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Chinese Society of Dermatology

Chinese Society of Dermatology

Lebanese Dermatological Society

Belarusian Society of Dermatovenereologists and Cosmetologists

Lebanese Dermatological Society

Belarusian Society of Dermatovenereologists and Cosmetologists

North American Clinical Dermatologic Society

The Dermatologic & Aesthetic Surgery International League

ORIGINAL CONTRIBUTION Serum Antibodies to Melanocytes in Patients With Vitiligo Are Predictors of Disease Progression

Jimenez-Brito, de-La-Peña, Pérez-Romano, and Ruiz-Argüelles

REVIEW Inflammatory Lipid Mediators in Common Skin Diseases Kutlubay, Tüzün, Wolf, and Engin

Self-Assessment Examination Lambert

DEPARTMENTS PERILS OF DERMATOPATHOLOGY Benign Metastasis?! What an Oxymoron! Singh, John, and Lambert

NEW THERAPY UPDATE GARDASIL 9 (Human Papillomavirus 9-Valent Vaccine, Recombinant)

Gupta, MacLeod, and Abramovits

THE HEYMANN FILE Paraneoplastic Systemic Sclerosis: Focus on Anti-RNA Polymerase III Antibodies Heymann

The Dermatologic & Aesthetic Surgery International League

African Association for Dermatology

African Association for Dermatology

January/February 2016 • Volume 14 • Issue 1

January/February 2016 • Volume 14 • Issue 1 SOCIETY HIGHLIGHTS OF EDITORIAL THE 56TH ANNUAL MEETING The Power of One (I Matter…Please OF THE NORTH AMERICAN Report Me): The Case Study CLINICAL DERMATOLOGIC Petronic-Rosic SOCIETY A Tale of Four Cities: May 12–24, COMMENTARY 2015, Reykjavik, Amsterdam, Chikungunya Rotterdam, and Copenhagen Sehgal, Riyaz, and Parish

North American Clinical Dermatologic Society

Berger

PHOTO CAPSULE CREST Syndrome Kumar and Das

INFECTIOUS DISEASE CAPSULE It’s Not Always What It Seems: Necrotizing Fasciitis Mimicking Angioedema Warren, Droz, Wimalawansa, Mancho, and Bernstein

case studies Tenosynovial Giant Cell Tumor in the Dermis of the External Auditory Meatus Maghari, Zaleski, Jow, and Lambert

Addisonian-Like Hyperpigmentation as an Indicator of Uncontrolled Congenital Adrenal Hyperplasia

Tender Cystic Structure on the Back in an Infant Channual, Fleming, and Wu

Postherpetic Nevocentric Erythema Multiforme Sutton, Sutton, and Smith

CORRESPONDENCE Facial Cutaneous Angiosarcoma With Eyelid Involvement Benmously, Zaouak, Hammami, Koubaa, Debbiche, and Fenniche

Palmar Acral Fibrokeratoma—A Rare Entity Kulkarni, Chhabra, and Prabha

Primary Localized Cutaneous Amyloidosis and Human Leukocyte Antigen A and -B in a Chinese Population Cao, Shen, Tan, Ren, and Tey

BOOK REVIEW Handbook of Systemic Drug Treatment in Dermatology, Second Edition Heymann

Patel, Newman, and Norton

Palmoplantar Keratoderma as a Variant of Lichen Planus

Sehgal, Aggarwal, Syed, Rasool, Verma, and Sharma

Use of Oral Polypodium Leucotomos Extract in Chronic Photoinduced Hypersensitivity Dermatitis Luber, Calame, and Jacob

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TABLE OF CONTENTS January/February 2016 • Volume 14 • Issue 1

EDITORIAL

The Power of One (I Matter…Please Report Me): The Case Study ................................................................. 9

Vesna Petronic-Rosic, MD, MSc

COMMENTARy Chikungunya ............................................................................................................................................... 12

Virendra N. Sehgal, MD; Najeeba Riyaz, MD; Lawrence Charles Parish, MD, MD(Hon)

ORIGINAL CONTRIBUTION

Serum Antibodies to Melanocytes in Patients With Vitiligo Are Predictors of Disease Progression ............. 17

Gustavo Jimenez-Brito, MD; Eduardo Garza-de-La-Peña, MD; Beatriz Pérez-Romano, MSc; Alejandro Ruiz-Argüelles, MD

REVIEW

Inflammatory Lipid Mediators in Common Skin Diseases ............................................................................ 23

Zekayi Kutlubay, MD; Yalçın Tüzün, MD; Ronni Wolf, MD; Burhan Engin, MD

Self Assessment Examination ..................................................................................................................... 28

W. Clark Lambert, MD, PhD

Departments B:11”

T:10.75”

S:10.25”

Perils of Dermatopathology

W. Clark Lambert, MD, PhD, Section Editor

Benign Metastasis?! What an Oxymoron! ..................................................................................................... 29

Parmvir Singh, BS; Ann M. John, BA; W. Clark Lambert, MD, PhD

New therapy update

William Abramovits, MD; Aditya K. Gupta, MD, PhD, FRCPC, Section Editors

GARDASIL 9 (Human Papillomavirus 9-Valent Vaccine, Recombinant) ....................................................... 33

Aditya K. Gupta, MD, PhD, FRCPC; Melissa A. MacLeod, MSc; William Abramovits, MD

The Heymann File

Warren R. Heymann, MD, Section Editor

Paraneoplastic Systemic Sclerosis: Focus on Anti-RNA Polymerase III Antibodies ...................................... 39

Warren R. Heymann, MD

Society Highlights of the 56th Annual Meeting of the North American Clinical Dermatologic Society

A Tale of Four Cities: May 12–24, 2015, Reykjavik, Amsterdam, Rotterdam, and Copenhagen .................... 41

Robert S. Berger, MD

Photo Capsule

CREST Syndrome ....................................................................................................................................... 43

Piyush Kumar, MD; Anupam Das, MD

1


TABLE OF CONTENTS January/February 2016 2016 •• Volume Volume 14 14 •• Issue Issue 11 January/February

Infetious Disease Capsule

It’s Not Always What It Seems: Necrotizing Fasciitis Mimicking Angioedema ............................................ 45

Whittney A. Warren, DO; Nicole C. Droz, MD; Sunishka M. Wimalawansa, MD, MBA; Salim N. Mancho, MD; Jack M. Bernstein, MD

case studies

Vesna Petronic-Rosic, MD, MSc, Section Editor

Tenosynovial Giant Cell Tumor in the Dermis of the External Auditory Meatus ........................................... 48

Amin Maghari, MD; Theresa A. Zaleski, MSIV; Tiffany Jow, MSIII; W. Clark Lambert, MD, PhD

Addisonian-Like Hyperpigmentation as an Indicator of Uncontrolled Congenital Adrenal Hyperplasia ........ 53

Forum B. Patel, MD; Sabrina A. Newman, MD; Scott A. Norton, MD, MPH

Palmoplantar Keratoderma as a Variant of Lichen Planus .......................................................................... 56

Virendra N. Sehgal, MD; Ashok Aggarwal, MD; Nazim Hussain Syed, MD; Farhan Rasool, MD (Russia); Prashant Verma, MD; Sonal Sharma, MD

Use of Oral Polypodium Leucotomos Extract in Chronic Photoinduced Hypersensitivity Dermatitis............. 62

Adam J. Luber, MD; Antoanella Calame, MD; Sharon E. Jacob, MD

Tender Cystic Structure on the Back in an Infant.......................................................................................... 65

Stephanie Channual, MD; Kristy Fleming, MD; Jashin J. Wu, MD

Postherpetic Nevocentric Erythema Multiforme........................................................................................... 68

Elizabeth Sutton, BA; Stephanie Sutton, MD; Christopher J. Smith, MD

CORRESPONDENCE

Snejina Vassileva, MD, PhD, Section Editor

Facial Cutaneous Angiosarcoma With Eyelid Involvement............................................................................. 71

Rym Benmously, MD; Anissa Zaouak, MD; Houda Hammami, MD; Wafa Koubaa, MD; Achraf Debbiche, MD; Samy Fenniche, MD

Palmar Acral Fibrokeratoma—A Rare Entity ................................................................................................ 73

Sandeep Kulkarni, MBBS, DNB, MNAMS; Namrata Chhabra, MBBS, MD; Neel Prabha, MBBS, MD

Primary Localized Cutaneous Amyloidosis and Human Leukocyte Antigen A and -B in a Chinese Population...................................................................................................................................... 75

Taige Cao, MBBS; Meixin Shen, PhD; Virlynn Tan, Msc; Ee Chee Ren, PhD; Hong Liang Tey, MBBS, FRCP(Edin)

book review

Jennifer L. Parish, MD, Section Editor

Handbook of Systemic Drug Treatment in Dermatology, Second Edition...................................................... 78

Warren R. Heymann, MD

2


January/February 2016

Volume 14 • Issue 1

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. 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.

MANAGING EDITOR Marla Kipp marla@skinmedjournal.com

COPYEDITOR Elizabeth Holcomb eholcomb@skinmedjournal.com

MEDIA WEB DIRECTOR Joan Osgoodby joan@skinmedjournal.com

Composition Paul Bennett paul@skinmedjournal.com

Publishing PUBLISHER Art Kalaka

Associate Publisher James R. Adams jadams@skinmedjournal.com

Corporate President Arthur Kalaka akalaka@skinmedjournal.com

Copyright: © 2016 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.

Chief Executive Officer Jo-Ann Kalaka-Adams jadams@skinmedjournal.com

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

Chinese Society of Dermatology

Lebanese Dermatological Society

Belarusian Society of Dermatovenereologists and Cosmetologists

North American Clinical Dermatologic Society

African Association for Dermatology

The Dermatologic & Aesthetic Surgery International League

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SKINmed. 2016;14:000–000

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January/February 2016

Volume 14 • Issue 1

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

Andrew P. Lazar, MD Washington, DC

Noah Scheinfeld, MD, JD New York, NY

Robert L. Baran, MD Cannes, France

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

Jasna Lipozencic, MD, PhD Zagreb, Croatia

Virendra N. Sehgal, MD

Ada Lo Schiavo, MD Naples, Italy

Charles Steffen, MD Oceanside, CA

Anthony V. Benedetto, DO Philadelphia, PA

Anthony A. Gaspari, MD Baltimore, MD

Brian Berman, MD, PhD Miami, FL Mark Bernhardt, MD Ft. Lauderdale, FL

Henry H.L. Chan, MB, MD, PhD, FRCP Hong Kong, China Joel I. Cohen, MD Engelwood, CO Noah Craft, MD, PhD, DTMH Torrance, CA Natalie M. Curcio, MD, MPH Nashville, TN Ncoza C. Dlova, MBChB, FCDerm Durban, South Africa Richard L. Dobson, MD Mt Pleasant, SC

George M. Martin, MD Kihei, HI

Michael H. Gold, MD Nashville, TN

Jack M. Bernstein, MD Dayton, OH Sarah Brenner, MD Tel Aviv, Israel

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

Michael Geiges, MD Zurich, Switzerland

Marc S. Micozzi, MD, PhD Rockport, MA

Orin M. Goldblum, MD Indianapolis, IN

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

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 Rochester, MN

Camila K. Janniger, MD Englewood, NJ

Donald Rudikoff, MD New York, NY

Abdul-Ghani Kibbi, MD Beirut, Lebanon

Robert I. Rudolph, MD Wyomissing, PA

William H. Eaglstein, MD Menlo Park, CA Charles N. Ellis, MD Ann Arbor, MI

SKINmed. 2016;14:5

5

Delhi, India

Alexander J. Stratigos, MD Athens, Greece James S. Studdiford III, MD Philadelphia, PA Robert J. Thomsen, MD Los Alamos, NM 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

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INDICATION AND USAGE Enstilar® (calcipotriene and betamethasone dipropionate) Foam is indicated for the topical treatment of plaque psoriasis in patients 18 years of age and older. Apply Enstilar® to affected areas once daily for up to 4 weeks. Patients should discontinue use when control is achieved. Instruct patients not to use more than 60 g every 4 days. IMPORTANT SAFETY INFORMATION For topical use only. Enstilar® is not for oral, ophthalmic, or intravaginal use. Instruct patients to avoid use on the face, groin, or axillae, or if atrophy is present at the treatment site, and not to use with occlusive dressings, unless directed by a physician. The propellants in Enstilar® are flammable. Instruct patients to avoid fire, flame, or smoking during and immediately after using this product. Hypercalcemia and hypercalciuria have been observed with use of Enstilar®. If hypercalcemia or hypercalciuria develop, patients should discontinue treatment until parameters of calcium metabolism have normalized. Topical corticosteroids can produce reversible hypothalamicpituitary-adrenal (HPA) axis suppression with the potential for glucocorticosteroid insufficiency. Risk factors include use of high-potency topical corticosteroids, use over a large surface area or on areas under occlusion, prolonged use, altered skin barrier, liver failure, and use in pediatric patients. If HPA axis suppression is documented, gradually withdraw the drug, reduce the frequency of application, or substitute with a less potent steroid. Systemic effects of topical corticosteroids may also include Cushing’s syndrome, hyperglycemia, and glucosuria. Use of more than one corticosteroid-containing product at the same time may increase total systemic corticosteroid exposure. Adverse reactions reported in <1% of subjects treated with Enstilar® in clinical trials included application site irritation, application site pruritus, folliculitis, skin hypopigmentation, hypercalcemia, urticaria, and exacerbation of psoriasis. Patients who apply Enstilar® to exposed skin should avoid excessive exposure to either natural or artificial sunlight, including tanning booths, sun lamps, etc. You may wish to limit or avoid use of phototherapy in patients who use Enstilar®. There are no adequate and well-controlled studies of Enstilar® in pregnant women. Enstilar® should be used during pregnancy only if the potential benefit to the patient justifies the potential risk to the fetus. Because many drugs are excreted in human milk, caution should be exercised when Enstilar® is administered to a nursing woman. Do not use Enstilar® on the breast when nursing. The safety and effectiveness of Enstilar® in pediatric patients have not been studied. Please see Brief Summary on following page. *Must be 18 years of age or older to be eligible. For specific eligibility requirements and program restrictions, visit www.enstilar.com or call 1-855-772-7224. Reference: 1. Enstilar® [prescribing information]. Parsippany, NJ: LEO Pharma Inc.; October 2015.

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Enstilar ® (calcipotriene and betamethasone dipropionate) Foam, 0.005%/0.064% for topical use Initial U.S. Approval: 2006 BRIEF SUMMARY: Please see package insert for full Prescribing Information. INDICATIONS AND USAGE Enstilar ® (calcipotriene and betamethasone dipropionate) Foam is indicated for the topical treatment of plaque psoriasis in patients 18 years of age and older. CONTRAINDICATIONS None. WARNINGS AND PRECAUTIONS Flammability The propellants in Enstilar ® Foam are flammable. Instruct the patient to avoid fire, flame, and smoking during and immediately following application. Hypercalcemia and Hypercalciuria Hypercalcemia and hypercalciuria have been observed with use of Enstilar ® Foam. If hypercalcemia or hypercalciuria develop, discontinue treatment until parameters of calcium metabolism have normalized. The incidence of hypercalcemia and hypercalciuria following Enstilar ® Foam treatment of more than 4 weeks has not been evaluated. Effects on Endocrine System Systemic absorption of topical corticosteroids can produce reversible hypothalamic-pituitary-adrenal (HPA) axis suppression with the potential for clinical glucocorticosteroid insufficiency. This may occur during treatment or upon withdrawal of the topical corticosteroid. Factors that predispose a patient to HPA axis suppression include the use of high-potency steroids, large treatment surface areas, prolonged use, use of occlusive dressings, altered skin barrier, liver failure, and young age. Evaluation for HPA axis suppression may be done by using the adrenocorticotropic hormone (ACTH) stimulation test. If HPA axis suppression is documented, gradually withdraw the drug, reduce the frequency of application, or substitute with a less potent corticosteroid. Systemic effects of topical corticosteroids may also include Cushing’s syndrome, hyperglycemia, and glucosuria. Pediatric patients may be more susceptible to systemic toxicity due to their larger skin surface to body mass ratios. Use of more than one corticosteroid-containing product at the same time may increase total systemic corticosteroid exposure. Allergic Contact Dermatitis Allergic contact dermatitis has been observed with topical calcipotriene and topical corticosteroids. Allergic contact dermatitis to a topical corticosteroid is usually diagnosed by observing a failure to heal rather than a clinical exacerbation. Corroborate such an observation with appropriate diagnostic patch testing. Risks of Ultraviolet Light Exposures Patients who apply Enstilar ® Foam to exposed skin should avoid excessive exposure to either natural or artificial sunlight, including tanning booths, sun lamps, etc. Physicians may wish to limit or avoid use of phototherapy in patients who use Enstilar ® Foam. ADVERSE REACTIONS 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. The rates of adverse reactions given below were derived from three randomized, multicenter, prospective vehicle and/or active-controlled clinical trials in subjects with plaque psoriasis. Subjects applied study product once daily for 4 weeks, and the median weekly dose of Enstilar ® Foam was 24.8 g. Adverse reactions reported in <1% of subjects treated with Enstilar ® Foam included: application site irritation, application site pruritus, folliculitis, skin hypopigmentation, hypercalcemia, urticaria, and exacerbation of psoriasis. Postmarketing Experience Because adverse 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. Postmarketing reports for local adverse reactions to topical steroids include atrophy, striae, telangiectasia, dryness, perioral dermatitis, secondary infection, and miliaria.

USE IN SPECIFIC POPULATIONS Pregnancy Teratogenic Effects: Pregnancy Category C There are no adequate and well-controlled studies in pregnant women. Pregnant women were excluded from the clinical studies conducted with Enstilar ® Foam. Enstilar ® Foam should be used during pregnancy only if the potential benefit to the patient justifies the potential risk to the fetus. Animal reproduction studies have not been conducted with Enstilar ® Foam. Enstilar ® Foam contains calcipotriene that has been shown to be fetotoxic and betamethasone dipropionate that has been shown to be teratogenic in animals when given systemically. Nursing Mothers Systemically administered corticosteroids appear in human milk and can suppress growth, interfere with endogenous corticosteroid production, or cause other untoward effects. It is not known whether topically administered calcipotriene or corticosteroids could result in sufficient systemic absorption to produce detectable quantities in human milk. Because many drugs are excreted in human milk, caution should be exercised when Enstilar ® Foam is administered to a nursing woman. Instruct the patient not to use Enstilar ® Foam on the breast when nursing. Pediatric Use Safety and effectiveness of the use of Enstilar ® Foam in pediatric patients have not been studied. Because of a higher ratio of skin surface area to body mass, children under the age of 12 years are at particular risk of systemic adverse effects when they are treated with topical corticosteroids. They are, therefore, also at greater risk of HPA axis suppression and adrenal insufficiency with the use of topical corticosteroids. Cushing’s syndrome, linear growth retardation, delayed weight gain, and intracranial hypertension have been reported in pediatric patients treated with topical corticosteroids. Local adverse reactions including striae have been reported with use of topical corticosteroids in pediatric patients. Geriatric Use Of the total number of subjects in the controlled clinical studies of Enstilar ® Foam in plaque psoriasis, 97 were 65 years or older, while 21 were 75 years or older. No overall differences in safety or effectiveness of Enstilar ® Foam were observed between these subjects versus 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. PATIENT COUNSELING INFORMATION [Advise the patient to read the FDA-approved patient labeling (Patient Information and Instructions For Use)] Inform patients of the following: • Instruct patients to shake before use. • Instruct patients not to use more than 60 g every 4 days. • Discontinue therapy when control is achieved unless directed otherwise by the physician. • Avoid use of Enstilar ® Foam on the face, underarms, groin or eyes. If this medicine gets on face or in mouth or eyes, wash area right away. • Wash hands after application. • Do not occlude the treatment area with a bandage or other covering unless directed by the physician. Instruct the patients not to use other products containing calcipotriene or a corticosteroid with Enstilar ® Foam without first talking to the physician. • Instruct patients who use Enstilar ® Foam to avoid excessive exposure to either natural or artificial sunlight (including tanning booths, sun lamps, etc.). Physicians may wish to limit or avoid use of phototherapy in patients who use Enstilar ® Foam. • Enstilar ® Foam is flammable; avoid heat, flame, or smoking when applying this medication. •The foam can be sprayed holding the can in any orientation except horizontally. Manufactured by: Colep Laupheim GmbH & Co. KG Fockestraße 12 88471 Laupheim Germany (DE)

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LEO, the LEO Lion Design, and Enstilar are registered trademarks of LEO Pharma A/S. ©2015 LEO Pharma Inc. All rights reserved. November 2015 MAT-01533


January/February 2016

Volume 14 • Issue 1

Editorial

The Power of One (I Matter…Please Report Me): The Case Study Vesna Petronic-Rosic, MD, MSc “The best teaching of medicine is that taught by the patient.”––Sir William Osler (1849–1919)

I

n the era of “self ” when “GenMe” is expressing distinct preferences about everything from compensation to worklife balance to having a personal impact, the drive toward evidence-based medicine is drowning the individual for the good of the collective. It is a peculiar dichotomy. On the one hand, individual stories like that of Mark Zuckerberg and Bill Gates are revered and idolized, while, on the other hand, individual case reports of novel or exceptional medical occurrences are marginalized and deemed unworthy.

So, why have case reports been losing the battle to the new millennium? This is, at least partly, the result of the effect of impact factors. Journal Citation Reports provides quantitative tools for ranking, evaluating, categorizing, and comparing journals. The impact factor is one of these; it is a measure of the frequency with which the “average article” in a journal has been cited in a particular year or period. In market research, the impact factor provides quantitative evidence for editors and publishers for positioning their journals in relation to the competition—especially others in the same subject category, in a vertical (in order of rank) rather than a horizontal (intradisciplinary) comparison. Because case reports may not receive high numbers of citations, many journals have opted not to publish them. Those that do often restrict the frequency with which they may appear in the print run, because this has an adverse effect on the journal’s impact factor. Others have resorted to “spin-offs” that publish case reports only, with a fee that is unattainable for many would-be contributors. Then there are journals that will only publish case reports in e-format, while still requiring a subscription for access to the content.

The Scenario B:11 in

T:10 .75 in

S:10 in

Case reports provide important and detailed information about an individual. Such information can often be lost in research studies, where individual results are aggregated. They can serve as an early warning signal of the adverse effects of new medications or the presentations of new and emerging disease. The detailed findings can illuminate the possible pathogenesis of a disease or an adverse effect.1 In the age of personalized medicine, there is an ever present need for case reports to illustrate unique, novel, and unusual findings. Accurate recounting of clinical experience continues to be essential to the progress of medicine. It stimulates thought, brings about new ideas, and triggers discussions and investigations that lead to better outcomes.

Hope Springs Eternal Wouldn’t it be nice if the impact factor of a journal were measured by how many times a contribution was retrieved rather than cited? As practicing clinicians, we have all found relief in finding that one case report that mirrors the patient we have in the examination room. The case report may just prove to the insurance company that there is precedent for an off-label use of a medication in a patient who has failed all traditional modalities.

Case reports are the cornerstones of medical progress, as they are the most sensitive way of reporting novelty. A case report can change clinical practice. After all, AIDS was first reported as an account of five cases.2 Likewise, recognition of the link between administration of thalidomide to mothers and malformations in their babies was triggered by the report of a particular case.3

How are we to learn of a new disease or an as-yet unreported side effect of a novel therapeutic agent if not through case reports?

From the Section of Dermatology, The University of Chicago Pritzker School of Medicine, Chicago, IL Address for Correspondence: Vesna Petronic-Rosic, MD, MSc, Associate Professor of Dermatology, The University of Chicago Pritzker School of Medicine, 5841 South Maryland Avenue, Chicago, IL 60637 • E-mail: vrosic@medicine.bsd.uchicago.edu

SKINmed. 2016;14:9–10

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January/February 2016 Where will the ideas for research and clinical trials originate if we have no avenue for tracking down that first reported case? Case reports are invaluable tools for the progression of the science of medicine and often the only means of communicating progress in the diagnosis and management of rare and/or orphan diseases. Case reports are those little steps that will lead to the leap.4

Editorial dotal, to serve as a pillar for progress in the field. It is just as important as a review, original contribution, or any contribution that a journal has accepted for publication. References 1 Kidd M, Hubbard C. Introducing journal of medical case reports. J Med Case Rep. 2007;1:1. 2 Centers for Disease Control and Prevention (CDC). Pneumocystis pneumonia––Los Angeles. MMWR Morb Mortal Wkly Rep. 1981;30:250–252.

Conclusions

3 Speirs AL. Thalidomide and congenital abnormalities. Lancet. 1962;1:303–305.

Whether labeled Case Study, Photo Capsule, another Capsule, Letter to the Editor, or Correspondence, the case report must endure as a published piece of scientific evidence, albeit anec-

4 Petronic-Rosic V. O case report, where art thou? Skinmed. 2002;1:16–17.

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The Power of One (I Matter…Please Report Me): The Case Study


January/February 2016

Volume 14 • Issue 1

COMMENTARY

Chikungunya Virendra N. Sehgal, MD;1 Najeeba Riyaz, MD;1 Lawrence Charles Parish, MD, MD(Hon)2

C

through bites of Aedes mosquitoes, the main vector being Aedes aegypti.6,7 More recently, Aedes albopictus has emerged as an important vector.1 It has been imported through used tires and ornamental plants.8

Indian Scenario

CKG shows secular, cyclic seasonal trends. Epidemics are characterized by explosive outbreaks alternating with spells of complete absence of disease for several years. A complex interplay of factors, namely susceptibility of mosquito and humans to the virus, mosquito breeding, vector density, and ability of the vector to transmit the disease, determine the pattern of the disease.

hikungunya (CKG) is an arboviral disease that is transmitted by Aedes mosquitoes. It is typically an acute illness characterized by fever, skin eruption, and incapacitating polyarthralgia.1 It is a disease specific to tropical areas but is geographically restricted, and outbreaks are relatively uncommon. It is a self-limiting viral infection that is rarely fatal.2 It has become increasingly prominent due to re-emerging epidemics and is marked by its rapid onset, a multitude of clinical manifestations, and associated morbidity.

