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Dermatology study guide 2013 2014 Document Transcript

  • 1. The 2013/2014 Dermatology In-Review Study Guide Companion to the Dermatology In-Review Online Study System Edited by C. William Hanke, MD, MPH, FACP Associate Editors Michael K. Lichtman, MD Cynthia Bartus, MD Emily Tierney, MD Aimee L. Leonard, MD Ross Levy, MD Sherry Hsiung, MD Bruce Strober, MD   Sponsored by
  • 2. The questions and answers, statements or opinions contained in this Study Guide or Web Site have not been approved by Galderma Laboratories, L.P., and Galderma Laboratories, L.P. will not be held responsible for any questions and answers, statements or opinions, contained in the Study Guide, Web Site, or any supplementary materials. Any questions about the content of Dermatology In-Review should be directed to Educational Testing and Assessment Systems, Inc. which controls the content and owns all copyrights in the materials. All components are intended for use by U.S. dermatology physicians only. The publishers of this guide will use reasonable efforts to include up-to-date and accurate information on this guide, but make no representations, warranties, or assurances as to the accuracy, currency or completeness of the information provided. The publishers of this guide shall not be liable for any damages or injury resulting from your access to this guide, or from your reliance on any information provided in this guide. This guide is intended for U.S. physicians only and is not in any means intended for use by the general public. ISBN 978-0-9858025-0-9 © 2013 Published by Educational Testing and Assessment Systems, a product of SanovaWorks Edited by C. William Hanke MD, MPH, FACP All rights reserved. No part of this book may be reproduced in any form or by any means, without permission in writing from the publisher. Printed in the United States of America
  • 3. K E Y F E A T U R E S The 2013/2014 Dermatology In-Review Study Guide is formatted for quick study and easy reference. The below elements will appear throughout the text to aid in the preparation for your exams. Note that the Study Guide intentionally uses redundancy to further your learning by repetition. Tip Boxes Tip Boxes highlight exam-relevant information for quick study. u TIP P ahenol is cardiotoxic, nephrotoxic and hepatotoxic. Patients must have cardiac monitoring during phenol peeling to detect cardiac arrhythmias a hemical peeling of the neck is generally avoided C because of the risk of hypertrophic scarring Call-Outs Look for the Call-Out arrows within the text. They are used in different ways to highlight key information. Call-Out arrows can be seen before pertinent bullet points throughout the chapters.  •  Seen in Birt-Hogg-Dube Keep an eye out for arrows sitting in a shaded box. These signify more than one important bullet point.  • Caused by a deficiency in uropoprhyrinogen decarboxylase (UROD); may be inherited, sporadic or associated with Hepatitis C • Sporadic form may occur in association with HCV; in one study 82% of patients with PCT had HCV-antibodies Call-Outs may also appear before paragraphs. When this is seen, the whole paragraph is high-yield information. It is defined as a sudden appearance and increment in size of multiple SKs. The eruption is classically described to appear in a “Christmas tree” pattern and may occur anywhere in the body; however; the most common location is the back and the chest. Its association with an internal malignancy remains controversial.  Red Text The online study guide features red text which indicates that the material is NEW for the 2013/2014 year. Reference Chapter 16 for an example. iv  2013/2014 Dermatology In-Review l Committed to Your Future
  • 4. K E Y F E A T U R E S Shaded Text Shaded text emphasizes certain words or phrases that should be focused on. It is presented in a variety of ways: within Call-Outs, in tables, and throughout the chapter’s text. It is defined as a sudden appearance and increment in size of multiple SKs. The eruption is classically described to appear in a “Christmas tree” pattern and may occur anywhere in the body; however; the most common location is the back and the chest. Its association with an internal malignancy remains controversial. Mnemonic Boxes Helpful mnemonic memory cues are displayed in Mnemonic Boxes throughout the chapters. MNEMONIC Subepidermal Split PLAID Pemphigoid (bullous) Lupus (bullous SLE) Acquisita (EBA) IgA, linear Dermatitis herpetiformis Pearl Boxes Pearl Boxes are used to stress information that is commonly found on exams. PEARL w  ariant: Brunsting-Perry pemphigoid: no mucosal V involvement, blisters on patches of erythema on head/neck with scarring/scarring alopecia w  reatments: Topical/intralesional/PO steroids, T dapsone, cyclophosphamide, azathioprine Note Pages Each chapter is followed by a series of Note Pages that should be used for your own annotations, study tips, and mnemonics. These pages should be taken out of your three-ring binder each year and placed in your new edition of Dermatology In-Review. Key Features  v
  • 5. Dear Colleague, With great pleasure we provide you with the 2013/2014 Dermatology In-Review Study Guide from Educational Testing and Assessment Systems (ETAS), a product of SanovaWorks. Authored by over 20 leading academic faculty from all the various fields within dermatology, the contributing authors have provided a study guide that is essential for residents seeking comprehensive yet concise Board review material. The purpose of this study guide is to provide a source of high-yield Board study content to be used with the Online Study System (DermatologyInReview.com/Galderma). Together these tools provide relevant information and methods to prepare you for your exams. This program has been made possible through the support of Galderma Laboratories, L.P. We are grateful for their commitment to education. Good luck on your exams! Sincerely, C. William Hanke, MD, MPH, FACP Professor of Dermatology University of Iowa Carver College of Medicine Iowa City, IA Clinical Professor of Otolaryngology-Head and Neck Surgery Indiana University School of Medicine Indianapolis, IN vi  2013/2014 Dermatology In-Review l Committed to Your Future
  • 6. F A C U L T Y Authors Andrew F. Alexis, MD, MPH Director, Skin of Color Center St. Luke’s-Roosevelt Hospital Assistant Clinical Professor of Dermatology Columbia University College of Physicians & Surgeons New York, NY Sonal Choudhary, MD Post-Doctoral Research Fellow, Department of Dermatology and Cutaneous Surgery University of Miami, Miller School of Medicine Miami, FL George W. Elgart, MD Professor of Dermatology Director of Dermatopathology Department Department of Dermatology and Cutaneous Surgery University of Miami School of Medicine Miami, FL Adam Friedman, MD, FAAD Director of Dermatologic Research Director of the Basic Science/Translational Research Fellowship Associate Residency Program Director Albert Einstein College of Medicine Bronx, NY Anthony Gaspari, MD Chairman of Dermatology Director, Cutaneous Immunopathology Laboratory Professor of Dermatology University of Maryland Medical Center Baltimore, MD Valerie Harvey, MD Assistant Professor of Dermatology Eastern Virginia Medical School Norfolk, VA Alysa R. Herman, MD Voluntary Instructor of Dermatology and Cutaneous Surgery University of Miami School of Medicine Miami, FL Eric Huang, MD, PhD Private Practice New York, NY Ming H. Jih, MD, PhD DermSurgery Associates Houston, TX Arash Kimyai-Asadi, MD DermSurgery Associates Houston, TX Christine J. Ko, MD Associate Professor of Dermatology and Pathology, Department of Dermatology Yale University New Haven, CT Evelyn K. Koestenblatt, MS, MT (ASCP) Clinical Research Administrator, Department of Opthalmology and Visual Sciences Montefiore Medical Center Bronx, NY Jennifer Ledon, MD Medical Student Research Fellow University of Miami Miller School of Medicine Department of Dermatology & Cutaneous Surgery Miami, FL Faculty  vii
  • 7. F A C U L T Y Erika Gaines Levine, MD Maria Patricia Rivas-Bondavalli, MD Private Practice Haddonfield, NJ Private Practice Hollywood, FL William R. Levis, MD Ellen Roh, MD Clinical Assistant Professor, Departments of Medicine and Dermatology New York University Langone Medical Center New York, NY Instructor of Dermatology Harvard Medical School/Massachusetts General Hospital, Department of Dermatology Boston, MA Michael K. Lichtman, MD Jessica Savas, MD Assistant Professor of Dermatology Boston University School of Medicine Boston, MA Medical Student Research Fellow University of Miami Miller School of Medicine Department of Dermatology & Cutaneous Surgery Miami, FL Jeffrey L. Marx, MD Clinical Associate Professor, Department of Dermatology New York University Langone Medical Center New York, NY Keyvan Nouri, MD Associate Professor of the Department of Dermatology and Otolaryngology Director of the Mohs, Dermatologic and Laser Surgery Director of Surgical Training for the Department of Dermatology and Cutaneous Surgery University of Miami School of Medicine Miami, FL Georgia B. Schuller-Levis, PhD Head - Laboratory of Cellular Immunology Department of Immunology New York State Institute for Basic Research Staten Island, NY Peter C. Schalock, MD Assistant Professor of Dermatology Harvard Medical School/Massachusetts General Hospital, Department of Dermatology Boston, MA Bruce E. Strober, MD, PhD Jennifer B. Perone, MD Assistant Professor New York University Langone Medical Center New York, NY Surgical Dermatology Associates, PA Denton, TX Jeffrey M. Weinberg, MD Private Practice Coronado, CA Attending, Department of Dermatology St. Luke’s-Roosevelt Hospital Center, and Beth Israel Medical Center New York, NY Kelley Pagliai Redbord, MD Voraphol Vejjabhinanta, MD Dermatology and Dermatologic Surgery Group of Northern Virginia Vienna, VA Post-doctoral Fellow in Mohs, Laser and Dermatologic Surgery, Department of Dermatology and Cutaneous Surgery Dori Rausch, MD viii  2013/2014 Dermatology In-Review l Committed to Your Future
  • 8. F A C U L T Y L. Magaly Villafradez-Diaz, MD Research Fellow, Mohs, Dermatologic and Laser Surgery Department of Dermatology and Cutaneous Surgery University of Miami School of Medicine Miami, FL Katherine L. White, MD Northampton Dermatology Associates Northampton, MA Andrea L. Zaenglein, MD Associate Professor of Dermatology and Pediatrics Penn State/Milton S. Hershey Medical Center Hershey, PA Priya Swamy Zeikus, MD Private Practice Faculty at Univeristy of Texas Southwestern Medical School Dallas, TX Resident Advisory Board Taylor DeFelice, MD, MPH 2011/2012 Chief Resident New York University School of Medicine Program New York, NY Alicia Ogram, MD 2011/2012 Chief Resident Washington Hospital Center/Georgetown University Washington, DC Special Recognition Cynthia Bartus, MD Dermatology In-Review Cram Pack Updates Private Practice Atlanta, GA Adam Friedman, MD Workshop Chapter Editor Exam Cram Live Moderator and Contributor Dermatology In-Review Reviewer Director of Dermatologic Research Director of the Basic Science/Translational Research Fellowship Associate Residency Program Director Albert Einstein College of Medicine Bronx, NY John G. Hancox, MD Dermatology In-Review Cram Pack/Boot Camp Mountain State Dermatology Clarksburg, WV Christine Liang, MD Dermatology In-Review Exam Cram Pack Update Clinical Instructor, Department of Dermatology Brigham and Women’s Hospital Boston, MA Stephen Z. Smith, MD Dermatology In-Review Recertification Cram Pack Update Private Practice Louisville, KY William E. Rietkerk, MD, MBA 2011/2012 Chief Resident New York Medical College Metropolitan Hospital Center New York, NY Faculty  ix
  • 9. Contents Chapter 1  Basic Science and Structure of Skin. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 1.1 Epidermis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 1.2 Dermis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14 1.3  Antigens Implicated in Autoimmune Diseases and Other Annoying Factoids. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18 1.4 Wound Healing. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19 1.5 Maturational. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21 1.6 Hair Follicle Biology. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22 1.7 Sebaceous Glands. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26 1.8 Eccrine Glands. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26 1.9 Apocrine Glands. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27 1.10 Nails . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27 1.11 Nerves and Receptors of the Skin. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27 1.12 Immunofluorescence Patterns - Direct. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28 1.13 Connective Tissue Diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30 Chapter 2  Immunodermatology. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33 2.1 The Innate and Adaptive Immune Systems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35 2.2 Cells of the Innate and Adaptive Immune System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36 2.3  Cytokines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40 2.4  Antibodies and Complement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 42 2.5  Major Histocompatibility Complex and HLA Disease Associations. . . . . . . . . . . . . . . . . . . . . . . . . . . . 45 2.6  Non-Steroidal Immunologic Therapies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46 Chapter 3 Genodermatoses. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51 3.1 X-linked Recessive Syndromes. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53 3.2 X-linked Dominant Syndromes. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53 3.3 Hereditary Blistering Disorders. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53 3.4 Ichthyoses. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 54 3.5 Palmoplantar Keratodermas. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 55 3.6 Disorders with Hypopigmentation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 56 3.7 Disorders with Pigmented Lesions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 57 3.8 Vascular Disorders. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 58 3.9 Connective Tissue Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 60 3.10 Diseases of the Hair and Nails. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 62 3.11 Diseases with Malignant Potential. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 63 3.12 Disorders with Immunodeficiency . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 65 3.13 DNA and Chromosomal Disorders. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 66 3.14 Keratinopathies. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 67 3.15 Disorders of Metabolism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 67 Chapter 4  General Dermatology. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 75 4.1 Acne Vulgaris. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 78 4.2 Rosacea. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 81 4.3 Psoriasis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 83 4.4 Psoriatic Arthritis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 88 4.5 Reiter’s Syndrome. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 88 4.6 SAPHO Syndrome. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 89 4.7 Sneddon-Wilkinson Disease. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 90 4.8 Lichen Planus. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 90 4.9 Atopic Dermatitis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 94 4.10 Alopecia Areata . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 97 4.11 Alopecia: Other Forms. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 98 4.12 Vitiligo. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 100 4.13 Pityriasis Rubra Pilaris . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 101 x  2013/2014 Dermatology In-Review l Committed to Your Future
  • 10. 4.14 Lichen Sclerosus. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 101 4.15 Granuloma Annulare. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 102 4.16 Hirsutism. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 103 4.17 Amyloidosis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 104 4.18 Calciphylaxis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 106 4.19 Angioedema. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 107 4.20  Carcinoid Syndrome and Flushing Disorders. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 108 4.21 Lupus Erythematosus. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 109 4.22 Scleroderma. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 112 4.23 Dermatomyositis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 115 4.24 Sjogren’s Syndrome. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 117 4.25  Connective Tissue Disease: Serology. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 117 4.26 Relapsing Polychondritis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 119 4.27 Behçet’s Disease. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 120 4.28 Livedo Reticularis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 121 4.29 Leukocytoclastic Vasculitis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 121 4.30  Cryoglobulinemia and Cryofibrinogenemia. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 124 4.31 Acanthosis Nigricans. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 125 4.32 Lipodystrophy. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 126 4.33 Hyperlipoproteinemias. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 127 4.34 Xanthomatosis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 128 4.35 Vitamin Deficiencies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 128 4.36  Diabetes and Skin Disease. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 132 4.37  Langerhans Cell Histiocytosis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 134 4.38  Cutaneous T-Cell Lymphoma. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 135 4.39 Pyoderma Gangrenosum. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 138 4.40 Sweet’s Syndrome. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 139 4.41  Erythema Annulare Centrifugum . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 140 4.42  Erythema Elevatum Diutinum . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 140 4.43 Erythema Nodosum . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 141 4.44 Mastocytosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 142 4.45 Cutaneous Sarcoidosis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 144 4.46 Perforating Disorders. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 146 4.47  Elastosis Perforans Serpiginosa. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 146 4.48  Reactive Perforating Collagenosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 147 4.49  Cutaneous Features and Disorders of Pregnancy. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 147 4.50 Pruritus. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 149 4.51 Scleredema. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 150 4.52  Nephrogenic Fibrosing Dermopathy/Nephrogenic Systemic Fibrosis. . . . . . . . . . . . . . . . . . . . . . . . . 151 Chapter 5 Dermatopathology. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 155 5.1 Normal Skin. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 157 5.2 Stains. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 158 5.3 Immunohistochemistry. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 159 5.4 Acantholytic Disorders. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 160 5.5 Adnexal/Epithelial Neoplasms. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 162 5.6 Alopecias. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 170 5.7 Bullous Disorders. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 170 5.8 Cysts. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 171 5.9 Deposition Disorders. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 173 5.10  Drug Reactions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 175 5.11  Fat Disorders. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 176 5.12 Fibrous/Fibrohistiocytic Disorders. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 177 5.13 Genodermatoses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 181 5.14 Granulomatous Disorders. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 182 Table of Contents  xi
  • 11. 5.15 Histiocytoses. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 183 5.16 Infections. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 184 5.17 Inflammatory. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 188 5.18 Lymphomas and Markers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 194 5.19  Melanocytic Lesions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 197 5.20 Muscle . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 200 5.21 Neural. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 201 5.22 Pagetoid Spread. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 203 5.23 Palisading Reactions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 204 5.24 Vascular. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 205 5.25 Miscellaneous. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 208 5.26 Clues for Board Purposes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 212 5.27 “Bodies”. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 214 Chapter 6  Benign and Malignant Neoplasms. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 221 6.1 Seborrheic Keratosis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 223 6.2 Actinic Keratosis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 225 6.3 Bowen’s Disease. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 227 6.4 Non-melanoma Skin Cancer. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 229 6.5 Basal Cell Carcinoma. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 229 6.6 Squamous Cell Carcinoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 232 6.7 Keratoacanthoma. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 234 6.8 Malignant Melanoma. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 237 6.9 Merkel Cell Carcinoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 241 6.10 Cutaneous T-Cell Lymphoma. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 243 6.11 Angiosarcoma. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 246 6.12 Desmoplastic Trichoepithelioma. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 247 6.13 Dermatofibrosarcoma Protuberans. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 248 6.14 Microcystic Adnexal Carcinoma. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 249 Chapter 7 Medical Mycology. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 257 7.1 Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 259 7.2 Superficial Mycoses. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 260 7.3 The Dermatophytes. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 262 7.4 Subcutaneous Mycosis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 273 7.5 Dimorphic Fungi Causing Systemic Disease. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 277 7.6 Opportunistic Organisms. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 280 7.7  Miscellaneous Organisms Causing Fungus-like Infections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 286 7.8 Chapter 8  Random Facts and Summary Table. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 287 Infectious Diseases of the Skin. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 291 8.1 Bacterial Infections. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 293 8.2 Viral Infections. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 298 8.3 Mycobacterial Infections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 303 8.4 Sexually Transmitted Diseases. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 306 8.5 Nonvenereal Trepanomatoses. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 309 8.6 Parasitic Infections. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 309 8.7 Rickettsial Diseases. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 312 xii  2013/2014 Dermatology In-Review l Committed to Your Future
  • 12. Chapter 9  Pediatric Dermatology. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 315 9.1 Neonatal and Infantile Dermatology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 317 9.2 Childhood Infectious Diseases. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 322 9.3 Pigmented Lesions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 324 9.4 Dermal Tumors and Disorders. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 328 9.5 Vascular Lesions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 330 9.6 Genodermatoses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 335 Chapter 10  Cutaneous Manifestations of Systemic Disease. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 359 10.1 Cutaneous Manifestations of Hepatitis C Virus. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 361 10.2 Cutaneous Manifestations of Thyroid Disease. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 363 10.3 Cutaneous Manifestations of Renal Disease. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 365 10.4 Cutaneous Manifestations of Gastrointestinal Disorders. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 369 10.5  Cutaneous Manifestations of Neurologic Disease. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 373 10.6  Cutaneous Manifestations of Diabetes Mellitus. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 377 10.7 Cutaneous Manifestations of Cardiac Disease. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 380 10.8 Porphyrias. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 389 Chapter 11  Disorders of the Hair and Nails. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 397 11.1 Hair Disorders. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 399 11.2 Hirsutism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 410 11.3 Hypertrichosis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 412 11.4 Nails. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 413 Chapter 12 Bullous and Vesicular Dermatoses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 423 12.1 Molecular Level . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 425 12.2 Microscopic Level. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 427 12.3 Bullous Disorders. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 428 12.4 Diseases that Can Present with Bullae. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 435 12.5 Vesicular Disorders. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 436 12.6 Common Allergens. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 439 12.7 Plant Allergens. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 441 12.8 Tips . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 442 12.9 Plant Irritants. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 443 Chapter 13  Photobiology and Photosensitivity Disorders. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .447 13.1 Basic Facts about Ultraviolet Light. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 449 13.2 Photoimmunology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 450 13.3 Phototesting. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 451 13.4 Idiopathic Photosensitivity Disorders. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 452 13.5 Photosensitivity from Exogenous Agents. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 456 13.6 Diseases Exacerbated by Sunlight. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 458 13.7 Phototherapy. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 459 13.8 Photochemotherapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 459 13.9 Sunscreens . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 460 Chapter 14  Plants and Creatures of Dermatologic Significance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 465 14.1 Plant Dermatoses. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 467 14.2 Dermatologic Diseases Caused by Creatures. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 472 14.3 Lice, Spiders, Bugs, and Other Creatures. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 475 14.4 Ticks. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 481 14.5 Mites . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 483 14.6 Exotic Pets. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 485 14.7 Skin Eruptions Caused by Marine Life. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 486 14.8 Medications Derived from Plants and Creatures. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 489 Table of Contents  xiii
  • 13. Chapter 15  Dermatologic and Cosmetic Surgery. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 497 15.1 Anatomy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 499 15.2 Anesthetics. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 505 15.3 Antimicrobial Agents. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 507 15.4 Prophylactic Antibiotics. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 507 15.5 Wound Healing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 509 15.6 Sutures. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 512 15.7 Flaps and Grafts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 514 15.8 Chemical Peels. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 517 15.9 Botox and Cosmetic Fillers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 518 15.10 Photoaging and Cosmeceutical Rejuvenation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 519 15.11 Liposuction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 519 15.12 Lasers and Radiofrequency. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 520 15.13 Mohs Surgery. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 522 15.14 Chemotherapeutic Agents. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 523 15.15 Complications. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 523 15.16 On the Horizon. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 524 Chapter 16 Dermatopharmacology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 531 16.1 Antibiotics. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 535 16.2 Antivirals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 536 16.3 Antifungals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 538 16.4 Topical and Systemic Corticosteroids. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 540 16.5 Cytotoxic Agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 540 16.6 Immunosuppressants. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 543 16.7 Dapsone and Sulfapyridine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 543 16.8 Antimalarials. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 544 16.9 Retinoids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 545 16.10 Sunscreens . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 546 16.11 Antiparasitics. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 547 16.12 Antihistamines. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 548 16.13 Hormone-related Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 548 16.14 Miscellaneous Drugs. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 549 16.15 Biologic Therapy. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 550 16.16 Drugs in Pregnancy. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 551 16.17 Drug Interactions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 553 16.18 Drug Vehicles and Absorption Mechanism of Actions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 556 Chapter 17 Literature Review . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 565 2003. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 567 2004. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 573 2005. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 578 2006. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 585 2007 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 591 2008. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 598 2009. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 605 2010. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 611 2011. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 618 2012. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 627 Index. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 635 xiv  2013/2014 Dermatology In-Review l Committed to Your Future
  • 14. 1 Basic Science and Structure of Skin Kelley Redbord, MD Peter Schalock, MD Bruce E. Strober, MD, PhD C o n t e n t s 1.1 1.2 Dermis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14 1.3 Antigens Implicated in Autoimmune Diseases and Other Annoying Factoids . . . . . . . . . . . . . . . . . . 18 1.4 Wound Healing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19 1.5 Maturational . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21 1.6 Hair Follicle Biology . . . . . . . . . . . . . . . . . . . . . . . . . . 22 1.7 Sebaceous Glands . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26 1.8 Eccrine Glands . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26 1.9 Apocrine Glands . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27 1.10 Nails . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27 1.11 Nerves and Receptors of the Skin . . . . . . . . . . . . . . 27 1.12 Immunofluorescence Patterns - Direct . . . . . . . . . 28 1.13 Report a Problem/Feedback Epidermis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 Connective Tissue Diseases . . . . . . . . . . . . . . . . . . . 30 Basic Science and Structure of Skin    1
  • 15. 1.1 EPIDERMIS Epidermis • Compliled of the following cells: –  Keratrocytes - 80% –  Melanocytes - base layer –  Langerhans cells suprabasal 2-8% –  Merkel cells basal layer Keratinocyte  • Ectodermal derivation during first few weeks of embryonic dulp • 90% of total population of epidermis • 30 different keratins: 20 epithelial and 10 nail keratins -> 40–70 kD –  Bind to each other in the rod region • Acidic keratins: K9–K20, chromosome 17 • Basic keratins: K1–8, chromosome 12 • Intermediate Filaments (see also Bullous and Vesicular Dermatoses chapter) –  Type I = acidic keratins 9–20, chromosome 17 –  Type II = basic keratins 1–8, chromosome 12 –  Type III = vimentin, glial fibrillary acidic protein (GFAP), desmin, peripherin –  Type IV = neurofilaments –  Type V = nuclear lamins –  Type VI = nestin Table 1-1. Intermediate Filaments Type 1 Type 2 Type III Type VI Type V Others Keratins Keratins Vimentin NF-L Lamin A/C Filensin Desmin NF-H Lamin B1 Phakinin GFAP NF-M Lamin B2 Periperin a-Internexin Syncoilin Nestin Synemin • Keratinocytes are able to release, respond to, uTIP a cidic and basic keratins are co-expressed in order to A and produce TNF-alpha. Causes increased form filamentous structure - "obligate heteropolymers” differentiation (Bikle, 1991) Report a Problem/Feedback Basic Science and Structure of Skin    3
  • 16. Table 1–2. Keratin Expression Patterns Type II Type I Location Hereditary Disease Association 1 Suprabasal keratinocytes Ichthyosis hystrix of Curth-Macklin Diffuse non-epidermolytic PPK (Unna-Thost) 1 10 Suprabasal keratinocytes Bullous congenital ichthyosiform erythroderma, EHK (corrugated scale) 1 9 Palmoplantar suprabasalar keratinocytes Epidermolytic PPK, diffuse nonepidermolytic PPK 2e 10 Upper spinous and granular layers Ichthyosis bullosa of Siemens (milder EHK) 3 12 Cornea Meesmann’s corneal dystrophy 4 13 Mucosal epithelium White sponge nevus (Cannon) - buccal 5 14 Basal keratinocytes Epidermolysis bullosa simplex 1.) Dowling Meara (head or tail of central rod domain) 2.) Koebner (segment 1a or 2b of rod domain) 3.) Weber Cockayne (nonhelical parts) 5 15 Mucosal basal layer 6a 16 Outer root sheath, hyperproliferative Pachyonychia congenita Jadassohn Lewandowsky keratinocytes type I, focal nonepidermolytic PPK 6b 17 Nail bed Pachyonychia congenita type II, steatocystoma multiplex (Jackson-Lawler) 8 18 Simple epithelium Cryptogenic cirrhosis Hair follicle Monilethrix 19 Bulge cells & simple epithelium Paget's = ck7, ck20 20 Merkel cell carcinoma hHb1 b6 1 16 Non epidermolytic PPK 17 Steatocystoma Multiplex 5 EBS Mottled pigmentation (non helical V1 domain) 14 EBSC Autosomal recessive 14 Naegeli - Franceschetti - Jadassohn syndrome Stratum Germinativum (Basale) Basal cells contain ornithine decarboxylase (marker for proliferative activity) Stimulated by: trauma, UV, EGF, estrogens, β agonists, tumor promoters Inhibited by: protein deprivation in psoriatic skin (by retinoids and steroids) • The basal layer • K5 and K14 expressed - defective in epidermolysis uTIP a  eratin filaments in basal cells insert into K bullosa simplex desmosomes and hemidesmosomes • K19 found in basal cells at transitional boundaries between different types of epithelia •  icrofilaments (actin, myosin, and alpha-actinin) assist in upward movement of cells as they M differentiate 4  2013/2014 Dermatology In-Review l Committed to Your Future Report a Problem/Feedback
  • 17. • Integrins regulate adhesion and initiation of differentiation • Not all basal cells have potential to divide • Stem cells give rise to transient amplifying cells •  nce basal cell leaves basal layer in humans, normal transit time to stratum corneum is at O least 14 days, and transit through stratum corneum to desquamation requires 14 days, 28 days total Stratum Spinosum • Rounder nucleus, more flattened appearance • Contain lamellar granules • Lamellar granules contain ceramides • K5/K14 still present, but not made de novo in this layer • New synthesis of K1/K10 -> keratinization-specific keratins, characteristic of epidermis, markers of terminal differentiation • n psoriasis, actinic keratoses, and wound healing suprabasal keratinocytes downregulate I K1/K10 and make K6/K16 (mRNA always present for K6/K16, but only translated during proliferation) • Hyperproliferative states k6, k16, ki-67, α3β, integrin • Desmosomes form “spines,” calcium-dependent structures that promote adhesion •  esmosomal plaque: Six polypeptides, plakoglobin, desmoplakins I and II, keratocalmin, D desmoyokin, demoyokin, and band 6 protein (see Table 1.2 for listing of desmosomal proteins and associated diseases) Table 1-3. Desmosomal Proteins Protein Plakoglobin Desmoplakin I/II Keratocalmin Desmoyokin band 6 protein Plakophilin Envoplakin Desmocalmin Desmoglein I Desmoglein III Desmocollin I Desmocollin III Location Plaque Plaque Plaque Plaque Plaque Plaque Plaque Plaque Transmembrane Transmembrane Transmembrane Transmembrane Disease Association(s) Naxos syndrome Carvajal syndrome None described to date None described to date Ectodermal dysplasia/skin fragility syndrome Ectodermal dysplasia/skin fragility syndrome Paraneoplastic Pemphigus (210 kD antigen) None described to date AD Striate PPK/Pemphigus foliaceus Pemphigus vulgaris Subcorneal Pustular Dermatosis None described to date u TIP •  ransmembrane cadherins T a isease relating to gap junctions: D provide adhesive properties 26 Vohwinkel’s syndrome, KID syndrome, PPK with deafness - contain desmoglein I and III, 30.3 & 31 erythrokeratoderma variabilis intracellular domains link with intermediate filament 30 hidrotic ectodermal dysplasia cytoskeleton • Gap junctions more abundant in stratum spinosum compared to stratum basale – Communication between cells – More differentiated keratinocytes have more abundant gap junctions (few in basal cell layer) Report a Problem/Feedback Basic Science and Structure of Skin    5
  • 18.  •  amellar granules—A type of membrane bound uTIP L a amellar granules deliver lipid precursors into L intracellular structure, 0.2–0.3 micrometers intercellular space: glycoproteins, glycolipids, in diameter; a lysosome with secretory funcphospholipids, free sterols, and glucosylceramides tion. They are lamellated bodies, containing ceramide, are found intracellularly in upper level keratinocytes; they discharge. Ceramide is the major lipid for barrier function of the skin – First appear in stratum spinosum, but primary activity in stratum corneum – Discharge their contents into the extracellular space at the junction of the granular and horny layers, establishing a barrier to water loss, and, with filaggrin, mediate stratum corneum adhesion – Deliver lipid precursors into intercellular space: glycoproteins, glycolipids, phospholipids, free sterols, and glucosylceramides (predominant lipid of stratum corneum) – Commonly used synonym is “Odland bodies” – Flegel’s disease—Decreased lamellar granules – Harlequin ichthyosis—Lamellar granules uniformly abnormal or absent. Defect in ABCA12 at 2q34 (also defective in lamellar ichthyosis type II) – X-linked ichthyosis—Steroid sulfatase missing in lamellar granules. Increased levels of the beta fraction of cholesterol sulfate can be identified by serum lipoprotein electrophoresis. Prenatal diagnosis can be accomplished by measurement of decreased estrogen levels and the presence of nonhydrolyzed sulfated steroids in maternal urine Stratum Granulosum • Keratohyalin granules contain profilaggrin (F granules) and loricrin (L granules contain loricrin at periphery and help form cornified cell envelope) + KIF • K1 modified to K2, and K10 to K11 by proteolysis and phosphorylation • Lamellar granules originated in golgi  •  ornified cell envelope (CE): Proteins synthesized in spinous/granular layers C – Durable, protein/lipid polymer formed within differentiating keratinocytes  – Eventually exists outside of cornified cells – Components include: • Envoplakin – Homologous to desmoplakin. May link the CE to desmosomes and to keratin filaments • Involucrin – Cross-linked by transglutaminase in granular layer to an insoluble cell boundary • Loricrin – In upper spinous layer and throughout the stratum granulosum – 75% of CE’s mass (major protein component of CE) – Vohwinkel syndrome variant associated – Filament aggregating activity – In Psoriasis: i loricrin, h involucrin, i filaggrin • Filaggrin (histadine rich) Filament Aggregating Activity - defect causes Ichthyosis vulgaris – Profilaggrin converted to monomeric filaggrin subunits when granular layer transformed to cornified layer; a calcium-dependent process – Thought to promote aggregation and disulfide bonding of keratin filaments in cornified cell (like a glue) 6  2013/2014 Dermatology In-Review l Committed to Your Future Report a Problem/Feedback
  • 19. – Degraded into urocanic acid and pyrrolidone carboxylic acid; both hydrate stratum corneum and block UV radiation – Stored in kit granule  •  ransglutaminase: 3 versions that function in T crosslinking the CE (calcium-dependent process). Forms gamma-glutamyl-lysine isodipeptide bonds in the CE, most prominently with involucrin u TIP Basal layer k5, 14 Spinous layer k1, 10 Lamellar granules (k6, 16 in psoriasis) k2, 11 Keratohyalin granules Granular layer Keratin filaments  –  G-1 (type K) - keratinocyte transglutaminase, membrane associated, defect causes lamelT lar ichthyosis type I (TGM1 gene) and non-bulluous congenital ichthyosiform erythroderma (T9M1 + ALOX12B + ALOXE3) – TG-2 (type C) - fetal epidermis and basal layer of adult epidermis, soluble – TG-3 - present in hair follicles and differentiated epidermal cells, soluble. Present in sublamina densa - antigen for dermatitis herpetiformis. 77 kDa •  rogrammed destruction of granular cell - loss of nucleus, yet retention of keratin filaments P and filaggrin matrix – Destruction involves apoptosis transition cells (“T” cells) – Terminal differentiation is initiated by increase in calcium gradient in suprabasal epidermis Stratum Corneum • Transition from Stratum Granulosum accompanied by loss of 45–86% in dry weight •  rovides mechanical protection, barrier to water loss and barrier preventing permeation of P environmental soluble substances • Keratin in filaggrin rich matrix • Normal SC cells have no nuclei; may persist in incompletely keratinized cells (parakeratosis) • Bricks - Corneocytes; Mortar-extracellular lipid matrix (from loricrin)/lamellar lipid barrier Epidermal Differentiation • Triggered by calcium • CE: 1.) crossed linked envoplakin, periplakin, involving along innes cell membrane, 2.) lamellar granule 6 extrusion into extracellular space 3.) loricrin crosslinks envelope 4.) keratin and filaggrin crosslink Report a Problem/Feedback Basic Science and Structure of Skin    7
  • 20. Figure 1-1. Skin Adhesion Molecules with Corresponding Diseases 8  2013/2014 Dermatology In-Review l Committed to Your Future Report a Problem/Feedback
  • 21. Table 1-4. Epidermolysis Bullosa Condition Defect EBS K5, K14, plectin EBS –herpetiformis (Dowling Meara) K5, K14 (head or tail of central rod domain) EBS –Weber Cockayne (palms/soles) K5, K14 (nonhelical parts) EBS –Koebner K5, K14 (segment 1a or 2b of rod domain) EBS –muscular dystrophy Plectin JEB –lethal, Herlitz Laminin 5 (LAMB3 gene) JEB –pyloric atresia Alpha-6-Beta-4 integrin Dominant DEB (Cockayne Touraine, hyperplastic, Albopapuloid Pasini) atrophic white scars Collagen VII (Col 7A1) RDEB Hallopeau-Siemens Collagen VII (Col 7A1) Bart’s syndrome Collagen VII EB acquisita Collagen VII EBS - mottled pigmentation K5 (nonhelical VI domain) EBS -AR K14 Basement Membrane Zone (Refer to Figure 1-2) • Site of interaction between epidermis and dermis • Three layers – 1.) Lamina lucida, 2.) Lamina densa, 3.) Sub-lamina densa •  emidesmosomal adhesion complex: 1.) hemidesmosomal plaque, 2.) anchoring filaments, and H 3.) anchoring fibrils • Know the electron microscopy picture of the basement membrane zone Figure 1-2. Dermal-Epidermal Junction Components Report a Problem/Feedback Basic Science and Structure of Skin    9
  • 22. Table 1-5. Keratinocyte Integrin Receptors Integrin Ligand b1 Family a1b1 Fibrillar collagen, laminin a2b1 Fibrillar collagen, laminin a3b1 Fibronectin, laminin 5, denatured collagen a5b1 Fibronectin a6b1 b4 Family Laminin a6b4 av Family Laminin 5 avb1 Fibronectin, vitronectin avb3 Vitronectin, fibronectin, fibrinogen, denatured collagen avb5 Vitronectin avb6 Fibronectin, tenascin Lamina Lucida Hemidesmosome • Attachment complex for basal keratinocytes and extracellular matrix •  lectron-dense domain on the ventral surface of basal keratinocytes - bridge cytoskeleton E and cutaneous basement membrane • Proteins: – BPAg1—230 kD protein (desmoplakin) noncollagenous glycoprotein • Intracellular at attachment plaque • Member of the plakin family and homologous to desmoplakin • Attaches intermediate filaments (keratins) to hemidesmosomal plaque • Belongs to the gene family including desmoplakin I – BPAg2—180 KD protein (collagen XVII) • Transmembrane protein • Interacts with BPAg1, beta-4 integrin, and plectin intracellularly  • ts NC16A domain (target of I u TIP autoantibodies in bullous pem- a isease Associations (see chapter 12 for more details) D phigoid) interacts with alpha-6 BPAg1/BPAg2-NC16A bullous pemphigoid integrin extracellularly BPAg2 lichen planus pemphigoides • Also interacts with laminin 5 portion of BPAg2 linear IgA disease extracellularly • Two forms: full-length BPAg2-NC16A herpes gestationis transmembrane and soluble 120 BPAg2 C terminal domain cicatricial kDa ectodomain that is shed pemphigoid from cell surface • Integrins: Transmembrane proteins – alpha-6-beta-4 integrin found at sites where keratin intermediate filaments attach 10  2013/2014 Dermatology In-Review l Committed to Your Future Report a Problem/Feedback
  • 23. – Expression limited to basal layer of epidermis – Coordinates linkage between intermediate filaments and extracellular matrix of the basement membrane – Beta-4 membrane proximal domain interacts with plectin and its distal domain interacts with BP180; absence of beta-4 prevents hemidesmosomal assembly – Extracellular alpha-6 domain binds laminin 5 – Defect in beta-4 seen in cicatricial pemphigoid with ocular involvement only – Defects in alpha-6-beta-4 results in JEB with pyloric atresia • Plectin: Member of the plakin family – Links intermediate filaments to the plasma membrane and crosslinks various hemidesmosomal proteins – Mutations result in epidermolysis bullosa simplex with muscular dystrophy Anchoring Filaments • Laminin 5 and BP180 are major components • Laminins – Glycoproteins with at least 14 members of the family – Cross-shaped assembly of three classes of polypeptides – Span from plasma membrane of basal keratinocytes to lamina densa – Two major roles: 1.) structural network in basement membrane to which other proteins attach; 2.) signaling – Molecules that interact with other proteins (such as integrins) to transmit morphogenetic information to the cell’s interior – Laminin 5 (major component of anchoring filaments; also called epiligrin) and laminin 6 isoforms are found in the DE junction of human skin and mucous membranes • Uncein – 19DEJ1-Ag – Associated with anchoring filaments • Fibronectin – Central function in wound healing – Secreted by myofibroblasts -> stimulated by EGF and thrombin – Allows fibroblasts to adhere to ECM, provides “scaffolding” for collagen fibrils (Bolognia) and assists in wound contraction • Nidogen – Also called entactin – Dumbbell-shaped – Binds to laminin 1 Lamina Densa Type IV Collagen • Functions in structural support and confers flexibility to basement membrane • Highly cross-linked, forming a lattice • Primary component of anchoring plaques Heparan Sulfate Proteoglycan • Negatively charged, thus is a permeability barrier Report a Problem/Feedback Basic Science and Structure of Skin    11
  • 24. Sublamina Densa Type VII Collagen • Targeted auto-antigen in epidermolysis bullosa acquisita and bullous lupus erythematosus • Mutated in dystrophic epidermolysis bullosa • Primary constituent of anchoring fibrils • Homotrimeric protein Anchoring Plaques • Composed of type IV collagen •  oint of attachment for anchoring fibrils composed of type VII collagen (from “above”) and P collagens I and III from the dermis “below” Melanocytes • Dendritic cell derived from neural crest •  ound in multiple tissues: epidermis, hair matrix, retinal pigment epithelium, ear (stria vascuF laris), leptomeninges, mucous membranes, ciliary body, choroid, iris, and enteric ganglion cells Skin Melanocytes • In skin, localized to basal layer of epidermis •  unctions include: melanin production (melanogenesis), arborize with processes that conF tact keratinocytes (epidermal melanin unit = approximately 36 keratinocytes in contact with one melanocyte), and transfer pigment to keratinocytes • Keratinocytes can produce both growth and inhibitor factors for melanocytes – Growth—beta-FGF and TGF-alpha – Inhibitory—IL-1, IL-6, TGF-beta • Be able to recognize a melanocyte on electron microscopy Melanin Synthesis •  yrosine->DOPA-> DOPAquinone, both steps catalyzed by tyrosinase, a copper containing T enzyme • DOPAquinone converted to pheomelanin or eumelanin uTIP M •  yrosine hydroxylase is not expressed in melanocytes a elanin has two forms: T •  Eumelanin - brown-black, insoluble (only in neurons) •   heomelanin - red-yellow, alkali-soluble, P •  elanin absorbs and scatters ultraviolet radiation M sulfur-containing (280-400 nm), and thus protects from UV-induced a oth types of melanin made from tyrosine B via action of the enzyme tyrosinase DNA mutations Melanosomes • Stages of melanosomes – Stage 1: spherical – Stage 2: episoidal – Stage 3: matrix is melanized – Stage 4: melanization is completed • Contain melanin • Related to lysosomes: positioned after the Golgi apparatus in the secretory pathway •  lliptical melanosomes synthesize brown or black eumelanin; have longitudinally oriented, E concentric lamellae 12  2013/2014 Dermatology In-Review l Committed to Your Future Report a Problem/Feedback
  • 25. • Spheroid melanosomes produce yellow or red pheomelanin; have microvesicular internal structure •  elanin transfer involves the active phagocytosis of the dendritic tips of melanocytes by the M keratinocytes and hair cortex cells • Melanin distributed preferentially to more basally located keratinocytes • Oculocutaneous albinism (OCA) – Defect in melanin synthesis due to: • Tyrosinase (OCA1) (melanosomes arrest in stage I or II) • P-gene (OCA2) • TRP-1 gene (OCA3) Differences in Skin Color: More Darkly Pigmented Races Show • A greater production of melanosomes in the melanocytes • Individual melanosomes with a higher degree of melanization • Larger melanosomes • Higher degree of dispersion of melanosomes in the keratinocytes • A slower rate of melanosome degradation Hair Melanocytes • Melanin unit exists in proximal anagen bulb: one melanocyte and five keratinocytes •  ollicular melanogenesis coupled to hair growth cycle: melanocyte proliferation occurs during F early period of anagen • Hair follicle contains melanocyte precursors that can repopulate the interfollicular epidermis •  raying caused by gradual decline in the number of follicular melanocytes; influenced by G both age and genes • MC1-R gene mutations associated with red hair Merkel Cells • Mechanoreceptors at sites of high tactile sensitivity • Located at the basal level of the epidermis • Keratinocytic deformation induces secretion of chemokines by Merkel cells • Location varies: hair-bearing skin and glabrous skin of the digits and lips, oral cavity, and ORS hair follicle  • Keratin 20 (ck20) is a specific and reliable marker of Merkel cells and perinuclear dots •  ake synaptic connection with neurons (the Merkel cell-neurite complex); neurochemical M transmission occurs between an activated Merkel cell and its neuron Langerhans Cells •  one-derived, CD34+, antigen-processing and presenting cells of monocyte/macrophage B lineage migrate from bone marrow in embryonic development and continue to repopulate epidermis during lifetime •  ontains CD207 (Langerin) C •  ound in the skin and other epithelial tissues: oral mucosa, esophagus, vagina F • Also found in lymph nodes and dermis Report a Problem/Feedback Basic Science and Structure of Skin    13
  • 26. • Two stages in the Langerhans life cycle: 1.) In epidermis, ingest and process antigens, are weak stimulators of T-cells 2.) Activated Langerhans cells that have contacted antigen and can strongly stimulate naïve T-cells u TIP •  nce a Langerhans cell encounters and processes O T a given antigen it “matures” and migrates to a local a he most important cells for recognition, uptake and processing of antigens in the skin lymph node, where it then presents the antigen to a and presenting these antigens to naï e T-cells v naïve (or resting) T-cell, activating that T-cell aCharacteristic finding on electron microscopy •  entral to the pathogenic processes of atopic derC Birbeck granules- tennis racket shaped bodies in matitis, psoriasis, allergic contact dermatitis, and the cell. Be able to identify an electron microsinfections such as Leishmaniasis copy image of a Langerhans Cell •  unctionally impaired by ultraviolet radiation. After F UV radiation, Langerhans cells are impaired in the ability to present antigen and are depleted in number • Located in all layers of epidermis, but mostly in suprabasal layer • Adheres to cells by e-cadherin, produce IL-1 • Disease processes involving Langerhans Cells (all S-100 and CD1a + with Birbeck granules in cytoplasm): – Letterer-Siwe disease – Hand-Schüller-Christian disease – Eosinophilic granuloma – Hashimoto-Pritzker disease – Can be infected with HIV – Produces IL-I, expresses E-Cadherin (to adhere to KC) • Stains (+) CD45 (ICA or OKTG), ATP ase (1st marker to develop), S100, Fc Receptor (+), C3, CD1a, actin, vimentin • Kidney shaped nucleus, Birbeck granules on EM 1.2 DERMIS Dermis • Collagen, elastic fibers, Matrix, Cells (fibroblasts, monocytes, phagocytes, mast cells, dermal dendrocytes, glomus cells) Collagen • Primary dermal constituent 75% of dry weight of skin • Provides tensile strength and elasticity •  dult dermis: types I, III, and V; type I accounts for 85% of collagen; type III accounts for A 10%; type V accounts for 5% u TIP •  ysyl hydroxylase and proline hydroxylase crosslinks col- a omposed of three chains that vary L C lagen (desmosine residues) - vitamin C required cofactor according to collagen type. All have Gly-X-Y amino acid motif that repeats (copper and Vitamin B6 also) for function of enzyme where X and Y are proline an hydroxyvitamin C deficiency = Scurvy proline •  ype I & III are major interstitial fiber forming collagens T 14  2013/2014 Dermatology In-Review l Committed to Your Future Report a Problem/Feedback
  • 27. Table 1–6. Types of Collagen and Tissue Distribution I (85%) Mature Skin, Bone, Tendon (except bone marrow and cartilage) COL1A1/2—Ehlers-Danlos syndrome (EDS) Arthrochalasia type & Osteogenesis Imperfecta II Cartilage, Vitreous Relapsing polychondritis III (10%) Fetal Skin, Blood Vessels, Intestines Wound repair, COL3A1—EDS Vascular type IV Basement Membranes Alport and Goodpasture syndrome V (5%) Ubiquitous COL5A1/2—EDS Classical type VI Aorta, Placenta Congenital muscular dystrophy without skin findings VII Anchoring Fibrils, Amnion Dystrophic epidermolysis bullosa (EB), bullous lupus, cicatricial pemphigoid VIII Cornea—Descemet’s membrane Corneal dystrophy IX Cartilage No associated skin disease X Cartilage No associated skin disease XI Cartilage No associated skin disease. Stickler & Marshall syndromes (ophthalmic disease) XII Cartilage & fibroblasts No associated skin disease XIII Fibroblasts No associated skin disease XIV Skin, placenta, tendon, Cartilage, muscle No associated skin disease XV Placenta No associated skin disease XVI Placenta No associated skin disease XVII Anchoring filaments Junctional EB, generalized atrophic benign EB, bullous pemphigoid XVIII Liver, kidney, placenta XIX Rhabdomyosarcoma Rhabdomyosarcoma Collagen Diseases Ehlers-Danlos Syndromes •  xcessive stretchability and fragility of the skin with a tendency toward easy scar formation E (“fish-mouth” scars) • Calcification of the skin to produce pseudotumors • See Chapter 3, Genodermatoses, for description of types Random Associated Diseases: • Osteogenesis Imperfecta abnormal type I collagen • Homocystinuria: Abnormal crosslinking of collagen because of mutated β cystathione synthase • Tenascin-X: Autosomal recessive type EDS similar to Classic type. Associated with collagen fibrillinogenesis Elastic Fibers • 4% of dry weight of the skin •  orms complex meshwork extending from lamina densa of the DEJ through the dermis F and into the hypodermis Report a Problem/Feedback Basic Science and Structure of Skin    15
  • 28. • Returns skin to normal configuration after being stretched • Elastic fibers: 90% elastin, wrapped by fibrillin microfibrils (mutated in Marfan’s) •  esmosine and isodesmosine are typical amino acids found in elastic fibers, and crosslink D fibrillin requires lysyl oxidase (copper-dependent process) • Oxytalan fibers: contain no elastin; run perpendicular from DEJ within superficial papillary dermis • Elaunin fibers: have less elastin and more fibrillin; run parallel in thin bands within the reticular dermis • Elastic fibers turn over slowly in the skin and are damaged by ultraviolet radiation Elastin Diseases Cutis laxa • Fibulin 5 gene defect • Decreased desmosine and lysyl oxidase • Fragmentation and loss of elastic fibers Marfan’s Syndrome • Decreased fibrillin I • Fragmentation of elastic fibers, especially aortic Congenital Contractural Arachnodactyly • Mutation in fibrillin 2 Pseudoxanthoma Elasticum • MDRP (multiple drug resistant protein) • ABCC6 gene defect—(adenosine triphosphate binding cassette subfamily C member 6) • Increased glycosaminoglycans on elastic fibers • Calcium deposition • Accumulation of fragmented and calcified elastic fibers Buschke-Ollendorf Syndrome • LEMD3 (a.k.a. MAN1) gene defect • Increased desmosine • Increased amount of thickened elastic fibers Anetoderma • Decreased desmosine • Loss of and fragmentation of elastic fibers Dermal Matrix Components •  roteoglycans and glycosaminoglycans → ground substance that surrounds the fibrous P constituents of the dermis; 0.2% of dry weight of the dermis •  roteoglycans consist of a “core protein” with a glycosaminoglycan such as hyaluronic acid P binding to the core protein; other glycosaminoglycans include dermatan sulfate, heparan sulfate, and chondroitin sulfate  • Can bind up to 1000 times their volume and regulate water-binding capability of the dermis •  ucopolysaccharidoses represent genetic storage diseases resulting from abnormal lysoM somal function and subsequent accumulation of these substances. → Hurler’s (Alpha-Liduronidase), Hunter’s (Iduronate sulfatase), for example. See Genodermatoses Chapter for more detail on these conditions 16  2013/2014 Dermatology In-Review l Committed to Your Future Report a Problem/Feedback
  • 29. Papillary Dermis • Young or healthy skin: small diameter collagen fibrils and oxytalan elastic fibers • Aging or actinically damaged skin: mature elastic fibers that are large and dense • High density of fibroblast cells that proliferate rapidly Reticular Dermis • Large diameter collagen fibers with mature, branching elastic fibers • Elastic and collagen bundles increase in size progressively toward the hypodermis Cells of the Dermis Fibroblast • Derived from mesenchyme • Produces extracellular matrix framework • Synthesizes soluble mediators that may constitute signaling between the dermis and epidermis • Wound healing - produce fibroplasia and wound contraction (myofibroblasts) Mononuclear Phagocytic Cells • Monocytes, macrophages, and dermal dendrocytes from bone marrow • All phagocytic skin macrophages express CD11c, CD6; CR4 (CD11c) = b2 integrin that binds; C3b+ stimulates phagocytosis • Macrophage functions – Phagocytic – Processing and presenting antigens to naïve T-cells – Microbiocidal through production and release of lysozyme, peroxide, and superoxide – Tumoricidal – Secretory (cytokines, growth factors, etc.) – Involved in coagulation, atherogenesis, wound healing and tissue remodeling – CD11a = LFA (binds to (CAM-2) – CD11b = Mac-1 on phagocytes binds to LCAM Mast Cells Table 1–7. Mast Cells Mast Cell Type Mediator Location T Type Tryptase only Bowe and respiratory mucosa TC Type Typrtase and Chymase Skin, GI, submucosa C Type Chymase only Skin, lymph node •  reatest density in the papillary dermis, in sheaths of the appendages, and around blood G vessels and nerves of the subpapillary plexus •  iseases: Mastocytosis, solitary mastocytoma, diffuse erythrodermic mastocytosis, TMEP, UP D • Derived from bone marrow-residing CD34+ stem cells  •  roliferation depends on the c-kit receptor and its ligand stem-cell factor (SCF). Mutations P in c-kit (CD117) may result in mastocytosis or piebaldism • Stain CD34+, C-Kit, stem cell factor (SCF), giemsa, teledyne, leder stain (naphthol chloroac etate esterase) •  roduced and stored in preformed secretory granules - many inflammatory mediators such P as histamine, heparin, tryptase, chymase, carboxypeptidase, neutrophil chemotactic factor, Report a Problem/Feedback Basic Science and Structure of Skin    17
  • 30. and eosinophilic chemotactic factor of anaphylaxis. Produce IL-8 (strong neutrophil chemotactic factor) - Produce PqD2 and tryptase • Release without storing - growth factors, cytokines, and leukotrienes including prostaglandin D2 • Preformed mediator in mast cell - serine proteases (tryptase), heparin, histamine •  ecretory granules are released by a variety of stimuli, and process. Degranulation is identical S regardless of stimulus •  egranulation produces vascular smooth muscle contraction, increases vascular permeability, D tissue edema, and the recruitment of inflammatory cells •  esponsible for immediate-type hypersensitivity reactions and participate in chronic inflamR matory conditions • Histologically: Round or oval nucleus and dark staining granules • Mast cell mediators: tryptase, chymase, cathepsin G, histamine, heparin, IL-4, IL-13, IL 3, IL5, GMCSF, TNF-alpha, CCL3, leukotrienes C4D4EF, platlet activating factor Mast Cell Mediators • Tryptase, chymase, cathepsin a, histamine, heparin, IL-4, IL-V, IL3, IL5, GM-CSF, TNF-alpha, CCL3, leukotrienes C4D4E, Platelet activity factor Dermal Dendrocytes • Subset of antigen-presenting cells function in the afferent limb of the immune response • Derived from bone marrow • Found in papillary dermis and upper reticular dermis • Highly phagocytic, same as melanophages in the dermis that contain ingested pigment • Likely the cell of origin in benign proliferative tumors such as dermatofibromas or fibroxanthomas Glomus Cells • Derived from Susquet-Hoyer canals • Vascular smooth muscle cells •  llow the rapid shunting of blood from the arterioles to venules, bypassing capillaries A occurs primarily in palms and soles • Disease processes include glomus tumor and glomangioma 1.3  NTIGENS A IMPLICATED IN AUTOIMMUNE DISEASES AND OTHER ANNOYING FACTOIDS Paraneoplastic Pemphigus • Plectin (500 kd) • Desmoplakin I (250 kd), II (210 kd) • BPAg1 (230 kd) • Envoplakin (210 kd) • Periplakin (190 kd) • Unknown 170 kd antigen • Dsg 1, 3 (160 kd, 130 kd) Pemphigus Vulgaris • Desmoglein 3 (130 kd), coprecipitates with plakoglobin (85 kd) Pemphigus Foliaceus • Desmoglein 1 (160 kd) 18  2013/2014 Dermatology In-Review l Committed to Your Future Report a Problem/Feedback
  • 31. Linear IgA Disease • BPAg2 (180kD) (Collagen XVII) - may be the 97 kd fragment Subcorneal Pustular Dermatosis (IgA Pemphigus, Sneddon-Wilkinson Disease) • Desmocollin 1 (115 and 105 kd) Intraepidermal Neutrophilic IgA Dermatosis • Desmoglein 3 Pemphigoid Gestationis • BPAg2 (180 kd) Cicatricial Pemphigoid (Mucous Membrane) • BPAg2 (180 kd) C-terminal domain • Laminin 5 - antiepiligrin CP • Laminin 6 • β-4 integrin - Ocular CP • Type VII collagen The Plakin Family • Envoplakin (210 kd) • Periplakin (190 kd) • Desmoplakin (250 kd) • BPAg1 (230 kd) • Plectin (500 kd) Table 1–8. Blistering D/O Antigen Inherited K5, 14 EBS Dowling Meara AI Plectin EBS - MD PNP BPAG2 Generally atrophic benign EB EB, CP Antigen Inherited AI a6b4 Integrin JEB = gatric atresia b4 integrin ocular CP Laminin V JEB CP with maln Collagen VII DEB Collayenous domain EBA noncollagenous domain Bullous LE Collapse domain 1.4 WOUND HEALING Inflammatory Stage Clot Formation • Initial step in wound healing • Provisional matrix for cell migration • Functions in hemostasis Coagulation •  ritical event is availability of surface that promotes adsorption and activation of specific C coagulation pro-enzymes • Clot provides a scaffolding for recruitment of cells to injured site Report a Problem/Feedback Basic Science and Structure of Skin    19
