Fundamentals of Pathology of Skin [4 ed.] 9789351293286, 9351293289

Table of contents :
Cover
Title page
Copyright page
Dedication
Preface to the Fourth Edition
Preface to the First Edition
Abbreviations Used in the Book
Introduction
Table of Contents
SECTION I Inflammatory Diseases
Biopsy
Structure of Normal Skin
Stains Used in Dermatology
Definitions in Dermatopathology
Approach to Diagnosis
Spongiotic Dermatosis
Reactive Erythemas
Lichenoid Tissue Reactions
Psoriasiform Reactions
Bullous Diseases
Connective Tissue Diseases
Vasculitis
Granulomas
Disorders of Pigmentation
Appendageal Diseases
Panniculitis
Genodermatoses
Deposition Disorders
Perforating Disorders
Histopathology of Infections
Immunofluorescence and Other Immunomethods of Diagnosis
SECTION II Tumors
Tumors of Epidermis
Premalignant and MalignantTumors of Epidermis
Appendageal Tumors
Connective Tissue Tumors
Melanocytic Tumors
Cutaneous Infiltration Disorders
Clues in Dermatopathology

Citation preview

FUNDAMENTALS OF PATHOLOGY OF SKIN FOURTH EDITION

FUNDAMENTALS OF PATHOLOGY OF SKIN FOURTH EDITION Venkataram Mysore MD, DNB, DipRCPath (Lond), FRCP (Glasgow) Consultant Dermatologist & Dermatopathologist Venkat Charmalaya — Centre for Advanced Dermatology and Postgraduate Training Bengaluru, Karnataka

Manager Commissioning: P. Sangeetha Production Editor: Pooja Chauhan Senior Manufacturing Executive: Sumit Johry Copyright © 2015 Wolters Kluwer Health (India) 10th Floor, Tower C, Building No. 10 Phase – II, DLF Cyber City, Gurgaon, Haryana - 122002 All rights reserved. This book is protected by copyright. No part of this book may be reproduced in any form or by any means, including photocopying, or utilized by any information storage and retrieval system without written permission from the copyright owner. The publisher is not responsible (as a matter of product liability, negligence, or otherwise) for any injury resulting from any material contained herein. This publication contains information relating to general principles of dermatology and dermatopathology that should not be construed as specific instructions for individual patients. Manufacturers’ product information and package inserts should be reviewed for current information, including contraindications, dosages, and precautions. All products/brands/names/processes cited in this book are the properties of their respective owners. Reference herein to any specific commercial products, processes, or services by trade name, trademark, manufacturer, or otherwise is purely for academic purposes and does not constitute or imply endorsement, recommendation, or favoring by the publisher. The views and opinions of authors expressed herein do not necessarily state or reflect those of the publisher, and shall not be used for advertising or product endorsement purposes. Care has been taken to confirm the accuracy of the information presented and to describe generally accepted practices. However, the authors, editors, and publishers are not responsible for errors or omissions or for any consequences from application of the information in this book and make no warranty, expressed or implied, with respect to the currency, completeness, or accuracy of the contents of the publication. Application of this information in a particular situation remains the professional responsibility of the practitioner. Readers are urged to confirm that the information, especially with regard to drug dose/usage, complies with current legislation and standards of practice. Please consult full prescribing information before issuing prescription for any product mentioned in the publication. The publishers have made every effort to trace copyright holders for borrowed material. If they have inadvertently overlooked any, they will be pleased to make the necessary arrangements at the first opportunity. ISBN-13: 978-93-5129-328-6 Published by Wolters Kluwer (India) Pvt. Ltd., New Delhi, 10th Floor, Tower C, Building No. 10, Phase – II, DLF Cyber City, Gurgaon, Haryana – 122002 For product enquiry, please contact – Marketing Department ([email protected]) or log on to our website www.wolterskluwerindia.co.in.

Dedicated to My beloved Professor (Late) Dr R. Shivakumar Formerly, Professor and Head, Department of Dermatology Government Medical College, Mysore

Preface to the Fourth Edition It has been a matter of great satisfaction that what started as an effort to teach dermatopathology to dermatology residents and postgraduate students during weekly seminars in the laboratory has resulted in educating residents both in dermatology and pathology at large, across India and abroad. The first edition of Fundamentals of Pathology of Skin was released in 2003. Since then it has remained popular among the students, residents, practicing dermatologists, and pathologists. The book has seen several reprints after that and it gives us immense pleasure to release the fourth edition of the book. This edition is thoroughly revised and several new topics and facts have been added. The

number of photographs used in this revised edition are considerably more as compared to the previous editions. However, the essence of the book remains unchanged; the objective continues to be providing basic information in a reader-friendly format using simple and lucid language. Similar to earlier editions, this book is meant to be, and will always be, a ready reckoner and a desktop reference for postgraduate students of dermatology and pathology, particularly for those who are preparing for exams. In addition, it can also serve as a source of ready information for the practicing dermatologists and pathologists.

The schematic diagrams are drawn artistically by Dr Madhulika and Dr Namitha. I gratefully acknowledge my fellow dermatopathologists: Dr M Ramam, Dr Meera Mahalingam, Dr Jag Bhawan, and Dr G Nanda Kumar for providing photomicrographs used in this edition. During the preparation of the draft of this edition, I spent delightful moments interacting with my fellows, Dr Madhulika, Dr Annapurna, Dr Vijay Kumar, and Dr Vignessh. My sincere thanks to them all. The earlier editions received complements on the nature and content of the book from scores of students and practitioners. I sincerely hope that this edition too will be received in the same way. Authoring a book always means spending time away from the family. Nothing I say can ever fully express the support that I received from my loving wife, Jayashree Venkataram. I am thankful for her patience and support during the development of this project.

Venkataram Mysore

Preface to the First Edition What is most difficult of all? It is to see what is in front of your eyes! – Goethe A dermatologist needs to know and understand pathology thoroughly. This is partly because clinicopathological correlation is of utmost necessity in most dermatological diseases. Also, dermatopathology is a subspecialty most general pathologists dislike. This makes it essential that a student in dermatology should learn dermatopathology in detail. The idea for this book originated while lecturing postgraduate residents at the Al Nahda Hospital, Muscat, and Salmaniya medical complex, Bahrain. The book is meant as a ready reckoner – a desktop reference for postgraduate students of dermatology and pathology – particularly for those who are preparing for their board exams. In addition, it can also serve as a source of ready information for the practicing dermatologists and pathologists. I make no claims that this is my original work. I surely have nothing to say what the masters such as Lever, Ackerman, Mehregan, and others have not already said. This book is not a replacement for standard textbooks of dermatopathology, of which there are many. The student is advised to read these books for a full understanding of the subject. The standard textbooks, useful as they are, often load the student with a plethora of information, which may be both confusing and difficult to remember. There are very few concise books which supply data in a capsule form. This book seeks to fill that void. The book is designed to provide information in a format which can be easily remembered by a student, in the form of numbered points. Key points are highlighted in italics and textboxes. A number of tables help the reader to remember facts easily. Simple explanations are provided to explain concepts, wherever necessary. A separate section on immunofluorescence is included. There is also a section which provides a set of clues to the practicing pathologist. It is hoped that students of dermatopathology will find these features useful. The necessity of keeping the book as a short concise guide also meant that many diseases could not be included. The student may refer any of the eminent textbooks of dermatopathology for such needs. Again, for reasons of simplicity and brevity, I have avoided extensive references. A section on recommended reading is provided at the end. I humbly accept any errors and inaccuracies that may have crept in and welcome suggestions for improvement from the readers.

x A venture of this type is never possible without the active help and co-operation of many people. I am grateful to Dr Khaleel Arrayed, Chief of Dermatology and Asstt. Undersecretary, Salmaniya medical complex, for his continuous encouragement. My sincere thanks to Dr Abdul Raouf Al Suwaid, who encouraged me in many different ways during my long stint in Al Nahdha Hospital. (Late) Dr Shiva Kumar, Professor of Dermatology, Medical College, Mysore, was instrumental in my entry into the speciality in the early days of my career. Professor S.R. Bhushnurmath and Dr Leenadevi have been helpful at the time of my entry into the field of dermatopathology. Professor K.S. Rathnakar, Consultant Pathologist, Salmaniya Hospital, has been a constant source of inspiration and guidance. My postgraduate residents at the Salmaniya Hospital, particularly Dr Haitham Al Qari, Dr Wassam Al Arrayedh, Dr Hussain Al Mahdi, Dr Rania Abbas, and Dr Mersal Al Arrayed, have assisted me in many ways. And lastly, I wish to thank my family – my mother who has been a source of continuous support and understanding. My loving wife Jayashree, a gynecologist, has been ever understanding and supportive of my ventures despite her extremely busy schedule. My son Aniketh and daughter Ankitha have provided much needed diversion by their antics during the preparation of this manuscript. My humble thanks to all. Venkataram Mysore

Editorial Team EDITORIAL CONSULTANT Nanda Kumar G MD (Dermatology), MD (Pathology) Additional Professor Department of Pathology Government Medical College Trivandrum, Kerala EDITORIAL ASSISTANTS Vijayakumara Adavi MBBS, MD (Dermatology) (FRGUHS) Fellow Venkat Charmalaya–Center for Advanced Dermatology & Postgraduate Training Bengaluru, Karnataka Vignessh Raj B MBBS, DDVL (FRGUHS) Fellow Venkat Charmalaya–Center for Advanced Dermatology & Postgraduate Training Bengaluru, Karnataka Madhulika A Mhatre MBBS, MD (Dermatology), FRGUHS Venkat Charmalaya–Center for Advanced Dermatology & Postgraduate Training Bengaluru, Karnataka T Annapurna MBBS, DDVL, FRGUHS Venkat Charmalaya–Center for Advanced Dermatology & Postgraduate Training Bengaluru, Karnataka Shamanth S MBBS, DDVL, FRGUHS Paediatric Dermatologist Venkat Charmalaya–Center for Advanced Dermatology & Postgraduate Training Bengaluru, Karnataka

xii Namitha Chathra MBBS, MD (FRGUHS) Fellow Venkat Charmalaya–Center for Advanced Dermatology & Postgraduate Training Bengaluru, Karnataka Gayatri Khatri MBBS, MD (FRGUHS) Fellow Venkat Charmalaya–Center for Advanced Dermatology & Postgraduate Training Bengaluru, Karnataka Nazneen Jahan MBBS, MD (Dermatology) Venkat Charmalaya–Center for Advanced Dermatology & Postgraduate Training Bengaluru, Karnataka

Abbreviations Used in the Book ABD: Airborne dermatitis AFB: Acid fast bacilli ANA: Anti-nuclear antibodies BCC: Basal cell carcinoma BL: Borderline lepromatous leprosy BMZ: Basement membrane zone BP: Bullous pemphigoid BSLE: Bullous systemic lupus erythematosus C3: Complement 3 CAL: Cafe au lait macules CBDC: Chronic bullous disease of childhood CD1a: Cluster differentiation 1a CEA: Carcino embryonic antigen CL: Cutaneous leishmaniasis CP: Cicatricial pemphigoid CREST: Calcinosis, Raynaud phenomenon, esophageal dysmotility, sclerodactyly, and telangiectasia CTCL: Cutaneous T-cell lymphoma DEJ: Dermoepidermal junction DFSP: Dermatofibrosarcoma protuberans DH: Dermatitis herpetiformis DIF: Direct immunofluorescence DLE: Discoid lupus erythematosus Dopa: Di-hydroxy phenylalanine EB: Epidermolysis bullosa EBA: Epidermolysis bullosa acquisita EED: Erythema elevatum diutinum EHK: Epidermolytic hyperkeratosis EMF: Erythema multiforme EN: Erythema nodosum FDE: Fixed drug eruption GMS stain: Gomori’s methenamine silver stain GVHD: Graft vs. host disease H&E: Hematoxylin and eosin HG: Herpes gestationis HPV: Human papilloma virus HSP: Henoch-Schonlein purpura HSV: Herpes simplex virus ICS: Intercellular substance Ig: Immunoglobulin IgABD: IgA bullous disease

xiv IIF: IL: IRS: KS: LCA: LCV: LE: LMDF: LP: LPP: LSA: LSC: MCTD: MF: MPS: NLD: ORS: PAN: PAS: PCR: PCT: PLC: PLE: PLEVA: PMN: PNGD: PPP: PRP: PSS: PUPP: PUVA: RBCs: RF: SCC: SCE: SCLE: SCPD: SJS: SLE: SSS: TBVC: TEE: TEN: TT: VVG:

Indirect immunofluorescence Indeterminate leprosy Inner root sheath Kaposi’s sarcoma Leucocyte common antigen Leucocytoclastic vasculitis Lupus erythematosus Lupus miliaris disseminatus fascei Lichen planus Lichen planus pigmentosus Lichen sclerosus et atrophicus Lichen simplex chronicus Mixed connective tissue disease Mycosis fungoides Mucopolysaccharides Necrobiosis lipoidica diabeticorum Outer root sheath Polyarteritis nodosa Periodic acid Schiff Polymerase chain reaction Porphyria cutanea tarda Pityriasis lichenoides chronica Polymorphic light eruption Pityriasis lichenoides et varioliformis acuta Polymorphonuclear cells Palisading neutrophilic granulomatous dermatitis Progressive pigmented purpura Pityriasis rubra pilaris Progressive systemic sclerosis Pruritic papules and plaques of pregnancy Psoralin+UVA Red blood cells Radiofrequency Squamous cell carcinoma Squamous cell epithelioma Subacute cutaneous lupus erythematosus Subcorneal pustular dermatosis Steven Johnson syndrome Systemic lupus erythematosus Scalded skin syndrome Tuberculosis verrucosa cutis Transepidermal elimination Toxic epidermal necrolysis (10x) Tuberculoid leprosy Verhoeff-van Gieson stain

Introduction What makes dermatology, and therefore dermatopathology, different from other disciplines of medicine? 1. Dermatology, like pathology and radiology, is a visually oriented speciality. Both the physician and the patient can see and follow the lesion throughout its life. 2. A dermatopathologist needs to possess a variety of skills in order to be able to diagnose skin diseases; and the development of these skills needs time, effort, and training. 3. Dermatology is a descriptive speciality, and diseases have long names. Each lesion and hence each disease can be described according to what one sees. This has resulted in many diseases with long names. Since the names of the diseases are long, they are abbreviated into acronyms, e.g., Pityreasis lichenoides ­varioliformis acuta is abbreviated as PLEVA. As in medicine, Latin and Greek terms have been liberally used in the dermatological jargon. For example, pityr means scale; tinea means an insect; vulgaris means common; lichen means leaf-like (lichens are low-­ level plants!). This jargon is often incomprehensible to the nondermatologist and can be overwhelming to a beginner. 4. However, most of the long names actually indicate the manifestations of disease; so that once a student has understood the jargon, the long name actually becomes an advantage, because it explains the manifestations of the disease. The following are some examples. (a) Pityreasis lichenoides varioliformis acuta indicates “scaly lichen planus-like lesions healing depressed scars with acute manifestations.” (b) Pityreasis lichenoides chronica indicates “scaly and lichen planus-like lesions which are chronic.” (c) Keratosis follicularis means “keratotic lesions of the hair follicle.” (d) Pityreasis rosea means “scaly lesions which are pink in color.” 5. Dermatological diagnosis follows a unique pattern of morphological, clinical, and etiological diagnosis. Keen observation is the essence of dermatology; ability to recognize subtle differences leads to efficiency in diagnosis. Dermatologist is like an ornithologist, spotting and naming a bird in jiffy, while a novice may not have spotted the bird at all! Power of observation, ability to store the imagery in brain, and finally the ability to retrieve what one has seen in the past are all necessary for a quick and spot diagnosis. The famous dermatologist Dr Graham Dowling was known to teach as follows: What is this? This is lichen planus. Why is this lichen planus? Because it looks like it!! These aspects of dermatology are shared by pathology also, and hence, the close relationship between dermatology and dermatopathology. It is therefore not entirely surprising that some of the most popular dermatopathology books have been written by dermatologists!!!

Table of Contents Preface to the Fourth Edition

vii

Preface to the First Edition

ix

Editorial Team

xi

Abbreviations Used in the Bookxiii Introductionxv SECTION I: INFLAMMATORY DISEASES Chapter 1: Biopsy Chapter 2: Structure of Normal Skin

1 3 6

Chapter 3: Stains Used in Dermatology

20

Chapter 4: Definitions in Dermatopathology

26

Chapter 5: Approach to Diagnosis

54

Chapter 6: Spongiotic Dermatosis

61

Chapter 7: Reactive Erythemas

69

Chapter 8: Lichenoid Tissue Reactions

73

Chapter 9: Psoriasiform Reactions

85

Chapter 10: Bullous Diseases

96

Chapter 11: Connective Tissue Diseases

111

Chapter 12: Vasculitis

120

Chapter 13: Granulomas

137

Chapter 14: Disorders of Pigmentation

164

Chapter 15: Appendageal Diseases

169

Chapter 16: Panniculitis

182

Chapter 17: Genodermatoses

191

Chapter 18: Deposition Disorders

198

Chapter 19: Perforating Disorders

203

Chapter 20: Histopathology of Infections

206

Chapter 21: Immunofluorescence and Other Immunomethods of Diagnosis

219

SECTION II: TUMORS237 Chapter 22: Tumors of Epidermis

239

Chapter 23: Premalignant and Malignant Tumors of Epidermis

246

Chapter 24: Appendageal Tumors

258

Chapter 25: Connective Tissue Tumors

269

Chapter 26: Melanocytic Tumors

279

Chapter 27: Cutaneous Infiltration Disorders

289

Chapter 28: Clues in Dermatopathology

305

Recommended Readings

311

Index

319

SECTION I

Inflammatory Diseases

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1 Biopsy 1. Dermatologists have the unique advantage of performing biopsy with minimum of effort. It should be done not only when the clinician wants to know what is going on, but also when he does not know what to do. It gives time to think! So just do it. 2. Fill up the biopsy forms properly, providing full details of the patient. 3. Perform face, scalp, nail, and mucosal biopsies frequently—do not be hesitant. 4. Remember that any biopsy has four dimensions: length, breadth, depth, and time. Pathologist sees the first three dimensions. Clinician has the advantage of watching the fourth dimension, i.e., time, as only he can follow-up the lesion. Hence, clinicopathological correlation provides all the four dimensions.

