Mosaad Megahed Histopathology of Blistering Diseases With Clinical, Electron Microscopic, Immunological and Molecular Biological Correlations

Mosaad Megahed Histopathology of Blistering Diseases With Clinical, Electron Microscopic, Immunological and Molecular Biological Correlations

Springer-Verlag Berlin Heidelberg GmbH

Mosaad Megahed Histopathology of Blistering Diseases With Clinical, Electron Microscopic, Immunological and Molecular Biological Correlations Textbook and Atlas Forewords by Rona MacKie and Jouni Uitto With 371 Figures in 532 Separate Illustrations and 72 Tables 123

Mosaad Megahed,Prof.Dr. Department of Dermatology Heinrich Heine University Moorenstr. 5 40225 Düsseldorf Germany ISBN 978-6-642-62223-6 Library of Congress Cataloging-in-Publication Data Megahed, Mosaad. Histopathology of blistering diseases: with clinical, electron microscopic, immunological, and molecular biological correlations/mosaad Megahed. p.; cm. Includes bibliographical references and index. ISBN 978-3-642-62223-6 ISBN 978-3-642-18651-6 (ebook) DOI 10.1007/978-3-642-18651-6 1. Blisters Histopathology. I. Title. [DNLM: 1. Skin Diseases, Vesiculobullous pathology. 2. Blister pathology. 3. Desmosomes ultrastructure. 4. Microscopy, Electron methods. WR 200 M496h 2004] RL221.M445 2004 616.5 2 dc22 This work is subject to copyright. All rights are reserved, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilm or in any other way, and storage in data banks. Duplication of this publication or parts thereof is permitted only under the provisions of the German Copyright Law of September 9, 1965, in its current version, and permission for use must always be obtained from Springer-Verlag. Violations are liable for prosecution under the German Copyright Law. springeronline.com Springer-Verlag Berlin Heidelberg 2004 Originally published by Springer-Verlag Berlin Heidelberg New York in 2004 Softcover reprint of the hardcover 1st edition 2004 The use of general descriptive names, registered names, trademarks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. Product liability: The publishers cannot guarantee the accuracy of any information about dosage and application contained in this book. In every individual case the user must check such information by consulting the relevant literature. Cover design: design & production, Heidelberg Product management and layout: B. Wieland, Heidelberg Reproduction and typesetting: AM-production, Wiesloch 24/3150 5 4 3 2 1 0 Printed on acid-free paper

V To my parents, my son Jonas, my wife and my brothers and sisters for their love and appreciation

VII Foreword I Research into blistering diseases has been one of the success stories of the last 20 years in dermatology. Blistering diseases divide naturally into the autoimmune variants, seen mainly in adults, and inherited varieties, mainly presenting in early childhood. Studies on all continents looking at the clinical aspects, traditional pathology, detailed electron microscopy, and subsequent correlation of these three aspects with modern molecular biology have greatly increased our understanding of the mechanisms at fault in both autoimmune and inherited blistering disorders. The range of genetic defects identified have lowered the age of gestation at which the molecular diagnosis of a foetus at risk can be investigated in high-risk pregnancies. It is therefore essential that the modern dermatologist, paediatrician, geriatrician and primary care physician have a clear understanding of our current knowledge of blistering diseases. Professor Megahed has brought all aspects of this knowledge together in this excellent monograph, which should be required reading for all those involved in the diagnosis or management of patients with this group of disorders. Rona MacKie MD DSc FRCP FRCPath Professor of Dermatology University of Glasgow

