Skinmed May / Jun 2016

Chinese Society of Dermatology

Chinese Society of Dermatology

Parish and Lambert

COMMENTARY Erectile Dysfunction in Dermatology: It’s Not As Hard As You Think Daunton and Goulding

Belarusian Society of Dermatovenereologists and Cosmetologists

Lebanese Dermatological Society

Belarusian Society of Dermatovenereologists and Cosmetologists

EDITORIAL Dermatologic Jottings I: George Orwell’s Animal Farm Has Arrived

Lebanese Dermatological Society

North American Clinical Dermatologic Society

The Dermatologic & Aesthetic Surgery International League

African Association for Dermatology

May/June 2016 • Volume 14 • Issue 3 DEPARTMENTS

Su, Heng, Aw, and Tan

Clinical Efficacy and Safety of a Monopolar Radiofrequency Device With Comfort Pulse Technology for the Treatment of Facial and Neck Laxity in Men Fabi, Massaki, and Goldman

REVIEW What Is Vitamin D3 and Its Potential Use in Dermatology?

Sánchez-Armendáriz, García-Gil, and Domínguez-Cherit

Self Assessment Examination Lambert

CORE CURRICULUM Oral Mucosal Lesions: Miscellaneous––Part III

Sehgal, Syed, Aggarwal, and Sehgal

The Dermatologic & Aesthetic Surgery International League

African Association for Dermatology

May/June 2016 • Volume 14 • Issue 3

PERILS OF DERMATOPATHOLOGY A Leopard Can’t Change Its Spots, but a Melanocyte Can! False-Negative MART-1 Staining

Four Diseases, Two Associations, One Patient: A Case of Frontal Fibrosing Alopecia, Lichen Planus Pigmentosus, Acne Rosacea, and Morbihan Disease Walker, Robinson-Bostom, and Landow

NEW THERAPY UPDATE JUBLIA (Efinaconazole): An Update

Epidermal Nevus Presenting in a Pediatric Patient With PallisterKillian Syndrome

Singh, Kim, John, Handler, and Lambert

Gupta, Cernea, and Abramovits

ORIGINAL CONTRIBUTIONS Characteristics of Eccrine Tumors in a Tertiary Institution: A 5-Year Retrospective Study

North American Clinical Dermatologic Society

THE HEYMANN FILE Adult-Onset Still Disease Is on the Move Heymann

HISTORY OF DERMATOLOGY SOCIETY NEWSLETTER Dermatology in a Bygone Era: Part II Lowenstein

PHOTO CAPSULE Lymphangioma Circumscriptum of the Vulva

Nelson, Iyengar, and Shenefelt

Penile Granuloma Annulare Mercieca, Carabot, and Boffa

Scrotodynia: Diagnostic and Therapeutic Challenge Hosthota, Bondade, Monnappa, and Basavaraja

Facial Blanching After Cosmetic Botulinum Toxin Injection: Case Series Warren, Woody, and Vickers

Sehgal, Prasad, Lal, Kaviarasan, and Sharma

case studies A Souvenir From France: Acrodermatitis Chronica Atrophicans Presenting in the United States Correa-Selm, Bronsnick, Rao, Kirkorian, Marcus, and Cha

Porokeratotic Adnexal Ostial Nevus—Report of a Case With Unusual Clinical and Histologic Features

Lanoue, Jacobson, Ooka, Singh, Camacho-Vanegas, Martignetti, Levitt, and Phelps

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TABLE OF CONTENTS May/June 2016 • Volume 14 • Issue 3

EDITORIAL

Dermatologic Jottings I: George Orwell’s Animal Farm Has Arrived .......................................................... 168

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

COMMENTARy

Erectile Dysfunction in Dermatology: It’s Not As Hard As You Think ......................................................... 171

Adam Daunton, BSc, MBChB; Jon Goulding, BSc, BMBCh, MMedEd, FRCP

ORIGINAL CONTRIBUTIONS

Characteristics of Eccrine Tumors in a Tertiary Institution: A 5-Year Retrospective Study ......................... 175

Peiqi Su, MBBS; Jun Khee Heng, MBBS; Derrick Chen Wee Aw, MBBS; Kong Bing Tan, MBBS

Clinical Efficacy and Safety of a Monopolar Radiofrequency Device With Comfort Pulse Technology for the Treatment of Facial and Neck Laxity in Men ................................................................. 181

Sabrina Guillen Fabi, MD; Ane B. M. Niwa Massaki, MD; Mitchel P. Goldman, MD

REVIEW

What Is Vitamin D3 and Its Potential Use in Dermatology? ........................................................................ 187

Karen Sánchez-Armendáriz, MD; Ana García-Gil, MD; Judith Domínguez-Cherit, MD

Self Assessment Examination ................................................................................................................... 191

B:11”

T:10.75”

S:10.25”

W. Clark Lambert, MD, PhD

CORE CURRICULUM Virendra N. Sehgal, MD, Section Editor

Oral Mucosal Lesions: Miscellaneous––Part III ........................................................................................ 193

Virendra N. Sehgal, MD; Nazim Hussain Syed, MD; Ashok Aggarwal, MD; Shruti Sehgal, MDS

Departments Perils of Dermatopathology

W. Clark Lambert, MD, PhD, Section Editor

A Leopard Can’t Change Its Spots, but a Melanocyte Can! False-Negative MART-1 Staining ..................... 203

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

New Therapy Update

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

JUBLIA (Efinaconazole): An Update ......................................................................................................... 207

Aditya K. Gupta, MD, PhD, FRCPC; Maria Cernea, PhD; William Abramovits, MD

The Heymann File

Warren R. Heymann, MD, Section Editor

Adult-Onset Still Disease Is on the Move .................................................................................................. 211

Warren R. Heymann, MD

161

TABLE OF CONTENTS May/June 2016 2016 •• Volume Volume 14 14 •• Issue Issue 33 May/June

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

Dermatology in a Bygone Era: Part II ........................................................................................................ 213

Eve J. Lowenstein, MD, PhD

Photo Capsule

Lymphangioma Circumscriptum of the Vulva ............................................................................................ 215

Virendra N. Sehgal, MD; Pullabatla V. S. Prasad, MD; Jangid B. Lal, MD; Pichai Kaliaperumal Kaviarasan, MD; Sonal Sharma, MD

case studies

Vesna Petronic-Rosic, MD, MSc, Section Editor

A Souvenir From France: Acrodermatitis Chronica Atrophicans Presenting in the United States ............... 217

Lilia M. Correa-Selm, MD; Tara Bronsnick, BA; Babar K. Rao, MD; A. Yasmine Kirkorian, MD; Alan Marcus, MD; Jisun Cha, MD

Porokeratotic Adnexal Ostial Nevus—Report of a Case With Unusual Clinical and Histologic Features ................................................................................................................................................... 221

Julien Lanoue, BA; Karen B. Jacobson, MPH; Kohtaro Ooka, MD; Chanpreet Singh; Olga Camacho-Vanegas, PhD; John A. Martignetti, MD, PhD; Jacob Levitt, MD; Robert G. Phelps, MD

Four Diseases, Two Associations, One Patient: A Case of Frontal Fibrosing Alopecia, Lichen Planus Pigmentosus, Acne Rosacea, and Morbihan Disease .................................................................... 225

Joanna L. Walker, MD; Leslie Robinson-Bostom, MD; Shoshana Landow, MD

Epidermal Nevus Presenting in a Pediatric Patient With Pallister-Killian Syndrome ................................ 230

Garrett Nelson, MD; Sanjana Iyengar, BA; Philip Shenefelt, MD

Penile Granuloma Annulare ..................................................................................................................... 233

Liam Mercieca, MD, MRCP(UK); Philip Carabot, MD, Dip Ven, FRCP(Lond); Michael J. Boffa, MD, FRCP(Lond), MSc(Lond)

Scrotodynia: Diagnostic and Therapeutic Challenge ................................................................................. 237

Abhineetha Hosthota, MD, MBBS; Swapna Bondade, MD, MBBS; Divya Monnappa, MD, MBBS; Vinay Basavaraja, MD, MBBS

Facial Blanching After Cosmetic Botulinum Toxin Injection: Case Series.................................................... 239

Donald Warren, MD; Meghan Woody, MPH; Jennifer Vickers, MD

162

May/June 2016

Volume 14 • Issue 3

Editorial

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

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Chinese Society of Dermatology

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Belarusian Society of Dermatovenereologists and Cosmetologists

North American Clinical Dermatologic Society

African Association for Dermatology

The Dermatologic & Aesthetic Surgery International League

May/June 2016

Volume 14 • Issue 3

EDITOR IN CHIEF

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

DEPUTY EDITORS William Abramovits, MD

Aditya K. Gupta, MD, PhD, FRCPC

W. Clark Lambert, MD, PhD

Vesna Petronic-Rosic, MD, MSc

Dallas, TX

London, Ontario, Canada

Newark, NJ

Chicago, IL

Larry E. Millikan, MD

Marcia Ramos-e-Silva, MD, PhD

Jennifer L. Parish, MD

Meridian, MS

Rio de Janeiro, Brazil

Philadelphia, PA

EDITORIAL BOARD Mohamed Amer, MD Cairo, Egypt

Howard A. Epstein, PhD Philadelphia, PA

Jasna Lipozencic, MD, PhD Zagreb, Croatia

Todd E. Schlesinger, MD Charleston SC

Robert L. Baran, MD Cannes, France

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

Ada Lo Schiavo, MD Naples, Italy

Virendra N. Sehgal, MD Delhi, India

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

Charles Steffen, MD Oceanside, CA

George M. Martin, MD Kihei, HI

Alexander J. Stratigos, MD Athens, Greece

Marc S. Micozzi, MD, PhD Rockport, MA

James S. Studdiford III, MD Philadelphia, PA

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

Robert J. Thomsen, MD Los Alamos, NM

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

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

Mark Bernhardt, MD Ft. Lauderdale, FL Jack M. Bernstein, MD Dayton, OH Sarah Brenner, MD Tel Aviv, Israel Henry H.L. Chan, MB, MD, PhD, FRCP Hong Kong, China Joel L. Cohen, MD 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 William H. Eaglstein, MD Menlo Park, CA Charles N. Ellis, MD Ann Arbor, MI

Michael H. Gold, MD Nashville, TN Orin M. Goldblum, MD Indianapolis, IN

Oumeish Youssef Oumeish, MD, FRCP Amman, Jordan

Lowell A. Goldsmith, MD, MPH Chapel Hill, NC Seung-Kyung Hann, MD, PhD Seoul, Korea

Joseph L. Pace, MD, FRCP Naxxar, Malta

Roderick J. Hay, BCh, DM, FRCP, FRCPath London, UK

Art Papier, MD Rochester, NY

María Daniela Hermida, MD Buenos Aires, Argentina

Johannes Ring, MD, DPhil Munich, Germany

Warren R. Heymann, MD Camden, NJ

Roy S. Rogers III, MD Rochester, MN

Tanya R. Humphreys, MD Bala-Cynwyd, PA

Donald Rudikoff, MD New York, NY

Camila K. Janniger, MD Englewood, NJ

Robert I. Rudolph, MD Wyomissing, PA

Abdul-Ghani Kibbi, MD Beirut, Lebanon

Noah Scheinfeld, MD, JD New York, NY

SKINmed. 2016;14:165

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

Andrew P. Lazar, MD Washington, DC

165

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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 highpotency 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 Reference: 1. Enstilar® [prescribing information]. Parsippany, NJ: LEO Pharma Inc.; October 2015.

LEO, the LEO Lion Design, and Enstilar are registered trademarks of LEO Pharma A/S. ©2016 LEO Pharma Inc. All rights reserved. March 2016 MAT-02406

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 corticosteroidcontaining 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 Enstilar.com or call 1-855-772-7224.

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.

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• 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.).

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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

May/June 2016

Volume 14 • Issue 3

Editorial

Dermatologic Jottings I: George Orwell’s Animal Farm Has Arrived Lawrence Charles Parish, MD, MD (Hon);1 W. Clark Lambert, MD, PhD2

O

ccasionally, the practice of medicine, more specifically dermatology, presents situations that are hard to fathom. They may seem like aberrations in the scheme of things; other times, they appear to be fiction divorced from reality.

When we first learned of Animal Farm,1 we even wondered why undergraduates would be asked to read this book or perhaps another of Orwell’s, Nineteen Eighty-Four.2 As time passed, however, we came to realize that George Orwell, the pen name for Eric Arthur Blair (1903–1950), would prove to be right on target.