Kolkota3 recorded the first outbreak from India in 1963–1964, followed by Chennai in 1965.4 In 1973, a major outbreak in Barsi, Maharashtra, affected almost one third of the population. Subsequently, CKG seemed to have vanished from the Indian subcontinent until its resurgence1 in Karnataka and Andhra Pradesh in 2005, precisely 32 years later.1 The reason for the disappearance could be the decrease in viral activity or loss of its pathogenic potential. During the outbreaks, nearly 1.4 million cases were reported among 210 districts. There was yet another epidemic in 2008, affecting millions of people in South India. In 2009 in Calicut, another city in the south, thousands of people were affected by outbreaks, which caused myriads of cutaneous manifestations and debilitating polyarthralgia.5 Epidemiology The chikungunya virus is an insect-borne virus, of the genus Alphavirus. It is a class 4 arbovirus (Ar-arthropod, bo-borne) belonging to the Togaviridae family of the genus Alphavirus, consisting of a linear, positive-sense, approximately 1.8-kb single-stranded ribonucleic acid molecule, a 60-to 70-nm diameter capsid, and a phospholipids envelope.1 CKG generally spreads

Clinical Connotations CKG is identified by a triad comprising typical fever, arthralgia, and dermatitis. Joints are severely affected, and the skin is only mildly affected. Occasionally, a pruritic eruption develops in the course of the first 3 days of infection.9 It arises as a flush over the face and neck, ultimately evolving to macular and/or maculopapular dermatitis, lasting 1 to 5 days, that may later fade or desquamate.10 Several inflammatory cutaneous vascular responses are known to occur in CKG. They are characterized by facial flush,11 transient nasal erythema,11 localized erythema, swelling of pinnae mimicking the Milian’s scar sign,5 erythema and edema of Bacillus Calmette-Guérin (BCG), pre-existing scars, striae resembling the scar phenomenon of sarcoidosis,5 pedal edema/lymphedema in acral distribution,5 and erysipelas-like erythema.5 Leg ulcers, targetoid, toxic epidermal necrolysis–like (TEN)5 (Figure 1), and purpuric lesions, as well as fixed-drug eruption,12 can also occur. Desquamation of palms and soles,5 xerosis,14 acquired ichthyosis, photosensitivity,5 and lichenoid eruption are some

From the DermatoVenereology (Skin/VD) Center, Sehgal Nursing Home, Panchwati-Delhi, Professor & Head Department of Dermatology, Government Medical College, Calicut Kerala, South India;1 and the Department of Dermatology and Cutaneous Biology and the Jefferson Center for International Dermatology, Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia, PA2 Address for Correspondence: Virendra N. Sehgal, MD, FNASc, FAMS, FRAS (Lond), DermatoVenerology (Skin/VD) Center, Sehgal Nursing Home, A/6 Panchwati, Delhi-110 033 (India) • E-mail: drsehgal@ndf.vsnl.net.in

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Figure 1. Chikungunya: toxic epidermal necrolysis depicting blistering and pigmentation.

of its other features. Vesiculobullous lesions constitute 8.2% of cases.5 In the Calicut series, 7 infants presented with spotty, discrete, and confluent charred macules; flaccid bullae; and peeling resembling TEN.5 Mucosal lesions occur in 15% to 18% of CKG patients,5,14 lasting for 7 to 10 days and subsiding completely, thereafter. A high incidence of genital ulcers has been recorded.5,11,15 Penoscrotal/vulval ulcerations may develop 2 to 6 weeks after the onset of fever5 and/or during the acute illness.11 Nail manifestations include black lunulae, diffuse and longitudinal melanonychia, leukonychia, onychomedesis, and subungual hemorrhage.5 Psoriasis, psoriatic arthritis, lichen planus, pityriasis rosea, pityriasis alba, stasis dermatitis, pemphigus vulgaris, and herpes zoster5,11 can be precipitated by CKG. A lepra (type 1) reaction may occur for the first time following CKG.5 Results include frecklelike, confetti-like, and melasma-like brownish black centrofacial pigmentation,5,11,16 in addition to flagellate and Addisonian-type pigmentation.5 The peculiar pigmentation of the nose (Figure 2), a salient feature termed the “chik sign,” was seen the in Calicut study,5 which has a tendency to persist for 3 to 6 months. This sign may help in its retrospective diagnosis. SKINmed. 2016;14:12–15

Figure 2. Chikungunya: displaying a peculiar pigmentation on and around the nose: the “chik sign.”

Systemic Features of CKG Persistent crippling arthritis,17 higher incidence of neurologic complications,18 and a variety of mucocutaneous manifestations are its outstanding systemic features.5 Polyarthralgia, affecting the fingers, wrists, toes, ankles, and knee joints, usually lasts for 1 to 10 days;18,19,20 whereas, its neurologic complications are encephalitis, myelopathy, peripheral neuropathy, myopathy, and transverse myelitis. Ocular manifestations21 are characterized by uveitis, episcleritis, iridocyclitis, optic neuritis, sixth nerve palsy, retrobulbar neuritis, keratitis, central retinal artery occlusion, retinal detachment, and secondary glaucoma. Hematologic changes include lymphocytosis and thrombocytopenia. Miscarriages and neonatal infections can occur. Mortality is generally due to neurologic complications and hepatitis. Typically, mortality associated with CKG is caused by neurologic complications and hepatitis.20 Diagnosis Enzyme-linked immunosorbent assay (ELISA) may detect IgM and IgG antibodies within 2 to 3 days. IgM antibody levels may be highest in the course of 3 to 5 weeks after the onset of illness and may persist for about 8 weeks. False-positive results may occur as a result of related viruses, such as O’nyong’nyong and Semliki Forest virus.22

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IgM antibody capture ELISA (MAC-ELISA), is the most sensitive serologic assay.23 Results may be obtained within 2 to 3 days. Indirect ELISA, based on antigen detection, is not only confirmatory, but is also useful in the prodromal and subclinical stages. It has higher sensitivity than antibody detection.24 Virus isolation provides the most definitive diagnosis.22 Reverse transcriptase-PCR (RT-PCR), using nested primer pairs, helps to amplify specific components capsid (c), envelope (E2), and part of the envelope (E1). RT-PCR may be positive for the chikungunya virus in plasma, cerebrospinal fluid, and placenta. Another simple, rapid, and cost-effective isothermal gene amplification reverse transcription loop-isothermal amplification (RT-LAMP) helps in early detection and quantification of viral genomes in acute-phase serum samples.25 Prevention and Control

1 Mohan A, Kiran DH, Manohar IC, Kumar DP. Epidemiology, clinical manifestations and diagnosis of chikungunya fever: lessons learned from the reemerging epidemic. Indian J Dermatol. 2010;55:54–63. 2 World Health Organization Regional Office for SouthEast Asia. Chikungunya fever: a re-emerging disease in Asia. 2008. 3 Sarkar JK, Chatterjee SN, Chakravarthy SK. Haemorrhagic fever in Calcutta: Some epidemiological observations. Indian J Med Res. 1964;52:651–659. 4 Thiruvengadam KV, Kalyanasundaram V, Rajgopal J. Clinical and pathological studies in chikungunya fever in Madras city. Indian J Med. 1965;53:729–744. 5 Riyaz N, Riyaz A, Rahima A, et al. Cutaneous manifestations of Chikungunya during a recent epidemic in Calicut, North Kerala, South India. Indian J Dermatol Venereol Leprol. 2010;76:671–676. 6 Jeandel P, Josse R, Durand JP. Exotic viral arthritis: role of alphavirus. Med Trop (Mars). 2004;64:81–88.

Prevention of CKG epidemics by adequate vector control measures at the individual and community levels is of paramount importance. The proximity of mosquito vector breeding sites to human habitation is a significant risk factor for CKG. Prevention and control rely heavily on reducing the number of natural and artificial water-filled container habitats that support breeding of mosquitoes.26

7 Zeller HG. Dengue, arbovirus, and migrations in the Indian Ocean. Bull Soc Pathol Exot. 1998;91:56–60. 8 Knudsen AB. Global distribution and continuing spread of Aedes albopictus. Parassitologia. 1995;37:91–97. 9 Kannan M, Rajendran R, Sunish TP, et al. A study on Chikungunya outbreak during 2007 in Kerala South India. Indian J Med Res. 2009;129:311–315.

Long-sleeved clothing and trousers minimize skin exposure to vectors. Garments should be treated with mosquito repellents, such as pyrethroids.27 Insecticide-treated mosquito nets, mosquito coils, or insecticide vaporizers may reduce indoor biting. Mosquito nets on windows and doors will keep mosquitoes out of the house. It is considered a re-emerging, usually self-limiting, viral infection, that is rarely fatal.2 Although specifically a tropical disease, it is geographically restricted, and outbreaks are relatively uncommon. Treatment There are no specific antiviral agents for CKG. Because it is selflimiting, therapy is symptomatic with paracetamol or nonsteroidal anti-inflammatory drugs.3 Hydroxychloroquine is also useful for the viral arthropathy.28 Mucocutaneous lesions are managed with antihistamines and soothing agents. Persistent hyperpigmentation is treated with hydroquinone and topical steroids. Photoprotection and sunscreens may be advised. Several vaccines are undergoing trial, including a live attenuated vaccine and a DNA candidate vaccine.29,30 SKINmed. 2016;14:12–15

References

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10 Bandyopadhyay D, Ghosh SK. Mucocutaneous features of Chikungunya fever: a study from an outbreak in West Bengal, India. Int J Dermatol. 2008;47:1148–1152. 11 Inamdar AC, Palit A, Sampagavi NV, Raghunath S, Deshmukh NS. Cutaneous manifestations of Chikungunya fever: observations made during a recent outbreak in South India. Int J Dermatol. 2008;47:154–159. 12 Prashant S, Kumar AS, Basheeruddin DD, Chowdhary TN, Madhu B. Cutaneous manifestations in patients suspected of Chikungunya disease. Indian J Dermatol. 2009;54:128–131. 13 Pakran J, George M, Riyaz N, et al. Purpuric macules with vesiculobullous lesions: a novel manifestation of Chikungunya. Int J Dermatol. 2011;50:61–69. 14 Bandyopadhyay D, Ghosh SK. Mucocutaneous manifestations of Chikungunya fever. Indian J Dermatol. 2010;55:64–67. 15 Valamparambil JJ, Chirakkarot S, Letha S, Jayakumar C, Gopinathan KM. Clinical profile of Chikungunya in infants. Indian J Pediatr. 2009;76:151–155. 16 Shivakumar V, Rajendra O, Rajkumar V, Rajasekhar TV. Unusual facial melanosis in viral fever. Indian J Dermatol. 2007;52:116–117. 17 Mohan A, Sharma SK. In: Singal RK, ed. Medicine Update. Mumbai: Association of Physicians of India; 2007:634–638. 18 Chandak NH, Kashyap RS, Kabra D, et al. Neurological complications of chikungunya virus infection. Neurol India. 2009;57:177–180.

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19 Suryawanshi SD, Dube AH, Khadse RK, et al. Clinical profile of chikungunya fever in patients in tertiary care centre in Maharashtra, India. Indian J Med Res. 2009;129:438–441.

25 Parida MM, Santhosh SR, Dash PK, Laxman Rao KV. Rapid and real-time assay for the detection and quantification of Chikungunya virus. Future Virology. 2008;3:179– 192.

20 Lakshmi V, Neeraja M, Subalaxmi MV, et al. Clinical features and molecular diagnosis of chikungunya fever from South India. Clin Infect Dis. 2008;46:1436–1442.

26 Centers for Disease Control and Prevention (CDC) (September 29, 2006). Chikungunya fever diagnosed among international travelers—United States, 2005-2006. MMWR Morb Mortal Wkly Rep. 2006;55:1040–1042.

21 Mahesh G, Giridhar A, Shedbelle A, Kumar R, Saikumar SJ. A case of bilateral presumed chikungunya neuroretinitis. Indian J Ophthalmol. 2009;57:148–150. 22 Ravi V.Re-emergence of chikungunya virus in India. Indian J Med Microbiol. 2006;24:83–84. 23 Grivard P, Le Roux K, Laurent P, et al. Molecular and serological diagnosis of chikungunya virus infection. Pathol Biol (Paris). 2007;55:490–494. 24 Kashyap RS, Morey SH, Ramteka SS, et al. Diagnosis of chikungunya fever in an Indian population by an indirect enzyme linked immunosorbent assay protocol based on an antigen detection assay: a prospective cohort study. Clin Vaccine Immunol. 2010;17:291–297.

27 Chikungunya—fact sheet. European Centre for Disease Prevention and Control. January 23, 2008. Accessed March 25, 2008. 28 Hochedez P, Jaureguiberry S, Debruyne M, et al. Chikungunya infection in travelers. Emerg Infect Dis. 2006;12:1565–2567. 29 Edelman R, Tacket CO, Wasserman SS, et al. Phase II safety and immunogenicity study of live chikungunya virus vaccine TSI-GSD-218. Am J Trop Med Hyg. 2000;62:681–685. 30 Muthumani K, Lankaraman KM, Laddy DJ, et al. Immunogenicity of novel consensus-based DNA vaccines against Chikungunya virus. Vaccine. 2008;26:5128–5134.

Pogonology

Courtesy of Diana Garrisi, PhD, London, UK SKINmed. 2016;14:12–15

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January/February 2016

Volume 14 • Issue 1

Original contribution

Serum Antibodies to Melanocytes in Patients With Vitiligo Are Predictors of Disease Progression Gustavo Jimenez-Brito, MD;1 Eduardo Garza-de-La-Peña, MD;2 Beatriz Pérez-Romano, MSc;2 Alejandro Ruiz-Argüelles, MD2 Abstract The aim of this study was to investigate whether the amount of serum antibodies to melanocyte antigens could predict clinical activity or disease progression in patients with vitiligo. A solid-phase enzyme immunoassay was developed to semiquantitate serum antibodies to a human melanocyte extract and was used in 127 patients, 93 of whom showed clinical progression of the disease, while the remaining 34 were quiescent. Results showed different values for clinical sensitivity and specificity depending on the cutoff level for decision, but the overall performance of the test was adequate and supported statistical significance to predict clinical activity/progression or quietness of the disease process. The test might prove useful in deciding the indication and aggressiveness of immunosuppressive therapy in patients with vitiligo. Previous findings suggest that melanocyte-specific antibodies might play a pathogenetic role in the depletion of melanocytes, which characterizes this disorder, and that this depletion might be due to apoptosis following antibody internalization. (SKINmed. 2016;14:17–21)

A

lthough it is known that melanocyte-specific antibodies can be found in the serum of the majority of patients with vitiligo, the diagnosis of this condition does not need to rely on this or other laboratory tests.1–11 Since melanocyte-antibodies have been implicated to bear a pathogenetic role in melanocyte depletion,1 it is possible that disease progression is related to their titers. The purpose of this study was to investigate whether the relative amount of serum antibodies to melanocyte antigens was associated with clinical activity or progression of the disease. A solid-phase enzyme-linked immunosorbent assay (ELISA) was developed and used to search for melanocyte serum antibodies in a large group of patients with vitiligo, and a statistical association was found between the arbitrary concentration of such antibodies and the clinical activity or progression of the disease. Moreover, an increase in the amount of melanocyte-specific antibodies behaves as a reliable predictor of disease worsening.

Material and Methods

Patients A total of 127 patients with vitiligo were investigated in this prospective study. All patients were seen consecutively in the dermatology practice of one of the authors (G.J-B.) and the only exclusion criteria were the presence of other autoimmune diseases and/or the usage of systemic immunosuppressant drugs or chemotherapy. These patients were seen on at least two occasions 30 to 60 days apart. Patients who presented with new achromic maculae in the second or consecutive visits or who showed Koebner response were classified as having progressive or active disease, while those who showed no changes or clinical improvement of the disease during the observation period were classified as quiescent cases. A single blood sample for melanocyteantibody testing was obtained during the first visit, ie, before knowing the clinical progression of the disease.

From the Colegio Poblano de Dermatología,1 Laboratorios Clínicos de Puebla, and the Faculty of Medicine,2 Universidad Popular Autónoma del Estado de Puebla, Puebla, México Address for Correspondence: Alejandro Ruiz-Argüelles, MD, Laboratorios Clínicos de Puebla, Diaz Ordaz 808, Puebla, PUE 72530 México • E-mail: aruiz@clinicaruiz.com

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Samples

Statistical analysis

After obtaining written consent, a fasting peripheral blood sample was taken from each patient into sterile serum separating tubes (BD Systems, Franklin Lakes, NJ). Serum was separated by centrifugation, aliquoted, and stored at –20°C until tested.

Descriptive statistics, statistic t test for independent unpaired observations, and receiver operating characteristic (ROC) curve were calculated with the aid of MedCalc statistical software (Mariakerke, Belgium).

Detection of antibodies

Results

A crude protein extract was obtained from the skin of the areola of a mastectomy surgical specimen to be used as the antigenic substrate. The extract was prepared basically through mechanical disruption/mincing of the tissue in the presence of 0.01 M phosphate buffer, Ph 7.1 containing 1% 2-mercaptoethanol, and its suitability to be used in immunoassays had been previously validated by showing that serum samples from 14 patients with active vitiligo were capable to stain at least 6 different molecular weight proteins by Western blots.1 These proteins, ranging from 40 kDa to 175 kDa, correspond to the antigens that have been most commonly described as involved in this disease.1 After adjusting the protein concentration to 3 g/mL by dilution in carbonate buffer (0.15 M Na2CO3, 0.34 M NaHCO3), it was used to coat flat-bottomed 96 well microtiter ELISA plates (NUNC Brand Products, Rochester, NY) by overnight incubation at room temperature in a humid chamber. Uncoated sites of the plates were blocked by the addition of bovine serum albumin diluted (1%) in phosphate buffer saline pH 7.4 (PBS) for 30 minutes at 37°C. Serum samples diluted 1:10 in PBS were added into duplicate wells and allotted to react for 60 minutes at 37°C. When the incubation time was completed, the plates were washed 3 times with PBS additioned with 0.5% tween 20 (ALDRICH Chemical Company, Inc, Milwaukee, WI) (PBS-Tween). An alkaline phosphatase-labelled goat anti-human IgG antiserum (SIGMA) was added and incubated for 60 minutes more. At the end of this period, plates were washed 3 more times with PBS-Tween before the addition of a solution of p-nitro-phenyl-phosphate (SIGMA) in 0.1 M glycine and 1 mM magnesium chloride, which was followed by the addition of a 3N NaOH aqueous solution 30 minutes later to stop the enzyme reaction. The color developed in each well of the plate was read at 405 nm with the aid of an automated ELISA microplate reader (Biotek Instruments, Winooski, VT) and the absorbance/optical density (OD) of duplicates was averaged. Arbitrary antibody units were estimated as the differences of OD of each patient’s sample minus the median OD value obtained from the assay of serum samples from 10 healthy individuals that were simultaneously analyzed in each run.

Patients were classified according to the aforementioned clinical criteria into 93 cases showing clinical activity or progression of the disease, while the remaining 34 were considered to be quiescent at the time of the study. Figure 1 depicts the individual values of arbitrary antibody units in both groups. The arithmetic mean (and 95% confidence intervals) were 1.2092 (1.0917–1.3267) and 0.8326 (0.7263–0.9390) in the active and quiescent groups, respectively, and this difference proved to be statistically significant (Test statistic t=3.656; P=.0004).

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Despite the overlapping of several individual results from both groups of patients, the ROC curve and analysis showed that the test may be useful in discriminating patients with progressive disease, which could prove particularly useful in patients who are seen for the first time and the decision to prescribe local or systemic immunosuppressive therapy is made. Figure 2 depicts the ROC curve and the Table shows the values of sensitivity and specificity for active/progressive disease at different cutoff levels. The intra-assay and interassay reproducibility of the test was found to be 6% and 9%, respectively. The latter is affected by the change of lot of the protein extract; hence, it is necessary to re-establish blank values when using a new batch of the extract. Inasmuch as the arbitrary antibody “units” are defined by a daily intra-assay subtraction, the clinical decision values are not affected by this variation. Discussion Vitiligo in its primary form, ie, non-associated to other autoimmune diseases, is a very benign disease that, by itself, does not endanger the patient’s life.2–14 The emotional and psychologic impact of this disorder, however, might be overwhelming in a large proportion of the estimated 65 million people affected by the disease worldwide.2–4 Rationale for treatment should be supported by a better understanding of the physiopathology of this disorder, while timeliness to onset of treatment should be based on objective evidence.1,6,12 It has been repeatedly reported that serum antibodies to melanocyte-derived antigens such as antibodies to surface cell pigmented cell antigens, intracellular pigment cell antigens, and nonpigmented cell antigens, are present in a large proportion of patients with vitiligo, and it has Serum Antibodies to Melanocytes in Patients With Vitiligo


January/February 2016

ORIGINAL CONTRIBUTION

Figure 2. Receiver operating characteristic curves showing the performance of the relative amount of melanocyte antibodies to detect activity of the disease in terms of specificity and sensitivity. The solid line indicates the estimated value, while the dotted lines indicates the 95% confidence intervals.

Figure 1. Individual results of melanocyte-antibodies in 93 clinically active vitiligo patients and 34 cases of quiescent disease. Results are expressed in the Y axis as arbitrary units (see text).

Table. Sensitivity and Specificity of Serum Melanocyte Antibodies to Define Activity/Progression of Vitiligo at Different Cutoff Values Cutoff Value

Sensitivity

95% CI

Specificity

95% CI

>0.8

81.7

72.4–89.0

52.9

35.1–70.2

>0.82

76.3

66.4–84.5

52.9

35.1–70.2

>0.84

74.2

64.1–82.7

55.9

37.9–72.8

>0.86

73.1

62.9–81.8

55.9

37.9–72.8

>0.89

73.1

62.9–81.8

64.7

46.5–80.2

>0.9

72.0

61.8–80.9

64.7

46.5–80.2

>0.92

72.0

61.8–80.9

73.5

55.6–87.1

Abbreviation: CI, confidence interval.

been shown that tyrosinase (and tyrosinase-related proteins 1 and 2), a key enzyme in melanin synthesis located in melanosomes, serves as a self-antigen recognized by vitiligo antibodies, as well.1,2,5,7,14,29 Most physicians who deal with patients with vitiligo agree, however, that the diagnosis of this disease does not need to rely on the demonstration of such antibodies since the percentage of vitiligo patients with antibodies to these antigens has varied greatly and their pathogenic role remains undefined.29 Nevertheless, our previous findings1 as well as others’6,15 suggest that melanocyte-specific antibodies might play a pathogenetic role SKINmed. 2016;14:17–21

in the depletion of melanocytes, which characterizes this disorder, and that this depletion might be due to apoptosis following antibody internalization.1,16–25 Accordingly, the relative amounts of serum melanocyte-antibodies should be higher in patients with active/progressive disease than in individuals with quiescent forms of the disorder, and this expectation prompted us to search for an association between these two parameters, aiming at a simple laboratory test that could be used to aid the decision of prescribing immunosuppressive therapy in patients with active progressive disease. A simple enzyme immunoassay was developed to test this hypothesis, and the results indicate that although there was an im-

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portant overlap of individual results from patients with progressive and quiescent disease, the overall performance of the test to define clinical progression is convenient and supported by statistical significance. As is the case with most quantitative or semiquantitative laboratory tests, the cutoff value for decision plays for sensitivity against specificity, and vice versa; therefore, the decision level should be individualized and should take into consideration all clinical facts and circumstances. Purification of one or several protein fractions from the crude skin extract, or the use of recombinant antigens, seems to be the logical next step to improve the performance and usefulness of this simple test,26–28 and experiments toward this goal are currently being undertaken in our laboratory; however, preliminary data show that the proportion of patients who bear serum antibodies to isolated purified antigens is lower than that reacting with the crude extract, in spite of having active or quiescent disease. We have previously shown with the use of western blots that most but not all (71%) of serum samples from patients with vitiligo react with a 75 kDa protein—most likely tyrosinase— while reactivity with other proteins, eg, a 40 kDa band (Vit-40), might be as low as 21%.1 Conclusions The finding of a “clinically useful” antigen to define disease activity appears to be more complicated than originally thought, and perhaps the use of a pool of purified antigens may prove to be the best approach. The satisfactory clinical utility of the current test and the benefit that patients might receive from timely onset of therapy encouraged us to publish the findings described herein. References 1 Ruiz-Argüelles A, Jimenez-Brito G, Reyes-Izquierdo P, Pérez-Romano B, Sánchez-Sosa S. Apoptosis of melanocytes in vitiligo results from antibody penetration. J Autoimmun. 2007;29:281–286. 2 Kovacs SO. Vitiligo. J Am Acad Dermatol. 1998;38:647–666. 3 Porter J, Beuf AH, Lerner AB, Nordlund JJ. Response to cosmetic disfigurement: patients with vitiligo. Cutis. 1987;39:493–494. 4 Porter JR, Beuf AH, Nordlund JJ, Lerner AB. Psychological reaction to chronic skin disorders: A study of patients with vitiligo. Gen Hosp Psychiatry. 1979;1:73–77. 5 Van den Wijngaard R, Wankowicz-Kalinska A, Pals S, Weening J, Das P. Autoimmune melanocyte destruction in vitiligo. Lab Invest. 2001;81:1061–1067. 6 Kemp EH, Waterman EA, Weetman AP. Immunological pathomechanisms in vitiligo. Exp Rev Mol Med. 2001;3:1–22. 7 Uchi H, Stan R, Turk MJ, et al. Unraveling the complex relationship between cancer immunity and autoimmu-

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nity: lessons from melanoma and vitiligo. Adv Immunol. 2006;90:215–241. 8 Halder RM, Grimes PE, Cowan CA, et al. Childhood vitiligo. J Am Acad Dermatol. 1987;16:948–954. 9 Park S, Albert DM, Bolognia JL. Ocular manifestations of pigmentary disorders. Dermatol Clin. 1992;10:609– 622. 10 Ochi Y, DeGroot LJ. Vitiligo in Graves’ disease. Ann Intern Med. 1969;71:935–940. 11 Gould IM, Gray RS, Urbaniak SJ, Elton RA, Duncan LJ. Vitiligo in Diabetes mellitus. Br J Dermatol. 1985;113:153– 155. 12 Cato AC, Wade E. Molecular mechanisms of antiinflammatory action of glucocorticoids. Bioessays. 1996;18:371–378. 13 Hill LL, Shreedhar VK, Kripke ML, Owen-Schaub LB. A critical role for Fas ligand in the active suppression of systemic immune responses by ultraviolet radiation. J Exp Med. 1999;189:1285–1294. 14 Song YH, Connor E, Li Y, et al. The role of tyrosine in autoinmune vitiligo. Lancet. 1994;344:1049–1052. 15 Gulhar A, Zelickson B, Ulman Y, Etzioni A. In vivo destruction of melanocytes by the IgG fraction of serum from patients with vitiligo. J Invest Dermatol. 1995;105:683– 686. 16 Kanduc D, Mittelman A, Serpico R, et al. Cell death: apoptosis versus necrosis (review). Int J Oncol. 2002;21:165– 170. 17 Alarcón-Segovia D, Ruíz-Argüelles A, Llorente L. Broken dogma: penetration of autoantibodies into living cells. Immunol Today. 1996;17:163–164. 18 Ruíz-Argüelles A. Flow cytometry in the clinical laboratory. Principles, applications and problems. Clin Chim Acta. 1994:211:S13–S27. 19 Ruiz-Argüelles A, Rivadeneyra-Espinoza L, Alarcón-Segovia D. Antibody penetration into living cells: pathogenic, preventive and immunotherapeutic implications. Curr Pharm Des. 2003;9:1881–1887. 20 Ruiz-Argüelles A, Pérez-Romano B, Llorente L, AlarcónSegovia D, Castellanos JM. Penetration of anti-DNA antibodies into immature live cells. J Autoimmun. 1998; 11: 547–556. 21 Portales-Pérez D, Alarcón-Segovia D, Llorente L, et al. Penetrating Anti-DNA monoclonal antibodies induce activation of human peripheral blood mononuclear cells. J Autoimmun. 1998;11:563–571. 22 Rivadeneyra-Espinoza L, Ruiz-Argüelles A. Cell-penetrating anti-native DNA antibodies trigger apoptosis through both the neglect and programmed pathways. J Autoimmun. 2006;26:52–56. 23 Shcmidt-Acevedo S, Perez-Romano B, Ruiz-Argüelles A. LE cells result from phagocytosis of apoptotic bodies induced by antinuclear antibodies. J Autoimmun. 2000;15:15–20. 24 Alarcón-Segovia D, Llorente L, Ruiz-Argüelles A. The penetration of autoantibodies into cells mat induce tolerance to self by apoptosis of autoreactive lymphocytes

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and cause autoimmune disease by dysregulation and/or cell damage. J Autoimmun. 1996;9:295–300.

from patients with vitiligo. Int J Dermatol. 2000;39:840– 843.

