forms lipoblastomatosis. In subcutaneous sites, localized lobulated lesions smaller than 5 cm in diameter are most common. Although 15% to 20% of lesions recur (usually of the diffuse type), no metastases or deaths have been reported. HISTOPATHOLOGIC FEATURES Histologically, the lesions mimic and may be almost identical to well-differentiated or myxoid liposarcomas (Table 32-8). At low power, the tumor is distinctly lobulated or nested (Fig. 32-11). At high power, numerous lipoblasts, a rich plexiform

Table 32-8 Lipoblastoma

864

Clinical Features Children Boys > girls Extremities Localized or diffuse Histopathologic Features Lipoblasts Lobular growth pattern Mature adipose tissue Differential Diagnosis ALT/WDL

 FIGURE 32-11 Lipoblastoma. Fibrous septae dividing the fatty tumor into lobules with varying degrees of maturation.

capillary network, and a myxoid matrix resemble myxoid liposarcoma. Lesions with mature adipocytes interspersed with lipoblasts and spindled or stellate mesenchymal cells resemble WDL. In general, however, nuclear atypia is absent in contrast to that in liposarcoma. Maturing lipoblastomas display few lipoblasts but still have distinct lobularity and possibly increased vascularity.41 Fibrous septa may be pronounced. Signet ring and multivacuolated lipoblasts are both present. In contrast to liposarcomas, rearrangements of chromosome 8 are often found cytogenetically.42 Although lipoblastomas are asymptomatic and lack metastatic potential, they may cause dysfunction of other organ systems due to mass effect. Complete surgical excision with clinical follow-up is the preferred therapy.43 DIFFERENTIAL DIAGNOSIS The primary differential diagnosis is with WDL/ALT. Liposarcoma is rare in children, and the diagnosis must be made with caution. Liposarcomas in children occur at an older age, are more common in girls, are often located in the thigh, and usually involve deep soft tissues rather than subcutaneous sites.44 Histologically, they are less uniformly lobular than lipoblastoma, often show increased cellularity at the periphery of tumor lobules, and have more nuclear atypia. As previously mentioned, lipoblastomas exhibit maturation with time. Cytogenetic analysis may be of value in difficult cases.

Malignant Neoplasms Malignant adipocytic tumors as a group exhibit considerable morphologic and genetic heterogeneity. Histologic observation and genetic studies over the past decade have been successfully integrated. This has resulted in significant changes to the way these tumors are categorized, as reflected in the most recent WHO classification (Table 32-9). New concepts regarding their relationship to one another as well as their biologic potential pose controversial questions and are a source of considerable debate.

Liposarcoma Liposarcoma is the most common soft tissue sarcoma in adults and accounts for approximately 20% of all mesenchymal malignancies.45 Liposarcomas are most common in deep soft tissues, especially the thigh and retroperitoneum;

Table 32-9 WHO Classification of Malignant Adipocytic Tumors ALT/WDL Myxoid liposarcoma Round cell liposarcoma Pleomorphlic liposarcoma Dedifferentiated liposarcoma Mixed-type liposarcoma

Well-Differentiated Liposarcoma/Atypical Lipomatous Tumor WDL of deep soft tissues is a wellrecognized entity. When the same lesion occurs subcutaneously or in an intramuscular location, the preferred term is ATL. This distinction is made to indicate the markedly better prognosis of the latter, perhaps related to earlier detection and easier wide excision.49,50 However,

A

Table 32-10 Atypical Lipomatous Tumor/ Well-Differentiated Liposarcoma

Clinical Features Adults Proximal extremities (for atypical lipomatous tumor) Histopathologic Features Mature adipose tissue with variably sized adipocytes Hyperchromatic stromal cells Lipoblasts Differential Diagnosis Lipoma Pleomorphic lipoma Lipoblastoma

both terms describe lesions identical both morphologically and karyotypically, thus the different terms are essentially synonyms. Terminologic preference depends heavily on liaison between surgeon and pathologist, and in most instances we prefer to use both terms in the histology report. In this chapter we will use the term ALT/WDL. CLINICAL FEATURES WDL occurs in adults of either gender, mainly in the fourth to eighth decades of life (Table 32-10). Subcutaneous tumors are well circumscribed, 2 to 20 cm in diameter (mean 10 cm), and have a predilection for the upper and lower limb girdles. In subcutaneous lesions, recurrence is relatively infrequent. Metastases do not occur in an otherwise conventional well-differentiated liposarcoma. However, dedifferentiation may

take place with subsequent metastatic potential in deep, and rarely superficial, lesions.51 HISTOPATHOLOGIC FEATURES Histologically, these lesions superficially resemble lipomas. However, the adipocytes vary in size, and fibrous septae containing hyperchromatic pleomorphic stromal cells are often present. A varying number of monovacuolated or multivacuolated lipoblasts may be seen (Fig. 32-12). It is important to emphasize that the presence of lipoblasts does not make, and is not required, for a diagnosis of liposarcoma. Lipoblasts are strictly defined by the presence of single or multiple discrete, optically clear, round and sharply demarcated cytoplasmic vacuoles that indent an enlarged hyperchromatic nucleus. When these atypical cells are identified among the adipocytes, the term lipoma-like liposarcoma is used. When the atypical cells are associated with a predominant diffuse pattern of fine fibrosis and a relatively sparse adipocytic component, the term sclerosing liposarcoma is used. Some tumors have areas with spindle cells and have been termed spindle cell liposarcoma.52 Cytogenetically, WDLs are associated with a ring or giant chromosome derived from the long arm of chromosome 12q13-15, leading to amplification of the protooncogenes MDM2 and CDK4.53,54 DIFFERENTIAL DIAGNOSIS It must be emphasized that a number of entirely benign adipocytic tumors, such as lipoblastoma and pleomorphic lipoma, may contain lipoblasts. Thus, the presence of

CHAPTER 32 ■ TUMORS OF ADIPOSE TISSUE, MUSCLE, CARTILAGE, AND BONE

however, they also occur, albeit relatively infrequently, in subcutaneous sites and rarely even in the dermis.46 The current WHO classification includes one neoplasm in the intermediate category and five categories of malignant fatty neoplasms with incorporation of relevant genetic findings.47 The solitary entity within the intermediate (locally aggressive) category is ALT/WDL. Five distinct variants are recognized in the malignant category: myxoid liposarcoma, round cell liposarcoma, pleomorphic liposarcoma, dedifferentiated liposarcoma, and mixed liposarcoma.10 Despite this formal segregation, functionally, it is convenient to regard them as kindred entities, with dedifferentiated liposarcoma representing a unique biologic event occurring exclusively within ALT or WDL and myxoid or round cell liposarcoma representing a spectrum of the same entity. Taken together, most series show a male predominance and a mean age of 50 years (range, 30-80 years).48 However, myxoid or round cell tumors tend to occur 10 years earlier than welldifferentiated and pleomorphic tumors.

B

 FIGURE 32-12 Well-differentiated liposarcoma or atypical lipomatous tumor. (A) A variably-sized adipocytes with scattered hyperchromatic stromal cells. (B) A single multivacuolated lipoblasts (center of the field), hyperchromatic stromal cells, and adipocytes.

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PART IV ■ PROLIFERATIONS—HAMARTOMAS, HYPERPLASIAS, AND NEOPLASIAS 866

lipoblasts does not equate to a diagnosis of malignancy.45 With this in mind, the differential diagnosis includes benign, reactive, and malignant processes. The differential diagnosis includes lipoma, pleomorphic lipoma, spindle cell lipoma, lipoblastoma, xanthomatous reactions, fat necrosis, diffuse neurofibroma, and dermatofibrosarcoma protuberans (DFSP). The hyperchromatic stromal cells distinguish this tumor from a lipoma. Pleomorphic lipomas have a rather well-defined clinical context (see the preceding text), and floret cells are usually noted rather than the smudgy atypical cells observed in WDL. Spindle cell lipomas have distinctive ropey (thick bundles of) collagen and usually lack lipoblasts. Lipoblastomas may be identical but generally occur in children younger than 7 years of age, when the diagnosis of liposarcoma is rare, indeed. Xanthomatous reactions have numerous foamy cells rather than cells with large, fat vacuoles (adipocytes); are associated with inflammation; and lack atypia. Likewise, fat necrosis shows aggregates of foamy histiocytes and lacks atypia. Spindle cell liposarcoma may be confused with either diffuse neurofibroma or DFSP. Recognition of the atypical adipocytes is most important for the correct diagnosis. Immunoreactivity for S-100 protein in neurofibroma and CD34 in DFSP may be helpful. Detection of MDM2-CDK4 amplification by varying techniques, including fluorescence in situ hybridization, immunohistochemistry, and reverse transcription polymerase chain reaction (RT-PCR), may be helpful in difficult cases.53

A

B  FIGURE 32-13 Dedifferentiated liposarcoma. (A) Abrupt transition from well-differentiated liposarcoma/atypical lipomatous tumor (right) to a dedifferentiated liposarcoma (left). (B) The dedifferentiated component is nonlipogenic. Immunohistochemistry for MDM2 is confirmatory (inset).

Dedifferentiated Liposarcoma CLINICAL FEATURES Dedifferentiated liposarcoma usually presents as a longstanding, painless mass exhibiting a recent increase in size.10 Dedifferentiation may occur in either the primary tumor (90%) or in a recurrence (10%) generally in deep soft tissues, though rarely in superficial anatomic sites.55 Although up to 50% recur and at least 15% metastasize, patients with these dedifferentiated tumors may have a better prognosis than patients with other “pleomorphic” sarcomas, even in the presence of heterologous differentiation.56 HISTOPATHOLOGIC FEATURES Dedifferentiated liposarcoma is a malignant adipocytic neoplasm that morphologically exhibits an abrupt transition from WDL to nonlipogenic sarcoma (Fig. 32-13). The dedifferentiated component is often a high-grade sarcoma

but may also be a low-grade spindle cell or myxoid sarcoma. Some are composed mainly of dedifferentiated areas with a largely obscured or absent a welldifferentiated component. The dedifferentiated component may display heterologous differentiation, generally toward rhabdomyosarcoma, osteosarcoma, or chondrosarcoma. Recently, the degree of cellularity and mitotic activity required for the diagnosis of dedifferentiation has come under question. Traditionally, dedifferentiated liposarcoma consists of a combination of WDL and a cellular nonlipogenic sarcoma having significant mitotic activity (at least 5 mitotic figures per 10 highpower fields [hpf]).57 A diagnostic dilemma arises when WDLs contain areas whose cellularity and mitotic rate are increased but lower than in the classically defined dedifferentiated component of dedifferentiated liposarcoma. Although some

consider this finding to represent “lowgrade dedifferentiation,” this term has come under recent scrutiny because it has no effect on patient survival and may be best regarded as part of the spectrum of findings within ALT/WDL.58,59 DIFFERENTIAL DIAGNOSIS Several studies have shown that many sarcomas previously diagnosed as malignant fibrous histiocytomas, fibrosarcomas, and malignant hemangiopericytomas likely represented dedifferentiated liposarcomas.60,61 This serves to underscore the wide morphologic spectrum of dedifferentiated liposarcoma and the subsequent need to include this entity when considering the differential diagnosis of many malignant mesenchymal neoplasms. The potential for heterologous differentiation within dedifferentiated liposarcoma further complicates this matter. Those with more low-grade appearance may

be confused for leiomyosarcoma and dermatofibrosarcoma, but those with more high-grade histology should be differentiated from pleomorphic rhabdomyosarcoma and metastatic melanoma. Identification of a well-differentiated component or immunohistochemistry for MDM2 and CDK4 can be key to the diagnosis.62

Myxoid Liposarcoma

HISTOPATHOLOGIC FEATURES Pure myxoid liposarcoma consists of a uniform myxoid matrix, a characteristic “chicken wire”–like plexiform capillary network; numerous small relatively bland spindle cells; and a variable number of small lipoblasts, commonly of signet ring or bivacuolated type (Fig. 32-14 and

A

Clinical Features Adults Proximal extremities (for atypical lipomatous tumor) Histopathologic Features Mature adipose tissue Myxoid matrix Lipoblasts, often signet ring–like Chicken wire–like capillary network Differential Diagnosis Myxofibrosarcoma

Table 32-11). The most characteristic feature is the capillary network. The capillaries are evenly spaced, thin-walled, and slightly curved. Frequently, the myxoid matrix may coalesce to form acellular pools with an alveolar appearance. Round cell change in myxoid liposarcoma is characterized by a significant increase in cellularity, with nuclear overlapping and obscuring of the capillaries (Fig. 32-14B). The cells are smaller than adipocytes and have enlarged hyperchromatic nuclei and prominent nucleoli. The cytoplasm may be scant or vacuolated. Despite the aggressive nature of the lesion (including eventual metastasis in more than 50% of patients), mitoses are usually sparse. Myxoid liposarcoma may display areas of increased cellularity in which the cells remain spindled, do not have overlapping nuclear borders, and retain an easily discernible plexiform

vascular pattern. This histologic finding, termed transitional areas, should not be confused for a round cell component because it carries no effect on prognosis.63,66 Pure round cell liposarcoma is a rare neoplasm in which round cell differentiation accounts for more than 80% of the tumor.45 Cytogenetically, myxoid or round cell liposarcoma almost always has a t(12;16) (q13;p11) translocation that fuses the transcription factor gene CHOP on chromosome 12 to the TLS/FUS gene on chromosome 16.67 Rarely, a t(12;22) translocation linking the EWSR1 gene with the DDIT3 gene occurs.68 DIFFERENTIAL DIAGNOSIS Myxoid liposarcoma may be confused with soft tissue myxoma, superficial angiomyxoma, and myxofibrosarcoma. Myxomas are less cellular, lack the vascular network, and do not contain lipoblasts. Angiomyxomas lack lipoblasts and are characterized by numerous isolated vessels rather than a plexiform network of capillaries. Myxofibrosarcoma, similar to myxoid liposarcoma, is characterized by a prominent vascular network and spindle cells. However, the vessels are not as profuse and are typically thicker and straighter than those in myxoid liposarcoma, and the spindle cells are more atypical in myxofibrosarcoma. In addition, lipoblasts are not present, and the lesion often has a distinctly multinodular growth pattern. When a tumor is purely round cell, the diagnosis may be very difficult and requires a thorough search for lipoblasts. This type of liposarcoma also distinctively shows S-100 protein

CHAPTER 32 ■ TUMORS OF ADIPOSE TISSUE, MUSCLE, CARTILAGE, AND BONE

CLINICAL FEATURES The clinical presentation of myxoid liposarcoma is similar to that of WDL, although it usually occurs at an earlier age and arises in the lower limb (particularly the thigh) in the vast majority of cases. Similar to WDL, pure myxoid liposarcoma is a low-grade tumor. Myxoid liposarcoma is unique in that metastases tend to occur in unusual soft tissue sites, such as the extremities and chest wall, rather than the visceral organs. Transformation to a higher-grade lesion with a variably prominent round cell component may occur (round cell liposarcoma), conferring a poorer prognosis.63,64 The quantity of round cell differentiation has prognostic significance, with tumors exhibiting 5% to 25% round cell component displaying a lower rate of metastasis than those exceeding 25% (metastasis rate, 35% versus 58%).65

Table 32-11 Myxoid Liposarcoma/Round Cell Liposarcoma

B

 FIGURE 32-14 Myxoid liposarcoma. (A) Arborizing “chicken wire” vasculature and bland mesenchymal cells characterize the typical myxoid liposarcoma. No lipoblasts are seen in this field. (B) Nodules of round cell differentiation (round cell liposarcoma) confer a poor prognosis. A few lipoblasts can be identified.

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Table 32-12 Pleomorphic Liposarcoma

PART IV ■ PROLIFERATIONS—HAMARTOMAS, HYPERPLASIAS, AND NEOPLASIAS

Clinical Features Adults Deep soft tissues Histopathologic Features Pleomorphic cells Spindle cells Lipoblasts Differential Diagnosis Myxofibrosarcoma Pleomorphic lipoma Pleomorphic rhabdomyosarcoma

868

positivity in the nonlipogenic cells in most cases. Fluoresence in situ hybridization may be useful in diagnostically challenging cases.69

Pleomorphic Liposarcoma CLINICAL AND HISTOPATHOLOGIC FEATURES Pleomorphic liposarcomas are the least common type of liposarcoma, they occur most often in elderly individuals, and subcutaneous examples are especially rare (Table 32-12). These tumors generally exhibit three morphologic pictures: a high-grade pleomorphic spindle cell sarcoma containing scattered multivacuolated lipoblasts, a cellular neoplasm containing sheets of bizarre pleomorphic monovacuolated as well as multivacuolated lipoblasts (Fig. 32-15), and an epithelioid variant composed of sheets of pleomorphic epithelioid cells with distinct cell borders.70 The prognosis for patients with dermal pleomorphic liposarcomas appears to be substantially better than that of patients with more deeply seated lesions, based on a small number of reported cases.46 Cytogenetically, the majority of pleomorphic liposarcomas display complex karyotypes.71 DIFFERENTIAL DIAGNOSIS The differential diagnosis includes other pleomorphic high-grade sarcomas, such as pleomorphic rhabdomyosarcoma. The identification of lipoblasts is key. The epithelioid morphology in these pleomorphic tumors may closely simulate other malignant epithelial neoplasms, mainly adrenal cortical carcinoma.72 In this context, immunohistochemical stains must be interpreted prudently because overlap between these two entities may be seen, with focal expression of Melan-A and pan-keratin. Inhibin immunoreactivity, however, has not been reported in pleomorphic liposarcoma.72 The immunohistochemical profile of pleomorphic

 FIGURE 32-15 Pleomorphic liposarcoma. Numerous pleomorphic multivacuolated lipoblasts.

liposarcoma in nonlipogenic regions is heterogeneous; however, reactivity with S-100 protein in lipoblasts also may be helpful.73,74

TUMORS OF MUSCLE

Smooth Muscle Smooth muscle tumors occur mainly but not exclusively in adults (Tables 32-13 and 32-14). Determining the prognosis of these lesions may be a difficult task for the pathologist. Prognosis is very dependent on site. Extremely bland lesions in

Table 32-13 WHO Classification of Smooth Muscle Tumors Angioleiomyoma Deep leiomyoma Genital leiomyoma Leiomyosarcoma

Table 32-14 Generalized Approach to Tumors of Smooth Muscle Smooth Muscle No other features Vessels Mitoses, necrosis, atypia

Leiomyoma Angioleiomyoma Leiomyosarcoma

some sites may still carry a risk for recurrence, although this may occur late.

Congenital Smooth Muscle Hamartoma CLINICAL AND HISTOPATHOLOGIC FEATURES Smooth muscle hamartoma of the skin is a rare congenital lesion presenting in children up to 18 years old.75,76 Clinically, they are most common on the torso; measure up to 10 cm in diameter; and may or may not occur in association with Becker nevus (melanosis), an epidermal hamartoma exhibiting hyperpigmentation and hypertrichosis. Histologically, the lesion is composed of well-ordered noncohesive fascicles of smooth muscle arranged in various directions within the dermis and subcutaneous tissue (Fig. 32-16). Adipocytes may also be present unusually high in the dermis. There may be an artifactual cleft between the lesion and the surrounding dermis. DIFFERENTIAL DIAGNOSIS Diagnostically, the lesion may be associated with or distinct from Becker nevus, which may have similar smooth muscle hyperplasia. However, Becker nevus is usually not congenital, and the distinction is primarily clinical. Leiomyomas are also composed of smooth muscle, but the muscle bundles tend to form a single mass; in hamartoma, the bundles are discrete and surrounded by ordered collagen.

 FIGURE 32-16 Congenital smooth muscle hamartoma. Irregularly arranged smooth muscle bundles in the reticular dermis are interspersed with collagen, adipocytes, and adnexae.

Leiomyoma CLINICAL FEATURES Smooth muscle tumors of the skin and subcutaneous tissues are uncommon and can be divided into pure leiomyomas and those arising in association with vascular structures, namely angioleiomyomas.77 Pure leiomyomas have no gender preference and generally arise in early adulthood. They can be separated into those that arise in the skin and those associated with the external genitalia (including the nipple, vulva, and scrotum). Leiomyomas of the skin arise from the erector pilae muscles and tend to occur on the extensor surface of the extremities and the trunk (Table 32-15). They are often multiple, painful, firm reddish-brown papules or nodules, commonly smaller than 2 cm in diameter. Familial leiomyomatosis, in which multiple cutaneous and uterine leiomyomas occur, is an autosomal dominant condition, with a predisposition to an aggressive form of renal cell carcinoma.78 Nipple lesions are similar and arise from areolar smooth muscle. Genital leiomyomas arise from dartos or vulvar smooth muscle. They are solitary, painless, wellcircumscribed masses that may grow up to 15 cm in diameter and may be located in the subcutaneous tissue.77

Separation of dermal and genital leiomyomas is most important for prognosis. Small, solitary dermal leiomyomas tend not to recur. Patients with multiple dermal leiomyomas often experience recurrence (50%) and tend to develop subsequent lesions. Patients with genital leiomyomas tend usually to be disease free after 5 years of follow-up, but longer follow-up has shown the development of recurrences after periods as long as 15 years.79

Table 32-15 Pilar Leiomyoma

Clinical Features Adults Skin, nipple Painful, often multiple Histopathologic Features Fasiculated Spindle shaped (sometimes epitheloid) Boxcar-shaped nuclei Eosinophilic cytoplasm Differential Diagnosis Leiomyosarcoma Benign fibrous histiocytoma Dermatofibrosarcoma protuberans

DIFFERENTIAL DIAGNOSIS The differential diagnosis for these lesions includes dermatofibroma, DFSP, neurofibroma, fibromatosis, and leiomyosarcoma. Dermatofibroma is less fascicular, the cells tend to be rounder and more polymorphic and may surround collagen, and foamy macrophages may be present. DFSP has spindle cells, but these tend to be wavy rather than straight, have pale rather than eosinophilic cytoplasm, form storiform patterns rather than fascicles, and are CD34 positive. Neurofibroma also has wavy nuclei, does not form fascicles, and is immunoreactive for S-100 protein and neurofilament. Fibromatosis tends to have cells with more variable nuclei and paler cytoplasm and generally a less well-developed fascicular pattern. Low-grade leiomyosarcoma may be difficult to distinguish. Tumors larger than 2 cm that extend deep into the subcutis always should raise the suspicion of malignancy. The presence of nuclear atypia, mitotic activity of 1 or more per 50 hpf or necrosis should prompt the diagnosis of leiomyosarcoma.82

CHAPTER 32 ■ TUMORS OF ADIPOSE TISSUE, MUSCLE, CARTILAGE, AND BONE

HISTOPATHOLOGIC FEATURES Histologically, dermal pilar leiomyomas are composed of numerous fascicles of smooth muscle and variable amounts of collagen arranged randomly throughout the dermis or subcutaneous tissue (Fig. 32-17). They are unencapsulated and infiltrative; involvement of hair follicles and adnexal glands is typical. The cells have abundant eosinophilic cytoplasm that may have a perinuclear vacuole; the nuclei are oval with blunt ends and evenly dispersed chromatin. Genital tumors are larger, usually better circumscribed, and centered in the subcutaneous tissues. They may have a pseudocapsule, focal calcifications, stromal myxoid change, and focal mitotic activity.79 Any mitotic activity in a smooth muscle tumor with any degree of nuclear atypia should raise the suspicion of malignancy.80,81

Angioleiomyoma (Angiomyoma, Vascular Leiomyoma) CLINICAL FEATURES Angioleiomyomas are solitary, often painful tumors of adults (average age, 47 years) with a predilection for women (Table 32-16). They occur mainly in the lower extremities, especially the lower leg and foot.83 The lesion is benign and only rarely recurs. HISTOPATHOLOGIC FEATURES Histologically, angioleiomyomas are well-circumscribed solid masses composed of coalesced vessels with prominent walls

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A

B

 FIGURE 32-17 Pilar leiomyoma. (A) Short, intersecting fasicles of bland spindled cells with eosinophilic cytoplasm and boxcar-shaped nuclei. (B) At the deep aspect, the tumor entraps adnexal structures.

consisting of smooth muscle and collagen (Fig. 32-18). They are commonly located in the subcutis. They have been divided into three types, termed solid, cavernous, and venous.83 The vascular lumina are usually compressed, but they are occasionally large and dilated in the cavernous angioleiomyoma. The muscle of the vessel walls forms irregular, often concentric bundles that merge with those of their neighbors. Stromal hyalinization or myxoid change is common. Rarely, mature adipose tissue is present. Small nerve fibers are detectable immunohistochemically.84 Atypia, mitoses, and necrosis are not seen.

poorly circumscribed and lacks the vascular spaces, and the muscle does not emerge from vascular walls. Most leiomyosarcomas also lack the vascular spaces, although vascular leiomyosarcomas have also been described.85 Most important, leiomyosarcomas have cytologic atypia, mitoses, and necrosis. Cutaneous angiolipoleiomyomas (also reported as angiomyolipomas) are rare tumors composed of mature adipose tissue, smooth muscle, and vessels.86 They lack expression of melanocytic markers and

likely represent involutional metaplasia in an angioleiomyoma. Myopericytomas may exhibit immunohistochemical and morphologic overlap with angioleiomyoma. The perivascular concentric arrangement of cells, which is a salient feature of myopericytoma, is a useful feature.87

Leiomyosarcoma CLINICAL FEATURES Superficial (ie, dermal and subcutaneous) leiomyosarcoma is most common between the ages of

DIFFERENTIAL DIAGNOSIS The lesion should be distinguished from pilar leiomyoma and leiomyosarcoma. Leiomyoma is

Table 32-16 Angioleiomyoma

Clinical Features Adults; female predominance Lower extremities Painful, often solitary Histopathologic Features Well-circumscribed Blood vessels Smooth muscle of vessel walls in irregular concentric bundles Three variants: solid, cavernous, venous Stromal hyalinization Myxoid change Differential Diagnosis Leiomyoma Leiomyosarcoma Hemangioma

 FIGURE 32-18 Angioleiomyoma. Bland smooth muscle fibers intimately merge with smooth muscle cells in the wall of blood vessels.

HISTOPATHOLOGIC FEATURES Histologically, leiomyosarcomas, particularly of the dermis, may closely resemble their benign counterparts with well-formed fascicles of spindle cells with abundant eosinophilic cytoplasm and elongated, blunt-ended nuclei (Table 32-17 and Fig. 32-19). The nuclei may be more vesicular and have nucleoli. The fascicles typically run at right angles to each other. Unlike leiomyomas, most tumors display some pleomorphism, mitotic activity, or necrosis;

Table 32-17 Leiomyosarcoma

Clinical Features Adults Extremities Dermal or subcutaneous Histopathologic Features Smooth muscle Mitoses Atypia Necrosis Differential Diagnosis Leiomyoma Benign fibrous histiocytoma Dermatofibrosarcoma protuberans Spindle cell rhabdomyosarcoma Malignant melanoma Granular cell tumor Metastasis

however, well-differentiated tumors may be difficult to differentiate from leiomyomas. Some tumors are epithelioid and are composed of rounded cells that do not form fascicles and often have clear cytoplasm. These are more common in the head and neck.93 Rarely, these tumors may exhibit cells with abundant granular cytoplasms.94 As with leiomyomas, the matrix may undergo myxoid degeneration or become desmoplastic, obscuring

 FIGURE 32-19 Leiomyosarcoma. Fascicles of spindled cells with eosinophilic cytoplasm and hyperchromatic nuclei. Brisk mitotic activity is present (inset).

the diagnosis.95,96 Dermal lesions are often highly infiltrative; by contrast, subcutaneous lesions appear more circumscribed. Immunohistochemically, these tumors are typically reactive for actin and often desmin, and some ( Females Head and neck, urogenital region, extremities Histopathologic Features Small, round, blue cells Eosinophilic cytoplasm Strap or tadpole cells Solid or alveolar pattern Differential Diagnosis Ewing sarcoma/PNET Lymphoma Neuroblastoma Poorly differentiated synovial sarcoma Rhabdomyoma

 FIGURE 32-22 Embryonal rhabdomyosarcoma. Primitive small, round, blue cells with scattered ovoid and spindled rhabdomyoblasts exhibiting more abundant eosinophilic cytoplasm.

Mitoses and necrosis may be present. When submucosal, the lesion may present as a polypoid mass protruding into the lumen, and there may be a so-called cambium layer characterized by increased cellularity immediately beneath the epithelium. This subtype is termed botryoid. Another subtype, predominantly in the paratesticular region, has spindle cells in a fascicular or storiform pattern and is termed spindle cell rhabdomyosarcoma.101,102 Immunohistochemically, reactivity for muscle actin, desmin, myo-D1, and myogenin are characteristic.117 Ultrastructurally, alternating thin and thick filaments with occasional Ζ bands can be demonstrated. Focal anaplastic features may be seen, as well as bizarre multipolar mitotic figures. Whether these findings portend a worse outcome is still unclear.118 Allelic loss in chromosomal region 11p15 is seen in most embryonal rhabdomyosarcomas.119 Patients with Beckwith-Wiede-mann syndrome exhibit similar genetic losses, and not surprisingly, are at increased risk of developing embryonal rhabdomyosacoma, among other tumors. 120 Recently, a peculiar type of adult rhabdomyosarcoma characterized by prominent hyaline sclerosis and a pseudovascular growth pattern has been described. This variant has been termed sclerosing rhabdomyosarcoma.121,122 The relationship between sclerosing rhabdomyosarcoma

and conventional rhabdomyosarcoma remains uncertain, although cytogenetic studies suggest a link with embryonal rhabdomyosarcoma.123 DIFFERENTIAL DIAGNOSIS The differential diagnosis is long and encompasses a variety of malignant round cell tumors. Both Ewing sarcoma/primitive neuroectodermal tumor (PNET) and lymphoma usually display more uniformity in cellular size and shape than the majority of rhabdomyosarcomas and obviously lack muscle markers (desmin, myo-D1, myogenin). CD99, a highly sensitive marker of Ewing sarcoma/PNET, is also present focally in rhabdomyosarcomas and thus potentially represents a diagnostic pitfall to those unfamiliar with this fact. Neuroblastoma is distinguished by a background of neutropils, focal or partial ganglionic differentiation, and reactivity for neural markers. The spindle cell subtype of rhabdomyosarcoma may be confused with a leiomyosarcoma or fibrosarcoma. Both lesions are uncommon in children. Leiomyosarcoma does not have cross-striations by light microscopy and does not express myoD1 or myogenin. Rhabdomyoblastic heterologous differentiation may be seen in a variety of neoplasms, generally as a focal histologic finding. These include germ cell tumors, malignant peripheral nerve sheath tumor (malignant Triton tumor), metastatic Wilms

tumor, and congenital melanocytic nevus. Care must be taken when interpreting myogenic markers because they may be expressed in entrapped atrophic muscle.124 Due to the presence of heavily hyalinized collagenous matrix and occasional pseudovascular growth pattern, sclerosing rhabdomyosarcoma is frequently misdiagnosed as angiosarcoma, chondrosarcoma, or osteosarcoma.121

Alveolar Rhabdomyosarcoma

HISTOPATHOLOGIC FEATURES The initial descriptions emphasized the alveolar pattern, with cells lining up against thin fibrous septa to produce small spaces resembling lung tissue (Fig. 32-23). The cells may have a hobnail appearance and are discohesive, with isolated cells lying free within these spaces. In contrast to embryonal rhabdomyosarcoma, the cells tend to be round rather than oval with larger nuclei and sometimes with more abundant eosinophilic cytoplasm. Multinucleated cells with the nuclei forming a peripheral wreath are a characteristic finding, and some cases have strap cells as well. Greater emphasis has been placed on the nuclear rather than the architectural features.127 Cases with a solid pattern without any evidence of alveolar septa but containing cells with larger, more pleomorphic nuclei, coarse chromatin, and prominent nucleoli may occur. ARMS is associated with t(2;13) or t(1;13) chromosomal translocations, which generate PAX3FKHR and PAX7-FKHR fusion products, respectively. Distinction from Ewing’s sarcoma/PNET can be made by cytogenetic analysis or reverse transcriptase polymerase chain reaction.129,130 DIFFERENTIAL DIAGNOSIS The alveolar pattern may suggest a vascular or epithelial neoplasm. Markers for CD31, CD34, and keratin are most helpful in these situations. As with embryonal rhabdomyosarcoma in fact, more so in view of the larger nuclear size, Ewing sarcoma/PNET is also in the differential. The more prominent eosinophilic cytoplasm, the eccentric

 FIGURE 32-23 Alveolar rhabdomyosarcoma. Aggregates of small, round, blue cells exhibiting a central loss of cohesion separated by hyalinized fibrous septae.

nuclei, and desmin staining are again helpful. Lymphoma is ruled out by reactivity for CD45.

Pleomorphic Rhabdomyosarcoma CLINICAL AND HISTOPATHOLOGIC FEATURES Pleomorphic rhabdomyosarcoma is a

 FIGURE 32-24 Pleomorphic rhabdomyosarcoma.

high-grade sarcoma that occurs almost exclusively in older adults (median, sixth decade of life). The limbs and limb girdles are the most common locations. Histologically, the tumor is composed of bizarre large polygonal and spindle cells with abundant eosinophilic cytoplasms forming irregular fascicles (Fig. 32-24).131

CHAPTER 32 ■ TUMORS OF ADIPOSE TISSUE, MUSCLE, CARTILAGE, AND BONE

CLINICAL FEATURES Alveolar rhabdomyosarcomas (ARMs) are most common in adolescent boys and young men. The average age at presentation (12 years) is distinctly older than that of embryonal tumors (6 years) and younger than that of the pleomorphic subtype (50 years).125-127 Most tumors arise in the extremities, usually intramuscularly. ARMS carry a poorer prognosis compared with embryonal rhabdomyosarcoma.128

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Cytogenetically, these tumors have complex karyotypes. Increasing age and stage and deep location are poor prognostic factors.10 DIFFERENTIAL DIAGNOSIS The differential diagnosis includes pleomorphic leiomyosarcoma. Myo-D1 and myogenin are somewhat less often positive in pleomorphic rhabdomyosarcoma than in other types of rhabdomyosarcoma.132 Demonstration of myoid differentiation should be sought, as clinically, pleomorphic rhabdomyosarcomas carry a worse prognosis compared with undifferentiated pleomorphic sarcomas.133 Ultrastructural demonstration of Z bands may be necessary for definitive separation. As mentioned previously, focal heterologous rhabdomyoblastic differentiation may be seen with a variety of tumors, including dedifferentiated liposarcoma, malignant peripheral nerve sheath tumor, and carcinosarcoma.

TUMORS OF CARTILAGE Cartilage tumors in the skin and subcutaneous sites are infrequent (Table 32-23). Most occur in the hands and feet and are benign despite worrisome histologic features. In large cartilaginous masses occurring in superficial sites and showing significant cytologic atypia, the possibility of local spread or metastasis from a primary bone tumor always should be considered. Extraskeletal mesenchymal chondrosarcoma virtually never involves skin or subcutaneous tissue and is not discussed further here.

Extraskeletal Chondroma CLINICAL AND HISTOPATHOLOGIC FEATURES Extraskeletal chondromas are uncommon and present mainly in the hands and feet of adults in their fourth and fifth decades.134-136 They are solitary, well circumscribed, and usually smaller than 2 cm in greatest diameter, although large tumors have been reported occasionally. They are composed of variably cellular but generally mature hyaline

Table 32-23 WHO Classification of Chondro-Osseous Tumors

876

Soft tissue chondroma Mesenchymal chrondrosarcoma Extraskeletal osteosarcoma

 FIGURE 32-25 Soft tissue chondroma. A pseudoencapsulated cartilaginous tumor with focal hypercellularity.

cartilage that may calcify and even ossify (Fig. 32-25). Plump chondroblasts and giant cells may be present. Myxoid areas and fibrosis may occur. In one series, all lesions had areas with marked nuclear pleomorphism, hyperchromasia, binucleation, and myxoid change. The lesion may appear more mature peripherally. Although these lesions may recur, multiple recurrences and metastases have not been reported in cases occurring in typical sites. DIFFERENTIAL DIAGNOSIS The differential diagnosis includes osteochondroma, fibroosseous pseudotumor, synovial chondromatosis, giant cell tumor of tendon sheath, tumoral calcinosis, extraskeletal chondrosarcoma of myxoid or mesenchymal types, and mixed tumor (chondroid syringoma). Osteochondromas, as well as periosteal and juxtacortical chondromas, can be distinguished radiographically. Fibroosseous pseudotumor is discussed in the following pages. Calcifying aponeurotic fibroma occurs in the hands of young adults and exhibits small foci of cartilaginous metaplasia within a densely fibrous background. Synovial chondromatosis is located within a joint or synovial tissue and usually consists of multiple nodules. Giant cell tumor of tendon sheath does not contain cartilage. Tumoral calcinosis contains abundant basophilic debris, and although it may show vaguely chondroid

foci, it does not contain true hyaline cartilage. Extraskeletal myxoid chondrosarcoma has more prominent myxoid rather than cartilagenous areas, is less circumscribed, has cells in chains and nests rather than isolated in lacunae, is more cellular, and has smaller cells. Mesenchymal chondrosarcoma may present in soft tissue and rarely in the hands and feet. Diagnosis requires identification of the generally predominant small cell undifferentiated component that rarely may be missing in small biopsies. Mixed tumors usually show a significant epithelial component that often contains ducts. Rarely, mixed tumors contain a single-cell dispersion of epithelium indistinguishable from chondroma. However, the epithelial cells are positive for cytokeratin or EMA. Epitheloid hemangioendothelioma enters the differential diagnosis due to the presence of myxohyaline matrix; however, this tumor is positive for the vascular markers CD31 and CD34.

Extraskeletal Myxoid Chondrosarcoma CLINICAL FEATURES Extraskeletal myxoid chondrosarcoma is uncommon and occurs mainly in adults, with a peak incidence in the fifth decade of life.137-139 Men are affected more commonly (2:1). It favors the lower extremity and may present in subcutaneous tissue. Rare

TUMORS OF BONE Primary bone-forming lesions in the skin and soft tissues are unusual; the most common lesion is myositis ossificans, a reactive lesion that can mimic osteosarcoma histologically (see Table 32-21). Metaplastic bone formation in other lesions, such as pilomatrixoma or intradermal nevus, is probably more frequent and referred to as osteoma cutis.

Osteoma Cutis

cases may present in children.140 There is a 5-year survival of approximately 85%. However, the lesion is persistent, and long-term follow-up is not as favorable.141 HISTOPATHOLOGIC FEATURES Histologically, the tumor is lobulated and consists of isolated strands, ribbons, or small nests of cells in a myxoid background (Fig. 32-26). The cells are oval and small and have scant amounts of eosinophilic cytoplasm and round nuclei. Occasional cytoplasmic vacuoles can be found, but extensive vacuolization, as in the physalliphorous cells of chordoma, is not seen. Lacunae formation occurs rarely. Some areas can be quite cellular, and focal areas of true cartilage and rarely metaplastic bone can be found. Some cases have cytoplasmic rhabdoid inclusions. Mitotic activity is low (10 cm in diameter), irregularly shaped, reddish and fairly welldemarcated lesions with pityriasiform scaling are located on the trunk, extremities, or both. The prognosis for patients with SPP is exceptionally good without any influence on survival. Fatal outcome of SPP has so far not been reported.65

 FIGURE 34-11 Pagetoid reticulosis. Spongelike disaggregation of epidermis by haloed atypical lymphoid cells.

HISTOPATHOLOGIC FEATURES The epidermis shows slight acanthosis with patchy parakeratosis. Scant perivascular infiltrates of small lymphocytes may be seen in the upper dermis, with or without subtle single-cell epidermotropism. In general, a few eosinophils are present, but plasma cells are not observed (Fig. 34-12). Phenotypically, the infiltrate in SPP and LPP is mainly composed of CD4+, CD8−, and CD45RO+ T cells intermingled with a few CD8+ cells. Clonal rearrangement of TCR genes is found occasionally in SPP and LPP.64,66

CHAPTER 34 ■ LYMPHOID, LEUKEMIC, AND OTHER CELLULAR INFILTRATES

 FIGURE 34-10 Granulomatous slack skin. Dense lymphoid infiltrate in all dermal layers with a prominent scattered multinucleated giant cell exhibiting numerous peripherally located nuclei.

Although described more than 100 years ago,62 there is considerable debate on the terminology and nosologic relation of parapsoriasis (PPS) to MF. A subset of patients with large-plaque PPS (LPP) shows progression from LPP to overt MF.63,64 Thus, some authors, including ourselves, consider LPP as variant of MF with usually very slowly progressive course and low-grade potential for evolution to conventional MF. In contrast to LPP, in our experience small-plaque PPS (SPP) behaves biologically similar to a chronic benign inflammatory disorder. In our opinion, SPP does not represent a precursor of MF.

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lymphomatoid papulosis (type B) and tumor-stage lesions of MF from CD30+ anaplastic large-cell lymphoma as well as from peripheral T-cell lymphoma, not otherwise specified, which may present with identical cytomorphology.

Sézary Syndrome

PART IV ■ PROLIFERATIONS—HAMARTOMAS, HYPERPLASIAS, AND NEOPLASIAS

SS is a leukemic and erythrodermic peripheral T-cell NHL with distinct clinical features, circulating tumor cells, and lymphadenopathy72,73 (Table 34-5). It is listed as a separate entity in the WHO-EORTC classification.3,4

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 FIGURE 34-12 Parapsoriasis (small plaque form). Sparse perivascular lymphocytic infiltrate. No significant epidermotropism is seen. Subtle acanthosis and focal parakeratosis is present.

DIFFERENTIAL DIAGNOSIS The major differential diagnosis of SPP and LPP includes early-stage MF and chronic eczema, which usually cannot be distinguished on histologic grounds alone. Additional information, including clinical presentation and course of the disease, are needed for the diagnosis. However, in some cases, only the stable course of the condition without progression allows one to differentiate SPP from MF retrospectively. OTHER VARIANTS OF MF Other variants include bullous, verrucous, or hyperkeratotic; pustular and acanthosis nigricans–like; and hypo- and hyperpigmented and purpuric forms of MF.44,67,69 IMMUNOPHENOTYPIC FEATURES OF MF The characteristic phenotype in classic MF is CD3+, CD4+, CD45RO+, CD8−, CD30−, and βF1+ (TCRβ+). Rare cases display a CD3+, CD4−, CD8+ cytotoxic/ suppressor T-cell phenotype or a CD4−, CD8−, or a CD56+ phenotype. CD8+ MF and CD56+ cases often manifest with hypo- or hyperpigmented patches and plaques but behave biologically identical to classic CD4+ MF.68,69 Poikiloderma is also a common feature of CD56+ variants of MF. Loss of T-cell antigens such as CD2, CD5 or CD7 is commonly found, with CD7 being expressed in one-third of the lesions. In the tumor stage, an aberrant phenotype with loss of several T-cell antigens and occurrence of CD30 expression are common findings.

GENOTYPIC FEATURES OF MF Clonal rearrangement of TCR beta or gamma chain genes can be detected in most (90%) plaque- and tumor-stage MF lesions.16 In cases with extracutaneous involvement, the same clone may be detected in either site. In early-stage MF, however, a clonal T-cell population is only found in half of the biopsies from patch lesions. This finding limits the value of detection of clonal T-cells as a diagnostic marker in early stage MF. Many structural and numerical chromosomal abnormalities on several chromosomes, such as chromosomes 1, 6, 8, 9, 11, 13, 15, and 17, have been identified in MF, with most of them being more common in patients with advanced stage disease.21 Chromosomal loss at 10q and abnormalities in p15, p16, and p53 tumor suppressor genes are commonly found in patients with MF.70 DIFFERENTIAL DIAGNOSIS In the early stages of MF, differentiation from chronic eczema and SPP on histologic grounds alone may be challenging or even impossible. Loss of T-cell antigens is a useful adjunctive diagnostic marker but is not definitive. Clinicopathologic correlation is mandatory in appropriate diagnosis and management of patients.71 Differentiation of plaque-stage MF from SS is based on clinical and hematologic parameters. PR shows characteristic clinical features and a prominent epidermotropic infiltrate of haloed cells. The patient’s history and clinical presentation are crucial to distinguish patch- and plaque-stage MF from

CLINICAL FEATURES SS is characterized by an erythroderma with scaling and edematous swelling of the skin, palmoplantar hyperkeratosis, hair loss, onychodystrophy, and enlargement of lymph nodes and intense pruritus. Infiltration of bone marrow is a rare event. SS affects patients in their 5th to 7th decades of life. The prognosis is worse than in MF, with a 5-year-survival rate of 24%.3 Transformation may occur in the skin with ulcerated tumors or in the lymph nodes.74 In the advanced stages, tumorous infiltration may result in leonine facies. HISTOPATHOLOGIC FEATURES In most cases, a nonspecific perivascular or bandlike infiltrate with or without atypical lymphocytes is observed.40,75,76 Epidermotropism of atypical lymphocytes with formation of

Table 34-5 Sézary Syndrome

Clinical Features Pruritic erythroderma with edematous swelling of the skin Palmo-plantar hyperkeratosis Alopecia and onychodystrophy Lymphadenopathy Histopathologic Features Bandlike infiltrate and edema in the upper dermis Epidermotropism with Pautrier abscesses in only 40% of the biopsies Small lymphocytes with or without convoluted or cerebriform nuclei Immunohistologic Features CD2+, CD3+, CD5+, CD8−, CD30−, CD45RO+ Peripheral blood: >1000 Sézary cells/mm3; CD4/CD8 ratio >10 Differential Diagnosis Red man syndrome/idiopathic erythroderma Generalized (atopic) eczema Drug reactions Mycosis fungoides

A

B

Pautrier microabscesses (ie, collections) is found in only up to 40% of biopsies76 (Fig. 34-13). Lymph nodes may show dermatopathic changes without histologic signs of involvement by tumor cells. Specific involvement is characterized by the effacement of lymph nodes by small cerebriform tumor cells. In transformation of SS to a high-grade lymphoma, dense sheets of large lymphoid cells with pleomorphic nuclei or immunoblasts are found in cutaneous tumors or lymph nodes.74 IMMUNOPHENOTYPIC AND GENOTYPIC FEATURES The lymphoid cells express CD2+, CD3+, CD5+, CD45RO+, CD8−, and CD30−. There is clonal rearrangement of TCR genes in most of the cases in skin infiltrates, peripheral blood, and tumor-affected lymph nodes. DIAGNOSIS AND DIFFERENTIAL DIAGNOSIS Based on the histologic features, SS cannot be distinguished from MF in the patch or plaque stage.77 Similar clinical and histologic changes are seen in the “red man syndrome,”78 or “pre-Sezary syndrome”,79 generalized eczema, and drug reactions.80 CD8+ cases have to be differentiated from actinic reticuloid. SS must be distinguished from erythrodermas with polyclonal lymphoid infiltrates. Detection of clonal rearrangement of TCR genes in the skin and peripheral blood, demonstration of at least 1000/mm3 Sézary cells, and the presence of a strikingly elevated CD4+ T-cell population resulting in a significantly increased CD4/CD8 ratio (>10)

are useful diagnostic criteria for the distinction of SS from other erythrodermas.72,73

Adult T-Cell Lymphoma/Leukemia (ATLL) ATLL is a systemic LPD etiologically associated with human T-cell leukemia virus I or II (HTLV-I/II), which is endemic in Japan, Central Africa, South America, and Caribbean islands. CLINICAL FEATURES Skin involvement occurs in about 50% of patients during the course of the disease81; the most prevalent form is acute ATLL, which includes papules, nodules, tumors or erythroderma, and leukemia, lymphoadenopathy, and hypercalcemia. In the chronic and smoldering forms, patients show patches and plaques resembling MF, but leukemic cells are few in number or absent. HISTOPATHOLOGIC FEATURES The skin lesions usually show a superficial or diffuse infiltrate of medium- to large-sized pleomorphic cells with or without epidermotropism.82 The findings are similar to MF. In chronic or smoldering forms, there are only a few atypical cells in a subtle perivascular infiltrate. IMMUNOPHENOTYPIC AND GENOTYPIC FEATURES The tumor cells express a CD3+, CD4+, CD8−, CD25+ phenotype.81,82 Characteristically, they express CD62L, but cases of MF and related prelymphomatous T-cell dyscrasias typically

show a loss of CD62L. In the endemic variants, integration of retroviral DNA into the host cell genome has been shown. The tumor cells are often FoxP3 positive (CD4+, CD25+). DIFFERENTIAL DIAGNOSIS Clinically and histologically, the most important differential diagnoses are MF and SS, which differ by the lack of HTLV I/II. If tumors are present, the differential diagnoses include transformation of MF and SS as well as ALCL and PTL, NOS.

Primary Cutaneous CD30+ Lymphoproliferative Disorders Primary cutaneous CD30+ LPD represent a spectrum of low-grade malignant CTCL. They are characterized by highly atypical (ie, pleomorphic and anaplastic) tumor cells expressing CD30 (Ki-1) antigen. CD30+ LPD consist of lymphomatoid papulosis (LyP), primary cutaneous (CD30+) anaplastic large cell lymphoma (CD30+ ALCL), and so-called borderline cases.2,3,83 All forms of CD30+ LPD have a tendency for spontaneous regression of tumoral lesions but also recurrences and exhibit a favorable prognosis, with 5-year-survival rates of over 90%.84,85

CHAPTER 34 ■ LYMPHOID, LEUKEMIC, AND OTHER CELLULAR INFILTRATES

 FIGURE 34-13 (A) Sézary syndrome with epidermotropism of lymphoid cells and formation of Pautrier’s microabscesses. (B) Critical to the diagnosis of Sézary syndrome are the peripheral blood abnormalities. Rendering a diagnosis of Sézary syndrome from a peripheral blood morphologic perspective requires the identification of 1000/mm3 or more Sézary cells in the peripheral blood. This particular peripheral blood smear shows a classic cerebriform lymphocyte exhibiting nuclear hyperchromasia and gyrate nuclear contours.

Lymphomatoid Papulosis (LyP) LyP (Table 34-6) is a lymphoproliferative disease with a benign course but is nonetheless characterized by tumor cells with a histologic appearance suggesting malignancy. 86

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Table 34-6 Lymphomatoid Papulosis

Clinical Features Recurrent, often grouped papulonodular self-regressing eruptions Preferential localization on the trunk and extremities Healing often with hyper- or hypopigmented scars Course over years or decades Histopathologic Features Superficial and deep, wedge-shaped dermal infiltrate Medium-sized or large pleomorphic lymphoid cells with atypical mitoses, that are scattered (type A), epidermotropic (MF-like, type B), or in cohesive sheets (type C) Numerous small lymphocytes, neutrophils and eosinophils admixed Ulceration Immunohistologic Features CD3+, CD4+, CD5+, CD8−, CD30+, TIA-1+, Ki-67+ Differential Diagnosis Primary cutaneous CD30 anaplastic large cell lymphoma Pityrasis lichenoides varioliformis et acuta Bite reaction, infestation Pseudolymphoma

CLINICAL FEATURES LyP is a chronic, recurrent disease with papulonodular lesions that undergo spontaneous regression after several weeks, sometimes leaving behind hypo- or hyperpigmented varioliform scars (Fig.34-14A).86 The lesions are located mainly on the trunk and

A

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extremities. Their number can range from only a few grouped lesions to hundreds of disseminated lesions.87 LyP mainly affects individuals in the third and fourth decades of life, with a slight male preponderance. Despite its malignant histologic appearance, the disease may persist over many years or decades as an indolent process.85 A subset of patients (~10%-20%) develop a second malignant lymphoma such as MF, Hodgkin lymphoma, or nodal or cutaneous CD30+ anaplastic large cell lymphoma.85 Molecular studies indicate a clonal relationship between the tumor cells in LyP and these secondarily developing lymphomas in some, but not all, patients. 88,89 HISTOPATHOLOGIC FEATURES The histologic features vary considerably in LyP and depend on the stage of the disease.90-92 The most common histologic presentation (80% of cases) is that of LyP type A lesions. The fully developed LyP lesion is typified by a wedge-shaped dermal mixed cellular infiltrate (see Fig. 34-14). Cytomor-phologically, the infiltrate is composed of scattered medium- or large-sized pleo-morphic or anaplastic lymphoid cells admixed with numerous neutrophils and eosinophils; mitoses are commonly observed. There is a variable degree of epidermotropism of lymphoid cells. In LyP type C, cohesive sheets of tumor cells with only limited numbers of neutrophils and eosinophils are found. Rarely, an epidermotropic infiltrate of small- to medium-sized tumor cells indistinguishable from MF is present and defines the LyP type B variant. Despite the delineation of these three

histologic types of LyP, one must recognize that there is a considerable overlap and that the composition of the lesions may vary from lesion to lesion in any individual patient.92 IMMUNOPHENOTYPIC AND GENOTYPIC FEATURES The proliferating cells in LyP are activated helper T-cells and express CD3+, CD4+, CD5+, CD8−, CD15−, EMA−, and CD30+ (Ki-1) as the immunophenoytpic hallmark93,94 (Fig. 34-15). Interestingly, TIA-1 expression and a high proliferative activity are common features of the tumor cells.95 MUM1 and TRAF-1 are expressed in the vast majority of LyP cases and represent adjunctive differential diagnostic markers because they are expressed only in a minority of pcALCL.96,97 Expression of fascin by tumor cells in LyP may be associated with an increased risk for the development of a second lymphoma.98 Clonal rearrangement of TCR genes can be demonstrated in fresh-frozen tissue but may not be detected in archival specimens, thus limiting its diagnostic value.99 DIFFERENTIAL DIAGNOSIS Clinically, LyP resembles pityriasis lichenoides et varioliformis acuta (PLEVA) (MuchaHabermann disease), but the latter lesions show pronounced epidermal changes with necrotic keratinocytes, exocytosis of CD8+ lymphocytes, and a lack of large anaplastic CD30+ cells. Arthropod bite reactions may occasionally contain smallto medium-sized CD30+ activated lymphocytes. In addition, viral infections (eg, herpesvirus, molluscum contagiosum) and infestations (eg, scabies) may harbor

B

 FIGURE 34-14 Lymphomatoid papulosis. (A) Scattered erythematous papules and nodules on the trunk. (B) Medium- to large-sized pleomorphic lymphoid cells intermingled with reactive inflammatory cells.

cells are disposed in dense cohesive sheets reminiscent of melanoma or an undifferentiated carcinoma90,91 (Figs. 34-16A-D). Clusters of small reactive lymphocytes and eosinophils are found within and around the tumor.104 In neutrophil-rich variants of ALCL, the tumor cells are obscured by an profuse infiltrate of neutrophils.105 Cases with pseudocarcinomatous hyperplasia of the overlying epidermis mimicking keratoacanthoma have been described.106

CD30+ atypical-appearing lymphoid cells and thus may be misinterpreted as LyP.100

Primary Cutaneous Anaplastic Large Cell Lymphoma Primary cutaneous anaplastic large cell lymphoma (pcALCL) is a low-grade malignant CTCL that differs from its systemic counterpart by a different biology and prognosis.85,101 CLINICAL FEATURES Solitary or multiple large nodular tumoral lesions confined to one anatomic region are the most common presentation.102 These tumorous lesions occur on normal-appearing skin without preceding patches or plaques and tend to ulcerate. Mostly patients in their fifth to sixth decades of

A

life are affected, with a male-to-female ratio of 2:1. Nevertheless, pcALCL may also occur in children. Up to 20% to 25% of tumoral lesions have been reported to undergo spontaneous regression.85 ALCLs are one of the most common forms of CTCL arising in transplant recipients.103 HISTOPATHOLOGIC FEATURES The histology shows a nodular dermal infiltrate often extending into the subcutis. The morphologic hallmark are large, pleomorphic, anaplastic, and immunoblastic cells with large, irregularly shaped nuclei and dispersed chromatin; one or multiple nucleoli; and abundant pale or eosinophilic cytoplasms. Multinucleate giant cells with nuclei arranged in annular configurations are characteristic. Tumor

DIFFERENTIAL DIAGNOSIS The clinical differential diagnosis includes LyP (type C), large cell transformation of MF or SS, CD30− large cell PTL, type unspecified. PcALCL must be differentiated from

CHAPTER 34 ■ LYMPHOID, LEUKEMIC, AND OTHER CELLULAR INFILTRATES

 FIGURE 34-15 Lymphomatoid papulosis.Expression of CD30 antigen (Ki-1) by pleomorphic tumor cells. Note the perinuclear dotlike staining of the Golgi apparatus.

IMMUNOPHENOTYPIC AND GENOTYPIC FEATURES The most striking feature is expression of CD30 by the large anaplastic cells (Fig. 34-16 E-G). T-cell-associated antigens (CD43, CD45RO) are expressed with variable loss of pan T-cell antigens (CD2, CD3, CD5, CD7). In contrast to nodal ALCL, primary cutaneous forms may lack EMA and typically express the cutaneous lymphocyte antigen (CLA, HECA-452).101 CLA expression can, however, be seen in nodal ALCLs that disseminate to the skin. They may express perforin, TIA, and perforin. In addition, expression of homeobox gene HOXC5 as well as lack of MUM1 and TRAF-1 expression are found pcALCL in contrast to LyP and systemic (CD30+) ALCL, which may involve the skin secondarily.96,97 Alk (p80) and the (2;5) translocation are usually absent in pcALCL.22 Clonal rearrangement of TCR genes is found in most patients with pcALCL.

B

 FIGURE 34-16 (A) Primary cutaneous anaplastic large-cell lymphoma. Cohesive sheets of large anaplastic lymphoid cells. (B) This patient presented with an ulcerating tumor nodule of a few weeks’ duration. An effacing superficial and deep nodular infiltrate with associated ulceration of the surface is seen.

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C

D

E

F

G  FIGURE 34-16 (C) and (D) The cells that make up the infiltrate are large and pleomorphic, including the presence of classic binucleated (Reed Sternberg like) and multinucleated cells with a horseshoe arrangement of nuclei. (E) The tumor cells express CD30 in cytoplasmic membrane and perinuclear golgi patterns. (F) The tumor cells are extensively epithelial membrane antigen positive. (G) The tumor cells are granzyme positive. Note the granular staining within the tumor cells.

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secondary cutaneous involvement of systemic ALCL and Hodgkin lymphoma by immunophenotyping and staging examinations. Furthermore, phenotyping is essential to differentiate CD30+ ALCL from nonlymphoid undifferentiated neoplasms such as melanoma and various carcinomas.

Cytotoxic Cutaneous Lymphomas

Clinical Features Subcutaneous nodules simulating panniculitis with or without ulceration Preferential localization: trunk, extremities (legs) Histopathologic Features Subcutaneous infiltrate simulating lobular panniculitis Small or medium-sized to large pleomorphic lymphoid cells Rimming of fat cells by proliferating (Ki-67+) lymphoid cells Possible involvement of dermis, especially in γ/δ (TCRδ-1+) cases Immunohistologic Features Various phenotypes: T-cell: CD3+, CD4−/+, CD5+, CD8+/−, CD30−, TIA-1+, Ki-67+ TCR α/β (βF1+) more frequent than TCR γ/δ (TCRδ-1+) NK and NK/T-cell: CD56+ TCR α/β (βF1+): usually rather indolent course. TCR γ/δ (TCRδ-1+) or CD56: usually aggressive course Differential Diagnosis Panniculitis, especially lupus panniculitis Cytophagic histiocytic panniculitis

Subcutaneous Panniculitis-Like T-Cell Lymphoma According to the WHO-EORTC classification and the 2008 WHO classification, SPTCL is defined by its primary subcutaneous localization (Table 34-7) and the alpha/beta TCR+ as well as cytotoxic phenotype.3,4,109,110 Subcutaneous lymphomas with gamma/delta TCR+ phenotype belong to cutaneous gamma/delta T-cell lymphomas. CLINICAL FEATURES SPTCL presents clinically as panniculitis mimicking erythema nodosum, with erythematous, firm subcutaneous nodules favoring the legs.111 The lesions are persistent and may become ulcerated. Systemic signs may be present. In a subset of patients, a hemophagocytic syndrome may accompany SPTCL.110,112 The course is usually slowly progressive. Prognosis of SPTCL is favorable, with 5-year-survival rate of 82%.110 HISTOPATHOLOGIC FEATURES The histopathologic criteria for this type of CTCL include the primary subcutaneous location and a growth pattern of lymphoid infiltrates simulating a lobular panniculitis113,114 (Fig. 34-17). Cytomorphologically, the tumor cells may be small, medium, or large in size and pleomorphic.

Margination (rimming) of lipocytes by tumor cells is a common but nonspecific finding.115 IMMUNOPHENOTYPIC AND GENOTYPIC FEATURES The tumor cells have a cytotoxic T-cell profile (CD2+, CD3+, CD5+, CD4−, CD8+, CD43+, T1A-1+, granzyme B+, perforin+)(see Fig. 34-17A-C). By definition, they are TCR α/β+ (βF1+) (3). There is no association with EpsteinBarr virus (EBV). Clonal rearrangement of α/β of the T-cell receptor is found. DIFFERENTIAL DIAGNOSIS SPTCL must be differentiated from subcutaneous γ/δ+ T-cell lymphoma, which exhibits a poor prognosis.110,116 Among the nonneoplastic disorders, the differential diagnosis includes atypical lymphocytic lobular panniculitis; lupus panniculitis; and other forms of inflammatory panniculitis, especially histiocytic cytophagic panniculitis. The latter is a reactive process associated with a number of systemic diseases and presents with a hemorrhagic diathesis owing to hemophagocytosis in the absence of an LPD (see Chapter 11). Atypical lymphocytic lobular panniculitis is a

distinct form of subcutaneous T-cell dyscrasia characterized by clonal infiltrates of T cells whereby lymphoid atypia is mild, density of infiltration is low, and there is minimal to absent necrosis. This condition may potentially correspond to the waxing and waning phase that may presage subcutaneous panniculitis-like T cell lymphoma.

Extranodal NK/T-Cell Lymphoma, Nasal Type The skin represents the second most common site of involvement by this rare lymphoma. Cutaneous lesions may be the primary or secondary manifestation of the disease. CLINICAL FEATURES Papulonodular lesions with ulceration are the most prevalent clinical manifestations.117 Systemic symptoms, including fever, malaise, and weight loss, are noted commonly. In addition, hemophagocytic syndrome may be observed. Most NK/T-cell lymphomas have an aggressive course. The median survival time is 12 to 15 months.118 HISTOPATHOLOGIC FEATURES The dermal and often subcutaneous infiltrates display an angiocentric and angiodestructive growth pattern with necrosis and ulceration117 (Fig. 34-18). The lymphocytes are of variable size but are mostly medium sized. Lymphocytes have round or oval nuclei. IMMUNOPHENOTYPIC GENOTYPIC FEATURES Pale cytoplasms numerous small lymphocytes, eosinophils, plasma cells, and macrophages may be present. The true NK lymphomas express CD2; cytoplasmic CD3 (CD3 epsilon); CD56; and cytotoxic proteins T1A-1, granzyme B, and perforin. EBV is found in nearly all cases of secondary cutaneous NK lymphomas but rarely in primary cutaneous forms. 118 NK lymphomas exhibit a germline configuration; however, in the NK-like T-cell lymphomas, clonal TCR rearrangement can be detected, defining a critical discriminatory factor separating NK lymphoma from NK-like T-cell lymphoma. In addition, in the NK T-cell lymphomas, there is surface expression of CD3. The polyclonal CD3 used on paraffin-embedded tissue cannot reliably discriminate between CD3 epsilon and surface CD3; hence, both NK and NK-like T-cell lymphomas may show CD3 expression on routine immunohistochemical staining for CD3 on paraffinembedded tissue.

CHAPTER 34 ■ LYMPHOID, LEUKEMIC, AND OTHER CELLULAR INFILTRATES

Cytotoxic CLs are a heterogeneous group of disorders linked by the common expression of a cytotoxic phenotype by the tumor cells.107 Cytotoxic proteins such as perforin, granzymes, and granule membrane-associated cytotoxic protein TIA-1 are mainly expressed by cytotoxic T cells, NK/T cells, and NK cells and mediate cell lysis.108 Four main groups of cytotoxic CLs can be distinguished: (1) primary cutaneous aggressive epidermotropic CD8+ cytotoxic T-cell lymphoma; (2) cutaneous gamma/delta-positive T-cell lymphomas, which both belong to the group of peripheral T-cell lymphomas; (3) extranodal NK/T-cell lymphomas, in which skin involvement often occurs secondarily; and (4) subcutaneous panniculitis-like T-cell lymphoma (SPTCL).

Table 34-7 Subcutaneous Panniculitis-like Lymphoma

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A

920

B

C  FIGURE 34-17 (A) Subcutaneous panniculitis-like T-cell lymphoma. Infiltration of subcutaneous fat tissue by small- to medium-sized pleomorphic cells surrounding adipocytes. (B) There is permeation of the interstitial spaces of the fat by small- to intermediate-sized lymphocytes. In many cases, the cells may appear only mildly atypical. (C) Subcutaneous panniculitis–like T-cell lymphoma is a tumor of cytotoxic CD8 lymphocytes in the majority of cases. Illustrated here is a CD8 preparation showing extensive staining.

 FIGURE 34-18 Extranodal natural killer/T-cell lymphoma, nasal type. Angiocentric and angiodestructive growth of atypical lymphoid cells is seen.

DIFFERENTIAL DIAGNOSIS The differential diagnosis includes other CD56+ CLs119 and lymphomas with angioinvasive growth. Detection of EBV is useful to distinguish extranodal NK/T-cell lymphoma from other SPTCL and peripheral T-cell lymphomas, unspecified.

Hydroa Vacciniforme-Like Lymphoma

Primary Cutaneous Peripheral T-Cell Lymphoma, Unspecified (PTL) PTL, unspecified represents a phenotypically and prognostically heterogenous group of CTCL. According to the WHOEORTC classification and WHO classification, the designation PTL, unspecified refers to CTCLs that do not fit into any of the other better-defined subtypes of CTCL.3,4 Among PTLs, three (provisional) entities have been identified based on their characteristic clinicopathologic, immunophenotypic, and prognostic features, which are discussed below. For the remaining diseases that do not fit into these three provisional entities the designation PTL, unspecified (sensu stricto) is maintained.

Primary Cutaneous CD4+ Small- to Medium-Sized Pleomorphic T-Cell Lymphoma (SM-PTL) This lymphoma predominantly consists of small- to medium-sized pleomorphic tumor cells that do not express CD30 and differs from other entities within the group of PTL because of its excellent prognosis.5,122 CLINICAL FEATURES SM-PTL manifests skincolored or red-brown nodules without ulceration. The prognosis is favorable, with a 5-year survival of more than 90%.123 HISTOPATHOLOGIC FEATURES Histologically, there is a nodular dense monomorphous

 FIGURE 34-19 Primary cutaneous CD4+ small- to medium-sized pleomorphic T-cell lymphoma. Nodular dense infiltrate of lymphocytes throughout the entire dermis. Note the Grenz zone and absence of epidermotropism.

lymphocytic infiltrate (Fig. 34-19). Epidermotropism is usually absent or only focally present. The monomorphous infiltrate extends throughout the entire dermis and is composed of smallto medium-sized lymphocytes with pleomorphic moderately chromatindense nuclei and a small cytoplasmic rim. Eosinophils, plasma cells, and histiocytes may be admixed, and granulomatous features may be present.123 Clusters of B cells are commonly noted. IMMUNOPHENOTYPIC AND GENOTYPIC FEATURES The tumor cells have a CD3+, CD4+, CD8−, CD30− T-helper phenotype. There may be loss of T-cell antigens. Clonal rearrangement of TCR genes has been detected in almost all cases reported and may be useful in the distinction of SM-PTL from T-cell PSL. DIFFERENTIAL DIAGNOSIS SM-PTL must be distinguished from MF by the absence of patches and plaques and the lack of epidermotropism. T-cell pseudolymphoma differs from SM-PTL by the lack of clonality and lack of T-cell antigen loss of .38 Recently, a nodular proliferation of CD3+, CD8+, CD4−, TIA-1+ blast-like medium-sized clonal lymphocytes was reported that clinically mimics SM-PTL because of a slowly growing nodule on the ear and an indolent course.124

Primary Cutaneous Aggressive Epidermotropic CD8+ T-Cell Lymphoma (AE-TCL) This rare aggressive form of CD8+ CTCL with rapid course, poor prognosis,

and involvement of mucosal areas and visceral organs was identified by Berti and coworkers.125 CLINICAL FEATURES Patients of all ages are affected. This type of lymphoma often exhibits widespread erosive and occasionally hyperkeratotic patches, plaques, or papules and nodules undergoing ulceration.125 The disease may spread to extracutaneous sites, particularly the visceral organs, oral mucosa, and central nervous system (CNS). The disease has an aggressive course, with a median survival of less than 3 years. HISTOPATHOLOGIC FEATURES There is prominent epidermotropism of smallmedium or medium-large lymphocytes with pleomorphic chromatin-dense nuclei. Apoptotic keratinocytes, epidermal necrosis, and spongiosis with blister formation are commonly found (Fig. 34-20). Angiocentric growth and destruction of adnexal structures may be present.

CHAPTER 34 ■ LYMPHOID, LEUKEMIC, AND OTHER CELLULAR INFILTRATES

This is a rare CD8+ LPD associated with chronic EBV infection. Most affected patients are children or young adults of Asian and Latin American origin, presenting with edema, vesiculopapular lesions, crusts, necrotic areas, and scars predominately on the face and limbs.120,121 Clinical manifestations resemble those of severe hydroa vacciniforme. Histologically, there is necrosis of the epidermis and dense perivascular and periadnexal nodular infiltrates in the dermis containing medium sized lymphocytes with irregular, hyperchromatic nuclei. The infiltrate displays a prominent angiocentric or angiodestructive pattern. The atypical cells express a CD8+ phenotype. EBV is detected in the majority of patients.

IMMUNOPHENOTYPIC AND GENOTYPIC FEATURES The tumors exhibit a CD3+, CD4−, CD8+, CD45RA+, CD45RO−, TIA-1+ phenotype (Fig. 34-21). No association with EBV has been found. A CD2− CD7+ phenotype seems to be associated with a more aggressive course.126 Clonal rearrangement of TCR genes can be demonstrated in most cases. DIFFERENTIAL DIAGNOSIS Clinical features are essential to distinguish AE-TCL from CD8+ variant of MF, which is characterized by long-standing, often hypo- or hyperpigmented patches and plaques

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are negative for TCR α/β (βF1).3 Primary and secondary cutaneous forms appear to have a similar poor prognosis. CLINICAL FEATURES The clinical manifestations include disseminated, often necrotic or ulcerated, plaques or nodules.129 Involvement of the oral mucosa is common, and other extranodal sites may often become involved; the lymph nodes and bone marrow are usually spared. The disease may be accompanied by a hemophagocytic syndrome, especially in patients with subcutaneous form of CGD-TCL. The clinical course of CTCL with a γ/δ+ phenotype is usually aggressive, with a median survival of 15 months.130

 FIGURE 34-20 Primary cutaneous aggressive epidermotropic CD8+ T-cell lymphoma. Prominent lining up of lymphoid cells along junctional zone, epidermotropism, and apoptotic keratinocytes are present. .

IMMUNOPHENOTYPIC AND GENOTYPIC FEATURES Tumor cells exhibit a CD3+ CD56+ phenotype and are often CD4-, CD8- double negative. By definition, they do not express betaF1 but are TCRdelta positive. The latter can be demonstrated on frozen sections only. TCR gamma genes are clonally rearranged. Isochromosome 7q is a common genetic abnormality.

 FIGURE 34-21 Primary cutaneous aggressive epidermotropic CD8+ T-cell lymphoma. Expression of CD8+ by the intraepidermal lymphoid cells.

922

HISTOPATHOLOGIC FEATURES Epidermotropic (pagetoid), dermal (diffuse or nodular) and subcutaneous patterns are distinguished (Fig. 34-22A). Epidermal and dermal involvement, however, may also occur in predominantely subcutaneous CGD-TCL and may be associated with production of large amounts of γ-interferon (132). Tumor cells are medium to large sized with chromatin-dense irregular nuclei (Fig. 34-22B). Angioinvasive infiltrates and necrosis are common.

and the slowly progressive course of classic CD4+ MF.68,69 In addition, the vast majority of cases of MF are CD45 RO positive and only rarely are the neoplastic cells CD45RA positive. Pityriasis rosea may present with similar histologic features, but it is clinically characterized by a “herald patch”. Febrile ulcero-necrotic PLEVA may simulate clinically and histologically AE-TCL but does not express CD45RA. Because clonality has been

demonstrated in pityrasis lichenoides,127 detection of clonality does not serve as a discriminating marker. Moreover, transition from febrile ulceronecrotic PLEVA to CD8+ AE-TCL has been reported.128

Cutaneous γ/δ+ T-Cell Lymphoma (CGD-TCL) CGD-TCL is characterized by clonal Tcells expressing γ/δ TCR (TCRδ+) but

DIFFERENTIAL DIAGNOSIS Subcutaneous CGD-TCL has to be distinguished from its TCRalpha/beta+ counterpart SPTCL, which has an often indolent course with a favorable prognosis. EBV is generally negative in CGD-TCL in contrast to CD3(epsilon)+, CD56+ NK/T-cell lymphoma, nasal type.

Primary Cutaneous Peripheral T-Cell Lymphoma, Unspecified The clinicopathologic features of this CTCL entity are still poorly characterized. Thus far, only a few case series have been reported in the literature.133 These are rare primary CTCLs composed predominantly of medium- to large-sized pleomorphic or immunoblastic T cells. Cases of the d’emblee form of MF reported in the literature belong to this entity.

B

 FIGURE 34-22 Cutaneous gamma/delta T-cell lymphoma. (A) Medium to large lymphoid cells infiltrating the subcutaneous fat. (B) The nuclei are irregular with dense chromatin.

CLINICAL FEATURES This form of CTCL presents usually in adults with solitary, grouped, or disseminated nodules without preceding patches or plaques. 133 The prognosis is poor,

A

with a 5-year-survival rate of less than 20%.133,134 HISTOPATHOLOGIC FEATURES The tumors are characterized by nodular infiltrates

composed of medium-sized to large cells with pleomorphic nuclei and pale cytoplasms and a few associated reactive cells.135 Epidermotropism is not a prominent feature (Fig. 34-23).

B

CHAPTER 34 ■ LYMPHOID, LEUKEMIC, AND OTHER CELLULAR INFILTRATES

A

C  FIGURE 34-23 Peripheral T cell lymphoma, type unspecified. The patient was a 45-year-old woman who presented with three tender nodules on the back of a few weeks’ duration. The biopsy shows an effacing deep dermal and subcutaneous infiltrate composed of large atypical cells.

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IMMUNOPHENOTYPIC AND GENOTYPIC FEATURES Tumor cells express a T-helper phenotype (CD2, CD3, CD5) but show T-cell antigen loss (eg, CD7). In some cases, however, there may be relative preservation of CD7 but a diminution in the extent of staining for CD2. By definition, the tumor cells lack expression of CD30. Molecular biology reveals a clonal rearrangement of TCR genes (Fig. 34-24).

924

DIFFERENTIAL DIAGNOSIS The differential diagnoses includes transformation of MF and SS, which differ by clinical features, as well as ALCL expressing CD30 by at least 75% of the tumor cells.3 Secondary cutaneous involvement by nodal PTL has to be excluded by staging examinations.

A

Secondary Skin Involvement by Nodal Lymphomas ANGIOIMMUNOBLASTIC T-CELL LYMPHOMA (AITL) Patients typically present with nodal disease and type B symptoms. They may also have hepatosplenomegaly. Skin involvement is seen in 30% to 40% of patients. Skin involvement occurs mostly as a generalized maculopapular eruption with a predilection for the trunk and mimics a viral exanthem or drug eruption. Patients present with fever, weight loss, night sweats, lymphadenopathy, hepatosplenomegaly, and abnormalities in the peripheral blood. The lymph node changes are characteristic. The nodal architecture is effaced, with proliferation of high endothelial venules associated with follicular dendritic cells. The lymphocytic infiltrate is relatively sparse with medium-sized tumor cells with a clear cytoplasm. Histologic findings in the skin vary from a nonspecific pattern typified by scant superficial perivascular infiltrates composed of eosinophils and normal-looking lymphocytes around hyperplastic capillaries to distinctive patterns suggesting AITL. The latter findings include prominent vascular endothelial hyperplasia and the presence of pleomorphic lymphocytes with medium- to large-sized reniform nuclei (Fig. 34-25). Immunohistochemically, the neoplastic lymphocytes express the phenotype of mature T-helper cells (CD3+, CD4+, CD86+) with aberrant loss of T-associated antigens in some cases. 136 In addition there may be a proliferation of CD 21 positive dendritic cells (Fig. 34-26). CD10 serves as a useful marker for tumor cells in AITL.137 EBV may be found in a few cells138

B

C  FIGURE 34-24 Peripheral T-cell lymphoma, type unspecified. Phenotypic studies conducted on the tumor revealed a (A) CD30− (B) CD25+ and (C) CD4+ T-cell lymphoma.

B

 FIGURE 34-25 Angioimmunoblastic lymphadenopathy. (A) The patient presented with skin nodules, constitutional symptoms, anemia, and polyclonal hypergammaglobulinemia. The biopsy showed a striking lymphocytic infiltrate localized to the subcutaneous fat. (B) Higher power magnification reveals a welldifferentiated small lymphocytic infiltrate with an arborizing vascular network and scattered eosinophils.

B

A

CHAPTER 34 ■ LYMPHOID, LEUKEMIC, AND OTHER CELLULAR INFILTRATES

A

C  FIGURE 34-26 Angioimmunoblastic lymphadenopathy The immunophenotypic profile is compatible with angioimmunoblastic lymphadenopathy. (A) The lymphocytes are CD10 positive. (B) In addition, the extent of vascularity is highlighted by the CD34 stain. (C) There is a prominent dendritic cell network, as demonstrated by the CD21 stain.

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PART IV ■ PROLIFERATIONS—HAMARTOMAS, HYPERPLASIAS, AND NEOPLASIAS

Precursor Hematologic Neoplasms

926

PRECURSOR T-LYMPHOBLASTIC LYMPHOMA T-lymphoblastic lymphoma (precursor T-lymphoblastic lymphoma) presenting solely as a cutaneous process is uncommon. Histopathologically, there is a dermal proliferation of cells with a high nuclear-to-cytoplasmic ratio. Cytologic variations include the presence of cells with round, oval, or convoluted nuclei; the size of the nuclei (from small to large); and chromatin appearance (condensed with inconspicuous nucleoli to finely dispersed with prominent nucleoli).139,140 A common finding is the presence of numerous mitotic figures and apoptotic cells imparting the typical “starry sky” appearance of the neoplastic infiltrate.140 The lymphoblasts are TdT+ in most cases. The expression of T-associated antigens and CD99 and CD34 is typical but variable. CD3 is considered to be lineage-specific.7 The diagnosis of primary cutaneous T-lymphoblastic lymphoma requires the exclusion of systemic disease (precursor T-lymphoblastic leukemia/lymphoma) by staging.139

CD4+, CD56+ Hematodermic Neoplasm This lymphoma has originally been referred to as blastic NK-cell lymphoma. Because recent studies have demonstrated that this neoplasm is the neoplastic counterpart of plasmacytoid dendritic cells (PDCs),141 it has been renamed plasmacytoid dendritic cell neoplasia in the 2008 WHO classification. CLINICAL FEATURES The disease usually presents with contusiform, bruiselike disseminated plaques and nodules.142,143 The trunk and head are the most common sites, and mucosal involvement is common. Usually, there is already systemic involvement at the time of diagnosis with circulating malignant cells, lymph node and bone marrow involvement, and CNS infiltrates. The course is aggressive, with rapid dissemination and fatal outcome within 2 years of diagnosis. In some patients, the disease develops in the setting of preexisting myelodysplastic syndrome.144 HISTOPATHOLOGIC FEATURES Histologically, there is a monomorphous infiltrate of blast cells that is bandlike in the upper and mid-dermis with column-like extensions into the deeper dermis and subcutis.143 Neither a grenz zone nor epidermotropism of tumor cells is observed. The tumor cells display nuclei with fine-dispersed

 FIGURE 34-27 CD4+, CD56+ hematodermic neoplasm. Cohesive sheets of medium-sized blastlike cells are seen. Note the prominent extravasation of erythrocytes.

chromatin and a sparse cytoplasm. Extravasated erythrocytes are found within the tumorous infiltrates. IMMUNOPHENOTYPIC AND GENOTYPIC FEATURES The tumor cells express CD4, CD56, CD123, and TCL-1 but are negative for T- and B-cell as well as myeloidmonocytic markers145 (Fig. 34-27). There usually is no clonal rearrangement of TCR detectable. There is no association with EBV. The tumor cells express other plasmacytoid dendritic cell markers such as myxovirus protein(MXA), CD83, and BDCA-2. In addition, there may be expression of CD2 and CD7. DIFFERENTIAL DIAGNOSIS The neoplasm has primarily to be distinguished from specific infiltrates of myeloid/monocytic leukemia, which expresses myeloid–monocytic markers such as CD14 and MPO and is negative for TCL-1 in most cases.145 Some CD56+ variants of monocytic leukemia typically follow an even more aggressive clinical course compared with cases of CD56- monocytic leukemia . The phenotypic profile is very similar to that of hematodermic neoplasm. There may also be CD123 expression, although the extent of CD56 and CD123 expression are typically not as extensive as the prominent staining observed for both markers in patients with hematodermic neoplasm. Phenotyping is useful to differentiate CD4+ CD56+ hematodermic neoplasms from B-cell lymphomas.

Cutaneous B-Cell Lymphoid Hyperplasia and Cutaneous B-Cell Lymphomas Lorenzo Cerroni Helmut Kerl

CUTANEOUS B-CELL LYMPHOID HYPERPLASIA Synonyms: lymphadenosis benigna cutis, lymphocytoma cutis, pseudolymphoma of Spiegler-Fendt In the recent past, many lymphoid proliferations that were classified previously as cutaneous B-cell lymphoid hyperplasia (pseudolymphoma) have been reclassified as low-grade malignant B-cell lymphomas with a favorable clinical behavior. The term cutaneous B-cell lymphoid hyperplasia is still used, but it is not a specific diagnosis.146,147 It is descriptive and refers to a heterogeneous spectrum of diseases that simulate malignant B-cell lymphomas clinically, histopathologically, or both. Whenever possible, a diagnosis of cutaneous lymphoid hyperplasia should be avoided in favor of specific designations using the language of clinical dermatology. The classical example of a cutaneous B-cell lymphoid hyperplasia (Table 34-8)

Table 34-8 Cutaneous B-Cell Lymphoid Hyperplasia

is lymphadenosis benigna cutis (synonyms are lymphocytoma cutis and pseudolymphoma of Spiegler-Fendt). CLINICAL FEATURES Erythematous or redbrown to red-purple solitary nodules with a smooth surface are usually found. Agminated lesions in a region or disseminated papules may be observed rarely. Favored sites of involvement are the face (cheek, nose, earlobe), mammary area, and scrotum.147,148 Children and adults may be affected. The course of cutaneous B-cell lymphoid hyperplasia varies. The lesions may resolve with or without treatment. Various stimuli may induce lesions of cutaneous B-cell lymphoid hyperplasia, including insect bites, persistent nodules of scabies, drugs (antidepressant therapy), vaccinations, injections of antigens for hyposensitization, and tattoos. Cases of cutaneous B-cell lymphoid hyperplasia are often associated with infection by Borrelia burgdorferi (Borreliainduced lymphocytoma).148 In many cases, however, a precise cause is not found. HISTOPATHOLOGIC FEATURES Relatively symmetrical, rather well-circumscribed nodular infiltrates within the dermis and sometimes within the subcutaneous fat can be observed.147,148 As a rule, the infiltrates are more dense in the upper part of the dermis than in the lower part (in Borrelia-associated lymphocytoma cutis arising on the nipple, however, the infiltrate has usually a “bottom-

 FIGURE 34-28 Cutaneous B-cell lymphoid hyperplasia (lymphadenosis benigna cutis). Nodular infiltrates with a follicular pattern. Stained with Giemsa stain.

heavy” arrangement).148 Germinal centers are frequently present (follicular type of pseudolymphoma) (Fig. 34-28). Sometimes a nonfollicular pattern without formation of germinal centers can be observed. An important diagnostic criterion is the mixed character of the infiltrate (Fig. 34-29). Although lymphocytes, especially small ones, are nearly always predominant, eosinophils, plasma cells, histiocytes, and giant cells are often found as well. The epidermis is not involved and is usually separated

from the infiltrates of inflammatory cells by a thin zone composed of normal collagen bundles. Adnexal structures are spared. These histopathologic features frequently represent responses to infectious agents such as B. burgdorferi, but other etiologies may be responsible.148,149 Drug-associated cutaneous lymphoid hyperplasia (most commonly associated with antidepressant therapy) usually reveal a mycosis fungoides-like pattern, but can occasionally also induce

 FIGURE 34-29 Cutaneous B-cell lymphoid hyperplasia. Mixed-cell infiltrate with small lymphocytes, lymphoplasmacytoid cells, eosinophils, and histiocytes.

CHAPTER 34 ■ LYMPHOID, LEUKEMIC, AND OTHER CELLULAR INFILTRATES

Clinical Features Preferential locations (Borrelia-induced lymphocytoma): nipple, earlobe, scrotum Solitary (or rarely multiple) nodules Both children and adults affected Histopathologic Features Nodular, "top-heavy", mixed cell infiltrates Small lymphocytes predominate, plasma cells, eosinophils, and histiocytes Reactive lymphoid follicles frequently present Immunohistologic Features CD20+ CD79a+ Polyclonal pattern (κ+, λ+) Bcl-2− (germinal center cells) CD10 −, Bcl-6− (outside lymphoid follicles) Regular pattern of CD21+ follicular dendritic cells CD3+ reactive cells

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histopathologic features similar to lymphadenosis benigna cutis.150 It should be emphasized that a “pseudolymphomatous” appearance does not necessarily mean that a tumor is benign; rarely, malignant nonlymphoid tumors may present with histopathologic features simulating a lymphoproliferative disorder (eg, lymphoepithelial-like carcinoma, pseudolymphomatous angiosarcoma).151

928

IMMUNOLOGY AND RELATED FEATURES Immunohistological investigations reveal the presence of B-cell compartments (CD20+) surrounded by T-cell aggregations. The T-cells (CD3+, CD45RO+) may even predominate. Cases with germinal center formation (CD10+, Bcl6+, Bcl2−) are associated with a regular network of dendritic reticulum cells (CD21+). Analysis of Ig-light chain expression usually discloses a polyclonal proliferation of B cells that express both κ and λ light chains. Very few systematic molecular studies have been performed. Polyclonal Ig-gene rearrangements are observed as a rule. DIFFERENTIAL DIAGNOSIS Certain clinical features may be helpful in the differential diagnosis of benign versus malignant B-cell infiltrates of the skin. Whereas benign B-cell lymphoid hyperplasias often present as a single papule or nodule with a smooth surface on a special location (eg, earlobe, nipple, genital area), lymphomas tend to be associated with clusters of papules, plaques, and tumors that may be ulcerated. B-cell lymphoid hyperplasias occur frequently in children, in contrast to CBCLs. In B-cell lymphoid hyperplasia, there may be a history of a causative event (eg, drug intake, B. burgdorferi infection), but in lymphomas, the cause is usually obscure. The histologic differentiation of cutaneous B-cell lymphoid hyperplasia from malignant CBCLs is one of the most difficult problems in diagnostic dermatopathology (Table 34-9).147,152 As a rule, but not in all cases, cellular infiltrates in cutaneous B-cell lymphoid hyperplasia are relatively symmetrical, rather well-circumscribed, and more dense in the upper part of the dermis than in the lower part (“top heavy”). In contrast, infiltrates in malignant B-cell neoplasms are more massive, asymmetrical, poorly circumscribed, and are frequently more or less equally distributed in the superficial and deep dermis or more dense in the lower part of the dermis and subcutaneous fat (“bottom heavy”). There is a mixed character of the infiltrate in B-cell cutaneous

Table 34-9 Histopathologic Criteria: B-Cell Cutaneous Lymphoid Hyperplasia Versus Malignant B-Cell Lymphoma Cutaneous B-Cell Hyperplasia

Malignant B-Cell Lymphoma

Symmetry Wedge-shaped pattern Involvement of upper part of the dermis usually greater than that of the lower dermis Adnexal structures spared Lymphoid follicles with normal mantle zone Tingible body macrophages present in lymphoid follicles

Asymmetry Lack of wedge-shaped pattern Involvement of the lower part of the dermis equal or greater that that of the upper dermis Adnexal structures often obliterated Lymphoid follicles devoid of mantle zone Tingible body macrophages absent or reduced in lymphoid follicles

lymphoid hyperplasia. In addition to lymphocytes, eosinophils, plasma cells, histiocytes, and giant cells are often present, but similar features can be observed in many low-grade malignant B-cell lymphomas, especially marginal zone lymphoma.153 Nuclear atypia is found more frequently in malignant lymphomas. However in low grade B-cell lymphomas nuclear atypica may be minimal. The histologic features of distinct lymphoid follicles with germinal centers, which have been misinterpreted in the past as characteristic criteria of a benign inflammatory process, are not reliable for the differential diagnosis of lymphoma versus pseudolymphoma. Reactive follicles may also be present in lymphomas. Other findings helpful in the differential diagnosis are the tendency of the cellular infiltrates in cutaneous lymphoid hyperplasia to spare the epithelium of adnexa, in contrast to lymphomas, in which the adnexal epithelium structure is frequently involved by neoplastic infiltrates, and the presence of tingible bodies (lymphocytic nuclear debris engulfed by macrophages) in germinal centers in cutaneous lymphoid hyperplasia but not in neoplastic follicles in lymphomas. Immunohistologic features are very important for the differential diagnosis. Whereas malignant populations of B lymphocytes usually show a monoclonal restriction to either κ or λ immunoglobulin light chain, benign infiltrates exhibit a polyclonal pattern with expression of both light chains. Unfortunately, however, there are several cases of B-cell lymphoproliferative disorders, both benign and malignant, in which the cells do not express immunoglobulins (or expression cannot be demonstrated in routinely fixed, paraffin-embedded specimens). A useful clue for the diagnosis of follicle center lymphoma with a follicular growth pattern is the diminished prolif-

erative activity of malignant follicular cells as outlined by the Ki67/MIB-1 antibody (70 years of age). Relapses and

A

936

Table 34-14 Large B-Cell Lymphoma, Leg Type

extracutaneous involvement are common. The prognosis is more unfavorable than that in the other primary CBCLs, and the 5-year survival rate is approximately 55%.156,187 HISTOPATHOLOGIC FEATURES Dense, diffuse infiltrates (Fig. 34-43A) are seen within the dermis and subcutis. Infiltration of the epidermis (epidermotropism) simulating a T-cell lymphoma can be observed rarely. Cytomorphologically, the neoplastic cells resemble either immunoblasts (Fig. 34-43B) or centroblasts.

