SkinMed: May/June, 2017

Chinese Society of Dermatology

Chinese Society of Dermatology

Weiss, Lambert, and Parish

COMMENTARY Why Me? Coping with the Uncertainties of Antigen Exposures in the Twenty-First Century Lambert and Lambert

Belarusian Society of Dermatovenereologists and Cosmetologists

Lebanese Dermatological Society

Belarusian Society of Dermatovenereologists and Cosmetologists

EDITORIAL Predatory Journals: Harmful to Patients, the Public, and the Integrity of Scientific Research

Lebanese Dermatological Society

North American Clinical Dermatologic Society

The Dermatologic & Aesthetic Surgery International League

African Association for Dermatology

May/JuneDEPARTMENTS 2017 • Volume 15• Issue 3 PERILS OF DERMATOPATHOLOGY Fine and Benign, Until It Becomes Malignant: The Enigmatic Keratoacanthoma

John, Holahan, Singh, Kim, Handler, and Lambert

Tumer, Jow, McElligott, Schwartz, and Lambert

Evaluation of Autoimmune Bullous Diseases in Elderly Patients in Iran: A 10-Year Retrospective Study Ghiasi, Daneshpazhooh, Ismonov, and Chams-Davatchi

Spectrum of Autoimmune Bullous Diseases in the Middle East: A 15-Year Review Haber, Helou, Habr, and Tomb

REVIEWS History of Seborrheic Dermatitis: Conceptual and Clinico-Pathologic Evolution

Mameri, Carneiro, Mameri, da Cunha, and Ramos-e-Silva

Self Assessment Examination Lambert

Smoking and the Skin Wollina

Self Assessment Examination Lambert

The Dermatologic & Aesthetic Surgery International League

African Association for Dermatology

May/June 2017 • Volume 15• Issue 3

Crossed Total Hemiatrophy Associated with Atrophoderma of Pasini-Pierini Zhang and Zhu

Lichenoid Dermatitis in an Adult with Immune Dysregulation, Polyendocrinopathy, Enteropathy, X-Linked (IPEX) Syndrome

THE HEYMANN FILE Infundibulocystic Basal Cell Carcinomas and the SUFU Snafu

Choi, Wang, Geng, Garcia-Lloret, and Smart

HISTORY OF DERMATOLOGY SOCIETY NEWSLETTER Picturing in Dermatology— From Wax Models to Teledermatology, Part I

Lavery and Cooke

Heymann

ORIGINAL CONTRIBUTIONS Telangiectasia Macularis Eruptiva Perstans: Report of Three Cases

North American Clinical Dermatologic Society

Lowenstein

case studies Childhood-Onset Keratosis Lichenoides Chronica Accompanied

by Severe Hair Loss

A Case of Ischemia-Induced Perianal Ulceration Mimicking Pyoderma Gangrenosum

BOOK REVIEWS Skin and Psyche Bernhardt

Molecular Mechanisms of Skin Aging and Age-Related Diseases Hoenig

Dogan, Kılınç, Özaygen, Atakan, Gököz, and Evans

Giant Pigmented Squamous Cell Carcinoma in Situ: A Diagnostic and Therapeutic Challenge Ochoa, Cohen, and MacFarlane

Generalized Discoid Lupus Erythematosus as the Presenting Sign of Small Cell Lung Carcinoma Santiago, Wetter, Lowe, and Sciallis

Chemical Tattoo Treatment Leading to Systemic Cobalt Hypersensitivity Zajdel, Smith, Taintor, Jacob, and Olasz

Association of Piebaldism with Café-au-Lait Macules Kansal and Agarwal

Scan this QR code with your QR reader

Finacea® (azelaic acid) Foam, 15% is indicated for topical treatment of the inflammatory papules and pustules of mild to moderate rosacea.

The first and only prescription foam approved by the FDA for the treatment of rosacea In the art of rosacea therapy...

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IMPORTANT SAFETY INFORMATION Warnings and Precautions Skin Reactions: There have been isolated reports of hypopigmentation after use of azelaic acid. Because azelaic acid has not been well studied in patients with dark complexion, monitor these patients for early signs of hypopigmentation.

Eye and Mucous Membranes Irritation: Azelaic acid has been reported to cause irritation of the eyes. Avoid contact with the eyes, mouth and other mucous membranes. If Finacea® Foam does come in contact with the eyes, wash the eyes with large amounts of water and consult a healthcare professional if eye irritation persists.

Flammability: The propellant in Finacea® Foam is flammable. Instruct the patient to avoid fire, flame, and smoking during and immediately following application. Do not puncture and/or incinerate the containers. Do not expose containers to heat and/or store at temperatures above 120°F (49°C).

Most Common Adverse Reactions In clinical studies, the most frequently observed adverse reactions in ≥ 0.5% of subjects treated with Finacea® Foam included local site pain (6.2%), pruritus (2.5%), dryness (0.7%), and erythema (0.7%).

For Topical Use Only Finacea® Foam is not for oral, ophthalmic or intravaginal use.

Avoid the use of occlusive dressings or wrappings at the application site.

Avoid use of alcoholic cleansers, tinctures and astringents, abrasives and peeling agents.

Patients should be reassessed if no improvement is observed upon completing 12 weeks of therapy.

You are encouraged to report negative side effects of prescription drugs to the FDA. Visit www.fda.gov/medwatch, or call 1-800-FDA-1088.

For important risk and use information, see the full Prescribing Information at www.finaceafoam.com.

For important risk and use information, see the Brief Summary on the following page.

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© 2016 Bayer. Whippany, NJ 07981.

Bayer, the Bayer Cross, and Finacea are registered trademarks of Bayer.

All rights reserved. PP-825-US-0518 January 2016

FINACEAÂŽ

(azelaic acid) Foam, 15% for topical use

For Topical Use Only–Not for Oral, Ophthalmic or Intravaginal Use Rx only BRIEF SUMMARY CONSULT PACKAGE INSERT FOR FULL PRESCRIBING INFORMATION 1 INDICATIONS AND USAGE Finacea (azelaic acid) Foam, 15% is indicated for topical treatment of the inflammatory papules and pustules of mild to moderate rosacea.

5 WARNINGS AND PRECAUTIONS 5.1 Skin Reactions There have been isolated reports of hypopigmentation after use of azelaic acid. Because azelaic acid has not been well studied in patients with dark complexion, monitor these patients for early signs of hypopigmentation.

5.2 Eye and Mucous Membranes Irritation Azelaic acid has been reported to cause irritation of the eyes. Avoid contact with the eyes, mouth and other mucous membranes. If Finacea Foam does come in contact with the eyes, wash the eyes with large amounts of water and consult a physician if eye irritation persists.

5.3 Flammability The propellant in Finacea Foam is flammable. Instruct the patient to avoid fire, flame, and smoking during and immediately following application. Do not puncture and/or incinerate the containers. Do not expose containers to heat and/or store at temperatures above 120°F (49°C).

6 ADVERSE REACTIONS The following adverse reactions are described elsewhere in the prescribing information: t )ZQPQJHNFOUBUJPO [see Warnings and Precautions (5.1)]. t Eye and Mucous Membranes Irritation [see Warnings and Precautions (5.2)].

6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Finacea Foam was evaluated for the treatment of papulopustular rosacea in two multicenter, randomized, double-blind, vehicle-controlled, 12-week clinical trials involving a total of 1362 (Finacea Foam, 15%: 681; vehicle: 681) subjects. Overall, 95.7% of subjects were White, 73.4% were female, and the mean age was 50.6 years.

Table 1: Adverse Reactions Occurring in ≼ 0.5% of Subjects Treated with Finacea Foam Compared with Subjects Treated with Vehicle System/Organ Class Preferred

Finacea Foam, 15% (N=681) n (%)

Vehicle (N=681) n (%)

General disorders and application site conditions Application site pain* Application site pruritus Application site dryness Application site erythema

42 (6.2%) 17 (2.5%) 5 (0.7%) 5 (0.7%)

10 (1.5%) 2 (0.3%) 5 (0.7%) 6 (0.9%)

* “Application site pain� is a term used to describe disagreeable skin sensations, including burning, stinging, paraesthesia and tenderness.

6.2 Post-Marketing Experience )ZQFSTFOTJUJWJUZ SBTI BOE XPSTFOJOH PG BTUINB IBWF CFFO SFQPSUFE GSPN the postmarketing experience of azelaic acid-containing formulations.

Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Local Tolerability Studies In a 21-day cumulative irritation study under occlusive conditions, mildto-moderate irritation was observed for azelaic acid pre-foam emulsion. In B IVNBO SFQFBU JOTVMU QBUDI UFTU )3*15 TUVEZ OP TFOTJUJ[BUJPO QPUFOUJBM was observed for azelaic acid pre-foam emulsion.

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Teratogenic Effects: Pregnancy Category B There are no adequate and well-controlled studies in pregnant women.

Therefore, Finacea Foam should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Dermal embryofetal developmental toxicology studies have not been performed with azelaic acid, 15% foam. Oral embryofetal developmental studies were conducted with azelaic acid in rats, rabbits, and cynomolgus monkeys. Azelaic acid was administered during the period of organogenesis in all three animal species. Embryotoxicity was observed in rats, rabbits, and monkeys at oral doses of azelaic acid that generated some maternal toxicity. Embryotoxicity was observed in rats given 2500 mg/kg/day [162 UJNFT UIF NBYJNVN SFDPNNFOEFE IVNBO EPTF .3)% CBTFE PO CPEZ surface area (BSA)], rabbits given 150 or 500 mg/kg/day (19 or 65 times UIF .3)% CBTFE PO #4" BOE DZOPNPMHVT NPOLFZT HJWFO NH LH EBZ UJNFT UIF .3)% CBTFE PO #4" B[FMBJD BDJE /P UFSBUPHFOJD FGGFDUT were observed in the oral embryofetal developmental studies conducted in rats, rabbits and cynomolgus monkeys.

An oral peri- and post-natal developmental study was conducted in rats.

Azelaic acid was administered from gestational day 15 through day 21 postpartum up to a dose level of 2500 mg/kg/day. Embryotoxicity was PCTFSWFE JO SBUT BU BO PSBM EPTF PG NH LH EBZ UJNFT UIF .3)% based on BSA) that generated some maternal toxicity. In addition, slight disturbances in the post-natal development of fetuses was noted in rats at oral doses that generated some maternal toxicity (500 and 2500 mg/ LH EBZ BOE UJNFT UIF .3)% CBTFE PO #4" /P FGGFDUT PO TFYVBM maturation of the fetuses were noted in this study.

8.3 Nursing Mothers It is not known if azelaic acid is secreted into human milk in vivo /P XFMM controlled studies of topically administered azelaic acid in nursing women BSF BWBJMBCMF /FWFSUIFMFTT UIF EFDJTJPO UP EJTDPOUJOVF OVSTJOH PS UP discontinue the drug should take into account the importance of the drug to the mother.

8.4 Pediatric Use The safety and efficacy of Finacea Foam in children below the age of 18 years have not been established.

8.5 Geriatric Use Of the total number of subjects in clinical studies of Finacea Foam, 18.8 QFSDFOU XFSF BOE PWFS XIJMF QFSDFOU XFSF BOE PWFS /P PWFSBMM differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

17 PATIENT COUNSELING INFORMATION Inform patients using Finacea Foam of the following information and instructions: t 'PS FYUFSOBM VTF POMZ t $MFBOTF BGGFDUFE BSFB T XJUI B WFSZ NJME TPBQ PS B TPBQMFTT DMFBOTJOH lotion and pat dry with a soft towel. t 4IBLF XFMM CFGPSF VTF t "WPJE VTF PG BMDPIPMJD DMFBOTFST UJODUVSFT BOE BTUSJOHFOUT BCSBTJWFT BOE peeling agents. t "WPJE DPOUBDU XJUI UIF FZFT NPVUI BOE PUIFS NVDPVT NFNCSBOFT *G Finacea Foam does come in contact with the eyes, wash the eyes with large amounts of water and consult your physician if eye irritation persists. t *G BMMFSHJD SFBDUJPOT PDDVS EJTDPOUJOVF VTF BOE DPOTVMU ZPVS QIZTJDJBO t 8BTI IBOET JNNFEJBUFMZ GPMMPXJOH BQQMJDBUJPO PG 'JOBDFB 'PBN t $PTNFUJDT NBZ CF BQQMJFE BGUFS UIF BQQMJDBUJPO PG 'JOBDFB 'PBN IBT ESJFE t "WPJE UIF VTF PG PDDMVTJWF ESFTTJOHT BOE XSBQQJOHT t 5P IFMQ NBOBHF SPTBDFB BWPJE BOZ USJHHFST UIBU NBZ QSPWPLF FSZUIFNB flushing, and blushing. These triggers can include spicy and thermally hot food and drinks such as hot coffee, tea, or alcoholic beverages. t 5IF QSPQFMMBOU JO 'JOBDFB 'PBN JT nBNNBCMF "WPJE mSF nBNF PS smoking during and immediately following application. t %JTDBSE QSPEVDU XFFLT BGUFS PQFOJOH Š #BZFS )FBMUI$BSF 1IBSNBDFVUJDBMT *OD "MM SJHIUT SFTFSWFE Manufactured for:

#BZFS )FBMUI$BSF 1IBSNBDFVUJDBMT *OD 8IJQQBOZ /+ Manufactured in Switzerland

6798100BS

TABLE OF CONTENTS May/June 2017 • Volume 15 • Issue 3

EDITORIAL

Predatory Journals: Harmful to Patients, the Public, and the Integrity of Scientific Research ................... 167

Amy Weiss, BA; W. Clark Lambert, MD, PhD; Lawrence Charles Parish, MD, MD(Hon)

COMMENTARy

Why Me? Coping with the Uncertainties of Antigen Exposures in the Twenty-First Century ........................ 169

W. Clark Lambert, MD, PhD; Peter C. Lambert, MA, MD

ORIGINAL CONTRIBUTIONS

Telangiectasia Macularis Eruptiva Perstans: Report of Three Cases ......................................................... 171

Gizem Tumer, MD; Tiffany Jow, BS; Sean McElligott, MD; Robert A. Schwartz, MD, MPH; W. Clark Lambert MD, PhD

Evaluation of Autoimmune Bullous Diseases in Elderly Patients in Iran: A 10-Year Retrospective Study ... 175

Maryam Ghiasi, MD; Maryam Daneshpazhooh, MD; Muhammadkhuja Ismonov, MD; Cheyda Chams-Davatchi, MD

Spectrum of Autoimmune Bullous Diseases in the Middle East: A 15-Year Review .................................... 181

Roger Haber, MD; Josiane Helou, MD; Carla Habr, MD; Roland Tomb, MD, PhD

REVIEWS

History of Seborrheic Dermatitis: Conceptual and Clinico-Pathologic Evolution ........................................ 187

Angela Cristina Akel Mameri, MD, MSc; Sueli Carneiro, MD, PhD; Letícia Maria Akel Mameri, MD; José Marcos Telles da Cunha, MD, PhD; Marcia Ramos-e-Silva, MD, PhD

Self Assessment Examination ................................................................................................................... 195

W. Clark Lambert, MD, PhD

Smoking and the Skin ............................................................................................................................... 197

Uwe Wollina, MD

Self Assessment Examination ................................................................................................................... 203

W. Clark Lambert, MD, PhD

Departments Perils of Dermatopathology

W. Clark Lambert, MD, PhD, Section Editor

Fine and Benign, Until It Becomes Malignant: The Enigmatic Keratoacanthoma ....................................... 205

Ann M. John, BA; Heather H. Holahan, MD; Parmvir Singh, BS; Hee J. Kim, BS; Marc Z. Handler, MD; W. Clark. Lambert, MD, PhD

The Heymann File

Warren R. Heymann, MD, Section Editor

Infundibulocystic Basal Cell Carcinomas and the SUFU Snafu .................................................................. 207

Warren R. Heymann, MD

History of Dermatology Society Newsletter Eve J. Lowenstein, MD, PhD, Section Editor

Picturing in Dermatology—From Wax Models to Teledermatology, Part I .................................................. 209

Eve J. Lowenstein, MD, PhD

162

TABLE OF CONTENTS May/June 2017 • Volume 15 • Issue 3

case studies

Vesna Petronic-Rosic, MD, MSc, Section Editor

Childhood-Onset Keratosis Lichenoides Chronica Accompanied by Severe Hair Loss ............................... 211

Sibel Dogan, MD; Efsun Kılınç, MD; Gül Erkin Özaygen, MD; Nilgün Atakan, MD; Özay Gököz, MD; Sibel Ersoy Evans, MD

Giant Pigmented Squamous Cell Carcinoma in Situ: A Diagnostic and Therapeutic Challenge .................. 215

Blanca E. Ochoa, MD; Philip R. Cohen, MD; Deborah F. MacFarlane, MD, MPH

Generalized Discoid Lupus Erythematosus as the Presenting Sign of Small Cell Lung Carcinoma ............ 218

Tania M. Gonzalez Santiago, MD; David A. Wetter, MD; Garrett C. Lowe, MD; Gabriel F. Sciallis, MD

Chemical Tattoo Treatment Leading to Systemic Cobalt Hypersensitivity .................................................. 221

Nicholas J. Zajdel, BS; W. Austin Smith, MD; Adam R. Taintor, MD; Sharon E. Jacob, MD; Edit B. Olasz, MD, PhD

Association of Piebaldism with Café-au-Lait Macules ............................................................................... 223

Naveen Kumar Kansal, MD; Saurabh Agarwal, MD

Crossed Total Hemiatrophy Associated with Atrophoderma of Pasini-Pierini ............................................ 227

Ru-zhi Zhang, MD; Wen-yuan Zhu, MD

Lichenoid Dermatitis in an Adult with Immune Dysregulation, Polyendocrinopathy, Enteropathy, X-Linked (IPEX) Syndrome ........................................................................................................................ 231

Young M. Choi, BS; Yen T. Wang, MD; Bob Geng, MD; Maria Garcia-Lloret, MD; Chandra N. Smart, MD

A Case of Ischemia-Induced Perianal Ulceration Mimicking Pyoderma Gangrenosum ............................... 235

Michael Joseph Lavery, MB BCh BAO, MRCP (UK); Nicola Cooke BM BS, FRCP, MPhil

BOOK REVIEWS

Jennifer L. Parish, MD, Section Editor

Skin and Psyche ........................................................................................................................................ 239

Mark Bernhardt, MD

Molecular Mechanisms of Skin Aging and Age-Related Diseases .............................................................. 240

Leonard J. Hoenig, MD

163

May/June 2017

Volume 15 • Issue 3

Editorial

ABOUT OUR JOURNAL SKINmed: Dermatology for the Clinician®, print ISSN 1540-9740, online ISSN 1751-7125, is published bimonthly by Pulse Marketing & Communications, LLC, located at 4 Peninsula Avenue, Sea Bright, NJ 07760.

Printed in the USA.

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Publishing PUBLISHER Art Kalaka

Disclaimer: The Publisher, Editors, and Editorial Board cannot be held responsible for errors or any consequences arising from the use of information contained in this journal; the views and opinions expressed herein do not necessarily reflect those of the Publisher, Editors, and Editorial Board, neither does the publication of advertisements constitute any endorsement by the Publisher, Editors, and Editorial Board of the products or services advertised. The Publisher, Editors, Editorial Board, Reviewers, Authors, and Affiliated Agents shall not be held responsible or in any way liable for the continued accuracy of the information or for any errors, inaccuracies, or omissions of any kind in this publication, whether arising from negligence or otherwise, or for any consequences arising thereafter.

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Copyright: © 2017 Pulse Marketing & Communications, LLC. All rights reserved. No part of this publication may be reproduced, stored, or transmitted in any form or by any means without the prior permission in writing from the Publisher. Requests should be addressed to the Permissions Editor at: Pulse Marketing & Communications, LLC, 4 Peninsula Avenue, Sea Bright, NJ 07760.

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Abstracting & Indexing: The journal is indexed in Index Medicus/MEDLINE.

Chinese Society of Dermatology

Lebanese Dermatological Society

VINTAGE LABEL

Courtesy of BuyEnlarge, Philadelphia, PA

164

Belarusian Society of Dermatovenereologists and Cosmetologists

North American Clinical Dermatologic Society

African Association for Dermatology

The Dermatologic & Aesthetic Surgery International League

May/June 2017

EDITOR IN CHIEF

Lawrence Charles Parish, MD, MD (Hon) Philadelphia, PA

DEPUTY EDITORS William Abramovits, MD

Aditya K. Gupta, MD, PhD, FRCPC

W. Clark Lambert, MD, PhD

Vesna Petronic-Rosic, MD, MSc

Dallas, TX

London, Ontario, Canada

Newark, NJ

Chicago, IL

Larry E. Millikan, MD

Marcia Ramos-e-Silva, MD, PhD

Jennifer L. Parish, MD

Meridian, MS

Rio de Janeiro, Brazil

Philadelphia, PA

EDITORIAL BOARD Mohamed Amer, MD Cairo, Egypt

Howard A. Epstein, PhD Philadelphia, PA

Jasna Lipozencic, MD, PhD Zagreb, Croatia

Todd E. Schlesinger, MD Charleston SC

Robert L. Baran, MD Cannes, France

Ibrahim Hassan Galadari, MD, PhD, FRCP Dubai, United Arab Emirates

Ada Lo Schiavo, MD Naples, Italy

Virendra N. Sehgal, MD Delhi, India

Eve J. Lowenstein, MD, PhD New York, NY

Charles Steffen, MD Oceanside, CA

George M. Martin, MD Kihei, HI

Alexander J. Stratigos, MD Athens, Greece

Marc S. Micozzi, MD, PhD Rockport, MA

James S. Studdiford III, MD Philadelphia, PA

Venkataram Mysore, MD, FRCP (Hon, Glasgow) Bangalore, India

Robert J. Thomsen, MD Los Alamos, NM

Anthony V. Benedetto, DO Philadelphia, PA Brian Berman, MD, PhD Miami, FL

Anthony A. Gaspari, MD Baltimore, MD Michael Geiges, MD Zurich, Switzerland

Mark Bernhardt, MD Ft. Lauderdale, FL Jack M. Bernstein, MD Dayton, OH Sarah Brenner, MD Tel Aviv, Israel Henry H.L. Chan, MB, MD, PhD, FRCP Hong Kong, China Joel L. Cohen, MD Greenwood Village, CO Noah Craft, MD, PhD, DTMH Torrance, CA Natalie M. Curcio, MD, MPH Nashville, TN Richard L. Dobson, MD Mt Pleasant, SC William H. Eaglstein, MD Menlo Park, CA Charles N. Ellis, MD Ann Arbor, MI

Michael H. Gold, MD Nashville, TN Lowell A. Goldsmith, MD, MPH Chapel Hill, NC

Oumeish Youssef Oumeish, MD, FRCP Amman, Jordan

Seung-Kyung Hann, MD, PhD Seoul, Korea Roderick J. Hay, BCh, DM, FRCP, FRCPath London, UK

Joseph L. Pace, MD, FRCP Naxxar, Malta

María Daniela Hermida, MD Buenos Aires, Argentina

Art Papier, MD Rochester, NY

Warren R. Heymann, MD Camden, NJ

Johannes Ring, MD, DPhil Munich, Germany

Tanya R. Humphreys, MD Bala-Cynwyd, PA

Roy S. Rogers III, MD Scottsdale, AZ

Camila K. Janniger, MD Englewood, NJ

Donald Rudikoff, MD New York, NY

Abdul-Ghani Kibbi, MD Beirut, Lebanon

Robert I. Rudolph, MD Wyomissing, PA

Andrew P. Lazar, MD Washington, DC

Noah Scheinfeld, MD, JD New York, NY

SKINmed. 2017;15:166

166

Julian Trevino, MD Dayton, OH Graham Turner, PhD, CBiol, FSB Port Sunlight, UK Snejina Vassileva, MD, PhD Sofia, Bulgaria Daniel Wallach, MD Paris, France Michael A. Waugh, MB, FRCP Leeds, UK Wm. Philip Werschler, MD Spokane, WA Ronni Wolf, MD Rechovot, Israel Jianzhong Zhang, MD Beijing, China Matthew J. Zirwas, MD Columbus, Ohio

© 2017 Pulse Marketing & Communications, LLC

May/June 2017

Volume 15 • Issue 3

Editorial

Predatory Journals: Harmful to Patients, the Public, and the Integrity of Scientific Research Amy Weiss, BA;1 W. Clark Lambert, MD, PhD;2,3 Lawrence Charles Parish, MD, MD(Hon)4,5

I

n an era of open access publishing and pressure for physicians, residents, and medical students to publish an excessive amount of papers, the phenomenon of predatory open access journals has become increasingly prevalent. The term “predatory publishers” was coined by Jeffrey Beall to describe how journals and publishers take advantage of open access publishing for their own profit. Jeffrey Beall is an academic and research librarian at Auraria Library of the University of Colorado, Denver. He describes how predatory publishers aggressively and often dishonestly advertise to unsuspecting authors and invite submissions to questionable journals, often charging the authors a large fee for publication in a journal that may not be peer-reviewed.

and content licenses.1,2 (It is true that medical publishers in the 19th century often charged authors for publishing in journals or in books, which morphed into the vanity press of the 20th century.) The potential to increase revenue by recruiting authors has led to these pop-up journals that exist only for the collection of fees.1,3 Some fraudulent journals also exist, because some commercial and professional societies create journals to increase their journal portfolios. These journals generally work by spamming the e-mails of clinicians, researchers, and academic faculty with the “opportunity” to publish in a new journal, to serve as a reviewer or editor of a new journal, or to speak at “renowned” conferences.1,3

Not only does this hurt unknowing authors who are trying to publish their work, but it also provides a route for the publication of low-quality and inaccurate work. Its inclusion as legitimate information dilutes the wealth of scientific knowledge used to educate physicians, researchers, and the general public. It is important to raise awareness and educate. Unsuspecting authors should be made aware of this unfortunate phenomenon, as it not only harms the integrity of the peer-review process and scientific research but also has the potential to harm patients.

These journals are often deceptive about their legitimacy. Contributions are often not peer-reviewed, and the reviewers and journal editor often have no credentials.1,2 Some try to lure authors by giving the journal a name similar to those of reputable journals and a logo reminiscent of a reputable journal’s.1 After authors sign away the copyright, they may be asked to pay unexpected fees that can reach as high as $1,800,1,2,4 only to find their published papers inaccessible through established search mechanisms.2

BACKGROUND

Little empirical research has been done on predatory publishing.2 Beall recognized as a leading expert in the field, estimates that it accounts for 5% to 10% of author-pays.5 One assessment found that predatory journals published 400,000 papers in 2014, at an average cost to the author of $178 per paper.6 In 2015, the Federal Trade Commission set an example with its first lawsuit against the academic journal publishers OMICS Group and two of its subsidiaries, announcing that the publisher was deceiving scholars and misrepresenting the editorial rigor of its journals.4

Journals offer a range of traditional and open access options for authors. In the open access model, authors pay contributionprocessing charges for immediate availability to the public on the Internet.1,2 There are also options to pay fees for various levels of delayed public access for specific types of papers.1 Before the era of online access, journal owners and publishers relied not on fees from authors, but on journal subscriptions

From the Rutgers New Jersey Medical School,1 the Department of Dermatology, Rutgers New Jersey Medical School,2 and the Department of Pathology and Laboratory Medicine,3 Rutgers New Jersey Medical School, Newark, NJ; and the Department of Dermatology and Cutaneous Biology,4 and the Jefferson Center for International Dermatology,5 Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia, PA Address for Correspondence: Lawrence Charles Parish, MD, MD (Hon), Clinical Professor of Dermatology and Cutaneous Biology, Sidney Kimmel Medical College at Thomas Jefferson University, 1845 Walnut Street, Suite 1650, Philadelphia, PA • E-mail: larryderm@yahoo.com

SKINmed. 2017;15:167–168

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© 2017 Pulse Marketing & Communications, LLC

May/June 2017

Volume 15 • Issue 3

OBSERVATIONS

money. Conversely, it is not as evident why researchers are falling

Although the prevalence of these fraudulent journals is alarming, we should keep in mind that they represent a tiny minority of open access journals. Most open access journals do, indeed, follow the standard practices and standards of scholarly work.3 Because a journal is for profit does not necessarily mean that the quality or integrity of the work is any less, as many reputable open access journals use contribution-processing charges to cover costs.3 Unfortunately, the predatory publishers and journals give bad publicity to the open access paradigm, which has provided many benefits in terms of making scientific data available to as many readers as possible.

prey to these journals. Hopefully, this is due, in large part, to a lack of awareness of these journals, highlighting the importance of educating the medical community, in particular, about this problem. The fact that nonpeer-reviewed research and information is being added to the body of knowledge that we, as scientists, rely on is dangerous in the field of medicine. We should not use predatory journals, and many experts have even proposed they be excluded from databases.9,10 References

Because the integrity of journals falls on a spectrum,5,7 Beall has devised useful criteria for choosing legitimate journals. He suggests that the direct contact information for the editor should be provided and that the names and roles of the review panel and editorial board should be clearly delineated. The journal should show an impact factor, and the name of the journal should not sound similar to the name of another journal. He also cautions to be wary of e-mail invitations, to read the journal, and to contact previous authors. Additionally, the editorial board should include experts in the field with full affiliations.1,3,4,8 There is a fine line between low-quality and predatory publishers, so the Directory of Open Access Journals has created lists of vetted journals rather than a list of blacklisted journals. In essence, to make the list, the journal must be scholarly, make the content immediately available, have a peer-review process, and provide a registered International Standard Serial Number.3,7 Some argue that additions to this process will not be fast enough to keep up with the surge of new journals and publishers and that a blacklist, like Beall’s, is better, because it would be able to keep pace.4 Beall updated his lists continually for viewing, until January 15, 2017, when they abruptly went dark.

CONCLUSIONS The recent success of predatory publishers has been due to a combination of authors wanting a large number of publications on their resumes, and the fact that, in the open access era of publishing, for-profit journals and publishers compete with each other for writers. Although it is questionable ethics, the motive for the creation of fraudulent journals is obvious—to make

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168

1 Proehl J, Hoyt S. Predatory publishing: What editors need to know. Adv Emerg Nurs J. 2015;37:1–4.

2 Bowman JD. Predatory publishing, questionable peer review, and fraudulent conferences. Am J Pharm Educ.

2014;78:176.

3 Berger M, Cirasella J. Beyond Beall’s list: Better understanding predatory publishers. Coll Res Libr News.

2015;76:132–135.

4 Straumsheim C. “Predatory” publishing up. Inside Higher ED. 2015. https://www.insidehighered.com/ news/2015/10/01/study-finds-huge-increase-articlespublished-predatory-journals 5 Butler D. Investigating journals: The dark side of publishing. Nature. 2013;495:433–445.

6 Shen C, Bjork, B. Predatory open access: A longitudinal study of article volumes and market characteristics.

BMC Med. 2015;13:230.

7 Frequently asked questions: what are the basic standards that a journal must meet for the application to be considered?” Directory of Open Access Journals. Accessed December 5, 2016. https://doaj.org/ 8 Beall J. Criteria for determining predatory open-access publishers. 3rd ed. Scholarly Open Access. Originally accessed December 5, 2016. https://clinicallibrarian. wordpress.com/2017/01/23/bealls-list-of-predatorypublishers/ 9 Beall J. Predatory journals: Ban predators from the scientific record. Nature. 2016;534:326.