  • 32. • Fibrin and fibronectin act as provisional matrix for infiltrating monocytes, fibroblasts, and newly formed blood vessels •  learance of clot matrix is as important as deposition, and inadequate removal of provisionC al matrix may lead to fibrosis; proteolytic enzymes such as plasminogen and plasmin are the major proteins Platelets in Wound Healing (First Response) • Aggregation and adhesion required • Release many mediators, including ADP, and clotting factors • Fibrin clot and thrombin act as nidus for further adhesion and aggregation • Platelets release PDGF, EGF, fibronectin, and TGF-alpha and –beta which promote new tissue growth Neutrophils in Wound Healing •  igrate with monocytes concurrently, but arrive first in great numbers because of their M abundance in circulation • Chemoattractants for PMNs: Fibrinogen/fibrin split products, C5a, leukotrienes • f wound contamination controlled, PMN migration ceases within a few days, and PMN’s I become entrapped within the wound clot, undergo apoptosis or phagocytosed by macrophages Monocytes in Wound Healing  • Macrophages are REQUIRED for wound healing - without macrophages, there is no healing • Monocyte chemoattractants include fragments of collagen, elastin, and fibronectin • Macrophages debride tissue through phagocytosis and digestion of organisms, tissue debris, and effete PMN’s • Secrete collagenase •  dherence to matrix stimulates expression of cytokines and growth factors FGF, IL-1, TGFA alpha, PDGF, and TGF-beta, therefore facilitating transition from inflammation to repair •  roliferation phase: epithelization granulation collagen deposit; Angiogenesis (stimulated by P TNFα) Epithelialization • Begins hours after injury • Keratinocytes from residual epithelial structures leapfrog each other • Wound epidermal cells have lateral mobility by virtue of dissolution of intercellular desmosomes •  ells in all layers of migrating epidermis contain keratins 5 and 14 (usually only found in C basal epidermis) and keratins 6 and 16; this phenotype resembles that found in lesional psoriatic skin • One to two days after injury, cells at wound margin proliferate • f basement membrane destroyed, migration occurs over provisional matrix of collagen type I V, fibrin, fibronectin •  igrating cells both traverse over wound coated with provisional matrix and through M wound using an array integrin receptors to guide the path • Collagenase is produced to assist in migration • Migration and dissection results in eschar sloughing 20  2013/2014 Dermatology In-Review l Committed to Your Future Report a Problem/Feedback
  • 33. •  igration is a result of a combination of chemotactic factors, direct guidance by contact, M and loss of nearest neighbor, but not by proliferation • Once basement membrane proteins reappear, epidermal cells revert to their normal phenotype • 1st degree burn - basement membrane intact • 2nd/3rd degree burn - basement membrane destroyed Granulation Tissue • Four days after injury, granulation tissue forms •  omposed of new capillaries, macrophages, fibroblasts and blood vessels, which move into C wound space as a unit • Formation of granulation tissue dependent on presence of fibronectin • Ordered sequence of matrix deposition: fibronectin → collagen III → collagen I • Granulation tissue primarily contains collagen type III 1.5 MATURATIONAL Fibroplasia and Wound Contraction •  ibroplasia is granulation tissue that arises from fibroblasts, and is a mixture of fibroblasts F and extracellular matrix (ECM) •  onocytes → macrophages → secretion of growth factors (also from platelets) → fibroblast M proliferation and activation of fibroplasia • Once migrated into a wound, protein synthesis occurs to create the ECM/collagen matrix •  ound contraction ensues during second week of healing → governed by wound fibroW blasts’ ability to act like smooth muscle cells (myofibroblasts), anchored by collagen bundles • Large bundles of actin-containing microfilaments appear in these fibroblasts • Fibroplasia in wound repair ends with apoptosis of fibroblasts at or around day ten of healing • 30% of normal strength Neovascularization • Soluble factors that stimulate angiogenesis: VEGF, TGF, angiogenin, angiotropin, and others • Angiogenesis occurs during first week of wound repair •  ngiogenesis initiated by plasma leak, release of FGF, and subsequent activation of collageA nase to break down the basement membrane on which the endothelial cells rest •  he endothelial cells project pseudopods through the basement membrane and subseT quently migrate into the connective tissue space Tissue Remodeling • Endothelial cells are first to apoptose, then myofibroblasts, and macrophages, leaving an acellular scar • Progression of events over time: early formation of types I, III, and V collagen, collagen bundles grow in size • Increasing wound tensile strength, and proteoglycans are deposited increasing wound resilience to • Deformation Report a Problem/Feedback Basic Science and Structure of Skin    21
  • 34. •  ibrin: First extracellular matrix to be deposited; for effective hemostasis, interaction must F occur with platelets (via GPIIb-IIIa integrin); fibroblasts require fibronectin for migration into a fibrin clot • Fibronectin: circulates in blood and binds fibrin •  yaluronan (hyaluronic acid): linear polymer (member of glycosaminoglycans); major comH ponent of early granulation tissue; produced by fibroblasts Strength of Scar • 5% at one week • 20% at three weeks • 70% at one year 1.6 HAIR FOLLICLE BIOLOGY Embryology • First primordial hair follicles form at nine weeks gestation on eyebrows, upper lip, and chin • Remaining follicles develop at four to five months in a cephalad to caudal direction • New follicles cannot develop in adult skin • Ectodermal origin, hair papilla - mesoderm Follicular Morphogenesis • Exchange of signals between epithelial and mesenchymal cells •  regerm stage: focal crowding of epidermal basal nuclei match by a cluster of mesenchyP mal cells beneath the basement membrane •  rowding of basal keratinocytes causes a slight bud on underside of epidermis—termed the C follicle germ or primitive hair germ •  ollicle peg: Result of the elongation of follicle germ into a cord of epidermal cells that F grows into dermis perpendicular to skin surface • Tip of the epithelial cord becomes matrix portion of the bulb •  utgrowths of cells from the outer root sheath give rise to the presumptive sebaceous O gland (uppermost) and the bulge (lowermost)—the insertion site of the arrector pili muscle •  ermal papilla: Deepest portion of the bulbous hair peg that forms an invagination surD rounding the bulk of the underlying mesenchymal cells •  atrix keratinocytes: Above the BM overlying the dermal papilla—give rise to hair shaft M and inner root sheath; melanocytes responsible for the pigmentation of the hair dispersed among these matrix cells • Outer root sheath: Most peripheral epithelial cells of the follicle; most likely not formed from matrix cells Hair Follicle Organization • Outer root sheath (trichilemmal keratin): most peripheral of cellular components • Inner root sheath: Three compartments, stains red because citrulline 1.) Henle’s layer - keratinizes first uTIP 2.) Huxley’s layer anside to outside. Cuticle - IRS - Huxley-Henle - ORS - glassy/vitreous I 3.) Cuticle • Hair shaft: Three compartments 1.) Cuticle No keratohyalin granules 2.) Cortex—forms bulk of hair 3.) Medulla—central > 22  2013/2014 Dermatology In-Review l Committed to Your Future Report a Problem/Feedback
  • 35. •  ritical line of Auber: Widest diameter of the bulb; bulk of mitotic activity that gives rise to C the hair and the inner root sheath occurs below this level The Hair Cycle Anagen • 84%, 3-4 years • Follicle traverses entire epidermis •  atrix keratinocytes in the bulb region proliferate rapidly; these cells are pluripotent cells M capable of differentiating into cuticle, cortex and medulla of hair shaft •  ivided into six substages (I to VI): the first five called collectively proanagen—defined by D progressively higher levels of new hair tip position within the follicle; the 6th stage, metanagen defined by emergence of hair shaft above the skin surface • End of anagen: apoptosis • Scalp: Lasts 2 to 6 years • Leg: 19–26 weeks • Arm: 6–12 weeks • Mustache: 4–14 weeks Anagen Effluvium • Frequently seen following administration of cancer chemotherapeutic agents  •  timulus induces the abrupt cessation of mitotic activity in rapidly dividing hair matrix cells ; S hair shaft thins and then breaks at skin surface • Occurs within days to weeks of the stimulus • Entirely reversible with cessation of drug therapy Causes • Antimetabolites • Alkylating agents • Mitotic inhibitors • Thallium • Boron • Examples: doxorubicin, the nitrosureas, and cyclophosphamide Catagen • 2%, club ends, 3 weeks • Scalp hairs show gradual thinning and lightening of uTIP E aarly and excessive loss of club hairs from the pigment at the base of the hair shaft • Melanocytes in the matrix cease producing melanin, the normal resting follicles in the scalp •   hysical stress such as: surgery, anemia, P and undergo apoptosis traction or systemic illness • Involution lower 2/3rds by keratinocyte apoptosis •   sychological stress P • Matrix keratinocytes abruptly cease proliferating, •   ndocrine causes such as: hypo or hyperthyE roidism or peri-/postmenopausal states undergo terminal differentiation •   utritional deficiencies: biotin, iron, protein N •  t end of catagen, the follicular papilla comes to A (Kwashiorkor), zinc, essential fatty acid or rest at the bottom of the permanent calorie deficiency (marasmus or starvation portion of the hair follicle diets) Telogen • ~14%, duration 3 months • Hair has club-shaped proximal end, and is typically shed from the follicle Report a Problem/Feedback •  Hypervitaminosis A •  Parturition •  Fever •  Drugs Basic Science and Structure of Skin    23
  • 36. • The inner root sheath is totally absent from the telogen follicle •  air growth occurs in a “wave pattern” in humans in utero, with the first telogen entered H near the time of birth with shedding two to three months later • Mosaic growth present by end of first postnatal year Molecules Important for Transition from Anagen to Telogen • FGF5: Mut lead to angora phenotype; hair is 30-50% longer than normal • Hairless: Mut causes atrichia • Vit D receptor: Atrichia Molecules Important for Transition Telogen to Anagen • Sonic hedgehog (SHH) • Pathced (receptor for SHH) • Beta-catenin Molecules Controlling Size of Follicle • SHH, beta-catenin, noggin, BMP, FGFs, TGFb, laminin 10 Telogen Effluvium •  hese factors push the follicle from anagen to catagen and telogen T • There is no disease, and no inflammation Drugs Implicated • Amphetamines • Aminosalicylic acid • Angiotensin-converting enzyme inhibitors • Anticoagulants • Beta-blockers • Bromocriptine • Carbamazepine • Cimetidine • Danazol • Etretinate • Interferon • Lithium • L-dopa • Oral contraceptives • Valproic acid Clinical • Diffuse loss • Only rarely involves greater than 50% of the scalp •  ull test abnormal: Pull 40 hairs and more than 6 pulled out is abnormal (only 10–15% in P telogen)- make certain patient hasn’t shampooed that day •  otal number of hairs on scalp: 100,000 with 100–150 normally lost on a daily basis; T telogen effluvium results in 150–400 lost per day • In many, no specific cause identified •  ost cases stop spontaneously within a few months and hair regrows. Takes 6–12 M months for hair density to return to normal Therapy • No specific therapy 24  2013/2014 Dermatology In-Review l Committed to Your Future Report a Problem/Feedback
  • 37. Factoids • At any one time, 85% of human scalp hair in anagen, 14% in telogen, 1% in catagen • Glassy membrane can be seen as the hair follicle resorbs in catagen (remnants of basement membrane) • Hairs grow 0.4 mm per day • Hair follicles in scalp: 100,000 in brown/black hair, with 10% more in blondes, and 10% less in redheads Structure of Hair • Non-living biologic fibers • Cortex contains the bulk of the hair keratins •  eratins are intermediate filaments in which 400–500 aa residues of individual chains K arranged in sequences containing heptad repeats; pair together to form coiled coils •  ther proteins: the keratin-associated proteins (KAPs): 1) high sulfur protein rich in cysteine O and 2) high glycine/tyrosine-containing proteins •  isulfide bonding contributes to the physical properties of the fiber and these bonds are D broken during hair styling and reformed when the desired change accomplished •  uticle maintains the integrity of the fiber. If damaged by physical or chemical means, the C fiber is more likely to break—trichoptilosis (“split ends”) Hair Pigmentation •  air color determined by melanocytes, and hair is pigmented only when it grows—melanoH cytic activity of follicular melanocytes coupled to anagen stage • Hair color: melanocytes in matrix close to papilla • Melanin formation absent through telogen and catagen • Melanocytes located in matrix area of follicle, above the follicular papilla, produce the pigment • Eumelanin is the pigment of brown/black hairs and pheomelanin is the pigment in red/ blond hairs • ntensity of color proportional to the amount of pigment, and absence of pigment produces I white hair; markedly reduced pigment produces gray hair Types of Hair • Lanugo: Soft, fine hair that covers much of the fetus and usually shed before birth • Vellus scalp hair: Lengths less than 1 cm • Indeterminate scalp: Approximately 1 cm • Terminal scalp: Longer than 1 cm • Eyelash and eyebrow hairs are considered terminal Bulge-Activation Hypothesis •  he follicular epithelial stem cells located in the bulge region of the outer root sheath underT go transient proliferation during early anagen, producing the transient amplifying (TA) cells. TA cells rapidly proliferate, migrate downward, and eventually become matrix keratinocytes. Because TA cells have a limited proliferative capacity, they exhaust their proliferative reserve and undergo terminal differentiation (catagen) Defects of Hair Shaft • Monilethrix: Mut hair keratin hHb6; alternating thick and thin areas, beaded hair • Netherton’s syndrome: Trichorhexis invaginatum (bamboo hair); mut in serine-protease inhibitor Report a Problem/Feedback Basic Science and Structure of Skin    25
  • 38. • Pili annulati: Banded hair • Menkes disease: Twisted hair (pili torti); def in copper transporter • Uncombable hair syndrome: Triangle-shaped hair • Hereditary mucoepithelial dysplasia: Red gums, KP, episodic hair loss • Nanos syndrome: Mut in plakoglobin; wooly hair hyperkeratotis of palms and soles, cardiac arrhythmia 1.7 SEBACEOUS GLANDS • Enlarge at puberty in response to increased androgens • Often consists of several lobules that empty into a sebaceous duct • Holocrine glands/secretion •  ound in association with hair structures, but there is no relationship between the size of F the sebaceous gland and the size of the associated hair • Under androgenic hormonal control not neutral control  • Free sebaceous glands not associated with hairs are found in specific locations – Nipple and areola → Montgomery’s areolar tubercles – Fordyce’s condition → free sebaceous glands on vermillion border of the lips and on the buccal mucosa – Meibomian glands → located deep on the eyelids, usually embedded in tarsal plate, are modified sebaceous glands. Forms the most exterior (lipid) layer of the tear film, preventing evaporation. Inflammation = chalazion. Empties to mucosa – Glands of Zeis → located on superficial eyelid margin. Also contributes to exterior tear film layer. Inflammation = hordeolum. Empty to skin – Glands of Moll apocrine glands on lid margin – Tyson’s glands → free sebaceous glands located on the genitalia • Found everywhere on the skin except the palms and soles (prepuce) Table 1-9. Sebum and Epidermal Components Sebum Components: Epidermis: Glycerides 57.5% 65% Wax esters 26% 0 Squalene 12% 0 Cholesterol esters 3% 15% Cholesterol 1.5% 20% • Rate of sebum proction 1mg/10cm2 • Thermoregulatory role • Human sebum different from other lipids by wak esters 1.8 ECCRINE GLANDS u TIP • Thermoregulatory a holinergic stimulation regulates activity C (thus, efficacy of botulinum toxin) • Postganglionic sympathetic fibers •  omposed of three segments: intraepidermal duct C (acrosyringium), the intradermal duct, and the secretory portion •  asal coil exists either in the lower portion of the dermis or at the border of the dermis and B the subcutaneous fat 26  2013/2014 Dermatology In-Review l Committed to Your Future Report a Problem/Feedback
  • 39. • S100, CEA, keratin positive •  resent everywhere on the skin, but absent in modified skin that lacks cutaneous appendP ages: Vermillion border of the lips, nail beds, labia minora, glans penis, clitoris, ext auditory canal. Highest density on palms and soles •  weat formed in two steps: secretion of primary fluid, isotonic NaCl concentrations; then S reabsorption of NaCl by the duct. Sweating rate most important determinant of NaCl concentration in final sweat fluid. Other components: lactate, urea, ammonia, amino acids, proteins and proteases •  ne of few fetal structures that does not develop craniocaudal (develop 1st on palms and O soles 4th month, body 5th month). Fully formed at birth not fully functional •  ong thin duct open to skin L 1.9 APOCRINE GLANDS • Innervated by sympathetic fibers • Develop from mantle of hair follicle. 1st seen week 24 on scalp • Tubular glands that demonstrate decapitation secretion; part of cell pinched off during secretory process •  ike eccrine glands, composed of three segments: intraepidermal duct, intradermal duct, L and the secretory portion •  uct of apocrine gland usually leads to a pilosebaceous follicle above entrance of the sebaD ceous duct •  pocrine glands found in axillae, anogenital region, external ear canal (ceruminous glands), A in the eyelids (Moll’s glands), in the breast (mammary glands), and periumbilical region • Function begins at puberty. Unclear role - ? olfactory communication •  ecretion in response to emotive stimuli—through action of epinephrine/norepinephrine. S Denervation does not abolish this response, though apocrine sweating requires intact nerve supply • nitial secretion is odorless, and odor derived from C6–C11 acids - the most abundant is I 3-methyl-2-hexenoic acid • Stain + keratin, S100, CEA, lysozyme • Short thick duct opens into follicular canal; decapitation secret – Disease: Fox fordyce disease (occlusion of apocrine ducts); chromhidrosis - pigmented sweat due to lipofuscin context. Bromhidrosis - abnormal body odor by apocrine gland secretion 1.10 NAILS • (see Chapter on Disorders of the Hair and Nails) 1.11 NERVES AND RECEPTORS OF THE SKIN •  ensory nerve fibers may exist alone (free nerve endings) or in conjunction with specialized S receptors of touch, pain, temperature, itch, and mechanical stimuli • Receptors especially dense in hairless areas •  fter sweat glands (cholinergic for eccrine; adrenergic for apocrine - after vascular smooth A muscle (adrenergic → vasoconstriction) after hair follicles (adrenergic → contracting) • Innervation of the skin derived from the musculocutaneous branches of the spinal nerves • Sensory nerves are roughly distributed in dermatomes, but overlap occurs Report a Problem/Feedback Basic Science and Structure of Skin    27
  • 40. • Itch is transmitted via afferent fibers of the A-delta and C-polymodal nociceptor class • Adrenergic innervation controls vasoconstriction, apocrine secretion, and contraction of arrector pili muscles • Eccrine sweating is under the control of cholinergic nerves • Sebaceous glands are not under neural control, and only respond to chemical stimuli such as hormones Free Nerve Endings • Most widespread and important type • Penicillate fibers found subepidermally in hair-bearing skin: detect touch, pain, temperature, and itch; function in fine discrimination in the non-hairy, ridged areas of skin • Papillary nerve endings are found at the orifice of the hair follicle and particularly sensitive to cold • Free nerve endings also penetrate the epidermis to contact Merkel cells Corpuscular Receptors • Contain a capsule and inner core, and contain both neural and nonneural constituents • Meissner’s corpuscle: Ovoid, elongated mechanoreceptor located in the dermal papillae of digital skin; detect touch and light pressure • Pacinian (Vater-Pacini) corpuscle: Exists in deep dermis and within subcutis in weight-bearing sites of the body; functions as an adapting mechanoreceptor that responds to vibrational stimuli; perineural capsule •  rause end bulbs: Mucocutaneous receptors found on glans penis, clitoris, labia minora, periK anal area, and vermillion border of the lips 1.12 IMMUNOFLUORESCENCE PATTERNS - DIRECT Immunofluorescence Intercellular Space (ICS) Deposition • Majority show IgG → all types of pemphigus, except IgA pemphigus • Similar pattern seen in PV, PF, and their variants (P. vegetans and P. erythematosus) • Complement C3 may be seen in ICS, too • IgA → IgA pemphigus, target protein is desmocollin I (115 kd) • Positive predictive value of DIF in diagnosis of pemphigus is 100%, the negative predictive value is 85% Intercellular Space and BMZ Combination • Paraneoplastic pemphigus → antibodies to BMZ proteins and desmosomal proteins • Drug-induced pemphigus → antibodies to desmoglein 1 (2/3 of patients) and desmoglein 3 (1/3 of patients) BMZ Deposition Alone • gG and/or C3 at BMZ→ bullous pemphigoid, mucosal pemphigoid, pemphigoid gestationis, I EBA, and bullous SLE • C3 much higher intensity than IgG favors pemphigoid group of diseases • IgG much higher intensity than C3 favors EBA and bullous SLE • Differentiation between BP and PG is not possible using either histology or IF • Multiple deposits at the BMZ favors bullous SLE and EBA over the pemphigoid group •  seful for differentiating between bullous SLE and EBA based on underlying diagnosis of U SLE by clinical and serologic criteria 28  2013/2014 Dermatology In-Review l Committed to Your Future Report a Problem/Feedback
  • 41. • Linear deposition of IgA at BMZ → Linear IgA bullous dermatosis or chronic bullous disease of childhood DIF Using Salt-split Specimens • 1 molar NaCl splits BMZ at lower lamina lucida •  ifferentiates BP from EBA: Pemphigoid deposits seen at epidermal side of split; EBA and D bullous SLE show deposits at dermal side • Anti-epiligrin pemphigoid → dermal staining Mucosal Disease • Seen with mucosal pemphigoid, EBA, cicatricial pemphigoid, and linear IgA disease • Mucosal LP shows cytoid bodies with thick band of fibrinogen • IgG and C3 deposit in mucosal pemphigoid and antiepiligrin disease Blood Vessel Deposition •  CT, pseudoporphyria, and EPP → homogeneous deposits of multiple immunoreactants P within superficial dermal blood vessel walls, in addition to BMZ deposition • IgG and IgA most common Papillary Dermal Deposition • Dermatitis herpetiformis → IgA and C3 in papillary dermis and along the BMZ • DH: IgA deposition in 100% of patients when biopsy taken from normal-appearing perilesional skin Indirect Immunofluorescence IgG Anti-intracellular Antibodies • Pemphigus vulgaris, pemphigus foliaceus, paraneoplastic pemphigus, and drug-induced pemphigus • Patients with burns, penicillin drug eruptions, skin grafts, bullous pemphigoid, and mucosal pemphigoid • Paraneoplastic pemphigus: rat bladder epithelium (75% sensitive, 83% specific); stains desmosomes IgA Anti-intracellular Antibodies • IgA pemphigus (50% of patients) IgG Anti-BMZ Antibodies • 75% of patients with BP • 50% of patients with EBA IgA Anti-BMZ Antibodies • Adult and childhood forms of linear IgA disease Dermatitis Herpetiformis • Antiendomysial, antireticular, and antigliadin antibodies • Not diagnostic Bullous Pemphigoid vs EBA: IIF • Salt-split skin - EBA shows dermal staining (collagen VII) • Pemphigoid disorders show epidermal and dermal staining Herpes Gestationis Factor • Amplified IIF procedure • Positive in 50% of patients with HG Report a Problem/Feedback Basic Science and Structure of Skin    29
  • 42. 1.13 CONNECTIVE TISSUE DISEASES Table 1–10. DIF Pattern in Connective Tissue Disease Disease Direct Immunofluorescence Pattern/Useful Info DLE • Immune deposits along the DE junction → IgG and IgM • Cytoid bodies → d egenerated basal keratinocytes d ropped into the papillary dermis → IgM and IgA • Patterns: shaggy, granular, linear • Biopsy the oldest, untreated lesion on non-sun-exposed skin SCLE • Immune deposits along the DE junction and basal keratinocytes → IgG and IgM • Cytoid bodies → IgM and IgA • Granular fluorescence throughout the cytoplasm and nucleus of basal keratino cytes (unique to SCLE) → reflects binding to Ro and La antigens Mixed Connective Tissue Disease • Deposits within epidermal cell nuclei (IgG) • Rarely along the DEJ Scleroderma, Morphea • DIF of no value and Neonatal LE Erythema Multiforme • DIF shows immunoglobulin within superficial vessel walls, DEJ, and cytoid bodies Dermatomyositis • Pattern similar to LE, but intensity of fluorescence pattern is usually lower in DM Vasculitis • Deposition of C3 within superficial blood vessel walls • In HSP, IgA is the primary immunoglobulin (75% of patients) Disease Direct Immunofluorescence Pattern/Useful Info Lichen Planus • DIF positive in vast majority • Deposition within cytoid bodies in superficial dermis → IgM and fibrinogen • DEJ deposition is granular SLE • Serology more reliable than DIF • DEJ deposition → lupus band test, lesional and nonlesional skin • Cytoid bodies → IgM and IgA • Immune deposits may be located in superficial dermal blood vessel walls similar to vasculitis • Epidermal keratinocyte nuclei staining, seen in patients with antibodies to U1RNP RE F E REN C E S 1. Freedberg IM, Eisen AZ, Wolff K, et al., eds. Fitzpatrick’s Dermatology in General Medicine. 6th ed. New York McGraw-Hill, Health Professions Division, 2003. 2. Odom RB, James WD, Berger TG. Andrew’s Diseases of the Skin: Clinical Dermatology 9th ed. Philadelphia: WB Saunders Company, 2000. 3. Elder DE, et al. eds. Lever’s Histopathology of the Skin. 8th Ed.: Lippincott Williams & Wilkens, 1997. 4. Bikle DD, Pillai S, Gee E, Hincenbergs M. Tumor necrosis factor-alpha regulation of 1,25-dihydroxyvitamin D production by human keratinocytes. Endocrinology. 1991 Jul;129(1):33-8. 5. Bolognia, J, et al. eds. Dermatology. 1st Ed.: Mosby, 2003. 30  2013/2014 Dermatology In-Review l Committed to Your Future Report a Problem/Feedback
  • 43. NOTES Report a Problem/Feedback Basic Science and Structure of Skin    31
  • 44. NOTES 32  2013/2014 Dermatology In-Review l Committed to Your Future Report a Problem/Feedback
  • 45. 2 Immunodermatology Eric Huang, MD, PhD William R. Levis, MD Georgia B. Schuller-Levis, PhD C o n t e n t s 2.1 2.2 Cells of the Innate and Adaptive Immune System . . . 36 2.3 Cytokines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40 2.4 Antibodies and Complement . . . . . . . . . . . . . . . . . . . . 42 2.5 Major Histocompatibility Complex and HLA Disease Associations . . . . . . . . . . . . . . . . . . . . . . 45 2.6 Report a Problem/Feedback The Innate and Adaptive Immune Systems . . . . . . 35 Non-Steroidal Immunologic Therapies . . . . . . . . . . 46 Immunodermatology 33
  • 46. 2.1 THE INNATE AND ADAPTIVE IMMUNE SYSTEMS It is helpful to divide the immune system into two complementary branches based upon the plasticity of their responses. The innate immune system is often ascribed non-specific receptors, but it is more accurate and useful to understand that it uses pre-determined receptors that specifically recognize non-self pathogens but not self antigens. In contrast, the adaptive immune system relies upon gene rearrangement to produce receptors specific for individual antigens, and these receptors may potentially bind both non-self and self antigens. The immune system is composed of both cellular and non-cellular components. Keratinocytes and mucosal epithelia provide a physical barrier against pathogens and can also secrete cytokines such as TNF and IL-1. Soluble factors such as antimicrobial peptides and canthelicidins, complement, cytokines, and antibodies assist the cellular components (leukocytes). Leukocytes are subdivided by function into granulocytes (neutrophils, eosinophils, mast cells, basophils), lymphocytes (B cells, T cells, natural killer cells), and monocytes (called histiocytes in tissue; Langerhans cells in the epidermis). Innate Immunity u TIP • Rapid response, “first line of defense” aTLR7 binds imiquimod; native • Lack of memory: Repeated exposure does not change the ligand is ssRNA response • Provides initial inflammatory signals which recruit lymphocytes (adaptive immunity) • Lack of innate inflammatory signal may induce tolerance by adaptive immunity Receptors • No gene rearrangement, limited antigen recognition repertoire • Germline-encoded, distinguish non-self from self u TIP •  attern recognition receptors include toll-like receptors (TLR) P a ecreased expression of antiD and nucleotide oligomerization domain receptors (NODs); these microbial peptides in atopics vs. psoriatics may explain receptors recognize PAMPs (pathogen-associated molecular  increased cutaneous infection patterns) in the former • TLR family has 13 members. Highest expression levels are found in monocytes, dendritic cells, and B cells • TLR7 binds imiquimod, expressed on melanocytes, native ligand is ssRNA • TLR7 activation results in pleiotropic responses, including u TIP antigen presenting cell (APC) activation and cytokine aCytokines: particularly TNFα, IL-1, IL-10, IL-12, IFNα, IFNβ production (IL-12, IFNα, TNFα) • TLR2 may be activated in inflammatory acne • TLR2 and TLR9 polymorphisms associated with atopic dermatitis Non-Cellular Components • Antimicrobial peptides: defensins and canthelicidins are u TIP produced by phagocytes and keratinocytes and directly kill a  igher β-defensin 2 levels in H bacteria, fungi, and viruses psoriatic lesions are associated • DEFB4 encodes β-defensin 2, which is strongly expressed in with more severe disease activity active psoriatic lesions • Complement: see below Cellular Components • Macrophages, neutrophils, natural killer cells, mast cells, eosinophils, intraepithelial lymphocytes Report a Problem/Feedback Immunodermatology 35
  • 47. Adaptive Immunity • Delayed response (initially) • Memory (stronger elicitation responses upon re-exposure) Receptors • Gene rearrangement leads to randomly generated receptors with ability to recognize millions of antigens  •  o not distinguish self from non-self D • Require antigen presentation in context of MHC molecules Non-Cellular Components • Antibodies: see below Cellular Components • T cells, B cells, Langerhans cells 2.2  CELLS u TIP aCytokines: particularly IL-2, IL-4, IL-5, IFNγ, TGFβ OF THE INNATE AND ADAPTIVE IMMUNE SYSTEM Phagocytes (Macrophages and Neutrophils) • Identify microbes using receptors for mannose, opsonins, and TLRs • Ingest pathogens •  estroy pathogens by producing reactive oxygen intermediates via phagocyte oxidase, D nitric oxide via inducible NO synthase, and lysosomal enzymes such as lysozyme, elastase, and collagenase u TIP • Activated by CD4+ and CD8 + T cells through IFNγ and CD40L aDefect in phagocyte oxidase • Phagocytes are unable to kill intracellular organisms (screening test nitroblue tetrazolium reduction assay) leads to chronic granulomatous disease Mononuclear Phagocytes • Once localized in tissues, are called macrophages • In addition to phagocytosis, macrophages degrade foreign antigens or cells into peptide antigens for presentation to T cells • Express Fc receptors for IgG • Produce cytokines which recruit other inflammatory cells Neutrophils • The most abundant leukocyte • Major function is phagocytosis • Have receptors for IgG and complement • Have many storage granules • Hereditary deficiencies of neutrophil function lead to overwhelming bacterial infection, which can be fatal Granulocytes •  Neutrophils, eosinophils, mast cells, and basophils are collectively known as granulocytes Eosinophils •  Provide protection against helminths •  Function through antibody-dependent cell-mediated cytotoxicity via IgG and IgE (independent of complement) • Release major basic protein (toxic to all cells, but particularly helminths) and leukotrienes  • Activated by IL-5 36  2013/2014 Dermatology In-Review l Committed to Your Future Report a Problem/Feedback
  • 48.  Mast Cells •  Provide protection against bacteria and parasites •  Express high levels of FcεRI (receptor for IgE) •   elease histamine, prostaglandins, leukotrienes, cytokines, tryptase (elevated in serum of R patients with mastocytosis) u TIP •  Central cell in immediate-type hypersensitivity a dult mastocytosis most frequently A through IgE-mediated release of histamine related to activating mutations in c-kit tyrosine kinase (but not childhood •  Many cases of idiopathic urticaria have circulating disease) autoantibodies directed against the chain of high affinity IgE receptor on the mast cell surface Monocytes  Langerhans Cells • Immature dendritic cells found in epidermis and mucosa • Migrate to regional lymph nodes upon Ag capture, undergoing maturation to become antigen presenting cell (APC) • Present processed peptide associated with MHC II to T cells (primarily CD4+), resulting in T cell activation u TIP •  xpress surface marker CD1a E a irbeck granules (characteristic B • Adhesion to keratinocytes mediated by e-cadherin racket shape on EM) are part of endosomal recycling compartment • Express B7 molecules (CD80 or CD86) only after activation by antigen or other exogenous stimuli • TGFβ upregulates e-cadherin expression and maintains Langerhans cells in immature state • Adjuvants work through APCs to increase costimulatory molecule expression and cytokine expression Lymphocytes These cells are primarily responsible for the specificity of the immune response. Lymphocytes are triggered by a specific antigen to produce antibodies (B cells), cytokines (CD4+ T cells) or cause direct cytotoxicity (CD8+ T cells).  Natural Killer Cells • dentify virally-infected or transformed (tumor) host cells via their down-regulation of selfI MHC I • Possess activating and inhibitory receptors • Activating receptors bind ligands common to self • Inhibitory receptors identify self-MHC I; if stimulated, dominantly inhibit NK cell activity • Destroy cells via perforins and granzymes (same as T effector cells) • Activated by IL-12 and IL-15, secrete IFNγ • Mediate antibody-dependent cellular cytotoxicity B Cells •  rogenitors in the bone marrow develop into immature B lymphocytes that express an P antigen-specific receptor • Interaction between the antigen and the surface bound antibody (receptor) initiates B cell activation • Express MHC II molecules, receptors for complement, and Fc receptor  •  ithin lymph node, located in lymphoid follicle W • In the presence of particular cytokines, undergo isotype switching of antibodies Report a Problem/Feedback Immunodermatology 37
  • 49. T Cells • Progenitors arise in the bone marrow, but migrate to thymus for maturation • Subdivided into functionally distinct populations of helper (CD4+) and cytotoxic (CD8+) T cells • Respond to stimulation by production of cytokines or causing cell lysis • Require two signals for activation u TIP • Signal 1 comprised of T cell receptor binding to MHC a ocated in paracortex of lymph nodes L molecule on APC • Signal 2 involves CD28 on T cell interacting with B7 molecule located on APC • MHC/TCR engagement in absence of costimulation results in anergy CD4+ T Cells • CD4+ T cells (helper T cells) may be divided into four subtypes: TH1, TH2, TH17, Treg • TH1 cells augment T cell-mediated immunity, activate macrophages, and downregulate TH2 responses via IFNγ  •  H2 cells suppress macrophage activity, activate eosinophils, induce isotype switching to T IgE and IgG4, and downregulate TH1 responses via IL-10 u TIP •  H17 cells are proinflammatory; implicated in the pathoT a H2 diseases: atopic dermatitis, CTCL, T lepromatous leprosy, disseminated genesis of psoriasis and other autoimmune diseases such cutaneous (chronic) leishmaniasis as RA, MS, and IBD •  H17 cells secrete IL-17A, IL-17F, IL-21, IL-22, IL-23, and T TNFα • TH17 differentiation induced by TGFβ. Proliferation and survival mediated by IL-23 • Treg cells are important in down-regulation the immune response, and likely play a role in diseases associated with autoimmunity, immune dysregulation, and tumor biology • Treg cells express high levels of CD25 (IL-2 receptor alpha chain) and are characterized by expression of transcription factor FOXP3 • Treg cells suppress immune response through direct contact inhibition, secretion of IL-10, or TGFβ • Mutation of FOXP3 results in absence of Treg and is the cause of IPEX syndrome (Immune dysregulation, Polyendocrinopathy, Enteropathy, X-Linked syndrome) IL-4 IL-5 IL-10 IL-10 TH2 Treg IL-4 TGFb CD4+ IFNg IL-12 TGFb+ IL-6 TH17 IL-1 IL-21 TH1 IL-17 IL-22 IL-2 IFNg Figure 2-1. CD4+ T Cell Differentiation and Associated Cytokines 38  2013/2014 Dermatology In-Review l Committed to Your Future Report a Problem/Feedback
  • 50. CD8+ T Cells • Kill by releasing granules containing perforin and granzymes, which induce apoptosis • May also induce apoptosis by presenting FasL to Fas receptor on target cells γδ T Cells •  T Cells which possess a γδ T Cell receptor (TCR) as opposed to the more common αβ TCR (as seen in CD4+ and CD8+ T cells) • Primarily found in epithelia and appear to play a role in immunoregulation and immunosurveillance • Suppress TH1 cells through release of IL-10 • May play important roles in cancer surveillance and resistance to graft-vs.-host disease Table 2-1. T Cell Surface Receptors Receptor Location Binding Partner Location Effect TCR T cell Ag-MHC I or II APC Activation CD2 T cell LFA-3 Endothelial cells, APC Adhesion, activation CD4 T cell MHC II APC Activation CD8 T cell MHC I APC Activation CD28 T cell B7 (CD80, CD86) APC, target cell Activation (2nd signal) CTLA-4 Activated T cell B7 (CD80, CD86) APC Inhibition CD40L T cell CD40 APC, B cell Activation PD1 Activated T cell PD-L1, PD-L2 APC, normal tissue Inhibition LFA1 (CD18 + CD11a) T cell ICAM-1 Endothelial cells, APC Migration, adhesion Mac-1 (CD18 + CD11b) Macrophages, neutrophils, NK cells ICAM-1 Endothelial cells, APC Migration, adhesion *Mutation in CD18 causes leukocyte adhesion deficiency I Figure 2-2. T Cell - APC Interactions Report a Problem/Feedback Immunodermatology 39
  • 51. 2.3 CYTOKINES Cytokines are a structurally diverse group of molecules that have important local and systemic effects contributing to both innate and adaptive immunity. There are three major structural families: the hematopoietin family, which includes interleukins and growth hormones, the tumor necrosis factor (TNF) family, and the chemokine family. Most cytokines produced by T cells are given the name interleukin (IL) followed by a number. TH1 and TH2 cells release different but overlapping sets of cytokines. TH1 cells secrete IFNγ, which is the main macrophage-activating cytokine, TNFα, and lymphotoxin. TH2 cells upregulate humoral immunity by secreting IL-4 and IL-5, and inhibit macrophage activation via IL-10. The main cytokine released by CD8+ effector cells is IFNγ. u TIP a ajor producers are helper M • Small secreted proteins with pleomorphic effects, including T Cells and macrophages cell growth and differentiation, inflammation and immunity (phagocytosis, intracellular killing, effector function), and cell migration (chemokines) • Cellular response mediated by binding to specific receptors • Expressed in groups (skewing towards TH1 or TH2 responses) TH1 Cytokines  • IFNγ: Differentiation toward TH1 cells; increased MHC I and II on APCs; enhanced macrophage activity • IL-2: Proliferation and activation of T cells (clonal expansion), B cells (antibody production), and NK cells • IL-12: Heterodimer of p40 and p35 subunits. Increased cytolytic activity and IFNγ production by T cells and NK cell. IL-12B encodes p40 Figure 2-3. IL-12 and IL-23 Cytokines and Receptors Share Similar Subunits 40  2013/2014 Dermatology In-Review l Committed to Your Future Report a Problem/Feedback
  • 52. TH2 Cytokines • IL-4: Differentiation toward TH2 cells; isotype switching to IgE and IgG4, inhibition of macrophage activation • IL-5: Activates eosinophils + B Cell differentiation • IL-6: Proliferation and differentiation of B cells • IL-10: Decreases expression of MHC II and costimulatory molecules on APCs; decreases IL-12 • IL-13: Related to IL-4; implicated in allergic inflammation  TH17 Cytokines • IL-17: Family of cytokines that are proinflammatory, resulting in production of many cytokines including IL-6 and TNFα u TIP U • IL-17 members include IL-17A and IL-17F, which are implicated a stekinumab targets p40 subunits of IL-12 and IL-23; approved for in allergic and autoimmune inflammation as seen in asthma, treatment of psoriasis SLE, and RA • IL-22: Members of IL-10 family that mediates inflammation u TIP through STAT transcriptional activation pathway; stimulates aL-17 and IL-22 enhance keratinoI cyte expression of antimicrobial keratinocyte proliferation peptides, and IL-22 stimulates kera• IL-23: Heterodimer of p40 (as in IL-12) and p19 subunits. tinocyte proliferation as seen in Required for survival and proliferation of TH17; may be key psoriasis cytokine in development of psoriasis. IL-23A encodes p19 u TIP • IL-36: members of IL-1 family of cytokines. Expression a omozygous mutation in IL-36Ra H induced in keratinocytes by IL-17A and TNFα. Increased gene leads to unregulated IL-1 familyexpression of IL-36 correlates with Th17 cytokines in psoriatic mediated inflammation, causing lesions. IL-36 Ra is a protein antagonist for IL-36 receptor generalized pustular psoriasis Other  u TIP a NFα expression inhibited by T •   NFα: Primary mediator of acute inflammation, fever, T hepatic production of acute phase reactants thalidomide Table 2-2. Cytokine Activities Cytokine Produced by Target cells Action GM-CSF Helper T cells Leukocyte progenitors Growth and differentiation IL-1 Macrophages B cells Helper T Cells Co-stimulation B Cells Maturation and proliferation IL-2 TH1 B, T, NK cells Growth, proliferation, and activation IL-4 TH2 Macrophages B Cells Naive CD4+ T Cells Increase MHC II expression Proliferation, IgG4 and IgE T cells synthesis Proliferation, differentiation to TH2 B Cells TH2, macrophages B cells Eosinophils Proliferation and differentiation, IgA synthesis Activation Report a Problem/Feedback Immunodermatology 41
  • 53. Table 2-2. Cytokine Activities (cont.) Cytokine Produced by Target cells Action IL-5 TH2 B Cells Naive CD4+ T Cells Differentiation to plasma cells Differentiation to TH17 cells IL-6 Macrophages B cells Macrophages B Cells Inhibit cytokine production Activation IL-10 TH17 T Cells Naive CD4+ T Cells Differentiation to effector T cells Differentiation to TH1 cells IL-12 TH17 T Cells Naive CD4+ T Cells Differentiation to effector T cells Differentiation to TH1 cells IL-17 TH17 Multiple targets Inflammation IL-21 Activated APCs Naive CD4+ T Cells Differentiation to TH17 cells IL-22 Leukocytes Fibroblasts Multiple targets Inflammation; keratinocyte proliferation IL-23 TH1 Cytotoxic T cells NK cells TH17 Survival and proliferation IL-36 Langerhans cells keratinocytes CD4+ T cells Dendritic cells Differentiation to TH17 cells IFNα, IFNβ Leukocytes Fibroblasts Multiple cell types Inhibit viral replication; increase MHC I expression IFNγ TH1 Cytotoxic T cells NK cells Macrophages Increase MHC expression, killing TH2 B Cells Inhibit proliferation Switch to IgG2a 2.4 ANTIBODIES AND COMPLEMENT Antibodies All antibodies have the same overall structure and are known collectively as immunoglobulins (Ig). Antibodies are produced by plasma cells in response to infection or immunization. They bind to and neutralize toxins or pathogens and prepare them for uptake and destruction by phagocytes. Each antibody has a unique antigen-binding domain which recognizes the antigen epitope. •  ntibodies are divided into several classes based upon differences in the structure of the A heavy chain •  ntibody molecules in each class are defined as having the same isotype. The basic structure A of antibody molecules is similar between the various classes and is depicted in Figure 2 •  roteolytic cleavage with papain generates two basic functional domains: two Fab fragments P and one Fc fragment  •  he Fab fragment consists of the light chain and the amino terminal half of the heavy chain, T bound to each other by disulfide bonds. The Fab fragment contains antigen-binding activity • The Fc domain functions in complement activation and opsonization mediated by Fc recep- tors on phagocytes 42  2013/2014 Dermatology In-Review l Committed to Your Future Report a Problem/Feedback
  • 54. Antibody Functions • Neutralization of microbes and toxins by direct binding (e.g., Staphylococcal toxin; children are more susceptible than adults due to lack of antibodies) • Enhance opsonization of microbes via Fc receptors on phagocytes or by fixing complement • Lysis of microbes and inflammation via complement activation • In typical humoral response, isotype switching occurs subsequent to exposure to antigen • Switching is regulated by T cell-derived cytokines (IgG by IL-4, IL-6, IL-2, and IFNγ; IgA by IL-5 and TGFβ; IgE by IL-4) • Gardasil vaccine directed against HPV 6, 11, 16, 18. Indicated in females 9-26 years old. Indicated in males 9-26 years old for prevention of genital warts caused by HPV 6 and 11 • Cervarix vaccine directed against HPV 16, 18. Approved for females 10-25 years old • Zostavax indicated for prevention of herpes zoster in men and women at least 50 years old Distinguishing Features of Isotypes • Opsonizing antibodies: IgG1 and IgG3 • FcgRI has highest affinity for IgG (isotype 1 and 3) and is located on macrophages, neutrophils, eosinophils, leading to phagocytosis u TIP • Neutralizing antibodies: IgA1 and IgA2 at mucosal surfaces, a yper IgE syndrome patients H IgG2 and IgG4 in tissue have constitutive high IgE levels, • Complement fixing antibodies: IgG1, IgG3, IgM deficient Th1 responses, and suffer from cold abscesses and • IgA primarily at mucosal surfaces, prevent colonization by eczematous dermatits pathogens, important neutralizing function • IgD functions as antigen receptor on mature B cells • IgE binds allergens, stimulates mast cells; increased in atopic individuals uTIP agG crosses the placenta I • IgG is the predominant antibody in a secondary immune response, most abundant in serum, best for opsonization. Also neutralizes pathogens and fixes complement • IgM is the first antibody produced by B cells, secreted by plasma cells as a pentamer • IgM doesn’t enter tissue well due to size; most efficient Ig at fixing complement • High-affinity receptor for the Fc region of IgE expressed on mast cells, basophils and Langerhans cells Ag binding heavy variable Fab light chain papain cleavage constant Fc Figure 2-4. Antibody Structure Report a Problem/Feedback Immunodermatology 43
  • 55. Complement Complement consists of a series of 25 serum and membrane proteins. These glycoproteins act as effectors in both innate and adaptive immunity. The complement cascade system has two important effects on cells, opsoniza-tion and membrane damage. Biologic activities of complement also include chemotaxis, anaphylaxis, immune complex solubilization, and B cell activation (provides second signal). The cascade has three pathways: the classical, alternate, and mannosebinding lectin. All act via sequential recruitment, proteolytic activation and assembly, with the ultimate endpoint being formation of membrane attack complex (MAC), which inserts into lipid membranes and causes osmotic lysis of cells. Classical Pathway • Activated by antigen-antibody (IgM or IgG) complexes • The proteins of the classical pathway are C1, C2, C3, and C4 • C1 binds, recruits C2 and C4 forming C3 convertase, cleaves C3 and C5 • C1 INH prevents C1 protease activity • C3a: Neutrophil chemoattractant (inflammation) • C3b: Opsonin (binds to pathogen, enhancing phagocytosis) • C5a: Anaphylatoxin (chemotaxis, increased vascular permeability, mast cell activation) • C5b: Combines with C6,7,8,9 to form membrane attack complex Alternate Pathway • Activated by bacterial products, including lipopolysaccharide (LPS) from gram negative bacteria • Proteins in the alternate complement pathway are Factor B, Factor D, Factor H, properdin and C3 Mannose-Binding Lectin Pathway • Activated by inflammatory macrophage cytokines Complement Receptors • Eight receptors have been identified • CR1 (also known as CD35) in main receptor for C3b. Plays important role in mediating clearance of immune complexes, phagocytosis, and immune adherence of antibodycoated bacteria to erythrocytes • CR2 (also known as CD21) presents antigen to B cells and is a co-receptor for B cell signaling u TIP • CR3 (CD11b/CD18 heterodimer) and CR4 (CD11c/CD18 a BV utilizes the CR2 receptor E heterodimer) are members of the beta-2 integrin family for cell entry and infection (remember CD11a/CD18 is also known as LFA-1) and bind ICAM-1 u TIP • Other receptors include C1qRP, C3aR, C4aR, and C5aR; aAD type 1 patients suffer from L the latter three mediate anaphylactic reactions mucositis, poor wound healing, and • Acquired deficiency of CR1 is associated with frequent skin infections without puss or inflammation that can resemble autoimmune disorders such as SLE pyoderma gangrenosum • Deficiencies in CR3 and CR4 are found in leukocyte adhesion deficiency (LAD) type 1 Complement Deficiencies  •  arly defects (C1, 2, 3, 5) lead to susceptibility to encapsulated E organisms, especially Pneumococcus 44  2013/2014 Dermatology In-Review l Committed to Your Future u TIP a ate defects (C5-9) confer L susceptibility to Neisseria Report a Problem/Feedback
  • 56.   • Association of C1-5 deficiency with SLE may be due to genetic linkage • Late defects (C5-9) confer susceptibility to Neisseria • C3 deficiency associated with partial lipodystrophy • Hereditary angioedema (HAE) type I is most common, due to low levels of C1 INH with normal function • HAE type II is less common, due to normal levels of non-functional C1 INH • Acquired angioedema (AAE) is due to consumptive processes, so C1 INH levels are low • To differentiate AAE and HAE, measure C1q (normal in HAE, low in AAE) 2.5  AJOR M HISTOCOMPATIBILITY COMPLEX & HLA DISEASE ASSOCIATIONS The molecules that display peptide antigen to T cells are cell-surface glycoproteins named the major histocom-patibility complex (MHC). There are two types of MHC molecules, Class I and Class II. These differ in several subtle ways but share most of their major structural features. MHC Class I and II molecules display protein antigens for recognition by CD4+ or CD8+ T cells. MHC Class I molecules bind stably to peptides derived from proteins synthesized and degraded in the cytosol (all cells) and MHC Class II molecules bind stably to peptides derived from proteins degraded in endocytic vesicles (APCs). The two classes of MHC are differentially recognized by the two co-receptor molecules, CD8 and CD4. CD8+ T cells recognize MHC Class I/peptide. CD4+ T cells recognize MHC Class II peptide complexes. Every individual is polygenic at the MHC and expresses several MHC I and II genes with different peptide-binding specificities. Class I • Expressed on all nucleated cells (HLA-A, B, C) • Recognized by CD8 on cytotoxic T cells • Present intracellular proteins (e.g., viral peptides) to TCR u TIP a LA-Cw6 has the most definitive H genetic association with psoriasis Class II • Expressed on B cells, monocytes, dendritic cells, and are inducible on keratinocytes and endothelial cells (HLA-DR, DQ, DP) • Recognized by CD4 on helper T cells • Class II molecules complexed with antigen triggers helper T cells • Present peptides derived from extracellular pathogens taken up into vesicles to TCR Other • Level of Class I and II molecule expression is regulated by cytokines • MHC III region encodes or soluble proteins of the complement cascade and the tumor necrosis family • The polygenic and polymorphic nature of the MHC contributes to the ability of the immune system to respond to the multitude of different and rapidly evolving pathogens • HLA associations seen in human skin disease reflect the ability of that particular MHC molecule to present a disease-relevant peptide to T cells HLA Disease Associations Class I • Psoriasis: HLA-Cw6 (more associated with guttate), B17, B27 (more associated with vulgaris): relative risk 10 times normal. Mechanism postulated to be through antigen presentation to CD8+ T cells leading to epidermal migration Report a Problem/Feedback Immunodermatology 45
  • 57. • Psoriatic Arthritis, Reiter’s syndrome: HLA-B27, especially if spondylitis present • Behçet’s disease: HLA-B51 Class II • Chronic Idiopathic Urticaria: HLA-DR4, HLA-DRB4, HLA-DQ8 • Herpes gestationis: HLA-DR3, HLA-DR4 • Pemphigus vulgaris: HLA-DR4, DRw6 Both Class I and Class II • Dermatitis Herpetiformis: HLA-A1, HLA-B8, HLA-DR3, HLA-DQ2 • Lichen Planus: HLA-B7, HLA-DR1 and DR10 • Vitiligo: HLA-A33, HLA-B13, HLA-B44, HLA-DRB1, HLA DR4 2.6 NON-STEROIDAL IMMUNOLOGIC THERAPIES Calcineurin Inhibitors T cell activation follows a complex cascade of intracellular signaling events after ligation of the TCR. A key regulatory step is the activation of calcineurin via calmodulin. Calcineurin phosphatase activity dephosphorylates NFATc, resulting in nuclear translocation and subsequent transcriptional activation of cytokine expression. Cyclosporine (Neoral, Sandimmune) • Forms complex with cyclophilin, which inhibits calcineurin activity  Tacrolimus (Protopic) and Pimecrolimus (Elidel)  • Forms complex with FK506 binding protein (FKBP12), which inhibits calcineurin activity • Effective topically due to their small size (as opposed to cyclosporine) • Tacrolimus is a macrolide; Pimecrolimus is a derivative of ascomycin • Both decrease pro-inflammatory cytokine release (e.g., TNFα) and histamine release from mast cells TNF Inhibitors Entanercept (Enbrel) u TIP • Human fusion protein of TNFα type II receptor and IgG1 Fc region a inds soluble TNFα, cannot B cause cell lysis • Binds soluble TNFα, cannot cause cell lysis • Most common side effect is injection site reaction • Approved for treatment of psoriasis, psoriatic arthritis, RA, JRA, and ankylosing spondylitis Infliximab (Remicade) • Chimeric mouse/human IgG1 binds TNFα (monoclonal Ab) • Approved for psoriatic arthritis, RA, Crohn’s, UC, ankylosing spondylitis u TIP aBinds surface and soluble TNFα Adalimumab (Humira) • Human monoclonal Ab IgG1 against TNFα • Approved for treatment of psoriatic arthritis, RA, ankylosing spondylitis T Cell Function Inhibitors  Alefacept (Amevive) • Human fusion protein of LFA-3 with Fc portion of IgG1 • Binds CD2 (receptor molecule) on CD45RO+ memory effector T cells (also found on NK cells) • LFA-3 found on endothelial cells; interaction provides cell-cell adhesion distinct from LFA-1/ ICAM1 46  2013/2014 Dermatology In-Review l Committed to Your Future Report a Problem/Feedback
  • 58. • LFA-3 also on APCs for activating T cells • Blocks 2nd signal, causing apoptosis of T cells • Prevents T cell activation, reduces CD4+ and CD8+ T cell counts (need to monitor) • Approved for psoriasis Other Ustekinumab (Stelara) • Human monoclonal antibody that binds p40 subunit of IL-12 and IL-23 • Mechanism of action probably mediated primarily through IL-23 blockade • Approved for treatment of psoriasis • Associated with Reversible Posterior Leukoencephalopathy syndrome (RPLS) Ipilimumab (Yervoy) • Human monoclonal antibody that binds CTLA-4 • Prevents inhibition of activated T cells through CTLA-4 • Metastatic melanoma patients treated with ipilimumab have demonstrated increased 1 year survival rates • 13% of patients suffered severe or fatal autoimmune reactions Rituximab (Rituxan) • Monoclonal Ab against CD20 (on B cells; not on B cell progenitors) • Approved for treatment of B cell NHL Denileukin Diftitox (Ontak) • Fusion of a fragment of diphtheria toxin and IL-2 • Binds to high affinity IL-2 receptor (CD25) on T cells; cells are killed when toxin is internalized • Approved for treatment of CTCL Cetuximab (Erbitux) • Chimeric monoclonal Ab against epidermal growth factor receptor (EGFR) • Approved for treatment of metastatic colorectal cancer • Other EGFR anti-cancer treatments include gefitinib (Iressa) and erlotinib (Tarceva) • All are associated with acneiform eruptions REF E R E NC E S 1. Janeway et al. Immunobiology 5. New York: Garland Publishing, 2001. 2. Robins P. Review Notes for Dermatology New York: Physicians Continuing Education, 20. 3. Robert C and Kupper JS. Mechanisms of Disease: Inflammatory Skin Diseases, Surveillance. New Engl J Med 341: 1817–1828, 1999. 4. Kupper JS. Immunologic Targets in Psoriasis. New Engl J Med 349: 1987–1990, 2003. 5. Asadi AK. Relapsing polychonditis. Dermatol Online J. 2003; 9(4): 3. 6. Burnett PE, Burgin S. Erythema elevatum Dermatol diutinum. Online J. 2003; 9(4): 37. 7. Chen X, Wolin SL. The Ro 60 kDa autoantigen: insights into cellular function and J role. Mol Med 2004. 8. Costedoat-Chalumeau N, Amoura Z, Le Thi Hong D, Georgin S, et al. Neonatal lupus syndrome: review of the literature. Rev Med Interne. 2003; 24(10): 659–71. 9. Dang CV, LaDuca FM, Bell WR. Histidyl-tRNA synthetase, the myositis Jo–1 antigen, is cytoplasmic and unassociated with the cytoskeletal framework. Exp Cell Res. 1986; 164: 261–6. Report a Problem/Feedback Immunodermatology 47
  • 59. 10. Ebo DG, Bridts CH, Hagendorens MM, De Clerck LS, Stevens WJ. The prevalence and diagnostic value of spe-cific IgE antibodies to inhalant, animal and plant food, and ficus allergens in patients with natural rubber latex allergy. Acta Clin Belg. 2003; 58(3):183–9. 11. Fernandez-L A, Sanz-Rodriguez F, Blanco FJ, Bernabeu C, Botella LM. Hereditary hemorrhagic telangiectasia, a vascular dysplasia affecting the TGF-beta signaling pathway. Clin Med Res. 2006; 4(1):66-78. 12. Galvani AP, Slatkin M. Evaluating plague and smallpox as historical selective pressures for the CCR5-Delta 32 HIV-resistance allele. Proc Natl Acad Sci U S A. 2003; 100:15276–9. 13. Garcia Bracamonte B, Ortiz de Frutos FJ, Iglesias Diez L. Occupational allergic contact dermatitis due to formaldehyde and textile finish resins. Contact Dermatitis. 1995; 33(2): 139–40. 14. Hacker-Foegen MK, Fairley JA, Lin MS. T cell receptor gene usage in desmoglein-3-specific T lymphocytes from patients with pemphigus vulgaris. J Invest Dermatol. 2003; 121(6): 1265–72. 15. Hsu RC, Lazarova Z, Lee HG, Tung YC, Yu HS. Antiepiligrin cicatricial pemphigoid. JAm Acad Dermatol. 2000; 42(5 Pt 1): 841–4. 16. K.E. Birch, M. Vukmanovic-Stejic, J.R. Reed, A.N. Akbar and M.H.A. Rustin, The immunomodulatory effects of regulatory T cells: implications for immune regulation in the skin. Br J Dermatol 2005; 152:409–17. 17. Kelly B, Petitt M, Sanchez R. Nephrogenic systemic fibrosis is associated with transforming growth factor β and smad without evidence of renin-angiotensin system involvement. J Am Acad Dermatol. 2008; 58(6): 1025-30. 18. Kimura Y, Pawankar R, Aoki M, Niimi Y, Kawana S. Mast cells and T cells in Kimura’s disease express increased levels of interleukin-4, interleukin-5, eotaxin and RANTES. Clin Exp Allergy. 2002; 32(12): 1787–93. 19. Kobie JJ, Wu RS, Kurt RA, Lou S, Adelman MK, Whitesell LJ, Ramanathapuram LV, Arteaga CL, Akporiaye ET. Transforming growth factor beta inhibits the antigen-presenting functions and antitumor activity of dendritic cell vaccines. Cancer Res. 2003;63(8):1860–4. 20. Krueger JG. The immunologic basis for the treatment of psoriasis with new biologic agents. J Am Acad Dermatol. 2002; 46: 1–23. 21. Lamprecht P, Gutzeit O, Csernok E, Gause A, et al. Prevalence of ANCA in mixed cryoglobulinemia and chronic hepatitis C virus infection. Clin Exp Rheumatol. 2003; 21(6 Suppl 32): S89–94. 22. Liu M, Wallmon A, Olsson-Mortlock C, Wallin R, Saldeen T. Mixed tocopherols inhibit platelet aggregation in humans: potential mechanisms. Am J Clin Nutr. 2003; 77(3): 700–6. 23. Mizuki N, Yabuki K, Ota, M, Katsuyama Y, et al. Analysis of microsatellite polymorphism around the HLA-B locus in Iranian patients with Behcet’s disease. Tissue Antigens. 2002; 60(5): 396–9. 24. Ng PP, Sun YJ, Tan HH, Tan SH. Detection of herpes simplex virus genomic DNA in various subsets of erythe-ma multiforme by polymerase chain reaction. Dermatology. 2003; 207(4): 349–53. 25. Ong PY, Ohtake T, Brandt C, Strickland I, et al. Endogenous antimicrobial peptides and skin infections in atopic dermatitis. NEngl J Med. 2002; 347(15): 1151–60. 26. Ranta PM, Ownby DR. A review of natural-rubber latex allergy in health care workers. Clin Infect Dis. 2004; 38(2): 252–6. 27. Reif S, Lerner A. Tissue transglutaminase-the key player in celiac disease: a review. Autoimmun Rev. 2004; 3: 40–5. 28. Riedl E, Stockl J, Majdic O, Scheinecker C, Knapp W, Strobl H. Ligation of E-cadherin on in vitro-generated immature Langerhans-type dendritic cells inhibits their maturation. Blood. 2000; 96(13):4276–84. 29. Romaguera C, Grimalt F, Lecha M. Occupational Purpuric textile dermatitis from formaldehyde resins. Contact Dermatitis. 1981; 7(3): 152–3. 30. Tarshish P, Bernstein J, Edelmann CM Jr. Henoch-Schonlein purpura nephritis: course of disease and efficacy of cyclophosphamide. Pediatr Nephrol. 2004; 19(1):51–6. 31. Torti DC and SR Feldman. Interleukin-12, interleukin-23, and psoriasis: current prospects. J Am Acad Dermatol. 2007; 57(6): 1059-68. 32. Unchern S, Laoharuangpanya N, Phumala N, Sipankapracha P, et al. The effects of vitamin E on platelet activity in beta-thalassaemia patients. Br J Haematol. 2003; 123(4): 738–44. 48  2013/2014 Dermatology In-Review l Committed to Your Future Report a Problem/Feedback
  • 60. 33. Urman CO and AB Gottlieb. New viral vaccines for dermatologic disease. J Am Acad Dermatol. 2008; 58(3): 361-70. 34. Vasil KE and CM Magro. Cutaneous vascular deposition of c5b-9 and its role as a diagnostic adjunct in the setting of diabetes mellitus and porphyria cutanea tarda. J Am Acad Dermatol. 2007; 56(1): 96-104. 35. Wagner TL, Ahonen CL, Couture AM, Gibson SJ, et al. Modulation of TH1 and TH2 cytokine production with the immune response modifiers, R-848 and Imiquimod. Cell Immunol. 1999; 191: 10–9. 36. Walker EJ, Tymms KE, Webb J, Jeffrey PD. Improved detection of anti-Jo-1 antibody, a marker for myositis, using purified histidyl-tRNA synthetase. J Immunol Methods. 1987; 96(2): 149–56. 37. Yancey KB, Kirtschig G, Yee C, Lazarova Z. Studies of patients with anti-epiligrin cicatricial pemphigoid. J Dermatol. 1995; 22(11): 829–35. 38. Yiannias JA, el-Azhary RA, Gibson LE. Erythema elevatum diutinum: a clinical and histopathologic study of 13 patients. J Am Acad Dermatol. 1992; 26: 38–44. 39. Zhu YI, Stiller MJ. Dapsone and sulfones in dermatology: overview and update. J Am Acad Dermatol. 2001; 45(3): 420–34. 40. Kim J, Ochoa MT, Krutzik SR, Takeuchi O, Uematsu S, Legaspi AJ, Brightbill HD, Holland D, Cunliffe WJ, Akira S, Sieling PA, Godowski PJ, Modlin RL. Activation of toll-like receptor 2 in acne triggers inflammatory cytokine responses. J Immunol. 2002;169(3):1535–41. 41. Leonardi C, Kimball A, Papp K, Yeilding N, Guzzo C, Wang Y, Li S, Dooley L, Gordon K. Efficacy and safety of ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with psoriasis: 76-week results from a randomised, double-blind, placebo-controlled trial (PHOENIX 1). The Lancet. 2008;371(9625):1665-1674. 42. Hodi FS et al. Improved survival with Ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010; 363:711-23. 43. Carrier Y et al. Inter-regulation of Th17 cytokines and the IL-36 cytokines in vitro and in vivo: implications in psoriasis pathogenesis. J Invest Dermatol 2011 Dec; 131(12): 2428-37. 44. Marrakchi S et al. Interleukin-36–receptor antagonist deficiency and generalized pustular psoriasis. N Engl J Med 2011 Aug 18; 365:620. 45. Jansen PAM et al. 2009 b-Defensin-2 Protein Is a Serum Biomarker for Disease Activity in Psoriasis and Reaches Biologically Relevant Concentrations in Lesional Skin. PLoS ONE 4(3): e4725. epub 2009 Mar 6. Report a Problem/Feedback Immunodermatology 49
  • 61. NOTES 50  2013/2014 Dermatology In-Review l Committed to Your Future Report a Problem/Feedback
  • 62. 3  Genodermatoses Arash Kimyai-Asadi, MD Irene Vergilis-Kalner, MD C o n t e n t s 3.1 3.2 X-linked Dominant Syndromes . . . . . . . . . . . . . . . . 53 3.3 Hereditary Blistering Disorders . . . . . . . . . . . . . . . . 53 3.4 Ichthyoses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 54 3.5 Palmoplantar Keratodermas . . . . . . . . . . . . . . . . . . 55 3.6 Disorders with Hypopigmentation . . . . . . . . . . . . . 56 3.7 Disorders with Pigmented Lesions . . . . . . . . . . . . . 57 3.8 Vascular Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . 58 3.9 Connective Tissue Disorders . . . . . . . . . . . . . . . . . . 60 3.10 Diseases of the Hair and Nails . . . . . . . . . . . . . . . . . 62 3.11 Diseases with Malignant Potential . . . . . . . . . . . . . 63 3.12 Disorders with Immunodeficiency . . . . . . . . . . . . . 65 3.13 DNA and Chromosomal Disorders . . . . . . . . . . . . . 66 3.14 Keratinopathies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 67 3.15 Report a Problem/Feedback X-linked Recessive Syndromes . . . . . . . . . . . . . . . . 53 Disorders of Metabolism . . . . . . . . . . . . . . . . . . . . . . 67 Genodermatoses  51