There are many mitotic figures. A “starry sky” pattern is sometimes present. IMMUNOLOGY AND RELATED FEATURES Surface Ig or cytoplasmic Ig can be demonstrated in some cases. The neoplastic cells are CD20, CD79a (loss of antigen expression can be observed), MUM-1, and Bcl-2 positive.188 In many cases, a proportion of neoplastic cells is positive for Bcl-6.188 Molecular studies have revealed that cutaneous large B-cell lymphoma, leg type, is characterized by the monoclonal proliferation of postgerminal center B lymphocytes.189 DIFFERENTIAL DIAGNOSIS Large B-cell lymphoma, leg type, must be distinguished from large cell anaplastic lymphoma, which consists of CD30-positive large T cells with irregularly shaped nuclei admixed with giant cells resembling Reed-Sternberg (RS) cells. In this context, it must be emphasized that there is a variant of large B-cell lymphoma that is characterized by anaplastic B lymphocytes positive for CD30. This variant should not be included in the group of CD30positive anaplastic large cell lymphoma but should rather be classified among the large B-cell lymphomas.190 Granulocytic sarcoma, histiocytic neoplasms, metastases, and other nonhematopoietic tumors can be excluded not only by morphology but also by applying a panel of monoclonal antibodies.

LARGE B-CELL LYMPHOMAS, OTHER This group of CBCL consists of rare cases that do not fit into the category of primary CBCL, leg type, including cases of diffuse large B-cell lymphoma

B

 FIGURE 34-43 Primary cutaneous large B-cell lymphoma, leg-type. (A) Dense diffuse infiltrate. (B) Immunoblasts predominate.

without Bcl-2 expression, intravascular large B-cell lymphoma, and rare examples of large B-cell lymphomas in the setting of immune suppression.147,156,188

Intravascular Large B-Cell Lymphoma

CLINICAL FEATURES Patients present with indurated, erythematous, or violaceous patches and plaques, preferentially located on the trunk and thighs. The clinical appearance is not typical of lymphoma and may sometimes suggest a diagnosis of panniculitis or of purpura.

Table 34-15 Intravascular Large B-Cell Lymphoma

Clinical Features Preferential location: extremities Infiltrated patches and plaques Sometimes confined to cherry hemangiomas Usually systemic disease with involvement of the central nervous system; primary cutaneous disease possible Poor prognosis Histopathologic Features Aggregates of large B cells within dilated blood vessels in the dermis and superficial subcutis Cytomorphology: immunoblasts, centroblasts-like cells Immunohistologic Features CD20+ CD79a+ Bcl-2+ MUM-1+ CD5 −/+ Differential Diagnosis Intravascular histiocytosis

 FIGURE 34-44 Intravascular large B-cell lymphoma. Note the large lymphocytes within a dilated blood vessel.

Intravascular large B-cell lymphoma has been observed confined to lesions of cherry hemangiomas.192 HISTOPATHOLOGY, IMMUNOLOGY AND RELATED FEATURES Intravascular large B-cell lymphoma is characterized by a proliferation of large lymphocytes filling dilated blood vessels within the dermis and superficial subcutaneous tissues (Fig. 34-44).193 In some cases, atypical cells may also be observed around blood vessels. The malignant cells are large, with scanty cytoplasm and often prominent nucleoli. Neoplastic cells are positive for B-cell– associated markers and in a subset of cases show aberrant CD5 expression. Staining with endothelial cell–related antibodies (eg, CD31, CD34) highlights the characteristic intravascular location of the cells. Molecular analysis shows monoclonal rearrangement of the Ig genes. DIFFERENTIAL DIAGNOSIS Intravascular large B-cell lymphoma should be differentiated from other large B-cell lymphomas. The typical location of neoplastic cells within dilated blood vessels is almost pathognomonic of this rare variant of B-cell lymphoma.

Large B-Cell Lymphomas in Immunocompromised Patients Patients are adults or children who have received allogenic solid organ or bone marrow transplantation and are

under immunosuppressive treatment (Table 34-16). CLINICAL FEATURES The cutaneous lesions are variable, including erythematous plaques, nodules, and tumors that are sometimes ulcerated. Cutaneous lesions may be solitary, localised to a single anatomical region, or generalized. Concomitant involvement of other organs can be observed and is usually associated

Table 34-16 Large B-Cell Lymphomas in Immunocompromised Patients

Clinical Features Patients under immunosuppressive treatment Erythematous plaques, nodules, and tumours, sometimes ulcerated Histopathologic Features Polymorphic posttransplant lymphoproliferative disorder: monoclonal infiltrates composed of plasma cells, immunoblasts, and intermediate-sized lymphoid cells Monomorphic posttransplant lymphoproliferative disorder: picture of diffuse large B-cell lymphoma, Burkitt lymphoma, plasma cell myeloma, or extramedullary plasmacytoma Immunohistologic Features CD20+ CD79a+ Monoclonal IgL Differential Diagnosis Marginal zone B-cell lymphoma Other types of large B-cell lymphoma

CHAPTER 34 ■ LYMPHOID, LEUKEMIC, AND OTHER CELLULAR INFILTRATES

Intravascular large B-cell lymphoma is a malignant proliferation of large B-lymphocytes within blood vessels (Table 34-15).191 This disease was formerly classified as a vascular neoplasm (malignant angioendotheliomatosis). Most cases show a B-cell phenotype, but a T-cell variant has also been reported. In rare patients, the skin may be the only affected site, but more often, there is systemic dissemination with common involvement of the CNS. It has been reported that the prognosis for patients with intravascular large B-cell lymphoma limited to the skin is better than for patients with generalized disease, but only a very limited number of cases have been observed.

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the skin, that is, staging investigations are negative. This variant is observed especially in young patients on the head (scalp) and neck region and is characterized by solitary or localized reddishbrown to bluish tumors.146,194,195 Patients with localized skin disease appear to have a relatively good prognosis, but treatment strategies should be the same applied for those with systemic variants of the disease.

 FIGURE 34-45 Cutaneous B-cell lymphoma in immunosuppressed patient (iatrogenixc immunosuppression). Note the large cells admixed with atypical plasmacytoid cells and plasma cells.

with systemic symptoms, including elevated serum levels of lactate dehydrogenase. Precise staging investigations should be always performed to evaluate the extent of involvement before planning the treatment. HISTOPATHOLOGY, IMMUNOLOGY, AND RELATED FEATURES The histopathologic features vary according to the subtype of posttransplant lymphoproliferative disorder (Fig. 34-45). Early lesions show polyclonal (rarely monoclonal) proliferations of mature plasma cells with rare immunoblasts. Polymorphic posttransplant lymphoproliferative disorder is characterized by the presence of a monoclonal infiltrate of B lymphocytes comprising the whole spectrum of maturation and including plasma cells, immunoblasts, and intermediate-sized lymphoid cells. In monomorphic posttransplant lymphoproliferative disorder, the histopathologic picture is that of a malignant lymphoma (diffuse large B-cell lymphoma, Burkitt lymphoma, plasma cell myeloma, or extramedullary plasmacytoma). Cases involving the skin present mostly with the features of diffuse large B-cell lymphoma.

B-Lymphoblastic Lymphoma

938

B-lymphoblastic lymphomas are neoplasms of precursor-B cells (pre-pre-B lymphoblasts, pre-B lymphoblasts, and “mature” B lymphoblasts) (Table 34-17).

CLINICAL FEATURES Patients usually have acute lymphoblastic leukemia with bone marrow and peripheral blood involvement and secondary skin manifestations. However, in some cases, these lymphomas may arise “primary” in

Table 34-17 B-Lymphoblastic Lymphoma

Clinical Features Preferential location: head (scalp) Usually solitary tumors Sometimes primary cutaneous involvement Histopathologic Features Dense, diffuse, monotonous infiltrates Medium-sized lymphoblasts with scanty cytoplasm, round or convoluted nuclei with fine chromatin and inconspicuous nucleoli High mitotic rate Immunohistologic Features CD79a+ CD20+ TdT+ CD10+ cMu+ CD34+ Differential Diagnosis Myelomonocytic leukemia Mantle cell lymphoma Merkel cell carcinoma Metastatic neuroendocrine carcinoma

HISTOPATHOLOGIC FEATURES Dense, diffuse monomorphous infiltrates are found within the dermis and the subcutaneous fat. Cytomorphologically, the lymphoblasts are medium-sized cells with round, oval, or convoluted nuclei; fine chromatin; inconspicuous nucleoli; and scant cytoplasm. Mitoses are frequent, and a “starry sky” pattern may be seen (Fig. 34-46). In some cases, neoplastic cells display a characteristic “mosaiclike” pattern. IMMUNOLOGY AND RELATED FEATURES The cutaneous lymphoblastic lymphomas usually express CD79a, CD19, CD20, TdT, CD10 (CALLA), CD34, and cytoplasmic μ heavy chain without surface immunoglobulin. Expression of the various markers is related to the stage of differentiation of the cells, and B-cell markers may be negative in some cases. Molecular studies show monoclonal rearrangement of the Ig genes in most cases. In rare instances, a concomitant monoclonal rearrangement of T-cell receptor gene can be observed, thus giving rise to potential pitfalls in the molecular features of the tumor.195 DIFFERENTIAL DIAGNOSIS One must consider in the differential diagnosis myelomonocytic leukemia that shows a proliferation of immature granulocytic and monocytic cells arranged in a figurate pattern. Mantle cell lymphoma may be confused with lymphoblastic lymphoma. However, the cytomorphology in mantle cell lymphoma with cleaved or irregularly shaped nuclei and the immunophenotype of the neoplastic mantle cells (sIg+, CD5+, CD10−) are distinct from lymphoblastic lymphoma. The differential diagnosis may also include cutaneous Merkel cell tumor and metastatic neuroendocrine carcinoma, which are characterized by the coexpression of cytokeratin filaments, neurofilament proteins, and various other neuroendocrine markers (eg, chromogranin-A).

Cutaneous Hodgkin lymphoma is usually manifested as advanced (stage IV) disease and carries a bad prognosis. In some patients, nodal Hodgkin lymphoma may be associated with second cutaneous lymphoproliferative diseases. MF, lymphomatoid papulosis, anaplastic large cell lymphoma, and granulomatous slack skin sometimes occur in the course of Hodgkin lymphoma or may presage the development of Hodgkin lymphoma.

Cutaneous Hodgkin Lymphoma Lorenzo Cerroni Helmut Kerl

Hodgkin lymphoma is regarded as a distinct malignant lymphoma (Table 34-18) characterized by the presence of neoplastic Reed-Sternberg (RS) cells in association with different patterns of reactive cells. The exact nature of RS cells has been elucidated, and it is now clear that more than 90% of cases of Hodgkin lymphoma represent variants of B-cell lymphomas (origin from a germinal center B lymphocyte).196,197 A viral etiology is possible because the EBV genome has been detected frequently. CLINICAL FEATURES Cutaneous involvement in patients with Hodgkin lymphoma may be “nonspecific” (zoster, prurigo, ichthyosis acquisita), or the skin may be affected by specific infiltrates with Hodgkin and RS cells.198,199 Specific cutaneous manifestations are uncommon, occurring in only about 1% of patients with systemic Hodgkin lymphoma.200 The incidence of specific cutaneous involvement, however, seems to be even lower since the introduction of more effective treatment modalities. The skin lesions are usually confined to the drainage area of affected lymph nodes (retrograde lymphatic spread).

In rare cases, direct extension from underlying lymph nodes or hematogenous spread may be observed. Primary cutaneous Hodgkin lymphoma also exists, as demonstrated in the literature.201,202 Clinically, the lesions appear as localized erythematous papules and plaques or reddish-brown to bluish, often ulcerated tumors. The trunk seems to be the most common site of involvement, but all other sites of the body may also be affected.

Table 34-18 Hodgkin Lymphoma

Clinical Features Solitary or multiple papules, plaques, or tumors Skin involvement most often results from retrograde lymphatic spread from involved lymph nodes Unfavorable prognosis Histopathologic Features All main subgroups can be observed in the skin Nodular or diffuse infiltrates Hodgkin cells, Reed-Sternberg cells (in about half of cases) Reactive component: lymphocytes, plasma cells, neutrophils, eosinophils, histiocytes Immunohistologic Features CD30+ CD15 +/− CD45− Differential Diagnosis Lymphomatoid papulosis Anaplastic large cell lymphoma

IMMUNOLOGY In classic Hodgkin lymphoma, the RS cells show constant positivity for CD30 and negativity for CD45 (LCA); CD15 is expressed frequently but may also be negative.202-204 In contradistinction, the lymphocyte-predominant form of Hodgkin lymphoma is phenotypically distinct whereby the cells are CD15 negative, leukocyte common antigen positive, and CD20 positive. Because these tumors are of B-cell derivation, B-cell clonality can be seen in both the classic and lymphocyte predominant forms of Hodgkin lymphoma. The accompanying reactive infiltrate is composed mostly of T-lymphocytes. DIFFERENTIAL DIAGNOSIS Lymphomatoid papulosis morphologically resembles Hodgkin lymphoma. Clinically, lymphomatoid papulosis differs by its benign course with generalized recurrent papular or papulonecrotic, self-healing eruptions. Histologically, lymphomatoid papulosis shows wedge-shaped epidermotropic infiltrates with large atypical (RS-like) cells. In contrast to Hodgkin lymphoma, the phenotype of these cells is usually CD3+, CD4+, CD30+, and CD15−, and as with anaplastic large cell lymphoma, the cells express cytotoxic proteins, including granzyme, TIA and perforin.

CHAPTER 34 ■ LYMPHOID, LEUKEMIC, AND OTHER CELLULAR INFILTRATES

 FIGURE 34-46 Cutaneous pre-B lymphoblastic lymphoma. Monomorphous population of lymphoblasts. Prominent starry-sky pattern.

HISTOPATHOLOGIC FEATURES All subtypes of Hodgkin lymphoma may be observed in the skin (Fig. 34-47). Nodular or diffuse infiltrates may be seen within the dermis extending into the subcutaneous fat. Areas of fibrosis, sclerosis, or both may be found. The epidermis is usually spared. Hodgkin cells are a constant finding, but typical RS cells are present only in about 50% of cases (Fig. 34-48). The background of the infiltrate contains lymphocytes, histiocytes, plasma cells, eosinophils, and neutrophils. It is well known that Hodgkin and RS cells are not a unique feature of Hodgkin lymphoma. These cells have been found in a variety of other conditions (lymphomatoid papulosis, anaplastic large cell lymphoma).

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In the differential diagnosis of cutaneous Hodgkin lymphoma, special attention should be given to exclude anaplastic large cell (CD30+) T-cell lymphoma. In Hodgkin lymphoma, Hodgkin and RS cells are found in small numbers together with an appropriate polymorphous background of inflammatory cells. Anaplastic large cell lymphoma is characterized by cohesive sheets of large blastic cells, occasionally with features of RS cells. The large blastic cells are CD30+ and CD15−, and frequently reveal an aberrant T-cell phenotype. The cells express cytotoxic proteins, granzyme, perforin, and T-cell intracellular antigen. It should be mentioned that in a few cases, a common cell of origin has been demonstrated for lesions of Hodgkin lymphoma, lymphomatoid papulosis, and anaplastic large T-cell lymphoma occurring in the same patient.205

 FIGURE 34-47 Cutaneous Hodgkin lymphoma (classical Hodgkin lymphoma, nodular sclerosis).

A

B

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 FIGURE 34-48 Cutaneous Hodgkin lymphoma. (A) Reed-Sternberg cells set in a background of lymphocytes, histiocytes, and eosinophils. (B) Hodgkin cell.

Cutaneous Leukemic Infiltrates Stanislaw A. Buechner W.P. Daniel Su

Hematopoietic malignancies may have their initial manifestations in the skin, they may present with concurrent cutaneous and hematologic involvement, or they may exhibit cutaneous disease some period of time after the initial hematologic diagnosis. There is a spectrum of lesions of which the commonest are observed in the context of overtly malignant infiltrates. However,they also include paraneoplastic lesions and infections secondary to a relative state of immunodeficiency.206,207 In some cases, the cutaneous lesions may be the initial manifestation of the underlying hematologic malignancy, whether it is in the context of aleukemic leukemia cutis or a sterile paraneoplastic neutrophilic dermatosis such as Sweet syndrome.208-210 A definitive diagnosis can be made in most instances based on combined light microscopic and immunophenotypic studies. However, it should be emphasized that in many cases, the presentation in the skin is in the context of an established diagnosis of leukemia whereby exhaustive flow cytometric and cytogenetic studies have already been conducted on liquid phase material. This allows the dermatopathologist to perform an array of stains that are

Table 34-19 French-American-British Classification of Leukemias

more directed based on the preexisting immu-nophenotypic and genotypic profiles. The purpose of this chapter is to briefly review the primary myeloid, T-cell and B-cell leukemic infiltrates that involve the skin. This chapter does not focus significantly on nonneoplastic skin lesions that could potentially be seen in the spectrum of these conditions. A more detailed analysis of these various leukemias can be obtained by consulting the various hematopathology textbooks currently available.

CLINICAL FEATURES Leukemia cutis lesions have been reported to occur in up to 10% of patients with AML subtypes M0 to M3.10 Clinically, the skin lesions are erythematous or violaceous, slightly elevated papules or nodules (Fig. 34-49 and Table 34-20).204,206,209,210 The eruption of lesions is usually widespread, but in general, the most frequent areas of involvement are the trunk and extremities.9 Hemorrhagic lesions may occur, and nodules may

ulcerate, especially if they enlarge progressively. Painful hemorrhagic infiltrated plaques and nodules involving both the palm and fingers have also been observed.216 Bullous hemorrhagic lesions and painful genital ulcers have been reported as an initial presentation of AML.206,217 Oral involvement occurs in about 4% of patients and may be the initial presentation of the disorder.218 HISTOPATHOLOGICAL FEATURES Biopsy specimens from specific skin lesions of AML show a dense leukemic infiltrate in the upper and deep dermis that usually extends to the subcutaneous tissue (Fig. 34-49B). It is generally separated from the epidermis by a narrow grenz zone, although the dermal-epidermal interface may be obliterated. The infiltrates typically surround the dermal blood vessels, hair follicles, and sweat glands.219-221 Transmural infiltration of dermal blood vessels and intravascular collections of atypical myeloid cells may be found. In some instances, the vessel is not only permeated by leukemic cells but may show evidence of vascular

CLASSIFICATION OF LEUKEMIAS The French-American-British (FAB) classification of leukemias is based on the morphologic appearance of bone marrow and blood leukemic blasts, supplemented by cytochemical and immunohistochemical stains.211-213 The FAB classification of leukemias in which leukemic skin infiltrates occur is shown in Table 34-19.

A

CHAPTER 34 ■ LYMPHOID, LEUKEMIC, AND OTHER CELLULAR INFILTRATES

Acute Leukemias M0 Acute myeloid leukemia with minimal evidence of myeloid differentiation M1 Acute myeloid leukemia without maturation M2 Acute myeloid leukemia with maturation M3 Acute promyelocytic leukemia M4 Acute myelomonocytic leukemia M5 Acute monocytic leukemia M6 Acute erythroleukemia M7 Acute megakaryoblastic leukemia Acute lymphoblastic leukemia Chronic Leukemias Chronic myeloid leukemia Chronic lymphocytic leukemia T-cell prolymphocytic leukemia Adult T-cell leukemia/lymphoma Hairy cell leukemia Chronic myelomonocytic leukemia

essential requirement for diagnosis. The AML types differ with respect to cell line and degree of differentiation. In AML with minimal evidence of myeloid differentiation (M0) or without maturation (M1), the predominant cell is undifferentiated by light microscopy, is peroxidase negative, and expresses CD34 and CD33 but lacks CD15. In AML with maturation (M2), myeloblasts with granules and promyelocytes account for more than 50% of nucleated cells. Acute promyelocytic leukemia (APL, M3) is recognized by a predominance of promyelocytes.215

Acute Myeloid Leukemia Acute granulocytic (myeloid) leukemia (AML) (M0-M3) accounts approximately for 40% to 50% of all acute leukemias, with the incidence of the different FAB types reported as 18% for M1, 28% for M2, and 8% for M3.214 Demonstration of the accumulation of blasts resulting from the block in differentiation characteristic of AML is the

B  FIGURE 34-49 (A) Leukemia cutis involving face. (B) Acute myelocytic leukemia (AML, M2). Diffuse dermal infiltrate of leukemic cells.

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Table 34-20 Leukemic Skin Infiltrates of Myeloid Leukemias

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Clinical Features Erythematous papules and nodules Usually widespread, mainly on the trunk Sometimes solitary nodule Ulceration may occur Gingival involvement, especially in AMoL Aleukemic leukemia cutis may occur Histopathologic Features Nodular or diffuse infiltrates of atypical myeloid cells Subcutaneous tissue mostly involved Grenz zone mostly present Medium to large mononuclear cells with large nuclei (myeloblasts and myelocytes, AML) Medium-sized or large mononuclear cells with indented or kidney-shaped nuclei (AMMoL,AMoL) Thin rows of neoplastic cells between collagen bundles (“Indian file”) Concentric layering of neoplastic cells around blood vessels Mitotic figures frequent Immunohistochemistry Predominant reactivity for lysozyme, myeloperoxidase, CD68, CD74, CD43, CD45 Differential Diagnosis Metastatic carcinoma Malignant melanoma Merkel cell carcinoma B-lymphoblastic lymphoma Sweet syndrome Cutaneous extramedullary hematopoiesis

compromise as evidenced by red blood cell extravasation in concert with mural and/or luminal fibrin deposition. Typically, the leukemic myeloid cells spread between the collagen bundles and permeate the interstitial spaces of the fat lobule.207,219 (see Table 34-20). The infiltrate of AML is composed predominantly of medium-sized or large atypical myeloblasts and myelocytes with round or oval basophilic nuclei and prominent nucleoli.220 Immature atypical myeloid cells with bizarre nuclei are frequently present.219 Also, there may be admixtures of polymorphonuclear leukocytes, although the numbers are small. AML M0 is characterized by a monomorphous infiltrate of mediumsized blasts with folded vesicular nuclei.222 Mitotic figures are a consistent finding in the infiltrate of AML.220 A prominent giant cell reaction occurring singly among the neoplastic cells or

 FIGURE 34-50 Acute myelocytic leukemia (AML, M2). Dense infiltrate of neoplastic cells showing positive staining for myeloperoxidase.

forming granulomas in the leukemic infiltrate of AML FAB subtype M1 has been reported.223 HISTOCHEMICAL AND IMMUNOHISTOCHEMICAL FINDINGS Staining for lysozyme and myeloperoxidase usually shows positivity in specific infiltrates of AML subtypes (Fig. 34-50).219,224-226 However, staining for chloroacetate esterase is variable and may be negative in some M1 to M3 subtypes of AML.220 In addition, neoplastic cells are usually positive for CD68.226 Expression of CD56 has been reported in specific skin infiltrates of some patients with AML.220,227 CD56 expression in AML has been associated with an increased incidence of leukemia cutis and a poor prognosis.228,229

Monocytic Leukemia Acute monocytic leukemia (AMoL, FAB M5) accounts for approximately 10% of all cases of acute nonlymphocytic leukemia.230 Extramedullary disease is more common in AMoL than in other subtypes of leukemia and is associated with a worse prognosis. Leukemic skin infiltrates are present in 10% to 30% of patients with AMoL.206,210 CLINICAL FEATURES The neoplastic skin lesions in AMoL are violaceous to red-brown papules, nodules, and

plaques. 220,231,232 The eruption occurs all over the body and may involve the face and scalp. Leukemic gingival hyperplasia is a characteristic feature of AMoL, occurring in up to 60% of patients.218 Rarely, leukemic skin infiltrates may be observed before evidence of leukemic involvement is found in the bone marrow.233-236 This condition, known as aleukemic leukemia cutis, has a poor prognosis in adults. Aleukemic skin lesions present as solitary or multiple red or violaceous papules or cutaneous and subcutaneous nodules.235 Congenital monocytic leukemia is a rare form. Among 175 cases of congenital leukemia, 14 of the 41 patients with leukemic skin infiltrates had AMoL.237 Skin lesions present as red-brown to purple papules and nodules and may have a “blueberry muffin” appearance.238 HISTOPATHOLOGIC FEATURES A dense perivascular or a more diffuse and confluent infiltrate is found predominantly in the dermis but may often involve the lower part of the dermis and extend into the subcutis (Figs. 34-51 and 34-52).219,220,239 The epidermis is uninvolved. Usually, there is a concentric layering of neoplastic cells around blood vessels and adnexal structures. Infiltration and disruption of the cutaneous adnexa by leukemic infiltrates are present in some biopsy specimens. In most cases, thin rows of atypical cells migrating between collagen bundles, called an Indian file array, can be identified

esterase may be present in AMoL; however, in some patients, negative staining or only a weak reactivity is seen. Myeloperoxidase is less useful, and some cases show little or no positivity. The atypical cells are negative for CD20, CD3, CD34, and CD117. CD56 expression may be observed.228 In addition, the cells are characteristically CD4 positive.

Myelomonocytic Leukemia Myelomonocytic leukemia (AMMoL, FAB M4) represents about 25% of all cases of acute nonlymphocytic leukemia.230 In AMMoL, both granulocytic and monocytic precursors are present in varying proportions, and each cell line accounts for at least 20% of nucleated bone marrow cells. Leukemic mucocutaneous lesions are found in 13% to 27% of patients.207,218

 FIGURE 34-52 Acute monocytic leukemia (AMoL, M5) showing a dense infiltrate in the subcutaneous tissue.

at the periphery of the infiltrate (Fig. 34-53 and Table 34-20). Cytologically, the infiltrate is composed of a monomorphous population of medium-sized, round to oval neoplastic cells with large folded or kidney-shaped basophilic nuclei and a basophilic cytoplasmic seam (Fig. 34-54).219,220 Large, atypical mononuclear cells with hyperchromatic, irregular nuclei are frequently present in the infiltrate. Atypical mitotic figures vary

in number but may be frequent. A few granulocytes and extravasated erythrocytes are intermingled with the tumor cells. There may be prominent interstitial mucin deposition. HISTOCHEMICAL AND IMMUNOHISTOCHEMICAL FINDINGS The leukemic infiltrate in most cases of AMoL show strong reactivity for CD68 and lysozyme (Fig. 34-55A).225,226,240 Chloroacetate

CLINICAL FEATURES Most patients have multiple red or purple asymptomatic papules, nodules, or plaques on the head, trunk, or extremities.207,218,220 The gums are involved in about 18% of patients.218 Specific infiltrations into scars of previous sites of catheter placement, trauma, burns, and herpes simplex may occur.207 In rare cases, the clinical features of the lesions may be atypical, with the initial appearance being reported as a bullous,241 conjunctival lesion242 or as a vesiculopapular rash mimicking chickenpox.243 CD56 positivity in patients with AMMoL presenting with fast-growing tumors appears to be associated with a highly aggressive clinical course and a poor prognosis. Less commonly, the leukemic skin infiltrates

CHAPTER 34 ■ LYMPHOID, LEUKEMIC, AND OTHER CELLULAR INFILTRATES

 FIGURE 34-51 Acute monocytic leukemia (AMoL, M5). Nodular to diffuse infiltrate of atypical cells in the dermis. There is a sparing of the papillary dermis.

DIFFERENTIAL DIAGNOSIS A tumor showing both CD4 and CD56 positivity may be confused with CD4+, CD56+ hematodermic neoplasm (Fig. 34-55B to 3455E). Figure 34-55B illustrates a striking interstitial and angiocentric infiltrate composed of a monomorphic infiltrate of small- to intermediate-sized mononuclear cells with a finely dispersed chromatin and inconspicuous nucleoli. The cytoplasms are minimal. There is a paucity of other inflammatory elements. The tumor cells that define this neoplasm have a highly characteristic phenotypic profile that includes CD4 (Fig. 3455C), CD56 (Fig. 34-55D), and CD123 positivity (Fig. 34-55E). Nevertheless, some cases of AMoL may be CD123 positive. Perhaps the most useful differentiating stains are CD68 and lysozyme, which are negative in CD4+, CD56+ hematodermic neoplasms.

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(Fig. 34-57). In addition, infiltration and destruction of vessels and skin appendages are characteristic of AMMoL. Rarely, a granulomatous pattern of the leukemic infiltrate may occur (see Table 34-20).244 HISTOCHEMICAL AND IMMUNOHISTOCHEMICAL FINDINGS Most leukemic cells in the infiltrate show strong immunoreactivity for CD68 and lysozyme (Fig. 34-58).220,226,240 Staining for chloroacetate esterase is variable, and positive as well as negative reactions may occur.220 Most cases also show a strong positive reaction for myeloperoxidase, although negative staining may be observed in some cases. A variable expression for CD4, CD56, and CD117 has been observed.226

 FIGURE 34-53 Acute monocytic leukemia (AMoL, M5). Leukemic cells with large round to oval or folded basophilic nuclei infiltrate between the collagen bundles.

Chronic Myeloid Leukemia Chronic myeloid leukemia (CML) is a disorder of hematopoietic stem cells accounting for 15% of adult leukemias. The median age at presentation is between 50 and 60 years. The majority of patients present in the chronic phase with relatively stable disease. Unpredictably, the disease eventually transforms into accelerated and blastic phases, becoming more resistant to treatment. CML was one of the first diseases in which a specific chromosomal abnormality was identified, a Philadelphia (Ph’) chromosome resulting from the t(9;22)(q34;q11) chromosomal translocation.245,246 Juvenile CML, a rare malignancy in childhood, is characterized by a rapidly progressive course.  FIGURE 34-54 Acute monocytic leukemia (AMoL, M5). Dense nodular infiltrate of atypical mononuclear cells in the deep dermis.

may be evident before leukemia is detected in the peripheral blood and bone marrow.244

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DIFFERENTIAL DIAGNOSIS As with acute monocytic leukemia, the differential diagnosis also encompasses CD4+, CD56+ hematodermic neoplasm. As a point of reiteration, these lesions (ie, CD4+, CD56+ hematodermic neoplasm) do not show immunoreactivity for CD68, lysozyme, and myeloperoxidase.

HISTOPATHOLOGIC FEATURES A dense infiltrate of atypical mononuclear cells is seen throughout the dermis and in the subcutaneous fat (Fig. 34-56). A distinct grenz zone overlies the infiltrate and separates it from the epidermis.219,220

Occasionally, focal involvement of the epidermis may be seen.240 There are medium- and large-sized atypical cells with large basophilic nuclei, single nucleoli, and slightly eosinophilic cytoplasms.219,220 Scattered eosinophils and lymphocytes are present throughout the lesion. Mitotic figures may be seen. The tumor cells are arranged in strands and cords, spreading between collagen bundles

CLINICAL FEATURES Specific (ie, neoplastic) skin lesions in CML are uncommon, with a reported incidence of 2% to 8%. The lesions are erythematous papules, plaques, or nodules (Table 34-21). They occur anywhere on the skin and may be generalized in distribution. Occasionally, only a single lesion is present.247 Circinate erythematous annular plaques and nodules have been described in a few patients with juvenile CML.248 HISTOPATHOLOGIC FEATURES A dense nodular to diffuse infiltrate is present.

B

C

D

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A

E  FIGURE 34-55 (A) Acute monocytic leukemia (AMoL, M5). The neoplastic cells strongly express CD68. (B) Hematodermic neoplasm. There is a striking interstitial and angiocentric infiltrate composed of a monomorphic infiltrate of small- to intermediate-sized mononuclear cells with a finely dispersed chromatin and inconspicuous nucleoli. The cytoplasms are minimal. There is a paucity of other inflammatory elements. (C) The tumor cells which define this neoplasm have a highly characteristic phenotypic profile which includes CD4 positivity. (D) Characteristically the tumor cell express CD56 and (E) CD123.

945

HISTOCHEMICAL AND IMMUNOHISTOCHEMICAL FINDINGS In CML, leukemic cells strongly stain for CD43, CD45, CD68, lysozyme, and myeloperoxidase.220 In addition, the presence of CD56 expression in specific skin infiltrates of CML has been reported.227

PART IV ■ PROLIFERATIONS—HAMARTOMAS, HYPERPLASIAS, AND NEOPLASIAS

Granulocytic Sarcoma Granulocytic sarcoma is an extramedullary tumor mass composed of immature cells of the myeloid series that may occur specifically as a manifestation of AML, in the course of myelodysplastic syndrome, or as an isolated tumor in patients without evident hematologic disorders.249 The disease has been reported to occur in 2% to 8% of patients with acute nonlymphoblastic leukemia.250,251

 FIGURE 34-56 Acute myelomonocytic leukemia (AMMoL, M4). Diffuse infiltrate of atypical cells in the dermis.

 FIGURE 34-57 Acute myelomonocytic leukemia (AMMoL, M4). Rows of atypical cells migrating between collagen bundles.

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The infiltrate is most often concentrated in the dermis but may also involve the subcutaneous fat. In CML, the infiltrate is more pleomorphic and dominated by granulocytes in various stages of differentiation, including atypical myelocytes,

metamyelocytes, eosinophilic metamyelocytes, and neutrophils.219,220 The neutrophils characteristically exhibit dysplastic features characterized by hyperlobation, nuclear lobe asymmetry, and hypogranularity.

CLINICAL FEATURES Clinically, the patients present with single or multiple erythematous or violaceous nodules.224,252 When cut, the nodules may also have a diagnostic yellow-green coloration caused by the high concentration of myeloperoxidase, which changes color on exposure to air. The trunk, head, and extremities are the most commonly affected sites. Occasionally, the oral mucosa and conjunctiva are also involved.224,253 In patients with underlying myelodysplastic syndrome (MDS), the development of granulocytic sarcoma portends an aggressive clinical course with blast transformation. Granulocytic sarcoma rarely occurs in the setting of MDS, and factors that have been associated with its development include CD56 expression, trisomy 8, and an 8;21 translocation. In one comprehensive review of MDSassociated granulocytic sarcoma, 32 of the 46 cases occured in the absence of AML. Of the 32 patients, 47% developed AML 38 weeks after the initial diagnosis of the granulocytic sarcoma; the other patients did not develop AML. HISTOPATHOLOGIC FEATURES In granulocytic sarcoma, a diffuse, confluent infiltrate consisting of a mixture of immature myeloid cells is present throughout the dermis and in the subcutaneous tissue (Fig. 34-59).224,250 The atypical hematopoietic cells may show marked variation in size and nuclear configuration. An inflammatory infiltrate of eosinophils, neutrophils, and small lymphocytes may be present. HISTOCHEMICAL AND IMMUNOHISTOCHEMICAL FINDINGS In most cases of granulocytic sarcoma, the tumor cells show

Myelodysplastic Syndrome MDS consists of a heterogeneous group of stem cell disorders that includes refractory anemia, refractory anemia with ring sideroblasts, refractory anemia with excess of blasts, refractory anemia with excess of blasts in transformation, and chronic myelomonocytic leukemia (CMMoL).254,255

strong reactivity for myeloperoxidase and lysozyme. 224 There is a variable expression for CD45, CD43, CD68, and CD15.224,249 A percentage of these cases may be CD56 positive. DIFFERENTIAL DIAGNOSIS In terms of distinguishing granulocytic sarcoma from CD4+, CD56+ hematodermic neoplasms, most cases of the latter express plasmacytoid dendritic cell markers such as MXA, CD83, and CD123, and TCL1 oncogene

is negative. Conversely, lysozyme and CD68 are positive in granulocytic sarcoma and negative in CD4+, CD56+ hematodermic neoplasm. One caveat is that CD123 can be expressed at lower levels by monocyte precursors, so expression of CD123 does not rule out a diagnosis of myelomonocytic leukemia.

HISTOPATHOLOGIC FEATURES In MDS, the predominant microscopic finding is a dense infiltrate of medium- to large-sized cells with indented hyperchromatic nuclei in the dermis and subcutaneous fat. The infiltrate tends to surround and invade dermal blood vessels, hair follicles, and sweat glands. Vasculitis with leukemic infiltration may be seen in cutaneous

CHAPTER 34 ■ LYMPHOID, LEUKEMIC, AND OTHER CELLULAR INFILTRATES

 FIGURE 34-58 Acute myelomonocytic leukemia (AMMoL, M4). Atypical myeloid cells show strong reactivity for lysozyme.

CLINICAL FEATURES Specific skin lesions are uncommon in MDS, and only a few cases have been reported.8,256,257 The appearance of specific lesions is a poor prognostic indicator and is usually associated with transformation into the blastic phase. The specific skin lesions in MDS are described as multiple red to violaceous papules and nodules.257 Hemorrhagic lesions may be present on the hands and feet. Unusual specific cutaneous lesions are ecchymoses, necrotic plaques or ulcers, and prurigo-like lesions.258 Specific cutaneous involvement is rare in CMMoL.259 An erythematous, infiltrated plaque as a first sign of CMMoL has been reported.260

Table 34-21 Leukemic Skin Infiltrates of Chronic Myeloid Leukemia

Clinical Features Age 50-60 years Rare juvenile form Erythematous papules, plaques or nodules Almost any location Histopathologic Features Dense nodular to diffuse infiltrate Subcutaneous tissue frequently involved Pleomorphic infiltrate Atypical myelocytes, metamyelocytes and neutrophils Immunohistochemistry Predominant reactivity for lysozyme, myeloperoxidase, CD43, CD45, CD68

 FIGURE 34-59 Granulocytic sarcoma.

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lesions and is generally an indicator of a poor prognosis.261,262

PART IV ■ PROLIFERATIONS—HAMARTOMAS, HYPERPLASIAS, AND NEOPLASIAS

HISTOCHEMICAL AND IMMUNOHISTOCHEMICAL FINDINGS On paraffin-embedded sections, neoplastic cells express CD43 and CD68 and usually show positivity for lysozyme and myeloperoxidase. A weaker variable expression for CD34,CD117, CD123, and CD4 may be observed.226

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DIFFERENTIAL DIAGNOSIS OF LEUKEMIC MYELOID INFILTRATES The diagnosis of leukemic myeloid skin infiltrates may be extremely difficult with routine histologic examination. The histologic differential diagnosis includes cutaneous B-cell lymphoma, cutaneous lesions of Hodgkin disease, malignant histiocytosis, lymphomatoid papulosis, metastatic undifferentiated carcinomas, Merkel cell carcinoma, and various benign dermatoses (eg, granuloma faciale, erythema elevatum diutinum, mastocytosis, secondary syphilis, acute febrile neutrophilic dermatosis [Sweet syndrome], and neutrophilic eccrine hidradenitis).263-265 The histologic differentiation may be problematic, and a clinicopathologic correlation is important in establishing a diagnosis. Leukocyte common antigen (CD45) helps to exclude poorly differentiated carcinomas. Positive staining for lysozyme, myeloperoxidase, chloroacetate esterase, and CD68 favors the diagnosis of a specific skin infiltrate of myeloid leukemia.220,226 Cutaneous lesions of Hodgkin lymphoma express CD30, CD15, CD25, and HLA-DR and are negative for CD45R. Blastic NK-cell lymphoma should show immunoreactivity for CD4, CD56, and CD123 but is negative for myeloid markers. The tumor cells of B-cell lymphoma express B-cell associated antigens. Lymphomatoid papulosis is of T-cell origin with a CD3+, CD4+, CD8−, and CD30+ phenotype. The presence of immature myeloid cells and dysplastic-appearing neutrophils are indicative of malignancy and should be differentiated from benign neutrophilic infiltrates. Erythema elevatum diutinum is ruled out by the presence of leukocytoclastic vasculitis. Neutrophils, pyknotic neutrophil nuclei, and neutrophil fragments are hallmarks of acute febrile neutrophilic dermatosis.266 Sweet syndrome is typically characterized by a benign neutrophilic infiltrate, but in a biopsy taken from a patient with AML, the dermal infiltrate may contain leukemic cells especially in regards to those cells lying in close apposition to blood vessels.267 It should be kept in mind that vasculitis

composed of leukemic cells may accompany the leukemic skin infiltrates and is generally associated with an aggressive clinical course.262

Chronic Lymphocytic Leukemia, B-Cell Type Chronic lymphocytic leukemia (B-CLL) is a B-cell neoplasm and the most frequent form of leukemia in Western countries, accounting for nearly 25% of all leukemias with an estimated annual age-adjusted incidence of three to five per 100,000 persons. The median age at diagnosis is approximately 70 years, and the disease affects men twice as frequently as women.268,269 CLINICAL FEATURES Specific skin lesions occur in approximately 8% of patients with CLL. The reported incidence of cutaneous lesions ranges from 4% to 45% if one takes into account nonspecific findings including purpura, ecchymoses, and maculopapular eruptions.10,270 The lesions are solitary, or more often multiple, red or violaceous macules, papules or nodules (Table 34-22). 270,271 Large

Table 34-22 Leukemic Skin Infiltrates of Chronic Lymphocytic Leukemia

Clinical Features Most common form of leukemia in adults Older than 60 years old Men and women affected equally Red or violaceous macules, papules, and nodules Often ulcerated, large nodules Located on face, scalp, trunk, and extremities Sometimes at site of herpes zoster and herpes simplex scars Histopathologic Features Patchy perivascular and periadnexal lymphoid infiltrate Nodular or diffuse infiltrate Bandlike infiltrate in the upper and middle dermis May involve subcutaneous tissue Immunophenotype CD5+, CD19+, CD20+, CD23+ Monoclonal expression of either κ or γ chain Molecular Biology Clonal rearrangement of Ig heavy (IgH) Differential Diagnosis Immunocytoma Cutaneous B-cell lymphoma Cutaneous B cell pseudolymphoma Lymphocytic infiltration Jessner-Kanof Mycosis fungoides

nodules may become necrotic and ulcerated. The lesions tend to occur on limited areas of the body, mainly the trunk, extremities, face, and scalp, but often spread and become generalized.9,272 Specific cutaneous infiltrates arising at the site of herpes zoster and herpes simplex scars are common.273,274 These lesions may be a temporary phenomenon and frequently regress without treatment.275 In patients with CLL, infection with B. burgdorferi may also trigger the development of specific cutaneous infiltrates at sites typical for lymphadenosis benigna cutis such as the nipple, scrotum, and earlobe.276 In addition, a predilection for specific infiltrates to arise at the site of squamous cell carcinoma, basal cell carcinoma, and actinic keratosis has been observed.277 The clinical lesions may have striking variations in their morphologic features and distribution. Atypical manifestations may present as chronic paronychia,278 subungual nodules, plaques on the volar surface of the hands and fingers,279 finger clubbing with periosteal bone destruction,280 and papulovesicular eruptions.281 Involvement of the mucous membranes is rare. The prognosis of patients with specific skin lesions is probably not affected by skin involvement.272 HISTOPATHOLOGIC FEATURES Three main patterns of skin infiltrates can be distinguished in CLL: a superficial and deep perivascular and periadnexal infiltrate, a nodular-diffuse infiltrate and a bandlike infiltrate (Fig. 34-60 and Table 34-22). 272 Extensive involvement of the subcutaneous tissue is usually seen, particularly in large nodular lesions. A grenz zone of normal dermis is seen between the uninvolved epidermis and the dermal infiltrate, although the infiltrate occasionally extends close to the dermal-epidermal junction, with isolated epidermotropic lymphoid cells.219,272 Occasionally, a subepidermal bullous separation, accompanied by edema of the superficial dermis, may be present. Less commonly, leukemic infiltrates may invade the walls of blood vessels. Cyclic lymphocytic vasculitis associated with CLL has been reported.282 A granulomatous reaction composed of epithelioid and giant cells may occur, especially in skin infiltrates at sites of previous herpes infections.273 At higher magnification, the infiltrate is monomorphous and composed mainly of small- to medium- sized lymphocytes with a round nucleus and dense nuclear chromatin.219,272 Eosinophils, neutrophils, and plasma cells also may be present in the infiltrate (Fig. 34-61).

CD20, CD23, and CD5 positivity.269,272 The detection of a monoclonal restriction to either κ or λ immunoglobulin light chain is an important feature of malignant cells in B-CLL. The neoplastic cells express monoclonal sIgM or sIgM and sIgD. Demonstration of light-chain restriction may be difficult in formalin-fixed tissue and frozen sections are usually required for optimal analysis. MOLECULAR BIOLOGY Clonal rearrangement of Ig heavy (IgH) is demonstrable in most cases.272

 FIGURE 34-60 Chronic lymphocytic leukemia (B-CLL) showing a nodular-diffuse pattern of infiltrate in the dermis.

The entity T-cell chronic lymphocytic leukemia has been reclassified as T-cell prolymphocytic leukemia (T-PLL) according to the WHO classification.283 T-PLL is a rare and aggressive neoplasm of T cells, usually with a mature immunophenotype. It accounts for approximately 2% of all forms of small lymphocytic leukemias in adults older than age 30 years.284,285 CLINICAL FEATURES T-PLL is characterized by the presence of lymphocytosis, lymphadenopathy, splenomegaly, and skin involvement.283-286 The median age at presentation is 63 years (range, 33-91 years). The skin is frequently involved, with a reported incidence between 25% and 30%.287 Patients with T-PLL present with edema, petechial or purpuric rash, and macular and papular lesions. Other manifestations include diffuse infiltrative erythema, nodules, and erythroderma. The lesions are usually found on the face and trunk and may show a symmetrical and linear distribution.286,288 Facial involvement with or without associated swelling is a characteristic finding.286,287

 FIGURE 34-61 Chronic lymphocytic leukemia (B-CLL). There is a periadnexal infiltrate of small- to medium-sized lymphoid cells. Note the presence of eosinophils.

IMMUNOHISTOCHEMICAL FINDINGS B-CLL cells are characterized by a CD19+, CD20+, CD43+, CD23+, and CD5+ immunophenotype (Fig. 34-62A). In Fig. 34-62B to 34-62E, one sees a well-differentiated

small lymphocytic infiltrate that was found peripheral to an infiltrating squamous cell carcinoma. The lymphocytes showed a typical chronic lymphocytic leukemia phenotypic profile comprising

HISTOPATHOLOGIC FEATURES A bandlike infiltrate involving the superficial dermis or a perivascular or periadnexal infiltrate in the dermis are the most prevalent findings in skin biopsies of T-PLL patients.286-288 Focal epidermotropism is usually present. In some cases, the infiltrate extends to the subcutaneous tissue. Prominent red cell extravasation is a frequent finding. Fig. 34-63A shows a predominantly angiocentric lymphocytic infiltrate surrounding and permeating vessels. The cells are intermediate in size with finely dispersed chromatin, somewhat eccentrically disposed nuclei, and eosinophilic rims of cytoplasm. There is attendant red cell extravasation (Fig. 34-63B). The infiltrate usually consists of small- and medium-sized

CHAPTER 34 ■ LYMPHOID, LEUKEMIC, AND OTHER CELLULAR INFILTRATES

T-Cell Prolymphocytic Leukemia

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PART IV ■ PROLIFERATIONS—HAMARTOMAS, HYPERPLASIAS, AND NEOPLASIAS

A

B

C

D

E  FIGURE 34-62 (A) Chronic lymphocytic leukemia (B-CLL). Perivascular pattern of infiltrate of CD20+ cells. (B) Chronic B-CLL. In this collage, one sees a well-differentiated small lymphocytic infiltrate that was found peripheral to an infiltrating squamous cell carcinoma. The lymphocytes showed a typical chronic lymphocytic leukemia phenotypic profile composed of (C) CD20 positivity, (D) CD23 positivity, and (E) CD5 positivity.

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lymphoid cells with a finely dispersed heterochromatin and a single nucleous. However, tumor cells may show a significant degree of nuclear pleomorphism, and large tumor cells with irregularly shaped nuclei or atypical lymphoid

cells with cerebriform or Sézary cell-like nuclei can be observed.286,288 IMMUNOHISTOCHEMICAL FINDINGS In the majority of cases, the tumor cells express CD4, CD3, CD7, CD52, and TCL-1

(T-cell leukemia 1 proto-oncogene antibody). Whereas CD4 and CD8 are coexpressed in 25% of cases, the CD4−/CD8+ phenotype is rare. Twenty percent of cases of T-PLL are CD3-.285,286,289 Clonal rearrangement of the T-cell receptor

B

 FIGURE 34-63 (A) T-cell prolymphocytic leukemia (T-PLL). The biopsy shows a predominantly angiocentric lymphocytic infiltrate surrounding and permeating vessels. The cells are intermediate in size with finely dispersed chromatin, somewhat eccentrically disposed nuclei, and eosinophilic rims of cytoplasm. (B) The neoplastic cells in T-PLL express CD7. This is an important finding because most cutaneous T-cell malignancies show a loss of CD7 expression.

(TCR) can be demonstrated in all cases. The expression of CD7 is a very important finding because most T-cell dyscrasias are associated with a loss in the expression of CD7.

Hairy Cell Leukemia Hairy cell leukemia (HCL) is a rare B-cell lymphoproliferative disease characterized by splenomegaly, pancytopenia and circulating leukemic cells that infiltrate the bone marrow, liver, and spleen but rarely the lymph nodes.290 HCL accounts for about 2% to 3% of all leukemias in adults in the Western world. The cells of typical HCL have characteristic prominent cytoplasmic projections and are strongly positive for tartrate-resistant acid phosphatase.

surrounds dermal blood vessels and skin appendages. Less commonly, the infiltrate extends deeply throughout the entire dermis and into subcutaneous tissue.294 The HCL cells are small to medium in size and have an abundant pale cytoplasm and hyperchromatic rounded or indented nuclei. In the bone marrow biopsy specimen shown in Fig. 34-64, the cells have a well differentiated monotypic appearance with clear cytoplasms and sharp cytoplasmic borders. The cells are juxtaposed to one another

without any overlap, imparting an orderly mosaic-like arrangement to the infiltrate. Typically, the nuclei are separated from each other by clear cytoplasmic spaces.Cytoplasmic hairy projections cannot be seen in fixed tissue sections. Usually, there are a small number of neutrophils, eosinophils, and histiocytes. Mitoses are absent.291,295 HISTOCHEMICAL AND IMMUNOHISTOCHEMICAL FINDINGS Most infiltrating hairy cells stain strongly with tartrate-resistant

CLINICAL FEATURES Leukemic skin infiltrates are rarely observed in patients with HCL, and their presence should be proven by skin biopsy.291 Specific skin lesions were seen in 48 (8%) of the 600 cases reported in the literature, but only eight cases were proven by skin biopsy.291 In another series of 113 patients, only one patient had skin infiltration by leukemic cells.292 The lesions usually are erythematous maculopapular eruptions.291 Deep infiltrated nodules of HCL may be present. HCL is also frequently associated with vasculitis.264,292,293 HISTOPATHOLOGIC FEATURES A dense, diffuse or patchy infiltrate of uniform mononuclear cells is present predominantly in the upper dermis. The epidermis is not involved. The infiltrate usually

 FIGURE 34-64 Hairy cell leukemia. In this peripheral blood sample, one can see discernible hairylike, fine cytoplasmic projections.

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A

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acid phosphatase. Hairy cells typically express the B-cell-associated antigens CD19, CD20, CD22, and CD79a. They are usually positive for CD11c, CD25, and CD103 and negative for CD5, CD10, and CD23.290

PART IV ■ PROLIFERATIONS—HAMARTOMAS, HYPERPLASIAS, AND NEOPLASIAS

Adult T-Cell Leukemia/Lymphoma

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Adult T-cell leukemia/lymphoma (ATLL) is an aggressive lymphoproliferative disorder of CD4+ T cells caused by the human T-cell leukemia virus type I (HTLVI).296-299 Leukemic cells usually have large, highly convoluted nuclei, called flower cells, and characteristically display the mature T-cell phenotype.299,300 ATLL is endemic in the southwestern district of Japan, the Caribbean, South America, and central Africa.298,301 The lifetime risk of developing ATLL among HTLV-I–infected persons is 2.5%.297 ATLL occurs only in adults. The age at onset ranges from 24 to 85 years (average, 58 years).297 CLINICAL FEATURES The classification of ATLL is based on clinical manifestations and laboratory findings and includes four types: the acute, chronic, smoldering, and lymphoma types.296,297,299 Acute ATLL is the best characterized form of the disease and is characterized by a high-grade leukemia, generalized lymphadenopathy, hepatosplenomegaly, skin lesions, leukemic involvement of the bone marrow, and rapid clinical progression. Smoldering ATLL, in particular, presents with predominantly cutaneous manifestations and a protracted clinical course before progressing to an acute, aggressive terminal phase. In addition to the clinical features, the diagnosis of ATLL is based on the immunophenotype of atypical lymphocytes, the presence of circulating antibodies against HTLV-I, and monoclonal integration of the HTLV-I provirus in the tumor cell DNA.296,297,299 In up to 50% of ATLL cases, there is a cutaneous infiltration of malignant T cells. Cutaneous manifestations of ATLL can be quite variable.302 Nodules, tumors, and red papules are the most frequent manifestation. ATLL also presents as generalized erythroderma.303,304 Manifestation as solitary nodule has been reported.305 Patients with papules and nodules have a poorer prognosis than those with erythematous lesions. A median survival time of 14 months for patients with monoclonal proviral DNA integration in cutaneous lesions was reported.306 Spontaneous regression of cutaneous lesions may occur in patients with ATLL.307

HISTOPATHOLOGIC FEATURES There is a dense lymphoid infiltrate that is often concentrated around blood vessels and appendages. The infiltrate may diffusely involve the full thickness of the dermis and the subcutaneous fat. Exocytosis of atypical lymphoid cells into the epidermis, with or without intraepidermal clusters of cells forming Pautrier microabscesses, is seen frequently.308 However, a nonepidermotropic pattern of infiltration may occur. The cells have medium- to largesized pleomorphic nuclei. Mitotic figures are common. Dermal edema may be prominent. Occasionally, eosinophils and a few plasma cells are present in the infiltrate. The perivascular infiltration is frequently associated with evidence of vasculitis, with destructive changes of blood vessels and extravasation of erythrocytes.303 Rarely, epithelioid granulomas or dermal aggregates of lymphocytes and macrophages resembling granulomas are observed in the cutaneous skin lesions of ATLL.309,310 IMMUNOHISTOCHEMICAL FINDINGS Immunophenotyping with monoclonal antibodies shows that the principal phenotype of the neoplastic cells in the skin of patients with ATLL is the helper T cell that predominantly expresses CD4, CD25, CD62 and CD45RO and usually not CD7, CD8, and CD19.300,303,308 MOLECULAR BIOLOGY Clonal rearrangement of TCR genes is found in the majority of ATLL cases. DIFFERENTIAL DIAGNOSIS OF LEUKEMIC T- AND B-CELL LYMPHOID INFILTRATES Differential diagnosis of the T- and B-cell leukemic lymphoid infiltrates may present difficulties because a myriad of clinical and pathological entities are characterized by an extensive lymphocytic infiltrate. In this regard, one could consider many different histomorphologic possibilities, although they all have distinguishing light microscopic and phenotypic features and they include infiltrates of lupus erythematosus, pityriasis lichenoides, lymphomatoid papulosis, cutaneous lymphoid hyperplasia, actinic reticuloid, angioimmunoblastic lymphadenopathy, and cutaneous lymphomas. The presence of marked epidermotropism usually favors the diagnosis of cutaneous T-cell lymphoma over CLL. Reactive lymphoid hyperplasia exhibits a dominant angiocentric disposition and is characterized by a predominance of T cells. In addition, deposition of mucin may be seen in the reticular dermis. Pityriasis lichenoides is

a form of prelymphomatoid cutaneous lymphoid dyscrasia characterized by an almost pure T-cell lymphocytic infiltrate in an angiocentric and epidermotropic array. The extent of epitheliotropism may be striking. Lymphomatoid papulosis demonstrates an angiocentric infiltrate composed of large atypical mononuclear cells with an admixture of neutrophils and eosinophils. The large aberrant cell populace shows a distinctive phenotypic profile, namely, one exhibiting CD3, CD4, CD30, and granzyme positivity along with other activation markers such as HLA-DR and CD25. In contrast, the leukemic cells in HCL are morphologically uniform and typically stain with a B-cell marker.192 At low-power magnification, leukemic infiltrates of CLL may be difficult to differentiate from cutaneous B-cell pseudolymphomas, but the presence of a nodular dermal infiltrate with reactive follicles together with the demonstration of a polyclonal B-cell proliferation usually helps to exclude a malignant process. Insect bite–like reactions may clinically resemble specific skin lesions of CLL. However, the characteristic histopathologic findings of an insect bite–like reaction are a T cell–dominant lymphocytic infiltrate accompanied by eosinophils.311 The differentiation of ATLL from other cutaneous T-cell lymphomas, such as mycosis fungoides and Sézary syndrome, may be difficult. Knowledge of the clinical features of ATLL and clinical shrewdness can usually solve these diagnostic dilemmas. The lack of damage to blood vessels and the demonstration of HTLV-I proviral integration in the clonal population of malignant T cells can help to differentiate ATLL from cutaneous T-cell lymphoma when the clinical presentation overlaps. T-PPL with a cutaneous infiltrate of Sézary-like cells can usually be distinguished from Sézary syndrome by the clinical, cytogenetic, and molecular features.

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34. Rijlaarsdam JU, Scheffer E, Meijer CJ, et al: Cutaneous pseudo-T-cell lymphomas. A clinicopathologic study of 20 patients. Cancer. 1992;69:717. 35. Medeiros LJ, Picker LJ, Abel EA, et al: Cutaneous lymphoid hyperplasia. Immunologic characteristics and assessment of criteria recently proposed as diagnostic of malignant lymphoma. J Am Acad Dermatol. 1989;21(5, pt 1): 929-942. 36. Guitart J, Variakojis D, Kuzel T, et al: Cutaneous CD8 T cell infiltrates in advanced HIV infection. J Am Acad Dermatol. 1999;41:722. 37. Kempf W, Willemze R, Jaffe ES, et al: CD30+ T-cell lymphoproliferative disorders, in LeBoit, P, Burg G, Weedon D, et al (eds). World Health Organization Classification of Tumours. Pathology and Genetics of Skin Tumours. Lyon: IARC Press; 2006:179. 38. Magro CM, Magro CM, Crowson AN, Kovatich AJ, Burns F: Drug-induced reversible lymphoid dyscrasia: a clonal lymphomatoid dermatitis of memory and activated T cells. Hum Pathol. 2003; 34(2):119-129. 39. Massone C, Kodama K, Kerl H, et al: Histopathologic features of early (patch) lesions of mycosis fungoides: a morphologic study on 745 biopsy specimens from 427 patients. Am J Surg Pathol. 2005;29:550. 40. Shapiro PE, Pinto FJ: The histologic spectrum of mycosis fungoides/Sezary syndrome (cutaneous T-cell lymphoma). A review of 222 biopsies, including newly described patterns and the earliest pathologic changes. Am J Surg Pathol. 1994;18:645. 41. Santucci M, Biggeri A, Feller AC, et al: Efficacy of histologic criteria for diagnosing early mycosis fungoides: an EORTC cutaneous lymphoma study group investigation. European Organization for Research and Treatment of Cancer. Am J Surg Pathol. 2000;24:40. 42. Cerroni L, Rieger E, Hodl S, et al: Clinicopathologic and immunologic features associated with transformation of mycosis fungoides to large-cell lymphoma. Am J Surg Pathol. 1992;16:543. 43. Vergier B, de Muret A, Beylot-Barry M, et al: Transformation of mycosis fungoides: clinicopathological and prognostic features of 45 cases. French Study Group of Cutaneious Lymphomas. Blood. 2000;95:2212. 44. Kazakov DV, Burg G, Kempf W: Clinicopathological spectrum of mycosis fungoides. J Eur Acad Dermatol Venereol. 2004;18:397. 45. van Doorn R, Scheffer E, Willemze R: Follicular mycosis fungoides, a distinct disease entity with or without associated follicular mucinosis: a clinicopathologic and follow-up study of 51 patients. Arch Dermatol. 2002;138:191. 46. Flaig MJ, Cerroni L, Schuhmann K, et al: Follicular mycosis fungoides. A histopathologic analysis of nine cases. J Cutan Pathol. 2001;28:525. 47. Gerami P, Guitart J: The spectrum of histopathologic and immunohistochemical findings in folliculotropic mycosis fungoides. Am J Surg Pathol. 2007;31:1430. 48. Burg, G,Schmockel C: Syringolymphoid hyperplasia with alopecia—a syringotropic

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5. Willemze, R, Kerl H, Sterry W, et al: EORTC classification for primary cutaneous lymphomas: a proposal from the Cutaneous Lymphoma Study Group of the European Organization for Research and Treatment of Cancer. Blood. 1997; 90:354. 6. Jaffe ES, Harris NL, Stein H, et al: World Health Organization Classification of Tumors. Pathology and Genetics of Tumours of Haematopoietic and Lmyphoid Tissues. Lyon: IARC Press; 2001. 7. UICC: TNM Classification of Malignant Tumors, 6th ed. New York: Wiley-Liss; 2002. 8. Olsen, E, Vonderheid E, Pimpinelli N, et al: Revisions to the staging and classification of mycosis fungoides and Sezary syndrome: a proposal of the International Society for Cutaneous Lymphomas (ISCL) and the cutaneous lymphoma task force of the European Organization of Research and Treatment of Cancer (EORTC). Blood. 2007;110:1713. 9. Kim YH, Willemze R, Pimpinelli N, et al: TNM classification system for primary cutaneous lymphomas other than mycosis fungoides and Sezary syndrome: a proposal of the International Society for Cutaneous Lymphomas (ISCL) and the Cutaneous Lymphoma Task Force of the European Organization of Research and Treatment of Cancer (EORTC). Blood. 2007;110:479. 10. Dummer R, Schwarz T: Cytokines as regulatory proteins in lymphoproliferative skin infiltrates. Dermatol Clin. 1994; 12:283. 11. Lessin SR, Vowels BR, Rook AH: Th2 cytokine profile in cutaneous T-cell lymphoma. J Invest Dermatol. 1995;105: 855. 12. Burg G, Zwingers T, Staegemeir E, et al: Interrater and intrarater variabilities in the evaluation of cutaneous lymphoproliferative T-cell infiltrates. EORTCCutaneous Lymphoma Project Group. Dermatol Clin. 1994;12:311. 13. Kempf, W, Haeffner AC, Mueller B, et al: Experts and gold standards in dermatopathology: qualitative and quantitative analysis of the self-assessment slide seminar at the 17th colloquium of the International Society of Dermatopathology. Am J Dermatopathol. 1998;20: 478. 14. Santucci M, Burg G, Feller AC: Interrater and intrarater reliability of histologic criteria in early cutaneous T-cell lymphoma. An EORTC Cutaneous Lymphoma Project Group study. Dermatol Clin. 1994; 12:323. 15. Holm N, Flaig MJ, Yazdi AS, et al: The value of molecular analysis by PCR in the diagnosis of cutaneous lymphocytic infiltrates. J Cutan Pathol. 2002; 29:447. 16. Wood, GS, Uluer AZ: Polymerase chain reaction/denaturing gradient gel electrophoresis (PCR/DGGE): sensitivity, band pattern analysis, and methodologic optimization. Am J Dermatopathol. 1999;21:547. 17. Bruggemann M, White H, Gaulard P, et al: Powerful strategy for polymerase chain reaction-based clonality assessment in T-cell malignancies Report of the BIOMED-2 Concerted Action BHM4 CT98-3936. Leukemia. 2007;21:215.

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49.

50.

51.

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52.

53.

54. 55. 56.

57.

58. 59.

60.

61.

62. 63.

64.

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CHAPTER 34 ■ LYMPHOID, LEUKEMIC, AND OTHER CELLULAR INFILTRATES

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PART IV ■ PROLIFERATIONS—HAMARTOMAS, HYPERPLASIAS, AND NEOPLASIAS 956

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244. Tomasini C, Quaglino P, Novelli M, et al: “Aleukemic” granulomatous leukemia cutis. Am J Dermatopathol. 1998;20:417. 245. Kalidas M, Kantarjian H, Talpaz M: Chronic myelogenous leukemia. JAMA. 2001;286:895. 246. Holyoake T: Recent advances in the melecular and cellular biology of chronic myeloid leukaemia: lessons to be learned from the laboratory. Br J Haematol. 2001;113:11. 247. Buechner S, Su WPD: Chronic myeloid leukemia (CML), in Burg G, Kempf W (eds). Cutaneous Lymphomas. Boca Raton, FL: Taylor & Francis; 2005:383. 248. Heskel NS, White CR, Fryberger S, et al: Aleukemic leukemia cutis: juvenile chronic granulocytic leukemia presenting with figurate cutaneous lesions. J Am Acad Dermatol. 1983;9:423. 249. Breccia M, Mandelli F, Petti MC, et al: Clinico-pathological characteristics of myeloid sarcoma at diagnosis and during follow-up: report of 12 cases from a single institution. Leuk Res. 2004;28:1165. 250. Sun NCJ, Ellis R: Granulocytic sarcoma of the skin. Arch Dermatol. 1980;116:800. 251. Yamauchi K, Yasuda M: Comparison in treatments of nonleukemic granulocytic sarcoma. Cancer. 2002;94:1739. 252. Buechner S, Su WPD: Granulocytic sarcoma (Chloroma), in Burg G, Kempf W (eds). Cutaneous Lymphomas. Boca Raton, FL: Taylor & Francis; 2005:403. 253. Hon C, Shek T, Liang R: Conjunctival chloroma (granulocytic sarcoma). Lancet. 2002;359:2247. 254. Bennett JM, Catovsky D, Daniel MT, et al: Proposals for the classification of the myelodysplastic syndromes. Br J Haematol. 1982;51:189. 255. Wood BL: Myeloid malignancies: myelodysplastic syndromes, myeloproliferative disorders, and acute myeloid leukemia. Clin Lab Med. 2007;27:551. 256. Avivi I, Rosenbaum H, Levy Y, et al: Myelodysplastic syndrome and associated skin lesions: a review of the literature. Leuk Res. 1999;23:323. 257. Morand J, Lightburn E, Richard M, et al: Skin manifestations associated with myelodysplastic syndromes. Rv Med Interne. 2001;22:845. 258. Aractingi S, Bachmeyer C, Miclea JM, et al: Unusual specific cutaneous lesions in myelodysplastic syndromes. J Am Acad Dermatol. 1995;33:187. 259. O'Connell DM, Fagan WA, Skinner SM, et al: Cutaneous involvement in chronic myelomonocytic leukemia. Int J Dermatol. 1994;33:628. 260. Braga D, Manganoni A, Boccaletti V, et al: Specific skin infiltration as first sign of chronic myelomonocytic leukemia with an unusual phenotype. J Am Acad Dermatol. 1996;35:804. 261. O'Donnell, B, Williams H, Carr R: Myelodysplastic syndrome presenting as cutaneous vasculitis. Clin Exp Dermatol. 1995;20:439. 262. Paydas, S, Zorludemir S: Leukaemia cutis and leukaemic vasculitis. Br J Dermatol. 2000;143:773. 263. Wong TY, Suster S, Bouffard D, et al: Histologic spectrum of cutaneous involvement in patients with myelogenous leukemia including the neutrophilic dermatoses. Int J Dermatol. 1995;34:323.

264. Kurzrock R, Cohen PR: Mucocutaneous paraneoplastic manifestations of hematologic malignancies. Am J Med. 1995; 99:207. 265. Hensley C, Caughman S: Neutrophilic dermatoses associated with hematologic disorders. Clin Dermatol. 2000; 18:355. 266. Jordaan HF: Acute febrile neutrophilic dermatosis. A histopathological study of 37 patients and a review of the literature. Am J Dermatopathol. 1989;11:99. 267. Morgan K, Callen J: Sweet's syndrome in acute myelogenous leukemia presenting as periorbital cellulitis with an infiltrate of leukemic cells. J Am Acad Dermatol. 2001;45:590. 268. Wierda WG, Kipps T: Chronic lymphocytic leukemia. Curr Opin Hematol. 1999;6:253. 269. Yee KOBS: Chronic lymphocytic leukemia: Diagnosis and treatment. Mayo Clin Proc. 2006;81:1105. 270. Robak E, Robak T: Skin lesions in chronic lymphocytic leukemia. Leuk Lymphoma. 2007;48:855. 271. Buechner S, Su WPD: Chronic lymphocytic leukemia, B-cell type (B-CLL), in Burg G, Kempf W (eds). Cutaneous Lymphomas. Boca Raton, FL: Taylor & Francis; 2005:375. 272. Cerroni L, Zenahlik P, Hofler G, et al: Specific cutaneous infiltrates of B-cell chronic lymphocytic leukemia: a clinicopathologic and prognostic study of 42 patients. Am J Surg Pathol. 1996;20:1000. 273. Cerroni L, Zenahlik P, Kerl H: Specific cutaneous infiltrates of B-cell chronic lymphocytic leukemia arising at the site of herpes zoster and herpes simplex scars. Cancer. 1995;76:26. 274. Ziemer M, Bornkessel A, Hahnfeld S, et al: 'Specific' cutaneous infiltrate of B-cell chronic lymphocytic leukemia at the site of a florid herpes simplex infection. J Cutan Pathol. 2005;32:581. 275. Wakelin S, Young E, Kelly S, et al: Transient leukemia cutis in chronic lymphocytic leukemia. Clin Exp Dermatol. 1997;22:37. 276. Cerroni L, Höfler G, Bäck B, et al: Specific cutaneous infiltrates of B-cell chronic lymphocytic leukemia (B-CLL) at sites typical for Borrelia burgdorferi infection. J Cutan Pathol. 2002;29:142. 277. Smoller B, Warnke R: Cutaneous infiltrate of chronic lymphocytic leukemia and relationship to primary cutaneous epithelial neoplasms. J Cutan Pathol. 1998;25:160. 278. High DA, Luscombe HA, Kauh YC: Leukemia cutis masquerading as chronic paronychia. Int J Dermatol. 1985;24:595. 279. Simon CA, Su WPD, Li CY: Subungual leukemia cutis. Int J Dermatol. 1990;29: 636. 280. Calvert RJ, Smith E: Metastatic acropachy in lymphatic leukemia. Blood. 1955;10:545. 281. Desvignes V, Bosq J, Guillaume JC, et al: Eruption papulo-vésiculeuse du visage au cours des leucémies lymphoides chronique. Ann Dermatol Venereol. 1990; 117:880. 282. Cabuk M, Inanir I, Turkdogan P, et al: Cyclic lymphocytic vasculitis associated with chronic lymphocytic leukemia. Leuk Lymphoma. 2004;45:811. 283. Jaffe,ES, Harris NL, Stein H, Vardiman JW: World Health Organization Classification of

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of adult T-cell leukemia/lymphoma with cutaneous manifestations:the smouldering type with skin manifestations has a poorer prognosis than previously thought. J Dermatol. 1999;26:785. 305. Shimizu S, Yasui C, Koizumi K, et al: Cutaneous-type adult T-cell leukemia/ lymphoma presenting as a solitary large skin nodule: a review of the literature. J Am Acad Dermatol. 2007;57(suppl):S115. 306. Yamaguchi T, Ohshima K, Karube K, et al: Clinicopathological features of cutaneous lesions of adult T-cell leukaemia/ lymphoma. Br J Dermatol. 2005;152:76.

307. Kawabata H, Setoyama M, Fukushige T, et al: Spontaneous regression of cutaneous lesions in adult T-cell leukaemia/lymphoma. Br J Dermatol. 2001;144:434. 308. Kempf W, KazakovDV, Burg G: Adult T-cell leukemia/lymphoma, in Burg G, Kempf W (eds). Cutaneous Lymphomas. Boca Raton, FL: Taylor & Francis; 2005: 215. 309. DiCaudo D, Perniciaro C, Worrell J, et al: Clinical and histologic spectrum of human T-cell lymphotropic virus type-1 associated lymphoma involving the skin. J Am Acad Dermatol. 1996;34:69.

310. Setoyama M, Katahira Y, Kanzaki T, et al: Adult T-cell leukemia/lymphoma associated with noninfectious epithelioid granuloma in the skin: a clinicopathologic study. Am J Dermatopathol. 1997;19:591. 311. Ulmer A, Metzler G, Schanz S, et al: Dapsone in the management of “insect bite-like reaction” in a patient with chronic lymphocytic leukaemia. Br J Dermatol. 2007;156:172.

CHAPTER 34 ■ LYMPHOID, LEUKEMIC, AND OTHER CELLULAR INFILTRATES 959

CHAPTER 35 Cutaneous Metastases

PART IV ■ PROLIFERATIONS—HAMARTOMAS, HYPERPLASIAS, AND NEOPLASIAS

Michael S. Rabkin

960

A metastasis is a neoplasm that has spread from its original site such that it is no longer in continuity with, and often not in close proximity to, the primary lesion. Neoplasms may invade the skin by contiguous spread or may spread into the skin by direct extension into surgical scars and needle biopsy tracts, but the usual pathway of regional or distant metastases is believed to involve lymphatic or blood vessels.1-3 The frequency of cutaneous metastases in patients with cancer ranges from 0.6% to 9% in various studies.4-10 In a study of 4020 patients with metastatic carcinoma and melanoma, 420 patients (10.4%) had cutaneous metastases, and cutaneous metastases were the first sign of extranodal metastatic disease in 306 patients (7.6%).10 In another study of 7316 cancer patients, 5% had skin involvement. Skin involvement was the first sign of cancer in 59 patients (0.8%).9 Twenty-two of the latter patients had direct extension of the primary cancer into the skin, 20 had local (satellite) metastases, and 17 had distant metastases. Thus, although skin

metastases are in general relatively uncommon, they may be the initial presentation of an internal malignancy. Cutaneous metastases reflect the biologic behavior and population-based incidence of their associated primary tumors. The greatest incidence of cutaneous metastases is therefore in the fifth, sixth, and seventh decades of life, and the incidence and distribution of cutaneous metastases are correlated with gender. The incidence of primary tumors in women and men with skin metastases from studies by Brownstein and Helwig on 724 patients is listed in the left-hand columns of Table 35-1.4,5 These authors found that the most common primary tumors in women were breast at 69%, followed by large intestine, melanoma, lung and other internal sites. In men, the lung and large intestine were the most common sources (Table 35-1). Skin metastases were the presenting sign of malignancy in men in 37% of cases and in women in 6% of cases, presumably because primary breast cancer in women is often diagnosed at an earlier stage than primary lung and colorectal cancer are diagnosed in men. In a later study by Lookingbill et al.10 of cutaneous metastases in a population of patients with metastatic carcinoma and melanoma (right-hand columns of Table 35-1), the most frequent tumors to metastasize to the skin in 300 women were the breast and melanoma. In 127 men, the most frequent cutaneous metastases were melanoma, the lung, the large intestine, and the oral cavity. The relative proportion

Table 35-1 Sites of Origin of Skin Metastases PRIMARY SITE

WOMEN (%)

MEN (%)

Breast Large intestine Melanoma Lung Ovary Sarcoma Uterine cervix Pancreas Oral cavity Bladder Kidney Stomach Esophagus Salivary gland Prostate Unknown primary site

69/70.7 9/1.3 5/12 4/2 4/3.3 2/0 2/0.7 2/0.3 1/2.3 1/1.3 0/0 0/0.7 0/0 0/0

2/2.4 19/11 13/32.3 24/11.8

0/3

SOURCES: Data from Brownstein and Helwig5 and Lookingbill et al.10

3/0 2/0.8 12/8.7 2/2.4 6/4.7 6/0.8 3/2.4 2/0 1/0 0/8.7

of cutaneous metastases may change with population-based trends in the incidence of the associated primary tumor. For example, the incidence of cutaneous metastases from lung carcinoma in women is higher in more recent series, reflecting the rising incidence of primary lung carcinoma in women.11,12

CLINICAL AND MORPHOLOGIC FEATURES Cutaneous metastases can take a variety of forms and occur in a variety of locations, but these forms and locations are not entirely specific either for the type of tumor or the site of the primary malignancy. Metastatic tumors frequently are fleshcolored nodules or plaques; multiple lesions are more common than solitary lesions, and sometimes multiple lesions are distributed in a zosteriform pattern.10,13-21 Lookingbill et al.10 reported ulceration in 10% of cutaneous breast carcinoma metastases and clinical pigmentation in 36% of cutaneous melanoma metastases. Metastases of renal cell carcinomas and choriocarcinomas are frequently red-purple and hemorrhagic.22-27 In one series from a cancer center, 45% of cutaneous metastases were not initially suspected of being metastases owing to unusual clinical presentations, including inflammatory lesions or rash in 15%, and several metastatic sarcomas and small cell carcinomas would have been misinterpreted as primary skin tumors by experienced pathologists in the absence of adequate clinical history.12 A recent report described clinically incognito cutaneous metastases discovered as an incidental histologic finding in skin specimens.28 Breast carcinoma is associated with eight types of cutaneous metastases if one includes Paget disease.29 These patterns are not unique to breast carcinoma. Inflammatory carcinoma is a red patch that may resemble cellulitis or a figurate or gyrate erythema. Inflammatory carcinoma results from congestion of capillaries and the dilatation and obstruction of lymphatics by tumor cells.30-35 En cuirasse (encasement in armor) metastases demonstrate diffuse morpheiform induration of the skin resulting from dermal sclerosis in association with tumor cells.36-38 Telangiectatic metastases are composed of clustered, violaceous papulovesicles that may demonstrate pigmentation so prominent as to resemble metastatic melanoma. Telangiectatic metastases

tumors in the cervix, urinary tract, prostate, and rectum.4,5,71-74 Local metastases may also develop at the site of scars from previous surgical incisions, usually within 1 year of the procedure; in needle biopsy tracts; or in unrelated surgical or traumatic scars.6,75-80 Scar metastases at the excision site or as the first sign of metastatic disease have been seen with breast, ovarian, colorectal, liver, oral, laryngeal, lung, renal, and endometrial carcinomas and melanoma.6,10 Metastatic tumors may also be seen in persistent abscesses and fistulas after surgery.9,81,82 Distant metastases have been reported in up to 39% of patients with cutaneous metastases.10 Metastases to distant cutaneous sites have been most frequently associated with melanoma and primary carcinomas of the lung and breast. Tumors associated with vascular invasion are more frequently associated with distant metastases.4,83,84 Such tumors include melanoma, renal cell carcinoma, thyroid follicular carcinoma, and choriocarcinoma. Scalp metastases are disproportionately common in renal cell and thyroid carcinomas. Metastatic tumors were the third most common malignant cutaneous tumors of the scalp (12.8%) in a recent series from Taiwan.85 Most of these metastases resulted from primary tumors in the lung. Metastases to extremities are uncommon; usually occur late; and are seen most often with melanoma and less often with breast, lung, kidney, and large intestine carcinomas.4,10 The time of onset of a cutaneous metastasis is variable and reflects the characteristics of the underlying malignancy. However, when a cutaneous metastasis does occur, it usually portends a poor prognosis.4 In one series, half of 200 patients with cutaneous metastases died within the first 6 months after the diagnosis.86 Metastases to the skin can be delayed from 6 to 32 years after diagnosis of the primary lesion with some tumors, notably malignant melanoma and breast, renal cell, thyroid, colon, larynx, ovary, and bladder carcinomas.4,71,87 Epithelioid cell sarcoma is a sarcoma that occurs on the extremities of young adults and is characterized by a long clinical course of local recurrences and distant metastases.88,89

GENERAL APPROACH TO CUTANEOUS METASTASES Metastatic carcinomas can be classified broadly as adenocarcinoma, squamous carcinoma, undifferentiated carcinoma, or miscellaneous carcinomas. The site of

origin is often unclear from the histologic appearance of the metastasis. Metastatic tumors also include melanomas, sarcomas, and cutaneous involvement by hematopoietic malignancies.6,9 Clinical and histologic features and special studies such as immunoperoxidase staining often help identify the primary site of a cutaneous metastasis, but in some instances, a primary tumor is not identified despite a thorough investigation. As detailed elsewhere in this chapter, the age and gender of the patient and the location, distribution, and clinical appearance of the metastasis are of statistical value in identifying a primary tumor. A history of a known primary tumor can, of course, be of great value. It may be helpful to specifically query the clinician on this possibility if a history of malignancy is not supplied on the request slip because a metastasis may not have entered into the clinical differential because of a nonspecific or atypical clinical appearance, a remote history of malignancy (some malignancies may metastasize decades after treatment of the primary lesion),6 or localization of the metastasis far from the primary tumor. Caution in interpretation is necessary in this area because patients may develop more than one primary malignancy, and a cutaneous metastasis may be the presenting sign of a previously occult primary lesion. Histologic and immunohistochemical comparison of the metastasis with the putative primary lesion (if available) may be of value, with the proviso that a metastasis may be more or less differentiated than and otherwise differ from its associated primary lesion. A series of technical advances has made it possible to apply immunohistochemical methods of antigen detection to routinely fixed and embedded tissues. Convenient application to routine and archival specimens, straightforward correlation with conventional histopathology, identification of a broad range of possible target antigens, and in some instances relatively high specificity have led immunohistochemical staining to largely supplant many histochemical stains and ultrastructural examination as a supplement to morphologic judgments based on gross and hematoxylin and eosin morphology.90,91 Molecular methods such as in situ hybridization, polymerase chain reaction, and gene arrays hold great future promise but as of this writing are not in widespread use in surgical pathology laboratories. As with other techniques, the limitations of immunohistochemical studies must be recognized and the studies interpreted

CHAPTER 35 ■ CUTANEOUS METASTASES

demonstrate tumor cells in blood vessels as well as lymphatics. The obstructed lymphatics are more superficial than the obstructed lymphatics in inflammatory carcinoma.36,39,40 Metastatic lesions from the breast may be pigmented and mimic pigmented basal cell carcinoma or malignant melanoma.41-45 Metastatic tumors of the inframammary crease may present as exophytic nodules suggestive of a primary squamous or basal cell carcinoma or may simulate intertriginous dermatitis.46 Alopecia neoplastica is a form of scarring alopecia that results from a neoplastic process such as metastatic breast carcinoma. Alopecia neoplastica is characterized by alopecia, a smooth surface, and erythema in some instances. Alopecia neoplastica may be the initial presentation of a tumor, primary or metastatic, and must be distinguished from other forms of scarring alopecia47-50 (see Chapter 10). Involvement of the eyelids by metastases has been reported as asymptomatic papules that in eight of 13 cases demonstrated histiocytoid cells resembling xanthoma, histiocytoma, or granular cell tumor cells.51 In 1874, Paget first noted the association of breast carcinoma and “long persistent eczema” of the nipple and areola, now known as Paget disease of the breast.52 A process clinically and histologically similar to Paget disease may involve the skin of areas outside the breast. Although extramammary Paget disease may be a primary adnexal carcinoma, this process sometimes represents epidermal extension of primary visceral carcinomas. Extramammary Paget disease may involve the vulva, male genital area, perianal area, and rarely the axilla, external ear, and eyelid.53-63 Metastases are seen most often in the vicinity of the primary tumor.10 Squamous cell carcinomas of the head and neck tend to metastasize to regional actinically damaged skin, and it may be impossible to distinguish such metastases from primary cutaneous squamous cell carcinomas.5 Breast and lung cancers frequently metastasize to the chest wall.10 Abdominal tumors, such as those arising in the gastrointestinal (GI) tract, ovary, or bladder, most often metastasize to the abdominal wall.10 Umbilical metastases are called Sister Mary Joseph nodules after the nursing superintendent credited with first noting their significance, and they usually result from intraabdominal malignancies, including tumors from the stomach, colon, pancreas, and male and female genitourinary tract.64-70 Lower abdominal and groin metastases may originate from primary

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in context. Very few antigens have proven to be totally specific for a given tissue or tumor. Initial studies suggesting high specificity are often followed by larger series that demonstrate a considerably wider and more variable antigen distribution. Malignant tumors may not express detectable amounts of certain antigens characteristically expressed by their related cells of origin (eg, failure of some large cell lymphomas to express CD45RB [leukocyte common antigen [LCA]), and tumors may express antigens not usually seen in their cells of origin eg,(vimentin expression in many spindle cell carcinomas)92 and cytokeratin (CK) expression in epithelioid angiosarcomas.93 Because of these considerations, in most cases when immunohistochemical data are desired, a panel of multiple markers should be applied to confirm or refute the diagnosis or narrow the differential diagnosis. This panel should be chosen in light of a probable diagnosis or reasonable differential diagnosis constructed on the basis of clinical and histopathologic features, and the panel should include markers chosen to both confirm and refute specific diagnoses. When evaluating a neoplasm that is undifferentiated on routine examination, an initial panel of antibodies may be designed to classify the lesion into one of a number of broad categories, and secondary and sometimes tertiary panels are then applied to confirm the initial judgment or to further subclassify the process.90,94 The pathologist’s general approach to a metastatic tumor when the origin is not obvious is to first determine the cell line of differentiation (carcinoma, lymphoma, melanoma, sarcoma, or germ cell) and then to more narrowly classify the process by expression of various classes of antigens such as intermediate filament proteins (CKs, vimentin, neurofilament proteins, glial fibrillary acidic protein); supplemental antigens such as carcinoembryonic antigen (CEA) or epithelial membrane antigen (EMA); and cell-specific products, structures, or receptors such as neuroendocrine granule constituents, prostate-specific antigen (PSA), or thyroid transcription factor 1 (TTF-1). Because most cutaneous metastases are carcinomas,9 the expression of CK subsets as recognized by broad-spectrum antibodies such as MNF116, broad-spectrum antibody cocktails such as AE1/AE3, or more specific antibodies such as CAM5.2 and antibodies to CK7 and CK20 is often of diagnostic utility.90,91 Simple epithelial keratins, as may be detected by antibodies such as CAM5.2, are expressed in almost all

simple (nonstratified), stratified, and ductal epithelial tissues, and these CKs are expressed by almost all mesotheliomas and carcinomas except squamous cell carcinomas.90,91 Complex keratins of high-molecular-weight such as CK5/6 are expressed in stratified epithelia; myoepithelial cells; duct-derived epithelium; and transitional, ovarian, and mesothelial tissues and their associated malignancies.90,91 CK expression, as detected with AE1/AE3, 34BE12/CK903, or MNF116, is a useful screening test for epithelial tumors, including many carcinomas.90-92 Antibodies to CK5/6 stain many spindle cell squamous cell carcinomas as well as conventional squamous cell carcinomas, epithelial mesotheliomas, many transitional cell carcinomas and undifferentiated large cell carcinomas, and some adenocarcinomas. Some tumors that stain with antibodies to CK5/6 do not stain well with screening antibodies such as AE1/AE3.92,96-98 As covered in more detail under the discussions of individual tumors, differential expression of CK7 and CK20 is often useful in combination with other antigens in identifying likely primary sites of metastatic carcinomas, including some adenocarcinomas, small cell carcinomas, transitional carcinomas, and squamous cell carcinomas.98,99 CK20 is also very useful in the evaluation of possible Merkel cell carcinomas.100-103 CKs are well documented to occur in some mesenchymal and neuroectodermal tumors, including epithelioid sarcomas, epithelioid angiosarcomas, leiomyosarcomas, and melanomas.92,93 As with the characteristics of vimentin (discussed later), this fact emphasizes the importance of a panel approach and of correlation of immunohistochemical findings with the clinical setting and histopathology. Vimentin is primarily associated with mesenchymal tissues, but it is also expressed in benign and malignant melanocytes (of neuroectodermal origin)104 and in many malignancies not of mesenchymal origin. Many carcinomas, including renal cell carcinoma, endometrial adenocarcinoma, thyroid follicular carcinoma, and many spindle cell carcinomas, express vimentin, which limits the diagnostic utility of vimentin expression as a marker of mesenchymal differentiation.90,91 Desmin and h-caldesmon are specific markers for myogenic differentiation and hence for benign and malignant tumors of smooth and skeletal muscle, myofibromatoses, and some neoplasms of “divergent” phenotypes such as primitive neuroectodermal tumors and desmoplastic small cell tumors.105 Neurofilament proteins may be useful in the detection

of neuroblastoma variants and of neuroendocrine carcinomas, including Merkel cell carcinomas.100,106,107 Glial fibrillary acidic protein (GFAP) is not usually relevant to the evaluation of cutaneous metastases. Many cutaneous metastases represent metastatic malignant melanoma.10 Markers useful in the evaluation of possible metastatic malignant melanoma include sensitive but less specific antigens such as vimentin and S-100 protein and more specific monoclonal antibodies such as the gp100/PMel 17–related monoclonal antibodies HMB-45 and MART1/Melan-A, tyrosinase-related antibodies, and microphthalmia transcription factor protein.104 These markers are discussed in more detail in the chapters on melanocytic lesions (see Chapter 27). In general, the more specific melanocyte markers tend to label a substantially smaller proportion of spindle cell or desmoplastic lesions than do the less specific melanoma markers.104,108 The oncofetal protein carcinoembryonic antigen (CEA) and EMA are markers that can be useful for the detection of glandular differentiation in primary and metastatic cutaneous neoplasms. The polyclonal antibodies to CEA (p-CEA) that many literature studies are based on often cross-react with tissue-nonspecific cross-reacting antigen and biliary glycoprotein I.94,109 Some monoclonal antibodies to CEA (m-CEA), such as CEAD14, have a narrower range of reactivity then p-CEA, which may be of diagnostic utility. For example, primary adenocarcinomas of the lung and colorectal carcinomas stain for both p-CEA and CEAD-14, but most ductal carcinomas of the breast react with p-CEA but not CEAD-14.94,109,110 Evaluation of CEA staining in a metastasis can help narrow the search for a primary site. Antibodies to EMA were originally raised against human milk fat globule proteins. EMA is expressed in many benign and malignant lesions exhibiting glandular differentiation, including many metastatic adenocarcinomas, and occasional epithelial malignancies stain for EMA but not for CKs.111,112 As with many markers, EMA is not totally specific. EMA is expressed by many epithelial malignancies that do not demonstrate morphologic glandular differentiation, including many squamous cell carcinomas, small cell carcinomas, and mesotheliomas. EMA is also expressed by a number of mesenchymal lesions, including perineural cells and their associated neoplasms, many leiomyosarcomas, and many large cell anaplastic lymphomas.111,112

gender-specific prevalence of primary breast cancer.10 CLINICAL FEATURES Cutaneous metastases of breast cancer frequently occur on the trunk, but they are seen with lower frequency on other parts of the body such as the upper extremities and scalp10 In addition to the previously described clinical presentations that are most specifically associated with metastatic breast carcinoma, less specific non-inflamed cutaneous nodules may be seen. Although infiltrating ductal carcinoma is the most common form of primary and metastatic breast cancer, breast cancer can have many other patterns, including lobular, tubular, cribriform, mucinous, and medullary variants.167 HISTOPATHOLOGIC FEATURES The histopathology of breast carcinoma metastatic to the skin may closely resemble the corresponding histologic pattern of the primary tumor. Some clinical patterns of cutaneous metastasis reflect additional histopathologic features that may develop in the metastasis. In inflammatory carcinoma, tumor cells fill dermal lymphatics, and in some cases, lymphatics in the subcutaneous fat (Fig. 35-1).30,35 Telangiectatic carcinoma has tumor cells in more superficially located lymphatics and blood vessels congested with erythrocytes.36,39 In nodular metastases, some stromal fibrosis may be present,

but tumor cells predominate.6 In contrast, cancer en cuirasse is characterized by a smaller proportion of tumor cells set in a prominent fibrous stroma and alopecia neoplastica by dermal fibrosis, an infiltrate of tumor cells, and loss of hair follicles.6,36,37,47-49 Tumor cells of primary and metastatic infiltrating ductal carcinoma are variably pleomorphic. The tumor cells infiltrate their stroma in sheets or cords that sometimes demonstrate glandular structures, signet ring cells, or both (Figs. 35-1 and 35-2).167 Tumor cells of infiltrating lobular carcinoma are small round to ovoid cells with scant cytoplasms, eccentric nuclei with little pleomorphism, and few mitoses. Intracytoplasmic lumina are more frequent in lobular carcinoma than in infiltrating ductal carcinoma and are best seen with histochemical special stains such as the PAS–Alcian blue stain or with immunohistochemical stains such as antibodies to EMA. The single-file pattern of infiltration that is associated most often with lobular carcinoma consists of cords of cells arranged in one-cell width files in a fibrotic stroma; this pattern of infiltration is not associated exclusively with lobular carcinoma (Fig. 35-3).38,167,168 Mucinous carcinoma (also referred to as colloid or mucoid carcinoma) consists of islands of uniform, small epithelial cells with hyperchromatic nuclei and a cribriform or papillary pattern floating in lakes of mucin (Fig. 35-4). It can be difficult or

CHAPTER 35 ■ CUTANEOUS METASTASES

Some relatively specific markers that may be useful in the evaluation of cutaneous metastases include thyroglobulin and TTF-1 for thyroid carcinomas (TTF-1 also stains many carcinomas of the lung)100,101, 103,113-120; mammaglobin and gross cystic disease fluid protein (GCDFP15) for breast cancer (these antibodies also stain many primary cutaneous sweat gland tumors)95,119,121-126; chromogranin, synaptophysin, and specific peptide hormones such as bombesin and glucagon for neuroendocrine tumors such as small cell (oat cell) neuroendocrine carcinoma of the lung and Merkel cell carcinoma107,127-132; calretinin, podoplanin, and D2-40 for epithelioid mesothelioma133-139; CDX2 and villin for GI tumors95,119,122,140149 ; renal cell carcinoma marker (RCCMA), CD10, and PAX-2 for renal cell carcinoma150-153; PSA and prostate-specific membrane antigen (PSMA) for prostate cancer95,142,154-158; placenta-like alkaline phosphatase (PLAP) and human chorionic gonadotropin (hCG) for germ cell neoplasms26,159; CD45RB (LCA)160 PAX5,161 and CD30162 for malignant lymphomas; MyoD1 and myogenin for skeletal muscle105,163; Wilms tumor protein (WT1) for Wilms tumor and desmoplastic small round cell tumor (also positive in malignant mesotheliomas and some Müllerian tumors)117,164-166; and CD99 for Ewing sarcomas and peripheral neuroectodermal tumors (PNETs).102,106,164 (CD99 also stains many lymphoblastic lymphomas, including tumors that exhibit little or no reactivity for LCA.) Some of these markers are discussed below in conjunction with their associated malignancies. Many of these antigens are probably more specific for particular lines of cellular differentiation than is the case for most of the antigens such as CKs, EMA, and CEA described in the preceding paragraphs. However, it should be kept in mind that the known distribution of tumor antigens tends to broaden over time as they are subjected to widespread use and further study, that most antigens are not absolutely restricted to a specific tissue or tumor, and that the expression of many relatively specific antigens tends to be lost in highgrade malignancies.90,91

SITES OF ORIGIN OF METASTATIC TUMORS

Breast Carcinoma Metastases from breast carcinoma account for 71% of cutaneous metastases in women and 2.4% of cutaneous metastases in men, with this difference owing primarily to the difference in

 FIGURE 35-1 Metastatic inflammatory breast carcinoma. Nests of tumor cells fill and expand lymphatics. Tumor cells also infiltrate between dermal collagen bundles.