IX Foreword II Since the early days of modern dermatology, blistering diseases as a group of skin disorders have fascinated and occasionally puzzled clinicians and scientists alike. It has been clear for decades that we are dealing with a spectrum of disorders with diverse phenotypic manifestations and overlapping features, yet with a single unifying diagnostic feature, i. e., blistering of the skin. What has been puzzling in the past is that the natural outcome and the response to medication were often unpredictable, and not infrequently, the clinical presentation shifted from one established disease category to another. Adding to the complexity were the observations that in some cases the blistering was present at birth, often with familial occurrence, while in other cases blistering developed late in life without any family history. Furthermore, blistering was occasionally associated with seemingly unrelated extracutaneous diseases, such as various malignancies and lymphoproliferative disorders. Over the past three decades, the seemingly confusing picture has been considerably clarified. With the advent of research in cutaneous biology and pathology, it first became clear that certain blistering diseases are due to circulating autoantibodies. The specificity of these antibodies recognizing autoantigens within the skin determines the distinctive features and allows subclassification of these conditions, as illustrated by the pemphigus group of disorders. Subsequently, the heritable blistering disorders, exemplified by different forms of epidermolysis bullosa, were shown to result from mutations in the structural genes expressed within the cutaneous basement membrane zone. Today, mutations are known to reside in as many as ten distinct genes, providing the molecular explanation for the spectrum of phenotypic severity in this group of heritable disorders. Identification of specific mutations in patients with epidermolysis bullosa has now provided the basis for development of a refined, molecularly based classification system with prognostic implications. This progress has also improved our capability for accurate genetic counseling and has provided the basis for DNA-based prenatal testing and preimplantation genetic diagnosis. In addition to providing etiologic explanations for different forms of blistering disorders both acquired and heritable research on these conditions has provided new understanding of the biology of normal skin. For example, early characterization of autoantigens by utilizing circulating autoantibodies as diagnostic tools has allowed identification of specific structural proteins of the epidermis. These include desmosomal desmogleins as well as hemidesmosomal bullous pemphigoid antigens, discovered by the use of sera from pemphigus and bullous pemphigoid patients, respectively. Furthermore, identification of pathogenic mutations in epidermolysis bullosa which reside in distinct genes encoding proteins expressed at the cutaneous basement membrane zone has provided unequivocal genetic evidence for the importance of adhesion complexes, such as hemidesmosomes, anchoring filaments and anchoring fibrils, in providing stability to the dermal-epidermal adhesion zone. In fact, examination of the epidermolysis bullosa mutation database has allowed development of the concept of a protein network extending from the intracellular milieu of the basal keratinocytes to the sublamina densa compartment at the upper papillary dermis as a critical structural element necessary for stable association of epidermis with the underlying dermis. Thus, genetic mutations in these structural components of the dermal-epidermal junction or their perturbations by immunologic means explain the fragility of skin, as seen in heritable and acquired forms of blistering disorders. This treatise compiled by Professor Megahed chronicles the journey of increased understanding of blistering diseases from the the early history of medicine to the era of molecular dermatology. It highlights the progress made in understanding blistering diseases over more than two centuries as a result of astute clinical observations and relentless investigative research. In a masterful way, the book combines both clinical, histopathological, electron microscop-

X Foreword II ic, immunological and molecular biological aspects of blistering diseases, with the culmination of current understanding of the molecular basis of this fascinating group of disorders. The summary of blistering diseases, as presented in this textbook, serves as an instructive paradigm of the progress in modern dermatology. Professor Megahed should be congratulated for this outstanding work. Jouni Uitto, MD PhD Professor and Chair Jefferson Medical College Philadelphia, Pennsylvania