10 Wikipedia: Jeffrey Beall. https://en.wikipedia.org/wiki/ Jeffrey_Beall. Accessed June 20, 2017.

Predatory Journals

May/June 2017

Volume 15 • Issue 3

Commentary

Why Me? Coping with the Uncertainties of Antigen Exposures in the Twenty-First Century W. Clark Lambert, MD, PhD; Peter C. Lambert, MA, MD

Z

ajdel et al, in an outstanding paper in this issue of SKINmed, report a remarkable case of a patient with a blue (due to cobalt) tattoo who experienced a severe systemic reaction after attempting removal of the tattoo with a 50% trichloroacetic acid tattoo removal solution.1 This was despite having neither atopy nor dermatitis as a predisposing factor. The reaction only abated after surgical excision of the tattoo with its cobalt-based pigment. This appears to be the first such reaction due to cobalt ever reported, but even if someone finds another one, it is rare and certainly unusual.

The patient is no doubt grateful for having been cured, but may sensibly ask “why me?” It is a reasonable question deserving of the attention of all of us.

HISTORICAL BACKGROUND In 1900, Paul Ehrlich (1854–1915) proposed what is probably the first modern mechanism to account for antigen recognition and antibody formation. In his “side-chain hypothesis,” Ehrlich proposed that some unnamed cells have side chains, which react with a foreign antigen against which they then produce antibody.

In 1955, Niels Kaj Jerne (1911–1994), who won the Nobel Prize in Physiology or Medicine in 1984, noted that the human body contains a vast array of “background” antibody before de novo antigen exposure, which might be expected to react with virtually any antigen encountered.1–5

Lederberg (1925–2008), who showed experimentally that one B lymphocyte only produces antibody with a single antigenic specificity.6 In 1957 and again in a book published in 1959, Sir Frank Macfarlane Burnet (1899–1985) published his “clonal selection theory of acquired immunity.” In this, one or more mechanisms were proposed to expose an array of immunocompetent cells to foreign antigens, allowing the clones that produced antibody reacting with that antigen to be stimulated to divide; this would lead in a logarithmic fashion to additional cells synthesizing that reactive antibody. As the process progressed, only those clones that produced the antibody with the higher affinities would continue to be stimulated, so that the affinity of the antibody would increase as the process continued, an observation observed clinically and experimentally and that had to be explained by the theory.1 This system, which is duplicated in the B-cell and T-cell systems, acts in concert with similar systems, including particularly the more germline-based “innate” immune system.7

THE ANTIBODY-PRODUCING CELL

This provides us with an explanation of how the basic immune system works, but to the discerning eye it raises more questions than it answers. Interestingly, this is as far as the account on Wikipedia takes us; apparently, the authors considered all the important questions to be addressed by the above. To the contrary, this is just where things get interesting, and where the field becomes most relevant to dermatologists.

In 1957, David W. Talmage (1919–2014) proposed that every antibody-producing cell produces only one unique sort of antibody (ie, antibody with one antigen-binding site). This concept was refined in 1958 by Gustave Nossal (b. 1931) and Joshua

The antibody diversity that characterizes the acquired immunity with which we address and cope with the vast majority of environmental antigens is not accounted for by genes for the variable binding sites of antibody. These are not present in the germline;

See also Zajdel et al, page 221 in this issue.

From the Departments of Dermatology and Pathology and Laboratory Medicine, Rutgers – New Jersey Medical School, Newark, NJ Address for Correspondence: W. Clark Lambert, MD, PhD, Departments of Dermatology and Pathology and Laboratory Medicine, Room H576 Medical Science Building, Rutgers – New Jersey Medical School, 185 South Orange Avenue, Newark, NJ 07103 • Email: lamberwc@njms.rutgers.edu

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they must be generated by mutations that arise in the precursors of our antibody-producing clones of cells that are selected to proliferate upon antigen exposure as per the clonal selection model.

STIMULATING LYMPHOCYTES But herein lies a problem. One should expect that this population would be a heterogeneous group, with some cells showing multiple mutations, and thus possessing excellent antibody diversity, but far, far more cells showing far fewer mutations and poor antibody diversity. For this system to work, there must be a powerful mechanism that begins by stimulating the target cells to replicate, and then, over time, selectively favors those which have undergone multiple mutations, while slowly but surely eliminating those that have undergone only a few mutations.

This is achieved by strongly stimulating lymphocytes in development with major transplantation “HLA” antigens (in humans), which then slowly grow more toxic to cells that have undergone too few mutations in their antibody-binding sites.

Modern societies protect their children, who subsequently do not become exposed to many antigens during development.

This has many benefits, such as reduced infections, but may also contribute to unusual reactions, such as that experienced by this patient. It may also contribute to the high incidence of skin diseases such as atopy and dermatitis experienced by members of our society, not to mention autoimmune diseases, some of which are quite serious.

CONCLUSIONS More attention needs to be paid to examining the incidence of such diseases in developed, “first-world” environments versus less developed areas, where protecting children from such “hazards” is less rigorous.

References

There are good and bad things about the resulting diverse pool of potential reactive lymphocytes. A major benefit is that a very wide range of antibody is created. A major flaw is that it is sometimes not quite wide enough. The histocompatibility antigens that stimulate the lymphocytes can only stimulate so many clones; in most cases, some that would otherwise be possible are simply not stimulated by this particular set of major histocompatibility antigens. The result is that certain major histocompatibility antigens are linked to certain autoimmune diseases, and there is considerable variability in the ability of different individual people to respond to certain antigens.8,9 ANTIGENIC EXPOSURE Even this, however, does not completely explain why our erstwhile patient suffered her reaction to cobalt. The patient’s antigenic exposure experience may have also played a role. There are a number of interesting inbred animal models in which a high proportion of the animals develop a severe autoimmune disease unless they receive a strong antigen exposure, such as a nematode infection, at an early age; this, after treatment and elimination of the source of antigen, prevents the autoimmune disease from developing.10

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1 Zajdel NJ, Smith WA, Taintor AR, Jacob SE, Olasz EB. Chemical tattoo treatment leading to systemic cobalt hypersensitivity. SKINmed 2017; 15:221–222.

2 Burnet FM. A modification of Jerne’s theory of antibody production using the concept of clonal selection. CA Cancer J Clin. 1976;26:119–121.

3 Cohn M, Mitchison N, Paul WE, et al. Reflections on the clonal-selection theory. Nat Rev Immunol. 2007;7:823– 830.

4 Rajewsky K. Clonal selection and learning in the antibody system. Nature. 1996;381:751–758.

5 Jordan MA, Baxter AG. Quantitative and qualitative approaches to GOD: The first 10 years of the clonal selection theory. Immunol Cell Biol. 2007;86:72–79.

6 Nossal GJV, Lederberg J. Antibody production by single cells. Nature. 1958;181:1419–1420.

7 Medzhitov R. Pattern recognition theory and the launch of modern innate immunity. J Immunol. 2013;191:4473– 4474.

8 Hodgkin PD, Heath WR, Baxter AG. The clonal selection theory: 50 years since the revolution. Nature Immunol.

2007;8:1019–1026.

9 Howell WM, Carter V, Clark B. The HLA system: Immunobiology, HLA typing, antibody screening and crossmatching techniques. J Clin Pathol. 2010;63:387–390.

10 Ochsenbein AF, Pinschewer DD, Sierro S, et al. Protective long-term antibody memory by antigen driven and T help-dependent differentiation of long-lived memory B cells to short-lived plasma cells independent of secondary lymphoid organs. Proc Natl Acad Sci U S A. 2000;97:13263–13268.

Why Me? Coping with the Uncertainties of Antigen Exposures

May/June 2017

Volume 15 • Issue 3

ORIGINAL CONTRIBUTION

Telangiectasia Macularis Eruptiva Perstans: Report of Three Cases Gizem Tumer, MD; Tiffany Jow, BS;2 Sean McElligott, MD; Robert A. Schwartz, MD, MPH;2 W. Clark Lambert MD, PhD2 Abstract Telangiectasia macularis eruptiva perstans (TMEP) is a rare, heterogeneous disease of mast cell proliferation. The variable clinical presentation of TMEP, coupled with its rarity, makes the recognition and diagnosis of this disease difficult and challenging for clinicians. The histopathologic findings with hematoxylin and eosin staining that distinguish TMEP from a normal skin biopsy can be so subtle that confirmation of the diagnosis with additional special stains (c-Kit, Giemsa, toluidine blue) is strongly recommended. We describe three cases that highlight the variable clinical presentation of TMEP. One patient experienced only a localized skin manifestation, another an aggressive clinical course with systemic involvement, and a third diffuse skin involvement with mild fatigue, muscle pain, and weight gain.

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MEP represents a rare clinical form of cutaneous mastocytosis that is most commonly seen in adults, but also rarely in children. Conventionally, TMEP has been thought to be limited to the skin, but systemic manifestations have been documented. Reports have also demonstrated associations between TMEP and myelodysplasia, myeloproliferative disorders, acute myeloid leukemia, and/or lymphoproliferative disease—an association that has not gained much recognition among hematologists.1 We describe three varied and atypical cases of TMEP. In doing so, we aim to further contribute to the literature on the classification of this rare but fascinating disease.

CASE 1 A 73-year-old woman presented with hyperpigmented patches on her thighs, knees, ankles, and dorsum of the feet. Laboratory tests and physical examination did not reveal any systemic involvement. A skin biopsy was performed, and histological examination demonstrated dilated vessels and associated perivascular mast cells, indicative of TMEP (Figure 1). Metachromasia of the mast cells’ cytoplasmic granules was revealed on toluidine blue staining, which highlighted an increased number mast cells around the superficial vessels in the papillary dermis (Figure 1). Some mast cells in the superficial region of the dermis also showed c-Kit immunoreactivity, further confirming the diagno-

sis of TMEP. After 4 years, she was still asymptomatic, and no further studies had been performed.

CASE 2 A 28-year-old woman presented to a doctor’s office with a 3-day history of oral labial edema with burning and pruritus. She had taken Benadryl® at home and had also received a Benadryl® injection, albeit without relief. Initially, she presented with lesions on her forehead, which eventually spread to involve the remainder of her body and continued to persist from 5 minutes to several hours. Systemic involvement was noted as she also experienced flushing, dizziness, tinnitus, dyspnea, wheezing, cough, arthralgia, and daily abdominal cramps with diarrhea. A referral was made for further evaluation from a bone marrow biopsy, and the report came back negative for bone marrow involvement.

A diagnosis of TMEP was suspected, and confirmation was attained through laboratory examination demonstrating positive toluidine blue and Giemsa stains as well as positive c-Kit immunoreactivity (Figure 2).

CASE 3 A 36-year-old woman was seen with an eruption that had been present for more than a year. It had initially started on her face

From the Departments of Pathology and Dermatology, Rutgers University – New Jersey Medical School, Newark, NJ Address for Correspondence: W. Clark Lambert, MD, PhD, Room H576 Medical Science Building, Rutgers University – New Jersey Medical School, 185 South Orange Avenue, Newark, NJ 07103 • E-mail: lamberwc@njms.rutgers.edu

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and subsequently spread to her chest, the upper regions of her arms, and her hands. Her description of the eruption was that it was focally pruritic and painful. She also complained of systemic features such as fatigue, muscle pain in the shoulders, and weight gain. Physical examination demonstrated diffuse scattered telangiectasias of the face, upper part of the palate, buccal-labial mucosa, neck, upper areas of the chest and arms, palms, and fingers.

A skin biopsy was performed, and histological examination revealed dilated blood vessels and an increased number of mast cells in the superficial part of the dermis (Figure 3). To confirm the diagnosis of TMEP, laboratory examination with toluidine blue and Giemsa stains was performed (Figure 4). This revealed perivascular mast cells, which then were found to be positive for CD117 (c-Kit) on immunostaining (Figure 4).

Figure 1. (A) Hematoxylin and eosin–stained, medium-power image demonstrating the papillary dermis with dilated vessels surrounded by mast cells. (B) Toluidine blue–stained, medium-power image highlights the cytoplasmic granules of the mast cells (arrow).

Figure 2. (A) Hematoxylin and eosin–stained, medium-power image showing dilated vessels in the papillary dermis with an increased number of mast cells. (B) c-Kit immunohistochemical staining illuminating mast cells (arrow).

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Figure 3. (A) Photograph of the face of the patient with purpuric eruptions. (B) Hematoxylin and eosin–stained, medium-power image depicting dilated blood vessels with marked perivascular mast cell infiltration.

Figure 4. (A) c-Kit immunohistochemical staining showing mast cells with bright immunoreactivity (arrow). (B) Giemsa staining demonstrating the increased number of mast cells (arrow).

DISCUSSION Cutaneous mastocytosis is a mast cell proliferative disorder with at least four different clinical forms: urticaria pigmentosa, solitary mastocytoma, diffuse cutaneous mastocytosis, and TMEP.1– 3 Clinically, TMEP presents as patchy erythematous lesions consisting of reddish-brown macules with telangiectasias and hyperpigmentation. These lesions typically range between a few millimeters and several centimeters in diameter. They tend to be SKINmed. 2017;15:171–174

located symmetrically over the trunk and extremities, and rarely occur on the face.1,2,4,5 Accurate diagnosis of TMEP can be difficult as Darier sign (urtication on rubbing) is often minimal or absent, contrasting with other forms of mastocytosis. This is because the lesions are characteristically paucicellular, and the few mast cells may not yield significant degranulation to exhibit dermographism and the characteristic Darier sign seen in most mastocytoses.2,5,6

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Occasionally, urticaria pigmentosa coexists with this lesion, but TMEP may be distinguished from urticaria pigmentosa by the presence of overlying telangiectases in TMEP. Systemic involvement may be present and is the result of mast cell degranulation with subsequent release of multiple mediators.

Features of systemic involvement in TMEP include flushing, blistering, pruritus, cardiac arrhythmias, dyspnea, asthma exacerbations, hypotension, gastrointestinal upset, acid reflux, peptic ulcer disease, diarrhea, splenomegaly, increased numbers of mast cells in the bone marrow, abnormal skeletal radiographs, irritability, and nonspecific neuropsychiatric clinical manifestations.1,3,5,6 Histologically, TMEP is characterized by subtly increased numbers of ovoid to spindle-shaped mast cells that have a tendency to infiltrate the papillary dermis and surrounding dilated superficial capillaries and venule.3,7 Giemsa and toluidine blue stains may then be used to help distinguish mast cells from histiocytes. Tissue sections showing more than 5 to 10 mast cells are confirmatory for the diagnosis. In addition, a c-Kit (CD117) immunohistochemistry assay can be used to further confirm the diagnosis, as c-Kit is a proto-oncogene that codes for a tyrosine kinase receptor (CD117) present on mast cells and melanocytes.7

plus UVA therapy is often reserved for severe cases of TMEP and treats the pruritus by suppressing the histamine release.7 Intralesional triamcinolone or potent topical steroids may also be used to cutaneous lesions, but recurrence is frequent and this treatment seems to work only temporarily.8 In addition, skin atrophy, striae, and risk of systemic absorption tend to limit the use of corticosteroids.9 Conclusions The cases presented here illustrate the diverse presentations of systemic manifestations of mastocytosis that may accompany TMEP. Whereas no systemic features were noted in case 1, significant systemic involvement was demonstrated in cases 2 and 3; furthermore, in case 3, lesions started on the face, an unusual location for TMEP. These various presentations of TMEP emphasize the difficulty, albeit importance, of recognizing this disease, as appropriate workup is mandatory to determine the proper course of treatment in any cases that present with suspicion for TMEP. References 1 Briley LD, Phillips CM. Cutaneous mastocytosis: a review focusing on the pediatric population. Clin Pediatr (Phila).

2008;47:757–761.

Once suspected from the clinical presentation, the diagnosis should be confirmed by a skin biopsy and further diagnostic tests. Caution should be taken during the skin biopsy to use lidocaine without epinephrine, and to inject around the biopsy site, not directly into it, as direct trauma and epinephrine can stimulate mast cell degradation.8 For adults with cutaneous mastocytosis, it is recommended that a skin biopsy, complete blood count with differential, and bone marrow biopsy be performed to exclude the presence of an associated hematologic condition.

If systemic involvement is suspected, further evaluation is needed depending on the patient’s clinical manifestations.3,8

2 Kalayciyan AK, Kotogyan A. Telangiectasia macularis eruptiva perstans. J Eur Acad Dermatol Venereol.

2001;15:263–264.

As TMEP is a rare condition; a definitive treatment has yet to be documented. However, individual cases have reported good responses to psoralen plus UVA therapy, 585 nm flash lamppumped dye laser, antihistamines, cromolyn sodium, topical and oral corticosteroids, leukotriene antagonists, and some chemotherapeutic agents such as interferon-α2b and cladribine.3,4,6,7 Treatment depends on the presence or absence of systemic involvement, which further emphasizes the importance of accurate initial diagnosis.

6 Turchin I, Barankin B, Schloss E. Unusual cutaneous findings of urticaria pigmentosa and telangiectasia macularis eruptiva perstans associated with marked myelofibrosis. Int J Dermatol. 2006;45:1215–1217.

Antihistamines decrease pruritus, flushing, urticaria, and gastrointestinal clinical manifestations. Oral cromolyn sodium may relieve cutaneous and systemic clinical manifestations.8 Psoralen

9 Cengizlier R, Hucumenoglu S, Ozen A, Tulin Sayli R. Treatment of telangiectasia macularis eruptiva perstans with montelukast. Allergol Immunopathol (Madr).

2009;37:334–336.

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3 Soter NA. Mastocytosis and the skin. Hematol Oncol Clin North Am. 2000;14:537–555, vi.

4 Kowalzic L, Eickenscheidt L, Seidel C, Kribus S, Ziegler H, Komar M. Telangiectasia macularis eruptiva perstans, a form of cutaneous mastocytosis, associated with malignant melanoma. J Dtsch Dermatol Ges. 2009;7:360– 362.

5 Betti R, Vergani R, Tolomio E, Martino P, Crosti C. Guess what! Telangiectasia macularis eruptiva perstans involving the upper arms in an adult male. Eur J Dermatol.

2000;10:563–564.

7 Sotiriou E, Apalla Z, Ioannides D. Telangiectasia macularis eruptive perstans successfully treated with PUVA therapy. Photodermatol Photoimmunol Photomed.

2010;26:46–47.

8 Alto WA, Clarcq L. Cutaneous and systemic manifestations of mastocytosis. Am Fam Physician. 1999;59:3047– 3054, 3059–3060.

Telangiectasia Macularis Eruptiva Perstans

May/June 2017

Volume 15 • Issue 3

ORIGINAL CONTRIBUTION

Evaluation of Autoimmune Bullous Diseases in Elderly Patients in Iran: A 10-Year Retrospective Study Maryam Ghiasi, MD; Maryam Daneshpazhooh, MD; Muhammadkhuja Ismonov, MD; Cheyda Chams-Davatchi, MD Abstract Autoimmune bullous diseases (ABDs) are uncommon but significant skin disorders with relatively high morbidity and mortality. Some surveys have been carried out to describe the spectrum of ABDs in a region, but this is the first that has focused on ABDs in elderly patients. This study was conducted to determine the clinicoepidemiologic features of ABDs in elderly patients. Medical records of all ABD patients with disease onset after the age of 60 years who presented to the Autoimmune Bullous Diseases Research Center, Tehran, Iran between April 2003 and March 2013 were reviewed. Patients with dermatitis herpetiformis were not included. During the 10-year period studied, 296 patients with ABD and disease onset after 60 years of age were diagnosed. Bullous pemphigoid (BP) was observed to be the most common ABD (48.3%), followed by pemphigus vulgaris (45.3%), pemphigus foliaceus (3.7%), mucous membrane pemphigoid (1.4%), paraneoplastic pemphigus (0.7%), epidermolysis bullosa acquisita (0.3%), and linear IgA bullous disease (0.3%). A predominance in women was observed for total ABDs, BP, and pemphigus vulgaris. Although Iran is known to have a high prevalence of pemphigus, BP is the most frequent ABD among elderly patients in Iran, highlighting the importance of the clinical diagnosis of BP in elderly patients.

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A

utoimmune bullous diseases (ABDs) are acquired disorders characterized by overlapping features with involvement of the skin and mucous membranes, and significant morbidity and mortality. The main pathogenic factors in these disorders are autoantibodies against desmosomal and hemidesmosomal structural proteins in the skin. In the pemphigus group, intraepidermal loss of cell adhesion occurs due to autoantibodies against desmosomal proteins. This group includes pemphigus vulgaris (PV), pemphigus foliaceus (PF), IgA pemphigus, and paraneoplastic pemphigus. Pemphigus vegetans is considered a variant of PV, and pemphigus erythematosus a variant of PF. In subepidermal ABDs, autoantibodies against structural proteins of the dermoepidermal junction result in bulla formation at the level of the dermoepidermal junction. This group includes bullous pemphigoid (BP), mucous membrane pemphigoid, pemphigoid gestationis, epidermolysis bullosa acquisita, and linear IgA bullous disease.1 ABDs occur in all ages, and their incidence varies greatly in different regions of the world. Many published epidemiologic stud-

ies have focused on pemphigus, but few have encompassed the total spectrum of ABDs. Few surveys have been carried out to determine the entire spectrum of ABDs in Iran.2,3 Pemphigus is known to be especially common in Iran.4–7 To the best of our knowledge, this is the first study to evaluate ABDs in elderly patients; it was conducted to determine the subtypes of ABDs in elderly patients in Iran over a 10-year period. We also collected data on the clinical manifestations, interval between onset of disease and diagnosis, and methods of treatment in our patients.

METHODS This retrospective, cross-sectional study was carried out in the Autoimmune Bullous Diseases Research Center (ABDRC) at Razi Hospital, Tehran, Iran. ABDRC at Razi Hospital is the major tertiary referral center caring for patients with ABDs. The medical records of all newly diagnosed patients presenting to the ABDRC between April 2003 and March 2013 were examined. Patients with an onset of the disease after 60 years of age were included in the study. The diagnoses in all patients were

From the Department of Dermatology, Autoimmune Bullous Diseases Research Center, Tehran University of Medical Sciences, Tehran, Iran Address for Correspondence: Maryam Ghiasi, MD, Razi Hospital, Vahdat Eslami Square, Tehran, Iran • E-mail: mghiasi@tums.ac.ir

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suspected clinically and confirmed by histopathology and direct immunofluorescence. Enzyme-linked immunosorbent assay for the detection of anti-desmoglein 1 and 3 antibodies in serum and indirect immunofluorescence were performed in some of the patients. Direct immunofluorescence on salt-split skin was performed to confirm epidermolysis bullosa acquisita. Patients with dermatitis herpetiformis were not included in our study because they are seen and managed in general dermatology clinics.

RESULTS A total of 296 patients, 60 years old or older, were diagnosed with ABD and a disease onset during the study period. There were 168 (56.8%) women and 128 (43.2%) men. The most common disease was BP, and the second most common, with little difference, was PV. The frequencies of ABDs and mean age,

age range, and sex ratio of the patients are shown in Table I. A total of 108 patients (36.4%) were between 60 and 70 years of age, 100 patients (33.7%) between 70 and 80 years, 76 patients (25.6%) between 80 and 90 years, and 12 patients (4%) over 90 years.

Patients were divided into three groups for clinical manifestations: skin lesions alone, mucosal lesions alone, and skin and mucosal lesions together. The patients’ clinical manifestations are summarized in Table II. The interval between the onset of disease manifestations and the final diagnosis ranged from 10 days to 2.5 years, with a mean of 4.5±8.3 months. Table III shows these interval periods in different subtypes of ABDs. Table IV shows treatment modalities for the ABDs.

Table I. Characteristics of patients with different autoimmune bullous diseases Number

Percent

Age at Onset, Years, Mean ±SD

Age Range, Years

F:M Ratio

Pemphigus

147

49.6

70.0±7.1

60–91

1.1:1

Pemphigus vulgaris

134

45.2

69.5±6.9

60–91

1.16:1

Pemphigus foliaceus

11

3.7

76.4±8.1

63–91

1:1.75

Paraneoplastic pemphigus

2

0.6

75±5

69–81

1:1

Subepidermal ABD

149

50.3

77.3±7.5

60–94

1.56:1

Bullous pemphigoid

143

48.3

77.6±7.8

60–94

1.6:1

ABD

Mucous membrane pemphigoid

4

1.3

71.5±4.6

62–89

1:1

EBA

1

0.3

70

70

One man

LABD

1

0.3

69

69

One woman

Total

296

100

73.8±8.3

60–94

1.31:1

Abbreviations: ABD, autoimmune bullous disease; EBA, epidermolysis bullosa acquisita; F, female; LABD, linear IgA bullous disease; M, male; SD, standard deviation.

Table II. Clinical manifestations of different autoimmune bullous diseases Skin Lesions Alone, n (%)

Mucosal Lesions Alone, n (%)

Mucosal and Skin Lesions Together, n (%)

Pemphigus vulgaris

33 (24.6)

19 (14.1)

82 (61.1)

Pemphigus foliaceus

10 (90.9)

0

1 (9.0)

0

0

2 (100)

127 (88.8)

0

16 (11.1)

0

1 (25)

3 (75)

EBA

1 (100)

0

0

LABD

1 (100)

0

0

ABD

Paraneoplastic pemphigus Bullous pemphigoid Mucous membrane pemphigoid

Abbreviations: ABD, autoimmune bullous disease; EBA, epidermolysis bullosa acquisita; LABD, linear IgA bullous diseases.

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Table III. Interval between onset of clinical manifestations and final diagnosis in different autoimmune bullous diseases ABD

Time to diagnosis, months, mean±SD

Pemphigus Vulgaris

Pemphigus Foliaceus

Paraneoplastic Pemphigus

Bullous Pemphigoid

Mucous Membrane Pemphigoid

EBA

5.2±6.4

9.6±9.4

2.5±0.7

3.6±5.0

5.2±4.5

24

LABD

24

Abbreviations: ABD, autoimmune bullous disease; EBA, epidermolysis bullosa acquisita; LABD, linear IgA bullous diseases; SD, standard deviation.

Table IV. Treatment modalities used in different autoimmune bullous diseases Treatment Modalities

Pemphigus Vulgaris

Pemphigus Foliaceus

Paraneoplastic Pemphigus

Bullous Pemphigoid

Mucous Membrane Pemphigoid

EBA

LABD

Pred

19

0

0

41

0

0

0

Pred+AZA

66

3

2

5

0

1

0

Pred+CellCept®

13

4

0

3

3

0

0

Pred+MTX

5

0

0

2

0

0

0

Clo

1

0

0

32

0

0

0

Pred+Clo

7

4

0

45

0

0

0

Pred+AZA+Clo

11

0

0

5

0

0

0

Pred+CellCept®+Clo

3

0

0

2

0

0

0

Pred+MTX+Clo

1

0

0

8

0

0

0

Pred+IVIG

4

0

0

0

0

0

0

Pred+rituximab

3

0

0

0

0

0

0

CellCept®

1

0

0

0

0

0

0

Dapsone

0

0

0

0

1

0

1

134

11

2

143

4

1

1

Total

AZA; azathioprine; Clo, clobetasol; EBA, epidermolysis bullosa acquisita; IVIG, intravenous immunoglobulin; LABD, linear IgA bullous diseases; MTX, methotrexate; Pred, prednisolone.

DISCUSSION With increasing age, the cutaneous immune system undergoes some changes, resulting in immune dysregulation, termed immunosenescence. Age-related changes in T cells and cell-mediated immunity may explain why elderly individuals have an increased risk, not only for infections and malignancies, but also for autoimmune diseases.8 A vast array of alterations occur in the cutaneous immune system. At advanced ages, T cells undergo a shift from the naive to the memory phenotype, associSKINmed. 2017;15:175–180

ated with a change in cytokine profile. In addition, they have a reduced proliferative response after activation, a diminution of T cell receptor antigen collection, and decreased cytolytic activity.9 Age-related changes in macrophages and keratinocytes lead to alterations in cytokine production and increased susceptibility to endotoxins in elderly patients.9 Although the pemphigus group comprised the most common ABDs in our study, BP represented the most common individual disease. The ratio of BP to pemphigus has been reported to be

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1:8 in ABDs at all ages in Iran,2 but this ratio was 1:1.02 in elderly patients in our study. The ratio of BP to PV in our study was 1:0.93. This finding is expected, as the incidence of BP clearly increases with age.

BP is the most common ABD in central and western Europe (Switzerland,10 Germany,11 the UK,12 France,13 Italy13) and Singapore.14 BP is a disease of elderly patients. Its frequency increases after the age of 70 and it has its highest frequency above the age of 90.10 In a study in northern Iran, 78% of patients with BP were 60 years or older.15 In another report, the mean age of onset of BP was 59.4 years in Iranian patients, lower than in other countries, where presentation occurred between the seventh and nine decades.2,10–12,16–22 Likewise, another study in south-western Iran reported a mean age of 64.1 years.23 BP is more common in women in most countries, except China, Germany, and Tunisia, where a predominance of men has been reported.24–26 Some studies have reported that the overall incidence of BP is higher in women, but after the age of 80 years, higher in men.10,11 The ratio of women to men in our study was 1.6:1, higher than the 1.36:1 that has been previously reported in BP patients of all ages.2 This may mean that BP is more common in women in older patients in comparison to younger patients in Iran.

Mucosal involvement is not common in BP. We found mucosal lesions in 11.1% of patients, which was lower than previous reports from northern Iran and Croatia (31.1% and 16.6%, respectively).15,27

to be the most common ABD worldwide, except in Switzerland, Germany, the United Kingdom, France, Italy, and Singapore, where BP is more prevalent.10–14 In Iran and most other countries, PV is the most frequent form of pemphigus. The PV to PF ratio was 12.1:1 in our study, which is very close the results of a previous study in Iran.2 In our study, pemphigus was more frequent in women, which is in accordance with most studies worldwide. Interestingly, a dominance in men has been reported from Saudi Arabia,29 Kuwait,16 Bangladesh,30 and China.24 Pemphigus can occur at all ages. It is most frequently diagnosed between the ages of 40 and 60 years. The mean age is between 50 and 60 years in European countries, but in the remaining countries of the world, it is between 30 and 50 years.13 The mean age of presentation was reported to be 38, 41.1, 42, 43.3, 45.4, and 46 years in different studies from Iran.2–7 In our study, 61.1% of patients with PV had mucocutaneous involvement, 24.7% had skin lesions alone, and 14.1% had mucosal lesions alone. In addition, involvement of the mucous membranes were seen in 9% of PF patients. These findings are similar to the results of a previous study on pemphigus patients of all ages in Iran.4 It can be concluded that the clinical manifestations of pemphigus in elderly patients are relatively similar to those in other patients.

Systemic or potent topical corticosteroids represent the best validated treatment options for BP.10 Recent studies indicate that potent topical corticosteroids are able to control generalized BP with the same efficacy as oral corticosteroids but with fewer side effects and lower mortality.28 In our study, the most widely used treatment (31.4% of patients) was prednisolone plus topical clobetasol. Prednisolone alone and clobetasol alone were used in 28.6% and 22.3% of patients, respectively.

In the present study, the mean duration between onset of disease and final diagnosis was 9.6 months in PF, longer than in other ABDs (except epidermolysis bullosa acquisita and linear IgA bullous disease, which, because of the low number of cases, are not significant). In PF, a delay in diagnosis may be caused by the more subtle onset of disease, superficial bullae that rupture easily and lead to crusted lesions with no frank blisters or erosion, seborrheic distribution of lesions, and absence of mucosal lesions in most patients.

The pemphigus group comprised the most common ABDs in our study (45.2% PV, 3.7% PF, 0.6% paraneoplastic pemphigus). Among countries where the prevalence of pemphigus was identified, Iran has the third highest prevalence, after Brazil and Israel. In Brazil, the endemic form of PF (fogo selvagem) is very frequent. Although pemphigus can be seen in all races, it is more common among the Ashkenazi Jewish population.4,13 The incidence of pemphigus in Tehran is approximately 1.6 per 100,000 per year and in Iran 1.0 per 100,000 per year.4 The frequency of pemphigus was reported to be 86.1% and 78% of ABDs at all ages by two studies from Iran.2,3 Pemphigus has been reported

Systemic corticosteroid therapy is the main treatment for pemphigus. Immunosuppressive agents are often used for their steroid-sparing effect to reduce the side effects of corticosteroids.