  • 63. 3.1 X-LINKED RECESSIVE SYNDROMES • Chondrodysplasia punctata (Conradi-Hunerman syndrome) • Hypohidrotic ectodermal dysplasia with immunodeficiency (NEMO mutation) 3.2 X-LINKED DOMINANT SYNDROMES • Chondrodysplasia punctata (Conradi-Hunermann syndrome) • CHILD syndrome • Incontinentia Pigmenti • Focal Dermal Hypoplasia • Bazex syndrome • MIDAS syndrome • Oral-facial-digital syndrome • Goltz • Albright’s hereditary osteodystrophy 3.3 HEREDITARY MNEMONIC X-Linked Recessive Syndromes CHAD’S KINKY WIFE GOT LUCKY Chronic granulomatous disease Hunter’ disease s Anhidrotic ectodermal dysplasia Dyskeratosis congenita SCID Wiskott-Aldrich Ichthyosis, X-linked Fabry’s disease Ehler’s Danlos V and IX G6PD deficiency Lesch-Nyhan Menke’s Kinky hair disease BLISTERING DISORDERS • Epidermolysis bullosa simplex (EBS): AD, keratin 5 and 14 mutations resulting in bullae within basal cell keratinocytes. Rarely caused by mutations in the intracellular domain of bullous pemphigoid antigen 2 – Weber-Cockayne: Palmoplantar bullae developing in the 1st-3rd decade – Generalized (Koebner): Generalized bullae starting in infancy with mild mucosal involvement – Dowling-Meara: Widespread bullae (some herpetiform), significant mucous membrane and laryngeal/esophageal involvement, nail dystrophy, and early death – EBS with muscular dystrophy: Plectin mutation – EBS with pyloric atresia: Plectin mutation – EBS with mottle pigmentation: Keratin 5 mutation – Autosomal recessive EBS: Keratin 14 mutation – EBS Ogna variant: Plectin mutation. Above symptoms with generalized contusiform bruising • Junctional epidermolysis bullosa (JEB): AR, laminin 5 and bullous pemphigoid antigen 2 (BP180, collagen 17) mutations causing blisters in the lamina lucida – Herlitz type: Laminin 5 mutations. Generalized bullae, nonhealing perioral granulation tissue, nail dystrophy, tooth dysplasia (enamel defects), anemia, growth retardation, tracheobronchial infections. Fatal by age 3-4 – Non-Herlitz: Laminin 5 or BP180 mutations. Bullae that heal with atrophic scars, nail dystrophy, scarring alopecia. Normal lifespan – Non-Herlitz: Also b4 integrin – JEB localized: BP 180 mutation – Generalized atrophic benign epidermolysis bullosa (GABEB): BP180. Extensive atrophy of the anterior lower legs AD = autosomal dominant, AR = autosomal recessive Report a Problem/Feedback Genodermatoses  53
  • 64. – JEB with pyloric atresia: Mutations in either subunit of α6-β4 integrin – JEB inversa: Laminin 5. Acral bullae • Dystrophic epidermolysis bullosa: Collagen 7 mutations causing blisters in the sublamina densa – Dominant dystrophic EB: • Hyperplastic Cockayne-Touraine: Bullae localized to extremities resolving with milia and scarring, mild mucosal involvement, dystrophic nails • Albopapuloid Pasini variant: Widespread bullae healing with hypopigmented scar-like white papules, nail dystrophy, mild mucosal involvement • Bart’s syndrome: Congenital localized absence of skin usually of the shins, nail dystrophy • Transient bullous dermatosis of newborn: Transient form of the disease • Pretibial • Pruriginosa • With subcorneal cleavage (EB “simplex” superficialis) – Recessive dystrophic EB (Hallopeau-Siemens): Generalized bullae, healing with chronic scars that develop numerous fatal SCCs, digital fusion with mitten deformity, flexion contractures, significant mucosal scarring, dysplastic teeth, malnutrition, death • Non-Hallopeau Siemens • Inversa • Centripetalis • Epidermolytic hyperkeratosis: AD, keratins 1 & 10 gene. Bullae and erythroderma at birth, generalized verrucous ichthyosis later • Ichthyosis bullosa of Siemens: AD, keratin 2e gene. Fragile blisters at birth, hyperkeratotic plaques on the elbows and knees later • Hailey-Hailey disease: AD, calcium ATPase IIC1. Flexural erosions, acantholytic “dilapidated brick wall” appearance histologically • Kindler syndrome: AR, KIND1 (kindlin 1, expressed in basal keratinocytes, attaches actin cyctoskeleton to extracellular matrix). Acral blistering in infancy, photosensitivity, progressive poikiloderma, wrinkling (especially dorsal hands/feet), palmoplantar hyperkeratosis, nail dystrophy, dental caries, phimosis, digital webbing, pseudoainhum 3.4 ICHTHYOSES • Ichthyosis vulgaris: AD, decreased conversion of profilaggrin to filaggrin, diminished granular layer. Scale on extensors and sparing flexures starting at puberty, atopic diathesis, hyperlinear palms. Mutation in filaggrin gene • X-linked ichthyosis: X-linked recessive, steroid sulfatase (arylsulfatase C) gene. Brown scale sparing palms, soles, and flexures, comma-shaped corneal opacities, failure of labor progression, cryptorchidism • Lamellar ichthyosis: AR, Type I - transglutaminase 1 gene or Type II - ATP binding Cassette A12 gene (ABCA12). Collodion baby at birth, with subsequent large thick plates of scale especially on the flexures, ectropion, and eclabium • Nonbullous congenital ichthyosiform erythroderma: AR, transglutaminase 1 gene, or 12R lipoxygenase gene (ALOX 12B) or lipoxygenase 3 gene (ALOX E3). Collodion baby at birth, with subsequent generalized mild erythroderma with fine white scale • Sjogren-Larsson syndrome: AR, fatty aldehyde oxidoreductase/alcohol dehydrogenase deficiency. Ichthyosis, spastic ditetraplegia, mental retardation, epilepsy, glistening dot retinal pigmentation, dental enamel dysplasia 54  2013/2014 Dermatology In-Review l Committed to Your Future Report a Problem/Feedback
  • 65. • Refsum syndrome: AR, phytanoyl coenzyme A hydroxylase deficiency (PAHX gene) or peroxin 7 (PEX7) or PHYH gene. Mild ichthyosis, cerebellar ataxia, peripheral neuropathy, retinitis pigmentosa (salt & pepper), and deafness. Treatment: Diet low in green vegetable, dairy, and ruminant fats • Chondrodysplasia punctata (Conradi-Hunermann syndrome): Arylsulfatase E gene (X-Recessive), EBP gene (X-Dominant), PEX-7 (AR). Peroxisomal biogenesis disorder. Ichthyosiform erythroderma in lines of Blaschko, follicular atrophoderma, stippled epiphyses • CHILD syndrome: X-Dominant, lethal in males. NSDHL gene (NADPH steroid dehydrogenase-like protein). Peroxisomal biogenesis disorder. Unilateral ichthyosiform erythroderma, limb/visceral hypoplasia, and stippled epiphyses • Netherton syndrome: AR, SPINK 5 mutation. Ichthyosis linearis circumflexa (doubleedged scale), trichorrhexis invaginata (bamboo, ball and socket hair), atopic dermatitis, anaphylaxis from food allergy • Darier’s disease (keratosis follicularis): AD, calcium ATPase IIA2 (SERCA2). Hyperkeratotic papules in seborrheic areas, acrokeratosis verruciformis of Hopf, palmar keratoses and pits, red-white longitudinal nail bands, v-shaped distal nail nicks, cobblestoning of oral and rectal mucosae. Worsened by lithium • KID syndrome: AD, connexin 26 mutation, keratitis-ichthyosis-deafness, sporadic inheritance, generalized mild hyperkeratosis, erythematous, keratotic plaques, palmoplantar keratoderma, nonprogressive sensorineural deafness, progressive bilateral keratitis, with secondary blindness • Harlequin fetus: AR/sporadic, ABCA12 gene reported. Large diamond-shaped plaques of scale, low birth weight, ectropion and eclabium. High mortality rate. Cross-beta keratin tonofilament structure • Chanarin-Dorfman syndrome (Neutral lipid storage disease with ichthyosis): Mutation in ABHD5 gene. Cannot break down triglycerides and these fats accumulate in skin, liver, muscles, intestine, eyes, and ears. Ichthyosis usually present at birth. Additional features: hepatomegaly, cataracts, ataxia, hearing loss, short stature, myopathy, nystagmus, and mild intellectual disability 3.5 PALMOPLANTAR KERATODERMAS • Unna-Thost palmoplantar keratoderma (PPK) (non-epidermolytic): AD, keratin 1 • Vorner PPK (epidermolytic): AD, keratin 1 & 9 Diffuse symmetric, non-transgradient PPK • Striated PPK (Brunauer-Fohs-Siemens): AD, desmoglein 1 and desmoplakin 1 • Mal de Meleda: AR, SLURP-1. Malodorous transgradient PPK in glove and stocking distribution • Howel-Evans syndrome: AD, TOC gene. Focal, pressure-related, non-transgradient PPK; esophageal cancer; oral leukoplakia • Sclerotylosis (Huriez syndrome): AD. Sclerosis of skin, nail hypoplasia, PPK. 15% develop cutaneous SCC and increased risk of bowel cancer • PPK with deafness: AD, type 1: connexin-26; type 2: MTTS1. Mitochondrial serine tRNA mutation • Vohwinkel syndrome: AD, connexin 26 (GJB2 gene). Diffuse honeycombed PPK, pseudoainhum, starfish-shaped keratotic plaques over joints, deafness • Vohwinkel variant: AD, loricrin. Similar to classic Vohwinkel, plus ichthyosis but no deafness Report a Problem/Feedback Genodermatoses  55
  • 66. • Naxos syndrome: AR, plakoglobin. PPK + wooly hair + arrhythmogenic cardiomyopathy • PPK with dilated left-ventricular cardiomyopathy and wooly hair: Carvajal syndrome, AR, desmoplakin • Schopf-Schulz-Passarge syndrome: AR. PPK + cystic eyelids + hypodontia + eccrine tumors (eccrine syringofibradenoma) • Bart-Pumphrey syndrome: AD, connexin 26; PPK with knuckle pads, leukonychia, deafness • Olmsted syndrome: AD or XLR; mutilating PPK with periorificial plaques • Papillon-Lefevre syndrome: AR, Cathepsin C. Sharply demarcated, transgradient, stocking-glove PPK, periodontitis with tooth loss, asymptomatic dural calcification and choroids attachments • Haim-Munk syndrome: AR, Cathepsin C. PPK + periodontitis + acroosteolysis + onychogryphosis • Erythrokeratodermia variabilis: AD, connexin 31 & 30.3 mutations (gap junction components encoded by the GJB3, GJB4 genes). Erythematous migratory patches, fixed hyperkeratotic plaques, palmoplantar keratoderma • Symmetric progressive erythrokeratodermia: AD, loricrin. Hyperkeratotic plaques and palmoplantar keratoderma • Richner-Hanhart syndrome (tyrosenemia type II): AR, deficient hepatic tyrosine aminotransferases. Painful PPK, pseudoherpetic keratitis and blindness. Treatment: lowtyrosine/phenylalanine diet • Epidermal Nevus syndrome: Nevus unius lateris; sporadic inheritance, capillary malformations, café au lait macules, mental retardation and seizures, deafness, hemiparesis, hemihypertrophy of limbs, kyphoscoliosis; rare solid tumors. Biopsy to rule out epidermolytic hyperkeratosis, as if positive for EHK then offspring at risk for generalized EHK 3.6 DISORDERS WITH HYPOPIGMENTATION • Oculocutaneous albinism (OCA) type 1 (tyrosinase negative albinism): AR, tyrosinase deficiency. Generalized pink-white skin color, snow-white hair color, pink nevi, blue/gray eyes with severe nystagmus. Increased skin cancers, especially SCC • OCA 2 (tyrosinase + albinism): ROCA, AR, P gene. Most common OCA. Generalized cream color, pigmented nevi, light brown hair, nystagmus. Allelic variant is brown oculocutaneous albinism (BOCA) • OCA 3: BOCA, AR, tyrosinase related protein 1. Light brown hair/skin, blue/brown iris, nystagmus. Allelic variant is rufous oculocutaneous albinism (ROCA) • Chediak-Higashi syndrome: AR, lysosomal transport gene (LYST, CHS1). Oculocutaneous albinism, ataxia, muscle weakness, giant lysosomal granules. Accelerated phase characterized by lymphohistiocytic infiltration of reticuloendothelial system, pancytopenia and death • Griscelli syndrome: AR, GS1: myosin 5A; GS2, RAB27A; GS3: MLPH. Mild albinism, pancytopenia, immunodeficiency, neurologic symptoms GS1. Accelerated phase GS2 similar to Chediak-Higashi but no lysosomal granules on smear • Elejalde syndrome (neuroectodermal melanolysosomal disease): Variant of GS1; prominent features of GS plus severe neurologic dysfunction but not associated with immunodeficiency 56  2013/2014 Dermatology In-Review l Committed to Your Future Report a Problem/Feedback
  • 67. • Hermansky-Pudlak syndrome: AR, HPS (lysosomal transport protein), AP3B1 (endocytic/exocytic sorting). Oculocutaneous albinism, platelets without dense bodies causing excess bleeding, ceroid lysosomal storage disease resulting in pulmonary fibrosis, granulomatous colitis, cardiomyopathy, and renal failure • Piebaldism: AD, c-kit protooncogene. White forelock, depigmented patches on the face, extremities, and abdomen • Waardenburg syndrome: AD, PAX-3 gene (types 1 and 3), MITF gene (type 2), and SOX10, endothelin-3 ligand, endothelin 3-receptor genes (type 4). Dystopia canthorum, white forelock, synophrys, heterochromia irides, deafness. Type 2 has increased risk of deafness but no dystopia canthorum. Type 3 has axial limb defects. Type 4 is AR and has Hirschsprung disease • Hypomelanosis of Ito: Sporadic, male and female. Whorled hypopigmentation, occasional CNS defects, scoliosis, and anodontia • Tuberous sclerosis (Bourneville’s syndrome, epiloia): AD, TSC1 mutation (hamartin) and TSC2 mutation (tuberin) tumor suppressor genes. Ash leaf macule (1st sign), shagreen patch (collagenoma), adenoma sebaceum (facial angiofibroma), periungual angiofibroma (Koenen tumor), CALMs, seizures, retinal astrocytic hamartomas (phakomas), angioid streaks, renal angiomyolipoma (especially in familial cases), congenital cardiac rhabdomyomas, dental enamel pits • Westerhof syndrome: Similar to TS; growth retardation, mental retardation, hereditary congenital hypopigmented and hyperpigmented macules 3.7 DISORDERS WITH PIGMENTED LESIONS • Neurofibromatosis I: AD, neurofibromin (NF-1). Two or more of: 1.) >5 café au lait macules (CALMs) that are >5mm in a prepubertal person or >15 mm in a postpubertal person, 2.) >1 neurofibroma or 1 plexiform neurofibroma, 3.) axillary/inguinal freckling (Crowe’s sign), 4.) optic glioma, 5.) >1 Lisch nodule (iris hamartoma), 6.) sphenoid dysplasia, 7.) 1st degree relative with NF-1 • Neurofibromatosis II: AD, schwannomin/merlin. Cutaneous schwannomas and neurofibromas, bilateral vestibular schwannomas, juvenile posterior subcapsular lenticular opacities • Watson syndrome: AD, neurofibromin. Pulmonic stenosis + CALMs • Russell-Silver syndrome: Sporadic. CALMs, short stature, musculoskeletal and craniofacial defects including asymmetry, clinodactyly and syndactyly, precocious puberty, and cryptorchidism • McCune-Albright syndrome: Sporadic somatic mutation in GNAS1 gene Gs subunit of adenylate cyclase. “Coast of Maine” CALM, polyostotic fibrous dysplasia, precocious puberty • Albright hereditary osteodystrophy: GNAS Gs subunit of adenylate cyclase. Calcification/ ossification, pseudohypoparathyroidism (low Ca, high PTH), absent 4th knuckle, hypogonadism • Incontinentia pigmenti (Bloch-Sulzberger syndrome): X-linked-dominant, male lethal, NEMO gene. Four stages: vesicular, verrucous, hyperpigmented and hypopigmented. Peg or conical teeth, eye abnormalities, CNS defects, alopecia Report a Problem/Feedback Genodermatoses  57
  • 68. • Hypohidrotic ectodermal dysplasia with immunodeficiency: X-linked-recessive, NEMO gene (IKK-gamma). Recurrent GI, pulmonary, skin infections, hypogammaglobulinemia, failure to thrive, decreased teeth, conical shaped maxillary lateral incisors, decreased hair, but normal pigmentation • LEOPARD syndrome: AD, PTPN11 gene (allelic to Noonan syndrome). Lentigines, EKG conduction defects, ocular hypertelorism, pulmonic stenosis, abnormal genitalia, retardation of growth, deafness • Carney complex: NAME (nevi, atrial myxoma, myxoid neurofibroma, ephelids) syndrome, LAMB syndrome (Lentigenes, Atrial myxomas, Mucocutaneous myxomas, Blue nevi), AD, PRKAR1A (protein kinase A regulatory subunit 1-alpha). Cardiac, cutaneous and/or mammary myxomas, pigmented skin lesions, endocrine abnormalities (pituitary, testicular, thyroid, etc.), primary pigmented nodular adrenocortical disease, psammomatous melanotic schwannoma • Tay syndrome: AR; growth retardation, mental retardation, triangular face, cirrhosis, trident hands, CALMs, premature canities, vitiligo • Canty (hyperkeratosis-hyperpigmentation syndrome): AD; punctuate PPK, macules on face, arms, hands, and feet • Dowling-Degos disease: AD; keratin 5; reticulated hyperpigmentation of axilla, groin, inframammary and anticubital fossa; starts in adulthood • Laugier-Hunziker syndrome: Hyperpigmented macules on the lips, buccal mucosa, genitalia and longitudinal melanonychia 3.8 VASCULAR DISORDERS • Sturge-Weber syndrome: Sporadic, M = F. Facial capillary malformation at birth (trigeminal distribution, unilateral > bilateral); neurologic: seizures by 1–2 years, seizures, mental retardation, cerebral atrophy, ipsilateral leptomeningeal vascular malformations, tram-track cortical calcifications; opthmalmic: choroid malformations, ipsilateral glaucoma → blindness. Work-up: MRI, ophtho exam • Klippel-Trenaunay-Weber syndrome: Sporadic. Port-wine stains (lower > upper extremity), hemihypertrophy of limb, lymphatic and deep venous insufficiency of affected limb. Parkes-Weber syndrome has, in addition, arteriovenous fistulas • Beckwith-Wiederman syndrome (EMG) syndrome: Exophthalmos, macroglossia, gigantism: Sporadic 85%, 15% AD p57 (KIP2) gene (inhibitor of G1 cyclin/Cdk complexes). Facial capillary malformations, macroglossia, visceromegaly with omphalocele, hemihypertrophy associated with tumors (especially Wilm’s) • Von Hippel-Lindau syndrome: AD, VHL gene (tumor suppressor gene). Bilateral retinal hemangioblastomas, cerebellar and other CNS hemangioblastomas, renal cysts and renal cell carcinoma, pheochromocytomas, pancreatic cysts and carcinoma, capillary malformations • Proteus syndrome: Sporadic, mosaic mutation in PTEN. Subcutaneous lymphovenous malformations, capillary malformations, lipomas, connective tissue nevi of palms/soles, hemihypertrophy, frontal bossing, hyperostoses of epiphyses & skull (especially external auditory canal), scoliosis, bilateral ovarian cystadenomas, parotid monomorphic adenoma • Rubinstein-Taybi syndrome: Sporadic contiguous gene syndrome affecting transcriptional coactivator CREB-binding protein. Capillary malformation, short stature, broad thumbs, craniofacial abnormalities including beaked nose, mental retardation, congenital heart defects, cryptorchidism 58  2013/2014 Dermatology In-Review l Committed to Your Future Report a Problem/Feedback
  • 69. • Maffucci syndrome: Sporadic, PTH/PTHrP type I receptor. Venous malformation of distal extremities, benign enchondromas compromising bone strength and leading to chondrosarcoma, and other less common sarcomas • Blue Rubber Bleb Nevus syndrome: Sporadic, some AD (TIE2 tyrosine kinase activating mutation). Multiple tender venous malformations of skin and gastrointestinal tract with gastrointestinal bleeding • Ataxia Telangiectasia (Louis-Bar syndrome): AR, ATM gene (chromosomal strand break repair enzyme) and MREII gene (milder form). Cerebellar ataxia (1st sign), telangiectases of conjunctiva and skin, thymic hypoplasia with increased infections. Increases sensitivity to ionizing radiation with increased hematologic and solid tumors. Female carriers have increased risk of breast cancer. Increased alpha-fetoprotein and decreased or absent IgG2, IgE, and IgA • Osler-Weber-Rendu syndrome (Hereditary hemorrhagic telangiectasia): AD, endoglin (TGF-beta binding protein), activin-receptor kinase 1 (binds TGFB1 and activin A), and bone morphogenetic protein receptor type II (TGF-b family receptor) mutations. Epistaxis, telangiectases of skin, mucous membranes, and gastrointestinal tract with bleeding, pulmonary arteriovenous fistulas with cerebral emboli. ALK1 gene mutation associated with increased hepatic AVMs • Cornelia de Lange syndrome: Sporadic (some AD due to nipped-beta-like gene NIPBL; x-linked form due to structural maintenance of chromosomes 1-like SMC1L1 gene). Cutis marmorata, hirsutism, synophrys, trichomegaly, numerous craniofacial abnormalities, severe mental retardation, deafness, low-pitched cry, short stature, clinodactyly and other abnormalities of the hands and feet, genitourinary abnormalities including cryptorchidism, congenital heart defects, and deafness • Hereditary lymphedema (Nonne-Milroy disease): AD, Type 1, FLT4 gene (VEGF receptor-3). Congenital lymphedema, chylous ascites, scrotal swelling, intestinal tract protein loss with hypoproteinemia, and persistent bilateral pleural effusions • Lymphedema-distichiasis syndrome: AD, FOXC2 (forkhead family transcription factor gene MFH1). Late-onset lymphedema, distichiasis (double row of eyelashes), corneal irritation, ectropion, webbed neck, congenital heart defect. Late-onset hereditary lymphedema (Type 2) - meige lymphedema • Lymphedema and ptosis: AD, MFH1 • Diffuse congenital hemangiomatosis: Sporadic, multiple 0.2 to 2.0 cm hemangiomas in generalized distribution, involving any organ, liver hemangioma may be complicated by obstructive jaundice, portal hypertension, hemorrhage, high output CHF leading to death; hemangiomas undergo spontaneous regression • Hypotrichosis-lymphedema-telangiectasia: SOX18 mutation • Erythromelalgia: Burning, erythema, warmth of acral sites; associated with thrombocytopenia or SCN9A mutation (Na+ channels) • Familial Glomagioma: GLMN mutation • Capillary Malformation: Arteriovenous malformation: RASA1 mutation • CADASIL (Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy): NOTCH3 mutation • Hypotrichosis-Lymphedema-Telangiectasia: SOX18 mutation Report a Problem/Feedback Genodermatoses  59
  • 70. 3.9 CONNECTIVE TISSUE DISORDERS • Ehlers-Danlos syndrome (EDS) – Type 1 (Gravis): AD, collagen 5. Hyperextesible skin, gaping wounds, cigarette-paper scars, molluscoid pseudotumors, calcified subcutaneous nodules, bruises, hypermobile joints with dislocation, hernias, mitral valve prolapse, blue sclerae, Gorlin’s sign (tongue reaches nose), absence of lingual frenulum – Type 2 (Mitis): AD, collagen 5. Milder form of type 1 – Type 3 (Benign hypermobile): AD, collagen 3. Recurrent joint dislocations – Type 4 (Vascular): AD/AR, collagen 3: Translucent skin with visible venous network, arterial and visceral rupture resulting in early death – Type 5 (X-linked): X-recessive. Lysyl oxidase deficiency. Relatively mild – Type 6 (Ocular-scoliotic): AR, PLOD gene, lysyl hydroxylase deficiency. Severe kyphoscoliosis, retinal detachment and other eye abnormalities – Type 7 (Arthrochalasis multiplex congenita): AD/AR, COL1A/2, mutations in procollagen amino terminals (AD) or in procollagen aminopeptidase (AR), which cleaves the amino-terminals. Congenital hip dislocation, severe joint hypermobility (EDS Arthrochalasia type) – Type 8 (Periodontitis): Type 3 collagen. Mild symptoms of EDS with periodontitis and resulting tooth loss – Type 9 (Occipital horn syndrome): XR Lysyl oxidase. Mild symptoms of EDS with occipital exostoses and hernias – Type 10 (Fibronectin): AR, fibronectin. Ecchymoses and petechiae – Type 11 (Large joint hypermobile): AD: dislocation of large joints – Osteogenesis imperfecta: COL1A gene defect; Types 1 and 4: AD; Types 2 and 3: AD/ AR - most severe with fractures in utero – Progeroid EDS: AR, xylosylprotein 4-beta-galactotransferase. Thin, elastic skin, hair and teeth abnormalities, osteopenia, and hypotonia – EDS with congenital adrenal hyperplasia: AR, tenascin-X • Marfan syndrome: AD, fibrillin 1 and 2. Tall stature, arachnodactyly, pectus excavatum, high-arched palate, joint laxity, ectopia lentis with upward dislocation, aortic dilatation with rupture, mitral valve prolapse, striae, elastosis perforans serpiginosa • Congenital contractural arachnodactyly: AD, fibrillin 2. Long limbs, arachnodactyly, scoliosis, crumpled ear • Cutis laxa: AR, fibulin 4 gene, AD (elastin gene), X-Recessive (lysyl oxidase, allelic to EDS 9 and Menkes), acquired (Marshall syndrome). Loose, pendulous, inelastic skin, deep voice, lung abnormalities, arterial rupture, visceral diverticulae and hernias, and joint dislocation. Fibulin 5 (both AD and AR) • Pseudoxanthoma elasticum: AR, AD, sporadic, ABCC6 gene (anthracycline resistance protein, ATP-using cell transporter). Fragmented and calcified elastin of skin, eyes, and arteries. Plucked-chicken skin on flexures, yellow papules on mucous membranes, angioid streaks (rupture in Bruch’s membrane), gastric hemorrhage, arterial disease • Buschke-Ollendorf syndrome: AD. Dermatofibrosis lenticularis disseminata (elastomas) and osteopoikilosis (round opacities in bones). Caused by a loss-of-function mutation in LEMD3 (also called MAN1), which encodes an inner nuclear membrane protein. LEMD3 normally interacts with Bone Morphogenetic Protein and activin-TGF beta receptoractivated Smads and antagonizes both signaling pathways 60  2013/2014 Dermatology In-Review l Committed to Your Future Report a Problem/Feedback
  • 71. • Focal dermal hypoplasia (Goltz syndrome): X-linked dominant, male lethal, PORCN gene. Linear atrophy following Blaschko’s lines with areas of fat herniation, mucocutaneous papillomas and pits, alopecia, nail dystrophy, tooth abnormalities, musculoskeletal defects (osteopathia striata), colobomas • Lipoid proteinosis: AR extracellular matrix protein 1 gene (ECM1). Scars and yellow papules of the face and orophraynx, eyelid string of pearls, hoarse voice, verrucous nodules of elbows and knees, bean-shaped temporal and hippocampal calcification with occasional seizures. PAS+ deposits histologically • Progeria (Hutchinson-Gilford syndrome): AD mutation in lamin A (nuclear envelope protein). Lipoatrophic sclerodermoid skin, alopecia, nail atrophy, craniomegaly with small face, muscle/bone wasting, severe premature atherosclerosis with early death • Beare-Stevenson Cutis Gyrata syndrome: Mutations in fibroblast growth factor receptor 2. Craniosynostosis, cutis gyrata, acanthosis nigricans, anogenital anomalies, skin tags, prominent umbilical stump, furrowed palms/soles. Apert syndrome (same gene): cranial synostosis, syndactyly, severe acne. Nevus comedonicus (same gene) • Skeletal dysplasia syndrome with acanthosis nigricans: FGFR3 mutation • Pachydermoperiostosis: AD, mostly males; clubbing of digits, soft tissue hyperplasia, periostial proliferation of arms and legs, cutis vertices gyrata on scalp • Berardinelli-Seip congenital lipodystrophy: BSCL2 gene (encodes nuclear lamins). Generalized lipodystrophy, hyperlipemia, hepatomegaly, acanthosis nigricans, elevated basal metabolic rate, non-ketotic insulin-resistant diabetes mellitus. Acquired generalized lipodystrophy (Lawrence syndrome). AR; Type I (AGPAT gene). Type II (BSCL2 gene) • Familial partial lipodystrophy (Dunnigan): Type 1: Kobberling; Type 2: Dunnigan, AD, LMNA (nuclear lamins A/C). Type 3: PPARG gene mutation. Symmetric lipoatrophy of trunk and limbs (sparing neck, shoulders, buffalo hump area, genitalia), tuberoeruptive xanthomas, acanthosis nigricans, hypertriglyceridemia • Acquired partial lipodystrophy (Barraquer Simons syndrome): Sporadic or AD; LMNB2 gene mutation; decreased fat on face, medial thighs, buttocks; increased fat in hips and legs. Acquired generalized lipodystrophy (Lawrence syndrome) • Leprechaunism (Donohue syndrome): Insulin receptor gene mutation; generalized lipodystrophy and elfin faces; death in infancy • Loeys-Dietz syndrome: AD, TGFβ receptors 1 and 2; translucent skin, aortic aneurism, arterial tortuosity, craniofacial and skeletal anomalies, joint hypermobility • Poland syndrome: Unilateral absence of breast +/- pectoralis major, ipsilateral syndactyly • Joffe-Campacci syndrome: Disseminated non-ossifying fibromas of long bones and jaw bones, hypogonadism, cryptorchidism, MR, giant cell granuloma (jaw) • Familial multiple lipomatosis: AD. Multiple lipomas of the upper and lower extremities • Aplasia cutis congenita (ACC): AD/AR/sporadic: Well-demarcated erosions at birth healing with atrophic, alopecic scars. Adams-Oliver syndrome: AD, midline scalp ACC with limb hypoplasia. Bart’s syndrome: AD, ACC of lower extremity with dominant dystrophic epidermolysis bullosa. ACC can be caused by teratogens, particularly methimazole • Osteogenesis imperfecta: COL1A1 gene defect. Types I and IV (AD), Types II and III (AD/AR) – most severe, with fractures in utero. Thin skin, easy bruising, blue sclera (except type III), multiple fractures with wormian bones, mitral valve prolapse (especially Type I) Report a Problem/Feedback Genodermatoses  61
  • 72. 3.10 DISEASES OF THE HAIR AND NAILS • Menkes kinky hair syndrome: X-linked recessive, ATP7A, an ATP-dependent copper transporter, low levels of serum copper, pili torti most common, Trichorrhexis nodosa, Hypopigmented, sparse, short, brittle hair, sparse eyelashes and eyebrows, lax skin, Cupid’s bow upper lip, CNS progressive deterioration, seizures, skeletal abnormalities, tortuous arteries • Bjornstad syndrome: Pili torti, deafness, normal intelligence and lifespan • Argininocuccinic aciduria: AR, argininosuccinase, trichorrhexis nodosa, hyperammonemia, vomiting and hepatomegaly, seizures, lethargy, coma, ataxia, mental retardation • Monilethrix: mutations in hair cortex keratins 1 (hHb1 or KRT81) and 6 (hHb6 or KRT 86); Beaded hair → elliptical nodes along hair shaft, keratosis pilaris, brittle nails. Also mutation in the gene encoding K83. AR: mutation in gene encoding Desmoglein 4 • Uncombable hair syndrome: Pili trianguli et canaliculi, blonde hair • Autosomal recessive woolly hair: Mutation in P2RY5 gene – G protein coupled receptor, nested gene within the retinoblastoma 1 gene. Diffuse scalp woolly hair with variable hypotrichosis or sparse hair • Hypotrichosis simplex of scalp: Mutation in CDSN gene, encodes corneodesmosin. Normal hair at birth with progressive, gradual loss of scalp hair beginning at middle of the first decade to almost complete loss of scalp hair by third decade. Body hair, beard, eyebrows, axillary hair, teeth, and nails develop normally. Men and women are equally affected • Naxos disease: Plakoglobin, woolly hair, keratoderma, right sided cardiomyopathy • Trichothiodystrophy: AR, PIBIDS or Tay syndrome, photosensitivity, ichthyosis, brittle hair, intellectual impairment, decreased fertility, short stature, low cysteine or methionine content in hair and nails, defect in DNA repair; same complementation group as XP group D, but no increased skin cancer; hair shows trichoschisis (“tiger-tail” banding) → alternating light and dark bands with polarizing microscope, sparse or absent eyelashes, eyebrows, axillary, pubic, and body hair • Anhidrotic ectodermal dysplasia: Christ-Siemens-Touraine syndrome, X-linked recessive, mutation in ectodysplasin A or ectodysplasin A receptor (EDA and DL, respectively), smooth, soft, dry, fine wrinkles with periorbital hyperpigmentation, hypo- or anhidrosis with hyperpyrexia, atopic dermatitis, hypopigmented, fine, short, sparse scalp and body hair with longitudinal groove on EM, dystrophic nails, frontal bossing, saddle nose, supraorbital ridging, thick everted lips, hypo-anodontia, peg-shaped/conical incisors and canines • Hidrotic ectodermal dysplasia: Clouston syndrome, AD, connexin 30 (GJB6 mutation), palmoplantar keratoderma with transgradiens, dystrophic nails, sparse hair with absent body, eyelash, eyebrow hair after puberty • EEC syndrome (Ectrodactyly-Ectodermal Dysplasia-Cleft lip/palate): AD, EEC1, EEC2, EEC3; p63 gene mutation • AEC (Ankyloblepharon-Ectodermal Dysplasia-Clefting) syndrome (Hay-Wells): p63 gene, ankyloblepharon filiforme adenatum, ectodermal dysplasia, cleft palate • Rapp-Hodgkin syndrome: p63 gene, mild form of AEC with no akyloblepharon • Branchio-oto-renal syndrome: EYAI gene. Ear pits, deafness, renal dysplasia • Tricho-rhino-phalangeal syndrome: AR/AD (TRPS1 gene) - Sparse hair, pear-shaped broad nose, cone -shaped epiphyses • Trichodentoosseous syndrome: DLX3 homeobox gene. Curly hair, dental pits, increased bone density 62  2013/2014 Dermatology In-Review l Committed to Your Future Report a Problem/Feedback
  • 73. • Dermatopathia Pigmentosa Reticularis (DPR): AD, mutation in keratin-14 gene. Triad of cutaneous reticulate hyperpigmentation, noncicatricial alopecia, onychodystrophy. Keratin-14 mutation is shared with Naegeli-Franseschetti-Jadassohn syndrome. Shared clinical features in both are adermatoglyphia, palmoplantar keratoderma and hypohidrosis. However, alopecia is only seen in DPR and dental abnormalities are seen in only in NaegeliFranceschetti-Jadassohn syndrome • Naegeli-Franceschetti-Jadassohn syndrome: Mutation in keratin-14. Reticulate pigmentation starting at age 2 and fading with age. Palmoplantar hypohidrosis and hyperkeratosis. Hypoplasia of dermatoglyphics or adermatoglyphics. Poor dentition progressing to loss of teeth • Costello syndrome (Faciocutaneoskeletal syndrome): Mutation in HRAS gene. Thin anterior hair, curly hair. Nasolabial facial and perianal papillomas. Redundant and thickened skin around neck, palms, and soles.Congenital myopathy with excess muscle spindles. Coarse facies, short stature. Cardiac and developmental disability • Cardiofaciocutaneous syndrome: Mutations in KRAS, BRAF, MEK1, MEK2 – all part of the common RAS/ERK pathway regulating cell proliferation, differentiation and apoptosis. Sparse friable hair, patchy hyperkeratosis or more generalized icthyosis. Heart defects (pulmonic stenosis, atrial septal defects). Mental retardation and characteristic facies (high forehead with bitemporal constriction, antimongoloid slant of palpebral fissures, posteriorly angulated ears) • Pachyonychia congenita: Jadassohn-Lewandowsky syndrome, keratin 16 and 17 mutations – Type I: Mutations in keratins 6a and 16 → focal PPK, distinctively thickened hyperkeratotic fingernails and toenails (all 20) with onycholysis and frequent Staph or Candidal paronychial infection, pincer nails, follicular hyperkeratosis of elbows and knees, oral leukokeratosis, palmar and plantar keratoderma with hyperhidrosis – Type II (Jackson-Lawler) syndrome involves mutations in keratins 6b and 17 and clinically resembles the type I syndrome with the additional findings of both natal teeth and steatocystoma multiplex; less severe palmoplantar keratoderma with milder or absent oral lesions – Type III (Schafer-Branauer) syndrome that features all the findings of the type I disease associated with leukokeratosis of the corneas – Type IV, pachyonychia congenita tarda, applies to a late-onset of the disease during the second or third decade of life • White sponge nevus: Autosomal dominant; K4 and K13 mutations, white spongy overgrowth of the mucous membrane, buccal muccosa most common site • Nail-patella syndrome: AD, mutations in LMX1B; triangular lunulae, micronychia with hemonychia and longitutinal splitting, anonychia, palmoplantar hyperhidrosis, absent or hypoplastic patella, bilateral posterior iliac horns, radial head subluxation, thickened scapula, scoliosis, glomerulonephritis, Lester iris (hyperpigmentation of the pupillary margin of the iris) 3.11 DISEASES WITH MALIGNANT POTENTIAL • Nevoid Basal Cell Carcinoma syndrome (Gorlin syndrome): AD, patched gene (inhibits hedgehog signaling pathway). ↓ patched → ↑smoothened → uncontrolled cell proliferation through Gli 1-3 transcription factors. Innumerable BCCs, palmoplantar pits, painful odontogenic jaw keratocysts, frontal bossing, bifid ribs, calcification of falx cerebri, medulloblastoma, hypertelorism, and ovarian fibromas and fibrosarcomas Report a Problem/Feedback Genodermatoses  63
  • 74. • Bazex syndrome: X-Dominant > AD. Follicular atrophoderma, hypohidrosis, hypotrichosis, multiple BCCs • Rombo syndrome: AD. Vermicular atrophoderma, multiple BCCs, trichoepitheliomas, hypotrichosis, acrocyanosis. No follicular atrophoderma or hypohidrosis as seen in Bazex syndrome • Braun-Falco-Marghescu syndrome: Atrophoderma vermiculata, PPK, keratosis pilaris • Tuzin syndrome: Atrophoderma vermiculata and scrotal tongue • Rasmusen syndrome: Milia, trichoepitheliomas, and cylindromas • Familial cylindromatosis: AD. CYLD gene (binds organelles to microtubules). Numerous turban tumors (cylindromas), eccrine spiradenomas • Brook-Spiegler syndrome: Multiple trichoepitheliomas and cylindromas • Nicolau-Balus syndrome: Micropapular eruptive syringomas, milia, atrophoderma vermiculata • Birt-Hogg-Dube syndrome: AD; multiple fibrofolliculomas, trichodiscomas, acrocollagenomas, lipomas, oral fibromas, renal cell carcinoma, medullary thyroid carcinoma, and colon cancer. Mutation FLCN (folliculin gene). BHD gene • Schopf-Schulz-Passarge syndrome: AR; hidrocystoma of eyelids, hypotrichosis, hypodontia, nail abnormalities, and multiple palmoplantar eccrine syringofibroadenomas • Myotonic dystrophy with multiple pilomatricomas: Activating beta catenin mutations (encoded by CTNNB1) • Gardner syndrome: AD, APC gene (b-catenin mediated transcription). Colonic polyposis with cancer (100% by age 50), epidermoid cysts with foci of pilomatricoma and calcification, congenital hypertrophy of retinal pigment epithelium, facial/skull osteomas, extranumerary teeth, desmoid tumors • Cronkhite-Canada syndrome: Sporadic. Gastrointestinal polyposis, nail atrophy, alopecia, generalized pigmentation of skin, melanotic macules on fingers • Peutz-Jeghers syndrome: AD, STK11/LKB1 (serine threonine kinase tumor suppressor gene). Pigmented macules of the mouth, fingers, and mucosae, gastrointestinal hamartomatous polyps (especially small bowel) with bleeding and intussusception, gastrointestinal adenocarcinomas, ovarian sex cord tumor, and breast, pancreatic, and endometrial cancers. Laugier-Hunziker syndrome • Muir-Torre syndrome: AD, MSH2 gene (DNA mismatch repair) or MLH1 gene (same function). Multiple cutaneous sebaceous neoplasms, keratoacanthomas and multiple primary GI and larynx carcinomas • Cowden syndrome (multiple hamartoma syndrome): AD, PTEN (phosphatase that dephosphorylates tyrosine, serine, and threonine). Facial trichilemmomas, oral papillomas, acral keratotic papules, sclerotic fibromas, breast fibroadenomas and adenocarcinomas, thyroid adenomas and adenocarcinomas, and hamartomatous polyps of the gastrointestinal tract • Bannayan-Riley-Ruvalcaba syndrome: AD, PTEN. Macrocephaly, genital lentigines, hamartomas, lipomas, hemangiomas, and mental retardation • Multiple endocrine neoplasia type I (Werner syndrome): AD, menin. Parathyroid, pancreatic and pituitary tumors. Angiofibromas, collagenomas, CALMs, lipomas, hypopigmented macules, gingival macules • Multiple endocrine neoplasia type 2a (Sipple syndrome): AD, RET proto-oncogene. Parathyroid tumors, pheochromocytomas, medullary thyroid cancer. Familial macular/ lichen amyloidosis 64  2013/2014 Dermatology In-Review l Committed to Your Future Report a Problem/Feedback
  • 75. • Multiple endocrine neoplasia type 2b (multiple nucosal neuromas): AD, RET protooncogene. Pheochromocytoma, medullary thyroid cancer, rare parathyroid carcinoma. Mucosal neuromas, marfanoid habitus, GI ganglioneuromatosis • Dyskeratosis congenita: X-recessive—dyskerin gene (ribosomal RNA synthesis); AD— TERC gene (telomerase). Reticulate pigmentation of skin, poikiloderma, alopecia, nail atrophy, premalignant oral leukoplakia, Fanconi-type pancytopenia resulting in early death. Allelic to Hoyeraal-Hreidarsson syndrome (+ posterior fossa malformations) • Familial dysplastic nevi/melanoma: AD, CDKN2A (P16 tumor suppressor gene that inhibits cyclin dependent kinase 4), CDK4 (cyclin dependent kinase 4, proto-oncogene). Dysplastic nevi, melanoma, pancreatic cancer, and astrocytomas. Mutation in BRAF in common melanocytic nevi (ex: dermal) and in malignant melanoma • Familial multiple cutaneous leiomyomatosis (Reed syndrome): AD, fumarate hydratase. Multiple cutaneous leiomyomas, uterine leiomyomas and leiomyosarcoma, renal cell carcinoma • Li-Fraumeni syndrome: AD, p53 mutation; breast carcinoma, brain carcinoma, osteosarcoma, leukemia; skin cancers not typical 3.12 DISORDERS WITH IMMUNODEFICIENCY • Wiskott-Aldrich syndrome: X-linked recessive WASP gene, an Arp2/3 complex interacting protein, atopic dermatitis on face, scalp, flexures, thrombocytopenia with petechiae, purpura, epistaxis, bloody diarrhea, hematemesis, intracranial hemorrhage, recurrent bacterial infections → otitis media, pneumonia, meningitis, sepsis, increased susceptibility to HSV, PCP, HPV, increased IgA, IgD, IgE, decreased IgM, impaired cell-mediated and humoral immune response, 20% risk of lymphoreticular malignancy in adolescence/young adulthood • Chronic Granulomatous disease: AR: mutation in CYBA (cytochrome subunit), XLR: mutation in CYBB (cytochrome subunit), AR: NCF 1 and 2 (neutrophil cytosol factors 1 and 2), diagnosed by nitroblue tetrazolium reduction assay → abnormal WBC’s cannot reduce dye, inability to produce respiratory burst needed to kill catalase positive organisms after phagocytosis, recurrent pyoderma (S. aureus, most commonly), periorificial dermatitis, ulcerative stomatitis and chronic gingivitis in mouth, suppurative lymphadenitis with abscesses and fistulas, pneumonia with empyema, hepatosplenomegaly with granulomas, abscesses, chronic diarrhea, osteomyelitis • Hyper IgE syndrome: Job syndrome, AD, IgE level markedly increased, peripheral eosinophilia, excoriated papules, pustules, furuncles, and abscesses → some cold, some with S. aureus; coarse facies, broad nasal bridge, eczematous dermatitis in flexures, postauricular, hairline; bronchitis, lung abscesses, pneumonia, otitis media, sinusitis, mutation in STAT3 • Severe combined immunodeficiency: X-linked recessive: most common, gamma chain IL-2 receptor gene (IL2RG), AR: from Janus kinase 3 gene (JAK3), AD: IL7R gene mutation, mixed group of disorders all sharing defect in cell-mediated and humoral immunity; 20% secondary to adenosine deaminase deficiency (ADA and PNP genes mutated), candidal infections, mucocutaneous, bacterial pyodermas, seborrheic-like dermatitis/lichen planuslike sclerodermatous changes, aplastic thymus, pneumonia • Omenn syndrome: AR form of SCID with erthroderma, RAG-1 and RAG-2 genes • Chronic mucocutaneous candidiasis: AR or AD (ICAMI) or AD with thyroid disease. Candida, severe, of skin, mouth, nails Report a Problem/Feedback Genodermatoses  65
  • 76. • APECED: AR, AIRE gene (autoimmune regulator gene). Addison’s hypoparathyroidism, candidiasis • X-linked agammaglobulinemia (Bruton): BTK gene, all Igs decreased; also AR, AD • Common variable immunodeficiency: ICOS, TNFRSF13, TNFRSF13C, CD19 genes; IgG and IgA decreased; +/- decreased in IgM • Selective IgA deficiency: TNFRSF13B gene; IgA decreased • Selective IgM deficiency: IgM decreased • X-linked hyperIgM syndrome: CD40LG; AR hyperIgM syndrome: Increased IgM; decreased IgA, IgE, and IgG 3.13 DNA AND CHROMOSOMAL DISORDERS • Xeroderma pigmentosum: AR: defective DNA excision repair from UV. 8 complementation group: 1.) XPA: XPA gene 2.) XPB: ERCC3 gene 3.) XPC: XPC gene 4.) XPD: ERCC2 gene 5.) XPE: DDB2 gene 6.) XPF: ERCC4 gene 7.) XPG: ERCC5 gene 8.) XP variant: POLH gene. Acute sunburns from infancy, numerous lentigines, premalignant and malignant skin cancers including BCCs, SCCs, and melanomas, ectropion with vascularization, and mental retardation (some subtypes) • Cockayne syndrome: AR, several complementation groups (CSA, CSB, XP B/D/G, ERCC8), some overlapping with xeroderma pigmentosum complementation groups. CSA and CSB remove stalled RNA polymerase from damaged DNA. ↑ sister chromatid exchanges and chromosome breaks. Photosensitivity and poikiloderma, lipoatrophy on face with sunken eye appearance, cachectic dwarf with long contracted limbs, microcephaly, thin nose, large ears, diffuse CNS demyelination, peripheral neuropathy, mental retardation, intracranial calcification, deafness, salt/pepper retinal pigmentation, cataracts, optic atrophy, dental caries. No increased risk of cancer • Bloom syndrome: AR, BLM gene (RecQ protein-like-2, ATP-dependent DNA helicase activity), sister chromatid exchange and chromosome breaks/rearrangements. Photodistributed poikiloderma, facial dysmorphism, hypogammaglobulinemia with recurrent respiratory and gastrointestinal infections, hypogonadism, leukemias, lymphomas, gastrointestinal adenocarcinomas, oral/esophageal SCCs • Rothmund-Thompson syndrome (poikiloderma congenitale): AR, RECQL4 gene (DNA helicase). Poikiloderma of face and extensor extremities, photosensitivity, premalignant acral keratoses, alopecia, nail dystrophy, cataracts, hypogonadism, and solid tumors (uncommon) • Werner syndrome: AR, RECQL2 (DNA helicase). Sclerodermoid skin, chronic leg ulcers, alopecia and graying of hair, beaked nose, short stature, osteoporosis, hypogonadism, atherosclerotic disease, sarcomas and other tumors • Muir-Torre syndrome: AD, HMSH2 and MLH1 (DNA mismatch repair gene). Sebaceous adenomas, epitheliomas and carcinomas, keratoacanthomas, indolent colonic and other visceral adenocarcinomas [variant of HNPCC (Lynch syndrome)] • Down syndrome: Trisomy 21 (1:700 births, risk increased with maternal age). Single palmar crease, nuchal folds, syringomas, elastosis perforans serpiginosa, epicanthic folds with up-slanting palpebral fissures, Brushfield spots, scrotal tongue, mental retardation, atrioventricular septal defects, ventricular septal defects, numerous other defects. Prenatal diagnosis by low alpha-fetoprotein in maternal serum and amniocentesis • Trisomy 8: Short nail, no patella (Similar to nail-patella syndrome) 66  2013/2014 Dermatology In-Review l Committed to Your Future Report a Problem/Feedback
  • 77. • Kleinfelter syndrome: X-aneuploidy (47XXY, 48 XXXY, etc) from X-chromosome nondisjunction during maternal or paternal meiosis. Tall stature, varicose veins, arterial and venous leg ulcers, scant androgenic hair (body, pubis), gynecomastia, testicular hypoplasia, and antisocial behavior • Turner syndrome: XO, 1:2500, partial or total loss of one X chromosome from nondisjunction during gametogenesis. Webbed neck (remnant of cystic hygroma), keloids, hypoplastic nails, low-set ears with low posterior hairline, short stature, short 4th and 5th metacarpals, congenital lymphedema of hands and feet, primary amenorrhea from gonadal dysgenesis, cardiovascular abnormalities including coarctation of the aorta, and horseshoe kidneys • Noonan syndrome: AD or sporadic. PTPN11, encoding the nonreceptor protein tyrosine phosphatase SHP2 which contains 2 Src homology-2 (SH2) domains. Lower extremity lymphedema, nevi, CALMs, webbed neck, craniofacial abnormalities, short stature, cardiovascular defects including pulmonic valve stenosis, hypogonadism, and mental retardation • Familial Dysautonomia (Riley-Day syndrome): IKBKAP mutation; lack of pain sensation, decreased corneal sensation/tear flow, no fungiform papillae 3.14 KERATINOPATHIES Keratin is expressed in pairs. Keratin type I (keratins 9-20) is acidic, has a lower molecular weight, and is coded on chromosome 17q. Keratin type II (keratins 1-8) is basic, has a higher molecular weight, and is coded on chromosome 12q. Table 3-1. Keratins Type II Location of Expression Associated Disease 1 10 Suprabasal keratinocytes Epidermolytic hyperkeratosis, Unna-Thost PPK 1 9 Palmoplantar suprabasilar epidermis Epidermolytic PPK, Vorner PPK K2e 10 Granular layer Ichthyosis bullosa of Siemens 3 12 Cornea Corneal dystrophy 4 13 Mucosal epithelium White sponge nevus 5 14 Basal cells Epidermolysis bullosa simplex 6a 16 Outer root sheath, hyperproliferative keratinocytes Pachyonychia congenita type I (Jadassohn-Lewandowsky), focal PPK 6b 17 Nail bed Pachyonychia congenita type II (Jackson-Lawler) 8  Type I 18 Simple epithelium Cryptogenic cirrhosis 3.15 DISORDERS OF METABOLISM • Alkaptonuria: Ochronosis, AR, homogentisic acid oxidase, blue-gray pigmentation → face, ears, cartilage, tendons, acral surfaces, cerumen, sweat, blue-gray sclera, arthropathy, intervetebral disk calcification, cartilage of pubic symphysis, ear, nose, dark urine (pH > 7.0) Report a Problem/Feedback Genodermatoses  67
  • 78. • Fabry disease: Angiokeratoma corporis diffusum, X-linked recessive, α-galactosidase A, Accumulation of glycosphingolipids in vascular endothelium → ischemia and infarction, angiokeratomas between umbilicus and knees, urine → “maltese crosses,” mulberry cells, renal insufficiency with proteinuria, Painful crises, (paresthesias) on hands and knees relieved by phenytoin, angina, MI, CVA’s, peripheral neuropathy, corneal opacities (“whorllike” configuration), fucosidosis (a-L-fucosidase) and sialodosis are indistinguishable from Fabry’s on cutaneous exam, b-galactosidase deficiency and aspartylglucosaminururia show angiokeratomas, too • Gaucher disease: AR, acid beta-glucosidase (GBA) gene; Type I → adult; Type II → infants, Gaucher cells: glucocerebroside in histiocytes in spleen, liver, bone marrow, lymph nodes, brain. Ehrlenmeyer flask deformity in bone • Mucopolysaccharidoses: AR (except Hunter syndrome → X-linked recessive), deficiency of lysosomal enzymes responsible for breakdown of mucopolysaccharides; Skin findings: firm, ivory-colored papules between angles of scapula (Hunter), all patients have thick skin, increased dermatan and heparan sulfate (Hunter), all patients have generalized hirsutism, coarse facies with thick nose and depressed nasal bridge, thick lips and tongue, short neck, broad hands, short fingers, mental retardation, short stature, corneal clouding and retinitis pigmentosa, cardiac failure and valvular disease, bronchopneumonia, hepatosplenomegaly, dysostosis multiplex, osteoporosis, joint laxity – Hurler and Scheie: α-L-iduronidase – Hunter: Iduronate sulfatase – Sanfilippo: Multiple enzymes can be deficient – Maroteaux-Lamy: Arylsulfatase B – Morquio: Either hexosamine 6-sulfatase or b-galactosidase • Multiple Carboxylase deficiency: Biotinidase deficiency or holocarboxylase synthetase deficiency, decreased free serum biotin, periorificial/generalized dermatitis, Candida infection, alopecia, hypotonia, seizures, vomiting, optic atrophy, hearing loss, metabolic acidosis with hyperammonemia, treat with biotin 10 mg/day • Phenylketonuria: AR, phenylalanine hydroxylase (or its cofactor tetrahydrobiopterin), increased phenylalanine inhibits tyrosine in melanogenesis and toxic to CNS, generalized hypopigmentation, eczema, sclerodermoid changes to skin, blonde hair, blue eyes, mental retardation, urine with “mousy” odor • Homocystinuria: AR, cystathione β-synthase, increased homocystine and methionine levels in blood/urine, malar flush, DVT’s and emboli, cardiovascular disease, livedo reticularis, leg ulcers, blonde hair, fair complexion, downward lens dislocation (ectopia lentis), glaucoma, marfanoid habitus, mental retardation, seizures, psychiatric disorders • Acrodermatitis Enteropathica: AR (intestinal zinc specific transporter SLC39A4), bottlefed infants; after weaning, breast-fed older infants, defect in zinc-absorption, periorificial, scalp, and acral dermatitis, scaling, vesicles/bullae, erosions, alopecia, diarrhea, stomatitis, glossitis, irritability, photophobia, treat with lifelong zinc supplementation • Wilson disease: Hepatolenticular degeneration, AR (ATP 7B gene, ATPase coppertransporting beta polypeptide), Defect in biliary excretion of copper → accumulation of copper in liver, brain, cornea, pretibial hyperpigmentation, blue lunalae, hepatomegaly, cirrhosis, Kayser-Fleischer ring (yellow-brown copper deposition in Descemet’s membrane of cornea), ataxia, dysarthria, dementia 68  2013/2014 Dermatology In-Review l Committed to Your Future Report a Problem/Feedback
  • 79. • Hemochromatosis: AR (HFE gene, hemojuvelin HJV gene, hepcidin antimicrobial peptide HAMP gene, transferring receptor 2 TFR2 gene), AD (ferroprotein SCL40A1 gene) increased intestinal iron absorption → iron overload, generalized metallic-grey hyperpigmentation, koilonychia, alopecia → scant pubic/axillary hair, cardiac failure, arrythmias, heart block, hepatomegaly with cirrhosis, diabetes (“bronze diabetes”), polyarthritis with chondrocalcinosis, screen with ferritin, susceptible to Vibrio vulnificus and Yersinia infections • Porphyrias (see Chapters 10 and 12) • Nieman-Pick disease: AR, sphingomyelinase (sphingomyelin phosphodiesterase I-SMPD-1) gene: – Type A: Onset in infancy: CNS, cherry red spot - leads to blindness – Type B: Onset in infancy, childhood: no CNS problems – Type C: Onset in childhood: psychomotor deterioration, hepatosplenomegally Table 3-2. Radiologic Findings in Genodermatoses and Other Syndromes Findings Associated Disease Accordion hand Multicentric reticulohistiocytosis Asymptomatic dural calcification and choroids attachments Papillon-Lefevre Bifid ribs Nevoid Basal Cell Carcinoma syndrome Bilateral bean-shaped calcification of hippocampus Lipoid proteinosis Bilateral posterior iliac horns, radial head subluxation, hyperextensible joints, thickened scapula, absent patella,bilateral 1st rib hypoplasia Nail-patella Broad thumbs Rubinstein-Taybi Calcification of falx cerebri & basal ganglia Nevoid Basal Cell Carcinoma syndrome Calcification of ligament, intracranial calcification (dura, falx, pineal, choroids) Pseudoxanthoma elasticum Calcification of tubers in basal ganglia Tuberous sclerosis Cerebellar, spinal, medullary hemangioblastomas Von-Hippel-Lindau Chondrodysplasia punctata Conradi-Hunermann Clinodactyly Down’s, Cornelia de Lange, Russell-Silver Congenital hip dislocation EDS 7 Cystic defects in end of long bones and skull Infantile fibromatosis Double-contoured railroad tram track calcification (meningeal angiomas) Sturge-Weber Dysostosis multiplex Mucopolysaccharidosis Ehrlenmeyer flask deformity Gaucher Enchondromas, metacarpals with phleboliths, chondrosarcomas Maffucci Hyperostosis of external auditory canal Proteus syndrome Hypoplastic thumbs, radii, ulnae Rothmund-Thompson Intracranial calcification Cockayne, TORCH infections, dyskeratosis congenita Lytic bone cysts of hands with honeycombed pattern Sarcoid Report a Problem/Feedback Genodermatoses  69
  • 80. Table 3-2. Radiologic Findings in Genodermatoses and Other Syndromes Findings Associated Disease Medulloblastoma Nevoid Basal Cell Carcinoma syndrome Melorheostosis (liner hyperostosis under affected skin) Linear scleroderma Occipital horns (exostoses) EDS 9, Menkes kinky hair disease Osteomas in maxilla, mandible Gardner’s Osteomyelitis-like Sweet’s syndrome Osteopathia striata (stripes on metaphases of long bones) Focal dermal hypoplasia (Goltz syndrome) Osteopoikilosis (round densities in long bones) Buschke-Ollendorf syndrome Phalangeal thickening with periosteal cysts Tuberous sclerosis Polyostotic fibrous dysplasia McCune Albright syndrome Resorption of distal phalanges Scleroderma Sclerotic bone lesions POEMS syndrome Sphenoid wing dysplasia Neurofibromatosis type 1 Supernumerary vertebrae with extra ribs Incontinentia pigmenti Thickening of calvarium Clouston Tufted phalanges Clouston Waferlike calcification of cartilage (spine, pubis, ear, nose) Alkaptonuria Wormian bodies in sagittal suture and metaphyseal widening with spurs in long bones Menkes kinky hair Table 3-3. Tooth Findings in Genodermatoses Tooth Finding Associated Disease Anodontia Hypomelanosis of Ito Anodontia/pegged teeth Incontinentia pigmenti Dental pits Tuberous sclerosis Enamel dysplasia Sjogren-Larsson, Herlitz JEB Natal teeth Pachyonychia congenita type II (JacksonSertole) Odontogenic cysts Nevoid Basal Cell Nevus syndrome, Gardner syndrome Odontoid hypoplasia Down’s & Hurler’s syndromes Odontomas and supernumerary teeth Gardner syndrome Peg shaped conical incisors/canines, molars with hooked cusps Anhidrotic ectodermal dysplasia Periodontitis Papillon-Lefevre, Haim-Munk, Ehlers-Danlos type 8 Resorption of alveolar ridge (floating teeth) Letterer-Siwe Retention of primary teeth Hyper IgE syndrome 70  2013/2014 Dermatology In-Review l Committed to Your Future Report a Problem/Feedback
  • 81. MNEMONIC Blue Sclerae All DEMON Fly Past MNEMONIC Alkaptonuria Downs Ehlers Danlos Marfans Osteogenesis Imperfecta Nevus of Ota Fanconi’s PXE Angioid Streaks APPLES Anemia, Sickle cell Pseudoxanthoma elasticum Pagets disease of the bone Lead poisoning Ehlers Danlos Sclerosus tuberous Table 3-4. Eye Findings in Genodermatoses Eye Finding Associated Disease Angioid streaks (rupture of Bruch’s membrane) Pseudoxanthoma elasticum Ankyloblepharon CHANDS, Hay-Wells syndrome Atypical retinitis pigmentosa (glistening dot) Sjogren-Larsson Blue sclerae Osteogenesis imperfecta types 1, 2, and 3; Ehlers-Danlos syndrome Blue sclerae, retinal detachment, ruptured globe, keratoconus Ehlers-Danlos syndrome type 6 Blue to gray-blue eyes, prominent red reflex Tyrosinase negative albinism Blue to yellow-brown eyes Tyrosinase positive albinism Brushfield spots Down syndrome Cherry red spot Niemann-Pick, Tay-Sachs, generalized sialidosis, Sandhoff syndrome Choroid malformation Sturge-Weber syndrome Coloboma Focal dermal hypoplasia Comma-shaped corneal opacities X-linked ichthyosis Congenital hypertrophy of retinal pigment epithelium Gardner’s syndrome Corneal clouding, retinitis pigmentosa Mucopolysaccharidosis Corneal opacities, lipodermoid tumors Epidermal nevus syndrome Decreased corneal sensation to tear flow Riley-Day syndrome Dystopia canthorum with heterochromia irides Waardenburg syndrome Ectopia lentis (downward) Homocystinuria Ectopia lentis (upward) Marfan’s syndrome Eyelid papillomas Xeroderma pigmentosum Eyelid string of pearls Lipoid proteinosis Glaucoma Neurofibromatosis type 1, Sturge-Weber syndrome Juvenile posterior subcapsular lenticular opacity Neurofibromatosis type 2 Report a Problem/Feedback Genodermatoses  71
  • 82. Table 3-4. Eye Findings in Genodermatoses (cont.) Eye Finding Associated Disease Lester iris (hyperpigmentation of papillary margin of iris) Nail-patella syndrome Lisch nodules, optic gliomas Neurofibromatosis type 1 Optic atrophy Biotinidase deficiency Phakomas (astrocytic hamartomas of optic nerve) Tuberous sclerosis Pingeculae Gaucher syndrome Pseudoherpetic keratitis with blindness Richner-Hanhart syndrome Retinal hemangioblastomas Von-Hippel-Lindau syndrome Retinitis pigmentosa (salt & pepper) Refsum Salt and pepper retina Cockayne syndrome, Refsum syndrome 72  2013/2014 Dermatology In-Review l Committed to Your Future Report a Problem/Feedback
  • 83. NOTES Report a Problem/Feedback Genodermatoses  73
  • 84. NOTES 74  2013/2014 Dermatology In-Review l Committed to Your Future Report a Problem/Feedback
  • 85. 4  General Dermatology Priya Swamy Zeikus, MD Bruce E. Strober, MD, PhD Katherine L. White, MD C o n t e n t s 4.1 Acne Vulgaris . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 78 4.2 Rosacea . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 81 4.3 Psoriasis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 83 4.4 Psoriatic Arthritis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 88 4.5 Reiter’s Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 88 4.6 SAPHO Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 89 4.7 Sneddon-Wilkinson Disease . . . . . . . . . . . . . . . . . . . . . 90 4.8 Lichen Planus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 90 4.9 Atopic Dermatitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 94 4.10 Alopecia Areata . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 97 4.11 Alopecia: Other Forms . . . . . . . . . . . . . . . . . . . . . . . . . . 98 4.12 Vitiligo . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 100 4.13 Pityriasis Rubra Pilaris . . . . . . . . . . . . . . . . . . . . . . . . . . . 101 4.14 Lichen Sclerosus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 101 4.15 Granuloma Annulare . . . . . . . . . . . . . . . . . . . . . . . . . . . 102 4.16 Hirsutism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 103 4.17 Amyloidosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 104 4.18 Calciphylaxis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 106 4.19 Angioedema . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 107 4.20  Carcinoid Syndrome and Flushing Disorders . . . . . 108 4.21 Lupus Erythematosus . . . . . . . . . . . . . . . . . . . . . . . . . . 109 4.22 Scleroderma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 112 (Continued on next page) Report a Problem/Feedback General Dermatology  75
  • 86. 4.23 Dermatomyositis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 115 4.24 Sjogren’s Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 117 4.25  onnective Tissue Disease: Serology . . . . . . . . . . . . . 117 C 4.26 Relapsing Polychondritis . . . . . . . . . . . . . . . . . . . . . . . . 119 4.27 Behçet’s Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 120 4.28 Livedo Reticularis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 121 4.29 Leukocytoclastic Vasculitis . . . . . . . . . . . . . . . . . . . . . . 121 4.30  Cryoglobulinemia and Cryofibrinogenemia . . . . . . . 124 4.31 Acanthosis Nigricans . . . . . . . . . . . . . . . . . . . . . . . . . . . . 125 4.32 Lipodystrophy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 126 4.33 Hyperlipoproteinemias . . . . . . . . . . . . . . . . . . . . . . . . . . 127 4.34 Xanthomatosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 128 4.35 Vitamin Deficiencies . . . . . . . . . . . . . . . . . . . . . . . . . . . . 128 4.36  iabetes and Skin Disease . . . . . . . . . . . . . . . . . . . . . . . 132 D 4.37  angerhans Cell Histiocytosis . . . . . . . . . . . . . . . . . . . . 134 L 4.38  utaneous T-cell Lymphoma . . . . . . . . . . . . . . . . . . . . 135 C 4.39 Pyoderma Gangrenosum . . . . . . . . . . . . . . . . . . . . . . . . 138 4.40 Sweet’s Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 139 4.41 E  rythema Annulare Centrifugum . . . . . . . . . . . . . . . . 140 4.42  rythema Elevatum Diutinum . . . . . . . . . . . . . . . . . . . 140 E 4.43 Erythema Nodosum . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 141 4.44 Mastocytosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 142 4.45 Cutaneous Sarcoidosis . . . . . . . . . . . . . . . . . . . . . . . . . 144 4.46 Perforating Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . 146 4.47  lastosis Perforans Serpiginosa . . . . . . . . . . . . . . . . . 146 E 4.48  eactive Perforating Collagenosis . . . . . . . . . . . . . . . 147 R 4.49  Cutaneous Features and Disorders of Pregnancy . . 147 4.50 Pruritus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 149 4.51 Scleredema . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 150 4.52 Nephrogenic Fibrosing Dermopathy/ Nephrogenic Systemic Fibrosis . . . . . . . . . . . . . . . . . . 151 76  2013/2014 Dermatology In-Review l Committed to Your Future Report a Problem/Feedback
  • 87. 4.1 ACNE VULGARIS Key Pathogenic Factors • Abnormal keratinization (follicular retention hyperkeratosis) • Inflammation • Presence of Propionibacterium Acnes (P. acnes) in sebum • Sebum production, under hormonal control, starting at adrenarche Pathogenesis Overview • Precursor lesion of comedonal and inflammatory acne is the microcomedo • Human sebum is rich in triglycerides.1 P. acnes makes an enzymatic lipase which cleaves triglycerides into free fatty acids • Inflammation is triggered by follicular wall rupture and subsequent immune response. P. acnes itself is pro-inflammatory; it can activate complement, and neutrophil chemotaxis and activity • IL-1, a pro-inflammatory cytokine, may promote follicular plugging and microcomedo formation2 • Toll-like receptors (TLR’s) → a large group of receptors that recognize certain bacterial patterns. TLR-2 activation by P. acnes leads to intracellular signal transduction and upregulation of the immune response by stimulating pro-inflammatory cytokines.3 Certain topical retinoids have been shown to downregulate TLR-2 expression4 Clinical Variants Acne Vulgaris • Noninflammatory lesions are the microcomedo and the comedo (open and closed) • Inflammatory lesions are papules, pustules and nodules Acne Conglobata • A severe variant characterized by large, often multiple comedones, abscesses with sinus formation, and inflammatory nodules • Seen most frequently in young male patients • Follicular occlusion triad consists of acne conglobata, hidradenitis suppurativa, and dissecting cellulitis of the scalp. Treatment is with high dose isotretinoin Acne Fulminans • A rare, explosive form of severe cystic acne affecting young males • Marked by acute, suppurating nodules and plaques that ulcerate and form blackish eschar • The trunk is affected more severely than the face  • Patients may be systemically ill, with leukocytosis, fever, arthralgias, and myalgias. Lytic changes, indicative of a sterile osteomyelitis, can be seen on x-ray and bone scans. The sternoclavicular joint and the chest wall are most frequently affected • Treatment is with oral prednisone, intralesional steroids, antibiotics, and isotretinoin Miscellaneous Acne Variants Industrial Acne  • Chloracne is a form of industrial acne triggered by workplace exposure to chlorinated compounds  T •  he malar cheeks and postauricular scalp, as well as the scrotum, are affected. The lesions  are characterized by large comedones as well as inflammatory papules, pustules, and cysts • Insoluble cutting oils are the most frequent cause of industrial acne 78  2013/2014 Dermatology In-Review l Committed to Your Future Report a Problem/Feedback
  • 88. • Dioxin (2,3,7,8 tetrachlorobenzodioxin) is a well-known, potent trigger of acneiform eruptions5 Acneiform Eruptions • Numerous oral agents have been associated with acneiform eruptions, including the halogens bromide and iodide, androgenetic hormones such as testosterone, ACTH, corticosteroids, isoniazid (INH), lithium, erbitux, phenytoin, cyclosporine, and Vitamins B2, B6, and B126 Treatment of Acne Vulgaris Topical Retinoids • Tretinoin (all trans-retinoic acid), adapalene, and tazarotene are effective comedolytic agents which normalize follicular epithelial differentiation • Retinoid activity is mediated by retinoid receptors. Two groups exist: RA receptors (RAR) and RX receptors (RXR). Each has three receptor subtypes: α, β, γ. RAR-γ is the most important mediator of retinoid activity in the skin • Tretinoin and adapalene are pregnancy category C drugs; tazarotene is category X. Tretinion activates RAR receptors α, β, γ. Bexarotene selectively binds retinoid X receptors. Adapalene activates RAR β and γ. Tazorac binds RAR α, β, γ but shows selectively for RAR β and RAR γ Topical Antibiotics (Erythromycin and clindamycin)  • Decrease the population of P. acnes on the skin • Increasing antibiotic resistance has discouraged their use as monotherapy Benzoyl Peroxide (BPO) • Bactericidal agent with direct oxidizing effects, and thus no potential for resistance • Irritation, dryness, and bleaching of clothing or hair may occur Dapsone • Most common side effects include dryness, redness, oiliness, and peeling of the skin where applied. The use of benzoyl peroxide together with dapsone at the same time may cause your skin to temporarily turn yellow or orange at the site of application Combination Products (Clindamycin, erythromycin, BPO, adapalene, and tretinoin) • Synergistic efficacy and decreased potential for antibacterial resistance • May cause irritation Azelaic Acid • Dicarboxylic acid that has weak activity against P. acnes • Inhibits tyrosinase, and can be helpful in reducing post-inflammatory pigment alteration. Itching, burning or dryness at the initiation of treatment is not uncommon • Pregnancy category B Oral Antibiotics Tetracyclines • Tetracycline, doxycycline, and minocycline • Inhibit RNA-dependent protein synthesis by binding the bacterial 30s ribosomal subunit • Tetracycline is best absorbed on an empty stomach, and its absorption is inhibited by chelation with bi- and trivalent cations (e.g., calcium, bismuth, iron)  • Tetracycline can cause permanent brown discoloration of the teeth in children, and is not used routinely for children under the age of eight • Risk of photosensitivity Demecycline > Doxycycline > Tetracycline > Minocyline • Photo-onycholysis has been reported with Tetracycline Report a Problem/Feedback General Dermatology  79