We have gathered some of these instances for your edification. If there are other experiences, please share them with us.

In the Daily Practice of Dermatology A patient presents for treatment of tinea versicolor. Hardly has the diagnosis been made after our viewing the red, scaly patches, when the duly afflicted patient announces his/her relief that the physician concurs with what he/she has found on a self-help website. Then, we decide to confirm the diagnosis, his/hers and ours, by performing a potassium hydroxide (KOH) examination on scales collected from the lesion, only to be blocked by a federal law, the Clinical Laboratory Improvement Act (CLIA). Unless the dermatologist has a CLIA certificate, the scrapings should be sent to a pathology laboratory that does not want them to be read by a pathologist with little experience who also does not want to read the KOH test and does not want to abuse his/ her microscope with the caustic base used in the KOH test. The whole procedure, with transport to the lab, taking several days, provided the specimen arrives at the lab at all, becomes problematic. Your tax dollars at work!

A great deal of confidence is generated when a new patient confides that you are only second best, selected only because the insurance has changed. The previous dermatologist was allknowing, compassionate, and whatever else, and no other dermatologist would do. When the patient is confronted, there is reassurance that you too may be an outstanding clinician—that is, as long as the same regimen is continued, which was selected by the previous dermatologist to begin with, not because it was the best medical plan, but only because it was in compliance with the insurance scheme.

Mrs J has brought her 14-year-old for acne treatment. The teenager is none too happy to be corralled in the office, but the visit is happily concluded. The next morning, Mrs J is on the phone with the office manager, “Doesn’t the doctor know they don’t make the acne cream anymore? How can the doctor be any good, if the woman at the chain drug store says so?” Translated: the establishment did not have the dermatologic in stock and obtaining it from an outside wholesaler is not permitted.

In Clinical Research Conducting a trial of a new therapeutic agent is no longer a simple expedition into the forays of the pharmaceutical industry. There are the machinations of the SMO (site management organization), CRO (clinical research organization), the sponsor (the company that has great hopes for the dermatologic agent), and the IRB (institutional review board). The dermatologist is assured that he or she is the important cog in the whole process, but one would never know it. Take for example, the invitation to spend a day in another city, learning about the protocol and the stipulations put forth to conduct the trial. The meeting con-

From the Department of Dermatology and Cutaneous Biology, Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia, PA,1 and the Department of Dermatology, New Jersey Medical School, Rutgers University, Newark, NJ2 Address for Correspondence: Lawrence Charles Parish, MD, MD (Hon), Clinical Professor of Dermatology and Cutaneous Biology, Sidney Kimmel Medical College at Thomas Jefferson University, 1845 Walnut Street, Suite 1650, Philadelphia, PA 19107 • E-mail: larryderm@yahoo.com

SKINmed. 2016;14:168–169

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May/June 2016

Editorial

cludes with the third party involved in the travel demanding that travel expenses be turned in within 2 weeks but that reimbursement will take 6 to 8 weeks.

The trial has begun, and the participants have been enrolled in the study. The monitor arrives to review the data. There is no information about this clinical research associate (CRA) or even whether he or she is qualified, ie, has an understanding of medical conditions rather than whether a blue or black pen has been used. The investigator has been subjected to the third degree with all types of documents demanded and the wrong date might have been used to accompany one of many signatures, rendering the entire document invalid.

In recent years, there has been a demand for the investigator to enter their data into programs that would make the Affordable Care Act blush. The software becomes so convoluted in an attempt to please all varieties of regulators that often the purpose for the trial becomes lost: did the agent really do what it is supposed to do?

In Insurance

tion? After all, the topical agent could be substituted at the whim of either of these people. When the patient is no better at the follow-up visit as a result, the dermatologist will be castigated for not getting the patient healed in the appropriated time.

The treatment of acne with oral retinoids has been an accepted therapy for nearly three decades. In the United States, a course of isotretinoin is generally given for 5 months. As if we had thought the iPledge program provided interference, there is now the insurance company, which deems a 4-month course as appropriate. If the patient needs additional treatment, which he/she cannot afford, that is just too bad for the patient, although good for the insurance company’s profits.

Should there not have been enough insults, the insurance company has decided that alopecia areata is a cosmetic disorder.

Short-contact anthralin therapy or injected triamcinolone may not be permitted. We presume that hair loss should not be treated according to these dictates. Would the same rationale hold for a digestive disturbance that causes belching or for the proverbial halitosis?

Conclusions

Physicians are no longer doctors or even medical school graduates, but rather providers. Instead of receiving remuneration for the services rendered, they are reimbursed, as if dermatologists had provided an outlay of monies and now could receive the reimbursement.

Following 4 years of intensive studies followed by postgraduate activities, the physician is then allowed to practice medicine.

Now the doctor is at the mercy of the primary care facility (aka general practitioner, known currently as the family physician) for the insurance referral. The patient is seen, a diagnosis is made, and a prescription is created. Again, there is a new crisis. Will the pharmacist decide to substitute a cream instead of an ointment (the chain drug store clerk has determined that there is no difference) or will the clerk at the insurance company (the sibling of the aforementioned employee) permit the filling of the prescrip-

The practice of medicine has now been taken out of the hands of physicians and placed into the hands of other parties who often have vested interests in conflict with those of the patient.

We have spoken about such dilemmas in the past, when we recounted how Aunt Mabel knew best.3 Aunt Mabel was able to pontificate in the past century. Now, we have to confront every self-help group that can afford a website, and not infrequently they have the controlling hand. Have not things gone too far?

References 1 Orwell G. Animal Farm. New York, NY: Harcourt, Brace and Company; 1946:1–11.

2 Orwell G. Nineteen Eighty-Four. New York, NY: Harcourt, Brave and Company; 1949:1–381.

3 Witkowski JA, Parish LC. The most important medical source: Aunt Mabel knows best. Skinmed. 2010;8:7–8.

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Erectile Dysfunction in Dermatology: It’s Not As Hard As You Think Adam Daunton, BSc, MBChB; Jon Goulding, BSc, BMBCh, MMedEd, FRCP

M

ale erectile dysfunction (ED) has been defined as the persistent inability to attain and/or sustain an erection sufficient for sexual performance.1 ED is extremely common, and both prevalence and severity increases with age.2 Self-reported ED of any degree affects up to 52% of men aged 40 to 70 years, while complete impotence can affect 5% of men at age 40 and 15% of men aged 70 years.2 While traditionally perceived as a benign disorder, the deleterious impact of ED on the psychosocial health and quality of life of men with ED and their families is well recognized.3 Systemic Associations

It is now well established that ED is not only associated with cardiovascular disease, but itself constitutes an independent risk factor for atherosclerosis, with a predictive value equal to or greater than many traditional risk factors.4,5 Although ED is often multifactorial in etiology, a major cause is atherosclerosis affecting the pelvic vasculature.6 The involvement in this process of narrow-calibre penile arteries offers a window of opportunity to pick up occult disease in larger vessels, with the time lag between the onset of vasculogenic ED and cardiovascular events estimated at 3 to 5 years.7 Risk stratification, screening investigations, and timely modification of remediable risk factors should be conducted for all patients with ED to help reduce future cardiovascular events and mortality.7,8 In recent years, there has been increasing recognition of the relationship between skin disease and sexual dysfunction; however, it is an issue that may be neglected or go undetected in the dermatology clinic. Both male and female sexual dysfunction has been identified as a potential issue among patients with psoriasis,9-13 atopic dermatitis,12 chronic hand dermatitis,14 neurodermatitis,15 systemic sclerosis,16 vitiligo,17 chronic urticaria,17 and acne.12 ED has also been identified as a distinct issue in men

with psoriasis,10,13,18–20 atopic dermatitis,21 chronic hand dermatitis,14 and systemic sclerosis.16 Other manifestations of sexual dysfunction include reduced libido, reduced frequency of sexual activity, and impaired self-perceived sexual attractiveness and self-confidence.12 Psoriasis A recent study suggests that ED occurs significantly more frequently in adult male outpatients with psoriasis when compared with a control group with other dermatologic conditions (odds ratio, 2.007; P=.026).18 Rigorous multivariate analysis indicated that age and hypertension, but not psoriasis, were independent risk factors for ED in this group.18 Rates of smoking and diabetes mellitus were also more common in the psoriasis cohort, in keeping with the number of studies linking psoriasis with the full complement of cardiovascular risk factors and with development of the metabolic syndrome and overt atherosclerotic disease.22,23 Subsequent studies using a large Taiwanese dataset have suggested that psoriasis may indeed represent an independent risk factor for ED,19,20 although replication of these results in different populations would assist in confirming such findings. The precise etiopathogenetic relationship between psoriasis, ED, the metabolic syndrome, and atherosclerosis remains to be elucidated, although recent studies have attempted to shed further light on their association.24 Concomitant causative factors for ED include the well-documented heightened levels of psychologic distress, anxiety, and depression, which are prevalent in patients with psoriasis.9,12,24,25 ED is also well-known to be caused or exacerbated by drugs, such as alcohol and antihypertensive agents,1 both of which are consumed more often by patients with psoriasis.26,27 There are isolated case reports linking ED with drugs used to treat psoriasis, such as acitretin28 and methotrexate.29

From the Department of Dermatology, Heart of England NHS Foundation Trust, Birmingham, UK Address for Correspondence: Jon Goulding, FRCP, Solihull Hospital, Dermatology Department, Lode Lane, Solihull, B91 2JL, UK • E-mail: jmrgoulding@hotmail.com

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Atopic Dermatitis An association has also been demonstrated between atopic dermatitis and ED, independent of cardiovascular risk factors and alcohol intake.21 The nature of this association has yet to be characterized, but it has been suggested that low levels of testosterone may play a role in men with atopic dermatitis and ED.30 Impaired self-esteem and sexual self-image have also been described in this group with the potential for a marked impact on sexual well-being and the capacity for intimacy.12 Systemic Sclerosis ED is observed in up to 81% of men with systemic sclerosis,31 and its presence correlates with severity of the disease.32 The etiology is thought to differ in this condition, with both myointimal proliferation within small arteries and corporal fibrosis limiting penile blood flow.31 Endothelial dysfunction has also been implicated.33 Importantly, on-demand oral phosphodiesterase type 5 (PDE-5) inhibitors are not effective in this setting, while longer-acting agents of this type may be more beneficial.31 Treatment of ED Treatment options for ED have improved considerably over the past 20 years (Figure).34 The choice of first-line therapy depends on the presence or absence of hypogonadism. While there is no evidence to suggest it is more common in patients with psoriasis than in other groups, it should still be checked as part of the routine workup. Men with a total plasma testosterone level persistently <12 nmol/L can benefit from a trial of testosterone replacement, and, if deemed effective over a trial period of up to 6 months, it may be continued indefinitely.1 It may be administered as a long-acting (3-month) depot injection or as a daily application of a transdermal gel, which most men find acceptable. First-line pharmacologic therapy for ED in men with normal testosterone levels (or who fail to respond adequately to testosterone alone) was revolutionized by the introduction of PDE-5 inhibitors in the late 1990s. These agents increase the amount of cyclic guanosine monophosphate available for smooth muscle relaxation, thus increasing corporal blood flow.34 Their use is effective in 75% of patients and is very safe.1 The choice of PDE-5 agent depends on individual circumstances, the main distinction being between those approved only for on-demand use (such as sildenafil) and those taken on a regular basis (such as tadalafil). The latter may be more suitable for men who engage in frequent intercourse or who regard spontaneity of intercourse as very important.34 As many men with organic ED may develop progressively worsening performance anxiety, which further exacerbates their ED, psychosexual therapy SKINmed. 2016;14:171â&#x20AC;&#x201C;174

from a psychotherapist may sometimes be required in addition to pharmacotherapy for optimal results.