In localized forms of PF, superpotent topical corticosteroids may be sufficient to control the disease. In our study, prednisolone was prescribed in 98.5% of PV patients, and 100% of PF patients. The most frequently used immunosuppressive drug was azathioprine, which was prescribed in 57.4% of patients with PV. Clobetasol was used along with prednisolone in 36.3% of PF patients with the aim of reducing the dose of prednisolone.

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Mucous membrane pemphigoid represented 1.3% of ABDs in elderly patients in our study. Its frequency was reported as 0.7% of ABDs at all ages in Iran,2 1.1% in Tunisia,26 and 0.7% in Kuwait.16 A higher incidence has been reported in some European countries.18,19 Interestingly, among the patients with mucous membrane pemphigoid in our study, three patients had mucocutaneous involvement and only one patient had mucosal lesions alone. This may reflect that most patients with mucosal involvement are seen by other specialists, such as dentists, ophthalmologists, and otolaryngologists, and the incidence of mucous membrane pemphigoid may be underestimated by dermatologists.

5 Salmanpour R, Shahkar H, Namazi MR, Rahman-Shenas MR. Epidemiology of pemphigus in south-western Iran: A 10-year retrospective study (1991–2000). Int J Dermatol. 2006;45:103–105.

Paraneoplastic pemphigus was diagnosed in 0.6% of our patients. It was reported by another investigator that 0.2% of patients may have an underlying malignancy.2 This sounds reasonable, because the older age of our patients resulted in a higher incidence of malignancy.

10 Marazza G, Pham HC, Scharer l, et al. Incidence of bullous pemphigoid and pemphigus in Switzerland: A 2-year prospective study. Br J Dermatol. 2009;161:861–868.

Epidermolysis bullosa acquisita and linear IgA bullous disease each accounted for 0.3% of patients. Other studies from Iran,2 Tunisia,26 and Kuwait16 have confirmed the incidence of epidermolysis bullosa acquisita as 0.5%, 0.6%, and 2.3%, and the incidence of linear IgA bullous disease as 0.5%, 6.3%, and 7%, respectively.

12 Langan SM, Smeeth L, Hubbard R, et al. Bullous pemphigoid and pemphigus vulgaris– incidence and mortality in the UK: Population-based cohort study. BMJ. 2008;337:a180.

CONCLUSIONS

14 Wong SN, Chua SH. Spectrum of subepidermal immunobullous disorders seen at the National Skin Centre, Singapore: A 2-year review. Br J Dermatol. 2002;147:476– 480.

The results of our study showed that BP is the most frequent ABD in elderly patients in Iran. Although cases of PV outnumbered those of BP by a ratio of 8:1 in the previous study on patients of all ages in Iran, the ratio was 0.93:1 in patients over the age of 60 in our study. This point highlights the value of clinical diagnosis of BP in older patients. We found a female predominance in most subtypes of ABDs in elderly patients, as in previous studies on patients of all ages.

References 1 Zillikens D. Bullose Autoimmundermatosen. In: BraunFalco O, Plewig G, Wolf HH, Burgdorf W, Landthaler M, eds. Dermatologie. 5th ed. Heidelberg: Springer; 2005:607–638.

2 Daneshpazhooh M, Chams-Davatchi C, Payandemehr P, et al. Spectrum of autoimmune bullous diseases in Iran: A 10-year review. Int J Dermatol. 2012;51:35–41.

3 Sobhan M, Farshchian M, Tamimi M. Spectrum of autoimmune vesiculobullous diseases in Iran: A 13-year retrospective study. Clin Cosmet Investig Dermatol.

2016;9:15–20.

4 Chams-Davatchi C, Valikhani M, Daneshpazhooh M, et al. Pemphigus: Analysis of 1209 cases. Int J Dermatol.

2005;44:470–476.

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6 Shamsadini S, Fekri AR, Esfandiarpoor I, et al. Determination of survival and hazard function for pemphigus patients in Kerman, a southern province of Iran. Int J Dermatol. 2006;45:668–671.

7 Asilian A, Yooefi A, Faghihi G. Pemphigus vulgaris in Iran: epidemiology and clinical profile. Skinmed. 2006;5:69– 71.

8 Loo WJ, Burrows NP. Management of autoimmune skin disorders in the elderly. Drugs Aging. 2004;21:767–777.

9 Sunderkotter C, Kalden H, Luger TA. Aging and the skin immune system. Arch Dermatol. 1997;133:1256–1262.

11 Bertram F, Brocker EB, Zillikens D, Schmidt E. Prospective analysis of the incidence of autoimmune bullous disorders in Lower Franconia, Germany. J Dtsch Dermatol Ges. 2009;7:434–440.

13 Alpsoy E, Akman-Karakas A, Uzun S. Geographic variations in epidemiology of two autoimmune bullous diseases: Pemphigus and bullous pemphigoid. Arch Dermatol Res. 2015;307:291–298.

15 Banihashemi M, Zabolinejad N, Vahabi S, Razavi HS. Survey of bullous pemphigoid disease in northern Iran.

Int J Dermatol. 2015;54:1246–1249.

16 Nanda A, Dvorak R, Al-Saeed K, et al. Spectrum of autoimmune bullous diseases in Kuwait. Int J Dermatol.

2004;43:876–881.

17 Uzun S, Durdu M, Akman A, et al. Pemphigus in the Mediterranean region of Turkey: A study of 148 cases.

Int J Dermatol. 2006;45:523–528.

18 Bernard P, Vaillant L, Labeille B, et al. Incidence and distribution of subepidermal autoimmune bullous skin diseases in three French regions. Bullous Diseases French Study Group. Arch Dermatol. 1995;131:48–52.

19 Zillikens D, Wever S, Roth A, et al. Incidence of autoimmune subepidermal blistering dermatoses in a region of central Germany. Arch Dermatol. 1995;131:957–958.

20 Cozzani E, Parodi A, Rebora A, et al.; Gruppo Ligure di Studi in Dermatologia (GLIID). Bullous pemphigoid in Liguria: A 2-year survey. J Eur Acad Dermatol Venereol.

2001;15:317–319.

21 Gudi VS, White MI, Cruickshank N, et al. Annual incidence and mortality of bullous pemphigoid in the Grampian Region of north-east Scotland. Br J Dermatol.

2005;153:424–427.

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22 Parker SR, Dyson S, Brisman s, et al. Mortality of bullous pemphigoid: An evaluation of 223 patients and comparison with the mortality in the general population in the United States. J Am Acad Dermatol. 2008;59:582– 588.

23 Jowkar F, Sadaty MS, Tavana S, Agah MA. Epidemiology of autoimmune bullous diseases and therapeutic modalities during a 10 year period in Iran. Acta Dermatovenerol Croat. 204;22:246–249.

24 Jin P, Shao C, Ye G. Chronic bullous dermatoses in China. Int J Dermatol. 1993;32:89–92.

25 Jung M, Kippes W, Messer G, et al. Increased risk of bullous pemphigoid in male and very old patients: A population-based study on incidence. J Am Acad Dermatol.

1999;41:266–268.

26 Zarra I, Kerkeni N, Ishak F, et al. Spectrum of autoimmune blistering dermatoses in Tunisia: A 11-year study and a review of the literature. Int J Dermatol.

2011;50:939–944.

27 Budimir J, Mihic LL, Situm M, et al. Oral lesions in patients with pemphigus vulgaris and bullous pemphigoid.

Acta Clin Croat. 2008;47:13–18.

28 Joly P, Roujeau JC, Benichou J, et al. A comparison of oral and topical corticosteroids in patients with bullous pemphigoid. N Engl J Med. 2002;346:321–327.

29 Tallab T, Joharji H, Bahamdan K, et al. The incidence of pemphigus in the southern region of Saudi Arabia. Int J Dermatol. 2001;40:570–572.

30 Amin MN, Islam AZ. Clinical, histologic, and immunologic features of pemphigus in Bangladesh. Int J Dermatol.

2006;45:1317–1318.

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Spectrum of Autoimmune Bullous Diseases in the Middle East: A 15-Year Review Roger Haber, MD;1 Josiane Helou, MD;2 Carla Habr, MD;3 Roland Tomb, MD, PhD2 Abstract Characteristics of autoimmune bullous diseases (AIBDs) show wide geographic variation. The aim of this study was to determine retrospectively the characteristics of patients with AIBD admitted to Hôtel-Dieu de France Hospital in Beirut, Lebanon, between 1999 and 2014 and to compare them with those from other areas in the Middle East, the Far East, Asia, North Africa, Europe, and North America. For the patients with AIBDs and who were hospitalized at a major tertiary referral center between 1999 and 2004, we studied demographics, diagnosis, length of stay, department/floor, comorbidities, clinical features, in-hospital evolution, diagnostic tests, and treatment. Bullous pemphigoides was the most frequent bullous disease in Lebanon. This and other findings contrast with those of studies conducted in regional countries. This is the first report of AIBD from the Middle Eastern region. (SKINmed. 2017;15:181–186)

A

utoimmune bullous diseases (AIBDs) are caused by autoantibodies against one or more components of the basement membrane or desmosomal structural proteins of the skin. In the pemphigus group, which includes pemphigus vulgaris (PV), pemphigus foliaceus (PF), IgA pemphigus (IAP), pemphigus erythematous, and paraneoplastic pemphigus, autoantibodies are directed against desmosomal proteins, resulting in an intraepidermal loss of cell contact. In the subepidermal autoimmune bullous disorder, which includes bullous pemphigoid (BP), mucous membrane or cicatricial pemphigoid (CP), pemphigoid gestationis, linear IgA disease (LIAD), epidermolysis bullosa acquisita (EBA), lichen planus pemphigoides, and anti-p200 pemphigoid, the antibodies target hemidesmosomal proteins at the dermoepidermal junction, leading to a subepidermal bullae. Dermatitis herpetiformis and bullous systemic lupus erythematosus feature subepidermal blistering as well.1 Although AIBDs occur worldwide and are associated with high morbidity and mortality rates,2 their relative frequencies and characteristics show wide geographical variation. Their prevalence in the Middle East is still unknown because of a lack of research on the its frequency and demographic features. Outpatient and inpatient data on AIBD are unavailable to date in Lebanon. In this retro-

spective study, we aim to define the spectrum of AIBD over a 15-year period (1999–2014), estimate the incidence of each, describe key demographic features, and compare them with those reported from other parts of the world.

Patients and Methods The medical files of 55 patients were reviewed in this descriptive retrospective study. Patients were admitted for AIBD between January 1999 and December 2014 to the Hôtel-Dieu de France Hospital, which is a major tertiary referral center for bullous disease in Lebanon. All patients had been diagnosed on the basis of clinical findings, histopathology, and direct immunofluorescence with or without indirect immunofluorescence. Data analysis was performed using SPSS version 13 (SPSS Inc, Chicago, IL).

Results A total of 55 patients with documented AIBD were enrolled in this study. There were 29 (52.7%) men and 26 (47.3%) women, with age at the time of first presentation ranging from 0 to 94 years. The most frequent AIBD was BP (31 cases [56.3%]), followed by PV (17 cases [31%]), EBA and CP (two cases each

From the Department of Dermatology, Saint George Hospital University Medical Center, Balamand Faculty of Medicine, Achrafieh, Beirut, Lebanon;1 Department of Dermatology2 and Department of Internal Medicine,3 Hôtel-Dieu de France University Hospital, Faculty of Medicine, Saint Joseph University, Beirut, Lebanon Address for Correspondence: Roger Haber, MD, Department of Dermatology, Saint George Hospital University Medical Center, Balamand Faculty of Medicine, PO Box 166 378, Achrafieh, Beirut, Lebanon • E-mail: rogerhaber@hotmail.com

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[3.6%]), and PF, LIAD, and IAP (one case each [1.8%]). The proportion of these blistering diseases is seen in Figure 1.

Among the 31 patients with BP, the mean age of first presentation was 72.3 years (range 52–89 years), and 19 cases were in men (61.2%). The median time of hospitalization was 6 days.

The most common skin manifestations were cutaneous bullae (28 of 31), followed by pruritus and/or urticaria (23 of 31), oral erosions (10 of 31), and dermatitis (3 of 31). Four cases were attributed to medications (one vildagliptin, one valsartan, and two furosemide) and resolved after drug cessation. Eosinophilia was seen in 10 of 31 patients. A total of 21 patients underwent treatment with oral/intravenous (IV) prednisolone (mean dose of 0.7 mg/kg/day), 25 patients with topical steroids (mostly topical clobetasol, average of two tubes per day), two patients with azathioprine, two with mycophenolate mofetil, three with cyclophosphamide, two with methotrexate, one with dapsone, and one with plasmapheresis. Almost all patients had local wound care with eosine 2%, chlorhexidine, and silver nitrate 1%. Clinical criteria, rather than serum level of antibody, were used to guide the therapeutic regimen. Upon discharge, 93.3% of patients had significant clinical improvement and two patients left against medical advice.

the therapeutic regimen. Upon discharge, 94% patients had significant clinical improvement with drug tapering and one patient left against medical advice.

There were two cases of EBA and two cases of CP, with a mean age at presentation of 51 years. One patient was treated with IV corticosteroids and dapsone, and the other had ocular involvement and was treated with IV corticosteroids and cyclophosphamide. The only case of PF was in an 81-year-old woman who presented with flaccid bullae and erythematosquamous plaques and showed improvement with prednisone 1.5 mg/kg/day. Characteristics of patients with different AIBDs are summarized in the Table. The number of new cases of PB and PV according to year has been increasing through the past 15 years (Figure 2).

Among the 17 patients with PV, the mean age of first presentation was 63.8 years (range 36–94 years), and seven cases were in men (41.1%). Median time of hospitalization was 9 days. The most common skin manifestations were flaccid cutaneous bullae (16 of 17). Mucosal (oral and/or genital) lesions were seen in 10 of 17 patients. Other common clinical manifestations were pruritus (5 of 17). Twelve patients underwent treatment with oral/IV prednisolone (mean dose of 1.5 mg/kg/day), four patients with topical steroids (mostly topical clobetasol, one tube per day), three with azathioprine, two with cyclophosphamide, one with methotrexate, and one with cyclosporine. Almost all patients had the same local wounds care as that for BP. Clinical criteria, rather than serum level of antibody, were used to guide

BP

PV

EBA

CP

PF

LIAD

IAP

Figure 1. Proportion of autoimmune bullous diseases in a 15-year review. BP indicates bullous pemphigoid; CP, cicatricial pemphigoid; EBA, epidermolysis bullosa acquisita; IAP, IgA pemphigus; LIAD, linear IgA dermatosis; PF, pemphigus foliaceus; PV, pemphigus vulgaris.

Table. Characteristics of Autoimmune Bullous Diseases Variant of Disease

Patients, No. (%)

Male

Female

Mean Age (range), y

Bullous pemphigoid

31 (56.3)

19

12

72.3 (52–89)

Pemphigus vulgaris

17 (31.0)

7

10

63.8 (36–94)

Epidermolysis bullosa acquisita

2 (3.6)

1

1

68 (65–71)

Cicatricial pemphigoid

2 (3.6)

0

2

51 (47–55)

Pemphigus foliaceus

1 (1.8)

0

1

81

Linear IgA dermatosis

1 (1.8)

1

0

17

IgA pemphigus

1 (1.8)

1

0

41

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BP PV

Figure 2. Variations of bullous pemphigoid (BP) and pemphigus vulgaris (PV) through 15 years.

Discussion AIBDs in Lebanon are rare. On average, four new cases of AIBD are reported by us every year. Still, they are a major cause of hospitalization. A previous study conducted in the same center between 1998 and 2007 of 191 patients has shown that bullous diseases are the second major dermatological disease requiring hospitalization.3 There was a clear increase in PB and PV in the past 15 year in this country, probably due to aging of the population and improved diagnostic techniques. Similar results have been found in the United Kingdom, where the average yearly increase of BP and PV was 17% and 11%, respectively.4 All diagnoses of AIBD in this study were made upon clinical suspicion and confirmed with histopathology and direct immunofluorescence, with indirect immunofluorescence being inconsistently performed. Average overall time for hospitalization was 8 days, and the most common cause of prolonged hospitalizations was infectious complications (skin, pulmonary, and urinary) rather than resistant bullous disease.

BP was the most predominant type of bullous disease in our study, representing 56.3% of all cases. This is in agreement with reports from the United Kingdom,4 Germany,5 Singapore,6 and Switzerland,7 but not from Iran,8 Malaysia,9 China,10 or Kuwait,11 where PV predominates. The higher incidence of BP may be explained by aging of the Lebanese population as well as improved diagnostic techniques. Two schemes of treatment were used for BD. In the first, systemic corticosteroids were prescribed, and, in the second, immunosuppressive agents and corticosteroids were given simultaneously, with gradual tapering of corticosteroids depending on patient response to treatment; clinical response rather than biologic tests were used to monitor patient response. Topical steroids and local wound care with antiseptic and silver nitrate were used in almost all cases. The mean systemic corticosteroid dose was 0.7 mg/kg/day for PB and 1.5 mg/kg/day for PV, and topical steroids were two tubes per day for PB and one tube per day for PV. No deaths were noted. PreSKINmed. 2017;15:181–186

vious studies on BP have reported incidences between 0.2 and 3 per 100,000 persons per year.4,9,12 In the United Kingdom, a regional study estimated an incidence of 1.4 per 100,000 persons per year.13 As expected and similar to previous studies, the rate of BP progressively and significantly increased with age, with a mean age of diagnosis of 72.3 years, making BP an emerging major disease of the growing elderly population in Lebanon. This is higher than the mean age of BP in Iran, with 65 years,14 Tunisia 67.2 years,15 Poland 67.25 years,16 and Kuwait 65 years,17 but lower than France 83 years,18 Germany 77.3 years,19 and the United Kingdom 80 years.4 This study also showed that there was an overall slight male predominance (29 of 55), in contrast to reports from Malaysia,9,10 Kuwait,11 Switzerland,7 the United Kingdom,4 and Germany.5 This male predominance applied to PB (61.2%) but not to PV (41.1%). Of 31 cases of BP, 19 (61.3%) were in men, compared with 35.2% in Iran.14 In Tunisia and China, it is more common in men than women.10,14 In the United Kingdom, 61% are women.4 In Kuwait, however, the female to male ratio is 5:1.17 In the United States and Germany, the incidence in men and women is nearly equal.19,20 Clinically, cutaneous bullae are the most common initial sign of BP; 90% presented with bullae, and 73% with pruritus and/or urticaria.

Mucosal lesions were found in 33% of cases of PV, with similar results in Kuwait17 and in Taiwan.21 BP has previously been reported in association with diseases such as diabetes, multiple sclerosis, Parkinson disease, ulcerative colitis, and vitiligo.21,22 Fifteen cases with diabetes were found, along with seven cases of Parkinson disease, four cases of cerebrovascular accidents, and one case of Alzheimer’s disease. Because we lacked a control population, we are unable to confirm or reject the association of BP with these diseases that was reported in previous studies.23–25 Association with malignancies has also been reported and with higher frequency than with PV, probably because BP patients are generally older than patients with pemphigus.26 Here, three cases (10%) of concomitant cancers were found. Four cases were attributed to drugs (one vildagliptin, one aldactone, and two furosemide) and only resolved after drug cessation. BP has indeed been reported in association with various systemic drugs, of which spironolactone and furosemide are the most widely recognized.27 Several reports of gliptins inducing BP have also been reported.28 Eosinophilia was observed in 10 cases (33.3%), which is in agreement with previous reports.29 Recent studies indicate that potent topical corticosteroids are able to control generalized BP with the same efficacy as oral corticosteroids but with fewer side effects and less mortality.30 In this study, treatment of PB relied on topical steroids (clobetasol two tubes per day) in 83% of patients, which was associated with oral/IV prednisolone (mean dose of 0.7 mg/kg/day) in 64.5%

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of cases and with immunosuppressants in 29% of cases. Firstline therapy for mild to moderate PB remains topical steroids, and the high number of patients receiving systemic treatment (corticosteroids or immunosuppressants) is probably due to the fact that patients included in this study were hospitalized, thus having severe cases.

PV was shown to be the second most common bullous (27.8%) disease in Lebanon and the most common form of pemphigus, accounting for 90% of all cases of pemphigus (27 of 29). The next most common subtype was PF (1 of 29) and IAP (1 of 29).

Forms of pemphigus that were not found in this study are pemphigus erythematosus, pemphigus herpetiformis, drug-induced pemphigus, and paraneoplastic pemphigus. PV was also the most frequent type of pemphigus in most countries including India,31 Korea,32 Bangladesh,33 Saudi Arabia,34 Kuwait (in another study),35 Bulgaria,36 Serbia and Montenegro,37,38 Macedonia,39 Croatia,40 Greece,41 Italy,42,43 Germany,44 Spain,45 the United Kingdom,46 and Singapore,47 but not Tunisia,48 Mali,49 or South Africa.50 In this study, PV is mostly a disease of middle-aged adults, with a mean age of 63.5 years, affecting women more than men (59%). The mean age of onset of BP was 71 years in the United Kingdom,4 74.6 years in Germany,20 77.2 years in Switzerland,7 and 66 years in Kuwait.35 Older age at onset of BP was noted in industrialized populations and further studies are needed to investigate whether this is due to aging of the population in these countries. Here, 70% of patients with PV had treatment with oral/IV prednisolone (mean dose of 1.5 mg/kg/day); immunosuppressants were added in 41% of all patients with PV, which corresponds to more severe cases. All patients had clinical improvement before discharge.

Only one case of PF was reported (1.8% of all BD), in contrast to reports from Iran where it was the third most common AIBD, with a frequency of 4.4% in Brazil8 and Tunisia48 where the incidence of PF has been reported to approach endemic levels. CP was seen in two cases, accounting for 3.6% of all bullous diseases in Lebanon, which might also be an underestimation of the incidence of this disease due to a referral bias because many patients are diagnosed and seen by dentists and ophthalmologists. EBA is one of the rarest forms of AIBD in Western Europe; yet, in our study, EBA was the third most common acquired bullous disease, just behind PB and PV.

ever, since mild cases of these diseases may have been missed clinically or might have been managed by private practitioners in general outpatient dermatology clinics because the disease is not generally chronic or severe and therefore may not have been referred to our center. The same reasons may also be behind the low frequency of LIAD and IAP, which were only seen each in 1.8% of patients in our study. The cases of paraneoplastic pemphigus, on the other hand, might have been referred or seen by oncologists.

Study Limitations Similar to the majority of dermatologic skin diseases, patients with mild AIBDs are treated as outpatients and do not require hospitalization. Because our site is a tertiary center, most of the cases referred are complex or life-threatening. The patients included in this study likely represent the most severe forms of bullous diseases in this country. In addition, data from this study were from hospital records rather from a well-designed prospective survey. The lack of a central registry for bullous diseases at the moment and the presence of another university referral center in Beirut that covers the same patient population made it impossible in this study to accurately estimate the incidence of bullous diseases in this country.

Conclusions This is the first study in a Middle Eastern country to examine the spectrum of subepidermal AIBDs and compare them with data from the Far East, Asia, North Africa, Europe and North America. It provides a basis on which future research activities can be built. Studies with a larger sample size are necessary for achieving additional findings on these diseases and for explaining the ethnic, environmental, and genetic reasons behind their demographic variations.

References

Cases of pemphigus vegetans were possibly included with PV. No cases of pemphigoid gestationis, lichen planus pemphigoides, vesiculobullous systemic lupus erythmatosus, porphyria cutanea tarda, erythematous pemphigus, or pemphigus herpetiformis were seen. This figure might be an underestimation, howSKINmed. 2017;15:181–186

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1 Duvert-Lehembre S, Joly P. Autoimmune blistering diseases. Rev Med Interne. 2014;35:166–173.

2 Mutasim DF. Management of autoimmune bullous diseases: pharmacology and therapeutics. J Am Acad Dermatol. 2004;51:859–877.

3 Maatouk I, Moutran R, Tomb R. Hospitalization due to skin diseases at Hôtel-Dieu de France Hospital (Beirut), 1998–2007. J Med Liban. 2012;60:99–102.

4 Langan SM, Smeeth L, Hubbard R, et al. Bullous pemphigoid and pemphigus vulgaris––incidence and mortality in the UK: population-based cohort study. BMJ. 2008;337:a180.

5 Bertram F, Bröcker EB, Zillikens D, Schmidt E. Prospective analysis of the incidence of autoimmunebullous disorders in Lower Franconia, Germany. J Dtsch Dermatol Ges. 2009;7:434–440.

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6 Wong SN, Chua SH. Spectrum of subepidermal immunobullous disorders seen at the National Skin Centre Singapore: a 2-year review. Br J Dermatol. 2002;147:476–480.

24 Cordel N, Chosidow O, Hellot MF, et al. Neurological disorders in patients with bullous pemphigoid. Dermatology. 2007;215:187–191.

7 Marazza G, Pham HC, Schärer L, et al. Incidence of bullous pemphigoid and pemphigus in Switzerland: a 2-year prospective study. Br J Dermatol. 2009;161:861–868.

25 Stinco G, Codutti R, Scarbolo M, et al. A retrospective epidemiological study on the association of bullous pemphigoid and neurological diseases. Acta Derm Venereol (Stockh). 2005;85:136–139.

8 Daneshpazhooh M, Chams-Davatchi C, Payandemehr P, et al. Spectrum of autoimmune bullous diseases in Iran: a 10-year review. Int J Dermatol. 2012;51:35–41.

9 Adam BA. Bullous diseases in Malaysia: epidemiology and natural history. i. 1992;31:42–45.

10 Jin P, Shao C, Ye G. Chronic bullous dermatoses in China. Int J Dermatol. 1993;32:89–92.

11 Nanda A, Dvorak R, Al-Saeed K, et al. Spectrum of autoimmune bullous diseases in Kuwait. Int J Dermatol.

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12 Rzany B, Partscht K, Jung M, et al. Risk factors for lethal outcome in patients with bullous pemphigoid: low serum albumin level, high dosage of glucocorticosteroids, and old age. Arch Dermatol. 2002;138:903–908.

13 Gudi VS, White MI, Cruickshank N, et al. Annual incidence and mortality of bullous pemphigoid in the Grampian Region of North-east Scotland. Br J Dermatol.

2005;153:424–427.

26 Lindelöf B, Islam N, Eklund G, Arfors L. Pemphigoid and cancer. Arch Dermatol. 1990;126:66–68.

27 Bastuji-Garin S, Joly P, Picard-Dahan C, et al. Drugs associated with bullous pemphigoid. A case-control study.

Arch Dermatol. 1996;132:272–276.

28 Aouidad I, Fite C, Marinho E, et al. A case report of bullous pemphigoid induced by dipeptidyl peptidase-4 inhibitors. JAMA Dermatol. 2013;149:243–245.

29 Bushkell LL, Jordon RE. Bullous pemphigoid: a cause of peripheral blood eosinophilia. J Am Acad Dermatol.

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30 Joly P, Roujeau JC, Benichou J, et al. A comparison of oral and topical corticosteroids in patients with bullous pemphigoid. N Engl J Med. 2002;346:321–327.

31 Kumar KA. Incidence of pemphigus in Thrissur district, south India. Indian J Dermatol Venereol Leprol.

2008;74:349–351.

14 Esmaili N, Hallaji Z, Soori T, Chams Davatchi C. Bullous pemphigoid in Iranian patients: a descriptive study on 122 cases. Acta Med Iran. 2012;50:335–338

32 Seo PG, Choi WW, Chung JH. Pemphigus in Korea: clinical manifestations and treatment protocol. J Dermatol.

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15 Triki Ben Ammar S, Mokhtar I, Fazaa B, Kharfi M, Kamoun MR. Profile of bullous pemphigoid. A report of 47 cases. Tunis Med. 2000;78:584–588.

33 Amin MN, Islam AZ. Clinical, histologic and immunologic features of pemphigus in Bangladesh. Int J Dermatol.

2006;45:1317–1318.

16 Serwin AB, Bokiniec E, Piascik M, Masny D, Chodynicka B. Epidemiological and clinical analysis of pemphigoid patients in northeastern Poland in 2000–2005. Med Sci Monit. 2007;8:360–364.

34 Tallab T, Joharji H, Bahamdan K, et al. The incidence of pemphigus in the southern region of Saudi Arabia. Int J Dermatol. 2001;40:570–572.

17 Nanda A, Al-Saeid K, Al-Sabah H, Dvorak R, Alsaleh QA. Clinicoepidemiological features and course of 43 cases of bullous pemphigoid in Kuwait. Clin Exp Dermatol.

2006;31:339–342.

18 Joly P, Benichou J, Lok C, et al. Prediction of survival for patients with bullous pemphigoid: a prospective study.

Arch Dermatol. 2005;141:691–698.

19 Colbert RL, Allen DM, Eastwood D, Fairley JA. Mortality rate of bullous pemphigoid in a US medical center. J Invest Dermatol. 2004;122:1091–1095.

20 Zillikens D, Wever S, Roth A, et al. Incidence of autoimmune subepidermal blistering dermatoses in a region of central Germany. Arch Dermatol. 1995;131:957–958.

35 Alsaleh QA, Nanda A, Al-Baghli NM, Dvorak R. Pemphigus in Kuwait. Int J Dermatol. 1999;38:351–359.

36 Tsankov N, Vassileva S, Kamarashev J, et al. Epidemiology of pemphigus in Sofia, Bulgaria. A 16-year retrospective study (1980–1995). Int J Dermatol.

2000;39:104–108.

37 Seidenbaum M, David M, Sandbank M. The course and prognosis of pemphigus. A review of 115 patients. Int J Dermatol. 1988;27:580–584.

38 Golusin Z, Poljacki M, Jovanoviç M, et al. Some epidemiological features of pemphigus chronicus in South Vojvodina: a 12-year retrospective study. Int J Dermatol.

2005;44:792–793.

21 Chang YT, Liu HN, Wong CK. Bullous pemphigoid: a report of 86 cases from Taiwan. Clin Exp Dermatol.

1996;21:20–22.

39 V’lckova-Laskoska MT, Laskoski DS, Kamberova S, et al. Epidemiology of pemphigus in Macedonia: a 15year retrospective study (1990–2004). Int J Dermatol.

2007;46:253–258.

22 Chuang TY, Korkij W, Soltani K, et al. Increased frequency of diabetes mellitus in patients with bullous pemphigoid: a case-control study. J Am Acad Dermatol.

1984;11:1099–1102.

40 Sustic N, Rucevic I, Barisic-Drusko V. Epidemiology of acquired bullous diseases in Eastern Croatia: a retrospective prewar to postwar study. Acta Dermatovenerol Croat. 2005;13:228–232.

23 Masouye I, Schmied E, Didierjean L, et al. Bullous pemphigoid and multiple sclerosis: more than a coincidence?

J Am Acad Dermatol. 1989;21:63–68.

41 Kyriakis K, Tosca A, Lehou J, et al. A 5-year retrospective study on pemphigus and pemphigoid. Australas J Dermatol. 1989;30:33–36.

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42 Naldi L, Bertoni M, Cainelli T. Feasibility of a registry of pemphigus in Italy: two years experience. Gruppo Italiano Studi Epidemiologici in Dermatologia (GISED). Int J Dermatol. 1993;32:424–427.

46 Wilson C, Wojnarowska F, Mehra NK, Pasricha JS. Pemphigus in Oxford, UK, and New Delhi, India: a comparative study of disease characteristics and HLA antigens.

Dermatology. 1994;189:108–110.