  • 89. • Unlike other tetracyclines, doxycycline is excreted via the GI tract rather than the kidneys, and thus is the tetracycline of choice in renally compromised patients • Minocycline has been associated with CNS symptoms, including vertigo and headache, autoimmune hepatitis, drug-induced anti-histone Ab positive SLE-like syndrome, and hyperpigmentation • Minocycline can cause hyperpigmentation of the skin. Three types are generally  described: - Blue-Black Discoloration: Appearing in areas of prior skin injury, such as acne scars - Blue-Gray Discoloration: Often at the lower anterior legs and forearms - Muddy Brown Discoloration: Found on sun-exposed areas. The least common type of hyperpigmentation • The first two types show staining for both iron and melanin [Fontana Masson stains melanin black; Perls stain stains iron (hemosiderin) blue]. The third type shows increased melanin at the basal layer and within macrophages • Doses of tetracyclines below the minimum inhibitory concentration (MIC) can inhibit neutrophil chemotaxis, pro-inflammatory cytokine cascades, and reduce P. acnes production of lipase Macrolides • Include erythromycin and azithromycin • Inhibit RNA-dependent protein synthesis by binding the 50s ribosomal subunit • Erythromycin can cause gastrointestinal distress and potentially significant drug interactions • Erythromycin inhibits the hepatic cytochrome P450 system and can increase serum levels and potential toxicities of carbamazepine, theophylline, warfarin, digoxin, methylprednisolone Trimethoprim-sulfamethoxazole (TMP-SMX) • Considered second-line therapy for acne, due to increased risk of serious adverse reactions, including hypersensitivity reactions • TMP-SMX inhibits bacterial folic acid synthesis • Drug hypersensitivity syndrome is characterized by fever, skin eruption and internal organ involvement Isotretinoin • Gold standard for treating nodular acne and recalcitrant acne • Reduces sebum production by reducing sebaceous gland size, normalizes follicular keratinization, and indirectly reduces P. acnes and its inflammatory sequelae • A potent teratogen • Half-life of isotretinoin is 10-20 hours13 • Doses range from 0.5-2.0 mg/kg/day for 4 to 6 months (or 120-150 mg/kg total dose) • Patients are monitored monthly for changes in the plasma lipids, liver function tests and complete blood counts. Monthly pregnancy tests for women are also required. The most common laboratory abnormalities are increased triglycerides, followed by elevation of ALT and AST; decreased blood counts are rare; increased exercise can cause elevation of creatinine phosphokinase • Almost all patients experience cheilitis, xerosis, dry nasal mucosa, dry eyes • Other, less common side effects: hair thinning (usually reversible), skin infection, petechiae, abdominal pain, corneal opacities, bone and joint pain, headache, diffuse idiopathic skeletal hyperostosis (DISH) 8 80  2013/2014 Dermatology In-Review l Committed to Your Future Report a Problem/Feedback
  • 90. u TIP • Screen for papilledema if headache, nausea, and vomiting aseudotumor cerebri occurs P occurs more often with co-adminis• Recent reports of serious psychiatric events possibly related tration of a tetracycline to isotretinoin have drawn considerable attention. A large population based study with control groups failed to show an increased risk of depression, suicide attempt and suicide among isotretinoin treated patients14 Hormonal Therapies • May be an important component of acne treatment in the female patient, especially for adult women with a predominance of acne at the lower face • Most common endocrinopathy associated with acne is polycystic ovary syndrome (PCOS), characterized by acne, obesity, hirsutism, amenorrhea and glucose intolerance • Congenital adrenal hyperplasia (CAH) is also associated with acne • Although rare, very high levels of DHEA-S may suggest an adrenal androgen-secreting tumor • A patient whose acne fails to respond to conventional therapy, whose acne flares cyclically, with hirsutism, alopecia or irregular menses warrants an endocrine work-up, including free and total testosterone, LH, FSH, and DHEA-S • Benefit from hormonally-based therapies, such as oral contraceptives (OCPs) • Usually ethinyl estradiol. OCP’s lead to a decrease in free testosterone levels by increasing the adrenal production of sex hormone binding globulin (SHBG) • Spironolactone, commonly dosed between 50 to 200 mg/day → blocks androgen receptors and adrenal androgen synthesis. Side effects include menstrual irregularities, breast tenderness, and intestinal symptoms, which can be mitigated by concomitant OCP use. Hyperkalemia is more likely in the setting of renal failure. Spironolactone is not FDAapproved for the treatment of acne. It is pregnancy category X 4.2 Rosacea • Papules and papulopustules in central region of face against a vivid background of telangiectases. Later, diffuse hyperplasia of connective tissue with enlarged sebaceous glands • Localized to nose, cheeks, chin, forehead, glabella; less commonly affected areas include the retroauricular, V-shaped chest area, neck, back, scalp • Flushing and blushing evoked by UV, heat, cold, chemical irritation, strong emotions, alcoholic beverages, hot drinks, and spices Variants of Rosacea Persistent Edema of Rosacea (Rosacea Lymphedema or Morbihan’s Disease) • Hard, nonpitting edema • Often misdiagnosed as cellulitis Ophthalmic Rosacea • Blepharitis, conjunctivitis, iritis, keratitis (inflammation of cornea) • The treatment of choice for ocular rosacea is oral antibiotics Report a Problem/Feedback General Dermatology  81
  • 91. Granulomatous Rosacea • Dozens of brown-red papules or nodules on diffusely reddened skin, frequently involving lower eyelids • Histopathology: perifollicular and perivascular noncaseating epithelioid granulomas • Chronic and unremitting Steroid Rosacea • Rosacea resulting from steroid use • Steroid atrophy with resultant telangiectases • Flaming red, scaling, papule-covered face • Severe pain, discomfort • Withdrawal of steroid accompanied by exacerbation of disease • Slow tapering of steroid over months is required Rosacea Fulminans (Pyoderma Faciale) • Occurs almost exclusively in post-adolescent women; lots of flushing and blushing • Large coalescent nodules and confluent draining sinus occupy most of the face • Prognosis is excellent, and recurrences rare Perioral Dermatitis • May be triggered or exacerbated by topical steroid use • Generally responds well to topical and/or oral antibiotic treatment Treatment Topical • Antibiotics – often effective – Topical clindamycin and erythromycin – Topical metronidazole active against papules and pustules, but not telangiectasia and flushing – Topical sulfur-based preparations • Azelaic acid • Sunscreens • Green-tinted makeup concealer can neutralize redness Systemic • Antibiotics – generally responds well – Doxycycline - low dose 40 mg and 100 mg – Tetracyclines – Erythromycin • Isotretinoin – indicated in phymas; but rosacea often rapidly recurs after discontinuation of isotretinoin Treatment for Rosacea Fulminans • Oral glucocorticoids, 1.0 mg/kg per day for 7-10 days, add isotretinoin, with slow tapering of steroid, for 3-4 months until all inflammatory lesions disappear • Do not incise draining abscesses • Topical steroids (potent) for first two weeks 82  2013/2014 Dermatology In-Review l Committed to Your Future Report a Problem/Feedback
  • 92. Phymas Rhinophyma • Occurs almost exclusively in men 1.) Gnathophyma – chin swelling 2.) Metophyma – forehead and nose saddle 3.) Otophyma – earlobes 4.) Blepharophyma – eyelids 4.3 Psoriasis Psoriasis is an immune dysregulatory disease resulting from persistent T-cell activation and the resultant release of TH1-based cytokines such as TNF-α and IL-2. These cytokines cause keratinocytic proliferation (acanthosis), and increased recruitment of inflammatory cells into the psoriatic skin. Epidemiology • Affects approximately 2% of population of U.S. • Usually begins in 3rd decade of life. Bimodal incidence: peaks at ages 29 and 55 • An early onset predicts more severe disease. Also, early onset more likely with positive family history Inheritance • Increased incidence in offspring of parents in which one or both affected • Monozygotic twin concordance HLA association with • HLA-B13 • HLA-B17 (earlier onset and more serious disease) • HLA-Bw57 • HLA-Cw6 (most definitive associated HLA type) – relative risk 9-15 times normal • Psoriatic arthritis in disequilibrium with HLA-B27, especially if spondylitis present Clinical Features Skin Lesions • Sharply demarcated papules and plaques • Non-coherent silvery scales • Auspitz sign → bleeding upon removal of scale • Koebnerization seen in 20% • Woronoff Ring: Area of blanching around psoriatic plaques secondary to decrease in prostaglandin, PGE2 Clinical Patterns Chronic Stationary/Psoriasis Vulgaris • Most frequent • Red, scaly lesions persist for years • Little alteration in shape/distribution of plaques • Areas of predilection: elbows, knees, scalp, retroauricular region, lumbar, umbilicus • When localized in the major skin folds, scaling is absent Report a Problem/Feedback General Dermatology  83
  • 93. Guttate (Eruptive) Psoriasis • Small (0.5 to 1.5 cm) lesions over upper trunk and proximal extremities • Early age of onset/young adults  • Streptococcal throat infection frequently precedes eruption Psoriatic Erythroderma • Affects all body sites • Erythema is most prominent feature, scaling less prominent Generalized Pustular Psoriasis  • Von Zumbusch type; acute variant • Usually no other forms on skin at same time  • Fever, lasting several days, with eruption of sterile pustules 2-3 mm diameter paralleling the fever • Distribution: Trunk, extremities including nail beds, palms, and soles • Pustules arise on highly erythematous skin • Fingertips may become anonychic and atrophic  • Hypocalcemia, hypoalbuminemia, leukocytosis Localized Pustular Psoriasis • Systemic symptoms absent • Two distinct conditions 1.) Pustulosis palmaris et plantaris 2.) Acrodermatitis continua of Hallopeau Psoriatic Nail Disease • May be of nail matrix or nail bed origin • Fingernails involved in 50%, toenails in 35% • Nail changes more frequent (80-90%) in patients with arthritis  •  Psoriatic nail changes of matrix → pits (the most common nail change of psoriasis and representing focal psoriasis of the proximal matrix) and leuconychia • Pits in psoriasis are generally more randomly distributed than the regular rows of pits seen in alopecia areata • Psoriatic nails changes of nail bed origin include: salmon spots, “oil spots,” onycholysis, subungual hyperkeratosis, and splinter hemorrhages16 Psoriatic Arthritis • Asymmetric oligoarthritis, small joints of hands • Associated onycholysis Trigger Factors • Warmer weather and sunlight reported to be beneficial • Physical trauma – Koebner reaction • Infection – 50% of children exacerbate existing psoriasis during 2-3 week interval after URI  –  cute guttate psoriasis frequently follows an A acute streptococcal infection by 1-2 weeks (5685%) and streptococcal infections may play a role in exacerbating other forms of psoriasis u TIP a rugs D –  teroids – withdrawal of systemic and S possibly topical) corticosteroids can result in severe flares – Lithium – Beta-blockers – Interferons – ACE inhibitors – Granulocyte-colony stimulating factors17 a ntimalarials and NSAIDS are not elieved to A truly exacerbate psoriasis in most patients 84  2013/2014 Dermatology In-Review l Committed to Your Future Report a Problem/Feedback
  • 94. – Infection with HIV may represent another trigger factor • Stress – psoriasis made worse by stress in 30-40% of cases  Systemic Associations • Psoriatic arthritis • Crohn’s disease and ulcerative colitis • HTN, obesity, diabetes, and chronic oropharyngeal infections found more frequently in psoriatic patients • Pustular psoriasis associated with HLA-B27, and arthropathy is common • Increased risk of lymphoma Keratinocyte Proliferation • 8-fold shortening of epidermal cell cycle (36 hrs vs. 311 hrs for normal) Treatment Anthralin (topical) • Advantage: lacks long-term side effects • Possesses antiproliferative activity on human keratinocytes • Also, strong anti-inflammatory effects by inhibiting PMNs and monocytes • Irritant reactions, especially after increasing concentration too fast • Can stain hair to purple • Brownish discoloration of surrounding skin—reversible Vitamin D3 Analogues • Calcipotriol, tacalciol, calcitriol • Inhibit keratinocyte proliferation and induce terminal differentiation • Anti-inflammatory • Used for plaque-type psoriasis QD or BID • Calcipotriol inactivated by salicylic acid or lactic acid (Lac-hydrin) • Should be used after UV-light (calcipotriol absorbs UV) • Local irritation Tazarotene • Retinoid • Reduces scaling and plaque thickness, with little effectiveness on erythema • May be beneficial in combination with phototherapy Tar • Unknown activity • 2-5% tar in various bases effective in chronic plaque-type psoriasis Topical Glucocorticoids PUVA • Oral ingestion of a potent photosensitizer such as 8-methoxypsoralen (8-MOP) or trimethoxypsoralen (0.6 mg/kg) and variable doses of UVA, 2 hours after ingestion • Treatments given TIW or QIW • Clearing usually occurs after 19 to 25 treatments • Overdosing results in sunburn, 24-48 hour post-treatment • Psoralens → intercalate with DNA, with energy of UVA covalently cross-link nucleic acids between opposing strands of duplex regions, leads to irreversible photo-inhibition of DNA synthesis and mitosis Report a Problem/Feedback General Dermatology  85
  • 95.  • Nausea, dizziness, headache • Photosensitivity during the 8-12 h after ingestion of psoralen, protective eyewear needed • Higher frequency of squamous cell carcinomas, and perhaps malignant melanoma risk, increases after 250 treatments Methotrexate  • Synthetic analog of folic acid that competitively inhibits dihydrofolate reductase • Inhibits S phase of cell cycle (like hydroxyurea) • 10-30 mg once per week PO or IM • Nausea, anorexia, fatigue, headaches, alopecia, stomatitis • Leukopenia and thrombocytopenia indicate overdose → leucovorin rescue required • Careful in kidney dysfunction → renal excretion • Acute interstitial pneumonitis (rare) • Hepatotoxicity; exclude those with liver disease or alcohol abuse; above a cumulative dose of 1.5 g, liver biopsy is often recommended before continuing with therapy • Also effective in treating psoriatic arthritis Cyclosporine  • Inhibits release of cytokines, specifically IL-2, by binding and deactivating calcineurin • Effective in erythrodermic and generalized pustular psoriasis • Start at 2.5 to 4 mg/kg per day, and can go as high as 5.5 mg/kg per day • Renal impairment (often reversible) → reduce dosage by 25% if creatinine increases to 30% or greater of baseline • Hypertension (Treat with ACE-inhibitors) • Elevated triglycerides • Hyperkalemia • Hypomagnesemia • Hepatotoxicity • Hypertrichosis (common), gingival hyperplasia, trichomegaly, nausea, vomiting, diarrhea, arthralgia, myalgia, tremor, acne, sebaceous hyperplasia, and fatigue may occur • Long-term risk of malignancy • Metabolized by P450, thus erythromycin or ketoconazole will increase drug levels Retinoids → Acitretin • Vitamin A derivatives • Effective in pustular and palmoplantar forms of psoriasis • Acitretin is most commonly used, given at 25 mg per day initially • Restrict use in women of childbearing age • Regulate growth and terminal differentiation of keratinocytes; modulate transcription of specific genes through retinoid response elements • Show lower response rates than other systemic modalities for treatment of plaque-type psoriasis → often ineffective as monotherapy for plaque-type psoriasis • Effective when combined with ultraviolet phototherapy (either UVB or PUVA)  • Treatment over 3-4 months necessary • Dose related adverse effects: cheilitis, sicca symptoms of eyes and mouth, generalized pruritus, dry skin, loss of stratum corneum of palms and soles, hair loss • Muscle and joint pain • Elevation in serum lipids, and also LFTs • Monitor liver and kidney function, blood glucose, lipid profile 86  2013/2014 Dermatology In-Review l Committed to Your Future Report a Problem/Feedback
  • 96. Biologic Agents (see Table 4.1) • Etanercept • Efalizumab • Alefacept • Infliximab • Adalimumab • Ustekinumab Table 4-1. Biologics Drug Mechanism Labs Etanercept Recombinant fusion protein to TNF receptor; binds soluble TNF-alpha Efaluzimab Humanized antibody that binds CD11a Weekly SC injections component of LFA1 which binds to ICAM1 on APC and endothelial cells 50 mg SC injections twice weekly Adalumimab Antibody towards human TNF-alpha IM injections once weekly or once weekly IV bolus B C Self administered IM injection qoweek Alefacept Infliximab Protein that blocks the interaction of LFA3 and Fc human IgG, LFA3 is the receptor for CD2 and increased in CD45 Ro T cells Monoclonal antibodies which inhibit TNF-alpha Pregnancy Other Class B CD4 B counts IV injections, first dose followed by dose at weeks 2, 6, then dosed 8 weeks Ustekinumab Human antibody that blocks IL-12 and SC injections once, PPD IL-23 then in 4 weeks then in 12 weeks B Contraindicated in CHF, may cause drug induced SLE B Systemic Glucocorticoids • Systemic steroids are very rarely used in the treatment of psoriasis as many better alternative therapies exist • Severe rebound psoriasis can occur after discontinuation • Chronic use leads to well-characterized side effects of systemic corticosteroid use Combination Therapies • Often desirable, as combinations can limit the toxicities of individual therapies; examples: – Topical steroids with UVB or PUVA – Retinoids with PUVA or narrow band UVB – Vitamin D analogues with UVB – Ingram method: coal tar baths, UVB, anthralin – Methotrexate with UVB – Methotrexate with cyclosporine – Etanercept with methotrexate Phototherapy, conventional systemic agents, and biologic agents treating psoriasis are discussed elsewhere in this text. Report a Problem/Feedback General Dermatology  87
  • 97. 4.4 Psoriatic Arthritis Features • 20-40% of psoriatic patients; higher frequency found in moderate to severe psoriasis patients • Age of onset: 18–50 years • Usually (80%) rheumatoid factor negative (seronegative) • Synovial, serum and lesional levels of TNF-α are increased in psoriasis and psoriatic arthritis18 Types of Psoriatic Arthritis • Asymmetric oligoarthritis or polyarthritis (most common) • Symmetric polyarthritis (RA-like) • Spondylitis (axial) • Distal interphalangeal joint (DIP) disease • Arthritis mutilans (least common) • Enthesopathy (inflammation of ligaments and tendons at insertion point on bones)19 Clinical • Morning stiffness of joints lasting more than 60 minutes • Inflammation of DIP joints → often with nail involvement (~80%) • Dactylitis: “sausage digits” • Enthesitis/Enthesopathy → Inflammation of tendons or ligaments or at sites of tendon insertion into bone • Spondylitis/sacroiliitis and axial disease • Reduced range of motion of shoulders, neck, and lower back • 80% of patients present with skin disease first Radiographic Features of Psoriatic Arthritis • “Sausage digits” • Large eccentric erosions • Pencil-in-cup deformities—erosive changes of the joint: phalangeal distral tip is pencil on an eroded cuplike joint space • Tuft resorption: (acroostcolysis) • Periostitis: inflammation of the periosteum • Sacroileitis Therapy for Psoriatic Arthritis • NSAIDs • Sulfasalazine • Methotrexate • Etanercept • Ustekinumab 4.5 Reiter’s Syndrome Chronic inflammatory disease similar to psoriasis with psoriatic arthritis. • Urethritis • Conjunctivitis • Arthritis 88  2013/2014 Dermatology In-Review l Committed to Your Future Report a Problem/Feedback
  • 98. Few patients present with classic triad, thus can be diagnosed with • Peripheral arthritis > 1 month duration • Associated urethritis (or cervicitis)  Occurs in young men of HLA-B27 genotype. Rarely occurs in women. Clinical • Any one of triad • Fever, weakness, and weight loss • Nonbacterial urethritis with painful and bloody urination and pyuria • May involve gastroenteritis • Cystitis, prostatitis, seminal vesiculitis • Keratitis may lead to corneal ulceration • Iritis common • Arthritis is asymmetric • Endocarditis, pericarditis, myocarditis, aortic insufficiency • Erythema nodosum Skin Lesions  • Multiple small, yellowish vesicles that break, become confluent, and form superficial erosions → frequently on genitals and palms • Crusted, hyperkeratotic papules and plaques on plantar surfaces → keratoderma blennorrhagicum • Penile lesions: Perimeatal balanitis; circinate lesions; similar lesions seen on vaginal mucosa of affected women • Buccal, palatal, and lingual mucosa may show painless, shallow, red erosions, and severe stomatitis • Nails become thick and brittle with heavy subungual hyperkeratotic deposits Etiology • Chlamydia trachomatis associated with cases involving infection of GU tract • HLA-B27 in 80% of cases u TIP Treatment a higella flexneri (most common) S of nonurethral form of Reiters, • Topical steroids Salmonella spp., Yersinia spp., • NSAIDs Ureaplasma urealyticum, Borrelia • Methotrexate burgdorferi, Cryptosporidia, Campylobacter fetus • Acitretin • Cyclosporine • TNF-inhibiting biologics such as etanercept • Course of disease marked by exacerbation and remission. A chronic deforming arthritis occurs in 20% 4.6 SAPHO Syndrome • Synovitis • Acne (Acne fulminans or conglobata) • Pustulosis (pustular psoriasis) • Hyperostosis • Osteomyelitis Report a Problem/Feedback General Dermatology  89
  • 99. 4.7 Sneddon-Wilkinson Disease • Subcorneal pustular dermatosis • Middle-aged women • Superficial pustules in annular and serpiginous patterns • Abdomen, axillae, groin • Pustules are sterile u TIP a ssociation with IgA monoclonal A gammopathy Histology • Pustules form below stratum corneum without acantholysis • Contains many neutrophils Treatment • Dapsone • Acitretin • Narrow band UVB Chronic condition, possibly related to psoriasis, with remissions of variable duration. 4.8 Lichen Planus Inflammatory disorder that affects the skin, mucous membranes, nails, and hair. • Purple, polygonal, pruritic, papule, planar • Scaling is not as prominent as other papulosquamous diseases • Prevalence: <1%, no racial preference • 2/3 cases between ages of 30 and 60 Etiology and Pathogenesis Classification Scheme • Idiopathic (classic) • Drug associated • Associated with other diseases (Ulcerative Colitis, Alopecia Areata, Vitiligo, Dermatomyositis, Myasthenia Gravis) Role of Infection  • Hepatitis C implicated in triggering LP • Association with syphilis, HSV2, HIV, amebiasis and chronic bladder infections Clinical Manfiestations • Erythematous to violaceous, flat-topped, polygonal papule, with occasional small central umbilication • Thin, transparent, adherent scale atop the lesion • Wickham’s striae – fine, whitish reticulated networks on surface of well-developed plaques • LP begins as erythematous macules that evolve over weeks; initial lesions always appear on the extremities • Generalized eruption develops over one to four months • Symmetrically involves flexural areas of wrists, arms, legs; also, oral mucosa and genitalia • Inverse LP: Axillae, groin, inframammary areas • LP is usually pruritic; oral involvement generally asymptomatic, unless erosive → extremely painful • Koebnerization (isomorphic response) occurs 90  2013/2014 Dermatology In-Review l Committed to Your Future Report a Problem/Feedback
  • 100. Clinical Variants Configuration Annular LP • Blacks more commonly affected • On penis and scrotum • Also, larger lesions reach 2-3 cm in diameter and become hyperpigmented with raised outer rim Linear LP • Secondary to trauma, often Hypertrophic LP • Shins, interphalangeal joints • Most pruritic • Heals with scar formation and hyper/hypopigmentation Atrophic LP • Rare • White, bluish papules or plaques with central superficial atrophy • Most common lower extremities and trunk • Resembles lichen sclerosus et atrophicus Vesiculobullous LP • Rare • Vesicles and bullae within lesions of LP • Bullae arise from papules of LP, not normal skin • Subepidermal separation Erosive Ulcerative LP • Chronic and painful bullae and ulcerations on feet • Usually associated with more typical LP lesions of nails, mucosal surfaces and skin • Loss of toenails and alopecia common u TIP  • SCC may develop in lesions of ulcerative LP, a rosive mucous membrane disease more E therefore biopsy may be indicated common in patients with Hepatitis C infection • In oral LP, oral mucosa, gingiva and tongue may be affected. Desquamative gingivitis may occur • Histology of mucosal LP differs from LP of the skin in that parakeratosis rather than orthokeratosis is seen, secondary to the lack of granular layer on mucosal surfaces21 Follicular LP (lichen planopilaris) • Individual keratotic and follicular papules and studded plaques • Trunk and medial aspects of proximal extremities • Affects scalp – cicatricial alopecia • Graham-Little-Piccardi-Lassueur syndrome: triad of  1.) Follicular LP of skin and/or scalp 2.) ultifocal cicatricial alopecia of scalp M 3.) onscarring alopecia of axillary and pubic areas N Lichen Planus Pigmentosus • Uncommon • Hyperpigmented, dark brown macules in sun-exposed areas and flexural folds • Occurs in darker-pigmented people • Similar to erythema dyschromicum perstans Report a Problem/Feedback General Dermatology  91
  • 101. Actinic LP • More common in Middle Eastern countries in spring/summer • Affects sun-exposed areas • Typical LP may be seen over extremities • Pruritus and scaling minimal Sites of Involvement LP of the Scalp • Lichen planopilaris or follicular LP: individual keratotic papules that coalesce and merge to form patches • Women > men • Uni- or multifocal hair loss • End-stage: scarring alopecia • Pseudopelade of Brocq: scarring alopecia and fibrosis; end stage of follicular fibrosis caused by primary inflammatory dermatosis such as LP, LE, pustular scarring forms of folliculitis, favus, scleroderma, and sarcoidosis Mucosal LP • Affects mouth, vagina, esophagus, conjunctiva, urethra, anus, nose, and larynx • 60-70% patients with LP • Only manifestation of LP in 20-30% • Forms: reticular, plaque-like, atrophic, papular, erosive-ulcerative, and bullous forms • Male genitalia: 25% of cases, glans penis most common site (annular lesions, frequently) • Female genitalia: leukoplakia/erythroplakia, erosive, or generalized desquamative vaginitis • Vulvar and gingival LP can exist together – erythema and erosions of gingivae and tongue and white reticulated plaques • Conjunctival LP: cicatricial conjunctivitis LP of the Nails • 10-15% of cases • Usually in combination with other LP lesions on skin • 20-nail dystrophy (trachyonychia) can be seen, but trachyonychia is not diagnostic of LP • Thinning, longitudinal ridging, and distal splitting of nail plate (onychoschizia) • Also, oncholysis, longitudinal striation (onychorrhexis), subungual hyperkeratosis, or anonychia • Classic finding: dorsal pterygium or forward growth of the eponychium with adherence of proximal nail plate; also “tenting” sign as nail plate elevated with longitudinal splitting • Pits common Inverse LP • Rare • Occurs in flexural areas such as axilla, under breast, groin • Reddish-brown, discrete papules Palmoplantar LP • Yellowish, compact keratotic papules and papulonodules on lateral margins of fingers and hand surfaces 92  2013/2014 Dermatology In-Review l Committed to Your Future Report a Problem/Feedback
  • 102. Special Forms of LP/Lichenoid Eruption Drug-induced LP • May be typical or atypical for classic LP, localized or generalized • Typically manifest postinflammatory hyperpigmentation, alopecia, without Wickham’s striae • Symmetric eruption on trunk and extremities—photodistribution common with these drugs: 5-FU, carbamazepine, chlorpromazine, diazoxide, ethambutol, quinine/quinidine, tetracyclines, thiazides and furosemide • Mucous membrane involvement often associated with specific drugs and chemicals— amalgam containing mercury; gold more common LP–Lupus Overlap • Classic lesions of LP not usually seen • Photosensitivity, pruritus, follicular plugging also uncommon • Lesions on extremities, commonly: atrophic plaques and patches with hypopigmentation and a livid red-to-blue violet color with telangiectasia and minimal scaling; bullae may develop • May progress to SLE • Prolonged course • Histo: Lichenoid reaction and histologic features of LE seen in same biopsy Lichen Planus Pemphigoides u TIP • Tense blisters atop lesions of LP, or development of vesicle a ichenoid drug eruptions have L been associated with β-blockers, de novo on uninvolved skin antimalarials, captopril, gold, peni• Differentiate from bullous LP, where blisters in lesions cillamine, HCTZ, NSAIDs of longstanding LP as a result of intense lichenoid inflammation and extensive liquefaction degeneration of u TIP basal keratinocytes a ichenoid contact dermatitis L – color film developers, dental • Histologically like LP, with linear deposition of IgG and C3 at restorative materials, musk DE junction ambrette, nickel, aminoglyco• Circulating IgG autoantibodies react to 180/200 kDa antigen sides, gold within BM zone Keratosis Lichenoides Chronica (Nekam Disease) • Violaceous papular and nodular lesions; hyperpigmented and hyperkeratotic, covered with gray scales • Often, linear and reticulate pattern on the dorsal hands and feet, extremities and buttocks • Very refractory to treatment LP and Malignant Transformation • Risk is very low to none at all • Risk increased by longstanding disease, erosive or atrophic types of LP, and tobacco use • Most common sites for malignant transformation are tongue, gingiva and buccal mucosa • Most patients developing SCC in cutaneous LP had a history of either arsenic or X-ray exposure Lichenoid Keratosis (Lichen Planus-like Keratosis) • Brown to red scaling papule or plaque found on sun-exposed skin of extremities • Histological features of LP with additional finding of parakeratosis • Frequently occur with solar lentigo, seborrheic keratosis, and actinic keratosis Report a Problem/Feedback General Dermatology  93
  • 103. Associated Conditions • Autoimmune chronic active hepatitis • Primary biliary cirrhosis • Postviral chronic active hepatitis • HCV in some populations Treatment • Spontaneous remissions and exacerbations • Oral/Mucosal LP– replacement of gold or amalgam dental restorations • Topical high potency steroids for mucosal and limited cutaneous disease • Topical immunomodulators such as tacrolimus ointment for oral/genital disease • Topical anesthetics for oral pain • Intralesional TAC • Systemic steroids for refractory cases • PUVA photochemotherapy successful in generalized LP • Oral retinoids Course and Prognosis • Typically persists 1-2 years • May follow chronic, relapsing course • Spontaneous remission on average after 15 months • Lichen planopilaris most chronic and progressive with little potential for hair regrowth • Hypertrophic LP follows protracted unremitting course • Oral LP does not usually spontaneously regress 4.9 ATOPIC DERMATITIS Clinical Features Major • Pruritus • Facial and extensor involvement in infants and children • Flexural lichenification in adults • Chronic or relapsing dermatitis • Personal/family history of atopy Associated Features • Xerosis • Cutaneous infection • Nonspecific dermatitis of hands/feet • Ichthyosis, palmar hyperlinearity, keratosis pilaris • Pityriasis alba • Nipple eczema • White dermatographism and delayed blanch response • Anterior subcapsular cataracts, keratoconus • Elevated serum IgE levels • Positive immediate-type allergy skin tests • Early age of onset • Dennie-Morgan infraorbital folds 94  2013/2014 Dermatology In-Review l Committed to Your Future Report a Problem/Feedback
  • 104. • Orbital darkening • Facial erythema or pallor • Perifollicular accentuation • Course influenced by environmental and/or emotional factors Genetics • Stronger correlation between siblings than between siblings and parents • Exposure to environmental factors during childhood is likely to be the major factor • Seen in families with atopic dermatitis, asthma, and allergic rhinitis • Filaggrin gene mutations are known risk factor Clinical Manifestations • Typically begins in infancy → 50% in first year of life, and an additional 30% between 1 and 5 years • Most children with AD eventually develop allergic rhinitis or asthma later in childhood Infancy • AD generally more acute and primarily involves the face, scalp, and the extensor surfaces of the extremities • Diaper area spared Older Children • Patient develops the chronic form of AD with lichenification and localization of the rash to the flexural folds of the extremities • Subsides as patient grows older, leaving adult with skin that is prone to itching and inflammation • Chronic hand eczema may be the primary manifestation of adults with AD Complications Ocular Problems • Eyelid dermatitis and blepharitis • Atopic keratoconjunctivitis • Keratoconus: conical deformity of cornea • Cataracts Infections u TIP • Frequently complicated by recurrent skin infections: annate antimicrobial peptides I – Kaposi’s varicelliform eruption → herpes simplex → results in include human β-defensin eczema herpeticum → incubation of 5-12 days, multiple, itchy, (HBD) and cathelicidins, such vesiculopustular lesions erupt in a disseminated pattern → as LL 37. Ong et al found a often become hemorrhagic and crusted deficiency of HBD-2 and LL 37 in lesions from patients – Molluscum contagiosum with atopic dermatitis com– HPV pared to those with psoriasis. – Superficial fungal infections—Trichophyton rubrum and This decreased expression of Pityrosporum ovale innate antimicrobial peptides may explain the increased sus– S. aureus – found in over 90% of AD skin lesions. Honey  ceptibility to colonization and colored crusting, folliculitis, and pyoderma are indicators of skin infection with S. aureus in secondary bacterial skin infection. Regional lymphadenopathy patients with atopic dermatitis common. Deep-seated S. aureus infections may indicate hyper-IgE syndrome 4 Report a Problem/Feedback General Dermatology  95
  • 105. Foods • Food allergens exacerbate skin rashes in at least a subset of patients with AD, particularly infants and young children • Eggs, milk, peanuts, soybeans, tree nuts, fish, and wheat are the most common allergens implicated in AD • Following positive oral food challenges in children with AD, histamine concentration increases in the plasma • Most AD patients do NOT have food allergy  Immunohistochemistry • Lymphocytes are CD3+, CD4+, and CD45RO+ memory T helper cells • Langerhans cells and macrophages infiltrating into AD skin lesions have surface-bound IgE • Activated eosinophils are present in significantly greater numbers in chronic as compared to acute AD lesions Immunologic Abnormalities in AD • Increased synthesis of IgE • Increased expression of CD23 (low affinity IgE receptor) on B cells and monocytes • Increased basophil histamine release • Impaired DTH response • Decreased CD8 suppressor/cytotoxic T-cell number and function • Increased secretion of IL-4 and IL-5 by TH2 cells • Decreased secretion IFN-gamma by TH1 cells An Immunologic Aside • TH1 cells → produce IL-2, IFN-γ, and TNF-β, associated with cell-mediated immunity • TH2 cells → produce IL-4, IL-5, IL-6, IL-10, and IL-13, associated with antibody mediated immune responses Management Allergens • Dust mites, molds, animal dander, pollens • Avoidance of triggering foods • Infants and young children more likely to have food allergies; older children and adults sensitive to environmental aeroallergens Infectious Agents • Anti-staphylococcal antibiotics helpful in those colonized • HSV: Antiviral treatment very important to prevent disseminated disease; IV treatment may be necessary for disseminated eczema herpeticum • Molluscum contagiosum → topical imiquimod, liquid nitrogen, topical salicylic acid, or no therapy Pruritus • Antihistamines → use sedating antihistamine at night Systemic Glucocorticoids • Rarely indicated, and risk of rebound flare after discontinuation • Short courses can be done while other modalities are started, and tapering dosage is critical 96  2013/2014 Dermatology In-Review l Committed to Your Future Report a Problem/Feedback
  • 106. UV Phototherapy • UVB useful adjunct to treatment of chronic recalcitrant AD • High intensity UVA can be fast-acting and effective with acute exacerbations of AD Systemic Cyclosporine or Tacrolimus • Oral cyclosporine or tacrolimus can help severe AD that is refractory to topical steroids • Discontinuation of treatment may result in rapid relapse of skin disease Probiotics • The utility of probiotics in primary prevention of atopic dermatitis has been studied • Lactobacillus GG cultures were given to pregnant women with a history of atopy to assess the effect of potentially beneficial gut flora on the prevention of atopic disease in their children • Frequency of atopic dermatitis in the probiotic group was half that in the placebo group at two years of life Prognosis • Disease more severe and persistent in young children • Periods of remission grow longer as patient ages • Mild disease at infancy: Spontaneous resolution occurs in 40% of patients after age 5 • Poor prognostic factors – Widespread AD in childhood – Associated allergic rhinitis or asthma – Family history of AD – Early age of onset 4.10 Alopecia Areata Genetics • High frequency of family history, especially in patients with early onset (37%) • Twin concordance = 55% (identical twins) Immunologic Factors  • Major associations: Vitiligo and thyroid disease (10%), with increased prevalence of antithyroid antibodies and thyroid microsomal antibodies in AA • Other autoimmune diseases shown to be associated: pernicious anemia, diabetes, LE, myasthenia gravis, RA, polymyalgia rheumatica, ulcerative colitis Emotional Stress • May be precipitating factor in some cases Clinical Features u TIP a ATTERNS of alopecia areata: patchy (most common); • Prevalence: 0.1-0.2%, with lifetime risk of 1.7% P reticulated; ophiasis (parietal/temporal/occipital); • Affects men and women equally ophiasis inversus (sisapho – bandlike pattern in fronto • 60% present before age 20 parietotemporal scalp); diffuse • Pull test may be positive at margins, indicating early disease • Usually asymptomatic, but some patients perceive pruritus, tenderness, burning, or pain preceding hair loss • Areata – partial loss of scalp hair Report a Problem/Feedback General Dermatology  97
  • 107. • Totalis – total loss of scalp hair • Universalis – 100% loss on scalp, eyebrows, eyelashes, and rest of body • Initial regrowth is white, followed by repigmentation • Nail dystrophy (10-66%), seen in one, some, or all nails, preceding, coinciding, or occurring after hair disease → pitting with irregular pattern or in organized rows; trachyonychia: longitudinal striations resulting in sandpaper appearance; Beau’s lines; onychorrhexis; thinning or thickening; koilonychia; red-spotted lunula; punctate or transverse leukonychia Prognosis • Unpredictable course and pattern • Most patients see complete regrowth within one year without treatment • 10% develop severe chronic form • Predictors for poor prognosis: atopic dermatitis, childhood onset, widespread involvement, ophiasis, duration for longer than five years, onychodystrophy Treatment • All local treatments help treated areas, but do not prevent further spread • Spontaneous recovery is extremely common, with most showing regrowth within 1 year • First line: IL steroids concentration of 5 mg/cc maximum of 3 cc per visit → 0.1 cc per site, approximately 1 cm apart; after 6 months and no response, d/c • Topical steroids as monotherapy generally ineffective • Minoxidil 5%: stimulates follicular DNA synthesis and regulates hair physiology independently of blood flow influences; effective with alopecia areata involving 20-99% involvement in 25-50% of patients → initial hair regrowth in 12 weeks • Anthralin 0.25-1.0% • Squaric acid dibutyl or DNCB or DPCP (diphenylcyclopropenone) – aim is to maintain lowgrade tolerable erythema, scaling, and pruritus, with weekly applications • PUVA, with either topical or systemic psoralen therapy; relapse after discontinuation occurs • Cyclosporine works, but systemic use associated with adverse effects and high recurrence rate 4.11 Alopecia: Other Forms Trichotillomania • Practice of plucking or breaking hair from the scalp or eyelashes • Areas of alopecia characteristically contain hairs of varying length • Girls under age of 10 • Treat with psychotherapy and antidepressant u TIP a iopsy shows high B number of catagen hairs, pigmentary defects and casts, trichomalacia, and hemorrhage Hot Comb Alopecia • African American women who straightened their hair with hot combs • Characteristically on the crown and spreads peripherally to form a large oval area of partial hair loss • Thermal damage to follicle by hot petrolatum, leading to destruction of hair follicle and follicular scar • May be same as follicular degeneration syndrome/central centrifugal scarring alopecia 98  2013/2014 Dermatology In-Review l Committed to Your Future Report a Problem/Feedback
  • 108. Pseudopelade of Brocq • Scarring alopecia where destruction of the hair follicle produces multiple round, oval, or irregularly shaped cicatricial patches of varying sizes • No pustules, crusts, or broken-off hairs are present • Onset is insidious • Female:male = 3:1 • Alopecia permanent • No inflammation with decreased or absent sebaceous glands, normal or atrophic epidermis Traction Alopecia • Prolonged tension on the hair from braiding, ponytails, rolling curlers, twisting with fingers Pressure Alopecia • Occipital areas of babies lying on their backs • In adults, prolonged pressure on the scalp during general anesthesia or after prolonged bedrest • People with chronic illness after prolonged bed rest in one position • Likely related to pressure-induced ischemia Loose Anagen Syndrome • Anagen hairs pulled from the scalp with little effort • Blonde girls • Usually improves with age Follicular Mucinosis • Deposition of mucin in the outer root sheath and sebaceous glands • Most commonly on scalp and beard area • Secondary type associated with CTCL with widespread and chronic lesions, and patients are older Meralgia Paresthetica • May have alopecia of the anesthetic area of the outer thigh Hypothyroidism • Hair coarse, dry, brittle, and sparse • Telogen hairs 3x more prevalent Hyperthyroidism • Hair becomes extremely fine and sparse Alopecia Neoplastica • Hair loss from metastatic tumors • Usually breast carcinoma Report a Problem/Feedback General Dermatology  99
  • 109. 4.12 Vitiligo • Half of all cases begin before age 20 • Depigmented white patches surrounded by normal or hyperpigmented border • Trichrome vitiligo: intermediate tan zones halfway between the normal skin color and the depigmentation • Hairs in vitiliginous areas become white Four Types 1.) Localized or focal (includes segmental) 2.) Generalized (most common) 3.) Universal 4.) Acrofacial Generalized • Symmetrical • Face, upper chest, dorsal hands, axillae, groin • Skin around all orifices • Areas of trauma (knees and elbows) Focal • Asymmetric • Treatment resistant • 5% of adult, 20% of childhood cases of vitiligo Universal • Entire body surface depigmented Associations • Insulin-dependent diabetes • Pernicious anemia • Hashimoto’s thyroiditis • Grave’s disease • Addison’s disease • Alopecia areata Genetics • Multifactorial • 30% of vitiligo patients have an affected relative Treatment • Topical corticosteroids • Ultraviolet phototherapy (Narrow band UVB and Psoralen with UVA) • Laser (308 nm excimer) • Topical tacrolimus • Re-pigmented surgery with punch minigrafts, dermoscopic dermal grafts 100  2013/2014 Dermatology In-Review l Committed to Your Future Report a Problem/Feedback
  • 110. 4.13 Pityriasis rubra pilaris • Small follicular papules → salmon-orange to reddish-brown color, pinhead size, and topped with scaly plug • Yellowish pink scaling patches, often begins on scalp • Solid confluent palmoplantar hyperkeratosis Progresses to: • Sides of the neck and trunk • Extensor surfaces of the extremities • Any portion of the body can be affected Clinical Features • Involvement generally symmetrical and diffuse, with characteristic small islands of normal skin within the affected areas • Palms and soles will be hyperkeratotic with fissuring • Nails: dull, rough, thickened, brittle, and striated; may crack and break; no pitting Treatment • Topical keratolytics • Systemic retinoids • Vitamin A 500,000 units daily • Systemic steroids for short term management • Methotrexate • Azathioprine • Cyclosporine 4.14 Lichen sclerosus • Presents from childhood to old age, and occurs in all races • Females predominate at all ages Clinical • White, polygonal, and flat-topped papules or plaques surrounded by erythematous to violaceous halo • Later, lesions coalesce into large atrophic patches, becoming smooth, slightly wrinkled, and white • Bullae may arise in patches • Pruritus can be severe, especially in anogenital area, where erosions and fissuring can occur • In women, normal anatomic structures may be obliterated • Balanitis xerotica obliterans → male involvement of the glans penis; hemorrhage is common in the glans • Extragenital lesions most frequent on the upper back, chest, and breasts, and are usually asymptomatic • + Koebnerization Cancer Risk • Increased risk of genital SCC in both men and women • Lifetime risk for women less than 5% Report a Problem/Feedback General Dermatology  101
  • 111. Etiology • Autoimmune phenomenon, likely • 20% of both men and women have at least one autoimmune disease (vitiligo, alopecia areata, or thyroid disease), and a larger proportion have circulating antibodies • Trauma can induce lesions, and boys do better after circumcision Childhood LS • Onset in childhood in 10-15% of cases • Girls outnumber boys 10:1 • Genital disease represents 90% of childhood LS • In girls: Symptoms include difficulty with defecation, dysuria, perineal pruritus, and perineal skin lesions • In boys: Phimosis is most common presenting sign • May resolve spontaneously, especially around puberty (50% of girls, after circumcision in boys) Treatment • Superpotent topical steroids twice daily to be tapered in either strength or frequency over time • Topical tacrolimus ointment or pimecrolimus cream, sometimes effective • Oral retinoids may work with anogenital lichen sclerosus in both men and women 4.15 Granuloma annulare Localized GA • Young adults • Lateral or dorsal surfaces of fingers, hands, elbows, feet, ankles • White, pink, flat-topped papules that spread peripherally • Never ulcerate and heal without scarring • 75% clear within 2 years Generalized GA • Diabetes in 20% • Diffuse papules • May be pruritic or asymptomatic • Lasts three months to four years Macular GA • Flat or slightly palpable lesions over feet, ankles, and upper medial thighs • Small papules can be felt in some cases Subcutaneous GA • Most common in children • Often a history of trauma to area • Multiple lesions may be present • Generally asymptomatic Perforating GA • Dorsum of hands 102  2013/2014 Dermatology In-Review l Committed to Your Future Report a Problem/Feedback
  • 112. • Papules with central keratotic core representing transepidermal elimination of the degenerated material in the center of GA lesions 4.16 Hirsutism Androgens in Women • Dehydroepiandrosterone (DHEA), adrenal • Androstenedione–adrenal, ovary • Testosterone–ovary, adrenal, extraglandular conversion of androstenedione and dehydroepiandrosterone – Adrenal androgen regulated by adrenocorticotropin – Ovarian androgen regulated by luteinizing hormone – The hair follicle requires conversion of testosterone to dihydrotestosterone for expression of androgen action u TIP a rugs → Hirsutism without D Virilization/Defeminization •  Phenytoin •  Minoxidil •  Diazoxide •  Cyclosporine •  Hexachlorobenzene Tumors → Rapid Onset of Hair Growth with or without Accompanying Virilization • Adrenal adenomas and carcinomas • Arrhenoblastoma • Kruckenberg tumors of ovary Polycystic Ovarian Disease • Most common cause of ovarian hyperandrogenism • Manifestations: Hirsutism, amenorrhea, virilization Congenital Adrenal Hyperplasia Congenital adrenal hyperplasia (defects in adrenal steroidogenesis) can occur at any point in life. • 21-hydroxylase deficiency • 11β-hydroxylase deficiency • 3β-hydroxysteroid dehydrogenase isomerase deficiency (3β-hsd) Idiopathic Hirsutism • Women with evidence of androgen excess but with normal menses, normal-sized ovaries, no evidence of tumors of adrenal or ovary, and normal adrenal function • Slight elevations of plasma androstenedione and testosterone common Signs of Virilization Signs of virilization → correlates with androgen overproduction • Deepening of the voice • Temporal balding • Clitoromegaly • Increased muscle mass in the limb girdles Signs of Cortisol Excess • Plethora • Central obesity • Striae • Dorsocervical/supraclavicular fat pads Report a Problem/Feedback General Dermatology  103
  • 113. Work-up • Pelvic exam: Search for palpable ovarian masses • Radiographic imaging of the pelvis/adrenal glands • Laboratory exam: DHEA > 8000 ng/ml or serum testosterone > 2 ng/ml suggest neoplasm • Plasma testosterone levels in the normal range are difficult to interpret → does not necessarily reflect the free or unbound levels of hormone under conditions when testosterone-binding globulin levels are either increased or decreased • Cushing syndrome, if suspected, should be evaluated with an overnight dexamethasone suppression test • Polycystic ovarian disease: Diagnosis from history and physical exam • Delayed onset adrenal hyperplasia: Short ACTH stimulation test and measurement of plasma 17-hydroxy-progesterone 4.17 Amyloidosis • Beta-pleated sheet forms of various host-synthesized molecules Classification 1.) Primary (often has skin findings) 2.) Secondary (rare skin manifestations) 3.) Primary localized 4.) Secondary cutaneous or tumor associated 5.) Familial syndromes Pathology • PAS positive and diastase resistant • Congo-red positive • Purple with crystal violet • Positive with thioflavin T • Secondary systemic amyloid (aa) loses its birefringence after treatment with potassium permanganate, but primary and localized forms do not u TIP Primary Systemic Amyloidosis arotein AL → derived from Ig P light chains (lambda subtype); • Involves tongue, heart, GI tract, and skin AL also found in nodular • Involves skin in 40% amyloidosis produced by a • Includes myeloma-associated amyloidosis plasmacytoma Clinical      • Shiny, smooth, firm, flat-topped papules of waxy color that coalesce into nodules or plaques • Commonly around nose, eyes, mouth, and mucocutaneous junctions •  Purpuric lesions result from amyloid infiltration of blood vessels; occurs after trauma (pinch purpura) • Glossitis → may lead to dysphagia; lateral aspects of tongue shows indentations from teeth • Bullous amyloidosis → subepidermal hemorrhagic bullae at areas of trauma • Carpal tunnel syndrome • RA-like arthropathy • Shoulder pad sign → enlarged deltoids • Cardiac arrythmias and chf cause death • Prognosis poor 104  2013/2014 Dermatology In-Review l Committed to Your Future Report a Problem/Feedback
  • 114. Secondary Systemic Amyloidosis • Amyloid in the adrenals, liver, spleen, and kidney as a result of some chronic disease, such as TB, leprosy, Hodgkin’s, Behçet’s, rheumatoid arthritis, ulcerative colitis, schistosomiasis, or syphilis • Skin not involved Primary Cutaneous Amyloidosis • Keratin is the protein component • No amyloid around the blood vessels u TIP a A amyloid fibrils → derived from SAA protein, an A acute phase reactant a A also seen in Muckle-Wells (renal amyloidosis, rtiA Macular Amyloidosis caria, fevers, limb pains, and deafness) and familial Mediterranean fever • Moderately pruritic, brown, rippled macules in interscapular region of the a ialysis-related amyloidosis: beta 2-microglobulin is the D protein component altered by uremia → carpal tunnel back syndrome, bone cysts, and spondyloarthropathy • May have associated notalgia paresthetica Lichen Amyloidosis • Bilateral shins • Type IIa MEN • Small, brown, discrete, scaly papules • Treat by reducing friction, occlusion, il steroids Nodular Amyloidosis • Single or multiple nodules on extremities, trunk, genitals, or face • Overlying epidermis may appear atrophic • Numerous plasma cells • AL type Secondary Cutaneous Amyloidosis • Seen following PUVA therapy and in benign and malignant neoplasms: nonmelanoma skin cancers, seborrheic keratoses, trichoepitheliomas • Also, keratin-derived amyloid Familial Syndromes Associated with Amyloidosis • Familial Mediterranean fever and Muckel-Wells syndrome → show AA protein • MEN IIa → keratin-derived amyloid Familial Amyloidotic Polyneuropathy (fap) • Fap I and fap II → mutations in transthyretin • Fap III → apolipoprotein a-1 • Fap IV → gelsolin mutation Report a Problem/Feedback General Dermatology  105
  • 115. Table 4-2. Amyloidosis Types Fibril Protein Other Features AL (lambda λ chain) Involves tongue, heart, GI tract, and skin. Petechiae, purpura, waxy skin colored papules, alopecia, carpal tunnel syndrome, neuropathy, arthropath AA Result of chronic disease: TB, leprosy, Hodgkin’s, RA, Reiter’s, syphilis No Skin involement Amyloid in the adrenals, liver, spleen, and kidney Macular Altered Keratin Rippled brown macules in interscapular region on back, notalgia paresthetica Lichen Altered Keratin Brown, scaly papules on bilateral shins Nodular AL chains Single or multiple nodules on extremities, genitals, trunk, or face Familial Mediterranean Fever AA AR, intermittent fevers, renal amyloidosis, peritonitis, pleurisy MEFV gene; marenostrin/pyrin protein Muckle Wells AA AD, periodic attacks of urticaria, fever, deafness, renal amyloidosis Hemodialysis Assoication β2 microglobulin Senile B amyloid protein Systemic Primary Secondary Localized Cutaneous Hereditary Senile or neuritic plaques, Alzheimer’s disease 4.18 Calciphylaxis • Painful violaceous eschar-like plaques associated with soft tissue necrosis • Metastatic cutaneous calcification from increased parathyroid hormone (and increased calcium phosphate product) secondary to renal failure • Treatment: Phosphate binding agents, parathyroidectomy 106  2013/2014 Dermatology In-Review l Committed to Your Future Report a Problem/Feedback
  • 116. 4.19 Angioedema Review of the Complement System Classic Pathway • C1 binds to Fc fragment of IgM or IgG in immune complexes • C1q does the binding to immunoglobulin • C1s fragment digests C4 and C2, activating them into a C4b, 2a complex, creating C3 convertase, that activates C5 convertase → membrane attack complex Alternative Aathway • Less clear, but C3 activated by a C3-convertase complex consisting of C3b, bb • During inflammation, low levels of C3b bind factor b, that undergoes cleavage by factor d to generate C3b, bb → acts as a C3 convertase C1 Esterase Inhibitor • Protease inhibitor • Inhibits the catalytic subunits of first components of classical pathway (C1r and C1s), kallikrein, plasmin • In absence of C1 esterase inhibitor, activated C1 and plasmin generate activated C2 kinin • C2 kinin mediates angioedema Angioedema Type I: u TIP anherited (Quincke’s edema) (Normal C1q levels) I • Detected in the first or second decade of  •  Occurs in setting of lymphoproliferative disease life (low-grade lymphoma, CLL, monoclonal gammo • Autosomal dominant pattern of inheriance pathy of undetermined significance, systemic • Serum C1q normal in inherited form D amyloidosis) or rheumatologic illness, where idio •  efect in synthesis and/or function of C1 esterase inhibitor type/anti-idiotype immune complexes consume •  ype I: Low amounts of normal C1 sterase T available C1q, and functionally and quantitatively inhibitor lower the amounts of C1 esterase inhibitor •  ype II: Normal amounts of dysfuncional C1 T esterase inhibor • Can also occur in setting of autoimmunity directed against the C1 esterase protein aAcquired (Low C1q) • Important point: in both the inherited and •  ffects adult or elderly with no family history A S acquired forms levels of C2 and C4 are decreased •  erum C1q decreased in acquired form because of the uncontrolled actions of C1s Clinical Presentation • Swelling of head, neck, and extremities • Abdominal symptoms • Upper airway symptoms • Recurrent symptoms, with intervening time of weeks to months Treatment • Androgen therapy: danazol or stanozolol → bring about dramatic decreases in frequency and severity of attacks • Glucocorticoids, but tapering results in relapse of symptoms • Therapy for underlying disease • Pretreatment with androgens prior to surgical procedures Report a Problem/Feedback General Dermatology  107
  • 117. Diagnosis  • Screen with C3 and C4 levels → C4 low, C3 normal in angioedema • C1q level low in acquired, but normal in hereditary 4.20 Carcinoid Syndrome and Flushing Disorders Menopausal Flushing • Perimenstrual flushing when estrogen levels low • Hot beverages and emotion can exacerbate • Pharmocologic menopause caused by drugs: danazol, tamoxifen, clomophene citrate, decapeptyl, leuprolide, and 4-hydroxyandrostenedione • Tubal ligation or any surgical loss of ovarian function • Clinical manifestations include drenching perspiration, waking episodes during the night, prodromal sensation of overheating before the onset of flushing and sweating • Treat with oral estrogen replacement or clonidine hydrochloride 0.05 mg bid Emotional Flushing • Can treat with biofeedback, hypnosis, and nadolol (40-80 mg qd) Foods • Monosodium glutamate • Scombroid group of fish (tuna and mackerel) • Spicy foods Mastocytosis • See separate section later in this chapter Medications • Nicotinamide, disulfiram, metronidazole Carcinoid Syndrome  • <4% with abdominal carcinoid tumors have the carcinoid syndrome • Presence of syndrome implies hepatic metastases, extraabdominal carcinoid tumor, or large enough tumor burden such that the liver cannot degrade the increased level of hormone • Tumors derived from enterochromaffin (Kulchitsky) cells • Appendix is most common site, followed by the ileum • Ileal tumors are the most common source of the classic carcinoid syndrome, and these tumors metastasize most frequently Clinical • Pellagra-like lesions caused by excessive utilization of tryptophan → hyperkeratosis, xerosis, scaling of legs, forearms, and trunk, angular cheilitis, and glossitis • Rosacea stigmata • Yellow-brown or brown-gray patches on the forehead, back, and wrists • Pruritus • Chronic watery diarrhea in 85% • Abdominal pain, constipation, nausea, vomiting, malabsorption, anorexia, weight loss, small bowel obstruction, and rectal bleeding • Respiratory symptoms of wheezing, stridor, dyspnea, coughing, and bronchospasm 108  2013/2014 Dermatology In-Review l Committed to Your Future Report a Problem/Feedback
  • 118. • Arthritis, psychiatric symptoms, osteoblastic bone lesions • Fibrotic reactions affecting the valves of the heart Diagnosis • Serotonin overproduction  • Elevated urinary 5-HIAA • Foods and drugs can affect the urinary excretion of 5-HIAA 4.21 Lupus Erythematosus Classification Chronic Cutaneous LE • Discoid • Verrucous (hypertrophic) • LE-LP overlap • Chilblain • Lupus Panniculitis Subacute Cutaneous LE • Papulosquamous • Annular • Neonatal • Complement deficiency syndromes Acute Cutaneous LE • Systemic LE with skin lesions → localized or generalized erythema with bullae Discoid Lupus • Young adults, women:men 2:1 • Dull red macules with adherent scales extending into patulous follicles • Plugged follicles • Patches heal with atrophy, scarring, dyspigmentation, and telangiectasia Localized • Above neck: scalp, nose, malar, lips, ears • Pruritus and tenderness common • Mucosal involvement of mouth, nose, eyes, vulva common Generalized • Less common than localized • Thorax and upper extremities, in addition to usual sites above the neck • Elevated ESR, positive ANA, or leukopenia more common Course  • 95% of cases confined to the skin at outset will remain so • Abnormal labs such as ANA, leukopenia, hematuria, or albuminuria identify those who progress; also, rash above and below the neck  • Relapses are common • BCC or SCC occur in scars, and a favored site is the lower lip Report a Problem/Feedback General Dermatology  109
  • 119. Treatment • Sun avoidance • Avoid exposure to heat, cold, trauma • Topical corticosteroids (potent) with or without occlusion • IL steroids Antimalarials • First hydroxychloroquine (Plaquenil), then chloroquine, or add quinacrine • Side effects: erythema multiforme, purpura, urticaria, ocular risks are very small, nausea, vomiting, tinnitus, abducens nerve paralysis, toxic psychoses, leukopenia, and thrombocytopenia • Exacerbate PCT • Bleach hair • Quinacrine yellows hair and conjunctivae become yellow Other Forms of Cutaneous LE Verrucous LE (Hypertrophic) • Non-pruritic, papulo-nodular lesions on arms and hands • Resembles KA’s or LP • Treat with IL TAC LE-LP Overlap Syndrome • See LP section Chilblain Lupus Erythematosus • Chronic, unremitting form with lesions on fingertips, ears, calves, and heels • Lesions are due to cold • Treatment is the same as LE LE Panniculitis • Deep dermal and subcutaneous nodules, rubbery-firm, sharply defined, and nontender • Head, face, upper arms, chest, buttocks, thighs • Chronic, in women 20-45 years old • DLE at other sites, commonly • Heals with atrophy and deep depressions • Treat with antimalarials for many months Subacute Cutaneous Lupus • Scaly papules that evolve into either psoriasiform or polycyclic annular lesions (more commonly) • Telangiectasia and dyspigmentation always present • No follicular involvement • No scarring • Occurs on sun-exposed surfaces of face and neck, inner arms, axillae and flanks • Spares knuckles u TIP • Photosensitivity in 40% a ajority positive for anti-Ro M • Hard palate involved in 40% • Concomitant DLE in 20% a rugs that may induce: HCTZ, D enicillamine, glyburide, griseofulvin, • At least half of the patients meet ARA criteria of SLE piroxicam, spironolactone, diltiazem, (usually have arthralgia, arthritis, leukopenia, positive ANA) ACE inhibitors, terbinafine • Disease runs a mild course 110  2013/2014 Dermatology In-Review l Committed to Your Future Report a Problem/Feedback
  • 120. Neonatal LE • Annular scaling erythematous macules and plaques on head and extremities within the first few months of life in babies born to mothers with LE, rheumatic disease, or other connective tissue disorders • 50% mothers asymptomatic at delivery • Lesions resolve spontaneously by 6 months, healing without scarring • Photosensitivity may be prominent u TIP • 75% of cases involve girls a 0% have congenital heart 5 block, which is permanent (this • Thrombocytopenia and hepatic disease as frequent as cardiac may be the only manifestation disease of disease) Complement Deficiency Syndromes • Most commonly C2 and C4 • Photosensitivity • Annular scle lesions • Ro antibody formation Systemic LE Criteria: 4 Needed • Malar erythema • Discoid LE • Photosensitivity • Oral ulcers • Nonerosive arthritis • Serositis (carditis or pleurisy) • Nephropathy • CNS disorder (seizure or psychosis) • Hematologic disorder • Immunologic disorder (positive LE cell preparation, anti-DNA or Sm, false-positive RPR) • Positive ANA Cutaneous manifestations • Butterfly facial erythema, may be associated with edema → lasts days to weeks and heals without scarring • Bullous lesions, sun-exposed areas → histologically like EBA with antibodies against collagen Type VII, but responds to dapsone (EBA does not) • Fingertips and toetips show puffy erythema, telangiectasias • Periungual telangiectasias • Red lunulae • Erythematous to purplish palms and soles • Telangiectasias on face or elsewhere • Diffuse nonscarring hair loss with short, broken-off hairs in frontal region • Multiple (>15) dermatofibromas • Vasculitis secondary to antiphospholipid antibody • Cryoglobulinemia, livedo reticularis, thrombophlebitis, cutaneous infarction • Erythema multiforme-like lesions (Rowell’s syndrome) • Calcinosis cutis • Plaque-like depositions of mucin Report a Problem/Feedback General Dermatology  111
  • 121. Pregnancy and SLE  • Miscarriages occur with greater frequency • LE may worsen, or go into remission during pregnancy • Fetal death risk increased with anti-cardiolipin or anti-Ro antibodies • Postpartum period shows the highest risk to the patient Drug-induced LE  • Usually benign course u TIP • Hydralazine → 14%, with slow acetylators (HLA-DR4) a  ydralazine, procainamide, sulfonH more prone amides, penicillin, anticonvulsants, minocycline, and INH • Procainamide → 50% of treated patients • Anti-histone antibody closely associated with symptomatic a  rug-induced LE not usually D associated with skin, renal, and CNS disease manifestations • Penicillamine induces native disease, with anti-dsDNA Ab’s • HCTZ induces SCLE 4.22 Scleroderma Chronic disease of unknown etiology affecting the microvasculature and loose connective tissue. Classification Localized Scleroderma • Morphea → most common type • Generalized morphea → morphea, symmetric and bilateral lesions; but absence of Raynaud’s, acrosclerosis, and organ involvement differentiates from SSc • Guttate morphea (LS&A) • Nodular morphea • Subcutaneous morphea (morphea profunda) • Linear scleroderma → bandlike lesions that may involve the deeper layers of the skin Systemic Sclerosis • Limited (lSSc): 60%, includes CREST syndrome; 70-80% have anti-centromere antibodies and systemic involvement may not appear for years; patients are older than dSSc and many outlive the disease; better survival rate (50% at 12 years) • Diffuse (dSSc): Abrupt onset of swelling of the hands and feet with Raynaud’s and hidebound changes in the skin; polyarticular symmetric synovitis, tenosynovitis and tendon friction rubs often present; nail fold capillary dilatation and destruction •   arly onset of internal organ involvement; anti-topoisomerase 1 antibodies (SCL-70) in   E 30%; worse survival rate (15% at 12 years) Epidemiology Localized Scleroderma • Women:men 3:1 • More common in whites Systemic Sclerosis • Women:men 4:1 • More common in black women, with diffuse disease more likely to affect black women • 7-year survival 75% 112  2013/2014 Dermatology In-Review l Committed to Your Future Report a Problem/Feedback