Second-line therapies for those in whom the above measures fail or are contraindicated include direct intraurethral or intracavernosal patient-administered injection therapy, using vasodilator drugs, such as alprostadil, or vacuum pump constrictor therapy.34 While effective, these are both less acceptable and convenient for patients compared with oral therapy. In addition, injection therapy may cause adverse effects including local penile pain, hematomas, and palpable nodules, and can occasionally lead to priapism, whereas vacuum constrictors may cause pain at the site of the ring, blocked ejaculation, and numbness or pivoting of the penis. Penile prosthetic implants are reserved for patients in whom first- and second-line therapies have failed, although their satisfaction rates are relatively high among those who have failed all other therapies.34 Conclusions ED is extremely common among dermatology patients and the population at large; yet, active enquiry about it from healthcare professionals is rare.18 It is now recognized that the potential for ED, where relevant, needs to be addressed within the standard outpatient dermatology consultation, in an attempt to provide a holistic assessment of patient needs.18,35 When approached in a straightforward but sensitive manner, there should be no need to fear an awkward or embarrassing exchange. Asking a quick screening question about patient satisfaction with erectile function does not offer great sensitivity in picking up ED, because there may be understandable reluctance to reveal the existence or true extent of patient difficulties.18 Instead, use of a validated measure is recommended, such as the abridged five-item version of the International Index of Erectile Function (IIEF-5),36 which may be administered alongside standard scales assessing the severity of skin disease.

There is now a clear international consensus that all men with a new diagnosis of ED require a careful workup to establish likely causation and initiate investigations to confirm or refute the possibility of occult atherosclerotic disease.1,7,8 This may be conducted in primary or secondary care and should include a focused history and physical examination (including measurement of body mass index and blood pressure), followed by blood tests including serum testosterone, fasting glucose, and lipid profile (Figure).1,7 All patients should undergo risk stratification and modification of remediable risk factors.1,7,8 Patients at high risk for cardiovascular disease should be referred to a cardiologist for specialist evaluation and management.1,7,8

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Obtain comprehensive medical, sexual, and psychosexual history Perform cardiovascular, neurological and genitourinary examinations as indicated

Measure body mass index, blood pressure, fasting plasma glucose, lipid profile, thyroid function, and serum testosterone

Cardiovascular disease risk stratification

First-line treatment:

Refer high-risk patients to cardiologist

Modify remediable cardiovascular risk factors

– oral therapy with phosphodiesterase type 5 inhibitors and/or – testosterone supplementation if persistent testosterone deficiency and/or – psychosexual therapy if appropriate

Second-line treatment: – intraurethral or intracavernosal injection therapy – vacuum pump constrictor therapy

Third-line treatment: – penile prosthetic implants Figure. Diagnostic workup and management of erectile dysfunction.

References 1 British Society for Sexual Medicine. Guidelines on the Management of Erectile Dysfunction (2013 edition). http://www.bssm.org.uk/downloads/BSSM_ED_Management_Guidelines_2013.pdf. Accessed August 1, 2014).

2 Feldman HA, Goldstein I, Hatzichristou DG, et al. Impotence and its medical and psychosocial correlates: results of the Massachusetts Male Aging Study. J Urol.

1994;151:54–61.

3 San Martín C, Simonelli C, Sønksen J, et al. Perceptions of men and women on a man’s sexual confidence and its relationship to ED: results of the European Sexual Confidence Survey. Int J Impot Res. 2012;24:234–241.

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4 Thompson IM, Tangen CM, Goodman PJ, et al. Erectile dysfunction and subsequent cardiovascular disease.

JAMA. 2005;294:2996–3002.

5 Miner M, Seftel AD, Nehra A, et al. Prognostic utility of erectile dysfunction for cardiovascular disease in younger men and those with diabetes. Am Heart J. 2012;164:21–28.

6 Meuleman EJ, Diemont WL. Investigation of erectile dysfunction. Diagnostic testing for vascular factors in erectile dysfunction. Urol Clin North Amer. 1995;22:803–819.

7 Jackson G, Boon M, Eardley I, et al. Erectile dysfunction and coronary artery disease prediction: evidence-based guidance and consensus. Int J Clin Pract. 2010;64:848–857.

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8 Miner M, Nehra A, Jackson G, et al. All men with vasculogenic erectile dysfunction require a cardiovascular workup. Am J Med. 2014;127:174–182.

23 Gelfand JM, Dommasch ED, Shin DB, et al. The risk of stroke in patients with psoriasis. J Invest Dermatol.

2009;129:2411–2418.

9 Gupta MA, Gupta AK. Psoriasis and sex: a study of moderately to severely affected patients. Int J Dermatol.

1997;36:259–262.

24 Tasliyurt T, Bilir Y, Sahin S, et al. Erectile dysfunction in patients with psoriasis: potential impact of the metabolic syndrome. Eur Rev Med Pharmcol Sci. 2014;18:581– 586.

10 Türel Ermertcan A, Temeltaç G, Deveci A, et al. Sexual dysfunction in patients with psoriasis. J Dermatol.

2006;33:772–778.

11 Sampogna F, Gisondi P, Tabolli S, Abeni D. Impairment of sexual life in patients with psoriasis. Dermatology.

2007;214:144–150.

12 Magin P, Heading G, Adams J, Pond D. Sex and the skin: a qualitative study of patients with acne, psoriasis and atopic eczema. Psychol Health Med. 2010;15:454–462.

13 Meeuwis KA, de Hullu JA, van der Nieuwenhof HP, et al.

Quality of life and sexual health in patients with genital psoriasis. Br J Dermatol. 2011;164:1247–1255.

14 Ergün M, Türel Emertcan A, Oztürkcan S, et al. Sexual dysfunction in patients with chronic hand eczema in the Turkish population. J Sex Med. 2007;4:1684–1690.

15 Mercan S, Altunay IK, Demir B, et al. Sexual dysfunctions in patients with neurodermatitis and psoriasis. J Sex Marital Ther. 2008;34:160–168.

16 Walker A, Tyndall A, Ruszat R. Erectile dysfunction in systemic sclerosis. Ann Rheum Dis. 2009;68:1083–1085.

17 Sukan M, Maner F. The problems in sexual functions of vitiligo and chronic urticaria patients. J Sex Marital Ther.

2007;33:55–64.

18 Goulding JM, Price CL, Defty CL, et al. Erectile dysfunction in patients with psoriasis: increased prevalence, an unmet need, and a chance to intervene. Br J Dermatol.

2011;164:103–109.

19 Chung S, Keller J, Chu T, Lin H. Psoriasis and the risk of erectile dysfunction: a population-based case-control study. J Sex Med. 2012;9:130–135.

20 Chen Y, Chen C, Lin M, et al. Increased risk of sexual dysfunction in male patients with psoriasis: a nationwide population-based follow-up study. J Sex Med. 2013;10:1212–1218.

21 Chung S, Keller J, Lin H. Association of erectile dysfunction with atopic dermatitis: a population-based casecontrol study. J Sex Med. 2012;9:679–685.

22 Gelfand JM, Neimann AL, Shin DB, et al. Risk of myocardial infarction in patients with psoriasis. JAMA. 2006;296:1735–1741.

25 Han C, Lofland JH, Zhao N, Schenkel B. Increased prevalence of psychiatric disorders and health care-associated costs among patients with moderate-to-severe psoriasis. J Drugs Dermatol. 2011;10:843–850.

26 Adamzik K, McAleer MA, Kirby B. Alcohol and psoriasis: sobering thoughts. Clin Exp Dermatol. 2013;38:819–822.

27 Armstong AW, Harskamp CT, Armstrong EJ. The association between psoriasis and hypertension: a systematic review and meta-analysis of observational studies. J Hypertens. 2013;31:433–442.

28 Rossi M, Pellegrino M. Acitretin-associated erectile dysfunction: a case report. Cases J. 2009;19:210.

29 Wylie G, Evans CD, Gupta G. Reduced libido and erectile dysfunction: rarely reported side-effects of methotrexate. Clin Exp Dermatol. 2009;34:e234.

30 Canguven O. The role of low testosterone associated with erectile dysfunction with atopic dermatitis. J Sex Med. 2013;10:618.

31 Walker UA, Tyndall A, Ruszat R. Erectile dysfunction in systemic sclerosis. Ann Rheum Dis. 2009;68:1083– 1085.

32 Foocharoen C, Tyndall A, Hachulla E, et al. Erectile dysfunction is frequent in systemic sclerosis and associated with severe disease: a study of the EULAR Scleroderma Trial and Research group. Arthritis Res Ther.

2012;14:R37.

33 Rosato E, Barbano B, Gigante A, et al. Erectile dysfunction, endothelium dysfunction, and microvascular damage in patients with systemic sclerosis. J Sex Med. 2013;10:1380–1388.

34 McMahon C. Erectile 2014;44:18–26.

dysfunction.

Intern Med J.

35 Ladizinski B, Federman DG. Approaching erectile dysfunction in dermatology patients. JAMA Dermatol.

2013;149:783–784.

36 Rosen RC, Cappelleri JC, Smith MD, et al. Development and evaluation of an abridged, 5-item version of the International Index of Erectile Function (IIEF-5) as a diagnostic tool for erectile dysfunction. Int J Impot Res. 1999;11:319-326.

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Volume 14 • Issue 3

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Characteristics of Eccrine Tumors in a Tertiary Institution: A 5-Year Retrospective Study Peiqi Su, MBBS;1 Jun Khee Heng, MBBS;1 Derrick Chen Wee Aw, MBBS;1 Kong Bing Tan, MBBS2 Abstract Eccrine tumors are adnexal tumors with a varied clinical presentation and wide histological spectrum. This study aims to consolidate data on the clinical characteristics of eccrine tumors to help improve clinical acumen and management of such tumors. Histopathological records from January 2008 to December 2012 were retrieved. Clinical characteristics of the tumor including site, appearance, symptoms, color, duration prior to presentation, and clinical and histological diagnosis were recorded. Eighty-four patients with eccrine tumors were identified, with seven main types of tumors recognized—hidradenoma (33.3%), poroma (29.8%), mixed tumors (14.3%), spiradenoma (8.3%), porocarcinoma (6.7%), eccrine adenoma (3.6%), and syringoma (3.6%). A total of 50% of mixed tumors were misdiagnosed as epidermal cysts. Eccrine tumors have a wide array of clinical presentations and are often clinically misdiagnosed as cysts. Recognizing certain clinical features may aid in the diagnosis, but, if in doubt, a biopsy should be performed. (SKINmed. 2016;14:175–180)

E

ccrine tumors are uncommon sweat gland neoplasms that are generally benign, although malignant types exist.

They belong to a wider group of cutaneous adnexal tumors, which also encompass apocrine, follicular, and sebaceous tumors. Developmentally, eccrine sweat glands originate from epidermal epithelial germs, a collection of deeply basophilic cells in the basal cell layer of the epidermis, protruding into the dermis.1 They are widely distributed in the skin, occurring in almost any site.

Histological classification of eccrine tumors is complex and can occasionally be challenging, even for an experienced pathologist.2 Many benign sweat gland tumors have malignant counterparts. The latter may arise from preexisting benign tumors. Thus, complete excision of all skin adnexal lesions is always advisable.

The clinical presentation of eccrine tumors may differ in terms of distribution, appearance, and color. Poromas classically show a predilection for acral sites and may be solitary or multiple; however, they may “atypically” present at other sites including the head and neck.3 Hidradenoma is a benign adnexal tumor that is regarded as being of eccrine and/or apocrine nature. It

usually presents as a solitary skin-colored or red-to-blue nodule more often found in women.4,5 Much of the literature on eccrine tumors has focused on isolated case reports. Few studies have investigated their collective clinical characteristics. In this study, we aim to examine the clinical features of eccrine tumors, correlate them with histopathological features, and raise awareness of how these may give rise to pitfalls in clinical diagnosis.

Materials and Methods Histopathological records from January 1, 2008, to December 31, 2012, were retrieved. Retrospective analysis of data was conducted on all patients with a diagnosis of an eccrine tumor.

They were further subdivided based on the type of eccrine tumor diagnosed. Data extraction was conducted by two independent reviewers with a standardized data collection sheet. Clinical characteristics of the tumor (site, appearance, symptoms, color, duration prior to presentation, clinical and histological diagnosis) were recorded.

From the Department of Medicine, Division of Dermatology,1 and the Department of Pathology, Yong Loo Lin School of Medicine,2 National University Health System and National University of Singapore Address for Correspondence: Peiqi Su, MBBS, National University Hospital, 1E Kent Ridge Road, NUHS Tower Block, Level 10, Singapore 119228 • E-mail: peiqi_su@nuhs.edu.sg

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Eccrine poromas and porocarcinomas

Figure 1. A pinkish nodule representing an eccrine poroma on the heel.

Figure 2. An ulcerated nodule representing an eccrine porocarcinoma with a hemorrhagic crust over the forearm.