25 Alarcón-Segovia D, Ruiz-Argüelles A, Llorente L. Antibody penetration into living cells iii. Effect of anti-ribonucleoprotein IgG on the cell cycle of human peripheral blood mononuclear cells.” Clin Immunol Immunopathol. 1982;23:22–26.

28 Park YK, Kim NS, Hann SK, Im S. Identification of autoantibody to melanocytes and characterization of vitiligo antigen in vitiligo patients. J Dermatol Sci. 1996;11:111– 120

26 Baharav E, Merimski O, Shoenfeld Y, Zigelman R, Gilbrud B. Tyrosinase as an autoantigen in patients with vitiligo. Clin Exp Immunol. 1996;105:84–88.

29 Alikhan A, Felsten LM, Daly M, Petronic-Rosic V. Vitiligo: a comprehensive overview Part I. Introduction, epidemiology, quality of life, diagnosis, differential diagnosis, associations, histopathology, etiology, and work-up. J Am Acad Dermatol. 2011;65:473–491.

27 Rocha IM, Oliveira LJ, De Castro LC, et al. Recognition of melanoma cell antigens with antibodies present in sera

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 37)

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Inflammatory Lipid Mediators in Common Skin Diseases Zekayi Kutlubay, MD;1 Yalçın Tüzün, MD;1 Ronni Wolf, MD;2 Burhan Engin, MD1 Abstract Lipid mediators play a main role in the complex course of cutaneous inflammatory reactions. They regulate a wide spectrum of cellular processes such as cell proliferation and apoptosis. In the early phase of inflammation, excessive amounts of lipid mediators are released and play a major role in the pathogenesis of skin diseases. Recent data suggest that lipid mediators are able to interfere with the pathogenesis of certain dermatologic diseases, seriously affecting patient quality of life. Acne, psoriasis, and atopic dermatitis are specific examples of skin diseases that may respond to treatment with medication affecting these metabolic pathways. The authors briefly present the current knowledge about the role of lipid mediators in common skin pathologies. (SKINmed. 2016;14:23–27)

L

ipid mediators (eicosanoids), platelet-activating factor, and phospholipase A2 (PLA2) are generated during cutaneous inflammation, but their contributions to certain dermatologic diseases remain to be established. Lipid mediators regulate many important aspects of immunity such as cytokine production, antibody formation, differentiation, cell proliferation, migration, and antigen presentation. Cells of the innate immune system, including tissue macrophages, sentinel dendritic cells, and neutrophils, are major producers of lipid mediators, which act locally at nanomolar concentrations on target cells. It has become increasingly apparent that lipid mediators and their receptors cooperate with other signaling molecules, particularly cytokines and chemokines. Inflammation triggers production of lipid mediators, which are involved in the pathogenesis of various pathologies related to immune functions. Pharmacologic inhibition of lipid mediator biosynthesis might, however, simultaneously be beneficial and deleterious.1

The PLA2 produces free fatty acids such as arachidonic acid (AA) and the phospholipid backbone. Eicosanoids (such as prostaglandins, prostacyclin, thromboxane, and leukotrienes [LTs]) are produced through the cyclooxygenase (COX) and lipoxygenase (LO) pathways.

Infiltrating leukocytes and platelets are the principal source of increased levels of lipid mediators in some inflammatory diseases. Abnormalities of organ function initially attributed to the cause of inflammation or to hydrolases and free radicals produced by infiltrating leukocytes may be reversed in some instances by inhibition of both COX and LO activities without reductions in the number of inflammatory cells. Pharmacologic agents that inhibit lipid mediators have been developed. Systemic administration of several such drugs have had beneficial effects and topical application has led to improvements in atopic dermatitis and psoriasis. These agents should be used in conjunction with inhibitors of other types of mediators to obtain the greatest effectiveness.2 Atopic Dermatitis Atopic dermatitis (AD) is a chronic inflammatory skin disease that is associated with a history of atopy. An elevation of serum IgE levels is frequently detected and skin reactions can be demonstrated with common allergens. AD affects more than 10% of children in most countries. Approximately 60% to 70% of patients with mild to severe dermatitis will continue to experience symptoms into adulthood. Intense pruritus is the main symptom of the disease. The condition has a course marked by exacerbations and remissions. Patients with AD may have disrupted sleep

From the Istanbul University, Cerrahpasa Medical Faculty, Department of Dermatology, Istanbul, Turkey;1 and the Dermatology Unit, Kaplan Medical Center, Rechovot, Israel2 Address for Correspondence: Zekayi Kutlubay, MD, Istanbul University, Dermatology Department, Cerrahpasa Medical Faculty, Istanbul, 34098, Turkey • E-mail: zekayikutlubay@hotmail.com

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with consequent daytime fatigue and compromised school and work quality.3 Nearly 80% of children with AD eventually develop allergic rhinitis or asthma. AD can be classified as “mixed” (cases associated with respiratory allergies) and “pure.” Pure AD has intrinsic and extrinsic variants. In the extrinsic type, T cells isolated from spontaneous lesions secrete interleukin (IL) 4 and skin-derived T lymphocytes express more IL-13. The fact that anti-LT agents may be more successful in the treatment of the extrinsic subgroup has been suggested because of the different immunopathogenesis.4

In addition, epidermal edema, marked dilatation of the capillaries, and activation of endothelial cells are determined in histopathologic examination of the tissue after injection. Cysteinyl LTs produce a more pronounced effect, while LTB4 injections tend to cause more perivenular neutrophil infiltration. This suggests that LTB4 may be a more important mediator in the manifestations of AD than previously thought.10 Although LTB4 can produce a wheal-and-flare response, the relatively low number of neutrophils in lesional skin suggests that cys-LTs could primarily mediate the characteristic erythema. Skin of atopic patients was found to produce LTC4, which increased almost 5-fold with antigen challenge, and, in a similar study, the increase in LTC4 coincided with late-phase erythema and swelling.8

An elevation in circulating eosinophils is determined in most patients. These signs are the result of an abnormal shift to a Th2 phenotype causing increased T-cell production of the eosinophilopoietic cytokine, IL-5, and the cytokines IL-4 and IL-13 that promote IgE biosynthesis. Cytokines, genetic differences in cytokine (IL-4) production, pharmacologic factors (monocytes with increase cAMP phosphodiesterase activity), and antigenpresenting cells (increased IgE-bearing Langerhans cells with a role in cutaneous allergen presentation to Th2 cells) are factors that contribute to Th2 cell development in AD.5 Both IL-4 and IL-13 are the only cytokines that promote an increase in IgE production. IL-5 induces eosinophilopoiesis, activation and chemotaxis.4 The fact that enhanced LT production plays a role in the pathogenesis of AD has been reported. LTs are divided into two groups according to their chemical structure: those with a sulfur linkage (cysteinyl LTs: LTC4, LTD4, LTE4) and those without (LTB4). The cysteinyl LTs affect skin blood vessels and increase vascular permeability. The most important sources of LTs are eosinophils, basophils, and mast cells. Epidermal cells can transform neutrophil-derived LTA4 into LTB4 and LTC4. LTC4 has been found in the skin of patients with AD using the suction blister technique.6 Patients with AD have activated circulating basophils and increased basophil releasability of LTC4. Cysteinyl LT released from basophils and eosinophils isolated from patients with AD is increased compared with that in healthy controls.7 The exact mechanism of action of LT receptor antagonists in AD is unknown; however, a pathophysiologic rationale for the use of cysLT receptor blockers in the treatment of AD has been reported.4 An increase in both spontaneous and stimulated release of LTB4 and LTC4 was detected in the circulating leukocytes of patients with AD.8 Epidermal cells can make both LTB4 and cys-LTs via transcellular metabolism of LTA4. In skin chambers on patients with AD, antigen challenge significantly increased LTB4 release.9 Studies examining the local effects of LTs through intracutaneous injections have noted that wheal-and-flare reactions occur. SKINmed. 2016;14:23–27

There are at least two types of LT receptors: cysLT1 and cysLT2. LT receptor antagonists demonstrating high-affinity binding to the cysLT1 receptor are montelukast, zafirlukast, and pranlukast. They are responsible for vasodilation, plasma exudation, bronchospasm, and eosinophil recruitment. Montelukast might be a safe and effective alternative or steroid-sparing therapy in the management of patients with AD. Montelukast has been shown to decrease eosinophils by 15%.11 LTD4 stimulates proliferation of eosinophil hematopoietic progenitor cells, and this increase can be suppressed by montelukast. Zafirlukast has been shown to inhibit LTD4 and histamine-mediated cutaneous vascular permeability.4 There was a significant reduction in eosinophilic cationic protein and eosinophilic protein X levels compared with their baseline in a patient series treated with montelukast.12 When we look at clinical trials performed with either zafirlukast or montelukast for AD, a notable reduction in disease activity and alleviation of symptoms was detected in 5 of 7 trials. The results of these trials are encouraging and suggest that 5-LO pathway inhibitors are useful in the therapy of AD.13 An inhibitor of the 5-LO enzyme is zileuton, preventing the production of not only the cysteinyl LTs but also of LTB4. The production of other metabolites in the arachidonic acid cascade, including 5-HETE and 5-oxo-ETE, are blocked. This is important in AD because LTB4 and 5-oxo-ETE are chemoattractants for eosinophils. In a prospective open-label pilot study, 6 women with severe AD received 600 mg of zileuton 4 times a day for 6 weeks.14 All 6 patients experienced a significant reduction in disease dissatisfaction. There was no significant difference in the subjective report of pruritus. Zileuton was chosen for the reasons mentioned previously, namely that it can decrease levels of LTB4, whereas the LT antagonists do not. Studies in pharmacodynamics have shown that zileuton can decrease LTB4 production by 70% to 100% and that it additionally decreases the production of

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LTC4, LTD4, and LTE4. Because the LT antagonists act at the CysLT1 receptor, they do not affect LTB4 and are specific for the cysteinyl LTs. Acne Acne is a complex chronic pilosebaceous unit inflammatory disease with 4 main factors that contribute to lesion development: (1) sebaceous gland output is increased; (2) cell proliferation increases with desquamation of follicular epithelial cells that intermix with sebum to form open comedones (blackheads) and as proliferation advances, the glandular neck or infundibulum closes to form closed comedones (whiteheads); (3) Propionibacterium acnes typically settles the sebaceous duct, producing inflammatory bacterial products; and (4) perifollicular inflammation, related to erythema and the accumulation of neutrophils, macrophages, and T cells. Both LTB4 and LTC4 show a mitogenic effect on keratinocytes and may therefore participate in mediating hyperproliferation in the pilosebaceous unit. Keratinocytes express LTA4 hydrolase and can produce substantial amounts of both LTB4 and LTC4.8 Sebocytes express both 5-LO and LTA4 hydrolase.15 In patients with acne, human sebaceous glands possess the enzymatic pathway for a functional LT pathway. 5-LO overtakes the downstream AA metabolism and is responsible for the enhancement of the pathway activity in the sebaceous glands of patients with acne.16

flammatory mediators, such as LTs and prostaglandins, have been implicated in the initiation of acne lesions. As indicated previously, the most potent leucocyte chemotactic mediator is LTB4. It activates complement and induces IL-8 production by neutrophils and superoxide radicals. LTB4 may not only induce IL-8 production by macrophages, neutrophils, and lymphocytes attracted to the acne-involved sebaceous follicles and stimulate lymphocyte proliferation, but may also stimulate sebocytes to produce IL-6 and, in the presence of Ca2+, IL-8. When we inject LTB4 intradermally, it leads to the formation of transient erythema and wheal. It also provokes the local attraction of neutrophils and monocytes. Moreover, LTB4 stimulates DNA synthesis and proliferation of cultured human keratinocytes. Both latter phenomena are present in acne comedones, which is the initial acne lesion.16 Seborrhea is another major factor that contributes to the occurrence of acne lesions. Increased sebum secretion is a characteristic of patients with acne even if the amount of seborrhea is deficient. It is caused by increased sebaceous lipid synthesis and regulated by androgens and peroxisome proliferator-activated receptor (PPAR) ligands. PPAR are expressed in human sebocytes. Interestingly, LTB4 and 15-HETE were shown to be PPAR-α and -γ ligands, respectively. AA stimulates lipid synthesis in human sebocytes. Activation of PPAR-α was found to induce genes that are associated with β-oxidation and lipid catabolism. PPAR-γ activation stimulates lipogenesis.15,16

Human sebum contains triglycerides, wax esters, squalene, cholesterol esters, cholesterol, and free fatty acids. Triglycerides together with fatty acids form the predominant proportion (57.5%), followed by wax esters (26%) and squalene (12%). The least abundant lipid in sebum is cholesterol. As a result of the complex composition, different hypotheses have been formulated to explain the ultimate function of sebum. Sebaceous lipids contribute to the integrity of the skin barrier supplying the stratum corneum with hydration.17 Lipid analysis of sebum detects no free AA, but AA can be found as an esterified form within cellular membrane lipids. The PG pathway is switched on in sebaceous glands of acne-involved skin. Linoleic acid being a component of sebum in the free and esterified form can also serve as LO or COX substrates in sebaceous glands.16

Likewise, overexpression of COX-2 in the basal compartment of the epidermis of the mouse and increased PGE2 levels caused sebaceous gland hyperplasia pointing to a role of COX-2–mediated PGE2 synthesis in this process.15,16

Inflammation is one of the major etiologic factors that cause acne, the most common disease of the pilosebaceous unit. Although inflammation has been proposed to be secondary to bacterial colonization, both the detection of abundant IL-1 in comedones and the presence of lymphocytes and macrophages in early noninflammatory acne lesions18 support a major role of inflammatory signaling in acne. Beside cytokines, other in-

Pharmacologic studies also support the role for 5-LO eicosanoids in acne. Adapalene, an effective retinoid, has been shown to block the 5-LO pathway as demonstrated both in vitro and in vivo,19 and sebum production was significantly reduced in the skin of acne patients by topical ETYA, an inhibitor of LT production. Zileuton was reported in a 10-patient open-label clinical trial in acne patients for 12 weeks to be effective in reducing

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It has been demonstrated that expression and activation of COX-2 is PPAR mediated. General oxidative stressors, including lipid-oxidizing agents, have been shown to activate PPAR and to induce lipogenesis in sebocytes. All these findings allow to hypothesize that sebocytes proliferation and/or lipogenesis as well as inflammatory reactions may be regulated by PPARmediated pathways. Upregulated expression of both COX-2 and PPAR within the skin with acne support this hypothesis and helps to explain acne pathogenesis.17

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both the frequency and severity of acne lesions. A significant reduction in sebum production and in total output of sebum lipids and sebum free fatty acids were also detected. Both AA and linoleic acid stimulate lipid synthesis in human sebocytes.20 The fact that the 5-LO pathway has a major role in both seborrhea and lesion development in acne is apparent. A lower amount of linoleic acid in the sebum has been suggested to affect the composition of sphingolipids in the follicular unit. Acne patients show a decreased percentage of acyl-ceramides containing linoleic acid. Depletion of linoleic acid in sphingolipids has been hypothesized to be involved in follicular hyperkeratosis, which is a crucial event involved in the formation of comedones.17 The mechanism of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) in patients with acne seem to be related to the inhibition of neutrophil chemotaxis. A significant positive correlation between clinical acne grade and neutrophil chemotaxis has reported in some papers. This may partly explain why tetracycline, a known inhibitor of neutrophil chemotaxis, is an effective treatment for acne.21 All these findings suggest a comprehensive link between inflammation and sebogenesis supporting the definition of acne as an inflammatory disease in which lipid mediators play a central role.

sis. LTB4, LTC4, and mono-HETEs are significantly present in psoriatic lesions. Among the eicosanoid mediators, 12(R)-hydroxy-5,8,10,14-eicosatetraenoic acid (12R-HETE) is increased in psoriasis and found in psoriatic lesions at levels approximately 1000-fold greater than LTB4.23,24 Like LTB4, 12-oxo-ETE, 12(R)-HETrE, 12(R)-HETE, and 5-oxo-ETE are potent neutrophil chemotactic factors.25 Eicosanoid activity involved in the pathology of psoriasis is mediated through Cys-LT1, Cys-LT2, BLT1, and BLT2 receptors and proposed receptors for 12(R)-HETE and 5-oxo-ETE. Epidermal hyperplasia is a characteristic of psoriasis markedly enhanced by LTs in vivo. The effect of LTB4 is stereospecific, suggesting the involvement of specific LTB4-binding sites/receptors. Cys-LTs were 10-fold less potent proliferative agents than LTB4, and their effect was blocked by the Cys-LT antagonistlike FPL 55712.23 One study showed that the level of PLA2 activity is increased in the uninvolved epidermis of psoriasis.26 Another study reported that 8 of 13 psoriatic patients with fish oil–supplemented diets demonstrated mild to moderate improvement.27 Improved clinical response correlated with high EPA/DHA ratios attained in epidermal tissue specimens. No serious side effects were seen in any of the patients. The remaining 5 patients showed improvement, but this change was not rated as significant. Conclusions

Psoriasis The function of lipid mediators in psoriasis pathogenesis remains unclear. Psoriatic lesions have more elevated levels of free AA, mono-HETES, LTB4, LTC4, and LTD4 than uninvolved skin. Increased levels of PGE2 and PGF2α suggest that both the LO and CO pathways of AA metabolism in skin may be important in the pathogenesis of psoriasis. Elevated LTB4 levels are caused by polymorphonuclear leukocytes and not from the keratinocytes themselves.4 Levels of PGE and F2α are increased less than two-fold.22 Proinflammatory cytokines such as tumor necrosis factor alpha (TNF-α) and IL-6, IL-8, and IL-1b are implicated in the pathogenesis of chronic inflammatory diseases such as psoriasis. Although TNF-α plays an important role in the host-immune response, excess TNF-α contributes to many chronic inflammatory diseases. Since current therapy for chronic inflammatory conditions is often limited by side effects, there is a real medical need for new, efficient, and safe anti-inflammatory drugs.23

Substantial evidence exists that lipid mediators may be important in the pathophysiologic processes of some skin diseases, and specific inhibitors of these substances may be valuable in evaluating cutaneous inflammation. A wide variety of physiologic responses and pathologic processes are regulated by a complex family of lipid mediators. They are produced through distinct enzymatic pathways and act on target cells via specific G-protein–coupled receptors. Although originally recognized for their capacity to elicit biological responses such as vascular homeostasis, protection of the gastric mucosa, and platelet aggregation, lipid mediators are now understood to regulate immunopathologic processes ranging from inflammatory responses to chronic tissue remodeling, skin inflammation, cancer, asthma, and autoimmune disorders.

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References 1 Harizi H, Corcuff JB, Gualde N. Arachidonic-acid-derived eicosanoids: roles in biology and immunopathology. Trends Mol Med. 2008;14:461–469. 2 Goetzl EJ, An S, Smith WL. Specificity of expression and effects of eicosanoid mediators in normal physiology and human disease. FASEB J. 1995;9:1051–1058.

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3 Bender B. Psychologic dysfunction associated with atopic dermatitis. Immunol Allergy Clin North Am. 2002;22:43–54.

16 Alestas T, Ganceviciene R, Fimmel S, Müller-Decker K, Zouboulis CC. Enzymes involved in the biosynthesis of leukotriene B4 and prostaglandin E2 are active in sebaceous glands. J Mol Med. 2006;84:75–87.

4 Rackal JM, Vender RB. The treatment of atopic dermatitis and other dermatoses with leukotriene antagonists. Skin Therapy Lett. 2004;9:1–5.

17 Ottaviani M, Camera E, Picardo M. Lipid mediators in acne. Mediators Inflamm. 2010;2010:858176.

5 Leung DY. Immunopathogenesis of atopic dermatitis. Immunol Allergy Clin North Am. 2002;22:73–90.

18 Jeremy AH, Holland DB, Roberts SG, Thomson KF, Cunliffe WJ. Inflammatory events are involved in acne lesion initiation. J Invest Dermatol. 2003;121:20–27.

6 James JM, Kagey-Sobotka A, Sampson HA. Patients with severe atopic dermatitis have activated circulating basophils. J Allergy Clin Immunol. 1993;91:1155–1162.

19 Pawin H, Beylot C, Chivot M. et al. Physiopathology of acne vulgaris: recent data, new understanding of the treatments. Eur J Dermatol. 2004;14:4–12.

7 Taskapan M. Zileuton and atopic dermatitis. Ann Allergy Asth Immunol. 2001;87:162–163.

20 Zouboulis CC, Adler YD, Picardo M, Cunliffe WJ. A new concept for acne therapy: a pilot study with zileuton, an oral 5-lipoxygenase inhibitor. Arch Dermatol. 2003;139:668–670.

8 Rubin P, Mollison KW. Pharmacotherapy of diseases mediated by 5-lipoxygenase pathway eicosanoids. Prostaglandins Other Lipid Mediat. 2007;83:188–197.

21 Schaffer HK. Essential fatty acids and eicosanoids in cutaneous inflammation. Int J Dermatol. 1989;28:281–290.

9 Koro O, Furitani K, Hide M, Yamada S, Yamamoto S. Chemical mediators in atopic dermatitis: involvement of leukotriene B4 released by a type I allergic reaction in the pathogenesis of atopic dermatitis. J Allergy Clin Immunol. 1999;103:663–670.

22 Gudjonsson JE, Elder JT. Psoriasis. In: Wolff K, Goldsmith LA, Katz SI, et al, eds. Fitzpatrick’s Dermatology in General Medicine. 7th ed. New York, NY: McGraw Hill; 2008:169–193.

10 Chari S, Clark-Loeser L, Shupack J, Washenik K. A role for leukotriene antagonists in atopic dermatitis? Am J Clin Dermatol. 2001;2:1–6.

23 Khanapure SP, Garvey DS, Janero DR, Letts LG. Eicosanoids in inflammation: biosynthesis, pharmacology, and therapeutic frontiers. Curr Top Med Chem. 2007;7:311–340.

11 Braccioni F, Dorman SC, O’Byrne P, et al. The effect of cysteinyl leukotrienes on growth of eosinophil progenitors from peripheral blood and bone marrow of atopic subjects. J Allergy Clin Immunol. 2002;110:96–101.

24 Kragballe K, Desjarlais L, Voorhees JJ. Leukotrienes B4, C4 and D4 stimulate DNA synthesis in cultured human epidermal keratinocytes. Br J Dermatol. 1985;113:43– 52.

12 Erbagci Z. The leukotriene receptor antagonist montelukast in the treatment of chronic idiopathic urticaria: a single-blind, placebo controlled, crossover clinical study. J Allergy Clin Immunol. 2002;110:484–488.

25 Fretland DJ, Djuric SW. 12(R)- and 12(S)-hydroxyeicosatetraenoic acids: chemistry, biology and pharmacology. Prostaglandins Leukot Essent Fatty Acids. 1989;38:215– 228.

13 Carucci JA, Washenik K, Weinstein A, Shupack J, Cohen DE. The leukotriene antagonist zafirlukast as a therapeutic agent for atopic dermatitis. Arch Dermatol. 1998;134:785–786.

26 Forster S, Ilderton E, Summerly R, Yardley HJ. The level of phospholipase A2 activity is raised in the uninvolved epidermis of psoriasis. Br J Dermatol. 1983;108:103– 105.

14 Woodmansee DP, Simon RA. A pilot study examining the role of zileuton in atopic dermatitis. Ann Allergy Asthma Immunol. 1999;83:548–52.

27 Ziboh VA, Cohen KA, Ellis CN, et al. Effects of dietary supplementation of fish oil on neutrophil and epidermal fatty acids. Modulation of clinical course of psoriatic subjects. Arch Dermatol. 1986;122:1277–1282.

15 Koreck A, Pivarcsi A, Dobozy A, Kemeny L. The role of innate immunity in the pathogenesis of acne. Dermatology. 2003;206:96–105.