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 FIGURE 35-2 Metastatic infiltrating ductal breast carcinoma, low power. Infiltration of tumor cells in a single file between dermal collagen bundles results in a resemblance to granuloma annulare.

impossible to distinguish primary cutaneous mucinous carcinoma from mucinous carcinoma metastatic from the breast or GI tract on the basis of histology, but immunohistochemistry can be

very useful in this regard.169-173 Other patterns of primary breast cancer, such as alveolar, solid, tubular, tubulolobular, cribriform, and medullary, are seldom seen in cutaneous metastases.

 FIGURE 35-3 Metastatic infiltrating ductal breast carcinoma, high power. Cytological atypia and intracytoplasmic duct formation are better seen at high power.

DIFFERENTIAL DIAGNOSIS The various patterns of breast carcinoma each have their own list of conditions from which a cutaneous metastasis must be distinguished. A history of primary breast carcinoma is helpful, but patients may have more than one malignancy, so care must be taken not to overlook alternative cutaneous primary or metastatic tumors. Fibrotic nodules with diffuse infiltration by sheets and cords of uniformly atypical cells may suggest dermatofibroma, sarcoma, and small cell or desmoplastic melanoma. A primary ductal eccrine adenocarcinoma may be considered when solid cords, tubules, and lumina formation are noted (see Chapter 29). When single-file rows or cords of deeply basophilic cells predominate, one may need to consider primary Merkel cell or metastatic neuroendoctine carcinoma, hematolymphoid malignancies, sclerosing or morpheaform basal cell carcinoma, and malignant sweat gland tumors.174-176 When there is gland formation with mucin, one should consider malignant sweat gland tumors as well as adenocarcinomas metastatic from locations other than breast such as GI tract, lung, salivary gland, or lacrimal gland.5,174 When islands of tumor cells are surrounded by abundant mucin, one should consider primary mucinous carcinoma of eccrine glands as well as metastases from the breast, lung, or large intestine.169-172,177,178 SPECIAL STAINS AND IMMUNOHISTOCHEMISTRY Breast cancer and Paget disease of the breast commonly express low-molecular-weight CKs, including CAM5.2 and CK7. Many primary and metastatic breast tumors also express high-molecular-weight CKs such as CK5/6. CK20 expression is uncommon. Breast tumors often express pankeratin markers (eg, AE1/AE3), EMA, gross cystic disease fluid protein-15 (GCDFP-15), mammaglobin/MGB1, p-CEA but not usually m-CEA, and estrogen and progesterone receptors.54,58-183 The presence of mammaglobin, GCDFP-15, and progesterone or estrogen receptors and the absence of CK20, m-CEA, and TTF-1 differentiate most metastatic breast cancers from adenocarcinomas metastatic from other common primary sites, especially if ovarian cancer can be excluded clinically (ie, ovarian cancer can exhibit tremendous phenotypic overlap with breast cancer). Mammaglobin and GCDFP-15 have recently been reported to occur in some primary adenocarcinomas of the lung, but these tumors can be separated from

patients with lung cancer develop cutaneous metastases, such metastases are noted before the lung primary tumor was first recognized in 52% to 60% of patients.4,10,21,207 The chest, back, and abdomen are the most frequent sites of cutaneous metastasis of lung cancer, followed by the scalp and neck.5

 FIGURE 35-4 Metastatic mucinous breast carcinoma. Nests of relatively bland tumor cells float in pools of mucin.

breast cancer because they express TTF-1,182,184 Paget disease and epidermotropic metastases of breast cancer may contain melanin and mimic melanoma clinically and histopathologically,41,42,44,45 and approximately 50% of breast carcinomas are positive for S-100 protein,185 which can pose diagnostic pitfalls. Epidermotropic metastases have also been reported from primary sites other than breast, including the prostate, colon, and skin.186-189 A panel of markers, including CKs, CEA, EMA, and more specific melanoma markers such as HMB-45 and MART-1, will allow the exclusion of melanoma, but it should be recognized that epidermotropism may be seen in metastatic as well as primary melanoma.17,108,190,191 There is considerable morphologic and immunohistochemical homology between some carcinomas of the breast, skin, and salivary glands.175,192 Malignant adnexal neoplasms with eccrine or apocrine differentiation may express CAM5.2, CK7, CK5/6, and other high and low-molecular-weight CKs, EMA, CEA, mammaglobin, GCDFP-15, S-100 protein, and estrogen and progesterone receptors,108,121,174,192-197 contributing to the often considerable difficulty of distinguishing between primary or metastatic sweat gland carcinomas and metastatic breast cancer. Cutaneous adenocarcinomas can be taken as primary in cases in which an in situ component can be

demonstrated. Many, but not all, primary sweat gland carcinomas contain an in situ component that may be highlighted by basal cell and myoepithelial markers such as p63, CK 5/6, and calponin.169,174,177 A number of recent articles have suggested that a p63-positive, CK 5/6-positive, and CK20-negative immunophenotype strongly favors a primary adnexal tumor over a metastasis from a noncutaneous primary tumor.96,169,173,198-201 Immunoreactivity for D2-40 and other podoplanin-related antibodies also seems to be much more common in primary skin tumors than in metastases.202,203 However, it must be emphasized that none of these markers are totally sensitive or specific and that clinical information is often necessary to distinguish with confidence between primary adnexal carcinomas and cutaneous metastases.98,136,202,204-206

LUNG CARCINOMA In older case series, cutaneous metastases from lung carcinoma represent 12% to 24% of cutaneous metastases in men and 2% to 4% in women. More recent series have shown an increase in cutaneous metastases from lung cancer in women, reflecting the increasing incidence of primary lung cancer in women.11,12 Although only 1.5% of

HISTOPATHOLOGIC FEATURES The carcinomas of the lung most commonly observed as cutaneous metastases are adenocarcinoma (30%), squamous cell carcinoma (30%), large cell undifferentiated carcinoma, and small cell neuroendocrine (oat cell) carcinoma. Metastases of bronchioalveolar and mucoepidermoid carcinomas, carcinoid tumors, and pulmonary sarcomas are much less commonly seen.5,6,85,207,208 Metastatic squamous cell carcinomas from the lung are usually moderately to poorly differentiated. The tumor cells are dispersed in sheets and islands of epithelial cells with varying degrees of keratinization and intercellular bridges, often with only a small number of whorls of squamous cells (pearls). More atypical features of the keratinizing cells may include large, bizarre cells, spindle cells, and clear cells with abundant mitotic figures. Central necrosis may occur in larger foci of tumor. Metastatic pulmonary adenocarcinomas are usually moderately differentiated tumors that may include small tubular and glandular structures and scattered, individual tumor cells containing intracytoplasmic mucin (Fig. 35-5). The tumor cells tend to have pleomorphic, hyperchromatic nuclei with numerous mitotic figures. Large cell undifferentiated tumors consist of sheets of large pleomorphic tumor cells with abundant cytoplasms, prominent nucleoli, and numerous mitoses. The giant cell variant has monster cells with bizarre nuclei and cells that frequently contain leukocytes. The clear cell variant is composed of sheets and islands of clear cells without other forms of differentiation. Small cell neuroendocrine carcinomas are composed of islands, trabeculae, and sometimes

CHAPTER 35 ■ CUTANEOUS METASTASES

CLINICAL FEATURES The most common presentation of cutaneous metastatic lung cancer is a localized cluster of discrete, firm, nontender, flesh-colored nodules of recent onset and rapid growth to a certain size followed by a stationary period.6 Some cutaneous metastases from the lung have a vascular appearance clinically, suggesting hemangioma, pyogenic granuloma, or Kaposi sarcoma.

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A

B

 FIGURE 35-5 Metastatic adenocarcinoma of the lung, low power. (A) Irregular glands infiltrate a fibrotic stroma. The process is centered in the reticular dermis. (B) Metastatic adenocarcinoma of the lung, high power. An irregular architecture, fibrotic stroma, and atypical cytology are seen.

rosettes of mildly pleomorphic cells that are somewhat larger than lymphocytes, with scant cytoplasms and hyperchromatic nuclei. There are frequent mitoses, and crush artifact is a common characteristic of these cells.209 DIFFERENTIAL DIAGNOSIS Cutaneous metastases consistent with metastatic lung carcinoma must be correlated with the clinical history of the patient and distinguished from other tumors with a similar histopathologic pattern. Squamous cell carcinomas metastasizing to the skin usually arise from the lung, oral cavity, or esophagus and less often from the uterine cervix, penis, or a distant skin site. Cutaneous metastases classically do not demonstrate the association with the overlying epidermis commonly seen in primary cutaneous squamous cell carcinomas, but squamous cell carcinomas metastasic to the skin have been reported to show direct continuity with the epidermis, epidermotropism, and even a Bowenoid histologic appearance.188,189,210-212 Squamous cell carcinoma of the esophagus and (rarely) esophageal adenocarcinoma may present as cutaneous metastases. Squamous cell carcinomas metastatic from the oral cavity are often better differentiated than those metastatic from the lung, usually appear in the region of the head and neck, and usually develop after the primary tumor has been recognized.6 Cutaneous metastases of squamous cell carcinoma from other sites usually occur after recognition of the primary tumor. Most adenocarcinomas metastatic to the skin originate from the large intestine, lung, or breast. Those from the large intestine are often better differentiated than those from the lung. Metastatic

colonic adenocarcinomas often show well-formed mucinous glandular epithelium or even large pools of mucin with a small amount of epithelium and hence resemble mucinous carcinoma of the skin and metastatic mucinous carcinoma from the breast. Mucinous carcinoma of colonic origin is much more likely then other mucinous carcinomas to show zones of so-called “dirty” necrosis (eosinophilic necrotic foci containing nuclear debris).177 The signet ring cells commonly associated with adenocarcinoma of the stomach are seen only occasionally in metastases from the lung. Cutaneous metastatic lesions of undifferentiated type are usually from the breast or lung and less often from the stomach, liver, or urinary bladder. Large cell undifferentiated lung cancer and its giant cell, clear cell, and large cell neuroendocrine variants need to be differentiated from sarcomas such as rhabdomyosarcoma and malignant fibrous histiocytoma, renal cell carcinoma, sebaceous carcinoma, neuroendocrine tumors from other sites, and melanoma.5,6,209 The differential diagnosis of small cell neuroendocrine carcinoma includes a variety of small round cell tumors, including cutaneous adnexal carcinomas, primary or metastatic melanoma, primary or other metastatic neuroendocrine tumors such as Merkel cell carcinoma primary to the skin and neuroendocrine carcinomas metastatic from another organs, malignant lymphoma, a Ewing sarcoma family tumor, and rhabdomyosarcoma.100,101,105,128,164,209,213-217 SPECIAL STAINS AND IMMUNOHISTO-CHEMISTRY Immunohistochemistry is not currently useful in determining the site of

origin of most squamous cell carcinomas. Squamous cell carcinomas of the lung usually stain for CKs in a similar pattern to squamous cell carcinomas of other organs. Most of these tumors are AE1/AE3 and CK5/6 positive and CK7 and CK20 negative, most stain for EMA, and about half stain with polyclonal antibodies to carcinoembryonic antigen (p-CEA).94,96,128,201 Squamous cell carcinomas of the lung express TTF-1 less commonly then do adenocarcinomas of the lung.218 Squamous carcinomas of the lung frequently show spindle cell features. Neoplastic spindle cells in squamous carcinomas primary to the lung and many other locations often coexpress keratin and vimentin, and these carcinomas may express predominantly vimentin.91,128 Expression of p63 may provide evidence that a vimentin-positive, keratin-negative primary or metastatic spindle cell malignancy is a carcinoma rather than a sarcoma.96,198,201,218-221 Primary pulmonary adenocarcinomas usually express CKs (commonly AE1/AE3 and CK7 positive and CK5/6 and CK20 negative), EMA, m-CEA, p-CEA, p63, and TTF-1 but not GCDFP-15 or mammaglobin.94,119,120,122,126,128,182,209,218 TTF-1 is the most specific antibody for pulmonary adenocarcinoma (TTF-1 is also positive in many other lung cancers and in most thyroid cancers), but TTF-1 staining is negative in 25% to 40% of pulmonary adenocarcinomas. Positive staining for TTF-1, m-CEA, and CK7 and negative staining for mammaglobin, GCDFP-15, and CK20 are consistent with a lung primary in a metastatic adenocarcinoma. Large cell undifferentiated carcinomas from the lung are usually positive for AE1/AE3, CK5/6, and p63 and

gallbladder and bile duct have been noted at the time that the initial tumor was recognized and as late as 40 years after resection of the primary tumor. Cutaneous metastases from the stomach and pancreas usually occur before the discovery of the primary tumor. The usual sites of metastases from GI carcinomas are the abdominal wall, the perineum, and the umbilicus (Sister Mary Joseph nodule). In one series, 10% of metastases to the abdominal wall occurred in the umbilicus, and 28% of those tumors were of gastric origin.226 Esophageal carcinomas occasionally metastasize to the skin. These are usually squamous cell carcinomas that metastasize to the upper trunk and neck as single or multiple nodules, but distant metastases and metastases of esophageal adenocarcinomas have also been reported.10,227,228 CLINICAL FEATURES Cutaneous metastases from the colon and rectum may present as flesh-colored sessile or pedunculated nodules, inflammatory carcinoma, grouped vascular nodules, or occasionally a nodular and inflamed perianal lesion suggestive of hidradenitis suppurativa.9,32,Eleven of 18 patients in one study had only local metastases, and most of these occurred in an abdominal incision site.10 Colorectal carcinoma may also metastasize to a colostomy site.9 Gastric, pancreatic, and gallbladder carcinomas that metastasize to the skin usually present as nodules, sclerodermoid plaques, or Sister Mary Joseph nodules.6,10,64,67,69,70,226,229-231 At least one case of gastric carcinoma that metastasized

to the scalp was associated with alopecia (alopecia neoplastica).6 HISTOPATHOLOGIC FEATURES Cutaneous metastases of colorectal carcinomas are predominantly well-differentiated, mucinsecreting adenocarcinomas that may have a pattern of mucinous carcinoma in some cases (see Fig. 35-4). Poorly differentiated metastases are less common, but on rare occasions, metastatic colorectal carcinomas may be so anaplastic that it is difficult to discern that they are of epithelial origin.5,6 Cutaneous metastases from the stomach are frequently anaplastic, infiltrating carcinomas in a loose or fibrotic stroma with varying numbers of signet ring cells containing intracytoplasmic mucin (Fig. 35-6). Well-formed acini and mucinous carcinoma are occasionally observed. Esophageal carcinomas that metastasize to the skin are usually squamous cell carcinomas.10 DIFFERENTIAL DIAGNOSIS Most cutaneous metastases from the GI tract are adenocarcinomas, and those from the large intestine are often well-differentiated mucin-secreting tumors.5,6,11 Although metastatic mucinous carcinomas from the GI tract usually originate from the large intestine, these tumors may be histologically indistinguishable from primary mucinous carcinoma of the skin and metastases from other organs such as the breast, lung, or less often other sources such as salivary gland, lacrimal gland, pancreas, esophagus, or ovary. Cutaneous metastases of visceral mucinous

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negative for CK20, S-100 protein, and LCA. They are variable with regard to CK7, EMA, p63, and CEA and may coexpress vimentin.128,209 Large cell undifferentiated carcinomas must be differentiated from sarcomas such as rhabdomyosarcoma, which is positive for myoid markers such as desmin, MyoD1, and myogenin; lymphoma, which is usually positive for LCA; and melanoma, which is positive for S-100 protein and often for MART-1 and HMB-45. Small cell neuroendocrine carcinomas from the lung usually stain with AE1/AE3 and with antibodies to low molecular CKs in a punctate pattern. These tumors often stain for synaptophysin and sometimes for chromogranin A and CK7.128 CK20 and neurofilament protein staining in a punctuate perinuclear pattern is much more common in Merkel cell carcinomas than in neuroendocrine carcinomas of the lung, and CK7 staining is less common in Merkel cell carcinomas than in lung carcinomas.99,100,222 Positive staining for CK7 and TTF-1 and negative staining for CK20 and neurofilament protein favors metastatic small cell carcinoma of lung origin over Merkel cell carcinoma.99-101,117,120,222,223 Small cell carcinomas from areas other than the lung and skin such as the gut, uterine cervix, and salivary glands may also express TTF-1 and less commonly CK20.101 Although positive staining with antibodies to CD 56 is often used to help identify natural killer (NK) cell lymphomas, many neuroendocrine carcinomas, including primary neuroendocrine carcinomas of the lung and Merkel cell carcinomas, stain strongly with antibodies to CD 56.100,224 Many Merkel cell carcinomas also stain with antibodies to terminal deoxynucleotidyl transferase (TdT), a DNA polymerase that is usually considered to be sensitive and specific antibody for blastic hematologic malignancies. It is not clear at this time whether neuroendocrine malignancies of other organ systems express TdT.225

GASTROINTESTINAL CARCINOMA Carcinomas of the colon and rectum are among the most common primary tumors, and colorectal carcinomas are among the most frequent visceral tumors to metastasize to the skin in both men and women, accounting for 11% to 19% of cutaneous metastases in men and 1.3% to 9% in women. 4-6,9-11,64,67,70 Carcinoma of the large intestine is usually discovered before the cutaneous metastasis. Cutaneous metastases from

 FIGURE 35-6 Sister Mary Joseph nodule resulting from metastasis of an adenocarcinoma of gastrointestinal primary. Variable-sized glands lined by cytologically atypical cells infiltrate a fibrotic stroma.

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carcinomas usually occur in the setting of long-standing, disseminated disease. Mucinous carcinoma of colonic origin is much more likely than other mucinous carcinomas to show zones of so-called “dirty” necrosis.177 Immunohistochemical demonstration of an in situ component can be of great value in proving that a mucinous carcinoma in the skin is primary.169-173 Less well-differentiated adenocarcinomas are more likely to come from sites in the GI tract other than the large intestine such as the stomach, pancreas, or gallbladder, or from other areas such as lung, breast, prostate, endometrium, ovaries, and endocervix. Gastric carcinomas are most often anaplastic, with varying degrees of cellularity and signet ring cells set in a loose stroma. Especially in women, cutaneous metastases with this signet ring pattern are more likely to come from the breast and may rarely originate in other organs. SPECIAL STAINS AND IMMUNOHISTOCHEMISTRY GI adenocarcinomas commonly are reactive with AE1/AE3 and with antibodies to CK20 and express p-CEA, m-CEA, and EMA but not mammaglobin, GCDFP-15, or estrogen and progesterone receptors.99,232-235 Colorectal carcinomas are usually CK20 positive and CK7 negative. Pancreatic, mucinous ovarian, and transitional cell carcinomas often strongly coexpress CK20 and CK7, as do some Merkel cell carcinomas. Many primary and metastatic GI carcinomas express homeobox transcription factor CDX2 and brush border protein villin.95,119,122,140-149 The latter markers are not usually expressed by primary tumors of the breast, lung, skin, prostate, or urothelium, but they may be expressed by adenocarcinomas of the ovary, endometrium, kidney, and bladder. Gastric adenocarcinomas commonly express p-CEA, m-CEA, AE1/AE3, and low-molecular-weight CKs such as CAM5.2, but gastric carcinomas are highly variable in their CK7 and CK20 staining patterns. Positive staining (when present) for CDX2, m-CEA, and CK20 and lack of reactivity with mammaglobin, GCDFP-15, or estrogen or progesterone receptors can help distinguish metastatic gastric adenocarcinomas, including signet ring carcinomas, from metastatic breast cancer. Hepatocellular carcinomas usually stain with CAM5.2 and HepPar1, and low-grade lesions often show a canalicular staining pattern with p-CEA. Hepatocellular carcinomas often do not stain with antibodies to CK 7, CK 20, or m-CEA, and many of these tumors stain weakly or not at all with AE1/AE3.232,234,235

Cholangiocarcinomas (carcinomas of the intrahepatic bile ducts) and extrahepatic pancreatobiliary adenocarcinomas are usually positive for AE1/AE3, CK7, CAM5.2, p-CEA, m-CEA, and CDX2, and many cholangiocarcinomas are CK20 negative.

ORAL CAVITY AND SINONASAL CARCINOMAS In one study, 11.1% of cutaneous metastases in men and 2.3% in women originated from the oral cavity and nasal sinuses. Oral cavity and nasal sinuses carcinomas that metastasize to the skin are usually squamous cell carcinomas that present after the diagnosis of the primary tumor, and cutaneous metastases are usually localized to the head and neck.5 CLINICAL FEATURES Cutaneous metastases derived from neoplasms of the oral and sinonasal cavities are frequently single or multiple nodules with or without ulceration. The cutaneous metastases occurred at the site of surgery in 10 of 18 patients in one series.10 Direct extension of tumor and implantation in surgical scars are often considerations in this setting. HISTOPATHOLOGIC FEATURES Most cutaneous metastases of oral cavity and sinonasal carcinomas are moderately to well-differentiated squamous cell carcinomas presenting in the deeper dermis and subcutaneous fat without connection to the overlying epidermis. Tumor cells sometimes involve perineural spaces and lymphatic vessels.5 Nasopharyngeal squamous cell carcinomas include keratinizing, nonkeratinizing, and undifferentiated variants. The undifferentiated variant may have prominent non-neoplastic lymphoid and plasma cell components that may obscure the epithelial nature of the tumor.236Basaloid squamous cell carcinomas may occur in a variety of upper and lower aerodigestive tract sites and frequently follow an aggressive clinical course. Basaloid squamous cell carcinomas are composed of collections of basaloid cells with pleomorphic, hyperchromatic nuclei that may demonstrate peripheral nuclear palisading. They often demonstrate single cell and comedo necrosis, focal squamous differentiation, and associated conventional squamous cell carcinoma and may have a pseudoglandular appearance.236, 237 DIFFERENTIAL DIAGNOSIS Squamous cell carcinomas that metastasize to the skin usually originate in the oral cavity,

esophagus, or lung, with the lung being the most common site of origin.4-6 The primary tumor less frequently originates in other sites such as the uterine cervix or penis or a distant cutaneous site. Cutaneous metastases of squamous cell carcinomas and basaloid squamous cell carcinomas may show continuity with the overlying epidermis and epidermotropism mimicking Bowen disease.188,210,212 Conversely, an epidermal connection is often not apparent in ulcerated primary cutaneous squamous cell carcinomas, especially in small biopsies. Therefore, in some cases, it may not be possible to histologically or immunohistochemically distinguish between a cutaneous metastasis and a primary squamous cell carcinoma. 188,210,212 Basaloid squamous cell carcinomas must be distinguished from adenoid cystic carcinoma, small cell neuroendocrine carcinoma, and adenosquamous or mucoepidermoid carcinoma.213,236,237 SPECIAL STAINS AND IMMUNOHISTOCHEMISTRY Similar to squamous cell carcinomas derived from other sites, primary and metastatic oral cavity and sinonasal carcinomas usually stain AE1/ AE3, CK5/6, EMA, and p63 and may coexpress or predominately express vimentin in spindle cell areas.213,236,237 Basaloid squamous cell carcinomas usually demonstrate focal squamous differentiation, stain with AE1/AE3 and antibodies to CK5/6 and p63, and may stain for low-molecularweight CKs such as CAM5.2, CK7, and EMA, but not glandular or neuroendocrine markers.

URINARY TRACT TUMORS A total of 4.6% of cutaneous metastases have been reported to originate from the kidney and 8.2% from the urinary bladder.10 Metastases from either organ are seen more frequently in men than in women. Metastases from the urinary bladder usually occur after recognition of the primary tumor. Cutaneous metastases from renal cell carcinoma may be the first sign of the malignancy, but alternatively may occur 10 or more years after resection of the primary tumor.6,10,71 CLINICAL FEATURES Cutaneous metastases from renal cell and transitional cell carcinomas may occur as local metastases, often in surgical scars, or as distant metastases. Metastases from renal cell carcinoma (hypernephroma) are seen most commonly on the head and neck, particularly the scalp, and cutaneous

metastatic transitional cell carcinoma presents most often on the trunk and extremities.10,14,16,22,71,238,239 Renal cell carcinoma may metastasize as solitary or widespread dermal nodules. The nodules can be flesh colored, but they are more commonly violaceous with prominent vascularity resembling Kaposi sarcoma or pyogenic granuloma. Transitional cell carcinoma metastases usually present as one or more fleshcolored dermal nodules. Less common presentations of metastases include zosteriform lesions, warty papules, and inflammatory plaques.

A

DIFFERENTIAL DIAGNOSIS Renal cell carcinoma must be differentiated from other clear cell carcinomas that occasionally metastasize to the skin. These include primary tumors of the lung, liver, ovary, endometrium, cervix, and vagina.12,243 Primary tumors of the skin that may resemble renal cell carcinoma include clear cell hidradenoma (eccrine acrospiroma) and sebaceous tumors.244,245 In contrast to renal cell carcinoma, clear cell hidradenoma is usually multilobular and has prominent ductal structures but is not associated with prominent vascularity, hemorrhage, or hemosiderin deposition. Sebaceous tumors are not as vascular as renal tumors and have fine, vacuolated cytoplasms. Transitional cell carcinomas from the urinary tract that metastasize to the skin usually are moderately to poorly differentiated and may be difficult to differentiate from similar epithelial tumors from other sites and primary or metastatic cutaneous squamous cell carcinoma. Papillary metastases are more suggestive of a primary tumor derived from the urinary tract but must be differentiated from transitional cell carcinomas from other sites such as the ovary and nasal pharynx.12,240,242 SPECIAL STAINS AND IMMUNOHISTOCHEMISTRY Most urothelial carcinomas, including many metastases, express p63 and high-molecular-weight CKs such as CK5/6 and 34BE12.98,219,246 Most urothelial carcinomas also stain positively for

both CK7 and CK20. This pattern is also seen in many pancreatic and some mucinous ovarian carcinomas but is uncommon in other settings.99,246 Uroplakins are a family of transmembrane proteins present only in urothelia. Expression of uroplakins may be specific for urothelial carcinomas, but as with many other tissue-specific markers, uroplakin expression is reduced or absent in many highgrade and metastatic lesions.246-248 Renal cell carcinomas usually stain with broad-spectrum anti-CK antibodies such as AE1/AE3 and with antibodies to low-molecular-weight CKs (CAM 5.2), EMA, and vimentin but not for CK5/6, p63, CK7, CK20, CEA, or S-100 protein.96,240,246 Vimentin expression is much less common in hidradenomas than in renal cell carcinomas. Hidradenomas may focally express CK7 and CEA, as may clear cell carcinomas from other locations such as the lung.245,249,250 Sebaceous carcinomas stain with antibodies to broad-spectrum CKs, low-molecular-weight CKs including CAM 5.2 and CK7, and EMA but not usually with specific or monoclonal antibodies to CEA.192,244,251,252 Most primary hidradenomas and sebaceous neoplasms stain with antibodies to p63, CK5/6, and D240/podoplanin, and most metastatic renal carcinomas do not stain with these antibodies.173,198-200,202,203,220 Many metastatic renal carcinomas express CD10, but this antigen is also expressed by many primary cutaneous tumors, especially sebaceous tumors.181,253,254 Renal cell carcinoma marker (RCC-Ma) appears to be more specific but is also less sensitive than CD10 as a marker for metastatic renal carcinoma to the skin.150

CHAPTER 35 ■ CUTANEOUS METASTASES

HISTOPATHOLOGIC FEATURES The most common renal cell carcinomas are clear cell adenocarcinomas.240 Metastatic nodules in the dermis are composed of large polyhedral cells with clear to finely granular cytoplasm and a central nucleus with little pleomorphism (Fig. 35-7). The cells are arranged in sheets and cords with some gland formation and often a papillary component. The tumor cells are embedded in a delicate, highly vascular stroma containing extravasated erythrocytes and hemosiderin.240,241 Transitional cell carcinoma metastatic to the skin usually consists of well-demarcated sheets and strands of large oval cells with small amounts of faintly basophilic to clear cytoplasm, some nuclear pleomorphism, and varying numbers of mitoses.12,240,242 These tumors may demonstrate focal squamous differentiation and papillary configurations with varying thicknesses of atypical epithelial cells covering a fine fibrovascular core. The metastatic tumor cells may be located in the dermis in between collagen bundles or sometimes

associated with a desmoplastic stroma, in the subcutaneous fat, or in the lumina of vessels.

B

 FIGURE 35-7 Metastatic clear cell adenocarcinoma from the kidney. (A) Well-demarcated nodule of tumor in the reticular dermis with clear cell and prominent extravasation of erythocytes. (B) Sheets and cords of clear cells embedded in a delicate vascular stroma with some extravasated erythocytes and hemosiderin deposition.

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GENITAL TRACT TUMORS

970

In women, the genital tract tumors that most commonly metastasize to the skin are of ovarian (4%), endometrial (4%), and cervical (2%) origin.4,10 A cutaneous metastasis from the ovary may be the initial manifestation of disease, but metastases from the latter tumors usually occur after recognition of the primary tumor. The trunk and pelvic areas are the primary sites of cutaneous metastases for each of these tumors, and ovarian metastases may involve the umbilicus.70,255 Choriocarcinomas frequently present as a consequence of a metastasis, and metastases to the skin are not uncommon.25-27 In men, the primary site of genital tract tumors is the prostate. Cutaneous metastases from prostate cancer are rare relative to the incidence of primary prostate carcinoma. Metastases are seen most commonly in the pelvic area; however, unusual umbilical, epidermotropic, and telangiectatic lesions have also been reported.25,26,186,187,256-260 CLINICAL FEATURES Cutaneous metastases from the ovary, endometrium, and cervix usually manifest as one or more skin-colored nodules that arise in normal skin, incisional scars, or the umbilicus. Ovarian metastases with erysipelas-like features have been reported. Prostate carcinomas in the skin usually consist of flesh-colored or violaceous nodules. Metastases resembling a pyoderma or having a zosteriform pattern, possibly from growth along nerve sheaths, have also been described. HISTOPATHOLOGIC FEATURES The usual histologic pattern of metastatic carcinoma of the ovary is a moderately to well-differentiated adenocarcinoma, often with a papillary configuration and psammoma bodies (small, laminated, calcified spherules). Less commonly, ovarian metastases may be mucinous. Endometrial carcinoma often presents as adenocarcinoma with solid and glandular patterns. Cutaneous metastases from the cervix are usually poorly differentiated squamous cell carcinomas.5,72,261-265 Choriocarcinomas are usually gestational tumors composed of cytotrophoblasts, which are large, cuboidal cells with vesicular nuclei and pale cytoplasms, and syncytiotrophoblasts, which are large cells with irregular nuclei and basophilic cytoplasms. Clusters of cytotrophoblasts are surrounded by sheets and cords of syncytiotrophoblasts in a plexiform pattern resembling chorionic villi.266 Prostatic

metastases to the skin are usually poorly differentiated adenocarcinomas composed of clusters and cords of cells with little glandular formation that infiltrate dermal collagen bundles.186,257,260 DIFFERENTIAL DIAGNOSIS Metastatic papillary adenocarcinoma from the ovary resembles papillary tumors from other sites such as the colon, thyroid gland, stomach, and lung. Psammoma bodies may be observed in both ovarian carcinoma and papillary carcinoma of the thyroid gland.243,261,267 Mucinous ovarian carcinomas vary considerably in their microscopic appearance and may be difficult to distinguish from endocervical, colorectal, and breast carcinomas.261 Metastatic endometrial carcinoma usually does exhibit histologic features allowing distinction from adenocarcinomas from other organs. Similarly, metastatic cervical carcinoma cannot be readily discriminated from squamous cell carcinoma from other organs.72,263-265 Choriocarcinomas may arise from sites other than the uterus such as the testes, ovaries, and mediastinum.25,26,268,269 Prostate carcinoma in the skin commonly has an infiltrative single-file pattern that also may be observed in other cutaneous metastates such as breast, stomach, pancreas, and oat cell carcinomas.186,243,257,260 Unusual variants, including inflammatory carcinoma and several cases with pronounced epidermotropism, have been reported.187,270,271 SPECIAL STAINS AND IMMUNOHISTOCHEMISTRY Many ovarian carcinomas focally demonstrate a papillary architecture that suggests papillary thyroid carcinoma. Serous ovarian adenocarcinomas often stain with CK7 and estrogen and progesterone receptors but usually not with CK20, CEA, or GCDFP-15, which facilitates distinction from colorectal adenocarcinomas (which are usually CK7 and ER negative and CK20 and CEA positive) and breast carcinoma (which is GCDFP-15 positive).94,119,232,272,273 Many mucinous ovarian tumors have an intestinal phenotype and express antigens such as CK20, CDX2, and villin.140,146,147,261,272 Significant expression of CK7 and CA125 with weaker and less diffuse staining for CK20 favors a mucinous ovarian carcinoma over a true intestinal carcinoma, but exceptions exist. 95,166,273 CA125 is also negative in most breast cancers. Endometrial adenocarcinomas resemble serous ovarian adenocarcinomas with respect to immunophenotype except that CEA staining and coexpression of CKs and

vimentin are common. Thyroid papillary carcinomas usually stain for a broad range of low- and high-molecular weight CKs, including CK7, but also for relatively specific markers such as thyroglobulin and TTF-1.127 Choriocarcinomas express human chorionic gonadotropin (hCG), PLAP, and with a recently described marker Mel-CAM/CD 146.159,246,272,274,275 PSA, and PSMA are sensitive and specific for metastatic prostate carcinoma.154,155

THYROID TUMORS The various forms of thyroid carcinoma occasionally metastasize to the skin, especially the scalp. Of particular note, papillary thyroid carcinoma metastases have been described after intervals as long as 20 to 30 years.5,83,87,276 CLINICAL FEATURES Thyroid carcinoma metastases may be flesh-colored or redviolet cutaneous nodules, often involving the scalp and abdomen. Thyroid follicular carcinoma metastases may be pulsatile or manifest bruits.83,84,87,115,276-279 HISTOPATHOLOGIC FEATURES Papillary carcinoma of the thyroid gland has an infiltrative pattern that consists of tubulopapillary structures with occasional psammoma bodies and dark, eosinophilicstaining colloid.127,267 The “orphan Annie” nuclei of papillary carcinoma of the thyroid are large, ovoid, ground glass–appearing, and grooved nuclei with small nucleoli. Follicular thyroid carcinoma has trabeculae and follicles with intraluminal colloid. Medullary carcinoma of the thyroid is a neuroendocrine carcinoma that is most commonly composed of sheets of polygonal or plump, spindled cells in a fibrovascular stroma that often contains lymphocytes and amyloid. DIFFERENTIAL DIAGNOSIS The differential diagnosis of papillary tumors with metastases to the skin includes papillary carcinomas of the thyroid and ovary, which may have psammoma bodies, as well as papillary carcinoma from the GI tract, kidney, and lungs and papillary transitional cell carcinomas.83,243 Differentiated follicular carcinoma of the thyroid has a unique appearance because of the colloid in the follicles. The small cell variant of medullary carcinoma of the thyroid must be differentiated from other small cell carcinomas and from malignant lymphoma. SPECIAL STAINS AND IMMUNOHISTOCHEMISTRY TTF-1 stains the nuclei of all types of thyroid carcinomas as well as

NEUROENDOCRINE TUMORS Neuroblastoma is the most common carcinoma seen at birth, is usually of adrenal origin, and is associated with cutaneous metastases in 32% of neonatal patients and 3% of patients of all ages.280,281 In older patients, carcinoid tumors (low-grade neuroendocrine neoplasms) from sites such as the bronchi and small intestines, including the appendix, occasionally metastasize to the skin and may be the first manifestation of the tumor.130,131,243,282-284 Merkel cell carcinoma frequently recurs locally and metastasizes to distant sites, including the skin.132 CLINICAL FEATURES Neuroblastoma metastases are randomly scattered, firm, nontender, mobile, blue subcutaneous nodules that blanch after being stroked.285,286 Carcinoid tumors appear as single or multiple dermal or subcutaneous nodules that may be painful, and the patient may manifest the carcinoid syndrome.130,282-284 Metastases from Merkel cell carcinoma are usually firm, red-pink, nonulcerated nodules 0.4 to 0.8 cm in diameter.132,287,288 HISTOPATHOLOGIC FEATURES Neuroblastoma exhibits clusters of small basophilic cells that have numerous mitoses and form rosettes in a fine, fibrillar, eosinophilic stroma.289 Carcinoid tumor metastases to the dermis and subcutaneous fat are composed of islands, nests, and cords of uniform cells with round nuclei and clear or eosinophilic cytoplasms that occasionally contain eosinophilic granules.282-284 Merkel cell carcinoma is characterized by anastomosing cords, bands, sheets, and clusters of uniform, round basophilic cells with vesicular nuclei, scant cytoplasm, and numerous mitoses.132,287,290-295 Necrosis

and apoptosis may be seen throughout the tumor. Keratin pearls and focal squamous, sweat gland, and sarcomatous differentiation may be seen, and combined carcinomas, including Merkel cell carcinoma in association with squamous cell, basal cell, and sweat gland carcinoma, have been reported. DIFFERENTIAL DIAGNOSIS Neuroblastoma and Merkel cell carcinoma must be differentiated from other small, round, blue cell tumors such as small (oat) cell neuroendocrine carcinoma from the lung and other sites, poorly differentiated sweat gland carcinoma, metastatic melanoma, and malignant lymphoma.105,296-298 Especially in the pediatric population, the Ewing sarcoma family of tumors (skeletal and extraskeletal Ewing sarcoma, PNET, Askin tumor), rhabdomyosarcoma, small cell desmoplastic tumor, lymphoblastic lymphoma, malignant rhabdoid tumors and organ-specific blastomas such Wilms tumor may be diagnostic considerations. The uniform small cells of a carcinoid tumor may resemble those of a primary adnexal tumor or glomus tumor.283,284,299,300 SPECIAL STAINS AND IMMUNOHISTOCHEMISTRY Neuroblastomas may stain for neurofilaments and neural crest markers such as chromogranin A and synaptophysin.164,289,296-298 They are separated from other pediatric small round cell tumors by morphology, positive staining for these markers, and a failure to express vimentin and markers of muscle, lymphoid, and epithelial differentiation. Ewing sarcoma family tumors usually express vimentin, CD99, and FLI-1 but not muscle, lymphoid, and epithelial markers. Rhabdomyosarcomas often express muscle antigens such as muscle-specific actin and desmin and myogenic transcriptional regulatory proteins such as myogenin and Myo-D1. Carcinoid tumors usually stain with broad-spectrum anti-CK antibodies such as AE1/AE3 and low-molecular-weight anti-CK antibody CAM5.2 and neuroendocrine markers such as chromogranin A or synaptophysin.127,209,232,233 The primary site of neuroendocrine carcinomas, including carcinoid tumors, cannot be identified with certainty because tumors from different sites demonstrate phenotypic overlap. Merkel cell carcinomas have features of both neuroendocrine and epithelial differentiation. They demonstrate globular “dotlike” paranuclear staining with CAM5.2, AE1/AE3 and antibodies to CK20, and neurofilaments and sometimes stain with antibodies to EMA,

CK7, chromogranin A, and synaptophysin but not with antibodies to CEA or LCA. Positive staining for CK20 and neurofilaments in a paranuclear pattern and negative staining for CK7 and TTF1 favor Merkel cell carcinomas over metastatic small cell carcinoma of lung origin.99-101,117,120,222,223 A series of CK20-/CK7+ Merkel cell carcinomas has been reported. All of these tumors were TTF-1 negative,301 Small cell carcinomas from other locations, such as the gut, uterine cervix, and salivary glands, sometimes express TTF1 and CK20. Many neuroendocrine carcinomas, including primary neuroendocrine carcinomas of the lung and Merkel cell carcinomas, stain strongly with antibodies to CD56.100,224 Many Merkel cell carcinomas also stain with antibodies to TdT, a DNA polymerase that is usually considered to be sensitive and specific antibody for blastic hematologic malignancies.225

SARCOMAS Sarcomas metastasize to the skin in 3% of men and 2% of women with cutaneous metastases.5 Distant cutaneous metastases may also be seen from sarcomas that arise in the dermis, subcutaneous fat, or underlying soft tissue such as epithelioid cell sarcoma and atypical fibroxanthoma.88,89,302 The metastases occur on the scalp, trunk, and extremities. Most metastases of sarcomas occur after recognition of the primary lesion.4

CHAPTER 35 ■ CUTANEOUS METASTASES

many lung cancers. Positive staining for thyroglobulin and negative staining for CEA distinguish nonmedullary thyroid cancer from most lung cancers.94,127,128,209,267 Most metastatic papillary and follicular thyroid carcinomas stain for thyroglobulin and TTF-1. Medullary carcinomas of the thyroid usually express TTF-1, calretenin, and less specific neuroendocrine markers such as chromogranin and synaptophysin but not thyroglobulin. The origin of neuroendocrine and small cell carcinomas cannot be identified with certainty because tumors from different sites demonstrate a certain amount of phenotypic overlap with virtually every marker studied.

CLINICAL FEATURES Metastatic sarcomas in the skin are firm, skin-colored or redpurple nodules that may be ulcerated or painful.89,286 HISTOPATHOLOGIC FEATURES Leiomyosarcoma is often a well-demarcated or infiltrating nodule in the dermis or subcutaneous fat composed of fascicles of spindle cells with eosinophilic cytoplasms and varying degrees of cytological atypia (Fig. 35-8).303,304 Rhabdomyosarcomas are usually poorly differentiated tumors that may have large, atypical cells with abundant eosinophilic cytoplasms and multinucleated giant cells or small, hyperchromatic cells with scant cytoplasms, in which case they are included in the differential diagnosis of small, round, blue cell tumors.163,281,296,298,304,305 Elongated eosinophilic “strap cells” and recognizable rhabdomyoblasts with cross-striations in their cytoplasms are seen in some but not all rhabdomyosarcomas.

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A

B

 FIGURE 35-8 Metastatic leiomyosarcoma. (A) Well-demarcated nodule of tumor in the subcutaneous fat with brightly eosinophilic cells. (B) Interlacing fascicles of eosinophilic spindle cells with nuclear pleomorphism.

Fibrosarcomas exhibit fascicles of spindle cells often arranged in a herringbone pattern with few polygonal and giant cells. Whereas better-differentiated tumors show more significant numbers of spindle cells and collagen production, poorly differentiated tumors manifest anaplastic cells and mitoses.304 Malignant fibrous histiocytoma (a controversial term that has been to some extent supplanted by undifferentiated pleomorphic sarcoma) has several variants that include storiform-pleomorphic, xanthomatous, inflammatory, myxoid, angiomatoid, and giant cell types.304 Chondrosarcomas are composed of undifferentiated round to spindle-shaped cells with malignant cartilage or chondroblasts in a myxoid matrix.304,306 Osteogenic sarcoma is composed of varying admixtures sof malignant osteoid and bone along with a spindle cell component that resembles fibrosarcoma or malignant fibrous histiocytoma.304,306 Ewing sarcoma family tumors are characterized by lobules of uniform small, round or oval cells, sometimes with perilobular fibrosis.106,306 Epithelioid sarcoma is composed of nodules of polygonal, epithelioid, and spindle cells with abundant eosinophilic cytoplasms and atypical nuclei that palisade around central areas of necrosis in association with lymphocytic infiltrates at the peripheries.89,307 DIFFERENTIAL DIAGNOSIS The definitive interpretation of the various sarcomas and their discrimination from other

spindle cell or round cell tumors of epithelial origin has been facilitated by the advent of immunohistochemistry. However, particular light-microscopic findings continue to be critical in the differential diagnosis of sarcomas and their distinction from epithelial tumors. The principal entity in the differential diagnosis of metastatic fibrosarcoma in the skin is primary dermatofibrosarcoma protuberans (DFSP). DFSP is centered in the reticular dermis and demonstrates uniform spindle cells and a more pronounced storiform pattern compared with fibrosarcoma.308-312 DFSP may show myxoid areas and extensive portions of the tumor indistinguishable from primary fibrosarcoma. Nodular fasciitis is a benign “pseudosarcomatous” lesion that may arise from the fascia and occasionally from the septa of the subcutaneous fat. Nodular fasciitis is characterized by generally uniform “tissue culture”–appearing fibroblasts and, in some cases, giant cells haphazardly arranged in a highly vascular, myxoid stroma.304 Some authors regard atypical fibroxanthoma as a superficial variant of malignant fibrous histiocytoma with less aggressive clinical behavior; however, atypical fibroxanthoma has traditionally been differentiated from malignant fibrous histiocytoma because of its smaller size and more superficial location.312-314 Well-differentiated metastatic leiomyosarcoma may have a similar infiltrative or well-demarcated pattern in the dermis or subcutaneous fat as that seen in

primary leiomyosarcomas or even leiomyomas.303,304 Metastatic leiomyosarcoma does not have a vascular origin, as observed in angioleiomyoma and many subcutaneous leiomyosarcomas. It is composed of smooth muscle cells that are more atypical than those of leiomyoma and often with significant mitotic activity. Anaplastic leiomyosarcomas with bizarre giant cells may resemble malignant fibrous histiocytoma. Rhabdomyosarcomas composed of small, round, blue cells need to be differentiated from other primary or metastatic tumors with similar morphologic features.163,164,304,305 Pleomorphic rhabdomyosarcomas with a storiform pattern and bizarre multinucleated cells may resemble malignant fibrous histiocytoma. As with rhabdomyosarcomas, Ewing sarcoma raises the differential diagnosis of small round cell tumors.164,298,304,315 Epithelioid sarcoma must be distinguished from infectious and palisading granulomas.89,304 Epithelioid sarcoma differs from malignant fibrous histiocytoma because of the absence of bizarre multinucleated cells and foam cells. SPECIAL STAINS AND IMMUNOHISTOCHEMISTRY The immunohistochemistry of sarcomas are not covered in great detail here because cutaneous metastases of sarcomas usually bear a close clinical relationship to a known primary tumor.4 Epithelioid sarcoma is of special interest because it may be mistaken for granulomatous inflammation. These

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variant analyzed in a series of 23 cases. Am J Surg Pathol. 2007;31:1371-1377. Santa Cruz D: Tumors of the skin, in Fletcher C (ed). Diagnostic Histopathology of Tumors, vo1 2, 3rd ed. New York: Churchill Livingston; 2007:1423-1526. Soule E, Enriquez P: Atypical fibrous histiocytoma, malignant fibrous histiocytoma, malignant histiocytoma, and epithelioid sarcoma. A comparative study of 65 tumors. Cancer. 1972;30(1): 128-143. Silvis N, Swanson PE, Mannivel JCet al: Spindle-cell and pleomorphic neoplasms of the skin. A clinicopathologic and immunohistochemical study of 30 cases, with emphasis on “atypical fibroxanthomas.” Am J Dermatopathol. 1988;10(1):9-19. Izquierdo MJ, Pastor MA, Carrasco L, et al: Cutaneous metastases from Ewing’s sarcoma: report of two cases. Clin Exp Dermatol. 2002;27:123-128. Pai KK, Pai SB, Sripathi H, et al: Epithelioid sarcoma: a diagnostic challenge. Indian J Dermatol Venereol Leprol. 2006;72:446-448.

CHAPTER 35 ■ CUTANEOUS METASTASES

305.

neoplasms: another distinctive, previously unrecognized pattern in extraocular sebaceous carcinoma and sebaceoma. Am J Dermatopathol. 2005;27:195-203. Calder KB, Coplowitz S, Schlauder S, Morgan MB: A case series and immunophenotypic analysis of CK20/CK7+ primary neuroendocrine carcinoma of the skin. J Cutan Pathol. 2007; 34:918-923. Giuffrida T, Kligora, GD G: Localized cutaneous metastases from an atypical fibroxanthoma. Dermatol Surg. 2004;30: 1561-1564. Vandergriff T, Krathen RA, Orengo I: Cutaneous metastasis of leiomyosarcoma. Dermatol Surg. 2007;33:634-637. Fletcher C: Soft tissue tumors, in Fletcher C (ed). Diagnostic Histopathology of Tumors, vol 1, 3rd ed. New York: Churchill Livingston; 2007:1527-1592. Cessna MH, Zhou H, Perkins SL,, et al: Are myogenin and myoD1 expression specific for rhabdomyosarcoma? A study of 150 cases, with emphasis on spindle cell mimics. Am J Surg Pathol. 2001;25(9):1150-1157. Unni K, Inwards C: Tumors of the osteoarticular system, in Fletcher C (ed).

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5 PART

Disorders of Nails and the Oral Mucosa

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CHAPTER 36 Disorders of the Nail Apparatus Aldo González-Serva

MICROSCOPIC SIGNS OF NAIL DISEASES Relatively few histologic signs characterize nail disease.5,6 Some of the signs are noted in subungual horn and nail plate and thus may be diagnosed by noninvasive methods. Other signs are tissue based and need a biopsy for their detection. Excellent monographs and chapters of clinical and histologic features of nail diseases are available.7-10 The types of signs needed to secure a specific diagnosis should influence the choice of biopsy method. Many diseases can be diagnosed or strongly suspected from scrapings and clippings of the nail. Plate dystrophy, subungual hyperkeratosis, and gross pigmentary deposits are the most important. However, knowing the source of the latter requires tissue examination. This more invasive approach reveals epithelial changes such as epidermidalization, matrical hypergranulosis, or atypia. The presence of pigmented material or cells; atypical melanocytes; misplaced tissues; or neoplastic cells of other lineages, hemorrhage, and stromal changes (eg, cellular infiltrates and myxoid degeneration) requires tissue for histologic examination as well. More generalized skin disorders tend to be recognized in the perionychium because, essentially, this is skin with the

same characteristic response to disease as elsewhere.

RESOURCES FOR HISTOLOGIC DIAGNOSIS Most biopsies for the diagnosis of nail diseases are taken by shave of the cutaneous framework of the nail. Lately, shave biopsies of the matrix and bed have also been used. Punch biopsies are a satisfactory method for most nail diseases. Care should be exerted in also exploring the often detached nail plate core that is produced when the matrix or the bed are punched out. In demanding cases for diagnosis, a longitudinal nail biopsy may be the best solution. Regardless of the method of biopsy taking, the study of keratinous or tissue products of the nail with routine histology stained with hematoxylin and eosin is the mainstay of the diagnosis of nail diseases. Particularly helpful is the periodic acid-Schiff (PAS) stain, which should habitually accompany every study. For pigmentary disorders, iron, melanin, and hemoglobin stains are mandatory. Immunohistochemistry and electron microscopy are used sparingly in common diagnostic practice with the same frequency as in other areas of dermatopathology generally to define histogenetic and differentiation traits of neoplasms, deposits, or genodermatotic disorders.5 More recently, the approach to the diagnosis of some nail diseases is through the nail plate biopsy (NPB), a noninvasive technique that is gaining popularity. The mainstay of NPB is the search for fungi. In the past few years, there has been a clear shift from cultures to this method of detection of fungal pathogens. In addition, the use of the NPB to determine the presence, pattern, and percentage of melanin pigment within the plate has become an alternative to more invasive nail matrix biopsies. The following sections outline the principles of these methods.

CHAPTER 36 ■ DISORDERS OF THE NAIL APPARATUS

The pervasive misunderstanding of the nail unit as a skin equivalent rather than as an adnexal unit such as the hair follicle has complicated the evaluation and diagnosis of nail diseases.1 After recognizing that the matrical and bed epithelia and stroma are not epidermis and dermis, a better understanding of the microscopic findings in nail diseases has emerged. The nail can be considered to resemble a flattened, cubist-like hair follicle that is asymmetric (Fig. 36-1). The plate is laminar and enclosed by lip-shaped sides of unequal length. The plate-forming matrix is lateralized rather than enclosing the nail root (Fig. 36-2A). The intermediary epithelia surrounding the matrix, especially the bed epithelium, are its products as well, as are ultimately the resulting cuticular keratins that ensheath the plate (Fig. 36-2B).2 Regarding the dynamics of migration of the nail components, every layer of the nail unit moves forward alongside the plate in unison. Thus, the plate does not glide over the bed epithelium but is firmly attached to it in a parallel course. The bed ends at a predetermined site (the onychodermal band, which may be recognized clinically; see Fig. 36-2C) and keratinizes fully in a zone known histologically as the solehorn. This keratinization may be described as onycholemmal keratinization.3 On the opposite side, the true cuticle, which originates on the ventral side of the proximal nail fold, apposes the plate as it emerges, thus sealing the virtual space that otherwise would occur. All of the described onychal structures are encircled by cutaneous structures more akin to epidermis, which intersects with the emerging plate and epithelial and keratinous coverings. The rim of epidermoid keratin above the plate and the true cuticle is the rough eponychium, a nonessential and disposable semilunar spur that has erroneously been called the cuticle. Beneath the site of plate launching, beyond the solehorn, is the product of the bed epithelium—the hyponychial horn (or ventral cuticle). The latter structure lies above an intermediate epithelium, closer

to epidermis, which is termed the hyponychium. Keratins of onychal and epidermoid origin are blended in this hyponychial angle. This area of collision of nail and cutaneous epithelia—a half ostium of sorts—is a reservoir of information about past events in the matrix and bed. The nail plate is also a mirror of the same events. This understanding facilitates the interpretation of nail diseases, from either scrapings or clippings of nail horn or plate, that had their initiation at some earlier point in time and may or may not be active at the time of the study. Thus, fungi of the bed will also be at the subungual or hyponychial horn. Pigment associated with keratins will reflect a pigment-forming lesion of the matrix or bed. The melanocytic system of the nail consists of inconspicuous, nonpigmented cells in both the matrix and bed, particularly in whites. In the matrix, whereas the functional melanocytes are more abundant in the distal matrix, even if functionally dormant, the total numbers of melanocytes predominate in the proximal matrix.4

NAIL PLATE BIOPSY IN SEARCH OF FUNGI

Definition A positive PAS stain result in an NPB in patients suspected to harbor onychomycosis is rewarding, but a negative result is vexing and may be falsely negative. Therefore, steps refining positivity or asserting true negativity are needed to insure that onychomycosis is not missed.

983

Anatomy of the Nail Eponychium (false cuticle)

Cuticle

Hyponychium* (space) Solehorn* (ventral cuticle)

PART V ■ DISORDERS OF NAILS AND THE ORAL MUCOSA

Onychodermal band

Lunula (distal matrix)

A

Fungal Morphology

Bed *Under nail plate

Histology/Anatomy of the Nail Proximal nail fold

Eponychium

Hyponychium Plate

Cuticle

Solehorn Onychodermal band

In positive nail plate biopsies, the fungal morphology (hypha, mold, yeast) directs the diagnosis and therapy, and their distribution and density allow an assessment of the type of treatment and likely therapeutic response. Table 36-1 shows a list of salient morphologic aspects of fungal and related pathogens inducing a similar “mycotic” nail appearance.

Additional Steps to Increase Yield of Diagnosis

Matrix

Bed

Pulp

Nail as homologue of hair follicle: Matrix produces, besides plate, nearby

B epithelia and ensheathing keratins (not proportionally depicted).

 FIGURE 36-1 (A) Clinical anatomy of the nail. The morphology of the plate is the result of intimate accommodation of the nail structures to the subjacent bone. The nail root rests over the proximal epiphysis of the distal phalanx, and the distal groove (at the site of onychodermal band and hyponychium) arches around (and actually inserts, by specialized nail ligaments, on) the tuberositas unguium. (B) Diagram of nail structures.

Flowchart The traditional flowchart for the search of fungi has started with direct microscopy (potassium hydroxide examination) followed by culture to either speciate or confirm the negative examination results. Histologic examination of nail material stained with PAS is emerging as the first line diagnostic test in this workup for onychomycosis.11

Rationale 984

double-observer examination of initially negative PAS stains and Giemsa (GMS) stain were added to the basic steps16 (Fig. 36-3). In the same series, the referring clinicians had an index of suspicion of onychomycosis varying between 49% and 94% with a median of 68%. These values closely equate the index of suspicion by the clinician to the harvest of positive PAS stains by the pathologist and establish that not every nail that looks mycotic is truly so. Unfortunately, the exact causes of those pseudomycotic appearances are not always clear. The quandary is whether occult onychomycosis is still present or if eczema, ischemic and trophic changes, trauma, bacteriosis, and psoriasis mimic it.

It is now obvious that PAS stain in nail clippings or curettages is more sensitive

and specific than direct microscopy or, surprisingly, than fungal cultures. Reported series of positivity for PAS vary from 33.3% to 92% in the rate of detection of fungi. Most series, though, approximate 48% success in demonstrating fungi in nails clinically suspected of harboring onychomycosis.12-15

Results The author and colleagues have recently reported a consistent 65% positive rate of fungal detection in a large series of more than 2561 nail clippings when

Microbial culture after a positive PAS stain may allow fungal speciation in nail plate biopsies. A second look at an initially negative PAS stain, possibly supplemented with GMS stain, should be the next steps in this histology-based flowchart. Microbial culture, even if culture is less sensitive than PAS, may even rescue on occasion some falsely negative PASor GMS-stained specimens (2.5%). Of those isolates, it is difficult to say which organisms other than dermatophytes (generally molds) are contaminants or true pathogens. Clinicopathologic correlation may then arbitrate the decision of treating the patient with potent antimycotic drugs or reinitiating the workup. Persistent negativity reassures the clinician that the pseudomycotic plate dystrophy is not infectious.

Rescue of False-Negative Cases of Onychomycosis Further steps to rescue occult cases of onychomycosis are the repeat of the NPB and the procurement of nail samples of increased quality, that is, those leading to high harvest of subungual horn, which is the seat of most infections. The use of still experimental, not

A

B

 FIGURE 36-2 Histology of the nail (in a newborn). (A) The matrix epithelium is stratified and produces an eosinophobic nail plate, mirrored by concurrent keratin of the ventral portion of the proximal nail fold (true cuticle). (B) The nail bed epithelium is less stratified than the matrical one, with relatively monotonous upper and lower keratinocytes. (C) The onychodermal nail band occurs where the bed epithelium clashes with the epidermis of the hyponychium. The entirety of the bed epithelium keratinizes and is extruded as the solehorn (ventral cuticle).

CHAPTER 36 ■ DISORDERS OF THE NAIL APPARATUS

C

yet practical methods of fungal detection, such as confocal laser microscopy and molecular techniques, is not warranted in day-to-day practice.

MELANIN MAPPING OF THE NAIL PLATE AND MATRIX

Definition

 FIGURE 36-3 (A) and (B) Nail plate biopsy for fungi. A Giemsa stain can reinforce a negative periodic acid-Schiff stain or more starkly show the presence of hyphae. A preparation with low precipitation of silver granules is ideal but is often difficult to achieve.

The noninvasive mapping of the pattern of intralaminar melanin in an NPB mirrors the position and morphology of a melanin-producing melanocytic lesion in the ungual matrix.17 The analysis of the trail of intracorneal melanin present in some pigmented nail diseases in sections of the nail plate, unstained or stained with Fontana-Masson, is based on the fact that whereas the proximal matrix produces the most superficial sheets of the nail plate, the distal matrix produces the deepest sheets (Fig. 36-4).

985

Table 36-1 Morphology of Fungi With PAS Stain of the Nail Keratins FINDINGS

DISORDER Dermatophytes (91%): Trichophyton rubrum (71%), Trichophyton mentagrophytes (20%), Trichophyton tonsurans, and Epidermophyton floccosum (rare)

Yeasts (5%): Candida albicans

PART V ■ DISORDERS OF NAILS AND THE ORAL MUCOSA

Pityrosporum ovale (Malassezia furfur)

Nondermatophyte molds (4%) Scopulariopsis brevicaulis (most frequent)

Scytalidium dimidiatum (or hyalinum)

Aspergillus spp Pseudoonychomycosis (rare) Prototheca wickerhamii (or zopfii) (alga)

Corynebacterium minutissimum [bacterium]

In addition, the true cuticle and the subungual (hyponychial) horn are ultimately matrical products as well, as are the matrix-derived epithelia of the ventral proximal nail fold and the bed.

Slender septate cylindrical hyphae, 2-5 μm wide (if pigmented, T. rubrum nigricans), mainly at the lateral aspects of the nail plate Frequent sporulation, often at the midline under the nail plate; arthrospores, 2-4 μm wide, in regular chains Budding oval yeasts, 3-4 μm wide; pseudohyphae; septate hyphae (rare) Small, oval or bottle-shaped budding yeasts, 2-5 μm wide; truncate short hyphae are exceptional on the nail crevices (saprophyte vs. pathogen?) Masses of thin, short hyphae, 5-7 μm wide, with large lemon-shaped, rough-surfaced conidiospores Short, hyaline branched filaments, 2.5-7.0 μm wide, with thick walls and arthrospores (if pigmented, S. dimidiatum) Irregular septate hyphae, 2.5-3.5 μm wide, often branching dichotomously; heads and conidia Moruloid spherical, ovoid, or elliptical sporangia, 6-10 μm wide, with a crown of molded endospores around a central rounded one Irregular, minute rods and thin, fragmented filaments, 1 μm in diameter (gram+)

Premise Represented in the sheets of the plate are pigmented and keratinous reflections of events in matrical onychometameres. An onychometamere is the transversal file

of onychocytes that from one side to the other of the nail field conjointly produce each sheet of the plate. If the onychometameres are abnormal, the nail plate sheets will be equally abnormal. The number of matrical onychometameres, from nail root to the lunular border, equals the number of nail plate sheets. For example, 50 onychometameres—occupying one after another a matrix of approximately 1 cm or more in length—emit 50 plate sheets now compacted in a nail plate 1 mm or less in thickness. The thin plate is the product of a long matrix, only after matrical dynamics compresses the plate and forces it to grow forward horizontally and thinned down approximately 10 times the length of the matrix, rather than as an upward-bound and broad-based horn.

Analysis of Intralaminar Melanin The understanding that the matrix projects itself into the plate, leaving a trail of intralaminar melanin in nails with melanotic lesions, leads to the analysis of such lesions on the basis of the presence of pigment in few or all levels of the plate. The position of the melanin “smokestack” in the nail plate is paramount to predict the dimensions of a nevus or a melanoma. The pigment will occupy perpendicularly a space that is proportional to the area of the matrix occupied by the pigmented lesion. The portion of the melanin-containing plate will be representative of the matrical onychometameres producing melanin. In benign lesions, the abnormal matrical space tends to be small, but in a melanoma, the space is large and tends to occupy the whole length of the matrix (Fig. 36-5).

Percentage of Pigmented Plate and Calculation of Matrical Area

986

 FIGURE 36-4 Nail plate biopsy for melanin. The understanding that the most superficial sheets originate in the proximal matrix and the deepest ones from the distal matrix allows for “histographic mapping” of melanin pigment to the matrical onychometameres containing the pigment-producing lesion.

Besides the general position of the intralaminar melanin, the percentage of the nail plate containing melanin is of value. The “homunculus” of pigment reflected in the nail plate allows a noninvasive look at the dimensions and characteristics of a pigmented lesion in the matrix. Ideally, the dimensions of the pigment-producing lesion could be calculated combining the estimate in millimeters of the length of the melanocytic lesion that extrudes melanin into the plate given by this method and the width of the same lesion given by the width of the pigmented band determined clinically or histologically. If the position of the pigment is matrical and

Diseases of the Nail  FIGURE 36-5 Dimensions of a matrical melanocytic lesion by means of analysis of a nail plate biopsy (NPB). The percentage of matrix involved by a pigment-producing lesion is manifested in an NPB. Correlation with clinical or histologic width of the pigmented band allows for a full picture of matrical involvement. (A) The plate is a mirror of the matrix, although 10-13 times thinner. (B) A small proximal matrical lesion produces a limited focus melaninization of the upper plate sheets (eg, a lentigo). (C) A narrow but full-length matrical lesion will induce melanin throughout the entire vertical thickness of the plate (eg, a nevus). (D) A long and broad matrical lesion will give rise to a wide and full-thickness melanin trail in the plate (eg, melanoma). (The nail plate is depicted in the coronal view, matrix viewed en face [ie, from above]).

This chapter emphasizes the disorders that are likely to be diagnosed initially from histologic evaluation of the nail unit.20,21 Many other disorders not discussed here can be diagnosed from other cutaneous or systemic signs. It is important to recognize that the nail unit is a domain of the skin, rather than a region, that expresses a wide spectrum of disorders, even if not diagnosable specifically by means of a biopsy.22

Onychomycosis the percent of melanonychia is high, the melanin mapping of the NPB could predict the presence of a melanoma and leads to the taking of a punch or shave biopsy or, better, a longitudinal nail matrix biopsy (Fig. 36-6). This histopathologic mapping of melanin in the plate has lagged the dermatoscopists’ attempts to define through dermatoscopy, from above or across the leading edge of the plate, the position of matrical melanocytic proliferations producing melanin and thus be guided where to take a biopsy.18 The author anticipates that the histologic melanin mapping will become more popular as clinicians and pathologists clarify the correlations needed to achieve confident diagnoses by means of what essentially is “corneal exfoliative cytology” of sorts. In brief, the intralaminar melanotic mapping is a portrait in time (represented by the edge of the nail plate) of what has already occurred—but is likely to be still happening—in the nail matrix in times past when it produced the pigment that

then reached the distal plate. This mirroring in the plate of matrical events could become a crucial method in the difficult workup of melanonychia striata. Although not a full substitute for a biopsy, the NPB becomes the clear first-hand choice for a potentially broader workup of melanonychia, even if a biopsy is performed later.

DIAGNOSIS OF NAIL DISEASES The first issue to be addressed is whether the nail disorder is a plate dystrophy, a mass, or a pigmented lesion. Most biopsies are obtained for the evaluation of nail dystrophy. This is the most difficult group of diseases to diagnose specifically; fortunately, most specimens fall into the triad of tinea, psoriasis, and (much more rarely) lichen planus. Regarding pigmentation of the plate or adjoining tissues, the quandary is often the discrimination between melanin or hemoglobin deposition. A more difficult problem is posed by longitudinal melanonychia because the distinction

CHAPTER 36 ■ DISORDERS OF THE NAIL APPARATUS

between benign and malignant pigment-producing lesions is difficult in the nail field, given the restrained ability for a biopsy of the nail tissues to be ample and free of artifacts and to show to good advantage all criteria to reach a diagnosis of early malignancy (ie, malignant melanoma in situ). The workup of a mass in the nail unit is more frequently related to evaluation of a verrucous papule than to a deeper soft or hard tissue tumor. When this is the situation, the distinction is between verruca and more serious tumors such as keratoacanthoma or squamous cell carcinoma. Fortunately, reliable criteria for these microscopic diagnoses now are available,19 but not every case is readily solved by biopsy alone. In those dilemmas, observation, clinicopathologic correlation, and repeat biopsy by a more invasive method become paramount.

Synonyms: Tinea unguium, dermatophytosis, nail ringworm Fungal infections of the nail, the most frequent cause of nail disease, can be dermatomycetic (encompassing the cited synonyms), nondermatomycetic (eg, mold infections), and yeast-related infections (mostly candidiasis).23 CLINICAL FEATURES Regardless of the etiologic agent, the onychomycoses have been grouped as distal or lateral subungual, superficial white or black, proximal subungual, total dystrophic, and (more recently) endonyx (nail plate only without any other changes). The type of dystrophy may suggest the type of onuchomycosis involved.15 Candidal onychomycosis stands apart. Isolation of the agent may be difficult, even if direct microscopy shows positive findings. HISTOPATHOLOGIC FEATURES The findings on direct microscopy may help to broadly identify organisms in nail plate or other nail tissue biopsies.13,24-26 Besides the presence of the fungi, the nail tissues undergo

987

PART V ■ DISORDERS OF NAILS AND THE ORAL MUCOSA

C

988

A

D

B

 FIGURE 36-6 Nail plate biopsy for melanin in melanoma in situ. (A) Low power and (B) Higher power Fontana-Masson stain shows full-thickness involvement by coarse melanin granules, most noticeable in the lower 87% of the plate. (C) and (D) Low and high power respectively Longitudinal nail biopsy with immunoperoxidase stain for MART-1 reveals malignant melanoma in situ, extending as Hutchinson sign into the proximal nail fold.

plate dystrophy and variable degrees of psoriasiform onychitis. The hyphae of dermatophytes are tubular, colorless, often refractile, and usually septate. In contrast, those of nondermatophytes are thinner; more irregular and tortuous; and occasionally, tan-brown. Conidia can also be seen with the latter infection. If this type of infection is suspected, fungal culture should be used for confirmation. Yeasts occur as pseudohyphae and spores. In recent years, the biopsy of the plate alone, as clippings, has burgeoned as the method of choice for fast recognition leading to early treatment of onychomycosis.27,28 Fungi in tunnels containing air variably penetrate the plate, but more reliably, the subungual horn invariably contains most organisms. PAS stain suffices in most cases for confirmation. If a biopsy is done, the skin or epidermalized bed epithelium shows hyperkeratosis, both ortho- and parakeratotic, with Munro-like intracorneal microabscesses. Other than the presence of the fungi, the changes are similar to those of psoriasis (Fig. 36-7). In superficial white onychomycosis, short and

A

B

 FIGURE 36-7 Onychomycosis. Nail plate dystrophy, Munro’s microabscess and epidermidalization of the nail bed epithelium are identical to psoriasis, (A) except for the presence of hyphae with periodic acid-Schiff stain. (B) This type of biopsy has been superseded in tinea unguium by the increasing use of more conservative nail plate biopsies.

gnarled fungi are present in the superficial sheets of the plate. In contrast, fungi are present throughout the plate in proximal subungual onychomycosis and dystrophic onychomycosis. Candida also involves the whole thickness of the plate, but pseudohyphae are distinct and accompanied by spores.

 FIGURE 36-8 Psoriasis. The receding hyponychium, now occupying the space of former nail bed (onycholysis), is epidermidalized and hyperkeratotic. Besides keratinocytic pallor and agranulosis of the epithelium and papillomatosis of the bed stroma, there is a microabscess within the horn. No fungi are demonstrated with special stains.

Psoriasis Synonyms: Pustular psoriasis, acrodermatitis continua of Hallopeau CLINICAL FEATURES Involvement of the nail is seen commonly in up to 50% of patients with psoriasis and is even more prevalent in patients with psoriatic arthropathy.32 The abnormalities are zonal and related to the involved portion of the nail apparatus. Pits, transverse grooves, and other surface irregularities in the plate are related to damage to the matrix. An affected nail bed may exhibit discolorations, onycholysis, and splinter hemorrhages. If the nail bed and hyponychium are involved, subungual hyperkeratosis will be prominent. HISTOPATHOLOGIC FEATURES The histopathologic alterations depend on the site of the disease, which may involve any part of the nail33,34 (Fig. 36-8). However, the basic pattern is that of psoriasiform onychitis with spongiform pustulation. In the proximal nail fold, the process is similar to psoriasis elsewhere in the skin. Matrical involvement results in pits, which are dislodged psoriatic scalelike islands of variable width and length, according to the breadth and duration of injury to the proximal matrix. If these parakeratotic islands with neutrophils originate in papules of the middle and distal matrix, punctate leukonychia will follow. The matrical damage will result in an overall thick, crumbly plate. When

the matrix and nail bed are affected, the spongiform pustulation will be the basis for the salmon patch and onycholysis. Involvement in the bed will produce epidermalization of its epithelium with resulting subungual hyperkeratosis. If the longitudinally oriented ectatic vessels of the bed exude erythrocytes, splinter hemorrhages will ensue. Many of these changes will be reflected in changes in the plate that are recognizable through clippings alone. DIFFERENTIAL DIAGNOSIS The main differential diagnosis is onychomycosis. The microscopic changes may be identical, but psoriasis is usually more parakeratotic. The mainstay of the discrimination is the finding of fungi in onychomycosis. Another distinction is with eczematous onychitis, given that psoriasis in the nail may show eczematoid features. Other psoriasiform disorders, such as Reiter syndrome and parakeratosis pustulosa, are either indistinguishable or very hard to separate from psoriasis.

Eczematous Onychitis Synonyms: Trachyonychia (20-nail dystrophy), eczematous dermatitis The ubiquitous eczematoid changes in nail biopsies point to the recognition as an entity of eczematous onychitis, even if such processes may precede or be

concurrent with more distinct nail inflammatory conditions. CLINICAL FEATURES Among the entities that clinically resemble onychomycosis, spongiotic or psoriasiform onychitides are frequently seen after fungal infection has been ruled out. This is due to the fact that onchomycosis entails eczematoid features as part of its clinical and histologic spectrum of features, which accounts for the clinical overlap with the dermatitides. Moreover, nail dystrophy is relatively common (16%) in atopic dermatitis of the hand.35 Trachyonychia is the most widely recognized expression of eczema in the nail unit, which is also associated with Beau lines, subungual hyperkeratosis, and onycholysis, among other manifestations.9,36

CHAPTER 36 ■ DISORDERS OF THE NAIL APPARATUS

DIFFERENTIAL DIAGNOSIS The most important differential diagnosis, before recognizing the fungal agents, is that of psoriasis. After this relatively simple distinction is reached, one should realize that most fungal organisms identified in nails are not causing true infection. Commensal fungi can be seen in many biopsies, but the role of small yeasts (now mostly identified as Malassezia furfur) is being reevaluated as possibly pathogenetic.29 Even secondarily colonizing fungi may be observed in nonmycotic disorders such as lichen planus and psoriasis. Unusual pathogens, such as Prototheca spp and Corynebacterium minutissimum, replicate the histologic signs of onychomysis.30,31

HISTOPATHOLOGIC FEATURES In addition to nail plate dystrophy and subungual orthokeratosis, eczematous onychitis shows extensive subungual parakeratosis, often admixed with sometimes large pools of spongiotic (serum-like) fluid (Fig. 36-9). Smaller subungual “scale-crusts” are also noted. The nail matricolectual epithelium may exhibit spongiosis or psoriasiform hyperplasia, depending on the phase of the process. DIFFERENTIAL DIAGNOSIS Onychomycosis is the main distinction because without

989

PART V ■ DISORDERS OF NAILS AND THE ORAL MUCOSA

nonspecific end stage. The most diagnostic pattern is one that is similar to lichen planus in skin, namely, lichenoid onychitis with a bandlike lymphocytic infiltrate near vacuolated basal keratinocytes. There is also hyperkeratosis with hypergranulosis. Plasma cells may be present. If burnt out, the nail field will become atrophic and epidermalized, often permanently, and difficult to discriminate from that resulting from external trauma.

A

Paronychia B  FIGURE 36-9 (A) and (B) Eczematous onychitis. Low and high power respectively. Many changes of onychomycosis, minus the presence of fungi with periodic acid-Schiff or Giemsa stains or in cultures, are shared by eczematous disease of the nail field, perhaps a kindred of dyshidrotic dermatitis. This entity is probably more common than previously thought and may explain cases clinically suggestive of onychomycosis that are repeatedly negative for fungi. However, the presence of fungi may amplify a concomitant eczematous component in some cases of tinea unguium, making differential diagnosis on hematoxylin and eosin–stained sections of these entities nearly impossible.

the presence of fungal mycelia, the histologic changes are practically identical.

Lichen Planus

990

DIFFERENTIAL DIAGNOSIS If the highly characteristic features of lichen planus are identified, few other differential diagnoses need to be considered. The main problem is with healed lichen planus, in which the residual changes will be less than pathognomonic and essentially indistinguishable from lichen simplex chronicus of the nail after external rubbing or other mechanical trauma. If onychomycosis supervenes, care should be taken not to overlook lichen planus that may be obscured by infection. Other lichenoid disorders, such as lichen striatus, graft-versus-host disease, and even lichen sclerosus, may histologically mimic lichen planus.42-44

CLINICAL FEATURES Onychal lichen planus may occur in 1% to 10% of patients with lichen planus elsewhere but may rarely be confined to the nails, particularly in children.37,38 The disorder varies in intensity, extension, and number of nails or portions of nails involved. Besides the common presentation, hypertrophic and ulcerative variants are recognized, as is the recently described nail degloving (shedding of nail plate and nearby tissues).39,40 Onychomycosis can supervene in lichen planus of the nail.

HISTOPATHOLOGIC FEATURES The most devastating clinical features result from involvement of the matrix41 (Fig. 36-10). According to the severity of damage, only dystrophic plates may develop, or in many cases, complete destruction of the matrix eventuates in a loss of the nail plate with scarring and adhesion of the proximal nail fold to the nail mesenchyme (pterygium) (see Fig. 36-4). If damage is limited, the impairment of the matrix will produce thinner or shorter plates. When the process is intermittent in the matrix, pits and irregularities are noticeable (20-nail dystrophy). Microscopic findings may not be sufficient for an unequivocal diagnosis because the disease evolves into a relatively

Paronychia is infectious onychitis of the nail folds. Acute paronychia is bacterial, secondary to Staphylococcus aureus. Chronic paronychia is a disorder often associated with Candida albicans infection. Contact irritants may exacerbate the appearance and persistence of paronychia.45 Pseudomonas spp may be an offender, either primary or supervening on a psoriatic nail.46 CLINICAL FEATURES The features of acute paronychia are those of acute pyogenic infection, namely, an abscess or cellulitis. Chronic paronchia combines the proliferative elements of fibrosing granulation tissue with foci of suppuration. Children are affected frequently.47 HISTOPATHOLOGIC FEATURES In acute paronchia, a collection of purulent exudate is situated near a disrupted lateral or proximal fold (Fig. 36-11). A hangnail may be a preceding event. Interstitial neutrophilic exudate may be seen as well. Chronic paronchia has minimal or variable epidermal hyperplasia with spongiosis and scale-crust. The dermal infiltrate is composed of lymphocytes, histiocytes, and numerous plasma cells. Dilated vessels in an edematous stroma are prominent. If Candida organisms are present, they are located in the cornified

Traumatic Onychitis

 FIGURE 36-10 Lichen planus. The epidermidalized nail bed epithelium, appearing under dystrophic plate, is associated with a lichenoid lymphocytic infiltrate.

 FIGURE 36-11 Acute paronychia. The proximal nail fold, which is protuberant and crusted (similar to a hangnail), contains mixed inflammatory cell infiltrate (mostly suppurative) along with a fibrosing granulation tissue reaction.

layer and are neither invasive nor associated with granulomas. DIFFERENTIAL DIAGNOSIS Each paronychia has to be distinguished on the basis of etiology. Chronic paronychia can

conceivably be bacterial, and candidal paronychia may be acute. Some tumors, including amelanotic melanoma, may mimic paronychia. Rarely, fixed drug eruption may clinically resemble paronychia,48 as may Langerhans cell histiocytosis.49

HISTOPATHOLOGIC FEATURES Hemorrhage can be recognized histologically by extravasation of erythrocytes in the matrical-bed stroma and beneath or within the plate. Hematoidin (negative for iron stain), rather than hemosiderin, is identified. Benzidine stain may be used to detect disintegrated red blood cells and their products.51 Lichenification is a common final pathway to many disorders of the nail unit (Figs. 36-12 and 36-13). Whether it is derived from associated external trauma or, possibly, from self-perpetuating damage by abnormal epidermoid horn of various inflammatory disorders lodged between the plate and epithelia, the process is the same and may be erroneously taken for the primary disorder. The macerated lichenification of heloma durum, with clavus-like hyperkeratosis, is the equivalent of cutaneous picker’s nodule. Scar results from mechanical damage tearing the tissues. A protruding scar in the matrix will result in a split nail plate. If present in the bed or in the proximal nail fold, a scar also will induce dystrophic change in the plate. In fact, deformity of the nail bed is the most common result of serious nail trauma. Nail degloving, the partial or total shedding of the plate and neighboring tissues, has been recently described as an effect of trauma (besides other inducers such as other insults, dermatologic diseases, and drug reactions).40 DIFFERENTIAL DIAGNOSIS Nail hemorrhage is the common differential diagnosis for pigmented lesions. An NPB will usually discriminate between blood and melanin. The former may be freshly extravasated erythrocytes or hemolyzed products and pigments in or under the nail plate. Melanin, in contrast, can be discerned

CHAPTER 36 ■ DISORDERS OF THE NAIL APPARATUS

CLINICAL FEATURES The results of trauma in the nail field include hemorrhage, lichenification, and scar. Nail hemorrhage may be of splinter type or more overt and of an acute nature, such as intralaminar hemorrhage (within the plate) and subungual hematoma. The effects of trauma can be enhanced by an abnormal protuberance of bone or cartilage under the nail plate, as in the case of a subungual corn (heloma durum) above an exostosis or osteochondroma. Other complications of external trauma are Beau lines, plate dystrophy, misplacement of the matrix, pyogenic granulomas, anomalous growth of a new nail plate, and even longitudinal melanonychia.50

991

by evidence of mechanical trauma such as hemorrhage or fibrosis. A scar must be distinguished from sclerosing conditions of the lamina propria of the nail, such as that that occurs after lichen planus or inherent to lichen sclerosus.

PART V ■ DISORDERS OF NAILS AND THE ORAL MUCOSA

Verruca CLINICAL FEATURES This human papillomavirus (HPV)–induced lesion can be either periungual or subungual. If under the nail plate, the latter can be minimally affected. Trauma may contribute to persistence and refractoriness to treatment. HISTOPATHOLOGIC FEATURES The ungual wart is similar to verruca vulgaris of skin. There is prominent digitated epithelial hyperplasia with koilocytotic (clear cell) changes of the upper strata and hyperkeratosis. The cytopathic changes are less pronounced than in palmoplantar verruca. The lesion may become inflamed after trauma.  FIGURE 36-12 Traumatic onychitis (lichen simplex chronicus onychalis). The lichenified bed epithelium, now with mature squamous metaplasia (epidermidalization), is orthokeratotic. The bed stroma (inaccurately referred to as the dermis) is fibrotic, reflecting a subjacent scar.

easily in the plate as opaque brown granules that are argyrophilic. Hemorrhages from other causes, such as subacute bacterial endocarditis, cholesterol embolism,

and antiphospholipid syndrome, should be kept in mind.52,53 Lichenification, when secondary to protracted trauma, is usually accompanied

DIFFERENTIAL DIAGNOSIS Besides the common wart, there is an autochthonous variety of verruca known as the onycholemmal horn.54 This lesion develops at the proximal and lateral folds and shows onycholemmal differentiation, namely, a proliferation of large polygonal keratinocytes without a granular layer, resembling that of trichilemmal and onycholemmal cysts. A much rarer entity that may be warty is mucinous syringometaplasia of the distal bed.55 This process is characterized by a focal invagination lined by squamous epithelium. Eccrine coils and ducts are present with mucinous cells. The ducts drain into the epidermoid invagination. Finally, the verrucous lesions of incontinentia pigmenti56 and epidermal nevus must be distinguished from viral warts. Another condition to be excluded when a “wart” is noted clinically is Bowen disease.57

Cysts

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 FIGURE 36-13 Traumatic onychitis (above exostosis). The macerated bed epithelium, also epidermidalized and hyperkeratotic, shows hydropic swelling and degeneration of keratinocytes. Subungual hyperkeratosis also indicates compression trauma of nail structures against the hard nail plate (and shoe).

The cysts in the nail are a broad group of lesions that differ in histogenesis and clinical expression. They may be minuscule and subclinical, such as subungual epidermoid inclusions (epidermoid buds), or similar to epidermoid buds but with nail dystrophy. Others are indistinguishable from so-called epidermal inclusion cysts of the skin and are known as implantation epidermoid cysts (keratin cyst, squamous epithelial cyst, traumatic cyst).58

associated with longitudinal melanonychia and may harbor onychomycosis.63 Some giant presentations of the neoplasm are known,64 as is a very rare occurrence in a child.65

 FIGURE 36-14 Onycholemmal cyst. In a subungual location, a cyst resembling a trichilemmal (pilar) cyst is identified. The content is parakeratotic, not separated from the epithelium by a granular layer.

CLINICAL FEATURES Cysts of sufficient size will produce a subungual mass. Some of them involve subjacent bone. A history of trauma is almost always elicited, except in the incidentally found subungual epidermoid inclusions. HISTOPATHOLOGIC FEATURES The implantation epidermoid cyst is unilocular, lined by thin epidermoid epithelium, and filled with orthokeratin. Subungual epidermoid inclusions are protrusions of the bed epithelium into the uppermost bed stroma. Although often asymptomatic, many of them may be associated with marked hyperplasia of the bed epithelium. This disorder results in subungual hyperkeratosis; onycholysis; and rarely, a shortened dystrophic nail plate. Calcification of the cyst contents may be also present.59 Finally, some cysts may contain epithelium that resembles that of the nail bed (and trichilemmal cysts) and hence are called onycholemmal cysts (Fig. 36-14).

CLINICAL FEATURES This neoplasm produces a markedly overcurved plate (in transverse fashion) with excessive longitudinal ridging and a yellow longitudinal band. When the plate is avulsed, the exophytic tumor in the matrix is digitated and filiform, being encased in a curved plate that offers a mirror-like funnel to the exuberant proliferation. It may be

DIFFERENTIAL DIAGNOSIS Unlike onychomatricoma, a verruca is epidermoid rather than basaloid and matrical. It also shows prominent keratinization and thick epithelium. The invaginated fibrokeratoma with matrix differentiation is mainly composed of a broad-based stromal fibrous nodule.69 However, this and even the more common fibrokeratoma of the nail bed may bear a superficial resemblance to onychomatricoma.70

Fibroma This is a complex group of hamartomas and benign neoplasms that overlap and

CHAPTER 36 ■ DISORDERS OF THE NAIL APPARATUS

HISTOPATHOLOGIC FEATURES Microscopically, the neoplasm is matrical, of lobular pattern, formed by basaloid keratinocytes (Fig. 36-15). At the base of the lobules are narrow columns of densely arranged elongated cells with dark nuclei (similar to those in the matrical keratogenous zone). If these columns become dislodged, invaginations resembling hair follicle infundibula replace the formerly solid cores in the endophytic columns of cells.66,67 According to the predominance of epithelium or stroma in the tumor, the terms unguioblastoma and unguioblastic fibroma have been proposed.68

DIFFERENTIAL DIAGNOSIS Some malignant neoplasms may be partly or largely cystic, such as the malignant proliferating onycholemmal cyst.60 When solid, the tumor has now been termed onycholemmal carcinoma.61,62

Onychomatricoma Synonym: Filamentous tufted tumor in the matrix of a funnel-shaped nail

 FIGURE 36-15 Onychomatricoma. The matrical epithelium is digitated and lines stalks of stroma. No significant proliferation of either is noted other than the abnormal fingerlike projection impaling the nail plate.

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PART V ■ DISORDERS OF NAILS AND THE ORAL MUCOSA

are sometimes difficult to distinguish unequivocally. CLINICAL FEATURES The periungual fibromas and fibrokeratomas are sessile or filiform masses that occur in digital skin or around the nail field, as well as in nail tissues, where they arise in the proximal or distal nail fold or under the plate. A true fibroma, in contrast, is nodular and deep and always endophytic, even though it may be protuberant. However, it does not exhibit hyperkeratosis or epidermal collarettes, as observed in fibrokeratomas and periungual fibromas. Recently, multiple acral fibromas, either periungual or subungual, have been associated not only with tuberous sclerosis71 and neurofibromatosis but also with familial retinoblastoma.72 HISTOPATHOLOGIC FEATURES The periungual fibroma is essentially an angiofibroma. The accompanying epidermal hyperplasia is ancillary. On the other hand, the fibrokeratoma is a fibrotic proliferation, with numerous fibroblasts, lined by prominent epidermal hyperplasia with hyperkeratosis. This lesion may be very large and invaginated.69,73 Collagenous, cellular (fibroblastic), and edematous patterns are known. The true fibroma is composed of dense and hyaline collagen bundles, both aligned irregularly and interspersed among few fibroblasts. Elastic fibers are often few in numbers or absent. It is a deep and poorly circumscribed nodule located in reticular dermis or nail stroma. DIFFERENTIAL DIAGNOSIS The most important differential diagnosis of each fibroma of this taxonomically confusing group is with the other entities in this group, given the subtle variations that distinguish each one. It is noteworthy that periungual warts may resolve as relatively persistent angiofibromatous papules. A fibrokeratoma differs from a supernumerary digit in that the latter contains nerve trunks in its core, mainly near the base of the lesion. Infantile digital fibromatosis is richly spindle celled, with frequent paranuclear inclusion bodies in up to 2% of fibroblasts. Table 36-2 summarizes the spindle cell tumors that are worthy of consideration in the ungual field.