Fifteen Commandments of Biopsy 1. There are several types of biopsies: punch, superficial, deep shave, deep incisional, complete excision, and curettage. 2. An ideal lesion for biopsy should not have been scratched/traumatized or treated by topical and systemic therapies. 3. Always take a deep, large biopsy. Include subcutaneous tissue. 4. Avoid curettage biopsy, except in superficial lesions such as seborrheic keratosis and molluscum contagiosum. 5. Prefer excision biopsies for bullous lesions, panniculitis, granulomas, and scleroderma. 6. For punch biopsy, usually 4-mm punch is required for adequate histological study. A 3-mm punch may be preferable for small lesions or biopsies from the face. 7. Resort to multiple biopsies from multiple sites in difficult diagnosis, for example, mycosis fungoides, leprosy. 8. Lesions can change with time; repeat biopsies in evolving lesions. 9. Choose an early lesion for biopsy in bullous, ulcers, pustular lesions, and vasculitis. 10. Choose an established and fully evolved lesion in psoriasis, discoid lupus erythematosus, and leprosy. 11. Avoid excoriated and secondarily infected lesions. 12. In case of scalp lesions, two specimens are ideally needed—one for horizontal section and the other for vertical section. 13. Include surrounding skin for comparison, in morphea, anetoderma, and in situ malignancies.

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4  Fundamentals of Pathology of Skin 14. The specimen should be handled gently and not to be handled with forceps except at the edges to avoid crush artifact (Figs 1.1 and 1.2). 15. Aluminium chloride is preferred over electrocautery or radiofrequency (RF) for hemostasis. RF can lead to artifactual changes (Fig. 1.3). Unfixed Fresh Specimens Used for: • Direct immunofluorescence • Immunoperoxidase • Monoclonal antibodies • Enzyme studies: dihydroxyphenylalanine test, eccrine, and apocrine enzymes • Mucin: scleredema of Buschke • Gout • Amyloid

Fixatives 1. Always use 10% buffered formalin to avoid artifacts such as formazan pigment and crystal formation. Fixation time is 1–2 hours per millimeter thickness of specimen. 2. Use glutaraldehyde for electron microscopy. 3. After fixation, routine specimens are processed in an automatic processor, except for the specimens that are to be stained for lipids as xylene is used for extracting lipids. 4. Use Michael’s solution for direct immunofluorescence. If this is not available, saline is enough, if you can transport it immediately to the laboratory!! 5. Use adequate amounts—at least eight times the volume of the sample.

Figure 1.1.  Crush artifact. Part of epidermis crushed by forceps (4×) (scanner).

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Biopsy 5

Figure 1.2.  Crush artifact. Part of dermis crushed by forceps (4×) (scanner).

Figure 1.3.  Changes after RF. Seborrheic keratosis removed with RF showing secondary acantholysis resembling Hailey–Hailey disease (10×).

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2 Structure of Normal Skin 1. Skin is the largest organ in the body; it comprises of about 16% of body weight and has a surface area of 1.8 m2. 2. Structure and thickness of skin vary with the site. The thickness varies between 0.6 mm (e.g., eyelids) and 3 mm (e.g., back and soles). 3. The epidermis, mainly composed of keratinocytes, is arranged in four layers: ­stratum corneum, stratum granulosum, stratum spinosum, and stratum basale (Fig. 2.1). 4. Stratum granulosum, stratum spinosum, and stratum basale together form the stratum malpighii or the living layer and constitute the site of synthesis of keratin. 5. Stratum corneum is the dead layer and acts as the main barrier. 6. The other cells in the epidermis are melanocytes, Langerhans cells, and Merkel cells. 7. Dermis is made of papillary dermis, just beneath the epidermis and deeper reticular dermis. Hair

Stratum corneum Granular cell layer 1

Spinous cell layer Basal cell layer Sebaceous gland Arrectores pili muscle

2

Sweat gland Nerves Hair follicle Collagen and elastin fiber 3

Artery Vein

1

Epidermis

3

Subcutaneous tissue

2

Dermis

Fat (adipose) tissue

Figure 2.1.  Structure of normal skin.

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Structure of Normal Skin  7 8. Dermis consists of supportive connective tissue, mainly collagen, elastin, and glycosamingolycans. 9. Dermis has a resident population of fibroblasts, lymphocytes, and dermal dendritic cells. 10.  Subcutis, the lowermost layer, has a plexus of nerves, vessels, and nerves. 11.  Appendages of skin include hair, sweat glands, and sebaceous glands. 12. Skin has an extensive nerve network with specialized nerve endings in papillary dermis. 13. Vessels in skin run up from a deeper horizontal plexus in subcutis, run upward vertically parallel to each other, and form a superficial horizontal plexus in papillary dermis. 14. Lymphatics drain to regional lymph nodes.

Embryology of the Skin By 12 weeks, early development of all components of skin is evident. This fact is important in prenatal diagnosis of inherited diseases of skin (genodermatoses) such as epidermolysis bullosa and ichthyosis. Development of Skin Sources of skin structures • Ectoderm: epidermis, hair follicles, sweat coils, sebaceous glands • Mesoderm: dermis, arrectores, vessels, nerves • Neural crest: melanocytes Langerhans cells are derived from mesenchyme. Chronology of development of skin • Epidermis: 4–7 weeks • Dermis: 11 weeks • Nail: 10 weeks • Sweat glands: 12 weeks • Primitive hair structures: 12 weeks • Melanocytes: 12 weeks • Dermoepidermal junction: 12 weeks • Fingerprints: 17 weeks

Detailed discussion of the structure of skin is beyond the scope of this book. What follows is a guide for identification of normal structures.

Epidermis (Fig. 2.2) The epidermis is a multilayered structure (stratified epithelium) which renews itself continuously by cell division in its deepest layer, the basal layer. The principle cell of epidermis is the keratinocyte. Keratinocytes undergo a series of changes as they move upwards.

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8  Fundamentals of Pathology of Skin

Figure 2.2.  Normal skin from dorsum of foot. Note thick stratum corneum and the stratum lucidum.

(A) Basal Cell Layer The basal cells lie on the basement membrane and are columnar. These cells contain filaments called tonofibrils which are precursors of keratin. The basal cell undergoes mitosis and each basal cell multiplies and produces keratinocytes which move up—the so-called epidermal proliferation unit. The basal cell sits on the basal lamina of the basement membrane, to which it is attached by hemidesmosomes.

(B) Prickle Cell Layer As the cells move up, the columnar cells become flatter, change into the spinous layer or the prickle cell layer whose prickly appearance is due to the presence of prominent intercellular desmosomal connections. Desmosomes are connected to tonofilaments in cytoplasm. The junction between the cells is filled up with the intercellular cement substance (glycosaminoglycan). Desmosomes contain adhesion molecules, which play an important role in the organization of epidermis, transfer of signals, and immune response.

(C) Granular Layer It is composed of diamond-shaped cells with bluish granules called keratohyalin granules. These granules contain a protein called filaggrin which is responsible for aggregation of keratin filaments, synthesized in the spinous layer. This layer also contains membrane-coating granules or Odland bodies. Odland bodies contain lipids, which are responsible for barrier function in stratum corneum. Granular layer together with prickle cell layer forms the stratum malpighii.

(D) Horny Layer Finally, the cells become flat, polyhedral, fully keratinized, and lose their nuclei and end up as anucleate dead cells in stratum corneum.

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Structure of Normal Skin  9

Identification of Structures of Epidermis Layers of Epidermis 1. Stratum corneum: It appears as a pink, lamellated (layered), or compact layer consisting of flat, anucleate cells. Normally, it is less than one-third of the thickness of the epidermis. The characteristic basket weave pattern is due to a formalin-induced change. 2. Stratum granulosum: It is made up of 1–3 layers of diamond-shaped, horizontally arranged cells with dark purple granules. 3. Stratum spinosum: It is made up of 5–10 layers of polygonal cells with spike-like processes and elongated nucleus. Prominent spike-like intercellular connections (which have given the name, stratum spinosum) are seen. 4. Stratum basale: These are columnar cells lying side by side with elongated nuclei. 5. Stratum lucidum: It is an amorphous pink layer beneath stratum corneum seen only on palms and soles.

Cells in Epidermis Melanocytes These appear as round nuclei in clear spaces in the basal layer. Melanocytes are cells with dendritic processes, located in the basal layer. Normally, one melanocyte is found for every 10–14 basal cells. The number of melanocytes varies from region to region, and a maximum number of melanocytes are found on the genitals. Melanocytes are derived from the neural crest and migrate into the skin. Melanocyte is the factory which synthesizes melanin in oval or round bodies called melanosomes and transfers it to keratinocytes. Melanocyte, together with the keratinocyte it supplies, is referred to as the epidermal melanin unit. Melanocytes do not normally multiply in epidermis. Besides the skin, melanocytes are also found in hair follicles, and to a lesser extent in sweat glands. They are also found elsewhere in the body such as choroid membrane of the eye, inner ear, and leptomeninges in brain. The function of these extracutaneus melanocytes is not precisely known. Melanocytes produce melanin, which protects the skin from the harmful effects of ultraviolet rays.

Langerhans Cells These are clear cells found in stratum spinosum. These are also dendritic cells, located at a higher level in stratum spinosum. They are derived from primitive mesenchyme and function as epidermal macrophages (antigen-processing cell). They contain characteristic tennis racquet-shaped granules called Birbeck granules. These cells are not seen in ordinary hematoxylin and eosin (H&E) sections and need special immunostains such as CD1a for identification. These cells are immunologically competent and have class II human leukocyte antigens on their surface. Similar dendritic cells (called dermal dendritic cells) are found in dermis also, but they do not contain Birbeck granules.

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10  Fundamentals of Pathology of Skin

Figure 2.3.  Thickened basement membrane zone.

Merkel Cells These cells are derived from neural crest and are present in the basal layer, in close apposition to nerve endings. These cells play an important role in touch sensation. They are not discernible in H&E-stained specimen.

Basement Membrane It is normally seen as a thin pink line at dermoepidermal junction. It is better visible under H&E stain only when thickened (Fig. 2.3) .

Dermis Epidermis folds into the dermis in the form of downgrowths called rete ridges, while dermal papillae project as finger-like processes, up into the epidermis in between rete ridges as dermal papillae. Dermis consists of two parts: 1. Papillary dermis: It is located just beneath epidermis, and consists of loose areolar tissue, superficial capillaries, and nerve endings. 2. Reticular dermis: It is the lower part of dermis and consists of dense collagen fibers, elastic fibers, arterioles, venules, and appendages.

Blood Vessels (Fig. 2.4) Vessels in skin form two plexuses: superficial horizontal plexus defines the boundary between the papillary and reticular dermis and envelops adnexal structures. Second, the deep vascular plexus separates the reticular dermis from the subcutaneous fat and is connected to the first by vertically oriented reticular dermal vessels, consisting of small vessels such as arterioles, capillaries, and venules.

Capillaries These are thin-walled vessels with single layer of flat endothelial cells. They are distinguished from lymphatic vessels by the presence of red blood cells (RBCs) in lumen.

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Structure of Normal Skin  11

c

a b

d

Figure 2.4.  Different types of blood vessels (40×): (a) capillary, (b) arteriole, (c) venule, and (d) collagen fibers.

Venules These are elongated larger vessels with single layer of endothelial cells, surrounded by connective tissue stroma (tunica externa), the site of most dermal inflammations.

Veins (Fig. 2.5) These are endothelial cells lining the lumen, surrounded by smooth muscle cells and connective tissue stroma.

Arteriole These are thick-walled round vessels, with three layers: tunica externa of connective tissue fibers, tunica media of muscle, and tunica intima of endothelial cell.

Artery In addition to the above-mentioned layers, there is also an internal elastic lamina called artery.

a b

Figure 2.5.  Large vein: (a) endothelial layer and (b) tunica media (40×).

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12  Fundamentals of Pathology of Skin

Lymph Vessels These are similar to capillaries, but without RBCs.

Collagen Fibers Collagen fibers are seen as wavy, pink non-branching parallel fibers often interlacing with each other. They constitute 70% of dermis and give tensile strength to the skin. Different Types of Collagen in Skin Type I: Collagen in reticular dermis Type III: Collagen in papillary dermis Type IV: Collagen in basement membrane Type VIII: Collagen in endothelial cells

Elastic Fibers They are not seen with H&E stain, but seen as straight and branching fibers with special stains. They are responsible for the elastic property of the skin.

The Ground Substance It is the semisolid substance in the dermis and contains the mucopolysaccharide (glycosaminoglycan). Note:  Normally, dermis contains only a few resident cells such as fibroblasts, occasional mast cells, macrophages, lymphocytes, and specialized cells called dermal dendritic cells.

Subcutis The panniculus or subcutis consists of subcutaneous fat. The fat is arranged in lobules separated from each other by septae. The septae contain blood vessels, lymphatics, and nerve fibers.

Nerves Nerves appear as wavy light pink fibers with central elongated nucleus which has pointed ends. The larger nerve fibers enter subcutis and then branch into smaller fibers. A number of specialized nerve endings are seen in papillary dermis. Free nerve endings mediate superficial touch, pain, and temperature sensations. Specialized nerve endings such as pacinian corpuscles, ruffini end organ, and Klause’s end bulb mediate different sensations such as superficial touch, pain, and temperature. Note:  Itch sensation is not mediated by specialized nerve endings. It is mediated by the free nerve endings which mediate light touch.

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Structure of Normal Skin  13

Skin Appendages Sweat Glands (Figs 2.6–2.8) There are two types of sweat glands: eccrine (eccrine means excretion of the secretion) and apocrine glands (so-called because the apex of the secretory cells lining the gland is cast off as part of the secretion. This type of secretion is also called decapitation secretion). Humans have several million eccrine sweat glands distributed over the entire body surface (except labia minora and glans penis). Each sweat gland consists of a secretory coil deep in the dermis, and a duct that conveys the secreted sweat to the surface (Fig. 2.6). Sweat which is produced by the coils is carried up the ducts.

Figure 2.6.  Sweat coil going up through stratum corneum (40×).

a

b

Figure 2.7.  Sweat coils and sweat ducts (eccrine) (40×). (a) Two layers of cuboidal cells in sweat duct and (b) dark and clear cells lining secretory coil.

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14  Fundamentals of Pathology of Skin

a

b c

d

Figure 2.8.  (a) Sebaceous glands, (b) arrectores muscle, (c) hair follicle, and (d) apocrine gland showing decapitation secretion (40×).

Eccrine Coils These are large irregular coils with inner layer lined by dark and light cells surrounded by an outer layer of flat myoepithelial cells (Fig. 2.7).

Apocrine Coils These are lined by an inner layer of dark and light cells surrounded by an outer layer of flat myoepithelial cells (as in eccrine coils). The coils are 10 times larger than eccrine coils, up to 200 microns in diameter, cells show decapitation secretion (apex of the cell is pinched off into parts), and thick viscid secretions are seen within the lumen (Fig. 2.8).

Sweat Ducts Both apocrine and eccrine ducts show the same structure. They are lined by two layers of cuboidal cells. The mature glands are composed of an intraepidermal duct (acrosyringium), intradermal duct, and the secretory portion.

Sebaceous Glands Sebaceous glands (Fig. 2.9) are found on all areas of the skin with the exception of the palms, soles, and dorsa of the feet. Sebaceous glands secrete a greasy secretion rich in fatty substances. Most sebaceous glands have their ducts opening into hair follicles (pilosebaceous apparatus). Free sebaceous glands (not associated with hair follicles) open directly to the surface of the skin, for example, meibomian glands of the eyelids, Tyson’s glands of the prepuce, and free glands in the female genitalia and in the areola of nipples. Sebaceous glands are holocrine glands, that is, their secretion (consisting of lipids) is due to complete destruction of the cells. Sebaceous glands on the scalp harbor a fungus called Pityrosporum ovale which has a role in the causation of dandruff (seborrheic dermatitis). A bacterium called Corynebacterium acne is present in the sebaceous glands

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Structure of Normal Skin  15

Figure 2.9.  Sebaceous gland and sweat coil (40×).

on the face and plays an important role in the causation of acne vulgaris. A mite called Demodex folliculorum is also present in sebaceous glands as a commensal. Sebaceous glands are small during childhood, and under the influence of androgens, they become prominent at puberty. The lipids secreted by sebaceous glands contribute to the barrier function and have bacteriostatic and fungistatic properties. Sebaceous gland consists of lobules of foam cells with central nucleus. The cells show holocrine secretion, that is, cells degenerate to become part of the secretion.