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SELF ASSESSMENT EXAMINATION W. Clark Lambert, MD, PhD Instructions for questions 1–3: For numbered item, answer the single most appropriate lettered response.

Instructions for questions 4 and 5: For each numbered item, choose as many lettered responses as apply. All, some of the answers, or none of the answers may be correct.

1. The most common disease of the pilosebaceous unit is: a. Acne. b. Alopecia areata. c. Fox–Fordyce disease. d. Kyrle disease. e. Trichotilomania. Leukotriene receptor antagonists include: Montelukast. Pranlukast. Zafirlukast. All of the above. None of the above.

3. Of the following, the one without a sulfur (cysteinyl) linkage and the most potent chemoattractant is: a. LTA4. b. LTB4. c. LTC4. d. LTD4. e. LTE4.

Lipid mediators (eicosanoids) regulate: Antibody formation. Antigen presentation. Cell proliferation. Differentiation. Cell migration.

5. Lipid mediators (eicosanoids) regulate immunopathologic processes including: a. Asthma. b. Autoimmune disorders. c. Cancer. d. Chronic tissue remodeling. e. Cutaneous (skin) inflammation.

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

2. a. b. c. d. e.

4. a. b. c. d. e.

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

Benign Metastasis?! What an Oxymoron! Parmvir Singh, BS;1 Ann M. John, BA;1 W. Clark Lambert, MD, PhD2 “If my father was alive to hear that, he’d turn over in his grave.” ––Yogi Berra

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he word metastasis is Greek, meaning “changed location.”1 In most textbooks, metastasis is synonymous with the word malignant. Benign metastasis challenges the traditional dichotomy of benign vs malignant. Benign metastasis implies normal tissue or a benign tumor spreading to lymph nodes or a distant structure. Histologically, benign tumors with definite but limited biologic aggressiveness have been documented, making determination of the prognosis difficult.1 Lesions associated with “benign metastasis” include epithelial (breast, thyroid, parathyroid, salivary gland, renal, mullerian, and decidual), mesothelial, and mesenchymal tumors.1 Many others have been documented with some discussed here. Nodular hidradenoma (NH) characteristically demonstrates nodular dermal growth without epidermal involvement. Microcyst formation and eosinophilic/clear cells are also typical (Figures 1 and 2). One theory contends that benign metastases can be explained by mechanical squeezing of neoplastic cells into the lymphatics after tumor overgrowth or trauma.1 There were eight of 214 cases of NH at St. John’s Dermatopathology Consultation Service, London, UK, described having morphologically benign NH with involvement of the lymphatics. Ki-67 staining and low proliferative rate, CD31, and podoplanin staining showed neoplastic cells in lymph vessels. All patients were treated with a conservative surgical approach. After 2 to 11 years of follow-up, none recurred or showed advancement. The authors concluded that despite lymphatic spread, histologically benign NH still had an excellent prognosis. NH can be considered benign if it lacks infiltrative growth, deep extension, necrosis, nuclear pleomorphism, and more than four mitoses/ high-power field.1

Pleomorphic salivary adenoma Pleomorphic salivary adenomas (PSAs) are the most common benign tumor of the salivary gland.2 PSAs most commonly affect the parotid gland. Histologically benign, metastatic PSAs have occasionally been reported. PSAs are composed of both epithelial and mesenchymal components. There is a report of a patient with parotid PSA and metastasis to the nasal cavity, scalp, and brain, while appearing histologically benign. This phenomenon is termed metastasizing pleomorphic adenoma. The mechanism of metastasis in this tumor has not been determined. Due to the fact that most cases occur after surgery, it is hypothesized that surgical manipulation may dislodge tumor cells into the vasculature. Another theory contends that aspiration may cause spread to the lungs. Lymphatic spread has also been described. Unlike primary PSA, benign metastases are associated with a mortality rate of 20%, pointing to aggressive biologic behavior.2 Dermatofibroma Dermatofibroma (DF) is also known as benign fibrous histiocytoma (Figure 3).3 Several histologic variants have been described.4 The cellular and aneurysmal subtypes have potential to metastasize to regional lymph nodes and the lungs.3 The following characteristics are associated with DF that metastasize: young adult age group; location on the thighs, back, and neck; and large, solitary, well-demarcated, and nonulcerated. Metastases do not display an increase in cellular atypia, mitotic rate, or pleomorphism. They are slow-growing, behaving like low-grade sarcomas. Lung metastases tend to undergo cystic changes. They occur months to years after excision of the primary tumor. One theory contends that spread may occur by direct extension. Another study reported two patients with thigh nodules and inguinal metastasis and one patient with a neck nodule with cervical

From Rutgers – New Jersey Medical School,1 and the Departments of Dermatopathology, Dermatology, and Pathology and Laboratory Medicine,2 Rutgers – 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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Figure 1. Eccrine nodular hidradenoma (hematoxylin and eosin stain, original magnification ×67.5).

Figure 3. Dermatofibroma (hematoxylin and eosin stain, original magnification ×270).

Figure 2. Eccrine nodular hidradenoma (hematoxylin and eosin stain, original magnification ×270).

metastasis.3 Another metastasis was recognized 19 years after excision of the primary lesion. These lesions were well circumscribed but nonencapsulated. The differential diagnosis for metastasizing DF includes dermatofibrosarcoma protuberans.3 SKINmed. 2016;14:29–31

Figure 4. Blue nevus (hematoxylin and eosin stain, original magnification ×270).

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Tuberous sclerosis The most common tumors in tuberous sclerosis are giant cell astrocytomas, facial angiofibromas, cardiac rhabdomyomas, and renal angiomyolipomas.5 Lymphangiomatosus (LAM) involves proliferation of smooth muscle cells in the lung and resulting cystic changes in lung parenchyma. Genetic analysis support the theory that LAM arises from metastatic spread of benign smooth muscle cells from renal angiomyolipoma. LAM is also histologically benign; however, LAM causes considerable morbidity and mortality. Interestingly, LAM mainly afflicts women.5

a result of hematogenous dissemination, perhaps caused by dislodgement during a uterine myomectomy. The metastatic lesions are well-circumscribed, bilateral, multiple, and nodular. Histologically, they lack necrosis, nuclear heterogeneity, and cellular atypia. BML must be differentiated from low-grade leiomyosarcoma, lymphangiomatosis, and pulmonary hamartoma. BML is treated with surgical resection and hormonal therapy. Investigators9 reported a case of BML with metastasis to the pelvis and lungs, with estrogen receptor positivity in the lung tissue. The patient had recurrence-free survival after 3 years of follow-up after surgical and hormonal treatment with megestrol (progesterone).

Nevi

Conclusions

The blue nevus is a proliferation of melanocytes in the dermis thought to correspond to cells in other species responsible for color change. Most are composed primarily of spindle cells (Figure 4). Cellular blue nevus is a large, dermal melanocytic proliferation composed of more cuboidal cells that may produce small, well-differentiated, and nonprogressive metastases to the marginal sinuses and regional lymph nodes.6,7 Rarely, benign metastases grow and become necrotic. These necrotic lesions should be differentiated from malignant melanoma with lymph node involvement in patients with a concomitant blue nevus. Malignant melanomas show more cellular atypia, local tissue destruction, infiltration, epidermal invasion, and necrosis. A representative patient was reported with a .7-cm nodular lesion on the right leg that spread to the inguinal lymph nodes. The patient was treated with a conservative surgical approach and remained disease free after 3.5 years of follow-up. There are many other reports of similar occurrences.6

A distinction should be considered when using terminology such as malignancy and metastasis. Metastasis implies changed location but does not speak to the potential of morbidity and mortality. We present examples of diseases that are normally regarded as benign but have shown metastatic potential with varying prognoses. Dermatopathologists should be alert for considering benign metastasis, especially when a primary malignancy cannot be found.

Benign metastases have also been reported in conjunction with congenital nevi.8 These nevus cells are believed to occur in lymph nodes caused by embolism, lymphatic spread, and abnormal embryologic migration of melanocytes from the neural crest. The presence of a congenital nevus itself is evidence of aberrant embryologic migration. Nevus cells in lymph nodes occur as nests or stands in the fibrous framework of the capsule or trabeculae. In contrast, true metastatic disease usually spreads to the subcapsular sinuses. The incidence of nevus cells in lymph nodes is between 1% and 22%. Nevus cells have only been found in superficial lymph node basins that drain the skin, not deeper basins that drain internal organs. Leiomyoma There have been about 80 reported cases of benign metastatic leiomyoma (BML).9 It consists of benign smooth muscle cells originating in the uterus but spreading elsewhere. The most common location of metastasis is the lungs. BML is believed to occur as SKINmed. 2016;14:29–31

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References 1 Stefanato CM, Ferrara G, Chaudhry IH, et al. Clear cell nodular hidradenoma involving the lymphatic system: a tumor of uncertain malignant potential or a novel example of “metastasizing” benign tumor? Am J Surg Pathol. 2012;36:1835–1840. 2 Tarsitano A, Foschini MP, Farneti P, Pasquini E, Marchetti C. Metastasizing “benign” pleomorphic salivary adenoma: a dramatic case-report and literature review. J Craniomaxillofac Surg. 2014;42:1562–1565. 3 Guillou L, Gebhard S, Salmeron M, Coindre JM. Metastasizing fibrous histiocytoma of the skin: a clinicopathologic and immunohistochemical analysis of three cases. Mod Pathol. 2000;13:654–660. 4 Parish LC, Yazdanian S, Lambert WC, Lambert PC. Dermatofibroma: a curious tumor. Skinmed. 2012;10:268–270. 5. Henske EP. Metastasis of benign tumor cells in tubeous sclerosis complex. Genes Chromosomes Cancer. 2003;38;376–381. 6 Gonzalez-Campora R, Diaz-Cano S, Vazquez-Ramirez F, et al. Cellular blue nevus with massive regional lymph node metastases. Dermatol Surg. 1996;22:83–87. 7 Lambert W, Brodkin RH. Nodal and subcutaneous cellular blue nevi: A pseudometastasizing pseudomelanoma. Arch Dermatol. 1984;120:367–370. 8 Fontaine D, Parkhill W, Greer W, Walsh N. Nevus cells in lymph nodes: an association with congenital cutaneous nevi. Am J Dermatopathol. 2002;24:1–5. 9 Wentling GK, Sevin BU, Geiger XJ, Bridges MD. Benign metastasizing leiomyoma responsive to megestrol: case report and review of the literature. Int J Gynecol Cancer. 2005;15:1213–1217.

Benign Metastasis?! What an Oxymoron!


January/February 2016

Volume 14 • Issue 1

New Therapy Update William Abramovits, MD; Aditya K. Gupta, MD, PhD, FRCPC, Section Editors

GARDASIL 9 (Human Papillomavirus 9-Valent Vaccine, Recombinant) Aditya K. Gupta, MD, PhD, FRCPC;1,2 Melissa A. MacLeod, MSc;2 William Abramovits, MD3,4,5

T

here are roughly 100 types of human papillomavirus (HPV), of which 40 are sexually transmitted and 15 are known to be high-risk variants.1 Persistent infection with high-risk HPV types can lead to cellular abnormalities, which, if left untreated, may develop into cervical, vulvar, vaginal, anal, or oropharyngeal cancer as well as genital warts and precancerous lesions.1–4 GARDASIL 9 (9vHPV; Merck Sharp & Dohme Corp, a subsidiary of Merck & Co., Inc, Whitehouse Station, NJ) is one of three HPV vaccines approved by the US Food and Drug Administration, joining GARDASIL (qHPV; Merck & Co., Inc) and CERVARIX (GlaxoSmithKline, Research Triangle Park, NC). 9vHPV was approved on December 10, 2014, and prevents HPV types 6, 11, 16, 18, 31, 33, 45, 52, and 58. In comparison, qHPV prevents HPV types 6, 11, 16, and 18, and CERVARIX prevents HPV types 16 and 18.5 9vHPV has the potential to prevent an additional 30% of highgrade cervical intraepithelial neoplasias, 20% of cervical cancers, 10% of vaginal/vulvar cancers and high-grade vaginal/vulvar intraepithelial neoplasias, and 5% of anal cancers and high-grade anal intraepithelial neoplasias when compared with qHPV.6,7 9vHPV is indicated for use in girls and women aged 9 to 26 years for the prevention of cervical, vulvar, vaginal, and anal cancer; genital warts; and several forms of intraepithelial neoplasias caused by the HPV types listed above.5 It is also indicated for use in boys aged 9 to 15 years for the prevention of anal cancer, genital warts, and anal intraepithelial neoplasia.5 It has not been shown to provide protection after disease exposure or eliminate the need for cervical cancer screening.5

9vHPV Compared With qHPV Two phase III clinical trials examined the immunogenicity and tolerability of 9vHPV compared with qHPV. The first was a randomized, double-blind, multicenter study of women aged 16 to 26 years (N=14,215).8 Participants were randomized to receive three doses of either 9vHPV (n=7106) or qHPV (n=7109) at day 1, month 2, and month 6 (dosing procedure for all trials). This study also examined efficacy, which was measured after 7 months based on a combined endpoint of cervical intraepithelial neoplasia grade 2 or 3, adenocarcinoma in situ, invasive cervical carcinoma, vulvar intraepithelial neoplasia grade 2 or 3, vaginal intraepithelial neoplasia grade 2 or 3, cervical cancer, vulvar cancer, or vaginal cancer, hereafter referred to as high-grade cervical, vulvar, and vaginal disease.5 This is the only clinical trial to date that directly examined the efficacy of 9vHPV. Efficacy in other populations is inferred by comparing immunogenicity profiles with those observed in people older than 16 years. In the modified intention-to-treat efficacy subgroup without HPV infection, the incidence of high-grade cervical, vulvar, and vaginal disease was 2.4 per 1000 person-years in the 9vHPV group compared with 4.2 per 1000 person-years in the qHPV group, resulting in an efficacy of 42.5% (Table I). The efficacy for diseases related to the nine vaccine-covered HPV types was 100% compared with 19.7% for diseases related to other HPV types. In the per-protocol efficacy population, the incidence of HPV 31-, 33-, 45-, 52-, and 58-related high-grade cervical, vulvar, and vaginal disease was 0.1 per 1000 person-years in the 9vHPV group compared with 1.6 per 1000 person-years in the

From the Department of Medicine, University of Toronto School of Medicine, Toronto, Ontario, Canada;1 Mediprobe Research Inc, London, Ontario, Canada;2 and the Department of Medicine, Baylor University Medical Center,3 the Departments of Dermatology and Family Practice, University of Texas Southwestern Medical School,4 and the Dermatology Treatment and Research Center,5 Dallas, TX Address for Correspondence: Aditya K. Gupta, 645 Windermere Road, London, Ontario, Canada N5X 2P1 • E-mail: agupta@execulink.com

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Table I. Efficacy of 9vHPV Among Girls and Women Aged 16 to 26 Years8 Endpoints

Efficacy, % (95% Confidence Interval)

Intention-to-treat population All high-grade cervical, vulvar, vaginal disease

42.5 (7.9–65.9)

Caused by HPV types 6, 11, 16, 18, 31, 33, 45, 52, and 58

100 (70.4–100)

Caused by other HPV types

19.7 (–34.5 to 52.5)

Per-protocol population (HPV types 31-, 33-, 45-, 52-, 58-related) High-grade cervical, vulvar, vaginal disease

96.7 (80.9–99.8)

Persistent infection (6 months or more)

96.0 (94.4–97.2)

Abnormal Papanicolaou test result

92.6 (89.7–94.8)

Cervical and external genital biopsy

96.9 (93.6–98.6)

Definitive therapya

87.5 (65.7–96.0)

a Included loop electrosurgical excision procedure and conization. Note: Efficacy was based on the incidence of the endpoints among women who received 9vHPV compared with those who received qHPV.

qHPV group, resulting in an efficacy of 96.7%. The incidence of persistent infection (lasting 6 months or more) was 2.1 per 1000 person-years in the 9vHPV group compared with 52.4 per 1000 person-years in the qHPV group (efficacy: 96.0%). 9vHPV efficacy was also high for patients with abnormal Papanicolaou (Pap) test results (92.6%), cervical and external genital biopsy results (96.9%), and definitive therapy (loop electrosurgical excision procedure and conization) (87.5%)5; however, the efficacy may have been underestimated as qHPV provides some cross protection against HPV types 31, 33, 45, 52, and 58. One month after the third dose, noninferiority of the immune response to 9vHPV relative to qHPV was established based on equivalent geometric mean titers (GMTs). The number of cases of infection and disease for HPV types 6, 11, 16, and 18 were also similar between groups. Almost 100% of women in the per-protocol population became seropositive for each HPV type. Women receiving 9vHPV were numerically more likely to report adverse events (AEs) related to the injection site (90.7% vs 84.9% for qHPV), including pain (89.9% vs 83.5%), swelling (40.0% vs 28.8%), erythema (34.0% vs 25.6%), and pruritus (5.5% vs 4.0%). This was expected as a result of the higher amounts of HPV virus–like particles, antigens, and amorphous aluminum hydroxyphosphate sulfate adjuvant. Systemic AEs were similar between women receiving 9vHPV and qHPV (55.8% vs 54.9%), with headache (14.6% vs 13.7%), pyrexia (5.0% vs 4.3%), nausea (4.4% vs 3.7%), dizziness (3.0% vs SKINmed. 2016;14:33–37

2.8%), and fatigue (2.3% vs 2.1%) reported. Overall, 3.3% of women receiving 9vHPV reported a serious AE compared with 2.6% of women receiving qHPV. Less than 0.1% of participants discontinued the study because of AEs. The second phase III randomized, double-blind, multicenter clinical trial examined immunogenicity and tolerability of 9vHPV (N=300) compared with qHPV (N=300) among girls aged 9 to 15 years.7,9 The GMT ratios comparing 9vHPV with qHPV for anti-HPV type 16 and anti-HPV type 18 were both noninferior. GMT ratios for anti-HPV type 6 and anti-HPV type 11 were numerically similar. Seroconversion was present in at least 99.7% of girls for each HPV type.5 Among girls receiving 9vHPV, rates of injection-site pain were similar across the three doses (around 70%), whereas injection-site swelling and injection-site erythema increased with each successive dose.5 The overall rates of injection-site AEs following any dose among girls vaccinated with 9vHPV compared with qHPV were as follows: pain (89.3% vs 88.3%), swelling (47.8% vs 36.0%), erythema (34.1% vs 29.3%), and temperature ≥100°F (6.7% vs 3.3%), respectively.9 Systemic AEs for 9vHPV reported 1 to 5 days after vaccination included pruritus (4.0%), hematoma (3.7%), hemorrhage (1.0%), induration (2.0%), warmth (0.7%), and reaction (0.3%). Systemic AEs for 9vHPV reported 1 to 15 days after vaccination included headache (11.4%), pyrexia (5.0%), and nausea (3.0%).

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9vHPV Among Boys and Girls 9 to 15 Years Compared With Women 16 to 26 Years

Table II. Adverse Events Among Girls and Women Aged 12 to 26 Years Previously Vaccinated With qHPV13

One phase III, randomized, multicenter, uncontrolled, openlabel clinical trial examined the immunogenicity and tolerability of 9vHPV among 9- to 15-year-old boys (n=669) and girls (n=1935) compared with 16- to 26-year old women (n=470).10,11 Noninferiority of the immune response was met at 4 weeks following dose 3 by comparing GMTs of participants aged 9 to 15 years with GMTs of participants aged 16 to 26 years. Seroconversion was present in more than 99% of participants for each HPV type by month 7. AEs reported by girls, boys, and women respectively were any injection-site AE (81.9%, 72.8%, and 85.4%), injection-site erythema (29.5%, 24.2%, and 28.3%), injection-site pain (80.3%, 70.2%, and 83.9%), injection-site swelling (34.7%, 26.0%, and 32.4%), any systemic AE (45.0%, 41.8%, and 57.1%), temperature ≥100°F (8.4%, 10.0%, and 8.4%), pyrexia (10.2%, 12.8%, and 9.2%), and headache (18.3%, 14.8%, and 22.3%). Overall, 0.8% of girls, 1.7% of boys, and 3.4% of women had serious AEs and one boy did not complete the study because of AEs.

Adverse Event

9vHPV (n=608), %

Saline (n=305), %

Injection-site pain

90.3

38.0

Injection-site erythema

42.3

8.5

Injection-site swelling

49.0

5.9

Temperature ≥100°F

6.5

3.0

Pruritus

7.7

1.3

Hematoma

4.8

2.3

Reaction

1.3

0.3

Mass

1.2

0.7

Headache

19.6

18.0

Pyrexia

5.1

1.6

Nausea

3.9

2.0

Dizziness

3.0

1.6

Upper abdominal pain

1.5

0.7

Influenza

1.2

1.0

9vHPV Among Men 16 to 26 Years Compared With Women 16 to 26 Years A nonrandomized, uncontrolled, multicenter study examined the immunogenicity and tolerability of 9vHPV in 16- to 26-year-old heterosexual men (n=1106) and men who have sex with men (MSM; n=313) compared with women 16 to 26 years (n=1101).12 GMTs comparing heterosexual men with women were noninferior for each HPV type at month 7 (numerically lower for MSM vs women). In all groups, more than 99% of participants underwent seroconversion. The most common injection-site AEs for men (combined) compared with women were pain (63.4% vs 82.5%), swelling (20.2% vs 37.5%), and erythema (20.7% vs 32.3%). Slightly fewer men reported any systemic AEs compared with women (37.1% vs 48.8%), including headache (7.3% vs 12.8%), pyrexia (2.4% vs 3.7%), and nausea (1.0% vs 2.9%). Overall, 1.6% of men and 2.4% of women reported a serious AE and 0.1% of men and 0.3% of women discontinued the study because of AEs. 9vHPV Among Girls and Women Previously Vaccinated With qHPV One phase III, randomized, international, placebo-controlled, double-blind clinical trial examined the tolerability and seroconversion of 9vHPV among girls and women aged 12 to 26 years who were previously vaccinated with qHPV (in the past 12 to 36 months).13 There were 608 girls and women who received 9vHPV and 305 who received a saline placebo. The most comSKINmed. 2016;14:33–37

mon AEs among girls and women receiving 9vHPV compared with placebo were injection-site pain (90.3% vs 38.0%), erythema (42.3% vs 8.5%), and swelling (49.0% vs 5.9%) (Table II). Overall, 0.5% of participants discontinued the study because of AEs. The seroconversion rate was more than 98% for all HPV types. 9vHPV Administered Concomitantly With Other Vaccines A randomized, multicenter, open-label clinical trial of 1241 boys and girls aged 11 to 15 years examined the immunogenicity and tolerability of 9vHPV given concomitantly with the meningococcal meningitis vaccine Menactra (MCV4; Sanofi Pasteur Inc, Swiftwater, PA) and the tetanus, diphtheria, pertussis vaccine Adacel (Tdap; Sanofi Pasteur Inc).14 Participants were stratified by sex and randomized into two groups. The first group (n=621) received the first dose of 9vHPV in one limb and both the MCV4 and Tdap vaccines as separate injections in the opposite limb on the same day (concomitant). The second group (n=620) received the first dose of 9vHPV in one limb on day 1 and MCV4 and Tdap 1 month later in the opposite limb (nonconcomitant). Both groups received the second dose of the 9vHPV at month 2 and the third dose at month 6. Concomitant administration of 9vHPV with MCV4 and Tdap did not interfere with the immune response of any of the vaccines com-

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pared with nonconcomitant administration. GMTs for all HPV types at month 7 were similar between the two groups, meeting noninferiority criteria, and seroconversion rates were 100% for each HPV type. All meningitis, diphtheria, tetanus, and pertussis titers were likewise noninferior. AEs were similar between the two groups, although there was more injection-site swelling (mostly mild to moderate) among participants in the concomitant group (14.4%) compared with those in the nonconcomitant group (9.4%, P=.007). Rates of injection-site erythema and pain were similar in both groups for 9vHPV and MCV4/Tdap injections, while rates of swelling were similar in both groups for MCV4/Tdap injections. Around 0.2% of participants discontinued the study because of AEs. Another randomized, open-label, multicenter study examined the immunogenicity and tolerability of 9vHPV when given concomitantly with the tetanus, diphtheria, pertussis, inactivated poliomyelitis vaccine Repevax (Tdap-IPV; Sanofi Pasteur, Lyon, France) among girls and boys aged 11 to 15 years.15 Participants were stratified by sex and assigned to two groups: the first group (n=526) received the first dose of 9vHPV in one arm and TdapIPV in the other arm on the same day (concomitant); the second group (n=528) received the first dose of the 9vHPV in one arm on day 1 and Tdap-IPV 1 month later in the other arm (nonconcomitant). Both groups received the second dose of 9vHPV at month 2 and the third dose at month 6. Noninferiority of the immune response comparing the concomitant group with the nonconcomitant group was found based on GMTs for each HPV type at 4 weeks after dose 3. Seroconversion was present in over 99% of participants. Noninferiority was also met for tetanus, diphtheria, pertussis, and poliovirus titers.

cacy was 96.7% for preventing high-grade cervical, vulvar, and vaginal disease.8 Efficacy was also high for preventing persistent infections, abnormal Pap test results, cervical and external genital biopsies, and definitive therapy. Efficacy was inferred in younger age groups and in men by examining immunogenicity. In all studies, almost 100% of participants demonstrated seroconversion for all HPV types. GMTs were consistently equivalent (noninferior) for each vaccine-covered HPV type when comparing age groups and when comparing 9vHPV with qHPV and concomitant 9vHPV administration with nonconcomitant administration. 9vHPV was shown to be safe and effective when administered concomitantly with Menactra and Adacel or Repevax.14,15 Concomitant administration with other vaccines may minimize the number of medical visits required to deliver each vaccine and improve coverage and adherence to treatment for 9vHPV. The most common AEs were injection-site pain, swelling, erythema, and headache. In summary, 9vHPV appears to be effective and well-tolerated in male and female patients aged 9 to 26 years and has the potential to improve prevention of HPV 6-, 11-, 16-, 18-, 31-, 33-, 45-, 52-, and 58-related cancers, neoplasias, and genital warts by 5% to 30% over qHPV.7

More participants in the concomitant group reported injection-site swelling from the 9vHPV injection (13.0%) than in the nonconcomitant group (8.2%, P=.011). This was also the case for the Tdap-IPV injection (39.4% vs 31.3%, P=.006). In both cases, most of the swelling was mild to moderate. Numerically more cases of injection-site erythema were reported in the concomitant group compared with the nonconcomitant group for 9vHPV (8.2% vs. 5.7%) and Tdap-IPV (26.9% vs 21.7%). Headache was the most common systemic AE related to 9vHPV injection and was numerically higher in the concomitant group than in the nonconcomitant group (25.1% vs 21.4%). No participants discontinued the study because of AEs.