Digital Myxoid Pseudocyst Synonyms: Synovial cyst, dorsal finger cyst, cutaneous myxoid or mucoid cyst

994

CLINICAL FEATURES This common disorder occurs in the proximal nail fold or

under the proximal matrix (see Chapter 16).93 They can be subungual and multiple.94 Attachment, through a stalk, to the distal interphalangeal joint has been proposed and found occasionally. This is not, however, sufficient evidence to claim herniation of synovium as the source of the cavity of the pseudocyst. It may just reflect the ganglion-like degeneration of nail stroma or a surrogate of tenosynovial tissue or of nearby real tenosynovial structures. HISTOPATHOLOGIC FEATURES The lesion is a pseudocyst without a genuine epithelial or even synovial lining. Some alignment and compression of marginal fibroblasts may give the impression of pseudosynovial lining, but the changes are not those of pseudosynovial metaplasia elsewhere. An ill-defined wall of fibroconnective tissue surrounds the lesion. The cavity is filled with mucoid material. The area initially is traversed by cobweb-like, loose myxomatous tissue with few fibroblasts before cavitation. If the tense mucin-filled cavity erodes upward, the epidermis or the nail epithelia may rupture, and evacuation of mucin may occur. Resealing of the defect and ongoing myxoid degeneration of soft tissues will be responsible for recurrence of the lesion unless it is fully treated. DIFFERENTIAL DIAGNOSIS A resolving abscess from chronic paronychia may enter into the differential diagnosis. If the mucin is drained, the resulting changes may suggest a scar. When epithelial necrosis occurs above a myxoid cyst, the traumatic changes may resemble those overlying exostosis or osteochondroma. A true myxoma or superficial acral fibromyxoma is never cavitated and contains numerous and prominent stellate fibroblasts.

Superficial Acral Fibromyxoma CLINICAL FEATURES This relatively recently described benign tumor of the hand and, most commonly, feet has a predominant location in the nail field. It can be slow growing and reach a large size, up to 5 cm. Most are around 1.75 cm, however,88 and could rarely erode the distal phalanx. Complete surgical excision is generally curative, but recurrence or persistence occurs in fewer than 10% of cases. HISTOPATHOLOGIC FEATURES The neoplasm is composed of spindle and stellate cells, only occasionally multinucleated, embedded in a myxoid or collagenous

matrix with increased vascularity and scattered mast cells.86 Atypia can be noted, at least in substantial grade in near 10% of cases. Mitoses, however, are absent or infrequent (Fig. 36-16). The tumor cells can be positive for CD34, epithelial membrane antigen, and CD99 but not every such marker is expressed in individual tumors. DIFFERENTIAL DIAGNOSIS Besides other benign soft tissue tumors with spindle or stellate cells, at least two malignant conditions should be excluded: dermatofibroma protuberans and acral myxoinflammatory fibroblastic sarcoma, a low-grade neoplasm of usually greater size and higher degree of atypia.92 Besides myxoid neurofibroma,95 another benign myxoid tumor to be considered is perineurioma.91

Osteocartilaginous Tumors This group of entities is related because of common clinical signs and histologic features. It includes exostosis, osteochondroma, enchondroma, osteoid osteoma, and solitary bone cyst. The first two conditions constitute the bulk of the presentations. Recently, it has been suggested that osteochondromas are exostoses and that either is a posttraumatic reactive process. CLINICAL FEATURES The classic triad for exostosis (pain, nail deformity, and radiographic abnormalities) may apply to the rest of these entities. A history of trauma is often noted.96 Exostosis is an exophytic lesion, either single or multiple (as in the multiple exostosis syndrome). Osteochondroma, enchondroma, osteoid osteoma, and solitary bone cyst are intraosseous disorders.97,98 The former may be multiple (as in Ollier dyschondroplasia and Maffucci syndrome, in which there are also multiple vascular malformations in soft tissue). HISTOPATHOLOGIC FEATURES The exostosis is a protuberant proliferation of mature bone surmounted by a fibrocartilaginous cap. An osteochondroma, not clearly distinguished from exostosis, is also a sessile or polypoid tumor of mature bone capped by mature cartilage. The enchondroma is a nodule of hyaline cartilage with haphazardly disposed chondrocytes that are often pleomorphic. The osteoid osteoma contains a nidus of disarrayed thick bone trabecules. The very rare subungual bone cyst is cavitated reparative fibrotic tissue with giant cells.

Table 36-2 Differential Diagnosis of Spindle Cell Tumors of the Nail Unit Propera SUBTYPE I. Mainly Fibrous Tumors Periungual or subungual fibroma71,72,74-77 Subungual pleomorphic fibroma4

Solitary sclerotic fibroma75

II. Both Fibrous and Epithelial Tumors Acquired periungual or subungual fibrokeratoma21,69,73,79,80

Unguioblastic or matrix fibroma68

III. Tumors with Myxoid Stroma Superficial acral fibromyxoma81-88

Cellular digital fibroma74,82

Sclerosing perineurioma89,90

Myxoinflammatory fibroblastic sarcoma92

IMMUNOHISTOCHEMISTRY

Polypoid or sessile tumor with dense collagenous matrix containing few fibroblasts (Also known as Koenen tumor or angiofibroma) Pleomorphic, hyperchromatic cells or giant multinucleated cells embedded in a collagenous stroma

Factor XIIIa+

Well-circumscribed dermal storiform nodule of sparse spindle cells with alternating wavy collagen fibers resembling the sclerotic ones in Cowden syndrome (Probable variants: subungual pleomorphic fibroma; storiform collagenoma6) Hypocellular, ill-defined nodule composed of dense collagen bundles and reduced elastic fibers and resembling DF elsewhere in the skin (very rarely, more cellular and sclerosing hemangioma-like) Hyperkeratotic large tumor, carrot shaped, with thick collagen bundles arrayed along the axis of the tumor and pseudo-nail plate formation above an accessory germinal matrix Invaginated fibrokeratoma69: variant occurring at the proximal nail fold, parallel but more proximal than the normal matrix Stroma-rich variant of onychomatricoma

(1) Dermal or subcutaneous proliferation of spindle and stellate cells (occasionally multinucleated) with slight nuclear atypia, arranged in a random, loose storiform or partly fascicular patterns (2) Slight to mild nuclear atypia (substantial atypia rarely) and infrequent mitoses (3) Myxoid stroma with mildly to moderately increased small blood vessels and scattered mast cells Intersecting fascicles of thin delicate bland spindle cells in the superficial reticular dermis with a fibrotic-to-slight myxoid stroma (Variant of superficial acral fibromyxoma?74,82) Other nail-located variant: tendon sheath fibroma-like91 Potential variants: storiform, intraneural, extraneural, reticular, and plexiform (1) Vaguely lobular architecture and oval, spindle, and epithelioid neoplastic cells with scattered, focally aggregated inflammatory cells (2) Bizarre giant cells (some resembling Reed-Sternberg cells, lipoblasts or ganglion cells) with large, lobulated, or multiple nuclei containing distinct nucleoli or intranuclear inclusions (3) Myxoid areas in variable proportions

(a) Vimentin+ (b) S-100, cytokeratin, smooth muscle actin, factor XIIIa, CD34: negative (a) CD34+ and O13+ (b) CD31, S-100, and CD68: negative (c) Factor XIIIa+ (storiform collagenoma) (a) Factor XIIIa variably + (b) CD34-

(a) Cd34+ and factor XIII+ (in some cells) (b) Vimentin+ and actin+ (one case) (a) CD34+ (b) EMA, actin, desmin, keratins, S100 protein, CD99, and HMB45 all negative

CHAPTER 36 ■ DISORDERS OF THE NAIL APPARATUS

Fibrous dermatofibroma75,78

HISTOLOGIC FEATURES

(a) CD34: +strongly in spindle cells in all cases (b) Factor XIIIa:+ only scattered stromal cells (a) EMA, vimentin, type IV collagen and laminin: positive (b) Perineurial markers claudin-1 and GLUT-1 + Vimentin+; CD68+ and CD34+ (some cells)

a

Tumors near the nail unit, such as infantile digital fibromatosis, keloid, giant cell tumor and fibroma of the tendon sheath, and juvenile hyaline fibromatosis, have not been expressly reported in the journal literature as ungual proper but are dealt with in nail textbooks.6,8

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PART V ■ DISORDERS OF NAILS AND THE ORAL MUCOSA

HISTOPATHOLOGIC FEATURES Squamous cell carcinoma in situ is similar to that noted in skin, namely, a keratinizing proliferation of atypical keratinocytes throughout the epithelium of the periungual epidermis, nail bed, or matrix. It may be pigmented. Squamous cell carcinoma consists, as in other sites, of a bulky and invasive proliferation of atypical keratinocytes with anaplasia and dyskeratosis. The invasion of nearby stroma is jagged and irregular and more infiltrative than pushing. Verrucous carcinoma (epithelioma cuniculatum) is an exo- or endophytic neoplasm with deep burrows and fistulas that are strikingly well differentiated and deeply invasive, with expansive and pushing rather than classically infiltrating margins. Bone invasion is noted frequently.107  FIGURE 36-16 Superficial acral fibromyxoma. The neoplasm is composed of spindle and stellate cells, only occasionally multinucleated, embedded in a myxoid or collagenous matrix with increased vascularity and scattered mast cells.

DIFFERENTIAL DIAGNOSIS First of all, exostosis and osteochondroma must be distinguished, but this is difficult histologically because both may have cartilaginous caps (fibrocartilaginous and hyaline, respectively), although mature exostoses lose their cartilaginous caps. Enchondroma must be differentiated cytologically from chondrosarcoma (the latter is a distinct yet rare complication of osteochondroma and enchondroma). Osteoid osteoma is identical histologically to benign osteoblastoma.97 If protuberant, any of the ossified and, therefore, calcified tumors may be mimicked by occasional subungual calcifications of the nail bed or nearby soft tissues and by circumscribed calcinosis cutis.

HISTOPATHOLOGIC FEATURES This wellcircumscribed and encapsulated solid tumor is biphasic and highly organoid. Besides afferent arterioles and efferent venules, there are numerous vessels enmeshing small and round cuboidal cells. The cells are uniform and contain dark nuclei and comparatively pale cytoplasm. Many nerves are also present. DIFFERENTIAL DIAGNOSIS Other vascular tumors may resemble the glomus tumor on cursory examination. Among them, angioleiomyoma may have a complex net of vessels as well, but eosinophilic spindle-shaped smooth muscle bundles define the latter.101

Squamous Cell Carcinoma Glomus Tumor This rare tumor is observed mostly in the hand, particularly in the subungual area.

996

CLINICAL FEATURES The glomus tumor is a small (1 year), rapidly erodes bone, and often does not regress, except exceptionally.111 HISTOPATHOLOGIC FEATURES Subungual KA has a narrow, more vertically oriented profile than common KA but otherwise is composed of deeply infiltrating aggregates of large pale (glassy) keratinocytes with keratohyalin granules and prominent dyskeratosis21 (Fig. 36-17). The structure is centered around a keratin-plugged crater delimited by prominent lips. Compared with conventional KA, it is less inflamed (with fewer neutrophils and eosinophils), does not show fibrosis at the base, and readily infiltrates the subjacent bone. Even following these criteria, a

 FIGURE 36-17 Keratoacanthoma. A cluster of glassy keratinocytes, one among many, is identified. Prominent dyskeratosis and a small neutrophilic abscess are noted toward the center of the cluster.

confident distinction from conventional squamous cell carcinoma is difficult.110 DIFFERENTIAL DIAGNOSIS Given the peculiar features of subungual KA, its distinction from squamous cell carcinoma can be difficult. Despite a similar gender distribution (male > female) to that of squamous cell carcinoma, KA often presents as a mass, occurs in a younger population, is rarer, grows faster, and is of shorter duration than squamous cell carcinoma. It may also be multiple, may erode bone (which may be reconstituted), and is rarely associated with a history of trauma. The tumors of incontinentia pigmenti are indistinguishable those of from KA.112 Histologically, the well-differentiated appearance of large keratinocytes arranged in large aggregates with central dyskeratosis and at the base of a crater favors KA. The occasionally progressive course of KA raises the differential diagnosis of endophytic—rather than more easily recognized exophytic—verrucous carcinoma. In the author’s opinion, some KAs that do not regress but rather destroy structures inexorably are, in fact, verrucous carcinomas, an idea posed several years ago.113 More recently, transition from KA to verrucous carcinoma has been suggested.114 An important point is that the subungual tumors associated with incontinentia pigmenti are indistinguishable from keratoacanthoma.112

Typical Melanocytic Proliferations (Benign Melanocytic Hyperplasia), Including Ephelis, Simple Lentigo, and Melanocytic Nevi These entities are very frequent causes of longitudinal melanonychia. The latter feature results from melanin granules in the growing plate derived from the segment of matrix involved by the melanocytic activation or proliferation.115 Dermatoscopy has gained ground in the management of longitudinal bands, but a biopsy is the gold standard in definitively excluding malignant melanoma.116,117 CLINICAL FEATURES Longitudinal melanonychia is a brown-black band that indicates a melanin-producing lesion of the matrix. The same type of lesion in the bed, a non–plate-forming portion of the nail, results in a pigmented spot that is discrete and immobile. All of the preceding entities may produce a band that is narrow, sharply circumscribed, and homogeneous.118 The current workup of melanonychia includes careful clinical assessment, dermatoscopy, and one of three types of matrical biopsy (punch, shave or lateral longitudinal).116,119 HISTOPATHOLOGIC FEATURES The description of microscopic findings in pigmented longitudinal bands has been relatively unchanged for many years. Melanocytic hyperplasia or macule, which may be the

DIFFERENTIAL DIAGNOSIS The longitudinal melanonychia derived from neoplastic disorders (lentigo and nevus) must be distinguished from the same phenomenon secondary to the freckle-like lesions with hyperactive melanocytes. The latter lesions may be related to ethnicity (Africans and Asians), may be spontaneous or congenital, may develop after trauma (such as friction or radiation), or may be associated with the LaugierHunziker-Baran syndrome.125 These benign causes of longitudinal melanonychia have, in turn, to be distinguished from early melanoma, also characterized by a pigmented band. However, this band usually is wider, darker or variegated, and less well circumscribed than a benign pigmented band. It reflects a larger, more irregular, and heterogeneous neoplasm of the matrix.

CHAPTER 36 ■ DISORDERS OF THE NAIL APPARATUS

equivalent of an ephelis (freckle), shows hyperpigmentation either with or without a (functional) slightly increased numbers of melanocytes. It is essentially a well-demarcated pigmented macule in the matrix.120 A simple lentigo exhibits an increased number of melanocytes singly disposed in a variably hyperplastic epithelium. These two entities tend to appear early in life.121 The acquired or congenital melanocytic nevus, which is uncommon in the nail unit, contains nests of melanocytes in variably hyperpigmented rete ridges. Most of the ungual nevi are junctional and only rarely compound.122 Blue nevus shows up very rarely in subungual location,123 where a regressed melanoma may mimic it.124

Atypical Melanocytic Proliferation, Including Melanoma in Situ Under this rubric are included the atypical melanocytic proliferations and the early stage of melanoma in situ. Also included is recurrent or persistent melanocytosis with histologic features that simulate melanoma. CLINICAL FEATURES The early phase of acral melanoma may present as longitudinal melanonychia that is broader than 5 mm and associated with nail dystrophy, a bleeding mass,118 and Hutchinson sign (spread of pigmentation in the nail folds). HISTOPATHOLOGIC FEATURES On biopsy of the nail plate, the melanin granules are distributed broadly and, more important, throughout the whole thickness of the plate. This is a reflection of the usually wide and lengthy extension of the primary lesion. A problem in its

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PART V ■ DISORDERS OF NAILS AND THE ORAL MUCOSA

recognition is the relatively uniform pattern of melanocyte proliferation near the junction of the matrix (practically always the source of melanoma in situ). However, the process may be cellular, and nuclear pleomorphism and other signs of malignancy may be obvious (prominent nucleoli, increased or abnormal mitoses, longitudinally branching dendritic melanocytes). A suprabasal location of melanocytes throughout the lower half of the matrix has been described.126 If nests are formed, they are usually small, only slightly pleomorphic, and almost always nevoid. The latter characteristics account for the relative reluctance of pathologists to accept such a subtle proliferation as malignant. Regardless of the terminology applied to such a lesion, complete removal of the lesion is mandatory. However, dermatoscopy has been claimed as a means of follow-up in some instances.116 Hutchinson sign may be seen histologically as the continuation of the same matrical or bed-extended proliferation of melanocytes in the epidermoid epithelia of epo- and hyponychium or the epidermis of the nail folds. The diagnostic utility of Hutchinson sign is limited by its presence in some nevi, so far only dermatoscopically proven,127 or the existence of a pseudo-Hutchinson sign given by pigmented Bowen disease or by overly transparent nail folds that would appear falsely pigmented.128 DIFFERENTIAL DIAGNOSIS The differential diagnosis includes the entities discussed previously, namely ephelis, lentigo, nevus, and invasive melanoma. As mentioned earlier, the diagnosis of these various lesions is based on the frequency, disposition, and degree of atypia of melanocytes (see Chapter 27).

Melanoma

998

CLINICAL FEATURES Besides the predominant acral lentiginous pattern, malignant melanoma may be nodular and, less frequently, desmoplastic or even neurotropic (see also Chapter 27).129-131 Although early melanomas may present with a longitudinal melanotic streak, more advanced tumors may give rise to a fully pigmented flat or tumorous mass in the nail field and periungual tissues. The pigmented band usually has the same characteristics as in melanoma in situ.118 More advanced melanomas may be amelanotic and may be accompanied by destruction of the plate, ulceration, and occasional longitudinal erythronychia.132 Melanotic whitlow (Hutchinson

 FIGURE 36-18 Melanoma, microinvasive. In the matrical epithelium, mostly basally located, are small yet hyperchromatic melanocytes that are irregularly arranged as single cells and in variably confluent nests. Few melanocytes are subtly present in the bed stroma.

sign) is found very frequently at advanced stages of the disease.128 HISTOPATHOLOGIC FEATURES As discussed in Chapter 27, the criteria for diagnosis include variable degrees of the following: a lesion of sufficient breadth, asymmetry, poor circumscription, increased numbers of atypical basilar melanocytes reaching confluence (Fig. 36-18), aggregates of atypical melanocytes that are irregularly sized and shaped, and pagetoid spread.132 The presence of microscopic Hutchinson sign in proximal or lateral nail fold epithelia, but not so in the hyponychium (which is still part of the matrical stream of cells and keratins), is a valuable microscopic sign of melanoma. Extension of atypical melanocytes into subungual epidermoid inclusions (adnexal-like extension) may show greater relative thickness than actual malignant melanocytes in the subungual stroma. DIFFERENTIAL DIAGNOSIS The main pitfall is the misdiagnosis of melanoma as a simple lentigo, nevus, or atypical intraepithelial melanocytic proliferation. The false-negative diagnosis of one of those entities, particularly misconstrued diagnostically as an “atypical melanocytic proliferation,” is always involved when a delay in the diagnosis of malignant melanoma happens. Another pitfall is the erroneous assumption, for example, that melanoma is not an occurrence in

children, although such diagnoses should always be carefully made.133,134

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51. Hafner J, Haenseler E, Ossent P, et al: Benzidine stain for the histochemical detection of hemoglobin in splinter hemorrhage (subungual hematoma) and black heel. Am J Dermatopathol. 1995;17(4):362367. 52. Vanhooteghem O, Papadopoulos T, Sass U, et al: Clinical manifestations of cholesterol crystal embolism with subungual haemorrhages: a possible relationship? Dermatology. 1996;192(4): 395397. 53. Mujic F, Lloyd M, Cuadrado MJ, et al: Prevalence and clinical significance of subungual splinter haemorrhages in patients with the antiphospholipid syndrome. Clin Exp Rheumatol. 1995;13(3): 327-331. 54. Haneke E: “Onycholemmal” horn. Dermatologica. 1983;167(3):155-158. 55. Scully K, Assaad D: Mucinous syringometaplasia. J Am Acad Dermatol. 1984; 11(3):503-508. 56. Young A, Manolson P, Cohen B, et al: Painful subungal dyskeratotic tumors in incontinentia pigmenti. J Am Acad Dermatol. 2005;52(4):726-729. 57. Kaiser JF, Proctor-Shipman L: Squamous cell carcinoma in situ (Bowen’s disease) mimicking subungual verruca vulgaris. J Fam Pract. 1994;39(4):384-387. 58. Saez-de-Ocariz MM, Dominguez-Cherit J, Garcia-Corona C: Subungual epidermoid cysts. Int J Dermatol. 2001;40(8):524526. 59. Telang GH, Jellinek N: Multiple calcified subungual epidermoid inclusions. J Am Acad Dermatol. 2007;56(2):336-339. 60. Alessi E, Zorzi F, Gianotti R, Parafioriti A: Malignant proliferating onycholemmal cyst. J Cutan Pathol. 1994;21(2):183188. 61. Alessi E, Coggi A, Gianotti R, et al: Onycholemmal carcinoma. Am J Dermatopathol. 2004;26(5):397-402. 62. Inaoki M, Makino E, Adachi M, Fujimoto W: Onycholemmal carcinoma. J Cutan Pathol. 2006;33(8):577-580. 63. Fayol J, Baran R, Perrin C, Labrousse F: Onychomatricoma with misleading features. Acta Derm Venereol. 2000;80(5):370372. 64. Estrada-Chavez G, Vega-Memije ME, Toussaint-Caire S, et al: Giant onychomatricoma: report of two cases with rare clinical presentation. Int J Dermatol. 2007;46(6):634-636. 65. Piraccini BM, Antonucci A, Rech G, et al: Onychomatricoma: first description in a child. Pediatr Dermatol. 2007;24(1):46-48. 66. Perrin C, Goettmann S, Baran R: Onychomatricoma: clinical and histopathologic findings in 12 cases. J Am Acad Dermatol. 1998;39(4, pt 1):560-564. 67. Perrin C, Baran R, Pisani A, et al: The onychomatricoma: additional histologic criteria and immunohistochemical study. Am J Dermatopathol. 2002;24(3):199-203. 68. Ko CJ, Shi L, Barr RJ, et al: Unguioblastoma and unguioblastic fibroma—an expanded spectrum of onychomatricoma. J Cutan Pathol. 2004;31(4):307-311. 69. Perrin C, Baran R: Invaginated fibrokeratoma with matrix differentiation: a new histological variant of acquired fibrokeratoma. Br J Dermatol. 1994;130(5):654-657. 70. Fraga GR, Patterson JW, McHargue CA: Onychomatricoma: report of a case and its comparison with fibrokeratoma of

CHAPTER 36 ■ DISORDERS OF THE NAIL APPARATUS

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Dermatology, 2nd ed. New York: Mosby Elsevier; 2008:1019-1036. Sobera JO, Elewski BE. Fungal diseases, in Bolognia JL, Jorizzo JL, Rapini RP (eds). Dermatology, 2nd ed. New York: Mosby Elsevier; 2008:1135-1163. Grover C, Reddy BS, Chaturvedi KU: Onychomycosis and the diagnostic significance of nail biopsy. J Dermatol. 2003;30(2):116-122. Reisberger EM, Abels C, Landthaler M, Szeimies RM: Histopathological diagnosis of onychomycosis by periodic acid-Schiff-stained nail clippings. Br J Dermatol. 2003;148(4):749-754. Weinberg JM, Koestenblatt EK, Jennings MB: Utility of histopathologic analysis in the evaluation of onychomycosis. J Am Podiatr Med Assoc. 2005;95(3):258263. Walling HW, Sniezek PJ: Distribution of toenail dystrophy predicts histologic diagnosis of onychomycosis. J Am Acad Dermatol. 2007;56(6):945-948. Hernández M, Harrist TJ, GonzálezServa A: Flowcharting the nail plate biopsy in search of fungi [abstract]. Am J Dermatopathol. 2007;29(5):503. González-Serva A: Pigmented sheets in a nail-plate biopsy: Mirrors of melaninproducing onychometameres [abstract]. Am J Dermatopathol. 2007;29(2):204. Braun RP, Baran R, Saurat JH, Thomas L: Surgical pearl: dermoscopy of the free edge of the nail to determine the level of nail plate pigmentation and the location of its probable origin in the proximal or distal nail matrix. J Am Acad Dermatol. 2006;55(3):512-513. Grover C, Nanda S, Reddy BS, Chaturvedi KU: Nail biopsy: assessment of indications and outcome. Dermatol Surg. 2005; 31(2):190-194. Holzberg M: Common nail disorders. Dermatol Clin. 2006;24(3):349-354. Baran R, Richert B: Common nail tumors. Dermatol Clin. 2006;24(3):297-311. Kovich OI, Soldano AC: Clinical pathologic correlations for diagnosis and treatment of nail disorders. Dermatol Ther. 2007;20(1):11-16. Gupta AK, Ryder JE, Summerbell RC: Onychomycosis: classification and diagnosis. J Drugs Dermatol. 2004;3(1):51-56. Gupta AK, Ricci MJ: Diagnosing onychomycosis. Dermatol Clin. 2006;24(3): 365-369. Cabral A, Berger TH, Middag-Broekman JH, Boon ME: Unequivocal morphological diagnosis of fungi in morphologically abnormal nails. Histopathology. 2006; 48(7):862-867. Karimzadegan-Nia M, Mir-AminMohammadi A, Bouzari N, Firooz A: Comparison of direct smear, culture and histology for the diagnosis of onychomycosis. Australas J Dermatol. 2007; 48(1):18-21. Chang A, Wharton J, Tam S, et al: A modified approach to the histologic diagnosis of onychomycosis. J Am Acad Dermatol. 2007;57(5):849-853. Machler BC, Kirsner RS, Elgart GW: Routine histologic examination for the diagnosis of onychomycosis: an evaluation of sensitivity and specificity. Cutis. 1998;61(4):217-219. Chowdhary A, Randhawa HS, Sharma S, et al: Malassezia furfur in a case of

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the nailbed. Am J Dermatopathol. 2001; 23(1):36-40. Ruiz-Villaverde R, Blasco-Melguizo J, Hernandez-Jurado I, et al: Bilateral and multiple periungual fibromas as an oligosymptomatic form of tuberous sclerosis. Dermatology. 2004;209(2):160-161. Dereure O, Savoy D, Doz F, et al: Multiple acral fibromas in a patient with familial retinoblastoma: a cutaneous marker of tumour-suppressor gene germline mutation? Br J Dermatol. 2000;143(4):856-859. Hashiro M, Fujio Y, Tanaka M, Yamatodani Y: Giant acquired fibrokeratoma of the nail bed. Dermatology. 1995;190(2):169-171. McNiff JM, Subtil A, Cowper SE, et al: Cellular digital fibromas: distinctive CD34-positive lesions that may mimic dermatofibrosarcoma protuberans. J Cutan Pathol. 2005;32(6):413-418. Mahmood MN, Salama ME, Chaffins M, et al: Solitary sclerotic fibroma of skin: a possible link with pleomorphic fibroma with immunophenotypic expression for O13 (CD99) and CD34. J Cutan Pathol. 2003;30(10):631-636. Hsieh YJ, Lin YC, Wu YH, et al: Subungual pleomorphic fibroma. J Cutan Pathol. 2003;30(9):569-571. Tosti A, Cameli N, Peluso AM, et al: Storiform collagenoma of the nail. Cutis. 1999;64(3):203-204. Kinoshita Y, Kojima T, Furusato Y: Subungual dermatofibroma of the thumb. J Hand Surg [Br]. 1996;21(3):408-409. Carlson RM, Lloyd KM, Campbell TE: Acquired periungual fibrokeratoma: a case report. Cutis. 2007;80(2):137-140. Saito S, Ishikawa K. Acquired periungual fibrokeratoma with accessory germinal matrix. J Hand Surg [Br]. 2002; 27(6):549-555. Oteo-Alvaro A, Meizoso T, Scarpellini A, et al: Superficial acral fibromyxoma of the toe, with erosion of the distal phalanx. A clinical report. Arch Orthop Trauma Surg. 2008;128(3):271-274. Guitart J, Ramirez J, Laskin WB: Cellular digital fibromas: what about superficial acral fibromyxoma? J Cutan Pathol. 2006;33(11):762-764. Abou-Nukta F, Fiedler P, Parkash V, Arons J: Superficial acral fibromyxoma of the distal phalanx of the thumb. J Hand Surg [Br]. 2006;31(6):619-620. Quaba O, Evans A, Al-Nafussi AA, Nassan A: Superficial acral fibromyxoma. Br J Plast Surg. 2005;58(4):561-564. Meyerle JH, Keller RA, Krivda SJ: Superficial acral fibromyxoma of the index finger. J Am Acad Dermatol. 2004; 50(1):134-136. Andre J, Theunis A, Richert B, de SaintAubain N: Superficial acral fibromyxoma: clinical and pathological features. Am J Dermatopathol. 2004;26(6):472-474. Kazakov DV, Mentzel T, Burg G, Kempf W: Superficial acral fibromyxoma: report of two cases. Dermatology. 2002; 205(3):285-258. Fetsch JF, Laskin WB, Miettinen M: Superficial acral fibromyxoma: a clinicopathologic and immunohistochemical analysis of 37 cases of a distinctive soft tissue tumor with a predilection for the fingers and toes. Hum Pathol. 2001; 32(7):704-714.

89. Smith K, Skelton H: Cutaneous fibrous perineurioma. J Cutan Pathol. 1998; 25(6):333-337. 90. Mentzel T, Kutzner H: Reticular and plexiform perineurioma: clinicopathological and immunohistochemical analysis of two cases and review of perineurial neoplasms of skin and soft tissues. Virchows Arch. 2005;447(4):677-682. 91. Baran R, Perrin C: Perineurioma: a tendon sheath fibroma-like variant in a distal subungual location. Acta Derm Venereol. 2003;83(1):60-61. 92. Jurcic V, Zidar A, Montiel MD, et al: Myxoinflammatory fibroblastic sarcoma: a tumor not restricted to acral sites. Ann Diagn Pathol. 2002;6(5):272-280. 93. de Berker D, Goettman S, Baran R: Subungual myxoid cysts: clinical manifestations and response to therapy. J Am Acad Dermatol. 2002;46(3):394-398. 94. Kivanc-Altunay I, Kumbasar E, Gokdemir G, et al: Unusual localization of multiple myxoid (mucous) cysts of toes. Dermatol Online J. 2004;10(1):23. 95. Baran R, Haneke E: Subungual myxoid neurofibroma on the thumb. Acta Derm Venereol. 2001;81(3):210-211. 96. Lee SK, Jung MS, Lee YH, et al: Two distinctive subungual pathologies: subungual exostosis and subungual osteochondroma. Foot Ankle Int. 2007;28(5):595-601. 97. Ekmekci P, Bostanci S, Erdogan N, et al: A painless subungual osteoid osteoma. Dermatol Surg. 2001;27(8):764-765. 98. Bostanci S, Ekmekci P, Ekinci C, et al: Subungual osteochondroma: a case report. Dermatol Surg. 2001;27(6):591-593. 99. Maalla R, Hmid M, Mellouli O, Klila M: [Glomus tumours of the hand. About 10 cases]. Tunis Med. 2007;85(6):469-472. 100. Okada O, Demitsu T, Manabe M, Yoneda K: A case of multiple subungual glomus tumors associated with neurofibromatosis type 1. J Dermatol. 1999; 26(8):535-537. 101. Baran R, Requena L, Drape JL: Subungual angioleiomyoma masquerading as a glomus tumour. Br J Dermatol. 2000; 142(6): 1239-1241. 102. Koch A, Schonlebe J, Haroske G, et al: Polydactylous Bowen’s disease. J Eur Acad Dermatol Venereol. 2003;17(2):213-215. 103. Figus A, Kanitkar S, Elliot D: Squamous cell carcinoma of the lateral nail fold. J Hand Surg [Br]. 2006;31(2):216-220. 104. Dalle S, Depape L, Phan A, et al: Squamous cell carcinoma of the nail apparatus: clinicopathological study of 35 cases. Br J Dermatol. 2007;156(5):871-874. 105. Zabawski EJ Jr, Washak RV, Cohen JB, et al: Squamous cell carcinoma of the nail bed: is finger predominance another clue to etiology? A report of 5 cases. Cutis. 2001;67(1):59-64. 106. Dobson CM, Azurdia RM, King CM: Squamous cell carcinoma arising in a psoriatic nail bed: case report with discussion of diagnostic difficulties and therapeutic options. Br J Dermatol. 2002;147(1):144-149. 107. Tosti A, Morelli R, Fanti PA, et al: Carcinoma cuniculatum of the nail apparatus: report of three cases. Dermatology. 1993;186(3):217-221. 108. Van Geertruyden JP, Olemans C, Laporte M, Noel JC: Verrucous carcinoma of the nail bed. Foot Ankle Int. 1998;19(5):327-328.

109. Cohen PR: Metastatic tumors to the nail unit: subungual metastases. Dermatol Surg. 2001;27(3):280-293. 110. Baran R, Mikhail G, Costini B, et al: Distal digital keratoacanthoma: two cases with a review of the literature. Dermatol Surg. 2001;27(6):575-579. 111. Sinha A, Marsh R, Langtry J: Spontaneous regression of subungual keratoacanthoma with reossification of underlying distal lytic phalynx. Clin Exp Dermatol. 2005;30(1):20-22. 112. Baran R, Goettmann S: Distal digital keratoacanthoma: a report of 12 cases and a review of the literature. Br J Dermatol. 1998;139(3):512-515. 113. Scarani P, Ghigi G, Bertarelli C, Eusebi V: Subungual keratoacanthoma: a variant of verrucous squamous cell carcinoma of the skin. Appl Pathol. 1983;1(6):339-342. 114. Baran R, Tosti A, De Berker D: Periungual keratoacanthoma preceded by a wart and followed by a verrucous carcinoma at the same site. Acta Derm Venereol. 2003;83(3):232-233. 115. Andre J, Lateur N: Pigmented nail disorders. Dermatol Clin. 2006;24(3):329-339. 116. Braun RP, Baran R, Le Gal FA, et al: Diagnosis and management of nail pigmentations. J Am Acad Dermatol. 2007; 56(5):835-847. 117. Thomas L, Dalle S: Dermoscopy provides useful information for the management of melanonychia striata. Dermatol Ther. 2007;20(1):3-10. 118. Haneke E, Baran R: Longitudinal melanonychia. Dermatol Surg. 2001;27(6): 580-584. 119. Jellinek N: Nail matrix biopsy of longitudinal melanonychia: diagnostic algorithm including the matrix shave biopsy. J Am Acad Dermatol. 2007;56(5):803-810. 120. Husain S, Scher RK, Silvers DN, Ackerman AB: Melanotic macule of nail unit and its clinicopathologic spectrum. J Am Acad Dermatol. 2006;54(4):664-667. 121. Goettmann-Bonvallot S, Andre J, Belaich S: Longitudinal melanonychia in children: a clinical and histopathologic study of 40 cases. J Am Acad Dermatol. 1999;41(1):17-22. 122. Tosti A, Baran R, Piraccini BM, et al: Nail matrix nevi: a clinical and histopathologic study of twenty-two patients. J Am Acad Dermatol. 1996;34 (5, pt 1):765-771. 123. Causeret AS, Skowron F, Viallard AM, et al: Subungual blue nevus. J Am Acad Dermatol. 2003;49(2):310-312. 124. Yang CH, Yeh JT, Shen SC, et al: Regressed subungual melanoma simulating cellular blue nevus: managed with sentinel lymph node biopsy. Dermatol Surg. 2006;32(4):577-580; discussion 580-581. 125. Moore RT, Chae KA, Rhodes AR: Laugier and Hunziker pigmentation: a lentiginous proliferation of melanocytes. J Am Acad Dermatol. 2004;50(5 suppl): S70-S74. 126. Tomizawa K: Early malignant melanoma manifested as longitudinal melanonychia: subungual melanoma may arise from suprabasal melanocytes. Br J Dermatol. 2000;143(2):431-434. 127. Kawabata Y, Ohara K, Hino H, Tamaki K: Two kinds of Hutchinson’s sign, benign and malignant. J Am Acad Dermatol. 2001;44(2):305-307.

128. Baran R, Kechijian P: Hutchinson’s sign: a reappraisal. J Am Acad Dermatol. 1996; 34(1):87-90. 129. Parodi PC, Scott CA, De Biasio F, et al: Desmoplastic melanoma of the nail. Ann Plast Surg. 2003;50(6):658-662. 130. Tan KB, Moncrieff M, Thompson JF, et al: Subungual melanoma: a study of 124 cases highlighting features of early lesions, potential pitfalls in diagnosis, and guidelines for histologic reporting. Am J Surg Pathol. 2007;31(12):1902-1912.

131. Cohen T, Busam KJ, Patel A, Brady MS: Subungual melanoma: management considerations. Am J Surg. 2008;195(2):244248. 132. Harwood M, Telang GH, RobinsonBostom L, Jellinek N: Melanoma and squamous cell carcinoma on different nails of the same hand. J Am Acad Dermatol. 2008;58(2):323-326. 133. Antonovich DD, Grin C, Grant-Kels JM: Childhood subungual melanoma in situ in diffuse nail melanosis beginning as

expanding longitudinal melanonychia. Pediatr Dermatol. 2005;22(3):210-212. 134. Motta A, Lopez C, Acosta A, Penaranda C: Subungual melanoma in situ in a Hispanic girl treated with functional resection and reconstruction with onychocutaneous toe free flap. Arch Dermatol. 2007;143(12):1600-1602.

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CHAPTER 37 Disorders of the Oral Mucosa

PART V ■ DISORDERS OF NAILS AND THE ORAL MUCOSA

Mark A. Lerman Sook-Bin Woo Oral and maxillofacial pathology is the specialty of dentistry and pathology that concerns itself with the study, diagnosis, and management of developmental, inflammatory, infectious, neoplastic, and metabolic diseases relating to the teeth, the maxilla and mandible, the major and minor salivary glands, and the oral mucosa. This chapter focuses on the more common oral mucosal diseases encountered in a pathology practice. As in the practice of dermatopathology, the importance of a thorough understanding of the clinical aspects and dynamic evolution of each entity cannot be overemphasized.

DEVELOPMENTAL CONDITIONS

Fordyce Granules Synonym: Ectopic sebaceous glands. Fordyce granules are intraoral sebaceous glands that are present in approximately 80% of the population1 and are viewed as a normal anatomic variation. They become prominent after puberty because of hormonal influences. CLINICAL FEATURES They occur as yellow to white papules measuring 1 to 3 mm in diameter and present symmetrically on the buccal mucosa, upper and lower labial mucosa, lip vermilion, and the retromolar areas. Rarely, they also may be seen on the tongue, gingiva, and palate. HISTOPATHOLOGIC FEATURES They consist of normal sebaceous glands that may communicate with the surface epithelium via a duct. Occasionally, there may be hyperplasia of the sebaceous acini, retention of secretions with pseudocyst formation, and even adenomatous change.2 In one report, a hair follicle and hair shaft were present.

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DIFFERENTIAL DIAGNOSIS Most Fordyce granules are diagnosed on clinical findings alone, and there is usually no need for a biopsy. Some salivary gland neoplasms (especially those in the major

glands) may exhibit focal sebaceous differentiation within an obviously neoplastic process.

White Sponge Nevus Synonyms: Leukoedema exfoliativum mucosae oris, congenital leukokeratosis mucosa oris, naevus spongiosus albus mucosae. White sponge nevus is an uncommon mucosal condition transmitted in an autosomal dominant fashion with a high degree of penetrance and variable expressivity that affects primarily the oral mucosa, although genital, anal, laryngeal, and esophageal mucosal involvement also has been documented. There are no concomitant skin lesions and ocular coloboma have been described in one report. White sponge nevus is the result of abnormal keratinization and faulty desquamation. This condition is caused by a mutation in differentiation-specific keratins K4 (on chromosome 12q) and/or K13 (on chromosome 17q) in a domain critical for keratin filament stability.3 CLINICAL FEATURES Onset is in early childhood. The buccal mucosa is thickened, boggy, and white with soft, spongy folds and creases. Involvement is usually bilateral and the labial mucosa, alveolar ridge mucosa, floor of the mouth, and tongue may show similar changes. It is asymptomatic and may undergo periods of exacerbation and remission. Tetracycline and penicillin have been reported to improve lesions. HISTOPATHOLOGIC FEATURES There is parakeratosis, spongiosis in the absence of inflammation, epithelial hyperplasia with cytoplasmic clearing of the spinous cells, and eosinophilic para- and perinuclear condensations. These condensations are the most characteristic feature of white sponge nevus (Fig. 37-1). Some spinous cells may exhibit nuclear degeneration and anucleation. Bacterial colonization is a result of chronic trauma. The lamina propria is usually devoid of inflammation. Rarely, epidermolytic changes are noted. Ultrastructurally, the cells show segregation of organelles with some areas being completely devoid of organelles. There is abnormal aggregation of tonofilaments into dense clumps corresponding to the para- and perinuclear condensations, and the superficial cells contain Odland bodies (membrane-coating granules) but without transfer of granules into the intercellular space.

DIFFERENTIAL DIAGNOSIS Leukoedema does not show para- and perinuclear eosinophilia. Hereditary benign intraepithelial dyskeratosis (HBID) also lacks eosinophilic condensations and often demonstrates a “cell-within-a-cell” phenomenon, in which an epithelial cell appears to be surrounded or engulfed by an adjacent epithelial cell.4 Chronic bite injury is characterized by hyperparakeratosis with superficial bacterial colonization, acanthosis, and intrakeratinocyte edema without eosinophilic condensations. In some cases of white sponge nevus, there may be a component of chronic cheek chewing present histologically because the lesions protrude and may be traumatized inadvertently.

Leukoedema Leukoedema is a fairly common mucosal condition reported to be present in 4% to 90% of the general population and therefore sometimes considered a normal variation.5 This wide variation in prevalence figures is likely a reflection of the variation in criteria used for diagnosis, differences in examination conditions, and differences in population groups and oral habits. The prevalence of leukoedema may appear to be higher in African Americans than in other races because the pigmented nature of their mucosa contrasts more sharply with this white lesion. Its occurrence has been associated with the use of tobacco products, chewing of coca leaves, and smoking of cannabis.6 It is believed that leukoedema occurs as a result of local insult to the mucosa because in some cases cessation of smoking results in resolution of the lesions.7 CLINICAL FEATURES The condition affects both children and adults. The buccal mucosa and sometimes the labial mucosa have a pale milky white or gray opalescent appearance with crinkly folds and wrinkles. When the mucosa is stretched, the white crinkly appearance diminishes or disappears.5 HISTOPATHOLOGIC FEATURES The mucosa may or may not be thinly parakeratotic. There is acanthosis with the formation of broad rete ridges. The midlevel spinous cells are swollen and vacuolated (Fig. 37-2). The cells in the outermost layer are vacuolated and ballooned and usually anucleate; outlines of plasma membranes have a “jigsaw puzzle” effect. Ultrastructurally, the swollen cells of the midepithelium contain clumped

glycogen-like material and abnormal mitochondria. The superficial ballooned cells have membrane-bound spaces that contain fragmented organelles, abnormal keratohyalin-like granules, and dispersed tonofilaments. These features have been interpreted as reversible degenerative changes in the midepithelium and irreversible degenerative changes in the superficial cells.

Oral Lymphoepithelial Cyst

 FIGURE 37-1 White sponge nevus. Keratinocytes exhibit perinuclear eosinophilic condensations.

Oral lymphoepithelial cysts are cystic structures that develop most commonly on the ventrolateral tongue, the soft palate, the floor of the mouth, or within the tonsils. Their etiology is unknown, but they may develop from inflammation of, or trauma to, deep tonsillar crypts.9 CLINICAL FEATURES Lymphoepithelial cysts are seen most commonly in young adults. They are generally yellow in color and approximately 1 cm in diameter. They present as asymptomatic mucosal masses that may be either soft or firm to palpation. They have occasionally been reported in association with epidermoid cysts.10

CHAPTER 37 ■ DISORDERS OF THE ORAL MUCOSA

DIFFERENTIAL DIAGNOSIS Biopsies of the linea alba may be identical to leukoedema, supporting superficial mucosal injury as an etiologic factor. A similar histology is noted in the sucking pads of neonates.8 Chronic bite injury (morsicatio mucosae oris) also exhibits leukoedema but in addition shows marked hyperparakeratosis with fissures and clefts rimmed by bacteria (impetigination).

HISTOPATHOLOGIC FEATURES The lumen is usually filled with parakeratin. They are lined by parakeratinized stratified squamous epithelium and exhibit lymphocyte exocytosis. The wall of the cyst contains diffuse sheets of lymphocytes, often demonstrating germinal center formation (Fig. 37-3).11 DIFFERENTIAL DIAGNOSIS Papillary cystadenoma lymphomatosum (Warthin tumors) are benign salivary gland tumors that also feature an epithelial lining and prominent lymphoid component. However, this tumor is seen primarily within the parotid gland and exhibits multiple papillary infoldings and oncocytic metaplasia of the epithelium.

Gingival Cyst of the Adult  FIGURE 37-2 Leukoedema. Ballooned cells, compact cells, and superficial, degenerated, and anucleate cells are demonstrated.

The gingival cyst of the adult is a developmental odontogenic cyst that is believed to be derived from rests of the dental

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patients with this condition rarely demonstrate candidiasis elsewhere in the mouth, and the clinical lesion persists even after treatment with antifungal medications.

PART V ■ DISORDERS OF NAILS AND THE ORAL MUCOSA

CLINICAL FEATURES This condition is rare in children and is present in 0.1% to 1.0% of adults. The lesion presents as a slightly painful, oval to rhomboidal, discrete, erythematous, depapillated, often nodular area in the midline posterior dorsum of the tongue anterior to the circumvallate papillae.

 FIGURE 37-3 Lymphoepithelial cyst. A keratin-filled lumen is surrounded by stratified squamous epithelium and lymphoid tissue.

lamina or from junctional epithelium within the gingival sulcus.12 It is to be distinguished from the gingival (dental lamina) cyst of the newborn, a common cyst which resolves spontaneously very early in life. CLINICAL FEATURES Gingival cysts of the adult develop primarily on the facial mandibular gingiva in the canine-premolar region. They present as soft tissue nodules that are typically asymptomatic and colored pink to blue. There is a slight female predilection and they are noted most often in the fifth or sixth decade.13

Median rhomboid glossitis represents a form of erythematous candidiasis that involves the posterior midline tongue dorsum.14 It is unclear why this particular area is predisposed to candidal infection. A previous theory of this being a developmental anomaly has fallen into disfavor. However, it is possible that this is a developmental malformation that facilitates candidal colonization since

HISTOPATHOLOGIC FEATURES There is atrophy of the filiform papillae with parakeratosis and the presence of spongiotic pustules associated with candidal hyphae (Fig. 37-4). There is psoriasiform epithelial hyperplasia with confluent rete ridges, papillary edema, and a variable chronic inflammatory infiltrate in the connective tissue. Some biopsies, if deep and taken from the midline, may contain the median raphe of the tongue, a homogeneously hyalinized, hypocellular, and avascular band into which the muscle fibers of the tongue decussate. DIFFERENTIAL DIAGNOSIS Benign migratory glossitis and oral psoriasis will show psoriasiform mucositis but will not contain evidence of candidal infection unless secondarily infected.15

HISTOPATHOLOGIC FEATURES Gingival cysts of the adult are classically lined by a thin layer of squamous or cuboidal epithelium 4 to 5 cells thick. Within the lining may be noted focal epithelial plaques containing glycogen-rich clear cells arranged in a whorling pattern. DIFFERENTIAL DIAGNOSIS A lateral periodontal cyst features identical histopathology but develops within the alveolar bone. Glandular odontogenic cysts demonstrate a similar thin lining of odontogenic epithelium with epithelial plaques, but also exhibit numerous mucous cells and duct-like structures.

INFECTIOUS CONDITIONS

Median Rhomboid Glossitis 1004

Synonym: Central papillary atrophy of the tongue.

 FIGURE 37-4 Median rhomboid glossitis. A hyalinized band (median raphe) underlies elongated rete ridges and inflammatory cells. Spongiotic pustules are noted within the surface epithelium.

Oral Hairy Leukoplakia

CLINICAL FEATURES The ventrolateral border of the tongue is the most frequently involved site, sometimes with extension onto the dorsum. Less commonly, the buccal and labial mucosae are involved. Hairy leukoplakia occurs as a painless white plaque that has a corrugated, shaggy (“hairy”) surface with parallel furrows running at right angles to the lateral tongue border. When on the dorsum or the buccal mucosa, the condition may appear as a homogeneous dense white plaque. HISTOPATHOLOGIC FEATURES OHL demonstrates corrugated parakeratosis and acanthosis as well as clusters of pale-staining cells in the superficial epithelium subjacent to the keratin. These pale cells exhibit condensation of chromatin against the nuclear membrane and dense Cowdrytype nuclear inclusions (Fig. 37-5).19 This “chromatin beading” is an important and consistent finding in OHL. There is no evidence of dysplasia and inflammation in the lamina propria is insignificant. EBV is demonstrated by immunohistochemical stains, in situ hybridization, or polymerase chain reaction (PCR) within the superficial keratinocytes.20 Candidal hyphae are present in the keratin layer in 80% of patients and, importantly, are usually unassociated with spongiotic pustules.21 DIFFERENTIAL DIAGNOSIS Vacuolated cells are seen in leukoedema, chronic bite injury, or white sponge nevus, but chromatin beading and nuclear inclusions are absent in these entities. Candidal colonization, when present, is a secondary phenomenon, and the lack of spongiotic

 FIGURE 37-5 Oral hairy leukoplakia. Ballooned cells show nuclear condensations and eosinophilic dense nuclear inclusions.

pustules should raise the suspicion for hairy leukoplakia.

Squamous Papilloma Squamous papillomas are common benign epithelial proliferations exhibiting a verrucous or papillary surface. They are often associated with human papillomavirus (HPV) types 6 and 11, though the exact nature of the relationship is unclear. CLINICAL FEATURES Papillomas may occur at any age and on any oral mucosal surface; they are seen most commonly on the palate or tongue. They are typically pedunculated exophytic lesions that are white but may be red or normal in color, depending on their extent of keratinization.22 They generally do not exceed 0.5 cm in size. HISTOPATHOLOGIC FEATURES Papillomas demonstrate an exophytic, papillary proliferation of stratified squamous epithelium. Subjacent fibrovascular connective tissue cores may show hyalinization. Koilocytes representative of HPV infection may be noted in the

surface epithelium. Lesions on the soft palate often exhibit prominent intracellular edema, while those on the tongue are often thickly keratinized.

CHAPTER 37 ■ DISORDERS OF THE ORAL MUCOSA

Synonym: Viral leukoplakia. First described in human immunodeficiency virus (HIV)–infected individuals, oral hairy leukoplakia (OHL) is an Epstein-Barr virus (EBV) infection of the mucosa that also occurs in non-HIVinfected immunocompromised individuals, particularly organ transplant recipients, and rarely in immunocompetent individuals.16,17 In OHL, EBV is found in epithelial cells, which is unusual for this primarily lymphotrophic virus. In HIV infection, hairy leukoplakia is predictive of AIDS, which generally develops within 2 years of the diagnosis of hairy leukoplakia.18 OHL is a benign process and should not be mistaken for true oral leukoplakia (discussed later), a clinical entity often associated with premalignant changes and progression to carcinoma.

DIFFERENTIAL DIAGNOSIS Verruca vulgaris is distinguished by marked hyperkeratosis, coarse keratohyaline granules, axially inclined rete ridges, and more prominent koilocytes. Condylomas are sessile and display rete ridges that are broader than those of papillomas; koilocytes are consistently present. Verrucous hyperplasia demonstrates a proliferation of hyperkeratotic and acanthotic surface epithelium arranged in prominent papillary projections.23

Focal Epithelial Hyperplasia Synonyms: Heck disease, multifocal papillomavirus epithelial hyperplasia. Focal epithelial hyperplasia is a squamopapular mucosal disorder caused by HPV-13 and/or 32. It has been reported frequently in Inuit and native American populations, Africans, Cape Malays, Caucasians, and Arabs. The prevalence rate varies from 7% to 13% of susceptible populations. Up to 25%

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PART V ■ DISORDERS OF NAILS AND THE ORAL MUCOSA

of patients may have another member of the household similarly affected, and in general, most afflicted individuals come from a low socioeconomic group, suggesting horizontal transmission.24 It also has been reported in patients infected with HIV.25 CLINICAL FEATURES Although most often noted in children, adults also may be affected. The disorder presents as multiple mucosa-colored or pale pink papules with smooth or slightly papillary surfaces. Individual papules may coalesce to form larger plaques.24 The labial mucosa, buccal mucosa, and tongue are frequently involved. The lesions regress after a few months or years. HISTOPATHOLOGIC FEATURES There is an exophytic squamous epithelial proliferation with only slight surface undulations. Hyperparakeratosis, if present, is mild. Rete ridges are usually broad and may be confluent at their tips. Koilocytes are noted superficially, as in other HPV-associated lesions. The so-called “mitosoid figures” represent nuclear degeneration and karyorrhexis due to HPV infection. Identification of HPV-13 or HPV-32 clinches the diagnosis. DIFFERENTIAL DIAGNOSIS Condylomas and papillomas have obviously papillary surfaces, and acanthosis is much more pronounced in condylomas than in focal epithelial hyperplasia. Oral bowenoid papulosis and koilocytic dysplasia may exhibit similar nuclear changes, but significant epithelial atypia is present.26,27

REACTIVE AND IMMUNEMEDIATED CONDITIONS

Recurrent Aphthous Ulcer

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Synonyms: Canker sore, aphthous stomatitis. Aphthous ulcers of the minor variety constitute a recurrent ulcerative condition of the mouth that afflicts approximately 20% of the population and is the most common cause of oral ulcers in North America. Predisposing local and systemic conditions include trauma, hypersensitivity to food, hematinic deficiencies, inflammatory bowel disease, immunoglobulin deficiencies, Behçet disease, neutropenia, and some collagenvascular disorders.28 In addition, HIV infection is associated with major aphthous ulcers. One variant of minor aphthous ulcers occurs in early childhood as part of the FAPA (fever, adenitis, pharyngitis, aphthae) syndrome.29 Aphthous

ulcers are likely associated with mild immune dysregulation and may be linked to mucocutaneous and rheumatologic disorders, a condition referred to as complex aphthosis. Cross-reaction of antigens of Streptococcus mutans with a mitochondrial heat shock protein may play role in ulcer development.30 Helicobacter pylori has not been found to be associated with this condition.31

the patients. The term Riga-Fede disease refers to tongue ulcers in infants and young children caused by the trauma of rubbing the tongue against erupting teeth.33 It is also seen in patients with familial dysautonomia who are indifferent to pain.34 Unlike traumatic ulcers or even aphthous ulcers, the inflammation is deeply penetrating and results in muscle damage and chronicity.

CLINICAL FEATURES The minor form occurs in teenagers and adults. Lesions are evanescent, painful, discrete ulcers, single or multiple, that are less than 1 cm in diameter with an erythematous border, occur on the nonkeratinized mucosa, and heal within 1 to 2 weeks. Common sites are the buccal and labial mucosa, ventral/lateral tongue, and soft palate—all areas of the mouth that are not normally keratinized. The herpetiform type occurs in crops of many small ulcers, whereas major ulcers measure greater than 1 cm and take weeks, if not months, to heal, often with scarring.

CLINICAL FEATURES TUG affects males 2 to 5 times more often than females. It occurs both in infants, during eruption of the primary dentition (Riga-Fede disease), and in adults. Although most traumatic ulcers of the oral mucosa heal within a 2-week period, TUG may persist for more than 1 month, raising the suspicion for a carcinoma, especially if the lesion is painless. The tongue is affected in 50% to 75% of patients; the lip and buccal mucosa are the next most frequently involved sites. TUG may present as an indurated ulcer or as a rapidly enlarging ulcerated mass. It heals uneventfully after biopsy or on its own, although it may take several weeks. Lesions may be multifocal or relapsing.

HISTOPATHOLOGIC FEATURES The ulcer base contains granulation tissue with acute and chronic inflammatory cells and an overlying fibrin clot that contains many neutrophils unless the patient is neutropenic. The adjacent epithelium may exhibit reactive atypia. Underlying skeletal fibers, if penetrated by inflammatory cells, exhibit myositis. Vasculitis, if present, is usually a secondary phenomenon. DIFFERENTIAL DIAGNOSIS If there is significant stromal eosinophilia associated with myositis and proliferation of large mononuclear histiocyte-like cells, a diagnosis of traumatic ulcerative granuloma should be made (see the following section). The presence of true vasculitis may be seen in the oral ulcers of Behçet disease.32 A search for herpes simplex virus (HSV) and cytomegalovirus (CMV) should be made in biopsies from ulcerated lesions in HIV-seropositive individuals.

Traumatic Ulcerative Granuloma Synonyms: Traumatic ulcerative granuloma with stromal eosinophilia, traumatic eosinophilic granuloma/ulcer of the tongue, granuloma eosinophilium diutinum, Riga-Fede disease. Traumatic ulcerative granuloma (TUG) is a condition that is most likely of traumatic origin because a clinically and histologically identical lesion has been reproduced experimentally in rat tongues after crush injury. However, a history of trauma may be present in less than half

HISTOPATHOLOGIC FEATURES Beneath the ulcerated epithelium is a mass of granulation tissue that may be exuberant and exophytic. There is a polymorphous inflammatory infiltrate with many eosinophils that extends deep into the tissues, often into the muscle and salivary gland. A large number of large mononuclear histiocyte-like cells with pale vesicular nuclei and eosinophils is a typical finding. These histiocyte-like cells stain for CD68 or factor XIIIa.35 Clusters of CD30+ lymphocytes may be noted within these infiltrates.36 In almost all cases, degenerating muscle fibers are also identified.37 DIFFERENTIAL DIAGNOSIS The atypical histiocytic granuloma contains sheets of transformed lymphocytes and centroblasts, often with cellular pleomorphism and mitoses, resembling a lymphoma. The presence of CD30+ lymphocytes has led to speculation that some lesions that resemble TUG clinically may histologically represent a low-grade lymphoproliferative disorder.38 For the most part, TUGs are polyclonal and self-limiting, and CD30+ cells have also been noted in benign lesions. The cells in TUG do not stain for S100 or CD1a and they lack the grooved nuclei typical for Langerhans cell histiocytosis.

Chronic Bite Injury Synonyms: Morsicatio mucosae oris, pathominia mucosae oris, morsicatio buccarum. The term chronic bite injury should be reserved for lesions that result from chronic mucosal chewing or a biting habit. Histologic changes of secondary chronic bite trauma may occur as an incidental finding in a localized fashion associated with another lesion such as a fibroma.

HISTOPATHOLOGIC FEATURES Chronic bite injuries are characterized by varying degrees of hyperparakeratosis that may be marked; the surface of the keratin is shaggy and irregular with fissures and clefts rimmed by many bacterial colonies and rarely candidal hyphae in the absence of intraepithelial inflammation. There is benign epithelial hyperplasia, variable papillomatosis, and intracellular edema. Dysplasia is never present in primary chronic bite injury. DIFFERENTIAL DIAGNOSIS Biopsies of the linea alba are identical to lesions of chronic bite injury because they share a similar etio-pathogenesis; the difference is in clinical presentation. Linea alba presents clinically as a white line along the mid-buccal mucosa bilaterally at the level of the occlusal plane and shows milder histologic changes. Primary leukoedema does not show hyperparakeratosis or surface bacterial colonization but will exhibit benign epithelial hyperplasia and intracellular edema. Unlike oral hairy leukoplakia, there is no clumping of the chromatin against the nuclear membrane, and EBV is not identified.

Oral Lichen Planus Oral lichen planus (OLP) is a common immunologically mediated condition of the mucosa with a prevalence rate of 1% to 2%. Although many cases are idiopathic, a lichenoid mucosal reaction (similar clinically and histologically) may be seen in mucosal drug eruptions and in contact stomatitides associated

CLINICAL FEATURES Females are affected twice as often as males, and most are adult or middle aged. Concurrent skin lesions are present in 4% to 44% of patients. Three clinical types have been identified, to wit: reticular/papular, erythematous/erosive/atrophic, and ulcerative/bullous types, associated with increasing symptomology. The bullous type is

rare because most bullae in the mouth rupture within a short time after their appearance. Many patients have combinations of these types, and generally, reticular white areas suggestive of Wickham striae are present at the periphery of erythematous and ulcerative lesions. Stress may cause exacerbations. Involvement of the vulva has been reported in the vulvovaginal-gingival syndrome. Any part of the mucosa may be affected by OLP, with the favored sites being buccal mucosa, labial mucosa, tongue, and gingiva; dorsal tongue lesions may not be reticulated. Desquamative gingivitis (DG) is a clinical term used to describe an erythematous condition of the gingiva that represents one of several pathologic entities, most commonly erosive OLP or mucous membrane pemphigoid. DG exhibits a 4:1 female predilection. The gingiva is painful and diffusely erythematous with areas of vesiculation, erosion, and desquamation, often covered by a white membrane that may represent a fibrin clot or the roof of a collapsed bulla. A positive Nikolsky sign may be present. OLP and mucous membrane pemphigoid represent up to 80% of DG followed by hypersensitivity reactions and other autoimmune conditions such as pemphigus vulgaris, linear IgA disease and epidermolysis bullosa acquisita.47,48 HISTOPATHOLOGIC FEATURES OLP demonstrates hyperorthokeratosis or even parakeratosis in the oral cavity. The epithelium is attenuated or eroded in the atrophic/erosive type, often with small ulcerations, and somewhat hyperplastic in the reticular/papular type. There is leukocyte exocytosis, an increase in the number of Langerhans cells, and variable numbers of colloid (Civatte) bodies. Sawtooth rete ridges may be seen. The basal cells are degenerated, and the basement membrane is thickened. A bandlike lymphohistiocytic infiltrate hugs the connective tissue-epithelium interface (Fig. 37-6).49 Some lesions exhibit subepithelial bullae formation or complete desquamation of the epithelium. Melanophages and incontinent melanin may be present in the lamina propria and plasma cells are prominent if there is overlying ulceration. Eosinophils are not usually encountered. In some cases, nodular peri- and paravascular lymphocytic aggregates may be a prominent feature, sometimes with lymphoid follicles within the lymphoid band. Some but not all of such cases are

CHAPTER 37 ■ DISORDERS OF THE ORAL MUCOSA

CLINICAL FEATURES Chronic chewing habits are encountered in the teenage years and adulthood and patients may be unaware of the habit. The most common locations are the buccal and labial mucosa and lateral tongue, all sites readily traumatized by teeth. The lesion is typically nontender and appears as grayish white papules and plaques with irregular, shaggy, peeling surfaces, focal erosions, erythema, and sometimes ulcerations.

with dental restorations.39 The use of cinnamon-flavored products may result in the occurrence of oral lichenoid reactions, although more commonly they present as painful erythematous areas with only faint peripheral lichenoid striations. Among the drugs that have been implicated are antihypertensive agents, nonsteroidal anti-inflammatory drugs, cholesterol-lowering medications, and drugs used to treat rheumatologic conditions. Discoid lupus erythematosus and chronic oral graft-versus-host disease may result in oral lesions that are clinically and histologically similar to oral lichen planus. There may be an association of lichen planus with hepatitis C in some cases. There is an increased incidence of HLA-Bw57, HLA-DR1, HLADR2, HLA-DR3, HLA-DR9, and HLADR10 as well as a decreased incidence of HLA-DQ1 in some patients.40-42 Allele HLA-DR6 has been significantly expressed in patients with lichen planus and HCV infection.43 The rate of malignant transformation of lichen planus has been reported to be between 0.4% and 6.0%. Some investigators believe that oral lichen planus has an innate premalignant potential. Others believe that preexisting lesions previously misdiagnosed as OLP are actually premalignant epithelial dysplasias with lichenoid features that subsequently progress to carcinomas. Supporting this latter theory is the finding that many of the patients with reported malignant transformation have a history of tobacco use. Among all lichenoid lesions, loss of heterozygosity on chromosome arms 3p, 9p, and 17p is only found in those that also exhibit epithelial dysplasia.44,45 OLP results from a complex interplay between cellular and molecular signals that begin with alteration of keratinocyte antigens by an endogenous or exogenous agent that subsequently are ingested by Langerhans cells. T-lymphocytes migrate to the area, facilitated by adhesion molecules and cytokines (such as tumor necrosis factor alpha) secreted by mast cells and endothelial cells. Basal cell lysis ensues, and continued recruitment of cells and secretion of cytokines lead to progression and chronicity.46

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PART V ■ DISORDERS OF NAILS AND THE ORAL MUCOSA

developing oral cancer among snuff dippers compared to non-tobacco users is 4.2.57 Snus, a form of smokeless tobacco commonly used in Sweden, appears to be associated with no increased risk of oral cancer, although it was found to be a risk factor for pancreatic cancer.58

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CLINICAL FEATURES Early lesions of STK appear as asymptomatic gray or white macule or plaque that may be fissured, usually in the mandibular vestibule where the tobacco is placed. Long-standing lesions have a leathery or velvety feel and represent leukoplakia arising within STK and are less likely than early lesions to regress upon cessation of the habit.

 FIGURE 37-6 Lichen planus. Para- or orthokeratin, saw-tooth rete ridges, squamatization of basal cells, and a bandlike inflammatory cell infiltrate characterize oral lichen planus.

associated with hypersensitivity reactions to cinnamon-flavored products. Direct immunofluorescence (DIF) studies reveal fibrinogen in a stalactite pattern in the basement membrane zone and IgM in apoptotic cells.50 There are rare reports of circulating antibodies against basal cells, but how important these antibodies are to the pathogenesis of lichen planus has been a subject of debate.51,52 DIFFERENTIAL DIAGNOSIS In mucous membrane pemphigoid, the basal cells are intact, and the lymphocytic band is usually not as dense. Lupus erythematosus shows hydropic degeneration of the basal cells, alternating epithelial atrophy and hyperplasia of rete ridges, perivascular lymphocytic infiltrates, and patchy subepithelial periodic acid-Schiff (PAS)positive deposits. Both these entities exhibit linear IgG (and/or C3 in the case of mucous membrane pemphigoid) deposition at the basement membrane zone with DIF studies. The epithelial changes are less marked, and the lymphocytic infiltrate is sparse in oral chronic graftversus-host disease because of systemic immunosuppression. Lichenoid dysplasias represent epithelial dysplasias that incite a lichenoid tissue reaction. An entity that clinically and histologically resembles erosive lichen planus called chronic ulcerative stomatitis exhibits speckled nuclear anti-IgG deposits on DIF directed against a 70-kDa chronic ulcerative stomatitis protein (CUSP).53,54

Nicotine (Nicotinic) Stomatitis This is a rare benign reactive lesion of the hard palate that is associated with excessive heat, typically generated by pipes or cigars.55Although it is almost always seen in smokers, it appears to have no premalignant potential. CLINICAL FEATURES Nicotine stomatitis is seen most often in older men because this population accounts for the majority of cigar and pipe smokers. The palatal mucosa appears white; red papules within these hyperkeratotic areas represent inflamed minor salivary gland duct orifices.56

HISTOPATHOLOGIC FEATURES STK is characterized by slight hyper ortho or parakeratosis, often with keratin spires called “chevrons.” More typically, beneath the keratin is a band of degenerated cells of varying thickness that exhibit intracellular edema or hydropic degeneration with loss of nuclei. Epithelial dysplasia may be seen in long-standing lesions where the keratin layer is usually more pronounced. Amyloid-like material may be seen in the lamina propria and within interstitium of minor salivary glands. This represents altered collagen and is not congophilic. DIFFERENTIAL DIAGNOSIS In its early stages, STK represents direct topical injury to the mucosa, producing the superficial layer of degenerated cells. Leukoedema does not exhibit chevron formation and does not have the distinct band of degenerated cells. Other noxious contactants such as aspirin usually result in ulceration.

Benign Migratory Glossitis HISTOPATHOLOGIC FEATURES Hyperkeratosis and acanthosis are characteristic findings, as is an inflammatory cell infiltrate surrounding the salivary gland excretory ducts that usually exhibit squamous metaplasia.56 Epithelial dysplasia is generally not present. DIFFERENTIAL DIAGNOSIS Necrotizing sialometaplasia exhibits necrosis of the salivary gland acini and squamous metaplasia is often more pronounced and pseudoepitheliomatous in nature.

Smokeless Tobacco Keratosis Smokeless tobacco keratosis (STK) typically presents as an area of leukoplakia and is seen in patients who use snuff or chewing tobacco. The relative risk of

Synonyms: Geographic tongue, erythema areata migrans, erythema circinata, migratory stomatis. This evanescent inflammatory tongue condition occurs in between 1% and 25% of the population.59 Patients with generalized pustular psoriasis and Reiter syndrome may exhibit lesions of migratory glossitis in 7% to 10% of cases.60 An atopic diathesis has been suggested as a contributory factor in its development.61 A recent study suggested that benign migratory glossitis (BMG) is not associated with diabetes, as had been previously reported, and is inversely associated with cigarette smoking.62 There is an increased incidence of HLA-Bw62, HLA-Bw63, HLA-Cw6, and HLA-B13 with a reduced incidence of HLA-Cw4.63

CLINICAL FEATURES This condition affects adults in a male-to-female ratio of 1:2. The tongue presents with irregular maplike areas of depapillation and atrophy that are erythematous, often but not invariably outlined by a slightly raised, yellow-white serpiginous or circinate border. The lesions wax and wane, and there may be pain, burning, and sensitivity to acidic and spicy foods. When located on mucosa other than the tongue, the term erythema areata migrans, migratory stomatitis, or ectopic geographic tongue is used. Usage of the term erythema areata migrans is independent of site.64

DIFFERENTIAL DIAGNOSIS Candidiasis, oral psoriasis, and the edge of ulcers often exhibit spongiotic pustulosis; stains for fungi should be performed routinely.

This is a rare, nonautoimmune, pustular and vegetating mucosal disorder that is associated with inflammatory bowel disease (most often ulcerative colitis) in 50% to 70% of patients and is thought to represent the mucosal counterpart of pyodermatitis vegetans. There is also an association with liver diseases including sclerosing cholangitis.66 Approximately 90%of cases are associated with peripheral blood eosinophilia.67 CLINICAL FEATURES Multiple painful small yellowish-white papules, ulcers, and pustules appear on the mucosa, sometimes with a linear, serpentine, or “snail track” configuration and sometimes in clusters and crops.66 The surrounding mucosa may be markedly erythematous and friable with nodular excrescences and vegetative plaques. Generally, the bowel symptoms precede the oral lesions by about 1 year, although oral lesions may appear first. Skin lesions are present in approximately 50% of cases. HISTOPATHOLOGIC FEATURES There is epithelial hyperplasia with marked spongiosis and the formation of suprabasilar clefts. Intraepithelial abscesses composed of neutrophils and numerous eosinophils are characteristic, and often there are similar abscesses in the edematous connective tissue papillae. A polymorphous inflammatory infiltrate is present in the

 FIGURE 37-7 Benign migratory glossitis. Parakeratosis, atrophy of filiform papillae, and spongiotic pustules (in the absence of candida) characterize migratory glossitis.

lamina propria, sometimes in a perivascular distribution. Direct immunofluorescence studies may reveal weak, patchy, and granular positive staining for IgG and C3.68 It has been suggested that such immunoreactivity may be a secondary phenomenon owing to vascular leakage. DIFFERENTIAL DIAGNOSIS Pemphigus vegetans may be histologically indistinguishable from pyostomatitis vegetans, but DIF studies usually are strongly positive for intercellular deposition of IgG in pemphigus lesions and weak to absent in pyostomatitis vegetans. The epithelial hyperplasia may be so florid that the differential diagnosis of acantholytic squamous cell carcinoma may be suggested. The latter would show cytologic atypia and pleomorphism beyond the range encountered in reactive lesions, and DIF studies are negative.

Orofacial Granulomatosis Synonyms: Cheilitis granulomatosa, Miescher disease, Melkersson-Rosenthal syndrome. Some investigators use this term to refer only to granulomatous inflammation not associated with other systemic conditions such as Crohn disease or sarcoidosis, whereas others use it to designate a condition characterized by orofacial swelling that histologically consists of noninfectious granulomatous inflammation regardless of whether there is a known systemic eiotlogy. Oral manifestations of the systemic conditions may predate systemic findings. Orofacial granulomatosis has been attributed to an abnormal immune response to a variety of antigens, including food, and food additives including cinnamon products.69 There may be a genetic predisposition (increased HLA-A3, HLA-B7 and HLA-DR2 expression), and many patients have been reported to be atopic.70 CLINICAL FEATURES The most common clinical presentation is painless, persistent swelling of the upper and/or lower lips. If only the lips are involved, the clinical diagnosis of cheilitis granulomatosa is made. If the patient presents with the triad of cheilitis granulomatosa, fissured tongue, and facial nerve palsy, the diagnosis of Melkersson-Rosenthal syndrome applies. Some consider cheilitis granulomatosa alone as the oligosymptomatic form of Melkersson-Rosenthal syndrome. In addition, patients may present with gingival swelling (up to 30%), erythema, and erosions, not unlike what may be seen in oral Crohn disease.71

CHAPTER 37 ■ DISORDERS OF THE ORAL MUCOSA

HISTOPATHOLOGIC FEATURES There is atrophy of the filiform papillae on the tongue dorsum with or without parakeratosis. Spongiotic pustules and sometimes microabscesses unassociated with candidal hyphae are present and may involve one-third to one-half the epithelium (Fig. 37-7). The epithelium is acanthotic, with leukocyte exocytosis and often confluence of the rete ridges at the bases. There is edema of the papillary lamina propria, thinning of the suprapapillary epithelium, vascular ectasia, and a variable lymphoplasmacytic infiltrate, all features of a psoriasiform mucositis.65

Pyostomatitis Vegetans

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PART V ■ DISORDERS OF NAILS AND THE ORAL MUCOSA

HISTOPATHOLOGIC FEATURES Within the lamina propria are nonnecrotizing granulomas often containing multinucleated giant cells. These granulomas usually are present in small numbers and may be poorly formed, so multiple sections may be needed before they can be identified definitively. The surrounding tissues may be edematous and contain scattered chronic inflammatory cells, often in a peri- and paravascular location.72 Dilated lymphatics may be present superficially. If salivary glands are present, granulomas should be sought within the gland parenchyma. Stains for organisms are negative, and the granulomas should contain no identifiable foreign material. Since the condition may wax and wane, the appearance of granulomas may not be demonstrable in all patients. DIFFERENTIAL DIAGNOSIS The granulomas of orofacial granulomatosis are indistinguishable from those of Crohn disease, and the patient should be evaluated for gastrointestinal signs and symptoms. Granulomas of sarcoidosis usually contain asteroid bodies and tend to be well formed. ANCA-associated granulomatous vasculitis (Wegener granulomatosis) presents clinically with “strawberry gingivitis” and histologic features of pseudoepitheliomatous hyperplasia, vasculitis, geographic necrosis, abscesses, and a mixed inflammatory infiltrate in addition to subtle granulomas.73 Foreign material eliciting a chronic granulomatous reaction should be ruled out.

may be present. The lamina propria contains sheets of plasma cells that do not display atypia and are polyclonal with immunohistochemical studies. Dilated capillaries and scattered lymphocytes are noted in areas where the plasma cell infiltrate is less dense. Eosinophils are not a feature.75,76 DIFFERENTIAL DIAGNOSIS Monoclonality of the plasma cell infiltrate must be ruled out because the differential diagnosis includes extramedullary plasmacytoma. An intense plasmacytic infiltrate in the gingival tissues and periodontium is not uncommon in severe chronic gingivitis and periodontal disease but would not resemble plasma cell gingivitis clinically. Such lesions may form masses known as plasma cell granulomas.77 Foreign-body gingivitis is associated with a dense lymphocytic or plasmacytic infiltrate, nonnecrotizing granulomas, and particulate foreign material, which usually represents dental abrasives.78

Mucocele Synonym: Mucous escape reaction. This is a common condition caused by mucous extravasation and pooling in the interstitium as a result of traumatic disruption of the integrity of the excretory salivary duct. Floor of mouth lesions are instead referred to as ranulas. If a distal

obstruction causes retention of mucous within the cystically dilated duct, the appropriate terms are salivary duct cyst, mucous retention cyst or mucous cyst. CLINICAL FEATURES The mucocele occurs as a dome-shaped, sessile, bluish, translucent, usually painless swelling on any site that has underlying salivary glands, in particular the lower labial mucosa, ventral tongue or floor of mouth. There may be a history of the cyst repeatedly increasing and decreasing in size. Superficial mucoceles are 2 to 3 mm blister-like lesions located on the hard and soft palate.79 HISTOPATHOLOGIC FEATURES In the mucocele of mucous escape etiology, a pool of mucinous material containing muciphages and often neutrophils is present in the interstitium, sometimes abutting the epithelium. It is surrounded by condensed granulation tissue containing muciphages and variable numbers of chronic inflammatory cells and is therefore not a true cyst (Fig. 37-8). A portion of the salivary duct, often exhibiting squamous metaplasia, may be present at the periphery, and the associated minor salivary glands exhibit varying degrees of chronic inflammation, ductal ectasia, acinar atrophy, and interstitial fibrosis (all signs of obstruction). In late stages, only a nodule of granulation tissue with occasional muciphages remains. Salivary duct cysts consist

Plasma Cell Stomatitis Synonyms: Plasma cell gingivitis, mucous membrane plasmacytosis This condition was first described in the early 1970s, and its etiology was putatively ascribed to a hypersensitivity reaction to a component of chewing gum.74 Sporadic cases continue to be reported. CLINICAL FEATURES The gingiva (usually in the anterior maxilla) is markedly erythematous, edematous, and painful. Ulceration is unusual. In the original chewing gum–associated cases, there was concomitant cheilitis and glossitis. In some idiopathic cases, there is accompanying supraglottic and laryngeal involvment with accompanying hoarseness and/or sore throat.75

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HISTOPATHOLOGIC FEATURES The epithelium is markedly hyperplastic with spongiosis and sometimes superficial microcyst and pustule formation in a psoriasiform pattern. Dyskeratotic cells

 FIGURE 37-8 Mucocele. A cystlike cavity is filled with mucous and surrounded by granulation tissue and histiocytes.

of cystically dilated excretory ducts filled with mucus; they usually exhibit squamous, oncocytic, and/or mucous cell metaplasia of the lining epithelium; they are termed oncocytic sialocysts if oncocytes are prominent and are more common in the upper labial mucosa, where they may be associated with sialoliths. DIFFERENTIAL DIAGNOSIS The partially organized mucocele may be mistaken for a minor salivary gland or a histiocytic tumor. The absence of proliferation of ductal, myoepithelial, epidermoid, mucous or clear cells differentiate a mucocele from a neoplastic process.

Necrotizing sialometaplasia is an uncommon inflammatory condition characterized by ulceration of the mucosa overlying infarcted salivary glands. It is believed to result from ischemia to the gland.80 Such vascular compromise has been variably attributed to local trauma, epinephrine from local anesthetics, Raynaud phenomenon, adjacent tumors impinging on the blood supply, and bulemia.81 Nevertheless, many cases occur idiopathically. It may be confused with a malignant process because of rapid onset, the clinical appearance, and histopathology. CLINICAL FEATURES There is a slight 2:1 male predilection, and it tends to occur in middle age. The mucosa of the posterior hard palate and associated glands is affected in 70% to 80% of patients, with two-thirds of cases occurring unilaterally.82 Necrotizing sialometaplasia also may occur in the labial mucosa, retromolar pad, tongue, major salivary glands, and upper respiratory tract. The lesion usually begins as a swelling that ulcerates; pain may or may not be present. After a few weeks, a sizable mass of necrotic tissue may exfoliate, and rapid healing ensues. The average duration of the ulcer is 5 weeks. HISTOPATHOLOGIC FEATURES The salivary glands exhibit preservation of their usual lobular architecture, and this is a very important feature present in all lesions, provided that an adequate biopsy is obtained. Early lesions feature coagulative necrosis of salivary glands but with preservation of the acinir outlines (Fig. 37-9). There may be extensive mucous pooling around acini even in early lesions with accompanying acute and chronic inflammation. In more advanced lesions, squamous metaplasia of the ducts and pseudoepitheliomatous hyperplasia of

 FIGURE 37-9 Necrotizing sialometaplasia. Minor salivary gland acini undergo necrosis with preservation of their outlines; squamous metaplasia is also noted.

the overlying mucosa may be pronounced.82 The islands of squamous epithelium usually are cytologically bland with occasional evidence of reactive atypia. Small vessels in the area often exhibit thrombosis and occlusion. DIFFERENTIAL DIAGNOSIS The preservation of the normal lobular architecture of the glands is the single most important histologic parameter that helps to distinguish necrotizing sialometaplasia from mucoepidermoid carcinoma and squamous cell carcinoma. In mucoepidermoid carcinoma, there is proliferation of mucous and squamous cells in a disorganized fashion, forming islands of tumor cells that vary in shape and size with infiltration of the adjacent structures. Squamous cell carcinoma exhibits significant cytologic atypia and pleomorphism with infiltration of the adjacent tissues. In subacute necrotizing sialadenitis, the glands are diffusely infiltrated by a mixed inflammatory infiltrate with focal necrosis and little metaplasia.83

Cheilitis Glandularis This is an unusual inflammatory condition of the lip (usually lower) of unknown etiology, although there is an association with actinic cheilitis, atopic diatheses, and factitial injury. CLINICAL FEATURES Cheilitis glandularis (CG) is a disorder of adults, typically

elderly men. Three clinical forms are recognized: simple, superficial suppururative (Baelz disease), and deep suppurative (cheilitis glandularis apostematosa). In all cases, the lip is enlarged and often everted with areas of nodularity.84 In the simple type, crusting may occur with associated beads of mucus on the lip surface. Pain and crusting are more prominent in the suppurative type, and ductal orifices may exude purulent material. Up to one-third of cases have been associated with the development of squamous cell carcinoma, although this may be a reflection of increased exposure to the sun because of lip eversion and tobacco products rather than cheilitis glandularis, representing a premalignant process.

CHAPTER 37 ■ DISORDERS OF THE ORAL MUCOSA

Necrotizing Sialometaplasia

HISTOPATHOLOGIC FEATURES The glands contain a chronic interstitial inflammatory infiltrate with acinar atrophy, sialodochitis, and often a purulent exudate within dilated and metaplastic ducts.85 In the simple type, the findings are less severe, and suppuration is usually absent. In many cases, actinic cheilitis may be concurrently present. The finding of hyperplasia of the mucous glands has been disputed.86 DIFFERENTIAL DIAGNOSIS Distal obstruction of the salivary glands of the upper lip by sialoliths may cause similar histologic changes of a chronic sclerosing sialadenitis. In such cases, the sialoliths

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are identified in the ducts. CG may be misdiagnosed as papillary cystadenoma based on the presence of tortuous ductlike spaces.87

noted. Although some fibromas may contain a few lipocytes, others contain significant amounts of fat, in which case a diagnosis of “fibrolipoma” is appropriate.

Fibromas

DIFFERENTIAL DIAGNOSIS The giant cell fibroma often has a papillary surface configuration and usually exhibits epithelial hyperplasia in the form of spiky rete ridges. Numerous plump stellate-shaped and often bi- or multinucleated giant fibroblasts are scattered throughout (Fig. 37-10B). Occasionally, the nuclei may have a wreath-like configuration. These giant cells stain for vimentin, occasionally for factor XIIIa, but not for S100 protein or CD68.88 Ultrastructurally, the giant fibroblasts have been noted to contain microfilaments, dense bodies, and junctional complexes, thus resembling myofibroblasts. Sclerotic fibromas are sharply circumscribed tumors that exhibit thick collagen bundles arranged in a storiform pattern and separated by prominent clefts. Mast cells are present throughout the stroma. The tumor demonstrates CD34 and factor XIIIa reactivity.89

PART V ■ DISORDERS OF NAILS AND THE ORAL MUCOSA

Synonyms: Fibrous hyperplasia, fibroepithelial polyp, bite fibroma, irritation fibroma. A fibroma a very common condition of the oral mucosa and occurs at sites that are commonly traumatized. It is not a true neoplastic process, but rather a reactive proliferation of fibrous scar tissue. CLINICAL FEATURES Fibromas usually present on the buccal mucosa, lower labial mucosa, or lateral border of the tongue, all common sites of bite trauma. The nodule usually is dome-shaped, sessile or pedunculated, soft, mucosa-colored, and may show areas of ulceration and/or whiteness. A variant of fibroma called the giant cell fibroma tends to be located on the gingiva or tongue and often has a papillary surface clinically.88 Giant cell fibromas on the lingual gingiva near the mandibular canines are termed retrocuspid papillae. HISTOPATHOLOGIC FEATURES There is a proliferation of fibrous tissue, usually with low cellularity, and scattered blood vessels; occasionally the collagen may appear keloidal. The overlying epithelium may be attenuated or hyperplastic, and there is usually hyperkeratosis (Fig. 37-10 A). Focal areas of myxoid degeneration and mucinous change may be encountered, and scattered lymphocytes are occasionally

A

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Epulis Fissuratum

obvious reasons, occurs in older individuals. There are papulous and ridged folds of soft tissue, usually in the buccal maxillary and mandibular sulci, and often with a prominent central fissure into which the denture flange fits. The surface may have papillary, ulcerated, or erythematous areas.90 HISTOPATHOLOGIC FEATURES The overlying epithelium is often hyperplastic and pseudoepitheliomatous hyperplasia is not unusual. There may be parakeratosis, focal ulcerations, and areas of candidal infection. The bulk of the tissue consists of hyperplasia of fibrous tissue, sometimes with many ectatic vessels. A lymphocytic infiltrate is invariably present; sometimes, lymphoid nodules, minor salivary glands, and osseous and cartilagenous metaplasia also may be noted, the latter especially in the maxilla.90 Salivary glands, if present, may demonstrate chronic sialadenitis. DIFFERENTIAL DIAGNOSIS Pseudoepitheliomatous hyperplasia may be mistaken for squamous cell carcinoma in this elderly population, but there is a lack of atypia, true invasion, or mitotic activity.

Synonyms: Inflammatory fibrous hyperplasia, denture-associated epulis. The benign overgrowth of fibrous tissue that characterizes this condition is caused by an ill-fitting denture sliding on and traumatizing the soft tissues at the edges of a denture flange.

Inflammatory Papillary Hyperplasia of the Palate

CLINICAL FEATURES There is a female predilection for this condition that, for

CLINICAL FEATURES The palatal mucosa under the denture is covered by soft,

This condition is caused by wearing an ill-fitting maxillary denture and/or wearing a denture continuously, even when asleep at night.

B

 FIGURE 37-10 (A) Fibroma. Fibrous scar tissue proliferates in the absence of significant inflammation. (B) Giant cell fibroma. Tapered rete ridges overlie dense collagen. Stellate-shaped giant fibroblasts are present within the connective tissue.

pebbly, fibrous nodules that coalesce, resulting in a cobblestone appearance. The tissue often appears erythematous secondary to candidiasis. HISTOPATHOLOGIC FEATURES This is essentially similar to the histopathology of epulis fissuratum except that the fibrous hyperplasia has a papillary configuration. Candida organisms may be noted in the superficial epithelium. DIFFERENTIAL DIAGNOSIS See “Epulis Fissuratum,” earlier in this chapter.

The term “epulis” refers to any growth on the gingiva or alveolar mucosa. Six of the most common gingival lesions are

A

may be mucosa-colored when small. Larger ones are usually erythematous and/or ulcerated. Drug-induced hyperplasias affect the gingiva diffusely over time and occur in 15% to 50% of patients taking phenytoin, calcium channel blockers, and cyclosporine.91-93 Nongingival soft tissue hyperplasia induced by cyclosporine administration has also been reported in patients taking this medication for chronic graft-versus-host disease.94 The mechanism is unclear but believed to be related to an alteration of collagen metabolism mediated by transforming growth factor beta 1, which promotes synthesis of extracellular matrix components and inhibits degradation.95 The parulis usually occurs on attached or nonattached gingiva at a distance from

CHAPTER 37 ■ DISORDERS OF THE ORAL MUCOSA

Other Gingival Epulides

the fibroma (discussed previously), pyogenic granuloma (granuloma gravidarum if the patient is pregnant), peripheral giant cell granuloma, peripheral ossifying fibroma, drug-induced gingival hyperplasia, and parulis (Fig. 37-11 A to C). Each of the first four entities arises as a reparative process in response to chronic irritation from deposits of dental calculus, poorly adapted dental restorations, orthodontic braces, or other local factors. They often occur on the marginal gingiva with at least a portion of the lesion resting against the teeth. Histopathologically, it is not unusual to see combinations of pyogenic granuloma, peripheral ossifying fibroma, and peripheral giant cell fibroma within one lesion. All present as nodules varying in size from a few mm to 1 to 2 cm. They

B

C  FIGURE 37-11 (A) Pyogenic granuloma. There is a proliferation of granulation tissue; the overlying epithelium may be intact or ulcerated. (B) Peripheral giant cell granuloma. Multinucleated giant cells are present within a vascular stroma. (C) Peripheral ossifying fibroma. A cellular proliferation of fibroblasts deposits foci of metaplastic osteoid or woven bone.

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Table 37-1 Gingival Nodules ENTITY

CLINICAL FEATURES

HISTOPATHOLOGIC FEATURES

DIFFERENTIAL DIAGONIS

Pyogenic granuloma

Often seen during pregnancy; may regress postpartum Marginal gingiva

Proliferation of endothelial cells and capillaries Cellular fibroblast-like proliferation with deposition of osteiod, woven bone or cementum-like droplets Proliferation of multinucleated giant cells of osteoclast-type, mononuclear cells in stroma, siderophages, dilated capillaries; “Grenz” zone may be present Proliferation of fibrous tissue and some granulation tissue with variable inflammation. In dilantin hyperplasia, elongated “test tube” ridges may be present Edematous granulation tissue, acute and chronic inflammation and microabscesses, may see neutrophil “tract”

Capillary hemangiomas are similar histologically A bony spicule is composed of lamellar bone with periosteum and no spindle cell proliferation Central giant cell granuloma eroding through bone; lack of foreign material and epithelioid histiocytes excludes other granulomatous proceses

PART V ■ DISORDERS OF NAILS AND THE ORAL MUCOSA

Peripheral ossifying fibroma

Peripheral giant cell granuloma

May rest in a cup-shaped depression in the bone; 10% recurrence rate; unlike intraosseous counterpart, no association with hyperparathyroidism

Drug-induced fibrous hyperplasia

Usually involves gingiva diffusely and rare in edentulous areas; dilantin, cyclosporine and Ca2++ channel blockers are common etiologic agents Usually not on marginal gingiva; indicates tooth has pulpal or periodontal infection

Parulis

the teeth. Its presence almost always indicates an underlying odontogenic infection within the bone. Table 37-1 summarizes the clinical and histologic findings, as well as the differential diagnoses of these lesions.

Essential to the diagnosis of VX are numerous CD68+ foamy macrophages within the connective tissue papillae (Fig. 37-12). Rarely, these macrophages extend beyond the tips of the rete ridges.

Gingival fibromatoses is similar histologically but tends to be hereditary and presents at an early age Lack of mucin and muciphages as well as location excludes mucocele

DIFFERENTIAL DIAGNOSIS Squamous papillomas, condylomas, and verruca vulgaris lack the presence of foamy macrophages. Papillary squamous cell carcinoma demonstrates features of cytologic atypia.