  • 122. u TIP Scleroderma-like Disorders P •  leomycin: Pulmonary Fibrosis, Raynaud’s, and cutaneous a olyvinyl chloride → scleroderma B with hepatic and pulmonary fibrosis changes indistinguishable from SSc (reversible upon discontinuation of drug) • Scleroderma-like skin changes seen in scleromyxedema, PCT, GVHD Clinical Localized Morphea • Circumscribed sclerotic plaques with ivory-colored centers and violaceous borders (if disease active) • Plaques may be elevated or depressed, are indurated but not bound to the deeper structures • May occur after radiation therapy • All forms of localized morphea have good prognosis with disease becoming inactive in three to five years Generalized Morphea • Widespread involvement • Multiple indurated plaques and hyperpigmentation • Upper trunk, abdomen, buttocks, and legs • Not associated with systemic disease Guttate Morphea (LS&A) • Multiple small chalk-white lesions that lack the firm character of morphea Nodular Morphea • Lesions resemble keloids • May coexist with more typical lesions of morphea Morphea Profunda (Subcutaneous Morphea) • Deep, bound-down, sclerotic plaques Atrophoderma Pierini and Pasini • Idiopathic atrophy of the skin characterized by single or several depressed areas of skin • Lesions are well-defined with a “cliff drop” border Linear Scleroderma • Single, unilateral linear band • Lower extremities are most frequent site • Upper extremities, frontal head (coup de sabre), thorax also involved • Differentiate from morphea by involvement of deeper layers of skin with fixation to underlying structures • May cause severe deformity • May be associated with spina bifida occulta Melorheostosis • Linear, dense, cortical hyperostosis • Affects an involved limb usually, but may be widespread Parry-Romberg Syndrome • Facial hemiatrophy; may be form of linear scleroderma • Hyperpigmentation followed by atrophy of the dermis, subcutaneous fat, muscle, and sometimes the bone Report a Problem/Feedback General Dermatology  113
  • 123. Systemic Sclerosis • Initial complaints related to Raynauld’s or chronic nonpitting edema of the hands and fingers • Pain and stiffness of the fingers and knees • First manifestation may be migratory polyarthritis • Usually, skin changes precede visceral involvement by several years • Disease extends to upper extremities, trunk, face, and finally the lower extremities • Periorbital edema may occur in the early edematous phase • Face becomes mask-like • Lips thin, and opening of the mouth becomes constricted (microstomia) • Painful induration of the gums and tongue • Matlike telangiectases • Thinning or complete loss of hair and anhidrosis • Generalized hyperpigmentation without adrenal insufficiency • Focal hyper/hypopigmentation • Periungual telangiectasia occurs like in SLE and DM; 75% of those with ssc have enlarged, dilated nail fold capillaries forming giant loops • Recurrent painful ulceration of the fingertips and slow-healing ulcers of the knuckles • Bone resorption causing dissolution of the terminal phalanges • Cutaneous calcification over fingertips and over bony prominences → may ulcerate Systemic Involvement in SSC  • Esophageal dysfunction is most common (>90%) • Dysphagia from decreased peristalsis, and may occur before skin findings seen • Heartburn • Small intestine involvement gives rise to constipation, diarrhea, bloating, and malabsorption • Pulmonary Fibrosis • Early pulmonary involvement with lowered diffusing capacity of the alveolocapillary membrane correlates with changes of the nail fold capillaries • Cardiac conduction defects, heart failure, pericarditis with effusion; myocardial fibrosis seen in 50-70% of SSc • Renal disease with slowly progressive uremia CREST Syndrome • Telangiectasias on face, upper trunk, hands • Develops later in life • Esophageal dysfunction is identical to that of the more severe forms of the disease • Anti-centromere antibodies in 50-96%, but only 12-25% in those with dSSc • Mixed connective tissue disease: combined features of scleroderma, LE, and myositis → high titers to ribonucleoprotein Pathogenesis Three processes occur • Damage to vascular endothelium • Immunologic and inflammatory activation • Dysregulated extracellular matrix metabolism Course • Morphea and linear scleroderma → few months to many years • 50% of patients with lesions that disappear are left with areas of hypo- or depigmentation 114  2013/2014 Dermatology In-Review l Committed to Your Future Report a Problem/Feedback
  • 124. • Coup de sabre lesions may remain unchanged or become more extensive • Limited SSc rarely progresses to dSSc • Visceral involvement ultimately develops in dSSc • 5 year mortality for dSSc is about 50% → pulmonary fibrosis and renal hypertensive crisis in dSSc; pulmonary hypertension in lSSc Management Localized Scleroderma • Generally self-limited, so no treatment necessary • High potency topical steroids to lesions augmented by IL steroids • Antimalarials, phenytoin, colchicine, and systemic steroids have little benefit in generalized morphea • D-penicillamine may soften skin, allow the resumption of skin growth, and the cessation of new lesions • High dose UVA1 (340-450 nm) for morphea Systemic Sclerosis • Azathioprine, chlorambucil, methotrexate, cyclophosphamide variably successful • Systemic steroids do not alter the overall disease course • Cyclosporine may result in decrease in skin thickness, but pulmonary function remains unchanged and renal function may worsen • Extracorporeal photophoresis very controversial • D-penicillamine may be effective if used in early disease, with improved survival curves in patients because of lower incidence of renal disease; side effects limit long-term use: autoimmune lupus/polymyositis, pemphigus, nephrotic syndrome, myasthenia gravis, and Goodpasture syndrome • ACE-inhibitors markedly improve survival by treating renal disease • Peripheral vasospasm treated with diltiazem • Calcinosis treated with calcium channel blockers • Reflux esophagitis with proton-pump inhibitors • Physical therapy • Cessation of smoking decreases morbidity in those patients with documented Raynaud’s 4.23 Dermatomyositis With or without skin lesions, weakness of proximal muscle groups is the prominent feature. Cutaneous Findings • Heliotrope rash: Violaceous erythema and swelling of periorbital skin • Gottron’s papules: Flat-topped, violaceous papules over MCP, PIP, DIP joints • Periungual telangiectasias with frayed cuticles • Erythematous or urticarial patches and plaques on upper portion of face and extremities • Photosensitivity • Hyperkeratosis, scaling, fissuring, and hyperpigmentation over the fingertips, sides of thumb, and fingers • “Mechanic’s hands” • Raynaud’s phenomenon • Poikiloderma of chest or back (Shawl sing), Oron lateral thighs (Holster sign) • Calcinosis cutis: More often in kids with Dermatomyositis Report a Problem/Feedback General Dermatology  115
  • 125. Muscle Changes • Symmetric weakness with swelling and pain, involving shoulder • Difficulty swallowing, talking, or breathing • Cardiac disease late in disease • Skin eruption precedes muscle symptoms by two to three months • Amyopathic dermatomyositis: lack of muscle inflammation after a year or longer Associated Diseases  • Sclerodermatous changes → sclerodermatomyositis (anti-KU antibodies) • Other collagen vascular diseases • Presence of anti-Jo-1 antibody, as well as anti-PL-7, anti-PL-12 (anti-synthetase antibodies) correlates well with pulmonary disease Neoplastic Risk • Cancer can precede, occur simultaneously as, or follow DM • Malignancy usually in 5th or 6th decade of life, and more common in women u TIP aOvarian cancer is overrepresented Incidence u TIp • Twice as prevalent in women aChildhood DM • Bimodal peak: Small peak in children and large peak in •   runsting Type: more common, slow B adults between 40 and 65 course, progressive weakness, calcinosis, Laboratory Findings • Creatinine kinase, aldolase, LDH, and transaminase elevations (AST>ALT) • Perform EMG and MRI to find disease activity • Pulmonary function tests • Barium swallow for esophageal dysmotility teroid responsive •   anker Type: vasculitis of muscles and GI B tract, rapid onset of severe weakness, steroid unresponsive, and death Myositis Specific Antibodies (MSAS) • Positive ANA in 60-80% of patients • Anti-Mi-2 • Anti-p-155 (linked to cancer associated myositis and amyopathic dermatomyositis) • Anti-Jo-1 • Anti-CADM-140 (in patients with amyopathic DM) • Anti-Ku, Anti-Srp Treatment • Systemic corticosteroids • Azathioprine • Methotrexate • Sunscreens • Antimalarials • Mycophenolate mofehl • Cyclophosphamide • Treat calcinosis with aluminum hydroxide, diphosphonates, diltiazem, colchicine, low dose warfarin 116  2013/2014 Dermatology In-Review l Committed to Your Future u TIp a nti-Mi-2 AB’s correlate with shawl A sign, cuticular changes, and good prognosis a nti-Jo-1 AB’s correlate with A pulmonary fibrosis, Raynaud’s, polyarthritis a nti-SRP AB’s correlate with A cardiac disease and poor rognosis a nti-Ku AB’s correlate with A sclerodermatomyositis Report a Problem/Feedback
  • 126. Course • Major causes of death are cancer, ischemic heart disease, and lung disease 4.24 Sjogren’s syndrome Triad  • Keratoconjunctivitis sicca • Xerostomia • Rheumatoid arthritis • More than 90% women • Vasculitis → palpable purpura • Patients develop lymphoreticular malignancy such as NHL Laboratory  • Labial salivary gland biopsy • Schirmer Test for xerostomia detects diminished glandular secretion • RF positive • Positive cryoglobulins • Anti-Ro • Anti-La • Antibodies to fodrin (93% specific) 4.25 Connective tissue disease: serology Double-Stranded DNA Antibodies (dsDNA) • ELISA used more than IF • Performed on Crithidiae Luciliae → possesses giant mitochondrion with no ssDNA • Positivity highly characteristic of SLE → highly correlative with positive DIF in patient’s normal skin (lupus band), low complement levels, renal disease, and poor prognosis • Highly positive levels confirm diagnosis of SLE; low levels found in RA, Hashimoto’s, Grave’s, Waldenstrom’s, MCTD, SSc, Sjogren’s, autoimmune liver disease • Negative test does not exclude SLE (50-83% sensitive) Single-stranded Antibodies • Very low diagnostic value → detected in LE and other CTD’s (DM, morphea, Sjogren’s, and linear morphea of children) RNP Antibodies • Small ribonucleoproteins (SRNP) • SS-A (Ro), SS-B (La), SM, and U1RNP u TIP aHistone Antibodies •   haracteristic of drug-induced C SLE → >90% of patients •   0% of patients with idiopathic 3 Anti-Ro Antibodies SLE have anti-histone Ab’s • Found in LE (varying percentages based on subset of LE) and Sjogren’s (50%) • Strongly associated with photosensitivity (especially in SCLE) Anti-La Antibodies • More than 90% with positive anti-La also positive for anti-Ro • Associated diseases similar to those associated with anti-Ro Report a Problem/Feedback u TIP a 100% of patients with MCTD General Dermatology  117
  • 127. Ro and La Helpful in Workup of Photosensitivity • Confirm clinical diagnosis of SCLE, Sjogren’s, or neonatal LE • Patients with chronic idiopathic vasculitis • Useful in testing ANA negative patients with clinical manifestations of sle or scle Anti-U1RNP • 30% of patients with SLE; patients with SLE and anti-U1RNP also have other positive serologies • Majority of patients with positive U1RNP have SLE rather than MCTD • Presence associated with sclerodactyly, Raynaud’s, esophageal dysmotility Anti-Sm • Diagnostic of SLE, and not reported in patients with other ctd’s • Found in 15-40% of patients with sle • Most patients with anti-sm also have u TIP antibodies to u1rnp (converse is not aOther Antibodies true) •  cl-70 (anti-topoisomerase) → characteristic of SSc, S ANA substrate → human Hep-2 cells; a serum and defines presence of systemic involvement •  nti-centromere → marker for crest syndrome A negative on animal substrate may be positive •  nti–jo-1 (histidyl trna synthetase) seen in minority A on human cells Titer → negative or low in young of patients with dm and polymyositis → associated and healthy persons; high in those with systemic with pulmonary involvement and mechanic’s hand skin CTD; less than 1:80 has no diagnostic value. lesions Patterns – Peripheral → sle → staining native DNA (most specific pattern for SLE) – Homogeneous → sle → staining native DNA, histones – Nucleolar → SSc, sle → staining nucleolar RNA – Centromere → crest → staining kinetochore – Speckled → mctd, sle, ssc, sjogren’s → staining ribonucleoproteins • ANA-negative sle → determined often on animal substrates, yet later found to be positive on human cells, or if patient only makes antibodies to ssdna (not detected by most tests) • Almost all patients with SLE have positive ANAs • Ana: high negative predictive value, low positive predictive value Antiphospholipid Antibodies • Also called the lupus anticoagulant and anticardiolipin antibodies • Associated with thrombosis (not bleeding) • Most prevalent in sle patients • Seen in patients taking certain drugs (cocaine, ifn-α, procainamide, hydralazine, quinine, quinidine, phenytoin, fansidar, phenothiazines), chronic infections • Indications for testing – Livedo reticularis – Purpura and necrosis – Ulcers – Internal organ thrombosis – Recurrent miscarriages – Screening in patients with SLE 118  2013/2014 Dermatology In-Review l Committed to Your Future Report a Problem/Feedback
  • 128. Table 4-3. Antinuclear Antibody Patterns Pattern Associated Antibody Associated Disorder Homogenous anti-histone SLE false +, Drug induced LE, SLE Rim (peripheral) anti-ds DNA SLE nephritis Speckled (fine speckled) anti-Sm anti Ro and La (SSA/B) anti-U1RNP anti-Ku anti-topoisomerase (Scl-70) SLE SLE, Sjogrens syndrome SLE, MCTD SLE, scleroderma, myositis Scleroderma, SLE Centromere (discrete speckled) anti-kinetochore CREST Nucleolar anti-RNA polymerase anti-PM-Scl anti-U1RNP Scleroderma, SLE 4.26 Relapsing Polychondritis • Intermittent episodes of inflammation of the articular and nonarticular cartilage • Results in chondrolysis, dystrophy, and atrophy of the cartilage • Both sexes equally affected • Onset in 4th to 5th decade Clinical • Beefy red involvement of the ears confined to the cartilaginous portion • Often unilateral • Acute flare of inflammation lasts 1-2 weeks • 85-90% of patients develop auricular chondritis • Conductive deafness because of swollen cartilage • Recurrent episodes of chondritis result in destruction of normal cartilaginous structures and their fibrotic replacement → floppy or cauliflower ears • Nasal septal cartilage inflamed (50-70%) → rhinitis, crusting, bleeding, and saddle-nose deformity • Involvement of bronchi results in hoarseness, coughing, and dyspnea • Migratory arthralgia seen in 50-80% • Ocular disease: conjunctivitis, scleritis, iritis (any part of the eye may be affected) • Cardiovascular: aortic regurgitation and aortic aneurysm • 1/3 have associated rheumatic or autoimmune disease and many have LCV Laboratory • Elevated ESR MAGIC Syndrome • Behçet’s and relapsing polychondritis simultaneously (mouth and genital ulcers with inflamed cartilage) Report a Problem/Feedback General Dermatology  119
  • 129. Pathophysiology • Autoimmunity: IgG anti-type II collagen antibodies with titers corresponding to disease activity → found in up to 50% of patients with relapsing polychondritis (in only 15% in those with RA) • Antibodies directed against native and not denatured collagen II • Type II collagen restricted to cartilage Course • Unpredictable; chronic and variable with episodic flares (usually 1-4 weeks) and spontaneous remissions • Peripheral arthritis predicts a worse course • Causes death in 1/3 of patients secondary to airway collapse, cardiovascular complications, and infection (secondary to systemic steroids) Treatment • Dapsone 100 mg QD to BID with maintenance dose for 4-6 months → but may be ineffective in controlling scleral inflammation • Systemic steroids • Cyclosporine • NSAIDs • TNF-alpha inhibitors 4.27 BehCet’s disease Recurrent Oral Ulceration • Recurred at least 3 times in 12 month period Plus 2 of the Following: • Recurrent genital ulceration • Eye lesions (posterior uveitis) • Skin lesions (erythema nodosum, pseudofolliculitis, papulopustular lesions, or acneiform nodules) • Positive pathergy test Clinical Features  • Lesions are painful • CNS lesions occur and give picture of multiple sclerosis • Thrombophlebitis • Thrombosis of the superior vena cava • Asymmetric, non-erosive polyarthritis • Associated with hla-b51 Treatment • Sucralfate • Colchicine • Dapsone • Thalidomide • Tnf-inhibiting agents such as infliximab and etanercept 120  2013/2014 Dermatology In-Review l Committed to Your Future Report a Problem/Feedback
  • 130. 4.28 Livedo Reticularis Physiologic • Cutis marmorata Intravascular Obstruction • Stasis • Cardiac failure • Emboli • Cryoglobulinemia • Anticardiolipin syndrome • Hyperoxaluria • Arteriosclerosis • Hyperparathyroidism • Arteritis (pan, rheumatoid arteritis, le, dm, syphilis, tb, pancreatitis) Drugs • Amantadine, quinine, quinidine 4.29 Leukocytoclastic Vasculitis Diverse group of disorders: combine segmental inflammation with necrosis of blood vessels. May be primary, a feature of a systemic disorder, or idiopathic. Pathogenesis • Postulated that circulating immune complexes are locally deposited. The complexes activate complement, and thus attract neutrophils, which release lysosomal enzymes and damage tissue • ANCAs, antineutrophilic autoantibodies – C-ANCAs (cytoplasmic)—specific for proteinase 3  – P-ANCAs (perinuclear)—specific for myeloperoxidase • Seen with hepatitis C infection. ANCAs produce necrotizing vasculitis by activating circulating pmns and monocytes, which then adhere to blood vessels, degranulate, and release toxic oxygen metabolites to cause vascular injury Clinical Manifestations • Palpable purpura – non-blanching erythematous papules • Papules, urticaria, angioedema, pustules, vesicles, ulcers, necrosis, and livedo reticularis • Usually occurs on lower extremities or over dependent areas such as the back and gluteal regions. Uncommon on face, palms, soles, and mucous membranes • Palpable purpura persists 1-4 weeks, resolving often with transient hyperpigmentation and/ or atrophy • Symptoms: pruritus, burning, and pain less commonly. Episode associated with fever, malaise, arthralgias, and myalgias Associated Chronic Disorders • Rheumatoid arthritis • Sjogren’s syndrome • Sle Report a Problem/Feedback General Dermatology  121
  • 131. • Dermatomyositis • Hypergammaglobulinemic purpura • Mixed connective tissue disease, relapsing polychondritis, and scleroderma • Paraneoplastic vasculitis • Associated malignancies such as Hodgkin’s, lymphosarcoma, adult T-cell leukemia, mycosis fungoides, myelofibrosis, aml, cml, iga myeloma, diffuse large cell leukemia, hairy cell leukemia, squamous cell bronchiogenic carcinoma, prostate cancer, renal cell carcinoma, and colon carcinoma • Cryoglobulinemia • Particularly mixed types II and III • Occur in idiopathic LCV • Associated with hepatitis A, B, and C • Cystic fibrosis • IBD of the colon • Behçet’s disease ANCA’s • Seen with hepatitis C infection • Palpable purpura Antiphospholipid Antibodies • Livedo reticularis is most common finding Precipitating Infections • Group A β hemolytic streptococci • Staphylococcus aureus • Mycobacterium leprae – erythema nodosum leprosum, cutaneous nodular lesions of leprosy, involves capillaries, venules, arterioles, veins, and small to medium sized arteries • Hepatitis B • HIV • N. meningitidis • Rocky Mountain spotted fever • Catheter infections Precipitating Drugs • Penicillin • Sulfonamides • Thiazides • Allopurinol • Phenytoins • Nsaids • Ptu and hydralazine in association with ancas • Streptokinase • Radiocontrast media • Monoclonal antibodies • G-CSF 122  2013/2014 Dermatology In-Review l Committed to Your Future Report a Problem/Feedback
  • 132. Idiopathic Disorders Henoch-Schonlein Syndrome • Most widely recognized subgroup • Mostly children • Recent URI in 75% • Involves skin, synovia, GI tract, kidneys • Skin lesions of adults show blisters and necrosis • Long-term morbidity from kidney disease, which is predicted by the spread of purpura to the upper trunk Acute Hemorrhagic Edema of Childhood • Affects children and infants < 2 years of age • Painful, edematous petechiae and ecchymoses on head and distal extremities • Triggering factors: Infection, drugs, immunization • Lacks systemic features of HSP, and resolves within 1-3 weeks without sequelae Urticarial Vasculitis • Episodes of recurrent urticaria and angioedema • Occurs with serum sickness, connective tissue disorders, infections (Hep B and C, infectious mononucleosis), physical urticarias, colon carcinoma, administration of potassium iodide, fluoxetine, NSAIDs, and as an idiopathic disorder • Lesions often persist from 3-5 days, and usually heal without residua. Episodes are chronic, range in duration from months to years • 70% afflicted are women • General features: Fever, malaise, and myalgia, with possible lymphadenopathy and hepatosplenomegaly • Episodic arthralgias u TIP a chnitzler’s syndrome: episodes of urticarial vasculitis that S • Renal: Diffuse GN or glomerulitis occur in association with monoclonal IgM M component. • GI: Diarrhea, nausea, vomiting Fever, lymphadenopathy, hepatosplenomegaly, bone pain, • Pulm: Laryngeal edema and sensorimotor neuropathy • Eye: Conjunctivitis, uveitis, episcleritis • CNS: Headaches, pseudotumor cerebri Nodular Vasculitis • Recurrent, tender, red, subcutaneous nodules over lower extremities, especially the calves; lesions can occur on thighs, buttocks, trunk, and arms • No systemic manifestations • Women between 30 and 40 • Erythema induratum: form of nodular vasculitis associated with M. tuberculosis Livedoid Vasculitis (Atrophie Blanche) • Recurrent painful ulcers of lower extremities in association with persistent livedo reticularis; often deep purple in color • Atrophie blanche: Healed lesions result in sclerotic pale areas surrounded by telangiectases • Associated with arteriosclerosis or stasis • Pathogenesis may be secondary to fibrin thrombi in lumens of superficial vessels • Sneddon’s syndrome: Livedo reticularis and livedoid vasculitis associated with ischemic cerebrovascular lesions, hypotension, and extracerebral arterial and venous thromboses Report a Problem/Feedback General Dermatology  123
  • 133. Genetic Domplement Deficiencies • C2, C4a and C4b seen in some patients Eosinophilic Vasculitis • Idiopathic syndrome with recurrent pruritic, purpuric, papular skin lesions with angioedema • Also, urticarial plaques and palpable purpura present • Infiltrate of eosinophils LCV Treatment • H1 antihistamines used with palpable purpura to alleviate lesional symptoms • H1 blockers with NSAIDs • Colchicine or hydroxychloroquine can be added to or substituted for these agents; no benefit, then use dapsone • Systemic steroids, azathioprine, cyclophosphamide, plasmapheresis, cyclosporine • IFN-alpha clears lesions in Hep C Urticarial Vasculitis • H1 blockers, indomethacin, colchicine • Systemic steroids alleviates urticaria and systemic problems Erythema Elevatum Diutinum • Dapsone Nodular Vasculitis • NSAIDs, colchicine, systemic steroids Erythema Nodosum Leprosum • Thalidomide Livedoid Vasculitis • Aspirin, dipyridamole, colchicine, low-dose heparin, systemic glucocorticoids, and low molecular weight dextran, nifedipine, pentoxyfylline 4.30 Cryoglobulinemia and cryofibrinogenemia Cryoglobulinemia Circulating immunoglobulins complexed with other immunoglobulins or proteins that reversibly precipitate in the cold. Type I  • Single monoclonal immunoglobulin, usually IgG or IgM • Usually an underlying β-cell malignancy such as myeloma or lymphoma • Associated also with CLL and Waldenstrom’s macroglobulinemia • Purpura, acrocyanosis, retinal hemorrhage, Raynaud’s phenomenon, and arterial thrombosis Type II (Mixed Cryoglobulinemia)  • Monoclonal IgM rheumatoid factor complexed with polyclonal IgG • Multiple myeloma, Waldenstrom’s, CLL, rheumatoid arthritis, Sjogren’s, Hepatitis C • Lcv with palpable purpura, arthritis/arthralgias, and vascular purpura 124  2013/2014 Dermatology In-Review l Committed to Your Future Report a Problem/Feedback
  • 134. Type III (Mixed Cryoglobulinemia)  • Rheumatoid factors that are polyclonal IgM and IgG, complexed with each other or with another protein • Often complement activated and complement levels are lower • Sle, ra, sjogren’s, infectious mononucleosis, CMV infection, primary biliary cirrhosis, Hepatitis B, Hepatitis C • LCv with palpable purpura, arthritis/arthralgias, and vascular purpura Essential Mixed Cryoglobulinemia • Cryoglobulins and the manifestation of symptoms without an identifiable connective tissue, neoplastic, or infectious process • Often HCV infection coincides Clinical Features • Purpura, livedo, Raynaud’s, distal ulcerations • Affected organs are skin, kidneys, liver, musculoskeletal, and nervous systems Cryofibrinogenemia • Cryoproteins in anticoagulated blood or plasma that reversibly precipitate in the cold • Composed of fibrinogen • Cutaneous manifestations: purpura, ecchymoses, gangrene, ulcers • Associated with malignancy, thromoembolic disease, diabetes, pregnancy, oral contraception, and pseudotumor cerebri 4.31 Acanthosis nigricans Cutaneous marker of either insulin resistance, malignancy or obesity. Clinical • Grayish-brown, velvety plaques, hyperpigmentation, papillomatous • Most common to least common areas: axillae, neck, external genitalia, groin, face, inner thighs, antecubital and popliteal fossae, umbilicus, perianal area • Achrochordons • Tylosis: Palmoplantar hyperkeratosis with acanthosis palmaris or pachydermatoglyphy (exaggeration of fingerprints, or tripe palms) • Mucosal involvement consisting of thickening and papillomatosis with minimal hyperpigmentation Associated Conditions • Insulin resistance, associated with obesity, with positive correlation between degree of AN and severity of obesity • Lipodystrophies (Lawrence-Seip syndrome) • Leprechaunism – elfin appearance of face, thickened skin, absence of subcutaneous fat, and hirsutism • Type A syndrome: Severe acanthosis nigricans, hirsutism, clitoromegaly, and masculine habitus • Type B syndrome: AN after teenage years with less extensive involvement, with often underlying SLE (anti-insulin receptor auto-antibodies) • Malignancy: More extensive and involves mucosal surfaces; usually adenocarcinomas (gastric) • Drugs: testosterone, nicotinic acid, diethylstilbestrol, oral contraceptives, triazinate, glucocorticoids, topical application of fusidic acid Report a Problem/Feedback General Dermatology  125
  • 135. 4.32 Lipodystrophy Partial Lipodystrophy • Etiology unknown • Loss of subcutaneous fat in clearly demarcated, generally symmetric areas • Begins on face, spreads downward, stopping at any level → face become cachectic, with disappearance of buccal fat pads; premature aged expression; sunken eyes; easy visualization of veins • Lower part of body may be affected without upper part being affected • Excess fat deposition over hips and thighs frequently in women • 80% female, and usually begins before age 15 Laboratory  • Hypertriglyceridemia and insulin resistance • Clinically apparent diabetes in 20% • Decreased serum complement (C3) • Increased C3 nephritic factor → immunoglobulin that binds Factor H, an inhibitor of C3, allowing uncontrolled C3 activation • Glomerulonephritis (unknown frequency) Treatment • No effective therapy Generalized Lipodystrophy • Etiology unknown • Lack both subcutaneous fat and extracutaneous adipose tissue • Congenital (Seip-Lawrence syndrome) • Acquired (Berardinelli-Seip syndrome) • Often, acanthosis nigricans, hypertrichosis, generalized hyperpigmentation, and thick, curly scalp hair • Patients have voracious appetites, perspire excessively, and may be heat-intolerant despite normal thyroid function (elevated basic metabolic rate) • Muscles, genitalia appear hypertrophic • Mental retardation is common Laboratory and Internal Disease • Glucose intolerance (lipoatrophic diabetes); insulin resistance detected earlier than diabetes • Hepatomegaly resulting from increased fat; cirrhosis may develop • Renal, retinal, and neuropathic diabetic changes • CT and ultrasound show reduced fat around viscera • Eruptive xanthomas may appear Treatment • No effective treatment 126  2013/2014 Dermatology In-Review l Committed to Your Future Report a Problem/Feedback
  • 136. 4.33 Hyperlipoproteinemias Type I • Familial lipoprotein lipase deficiency (AR) or apoprotein CII deficiency • Increased chylomicrons • Eruptive xanthomas, lipemia retinalis • Associated with hepatomegaly, pancreatitis, abdominal pain (“horrible, screaming pain”) Type IIa • Familial hypercholesterolemia, common hypercholesterolemia (AD) • Increased LDL • Tendinous, tuberous, xanthelasma, arcus juvenilis, planar, eruptive •  econdarily caused by hepatoma, obstructive biliary disease, porphyria, hypothyroidism, S anorexia, nephrotic syndrome, Cushing’s • Atherosclerosis Type IIb • Familial hypercholesterolemia (AD) • Increased LDL and VLDL • Tendinous, tuberous, xanthelasma, arcus juvinilis, planar • Secondarily caused by nephrotic syndrome and Cushing’s syndrome • Atherosclerosis Type III • Familial Dysbetalipoproteinemia (AR) • Increased IDL • Palmar, planar, tendinous, tuberous, eruptive, intertriginous xanthomas • Secondarily caused by paraproteinemia • Atherosclerosis • Associated with diabetes, gout, and obesity Type IV • Familial hypertriglyceridemia (AD) • Increased VLDL • Eruptive, tendinous, tuberous • Secondarily caused by diabetes, uremia, paraproteinemia, alcoholism, lipodystrophy, obesity • Atherosclerosis Type V • Familial type V hyperlipoproteinemia, familial lipoprotein lipase deficiency (AD) • Increased chylomicrons and VLDL • Eruptive, lipemia retinalis • Secondarily caused by diabetes, obesity, and pancreatitis • Associated with hepatomegaly Report a Problem/Feedback General Dermatology  127
  • 137. 4.34 Xanthomatosis Clinical Types and Associations   Tuberous Xanthoma • Flat or elevated, rounded, grouped, yellowish, or orange nodules over joints (particularly elbows and knees) • Types II, III, and IV • Biliary cirrhosis Tendinous Xanthoma • Papules or nodules over tendons (extensor tendons on dorsum of hands, feet, and achilles) • Types II, III Eruptive Xanthoma • Small yellow/orange/red papules appearing in crops over entire body → buttocks, flexor surfaces, arms, thighs, knees, oral mucosa and may koebnerize • Associated with markedly elevated or abrupt increase in triglycerides (elevated chylomicrons) • Types i, iii, iv, and v • Diabetes, obesity, pancreatitis, chronic renal failure, hypothyroidism, estrogen therapy, corticosteroids, isotretinoin, acitretin Planar Xanthoma • Flat macules or slightly elevated plaques with yellow/tan color, spread diffusely over large areas • Frequently associated with biliary cirrhosis, biliary atresia, myeloma, HDL-deficiency, monoclonal gammopathy, lymphoma, leukemia, serum lipoprotein deficiency, xanthomas following erythroderma, ra, acquired c1 esterase deficiency • Characteristically around eyelids, neck, trunk, shoulders, or axillae • Types ii, iii   Palmar Xanthoma • Nodules and irregular plaques on palms and flexural surfaces of fingers • Type III u TIP Xanthelasma a anthoma striata palmaris: diagnostic of type III X dysbetalipoprotinemia (broad beta disease) • Most common type of xanthoma • Eyelids, 2-30 mm in length • Frequent symmetry • Usually present without any other disease, but may occur concomitantly with other xanthomas; can occur in types II and III, particularly • Common among women with hepatic or biliary disorders, also seen in myxedema, diabetes, and phytosterolemia • Best treated with surgical excision 4.35 Vitamin Deficiencies Alcoholism is the main cause of nutritional disease in developed nations. Other conditions: • Postoperative patients • Psychiatric patients • Unusual diets • Inflammatory bowel disease 128  2013/2014 Dermatology In-Review l Committed to Your Future Report a Problem/Feedback
  • 138. • Cystic fibrosis • Surgical bowel dysfunction • Inborn errors of metabolism Vitamin A Phrynoderma (Hypovitaminosis A) • Diseases of fat malabsorption: Crohn’s, celiac disease, CF, cholestatic liver disease • Required for normal keratinization • Deficiency leads to inflammatory disease of gut and lung • Supplementation required in rubeola (200,000 IU/day for 2 d) Clinical • Phrynoderma → toadskin, keratotic papules over extremities and shoulders surrounding pilosebaceous follicles • Spreads to involve abdomen, back, buttocks • Whole skin dryness and fine scaling • Night blindness • Xerophthalmia • Keratomalacia Hypervitaminosis A • Similar to side effects of synthetic retinoid therapy • Prone individuals: Children, hepatic disease, dialysis patients • All Vitamin A supplementation should be stopped if patient taking a retinoid Clinical Children • Loss of hair and coarseness of remaining hair • Loss of eyebrows • Exfoliative cheilitis • Generalized exfoliation and pigmentation of skin • Clubbing of fingers • Bone growth retardation • Pseudotumor cerebri (bulging fontanelles in infants) Adults • Dryness of lips • Anorexia • Joint and bone pains • Follicular hyperkeratosis • Desquamation of skin • Fissuring of corners of mouth and nostrils • Loss of scalp hair and eyebrows • Nail dystrophy Vitamin D • Deficiency: Alopecia only skin manifestation • Elderly: Results from decreased sun exposure and poor intake • Those taking anticonvulsants • Fat malabsorption • Extensive sun protection and sunscreen does not lead to Vitamin D deficiency • Excess: Hypercalcemia and generalized calcinosis Report a Problem/Feedback General Dermatology  129
  • 139. Vitamin K • Does not occur in adults (synthesized by bacteria in gut) • Deficiencies occur because of malabsorption caused by biliary disease, malabsorption syndromes, CF, anorexia nervosa, liver disease of all causes • Drugs such as coumadin, salicylates, cholestyramine, cephalosporins • Cutaneous manifestations: purpura, hemorrhage, ecchymosis Vitamin B2 Deficiency (Riboflavin)  • Most often in alcoholics • Oral-ocular-genital syndrome • Angular cheilitis • Atrophic tongue that is magenta • Seborrheic-like dermatitis around nose • Genital dermatitis → scrotal dermatitis sparing midline and extending to thighs • Photophobia and blepharitis Vitamin B6 Deficiency (Pyridoxine) • Caused by uremia and cirrhosis; pharmacologic agents • Seborrheic dermatitis-like eruption • Atrophic glossitis with ulceration • Angular cheilitis • Conjunctivitis • Intertrigo • Neurologic symptoms: somnolence, confusion, neuropathy Vitamin B12 Deficiency • Deficiency of intrinsic factor, achlorhydria, ileal disease, congenital absence of transcobalamin II • Occurs 3-6 years after GI abnormalities • Glossitis → bright red, atrophic tongue • Hyperpigmentation → resembles Addison’s disease • Canities • Neurologic findings Folic Acid Deficiency • Hyperpigmentation, glossitis, cheilitis, and megaloblastic anemia, identical to Vitamin B12 deficiency Vitamin C Deficiency (Scurvy)  • Male alcoholics and psychiatric patients • Hemorrhagic signs, hyperkeratosis of the hair follicles, hypochondriasis, and hematologic abnormalities • Perifollicular petechiae • Subperiosteal hemorrhage leading to pseudoparalysis • Subungual, subconjunctival, intramuscular, and intraarticular hemorrhage • Hemorrhagic gingivitis • Epistaxis • Delayed wound healing 130  2013/2014 Dermatology In-Review l Committed to Your Future Report a Problem/Feedback
  • 140. Niacin Deficiency (Pellagra) • Can result from deficiency in niacin (Vitamin B3 or nicotinic acid) or its precursor tryptophan • Alcoholics • Carcinoid tumors • Hartnup disease (impaired absorption of tryptophan) • GI disorders • Prolonged IV supplementation • Anorexia nervosa • Medications: INH, azathioprine, 5-FU Clinical  • Photosensitive eruption on face, neck, and upper chest (Casal’s necklace); may be vesiculobullous • Thickening and pigmentation over bony prominences • Seborrheic dermatitis-like eruption on the face • Diarrhea, depression, abdominal pain, dementia, coma • Patients die in four to five years if untreated Pathology • Most characteristic → pallor and vacuolar changes of keratinocytes in the upper layers of the stratum malphighii, just below the granular layer; a cleft may develop in upper epidermis Biotin Deficiency • Patients with short gut or malabsorption • Ingestion of avidin (raw egg whites) binds biotin causing deficiency • Multiple carboxylase deficiency • Holocarboxylase synthetase deficiency Clinical • Dermatitis is similar to zinc deficiency → periorificial and marked by patchy, red, eroded lesions of face and groin • Conjunctivitis • Alopecia Zinc Deficiency • Inherited abnormality, or acquired • Presentation in infancy most common → especially premature infants • Human breast milk has adequate zinc, and weaning precipitates deficiency in premature infants and those with acrodermatitis enteropathica • Low maternal breast milk zinc levels or higher infant requirements can precipitate deficiency in full-term infants • Zinc requirements increase during metabolic stress (infection) Clinical • Pustular and bullous lesions in an acral and periorificial distribution • Patchy, red, dry scaling with exudation and crusting • Angular cheilitis and stomatitis • Periungual erythema, scaling, and pustules • Patients are irritable and emotionally labile Report a Problem/Feedback General Dermatology  131
  • 141. Labs • Low serum zinc levels • Low alkaline phosphatase (a zinc-dependent enzyme) Essential Fatty Acid Deficiency • Infants with low birth weight • GI anomalies • Inflammatory bowel disease • Intestinal surgery • Parenteral nutrition (prolonged) Clinical • Similar dermatitis to that of zinc and biotin deficiency • Widespread erythema and intertriginous weeping eruption • Diffuse alopecia • Ratio of eicosatrienoic acid to arachidonic more than 0.4 diagnostic of EFA deficiency Iron Deficiency  • Koilonychia, glossitis, angular cheilitis, pruritus, and telogen effluvium • Plummer-Vinson: Microcytic anemia, dysphagia, and glossitis seen nearly entirely in middleaged women; lips are thin and opening of mouth is small and inelastic Marasmus  • Prolonged deficiency of both protein and calories • Children 60% of their ideal body weight • No edema or hypoproteinemia • Skin is dry, wrinkled, and loose u TIP aKwashiorkor •   rotein deficiency but adequate P caloric intake •  Edema and potbelly •   ypopigmented hair → reddish H yellow to gray or white Carotenemia •   Flag sign” → hair grown during “ periods of poor nutrition is pale • Excessive ingestion of carrots, oranges, squash, spinach, yellow corn and beans, butter, eggs, rutabagas, pumpkins, yellow turnips, sweet potatoes, or papaya leading to yellowish discoloration of skin • Prominent on palms, soles, and central face Lycopenemia • Excessive ingestion of red foods like tomatoes, beets, chili beans, and various fruits leads to reddish discoloration of skin 4.36 Diabetes Infections and skin disease • Staph pyodermas • Candidiasis • Erythrasma • Epidermophytosis Xanthomatosis • Chylomicronemia with xanthomas • Regression when diabetes brought under control 132  2013/2014 Dermatology In-Review l Committed to Your Future Report a Problem/Feedback
  • 142. • Xanthelasma: Occurs in hyperlipidemic states (including diabetes) and may occur without demonstrable abnormality of plasma lipids Diabetic Dermopathy • Asymptomatic, irregularly shaped patches over anterior lower legs • Depressed and brown surfaces • Often accompanied by significant microangiopathy elsewhere in body Bullous Lesions/Bullous Diabeticorum • Spontaneous bullae on extremities, especially of the feet • Heal without scarring within weeks • Bullae occur in plane of basement membrane above basal lamina Thickened Skin and Stiff Joints • 1/3 of patients have tight, thickened and waxy skin over dorsa of the hands • Multiple, minute, flesh-colored papules on dorsum of fingers, knuckle pads, and periungual areas • Contractures of hands • Scleredema adultorum Cutaneous Neuropathy • Autonomic disturbances that accompany neuropathy including anhidrosis Necrobiosis Lipoidica • 0.3% of diabetics • 3:1 female:male • Only a minority of those with NLD actually have diabetes • Anterior and lateral surfaces of lower legs, usually (also face, arms, and trunk) • Begins as small, dusky-red elevated nodule with sharply circumscribed border, enlarging to an atrophic plaque • Brownish-yellow center, red border • Extremely chronic and indolent • Diabetes may precede (80%) or occur subsequent to development of lesions (10%); rest have no glucose intolerance; most have abnormal glucose tolerance in response to glucocorticoids Granuloma Annulare • Generalized form more common in DM Vitiligo • Greater than expected incidence in patients with DM Type 1 • May precede clinically evident diabetes Acanthosis Nigricans • See separate discussion Report a Problem/Feedback General Dermatology  133
  • 143. 4.37 Langerhans Cell Histiocytosis Histiocytosis X • Proliferation of dendritic or Langerhans histiocytes Morphology • Rose-colored papules, some scaling, crusting, and ulceration • Merging of lesions on scalp gives seborrheic dermatitis appearance • Nail changes: Paronychia, nail fold destruction, onycholysis, subungual hyperkeratosis (poor prognostic signs) Systemic Manifestations • Extremely variable • Pulmonary involvement in >50% → lungs show honeycomb appearance; dyspnea, cyanosis, and pneumothorax • Hepatosplenomegaly: Never the initial sign of disease • Bone lesions (60%) • Hematopoietic involvement (rare) • Fever Classification Letterer-Siwe Disease • Acute, disseminated LCH • First year of life • Cutaneous disease more common in this entity (80%), and usually initial sign • Fever, anemia, thrombocytopenia, enlargement of liver and spleen (never presenting sign) • Potentially fatal visceral involvement • Only osteolytic lesion is in mastoid bone (looks like otitis media) Hand-Schuller-Christian Disease • Early childhood • Less extensive visceral involvement • Chronic, multifocal disease • Cutaneous disease in only 30% • Osseous lesions, especially of cranium (80%) • Exophthalmos (10-30%) • Can cause diabetes insipidus (50%), caused by granulomatous infiltration of posterior pituitary gland Eosinophilic Granuloma • Older children and adults • Benign • One or a few bone lesions • Affects skull, ribs, and vertebrae most frequently • Can affect mucosa Hashimoto-Pritzker Disease (Congenital, Self-healing Reticulohistiocytosis) • Present at birth, usually • No mucous membrane lesions • Systemic signs absent • Rapid spontaneous regression 134  2013/2014 Dermatology In-Review l Committed to Your Future Report a Problem/Feedback
  • 144. Course and Prognosis • Skin and bone involvement good signs, and organ involvement bad • 10% with multifocal disease die, 60% have chronic course, 30% show complete remission Management Treatment based on age, extent of disease, and location of lesions Children • Nonaggressive management • Observation • Topical nitrogen mustard for persistent lesions Adults • Topical nitrogen mustard • PUVA • CO2 laser • Thalidomide • Isotretinoin Bone Involvement • Surgical excision • Glucocorticoid injections • Radiotherapy in adults • Monochemotherapy for multiple bone lesions 4.38 Cutaneous T-Cell Lymphoma Clinical Types Patch and Plaque Stage • Flat lesions associated with inflammation and pruritus, that can persist for years or resolve spontaneously • Patch stage can last for months to years before progressing • Plaques can arise de novo Hypopigmented MF • Darker-skinned patients • Patients respond to therapy by regaining pigment Pigmented Purpura • Capillaritis Granulomatous CTCL and Slack Skin • Primarily in females • Large regions of slack skin accompanied by fibrotic bands Pagetoid Reticulosis (Woringer-Kolopp Disease or Acral MF) • Typically presents as a solitary plaque (localized) • Long duration, slow growing • Benign; long duration without progression • Pronounced epidermotropism • Follicular MF Report a Problem/Feedback General Dermatology  135
  • 145. Alopecia Mucinosa • Follicular mucinosis • Grouped follicular papules or red, raised, boggy, occasionally nodular plaques • Alopecia may be presenting sign • Histology: Sebaceous glands and outer root sheaths disrupted with increased mucin deposition • CTCL may be present before development of alopecia mucinosa Erythrodermas • De novo or as a progression from pre-existing CTCL lesions • May lead to leonine facies • Alopecia, ectropion, nail dystrophy, ankle edema • Sezary syndrome may cause Tumor Stage MF • Predilection for face and body folds • May occur in pre-existing plaques and patches of CTCL • Neoplastic cells more malignant biologically • Nodules may ulcerate • May spontaneously resolve, but prognosis is poor • Infiltrate denser than plaque stage, and extends to subcutaneous fat • Epidermotropism is not a prominent feature, and grenz zone may appear Diagnosis • Diagnosis made by biopsy • Multiple punch biopsies at 3 month intervals may be needed • Any patient with chronic, refractory dermatosis (acd, ad, psoriasis, prp) should be biopsied to rule out ctcl • Clonality assists in diagnosis, but is not pathognomonic Peripheral Blood   • Malignant clonal T-cell populations recirculate from skin to lymph nodes, and then to blood, even in patch stage disease, CD4+/CD7• Elevated CD4/CD8 ratio indicates disease expansion into blood • Flow cytometry must be a component in the staging process (CD4/CD8), CD3, CD45RO • Memory cell marker CD45RO is elevated often in cases of peripheral blood involvement by CTCL Sezary Cells  • Hyperchromatic and hyperconvoluted nuclei • Represent an activated T-cell • Can be seen in inflammatory dermatoses, and in Dilantin (phenytoin) hypersensitivity syndrome • 100 cells counted to assess percentage, and >5% associated with poor prognosis Prognosis • Involvement of 10% or less with patch disease: median survival of 12 years • Tumors, erythroderma, or node involvement: median survival 2-3 years • Sezary syndrome: 2-3 years 136  2013/2014 Dermatology In-Review l Committed to Your Future Report a Problem/Feedback
  • 146. Topical Chemotherapy • Nitrogen mustard (bis-chloro nitrosurea, BCNU); mechlorethamine (10 mg in 50 ml tap water as initial dose) • Ointment-based mechlorethamine has longer shelf life • Side effects: Hypersensitivity, primary irritation, second cutaneous malignancies, hypo and hyperpigmentation • Daily whole-body application required until remission, after which frequent maintenance therapy used Radiotherapy • Electrons penetrate only to upper dermis • Whole body irradiation induces complete remission in >80%; with relapse rate higher in later stages of CTCL • Most relapses occur within first year after cessation of treatment • Local side effects: Alopecia, atrophy of sweat glands and skin, radiodermatitis, and edema; fractionating dose reduces side effects • SCC incidence increased • 2nd and 3rd courses acceptable if needed Photochemotherapy • PUVA • Induces remission even in tumor stages Extracorporeal Photochemotherapy • Photoinactivation of a portion of the patient’s lymphocyte compartment with 8-methoxypsoralen + UVA, followed by reinfusion • Two consecutive days every four weeks • Effective for erythroderma • Requires 4-12 months for response Alpha and Gamma Interferon • 10-27% complete response within 6 months using monotherapy • 3 million units 3x/week, and can be increased to 20 million units per day as tolerated • Maintenance dose of 1 million units daily • Toxicities: Flu-like symptoms first week. Side effects: chronic fatigue; long-term neurologic toxicity may occur, and autoimmune phenomena such as proteinuria, thrombocytopenia, and anemia DAB-IL-2 Toxin/Denileukin Diftitox • Diphtheria toxin fused to IL-2, binding to receptor, killing cells • Infiltrates must contain high levels of IL-2 receptor-positive cells • May cause fluid retention, diffuse erythema, and liver abnormalities, which are all reversible Systemic High-Dose Chemo • Palliative • Glucocorticoids, adriamycin, CHOP therapy Report a Problem/Feedback General Dermatology  137
  • 147. 4.39 Pyoderma gangrenosum Four Types Ulcerative • Inflammatory pustule with surrounding halo • Enlarges over days and ulcerates • Many lesions begin at sites of trauma (pathergy) • Distinct rolled edges and show satellite violaceous papules that break down and fuse with central ulcer • Painful • Adults 40-60 years old on lower extremities and trunk • Heal with thin, atrophic scars Pustular • Describes the primary pustular lesions that may or may not progress on to ulcerative lesions • Often seen associated with IBD • Associated with pyostomatitis vegetans and subcorneal pustular dermatosis Bullous • Less destructive, more superficial • Overlap with atypical Sweet’s • Patients with leukemia or polycythemia vera • Red inflammatory plaques that become dusky and develop superficial erosion of the epidermis • Less painful than ulcerative Vegetative • Least aggressive form • Cribiform chronic superficial ulcerations on the trunk, usually • Not painful • Not often associated with systemic disease u TIP Clinical Associations a50% have associated disease, most commonly is IBD (UC > Crohn’s) • 1.5-5% of patients with IBD develop PG • Diseases run separate courses  • Associated with leukemia, myeloma, monoclonal gammopathy (IgA), polycythemia, chronic active hepatitis, hcv, hiv, sle, pregnancy, and Takayasu’s Arteritis • Associated with PAPA syndrome → pyogenic arthritis, pyoderma gangrenosum, severe cystic acne • 33% have arthritis → asymmetrical, seronegative, monoarticular arthritis of the large joints • Children with congenital deficiency of leukocyte-adherence glycoproteins Histology • Massive dermal edema with epidermal neutrophilic abscesses at the violaceous undermined border Treatment • If lesions pustular, seek and treat for underlying IBD • Aggressiveness of treatment determined by severity of disease 138  2013/2014 Dermatology In-Review l Committed to Your Future Report a Problem/Feedback
  • 148. • Local treatment: Compresses or whirlpool baths with use of ointment occlusive dressings • Potent topical steroids or IL steroids • Topical tacrolimus • Systemic steroids, and if not responding, pulse methylprednisolone • Sulfapyridine, sulfasalzine, and dapsone • Clofazamine 200-400 mg qd • Cyclosporine is the next choice, with 85% of reported cases responding dramatically: start at 5 mg/kg • Infliximab • Other agents: thalidomide, SSKI, azathioprine, cyclophosphamide, chlorambucil 4.40 Sweet’s syndrome Acute Febrile Neutrophilic Dermatosis • Recurrent painful plaque-forming inflammatory papules, fever, peripheral leukocytosis, a diffuse dermal infiltrate, and prompt resolution of symptoms and lesions with glucocorticoid therapy Clinical Skin • Sudden eruption of tender red or bluish red papules or nodules uTIP a ace, upper extremities, and F over face, neck, upper extremities neck, most commonly • Coalesce to form irregular sharply bordered plaques (“relief of a mountain range”) • Transparent vesicular appearance, though solid (“illusion of vesiculation”) • Eventually resolve without scarring after weeks or months Systemic • Fever, leukocytosis, with patients appearing dramatically ill • Headache, arthralgia, myalgia, and general malaise, conjunctivitis, and episcleritis • Bone: Sterile osteomyelitis • Neuro: Aseptic meningitis, neurologic and psychiatric symptoms, with neutrophils in the CSF • Renal: Proteinuria, hematuria, glomerulonephritis • Hepatic: Infiltration of portal triad and tracts with elevated LFT’s • Pulmonary: Culture-negative infiltrates Laboratory • Elevated ESR • Peripheral leukocytosis with neutrophilia • Malignancy-associated Sweet’s: anemia, normal or low neutrophil count and abnormal platelet count • Proteinuria if renal involvement Etiology • No known cause. Thought to be a hypersensitivity reaction u TIP • Majority of patients have a febrile upper respiratory tract aCan be drug-induced (GCSF) infection, tonsillitis, or influenza-like illness that precedes their skin lesions by 1-3 weeks • Can be associated with intestinal infection with Yersinia enterocolitica Report a Problem/Feedback General Dermatology  139
  • 149. Pathology • Edema of the dermal papillae and dense infiltrate composed largely of neutrophils, with some lymphocytes and histiocytes, and occasional eosinophils • Infiltrate is bandlike in papillary dermis (“Sea of neutrophils”) • Leukocytoclasia common Associated Diseases Probable Association • Infection: Usually upper respiratory tract and GI tract • Inflammatory bowel disease • Medications: G-CSF – anemia commonly associated, and tmp-sfx • Pregnancy Treatment • Corticosteroids • Potassium Iodide 4.41 Erythema u TIP a alignancy, most commonly M hematologic (AML); lesions may precede diagnosis of leukemia Annulare Centrifugum • Polycyclic erythematous lesions that grow eccentrically and slowly • Often recurrent • Characteristic trailing scale at inner border • Characteristic lymphocytic coat sleeving of vascular/adnexae on pathology Associations  • Idiopathic • Malignancy • Dermatophyte (feet and groin) But no extensive workup necessary 4.42 Erythema Elevatum Diutinum Clinical Features and Course Morphology • Multiple lesions: Papules plaques or nodules • Early lesions often pink or yellow. Older lesions are red or purple and harder. Lesions may be round or oval, and surface is smooth with occasional scale. Also, freely movable from underlying tissues Distribution • Symmetric on extensor surfaces, especially skin overlying joints, especially on hands and knees. Also involve the buttocks and skin overlying the achilles tendon Symptoms • Asymptomatic to very painful Associated Symptoms and Conditions • Arthralgia (most common) • Recurrent pharyngeal and sinopulmonary infection, usually streptococcal • Inflammatory bowel disease 140  2013/2014 Dermatology In-Review l Committed to Your Future Report a Problem/Feedback
  • 150. Course • Variable, but often progressive over 5-10 years, with long-term remission possible • Periods of waxing and waning u TIP Laboratory Findings aIgA (mainly) or IgG or IgM monoclonal gammopathies or even myeloma • Elevation in ESR Treatment • Dapsone or sulfapyridine – with exacerbation after the drug’s withdrawal • Glucocorticoids not effective systemically, but intralesional and topical high potency steroids may decrease the size of lesions 4.43 Erythema Nodosum Extensor surfaces, lower extremities: inflammatory, spontaneously regressing, tender, nodular lesions. Clinical M NEM ON I C Erythema Nodosum SHOUT BCG Sarcoid, Sulfa, Strep Histoplasmosis Oral contraceptives Ulcerative colitis TB • Erythematous, tender nodules on anterior shins; also seen on thighs, lateral aspects of lower legs, arms, and face • Onset of new lesions often accompanied by fever, chills, malaise, and leukocytosis Bechet’s • Often progresses into a violaceous blue color Crohns • 70% have associated arthropathy that may persist after GI (Yersinia) disappearance of eruption • Occurs at any age, but most prevalent between 20 and 30 years of age • Results from immunologic reaction triggered by drugs, benign and malignant systemic illness, bacterial, viral, and fungal infections Infections • Streptococcal, beta hemolytic: cutaneous lesions develop within three weeks of infection • Tuberculosis: Associated with primary infection • Yersinia • Blastomycosis, coccidioidomycois, histoplasmosis; dermatophytes, particularly those causing tinea capitis with kerion formation • Often occurs after acute respiratory illness that is nonstreptococcal for which no agent identified • Viruses: paravaccinia, infectious mononucleosis, lymphogranuloma venereum, cat-scratch disease, psittacosis, Hepatitis B Sarcoidosis  • May be presenting sign along with hilar adenopathy • Lofgren’s syndrome: sarcoidosis, erythema nodosum (good prognosis) Drugs • Sulfonamides • Bromides • Oral contraceptives Report a Problem/Feedback General Dermatology  141
  • 151. Enteropathies • Ulcerative colitis more frequently than Crohn’s disease Miscellaneous Causes • Behçet’s syndrome • Malignancy: Lymphoma, leukemia, cervical cancer • Onset of radiation therapy for cancer Treatment • Spontaneous resolution usually occurs within three to six weeks without scarring • NSAIDs such as indomethacin or naproxen • Systemic steroids effective in severe cases and can be dangerous if infection is etiology • Potassium iodide 400 to 900 mg daily 4.44 Mastocytosis • Mast cell hyperplasia in the bone marrow, liver, spleen, lymph nodes, GI tract, and skin • Clinical: Pruritus, flushing, urtication, abdominal pain, nausea, vomiting, diarrhea, bone pain, vascular instability, headache, and neuropsychiatric difficulties Etiology and Pathogenesis  • Originate from pluripotent (CD34+) bone marrow cells → circulate through blood → mature into fully granulated cells • Mutations in c-kit → associated with enhanced receptor function • Increased production of mast cell mediators: – Histamine – Heparin – Tryptase – Leukotrienes – Prostaglandin D2 – Platelet activating factor – Cytokines – growth enhancing and proinflammator Clinical • Features are due to excess production of mast cell-dependent mediators • Patients in every category of mastocytosis sometimes experience flushing or vascular collapse → provoked by alcohol, aspirin, narcotics, contrast agents (iodinated), insect stings, exercise, or infections Major Types of Mastocytosis • Urticaria pigmentosa – Most common skin manifestation in children and adults – 90% of those with indolent mastocytosis – Small, yellow-tan to reddish-brown macules or slightly raised papules – Darier’s sign: Trauma/rubbing of lesions causes urtication and erythema – Associated with pruritus exacerbated by changes in temperature, friction on skin, ingestion of hot beverages or spicy foods, ethanol, and certain drugs • Diffuse cutaneous mastocytosis – Diffuse mast cell infiltration without discrete lesions 142  2013/2014 Dermatology In-Review l Committed to Your Future Report a Problem/Feedback
  • 152. – Usually occurs before age of three – Entire skin involved – Skin normal to yellow-brown and thickened • Solitary mastocytomas – Rare – Onset before six months of age – Involute spontaneously, usually • Bullous eruptions with hemorrhage – Neonates – Blisters may erupt spontaneously • Telangiectasia macularis eruptiva perstans – <1% of patients – Tan-to-brown macules and patchy erythema – Telangiectasias observed – Exclusively in adults Systemic Features Gastrointestinal Disease • Gastric hypersecretion secondary to elevated histamine → gastritis with peptic ulcer disease • Diarrhea and abdominal pain • Malabsorption • LFT’s abnormal in half of patients → alkaline phosphatase elevated Splenomegaly • 50% of patients • Mast cell infiltrates with fibrosis • Extramedullary hematopoiesis Bone Marrow • Radiographically detectable lesions in majority of patients → proximal long bones most often affected; pathologic fractures may occur • Anemia, leukopenia, thrombocytopenia and eosinophilia may occur Neuropsychiatric • Decreased attention span • Memory impairment • Irritability Mastocytic Leukemia • Rarest form and has most fulminant behavior; peripheral blood shows numerous immature mast cells Work Up 1.) Skin exam – gross and microscopic 2.) Bone marrow biopsy 3.) 24 hour urine • Suspicion should prompt a bone marrow biopsy and aspirate for diagnosis and categorization of the type of mastocytosis • Obtain 24 hour urine for 5-hydroxyindoleacetic acid (5-HIAA) and urinary metanephrines to rule out carcinoid tumor or pheochromocytoma Report a Problem/Feedback General Dermatology  143
  • 153. Treatment • H1 blockers reduce pruritus, flushing, tachycardia • H2 blockers added • Cromolyn sodium, particularly for GI complaints • Ketotifen and azelastine, antihistamines that stabilize mast cells • Epinephrine for vascular collapse (patients should be prepared to self-administer) • PUVA (with methoxsalen) relieves pruritus and whealing after 1-2 months, but recurs after 3-6 months • Topical glucocorticoids under occlusion for 8 hours per day over 8-12 weeks can be used for extensive UP; lesions recur after discontinuation • Radiotherapy for bone pain Survival • 50% of children with UP resolve by adulthood • Adults with UP usually progress gradually to systemic disease and rarely develop hematologic disease • Diffuse cutaneous mastocytosis is usually associated with indolent systemic disease • Mast cell leukemia: survival less than six months • Lymphadenopathic mastocytosis with eosinophilia: two to four years without therapy 4.45 Cutaneous Sarcoidosis • Skin lesions occur in 25% of patients with sarcoidosis Lupus Pernio • Middle aged females, increased in African Americans • Chronic, violaceous, indurated plaques • Predilection for nose, ears, lips, and face • Persistent sarcoidosis characterized by extensive pulmonary infiltration and fibrosis, chronic uveitis, and bone lesions • Nose lesion accompanied by granulomatous infiltration of nasal mucosa and upper respiratory tract, and bony nasal septum may be destroyed • Bulbous or sausage-shaped finger in a patient with lupus pernio indicates presence of underlying bone lesion Plaques • Violaceous, elevated, indurated • Limbs, face, back, and buttocks • Distribution is symmetric • In African Americans, hypopigmented appearance: “hypomelanotic umbrella” • Sarcoid lesions may appear psoriatic Papular Eruptions • Most common skin manifestations in African Americans • Waxy, translucent, flat top, 2-6 mm • Occur on face, lids, around orbits, neck, upper back 144  2013/2014 Dermatology In-Review l Committed to Your Future Report a Problem/Feedback
  • 154. Subcutaneous Nodules/Darier Roussy Sarcoidosis • Oval, firm, painless • Arise deep in dermis and subcutis • Found on trunk and extremities • Rarely, ulcerate Erythema Nodosum • Most common nonspecific cutaneous manifestation of sarcoidosis (Lofgren’s syndrome) • Hallmark of acute sarcoidosis, predominantly of women of childbearing age • May be associated with fever, malaise, polyarthralgia • Associated with good prognosis in sarcoidosis Laboratory Investigations  • Hypercalcemia: due to increased intestinal absorption secondary to active form of Vitamin D3 overproduction (in lungs) • ACE level: raised in 60%, higher in patients with hilar adenopathy and pulmonary infiltration (stage II) and positive in patients with extrathoracic sarcoidosis; ACE derived from epithelioid cells of granulomas and thus reflects granuloma load in the body • ACE used for monitoring clinical course, not for diagnosis (60% sensitive, and 90% specific) Immunology Cutaneous Anergy  • Depression of DTH reactions; negative PPD in 66% • Anergy does not correlate with disease activity—persists even during recovery Humoral Responses • Exaggerated circulating antibody • Hypergammaglobulinemia occurs in half the patients Kveim Test • Intradermal injection of homogenized tissue from sarcoidosis patient • Requires four to six weeks for nodule to develop Treatment Glucocorticoids • Prednisone, 20-40 mg qd, is treatment of choice • Dose is reduced gradually to 10 mg daily • After 4-6 weeks of daily treatment, dose can be reduced to 10-20 mg every other day • IL triamcinolone to disfiguring lesions • Topical glucocorticoids to individual lesions Antimalarials • Chloroquine • Hydroxychloroquine Immunosuppressive Drugs • Methotrexate • Infliximab Surgery • Excision of small lesions • Grafting of extensive sarcoid ulcers Report a Problem/Feedback General Dermatology  145
  • 155. 4.46 Perforating Disorders Perforating Folliculitis Pathogenesis • Lesions may be related to superficial trauma Clinical • Keratotic follicular papules over extensor surfaces • Association with chronic renal failure Reactive Perforating Collagenosis Pathogenesis • Lesions precipitated by superficial trauma altering collagen in the dermal papillae Clinical • Pinhead keratotic papules that grow to 6-10 mm in diameter • Center of lesion becomes umbilicated containing tightly adherent plug • First lesions usually appear in infancy after minor trauma or arthropod bite Kyrle’s Disease (Hyperkeratosis folliculitis) Pathogenesis • Absence of collagen • Follicular plug in an epidermal invagination Clinical • Scaly folliculo-centric papules Elastosis Perforans Serpiginosum (EPS) Pathogenesis • Altered elastic fibers in dermis and concomitant alteration of collagen fibers • Elastic fibers act as a foreign body and are eliminated through transepidermal channels Clinical • Patients with MADPORES: Marfans, Acrogeria, Down syndrome, Penicillamine, Osteogenesis Imperfecta, Ehlers Danlos • Flesh colored to erythematous umbilicated papules 2-3 mm arranged in arcuate serpiginous or grounded fashion • Nape and sides of neck, upper extremities MNEMONIC MAD PORES Marfan’s Acrogeria Down’s Penicillamine Osteogenesis Imperfecta Rothmund-Thomson Ehlers Danlos Scleroderma Treatment • Cryotherapy 4.47 Elastosis perforans serpiginosa Pathogenesis • Altered elastic fibers in dermis and concomitant alterations of collagen fibers • Elastic fibers act as a foreign body and are eliminated through transepidermal channels 146  2013/2014 Dermatology In-Review l Committed to Your Future Report a Problem/Feedback