References 1 National Institutes of Health. Cervical Cancer Fact Sheet. October 2010. http://report.nih.gov/nihfactsheets/viewfactsheet.aspx?csid=76. Accessed September 10, 2015. 2 Schiffman M, Castle PE, Jeronimo J, Rodriguez AC, Wacholder S. Human papillomavirus and cervical cancer. Lancet. 2007;370:890–907. 3 Centers for Disease Control and Prevention. Human papillomavirus (HPV) and Oropharyngeal Cancer––Fact Sheet. November 2013. http://www.cdc.gov/std/hpv/ stdfact-hpvandoralcancer.htm. Accessed September 14, 2015. 4 Walboomers JM, Jacobs MV, Manos MM, et al. Human papillomavirus is a necessary cause of invasive cervical cancer worldwide. J Pathol. 1999;189:12–19. 5 GARDASIL 9 [package insert]. Whitehouse Station, NJ: Merck & Co., Inc.; 2014. 6 Serrano B, Alemany L, Tous S, et al. Potential impact of a nine-valent vaccine in human papillomavirus related cervical disease. Infect Agent Cancer. 2012;7:38.

Conclusions

7 Vesikari T, Brodszki N, van Damme P, et al. A randomized, double-blind, phase III study of the immunogenicity and safety of a 9-valent human papillomavirus L1 virus-like particle vaccine (v503) versus GARDASIL® in 9-15-year-old girls. Pediatr Infect Dis J. 2015;34:992– 998.

Efficacy of 9vHPV was directly measured in one clinical trial of 16- to 26-year-old women. In the per-protocol population, effi-

8 Joura EA, Giuliano AR, Iversen OE, et al. A 9-valent HPV vaccine against infection and intraepithelial neoplasia in women. N Engl J Med. 2015;372:711–723.

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9 Sanofi Pasteur MSD. Immunogenicity and Tolerability of V503 Versus GARDASIL. In: ClinicalTrials.gov [Internet]. Bethesda, MD: National Library of Medicine (US), 2000 [cited 2015 Sept 17]. https://clinicaltrials.gov/ct2/ show/study/NCT01304498. Identifier: NCT01304498. Accessed December 29, 2015. 10 Merck Sharp & Dohme Corp. A Study of V503 (A Multivalent Human Papillomavirus [HPV] L1 Virus-Like Particle [VLP] Vaccine) in Preadolescents and Adolescents (V503-002). In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US), 2000 [cited 2015 Sept 16]. https://clinicaltrials.gov/ct2/show/ study/NCT00943722. Identifier: NCT00943722. Accessed December. 11 Van Damme P, Olsson SE, Block S, et al. Immunogenicity and safety of a 9-valent HPV vaccine. Pediatrics. 2015;136:e28–e39. 12 Castellsagué X, Giuliano AR, Goldstone S, et al. Immunogenicity and safety of the 9-valent HPV vaccine in men. Vaccine. 2015;33:6892–6901.

13 Merck Sharp & Dohme Corp. A study of V503, a 9-valent Human Papillomavirus (9vHPV) Vaccine in Females 1226 Years of Age Who Have Previously Received GARDASIL (V503-006). In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US), 2000 [cited 2015 Aug 29]. https://clinicaltrials.gov/ct2/show/ NCT01047345. Identifier: NCT01047345. Accessed December 29, 2015. 14 Schilling A, Parra MM, Gutierrez M, et al. Coadministration of a 9-valent human Papillomavirus vaccine with meningococcal and Tdap vaccines. Pediatrics. 2015;136:e563–e572. 15 Kosalaraksa P, Mehlsen J, Vesikari T, et al. An openlabel, randomized study of a 9-valent human papillomavirus vaccine given concomitantly with diphtheria, tetanus, pertussis and poliomyelitis vaccines to healthy adolescents 11-15 years of age. Pediatr Infect Dis J. 2015;34:627–634.

Historical Diagnosis and treatment: epithelioma

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Volume 14 • Issue 1

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

Paraneoplastic Systemic Sclerosis: Focus on Anti-RNA Polymerase III Antibodies Warren R. Heymann, MD

I

f you ask a dermatology resident which connective tissue disease is associated with cancer, most would answer “dermatomyositis.” If you inquire about the association of malignancies with scleroderma (systemic sclerosis [SS]), their response would likely be, “really?”

Patients with SS are at increased risk for cancer in those organs and tissues subject to fibrosis, notably the lung, esophagus, skin, and breast. They are also at increased risk for lymphoproliferative malignancies. Such patients are reported to have a 1.5- to 10.7-fold increased risk for these cancers. Older age at the time of diagnosis and protracted disease duration appear to be major risk factors for the development of cancer in SS.1 Genetic predisposition and exposure to immunomodulatory therapeutic agents may also be pathogenic factors in select patients.

Association of RNAP Antibodies and Malignancy in SS The close temporal relationship of RNAP antibodies and cancer was noted in a study of 23 patients with scleroderma and a new or prior diagnosis of cancer: six tested positive for anti-RNAP, five for anti-Scl-70, and eight for ACA, and four tested negative for antibodies. All patients who produced the RNA polymerase antibodies developed scleroderma within 2 years of the cancer diagnosis. The range of scleroderma duration for patients with anti-RNAP antibodies at cancer diagnosis ranged from 2 years before to 1.3 years after; the diagnosis of cancer closely preceded the onset of SS in four patients. Of the six patients with RNAP, three had breast cancer.5

Clinical Utility of the Anti-RNAP Antibody

In another cohort of 466 consecutive Italian patients with SS, 360 patients demonstrated isolated positivity for RNAP (16 patients), anti-Scl-70 (101 patients), or ACA (243 patients) were identified. Malignancies were more frequent in the RNAP group (7 of 16 patients) than in the anti-Scl-70 group (11 of 101 patients) and the ACA group (21 of 243 patients), which was statistically significant. The authors defined synchronous cancers being noted from 6 months before to 1 year after the diagnosis of SS. Three of the 16 patients with RNAP antibodies and cancer were synchronous, while none in the 101 anti-Scl-70 group and only one of 243 in the ACA group had synchronous malignancies, which were also statistically significant.6

The clinical sensitivity of anti-RNAP antibodies in SS is 10.7%, but the specificity is excellent at 98.8%, based on a study of 354 patients with SS. Patients with anti-RNAP antibodies demonstrated more severe cutaneous and renal involvement.3 The prevalence of anti-RNAP antibodies is greater in men.4

A third study revealed that among 2177 patients with SS, 7.1% had a history of cancer, with 26.6% positive for RNAP, 26% positive for ACA, and 18.2% positive for anti-Scl-70. The major cancer types were breast (42.2%), hematologic (12.3%), gastrointestinal (11.0%), and gynecologic (11%). The frequency of

Types of SS SS is divided into limited and diffuse cutaneous types. The limited type is associated with the anti-centromere antibody (ACA), while diffuse disease is associated with the anti-topoisomerase antibody (anti-Scl-70) and anti-RNA polymerase III (RNAP) antibodies.2 Recently, there have been an increasing number of reports correlating the relationship of anti-RNAP antibodies with so-called paraneoplastic scleroderma—cases where the appearance of cancer and SS are synchronous.

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

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The Heymann File

cancers among patients with RNAP (14.2%) was significantly increased compared with those with anti-Scl-70 (6.3%) and ACA (6.8%). Among the patients who were diagnosed with cancer within 36 months of the diagnosis of SS, there were more patients with RNAP (55.3%) than with ACA (23.5%) and antiScl-70 (13.6%), which was also statistically significant.7

especially in patients older than 50 years with constitutional symptoms (fever, night sweats, and weight loss).11 Much remains to be learned about the association of cancer and scleroderma. Recognizing patients who are at risk is paramount in patient care—this association should no longer be a secret.

An analysis of 261 Japanese patients with SS found that the prevalence of malignancy was significantly higher in patients with RNAP (7 of 22, 31.8%) than those with ACA (8 of 137, 5.8%) or those with anti-Scl-70 antibodies (2 of 82, 2.4%). Among the seven patients with RNAP and malignancy, three (42.9%) developed their cancer from 6 months before to 1 year after the onset of SS.8

1 Szekanecz Z, Szekanecz E, Bakó G, Shoenfeld Y. Malignancies in autoimmune rheumatic diseases—a minireview. Gerontology. 2011;57:3–10.

Pathogenesis of SS and Cancer in Patients With RNAP The temporal relationship of SS and malignancies in patients with RNAP suggests a pathogenic relationship, although the precise mechanisms by which this occurs awaits further elucidation. A unique nucleolar RNAP expression pattern has been identified in malignant tissue from these SS patients. This suggests that cross-reactive immune responses may target autoantigens expressed in both cancers and other tissues displaying autoimmune pathology, such as the skin and kidney.9 Another study of cancer in scleroderma patients demonstrated genetic alterations (somatic mutations or loss of heterozygosity) of the POLR3A locus in six of eight patients to RNA polymerase subunit (RPC1), but not in eight patients without antibodies to RPC1.10 Presumably, these mutations trigger cellular immunity and cross-reactive humoral responses that could explain the synchronous association of cancer with SS.

2 Honma, Komatsu S, Igawa S, Murakami M, Iizuka H. Rapidly progressive sclerosis associated with breast carcinoma: report of a case with anti-RNA polymerase III antibody. J Dermatol. 2012;39:574–576. 3 Satoh T, Ishikawa O, Ihn H, et al. Clinical usefulness of anti-RNA polymerase III antibody measurement by enzyme-linked immunosorbent assay. Rheumatology (Oxford). 2009;48:1570–1574. 4 Motegi S, Toki S, Yamada K, Uchiyama A, Ishikawa O. Demographic and clinical features of systemic sclerosis patients with anti-RNA polymerase III antibodies. J Dermatol. 2015;42:189–192. 5 Shah AA, Rosen A, Hummers L, Wigley F, Casciola-Rosen L. Close temporal relationship between onset of cancer and scleroderma in patients with RNA polymerase I/III antibodies. Arthritis Rheum. 2010;62:2787–2795. 6 Airo’ P, Ceribelli A, Cavazzana I, et al. Malignancies in Italian patients with systemic sclerosis positive for anti-RNA polymerase III antibodies. J Rheumatol. 2011;38:1329–1334. 7 Moinzadeh P, Fonseca C, Hellmich M, et al. Association of anti-RNA polymerase III autoantibodies and cancer in scleroderma. Arthritis Res Ther. 2014;16:R53. 8 Saigusa R, Asano Y, Nakamura K, et al. Association of anti-RNA polymerase III antibody and malignancy in Japanese patients with systemic sclerosis. J Dermatol. 2015;42:524–547. 9 Shah AA, Rosen A. Cancer and systemic sclerosis: novel insights into pathogenesis and clinical implications. Curr Opin Rheumatol. 2011;23:530–535.

Conclusions Although rare, paraneoplastic scleroderma is a genuine entity. It should be considered in patients presenting with acute-onset, severely progressive SS. Serologic studies for anti-Scl-70, ACA, and RNAP should be obtained. If RNAP serology is positive, a careful malignancy workup is warranted, with a particular emphasis on the breasts and pulmonary and hematopoietic systems,

SKINmed. 2016;14:39–40

References

10 Joseph CG, Darrah E, Shah AA, et al. Association of the autoimmune disease scleroderma with an immunologic response to cancer. Science. 2014;343:152–157. 11 Reynolds TD, Knights SE. Recurrent metastatic breast cancer presenting with paraneoplastic scleroderma. BMJ Case Rep. 2014;2014. pii: bcr2014206070. doi: 10.1136/bcr-2014-203575 .

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Paraneoplastic Systemic Sclerosis


January/February 2016

Volume 14 • Issue 1

Society Highlights of the 56th Annual Meeting of the North American Clinical Dermatologic Society

A Tale of Four Cities: May 12–24, 2015, Reykjavik, Amsterdam, Rotterdam, and Copenhagen Robert S. Berger, MD Reykjavik 13 May: Meeting at the Radisson Blu Hotel

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nthony V. Benedetto, DO (Philadelphia, PA), began the meeting in Iceland with a discussion of the use of postoperative antibiotics after excisional surgeries on the nose, ears, lips, anogenital area, and sites below the knee. They are also appropriate after prolonged, and excessively traumatic procedures in elderly and immunocompromised patients. The antibiotic coverage should parallel what is required for the current community and local hospital organism sensitivity results. Stephen P. Stone, MD (Springfield, IL ), discussed comorbidities of psoriasis, with systemic inflammation being evaluated for its relationship with the metabolic syndrome and heart disease, as well as the link between psoriasis, depression, and alcohol abuse. James B. Stewart, MD (Oklahoma City, OK), presented areas best suited for secondary intention healing, either due to size of defect or patient’s age, health, or desire for not wanting complex closures. Prime locations were extremities, ears, nose, and scalp. Darius Mehregan, MD (Detroit, MI), presented the pitfalls of improper biopsy site selection, biopsy technique, and clinical– pathologic correlation, any of which can lead to an incorrect pathologic diagnosis with possible medical-legal complications. Examples include melanoma and basal cell mixed tumor, microcystic adnexal carcinoma, recurrent nevus, and recurrent/ traumatized nevus. Richard L. Spielvogel, MD (Philadelphia, PA), discussed the classification of lymphomas, with several new entities on the horizon. Carisa R. Champion-Lippmann, OMS V (Miami, FL), presented a variety of oral manifestations of dermatologic diseases, such as lichen planus, trauma, and blistering disorders such as bullous pemphigoid.eeting at the Radisson Blu Hotel

Reykjavik 15 May The highlight of the meeting in Iceland was the visit to the Blue Lagoon treatment facility with the following presentations (Figure 1). Darius Mehregan, MD (Detroit, MI), presented clinical correlations and dermatoscopy, focusing primarily on melanocytic lesions and the difference between benign and malignant/ premalignant dermatoscopic findings. Melanoma, melanoma in situ, and nevi with atypical cells were discussed, as were basal cell carcinomas, and squamous cell carcinomas. Jon Olafsson, MD, PhD (Iceland), discussed the treatment of hemangiomas in children with propranolol as being preferred over laser therapy, primarily due to its better efficacy with no risk of scarring. Jenna Eysteinsdottir, MD (Iceland), presented fascinating data regarding the therapeutic benefits of blue lagoon immersion therapy coupled with narrowband UVB light therapy gaining relapse

Figure 1. Drs Hamill, Stewart, Eysteinsdottir, Spielvogel, Olafsson, Berger, and Benedetto at the meeting at the Blue Lagoon treatment facility.

From Department of Dermatology, Johns Hopkins University, Baltimore, MD, and Charles County Dermatology Associates, White Plains, MD. Address for Correspondence: Robert S. Berger, MD, Charles County Dermatology Associates, 4225 Altamont Place, Unit 3, White Plains, MD 20695 • E-mail: rsbcsb@aol.com

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56th Annual Meeting of the NACDS

free periods of 200+ days. While the results are preliminary, the waters of the lagoon seem to have an anti-inflammatory effect, with results approximating or exceeding current therapies (methotrexate/tumor necrosis factor inhibitors, narrowband UVB).

Rotterdam 19 May

Amsterdam 18 May: Meeting at the Intercontinental Hotel Richard L. Spielvogel, MD (Philadelphia, PA), highlighted controversies in dermatpathology, with a focus on communication between providers using the classification of atypical melanocytic lesions and the resultant treatment decisions. Anthony V. Benedetto, DO (Philadelphia, PA), presented the ideal locations for the injection of different hyaluronic acid fillers to enhance the lips and the perioral area. Christine Burns, MD (Tampa, FL), discussed using a new diagnostic test called transient receptor potential melastatin 1 autoantibody testing for melanoma and adipophilin immunostain for sebaceous carcinoma diagnosis, and the treatment of periocular xanthogranuloma with rituximab. Stephen P. Stone, MD (Springfield, IL), discussed paraneoplastic syndromes, most commonly seen in lung, ovarian, breast, or lymphatic cancers. Clinical manifestations are varied, with dermatitis to neurologic involvement. David Harris, MD (San Francisco, CA), reviewed significant advances over the past 50 years of dermatology, highlighting the development of tretinoin, corticosteroids, calcineurin inhibitors, isotretinoin, and biologics. John R. Hamill, MD (Tampa, FL) discussed a unique modified butterfly dermal suture technique to improve wound closure in high tension areas.

In Rotterdam, Martino Neumann, MD (Rotterdam), discussed venous ulcers, emphasizing early intervention after an accurate diagnosis as to etiology, especially with recalcitrant cases (Figure 2). Celine Eggen, MD (Rotterdam), discussed the dilemmas in treating congenital nevi and the controversy surrounding the need for the removal of giant congenital nevi. Renate van de Bos, MD (Rotterdam), reviewed the status of Mohs surgery in the Netherlands and the difficulties in establishing Mohs clinics and in gaining acceptance by the medical community. Bing Thio, MD (Rotterdam), presented data about the successful use of diethyl and monoethyl fumarates in the treatment of mild to severe psoriasis. The mechanism is unknown, the treatment is cost-effective, the side effects are rare, and the results are comparable to conventional therapies (topical, nbuvb, methotrexate). Copenhagen 21 May: Meeting at the Hotel Phoenix James Stewart, MD (Oklahoma City, OK), presented simple fixes for common/unusual office situations, a novel technique for removing a fish hook, and using tape to pick up dropped sharps (eg, blades) from the floor. Sarah Porkka, MD (Napa, CA), discussed the steps required to close a private practice, with emphasis on contracts, with vendors and patient notification requirements being the most difficult aspects. Allan Wirtzer, MD (Los Angeles, CA), discussed E/M coding in the new healthcare environment, concentrating on correct chart documentation by combining the review of systems, diagnostic impressions, and physical examination documentation.

Copenhagen 22 May

Figure 2. Drs Berger, Spielvogel, Benedetto, Neumann, Stewart, and Thio at the meeting at the University Hospital Rotterdam, Department of Dermatology. SKINmed. 2016;14:41â&#x20AC;&#x201C;42

Hans Christian Wulf, MD (Copenhagen), discussed the protocol for photodynamic therapy of actinic keratoses using natural sunlight instead of artificial light sources. Discomfort is much less and the cure rates are similar. Tonny Karlsmark, MD (Copenhagen), reviewed the therapy of skin ulcers and wounds, emphasizing a multidisciplinary approach, telemedicine, and the importance of diagnosis of etiologic factors to guide therapeutic options. Jorgen Serup, MD (Copenhagen), lectured on the risks faced by an unregulated tattoo industry in northern Europe, with allergic reactions being the most common complication and occasional fatal infections seen. Merete Haedersdal, MD (Copenhagen), presented the current laser treatment options for scars, based primarily on scar type, patient age, and scar color. The North American Clinical Dermatologic Society will hold its 2016 meeting in Greece May 20â&#x20AC;&#x201C;29, in Thessaloniki and Athens.

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A Tale of Four Cities


January/February 2016

Volume 14 • Issue 1

PHOTO CAPSULE

Crest Syndrome Piyush Kumar, MD;1 Anupam Das, MD2

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28-year-old man presented with tight facial skin and hands for 6 years, along with firm growth on the right palm and elbow for 3 years. There was a history of extrusion of white chalky material from the palm lesion. He also complained of pain, swelling, and numbness of his fingers in the winter for 10 years. In addition, he complained of heartburn. Mucocutaneous examination revealed dyspigmentation and induration of skin of the face and hands. The skin proximal to the wrist and over the trunk was not indurated. There were multiple grouped firm, whitish papulonodules over the thenar eminence of the right hand and right elbow (Figure 1). Multiple fingertips showed pitted scars (Figure 2). Laboratory investigations revealed mild leukocytosis, normocytic-normochromic anemia, thrombocytosis, elevated erythrocyte sedimentation rate, and elevated C-reactive protein. Radiography findings of the hands revealed subcutaneous radiodense deposits. Results from antinuclear antibody test in HEp-2 cells were positive (up to 1:1280) and the pattern was nucleolar. Findings from biopsy of the neck showed epidermal atrophy, markedly thickened and closely packed dermal collagen bundles, and perivascular lymphohistiocytic infiltrate. A diagnosis of CREST syndrome was made. CREST syndrome is a limited type of scleroderma that refers to the five main features: calcinosis cutis, Raynaud phenomenon, esophageal dysmotility, sclerodactyly, telangiectasia).1 Calcinosis is the pathologic calcification of soft tissues that can ulcerate, leading to drainage of a chalky white substance. Raynaud phenomenon is characterized by episodes of pallor, cyanosis, and/or redness on the extremities in response to cold or emotional stress. Esophageal dysmotility and gastroesophageal reflux is present in 75% to 80% of cases. Sclerodactyly refers to thickening of the skin on the digits of the hands and feet. Telangiectasias are often noted on the face, upper trunk, hands, and mucosae.1,2 Calcium channel blockers are the mainstay of medical therapy. Smoking and β-blockers should be strictly avoided.3 Telangiectasia can be treated by 585-nm flash lamp pumped pulsed dye lasers.4

Figure 1. Firm whitish plaque on the thenar eminence and wrist of the right hand.

Figure 2. Multiple digits showing pitted scars on their tips.

References 1 James WD, Berger TG, Elston DM. Andrews’ Diseases of the Skin: Clinical Dermatology. 11th ed. Philadelphia, PA: Saunders Elsevier; 2011: 170. 2 Viswanath V, Phiske MM, Gopalani VV. Systemic sclerosis: current concepts in pathogenesis and therapeutic aspects of dermatological manifestations. Indian J Dermatol. 2013;58:255–268. 3 Thompson AE, Pope JE. Calcium channel blockers for primary Raynaud’s phenomenon: a meta-analysis. Rheumatology (Oxford). 2005;44:145–150. 4 Ciatti S, Varga J, Greenbaum SS. The 585 nm flashlamppumped pulsed dye laser for the treatment of telangiectases in patients with scleroderma. J Am Acad Dermatol. 1996;35:487–488.

From the Department of Dermatology, Katihar Medical College and Hospital, Katihar;1 and KPC Medical College and Hospital, Kolkata, West Bengal,2 India Address for Correspondence: Piyush Kumar, MD, Department of Dermatology, Katihar Medical College and Hospital, Karim Bagh, Katihar, Pin 854105, Bihar, India • E-mail: docpiyush99@gmail.com

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MEDIA PARTNER


January/February 2016

Volume 14 • Issue 1

INFECTIOUS DISEASE CAPSULE Jack M. Bernstein, MD, Section Editor

It’s Not Always What It Seems: Necrotizing Fasciitis Mimicking Angioedema Whittney A. Warren, DO;1,2 Nicole C. Droz, MD;1 Sunishka M. Wimalawansa, MD, MBA;3,4 Salim N. Mancho, MD;3 Jack M. Bernstein, MD1,5

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42-year-old woman presented to the emergency department with a complaint of lip swelling. She was treated for angioedema of the lip and discharged on oral prednisone. Several days later, she returned with increased lower lip swelling and an inability to open her mouth because of severe pain. Prior to presentation, she had self-administered an EpiPen, with no improvement in symptoms. On physical examination, she had swelling of the lower lip, with a 1-cm purulent wound, midline and inferior to the lower lip and a corresponding 1-cm lesion on the internal mucosal surface of the lip (Figure). Erythema and induration extended across the surface of the entire lower jaw with extension down the neck. Oral examination revealed normal dentition. Empiric antibiotics, including coverage for methicillin-resistant Staphylococcus aureus, were started. By the next morning, she developed extreme tenderness to palpation of the neck and chest extending beyond the areas of erythema and induration. Results from blood and wound cultures from admission were positive for gram-positive cocci subsequently identified as methicillin-sensitive Staphylococcus aureus (MSSA). Radical debridement of the lips, cheek, and neck revealed necrotizing fasciitis. Subsequently, after a full course of antibiotics directed against MSSA, plastic surgical reconstruction was necessary to close her wounds. Lip and facial swelling are commonly encountered complaints that can require hospitalization for close monitoring because of possible airway compromise. Anaphylaxis and allergic reaction comprise the majority of cases; however, infectious etiologies are important in the differential diagnosis. Necrotizing fasciitis

(NF) of the face is a rare but life-threatening cause of facial swelling. NF results from a cutaneous or soft tissue infection that spreads to involve the underlying fascial planes and often involves the extremities or perineum caused by the preponderance of anaerobes and synergistic infections with aerobes.1 The majority of necrotizing infections of the head and neck are derived from odontogenic or pharyngeal pathogens and involve the neck.1 An inciting break in the skin often precedes NF of the face. Underlying systemic disease such as diabetes mellitus, alcoholism, and renal failure are risk factors for developing NF.2 Necrotizing infections in the face are rare and are usually caused by Streptococcus pyogenes.3 NF of the face secondary to community-acquired methicillin-resistant Staphylococcus aureus (MRSA) is occasionally seen; however, methicillin-sensitive Staphylococcus aureus (MSSA) is a rare cause. Interestingly, studies have shown that MSSA may be more virulent than MRSA in the normal host.4 Patients with NF of the face typically complain of pain in the face with erythema and marked swelling.5 Patients may demonstrate numbness secondary to superficial nerve involvement or crepitus over the involved area. Crepitus, however, is not a widely reported feature in NF of the face and its absence does not exclude NF.6 Alternatively, patients may present with symptoms of severe illness such as sepsis and shock. Treatment includes emergency debridement and broad-spectrum antibiotic therapy. Failure to recognize NF as a source of

From the Department of Medicine, Boonshoft School of Medicine, Wright State University, Dayton, OH;1 Wright Patterson AFB, Warren, OH;2 the Division of Plastic Surgery, Wright State University, Dayton, OH;3 the Division of Hand Surgery, Department of Surgery, Christine M. Kleinert Institute for Hand and Microsurgery, University of Louisville, Louisville, KY;4 and Research Service, Dayton Veterans Affairs Medical Center, Dayton, OH5 Address for Correspondence: Whittney A. Warren, DO, 8901 Rockville Pike, Bethesda, MD 20889 • E-mail: whittney.warren@gmail.com

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INFECTIOUS DISEASE CAPSULE Conclusions NF is a rare but deadly cause of lip swelling. While allergic reactions and anaphylaxis are common causes of facial swelling, infectious etiologies must also be considered. Treatment of NF requires early antibiotic therapy and aggressive debridement. This case demonstrates the importance of a broad differential diagnosis in patients presenting with swelling of the face and lips. Failure to identify infectious etiologies can significantly increase morbidity and death. References 1 Shindo ML, Nalbone VP, Dougherty WR. Necrotizing fasciitis of the face. Laryngoscope. 1997;107:1071–1079. 2 Singh DV, Thomas S, Nair PP, Cyriac S, Tripathi GM. Necrotizing fasciitis of face--our experience in its management.BMJ Case Rep. 2011;2011. 3 Benavides G, Blanco P, Pinedo R. Necrotizing fasciitis of the face: a report of one successfully treated case. Otolaryngol Head Neck Surg. 2003;128:894–896.