Verruciform Xanthoma Verruciform xanthoma (VX) is a rare reactive lesion primarily seen in the oral cavity that was first described in 1971. The etiology is unclear, but it is believed that epithelial breakdown releases lipids that draw xanthoma cells to the site. An association with human papillomavirus has not been identified.96 Cases have been associated with pemphigus vulgaris, graft-versus-host disease, epidermolysis bullosa, warty dyskeratoma, and lichen planus.97-99 CLINICAL FEATURES Most VXs are seen on the gingiva and palatal mucosa. They typically present as papillary or verrucous lesions that may be pink, red, or white. Most examples are no larger than 2 cm in size.

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HISTOPATHOLOGIC FEATURES VX characteristically exhibits bright orange hyperparakeratosis, loose keratin squames ,and keratin plugging between papillary projections. Rete ridges extend to a uniform depth within the lamina propria.

 FIGURE 37-12 Verruciform xanthoma. Beneath a papillary proliferation of the squamous epithelium, foamy macrophages are situated within the connective tissue papillae.

PIGMENTED CONDITIONS

Amalgam Tattoo Amalgam used in dental restorations is the most common cause of exogenous pigmentation in the oral cavity. It is usually inadvertently traumatically implanted during placement or removal of a restoration or retrograde root canal filling or may fall from an extracted tooth into its socket.

HISTOPATHOLOGIC FEATURES Dark brownto-black, coarse and/or fine granules are present in three patterns. Most commonly, fine particles are disposed parallel to and along the reticulin and elastic fibers within the stroma, the basement membranes of blood vessels, the epithelium, and sometimes endoneurium and endomysium, while larger particles are found within foreign body giant cells and macrophages. Less commonly, the fibers are stained golden brown without particulate deposition.101 (Fig. 37-13). Fibrosis/scarring is a common finding. DIFFERENTIAL DIAGNOSIS Graphite tattoos are often seen in the palatal mucosa of children who fall with pencils held between the teeth. The particles tend to be coarser and do not stain the reticulin fibers. In cases where the diagnosis is not immediately apparent, energy dispersive x-ray microanalysis of the content of the particles may be helpful.102

 FIGURE 37-13 Amalgam tattoo. The silver in dental amalgam stains the basement membrane of blood vessels and epithelium and stains collagen fibers.

of melanin in the basal cells, especially at the tips of the rete ridges (Fig. 37-14).103 Melanocytic hyperplasia, if present, is usually very mild with no atypia and no nesting, and is not lentiginous. Melanin is present in the lamina propria, and there

are variable numbers of melanophages and scattered lymphocytes. DIFFERENTIAL DIAGNOSIS Unlike ephelides, oral melanotic macules are not related to sun exposure, and the color varies

CHAPTER 37 ■ DISORDERS OF THE ORAL MUCOSA

CLINICAL FEATURES The most common locations for amalgam tattoos are the gingiva and the buccal mucosa adjacent to a restoration.100 The tattoo is macular and appears uniformly black or slate gray; it may have discrete or ill-defined borders.

Oral Melanotic Macule This is a common condition of the oral mucosa caused by increased deposition of melanin and occasionally very mild melanocytic hyperplasia. It may represent post-inflammatory hypermelanosis. CLINICAL FEATURES This occurs mainly in adults with a male-to-female ratio of 1:2. Approximately one-third of cases occur on the vermilion of the lower lip (labial melanotic macule); other sites include the gingiva, buccal mucosa, and palate. They are discrete, usually solitary, evenly tan-brown or black macules that are less than 1 cm in diameter. HISTOPATHOLOGIC FEATURES There is absent or mild hyperkeratosis and usually insignificant or mild epithelial hyperplasia. There is an increase in the amount

 FIGURE 37-14 Oral melanotic macule. Melanin is present within basal cells, accentuated at the tip of rete ridges, and in the superficial lamina propria.

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little throughout the year. Unlike lentigo and melanoacanthosis, they show minimal melanocytic hyperplasia and insignificant epithelial hyperplasia. Malignant melanoma is characterized by a proliferation of atypical melanocytes. The melanotic macule may be indistinguishable from oral pigmentation associated with postinflammatory hypermelaninosis and from the pigmented macules of PeutzJegher, Albright, and Addison diseases and the Laugier-Hunziker syndrome.104

PART V ■ DISORDERS OF NAILS AND THE ORAL MUCOSA

Oral Melanoacanthosis Synonym: Oral melanoacanthoma. Oral melanoacanthosis is a reactive hypermelaninosis of the oral mucosa that has a characteristic clinical presentation. The original reports refer to it as “oral melanoacanthoma”105 and it shares some histologic similarities with skin melanoacanthoma. However, unlike skin melanoacanthomas, oral melanoacanthosis is macular, occurs in young adult African American females, and is self-remitting. CLINICAL FEATURES This is a condition that is most commonly encountered in young African American adults with a 1:3 male-to-female ratio. Typically, the lesion presents as a solitary dark brown macule on the buccal or labial mucosa that may have a slightly roughened surface.106 It spreads laterally and may grow several centimeters within a few weeks. It does not ulcerate and is not indurated. It regresses spontaneously or after removal of offending physical irritants, but may recur. HISTOPATHOLOGIC FEATURES There is acanthosis and increased deposition of melanin in the basal cells and hyperplasia of benign pigment-laden dendritic melanocytes throughout the thickness of the epithelium. Rarely, there may be spongiosis. A lymphocytic infiltrate is present in the lamina propria with scattered melanophages, eosinophils, and vascular ectasia.107 DIFFERENTIAL DIAGNOSIS Oral melanotic macules do not exhibit the marked acanthosis and dendritic melanocytic hyperplasia and trans-epithelial melanocytic migration seen in melanoacanthosis. The benign appearance of the melanocytes differentiates this entity from atypical melanocytic lesions and melanoma.

Medication-Associated Pigmentation 1016

Pigmentation of the oral mucosa has been associated with admininstration of

antimalarial medications, tetracyclines and minocycline. Chelation of melanin and/or hemosiderin to drug metabolites and/or pigmented metabolites of the associated medication have all been implicated as causes. Some of the reports of pigmentation caused by medications are likely post-inflammatory hypermelaninoses secondary to lichenoid and interface stomatitides. CLINICAL FEATURES The color and distribution of the pigmentation varies with the offending medication, but is generally bilateral and symmetrical. With the administration of antimalarials, the hard palate often takes on a characteristic slate-gray appearance. Tetracycline pigmentation primarily affects the bone (since tetracycline is avidly taken up by bone) and shows through the gingival or palatal mucosa as grayish discoloration. HISTOPATHOLOGIC FEATURES Drug metabolites chelate melanin or iron, and the resulting granules may appear 2 to 4 μm in size with a round and regular configuration, typically arranged in linear array between collagen fibers. They may be distributed within the lamina propria and within macrophages and may stain for melanin and/or iron. DIFFERENTIAL DIAGNOSIS Hemosiderin particles tend to be slightly larger, coarser, more orange, and less regular in appearance than melanin. Moreover, melanin does not usually have the characteristic linear configuration between collagen fibers.

DYSPLASTIC AND NEOPLASTIC CONDITIONS

Leukoplakia Synonym: Leukokeratosis. Leukoplakia is a clinical entity that the World Health Organization (WHO) defines as “any white patch that does not rub off and cannot be characterized clinically or pathologically as any other disease and is not associated with a physical or chemical agent except tobacco.”108,109 It is the most common premalignant mucosal lesion. The prevalence of leukoplakia in the general population ranges from 2% to 4%, and leukoplakia occurs in up to 14% of smokers. More than 70% of patients who have leukoplakia use tobacco products.110 CLINICAL FINDINGS Leukoplakia is twice as common in adult males as females, although smoking may account for this

discrepency. Several different clinical forms are recognized: homogeneous, speckled (erythroleukoplakia), verrucous, and nodular.111 Very often a plaque will exhibit combinations of these forms. Early leukoplakic plaques tend to be grayish white, and established lesions tend to be densely opaque with verrucous and/or nodular areas. Erythroleukoplakia (speckled leukoplakia) is associated with an even greater risk of dysplasia and malignant change.112,113 Although any oral site may present with leukoplakia, the two most common sites are the buccal mucosa and gingiva. Though encountered less commonly, lesions on the floor of mouth, ventral tongue, and soft palate have a higher association with dysplasia or carcinoma. Malignant transformation occurs in up to 24% of all patients with long-term follow-up and in 36% of patients with preexisting epithelial dysplasia.113 There is a form of extensive leukoplakia that tends to occur in elderly women called proliferative verrucous leukoplakia, of which only half the cases are associated with tobacco use. These extensive lesions develop over 10 or 20 years from homogeneous leukoplakias. 80% to 100% of cases develop squamous cell or verrucous carcinoma on long-term follow-up.114 HISTOPATHOLOGIC FEATURES Since at least 9% to 34% of all leukoplakias exhibit dysplasia, carcinoma in situ, or invasive carcinoma, all leukoplakias must be evaluated for epithelial dysplasia. There is usually hyperpara- or orthokeratosis with varying degrees of acanthosis. Architectural features of dysplasia include endophytic growth, significant papillomatosis and bud- or teardropshaped rete ridges. Cytologic features include maturation disarray, basal cell hyperplasia, increased nuclear to cytoplasmic ratio, pleomorphism, and increased mitotic activity. The convention is to grade the dysplasia mild if less than one-third of the epithelium is involved, moderate if more than onethird but less than two-thirds is involved, and severe if more than twothirds is involved. Full-thickness involvement is diagnosed as carcinoma in situ. Some use the term squamous intraepithelial neoplasia (SIN) or oral intraepithelial neoplasia (OIN) to designate such dysplasias.115,116 Koilocytic dysplasia exhibits histologic features of conventional oral epithelial dysplasia as well as those of HPV infection including koilo-cytosis. HPV infection has recently been recognized

DIFFERENTIAL DIAGNOSIS Inflammatory epithelial atypia may be seen in association with candidiasis and at the edge of ulcers. A lichenoid lymphocytic reaction to epithelial dysplasia should not be mistakenly underdiagnosed as lichen planus.

Erythroplakia Synonym: Erythroplasia. Erythroplakia (similar to erythroplasia of Queyrat) is another clinical entity that, like leukoplakia, cannot be attributed to any specific oral condition and is simply described as a clinical red plaque. CLINICAL FEATURES This is an uncommon condition of older men characterized by a discrete erythematous plaque that has a velvety surface. It is more often seen adjacent to or admixed with a leukoplakia (erythroleukoplakia or speckled leukoplakia).112,118 HISTOPATHOLOGIC FEATURES Most erythroplakias are nonkeratinized and may demonstrate epithelial atrophy. Up to 90% of patients exhibit epithelial dysplasia, carcinoma in situ, or squamous cell carcinoma at the time of biopsy.112,118 The criteria for diagnosis of epithelial dysplasia have been discussed in the previous section.

DIFFERENTIAL DIAGNOSIS This is similar to leukoplakia.

Oral Submucous Fibrosis This condition is associated with chewing betel quid (composed of areca nut, slaked lime, tobacco, and spices wrapped in betel leaf), which is a habit common in populations from the Indian subcontinent and southeast Asia. The areca nut stimulates collagen synthesis and inhibits degradation of collagen, leading to fibrosis. In populations that exclude tobacco from this preparation, early studies showed no increased risk of oral cancer. More recently, however, a link has been established between carcinogenesis and chewing betel quid in the absence of tobacco, believed to be releated to the presence of the areca nut alkaloid arecoline.119,120 CLINICAL FEATURES Submucous fibrosis involves the lips, buccal mucosa, retromolar areas and soft palate. Patients develop progressive limitation of mouth opening and a burning sensation. The mucosa develops a marble-like pallor and palpable fibrous bands. HISTOPATHOLOGIC FEATURES Early lesions may show little more than a mild inflammatory cell infiltrate within the lamina propria. Later-stage disease is characterized by atrophic epithelium overlying densely collagenized fibrous connective tissue with reduced vascularity. Epithelial dysplasia or carcinoma may be seen in 15% to 38% of cases at the time of biopsy. DIFFERENTIAL DIAGNOSIS Systemic sclerosis featurs positive serologic markers for autoimmune disease. Hyalinization associated with amyloidosis will stain with Congo red.

Squamous Cell Carcinoma Squamous cell carcinoma (SCCa) accounts for more than 90% of all intraoral malignancies and constitute 3% of all malignancies diagnosed in the United States. Many of them occur in the setting of preexisting leukoplakias or erythroplakias. Tobacco and areca nut use (in specific populations) are two of the most important risk factors for the occurrence of intraoral carcinoma; this risk is greatly increased by the synergistic effect of alcohol. Oral HPV infection is strongly associated with oropharyngeal cancer. Additional risk factors include ultraviolet light and immunocompromise.121,122

CLINICAL FEATURES The prevalence of SCCa increases with age. It presents most often as either a nonhealing ulcer, leukoplakia, erythroplakia, or a rapidly growing, fungating mass. The most common sites are the posterior tongue, the floor of the mouth, the soft palate, and the gingiva/alveolar mucosa. HISTOPATHOLOGIC FEATURES SCCas of the oral cavity may be well, moderately, or poorly differentiated with increasing anaplasia and decreasing production of keratin. There is variable pleomorphism, and stromal invasion must be present. Invasion on a broad front with large, broad pushing rete ridges carries a better prognosis than infiltration in small cords or single-cells.123 Perineural and bone invasion is associated with a poorer prognosis.124,125 Like melanomas, the thickness of the tumor may have some prognostic significance, with thickness less than 4 mm correlating with increased risk of metastasis and reduced survival.124,126 Low levels of E-cadherin expression has also been associated with late cervical metastasis. Sentinel node biopsy in patients without evidence of cervical disease found occult metastases in 20% to 50% of patients.123,127-139 Allelic imbalance and loss of heterozygosity involving in particular chromosome 3p, 9p, 11q, 13a, and 17p have been associated with squamous cell carcinoma.130 A high frequency of p53 mutations has been noted in patients with oral squamous cell carcinoma. There are many histologic variations of SCCa. It is sometimes difficult to differentiate between papillary well-differentiated squamous cell and verrucous carcinomas that are strongly associated with smokeless tobacco use. In the latter, there is marked hyperparakeratosis with parakeratin plugging, prominent endophytic frondlike epithelial proliferations (blunt invasion) and minimal cytologic atypia.23 Keratin pearl formation, especially in the depths of the tumor, occurs rarely, if at all, and there should be no evidence of individual cell invasion of the stroma. This should not be confused with papillary well-differentiated squamous cell carcinoma, which is papillary, may form abundant keratin, and usually exhibits single-cell infiltration of the stroma and significant atypia and pleomorphism. The papillary squamous cell carcinoma of the upper aerodigestive tract exhibits infiltration of the stroma and portions of it resemble a squamous papilloma with carcinoma in situ.131 Other less common variations of squamous cell carcinomas include the

CHAPTER 37 ■ DISORDERS OF THE ORAL MUCOSA

as a risk factor for the development of oropharyngeal squamous cell carcinoma. Papillomatosis is a constant feature of the entity verrucous hyperplasia that is a precursor to verrucous carcinoma or papillary well-differentiated squamous cell carcinoma.23 The term lichenoid dysplasia has been used to describe epithelial dysplasia associated with a lichenoid lymphocytic band at the interface. To avoid confusion, it is preferable to diagnose such cases as “epithelial dysplasia with an associated lichenoid infiltrate.” Some believe that these represent malignant transformation of oral lichen planus, though it is more likely that the lichenoid infiltrate is an immunologically mediated reaction to the epithelial dysplasia. Alterations in the cell cycle regulatory pathways led by the p53 gene and the Rb gene have been identified in oral carcinomas. Increased expression of p53 and cyclin D1, inactivation of p16 and pRb, and increased telomerase activity have been reported in dysplastic cells of leukoplakia.117 Alterations in the Rb pathway correlate with a worse prognosis.

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sarcomatoid (spindle cell) carcinoma, adenosquamous carcinoma, adenoid squamous carcinoma, and basaloid squamous cell carcinoma. In all these cases, a typical squamous cell carcinoma is always present, and the overlying surface epithelium is usually dysplastic. Half of all sarcomatoid carcinomas occur on the lower lip; the tongue is the second most common site, where it is often polypoid. There is a proliferation of spindled cells in a fasciculated configuration. The spindle cells stain for both vimentin and keratin but are uniformly S100-negative.132-134 Adenosquamous carcinoma consists of a combination of a surface squamous cell carcinoma and an adenocarcinoma that often, but not invariably, stains for mucin intracytoplasmically; the adenosquamous carcinoma resembles a mucoepidermoid carcinoma.135 Most adenoid squamous cell carcinomas (also known as pseudoglandular or acantholytic squamous cell carcinoma) arise on the lower lip vermilion. The tumor forms ductlike structures within islands of tumor cells as a result of acantholysis and marked dyscohesion of tumor cells.136 Unlike adenosquamous carcinoma, these are not true ducts; tumor cells do not contain mucin. Basaloid squamous cell carcinoma arises primarily in the base of the tongue and pharynx and consists of islands of basaloid cells usually with comedonecrosis, microcystic spaces filled with PAS-positive material and stromal hyalinization; a cribriform pattern may be present. In addition to being keratinpositive, the tumor cells also are often EMA- and CEA-positive; S100 and NSE positivity may be weak.137

noted in close proximity to skeletal muscle, GCTs were originally referred to as granular cell myoblastomas. Nearly half of GCTs display pseudoepitheliomatous hyperplasia. The cells stain for both S100 protein and CD68 because the granules represent lysosomes. DIFFERENTIAL DIAGNOSIS Superficial biopsies that capture only the pseudoepitheliomatous hyperplasia and not the granular cells may be mistaken for squamous cell carcinoma, though GCTs lack cytologic atypia. The congenital granular cell tumor (congenital epulis of the newborn) is rare tumor that presents as a red or pink nodule on the alveolar ridge of neonates; there is a 1:9 male-to-female ratio. They are unencapsulated but circumscribed lesions composed of large round or polyhedral cells with granular cytoplasm, but the stain for S100 protein is usually negative since these are not of neural differentiation.140,141 The primitive polypoid granular tumor (non-neural granular cell tumor) does not exhibit positive staining for S100 protein and may show pleomorphism.142,143

Ectomesenchymal Chondromyxoid Tumor This rare benign tumor seen primarily on the anterior tongue was first

described in 1995.144 Its histogenesis is uncertain; although many believe these represent a distinct entity,145 it has been suggested that ECTs may represent a variant of myoepitheliomas that are derived from minor salivary glands or from non-salivary gland-derived myoepithelial cells.146 CLINICAL FEATURES Ectomesenchymal chondromyxoid tumors (ECTs) are slow-growing painless nodules typically found on the anterior tongue. There is no sex predilection. A single case has been reported on the palate. HISTOPATHOLOGIC FEATURES These tumors are well-circumscribed nodules with lobules separated by fibrous septations. Tumor cells are arranged in sheets and cords, vary from spindled or polygonal, and are set in a myxoid background that may display chondroid areas (Fig. 37-15). Ductal structures are absent. ECTs exhibit variable positivity with keratin markers and generally stain for GFAP and S100 protein.147-149 DIFFERENTIAL DIAGNOSIS Pleomorphic adenomas of the minor salivary glands always contain ductal structures. Soft tissue myxomas lack chondroid features and GFAP positivity and they are hypocellular with abundant connective tissue mucin.

Granular Cell Tumor A granular cell tumor (GCT) is a benign soft tissue tumor of neural origin; more than half occur in the oral cavity. CLINICAL FEATURES The most common location for a GCT is the dorsal surface of the tongue, although some lesions are noted on the buccal mucosa. It typically presents as a deep-seated firm mass that varies in color from pink to yellowish. It is generally less than 2 cm in size. Although rare, some patients have multifocal lesions.138,139

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HISTOPATHOLOGIC FEATURES GCTs are characterized by sheets of polygonal cells that have finely granular eosinophilic cytoplasm. Cells have indistinct borders and small nuclei. Because they are often

 FIGURE 37-15 Ectomesenchymal chondromyxoid tumor. A well-circumscribed nodule contains polygonal and spindle-shaped cells set in a myxoid background.

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120. Yang YH, Lien YC, Ho PS. The effects of chewing areca/betel quid with and without cigarette smoking on oral submucous fibrosis and oral mucosal lesions. Oral Dis. 2005;11(2):88-94. 121. Johnson NW, Warnakulasuriy S, Tavassoli M. Hereditary and environmental risk factors; clinical and laboratory risk matters for head and neck, especially oral, cancer and precancer. Eur J Cancer Prev. 1996;5(1):5-17. 122. Scully C, Bagan JV. Recent advances in oral oncology. Oral Oncol. 2007;43(2):107-115. 123. Taylor RJ, Wahl RL, Sharma PK, et al. Sentinel node localization in oral cavity and oropharynx squamous cell cancer. Arch Otolaryngol Head Neck Surg. 2001; 127(8):970-974. 124. Shingaki S, Suzuki I, Nakajima T, Kawasaki T. Evaluation of histopathologic parameters in predicting cervical lymph node metastasis of oral and oropharyngeal carcinomas. Oral Surg Oral Med Oral Pathol. 1988;66(6):683-688. 125. Brandwein-Gensler M, Teixeira MS, Lewis CM, et al. Oral squamous cell carcinoma: histologic risk assessment, but not margin status, is strongly predictive of local disease-free and overall survival. Am J Surg Pathol. 2005;29(2):167-178. 126. Yuen AP, Lam KY, Wei WI, et al. A comparison of the prognostic significance of tumor diameter, length, width, thickness, area, volume, and clinicopathological features of oral tongue carcinoma. Am J Surg. 2000;180(2):139-143. 127. Shoaib T, Soutar DS, MacDonald DG, et al. The accuracy of head and neck carcinoma sentinel lymph node biopsy in the clinically N0 Neck. Cancer. 2001;91(11):2077-2083. 128. Hart RD, Nasser JG, Taylor M, Trites JT, Barnes D, Bullock MD. Sentinel lymph node biopsy in N0 squamous cell carcinoma of the oral cavity and oropharynx. Arch Otolaryngol Head Neck Surg. 2005;131(1):34-38. 129. Payoux P,Dekeister C, Lopez R, Lauwers F, Esquerre JP, Paoli JR. Effectiveness of lymphoscintigraphic sentinel node detection for cervical staging of patients with squamous cell carcinoma of the head and neck. J Oral Maxillofac Surg. 2005;63(8): 1091-1095. 130. Scully C, Field JK, Tanzawa H. Genetic aberrations in oral or head and neck squamous cell carcinoma 3: clinicopathological applications. Oral Oncol. 2000;36(5): 404-413. 131. Crissman JD, Kessis T, Shah KV, Fu YS, Stoler MH, Zarbo RJ. Squamous papillary neoplasia of the adult upper aerodigestive tract. Hum Pathol. 1988;19(12): 1387-1396. 132. Zarbo RJ, Crissman JD, Venkat H, Weiss MA. Spindle-cell carcinoma of the upper aerodigestive tract mucosa. An immunohistologic and ultrastructural study of 18 biphasic tumors and comparison with seven monophasic spindle-cell tumors. Am J Surg Pathol. 1986; 10(11):741-753. 133. Ellis GL, Langlos JM, Heffner DK, Hyams VJ. Spindle-cell carcinoma of the aerodigestive tract. An immunohistochemical analysis of 21 cases. Am J Surg Pathol. 1987;11(5):335-342.

134. Takata T, Ito H, Ogawa I, Miyauchi M, Ijuhin N, Nikai H. Spindle cell squamous carcinoma of the oral region. An immunohistochemical and ultrastructural study on the histogenesis and differential diagnosis with a clinicopathological analysis of six cases. Virchows Arch A Pathol Anat Histopathol. 1991; 419(3):177-182. 135. Gerughty RM, Hennigar GR, Brown FM. Adenosquamous carcinoma of the nasal, oral and laryngeal cavities. A clinicopathologic survey of ten cases. Cancer. 1968;22(6):1140-1155. 136. Ferlito A, Devaney KO, Rinaldo A, Milroy CM, Carbone A. Mucosal adenoid squamous cell carcinoma of the head and neck. Ann Otol Rhinol Laryngol.1996;105(5):409-413. 137. Coppola D, Catalano E, Tang C-K, Elfenbein IB, Harwick R, Mohr R. Basaloid squamous cell carcinoma of floor of mouth. Cancer. 1993;72(8): 2299–2305. 138. Lamey PJ,. Rennie JS, James J. Multiple granular cell tumors of the palate. Int J Oral Maxillofac Surg. 1987;16(2):236-238. 139. Goodstein ML, Eisele DW, Hyams VJ, Kashima HK. Multiple synchronous granular cell tumors of the upper aerodigestive tract. Otolaryngol Head Neck Surg. 1990;103(4):664-668. 140. Kaiserling E,Ruck P, Xiao JC. Congenital epulis and granular cell tumor: a histologic and immunohistochemical study. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 1995;80(6):687-697. 141. Lapid O, Shaco-Levy R, Krieger Y, Kachko L, Sagi A. Congenital epulis. Pediatrics 2001;107(2):E22. 142. Basile JR, Woo SB. Polypoid s-100-negative granular cell tumor of the oral cavity: a case report and review of literature. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2003;96(1):70-76. 143. Lerman M, Freedman PD. Nonneural granular cell tumor of the oral cavity: a case report and review of the literature. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2007;103(3):382-384. 144. Smith BC,Ellis GL, Meis-Kindblom JM, Williams SB. Ectomesenchymal chondromyxoid tumor of the anterior tongue. Nineteen cases of a new clinicopathologic entity. Am J Surg Pathol. 1995;19(5):519-530. 145. Carlos R,Aguirre JM,Pineda V. Ectomesenchymal chondromyxoid tumor of the tongue. Med Oral. 1999; 4(1):361-365. 146. Woo VL, Angiero F, Fantasia JE, Myoepithelioma of the tongue. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2005;99(5):581-589. 147. De Visscher JG, Kibbelaar RE, Van Der Waal I. Ectomesenchymal chondromyxoid tumor of the anterior tongue. Report of two cases. Oral Oncol. 2003;39(1):83-86. 148. Kaplan I, Anavi Y, Calderon S. Ectomesenchymal chondromyxoid tumour of the anterior tongue. Int J Oral Maxillofac Surg. 2004;33(4):404-407. 149. Goveas N, Ethunandan M, Cowlishaw D, Flood TR. Ectomesenchymal chondromyxoid tumour of the tongue: unlikely to originate from myoepithelial cells. Oral Oncol. 2006;42(10):1026-1028.

CHAPTER 37 ■ DISORDERS OF THE ORAL MUCOSA

109.

mucocutaneous pigmentation (LaugierHunziker syndrome): a clinical, histopathological and ultrastructural review of 12 cases. Oral Dis. 1999;5(1):80-86. Schneider LC, Mesa ML, Haber SM. Melanoacanthoma of the oral mucosa. Oral Surg Oral Med Oral Pathol. 1981; 52(3):284-287. Goode RK, Crawford BE, Callihan MD, Neville BW. Oral melanoacanthoma. Review of the literature and report of ten cases. Oral Surg Oral Med Oral Pathol. 1983;56(6):622-628. Contreras E, Carlos R. Oral melanoacanthosis (melanoachantoma): report of a case and review of the literature. Med Oral Patol Oral Cir Bucal. 2005; 10(1):9-12. Axell T, Pindborg JJ, Smith CJ, van der Waal I. Oral white lesions with special reference to precancerous and tobaccorelated lesions: conclusions of an international symposium held in Uppsala, Sweden, may 18-21 1994. International collaborative group on oral white lesions. J Oral Pathol Med. 1996;25(2):49-54. Van Der Waal I, Schepman KP, Van Der Meij EH, Smeele LE. Oral leukoplakia: a clinicopathological review. Oral Oncol. 1997;33(5):291-301. Holmstrup P, Vedtofte P, Reibel J, Stoltze K. Long-term treatment outcome of oral premalignant lesions. Oral Oncol. 2006;42(5):461-474. Jaber MA, Porter SR, Speight P, Eveson JW, Scully C. Oral epithelial dysplasia: clinical characteristics of western European residents. Oral Oncol. 2003; 39(6):589-596. Shafer WG, Waldron CA. Erythroplakia of the oral cavity. Cancer. 1975;36(3): 1021-1028. Silverman S, Bhargava K, Mani NJ, Smith LW, Malaowalla AM. Malignant transformation and natural history of oral leukoplakia in 57,518 industrial workers of Gujarat, India. Cancer. 1976; 38(4):1790-1795. Zakrzewska JM Lopes V, Speight P, Hopper C. Proliferative verrucous leukoplakia: a report of ten cases. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 1996;82(4):396-401. Crissman JD, Visscher DW, Sakr W. Premalignant lesions of the upper aerodigestive tract: pathologic classification. J Cell Biochem Suppl.1993;17f:49-56. Kuffer R. Lombardi T. Premalignant lesions of the oral mucosa. A discussion about the place of oral intraepithelial neoplasia (oin). Oral Oncol. 2002. 38(2): 125-130. Soni S, Kaur J, Kumar A, et al. Alterations of Rb pathway components are frequent events in patients with oral epithelial dysplasia and predict clinical outcome in patients with squamous cell carcinoma. Oncology. 2005;68(4-6):314-325. Mashberg A. Erythroplasia: the earliest sign of asymptomatic oral cancer. J Am Dent Assoc. 1978;96(4):615-620. Chung CH, Yang YH, Wang TY, Shieh TY, Warnakulasuriva S. Oral precancerous disorders associated with areca quid chewing, smoking, and alcohol drinking in southern Taiwan. J Oral Pathol Med. 2005;34(8): 460-466.

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APPENDIX 1 Stem Cells and the Skin

APPENDEX 1 ■ STEM CELLS AND THE SKIN

Laurence Verneuil Anne Janin Raymond L. Barnhill

EPIDERMIS, HAIR FOLLICLE, AND EPIDERMAL STEM CELLS Stem cells (SCs) reside in the discrete microenvironment of the hair follicle bulge (Fig. A1-1) and give rise to several cell types in the hair follicle.1 During the hair cycle, bulge SCs are stimulated to exit the SC niche, proliferate, and differentiate along the lines of various cell types of mature HFs. In addition to serving as a source of various cell types during HF regeneration, the bulge SC is a reservoir for multipotent SCs that may be recruited during wound healing to reconstitute the epidermis.2 There is conflicting evidence as to whether follicular SCs contribute to the wounded epidermis only transiently, ultimately being replaced by the progeny of SCs derived from the original epidermal compartment before wounding or on a long-term basis. Ito M et al.3 suggest that SCs in the hair follicle bulge do not normally contribute cells to the epidermis, which is organized into epidermal proliferative units, as previously

Placode

Hair Germ

described. After epidermal injury, however, cells from the bulge are recruited into the epidermis and migrate in a linear manner toward the center of the wound in a striking radial pattern. Notably, although the bulge-derived cells acquire an epidermal phenotype, most appear to be eliminated from the epidermis over several weeks, indicating that bulge SCs respond rapidly to epidermal wounding by generating short-lived “transient amplifying” cells responsible for acute wound repair.3 In contrast, Levy et al.4 have reported that follicular cells participate in the initial resurfacing of the wound, and their progeny seem to persist in the wound epidermis months after wound healing. Levy et al.4 conclude that the follicular cells seem to undergo reprogramming to become long-term repopulating epidermal progenitors after wounding.4 In summary, hair follicle SCs have at the very least a dual function: continuous hair follicle remodeling and epidermal regeneration whenever skin integrity is severely compromised.5 Although it has not been clearly established whether other multipotent SCs are present in adult skin, substantial evidence shows that unipotent SCs exist in other cutanous locations.2 Thus, the question arises as to the relationship between the SCs of the bulge and those residing within the basal layer of the epidermis. One possibility is that multipotent bulge cells periodically migrate from their niche to populate the basal layer of the epidermis, the hair matrix, and sebaceous gland. What triggers a bulge cell to move upward or downward and execute a

Hair Peg

Mature Follicle

Sebaceous gland

Dermal condensate Bulge

Matrix (Mx) Dermal papilla (DP)

Inner root sheath (IRS)

Outer root sheath (ORS) Melanocytes (Mc)

1022

FIGURE A1-1 Epidermal and other stem cells reside in the bulge area of the hair follicle.

particular differentiation program? Although the answer to this question is still uncertain, some new information has emerged from studies on hair lineage. It seems likely that the process of activating bulge SCs depends on factors that are both intrinsic and extrinsic to the bulge cells themselves. Surrounded by a dermal sheath that is richly innervated and vascular, the bulge dwells in a fertile milieu of signaling networks. An attractive model is that some environmental cue stimulates bulge cells to divide asymmetrically, replenishing the bulge SCs and generating daughter cells that are less adhesive to the niche. Although not yet demonstrated for skin epithelial SCs, asymmetric divisions have been documented for some SCs.6-8 In this model, a reduction in the expression of integrins or cadherins could facilitate the departure of non–stem daughter cells from the niche.

MELANOCYTE STEM CELLS Although stem cells for melanocytes have been difficult to identify, there has been much greater interest in such stem cells recently. For example, a recent study demonstrated that melanocyte SCs (MSCs) may reside in the area of the hair follicle.9,10 These MSCs proliferate and migrate to the bulbar area to generate pigmented hair shafts, and the exhaustion or incomplete maintenance of this cellular populace from this region results in a loss of hair shaft pigmentation and gray hairs.10 Other studies have shown that related cells with broad differential potential, including expression of neuronal, glial, smooth muscle, keratinocytic, and melanocytic differentiation, originate from the hair follicular bulge and appear to be neural crest derived. 9 These apparent neural crest–related cells also express nestin, an intermediate filament protein in neural stem and progenitor cells, and Sox10, a neural crest SC marker. Thus, increasing evidence suggests that MSCs are present in the hair follicle bulge region. The cells may self-renew or migrate from the bulge niche and differentiate into melanocytes in the bulb of the hair follicle. In addition, other cell populations such as Merkel cells11 and Langerhans cells12 have also been detected in the bulge area, further indicating the importance of bulge environment in the homeostasis of the skin.13

TUMOR STEM CELLS AMONG HAIR FOLLICLE STEM CELLS

Hair Follicle Stem Cells are Uniquely Interesting Targets for Regenerative Medicine Adult SCs may have tremendous therapeutic potential, and the skin epithelium represents an enormous source of accessible SCs for generating cells to replace diseased tissue. In addition, the skin is an excellent model for studying the basic biology of organ regeneration and translational approaches to regenerative medicine. Because of the accessibility of the skin, a long history of regenerative approaches already exists. Identifying the commonalities between skin regeneration and the regeneration of other organs could provide major breakthroughs in regenerative medicine.

REFERENCES 1. Taylor G, Lehrer MS, Jensen PJ, et al: Involvement of follicular stem cells in forming not only the follicle but also the epidermis. Cell. 2000;102:451-461. 2. Blanpain C, Fuchs E: Epidermal stem cells of the skin. Ann Rev Cell Devel Biol. 22:339-373.

3. Ito M, Liu Y, Yang Z, et al: Stem cells in the hair follicle bulge contribute to wound repair but not to homeostasis of the epidermis. Nat Med. 2005;11(12):1351-1354. 4. Levy V, Lindon C, Zheng Y, et al: Epidermal stem cells arise from the hair follicle after wounding. FASEB J. 2007; 21(7):1358-1366. 5. Tiede S, Kloepper JE, Bodò E, et al: Hair follicle stem cells: walking the maze. Eur J Cell Biol. 2007;86(7):355-376. 6. Knoblich JA: Asymmetric cell division during animal development. Nat Rev Mol Cell Biol. 2001;2:11-20. 7. Lu B, Roegiers F, Jan LY, Jan YN: Adherens junctions inhibit asymmetric division in the Drosophila epithelium. Nature. 2001; 409:522-525. 8. Song X, Xie T: DE-cadherin-mediated cell adhesion is essential for maintaining somatic stem cells in the Drosophila ovary. Proc Natl Acad Sci. 2002;99:14813-14818. 9. Sommer L: Checkpoints of melanocyte stem cell development. Sci STKE. 2005; 298:pe42. 10. Nishimura EK, Granter SR, Fisher DE: Mechanisms of hair graying: incomplete melanocyte stem cell maintenance in the niche. Science.2005;307:720-724. 11. Narisawa Y Hashimoto K, Kohda H: Epithelial skirt and bulge of human facial vellus hair follicles and associated Merkel cell–nerve complex. Arch Dermatol Res. 1983;285:269-277. 12. Moresi JM, Horn TD: Distribution of Langerhans cells in human hair follicle. J Cutan Pathol. 1997;24:636-640. 13. Ohyama M: Hair follicle bulge: a fascinating reservoir of epithelial stem cells. J Dermatol Sci. 2007;46(2):81-89. 14. Morrison SJ, Kimble J: Asymmetric and symmetric stem-cell divisions in development and cancer. Nature. 2006;441:10681074. 15. So AW, Langston N, Daniallinia JL, et al: Long-term establishment, characterization and manipulation of cell lines from mouse basal cell carcinoma tumors, Exp. Dermatol. 2006;15:742-750. 16. Massoumi R, Podda M, Fassler R, Paus R: Cylindroma as tumor of hair follicle origin, J. Invest. Dermatol. 2006;126:1182-1184. 17. Yu BD, Mukhopadhyay A, Wong C: Skin and hair: models for exploring organ regeneration. Hum Mol Genet. 2008;15; 17(R1):R54-R59.

APPENDEX 1 ■ STEM CELLS AND THE SKIN

By definition, SCs must be able to self-renew and produce differentiated progeny. Asymmetric cell division can accomplish both. However, many SCs also divide symmetrically, allowing the SC population to increase in number. This type of division may be vital to development and regeneration but may also confer a risk for the development of cancer.14 Another related problem is how one can best distinguish potential tumor SCs 15 from normal adult hair follicle–related SCs that can safely be used (eg, for regenerative medicine and gene therapy purposes). This is an important issue because several studies suggest that hair follicle SCs may not only give rise to a variety of benign skin appendage tumors such as pilomatricoma and cylindroma16 but also to basal cell carcinoma, the most prevalent human malignancy.15

Recent studies suggest the epidermis and hair may have an untapped potential to form other organs. Understanding the mechanisms that regulate adult SC proliferation is a major goal for regenerative medicine. In the hair follicle, pharmacologic agents, recombinant proteins, and artificial cell-permeable proteins have been developed to manipulate the proliferation of the quiescent bulge SCs. These advances illustrate a potential roadmap for regenerative medicine using molecular tools developed for skin biology to promote organ regeneration by manipulating adult SCs in situ.17 In summary, the hair follicle and its immediately adjacent tissue environment contain unipotent, multipotent, and possibly even pluripotent SC populations of different developmental origin, which can differentiate along neuroectodermal and mesodermal pathways. Under physiologic circumstances, SCs of the hair follicle bulge serve as a cell pool for the cyclic regeneration of the anagen hair bulb, and they can also regenerate the sebaceous gland and the epidermis after injury. As such, hair follicle SCs are uniquely interesting for regenerative medicine applications, but many important issues (eg, the identification and elimination of tumor SCs) remain unresolved. Hair follicle SCs also offer highly instructive model systems for the study of central issues in SC biology such as SC gene and protein profiling, SC plasticity, and SC niches.5

1023

APPENDEX 2 ■ LABORATORY METHODS

APPENDIX 2

Table A2-1 Common Special Stains in Dermatopathology

Laboratory Methods

STAIN

APPLICATION

RESULTS

H&E

Routine

Klaus J. Busam Raymond L. Barnhill

PAS/diastase

Masson’s trichrome

Fungi, parasites Glycogen (eg, in trichilemmoma) Basement membrane thickening (eg, LE) Cryoglobulinemia Adenocarcinomas, Cryptococcus Mast cells Mast cells Leishmania Fibrosis

Nuclei: blue; cytoplasm; red Collagen, muscles, nerves: red Wall of organisms: red Glycogen: red on PAS; clear after diastase digestion Basement membrane: pink/red

Van Gieson Van Kossa Congo red Fontana Prussian blue Gram stain

Infantile digital fibromatosis Arterial injury Calcium Amyloid Melanin Hemosiderin/iron Bacteria

The mainstay of dermatopathology is the examination of skin biopsies after fixation in formalin, embedding in paraffin, and staining with hematoxylin and eosin (H&E). This technique has been quite durable in the history of histopathology because it offers many advantages: it is relatively quick, inexpensive, suitable for most practical needs, and relatively easy to master. However, it cannot answer all the questions that a case may pose at the diagnostic level. Therefore, pathologists have always searched for additional methods to analyze their histologic material.

SPECIAL STAINS There is an extensive battery of “special” stains listed in texts discussing histologic techniques.1,2 Few of them are of practical value for diagnostic dermatopathologists. A synopsis of some of the stains that appear relevant for a modern dermatopathology laboratory is listed in Table A2-1.

Stains for Microorganisms Perhaps the most important of all the special stains in the practice of dermatopathology are stains that help to identify microorganisms. This includes the modifications of the Gram stain, such as by Brown and Hopp, for most bacterial organisms; the methenamine silver stain or periodic acid-Schiff (PAS) stain for fungi and parasites; and the Ziehl-Neelson or Fite stain for acid-fast bacilli. Silver stains, such as according to Dieterle, Warthin-Starry, and Steiner, are commonly used to identify spirochetes (syphilis, Lyme disease) and the organisms in cat-scratch disease and bacillary angiomatosis (Rochalimea). Leishmania is best identified by a Giemsa stain.

Mucicarmine Toluidine blue Giemsa

Methenamine-silver Dieterle/Steiner/ Warthin-Starry AFB/Fite

Fungi, parasites Spirochetes, Rochalimea

Cryoprecipitates: bright red Mucin: red Capsule: red Metachromatically purple Metachromatically purple Blue Collagen: green; nuclei, muscle: dark red Hyaline globules: red Elastic fibers: black Black Green under polarized light Black Black Depending on method used (gram positive: usually blue; gram negative: usually red) Black Black

Acid-fast bacilli

Red

digestion. The staining reaction yields a pink to red color. An intensely bright red homogeneous material within vessels suggests cryoglobulins. The PAS stain is also useful in highlighting most types of fungi and parasites.

Stain for Hemosiderin In the Prussian blue reaction, hydrochloric acid splits off the protein bond to the iron, allowing the potassium ferrocyanide to combine specifically with the ferric iron to form ferric ferrocyanide. The reaction leaves a blue color.

Giemsa Stain This technique is very useful for the demonstration of lymphoreticular cells, including mast cells. It is also used to highlight microorganisms such as Leishmania.

Mucicarmine Stain This technique has been recommended for epithelial mucins (ie, adenocarcinoma), and to stain the capsule of Cryptococcus. A positive reaction yields a reddish color.

Stains for Melanin In the Fontana-Masson method, an ammoniacal silver solution is used without a reducing bath. Only substances capable of reducing directly silver salts (ie, argentaffin material) such as melanin are demonstrated as grayish black pigment. This stain is not entirely specific for melanin. Some metabolic products of minocin, for example, also stain with this method.

Toluidine Blue Periodic Acid-Schiff Stain

1024

This stain demonstrates mucosubstances, basement membrane material, fibrinoid material, and glycogen in a specific fashion when combined with diastase

This stain is used to document metachromasia. Most acid mucosubstances show metachromasia at higher pH values. Toluidine blue is used most often to identify mast cells.

Von Kossa Stain for Calcium In this technique, silver is substituted for calcium in calcium salts; this silver is then reduced to yield a black metallic color.

Trichrome Stains In this stain, phosphotungstic or phosphomolybolic acid is used in combination with several anionic dyes. This stain is primarily used in the evaluation of extracellular material, in particular collagen such as in fibromatoses or connective tissue nevi. Its practical application includes also peculiar phenomena such as the identification of small globular structures in infantile digital fibromatosis.

Reticulin Stain

Elastic Fiber Stain In the Verhoeff-van Gieson stain, elastic fibers are outlined with a strong black color. Its main applications are in the demonstration of arterial injury and in connective tissue nevi.

Amyloid Stains A number of stains are available to demonstrate amyloid material. Most laboratories use the Congo red stain. This stain needs to be combined with polariscopic examination, which yields an apple-green birefringent appearance. However, one needs to be cautious in interpreting this stain because excess dye retained in the tissue may give a false-positive signal.

and then allowed to incubate with substrate tissue. Subsequently, the target tissue is labeled with fluorescent-tagged antibodies as described above for DIF. If the patient’s serum contains circulating antibodies to antigens present in the target tissue, a positive signal is obtained. With IF, semiquantitative analysis can be performed by determining titers of antibodies.5 Saline split-skin preparations are an addition to the methodology of indirect immunofluorescence (Table A2-3), and they are mainly used in the distinction between bullous pemphigoid (BP) and epidermolysis bullosa acquisita.6 This technique requires that biopsies of normal skin must be obtained from human volunteers. They are subsequently incubated with 1M sodium chloride at 4°C for 72 hours, and then the epidermis is separated from the dermis manually. The cleavage occurs between the lamina lucida and the remainder of the epidermal basement membrane, which allows localization of the BP antigen to the roof of the artificially induced blister, whereas the epidermolysis bullosa acquisita antigen is located in its base. Although a properly done saline split-skin procedure is very valuable methodology, it is tedious, which explains why it is routinely used only in a few laboratories.

APPENDEX 2 ■ LABORATORY METHODS

This method highlights reticulin fibers. It has traditionally been used to distinguish carcinoma (groups of cells surrounded by fibers) from sarcoma (single cells surrounded by fibers).

complex method with an enzyme antibody conjugate.3 This conjugate is typically an enzyme, such as horseradish peroxidase or alkaline phosphatase. Enhancing techniques using biotin and avidin are frequently used. A number of steps have been suggested to increase the sensitivity of these procedures. The aim is to expose the epitope that may otherwise be masked. Such “unmasking” techniques include digestion of the tissue with proteolytic enzymes or treatment with microwaves. In addition to labeling an antibody with an enzyme, a number of fluorescent probes are also available. Immunofluorescence can be performed either directly (DIF) with a probe such as fluorescane isothiocyanade (FITC) label or indirectly (IF). For DIF, a skin biopsy is submitted in saline (Table A2-2), or if immediate processing cannot be performed, in Michelle medium. Upon arrival of the specimen in the laboratory, frozen sections are prepared, and these are labeled in a one-step method with fluorescence probe tagged antibodies that are directed against human immunoglobulins, serum proteins, or complement fractions. A signal is then obtained by visualizing antibody binding by excitation of the fluorescent label by ultraviolet light using a fluorescence microscope.4 IF differs from DIF in that it does not probe the patient’s skin directly but rather analyzes the presence of circulating antibodies against cutaneous antigens in the patient’s serum. For this method, the patient's serum is obtained

Applications in Nonneoplastic Diseases BULLOUS DISEASES Immunofluorescent studies play an important role in the evaluation of primary bullous disorders

ENZYME HISTOCHEMISTRY Due to the complexity of the techniques involved in enzyme histochemistry, the need for fresh material, and the relative nonspecificity of most of the reactions, this technique has only very limited applications at present. In dermatopathology, the methods most commonly used are chloracetate esterase, also known as Leder stain, for the identification of mast cells or hematopoietic cells of the myeloid lineage, and the Dopa reaction to identify cells of the melanocytic lineage.2

IMMUNOHISTOCHEMISTRY

Table A2-2 Optimal Sites for Skin Biopsy for Direct Immunofluorescence SITE

Pemphigous Pemphigoid, bullous and cicatricial Epidermolysis bullousa acquisita Herpes gestationalis Dermatitis herpetiformis Linear immunoglobulin A (IgA) dermatosis Lupus erythematosus, bullous Porphyria cutanea tarda Lesional Erythema multiforme Lichen planus

Technical Aspects Several methods are applicable to the evaluation of skin biopsies. The most commonly used technique is an immune

DISEASE

Perilesional

Distant normal Leukocytoclastic vasculitis

1025

Table A2-3 Split-Skin Indirect Immunofluorescence Preparation for Selected Cutaneous Diseases Site of Autoantibody to NaCl-Separated Normal Human Skin at the Dermal–Epidermal Junctiona Epidermal portion only Bullous pemphigoid (usual) Cicatricial pemphigoid Chronic bullous dermatosis of childhood (IgA) class autoantibody Epidermis and dermis Bullous pemphigoid (rare) Dermal portion only

APPENDEX 2 ■ LABORATORY METHODS

Epidermolysis bullosa acquisita Lupus erythematosus, bullous Cicatricial pemphigoid a Use of 1.0 M NaCl-split human skin increases the likelihood of detecting basement membrane autoantibodies to an 85% positive rate.

because some of these disorders show a fairly specific reaction pattern (Tables A2-4 to A2-6). INTRAEPIDERMAL BLISTERS These include mainly variants of pemphigus. Immunohistologically, one typically observes a mosaic-like intercellular labeling of the acantholytic epidermis by DIF in virtually all forms of pemphigus (Fig. A2-1). IgG, in particular IgG1, is the most common immunoreactant. Other immuno-

globulins are rarely deposited. Deposition of C3 occurs but is seen infrequently.6 In pemphigus erythematosus, linear deposits of IgG, IgM, IgA, or C3 may be detectable at the epidermal basement membrane zone in addition to the intercellular labeling typical of the other variants of pemphigus.7 SUBEPIDERMAL BLISTERS Immunofluorescence plays a critical role in the distinction among a number of subepi-

dermal bullous disorders.8-11 This disease group includes BP, herpes gestationis (HG), dermatitis herpetiformis (DH), bullous disease of childhood, linear IgA dermatosis, bullous lupus erythematosus, and epidermolysis bullosa acquisita. In all of these diseases, a blister is formed by cleavage of the skin at the basement membrane zone, either in the lamina lucida or lamina densa. BP, HG, and epidermolysis bullosa acquisita all demonstrate linear continuous staining of the basement membrane zone by DIF, for IgG, and for C3 (Fig. A2-2). The distinction of these three entities from each other depends mainly on the clinical findings. If epidermolysis bullosa cannot reliably be separated from BP on clinical grounds alone, IF on saline splitskin preparations would be helpful (see above). It has also been suggested that if this technique is not available, one might also attempt to localize the site of immune complex deposition by staining the tissue sections for type IV collagen. This type of collagen is a major component of the lamina densa. It remains in the base of the blister in BP and HG but resides in the roof of the bulla in epidermolysis bullosa acquisita. Linear IgA dermatosis and chronic bullous dermatosis of childhood share the same immunofluorescence pattern:

Table A2-4 Findings of Direct Immunofluorescence in Bullous Diseases LOCATION/PATTERN OF DEPOSITION Intraepidermal Epidermal cell surface Dermal–epidermal junction Linear, nonhomogeneous Linear, homogeneous

IMMUNOREACTANT PRESENT

DISEASE

IgG, complement IgA

Pemphigus family Intraepidermal IgA dermatosis

Multiple Igs, complement or fibrin Multiple Igs, complement or fibrin

Lupus erythematosus Cicatricial pemphigoid EBA Lupus erythematosus Bullous pemphigoid Cicatricial pemphigoid EBA Herpes gestationalis Chronic bullous dermatosis of childhood Linear IgA dermatosis (adult)

IgG, complement

IgA Other upper dermis Cytoid bodies Interstitial perivascular or dermal–epidermal junction Intravascular Granular

1026

Multiple Igs, complement or fibrin Multiple Igs, complement or fibrin

IgM, complement or fibrin

Dermatitis herpetiformis Lichen planus Porphyria cutanea tarda

Erythema multiforme Vasculitis

Table A2-5 Immunofluorescence Patterns in Autoimmune Bullous Diseases LOCATION

IMMUNOREACTANT

REPRESENTATIVE DISEASE

FREQUENCY

Epidermal cell surface Dermal–epidermal junction

IgG intercellular IgG class

Pemphigus vulgaris Bullous pemphigoid Cicatricial pemphigoid EBA Chronic bullous dermatosis of childhood

Majority of cases >80% 40% Majority of cases

IgA

Anti-bullous pemphigoid Antigen/anti-α6β4 integrin Antilaminin Anti-type IV collagen; anti-LDA-1

EB SIMPLEX

JUNCTIONAL EB

DYSTROPHIC EB

Dermal base

Dermal base

Epidermal roof

Dermal base Dermal base

Epidermal roof Dermal base

Epidermal roof Epidermal roof

linear deposits of IgA along the basement membrane zone. In DH, on the other hand, IgA deposits are found in a patchy granular distribution in the DP (Fig. A2-3). Complement C3 is also frequently deposited in each of these disorders. Occasionally, one may also find deposition of IgG or IgM. In bullous lupus erythematosus, usually a number of immunoglobulins and complements are deposited along the basement membrane in the blister base,

essentially showing the same patterns as in other lesion of lupus erythematosus.12 CONNECTIVE TISSUE DISEASE Immunofluorescence may also be helpful in the evaluation of connective tissue disease, in particular, for the diagnosis of lupus erythematosus. Immunoglobulins (IgG, IgM, IgA, IgE) and complements (C1q, C3, C4, C5) are commonly found along the basement membrane of lesional skin in discoid lupus erythematosus (DLE).12,13

 FIGURE A2-1 Immunofluorescence of pemphigus vulgaris. There is intercellular deposition of IgG in the epidermis.

APPENDEX 2 ■ LABORATORY METHODS

Table A2-6 Staining Patterns in Immunofluorescence Antigenic Mapping for Specific Antibodies to Inherited Epidermolysis Bullosa (EB)

The pattern of deposition is typically granular. In systemic lupus erythematosus (SLE), such granular deposits of immunoglobulins and complement are not only seen in lesional skin but also in clinically normal-appearing skin. The phenomenon that normal-appearing skin may show deposition of immunoglobulins and complements has been used diagnostically in the so-called lupus band test.14 This test may help in the distinction between SLE and DLE. In DLE, a lupus band test result should be negative. A positive test result is found in approximately 60% of patients with SLE. A positive test result in sunprotected normal skin in a patient with SLE has been suggested to also be of prognostic value, implying a worse prognosis. In patients with SLE, immunoglobulins and complements are not only found along the basement membrane zone but also around the vessels and diffusely between collagen bundles. Positive immunofluorescence findings are also commonly seen in a number of other examples of connective tissue disease, such as in mixed connective tissue disease, scleroderma, and dermatomyositis. In most cases, the immunofluorescence pattern is fairly nonspecific and usually adds little useful information. VASCULITIS Positive immunofluorescence findings are commonly seen in many cutaneous vasculitides.15 Many times, it is difficult to decide whether the deposition of immunoglobulins and complements in damaged vessels is primary or secondary. The diagnostically most useful application of immunofluorescence studies in vasculitides is in the evaluation of Henoch Schoenlein purpura.16

 FIGURE A2-2 Immunofluorescence of bullous pemphigoid. Note linear deposition of IgG in the basement membrane zone.

1027

APPENDEX 2 ■ LABORATORY METHODS

 FIGURE A2-3 Immunofluorescence of dermatitis herpetiformis. IgA is deposited in the dermal papillae in a delicate, speckled pattern.

In this clinical setting, the demonstration of IgA deposits by immunofluorescence is paramount for establishing the diagnosis (Fig. A2-4). LICHENOID DERMATITIS Positive immunofluorescence findings may also be seen in lichen planus or lichen planopilaris and some drug-induced dermatitides. Positive staining is often observed in socalled colloid bodies, which frequently represent immunoglobulin-encrusted keratinocytic material. Staining may be seen for IgM, IgG, IgA, C3, or fibrin. Drug-induced dermatitides may show a very broad spectrum of immunofluorescence patterns and lack specificity.17 IMMUNOHISTOLOGY OF INFECTIOUS DISEASES Direct antibodies have been developed for the detection of infectious agents. Most of them have been applied to formalin-fixed and paraffin-embedded tissue. The detection system usually relies on enzyme-conjugated antibodies (peroxidase or phosphatase) and not on immunofluorescence. One of the more frequently used antibodies in this context is antibodies to herpes simplex virus type I or II. A number of antibodies to other viral or bacterial organisms are available.

Applications in Neoplastic Skin Diseases

1028

CUTANEOUS LYMPHOID INFILTRATES Immunohistology plays an invaluable role in the characterization of lymphoid cells.18,19 A list of commonly used markers in the evaluation of lymphoid infiltrates is provided in Table A2-7. The application of these markers is guided

 FIGURE A2-4 Immunofluorescence of Henoch-Schoenlein purpura. Immunoreactants are deposited in the walls of microvessels.

by the differential diagnosis formulated based on the cytology and distribution of the infiltrate in routine H&E-stained sections. A thorough investigation of the cell phenotype requires the availability of fresh tissue for cryostat sections (Table A2-8). EPIDERMOTROPIC INFILTRATES These include cutaneous T-cell infiltrates, in particular, mycosis fungoides (MF), atypical T-cell reactions, such as lymphomatoid papulosis, lymphomatous drug reactions, lymphomatous lichenoid or spongiotic dermatitides, and actinic reticuloid. It has been said that the phenotype of the T-cell infiltrate in MF is different from other processes, such as

actinic reticuloid. MF, for example, typically has a predominant population of CD4-positive cells expressing other Tcell markers as well (CD2, CD3, CD5) and often some decrease in CD7.20,21 On the other hand, actinic reticuloid and some lymphomatoid dermatidities tend to retain pan T-cell markers and contain a larger proportion of CD8 cells.22 It is important not to put too much weight on these findings, however, because MF may have an uncharacteristic phenotype, and reactive lesions may mimic the immunophenotype of MF. CD30 is a useful antibody if lymphomatoid papulosis is suspected because the condition typically contains T-lymphocytes expressing this activation marker.23

Table A2-7 Lymphoid Markers

B-Cell Markers CD10 (CALLA): marks precursor B cells and granulocytes. Present in follicular center cell lymphomas (FCC), pre-all; absent in maltomas CD19: pan B-cell marker CD20 (L26): pan B-cell marker; best B-cell marker in paraffin sections CD22: pan B-cell marker CD45RA: pan B-cell marker Light chains: demonstration of monotypic plasma cells (cryostat or paraffin sections) T-Cell Markers CD1a (T6): Thymocytes and Langerhans’ cells CD2: pan T-cell marker CD3: pan T-cell marker CD4: T cells and macrophages, T-helper cells CD5: T cells and subsets of B cells CD7: precursor T, T subsets, and natural killer (NK) cells, one of the first markers lost in CTCL CD8: T subsets, NK cells, T suppressor cells CD43 (leu-22): T cells, macrophages, and granulocytes (e.g., chloromas) TdT: immature B and T cells UCHL-1: best pan T-cell marker in paraffin sections

Table A2-8 Lymphoma Panels

DEEP LYMPHOID INFILTRATES Bulky deep dermal lymphoid infiltrates generally suggest a B-cell phenotype. These infiltrates are readily identified as reactive if immunohistochemical studies demonstrate a mixture of B and T cells and the B cells lack light chain restriction. If frozen tissue is available, the demonstration of light chain restriction is perhaps the most useful test in diagnostic immunohistology of lymphoid infiltrates because it proves presence of a clonal neoplastic B cell population.24 Unfortunately, light chain immunostains are very difficult to perform technically, and many times they are difficult to interpret. Further light chains are not expressed in all B-cell lymphoproliferative disorders. If a deep T-cell infiltrate is present, CD30 may again be a useful marker if lymphomatoid papulosis or CD30-positive lymphoma is suspected.

Nonlymphoid Hematopoietic Infiltrates Immunohistochemical studies are also important in the evaluation of hematopoietic infiltrates other than lymphoid cells. These include Langerhans cell proliferations and leukemias.26,27 Langerhans cells are best recognized immunohistochemically by CD1a and a new marker langerin but also express S-100 protein, HLA-DR, and CD43. Most leukemic infiltrates of the skin are myeloid, which makes myeloperoxidase a very useful antibody in identifying a suspected leukemic population. Other less specific markers that are often positive in myelogenous leukemia are Leu-M1 (CD15) and KP-1 (CD68). EPITHELIOID NEOPLASMS Cytokeratins particularly cytokeratin 5/6 for cutaneous

Carcinoma Melanoma Lymphoma

CYTOKERATINS

S-100

HMB-45

LCA

+ − −

− + −

− + −

− − +

epidermoid carcinomas and epithelial membrane antigen (EMA) remain the most important markers of epithelial differentiation.28,29 Their application is usually needed for the evaluation of undifferentiated primary tumors or metastases. They need to be used in conjunction with the most likely mimics, such as melanoma or lymphoma (Table A2-9). Certain markers, such as thyroglobulin, GCDFG, calcitonin, and prostatespecific antigen, may be helpful in identifying possible primary sites.

Melanocytic Neoplasms A number of markers are available that aid in the identification of a lesion as melanocytic in origin (Table A2-10).29,30 This is most often needed in the evaluation of poorly differentiated (generally amelanotic) primary or metastatic tumors that suggest melanoma. Primary tumors that may mimic melanoma include spindle cell squamous cell carcinoma, atypical fibroxanthoma, leiomyosarcoma, malignant peripheral nerve sheath tumor, and neuroendocrine carcinoma. Whenever a lesion is suspected to be melanocytic, it is important to apply a panel of antibodies, including antibodies positive for lesions that enter into the differential diagnosis. Three markers are used on a regular basis for the evaluation of melanocytic lesions: S-100 protein, Melan-A (Mart-1), and gp100 (HMB-45). Nonetheless, tyrosinase and MITF are used with increasing frequency, particularly in the

setting of a panel of antibodies. However, S-100 protein remains the gold standard and is the most sensitive marker for melanocytes; however, it is not specific. It is also expressed in Schwann cells, astrocytes, Langerhans cells, chondrocytes, and several other cell types. MelanA (Mart-1) and tyrosinase approach S 100 protein in sensitivity because they are expressed by virtually all melanocytic nevi and epithelioid melanomas. HMB-45 stains melanocytes in several nevi, notably blue nevi, Spitz nevi, and the intraepidermal components of atypical (dysplastic) nevi and some ordinary nevi, as well as many melanoma cells. It is not entirely specific for melanocytes. Positive staining for this maker has been observed in a variety of nonmelanocytic lesions, including angiomyolipoma, some breast cancers, and gliosarcomas. It should be noted that the vast majority of spindle cell and desmoplastic neurotropic melanomas are negative for most melanocytic markers, including Melan-A, HMB-45, MITF, and tyrosinase. Almost all of them, however express, S-100 protein and to a lesser degree p75 neurotrophin receptor.

APPENDEX 2 ■ LABORATORY METHODS

Fixed tissue: suspected T-cell lymphoma CD3: to confirm T-cell phenotype CD30 (Ki-1): in LYP or large cell lymphoma CD20, CD79a: to evaluate for presence of B cells Suspected B-cell lymphoma CD2, CD20, CD19, CD22, CD79a: to confirm B-cell phenotype CD2,CD3,CD4,CD5,CD7,CD43,CD1a,CD30: to evaluate for presence of T cells Light chains: demonstration of monotypic cells: kappa, lambda Frozen tissue: suspected B-cell lymphoma Light chains: lambda, kappa

Table A2-9 Poorly Differentiated Tumors

Soft Tissue Neoplasms Immunohistology is essential in the evaluation of poorly differentiated soft tissue neoplasms. The main role is to confirm suspected histogenesis or differentiation. A list of markers relevant in the workup of sarcomas is provided in Table A2-11.

Table A2-10 Commonly Used Melanocyte Differentiation Markers for Paraffin-Embedded Tissue ANTIBODY

ANTIGEN

SENSITIVITY

SPECIFICITY

Anti-S100P T311 A103/ M2-7C10 HMB-45 D5/C5

S100 protein Tyrosinase Melan-A/ Mart-1 gp100 MITF

>95% 70%-90% 70%-85%

Low High High

60%-80% 60%-80%

High Intermediate

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APPENDEX 2 ■ LABORATORY METHODS

Table A2-11 Soft Tissue Tumors S-100

AE1/AE3

HHF-35

SM-ACT

DESMIN

CD34

OTHER

+ ± −

− − − ⫿

− − − ⫿

− − − ⫿

− − − ±

− − − −

− − EMA + −

− − −

− − −

± ± ±

+ − +

+ + −

− − −

− − − −

− − − −

⫿ ⫿ − ⫿

⫿ ⫿ − ⫿

− − − −

+ ⫿

Neural origin: Schwannoma Neurofibroma Perineurioma MPNST Muscle origin: Smooth muscle Skeletal muscle Glomus tumor Fibrous tumors: DFSP FH Fibroma SFT

Small Cell Neoplasms Many different neoplasms can assume a small cell phenotype. These include metastatic small cell carcinoma, cutaneous neuroendocrine (Merkel cell) carcinomas, small cell sweat gland carcinoma, sarcomas (eg, Ewing sarcoma or primary neuroendocrine tumor), neuroblastoma or alveolar rhabdomyosarcoma, small cell lymphomas, and small cell melanomas. Immunophenotypic studies are paramount in the differential diagnosis of small cell neoplasms (Table A2-12).

CYTOGENETICS The main application of solid tumor cytogenetics in dermatopathology is in the evaluation of sarcomas because a surprising number of sarcomas have

characteristic karyotypic abnormalities and gene rearrangements.31 A list of diagnostically useful cytogenetic alterations in cutaneous sarcomas is provided in Table A2-13. If fresh tissue is available, conventional karyotypes may be obtained. The development of fluorescence in situ hybridization (FISH) also allows cytogenetic analysis on archival material.

Comparative Genomic Hybridization and Fluorescence in Situ Hybridization Over the past decade, comparative genomic hybridization (CGH) has contributed significantly to a better understanding of the developmental biology of melanocytic neoplasms, particularly melanoma. 31 Although CGH largely

+

remains in the research sphere, this technique has also been successfully applied to the diagnostic evaluation of many ambiguous or controversial melanocytic neoplasms because such lesions showing the chromosomal aberrations usually associated with melanoma provide support for a lesion likely to be melanoma. CGH evaluation of primary melanomas has demonstrated losses at 6q, 8p, 9p, and 10q and gains at 1q, 6p, chromosome 7, 8q, 17q, and 20q to be the most frequent DNA copy number changes in melanoma. Significant differences in regions of gain and loss were found among the major “histogenetic” variants. For example, acral melanomas had significantly more aberrations of chromosomes 5p, 11q, and 12q than socalled superficial spreading melanoma (SSM), lentigo maligna melanoma (LMM), and nodular melanoma. Furthermore,

Table A2-12 Small Cell Neoplasms

Small cell CA Merkel cell CA Small cell sweat gland CA Ewing/PNET Alveolar rhabdomyosarcoma Neuroblastoma Lymphoma Melanoma

1030

LCA

PAS

013

DES

CK

CK20

NSE

NF

S-100

− − −

− − −

− − −

− − −

+ + +

− + −

⫿ ⫿ ?

− − ?

− − +

− − − + −

+ ⫿ − − −

+ − − − −

− + − − −

⫿ − − − −

− − − − −

⫿ ⫿ + − ⫿

⫿ − + − −

− − − − +

LCA = leukocyte common antigen; PAS = periodic acid-Schiff stain; 013 = CD99; Des = desmin; CK = cytokeratin; CK20 = cytokeratin 20; NSE = neuronspecific enolase; NF = neurofilament; S-100 = S-100 protein.

Table A2-13 Cytogenetics of Cutaneous Neoplasms KARYOTYPIC ABNORMALITY

GENES

Melanoma

Heterogeneous abnormality, various deletions (eg, 1, 6, 9) Ring chromosome (17,22), trisomy 5 t(2;13)(p36;q14) t(1;13)(p36;q14) +2q, +8, +20, del 1

?

t(11;22)(q24;q12) t(11;22)( q13;q12) del (1p) +1 Rearrangements of 12q14−15, 6p, 13q Rearrangements of 16q, 13q +7, +5

FLI-1-EWS ATF-1-EWS ? ? HMGC-1 ? ?

DFSP Alveolar Rhabdomyosarcoma Embryonal rhabdomyosarcoma ES/PNET Clear cell sarcoma Neuroblastoma MPNST Lipoma (ordinary) Spindle cell lipoma Giant cell tumor of tendon sheath

LMM showed marked loss of chromosomes 17p and 13q. On the other hand, the general absence of chromosomal gains or losses considered characteristic of melanoma argues against melanoma but does not altogether exclude that entity. The FISH applications for melanocytic neoplasms are generally derivative from CGH results and involve a combination of particular probes likely to correlate with progression to melanoma: RREB1 (6p25), MYB (6q23), CCND1 (11q13), and CEP6 (6p11.1–q11.1) probes. For the time being, FISH techniques also remain investigational and should not be considered the “standard of care.” At present and for some time to come, the gold standard for difficult melanocytic lesions will continue to be histopathologic diagnosis and clinical correlation.

ELECTRON MICROSCOPY The main applications of electron microscopy to diagnostic dermatopathology is in the field of congenital bullous disorders, certain storage diseases, and tumor pathology. Ultrastructural studies are the gold standard for the localization of the cleavage site in the disease group of epidermolysis bullosa congenita. Electron microscopy is very helpful in identifying intracellularly stored or deposited material, such as intra-lysosomal electron dense lamellar bodies in Fabre disease and characteristic fibrils in amyloid. In the differential diagnosis of neoplastic disorders, ultrastructural studies play a role in the identification of Bierbeck granules in Langerhans cell proliferations. They may also reveal useful information

? PAX3-FKHR PAX7-FKHR ?

in a number of other neoplasms, such as melanosomes in melanoma, desmosomes and tonofilaments in epithelial tumors, myofibrils in myogenic tumors, electrondense core granules in neuroendocrine neoplasms, perinuclear bundles of intermediate filaments in epithelioid sarcoma, Weibel-Palade bodies in angiosarcoma, and rhomboid crystals in alveolar soft part sarcoma.

POLARISCOPIC EXAMINATION Polariscopic examination is useful in evaluating certain foreign material such as suture material, wood splinters, beryllium, sirconium, and silica. It is also helpful in highlighting some endogenous deposits, such as uric acid crystals in gout and oxalate crystals. It should routinely be used in the evaluation of granulomatous tissue reactions. It is also an ancillary technique in the Congo red stain to evaluate for amyloid.

REFERENCES 1. Bancroft JD, Cook HC: Manual of Histological Techniques and Their Diagnostic Application. Edinburgh: Churchill Livingston; 1994. 2. Johnson WC: Histochemistry of the skin, in Spicer S (ed). Histochemistry in Pathologic Diagnosis. New York: Marcel Dekker; 1984:665-694. 3. Rosai J: Special techniques in surgical pathology, in Rosai J (ed). Ackerman’s Surgical Pathology, 8th ed. St. Louis: Mosby; 1996:29-62. 4. Rodriguez HA, McGavran MH: A modified dopa reaction for the diagnosis and investiagtion of pigment cells. Am J Pathol. 1969;52:219-227.

APPENDEX 2 ■ LABORATORY METHODS

TUMOR

5. Beutner EH, Chorzelski TP, Kumar V: Imuunopathology of the Skin, 3rd ed. New York: John Wiley & Sons; 1987. 6. Ceballos P, Jimenez-Acosta F, Penneys NS : Immunohistochemical techniques in non-neoplastic conditions. Semin Dermatol. 1989;8:276-282. 7. Gammon WR, Fine JD, Forbers M, Briggaman RA: Immunofluorescence on split skin for the detection and differentiation of basement membrane zone autoantibodies. J Am Acad Dermatol. 1992; 27:79-87. 8. Beutner EH, Jordan RE, Chorzelski TP: The immunopathology of pemphigus and pemphigoid. J Invest Dermatol 1968; 51:63-80. 9. Farmer ER: Subepidermal bullous diseases. J Cutan Pathol. 1985;12:316-321. 10. Helm KF, Peters MS: Immunodermatology update: the immunogogically-mediated vesiculobullous diseases. Mayo Clin Proc. 1991;66:187-202. 11. Gately LE III, Nesbitt LT Jr: Update on immunofluorescent testing in bullous diseases and lupus erythematosus. Dermatol Clin. 1994;12:133-142. 12. Mutasim DF, Pelc NJ, Supapannachart N: Established methods in the investigation of bullous disease. Dermatol Clin. 1993;11: 399-418. 13. Pardo RJ, Pennesy NS: Location of basement membrane type IV collagen beneath subepidermal bullous diseases. J Cutan Pathol. 1990;17:336-341. 14. Braverman IM, Yen A: Demonstration of immune complexes in spontaneous and histamine-induced lesions and in normal skin of patients with leukocytoclastic vasculitis. J Invest Dermatol. 1975;64: 105-112. 15. Faile-Kuyper Eh dela, Kater L, Koviker CJ, et al: IgA-deposits in cutaneous blood vessel walls and mesangium in HenochSchoenlein syndrome. Lancet. 1973; 1:892. 16. Knowles DM: Immunophenotypic markers useful in the diagnosis and classivation of hematopoietic neoplasms, in Knowles DM (ed). Neoplastic Hematopathology, 2nd ed. Baltimore: Williams & Wilkins; 2001:93-226. 17. Burke J: Malignant lymphomas of the skin: their differentiation from lymphoid and non-lymphoid cutaneous infiltrates that simulate lymphoma. Semin Diagn Pathol. 1985;2:169-182. 18. Perksin SL, Kjeldsberg CR: Immuno-phenotyping of lymphomas and leukemias in paraffin-embedded tissues. Am J Clin Pathol. 1993;99:362-373. 19. Kaplan EH, Leslie WT: Cutaneous T-cell lymphomas. Curr Opin Oncol. 1993;5:812818. 20. Filippa DA, Ladanyi M, Wollner N, et al: CD30 (Ki-1) positive malignant lymphomas: clinical, immunophenotypic, histologic, and genetic characteristics and differences with Hodgkin’s disease. Blood. 1996;87:2905-2917. 21. Emile JF, Wechsler J, Brousse N, et al: Langerhans’ cell histiocytosis. Definitive diagnosis with the use of monoclonaal antibody 010 on routinely paraffinembedded samples. Am J Surg Pathol. 1995; 19:636-641. 22. Ratnam KV, Khor CJL, Su WPD: Leukemia cutis. Dermatol Clin. 1994;12: 419-431. 23. Battifora H: Diagnostic uses of antibodies to keratins. Prog Surg Pathol. 1988; 8:1-15.

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24. Thomas P, Battifora H: Keratins vs. epithelial membrane antigen in tumor diagnosis. An immunohistochemical comparison of five monoclonal antibodies. Hum Pathol. 1987;18:728-734. 25. Wick MR, Swanson PE, Ritter JH, et al: The immunohistology of cutaneous neoplasia: a practical perspective. J Cutan Pathol. 1993;20:481-497. 26. Busam KJ, Barnhill RL: Biopsies, tissue processing and special studies, in Barnhill RL, Piepkorn M, Busam KJ (eds). Pathology of

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Melanocytic Nevi and Malignant Melanoma, 2nd ed. New York: Springer Verlag;, 2004. 27. Prieto VG, Shea CR: The use of immunohistochemistry in the evaluation of melanocytic lesions. J Cutan Pathol. 2008; 35(suppl 2):1-10. 28. Miettinen M, Fernandez M, Franssila K, et al: Microphthalmia transcription factor in the immunohistochemical diagnosis of metastatic melanoma. Comparison with four other melanoma markers. Am J Surg Pathol. 2001;25:205-211.

29. Miettinen M: Immunohistochemistry of soft tissue tumors. Possibilities and limitations in surgical pathology. Ann Pathol. 1990;5:1-36. 30. Ladanyi M: The emerging molecular genetics of sarcoma translocations. Diagn Mol Pathol. 1995;4:162-173. 31. Bastian BC, Olshen AB, LeBoit PE, Pinkel D: Classifying melanocytic tumors based on DNA copy number changes. Am J Pathol. 2003;163(5):1765-1770.

APPENDIX 3 Molecular Biologic Techniques for the Diagnosis of Cutaneous Lymphomas Gary S. Wood

ANTIGEN RECEPTOR GENES Immunoglobulin (Ig) molecules are the antigen-specific receptor of B cells.1,2 Each Ig molecule is a protein heterodimer consisting of two heavy chains and two light chains linked by disulfide bridges. Each B cell and its clonal progeny express Ig molecules containing only one of two possible types of Ig light chains (κ or λ). This is known as Ig light chain restriction. Tcell receptors (TCRs) are glycoproteins composed of two possible combinations of heterodimers usually linked by disulfide bridges in association with the CD3 complex.1,2 Four different protein chains of the human TCR are involved in antigen binding: α, β, γ, and δ. The TCR is expressed on the cell surface of lymphocytes as an αβ or γδ heterodimer and is responsible for antigen recognition. Each Ig and TCR protein chain consists of three to four distinct regions encoded by gene segments called variable (V), diversity (D), joining (J), and constant (C). Whereas V, J, and C segments are found in each gene, D segments are only present in the TCR β and δ genes. The V, D, and J genes are involved in forming the variable region of the Ig and TCR proteins. This region includes the antigen-recognition site. The C region is responsible for other functions such as signal transduction, oligomerization, secretion, passage across physiologic barriers, and interaction with other immune molecules such as complement and Fc receptors.

chain genes are rearranged. Because κ rearrangements are successful more often than not, there is usually a 2:1 ratio of B cells expressing κ versus λ light chains. As with T cells, if a B cell fails to rearrange its Ig genes successfully, then it is deleted via apoptosis. As B cells mature, they progress through a series of phenotypic and genetic alterations involving Ig genes.2 When a naive B cell migrates to the lymph node from the marrow, it is IgM+ IgD+ and has functional IgH gene rearrangements; however, the VH region within the rearranged Ig gene retains its germline sequence and has not yet undergone any of the VH somatic point mutations involved in the antigen selection phase of B-cell differentiation that results in a better fit between antibody and antigen. After the naive B cell is exposed to its corresponding antigen, it enters the germinal center, where it loses IgD expression and undergoes successive rounds of VH somatic point mutation and proliferation. After this process is completed, the B cell enters the post–germinal center memory B-cell phase in which it has stable VH point mutations and is either IgM+ or has switched to another Ig heavy chain isotype. These phenotypic and genetic alterations will allow us to determine the differentiation (or point of maturational arrest) exhibited by B-cell lymphoma tumor clones. In addition, the distribution of point mutations within antigen-relevant (eg, complementarily determining) versus antigen-irrelevant (eg, framework) regions of the VH gene allows us to determine the degree to which these B-cell clones have been antigen selected.

SOUTHERN BLOT ANALYSIS In this and the following sections, the most common molecular biologic assays for assessing B- and T-cell clonality are described. Key features of these assays are summarized in Table A3-1. Southern blot analysis is an assay that detects rearrangement of Ig and TCR genes from their germline configuration.2,3 As generally performed, however, it offers no information about clone-specific nucleotide sequence or the particular V, D, J, and C segments involved in the rearrangement. The sensitivity limit of this method is about 5% (ie, the percentage of clonal DNA in the DNA sample has to be at least 5%). In nonlymphatic tissues such as skin, in which a considerable amount of DNA is

APPENDEX 3 ■ MOLECULAR BIOLOGIC TECHNIQUES FOR THE DIAGNOSIS OF CUTANEOUS LYMPHOMAS

This section focuses on the principal molecular biologic methods that have been developed to study cutaneous lymphoid infiltrates. It is presented as a review divided into six parts: antigen receptor genes, Southern blot analysis, gene amplification techniques, major findings, clinical applications, and conclusions.

During maturation of T cells and B cells from hematopoietic progenitor cells into functionally active lymphocytes, antigen receptor genes are assembled from one segment each of the V, D, J, and C gene sets through a series of DNA recombination events collectively referred to as gene rearrangement, followed by postranscriptional splicing and translation. The VDJ joining is mediated by specific enzymes collectively referred to as recombinases and is orchestrated by recombinase activation gene-1 (RAG-1) and RAG-2. These two genes are coexpressed at substantial levels only in primary lymphoid tissue and in cell lines that resemble precursor lymphocytes. The result is the creation of one intact continuous V, (D) J coding sequence at an antigen receptor gene locus. This is subsequently joined to a C-region coding segment by posttranscriptional splicing of mRNA. The diversity of Igs and TCRs is due to the many possible combinations among the different gene segments. In addition, the rearrangement itself creates diversity by small deletions or insertions of nucleotides at the V–D, D–J, and V–J junctions. The random nucleotide insertions are known as N regions. Consequently, the amino acid sequences at the junctions of V, D, and J segments demonstrate extreme hypervariability. During thymic development, T-lymphocytes are generated by several molecular events and by positive and negative selection. The present model of thymic T-cell development suggests that hematopoietic stem cells enter the thymus though the cortex with their TCR genes in the germline (unrearranged) configuration. In addition to the acquisition of T-cell differentiation antigens on their surface, many T-lymphocytes undergo rearrangement of the TCR β and δ chain genes. Some of these T cells then express the TCR γδ protein heterodimer throughout their lives. Others undergo subsequent rearrangement of their TCR α and β genes and replace their TCR γδ heterodimer with a TCR αβ heterodimer. TCR δ gene rearrangements are frequently deleted during TCR α gene rearrangement because the δ gene is embedded within the α gene. Although its expression is suppressed, the rearranged TCR γ chain remains intact within the genome. During their development, B cells also undergo a hierarchy of antigen receptor gene rearrangements. The heavy chain (IgH) genes are rearranged first. If a productive rearrangement occurs, then the κ light chain genes are rearranged. If these genes are abortive, then the λ light

1033

APPENDEX 3 ■ MOLECULAR BIOLOGIC TECHNIQUES FOR THE DIAGNOSIS OF CUTANEOUS LYMPHOMAS

Table A3-1 Molecular Biologic Techniques for the Detection of Cutaneous T-Cell Lymphoma

1034

METHOD

SENSITIVITY

TIME

COMMENTS

Southern blot analysis

10−2

1-2 weeks

Non–tumor-specific PCR clonality assays

10−3 -10−4

A few days

Tumor-specific PCR clonality assays

10−5 -10−6

Initially, one to several weeks to obtain tumor-specific oligonucleotides; thereafter, a few days to analyze new specimens

Not optimal for small specimens or sparse CTCL infiltrates Reasonable compromise among sensitivity, specificity, simplicity, and rapidity of assays Requires diagnostic index specimen from which tumor-specific primers or probes are made; best suited for detailed case studies

contributed by various cell types, this limitation can be particularly problematic. Figure A3-1 summarizes the most important steps involved in this procedure, and Figure A3-2 illustrates representative results. Key factors in Southern blot analysis include restriction enzymes, hybridization probes, and the stringency of hybridization and wash conditions. Restriction enzymes are bacteria-derived endonucleases that cleave double-stranded DNA at or near a specific nucleotide sequence recognized by that enzyme.

At present, more than 100 different restriction enzymes are available. The incubation of genomic DNA with one of these enzymes results in DNA restriction fragments of many lengths. These fragments are

TISSUE

DNA EXTRACTION

DIGESTION

ELECTROPHORESIS (AGAROSE GEL)

TRANSFER TO NYLON MEMBRANE

HYBRIDIZATION WITH LABELED PROBE

AUTORADIOGRAPHY

 FIGURE A3-1 Southern blot analysis. The major steps involved in Southern blot analysis of T-cell receptor and Ig gene rearrangements in genomic DNA extracted from lesional tissues are summarized.

 FIGURE A3-2 Detection of clonal T-cell receptor β gene rearrangements by Southern blot analysis. Shown is an autoradiogram of genomic DNA digested with BglII restriction endonuclease and probed with a radiolabeled Jβ1/Jβ2 DNA probe. Germline bands are marked with dashes, and clonally rearranged bands are marked with an arrow. BL = blank lane; NC = negative control; MF = mycosis fungoides; LCL = CD30+ large cell lymphoma from the same patient showing an identical clonal band. This was confirmed by nucleotide sequencing.

separated according to their lengths using agarose gel electrophoresis. Separated DNA fragments are transferred by vacuum or capillary action onto a nylon membrane. The membrane is incubated with a DNA fragment (probe) that is known to hybridize with (be complementary to) the sequence of interest. Radiolabeled IgH and TCR β probes are the ones used most commonly to investigate the clonality of Ig and TCR gene rearrangements in lymphoproliferative disorders. Autoradiography is used to detect the band(s) where the radiolabeled probe has hybridized and to compare these bands with known germline and positive control bands. The number of bands varies depending on the restriction enzyme used. The positions of these bands reflect the difference in size of the rearranged DNA fragment(s) compared with the fragment(s) characteristically produced from DNA in the unrearranged or germline configuration of the relevant gene. There is no combination of a single restriction enzyme with a single probe that detects all corresponding gene rearrangements. Thus, more than one restriction enzyme digest is usually studied by Southern blot analysis (Table A3-2).

POLYMERASE CHAIN REACTION–BASED ASSAYS Polymerase chain reaction (PCR) is a procedure in which small regions of DNA can be amplified geometrically in vitro by means of a thermostable DNA polymerase purified from the bacterium Thermophilus aquaticus (so-called Taq polymerase).1-4 Short fragments of singlestranded DNA known as oligonucleotide primers are used in repeated cycles of heating and cooling. This allows denaturation of the double-stranded

Table A3-2 Cutaneous Lymphoproliferative Disorders: T-Cell and B-Cell Clonality as Determined by Southern Blot Analysis DISORDER

DOMINANT CLONALITY a

Mycosis fungoides/Sézary syndrome Other cutaneous lymphomas Regressing atypical histocytosis Granulomatous slack skin Lymphomatoid papulosis Pityriasis lichenoides and varioliformis acuta Angioimmunoblastic lymphadenopathy Malignant histiocytosis Cutaneous B-cell lymphomas Cutaneous lymphoid hyperplasia

T cellb T cell T cell T cell T cell > none T cell T cell > none T cell > B cell B cell None > B cell > T cell

Usually dominant clonality is monoclonal, but in some cases may be biclonal or oligoclonal. b Some early patch and thin-plaque lesions lack dominant clonality, by Southern blot analysis due to the limited sensitivity of this assay.

template DNA into single-stranded DNA, annealing of the primers to complementary sequences on the single-stranded template DNA, and synthesis of new copies of the template DNA by primer extension.

TCR-Based PCR Clonality Assays As a result of genetic events occurring during their thymic development, many T-lymphocytes expressing the αβ heterodimer also contain clonal TCR γ rearrangements.4,5 Therefore, molecular approaches for the analysis of clonality may focus on either TCR β or TCR γ rearrangements. In the TCR β gene, only the V and C genes contain consensus sequences that are highly conserved and thus the most suitable as templates for PCR consensus primers capable of detecting the vast majority of TCR β gene rearrangements. Because these V and C regions are separated by large introns within the rearranged gene, genomic DNA cannot be used for PCR amplification of the TCR β rearrangement. Instead, the target sequence must be transcribed from TCR β mRNA into TCR β cDNA. These extra steps are a relative disadvantage of methods involving TCR β amplification because handling RNA is much more complicated than handling DNA owing to its fast degradation by ubiquitous RNase. Attempts to circumvent this problem by using Vβ and Jβ consensus primers have been less than fully successful because of the sequence diversity of these regions. In contrast, conserved regions

in the Vγ and Jγ gene segments are close together (400-700 base pairs) in the rearranged TCR γ gene. This allows the use of genomic DNA for PCR amplification of TCR γ gene rearrangements. Furthermore, the relatively high degree of homology among various Vγ segments and among Jγ segments means that only a small number of different consensus primers are required to amplify most TCR γ gene rearrangements. Therefore, several PCR-based T-cell clonality assays focus on the rearranged TCR γ gene. After amplification using Vγ and Jγ primers, the TCR 1γ PCR products must be screened for dominant clonal TCR gene rearrangements. Several methods have been used to accomplish this.2-4 Fig. A3-3 shows the key steps of TCR γ PCR in combination with denaturing gradient gel electrophoresis (DGGE). Representative results are illustrated in Fig. A3-4. DGGE involves the electrophoresis of PCR products in a polyacrylamide gel that contains an increasing gradient of chemical denaturants, specifically formamide and urea. This type of electrophoresis separates the PCR products according to their nucleotide sequence as well as their size. The gradient in the gel causes local denaturation of domains within doublestranded DNA fragments, and the resulting formation of melted single-stranded DNA domains at various points along the gradient in the gel. This alteration reduces the mobility of the DNA fragment in the gel, causing all fragments of identical sequence to accumulate at the

DNA EXTRACTION

PCR AMPLIFICATION

DENATURING GRADIENT GEL ELECTROPHORESIS

ETHIDIUM BROMIDE STAINING

 FIGURE A3-3 Polymerase chain reaction/denaturing gradient gel electrophoresis. The major steps involved in the amplification and separation of T-cell receptor γ gene rearrangements in genomic DNA extracted from lesional tissues are summarized.

same position in the gel. Whereas polyclonal PCR products appear as a diffuse smear, bands are seen in the case of a dominant clone, constituting at least 0.1% to 1.0% of the total specimen DNA. The sensitivity threshold depends on the background content of polyclonal T cells in the specimen. Temperature gradient gel electrophoresis (TGGE) is similar in principle to DGGE except that a gradient of temperature rather than chemical denaturants provides the conditions for the sequence-dependent melting of PCR products. There are many additional methods for separating and analyzing TCR γ PCR products, including single-stranded DNA conformational polymorphism analysis (SSCP) and capillary gel electrophoresis. In addition to these TCR γ gene–based methods, non–tumor-specific PCR assays have been developed for the detection of clonal TCR β rearrangements. One of these methods involves reverse transcription of TCR β mRNA into cDNA followed by multiple separate PCRs, each specific for TCR β gene rearrangements involving one or two of the 24 known Vβ families. PCR products are then electrophoresed in a special agarose gel. The presence of a sharp band indicates a dominant clonal TCR β gene rearrangement. The sensitivity of this method ranges from 0.01% to 10% of the total cDNA depending on whether the clone is diluted by nonlymphoid or polyclonal T-cell cDNA, respectively.

APPENDEX 3 ■ MOLECULAR BIOLOGIC TECHNIQUES FOR THE DIAGNOSIS OF CUTANEOUS LYMPHOMAS

a

TISSUE

1035

requires neither analysis of nucleotide sequences nor synthesis of tumor-clonespecific DNA primers or probes. It involves analysis of TCR γ gene rearrangements and has a sensitivity of 0.001% or 1 in 105 cells. 6,7

APPENDEX 3 ■ MOLECULAR BIOLOGIC TECHNIQUES FOR THE DIAGNOSIS OF CUTANEOUS LYMPHOMAS

PCR Assays Other Than Clonality

1036

In addition to their use for detecting dominant clonality, genomic Southern blot and PCR assays can be used to study other tumor cell characteristics such as whether they contain the t(14;18) translocation (common among follicular B-cell lymphomas), the t(2;5) translocation (common among lymph node-based CD30+ anaplastic large cell lymphomas), or HTLV-1 retrovirus (a defining feature of adult T-cell leukemia/lymphoma).3

MOLECULAR BIOLOGIC FINDINGS

 FIGURE A3-4 Polymerase chain reaction (PCR)/denaturing gradient gel electrophoresis (DGGE). Detection of clonal Tcell receptor (TCR) γ gene rearrangements by PCR combined with DGGE. Shown is a photograph of an ethidium bromide–stained gel after DGGE of TCR γ PCR products that were amplified using consensus primers for Vγ 1-8 and Jγ 1-2. CO = carryover negative control; PC = positive control; LCL = CD30+ large cell lymphoma; LYP = lymphomatoid papulosis from the same patient showing a matching clonal band (upper arrow) indicating an identical nucleotide sequence. The lower arrow shows the position of the clonal band in the PC lane.