Hair Hairs are found everywhere on the skin except palms, soles, glans penis, and vaginal introitus. Nonhairy skin is also referred to as glabrous skin. Hair and sebaceous gland together constitute the pilosebaceous unit; hence, both structures are often involved in many skin diseases such as acne vulgaris. Three types of hair are found: 1. Lanugo hairs are found in fetus. 2. Vellus hairs are the short fine brown hairs present all over the body. 3. Terminal hair which is the black thick hair is present on scalp, face, chest, pubic area, etc. Note:  Vellus hairs do not have melanin and normally present in children and in women; they are converted to terminal hairs under the influence of androgens. The differences between terminal and vellus hairs are given in Table 2.1. The hair follicle (Fig. 2.10) consists of the following: 1. Inferior segment: It is from the root to the insertion of arrectores pilorum muscle. This segment is the temporary part of the hair follicle, and is present only in the growth or anagen phase and disappears with the onset of the catagen (resting phase).

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16  Fundamentals of Pathology of Skin Table 2.1  Differentiation Between Terminal and Vellus Hair Terminal Hair

Vellus Hair

Large bulb in subcutis

Small bulb in upper dermis

Arrectores muscle present

No arrectores

Has cortex and medulla

No cortex and medulla

Pigment present

No pigment

Figure 2.10.  Anagen hair (40×).

2. Isthmus: It is the segment between arrectores and sebaceous gland. 3. Infundibulum: It is the segment from the level of sebaceous gland to the opening at the surface. The arrectores pili muscle is a small bundle of smooth muscle fibers, attached to the side of the follicle at an angle. It is seen adjacent to hair shaft as dark pink straight broad fibers, with central plump nuclei which have rounded ends (called eel-shaped nuclei). Arrectores pili muscles are supplied by adrenergic nerves and are responsible for the erection of hair during cold or emotional stress (“goose flesh”). The sebaceous gland is attached to the follicle just above the point of attachment of the arrectores pili. At the lower end of the follicle is the hair bulb. Hair bulb contains hair matrix, which is a zone of rapidly dividing cells responsible for the formation of the hair shaft. Hair pigment is produced by melanocytes in the hair bulb. The hair root encircles the flame-shaped dermal papilla which exerts a strong influence on the growth phase of hair. Cells produced in the hair bulb become densely packed, elongated, and arranged parallel to the long axis of the hair shaft. They gradually become keratinized as they ascend in the hair follicle. The keratin found in hair and nail contains more cysteine and is referred to as hard keratin in contrast to the epidermal keratin called soft keratin. The hair shaft is composed of following three parts: 1. The cuticle: It is the outer part of the hair shaft and is composed of 5–8 layers of flattened cells with an overlapping pattern and free edge oriented upwards.

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Structure of Normal Skin  17 2. The cortex: It is composed of flattened and tight cells known as hair fibers. They are elongated and pigmented. 3. The medulla: It is present only in terminal hairs and is made up of polyhedric cells, scarcely cornefied and rich in glycogen and air bubbles.

Microscopic Anatomy of Hair Follicle The terminal hair follicles can be viewed on vertical and horizontal plane of sections. The terminal hair follicle penetrates deep into the dermis extending to subcutaneous tissue. The horizontal cross-sectional view of the hair follicle, from the outermost to innermost, includes the dermal sheath hyaline membrane, outer root sheath (ORS), inner root sheath (IRS), cuticle, hair shaft cortex, and hair shaft medulla. The infundibulum opens from the epidermal surface and ends at the entry of sebaceous duct into the hair follicle. The isthmus extends from the entry of the sebaceous duct and ends at the insertion of arrector pili muscle. The follicular root consists of the hair bulb, the deepest portion of hair follicle.

Follicular Keratinization Infundibulum has epidermal type of keratinization (has basophilic, keratohyalin granules). ORS has trichilemmal keratinization. There is no granular layer, and keratinization results in amorphous pink keratin. IRS has trichohyaline granules which are eosinophilic.

Stages of Hair (Figs 2.10 and 2.11) Features of different stages of hair are given in Table 2.2. Proper differentiation of stages of hair is important for identification of cause of alopecia of non-scarring type. Differentiation of stages is possible only in the inferior segment. All the stages look alike in the upper two segments.

Desquamating inner root sheath

Inner root sheath

Sebaceous duct Outer root sheath

Remnant of inner root sheath Outer root sheath

Club

Inner root sheath

Bulb

Medulla Basal Lamina

Dermal papilla

Dermal papilla

Dermal papilla Anagen hair

Club

Basal lamina

Cortex

Catagen hair

Telogen hair

Figure 2.11.  Hair cycle.

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18  Fundamentals of Pathology of Skin Table 2.2  Features of Different Stages of Hair Feature

Anagen

Catagen

Telogen

Location of root

Lower dermis

Mid/lower dermis

Mid/upper dermis

Root

Bulbous, fully formed

Small

Club shaped

Pigmentation of root

Pigmented

No melanocytes

No melanocytes

Inferior segment

Present

Replaced by epithelial cord

Replaced by fibrous cord

Mitotic figures

Present

Absent

Absent

Colloid bodies

Absent

Present

Absent

Vitreous sheath*

Absent

Thick

Dermal papilla

Large, flame shaped Small

Absent Small

*Vitreous sheath indicates the thick corrugated pink amorphous layer seen in catagen hair.

Anagen (Growing) Hair 1. Located in lower dermis 2. Larger, pigmented root 3. Cells show mitosis 4. The root encircles a flame-shaped papilla made of loose connective tissue 5. IRS can be easily identified, consisting of trichohyaline granules, which are eosinophilic (in contrast to the basophilic keratohyalin granules in epidermis)

Catagen (Resting) Hair 1. Inferior segment has disappeared and so has IRS. It is replaced by an epithelial streamer. 2. Root, located beneath the epithelial streamer, has become small and the cells show plenty of colloid bodies. The melanocytes are absent. 3. The hair is covered by thick corrugated glassy basement membrane (also called vitreous layer), which is periodic acid-Schiff positive.

Telogen Hair 1. The root is small, club shaped, without melanin. 2. The small root is located in mid-dermis. 3. Beneath the root is the small dermal papilla followed by a streamer of connec­tive  tissue.

Nails The nail acts as a protective covering to the end of the digit and assists in grasping small objects. The nail also has a cosmetic function. The major part of this appendage is the hard nail plate, which arises from the matrix. The nail plate is roughly rectangular and flat in shape but shows considerable variation in different persons. The pink color

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Structure of Normal Skin  19 of the nail bed is due to the extensive vascular network and can be seen because of the transparency of the plate. Usually in the thumbs, uncommonly in other fingers and in the large toenails, a whitish crescent-shaped lunula is seen projecting from under the proximal nail folds. The lunula is the most distal portion of the matrix and determines the shape of the free edge of the nail plate. Its color is due, in part, to the effect of light scattered by the nucleated cells of the matrix and in part to the thick layer of epithelial cells making up the matrix. As the nail plate emerges from the matrix, its lateral and proximal borders are enveloped by folds of the skin termed the lateral and proximal nail folds. The skin underlying the free end of the nail is referred to as the hyponychium and is contiguous with the skin on the tip of the finger. The nail plate is formed by a process that involves flattening of the basal cells of the matrix, fragmentation of the nuclei, and condensation of cytoplasm to form horny flat cells which are strongly adherent to one another. The nail grows at the rate of about 0.1 mm/day. The keratin in nail is hard keratin and is rich in cysteine.

Regional Variation of the Skin It is important to emphasize that although the skin has basically the same components at different anatomical sites, the distribution of these components is variable, so that the skin has different morphology at different anatomical sites. 1. Skin from palms and soles has thickened and compact stratum corneum along with stratum lucidum, numerous eccrine glands, and no pilosebaceous units. 2. Skin from the trunk and especially back has a significantly thicker reticular dermis compared to other regions. 3. Scalp has numerous terminal hair follicles, with most of their bulbs in the subcutaneous tissue. 4. The skin of face has prominent sebaceous glands in vellus hairs. 5. Skeletal muscle fibers may be seen on the face, particularly lips and periorbital areas. 6. The eyelid epidermis is thin (2–3 layers thick) with basaloid buds. Modified apocrine glands (Moll’s glands) and vellus hairs are seen in the dermis. 7. Smooth muscle fibers are numerous in the dermis of the areola and nipple and are also seen in the dartos layer in foreskin and scrotum. 8. Skin biopsies from the legs, especially in adults, may show prominent thickwalled blood vessels due to gravity and stasis.

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3 Stains Used in Dermatology Different stains are used in dermatopathology. Although the most common stain used is hematoxylin and eosin (H&E), periodic acid Schiff (PAS) and Giemsa are also commonly used. Special stains are used in specific situations. In most cases, H&E stain is enough, and it has been rightly remarked, with respect to too frequent use of special stains, that they only show in other colors what is seen as pink and blue with H&E stain. Different stains and tissues stained by them are given in Table 3.1.

H&E Stain This is the most commonly used stain—stains all tissues in skin except the elastic tissue. Cytoplasm is stained pink and nucleus is stained blue. Melanin appears brown, so does hemosiderin.

PAS (Fig. 3.1) This is the second most commonly used stain, the first being H&E stain. The principle of PAS stain is the formation of Schiff complexes between aldehyde and the Schiff reagent (made from pararosanilin treated with sulfurous acid), which leads to the staining pattern. The staining can be diastase sensitive (PAS positivity is

Figure 3.1.  PAS staining for amyloid (pink) (10×).

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Stains Used in Dermatology  21 Table 3.1.  Different Stains and the Tissues Stained by Them Stain

Tissue

Appearance

H&E

All tissues except elastic fibers

Cytoplasm (pink) and nucleus (blue)

PAS

Fungi, basement membrane, fibrin, glycogen (diastase sensitive), mucopolysaccharide (diastase resistant)

Red

Histoplasma, Donovon bodies in donovanosis

Purple

Lymphoid infiltrates

Red

Masson Fontana

Melanin

Black

Dihydroxyphenylalanine stain

Tyrosinase

Black

Leder stain

Mast cell granule

Red

Mast cell granules

Purple

Acid MPS

Blue

Colloidal iron

Acid MPS

Blue

Phosphotungstic acid hematoxylin

Fibrinoid

Purple

Von Kossa

Calcium

Black

Alizarin red

Calcium

Red

Congo red

Amyloid

Khaki color and apple green birefringence

Crystal violet

Amyloid

Metachromatic purple

Thioflavin T

Amyloid

Red fluorescence

De galantha

Urates

Brown

Alcian blue

Neutral MPS

Metachromatically purple

Alcian blue at pH 2.5

Non-sulfated acid MPS

Metachromatically purple

Alcian blue at pH 0.5

Sulfated acid MPS

Metachromatically purple

Methyl green pyronin

Plasma cells

Purple

Van Gieson

Collagen

Red

Verhoeff’s stain, Wiegert’s stain, acid orcein Giemsa

Elastic tissue

Black

Sudan Black

Triglycerides and cholesterol

Black

Oil red O

Triglyceride and cholesterol

Red

Scarlet red

Lipids

Red

Muscle

Red

Collagen

Blue or green

Bacteria

Gram positive (blue) and Gram negative (red)

Giemsa stain

Toluidine blue

Masson trichrome Brown Brenn

(Continued)

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22  Fundamentals of Pathology of Skin Table 3.1.  (Continued)

Stain

Tissue

Appearance

Fite-Faraco

M. leprae

Red

Warthin–Starry stain

Spirochetes

Black

Grocott-Gomori’s stain

Fungi

Black

Silver nitrate

Melanin, reticulum fibers

Black

Perl’s potassium ferrocyanide

Hemosiderin

Blue

Ziehl Neelsen

Acid-fast bacilli

Red

dissolved by diastase), as with glycogen, or diastase resistant (PAS positivity is not dissolved by diastase), as with mucopolysaccharide. This stain is highly useful for identifying fungi, basement membrane, glycogen, and mucopolysaccharide. It also stains fibrin. Glycogen is found in epidermal tumors such as Bowen’s disease, clear cell ­acanthoma, hair tumors such as trichilemmoma and sweat gland tumors such as clear cell hidradenoma. Diastase-resistant staining is seen in colloid bodies, Kamino bodies in Spitz nevus, porphyria, Fabry’s disease, Paget’s disease, and fungi.

Giemsa Stain It is a versatile Romanowsky stain used for mast cell granules (stains purple), Leishmaniasis (stains red), Histoplasma, and Donavon bodies. It is preferred in all lymphoid and leukemic infiltrates as the cytoplasmic and nuclear characters are seen clearly.

Acid Orcein Giemsa It is recommended by Drs Pinkus and Mehregan. It has the advantage of staining elastic tissue in addition to the tissues stained by H&E.

Stains for Melanin and Melanocytes Masson Fontana stain is a silver stain. It stains melanin black because of its affinity for silver. Dopa stain is a stain used for detecting the activity of tyrosinase and hence it is ­useful in albinism.

Stains for Langerhans Cells Gold stains are preferred to stain Langerhans cells, but to a lesser extent silver stains are also used. Enzyme histochemical stains such as ATPase and aminopeptidase also highlight them. However, these stains have been replaced by immunostains CD1a and S100.

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Stains Used in Dermatology  23

Figure 3.2.  Giemsa stain showing metachromatic purple staining of mast cells. (Courtesy: Dr Nanda Kumar, Trivandrum, India.)

Stains for Mast Cells Giemsa stain (Fig. 3.2) and Toluidine blue stain are useful to detect metachromasia. Recently, Leder stain that stains the granules red has been shown to be superior. Note:  Metachromasia is the property by which the stained tissue shows a different color from that of the stain, for example, purple color of mast cell granules shows blue color when stained with toluidine. It occurs due to polymerization of the dye when it reacts with such tissues.

Calcium Von Kossa stains black and alizarin red stains red. Von Kossa stain is a stain for phosphate, whereas alizarin red is a stain for calcium and hence it is more specific; however, calcium never occurs alone in tissue and hence Von Kossa stain is used widely.

Stains for Amyloid There are many stains for amyloid. Unfixed sections give better results though formalinfixed tissues can also be used. It appears as pink homogenous material in H&E, a property also shared by other deposits such as colloid and the material in porphyrias. 1. Congo red (Fig. 3.3): It is the gold standard stain. It shows a khaki color on light microscopy and apple green birefringence on polarizer. 2. Crystal violet: It shows metachromatic purple color. 3. Thioflavin T: It shows red fluorescence under a fluorescent microscopy. 4. Pagoda red: It is regarded by many as the most specific stain.

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24  Fundamentals of Pathology of Skin

Figure 3.3.  Congo red staining for amyloid (Khakhi) (10×).

Mucopolysaccharides 1. Neutral mucopolysaccharide: It is PAS-positive (which is diastase resistant) and seen in basement membrane, fibrinoid, and colloid. 2. Non-sulfated acid MPS: It is seen in dermal ground substance. Alcian blue stains metachromatically purple at pH 2.5. 3. Sulfated MPS (chondroitin sulfate is found only in cartilage). Alcian blue stains metachromatically purple at pH 0.5. Other stains for MPS include mucicarmine, aldehyde fuchsin, and colloidal iron.

Stain for Urates De galantha stains urates brown. Fixation in alcohol is necessary.

Stain for Collagen Von Gieson is a stain that stains collagen red.

Stain for Elastic Tissue Elastic fibers are stained black using Verhoeff’s stain, Wiegart’s stain, and acid orcein Giemsa.

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Stains Used in Dermatology  25

Stain for Plasma Cells Methyl Green pyronin is used to stain plasma cells.

Lipid Stains Sudan Black stains triglycerides and cholesterol black. Oil red O stains triglycerides and cholesterol red. It is useful to identify Fabry’s and Gaucher’s disease.

Muscle Masson trichrome is used to stain muscles. It stains red.

Stains for Micro-Organisms Bacterial Stains 1. Brown–Brenn stain is the tissue equivalent of gram stain. 2. Fite-Faraco stain is the tissue equivalent of Ziehl Neelsen for Mycobacterium leprae (refer to Fig. 13.9). 3. Warthin–Starry stain, which is a silver stain, is useful for spirochetes.

Fungal Stains Grocott-Gomori and PAS are the useful stains. Grocott-Gomori stain is a silver stain. It is superior to PAS because it stains only the living fungi, whereas PAS stains both living and dead fungi.

Birefringence Birefringence indicates the property of a substance being doubly refractile, when examined under the microscope with polarized light. Polarized light is the light which has all rays vibrating in one plane. A polarizer, an instrument used to detect this property, has two pieces—one is kept just above the condenser and acts as the polarizer and the other is kept in the eyepiece and acts as the analyzer. If the object is doubly refractile, it appears shiny against dark background. Amyloid, gouty crystals, foreign bodies, and certain lipids such as cholesterol esters in tuberous xanthomas are birefringent. Polarizing microscope is useful in the evaluation of disorders of the hair, for example, trichothiodystrophy.

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4 Definitions in Dermatopathology Hyperkeratosis The thickening of stratum corneum to more than one-third of the total thickness of epidermis is called hyperkeratosis. Orthohyperkeratosis is the term for hyperkeratosis with normal stratum corneum and normal granular layer. It may be either of the basket weave type (Fig. 4.1) as in retention forms of ichthyosis such as ichthyosis vulgaris or of the compact type (Fig. 4.2) as in lamellar ichthyosis and lichen simplex chronicus.