Figure. Swelling of the lower lip with an advancing erythematous border on hospital day 1. (Photograph used with permission from the patient.)

4 Mizobuchi S, Minami J, Jin F, Matsushita O, Okabe A. Comparison of the virulence of methicillin-resistant and methicillin-sensitive Staphylococcus aureus. Microbiol Immunol. 1994;38:599–605.

facial swelling is common and leads to delayed medical as well as surgical therapy, increasing morbidity and death.7 Adjunctive therapies that may be beneficial include hyperbaric oxygen therapy and intravenous immunoglobulin G.8,9 Facial reconstruction should be attempted only after infection has resolved and the recipient’s wound bed is disease free. The frequent delay in making the diagnosis of necrotizing facial infections may be related to the reported mortality rate of 9% to 31%.10 NF of the face is often complicated by extension of the infection down the cervical fascia, resulting in mediastinitis with an attendant mortality rate of 40%.6 Overly cautious initial debridement with the intent to preserve fascial structures increases morbidity and mortality as a result of poor source control. Patients who have undergone significant debridement of the face experience a number of long-term complications including loss of oral competence and ocular exposure.

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5 Lin C, Yeh FL, Lin JT, et al. Necrotizing fasciitis of the head and neck: an analysis of 47 cases. Plast Reconstr Surg. 2001;107:1684–1693. 6 Park E, Hirsch EM, Steinberg JP, Olsson AB. Ascending necrotizing fasciitis of the face following odontogenic infection. J Craniofac Surg. 2012;23:e211–e214. 7 Stoykewych AA, Beecroft WA, Cogan AG. Fatal necrotizing fasciitis of dental origin. J Can Dent Assoc. 1992;58:59–62. b Whitesides L, Cotto-Cumba C, Myers RA. Cervical necrotizing fasciitis of odontogenic origin: a case report and review of 12 cases. J Oral Maxillofac Surg. 2000;58:144– 151. 9 Skitarelic N, Mladina R, Morovic R. Cervical necrotizing fasciitis: sources and outcomes. Infection. 2003;31:39– 44. 10 Buchanan CS, Haserick JR. Necrotizing fasciitis due to group A B-hemolytic streptococci. Arch Dermatol. 1970;101:664–668. 11 Yadav S, Verma A, Sachdeva A. Facial necrotizing fasciitis from an odontogenic infection. Oral Surg Oral Med Oral Pathol Oral Radiol. 2012;113:e1–e4.

Necrotizing Fasciitis Mimicking Angioedema


MEDIA PARTNER


January/February 2016

Volume 14 • Issue 1

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

Tenosynovial Giant Cell Tumor in the Dermis of the External Auditory Meatus Amin Maghari, MD;1,2 Theresa A. Zaleski, MSIV;3 Tiffany Jow, MSIII;1,2 W. Clark Lambert, MD, PhD1,2 A 26-year-old African American woman with a history of a recurring “oozing papule” in the right ear presented to the emergency department in July 2010 with a 2-month history of an enlarging, painful growth in the right ear canal. Physical examination revealed a 1-cm round cystic lesion along the right, anterior external auditory canal wall, just medial to the tragus. Initial diagnosis was an infected cyst of the external ear canal. The patient was instructed to follow-up with an ear, nose, and throat (ENT) office. Two months following the emergency department visit, inspection by ENT revealed a 3- to 4-mm round, firm subcutaneous nodule that did not extend into the ear canal or cartilage. According to the patient, this lesion had recurred with several infections. The lesion was biopsied in the outpatient setting and demonstrated ulceration with marked acute and chronic inflammation in addition to granulation tissue. Two months later, the lesion was surgically excised. The final diagnosis of giant cell tumor, tenosynovial type with lesion-free margins, and no involvement of the cartilage was made (Figures 1–3). No further treatment was recommended. Gross examination of the excised lesion revealed tan to white soft tissue measuring 1.0×0.7×0.3 cm. Results from factor XIII A immunostain was negative, confirming that the lesion did not represent an unusual variant of fibrous histiocytoma (Figure 4). To date, recurrence of this lesion has not been appreciated. (SKINmed. 2016;14:48–51)

T

enosynovial giant cell tumor of the localized type, also known as giant cell tumor of the tendon sheath (GCTTS), is a benign, slow-growing tumor that most commonly occurs within or near the joints of the extremities.1,2 The most common location for this tumor is on the hand. Of note, tenosynovial giant cell tumor is also the second most common tumor to occur in this location.2 GCTTS have also been reported to occur in locations other than the hand such as the feet, knee, and, rarely, the elbow or hip.2 This entity should not be mistaken for the similarly named giant cell tumor of soft parts or its counterpart in the bone, as tenosynovial giant cell tumor of the localized type carries a more favorable prognosis.1 Discussion GCTTS is a benign tumor of unknown etiology that is thought to arise from the tendon sheaths, bursae, synovium, and joints.3,4 Tenosynovial giant cell tumors are categorized into one of two

groups: diffuse or localized type, depending on the growth pattern and distribution of joint involvement.5,6 While the localized type of tenosynovial giant cell tumor usually affects the smaller joints of the hand and fingers, the diffuse type more commonly affects larger joints such as the knee and hip. Whereas the localized form of this lesion most commonly occurs between 30 and 50 years of age and is twice as common in women than in men, the more aggressive diffuse form generally occurs in younger patients.3,5 It is important to note that the diffuse type has been shown to be more locally aggressive and destructive, often resulting in multiple recurrences. In addition, there have also been a rare number of cases of a malignant counterpart of this disease entity described in the literature, in which in the presence of sarcomatous transformation, distant metastases have been documented. Clinically, tenosynovial giant cell tumor, localized type, appears as a slow-growing, painless multi-lobulated mass with a duration

From the Departments of Dermatology1 and Pathology,2 Rutgers University—New Jersey Medical School, Newark, NJ; and the Rowan University, School of Osteopathic Medicine, Stratford, NJ3 Address for Correspondence: W. Clark Lambert, MD, PhD, University of Medicine and Dentistry of New Jersey—New Jersey Medical School, Department of Pathology and Laboratory Medicine 185 South Orange Avenue, Newark, NJ 07101 • E-mail: lamberwc@umdnj.edu

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CASE STUDY of symptoms averaging 1 to 2 years.1 Skin involvement can occur with this lesion; however, it is usually caused by direct extension from a tumor attached to an underlying joint or tendon sheath.1,7,8 A tenosynovial giant cell tumor has never before been reported in this location, nor has it been reported to occur exclusively in the dermis without underlying joint or tendon sheath involvement.

Figure 1. Well-circumscribed, intra-dermal mass consisting of mononuclear cells and osteoclast-like giant cells (hematoxylin and eosin stain, original magnification ×10).

It is important to differentiate tenosynovial giant cell tumor from giant cell tumor of bone and giant cell tumor of soft parts, as the latter may behave in a more aggressive fashion and thus herald a worse prognosis.1,9,10 These entities can be distinguished by both immunohistochemistry as well as histology, as tenosynovial giant cell tumors lack the characteristic spindle stromal cells seen in giant cell tumor of soft tissue and its osseous counterpart (Figures 1 and 2).11 Moreover, tenosynovial giant cell tumor consistently demonstrates immunoreactivity to muscle actin (SMA), while giant cell tumor of the bone and soft parts does not.11,12 Histologically, the giant cells in tenosynovial giant cell tumor show a decreased amount of nuclei and a haphazard nuclear arrangement when compared with the peripherally situated nuclei seen in giant cell tumor of the bone (Figure 2).13 The nuclei of the giant cells found in giant cell tumor of bone are classically

Figure 2. Mononuclear cells (small round to oval, with pale cytoplasm and round occasionally grooved nuclei) and multi-nucleated giant cells in dense fibrous stroma (hematoxylin and eosin stain, original magnification ×40). SKINmed. 2016;14:48–51

Figure 3. Tumor adjacent to ceruminous glands of the external auditory canal (right) (hematoxylin and eosin stain, original magnification ×10).

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Tenosynovial Giant Cell Tumor in the Dermis


January/February 2016

CASE STUDY

a

b

Figure 4. (a)Tumor cells nonimmunoreactive for factor XIII A, although there is some background staining (right) (hematoxylin and eosin stain, original magnification ×20). (b) Superficial dendritic cells as positive internal control (left) (hematoxylin and eosin stain, original magnification ×20).

described as identical to the nuclei of the surrounding mononuclear cells in the lesion, a finding that was not present in our case, thus helping differentiate GCTTS from that of bone or soft tissue.13 The location of the lesion in this case would lead one to suspect giant cell tumor of soft tissue because of the lack of tendon sheaths and synovial joints in the ear canal as well as the exclusive dermal involvement of the tumor; however, the characteristics of the giant cells as well as the lack of cellular pleomorphism, a low mitotic rate, and absence of spindle cells in the specimen led to the diagnosis of tenosynovial giant cell tumor, localized type.13 If this lesion was classified as a superficial giant cell tumor of soft tissue, one would expect to see histological features resembling that of giant cell tumor of the bone.14 Fibrous histiocytoma was also part of the differential diagnosis; however, this entity was ruled out by the presence of osteoclast-like giant cells and absence of factor XIII A positivity in our specimen (Figure 4).

Haddad revealed that the majority of the lesions in that study occurred on the right hand or fingers.2 This observation, along with the fact that most individuals are right-hand dominant and thus subject the right hand to more trauma, would favor the reactive process, as trauma has been cited as a preceding event in many cases. This theory might explain why tenosynovial giant cell tumors have been observed most often in individuals who participate in hand-intensive labor. Our case demonstrates the occurrence of a tenosynovial giant cell tumor after multiple ear infections of the external ear canal, also supporting a reactive process. Recent studies, however, have shown a translocation affecting chromosome 1p11 to be present in many giant cell tumors of the tendon sheath, thus pointing toward a clonal neoplastic origin.16 An additional study proposes that giant cell tumors of the tendon sheath show features of both a reactive and neoplastic process, thus finding a middle ground.16

Although tenosynovial giant cell tumor is a common entity, the pathogenesis is still debated. While some authors believe that there is an inflammatory reactive process responsible, others favor a neoplastic origin. A reactive process was proposed by Jaffe in 1941, when this tumor was first described.15 In fact, a review of 52 cases of tenosynovial giant cell tumor by Darwish and

The recommended treatment for tenosynovial tumor of the localized type is surgical excision with free margins.1–8 Although this lesion is considered to be benign, local recurrence is a common feature, with rates of 5% to as high as 50% being reported.1,2,5,17 One possibility for such a high recurrence rate is incomplete excision secondary to the tumor’s ability to form long finger-like extensions that pass into and around delicate structures such as

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CASE STUDY

the neurovascular bundle.1,2,18 Some authors have suggested adjuvant radiotherapy as a treatment option to reduce the risk of tumor recurrence.2,19

8 Rustin MHA, Robinson TW. Giant-cell tumour of the tendon sheath––an uncommon tumour presenting to dermatologists. Clin Exp Dermatol. 1989;14:466–468. 9 Dodd L, Major N, Brigman B. Malignant giant cell tumor of soft parts. Skeletal Radiol. 2004;33:295–299.

Conclusions Tenosynovial giant cell tumors are a group of generally benign intra-articular and soft tissue tumors, which can be roughly divided into localized and diffuse types, with diffuse types being much more aggressive. We describe a novel case of a giant cell tumor, tenosynovial type occurring in the external auditory meatus, a highly atypical location for presentation of this entity, especially in the absence of an underlying joint or tendon sheath in which direct extension may have occurred. References 1 Glowacki KA. Giant cell tumors of the tendon sheath. J Hand Surg. 2003;3:100–107. 2 Darwish FM, Haddad WH. Giant cell tumour of tendon sheath: experience with 52 cases. Singapore Med J. 2008;49:879–882. 3 Mahmood A, Caccamo DV, Morgan JK. Tenosynovial giant-cell tumor of the cervical spine. J Neurosurg. 1992;77:952–955. 4 Muramatsu K, Mine T, Ichihara K. Atypical tenosynovial giant cell tumor of the extensor hallicus longus tendon. JAPMA. 2006;96:359–361. 5 Yasuda T, Kanamori M, Ishizawa S, et al. Multicentric diffuse-type giant cell tumor of the hand. Mod Rheumatol. 2008;18:67–71.

10 Lentini M, Zuccalá V, Fazzari C. Polypoid giant cell tumor of the skin. Am J Dermatopathol. 2010;32:95–98. 11 Tejera-Vaquerizo A, Ruiz-Molina I, González-Serrano T, et al. Primary giant cell tumor of soft tissue in the finger. Dermatol Online J. 2008;14:7. 12 Folpe AL, Morris RJ, Weiss SW. Soft tissue giant cell tumor of low malignant potential: a proposal for the reclassification of malignant giant cell tumor of soft parts. Mod Pathol. 1999;12:894–902. 13 Schajowicz F. Giant-cell tumors of bone (osteoclastoma): a pathological and histochemical study. J Bone Joint Surg Am. 1961;43:1–29. 14 Sunil Kumar Y, Raghupathi AR, Chidananda. Giant cell tumor of the skin. Indian J Dermatol Venereol Leprol. 2006;72:145–146. 15 Jaffe HL, Lichtenstein L, Sutro CJ. Pigmented villonodular synovitis, bursitis and tenosynovitis. Arch Pathol. 1941;31:731–765. 16 West RB, Rubin BP, Miller MA, et al. A landscape effect in tenosynovial giant-cell tumor from activation of CSF1 expression by a translocation in a minority of tumor cells. PNAS. 2006;103:690–695. 17 Ozdemir HM, Yildiz Y, Yilmaz C, et al. Tumors of the foot and ankle: analysis of 196 cases. J Foot Ankle Surg. 1997;36:403.

6 Singh PJ, Constable L, O’Donnell J. Arthroscopic excision of a giant-cell tumour of the ligamentum teres. J Bone Joint Surg [Br]. 2009;91-B(6):809–811.

18 Lorea P, Medina J, Navarro R, et al. Recurrence of finger tendon giant cell tumors after excision through a shark teeth approach. Report of 25 cases. Ann Chir Plast Esthet. 2001;46:607–610.

7 King DT, Millman AJ, Gurevitch AW, Hirose FM. Giant cell tumor of the tendon sheath involving skin. Arch Dermatol. 1978;114:944–946.

19 Kotwal PP, Gupta V, Malhtra R. Giant cell tumor of tendon sheath. Is radiotherapy indicated to prevent recurrence after surgery? J Bone Joint Surg Br. 2000;82:571–573.

“Herpes simples febrilis.” Moulage No. 73, made by Lotte Volger in 1931 in the Clinic for Dermatology Zurich. Museum of Wax Moulages Zurich, www.moulagen.ch Courtesy of Michael Geiges, MD SKINmed. 2016;14:48–51

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Tenosynovial Giant Cell Tumor in the Dermis


愀 渀甀

渀 䄀   搀

䴀愀礀 ㈀ ⴀ㈀㌀Ⰰ ㈀ ㄀㘀   ⴀ   䌀漀攀甀爀 搀ᤠ䄀氀攀渀攀Ⰰ 䤀搀愀栀漀

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刀䔀䜀䤀匀吀䔀刀 一伀圀 戀礀 瘀椀猀椀椀渀最 䄀䴀䐀猀礀洀⸀挀漀洀 


January/February 2016

Volume 14 • Issue 1

CASE STUDY

Addisonian-Like Hyperpigmentation as an Indicator of Uncontrolled Congenital Adrenal Hyperplasia Forum B. Patel, MD;1 Sabrina A. Newman, MD;1 Scott A. Norton, MD, MPH2 A 20-year-old man of Indo-Malaysian ancestry presented with a complaint of increased facial pigmentation that he first noticed at age 13. He had congenital adrenal hyperplasia (21-hydroxylase deficiency, salt-wasting variant; OMIM 201910), diagnosed during infancy. Glucocorticoid and mineralocorticoid therapy was started at that time, but he had several episodes of salt craving during adolescence. During the past 7 years, the degree of facial pigmentation waxed and waned but never returned to baseline of early adolescence. Progressive skin darkening was also observed in annual family photos, which also showed a vast difference in skin tones between the patient and other members of his immediate family. (SKINmed. 2016;14:53–54)

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examethasone and fludrocortisone were his only medications. He denied prior use of antimalarials, minocycline, or phenothiazines. Results from a skin biopsy showed an increase in melanin pigment within the epidermal basal layer, densely pigmented dermal melanophages, and free melanin in the papillary dermis. Findings from laboratory tests over several years showed persistently elevated 17-hydroxyprogesterone and renin levels, with low testosterone and dehydroepiandrosterone levels. He also has bilateral testicular adrenal rest tumors, indicative of poor hormonal control and inadequate suppression of adrenocorticotropic hormone (ACTH) secretion. He acknowledged noncompliance with his medications. Consequently, elevated ACTH levels generated hyperpigmented skin and mucosa. Over 90% of cases of congenital adrenal hyperplasia are caused by deficiency of 21-hydroxylase (Figure 2).1,2 Due to this inborn error in the adrenal pathway, patients can present with either salt-wasting congenital adrenal hyperplasia (CAH) or simple virilizing (SV) CAH (Figure 1). Female SV-CAH patients are generally diagnosed at birth as a result of the presence of ambiguous genitalia. Male patients are usually diagnosed later, because there are no genital abnormalities to induce a workup. CAH, particularly late-onset CAH, can develop Addisonian-like hyperpigmentation, as a result of increased pituitary secretion of ACTH.1 Of note, ACTH is a more potent stimulator of melanin synthesis than α-melanocyte–stimulating hormone.

Hyperpigmentation may be the only clinical sign of uncontrolled or late-onset CAH, which is conspicuous in people with fair complexions.1 Identifying hyperpigmentation in patients with darker skin tones, however, can be challenging.3 In these patients, acquired hyperpigmentation is often limited to mucosal areas, such as the buccal mucosa, gingivae, and tongue (Figure 2). The sublingual area, however, is typically spared3,4 (Figure 2). Skin on the head and neck is also commonly involved, but hyperpigmentation on other sun-exposed areas may not be as evident. Hyperpigmentation in flexural areas, such as the antecubital fossae and axillae, is also seen. In addition, hyperpigmentation overlying pressure points, such as over the spinous processes, along the beltline, and above joints, is common. Conclusions Examination of these areas is an important part of the evaluation of patients with suspected CAH. In addition, in patients with known CAH, this pattern of hyperpigmentation may indicate a subtherapeutic treatment regimen, possibly the result of noncompliance. Because skin changes are caused by increased levels of ACTH, adequate treatment with dexamethasone can reduce the overproduction of ACTH, thus ameliorating the hyperpigmentation.

From the Departments of Dermatology, George Washington University School of Medicine1 and Georgetown University School of Medicine,2 Washington DC Address for Correspondence: Sabrina Newman, MD, Medical Faculty Associates of George Washington University School of Medicine, Department of Dermatology, 2150 Pennsylvania Avenue, NW, 2nd Floor, Washington, DC 20037 • E-mail: sab0403@yahoo.com

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Figure 1. Synthetic pathway of the adrenal medulla. Congenital adrenal hyperplasia is most commonly caused by a deficiency in 21-hydroxylase (blue), as seen in our patient. Adrenal insufficiency becomes apparent as a result of decreased synthesis of glucocorticoids and mineralocorticoids causing hyponatremia (salt-wasting) and hyperkalemia. The pathway is diverted to increased synthesis of androgens, specifically androstenedione and testosterone (simple virilization type).3,4 Diagnosis is usually made by detecting elevated levels of 17-hydroxyprogesterone. Other subtypes of CAH are caused by either deficiency of 11β-hydroxylase (green), which causes hypertension and virilization, or 17α-hydroxylase (yellow), which leads to hypertension but absence of virilization.5

Figure 2. Marked hyperpigmentation of the gingival area (left) with sparing of the sublingual area (right).

References 1 Lee CT, Tung YC, Hsiao PH, Lee JS, Tsai WY. Clinical characteristics of Taiwanese children with congenital adrenal hyperplasia caused by 21-hydroxylase deficiency in the prescreening era. J Formos Med Assoc. 2010;109:148–155. 2 White PC, Speiser PW. Congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Endocr Rev. 2000;21:245.

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3 Bergner GE, Eisenstein AB. Addison’s disease in the Negro. J Clin Endocrinol Metab. 1951;11:322–329. 4 Guinovart RM, Carrascosa JM, Bielsa I, Rodriguez C, Ferrandiz C. A black tongue in a young woman. Clin Exp Dermatol. 2011;36:429–430. 5 Bolognia JL, Jorizzo JL, Rapini RP. Dermatology. Vol 1. 2nd ed. Philadelphia, PA: Mosby Elsevier; 2008:1013– 1014.

Addisonian-Like Hyperpigmentation


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January/February 2016

Volume 14 • Issue 1

CASE STUDY

Palmoplantar Keratoderma as a Variant of Lichen Planus Virendra N. Sehgal, MD; Ashok Aggarwal, MD;1 Nazim Hussain Syed, MD;1 Farhan Rasool, MD (Russia);1 Prashant Verma, MD;2 Sonal Sharma, MD2

A 52-year-old air conditioner mechanic presented with progressively itchy grayish white eruptions affecting the skin and mucous membranes, including his palms and soles for the past 2 months. The inner aspects of the palms and weight-bearing areas of the soles were the initial sites of presentation, resulting in a diffuse thickness of the palms and soles, which inhibited his everyday activity. The eruptions were asymptomatic but conspicuous. There was marked presence of multiple erythematous to grayish white (violaceous) flat-topped polygonal papules of varying sizes, with a few coalescing to form plaques. The papules varied in size from 5 mm to 4 cm and had prominent adherent scales on top when examined after smearing with mineral oil. Koebnerization was seen over the shin. The lesions were found on the wrists, forearms, ankles, legs, and thighs. There was a yellow to brown thick symmetric hyperkeratosis of the palms and soles, including the medial and lateral aspect of the fingers and toes, sparing the dorsal surfaces of the hands and feet (Figure 1). In addition, the medial arch and weight-bearing region of both soles were involved. The nails showed subungual hyperkeratosis, nail plate discoloration, and paronychia of the toes and fingers. Hyperkeratosis and scaly plaques were also identified in the web spaces (Figure 2). The buccal mucosa showed symmetrical white plaques with a lacy white pattern. (SKINmed. 2016;14:56–60)

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he patient had no history of jaundice or drug intake prior to the onset of the current episode. Results from renal and liver function tests, total and differential leukocyte count, complete hemogram, and erythrocytic sedimentation rate (Westergren) were normal. Serologic markers for hepatitis C virus and hepatitis B virus were normal. A VDRL was nonreactive, and results for Treponema pallidum hemagglutination was negative. Sections prepared with hematoxylin and eosin stain from the biopsy of representative palmar lesion showed basal cell damage/ alteration, comprising vacuolization, and liquefaction degeneration. Occasional melanin incontinence was also identified. In addition, there were multiple eosinophilic hyaline spherical bodies (Civatte bodies) seen in or just beneath the epidermis. A band-like dermal infiltrate comprising lymphocytes and a few macrophages, were prominent and was approximating the under

Figure 1. Multiple erythematous to grayish, white flattopped polygonal papules of varying sizes coalescing to form plagues.

From the Dermato-Venereology (Skin/VD) Center, Sehgal Nursing Home, Panchwati, Delhi, India, Skin Institute, and the School of Dermatology, Greater Kailash, New Delhi;1 and the Department of Dermatology and STD, and the Department of Pathology, University College of Medical Sciences and Associated Guru Teg Bahadur Hospital, Shahdra,2 Delhi, India Address for Correspondence: Virendra N Sehgal MD, Dermato Venerology (Skin/VD) Center, Sehgal Nursing Home, A/6 Panchwati, Delhi-110 033 India • E-mail: drsehgal@ndf.vsnl.net.in

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Figure 2. Subungual hyperkeratosis, nail plate discoloration, and paronychia of the toe.

Figure 4. Biopsy from the palm showing compact hyperkeratosis, hypergranulosis, and irregular acanthosis, accompanied by a band-like inflammatory infiltrate (hematoxylin and eosin stain, original magnification Ă&#x2014;40).

hyperkeratosis, hypergranulosis, and variable acanthosis, giving a saw-tooth appearance, was apparent (Figure 4). Discussion Lichen planus (LP) is a specific, relatively common, inflammatory dermatosis also affecting the mucocutaneous surfaces. It is characterized by pruritic, violaceous/grayish white, flat-topped, papule(s) and/or plaque(s) and a network of fine white lines (Wickham striae) on the surface. The lesions have a predilection for the flexor surface of the wrists, trunk, thighs, and genitalia. It has several well-recognized clinical variants; namely atrophic, annular, hypertrophic, linear, zosteriform, erosive, actinic, lichen planopilaris, erythematous, and bullous. In addition, the crossover syndrome of LP and bullous pemphigoid or lupus erythematous may also be seen.1 Lichenoid tissue reaction/interface dermatosis is another variant. The current report focuses on the palmoplantar LP, because this variant is uncommon and subsequently poses a diagnostic dilemma, especially if manifested in isolation.