XI Preface The idea of writing this book first arose during my stay in the laboratories of Professor Jouni Uitto at Thomas Jefferson University, Philadelphia. There I had the opportunity to work with many gifted scientists and able physicians who were interested in studying the cellular and sub-cellular pathology of blistering diseases. I observed, however, that although the scientists clearly had a very detailed knowledge of the genes and proteins involved in the blistering diseases, it was evident that they knew much less about the disease processes from both a clinical and a histopathological perspective. Conversely, although many of the physicians were very aware of the clinical manifestations of the blistering diseases, they often lacked detailed knowledge of both the skin pathology and the rapidly expanding molecular and cellular biology findings that were emerging from this and other laboratories. Furthermore, I also noted that pathologists and dermatopathologists were also experiencing difficulties in finding a single comprehensive source of information that encompassed the new molecular data while also providing a clinical link. Finally, I was aware that other clinicians, including ophthalmologists, gynaecologists, oral surgeons and otolarygologists, who occasionally encounter patients with blistering diseases in their clinical practices, were also lacking reference to information that would help them better diagnose and understand these disorders. For all of these reasons, I felt encouraged to write a new type of book that could present these diseases in an integrated modern style, combining the clinical picture, histopathology, molecular biology and molecular genetics within one presentation. The book consists of five chapters and contains 532 high-quality images. In the first chapter, I have provided a historical overview of these diseases to allow the reader to appreciate the huge developments and progress that has taken place in studies of blistering disorders. The second chapter then focuses on the molecular anatomy of the proteins involved in the pathogenesis of these diseases, including the most recent discoveries. In the third, fourth and fifth chapters, the blistering diseases are presented. For each disorder, the format is first to describe the clinical picture and to outline new discoveries regarding disease aetiology. The histopathology is then documented in detail, with particular reference to the various stages of the disease development, since this is vital in more accurately understanding the clinicopathological correlation. Finally, the recent discoveries in molecular biology and molecular genetics are added to complete the reader's integrated knowledge of the specific blistering diseases. Although this book is a personal compilation that tries to combine clinical medicine, histopathology and molecular biology in a novel way, bringing it to publication has relied on the support and assistance of a number of other colleagues. Special thanks must be given to Mr. Neuse for taking the superb clinical photographs and for designing pages 1, 15 and 47. I am particularly grateful to Mrs. Winkler and Mrs. Moritz for their help with the histology slides and Mrs. Freudenberg for her assistance with electron microscopy images. Mosaad Megahed

XIII Contents 1 Historiography of Blistering Diseases.... 3 The Clinical Period................. 4 The Histological Period............... 8 The Immunological Period............ 11 The Molecular Biological Period.......... 12 2 Ultrastructure and Molecular Anatomy of Desmosomes and the Cutaneous Basement Membrane Zone.......... 17 Ultrastructure and Molecular Anatomy of Desmosomes................... 18 Desmogleins................... 19 Desmocollins................... 19 Plakoglobin.................... 21 Desmoplakins.................. 21 Plakophilins................... 22 Envoplakin and Periplakin........... 22 Plectin....................... 22 Ultrastructure and Molecular Anatomy of Cutaneous Basement Membrane Zone..... 26 Bullous pemphigoid antigen 1......... 27 Plectin....................... 28 Bullous pemphigoid antigen 2......... 29 a6b4 Integrin................... 29 CD151....................... 31 Laminin 5..................... 32 Laminin 6..................... 32 Laminin 10.................... 33 Type IV collagen................. 34 Nidogen...................... 36 Perlecan...................... 36 Type VII collagen................. 38 Keratin Intermediate Filaments.......... 42 3 Intraepidermal Blistering Diseases.... 49 Hereditary Intraepidermal Blistering Diseases. 50 Familial benign chronic pemphigus..... 50 Epidermolysis bullosa simplex........ 55 Bullous congenital ichthyosiform erythroderma................ 61 Ichthyosis bullosa of Siemens......... 68 Incontinentia pigmenti............. 70 Autoimmune Intraepidermal Blistering Diseases................. 74 Pemphigus vulgaris............... 74 Pemphigus vegetans.............. 78 Pemphigus foliaceus.............. 93 Pemphigus erythematosus........... 95 Fogo selvagem.................. 95 Paraneoplastic pemphigus.......... 103 IgA pemphigus................. 109 Pemphigus herpetiformis........... 116 Bacterial and Viral Induced Intraepidermal Blistering Diseases................. 122 Bullous impetigo............... 122 Staphylococcal scalded skin syndome.... 127 Herpes simplex, Varicella, Herpes zoster... 130 Herpes simplex................. 130 Varicella and Herpes zoster.......... 133 Varicella..................... 133 Herpes zoster.................. 135 Hand-foot-and-mouth disease......... 143 Miscellaneous Intraepidermal Blistering Diseases................. 145 Dyshidrotic eczema.............. 145 Friction blister................. 149 Hydroa vacciniforme.............. 149 Miliaria crystallina............... 152