Figure 4.1.  Lamellated hyperkeratosis with hypergranulosis (40×).

Figure 4.2.  Compact hyperkeratosis (10×).

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Definitions in Dermatopathology  27

a

b

Figure 4.3.  (a) Focal parakeratosis and (b) acanthosis (10×).

Parakeratosis Parakeratosis is the retention of nuclei in stratum corneum. It indicates delayed maturation process and altered process of keratinization. Parakeratosis (Fig. 4.3) appears as bluish nuclei within pink stratum corneum. Parakeratosis can be of different types: 1. Focal and scattered as in dermatitis 2. Cap-like, limited to one focus as in lichen nitidus 3. Alternating with orthokeratosis and vertically arranged as in viral warts 4. Alternating with orthokeratosis and horizontally arranged as in actinic keratosis 5. Punctate as in pityriasis lichenoides chronica 6. With polymorphonuclear cells, as in psoriasis 7. In a vertical column, as in cornoid lamella of porokeratosis 8. Penetrating as in perforating disorders such as reactive perforating collagenosis; and 9. Vertical and massive as in epidermolytic hyperkeratosis Note:  Parakeratosis is usually associated with the absence of granular layer; the only exception being a condition called axillary granular keratosis in which parakeratosis is found with normal granular layer.

Acanthosis It implies thickened stratum malpighii (Fig. 4.3), which is seen often with hyperkeratosis, a nonspecific change in most chronic skin diseases. 1. It is seen in epidermal proliferative disorders such as psoriasis, lichen simplex chronicus, lamellar ichthyosis, and epidermolytic hyperkeratosis. 2. It is also seen in many benign skin tumors such as seborrheic keratosis and actinic keratosis. 3. It is seen in all conditions with papillomatosis and pseudoepitheliomatous hyperplasia (discussed in the next page).

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28  Fundamentals of Pathology of Skin

Papillomatosis It is the gross hyperplasia of epidermis, with elongated dermal papillae pushing up the entire epidermis, in the form of finger-like processes. Inflammatory diseases: Verrucous skin lesions such as verrucous tuberculosis, subcutaneous fungal infections, pemphigus vegetans, pyoderma vegetans, milker’s nodule, viral warts (refer to Fig. 20.2; page 209), and acrokeratosis verruciformis of Hopf. Tumors: Seborrheic keratosis (refer to Fig. 22.1; page 242), hypertrophic form of actinic keratosis, some cases of intradermal nevi, epidermal nevi, and nevus sebaceous.

Pseudoepitheliomatous Hyperplasia It is the gross hypertrophy of epidermis resembling squamous cell carcinoma (see page 253).

Hypergranulosis It is an increased thickness of granular layer to more than five layers (Fig. 4.4). Classically, it is seen in viral warts, lichen planus, epidermolytic hyperkeratosis, and lichen simplex chronicus.

Hypogranulosis It is seen in all cases of parakeratosis as mentioned earlier. It is seen with orthokeratosis in ichthyosis vulgaris, which is a specific diagnostic sign.

Figure 4.4.  Wedge-shaped hypergranulosis (40×).

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Definitions in Dermatopathology  29

Epidermal Atrophy It is the decreased thickness of stratum malpighii (to less than five layers). It is seen in the following conditions: 1. Steroid induced 2. Poikilodermas 3. Atrophic lichen planus 4. Lupus erythematosus 5. Scleroderma 6. Lupus vulgaris 7. Lichen sclerosus et atrophicus 8. Progeria 9. Necrobiosis lipoidica diabeticorum 10. Epidermis overlying tumors in dermis such as dermatofibrosarcoma protuberans

Crust Crust, a clinical term, is seen histologically as oozed out fluid with inflammatory cells.

Acantholysis It is the loss of cohesion or loosening (due to loss of intercellular bridges) of keratinocytes (Fig. 4.5).

Figure 4.5.  Acantholysis in Hailey-Hailey disease (40×).

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30  Fundamentals of Pathology of Skin

A. Acantholysis in Benign Conditions 1. Primary acantholysis (without any cell lysis) (a) Pemphigus—all types (refer to Figs 10.2 and 10.4; pages 99 and 101) (b) Hailey–Hailey disease (refer to Fig. 10.5; page 102) (c) Darier’s disease (d) Transient acantholytic dyskeratosis (e) Warty dyskeratoma 2. Secondary to cell degeneration (a) Subcorneal pustular dermatosis (refer to Fig. 10.6; page 103) (b) Viral blisters (herpes simplex and zoster)

B. Neoplastic Acantholysis 1. Actinic keratosis 2. Squamous cell carcinoma

Spongiosis (refer to Fig. 6.1; page 62) It is the accumulation of fluid in between keratinocytes (intercellular edema) in stratum malpighii, causing the intercellular bridges to appear stretched. Cells appear separated and intercellular connections stand out clearly. It is always associated with exocytosis of cells.

Exocytosis (refer to Fig. 6.1; page 62) It refers to migration of cells into epidermis in the presence of spongiosis. The cells are present at all levels, reaching even the stratum corneum, a distinguishing feature from epidermotropism. Exocytosis is seen in spongiotic diseases.

Epidermotropism It refers to the presence of mononuclear cells in epidermis in the absence of spongiosis. The cells are present only in the lower one-third of epidermis and do not reach beyond stratum spinosum. Classically, it is seen in mycosis fungoides (refer to Fig. 27.6; page 297), adult T-cell lymphoma, leukemia, and Langerhans cell histiocytosis (refer to Fig. 27.1; page 290). Note:  Exocytosis is inflammatory, whereas epidermotropism is neoplastic.

Microabscesses They are focal collection of cells either in epidermis or in dermis.

Epidermal Microabscesses 1. Polymorphonuclear microabscesses: Munroe’s type (seen in psoriasis) (refer to Fig. 9.4; page 87) and candida infection 2. Lymphocytic microabscesses: Pautrier microabscess in mycosis fungoides

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Definitions in Dermatopathology  31

Dermal Microabscesses It is seen in dermatitis herpetiformis, some forms of vasculitis (refer to Fig. 12.5, page 123), and infections such as furuncle and cellulitis.

Ballooning Degeneration In ballooning degeneration, cells become swollen with fluid, appear balloon like, with a central nucleus (Fig. 4.6). It is seen in herpes simplex, herpes zoster, and chicken pox.

Reticular Degeneration When ballooning degeneration becomes more severe, the cells rupture and margins fuse to form a reticular network, called reticular degeneration, as seen in herpes zoster and chicken pox. Ballooning degeneration is seen in lower epidermis and is prominent in herpes simplex. Reticular degeneration is seen in upper epidermis and is prominent in herpes zoster.

Necrotic Keratinocytes Cells which undergo sudden cell death are seen as pink bodies with small bluish pyknotic nuclei seen in stratum malpighii (Fig. 4.7). These are seen in erythema multiforme, pityriasis lichenoides et varioliformis acuta, graft versus host disease, and photodermatitis. Note:  Necrotic keratinocytes appear similar to colloid bodies (seen in apoptosis or programmed cell death), which however, are found in dermis and in stratum basale and do not have a central pyknotic nucleus.

Figure 4.6.  Ballooning degeneration (40×).

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32  Fundamentals of Pathology of Skin

Figure 4.7.  Necrotic keratinocytes in PLEVA (40×).

Basal Cell Degeneration It is also called vacuolar degeneration, hydropic degeneration, and liquefaction degeneration. It refers to the appearance of tiny vacuoles in basal cells, leading ultimately to vacuolated appearance and later indistinct basal layer (refer to Figs 8.2–8.4; page 75). 1. Extensive in lichen planus and leads to cleft formation (Max Joseph spaces) 2. Focal in discoid lupus erythematosus 3. Fixed drug eruption 4. Lichen sclerosus et atrophicus 5. Other lichenoid reactions such as secondary syphilis, benign lichenoid keratosis, drug-induced lichenoid reactions, etc. 6. Erythema multiforme 7. Pityriasis lichenoides et varioliformis acuta (PLEVA) 8. Poikiloderma 9. Graft versus host disease 10. Radiation dermatitis Note:  Basal cell degeneration is seen in all interface dermatitis.

Interface Dermatitis It is an inflammatory pattern in which primary pathology is seen at dermoepidermal junction, characterized by basal cell vacuolization, apoptotic keratinocytes (colloid or Civatte bodies), and obscuring of the dermoepidermal junction by inflammatory cells. It is of two types: 1. Interface dermatitis of vacuolar type: It is seen in erythema multiforme and pityriasis lichenoides et varioliformis acuta (refer to Figs 12.6 and 12.7; pages 125 and 126). 2. Interface dermatitis of lichenoid type: It is seen in lichen planus and other lichenoid reactions (refer to Figs 8.2–8.4; page 75).

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Pigment Incontinence It is the dropping of pigment into the upper dermis, where it may be found either free or inside macrophages (melanophages) (Fig. 4.8). It should be distinguished from hemosiderin by the use of Masson Fontana or Perl’s sign. 1. It is seen in all conditions with basal degeneration. 2. It may also be seen in chronic itchy lesions. 3. It is seen in incontinentia pigmenti. 4. It is seen in post-inflammatory pigmentation.

Thickened Dermoepidermal Junction Normally, dermoepidermal junction is seen as a thin pink line with periodic acid-Schiff (PAS). When thickened, it appears band-like, with extensions into dermis. It is a very useful sign for diagnosis of lupus erythematosus (refer to Fig. 11.2; page 112), but is also seen in dermatomyositis.

Figure 4.8.  Pigment incontinence and basal cell degeneration (10×).

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34  Fundamentals of Pathology of Skin

Epidermolytic Hyperkeratosis (Granular Degeneration) (refer to Figs 17.1 and 17.2; page 192) It indicates the combination of the following: 1. Gross hyperkeratosis 2. “Lysed” appearance caused by extensive and severe vacuolation of keratinocytes (hence, the name epidermolytic and the term degeneration) 3. Granular appearance caused by parakeratosis and hypergranulosis It is seen classically in bullous ichthyosiform erythroderma and some types of palmoplantar keratoderma. It is seen incidentally in pityriasis rosea and in some types of epidermal nevus.

Dyskeratosis It indicates abnormal and premature keratinization of individual cells, which appear as deeply pinkish cells with small dark blue nucleus (Fig. 4.9). 1. Acantholytic dyskeratosis: It is seen in Hailey–Hailey disease and Darier’s disease (refer to Fig. 17.5; page 194); transient acantholytic dyskeratosis is seen in corps ronds and grains 2. Neoplastic dyskeratosis: for example, Bowen’s disease, actinic keratosis, and squamous cell carcinoma 3. Genodermatoses such as incontinentia pigmenti

Acantholytic Dyskeratosis It is the combination of acantholysis and dyskeratosis as mentioned earlier; classically, it is seen in Darier’s disease (refer to Fig. 17.5; page 194), Gower’s disease, and warty dyskeratoma. It is seen incidentally in actinic keratosis and squamous cell carcinoma.

Figure 4.9.  Neoplastic dyskeratosis in Bowen’s disease (40×).

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Definitions in Dermatopathology  35

Horn Pearl It denotes the presence of concentric layer of squamoid cells with keratinization in the center (refer to Fig. 23.11; page 256). Squamous eddy is a concentric whorled arrangement of keratinocytes, with incomplete keratinization toward the center; hence the whorl, which is bluish in the periphery, gradually and progressively becomes pinkish toward the center. It is seen in the following conditions. 1. Squamous cell carcinoma 2. Irritated seborrheic keratosis 3. Irritated verruca vulgaris 4. Keratoacanthoma 5. Pseudoepitheliomatous hyperplasia 6. Proliferating trichilemmal cyst

Horn Cysts These are round structures, located within stratum malpighii, with central pink keratin similar to normal stratum corneum, surrounded by keratinocytes (Fig. 4.10). These are the result of endokeratinization, that is, keratinization occurring in stratum malpighii itself, instead of stratum corneum. In contrast to gradual progressive keratinization seen earlier, it is more sudden; bluish whorl suddenly turning pink as it happens in normal epidermis. These are seen in the following conditions: 1. Seborrheic keratosis 2. Basal cell carcinoma 3. Trichoepithelioma 4. Sweat gland carcinoma Note:  Pseudohorn cysts represent structures resembling horn cysts, caused by tangential ­sectioning during processing of biopsy.

Figure 4.10.  Horn cysts in seborrheic keratosis (40×).

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36  Fundamentals of Pathology of Skin

Anaplasia It is an atypical appearance of nuclei (Fig. 4.11), which are irregular in size and shape, staining densely (hyperchromatic), often with mitotic figures; such nuclei are called pleomorphic.

Figure 4.11.  Atypical cells with hyperchromatic nuclei (40×).

Metaplasia It is a condition in which one type of tissue is changed to another; for example, formation of bone in basal cell carcinoma/pilomatricoma.

Follicular Plugging It is characterized by plugs of compact keratin in hair follicle (Fig. 4.12). 1. Classically in discoid lupus erythematosus (cone-shaped plug) 2. Follicular lichen planus (flask-shaped plug) 3. Lichen sclerosus et atrophicus 4. Acne vulgaris 5. Keratosis pilaris 6. Pityriasis rubra pilaris 7. Phrynoderma 8. Follicular seborrheic dermatitis

Cornoid Lamella It is a focal vertical parakeratotic column; classically, it is seen not only in porokeratosis of Mibelli, but also in other types of parakeratosis and in some epidermal nevi.

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Figure 4.12.  Follicular plugging (10×).

Transepidermal Elimination (refer to Figs 19.1 and 19.2) Transepidermal elimination is the elimination of dermal material through channels in epidermis which cause a perforation in epidermis. It is seen in perforating diseases, foreign bodies, and fungal diseases.

Free Grenz Zone It is a clear zone just beneath the epidermis (Grenz means boundary in German). It is seen in the following conditions: 1. Lepromatous leprosy (refer to Fig. 13.7; page 147) 2. Intradermal nevus 3. Lymphocytoma cutis 4. Granuloma faciale 5. Acrodermatitis chronica atrophicans 6. Pseudolymphoma cutis 7. Colloid milium

Thick Bundles of Collagen in Upper Dermis Thick vertical bundles of collagen are the result of chronic scratching and are present in all chronic itchy dermatoses.

Clefts It indicates the small empty spaces.

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38  Fundamentals of Pathology of Skin 1. Clefts in epidermis (a) Bullous diseases such as pemphigus and Hailey–Hailey disease (b) Darier’s disease (c) Warty dyskeratoma 2. Clefts in dermoepidermal junction (a) Lichen planus (Max Joseph spaces) (Fig. 4.13a) and Spitz nevus 3. Clefts in dermis (a) Squamous cell carcinoma (b) Basal cell carcinoma (retraction spaces) (c) Cholesterol clefts in subcutaneous fat necrosis of newborn (d) Gout (e) Amyloidosis (Fig. 4.13b)

Villae These are finger-like extensions into a bulla cavity and lined by a single layer of cells. They are seen in acantholytic bullous diseases such as pemphigus (refer to Fig. 10.3; page 100).

Extravasation of Red Blood Cells Into epidermis: It is seen in pityriasis lichenoides et varioliformis acuta (Fig. 4.14) and lymphomatoid papulosis. In dermis: It is seen in pityriasis rosea, stasis dermatitis, all forms of vasculitis, lymphomatoid papulosis, and Kaposi’s sarcoma.

Dermal Edema It appears as a pale area due to absorption of water during fixation. 1. Erythema multiforme 2. Dermatitis 3. Pityriasis lichenoides et varioliformis acuta 4. Toxic epidermal necrolysis 5. Acute lupus erythematosus 6. Blistering diseases, particularly subepidermal diseases such as herpes gestationis and dermatitis herpetiformis 7. Vasculitis 8. Sweet’s syndrome 9. Insect bite reactions 10. Lichen sclerosus et atrophicus

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(a)

(b) Figure 4.13.  (a) Clefts at dermoepidermal junction (Max Joseph spaces) (10×) and (b) clefts in amyloid deposits (40×).

Vasculitis The following are the criteria for vasculitis (Fig. 4.15): 1. Damage to vessel wall leading to hyalinization of vessel wall 2. Infiltration of vessel ware by inflammatory cells (polymorphs) 3. Deposition of fibrinoid (PAS-positive material composed of fibrin, immunoglobulin, and complement) in and around vessel

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40  Fundamentals of Pathology of Skin

Figure 4.14.  Trapped RBCs seen in pityriasis lichenoides et varioliformis acuta (10×).

4. Extravasation of red blood cells (RBCs) 5. Presence of nuclear dust (remains of nuclei seen as dark blue particles) Note:  It should be distinguished from perivasculitis which includes only accumulation of inflammatory cells around blood vessels without any evidence of damage to vessel wall.

Nuclear Dust (Leukocytoclasis) These are remnants of nuclei seen as bluish particles scattered in dermis. They are seen in all types of leukocytoclastic vasculitis (refer to Fig. 12.4; page 122), Sweet’s syndrome, and erythema nodosum leprosum.

Figure 4.15.  Vasculitis with nuclear dust (40×).