Figure 3. Lichenoid reaction associated with apoptotic keratinocytes (Civatte bodies [arrows]) (hematoxylin and eosin stain, original magnification Ă&#x2014;200).

surface of the epidermis. Several cells invaded the basal cell layer; however, the lymphohistiocytic infiltrate did not obscure, interface, or extend into the mid-epidermis (Figure 3). The characteristic epidermal change in the form of compact orthokeratotic SKINmed. 2016;14:56â&#x20AC;&#x201C;60

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January/February 2016

CASE STUDY

Table. Differential Diagnosis of Palmoplantar Keratoderma Conditions

Histopathologic Features

Salient Clinical Features

Epidermal

Chronic dermatitis of Thick, hyperkeratotic lesions Presence of blisters/vesicles the palms and soles3 Psoriasis4

Nonspecific dermatitis

Well-demarcated, erythematous plaques and adherent silvery scales involving the extensor aspects of extremities symmetrically Nail involvement in about 50%, with an estimated lifetime risk of 80% to 90%

Parakeratosis: Initially in mounds that becomes confluent with time Intracorneal collections of neutrophils, Munro microabscesses Hypogranulosis, decreased thickness of the stratum granulosum Regular acanthosis, elongated and clubshaped rete ridges Relatively thin suprapapillary plates Collections of neutrophils in the spinous layer, the spongiform pustules of Kogoj

Pityriasis rubra pilaris Reddish orange scaly plaques, follicular hyperkeratotic papules, and palmo-plantar (PRP)5 keratoderma. â&#x20AC;&#x2DC;Islandsâ&#x20AC;&#x2122; of unaffected skin, the Nappes claires

Porokeratosis6

Syphilitic keratoderma7

Hereditary palmoplantar keratodermas8

Dermal

Alternating ortho-keratosis, and parakeratosis in vertical and horizontal directions Parakeratotic mounds at follicular ostia, the shoulder parakeratosis Follicular plugging Focal and/or confluent hypergranulosis Irregular acanthosis Irregular, elongated, and thickened, rete ridges Thickened suprapapillary plates and mild spongiosis

An inherited disorder of keratinisation. Atrophic patches surrounded by a hyperkeratotic ridge-like border. levels do not decrease variants include classic porokeratosis of Mibelli, disseminated superficial actinic porokeratosis, linear porokeratosis, and porokeratosis palmaris et plantaris disseminate Porokeratosis palmaris et plantaris disseminate usually appearing in early 20s and Wartlike, porokeratotic lesions affecting the palms and soles are characteristic. Punctuate porokeratosis is limited only to the hands and feet

Elongation and edema of dermal papillae containing dilated and tortuous capillaries Mild inflammatory infiltrate in the upper portion dermis and papillae

Superficial, perivascular lymphocytic infiltrate Moderately dilated blood vessels

Keratin-filled invagination of the epidermis Edema and patchy, containing parakeratotic column in the band-like incenter of the coronoid lamella approximatfiltrates, with ing markedly reduced granular zone presscattered apoptotic ence of dyskeratotic cells in the spinous bodies may be a layer may be prominent feature within the papillary dermis subjacent to the inner zone of a porokeratotic lesion

Cutaneous manifestation of secondary syphilis, characterized by symmetrical and diffuse hyperkeratosis of the palms and soles

Psoriasiform hyperplasia Rare spongiform postulation Lichenoid/vacuolar interface dermatitis

Lympho-histiocytic and plasma cellular infiltrate Granulomata end obliterative endovasculopathy

Diffuse, punctate, and linear forms of congenital keratoderma; affirmative family history, the lesions appear inflamed/verrucous

Palmoplantar LP is a morphologic expression that may either be

one-fourth of the typical lesions of LP might be present on the

a component of typical LP or an exclusive manifestation char-

skin and/or mucosal surfaces.2,3 The palmoplantar variant of LP

acterized by moderate to severe hyperkeratosis. One-third to

is more commonly seen in men than in women. Charcteristic

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CASE STUDY

Table. Differential Diagnosis of Palmoplantar Keratoderma – Continued Histopathologic Features

Conditions

Salient Clinical Features

Keratoderma climactericum9

Presents in women of menopausal age, initially affecting pressure areas on the soles. Erythema, hyperkeratosis and fissuring are its salient features and walking is painful. Subsequently, palmar involvement may occur. Discrete and centrally confined hyperkeratoses are characteristic. Obesity and hypertension may be associated

Aquagenic keratoderma10

Occurs during the second decade of life. Clinically, within minutes of immersion in water, translucent whitish papules and plaques appear on the palms and, less commonly, on the soles. The lesions resolve in due course, in minutes to hours after drying.

Bazex syndrome/ acrokeratosis paraneoplastica11

Red violaceous, scaly, psoriasiform plaques with ill-defined margins; affecting the acral parts of the hands, feet, nose, and earlobes bilaterally

Epidermal

Dermal

Compact orthokeratotic hyperkeratosis Hypergranulosis Irregular acanthosis with alternating thick and thin interpapillary ridges Spongiosis with exocytosis of lymphocytes

Perivascular lymphocytic infiltrate

The epidermis and dermis may either be normal or depict mild orthohyperkeratosis, hypergranulosis, acanthosis, and dilated eccrine ostia

Histopathologic changes are not diagnostically specific and include: Hyperkeratosis Focal parakeratosis Acanthosis (psoriasiform, or mild and irregular) Spongiosis Exocytosis of lymphocytes Basal vacuolar change Scattered apoptotic keratinocytes Rarely, intra-epidermal or subepidermal blisters have occurred. Mild perivascular lymphocytic infiltrate in the papillary dermis Scattered “pyknotic” neutrophils

Tripe palms/ acanthosis palmaris12

Cutaneous paraneoplastic syndrome associated with malignancy of the stomach/lung The palms are diffusely thickened, velvety in texture, and have a ridged appearance

Histologic appearance resembles that of acanthosis nigricans and the Leser-Trélat sign, hyperkeratosis, acanthosis, and papillomatosis.

Cutaneous T-cell lymphoma/mycosis fungoides13

May present in the form of hyperkeratosis of the palms and soles

Microscopic pathology is mandatory and has the following features: Hyperkeratotic epidermis, with acanthosis and hypertrophy of interpapillary ridges. Lymphoid proliferation was observed in the superficial dermis, with exocytosis and beginning epidermotropism. Lymphocytes depict an irregular and cerebriform nucleus, the Sézary cells.

Keratoses lichenoides vhronica/Nekam’s disease14

May rarely present with palmoplantar keraHistopathologic features of palmoplantar lichen planus are similar toderma. Diagnosis is supplemented by to those of classical lichen planus; however, unlike classical lichen lichenoid dermatitis with hyperkeratosis planus, parakeratoses may be seen in more than 50% of the biopsy and parakeratosis, loss of the granular layer, specimens a band-like inflammatory subepidermal infiltrate and colloid bodies

findings include the presence of pruriginous, erythematous scaly, and/or hyperkeratotic plaques with well-defined edges located on the internal plantar arch without involvement of the fingertips, which usually disappear in a few months. The current case is an example, where explicit hyperkeratosis of the palms and soles SKINmed. 2016;14:56–60

59

is the main feature, along with the other characteristic features of LP. Koebnerization was a predictable manifestation documented in the patient. The mechanical trauma may have aggravated the Palmoplantar Keratoderma as a Variant of Lichen Planus


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CASE STUDY

lesions. Palmar and plantar manifestations of LP alone might pose a diagnostic challenge, without the benefit of histpathologic confirmation. Palmoplantar lesions, in contrast to classic LP lesions, are not associated with Wickham striae and are not shiny; hence, histopathology is necessary to rule out the hyperkeratotic plaques of palms and soles found in several conditions (Table).

5 Sehgal VN, Srivastava G, Dogra S. Adult onset pityriasis rubra pilaris. Indian J Dermatol Venereol Leprol. 2008;74:311–321.

Hyperkeratotic papules, erythematous scaly plaques, diffuse keratoderma, ulcerated lesions, vesicle-like papules, umblicated papules, and diffuse palmar hyperpigmentation are a few of the well-recognized morphologic variants.15–17 In some cases, lesions may mimic secondary syphilis18 and should be excluded through appropriate blood serology. Conventional treatment of palmoplantar LP includes topical and/or systemic corticosteroids.3 Surgical excision with split-thickness skin grafting, oral acitretin, oral cyclosporine, and subcutaneous enoxaparin are other modalities shown to be effective for palmoplantar LP.

8 Sehgal VN, Sardana K, Sharma S, et al. Hereditary palmoplantar (epidermolytic) keratoderma: illustration through a familial report. Skinmed. 2004;3:323–332.

Conclusions

6 Sehgal VN, Dube B. Porokeratosis (Mibelli) in a family. Dermatologica. 1967;134:219–224. 7 Kirby JS, Goreshi R, Mahoney N. Syphilitic palmoplantar keratoderma and ocular disease: a rare combination in an HIV-positive patient. Cutis. 2009;84:305–310.

9 Deschamps P, Leroy D, Pedailles S, et al. Keratoderma climactericum (Haxthausen’s disease): clinical signs, laboratory findings and etretinate treatment in 10 patients. Dermatologica. 1986;172:258–262. 10 Phillips R. Aquagenic palmoplantar keratoderma: a new sign of cystic fibrosis? Br J Dermatol. 2011;164:224– 225. 11 Pecora AL, Landsman L, Imgrund SP. Acrokeratosis neoplastica (Bazex syndrome). Arch Dermatol. 1983;120:820–826. 12 Koulaouzidis A, Leiper K. Tripe palms or acanthosis palmaris. Intern Med J. 2007;37:502.

Palmarplantar keratoderma, as a variant of LP, should be considered in the differential diagnosis of palmar and plantar lesions.

13 Ghislain PD, Morant I, Alcaraz I, et al. Mycosis fungoides restricted to the palms: efficacy of methotrexate. Acta Derm Venereol. 2003;83:63–64.

References 1 Lehman JS, Tollefson MM, Gibson LE. Lichen planus. Int J Dermatol. 2009;48:682–694. 2 Black MM. Lichen planus and lichenoid disorders. In: Champion RH, Burton JL, Bruns DA, Breathnach SM, eds. Textbook of Dermatology. 6th ed. Vol 41. Oxford, England: Blackwell Science Inc; 1998:1899–1926. 3 Sanchez-Perez J, Rios Buceta L, Fraga J, et al. Lichen planus with lesions on the palms and/or soles: prevalence and clinicopathological study of 36 patients. Br J Dermatol. 2000;142:310–314. 4 Menter A, Gottlieb A, Feldman SR, et al. Guidelines of care for the management of psoriasis and psoriatic arthritis: Section 1. Overview of psoriasis and guidelines of care for the treatment of psoriasis with biologics. J Am Acad Dermatol. 2008;58:826–850.

14 Lombardo GA, Annessi G, Baliva G, et al. Keratosis lichenoides chronica. Report of a case associated with B-cell lymphoma and leg panniculitis. Dermatology. 2000;201:261–264. 15 Sanchez-Perez J, Rios Buceta L, Fraga J, et al. Lichen planus with lesions on the palms and/or soles: Prevalence and clinicopathological study of 36 patients. Br J Dermatol. 2000;142:310–314. 16 Cram DL, Kierland RR, Winkelmann RK. Ulcerative lichen planus of the feet. Arch Dermatol. 1966;93:692–701. 17 Kim MJ, Choi M, Na SY, et al. Two cases of palmoplantar lichen planus with various clinical features. J Dermatol. 2010;37:985–989. 18 Kim YS, Kim MH, Kim CW, et al. A case of palmoplantar lichen planus mimicking secondary syphilis. Ann Dermatol. 2009;21:429–431.

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January/February 2016

Volume 14 • Issue 1

CASE STUDY

Use of Oral Polypodium Leucotomos Extract in Chronic Photoinduced Hypersensitivity Dermatitis Adam J. Luber, MD;1 Antoanella Calame, MD;2 Sharon E. Jacob, MD3,4 A 52-year-old man with Fitzpatrick type V skin presented for evaluation of a photodistributed eruption of unknown origin. The patient reported a 20-year history of the dermatitis, with worsening severity during the past 6 years. He had required one hospital admission with intravenous methylprednisolone and two extended courses of oral prednisone (starting dose of 60 mg/d). He complained of pruritus and swelling localized to the sun-exposed areas of the forearms, face, and neck, with notable sparing of photoprotected areas of his skin. He denied new medications, and a systemic review of systems was noncontributory. (SKINmed. 2016;14:62–63)

O

n physical examination there were confluent eczematoid plaques with microvesiculation and erosions on the bilateral extensor forearms, face, and neck (Figure 1). Notably, the involved areas were in a photodistribution and spared the skin of the eyelids and the postauricular and submental regions. Results from patch testing revealed a positive contact allergy to p-Phenylenediamine. Findings from phototesting with UV-A light (up to 15 J/cm2) were normal. Results from photopatch testing of the patient’s commercial sunscreen products, the active ingredients of these products, and other potential photocontact allergens using 10 J/cm2 of UV-A were negative. Biopsy results demonstrated irregular epidermal acanthosis and spongiosis with overlying serum crust and bacteria, representing impetiginization. Scattered dyskeratotic keratinocytes were present in the epidermis. A superficial and mid-dermal infiltrate composed of lymphocytes, histiocytes, and numerous eosinophils was seen (Figure 2a and 2b). Histologic findings were consistent with those of a photoinduced or photoexacerbated hypersensitivity reaction. The patient was counseled about sun protection and discontinued from all possible photosensitizing medications, including hydrochlorothiazide, valproic acid, naproxen, citalopram, and trazodone. In addition, he was prescribed strict sun avoidance measures and standard topical and systemic therapies including triamcinolone ointment, clobetasol ointment twice daily, tacro-

limus ointment twice daily, aforementioned prednisone courses, hydroxyzine 25 mg every 6 hours, and hydroxychloroquine sulfate 400 mg daily for 7 months with minimal clinical improvement. After 2 years of sustained and unremitting dermatitis with subtherapeutic results, thiopurine methyltransferase levels were measured in anticipation of prescribing azathioprine. The patient was weary of the side effects and requested we try an alternative therapy. Oral Polypodium leucotomos extract (PLE) 240 mg daily was prescribed, while he was also using tacrolimus and triamcinolone ointment for the face and extremities, respectively. There were no other medication changes, no occupational or avocational changes, and no further changes in sun avoidance (ie, protective clothing, remaining indoors, increased sunscreen use). Within 3 months of PLE therapy and strict sun avoidance during the summer, the patient had complete clearance of the eruption on the photoexposed areas of his arms, face, and neck. Discussion PLE is an antioxidant oral supplement derived from the Polypodiaceae fern family, which is native to South America.1 For centuries, the fern has been used in traditional South American medicine due to its photoprotective effects. The extract has been shown to inhibit DNA damage and mutagenesis by interfering with the generation of reactive oxygen species (specifically, per-

From the Department of Dermatology, The Warren Alpert Medical School of Brown University, Providence, RI;1 Compass Dermatopathology, La Jolla, CA;2 Department of Dermatology, Loma Linda University, Loma Linda, CA;3 and the Dermatitis Academy, Redlands, CA4 Address for Correspondence: Sharon E. Jacob, MD, Loma Linda University, 11370 Anderson Street, Suite 2500, Loma Linda, CA 92354 • E-mail: sjacob@contactderm.net

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a

Figure 1. Photograph of the right forearm revealing erythematous, scaly, and lichenified lesions. b Figure 2. Histopathology showing acanthosis and spongiosis with overlying crusting and a dermal infiltrate composed of lymphocytes, histiocytes, and numerous eosinophils. (a) Low-power view (20×) and (b) high power view (400×).

oxide and nitric oxide), tumor necrosis factor α, NF-κB, and UV-induced activator protein-1.1–3 There are reports of PLE used in subacute cutaneous lupus erythematosus,1 polymorphic light eruption,4 and general chemophotoprotection.5 To our knowledge, this is the first report of the use of PLE to treat a chronic photoinduced hypersensitivity reaction. Pharmacologic studies demonstrate that the photoprotective dose of PLE in humans is 7.5 mg/kg with negligible toxicities at high doses.2

2 Gonzalez S, Gilaberte Y, Philips N, Juarranz A. Fernblock, a nutriceutical with photoprotective properties and potential preventive agent for skin photoaging and photoinduced skin cancers. Int J Mol Sci. 2011;12:8466– 8475.

Notably, UV-B testing was unfortunately not performed in our patient, as it was not available at the time. With the chronicity of his reaction, the diagnosis of a UV-B hypersensitivity reaction was entertained. It was strongly recommended to the patient that he return to have UV-B phototesting performed with and without PLE to better ascertain the true photoprotective and clinical impact of PLE, but he deferred.

3 Rodríguez-Yanes E, Juarranz Á, Cuevas J, et al. Polypodium leucotomos decreases UV-induced epidermal cell proliferation and enhances p53 expression and plasma antioxidant capacity in hairless mice. Exp Dermatol. 2012;21:638–640. 4 Tanew A, Radakovic S, Gonzalez S, et al. Oral administration of a hydrophilic extract of Polypodium leucotomos for the prevention of polymorphic light eruption. J Am Acad Dermatol. 2012;66:58–62.

References

5 Middelkamp-Hup MA, Pathak MA, Parrado C, et al. Oral Polypodium leucotomos extract decreases ultravioletinduced damage of human skin. J Am Acad Dermatol. 2004;51:910–918.

1 Breithaupt AD, Jacob SE. Subacute cutaneous lupus erythematosus: a case report of Polypodium leucotomos as an adjuvant therapy. Cutis. 2012;89:183–184.

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Edward L. Keyes Resident Contest for Outstanding Case Reports 11th World Congress of the International Academy of Cosmetic Dermatology June 23–25, 2016 Panama City, Panama Abstract deadline: April 15, 2016 To be awarded for the best Case Report submitted by a physician in training (resident, fellow, or registrar) for presentation at the 11th World Congress of the International Academy of Cosmetic Dermatology in Panama City, Panama, June 23–25, 2016. 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, or cosmetic (or combined) in nature. The author, whose abstract receives the highest score during the review process, will be awarded a scholarship by the IACD to present the full paper at the 11th World Congress of the International Academy of Cosmetic Dermatology in Panama City, Panama, June 23–25, 2016. The scholarship will provide reasonable travel expenses, lodging for 3 nights, the Congress registration fee, and a basic spending stipend. Abstracts should be submitted via email to vrosic@medicine.bsd.uchicago.edu before noon, CDT, April 15, 2016, and 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-thought-out, 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 31st, 2016. 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 1st, 2016. Vesna Petronic-Rosic, MD, MSc Chair, Resident Contest Committee Associate Professor The University of Chicago Pritzker School of Medicine Section of Dermatology Tel: +1.773.702.6559 vrosic@medicine.bsd.uchicago.edu


January/February 2016

Volume 14 • Issue 1

CASE STUDY

Tender Cystic Structure on the Back in an Infant Stephanie Channual, MD;1 Kristy Fleming, MD;2 Jashin J. Wu, MD3

A 1-year-old Hispanic boy with multiple congenital anomalies including a double-outlet right ventricle, significant scoliosis, kyphosis, and multiple hemivertebrae and hemilamina presented with recurrent febrile episodes. He was found to have Staphylococcus epidermidis meningitis, which persisted despite medical management. On physical examination, a 1×1-cm, tender, erythematous cystic structure with a purulent focus was discovered on the upper portion of his back (Figure 1). His mother noted that the structure was not present at birth, but there was a small red area at the time of delivery that had slowly developed into the lesion shown. T2-weighted sagittal magnetic resonance imaging showed a 4-mm sinus connection from the superficial cystic structure (white arrow) to another 2.4×1.5-cm cystic structure (black arrow) at the level of the hemivertebrae (Figure 2). (SKINmed. 2016;14:65–66)

H

istopathology of the cutaneous lesion revealed keratin and foreign body giant cells, findings characteristic of a ruptured epidermal inclusion cyst (Figure 3). Histopathology of the intradural cystic structure demonstrated neural tissue surrounded by a neutrophilic abscess with multinucleated giant cells (Figure 4). The vertebral abnormalities and pathologic and radiologic findings of the intradural cyst led to the diagnosis of a neurenteric cyst. The patient’s recalcitrant meningitis was determined to be secondary to a continual seeding of skin flora from the ruptured inclusion cyst, ventrally through the dermal sinus tract, to the neurenteric cyst in the posterior mediastinum, which had direct access to the spinal fluid. Discussion Neurenteric cysts are rare congenital disorders, bronchopulmonary foregut malformations, believed to arise from duplication and separation of the notochord (split notochord syndrome), which results in posterior enteric remnants.1 This separation leads to a gap through which yolk sac or primitive gut can herniate and eventually adhere to the dorsal ectoderm or skin.1 As a result, midline fistulae, sinuses, enteric diverticula, or posterior enteric cysts may develop, associated with malformations in the spinal column or cord.1 Spinal cord malformations include hemivertebrae, anterior and posterior spina bifida, absence of vertebrae, and diastematomyelia.2

The most common symptoms of neurenteric cysts are dyspnea and dysphagia, with patients typically presenting within the first month of life with respiratory distress from mechanical displacement of the lungs by the mass, anemia and melena (secondary to hemorrhage when the cyst is lined with gastric epithelium), vomiting, bowel obstruction, or less commonly meningitis.2,3 Cases have been described, however, with patients presenting later in life and with only cutaneous findings. One such case was reported of a 59-year-old woman with a recurrent sebaceous cyst midline on the back of her neck who was diagnosed with a neurenteric cyst after cervical magnetic resonance imaging revealed the characteristic findings of a dural cyst with vertebral abnormalities and connecting sinus tract.4 The triad of respiratory distress, a chest x-ray with vertebral abnormalities, and a posterior mediastinal mass at the level of the vertebral abnormalities is suggestive of a neurenteric cyst.5 Magnetic resonance imaging or computed tomography is also typically employed in order to provide a complete assessment of the anatomic structures involved, including the presence of sinus tracts, prior to surgery. In general, neurenteric cysts are treated with complete surgical excision of the lesion, often requiring the skills of a pediatric neurosurgeon. The prognosis varies on a caseby-case basis. Our patient underwent complete surgical excision of the neurenteric cyst, sinus tract, and ruptured epidermal inclusion cyst, and his meningitis promptly resolved.

From the Department of Radiology, David Geffen School of Medicine at University of California at Los Angeles, Ronald Reagan UCLA Medical Center, Los Angeles, CA;1 Island Dermatology, Newport Beach, CA;2 and the Department of Dermatology, Kaiser Permanente Los Angeles Medical Center, Los Angeles, CA3 Address for Correspondence: Jashin J. Wu, MD, Kaiser Permanente Los Angeles Medical Center, 1515 North Vermont Avenue, 5th Floor, Los Angeles, CA 90027 • E-mail: jashinwu@hotmail.com

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Figure 1. A 1-year-old boy with a 1-cm tender, erythematous cystic structure with a purulent focus located on the upper portion of hisback.

Figure 3. Hematoxylin and eosin stain of the intradural cystic structure demonstrating neural tissue surrounded by a neutrophilic abscess with multinucleated giant cells (original magnification ×10).

Figure 2. Results from sagittal T2-weighted magnetic resonance imaging reveal a 4-mm sinus connection from a superficial cystic structure (white arrow) to another 2.4×1.5-cm cystic structure (black arrow) at the level of the hemivertebrae.

Figure 4. Hematoxylin and eosin stain of the cutaneous lesion revealing keratin and foreign body giant cells (original magnification ×40).

Conclusions While neurenteric cysts are rare, this case highlights the need for caution in the excision of midline cutaneous lesions. Excision of a midline cutaneous lesion without prior radiologic evaluation may lead to exposure of cerebrospinal fluid and serious complications. References 1 Bentley JF, Smith JR. Developmental posterior enteric remnants and spinal malformations: the split notochord syndrome. Arch Dis Child. 1960;35:76–86.

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2 Fernandes ET, Custer MD, Burton EM, et al. Neurenteric cyst: surgery and diagnostic imaging. J Pediatr Surg. 1991;26:108–110. 3 Schurink M, van Herwaarden-Lindeboom MY, Coppes MH, et al. Neurenteric cyst—a case report of this rare disorder. J Pediatr Surg. 2007;42:E5–E7. 4 Becker GW, Battersby RD. Spinal neurenteric cyst presenting as recurrent midline sebaceous cyst. Ann R Coll Surg Engl. 2005;87:W1–W4. 5 Gilchrist BF, Harrison MW, Campbell JR. Neurenteric cyst: current management. J Pediatr Surg. 1990;25:1231– 1233.