43 Micali G, Musumeci ML, Nasca MR. Epidemiologic analysis and clinical course of 84 consecutive cases of pemphigus in eastern Sicily. Int J Dermatol. 1998;37:197– 200.

47 Goon AT, Tan SH. Comparative study of pemphigus vulgaris and pemphigus foliaceus in Singapore. Australas J Dermatol. 2001;42:172–175.

44 Hahn-Ristic K, Rzany B, Amagai M, et al. Increased incidence of pemphigus vulgaris in southern Europeans living in Germany compared with native Germans. J Eur Acad Dermatol Venereol. 2002;16:68–71.

45 Coronel-Pérez IM, Rodríguez-Rey EM, Pérez-Bernal AM, Camacho FM. [Epidemiology of pemphigus in the Hospital Universitario Virgen Macarena, Seville, Spain, 2005–2006]. Actas Dermosifiliogr. 2009;100:121–125.

48 Bastuji-Garin S, Souissi R, Blum L, et al. Comparative epidemiology of pemphigus in Tunisia and France: unusual incidence of pemphigus foliaceus in young Tunisian women. J Invest Dermatol. 1995;104:302–305.

49 Mahé A, Flageul B, Cissé I, et al. Pemphigus in Mali: a study of 30 cases. Br J Dermatol. 1996;134:114–119.

50 Aboobaker J, Morar N, Ramdial PK, Hammond MG. Pemphigus in South Africa. Int J Dermatol. 2001;40:115–119.

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History of Seborrheic Dermatitis: Conceptual and Clinico-Pathologic Evolution Angela Cristina Akel Mameri, MD, MSc;1,2 Sueli Carneiro, MD, PhD;1 Letícia Maria Akel Mameri, MD;2 José Marcos Telles da Cunha, MD, PhD;1 Marcia Ramos-e-Silva, MD, PhD1 Abstract Seborrheic dermatitis is an inflammatory and chronic disease with a high incidence and prevalence (1% to 3% in the general population, 3% to 5% in young adults, and 40% to 80% in HIV-positive individuals). Although the condition was first described in 1887, its clinical aspects and clinical forms have still not been well individualized, nor has its etiopathogenesis been fully elucidated. The disease, despite having clinical features similar to dermatitis, does not have the same histopathologic features or the same progressive clinical behavior. This contribution reviews the history of seborrheic dermatitis. (SKINmed. 2017;15:187–194)

S

eborrheic dermatitis has often been studied under the heading of eczema, even though it has been separated from this group of diseases since its description by Paul Gerson Unna (1850–1929) in 1887.1 During the 19th century, the term eczema was employed to denote all dermatoses with a sudden onset, among which are erythema, pemphigus, erysipelas, and zoster. Since the studies of two English physicians (Robert Willan (1757–1813) and Thomas Bateman (1778–1821) in 1808, eczema has, however, been regarded as a separate eruption.2 In 1819, Laurent Theodor Biett (1780–1840) distinguished two types of eczema—acute and chronic. In 1823, Pierre François Rayer (1793–1867), in his Traité des Maladies de la Peau, described for the first time the topographic forms and evolution of the dermatitis, emphasized its genetic predisposition, and distinguished eczema from other “artificial dermatites” (eczematizations).2 In 1886, during the International Congress of Medicine in Washington and in his famous lecture “Seborrhoeal eczema,” subsequently published in the Journal of Cutaneous and Geni-

to-Urinary Diseases (1887),3 Unna distinguished from the eczema group what he described as seborrheic eczema and pointed to the scalp as the disease’s starting point. He stated that it had three characteristics: (1) desquamation (pityriasis capitis or dandruff); (2) crusts (seborrhea sicca capitis); and (3) a moist nature (eczema chronicum capitis). Unna described rounded and oval lesions that could merge and acquire serpiginous and polycyclic forms with defined borders, having yellowish scales that resembled cerumen. They occurred on the temples, alae nasi, nasolabial furrows, malar and cervical regions, external auditory canals, upper trunk, especially the sternal region, perianal region, shoulders, and arms (but never the elbows). As the lesions were found to be distributed in areas with a high density of sebaceous glands, Unna associated seborrhea with sebaceous secretion, even without an increase in this secretion, and called this form seborrhea sicca, differentiating it from “oily seborrhea.”

In 1894,4 Unna described what was supposed to be the main histopathology of the eruption—the spongiotic or spongioid state of the epidermis—attributed to a coccus (Morococcus), and considered the edema of the horny layer to be the initial

From the Sector of Dermatology and Post-Graduation Course in Dermatology, School of Medicine and University Hospital, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil;1 and Private Practice, Vitoria, Brazil2 Address for Correspondence: Marcia Ramos-e-Silva, MD, PhD, Rua Dona Mariana 143/C-32, 22280-020, Rio de Janeiro, Brazil • E-mail: ramos.e.silva@dermato.med.br

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factor in the process. In 1902, the name pityriasis was given to this group of lesions that had been described by Unna, and suggested that at least one third of them were forms of psoriasis.5

acneic eczema, Duhring’s seborrhea corporis), psoriasiformshaped lesions (seborrhea or Brocq’s psoriasiform parakeratosis), and pityriasisform lesions (seborrhea or Brocq’s pityriasisform parakeratosis, Sabouraud’s pityriasis simplex).15

Years later, in 19216 and 1925,7 Achille Civatte (1877–1956) explained that the initial eczema lesion always started in more superficial portions of the horny layer, from a small (three or four) group of Malpighian cells. These would detach and form a small cavity, immediately distended by serous fluid.

This cavity was replenished by lymphocytes and histiocytes (mononuclear cell exocytosis). During the development of spongiosis, parakeratosis, acanthosis, and an inflammatory infiltrate of round cells, consisting mainly of lymphocytes and mononuclear cells, would develop in the epidermis.

Civatte believed that the papular nature of some eczemas was caused by an abundance of edema and especially by cellular infiltrates.

To group and select some aspects of the disease addressed by different previous authors, Davies16 called it exudative seborrhea, making the term even more confusing. He presented erythema as the essential clinical lesion in all forms of exudative seborrhea, and considered that any disorder affecting the skin (from the acceleration of epithelial growth through blistering until complete necrosis) could occur in seborrheic eczema, which would account for the wide variety of clinical aspects observed, the systemic manifestations, and the relation to or dependence on emotional stress.

In 1928, J.M.H. Macleod (1870–1954) and Geoffrey B.Dowling (1892–1976),8 using what they imagined to be a Pityrosporum culture (but was, in fact, a Candida sp. suspension), managed to reproduce seborrheic dermatitis lesions through intradermal injection or scarification. Only transitional papules were obtained in nonseborrheic volunteers; however, in 1936 they reproduced the same lesions were reproduced with a Pityrosporum suspension.9 In 1938, Pityrosporum was shown to be a universal resident of the scalp, albeit in greater numbers in seborrheic patients.10 A 1931 study showed that hormonal imbalance was related to the high incidence of seborrheic manifestations occurring at puberty and menopause.

11

In 1938, Unna’s seborrheic eczema was described as a poorly defined and inaccurate disease, especially in relation to its etiology (Morococcus) and clinical findings (location in areas of a greater concentration of sebaceous glands).12 Another study in 1938 ranked the seborrheic manifestations of eczema as infectious, physiologic, and constitutional, considering it to be septic in etiology.13 In the following year, Percival14 divided the manifestations of seborrheic dermatitis into three distinct groups: pityriasis capitis (eczematids), infectious flexural dermatitis (intertrigo), and pustular-eczematoid eruptions of hairy areas.

In 1947, seborrheic dermatitis was classified as an eczematid that could manifest with steatoid figured shapes (Brocq’s mediothoracic seborrhea, Sabouraud’s steatoid pityriasis, Bazin’s SKINmed. 2017;15:187–194

The patient’s “seborrheic state,”17 was defended at the Annual Meeting of the American Academy of Dermatology in 1957; it was believed that the clinical presentation varied according to the individual and that several systems could be involved, in particular the endocrine, nutritional, and emotional systems.

Seborrheic dermatitis was placed under the same heading as psoriasis in 196318 and described as a chronic inflammatory skin disease characterized by dry, oily, or moist scales, yellowish and crusty macules of various sizes and shapes, and remissions and exacerbations.

The histologic sequential lesions of seborrheic dermatitis were described in 1966,19 taking a petaloid lesion of the pre-sternal region as a model. Tortuous and dilated capillaries and edematous papules without epidermal alterations were noted.

Leukocytes appeared afterwards, forming a small group at the top of the papilla, with disappearance of the grainy layer and spongiotic edema. In the next stage, with the disorganization of the suprapapillary area, most cells formed a parakeratotic scale. The scale was formed as an isolated elevation, while the Malpighian cells seemed to become organized underneath, with normalization of the papilla, detachment of the scale, and emergence of the granular layer, and finally an edematous papilla with resumption of the process.

In 1967, a study20 discussing the “general concept of seborrheic eczema” placed seborrheic dermatitis within the general condition of eczema, as a subtype of so-called constitutional eczema. It was defined as a “sui generis,” scaly erythematodermatosis of an inflammatory nature, with acanthosis, spongiosis, and parakeratotic epidermal changes, a clinical presentation that was regional (classical type) or eruptive (eczematid,

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sensu stricto), and an etiopathogenesis that was subject to a genetically determined constitutional state.

blepharitis, external otitis, and suboccipital and umbilical dermatitis.

Others considered it as “a clinical eczematous syndrome,”21 a “process with torpid evolution able to persist for months or years and to disseminate into the form of an exfoliative erythroderma,” with the same endogenous nature as atopic eczema, “appearing on a seborrheic background, perhaps partially due to the action of certain microbes and, notwithstanding, retaining many affinities with psoriasis.”

Twenty-five skin biopsies from 25 AIDS patients, who presented with “seborrheic dermatitis,” were studied and compared to the same number of skin biopsies from patients with seborrheic dermatitis who did not have AIDS or its risk factors.24 Findings showed that although the cutaneous eruption in AIDS clinically looked very similar to seborrheic dermatitis, the histologic aspects were very different.

In 1977, eczematous dermatitis was distinguished from seborrheic dermatitis, based on histopathologic criteria.22 Dermatitis was defined as “inflammation of the dermis;” however, the definition that best matched the term eczema was the one that associated the description of the clinical aspects (superficial, erythematous, papulovesiculous, edematous and crusty process at the beginning, and later purple, scaly, lichenified, and even pigmented) with the histologic certainty of a primary epidermal lesion, in the form of an intracellular edema, spongiosis, or blistering. Such characteristics are observed in allergic contact dermatitis, superficial dermatitis caused by primary agents, superficial viral, bacterial, and fungal infections, and some conditions of unknown cause, such as nummular eczema.

In 1994, the disease was included in a chapter on eczemas,25 and seborrheic dermatitis was approached as a chronic disease, difficult to conceptualize but with a distinctive morphology, being found in areas with a greater density of sebaceous glands. Seborrheic dermatitis has also been described as a chronic erythemato-papulous-scaly dermatosis, located in areas with an increased density of sebaceous glands, that children and adults not necessarily associated with an increase in sebum production.26 Others also included seborrheic dermatitis in a chapter on eczema, describing it as a chronic dermatitis of constitutional character that is associated with physiopathologic elements of epidermal proliferation.27

The term eczema was found to be dispensable; therefore, the term “eczematous dermatitis” was replaced by “spongiotic dermatitis,” and seborrheic dermatitis was considered one of many spongiotic dermatoses. Chronic seborrheic dermatitis presents follicular horns of ortho- and parakeratocytic cells, mounds of parakeratosis at the borders of the follicular infundibulum, long, narrow areas of epithelial hyperplasia, highly dilated capillaries and venules in the upper portion of the dermis, and a sparse lymphohistiocytic infiltrate. In acute lesions, scaly crusts with neutrophils at the border of the follicular infundibulum, spongiosis, and light epithelial hyperplasia, as well as a mixed cellular inflammatory infiltrate of lymphocytes, were seen. Histiocytes and neutrophils around the dilated blood vessels of the superficial plexus were also observed.22 Seborrheic dermatitis was also described in a chapter on eczema,23 as a constitutional diathesis, with mild to moderately erythematous, desquamative macules with undefined borders and a central distribution with loose, diffuse scales.

Mild forms affect the scalp, whereas severe forms can affect the eyebrows, forehead, paranasal folds, retroauricular regions, trunk, interscapular and presternal areas, axilla, pubis, and inframammary and intergluteal folds. It can also cause SKINmed. 2017;15:187–194

Giving seborrheic dermatitis the synonyms of seborrheic eczema and eczematid, allows it to be described in a chapter on erythemato-scaly eruptions. It has a familial predisposition and immune component, affecting areas rich in sebaceous glands as well as some intertriginous areas.28 In 2010, seborrheic dermatitis was mentioned along with other eczematous dermatoses in the book Fundamentos de Dermatologia as seborrheic dermatitis with a hormonal influence that occurs in areas with an abundance of sebaceous glands. There is no mention of changes in sebum secretion when compared to healthy individuals.29 Despite the large number of Malassezia organisms in the lesions, there is no proven relation between the number of yeasts and the severity of the disease.

In its 131 year history, seborrheic dermatitis has been described any number of times. The disease has various presentation,2,30–35 including psoriasiform and pityriasisform patterns. Although some authors consider that it can develop into erythroderma,36 it does not, according to Unna’s descriptions, affect the extremities. As to infantile seborrheic dermatitis, it may resemble atopic dermatitis, when a family history of atopy is obtained. In relation to infantile seborrheic dermatitis, the clinical manifestations are of a difficult differential diagnosis in relation to atopic dermatitis, including

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in relation to the itching and familial history of atopy. Many children finally diagnosed as having infantile seborrheic dermatitis did not at first have this diagnosis confirmed during the evolution of the disease.34,37

tion of the form in which the disease manifests according to its

Despite the recognition of dermatologic lesions (erythema, papules, scales), there has not yet been an objective descrip-

moderate and severe in terms of the immunohistochemical

severity. The Table shows the characteristics of seborrheic dermatitis as described by different authors since 1886. Recently, some authors have separated the clinical manifestations into profile of the seborrheic dermatitis.38,39 The disease, however,

Table. Seborrheic Dermatitis Characteristics as Given by Different Authors Since 1886 Author

Year

Name

Clinical aspects

Histopathologic aspects

1

Unna

1886

Seborrheic eczema

Scalp. Three characteristics: desquamative (pityriasis capitis or dandruff), crusty (seborrhea sicca capitis) and moist (eczema chronicum capitis). Rounded and oval lesions, confluent and serpiginous, polycyclic, sharp borders, yellowish scales. Lesions in the armpits, arms (sparing the elbows), temples, bridge of the nose, nasolabial groove, malar, cervical, and perianal regions, external auditory canal, and upper region of the trunk, especially the sternal region

Spongiotic or spongioid state of the epidermis. Edema of the horny layer as the initial factor in the process.

Perinuclear edema and swelling of the basal cells and vacuoles in squamous cells are secondary to the interstitial edema

Sabouraud5

1902

Pityriasis

Same lesions described by Unna, with the exception of dry and scaly lesions (considered by Sabouraud as forms of psoriasis)

Spongiosis and vesiculation resulting from the papillary dermis blood vessel transudate (Sabouraud’s exoserosis), which spreads into intercellular spaces in the basal layer immediately above the papilla, and then to the squamous layer

Civatte,6,7 Darier et al15

1924

Eczematide

Same lesions described by Unna, but without clinicalpathologic consensus, with a great variability of clinical expression and evolutionary inconsistency. A variety of eczema

Primary histological lesion consisting of small vesicles, the result of a spongiotic process in the cells of the squamous layer. Interspersed with mononuclear cells

Chevallier12

1938

Parakeratotic eczema, seborrheic eczema, eczematide, psoriasiform parakeratoses

Considered seborrheic eczema as described by Unna as Not described inaccurate in its clinical delimitations, as it encompassed clinical features of other entities already recognized by other dermatologists as individual conditions.

Questioned the anatomic basis of the disease (there were no lipids in the epidermal cells) and did not accept Morococcus as the causative agent

Ingram13

1939

Eczema

Aspects: infective—pityriasis capitis, seborrhea corporis, and eczematid; physiologic —acne and rosacea; constitutional—eczematous forms

Not described

Percival14

1939

Would not accept the term seborrheic dermatitis

Pityriasis capitis (eczematids), infectious flexural dermatitis (intertrigo), pustular rashes, hairy area eczematids. A clinically distinct entity

Not described

Darier et al15

1947

Eczematide

Steatoid figurated forms (Brocq’s mediothoracic seborrhea, Sabouraud’s steatoid pityriasis, Bazin’s acneic eczema, Duhring’s corporis seborrhea), psoriasiform forms (seborrhea, Brocq’s psoriasiform parakeratosis), and pityriasis-like (seborrhea or Brocq’s pityriasis-like parakeratosis, Sabouraud’s pityriasis simplex)

Same aspect of the eczema first described by Willan

Continued SKINmed. 2017;15:187–194

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Table. Seborrheic Dermatitis Characteristics as Given by Different Authors Since 1886 (Continued) Author

Year

Name

Clinical aspects

Histopathologic aspects

Davies

1952

Seborrheic eczema

Universal disease. Pure vascular response— erythematous, erysipeloid. and urticarial forms.

Primary vascular response with secondary epithelial participation—exudative seborrhea. Epidermal response concealing the vascular-macular eczema component on the limbs

Not described

Andrews and Domonkos8

1963

Seborrheic eczema, seborrheic dermatitis

Chronic inflammatory skin disease beginning on the scalp, spreading to the supraorbital region, eyelids, nasolabial groove, lips, ears, sternal area, armpits, submammary folds, groin, and intergluteal cleft.

Characterized by dry, oily, or moist scales, and yellowish and crusted stains of various sizes and shapes.

Remissions and exacerbations

Mild inflammatory process. Epidermis with focal parakeratosis, acanthosis, and spongiosis, and occasional vesicle formation. Dilated vessels in the subpapillary dermis with moderate lymphocyte infiltrate

RamosSilva20

1967

Seborrheic dermatitis

Spectrum of papular, scaly, and crusty lesions, characterized by a mild chronic inflammatory reaction in the seborrheic areas, dry lesions or papular-scaly, and moist and crusty in folds

Not described

Rabello and Fraga21

1970

Seborrheic eczema

"Clinical eczematous syndrome"—torpid evolutionary process that can persist for months or years and may be generalized as an exfoliative erythroderma. Same endogenous nature as atopic eczema, "appearing on a seborrheic background due to the action of certain microbes, and nevertheless, keeping many affinities with psoriasis"

Not described

Ackerman22

1977

Seborrheic dermatitis

Not described

Acute lesions: squamous crusts containing neutrophils at the edge of the follicular infundibulum, mild spongiosis, mild epithelial hyperplasia, and a mixed cellular inflammatory infiltrate of lymphocytes, histiocytes, and neutrophils, perivascular and dilated in the superficial plexus.

Plewig and Jansen26

1999

Seborrheic dermatitis

Chronic papular-erythematous-scaly dermatosis, located in areas with greater density of sebaceous glands, affecting children and adults, and not always associated with increased production of sebum on the scalp, face, and trunk

Not described

16

Continued

can present with a mild form (light clinical inflammation), the classically recognized moderate form (more accentuated clinical inflammation), and a severe form (an intense clinical inflammatory reaction).

Seborrheic dermatitis is one of the most common dermatologic manifestations in HIV infection; it is included in the spectrum of idiopathic lesions and should be carefully evaluated in high-risk patients.40 Its incidence and severity are directly linked to the stage of the HIV infection and are conSKINmed. 2017;15:187–194

versely correlated to the absolute CD4 T cell count.41,42 As the disease advances and progresses, the lesions of seborrheic dermatitis spread and worsen.43 It is known that the HIV virus destroys regulatory T cells44 and is possibly involved in the pathogenesis of seborrheic dermatitis.

FINAL CONSIDERATIONS There are few facts but much speculation regarding seborrheic dermatitis, a disease that is morphologically distinct from eczema but has been without clinically/pathologically defined

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Table. Seborrheic Dermatitis Characteristics as Given by Different Authors Since 1886 (Continued) Author

Year

Name

Clinical aspects

Histopathologic aspects

27

Cestari et al

2006

Eczemaseborrheic dermatitis

Not described Macular-papular lesions, erythematous or yellowish, dull, delimited, and covered by scales of a greasy nature, distributed throughout seborrheic areas (scalp, face, presternal region, and interscapular, axillary, and anogenital folds). Scalp almost always affected, very often alone. Early forms such as dandruff (pityriasis capitis) may progress gradually with the appearance of erythema, thicker scales, and transgression of the scalp’s borders. May be erythema, desquamation, and outer ear and retroauricular fissures. On the face, involvement occurs on the inner side of the eyebrows, glabella, nasolabial groove, bridge of the nose, and paranasal region; also common are erythema and marginal scaling of the eyelashes. On the trunk, petaloid lesions, often in interscapular and presternal regions (erythematous, desquamative papules, initially follicular that originate annular pattern lesions, with thin central desquamation and higher borders). Axillary, anogenital, and inframammary folds are the most involved (intertrigo), with an erythematousdesquamative aspect sharper at the center

Sampaio and Rivitti28

2007

Seborrheic eczema and eczematide

Chronic, frequent, recurring, noncontagious eruption in areas rich in sebaceous glands and eventually some intertriginous areas. The lesions are erythematousscaly and affect the scalp, face, nasogenian groove and glabella, retroauricular area, median portions of the chest (Brocq’s mediothoracic dermatitis), and pubic and axillary regions. On the scalp, "dandruff" is described as a minimal form of the disease (steatoid pityriasis).

Authors also consider blepharitis and external auditory canal "eczema" as clinical manifestations of seborrheic dermatitis

Chronic dermatitis with areas of parakeratosis, mild to moderate acanthosis and spongiosis, exocytosis and a mononuclear infiltrate in the dermis

Accioly Filho29

2010

Seborrheic dermatitis

Described together with other eczematous dermatoses such as seborrheic dermatitis with hormonal influence, occurring in areas with many sebaceous glands, but without reference to the change in the secretion of sebum compared to healthy individuals. Despite the large number of Malassezia organisms in the lesions, refers to no proven relation between the number of yeasts and disease severity

Not described

patterns since its initial description by Unna; instead, the topography of the disease is the factor, making the differential diagnosis from other dermatoses, among which is atopic dermatitis. The natural course of this chronic disease has not yet been described. There are, in addition, questions to be answered: Are the clinical forms static or do they evolve from mild to severe? Do the variations in clinical picture (localized or disseminated lesions) fall within the same form (mild, SKINmed. 2017;15:187–194

moderate, or severe), or are there patients who change from one clinical form to another?

In fact, Pityrosporum is an aggravating factor for the disease, but the fungus is not always found in the lesions. The term “individual susceptibility” is related to human leukocyte antigens and T lymphocytes; this shows that there is still an insufficient understanding of the disease’s physiopathogenesis.

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References 1 Unna PG. Das seborrhoiche Ekzem. Monatsh Prakt Dermatol. 1887;6:827–846.

2 Sézary A, Horowitz A. Eczema. In: Darier J, Sabouraud R, Gougerot H, et al. Nouvelle Pratique Dermatologique.

Mason et Cie; 1936:36–124.

20 Ramos-Silva J. [General concept of “dermatitis seborrheica”]. Hospital (Rio J). 1967;72:325–334.

21 Rabello FE, Fraga S. Eczema. In: Rabello FE, Fraga S. Atlas de Dermatologia. Rio de Janeiro: Guanabara Koogan; 1970:100–109.

J Cutan Dis.

22 Ackerman AB. Histopathologic differentiation of eczematous dermatitis from psoriasis and seborrhoeic dermatitis. Cutis. 1997;20:619–623.

4 Unna PG. Die Histopathologie der Hautkrankheiten. Berlin: Hirschwald; 1894.

23 Solomon LM. Eczema. In: Moschella SL, Hurley HJ, eds. Dermatology. 2nd ed. Philadelphia, PA: WB Saunders; 1985:354–388.

3 Unna PG. Seborrhoeae 1887;5:449–459.

eczema.

5 Sabouraud R. Apud. In: MacKenna RMB, ed. Modern Trends in Dermatology. New York, NY: Hoeber PB; 1948:122.

6 Civatte A. Cytologie des lésions élémentaires de l’éczema, des éczematides et du psoriasis. C R Soc Biol. 1921;84:546–548.

7 Civatte A. Psoriasis and seborrhoeic eczema: Pathological anatomy and diagnostic histology of the two dermatoses. Proc R Soc Med. 1925;18:1–11.

8 MacLeod JMH, Dowling GB. An experimental study of the pityrosporum of Mallassez: Its morphology, cultivation and pathogenicity. Br J Dermat Syph.

1928;40:139–148.

9 Moore M, Kile RL, Engham Jr MF, Engham MF. Pityrosporum ovale (bottle bacillus of Unna, spore of Mallassez): Cultivation and possible role in seborrheic dermatitis. Arch Dermatol Syph.1936;33:457–471.

10 Benham RW. The cultural characteristics of Pityrosporum ovale—a lipophilic fungus. J Invest Dermatol.

1939;2:187–203.

11 Ingram JT, Fowweather FS. Acidosis and seborrhoea.

Br Med J. 1931;1:839–841.

24 Soeprono FF, Schinella RA, Cockerell CJ, Comite SL. Seborrheic-like dermatitis of acquired immunodeficiency syndrome. A clinicopathologic study. J Am Acad Dermatol. 1986;14(2 Pt 1):242–248.

25 Burton JL. Eczema, lichenification, prurigo and erythroderma. In: Champion RH, Burton JL, Ebling FJG, eds. Rook, Wilkinson, Ebling Textbook of Dermatology.

5th ed. Oxford: Blackwell; 1992:584–588.

26 Plewig G, Jansen T. Seborrheic dermatitis. In: Fitzpatrick TB, Eisen AZ, Wolff K, Freedberg IM, Austen KF, eds. Fitzpatrick’s Dermatology in General Medicine. 5th ed. New York, NY: McGraw-Hill; 1999:1482–1489.

27 Cestari SCP, Azulay DR, Azulay RD. Eczemas e dermatites afins. In: Azulay RD, Azulay DR, eds. Dermatologia. 4th ed. Rio de Janeiro: Guanabara Koogan; 2006: 149–167.

28 Sampaio SAP, Rivitti E. Erupções eritemato-escamosas. Dermatologia. São Paulo: Artes Médicas.

2007:227–246.

29 Accioly Filho JW. Dermatite seborréica. In: Ramos-eSilva M, Carneiro MCR, eds. Fundamentos de Dermatologia. Rio de Janeiro: Atheneu; 2010:449–452.

12 Chevalier P. Le syndrome eczema. In: Belot J, Chevallier P, Gaté J, Joulia P, Pinard M, eds. Traité de dermatologie clinique et therapeutique. Paris: Gaston Doin; 1933:147–155.

30 Vallia RG. Etiopathogenesis of seborrhoeic dermatitis.

Indian J Dermatol Venerol Leprol. 2006;72:253–255.

13 Ingram JT. Seborrheic 1938;50:59–66.

32 Hay RJ, Graham-Brown RA. Dandruff and seborrhoeic dermatitis: Causes and management. Clin Exp Dermatol. 1997;22:3–6.

sycosis.

Br J Dermatol.

14 Percival GH. The ætiology of seborrheic dermatitis. Br J Dermatol. 1939;51:7–13.

15 Darier J, Civatte A, Tzanck A. Taches squameuses et érythemato-squameuses. In: Darier J, Civatte A, Tzanck A, eds. Précis de Dermatologie. Paris: Masson;1947:122–140.

31 Gupta AK, Bluhm R. Seborrhoeic dermatitis. J Eur Acad Dermatol Venerol. 2004;18:13–26.

33 Bonifazi E. Infantile seborrhoeic dermatitis: Pathogenetic considerations and nosological aspects. Pediat Dermatol News. 1988;7:16–21.

34 Prigent F. Seborrheic dermatitis in children. Ann Dermatol Venereol. 2002;129(1 Pt 1):68.

16 Davies JHT. Seborrhoeic eczema: An attempt to define the scope of the term. Br J Dermatol. 1952;64:213– 224.

35 Podmore P, Burrows D, Eedy DJ, Stanford CF. Seborrhoeic eczema – a disease entity or a clinical variant of an eczema? Br J Dermatol.1986;115:341–350.

17 Ingram JT. The seborrheic diathesis. Arch Dermatol.

1957;76:157–161.

36 Messaritakis J, Katamis C, Karabula C. Generalized seborrhoeic dermatitis: Clinical and therapeutic data of 25 patients. Arch Dis Child. 1975;50:871–874.

18 Andrews GC, Domonkos AN. Seborrheic dermatitis and psoriasis. In: Andrews GC, Domonkos AN, eds. Diseases of the Skin. Philadelphia: WB Saunders;1963:152–155.

19 Pinkus H, Mehregan A. The primary histologic lesion of seborrheic dermatitis and psoriasis. J Invest Dermatol. 1966;46:109–116.

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37 Menni S, Piccinno R, Baietta S, Ciuffreda A, Scotti L. Infantile seborrhoeic dermatitis: Seven-year followup and some prognostic criteria. Pediatr Dermatol.

1989;6:13–15.

38 Faergemann J, Bergbrant IM, Dohse M., Scott A, Westgate G. Seborrhoeic dermatitis and Pityrosporum

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(Malassezia) folliculitis: Characterization of inflammatory cells and mediators in the immunohistochemistry. Br J Dermatol. 2001;144:549–556.

39 Molinero LL, Gruber M, Leoni J, Wolcoff A, Zwirner NW. Up-regulated expression of MICA and proinflammatory cytokines in skin biopsies from patients with seborrhoeic dermatitis. Clin Immunol. 2003;106:50– 54.

40 Ippolito F, Passi S, Di Carlo A. Is seborrhoeic dermatitis a clinical marker of HIV disease? Minerva Ginecol 2000;52:54–58.

41 Schaub NA, Drewe J, Sponagel L, et al. Is there a relation between risk groups or initial CD4 T cell counts

and prevalence of seborrhoeic dermatitis in HIV-infected patients? Dermatology. 1999;198:126–129.

42 Montella F, Pezotti P, Dibora F, et al. Improving the prognostic value of CD4+ count using 1g A and clinical signs in HIV-seropositive i.v. drug users. Infection.

1997;25:117–120.

43 Rosatelli JB, Machado AA, Roselino AM. Dermatoses among Brazilian HIV-positive patients: Correlation with the evolutionary phases of AIDS. Int J Dermatol.

1997;36:729–734.

44 Eggena MP, Barugahare B, Jones N, et al. Depletion of regulatory T cells in HIV infection is associated with immune activation. J Immunol. 2005;174:4407–4414.

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SELF ASSESSMENT EXAMINATION

SELF ASSESSMENT EXAMINATION W. Clark Lambert, MD, PhD Instructions: Unless instructed otherwise, for each numbered item choose the single most appropriate lettered response.

2. Seborrheic dermatitis, as originally described, affects each of the following sites except: a. Ala nasi. b. Ear canals. c. Elbows. d. Mid-chest. e. Nasolabial folds. f. Scalp.

3. Clinical seborrheic dermatitis occurs with increased frequency in patients who are or have: a. Delusions of parasitosis. b. HIV positive. c. Slavian d. Liver failure. e. Renal failure.

5. a. b. c. d. e.

Pityrosporum is a fungus which (is): Causative of seborrheic dermatitis in rare patients.

Causative of seborrheic dermatitis in some patients.

Causative of seborrheic dermatitis in many patients.

Causative of seborrheic dermatitis in most patients.

Contributes to causation but is not causative of seborrheic dermatitis.