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Amorphous Pink Deposits in Dermis The pink deposits (eosinophilic bodies) in dermis include colloid bodies, fibrinoid in vasculitis, amyloid (Fig. 4.13b), lipoid protienosis, colloid in colloid milium, and porphyria. 1. Colloid bodies: These are pink, homogenous, oval, amorphous bodies of size 7–14 microns, found in lower epidermis as well as in upper dermis. They are seen in all lichenoid reactions, erythema multiforme, and pityriasis lichenoides et varioliformis acuta. 2. Elastoglobes: These are seen in sun exposed areas (clinically normal skin) and are derived from elastic microfibrils. 3. Fibrinoid: It is an eosinophilic, homogenous material seen in leukocytoclastic vasculitis. It is a combination of fibrin, immunoglobulins, and extravasated serum components. It stains with PAS and also with phosphotungstic acid hematoxylin.

Amorphous Blue Deposits Mucin, calcium, solar elastosis, and nuclear dust appear as amorphous blue deposits.

Mucin Deposits These are seen as bluish strands. These are seen in the following conditions: 1. Granuloma annulare 2. Papular mucinosis 3. Scleredema Buschke 4. Reticular erythematous mucinosis syndrome 5. Lupus erythematosus and dermatomyositis 6. Myxedema 7. Follicular mucinosis 8. Neural tumors 9. Metastatic mucinous carcinoma 10. Mucinous sweat gland carcinoma

Calcinosis Cutis (refer to Fig. 24.10; page 265) Calcium can easily be recognized by its dense amorphous nature and dark blue color on hematoxylin and eosin (H&E) stain. Specific stains for calcium include Von Kossa and Alizarin red stains. For details of calcinosis cutis, see page 201.

Brown Deposits 1. Melanin 2. Hemosiderin 3. Gout crystals

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42  Fundamentals of Pathology of Skin 4. Ochronosis (refer to Fig. 14.2; page 165) 5. Acid formazan is formalin–hemoglobin compound formed when ordinary formalin (with pH less than 6) is used instead of buffered formalin. 6. Some fungi called dematiaceous (colored) appear brown, for example, chromoblastomycosis 7. Foreign bodies

Hemosiderin It appears brown, similar to melanin, on H&E stain, but can be stained with Perl’s stain as bluish pigment. It is seen in the following conditions: 1. Stasis dermatitis 2. Progressive pigmented purpura 3. Kaposi’s sarcoma 4. Sclerosing hemangioma (a variant of dermatofibroma)

Granuloma Granuloma is defined as a reaction of mononuclear phagocytic system (previously called reticulo-endothelial system) to a poorly soluble or a partially soluble antigen characterized by focal collection of inflammatory cells (macrophages, polymorphs, eosinophils, lymphocytes, macrophages, epithelioid cells, giant cells, plasma cells, etc.), with connective tissue and vessels. It should be recognized that macrophage or one of its derivative cells (epithelioid cell) is the primary cell of granuloma. A histiocyte is a macrophage which is participating (fixed) in the granuloma.

Necrobiosis It denotes the presence of focal alteration (also called erroneously as degeneration) of collagen, which appears pale, disordered, and washed out. The altered collagen is surrounded by palisading histiocytes and hence it is called palisading granuloma. Classically, it is seen in granuloma annulare, necrobiosis lipoidica, rheumatoid nodule, syphilis, and foreign body reactions.

Tuberculoid Granuloma It is characterized by the presence of focal collection of epithelioid cells, lymphocytes, and Langhan’s giant cells with or without necrosis (Fig. 4.16). Presence of caseation is not a prerequisite for the diagnosis of tuberculoid granuloma, for example, cutaneous tuberculosis, tuberculoid leprosy, some fungal granulomas such as sporotrichosis, cutaneous leishmaniasis, foreign body granulomas such as silicon, zirconium, aluminum, late syphilis, acne rosacea, lupus miliaris disseminatus et faciei.

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Figure 4.16.  Tuberculoid granuloma (10×): central pinkish epithelioid mass of cells surrounded by bluish lymphocytes.

Caseation Necrosis It is a homogenous pale amorphous mass in the center of granuloma. Previously, it was regarded as specific for tuberculosis, but it is now considered synonymous with other types of necrosis such as ischemic necrosis and coagulation necrosis.

Sarcoid Granuloma (refer to Figs 13.10 and 13.11; page 151) It is similar to a tuberculoid granuloma, but lacks the peripheral cuffing of lymphocytes and hence is called naked granuloma. Classically, it is seen not only in sarcoidosis, but also in certain other infections such as syphilis, fungal granulomas and foreign bodies such as zirconium and silicon.

Suppurative Granuloma (Mixed Cell Granuloma) Mixed cell granuloma is characterized by an admixture of polymorphs, macrophages, eosinophils, plasma cells, and lymphocytes. Polymorphs may be present as focal abscesses. It is seen in fungal granuloma, atypical mycobacterial infection, cutaneous leishmaniasis, malakoplakia, botryomycosis, hidradenitis suppurativa, acne vulgaris, and foreign bodies such as cactus.

India Filing (Single Filing) of Cells These are cells in single file in between collagen fibers. 1. Granuloma annulare 2. Lymphocytoma cutis

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Figure 4.17. Secondaries in skin: cells extending in between collagen fibers “India filing pattern” (10×).

3. B-cell lymphoma 4. Congenital melanocytic nevus 5. Metastatic carcinoma particularly from carcinoma breast (Fig. 4.17)

Dermal Atrophy It is indicated by the loss of collagen and elastic fibers.

Invisible Dermatosis (Normal Appearing Skin) These are diseases with definite clinical features, but with very subtle and often insignificant histologic features (refer to Chapter 28; page 308).

Pseudomalignancy It is a condition in which lesions show benign clinical picture and simulate malignancy histologically. 1. Pseudocarcinoma (a) Keratoacanthoma (b) Bowenoid papulosis (c) Proliferating trichilemmal tumor (d) Irritated seborrheic keratosis 2. Pseudomelanoma (Spitz nevus) 3. Pseudolymphoma (lymphomatoid papulosis) 4. Pseudosarcoma (nodular fasciitis)

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Encapsulated or Sharply Demarcated Tumors 1. Pilomatricoma 2. Eccrine poroma 3. Clear cell hidradenoma 4. Eccrine spiradenoma 5. Neurilemmoma 6. Neurofibroma 7. Angioleiomyoma 8. Lipoma

Spindle Cell Tumors These tumors are composed of spindle-shaped tumor cells. 1. Neurofibrosarcoma 2. Leiomyosarcoma 3. Atypical fibroxanthoma 4. Spindle cell carcinoma 5. Spindle cell melanoma 6. Angiosarcoma

Round Cell Tumors These tumors are composed of small, uniform round cells. 1. Lymphoma 2. Leukemoid infiltrate 3. Metastatic oat cell carcinoma of lung 4. Merkel cell tumor 5. Metastatic Ewing’s sarcoma

Clear Tumors These tumors are composed of pale or clear cells. 1. Clear cell acanthoma 2. Clear cell hydradenoma 3. Clear cell syringoma 4. Metastatic renal cell carcinoma 5. Trichilemmoma

Tumors Arising from Basaloid Cells 1. Basal cell carcinoma 2. Seborrheic keratosis (Fig. 4.18) 3. Sebaceous tumors such as sebaceous adenomas

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Figure 4.18.  Basaloid cells (40×).

4. Follicular tumors such as pilomatricoma and trichoepithelioma 5. Sweat gland tumor: eccrine poroma

Pagetoid Growth or Paget’s Phenomenon It is a group of pale cells found in epidermis, amidst keratinocytes. 1. Paget’s disease 2. Pagetoid Bowen’s disease 3. Pagetoid malignant melanoma 4. Pagetoid reticulosis (Woringer-Kolopp disease)

Borst–Jadassohn Phenomenon This phenomenon is the presence of atypical cells in groups or clones amidst normal keratinocytes. The following tumors show this phenomenon: 1. Clonal seborrheic keratosis (Fig. 4.19) 2. Clonal Bowen’s disease 3. Borst–Jadassohn type of intraepidermal epithelioma 4. Eccrine poroma

Cells Different types of cells and their appearance are shown in Figure 4.20.

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Figure 4.19.  Borst–Jadassohn showing clonal proliferation of atypical cells in groups amidst normal keratinocytes (10×).

Polymorphonuclear Cells The polymorphonuclear cell has a size of 10 microns with light pink cytoplasm, which contains granules and a multilobed nucleus—the lobes appear as blue black dots amidst white back ground or “salt and pepper” in the dermis. 1. Epidermal microabscesses or pustules: When in epidermis, polymorphs form microabscesses (a) Psoriasis (Fig. 4.21) (b) Impetigo (c) Dermatophytosis and candidal infection (d) Scabies (e) Transient neonatal pustular melanosis (f) Pyoderma vegetans (g) Subcutaneous fungal infections (h) Necrolytic migratory erythema (i) Pustular vasculitis (j) Halogenoderma

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Langhan's type giant cell

Foreign-body giant cell Touton giant cell

Mast cell

Histiocyte Eosinophil

Fibroblast Polymorph

Lymphocyte

RBC

Plasma cell

Figure 4.20. Schematic diagram of different cells.

2. Dermal polymorphonuclear infiltrates (Fig. 4.22) (a) Leukocytoclastic vasculitis (b) Sweets syndrome (c) Dermatitis herpetiformis

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Figure 4.21. Large unilocular pustule with accumulation of neutrophils in stratum ­corneum (scanner).

Figure 4.22. Dermal polymorphonuclear infiltrate (40×).

(d) Erythema nodosum in early stages (e) Erythema nodosum leprosum (f) All suppurative granuloma (g) Ruptured cyst (h) Infectious processes: furuncle and cellulitis (i) Granulocytic leukemia

Eosinophils These are 12 microns in size with intracytoplasmic granules; cytoplasm appears red (because of its red granules), with an indented or bilobed nucleus. Any red cell is an eosinophil.

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50  Fundamentals of Pathology of Skin 1. Epidermal eosinophilic infiltrate: It is seen in eosinophilic spongiosis in pemphigus, bullous pemphigoid, insect bite reactions, dermatophyte infections, incontinentia pigmenti, and eosinophilic pustular folliculitis. 2. Dermal eosinophilic infiltrate (a) Atopic dermatitis (b) Erythroderma, particularly atopic type (c) Parasitic infestations such as scabies, onchocerciasis, and larva migrans (d) Allergic granulomatosis of Churg–Strauss (e) Eosinophilic fasciitis (f) Bullous pemphigoid and herpes gestationis (g) Granuloma faciale (h) Granuloma annulare ±± Mycosis fungoides ƒƒ Histiocytosis X-eosinophilic granuloma ƒƒ Urticaria and urticaria pigmentosa

Plasma Cells Plasma cell appears as a cell of 10 microns, with amphophilic cytoplasm, ectopic nucleus, and coarse chromatin. Cart wheel nucleus is not usually recognizable. Because of the ectopic location of the nucleus, plasma cells appear oddly placed; some cells appear very close to each other (when the two nuclei are on apposing ends of the cells); others appear far from each other at places where the nuclei are on the opposing ends of the cells. Predominant plasma cell infiltrate is found in the following conditions: 1. Infections such as syphilis, rhinoscleroma, rhinosporidiosis, borreliosis, leishmaniasis, and some fungal infections 2. Mucosal diseases such as plasma cell cheilitis and balanitis, oral lichen planus, actinic cheilitis 3. Chronic folliculitis and folliculitis decalvans 4. Necrobiosis lipoidica 5. Granuloma faciale 6. Pseuodolymphoma cutis 7. Lupus erythematosus and scleroderma 8. Tumors such as actinic keratosis, squamous cell carcinoma, syringocystadenoma papilliferum, and multiple myeloma Note:  Russell bodies are intense red bodies, which consist of immunoglobulins , and are found in plasma cells, at times filling them completely.

Lymphocyte It is a round cell with a large dark nucleus, which seems to fill the entire cell, leaving only a rim of cytoplasm in the periphery. A blue cell is a lymphocyte (Fig. 4.23).

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a

c

b

Figure 4.23.  Cells (40×): (a) lymphocytes, (b) macrophages, and (c) RBCs.

It is difficult to distinguish a lymphocyte from monocyte in histological sections and hence the term lymphomononuclear infiltrate is used. Immunomarkers are needed to distinguish the two cell types. Leukocyte common antigen is a common immunomarker used for preliminary identification of lymphocyte, whereas antitrypsin and antichymotrypsin identify monocyte. Lymphocytic or mononuclear infiltrates are so common that it is difficult to provide a list; all inflammatory diseases may have a mononuclear infiltrate. Note:  It is important to note that in skin, paradoxically, acute diseases often have an infiltrate of lymphocytes, which are otherwise considered as cells of chronic inflammation.

Macrophage It is a cell with large pale nucleus, with well-defined nuclear membrane and abundant cytoplasm (Fig. 4.23). The nucleus is called vesicular because of clear appearance (like a vesicle). It is derived from monocyte and the hallmark of macrophage is its motility and phagocytic function. However, when in a granuloma, it is fixed to the tissue and is called a histiocyte. Macrophages under the influence of lymphokines are transformed into epithelioid cell, which has greater phagocytic activity but less motility. Macrophages with melanin are called melanophages. Macrophages are seen in chronic inflammations such as lepromatous leprosy, leishmaniasis, fungal infections such as histoplasmosis, donovanosis, all xanthomas, and juvenile xanthogranuloma.

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52  Fundamentals of Pathology of Skin

Epithelioid Cells These cells have a large vesicular nucleus with well-defined nuclear membrane, and pale pink cytoplasm (Fig. 4.16). Cell margins are indistinct and the cells appear fused as a symplasmic mass (as in epithelial cells). The term epithelioid cell is never used in singular. Epithelioid cells are seen in all tuberculoid and sarcoid granulomas. Note:  The term epithelioid is also used to describe certain tumor cells which are large and have a similar (epithelium like) appearance, for example, epithelioid melanocytes in melanoma, epithelioid histiocytoma, epithelioid sarcoma, spindle and epithelioid cell nevus of Spitz.

Foam Cells These are macrophages filled with lipids. These are seen in the following conditions: 1. Lepromatous leprosy 2. Xanthomas 3. Xanthogranuloma 4. Necrobiotic xanthogranuloma 5. Panniculitis, particularly of Weber Christian type 6. Histiocytosis X 7. Atypical fibroxanthoma 8. Involuting intradermal nevi 9. Tumors such as atypical fibroxanthoma and sebaceous gland tumors

Giant Cells These cells are formed when several cells are fused together. 1. Epidermal giant cell is seen in herpes simplex and herpes Zoster, and Bowen’s disease. 2. Melanocytic giant cell is seen in intradermal nevi, spitz nevus, and melanoma. 3. Tumor giant cell is seen in the following cells: (a) Fibrous tumors: Dermatofibroma, malignant fibrous histiocytoma, giant cell tumor of tendons, and atypical fibroxanthoma. (b) Lymphomas: Reed Sternberg cell in Hodgkin’s disease and lymphomatoid papulosis. (c) Fat cell: Floret giant cell in pleomorphic lipoma. 4. Foreign-body giant cell is formed by fusion of many macrophages as in foreign body granuloma and suppurative granuloma. 5. Langhan’s giant cell (Fig. 4.24) is formed by fusion of many epithelioid cells, formed under the influence of good host cell-mediated immunity seen in tuberculoid granulomas. 6. Endothelial giant cell is seen in cytomegalovirus infection. 7. Touton giant cell—a cell with a central foamy cytoplasm (due to the presence of lipids), surrounded by floret or wreath-shaped arrangement of nuclei. It is found in xanthomas and juvenile xanthogranuloma.

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Figure 4.24. Langhan’s giant cell with horseshoe-shaped arrangement of nuclei (40×).

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5 Approach to Diagnosis 1. Diagnosis in dermatopathology is often considered difficult by general pathologists, which is partly because of the lack of familiarity of the pathologist with the subject of dermatology, and also because of the plethora of descriptive terms that abound in the speciality. Most importantly, unlike other branches of pathology, the description of gross pathology of the lesion in skin is done by the clinician himself, not by the pathologist. And finally, most inflammatory dermatoses are reaction patterns and are not histologic entities. They are processes which need to be explained to fit into the clinical manifestations that they cause. These reasons explain why dermatologists need to learn dermatopathology. 2. It should be appreciated that the diagnosis of inflammatory diseases is the toughest, whereas diagnosis of tumors is the easiest. The diagnosis of granuloma is of intermediate difficulty. This is because inflammatory diseases are clinicopathological reaction patterns as explained earlier. 3. The concept of reaction patterns in dermatopathology has enabled the formulation of algorithms for diagnosis. Pinkus was the first to suggest an approach based on tissue reactions in inflammatory dermatoses. Later, it was further delineated by Clark and finally, perfected by Ackerman. 4. While interpreting a skin biopsy, particularly in inflammatory diseases, it should be emphasized that the scanner and low-power views are more important than high-power view, which is used to identify only the cellular morphology. 5. Naked-eye examination of a slide can be of some help too, in diseases such as seborrheic keratosis and keratoacanthoma. 6. Walter Burgdorf said just as in love and war, everything is fair in studying a slide. So a histologist should make good use of all the information available to him, in interpreting the slide. 7. Proper description of findings using specific terms helps in the interpretation. 8. Although each pathologist has his own style of diagnosis, it is good for a beginner to be systematic and follow a slide downwards from stratum corneum, right down to subcutis, to localize the area of most significant pathology. 9. Sutton’s law states go where the money is. Likewise, while interpreting a slide go where the pathology is—epidermis/dermis/subcutis. In other words, identify the most prominent locus of pathology, also called center of gravity of the lesion!!! 10. The next step is to determine the basic type of pathology—inflammation/tumors or degeneration.