  • 156. Patients • Idiopathic • Patients with Down’s syndrome, heritable connective tissue disorders (Ehlers-Danlos Type IV, osteogenesis imperfecta, Marfan’s syndrome, Rothmund-Thomson, scleroderma, and acrogeria), penicillamine Clinical • 2nd decade of life • Flesh-colored to erythematous umbilicated papule 2-3 mm, with central, tightly adhering plug that bleeds when removed • Nape and sides of neck, upper extremities • Arcuate, serpiginous, grouped, scattered, discrete • Regression leaves atrophic, wrinkled, and hypopigmented scars Treatment • Cryotherapy • Avoid electrocautery, dermabrasion, and surgery 4.48 Reactive Perforating Collagenosis Pathogenesis • Perhaps genetic predisposition • Development of lesions likely precipitated by minor superficial trauma altering collagen in the dermal papillae • No associated metabolic disorders Clinical • Lesions start as pinhead-sized keratotic papules and grow to 6-10 mm in diameter over one month • Center of lesion becomes umbilicated containing a tightly adherent leathery plug that if removed leaves a bleeding crater • Heals with a minor scar of hypopigmented macule • First lesions usually appear in infancy after minor trauma or arthropod bite • Asymptomatic Treatment • No consistently successful therapy • Maybe phototherapy 4.49 Cutaneous features and disorders of Pregnancy Pemphigoid Gestationis   • Seen only in pregnancy or with trophoblastic tumors • Begins in 2nd or 3rd trimester • Urticarial or papulovesicular lesions on trunk; spreads rapidly and may involve face and palms/soles, evolving into bulla • Pruritus may precede lesions • May remit prior to delivery, but 75% flare post-partum • Recurs with pregnancy, OCP’s, or menses Report a Problem/Feedback General Dermatology  147
  • 157. Laboratory • Severity may correlate with eosinophilia • Increased anti-thyroid antibodies   Immunofluorescence • Direct: C3 in homogeneous, linear band at BMZ (perilesional and lesional skin); IgG in 30-40% • Indirect: Complement fixation at BMZ; HG factor = complement fixing IgG antibody; almost all patients show IgG1 against BMZ Pathophysiology • IgG against 180 kd BP antigen; → extracellular domain • Theory: Cross reaction of antibodies directed against amniotic BMZ • Pregnancies can skip disease Treatment and Course • Prednisone 0.5 mg/kg/day (topical steroids often ineffective) • Increased risk for small for gestational age infant and prematurity • Mother: Increased lifetime risk of Grave’s disease Cholestasis of Pregnancy  • The same as prurigo gravidarum +/- jaundice • Cholestatic jaundice of pregnancy = abnormal LFT’s • Prurigo gravidarum = pruritus and abnormal bile acids without jaundice Clinical • Usually 3rd trimester • 50% associated with UTI • <50% develop jaundice • Intense pruritus without lesions • Resolves within 2 days post-partum Laboratory • Bile acids elevated 3-1000x normal • Direct bilirubin not more than 2-5 mg/dl • Hepatic ultrasound is normal  Course and Prognosis • Mother: Low Vitamin K → post-partum hemorrhage • May recur with future pregnancy • Increased risk of cholelithiasis • Fetus: Premature labor (common), fetal distress, perinatal death Treatment • UVB phototherapy for symptoms • Cholestyramine given with Vitamin K • Rest and low fat diet • Ursodeoxycholic acid or UDCA (16 mg/kg/day) → reduces risk of premature delivery and pruritus • Dexamethasone 12 mg/day x 7 days → decreases lab abnormalities and pruritus, used in conjunction with UDCA • Deliver at 38 weeks or earlier 148  2013/2014 Dermatology In-Review l Committed to Your Future Report a Problem/Feedback
  • 158. Polymorphous Eruption of Pregnancy (or PUPPP)  u TIP Clinical a rimigravidas, increased with maternal P • Papules begin in striae and spread to trunk and obesity and twin gestation extremities • Usually in 3rd trimester • Resolves 15 days post-partum, sometimes prior to delivery Laboratory • Normal Treatment and Course • Topical steroids • Antihistamines • Systemic steroids • No maternal or fetal morbidity Pustular Psoriasis of Pregnancy • Also called “impetigo herpetiformis”  Clinical • Late 1st trimester to 3rd trimester • Often begins in intertriginous regions and spreads to trunk and extremities • Spares face, palms, and soles • Erythematous plaque with ring of pustules, that enlarges at periphery and erodes or crusts at periphery • Mucosa can be involved • Onycholysis • No pruritus • Malaise, anorexia, fever, chills, nausea, vomiting, diarrhea Course • Remits quickly post-partum  • Recurs with subsequent pregnancies, menses and OCP’s • Fetus at risk for placental insufficiency Laboratory • Hypocalcemia • Leukocytosis • Elevated ESR • Pustule culture negative Treatment • Prednisolone 80 mg/d → decreases mortality risk for mother • Treat hypocalcemia • May require early delivery 4.50 Pruritus Pathophysiology • The only peripheral tissue from which itch evoked is skin, with the exception of the cornea • The C and A delta fibers in the uppermost skin unique in their ability to produce itch • Histamine produces itch via the H1 receptor Report a Problem/Feedback General Dermatology  149
  • 159. • Other substances that produce itch: papain, trypsin, serotonin, bradykinin, kallidin, kallikrein, substance P and VIP • Prostaglandins exaggerate existing itch • Opiates have both central and peripheral itch-producing action Conditions that Cause Pruritis Chronic Renal Disease • Affects 80% of those on dialysis • Dialysis causes temporary relief • Emollients, antihistamines ineffective • Antihistamines rarely work • Secondary hyperparathyroidism is an occasional cause of uremic pruritus • Increased population of mast cells in skin • UV phototherapy may benefit Cholestasis • High level of bile salts, and cholestyramine causes symptomatic improvement Endocrine Disease • Thyrotoxicosis – often due to increased skin blood flow which raises skin temperature • Hypothyroidism – pruritus secondary to the dry skin of myxedema • Postmenopausal pruritus may be generalized or localized, usually in anogenital area Malignancy • Most common association: Hodgkin’s disease and polycythemia vera Polycythemia Vera  •  50% have water-induced pruritus; referred to as “bath itch” or aquagenic pruritus • May precede development of PV by years • Itch is independent of temperature of water HIV Infection • Increased itching secondary to scabies, pediculosis, candidiasis, or seborrheic dermatitis, or renal/hepatic dysfunction • Eosinophilic folliculitis • Pruritus of HIV • May respond to UVB, PUVA, or dapsone Workup of Generalized Pruritus • Physical exam, including pelvic and rectal • CBC • Stool for O&P, occult blood  • CXR • Thyroid, renal, and liver function tests • Drug history 4.51 SCLEREDEMA Clinical Manifestations • Skin involvement may be preceded by prodrome of low-grade fever, malaise, myalgia, arthralgia • 65% develop infection usually of streptococcal origin a few days to 6 weeks before onset 150  2013/2014 Dermatology In-Review l Committed to Your Future Report a Problem/Feedback
  • 160. • Marked, nonpitting, symmetric induration of the skin • Affects posterior and lateral aspects of neck, spreads to face, shoulders, back, arms, and thorax • Induration is waxy white or shiny, and diffuse without sharp demarcation between involved and uninvolved areas Laboratory Findings • Increase in ASO titer in some patients • Glucose tolerance test may be warranted • Hyperinsulinemia may be present Pathogenesis  • Unknown • Syndrome of long duration, obesity, adult onset, and latent or overt diabetes associated with cardiovascular disease noted • Dermis markedly increased in size with increase in hydroxyproline and hexosamines • Association with monoclonal gammopathy, IgG type Treatment • None Course and Prognosis • Spontaneously resolves in 6 months to 2 years • 25% show no resolution, especially in those with DM Table 4-4. Monoclonal Gammopathy and Disease Associations Type IgA EED, pyoderma ganrenosum, subcorneal pustular dermatosis, IgA pemphigus, POEMS, Sweet’s syndrome IgM Schnitzler syndrome, Waldenstrom macroglobulinemia IgG  Disease NXG (IgG κ), scleredema (IgG κ > λ), scleromyxedema (IgG λ > κ) 4.52 Nephrogenic fibrosing dermopathy (Nfd)/ nephrogenic systemic fibrosis (nsf) Pathogenesis • Occurs in patients with renal insufficiency who have had imaging studies with gadolinium Clinical Manifestations • Induration, thickening, hardening of skin with brawny hyperpigmenting • Flexion contractures, stiffening of the hands • Pain, pruritus common • Extremities most commonly involved, then trunk • Affected skin is shiny, with peau d’orange appearance Treatment • Extracorporeal pholophoresis • Limited options • Increased morbidily/mortality because of contractures, mobility problems, falls, and fractures • Prognosis Report a Problem/Feedback General Dermatology  151
  • 161. References 1. Freedberg IM, Eisen AZ, Wolff K, et al., eds. Fitzpatrick’s dermatology in general medicine. 5th ed. New York: McGraw-Hill, Health Professions Division, 1999. 2. Ingham E et al. Proinflammatory levels of interleukin-1 alpha-like bioactivity are present in the majority of open comedones in acne vulgaris. J Invest Dermatol. 1992; 98: 895-901. 3. Kim J et al. Activation of toll-like receptor 2 in acne triggers inflammatory cytokine responses. J Immunol. 2002; 169:1535-1541. 4. Wolf JE. Potential anti-inflammatory effects of topical retinoids and retinoid analogues. Adv Ther 2002; 19:109-118. 5. Odom, RB. Andrews’ diseases of the skin, 9th ed. Philadelphia: WB Saunders, 2000; 96. 6. Goldstein SM and Wintroub BU, Adverse cutaneous reactions to medications. Baltimore: Williams and Wilkins, 1996; 55-57. 7. Wolverton, SE. Comprehensive dermatologic drug therapy. Philadelphia: WB Saunders, 2001; 277. 8. Wolverton, SE. Comprehensive dermatologic drug therapy. Philadelphia: WB Saunders, 2001; 41. 9. Elder D et al. Lever’s histopathology of the skin, 8th ed. Philadelphia: Lipincott Raven, 2001; 295. 10. Webster GF et al. Suppression of polymorphonuclear leukocyte chemoactic factor production in Propionibacterium acnes by subminimal inhibitory concentrations of tetracycline, ampicillin, minocycline and erythromycin. Antimicrob agents chemother. 1982; 21:770-772. 11. Wolverton, SE. Comprehensive dermatologic drug therapy. Philadelphia: WB Saunders, 2001; 872. 12. Archer JS, Archer DF. Oral contraceptive efficacy and antibiotic interaction: a myth debunked. J Amer Acad Dermatol. 2002 June; 46 (6): 917-23. 13. Wolverton, SE. Comprehensive dermatologic drug therapy. Philadelphia: WB Saunders, 2001; 277. 14. Jick SS et al. Isotretinoin use and risk of depression, psychotic symptoms and attempted suicide. Arch Dermatol 2000; 136: 1231-1236. 15. Wolverton, SE. Comprehensive dermatologic drug therapy. Philadelphia: WB Saunders, 2001: 396. 16. Baran R and Tosti A. Nails. ­ ermatology in General Medicine, 5th Edition. New York, McGraw-Hill, 1999, p D 757-759. 17. Kavanaugh A. Flare of psoriasis and psoriatic arthritis following treatment with granulocyte colony stimulating factor. Am J Med 1996; 101(5): 567-8. 18. Partsch G et al. Highly increased levels of tumor necrosis factor alpha and other proinflammatory cytokines in psoriatic arthritis synovial fluid. J Rheumatol 1197; 24(3): 518-23. 19. Odom, RB. Andrews’ diseases of the skin, 9th Edition. Philadelphia: WB Saunders, 2000; 220. 20. Rapp SR et al. Psoriasis causes as much disability as other major medical diseases. J Am Acad Dermatol. 1999; 41: 401-407. 21. Elder D et al. Lever’s Histopathology of the Skin, 8th ed. Philadelphia: Lipincott Raven, 1997; 169. 22. Bach JF, The effect of infections on susceptibility to autoimmune and allergic diseases. N Engl J Med 2002; 347 (12); 911-920. 23. Boner A, Valetta E, Bellanti JA. Improvement of atopic dermatitis following nature measles virus infection: Four case reports. Ann Allerg 1985; 55:605-608. 24. Ong PY et al. Endogenous antimicrobial peptides and skin infections in atopic dermatitis. N Engl J Med 2002; 347 (15); 1151-1159. 25. Kalliomaki M et al. Probotics in primary prevention of atopic disease: A randomized placebo controlled trial. Lancet. 2001; 357: 1076-9. 26. Cerroni L, Kerl H. B cell lymphomas of the skin. In Bolognia JL, et al., Eds. Dermatology. Mosby: London, 2003: 1497. 27. Fairley J. Cacifying and ossifying diseases of the skin. In Bolognia JL. et al., Eds. Dermatology. Mosby: London. 2003: 692-3. 28. Callen JP, Wortman RL. Dermatomyositis. Clinical Dermatolo. Sept-Oct 2006; 24(5) 363-73. 29. Cowper SE, Kuo PH, Bucala R. Nephrogenic systemic fibrosis and gadolinium exposure: association and lessons for idiopathic fibrosing disorders. Arthritis Rheun. Oct 2007; 56(10):3173-5. 152  2013/2014 Dermatology In-Review l Committed to Your Future Report a Problem/Feedback
  • 162. NOTES Report a Problem/Feedback General Dermatology  153
  • 163. NOTES 154  2013/2014 Dermatology In-Review l Committed to Your Future Report a Problem/Feedback
  • 164. 5 Dermatopathology Christine J. Ko, MD C o n t e n t s 5.1 Normal Skin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 157 5.2 Stains . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 158 5.3 Immunohistochemistry . . . . . . . . . . . . . . . . . . . . . . . . . 159 5.4 Acantholytic Disorders . . . . . . . . . . . . . . . . . . . . . . . . . 160 5.5 Adnexal/Epithelial Neoplasms . . . . . . . . . . . . . . . . . 162 5.6 Alopecias . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 170 5.7 Bullous Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 170 5.8 Cysts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 171 5.9 Deposition Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . 173 5.10  Drug Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 175 5.11  Fat Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 176 5.12 Fibrous/Fibrohistiocytic Disorders . . . . . . . . . . . . . 177 5.13 Genodermatoses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 181 5.14 Granulomatous Disorders . . . . . . . . . . . . . . . . . . . . . . 182 5.15 Histiocytoses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 182 5.16 Infections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 184 5.17 Inflammatory . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 188 5.18 Lymphomas and Markers . . . . . . . . . . . . . . . . . . . . . . 194 5.19  Melanocytic Lesions . . . . . . . . . . . . . . . . . . . . . . . . . . . 197 5.20 Muscle . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 200 5.21 Neural . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 201 5.22 Pagetoid Spread . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 203 5.23 Palisading Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . 204 5.24 Vascular . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 205 5.25 Miscellaneous . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 208 5.26 Clues for Board Purposes . . . . . . . . . . . . . . . . . . . . . . 212 5.27 “Bodies” . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 214 Report a Problem/Feedback Dermatopathology  155
  • 165. 5.1 NORMAL SKIN Apocrine Glands • Decapitation secretion • Found in axillae, anogenital, external ear canal (ceruminous), eyelid (Moll’s), breast (mammary) • Apocrine glands have an inner layer of secretory cells that vary in height and demonstrate “snouts” of apocrine secretion with a layer of myoepithelial cells surrounding the glands • Stain with gross cystic disease fluid protein 15 (GCDFP-15) u TIP • Also stain with keratin AE1 (stains ducts), CAM 5.2, EMA aeen ectopically in nevus S sebaceus (a nice clue) Eccrine Glands • Merocrine secretion • Eccrine glands are composed of one distinct layer of cells with 2 populations, clear cells and darker cells; myoepithelial cells surround glands, but are often difficult to appreciate • Stain with S100, CEA, CAM 5.2 u TIP a resent all over the body P except on vermilion of lips, glans, labia minora, nail beds, inner prepuce Sebaceous Glands • Holocrine secretion M  •   eibomian and Wolf (on eyelid), Fordyce (on vermilion, oral/mucosae), Tyson (on penis), Montgomery (on nipple) Hair Follicle • Infundibulum = portion above insertion of sebaceous duct; identical to normal epidermis in keratinization pattern • Isthmus = portion between insertions of sebaceous duct and arrector pili; trichilemmal keratinization • Lower portion = from arrector to the base of follicle u TIP • Inner root sheath not present at isthmus a ayers of the lower portion (from L • Epidermis and infundibulum undergoes keratinization with outer to inner): fibrous root sheath, keratohyaline granules (basophilic); outer root sheath glassy/vitreous layer, outer root sheath, inner root sheath (Henle, undergo trichilemmal keratinization (without forming Huxley, cuticle of inner root sheath), granules) in the isthmus; lower part of the follicle’s inner hair cuticle, hair cortex, hair medulla root sheath undergoes keratinization with trichohyaline granules (eosinophilic); hair keratinizes without forming granules and forms hard keratin Nail Bed • Expresses keratin 6, 16, 17 u TIP an pachyonychia congenita type I 6a/16 (Jadassohn-Lewandowsky), keratins 6a and 16 are mutated an pachyonychia congenita type I 6b/17 (Jackson-Lawler), keratins 6b and 17 are mutated, and patients have multiple steatocysts Report a Problem/Feedback Dermatopathology  157
  • 166. 5.2 STAINS Bodian • Nerve fibers black Feulgen • DNA magenta Fontana Masson • Melanin Foote’s or Snook’s • Reticulin fibers black Giemsa • Mast cell granules purple (it is the heparin in the mast cells that is staining) • Leishmania Leder • Mast cell granules red Masson Trichrome • Collagen blue/green, muscle/nerve/keratin red Methyl-green Pyronin • RNA pink, DNA green Perls (Prussian Blue) • Iron/hemosiderin bright blue PTAH (Phosphotungstic Acid Hematoxylin) • Stains fibrin u TIP a  tains the inclusions in S infantile digital fibromatosis For Amyloid • Congo red (stains red, green birefringence on polarization) • Crystal violet (more specific; stains purple) • Thioflavin T (fluoresces green-blue) • Acid orcein Giemsa (stains sky blue) For Bacteria • McCallum-Goodpasture • Brown-Brenn • Brown-Hopps • Ziehl-Neelsen and Fite-Faraco for acid-fast bacteria For Calcium • Von Kossa (blue-black) • Alizarin red (red) • Pentahydroxy flavanol (fluoresces) • Aldehyde fuchsin (brown) 158  2013/2014 Dermatology In-Review l Committed to Your Future Report a Problem/Feedback
  • 167. For Elastic Tissue • Verhoeff von Gieson (blue-black) • Gomori’s aldehyde-fuchsin (purple) • Orcein-Giemsa (black) For Fat (Need Fresh/Frozen Tissue) • Scarlet red • Oil red O • Sudan black (also stains lipofuscin) • Osmium tetroxide (differentiates animal fat from mineral oil) For Fungi • PAS • GMS (Gomori methenamine silver) For Mucin/Mucopolysaccharides (MPS) • Alcian Blue 2.5 (blue) - acid MPS • Alcian Blue 0.5 (blue) - sulfated MPS • Colloidal iron (blue) - acid MPS • Mucicarmine (pink) • Toluidine blue (blue) - acid MPS For Mycobacteria • Ziehl-Neelsen • Fite-Faraco For Nerve Fibers • Bodian (nerve fibers black) • PGP 9.5 • Neurofilament For Ochronosis • Cresyl violet or methylene blue stains the pigment black For Spirochetes • Silver stains like Warthin Starry or Dieterle or Steiner 5.3 IMMUNOHISTOCHEMISTRY Table 5-1. Commonly Used Immunohistochemical Stains Antigen Major Targets Cytokeratin (AE1/AE3, 34BE12, MNF116, 5/6, etc.) NORMAL: Epidermis and adnexal epithelium USEFUL FOR: Squamous cell carcinoma S-100 protein NORMAL: Melanocytes, Langerhans cells, eccrine glands, chondrocytes, adipose tissue, nerves USEFUL FOR: Melanoma, adnexal tumors, neural tumors HMB-45 NORMAL: Melanocytes USEFUL FOR: Some melanomas, nevi Report a Problem/Feedback Dermatopathology  159
  • 168. Table 5-1. Commonly Used Immunohistochemical Stains (cont) Antigen Major Targets MelanA/MART-1 NORMAL: Melanocytes USEFUL FOR: Melanoma, some nevi Mel-5 NORMAL: Melanocytes USEFUL FOR: Some melanomas/nevi, vitiligo Vimentin NORMAL: Tissue with mesenchymal derivation USEFUL FOR: Atypical fibroxanthoma, sarcomas, melanomas, some squamous cell carcinomas Desmin NORMAL: Smooth/skeletal muscle USEFUL FOR: Muscle tumors Smooth muscle actin (SMA) NORMAL: Smooth muscle, myofibroblastic cells USEFUL FOR: Smooth muscle tumors, some atypical fibroxanthomas Carcinoembryonic antigen (CEA) NORMAL: Eccrine/apocrine glands USEFUL FOR: Adnexal tumors, Paget’s disease of the breast, extramammary Paget’s Epithelial membrane antigen (EMA) NORMAL: Sebaceous, eccrine, apocrine glands USEFUL FOR: Sebaceous tumors, squamous cell carcinoma, epithelioid sarcoma, systemic (nodal) anaplastic large cell lymphoma Neuron-specific enolase (NSE) NORMAL: Non-specific neuroendocrine marker USEFUL FOR: Merkel cell carcinoma Chromogranin NORMAL: Neuroendocrine cells USEFUL FOR: Merkel cell carcinoma Synaptophysin NORMAL: Neuroendocrine cells USEFUL FOR: Merkel cell carcinoma Cytokeratin 20 NORMAL: Neuroendocrine cells USEFUL FOR: Merkel cell carcinoma, trichoepithelioma Factor VIII-related Antigen NORMAL: Endothelial cells, platelets, megakaryocytes USEFUL FOR: Vascular tumors CD34 NORMAL: Endothelial cells, stem cells USEFUL FOR: Dermatofibrosarcoma protuberans, vascular tumors Factor XIIIa NORMAL: Dermal dendrocytes USEFUL FOR: Dermatofibroma Cytokeratin 5/6 P63 NORMAL: Epithelial cells P63 USEFUL FOR: Primary cutaneous adnexal tumors; negative in metastatic adenocarcinomas TTF-1 NORMAL: Thyroid tissue USEFUL FOR: Lung carcinoma; negative in Merkel cell carcinoma 5.4 ACANTHOLYTIC DISORDERS Darier’s Disease (Keratosis Follicularis) • Column of parakeratosis above a focus of acantholytic dyskeratosis (corps ronds and grains) u TIP a utosomal dominant, ATP2A2 gene that encodes the A sarcoplasmic/endoplasmic reticulum Ca2+ ATPase (SERCA) 160  2013/2014 Dermatology In-Review l Committed to Your Future Report a Problem/Feedback
  • 169. Grover’s Disease • Often smaller foci than those in Darier’s, without the column of parakeratosis Hailey-Hailey • “Full-thickness acantholysis,” the so-called dilapidated brick wall, although sometimes the upper layers of the epidermis are not acantholytic u TIP aAutosomal dominant, ATP2C1 gene Paraneoplastic Pemphigus Figure 5-1. Darier’s Disease • Clinical presentation is with intractable oral u TIP for Grover's ulcers/erosions, conjunctivitis, target-like lesions a ften there are several foci of acantholytic dyskeratosis, O (EM-like) sometimes with different patterns in different foci, for example, one focus that appears more spongiotic with • Suprabasilar acantholysis (like PV) and EM-like another that looks like PV and another that looks like changes (necrotic keratinocytes and vacuolar Darier's or Hailey-Hailey or superficial pemphigus change of the basal layer) u TIP antercellular and linear DEJ antibodies against desmoplakins I (250 kDa, 230 kDa bullous pemphigoid antigen 1), envoplakin (210 kDa), periplakin (190 kDa), 170 kDa antigen, PV Ag (130 kDa) Pemphigus Foliaceus (PF) • Intraepidermal acantholytic blister, through the subcorneal/granular layer, granular cells often appear more prominent • Differential includes bullous impetigo, subcorneal pustular dermatosis, pemphigus erythematosus • Clues to PF rather than bullous impetigo are “cling-ons,” which are acantholytic cells that are still attached to the stratum corneum on the roof of the blister, and less neutrophils in the blister cavity •  Intercellular antibodies against desmoglein 1,  160 kDa Figure 5-2. Hailey-Hailey Pemphigus Vegetans • Variant of pemphigus vulgaris  •  Marked hyperplasia of the epidermis with characteristic eosinophilic abscesses, acantholysis may be minimal Figure 5-3. Pemphigus Foliaceus Report a Problem/Feedback Dermatopathology  161
  • 170. Pemphigus Vulgaris (PV) • Intraepidermal acantholytic suprabasal blister, non-dyskeratotic, with tombstoning of the basal layer  •  Acantholysis extends down adnexae, unlike in Hailey Hailey  •  Intercellular antibodies against desmoglein  3, 130 kDa Squamous Cell Carcinoma, Adenoid Type • Also called acantholytic SCC • Because of dyskeratosis and subsequent acantholysis, SCC’s may show tubular and alveolar formations on histology; often, an AK of the acantholytic type is seen overlying the lesion Figure 5-4. Pemphigus Vegetans Warty Dyskeratoma • Can look exactly like Darier’s, but ideally it is a larger lesion (solitary clinically) that sometimes has a cyst-like architecture 5.5 ADNEXAL/EPITHELIAL NEOPLASMS Acrospiroma • Includes hidroacanthoma simplex (located intraepidermally) (see Figure under Hidroacanthoma Simplex), poroma, dermal Figure 5-5. Warty Dyskeratoma duct tumor, hidradenoma (deeper dermis) • Poroma: Uniform blue cells coming off in a plate-like fashion off of the epidermis, ductal areas within • Hidradenoma: Variable composition of poroid, squamoid, clear cells with ductal areas; may be solid and/or cystic; based in deeper dermis Adenoid Cystic Carcinoma • Also fairly characteristic pattern • Cribriform pattern of epithelium and ductal areas Clear Cell Hidradenoma (Eccrine Hidradenoma, Eccrine Acrospiroma, Nodular Hidradenoma, Solid-cystic Hidradenoma) • Large, circumscribed, but not encapsulated • Occasionally connects to overlying epidermis or extends into subcutis • Biphasic cellular population: round cells with eosinophilic cytoplasm and oval vesicular nucleus or cells with clear cytoplasm with small dark eccentrically located nucleus Figure 5-6. Adenoid Cystic Carcinoma 162  2013/2014 Dermatology In-Review l Committed to Your Future Report a Problem/Feedback
  • 171. • May contain some ducts; characteristic hyaline stroma; important to distinguish variants with a predominance of clear cells from metastatic renal cell carcinoma Cylindroma • Thought to be apocrine in origin • Upper dermis without connection to overlying epidermis • Multiple, puzzle-like lobules in jigsaw or mosaic pattern, each lobule has basement membrane (PAS positive, dense pink stroma) around it  • CYLD gene  •  Brooke-Spiegler syndrome: multiple  trichoepitheliomas, cylindromas, spiradenomas Figure 5-7. Clear Cell Hidradenoma Desmoplastic Trichoepithelioma • Quite different from conventional trichoepithelioma • Slight indentation of the epidermis; small areas look like syringomas • Narrow epithelial strands embedded in dense collagenous stroma, horn cysts, calcification frequently seen, symmetric; rounded base • Doesn’t penetrate like morpheaform BCC; lots of horn cysts and calcium deposits; no retraction artefact; has CK20-positive cells Figure 5-8. Desmoplastic Trichoepithelioma Dilated Pore of Winer • Keratin-plugged, cystically dilated hair follicle, usually superficial, but can extend into subcutaneous fat • Lined by acanthotic epithelium, with buds of proliferation extending away as irregular strands Fibrofolliculoma • Loose stroma around hair follicles with reticulated, thin strands of epithelium radiating from follicles • On a spectrum with trichodiscoma • Seen in Birt-Hogg-Dubé syndrome Report a Problem/Feedback Dermatopathology  163
  • 172. Fibroepithelioma of Pinkus • Polypoid shape; basaloid epithelial strands, 2-3 cells thick, arising from many foci along the epidermis and anastomosing to compartmentalize the fibrous stroma Hidradenoma Papilliferum • Vulvar area • Well-demarcated nodule in dermis and may be continuous with overlying epithelium • Papillated projections into cystic spaces, decapitation secretion Hidroacanthoma Simplex (Intraepidermal Poroma) Figure 5-9. Fibroepithelioma of Pinkus • Hyperkeratosis with acanthosis • Epidermis shows discrete collections of regular tumor cells that resemble those of an eccrine poroma • Tumor cells can be spindle shaped also; the dermis is unaffected Inverted Follicular Keratosis • Endophytic with whorls of maturing squamous epithelium (squamous eddies) near hair follicle ostium; some lesions contain horn cysts; no koilocytes Irritated Seborrheic Keratosis • Characteristic squamous eddies of eosinophilic squamous cells in a downward proliferation (endophytic) with minimal to mild inflammation at the base • Some say that this is the same as an inverted follicular keratosis Figure 5-10. Hidradenoma Papilliferum Keratoacanthoma • Crateriform architecture, symmetric, large central keratin plug, well-formed flanking collarette • Well-differentiated, often pale-staining, eosinophilic, glassy cytoplasm with tendency toward keratinization, no abnormal mitotic figures Figure 5-11. Hidroacanthoma Simplex 164  2013/2014 Dermatology In-Review l Committed to Your Future Report a Problem/Feedback
  • 173. Microcystic Adnexal Carcinoma • “Syringoma gone mad”; grows deep without metastasizing • Round balls (syringoma-like) up high, and more linear and cord-like down low • Numerous small to medium-sized squamous microcysts, superficially located, and solid strands of cells, many with ductular lumina, dense fibrous stroma surrounds all components and is more sclerotic in infiltrative areas • Perineural invasion frequently observed Mixed Tumor of the Skin (Chondroid Syringoma) • Areas that look like cartilage with ductal/adnexal structure-like cords/ strands of cells • Multilobulated within deep dermis and/or subcutaneous fat • Abundant stroma with basophilic pseudocartilaginous appearance • Lobules separated by fibrous septa • Nests and cords of cuboidal cells with copious eosinophilic cytoplasm and basophilic nuclei, tubuloalveolar structures lined by two or more rows of epithelial cells Figure 5-12. Inverted Follicular Keratosis Morpheaform Basal Cell Carcinoma (BCC) • Thin cords of basaloid cells, getting thinner as the cords go deeper; some retraction artefact may be present • Haphazard downward growth that infiltrates • Can resemble desmoplastic trichoepithelioma, but often infiltrates deeper into the dermis •  Bcl-2 stains BCCs diffusely •  Generally absent CK20-positive cells Figure 5-13. Mixed Tumor of the Skin Mucinous Carcinoma • Dermal tumor that may extend into subcutaneous fat, with very characteristic, “floating” compartmentalized islands of tumor cells suspended in a lake of mucin Report a Problem/Feedback Figure 5-14. Nevus Sebaceus of Jadassohn Dermatopathology  165
  • 174. • Tumor cells are sometimes vacuolated with eosinophilic cytoplasm and small hyperchromatic nuclei  • MUST rule out metastatic cancer Nevus Sebaceus of Jadassohn  • Epidermal acanthosis and papillomatosis • Foci of abortive hair papillae • Sebaceous glands located abnormally high in dermis, opening directly onto surface, and can appear unrelated to hair follicle • Has a different look pre-pubertal (smaller sebaceous glands) and post-pubertal (larger sebaceous glands) • A clue is apocrine glands in the reticular dermis • Tumors can arise within nevus sebaceus, with trichoblastoma thought to be the most common, followed by syringocystadenoma papilliferum Figure 5-15. Pilomatricoma Pilomatricoma (Calcifying Epithelioma of Malherbe) • Basaloid blue cells (matrical cells) and pale pink amorphous areas that on higher power have “shadows” of nuclei (shadow cells), areas of calcification or sometimes ossification  • Mutations found in beta-catenin PEARL Figure 5-16. Proliferating Trichilemmal Tumor w ultiple pilomatricomas seen in M  Rubinstein-Taybi, Gardner’s (cyst-like pilomatricomas), Turner’s, sarcoidosis, sternal cleft and coagulation defects, myotonic dystrophy (Steinert’s) Proliferating Trichilemmal Tumor • Looks like a pilar cyst gone wild • Lobulated intradermal mass of squamous epithelium • Individual lobules with sharply defined and non-infiltrating border • May be surrounded by a thickened basement membrane Figure 5-17. Sebaceous Adenoma 166  2013/2014 Dermatology In-Review l Committed to Your Future Report a Problem/Feedback
  • 175. • Striking peripheral palisading of lobule edges • Tricholemmal keratinization with absent granular layer Sebaceous Adenoma • Lobules of sebocytes with rims of basal cells • May replace surface epithelium • Individual lobules mirror structure of normal sebaceous gland, periphery of lobule shows small germinative cells with scanty cytoplasm • >50% lobule contains mature sebaceous cells • Sebaceous epitheliomas are more asymmetric and disorganized with >50% of cells being basaloid germinative cells • If there are mitoses, an infiltrative growth pattern, and atypical cells, think of sebaceous carcinoma  Figure 5-18. Spiradenoma • Associated with Muir-Torre syndrome Spiradenoma • “Blue balls in the dermis” (no epidermal connection) → tumor lobules in dermis and occasionally into subcutaneous fat • Lobules are intensely basophilic with cells arranged in intertwining cords, dark and light cells  • A clue is focal pockets of hyaline material within the cellular areas and lymphocytes peppering the islands • Now thought to be apocrine Figure 5-19. Syringocystadenoma Papilliferum Syringocystadenoma Papilliferum • Papillated tumor with abundant plasma cells in the stroma • Invagination from overlying epidermis • Double-layered epithelium with outer zone of small cells and inner zone of tall columnar cells • May show decapitation secretion Report a Problem/Feedback Dermatopathology  167
  • 176. Syringoma • Duct-like “tadpoles” and cords of peripheral blue cells around central clear cells in a fibrous stroma • Increased incidence in patients with  Down’s   • Clear-cell variant is associated with diabetes Trichilemmoma  • Proliferation of outer root sheath • Small solitary lobule or group of lobules connected to epidermis with vertical growth • Peripheral palisading of lobules • Many of the tumor cells contain glycogen and have a clear cell appearance (PASpositive) • Thickened basement membrane • Multiple ones seen in Cowden’s Figure 5-20. Syringoma Trichoadenoma • In dermis, numerous horn cysts surrounded by eosinophilic epithelium • Well-defined fibroepithelial tumor composed of horn cysts and conspicuous fibrovascular stroma • Scattered islands of tumor cells • Midway between a trichoepithelioma and a trichofolliculoma in terms of differentiation Trichoblastoma Figure 5-21. Trichilemmoma • More primitive than trichoepithelioma; usually lacks horn cysts • Features similar to trichoepithelioma, but centered in mid dermis and can involve subcutaneous fat • Lobules of basaloid cells intimately associated with conspicuous fibromyxoid stroma • Clue is the papillary mesenchymal body, which resembles a very early hair bulb (follicular germ) surrounded by loose spindle cells, although this can be seen in trichoepitheliomas Figure 5-22. Trichoadenoma 168  2013/2014 Dermatology In-Review l Committed to Your Future Report a Problem/Feedback
  • 177. Trichodiscoma • Flattened epidermis, with lateral collarette • Unencapsulated, elliptical, loosely woven admixture of collagen, reticulin, and thin elastic fibers • Always topographically related to hair follicle • Seen in Birt-Hogg-Dubé; on a spectrum  with fibrofolliculoma Trichoepithelioma • Numerous horn cysts both in dermis and within lobules of basaloid cells, tumor cells indistinguishable from those of BCC, showing peripheral palisading, perilobular connective tissue sheath more conspicuous (more fibrotic) and associated with formation of papillary mesenchymal bodies (primitive hair bulbs), foreign body giant cell reaction to free keratin, clefts between stroma and stroma, and no clefts between cells and stroma Figure 5-23. Trichoepithelioma PEARL w R  asmussen's syndrome: multiple trichoepitheliomas, cylindromas, and milia w  Rombo syndrome: multiple trichoepitheliomas, milia, vermiculate atrophy, BCC, peripheral vasodilation and cyanosis Trichofolliculoma Figure 5-24. Trichofolliculoma • Dilated hair follicle (cystic cavity) with granular layer and containing keratinous debris and hair shaft fragments • Arises from surface epithelium • Numerous hair follicles arise from its wall, each surrounded by a clearly defined perifollicular sheath • Clinically has one or more silky white hairs extending out from lesion Verrucous Carcinoma • “Condyloma gone wild”; takes up one-half the size of the slide • Acanthotic papillary processes with massive hyperkeratosis and often parakeratosis • Endophytic component has well-differentiated squamous epithelium growing down into the underlying tissues as deeply penetrating, bulbous processes showing a characteristic “pushing” margin (in contrast to the infiltrative border of an ordinary SCC) • Keratinization is massive, with accompanying sinuses; no cytologic atypia Report a Problem/Feedback Dermatopathology  169
  • 178. 5.6 ALOPECIAS Alopecia Areata • Peribulbar lymphohistiocytic infiltrate around anagen follicles near dermal/ subcutaneous junction (“swarm of bees”) • There may be increased catagen hairs and miniaturized hairs Androgenetic Alopecia • Scalp skin • Many follicles show diminished size (miniaturization) • Little inflammation Discoid Lupus Erythematosus Figure 5-25. Discoid Lupus Erythematosus • Scalp skin often • Epidermal atrophy, follicular plugging, dense lymphohistiocytic periadnexal infiltrate, area of scarring • Vacuolar change at DE junction • Basement membrane thickening • Mucin between collagen bundles • Pigmentary incontinence Lichen Planopilaris • Focally dense perivascular and periadnexal lymphohistiocytic infiltrate • Focal areas of hypergranulosis, keratin plugging, vacuolar changes of basal layer of the follicular epithelium • Advanced disease shows fibrous scars vertically oriented • Adjacent interfollicular epithelium may show typical lichenoid infiltrate • Basal cell hydropic degeneration may or may not be present • Differential diagnosis is LE, which would not show normal epidermis between the follicles Pseudopelade of Brocq • Presence of normal epidermis and reduced numbers or absence of sebaceous glands • No evidence of inflammatory folliculitis • Vertically-oriented fibrous scarring replaces hair follicles, with arrector pili still attached Trichotillomania • Trichomalacia → hair shafts fragmented, bent, and distorted • Pigmented casts 5.7 BULLOUS DISORDERS Bullous Pemphigoid (BP) u TIP aA clue to early BP is eosinophilic spongiosis and eosinophils lined up along the DEJ • Subepidermal separation with eosinophils (but sometimes there is re-epithelialization at the base, so the blister can look intraepidermal) • A clue to early BP is eosinophilic spongiosis and eosinophils lined up along the DEJ • Rarely BP can be neutrophilic or “cell-poor” (non-inflammatory) 170  2013/2014 Dermatology In-Review l Committed to Your Future Report a Problem/Feedback
  • 179. • Linear IgG and C3 at the DEJ on direct immunofluorescence (DIF) • Two antigens: Bullous pemphigoid antigen-1 (BPAg-1) (230 kDa) and Bullous pemphigoid antigen-2 (BPAg­ 2) (180 kDa); the BPAg-2 is thought to be the pathogenic antigen • Herpes gestationis can be indistinguishable from BP on biopsy but on DIF has linear C3 and less commonly IgG Cicatricial Pemphigoid (CP) • Sparse inflammation, subepidermal separation, scarring of papillary dermis • Look for plasma cells to indicate a mucosal surface • Anti-epiligrin CP is associated with malignancy, especially adenocarcinomas (epiligrin is another name for laminin 5) Dermatitis Herpetiformis uTIP • DIF shows granular IgA in dermal papillae aClue is neutrophils clustered in dermal • Linear IgA disease (or chronic bullous disease of papillae adjacent to a subepidermal split childhood) can look histologically the same, but DIF shows linear IgA at the DEJ • Differential diagnosis includes bullous SLE, EBA, neutrophil-rich BP, cicatricial pemphigoid Epidermolysis Bullosa Acquisita (EBA)  • Subepidermal separation • Can look histologically like BP or like DH (with neutrophils) or non-inflammatory • Salt-split skin differentiates EBA from BP • Antibodies to type VII collagen (290 kDa) Porphyria Cutanea Tarda (PCT)  • Subepidermal blister with clean break • Minimal lymphocytic infiltrate, prominent solar elastosis, slightly eosinophilic necrotic keratinocytes, erythrocytes within blister • Festooning of dermal papillae • “Caterpillar bodies” → eosinophilic elongated, wavy structures in lower and midepidermis lying parallel to BM zone • DIF with IgG, IgM, IgA, C3 at DEJ and around vessels • Pseudoporphyria can look histologically exactly like PCT 5.8 CYSTS Apocrine Hidrocystoma • The cyst lining shows apocrine-type decapitation secretion • Fibrous pseudocapsule • Lined by a double layer of epithelial cells: outer flattened vacuolated myoepithelial cells, and inner tall columnar cells • Unilocular or multilocular Report a Problem/Feedback Figure 5-26. Apocrine Hidrocystoma Dermatopathology  171
  • 180. Branchial Cyst • Most common site is along the side of the neck • The cyst lining is stratified squamous or pseudo-stratified columnar with cilia • Prominent lymphoid follicles deep to the wall Bronchogenic Cyst • Majority present on precordium or suprasternal • In dermis or subcutis, epithelial lining thrown into folds → pseudostratified cuboidal or columnar and ciliated with mucus secreting goblet cells, which distinguish this cyst from others Cutaneous Ciliated Cyst • Majority present on the thighs of women • Epithelial lining is cuboidal or columnar with cilia on the surface and collagen/vessels deep to the wall Dermoid Cyst • Most common site is the lateral eyebrow area • The epithelial lining is stratified squamous with adnexal structures (hair follicles, sebaceous glands, eccrine/apocrine glands) Epidermoid Cyst (Infundibular Cyst) • Punctum usually present, unilocular and spherical, lined by epidermis-like epithelium with a granular layer • Rupture associated with a foreign body granulomatous reaction Median Raphe Cyst • Majority present on the ventral penis; sometimes ventral scrotum or perineum • Epithelial lining pseudostratified columnar +/- mucinous cells Pilar (Trichilemmal) Cyst • Fibrous capsule surrounding layer of dark-staining basal cells • Keratinization without granular layer, most superficial cyst cells are larger with more abundant cytoplasm • Cholesterol clefts seen in most lesions, and some show calcification Steatocystoma • The keratin inside the cyst can resemble the keratin of an epidermal inclusion cyst, but the lining of the cyst is more corrugated with a bright pink ribbonlike surface; sebaceous glands are seen connecting to or adjacent to the wall  • Multiple steatocysts associated with pachyonychia congenita type 6b/17 (Jackson-Lawler) Figure 5-27. Steatocystoma 172  2013/2014 Dermatology In-Review l Committed to Your Future Report a Problem/Feedback
  • 181. Thyroglossal Duct Cyst • Cyst lining is stratified squamous or pseudostratified cuboidal/columnar +/cilia • Deep to the wall are mucous glands, thyroid follicles, lymphocytic infiltrate Vellus Hair Cysts • Mid-dermal cyst with follicular lining, containing laminated keratin and many vellus hairs 5.9 DEPOSITION DISORDERS Calcinosis Cutis • Chunky dark blue material in the dermis • May be idiopathic, dystrophic, or metastatic Figure 5-28. Vellus Hair Cysts Colloid Milium • Deposits generally larger (can extend from the papillary dermis into the reticular) than in macular or lichen amyloidosus, with a cracked/clefted appearance • There may be solar elastosis • Juvenile colloid milium is histochemically indistinguishable from amyloid derived from keratin Focal Cutaneous Mucinosis • Papule or polypoid (unlike pretibial myxedema) • Location shows no thickened stratum corneum • Lesion located in mid and upper dermis Figure 5-29. Calcinosis Cutis Follicular Mucinosis (Alopecia Mucinosis) • Mucinous degeneration of the external root sheath and sebaceous glands, accompanied by variable inflammatory infiltrate • Mucin in the follicle • If associated with mycosis fungoides, may show atypical lymphocytes and Pautrier microabscesses • Mucin stains positive with alcian blue; perifollicular scarring can be a feature Report a Problem/Feedback Dermatopathology  173
  • 182. Macular and Lichen Amyloidosus  • Lichen amyloidosus has a hyperplastic epidermis compared to the macular form • Both conditions have pink globs of material within the papillary dermis high up against the rete •  Associated with MEN IIa Mucocele • On mucous membranes • If intact it can look like a subepidermal vesicle • Often ruptured, so there is light blue material with numerous inflammatory cells and muciphages and granulation tissue • Clue is the presence of salivary glands Figure 5-30. Macular and Lichen Amyloidosus Myxoid Cyst  • Not a true cyst; devoid of lining • Consists of large pool of mucin containing spindle/stellate fibroblasts • Compressed collagen at the periphery • Overlying epithelium is atrophic and hyperkeratotic • Look for acral location • Pool of mucin with spindle cells, often with an epidermal collarette Nodular Amyloid • Deposits of amyloid in papillary and reticular dermis and may involve subcutaneous fat • Plasma cells around blood vessels at margin of amyloid deposits • Amyloid deposits may thicken blood vessel walls • Colloid milium is more focal and involves only the upper dermis Osteoma Cutis • Within the dermis, well-circumscribed nodule of mature lamellar bone, often containing narrow spaces • No ghost cells seen, so don’t confuse with ossified pilomatricoma Papular Mucinosis (lichen myxedematosus) • Collagen fibers widely separated by mucin deposits, increased numbers of fibroblasts • Epidermis may be normal, acanthotic, or atrophic • In scleromyxedema variant, fibroblasts are numerous (increased in number) with consequent fibrosis (increased collagen) and thickening of dermis with mucin • More cellular than pretibial myxedema Pretibial Myxedema • Epidermis often hyperkeratotic with follicular plugging • Dermis shows separation of collagen bundles by large quantities of mucin 174  2013/2014 Dermatology In-Review l Committed to Your Future Report a Problem/Feedback
  • 183.  • Stellate fibroblasts are evident; relatively acellular and non-inflammatory • No increase in fibroblasts • Square biopsy • Associated with Grave’s disease and thyroid acropachy Scleredema  • Reticular dermis greatly thickened, often with loss of subcutaneous fat • Eccrine trapping, broadened collagen fibers • Mucin demonstrated by Alcian blue or colloidal iron stain • Associated with diabetes, streptococcal infection, paraproteinemia Scleromyxedema • Fibroblasts are greatly increased with consequent fibrosis (increased collagen) and thickening of dermis • Mucin is increased • More cellular than pretibial myxedema •  Associated with paraproteinemia, generally IgG lambda • Square biopsy 5.10 DRUG REACTIONS Fixed Drug Eruption • Basketweave stratum corneum • Interface dermatitis • Necrotic epidermis with possible subepidermal blister • Civatte bodies • Superficial and deep lymphohistiocytic infiltrate with scattered eosinophils and neutrophils (before you choose EM, check for eos) • Pigment incontinence with melanophages u TIP a  emember: PLEVA has parakeratosis and lacks R Figure 5-31. Fixed Drug Eruption the eosinophils Lichenoid Drug • Band-like lichenoid infiltrate at the DE junction • Basal cell hydropic degeneration at the basal layer of the epidermis • Presence of eosinophils and parakeratosis u TIP a 3  types: blue-black in scars on the face, blue-gray on legs, muddy-brown on sun-exposed areas; first 2 may be secondary to a drug metabolite-protein complex Minocycline-induced Pigmentation • The blue-black color in scars on the face stains like hemosiderin (Perls-positive) • Blue-gray on legs stains like iron and melanin (stains with Perls and Fontana Masson) • Muddy-brown color on sun-exposed areas shows increased basal melanization and melanophages (probably secondary to phototoxicity) Report a Problem/Feedback Dermatopathology  175
  • 184. Neutrophilic Eccrine Hidradenitis  • Most commonly secondary to chemotherapy, especially cytarabine • On biopsy there is a dense neutrophilic infiltrate around the eccrine glands 5.11 FAT DISORDERS Alpha-1-Antitrypsin Deficiency Panniculitis • Lobular panniculitis • Focal inflammation with large numbers of neutrophils that pour into the dermis • Fat necrosis is common • Loss of elastic tissue on special staining, no vasculitis • Lipid-laden foamy macrophages sometimes evident Angiolipoma • A lipoma with blood vessels • Usually encapsulated, mature adipocytes admixed with anastomosing small blood vessels • Luminal microthrombi always present Erythema Induratum (Nodular Vasculitis) • “Messy-looking,” diffuse process • Nodular granulomatous panniculitis, predominantly lobular with spill over into the fibrous septa • Fat necrosis, with dense neutrophilic infiltrate • Infiltrate consists of neutrophils, lymphocytes, histiocytes, epithelioid cells and giant cells, lipid-laden foamy histiocytes • Vasculitis (often at dermal/SC junction) with endothelial swelling Erythema Nodosum • Septal panniculitis, with widened fibrous septa • Lymphohistiocytic infiltrate with multinucleated giant cells (Touton giant cells), scattered eosinophils • No evidence of either vasculitis or necrosis • Sparse lymphohistiocytic infiltrate also around blood vessels in dermis Hibernoma • Deep benign tumor, resembles normal brown fat Figure 5-32. Erythema Nodosum • “Ping pong balls” stuffed into cells → admixture of mature univacuolated adipocytes and multivacuolated large adipocytes with central nuclei and granular eosinophilic cytoplasm • Highly vascularized septa; don’t mistake for a granular cell tumor • “Mulberry cells” with scalloped nuclei secondary to vacuoles (cells have increased mitochondria) 176  2013/2014 Dermatology In-Review l Committed to Your Future Report a Problem/Feedback
  • 185. Lipodermatosclerosis (Lipomembranous Panniculitis) • Lobular panniculitis • Fatty cysts lined by eosinophilic hyaline membranes that present a “ragged border” → lipomembranous change • Superimposed venous stasis changes in the dermis Lupus Profundus • Overlying epithelium and superficial dermis may show features of DLE, or be unaffected • Within deep dermis and extending into widened septae of subcutaneous fat is a Figure 5-33. Lupus Profundus dense chronic inflammatory cell infiltrate of plasma cells and lymphocytes • Hyaline necrosis of fat with a mostly lobular panniculitis • Lymphoid follicles sometimes present Pancreatic Panniculitis • Lobular panniculitis, fat necrosis with “ghost cells” having no nuclei • Adipocytes contain granular eosinophilic or basophilic (calcified) debris • Neutrophil infiltrate around foci of fat necrosis, hemorrhage, uninvolved surrounding fat is heavily infiltrated by inflammatory cells, some of which are foamy due to ingested lipid, often there are multinucleated giant cells Polyarteritis Nodosa • Septal panniculitis with medium-sized vessel vasculitis • Inflammation tightly localized around vessel • More fibrinous change and thus REDDER than thrombophlebitis Subcutaneous Fat Necrosis of the Newborn  • Intense necrosis • Adipocytes swollen and contain radially arranged eosinophilic crystalline crystals • Heavy inflammatory cell infiltrate including foreign body giant cells • Older lesions may show calcification and fibrosis • Similar findings in post-steroid panniculitis 5.12 FIBROUS/FIBROHISTIOCYCTIC DISORDERS Acrochordon • Normal or hyperplastic epidermis surrounding a core of fibrovascular tissue with loose or dense collagen fibers • Absence of adnexal structures • Fat cells may be present → nevus lipomatosus superficialis Report a Problem/Feedback Dermatopathology  177
  • 186. Acquired Digital Fibrokeratoma • Acral location • Pedunculated and covered by variably acanthotic and hyperkeratotic skin • Core composed of dense collagen fibers oriented in the direction of the vertical axis of the lesion • No nerve bundles and no koilocytes Angiofibroma (Fibrous Papule of the Face, Pearly Penile Papules, Koenen’s Tumor) • Fibrosis, sometimes in an “onion-skin” pattern around vessels • Scattered stellate fibroblasts and increased vascularity • Localized area of fibroplasia and vascular proliferation in the upper dermis • Hypocellular • Fibrous banding around follicles • Stains positive for factor XIIIa • Multiple lesions seen in tuberous sclerosis and MEN I Figure 5-34. Acquired Digital Fibrokeratoma Atrophie Blanche (Segmental Hyalinizing Vasculitis) • Increased number of dermal vessels containing fibrinoid plugs • Thick red walls of the vessels • Frank vasculitis is not a feature • Variable degree of purpura with Figure 5-35. Angiofibroma hemosiderin pigment • In fully established plaques there is epidermal atrophy with scleroderma-like scarring Atypical Fibroxanthoma • Well-defined, dermal lesion • Often, epidermal collarette; the deep margin pushes rather than invades • High-grade atypia; composed of a pleiomorphic mix of spindle cells, histiocyte-like cells, atypical xanthomatous cells (classically seen), and multinucleated giant cells • Mitotic activity and hyperchromasia can be present Figure 5-36. Atypical Fibroxanthoma 178  2013/2014 Dermatology In-Review l Committed to Your Future Report a Problem/Feedback
  • 187. • Stains positive for CD68, alpha-1 antitrypsin, muscle-specific actin, CD10, CD99 u TIP aMake sure there isn’t an overt malignant melanoma in situ or SCC at epidermis Dermatofibroma (Fibrous Histiocytoma, DF) • Interlacing fascicles of slender spindle cells (running haphazardly) • Often storiform, within a loose collagenous or myxoid stroma, scattered foamy histiocytes, multinucleated giant cells • Periphery of lesion shows hyaline collagen bundles surrounded by tumor cells, grenz zone seen; don’t count on pigmented epidermal hyperplasia Figure 5-37. Dermatofibroma (Fibrous Histiocytoma)  • Multiple DFs seen in lupus erythematosus and immunosuppression/HIV  • Factor XIIIa-positive and stromelysin-3  positive u TIP aNot well-circumscribed on low power (don’t go to high power) Dermatofibrosarcoma Protuberans (DFSP)  • Dermal tumor, more cellular than DF Figure 5-38. Dermatofibrosarcoma Protuberans with smaller cells, irregular infiltration of subcutaneous fat • Uniform spindle cells with elongated nuclei showing little or no pleiomorphism • Storiform pattern with whorls; there is a myxoid variant • CD34-positive • Giant cell fibroblastoma is also CD34-positive, and is usually seen in male children on the neck/trunk → thought to be a juvenile counterpart of DFSP • Translocation t(17;22)(q22;q13) has been demonstrated; this translocation results in the fusion of two genes: collagen type I alpha 1(COL1A1) and platelet-derived growth factor B-chain (PDGFB) Epithelioid Sarcoma • Forearms of young adults • Epithelioid cells mixed with spindle cells with granulomatous inflammation in fibrotic stroma with necrosis (can look like a palisading granulomatous disorder), atypia, mitoses, and vascular invasion Report a Problem/Feedback Dermatopathology  179
  • 188. • Must rule out infectious causes (therefore, unlikely you would make this diagnosis on the Boards without clinical history) • Vimentin+, low molecular weight cytokeratin+ Giant Cell Tumor of Tendon Sheath • Deep tumor; lobulated and well-defined, often with a fibrous pseudocapsule • Xanthomatous cells, siderophages, and conspicuous giant cells (osteoclastic giant cells → purple and angulated) • Prominent collagenous stroma, mitotic figures may be numerous, CD68 positive staining Infantile Digital Fibromatosis • Irregular mass of proliferating spindle-shaped myofibroblasts embedded in a dense collagenous stroma extending deeply from the dermis • Finding brightly eosinophilic, PAS+, pink circular intracytoplasmic inclusions in the myofibroblasts is diagnostic → thought to be aggregates of actin Keloid • Nodular fibroblastic proliferation and the presence of hypocellular, glassy, eosinophilic, hyalinized and disordered collagen fibers in dermis  • Rubinstein-Taybi, Noonan’s, and Turner’s syndromes can have multiple keloids Nodular Fasciitis • Clinically presents as a rapidly-growing tumor in a younger person • Unencapsulated, deep mass of plump spindle cells set in a loose myxoid and collagenous stroma • Thin-walled blood vessels, ramify through lesion in a radial arrangement; foci of extravasated RBC’s • Mitotic cells but without atypia • More heterogeneous than a DFSP • Immunohistochemistry positive for muscle actin, but desmin is negative Figure 5-39. Keloid Hypertrophic Scar • Nonspecific dermal fibroblastic proliferation, often with epidermal atrophy • More cellular than keloids • Hyalinized collagen fibers less prominent; fascicles and bundles seen Figure 5-40. Nodular Fascilitis 180  2013/2014 Dermatology In-Review l Committed to Your Future Report a Problem/Feedback
  • 189. Scar • Spindle-shaped cells intermixed with varying amounts of collagen (dependent on the age of the scar) with vessels oriented perpendicularly to the epidermis • Lack of adnexae 5.13 GENODERMATOSES Birt-Hogg-Dubé Syndrome    • Triad of fibrofolliculomas, skin tags, and trichodiscomas • Increased risk of renal cancer and spontaneous pneumothorax • Autosomal dominant, molecular defect in folliculin Cowden’s Disease • Multiple trichilemmomas, sclerotic fibromas (storiform collagenoma), acral keratoses, oral fibromas • Increased risk of breast/thyroid cancer • Autosomal dominant, mutation in PTEN gene   Epidermolytic Lchthyosis (Bullous Congenital Ichthyosiform Erythroderma)  • Hypergranulosis • Prominent vacuolization of the superficial epidermal cells • Stippled keratohyaline granules; higher up there is “drop out” of nuclei • Seen in bullous CIE, benign keratoses, epidermal nevi, or incidental • Autosomal dominant, defect in keratins 1/10 Figure 5-41. Cowden’s Disease Ichthyosis Vulgaris  • Orthokeratosis with hypogranulosis/absent granular layer • Autosomal dominant, defect in filaggrin/profilaggrin Incontinentia Pigmenti   • Eosinophilic spongiosis with dyskeratotic cells • Pigment incontinence with melanophages in dermis in later stages • Verrucous lesions show hyperkeratosis, acanthosis, papillomatosis and focal dyskeratosis • X-linked dominant, mutation in NEMO gene Report a Problem/Feedback Dermatopathology  181
  • 190. Porokeratosis • Keratin-filled epidermal invagination with an angulated parakeratotic tier, the cornoid lamella • Epithelium deep to tier is devoid of granular cell layer, adjacent epithelium toward lesion’s center is often atrophic • Always look to periphery of a lichenoid  infiltrate to check for the cornoid lamella Pseudoxanthoma Elasticum • Degenerative changes of elastic fibers of middle and lower dermis • Elastic fibers readily identifiable on H&E, appearing “pink and squiggly” → widely dispersed granular material amidst Figure 5-42. Porokeratosis normal collagen fibers • Elastic fibers stain positive with von Kossa stain • Transepidermal elimination of degenerate elastic tissue may be seen; calcification seen in older lesions • Autosomal recessive or dominant 5.14 GRANULOMATOUS DISORDERS Leprosy, Borderline • Multiple nodules consisting of epithelioid tubercles in the superficial and deep dermis • Nodules are not rounded, but more irregular and elliptical • The infiltrate within these nodules is lymphohistiocytic • Infiltrate found around nerve bundles Leprosy, Lepromatous • Histiocytes in poorly circumscribed masses in the dermis with few, if any, lymphocytes • Histiocytes are often foamy (dermis shows lots of pallor), and distended (termed virchow cells) with large groups (globi) of leprosy bacilli (revealed by Ziehl-Neelsen or Fite stain) • Grenz zone seen → may destroy cutaneous appendages and extend into subcutaneous fat Leprosy, Tuberculoid • Epithelioid non-caseating granulomatous response around small cutaneous nerves • Often extending into adjacent dermis • Langerhans giant cells, scarce bacilli Lichen Nitidus • Atrophic epidermis covered by a parakeratotic tier • Interface dermatitis • Claw-like extension of the epidermal ridges mark lateral boundaries of an lymphohistiocytic infiltrate (“ball and claw”) • Giant cells and granulomata may be seen 182  2013/2014 Dermatology In-Review l Committed to Your Future Report a Problem/Feedback
  • 191. Sarcoidosis • Fairly normal epidermis • “Naked,” noncaseating epithelioid tubercles (sparse lymphocytic infiltrate) located throughout the mid and deep dermis • Diagnosis of exclusion; can be identical to foreign body reaction (silica, beryllium, etc.) and granulomatous rosacea  •  chaumann body (basophilic, rounded S structure composed of calcium carbonate, phosphate, and iron) and asteroid body (lipoprotein, eosinophilic, starshaped), neither body is specific for sarcoid (seen also in TB, leprosy, berylliosis) Figure 5-43. Lichen Nitidus 5.15 HISTIOCYTOSES Juvenile Xanthogranuloma • Intradermal collection of uniform lipid-laden histiocytes, admixed with multinucleated giant cells of Touton and foreign body types (but Touton giant cells not specific for JXG, and can be seen in any xanthomatous process) • Variable numbers of neutrophils, eosinophils, mast cells, and lymphocytes, no epidermal involvement • JXGs are associated with ocular involvement; even 1 JXG associated with neurofibromatosis and CML Figure 5-44. Sarcoidosis Langerhans Cell Histiocytosis • Infiltrate in upper dermis → uniform cells with pale reniform vesicular nuclei and pale-staining or eosinophilic cytoplasm • An edematous zone of “floating cells” in the upper dermis → each cell seen individually • Epidermotropism is characteristic; scattered eosinophils • Birbeck granules    • S100 and CD1a positive; langerin (CD207) positive (most specific) Figure 5-45. Juvenile Xanthogranuloma Report a Problem/Feedback Dermatopathology  183
  • 192. Reticulohistiocytosis  •  ulticentric type seen more often in older women, associated with arthritis mutilans, often M seen clustered around the nail → “coral bead sign,” associated with breast cancer • Well-defined collection of uniform pink histiocytes and multinucleated giant cells with “ground glass” (not foamy) cytoplasm → located predominantly in dermis Verruciform Xanthoma • Clinically often on oral mucosae or genital area • Regular acanthosis, parakeratosis, and hyperkeratosis • Bulbous epidermal ridges penetrate to same depth, giving level lower border, expanded ridges with marked central keratinocyte necrosis and heavy neutrophil infiltrate • Papillary dermis between elongated epidermal ridges contains large numbers of eosinophilic foamy xanthoma cells, but no Touton cells present 5.16 INFECTIONS Actinomycosis • Contains sulfur granule (organism tangled together in matted colony) with an eosinophic rim – Splendore-Hoeppli phenomenon – with dense surrounding neutrophilic infiltrate Blastomycosis • Pseudoepitheliomatous hyperplasia overlying abscesses • Organisms (8-15 microns) with broadbased budding Chromoblastomycosis • Pseudoepitheliomatous hyperplasia overlying abscesses with presence of “copper pennies” = sclerotic bodies = medlar bodies = hot cross buns (6-12 microns) Figure 5-46. Actinomycosis Coccidioidomycosis • Spherules (which contain and can collapse to release endospores → 10-80 microns) • Combination of suppuration with pseudoepitheliomatous hyperplasia • Rhinosporidiosis sporangium is bigger Condyloma Acuminatum • Marked acanthosis, papillomatosis, with hyperkeratosis and parakeratosis Figure 5-47. Chromoblastomycosis 184  2013/2014 Dermatology In-Review l Committed to Your Future Report a Problem/Feedback
  • 193. • Sharp margination, superficial vacuolated keratinocytes (koilocytes) Cryptococcosis  • Spherical yeast, narrow-based single budding • Mucinous capsule showing gelatinous clearing • May be a granulomatous pattern that has rare organisms •  ucicarmine positivity of capsule disM criminates between cryptococcus and other tissue fungal infections such as histoplasmosis and blastomycosis • Gelatinous pattern shows numerous vacuolated-like areas containing abundant encapsulated organisms 4-20 microns (larger than histoplasmosis) Figure 5-48. Condyloma Acuminatum Epidermodysplasia Verruciformis • Bluish change in the granular layer (thought to be ribosomes) • Associated with HPV types 5, 8 • Associated with immunosuppression/HIV in sporadic form and is also inherited in an autosomal recessive form • Mutations have been found in the EVER1 and EVER2 genes; these genes are on 17q25, the location of the PSORS2 gene (one of the genes implicated in the inheritance of psoriasis) Figure 5-49. Cryptococcosis Herpes Simplex Virus Infection • Suprabasilar intraepidermal bullae (ballooning) • Mixed cell infiltrate consisting of neutrophils and eosinophils • Multinucleated giant cells with marginated chromatin, steel-gray nuclei, ballooning degeneration • May have subepidermal bullae; can look identical to erythema multiforme in the lateral aspects of lesion • May see Cowdry A bodies (Lipschutz bodies) Figure 5-50. Herpes Simplex Virus Infection Report a Problem/Feedback Dermatopathology  185
  • 194. Histoplasmosis • Not encapsulated; 2-4 microns yeast within distended macrophages as a basophilic dot with surrounding artefactual halo (pseudocapsule) • Similar to Leishmania, but lacking in the kinetoplast • Stains positive with PAS and methenamine silver Leishmaniasis • Amastigotes (little dots) within macrophages (Leishman-Donovan bodies), 2-4 microns, kinetoplast present • Acanthotic epithelium, with frequently ulceration • Epidermis may show pseudoepitheliomatous hyperplasia and intraepidermal neutrophilic abscesses, dermis contains intense infiltrate of histiocytes, lymphocytes, and plasma cells • Organisms best seen with Giemsa stain • Looks like histoplasmosis, but histoplasmosis has a tiny “halo” around the organism Figure 5-51. Histoplasmosis Molluscum Contagiosum • Lobulated, endophytic hyperplasia • Keratinocytes contain very large Figure 5-52. Leishmaniasis intracytoplasmic inclusions, that compress the nucleus against the cell membrane (Henderson-Paterson bodies) → fill the cells in a cup-shaped invagination of the epidermis, often at the hair follicle Orf (Ecthyma Contagiosum) • Acral skin; symmetric nodule • Parakeratosis and acanthosis; early lesion shows intracytoplasmic eosinophilic inclusion bodies in the upper 1/3 of the epidermis • Reticular degeneration • Epidermis can be hyperplastic with down-growing rete, dermal inflammation and vasodilation of vessels • May show necrosis; cowpox is identical Protothecosis • Caused by an algae, most commonly Prototheca wickerhamii • Organism looks like a soccer ball on histopathology (6-10 mm) → the morula 186  2013/2014 Dermatology In-Review l Committed to Your Future Report a Problem/Feedback
  • 195. Scabies • Burrow within horny layer, with only blind end (with female mite) located in stratum malpighii • Spongiosis in stratum malpighii near mite • Dermal infiltrate of eosinophils and lymphocytes in lesions containing mites • Occasionally scybala (feces) can be seen Syphilis, Primary Chancre • Epidermal hyperplasia with intense lymphohistiocytic and neutrophil infiltrate in dermis • Plasma cells present • Overlying epidermis ulcerated, with adjacent epidermis showing pseudoepiltheliomatous hyperplasia Syphilis, Secondary • Papular lesions show superficial and deep perivascular infiltrates that may become band-like; plasma cells (which are often deep) and histiocytes (pale infiltrate) • Parakeratosis, acanthosis, spongiosis, and exocytosis • Thick-walled blood vessels with swollen enthothelial cells characteristic • Psoriasiform syphilides show parakeratosis and acanthosis with extended epidermal ridges • Spirochetes can be seen in lower epidermis and in blood vessels u TIP Figure 5-53. Syphilis, Secondary aExtravasated RBCs may be a feature of both papular and papulosquamous vari- ants; most commonly the infiltrate will be lichenoid → if you see lichenoid pattern, look for plasma cells Tinea Versicolor • Minimal spongiosis; organisms easily seen on H&E (unlike dermatophyte) in stratum corneum as spaghetti and meatballs (must see both) u TIP aThink of this diagnosis when skin appears normal or mildly inflamed Verruca Plana • Relatively flat lesion with the cells of the granular layer appearing to be clearer than usual (vacuolized) Figure 5-54. Verruca Plana Report a Problem/Feedback Dermatopathology  187