(a)

There were 25 poromas and 6 porocarcinomas. The majority of the patients were women (poromas, 56%; porocarcinomas, 83.3%). The average age of patients at presentation was similar (poromas, 54.6 years; porocarcinomas, 52.5 years). Eccrine poromas were most commonly located on the feet (n=9, 36%) (Figure 1), trunk (n=6, 24%), and head/neck (n=4, 16%), and were within 2 cm. In contrast, eccrine porocarcinomas were more common on the extremities (n=5, 83%) and none were smaller than 1 cm. All but two patients with eccrine poromas were asymptomatic. The two patients who experienced symptoms reported bleeding. The average duration of the lesion prior to the diagnosis of an eccrine poroma was 49.9 months.

All patients with eccrine porocarcinomas were asymptomatic but had a drastically shorter duration of 2 months prior to diagnosis.

Eccrine poromas presented as either nodular (59.1%), polypoidal (9.1%), papular (22.7%), or cystic (4.5%) lesions. Only 14 patients had the color of their lesions described. Twelve of these were skin-colored while the remaining two were brown. A total of 50% of the eccrine porocarcinomas were nodular, 33% polypoidal, and 17% ulcerated (Figure 2). Half of the lesions appeared skin-colored while the other half were brown. Only two patients with eccrine poromas were correctly diagnosed prior to histological examination (Figure 3a). None of the patients with porocarcinomas were correctly diagnosed prior to histological (b)

Figure 3. (a) Histological examination of the eccrine poroma from the patient in Figure 1. There is pushing downgrowths of uniform-appearing cells from the epidermis into the dermis (hematoxylin and eosin stain, original magnification Ă&#x2014;100). (b) Porocarcinoma showing infiltrative downgrowths of mitotically active atypical cells from the epidermis into the dermis (hematoxylin and eosin stain, original magnification Ă&#x2014;100).

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examination (Figure 3b). Figures 3a and 3b show the representative photomicrographic examination of an eccrine poroma and porocarcinomas, respectively.

Hidradenoma This group comprised the largest (n=28, 33.3%) cohort of patients with an eccrine tumor. There were more men (57.1%) with hidradenomas than women. The average age was 45.9 years (age range, 9–74 years). Hidradenomas were most commonly found on the trunk (n=12, 42.9%), head/neck (n=7, 25%), and lower limb (n=6, 21.4%). Most of these lesions were greater than 1 cm. Only one patient experienced pain while the remainder of the patients were asymptomatic. Few clinical appearances were described, including cystic (50%), nodular (35.7%), and papular (7.1%) (Figure 4). Seventeen patients had the color of their lesions recorded, with 12 skincolored, two brownish, one yellowish, one bluish, and one pinkish. The average duration of the lesions prior to diagnosis was 40.5 months. None of the patients were thought to have a hidradenoma at first consultation. Half (50%) were misdiagnosed as an epidermal cyst prior to biopsy. Histopathologically, the hidradenomas were subclassified as nodular, clear cell (Figure 5), solid-cystic, or atypical types.

Immunohistochemistry with polyclonal carcinoembryonic and/ or epithelial membrane antigen was performed in four cases to highlight the presence of ductal lumina, aiding in the diagnosis of the lesion.

Benign mixed tumor Mixed tumors (n=12, 14.3%) were slightly more common in women (58.3%). The mean age of patients with mixed tumors was 60.8 years (age range, 40–83 years). Half of the lesions were concentrated around the head/neck region while most lesions (83.3%) were between 1 cm and 2 cm. Patients were generally asymptomatic. A total of 50% of the lesions appeared nodular, 41.7% cystic, and 8.3% papular (Figures 6 and 7). The average duration of the lesions prior to diagnosis was 77.8 months, and half were initially diagnosed as an epidermal cyst.

Figure 4. A skin-colored forearm nodule representing a hidradenoma resembling a cyst.

Figure 5. Histopathology of hidradenoma showing a smooth-contoured dermal tumor composed of uniform, rounded cells with interspersed ductal lumina noted. The overlying epidermis is normal (hematoxylin and eosin stain, original magnification ×20).

Spiradenoma and syringoma eccrine adenoma These lesions comprised the smallest group of eccrine tumors, including spiradenomas (n=7, 8.3%), eccrine adenomas (n=3, 3.6%), and syringomas (n=3, 3.6%). The most common sites for spiradenomas were the upper (n=2, 28.6%) and lower (n=4, 57.1%) limbs. All three (one man and two women) of the patients who were diagnosed with syringomas had lesions located on the face (Figure 8).

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Figure 6. This patient was misdiagnosed as having an inflamed epidermal cyst. The biopsy featured a benign mixed tumor (chondroid syringoma) (Figure 7).

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Figure 7. Histopathology of benign mixed tumor showing a circumscribed dermal tumor nodule composed of branching bilayered ductal structures embedded within a fibromyxoid stroma. The overlying epidermis is intact (hematoxylin and eosin stain, original magnification ×40).

Figure 9. Spiradenoma showing a well-circumscribed dermal nodular cellular proliferation, composed of small basaloid cells and cells with more ample, clear cytoplasm (hematoxylin and eosin stain, original magnification ×100).

Figure 8. Site distribution of eccrine tumors.

Patients with spiradenomas had an average age of 56.1 years (age range, 42–81 years). A total of 42.9% had tumors between 1 cm and 2 cm and 42.9% were larger than 2 cm. Six patients had tumors that appeared nodular and one that appeared polypoidal. The average time of the tumor prior to diagnosis was 44.7 months. All except one of the patients were initially diagnosed as having a skin tag or lipoma. Histological examination showed a dermal proliferation of basaloid cells (Figure 9).

There were only three patients diagnosed with an eccrine adenoma (Figure 10). Their mean age was 53.1 years (age range, 42–67 years). All three patients had lesions larger than 1 cm.

One patient complained of itching. Two of the lesions appeared nodular while the third appeared cystic. Patients reported having the lesion for an average of 2 months prior to seeking consultation. Two were misdiagnosed as an epidermal cyst.

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Figure 10. Papillary eccrine adenoma showing a circumscribed dermal collection of variably dilated ducts lined by a few layers of bland epithelial cells. Some ducts show micropapillary structures (hematoxylin and eosin stain, original magnification ×40).

Discussion

Eccrine poroma and porocarcioma Eccrine poromas are benign, solitary, slow-growing papules or nodules that occur most frequently on the sole of the foot. Indeed, we found that the most common location for poromas was the feet, whereas eccrine porocarcinomas were found most commonly on the lower limb and less frequently on the upper limbs and head/neck region. This is comparable to findings in

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other studies where lesions manifested as nodules or plaques on the head, neck, trunk, or lower limbs.6 A striking finding is that the porocarcinomas had a much shorter duration of presentation (2 months) in contrast to the much longer duration of 49.9 months in patients with poromas. In addition, 17% of the porocarcinomas had ulceration, whereas none of the poromas did. Thus, features of ulceration and rapid growth should prompt the physician to excise the lesion early.

Hidradenoma Hidradenomas usually manifest as solitary, skin-colored or red nodules in middle-aged women.7 The most common site of hidradenomas in our study was the trunk. Other studies have also found such tumors to be prevalent on the head, trunk, and extremities.7 Although malignant hidradenomas do exist, there were no patients with these lesions included during the 5-year data collection period. In such cases, wide aggressive excision and lymphadenectomy may be required.8

Benign mixed tumor Mixed tumors consist of epithelial and stromal elements. They can be further classified into benign and malignant forms.

Chondroid syringomas are the main example of and are often regarded as being synonymous with benign mixed tumors. In contrast to syringomas, which commonly appear as multiple periorbital skin-colored papules, chondroid syringomas typically present as dermal or subcutaneous nodules. They are often confused with various skin lesions9 as demonstrated in our findings.

In line with previous studies, we found that mixed tumors were mainly distributed in the head and neck region.10,11 Many cases of hidradenomas and mixed tumors were misdiagnosed as epidermal cysts. Considering the histopathological features (Figures 5 and 7), such tumors would be expected to be more solid and firm as compared with epidermal cysts, and would not generally feature a punctum on the skin surface. In equivocal cases, it is therefore prudent for clinicians to have a low threshold for converting a punch extrusion to a complete excision for a presumed epidermal cyst if the typical cheesy content is not expressed during the procedure.

Spiradenoma This often appears as a solitary tender nodule on the upper body of young adults.12 In contrast, the mean age at presentation in our study was 56.1 years. Although there was no record of eccrine spiradenocarcinoma during our study, they are often larger than their benign counterpart and may enlarge rapidly.13 SKINmed. 2016;14:175–180

Syringoma Syringomas are benign eccrine sweat gland tumors that affect mainly women. Although the site of predilection is the face, in particular the lower eyelids, there have been rare reports of vulval syringomas presenting with pruritus.14

Eccrine adenomas Sometimes termed papillary eccrine adenomas, these lesions appear as well-circumscribed nodules most commonly found on the scalp. Only three patients were identified as having an eccrine adenoma, reflecting the poor description of such cases in the literature; however, 67% of our patients had lesions in the upper limb. Similar to the tumors described above, eccrine adenomas were most commonly misdiagnosed as cysts.

Cylindromas These are benign eccrine tumors that are normally found in the head and neck region, particularly on the scalp. We did not find any patients with cylindromas in the present study.

Histologically, they appear as islands of basaloid cells in the dermis that often fit together in a characteristic “jigsaw puzzle” arrangement.

Study Limitations First, due to the descriptive nature of the study, the information collected may have been subjective (eg, symptoms, perceived duration of the lesion prior to diagnosis) rather than objective. In addition, the study numbers were small; however, most of our findings were comparable to that of other studies. Second, some data were missing or not described in the records. For example, many of the patients did not have the color of their lesions described; however, this did not influence the overall results of the study, which focused on the site distribution and appearance of the lesions. Lastly, we did not conduct any follow-up studies on the outcome of these patients and thus are unable to comment on the adequacy of treatment following excision.

Conclusions This study shares some insights on the more “common” eccrine tumors and their clinicopathological characteristics. Attention to these would aid clinical diagnosis and institution of appropriate management for the majority of cases. Data regarding optimal treatment of some eccrine tumors, particularly malignant ones, are lacking. It may be useful to perform long-term studies on the treatment and complications of such tumors to better manage patients in the future.

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References 1 Alsaad KO, Obaidat NA, Ghazarian D. Skin adnexal neoplasms—part 1: an approach to tumours of the pilosebaceous unit. J Clin Pathol. 2007;60:129–144.

2 Obaidat NA, Alsaad KO, Ghazarian D. Skin adnexal neoplasms—part 2: an approach to tumours of cutaneous sweat glands. J Clin Pathol. 2007;60:145–159.

3 Betti R, Bombonato C, Cerri A, et al. Unusual sites for poromas are not very unusual: a survey of 101 cases.

Clin Exp Dermatol. 2014;39:119–122.

4 Kakinuma H, Miyamoto R, Iwasawa U, et al. Three subtypes of poroid neoplasia in a single lesion: ecrrine poroma, hidroacanthoma simplex, and dermal duct tumour. Histologic, histochemical, and ultrastructural findings. Am J Dermatopathol. 1994;16:66–72.

5 Kersting DW. Clear cell hidradenoma and hidradenocarcinoma. Arch Dermatol. 1963;87:323–333.

6 Robson A, Greene J, Ansari N, et al. Eccrine porocarcinoma (malignant eccrine poroma): a clinicopathologic study of 69 cases. Am J Surg Pathol. 2001;25:710– 720.

7 Laws RA, English JC 3rd, Elston DM. Acrospiroma: a case report and review. Cutis. 1996;58:349–351.

8 Cauthon DJ, Worthen T, Freed L, DeComas AM. Malignant eccrine hidradenoma. J Am Podiatr Med Assoc.

2013;103:333–336.

9 Yavuzer R, Basterzi Y, Sari A, Bir F, Sezer C. Chondroid syringoma: a diagnosis more frequent than expected.

Dermatol Surg. 2003;29:179–181.

10 Alfadley A, Al Aboud, Tulba A, Mourad MM. Multiple eccrine hidrocystomas of the face. Int J Dermatol.

2001;40:125–129.

11 Storm CA, Seykora JT. Cutaneous adnexal neoplasms.

Am J Clin Pathol. 2002;118 suppl:S33–S49.