Ig-Based PCR Clonality Assays

Tumor-Specific PCR Clonality Assays

PCR assays involving IgH gene rearrangements have been used to assess the clonality of B-cell lymphoproliferative disorders.5 Strategies range from a single VH/JH consensus primer set to nested consensus primers to a single consensus JH primer combined with a set of VH consensus primers, each specific for a different VH family or subfamily (VH 1, 2, 3, 4a, 4b, 5, and 6). PCR products are then electrophoresed through gels designed to produce a discrete band when a dominant clonal IgH rearrangement is present and diffuse smears when it is not. As with TCR-based PCR assays, these Ig-based PCR methods are more sensitive than genomic Southern blot analysis of Ig gene rearrangements.

These techniques depend on the strategy of isolating and sequencing the monoclonal antigen receptor gene rearrangement from a diagnostic specimen and then using this tumor-specific dominant sequence to generate tumor-specific probes or PCR primers.3 These tools can be applied to detect tumor involvement in additional nondiagnostic tissue samples from the same patient; however, they are not useful for studying other patients because they are specific for only one unique tumor clone. These tumor-specific assays use several different technical approaches that target various antigen receptor genes. The PCR-RNase protection assay (PCR-RPA) has the advantage that although it is clone specific, it

Molecular biologic studies combined with immunophenotypic analyses have significantly advanced our understanding of cutaneous lymphoproliferative disorders in recent years. Cutaneous T-cell lymphoma (CTCL) has been shown to be a neoplasm of mature CD4+ memory T cells belonging to the skin-associated lymphoid tissue (SALT), which includes lymphocytes and antigenpresenting cells that traffic between the skin and peripheral lymph nodes.3,4,6,7 Using PCR-based methods, the monoclonality of many cases of early CTCL as well as advanced CTCL has been established. In fact, PCR techniques have allowed the recognition that some cases of chronic nonspecific dermatitis harbor occult dominant T-cell clones. These cases are referred to as clonal dermatitis.4 Some of these patients have progressed to overt CTCL, indicating that at least some cases of clonal dermatitis represent a precursor to CTCL. Molecular staging studies have shown that small numbers of CTCL cells can be found throughout the body in samples of morphologically normal lymph node, marrow, and blood even in early-stage IA disease.7 This suggests that tumor cells can traffic throughout the SALT system at low levels and that CTCL is a neoplasm of a T-cell circuit rather than a particular tissue. Studies of diseases associated with CTCL, such as large cell lymphoma, lymphomatoid papulosis, and Hodgkin disease, have shown that these diseases share a common clonal origin when they arise in the same patient.8 Taken together, these findings allow us

CLINICAL APPLICATIONS

Diagnosis The detection of dominant clonal lymphoid populations has been used to confirm a suspected diagnosis of lymphoma in patients whose clinicopathologic features were suggestive but not diagnostic. The rationale for this approach is based on two observations. First, well-developed lymphoma lesions are clearly monoclonal tumors. Second, with noted exceptions, such as some lymphomatoid drug reactions and collagen vascular diseases,13,14 dominant lymphoid clones are not found in unequivocally inflammatory infiltrates or in normal tissues.2-4,12 For example, the molecular biologic demonstration of dominant T-cell clonality has been used to establish or confirm a diagnosis of CTCL in patients with patch-type MF, large-plaque parapsoriasis, idiopathic erythroderma, and follicular mucinosis. In some instances, Southern blot analysis has been sufficient, but in other cases, PCR-based techniques have been required to detect the dominant T-cell clone. This has been especially true for very small specimens or for those in which the neoplastic

T-cell clone was diluted excessively by normal cell constituents, reactive T cells, or a combination of both cell types. The diagnostic sensitivity of PCR analysis has been enhanced even further by applying it to tissue samples enriched for tumor cells by laser-capture microscopy or other forms of microdissection.16,17 Although it is generally true that TCR gene rearrangements are indicative of T-cell lymphomas and Ig gene rearrangements are indicative of B-cell lymphomas, some lymphomas may exhibit both. 1-3,12 Therefore, it is helpful to supplement gene rearrangement studies with immunophenotypic data to achieve the clearest possible interpretation of lineage and clonality during immunodiagnostic workup of an unknown case. In addition, it is important to emphasize that the demonstration of a monoclonal lymphoid population per se cannot be equated with the diagnosis of lymphoma. Clinicopathologic correlation is essential. Several clinically benign lymphoproliferative disorders are known to contain dominant T- or B-cell clones in a variable proportion of cases. These include lymphomatoid papulosis, pityriasis lichenoides, atypical pigmentary purpura, indeterminate lymphocytic lobular panniculitis, parapsoriasis en plaques, and cutaneous lymphoid hyperplasia.2,12-14

Staging Because molecular biologic analysis of Ig and TCR gene rearrangements is significantly more sensitive than light microscopy for the detection of tumor cells, molecular biologic methods have increased the sensitivity of lymphoma staging. For example, among lymph nodes not diagnostic for CTCL by light microscopy, some were positive for CTCL by Southern blot analysis. 4,18 Southern blot analysis also has proven superior to light microscopy in detecting involvement of the peripheral blood in CTCL. 4,18 PCR-based techniques have further enhanced this sensitivity and have detected sites of involvement missed by Southern blot analysis. PCR techniques have detected CTCL involvement in microscopically uninvolved extracutaneous tissues and even in clinically normal-appearing skin containing only very sparse nonspecific lymphoid infiltrates histopathologically.7,15,19 The impressive sensitivity of molecular biologic analysis for detecting dominant Ig and TCR gene rearrangements (~10−2 for Southern blot analysis and 10−3-10−6 for various PCR techniques) raises important questions regarding

clinical relevance. For example, although we know that histopathologically detectable lymph node involvement is a poor prognostic sign in CTCL, the clinical relevance of histopathologically occult involvement detected solely by molecular biologic means remains to be determined fully.15,18 A key factor concerning assessment of blood involvement in CTCL is the recognition of apparently benign circulating T-cell clones in some elderly people.20 This phenomenon makes it essential to determine whether a circulating T-cell clone in the blood of a CTCL patient matches the one present in lesional skin before drawing any conclusions about blood involvement.18

Disease Monitoring In addition to their use in the initial diagnosis and staging of cutaneous lymphoma patients, molecular biologic techniques also have been used to monitor the response of the disease to treatment. For example, it has been shown that the skin can serve as a reservoir of clinically occult residual disease in CTCL.15

CONCLUSIONS It is apparent that in addition to their value for the early diagnosis and staging of cutaneous lymphomas, molecular biologic assays are proving valuable for monitoring the response to therapy, detecting early relapse, and enhancing our understanding of the compartmentalization and trafficking of tumor cells. To reap the full clinical benefit from this new information, however, it will be important to perform prospective longterm studies designed to determine the clinical significance of molecular biologic data. In addition, the complexity of cutaneous lymphoproliferative disorders dictates that molecular biologic clonality data should never be interpreted in a vacuum. In skin disease, dominant clonality does not always imply clinical malignancy. The proper diagnosis of CTCL and other cutaneous lymphoproliferative diseases requires the thoughtful integration of molecular biologic data with clinicopathologic and immunophenotypic findings.

APPENDEX 3 ■ MOLECULAR BIOLOGIC TECHNIQUES FOR THE DIAGNOSIS OF CUTANEOUS LYMPHOMAS

to conceptualize CTCL and associated diseases as an array of lymphoproliferative disorders sharing a common clonal ancestry beginning with a single mature SALT T cell that undergoes one or more genetic alterations during the clonal dermatitis phase and its later progression to early CTCL, followed by additional somatic mutations responsible for creating subclones of the original tumor that manifest themselves clinically as advanced-stage CTCL and other CTCLassociated diseases. The early stages of this process (clonal dermatitis and early CTCL) may involve additional clones from which the dominant one emerges. Similarly, CBCL has been shown to be a monoclonal B-cell neoplasm of the skin that in some cases is preceded by cutaneous lymphoid hyperplasia (CLH), a clinicopathologically benign lymphoid infiltrate usually containing immunophenotypically polyclonal B cells.9-12 Molecular biologic studies have shown that up to one-third of CLH cases harbor occult dominant B-cell clones and that some may progress to overt CBCL containing the same dominant clone.12 In aggregate, these studies suggest that CLH, clonal CLH, and CBCL exist as clinicopathologically defined points along a continuum of cutaneous B-cell lymphoproliferative disease.

REFERENCES 1. Tamaru J, Hummel M, Marafioti T, et al: Burkitt’s lymphomas express VH genes with a moderate number of antigen-selected somatic mutations. Am J Pathol. 1995;147:1398-1407.

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2. Wood GS: The benign and malignant cutaneous lymphoproliferative disorders including mycosis fungoides, in Knowles DM (ed). Neoplastic Hematopathology, 2d ed. Baltimore: Williams & Wilkins; 2001: 1183-1233. 3. Wood GS: Cutaneous lymphoproliferative disorders: strategies for molecular biological analysis and their major findings. Springer Semin Immunopathol. 1992; 13:387-399. 4. Wood GS, Tung RM, Haeffner AC, et al: Detection of clonal T-cell receptor _gene rearrangements in early mycosis fungoides/Sézary syndrome by polymerase chain reaction and denaturing gradient gel electrophoresis (PCR/DGGE). J Invest Dermatol. 1994;103:34-41. 5. Ramasamy I, Brisco M, Morley A: Improved PCR method for detecting monoclonal immunoglobulin heavy chain rearrangement in B cell neoplasms. J Clin Pathol. 1992;45:770-775. 6. Veelken H, Sklar JL, Wood GS: Detection of low-level tumor cell trafficking to allergic contact dermatitis induced by mechlorethamine in patients with mycosis fungoides. J Invest Dermatol. 1996;106: _685-688. 7. Veelken H, Wood GS, Sklar J: Molecular staging of cutaneous T cell lymphoma: evidence for systemic involvement in early disease. J Invest Dermatol. 1995;104: 889-894. 8. Wood GS, Crooks CF, Uluer AZ: Lymphomatoid papulosis and associated cutaneous lymphoproliferative disorders

9.

10.

11.

12.

13.

14.

15.

exhibit a common clonal origin. J Invest Dermatol. 1995;105:51-55. Wood GS, Ngan B-Y, Tung R, et al: Clonal rearrangements of immunoglobulin genes and progression to B-cell lymphoma in cutaneous lymphoid hyperplasia. Am J Pathol. 1989;135:13-19. Rijlaarsdam U, Bakels V, van Oostveen JW, et al: Demonstration of clonal immunoglobulin gene rearrangements in cutaneous B-cell lymphomas and pseudoB-cell lymphomas: differential diagnostic and pathogenetic aspects. J Invest Dermatol. 1992;99:749-754. Hammer E, Sangueza O, Suwanjindar P, et al: Immunophenotypic and genotypic analysis in cutaneous lymphoid hyperplasia. J Am Acad Dermatol. 1993; 28:426-433. Nihal M, Mikkola D, Horvath N, et al: Cutaneous lymphoid hyperplasia: a lymphoproliferative continuum with lymphomatous potential. Hum Pathol. 2003; 34:617-622. Magro CM, Nuovo GJ, Crowson AN: The utility of the in-situ detection of T-cell receptor beta rearrangements in cutaneous T-cell infiltrates. Diagn Mol Pathol. 2003;12: 133-141. Plaza JA, Morrison C, Magro CM: Assessment of TCR-beta clonality in a diverse group of cutaneous T-cell infiltrates. J Cutan Pathol. 2008;35(4):358-365. Lessin SR, Benoit BM, Jaworsky C, et al: Skin as a reservoir of minimal residual disease in cutaneous T cell lymphoma after complete clinical response to

16.

17.

18.

19.

20.

biological response modifier therapy. J Invest Dermatol. 1993;100:507. Ke M, Kamath NV, Nihal M, et al: Folliculotropic mycosis fungoides with central nervous system involvement: documentation of tumor clonality in intrafollicular T cells using laser capture microdissection. J Am Acad Dermatol. 2003;48: 238-243. Gellrich S, Lukowsky A, Schilling T, et al: Microanatomical compartments of clonal and reactive T cells in mycosis fungoides: molecular demonstration by single cell polymerase chain reaction of T cell receptor gene rearrangements. J Invest Dermatol. 2000;115:620-624. Olsen E, Vonderheid E, Pimpinelli N, et al: Revisions to the staging and classification of mycosis fungoides and Sezary syndrome: a proposal of the International Society for Cutaneous Lymphomas (ISCL) and the cutaneous lymphoma task force of the European Organization of Research and Treatment of Cancer (EORTC). Blood. 2007;110: 1713-1722. Volkenandt M, Soyer HP, Kerl H, et al: Development of a highly specific and sensitive molecular probe for detection of cutaneous lymphoma. J Invest Dermatol. 1991;97:137. Posnett DN, Sinha R, Kabak S, Russo C: Clonal populations of T cells in normal elderly humans: the T cell equivalent of “benign monoclonal gammopathy.” J Exp Med. 1994;179:609-618.

INDEX

Acanthosis nigricans, 320–321, 557–558 clinical features, 321, 557 differential diagnosis, 321, 557–558 histopathological features, 321, 557 Acanthotic seborrheic keratosis, 565 Accessory auricle, 408 Accessory digit. See Supernumerary digit Accessory mammary tissue ossification, 408t Accessory nipple, 409–410 clinical features, 409 differential diagnosis, 410 histopathological features, 409–410 Accessory tragus, 408–409 clinical features, 408 differential diagnosis, 409 histopathological features, 408–409 ACD, VH and, 838 AGEP. See Acute generalized exanthematous pustulosis Acid-fast bacillus (AFB), 421 Ackerman tumor, 596 Acne, 12 variants, 236 clinical features, 236 histopathological features, 236–237 Acne keloidalis, 230–231, 238f clinical features, 230 histopathological features, 230–231 Acne rosacea clinical features, 99 differential diagnosis, 99 histopathological features, 99 Acne vermiculata, 233 Acne vulgaris, 241t Acneiform folliculitis, 236 Acoustic neuroma. See Schwannoma Acquired dermal melanocytosis, 642 clinical features, 642 Acquired ichthyosis, 315 clinical features, 315 differential diagnosis, 315 histopathological features, 315 Acquired immunodeficiency syndrome (AIDS), 104. See also HIV BA and, 817 KS and, 810, 820, 831 Acquired lymphangiectases, 850

Acquired melanocytic nevi, 616, 662–663 clinical features, 618 common, 617–618, 618t histopathological features, 618 variants of, 619–627 Acquired perforating dermatosis, 333, 333t, 334f clinical features, 333 histopathological features, 333–334 Acquired progressive lymphangioma (APL), 843–844, 843f, 843t CAT and, 811 lymphangioma simplex and, 842 MLT and, 811 THH and, 810, 811 Acquired tufted angioma. See Tufted angioma Acral arteriovenous malformation (aAVM), 845–846, 845t, 846f Acral arteriovenous tumor. See Acral arteriovenous malformation; Arteriovenous malformations Acral fibrokeratoma, 768–769 clinical features, 768 differential diagnosis, 769 histopathologic features, 768 Acral melanoma, 657, 659, 662t, 664 Acral skin lentiginous intraepithelial component, 661–662 lentiginous melanoma of, 665f Acral skin melanocytic nevi, 623–624 clinical features, 623 compound, 624f differential diagnosis, 623–624 histopathological features, 623 Acremonium, 479, 487 histopathological features, 487 Acroangiodermatitis (AAD), 818–819, 818t, 819f. See also Stasis dermatitis clinical features, 818 differential diagnosis, 819 histopathological features, 818–819 KS and, 823 Acrochordon, 766–767 clinical features, 766 differential diagnosis, 787 histopathological features, 766–767

INDEX

A AAD. See Acroangiodermatitis aAVM. See Acral arteriovenous malformation ABCA12, 316 Abrikosoff tumor, 894–895 Acanthamebiasis, 502, 524–525 differential diagnosis, 524–525 Acanthamoeba, 267 Acanthamoeba astronyxis, 524 Acanthamoeba castellani, 524 Acanthamoeba culbertsoni, 524 Acanthamoeba lenticulata, 524 Acanthamoeba palestinensis, 524 Acanthamoeba polyphaga, 524 Acanthamoeba rhysodes, 524 Acantholysis, 137 spinous layer vesiculation due to, 327–332 Acantholytic acanthoma, 564 clinical features, 564 differential diagnosis, 564 histopathological features, 564 Acantholytic dermatitis, 138–150 Darier disease, 147–148, 148f differential diagnosis, 140t drug-induced pemphigus, 144–145 fogo selvagem, 143 generalized staphylococcal scalded skin syndrome, 147 Haley-Haley disease, 148–149 IgA pemphigus, 145 paraneoplastic pemphigus, 145–147 pemphigus erythematosus, 143–144 pemphigus foliaceus, 143 pemphigus vulgaris, 138–143 transient acantholytic dermatosis, 149–150 Acantholytic squamous cell carcinoma, 593–594, 595, 1018 Acanthomas, 562–569 acantholytic, 564 clear cell, 78, 568–569 epidermolytic, 562–563 large cell, 569 pilar sheath, 697–698 Acanthosis, 5f, 837 epidermal, 27f

1039

INDEX 1040

Acrodermatitis chronica atrophicans, 55, 396–307 clinical features, 396–397 histopathological features, 397 Acrodermatitis enteropathica, 77 clinical features, 77 histopathological features, 77 Acrogeria, 400 histopathological features, 400 Acrokeratoelastoidosis, 404–405 of Costa, 320 Acrokeratosis neoplastica, 76 clinical features, 76 histopathological features, 76 Acromelanosis, 347 Acropigmentation symmetrica, 347 Acrospiroma eccrine, 731–733, 733f, 737 malignant, 739–740 Acrosyringeal nevus, 730 Acrosyringeal-eccrine coil unit, 728 Acrosyringium, 588 ACTH. See Adrenocorticotropic hormone Actin, 582, 594, 973 myolipoma and, 862 Actinic amyloidosis, 376 Actinic cheilitis, 572–573 clinical features, 573 differential diagnosis, 573 histopathological features, 573 Actinic elastosis, 402 Actinic granuloma, 107, 404 clinical features, 107 differential diagnosis, 107 histopathological features, 107 Actinic keratosis, 570–572, 591 bowenoid, 572 epidermolytic, 571 histopathological features, 571 lichenoid, 571, 572f Actinic prurigo, 90, 306f Actinic prurigo cheilitis, 305 Actinic reticuloid, 306 Actinomyces, 430, 478 Actinomycetoma, 480t Actinomycosis, 459t, 481–482, 481t, 482f clinical features, 481 differential diagnosis, 482 histopathological features, 481–482 Active viral infections, 495 Acute febrile neutrophilic dermatosis, 188–190 clinical features, 188–190 Acute generalized exanthematous pustulosis (AGEP), 287 Acute graft-versus-host disease, 44–46 clinical features of, 44–45 cutaneous, 45t differential diagnosis, 46 histopathological features, 45–46 host reaction, 46t Acute infantile hemorrhagic edema (AHE), 184 Acute lobular panniculitis, 262f Acute monocytic leukemia, 943f, 944f, 945f Acute myelogenous leukemia, MVH and, 809

Acute myeloid leukemia, 941–942 clinical features, 941 histochemical findings, 943 histopathologic features, 941–942 immunohistochemical findings, 943 skin infiltrates of, 942t Acute promyelotic leukemia (APL), 941 Acute systemic lupus erythematosus, 49–51 differential diagnosis, 51 Adalimumab, 297 Adamantinoid basal cell carcinoma, 581 Addison disease, 346, 474 differential diagnosis, 346 histopathological features, 346 Adenocarcinoma. See also specific types ductal eccrine, 745, 746–747 metastatic, 966f papillary digital eccrine, 741–743, 742f, 743f primary signet ring cell, 752–753 pulmonary, 966 Adenoid basal cell carcinoma, 580, 588, 741 Adenoid cystic carcinoma, 741, 742f clinical features, 741 differential diagnosis, 741 histopathologic features, 741 Adenoidal seborrheic keratosis, 565 Adenoma aggressive papillary digital, 742 infundibular, 692 mixed-lineage adnexal, 737 nevus sebaceous, 690 papillary eccrine, 731, 732f papillary tubular, 731 sebaceous, 690–691, 691f sebocrine, 692 syringomatous, of nipple, 745 tubular apocrine, 731, 735, 737f Adenoma sebaceum. See Facial angiofibroma Adenosquamous carcinoma, 598, 744 clinical features, 598 differential diagnosis, 598 histopathological features, 598 primary cutaneous, 745 Adipocytes, 862 Adipose tissue, 857–868, 857t hypertrophy of, 858 Adjacent intraepithelial component, 662, 663t melanoma with, 662 Admixed adipose tissue, 890 Adnexal adenomas, mixed-lineage, 737 Adnexal carcinoma. See also Microcystic adnexal carcinoma with mixed differentiation, 717–718, 754–755, 755f Adnexal epithelium, 595 Spitz nevus, 635 Adnexal tumors, 689 Adrenal cortical carcinoma, pleomorphic liposarcoma and, 868 Adrenocorticotropic hormone (ACTH), 346 Adult nematodes, 530–531 Adult progeria, 399 Adult rhabdomyoma, 873–874, 873f, 873t adult rhabdomyoma and, 873

Adult T-cell lymphoma/leukemia (ATLL), 915, 952 clinical features, 915, 952 definition, 915 differential diagnosis, 915, 952 genotypic features, 915 histopathological features, 915, 952 immunohistochemical findings, 952 immunophenotypic features, 915 molecular biology, 952 Adult trematodes, 531, 532 AE13, 716 AE14, 716 AFB. See Acid-fast bacillus AFH. See Angiomatoid fibrous histiocytoma Afipia felis, 440 African histoplasmosis, 474 clinical features, 474 histopathological features, 474 AFXs. See Atypical fibroxanthomas Aggregations, 909 Aggressive papillary digital adenomas, 742 AHE. See Acute infantile hemorrhagic edema AIDS. See Acquired immunodeficiency syndrome Ainhum, 396 AITL. See Angioimmunoblastic T-cell lymphoma Albinism, 343t oculocutaneous, 341–342 Albright hereditary osteodystrophy, 383 histopathological features, 384 Alcoholic cirrhosis, unilateral nevoid telangiectasia and, 835 Algal infections, 517–527 ALK1, HHT and, 834 Alkaptonuria, 384–385 histopathological features, 384–385 Allergic contact dermatitis, 17, 27f clinical features of, 17 histopathological features of, 17 Alopecia, 13 algorithm for, 214f androgenetic, 215–216, 218f, 219f clinical features, 215 female, 218f histopathological features, 215–216 male, 219f areata, 218–219, 222f, 223t, 224f, 967 clinical features, 218 differential diagnosis, 219 histopathological features, 218 central centrifugal scarring, 227–229 common causes, 215t difficulty to classify, 232–233 diffuse, 216–217, 219t, 220t, 221f, 222f causes of, 219t differential diagnosis, 217 drugs causing, 220t histopathological features, 217 drug-associated, 291 end-stage scarring, 235 histopathological features of, 214f lipedematous, 232 mucinosa, 229–230 clinical features, 229 differential diagnosis, 229–230 histopathological features, 229

Amyloidosis (Cont.): systemic, 371–374 secondary, 372–374 systemic amyloid A, 372–374 systemic amyloid light chain, 371–372, 373f tumoral, 378 Amyopathic dermatomyositis, 93 Anagen, 213 effluvium, 216, 222f hairs, 215t postfebrile, 216 postpartum, 216 short cycle, 216 Anaplasma, 454 Anaplastic cells, 910 Anaplastic syringoma, 743 Anatomic site, 4 ANCA. See Antineutrophil cytoplasmic antibodies ANCA-associated vasculitis, 184, 195–196 types, 196t Anchoring filaments, subepidermal blistering diseases, 156 Ancient schwannomas, 890, 891 Androgenetic alopecia, 215–216 clinical features, 215 female, 218f histopathological features, 215–216 male, 219f Anetoderma, 402 Aneuploidy, 578 Aneurysmal fibrous histiocytoma, 777f Angioblastoma. See Tufted angioma Angiodermatitis. See Acroangiodermatitis Angioedema, 83 Angioendothelioma. See Acquired progressive lymphangioma Angioendotheliomatosis, 817 Angiofibromas, 797 facial, 797 Angioimmunoblastic lymphadenopathy, 925f Angioimmunoblastic T-cell lymphoma (AITL), 924 Angiokeratoma, 836, 836t, 837f VH and, 838 Angiokeratoma of Mibelli, VH and, 838 Angioleiomyoma, 869–870, 870f, 870t Angioleiomyomas, 890 Angiolipoma, 858–859, 859f, 859t Angiolymphoid hyperplasia with eosinophilia. See Epithelioid hemangioma Angioma cherry, 849–850, 849f microcapillary, 808 Angioma serpiginosum, 835–836 VH and, 838 Angiomatoid fibrous histiocytoma (AFH), 777, 789–790, 789t, 790f clinical features, 790 differential diagnosis, 790 histopathologic features, 790 Angiomatoid Spitz nevus, 639 Angiomatosis of soft tissue (AST), 844, 844t, 845f CH and, 827 Angiomyolipoma, 862–863, 863f Angiomyoma, 869–870

Angiomyxoma, superficial, 795–796 Angiopathy, hyaline, 380 Angiosarcoma, 596, 829–831, 829t, 830f, 831f APL and, 844 capillary hemangioma and, 830 cavernous hemangioma and, 830 CD 31, 830 CD34 and, 830 D2-40 antibody, 830 epithelioid, 829, 831 foreign objects and, 829 intravascular disseminated, 817 KS and, 823, 831 laminin and, 830 LYVE and, 830 mastectomy and, 829 Milroy disease, 829 morbid obesity and, 829 PILA and, 826 radiation and, 829 RH and, 826 SCH and, 807, 830 spindle cell hemangioma and, 807, 830 TA and, 806 VEGFR and, 830 vimentin and, 830 von Willebrand factor and, 830 Angiotropic large cell lymphoma. See Angioendotheliomatosis Angiotropic melanoma, 669–670, 669f clinical, 670 Angiotropism, 669 Angiotumoral complex, 670 Animal poxviruses, 512 Anoplastic lymphoid cells, 906 Anorexia nervosa, 88 ANOTHER syndrome, 347 Anthrax, 433–435, 440f differential diagnosis, 435 histopathological features, 434 Antibody production, 495 Antibody-mediated reactions, 281 Anticytokeratin antibodies, 593 Anti-DNA antibodies, 92 Antigenic targets, in CP, 163t Antimalarials, 356 Antineutrophil cytoplasmic antibodies (ANCA), 12 Antiphospholipid syndrome, RAE and, 817 Antiretroviral therapy, PG and, 813 Anti-Ro antibodies, 284 Antistreptolysin O (ASO), 425 APL. See Acquired progressive lymphangioma; Acute promyelotic leukemia Aplasia cutis congenita, 395 clinical features, 395 histopathological features, 395 Apocrine adenoma, 696 Apocrine carcinoma ductal, 752, 753f ductopapillary, 749–750, 751f simulating metastasis, 752 Apocrine carcinomas, 749–750 primary, 749

INDEX

Alopecia (Cont.): neoplastica, 961 nonscarring, 13, 215–223 causes of, 221–223 clinical features, 221 differential diagnosis, 223 histopathological features, 222–223 differential diagnosis, 216 histopathological features, 217t, 222–223 scarring v., 215 pressure, 220–221, 226 primary scarring lymphocyte-associated, 225, 231t pustulofollicular, neutrophil-associated primary scarring, 230 scarring, 13, 215, 223–232, 238t central centrifugal, 227–229 end-stage, 235 nonscarring v., 215 primary, 224–225 lymphocyte-associated, 225, 231t pustulofollicular, neutrophil-associated primary, 230, 236t secondary, 224–225, 232, 238t syringolymphoid hyperplasia with, 911–912 traction, 220–221, 226, 227f, 228f Alpha-1 antitrypsin deficiency, 263, 263t clinical features, 263 histopathological features, 263 ALT. See Atypical lipomatous tumor Alternaria, 478 Alternariosis, 478 clinical features, 478 differential diagnosis, 478 histopathological features, 478 Aluminum chloride solution reaction, 124 clinical features, 124 Alveolar rhabdomyosarcomas (ARMs), 875, 875f Amalgam tattoo, 1015 clinical features, 1015 differential diagnosis, 1015 histopathologic features, 1015 AMART-1, 780 Amebiasis, 525–526 clinical features, 525 differential diagnosis, 525–526 histopathological features, 525 American Rheumatism Association, 68, 92t, 168 Amiodarone, 356 Amyloid deposition, 586 Amyloid elastosis, 372 Amyloid-hyaline-colloid deposition, 371t Amyloidosis, 191 actinic, 375 biphasic, 374–375 differential diagnosis, 375 histopathologic features, 374–375 epithelioma-associated keratin, 375–376 insulin, 376 lichen, 61, 375, 375f colloid milium, 374t nodular, 376–377, 377f secondary systemic, 372–374 skin-limited, 373t, 374–379

1041

INDEX 1042

Apocrine hidrocystomas, 756–757 clinical features, 756 differential diagnosis, 757 histopathological features, 756–757 Apocrine neoplasms, 733–735 Apocrine nevi, 755 Apocrine type Paget disease, differential diagnosis, 751–752 Apolipoprotein D, 777 Apophysomyces, 483 Apoptosis, 36, 587, 908 Arachnid reactions, 308 clinical features, 308 differential diagnosis, 308 Arachnidism, 308 Arao-Perkins bodies, 216 Architectural disorder, 630 compound nevus with, 653f, 654f junctional nevus with, 654f Argyria, 355 ARMs. See Alveolar rhabdomyosarcomas Arsenic, 355 histopathological features, 355 Arsenical keratosis, 573 clinical features, 573 differential diagnosis, 573 histopathological features, 573 Arterial spider, 832, 848–849, 849f Arteriovenous fistulas, RAE and, 817 Arteriovenous hemangioma, 834f Arteriovenous malformations (AVMs), 813, 844–847, 847f AAD and, 818, 819 Cobb syndrome, 833 HHT and, 834 Parkes Weber syndrome, 832–833 PWSs and, 832 VM and, 839 Arteriovenous shunt. See Arteriovenous malformations Arthritis, reactive clinical features, 68 differential diagnosis, 68 histopathological features, 68 Arthroderma, 458 Arthropod bite reactions, 167 Aschoff nodules, 109 Ascomycota, 458, 467 Ash leaf spots of tuberous sclerosis, 343 differential diagnosis, 343 histopathological features, 343 Ashkenazi Jews, KS and, 820 ASO. See Antistreptolysin O Aspergillosis, 459t, 486–487, 487f clinical features, 486 differential diagnosis, 486–487 histopathological features, 486 Aspergillus, 463, 484 AST. See Angiomatosis of soft tissue Asteatotic eczema, 23 Asteroid bodies, 101 Ataxia telangiectasia, 835 HHT and, 834 ATLL. See Adult T-cell lymphoma/leukemia Atopic dermatitis, 18–19, 28f, 29t clinical features of, 19 histopathological features of, 19 ATP2A2, 330

ATPases, 315 Atrichia, 321 Atrophic collagenoses, 395–397 Atrophic connective tissue panniculitis, 274 Atrophie blanche, 192, 206, 207f clinical features, 206 histopathological features, 206 Atrophoderma of Pasini and Pierini, 396 clinical features, 396 differential diagnosis, 396 histopathological features, 396 Atrophy, epidermal, 90 Attenuated yaws, 450 Atypical cellular blue nevus, 647 Atypical decubital fibroplasia, 772 Atypical dermal nodular melanocytic proliferation, 631f Atypical fibrous histiocytoma, 776–777, 778f Atypical fibroxanthomas (AFXs), 593, 778–780, 779t clinical features, 778 differential diagnosis, 779–780 histopathological features, 778–779 Atypical halo nevus, 663 Atypical lipomatous tumor (ALT), 858, 865–866, 865f, 865t lipoblastoma and, 864 Atypical lymphocytic hyperplasia, 908 Atypical melanocytic nevi, 651 cytologic features, 654 epithelioid cell variant, 655 grading of, 656 halo nevus variant, 655 histological features of, 655–656 junctional, 652 as melanoma precursors, 652 host response, 654 melanoma v., 655t severely, 655t significance of, 651–654 Atypical melanocytic proliferation, 997–998 clinical features, 997 differential diagnosis, 998 histopathologic features, 997–998 Atypical mycobacteria, 432, 434f, 435f clinical features, 432 histopathological features, 432 Atypical mycobacterial folliculitis, 235–236 Atypical Spitz nevus, 636 assessment of, 637t Atypical Sweet syndrome, 128 Atypical vascular proliferation with inflammation. See Epithelioid hemangioma Autoimmune diseases, diagnosis, 186 Autoimmune subepidermal blistering diseases, 157–160 bullous pemphigoid, 157–160 Autosomal recessive lamellar ichthyosis, 318t AVMs. See Arteriovenous malformations B B. afzelii, 55 B. burgdorferi, 55 B lymphocytes, marginal zone, 930 BA. See Bacillary angiomatosis

Bacillary angiomatosis (BA), 441–442, 442f, 817 cherry angioma and, 850 clinical features, 441 differential diagnosis, 441–442 histopathological features, 441, 502 in HIV, 501 KS and, 823 Bacillary peliosis, 441 Bacillus anthracis, 433 Backhart impetigo, 234 Bacterial folliculitis, 234, 239f clinical features, 234 Bacterial infections, 421–443. See also specific types differential diagnosis, 422t histological features, 422t Bacteroides, 427 Baker itch, 308 Balamuthia mandrillaris, 524 Balanitis circinata, 68, 464 Balloon cell melanoma (BCM), 620, 676–677 clinical features, 677 histopathological features, 677 Balloon cell nevus, 620 clinical features, 620 differential diagnosis, 620 histopathological features, 620 Bancroftian filariasis, 530 Bandlike growth pattern, 907f Bandlike infiltrates, 906 Bart syndrome, 170, 171t Bartonella, 439, 441, 501 Bartonella quintana, 817 Bartonellosis, 442 Basal cell carcinoma, 578–590, 729, 733, 961 aAVM and, 845t adamantinoid, 581 adenoid, 580, 588, 741 basosquamous, 583–584 clear cell, 581 clinical features, 579–580 derivation of, 579 differential diagnosis of, 587–588 with eccrine differentiation, 585f follicular, 585 granular, 581 halo, 580 histopathological features, 580 in HIV, 579 immune system in, 579 infiltrative, 583, 584f, 588, 706 inflammation in, 586 infundibulocystic, 584–585, 586 keratotic, 584–585 matrical, 585 metastatic, 580 metatypical, 583, 585 micronodular, 582, 583f with mixed histology, 582 morpheaform, 588, 706, 727 multicentric, 580 with myoepithelial differentiation, 585–586 necrosis in, 588 nevoid, 589–590 nodular, 580–582, 580f

Bednar tumor, 787 Behçet disease, 127, 186, 187t, 498 clinical features, 127, 186 histopathological features, 127, 186–187 Bejel, 451 Benign acquired vascular lesions, with radiation, 850 Benign adipocytic tumors, 858, 858t Benign adnexal neoplasm, 692 Benign cephalic histiocytosis, 119–120 clinical features, 119–120 differential diagnosis, 120 histopathological features, 120 Benign fibrohistiocytic tumors, 775–781 Benign fibrous tumors, 766–776 Benign hair follicle tumors, 697–714 Benign keratosis, 5f Benign lymphangioendothelioma. See Acquired progressive lymphangioma Benign lymphangiomatous papule, 850 Benign migratory glossitis, 1008–1009 clinical features, 1009 different diagnosis, 1009 histopathological features, 1009 Benign neoplasms distinguishing malignant from, 5f features of, 5 of umbilicus, 415t Benign proliferating pilar tumor (BPPT), 701–702 clinical features, 701 cytologic features of, 701–702 differential diagnosis, 702 histopathologic features, 701–702 Benign sebaceous proliferations, 689–692 Benign spiradenoma, 746 Benign sweat gland tumors, 725–733 Benign T-cell lymphoproliferations, 908–926 Benign tertiary syphilis, 446 Benign vascular tumors, 802–811 Benzene, 353 Bharma forest, 503 B-immunoblasts, 906, 929–930 BIOMED2, 908 Biphasic amyloidosis, 374–375 differential diagnosis, 375 histopathologic features, 374–375 Biphasic tumors, 797 Bipolaris spicifera, 477 Bird’s-eye cells, 509 Birt-Hogg-Dubé syndrome, 713 Bismuth, 355 Black piedra, 459t, 467 Blaschko lines, 835 Blastocladiomycota, 458 Blastomycosis-like pyoderma, 111, 113t, 428–429 clinical features, 111 differential diagnosis, 111 histopathological features, 111 Bleomycin, 390 Blistering distal dactylitis, 426 clinical features, 426 histopathological features, 426 Blistering drug eruptions, 288

Blisters, 136. See also Subepidermal blistering diseases coma, 174–175 friction, 150 intraepidermal, 136f, 137f, 139t suprabasal, 141f Bloch-Sulzberger syndrome, 349–350 Bloom syndrome, 59 ataxia telangiectasia and, 835 Blue nevi, 641, 642–643 atypical cellular, 647 cellular, 645, 646f lymph node involvement in, 647 common, 643, 644f compound, 645 epithelioid, 643, 644f hypopigmented, 645 malignant melanoma arising in, 675 clinical features, 675 differential diagnosis, 675 histopathological features, 675 patchlike, 647 plaque-type, 647–648 sclerosing, 645 target, 648 Blue rubber bleb nevus syndrome (BRBNS), 838 GVM and, 840 Blueberry muffin baby syndrome, 497 B-lymphoblastic lymphoma, 938 clinical features, 938 differential diagnosis, 938 histopathologic features, 938 immunology, 938 BM. See Basement membrane BMZ. See Basement membrane zone Bone, 381–383, 877–879 Bone deposits, 382t dystrophic type, 382 idiopathic type, 382–383 Borderline melanoma, 680 Borderline sebaceous tumors, 692–693 Borrelia burgdorferi, 110, 387, 451, 927, 928, 933, 948 Borst-Jadassohn phenomenon, 729 Bortezomib, 297 Botryoid embryonal rhabdomyosarcoma, 873 Botryomycoma. See Pyogenic granuloma Botryomycosis, 459t, 482–483 clinical features, 482 differential diagnosis, 483 histopathological features, 482–483 Bowel-associated dermatosis-arthritis syndrome, 127, 189f, 191 clinical features, 127, 191 differential diagnosis, 127 histopathological features, 127, 191 Bowen disease, 78, 509, 573–575, 591, 992, 996 clinical features, 574 differential diagnosis, 574–575 histopathological features, 78, 574 Bowenoid actinic keratosis, 572 Bowenoid papulosis, 508, 510f, 511f BPAC1. See Bullous pemphigoid antigen 1 BPAC2. See Bullous pemphigoid antigen 2 BPPT. See Benign proliferating pilar tumor BRAF mutations, 657

INDEX

Basal cell carcinoma (Cont.): occurrence of, 579 ossification within, 586 pigmented, 581f pilar, 584–585 pleomorphic, 582 polypoid, 580 prevalence of, 579 risk factors for, 579 sclerosing, 583 with sebaceous differentiation, 581f superficial, 582–583, 583f superficial multicentric, 582 tumors associated with, 579 Basal cell epithelioma, with monster cells, 582 Basal layer disorders, 326–327 Basal vacuolization, 36 Basaloid eccrine carcinoma, 749 clinical features, 749 differential diagnosis, 749 histopathologic features, 749 Basaloid follicular hamartomas, 588, 708–709, 709f clinical features, 708 differential diagnosis, 709 histopathologic features, 708–709 Basaloid sebaceous carcinomas, 694 Basement membrane (BM), 156 protein constituents of, 158f Basement membrane zone (BMZ) epidermolysis bullosa, junctional, 326 epidermolysis bullosa simplex, 326 mutations, 169–171 subepidermal blistering diseases and, 169–171 thickening, 90 Basidiobolus, 484–485 clinical features, 484–486 differential diagnosis, 486 histopathological features, 486 Basidiomycota, 458, 467 Basilar melanocytes, lesions composed of, 615–616 Basiomycota, 465 Basomelanocytic tumor, malignant, 581 Basophil degranulation, 82 Basosquamous basal cell carcinoma, 583–584 Bazex syndrome, 76 clinical features, 76 histopathological features, 76 B-cell lymphomas, large, in immunocompromised patients, 937–938 B-cell series, 929–932 B-chain gene (PDFGB), 785 bcl-2 protein, 705 BCM. See Balloon cell melanoma Beanbag cells, 264 Becker nevus, 719 clinical features, 719 congenital smooth muscle hamartoma and, 868 differential diagnosis, 719 histopathologic features, 719 Becker pigmented hairy nevus, 351–352 clinical features, 351 differential diagnosis, 351–352 histopathologic features, 351

1043

INDEX 1044

Branchial cleft cysts, 550, 551f differential diagnosis, 550 histopathological features, 550 BRBNS. See Blue rubber bleb nevus syndrome Breast carcinoma, 960, 963–965 clinical features, 963 differential diagnosis, 964 histopathologic features, 963–964 immunohistochemistry, 964–965 metastatic mucinous, 965f special stains, 964–965 Breast melanocytic nevi, 625 Breslow thickness, 661 Brevibacterium epidermidis, 462 Broders classification, 591 Bronchogenic cysts, 549–550, 551f differential diagnosis, 550 histopathological features, 550 Bronze baby syndrome, 355 Brooke-Fordyce syndrome, 703, 704 Brooke-Spiegler syndrome, 599 Brown recluse spider bite, 308f Brucella abortus, 435 Brucella canis, 435 Brucella melitensis, 435 Brucella suis, 435 Brucellosis, 435–436 clinical features of, 435–436 differential diagnosis, 436 histopathological features, 436 Brugia malayi, 533, 534 Brugia pahangi, 533 Brugia timori, 533 BSCL2, 274 Buerger disease, 201 clinical features, 201 differential diagnosis, 201 histopathological features, 201 Bullae, 136 Bullosis diabeticorum, 175 clinical features, 175 diagnosis, 175 differential diagnosis, 175 histopathological features, 175 Bullous congenital ichthyosiform erythroderma, 328–329, 328t Bullous ichthyosis, epidermolytic hyperkeratosis and, 328–329 Bullous impetigo, 152 clinical features, 152 histopathological features, 152 Bullous lichen planus, 39f Bullous lupus erythematosus, 167 Bullous pemphigoid, 157–160, 288 cell-poor, 159f clinical features, 158 diagnosis, 159 differential diagnosis, 159–160 direct immunofluorescence, 159 histopathological features, 158 indirect immunofluorescence, 159 urticarial lesion of, 160f Bullous pemphigoid antigen 1 (BPAC1), 156 Bullous pemphigoid antigen 2 (BPAC2), 156 Bullous systemic lupus erythematosus, 168–169 clinical features, 168–169

Bullous systemic lupus erythematosus (Cont.): diagnostic features, 169 differential diagnosis, 169 histopathological features, 169 Bunyaviruses, 503 Burns, thermal, 150–152 Buruli ulcers, 591 Buschke-Loewenstein tumor, 596, 597 clinical features, 597 differential diagnosis, 598 histopathological features, 597–598 C C5b-9, 93 CA-125 glycoprotein, 748, 970 CAFCA. See Cryopyrin-associated familial cold autoinflammatory syndrome Cafe-au-lait spots, 350–351, 886 differential diagnosis, 351 histopathological features, 350–351 Calcareous bodies, 537 Calcific uremic arteriopathy. See Calciphylaxis Calcifying aponeurotic fibroma, 774–775 clinical features, 774 differential diagnosis, 774–775 histopathologic features, 774 Calcinosis iatrogenic, 383 milia-like, 383 tumoral, 383f Calcinosis, Raynaud phenomenon, esophageal dysmotility, sclerodactyly, and telangiectasia (CREST), 847 Calcinosis cutis, 381 metastatic, 381–382 Calciphylaxis, 207–208, 208t, 209f, 258t, 381 clinical features, 207, 258 differential diagnosis, 207–208, 259 histopathological features, 207, 258 Calcium, 381–383, 382t dystrophic type, 382 idiopathic type, 382–383 Callitroga, 309 Callus, 602 clinical features, 602 differential diagnosis, 602 histopathological features, 602 Calymmatobacterium, 436 Candida, 77 Candida albicans, 152, 990 Candidal granuloma, 464 Candidiasis, 152–153, 459t, 463–465 chronic, 74 clinical features, 152 differential diagnosis, 464–465 disseminated, 464 histopathological features, 152, 464 mucocutaneous, 463t systemic, 464 Cantu syndrome, 348 Capillary aneurysm, 848 Capillary hemangioma, angiosarcoma and, 830 Capillary malformation-Arteriovenous Malformation (CM-AVM), 833 Capillary malformations (CMs), 813, 831–832, 833t VM and, 839

Carcinoembryonic antigen (CEA), 575, 739, 751, 962, 969, 970, 971 Carcinoma. See also specific types adenoid cystic, 741, 742f adenosquamous, 598, 744 adnexal, 717 apocrine, 749, 752, 753f, 754f basal cell, 578–590, 706, 727, 729, 733, 845t, 961 breast, 960, 963–965, 965f clear cell eccrine, 694, 739, 747–748 colloid, 963 cuniculatum, 598 ductal apocrine, 752, 753f, 754f ductopapillary apocrine, 749–750, 751f eccrine, 694, 738–755, 750t ex mixed tumors, 748 gastrointestinal, 967–968 intraepidermal, 573–576 lung, 965–967 lymphoepithelioma-like, 599–600, 753–754 Merkel cell, 515 microcystic adnexal, 699, 727, 728, 743–745, 744f mucinous, 740–741 mucinous eccrine, 740t mucoepidermoid, 598–599, 745 mucoid, 963 neuroendocrine, 673, 897t oral, 968 pilomatrix, 717, 718t primary cutaneous adenosquamous, 745 primary mucoepidermoid, 745 primary neuroendocrine, 896–897, 898f sclerosing sweat duct, 743 sebaceous, 690, 693–695, 694f, 695f sinonasal, 968 spindle cell, 962 squamous cell, 544, 590–596, 596t, 693, 961, 996, 1017–1018 sweat gland, 738, 753 syringoid, 743 thyroid, 961, 963 trichilemmal, 694, 715–716 verrucous, 596–598 Carcinoma ex dermal cylindroma, 745–746 histopathological features, 746 Carcinosarcoma, 599, 599t, 748–749 clinical features, 599 differential diagnosis, 599 histopathological features, 599 Carmustine, 356 Carney complex, 796 Carney syndrome, 348–349 Carotinoids, 356 Carrion disease, 442 Cartilage, 381–383, 876–877 Cartilage-like matrix, 736 Casal necklace, 77 Cast immobilization, PG and, 813 Castleman disease, 815 CAT. See Cutaneovisceral angiomatosis with thrombocytopenia Catagen, 213 Catagen hairs, 218 Caterpillar bodies, 380 Cathepsin C, 320

CD81, 670 CD87, 257 CD99, 780 CD206, KS and, 822 CD208c, 83 CD445R0, 711 CD681, 447 CDK4 gene, 865 dedifferentiated liposarcoma and, 867 CDX2, 970 CEA. See Carcinoembryonic antigen Cell-poor bullous pemphigoid, 159f Cell-poor interface dermatitis, 90 Cellular angiolipomas, 859 Cellular blue nevus, 645, 646f atypical, 647 clinical features, 645 histopathologic features, 645–646 lymph nodes in, 647 occasional, 646–647 Cellular dermatofibroma, 779f Cellular neurothekeoma, 894f extraskeletal myxoid chondrosarcoma and, 877 Cellular neurothekeomas, 892 Cellular schwannoma, 890, 892f Cellulitis, 426–427 infectious, 426t Center for Disease Control and Prevention, 421, 433, 500 Central centrifugal scarring alopecia, 227–229 clinical features, 228 differential diagnosis, 229 histopathological features, 228–229 Central nervous system (CNS), 468 Centroblasts, 929, 932 Centrocyte-like cells, 933 Centrocytes, 929, 932 Centrofacial neurodystrophic lentiginosis, 348 Cephalothoracobrachial lipodystrophy, 274 Cerebellar degeneration, 590 Cerebral angioendotheliomatosis. See Angioendotheliomatosis Cerebrospinal fluid (CSF), 447, 521 Cestodes, 530, 536–538 CGH. See Comparative genomic hybridization CH. See Composite hemangioendothelioma; Congenital hemangioma Chagas disease, 520, 521, 522f Chagoma, 522 Chalazion, 102–103 clinical features, 102 differential diagnosis, 102 histopathological features, 102 Chancroid, 437–438, 440t clinical features, 437 differential diagnosis, 437 histopathological features, 437 Charcot-Leyden crystals, 534 Chédiak-Higashi syndrome, 343 clinical features, 343 histopathological features, 343 Cheilitis actinic prurigo, 305 follicular, 305

Cheilitis glandularis, 1011–1012 differential diagnosis, 1011–1012 histopathological features, 1011 Cheilitis granulomatosa, 100, 101t Chemical panniculitis, 271 clinical features, 271 differential diagnosis, 272 histopathological features, 271 Chemokine, 93 Chemotherapeutic agents, 291–293, 356–357 clinical features, 291–292 differential diagnosis, 292 histopathological features, 292 Cherry angioma, 849–850, 849f Cheyletiella, 308 Chickenpox. See Varicella Chiggers, 308 Chikungunya, 503 Chilblains. See Perniosis Childhood melanoma, 627–632 Chlamydia, 438, 443 Chloasma, 350 differential diagnosis, 350 histopathologic features, 350 Chloramphenicol, 281 Chlorella, 526 Chlorellosis, 526, 526t clinical features, 526 differential diagnosis, 527 histopathological features, 526–527 Chlorhexidine, 421 Chlorpromazine, 289 Cholesterol emboli, RAE and, 817 Chondrodermatitis nodularis chronic helicis, 397 clinical features, 397 differential diagnosis, 397 histopathological features, 397 Chondrodysplasia punctata, X-linked dominant ichthyosis with, 316 Chondroid lipoma, 861, 862f Chondroid syringoma, 733, 735–737, 737t, 738f clinical features, 735–736 differential diagnosis, 736–737 extraskeletal myxoid chondrosarcoma and, 877 malignant, 588 Chondromas, cutaneous, 736 Chondrosarcomas, 972 Chordoma, extraskeletal myxoid chondrosarcoma and, 877 Choriocarcinomas, 960, 970 CHP. See Cytophagic histiocytic panniculitis Chromatin, 438 Chromhidrosis, 244 clinical features, 244 differential diagnosis, 244 histopathological features, 244 Chromoblastomycosis, 459t, 475–477 clinical features, 476 differential diagnosis, 476–477 histopathological features, 476 Chromogranin, 590, 901, 963 Chronic bite injury, 1007 clinical features, 1007 differential diagnosis, 1007 histopathologic features, 1007

INDEX

Cat-scratch disease, 439–441 clinical features, 440 differential diagnosis, 441 histopathological features, 441 Cave disease. See Classic histoplasmosis Cavernous angioleiomyomas, 870 Cavernous hemangioma, 802. See also Venous malformation angiosarcoma and, 830 Cavernous lymphangioma, 842, 842f Cavernous malformation. See Venous malformation CCA. See Clear cell acanthoma CCDPP-15, 751 CCND1, 657 CCS. See Clear cell sarcoma CD 5/6, 965 CD 31 alveolar rhabdomyosarcoma and, 875 angiosarcoma and, 830 APL and, 844 extraskeletal chondroma and, 876 KS and, 822 RAE and, 818 CD 34 alveolar rhabdomyosarcoma and, 875 APL and, 844 extraskeletal chondroma and, 876 KHE and, 824 KS and, 822 leiomyoma and, 869 leiomyosarcoma and, 871, 872 RAE and, 818 spindle cell lipoma and, 860 WDL/ALT and, 866 CD 45, alveolar rhabdomyosarcoma and, 875 CD 68 adult rhabdomyoma and, 874 chondroid lipoma and, 861 GH and, 816 CD 99 embryonal rhabdomyosarcoma and, 874 extraskeletal osteosarcoma and, 879 CD1a, 316 CD4, 218 CD4+, CD56+ hematodermic neoplasm, 926 clinical features, 926 definition, 926 differential diagnosis, 926 genotypic features, 926 histopathological features, 926 immunophenotypic features, 926 CD5, 711 CD8, 43, 306, 495, 711 CD10, 780 CD31, 802, 815 EH and, 812 GH and, 816 SCH and, 808 CD34, 802, 815 angiosarcoma and, 830 EH and, 812 SCH and, 808 CD48, 711 CD56, 907 CD57, 887, 893, 894, 896 CD68, 83, 116

1045

INDEX 1046

Chronic candidiasis, 74 clinical features, 74 histopathological features, 74 Chronic dermatophytosis, 74 clinical features, 74 histopathological features, 74 Chronic graft-versus-host disease, 46–48 clinical features, 46 differential diagnosis, 47 histopathological features, 46 Chronic lymphocytic leukemia, 146, 949f, 950f B-cell type, 948–949 clinical features, 948 histopathological features, 948–949 immunohistochemical findings, 949 molecular biology, 949 infiltrates in, 948t Chronic myeloid leukemia (CML), 944–946 clinical features, 944 histochemical findings, 946 histopathologic features, 944–945 immunohistochemical findings, 946 infiltrates of, 947t Chronic pulmonary histoplasmosis, 473 Chronic spongiotic dermatitides, 72–73 clinical features, 73 differential diagnosis, 73 histopathologic, 73 Chronic urticaria, 81 common forms of, 82t Chrysiasis, 355 Chrysomyia, 309 Churg-Strauss granuloma, 109, 184 clinical features, 197 histopathological features, 197 Churg-Strauss syndrome, 196–197 Chytridiomycota, 458 Cicatricial pemphigoid (CP), 162–163 antigenic targets in, 163t clinical features, 162 differential diagnosis, 163 histopathological features, 162 Ciliated cysts of vulva, 551–552 differential diagnosis, 552 histopathological features, 552 Circumscribed hypermelanosis, 347–348, 348t Cirsoid aneurysm. See Arteriovenous malformations Civatte body, 36 CK7, 966, 967, 969, 970 CK20, 966, 969, 970, 971 CL. See Cutaneous lymphadenoma Cladophialophora bantiana, 477 Cladophialophora carrionii, 476 Cladosporium werneckii, 477 Classic histoplasmosis, 473–474 clinical features, 473–474 differential diagnosis, 474 histopathological features, 474 HIV and, 473 Classic Sweet syndrome, 188–190 Clavus, 601–602 clinical features, 601 differential diagnosis, 601–602 histopathological features, 601

Clear cell acanthoma (CCA), 78, 568–569 clinical features, 568 differential diagnosis, 569 histopathological features, 78, 568–569 Clear cell basal cell carcinoma, 581 Clear cell cutaneous tumors, 716t Clear cell dermatofibroma, 777, 779f Clear cell eccrine carcinoma, 694, 739, 747–748 clinical features, 748 differential diagnosis, 748 histopathologic features, 748 Clear cell hidradenoma, 732 Clear cell sarcoma (CCS), 676 differential diagnosis, 676 histopathological features, 676 Clefts, 136 suprabasal, 141f Clofazamine, 356 Clofazimine-induced hyperpigmentation, 123 Clomeromycota, 458 Clonal seborrheic keratosis, 565 Clostridium, 427 CM, AVMs, 847 CM-AVM. See Capillary malformationarteriovenous malformation CML. See Chronic myeloid leukemia CMs. See Capillary malformations CMTC. See Cutis marmorata telangiectatica congenita CMV. See Cytomegalovirus CNS. See Central nervous system Coagulopathies, 203 clinical features, 203 histopathological features, 203 Cobb syndrome, 833 VH and, 838 Coccidioides immitis, 527 Coccidiomycosis, 459t, 471 clinical features, 471 differential diagnosis, 471–472 histopathological features, 471 Coccobacilli, 437 Coenuriasis, 537 COL7A1, 327 Cold panniculitis, 270 clinical features, 270 histopathological features, 270 Cold reactions, 303–304 clinical features, 303–304 differential diagnosis, 304 histopathological features, 304 Collagen, 291, 387–405 alterations of, 387 type IV, 889 Collagen bodies, 897 Collagenosis nuchae, 394 clinical features, 394 histopathological features, 394 Collagenous crystalloids, 586 Collagenous plaques, 392 Collagenous plaques of hands, 402 Collarette, 678 Collections, 909 Colloid body, 36

Colloid carcinoma, 963 Colloid milium, 374t, 378 of adult, 378–379, 379f juvenile, 376f Coma blisters, 174–175 clinical features, 174 histopathological features, 174–175 Combined nevus, 648 Comedo patterns, 693 Comedone, 242f Comel-Netherton syndrome, 318, 323 clinical features, 323 differential diagnosis, 323 histopathological features, 323 Common blue nevus, 643, 644f clinical features, 643 differential diagnosis, 643 histopathologic features, 643 Comparative genomic hybridization (CGH), 680 Complement, 274 membrane attack complex of, 92–93 Complex aphthosis, 1006 Composite hemangioendothelioma (CH), 827 Compound blue nevus, 645 Compound nevus, 618 of acral skin, 624f with architectural disorder, 653f, 654f and cytologic atypia, 653f, 654f of vulva, 626f Compound Spitz nevus, 637f Concurrent cutaneous B-cell lymphomas, 931 Condyloma acuminatum, 506, 507t, 508f, 509f, 598 Confluent and reticulate papillomatosis of Gougerot and Carteaud, 558 clinical features, 558 differential diagnosis, 558 histopathological features, 558 Congenital dysplasia angiopathies, 832 Congenital generalized phlebectasia. See Cutis marmorata telangiectatica congenita Congenital hemangioma (CH), 803, 803t, 804–805, 805f Congenital hemidysplasia, 322, 447 Congenital hypotrichosis, 228f Congenital lymphedema, 807 KHE and, 823 Congenital melanocytic nevi, 627–632 with atypical features, 630 architectural disorder, 630 cytologic atypia, 630 dermal nodular proliferations, 630 intraepidermal pagetoid spread, 630 giant, 632 histological features, 628 incidence, 628–630 clinical features, 628 histopathological features, 628 large, 632 melanoma in, 630–631 risk factors, 628–630 clinical features, 628 histopathological features, 628 small, histopathological features, 628–630

Cryopyrin-associated familial cold autoinflammatory syndrome (CAFCA), 190 Cryptococcosis, 459t, 468 clinical features, 468 differential diagnosis, 469 histopathological features, 469 Cryptococcus, 468, 527 Crystalline lamellae, in endothelial cells, 806 Crystal-related panniculitis, 265–266, 266t Crystal-storing histiocytosis, adult rhabdomyoma and, 873 CSF. See Cerebrospinal fluid CTCL. See Cutaneous T-cell lymphomas Ctenocephalides felis, 441 Cuniculatum, 596 Cunninghamella bertholletiae, 483 Curettage specimen, 3 Cutaneous adnexal polyp, 758–759 Cutaneous appendage disorders, 213–245 miscellaneous, 243–245 transverse section techniques, 213–215 vertical section techniques, 213–215 Cutaneous B-cell lymphoid hyperplasia, 926–940 clinical features, 927 differential diagnosis, 928–929 histopathologic features, 927–928 immunohistological features, 930–931 immunology, 928 Cutaneous B-cell lymphomas, 929–932 classification, 931–932 clinical features, 929 cytomorphological features, 929 histopathologic features, 929 molecular genetic analysis, 931 primary, 931 Cutaneous BM zone, 156 Cutaneous cholesterol embolism, 204 histopathological features, 204 Cutaneous chondromas, 736 Cutaneous ciliated cysts, 551 histopathological features, 551 Cutaneous Crohn disease, 100–101 clinical features, 100 differential diagnosis, 100–101 histopathological features, 100 Cutaneous cysticercosis, 536–537 clinical features, 536 differential diagnosis, 537 histopathological features, 536–537 Cutaneous cysts, 543–554 algorithm for, 543f branchial cleft, 550, 551f bronchogenic, 549–550, 551f ciliated, of vulva, 551–552 cutaneous ciliated, 551 dermoid, 548–549 digital mucous, 552–553 epidermoid, 543–544 with epithelial lining, 543–548 without epithelial lining, 552–554 eruptive vellus hair, 547 follicular hybrid, 548 histopathological features, 553 hybrid epidermoid and apocrine, 554 lined by mixed ciliated epithelium, 546t

Cutaneous cysts (Cont.): lined by stratified squamous epithelium, 534, 545t median raphe, 552 metaplastic synovial, 553–554 not lined by epithelium, 547t pigmented follicular, 548 pilar, 544 pilonidal, 553 proliferating epithelial, 554 proliferating pilar, 544 pseudostratified columnar epithelium, 552 thymic, 549 thyroglossal duct, 550–551, 551f vellus hair, 544–547 Cutaneous deciduosis, 412 Cutaneous dirofilariasis, 534–535 clinical features, 534 differential diagnosis, 535 histopathological features, 534–535 Cutaneous drug eruptions, 281–297 antibody-mediated reactions, 281 blistering drug eruptions, 288 clinical forms of, 282–296, 282t cytokines, 295–296 delayed-type hypersensitivity reactions, 281–282 dilantin hypersensitivity syndrome, 295 drug-associated ichthyosiform dermatoses, 293 drug-associated vasculitis, 292–293 drug-induced linear IgA disease, 288–289 drug-induced lupus erythematosus, 289 drug-induced pemphigoid, 288 drug-induced pemphigus, 288 drug-induced pseudoporphyria cutanea tarda, 288 eczematous, 287–288 erythema multiform, 293–294 erythroderma, 294–295 exanthematous, 282 fixed, 284–285, 285f halogenoderma, 294 histopathological features, 282–296 HIV and, 281 immediate hypersensitivity reactions, 281 immune-complex-mediated reactions, 281 immunologic drug reactions, 281 interstitial granulomatous drug reaction, 295 lichenoid, 283–284, 283t, 284t lymphomatoid, 290–291 photosensitivity, 285–287 pityriasiform eruptions, 293 psoriasiform, 293 pustular, 287 sclerodermatoid tissue reactions, 291 Stevens-Johnson syndrome, 293–294 toxic epidermal necrolysis, 293–294 Cutaneous epithelioid angiomatous nodules, 813 Cutaneous extravascular necrotizing granuloma, 109, 198 Cutaneous focal mucinosis, 368 differential diagnosis, 368 histopathological features, 368

INDEX

Congenital melanoma, 627–632 Congenital self-healing Langerhans histiocytosis, 117 clinical features, 117 differential diagnosis, 117 histopathological features, 117 Congenital smooth muscle hamartoma, 868, 869f Congenital telangiectatic erythema, 59 Conidiobolus, 484 clinical features, 484 histopathological features, 484 Conjunctival Lisch nodules, 886 Connective tissue diseases, 90 diagnosis, 186 seropositivity by, 91t vasculopathies and, 209 Connective tissue nevi, 391–392 clinical features, 392 differential diagnosis, 392 histopathological features, 392 Connective tissue panniculitis, 274 atrophic, 274 Conradi-Hunermann syndrome, 316 clinical features, 316 differential diagnosis, 316 histopathological features, 316 Contact dermatitis, 15–34 allergic, 26t clinical features of, 17 histopathological features of, 17 dermal/protein, 18, 28f irritant, 17 clinical features of, 17 histopathological features of, 17 Conventional melanoma, 663t Conventional spongiosis, 6f Copra itch, 308 Coral reef granuloma, 428 Cordylobia, 309 Corp grains, 147 Corp ronds, 147 Corticosteroids, 271, 274 atrophy, 396 injection sites, 381 Corynebacterium minutissimum, 429, 430, 989 Corynebacterium tenuis, 429 Cowden syndrome, 699, 703, 715 Cowpox, 512, 513 CP. See Cicatricial pemphigoid Crab yaws, 450 Cray-patch ringworm, 460 CREST. See Calcinosis, Raynaud phenomenon, esophageal dysmotility, sclerodactyly, and telangiectasia CREST syndrome, 382, 389 Crohn disease, 197 TA and, 805–806 Crow-Fukase syndrome, 347 Cryoglobulinemias, 185, 203–204 clinical features, 204 clinical-pathological associations of, 205t histopathological features, 204 mixed, 185 type I, 185, 204t type II, 185 type III, 185

1047

INDEX 1048

Cutaneous gamma/delta T-cell lymphoma, 922 clinical features, 922 definition, 922 differential diagnosis, 922 genotypic features, 922 histopathological features, 922 Cutaneous Hodgkin lymphoma, 939–940 clinical features, 939 differential diagnosis, 939 histopathologic features, 939 immunology, 939 Cutaneous horn, 600–601, 600f clinical features, 600 differential diagnosis, 601 histopathological features, 600–601 Cutaneous larva migrans, 535–536 differential diagnosis, 535–536 histopathological features, 535 Cutaneous leukemic infiltrates, 940–952 Cutaneous lupus mucinosis, 367 Cutaneous lymphadenoma (CL), 710–711, 712f clinical features, 710–711 differential diagnosis, 711 histopathological features, 711 Cutaneous lymphomas, clinical aspects of, 905–906 Cutaneous mastocytosis, 130–131 clinical features, 130 differential diagnosis, 131 histopathological features, 130 major, 130 minor, 130 Cutaneous melanoma anatomic levels of, 659t classification, 656–665 clinical features, 657–659 differential diagnosis, 662–665 histopathological features, 659–662 intraepithelial component, 659–660 invasive, 660 lentiginous, 656 metastatic, 678, 679t nested, 656 pagetoid, 656, 658f primary, 678, 679t Cutaneous meningioma, 898 differential diagnosis, 898 histopathological features, 898 Cutaneous metastases, 960–973 clinical features, 960–961 general approach to, 961–962 morphological features, 960–961 sites of origin, 960t, 963–965 Cutaneous mucinoses, 362–363, 363t follicular degenerative primary, 369 hamartomatous, 370–371 neoplastic, 370–371 primary, dermal degenerative, 363–369 Cutaneous myxoma, 370–371, 795–796 differential diagnosis, 370–371 histopathological features, 370 Cutaneous necrosis syndrome, 258 Cutaneous neural neoplasms, histopathological features, 885t

Cutaneous neutrophilic small vessel vasculitis, 182t Cutaneous ossification, 383–384 primary, 384 secondary, 384 Cutaneous paragonimiasis, 538 Cutaneous satellites, 677 Cutaneous strongyloidiasis, 536 Cutaneous T-cell lymphomas (CTCL), 7, 71, 74–75, 229, 276, 291 classifications of, 905t clinical features, 74–75 cytogenetic findings in, 908 cytomorphologic basis, 906–907 diagnosis of, 907–809 differential diagnosis, 75 etiopathogenesis of, 908 growth patterns, 906–907 histomorphologic basis, 906–907 histopathological features, 75 juvenile granulomatous, 912 reproduction of morphologic criteria in, 907 special features, 907 staging, 906 Cutaneovisceral angiomatosis with thrombocytopenia (CAT), 811 Cutis hyperelastica, 397–399 Cutis laxa, 403, 404f clinical features, 403 histopathological features, 403 Cutis marmorata telangiectatica congenita (CMTC), 835 Cyclooxgenase-2, 593 Cyclophosphamide, 276 Cyclops, 535 Cyclosporine, 264 CYLD gene, 704f Cylindroma, eccrine, 725 Cystadenoma, 756 Cystic hygromas, 842 IPEH and, 816 Cysticercosis, 530 cutaneous, 536–537 Cysts, 992–993. See also specific types Cytokeratin, 575, 588, 593, 901, 962 extraskeletal chondroma and, 876 Cytokine receptor blockers, 296–297 Cytokines, 295–296 Cytologic atypia, 630 in neurofibromas, 887 Cytologic features, atypical melanocytic nevi, 654 Cytolysis of keratinocytes, 137 spinous layer vesiculation due to, 327–332 Cytolytic dermatitis, 150–152 epidermolytic hyperkeratosis, 150 friction blisters, 150 thermal burns, 150–151 Cytomegalovirus (CMV), 87, 281, 495, 511–512, 511t, 524 acute exanthem of, 496t clinical features, 511 differential diagnosis, 512 histopathological features, 511–512 in HIV, 511

Cytophagic histiocytic panniculitis (CHP), 263–265 clinical features, 264 differential diagnosis, 265 histopathological features, 264 Cytotoxic cutaneous lymphomas, 919 Cytotrophoblasts, 970 D D2-40, 965, 969 D2-40 antibody, 802, 806 angiosarcoma and, 830 KHE and, 824 KS and, 822 LM and, 843 PILA and, 826 THH and, 809 DAA. See Ductal apocrine adenocarcinoma Dabska tumor. See Papillary intralymphatic angioendothelioma Darier disease, 76, 147–148, 148f, 328, 330–331 clinical features, 147, 330 differential diagnosis, 147–148, 330–331 histopathological features, 147, 330 Darier sign, 130 Darling disease. See Classic histoplasmosis Daughter yaws, 450 DCs. See Dendritic cells DDIT3 gene, 867 DEA. See Ductal eccrine adenocarcinoma Deafness syndromes, 319 clinical features, 319 differential diagnosis, 319 DEB. See Dystrophic epidermolysis bullosa Dedifferentiated liposarcoma, 866–867, 866f extraskeletal osteosarcoma and, 879 Deep granuloma annulare, 106–107 clinical features, 106 differential diagnosis, 106–107 histopathological features, 106 Deep penetrating nevus (DPN), 648, 649–650, 650t clinical features, 649–650 histopathologic features, 649–650 Deep perivascular dermatitis, 81–94 Degos lesion, 208f Degos syndrome, 206, 207t clinical features, 206 histopathological features, 206 DEJ. See Dermo-epidermal junction Delayed-type hypersensitivity reactions, 281–282 Dematiaceous fungi, 474–477 Demodex folliculitis, 234–235, 241t clinical features, 234–235 histopathological features, 235 Denaturing, 908 Dendritic cells (DCs), 500, 907 Dendritic reticulum cells, 930 Dengue fever, 499 clinical features, 499 histopathological features, 499 Deposition disorders, 362–385 calcium, bone, and cartilage, 381–383 corticosteroid injection sites, 381 cutaneous mucinoses, 362–363 cutaneous ossification, 383–384

Dermatitis (Cont.): follicular atopic, 19–20 infectious palisaded granulomatous, 110–111 interface, 9, 36–61 cell-poor, 90 of HIV infection, 44 leukocyte infiltration, 36 miscellaneous diseases with features of, 59–61 vacuolar alteration, 36–37 intraepidermal vesicular and pustular, 10t lichenoid interface, 37–40 histopathological features of, 38–39 major psoriasiform, 64–66 nummular, 21, 29f clinical features of, 21 histopathological features of, 21 palisaded granulomatous, 107t palisaded neutrophilic and granulomatous, 109–111 perioral, 99–100, 237–240 perivascular, 81–94 deep, 81–94 superficial, 81–94 photoallergic, 17–18, 28f clinical features of, 18 histopathological features of, 18 photosensitivity, 286 phototoxic, 18 clinical features of, 18 histopathological features of, 18 pityriasiform, 10 psoriasiform, 9, 64–78 radiation, 301–303, 302f, 303f, 394–395 rheumatoid neutrophilic, 126 seborrheic, 22, 31f, 73 clinical features, 22 histopathological features, 22 spongiotic, 7f, 8–9, 8t, 15–34, 138, 306 acute changes in, 7f, 15 algorithm for, 16f chronic changes in, 7f, 15 clinical features in, 17t differential diagnosis for, 16t histopathological features in, 17t secondary changes in, 24t skin diseases with, 16t subacute, 7f, 19f stasis, 25 subepidermal bullous, 10f subepidermal vesicular, 10t superficial perivascular, 11 vacuolar interface, 40–48 vesicular and bullous, 9–10 Dermatitis herpetiformis (DH), 163–165, 164f, 164t, 165f diagnostic tests, 164–165 differential diagnosis, 165 histopathological features, 164 Dermatitis-arthritis syndrome, 431 Dermatobia, 309 Dermatofibroma, 122–124, 775–778, 776t. See also Fibrous histiocytoma cellular, 779f characterizing, 776t clear cell, 777, 779f clinical features, 775

Dermatofibroma (Cont.): differential diagnosis, 777 histopathologic features, 775–777 leiomyoma and, 869 MVH and, 809 variants of, 775t Dermatofibrosarcoma protuberans (DFSP), 770, 786–788, 787f, 866, 972 clinical features, 786–787 dedifferentiated liposarcoma and, 867 differential diagnosis, 787–788 histopathological features, 787 leiomyoma and, 869 leiomyosarcoma and, 871 pigmented, 787, 788f Dermatomycoses, 463 Dermatomyofibroma, 770–771, 771f clinical features, 770 differential diagnosis, 770–771 histopathological features, 770 Dermatomyositis, 51f, 52f, 53, 90, 93–94, 523 amyopathic, 93 clinical features, 53, 93–94 differential diagnosis, 53, 94 histopathological features, 53, 94 immunofluorescence, 94 myopathic, 93t panniculitis in, 273–274 clinical features, 273–274 histopathological features, 273–274 poikiloderma accompanying, 59 Dermatopathia pigmentosa reticularis, 348 Dermatophilus congolensis, 430 Dermatophytosis, 458, 460t chronic, 74 Dermatosis acquired perforating, 333, 333t, 334f drug-associated ichthyosiform, 293 erosive pustular, 232 neutrophilic, 188–190 pigmented purpuric, 88, 193–194 reticulated pigmented, 348 subcorneal pustular, of SneddonWilkinson, 67 transient acantholytic, 149–150, 331–332 Dermatosis papulosa nigra, 567 clinical features, 567 differential diagnosis, 567 histopathological features, 567 Dermis inflammatory process in, 10–14 absence of vascular injury, 10–11 granulomatous reaction patterns, 12 hair follicle, 12–13 panniculitis, 13 presence of vascular injury, 12 skin appendages, 12 sweat apparatus, 13 papillary, alterations of, 14 reticular, alterations of, 14 Dermocystidium, 489 Dermo-epidermal junction (DEJ), 156 Dermoid cysts, 548–549 differential diagnosis, 549 histopathological features, 549

INDEX

Deposition disorders (Cont.): dermal degenerative and inflammatory primary cutaneous mucinoses, 363–369 endogenous pigment deposits, 384–385 follicular degenerative and inflammatory primary cutaneous mucinoses, 369 gout, 380–381 hamartomatous and neoplastic cutaneous mucinoses, 370–371 hyaline angiopathy, 380 hyaline depositions, 371 mucopolysaccharidoses, 384–385 porphyria, 379–380 skin-limited amyloidoses, 374–379 systemic amyloidoses, 371–734 Waldenstrom macroglobulinemia, 379 Dermacentor, 454 Dermal amyloid angiopathy, RAE and, 817 Dermal atrophying and sclerosing lesions, 452–453 Dermal component, Spitz nevus, 637–638 differential diagnosis, 638 Dermal cylindroma, carcinoma ex, 745–746 Dermal degenerative primary cutaneous mucinoses, 363–369 Dermal duct tumor, 730f Dermal inflammatory infiltrates, 11t Dermal leishmanoid, 518 Dermal melanocyte hamartoma, 642 in adipose tissue, 858 clinical features, 642 differential diagnosis, 642 histopathologic features, 642 Dermal melanocytosis, 641 acquired, 642 differential diagnosis of, 642t Dermal nevus, 619f melanoma in, 674–675 clinical features, 674–675 differential diagnosis, 675 histopathological features, 674–675 papillomatous, 672 Dermal nodular proliferations, 630 Dermal processes, 3 Dermal/protein contact dermatitis, 18, 28f Dermatitides, 72–73. See also specific types chronic spongiotic, 72–73 clinical features, 73 differential diagnosis, 73 histopathological features, 73 neutrophilic dermatitides, 275–276 subacute spongiotic, 72–73 clinical features, 73 differential diagnosis, 73 histopathological features, 73 Dermatitis. See also specific types acantholytic, 138–150 differential diagnosis of, 140t atopic, 18–19, 28f, 29t clinical features of, 19 histopathological features of, 19 contact, 15–34 allergic, 17 irritant, 17 dermal/protein contact, 18, 28f eczematous, 72 exfoliative, 24–25, 73

1049

INDEX 1050

Desert rheumatism, 471 Desmin, 962, 973 embryonal rhabdomyosarcoma and, 874 myolipoma and, 862 Desmoglein 1, 143, 288, 421 Desmoplasia, pathogenesis of, 666 Desmoplastic melanoma (DM), 639, 665–668 clinical features, 666 desmoplastic Spitz nevus v., 640t diagnosis of, 667 histopathologic features, 666–668 mixed, 668 mucin in, 669 with neurotropism, 665, 666t without neurotropism, 665 prognosis of, 668 pure, 668 Desmoplastic Spitz nevus, 638–639, 639t clinical features, 638 differential diagnosis, 639 DM v., 640t histopathologic features, 638–639 Desmoplastic trichoepithelioma (DTE), 705–706, 727 clinical features, 705 differential diagnosis, 706 histopathologic features, 705–706 Desmosomes, 587 Desquamative gingivitis (DG), 1007 DFSP. See Dermatofibrosarcoma protuberans DG. See Desquamative gingivitis Diagnosis algorithmic approach to, 3f ANCA-associated, 184 ancillary techniques in, 680 autoimmune diseases, 186 of borderline melanoma, 680 bullosis diabeticorum, 175 bullous pemphigoid, 159 bullous systemic lupus erythematosus, 169 connective tissue diseases, 186 CP, 162 cutaneous T-cell lymphoma, 907–809 DEB, 170 of desmoplastic melanoma, 667 DH, 164–165 drug-induced vasculitis, 186 epidermal changes in, 5f epidermolysis bullosa acquisita, 168 herpes gestationis, 161 HSP, 184 infectious vasculitis, 183–184 JEB, 170 Kindler syndrome, 171 linear IgA disease, 166–167 LPP, 162 of melanoma, 679–680 panniculitis, 251f–252f paraneoplastic vasculitis, 186 protozoal infections, 517 pseudoporphyria, 174 reaction patterns in, 5f serum sickness, 185–186 small-vessel neutrophilic vasculitis, 183–186 urticarial vasculitis, 184–185

DIC. See Disseminated intravascular coagulation Diethylcarbamazine, 532 Diffuse acromelanosis, 347 Diffuse alopecia, 216–217, 221f, 222f causes of, 219t differential diagnosis, 217 drugs causing, 220t histopathological features, 217 Diffuse dermal infiltrates, 11f, 98–133 Diffuse histiocytic infiltrates, 113–122 infectious causes of, 114t xanthomas, 113–114 Diffuse hyperpigmentation disorders, 346 Diffuse lymphocytic-plasma cellular infiltrates, infectious causes of, 128t Diffuse neurofibroma, WDL/ALT and, 866 Diffuse normolipemic plane xanthoma, 114 clinical features, 114 differential diagnosis, 114 histopathological features, 114 Diffuse panniculitis, 269 Digital mucous cyst, 368–369, 552–553 differential diagnosis, 552–553 histopathological features, 368, 552–553 Digital myxoid pseudocyst, 994 clinical features, 994 differential diagnosis, 994 histopathologic features, 994 Digital tumors, 797 DIL. See Drug-induced lupus erythematosus Dilantin hypersensitivity syndrome, 295 clinical features, 295 differential diagnosis, 295 Dilated pore of Winer (DPW), 698, 699f clinical features, 698 differential diagnosis, 698 histopathological features, 698 Diphtheria, 429 clinical features, 429 differential diagnosis, 429 histopathological features, 429 Direct immunofluorescence, 91–93, 165 bullous pemphigoid, 159 Dirofilaria immitis, 534 Dirofilaria repens, 534 Dirofilaria tenuis, 534, 535f Dirofilaria ursi, 534 Discoid lupus erythematosus, 48, 50f, 51–53, 225–226 clinical features, 225 differential diagnosis, 53, 226 histopathological features, 225–226 Dissecting cellulitis, 230, 237f clinical features, 230 differential diagnosis, 230 histopathological features, 230 Disseminated candidiasis, 464, 503 Disseminated cutaneous leishmaniasis, 518 Disseminated histoplasmosis, 473–474 Disseminated intravascular coagulation (DIC), 430, 455 Distal lateral subungual onychomycosis (DLSO), 462 Diuretics, 281 DLSO. See Distal lateral subungual onychomycosis DM. See Desmoplastic melanoma

Donovan bodies, 436, 438 Donovania, 436 DOPA stain, 338, 339 Dorfman syndrome, 318–319 Dorfman-Chanarin syndrome, 318–319 Dowling-Degos disease, 348, 556–557 clinical features, 557 histopathological features, 557 Down syndrome, 383 Downgrading reaction, 432 DPN. See Deep penetrating nevus DPW. See Dilated pore of Winer DQ7, 218 DR4, 218 DR11, 218 Dracontiasis, 535 clinical features, 535 histopathological features, 535 Dracunculus medinensis, 535 Drug deposits, 355 Drug eruptions blistering, 288 cutaneous, 281–297 antibody-mediated reactions, 281 blistering drug eruptions, 288 clinical forms of, 282–296, 282t cytokines, 295–296 delayed-type hypersensitivity reactions, 281–282 dilantin hypersensitivity syndrome, 295 drug-associated ichthyosiform dermatoses, 293 drug-associated vasculitis, 292–293 drug-induced linear IgA disease, 288–289 drug-induced lupus erythematosus, 289 drug-induced pemphigoid, 288 drug-induced pemphigus, 288 drug-induced pseudoporphyria cutanea tarda, 288 eczematous, 287–288 erythema multiform, 293–294 erythroderma, 294–295 exanthematous, 282 fixed, 43–44, 283–285, 285f halogenoderma, 294 histopathological features, 282–296 HIV and, 281 immediate hypersensitivity reactions, 281 immune-complex-mediated reactions, 281 immunologic drug reactions, 281 interstitial granulomatous drug reaction, 295 lichenoid, 283–284, 283t, 284t lymphomatoid, 290–291 photosensitivity, 285–287 pityriasiform eruptions, 293 psoriasiform, 293 pustular, 287 sclerodermatoid tissue reactions, 291 Stevens-Johnson syndrome, 293–294 toxic epidermal necrolysis, 293–294 exanthematous, 282 clinical features, 282 differential diagnosis, 282 histopathological features, 282

Dysplasia epithelioid cell, 654 lichenoid, 1017 Dysplastic conditions, 1016–1018 Dysplastic melanocytic nevi, 651 grading of, 656 Dystrophic epidermolysis bullosa (DEB), 170 abopapulidea, 171t clinical features, 170 Cockayne-Touraine, 171t diagnosis, 170 differential diagnosis, 170 Hallopeau-Siemens, 171t, 327 histopathological features, 170 non-Hallopeau-Siemens, 171t transient, 171t variants of, 171t Dystrophic type deposits, 382 Dystrophy, 988 E EAC. See Erythema annulate centrifugum EAH. See Eccrine angiomatous hamartoma Early-onset varicose veins, SCH and, 807 Ears, elastotic nodules of, 402 Ebola, 503 EBV. See Epstein-Barr virus E-cadherin, 570 Ecchymoses, 179 Eccrine acrospiroma, 731–733, 733f, 737 clinical features, 731–732 differential diagnosis, 733 histopathological features, 732–733 Eccrine angiomatous hamartoma (EAH), 755 Eccrine carcinomas, 738 basaloid, 749 clear cell, 694, 739, 747–748 mucinous, 740t primary tumors, 738–755 simulating metastatic tumors, 746 small cell, 749, 750t Eccrine cylindroma, 725, 727f clinical features, 725 differential diagnosis, 725 histopathologic features, 725 Eccrine differentiation, 585f Eccrine epithelioma, 584, 588 Eccrine glands, TA and, 806 Eccrine hidrocystomas, 756–757 clinical features, 756 differential diagnosis, 757 Eccrine nevi, 755 Eccrine porocarcinoma, 738–739, 739f clinical features, 738 differential diagnosis, 739 histopathologic features, 738–739 Eccrine poroma gap, 728–730, 729t clinical features, 729 differential diagnosis, 729 histopathologic features, 729 Eccrine spiradenoma, 725–726, 727t, 728t, 745–746 differential diagnosis, 726 histopathologic features, 726 Eccrine squamous syringometaplasia, 244

Eccrine syringofibroadenoma, 730–731 clinical features, 730 differential diagnosis, 730–731 histopathologic features, 730 Eccrine tumors, 725 Eclabium, 78 ECs. See Epidermoid cysts Ecthyma, 423 clinical features, 423 differential diagnosis, 423 histopathological features, 423 Ecthyma gangrenosum, 423–424 clinical features, 423 differential diagnosis, 424 histopathological features, 423 Ectomesenchymal chondromyxoid tumor, 1018 clinical features, 1018 different diagnosis, 1018 histopathologic features, 1018 Ectopic cutaneous endosalpingiosis, 413 clinical features, 413 differential diagnosis, 413 histopathological features, 413 Ectopic salivary glands, 414, 415f Ectopic thyroid tissue, 415 histopathological features, 415 Ectopic tissue, 408–417 Ectothrix, 231 Ectropion, 78 Eczema, 72 asteatotic, 23 dyshidrotic, 67 follicular, 19–20 differential diagnosis, 19–20 histopathological features, 19 pompholyx clinical features, 21–22 histopathological features, 21–22 Eczematid-like purpura of Doucas and Kapetanakis, 193 Eczematous dermatitis, 72 Eczematous drug reactions, 287–288 clinical features, 287–288 differential diagnosis, 288 histopathological features, 288 Eczematous onychitis, 989–990 clinical features, 989 differential diagnosis, 989–990 histopathological features, 989 Eddies, 700 Edema, malignant, 434 EGFR. See Epidermal growth factor receptor EH. See Epithelioid hemangioma EHE. See Epithelioid hemangioendothelioma Ehlers-Danlos syndrome, 397–399 clinical features, 397 histopathological features, 397–398 Ehrlichia, 454 Ehrlichia chaffeensis, 451 Elastic globes, 401 Elastic tissue changes, variable, 405 Elastic tissue decreases, 402–405 Elastic tissue increases, 400–401 Elastin, 387–405, 712 alterations of, 400 Elastofibroma, 400 Elastolysis, generalized, 403

INDEX

Drug eruptions (Cont.): fixed, 43–44, 284–285, 285f clinical features of, 43–44, 283 differential diagnosis, 44, 285 histopathological features, 44, 284–285 lichenoid, 39, 283–284, 283t causes of, 284t clinical features, 40, 283 differential diagnosis, 40, 283 histopathological features, 40, 283 lymphomatoid, 290–291 clinical features, 290 differential diagnosis, 291 histopathological features, 290–291 morbilliform, 61 photosensitivity, 285–287 differential diagnosis, 286–287 histopathological features, 286 spongiotic, 27–28 clinical features, 27–28 histopathological features, 27–28 Drug reactions. See Drug eruptions Drug-associated alopecia, 291 Drug-associated ichthyosiform dermatoses, 293 clinical features, 293 differential diagnosis, 293 histopathological features, 293 Drug-associated vasculitis, 292–293 Drug-induced linear IgA disease, 288–289 Drug-induced lupus erythematosus (DIL), 284, 289 clinical features, 289 histopathological features, 289–290 Drug-induced pemphigoid, 288 clinical features, 288 histopathological features, 288 Drug-induced pemphigus, 144–145, 288 clinical findings, 144–145 differential diagnosis, 145 histopathological features, 145 Drug-induced pseudoporphyria cutanea tarda, 288 Drug-induced vasculitis diagnosis, 186 examples of, 186t DTE. See Desmoplastic trichoepithelioma Ductal apocrine adenocarcinoma (DAA), 752 Ductal apocrine carcinoma, 752, 753f, 754f Ductal eccrine adenocarcinoma (DEA), 745, 746–747 clinical features, 746 differential diagnosis, 747 with fibromyxoid stroma, 747 histopathologic features, 746–747 Ductopapillary apocrine carcinoma, 749–750, 751f differential diagnosis, 750 histopathological features, 750 Dupuytren contracture, 773 Dusty melanin, 654, 660 Dwarfism, 385 Dyschromatosis symmetrica, 347 Dyschromatosis universalis hereditaria, 347 Dyskeratosis, 36, 148, 302, 588 Dyskeratosis congenita, 59, 350 histopathological features, 350

1051

INDEX 1052

Elastoma, 400 Elastophagocytosis, 105, 107 Elastosis perforans serpiginosa (EPS), 240, 334–335, 334t, 400–401 clinical features, 334, 400 differential diagnosis, 335, 401 histopathological features, 334–335, 400–401 Elastotic nodules of ears, 402 Elastotic plaques of hands, 402 Elephant skin, 532 Elephantiasis, 533 ELISA. See Enzyme-linked immunosorbent assay EMA. See Epithelial membrane antigen Embryonal rhabdomyosarcoma, 873, 874–875, 874f Enbrel, 297 Encapsulated fat necrosis, 270 Encapsulated lipoma, 270 mobile, 271 Encapsulated neuromas, 886t Encephalitozoon intestinalis, 527 Encephalotrigeminal angiomatosis. See Sturge-Weber syndrome Endemic syphilis, 451 histopathological features, 451 Endometrioma, 412 Endometriosis, 411–413 clinical features, 412 differential diagnosis, 413 histopathological features, 412–413 Endoneurium, 883 Endothelial cells crystalline lamellae in, 806 EH and, 813 IH and, 802 pericytes and, 802 PILA and, 826 Endothrix, 231 Endovascular papillary angioendothelioma, 827 CH and, 827 End-stage scarring alopecia, 235 ENL. See Erythema nodosum leprosum Entamebiasis, 525t Entamoeba histolytica, 517 Enterobacter, 234 Entomophthoromycoses, 484 Entomophthoromycotina, 458, 483 Enzyme-linked immunosorbent assay (ELISA), 533 Eosinophilia-myalgia syndrome, 260 Eosinophilic fasciitis, 259–261, 260t, 261f, 276, 390 clinical features, 260, 390 differential diagnosis, 261 histopathological features, 260–261, 390 Eosinophilic folliculitis, 241–242, 243t, 244f clinical features, 241–242 differential diagnosis, 242 histopathological features, 242 HIV-associated, 242 Eosinophilic infiltrates, 131–133 parasitic causes of, 131t Eosinophilic panniculitis, 275t clinical features, 275 histopathological features, 275

Eosinophilic spongiosis, 6f, 15, 25f Eosinophils, 592, 907 EPD. See Extramammary Paget disease Ephelides, 350 differential diagnosis, 350 histopathological features, 350 Epidermal acanthosis, 27f Epidermal atrophy, 90 Epidermal growth factor inhibition, 296–297 clinical features, 296–297 histopathological features, 297 Epidermal growth factor receptor (EGFR), 296 Epidermal hyperplasia, Spitz nevus, 635 Epidermal inclusion cysts, 992 Epidermal nevi, 556–561 differential diagnosis, 556 histopathological features, 556 Epidermal processes, 3 in diagnosis, 5f Epidermal stem cells, 1022 Epidermis, 1022 alterations of, 14, 313–335 inflammatory conditions without, 6f inflammatory reaction patterns of, 8–10 overlapping, 10 tumors of, 556–602 Epidermodysplasia verruciformis, 508, 591 Epidermoid cysts (ECs), 543–544 histopathological features, 543–544 Epidermolysis bullosa, junctional, 326–327 clinical features, 326–327 Epidermolysis bullosa acquisita, 167–168 classical lesions of, 168f clinical features, 167 diagnostic tests, 168 differential diagnosis, 168 inflammatory, 167 variants, 167 Epidermolysis bullosa dystrophica, 327 clinical features, 327 differential diagnosis, 327 histopathological features, 327 Epidermolysis bullosa simplex, 326 clinical features, 326 differential diagnosis, 326 histopathological features, 326 Epidermolytic acanthoma, 562–563 clinical features, 562 differential diagnosis, 563 histopathological features, 562–563 Epidermolytic actinic keratoses, 571 Epidermolytic disorders, 324–326 Epidermolytic hyperkeratosis, 150, 151f bullous ichthyosis and, 328–329 clinical features, 150 differential diagnosis, 150 histopathological features, 150 Epidermotropic metastatic melanoma, 679f Epidermotropism, 678, 910, 911 Epithelial membrane antigen (EMA), 410, 962 leiomyosarcoma and, 872 Epithelioid angiomatosis. See Bacillary angiomatosis Epithelioid angiosarcoma EHE and, 829 KS and, 831