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Approach to Diagnosis  55 11. In certain diseases, changes are too subtle and may be “invisible” to the untrained eye!! 12. Then on, one has to follow one of the following patterns of inflammation in case of inflammatory disorders.

Weedon’s Scheme Tissue Reactions 1. Major patterns (a) Eczematous (spongiotic) reactions (b) Psoriasiform reactions (c) Lichenoid reactions (d) Vasculopathies (e) Granulomatous reactions (f) Vesiculobullous reactions 2. Minor patterns (a) Epidermolytic hyperkeratosis (b) Acantholytic dyskeratosis (c) Cornoid lamella (d) Papillomatosis (e) Eosinophilic cellulitis (f) Transepidermal elimination 3. Cellular patterns (a) Superficial perivascular dermatitis (b) Superficial and deep perivascular dermatitis

Ackerman’s Schema It includes nine types of reaction patterns (Fig. 5.1): 1. Superficial perivascular dermatitis 2. Superficial and deep perivascular dermatitis 3. Vasculitis 4. Intraepidermal bullous diseases 5. Subepidermal bullous disorders 6. Nodular and diffuse dermatitis 7. Fibrosing dermatitis 8. Folliculitis and perifolliculitis 9. Septal and lobular panniculitis Another scheme based on the reaction levels in dermatopathology has been proposed. Four anatomical levels have been identified in the book by Maize et al.: 1. Epidermis 2. Epidermis, dermoepidermal junction, and papillary dermis 3. Reticular dermis and subcutis 4. Adnexa

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56  Fundamentals of Pathology of Skin

(a)

(b)

(c)

(d)

(e)

(f)

(g)

(h)

(i)

Figure 5.1. Reaction patterns of Ackerman’s schema. (a) Superficial perivascular dermatitis, (b) superficial and deep perivascular dermatitis, (c) vasculitis, (d) intraepidermal bullous disorder, (e) subepidermal bullous disorder, (f) nodular and diffuse dermatitis, (g) fibrosing dermatitis, (h) folliculitis and perifolliculitis, and (i) septal and lobular panniculitis.

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Approach to Diagnosis  57 Based on the reaction levels and combining different features of all the schemes mentioned earlier, the author proposed the following new scheme:

A. Epidermal Reactions Major patterns 1. Psoriasiform 2. Spongiotic 3. Vesiculobullous Minor patterns 1. Epidermolytic hyperkeratosis 2. Acantholytic dyskeratosis 3. Cornoid lamella 4. Papillomatosis 5. Atrophy

B. Reaction Patterns: Dermoepidermal Junction Major reaction pattern: It includes interface dermatitis: 1. Lichenoid 2. Vacuolar Minor reaction pattern: It includes transepidermal elimination.

C. Reaction Patterns: Dermal 1. Granulomatous reaction 2. Vasculopathic reaction 3. Fibrosing reactions 4. Subepidermal bullous diseases 5. Superficial perivascular inflammations 6. Superficial and deep perivascular inflammations

D. Reaction Patterns: Subcutis 1. Septal panniculitis 2. Lobular panniculitis

E. Reaction Patterns: Appendageal 1. Folliculitis 2. Perifolliculitis

F. Reaction Patterns: Invisible Dermatoses

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58  Fundamentals of Pathology of Skin

Approach to Histologic Interpretation and Diagnosis Systematic clinical approach in dermatology includes identification of primary lesion, secondary lesion, arrangement, localization and distribution of lesions, morphological diagnosis, and finally clinical/etiological diagnosis. Similarly, histopathological approach includes identification of different types of lesions. The following examples explain this concept.

Example 1 Step 1: Primary lesion: basal cell degeneration

Step 2: Secondary lesion: colloid body

Step 3: Arrangement: saw tooth appearance with infiltrate hugging the basal layer

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Approach to Diagnosis  59 Step 4: Morphological diagnosis: interface dermatitis

Step 5: Final histological diagnosis: lichen planus

Example 2 Step 1: Primary lesion: granuloma Step 2: Type of granuloma: epithelioid granuloma Step 3: Cause of granuloma: tuberculoid Hansen’s disease

Example 3 Step 1: Primary lesion: vasculitis Step 2: Type of vasculitis: leukocytoclastic vasculitis Step 3: Final diagnosis after direct immunofluorescence: Henoch–Schonlein purpura

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60  Fundamentals of Pathology of Skin In any histological diagnosis, it is always must to remember the following points: 1. Biology is consistent, but morphology is variable. It is important to explain the morphological variables based on consistent biological principles. It is also important to understand that different inflammatory dermatoses are interrelated, as shown in Figure 5.2. 2. Process should be explained. 3. Approach should be systematic. Do not indulge in snap diagnosis 4. Always ask what else can this be? Be your own devil’s advocate! Power of observation is everything that matters. The following passage was written by Verginia Wolf about Leo Tolstoy whose power of observation and description made him the most successful novelist of the twentieth century: Nothing seems to escape from him. Every twig, every feather sticks to his magnet. He notices the blue or red of a child’s frock; the way a horse shifts its tail; the sound of a cough; what his infallible eye reports, his infallible brain refers to something hidden in the character. We feel we have been sat on a mountain top and had a telescope put into our hands. Everything is astonishingly and absolutely clear.

Interrelation between Different Skin Diseases It is important to understand that different reaction patterns and diseases seem to be interrelated, for example, seborrheic dermatitis is a spongiotic dermatitis which is related to psoriasis through seborrheic psoriasis. Lichen planus and lupus erythematosus are interrelated. This is particularly so in inflammatory diseases (Fig. 5.2). Act ker

HH dis

Warty dys

Dariers

P.Vulgaris

TEN-SJS

Bull.LP P.eryt

LE

Pseudopelade

Atro.lp

Urticaria Ecz.D

Lymphoma

Ac LE

Hyp.LP

LSA

Scleroderma

MF

EMF

LP

Ben Lich Ker

Fol.LP

P. foliaceus

Vasculitis

Seb derm

Paraps

Psoriasis

Pust ps

Ly.Granulomatosis

Gr.vasculitis

SCPD Granulomatous disorder

Figure 5.2.  Interrelation between different skin diseases.

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6 Spongiotic Dermatosis Eczematous tissue reaction (spongiotic dermatitis) is characterized by the following: 1. Spongiotic vesicles (Fig. 6.1) 2. Exocytosis of inflammatory cells 3. Parakeratosis The above-mentioned changes are spotty or focal. 4. Dilated blood vessels in upper dermis

Spongiotic Diseases Spongiotic diseases are varied in their etiology and clinical manifestations. Histologically, they are classified as per the cell type associated with spongiosis as below.

Classification of Spongiotic Diseases 1. Lymphocytic spongiosis: It is a classic type with lymphocytic exocytosis (a) All forms of dermatitis (b) Superficial fungal infections: dermatophytes and candida (c) Pityriasis rosea (d) Pityriasis lichenoides et varioliformis acuta (e) Erythema multiforme (f) Insect bite reactions 2. Eosinophilic spongiosis: Spongiosis with eosinophilic exocytosis is seen in many bullous diseases such as pemphigus, pemphigoid, herpes gestationis, insect bite reactions, dermatophyte infections, and incontinentia pigmenti 3. Spongiform pustules: Spongiosis accompanied with polymorphs [e.g., psoriasis (Kogoj), candidiasis, geographic tongue, halodermas, and subcutaneous fungal infections] 4. Miliarial spongiosis: Spongiosis in acrosyringium (e.g., miliaria rubra) 5. Follicular spongiosis: Spongiosis in hair follicle (e.g., eosinophilic pustular folliculitis, seborrheic dermatitis, follicular eczema)

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62  Fundamentals of Pathology of Skin

b a

c d Figure 6.1.  (a) Focal spongiotic blister with (b) exocytosis of lymphocytes, (c) dermal edema, and (d) perivascular infiltrate (10×).

Clinicopathological Correlation in Spongiotic Diseases Scaling: parakeratosis Vesicle: spongiosis Erythema: vasodilatation

Features of Acute Dermatitis • Spongiosis • Parakeratosis • Exocytosis • Upper dermal edema • Vasodilatation • Perivascular mononuclear infiltrate in upper dermis Features of Chronic Dermatitis As dermatitis becomes chronic, • Spongiosis becomes less prominent and may even be difficult to find • Hyperkeratosis, acanthosis, and elongation of rete become more prominent • Dermal edema is replaced by fibrosis • With prolonged scratching, elongated fibers of collagen running vertically in upper dermis are seen

Note:  The four histological signs that suggest severe itching are as follows: • Excoriation in epidermis • Psoriasiform hyperplasia • Thick vertically running collagen bundles in upper dermis • Papillomatosis

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Spongiotic Dermatosis  63 Figure 6.2 and Table 6.1 show changes in dermatitis as it evolves from acute through subacute to chronic stages. Table 6.1. Clinical and Histological Signs of Dermatitis in Different Stages Stage

Clinical Picture

Histology

Acute

Vesicle and crust

Spongiosis, dermal edema, and vasodilatation

Subacute

Scale, change in color

Parakeratosis due to altered keratinization

Chronic

Lichenification (thickening and pigmentation of skin)

Thickening of stratum malpighii

A

B

C

D

E

Time Figure 6.2.  Schematic diagram of evolutionary stages of spongiotic dermatitis: (A) initial perivascular infiltrate; (B) papillary dermal edema and spongiosis with microvesicle formation; (C) parakeratosis with (D) progressive epidermal hyperplasia; and (E) chronic lesions showing vertically oriented fibrosis of dermal papilla with hyperkeratosis.

Special Features of Some Types of Dermatitis It is generally difficult to distinguish between different types of dermatitis, but some clues are often helpful.

Atopic Eczema Atopic eczema (Fig. 6.3) is usually chronic. Epidermis shows more acanthosis than psoriasiform hyperplasia, unlike other chronic dermatitis. Mast cells and eosinophils may be found in dermis.

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64  Fundamentals of Pathology of Skin

Figure 6.3.  Atopic dermatitis: 10× view showing mild hyperkeratosis, prominent acanthosis, and mild elongation of rete ridges.

Note:  A variant called dermal pattern of atopic eczema shows minimal epidermal changes. Dermis shows thick-walled blood vessels surrounded by dense infiltrate of mononuclear cells.

Seborrheic Dermatitis Seborrheic dermatitis shows features of both spongiotic dermatitis and psoriasiform hyperplasia in different types of lesions. Involvement of follicular and parafollicular epidermis and presence of polymorphs in epidermis are useful clues. 1. Follicular lesions (a) Parakeratosis occurs adjacent to the follicle (known as shoulder parakeratosis). (b) A follicular plug is seen within hair follicle (c) Follicular spongiosis is seen in infundibulum and adjacent epidermis (d) There is a dense mononuclear perifollicular infiltrate, which may involve the hair follicle 2. Non-follicular dry scaly lesions: These lesions show psoriasiform hyperplasia, with a scale—crust of polymorphonuclear cells 3. Non-follicular oozing lesions: In these lesions, spongiotic dermatitis as described earlier is seen

Stasis Dermatitis 1. Epidermal features of spongiotic dermatitis 2. Dermis shows numerous dilated, thick-walled blood vessels, with prominent endothelial cells and dermal fibrosis; sometimes cells may form lobular aggregates (glomeruloid proliferation) 3. Extravasated erythrocytes with hemosiderin deposition are common Note:  These changes in stasis dermatitis may be confused with early Kaposi’s sarcoma.

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Spongiotic Dermatosis  65

Nummular Eczema Corresponding to the clinical feature of pinpoint vesicle, one sees multiple, irregularly placed spongiotic vesicles of different sizes, giving an untidy appearance to the epidermis.

Dyshidrotic Eczema 1. Spongiotic blisters are large due to fusion of several smaller blisters. 2. The roof of the blister is thick due to the compact stratum corneum of palm and soles. Differential diagnosis: Pustular psoriasis of palms and soles—shows unilocular blisters with polymorphonuclear cells, in contrast to mononuclear cells in dyshidrotic eczema. Note:  Dermatophytosis: Always perform PAS stain to rule out dermatophytosis.

Autosensitization (Id Eruption) It shows features of acute dermatitis. Eosinophils may be seen in dermatitis.

Lichen Simplex Chronicus (Fig. 6.4) 1. Compact hyperkeratosis 2. Diffuse parakeratosis 3. Acanthosis with suprapapillary thickening (instead of thinning as in psoriasis) 4. Focal irregular hypergranulosis

Figure 6.4.  Lichen simplex chronicus showing massive hyperkeratosis, acanthosis, and irregular elongation of rete ridges (10×).

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66  Fundamentals of Pathology of Skin 5. Spongiosis is not prominent; usually small and may be difficult to find 6. Exocytosis of lymphocytes is not prominent 7. Irregular elongation of rete which are pointed (unlike regular and club-shaped rete in psoriasis) 8. Sebaceous gland and hair follicles become solid, filled with epidermoid plugs, the so-called alarm reaction 9. Thick vertical elongated collagen bundles in dermis (due to scratching) 10. Lymphomononuclear infiltrate around superficial blood vessels 11. Thick-walled blood vessels in upper dermis

Prurigo Nodularis It is a variant of lichen simplex chronicus manifesting with nodules. 1. Irregular epidermal hyperplasia 2. Focal dermal fibrosis 3. Inflammatory infiltrate of lymphocytes, eosinophils, and mast cells 4. Thickened collagen in reticular dermis

Irritant Contact Dermatitis 1. Large spongiotic blister with polymorphs 2. Necrosis of keratinocytes 3. Pustule formation In chronic irritant reactions, psoriasiform hyperplasia is seen.

Dermal Contact Dermatitis It is seen in dermatitis due to neomycin and nickel, and chronic photosensitizing dermatitis. 1. Acanthosis and parakeratosis 2. Dense, nodular mononuclear pseudolymphoma 3. Atypical cells may be seen

infiltrate

around

vessels—may

mimic

Photosensitizing Dermatitis 1. Acute type: It is similar to spongiotic dermatitis. However, the infiltrate extends into mid-dermis and even deep dermis. Dermal edema is prominent. Note:  Dyskeratotic keratinocytes, referred to as sunburn cells, are present in sunburn reaction. 2. Chronic type: Actinic reticuloid is a dense nodular mononuclear infiltrate with occasional atypical cells are seen, an example for pseudolymphoma.

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Spongiotic Dermatosis  67

Polymorphic Light Eruption It may show different histological features depending on the type of lesions. 1. Spongiotic dermatitis and upper dermal edema in a vesicular lesion 2. Dense dermal lymphoid infiltrate in a plaque lesion with localization around appendages. (One of the five “L”s, see page 115)

Erythroderma (Exfoliative Dermatitis) Erythroderma is a reaction pattern triggered by several causes. Histological signs of erythroderma are often nonspecific and are those of dermatitis—hyperkeratosis, parakeratosis, acanthosis, and psoriasiform hyperplasia. Identification of the cause is often difficult on histology. Multiple biopsies and clinical correlation are needed to identify the underlying cause. Careful study may reveal certain clues to the underlying etiology: 1. Spongiosis suggests dermatitis 2. Atypical mononuclear cells in epidermis in cutaneous T-cell lymphoma 3. Superficial cleft/blister in pemphigus foliaceus 4. Eosinophils in dermis in drug-induced and atopic erythroderma 5. Psoriasis which has gone for exfoliation may show only features of dermatitis

Approach to Diagnosis of Spongiotic Disorders 1. First step is to determine the presence of spongiosis. 2. Identify the type of spongiosis—epidermal, follicular, or acrosyringeal. 3. Identify the predominant type of cell—lymphocytes, eosinophils, and polymorphs. 4. Identify the associated features and follow the clues in Table 6.2. Note:  In all cases of spongiotic dermatitis, clinical correlation is a must for arriving at a proper diagnosis.

Table 6.2.  Summary of Spongiotic Dermatitis Disease

Histopathological Clues

Irritant contact dermatitis

Necrosis of keratinocytes and neutrophils in epidermis

Allergic contact dermatitis

Spotty spongiosis and vesiculation at different horizontal and vertical levels, in an “ordered” pattern; exocytosis; psoriasis form hyperplasia in chronic lesions; superficial dermal edema

Nummular dermatitis

Similar to allergic contact dermatitis but more disorderly

Seborrheic dermatitis

Scale crust and spongiosis localized to follicular ostia

(Continued)

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68  Fundamentals of Pathology of Skin Table 6.2.  (Continued) Disease

Histopathological Clues

Atopic dermatitis

More acanthosis than psoriasiform hyperplasia; prominence of vessels in the papillary dermis; eosinophils, and mast cells in dermis

Pompholyx

Vesiculation with peripheral displacement of acrosyringia. Thick overlying stratum corneum

Stasis dermatitis

Mild spongiosis only; proliferation of superficial dermal vessels; extravasation of RBCs and hemosiderin in dermis

Autosensitization

Spongiosis; edema of papillary dermis; activated lymphocytes often present

Pityriasis rosea

Focal mound-like parakeratosis; small spongiotic vesicles, lymphocyte exocytosis; extravasation of RBCs in papillary dermis; dry dermatosis with spongiotic vesicle

Light reactions

Mild spongiosis; superficial and deep perivascular dermal inflammation; scattered “sun burn cells” in phototoxic lesions

Dermatophytoses

Neutrophils in stratum corneum; “sandwich sign”; spongiotic vesicles may form on palms and soles

Arthropod bites

Spongiotic vesicles containing eosinophils; superficial and deep dermal inflammation with many eosinophils

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7 Reactive Erythemas Reactive erythemas are clinical reactions manifesting with erythema either fixed or migratory. In majority of cases of reactive erythemas, typical histological picture is seen in early evolving lesions.