12 Mambo NC. Eccrine spiradenoma: a clinical and pathologic study of 49 tumours. J Cutan Pathol. 1983;10:312–320.

13 Granter SR, Seeger K, Calonje E, Busam K, McKee PH. Malignant eccrine spiradenoma (spiradenocarcinoma): a clinicopathologic study of 12 cases. Am J Dermatopathol. 2000;22:97–103.

14 Nibhoria, Tiwana KK, Yadav A. Vulvar syringoma: a rare case report. J Clin Diagn Res. 2014;8:FD06.

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 224)

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Clinical Efficacy and Safety of a Monopolar Radiofrequency Device With Comfort Pulse Technology for the Treatment of Facial and Neck Laxity in Men Sabrina Guillen Fabi, MD; Ane B. M. Niwa Massaki, MD; Mitchel P. Goldman, MD

The objective of this study was to demonstrate the efficacy and safety of a monopolar radiofrequency treatment for fa-cial and neck laxity in men. Twelve men received one treatment of the face and upper portion of the neck using an RF system with comfort pulsed technology.

Standardized photographs were taken at baseline and at 1, 3, and 6 months of follow-up. Study investigators evaluated facial and neck laxity at baseline and all follow-up visits using the Fasil Laxity Scale. Patents and investigators assessed skin texture and overall appearance using the Quartile Improvement Scale. Average improvement in treated areas was statistically significant at 1-month (P<.01), 3-month (P=.02), and 6-month (P=.05) follow-up visits compared with baseline. Investigators rated greatest improvement in skin texture and overall appearance (mild to moderate) at the 3-month follow-up. Patient assessments demonstrated moderate improvement in skin laxity, skin texture, and overall appearance maintained out to 6 months after treatment. A total of 64% of patients were satisfied to very satisfied with treatment at the 6-month follow-up. One RF treatment of the face and neck yielded 20% reduction in facial laxity 1 month after treatment, with maintained improvement out to 6 months (15% reduction). (SKINmed. 2016;14:181–185)

A

lthough ablative laser technology and surgical treatment are considered the gold stand-ard for the rejuvenation of aging skin, the demand for procedures with less downtime and risk, such as nonablative laser and radiofrequency (RF) treatments, has increased over the past several decades. The development of minimally invasive procedures, such as nonablative laser and RF treatments, has steadily increased over the years as patients have opted for less dramatic, more natural results, due to minimal risk and recovery. RF devices are unlike other lasers in that they produce heat via an electric current (volumetric heating), rather than light, and, therefore, the energy produced is not reflected or absorbed by epidermal melanin as it passes through the skin. For this reason, RF devices are appropriate to use in all skin types. In addition, heating the dermal layer of the skin is associated with collagen denaturation and subsequent thickening and shorting of the collagen fibers leading to increased fibroblast activity and new collagen for-mation.1–3

One nonablative system, the Thermage CPT (Solta Medical, Hayward, CA) uses mono-polar capacitively coupled RF (MRF) to tighten skin and reduce laxity. The Thermage CPT sys-tem incorporates cryogen cooling bursts throughout the pulsed RF delivery. The handpiece con-sists of a vibration setting, which is delivered throughout the pulse and serves to decrease pain or discomfort as perceived by patients.4 Contouring and mild to moderate tightening is achieved through volumetric heating and dermal collagen remodeling, and epidermal cooling and the maintenance of an intact epidermis protects the skin from complications, such as infection, scar-ring, and changes in pigmentation.5 Treatment using RF represents a minimally invasive method of facial, eyelid, neck, and nonfacial rejuvenation with several clinical studies that have demonstrated clinical efficacy and safety of the device.6–9 This study sought to evaluate the efficacy and

From Goldman, Butterwick, Groff, Fabi & Wu, Cosmetic Laser Dermatology, San Diego, CA Address for Correspondence: Sabrina Guillen Fabi, MD, 9339 Genesee Avenue, Suite 300, San Diego, CA 92121 • E-mail: SFabi@CLDerm.com

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safety of using the Thermage CPT system for the treatment of facial and neck laxity, specifically in men.

This investigation was designed to assess the efficacy of a single RF treatment on the face and neck by evaluating the patients at 1, 3, and 6 months following a single treatment. In addition, patients were surveyed to self-assess improvement and rate satisfaction with treatment results at each follow-up study visit.

Methods Twelve men aged 43 to 65 years (mean 56±7 years), with a mean laxity severity score of 2.7±1.1 (range 0–5) and Fitzpatrick skin types 1 to 4, were enrolled at an investigational center. A history of pacemaker insertion, defibrillator, implants, tattoos, or radiation therapy in the treatment area served as exclusion criteria.

Patients with previous surgeries or procedures in the treatment area including RF treatment within the past 6 months were also excluded.

Patients were scheduled for one RF treatment followed by study visits to assess clinical improvement at 1, 3, and 6 months after treatment. The study was conducted according to Good Clinical Practice guidelines and informed consent was obtained from all patients prior to any study-related procedures.

Standardized digital photography of the treatment area was performed for each patient at baseline and each follow-up visit. At baseline, study investigators evaluated facial laxity in the treatment area using the Fasil Laxity Scale (Figure 1) and assigned skin type (Fitzpatrick I–VI).

Each patient received one treatment on the face and neck with the Thermage CPT system. Treatments were performed using an average treatment level of 3.6 (range 0.5–8.0), vibration of 1.6 (range 0–3), and an average total rep count of 749 reps on the face and neck. Treatment settings were dependent on patient tolerability and comfort.

Study investigators assessed the incidence of posttreatment responses and adverse events using a 0 to 3 scale (0=none, 1=mild/ minor, 2=moderate, 3=severe) during the course of the study at each visit.

Clinical improvement was assessed by study investigators and patients at 1, 3, and 6 months after treatment. Investigators assessed improvement in face and neck laxity using the Fasil Laxity Scale (Figure 1) and skin texture and overall appearance using a 0 to 4 scale (0 = no improvement, 1 = minor/mild improvement, 2 = moderate improvement, 3 = marked improvement, 4 = very significant improvement). Patients self-assessed improvement in SKINmed. 2016;14:181–185

skin laxity, skin texture, and overall appearance using the same 0 to 4 scale above. Patient satisfaction was also assessed at each follow-up visit using a 5-point Likert Satisfaction Scale (1 = very dissatisfied, 2 = dissatisfied, 3 = neither satisfied nor dissatisfied, 4 = satisfied, 5 = very satisfied).

Results Eleven of 12 patients (92%) completed the 6-month follow-up visit. One patient did not complete the study as a result of serious adverse events (death secondary to intracranial hemorrhage deemed unrelated to study treatment) after the 1-month followup visit.

Pain during treatment was reported to be mild to moderate (4.4 of 10). Immediate posttreatment responses included erythema observed in 67% of patients and edema observed in 75% of patients. At the 6-month follow-up visit, 18% of patients presented with mild erythema. No cases of edema, blistering, scarring, burns, or surface irregularities were reported during the study.

Study investigators noted the greatest improvement in facial laxity at the 1-month follow-up visit with a 20% reduction in facial laxity as compared with baseline (Figures 2 and 3). At the 3-month follow-up, investigators assessed a 17% reduction in facial laxity compared with baseline results maintained out to the 6-month follow-up visit, with a 15% reduction from baseline.

Results were statistically significant (P≤.05) as compared with baseline at all three follow-up visits (1 month, P<.01; 3 months, P=.02, and 6 months, P=.05).

Investigators rated skin texture and overall appearance as having the greatest improvement at the 3-month follow-up visit (1.7±1.1 and 1.4±1.2, respectively), corresponding to mild to moderate improvement (Figure 5).

Based on photo comparisons, patients noted the greatest clinical improvement in skin laxity, skin texture, and overall appearance at the 6-month follow-up visit (1.6±1.0, 1.6±1.0, and 1.7±1.1, respectively) (Figure 6). Patient-rated efficacy scores were similar to study investigator scores with an overall average of mild to moderate improvement.

In addition, patients were on average “satisfied” (3.7±0.0) with the treatment results at 6 months, according to the Likert Satisfaction Scale.

Discussion Study investigator and patient assessments demonstrated a positive clinical treatment effect for facial laxity, skin texture, and

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Figure 1. Fasil Laxity Scale.

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Figure 2. Study investigators assessed facial laxity at baseline and each follow-up visit using the Fasil Laxity Scale. Data points include 95% confidence intervals. The number of patients at each time point was 12, 11, 10, and 11, respectively. All follow-up time points were statistically significant compared with baseline.

Figure 5. Investigators rated clinical improvement in skin texture and overall appearance at 1 month, 3 months, and 6 months after treatment. A 95% confidence interval was included for all data sets. Quartile Improvement Scale: 0 = no improvement, 1 = minor/mild improvement, 2 = moderate improvement, 3 = marked improvement, 4 = very significant improvement. The number of patients at each time point was 11, 10, and 11, respectively.

Figure 3. A 52-year-old patient at baseline and at 30, 90, and 180 days after the procedure.

Figure 4. A 65-year-old patient at baseline and at 30, 90, and 180 days after the procedure.

overall appearance in men after one RF treatment of the face and neck. Treatment was well tolerated with mild to moderate discomfort reported. Expected clinical responses including mild erythema and mild edema were observed immediately after treatment with no reported instances of blistering, scarring, burns, or surface irregularities.

Numerous studies have demonstrated the efficacy and safety of RF treatment for noninvasive skin tightening and contouring.

In a study published in 2004, clinical improvement in nasolabial and mesolabial folds of the cheeks was observed in 93% of paSKINmed. 2016;14:181â&#x20AC;&#x201C;185

184

Figure 6. Patients rated clinical improvement in skin laxity, skin texture, and overall appearance at 1 month, 3 months, and 6 months after treatment as compared with before treatment (baseline). A 95% confidence interval was included for all data sets. Quartile Improvement Scale: 0 = no improvement, 1 = minor/mild improvement, 2 = moderate improvement, 3 = marked improvement, 4 = very significant improvement. The number of patients at each time point was 11, 10, and 11, respectively.

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tients while clinical improvement in submandibular and upper portion of the neck skin laxity was observed in 85% of patients after one RF treatment.7 Another study reported that 30% of patients noted significant improvement in skin laxity and texture at 1 month, 50% of patients reported significant improvement at 2 months, and 70% of patients reported significant improvement at 3 months after just one RF treatment.8 In the largest study conducted to date, an 83.2% improvement in periorbital wrinkles was reported at 6 months after a single RF treatment for 62 patients.9

tervention. Due to the small number of patients included in our study, further studies are warranted to determine the reproducibility of these results.

Disclosures Supported by a research grant from Solta Medical.

References

In this study, investigator assessments demonstrated an average 20% reduction in facial laxity at 1 month after treatment, which was maintained out to 6 months (15% reduction). In addition, investigator-rated improvement of treated areas using the Fasil Laxity Scale were statistically significant (P≤.05) at all follow-up visits as compared with baseline. Investigators rated the greatest improvement in skin texture (1.7±1.1) and overall appearance (1.4±0.8), corresponding to mild to moderate improvement at the 3-month follow-up visit.

Scores from patient photo assessments at each follow-up visit compared with baseline (pretreatment) demonstrated that moderate improvement in skin laxity (1.6±1.0), skin texture (1.6±1.1), and overall appearance (1.7±1.1) was maintained out to 6 months. A total of 64% of patients were on average satisfied to very satisfied with treatment results.

Conclusions Results of this study demonstrate that a single treatment with Thermage CPT Laser System proved safe, effective, and tolerable on facial and neck areas in men. All anticipated posttreatment skin responses were transient and resolved without medical in-

1 Hsu TS, Kaminer MS. The use of nonablative radiofrequency technology to tighten the lower face and neck.

Semin Cutan Med Surg. 2003;22:115–123.

2 Elsaie ML. Cutaneous remodeling and photorejuvenation using radiofrequency devices. Indian J Dermatol.

2009;54:201–205.

3 Sukal SA, Geronemus RG. Thermage: the nonablative radiofrequency for rejuvenation. Clin Dermatol.

2008;26,602–607.

4 Green JB, Dover JS, Kaminer MS. Tolerability of a monopolar radiofrequency facial skin tightening procedure: an observational study. Cosmet Dermatol. 2011;24:327– 330.

5 Polder KD, Bruce S. Radiofreqency: Thermage. Facial Plast Surg Clin N Am. 2011;19:347–359.

6 Fritz M, Counters JT, Zelickson BD. Radiofrequency treatment for middle and lower face laxity. Arch Facial Plast Surg. 2004;6:370–373.