  • 196. Verruca Vulgaris • Hyperkeratosis, papillomatosis, tiers of parakeratosis over tips of exophytic component • Prominent granular cell layer within which are vacuolated cells containing enlarged clumps of irregular keratohyalin granules (“owl’s eyes” or koilocytes) (seen in upper 1/3 of epidermis) • Dilated blood vessels in the dermal papilla 5.17 INFLAMMATORY Acne Keloidalis • Early: Dilated follicle may contain pus extending through epithelium, surrounded by neutrophils, lymphocytes, and perhaps plasma cells • Later: Marked fibrosis/scarring, free broken hair shafts with foreign body giant cell reaction; possible lateral lymphoplasmacytic infiltrate • Identical findings in hidradenitis suppurativa, but this condition also likely shows sinus tracts lined by stratified squamous epithelium and surrounded by fibrosis and inflammation Chronic Radiodermatitis • Hyperkeratosis, foci of parakeratosis, acanthosis or atrophy with flattened rete ridges • Spongiosis or basal cell liquefaction degeneration • Dermis is fibrotic, pale and sickly, and lacks inflammation (not square and red like morphea) • Bizarre (radiation) fibroblasts, thickened blood vessels with fibrointimal hyperplasia, or telangiectasia • Loss of appendages Cryoglobulinemia • Vascular dilatation, endothelial swelling, and plugging of vascular lumina by hyaline material (microthrombi) → red deposits • Same pattern for DIC, cryoglobulinemia, lupus anticoagulant, protein S and C deficiency, antithrombin III deficiency, coumadin and heparin necrosis, PNH Lichen Planus-like Keratosis (Benign Lichenoid Keratosis) • Hyperkeratosis, hypergranulosis, variable u TIP acanthosis, and basal cell liquefaction aBig clue → hyperpigmentation of the basal layer; no dysplasia like a lichenoid actinic keratosis degeneration • Parakeratosis commonly present (unlike LP) • Broadened, widened and irregular epidermal ridges (rather than sawtooth), dense bandlike lymphohisticytic infiltrate in superficial dermis that may contain eosinophils and plasma cells; seen near lentigo or seborrheic keratoses Erythema Annulare Centrifugum (Gyrate Erythema) • Well-demarcated perivascular infiltrate of lymphocytes and histiocytes → cuffing, but not always like this • Epidermis usually normal, but focal spongiosis can be seen • Make sure that there is no interface dermatitis of lupus, no papillary dermal edema of PMLE Erythema Elevatum Diutinum • Leukocytoclastic vasculitis • Epidermis may show acanthosis and parakeratosis 188  2013/2014 Dermatology In-Review l Committed to Your Future Report a Problem/Feedback
  • 197. • Fibrinoid necrosis and neutrophil infiltration of vessels • Older lesions show fibrous scarring and extracellular cholesterolosis Erythema Multiforme • Subepidermal blister, with necrotic keratinocytes at all levels of epidermis • Vacuolar interface change • Basket weave stratum corneum (PLEVA doesn’t show this) • Lymphohistiocytic infiltrate especially at DE junction • Usually no eosinophils (but not a hardand-fast rule) • Infiltrate can be deep Figure 5-55. Erythema Multiforme Granuloma Faciale • Dense, often nodular infiltrate in mid dermis • Grenz zone; involves both epidermis and hair follicles • Infiltrate involves eosinophils, neutrophils, plasma cells, mast cells, and lymphocytes, extravasated RBCs • Dilated blood vessels with fibrin deposition in their walls Graft Versus Host Disease (GVHD) Figure 5-56. Granuloma Faciale • Acute disease shows widespread basal cell hydropic degeneration with scattered necrotic keratinocytes that are found in adnexae • Lymphocytic exocytosis with satellite cell necrosis (not always present) • Dermal edema with dilated blood vessels • Pigmentary incontinence Leukocytoclastic Vasculitis • Subepidermal or intraepidermal blister with neutrophils, necrotic keratinocytes, basketweave stratum corneum • Edema of papillary dermis, with collection of neutrophils and nuclear dust around and obliteration of vessels • Fibrinoid degeneration of vessels, fibrin “blends into” surrounding collagen • Extravasated RBC’s Lichen Simplex Chronicus • Psoriasiform hyperplasia with orthokeratosis, prominent granular layer, focal parakeratosis • Vertically oriented collagen fibers in elongated dermal papillae Report a Problem/Feedback Dermatopathology  189
  • 198. • Superficial perivascular lymphohistiocytic infiltrate • Differential diagnosis includes hypertrophic LP, which shows a lichenoid infiltrate Lichen Planus  • Prototypical lichenoid inflammatory condition with a band-like infiltrate of lymphocytes sometimes obscuring the DEJ, with hyperkeratosis, wedge-shaped areas of hypergranulosis, irregular acanthosis, saw-toothing of the basal layer with squamotization of basal cells • Colloid/Civatte bodies • Parakeratosis and eosinophils should be absent • LP on mucosa: Plasma cells without hypergranulosis (often on the Boards) Figure 5-57. Lichen Planus Lichen Sclerosus et Atrophicus  • Often, epidermal atrophy with confluent orthokeratosis, follicular plugging • Subepidermal bulla containing RBC’s • Superficial perivascular and band-like lymphohistiocytic infiltrate under a pale and sclerotic zone • Telangiectases in papillary dermis, homogeneous collagen in upper dermis, dermal edema • Same as balanitis xerotica obliterans (BXO) • Patients may have circulatory autoantibodies to ECM-1 Figure 5-58. Lichen Sclerosus et Atrophicus Lichen Striatus • Mild parakeratosis, spongiosis; superficial perivascular inflammatory infiltrate of predominantly lymphocytes (rare plasma cells or eosinophils) that may be almost band-like superficially • Low power shows a nearly empty dermis, but deep dermis shows a dense infiltrate around the adnexal structures → very unique to this entity Figure 5-59. Lichen Striatus 190  2013/2014 Dermatology In-Review l Committed to Your Future Report a Problem/Feedback
  • 199. Lupus Erythematosus • Follicular plugging, mild hyperkeratosis, vacuolar change of basal layer, basement membrane thickening, pigment incontinence, increased dermal mucin • Superficial and deep perivascular infiltrate of lymphocytes and histiocytes that is periadnexal as well Morphea  • Square biopsy that is very red • Papillary dermis unaffected usually • Reticular dermis has swollen collagen bundles that are intensely eosinophilic and oriented parallel to surface, also septa of subcutaneous fat may be involved with atrophy of adipocytes and fibrosis, follicles and sebaceous glands are atrophic or absent • Eccrine trapping, dense, chronic inflammatory cell infiltrate of lymphocytes and plasma cells, mucin is not a large feature; there are no giant cells Perforating Folliculitis • Widely dilated hair follicle containing ortho- and parakeratotic keratin, basophilic necrotic debris • Connective tissue elements and inflammatory cells • A curled up hair sometimes is found within the keratinous plug Perniosis • Acral location, with interface dermatitis, occasionally • Papillary dermal edema; infiltrate involves deeper dermis • Similar to PMLE Pigmented Purpuric Dermatosis • Chronic capillaritis; superficial vessels dilated with endothelial cell hypertrophy and surrounding extravasated red blood cells • Perivascular lymphocytic infiltrate (no eosinophils or neutrophils) that may look lichenoid • Purpura in early lesions, and hemosiderinladen macrophages (siderophages) seen in older lesions; pigment is deep (stain with Perls Prussian blue) u TIP aVariants include: progressive pigmentary dermsis of Figure 5-60. Pigmented Purpuric Dermatosis Schamberg, lichen aureus (clinically usually asymmetrical), eczematid-like purpura of Doucas and Kapetenakis, lichenoid dermatitis of Gougerot and Blum, purpura annularis telangiectoides of Majocchi Report a Problem/Feedback Dermatopathology  191
  • 200. Pityriasis Lichenoides et Varioliformis Acuta (PLEVA)  • Parakeratosis, pallor of upper epidermis • Spongiosis and vacuolar alteration of the basal layer with some necrotic keratinocytes at different levels • Papillary dermal edema • Band-like interface infiltrate and deep infiltrate composed of mostly lymphocytes with exocytosis of lymphocytes • Extravasated RBC’s in upper dermis • Can look just like LyP but LyP has eosinophils and neutrophils and PLEVA doesn’t • Erythema multiforme doesn’t show parakeratosis Figure 5-61. Pityriasis Lichenoides et Varioliformis Acuta Pityriasis Rosea • Mounds of parakeratosis over slight acanthosis, and slight spongiosis • Superficial perivascular infiltrate predominantly lymphocytes • Extravasated RBC’s in papillary dermis with extension into the epidermis • Papillary dermal edema Pityriasis Rubra Pilaris  • Acanthosis with broad and short rete ridges with slight spongiosis • Thick suprapapillary plates, focal or confluent hypergranulosis (variable) • Alternating orthokeratosis and parakeratosis both vertically and horizontally • Dermis shows mild superficial perivascular lymphocytic infiltrate • Unique feature → conical hyperkeratotic follicular plug is far above the epidermis Figure 5-62. Pityriasis Rosea Polymorphous Light Eruption (PMLE) • Variable epidermal spongiosis • Dermal, perivascular lymphocytic cell infiltrate with marked papillary dermal edema Figure 5-63. Pityriasis Rubra Pilaris 192  2013/2014 Dermatology In-Review l Committed to Your Future Report a Problem/Feedback
  • 201. • May resemble SCLE, but infiltrate more commonly around blood vessels than pilosebaceous units, and no vacuolar interface changes • Infiltrate goes deeper than SCLE Psoriasis • Lengthened and multilayered parakeratosis with neutrophils (Munro’s microabscesses) • Pallor of the upper epidermis • Hypogranulosis • Regular acanthosis of epidermis • Spiraled dilated vessels under thinned suprapapillary plates • Early lesions may show spongiosis Figure 5-64. Polymorphous Light Eruption Rosacea, Granulomatous  • Perifollicular • Telangiectases and round epithelioid tubercles that may caseate in superficial dermis • Surrounding lymphocytes Sweet’s • Dense nodular infiltrate, composed primarily of neutrophils, histiocytes, and some lymphocytes • May be primarily histiocytoid • Nuclear dust (leukocytoclasis) is marked, the papillary dermis is edematous Figure 5-65. Psoriasis • Focal degeneration of collagen, extravasated RBC’s • No vasculitic changes; dermal edema should also make you think of PMLE, which has lymphocytes Stasis Dermatitis • Hyperkeratotic epidermis with areas of parakeratosis, acanthosis, and focal spongiosis • Superficial, perivascular lymphohistiocytic infiltrate that surrounds plump, thickened capillaries and venules • Superficial dermal vessels may be arranged in lobular aggregates • Reticular dermis is often fibrotic and hemosiderin is usually present deep Toxic Epidermal Necrolysis • Confluent wipe-out of the epithelium, full-thickness necrosis, subepidermal vesiculation, sparse inflammation Report a Problem/Feedback Dermatopathology  193
  • 202. 5.18 LYMPHOMAS AND MARKERS B-cell Lymphoma  u TIP • Often a diffuse, deep infiltrate aThe 2005 WHO-EORTC and 2008 WHO Classification of primary cutaneous B-cell lymphomas has 4 main categories: • Germinal centers may be present follicle center lymphoma; marginal zone lymphoma; diffuse (especially in primary cutaneous follicle large B-cell lymphoma, leg type or other/NOS center lymphoma with a follicular growth pattern) • Often can be “bottom heavy” involving subcutaneous fat lobules • Epidermis generally spared • CD20+ Leukemia Cutis • AMML is the most common (acute myelomonocytic leukemia; myeloid precursors); grenz zone present • Dense diffuse infiltrate in dermis and extending into subcutaneous fat; cells splayed out through the stroma → some Indian-filing; not always highly atypical, darkly staining small- to medium-sized cells • Infiltrate may be sparse or dense • Neoplastic cells stain positive for Leder, lysozyme, myeloperoxidase Lymphomatoid Papulosis (LyP)  • PLEVA-like architecturally, but cells more atypical; infiltrate is wedged-shaped with base of wedge in close apposition to the epidermis • Early lesions may not affect epidermis, while in older lesions the infiltrate may be lichenoid; interface might be obscured by infiltrate • LyP has eosinophils and neutrophils intermixed with atypical lymphocytes that look like “chunks of coal” • Most cells are CD3 positive and CD4 positive u TIP aType A: CD30-positive; pleomorphic cells are large with vesicular nuclei; Reed-Sternberg-like multinucleate giant cells; neutrophils, eosinophils, and plasma cells a ype B: MF type with preponderance of SezaryT type cells aType C: like anaplastic large cell lymphoma aType D: like aggressive epidermotropic CD8+ cytotoxic T=cell lymphoma Mantle Cell Lymphoma Figure 5-66. Lymphomatoid Papulosis • Clinically: Most patients have disseminated disease at the outset, 1/3 have leukemic involvement; cutaneous lesions have been reported to precede internal disease • Characteristically bcl-1 (Cyclin D1) positive [t(11;14) translocation involving bcl-1 and the immunoglobulin heavy chain gene] 194  2013/2014 Dermatology In-Review l Committed to Your Future Report a Problem/Feedback
  • 203. • Also positive with CD 19, CD 20, CD5 (like CLL), CD43, bcl-2 • Lack CD 23 (unlike CLL) • Mantle cells have cell surface immunoglobulins (often IgM and IgD) • Often has lambda light chain restriction Mycosis Fungoides (MF) • For Board purposes, a slide of MF should have most of these criteria: – Larger intraepidermal lymphocytes compared with smaller dermal lymphocytes – Pautrier’s abscesses – Disproportionate exocytosis in relation to spongiosis – Basilar lymphocytes lined up against the DEJ (“toy soldiers," “strings of pearls”) – Pagetoid spread of lymphocytes into the epidermis Figure 5-67. Mycosis Fungoides – 7-9 micron convoluted lymphocytes (a basal keratinocyte is about 7-9 microns) – Halo’d lymphocytes in the epidermis – Papillary dermal fibrosis, so-called “fettucine” collagen – CD4+ cells in the epidermis that have often lost CD5 and CD7 • Note that type B lymphomatoid papulosis can look exactly like MF histologically Pseudolymphoma (Reactive Lymphoid Hyperplasia) • Dense nodules consisting of small lymphocytes and histiocytes • Germinal center (centrocytes and centroblasts) morphology with surrounding mantle and then marginal zone, surrounding T-cells → nodules involve both the upper and lower dermis (more “top heavy”) • Lymphocytes, eosinophils, ectopic adipocytes • In center of reactive follicle are “tingible body macrophages” Subcutaneous Panniculitis-like T-cell Lymphoma • Clinically patients present with subcutaneous nodules on the extremities, can have a fatal hemophagocytic syndrome • Biopsy can be subtle; should see a septal and lobular panniculitis with medium to large atypical lymphocytes, rimming of fat cells with atypical lymphocytes, necrosis; there may be phagocytosis of lymphocytes/debris/erythrocytes • Two groups: 1.) Alpha-beta T-cells (by definition) that are CD 8+, more indolent clinically 2.) Gamma-delta T-cells that are CD 56+, more aggressive (fatal) with systemic hemophagocytosis - this subset is now considered a subset of cutaneous gammadelta T-cell lymphomas (a provisional diagnosis) Report a Problem/Feedback Dermatopathology  195
  • 204. u TIP Cell Markers w Markers •  CD1a •  CD2, CD3 – Langerhans cells •  CD4 – Pan T-cell – Helper T-cell – Also expressed by histiocytes (Langerhans cells) •  CD5 – Pan T-cell – Marker of CLL, mantle cell lymphoma – Lost in MF •  CD7 – T-cells – Lost in MF •  CD8 •  CD10 – Cytotoxic T-cell •  CD16 – Marker for primary cutaneous follicle center lymphomas •  CD19, CD20, CD79a – NK cell marker •  CD23 – B cell marker – Positive marker in CLL – Negative marker in Mantle cell lymphoma •  CD30 •  CD45 (aka LCA=leukocyte common antigen) – Marker for anaplastic large cell lymphoma, lymphomatoid papulosis, Hodgkin’s, transformed MF •  CD56 – T-cells, B-cells, myeloid cells, histiocytes •  CD57 – NK cell marker •  CD138 – T-cells with NK activity •  Bcl-1 – Plasma cell marker, CD79a •  Bcl-2 – Marker for mantle cell lymphoma – Anti-apoptotic – Marker for follicular cell lymphoma (nodal) – Primary cutaneous follicle center lymphomas are generally bcl-2 negative – Stains BCCs diffusely whereas stains only the outer rim of epithelium in trichoepitheliomas •  Bcl-6 •  MUM-1/IRF4 – Marker for primary cutaneous follicle center lymphomas – Marker for diffuse large B-cell lymphomas, leg type 196  2013/2014 Dermatology In-Review l Committed to Your Future Report a Problem/Feedback
  • 205. Figure 5-68. Immunohistochemical Stains for the Diagnosis of Some Cutaneous Lymphomas 5.19 MELANOCYTIC LESIONS Atypical Nevus (Dysplastic Nevus, Nevus with Architectural Disorder, Clark’s Nevus) • May be junctional or compound; in compound lesions, the epidermal component extends beyond the lateral border of the dermal nevus cells (shoulder phenomenon), little or no pagetoid spread, lentiginous melanocytic hyperplasia with elongation of rete ridges • Melanocytes have increased nuclear size, nuclear membrane irregularity, prominent nucleoli, and pleomorphism and are randomly distributed along basal layer; marked fixation artefact, fusion of adjacent nests, rare mitoses • Periepidermal fibroblastic response → lamellar fibroplasia; random atypia (not uniform) Balloon Cell Nevus  • Round or oval cells with abundant pale-staining or clear cytoplasm • The cells contain a central hyperchromatic or vesicular nucleus with very conspicuous nucleolus • Looks like a xanthoma, but distinguish by looking high in dermis as cells may go into epidermis (compound or intradermal), contain melanin, or show nesting Blue Nevus, Cellular • Large, often well-circumscribed, nodular mass that fills the dermis and may penetrate into subcutaneous fat • Gets more cellular as you look lower in dermis Report a Problem/Feedback Dermatopathology  197
  • 206. • Composed of a dual cell population: large numbers of closely aggregated large spindle and epithelioid cells • Tumor cells may be divided into nests and cords by collagenous septae, no atypia and rarely mitotic figures present • Very rarely, melanoma may develop within Blue Nevus, Common • Typically in upper dermis, heavily pigmented dendritic spindle cells with associated host-derived dense fibroblastic and collagenous spindle cell response • Often associated heavily pigmented melanophages • No mitotic figures and no pleomorphism • Overlying epidemis is normal • Completely benign lesion Blue Nevus, Combined • Association of a common blue nevus with an overlying melanocytic nevus Nevus, Congenital Figure 5-69. Blue Nevus, Common • Frequently hyperkeratosis, acanthosis, and papillomatosis • Neonatal lesions are compound and develop within acanthosis • Melanocytes may present as wellcircumscribed nests or as single cells scattered through all layers of epidermis • Nevus usually is a diffuse infiltrate of melanocytes from papillary dermis into deep reticular dermis and possibly subcutaneous fat • Nevus cells ensheath epidermal appendages and can be found within arrector pili muscles, hair follicles, Figure 5-70. Blue Nevus, Combined sebaceous glands and the walls of eccrine sweat ducts • With increasing depth the nevus cells adopt a single-cell array and Indian-file pattern Deep Penetrating Nevus • May be a variant of blue nevus or congenital nevus • Symmetrical, wedge-shaped, conglomerate of spindle and epithelioid cells that extend into deep reticular dermis/fat surrounded by melanophages • No upward extension of melanocytes (Pagetoid spread) • Often surrounds follicles/nerves/glands 198  2013/2014 Dermatology In-Review l Committed to Your Future Report a Problem/Feedback
  • 207. Halo Nevus • Raised dermal nodule, acanthotic and frequently hyperkeratotic epidermis • Nevus is usually compound and infiltrated extensively by lymphocytes and histiocytes with occasional mast and plasma cells, it looks lichenoid but it’s a deeper infiltrate than lichen planus • Fontana-Masson shows an absence of melanin at the periphery Malignant Melanoma, Superficial Spreading  • Asymmetric proliferation of atypical melanocytes scattered singly and in clusters at all levels of epidermis (buckshot scatter, or pagetoid spread) • Single cells > nests; cells are epithelioid with abundant cytoplasm • Vesicular nuclei with prominent nucleoli, scattered mitotic figures, atypia, tumor growth spreads from one epidermal ridge to another • Epidermis often acanthotic with partial/complete effacement of rete ridges • Associated with mutations in p16, CDKN4a, BRAF, sometimes p53, ras Malignant Melanoma, Desmoplastic Variant  • Diffusely infiltrative, sometimes paucicellular, markedly fibrotic dermis • Proliferation of atypical spindle-shaped melanocytes with hyperchromatic nuclei and occasional mitotic figures • Atypical melanocytes as single units and irregular nests in the overlying epidermis • Neurotropism • S100+, but HMB45 negative Malignant Melanoma, in Situ • Broad poorly circumscribed asymmetrical proliferation of enlarged atypical melanocytes as single units and irregular nests at DE junction • Many atypical melanocytes extending into the upper levels of the epidermis • No atypical melanocytes in the dermis Malignant Melanoma, Lentigo Maligna • Atypical dendritic melanocytes at basal epidermis showing marked cytoplasmic vacuolation and pleomorphic irregular hyperchromatic nuclei • Little tendency to involve upper epidermis • Cells can involve adnexae → goes up and down hair follicles • Pigment often abundant involving full-thickness of epidermis and stratum corneum • Epidermis often atrophic and there is solar elastosis (actinic damage) • Desmoplastic melanomas derive from these, usually Nevus of Ito/Ota/Mongolian Spot • No junctional activity • In upper and mid dermis are elongated, dendritic, highly pigmented melanocytes scattered among the collagen bundles • Less cellular or even acellular, very few to no melanophages Pigmented Spindle Cell Nevus of Reed • Lesion often shows breadth greater than height • Symmetric, cells are uniform, narrow, elongated, spindle-shaped, often heavily pigmented Report a Problem/Feedback Dermatopathology  199
  • 208. • Typically junctional or confined to epidermis and papillary dermis, may blend in with adjacent keratinocytes • Arranged in nests (> single cells) and vertically oriented • Associated with pigmented parakeratosis Figure 5-71. Pigmented Spindle Cell Nevus of Reed Recurrent Nevus • Directly overlying a scar, remnants of a previously excised nevus • Atypical melanocytes at the DEJ in a lentiginous pattern, sharply circumscribed • No mitotic figures • Sharp lateral demarcation, but there can be some upward spread Spitz Nevus • Symmetric lesion that is wedge-shaped • Presence of junctional cleavage artifact • No involvement of overlying epidermis • Kamino bodies (but not necessary) • Epidermal nests of spindle cells arranged vertically, with lack of cellular cohesion between adjacent cells • No nuclear pleomorphism, a little mitotic activity is okay • Little to no pigmentation classically • Presence of vascular ectasia • Maturation of lesion in deeper levels (decrease in the size of nests and melanocytes) • Associated with gain of chromose 11p in rare cases Figure 5-72. Spitz Nevus 5.20 MUSCLE Angioleiomyoma  • On low power, a deep tumor that is red and well-circumscribed • High power: Interlacing bundles of uniform smooth muscle cells distributed around numerous small vessels •  Few lesions are so well-circumscribed 200  2013/2014 Dermatology In-Review l Committed to Your Future Report a Problem/Feedback
  • 209. Leiomyoma   •  Familial multiple cutaneous leiomyomatosis – gene defect fumarate hydratase • Reddish/orange color → derived from arrector pili muscle • Uniform interlacing bundles or irregular collections of elongated cells with brightly eosinophilic cytoplasm and bluntended or cigar-shaped nuclei, mitoses are absent •  Stains positive for desmin and SMA Leiomyosarcoma • Ill-defined diffuse lesion, interlacing bundles of smooth muscle cells with eosinophilic cytoplasm and blunt-ended, cigar-shaped nuclei • Pleiomorphism in subcutaneous variant more common • Necrotic areas can be seen • Positive for SMA and desmin Figure 5-73. Angioleiomyoma 5.21 NEURAL Cellular Neurothekeoma (Dermal Nerve Sheath Myxoma) • Unencapsulated, lobulated mass in dermis with sparing of superficial papillary dermis • Tumor lobules separated by fibrous septa, and composed of stellate and spindle cells with pale indistinct cytoplasm set in an abundant myxoid matrix; occasionally there are bland multinucleated giant cells • Negative for S-100, positive for NKI C3 • Differential diagnosis includes desmoplastic melanoma, dermal Spitz, epithelioid cell histiocytoma Figure 5-74. Leiomyoma Granular Cell Tumor • 40% located on the tongue • Ill-defined, composed of nests of large round cells with brightly eosinophilic granular cytoplasm Figure 5-75. Cellular Neurothekeoma u TIP aAn important clue is pseudoepitheliomatous/epidermal hyperplasia at surface (reminiscent of the epidermis above a dermatofibroma) Report a Problem/Feedback Dermatopathology  201
  • 210.  • Cell borders are indistinct giving a syncytial appearance • Nuclei are uniformly small; commonly, pseudoepitheliomatous hyperplasia of overlying epithelium in tumors of dermis or tongue •  S-100+, Vimentin+, NSE+ Neurofibroma • Low power diagnosis • Well-defined, but unencapsulated dermal or subcutaneous; “bubble gum pink” collagenous stroma, nuclei are “tiny dots” • Engorged vessels throughout the tumor; scattered mast cells (a clue) and other inflammatory cells a prominent feature • No collagen trapping as seen in DF • May confuse with DFSP, but DFSP goes through the fat • A plexiform neurofibroma is highly suggestive of neurofibromatosis Figure 5-76. Granular Cell Tumor Palisaded Encapsulated Neuroma (PEN) • Higher in dermis, a well-circumscribed dermal nodule, typically, but may be multinodular or plexiform • Encapsulation is incomplete and superficial part of tumor appears to merge often with surrounding dermis • Cells are arranged in short fascicles separated by artefactual clefting and composed of wavy hyperchromatic nuclei and ill-defined pale eosinophilic cytoplasm • Most cells S-100 positive • Mucosal neuromas in MEN IIb resemble PENs Figure 5-77. Neurofibroma Schwannoma (Neurilemmoma) • Invariably encapsulated, in subcutaneous or deeper tissues; biphasic Antoni A and Antoni B areas • Antoni A → cellular component, closely packed spindle cells with tapering, elongated, wavy nuclei; nuclear palisading produces Verocay bodies; “fence of cells” on either side of a central pink area Figure 5-78. Palisaded Encapsulated Neuroma 202  2013/2014 Dermatology In-Review l Committed to Your Future Report a Problem/Feedback
  • 211. • Antoni B → irregularly scattered spindle or stellate cells in loose myxoid stroma at periphery; within are scattered inflammatory cells and small blood vessels with hyalinized walls • Composed of Schwann cells and are S-100 positive Supernumerary Digit • Clinically located near the base of the fifth finger • Architecture at low power looks like an acquired digital fibrokeratoma, but there are numerous nerve bundles in the dermis; sometimes there is bone/cartilage as well Traumatic Neuroma • Unencapsulated mass of numerous axons and Schwann cells embedded in scar tissue adjacent to the cut end of a damaged nerve • Nerve fascicles dispersed haphazardly 5.22 PAGETOID SPREAD Bowen’s Disease • Full-thickness dysplasia including intraepidermal portions of the cutaneous adnexae • Parakeratosis, marked acanthosis, with complete disorganization of the epidermal architecture, loss of maturation, and lack of polarity of cells • Nuclear pleomorphism and mitotic figures seen; clear-cell variant shows marked cytoplasmic vacuolization in upper layers • Sometimes with large keratinocytes that resemble the cells in Paget’s disease of the breast Figure 5-79. Bowen’s Disease • Dyskeratotic cells and acantholysis may be seen (Paget’s disease shows no dyskeratosis and no clear cells) • The basal layer is more uniform and looks like eyeliner (i.e., “eyeliner sign”) • Stain for high-molecular weight keratins (cytokeratin+) Metastatic Breast Carcinoma with Epidermotropism  • Epidermis can look like Paget’s disease • Key is in the dermis, where there are neoplastic cells infiltrating single-file through collagen, with some aggregation into duct-like structures • Lots of atypia (unlike microcystic adnexal carcinoma, which shows no atypia) • No grenz zone like AMML •  CEA+, CK7+ Pagetoid Melanoma • The basal layer should have atypical melanocytes • CEA-negative, S100+ Report a Problem/Feedback Dermatopathology  203
  • 212. Paget’s Disease of the Breast/Extramammary Paget’s • All variants show identical histology • Epidermis often acanthotic, with varying amounts of parakeratosis or hyperkeratosis • Infiltration with large cells with abundant pale-staining cytoplasm containing large vesicular nuclei; the unique feature is the gray/blue cytoplasm • Cells can be scattered throughout all layers of epidermis • Unlike melanoma, there are areas where proliferation is strictly above the basal layer • Frequently positive with Alcian blue pH 2.5, colloidal iron, or mucicarmine stains; stains positive for PAS, CEA, EMA, CAM5.2, u TIP and low molecular weight keratin aA clue to Paget’s disease of the breast is recognizing nipple (smooth muscle bundles in the dermis, sometimes ducts) Much Rarer • Pagetoid reticulosis (Woringer-Kolopp: localized disease in younger patients on acral areas; Ketron-Goodman: widespread disease) • Intraepidermal spread of sebaceous carcinoma or Merkel cell carcinoma 5.23 PALISADING REACTIONS Gout • Histiocytes, some palisaded, surrounding a basophilic aggregate, which on higher power has some crystalline features (silvery needle-like clefts) • Formalin fixation can destroy urate crytals (need alcohol fixation) Granuloma Annulare (GA) • Palisading granuloma, sometimes interstitial, with histiocytes surrounding a focus of altered collagen that often has a bluish tinge secondary to mucin; the palisading granulomas are in discrete foci in the dermis • Note that giant cells and plasma cells are more commonly seen in necrobiosis lipoidica diabeticorum • Note that deep GA can look exactly like a rheumatoid nodule, and the slide may lack epidermis Figure 5-80. Gout Necrobiosis Lipoidica Diabeticorum (NLD) • Square biopsy, thin epidermis with no rete ridges Figure 5-81. Granuloma Annulare 204  2013/2014 Dermatology In-Review l Committed to Your Future Report a Problem/Feedback
  • 213. • “Layered” superficial and deep dermal infiltrates (multifocal), separated by areas of degenerated collagen (necrobiosis, dripping of red areas through the dermis), infiltrate consists of lymphocytes, histiocytes, and plasma cells • Elastic-van-Gieson stain shows complete absence of elastic tissue • Plasma cells and giant cells are more numerous than in GA Necrobiotic Xanthogranuloma • Granulomatous inflammation surrounding central necrobiosis and cholesterol clefts, may see lymphoid follicles • Large areas of marked necrobiosis alternate with foci of xanthogranulomatous infiltrate in reticular dermis into subcutaneous fat • Necrobiotic collagen appears as amorphous eosinophilic debris • Infiltrate composed of lymphocytes, epithelioid cells, foamy histiocytes, and conspicuous giant cells, many of which are Touton type, and others are bizarre and angulated • Compared with NLD and subcutaneous GA, the necrobiosis of NXG is far more extensive, occurring in broad bands with extensive infiltrates of Touton giant cells and foamy histiocytes • Associated with paraproteinemia Rheumatoid Nodule • Epidermis is often not represented on the slide (a deep lesion) • Dense deposit of fibrin (confluent, large, eosinophilic) with surrounding palisading (“picket fence”) of histiocytes – palisade is tight, typically located in subcutaneous fat or in deep reticular dermis • Consider deep GA, especially if the specimen is from a child 5.24 VASCULAR Figure 5-82. Rheumatoid Nodule Acroangiodermatitis of Mali • Can look like Kaposi’s clinically • Biopsy shows exaggerated stasis changes with thick “reduplicated” vessels, extravasated RBCs, hemosiderin, fibrosis u TIP Angiokeratoma a5 types: • Numerous dilated and congested capillaries in the papillary dermis with overlying acanthosis and hyperkeratosis of the epidermis • Thrombosis is common • In Fabry’s disease there are cytoplasmic vacuoles representing lipids Mibelli Corporis diffusum Circumscripta Papular Fordyce Angiolymphoid Hyperplasia • Often on the face • Intradermal ill-defined, lobulated mass of numerous vascular channels lined by large rounded endothelial cells with copious eosinophilic cytoplasm → the endothelial cells are protuberant and extend into the vessel lumen Report a Problem/Feedback Dermatopathology  205
  • 214. • Each vessel is separate; sometimes prominent inflammatory cell infiltrate of lymphocytes, eosinophils and histiocytes Angiosarcoma • Often on scalp/sun exposed areas of elderly • Ill-defined infiltrative intradermal mass of numerous anastomosing, clefting vascular channels of varying caliber that dissect (carve) through the collagen • Endothelium that is single- or doublelayered and plump, pleomorphic and mitotically active (highly atypical) → forming papillae or solid nests within vascular lumina • Stains with CD31 • Under EM there are Weibel-Palade bodies Figure 5-83. Angiolymphoid Hyperplasia • Stewart-Treves: angiosarcoma devel- oping in lymphedematous area (originally described in post-mastectomy  lymphedema) Bacillary Angiomatosis  • Lobules of capillaries with prominent vascular endothelial cells with “blue clouds” of organisms located adjacent to vessels • Neutrophilic infiltrate with leukocytoclasis • Look for ulceration • Need to stain organisms with WarthinStarry Figure 5-84. Angiosarcoma Glomus Tumor • Common acrally (subungual), can be paroxysmally painful • Derived from contractile cells of the Sucquet-Hoyer canal and are desminpositive • Very uniform round cells around vascular spaces (the spaces can be quite dilated and resemble a cystic structure) • Solid tumors are composed of sheets of uniform cells that might only be two Figure 5-85. Glomus Tumor cells thick; don’t confuse with eccrine spiradenoma • Stains positive for smooth muscle actin, muscle-specific actin, and myosin • An inherited form is autosomal dominant with numerous tumors that are non-painful and located on the trunk/extremities; histologically are often glomuvenous malformations 206  2013/2014 Dermatology In-Review l Committed to Your Future Report a Problem/Feedback
  • 215. Intravascular Papillary Endothelial Hyperplasia (Masson’s) • Thrombosed vessel (circular space with pink fibrin within) with papillated fronds projecting into the center; the fronds are lined by a single layer of endothelial cells • No atypia Kaposi’s Sarcoma  • Early patch: Increase in dermal vessels showing minimal atypia and admixture of lymphocytes and plasma cells associated with hemosiderin deposits and purpura; vessels oriented parallel to epidermis and may dissect between collagen bundles; trapping of RBC’s; a clue is the promontory sign where there are new vessels (clefts) forming around other vessels/adnexae • Plaque stage: Obvious and extensive dermal vascular proliferation with lumina varying considerably in caliber; prominent inflammation • Nodular stage: Well-circumscribed dermal mass of variably eosinophilic spindle cells, scattered between cells are numerous irregular, slit-like, vascular spaces lacking endothelial lining • Spindle cells are CD34-positive and focally positive for CD31; Ulex – positive; Factor VIII positive • HHV-8 positive Figure 5-86. Kaposi’s Sarcoma Liposarcoma, Myxoid • Complex plexiform network of small thinwalled capillaries in a pattern resembling chicken-wire • Myxoid stroma • Deep lesion Figure 5-87. Kaposi’s Sarcoma Lymphangioma, Cavernous • Widely-dilated, irregularly shaped spaces in dermis and subcutaneous tissue lined by single layer of bland endothelial cells • Milky white substance in vessels Pyogenic Granuloma • Exophytic, lobulated, dermal mass of numerous small capillaries • Very cellular; often radiating from larger, more central vessels, in a loose edematous collagenous matrix • Mitoses commonly present, adjacent epidermis often acanthotic and forms collarette • No trapping of RBC’s Report a Problem/Feedback Dermatopathology  207
  • 216. Sclerosing Hemangioma • A fibrous histiocytoma with hemosiderin thrown in • The periphery of the tumor resembles an ordinary DF with collagen trapping; there can be foamy cells and multinucleated giant cells • Look for RBC’s trapped between spindle cells 5.25 MISCELLANEOUS Acanthosis Nigricans • Elongated papillomatosis • Hyperkeratosis • Slight acanthosis • Occasional keratin-filled cysts Figure 5-88. Pyogenic Granuloma Accessory Tragus • Polypoid papule • Periphery rimmed by vellus hairs (near epidermis) • Cartilage might not be present; if cartilage present it is at center of polyp and surrounded by abundant adipose tissue Amalgam Tattoo • Mucosal surface • Dermal pigment which is deposited in a very fine, wiggly pattern • Occasional clumping Figure 5-89. Accessory Tragus Chloroma  • Greenish tumor (grossly) in acute granulocytic leukemia • Green color secondary to myeloperoxidase • Diffuse infiltrate in dermis with many blast cells • Chloracetate esterase-positive Chondrodermatitis Nodularis Helicis  • Not always an ulcer; the key is fibrosis or degenerated collagen beneath an ulcer or hyperplastic epidermis Figure 5-90. Chondrodermatitis Nodularis Helicis • Granulation tissue flanks the fibrosis • Base contains abundant granulation tissue and heavy chronic inflammatory cell infiltrate, often degenerative changes in cartilage with hyalinization or calcification 208  2013/2014 Dermatology In-Review l Committed to Your Future Report a Problem/Feedback
  • 217. Clear Cell Acanthoma • Clue is that it looks like psoriasis, with regular acanthosis, but the cells are clear/pale, and at low power you can see an abrupt change on each lateral margin from clear/pale cells to normal-appearing, less acanthotic epidermis    •  Associated with ichthyosis •  Clear/pale cells secondary to increased glycogen content secondary to a deficiency of phosphorylase • PAS-positive Coma Blister • Akin to erythema multiforme of the sweat glands → eccrine glands are red and necrotic • Both intra- and subepidermal blister can form • Caused by hypoxemia Elastosis Perforans Serpiginosa (EPS) • Perforating disorder with elimination of basophilic elastic fibers through the epidermis • Increased elastic tissue in dermis and papillae filled with homogeneous coarse elastic fibers • Center of papule has a plug that fills a winding or straight canal unrelated to pilosebaceous unit, extending from papillary dermis to skin surface • Surrounding epidermis hyperplastic and acanthotic and sometimes pseudoepitheliomatous, growing downward to engulf abnormal elastic fibers in a claw-like fashion Figure 5-91. Electrodessication Artefact PEARL w  Associated with Down’s syndrome, EhlersDanlos type IV, Osteogenesis imperfecta, Rothmund Thompson, Marfan’s, Werner’s, acrogeria, penicillamine Electrodessication Artefact • Epithelial cells become elongated and spindled like “chafs of wheat” • Streaming of nuclei • Collagen amorphous and blue Endometriosis, Cutaneous Figure 5-92. Endometriosis, Cutaneous • Dilated ducts, endometrial glands lined by tall columnar epithelium • Fibrovascular core (stroma) around ducts that appear apocrine • Often deeper in dermis with associated hemorrhage Report a Problem/Feedback Dermatopathology  209
  • 218. Eosinophilic (Pustular) Folliculitis • Histologically the three forms look similar: eosinophil-rich pustule, spongiosis of outer root sheath of hair follicle, superficial and deep perifollicular and perivascular lymphocytic infiltrate with eosinophils, neutrophils PEARL w  linically there are probably three different C forms, one seen as crusted papules on the occipital scalp of babies, another seen more in Japanese patients on the face, and another consisting of pruritic papules on the trunk of HIV patients Figure 5-93. Eosinophilic (Pustular) Folliculitis Erythema Dyschromicum Perstans • Hyperkeratosis with normal or atrophic epidermis; basal cell vacuolar degeneration and cytoid body formation • Marked pigmentary incontinence • Mild perivascular or lichenoid inflammatory cell infiltrate in superficial dermis Freeze Artefact • Empty vacuoles throughout epidermis Gel Foam Artefact • Wavy foreign substance Figure 5-94. Erythema Dyschromicum Perstans Ochronosis • Exogenous and endogenous histopathology identical • Banana-shaped brownish to orangeyellow thickened, discolored collagen Merkel Cell Carcinoma • Very blue on low power but cells are very pale on high power • Shows nodules and sheets of basophilic cells with vesicular nuclei containing small nucleoli and inconspicuous cytoplasm • Tumor cells can dissect through collagen, marked mitotic activity; tumors stain positive for neuron specific enolase, EMA, Ber-EP4, CAM5.2, CD57 Figure 5-95. Gel Foam Artefact 210  2013/2014 Dermatology In-Review l Committed to Your Future Report a Problem/Feedback
  • 219.  • Characteristic paranuclear globular coexpression of simple epithelial cytokeratins (CK20) and neurofilament proteins • Metastatic oat cell carcinoma looks the same but stains negative for cytokeratin 20 and is positive with TTF-1 • Associated with Merkel cell polyomavirus Necrolytic Migratory Erythema • Necrosis of the superficial epidermis (relative sparing of the lower epidermis) (the necrosis can look like confluent parakeratosis) • Intraepidermal clefting and vesiculation • Differential includes other nutritional deficiencies like zinc deficiency (acrodermatitis enteropathica), pellagra, biotin deficiency Figure 5-96. Ochronosis Paraffinoma • Round or oval spaces within the dermis and subcutaneous fat in a “swiss cheese” pattern • Foamy histiocytes or giant cells may line edges of these cystic spaces, and dense fibrous scarring may be evident Reactive Perforating Collagenosis Figure 5-97. Merkel Cell Carcinoma • Widened dermal papilla contains basophilic debris without inflammation – “volcano effect” • Overlying epidermis thinned, and perilesional epidermis acanthotic and envelops altered collagen • Looks like an ulcer, and fibers carried to surface by widened intercellular spaces • In umbilicated lesions epidermis forms a cup-shaped depression with parakeratotic keratinocytic debris and degenerated vertically oriented collagen Renal Carcinoma, Metastatic • Blood vessels are the clue to the diagnosis → very vascular; bubbly, clear cells with some mitoses and cytologic atypia Storiform Collagenoma (Sclerotic Fibroma) • Well-circumscribed dermal nodule composed of hyalinized collagen bundles separated by clefts and arranged in a storiform pattern • Hypocellular • Cowden’s syndrome or Gardner’s syndrome Report a Problem/Feedback Dermatopathology  211
  • 220. Urticaria Pigmentosa • Mast cells seen predominantly in papillary dermis • Eosinophils present often, basal cell hyperpigmentation of overlying epidermis commonly, blistering can occur subepidermally  • Can stain with Giemsa, Leder, or toluidine blue; as well as tryptase and c-kit • Monomorphic cell differential diagnosis, which includes mastocytosis, glomus tumor, and poroma Xanthelasma • Important clue is recognizing eyelid skin, either by vellus hair follicles or skeletal muscle at the base of the biopsy • Lipid laden foam cells within superficial dermis Xanthoma, Eruptive • Foamy histiocytes within superficial reticular dermis • Lymphocytes and neutrophils may infiltrate • Always check for foam cells if you are thinking GA 5.26 CLUES FOR BOARD PURPOSES If the epidermis is absent, think of: • Angioleiomyoma • Giant cell tumor of tendon sheath • Nodular fasciitis • Rheumatoid nodule • Gout • Hibernoma If the section looks normal at low power, think of:  • Macular amyloidosis • Anetoderma • Argyria • Atrophoderma • Café-au-lait spot • Connective tissue nevus • Cutis laxa • Dermatophyte infection • Tinea versicolor • GVHD • Ichthyosis vulgaris • Myxedema • Parapsoriasis • Porokeratosis • Scleroderma • Scleromyxedema • Urticaria • TMEP • Vitiligo 212  2013/2014 Dermatology In-Review l Committed to Your Future Report a Problem/Feedback
  • 221. If there is necrosis in the epidermis, think of: • Nutritional deficiency (if confluent superficial necrosis below stratum corneum, with sparing of lower epidermis) • Erythema multiforme (if full-thickness necrosis with a normal basket-weave stratum corneum) • Herpes (if necrosis in small foci or associated with a follicle and intermixed with balloon cells/giant cells/cells with basophilic viral changes) • Coma bullae (look for necrosis of eccrine glands) If you see giant cells, think of: • Reticulohistiocytosis (if pale pink and “oncocytic”) • Juvenile xanthogranuloma (if Touton) • Xanthoma (if many Touton with foamy cells) • Tuberculosis (if Langhans and foreign-body) • Herpes (if associated with necrosis and balloon cells) • Scar (if foreign-body) • Ruptured cyst (if foreign-body) • Giant cell tumor of tendon sheath (if osteoclast-like) If you see regular acanthosis at low power, think of: • Psoriasis • Bowen’s (look for atypia/mitoses) • Clear cell acanthoma (look for pale cells with abrupt demarcation to normal) • Dermatophytosis (hyphae within stratum corneum) If you see neutrophils in the stratum corneum, think of: • Psoriasis • Dermatophytosis • Pityriasis lichenoides • Verruciform xanthoma If you see parakeratosis above basket-weave stratum corneum, think of: • Dermatophytosis • Resolving spongiotic disorder If you see pseudoepitheliomatous hyperplasia overlying abscesses, think of: • Blastomycosis (look for broad-based budding organisms 8-15 microns) • Paracoccidioidomycosis (look for 60 micron mariner’s wheel; single yeast cells will be 6-20 microns) • Chromoblastomycosis (look for pigmented 6-12 micron “copper pennies”) • Coccidioidomycosis (look for 10-80 micron spherules) • Sporotrichosis (cigar-shaped organisms that are very rare on biopsy) • Halogenoderma/Bromoderma (note that this diagnosis is history-dependent and needs exclusion of infections, so it is unlikely that you will make this diagnosis on the Boards) If you see grains, think of: • Botryomycosis (look for “blue clouds” of bacteria surrounded by eosinophilic material in the Splendore-Hoeppli reaction) Report a Problem/Feedback Dermatopathology  213
  • 222. • Actinomycosis/Nocardiosis (look for thin filaments at periphery of grain) • Eumycetoma (look for thick hyphae at periphery of grain) Gram-positive sulfur granules differential: • Staphylococcal abscess • Actinomycosis (pink and filamentous at the edge of lesion) • Nocardia (can visualize organisms with Fite stain) If you see hyperkeratosis over an atrophic epidermis, think of: • Lichen sclerosus et atrophicus • Flegel’s disease • Discoid lupus erythematosus If you see a dome-shaped/cone-shaped silhouette at low power, think of: • Accessory digit (look for nerves in dermis) • Acquired digital fibrokeratoma (hyperkeratosis, dermal fibrosis) • Accessory nipple (hyperpigmented acanthosis, smooth muscle bundles in dermis, ducts in deep dermis) • Accessory tragus (numerous vellus/small hair follicles in dermis/cartilage may be present) If you see a very rectangular-shaped punch biopsy “i.e., square biopsy sign,” think of: • Scleromyxedema • Scleredema • Scleroderma • Necrobiosis lipoidica diabeticorum If you see clear cells, think of: • Metastatic renal cell carcinoma (look for hemorrhage) • Clear cell squamous cell carcinoma/Bowen’s (look for atypia/mitoses/squamous pearls) • Trichilemmoma (look for palisading of basal layer and thick basement membrane) • Clear cell acanthoma • Hidradenoma • Note: make sure the cells are clear cells, not balloon cells or sebaceous cells If you see eosinophilic spongiosis, think of: • Incontinentia pigmenti, pemphigus, BP, chronic bullous disease of childhood, pemphigoid gestationis, PUPPP, insect-bite reactions, atopic dermatitis, contact dermatitis, Grover’s disease, drug reaction • There is clearing of keratinocytes with indwelling eosinophils, but no abscess formation 5.27 “BODIES” Asteroid Body • Eosinophilic amorphous material seen in sporotrichosis OR • Stellate inclusions seen in sarcoid, berylliosis Birbeck Granules • Seen on electron microscopy • Tennis-racquet-shaped cytoplasmic bodies in Langerhans cells 214  2013/2014 Dermatology In-Review l Committed to Your Future Report a Problem/Feedback
  • 223. Caterpillar Body • Pale amorphous pink linear structures in the epidermis of porphyria cutaneous tarda • Represents type IV collagen Civatte Body • Apoptotic cell remnants in epidermis Colloid Body • Apoptotic cell remnants in papillary dermis Comma-shaped Body • Seen on electron microscopy • Associated with histiocytoses like benign cephalic histiocytosis (non-specific) Cowdry A body (Lipschutz Body) • Intranuclear eosinophilic globules seen in herpes infection Cowdry B Body • Intranuclear inclusions seen in adenovirus and poliovirus infection Donovan Body • Intracytoplasmic bacteria in granuloma inguinale Dutcher Body • “Pseudo”-nuclear inclusions secondary to collections of immunoglobulin in the cytoplasm that push into the nucleus of plasma cells Guarnieri Body • Eosinophilic cytoplasmic inclusions seen in smallpox Henderson-Paterson Body • Large eosinophilic cytoplasmic inclusions that fill the cell seen in Molluscum lesions Kamino Body • Eosinophilic globular masses of varying sizes seen at and above DEJ • Considered to be a helpful marker for Spitz nevus Leishman-Donovan Body • Intracytoplasmic, nonflagellated parasite seen in leishmaniasis Lipschutz Body (Cowdry A Body) • Intranuclear inclusions in epithelial or neuronal cells seen in herpes infection Medlar Body • a.k.a. sclerotic body, “copper penny,” hot cross bun • Seen in chromoblastomycosis Michaelis-Gutman Body • Concentric, laminated, calcified bodies within and external to cells seen in malakoplakia Report a Problem/Feedback Dermatopathology  215
  • 224. Negri Body • Cytoplasmic inclusions (neuronal) seen in rabies Papillary Mesenchymal Body • Structure thought to be an abortive attempt of fibroblasts to form mesenchyme necessary for hair induction, reminiscent of early hair germ • Seen in trichoblastoma and trichoepithelioma Psammoma Body • Concentric, laminated, calcified bodies seen in papillary thyroid carcinoma, benign nevi, meningiomas, and other conditions Russell Body • Inclusions secondary to collections of immunoglobulin in the cytoplasm of plasma cells • Seen in rhinoscleroma, granuloma inguinale, syphilis Schaumann Body • Concentric, laminated, calcified inclusions seen in sarcoid and other granulomatous disorders Verocay Body • Palisaded nuclei on either side of a central pink area in schwannoma Weibel-palade Body • Cytoplasmic marker of endothelial cells Worm-shaped Body • Seen on electron microscopy • Associated with histiocytoses like benign cephalic histiocytosis (non-specific) Zebra Body • Seen on electron microscopy in mucopolysaccharidoses ACKNOWLEDGMENTS Ronald Barr, MD Scott Binder, MD Bruce E. Strober, MD, PhD REFE REN C ES 1. Alam M, Caldwell JB, Eliezri YD. Human papillomavirus-associated digital squamous cell carcinoma: Literature review and report of 21 new cases. J Am Acad Dermatol 2003; 48: 385-393. 2. Allee JE et al. Multiply recurrent trichilemmal carcinoma with perineural invasion and cytokeratin 17 positivity. Dermatol Surg. 2003; 29: 886-889. 3. Binder SW et al. The histology and differential diagnosis of Spitz nevus. Sem Diag Pathol 1993; 10: 36-46. 4. Elder D et al, eds. Lever’s Histopathology of the Skin, 8th ed. Philadelphia: Lippincott, 1997. 5. Fetil E et al. Multiple pilomatricoma with perforation. Int J Dermatol. 2002; 41: 892-893. 216  2013/2014 Dermatology In-Review l Committed to Your Future Report a Problem/Feedback
  • 225. 6. Glusac EJ. Criterion by Criterion, MF. Am J Dermatopathol 2003; 25: 264-269. 7. Hoque SR et al. Subcutaneous panniculitis-like T-cell lymphoma: a clinicopathological, immunophenotypic and molecular analysis of six patients. Br J Dermatol 2003; 148: 516-525. 8. Poniecka AW et al. An immunohistochemical study of basal cell carcinoma and trichoepithelioma. Am J Dermatopathol 1999; 21: 332-336. 9. Rutten A et al. Cystic sebaceous tumors as marker lesions for the Muir-Torre syndrome: a histopathologic and molecular genetic study. Am J Dermatopathol 1999; 21: 405-413. 10. Said J et al. Lymphoma including Hodgkin lymphoma. In Immuno and Molecular Microsocopy, in press. 11. Sardy M et al. Epidermal transglutaminase (TGase 3) is the autoantigen of dermatitis herpetiformis. J Exp Med 2002; 195: 747-757. 12. Terrier-Lacombe MJ et al. Dermatofibrosarcoma protuberans, giant cell fibroblastoma, and hybrid lesions in children: clinicopathologic comparative analysis of 28 cases with molecular data—a study from the French Federation of Cancer Centers Sarcoma Group. Am J Surg Pathol 2003; 27: 27-39. 13. Weedon D. Skin Pathology, 2nd ed. CITY: Churchill Livingston, 2002. 14. Wu H, Stanley JR, Cotsarelis G. Desmoglein isotype expression in the hair follicle and its cysts correlates with type of keratinization and degree of differentiation. J Invest Dermatol 2003; 120: 10521057. 15. Feng H. Shuda M, Chang Y. Moore PS. Clonal Integration of a Polyomavirus in Human Merkel Cell Carcinoma. Science 2008; 319: 1096-1100. Report a Problem/Feedback Dermatopathology  217
  • 226. NOTES 218  2013/2014 Dermatology In-Review l Committed to Your Future Report a Problem/Feedback
  • 227. NOTES Report a Problem/Feedback Dermatopathology  219
  • 228. NOTES 220  2013/2014 Dermatology In-Review l Committed to Your Future Report a Problem/Feedback
  • 229. 6 Benign and Malignant Neoplasms Keyvan Nouri, MD Sonal Choudhary, MD Jessica Savas, MD Jennifer Ledon, MD Maria Patricia Rivas, MD Voraphol Vejjabhinanta, MD L. Magaly Villafradez-Diaz, MD George W. Elgart, MD C o n t e n t s 6.1 6.2 Actinic Keratosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 225 6.3 Bowen’s Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 227 6.4 Non-melanoma Skin Cancer . . . . . . . . . . . . . . . . . . . . 229 6.5 Basal Cell Carcinoma . . . . . . . . . . . . . . . . . . . . . . . . . . 229 6.6 Squamous Cell Carcinoma . . . . . . . . . . . . . . . . . . . . . 232 6.7 Keratoacanthoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 234 6.8 Malignant Melanoma . . . . . . . . . . . . . . . . . . . . . . . . . . . 237 6.9 Merkel Cell Carcinoma . . . . . . . . . . . . . . . . . . . . . . . . . 241 6.10 Cutaneous T-Cell Lymphoma . . . . . . . . . . . . . . . . . . . 243 6.11 Angiosarcoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 246 6.12 Desmoplastic Trichoepithelioma . . . . . . . . . . . . . . . 247 6.13 Dermatofibrosarcoma Protuberans . . . . . . . . . . . . . 248 6.14 Report a Problem/Feedback Seborrheic Keratosis . . . . . . . . . . . . . . . . . . . . . . . . . . . 223 Microcystic Adnexal Carcinoma . . . . . . . . . . . . . . . . 249 Benign and Malignant Neoplasms  221
  • 230. 6.1 SEBORRHEIC KERATOSIS Epidemiology • Frequently found in individuals older than 30 years of age • Lesions are usually multiple and can occur in any location except mucosa, palms and soles Etiology The etiology of SKs is unknown. Risk factors: Genetic propensity may play a role, as patients with multiple lesions commonly have a positive family history. According to Kennedy et al , aging remains the strongest factor associated with the development of SKs; whereas, painful sunburns and a lifetime of sun exposure were not associated with an increased risk. 1 1,2 3 3 Clinical Presentation The lesions may begin as well-defined brown macules. Later on they become waxy, hyperkeratotic and hyperpigmented plaques with a stuck-on appearance. The surface has a “warty” appearance with multiple plugged follicles. Colors range from brown to black and may be located anywhere with the face, trunk and upper extremities being the predilected sites (Figure 6-1). Dermoscopic features: comedo-like openings, milia-like cysts, fissures (brain-like appearance), fingerprinting, lack of true pigment network, and telangiectasias arranged in regular loops (hairpin-like vessels). The absence of pigment network, branched streaks, and pigment globules are the key features that differentiate SKs from melanocytic neoplasms. 1,2 4,5 Figure 6-1. Hyperpigmented plaque with “stuck-on” appearance typical of Histopathology seborrheic keratosis There are several clinicopathological variants: • Common SK: The classic lesion is histologically characterized by a mushroom-like appearance, with sharply demarcated hyperplastic epidermis overhanging the surrounding skin. The tumor consists of uniform masses of keratinocytes or baseloid cells with tunnels filled with keratin that look like cysts when seen in cross-section. The number of keratinocytes present determines the color of the lesion (Figure 6-2 and Figure 6-3) • Reticulated SK: Histologically shown as thin cords of basaloid cells descending from the base of the epidermis. These cords may be surrounded by eosinophilic collagen stroma making up much of the lesion. Keratin cysts are also present (Figure 6-2 and Figure 6-3) 1,2 Report a Problem/Feedback Benign and Malignant Neoplasms  223
  • 231. Figure 6-2. SK, lower magnification. Figure 6-3. SK, higher magnification. Benign neoplasm of keratinocytes confined Keratin filled invaginations surrounded to the epidermis, composed of basaloid by strands of uniform basaloid uniformed cells that shows no signs of proliferations cellular atypia. The neoplasm is sharply circumscribed and has numerous invaginations that are filled with keratotic plugs called “pseudo-horn cysts”  • Stucco Keratosis: Also known as hyperkeratotic or verrucous SKs. Typically appear as multiple, skin colored papules or plaques, located symmetrically on the lower extremities. Histologic evaluation shows “church-spire” like projections of epidermal cells around a collagen core thrusting upward into a basket-weave type of hyperkeratosis. Vacuolated keratinocytes are not present in this type of lesion, thus differentiating it from verruca vulgaris • Irritated SK: Presents as a typical SK with eczematous and erythematous changes around it, usually due to trauma. Histologically, inflammation is seen, with eosinophilic flattened squamous cells arranged in onion-like pattern. This may resemble poorly differentiated keratin pearls seen in squamous cell carcinoma, but can be differentiated by their large number, small size, and circumscribed configurations. Keratinocytes in irritated SKs show a high degree of keratinization or maturation compared to the common SK • Pigmented SK: Also known as melanoacanthoma, characteristically presents as a dark colored SK. Dendritic melanocytes engorged with pigment are prominent within the lesion. The surrounding keratinocytes barely contain any melanin. The melanocytes proliferate as nests from the basal layer into the superficial layer of the epidermis. There is no malignant potential associated with this type of SK • SK with Squamous Atypia: Characterized by the presence of cellular atypia and dyskeratosis of unknown cause. The lesion mimics Bowen’s disease or invasive SCC. Therefore, complete removal is recommended • Dermatosis Papulosa Nigra: Multiple, small, hyperpigmented, sessile SKs typically found on the face of African American individuals. Except for the smaller size, there’s no difference found on histology compared to common SK Sign of Leser-Trélat  It is defined as a sudden appearance and increase in size of multiple SKs. The eruption is classically described to appear in a “Christmas tree” pattern and may occur anywhere in the body; however; the most common location is the back and the chest. Its association with an internal malignancy remains controversial. Adenocarcinomas of the colon, rectum, stomach and 224  2013/2014 Dermatology In-Review l Committed to Your Future Report a Problem/Feedback
  • 232. breast, among others, are the most common malignancies associated with this phenomenon. Therefore, depending on the clinical findings, further evaluation should include complete blood and chemistry studies, chest X-ray, endoscopy of the gastrointestinal tract, mammogram, cervical cytology, and prostate specific antigen.6 Malignant acanthosis nigricans is commonly seen in approximately 35% of patients with the sign of Leser-Trélat. 1,6 Treatment SKs are usually treated only in those cases when the lesion is not a typical SK, when they become symptomatic or cosmetically unacceptable for the patient. Surgical excision should be considered the treatment for those cases when the lesion is not a typical SK and histologic verification is needed. Other treatment alternatives include cryotherapy, electrodessication, laser therapy, topical 5-FU and dermabrasion. 5,7 6.2 ACTINIC KERATOSIS Epidemiology Actinic keratoses (AKs) are very common, premalignant lesions, with the potential of becoming invasive squamous cell carcinomas (SCC). It accounts for the third most common reason why individuals consult a dermatologist. Risk factors: Individual susceptibility (older age, male gender, fair skin phenotype, and light eye color), immunosuppression, lifetime sun exposure, and some genetic syndromes such as albinism and xeroderma pigmentosum. 8,9 Etiology Ultraviolet radiation B (UVB) from sunlight is responsible for AK development. It triggers the formation of thymidine dimers both in DNA and RNA, resulting in mutated keratinocytes. The mutations occur on the tumor suppressor gene p53 within the keratinocytes resulting in impairment of the mechanism of apoptosis. Therefore, clonal expansion of mutated keratinocytes may occur leading to the formation of AKs.10-12  Clinical Presentation Patients are usually elderly with fair complexion and evident solar elastosis due to a history of chronic sun exposure. Therefore, lesions are commonly found on sun-exposed areas (head, neck, forearms, dorsal hands) with 60% found on upper extremities.13 Typical AKs appear as erythematous, flat, rough macules or papules that are better felt than seen.9,13 Other clinical subtypes include hypertrophic AK, cutaneous horn and actinic cheilitis. The hypertrophic AK (HAK) lesions are thicker, scaly, skin colored or erythematous plaques. The cutaneous horn is defined as a type of HAK that presents as a conical hypertrophic protuberance emanating from an erythematous base (Figure 6-4). Actinic chelitis develops from the confluence of several AKs on the lips (usually the lower lip). The patient presents with red, scaly or chapped lips with erosions and fissures.13 (Figure 6-5) Histopathology The keratinocytes appear atypical, pleomorphic and disordered in arrangement. Foci of atypical keratinocytes are located in the basal layer protruding as buds into the papillary dermis. The epidermis also shows irregular acanthosis with columns of parakeratosis and hyperkeratosis. Changes due to solar elastosis and inflammatory infiltrate can be found in the dermis.9 (Figure 6-6 and 6-7) Report a Problem/Feedback Benign and Malignant Neoplasms  225
  • 233. Treatment Several forms of therapy are available for the treatment of AKs, including single lesion therapy, field-directed therapy and oral therapy. A recent Cochrane review on treatment for AKs found the following to be successful options for the treatment. Single Lesion • Cryotherapy: The most common treatment for AKs with a cure rate of 98.8% • Photodynamic Therapy (PDT) with Aminolevulinic Acid (ALA): Found to have similar effectiveness, but better cosmetic outcome, when compared to cryotherapy for single lesions Figure 6-4. Cutaneous Horn Figure 6-5. Hypopigmented, scaly plaque with fissures involving the lower lip of a male patient Figure 6-6. AK, lower magnification. Focal Figure 6-7. AK, higher magnification. parakeratosis alternating with orthokerato- Marked parakeratosis and absence of the sis. The neoplasm is confined to the epider- granular layer. Pleomorphism of the mis. There is prominent solar elastosis in atypical keratinocytes within the basal layer the subjacent papillary dermis. The tumor of the epidermis spares the hair follicles Field-directed Therapy • 5% Imiquimod: Is an immune response modifier that stimulates the innate and cell mediated immune pathways. It induces the synthesis and release of cytokines such as interferon, tumor necrosis factor, and interleukins 1,5,6,8,10, and 12, among others. Similar efficacy to 5-FU with better cosmetic outcome. 226  2013/2014 Dermatology In-Review l Committed to Your Future Report a Problem/Feedback
  • 234. • 0.5% 5-Fluorouracil (5-FU): Blocks the methylation reaction of deoxyuridylic acid to thymidylic acid, thus interfering with the synthesis of DNA and RNA with cure rates up to 93% when patients sustain treatment until adequate endpoint • 0.025-0.05% ingenol mebutate: Hydrophobic diterpene ester extracted from the plant Euphorbia peplus. Induces swelling of mitochondria in dysplatic keratinocytes leading to cell death by necrosis • 3% diclofenac in 2.5% hyaluronic acid: Non-steroidal anti-inflammatory drug that inhibits cyclo-oxygenase 2 (COX-2) and reduces prostaglandin synthesis, which are thought to be increased in exposed skin • PDT: The application of ALA leads to the formation of protoporphyrin IX (PpIX), which can be irradiated with certain wavelengths, leading to a photochemical reaction and ultimately reactive singlet oxygen formation • Mechanical resurfacing with both carbon dioxide (CO2) and Erbium: Yttrium Aluminum Garnet (Er:YAG) lasers • Trichloroacetic Acid (TCA) Peel Prevention • Sun avoidance • Low fat diets have been reported as useful in decreasing the incidence of AKs • Retinoids in transplant patients may also reduce the formation of AKs 18 19 Prognosis The risk of AK progression into invasive SCC ranges from 0.025% to 16% per year. Glogau concluded that the average rate of risk of progression of AK to SCC is approximately 8% among the studies reviewed. 10 20 6.3 BOWEN’S DISEASE Epidemiology Bowen’s disease (BD) is a form of squamous cell carcinoma (SCC) in situ than may occur both in skin and mucous membranes. The exact incidence of BD is unknown. It affects elderly adults of both sexes, with a slight predominance in the female gender.13,21,22 Etiology Multiple etiologic factors have been associated with the development of BD including chronic sun exposure, arsenic exposure, ionizing radiation, immunosuppression and the human papilloma virus (HPV).13,21 Clinical Manifestations BD typically appears as a slowly enlarging, well-demarcated, often scaly, erythematous patch or plaque. It may be located on any sun-exposed or non-sun-exposed areas of the skin, including mucous membranes.13,21-23 However, the most common locations include the head and neck, followed by the extremities and trunk (Figure 6-8). BD arising on the lower limbs is frequently found in women; whereas lesions located on the ears and scalp are more common in men.23 BD on the nail bed presents as a periungual erythematous scale, onycholysis, or an erosion with crusting and nail discoloration.13,21 Intertrigenous BD appears as an acute oozing, erythematous Report a Problem/Feedback Benign and Malignant Neoplasms  227