XIV Contents 4 Subepidermal Blistering Diseases..... 155 Autoimmune Subepidermal Blistering Diseases. 156 Bullous pemphigoid.............. 156 Bullous pemphigoid with atypical clinical presentations....... 158 Herpes gestationis............... 170 Lichen planus pemphigoides......... 175 Cicatricial pemphigoid............ 182 Dermatitis herpetiformis........... 198 Linear IgA disease............... 206 Linear IgA/IgG bullous dermatosis...... 212 Epidermolysis bullosa acquisita....... 223 Bullous systemic lupus erythematosus.... 236 Subepidermal Blistering Diseases Due to Mutations of Proteins of the Basement Membrane Zone......... 238 Junctional epidermolysis bullosa....... 238 Dystrophic epidermolysis bullosa....... 244 Kindler syndrome............... 251 Miscellaneous Subepidermal Blistering Diseases................. 256 Toxic epidermal necrolysis........... 256 Porphyria cutanea tarda............ 262 Pseudoporphyria................ 268 Bullosis diabeticorum............. 271 Coma blisters.................. 273 5 Diseases Occasionally or Frequently Associated with Blister Formation..... 277 Amyloidosis................... 278 Contact dermatitis............... 282 Allergic contact dermatitis........... 282 Irritant contact dermatitis........... 286 Drug eruptions................. 291 Erysipelas.................... 297 Erythema multiforme............. 303 Graft-versus-host disease........... 308 Insect bites................... 313 Leucocytoclastic vasculitis........... 319 Lichen planus.................. 324 Lichen sclerosus................ 329 Mastocytosis.................. 333 Mycosis fungoides............... 338 Polymorphous light eruption......... 340 Solar dermatitis................ 343 References..................... 347 Subject Index................... 392

XV Abbreviations μm Micrometer 1M One molar A.fib Anchoring fibrils A.fil Anchoring filaments ACD Allergic contact dermatitis AL Light chain amyloidosis ALA Aminolevulinic acid ANA Antinuclear antibody AP Anchoring plaque ARA American Rheumatism Association BCIE Bullous congenital ichthyosiform erythroderma BD Bullosis diabeticorum BM Basement membrane BMs Basement membranes BMT Bone marrow transplants BP Bullous pemphigoid BPAG1 Bullous pemphigoid antigen 1 BPAG2 Bullous pemphigoid antigen 2 BSLE Bullous systemic lupus erythematosus C3 Complement 3 cdna Complementary DNA CD Celiac disease Chr Chromosome Co Collagen COOH Carboxyl group CP Cicatricial pemphigoid CTCL Cutaneous T-cell lymphoma D Desmoglea DCM Diffuse cutaneous mastocytosis DEB Dystrophic epidermolysis bullosa DEB-CT Dystrophic epidermolysis bullosa, Cockayne-Touraine DEB-HS Dystrophic epidermolysis bullosa, Hallopeau-Siemens DEJ Dermal-epidermal junction Des Desmosome DH Dermatitis herpetiformis DIF Direct immunofluorescence DM Diabetes mellitus DNA Deoxyribonucleic acid DP Desmosomal plaque Dsc1 Desmocollin 1 Dsc2 Desmocollin 2 Dsc3 Desmocollin 3 Dscs Desmocollins Dsg1 Desmoglein 1 Dsg2 Desmoglein 2 Dsg3 Desmoglein 3 Dsg4 Desmoglein 4 Dsgs Desmogleins DTD Desmoglein terminal domain E Extracellular repeating element EA Extracellular anchoring domain EBA Epidermolysis bullosa acquisita EBS Epidermolysis bullosa simplex EBS-DM Epidermolysis bullosa simplex, Dowling-Meara EBS-K Epidermolysis bullosa simplex, Koebner EBS-MD Epidermolysis bullosa simplex with muscle dystrophy EBS-MP Epidermolysis bullosa simplex with mottled pigmentation EBS-WC Epidermolysis bullosa simplex, Weber-Cockayne ECM1 Extracellular matrix protein 1 ELISA Enzyme-linked immunosorbent assay EM Erythema multiforme ETA Exfoliative toxin A ETB Exfoliative toxin B GVHD Graft-versus-host disease H Homology region H&E Hematoxylin and eosin HD Hemidesmosome HDAP Hemidesmosomal attachment plaque HDs Hemidesmosomes HG Herpes gestationis HIP Helix initiation peptide HIV Human immunodeficiency virus HLA Human leukocyte antigen hrs Hours HSV Herpes simplex virus HSV-1 Herpes simplex virus 1 HSV-2 Herpes simplex virus 2