Epithelioid blue nevus, 643, 644f clinical features, 643 histopathologic features, 643 Epithelioid cell atypical melanocytic nevi, 655 Epithelioid cell dysplasia, 654 Epithelioid cells, 634 Epithelioid fibrous histiocytoma, 777 Epithelioid hemangioendothelioma (EHE), 827–829, 828f, 828t angiosarcoma and, 830 CH and, 827 EH and, 813 extraskeletal chondroma and, 876 SCH and, 808 Epithelioid hemangioma (EH), 811–813, 812f, 812t, 850 aAVM and, 845t BA and, 817 EHE and, 829 MVH and, 809 PILA and, 826 Epithelioid nevus cells, 671 Epithelioid sarcoma, 795, 972 clinical features, 795 differential diagnosis, 795 EHE and, 829 histopathologic features, 795 leiomyosarcoma and, 872 Epithelioid schwannoma, 890 Epithelioma basal cell, 579, 582 cuniculatum, 596 eccrine, 584 superficial, 691–692 Epithelioma-associated keratin amyloidosis, 375–376 EPS. See Elastosis perforans serpiginosa Epstein-Barr virus (EBV), 83, 264, 500, 511, 591, 599, 754 KS and, 819 Epulis fissuratum, 1012 clinical features, 1012 differential diagnosis, 1012 histopathologic features, 1012 Erdheim-Chester disease, 120 Erosive adenomatosis of nipple, 757–758 clinical features, 757 differential diagnosis, 758 histopathologic features, 757 Erosive adenosis, 409 Erosive pustular dermatosis of scalp, 232 Eruptive vellus hair cysts (EVHCs), 547 Erysipelas, 425–426 clinical features, 425 differential diagnosis, 425–426 histopathological features, 425 Erysipeloid, 426 clinical features, 426 histopathological features, 426 Erythema, toxic, of pregnancy, 84 Erythema ab igne, 402 histopathological features, 402 Erythema annulate centrifugum (EAC), 85 trigger factors, 86 Erythema chronicum migrans, 86, 451–452, 453f

EVHCs. See Eruptive vellus hair cysts EVMM. See Extravascular migratory metastasis Ewing sarcoma, 874 alveolar rhabdomyosarcoma and, 875 extraskeletal osteosarcoma and, 879 Ewing sarcoma family, 900, 971 Ewing sarcoma oncogene (EWS), 676 EWS. See Ewing sarcoma oncogene extraskeletal myxoid chondrosarcoma and, 877 EWSR1 gene, 867 Exanthematous drug eruptions, 282 clinical features, 282 differential diagnosis, 282 histopathological features, 282 Excisional specimen, 3 Exfoliative dermatitis, 24–25, 73 Exocytosis, 36 Exogenous agents, 301–310 arachnid reactions, 308 cold reactions, 303–304 heat reactions, 303–304 insect reactions, 308–310 irritation reactions, 301 marine agent reactions, 307–308 radiation reactions, 301–303 trauma reactions, 301 Exogenous pigment deposits, 384–385 Exophiala, 477 Extramammary Paget disease (EPD), 693, 729, 750, 752t, 961 Extraneural growth patterns, 887 Extranodal NK/T-cell lymphoma, 919–921, 920f clinical features, 919 differential diagnosis, 921 genotypic features, 919 histopathologic features, 919 immunophenotypic features, 919 Extraskeletal chondroma, 876 Extraskeletal mesenchymal chondrosarcoma, hemangiopericytoma and, 825 Extraskeletal myxoid chondrosarcoma, 861, 876–877, 877f Extraskeletal osteosarcoma, 878–879, 879f Extravascular migratory metastasis (EVMM), 669 F Fab portion, 517 Facial angiofibroma, 767 clinical features, 767 Factitial panniculitis, 271 clinical features, 271 differential diagnosis, 272 histopathological features, 271 Factor VIII, 595 Factor VIII- related antigen. See von Willebrand factor Factor XIIIa, 889 Familial amyloidotic polyneuropathy, 374 Familial dyskeratotic comedones, 560–561 clinical features, 560 differential diagnosis, 560–561 histopathological features, 560 Familial Hibernian fever, 191 Familial Mediterranean fever (FMF), 190 skin lesions of, 191

Fas/CD95, 43 Fasciitis, 46, 250–276, 276 eosinophilic, 259–261, 260t, 261f, 276, 390 necrotizing, 426, 427–428 nodular, 771–773, 972 proliferative, 772f tryptophan and, 260 Fasciitis ossificans, 878 Fasciitis panniculitis syndrome (FPS), 260, 276 Fasciola hepatica, 538 Fascioliasis, 538–539 clinical features, 538 differential diagnosis, 539 histopathological features, 539 Fat necrosis manifestations of, 250t WDL/ALT and, 866 Favre-Racouchot syndrome, 236 Favus, 231–232 clinical features, 231 differential diagnosis, 231–232 histopathological features, 231 FCH. See Folliculosebaceous cystic hamartoma Festooning, 380 Fetal rhabdomyoma (F-RM), 872–873, 873f Fibrin thrombi, 179 Fibrinoid degeneration, 179f, 182 Fibroblastic rheumatism, 394 clinical features, 394 differential diagnosis, 394 histopathological features, 394 Fibroblastoma, giant cell, 785–786, 786f Fibroblasts, 618 Fibroepithelial polyp, 766–767 clinical features, 766 differential diagnosis, 767 histopathologic features, 766–767 Fibroepithelioma of Pinkus, 585, 587f, 588, 730 Fibrofolliculoma, 712t, 713–714, 714f Fibrohistiocytic tumors, 766–797 benign, 775–781 of childhood, 781–786, 797 intermediate, 775–781 of intermediate malignancy, 786–791 malignant, 791–795 plexiform, 788–789 Fibrolipomas, 536 Fibroma, 993–994, 1012 clinical features, 994, 1012 differential diagnosis, 994, 1012 histopathologic features, 994, 1012 Fibroma of tendon sheath, 769–770 clinical features, 769 differential diagnosis, 770 histopathologic features, 769–770 Fibromatosis inclusion body, 781 infantile digital, 781–782 juvenile hyaline, 784 leiomyoma and, 869 palmar, 773–774 plantar, 773–774 Fibromyxoid proliferative responses, 700 Fibromyxoid stroma, 747

INDEX

Erythema elevatum diutinum, 187–188 clinical features, 187 differential diagnosis, 187–188 GCSF and, 127–128 histopathological features, 187 Erythema gyratum repens, 85–86 Erythema induratum of Bazin, 255, 268–269 histopathological features, 268–269 Erythema induratum of Whitfield, 268 Erythema infectiosum, 498 Erythema marginatum, 86 Erythema multiform, 40–42, 293–294 clinical manifestations of, 40–41 differential diagnosis, 42 histopathological features, 40–41 toxic epidermal necrolysis v., 42t Erythema nodosum, 252–255, 254f, 255t clinical features, 252–253 differential diagnosis, 255 histopathological features, 253–254 reaction pattern, 256f Erythema nodosum leprosum (ENL), 184, 269–270, 433 clinical features, 269–270 histopathological features, 270 HIV and, 270 Erythema toxicum neonatorum (ETN), 31–32, 154t clinical features, 154 differential diagnosis, 154 histopathological features, 154 Erythematous papules, 200f Erythrasma, 429 clinical features, 429 differential diagnosis, 429 histopathological features, 429 Erythroderma, 24–25, 32f, 72, 294–295 bullous congenital ichthyosiform, 328–329, 328t clinical features, 73, 294–295 histopathological features, 73 ichthyosiform, 322–323 ichthyotic, 318–319 Erythrodermatoderma variabilis, 320 clinical features, 320 differential diagnosis, 320 histopathological features, 320 Erythrokeratoderma variabilis, 320 clinical features, 320 differential diagnosis, 320 histopathological features, 320 Erythroleukoplakia, 1016 Erythroplakia, 1017 Erythroplasia of Queyrat, 575, 591 clinical features, 575 differential diagnosis, 575 histopathological features, 575 Escherichia coli, 123, 234, 482 Estrogen, unilateral nevoid telangiectasia and, 835 ETN. See Erythema toxicum neonatorum Etretinate, PG from, 813 Eumeces fasciatus, 451 Eumycetoma, 479–480 clinical features, 479 differential diagnosis, 480 histopathological features, 479–480

1053

INDEX 1054

Fibroosseous pseudotumor, 877–878, 878f extraskeletal chondroma and, 876 Fibroplasia, atypical decubital, 772 Fibrosarcoma, 793–794, 866 clinical features, 793 differential diagnosis, 793–794 histopathologic features, 793 Fibrosis, 392–393 differential diagnosis, 393 histopathological features, 393 Fibrous hamartoma of infancy, 784–785, 785f clinical features, 784 differential diagnosis, 785 histopathologic features, 784–785 Fibrous histiocytoma, 122–124, 669. See also Dermatofibroma aneurysmal, 777f angiomatoid, 777, 789–790 atypical, 776–777, 778f epithelioid, 777 Fibrous papule, 767 Fibrous tissue, 797 Fibrous tract, 213 Fibrous tumors, 766–797. See also specific types benign, 766–776 of childhood, 781–786, 797 of intermediate malignancy, 786–791 malignant, 791–795 solitary, 790–791 Fibroxanthomas, atypical, 778–780 Fifth disease, 496t, 498 Filoviruses, 503 Filterable agent, 495 Fite-Faraco acid-fast stain, 520 Fixed cutaneous disease, 475 Fixed drug eruption, 43–44, 284–285, 285f clinical features of, 43–44, 283 differential diagnosis, 44, 285 histopathological features, 44, 284–285 Flesh-eating bacteria, 427 Flexural skin melanocytic nevi, 625 Floret cells, 861 Florid intraepidermal melanoma, 667 Florid reactive periostitis. See Fibroosseous pseudotumor Flower cells, 952 Fluorouracil, 320 Fluoxetine, 304 FMF. See Familial Mediterranean fever Focal atypical epithelioid cell component, melanocytic nevi with, 649 differential diagnosis, 649 Focal dermal deposition, 364f Focal dermal hypoplasia, 395, 857 clinical features, 395 differential diagnosis, 395 nevus lipomatous superficialis and, 858 Focal epithelial hyperplasia, 1005–1006 clinical features, 1006 differential diagnosis, 1006 histopathologic features, 1006 Focal facial dermal dysplasia, 396 Focal melanocytic aggregates in lymph nodes, 632 in placenta, 632 in skin, 632

Focal panniculitis, 269 Focal parakeratosis, 74 Fogo selvagem, 143 Follicle center lymphoma, 932–933, 932t clinical features, 932 differential diagnosis, 933 immunology, 933 primary cutaneous, 934f Follicle-related mesenchyme, 711 pseudoneoplastic proliferations of, 718–720 Follicular atopic dermatitis, 19–20 Follicular basal cell carcinoma, 585 Follicular cheilitis, 305 Follicular cysts and sinuses, 111–113 clinical features, 112 histopathological features, 112 Follicular degeneration syndrome, 227–229 clinical features, 228 differential diagnosis, 229 histopathological features, 228–229 Follicular degenerative primary cutaneous mucinoses, 369 Follicular eczema, 19–20 differential diagnosis, 19–20 histopathological features, 19 Follicular hybrid cysts, 548 differential diagnosis, 548 histopathological features, 548 Follicular hyperkeratosis, 232–233 clinical features, 233 histopathological features, 233 Follicular infundibulum tumor, 697, 729 clinical features, 697 differential diagnosis, 697 Follicular mucinosis, 12, 910, 911f Follicular myxoma, 714 clinical features, 714 histopathologic features, 714 Follicular occlusion triad, 111, 230 clinical features, 111 differential diagnosis, 111 histopathological features, 111 Follicular spongiosis, 6f with lymphocyte exocytosis, 29f Follicular units, 213 description of, 215t Folliculitis, 233–242. See also specific types acneiform, 236 atypical mycobacterial, 235–236 bacterial, 234, 239f Demodex, 234–235, 241t eosinophlic, 241–242, 243t, 244f fungal, 234 herpes, 505 infectious, 234 Malassezia, 465–467 perforating, 240–241 subtypes, 239t ulerythematosa reticulata, 233 viral, 235 Folliculitis decalvans, 230, 237f clinical features, 230 differential diagnosis, 230 histopathological features, 230

Folliculosebaceous cystic hamartoma (FCH), 703 clinical features, 703 differential diagnosis, 703 histopathologic features, 703 Folliculotropic mycosis fungoides, 910, 911f Fonsecaea pedrosoi, 476 Fontana-Masson, 985 Forchheimer sign, 497 Fordyce granules, 1002 clinical features, 1002 differential diagnosis, 1002 histopathologic features, 1002 Foreign objects, angiosarcoma and, 829 Foreign-body granulomas, 103–104, 416–417 clinical features, 417 differential diagnosis, 103–104, 417 histopathological features, 417 Fowler solution, 573 Fox-Fordyce disease, 20–21, 243–244 clinical features, 243 differential diagnosis, 244 histopathological features, 243 FPS. See Fasciitis panniculitis syndrome Fragile X syndrome, 404 histopathological features, 404 Frambesia tropica, 449 Francisella tularensis, 435, 439 Freckles. See Ephelides French-American-British classification, 941t Friction blisters, 150 clinical features, 150 differential diagnosis, 150 histopathological features, 150 Friction melanosis, 352 histopathological features, 352 F-RM. See Fetal rhabdomyoma Frostbite, 303f, 591 Fungal folliculitis, 234 clinical features, 234 histopathological features, 234 Fungal infections, 458–490. See also specific types dematiaceous fungi, 474–477 histopathological features, 459t morphology, 987t nail plate biopsy, 983–985 systemic, 468–474 Fungal morphology, 984 Fusarium, 463, 484, 487 clinical features, 487 histopathological features, 487 G Ganglion cell choristomas, 900 Ganglioneuroblastoma, 901 Ganglioneuroma, 900, 901 Ganglions, 552 Gangosa, 450 GAP. See Granulomatous angiopanniculitis Gargoylism, 385 GAS. See Group A-beta hemolytic streptococci Gastroenteritis, 197

Giant cells, 618 Giant solitary sebaceous hyperplasia, 690 Giardiasis, 527 Giemsa, 438, 455, 521 Gingival cyst, 1003–1004 clinical features, 1004 differential diagnosis, 1004 histopathologic features, 1004 Gingival epulides, 1013–1014 Gingival nodules, 1014 Glandular lumina, 729 Glenosporella loboi, 488 Glenosporopsis, 488 Glial fibrillary acidic protein (GFAP), 962 Glial heterotopia, 415 Glomangioma. See Glomuvenous malformations Glomangiomatosis, 840–841 Glomangiomyomas, 840 Glomangiopericytoma, 841 hemangiopericytoma and, 825 SFTS and, 825 Glomangiosarcoma, 840–841 Glomeromycota, 483 Glomeruloid hemangioma (GH), 805, 806, 815–816, 816f Glomerulonephritis, 197 Glomus tumor, 839–841, 840f, 840t, 841f, 996 clinical features, 996 differential diagnosis, 996 histopathologic features, 996 Glomuvenous malformations (GVMs), 839–841, 840t VM and, 839 Glossina palpalis, 520 Glucagonoma syndrome, 77–78 clinical features, 77 histopathological features, 77–78 Glucose transporter molecule isoform 1 (GLUT-1), 803 KHE and, 824 NICH and, 805 RICH and, 805 VH and, 809 GLUT-1. See Glucose transporter molecule isoform 1 Glut-1, 261, 889 Glycosaminoglycans, 385, 581 GMCSF. See Granulocyte-macrophage colony-stimulating factor GMS. See Gomori methenamine silver Gnathostoma, 133, 275, 535 Gnathostoma spinigerum, 537f Gnathostomiasis, 536 Golberger, Joseph, 76 Gold deposition, 355 histopathological features, 355 Goldenhar syndrome, 408 Gomori methenamine silver (GMS), 429, 524 Gonococcal infections, 431 clinical features, 431 differential diagnosis, 431 histopathological features, 431 Good patterns, 5 Gorlin syndrome, 589 Gottran syndrome, 400 Gottron papule, 93

Gougerot-Blum disease, 193 Gout, 380–381 histopathological features, 381 Graft-versus-host disease, 285, 315 Graham-Little syndrome, 226 Gram stain, 455 Granular basal cell carcinoma, 581 adult rhabdomyoma and, 873 Granular cell tumor, 894–895, 895t clinical features, 894, 1018 different diagnosis, 1018 differential diagnosis, 895 histopathologic features, 894–895, 1018 Granular lumina, 412f Granular parakeratosis, 317, 592 clinical features, 322 differential diagnosis, 322 histopathological features, 322 Granulocyte colony-stimulating factor (GCSF), 295, 296 erythema elevatum diutinum and, 127–128 Granulocyte-macrophage colony-stimulating factor (GMCSF), 123 Granulocytic sarcoma, 946–947 clinical features, 946 differential diagnosis, 947 histochemical findings, 946–947 histopathologic features, 946 immunohistochemical findings, 946–947 Granuloma. See also specific types actinic, 107, 404 annulare, 104–105 clinical features, 104–105 deep, 106–107 interstitial form, 105–106 candidal, 464 Churg-Strauss, 109 coral reef, 428 cutaneous extravascular necrotizing, 109, 198 foreign-body, 103–104, 416–417 differential diagnosis, 103–104 lethal midline, 99 lipophagic, 257 Majocchi, 240f palisading, 261 pyogenic, 803t, 813–815, 814f, 814t, 823t, 1013f traumatic ulcerative, 1006 Granuloma faciale, 127–128, 187, 188, 189t clinical features, 188 differential diagnosis, 188 histopathological features, 188 Granuloma fissuratum, 561 clinical features, 561 differential diagnosis, 561 histopathological features, 561 Granuloma gravidarum. See Pyogenic granuloma Granuloma inguinale, 436–437, 440t clinical features, 436 differential diagnosis, 437 histopathological features, 436 Granuloma pyogenicum. See Pyogenic granuloma

INDEX

Gastrointestinal carcinoma, 967–968 clinical features, 967 differential diagnosis, 967–968 histopathologic features, 967 immunohistochemistry, 968 special stains, 968 GCDFP. See Gross cystic disease fluid protein GCSF. See Granulocyte colony-stimulating factor Generalized elastolysis, 403 Generalized eruptive histiocytosis, 120 clinical features, 120 differential diagnosis, 120 histopathological features, 120 Generalized essential telangiectasia, 832, 847, 848f HHT and, 834 Generalized exanthematous pustulosis, 153 Generalized hyperpigmentation disorders, 346 Generalized lentiginosis, 349 Generalized melanosis in metastatic melanoma, 352 Generalized myxedema, 363–364 histopathological features, 364 Generalized staphylococcal scalded skin syndrome, 147 clinical features, 147 histopathological features, 147 Genital rhabdomyoma, 873 Genital skin melanocytic nevi, 624–625 clinical features, 625 differential diagnosis, 625 histopathological features, 625 Genital tract tumors clinical features, 970 differential diagnosis, 970 histopathologic features, 970 immunohistochemistry, 970 special stains, 970 Genotyping, 907 Geographic tongue, 68 Germinal center cells, 929 Germinative follicular epithelium tumors, 702 GFAP. See Glial fibrillary acidic protein GH. See Glomeruloid hemangioma Gherkin-Goltz syndrome, 589 Ghost cells, 702 Gianotti-Crosti syndrome, 28–29, 34f, 498 clinical features of, 28–29 histopathological features of, 28–29 Giant cell arteritis, 203 Giant cell fibroblastoma, 785–786, 786f APL and, 844 clinical features, 785 differential diagnosis, 786 histopathologic features, 785–786 Giant cell tumor, 780–781 clinical features, 780–781 extraskeletal chondroma and, 876 Giant cell tumor of tendon sheath, 780–781 clinical features, 780 histopathological features, 781 Giant cell variant malignant fibrous histiocytoma, 791–792

1055

INDEX 1056

Granulomatosis orofacial, 1009–1010 vasculitis with, 194–195 Wegener, 109, 184, 197–199, 198t Granulomatous angiopanniculitis (GAP), 275 Granulomatous black skin, 404, 912 Granulomatous dermatitis infectious palisaded, 110–111 palisaded neutrophilic, 109–111 Granulomatous diseases, 404 Granulomatous infiltrates, 98–104 Granulomatous inflammation, inflammatory conditions with, 6f Granulomatous mycosis fungoides, 911–912, 912f Granulomatous reaction patterns, 12 Granulomatous rosacea, 243f Granulomatous slack skin, 913f Granulomatous vasculitis, 196f differential diagnosis, 196f Graphite, 354f Graves disease, 364 Grenz zone, 778 Grocer’s itch, 308 Groove sign, 443 Gross cystic disease fluid protein (GCDFP), 963 Group A-beta hemolytic streptococci (GAS), 276 Grover disease, 328, 331–332, 332f. See also Transient acantholytic dermatosis clinical features, 332 differential diagnosis, 332 histopathological features, 332 Guttate psoriasis, 66f, 67f GVMs. See Glomuvenous malformations Gyrate erythemas, 85–86 clinical features, 85–86 differential diagnosis, 86 histopathological features, 86 H HAART. See Highly active antiretroviral therapy Haber syndrome, 556 Haemophilus, 437 Haemophilus ducreyi, 437, 446 Hailey-Hailey disease, 331 clinical features, 331 differential diagnosis, 331 histopathological features, 331 Hair follicle, 1022 disorders, 12–13 pseudoneoplastic proliferations of, 718–720 Hair follicle hamartoma, 718 differential diagnosis, 718 Hair follicle nevus, 719 clinical features, 719 differential diagnosis, 719 histopathologic features, 719 Hair follicle tumors, 689–720 Hairs anagen, 215t catagen, 218 telogen, 215t terminal, 213, 215t vellus, 213, 215t vellus-like, 213

Hairy cell leukemia, 951–952 clinical features, 951 histochemical features, 951–952 histopathologic features, 951 immunohistochemical features, 951–952 Haley-Haley disease, 148–149 clinical features, 148 differential diagnosis, 148–149 histopathological features, 148 Hallermann-Streiff syndrome, 222 Hallopeau-Siemens syndrome, 171t, 327 Halo atypical melanocytic nevi, 655 Halo basal cell carcinoma, 580 Halo nevus, 620–621, 663 atypical, 663 clinical features, 620 differential diagnosis, 621 histopathological features, 620–621 Halo Spitz nevus, 639 Halogenodermas, 111, 113t, 294 clinical features, 111, 294 differential diagnosis, 111 histopathological features, 111, 294 Hamartomas, 857 basaloid follicular, 588, 708–709, 709f dermal melanocyte, 642 eccrine angiomatous, 755 fibrous, of infancy, 784–785, 785f hair follicle, 718 neurofollicular and pilar neurocristic, 719–720 of peripheral nerve, 883–884 pilar neurocristic, 648 Hamartomatous cutaneous mucinoses, 370–371 Hamazaki-Wasserman bodies, 101 Hand, foot, and mouth disease, 496t, 499 clinical features, 499 differential diagnosis, 499 histopathological features, 499 Hands collagenous plaques of, 402 elastotic plaques of, 402 Hanger-Rose test, 440 Hanging groin, 532 Hansen disease. See Leprosy Hantaviruses, 503 Harlequin ichthyosis, 316–317 clinical features, 316–317 differential diagnosis, 317 histopathological features, 317 Hartnup disease, 77 Hashimoto-Pritzker disease. See Congenital self-healing Langerhans histiocytosis Hat bulb, 215t HBID. See Hereditary benign intraepithelial dyskeratosis hCG. See Human chorionic gonadotropin HDs. See Hemidesmosomes Heat reactions, 303–304 clinical features, 303–304 differential diagnosis, 304 histopathological features, 304 Helicobacter pylori, 83, 1006 Helminthic diseases, 530–540. See also specific diseases

Helper T cells, 218 Hemangioma, 589 angiolipoma and, 859 epithelioid, 809, 811–813, 812f, 812t, 817, 826, 829, 850 aAVM and, 845t BA and, 817 EHE and, 829 MVH and, 809 PILA and, 826 glomeruloid, 805, 806, 815–816, 816f hobnail APL and, 844 PILA and, 826 RH, 826 infantile, 802–805, 803f, 804f clinical features of, 803t endothelial cells and, 802 KMS and, 824 platelets and, 802 lobular capillary AAD and, 819 BA and, 817 cherry angioma and, 850 IPEH and, 816 KS and, 821 MVH and, 809 PWSs and, 832 TA and, 805 microvenular, 808–809, 809f, 809t acute myelogenous leukemia and, 809 dermatofibroma and, 809 Epithelioid hemangioma (EH) and, 809 HHV and, 809 histologic features of, 823t KS and, 809 PG and, 809 POEMS and, 809 sclerosing hemangioma and, 809 TA and, 809 THH and, 809 Wiskott-Aldrich syndrome and, 809 papillary, 807, 807f GH and, 807 hyaline globules and, 807 NICH and, 807 POEMS and, 807 rapidly involuting congenital, 804–805 sclerosing, 776, 809, 811 sinusoidal, 838 spindle cell, 807–808, 807t, 808f angiosarcoma and, 807, 830 CD31 and, 808 CD34 and, 808 CH and, 827 early-onset varicose veins and, 807 epithelioid hemangioendothelioma and, 808 human herpes virus and, 808 Klippel-Trenaunay syndrome and, 807 KS and, 808, 823 Maffucci syndrome and, 807–808, 838 Milroy disease and, 807 phlebolith and, 808 Ulex europaeus lectin-1 and, 808 VM and, 839 von Willebrand factor and, 808

Herpes gestationis, 160, 161–162 clinical features, 161 diagnostic tests, 161 differential diagnosis, 161–162 histopathological features, 161 Herpes simplex virus, 504–515, 505f clinical features, 504 histopathological features, 504 Herpes zoster, 496t, 504–506 clinical features, 505–506 differential diagnosis, 506 histopathological features, 506 Herring-bone fascicles, 797 Herring-bone pattern, 896 Heterotopic meningeal tissue, 897–898 clinical features, 897 differential diagnosis, 897–898 histopathologic features, 897 Heterotopic neuroblastic tissue, 900–901 clinical features, 900–901 differential diagnosis, 901 histopathological features, 901 Heterotopic neuroglial tissue, 898–899 clinical features, 899 differential diagnosis, 900 histopathologic features, 899–900 HHF35, 116 HHT. See Hereditary hemorrhagic telangiectasia HHV. See Human herpes virus Hibernoma, 863–864, 863f, 863t adult rhabdomyoma and, 873 Hidradenitis, 13 neutrophilic eccrine, 244 palmoplantar eccrine, 245 Hidradenitis suppurativa, 114f, 238, 241t, 242f clinical features, 238 histopathological features, 238 Hidradenocarcinomas, 732, 748 Hidradenoma clear cell, 732 poroid, 729 solid and cystic, 732 tubulopapillary, 731 Hidradenoma papilliferum (HP), 731, 734–735, 736f clinical features, 734 differential diagnosis, 734–735 histopathological features, 734 Hidradenomas, nodular, 588 Hidroa vacciniforme-like lymphoma, 921 Hidrocystomas apocrine, 756–757 eccrine, 756–757 Hidrotic ectodermal dysplasia, 320 High magnification, 4 High-grade pleomorphic sarcoma, 791 Highly active antiretroviral therapy (HAART), 468, 473 Hirsutism, 385 Histamine, 81–82 Histiocytoid hemangioma. See Epithelioid hemangioendothelioma; Epithelioid hemangioma Histiocytoma aneurysmal fibrous, 777f angiomatoid fibrous, 777, 789–790, 789t, 790f

Histiocytoma (Cont.): atypical fibrous, 776–777, 778f epithelioid fibrous, 777 fibrous, 122–124, 669 hemosiderotic, 776 malignant fibrous, 791–792 giant cell variant, 791–792 hemangiopericytoma and, 825 pleomorphic, 791–792 progressive nodular, 122 Histiocytosis, 113 benign cephalic, 119–120 congenital self-healing Langerhans, 117 generalized eruptive, 120 hereditary progressive mucinous, 122 indeterminate cell, 118 Langerhans cell, 116–117 Histoid leprosy, 432 Histoplasma capsulatum, 465, 520 Histoplasmosis, 459t African, 474 chronic pulmonary, 473 classic, 473–474 disseminated, 473–474 HIV, 468. See also Acquired immunodeficiency syndrome acute exanthem of, 496t, 499–502 clinical features, 500 cutaneous manifestations of, 500–502 differential diagnosis of, 502 histopathological features, 500 bacillary angiomatosis in, 501 basal cell carcinoma in, 579 in classic histoplasmosis, 473 cutaneous drug eruptions and, 281 cutaneous manifestations of, 500t cytomegalovirus in, 511 in ENL, 270 eosinophilic folliculitis associated with, 242 interface dermatitis of, 44 clinical features, 44 differential diagnosis, 44 histopathological features of, 44 KHE and, 824 KS and, 819, 820 leishmaniasis in, 518 lipoatrophy and, 274 lipodystrophy and, 274 Pneumocystis carinii and, 501 in scabies, 75 spread of, 500 syphilis in, 501 HLA associations, 306 HLA-B6, 557 HLA-B51, 186 HLA-DR antigens, 587 HMB45, 669, 780, 962, 965 angiomyolipoma and, 862 leiomyosarcoma and, 872 HMGA2 gene, 858 Hobnail hemangioma. See also Targetoid hemosiderotic hemangioma APL and, 844 PILA and, 826 RH, 826 Hodgkin disease, 146 Homer-Wright rosettes, 901

INDEX

Hemangioma (Cont.): targetoid hemosiderotic, 809–811, 810f, 810t APL and, 810, 811 D2-40 antibody and, 809 HHV and, 810 histologic features of, 823t KS and, 810–811, 823 MVH and, 809 Retiform hemangioendothelioma and, 810 RH and, 811, 827 sclerosing hemangioma and, 811 Ulex europaeus lectin-1 and, 810 Vascular endothelial growth factor and, 809 von Willebrand factor and, 810 verrucous, 809, 836–838, 837f, 837t Hemangioma with Kaposi sarcoma-like features. See Kaposiform hemangioendothelioma Hemangiopericytoma, 824–825, 825f dedifferentiated liposarcoma and, 866 myolipoma and, 862 SFTS and, 825 Hematopoiesis, 384 Hematopoietic malignancies, 961 Hematoxylin, 105, 213, 341 Heme synthase, 380 Hemidesmosomes (HDs), 156, 587 Hemochromatosis, idiopathic, 354 Hemolymphatic malformation, 842 Hemosiderin, 354–355 KS and, 821 VH and, 837 Hemosiderotic histiocytoma, 776 Hendersonula toruloidea, 462, 463 Henoch-Schönlein purpura (HSP), 191, 196, 281, 498 angioma serpiginosum and, 836 diagnosis, 184 Heparin, 383 Hepatitis A virus, 503 Hepatitis B antibodies, 183 Hepatitis B virus, 503 Hepatitis C, 37, 183, 185, 365 unilateral nevoid telangiectasia and, 835 Hepatomegaly, 319 Hepatosplenomegaly, 385, 924 Herald patch, 73 Hereditary benign intraepithelial dyskeratosis (HBID), 1002 Hereditary benign telangiectasia, 832, 833 HHT and, 834 Hereditary hemorrhagic telangiectasia (HHT), 832, 833–834, 834t, 835f Hereditary progressive mucinous histiocytosis, 122 clinical features, 122 differential diagnosis, 122 histopathological features, 122 Hermansky-Pudlak syndrome, 342–343 clinical features, 342 histopathological features, 342–343 Herpes folliculitis, 505

1057

INDEX 1058

Horizontal growth phase, 657 Hortaea werneckii, 477 Host response, 654 HP. See Hidradenoma papilliferum HPV. See Human papillomavirus HRAS gene, 636 HSP. See Henoch-Schönlein purpura HTLV-1. See Human T-lymphotropic virus 1 Human chorionic gonadotropin (hCG), 963 Human growth hormone, 274 Human herpes virus (HHV), 73, 281, 498, 510, 850 APL and, 844 BA and, 817 KHE and, 824 KS and, 819, 823, 831 MVH and, 809 RH and, 827 SCH and, 808 THH and, 810 Human papillomavirus (HPV), 495, 506–510, 507t, 508f, 562, 567, 570, 590, 591, 1005 clinical features, 506–508 differential diagnosis, 509–510 infection with, 508–509 Human T-lymphotropic virus 1(HTLV-1), 908 Humira, 297 Hutchinson melanotic freckle, 655 Hutchinson sign, 659 Hutchinson-Gilford syndrome, 399–400 Hyaline angiopathy, 380 Hyaline depositions, 371 Hyaline globules KS and, 821 PH and, 807 Hyalinizing spindle cell tumor, 794 Hyalinizing Spitz nevus, 639 Hyalinosis cutis et mucosae, 378 differential diagnosis, 378 histopathological features, 378 Hyalohyphomycosis, 477, 487 Hyaluronic acid, 595, 792 Hybrid epidermoid and apocrine cyst, 554 differential diagnosis, 554 histopathological features, 554 Hydralazine, 289 Hydroa vacciniforme, 90, 305, 306 Hydrocephalus, 632 Hydroquinone, 353 Hyperchromatism, 671 Hypereosinophilic syndrome, 133 clinical features, 133 differential diagnosis, 133 histopathological features, 133 Hyperimmunoglobulinemia D, 190 Hyperkeratosis, 5f, 90, 314t, 837 epidermolytic, 150, 151f without epidermolytic change, 313, 313f follicular, 232–233 subungual, 983 Hyperkeratotic seborrheic keratosis, 565 Hyperorthokeratosis, 313–317, 314t clinical features, 314 histopathological features, 314–315 prominent stratum granulosum, 317–322 and prominent stratum granulosum, 317–322

Hyperoxaluria, 259 Hyperparakeratosis, 322–324 granular parakeratosis, 322 Hyperpigmentation disorders, 339f, 346–357 acromelanosis, 347 Addison disease, 346 clofazimine-induced, 123 Crow-Fukase syndrome, 347 diffuse, 346 generalized, 346 Nelson syndrome, 346 POEMS, 347 postinflammatory, 352 differential diagnosis, 352 histopathological features, 352 zosteriform, 352 Hyperplasia atypical lymphocytic, 908 cutaneous B-cell lymphoid, 926–929 focal epithelial, 1005–1006 inflammatory papillary, 1012–1013 lymphoid, 905 sebaceous, 689–691 syringolymphoid, 911–912 verrucous, 1017 Hypertensive portal gastropathy, RAE and, 817 Hypertrichosis, 380 Hypertriglyceridemia, 265 Hypertrophic collagenoses, 391–394 Hypertrophic keloid, 766 clinical features, 766 differential diagnosis, 766 histopathological features, 766 Hypertrophic lichen planus, 39f Hypertrophic lupus erythematosus, 48 Hypertrophic scars, 392–393, 766 clinical features, 766 differential diagnosis, 393, 766 histopathologic features, 766 histopathological features, 393 Hypervitaminosis D, 258 Hyphae, 458 Hypogranulosis, 67 Hypomelanosis of Ito, 344 differential diagnosis, 344 histopathological features, 344 Hypopigmentation disorders, 338–346, 342t Ash leaf spots, 343 Chédiak-Higashi syndrome, 343 Hermansky-Pudlak syndrome, 342–343 hypomelanosis, 345 hypomelanosis of Ito, 344 idiopathic guttate hypomelanosis, 344 incontinentia pigmenti achromians, 344 nevus anemicus, 345–346 nevus depigmentosus, 344–345 oculocutaneous albinism, 341–342 piebaldism, 338–339 pityriasis alba, 345 postinflammatory leukoderma, 345 vitiligo, 340–341 Vogt-Koyanagi-Harada syndrome, 340–341 Hypopigmented blue nevus, 645 Hypospadia, CMTC and, 835 Hypotrichosis, congenital, 228f

I Iatrogenic calcinosis, 383 histopathological features, 383 ICAM-1. See Intercellular adhesion molecule 1 Ichthyophorus, 489 Ichthyosiform erythroderma, 322 Ichthyosis, bullous, 328–329 Ichthyosis bullosa of Siemens, 329 clinical features, 329 differential diagnosis, 329 histopathological features, 329 Ichthyosis follicularis, 321 clinical features, 321 differential diagnosis, 321 histopathological features, 321 Ichthyosis hystrix of Curth and Macklin, 329 clinical features, 329 differential diagnosis, 329 histopathological features, 329 Ichthyosis vulgaris, 313–315 Ichthyotic erythroderma, neutral lipid storage disease, 318–319 Idiopathic guttate hypomelanosis, 344 clinical features, 344 histopathological features, 344 Idiopathic hemochromatosis, 354 differential diagnosis, 354 histopathological features, 354 Idiopathic lobular panniculitis, 261 Idiopathic type deposits, 382–383 IEE. See Intraepidermal epithelioma IFN. See Interferons IgA. See Immunoglobulin A IgA pemphigus, 145 clinical features, 145 differential diagnosis, 145 histopathological features, 145 IgC. See Immunoglobulin C IgE. See Immunoglobulin E IgG. See Immunoglobulin G IgM. See Immunoglobulin M IH. See Infantile hemangioma IL-1. See Interleukin 1 IL-5. See Interleukin 5 ILVEN. See Inflammatory linear verrucous epidermal nevus Immature nerve sheath myxomas, 892 Immediate hypersensitivity reactions, 281 Immune-complex-mediated reactions, 281 Immune-mediated conditions, 1006–1014 Immunoblasts, 910 Immunocytochemistry, 313 Immunofluorescence dermatomyositis, 94 direct, 91–93, 159, 165 IgG, 144 indirect, 92–93, 159 lupus erythematosus, 91t mixed connective tissue disease, 94 Immunoglobulin A (IgA), 183 Immunoglobulin C (IgC), 167 Immunoglobulin E (IgE), EH and, 813 Immunoglobulin G (IgG), 138, 140, 185, 340, 534 immunofluorescence, 144 Immunoglobulin M (IgM), 185, 523

Infectious cellulitis, 426t Infectious folliculitis, 234 Infectious mononucleosis, 496t, 502–503 clinical features, 502–503 Infectious palisaded granulomatous dermatitis, 110–111 clinical features, 111 differential diagnosis, 111 histopathological features, 111 Infectious vasculitis, diagnosis, 183–184 Infiltrates. See also specific types acute myeloid leukemia, 942t bandlike, 906 chronic lymphocytic leukemia, 948t of chronic myeloid leukemia, 947t cutaneous leukemic, 940–952 dermal inflammatory, 11t diffuse dermal, 11f, 98–133 diffuse histiocytic, 113–122 diffuse lymphocytic-plasma cellular, 128t eosinophilic, 131–133 parasitic causes of, 131t granulomatous, 98–104 interstitial lymphocytic, 160f Jessner lymphocytic, 86 leukemic, 905–952 lymphocytic-plasma cellular, 128–129 lymphoid, 905–952 mast cell, 130–131 neutrophilic, 124–127 infectious causes of, 125t nodular dermal, 11f, 98–133 palisaded granulomatous, 104–111 peribulbar lymphocytic, 219 perivascular inflammatory cell, 81t, 160f, 635 suppurative granulomatous, 111–113 Infiltrative basal cell carcinoma, 583, 584f, 588, 706 Inflammatory angiomatous nodules with abnormal blood vessels. See Epithelioid hemangioma Inflammatory conditions without epidermal alterations, 6f with granulomas, 6f with granulomatous inflammation, 6f without vascular injury, 6f Inflammatory lesions, features of, 5–8 Inflammatory linear verrucous epidermal nevus (ILVEN), 60, 76, 114, 558–559 clinical features, 76, 558 differential diagnosis, 76, 559 histopathological features, 76, 558–559 Inflammatory morphea, 387 Inflammatory papillary hyperplasia, 1012–1013 clinical features, 1012–1013 differential diagnosis, 1013 histopathologic features, 1013 Inflammatory primary cutaneous mucinoses, 363–369, 369 Inflammatory reaction patterns of dermis, 10–14 absence of vascular injury, 10–11 granulomatous reaction patterns, 12 hair follicle, 12–13 panniculitis, 13 presence of vascular injury, 12 skin appendages, 12 sweat apparatus, 13

Inflammatory reaction patterns (Cont.): of epidermis, 8–10 interface dermatitis, 9 overlapping, 10 psoriasiform dermatitis, 9 spongiotic dermatitis, 8–9 vesicular and bullous dermatitis, 9–10 major, 8–14 Inflammatory vascular reaction, 180f Infliximab, 297 Infrabasilar, 6f Infundibular adenoma, 692 Infundibular cysts, 543 Infundibulocystic basal cell carcinoma, 584–585, 586 Inherited autoinflammatory syndromes, 190–199 ANCA-associated systemic vasculitides, 195–196 bowel-associated dermatosis-arthritis syndrome, 191 Churg-Strauss syndrome, 196–197 lymphocytic vasculitides and vascular reactions, 192 lymphomatoid vascular reactions, 194 lymphomatoid vasculitis, 194 microscopic polyarteritis nodosum, 199 perniosis, 192–193 pigmented purpuric dermatitis, 193–194 pyoderma gangrenosum, 191–192 vasculitis with granulomatosis, 194–195 Wegener granulomatosis, 197–199 Inherited patterned lentiginosis, 347 Inherited pityriasis rubra pilaris, 321–322 clinical features, 321 differential diagnosis, 321–322 histopathological features, 321 Inhibin, pleomorphic liposarcoma and, 868 Insect reactions, 308–310 clinical features, 309 differential diagnosis, 310 Insulin, 274 Insulin amyloidosis, 376 α6β4 integrin, 156 Intercellular adhesion molecule 1 (ICAM-1), 39, 587 PILA and, 826 Interface dermatitis, 9, 36–61. See also specific types algorithm, 36 cell-poor, 90 of HIV infection, 44 clinical features, 44 differential diagnosis, 44 histopathologic features, 44 leukocyte infiltration, 36 miscellaneous diseases with features of, 59–61 vacuolar alteration, 36–37 Interferons (IFN), 295, 296 Interleukin 1 (IL-1), 81–82, 296, 425 Interleukin 5 (IL-5), 471 Intermediate lesions, 576–578 Intermediate magnification, 4 International Society for the Study of Vascular anomalies (ISSVA), 802, 802t, 831

INDEX

Immunohistochemical findings acute myeloid leukemia, 943 adult T-cell lymphoma/leukemia, 952 breast carcinoma, 964–965 chronic lymphocytic leukemia B-cell type, 949 chronic myeloid leukemia, 946 EHE and, 829 extraskeletal osteosarcoma and, 879 gastrointestinal carcinoma, 968 genital tract tumors, 970 granulocytic sarcoma, 946–947 hairy cell leukemia, 951–952 KS and, 831 leiomyosarcoma and, 871 lung carcinoma, 966–967 myelodysplastic syndrome, 948 myelomonocytic leukemia, 944 neuroendocrine carcinoma, 971 oral carcinomas, 968 sarcoma, 972–973 schwannoma, 890 sinonasal carcinomas, 968 sweat gland tumors, 758t, 759 T-cell prolymphocytic leukemia, 950–951 thyroid tumors, 970–971 urinary tract tumors, 969 Immunologic drug reactions, 281 Immunoperoxidase, 455 Immunophenotyping, 907, 912 Immunoreactants, 48 Impetigo, 152, 421–423 bullous, 152 clinical features, 152, 422 differential diagnosis, 152, 422–423 histopathological features, 152, 422 Implantation epidermoid cysts, 992 In situ hybridization (ISH), 517 Inclusion body fibromatosis, 781 Incontinentia pigmenti, 30–32, 34f, 349–350 clinical features of, 31 differential diagnosis, 31–32, 349–350 histopathological features of, 31, 349 Indeterminate cell histiocytosis, 118 Indirect immunofluorescence, 92–93 bullous pemphigoid, 159 Infantile acropustulosis clinical features, 154 differential diagnosis, 154 histopathological features, 154 Infantile digital fibromatosis, 781–782 clinical features, 781–782 differential diagnosis, 782 histopathological features, 782 Infantile hemangioma (IH), 802–805, 803f, 804f clinical features of, 803t endothelial cells and, 802 KMS and, 824 platelets and, 802 Infantile hemangiopericytoma, 783 Infantile myofibromatosis, 782–784, 783t clinical features, 782 differential diagnosis, 783 histopathologic features, 782–783 Infection-related panniculitis, 267–268, 269f clinical features, 267–268 differential diagnosis, 268 histopathological features, 268

1059

INDEX 1060

Interstitial granuloma annulare, 105–106 differential diagnosis, 105–106 histopathological features, 105 Interstitial granulomatous drug reaction, 295 clinical features, 295 histopathological features, 295 Interstitial lymphocytic infiltrates, 160f Intracellular edema, 137 Intracytoplastic lumina, 963 Intradermal poroma, 730f Intraepidermal blistering, 136f, 137f, 139t Intraepidermal carcinomas, 573–576 Intraepidermal component, 636 lentiginous, 660–662 pagetoid, 660 Intraepidermal epithelioma (IEE), 575 Intraepidermal melanoma, florid, 667 Intraepidermal pagetoid spread of melanocytes, 630 Intraepidermal vesicular and pustular dermatitis, 10t Intraepidermal vesiculopustular diseases, 136–154. See also specific disorders definitions, 136–138 Intraepithelial component adjacent, 662 in cutaneous melanoma, 659–660 Intraepithelial epithelioma, 575–576 of Borst-Jadassolm, 575 clinical features, 576 differential diagnosis, 576 histopathological features, 576 Intralaminar melanin, 986 Intramuscular myxoma, extraskeletal myxoid chondrosarcoma and, 877 Intraneural growth patterns, 887 Intrastratum spinosum, 6f Intravascular bronchioloalveolar tumor. See Epithelioid hemangioendothelioma Intravascular disseminated angiosarcoma, angioendotheliomatosis and, 817 Intravascular large B-cell lymphoma, 937 clinical features, 937 differential diagnosis, 937 histopathological features, 937 immunology, 937 Intravascular papillary endothelial hyperplasia (IPEH), 807, 816–817, 816t, 817f GH and, 816 PILA and, 826 Intravenous atypical vascular proliferation. See Epithelioid hemangioma Intravenous immunoglobulin (IVIG), 43, 93, 294 Invasive component, 665–669 Invasive melanoma, 660 Invasive pilomatricoma, 717, 718t clinical features, 717 differential diagnosis, 717 histopathologic features, 717 IPEH. See Intravascular papillary endothelial hyperplasia Irritant contact dermatitis, 17 clinical features of, 17 histopathologic features of, 17 Irritant contact vulvitis, 26f Irritated seborrheic keratosis, 566

Irritation reactions, 301 clinical features, 301 differential diagnosis, 301 histopathological features, 301 Ischemic necrosis, subcutaneous fat, 255 ISH. See In situ hybridization Islet amyloid polypeptide, 376 Isotretinoin, PG from, 813 ISSVA. See International Society for the Study of Vascular anomalies IVIG. See Intravenous immunoglobulin J JEB. See Junctional epidermolysis bullosa Jellyfish, 307 Jessner lymphocytic infiltrate, 86 Jones, Wilson, 805 Junctional atypical melanocytic nevi, 652 Junctional cleavage, Spitz nevus, 635 Junctional epidermolysis bullosa (JEB), 169–170 clinical features, 169 diagnostic measures, 170 differential diagnosis, 170 of Herlitz type, 170t of non-Herlitz type, 170t with pyloric, 170t variants, 170t Junctional nevus, 618 architectural disorder with, 654f Junin, 503 Juvenile granulomatous cutaneous T-cell lymphomas, 912 Juvenile hyaline fibromatosis, 784 clinical features, 784 differential diagnosis, 784 histopathologic features, 784 Juvenile xanthogranuloma, 893 Juxtaarticular nodes, 452 K K7 EH and, 812 EHE and, 828 K18, EHE and, 828 K19, EH and, 812 Kala-azar, 518 Kamino bodies, Spitz nevus, 635 Kaposi sarcoma (KS), 510–511, 804, 819–823, 820t, 821f, 822f, 850 AAD and, 819 AIDS and, 810, 820, 831 angiolipoma and, 859 APL and, 844 BA and, 817 histologic features of, 823t KHE and, 824 MVH and, 809 promontory sign and, 821 SCH and, 808 TA and, 806 THH and, 810–811 Kaposiform hemangioendothelioma (KHE), 803t, 804, 823–824 TA and, 805 Kaposi-like infantile hemangioendothelioma. See Kaposiform hemangioendothelioma

Kasabach-Merritt syndrome (KMS), 802 IH and, 824 KHE and, 823–824, 824 TA and, 805, 824 Kawasaki syndrome, 202 clinical features, 202 histopathological features, 202 Keloidal blastomycosis, 488–489 clinical features, 488 differential diagnosis, 488 histopathological features, 488–489 Keloids, 392–393 differential diagnosis, 393 histopathological features, 393 Keratin 9, 320 alveolar rhabdomyosarcoma and, 875 Keratin pseudocyst, 5f Keratinization, 983 Keratinocyte-keratinocyte adhesion, 137 Keratinocytes, 67, 302 cytolysis of, 137 fluorescence, 93 Keratinocytic dysplasia, 570–573 Keratoacanthoma, 330, 512, 556, 576–578, 996–997 clinical features, 577, 996 differential diagnosis, 578, 997 histopathological features, 577–578, 996 subungual, 577 Keratoacanthoma centrifugum, 577 Keratoderma blenorrhagicum, 68 Keratoderma climactericum, 320 Keratohyalin, 314 Keratolysis, pitted, 430 Keratomycosis, 478 Keratosis, 239f, 562–569, 570–572 arsenical, 573 benign, 5f lichenoid, 616 psoriasiform, 566 scarring follicular, 233 seborrheic, 5f stucco, 601 Keratosis follicularis, 76 Keratosis pilaris. See Follicular hyperkeratosis Keratosis pilaris atrophicans (KPA), 233, 396 differential diagnosis, 396 histopathological features, 396 Keratosis pilaris spinulosa decalvans (KPSD), 233 Keratotic basal cell carcinoma, 584–585 Kerion, 231–232 clinical features, 231 differential diagnosis, 231–232 histopathological features, 231 KHE. See Kaposiform hemangioendothelioma Ki-67, 575, 585 Kickxellomycotina, 458, 483 Kikuchi disease, 50 Kimura disease, EH and, 811–813 Kindler syndrome, 170–171, 172t clinical features, 170–171 diagnosis, 171 differential diagnosis, 171 histopathological features, 171 KIT gene, 338

L Lacazia loboi, 473 LAD-1. See Ladinin Ladinin (LAD-1), 289 Lagochilascariasis, 536 Lahore sore, 518 LAM. See Lymphangioleiomyomatosis LAMB3, 326 Lamellar bone, 384 Lamellar ichthyosis (LI), 78, 318 autosomal recessive, 318t clinical features, 318 differential diagnosis, 318 histopathological features, 318 Lamina densa (LD), 156–157 Lamina lucida (LL), subepidermal blistering diseases, 156 Laminin, 587, 700, 889 angiosarcoma and, 830 hemangiopericytoma and, 825 Laminin 5, 156 LANA-1, KS and, 823 Langerhans cell histiocytosis, 116–117 clinical features, 117 differential diagnosis, 117 histopathological features, 117 Langerhans cell microvesicles, 22f Langerhans cell proliferative disorders, 118t Langerhans cells (LCs), 306, 500, 586, 711 Langerhans histiocytosis, congenital self-healing, 117 Large B-cell lymphoma in immunocompromised patients, 937–938 clinical features, 937–938 histopathological features, 938 immunology, 938 leg type, 936 clinical features, 936 differential diagnosis, 936 histopathological features, 936 immunology, 936 Large cell acanthoma, 569 clinical features, 569 differential diagnosis, 569 histopathological features, 569 Large vessels, vasculitis of, 200–203

Large-plague parapsoriasis (LPP), 71 Larva currens, 536 Lassa, 503 Lateral viral infections, 495 Latrodectus mactans, 308 Laugler-Hunziker-Baran syndrome, 997 Lawrence-Seip syndrome, 557 LCA. See Leukocyte common antigen LCs. See Langerhans cells LCV. See Leukocytoclastic vasculitis LD. See Lamina densa Lead, 355 histopathological features, 355 Ledderhose disease, 773 Leiomyomas, 869 congenital smooth muscle hamartoma and, 868 leiomyosarcoma and, 872t Leiomyomas with fatty infiltration, myolipoma and, 862 Leiomyosarcoma, 589, 780, 870–872, 871f, 871t, 972 dedifferentiated liposarcoma and, 867 embryonal rhabdomyosarcoma and, 874 leiomyoma and, 869, 872t metastatic, 972f pilar, 718 Leishman-Donovan bodies, 519 Leishmaniasis, 517–520, 518t differential diagnosis, 519–520 disseminated cutaneous, 518 histopathological features, 519 in HIV, 518 mucocutaneous, 518 New World, 518 post-kala-azar dermal, 518 recidivans, 518 visceral, 518 Lentigines, 616, 617 Lentiginous compound nevus, 619f, 621 differential diagnosis, 621 Lentiginous cutaneous melanoma, 656 Lentiginous intraepidermal component, melanoma with, 660–662 Lentiginous intraepithelial component of acral skin, 661–662 of mucosal surfaces, 661–662 of nail apparatus, 661–662 Lentiginous junctional nevus, 621 differential diagnosis, 621 Lentiginous melanoma, 666 of acral skin, 665f Lentigo maligna, 655 Lentigo maligna melanoma, 657 Lentigo simplex, 341f, 997 clinical features, 616, 617 differential diagnosis, 616, 617 histopathological features, 616, 617 LEOPARD, 616 Leopard skin, 532 LEOPARD syndrome, 347–348 Leprechaunism, 405 Lepromatous leprosy, 438f, 439f Leprosy, 270, 437t clinical features, 432–433 differential diagnosis, 433 lepromatous, 438f, 439f tuberculoid, 438f

Leptomeningeal melanocytosis, 632 Lesions inflammatory, 5–8 reactive, 5–8 Lethal midline granuloma, 99 Leukemia, 276. See also specific types acute monocytic, 943f, 944f, 945f acute myeloid, 941–942, 942t, 943 acute promyelotic, 941 adult T-cell, 915, 952 chronic lymphocytic, 146, 948–949, 948t, 949f, 950f chronic myeloid, 944–946 classification of, 941 hairy cell, 951–952 monocytic, 942–943, 946f myelomonocytic, 943–944 T-cell prolymphocytic, 949–951 Leukemic infiltrates, 905–952 cutaneous, 940–952 Leukocyte common antigen (LCA), 962 Leukocyte infiltration, 36 Leukocytoclasis, 179 Leukocytoclastic vasculitis (LCV), 181, 182–183, 281 clinical features, 182 histopathological features, 182–183 Leukoderma patterned, 338–339 postinflammatory, 345 Leukoedema, 1002–1003 clinical features, 1002 differential diagnosis, 1002–1003 histopathologic features, 1002–1003 Leukoplakia, 464, 1016–1017 clinical features, 1016 differential diagnosis, 1017 histopathologic features, 1016–1017 Lewandowsky rosacea, 99 LI. See Lamellar ichthyosis Lichen amyloidosis, 61, 375, 375f colloid milium, 374t Lichen aureus, 193 Lichen myxedematosus, 365–366 clinical features, 365 differential diagnosis, 366 histopathologic features, 365–366 Lichen nitidus, 59–60 clinical features, 59 differential diagnosis, 60 histopathological features, 59–60 lichen striatus v., 60t Lichen planopilaris, 37, 226–227, 233f clinical features, 226 differential diagnosis, 227 histopathological features, 226 Lichen planus, 37t, 991f bullous, 39f clinical features, 990 differential diagnosis, 39–40, 990 histopathologic features, 990 histopathological features, 38–39 hypertrophic, 39f Lichen planus pemphigoides (LPP), 156, 162 clinical features, 162 diagnostic tests, 162 differential diagnosis, 162 histopathological features, 162

INDEX

Klebsiella, 234, 520 Klebsiella rhinoscleromatis, 438 Klippel-Trenaunay syndrome AAD and, 818 SCH and, 807 Klippel-Trenaunay-Weber syndrome, 832 KMS. See Kasabach-Merritt syndrome Knuckle pad, 773 clinical features, 773 differential diagnosis, 773 histopathologic features, 773 Koebner phenomenon, 580 Koebner response, 333 Koenen tumor, 392 Koplik spots, 496 KPA. See Keratosis pilaris atrophicans KPSD. See Keratosis pilaris spinulosa decalvans KS. See Kaposi sarcoma Kyrle disease, 240, 333

1061

INDEX 1062

Lichen sclerosus, 54–55 clinical features, 54 differential diagnosis, 55 histopathological features, 54 Lichen simplex chronicus, 24f, 70–71, 72f clinical features, 71 differential diagnosis, 71 histopathological features, 71 Lichen spinulosis. See Follicular hyperkeratosis Lichen striatus, 60 clinical features, 60 differential diagnosis, 60 histopathological features, 60 lichen nitidus v., 60t Lichenification, 991 Lichenoid actinic keratosis, 39, 571, 572f Lichenoid drug eruptions, 39, 283–284, 283t causes of, 284t clinical features, 40, 283 differential diagnosis, 40, 283 histopathological features, 40, 283 Lichenoid dysplasia, 1017 Lichenoid graft-versus-host reaction, 47f Lichenoid interface dermatitis, 37–40 histopathological features of, 38–39 Lichenoid keratosis, lichen planus-like keratosis, 40, 616 clinical features, 40 differential diagnosis, 40 histopathological features, 40 Lichenoid pigmented purpuric eruption of Gougerot and Blum, 60 Light reactions, 304–307, 305t differential diagnosis, 306–307 histopathological features, 305–306 Limb defects syndrome, 322–323 Linear IgA disease, 165–167 autoantigens of, 167t clinical presentation, 165 diagnosis, 166–167 differential diagnosis, 167 drug-induced, 288–289 histopathological features, 165–166, 166f Linear sebaceous hyperplasia, 690 Lining up, 909 Linuche unguiculata, 307 Lipedematous alopecia, 232 clinical features, 232 histopathological features, 232 Lipid-lowering agents, 93 Lipoatrophy, 274–275, 275f histopathological features, 274–275 HIV and, 274 Lipoblastoma, 864, 864f WDL/ALT and, 865, 866 Lipoblastomatosis, 864 Lipodermatosclerosis, 255–258, 257t, 258t clinical features, 255–257 differential diagnosis, 257–258 histopathological features, 257 Lipodystrophy, 274–275 centrifugal, 274 histopathological features, 274–275 HIV and, 274 Lipoid proteinosis, 375, 378

Lipoma, 858, 858f, 858t chondroid, 861, 862f encapsulated, 270 mobile encapsulated, 271 pleomorphic, 860–861, 860t, 861f, 865, 866 spindle cell, 859–860, 860f, 860t, 862, 866 WDL/ALT and, 866 Lipoma-like liposarcoma, 865 Lipomatous hemangiopericytoma, 860 Lipophagic granulomas, 257 Liposarcoma, 864–865 dedifferentiated, 866–867, 866f, 879 hibernoma and, 863 lipoblastoma and, 864 myolipoma and, 862 myxoid, 596, 796, 861, 867–868, 867f, 867t, 877 pleomorphic, 780, 868, 868f, 868t round cell, 596, 867–868 sclerosing, 860, 865 spindle cell, 865 well-differentiated, 858, 860, 862, 864, 865–866, 865f, 865t, 867 Liquefying panniculitis, 261 Livedo reticularis, 205 clinical features, 205 CMTC and, 835 histopathological features, 205 Liver disease HHT and, 834 unilateral nevoid telangiectasia and, 835 Lizard skin, 532 LL. See Lamina lucida LMNA, 274 Loa loa, 534 Loboa loboi, 488 Lobomyces loboi, 488 Lobomycosis, 460t Lobular capillary hemangioma AAD and, 819 BA and, 817 cherry angioma and, 850 IPEH and, 816 KS and, 821 MVH and, 809 PWSs and, 832 TA and, 805 Lobular panniculitis, 261–275 acute, 262f idiopathic, 261 Lobulated tumor, 797 Localized fibrosing small-vessel vasculitis, 187 Localized melanoma, 681t L’oedeme bleu, 270 Louis-Bar syndrome. See Ataxia telangiectasia Low-grade fibromyxoid sarcoma, 794–795, 794f clinical features, 794 differential diagnosis, 795 histopathologic features, 794–795 Loxosceles reclusa, 308 LPP. See Large-plague parapsoriasis; Lichen planus pemphigoides Lucio phenomenon, 270, 433 Lues maligna, 446

Luminal fibrin thrombi, 88 Lung carcinoma, 965–967 clinical features, 965 differential diagnosis, 966 histopathological features, 965–966 immunohistochemistry, 966–967 special stains, 966–967 Lupus band test, 91–93 Lupus erythematosus, 39, 48–55, 77, 90–91, 590 acute systemic, 49–51 bullous, 167 bullous systemic, 168–169 clinical features, 48–49, 90–91 differential diagnosis, 91 discoid, 48, 50f, 51–53, 225–226 drug-induced, 289 histopathological features, 49, 91 hypertrophic, 48 immunofluorescence manifestations, 91t neonatal, 48 nodular mucinosis in, 367 papular mucinosis in, 367 subacute, 50f subacute cutaneous, 48, 51 differential diagnosis, 51 subtypes of, 92t, 94t sun exposure, 92 systemic, 284 classification of, 92t tumid, 50 variants, 48t Lupus miliaris disseminatus faciei, 102–103 clinical features, 102–103 histopathological features, 103 Lupus panniculitis, 48, 272–273 Lupus vulgaris, 434f Lutzner cell, 906 Lutz-Splendore-Almeida disease. See Paracoccidioidomycosis Lyell syndrome. See Toxic epidermal necrolysis Lyme disease, 451 stage I, 451–452 differential diagnosis, 452 histopathological features, 452 stage III, 452–453 differential diagnosis, 453 histopathological features, 453 Lymph nodes in cellular blue nevus, 647 metastasis, 668 in Spitz nevus, 638 Lymphadenopathy, 472, 924 angioimmunoblastic, 925f Lymphadenosis benigna cutis, 928 Lymphangioendothelioma, KS and, 823 Lymphangioleiomyomatosis (LAM), 343 Lymphangioma circumscriptum, 841–842, 842f, 843, 850 APL and, 844 Lymphangioma simplex, 841 APL and, 842 Lymphangiomatosis (LM). See Lymphatic malformation Lymphangiosarcoma. See Angiosarcoma

Lymphoma (Cont.): primary cutaneous anaplastic large cell, 917–919 primary cutaneous CD8+ T-cell, 921–922 primary cutaneous follicle center cell, 931f primary cutaneous marginal zone B-cell, 935f primary cutaneous peripheral T-cell, 921 subcutaneous panniculitic, 263–265 subcutaneous panniculitis-like T-cell, 919, 920f unspecified primary cutaneous peripheral T-cell, 922–924 Lymphomatoid drug eruptions, 290–291 clinical features, 290 differential diagnosis, 291 histopathological features, 290–291 Lymphomatoid hypersensitivity reaction, 291t Lymphomatoid papulosis, 913, 915–917, 916f clinical features, 916 differential diagnosis, 916 genotypic features, 916 histopathologic features, 916 immunophenotypic features, 916 Lymphomatoid vascular reactions, 194 differential diagnosis of, 195t Lymphomatoid vasculitis, 194 differential diagnosis, 195t Lymphoplasmacytoid cells, 929 Lysozyme, 553 LYVE angiosarcoma and, 830 KS and, 822 M MAC. See Microcystic adnexal carcinoma Machupo, 503 Macrophages, 907, 929 Macular amyloidosus, 61, 375 Macular atrophy, 402 clinical features, 402 histopathological features, 402 Macular seborrheic keratosis, 565 Macules of McCune-Albright syndrome, 351 differential diagnosis, 351 histopathological features, 351 Maculopapular cutaneous mastocytosis/urticaria pigmentosa (MPCM/UP), 130 Madelung disease, 859, 864 Madurella grisea, 479 Madurella mycetomatis, 479 Maffucci syndrome CH and, 827 LM and, 838 phlebectasias and, 838 SCH and, 807–808 Spindle cell hemangioma and, 838 VM and, 838 Majocchi disease, 193 Majocchi granuloma, 240f Major inflammatory reaction patterns, 8–14 Major psoriasiform dermatoses, 64–66 Malakoplakia, 123, 442 clinical features, 123, 442 differential diagnosis, 123, 442 histopathological features, 123, 442

Malassezia folliculitis, 465–467 clinical features, 466 differential diagnosis, 467 histopathological features, 466–467 Malassezia furfur, 234, 463, 465, 989 Malignant acrospiroma, 739–740 clinical features, 739 differential diagnosis, 740 histopathologic features, 739–740 Malignant atrophic papulosis (MAP), 206 Malignant basomelanocytic tumor, 581 Malignant chondroid syringoma, 588 Malignant edema, 434 Malignant endovascular papillary angioendothelioma. See Papillary intralymphatic angioendothelioma Malignant fibrohistiocytic tumors, 791–795 Malignant fibrous histiocytoma, 791–792 giant cell variant, 791–792 hemangiopericytoma and, 825 pleomorphic, 791–792 Malignant fibrous tumors, 791–795 Malignant hemangioendothelioma. See Angiosarcoma Malignant lymphoma, 453–454 histopathological features, 453–454 Malignant melanoma, 656–665 blue nevus and, 675 clinical features, 675 differential diagnosis, 675 histopathological features, 675 EHE and, 829 histological diagnosis of, 679–680 historical classification of, 657t regression, 678t Malignant mixed tumors, 748–749 Malignant neoplasms distinguishing benign from, 5f features of, 5 Malignant peripheral nerve sheath tumor (MPNST), 887, 895–896, 896t clinical features, 895 differential diagnosis, 896 extra skeletal osteosarcoma and, 879 histopathological features, 895–896 Malignant pilar neoplasms, 715–718 Malignant proliferating pilar tumor, 716–717, 717f clinical features, 716 differential diagnosis, 716–717 histopathologic features, 716 Malignant pustule, 433 Malignant schwannoma, 895 hemangiopericytoma and, 825 Malignant sweat gland tumors, 737–738 Malignant trichoepithelioma, 717 Malignant tumors, 578–600 Mammaglobin, 963 Mammary Paget disease (MPD), 750, 752t Mansonella streptocerca, 532 Mantleomas, 713 MAP. See Malignant atrophic papulosis Marburg, 503 Marfan syndrome, 398, 405 clinical features, 398 histopathological features, 398 Marginal zone B lymphocytes, 930

INDEX

Lymphatic filariasis, 534 clinical features, 533 differential diagnosis, 534 histopathological features, 533–534 Lymphatic malformation, 823 angiokeratoma and, 836 APL and, 844 IPEH and, 816 Maffucci syndrome and, 838 PILA and, 826 VH and, 838 VM and, 839 Lymphatic malformation (LM), 806, 841–843, 842f Lymphoblasts, 929 Lymphocyte exocytosis, follicular spongiosis with, 29f Lymphocyte satellitosis, 36 Lymphocyte-associated primary scarring alopecia, 225 Lymphocytes, marginal zone, 930 Lymphocytic vascular reaction, 192 Lymphocytic vasculitides, 192 Lymphocytic vasculitis, differential diagnosis, 192t Lymphocytic vasculopathy, 193 Lymphocytic-plasma cellular infiltrates, 128–129 Lymphocytoma cutis, 453–454 differential diagnosis, 454 histopathological features, 453–454 Lymphoepithelioma-like carcinoma, 599–600, 711, 753–754 clinical features, 600 differential diagnosis, 600, 754 histopathological features, 600 Lymphogranuloma venereum, 443 clinical features, 443 differential diagnosis, 443 histopathological features, 443 Lymphoid hyperplasia, 905 Lymphoid infiltrates, 905–952 Lymphoma, 276. See also specific types alveolar rhabdomyosarcoma and, 875 B-cell, 937–938 B-lymphoblastic, 938 cutaneous, 905 cutaneous B-cell, 929–932 cutaneous gamma/delta T-cell, 922 cutaneous Hodgkin, 939–940 cutaneous T-cell, 7, 71, 74–75, 229, 276, 291, 905t, 906–907, 912 clinical features, 74–75 differential diagnosis, 75 histopathological features, 75 cytotoxic cutaneous, 919 extranodal NK/T-cell, 919–921 follicle center, 932–933, 932t hidroa vacciniforme-like, 921 intravascular large B-cell, 937 large B-cell leg type, 936 other, 936–938 malignant, 453–454 marginal zone, 129 marginal zone B-cell, 933–936 nodal, 924 precursor T-lymphoblastic, 926

1063

INDEX 1064

Marginal zone B-cell lymphoma, 933–936 clinical features, 933 differential diagnosis, 935–936 histopathologic features, 933–934 immunology, 935 primary cutaneous, 934f Marginal zone cells, 933 Marginal zone lymphoma, 129 Marine agent reactions, 307–308 clinical features, 307 differential diagnosis, 308 histopathological features, 307–308 Marjolin ulcers, 591 MART-1, 669, 676, 680, 795, 965 Mast cell degranulation, 82 Mast cell infiltrates, 130–131 Mastectomy, angiosarcoma and, 829 Mastocytomas, 841 Mastocytosis cutaneous, 130–131 systemic, 130 MATP. See Membrane-associated transporter protein gene Matrical basal cell carcinoma, 585 Matrix glutamic acid protein (MGP), 259 Matrix metalloproteinase-2 (MMP-2), 257, 578 Maturation (zonation), Spitz nevus, 635 Mayo Clinic, 197 Mazzotti reaction, 532 MC1R. See Melanocortin-1 receptor MCHR1. See Melanin-concentrating hormone receptor 1 MDM. See Minimal deviation melanoma MDM2 gene, 865 dedifferentiated liposarcoma and, 867 MDS. See Myelodysplastic syndrome Measles, 496–497, 496t clinical features, 497 differential diagnosis, 497 histopathological features, 497 Mechanobullous disorders, 313 Mechlorethamine, 356 Median raphe cysts, 552 histopathological features, 552 Median rhomboid glossitis, 1004–1006 clinical features, 1004 differential diagnosis, 1004 histopathologic features, 1004 Medication-associated pigmentation, 1016 clinical features, 1016 differential diagnosis, 1016 histopathologic features, 1016 Medium vessels, vasculitis of, 200–203 Medlar bodies, 476 Melan-A angiomyolipoma and, 862 pleomorphic liposarcoma and, 868 Melanin, 36, 568, 710, 729 dusty, 654, 660 intralaminar, 986 mapping of nail plate, 985–987 premise, 986 Melanin-concentrating hormone receptor 1 (MCHR1), 341

Melanoacanthoma, 568 clinical features, 568 differential diagnosis, 568 histopathological features, 568 Melanocortin-1 receptor (MC1R), 615 Melanocyte stem cells, 1022–1023 Melanocyte tumors, 615–681 basilar melanocyte-composed, 615–616 Melanocytes, 338 epidermal, 339f Melanocytic aggregates, 678–679 Melanocytic lesions, with phenotypic heterogeneity, 648 Melanocytic macules, 616–617 Melanocytic nevi, 997 acquired, 616, 662–663 clinical features, 618 common, 617–618, 618t histopathological features, 618 variants of, 619–627 acral skin, 623–624 clinical features, 623 compound, 624f differential diagnosis, 623–624 histopathological features, 623 of acral skin, 623–624 atypical, 651, 655 cytologic features, 654 epithelioid cell variant, 655 grading, 656 grading of, 656 halo nevus variant, 655 histological features of, 655–656 junctional, 652 as melanoma precursors, 652, 654 melanoma v., 655t severely, 655t significance of, 651–654 of breast, 625 congenital, 627–632 with atypical features, 630 giant, 632 histological features, 628 incidence, 628–630 large, 632 melanoma in, 630–631 risk factors, 628–630 small, 628–630 dysplastic, 651 embryonal rhabdomyosarcoma and, 875 flexural skin, 625 with focal atypical epithelioid cell component, 649 differential diagnosis, 649 genital skin, 624–625 clinical features, 625 differential diagnosis, 625 histopathological features, 625 with phenotypic heterogeneity, 648–649 clinical features, 648 histopathological features, 648–649 presentations of, 625t, 627 scalp, 625–627 clinical features, 626 differential diagnosis, 626–627 histopathological features, 626

Melanocytic nevi (Cont.): of scalp, 625–627 from special sites, 623–627 uncommon findings in, 625t, 627 Melanocytoma, pigmented epithelioid, 643 Melanocytosis dermal, 641, 642t leptomeningeal, 632 pagetoid, 667 Melanoma, 657, 795, 998 acral, 657, 659, 662t, 664 with adjacent intraepithelial component, 662 ancillary techniques in diagnosis of, 680 angiotropic, 669–670, 669f atypical melanocytic nevi as precursors, 652 clinical features, 652 histopathological features, 652–654 host response, 654 atypical melanocytic nevi v., 655t balloon cell, 620, 676–677 childhood, 627–632 classification of, 657t clinical features, 998 congenital, 627–632 congenital melanocytic nevi and, 630–631 conventional, 663t cutaneous, 656–665 anatomic levels of, 659t classification, 656–665 clinical features, 657–659 differential diagnosis, 662–665 histopathological features, 659–662 intraepithelial component, 659–660 invasive, 660 lentiginous, 656 metastatic, 678, 679t nested, 656 pagetoid, 656, 658f primary, 678, 679t with dermal nevi, 674–675 clinical features, 674–675 differential diagnosis, 675 histopathological features, 674–675 desmoplastic, 639, 640t, 665–669 diagnosis of borderline, 680 differential diagnosis, 998 florid intraepidermal, 667 histopathologic features, 998 histopathological reporting of, 681 invasive, 660 lentiginous, 665f, 666 with lentiginous intraepidermal component, 660–662 lentigo maligna, 657 localized, 681t malignant, 656–665, 657t, 675, 678t, 679–680, 829 blue nevus and, 675 clinical features, 675 differential diagnosis, 675 histopathological features, 675 EHE and, 829 histological diagnosis of, 679–680 historical classification of, 657t regression, 678t

Metastatic disease, umbilicus, 416 Metastatic leiomyosarcoma, 972f Metastatic melanoma, 677 cutaneous, 678, 679t diagnostic problems with, 678–679 epidermotropic, 679f generalized melanosis in, 352 melanosis in, 679 Metastatic mucinous breast carcinoma, 965f Metatypical basal cell carcinoma, 583, 585 Methenamine, 471 Methyldopa, 289 Methyltransferase, 289 Meyers-Kouvenaar (MK) body, 534 Mezomycetozoa, 527 MGP. See Matrix glutamic acid protein Microabscess, 136, 909 Microcapillary angioma, 808 Micrococcus sedentarius, 430 Microcystic adnexal carcinoma (MAC), 699, 727, 728, 743–745, 744f clinical features, 743 differential diagnosis, 744–745 histopathologic features, 743–744 Microglobulin amyloid, 374 Micrometastases, 678–679 Micronodular basal cell carcinoma, 582, 583f Microphthalmia transcription factor (MiTF), 893 Microscopic interpretation anatomic site in, 4 high magnification, 4 information integration in, 4 intermediate magnification, 4 microslide examination, 3–4 slide examination, 3 slide interpretation, 3 specimen type in, 3–4 Microscopic polyarteritis (MPA) nodosa, 184, 199 clinical features, 199 differential diagnosis, 199 histopathological features, 199 Microslide, examination of, 3–4 Microsporidia, 458, 527 Microsporidiosis, 527 Microsporum audouini, 221, 458 Microsporum canis, 221 Microvenular hemangioma (MVH), 808–809, 809f, 809t acute myelogenous leukemia and, 809 dermatofibroma and, 809 Epithelioid hemangioma (EH) and, 809 HHV and, 809 histologic features of, 823t KS and, 809 PG and, 809 POEMS and, 809 sclerosing hemangioma and, 809 TA and, 809 THH and, 809 Wiskott-Aldrich syndrome and, 809 Miescher-Melkersson-Rosenthal syndrome, 100, 101t clinical features, 100 differential diagnosis, 100 histopathological features, 100

Migratory, 259 Mikulicz cells, 438, 520 Milia, 547–548 histopathological features, 547–548 Milia-like calcinosis, 383 Miliaria, 32 algorithm for, 34 Miliaria crystallina, 13, 32–33 clinical features of, 32 differential diagnosis of, 33 histopathological features of, 32 Miliaria profunda, 13, 33 clinical features, 33 histopathological features, 33 Miliaria rubra, 13, 33 clinical features of, 33 differential diagnosis, 33 histopathological features of, 33 Miliarial spongiosis, 6f Milkers’ nodule, 512, 513, 514f Milroy disease angiosarcoma and, 829 SCH and, 807 Minimal deviation melanoma (MDM), 670 Minocycline, 287, 355–356 Minoxidil, 216 Miscellaneous ectopic tissue, 414–417 Miscellaneous seborrheic keratosis, 566 Mites, 75, 308 MiTF. See Microphthalmia transcription factor Mitosis, 588, 600 in Spitz nevus, 635 Mixed ciliated epithelium, cysts lined by, 546t, 549–552 Mixed connective tissue disease, 53, 54f, 93, 94, 390 clinical features, 94, 390 differential diagnosis, 94 histopathological features, 53, 94, 390 immunofluorescence, 94 Mixed epithelial and mesenchymal follicular proliferations, 708 Mixed tumors, malignant, 748–749 Mixed-lineage adnexal adenomas, 737 MK body. See Meyers-Kouvenaar body MLT. See Multifocal lymphangioendotheliomatosis MMP-2. See Matrix metalloproteinase-2 MNF116, 962 Mobile encapsulated lipoma, 271 Molluscum contagiosum, 105, 512–514, 514f, 515f, 589 Molting, 216 Mongolian spot, 641, 643f clinical features, 641 histopathological features, 641 Monkeypox, 512 Monoclonal gammopathy, RAE and, 817 Monocytic leukemia, 942–943, 946f acute, 943f, 944f, 945f clinical features, 942 differential diagnosis, 943 histopathologic features, 942–943 Monocytoid B cells, 933

INDEX

Melanoma (Cont.): markers, 651–652 metastatic, 352, 677, 678–679 minimal deviation, 670 neurotropic, 665, 668–669 nevoid, 670–672, 671t, 672f nodular, 657, 662, 663t, 664 with pagetoid intraepidermal component, 660 prognostic factors in, 680–681 rare presentations of, 677t regression, 677 simulating other neoplasms, 678 in situ, 739, 997–998 small cell, 631f, 670, 673–674 small-diameter, 670 solar, 660–661, 664f spindle cell, 668, 780 spitzoid, 670, 674 subungual, 659 unusual presentations of, 677t verrucous, 672–673 Melanophages, 36 Melanosis, in metastatic melanoma, 679 Melanotic macules, 617 Melasma, 350 differential diagnosis, 350 histopathologic features, 350 Meleney ulcer, 427 Membrane attack complex of complement, 92–93 Membrane-associated transporter protein gene (MATP), 342 Meningioma, cutaneous, 898 Meningococcal infections, 430–431 clinical features, 430 differential diagnosis, 431 histopathological features, 430–431 Menkes syndrome, 404 histopathological features, 404 Mental retardation, 590 Meperidine, 271 Mercury, 355 histopathological features, 355 Merkel cell carcinoma, 515 Merkel cell polyoma virus, 515 Merkel cells, 585, 588, 711, 896, 967 small cell melanoma mimicking, 673 Mesenchymal tumors, 631–632 Mesomycetozoae, 489 Metagonium yokogawai, 538f Metal deposition, 353t Metaplastic synovial cysts (MSCs), 553–554 differential diagnosis, 553–554 Metastasis apocrine carcinomas simulating, 752 cutaneous, 960–973 distant, 961 eccrine carcinomas simulating, 746 lymph nodes, 668 scalp, 961 telangiectatic, 960–961 Metastatic adenocarcinoma, 966f Metastatic basal cell carcinoma, 580 Metastatic calcinosis cutis, 381–382 histopathological features, 381–382 Metastatic Crohn disease, 100

1065

INDEX 1066

Monsel solution reaction, 123–124, 124f clinical features, 123 differential diagnosis, 124 histopathological features, 123 Montgomery syndrome. See Xanthoma disseminatum Morbid obesity, angiosarcoma and, 829 Morbilliform drug eruption, 61 Morbilliform viral exanthem, 61 Morphea, 387, 389t inflammatory, 387 Morphea profunda, 259–261, 260t clinical features, 260 differential diagnosis, 261 histopathological features, 260–261 Morpheaform basal cell carcinoma, 588, 706, 727 Morphine, 271 Morphological features, cutaneous metastases, 960–961 Mother patch, 73 Moynahan’s syndrome, 347–348 MPA nodosa. See Microscopic polyarteritis MPCM/UP. See Maculopapular cutaneous mastocytosis/urticaria pigmentosa MPD. See Mammary Paget disease MSCs. See Metaplastic synovial cysts MTB. See Mycobacterium tuberculosis Mucin, 586, 594, 598, 712, 713 desmoplastic melanoma, 669 Mucinous carcinoma, 740–741 clinical features, 740 differential diagnosis, 740–741 histopathologic features, 740 Mucinous eccrine carcinoma, 740t Mucinous nevus, 370 histopathological features, 370 Muckle-Wells syndrome, 373 Mucocele, 1010–1011 clinical features, 1010 differential diagnosis, 1011 histopathologic features, 1010–1011 Mucocutaneous candidiasis, 463t Mucocutaneous leishmaniasis, 518 Mucocutaneous lentigines, 616–617 Mucoepidermoid carcinoma, 598–599 clinical features, 599 differential diagnosis, 599 histopathological features, 599 primary, 745 Mucoid carcinoma, 963 Mucopolysaccharides, 385, 792 histopathological features, 385 Mucor, 483 Mucorales, 483 Mucormycosis, 459t, 484 clinical features, 484 differential diagnosis, 484 histopathological features, 484 Mucormycotina, 483 Mucosal surfaces, lentiginous intraepithelial component, 661–662 Muir-Torre syndrome, 576, 690, 691 Multicentric basal cell carcinoma, 580 superficial, 582

Multicentric Castleman disease, 129 clinical features, 129 differential diagnosis, 129 histopathological features, 129 Multicentric reticulohistiocytosis, 121 clinical features, 121 differential diagnosis, 121 histopathological features, 121 Multifocal lymphangioendotheliomatosis (MLT), 811 Multinucleate cell angiohistiocytoma, 122–123 clinical features, 122 differential diagnosis, 122–123 histopathological features, 122–123 Multinucleate giant cells, 646 Multiple lentigines syndrome, 347–348 Multiple sclerosis, 296 Multiple symmetric lipomatosis. See Madelung disease Münchhausen syndrome, 271 Munro microabscesses, 67, 68 Muscle, 868–876 MVH. See Microvenular hemangioma MXA. See Myxovirus protein Mycetoma, 459t, 478–483 clinical features, 479 differential diagnosis, 480 histopathological features, 479–480 organisms causing, 480t Mycobacterium avium-intracellulare, 123, 432, 501 Mycobacterium chelonei, 432 Mycobacterium fortuitum, 432 Mycobacterium haemophilum, 501 Mycobacterium leprae, 421, 432 Mycobacterium marinum, 236, 432 Mycobacterium tuberculosis (MTB), 268, 269, 431, 432, 481 Mycobacterium ulcerans, 435f Mycoplasma pneumoniae, 110, 294 Mycosis fungoides, 12, 74–75, 297f, 906 clinical features, 74–75, 909 clinicopathological variants, 910 definition, 909 d’emblée form of, 909 differential diagnosis, 75, 914 folliculotropic, 910 genotypic features of, 914 granulomatous, 911–912, 912f histopathological features, 75, 909–910 immunotypic features of, 914 patch stage, 910f plaque stage, 910f subtypes, 910 syringotropic, 911–912, 912f transformation, 909 tumor stage of, 911f Myeloblasts, 941 Myelodysplasia, 188 Myelodysplastic syndrome (MDS), 946, 947–948 clinical features, 947 differential diagnosis of, 948 histochemical findings, 948 histopathologic features, 947–948 immunohistochemical findings, 948

Myelomonocytic leukemia, 943–944 clinical features, 943 differential diagnosis, 944 histochemical findings, 944 histopathological features, 944 immunohistochemical findings, 944 Myeloperoxidase, 943 Myo-D1 embryonal rhabdomyosarcoma and, 874 leiomyosarcoma and, 871 pleomorphic leiomyosarcoma and, 876 Myoepithelial differentiation, 585–586 Myoepithelioma, 889 Myofibroma, solitary, 782–784, 783t Myofibromatosis, 783t infantile, 782–784, 783t Myogenin embryonal rhabdomyosarcoma and, 874 leiomyosarcoma and, 871 pleomorphic leiomyosarcoma and, 876 Myolipoma, 861–862, 862f Myopathic dermatomyositis, 93t Myopericytoma, hemangiopericytoma and, 825 Myosin, 586 Myositis ossificans, 877, 878, 878f Myxedema, 320, 362, 404 generalized, 363–364 pretibial, 364–365 Myxofibrosarcoma, 792–793, 867 clinical features, 792 differential diagnosis, 793 extraskeletal myxoid chondrosarcoma and, 877 histopathologic features, 792–793 leiomyosarcoma and, 871 Myxoid cyst, 368 Myxoid liposarcoma, 596, 796, 867–868, 867f, 867t chondroid lipoma and, 861 extraskeletal myxoid chondrosarcoma and, 877 Myxoid tumor, 797 Myxolipoma, 858, 859f Myxoma cutaneous, 370–371, 795–796 follicular, 714 nerve sheath, 668, 891–892, 893f, 894t Myxovirus protein (MXA), 926 N NADPH. See Nicotinamide adenine dinucleotide phosphate Nadroparin, 383 Naegeli-Franceschetti-Jadassohn, 348 Naevus anelasticus, 402 Nail diseases, 983–998. See also specific disorders biopsy, 983–985, 988f clinical anatomy of, 984f diagnosis of, 987–998 fungal morphology, 984 fungi in, 983–985 diagnosis yield, 984 flowchart, 984 rationale, 984 results, 984

Neuroendocrine carcinoma, 673, 897t immunohistochemistry, 971 primary, 896–897, 898f special stains, 971 Neuroendocrine tumors, 971 classification, 883 clinical features, 971 differential diagnosis, 971 histopathologic features, 971 Neurofibromas, 884–887, 887t, 888f clinical features, 886 cytologic atypia in, 887 histopathologic features, 886–887 leiomyoma and, 869 plexiform, 887, 888f Neurofollicular and pilar neurocristic hamartomas, 719–720 clinical features, 720 histopathologic features, 720 Neuromas, 883–884 clinical features, 884 differential diagnosis, 884 encapsulated, 886t palisaded, 886t traumatic, 886t, 887f Neurothekeoma, 668, 892–894 cellular, 894f clinical features, 892–893 differential diagnosis, 893–894 histopathological features, 893 Neurotized nevus, 621 Neurotropic melanoma, 665, 668–669 differential diagnosis, 668–669 Neurotropism, 668 desmoplastic melanoma with, 665, 666t desmoplastic melanoma without, 665 Neutral lipid storage disease, 318–319 with ichthyotic erythroderma, 318–319 Neutrophilic dermatitides, 275–276 Neutrophilic dermatosis, 188 acute febrile, 188–190 differential diagnosis, 190, 190t Neutrophilic eccrine hidradenitis, 244 clinical features, 244 differential diagnosis, 245 Neutrophilic infiltrates, 124–127 infectious causes of, 125t Neutrophilic spongiosis, 6f, 15, 26f skin diseases with, 26t Neutrophilic vascular reactions, 180, 188 Nevi. See specific types Nevoid basal cell carcinoma, 589–590 clinical features, 589–590 histopathological features, 590 Nevoid melanoma, 670–672, 671t, 672f clinical features, 671 differential diagnosis, 672 histopathologic features, 671 Nevus acquired melanocytic, 616, 662–663 clinical features, 618 common, 617–618, 618t histopathological features, 618 variants of, 619–627 apocrine, 755 atypical halo, 663 atypical melanocytic, 651

Nevus (Cont.): cytologic features, 654 epithelioid cell variant, 655 grading of, 656 halo nevus variant, 655 histological features of, 655–656 junctional, 652 as melanoma precursors, 652, 654 melanoma v., 655t severely, 655t significance of, 651–654 atypical Spitz, 636 assessment of, 637t balloon cell, 620 clinical features, 620 differential diagnosis, 620 histopathological features, 620 becker, 719 clinical features, 719 congenital smooth muscle hamartoma and, 868 differential diagnosis, 719 histopathologic features, 719 becker pigmented hairy, 351–352 clinical features, 351 differential diagnosis, 351–352 histopathologic features, 351 blue, 641, 642–643 atypical cellular, 647 cellular, 645, 646f, 647 common, 643, 644f compound, 645 epithelioid, 643, 644f hypopigmented, 645 malignant melanoma arising in, 675 patchlike, 647 plaque-type, 647–648 sclerosing, 645 target, 648 breast melanocytic, 625 cellular blue, 645, 646f atypical, 647 clinical features, 645 histopathologic features, 645–646 lymph nodes in, 647 occasional, 646–647 combined, 648 common blue, 643, 644f clinical features, 643 differential diagnosis, 643 histopathologic features, 643 compound, 618 of acral skin, 624f with architectural disorder, 653f, 654f and cytologic atypia, 653f, 654f of vulva, 626f compound blue, 645 compound Spitz, 637f congenital melanocytic, 627–632 with atypical features, 630 giant, 632 histological features, 628 incidence, 628–630 large, 632 melanoma in, 630–631 risk factors, 628–630 small, 628–630

INDEX

Nail diseases (Cont.): histology of, 985f keratins, 986t lentiginous intraepithelial component, 661–662 melanin mapping of, 985–987 matrical area calculation, 986–987 premise, 986 microscopic signs of diseases, 983 Nasal glioma, 899, 900f National Cancer Institute, 302 Nattrassia mangiferae, 463 Natural killer cells, 99, 907 NC-16A, 289 Necrobiosis, 261 Necrobiosis lipoidica (NL), 105, 107–108 clinical features, 108 differential diagnosis, 108 histopathological features, 108 Necrobiotic xanthogranuloma, 109 clinical features, 109 differential diagnosis, 109 histopathological features, 109 Necrosis, in basal cell carcinoma, 588 Necrotizing fasciitis (NF), 276, 426, 427–428 clinical features, 428 differential diagnosis, 428 histopathological features, 428 Necrotizing sialometaplasia clinical features, 1011 different diagnosis, 1011 histopathological features, 1011 Neisseria gonorrhoeae, 431 Neisseria meningitidis, 184, 430 Nematodes, 531–536 adult, 530–531 NEMO gene, 349 Neocallimastigomycota, 458 Neonatal lupus erythematosus, 48 Neoplasms, distinguishing benign from malignant, 5f Neoplastic angioendotheliosis. See Angioendotheliomatosis Neoplastic conditions, 13. See also specific neoplastic conditions Neoplastic cutaneous mucinoses, 370–371 Nephrogenic fibrosing dermopathy, 390–391, 391f clinical features, 391 differential diagnosis, 391 histopathologic features, 391 Nerve sheath myxoma, 668, 891–892, 893f, 894t clinical features, 891 histopathologic features, 891–892 immature, 892 Nested cutaneous melanoma, 656 Neural differentiation, 666 Neural heterotopias, 897–901 Neural nevus, 621 Neural tumors, 883–901 classification, 883 cutaneous, 883t Neuroblastic tumors, 900 Neuroblastoma, 900–901 embryonal rhabdomyosarcoma and, 874