ANSWERS TO EXAMINATION: 1. d; 2. c; 3. b; 4. a, b, c, d, e; 5. e.

1. Seborrheic dermatitis was originally described in 1877 by: a. Brocq. b. Civatte. c. MacLeod and Dowling. d. Unna. e. Willan and Bateman.

4. Clinical seborrheic dermatitis associated with HIV positive status: (Choose as many as apply. All, some, one, or none of the answers may be correct.) a. Is histologically quite different from other cases of clinical seborrheic dermatitis. b. Occurs with an incidence directly related to the stage of the HIV infection. c. Occurs with a severity directly related to the stage of the HIV infection. d. Occurs with an incidence inversely related to the CD4 lymphocyte count. e. Occurs with a severity inversely related to the CD4 lymphocyte count.

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Courtesy of BuyEnlarge, Philadelphia, PA From the Departments of Pathology and Dermatology, Rutgers University – New Jersey Medical School, Newark, NJ Address for Correspondence: W. Clark Lambert, MD, PhD, Room H576 Medical Science Building, Rutgers University – New Jersey Medical School, 185 South Orange Avenue, Newark, NJ 07103 • E-mail: lamberwc@njms.rutgers.edu

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Volume 15 • Issue 3

REVIEW

Smoking and the Skin Uwe Wollina, MD Abstract Smoking has been identified as a habit that carries great health risks. This review focuses on the consequences of smoking for skin diseases, treatment responses, and outcome. Diversification of the tobacco industry has led to new challenges, and careful documentation of risks for healthy skin is a continuing challenge. (SKINmed. 2017;15:197–202)

S

moking affects several aspects of health and increases the risks for cerebrovascular insults or cancers such as lung and breast cancer. Cigarette smoke contains thousands of chemical components, including nicotine. Cigarette smoke disrupts the mitochondrial respiratory chain and induces reactive oxygen compounds, leading to apoptosis and cell damage.

Smoking reduces life expectancy and quality of life. It can also negatively influence the normal function of healthy skin or modulate skin diseases and their response to treatment.1 SKIN AGING Aging in general has been linked to telomere-associated cellular senescence. Oxidative stress contributes to telomere shortening, and because smoking increases oxidative stress, it is therefore involved in exogenous aging of the skin.2 Tobacco smoking is an independent risk factor for facial wrinkles as a sign of aging,3 and extrinsic aging by ultraviolet irradiation is aggravated by smoking.4 Smoking is also a risk factor for eyelid sagging.5 Smoking contributes to premature hair graying in men: a longer than 5 pack-year history of smoking carries an odds ratio of 1.61. Smoking is the third most important factor after a positive family history and obesity, but is not related to severity of graying.6 Smokers develop microvascular dysfunctions in the skin. Postischemic percentage change from baseline, power spectral density in myogenic vasomotion, postischemic percentage increase of

endothelial-dependent vasomotion, and sympathetic-dependent vasomotion have all been shown to be reduced in smokers compared with never-smokers.7 SMOKING AND WOUND HEALING Smoking temporarily decreases tissue oxygenation. The inflammatory healing response becomes attenuated, fibroblast proliferation and migration are diminished, and collagen synthesis is downregulated. Cessation of smoking leads to an improved healing response within 4 weeks, but restitution remains incomplete.8 Cessation of smoking for less than 3 weeks, however, does not reduce the risk of postoperative complications.9 Smokers have an increased risk for tissue necrosis (odds ratio 3.60), delayed healing and suture dehiscence (odds ratio 2.07), surgical site infection (odds ratio 1.79), and wound complications (odds ratio 2.27).10 In reconstructive dermatosurgery, flap necrosis is another unwanted adverse effect of smoking.11 Wound healing is delayed in smokers undergoing nail matrix phenolization.12 INFLAMMATORY SKIN DISEASES

Eczema The term eczema refers to a range of inflammatory diseases including atopic dermatitis, allergic and irritant contact dermatitis, and seborrheic dermatitis. In a survey from West Sweden, its patient-reported lifetime prevalence was 40.7% and its point prevalence 11.5%, with a female predominance. Smoking increased the risk for coexistent asthma and rhinitis.13

From the Department of Dermatology and Allergology, Academic Teaching Hospital Dresden-Friedrichstadt, Dresden, Germany.

Address for Correspondence: Uwe Wollina, MD, Department of Dermatology and Allergology, Academic Teaching Hospital Dresden-Friedrichstadt, Friedrichstrasse 41, 01067 Dresden, Germany • E-mail: wollina-uw@khdf.de

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Tobacco smoking increases the risk for foot eczema with an odds ratio of 1.19.14 The Odense Adolescence Cohort Study on Atopic Diseases and Dermatitis (TOACS) calculated a 1-year prevalence of hand eczema in young adults of 14.3%; hand eczema was confirmed by clinical examination in 6.4%. In contrast to foot eczema, the authors could not find an association with smoking.15 A recent meta-analysis confirmed that tobacco smoking was not a risk factor for hand eczema. The authors concluded that they could not exclude that smoking might have an impact on the course of this disease, but that further studies were needed.16 The role of smoking habits on hand eczema has been analyzed in a study of 516 adult housewives; interestingly, smokers were mainly affected by milder disease than was seen in nonsmokers.17

Psoriasis Psoriasis is a chronic inflammatory disorder with cutaneous and extracutaneous manifestations. Oxidative stress contributes to the extent and severity of the disease. Current and past smoking increase the risk for psoriasis with an odds ratios of 1.78 and 1.62, respectively.18 In one study investigating smokers and nonsmokers with psoriasis, smokers had a higher Psoriasis Area and Severity Index score. Serum total oxidant status, total antioxidant capacity, and oxidative stress were higher in psoriasis patients than in healthy controls.

There was no statistical difference between smokers and nonsmokers. Arylesterase levels were significant lower among smokers.19 Smoking increases the incidence of psoriasis among men and women. The more cigarettes that are smoked per day, the higher the risk.

The relative risk was 2.29 for current smokers who smoked more than 25 cigarettes per day. A longer duration of smoking and higher number of pack-years also increased the risk. Cessation of smoking was associated with a decreased risk over time.20 One possible link between smoking and psoriasis could be the serotonin pathway, which affects chemotaxis, leukocyte activation, proliferation, and cytokine secretion.20 Patients with psoriasis have a higher risk of periodontal disease. Smoking increases the risk for severe periodontal disease sixfold.21 Smoking has negative impact on functional outcome in patients with psoriatic arthritis.22 Eventually, smoking may contribute to the increase cardiovascular risk reported for patients with psoriasis.23

Rosacea Rosacea is an inflammatory disease characterized by a disturbance in centrofacial blood flow regulation and the innate immune system. In a cross-sectional study, smoking was more prevalent among rosacea patients than controls. In particular, erythematotelangiectatic rosacea was associated with active smoking.24 SKINmed. 2017;15:197–202

Acne vulgaris Acne vulgaris is a disease that affects more than 80% of the general population after puberty. In a study of more than 27,000 young men aged 21 to 22 years, the prevalence of severe acne was significantly lower in active smokers than nonsmokers. There was an inverse relationship between the number of cigarettes smoked per day and the prevalence of acne.25 As a proof of concept, these authors suggested a trial with nicotine patches, but this has not yet been performed.

On the other hand, postadolescent acne among 26 women aged 25 to 50 years seems to be associated with smoking. Almost 73% of women with comedonal postadolescent acne were smokers, compared with fewer than 30% of those with papulopustular type.26 In conclusion, acne is not uniform in its response to smoking, and smoking cannot be advised as possible acne treatment.

Acne inversa (hidradenitis suppurativa) Acne inversa is a severe and debilitating chronic inflammatory disease, and smoking is the major risk factor for acne inversa.

Current smokers have an odds ratio for the disease of 4.34, which is higher than for obesity, another well-established risk factor. Past smoking carries an odds ratio of 6.34.27 Smoking is common among individuals with acne inversa. A total of 92.2% of 212 acne inversa patients in a recent Danish study were smokers. Remission of disease was reported by 40% of nonsmokers, compared with 29% of active smokers.28 These results suggest that smoking may contribute to ongoing inflammation and a reduced response to treatment.

AUTOIMMUNE CONNECTIVE TISSUE DISORDERS AND PEMPHIGUS

Lupus erythematosus Lupus erythematosus is an autoimmune disorder with manifestations in various organs, including the skin. In a retrospective analysis of 405 lupus patients, more patients with discoid lupus and lupus tumidus were smokers. The odds ratio for lupus tumidus was 4.5, and for discoid lupus was 2.05.29 Current smokers had higher disease activity, as measured by the Cutaneous Lupus Erythematosus Disease Area and Severity Index, than never-smokers and past smokers. This was also associated with a decreased quality of life. Never- and past smokers responded better to oral antimalarials.30 This has also been suggested by a recent European Society of Cutaneous Lupus Erythematosus study involving 1002 patients.31 A

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meta-analysis including 1398 patients with cutaneous lupus suggested a twofold lower percentage of patients achieving an improvement of their cutaneous lesions with oral antimalarials among smokers.32 In the Canadian SLE cohort study of 1346 patients, current smoking was associated with active systemic lupus eruptions (odds ratio 1.63), and current and/or past smoking increased the risk of discoid lesions (odds ratio 2.36), photosensitivity (odds ratio 1.47), and cutaneous involvement score (odds ratio 1.50).33 A recent meta-analysis suggested that smoking per se increases the risk of SLE with an odds ratios between 1.76 and 2.09.34 The Japanese Kyushu Sapporo SLE (KYSS) study found that current smoking increased the risk of systemic lupus erythematosus significantly (odds ratio 3.06).35

Systemic sclerosis Systemic sclerosis is the second most common classical autoimmune connective tissue disorder. Smoking has a strong negative impact on systemic sclerosis. The Canadian Scleroderma Research Group conducted a study of 606 scleroderma patients, which concluded that smoking has a cumulative and irreversible negative effect on cutaneous involvement.36 A French retrospective study on ischemic digital ulcers in scleroderma stated that active smokers had significantly more surgical amputation and osteitis than nonsmokers.37 It has been suggested that smoking has a negative and permanent impact on the outcome of scleroderma-associated interstitial lung fibrosis.38 On the other hand, smoking does not increase the risk for scleroderma, although it has a negative impact on disease course and severity.39 Current smoking increases the risk of Raynaud’s phenomenon but only in men.40 Clinical studies suggest a lower prevalence of smoking among patients with pemphigus than healthy controls. On the other hand, a study of 70 pemphigus patients suggested that smokers achieve more remissions within 2 years of treatment compared with nonsmokers.41 VASCULAR DISORDERS

Behçet’s disease Behçet’s disease is a multiorgan disorder with vasculitic features.

Behçet’s patients with the GSTM1 null glutathione-S-transferase polymorphism who were smokers had a decreased risk for developing papulopustular lesions and chronic arthritis. Conversely, risk for large-vessel vasculitis was increased among smokers.42 SKINmed. 2017;15:197–202

Thrombangiitis obliterans Thrombangiitis obliterans is a painful segmental inflammatory vascular disease affecting small- and medium-sized arteries of the hand and feet in tobacco users of younger ages. The disease progresses to claudication, skin ulcers, and gangrene.

Cessation of tobacco use is essential for any successful intervention.43 ORAL MUCOSAL LESIONS Oral mucosal lesions have been found in about 70% of tobacco users. The most prevalent lesion was melanosis (43.3%), followed by leukoedema (27.0%). Leukoplakia (3.17%) was the most commonly seen premalignant lesion.44 The prevalence is higher among tobacco chewers than tobacco smokers.45 Tobacco smokers show larger oral areas of oral melanosis compared with nonsmokers. This argues that there is increased melanin production among tobacco users. The condition is known as smoker’s melanosis.46 White oral lesions are more frequent among tobacco smokers than nonsmokers, but the difference did not reached significance in a study from Qatar. Patients who chewed or smoked paan displayed significantly more white and red lesions. A total of 8.9% of these patients presented oral precancerous lesions.47 Last but not least, smoking is a dose-dependent risk factor for the development of oral and oropharyngeal squamous cell carcinoma.48 Complex aphthosis, ie, recurrent oral and genital aphthosis without systemic disease, can be triggered by cessation of smoking in active smokers. Nicotine replacement therapy has therefore been suggested, but this has not yet been studied in trials of this disorder.49,50 SKIN CANCER

Melanoma Melanoma is a neoplastic disease of pigment-producing melanocytes and carries a significant morbidity and mortality. Cox proportional hazards regression analysis was used to evaluate the association between smoking and melanoma development. The incidence rate was lower in current smokers than in nonsmokers independent of sex. The death rate from melanoma was lower in current smokers (only for men) and past smokers (for both sexes) than nonsmokers.51 The lowered risk was most significant for head and neck melanomas.52 The cause of the reduced risk or melanoma, however, remains unclear.

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Nonmelanoma skin cancer

Betel quid chewing is a traditional habit in Asia. In the last decade, commercial products also containing tobacco have become popular in India and other countries. Betel quid carries a number of health risks, including oral submucous fibrosis and oral squamous cell carcinoma. The risk of oral cancer is further increased by tobacco.63,64

Nonmelanoma skin cancer is frequently seen in white populations. The most common skin cancer is basal cell carcinoma. A 16-year prospective study in Queensland, Australia, has investigated the possible link between smoking and basal cell carcinoma. There was a nonsignificant but inverse association between current smoking and development of basal cell carcinomas, although this was not the case for patients who had smoked for longer than 18 years and smoked more than 15 cigarettes per day. Among past smokers, the relative risk for basal cell carcinoma was not changed.53 These findings confirmed the results of a meta-analysis.54 In contrast to this, another study from the United States found a slightly increased risk for basal cell carcinoma among smokers versus nonsmokers, with a relative risk of 1.06.55 These data do not indicate a causal relationship between smoking and reduction of cancer risk.

The waterpipe (shisha or hookah) has become quite popular among young adults in developed countries. The associated toxicological hazards are not identical to those of smoking cigarettes, but waterpipe smoking is not a “healthier” alternative.65

On the other hand, smoking significantly increased the risk of cutaneous squamous cell carcinoma, with an odds ratio of 1.52 in one study,55 while another study calculated a relative risk of 1.19 for smokers versus never-smokers.54

References

The diversification of the tobacco market is also visible in the recent economic success of electronic nicotine delivery systems, including standard and nicotine-free electronic cigarettes. The aerosol, with its fine particles, additives, and solvents, bears significant health risks.66 Careful observation and documentation of health risks in dermatology is needed.67

Arsenic methylation in smokers may also contribute to the development of arsenic precancerous lesions in areas with a higher arsenic content in drinking water.56 VIRAL INFECTIONS Human papillomavirus infection has a worldwide prevalence of 9% to 13%. Smoking is associated with a higher incidence and prevalence of human papillomavirus infection, with an odds ratio of 1.5. Smoking also supports persistence of infection. The incidence and recurrence of anogenital warts are significantly increased among smokers,57 but a correlation could not be established between smoking and the size of anal warts in HIVinfected women.58 OUTLOOK AND CONCLUSIONS Smoking may exert various negative effects on skin diseases, aging, and wound healing. Smoking habits are not stable; for instance, a continuous decline in smoking prevalence has been observed in Sweden in the last 30 years. However, there has been a steady increase in the use of moist snuff called snus.59 It has been hypothesized that snus could be a treatment alternative in otherwise resistant pyoderma gangrenosum.60 A case of angioedema caused by snuff due to type I allergy to tobacco has been reported.61 In an animal study, even short-term exposure to snuff significantly increased the risk of random flap necrosis.62 SKINmed. 2017;15:197–202

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1 Nicita-Mauro V, Lo Balbo C, Mento A, et al. Smoking, aging and the centenarians. Exp Gerontol. 2008;43:95– 101.

2 Babizhayev MA, Vishnyakova KS, Yegorov YE. Oxidative damage impact on aging and age-related diseases: Drug targeting of telomere attrition and dynamic telomerase activity flirting with imidazole-containing peptides. Recent Pat Drug Deliv Formul. 2014;8:163–192.

3 Marínquez JJ, Cataldo K, Vera-Kellet C, Harz-Fresno I. Wrinkles. BMJ Clin Evid. 2014;2014:pii:1711.

4 Oldenburg M, Kuechmeister B, Ohnemus U, Baur X, Moll I. Extrinsic skin ageing symptoms in seafarers subject to high work-related exposure to UV radiation. Eur J Dermatol. 2013;23:663–670.

5 Jacobs LC, Liu F, Bleyen I, et al. Intrinsic and extrinsic risk factors for sagging eyelids. JAMA Dermatol.

2014;150:836–843.

6 Shin H, Ryu HH, Yoon J, et al. Association of premature hair graying with family history, smoking, and obesity: A cross-sectional study. J Am Acad Dermatol.

2015;72:321–327.

7 Rossi M, Pistelli F, Pesce M, et al. Impact of long-term exposure to cigarette smoking on skin microvascular function. Microvasc Res. 2014;93:46–51.

8 Sørensen LT. Wound healing and infection in surgery: The pathophysiological impact of smoking, smoking cessation, and nicotine replacement therapy: A systematic review. Ann Surg. 2012;255:1069–1079.

9 Wong J, Lam DP, Abrishami A, Chan MT, Chung F. Shortterm preoperative smoking cessation and postoperative complications: A systematic review and meta-analysis.

Can J Anaesth. 2012;59:268–279.

10 Sørensen LT. Wound healing and infection in surgery.

The clinical impact of smoking and smoking cessa-

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tion: A systematic review and meta-analysis. Arch Surg.

2012;147:373–383.

mated clinical features of postadolescent acne. J Am Acad Dermatol. 2010;63:782–788.

11 Gill JF, Yu SS, Neuhaus IM. Tobacco smoking and dermatologic surgery. J Am Acad Dermatol. 2013;68:167–172.

27 Tzellos T, Zouboulis CC, Gulliver W, et al. Cardiovascular disease risk factors in patients with hidradenitis suppurativa: A systematic review and meta-analysis of observational studies. Br J Dermatol. 2015;173:1142–1155.

12 Àlvarez-Jiménez J, Córdoba-Fernández A. Influence of smoking on wound healing in patients undergoing nail matrix phenolization: A prospective randomized clinical study. Adv Skin Wound Care. 2014;27:229–236.

13 Rönmark EP, Ekerljung L, Lötvall J, et al. Eczema among adults: prevalence, risk factors and relation to airway diseases. Results from a large-scale population survey in Sweden. Br J Dermatol. 2012;166:1301–1308.

14 Brans R, Hübner A, Gediga G, John SM. Prevalence of foot eczema and associated occupational and non-occupational factors in patients with hand eczema. Contact Dermatitis. 2015;73:100–107.

15 Mortz CG, Bindslev-Jensen C, Andersen KE. Hand eczema in The Odense Adolescence Cohort Study on Atopic Diseases and Dermatitis (TOACS): Prevalence, incidence and risk factors from adolescence to adulthood. Br J Dermatol. 2014;171:313–323.

16 Lukács J, Schliemann S, Elsner P. Association between smoking and hand dermatitis – a systematic review and meta-analysis. J Eur Acad Dermatol Venereol.

2015;29:1280–1284.

17 Patruno C, Ayala F, Zagaria O, Balato N. Is cigarette smoking dangerous for chronic hand eczema in housewives? Dermatitis. 2014;25:201–204.

18 Armstrong AW, Harskamp CT, Dhillon JS, Armstrong EJ. Psoriasis and smoking: A systematic review and metaanalysis. Br J Dermatol. 2014;170:304–314.

19 Emre S, Metin A, Demirseren DD, et al. The relationship between oxidative stress, smoking and the clinical severity of psoriasis. J Eur Acad Dermatol Venereol.

2013;27:e370–e375.

20 Li W, Han J, Choi HK, Qureshi AA. Smoking and risk of incident psoriasis among women and men in the United States: A combined analysis. Am J Epidemiol.

2012;175:402–413.

21 Antal M, Braunitzer G, Mattheos N, Gyulai R, Nagy K. Smoking as a permissive factor for peridontal disease in psoriasis. PLoS One. 2014;9:e92333.

22 Tillett W, Jadon D, Shaddick G, et al. Smoking and delay to diagnosis are associated with poorer functional outcome in psoriatic arthritis. Ann Rheum Dis. 2013;72:1358–1361.

23 Kimball AB, Leonardi C, Stahle M, et al. Demography, baseline disease characteristics and treatment history of patients with psoriasis enrolled in a multicenter, prospective, disease-based registry (PSOLAR). Br J Dermatol. 2014;171:137–147.

24 Kucukunal A, Altunay I, Arici JE, Cerman AA. Is the effect of smoking on rosacea still somewhat of a mystery?

Cutan Ocul Toxicol. 2015;35:110–114.

25 Klaz I, Kochba I, Shohat T, Zarka S, Brenner S. Severe acne vulgaris and tobacco smoking in young men. J Invest Dermatol. 2006;126:1749–1752.

26 Capitanio B, Sinagra JL, Bordignon V, et al. Underesti-

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28 Kromann CB, Deckers IE, Esmann S, et al. Risk factors, clinical course and long-term prognosis in hidradenitis suppurativa: A cross-sectional study. Br J Dermatol.

2014;171:819–824.

29 Böckle BC, Sepp NT. Smoking is highly associated with discoid lupus erythematosus and lupus erythematosus tumidus: Analysis of 405 patients. Lupus. 2015;24:669– 674.

30 Piette EW, Foering KP, Chang AY, et al. The impact of smoking in cutaneous lupus erythematosus. Arch Dermatol. 2012;148:317–322.

31 Kuhn A, Sigges J, Biazar C, et al. Influence of smoking on disease severity and antimalarial therapy in cutaneous lupus erythematosus: Analysis of 1002 patients from the EUSCLE database. Br J Dermatol. 2014;171:571– 579.

32 Chasset F, Francès C, Barete S, Amoura Z, Arnaud L. Influence of smoking on the efficacy of antimalarials in cutaneous lupus erythematosus: A meta-analysis of the literature. J Am Acad Dermatol. 2015;72:634–639.

33 Bourré-Tessier J, Peschken CA, Bernsatsky S, et al. Association of smoking with cutaneous manifestations in systemic lupus erythematosus. Arthritis Care Res (Hoboken). 2013;65:1275–1280.

34 Costenbader KH, Kim DJ, Peerzada J, et al. Cigarette smoking and the risk of systemic lupus erythematosus: A meta-analysis. Arthritis Rheum. 2004;50:849–857.

35 Kiyohara C, Washio M, Horiuchi T, et al, Kyushu Sapporo SLE (KYSS) Study Group. Cigarette smoking, alcohol consumption, and risk of systemic lupus erythematosus: A case-control study in a Japanese population. J Rheumatol. 2012;39:1363–1370.

36 Gyger G, Hudson M, Lo E, et al. Does cigarette smoking mitigate the severity of skin disease in systemic sclerosis? Rheumatol Int. 2013;33:943–948.

37 Agard C, Carpentier PH, Mouthon L, et al. Use of bosentan for digital ulcers related to systemic sclerosis: A real-life retrospective French study of 89 patients treated since specific approval. Scand J Rheumatol.

2014;43:398–405.

38 Samara KD, Margaritopoulos G, Wells AU, Siafakas NM, Antoniou KM. Smoking and pulmonary fibrosis: Novel insights. Pulmonary Med. 2011;2011:461439.

39 Dospinescu P, Jones GT, Basu N. Environmental factors in systemic sclerosis. Curr Opin Rheumatol. 2013;25:179– 183.

40 Suter LG, Murabito JM, Felson DT, Fraenkel L. Smoking, alcohol consumption, and Raynaud’s phenomenon in middle age. Am J Med. 2007;120:264–271.

41 Valikhani M, Kavusi S, Chams-Davbatchi C, et al. Impact of smoking on pemphigus. Int J Dermatol. 2008;47:567– 570.

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42 Özer HT, Günesaçar R, Dinkçi S, et al. The impact of smoking on clinical features of Behçet’s disease patients with glutathione-S-transferase polymorphism. Clin Exp Rheumatol. 2012;30(suppl 72):S14–S17.

43 Dargon PT, Landry GJ. Buerger’s disease. Ann Vasc Surg.

2012;26:871–880.

44 Chandra P, Govindraju P. Prevalence of oral mucosal lesions among tobacco users. Oral Health Prev Dent.

2012;10:149–153.

45 Aljabab MA, Aljbab AA, Patil SR. Evaluation of oral changes among tobacco users of Aljouf Province, Saudi Arabia. J Clin Diagn Res. 2015;9:ZC58–ZC61.

46 Sujatha D, Hebbar PB, Pai A. Prevalence and correlation of oral lesions among tobacco smokers, tobacco chewers, areca nut and alcohol users. Asian Pac J Cancer Prev.

2012;13:1633–1637.

the risk of nonmelanoma skin cancer: Systematic review and meta-analysis. Arch Dermatol. 2012;148:939– 946.

56 Lindberg AL, Sohel N, Rahman M, Persson LA, Vahter M. Impact of smoking and chewing tobacco on arsenic-induced skin lesions. Environ Health Perspect.

2010;118:533–538.

57 Kaderli R, Schnüriger B, Brügger LE. The impact of smoking on HPV infection and the development of anogenital warts. Int J Colorectal Dis. 2014;29:899– 908.

58 Luu HN, Amirian ES, Beasley RP, et al. Association between smoking and size of anal warts in HIV-infected women. Int J STD AIDS. 2012;23:792–798.

47 Hedin CA, Axéll T. Oral melanin pigmentation in 467 Thai and Malaysian people with special emphasis on smoker’s melanosis. J Oral Pathol Med. 1991;20:8–12.

59 Norberg M, Lundqvist G, Nilsson M, Gilljam H, Weinehall L. Changing patterns of tobacco use in a middle-aged population: The role of snus, gender, age, and education. Global Health Action. 2011;4: doi:10.3402/gha. v4i0.5613.

48 Tüzün B, Wolf R, Tüzün Y, Serdaroglu S. Recurrent aphthous stomatitis and smoking. Int J Dermatol.

2000;39:358–360.

60 Kluger N. Can snus (Swedish moist snuff) be used as a treatment of pyoderma gangrenosum? Med Hypotheses.

2012;78:619–620.

49 Hill SC, Stavrakoglou A, Coutts IR. Nicotine replacement therapy as a treatment for complex aphthosis. J Dermatol Treat. 201;21:317–318.

61 Plaza T, Nist G, Stetter C, von den Driesch P. Angioedema due to type I allergy to snuff tobacco. J Dtsch Dermatol Ges. 2007;5:300–302.

50 Kavarodi AM, Thomas M, Kannampilly J. Prevalence of oral pre-malignant lesions and its risk factors in an Indian subcontinent low income migrant group in Qatar.

Asian Pac J Cancer Prev. 2014;15:4325–4329.

62 Eroglu L, Orak I, Turhan Haktanir N. Effect of short-term use of oral smokeless tobacco on random-pattern skin flap survival in rats. Scand J Plast Reconstr Surg Hand Surg. 2005;39:272–276.

51 Rosenquist K. Risk factors in oral and oropharyngeal squamous cell carcinoma: A population-based casecontrol study in southern Sweden. Swed Dent J Suppl.

2005;(179):1–66.

63 Wollina U, Verma S, Parikh A, Parikh D. Oral disease caused by the chewing of betel nut and concoctions containing betel nut. J Eur Acad Dermatol Venereol.

2004;18:233–235.

52 DeLancey JO, Hannan LM, Gapstur SM, Thun MJ. Cigarette smoking and the risk of incident and fatal melanoma in a large prospective cohort study. Cancer Causes Control. 2011;22:937–942.

64 Wollina U, Verma SB, Ali FM, Patil K. Oral submucous fibrosis: An update. Clin Cosmet Investig Dermatol.

2015;8:193–204.

53 Hughes MC, Olsen CM, Williams GM, Green AC. A prospective study of cigarette smoking and basal cell carcinoma. Arch Dermatol. 2014;306:851–856.

54 Song F, Qureshi AA, Gao X, Li T, Han J. Smoking and risk of skin cancer: A prospective analysis and a metaanalysis. Int J Epidemiol. 2012;41:1694–1705.

55 Leonardi-Bee J, Ellison T, Bath-Hextall F. Smoking and

65 Wollina U. Water pipe smoking and dermatologic consequences. J Eur Acad Dermatol Venereol. 2015;29:1481– 1484.

66 Neuberger M. The electronic cigarette: A wolf in sheep’s clothing. Wiener Med Wochenschr.

2015;127:385–387.

67 Wolf R: Cigarette smoking and the skin. Clin Dermatol 1998;16:535–648.

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SELF ASSESSMENT EXAMINATION

SELF ASSESSMENT EXAMINATION W. Clark Lambert, MD, PhD Instructions: For each numbered question, answer the best single lettered response, unless instructed otherwise for that question.

c. Three weeks. d. Four weeks. e. None of the above is correct.

1. Smokers, compared to never-smokers, are at an increased risk for development of: a. Extrinsic ageing caused by ultraviolet light exposure. b. Eyelid sagging. c. Facial wrinkling. d. Microvascular dysfunction in the skin. e. All of the above. f. None of the above.

4. Studies have shown that smokers, compared to never-smokers, are at increased risk to develop: a. Basal cell carcinoma(s). b. Malignant melanoma(s). c. Squamous cell carcinoma(s). d. All of the above. e. None of the above.

2. Risk of which of the following adverse outcomes of dermatologic surgery is/are increased in smokers versus never-smokers? (Answer as many as apply.

Some, one, none, or all of the lettered responses may be correct.): a. Delayed healing. b. Flap necrosis. c. Surgical site infection. d. Suture dehiscence. b Tissue necrosis. f. Wound complications.

ANSWERS TO EXAMINATION: 1. e; 2. a, b, c, d, e, f; 3. e; 4. c; 5. b, d, e.

3. Complete restitution of the adverse effects of cigarette smoking on wound healing requires cessation of smoking for at least: a. One week. b. Two weeks.

5. Studies have shown that smokers, compared to never-smokers, are at increased risk to develop: (Answer as many as apply. Some, one, none, or all of the lettered responses may be correct.): a. Acne (i.e., teenage acne). b. Acne inversa (i.e., hidradenitis suppurativa). c. Hand eczema (i.e., pompholyx). d. Psoriasis. e. Rosacea.