XVI Abbreviations HTP HV IA IBS ICD ICS IEN IF IgA IgG IHDP IIF IP JEB JEB-H JEB-nH JEB-PA K kb kda KIF L LAD LD LL LP LPP LS LV M Mel MF MFB N NaCl NC NEMO Helix termination peptide Hydroa vacciniforme Intracellular anchoring domain Ichthyosis bullosa of Siemens Irritant contact dermatitis Intercellular catenin-binding site segment Intraepidermal neutrophilic IgA dermatosis Immunofluorescence Immunoglobulin A Immunoglobulin G Inner hemidesmosomal plaque Indirect immunofluorescence Incontinentia pigmenti Junctional epidermolysis bullosa Junctional epidermolysis bullosa of the Herlitz type Junctional epidermolysis bullosa of the non-herlitz type Junctional epidermolysis bullosa with pyloric atresia Keratinocyte Kilobase pair Kilodalton Keratin intermediate filaments Linker segment Linear IgA disease Lamina densa Lamina lucida Lichen planus Lichen planus pemphigoides Lichen sclerosus Leucocytoclastic vasculitis Melanocytes Melanosomes Mycosis fungoides Mycosis fungoides bullosa Nucleus Sodium chloride Non-collagenous Nuclear factor-kb essential modulator NF NH3 nm OMIM P component PAS PCT PF ANA PNP PLE PM PRL PUVA PV RUD SBDP SCC SDS-PAGE SJS SLE SPD SPPK1 SPPK2 SSSS T TEN TMEP UP UROD UV UV-A UV-B UV-C UVR V VIN VZV Nuclear factor Amino group Nanometer Online Mendelian Inheritance in Man Pentagonal component Periodic acid-schiff Porphyria cutanea tarda Pemphigus foliaceus Antinuclear antibody Paraneoplastic pemphigus Polymorphous light eruption Plasma membrane of keratinocyte Proline rich linker Psoralen plus ultraviolet A Pemphigus vulgaris Repetitive unit domain Subbasal dense plaque Squamous cell carcinoma Sodium dodecyl sulphatepolyacrylamide gel electrophoresis Stevens-Johnson syndrome Systemic lupus erythematosus Subcorneal pustular dermatosis Striate palmoplantar keratoderma I Striate palmoplantar keratoderma II Staphylococcal scalded skin syndrome Transmembrane Toxic epidermal necrolysis Telangectasia macularis eruptiva perstans Urticaria pigmentosa Uroporphyrinogen decarboxylase Ultraviolet Ultraviolet A Ultraviolet B Ultraviolet C Ultraviolet radiation Variable region Vulval intraepithelial neoplasia Varicella-zoster virus