Urticaria It is dermal edema, with few eosinophils, lymphocytes, polymorphonuclear cells, and mast cells. Dermal edema is identified by a pale appearance of dermis in which cells are located wide apart. Note:  Urticarial vasculitis refers to the presence of leukocytoclastic vasculitis in a clinical session of urticaria (refer to Fig. 12.1; page 120).

Erythema Multiforme (EMF) It is an example of interface dermatitis of vacuolar type (Fig. 7.1).

Figure 7.1.  Erythema multiforme: high-power view showing interface dermatitis of vacuolar type with perivascular lymphocytic infiltrate (40×).

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70  Fundamentals of Pathology of Skin

Figure 7.2.  EMF: low-power view showing extensive vacuolar degeneration of keratinocytes causing epidermal secondary acantholysis and dermal edema (10×).

Epidermal changes include the following: 1. Spongiosis/intraepidermal vesicle 2. Vacuolization of keratinocytes at all levels including basal layer (Fig. 7.2) 3. Necrotic keratinocytes in stratum malpighii 4. Exocytosis of mononuclear cells Dermal changes include the following: 1. Edema: Edema may be so intense that the epidermis is lifted passively by the pressure of the accumulated fluid, called Druckblase in German or pressure blister 2. Perivascular lymphocytic infiltrate 3. Extravasation of red blood cells (RBCs) Though EMF is often classified into epidermal and dermal types, both types are often coexistent, depending on the type of lesion biopsied. Note:  There is a spectrum of histological changes in urticaria—EMF—vasculitis (Table 7.1). The changes involved are edema (urticaria), vasodilatation, edema and extravasation of RBCs (EMF) ending in vessel wall damage in vasculitis (purpura).

Table 7.1.  Clinicopathological Correlation of Different Types of Lesions in Reactive Erythemas Lesion

Pathological Change

Urticaria

Edema of dermis; mild vasodilatation; minimal cellular infiltrate

Angioedema

Edema of subcutis and mucosae; mild vasodilatation; minimal cellular infiltrate

Erythema (viral/drug)

Vasodilatation of blood vessels with perivascular cellular infiltrate

Purpura (vasculitis)

Vasodilatation, extravasation of RBCs, infiltration of inflammatory cells into vessel wall, necrosis of vessel wall, fibrinoid deposition

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Reactive Erythemas  71 In EMF too, there is a clinical and histological spectrum of changes as mentioned in the box below. Clinical and Histological Spectrum of Changes in EMF • Macular lesions show dermal changes. • Epidermal changes are prominent in bullous lesions. • Target lesion shows mixed changes which are zonal—the central dark area showing epidermal features, and periphery showing dermal features. • Toxic epidermal necrolysis/Stevens–Johnson syndrome shows similar changes as in EMF, but epidermal necrosis is more prominent. Dermal infiltrate is sparse.

Differential Diagnosis 1. Pityriasis lichenoides et varioliformis acuta and EMF mimic each other both clinically and histologically. Table 7.2 helps to differentiate the two conditions. 2. Fixed drug eruption: Acute lesions of fixed drug eruption may mimic EMF. However, fixed drug eruption shows presence of a mixed infiltrate of polymorphs, eosinophils, and lymphocytes. The infiltrate extends to mid-dermis and sometimes, lower dermis. Pigment incontinence is more prominent. 3. Occasionally, targeted lesions may occur in bullous pemphigoid and herpes gestationis. In such cases, direct immunofluorescence (DIF) is helpful for differentiation. DIF shows perivascular deposits of immunoreactants in EMF.

Erythema Annulare Centrifugum Changes are classified as superficial and deep types. Superficial type (Fig. 7.3): 1. Epidermis: mild spongiosis and parakeratosis 2. Dermis: superficial dense perivascular mononuclear infiltrate in a “coat sleeve” ­pattern Deep type: In this type, epidermal involvement is minimal, with dense nodular perivascular mononuclear infiltrate in mid-dermis and lower dermis

Table 7.2.  Comparison of Pityriasis Lichenoides et Varioliformis Acuta and EMF Feature

Pityriasis Lichenoides et Varioliformis Acuta

EMF

Change in stratum corneum

Parakeratosis

Orthokeratosis

Necrosis of keratinocytes

Present

Present

RBCs in epidermis

Present

Absent

Dermal infiltrate

Superficial and deep, wedge shaped

Superficial

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72  Fundamentals of Pathology of Skin

Figure 7.3. Erythema annulare centrifugum showing dense lymphatic infiltrate around vessels (perivasculitis) (10×).

Insect Bite Reactions A variety of histological changes can be seen in insect bite reactions. 1. Urticarial type: vasodilatation with mast cells and eosinophils 2. EMF-like histology 3. Acute necrotic reaction: irritant dermatitis 4. In chronic stages, pseudolymphoma-like reaction 5. Granulomatous reaction, usually of mixed cell type, due to persistence of insect parts

Eosinophilic Cellulitis Epidermis may show spongiosis with infiltration by eosinophils. Changes in dermis include the following: 1. Edema is seen in both upper and lower dermis. 2. Prominent eosinophilic infiltrate is seen with occasional mononuclear cells. 3. Flame figures: flame-shaped, or triangular amorphous, homogenous eosinophilic bodies in dermis consisting of a major basic protein (derived from eosinophils), collagen, and serum proteins. For other diseases with eosinophils, see page 50. 4. In late stages, dermal fibrosis is seen. Note:  Flame figures can be seen in other diseases such as insect bite reaction and dermatophytosis.

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8 Lichenoid Tissue Reactions Interface Dermatitis Interface dermatitis is the term used to denote prominent cellular and tissue changes at the dermoepidermal junction. Primary changes of interface dermatitis include the following: 1. Basal cell vacuolation 2. Apoptosis of cells resulting in colloid bodies and necrotic keratinocytes 3. Infiltrate at dermoepidermal junction which often obscures it Secondary changes include the following: 1. Epidermal changes including atrophy (lupus erythematosus) and saw-tooth change (lichen planus), extensive vacuolation [erythema multiforme, pityriasis lichenoides et varioliformis acuta (PLEVA)] 2. Dermal changes including edema, perivascular infiltrate, and pigment incontinence Interface dermatitis is classified into two types: 1. Interface dermatitis of the lichenoid type in which band-like infiltrate is predominant, with lichen planus as its prototype. 2. Interface dermatitis of the vacuolar type in which vacuolation of keratinocytes is predominant with erythema multiforme and PLEVA as its prototype. Lichenoid reaction is seen in the following conditions:

1. Lichen planus 2. Drug-induced lichenoid eruptions 3. Lichen striatus 4. Benign lichenoid keratosis 5. Ashy dermatosis 6. Graft versus host disease 7. Lichen nitidus 8. Dermatomyositis (Gottron’s papule) 9. Lichenoid reactions in syphilis, HIV infection, and sarcoidosis 10. Lichenoid reactions in seborrheic keratosis, warts, halo nevus, porokeratosis, basal cell epithelioma, etc.

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74  Fundamentals of Pathology of Skin Lichenoid Reaction Characterized by • Basal cell degeneration • Superficial mononuclear infiltrate (in upper dermis) • Colloid bodies • Pigment incontinence

Lichen Planus Epidermis (Figs 8.1 and 8.2) 1. Mild hyperkeratosis 2. Irregular acanthosis 3. Focal hypergranulosis is wedge shaped with base upward. This feature is responsible for Wickham’s striae 4. Basal cell degeneration is severe and leads to the basal cells becoming indistinct and squamatized (flat). This indistinct basal layer causes the infiltrate to close to spinous layer. It may often be severe enough to cause clefts in dermoepidermal junction called Max Joseph spaces (Fig. 8.3) 5. Saw-tooth appearance of rete ridges (this corresponds to focal hypergranulosis) 6. Colloid bodies in lower epidermis and upper dermis (Fig. 8.4) 7. Dense band-like mononuclear infiltrate in upper dermis. The infiltrate has a sharp lower border, hugs the epidermis, causing the dermoepidermal junction to become indistinct 8. Pigment incontinence and presence of melanophages.

a b

f

d

c e

Figure 8.1.  Schematic diagram of lichen planus showing (a) hyperkeratosis, (b) wedge-shaped hypergranulosis, (c) saw-tooth elongation of rete ridges, (d) basal cell degeneration, (e) pigment incontinence, and (f) band-like lymphocytic infiltrate.

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Lichenoid Tissue Reactions  75

a b c

d e f

Figure 8.2.  Lichen planus (10× view): (a) hyperkeratosis; (b) wedge-shaped hypergranulosis; (c) acanthosis; (d) basal cell degeneration; (e) band-like infiltrate; and (f) pigment incontinence.

Figure 8.3.  Lichen planus showing Max Joseph space (scanner view).

Figure 8.4.  Colloid body seen as pink eosinophilic body (40×).

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76  Fundamentals of Pathology of Skin The changes mentioned in the preceding text are present in 90% of all cases of lichen planus and when present are diagnostic 9. Colloid bodies (Fig. 8.4): These are also called Civatte bodies/apoptotic bodies/ sabouraud bodies. They appear as pink, homogenous, acellular bodies in lower epidermis and upper dermis, 10–20 microns in size, oval or round in shape. They are periodic acid-Schiff (PAS) positive and diastase resistant. They are the result of apoptosis and can be seen in all lichenoid reactions and rarely in normal skin 10. Apoptosis: It is also called programmed cell death. It indicates a type of gradual orderly process of death of a cell. Cytoplasm shrinks, becomes condensed, nucleus becomes dark and small (pyknotic), leading ultimately to fragmentation of cell, resulting in colloid bodies. The process of apoptosis is controlled by the gene Bcl 70 and may represent a defense process against neoplasia. It may also be important in the causation of autoimmune diseases Note:  Presence of parakeratosis almost always rules out lichen planus. However, it may occur in oral lichen planus/drug-induced lichen planus/lichen planus lesion to which local irritant medication has been applied. The dense band-like infiltrate in papillary dermis (around the papillary nerve fibers and free nerve endings) explains the near absence of scratching in active lesions of lichen planus. Patients of lichen planus do not scratch much, as scratching in lichen planus causes pain and does not relieve the itch—the so-called Brocq phenomenon. Wedge-shaped hypergranulosis, irregular acanthosis, and pigment incontinence cause the Tyndall effect which explains the bluish color of the lesion in lichen planus.

Pathogenesis Different events in pathogenesis of lichen planus are shown in Flowchart 8.1.

Predisposed patient (Genetic? Racial? Stress?)

Virus-/drug-/chemical-mediated activation of T- lymphocytes

Role of Langerhans cell?

Epidermal basal cell damage

Dermal lymphocytic inflammation

Altered process of keratinization (hypergranulosis, acanthosis)

Pigment dropping into dermis

Severe pruritus

Lichen planus—itchy, violet-colored papules healing with pigmentation

Flowchart 8.1.  Events in etiopathogenesis of lichen planus.

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Lichenoid Tissue Reactions  77

Subtypes 1. Bullous Lichen Planus (Fig. 8.5) It shows a subepidermal bulla (caused by exaggerated Max Joseph Space) due to ­pronounced basal cell degeneration.

Differential Diagnosis 1. Lichen planus pemphigoides: It denotes association of lichen planus and bullous ­pemphigoid in the same patient.

2. Hypertrophic Lichen Planus (Fig. 8.6) Massive hyperkeratosis, acanthosis, papillomatosis, and elongation of rete ridges into dermis. Basal cell vacuolation may be confined to tips of rete ridges. Dermis shows vertical bands of collagen fibers.

Differential Diagnosis 1. Warty lesion: It is an important diagnostic dilemma faced in dermatology in clinical practice. A warty lesion, located often on lower leg, is biopsied with the following differential diagnosis: (a) Hypertrophic lichen planus (b) Hypertrophic lichen simplex chronicus (c) Viral wart (d) Granulomatous conditions such as tuberculosis verrucosa cutis, sporotrichosis, chromoblastomycosis, etc. Flowchart 8.2 is helpful in such ­situations.

3. Lichen Planus Atrophicus It shows atrophic, flat epidermis.

c a

d b

Figure 8.5.  Bullous lichen planus (10×): (a) subepidermal cleft (Max Jospeh spaces) due to extensive basal cell degeneration; (b) colloid body; (c) massive hyperkeratosis; and (d) hypergranulosis.

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78  Fundamentals of Pathology of Skin

a c b

Figure 8.6.  Hypertrophic lichen planus (scanner view). (a) Gross acanthosis, (b) elongated rete, and (c) wedge-shaped hypergranulosis.

Warty lesion

Granuloma

Tuberculoid granuloma AFB positive Tuberculosis verrucosa cutis

No granuloma

Koilocytes Viral wart Basal cell degeneration

Suppurative granuloma

Lichen planus Not specific

Infective

Non-infective Haloderma

Lichen simplex chronicus

Planate body Chromomycosis

Asteroid body Sporotrichosis

Flowchart 8.2.  Approach to diagnosis of a warty lesion.

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Lichenoid Tissue Reactions  79

4. Lichen Planopilaris (Fig. 8.7) 1. Basal cell degeneration limited to hair follicle—outer root sheath 2. Band-like infiltration limited to hair follicle—at the level of infundibulum and isthmus 3. Wedge-shaped hypergranulosis of infundibulum 4. Interfollicular epidermis is often spared

Differential Diagnosis 1. Lichen planopilaris should be distinguished from discoid lupus erythematosus of scalp (Table 8.1).

c

a

b

Figure 8.7.  Lichen planopilaris (10×): (a) basal cell degeneration of hair follicle; (b) band-like infiltrate around hair follicle; and (c) pigment incontinence. Table 8.1  Comparison of Features of Lichen Planopilaris and Discoid Lupus Erythematosus Scalp Feature

Lichen Planopilaris

Discoid Lupus Erythematosus Scalp

Plugging of hair follicle

Cone-shaped

Flask-shaped

Basal cell degeneration

Limited to hair follicle

Basal layer of epidermis and hair follicle

Infiltrate

Band-like infiltration limited to hair follicle

Patchy lymphocytic ­infiltrate in the interstitium and around follicles, blood vessels

Interstitial mucin deposition Absent

Present

Basement membrane

Not thickened

Thick and PAS positive

Direct immunofluorescence

Grape-like clusters of colloid body and fibrin band at IgG band at BMZ follicle

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80  Fundamentals of Pathology of Skin

5. Oral Lichen Planus 1. Parakeratosis: rather than showing acanthosis, epithelium is often atrophic 2. Plasma cells in addition to lymphocytes in dermis 3. Band-like infiltrate may not be present as papillary dermis is absent in oral mucosa

6. Drug-Induced Lichen Planus It shows parakeratosis and more numerous colloid bodies in epidermis and eosinophils in dermis

7. Lichen Planus Pigmentosus (Fig. 8.8) It shows a very prominent pigmentary incontinence with less prominent infiltrate. Ashy dermatosis (Erythema dyschromicum perstans): Ashy dermatosis and lichen planus pigmentosus are regarded as similar entities by many authors. Histological differentiation is very difficult, particularly, in late stages. Early lesions of ashy dermatosis show the following: 1. Focal basal cell degeneration 2. Infiltrate is patchy and perivascular, not band like 3. Pronounced pigment incontinence 4. Active infiltrated border of the lesion shows the characteristic perivascular cuffing with lymphocytes

Differential Diagnosis Flat pigmented lesion is an important clinical dilemma in dark-skinned patients. These lesions are frequently biopsied with the following differential diagnosis: 1. Lichen planus (particularly pigmentosus and actinic variants) 2. Ashy dermatosis

a

b

Figure 8.8.  Lichen planus pigmentosus (10×) showing (a) basal cell degeneration and (b) prominent dermal pigment incontinence which is out of proportion to the infiltrate.

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Lichenoid Tissue Reactions  81 3. Post-inflammatory pigmentation, following other inflammations such as dermatitis 4. Fixed drug eruption The histological differentiation of these conditions is often quite difficult and needs clinical correlation. They all show pigment incontinence. Flowchart 8.3 and Table 8.2 are helpful in such situations (This algorithm should be read in conjunction with algorithm on page 84.)