1067

INDEX 1068

Nevus (Cont.): connective tissue, 391–392 clinical features, 392 differential diagnosis, 392 histopathological features, 392 deep penetrating, 648, 649–650, 650t clinical features, 649–650 histopathologic features, 649–650 dermal, 619f melanoma in, 674–675 papillomatous, 672 desmoplastic Spitz, 638–639, 639t clinical features, 638 differential diagnosis, 639 DM v., 640t histopathologic features, 638–639 dysplastic melanocytic, 651, 656 eccrine, 755 epidermal, 556–561 differential diagnosis, 556 histopathological features, 556 epithelioid blue, 643, 644f clinical features, 643 histopathologic features, 643 epithelioid cell atypical melanocytic, 655 flexural skin melanocytic, 625 genital skin melanocytic, 624–625 clinical features, 625 differential diagnosis, 625 histopathological features, 625 hair follicle, 719 clinical features, 719 differential diagnosis, 719 histopathologic features, 719 halo, 620–621, 663 atypical, 663 clinical features, 620 differential diagnosis, 621 histopathological features, 620–621 halo atypical melanocytic, 655 halo Spitz, 639 hyalinizing Spitz, 639 hypopigmented blue, 645 inflammatory linear verrucous epidermal, 60, 76, 114, 558–559 clinical features, 76, 558 differential diagnosis, 76, 559 histopathological features, 76, 558–559 junctional, 618 architectural disorder with, 654f junctional atypical melanocytic, 652 lentiginous compound, 619f, 621 differential diagnosis, 621 lentiginous junctional, 621 differential diagnosis, 621 melanocytic, 997 acquired, 616, 619–627, 662–663 acral skin, 623–624 of acral skin, 623–624 atypical, 651–654, 654, 655, 655t, 656 of breast, 625 congenital, 627–632 dysplastic, 651 embryonal rhabdomyosarcoma and, 875 flexural skin, 625 with focal atypical epithelioid cell component, 649

Nevus, melanocytic (Cont.): genital skin, 624–625 with phenotypic heterogeneity, 648–649 presentations of, 625t, 627 scalp, 625–627 from special sites, 623–627 uncommon findings in, 625t, 627 mucinous, 370 neural, 621 neurotized, 621 nipple, 409 pagetoid Spitz, 636 papillomatous dermal, 672 patchlike blue, 647 pigmented spindle cell, 640 with atypical features, 640–641 clinical features, 640 differential diagnosis, 640–641 histopathologic features, 640 plaque-type blue clinical features, 647–648 histopathologic features, 647–648 plexiform spindle cell, 650 clinical features, 650 differential diagnosis, 650 histopathological features, 650 plexiform Spitz, 639 pseudoangiomatous melanocytic, 841 recurrent melanocytic, 622 clinical features, 622 differential diagnosis, 622 histopathological features, 622 scalp melanocytic, 625–627 clinical features, 626 differential diagnosis, 626–627 histopathological features, 626 sclerosing blue, 645 differential diagnosis, 645 histopathological features, 645 small congenital, 628–630 Spitz, 620, 632–635, 633f, 633t, 663 absent or rare mitosis in, 635 adnexal epithelium, 635 angiomatoid, 639 atypical, 636, 637t clinical features, 632–635 compound, 637f dermal component, 637–638 desmoplastic, 638–639, 639t, 640t epidermal hyperplasia, 635 halo, 639 histopathologic features, 634–635 hyalinizing, 639 intraepidermal component, 636 junctional cleavage, 635 kamino bodies, 635 lymph node involvement, 638 maturation (zonation), 635 pagetoid, 636 pagetoid spread, 635 perivascular inflammatory cell infiltrates, 635 plexiform, 639 prominent pagetoid spread, 636 tubular, 639 variants, 639 target blue, 648 tubular Spitz, 639

Nevus (Cont.): white sponge, 1003f clinical features, 1002 differential diagnosis, 1002 histopathologic features, 1002 Nevus anemicus, 345–346 Nevus araneus. See Arterial spider Nevus cells cytology of, 618–619 maturational sequence of, 618–619 Nevus comedonicus, 559–560 clinical features, 559 differential diagnosis, 560 histopathological features, 559 Nevus depigmentosus, 344–345 differential diagnosis, 345 histopathological features, 345 Nevus flammeus. See Port wine stains Nevus fuscoceruleus acromiodeltoideus, 642 Nevus fuscoceruleus ophthalmomaxillaris, 641 Nevus fuscoceruleus zygomaticus, 641–642 Nevus lipomatous superficialis, 857–858, 857f Nevus of Ito, 642 Nevus of Ota, 641 Nevus sebaceous, 695–696 clinical features, 695–696 histopathologic features, 696 Nevus sebaceous adenoma, 690 Nevus spilus, 622 clinical features, 622 differential diagnosis, 622 histopathological features, 622 NF. See Necrotizing fasciitis NHL. See non-Hodgkin lymphomas Niacin deficiency, 76–77 NICH. See Noninvoluting congenital hemangioma Nicotinamide adenine dinucleotide phosphate (NADPH), 322 Nicotine stomatitis, 1008 clinical features, 1008 differential diagnosis, 1008 histopathologic features, 1008 Nikolsky sign, 424 Nipple nevus, 409 NKIC3 gene, 871 NL. See Necrobiosis lipoidica NM. See Nodular melanoma NNN. See Novy-MacNeal-Nicolle Nocardia, 267, 459t, 475, 478, 480–481 differential diagnosis, 481 Nocardiosis, 480–481, 481t clinical features, 480–481 histopathological features, 480–481 Nodal lymphomas, 924 Nodular amyloidosis, 376–377, 377f Nodular angioblastic hyperplasia with eosinophilia and lymphofolliculosis. See Epithelioid hemangioma Nodular basal cell carcinoma, 580f histopathological features, 580–582 Nodular colloid degeneration, 379 Nodular dermal infiltrates, 11f, 98–133 Nodular fasciitis, 771–773, 772f, 772t, 877, 972 clinical features, 771 differential diagnosis, 773 histopathologic features, 771

O Ochronosis, 353–354, 384–385 histopathological features, 354, 384–385 Oculocutaneous albinism, 341–342 Oculocutaneous tyrosinosis, 320 Ohio Valley disease. See Classic histoplasmosis Oil red O, 693 OIN. See Oral intraepithelial neoplasia Omphalith, 416 clinical features, 416 histopathological features, 416 Omphalomesenteric duct remnants, 413–414, 414t differential diagnosis, 413–414 histopathological features, 413

Onchocerca volvulus, 531, 533, 534 Onchocerciasis, 531–533 clinical features, 531–532 histopathological features, 532 Onychitis eczematous, 989–990 traumatic, 991–992 Onychomatricoma, 993 clinical features, 993 differential diagnosis, 993 histopathologic features, 993 Onychomycosis, 462, 478, 987–988 clinical features, 987 differential diagnosis, 989 distal lateral subungual onychomycosis, 462 false-negative cases, 984–985 histopathologic features, 987–988 proximal subungual, 462–463 proximal white subungual, 463 O’Nyong-Nyong, 503 OPN. See Osteopontin Oral carcinomas, 968 clinical features, 968 differential diagnosis, 968 histopathologic features, 968 immunohistochemistry, 968 special stains, 968 Oral contraceptives, 287 Oral hairy leukoplakia, 1005 clinical features, 1005 differential diagnosis, 1005 histopathologic features, 1005 Oral hygiene, 596 Oral intraepithelial neoplasia (OIN), 1016 Oral lichen planus, 1007–1008 clinical features, 1007 differential diagnosis, 1008 histopathologic features, 1007–1008 Oral lymphoepithelial cyst, 1003, 1004f clinical features, 1003 differential diagnosis, 1003 histopathologic features, 1003 Oral melanoacanthosis, 1016 clinical features, 1016 differential diagnosis, 1016 histopathologic features, 1016 Oral melanotic macule, 1015–1016 clinical features, 1015 differential diagnosis, 1015–1016 histopathologic features, 1015 Oral mucosa, 1002–1018. See also specific disorders developmental conditions, 1002–1004 dysplastic conditions, 1016–1018 immune-mediated conditions, 1006–1014 infectious conditions, 1004–1006 neoplastic conditions, 1016–1018 pigmented conditions, 1015–1016 reactive conditions, 1006–1014 Oral mucous cyst, 369 histopathological features, 369 Oral submucous fibrosis, 1017 clinical features, 1017 differential diagnosis, 1017 histopathologic features, 1017

Oral verrucous carcinoma, 596 clinical features, 597 differential diagnosis, 598 histopathological features, 597 Orf, 512, 513f Organ transplants, squamous cell carcinoma nad, 591 Oriental sore, 518 Orientia, 454 Ornithodoros, 451 Orofacial granulomatosis, 1009–1010 clinical features, 1009 Oroya fever, 442 Orthohyperkaratosis, 52, 577 Orventral cuticle, 983 Osler disease. See Hereditary hemorrhagic telangiectasia Osler-Weber-Rendu disease. See Hereditary hemorrhagic telangiectasia Osteoblasts, 383 Osteocartilaginous tumors, 994–996 clinical features, 994 histopathologic features, 994 Osteochondroma, 384 extraskeletal chondroma and, 876 fibroosseous pseudotumor and, 877 Osteoclast-like giant cells, 593 Osteogenesis imperfecta, 398 histopathological features, 398 Osteogenic sarcoma, 972 Osteoma cutis, 384, 877 Osteomyelitis, 470, 591 Osteopoikilosis, 392 Osteopontin (OPN), 259 Osteosarcoma, fibroosseous pseudotumor and, 878 Osteosarcomas, soft tissue, 792 Oxalosis, 208, 259 clinical features, 208, 259 differential diagnosis, 208, 259 histopathological features, 208, 259 P p27, 575 p53, 297, 585, 587, 593, 744 Pachyonychia congenita, 320, 329–330 differential diagnosis, 330 histopathological features of, 330 Paecilomyces, 487 histopathological features, 487 Paget disease, 75, 409, 753f, 960 apocrine type, 750–752 clinical features, 751 histopathological features, 751 of breast, 961, 963 Pagetoid cutaneous melanoma, 656, 658f Pagetoid intraepidermal component, melanoma with, 660 Pagetoid melanocytosis, 667 Pagetoid reticulosis (PR), 910, 912–913, 913f clinical features, 912 differential diagnosis, 913 histopathologic features, 912 Pagetoid Spitz nevus, 636 Pagetoid spread, 671 prominent, 636 Spitz nevus, 635 Palisaded granulomatous dermatitis, 107t

INDEX

Nodular growth pattern, 907f Nodular hidradenomas, 588 Nodular melanoma (NM), 657, 662, 663t, 664 Nodular mucinosis, in lupus erythematosus, 367 Nodular vasculitis, 255, 268–269 Nodular venous malformations, 838 Nodular-cystic fat necrosis, 858 Nonbullous ichthyoses, 313 differential diagnosis of, 314t Non-Hallopeau-Siemens syndrome, 171t non-Hodgkin lymphomas (NHL), 905 Noninfectious granulomatous, panniculitis, 275–276 Noninfectious granulomatous panniculitis, 275–276 Noninflammatory conditions, 13–14 Noninflammatory disorders, 7f Noninflammatory purpura, 209 Noninvoluting congenital hemangioma (NICH), 804–805, 805f GLUT-1 and, 805 PH and, 807 Nonscarring alopecia, 13, 215–223 causes of, 221–223 clinical features, 221 differential diagnosis, 223 histopathological features, 222–223 differential diagnosis, 216 histopathological features, 217t, 222–223 scarring v., 215 Nonsteroidal anti-inflammatory drugs (NSAIDs), 66, 287 Nonvenereal treponematoses, 449–456 NOR1, extraskeletal myxoid chondrosarcoma and, 877 Normal skin, differential diagnosis of, 14t North American blastomycosis, 459t, 469–471, 470t clinical features, 469–470 differential diagnosis, 470–471 histopathological features, 470 Novy-MacNeal-Nicolle (NNN), 519 NSAIDs. See Nonsteroidal anti-inflammatory drugs Nuclear dust, 182 Nuclear hyperchromasia, 771 Nummular dermatitis, 21, 29f clinical features of, 21 histopathological features of, 21

1069

INDEX 1070

Palisaded granulomatous form, 105 histopathological features, 105 Palisaded granulomatous infiltrates, 104–111 actinic granuloma, 107 deep granuloma annulare, 106–107 granuloma annulare, 104–105 Infectious palisaded granulomatous dermatitis, 110–111 interstitial or incomplete form, 105–106 necrobiosis lipoidica, 107–108 necrobiotic xanthogranuloma, 109 palisaded granulomatous form, 105 palisaded neutrophilic and granulomatous dermatitis, 109–110 rheumatic fever nodule, 109 rheumatoid nodule, 108–109 Palisaded neuromas, 886t Palisaded neutrophilic and granulomatous dermatitis, 109–111 differential diagnosis, 110 histopathological features, 110 Palisading granulomas, panniculitis associated with, 261 Palisading schwannomas, 890 Palmar fibromatosis, 773–774 clinical features, 773 differential diagnosis, 774 histopathologic features, 773–774 Palmoplantar eccrine hidradenitis, 245 clinical features, 245 differential diagnosis, 245 histopathological features, 245 Palmoplantar keratoderma, 319–320 clinical features, 320 differential diagnosis, 320 Meleda type, 320 of Vomer, 329 Palmoplantar neutrophilic eccrine hidradenitis, 128 Palmoplantar pustular psoriasis of Barber, 67 Palmoplantar pustulosis, 67, 69f Palpable purpura, 179, 182 PAN. See Polyarteritis nodosa Pan T-cell marker, 907 Pancreatic panniculitis, 265, 266f clinical features, 265 differential diagnosis, 265 histopathological features, 265 Pan-keratin, pleomorphic liposarcoma and, 868 Panniculitis, 13, 90, 250–276 algorithm, 251f–252f atrophic connective tissue, 274 chemical, 271 cold, 270 connective tissue, 274 crystal-related, 265–266, 266t cytophagic histiocytic, 263–265 in dermatomyositis, 273–274 clinical features, 273–274 histopathological features, 273–274 diagnosis of, 251f–252f diffuse, 269 eosinophilic, 275t evaluation of, 250t factitial, 271 focal, 269

Panniculitis (Cont.): histopathological features, 253t idiopathic lobular, 261 infection-related, 267–268, 269f interpretation, 251 liquefying, 261 lobular, 261–275 acute, 262f idiopathic, 261 lupus, 48, 272–273 ossificans, 878 palisading granulomas and, 261 pancreatic, 265, 266f of Pinol, 252 in polymyositis, 273–274 clinical features, 273–274 histopathological features, 273–274 poststeroid, 265, 267 predominant patterns of, 253t septal, 251–261, 255t trauma-related, 270–271 of Villanova, 252 Papillae, squiring, 66 Papillary dermis, alterations of, 14 Papillary digital eccrine adenocarcinoma (PDEA), 741–743, 742f, 743f clinical features, 742 histopathologic features, 742–743 Papillary eccrine adenoma, 731, 732f clinical features, 731 differential diagnosis, 731 histopathological features, 731 Papillary hemangioma (PH), 807, 807f GH and, 807 hyaline globules and, 807 NICH and, 807 POEMS and, 807 Papillary intralymphatic angioendothelioma, GH and, 816 Papillary intralymphatic angioendothelioma (PILA), 825–826, 826f RH and, 827 Papillary squamous cell carcinoma, 595 Papillary tubular adenoma, 731 Papillomatosis, 837 Papillomatosis cutis, 596 Papillomatous dermal nevi, 672 Papillon-Lefèvre syndrome, 320 Papular hemangioma. See also Epithelioid hemangioma Papular mucinosis, 365–366 in lupus erythematosus, 367 Papular purpuric gloves and socks syndrome, 498 Papular xanthoma, 115–116 clinical features, 115 differential diagnosis, 115–116 histopathological features, 115 Papules, erythematous, 200f Parabasal mitoses, 597 Paracoccidioides brasiliensis, 472, 488, 489 Paracoccidioidomycosis, 459t, 472–473 clinical features, 472 differential diagnosis, 472 histopathological features, 472 pulmonary, 472

Paraffin, 271 Paragangliomas, adult rhabdomyoma and, 873 Paragonimiasis, 530, 538 clinical features, 538 cutaneous, 538 differential diagnosis, 538 histopathological features, 538 Paragonimus westermani, 548 Parakeratin, 448 Parakeratosis, 67, 448, 592 focal, 74 shoulder, 69 Paramyxovirus, 496 Paraneoplastic pemphigus, 61, 143, 145–147, 146f, 146t clinical features, 145–146 histopathological features, 146t Paraneoplastic vasculitis, diagnosis, 186 Parapoxviruses, 513 Paraproteins, 185 Parapsoriasis, 71–72, 913–914 clinical features of, 71–72, 913 differential diagnosis, 72, 914 histopathologic features, 913 histopathological features, 72 large-plague, 71 small-plague, 71 Parathormone, 266 Parinaud oculoglandular syndrome, 441 Parkes Weber syndrome, 832–833 Paronychia, 990–991 clinical features, 990 differential diagnosis, 991 histopathologic features, 990–991 Parosteal fasciitis. See Fibroosseous pseudotumor Parvovirus B9, 93 PAS. See Periodic acid-Schiff PATCHED gene, 587, 589, 591 Patchlike blue nevus, 647 Pathogenesis, polymorphous light eruption, 89 Pattern recognition, 5f Patterned hypermelanosis, 347–348 Patterned leukoderma, 338–339 Paucicellular nodule, 797 Paucicellular tumor, 797 Pauci-immune vasculitides, 196 Pautrier microabscesses, 286, 306 PAX3-FKHR, 875 PCR. See Polymerase chain reaction PDCs. See Plasmacytoid dendritic cells PDEA. See Papillary digital eccrine adenocarcinoma PDFGB. See B-chain gene PDGF. See Platelet-derived growth factor Pearly penile papules, 767–768 clinical features, 767–768 differential diagnosis, 768 histopathological features, 768 Peau d’orange, 270 PEComas, angiomyolipoma and, 862 PECs. See Proliferating epithelial cysts Pediculus humanus, 309 Pedunculated seborrheic keratosis, 565–566, 767

Perineural invasion, 666 Perineuriomas, 889 clinical features, 889 differential diagnosis, 889 histopathologic features, 889 soft tissue, 889f, 890t Perineurium, 883 Periodic acid-Schiff (PAS), 52, 66, 740, 894, 986t chondroid lipoma and, 861 TA and, 806 Perioral dermatitis, 99–100, 237–240 clinical features, 237–238 histopathological features, 100, 239–240 Peripheral nerve hamartomatous lesions of, 883–884 reactive lesions of, 883–884 Peripheral nerve sheath neoplasms, 884–896 Peripheral neuroectodermal tumor (PNET), 963 Periungual fibroma, 768–769 clinical features, 768 differential diagnosis, 769 histopathologic features, 768 Perivascular dermatitis, 81–94 Perivascular inflammatory cell infiltrates, 81t, 160f Spitz nevus, 635 Perniosis, 88–89, 94, 192–193, 304, 304f clinical features, 88 differential diagnosis, 89, 192–193 histopathological features, 88 Peutz-Jeghers syndrome, 348, 616 PEX1, 315 PEX6, 315 PG. See Epithelioid hemangioma; Lobular capillary hemangioma PH. See Papillary hemangioma PHACE. See Posterior fossa brain malformations, infantile hemangiomas, arterial anomalies, coarctation of the aorta and cardiac defects, and eye abnormalities syndrome Phaeohyphomycosis, 459t, 477, 478f clinical features, 477 differential diagnosis, 477 histopathological features, 477 Phagocytosis-inducing factor (PIF), 264 Phenol, 353 Phenotypic heterogeneity melanocytic lesions with, 648 melanocytic nevi with, 648–649 clinical features, 648 histopathological features, 648–649 Phenytoin-induced exanthems, 295t Phlebectasias, Maffucci syndrome and, 838 Phlebolith, SCH and, 808 Phlebotomus, 442 Phlebotomus, 517 Photoallergic dermatitis, 17–18, 28f clinical features of, 18 histopathologic features of, 18 Photochemotherapy-induced (PUVA) lentigo, 615 Photodermatosis, 90 Photophobia syndrome, 321 Photosensitivity dermatitis, 286

Photosensitivity drug eruptions, 285–287 differential diagnosis, 286–287 histopathological features, 286 Phototoxic dermatitis, 18 clinical features of, 18 histopathological features of, 18 Phrynoderma, 233 Phthirus pubis, 309 Physalia physalis, 307 Phytonadione, 390 Piannic onychia, 450 Piebaldism, 338–339 clinical features, 338–339 differential diagnosis, 339 histopathological features, 339 Piedra, 467–468 black, 459t, 467 differential diagnosis, 468 histopathological features, 468 white, 459t, 467t Piedraia hortae, 430, 467 PIF. See Phagocytosis-inducing factor Pigment deposits, 353 Pigmentation disorders, 338–357, 338t. See also specific disorders evaluation of, 341t hyperpigmentation, 339f, 346–357 acromelanosis, 347 Addison disease, 346 clofazimine-induced, 123 Crow-Fukase syndrome, 347 diffuse, 346 generalized, 346 Nelson syndrome, 346 POEMS, 347 postinflammatory, 352 differential diagnosis, 352 histopathological features, 352 zosteriform, 352 hypopigmentation, 338–346, 342t ash leaf spots, 343 Chédiak-Higashi syndrome, 343 Hermansky-Pudlak syndrome, 342–343 hypomelanosis, 345 hypomelanosis of Ito, 344 idiopathic guttate hypomelanosis, 344 incontinentia pigmenti achromians, 344 nevus anemicus, 345–346 nevus depigmentosus, 344–345 oculocutaneous albinism, 341–342 piebaldism, 338–339 pityriasis alba, 345 postinflammatory leukoderma, 345 vitiligo, 340–341 Vogt-Koyanagi-Harada syndrome, 340–341 Pigmented basal cell carcinoma, 581f Pigmented conditions, 1015–1016 Pigmented dermatofibrosarcoma protuberans, 787, 788f Pigmented epithelioid melanocytoma, 643 Pigmented follicular cyst, 548 Pigmented purpuric dermatoses, 88, 193–194, 195f clinical features, 193–194 differential diagnosis, 194 of Gougerot and Blum, 193 of Schamberg, 193

INDEX

Peeling skin syndrome, 332–333 clinical features, 332 differential diagnosis, 332 histopathological features, 332 Pellagra, 76–77 clinical features, 77 histopathological features, 77 PELVIS. See Perineal IH, external genitalia malformations, lipomyelomeningocele, vesicorenal abnormalities, imperforate anus, and skin tag syndrome Pemphigoid bullous, 157–160, 288 cell-poor, 159f clinical features, 158 diagnosis, 159 differential diagnosis, 159–160 direct immunofluorescence, 159 histopathological features, 158 indirect immunofluorescence, 159 urticarial lesion of, 160f cell-poor bullous, 159f cicatricial, 162–163 antigenic targets in, 163t clinical features, 162 differential diagnosis, 163 histopathological features, 162 drug-induced, 288 clinical features, 288 histopathological features, 288 Pemphigus erythematosus, 143–144 differential diagnosis, 144 histopathological features, 143–144 Pemphigus foliaceus, 143, 144f Pemphigus vegetans, 138, 143f, 428 differential diagnosis, 142–143 Pemphigus vulgaris, 138–143, 138f histopathological features, 140–142 Penicillin, 281 Penicillium, 458 Penicillium marneffei, 488 Penile fibromatosis, 774 clinical features, 774 differential diagnosis, 774 histopathologic features, 774 Penile lentigo, 617f Pentazocine, 271, 390 Perforating collagenoses, 397 reactive, 397 Perforating dermatoses, 332–335 acquired, 333, 333t, 334f Perforating folliculitis, 240–241 clinical features, 240 differential diagnosis, 240–241 histopathological features, 240 Peribulbar lymphocytic infiltration, 219 Pericytes, endothelial cells and, 802 Perifollicular elastolysis, 402 Perifollicular fibroma, 712t, 713 Perifollicular inflammation, 52 Perifolliculitis capitis abscedens et suffodiens. See Dissecting cellulitis Perineal IH, external genitalia malformations, lipomyelomeningocele, vesicorenal abnormalities, imperforate anus, and skin tag syndrome (PELVIS), 831

1071

INDEX 1072

Pigmented schwannomas, 890 Pigmented spindle cell nevus (PSCN), 640 with atypical features, 640–641 clinical features, 640 differential diagnosis, 640–641 histopathologic features, 640 PILA. See Papillary intralymphatic angioendothelioma PILA and, 826 Pilar basal cell carcinoma, 584–585 Pilar cysts, 544 differential diagnosis, 544 histopathological features, 544 proliferating, 544 Pilar leiomyoma, 714, 869t, 870f clinical features, 714 differential diagnosis, 714 histopathologic features, 714 Pilar leiomyosarcoma, 718 Pilar neoplasms, 696 malignant, 715–718 Pilar neurocristic hamartoma, 648 Pilar sheath acanthoma (PSA), 697–698 clinical features, 697 histopathologic features, 697–698 Pilar tumors benign proliferating, 701–702 clinical features, 701 cytologic features of, 701–702 differential diagnosis, 702 histopathologic features, 701–702 malignant proliferating, 716–717, 717f clinical features, 716 differential diagnosis, 716–717 histopathologic features, 716 proliferating, 702f benign, 701–702 malignant, 716–717 Pilomatricoma (PM), 702, 706, 706t, 708f clinical features, 706 differential diagnosis, 707 histopathological features, 706–707 invasive, 717, 718t Pilomatrix carcinoma, 717, 718t clinical features, 717 differential diagnosis, 717 histopathological features, 717 Pilonidal cysts, 553 Pilonidal sinus, 416–417 Pink amorphous deposits, 372t Pink nodule, 930 Pinkus follicular mucinosis, 369 differential diagnosis, 369 histopathological features, 369 Pinta, 450 histopathological features, 450 Pintids, 451 Pitted keratolysis, 430 clinical features, 430 differential diagnosis, 430 histopathological features, 430 Pityriasiform dermatitis, 10 Pityriasiform eruptions, 293 clinical features, 293 differential diagnosis, 293 histopathological features, 293

Pityriasis alba, 20–21, 345 clinical features, 20–21 differential diagnosis, 345 histopathological features, 20–21, 345 Pityriasis lichenoides, 87–88 clinical features, 87 differential diagnosis, 87–88 histopathological features, 87 Pityriasis lichenoides chronica (PLC), 42, 57–58 clinical features, 57–58 differential diagnosis, 58 histopathological features, 58 Pityriasis lichenoides varioliformis acuta (PLEVA), 42, 51, 55–58 clinical features, 55 differential diagnosis, 57 histopathological features, 55–57 Pityriasis rosea, 23–24, 32f, 72–74, 510 clinical features, 73–74 Pityriasis rubra pilaris (PRP), 68–70, 70t, 71f clinical features, 69 differential diagnosis, 70 histopathological features, 69–70 inherited, 321–322 Pityriasis versicolor, 459t, 465 histopathological features, 465 Pityrosporum orbiculare, 465 Pityrosporum ovale, 234, 240, 465 Placenta-like alkaline phosphatase (PLAP), 963 Plague, 436 Plakoglobin, 593 Plantar fibromatosis, 773–774 clinical features, 773 differential diagnosis, 774 histopathologic features, 773–774 Plantar verrucous carcinoma, 596 clinical features, 597 differential diagnosis, 598 histopathological features, 597 PLAP. See Placenta-like alkaline phosphatase Plaques of pregnancy, 29–30, 84 clinical features, 29, 84 differential diagnosis of, 30, 84 histopathological features, 29, 84 Plaque-type blue nevus clinical features, 647–648 histopathologic features, 647–648 Plasma cell stomatitis, 1010 clinical features, 1010 differential diagnosis, 1010 histopathologic features, 1010 Plasma cell vulvitis, 128 Plasma cells, 907, 929 Plasmacytoid dendritic cells (PDCs), 926 Plasmacytosis circumorificialis, 128 Plasmacytosis mucosae, 128–129 clinical features, 128 histopathological features, 128–129 Platelet-derived growth factor (PDGF), 785, 786 Platelets IH and, 802 KHE and, 824 PLC. See Pityriasis lichenoids chronica Plectin, 156

Pleomorphic basal cell carcinoma, 582 Pleomorphic lipoma, 860–861, 860t, 861f WDL/ALT and, 865, 866 Pleomorphic liposarcoma, 780, 868, 868f, 868t Pleomorphic malignant fibrous histiocytoma, 791–792 Pleomorphic rhabdomyosarcoma,875–876, 875f adult rhabdomyoma and, 873 Pleomorphism, 906 Pleurodynia, 503 PLEVA. See Pityriasis lichenoids varioliformis acuta Plexiform fibrohistiocytic tumor, 101, 788–789 clinical features, 788 differential diagnosis, 789 histopathologic features, 788–789 Plexiform neurofibromas, 887, 888f Plexiform schwannoma, 892f Plexiform spindle cell nevus, 650 clinical features, 650 differential diagnosis, 650 histopathological features, 650 Plexiform Spitz nevus, 639 Plexiform xanthoma, 116 clinical features, 116 differential diagnosis, 116 histopathological features, 116 PM. See Pilomatricoma PNET. See Peripheral neuroectodermal tumor; Primitive neuroectodermal tumor Pneumocystis carinii, HIV and, 501 POEMS. See Polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes Poikiloderma, 58–59 accompanying dermatomyositis, 59 of Civatte, 59 congenitale, 59 mycosis fungoides, 59 Polyarteritis nodosa (PAN), 179, 200t clinical features, 200–201 differential diagnosis, 201 histopathological features, 201 Polydactyly. See Supernumerary digit Polymerase chain reaction (PCR), 268, 269, 421, 446, 467, 517, 907, 928 APL and, 844 RH and, 827 Polymethylsiloxane, 271 Polymorphous light eruption, 89–90 clinical features, 89 differential diagnosis, 90 histopathological features, 89 pathogenesis, 89 Polymyositis, panniculitis in, 273–274 clinical features, 273–274 histopathological features, 273–274 Polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes (POEMS), 347, 806, 815 GH and, 816 MVH and, 809 PH and, 807 RAE and, 818 Polyoma virus, 515

Primary cutaneous CD4+ pleomorphic T-cell lymphoma (SM-PTL), 921 clinical features, 921 definition, 921 differential diagnosis, 921 genotypic features, 921 histopathological features, 921 immunophenotypic features, 921 Primary cutaneous CD8+ T-cell lymphoma, 921–922 clinical features, 921 differential diagnosis, 921–922 genotypic features, 921 histopathologic features, 921 immunophenotypic features, 921 Primary cutaneous CD30+ lymphoproliferative disorders, 915 Primary cutaneous follicle center cell lymphoma, 931f Primary cutaneous follicle center lymphoma, 934f Primary cutaneous marginal zone B-cell lymphoma, 934f, 935f Primary cutaneous melanoma, 678, 679t Primary cutaneous meningioma, 900f Primary cutaneous mucinoses dermal degenerative, 363–369 follicular degenerative, 369 inflammatory, 363–369, 369 Primary cutaneous ossification, 384 Primary cutaneous peripheral T-cell lymphoma, 921 unspecified, 922–924 clinical features, 923 definition, 922 differential diagnosis, 924 genotypic features, 924 histopathological features, 923 immunophenotypic features, 924 Primary mucoepidermoid carcinoma, 745 Primary neuroendocrine carcinoma, 896–897, 898f clinical features, 896–897 differential diagnosis, 897 histopathological features, 897 Primary scarring alopecia, 224–225 lymphocyte-associated, 225, 231t pustulofollicular, neutrophil-associated, 230, 236t Primary signet ring cell adenocarcinoma, 752–753, 754f clinical features, 752–753 differential diagnosis, 753 histopathologic features, 752–753 Primary syphilis, 446, 447–448, 447t differential diagnosis, 448 Primary yaws, 449–450 Primitive neuroectodermal tumor (PNET), 874, 897 alveolar rhabdomyosarcoma and, 875 extraskeletal osteosarcoma and, 879 Procainamide, 289 Proflaggrin, 314 Progeria, 399–400 adult, 399 clinical features, 400 histopathological features, 400

Progressive capillary hemangioma. See Tufted angioma Progressive nodular histiocytoma, 122 clinical features, 122 differential diagnosis, 122 histopathological features, 122 Progressive symmetric erythrokeratoderma, 320 clinical features, 320 differential diagnosis, 320 histopathological features, 320 Progressive systemic sclerosis (PSS), 388–390 Proliferating epithelial cysts (PECs), 543, 554 differential diagnosis, 554 histopathological features, 554 Proliferating pilar cysts, 544 Proliferating pilar tumor, 702f benign, 701–702 malignant, 716–717 Proliferative conditions, 13. See also specific proliferative conditions Proliferative fasciitis, 772f Prominent myxoid component, 797 Prominent pagetoid spread, Spitz nevus, 636 Promontory sign, KS and, 821 Prostaglandins, 81–82, 266 Prostate-specific antigen (PSA), 962 Prostate-specific membrane antigen (PSMA), 963 Protein tyrosine phosphatases, 593 Proteus, 276, 427, 428, 482 Prototheca wickerhamii, 526, 989 Prototheca zopfii, 526 Protothecosis, 526–527, 526t differential diagnosis, 527 Protozoal infections, 517–527 diagnosis, 517 Proximal subungual onychomycosis (PSO), 462–463 Proximal white subungual onychomycosis (PWSO), 463 PRP. See Pityriasis rubra pilaris Prurigo nodularis, 24f, 72f, 562t clinical features, 561 differential diagnosis, 562 histopathological features, 561 Prurigo pigmentosa, 352 differential diagnosis, 352 histopathological features, 352 Pruritic papules, 29–30 clinical features, 29 differential diagnosis of, 30 histopathological features, 29 Pruritic urticarial papules, 84 clinical features, 84 differential diagnosis of, 84 histopathological features of, 84 Pruritic urticarial papules of pregnancy clinical features, 84 histopathological features, 84 PSA. See Pilar sheath acanthoma; Prostatespecific antigen Psammoma, 99 bodies, 898 Psammomatous melanotic schwannomas, 796 PSCN. See Pigmented spindle cell nevus

INDEX

Polypoid basal cell carcinoma, 580 Polythelia. See Accessory nipple Pompholyx eczema clinical features, 21–22 histopathological features, 21–22 Porocarcinomas, 729 Poroid hidradenoma, 729 Porokeratosis, 323–324, 590 clinical features, 323 differential diagnosis, 324 histopathological features, 323–324 Poroma, 730f, 731f Porphyria, 379–380 histopathological features, 380 Porphyria cutanea tarda, 172–173, 173t, 380, 380f Port wine stains (PWSs), 813, 832, 834f AVMs, 847 Portuguese man-of-war, 307t Posterior fossa brain malformations, infantile hemangiomas, arterial anomalies, coarctation of the aorta and cardiac defects, and eye abnormalities syndrome (PHACE), 831 Postfebrile anagen, 216 Postinflammatory hyperpigmentation, 352 differential diagnosis, 352 histopathological features, 352 Postinflammatory leukoderma, 345 Post-kala-azar dermal leishmaniasis, 518 Postpartum anagen, 216 Poststeroid panniculitis (PSP), 265, 267 Povidone-iodine, 271, 421 Poxvirus infections, 512–514 animal, 512 clinical features, 512 differential diagnosis, 514 histopathological features, 513 PPARG, 274 PR. See Pagetoid reticulosis Precursor hematologic neoplasms, 926 Precursor lesions, 591. See also specific types Precursor T-lymphoblastic lymphoma, 926 Prednisone, 264 Pregnancy, PG and, 813 Premature aging syndromes, 399–400, 405 Pressure alopecia, 220–221, 226 clinical features, 220 differential diagnosis, 220 histopathological features, 220 Pretibial myxedema, 364–365 differential diagnosis, 364–365 histopathological features, 364 Primary apocrine carcinomas, 749 Primary cutaneous adenosquamous carcinoma, 745 clinical features, 745 differential diagnosis, 745 histopathologic features, 745 Primary cutaneous anaplastic large cell lymphoma, 917–919, 918f clinical features, 917 definition, 917 differential diagnosis, 917–919 genotypic features, 917 histopathological features, 917 immunophenotypic features, 917 Primary cutaneous B-cell lymphomas, 931

1073

INDEX 1074

Pseudoainhum constricting bands, 396 Pseudoallescheria boydii, 479, 487 Pseudoangiomatous melanocytic nevi, 841 Pseudocysts, 523 of auricle, 553 Pseudoepitheliomatous hyperplasia, 434f, 519, 561–562 Pseudofolliculitis barbae, 238 clinical features, 238 histopathological features, 238 Pseudoglandular squamous cell carcinoma, 1018 Pseudohyphae, 464 Pseudohypoparathyroidism, 384 Pseudo-Kaposi sarcoma. See Acroangiodermatitis Pseudolipoblasts, 792 Pseudolymphomas (PSLs), 298, 905 Pseudolymphomata, drugs implicated in, 291t Pseudomonas aeruginosa, 234, 276, 423, 428, 482, 990 Pseudoneoplastic lesions, 696 of sweat glands, 755–759 Pseudoneoplastic proliferations of follicle-related mesenchyme, 718–720 of hair follicles, 718–720 Pseudoneoplastic sebaceous proliferations, 695–696 clinical features, 695–696 differential diagnosis, 696 histopathologic features, 696 Pseudopelade, 227 Pseudoporphyria, 173–174 clinical features, 173–174 diagnosis, 174 differential diagnosis, 174 drug-induced, 288 histopathological features, 174 Pseudostratified columnar epithelium, 552 Pseudovascular adenoid squamous cell carcinoma, 594–595 Pseudovasculitis, 203–209, 204t atrophie blanche, 206, 207f calciphylaxis, 207–208, 208t, 209f coagulopathies, 203 cryoglobulinemias, 203–204 cutaneous cholesterol embolism, 204 Degos syndrome, 206 livedo reticularis, 205 vascular occlusive conditions, 203 Pseudoxanthoma elasticum, 401 clinical features, 401 differential diagnosis, 401 histopathological features, 401 Psittacosis, 442–443 clinical features, 443 differential diagnosis, 443 histopathological features, 443 PSLs. See Pseudolymphomas PSMA. See Prostate-specific membrane antigen PSO. See Proximal subungual onychomycosis Psoriasiform dermatitis, 9, 64–78 Psoriasiform drug reactions, 293 Psoriasiform keratosis, 566

Psoriasis, 64–66, 65t, 73, 989 clinical features, 64, 989 differential diagnosis, 66, 989 guttate, 66f, 67f histopathologic features, 989 histopathological features, 64–65 pustular, 66–68 clinical features, 67 differential diagnosis of, 67–68 histopathological features, 67 palmoplantar, of Barber, 67 of von Zumbusch, 67 verrucous, 66 Psorospermium, 489 PSP. See Poststeroid panniculitis PSS. See Progressive systemic sclerosis Psychotropic drugs, 356 PTCH gene, 872 Pulmonary adenocarcinoma, 966 Pulmonary paracoccidioidomycosis, 472 Punch specimen, 3 Punctate keratoses, 602 clinical features, 602 differential diagnosis, 602 histopathological features, 602 Purpura, 179. See also Henoch-Schönlein purpura eczematid-like, of Doucas and Kapetanakis, 193 noninflammatory, 209 palpable, 179, 182 senile, 209f Purpura annularis telangiectodes of Majocchi, 193 Pustular drug reaction, 153–154 clinical features, 153 histopathological features, 153 Pustular eruptions, 287 clinical features, 287 differential diagnosis, 287 histopathological features, 287 Pustular psoriasis, 66–68 clinical features, 67 differential diagnosis of, 67–68 histopathological features, 67 palmoplantar, of Barber, 67 of von Zumbusch, 67 Pustular secondary lues, 153 clinical features, 153 histopathological features, 153 Pustular vasculitis, 182 Pustule, 136 Pustulofollicular, neutrophil-associated primary scarring alopecia, 230, 236t Pustulosis, palmoplantar, 67, 69f PUVA lentigo. See Photochemotherapyinduced lentigo PWSO. See Proximal white subungual onychomycosis PWSs. See Port wine stains Pyoderma faciale, 99 Pyoderma gangrenosum, 126, 186t, 191, 428 clinical features, 126, 191 histopathological features, 126, 192 Pyoderma vegetans, 428–429 differential diagnosis, 429 histopathological features, 428

Pyogenic granuloma (PG), 803t, 813–815, 814f, 814t, 1013f histologic features of, 823t Pyostomatitis vegetans, 1009 clinical features, 1009 differential diagnosis, 1009 histopathologic features, 1009 Pyrazolone, 281 Pyridoxine, 259 Q Quinine, 353 R Radial growth phase, 657 Radiation angiosarcoma and, 829 benign acquired vascular lesions with, 850 Radiation dermatitis, 301–303, 302f, 303f, 394–395 differential diagnosis, 394 Radiation reactions, 301–303 clinical features, 301–302 differential diagnosis, 302–303 histopathological features, 302 Radiation-induced morphea, 301 RAE. See Reactive angioendotheliomatosis Ramichloridium obovoideum, 477 Rapamycin, 343 Rapid plasma regain (RPR), 437 Rapidly involuting congenital hemangioma (RICH), 804–805 GLUT-1 and, 805 RASA1 gene, 833 Raynaud disease, 93 Raynaud phenomenon, 388 Reaction patterns. See also specific types in diagnosis, 5f erythema nodosum, 256f Reactive angioendotheliomatosis (RAE), 806, 817–818, 818f angioendotheliomatosis and, 817 GH and, 816 Reactive conditions, 1006–1014 Reactive follicles, 928 Reactive lesions features of, 5–8 of peripheral nerve, 883–884 Reactive lymphocytes, 907 Reactive perforating collagenosis (RPC), 240, 397 REAL. See Revised European-American Classification of Lymphoid Neoplasms Recurrent aphthous ulcer, 1006 clinical features, 1006 different diagnosis, 1006 histopathologic features, 1006 Recurrent melanocytic nevus, 622 clinical features, 622 differential diagnosis, 622 histopathological features, 622 Recurring digital fibrous tumor of childhood, 781 Refsum syndrome, 315–316 clinical features, 315–316 differential diagnosis, 316 histopathological features, 316

Rhinosporidiosis, 460t, 489–490, 527 clinical features, 489 differential diagnosis, 489–490 histopathological features, 489 Rhinosporidium, 489, 490f Rhinosporidium seeberi, 527 Rhizomucor, 483 Rhizopus, 483 Ribonucleoprotein (RNP), 53 RICH. See Rapidly involuting congenital hemangioma Rickettsial and viral infections, 89, 454 clinical features, 454 differential diagnosis, 455–456 histopathological features, 454–455 Riga-Fede disease, 1006 Ringworm, 459 cray-patch, 460 Ritter disease, 147 clinical features, 147 histopathological features, 147 RMSP. See Rocky Mountain spotted fever RNP. See Ribonucleoprotein Rochalimaea, 501 Rocky Mountain spotted fever (RMSP), 184, 454, 455f, 497 Romanovsky stains, 521 Rosacea, 237–240, 241t, 243f clinical features, 237–238 granulomatous, 243f histopathological features, 239–240 Rosacea fulminans, 99 Rosal-Dorfman disease, 118–119 clinical features, 118 differential diagnosis, 118–119 histopathological features, 118 Roseola, 496t, 498–499 clinical features, 498–499 differential diagnosis, 499 histopathological features, 499 Ross River, 503 Rothmund-Thomson syndrome, 59 ataxia telangiectasia and, 835 Round cell liposarcoma, 596, 867–868 RPC. See Reactive perforating collagenosis RPR. See Rapid plasma regain RT-PCR. See Reverse transcription polymerase chain reaction Rubella, 496t, 497–498 clinical features, 497 differential diagnosis, 498 histopathological features, 497–498 Rudimentary digit. See Supernumerary digit Rue histiocytes, 421 Ruptured follicles, 111–113 clinical features, 112 histopathological features, 112 S S-100 protein, 593, 595, 600, 670, 676, 680, 694, 794, 889, 894, 962 chondroid lipoma and, 861 EHE and, 829 extraskeletal myxoid chondrosarcoma and, 877 extraskeletal osteosarcoma and, 879 leiomyoma and, 869 leiomyosarcoma and, 871, 872

S-100 protein (Cont.): myxoid liposarcoma and, 867 pleomorphic liposarcoma and, 868 spindle cell lipoma and, 860 WDL/ALT and, 866 SACRAL. See Spinal dysraphism, anogenital anomalies, cutaneous anomalies, renal and urologic anomalies, associated with angioma of lumbosacral localization syndrome Salicylates, 281 Salivary glands, ectopic, 414, 415f SAN. See Syringomatous adenoma of nipple Sarcoidosis, 101–102, 911 clinical features, 101 differential diagnosis, 101–102 histopathological features, 101 RAE and, 817 Sarcoma, 971–973. See also specific types clear cell, 676 clinical features, 971 differential diagnosis, 972 epithelioid, 795, 829, 872, 972 granulocytic, 946–947 high-grade pleomorphic, 791 immunohistochemistry, 972–973 low-grade fibromyxoid, 794–795, 794f osteogenic, 972 special stains, 972–973 synovial, 825, 879 undifferentiated pleomorphic, 791–792, 972 Sarcoptes scabiei, 75 Satellite cell necrosis, 36 Scabala, 75 Scabies, 75–76 clinical features, 75 histopathological features, 75–76 in HIV, 75 Scalp biopsies, 213 Scalp melanocytic nevi, 625–627 clinical features, 626 differential diagnosis, 626–627 histopathological features, 626 Scalp metastases, 961 Scanning magnification, microslide examination at, 3–4 Scarring alopecia, 13, 223–232 central centrifugal, 227–229 end-stage, 235 nonscarring v., 215 primary, 224–225 lymphocyte-associated, 225, 231t pustulofollicular, neutrophil-associated primary, 230, 236t secondary, 224–225, 232, 238t Scarring follicular keratosis, 233 Scars, hypertrophic, 392–393 Scedosporium, 487–488 SCH. See Spindle cell hemangioma Schaumann bodies, 101 Schistosoma haematobium, 539, 540 Schistosoma japonicum, 539 Schistosoma mansoni, 539, 540f Schistosomiasis, 539–540 differential diagnosis, 540 Schizophrenia, 590 Schwann cells, 618, 671, 887

INDEX

Regression of malignant melanoma, 678t melanoma, 677 Reiter syndrome, 68, 69t clinical features of, 68 differential diagnosis, 68 histopathological features of, 68 Relapsing polychondritis, 90, 398–399 clinical features, 398 histopathological features, 398–399 Related lesions, 543–554 Remicade, 297 Renal cell carcinomas, 960 marker, 963, 969 Renal transplantation KS and, 820 RAE and, 817 Resorcinol, 353 Reticular dermis, alterations of, 14 Reticular erythematous mucinosis, 366–367 differential diagnosis, 366–367 histopathological features, 366 Reticulated pigmented dermatosis, 348 Reticulin, EHE and, 828 Reticulohistiocytoma, 121–122 clinical features, 121 differential diagnosis, 121–122 histopathological features, 121 Reticulohistiocytosis. See Congenital selfhealing Langerhans histiocytosis Retiform hemangioendothelioma (RH), 826–827, 827f CH and, 827 PILA and, 826 THH and, 810, 811 Retinoids, PG from, 813 Reverse transcription polymerase chain reaction (RT-PCR), 866 alveolar rhabdomyosarcoma and, 875 Revised European-American Classification of Lymphoid Neoplasms (REAL), 264 RH. See Retiform hemangioendothelioma Rhabdomyoma, 872 Rhabdomyomatous mesenchymal hamartoma, 872, 872f Rhabdomyosarcoma, 874–876, 874t, 972, 973 leiomyosarcoma and, 871 Rheumatic fever nodule, 109 clinical features, 109 differential diagnosis, 109 histopathological features, 109 Rheumatoid arthritis, RAE and, 817 Rheumatoid neutrophilic dermatitis, 126 clinical features, 126 differential diagnosis, 126 histopathological features, 126 Rheumatoid nodule, 108–109 clinical features, 108 differential diagnosis, 108–109 histopathological features, 108 Rhinocladiella aquaspersa, 476 Rhinophyma, 241t Rhinoscleroma, 438–439, 520 clinical features, 438 differential diagnosis, 439 histopathological features, 438

1075

INDEX 1076

Schwannoma, 893t ancient, 891, 891f cellular, 890, 892f differential diagnosis, 890–891, 892 immunohistochemistry of, 890 malignant, 895 pigmented, 890 plexiform, 892f Schwannomas, 536, 889 ancient, 890 clinical features, 890 histopathologic features, 890 palisading, 890 psammomatous melanotic, 796 Scleredema adultorum, 367–368 histopathological features, 367–368 Sclerema neonatorum (SN), 265, 267 clinical features, 267 differential diagnosis, 267 histopathological features, 267 Scleroderma, 259–261, 260t, 387–390, 389t clinical features, 260 differential diagnosis, 261 histopathological features, 260–261 localized, 387–388 systemic, 388–390 Sclerodermatoid tissue reactions, 291 differential diagnosis, 291 histopathological features, 291 Sclerodermoid disorders, 390–391 Sclerodermoid reaction, 46 Scleromyxedema, 362, 365–366 clinical features, 365 differential diagnosis, 366 histopathologic features, 365–366 Sclerosing angiogenic tumor. See Epithelioid hemangioendothelioma Sclerosing basal cell carcinoma, 583 Sclerosing blue nevus, 645 differential diagnosis, 645 histopathological features, 645 Sclerosing endothelial tumor. See Epithelioid hemangioendothelioma Sclerosing epithelioid angiosarcoma. See Epithelioid hemangioendothelioma Sclerosing hemangioma, 776 MVH and, 809 THH and, 811 Sclerosing interstitial vascular sarcoma. See Epithelioid hemangioendothelioma Sclerosing liposarcoma, 860, 865 Sclerosing rhabdomyosarcoma, 874 Sclerosing sweat duct carcinoma, 743 Sclerotic bodies, 476 Sclerotic fibroma, 769 clinical features, 769 histopathologic features, 769 Scrotal angiokeratomas, VH and, 838 SCs. See Sebaceous carcinomas SCSCCs. See Spindle cell squamous cell carcinomas Sea urchin spines, 307f, 307t Seabather’s eruption, 307t Sebaceoma, 692

Sebaceous adenoma, 690–691, 691f clinical features, 690 Sebaceous carcinomas (SCs), 690, 693–695, 694f, 695f basaloid, 694 clinical features, 693 differential diagnosis, 694–695 grade of, 693 histopathological features, 693–694 Sebaceous differentiation basal cell carcinoma with, 581f superficial epithelioma with, 691–692 differential diagnosis, 692 histopathological features, 692 Sebaceous hyperplasia, 689–691 clinical features, 689–690 differential diagnosis, 690 giant solitary, 690 histopathological features, 690 linear, 690 Sebaceous tumors, 689–720 Sebocrine adenoma, 692 Sebomatricoma, 691 Seborrheic dermatitis, 22, 31f, 73 clinical features, 22 histopathological features, 22 Seborrheic keratosis, 5f, 565–567 acanthotic, 565 adenoidal, 565 clinical features, 565 clonal, 565 histopathological features, 565–567 hyperkeratotic, 565 irritated, 566 macular, 565 miscellaneous, 566 pedunculated, 565–566, 767 Secondary cutaneous B-cell lymphomas, 931 Secondary cutaneous ossification, 384 Secondary scarring alopecia, 224–225, 232, 238t Secondary syphilis, 58, 446, 447t, 448–449, 449f clinical features, 58 differential diagnosis, 78, 448–449 histopathological features, 58, 78 Secondary systemic amyloidosis, 372–374 histopathological features, 373–374 Secondary yaws, 450 Senile purpura, 209f Sentinel lymph node biopsy (SLNB), 638 Septa, 250 Septal panniculitis, 251–261, 255t Serotonin, 77 Serum sickness, 281 clinical features, 292 diagnosis, 185–186 drug-associated vasculitis, 292–293 drugs associated with, 186t histopathological features, 292 Sezary cell, 906, 950 Sezary syndrome, 73, 75 clinical features, 914 definition of, 914 diagnosis, 915 differential diagnosis, 915

Sezary syndrome (Cont.): genotypic features, 915 histopathologic features, 914–915 immunophenotypic features, 915 SFTS. See Solitary fibrous tumor of the skin Shadow cells, 702 Shagreen patches, 392 Shave specimen, 3 SHORT syndrome, 275 Shoulder parakeratosis, 69 Shulman syndrome, 259–261, 276 Signet ring cells, 966 Signet ring squamous cell carcinoma, 594f Silicone, 271 Silver deposition, 355 histopathological features, 355 SIMP, 655, 660, 664, 666 Simulium, 531 SIN. See Squamous intraepithelial neoplasia Sindbis, 503 Sinonasal carcinomas, 968 clinical features, 968 differential diagnosis, 968 histopathologic features, 968 immunohistochemistry, 968 special stains, 968 Sinusoidal hemangioma, 838 Sister Mary Joseph nodule, 416, 967f Sjögren syndrome, 90, 275, 452 Sjögren-Larsson syndrome, 319 clinical features, 319 differential diagnosis, 319 histopathological features, 319 SJS. See Stevens-Johnson syndrome Skeletal muscle, 872–876 Skin appendages, disorders of, 12 Skin tags, 766–767, 858 Skin-limited amyloidosis, 373t, 374–379 SLC89A4, 77 Slide initial examination of, 3 interpretation of, 3 SLNB. See Sentinel lymph node biopsy SM. See Spitzoid melanoma Small cell eccrine carcinomas, 749 differential diagnosis of, 750t Small cell melanoma, 631f, 670, 673–674 clinical features, 673–674 in elderly, 673–674 histopathologic features, 673–674 mimicking Merkel cell, 673 Small cerebriform lymphocyte, 906 Small congenital nevus, 628–630 Small lymphocytes, 906 B-type, 929 Small round cell cutaneous tumors, differential diagnosis, 899 Small-diameter melanoma, 670 Small-plague parapsoriasis (SPP), 71 Small-vessel neutrophilic vasculitis, 182–183 clinical features, 182 diagnostic approach to, 183–186 histopathological features, 182–183 Smokeless tobacco keratosis (STK), 1008 clinical features, 1008 differential diagnosis, 1008 histopathological features, 1008

Spindle cell hemangioma (SCH), 807–808, 807t, 808f angiosarcoma and, 807, 830 CD31 and, 808 CD34 and, 808 CH and, 827 early-onset varicose veins and, 807 Epithelioid hemangioendothelioma and, 808 Human herpes virus and, 808 Klippel-Trenaunay syndrome and, 807 KS and, 808, 823 Maffucci syndrome and, 807–808, 838 Milroy disease and, 807 phlebolith and, 808 Ulex europaeus lectin-1 and, 808 VM and, 839 von Willebrand factor and, 808 Spindle cell lipoma, 859–860, 860f, 860t myolipoma and, 862 WDL/ALT and, 866 Spindle cell liposarcoma, 865 Spindle cell melanomas, 668, 780 Spindle cell rhabdomyosarcoma, 874 Spindle cell squamous cell carcinomas (SCSCCs), 593 Spindle cell tumors, differential diagnosis of, 995t Spindle cells, 634 Spindle-shaped cells, 893 SPINK5, 323 Spinous layer vesiculation, 327–332 Spiradenoma, 728f benign, 746 eccrine, 725–726, 727t, 728t, 745–746 Spitz nevus or Spitz tumor, 620, 632–635, 633f, 633t, 663 absent or rare mitosis in, 635 adnexal epithelium, 635 angiomatoid, 639 atypical, 636, 637t clinical features, 632–635 compound, 637f dermal component, 637–638 differential diagnosis, 638 desmoplastic, 638–639, 639t, 640t epidermal hyperplasia, 635 halo, 639 histopathologic features, 634–635 hyalinizing, 639 intraepidermal component, 636 junctional cleavage, 635 kamino bodies, 635 lymph node involvement, 638 maturation (zonation), 635 pagetoid, 636 pagetoid spread, 635 perivascular inflammatory cell infiltrates, 635 plexiform, 639 prominent pagetoid spread, 636 tubular, 639 variants, 639 Spitzoid melanoma (SM), 670, 674 Splendore-Hoeppli phenomenon, 482, 486

Spongiosis, 137 conventional, 6f eosinophilic, 6f, 15, 25f follicular, 6f with lymphocyte exocytosis, 29f miliarial, 6f neutrophilic, 6f, 15, 26f skin diseases with, 26t Spongiotic dermatitis, 8–9, 8t, 15–34, 138, 306 acute changes in, 7f, 15 algorithm for, 16f chronic changes in, 7f, 15 clinical features in, 17t differential diagnosis for, 16t histopathological features in, 17t secondary changes in, 15, 24t skin diseases with, 16t subacute, 15, 19f Spongiotic drug eruptions, 27–28 clinical features, 27–28 histopathological features, 27–28 Sporothrix, 474 Sporotrichosis, 459t, 474–475 differential diagnosis, 475 histopathological features, 475 SPP. See Small-plague parapsoriasis Squamous cell carcinoma, 544, 590–596, 596t, 693, 961, 1017–1018 acantholytic, 593–594, 595, 1018 clinical features, 996, 1017 differential diagnosis, 595–596, 996 histopathological features, 591–595, 996, 1017 metastatic disease in, 591 papillary, 595 perineural invasion in, 591 pseudoglandular, 1018 pseudovascular adenoid, 594–595 signet ring, 594f spindle cell, 593 subcutaneous, 595 transplants and, 591 Squamous intraepithelial neoplasia (SIN), 1016 Squamous papilloma, 1005 clinical features, 1005 differential diagnosis, 1005 histopathologic features, 1005 Squirting papillae, 66 Staphylococcal scalded-skin syndrome, 424–425 clinical features, 424 differential diagnosis, 424–425 histopathological features, 424 Staphylococcal scarlet fever, 424 Staphylococcus aureus, 234, 267, 415, 421, 501, 990 Stasis dermatitis, 25, 32t, 33f. See also Acroangiodermatitis Steatocystoma, 548 differential diagnosis, 548 histopathological features, 548 Stela, 213 Stem cells, 736, 1022–1023 epidermal, 1022

INDEX

Smooth muscle, 868–872 Smooth muscle hamartoma, 719 clinical features, 719 differential diagnosis, 719 histopathological features, 719 myolipoma and, 862 SM-PTL. See Primary cutaneous CD4+ pleomorphic T-cell lymphoma SN. See Sclerema neonatorum Soft fibroma, 766–767 Soft tissue amyloidoma, 378 Soft tissue chondroma, 876f Soft tissue myxoma, 867 Soft tissue osteosarcomas, 792 Soft tissue perineuriomas, 889f, 890t Solar elastotic syndromes, 402 clinical features, 402 histopathological features, 402 Solar lentigo, 615–616 clinical features, 615 differential diagnosis, 616 histopathological features, 615–616 Solar melanoma, 660–661 in situ, 661, 664f Solid and cystic hidradenoma, 732 Solid angioleiomyomas, 870 Solitary fibrous tumor, 790–791 clinical features, 790–791 differential diagnosis, 791 histopathological features, 791 Solitary fibrous tumor of the skin (SFTS), hemangiopericytoma and, 825 Solitary myofibroma, 782–784, 783t clinical features, 782 differential diagnosis, 783 histopathologic features, 782–783 Solitary myofibromatosis, hemangiopericytoma and, 825 Solitary schwannoma, 891f Sonar elastotic syndromes, 402 Sotalia fluvialis, 488 South American blastomycosis. See Paracoccidioidomycosis SOX10, 341 SP. See Syringocystadenoma papilliferum Sparganosis, 537–538 clinical features, 537 differential diagnosis, 537–538 histopathological features, 537–538 Specimen curettage, 3 excisional, 3 punch, 3 shave, 3 type of, 3 Spider angioma. See Arterial spider Spider nevus. See Arterial spider Spider telangiectasis. See Arterial spider Spinal dysraphism, anogenital anomalies, cutaneous anomalies, renal and urologic anomalies, associated with angioma of lumbosacral localization syndrome (SACRAL), 831 Spindle cell carcinoma, 962 leiomyosarcoma and, 871

1077

INDEX 1078

Stevens-Johnson syndrome (SJS), 172, 293–294, 294t Stewart-Treves syndrome APL and, 844 IPEH and, 816 KS and, 820 STK. See Smokeless tobacco keratosis Storiform collagenoma, 769, 770f histopathologic features, 769 Storiform pattern, 796–797 Stratified squamous epithelium, cysts lined by, 534, 545t Stratum corneum, 90 alterations of, 14, 313–335 Stratum granulosum, hyperorthokeratosis and, 317–322 Streamer, 213 Streptococcus, 267, 415, 421, 501, 1006 Streptomyces, 478, 480 Striae disease, 393–394 clinical features, 393 differential diagnosis, 394 histopathological features, 394 Striatum spinosum, 448 Strongyloides, 535 Strongyloidiasis, 530, 531 cutaneous, 536 Stucco keratosis, 601 clinical features, 601 differential diagnosis, 601 histopathological features, 601 Sturge-Weber syndrome, 832 Subacute cutaneous lupus erythematosus, 48, 51 differential diagnosis, 51 Subacute lupus erythematosus, 50f Subacute spongiotic dermatitides, 72–73 clinical features, 73 differential diagnosis, 73 histopathological features, 73 Subcorneal pustular dermatosis of SneddonWilkinson, 67, 153 clinical features, 153 histopathological features, 153 Subcorneal substratum granulosum, 6f Subcutaneous fat ischemic necrosis, 255 microanatomy of, 250 necrosis, 265 reactions of, 250–251 vasculitis, 255 vasculopathic reaction, 255 Subcutaneous fat necrosis of newborn, 266–267 clinical features, 266 differential diagnosis, 267 histopathological features, 266–267 Subcutaneous panniculitic lymphoma, 263–265 clinical features, 264 differential diagnosis, 265 histopathological features, 264 Subcutaneous panniculitis-like T-cell lymphoma, 919, 920f clinical features, 919 definition, 919 differential diagnosis, 919

Subcutaneous panniculitis-like T-cell lymphoma (Cont.): genotypic features, 919 histopathologic features, 919 immunophenotypic features, 919 Subcutaneous processes, 3 Subcutaneous squamous cell carcinoma, 595 Subepidermal blistering diseases, 156–175 algorithm, 157f autoimmune, 157–160 basement membrane zone mutations, 169–171 coma blisters, 174–175 cutaneous BM zone, 156 histopathology of, 157–169 lamina densa, 156–157 lamina lucida, 156 miscellaneous, 172–174 ultrastructure and, 156 Subepidermal bullous dermatitis, 10f Subepidermal vesicular dermatitis, 10t Subungual exostosis, 384 Subungual hyperkeratosis, 983 Subungual keratoacanthoma, 577 Subungual melanoma, 659 Sudamina. See Miliaria crystallina Sudan IV stains, 693 Sulfamethoxazole-trimethoprim, 287 Sulfhydryl, 288 Sulzberger-Garbe syndrome, 23 Sun exposure, in lupus erythematosus, 92 Sun nevus. See Nevus fuscoceruleus zygomaticus Superficial, basal cell carcinoma, 582–583 Superficial acral fibromyxoma, 994 clinical features, 994 differential diagnosis, 996 histopathologic features, 994 Superficial angiomyxoma, 795–796, 867 clinical features, 795–796 differential diagnosis, 796 histopathological features, 796 Superficial arteriovenous hemangioma. See Arteriovenous malformations Superficial epithelioma, with sebaceous differentiation, 691–692 differential diagnosis, 692 histopathological features, 692 Superficial filamentous infections, 458–463 Superficial mucocele, 369 Superficial multicentric basal cell carcinoma, 582 Superficial perivascular dermatitis, 11, 81–94 Superficial spreading, 657 Superficial thrombophlebitis, 201–202 clinical features, 201 histopathological features, 201–202 Supernumerary digit, 410–411 differential diagnosis, 411 with focal nail formation, 411f histopathological features, 411 Supernumerary nipple. See Accessory nipple Suppurative granulomatous infiltrates, 111–113 blastomycosis-like pyoderma, 111 follicular cysts and sinuses, 111–113 follicular occlusion triad, 111

Suppurative granulomatous infiltrates (Cont.): halogenodermas, 111, 113t infectious causes, 112 ruptured follicles, 111–113 Suprabasilar, 6f Sweat apparatus, disorders of, 13 Sweat gland adenomas, 735–737 Sweat gland carcinoma, 738, 753 Sweat gland necrosis, 245 clinical features, 245 differential diagnosis, 245 histopathological features, 245 Sweat gland pseudoneoplastic lesions, 755–759 Sweat gland tumors, 725–759 benign, 725–733 differential diagnosis, 758t immunohistochemical findings in, 758t, 759 malignant, 737–738 Sweet syndrome, 124–126, 190f, 191, 940 atypical, 128 classic, 188–190 clinical features, 124–125 Swimmer’s itch, 307t, 539 Symmetrical lipomatosis. See Madelung disease Symplastic glomus tumor, 841 Synaptophysin, 963 Syndecan-1, 594 Synovial chondromatosis, extraskeletal chondroma and, 876 Synovial sarcoma extraskeletal osteosarcoma and, 879 hemangiopericytoma and, 825 Syphilis benign tertiary, 446 endemic, 451 in HIV, 501 primary, 446, 447–448, 447t secondary, 58, 78, 446–449 tertiary, 446, 447t, 449 venereal, 446–447 Syringoacanthoma, 729 Syringocystadenoma papilliferum (SP), 731, 734, 735f clinical features, 734 differential diagnosis, 734 histopathological features, 734 Syringoid carcinoma, 743 Syringolymphoid hyperplasia, 911–912 Syringoma, 729f anaplastic, 743 chondroid, 733, 735–737, 737t, 738f clinical features, 726–727 differential diagnosis, 727–728 histopathological features, 727 Syringomatous adenoma of nipple (SAN), 745 Syringometaplasias, 755–756, 756f Syringotropic mycosis fungoides, 911–912, 912f Systemic amyloid A amyloidosis, 372–374 Systemic amyloid light chain amyloidosis, 371–372, 373f histopathological features, 372

Systemic amyloidosis, 371–374 secondary, 372–374 Systemic candidiasis, 464 Systemic lupus erythematosus, 284 bullous, 168–169 classification of, 92t Systemic mastocytosis, 130 Systemic mycoses, 468–474 Systemic scleroderma, 388–390 clinical features, 388–389 differential diagnosis, 390 histopathological features, 389 Systemic vasculitis, 197

Tinea corporis, 461 clinical features, 461 differential diagnosis, 461 histopathological features, 461 Tinea cruris, 462 clinical features, 462 histopathological features, 462 Tinea favosa, 460 Tinea manuum, 462 clinical features, 462 differential diagnosis, 462 Tinea nigra, 477, 479f clinical features, 477 histopathological features, 477 Tinea pedis, 462 clinical features, 462 differential diagnosis, 462 histopathological features, 462 Tinea unguium, 462–463 clinical features, 462–463 differential diagnosis, 463 Tinea versicolor, 466f Tinea yaws, 450 Titanium, 355 histopathological features, 355 TL. See Trichilemmoma TLC. See Trichilemmal carcinoma T-lymphoblasts, 906 T-lymphocytes, 264, 499 TMEP. See Telangiectasia macularis eruptiva perstans TNF. See Tumor necrosis factor TNF-alpha, 240 TNM classification. See Tumor, node, metastasis classification Tobacco use, 596 Togaviruses, 503 Touton-type giant cells, 776 Townes-Brocks syndrome, 408 Toxic epidermal necrolysis, 42–43, 172, 293–294, 294t clinical features of, 42–43, 172, 173 differential diagnosis, 172, 173 erythema multiform v., 42t histopathological features, 43, 172, 173 Toxic erythema of pregnancy, 84 clinical features, 84 differential diagnosis, 84 histopathological features, 84 Toxic shock syndrome, 425 clinical features, 425 differential diagnosis, 425 histopathological features, 425 Toxocara canis, 133, 275 Toxoplasma gondii, 523 Toxoplasmosis, 523–524 clinical features, 523 differential diagnosis, 524 histopathological features, 523 TP1. See Telomerase-associated protein Traction alopecia, 220–221, 226, 227f, 228f clinical features, 220 differential diagnosis, 220 histopathological features, 220 Transglutaminase, 318

INDEX

T T cell clonality, 911 TA. See Tufted angioma Tachyzoites, 523 Taenia multiceps, 537f Taenia solium, 536 Takayasu arteritis, 202 clinical findings, 202 differential diagnosis, 202 histopathological features, 202 Tanapox, 512 TAP. See Transporter associated with antigen processing Tapeworm larvae, 531 Target blue nevus, 648 Targeted biological therapy reactions, 296–297 Targetoid hemosiderotic hemangioma (THH), 809–811, 810f, 810t APL and, 810, 811 D2-40 antibody and, 809 HHV and, 810 histologic features of, 823t KS and, 810–811, 823 MVH and, 809 Retiform hemangioendothelioma and, 810 RH and, 811, 827 sclerosing hemangioma and, 811 Ulex europaeus lectin-1 and, 810 Vascular endothelial growth factor and, 809 von Willebrand factor and, 810 Tattoos, 354 differential diagnosis, 354 histopathological features, 354 Tazarotene, PG from, 813 T-cell lymphoproliferations, benign, 908–926 T-cell prolymphocytic leukemia, 949–951 clinical features, 949 histopathologic features, 949–950 immunohistochemical findings, 950–951 T-cell pseudolymphomas, 908–909 clinical features, 908 definition, 908 differential diagnosis, 909 genotypic features, 909 histopathological features, 908–909 immunophenotypic features, 909 T-cell series, ontogeny of, 906 TdT. See Terminal deoxynucleotidyl transferase Telangiectasia, 579

Telangiectasia macularis eruptiva perstans (TMEP), 130 Telangiectatic metastasis, 960–961 Telangiectatic osteosarcoma, 879 Telogen, 216 effluvium, 217 Telogen hairs, 215t Telomerase-associated protein (TP1), 578 Temperature grading gel electrophoresis, 908 Temporal arteritis, 202–203 clinical features, 202 differential diagnosis, 203 histopathological features, 202–203 Tendon sheath fibroma, 769–770 Tendon sheath giant cell tumor, 780–781 Terbinafine, 93 Terminal deoxynucleotidyl transferase (TdT), 897, 967 Terminal hairs, 213, 215t Tertiary syphilis, 446, 447t, 449 benign, 446 Tertiary yaws, 450 histopathological features, 450 Tetanus toxoid, 271 Tetrasomy 12p, 344 TF. See Trichofolliculoma TGFβ, HHT and, 833 TGM5, 332 Th1. See T-helper lymphocyte type 1 Th2, 519 Thalidomide, 297 T-helper, 289, 519, 907 T-helper lymphocyte type 1 (Th1), 306 Thermal burns, 150–152 THH. See Targetoid hemosiderotic hemangioma Thiazides, 281 Thiol, 288 Thromboangiitis obliterans, 201t Thrombophlebitis, 259 Thrombosed capillary aneurysm, 848 Thrombospondins (TSPs), 259 Thymic cysts, 549 differential diagnosis, 549 Thymoma, 146 Thyroglossal duct cysts, 550–551, 551f differential diagnosis, 550–551 histopathological features, 550–551 Thyroid carcinomas, 961, 963 Thyroid transcription factor 1 (TTF-1), 962 Thyroid tumors, 970–971 clinical features, 970 differential diagnosis, 970 histopathologic features, 970 immunohistochemistry, 970–971 special stains, 970 Ticks, 308, 309f T-immunoblasts, 906 Tinea barbae, 461–462 clinical features, 461–462 differential diagnosis, 462 histopathological features, 462 Tinea capitis, 231–232, 238f, 458–461 clinical features, 231 differential diagnosis, 231–232, 461 histopathological features, 231, 460–461

1079

INDEX 1080

Transient acantholytic dermatosis, 149–150, 328, 331–332, 332f clinical features, 149, 332 differential diagnosis, 150, 332 histopathological features, 149, 332 Transient neonatal pustular melanosis, 154 clinical features, 154 differential diagnosis, 154 histopathological features, 154 Transitional areas, 867 Transporter associated with antigen processing (TAP), 196 Transverse section techniques advantages of, 217t disadvantages of, 217t vertical section techniques v., 213–215 TRAPS. See Tumor necrosis factor receptor superfamily 1A-associated periodic syndrome Trauma reactions, 301 clinical features, 301 differential diagnosis, 301 histopathological features, 301 Trauma-related panniculitis, 270–271 Traumatic neuromas, 886t, 887f Traumatic onychitis, 991–992 clinical features, 991 histopathologic features, 991 Traumatic pseudoaneurysm, 813 Traumatic ulcerative granuloma, 1006 Trematodes, 530, 538–540 adult, 531, 532 Treponema pallidum, 78 Treponemal diseases, 446–449 Tretinoin, PG from, 813 Triatomid bugs, 520 Trichilemmal carcinoma (TLC), 694, 715–716 clinical features, 715 differential diagnosis, 715–716 histopathologic features, 715 Trichilemmoma (TL), 696, 699–700, 700t, 701f, 715, 729 clinical features, 699 differential diagnosis, 700 histopathologic features, 699–700 Trichoadenoma, 698–699, 699f, 699t clinical features, 698 histopathologic features, 698–699 Trichoblastomas, 588, 708, 709–710, 710f clinical features, 710 differential diagnosis, 710 histopathologic features, 710 Trichoderma, 488–490 Trichodiscoma, 711, 712t, 713f clinical features, 711–712 differential diagnosis, 713 histopathological features, 712–713 Trichoepithelioma, 728 desmoplastic, 705–706 malignant, 717 Trichoepitheliomas, 588, 692, 703–705, 704f, 705f clinical features, 703 differential diagnosis, 704–705 histopathological features, 704

Trichofolliculoma (TF), 690, 702–703, 702t, 703f clinical features, 702 differential diagnosis, 702–703 histopathological features, 702 Trichogenic adnexal tumor, 709 Trichogerminoma, 707–708 clinical features, 707 differential diagnosis, 708 histopathologic features, 707–708 Trichomalacia, 219 Trichome vitiligo, 340 Trichomycosis, 429 clinical features, 430 differential diagnosis, 430 histopathological features, 430 Trichophyton schoenleinii, 221, 458 Trichophyton tonsurans, 221 Trichosporon asahii, 463, 468 Trichosporon cutaneum, 430 Trichosporonosis, 467 Trichothiodystrophy, 316 clinical features, 316 differential diagnosis, 316 histopathological features, 316 Trichotillomania, 218, 219–220, 225f, 226f clinical features, 219 differential diagnosis, 220 histopathological features, 219–220 Trisomy 18, 344 Triton tumor, 896 embryonal rhabdomyosarcoma and, 874 Trombiculid mites, 308 Tropheryma whippelii, 113 Trophozoites, 525 Trousseau sign, 259 Trypanosoma brucei gambiense, 520, 521, 522 Trypanosoma brucei rhodesiense, 520, 521, 522 Trypanosoma cruzi, 520–522 Trypanosomiasis, 520–523 clinical features, 520–521 differential diagnosis, 523 histopathological features, 521–523 Trypomastigotes, 520 Tryptophan, 77 fasciitis and, 260 TS. See Tuberous sclerosis TSPs. See Thrombospondins TTF-1. See Thyroid transcription factor 1 Tuberculoid leprosy, 438f Tuberculosis, 431–432, 433t differential diagnosis, 432 histopathological features, 432 Tuberculosis verrucosa cutis, 434f Tuberous sclerosis (TS), 341 ash leaf spots of, 343 Tubular apocrine adenoma, 731, 735, 737f clinical features, 735 differential diagnosis, 735 histopathologic features, 735 Tubular Spitz nevus, 639 Tubulopapillary hidradenoma, 731 Tufted angioma (TA), 803, 803t, 805–806, 806f angiosarcoma and, 806 Crohn disease and, 805–806 eccrine glands and, 806 GH and, 816

Tufted angioma (TA) (Cont.): Kaposiform hemangioendothelioma and, 805 KHE and, 824 KMS and, 805, 824 KS and, 806 Lobular capillary hemangioma and, 805 MVH and, 809 periodic acid-Schiff and, 806 Ulex europaeus lectin-1 and, 806 von Willebrand factor and, 806 Tularemia, 439–441 clinical features, 439 differential diagnosis, 439 histopathological features, 439 Tumid lupus erythematosus, 50 Tumor(s). See also specific types Abrikosoff, 894–895 Ackerman, 596 adnexal, 689 atypical lipomatous, 858, 864–866, 865f, 865t bednar, 787 benign adipocytic, 858, 858t benign fibrohistiocytic, 775–781 benign fibrous, 766–776 benign hair follicle, 697–714 benign proliferating pilar, 701–702 benign sweat gland, 725–733 benign vascular, 802–811 biphasic, 797 borderline sebaceous, 692–693 Buschke-Loewenstein, 596–598 clear cell cutaneous, 716t dermal duct, 730f digital, 797 eccrine, 725 ectomesenchymal chondromyxoid, 1018 fibrohistiocytic, 766–797 benign, 775–781 of childhood, 781–786, 797 intermediate, 775–781 of intermediate malignancy, 786–791 malignant, 791–795 plexiform, 788–789 fibrous, 766–797 benign, 766–776 of childhood, 781–786, 797 of intermediate malignancy, 786–791 malignant, 791–795 solitary, 790–791 follicular infundibulum, 697, 729 giant cell, 780–781, 876 glomus, 839–841, 840f, 840t, 841f, 996 clinical features, 996 differential diagnosis, 996 histopathologic features, 996 granular cell, 894–895, 895t clinical features, 894, 1018 different diagnosis, 1018 differential diagnosis, 895 histopathologic features, 894–895, 1018 hair follicle, 689–720 hyalinizing spindle cell, 794 Koenen, 392 lobulated, 797 malignant, 578–600 malignant basomelanocytic, 581

Tumoral amyloidosis, 378 Tumoral calcinosis, 383f extraskeletal chondroma and, 876 Tumors genital tract, 970 germinative follicular epithelium, 702 melanocyte, 615–681 mesenchymal, 631–632 osteocartilaginous, 994–996 small round cell cutaneous, 899 spindle cell, 995t Tunga penetrans, 309 Turk cells, 497 Tursiops truncatus, 488 Type 2 leprosy reaction, 270 Type A cells, 618 Type VII collagen, 157 Typical melanocytic proliferations, 997 clinical features, 997 differential diagnosis, 997 histopathologic features, 997 Tyrosinase, 680 TYRP1. See Tyrosinase U Ulcerative colitis, 197 Ulceroglandular disease, 434 Ulerythema ophryogenes, 233 Ulex, 596 Ulex europaeus lectin-1, 803, 815 angiosarcoma and, 830 APL and, 844 EHE and, 828 GH and, 816 hemangiopericytoma and, 825 KHE and, 824 KS and, 822 RAE and, 818 SCH and, 808 TA and, 806 THH and, 810 Ultrastructure, 156, 157f, 514 subepidermal blistering diseases, 156 Ultraviolet, 304, 338, 590 Ultraviolet B (UVB), 51 Umbilical lesions, 415–416 metastatic, 416 Umbilicus, benign neoplasms of, 415t Uncertain malignant potential, 871 Undifferentiated pleomorphic sarcoma, 791–792, 972 Unilateral nevoid telangiectasia, 832, 835 HHT and, 834 Urachal remnants, 416 clinical features, 416 differential diagnosis, 416 histopathological features, 416 Urinary tract tumors, 968–969 clinical features, 968–969 differential diagnosis, 969 histopathological features, 969 immunohistochemistry, 969 special stains, 969 UROD. See Uroporphyrinogen decarboxylase Uroporphyrinogen decarboxylase (UROD), 173

Urticaria, 81–84 chronic, 81 common forms of, 82t clinical features, 81–83 differential diagnosis, 83–84 histopathological features, 83 Urticarial papules, 29–30 clinical features, 29 differential diagnosis of, 30 histopathological features, 29 Urticarial vasculitis, diagnosis, 184–185 UVB. See Ultraviolet B V VACTERL, 408 Vacuolar interface dermatitis, 40–48 Varicella, 496t, 504–506 clinical features, 505–506 differential diagnosis, 506 histopathological features, 506 Vascular cell adhesion molecule-1 (VCAM-1), 587 Vascular endothelial growth factor (VEGF), 343 THH and, 809 Vascular endothelial growth factor receptor (VEGFR) angiosarcoma and, 830 KHE and, 824 KS and, 822 LM and, 843 PILA and, 826 Vascular injury absence of, 10–11 definitions of, 179t histopathological features of, 179t inflammatory conditions without, 6f Vascular leiomyoma, 869–870 Vascular malformations, 831–832, 832t Vascular markers, 802 Vascular occlusive conditions, 203 Vascular reactions, 192 inflammatory, 180 lymphocytic, 192 lymphomatoid, 194 neutrophilic, 180, 188 Vascular slits, 821 Vascular tumors, 802–850. See also specific types Vasculitis, 12t, 179–209. See also Pseudovasculitis ANCA-associated, 184, 195–196 approach to, 182t clinical features, 179–180 cutaneous neutrophilic small vessel, 182t definitions of, 180t drug-induced, 186 with granulomatosis, 194–195 granulomatous, 196f histopathological features, 179–180 infectious, 183–184 of large vessels, 200–203 leukocytoclastic, 181, 182–183, 281 localized fibrosing small-vessel, 187 lymphocytic, 192 lymphomatoid, 194 of medium vessels, 200–203 nodular, 255, 268–269

INDEX

Tumor(s) (Cont.): malignant fibrohistiocytic, 791–795 malignant fibrous, 791–795 malignant mixed, 748–749 malignant peripheral nerve sheath, 887, 895–896, 896t clinical features, 895 differential diagnosis, 896 extra skeletal osteosarcoma and, 879 histopathological features, 895–896 malignant proliferating pilar, 716–717, 717f malignant sweat gland, 737–738 myxoid, 797 neural, 883–901 neuroblastic, 900 neuroendocrine, 971 classification, 883 clinical features, 971 differential diagnosis, 971 histopathologic features, 971 paucicellular, 797 pilar benign proliferating, 701–702 malignant proliferating, 716–717, 717f proliferating, 702f plexiform fibrohistiocytic, 101, 788–789 primitive neuroectodermal, 874, 897 alveolar rhabdomyosarcoma and, 875 extraskeletal osteosarcoma and, 879 proliferating pilar, 702f recurring digital fibrous, 781 sebaceous, 689–720 silhouette, 5 solitary fibrous, 790–791, 825 sweat gland, 725–759 benign, 725–733 differential diagnosis, 758t immunohistochemical findings in, 758t, 759 malignant, 737–738 symplastic glomus, 841 tendon sheath giant cell, 780–781 thyroid, 970–971 clinical features, 970 differential diagnosis, 970 histopathologic features, 970 immunohistochemistry, 970–971 special stains, 970 trichogenic adnexal, 709 Triton, 874, 896 urinary tract, 968–969 clinical features, 968–969 differential diagnosis, 969 histopathological features, 969 immunohistochemistry, 969 special stains, 969 vascular, 802–850 Wilms, 874–875, 963 Tumor, node, metastasis (TNM) classification, 906 Tumor necrosis factor (TNF), 263, 270, 296, 297, 341 Tumor necrosis factor receptor superfamily 1A-associated periodic syndrome (TRAPS), 190, 191, 263

1081

INDEX 1082

Vasculitis (Cont.): paraneoplastic, 186 Pauci-immune, 196 physical factors, 186 pustular, 182 small-vessel neutrophilic, 182–183 subcutaneous fat, 255 systemic, 180t, 197 Wegener, 198 Vasculopathic reaction, 180f, 203–209, 204t atrophie blanche, 206, 207f calciphylaxis, 207–208, 208t, 209f coagulopathies, 203 connective tissue deficiency, 209 cryoglobulinemias, 203–204 cutaneous cholesterol embolism, 204 Degos syndrome, 206 livedo reticularis, 205 subcutaneous fat, 255 vascular occlusive conditions, 203 Vasculopathy, 180 lymphocytic, 193 Vasopressin, 274 VCAM-1. See Vascular cell adhesion molecule-1 VDRL. See Venereal Disease Research Laboratory VE-cadherin, KS and, 822 VEGF. See Vascular endothelial growth factor VEGFR. See Vascular endothelial growth factor receptor Velcade, 297 Vellus hair cysts, 544–547 differential diagnosis, 547 eruptive, 547 Vellus hairs, 213, 215t Vellus-like hairs, 213 Venereal Disease Research Laboratory (VDRL), 437, 447 Venereal syphilis, 446–447 Venolymphatic malformation, 842 Venous angioleiomyomas, 870 Venous lake, 847–848, 848f Venous malformation (VM), 838–839, 839f AVMs, 847 GVM and, 840 IPEH and, 816 Maffucci syndrome and, 838 Verocay bodies, 887, 890 Verruca, 992 clinical features, 992 differential diagnosis, 992 histopathological features, 992 Verruca plana, 507, 507t, 509, 510f Verruca plantaris, 507t, 508, 510f Verruca vulgaris, 507, 507t, 509, 700 VH and, 838 Verruciform xanthoma, 114–115, 1014 aAVM and, 845t clinical features, 115, 1014 differential diagnosis, 115, 1014 histopathological features, 115, 1014 Verrucous carcinoma, 596–598 clinical features, 597 differential diagnosis, 598 histopathological features, 597–598 oral, 596, 597f plantar, 596

Verrucous hemangioma (VH), 809, 836–838, 837f, 837t angiokeratoma and, 836 Verrucous hyperplasia, 1017 Verrucous melanoma, 672–673 clinical features, 672–673 histopathologic features, 672–673 Verrucous psoriasis, 66 Vertical growth phase, 660 Vertical section techniques, transverse section techniques v., 213–215 Vesicles, 136 Vesicopustule, 136 Vesicular and bullous dermatitis, 9–10 Vesiculopustular diseases, 152–154 Vessel wall alteration, 208–209 VH. See Verrucous hemangioma Vibrio cholerae, 435 Vide infra, 713 Vimentin, 582, 586, 593, 594, 595, 676, 889, 896, 962, 973 angiosarcoma and, 830 chondroid lipoma and, 861 extraskeletal osteosarcoma and, 879 hemangiopericytoma and, 825 Viral exanthems, 495–503, 498f clinical features, 503 differential diagnosis, 503 histopathological features, 503 Viral folliculitis, 235 clinical features, 235 histopathological features, 235 Viral infections, 495–515. See also specific types active, 495 general principles of, 495 lateral, 495 Visceral leishmaniasis, 518 Vitamin K, 271, 390 Vitiligo, 61, 340–341, 340f, 343t differential diagnosis, 341 histopathological features, 341 trichome, 340 VM. See venous malformation Vogt-Koyanagi-Harada syndrome, 340–341 Vohwinkel syndrome, 320 von Kossa stain, 316 von Recklinghausen disease, 887 von Willebrand factor, 802, 815 angiosarcoma and, 830 APL and, 844 EHE and, 828 GH and, 816 hemangiopericytoma and, 825 KHE and, 824 KS and, 822 RAE and, 818 SCH and, 808 TA and, 806 THH and, 810 Vulva ciliated cysts of, 551–552 compound nevus of, 626f Vulvitis, plasma cell, 128 Vulvovaginitis, 464

W Waldenstrom macroglobulinemia, 375, 379 histopathological features, 379 Wangiella dermatitidis, 477 Warfarin, 258 Warthin-Finkeldey giant cells, 497 EH and, 813 Warthin-Starry reaction, 261, 275, 437, 520 Warty dyskeratoma, 563–564 clinical features, 563 differential diagnosis, 563–564 histopathological features, 563 Waterhouse-Friderichsen syndrome, 430 Wattles, 408 WDL. See Well-differentiated liposarcoma Weber-Christian disease, 251, 261–263 Weber-Cockayne variant, 326 Wegener granulomatosis, 109, 184, 197–199, 198t clinical features, 198 differential diagnosis, 198–199 histopathological features, 198 Wegener syndrome, 198 Wegener vasculitis, 198 Weibel-Pelade bodies, 595 Well-differentiated liposarcoma (WDL), 858, 865–866, 865f, 865t lipoblastoma and, 864 myolipoma and, 862 myxoid liposarcoma and, 867 spindle cell lipoma and, 860 Wells syndrome, 131–133, 197, 275 clinical features, 131 differential diagnosis, 132–133 histopathological features, 131–132 Werner syndrome, 399 clinical features, 399 differential diagnosis, 399 histopathological features, 399 West Nile virus, 503 White piedra, 459t, 467t White sponge nevus, 1003f clinical features, 1002 differential diagnosis, 1002 histopathologic features, 1002 White superficial onychomycosis (WSO), 462 Wickham striae, 37 Wilms tumor, embryonal rhabdomyosarcoma and, 874–875 Wilms tumor protein (WT1), 963 Winterbottom sign, 498 Wiskott-Aldrich syndrome, MVH and, 809 Wohlfahrtia, 309 Woolsorter disease, 433 Wright stains, 521 WSO. See White superficial onychomycosis WT1. See Wilms tumor protein Wuchereria bancrofti, 533, 534 X Xanthogranuloma, 119 clinical features, 119 differential diagnosis, 119 histopathological features, 119 Xanthoma disseminatum, 120 clinical features, 120 histopathological features, 120

Y Yatapoxvirus, 512 Yaws, 449 attenuated, 450 crab, 450 daughter, 450 primary, 449–450 secondary, 450 tertiary, 450 tinea, 450 Yeast infections, 463–465 Yersinia enterocolitica, 435, 436 Yersinia pestis, 436 Yersinia pseudotuberculosis, 436

Yersiniosis, 436 clinical features, 436 differential diagnosis, 436 Z Ziehl-Neelsen staining, 270, 421, 520 Zip4, 77 ZMP-STE24, 274 Zoon balanitis, 128 Zoopagomycotina, 458, 483 Zosteriform hyperpigmentation, 347 Zygomycoses, 483–487 Zygomycota, 458

INDEX

Xanthomas, 113–114 clinical features, 113–114 differential diagnosis, 114 diffuse normolipemic plane, 114 histopathological features, 114 papular, 115–116 plexiform, 116 verruciform, 114–115 Xanthomatous reactions, 866 Xeroderma pigmentosum, ataxia telangiectasia and, 835 X-linked dominant ichthyosis with chondrodysplasia punctata, 316 focal dermal hypoplasia and, 857 X-linked recessive ichthyosis, 314, 317–318 clinical features, 317–318 differential diagnosis, 318 histopathological features, 318

1083