7 Alster TS, Tanzi E. Improvement of neck and cheek laxity with a nonablative radiofrequency device: a lifting experience. Dermatol Sur. 2004;30:503–507.

8 Iyer S, Suthamjariya J, Fitzpatrick RE. Using a radiofrequency energy device to treat the lower face: a treatment paradigm for a nonsurgical facelift. J Cosmet Dermatol.

2003;16:37–40.

9 Fitzpatrick R, Geronemus R, Goldberg D, et al. Multicenter study of noninvasive radiofrequency for periorbital tissue tightening. Lasers Surg Med. 2003;33:232–342.

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What Is Vitamin D3 and Its Potential Use in Dermatology?

Karen Sánchez-Armendáriz, MD;1 Ana García-Gil, MD;1 Judith Domínguez-Cherit, MD2 Abstract There are many clinical studies that show the importance of vitamin D in multiple skin disorders. Understanding the molecular elements of cathelicidin expression might lead to new treatments and help explain mechanisms of current therapies. Overall, current data are generating many questions and expectations and require larger trials to confirm the therapeutic use of vitamin D3 supplementation. Vitamin D now represents a vast and promising field of research to dermatologists. (SKINmed. 2016;14:187–190)

V

itamin D is a fat-soluble provitamin that can be assimilated in the diet or by UV-B–dependent skin photoproduction.1 The vitamin D obtained by epidermal photosynthesis, also known as calcitriol, is the active form of vitamin D (Figure 1) and it needs successive hydroxylation by 25-hydroxylase (CYP27A1) in the liver and 1α-hydroxylase (CYP27B1) in the kidney to yield 1α,25-dihydroxyvitamin D3 (vitamin D3).2 Immune Regulator Besides its crucial functions in calcium homeostasis, there is increasing evidence that vitamin D3 serves as an immune regulator with impact on both innate and adaptive immunity.3 Vitamin D3 activates the vitamin D receptor (VDR) in almost all cells of the adaptative immune system4 resulting in altered expression of genes involved in cell proliferation, differentiation, and apoptosis.5 Epidermal keratinocytes express both relevant enzymes and can, therefore, activate vitamin D3, independently.1,6 This property resulted in the successful introduction of topical vitamin D analogs to treat psoriasis almost 2 decades ago2,5; however, other dermatologic indications for vitamin D remained largely unexplored.

Cathelcidin In a distinct immune regulatory role, vitamin D3 affects innate antimicrobial defense mechanisms at epithelial barriers with

the production of cathelicidin.6 These antimicrobial peptides (AMPs) exhibit biologic effects on cytokine and chemokine production, processes that are crucial in inflammation, angiogenesis, and wound repair.7 In 1903, Niels Ryberg Finsen received the Nobel Prize for Medicine for discovering that UV irradiation had an immunostimulant and bactericidal function in the treatment of cutaneous tuberculosis and other infections.2,8 The latest research has shown that cathelicidin expression and function is altered in several common inflammatory skin disorders, so that the vitamin D3 pathway could result in novel therapeutic approaches6 (Figure 2).

Atopic Dermatitis One example is atopic dermatitis. Several clinical studies have demonstrated that skin inflammation in atopic dermatitis can be ameliorated by UV-B irradiation,9 either due to the effect of UV-B on T-cells or due to the UV-B–induced activation of AMPs and/or the UV-B–induced vitamin D3 synthesis and subsequent cathelicidin expression in the keratinocytes.10,11 Recently, vitamin D3-activated pathways leading to induced cathelicidin in keratinocytes in atopic skin have been demonstrated to be functional.12 In addition, increased cathelicidin has been found in results of skin biopsies in patients with atopic dermatitis following a course of oral vitamin D supplementation.13

From the Department of Dermatology, General Hospital “Dr. Manuel Gea González,” Mexico City;1 and the Department of Dermatology, National Institute of Medical Sciences and Nutrition Salvador Zubirán, Mexico City,2 México Address for Correspondence: Karen Sánchez-Armendáriz, MD, Consultorio 706 Torre II, Puente de Piedra 150, Toriello Guerra, 14050 Tlalpan, Mexico City, México • E-mail: kmosa7@yahoo.com

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Figure 1. Vitamin D is the generic name of a group of substances of similar chemical structure: steroid derivatives of 7-dehydrocholesterol (animals) or ergosterol (vegetables). When these molecules are exposed to UV radiation they become calcitriol (vitamin D3) and ergocalciferol (vitamin D2), respectively. Therefore, calcitriol originates from the skin but, as ergocalciferol, can be taken orally and absorbed from the gastrointestinal tract. Both forms of vitamin D go through an activation process: hydroxylation by 25-hydroxylase (CYP27A1) in the liver and 1Îą-hydroxylase (CYP27B1) in the kidney to yield 1Îą,25-dihydroxyvitamin D3 (vitamin D3), which is of greater biological activity. Parathyroid hormone is the most important regulator of calcium homeostasis and acts directly on bone and kidney.

Increasing vitamin D3 synthesis or elevating vitamin D3 serum levels by oral supplementation could help to strengthen the innate defense barriers to prevent cutaneous infections, which trigger skin inflammation in atopic dermatitis;6 however, as topical vitamin D3 has been reported to induce skin irritation and an atopic-dermatitis mimicking phenotype in mice, further clinical and experimental studies have to be performed to prove its benefits.14 Rosacea

Figure 2. Photochemical conversion of vitamin D in the skin requires UV-B irradiation. In keratinocytes, active vitamin D3 binds to and activates the vitamin D receptor (VDR) in an autocrine manner. Steroid receptor coactivator 3 complexes with the VDR and recruits histone acetyltransferases, which open up chromatin and facilitate access to the cathelicidin gene. Cathelicidin is synthesized as an inactive pro-peptide (hCAP18), which is cleaved upon release to active LL-37 by serine proteases.

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Rosacea is defined by abnormal inflammation and vascular reactivity in facial skin. Patients with rosacea have a VDR gene polymorphism and express abnormally high levels of cathelicidin, which is abnormally processed by serine proteases into the LL37 peptide form.15 Cathelicidin overexpression could be blocked by targeting the vitamin D3 pathway and the production of the disease-aggravating cathelicidin fragments could be inhibited.16 That is the case of oral minocycline treatment, which decreases cutaneous protease activity in rosacea, making a case for the development of more specific serine protease inhibitors as topical drugs for the disease.17

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Psoriasis Psoriasis is a chronic inflammatory and autoinmmune skin disease in which superinfection is rare, but there is also high expression of cathelicidin and other antimicrobial peptides. The autoimmune response in psoriasis is initiated by cathelicidin-DNA complexes triggering interferon-α production by plasmocytoid dendritic cells.18 Blocking or decreasing cathelicidin expression could disrupt the vicious circle of cutaneous inflammation driven by high levels of LL-37.19 Paradoxically, for a long time, vitamin D3 analogs have been used in the therapy of psoriasis. Vitamin D3 analogs bind to and activate the VDR and should increase cathelicidin in keratinocytes presumably worsening inflammation in psoriasis; however, the opposite occurs, and vitamin D analogues ameliorate cutaneous inflammation and reverse morphological changes within psoriatic plaques. Further studies are needed to elucidate the role of cathelicidin in psoriasis pathogenesis.

Vitiligo Another skin disorder related to vitamin D is vitiligo. A number of studies have recently reported that treatment with vitamin D compounds or their combination with UV light or corticosteroids enhances repigmentation.20 Topical vitamin D analogs exert important physiological roles through its nuclear receptor (VDR), and they have been increasingly recognized for their immunomodulatory potential to inhibit proliferation and promote differentiation of cells. They can effectively treat vitiligo by protecting skin melanin units and decelerating the destruction of melanocytes, likely via modulating local immune response in skin, promoting melanogenesis, counteracting oxidative stress and apoptosis, and restoring impaired calcium homeostasis. To further understand the mechanism of vitamin D3 analogs in the repigmentation of vitiligo may be substantially beneficial for the effective treatment of vitiligo.21 Wounds In addition to their anti-infective activity, AMP exhibit biological activities that provide benefit in the setting of skin injury, such as attraction for certain immune cells, epithelial repair, and angiogenesis.22 Defective antimicrobial peptide expression has been observed in chronic ulcers and thermal burns and may be responsible for retarded healing and susceptibility to infection.23,24

injury, declining to pre-injury levels upon wound closure. In chronic ulcers, however, LL-37 levels are low and immunoreactivity for LL-37 is absent in ulcer edge epithelium. This suggests that, in addition to being an AMP, LL-37 also plays a part in wound closure and that its reduction in chronic wounds impairs re-epithelialization and may contribute to their failure to heal.25 Other Findings There is some evidence about vitamin D and folliculogenesis particularly inducing anagen through transforming growth factor β (TGF-β2) and VDR in hair dermal papilla. This suggests a potential therapeutic approach for alopecia and hair transplantation.26–28 Growing evidence now indicates that the UV-B–mediated cutaneous photosynthesis of vitamin D (and the consecutive cutaneous production of vitamin D3) represents an evolutionary highly conserved endocrine system that protects the skin against environmental hazards that may promote skin cancerogenesis, including UV and ionizing radiation.29 Finally, significant associations with VDR polymorphisms and/or vitamin D3 serum levels have been reported in malignant melanoma (MM) as well as in nonmelanoma skin cancer (NMSC).30 More research is needed into the possible protective effects of vitamin D against cancer. Brief daily UV exposure stimulates vitamin D production and causes negligible skin damage.31 Conclusions What level of vitamin D is best? This question probably has a different answer depending on the particular health effect that is sought. Vitamin D serum levels are classified as sufficient (>30 ng/mL), insufficient (20–30 ng/mL), and deficient (<20 ng/ mL).33 The proponents of high vitamin D levels point out that protective effects against cancer are presumed to be achievable mainly with relatively high vitamin D levels (≥30 ng/mL). The therapeutic window for vitamin D3 is very wide: a toxic effect (hypercalcemia) is thought to arise only when the serum level exceeds 200 ng/mL. Oral vitamin D supplementation can be considered as an alternative, particularly for persons at high risk, such as the elderly and members of certain ethnic groups.34 References

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1 Vantieghem K, Kissmeyer AM, De Haes P, Bouillon R, Segaert S. UVB-induced production of 1,25-dihydroxyvitamin D3 and vitamin D activity in human keratinocytes pretreated with a sterol-∆7-reductase inhibitor. J Cell Biochem. 2006;98:81–92.

2 Segaert S. Vitamin D Regulation of cathelicidin in the skin: toward a renaissance of vitamin D in dermatology.

J Invest Dermatol. 2008;128:773–775.

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3 Bikle DD. What is new in vitamin D: 2006-2007. Curr Opin Rheumatol. 2007;19:383–388.

4 van Etten E, Stoffels K, Gysemans C, Mathieu C, Overbergh L. Regulation of vitamin D homeostasis: implications for the immune system. Nutr Rev. 2008;66:S125– S134.

19 Ganguly D, Chamilos G, Lande R, et al. Self-RNA-antimicrobial peptide complexes activate human dendritic cells through TLR7 and TLR8. J Exp Med. 2009;206:1983– 1994.

5 Reichrath J. Vitamin D and the skin: an ancient friend, revisited. Exp Dermatol. 2007;16:618–625

20 Birlea SA, Costin GE, Norris DA. Cellular and molecular mechanisms involved in the action of vitamin D analogs targeting vitiligo depigmentation. Curr Drug Targets.

2008;9:345–359.

6 Antal A, Dombrowski Y, Koglin S, Ruzicka T, Schauber J. Impact of vitamin D3 on cutaneous immunity and antimicrobial peptide expression. Dermatoendocrinol.

2011;3:18–22.

21 Birlea SA, Costin GE, Norris DA. New insights on therapy with vitamin D analogs targeting the intracellular pathways that control repigmentation in human vitiligo. Med Res Rev. 2009;29:514–546.

7 Schauber J, Gallo RL. Expanding the role of antimicrobial peptides in skin: alarming and arming keratinocytes.

J Invest Dermatol. 2007;127:510–512

22 Koczulla R, von Degenfeld G, Kupatt C, et al. An angiogenic role for the human peptide antibiotic LL-37/hCAP18. J Clin Invest. 2003;111:1665–1672.