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From the Departments of Pathology and Dermatology, Rutgers University – New Jersey Medical School, Newark, NJ Address for Correspondence: W. Clark Lambert, MD, PhD, Room H576 Medical Science Building, Rutgers University – New Jersey Medical School, 185 South Orange Avenue, Newark, NJ 07103 • E-mail: lamberwc@njms.rutgers.edu

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MEDIA PARTNER

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Volume 15 • Issue 3

Perils of Dermatopathology W. Clark Lambert, MD, PhD, Section Editor

Fine and Benign, Until It Becomes Malignant: The Enigmatic Keratoacanthoma Ann M. John, BA; Heather Holahan, MD; Parmvir Singh, BS; Hee J. Kim, BS; Marc Z. Handler, MD; W. Clark Lambert, MD, PhD “When she was good she was very, very good, And when she was bad she was horrid.”—Henry Wadsworth Longfellow (1807–1822)

K

eratoacanthoma (KA) is a tumor that characteristically arises as a single nodule, grows rapidly, and regresses quickly.1 It presents as a crater-shaped exophytic nodule with a central keratin plug. Rapid growth occurs within 6 to 8 weeks, followed by a stable stage lasting a few months. Rapid regression occurs in 4 to 6 weeks.1 During the initial rapid growth phase, the histology is similar to a well-differentiated squamous cell carcinoma (SCC). During the mature stage, histologic analysis shows well-differentiated squamous epithelium, encompassing the lesion with a keratin-filled core. Papillomatosis, acanthosis, eosinophilic keratinocytes, and the presence of horn pearls also mark the condition. An inflammatory infiltrate of lymphocytes and histiocytes is present. During the regression stage, the keratinocytes shrink, and granulation tissue and fibrosis are present. This stage is marked by an inflammatory infiltrate of Langerhans’ cells and CD4-positive T lymphocytes.2

excision. Excision is a risk factor for recurrence due to trauma to the skin; to avoid this, healing by secondary intention is recommended. Chemotherapy, radiotherapy, phototherapy, and observation have also been used. In addition, laser, electrosurgery, and cryosurgery can be used. With multiple or larger lesions, oral retinoids or systemic chemotherapy may be employed. One study also suggested supplementary use of topical 5-fluorouracil cream for more desirable cosmetic results.3 Regardless of the treatment, the rate of recurrence is 3% to 5%.4

KA has been associated with several cutaneous conditions, including Ferguson-Smith disease, Muir-Torre syndrome, xeroderma pigmentosum, hypertrophic lichen planus, nevus sebaceous, and prurigo nodularis. In addition, KA is difficult to distinguish from SCC. The keratin core is specific for KA; however, central necrosis of SCC can lead to a similar appearance. Histologically, KA has a central keratin plug composed of large cells with pale eosinophilic cytoplasm. Since it was first reported, the relationship between KA and SCC has been heavily debated, primarily due to the similar histology. The potential for misdiagnosis of SCC as KA warrants treatment.2

CASE REPORT A 67-year-old Caucasian woman developed a crateriform keratotic lesion on her right cervical region (neck; Figure). Histologically, the lesion was diagnosed as a KA, with the deep margin not quite clear. No further treatment was undertaken, because the clinician considered the entity benign; however, it recurred as an invasive SCC requiring four separate surgical procedures over the next 6 months to insure clear margins. There has been no metastasis 1 year after initial presentation.

Treatment of KA depends on the appearance, location, and size of the lesion. First-line therapy is usually an elliptical or full-shave

The rapid growth of KAs may lead to local destruction. In particular, there are three forms that are locally destructive—muti-

Although KA is almost always benign, there have been a few reports of malignant transformation or behavior with metastases and/or invasion. This leads to the question of what distinguishes a malignant KA requiring aggressive therapy from a benign KA. Here, we present a case of a benign-appearing KA that exhibited malignant behavior.

DISCUSSION

From the Departments of Dermatopathology, Dermatology, and Pathology and Laboratory Medicine, Rutgers – New Jersey Medical School, Newark, NJ Address for Correspondence: W. Clark Lambert, MD, PhD, H576 Medical Science Building, Rutgers-New Jersey Medical School, 185 South Orange Avenue, Newark, NJ 07103 • E-mail: lamberwc@njms.rutgers.edu

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PERILS OF DERMATOPATHOLOGY within a KA, likely due to the similar risk factor of ultraviolet irradiation for both cancers. Second, SCC can be easily confused with KA, specifically the infundibular and infudibulocystic variants. Finally, carcinoma metastasizing to the skin can present as a KA-like lesion. As such, we join many of our colleagues in recommending that all KAs be reported from the dermatopathology laboratory as “KA-like squamous cell carcinoma” and be treated with surgical excision.

References 1 Schwartz RA. Keratoacanthoma: A clinico-pathologic enigma. Dermatol Surg. 2004;30:326–333.

2 Davis BA, Monheit GD, Kline L. Metastatic skin cancer presenting as ptosis and diplopia. Dermatol Surg.

2006;32:148–158.

Figure. Benign-appearing keratoacanthoma that exhibited malignant behavior (hematoxylin and eosin stain, original magnification ×320).

3 Thompson BJ, Ravits M, Silvers DN. Clinical efficacy of short contact topical 5-fluorouracil in the treatment of keratoacanthomas: A retrospective analysis. J Clin Aesth Dermat. 2014;7:35–37.

lating KA, aggregated KA, and KA centrifugum marginatum.

While rare, these variants cause local infiltration, and may have persistent invasive growth with absent regression leading to severe defects. For instance, there have been previous reports of local invasion into the periosteum and muscle, requiring amputation of a limb; destructive infiltration of the left buccal region (cheek), nasal cartilage, cribiform plate, and conjunctiva; and growth on the right nasal wall, extending through the ala and nasal vestibule.5–7 In addition to local invasion, there have been reports of perineural invasion, presenting with lesion extension into facial muscles, cranial nerves, and cavernous sinus, metastasis to the parathyroid gland and lymph nodes, and recurrence of lesions.8 Perivascular invasion and metastasis have also been reported.9 Because the benign nature of KA is questionable, each KA must be thoroughly examined and investigated. First, SCC can arise

4 Nofal A, Assaf M, Nofal E, et al. Generalized eruptive keratoacanthoma: Proposed diagnostic criteria and therapeutic evaluation. J Europ Acad Dermatol Venereol.

2014;28:397–404.

5 Bogner PN, Cheney RT, Zeitouni NC. Giant keratoacanthoma: Case report and review of the English literature.

Am J Dermatopath. 2014;36:252–257.

6 Browne F, O’Connell M, Merchant W, et al. Spontaneous resolution of a giant keratoacanthoma penetrating through the nose. Clin Exp Dermatol. 2011;36:369–371.

7 Grevelhorster T, Micke O, Hampel G, et al. [High-dose multimodal radiotherapy of confluent destructively growing aggregated keratoacanthoma. 2 case reports].

Strahlenther Onkolo. 1996;172:395–400.

8 Zargaran M, Baghaei F. A clinical, histopathological and immunohistochemical approach to the bewildering diagnosis of keratoacanthoma. J Dent (Shiraz). 2014;15:91– 97.

9 Tschandl P, Rosendahl C, Williamson R, et al. A keratoacanthoma with venous invasion. Dermatol Pract Concept.

2012;2:204.

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Volume 15 • Issue 3

The Heymann File Warren R. Heymann, MD, Section Editor

Infundibulocystic Basal Cell Carcinomas and the SUFU Snafu Warren R. Heymann, MD

T

he revolution of molecular biology is enabling us to fit disparate pieces of a jigsaw puzzle into a coherent picture. This commentary will detail how overlapping features of multiple hereditary infudibulocystic basal cell carcinomas (BCCs), Gorlin syndrome (nevoid BCC), familial multiple meningiomas, and medulloblastomas are linked together

by SUFU mutations in the sonic hedgehog pathway.

CLINICAL CONUNDRUMS OF INFUNDIBULOCYSTIC BCC Controversy has always surrounded the diagnosis of the infundibulocystic BCC (IBCC), notably whether it is a true malignancy, or whether it is identical to the benign basaloid follicular hamartoma. A study comparing 36 cases of basaloid follicular hamartoma to 22 cases of IBCC, using routine microscopy and staining for CK20, found that most cases were indistinguishable, supporting the argument that these lesions are identical, and likely benign.1

The original contribution on multiple hereditary infudibulocystic BCCs detailed members of two families with multiple IBCCs. Each patient had multiple facial papular lesions, with none displaying jaw cysts or palmar pits, thereby distinguishing this syndrome from nevoid BCC.2 A subsequent report was of a 67-year-old man who started developing BCCs at age 50. Numerous shallow pits were present on his palms and fingers. No ondontogenic keratocysts were appreciated. Biopsies of several of the facial papules revealed BCCs with follicular differentiation, while others demonstrated infiltrative BCCs. A palmar pit biopsy showed basaloid proliferation but no BCC. There was no family history of similar lesions. Genetic mutational analysis for PTCH was negative. The authors speculated that patients

with generalized basaloid follicular hamartoma, nevoid BCC, multiple hereditary infudibulocystic BCC, and multiple trichoepitheliomas all represented abnormalities of the same signaling pathway.3 Future studies would prove them correct.

CASE HISTORIES A 55-year-old woman with facial papules (diagnosed as benign folliculosebaceous hamartomas) and dysmorphic facies (macrocephaly, hypertelorism, prognathism) had two children (each with a different father) succumb to medulloblastomas in infancy.

The patient stated that her father and a grown son shared her dermatologic features. Sequencing studies of the patient revealed a splice-site mutation of intron 6 of SUFU.4 A woman in her 60s started to develop approximately 60 facial and vulvar lesions that first appeared around 50 years of age. No palmar pits or jaw cysts were appreciated. Her medical history was remarkable for a meningioma. Biopsies of the facial lesions were consistent with IBCC. Her daughter had similar facial lesions. The patient was given a trial of vismodegib, but did not respond to therapy after 9 months of treatment; the drug was discontinued. Whole-exome sequencing demonstrated a conserved splice-site mutation in one copy of the SUFU gene in all tumor and normal tissue samples.5 Medulloblastomas are seen in 5% of patients with nevoid BCC.4 Sporadic and familial medulloblastomas and meningiomas have been associated with SUFU mutations.6,7 THE SONIC HEDGEHOG PATHWAY AND SUFU BCCs are primarily driven by the sonic hedgehog pathway. In a study of 293 BCCs, 85% of BCCs harbored mutations in sonic

From the Division of Dermatology, Departments of Medicine and Pediatrics, Cooper Medical School of Rowan University, Marlton, NJ Address for Correspondence: Warren R. Heymann, MD, Division of Dermatology, Departments of Medicine and Pediatrics, Cooper Medical School of Rowan University, 100 Brick Road, Suite 306, Marlton, NJ 08053 • E-mail: wrheymann@gmail.com

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hedgehog pathway genes: PTCH1 (73%), TP53 (61%), SMO (20%), and SUFU (8%). Additionally, 85% of the BCCs harbored additional driver mutations in other cancer-related genes such as MYCN, KRAS, and HRAS.8 The SUFU (suppressor of fused homolog) protein acts as a tumor suppressor by binding to and modulating the function of the transcription factor Gli. SUFU has a downstream position in the sonic hedgehog pathway.

be able to target SUFU mutations precisely, thereby obviating the snafus that have a potentially devastating impact.

References

Presumably, SUFU mutations are less disruptive to the pathway than are upstream mutations in PTCH1 or SMO.5 This could explain why IBCCs tend to be more indolent and unresponsive to vismodegib, and may even be considered benign by some authorities.

CONCLUSIONS When confronted with a patient with multiple facial papules, consider performing a biopsy—should the diagnosis be IBCC, basaloid follicular hamartoma, or multiple trichoepitheliomas, inquire about a personal or family history of similar cutaneous lesions and central nervous system tumors (meningiomas, medulloblastomas). The family history may be negative, as this situation may occur with a sporadic mutation in the context of an otherwise autosomal dominant disorder. With cutting-edge molecular studies, we can now appreciate how these syndromes overlap, resulting in variable phenotypic expressions of the sonic hedgehog pathway. Recognition of these clinical-molecular correlates will allow identification of patients at risk for life-threatening complications of SUFU mutations. Future discoveries will

1 Honarpisheh H, Glusac EJ, Ko CJ. Cytokeratin expression in basaloid follicular hamartoma and infundibulocystic basal cell carcinoma. J Cutan Pathol. 2014;41:916–921.

2 Requena L, del Carmen Fariña M, Robledo M, et al. Multiple hereditary infundibulocystic basal cell carcinomas: A genodermatosis different from nevoid basal cell carcinoma syndrome. Arch Dermatol. 1999;135:1227–1235.

3 Crawford KM, Kobayashi T. Nevoid basal cell carcinoma syndrome or multiple hereditary infundibulocystic basal cell carcinoma syndrome? J Am Acad Dermatol.

2004;51:989–995.

4 Mann K, Magee J, Guillarud-Bataille M, et al. Multiple skin hamartomata: A possible novel clinical presentation of SUFU neoplasia syndrome. Fam Cancer.

2015;14:151–155.

5 Schulman JM, Oh DH, Sanborn JZ, Pincus L, et al. Multiple hereditary infundibulocystic basal cell carcinoma syndrome associated with a germline SUFU mutation.

JAMA Dermatol. 2016;152:323–327.

6 Brugières L, Remenieras A, Pierron G, et al. High frequency of germline SUFU mutations in children with desmoplastic/nodular medulloblastoma younger than 3 years of age. J Clin Oncol. 2012;30:2087–2093.

7 Aavikko M, Li S_P, Saarinen S, et al. Loss of SUFU function in familial multiple meningioma. Am J Hum Genet.

2102;91:520–526.

8 Bonilla X, Parmentier L, King B, et al. Genomic analysis identifies new drivers and progression in skin basal cell carcinoma. Nat Genet. 2016;48:398–406.

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HISTORY OF DERMATOLOGY SOCIETY NEWSLETTER Eve J. Lowenstein, MD, PhD, Section Editor

Picturing in Dermatology—From Wax Models to Teledermatology, Part I Eve J. Lowenstein, MD, PhD Izena duen guzia omen da. (That which has a name exists.)—Basque proverb

M

auricio Goihman-Yahr (Caracas, Venezuela) spoke on Dermatology and vision: A homo sapiens approach. Graphics and sculpture have been used since prehistoric times, with their messages sometimes unclear and perspective-dependent. Interestingly, dermatology was one of the first subspecialties to individuate, perhaps due to its unique reliance on vision to transmit knowledge of diagnosis through media such as atlases.

Eve J. Lowenstein (Brooklyn, NY) discussed The largest mass poisoning in history: Arsenic in well water in Bangladesh. Arsenic in drinking water worldwide constitutes the largest cause of mass poisoning in history, dwarfing Chernobyl. Before the 1970s, Bangladesh had one of the highest infant mortality rates in the world, secondary to cholera and diarrheal diseases from contaminated hand-dug wells and ponds. While millions of tube wells were sunk in the 1970s to 90s to create “safe” water and save lives, the unintended consequence of this “colossally successful safe-water program” was the exposure of millions to arsenic in drinking water, in turn posing the highest cancer risk ever found via environmental exposure. With profound effects on health and culture, the full extent of the damage in Bangladesh remains to be determined.

W. Clark Lambert (Newark, NJ) presented Why most of what you were taught in medical school about cancer etiology is wrong.

He described how the current cancer dogma is incorrect. Carcinogenesis is not the consequence of sequential mutations but rather simultaneous events. While the Pasteur effect describes the cessation of fermentation in the presence of oxygen, this effect is ignored by the Warburg effect—cancer cells’ tendency to ferment despite the presence of oxygen.

THE TOOLS Robert Thomsen (Los Alamos, NM) spoke next about The melancholy instance of leprosy in England: A dermatologic engraving as evidence in a legal proceeding in 1824. Three atlases published in 19th century show beautiful images of leprosy presentations, but some of the pictures had other uses. The images were used in defense of a man against whom a legal suit had been brought for breach of marital promise.

Daniel Wallach (Paris, France) discussed Moulanges in Paris. He gave a brief history of the 19th-century era of l’Hôpital SaintLouis and its world-famous school of dermatology. In recognition of the hospital’s excellence in dermatology, a museum library was built in 1889 for the First Congress of Dermatology. It has more than 4000 downloadable images that can be accessed for free virtually under the history of health images and portraits section at http://www.biusante.parisdescartes.fr.

Robert Pariser (Norfolk, VA) presented Practical imaging in dermatology: Kodachrome, Ektachrome, and Fujichrome. He brought his own projector to show the slides, as in past days. He described the fascinating history of the rise and fall of Kodachrome, which had been patented in the 1920s, and how it gained popularity due to user-friendliness even for the amateur, affordability, and faithfulness to the image, as well as a long shelf life. Its use peaked in the 1960s and 70s, being replaced by the competing Ektachrome in the 1980s, Fujichrome in the 1990s, and finally digital photography in the 21st century.

Michel Lavery (Dublin, Ireland) spoke about Teledermatology: The practice of providing skin care remotely using technology. Store and forward, real-time and hybrid forms available with different

The 2017 meeting of the History of Dermatology Society was held on March 2 in Orlando, FL. The main topic was to look into the ways skin disease can be presented.

From the Department of Dermatology, SUNY Health Science Center at Brooklyn, Brooklyn, NY Address for Correspondence: Eve J. Lowenstein, MD, PhD, Department of Dermatology, SUNY Health Science Center at Brooklyn, Box 46, 450 Clarkson Avenue, Brooklyn, NY 11203 • E-mail: evlow13@yahoo.com

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practice models were reviewed. The history of technology-based remote medical care began with late 19th-century use of Morse code and evolved with the interactive televized transmission of information. Since the early 1990s and with the advent of universal mobile phone use, teledermatology has blossomed. The increased wait time to access a dermatologist promotes the need for further establishment of this as an integral format for skin care, especially in rural areas.

A FAMOUS ILLUSTRATOR AND SCULPTor Branka Marinovic (Zagreb, Croatia) recalled the famous illustrator Carl Heitzman (1836–1896). Born in what is today Croatia, he studied dermatology, surgery, and pathology, becoming famous as an illustrator and physician. His illustrations are not only artistic, but also show an excellent understanding of dermatology. He emigrated to New York and developed a large practice there.

Natalie Curcio (Nashville, TN) presented Enrique Zofio Davila (1835–1915), a master sculptor of the Olavide Museum in Madrid. He began as an anatomic sculptor, later focusing on dermatologic sculpture. Although he likely made thousands of sculptures, many were lost in fires and through time, with about 650 sculptures extant and on display today. His techniques remain undisclosed, even a century after his death. Zofio made all the sculptures in the Olavide, a museum established in honor of the father of Spanish dermatology, Jose Eugenio Olavide (1836– 1901), that remains open to the public today.

ATLASES Robert Norman (Tampa, FL) talked about the atlas Delineations of Cutaneous Disease by Thomas Bateman. Robert Willan (1757– 1812), the London physician, is recognized as the founder of our specialty. He was the first to propose a rational naming standard, based on the appearance of a skin disorder. In the treatise On Cutaneous Diseases, Willan was the first to classify skin diseases from an anatomic point of view. When Willan died in 1812, leaving his student Thomas Bateman to continue and expand on his work.

In 1813, Bateman published A Practical Synopsis of Cutaneous Diseases According to the Arrangement of Dr Willan, and in 1817 he published an atlas called the Delineations of Cutaneous Disease.

Willan, together with Bateman, provided the world with its first attempt at taxonomic classification of diseases affecting the skin.

Mark Valentine discussed Louis Duhring’s (1845–1913) Atlas of Skin Diseases. Born into an affluent family in Philadelphia,

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Duhring received his medical degree at the University of Pennsylvania and then trained for 2 years in Vienna, Paris, and London with some of the world’s pre-eminent dermatologists. His most important contribution to dermatology was the identification in 1884 of dermatitis herpetiformis (Duhring’s disease). His well-received atlas was published in 1876. It had 36 color plates and was the first of its kind in the United States. This self-funded project was pricey (the cost of the completed atlas was steep, at $25.00—about $600 at today’s value). This atlas focused on skin disease, commonly seen by the general practitioner.

Mark Bernhardt (Fort Lauderdale, FL) presented Photographic illustrations of skin diseases by George Henry Fox (1846–1937).

Fox is quoted as having said, “The study of skin diseases without cases or colored plates is like the study of osteology without bones, or the study of geography without maps.” His atlas images were of such quality as to become the gold standard of the time.

Gerd Plewig (Munich, Germany) presented Atlas der Hautkrankheiten by Keizo Dohi (Ishiwata). Dohi (1866–1931), was a monumental Japanese dermatologist. He was first trained in surgery, later turning to dermatology, with several educational trips to famous European departments. His atlas, printed in 1903–1910 in installments, was 120 pages long with 50 chromolithographic plates, and was printed fully in 1910. Few copies of this extraordinary atlas can be found today.

The final presentation, delivered by Shoko Mori, highlighted the Atlas of Disease of the Skin, including an epitome of pathology and treatment by Franz Mracek (1848–1908), the American edition of which was edited by Henry W. Stelwagon (1853–1919). Mracek and Stelwagon’s atlas gives us insight into the common dermatologic diseases seen during the 19th and early part of the 20th centuries. These colored depictions closely resemble the clinical picture, perhaps even better than early photographs. The illustrations/engravings were very true to life and form a well-executed, convenient, and wellpriced reference, making them accessible to the physician in general practice.

CONCLUSIONS While these presentations varied in scope, they provided a way of unification of our sense of the importance of history when viewing the skin.

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Volume 15 • Issue 3

CASE STUDY Vesna Petronic-Rosic, MD, MSc, Section Editor

Childhood-Onset Keratosis Lichenoides Chronica Accompanied by Severe Hair Loss Sibel Dogan, MD;1 Efsun Kılınç, MD;1 Gül Erkin Özaygen, MD;1 Nilgün Atakan, MD;1 Özay Gököz, MD;2 Sibel Ersoy Evans, MD1

A 37-year-old woman attended the dermatology outpatient clinic because of recent hair loss from the eyebrows and axillae. Her past medical history revealed mild generalized erythema and hyperpigmented papules and plaques since childhood. On dermatologic examination, there were flat-topped, purple to brown hyperkeratotic lichenoid papules and linear plaques on the elbows, trunk, and buttocks, some of which coalesced into hyperpigmented reticular plaques on the axillae, neck, and groin. Mild erythema was noted. There was thinning and loss of hair of the eyebrows; severe loss of hair was noted in the axillae and genital regions (Figure 1). One of the lichenoid papules was biopsied. The specimen showed histopathologic findings of focal parakeratosis, irregular acanthosis, an increased granular layer, and focal vacuolar degeneration of the basal layer. Necrotic keratinocytes were also observed. Hyalinization and abundant melanin in the papillary dermis and marked congestion of blood vessels were noted (Figure 2). Clinicopathologic correlation of the case was consistent with keratosis lichenoides chronica (KLC). (SKINmed. 2017;15:211–213)

K

LC (Nekam disease), also called lichen ruber moniliformis and lichen ruber acuminatus, was first described

by Moritz Kaposi (1837–1902) in 1895 in a patient with linear, warty lesions.1 Louis Nekam (1868–1957) described the disease as a separate entity in 1938.2 The term keratosis lichenoides chronica was used for the disease by Margolis et al. in 1972.3

In a detailed review by Boer, a remarkable number of KLC patients reported in the literature were in fact patients with lichen simplex chronicus, lichen planus, or lupus erythematosus; however, a few patients, who were diagnosed as KLC, showed similar clinical characteristics, including widespread lesions, which appear as scaly and seborheic dermatitis–like on the face, with keratotic papules and plaques forming linear or net-like shapes on the extremities and trunk.4 The oral lesions appear as aphthae, erythematous papules on the mucosa, and white patches on the tongue.4,5 Our patient had typical lichenoid papules on the extremities and net-like hyperpigmented plaques on the neck and axillae, accompanied by hair loss of the eyebrows, axillae, and genital regions; however, the oral mucosa was not involved.

Histopathologic findings may show a patchy lichenoid infiltrate along the basal layer and around the infundibula and acrosyringia, leading to permanent hair loss, as in our case.6 The differential diagnoses include other lichenoid dermatides such as lichen planus, lichenoid drug eruptions, lichen striatus, lichenoid keratosis, pityriasis lichenoides, and lichenoid graftvs-host disease. Although KLC is mainly a lichenoid eruption, the presence of parakeratosis, alternating atrophy and acanthosis, numerous plasma cells, and dermal telengiectasies are clues for diffentiating this entity from other lichenoid dermatoses.

Additionally, there may be focal atrophy of the epidermis, necrotic keratinocytes, uneven acanthosis, and keratotic plugs in the infundibula. Histologic features can be very similar to those of lichen planus, although in KLC the epidermis may show areas of acanthosis as well as atrophy; these may be covered by focal parakeratosis with hypogranulosis under the parakeratotic areas.

Follicular plugging often accompanies the lichenoid reaction.

Additionally, telengiectasia and proiminent blood vessel congestion can be observed, as in our case.7

From the Department of Dermatology and Venereology1 and Department of Pathology,2 Hacettepe University, Sıhhıye Ankara, Turkey Address for Correspondence: Sibel Dogan, Department of Dermatology and Venereology, Hacettepe University Faculty of Medicine, Sıhhıye Ankara, 06100 Turkey • E-mail: sibel.dogan@hacettepe.edu.tr

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Figure 1. Flat-topped, purple-brown hyperkeratotic papules on the elbows, extensor aspects of the lower extremities and feet, with erythematous and hyperpigmented reticular plaques on the axilla and neck. Additional thinning and loss of hair of the eyebrows and axillary region.

Figure 2. Focal parakeratosis, irregular acanthosis, increased granular layer, and focal vacuolar degeneration of the basal layer. Necrotic keratinocytes, abundant melanin and marked congestion of blood vessels are also seen. Red arrow, melanin in the papillary dermis; black arrow, necrotic keratinocytes; circle, parakeratosis; stars, congested dilated blood vessels (hematoxylin and eosin stain, original magnification from left to right ×40, ×100, ×100).

KLC may be divided into two subgroups according to disease onset. Childhood-onset KLC may be familial with possible autosomal recessive inheritance. Facial involvement along with alopecia of the eyebrows and eyelashes are more common findings in childhood-onset KLC.7 KLC facial lesions are mainly erythematous and purpuric in children, SKINmed. 2017;15:211–213

whereas in adult-onset KLC, seborrheic dermatitis–like or psoriasiform features are more prominent. 8,9 Adult-onset KLC may be rarely associated with glomerulonephritis, chronic lymphocytic leukemia, B-cell lymphoma, hypothyroidism, chronic hepatitis, and sarcoidal granulomatous inflammation.6,10

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Conclusions The clinical course of KLC is chronic and progressive, with available treatment being only symptomatic. This involves the use of topical and/or systemic corticosteroids, methotrexate, cyclosporine, retinoids, and ultraviolet B phototherapy, each with limited efficacy.6–11 References 1 Kaposi M. Lichen ruber acuminatus and lichen ruber planus. Arch Dermatol Syphilol. 1895;31:1–32.

2 Nekam L. Sur la question du lichen moniliforme. Presse Med. 1938;51:1000–1003.

3 Margolis MH, Cooper GA, Johnson SA. Keratosis lichenoides chronica. Arch Dermatol. 1972;105:739–743.

4 Böer A. Keratosis lichenoides chronica: Proposal of a concept. Am J Dermatopathol. 2006;28:260–275.

5 Torrelo A, Mediero IG, Zambrano A. Keratosis lichenoides chronica in a child. Pediatr Dermatol. 1994;11:46–48.

6 Mobini N, Toussaint S, Kamino H. Keratosis lichenoides chronica. In: Elder ED, ed. Lever’s Histopathology of the Skin. Philadelphia: Lipincott Williams & Wilkins; 2009:191–192.

7 David M, Filhaber A, Rotem A, Katzenelson-Weissman V, Sandbank M. Keratosis lichenoides chronica with prominent telangiectasia: Response to etretinate. J Am Acad Dermatol. 1989;21:1112–1114.

8 Ruiz-Maldonado R, Duran-McKinster C, Orozco-Covarrubias L, Saez-de-Ocariz M, Palacios-Lopez C. Keratosis lichenoides chronica in pediatric patients: A different disease? J Am Acad Dermatol. 2007;56:1–5.

9 Singh BE, Thomas M, George R. Pediatric onset keratosis lichenoides chronica: A case report. Pediatr Dermatol.

2012;29:511–512.

10 Mansur AT, Aydingöz IE, Kocaayan N, et al. Case of keratosis lichenoides chronica with atypical sarcoidal granulomatous inflammation. J Dermatol. 2007; 34:41–47.

11 Adisen E, Erdem O, Celepçi S, Gürer MA. Easy to diagnose, difficult to treat: Keratosis lichenoides chronica.

Clin Exp Dermatol. 2010; 35:47–50.

Historical Diagnosis and treatment Diagnosis and treatments have advanced over the past century. This feature depicts conditions from a collection of stereoscopic cards published in 1910 by The Stereoscopic Skin Clinic by, Dr S. I. Rainforth.

(Continued on page 222)

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Breast & Body Facial Rejuvenation Practice Management Aesthetic Dermatology New Technology Update Non-Invasive Skin Rejuvenation

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May/June 2017

Volume 15 • Issue 3

CASE STUDY

Giant Pigmented Squamous Cell Carcinoma in Situ: A Diagnostic and Therapeutic Challenge Blanca E. Ochoa, MD;1 Philip R. Cohen, MD;2 Deborah F. MacFarlane, MD, MPH1

A 91-year-old Hispanic man with a diffuse large B-cell lymphoma of the stomach that was currently being treated with immunosuppressive therapy was referred for evaluation of a biopsy-proven squamous cell carcinoma in situ (SCCis) on the left mid-region of his back. The lesion had apparently been present at birth and had recently started to itch, become red, and progressively enlarge. (SKINmed.

2017;15:215–216)

C

utaneous examination of the left mid-region of the back showed a 12.5 cm × 8.5 cm well-demarcated plaque with variable colors including areas that were red, tan, and brown (Figures 1 and 2). The texture also varied: there were thin patches with minimal epidermal change and thicker scaling plaques within the tumor.

An incisional biopsy was performed to exclude the possibility of malignant melanoma and extramammary Paget’s disease. Pathology showed atypical keratinocytes with large nuclei throughout all layers of the epidermis (Figure 3). Immunohistochemical studies for antibodies to HMB-45, anti-tyrosinase, and CK7 were all negative. The diagnosis of SCCis was confirmed. Scattered aggregates of dermal melanophages and focal hyperpigmentation of basal keratinocytes were also present. These pathologic changes accounted for the hyperpigmentation observed clinically.

scaling plaque.1 The risk of progression to invasive squamous cell carcinoma is estimated to range from 3% to 5% for nongenital SCCis.2,3 The clinical presentation of our patient’s tumor proved to be a diagnostic challenge due to the color variegation and the history—albeit probably inaccurate—of congenital onset. An incisional biopsy was performed to confirm the diagnosis and to rule

Treatment options were discussed with the patient and his family. It was decided to treat the tumor with curettage and desiccation. At 1-year follow-up, there was no tumor recurrence.

DISCUSSION SCCis is a common intraepidermal malignancy. It usually presents in sun-exposed areas as a gradually enlarging, erythematous

Figure 1. A large well-demarcated plaque with variable colors located on the left mid-region of the back.

From the Department of Dermatology, The University of Texas MD Anderson Cancer Center, Houston, TX;1 and the Department of Dermatology, University of California San Diego, La Jolla, CA2 Address for Correspondence: Deborah MacFarlane, MD, Department of Dermatology, The University of Texas MD Anderson Cancer Center, 1400 Pressler, Unit Number 1452, Houston, TX 77030 • E-mail: dmacfarl@mdanderson.org

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CASE STUDY inconvenience of their use for the patient; in addition, there was concern regarding the potential of systemic absorption with 5-fluorouracil 5% cream and failure of therapy (secondary to his immunosuppressed status) with imiquimod 5% cream.

Our patient’s tumor was successfully treated with curettage and desiccation. The patient tolerated the procedure well . The treatment site rapidly healed without any complications.

Conclusions Pigmented SCCis is an infrequent clinical variant of nonmelanoma skin cancer. Giant SCCis is an uncommon presentation of this cutaneous malignancy. The development of such a giant pigmented SCCis as in our patient is indeed rare, and provided us with not only a diagnostic dilemma, but also a therapeutic challenge. The diagnosis was confirmed by repeating the pathology evaluation on an additional incisional biopsy tissue sample with routine hematoxylin and eosin staining, and also immunohistochemical studies. Successful management, using curettage and desiccation, was well tolerated by the patient; the treatment site healed rapidly and there has been no recurrence of the cancer.

Figure 2. Areas of either minimal epidermal changes or thicker scaling appreciated on closer examination.

References 1 Kossard S, Rosen R. Cutaneous Bowen’s disease. J Am Acad Dermatol. 1992;27:406–410.

2 Peterkea EX, Lynch FW, Goltz RW. An association between Bowen’s disease and cancer. Arch Dermatol.

1961;84:623–629.