Tender Cystic Structure on the Back in an Infant


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January/February 2016

Volume 14 • Issue 1

CASE STUDY

Postherpetic Nevocentric Erythema Multiforme Elizabeth Sutton, BA; Stephanie Sutton, MD;1 Christopher J. Smith, MD2

A previously healthy 35-year-old Caucasian woman presented with abrupt onset of erythematous, mildly pruritic plaques surrounding the majority of the nevi present on her neck, chest, back, and upper and lower extremities. She denied history of any recent systemic illnesses and was not taking any medications. On further questioning, the patient reported a recent episode of recurrent herpes labialis 2 weeks prior. The patient has a Fitzpatrick type I skin type with more than 100 brown and reddish brown pigmented macules and papules over her entire body. Plaques ranged in size from 0.4 cm to 1.5 cm depending on the size of the corresponding nevus. The patient’s skin was examined in its entirety, and there were no lesions suspicious for melanoma. Two biopsies were performed from the patient’s back: one from the nevus itself and another from the surrounding erythematous plaque. The nevocentric erythematous plaques were visible for approximately 1 week at which time they gradually disappeared without treatment. As these areas improved, the patient noticed targetoid lesions on the dorsal hands without associated nevi. Two weeks later, the targetoid lesions had spontaneously resolved. (SKINmed. 2016;14:68–69)

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esults from the biopsy of the nevus itself revealed compound melanocytic proliferation with no cytologic atypia. There was intense lymphomononuclear infiltrate in the dermis and impinging on the epidermis, where there was basaloid degeneration and exocytosis. Results from biopsy of the surrounding erythematous plaque demonstrated vacuolar interface change with prominent lymphocytes arrayed along the basal zone. These findings were consistent with the clinical diagnosis of nevocentric erythema multiforme (NEM). Discussion

Erythema multiforme (EM) consists of an acute, immune-mediated skin condition commonly encountered by dermatologists and characterized by the acute onset of “polymorphous eruption composed of symmetrically distributed macules, papules, bullae, and typical target lesions with a central vesicle or bulla.”1 EM is typically found symmetrically on the extensor surfaces of extremities; however, it is also found on the palms, soles, face, and neck.2 Extracutaneous mucosal involvement may occur with erythema multiforme. Herpes simplex virus (HSV) is the most common cause of erythema multiforme. Other causes include Mycoplasma pneumoniae, malignancy, radiation, and systemic drugs.3 The incidence of EM is less than 1% in the general popu-

lation, but it occurs more frequently in young, healthy individuals, with a slight predilection for men.2,4 NEM is a subset of EM, which presents as erythematous halos surrounding nevi. Usually, EM lesions do not occur specifically around nevi. There have been very few cases of NEM reported in the literature.5 Similar to our patient’s case, most cases occurred after HSV infection.5 As with other forms of EM, NEM usually resolves spontaneously; however, it can be treated with corticosteroids to hasten recovery. Postherpetic EM with mucosal involvement can also be treated with an antiviral such as acyclovir if diagnosed early, and prophylactic treatment with acyclovir, valacyclovir, or famciclovir can be used for recurrent erythema multiforme.6 Other skin conditions that present in a nevocentric distribution include leukoderma acquisitum centrifugum, Meyerson nevus, and targetoid nevus. The most common form of leukoderma acquisitum centrifugum is called “halo nevus” or “Sutton nevus.”7 A halo nevus consists of a benign nevus in regression surrounded by a depigmented macule.7 Nearly 50% of patients with a halo nevus ultimately have regression of the nevus.8 A Meyerson nevus consists of a nevus surrounded by an eczematous plaque.9

From the Departments of Psychiatry1 and General Internal Medicine,2 University of Nebraska Medical Center, Omaha, Nebraska Address for Correspondence: Stephanie Sutton, 985575 Nebraska Medical Center, Omaha, NE 68198 • E-mail: stephanie.sutton@unmc.edu

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CASE STUDY ogy of EM include spongiosis, exocytosis, and focal liquefaction degeneration of the basal cell zone of the epidermis.14 Conclusions We present a case of a 35-year-old woman with biopsy-proven nevocentric erythema multiforme secondary to recurrent herpes labialis. Nevocentric erythema multiforme is a rare condition that should be in the differential when a dermatologist has identified halo lesions around nevi. An accurate diagnosis of NEM will enable the clinician to identify and possibly treat the underlying cause that has triggered the nevocentric lesions. References 1 Aurelian L, Ono F, Burnett J. Herpes simplex virus (HSV)associated erythema multiforme (HAEM): a viral disease with an autoimmune component. Dermatol Online J. 2004;9:1. 2 Hebra F. On Diseases of the Skin Including the Exanthemata. Translated by Fagge CH. London, England: New Sydenham Society; 1866;1:285–289.

Figure 1. Patient’s nevus surrounded by an erythematous plaque during the resolution stage of the lesion.

3 Huff JC, Weston WL, Tonnesen MG. Erythema multiforme: a critical review of characteristics, diagnostic criteria, and causes. J Am Acad Dermatol. 1983;8:763–775. 4 Hellgren L, Hersle K. Erythema multiforme. Statistical evaluation of clinical and laboratory data in 224 patients and matched healthy controls. Acta Allergol. 1966;21:45–51. 5 Monsalvez V, Chico RJ, Lopez-Comez S, et al. Exudative erythema multiforme around nevi. Actas Dermosifiliogr. 2009;100:333–334. 6 Woo SB, Challacombe SJ. Management of recurrent oral herpes simplex infections. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2007;103 suppl 12:e1–e18. 7 Sutton RL. Unusual varieties of vitiligo (leukoderma acquisitum centrifugum). J Cutan Dis. 1916;34:797–800.

Figure 2. Histopathology image of biopsy from an erythematous plaque surrounding the nevus shows vacuolar interface change with prominent lymphocytes arrayed along the basal zone (H&E stain, original magnification ×40).

8 Frank SB, Cohen HJ. The halo nevus. Arch Dermatol. 1964;89:367–373. 9 Meyerson LB. A peculiar papulosquamous eruption involving pigmented nevi. Arch Dermatol. 1971;103:510– 512.

Targetoid nevi have a second peripheral erythematous ring surrounding a halo nevus.10 Depigmentation can also occur around melanomas.11 As with other causes of nevocentric halo phenomena, NEM is thought to be mediated by antibodies directed against nevocellular antigens and the presence of mononuclear cell infiltrates.12 Histopathology reports show an increase in lymphocytes and histiocytes in a perivascular arrangement in the upper portion of the dermis.13 Other inflammatory changes seen on histopatholSKINmed. 2016;14:68–69

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10 del-Rio E, Aguilar A, Gallego MA, et al. Targetoid halo nevus. J Am Acad Dermatol. 1993;29:267–268. 11 Rubegni P, Nami N, Risulo M, Tataranno D, Fimiani M. Melanoma with halo. Clin Exp Dermatol. 2009;34:749– 750. 12 Zeff R, Freitag A, Grin Z, et al. The immune response in halo nevi. J Am Acad Dermatol. 1997;37:620–624. 13 Ackerman AB, Penneys NS, Clark WH. Erythema multiforme exudativium: a distinctive pathological process. Br J Dermatol. 1971;84:554–566. 14 Howland WW, Golitz LE, Weston WL, Huff JC. Erythema multiforme: clinical, histopathologic, and immunologic study. J Am Acad Dermatol. 1984;10:438–446.

Postherpetic Nevocentric Erythema Multiforme


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NEUROMODULATORS FILLERS COSMECEUTICALS EMERGING TECHNOLOGIES ENERGY-BASED DEVICES

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January/February 2016

Volume 14 • Issue 1

correspondence Snejina Vassileva, MD, PhD, Section Editor

Facial Cutaneous Angiosarcoma With Eyelid Involvement Rym Benmously, MD;1 Anissa Zaouak, MD;1 Houda Hammami, MD;1 Wafa Koubaa, MD;2 Achraf Debbiche, MD;2 Samy Fenniche, MD1 To the Editor: A 64-year-old man presented with a 2-month history of a progressively enlarging asymptomatic pigmented patch located on the upper region of the face and on the left and right preauricular regions (Figure 1). He presented 2 months later with bilateral yellowish periorbital edema. In addition, the pigmented plaque became violaceous and infiltrated. He was otherwise well and had no other skin lesions or generalized lymphadenopathy. Histologic examination revealed the dermis to have a vascular atypical proliferation. There were ill-defined narrow vascular channels often anastomosing and dissecting bundles of collagen. The lumina were lined by single or multilayered, plump and pleomorphic endothelium and were sometimes filled with clusters of endothelial cells (Figure 2A). There were also undifferentiated spindle cells with prominent nuclei and abnormal mitosis (Figure 2B). The tumor cells in both vascular and solid areas were strongly stained by CD31, confirming their endothelial nature (Figure 3A). They also stained positive for FLI1 and D2-40 (Figure 3B). The diagnosis of cutaneous angiosarcoma was assessed. Findings from routine laboratory studies were normal, and results from a computed tomographic scan of the head were also normal. The patient underwent chemotherapy and radiotherapy but died 1 year later.

Figure 1. Violaceous infiltrated frontal plaque with bilateral yellowish periorbital edema.

Discussion

the head and neck region in patients older than 55 years. Angiosarcomas may occur in any region of the body but 60% arise in skin or superficial soft tissue, and about 50% of cutaneous angiosarcomas occur in the head and neck, as in our patient.6

Cutaneous angiosarcoma is one of the rarest forms of soft tissue neoplasms. It is an uncommon malignant tumor originating from endothelial cells,1–3 first described by Wilson Jones in 1964.4 It constitutes less than 1% of all malignant mesenchymal lesions and accounts for 2% of soft tissue sarcomas,2,5 and occurs mainly in

The clinical aspect is variable. Ill-defined bruise-like areas as in our patient or facial edema with minimal erythema are the initial signs.7 The tumor often spreads horizontally as well as vertically, eroding into the skull and orbit with multifocal infiltrating growth often extending far wider than the clinical ap-

From the Departments of Dermatology1 and Anatomopathology,2 Habib Thameur Hospital, Tunis, Tunisia Address for Correspondence: Anissa Zaouak, MD, Department of Dermatology, Habib Thameur Teaching Hospital, Research Unit “Genodermatoses and Cancers” LR12SP03, N°8 Ali Ben Ayed Street, Montfleury, Tunis, Tunisia • E-mail: anissa_zaouak@yahoo.fr

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January/February 2016

CORRESPONDENCE

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B

Figure 2. (A) Malignant endothelial cells dissecting dermal collagen and forming dilated spaces (hematoxylin and eosin stain, original magnification ×40). (B) Undifferentiated spindle cells with prominent nuclei and abnormal mitosis (hematoxylin and eosin stain, original magnification ×100).

A

B

Figure 3. (A) Tumor cells stained positively for CD31 (hematoxylin and eosin stain, original magnification ×100). (B) Tumor cells stained positively for D2-40 (hematoxylin and eosin stain, original magnification ×100).

pearance of the margins.8 In addition to the violaceous frontal plaques, our patient had bilateral periorbital edema. This edema may be caused by the angiosarcoma infiltrating the lymphatics or lymphatic obstruction.9,10 Histologic examination is important for a correct diagnosis, because clinical features of angiosarcoma of the face can often resemble those of some inflammatory disorders, which have a different prognosis.11 The histologic pattern is characterized by

irregularly anastomosing vascular channels lined by a single layer of enlarged endothelial cells and by solid areas of pleomorphic cells with poor luminal differentiation. The atypical lining cells of the vascular channels and the cellular piling are clues to the correct diagnosis.11

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As a result of the late presentation, difficulty in diagnosis and the highly aggressive nature of the tumor, the overall prognosis is poor, with a 5-year survival rate of approximately 12% to 27%.12 Facial Cutaneous Angiosarcoma With Eyelid Involvement


January/February 2016

CORRESPONDENCE 6 Chan LY, Tang WY, Lam WY, Lo KK. Angiosarcoma of the face and scalp. Eur J Dermatol. 2001;11:261– 263.

Conclusions The present case is reported for its rare clinical presentation, characterized by a frontal violaceous infiltrated plaque with bilateral periorbital edema. Hence, the diagnosis of cutaneous angiosarcoma should be considered in the differential diagnosis of bilateral periorbital edema in the elderly.

7 Verleysen A, Dewolf K, Geerts ML, Naeyaert JM. Angiosarcoma of the face and scalp. Eur J Dermatol. 2000;10:403– 404. 8 Mentzel T, Kutzner H, Wollina U. Cutaneous angiosarcoma of the face: clinicopathologic and immunohistochemical study of a case resembling rosacea clinically. J Am Acad Dermatol. 1998;38:837–840.

References 1 Sluzevich JC, Gloster HG, Mutasim DF. A case of regressing central facial cutaneous angiosarcoma. J Am Acad Dermatol. 2008;58:S113–S115.

9 Cannavo SP, Lentini M, Magliolo E, Guarneri C. Cutaneous angiosarcoma of the face. J Eur Acad Dermatol Venereol. 2003;17:594–595.

2 Enzinger FM,Weiss SW. Malignant vascular tumors. In: Enzinger FM, Weiss SW, eds. Soft Tissue Tumors. 3rd ed. St Louis, MO: Mosby; 1995:641–677.

10 Gunduz K, Shields JA, Shields CL, et al. Cutaneous angiosarcoma with eyelid involvement. Am J Ophthalmol. 1998;125:870–871.

3 Rich AL, Berman P. Cutaneous angiosarcoma presenting as an unusual facial bruise. Age Ageing. 2004;33:512–514. 4 Jones EW. Malignant angioendothelioma of the skin. Br J Dermatol. 1964;76:21–39.

11 Brown MD. Recognition and management of unusual cutaneous tumors. Dermatol Clin. 2000;18:543– 552.

5 Tay YK, Ong BH. Cutaneous angiosarcoma presenting as recurrent angio-oedema of the face. Br J Dermatol. 2000;143:1346–1348.

12 Holden CA, Spittle MF, Jones EW. Angiosarcoma of the face and scalp, prognosis and treatment. Cancer. 1987;59:1046–1057.

Palmar Acral Fibrokeratoma—A Rare Entity Sandeep Kulkarni, MBBS, DNB, MNAMS; Namrata Chhabra, MBBS, MD; Neel Prabha, MBBS, MD To the Editor: A 33-year-old man presented with a solitary, well-circumscribed, asymptomatic, skin-colored, garlic clove–shaped protuberant skin lesion. It was 5 mm to 8 mm in length and 2 mm in diameter and located at the base just proximal to the first web space on the thenar eminence of the right palm near the first palmar crease, placed obliquely at an acute angle to the palmar surface. It had a whitish collarette rim at its base (Figure 1). It was sessile and soft to firm in consistency, with no evidence of bleeding from the lesion on manipulation. The patient had developed this lesion over the course of 1 year. There was no family history of any associated limb defects, nor was there a history of any antecedent trauma. Systemic examination revealed no abnormality, and the patient denied receiving

any past immunosuppressive medication or other treatment for the condition. Results from cutaneous biopsy on examination showed a hyperkeratotic stratum corneum, especially towards the summit of the lesion, with epidermal acanthosis and elongated rete ridges. The dermal core was comprised of entwined bundles of dense collagen and thin elastic fibers aligned along the vertical axis of the lesion with interspersed fibroblasts (Figure 2a and 2b). A diagnosis of acquired digital/acral fibrokeratoma/garlic-clove fibroma was made. Discussion Acquired digital fibrokeratoma is a rare, benign fibrous tumor (fibroepithelioma), usually occurring in men as solitary, asymp-

From Maulana Azad Medical College and Lok Nayak Hospital,1 and the Institute of Genomics and Integrative Biology, Sukhdev Vihar,2 New Delhi, India Address for Correspondence: Kabir Sardana, MD, 466, Sector 28, NOIDA, UP, India 201303 • E-mail: kabirijdvl@gmail.com

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Palmar Acral Fibrokeratoma—A Rare Entity


January/February 2016

CORRESPONDENCE tomatic, skin-colored protuberances of about less than 1 cm involving distal (acral) portions of the extremities. There is a slight male preponderance, with patients aged 14 to 60 years commonly affected, and an average age of affection of 40 years. A 1968 report revealed 10 cases of unusual acquired growth on the dorsa of the fingers labeled “acquired digital fibrokeratomas.”1 Pinkus,2 however, reported similar cases with lesions on the toes, soles, proximal hands, and even on the prepatellar region, coining a more appropriate term for the entity “acral fibrokeratoma.”

Figure 1. A solitary, sessile, garlic clove–shaped, skincolored protrusion arising from the right palm.

This condition represents a benign clinical entity with an insidious onset and slow progression. Preceding trauma and systemic immunosuppressive medications (cyclosporine)4 have been implicated in its etiology. Excisional biopsy is both diagnostic and therapeutic, and its reoccurrence is rare. Conclusions A precise degree of clinical vigilance and characteristic histology helps in differentiating it from other benign entities such as supernumerary digits, cutaneous horns, periungual fibromas,5 keratotic warts, and idiopathic digital fibromatosis. This case emphasizes its inclusion in the list of differential diagnoses for benign protuberant lesions of acral parts of the extremities.References A

1 Bart RS, Andrade R, Kopf AW, Leider M. Acquired digital fibrokeratomas. Arch Dermatol. 1968;97:120–129. 2 Pinkus H. Discussion—acquired digital fibrokeratoma. Arch Dermatol. 1968;97:128–129. 3 Verallo VV. Acquired digital fibrokeratomas. Br J Dermatol. 1968;80:730–736. 4 Qiao J, Liu YH, Fang K. Acquired digital fibrokeratoma associated with ciclosporin treatment. Clin Exp Dermatol. 2009;34:257–259. 5 Kint A, Baran R. Histopathologic study of Koenen tumors. Are they different from acquired digital fibrokeratoma? J Am Acad Dermatol. 1988;18:369–372.ß

B Figure 2. (A) ×4 view of a histopathologic section through the lesion showing marked hyperkeratosis, acanthosis, and avdermal fibrovascular core composed of dense collagen bundles. (B) The same lesion after 10× magnification. SKINmed. 2016;14:71–76

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Palmar Acral Fibrokeratoma—A Rare Entity


January/February 2016

CORRESPONDENCE

Primary Localized Cutaneous Amyloidosis and Human Leukocyte Antigen A and -B in a Chinese Population Taige Cao, MBBS;1 Meixin Shen, PhD;2 Virlynn Tan, Msc;1 Ee Chee Ren, PhD;2 Hong Liang Tey, MBBS, FRCP(Edin)1,3

To the Editor: Primary localized cutaneous amyloidosis (PLCA) is a chronic pruritic dermatologic disease in which itching and undesirable appearance of skin lesions can severely affect patients’ quality of life. Although there are no data on the prevalence of PLCA, it has been clinically observed that PLCA is relatively common among Southern Chinese and South Americans.1 Genetic mutations have been found in some families with PLCA,2 and a recent report indicated that deficient clearing of apoptotic keratinocytes by an abnormal innate immune system occurs in PLCA.3 In view of the involvement of ethnic, familial, and immunologic factors in the disease’s occurrence, we conducted an exploratory study to investigate whether variations in the human leukocyte antigen (HLA) system are associated with PLCA in our Southern Chinese population. Elucidation of an association of HLA in PLCA will provide valuable insights into the pathogenesis of the disease, which is currently largely unknown. Methods We conducted a controlled cross-sectional analytical study involving 20 Singapore Chinese patients with PLCA and 192 healthy ethnic-matched controls. In all of the patients, the diagnosis of PLCA was made clinically and confirmed histologically with the demonstration of focal amyloid deposits at the dermal papillae of lesional skin. There were 10 women and 10 men, ranging in age from 23 to 69 years (mean 59.5 years), with a median age of disease onset of 48.5 years. Five of them had a family history of PLCA. The control patients were comprised of randomly selected Singapore Chinese participants determined in a previous study.4

Deoxyribonucleic acid was extracted from whole EDTA-peripheral blood samples of the patients using QIAGEN Blood and Tissue kit (QIAGEN Inc, Hilden, Germany). Amplification of HLA-A and -B genes were carried out with locus-specific primers. The PCR products were purified with the QIAquick Gel Extraction Kit (QIAGEN Inc), labeled with BigDye Terminator v3.1 (Applied Biosystems, Foster City, CA) and analyzed by sequencing. HLA genotypes were determined using sequencingbased typing, and allele and haplotype frequencies were estimated with Python for Population Genomics (PyPop; version 0.7) thereafter.5 The data were analyzed by Fisher exact test in GraphPad Prism software (version 6; GraphPad Software, Inc, La Jolla, CA). The study was approved by the National Healthcare Group’s ethics review board. Results The most commonly occurring alleles and common haplotypes of HLA-A and -B in PLCA patients were identified. Seven of the alleles and three of the common haplotypes were present in at least 20% of the patients (Table). They were not significantly different when their frequencies were compared with controls. Discussion It is known that the genes encoding HLA molecules are highly polymorphic and vary in frequency between different ethnicities and geographical locations. There were two previous publications concerning HLA association in PLCA. One reported no apparent disease-associated HLA antigens in nine patients of German descent with familial PLCA,6 while another suggested an association of familial PLCA with the HLA-B complex in a Puerto Rican family.7 These studies were inconclusive because

From the National Skin Centre;1 Singapore Immunology Network—A*Star;2 and Lee Kong Chian School of Medicine,3 Singapore Address for Correspondence: Hong Liang Tey, MBBS, FRCP(Edin), 1 Mandalay Road, Singapore 308205 • E-mail: teyhongliang111@yahoo.com

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Primary Localized Cutaneous Amyloidosis


January/February 2016

CORRESPONDENCE

Table. Most Common Human Leukocyte Antigen (HLA) Alleles and Common Haplotypes in Primary Localized Cutaneous Amyloidosis Patients Compared With Healthy Controls Allele Frequency, % HLA Alleles/Haplotype

Patients (2n=40)

Controls (2n=384)

P Value

A*11:01

30

30

1.00

A*02:03

15

8

.14

A*33:03

15

10

.42

A*24:02

13

13

1.00

B*40:01

23

16

.26

B*58:01

15

9

.25

B*38:02

10

5

.28

A*33:03–B*58:01

15

8

.12

A*02:03–B*38:02

10

4

.09

A*11:01–B*40:01

10

5

.28

of the small number of patients involved. In addition, genomic tissue–typing techniques with high accuracy and high resolution were unavailable at the time. On the other hand, a few studies dealt with genetic associations in PLCA. A genome-wide association study (GWAS) on 50 Taiwanese familial patients identified a susceptibility locus on chromosome 5p13.1-q11.2 and linkage to another locus on chromosome 1q23.8,9 This finding was corroborated by other investigators who mapped the disorder in a large Brazilian family to chromosome 5p13.1-q11.2.10 Subsequently, mutations of OSMRβ and IL-31RA genes, which code for the subunits of the interleukin-31 receptor, were found in some pedigrees.

3 Shiao YM, Chung HJ, Chen CC, et al. MCP-1 as an effector of IL-31 signaling in familial primary cutaneous amyloidosis. J Invest Dermatol. 2013;133:1375–1378. 4 Lam TH, Shen M, Chia JM, Chan SH, Ren EC. Populationspecific recombination sites within the human MHC region. Heredity (Edinb). 2013;111:131–138. 5 Lancaster AK, Single RM, Solberg OD, Nelson MP, Thomson G. PyPop update—a software pipeline for largescale multilocus population genomics. Tissue Antigens 2007;69 suppl 1:192–197. 6 Vasily DB, Bhatia SG, Uhlin SR. Familial primary cutaneous amyloidosis. Clinical, genetic, and immunofluorescent studies. Arch Dermatol. 1978;114:1173–1176.

Conclusions

7 De Pietro WP. Primary familial cutaneous amyloidosis. a study of HLA antigens in a Puerto Rican family. Arch Dermatol. 1981;117:639–643.

We report the first HLA association study in Chinese PLCA patients, which demonstrated an absence of significant association between PLCA and the HLA system.

8 Lee DD, Lin MW, Chen IC, et al. Genome-wide scan identifies a susceptibility locus for familial primary cutaneous amyloidosis on chromosome 5p13.1-q11.2. Br J Dermatol. 2006;155:1201–1208.

References

9 Lin MW, Lee DD, Lin CH, et al. Suggestive linkage of familial primary cutaneous amyloidosis to a locus on chromosome 1q23. Br J Dermatol. 2005;152:29–36.

1 Tan T. Epidemiology of primary cutaneous amyloidoses in southeast Asia. Clin Dermatol. 1990;8:20–24. 2 Lin MW, Lee DD, Liu TT, et al. Novel IL31RA gene mutation and ancestral OSMR mutant allele in familial primary cutaneous amyloidosis. Eur J Hum Genet. 2010;18:26–32.

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10 Arita K, South AP, Hans-Filho G, et al. Oncostatin M receptor-beta mutations underlie familial primary localized cutaneous amyloidosis. Am J Hum Genet. 2008;82:73– 80.

Primary Localized Cutaneous Amyloidosis


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January/February 2016

Volume 14 • Issue 1

Book Review Jennifer L. Parish, MD, Section Editor

Handbook of Systemic Drug Treatment in Dermatology, Second Edition Warren R. Heymann, MD

M

y mother just turned 94. Of all the traits I have inherited from her, the most enduring is the worry gene. Perhaps that is a good trait for anyone practicing medical dermatology who uses systemic medications, because there is so much about which to be anxious. Any text that can organize the vast amount of information necessary to treat and monitor these patients is a gift. The second edition of the Handbook of Systemic Drug Treatment in Dermatology (by Sarah H. Wakelin, Howard I. Maibach, and Clive B. Archer [CRC Press: Boca Raton, FL; 2015: 332 pages. $79.95]) is an outstanding resource that helps to alleviate worrying by providing precise guidelines and advice in managing our most infirmed patients who require these medications. Analysis

Although this is a multi-authored text, the editors have done an admirable job in providing uniformity of the chapters. Each drug chapter is organized by the following sections: Classification and Mode of Action; Indications and Dermatological Uses; Formulations/Presentation; Dosages and Suggested Regimens; Baseline Investigations and Considerations; Monitoring; Contraindications and Cautions; Important Drug Interactions; Adverse Effects and Their Management; Use in Special Situations (including pregnancy, lactation, and use in children and the elderly); Essential Patient Information; and Further Reading (with selected references). The book’s chapters are organized alphabetically. Interestingly, some chapters are topic-specific (eg, Tumor Necrosis Factor Antagonists), while others are drug-specific (eg, ustekinumab). Worthwhile additions include chapters devoted to systemic therapy in children, liver disease, and kidney disease. A variety of useful Tables and Figures are presented throughout the text, which serves to crystallize and summarize key points of the text.

I lent the book to my residents (at all levels) to see whether the book would be useful during clinic. They found the information to be complete but “digestible.” They were impressed by the breadth of drugs presented (including potassium iodide and intravenous immunoglobulin) and the sections on pathophysiology, dosing, monitoring, and adverse effects. They appreciated practical advice, such as how to taper propranolol for infantile hemangioma and dosing griseofulvin in children. As speed is of the essence in the clinic setting, the most common frustration was in accessing the desired information, as some drugs have their own chapters, while others are grouped categorically. This necessitated their going to the index more often than they would have liked, rather than being able to use the alphabetical approach, as intended by the editors.

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

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book review

Just like the newly minted Lexus that comes off the assembly line and immediately depreciates in value, the literal explosion of medical knowledge dictates that any such reference will be obsolete by the time it is published, despite the most valiant efforts by the editors. Examples include the lack of mention of the interleukin 17 antagonist secukinumab for psoriasis or the newly approved hedgehog inhibitor sonidegib for the treatment of advanced basal cell carcinomas.

dermatology patients, drug information is needed at the point of care. Accessing that data in real time would be a tremendous benefit. While I remain a bibliophile, what would be especially useful is having this outstanding text either integrated into the electronic medical record system, or, at the very least, as an application for a smart phone.

Recommendations

My patients are always appreciative when I check for drug interactions on my device. If this textbook could be converted to an electronic format, with vigilant updating by the editorial staff, that would change the dynamic from this being an excellent, useful text, to an absolutely indispensable resource.

I have now been using an iPad, cloud-based electronic medical record for the past two years. When seeing complicated medical

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