8 Somolinos Palencia J. “Niels Ryberg Finsen (1860– 1904)”. Gac Méd Méx. 1990;126:526.

23 Zasloff M. Sunlight, vitamin D, and the innate immune defenses of the human skin. J Invest Dermatol.

2005;125:41–42.

9 Vahavihu K, Ala-Houhala M, Peric M, et al. Narrowband ultraviolet B treatment improves vitamin D balance and alters antimicrobial peptide expression in skin lesions of psoriasis and atopic dermatitis. Br J Dermatol.

2010;163:321–328.

10 Glaser R, Navid F, Schuller W, et al. UV-B radiation induces the expression of antimicrobial peptides in human keratinocytes in vitro and in vivo. J Allergy Clin Immunol.

2009;123:1117–1123.

11 Peric M, Lehmann B, Vashina G, et al. UV-B-triggered induction of vitamin D3 metabolism differentially affects antimicrobial peptide expression in keratinocytes. J Allergy Clin Immunol. 2010;125:746–749.

12 Mallbris L, Carlen L, Wei T, et al. Injury downregulates the expression of the human cathelicidin protein hCAP18/ LL-37 in atopic dermatitis. Exp Dermatol. 2009;19:442– 449.

13 Hata TR, Kotol P, Jackson M, et al. Administration of oral vitamin D induces cathelicidin production in atopic individuals. J Allergy Clin Immunol. 2008;122:829–831.

14 Li M, Hener P, Zhang Z, Kato S, Metzger D, Chambon P. Topical vitamin D3 and low-calcemic analogs induce thymic stromal lymphopoietin in mouse keratinocytes and trigger an atopic dermatitis. Proc Natl Acad Sci USA. 2006;103:11736–11741.

15 Schauber J, Gallo R. The vitamin D pathway: a new target for control of the skin’s immune response? Exp Dermatol. 2008;17:633–639.

16 Jansen T, Krug S, Kind P, Plewig G, Messer G. BsmI polymorphism of the vitamin D receptor gene in patients with the fulminant course of rosacea conglo-bata (rosacea fulminans). J Dermatol. 2004;31:244–246.

24 Klein GL, Chen TC, Holick MF, et al. Synthesis of vitamin D in skin after burns. Lancet. 2004;363:291–292.

25 Heilborn JD, Nilsson MF, Kratz G, et al. The cathelicidin anti-microbial peptide LL-37 is involved in re-epithelialization of human skin wounds and is lacking in chronic ulcer epithelium. J Invest Dermatol. 2003;120:379–389.

26 Millar SE. Molecular mechanisms regulating hair follicle development. J Invest Dermatol. 2002;118:216–225.

27 Oshimori N, Fuchs E. Paracrine TGF-signaling counterbalances BMP-mediated repression in hair follicle stem cell activation. Cell Stem Cell. 2012;10:63–75.

28 Noriyuki Aoi, Keita Inoue, Toshihiro Chikanishi, et al.

1,25-dihydroxyvitamin D3 modulates the hair-inductive capacity of dermal papilla cells: therapeutic potential for hair regeneration. Stem Cells Transl Med. 2012;1:615– 626 29 Trémezaygues L, Reichrath J. Our present understanding of the importance of the vitamin D endocrine system (VDES) for skin cancer. Dermatoendocrinol. 2001;3:11– 17.

30 Randerson-Moor JA, Taylor JC, Elliott F, et al. Vitamin D receptor gene polymorphisms, serum 25-hydroxyvitamin D levels, and melanoma: UK case-control comparisons and a meta-analysis of published VDR data. Eur J Cancer. 2009;45:3271–3281.

31 Reichrath J. The challenge resulting from positive and negative effects of sunlight: how much solar UV-exposure is appropriate to balance between risks of vitamin D deficiency and skin cancer? Prog Biophys Mol Biol.

2006;92:9–16.

17 Yamasaki K, Di Nardo A, Bardan A, et al. Increased serine protease activity and cathelicidin promotes skin inflammation in rosacea. Nat Med. 2007;13:975–980.

32 Zeeb H, Greinert R. The role of vitamin D in cancer prevention: does UV protection conflict with the need to raise low levels of vitamin D? Dtsch Arztebl Int. 2010;107:638–643.

18 Lande R, Gregorio J, Facchinetti V, et al. Plasmacytoid dendritic cells sense self-DNA coupled with anti-microbial peptide. Nature. 2007;449:563–568.

33 Heaney RP, Holick MF. Why the IOM recomendations for vitamin D are deficient. J Bone Miner Res. 2011;26:455– 457.

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SELF ASSESSMENT EXAMINATION W. Clark Lambert, MD, PhD

1. a. b. c. d. e.

Vitamin D3 has functions in: Calcium homeostasis.

Regulation or promotion of adaptive immunity.

Regulation or promotion of innate immunity.

All of the above.

None of the above.

2. In the adaptive immune system, vitamin D3 activates the vitamin D receptor (VDR) in almost all cells resulting in altered expression of genes involved in: a. Calcium homeostasis. b. Regulation or promotion of adaptive immunity. c. Regulation or promotion of innate immunity. d. All of the above. e. None of the above.

3. Vitamin D3 affects innate antimicrobial defense mechanisms at epithelial barriers via the production of: a. Cathelicidin. b. CYP27A1. c. CYP27B1. d. Ergosterol. e. All of the above. f. None of the above.

4. Which of the following statements regarding exposure to ultraviolet light (UV) such as that found in sunlight is correct? a. Brief daily UV exposure stimulates vitamin D production and causes negligible skin damage. b. Two hours or more of daily UV exposure stimulates vitamin D production and causes negligible skin damage. c. Prolonged daily UV exposure stimulates vitamin D production and causes negligible skin damage. d. All UV exposure should be avoided. e. None of the above statements is correct.

5. Diseases or processes in which vitamin D3 has a role in etiopathogenesis and/or a possible role in treatment include: (Answer as many as apply.) a. Atopic dermatitis. b. Psoriasis. c. Rosacea. d. Vitiligo. e. Wound healing.

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

Instructions: For each numbered question select the one best lettered response unless directed otherwise.

VINTAGE LABEL

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

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Hydrate Your Way to Healthy Skin

Hydrate. Nourish. Restore. Repair.

priyanamd.com

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Volume 14 • Issue 3

Core curriculum Virendra N. Sehgal, MD, Section Editor

Oral Mucosal Lesions: Miscellaneous––Part III Virendra N. Sehgal, MD;1 Nazim Hussain Syed, MD;1 Ashok Aggarwal, MD;1 Shruti Sehgal, MDS2

Oral mucosal lesions are a common occurrence in dermatology. In part III of this series, the authors discuss the epidemiology and etiopathology of these lesions, including clinical classifications, modifying factors, and incriminating agents. (SKINmed. 2016;14:193–201)

O

ral mucosal lesions (OMLs) have always been an intriguing subject in the literature because they embrace a wide variety of local and/or systemic conditions.

Their precise definition is therefore difficult. Nevertheless, it is useful to address commonly encountered manifestations in dayto-day practice among broad faculties of medicine. Herein we discuss the background of oral biology1 to facilitate the precise interpretation of OML including lichen planus and lichenoid eruption/lichenoid interface dermatitis.2

Table I. Clinical Conditions Associated With and Prevalence of Oral Mucosal Lesions

Prevalence

Clinical Conditions

Prevalence, %

Fordyce spots

6.55

Frictional keratosis

5.79

Fissured tongue

5.71

Leukoedema

3.78

Smoker's palate

2.77

Recurrent aphthae, oral submucous fibrosis

2.01

Oral malignancies

1.76

The prevalence of OMLs varies in different parts of the world and is influenced by different lifestyles and food habits (Table I).

OMLs have been reported in 41.2% of the Indian population.3

Leukoplakia

1.59

Median rhomboid glossitis

1.50

Candidosis

1.3

In one study,3 tobacco-related leukoplakia, smoker’s palate, oral submucous fibrosis, and oral malignancies were found to be more prevalent among men than women. While denture stomatitis, herpes labialis, and angular cheilitis were more frequently seen in the women.

Lichen planus

1.20

Varices

1.17

Traumatic ulcer and oral hairy leukoplakia

1.008

Denture stomatitis, geographic tongue, betel chewer's mucosa, and irritation fibroma

0.84

Herpes labialis, angular cheilitis

0.58

Mucocele

0.16

The overall prevalence of OML was found to be 8.4% in an Indian study,4 while it was 23.2% in a study of elderly patients in Mexico5 and 39% in a study in Spain.6 Smoking and chewing tobacco have been shown to be significant predictors of oral leukoplakia in an Indian population.7,8 Of 383 Saudi patients,9 15% had OMLs and the most commonly affected age group was 31 to 40 years. Fordyce granules,

followed by leukoedema and traumatic ulcer/erosion were frequent. Tongue abnormalities were present in 4% of all oral conditions, ranging from 1.4% for fissured tongue to 0.1% for bifid tongue. Torus palatinus, mandibular aphthous ulcer, herpes

From the Dermato-Venereology (Skin/VD) Center, Sehgal Nursing Home, Panchwati, Delhi, India, Skin Institute, and School of Dermatology, Greater Kailash, New Delhi,1 and the Department of Conservative Dentistry and Endodontics, Government Dental College, Raipur, India2 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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simplex, frictional hyperkeratosis, melanosis, lichen planus, and nicotinic stomatitis were also found. Furthermore, in a study of Mexican pediatric patients with an age range of 1 to 16 years, the most frequent lesions were fibrous hyperplasia, erythematous candidosis, and oral ulcers.10 A total of 70.93% were secondary to poor oral hygiene and the use of an orthodontic apparatus.

Its prevalence has been shown to decrease when aggressive oral hygiene is practiced.

OMLs were observed in 45% of institutionalized elderly patients in a study from Denmark11; however, nonpathologic mucosal changes of the tongue were not included in the evaluation. Likewise, in Brazil,12 oral mucosal alterations were observed in 60% of institutionalized elderly patients from a single institution using similar diagnostic criteria. The prevalence of oral lesions in this population has been documented in other parts of the world such as Mexico,5 Brazil,12 and Israel.13 In contrast, other studies14,15 conducted prevalence investigations based on the clinicopathologic correlation, evaluating the biopsies of the observed lesions.

The frequency of oral conditions in dermatologic practices in particular is important for establishing the diagnosis. A study from Mexico16 conducted in OPD patients identified pemphigus vulgaris, lichen planus, candidosis, recurrent aphthous ulcers, herpetic lesions, xerostomia, and traumatic lesions, in that order. Work from Israel has shown that the mouth is initially affected in 56% of pemphigus vulgaris cases, mouth plus other sites in 31%, and skin alone in 12.5%.17 The diagnosis of ulcers in the mouth can be difficult as a variety of conditions can appear clinically as ulcerations.18 In addition to recurrent apthous ulcers, other diseases such as pemphigus, herpetic lesions, lupus erythematosus, mucositis, Behçet disease, and erythema multiforme were seen as ulcerations.19

Socioeconomic Status A higher prevalence of orodental disorders was reported in patients with lower socioeconomic status,24 which may be the result of lower educational status, lack of awareness about oral hygiene and the significance of orodental diseases, and nonavailability of preventive and curative facilities. Orodental disorders have also been reported in patients in upper socioeconomic strata, which may partly be attributed to candy consumption in this group.25 Classification of OML There is currently no universally accepted classification of diseases that affect the oral cavity; however, they can be broadly classified into inherited disorders, genodermatoses, drugs, trauma, dental prostheses, nutritional deficiencies, and neoplasms that also present with a wide variety of oral cavity lesions.26 The establishment of a differential diagnosis for lesions of the oral mucosa is often problematic, and a systematic approach to nosology is needed.

Classification/grouping is largely based on etiopathogenesis and clinical presentation (Table II).27 Etiopathogenic Classification The etiopathogenic classification of OMLs uses the acronym MIND, where M stands for metabolic, I for inflammation, N for neoplastic, and D for development disease,28 which encompasses related subdivisions (Figure 1).