Figure 3. Full-thickness atypia of keratinocytes within the epidermis. Keratohyalin granules were present in the atypical cells, confirming the diagnosis of squamous cell carcinoma in situ.

3 Kao GF. Carcinoma arising in Bowen’s disease. Arch Dermatol. 1986;122:1124–1126.

out the possibility of malignant melanoma. Indeed, pigmented SCCis has previously been reported to mimic malignant melanoma.4,5 Effective treatment options for pigmented SCCis include excision, cryothereapy,6 imiquimod 5% cream,7 and combination therapy with 5-fluorouracil cream and cryotherapy.8

4 Krishman R, Lewis A, Orengo IF, Rosen T. Pigmented Bowen’s disease (squamous cell carcinoma in-situ): A mimic of malignant melanoma. Dermatol Surg. 2001;27:673– 674.

5 Gahalaut P, Rastogi MK, Mishra N, Chauhan S. Multiple pigmented Bowen’s disease: A diagnostic and therapeutic dilemma. Case Rep Oncol Med. 2012;2012:342030.

6 Mortimer PS, Sonnex TS, Pawher BPR. Cryotherapy for multicentric pigmented Bowen’s disease. Clin Exp Dermatol. 1983;8:319–322.

7 Yanagishita T, Akita Y, Nakanishi G, Tamada Y, Watanabe D. Pigmented Bowen’s disease of the digit successfully treated with imiquimod 5% cream. Eur J Dermatol.

2011;21:1021–1022.

Management of our patient’s SCCis proved to be a challenge because of the tumor’s size. Giant SCCis is uncommon;9,10 however, giant SCCis has previously been successfully treated with radiotherapy9 or combination photodynamic therapy and imiquimod cream10 after other treatment modalities failed.

8 Papageorgiou PP, Koumarianou AA, Chu AC. Pigmented Bowen’s disease. Br J Dermatol. 1998;138:515–518.

The approach to treating our patient’s tumor was also influenced by his elderly age, his cognitive ability, and his immunosuppressed status resulting from his lymphoma and its treatment.

Surgical excision was considered impractical due to the tumor size. Topical treatments were not recommended because of the

10 Sotiriou E, Lallas A, Apalla Z, Ioannides D. Treatment of giant Bowen’s disease with sequential use of photodynamic therapy and imiquimod cream. Photodermatol Photoimmunol Photomed. 2011;27:164–166.

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9 Mckenna DJ, Morris S, Kurwa H. Treatment-resistant giant unilateral Bowen’s disease of the scalp responding to radiotherapy. Clin Exp Dermatol. 2008;34:85–86.

Giant Pigmented Squamous Cell Carcinoma in Situ

Edward L. Keyes Resident Contest for Outstanding Case Reports 13th World Congress of the International Academy of Cosmetic Dermatology Dubrovnik, Croatia June 28–July 1, 2018 Abstract deadline: March 31, 2018 To be awarded for the best Case Report submitted by a physician in training (resident, fellow, or registrar) for presentation at the 13th World Congress of the International Academy of Cosmetic Dermatology in Dubrovnik, Croatia from June 28–July 1, 2018.

We invite you to submit original Case Reports that reflect the presentation of new ideas and original observations to the Academy membership and other attendees of the Congress. The case may be medical, surgical, and cosmetic (or combined) in nature.

The author whose abstract obtains the highest score during the review process will receive a scholarship by the IACD to present the full paper at the 13th World Congress of the International Academy of Cosmetic Dermatology in Dubrovnik, Croatia from June 28-July 1, 2018. The scholarship will provide reasonable travel expenses, lodging for 3 nights, the Congress registration fee, and a basic spending stipend.

Please submit your case report abstract via email to vrosic@medicine.bsd.uchicago.edu before noon, CDT, March 31, 2018. The abstract should be no longer than 2,500 characters including spacing. Material that was previously presented, published, or submitted for publication should not be offered. Applications will be graded based upon the educational value of the abstract and the extent to which it presents new and significant work. The Review Committee strongly recommends that abstracts have an organized, coherent, well-thoughtout, and complete presentation. Please note that no paper submitted for consideration will be eligible if it has already been, or is in consideration for, publication elsewhere at any time prior to the meeting. The winner(s) agree to publish their outstanding case report(s) in SKINmed: Dermatology for the Clinician, an official publication of the International Academy of Cosmetic Dermatology. By submitting your paper for consideration, you give SKINmed: Dermatology for the Clinician first-rights of refusal for publication through December 31, 2018.

The applicant must be in training at the time of the Congress presentation.

All applicants will receive e-mail notice of the Resident Case Report Review Committee’s decision by May 1, 2018.

Vesna Petronic-Rosic, MD, MSc Chair, Resident Contest Committee Professor and Chief The University of Chicago Pritzker School of Medicine Section of Dermatology Tel: +1.773.702.6559 vrosic@medicine.bsd.uchicago.edu

May/June 2017

Volume 15 • Issue 3

CASE STUDY

Generalized Discoid Lupus Erythematosus as the Presenting Sign of Small Cell Lung Carcinoma Tania M. Gonzalez Santiago, MD; David A. Wetter, MD; Garrett C. Lowe, MD; Gabriel F. Sciallis, MD

A 46-year-old woman with a 30 pack-year smoking history presented with a worsening eruption on the left cheek that failed to improve with metronidazole gel. The cutaneous eruption spread to most of her face and did not respond to a brief tapering course of prednisone.

During the initial evaluation at our institution, approximately 6 weeks after the onset of the cutaneous eruption, the patient had erythematous, crusted plaques on her face and scalp (Figure 1A); they were also present on the V-area of the anterior aspect of the neck and upper region of the chest, the shoulders, and the arms, with isolated lesions on the trunk and legs. Her oral mucosa had erythematous erosions on the hard palate and gingivae. A review of systems revealed pain and burning of her skin lesions, but no muscle weakness or other systemic clinical manifestations. The differential diagnosis included autoimmune connective tissue disease, pemphigus foliaceous, sarcoidosis, lichen planus, phototoxic drug eruption, and eczema herpeticum. (SKINmed. 2017;15:218–220)

H

istopathology (hematoxylin and eosin staining) of a skin biopsy specimen from the shoulder demonstrated interface dermatitis with vacuolar changes (Figure 2), and direct immunofluorescence microscopy showed granular immunoglobulin M and C3 deposition along the basement membrane.

Laboratory investigations showed leucopenia, thrombocytopenia, hyponatremia (due to syndrome of inappropriate antidiuretic hormone secretion), and elevated alkaline phosphatase. Serologic tests showed antinuclear antibody, anti-Smith antibody, low complement 3, and low complement 4. All other laboratory test results were negative or normal (Table). A chest radiograph showed a 6-cm, right-sided mass in the superior mediastinum, specifically the anterior and middle compartments; mediastinal biopsies were positive for small cell lung carcinoma. Further evaluation showed limited stage disease (T1N2M0), stage IIIA. Given the clinical, laboratory, histologic, and serologic findings, a diagnosis of generalized discoid lupus erythematosus with systemic lupus erythematosus attributable to underlying small cell lung carcinoma was made.

During the next 2 months, the patient underwent radiochemotherapy with cisplatin-etoposide and 4500 cGy in 30 fractions. After two cycles of radiochemotherapy, her skin lesions had markedly improved (Figure 1B). The tumor size was reduced from 6.0 cm to 3.6 cm.

DISCUSSION Cutaneous lupus erythematosus (CLE) in the setting of malignancy rarely is reported, although an association between subacute CLE (SCLE) and malignancy has been described.1 In 2005, Chaudhry et al1 reported a case of SCLE that preceded the diagnosis of laryngeal squamous cell carcinoma, adding to 11 other reports of SCLE occurring as a paraneoplastic phenomenon (2 of the 11 patients had small cell lung carcinoma). Since then, five other patients with SCLE in the setting of malignancy have been reported.2–4 Paraneoplastic dermatosis has two major diagnostic criteria: (1) the dermatosis arises after development of the malignant tumor, but it does not necessarily precede tumor diagnosis; and (2) the dermatosis and malignant tumor should follow a parallel course.5 Our patient met both criteria because her cutaneous disease preceded the diagnosis of the underlying malignancy, and both conditions improved after radiochemotherapy.

The risk of lung cancer increases in persons with systemic lupus erythematosus, and smoking is an important predictor of lung cancer development in systemic lupus erythematosus.6 A recent Swedish epidemiologic study of CLE patients (with or without systemic lupus erythematosus) nationwide described a nearly fourfold increased risk for certain cancers (buccal, lymphoma,

From the Department of Dermatology, Mayo Clinic, Rochester, MN Address for Correspondence: David A. Wetter, MD, Department of Dermatology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905 • E-mail: wetter.david@mayo.edu

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(a)

(b)

(b)

Figure 2. Hematoxylin and eosin–stained skin biopsy specimen showing interface dermatitis with epidermal atrophy and perivascular and perifollicular inflammation. (a) Original magnification ×40; (b) original magnification ×100.

respiratory, nonmelanoma) compared with a control cohort without CLE;7 moreover, CLE is worse in current smokers than past smokers and never-smokers.8

Figure 1. (a) Erythematous, hyperkeratotic, crusted plaques and papules on the head, neck, and upper chest. (b) Dramatic improvement of the cutaneous eruption after two cycles of radiochemotherapy.

SKINmed. 2017;15:218–220

We cannot completely exclude the simple concurrence of two separate entities (discoid lupus erythematosus and lung cancer in a smoker) in our patient, but their abrupt onset (within 6 weeks of each other) and simultaneous response to radiochemotherapy suggests paraneoplastic discoid lupus erythematosus as the most likely diagnosis. In cases of paraneoplastic SCLE, there is a possible stimulatory tumor antigen as the trigger for development of SCLE.1 In this scenario, cutaneous lesions may be due to episodic antigen expression by the tumor, and hence may reflect the

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Table I. Laboratory Studies Analyte

Measurement at Presentation

Hemoglobin (g/L)

Measurement After 2 Cycles of Radiochemotherapy

Reference Range

12.0

11.7

12.0–15.5

White blood cell (×10 /L)

1.9

2.7

3.5–10.5

Platelets (×10 /L)

102

149

150–450

Antinuclear antibody (U)

3.6

3.2

<1.0

Anti-Ro (U)

<0.2

<0.2

<1.0

Anti-La (U)

<0.2

<0.2

<1.0

Anti-dsDNA (IU/mL)

<12.3

<12.3

<30.0

Ribonucleoprotein Ab IgG (U)

<0.3

0.3

<1.0

Smith Ab IgG (U)

3.5

1.9

<1.0

Erythrocyte sedimentation rate (mm/h)

7

—

0–29

C-reactive protein (nmol/L)

45.7

—

<76.2

Sodium (mmol/L)

113

130

135–145

Potassium (mmol/L)

3.8

4.7

3.5–5.2

Osmolality (mmol/kg)

233

—

275–295

Creatinine (µmol/L)

53.0

—

53.0–97.2

Creatine kinase (µkat/L)

0.9

—

0.6–2.9

Alkaline phosphatase (µkat/L)

2.6

1.5

0.7–1.7

Total complement (U/mL)

41

—

30–75

C3 complement (g/L)

0.6

—

0.8–1.8

C4 complement (g/L)

0.1

—

0.1–0.4

9

9

Abbreviations: Ab, antibody; dsDNA, double-stranded DNA; Ig, immunoglobulin.

antigen load, rather than the absolute tumor mass;1 this may explain why the latency period can vary depending on the size and type of malignancy.

Conclusions In most of the previously reported cases, the cutaneous eruption was responsive to cancer therapy (eg, surgery or chemotherapy, or both). In our patient, there was a clear association between tumor shrinkage and improvement of cutaneous lesions. We suggest that the effect of cancer treatment on the skin was attributable to the tumor response, although we cannot completely exclude the possibility that chemoradiotherapy directly affected the discoid lupus erythematosus lesions.

References 1 Chaudhry SI, Murphy LA, White IR. Subacute cutaneous lupus erythematosus: A paraneoplastic dermatosis? Clin Exp Dermatol. 2005;30:655–658.

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2 Renner R, Sticherling M. Incidental cases of subacute cutaneous lupus erythematosus in association with malignancy. Eur J Dermatol. 2008;18:700–704.

3 Torchia D, Caproni M, Massi D, et al. Paraneoplastic toxic epidermal necrolysis-like subacute cutaneous lupus erythematosus. Clin Exp Dermatol. 2010;35:455–456.

4 Gantzer A, Regnier S, Cosnes A, et al. Subacute cutaneous lupus erythematosus and cancer: Two cases and literature review [in French]. Ann Dermatol Venereol.

2011;138:409–417.

5 McLean DI. Cutaneous paraneoplastic syndromes. Arch Dermatol. 1986;122:765–767.

6 Bernatsky S, Kale M, Ramsey-Goldman R, et al. Systemic lupus and malignancies. Curr Opin Rheumatol.

2012;24:177–181.

7 Gronhagen CM, Fored CM, Granath F, Nyberg F. Increased risk of cancer among 3663 patients with cutaneous lupus erythematosus: A Swedish nationwide cohort study.

Br J Dermatol. 2012;166:1053–1059.

8 Piette EW, Foering KP, Chang AY, et al. Impact of smoking in cutaneous lupus erythematosus. Arch Dermatol.

2012;148:317–322.

Generalized Discoid Lupus Erythematosus

May/June 2017

Volume 15 • Issue 3

CASE STUDY

Chemical Tattoo Treatment Leading to Systemic Cobalt Hypersensitivity Nicholas J. Zajdel, BS;1 W. Austin Smith, MD;2 Adam R. Taintor, MD;3 Sharon E. Jacob, MD;4 Edit B. Olasz, MD, PhD1

An otherwise healthy 36-year-old Caucasian woman, without prior history of atopic dermatitis or eczema, presented to an outside dermatologist with a generalized, severely pruritic eruption involving the entire body except the face. One month previously, she had used a 50% trichloroacetic acid tattoo removal solution on a blue-colored tattoo on the medial aspect of the left ankle. The patient’s eruption persisted for 7 months, and after several attempts to slowly taper her prednisone dose, she presented to our institution. On physical examination, there was a 3-cm erythematous, lichenified plaque surrounding the tattoo (Figure). On the trunk and upper regions of the arms, there were scattered, 1- to 2-cm, nummular patches and plaques. Biopsy of a truncal lesion revealed spongiotic pustules with a mixed dermal infiltrate and scattered eosinophils, consistent with subacute spongiotic dermatitis. (SKINmed. 2017;15:221–222)

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ne week after discontinuation of a 3-week oral prednisone taper, patch testing demonstrated neomycin 3+, bacitracin 3+, cobalt 1+, and carba mix 1+. As has been previously reported, “In tattoo reactions, patch testing may not be effective since the inflammatory response is triggered by material within the dermis. This is unlike contact dermatitis, in which antigen-presenting cells within the epidermis trigger the reaction.”1 We believe this is the reason the patch test reaction to cobalt was weak (1+) rather than exuberant.

Despite the patient being treated with topical steroids, she continued to experience flares of her pruritic eruption. Considering the positive patch testing result for cobalt and the patient’s history of chemical peel-induced erosive dermatitis in the cobalt-containing blue tattoo, the diagnosis of probable systemic sensitization to cobalt was made. The tattoo was removed with a two-step staged excision by plastic surgery. At 4 weeks after complete excision, her diffuse eruption had completely resolved.

Subsequent rechallenge with neomycin and bacitracin did not result in a systemic flare.

Local reactions have been reported to occur secondary to hypersensitivity to tattoo pigment, with blue ink tattoo reactions being linked to cobalt.1 Several cases of reactions to cobalt in tattoos have been previously described, including a contact urticaria, granulomatous reaction, and sarcoidal reaction, all of which were localized to the blue ink of tattoos.2–4 There are several reported cases of systemic tattoo reactions to other compounds contained in different pigmented inks, but to our knowledge this is the first case of systemic hypersensitivity to cobalt. In our case, a chemical peel and subsequent erosions likely unmasked or triggered sensitization to cobalt, and subsequently resulted in a systemic allergic reaction. We hypothesize that exposure of pigment in the dermis along with inflammation induced by an irritant peel resulted in antigen recognition, uptake, and maturation of dermal dendritic cells, initiating a subsequent delayed-type hypersensitivity reaction that potentially led to systemic response, as seen in Id reactions.5

From the Department of Dermatology, Medical College of Wisconsin, Milwaukee, WI;1 the Department of Dermatology, Scott and White Health, Temple, TX;2 the Department of Dermatology, Intermountain Healthcare, Sandy, UT;3 and the Department of Dermatology, University of San Diego, San Diego, CA4 Address for Correspondence: Edit B. Olasz MD, PhD, Department of Dermatology, Medical College of Wisconsin, 9200 West Wisconsin Avenue, Milwaukee, WI 53226 • E-mail: ebolasz@mcw.edu

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CASE STUDY Conclusions We illustrate the first case of systemic hypersensitivity to cobalt from tattoo ink and describe the seriousness of tattoo reactions that may require surgical treatment. Therapeutic options for systemic hypersensitivity to tattoo ink are limited; excision rather than laser treatment is recommended if the allergic reaction persists.

References 1 1. Zemtsov A, Wilson L. CO2 laser treatment causes local tattoo allergic reaction to become generalized. Acta Derm Venerol. 1997;77:497.

2 Bagnato GF, De Pasquale R, Giacobbe O, et al. Urticaria in a tattooed patient. Allergol Immunopathol (Madr).

1999;27:32–33.

3 Handler MZ, Tonkovic-Capin V, Brewster SD, Fritzlen TJ, Aires DJ. Granulomatous reaction confined to two blueink tattoos after H1N1 influenza vaccine. J Vaccines Vaccin. 2010;1:108.

4 Yoong C, Vun YY, Spelman L, Muir J. True blue football fan: Tattoo reaction confined to blue pigment. Australas J Dermatol. 2010; 51:21–22.

5 Elsaie ML, Olasz E, Jacob SE. Cytokines and Langerhans cells in allergic contact dermatitis. G Ital Dermatol Venereol. 2008;143:195–205.

Figure. Erythematous, lichenified plaque surrounding the blue-colored tattoo on the medial aspect of the left ankle.

Historical Diagnosis and treatment: epithelioma

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Chemical Tattoo Treatment

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Volume 15 • Issue 3

CASE STUDY

Association of Piebaldism with Café-au-Lait Macules Naveen Kumar Kansal, MD;1 Saurabh Agarwal, MD2

A 45-day-old infant was brought by his parents to the dermatology outpatient department with chief complaints of asymptomatic, depigmented lesions that had been present on his skin since birth. On mucocutaneous examination, large rhomboid-shaped depigmented macules were noted on the abdomen and lower extremities bilaterally (Figure 1). A depigmented macule was present on the forehead, with white hair (leukotrichia; a “developing forelock”) (Figure 2). Three hyperpigmented lesions (café-au-lait macules [CALMs]) were also noted on the chest (Figure 1a). There was no history of consanguinity, and the family history was negative. The infant was otherwise normal for his age. A diagnosis of “piebaldism with CALMs” was made, and his parents were counseled about the disease and its progression, and possible treatment options as the child grew. They were also informed about a currently unquantifiable risk of future development of Legius syndrome or neurofibromatosis type 1 (NF1), and were counseled for regular follow-up. (SKINmed. 2017;15:223–225)

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iebaldism is a rare, autosomal dominant genodermatosis secondary to the congenital absence of melanocytes in skin and hair, resulting in depigmented macules on the forehead, chest, abdomen, and extremities. A white forelock is seen in 80% to 90% of patients. Piebaldism is an uncommon disorder, with an estimated incidence of less than 1 in 20,000.1 Most cases of piebaldism are caused by a number of mutations in the KIT proto-oncogene on chromosome 4q11-12, which encodes the cellular receptor tyrosine kinase for the mast cell/ stem cell growth factor (the “Steel factor”), an embryonic growth factor. The mutations cause defects in the development or migration of melanoblasts from the neural crest during early embryonic life, which result in an absence of melanocytes in affected areas of skin and hair. Some cases of piebaldism are now also known to occur due to mutation of the SLUG (also known as the SNAI2) gene on chromosome 8q11. This gene encodes the slug protein (a zinc-finger neural crest transcription factor), which is also critical for the development of human melanocytes.2 Patients with piebaldism, however, are known to present with other hyperpigmented lesions, some of which have been present since birth.

Patients with piebaldism may present with three peculiar types of hyperpigmented lesions. First are the hyperpigmented macules most commonly interspersed through the congenital depigmented lesions; these usually develop late in the disease process.1 Much less commonly, CALMs, and axillary and inguinal freckling (identical to that seen in and leading to a clinical diagnosis of NF1) is present. Recently, there has been a case of piebaldism with atypical freckling on the limbs, but sparing the axillae and inguinal regions.3 There have been a number of case reports of association of piebaldism with NF1 (von Recklinghausen’s neurofibromatosis), as patients with piebaldism, multiple CALMs, and axillary/inguinal freckling (Crowe sign) also fulfill two of the seven updated diagnostic criteria of the National Institutes of Health Consensus Statement that are needed to clinically diagnose NF1.4,5 NF1 is one of the classical autosomal dominant neurocutaneous syndrome of tumor formation associated with characteristic pigmentary anomalies. The gene for NF1 is situated on chromosome 17q11.2 and encodes the “neurofibromin” protein, which, as it can downregulate Ras activity, acts as a suppressor of tumor activity. It is of par-

From the Department of Dermatology and Venereology, All India Institute of Medical Sciences, Rishikesh 249201,1 and the Department of Dermatology and Venereology, Government Medical College, Haldwani (Nainital) 263139,2 Uttarakhand, India Address for Correspondence: Naveen Kumar Kansal, MD, Department of Dermatology and Venereology, All India Institute of Medical Sciences, Rishikesh 249201, Uttarakhand, India • E-mail: kansalnaveen@gmail.com

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CASE STUDY dard as the sensitivity of molecular diagnosis of NF1 is 95%, and 5% to 10% mutations, being microdeletions in the NF1 gene, may be missed by standard polymerase chain reaction– based testing. They also state that mutation of the KIT gene, which controls the proper development of bone marrow–derived mast cells, may prevent neurofibroma formation, and thus “neurofibromas are not an appropriate clinical feature for the diagnosis of NF1” in cases of piebaldism.7 Legius syndrome (OMIM #611431) is a new disease entity that was described in 2007. It closely resembles NF1 but can be clinically distinguished by the absence of tumors, such as Lisch nodules, neurofibromas, or optic gliomas, and also by the absence of the NF1 gene mutation. Clinical features of Legius syndrome, caused by an autosomal dominant mutation of the SPRED1 gene on chromosome 15q13.2, include CALMs, axillary/inguinal freckling, macrocephaly, Noonan-like facies, and learning problems.8 A recent report has shown an association of piebaldism with CALMs, and intertriginous freckling, and postulate that the defective KIT tyrosine kinase in piebaldism leads to inadequate phosphorylation of SPRED1. This results in loss of inhibition of the Ras/MAPK pathway, resulting in a “Legius-type” phenotype, and does not indicate an association between piebaldism and NF1.9

Figure 1. Large depigmented macules on (a) the ventral aspect of the trunk and (b) right leg. Café-au-lait macules are present on the chest.

Some observers, however, have hypothesized that a separate, as yet unidentified, locus may be responsible for hyperpigmented macules in piebald individuals, which may explain the phenotypical variations in patterns of pigmentation and freckles.3 The recent novel missense mutation (heterozygous missense c.2431T>G mutation in exon 17 of the KIT gene in the proband and the affected son) in a Chinese family may well support the notion that CALMs and intertriginous freckling of piebaldism may be considered components of pigmentary anomaly in piebaldism, and may not necessarily represent a coexistence of NF1,2 except possibly in the case reported by Tay.5

Figure 2. Depigmented macule on the forehead, with leukotrichia.

Conclusions

ticular interest to note that in all cases of an association of NF1 and piebaldism that have been reported to date, tumor formation is conspicuous by its absence, except in a 15-yearold Chinese girl in whom Lisch nodules and scoliosis were reported.5 Some workers remain skeptical about whether a true association exists between these two disorders, and have stated that a diagnosis of NF1 should not solely be based upon pigmentary features.6 Another group, however, consider the National Institutes of Health clinical criteria to be gold stanSKINmed. 2017;15:223–225

Our patient, presenting with three CALMs of significant size, might in future develop NF1, or Legius syndrome, or neither. Around 40% of patients with NF1 have presented with a “CALMs-only subtype”,10 a condition also referred to as NF6 (CALMs-only NF6 of Riccardi and Eichner).5 From a review of the multiple reports that associate piebaldism with NF1, piebald patients usually do not develop some of the more morbid complications seen with NF1, particularly tumor formation,6 and an altered, less rigorous health care management plan should thus be considered appropriate for them.

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References 1 Agarwal S, Ojha A. Piebaldism: A brief report and review of the literature. Indian Dermatol Online J. 2012;3:144– 147.

2 Jia WX, Xiao XM, Wu JB, et al. A novel missense KIT mutation causing piebaldism in one Chinese family associated with café-au-lait macules and intertriginous freckling. Ther Clin Risk Manag. 2015;11:635–638.

3 Sarma N, Chakraborty S, Bhanja DC, Bhattachraya SR. Piebaldism with non-intertriginous freckles: What does it mean? Indian J Dermatol Venereol Leprol. 2014;80:163– 165.

4 Goldstein J, Guttmann DH. Neurofibromatosis type 1. In: Steve Roach E, Miller VS, eds. Neurocutaneous Disorders.

Cambridge: Cambridge University Press; 2004:42–49.

5 Tay YK. Neurofibromatosis 1 and piebaldism: A case report. Dermatology. 1998;197:401–402.

6 Spritz RA, Itin PH, Gutmann DH. Piebaldism and neurofibromatosis type 1: Horses of very different colors. J Invest Dermatol. 2004;122:xxxiv–xxxv.

7 Duarte A, Mota A, Baudrier T, et al. Piebaldism and neurofibromatosis: State of knowledge. Dermatol Online J. 2013;19:17.

8 Brems H, Chmara M, Sahbatou M, et al. Germline lossof-function mutations in SPRED1 cause a neurofibromatosis 1-like phenotype. Nat Genet. 2007;39:1120–1126.

9 Chiu YE, Dugan S, Basel D, Siegel DH. Association of piebaldism, multiple café-au-lait macules, and intertriginous freckling: Clinical evidence of a common pathway between KIT and SPRED1. Pediatr Dermatol.

2013;30:379–82.

10 Neurocutaneous syndromes. In: Caputo R, Tadini G. Atlas of Genodermatoses. London: Taylor & Francis; 2006:310–371.

“Neurofibromatosis” Made by Lotte Volger in 1928 in the Clinic for Dermatology Zurich. Museum of Wax Moulages Zurich, www.moulagen.ch Courtesy of Michael Geiges, MD

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May/June 2017

Volume 15 • Issue 3

CASE STUDY

Crossed Total Hemiatrophy Associated with Atrophoderma of Pasini-Pierini Ru-zhi Zhang, MD;1 Wen-yuan Zhu, MD2

A 45-year-old Chinese man had begun to show asymmetry of the face 30 years previously. Subsequently, he developed visual extinction of the right eye, slight numbness, and weakness of the left extremities. Simultaneously, multiple atrophic brownish patches occurred on his side. He denied prior trauma or tick bites at those sites. There was no report of preceding redness, induration, or a history of trauma.

The atrophic lesions extended and enlarged slowly. Ten years previously, some brownish patches with normal texture had appeared on the right side of the trunk. There was no further progression of the lesions. In November 2010, the patient consulted our department for the final diagnosis and prognosis of his disease. He did not suffer from epileptic seizures and had no history of a tick bite or Lyme disease.

(SKINmed. 2017;15:227–229)

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n examination, the patient had hemiatrophy of the right mandibular area and atrophy of the right side of the tongue. The right mandibular angle was more obtuse than the left. Hyperpigmentation was also noted along the right side of the chin (Figure 1A). The left extremities were shorter, the left hand and foot being shorter and narrower than their right-sided counterparts. A few depressed brownish patches were observed on the left shoulder, left arm, back, and lumbar region (Figure 1B), and the medial region of the left thigh (Figure 1C). In the centers of these patches, variciform superficial veins with no redness or induration could be seen clearly. Cranial nerve functions and extraocular movements were normal, and the pupils were of equal size. Right visual acuity was decreased but the optic fundus was normal. Muscle strength of the left extremities measured 4/5 on a manual muscle testing scale.

did not reveal any abnormalities. Histopathologic examination of the biopsy specimen from the hyperpigmented lesion in the right mandibular area showed normal epidermis with increased pigment granules in the basal layer, perivascular mononuclear infiltration of the atrophic dermis, and subcutaneous adipose tissue, in more superficial layers of the skin than usual (Figure 2). Magnetic resonance brain images taken on August 14, 2007 and January 14, 2011, respectively, characterized by an increased atrophy and decreased extension of the right white matter intensity, showed progress of the disease. Based on the clinical and histopathologic findings, the patient was diagnosed with crossed total hemiatrophy and atrophoderma of Pasini-Pierini (APP) on the back. Intramuscular injection of benzathine benzylpenicillin, once a week, contiguously for 3 weeks, was prescribed.

Laboratory examinations produced normal results except for positive antinuclear antibody (speckled pattern, titer 1:320). In particular, investigations for rheumatic disease were unremarkable.

Antibody screening for immunoglobulin G and M to Borrelia burgdorferi was performed, and the results were negative. Electrocardiography, abdominal ultrasonography, and a chest x-ray

Crossed total hemiatrophy implies facial atrophy and contralateral atrophy of the trunk and extremities. A few cases have been reported.1 APP is an uncommon dermatologic condition of unknown etiology, characterized by asymptomatic, violaceous brownish discolored patches, and usually presenting as one or more sharply demarcated depressed lesions.2

DISCUSSION

From the Department of Dermatology, the Third Affiliated Hospital of Suzhou University, Changzhou,1 and the Department of Dermatology, the First Affiliated Hospital of Nanjing Medical University, Nanjing,2 China Address for Correspondence: Wen-yuan Zhu, Department of Dermatology, the First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing 210029, China • E-mail: zhuwenyuan@yahoo.com

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CASE STUDY (c)

(b)

(a)

Figure 1. Clinical findings. (a) Hyperpigmentation was noted along the right side of the chin. A few brownish patches were apparent on the left shoulder and arm, back, and lumbar area (b), and the medial region of the left thigh (c). In the centers of these patches, variciform superficial veins with no redness or induration could be clearly seen.

(a)

(b)

Figure 2. Normal epidermis with increased pigment granules in the basal layer, perivascular mononuclear infiltration of the atrophic dermis, and subcutaneous adipose tissue in more superficial layers of the skin than usual. (Hematoxylin and eosin stain; (a) ×40; (b) ×100.)

Progressive facial hemiatrophy (PFH), or Parry-Romberg syndrome, is a sporadic and poorly understood disease of unknown etiology. Different reports about the onset of PFH after Lyme disease led to a controversial discussion about a possible association.3 Some findings indicated a possible relevance of autoimSKINmed. 2017;15:227–229

munity in the pathogenesis of the disease.4 The distribution of PFH along the branches of the trigeminal nerve, which carries a great number of sympathetic fibers, underscores the assumed importance of the sympathetic nervous system.5 Considerable controversy and confusion remain regarding whether PFH is a

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distinct disease or a form of linear scleroderma, although most authors would agree that these are closely related disorders. The timing of investigation appears to be a crucial factor in diagnosing either linear scleroderma or PFH, as linear scleroderma lesions have been reported to occur in 3 of 12 patients before the development of PFH.6 The authors proposed two subtypes of PFH, one restricted to the subcutaneous tissues and primarily affecting the cheek area, and one affecting primarily the skin and only later moving on to the deeper tissues.

hints at an immunologic mechanism involved in the pathogenesis of this condition; however, anti-Scl-70 and anticentromere antibodies, the most commonly encountered antibodies in scleroderma, were negative. We are not aware of any previous reports of total hemiatrophy associated with APP. Our observation could contribute toward a better understanding of the disease.