Pigmented macules

No basal cell degeneration

Basal cell degeneration

Band-like infiltrate

Spongiosis, increased basal and dermal pigmentation

Post-inflammatory pigmentation

LP

Patchy infiltrate Ashy dermatosis Mixed and deep infiltrate and occasional eosinophil FDE

Flowchart 8.3.  Differential diagnosis of lichen planus pigmentosus. FDE, fixed drug eruption; LP, lichen planus. Table 8.2.  Differential Diagnosis of Lichen Planus Pigmentosus Feature

Lichen Planus

Ashy Dermatosis

Fixed Drug Eruption: Late Lesion

Postinflammatory Pigmentation

Spongiosis

–

–

–

+

Basal cell degeneration

Diffuse

Focal

Focal

–

Colloid bodies

Plenty

Few

Few

–

Necrotic keratinocyte

–

–

Present in in stratum malpighii

–

Dermal infiltrate

Band-like superficial

Patchy perivascular superficial

Patchy, superficial Scant and deep

Cell type

Lymphocyte

Lymphocyte

Mixed

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82  Fundamentals of Pathology of Skin

Lichen Striatus The following are the typical features of lichen striatus: 1. Parakeratosis 2. Dyskeratosis (few dyskeratotic cells in epidermis), mild spongiosis and intracellular edema can be seen 3. Focal basal degeneration 4. Patchy papillary dermal infiltrate. Lymphocytes admixed with histiocytes 5. The above changes are focal and limited to 3–4 papillae, in conformity with the small size of the papule clinically 6. Another distinctive feature is the presence of inflammatory infiltrate in reticular dermis around hair follicles and eccrine glands

Lichen Nitidus (Fig. 8.9) 1. Focal parakeratosis, with delling (depression) of epidermis 2. Absent granular layer 3. Focal basal degeneration and focal subepidermal clefting 4. Infiltrate of mononuclear cells occasional giant cells and granuloma formation 5. These changes are limited to 1–2 papillae, in conformity with the small pinpoint clinical papule 6. Claw-shaped elongation of rete ridges, encircling the infiltrate—the so-called “ball in clutch appearance” Though there has been a debate about the possible relation of lichen nitidus and lichen planus, these diseases are best regarded as separate diseases.

a b

Figure 8.9.  Lichen nitidus (scanner view): (a) overlying epidermis is thinned out and (b) focal collection of lymphocytes and macrophages within the dermal papilla limited to two rete ridges.

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Lichenoid Tissue Reactions  83

Graft versus Host Disease It shows lichenoid lesions. 1. Satellite cell necrosis (apoptotic cell in epidermis surrounded by lymphocytes) 2. Dyskeratotic cells in epidermis 3. Perivascular patchy infiltrate

Poikiloderma Poikiloderma is a reaction pattern clinically manifesting as atrophy, spotty hyper and depigmentation, telangiectasia occurring in number of conditions such as mycosis fungoides, congenital poikiloderma, and dermatomyositis. Histopathological features of this pattern are as follows: 1. Thin, atrophic epidermis 2. Loss of rete ridges 3. Basal cell degeneration 4. Prominent pigment incontinence 5. Vasodilatation: telangiectasia Poikiloderma in mycosis fungoides shows epidermotropism and abnormal mononuclear cells in epidermis. A summary of features of interface dermatitis of vacuolar type is given in Flowchart 8.4.

Interface dermatitis

Lichenoid type

Vacuolar type Orthokeratosis Sup infiltrate

Erythema multiforme

Mixed infiltrate, pigment incontinence Fixed drug eruption Parakeratosis, mild infiltrate

Wedge-like infl, RBCs in epidermis

Pityriasis lichenoides chronica

Pityriasis lichenoides et varioliformis acuta

Flowchart 8.4  Algorithm for diagnosis of interface dermatitis of the vacuolar type. (For detailed discussion, see Flowchart 8.5; page 84)

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84  Fundamentals of Pathology of Skin A summary of features of interface dermatitis of lichenoid type is given in Table 8.3 and Flowchart 8.5. Table 8.3.  Summary of Features of Interface Dermatitis of Lichenoid Type Disease

Histopathological Features

Lichen planus

Prominent Civatte bodies, band-like inflammatory infiltrate, wedgeshaped hypergranulosis, pigment incontinence

Lichen nitidus

Focal changes limited to two papillae; few giant cells; dermal infiltrate often “clasped by down growths”

Lichen striatus

Irregular and discontinuous lichenoid reaction; changes limited to 3–4 papillae; dyskeratosis; infiltrate sometimes around follicles and sweat glands

Lichen planus-like Solitary; prominent Civatte body formation; parakeratosis; dyskerakeratosis tosis; solar lentigo often at margins Lichenoid drug eruptions

Focal parakeratosis; eosinophils, plasma cells, and melanin incontinence; deep extension of the infiltrate may occur

Lichenoid purpura

Patchy superficial infiltrate, RBCs, hemosiderin in upper dermis, capillaritis

Fixed drug eruptions

Superficial and deep infiltrate; cell death in stratum malpighii; mixed infiltrate with neutrophils; prominent pigment incontinence

Graft versus host disease

Basal vacuolation; scattered apoptotic keratinocytes, sometimes with attached lymphocytes (“satellite cell necrosis”); variable lymphocytic infiltrate

Lupus erythematosus

Mixed vacuolar change and Civatte bodies; superficial and deep infiltrate; follicular plugging; basement membrane thickening; vascular changes; pandermatitis Interface dermatitis Vacuolation of cells

Prominent infiltrate Lichenoid type

Vacuolar type

Band-like infiltrate

Patchy infiltrate

Classical

Many rete ridges—LP

Discoid lupus erythematosus

PAS + BMZ

Parakeratosis

3-4 rete ridges—Lichen striatus

Ashy dermatosis

Pig incontinence

Ball-socket

2 rete ridges—Lichen nitidus

Fixed drug eruption

Deep infiltrate, pigment incontinence

Dyskeratosis

LP-like keratosis

Lichenoid PPP

Hemosiderin

Eosinophil

Drug-induced LP

Secondary Syp

Plasma cell

Plasma cell

Secondary syphillis

Graft versus host disease

Satellite cell necrosis

Flowchart 8.5  Algorithm for differential diagnosis of interface dermatitis—lichenoid type.

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9 Psoriasiform Reactions The term psoriasiform is used histologically to describe diseases with elongation of rete in a regular pattern. Other features include acanthosis and presence of inflammatory cells in dermis (Fig. 9.1). Psoriasiform Reactions • Psoriasis • Lichen simplex chronicus • Prurigo nodularis • Chronic dermatitis of any cause • Some cases of dermatophytosis • Secondary syphilis • Sarcoidosis • Drug eruptions • Cutaneous lymphoma • Overlying dermatofibroma • Norwegian scabies • Pityriasis rubra pilaris • Seborrheic dermatitis • AIDS-related psoriasiform reaction • Erythroderma • Pellagra and acrodermatitis enteropathica

Psoriasis The histologic picture varies with the stage of the lesion. Diagnostic changes are typically seen in scaling papules and near the margin of advancing plaques. Thick hypertrophic lesions, very early pinpoint papules, and lesions on palms and soles are more difficult to diagnose (Fig. 9.2). Pathognomonic features of plaque psoriasis (Figs 9.1 and 9.3) include the following: 1. Focal parakeratosis 2. Focal hypogranulosis 3. Irregular acanthosis, with suprapapillary thinning of stratum malpighii 4. Regular, even elongation of rete ridges, with bulbous thickening at their lower ends

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86  Fundamentals of Pathology of Skin

Figure 9.1.  Schematic diagram of psoriasis showing hyperkeratosis, focal parakeratosis and hypogranulosis, regular acanthosis with club-shaped elongation of rete ridges, and dilated and tortuous blood vessels in papillary dermis.

A

B

C

D

E

Time

Figure 9.2.  Temporal evolution of a lesion of psoriasis from pinpoint papule to hypertrophic psoriasis. (A) Earliest manifestation: dilatation of blood vessels and few perivascular inflammatory cells. (B) Initial stage: mild parakeratosis and few neutrophils in the stratum corneum. (C) Parakeratosis with hypogranulosis. (D) Established lesion: elongation of rete ridges, Munro’s microabscesses in stratum corneum with regular elongation of rete ridges. (E) Hypertrophic psoriasis: thick hyperkeratosis with parakeratosis, tortuous capillary loops.

5. Accumulation of polymorphonuclear cells in stratum corneum, within foci of parakeratosis called Munro’s microabscesses (Fig. 9.4) 6. Accumulation of polymorphonuclear cells in a sponge-like network of degenerated keratinocytes in stratum granulosum called Kogoj’s pustules

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Psoriasiform Reactions  87

a

b

c

Figure 9.3.  Psoriasis (10×): (a) focal parakeratosis with underlying hypogranulosis; (b) regular elongation of rete ridges; and (c) dilated and tortuous blood vessels in papillary dermis.

Figure 9.4.  Accumulation of polymorphonuclear cells in stratum corneum—Munro’s microabscess (40×).

7. Irregular dilated tortuous blood vessels in dermal papillae 8. Perivascular lymphocytic infiltrate in upper dermis Features 4–6 mentioned above are pathognomonic of psoriasis. However, these changes are not always present. Note 1: Psoriasis is a disease of epidermal proliferation and dermal inflammation. Parakeratosis, acanthosis, and elongated rete reflect the epidermal proliferation, whereas dilated dermal vessels and the infiltrate both in epidermis and dermis represent the inflammatory component. Note 2: Parakeratosis and hypogranulosis are always patchy. This is because of periodic squirting of dermal papillae causing discharge of polymorphonuclear cells, which move up the epidermis. In other words, the process itself is periodic.

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88  Fundamentals of Pathology of Skin Polymorphonuclear cells may either get localized in stratum malpighii as Kogoj’s pustules or end up in the stratum corneum as Munro’s abscesses. Note 3:  There are intralesional variations within a lesion of psoriasis. There may be foci which do not reveal typical features of psoriasis within a plaque of psoriasis. Events in etiopathogenesis are presented in Flowchart 9.1.

Genetically predisposed individual (HLA antigens?) Precipitating factors (infection, stress, drugs, injury, hormones) Altered T-cell function

Production of different cytokines

Dermal inflammation

Altered cAMP/cGMP epidermal proliferation

Migration of polymorphs into epidermis raised (LTB4)

Dermal vasodilatation, lymphocytes

Elongated rete, parakeratosis, acanthosis

Munro’s abscess, Kogoj’s pustule

Erythema

Scaling

Pustule

Clinical lesion of psoriasis

Flowchart 9.1.  Events in etiopathogenesis of psoriasis. Clinicopathological Correlation in Psoriasis • Profuse scaling is due to accelerated epidermal proliferation, manifested histologically as acanthosis and elongated rete. • Parakeratosis is due to altered keratinization. • Auspitz’s sign is due to (a) suprapapillary thinning and (b) dilated tortuous blood vessels. • Erythematous color of the lesion is due to the dilated tortuous blood vessels. • Pustule is due to Kogoj’s macropustule.

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Psoriasiform Reactions  89

a b c

Figure 9.5.  Early psoriasis (scanner view): (a) focal parakeratosis (Munro’s abscess is yet to form); (b) acanthosis; and (c) blood vessel dilatation.

Variants of Psoriasis Guttate Psoriasis (Fig. 9.5) This may not show the classical features. 1. Focal mounds of parakeratosis just above the focus of hypogranulosis. This is often the earliest sign in a lesion called pin point psoriatic papule. 2. Few polymorphonuclear cells in stratum corneum, which herald a Munro’s abscess later. 3. Dilated blood vessels in the upper dermis. 4. Dermal mononuclear infiltrate which appears more prominent than in acanthosis. In contrast, in established psoriasis, epidermal changes appear far more prominent than dermal changes. Guttate scaly lesion is an important clinical problem. These lesions are frequently biopsied with a differential diagnosis of the following: 1. Guttate psoriasis 2. Guttate parapsoriasis or pityriasis lichenoides chronica (PLC) 3. Pityriasis rosea 4. Secondary syphilis Differentiation of these conditions can be quite difficult and need clinical, histological, and laboratory correlation (Table 9.1).

Hypertrophic Psoriasis 1. Gross hyperkeratosis with parakeratosis 2. Acanthosis 3. Bulbous elongation of rete ridges along with fused ones

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90  Fundamentals of Pathology of Skin Table 9.1.  Differential Diagnosis of Guttate Psoriasis Feature

Guttate Psoriasis

Pityriasis Lichenoides

Pityriasis Rosea

Secondary Syphilis

Parakeratosis

Mound-like

Diffuse

Mound-like

Focal

Spongiosis

Absent

Present

Focal

May be positive

Exocytosis of lymphocytes

Absent

Present

Present

Absent/ present

RBCs

Absent

Present in dermis and epidermis

Present in dermis

Absent

Polymorphs in ­stratum corneum

Present

Absent

Absent

Absent

Dermal changes

Dilated vessels

Superficial lymphocytic infiltrate

Superficial lymphocytic infiltrate

Plasma cells

4. Thick linear bands of collagen in upper dermis 5. Munro’s abscesses and Kogoj’s pustules

Differential Diagnosis The condition resembles lichen simplex chronicus closely. Munro’s abscesses and Kogoj’s pustules are absent in this condition and are the distinguishing features. Reiter’s disease: Features of Reiter’s disease are similar to psoriasis, with more pronounced compact hyperkeratosis and parakeratosis. Histological distinction is difficult and needs clinical correlation.

Pustular Psoriasis (Figs 9.6 and 9.7) Typical features of psoriasis are absent as the migration of polymorphs is too rapid to allow the typical epidermal features to develop. Histology of all the three variants of

Figure 9.6.  Pustular psoriasis: low-power view showing multilocular subcorneal pustules with polymorphs with overlying parakeratotic layer (10×).

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Figure 9.7.  Pustular psoriasis (high-power view; 40×). Note the salt and pepper appearance of polymorphs underneath parakeratotic stratum corneum.

pustular psoriasis—Von Zumbusch type, acropustulosis of Hallopeau, and impetigo herpetiformis—are similar. 1. Large subcorneal Kogoj’s macropustules which are multilocular 2. Parakeratosis 3. Elongated rete ridge 4. Mononuclear cells in dermis (eosinophils in impetigo herpetiformis)

Differential Diagnosis 1. Subcorneal pustular dermatosis shows unilocular pustules in stratum corneum (see page 103). 2. Bullous impetigo also shows unilocular pustules; clinical history and culture study are helpful to differentiate.

Localized Pustular Psoriasis of Palms and Soles 1. Unilocular, subcorneal pustule in a parakeratotic stratum corneum 2. Elongated rete ridges 3. Dilated blood vessels in upper dermis 4. Edema in upper dermis 5. Mononuclear infiltrate

Differential Diagnosis Dyshidrotic eczema shows multiple spongiotic vesicles with lymphocytes. Changes of psoriasiform hyperplasia are absent.

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92  Fundamentals of Pathology of Skin Table 9.2.  Differentiation of Psoriasis from Lichen Simplex Chronicus Feature

Psoriasis

Lichen Simplex Chronicus

Parakeratosis

Patchy

Diffuse

Suprapapillary epidermis

Thinning

Thickened

Spongiosis

Absent

Small foci present

Munro’s microabscess

Present

Absent

Kogoj’s pustules

Present

Absent

Rete ridges

Regular, uniform

Irregular

Vessels

Dilated and tortuous

Dilated

Collagen

Seen as linear bands

Thickened and vertically running

Other Psoriasiform Reactions Lichen Simplex Chronicus Differentiation of psoriasis from lichen simplex chronicus is quite difficult (Table 9.2).

Pityriasis Rubra Pilaris Typical changes are seen in the follicular lesions, as the name suggests. Follicular lesions show 1. Shoulder parakeratosis (parakeratosis on either sides of hair follicles) 2. Dilated infundibula with follicular plugging 3. Prominent arrectores pilorum 4. Perifollicular infiltrate of lymphocytes Non-follicular lesions show psoriasiform hyperplasia and may closely resemble psoriasis. 1. Parakeratosis, which is alternating with orthokeratosis, both vertically and horizontally— “checker board pattern” 2. Elongated rete ridges, which are pointed at the lower end 3. Acanthosis, with thickening of suprapapillary layer. No hypogranulosis 4. Dilated blood vessels in upper dermis 5. Sebaceous atrophy 6. Hypertrophic arrectores pilorum Differential diagnosis from psoriasis: Features 1, 3, 5, and 6 along with the absence of Munro’s microabscesses and Kogoj’s pustules differentiate this condition from psoriasis. Follicular lesions show the distinguishing features.

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Psoriasiform Reactions  93

Pityriasis Rosea 1. The histological features in this disease are usually mild and may not be diagnostic, unlike the typical clinical findings. Biopsies are performed in this condition, when lesions resembling pityriasis rosea persist for longer than 14 weeks and to differentiate from parapsoriasis. It is preferable that such biopsies should be delayed till the clinical course is established. 2. The disease is thus a classical example for invisible dermatosis. 3. Pityriasis rosea is also a classic example in which the morphology and the low-power view are of greater benefit in diagnosis than the cellular detail and high-power view. No individual feature is diagnostic, but a series of changes, followed in low-power view, give a sufficiently suggestive picture. 4. The main histopathological feature is spongiotic vesicle in a dry dermatosis. 5. There is an absence or decrease in the granular cell layer. 6. Erythrocytes are present in the papillary dermis and in the epidermis. 7. Further, if the architecture of the lesion is carefully studied, a characteristic pattern can be demonstrated. The lesion shows the following features: (a) Peripheral zone of normal epidermis. (b) Mid-zone of parakeratosis with underlying spongiosis and the middle zone may show the presence of RBCs in the underlying dermis. (c) An inner zone of a lifting off parakeratotic scale, which is free toward the center of the lesion, which corresponds to the centrifugal scale. (d) A herald patch, in addition, may have pronounced acanthosis, deeper and denser perivascular inflammatory infiltrate and papillary dermal edema.

Parapsoriasis The term parapsoriasis was originally used by Brocq to denote diseases which showed scaly lesions, with some resemblance to psoriasis, were chronic in behavior, and resistant to treatment. Pityriasis lichenoides, small plaque parapsoriasis, and large plaque parapsoriasis (LPP) were originally included under this category. Pityriasis lichenoides, both chronica and acuta variants, show lymphocytic vasculitis and are described in Chapter 12, Vasculitis. 1. Small plaque parapsoriasis: It is better called chronic superficial dermatitis (size of lesion is