  • 235. dermatitis or as a pigmented plaque.13,21 Mucosal BD may appear as a verrucous or polypoid plaque, as an erythroplakic patch or as a velvety red plaque.13,21 Erythroplasia of Queyrat is a term used to designate mucosal BD confined to the genitals. It is primarily seen in uncircumcised men and typically involves the inner surface of the foreskin, the glans penis, as well as the coronal sulcus. In women, it is most commonly found on the labia minora. Histopathology Epidermal dysplasia and keratinocytic disorganization is seen through the entire thickness of the epidermis, from the stratum corneum down to the basal layer. However, the basement membrane remains intact. Hyperkeratosis and parakeratosis is also present. Within the entire epidermis, pleomorphic keratinocytes show loss of polarity, atypia and mitosis, producing a “windblown” appearance. Chronic inflammatory infiltrate composed of lymphocytes, plasma cells and histiocytes is commonly found in the upper dermis. Other histologic variants have been reported including psoriasiform, atrophic, verrucous, acantholytic and pigmented BD.13,24 (Figure 6-9) Diagnosis and Differential Differential diagnosis include superficial BCC, chronic dermatitis, psoriasis, lichen planus, and actinic keratosis, among others. Arsenic-induced SCC in situ is difficult to distinguish clinically from the classic form of Bowen’s disease; however, the former is more commonly multi-focal and has a tendency to favor non sun-exposed areas on the trunk. Histologically, BD must be differentiated from Paget’s disease, melanoma, bowenoid papulosis, and podophyllin-induced changes in a wart. 13 Treatment • Simple excision(Recurrence rates of 5%) • Mohs micrographic surgery: in areas where there is an increased incidence of sub-clinical spreading, or when tissue sparing is a priority (e.g., face, genitals) • Cyosurgery, 5-FU, and imiquimod have been reported with conventional excision • The superficial, large, and sometimes multi-focal lesions of Bowen’s disease may be consiered an ideal indication for Photodynamic Therapy (PDT) • Radiotherapy can be used, but should not be considered first-line 25,26 13,21 Prognosis It is estimated that approximately 5% of patients with BD develop invasive SCC. Of these, about 30% have an increased risk of developing metastases.13,24 228  2013/2014 Dermatology In-Review l Committed to Your Future Report a Problem/Feedback
  • 236. Figure 6-8. Pink, scaly well-demarcated Figure 6-9. BD. Neoplasm confined to plaque located on the lower extremety of the epidermis. The proliferation of atypi- a white, female patient cal keratinocytes is present in all layers of the epidermis. The hyperchromatic pleomorphic cells exhibit atypical mitotic figures within the whole thickness of the epidermis. Some dyskeratotic cells with pyknotic nuclei are observed in the upper layers of the epidermis. The white line is pointing at a multinucleated tumor cell 6.4 NON-MELANOMA SKIN CANCER Non-melanoma skin cancer (NMSC) is the most common cancer in the United States. Basal cell carcinoma (BCC) accounts for approximately 80% of NMSC, whereas 20% corresponds to squamous cell carcinoma (SCC).22 6.5 BASAL CELL CARCINOMA Epidemiology BCC is the most common cancer that affects humans and occurs more commonly in men, with a male to female ratio of approximately 2:1. Over the past 30 years, the incidence has risen substantially, particularly in young women. While BCC rarely metastasizes or results in death, significant morbidity due to disability or disfigurement is not uncommon. Risk factor: UVR exposure, fair skin phenotype, immunosuppression, family history of skin cancer, genetic syndromes (e.g., nevoid basal cell carcinoma syndrome, and xeroderma pigmentosa, among others), and radiation therapy.30-33 Etiology When UVB damages the DNA it produces C-T transition mutations, better known as “UVB signature” or “fingerprinting.” The p53 and PTCH (patch) genes are the major targets of UVB for the development of BCC. The p53 is a tumor-suppressor gene, that regulates the cell cycle and apoptosis, and has been found to be mutated in approximately 56% of human BCC. Furthermore, the “UVB signature” is present in about 65% of them. The PTCH gene (located on chromosome 9q22) is involved in the Hedgehog signal transduction pathway and is found to be mutated in 30-40% of sporadic BCC, with 41% incidence of “UVB signature.” It is also responsible for the genetic defect in Gorlin syndrome. In approximately 50% of BCCs isolated from xeroderma pigmentosa both p53 and PTCH genes are mutated.11,32,34 Report a Problem/Feedback Benign and Malignant Neoplasms  229
  • 237. On the other hand, UV radiation induces a state of relative immunosuppression (by altering antigen-presenting mechanisms and producing immunosuppressive cytokines) that ultimately compromises tumor rejection.11,32 Other genes involved in the development of BCC include smoothened-activating mutations and PTCH2 mutation.34 Clinical Manifestations Sun-exposed areas are the most frequent location of BCCs, but it can be found in anywhere in the skin. There are several subtypes of BCC:31,33 The nodular subtype represents approximately half of all BCCs. It initially presents as a small, translucent, pearly papule with telangiectasias on its surface. As the lesion progresses, the center may become ulcerated and the borders become indurated, rolled and pearly. (Figure 6-10) This classic lesion is better known as “rodent ulcer.” While all subtypes of BCC may ulcerate, it is most commonly observed in the nodular subtype. This variant is frequently found on the face. The superficial BCC is commonly located on the thorax and limbs, and appears as a pink, scaly plaque with a slightly elevated pearly border. (Figure 6-11) The superficial BCC subtype is the most prevalent variant in younger patients with a mean age of onset of 57 years. Crusting and ulceration may sometimes be present. Pigmented BCCs may appear as the nodular or superficial variant, with central black or brown pigmentation in the form of specks, dots or globules. (Figure 6-12) The morpheaform BCC, also known as sclerosing BCC, presents as a skin-colored, pink or whitish, indurated plaque that resembles a scar. (Figure 6-13) This variant has ill-defined borders and an aggressive growth pattern. It represents approximately 5% of all BCCs. The fibroepithelioma, or Pinkus, BCC appears as pedunculated, pink, dome-shaped papule, frequently located on the back (lumbosacral area). Gorlin syndrome (i.e., Nevoid Basal Cell Carcinoma syndrome) is characterized by the appearance of multiple BCCs during childhood, odontogenic keratocysts of the jaw and skeletal defects (e.g., macrocephaly, hypertelorism, frontoparietal bossing, spina bifida, or rib abnormality, among others). Tumors associated with this disease include medulloblastoma and meningioma. It is inherited in an autosomal dominant pattern.31 Histopathology Several histologic patterns have been described: nodular, superficial, micronodular, infiltrative, morpheaform, and fibroepithelial (also known as fibroepithelioma of Pinkus). Regardless of the subtype, all BCCs share the charactersitic histopathologic feature of large aggregates of basaloid keratinocytes, also known as tumor islands. Another feature that is helpful in distinguishing BCCs on histology is the presence or absence of clefting caused by retraction of the stroma around the tumor islands. • The nodular pattern is the most common, and shows large, well defined, tumor masses with peripheral palisading • Superficial BCCs are characterized by the presence of tumor buds (Figure 6-14) or prolif erations originating in the epidermis and extending towards and into the dermis. Palisading is also evident • The micronodular variant shows small tumor masses surrounded by fibrous stroma. Palisading is not prominent • Infiltrative BCCs appear as tumor masses of variable size, with irregular, spiky outlines and scarce evidence of palisading or clefting • Morpheaform BCCs present with elongated strands of tumors cells within an abundant, sclerotic stroma 230  2013/2014 Dermatology In-Review l Committed to Your Future Report a Problem/Feedback
  • 238. • The Pinkus tumor shows long, branched, thin strands of tumor embedded in a fibromyx oid stroma, and connected to the overlying epidermis Diagnosis and Differential Some suggest that for morpheaform-appearing BCC a punch biopsy of the central, indurated area of the lesion should be done to establish the diagnosis. Whereas, for all other types of BCC, a shave biopsy is usually enough to confirm the diagnosis. Differential diagnosis include ulcerative SCC, amelanotic melanoma, and fibrous papule for noduloulcerative BCCs. Bowen’s disease, AK, psoriasis, and eczema for superficial BCCs. Whereas pigmented BCC can be confused with malignant melanoma or melanocytic nevi. Morpheaform BCCs must be distinguished from a scar or an isolated plaque of morphea.21,33 Treatment Conventional excision (margin of about 4 mm, has 5-year cure rates of 89.9% and 82.6%, for primary and recurrent BCC, respectively. 31,35) Figure 6-10. Nodular BCC. Notice the Figure 6-11. Superficial BCC appearing asa translucent appearance and pearly pink plaque with pearly borders and cen- surface with telangiectasias tral ulceration on an upper extremity Figure 6-12. Multiple pigmented BCCson the scalp of a white, elderly individual Report a Problem/Feedback Figure 6-13. Morpheaform BCC. Atrophic plaque with raised, pearly borders and center crust Benign and Malignant Neoplasms  231
  • 239. TIP a  ohs micrographic surgery is indicated for large lesions (equal or greater M than 1 cm on the face or 2 cm on the trunk), located on high-risk anatomic areas (ear, eyelid, lips, genitals, nose, and temples), of the morpheaform subtype, recurrent, and with an aggressive growth pattern (the 5-year cure rate for primary and recurrent BCCs is 99% and 94.4% respectively) a Curettage and electrodessication: the 5-year recurrence rate for primary BCC has been reported to be approximately 7.7% Figure 6-14. BCC. Nests of basal cells • Other methods: Cryosurgery, radiotherapy, topical 5-FU or imiquimod36,37 for superficial BCC are less often used techniques • PDT and lasers have recently gained popularity for the therapeutic management of low-risk, small, superficial BCCs. More evidence is needed before these interventions can be recom- mended as general practice Prognosis BCCs are characterized by their slow, indolent growth and progressive invasion of adjacent tissues. However, the metastatic potential is very low with rates ranging from 0.0028 to 0.1%.31,33,38 Those BCCs that do metastasize tend to be large, ulcerated, neglected lesions, with an aggressive growth pattern. Metastases commonly occur in the lymph nodes and lungs. These tumors typically recur regardless of multiple treatments.33,38 6.6 SQUAMOUS CELL CARCINOMA Epidemiology • SCC is the second most common skin cancer and accounts for approximately 20% of all NMSC • It is more common in the male gender (a lifetime risk 9-14% in men vs. 4-9% in women) • The incidence also increases with age (35 times higher in individuals older than 75 years of age when compared to ages 50-55 22,39) • The incidence of SCC doubles for each 8 to 10 degree decline in latitude; therefore populations living closer to the equator have a greater risk Risk factors: Chronic sun exposure, skin types I and II, chemical carcinogens (arsenic, tobacco, coal, tar), immunosuppression (due to immunosuppressive treatment in transplant patients, or immunodeficiency syndromes such as HIV), chronic ulcers, burn scars, and genetic syndromes (e.g., xeroderma pigmentosa). Etiology TIP Actinic keratosis (AK) is the precursor a VB radiation is the major causative agent for the U lesion of SCC. There is a sequence or condevelopment of SCC. It produces specific mutations tinuum between actinic keratoses, SCC in situ (C to T transitional mutations) in the tumor suppressor (Bowen’s disease) and invasive SCC. However, gene pg. 53 some SCCs develop de novo and do not form from a previous AK. Keratinocytes with one mutation in p53 after UV radiation may undergo apoptosis. However, if these keratinocytes with mutated p53 suffer a second hit or mutation, then u 232  2013/2014 Dermatology In-Review l Committed to Your Future Report a Problem/Feedback
  • 240. they become resistant to further apoptosis and instead experience clonal expansion, which is clinically evident as actinic keratoses. Uncontrolled proliferation of these abnormal keratinocytes leads to the development of SCC in situ and ultimately invasive SCC.11,22 Human papilloma virus (HPV) infection has been linked with cutaneous SCC. Lesions on the genitals have been associated with HPV 6 and 11, whereas HPV 16 has been found in periungual lesions.40 Clinical Manifestations SCCs usually present as firm, skin-colored to pink, papules or plaques, commonly found on the head and neck region of elderly individuals (Figure 6.15). Other locations include the trunk, arms, dorsal hands and legs. Hyperkeratosis, ulceration or crusting may be found on its surface. Symptoms such as itching, pain and bleeding may be associated with the lesion.22,40 Histopathology Histopathologic evaluation of SCC reveals a proliferation of atypical keratinocytes that extends beyond the basement membrane into the dermis. The proliferation of cells can be seen as slender, long strands or as bulky masses. Individual cells have a glassy eosinophilic cytoplasm, with large nuclei. Mitotic figures (Figure 6-16) and horn pearls are also seen. Various degrees of differentiation may be seen and is usually described as well-, moderately-, or poorly-differentiated. Increasing degrees of malignancy show less demarcation between the tumor masses and the stroma, greater atypia, less keratinization, and loss of intercellular bridges. Other histologic variants include acantholytic, adenosquamous, spindle-cell, verrucous, and desmoplastic SCC. 21,40,41 Treatment • Conventional excision for low risk SCCs (less than 2cms in diameter, well differentiated pattern, located on the trunk or extremities) • Mohs micrographic surgery (Overall cure rates are estimated to be as high as 98.1% for lesions less than 2 cms, but drop to 74.8% for those larger than 2 cms. Well differentiated SCCs have a 97% cure rate with Mohs, this rate drops to 67.4% for poorly differentiated lesions35). Mohs is nonetheless indicated for primary aggressive SCC’s of any size, in either immunocompetent or immunocompromised hosts, as well as in any location of the body. Mohs is not indicated for any primary AK with focal SCC in situ of any size or in any location, regardless of host immune status • Curettage and electrodessication • Radiation therapy used in combination with other modalities to treat aggressive, recurrent, or large, inoperable tumors or elderly patients that may not tolerate surgical procedures22 • Cryotherapy for small, superficial, low-risk lesions • Overall cure rates with non-Mohs modalities for tumors greater than 2 cms is 58.3%, for well-differentiated SCCs is 81%, and 46.4% for poorly differentiated lesions35 • Addition of chemotherapy to excision for high risk/aggressive SCC may not reduce recurrence u TIP a etastasis from a primary SCC is 0.3 to 16%.35,42-45 M Prognosis The 10-year survival rate for individuals with regional and distant metastases is 20% and less than 10%, respectively. T  he risk of metastatic disease increases with tumor size (>2cms), location (lips, ear, and eyelid, among others), depth of invasion, degree of differentiation, perineural invasion, immunosuppression, recurrent tumors, and SCCs arising in areas of chronic inflammation (i.e., osteomyelitis, burn scars, ulcers)35 Report a Problem/Feedback Benign and Malignant Neoplasms  233
  • 241. When metastases occur, regional lymph nodes are more commonly affected. Furthermore, hematogenous spread usually involve lungs, liver, brain, skin, and bone.22 Management of the patients with high-risk cutaneous SCC and no clinical nor radiological evidence of regional metastasis remains controversial. Some advocate the “watchful waiting” approach, while others prefer elective lymph node dissection. Recently, studies evaluating the usefulness of sentinel lymph node biopsy for the management of these patients have been reported.46,47 Figure 6-15. High-risk SCC Figure 6-16. SCC. Typical explosive located on the lower lip mitotic figures, necrotic keratinocytes, and highly pleomorphic cells of invasive SCC are observed 6.7 KERATOACANTHOMA Epidemiology Keratoacanthomas (KAs) are rapid growing cutaneous tumors believed to arise from the hair follicles. There is much controversy as to whether or not KAs are benign lesions or well differentiated variants of SCC capable of spontaneous degeneration. KAs usually present as a crateriform nodule in fair-skinned, elderly individuals. It is commonly found as a solitary lesion; however, other KA variants have been reported and consist of multiple lesions.41,48 Etiology The origin of KAs has not been established. Due to its usual location on sun-exposed areas, ultraviolet exposure has been proposed as an important etiologic factor. Exposure to chemical carcinogens such as tar and pitch, as well as smoking, has also been linked to the development of KAs. A viral etiology, specifically the human papilloma virus, has also been proposed but its role in the origin of KAs remains unclear.41,49 Clinical Manifestations KAs usually appear as solitary, firm, dome-shaped crateriform nodules with a large keratotic core. (Figure 6-17) Occasionally, KAs may be multiple. Patients are commonly fair-skinned, with history of sun-exposure, and pick incidence between 50 and 69 years of age.50 The lesion can be located on any sun-exposed area, but the majority occurs on the face, forearms and hands. Typical of this tumor is its rapid growth, reaching a size of 1 to 2 cms within a few weeks and resolving slowly over a few months, often leaving an atrophic scar. 234  2013/2014 Dermatology In-Review l Committed to Your Future Report a Problem/Feedback
  • 242. Figure 6-17. Dome-shaped nodule with cratiform center typical of keratoacanthoma KAs have three clinical stages: Proliferative, mature and resolving. The first stage (proliferative) is characterized by the sudden appearance of a firm, smooth, papule with fine telangiectasias. The papule may be skin-colored or erythematous. As stated before, the tumor grows rapidly during 2 to 4 weeks until reaching a size of approximately 2 cms. During the mature phase, the nodule acquires a dome-shaped or bud-shaped appearance with central, umbilicated, keratinous core. Its consistency is firm; however, fixation to underlying tissue is not present when palpating the nodule. KAs are largely asymptomatic; however, patients may or may not complain of tenderness. Tumor reabsorption occurs within 4 to 6 months (involution stage), ultimately resulting in a slightly depressed, and hypopigmented scar.49 Usually, the process from origin to spontaneous resolution takes place within four to six months.50 KA progressions to SCC with metastatic spread is rare but has been reported in immunosuppressed patients and those with Ferguson-Smith syndrome. There are several types of KAs including: • KA centrifugum is an unusual subtype of solitary KA that may reach a size of up to 20 cms in diameter. Enlargement and extension of the border with simultaneous central healing are characteristic of this type of KAs.52 It affects both men and women and usually occurs on the face, trunk or extremities. Spontaneous resolution may or may not occur.49 50 Diagnosis: foresee difficulties due to clinical similarities and histological to lesions such as halogenoderma, verrucous tuberculosis or deep fungal infections51 • The giant KA is characterized by rapid growth reaching a diameter of 9 cms or more. This type of tumor can invade underlying structures including cartilage49 • The subungual KA originates in the nail bed and is locally destructive to the underlying bone. It presents as a painful, umbilicated, red and swollen lesion, commonly located on the thumb and little finger. It is persistent, thus spontaneous involution is rarely seen 49, 50 • The Ferguson-Smith variant is characterized by the sudden appearance during childhood or adolescence, of multiple eruptive KAs that slowly resolve and re-appear later on. These may be located on any sun-exposed surface; however, face and extremities are the most common location. This condition is apparently inherited in an autosomal dominant pattern49 and seems to be a result of a single mutation that occurred in Scotland in the 1700’s.50 There is a 3:1 male predominance50 • Grzybowski type is typically diagnosed during adulthood, with the sudden appearance of hundreds to thousands of lesions in a disseminated fashion. Diameter of the lesions is usually 2-3 mm and can be found anywhere in the body including palms, soles, larynx and oral mucosa.49 Similar incidence between men and woman50 Report a Problem/Feedback Benign and Malignant Neoplasms  235
  • 243. • Intraoral or Mucosal Membrane KAs: Extremely rare. Appears as a painless ulcer particularly difficult to differentiate from SCC, especially in the tongue, where the malignancy is a common site. Negative history of exposure to known risk factors may light towards the KA52 • Multiple Persistent50 • KA in special situations: Occupational (tar-induced), immunosuppressed patients (rapid progression to SCC), xeroderma pigmentosum, in Muir-Torre syndrome (AD, associated with a defective DNA mismatch repair gene)50 Histopathology During the proliferative stage the tumor appears as a well-defined, keratin-filled invagination of the epidermis arising from contiguous hair follicles. Hyperkeratosis and acanthosis are also seen. Epidermal strands consisting of atypical squamous cells with mitotic figures extend into the dermis. A sparse dermal inflammatory infiltrate is usually found surrounding the tumor. Perineural and vascular invasion may be present and should not be considered a sign of malignancy, in opposition to SCC, where it is a sign of metastatic disease.50 Once the tumor progresses into the mature phase, the atypical squamous cells become less prominent. The fully developed crateriform nodule has a central depression filled with hyaline keratin. Irregular epidermal proliferations may be seen protruding into and around the base of the crater. Keratinization of the squamous cells is prominent, producing a glassy appearance. During involution, the lesion becomes flattened with a dense lichenoid infiltrate, fibrosis, and granulation tissue. The crater heals slowly, ultimately resulting in an irregularly shaped, atrophic scar.21,41,48,49 Diagnosis and Differential The most important differential diagnosis for KA is SCC. Other differential diagnosis are: Seboacanthoma (sebaceous adenoma + KA), exophytic pilomatricoma, cutaneous metastatic disease, verrucous carcinoma, deep fungal infection, and giant molluscum contagiosum. Clinically, the rapid growth of an exophytic, crateriform tumor is suggestive of KA. These distinctive features may sometimes be enough for the initial diagnosis of KA. Histological features such as the presence of a compact tumor, with a central crater filled with keratin, along with protruding epidermal proliferations surrounding the crater, pronounced keratinization and neutrophilic microabscesses further confirm the diagnosis. SCCs even when well-differentiated, show great pleomorphism, scarce keratin production, and ulceration is sometimes present.48,49 It is important to obtain a biopsy of the specimen down to the subcutaneous fat. This can be achieved either by complete excisional biopsy, full-thickness shave biopsy or fusiform incision through the entire KA including its center and sides.48,49,50 Even despite the fact that there are no adequately sensitive and specific criterion to distinguish KA from SCC, the five more significant are “epithelial lipping and sharp demarcation between tumor and stroma favoring KA and ulceration, numerous mitosis, and marked pleomorphism/anaplasia favoring SCC.”50 Sometimes it is difficult to differentiate KA from SCC, both clinically and histologically. Therefore, management of the tumor as an invasive SCC should be done when clear distinction between the two tumors has not been achieved. 21,48,49,50 Treatment Even though KAs resolve spontaneously, biopsy and treatment is usually undertaken to confirm the diagnosis and prevent further growth and discomfort, discomfort and scarring. Solitary KAs are usually treated by complete excision, which also provides an ideal specimen to confirm the diagnosis by histological evaluation. Mohs micrographic surgery is used in KAs 236  2013/2014 Dermatology In-Review l Committed to Your Future Report a Problem/Feedback
  • 244. when in critical anatomic areas and for large tumors. Recurrence after excision is seen in 4% to 8% and does not imply change in malignity. In multiple KAs, another options should be considered, but close follow up and excision if cases of non respondent lesions after four to six weeks. Radiotherapy or laser surgery has been successful in small solitary KAs located in difficult to treat body areas. In early and small either solitary or multiple KAs, cryosurgery with liquid nitrogen is indicated.48,49,50 Amputation of digits should be considered when bone involvement or failure to other therapies, specially in subungual lesions. Intralesional and topical therapies are also available. Intralesional 5-fluorouracil (5-FU) and methotrexate are widely used; nonetheless methotrexate is favored over 5-FU because fewer treatments are required.48,49,50 Corticosteroids were commonly considered in the 70s and 80s due to the rapid control of the inflammation and discomfort with minimal scarring and regression of about 70% of the KAs. In selected cases, such as multiple or recurrent KAs, consideration of this old therapeutic agent could benefit these patients.53 Intralesional bleomycin and interferon α-2a are other options. Topical 5% imiquimod every other day in solitary facial KAs for 4 to 12 weeks is an available treatment option.48,49,50 Systemic treatments are reserved for multiple lesions including the Ferguson Smith variant, the Grzybowski type and the centrifugum marginatum. Retinoids, methotrexate, 5-FU, and cyclophosphamide have been used. However, retinoids are the most widely used due to its less toxic profile. Prophylactic retinoid regimen in the Ferguson Smith variant is necessary to reduce outbreaks and minimize scarring.50 6.8 MALIGNANT MELANOMA Epidemiology Cutaneous malignant melanoma (MM) is a potentially fatal tumor that originates from malignant melanocytes. The incidence of MM has risen over the past decade. It was estimated that the lifetime risk for the development of melanoma in a u TIP person born in the year 2000 is 1 in 75. a isk factors for the development of MM include R The incidence between males and females in the sun exposure with tendency to freckle and sunUnited States is equal. MM affects younger populaburn, fair skin complexion, light colored eyes and tion in comparison with NMSC, with a peak incidence hair, presence of large number of nevi, family and in ages 20-45 years old.30 The most common locapersonal history of melanoma 3,30,54 tions are the back, chest, and upper extremities for u TIP men. However in women, the most common locaantermittent sun exposure (weekends and vacations) I tions are the back, lower legs, and upper extremities.54 with painful sunburns during childhood and adoles- Etiology cence may be the major predisposing risk factor for the development of melanocytic and atypical nevi, The etiopathogenesis of MM has not been clearly which could ultimately lead to MM determined. UV radiation causing DNA mutations has ahe most important mutated gene associated with T been associated with the development of MM. It has a predisposition to develop MM is the CDKN2A been reported that the risk is higher than twofold with (located on chromosome 9p21) 54,55 a history of five or more episodes of sunburn during adolescence.3,55 Report a Problem/Feedback Benign and Malignant Neoplasms  237
  • 245. Clinical Manifestations There are four types of melanoma: superficial spreading, acral lentiginous, nodular, and lentigo maligna melanoma. Superficial spreading melanoma (SSM) accounts for approximately 70% of all melanomas in the white population. It may be located anywhere, but the back and lower legs are the most common sites for men and women, respectively. It is usually diagnosed in individuals during their fourth or fifth decade of life. It may evolve from melanocytic nevi. It usually arises as a dark pigmented macule or slightly raised plaque. Mixed colors may be seen, such as dark brown or black, with shades of pink, blue or gray. The lesion is found to be well-demarcated and asymmetrical, with indented borders.54,56 Acral lentiginous melanoma (ALM) is the predominant type of melanoma in dark-skinned individuals. It is usually located on the soles, palms, and subungual region of older patients (fifth to sixth decade of life). It presents as a flat, brown to black, lesion with irregular borders. 54,56 Nodular melanoma (NM) is the second most common type of melanoma in persons of fair complexion (15%). This type of melanoma may be located anywhere on the body site of individuals with ages ranging from 40 to 50 years old. The lesion is characterized by the sudden appearance and growth of a dark brown, black or blue nodule, with well-defined and regular borders.54,56 Lentigo maligna melanoma (LMM) is the least common (approximately 5%) and arises from the precursor lesion, lentigo maligna (melanoma in situ). It usually affects older individuals (sixth to seventh decade of life) and involves sun-exposed regions, with cheeks, nose and temples being the predilected sites. LMM appears as a flat lesion with nodular areas, and different shades of brown and black colors. The borders are sharply demarcated and very irregular.54,56 Histopathology Histologic findings such as diameter greater than 6 mm, asymmetry, poor circumscription, and the presence of single melanocytes (especially pagetoid, see Figure 6-18) at and above the dermal-epidermal junction on sun-damaged skin are diagnostic for melanoma. Atypical melanocytes may also be distributed in the adnexal epithelial structures. MM has two growth phases, horizontal and vertical. During the horizontal growth period, atypical melanocytes are mainly located within the epidermis and may be singly seen infiltrating the papillary dermis. This phase is followed by a vertical growth period, in which large nests of malignant melanocytes invade the dermis and obtain the potential of metastasizing. Nodular melanomas exhibit mainly a vertical growth phase and become thick lesions in a short amount of time.54,56 Figure 6-18. Pagetoid Melanoma. Neoplastic proliferation of melanocytes forming irregular nests in the basal layer. Single atypical melanocytes are spreading within all the layers of the epidermis. The cells have large atypical nuclei and abundant eosinophilic cytoplasm and a surrounding halo resembling cells of Paget disease 238  2013/2014 Dermatology In-Review l Committed to Your Future Report a Problem/Feedback
  • 246. Diagnosis Identification of melanoma is initially done through visual examination of suspicious lesions. The ABCDE rule should be used, where A stands for asymmetry, B is for irregular borders, C is for diversity of colors, D is for diameter larger than 6 mm, and E is for evolving. Dermoscopy or epiluminiscence microscopy is another non-invasive technique used for the evaluation of pigmented lesions and diagnosis of MM. A more objective assessment of the lesion is made through identification of pigment network and patterns. Several dermoscopic diagnostic algorithms have been proposed including the ABCD rule of dermoscopy, the Menzies’ method, the seven-point checklist and more recently the three-point checklist. In general, the following dermoscopic features are suggestive of MM: 1.) asymmetry; 2.) multicomponent pattern; 3.) parallel-ridge pattern (for acral melanocytic lesions); 4.) atypical pigment network (characterized by black, brown or gray network, irregularly distributed within the lesion that usually ends abruptly in the periphery); 5.) uneven arrangement of streaks (radial streaming) throughout the lesion; 6.) blue-whitish veil; 7.) localized irregular and diffuse pigmentation; 8.) irregularly distributed or isolated globules (dark or slate blue); and 9.) regression structures seen as white (scar-like) or blue-gray areas; among others.57-59 Once clinical examination and dermoscopic features lead to the initial diagnosis of MM, a biopsy must be performed for histologic confirmation. Excisional biopsies provide adequate tissue specimen for histologic diagnosis and staging of the lesion. Incisional biopsies may be considered when the suspicion for melanoma is low, when the lesion is large, located in cosmetic areas such as the face, or when it is unfeasible to perform an excision.60 Immunohistochemistry, using S-100 or HMB-45, may also be used for the diagnosis of MM. Staging Table 6-1 shows the final version of the American Joint Committee on Cancer Staging System for cutaneous melanoma. 61 Table 6-1. Proposed Stage Groupings for Cutaneous Melanoma American Joint Committee on Cancer Staging System 2001 Stage TNM Criteria 0 Tis melanoma in situ IA† T1a N0M0: IB† T1b N0M0: tumor ≤1.0 mm without ulceration and mitosis <1/mm2 tumor ≤1.0 mm with ulceration or mitoses ≥1/mm2 T2a N0M0: tumor 1.01-2.0mm without ulceration IIA† T2b N0M0: tumor 1.01-2.0 mm with ulceration T3a N0M0: tumor 2.01-4.0 mm without ulceration T3b N0M0: tumor 2.01-4.0 mm with ulceration T4a N0M0: tumor >4 mm without ulceration IIC† T4b N0M0: tumor >4 mm with ulceration IIIA* T1-4a N1aM0: non-ulcerated tumor of any size with micrometastasis in 1 node T1-4a N2aM0: non-ulcerated tumor of any size with micrometastasis in 2-3 nodes IIB† IIIB* ulcerated tumor of any size with micrometastasis in 1 node ulcerated tumor of any size with micrometastasis in 2-3 nodes T1-4a N1bM0: Report a Problem/Feedback T1-4b N1aM0: T1-4b N2aM0: non-ulcerated tumor of any size with macrometastasis in 1 node Benign and Malignant Neoplasms  239
  • 247. Table 6-1. Proposed Stage Groupings for Cutaneous Melanoma (cont.) T1-4a N2bM0: T1-4a/b N2cM0: T1-4b N1bM0: ulcerated tumor of any size withmacrometastasis in 1 node ulcerated tumor of any size with macrometastasis in 2-3 nodes T1-4a/b N3M0: any tumor with 4 or more metastatic nodes, or matted nodes, or in transit met(s)/satellite(s) with metastatic nodes AnyT AnyN M1a: with distant skin, subcutaneous or nodal mets AnyT AnyN M1b: lung metastases AnyT AnyN M1c: IV† tumor of any size ulcerated or not with in transit met(s)/satellite(s) without metastatic nodes T1-4b N2bM0: IIIC* non-ulcerated tumor of any size with macrometastasis in 2-3 nodes all other visceral or any distant metastasis, plus elevated serum LDH Adapted from Balch et al. 54 AJCC Cancer Staging Manual, 7th edition. 97 † The stage I and IV subgroups are based on both, clinical and pathologic staging. * The stage III subgroups are based on pathologic staging only. Sentinel Lymph Node Biopsy (SNL) According to the American Society of Clinical Oncology and Society of Surgical Oncology joint clinical practice guideline, SLN biopsy is recommended for patients with intermediate-thickness melanomas (Breslow thickness, 1 to 4 mm) of any location.6 In patients with a positive SNL biopsy, complete lymph node dissection is recommended for regional control, however effect on overall survival is still uncertain.6 Treatment The treatment of choice for MM is surgery, and the goal is complete removal of the lesion histologically confirmed with negative margins. The current surgical margins recommended by the American Academy of Dermatology are: 0.5 cm for melanoma in situ, 1 cm for melanomas that measure <2 mm in thickness, and 2 cm for lesions ≥2 mm in thickness.60 Mohs micrographic surgery has been suggested for the treatment of MM. However, its use remains controversial and the current guidelines do not recommend this method as a treatment option.60 Mohs micrographic surgery can be used for primary or locally recurrent melanoma in situ in both healthy and immunocompromised hosts. Adjuvant therapy with interferon-alpha has been used for patients with high risk of recurrence(primary melanoma with tumor thickness ≥4.0 mm or level V invasion, primary melanoma with in-transit metastases, primary melanoma with regional lymph node metastases that are clinically apparent or detected at elective lymph-node dissection, regional lymph node recurrence, involved nodes were excised but there was no known primary melanoma, American Joint Committee on Cancer stage IIB, IIC and III). It has shown to improve disease-free and overall survival.54 Treatment options for distant metastases include surgical excision of isolated metastases (skin, subcutaneous tissue, lung, brain), radiation therapy, chemotherapy, and biologic therapy (interferon-alpha, interleukin-2), among others. The cytotoxic T-lymphocyte antigen-4 (CTLA-4) serves as one of the primary immune check points and downregulates T-cell activation pathways. Enhancing T-cell activation by antibody blockade of CTLA-4 provides a new approach to overcome tumor-induced immune tolerance. Recently, anti-CTLA-4 therapy demonstrated significant clinical benefits in patients with metastatic melanoma, which led to the approval of 240  2013/2014 Dermatology In-Review l Committed to Your Future Report a Problem/Feedback
  • 248. ipilimumab by the FDA in early 2011. However, the outcome for patients in stage IV remains unsatisfactory with an average survival of 6 months.54 Prognostic Factors Increasing age and male gender have a negative effect on survival. Patients with primary lesions located on the extremities have a better prognosis than those with tumors located on the head, neck or trunk. Increasing tumor thickness, invasion and ulceration are considered poor prognostic factors. In stage III melanoma, the fewer the number of nodes involved the better the prognosis. Furthermore, there is a significantly lower survival for those patients with palpable metastatic nodes (macrometastasis) when compared to those with micrometastatic nodes (nonpalpable). For stage IV melanoma, patients with non-visceral metastases (skin, subcutis, distant lymph nodes) have a better prognosis compared to those with visceral metastases.54,64 6.9 MERKEL CELL CARCINOMA Epidemiology Also known as cutaneous neuroendocrine carcinoma, this tumor is an unusual malignant neoplasm that arises from neuroendocrine cells with features of epithelial differentiation. Merkel cell carcinoma (MCC) is a biologically aggressive tumor that is difficult to diagnose and even more difficult to treat in advanced stages. It usually affects elderly individuals, but there have been reports of MCC in children and young adults.65 Etiology The origin of this neoplasm is unknown. UV radiation has been postulated as a risk factor.66 A newly identified virus, the Merkel cell polyomavirus, is present in approximately 80% of these tumors and appears to be associated with the development of Merkel cell carcinoma. Clinical Manifestations Caucasians older than 50 years of age are typically affected and a slight female preponderance has been noted. The tumor usually appears as a solitary, 1 to 2 cms, dome-shaped nodule, most frequently located on the head and neck region and extremities. The nodule is commonly found to be dark red or violaceous with a shiny surface that often has telangiectasias. The overlying skin may be intact or ulcerated.65,66 Histopathology • Light microscopy: There are three histologic patterns of MCC: trabecular, intermediatecell type, and small-cell type. The trabecular variant consists of interconnecting trabeculae separated by strands of connective tissue. Also pseudorosettes may be found. The majority of MCCs belong to the intermediate-cell type, characterized by large, solid nests of cells of intermediate size, with a trabecular pattern in the periphery. The least frequent variant is the small-cell type, which consists of diffusely infiltrating sheets of small neoplastic cells that may be mixed with intermediate cells. The tumors involve the dermis and spread into the subcutaneous fat, usually sparing the overlying epidermis. (Figure 6-19) The neoplastic cells are round and uniform in size, with a round to oval nucleus, small nucleoli, and evenly dispersed chromatin. A “ball-in-mitt” pattern is said to be typical, with one or two crescentic tumor cells wrapped around one central round tumor cell. Numerous mitotic figures, necrotic areas, in addition to neural and vascular invasion is often seen.65-67 Report a Problem/Feedback Benign and Malignant Neoplasms  241
  • 249. Figure 6-19. Merkel Cell Carcinoma. Basophilic aggregates of small-round cells are seen in the upper and mid-reticular dermis extending towards the deeper portions of the dermis. There is an uninvolved Grenz zone of papillary dermis. The tumor cells have prominent round vesicular nuclei and scant ill-defined cytoplasm. Occasional mitoses are present. The neoplastic cell islands tend to connect each other via anastomosing cords • Electron microscopy: The main ultrastructural features of MCC include dense core granules concentrated in cytoplasmic processes and paranuclear aggregates of intermediate filaments (cytokeratins, neurofilaments) which parallel or have a whorled arrangement near the nucleus. These characteristics are essential when making the diagnosis of MCC and differentiating it from other other neoplasms such as metastatic oat cell carcinoma, SCC, metastatic adult neuroblastoma, and malignant melanoma, among others65 • Immunohistochemistry: MCC exhibits both epithelial and neuroendocrine markers. The most commonly used markers for MCC are monoclonal antibodies to cytokeratins 8, 18 and 20; neuron specific enolase (the most constant marker); chromogranin A/B, and synaptophysin. This neoplasm may sometimes contain several neuropeptides including vasoactive intestinal peptide (VIP), calcitonin, ACTH, gastrin and somastatin, among others. Leukocyte common antigen, vimentin, desmin, glial fibrillary acidic protein, and S-100 are consistently absent in MCC 65,66 Diagnosis and Differential Both clinical and histopathological (light microscopy, electron microscopy and immunohistochemistry) evaluation are required for the diagnosis of MCC. A correct diagnosis of MCC may be confirmed by positive juxtanuclear labeling of tumor cells with anti-cytokeratins, cytoplasmic reactivity to neuron specific enolase, and focal presence of neurofilaments proteins in paranuclear location. Differential diagnosis include SCC, BCC, pyogenic granuloma, keratoacanthoma, amelanotic and melanotic malignant melanoma, adnexal tumors, lymphoma, metastatic oat cell carcinoma, undifferentiated anaplastic carcinomas, and neuroblastomas, among others.69 Treatment There is no standard protocol for the treatment of Merkel cell carcinoma. However, treatment modalities include wide local excision or Mohs micrographic surgery, with or without adjuvant therapy. 242  2013/2014 Dermatology In-Review l Committed to Your Future Report a Problem/Feedback
  • 250. • Surgical Treatment: Wide local excision with 2-3 cms margins has long been advocated as the treatment of choice. However, currently, Mohs micrographic surgery has successfully been used for the treatment of MCC yielding the lowest local recurrence rates.65, 67-69 Compared to conventional excision, Mohs surgery allows evaluation of all margins (including the deep sections) as well as maximal sparing of adjacent normal tissue • Adjuvant Therapy: MCCs are sensitive to radiation and chemotherapy. Controversy exists regarding the usefulness of radiation as adjuvant therapy for the treatment of MCC.61,63,66 Boyer et al concluded that radiation may be an option when tumor free margins are not achieved, complete excision is not feasible, or for large or recurrent tumors70 For patients with systemic disease, multiple cytotoxic agents have been employed including: cyclophosphamide, methotrexate, 5-FU, cisplatin, etoposide, and doxorubicin, among others. However, a standard regimen has not been established, and a combination of drugs that are usually used to treat small cell carcinoma of the lung is usually recommended65-67 • Sentinel Lymph Node Biopsy: Intraoperative mapping and sentinel lymph node biopsy has recently gained advocates for the treatment and prognosis of MCC. It is considered a low morbidity technique that can successfully identify micrometastatic or clinical occult disease in the regional lymph nodes of patients with MCC. The presence of metastatic disease in the sentinel node may be used as rationale for complete node dissection and additional adjuvant therapy67,71 Prognosis As stated before, MCC displays an aggressive behavior and has a high incidence of local recurrence, regional and systemic spread. The overall survival rates have been estimated to be 88% for one year, 72% for two years, and 55% for three years.65,66 The incidence of regional lymph node metastases has been reported to be between 50 and 60%.61,62 Distant or hematogenous metastases occur in 30-40% of patients, and usually involve the liver, bone, brain, or lung.65,66 6.10 CUTANEOUS T-CELL LYMPHOMA Epidemiology Cutaneous T-cell lymphoma (CTCL) is a neoplasm of helper T-cells (CD4+) that originate in the skin. There are many variants of CTCL but Mycosis Fungoides (MF) and Sezary syndrome (SS) are the most common. The incidence of cutaneous T-cell lymphomas (CTCL) has been increasing and is currently 6.4 per million persons, based on Surveillance, Epidemiology, and End Results (SEER) registry data, with the highest incidence rates being reported among males (male:female incidence rate ratio 1.9) and African–Americans (incidence rate ratio 1.5).72 Furthermore, black race and advanced aging are associated with a worse prognosis. MF acquired its name due to the mushroom-like appearance of the tumor. Sezary syndrome is considered the leukemic variant of MF. Etiology The etiopathogenesis of CTCL has not been established and several causative factors have been proposed. It has been postulated that patients with atopic dermatitis have an increased risk of developing CTCL due to chronic stimulation of T-cells that may induce its clonal proliferation. Other etiologic factors such as viral infections (HTLV-1) and chemical exposure have also been suggested.73 Report a Problem/Feedback Benign and Malignant Neoplasms  243
  • 251. Clinical Manifestations CTCL is a chronic and slowly progressive disease that initially manifests in the skin and may ultimately involve other organs. There are three main skin lesions: Patches, plaques and tumors. The earliest lesion is usually a flat, scaly, erythematous or violaceous patch. Lesions may be single or multiple and usually occur in areas not exposed to the sun (lower abdomen, upper thighs, buttocks, breasts which progress to develop in a “bathing suit” distribution). The patches may be pruritic or asymptomatic. During this stage, histologic evaluation may not be diagnostic for CTCL.73-74 The plaque stage starts to develop as the malignant T-cells invade and infiltrate the skin. Plaques may arise de novo or from existing patches. This phase is characterized well demarcated, irregularly shaped, elevated lesions that are red-brown or violaceous in color. An asymmetric distribution is usually present and pruritus remains a common complaint.73-74 The tumor stage represents a more aggressive period of vertical growth. It appears as expanding nodules arising from previous patches, plaques or non-affected skin. The tumors are initially dome-shaped with a smooth surface, and may later undergo necrosis and ulceration.73-74 Sezary syndrome, the leukemic variant of MF, is characterized by the triad of pruritic erythroderma, generalized lymphadenopathy, and the presence of Sezary cells (abnormal, large hyperconvoluted lymphocytes) in peripheral blood. The number of Sezary cells that must be present for the diagnosis remains controversial. However, the most common cutoff point is more than 1,000 cell/mm3. Other manifestations include scaling and fissuring of palms and soles, alopecia, pruritus, peripheral edema, and nail dystrophy.73-75 Histopathology Histologic evaluation may show scanty superficial dermal infiltrate of normal lymphocytes appearing. In more advanced stages, histologic evaluation shows a thickened epidermis and a dense infiltrate of lymphocytes in the dermis. Epidermal involvement with single-cell exocytosis of lymphocytes (epidermotropism) is often seen. The lymphocytes may also aggregate in the epidermis forming the Pautrier microabscesses. The cells look larger than normal and have a characteristic cerebriform nuclei.73-75 (Figure 6-20) The cell of origin of CTCL, as u TIP the name suggests are T-cells. Immunophenotyping studies have demaarly lesions usually do E onstrated that T-cells in leukemic variant of CTCL, i.e., Sezary syndrome, not show characteristic express CCR7 and L-selectin, which resembles central memory T-cells, findings for the diagnosis of CTCL while the malignant clone in MF lesions resembles effector memory T-cells. 106 Figure 6-20. MF. Plaque lesion. Mild epidermal hyperplasia is observed. The papillary dermis bears a band-like mononuclear cell infiltrate composed of hyperchromatic cerebriform cells with hyperchromatic cerebriform nuclei which are called mycosis cells. Some of the mycosis cells are seen also on the epidermis forming Pautrier microabscesses. The neoplastic cells have epidermothrophism not only in the form of Pautrier abscess, but single lymphocytes are present in the basal layer 244  2013/2014 Dermatology In-Review l Committed to Your Future Report a Problem/Feedback
  • 252. Diagnosis The accurate diagnosis of CTCL requires the combination of both clinical and histopathologic findings. Immunophenotyping and molecular techniques may also be used for the diagnosis of CTCL. The CD4+ T-helper cells typically express alpha/beta T-cell receptors CD2 and CD3, but lack the T-cell antigens CD7 and Leu-8. These features are useful in the diagnosis of CTCL. Another option for the diagnosis of CTCL is the determination of monoclonal rearrangement of T-cells gene receptors through PCR or Southern blotting techniques.73-75 Treatment Management of the patient with CTCL can be done through skin-directed or systemic therapy. Skin-directed therapies include topical corticosteroids, PUVA, UVB therapy, topical chemotherapy with mechlorethamine (nitrogen mustard), or topical bexarotene gel. Localized radiotherapy may be considered for lesions resistant to other treatments. Total skin electron beam therapy may be indicated for patients with widespread skin lesions or for those that did not respond to more conservative therapies. Photopheresis is usually reserved for patients with erythrodermic MF. Systemic therapy is indicated for patients that do not respond to topical therapy or more advanced disease. For advanced stage disease, multidisciplinary approach is required with combination of skin-directed therapies, biologic-response modifiers and sequential systemic corticosteroids. Treatment options include methotrexate, interferon-alpha, retinoids (such as Bexarotene), denileukin diftitox (a diphtheria fusion toxin that targets the interleukin-2 receptor), and systemic chemotherapy (cyclophosphamide + doxorubicin + vincristine + prednisone is the most widely used combination chemotherapy).72-75 A vascular leak syndrome involving hypoalbuminemia, hypotension and edema has been reported in ~25% of patients, usually within the first 2 weeks of treatment with denileukin diftitox. Corticosteriod pretreatment may benefit to prevent the occurrence of this syndrome. Newer therapies are underway. Histone deacetylases (HDACs) inhibitors, such as Vorinostat (suberoylanilide hydroxamic acid, SAHA) and romidepsin (depsipeptide), inhibit class I and II HDACs (i.e., pan-HDAC inhibitors), the former being widely expressed in various lymphoma subtypes. Multiple mechanisms may explain the clinical activity of HDAC inhibitors, including altered gene expression of cell-cycle and apoptotic regulatory proteins, acetylation of nonhistone proteins regulating cell growth and survival, angiogenesis, aggresome formation, and DNA repair. Additionally, HDAC inhibitors may have important effects on the tumor microenvironment via reactive oxygen species, enhanced antigen presentation and downregulation of immunomodulatory cytokines, like IL-10. Side effects range from gastrointestinal toxicities (nausea, vomiting, and diarrhea) to hematologic toxicities, including anemia or thrombocytopenia. Monoclonal antibodies directed against cell surface markers of neoplastic T-cells, such as zanolimumab (human IgG1mAb)against CD 4 and alemtuzumab (unconjugated humanized IgG1 kappa mAb) against CD 52, have been studied. While no studies evaluating the role of allogeneic stem cell transplants as compared to standard therapy have been conducted, patients with advanced CTCL may benefit from allogeneic stem cell transplants. Recommendations are currently inconclusive. 105 99,101 103,104 Report a Problem/Feedback Benign and Malignant Neoplasms  245
  • 253. 6.11 ANGIOSARCOMA Epidemiology u TIP a utaneous AS appear in three different clinical settings: Angiosarcoma (AS) is a very rare and C 1.) diopathic, arising in the head and neck region of white, elderly I aggressive tumor of endothelial origin. individuals Men are more commonly diagnosed with 2.) On the limbs in association with lymphedema the idiopathic form of this neoplasm.77 3.) In areas previously exposed to radiation therapy (latency 3-40 years) 76 The most common form of angiosarcoma is cutaneous angiosarcoma not associated with lymphedema. It generally occurs in patients over 40 years of age, with the highest incidence seen in patients older than 70. Lesions are most often observed in the head and neck region. Clinical Manifestations The lesion initially arises as a painless, purple macule-patch or plaque on the scalp or face. Evolution of the lesion occurs in a centrifugal pattern and may become quite large. Associated facial swelling or edema may also be noted. Later on it becomes an elevated, bluish or purple nodule that may ulcerate. Tumors may be single or multiple. Common symptoms include bleeding, edema, and ultimately pain. Cervical lymph node and hematogenous metastasis commonly occur.77 The lungs, spleen, and liver are the most common organs where distant metastasis occur.78,79 The overwhelming majority of angiosarcomas that arise in the presence of chronic lymphedema are associated with a previous history of mastectomy and lymph node dissection. Histopathology Angiosarcomas are commonly seen infiltrating the dermis, but may also invade the fascia and subcutis. Multiple anastomosing vascular spaces are found. The cells lining the vessels are large, pleomorphic and hyperchromatic with atypia. (Figure 6-21) Hemorrhage may also be seen.78,80 Immunohistochemistry markers such as CD31, CD34 and factor VIII are positive in angiosarcomas. These neoplasms are vimentin negative and cytokeratin positive.80 Figure 6-21. Angiosarcoma. Ill-defined neoplastic proliferation of plump-cuboidal mostly pleomorphic endothelial cells intermingled with slit-like spaces with many erythrocytes Prognosis Unfortunately, prognosis is poor with a reported 15% survival rate at 5 years. Treatment Wide surgical excision remains the treatment of choice. However, this tumor’s propensity for subcutaneous spreading make the achievement of true free margins very difficult and the 246  2013/2014 Dermatology In-Review l Committed to Your Future Report a Problem/Feedback
  • 254. possibility of recurrence and/or metastatic spread remains very high. Radiation therapy may be employed after surgical excision but often is purely palliative. 6.12 DESMOPLASTIC TRICHOEPITHELIOMA Epidemiology Desmoplastic trichoepithelioma is a variant of trichoepithelioma, an uncommon adnexal tumor with differentiation towards hair structures. It is three times more common in the female gender and usually occurs in young adults.21,81 Trichoepitheliomas are benign tumors arising from the undifferentiated germinative cells of the follicular-sebaceous-apocrine unit. Multiple trichoepithelioma (MT) and giant solitary trichoepithelioma (GST) are other variants of Trichoepithelioma. MT is an autosomal dominant trait that first manifests in puberty and occurs primarily in the facial area. The GST is not hereditary, appears later in life, and affects the perianal region.82 Clinical Manifestation It presents as a small, firm, umbilicated papule on the face.21,81 Histopathology The tumor is seen as a well circumbscribed lesion located in the upper dermis. Strands or columns of basaloid cells are seen surrounded by fibrotic or desmoplastic stroma. Horn cysts may also be seen, as well as foci of sebaceous cells, calcification and ossification.21,81 (Figure 6-22) Figure 6-22. Desmoplastic Trichoepithelioma. Observe the sclerotic stroma, small aggregations and cords of baseloid neoplastic cells within the reticular dermis. The neoplastic cells have round to oval basophilic nuclei and scant cytoplasm Diagnosis and Differential Differentiation from BCC, especially morpheaform BCC, can be challenging. SCC and microcystic adnexal carcinoma (MAC) should be considered. Positive PHLDA1 staining, a marker for follicular stem cells, may help differentiate desmoplastic trichoepithelioma from morpheaform BCC.7 The lack of mitotic figures and presence of keratocysts, keratin granulomas and calcifications may also help to differentiate desmoplastic trichoepithelioma from MAC.8 Treatment Local surgical excision.81 Report a Problem/Feedback Benign and Malignant Neoplasms  247
  • 255. 6.13 DERMATOFIBROSARCOMA PROTUBERANS Epidemiology Dermatofibrosarcoma protuberans (DFSP) is more common in individuals 30-50 years old, with a higher incidence in males with a 3:2 male-to-female ratio.88 It accounts for approximately 0.1% of all skin neoplasms. Etiology The histogenesis of DFSP has been proposed to be fibroblastic, histiocytic, or neuroectodermal.85 However, general agreement on its origin has not been determined. Chromosomal abnormalities are present in the vast majority of cases. A chromosomal reciprocal translocation t(17;22)(q22;q13), and supernumerary ring chromosome have been reported as cytogenetic characteristics of DFSP.87 More than 90% of DFSP present a translocation in different regions of chromosomes 17 and 22. Other translocations such as t(2;17), and t(9;22) have also been proposed.87 In the translocation t(17,22), an exon of the platelet-derived growth factor-B (PDGFB) in chromosome 22 is fused with the collagen 1 alpha 1 (COL1A1) in chromosome 17. The final COL1A1 –PDGF-B fusion oncogene produced mature and fully functional PDGFB protein. The identification of this deregulated expression of PDGFB provided new solid theoretical basis for the use of inhibitors of PDGFB receptors (PDGFRB), such as Imatinib, as an alternative therapy in this disease.89,92,93 Clinical Presentation DFSP is an uncommon monoclonal cutaneous soft tissue neoplasma, characterized by a slow, infiltrative growth pattern. DFSP has considerable morbidity because of its aggressive local invasiveness. It is typically located on the trunk, followed by extremities. Initially it arises as an asymptomatic, reddish or skin colored indurated plaque. Some telangiectasia may be present in the surrounding skin. (Figure 6-23) It may slowly enlarge, and become raised, firm, and multinodular until late in its course. (Figure 6-24). It is usually fixed to overlying skin but remains freely movable from deep tissue. At this stage, it may ulcerate, bleed, or become painful.85,88 Distant metastases occurred in 1 to 4 % of DPSP.81 Palpation of lymph nodes is necessary to detect rare cases of lymphatic (1%) or hematogenous dissemination (4%), predominantly to the lungs.86,90 Figure 6-23. Figure 6-24. Large DFSP located multinodular DFSP on the right clavicle located on the left area of a female patient hip of a female patient Histopathology DFSP is histologically characterized by the presence of monomorphic spindle cells arranged in a “storiform” or “cartwheel” pattern. The cells may show slight atypia. At later stages, the cells infiltrate the subcutaneous adipose tissue, resulting in a honeycomb pattern of entrapped adipocytes.84,85,88 (Figure 6-25) 248  2013/2014 Dermatology In-Review l Committed to Your Future Report a Problem/Feedback
  • 256. Figure 6-25. DFSP. Neoplasm composed of illdefined, dense, spindle cells within the reticular dermis extending towards the subcutaneous fat. The tumor cells are monomorphic and in some areas arranged in a whorl-like pattern. In the subcutaneous tissue the neoplastic cells are invading subcutaneous fat lobules in a lace-like fashion Diagnosis and Differential The final diagnosis of DFSP is done histologically by evaluation of the biopsy specimen. Immunohistochemistry of the specimen may also be done to confirm the diagnosis. Typically DFSP is CD34 positive and factor XIIIa negative, allowing its differentiation from dermatofibroma.84,85,88 Magnetic resonance imaging (MRI) is useful to determine deep tumor invasion, especially in recurrent lesions.86 Other differential diagnosis include scar, keloid, morphea plaque, fibrous histiocytoma, and morpheaform BCC, among others.84,85,86 Treatment DFSP is characterized by an overall high recurrence rate after wide local excision. The tumor shows a subclinical growth pattern through finger-like projections. Accurate removal with the least recurrence requires careful and extensive evaluation of all the margins. Therefore, Mohs micrographic surgery has become a favorite treatment alternative for DFSP. Recently, a review by Snow et al91 reported 136 patients with DFSP treated with Mohs surgery. Long term follow up of these patients showed a 6.6% (9/136) recurrence rate after the first Mohs procedure. However, in all of the recurrent cases there were extensive infiltration or discontinuous tumor growth. Treatment of the recurrent DFSPs with a second Mohs surgery yielded a 98.5% cure rate.83 Adjuvant radiotherapy (RT) reduces local recurrence in patients who have close or positive margins and patients with unresectable macroscopic disease.86,90 Imatinib mesylate is currently FDA-approved for adults with unresectable, recurrent, and/or metastatic DFSP with two small phase II trials reporting a 46% partial response rate in 24 total patients. 6.14 MICROCYSTIC ADNEXAL CARCINOMA Epidemiology Microcystic adnexal carcinoma (MAC), also known as sclerosing sweat duct carcinoma, is an uncommon locally aggressive adnexal tumor. Patients diagnosed with MAC are usually 40-60 years old. Sex distribution seems to be equal. It usually affects middle aged to elderly individuals of both sexes.21,94,95 Report a Problem/Feedback Benign and Malignant Neoplasms  249
  • 257. Etiology The origin of this tumor is unknown. Eccrine, follicular, apocrine or sebaceous differentiation has been reported.21,94,95 Clinical Presentation The most common tumor locations include the perioral, lip, nasolabial, or periorbital areas.21,94,95 Clinically MAC appears as a solitary, skin colored, indurated plaque or nodule. It is usually asymptomatic, but symptoms such as paresthesia, numbness and burning sensation may be present when perineural invasion has occurred.21,94,95 (Figure 6-26) Histopathology Histologically it presents with poorly demarcated tumor cells invading the dermal and subcutaneous tissue. Islands of basaloid keratinocytes, horn cysts and duct structures are also seen within a desmoplastic stroma. Cytologic atypia and mitotic figures are rarely observed.21,94,95 (Figure 6-27) BerEP4, a monoclonal antibody that marks epithelial tissues and not mesothelial tissue, may help differentiate MAC from morpheaform basal cell carcinoma.7 Presence of mitotic figures and lack of keratocysts, keratin granulomas and calcifications may also help to differentiate MAC from desmoplastic trichoepithelioma.8 Diagnosis and Differential Clinical and histological evaluation is required to diagnose MAC. A deep biopsy specimen is required for complete architectural examination.21,94,95 Differential diagnosis include desmoplastic trichoepithelioma, syringoma, and morpheaform BCC, among others. MAC shows deep subcutaneous and perineural invasion, as well as CEA positive staining, all features that may help differentiate it from desmoplastic trichoepitheliomas.94 Treatment Due to the high recurrence rate after conventional excision (approximately 47%), and its infiltrative and aggressive growth pattern, Mohs micrographic surgery has become the preferred treatment option for MAC.21,94,96 Figure 6-26. MAC arising in Figure 6-27. MAC. Irregular island perioral area, clinically of neoplastic baseloid cells with prominent oval resembling morpheaform BCC nuclei. The small aggregations of cells are surrounded by fibrotic desmoplastic stroma. The white line is pointing at neural invasion 250  2013/2014 Dermatology In-Review l Committed to Your Future Report a Problem/Feedback
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