References

Crossed hemiatrophy shows facial atrophy on one side and atrophy of the periphery and trunk on the other side. It is very rare, and its cause is not known. In previous reports, Hirata et al described a case of crossed total hemiatrophy with a right precentral to central arteriovenous malformation.7 The authors suggested that the ipsilateral facial atrophy might hypothetically be related to some brainstem dysfunction. Strenge et al reported a 35-yearold man presenting a neurocutaneous disorder with coup de sabre deformity, telangiectatic naevus, aneurysmatic malformation of the internal carotid artery, and crossed hemiatrophy.1 The cause and etiopathogenesis of APP remain elusive. Previous studies suggested that genetic factors, neurogenic causes, immunologic factors, and abnormal metabolism of dermatan sulphate might play a role in the pathogenesis of APP.8 The role of Borrelia burgdorferi remains controversial.9 The lesions of APP lesions may be asymptomatically solitary or multiple patches, which progress very slowly and remain stable for 10 to 20 years. Most commonly, they are distributed symmetrically on the trunk.

Some authors regard atrophoderma as a distinct entity, whereas others suggest that APP is a variant of morphea. Concurrence of APP and morphea has been reported.10 Conclusions In our patient, no redness or induration of these lesions was noted. Histopathologically, atrophic dermis and a slightly inflammatory infiltration were observed. Magnetic resonance images showed slight atrophy of the right cerebral hemisphere. Serologic investigations revealed positive antinuclear antibody, which

1 Strenge H, Cordes P, Sticherling M, Brossmann J. Hemifacial atrophy: A neurocutaneous disorder with coup de saber deformity, telangiectatic naevus, aneurysmatic malformation of the internal carotid artery and crossed hemiatrophy. J Neurol. 1996;243:658–673.

2 Kencka D, Blaszczyk M, Jablonska S. Atrophoderma Pasini-Pierini is a primary atrophic abortive morphea.

Dermatology. 1995;190:203–206.

3 Sahin MT, Baris S, Karaman A. Parry-Romberg syndrome: A possible association with borreliosis. J Eur Acad Dermatol Venereol. 2004;18:204–207.

4 Stone J. Parry-Romberg syndrome: A global survey of 205 patients using the internet. Neurology. 2003;61: 674–676.

5 Scope A, Barzilai A, Trau H, Orenstein A, Winkler E, Haik J. Parry-Romberg syndrome and sympathectomy—a coincidence? Cutis. 2004;73:343–344.

6 Sommer A, Gambichler t, Bacharach-Buhles M, et al.

Clinical and serological characteristics of progressive facial hemiatrophy: A case series of 12 patients. J Am Acad Dermatol. 2006;54:227–233.

7 Hirata K, Katayama S, Yamano K, Tsunashima Y, Fujinuma H. Arteriovenous malformation with crossed total hemiatrophy: A case report. J Neurol. 1988;235: 165–167.

8 Kernohan NM, Stankler L, Sewell HF. Atrophoderma of Pasini and Pierini. An immunopathologic case study. Am J Clin Pathol. 1992;97:63–68.

9 Buechner SA, Rufli T. Atrophoderma of Pasini and Pierini: Clinical and histopathologic findings and antibodies to Borrelia burgdorferi in thirty-four patients. J Am Acad Dermatol. 1994;30:441–446.

10. Saleh Z, Abbas O, Dahdah MJ, Kibbi AG, Zaynoun S, Ghosn S. Atrophoderma of Pasini and Pierini: A clinical and histopathological study. J Cutan Pathol.

2008;35:1108–1114.

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Volume 15 • Issue 3

CASE STUDY

Lichenoid Dermatitis in an Adult with Immune Dysregulation, Polyendocrinopathy, Enteropathy, X-Linked (IPEX) Syndrome Young M. Choi, BS;1 Yen T. Wang, MD;2 Bob Geng, MD;3 Maria Garcia-Lloret, MD;3 Chandra N. Smart, MD4

A 23-year-old man presented to our practice with erythroderma and an unusual retiform eruption, along with alopecia universalis and nail dystrophy. He had had no skin findings at birth, but since early infancy had had localized eczematous eruptions of his skin. At 10 years of age, he had developed a generalized eczematous flare requiring hospitalization, and another generalized episode occurred in October 2010.

He was prescribed prednisone 60 mg daily, which initially provided an improvement, but tapering of the corticosteroid resulted in another generalized flare. (SKINmed. 2017;15:231–234)

F

or the past 3 to 4 years, the patient had been managed with prednisone, tacrolimus, and sirolimus, with continued development of eczematous lesions and even ulcerations on his legs. Subsequently, he was switched from sirolimus to azathioprine; his medications on presentation were prednisone 35 mg daily, tacrolimus 8 mg daily, and azathioprine 50 mg twice daily. The patient’s medical history also included earlyonset type 1 diabetes mellitus diagnosed at 1.5 years of age, inflammatory bowel disease, and growth hormone deficiency.

Physical examination revealed erythroderma with lichenification of the neck, axillary fold, antecubital fossa, and abdomen. All his limbs showed yellow, eroded, retiform patches on a background of livedo reticularis. The patient also had alopecia universalis and nail dystrophy (Figure 1). Laboratory data revealed an elevated erythrocyte sedimentation rate of 63 mm per hour (normal 0 to 10 mm per hour), C-reactive protein of 2.0 (normal <0.8 mg/ dl), and elevated levels of interleukin-2R of 3310 IU/ml (normal 200 to 1100 U/ml) and tumor necrosis factor-α 27.7 pg/ml (normal 1.2 to 15.3 pg/ml). Serum immunoglobulin (Ig) G and IgE, as well as CD4 and CD8 counts, were within normal limits.

Biopsy of the anterior aspect of the right leg demonstrated a dense lichenoid lymphohistiocytic infiltrate with numerous necrotic keratinocytes in the basal cell layer, scattered eosinophils, and localized spongiosis. Periodic acid-Schiff-diastase, Gram, and Steiner stains were negative (Figure 2). In 2013, the patient underwent genetic testing in which a portion of the forkhead box P3 (FOXP3) gene (MIM #300292), which is known to be associated with immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome (MIM #304790), was sequenced using the Reference sequence database NM_014009.3. The patient’s DNA was found to harbor a hemizygous mutation of the FOXP3 gene (c.1150G>A), confirming a diagnosis of IPEX syndrome. The patient’s mother and two of his three sisters were also carriers of the FOXP3 gene mutation.

DISCUSSION First described in 1982, IPEX is an extremely rare X-linked immune dysregulation disorder characterized by the triad of enteropathy, autoimmune endocrinopathy, and cutaneous manifestations.1 It is caused by a mutation in the gene for FOXP3, an important DNA-binding protein necessary for the differentia-

From the David Geffen School of Medicine at University of California Los Angeles (UCLA),1 Division of Dermatology, David Geffen School of Medicine at UCLA,2 Division of Clinical Immunology and Allergy, UCLA,3 and Department of Pathology and Laboratory Medicine, UCLA,4 Los Angeles, CA Address for Correspondence: Yen T. Wang, MD, Division of Dermatology, David Geffen School of Medicine at UCLA, 200 UCLA Medical Plaza, Suite 450, Los Angeles, CA 90095 • E-mail: jywanga@gmail.com

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Figure 1. Clinical photographs of the patient’s skin and nails. (A) Erythroderma with retiform patches on both legs.

(B) Closer inspection demonstrates yellow, eroded, and ulcerated retiform patches on a background of livedo reticularis. (C) Alopecia universalis. (D) Onychodystrophy of many nails.

Figure 2. Histopathologic evaluation of stained sections from the anterior aspect of the right leg. (A) Dense lichenoid lymphohistiocytic infiltrate (hematoxylin and eosin stain, original magnification ×40). (B) Numerous necrotic keratinocytes in the basal cell layer, scattered eosinophils, and localized spongiosis (hematoxylin and eosin stain, original magnification, ×200).

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tion and development of CD4+CD25+ regulatory T cells. The absence of regulatory T cells leads to a loss of self-tolerance and immune dysregulation.2 Common sequelae include chronic diarrhea, early-onset diabetes mellitus, thyroiditis, dermatitis, susceptibility to infection, hemolytic anemia, and thrombocytopenia. A review of 39 patients with IPEX from 12 separate reports show that more than 90% of subjects developed enteropathy, 70% developed diabetes, more than 60% developed skin disease, 30% had thyroiditis, and only around 20% developed recurrent infections. Many IPEX patients do not develop signs of immunodeficiency.3 According to a study by Torgerson and Ochs, only half of 50 patients had a history of recurrent severe infections.

A disruption of the skin and gastrointestinal mucosal barrier may be additional contributing factors to the immunodeficiency state.4 Individuals with similar manifestations but who lack the FOXP3 gene mutation are said to have “IPEX-like” syndrome, which accounts for approximately 75% of cases.5 The particular gene mutation in our patient (c.1150G>A) has been reported several times in individuals with IPEX syndrome.6 IPEX must be considered in any infant with intractable diarrhea and type 1 diabetes mellitus. Preliminary studies should include complete blood count, serum glucose, anti-islet antibodies, thyroid function studies, antithyroid antibodies, antienterocyte antibodies, and immunoglobulin levels. Although autoantibodies are often detected, a degree of the autoimmune destruction may be secondary to T-cell–mediated infiltration of the target organs as well.3 Most patients with IPEX have elevated IgE levels, with half of those also exhibiting elevated IgA; however, IgG and IgM levels tend to be normal. On a cellular level, absolute neutrophil and lymphocyte counts are generally normal, but eosinophilia may be present.5 CD4+ and CD8+ subsets counts are generally within normal limits. Proliferation levels in response to mitogen and antigen may be either normal or mildly diminished.

Patients with IPEX exhibit defective interferon-γ, interleukin-2, and tumor necrosis factor-α production.3 Definitive diagnosis requires gene sequencing to identify a mutation in the FOXP3 gene.2 Food allergy testing, lymphocyte subsets, proliferation assays and genetic testing should be carried out in consultation with allergy and immunology departments.

In the literature, 92 of 136 patients (67.6%) reported with IPEX syndrome have skin manifestations.7 The most commonly described condition is an eczematous dermatitis, correlated with elevated serum IgE and peripheral blood eosinophil levels. Other reported cutaneous manifestations include erythroderma, psoriasiform dermatitis, pemphigoid nodularis, exfoliative dermatitis, cheilitis, alopecia universalis, and onychodystrophy.8 To date, only a few studies have correlated their skin findings with histoSKINmed. 2017;15:231–234

pathology. Most cases have described an eczematoid or psoriasiform pattern, with one case demonstrating histopathologic findings consistent with pemphigoid nodularis.9–11 Our case is the first documenting a lichenoid dermatitis in a patient with IPEX syndrome as well as an unusual clinical appearance of eroded, retiform patches on a background of livedo reticularis.

An autoimmune basis of the skin findings in IPEX syndrome is plausible given that these patients lack regulatory T-cell function.

One group9 has demonstrated linear immunofluorescence staining of C3 and IgG along the dermal-epidermal junction, and positivity for the 180 kDa bullous pemphigoid antigen in their patient with IPEX syndrome and pemphigoid nodularis. Another patient with IPEX syndrome developed bullous lesions with immunofluorescence showing linear IgG along the roof of the subepidermal separation and C3 deposition along the roof and the floor, consistent with bullous pemphigoid.12 Antiga et al13 showed that CD4+CD25+ regulatory T cells were significantly depleted in the skin lesions and peripheral blood of patients with bullous pemphigoid. Other studies have found that CD4+CD25+ regulatory T cells are also depleted in skin lesions of atopic dermatitis and psoriasis.14 The absence of these regulatory T cells may lead to dysregulation of effector T cells that are responsible for causing the eczematous or psoriasiform lesions seen in IPEX syndrome.

Usually, untreated IPEX patients die in the first 3 to 4 months of life from diarrhea and numerous infections, and even with treatment, the prognosis is poor. Patients are at increased risk for sepsis, meningitis, pneumonia, and osteomyelitis, with the most common culprits being enterococcus, Staphylococcus, Cytomegalovirus, and Candida species.4 Long-term management of the disease requires immunosuppression, which further increases the risk of infection. Prednisone and corticosteroid-sparing agents such as tacrolimus, cyclosporine, or sirolimus are commonly used.15 Management of acute flares may require admission to intensive care with increased levels of immunosuppression and isolation to prevent nosocomial infections. Avoidance of possible food allergens may be crucial, and vaccinations are generally avoided to prevent triggering life-threatening disease flares.

Hematopoietic stem cell transplantation is curative, but many of the endocrinopathies remain because of end-organ damage.15 CONCLUSIONS We describe a unique case of an adult patient with IPEX syndrome presenting with an unusual appearance of eroded, retiform patches and a lichenoid lymphohistiocytic infiltrate on histopathology. Further studies are necessary to determine the pathogenesis of cutaneous manifestations of IPEX syndrome in relation to CD4+CD25+ regulatory T-cell deficiency.

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References 1 Powell BR, Buist NR, Stenzel P. An X-linked syndrome of diarrhea, polyendocrinopathy, and fatal infection in infancy. J Pediatr. 1982;100:731–737.

2 Hannibal MC, Torgerson T. IPEX Syndrome. 2004 Oct 19 [Updated 2011 Jan 27]. In: Pagon RA, Adam MP, Ardinger HH, et al., eds. GeneReviews® [Internet]. Seattle, WA: University of Washington, Seattle; 1993–2014.

3 Moraes-Vasconcelos D, Cost-Carvalho BT, Torgerson TR, Ochs HD. Primary immune deficiency disorders presenting as autoimmune diseases: IPEX and APECED. J Clin Immunol. 2008;28:S11–S19.

4 Torgerson TR, Ochs HD. Immune dysregulation, polyendocrinopathy, enteropathy, X-linked: Forkhead box protein 3 mutations and lack of regulatory T cells. J Allergy Clin Immunol. 2007;120:744–750.

5 Ochs HD, Torgerson TR. Immune dysregulation, polyendocrinopathy, enteropathy, X-linked inheritance: Model for autoaggression. Adv Exp Med Biol. 2007;601:27–36.

6 Bennett CL, Christie J, Ramsdell F, et al. The immune dysregulation, polyendocrinopathy, enteropathy, Xlinked syndrome (IPEX) is caused by mutations of FOXP3. Nat Genet. 2001;27:20–21.

7 Martín-Santiago A, Hervás JA, Hervás D, et al. Diagnostic value of the skin lesions in immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome.

Pediatr Dermatol. 2013;30:e221–e222.

8 Halabi-Tawil M, Ruemmele FM, Fraitag S, et al. Cutaneous manifestations of immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome. Br J Dermatol. 2009;160:645–651.

9 McGinness JL, Bivens MM, Greer KE, et al. Immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) associated with pemphigoid nodularis: A case report and review of the literature. J Am Acad Dermatol. 2006;55:143–148.

10 Nieves DS, Phipps RP, Pollock SJ, et al. Dermatologic and immunologic findings in the immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome.

Arch Dermatol. 2004;140:466–472.

11 De Benedetti F, Insalaco A, Diamanti A, et al. Mechanistic associations of a mild phenotype of immunodysregulation, polyendocrinopathy, enteropathy, x-linked syndrome. Clin Gastroenterol Hepatol. 2006;4:653– 659.

12 Ferguson PJ, Blanton SH, Saulsburty FT, et al. Manifestations and linkage analysis in X-linked autoimmunity-immunodeficiency syndrome. Am J Med Genet.

2000;90:390–397.

13 Antiga E, Quaglino P, Volpi W, et al. Regulatory T cells in skin lesions and blood of patients with bullous pemphigoid. J Eur Acad Dermatol Venereol. 2014;28:222–230.

14 Verhagen J, Akdis M, Traidl-Hoffmann C, et al. Absence of T-regulatory cell expression and function in atopic dermatitis skin. J Allergy Clin Immunol. 2006;117:176– 183.

15 Burroughs LM, Torgerson TR, Storb R, et al. Stable hematopoietic cell engraftment after low-intensity nonmyeloablative conditioning in patients with immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome. J Allergy Clin Immunol. 2010;126:1000– 1005.

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A Case of Ischemia-Induced Perianal Ulceration Mimicking Pyoderma Gangrenosum Michael Joseph Lavery, MB BCh BAO, MRCP (UK);1 Nicola Cooke BM BS, FRCP, MPhil2

A 68-year-old woman, with a 75-pack-year smoking history and a history of chronic excess alcohol intake, presented with a 5-week history of worsening perianal pain and ulceration. She recently had an inpatient admission with back pain and urinary tract infection during which she developed diarrhea and fecal incontinence. Initially, the perianal ulceration was diagnosed as severe irritant contact dermatitis and treated with barrier creams and topical clobetasone 17-butyrate 0.05% weight for weight, oxytetracycline 3.0% weight for weight and nystatin cream (Trimovate®). Despite this, the ulceration progressed, resulting in hospital readmission 1 month later. There was no history of consumption of nicorandil (an antianginal therapy), of recurrent oral ulcers, or of inflammatory bowel disease. On examination, there were multiple areas of deep, sloughy ulceration bilaterally around the perianal and buttock regions with erythematous and violaceous edges (Figure 1). Complete blood count, blood film, rheumatoid factor, autoimmune and vasculitic profile, hepatitis screen, immunoglobulins and plasma protein electrophoresis were all normal. Punch biopsy revealed scanty dermal perivascular inflammatory cell infiltrate and occasional neutrophils (Figure 2). No evidence of granulomata, dysplasia, malignancy, or Langerhans histiocytes was identified, and periodic acid–Schiff staining was negative. (SKINmed. 2017;15:235–237)

D

uring this admission, the patient also complained of difficulty mobilizing, lower limb numbness, and paresthesia, which, after magnetic resonance imaging of the spine and a neurology consultation, was felt to be peripheral neuropathy secondary to nutritional deficiency and previous heavy alcohol intake. Clinically and histologically, the perianal ulceration was considered consistent with pyoderma gangrenosum (PG), and she was treated with intensive dressing regimens, high-dose oral prednisone, minocycline, and subsequently mycophenolate mofetil.

Although the perianal ulceration stabilized with this treatment, no significant improvement in clinical appearance was noted. Subsequent review revealed bilateral cold dusky feet with bilaterally absent posterior tibial and dorsalis pedis pulses. An urgent computed tomography angiogram revealed significant stenosis of the abdominal aorta distal to the renal vessels, occluded common iliac arteries, and small common femoral arteries with widespread calcified plaques throughout the arterial system (Figure 3).

The patient underwent a successful axillobifemoral bypass graft 5 months after presentation, with improvement in the perianal ulceration. Several months after her surgery, the perianal ulceration

had shown significant resolution, and she was gradually weaned off treatment for PG. By 15 months after presentation, the prednisone, minocycline, and mycophenolate mofetil had been discontinued, and the perianal ulceration had completely healed.

DISCUSSION Perianal ulceration can be caused by a myriad of conditions including infections, PG, Crohn’s disease, malignancy and medications; in particular nicorandil, an antianginal therapy used in the UK, is a common culprit (Table).1–3 PG, a disorder of impaired neutrophil function, has an incidence of around 3 to 10 per million population, with a female predominance.4,5 It classically presents as a small papule, rapidly progressing to a deep painful ulcer with an erythematous, irregular, undermined border and a necrotic center.6 However, ulcerations may be misdiagnosed as PG. Weenig et al reviewed 240 patients who had been diagnosed with PG. Of these, 95 patients (40%) had ulcerations that resembled PG, but later were found to have an alternative dignosis, for example vascular occlusive/venous disease, vasculitis, neoplasia, primary infection, and drug-induced and other

Recipient of the Edward L. Keyes Best Resident paper presented at the Xth IACD World Congress, Panama City, Panama, June 23, 2016.

From the Department of Dermatology/Temple Itch Center, Lewis Katz School of Medicine, Temple University, Philadelphia, PA;1 and the Department of Dermatology, Antrim Area Hospital, Antrim, Northern Ireland2 Address for Correspondence: Michael Joseph Lavery, MB BCh BAO, MRCP (UK), Department of Dermatology, Antrim Area Hospital, Antrim, Northern Ireland • E-mail: mlavery@doctors.org.uk

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Figure 1. Multiple areas of deep, sloughy ulceration bilaterally around the perianal and buttock regions with erythematous and violaceous edges.

Figure 3. Computed tomography angiogram (coronal view): stenosis at the abdominal aorta and common iliac ateries (arrows).

Table I. Causes of Perianal Ulceration Infection Sexually transmitted infection 1 Syphilis 2 LGV 3 Granuloma inguinale 4 Nonspecific ulceration Additional infections 1 Viral (e.g., HSV, CMV) 2 Bacterial 3 Fungal (e.g., sporotrichosis) 4 Mycobacterium (e.g., tuberculosis) 5 Protozoal (e.g., leischmaniasis) Inflammatory process Inflammatory bowel disease Pyoderma gangrenosum Malignancy Medication (e.g. Nicorandil) Vasculitis Other Langerhans histiocytosis Ischemia Abbreviations: CMV = cytomegalovirus; HSV = herpes simplex virus; LGV = lymphogranuloma venereum.

Figure 2. Scanty dermal perivascular chronic inflammatory cell infiltrate, epidermal hyperplasia, and occasional neutrophils.

inflammatory disorders. In addition, for the patients who were given treatment for PG, around a third showed no improvement, while 13% developed worsening of the ulceration.7 This SKINmed. 2017;15:235â&#x20AC;&#x201C;237

study highlighted that misdiagnosis can increase both the risks associated with treatment, and the risks associated with a delay in diagnosis. Our patient was also initially misdiagnosed as having PG, with treatment leading to only minimal improvement.

However once the patient developed features of vascular insufficiency, appropriate investigations and management were instigated, with subsequent resolution of the ulceration.

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We present a challenging case of a patient with ischemia-induced perianal ulceration, who was initially misdiagnosed as having PG; however, the ulceration subsequently resolved following surgical intervention for lower limb ischemia, secondary to stenosis of the abominal aorta and common iliac arteries. Anatomically, the common iliac artery branches into the external and internal iliac artery, with the small branches of the latter supplying the external genitalia, perineum and buttocks. As such, stenosis of these vessels will impede blood supply to the aforementioned anatomical sites, with subsequent cutaneous manifestations as witnessed in this case.

of considering all potential underlying causes of cutaneous ulceration, particularly in patients with limited or slow response to treatment.

References

To our knowledge, there are no reported cases of ischemia-induced perianal ulceration; moreover we could find only one case report of ischemia-induced PG. In this case, the patient, who had longstanding PG affecting the left lateral malleolus, developed worsening of the ulcerations with subsequent bleeding. Investigation revealed critical limb ischemia, with surgical intervention (lumbar sympathetic ganglion block with chemical sympathectomy), significantly improving the ulceration, similar to our case.8 This case highlights that impaired blood flow to the perineum can cause ulceration, which may mimic PG. While the clinical appearance of the perianal ulceration was initially felt to be consistent with PG, resolution of the cutaneous ulceration only occurred following correction of the underlying cause (vascular surgical intervention) and not with typical therapeutic options for PG alone. This case demonstrates the necessity

1 Robinson A, Baker P, Stevenson H. Nicorandil as a cause of perineal ulceration. Ulster Med J. 2012;81:97.

2 Williams C, Tamuno P, Smith AJ, Walker SL, Lyon CC. Perianal ulceration and other cutaneous ulcerations complicating nicorandil therapy. J Am Acad Dermatol.

2007;56 suppl 5:S116–S117.

3 Cooke NS, Tolland JP, Dolan OM. Nicorandil-associated perianal ulceration: A case series of 10 patients. Br J Dermatol. 2006;154:199–200.

4 Langan SM, Groves RW, Card TR, Gulliford MC. Incidence, mortality, and disease associations of pyoderma gangrenosum in the United Kingdom: A retrospective cohort study. J Invest Dermatol. 2012;132:2166–2170.

5 von den Driesch P. Pyoderma gangrenosum: A report of 44 cases with follow-up. Br J Dermatol. 1997;137:1000– 1005.

6 Mehrtens SH, Crawley JM. Pyoderma gangrenosum. Br J Hosp Med (Lond). 2015;76:C173–C176.

7 Weenig RH, Davis MD, Dahl PR, Su WP. Skin ulcers misdiagnosed as pyoderma gangrenosum. N Engl J Med. 2002;347:1412–1418.

8 Takahashi Y, Yamaguchi Y, Itoh K, Sano S, Morita A, Katayama I. Intractable wounds caused by pyoderma gangrenosum in a patient with critical limb ischemia treated with cyclosporine and adjuvant sympathectomy. Dermatol Surg. 2009;35:699–703.

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May/June 2017

Volume 15 • Issue 3

Book Review Jennifer L. Parish, MD, Section Editor

Skin and Psyche Nordlind, K. and Zalewska-Janowska, A, Editors, Skin and Psyche. Sharjah, UAE, Bentham Books; 2016: 253 pages. ebook only, $39.00 No offense to cave-dwellers, but I’m a troglodyte. A die-hard paper-and-ink fan, I was apprehensive when first asked to review this e-book. I have always been intrigued by the psychologic aspects of skin disease, so my curiosity overruled my technophobia. I was hoping this book would answer questions such as how stress aggravates so many eruptions and what gives with delusional parasitosis.

I was wrong. Maybe I should have been forewarned by the title.

I’m pretty sure I know what “skin” means, although after reading the chapter on psychoanalysis, even on that point I’m a bit disoriented. There is never a specific definition of “psyche”: are we talking about a tangible set of neurons or an ineffable spirit? The uneven quality of the individual chapters is annoying. Frequent redundancy suggests that none of the authors read any chapter other than the one he or she had personally written. Given the numerous misspellings, typographical errors, and (to be charitable) nonstandard English, I sometimes wondered if they read even that.

Enough of generalities. Chapter 2, “Psoriasis and Stress: A Review,” is nothing more than an exercise in cutting and pasting abstracts from previously published papers. The authors make no effort to synthesize their disparate collection into a meaningful whole, nor do they reconcile contradictory findings.

In Chapter 3, “Acne Vulgaris: Psychological State,” there is the transparently obvious, “We need to remember that the face is the most conspicuous part of our appearance,” and the totally obscure, “the biopsychosocial model takes into account factors such as social support and psychological stress as well as factors relating to physiological disorders or the presence of viruses” (emphasis mine).

Chapter 4, “Body Dysmorphic Disorder—Quick Guide to Diagnosis and Treatment,” contains one of the most obtuse sentences in this oftentimes difficult book: “many patients do not show habituation to mirroring, possibly explained by the decreased set-shifting capacity and impaired visual and emotional process resulting in frontostriatal systems unable to inhibit subcortical areas.”

Chapter 5, “Skin Picking Disorders and Dermatitis Artefacta,” reveals this book’s existential flaw when it states, “where possible, patients with SPD/Acne excoriee should be managed in a dedicated psychodermatology clinic.” Chapter 10, “Building a Psychodermatology Clinic,” explicitly concedes that such clinics are practical only within academic centers. Where does that leave a reader who is in private practice and for whom a psychiatry rotation is just a distant or repressed memory?

Chapter 6, “Understanding the Challenges in Management of Delusional Infestations,” offers practical treatment options for these extremely challenging patients.

As alluded to previously, Chapter 9, “Psychoanalysis in Psychodermatological Diseases,” left me feeling unhinged.

Qui bono? Anyone attached to a psychodermatology clinic will probably find this book unnecessary. Conversely, a typical dermatologic practice would be hard pressed to find the time for (or, quite frankly, absorb the unreimbursed costs of ) most of this book’s recommendations. The authors rightfully emphasize how crucial it is to be sensitive to the emotional, dare I say “psychic,” burdens of skin diseases. There is recognition that not only can psychologic factors affect the skin, but skin conditions can also have a profound impact on one’s sense of self and well-being.

This far-from-perfect book provides a useful reminder that we treat people not skin eruptions.

Reviewed by Mark Bernhardt, MD, Private Practice, 1601 East Broward Boulevard, Fort Lauderdale, FL 33301 Address for Correspondence: Mark Bernhardt, MD, Private Practice, 1601 East Broward Boulevard, Fort Lauderdale, FL 33301 • E-mail: cheesedb@aol.com

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Book Review

Molecular Mechanisms of Skin Aging and Age-Related Diseases Quan T., ed. Molecular Mechanisms of Skin Aging and AgeRelated Diseases. Boca Raton, FL, CRC Press, Taylor & Francis Group, 2016: 263 pp, $169.96 hardcover, $139.97 e-book “Youth is wasted on the young.”

This quote, probably based on the words of George Bernard Shaw, reminds us that youth is fleeting and gone before we grasp its significance. Then we age and become older. Can the aging process be slowed down? So far, there is no magical fountain of youth that can reverse all the effects of time and restore our childhood look and youthful vigor. Medicine, however, is making progress with a better understanding of the complexities of the human aging process. This knowledge may help us to find better ways to improve human longevity and the quality of life during later years.

Molecular Mechanisms of Skin Aging and Age-Related Diseases provides a superb review of recent progress in understanding the molecular mechanism of human skin aging. The book consists of 12 chapters written by 27 authors from all over the world. The information provided is comprehensive but easy to follow with the accompanying figures and chapter conclusions.

The study of skin aging is important, because skin appearance helps define whether one looks young or old. In addition, as noted in a fascinating chapter entitled “Aging Skin: A Window to the Body,” the skin can be considered a “keyhole” in observing the aging process of the whole organism. Clinically, aged skin is recognized by the appearance of wrinkles, sagging, age spots, and dryness, with many of the chapters elaborating on the pathology and molecular features of aging skin. I was awed by those chapters.

Aging skin, on a microscopic and molecular level, looks like a nuclear wasteland. There is collagen fragmentation and impaired dermal fibroblast function, accompanied by epidermal barrier

impairment and skin dryness. There is also mitochondrial DNA common deletion that occurs in the aging of human skin connective tissue. All of this just begins to scratch the surface of what goes wrong during the skin aging process on a molecular level. With all these molecular abnormalities going on, can we really hope to stop the aging process? The answer, I think, will not come through some magical revelation; rather, progress in the fight against aging will occur in smaller steps by using basic research to develop rational therapies that better treat and prevent age-related skin problems.

The book briefly mentions Hutchinson-Gilford progeria, a rare genetic disease with clinical features of premature aging. Impressive progress has already been made in unraveling the genetic defect in progeria and in instituting beneficial therapy for children suffering from this disorder. Readers may be interested to learn about a new condition, not discussed in the book, known as “syndrome X,”1 where children remain physically and cognitively similar to an infant or toddler despite increasing age. The amazing contrast between progeria, in which the aging process dramatically speeds up, and syndrome X, in which children seem to remain ageless, is most striking. These two seemingly opposite clinical disorders suggest that there exists a certain “relativity” to the human aging process that could, one day, be manipulated to slow down human aging and forestall its deleterious effects upon the body.

This book provides a nice overview of what is meant by the terms “intrinsic aging” and “extrinsic aging,” as well as a useful summary of skin conditions found in elderly patients and their clinical management.

Reference 1 Walker RF, Liu JS, Peters BA, et al. Epigenetic analysis of children who seem to be evading aging. Aging.

2015;7:334–339.

Reviewed by Leonard J. Hoenig, MD, Private Practice, 601 North Flamingo Road #201, Pembroke Pines, FL 33028 • E-mail: gooddocljh@gmail.com

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