Clinical Classification The clinical classification approach to the differential diagnosis of oral soft tissue lesions can be correlated with histopathologic findings.29–33 In many studies, a mixed classification system23 has been used to group OMLs. Table II. Clinical Classification of Oral Mucosal Lesions

Sites of OML Any part of the oral mucosa can be involved in OML, including the right and left buccal mucosa, followed by labial mucosa, tongue, gingival, hard/soft palate, and alveolar mucosa.4,19,20

Red Pigmented Brown

Age and Sex Distribution of OML OMLs have been reported to occur in all age groups including children aged 2 to 17 years and adults 17 years and older.21,22 A female predominance was shown in studies from Brazil19 and Saudi Arabia.9 The most common age group shown to be affected by OMLs was 45 to 64 years.5,23 Researchers have reported a prevalence of 10.14% and 9.41% of OMLs in men and women, respectively.20 SKINmed. 2016;14:193–201

White

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Etiopathic classification

Metabolic/systemic

Inflammatory

Neoplasia

Trauma Hormonal

Developmental

Malignant Infective

Nutritional

Genetic (heritable)

Premalignant Reactive

Benign

Acquired

Immunologic Hypersensitivity Bacterial

Viral Fungal Exogenous allergen

Endogenous allergen (autoimmune)

Figure 1. Etiopathogenic classification.

Clinical Groups/Connotation

Precancerous and cancerous lesions Some potentially malignant precancerous lesions that can progress to squamous cell carcinoma (SCC) are erythroplakia, leukoplakia, lichenoid dysplasia, discoid lupus erythematosus, oral submucous fibrosis,34 nicotine stomatitis, lichenoid dysplasia, adenosquamous carcinoma, basaloid squamous carcinoma, and atypia in immunocompromised patients.35 Leukoplakia is a clinical term used to describe patches of keratosis. It is apparent as adherent white patches on the mucous membranes of the oral cavity, including the tongue (Figure 2). The oral cavity is another possible location of malignant melanoma.36 Most intraoral carcinomas are SCC. It may be either exfoliate/ scaly, ulceroinfiltrative, or verrucous. The exophytic type is the most frequent, appearing as a papillary mass that becomes ulcerated when large. The ulceroinfiltrative variety appears as an ulcer that penetrates deep into the underlying structures, with surrounding induration. Verrucous carcinomas are uncommon variants of oral cavity carcinomas. In a study conducted in 1564 SKINmed. 2016;14:193–201

Figure 2. Leukoplakia.

cases of oral SCC,37 it was reported that oral SCC was more common in men than women, with a ratio of 3:1. The most common site affected was the gingiva followed by the lower lip.

This study also showed that early diagnosis resulted in early oral cancer detection.

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Vesiculobullous Diseases

Viral diseases Herpes simplex (ancient Greek: ρπης – herpes, lit. “creeping”) is a viral disease caused by both herpes simplex virus type 1 and type 2 (Figure 3). Other viral diseases that cause lesions include herpes varicella-zoster virus; hand, foot, and mouth disease (coxsackievirus type A16); herpangina; measles; and erythema multiforme (Figure 4).38

Immunologically Mediated Vesiculobullous Disorder Pemphigus vulgaris (paraneoplastic pemphigus), an autoimmune disorder, is almost invariably linked to an underlying lymphoproliferative disorder.39 It is characterized by erosions that can occur anywhere in the mouth and includes the buccal mucosa (Figure 5), cicatricial pemphigoid, bullous pemphigoid, dermatitis herpetiformis, linear IgA disease, herpes gestationis, and epidermolysis bullosa.38

Figure 3. Herpes simplex labialis.

Other Vesiculobullous Diseases Trauma or corticosteroid inhaler use can result in soft palate blood blisters.38 White and Pigmented Lesions Conditions associated with white and pigmented lesions include leukoderma, linea alba, morsicatio buccarum et labiorum, white sponge nevus, keratosis follicularis, dyskeratosis congenita, pachyonychia congenita, focal epithelial hyperplasia, discoid lupus erythematosus, pyostomatitis vegetans, proliferative verrucous leukoplakia, oral florid papillomatosis, syphilis mucous patches, candidosis (Figure 6), warts, leukoplakia, frictional keratosis, tylosis, nicotine stomatitis, tobacco pouch keratosis, viadent-associated leukoplakia, and squamous cell carcinoma.40

Figure 4. Erythema multiforme.

One study showed that nearly 25% of patients with lung diseases, namely brochogenic carcinoma, presented with abnormal pigmentation of the soft palate.41 They hypothesized that the pigmentation was a result of a high incidence of smoking in this population; however, others studies showed a much lower incidence of abnormal pigmentation in a population with similar rates of smoking but with no lung malignancies.

Tongue Lesions

Normal variations Tongue lesions include macroglossia, crenations, ankyloglossia, and fissured tongue42 (Figure 7). Studies have shown an association between generalized pustular psoriasis and oral lesions in the SKINmed. 2016;14:193–201

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Figure 5. Paraneoplastic pemphigus.

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Figure 6. Candidosis.

Figure 7. Fissured tongue.

form of geographic tongue.43 The geographic tongue/benign migratory glossitis is a benign condition that occurs in up to 3% of the general population and may represent with the oral counterpart of cutaneous psoriasis. In a clinical-histological review of 75 cases of migratory glossitis in which women represented 65.7% of the total, most cases occurred in patients older than 40 years.44 Histologic investigations showed an inflammatory reaction of the epithelium and of the underlying connective tissue. Patients should be reassured of the benign nature of the tongue lesion.

Developmental and traumatic lesions include lingual thyroid and Fordyce granules, which appear as rice-like white or yellow-white asymptomatic papules of 1 mm to 3 mm in greatest dimension61 (Figure 8). Other lesions of the tongue include leukoplakia, erythroplakia, traumatic ulcers, and traumatic fibroma.46 Erythroplasia is a moist, slightly raised, well-defined, red, smooth/velvety plaque, whereas leukoplakia, the earliest sign of asymptomatic oral cancer, is characterized by a white or grey patch that develops on the tongue or the inside of the cheek. It is the mouth’s reaction to chronic irritation of the mucous membranes. It can occur at any time in life, but it is common in the elderly. Hairy leukoplakia, on the other hand, is an unusual form that is seen only in patients who are infected with the human immunodeficiency virus, who have acquired immunodeficiency syndrome (AIDS), or who have AIDS-related complex. It consists of fuzzy/hairy white patches on the tongue and, less frequently, elsewhere in the mouth. Histopathology is mandatory, and is characterized by a prominent confluent parakeratotic cornified layer, a subcorneal horizontal band-like array of large ballooned epithelial cells with pale eosinophilic cytoplasm, and a clear perinuclear halo. Periodic acid-Schiff staining is useful in excluding candidosis.

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Figure 8. Fordyce’s granules.

Inflammatory and Infectious Lesions Inflammatory and infections lesions include geographic tongue, median rhomboid glossitis, hairy tongue, hairy leukoplakia, syphilis, tuberculosis, histoplasmosis, recurrent aphthous ulcers, minor aphthae, recurrent aphthous stomatitis, and canker sores.46 Nutritional deficiencies have been implicated as a cause of oral ulceration. As many as 15% to 25% of patients with complex aphthosis may have associated hematinic deficiencies, including iron deficiency anemia and folate, zinc, or vitamin B12 (cobalamin) deficiency; therefore, oral lesions can be corrected with basic laboratory testing.47,48 Various drugs are associated with oral ulcers.49 These ulcers are often large, isolated, and form along the

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lateral border of the tongue. Drugs such as hydroxyurea, antithyroid agents, alendronate, calcium channel blockers, nonsteroidal anti-inflammatory agents, piroxicam, indomethacin, ibuprofen, cytotoxic drugs, methotrexate, and doxorubicin are known to cause oral ulcers. Stevens-Johnson syndrome represents the severe end of the spectrum of drug-induced ulceration and can be seen in patients taking a number of medications, although sulfonamides are most frequently implicated.50 Chemical burns caused by pain relief medications such as aspirin51 placed near a painful tooth can become necrotic and painful, resulting in a desquamating white lesion.

One study has shown that about 15% of patients with complex aphthosis have a systemic disorder such as Behçet syndrome, inflammatory bowel disease, gluten-sensitive enteropathy/celiac disease, and rarely Wegener granulomatosis.53,53 Systemic Diseases Associated With OML A multitude of systemic diseases exist that exhibit consequential oral manifestations. Leukemia can first present in the mouth as generalized hyperplasia of gingiva, mucosal pallor, multiple petechiae, and ecchymosis of oral tissue.54 Gastrointestinal diseases have been associated with gastroesophageal reflux–associated dental problems, recurrent aphthous ulcerations associated with trauma, ulcerative colitis, Crohn’s disease, celiac disease, numerous vitamin deficiencies, and malabsorption disorders.55 Dermatologic Diseases of the Oral Mucosa Dermatologic disorders frequently involve intraoral and perioral tissues associated with bullous diseases such as pemphigus vulgaris, erythema multiforme, pemphigoid, dermatitis herpetiformis, epidermolysis bullosa, and Darier disease, as well as nonbullous diseases, such as lichen planus, psoriasis, lupus erythematosus, scleroderma, and perioral dermatitis.56 A significant proportion of the noninfectious diseases of the oral mucosa are either autoimmune in nature or are associated with lesions that are the result of immunologically mediated events. They include pemphigus, benign mucous membrane pemphigoid, linear IgA bullous dermatosis, dermatitis herpetiformis, epidermolysis bullosa acquisita, erythema multiforme, and lichen planus. Although each of these conditions has specific characteristics, all may produce bullae, erosions, and ulcers on the oral mucosa, resulting in similar clinical presentations. With careful clinical, histological, and immunofluorescence examination, it is possible to establish a definitive diagnosis in a high proportion of cases.57 According to localization criteria, pemphigus and pemphigoid can be distinguished, with the former recognized by the presSKINmed. 2016;14:193–201

ence of intraepidermal blister and desmosomal involvement, and the latter by subepidermal blister affecting the dermoepidermal junction. In two thirds of cases, pemphigus vulgaris begins with oral lesions that mainly affect the buccal mucosa and palate, rarely the gingiva. Skin lesions are typical. Except in paraneoplastic pemphigus, oral lesions are uncommon in other types of pemphigus. Cicatricial pemphigoid mainly involves the oral mucosa, frequently other mucous membranes, and rarely the skin. Gingival involvement is common. In desquamative gingivitis, the clip sign gives the diagnosis of cicatricial pemphigoid. Ocular involvement is frequent and causes blindness. Epidermolysis bullosa acquisita and immunoglobulin A linear dermatosis are rare. Bullous pemphigoid and bullous lupus erythematosus rarely involves the oral mucosa. Diagnosis of autoimmune bullous diseases requires a biopsy within the mucosal membrane lesion for pathology examination and another biopsy in a lesion-free area for direct immunofluorescence detection of antibody fixation.58 Incriminating and/or Modifying Factors Although the prevalence of oral mucosal disease has been found to be higher in older patients, age is not considered to be the only factor correlated with oral mucosal disorders. Factors, such as trauma, systemic diseases, presence of medications, and oral and denture hygiene, may also influence the development of oral mucosal diseases.59 In a study of noninstitutionalized elderly in China, those who wore dentures had a higher prevalence of OMLs than those who did not wear dentures.60 In other studies, elderly patients who wore dentures had a higher prevalence of lesions than those who did not wear dentures.61 It has been suggested that the length of denture use increases with age and that the elderly are reluctant to restore or replace old dentures; however, such practices can cause oral lesions.62 A study from south India conducted in 3030 patients was performed to determine the prevalence of oral soft tissue lesions in patients and to assess their clinicopathologic attributes. A total of 8.4% of the population studied had one or more oral lesions, associated with prosthetic use, trauma, and tobacco consumption. A total of 635 (21%) were smokers, 1272 (42%) were tobacco chewers, 341 (11%) were smokers and chewers, and 1464 (48%) neither smoked nor chewed tobacco. A total of 256 patients were found to have significant mucosal lesions.

Of these, 216 cases underwent scalpel biopsy confirmation, with 88 having leukoplakia, 21 oral submucous fibrosis, nine smoker’s melanosis, 17 dysplasia, six lichen planus, two squamous cell carcinoma, and one each with lichenoid reaction, angina bullosa hemorrhagica, allergic stomatitis, and nutritional stomatitis.4

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Drugs Associated With Oral Lesions

References

It has been shown that adverse drug reactions involving the mouth are frequent. Often there is a high index of suspicion in the diagnosis of these reactions, as they can mimic other disease states such as aphthae, swelling, erythema multiforme, and xerostomia. The reactions are often nonspecific but may mimic specific disease states such as erythema multiforme, lichen planus, and pemphigus. Other reactions such as gingival hyperplasia secondary to the administration of phenytoins, nifedipine, or cyclosporine are well-known and characteristic.

The pathogenic mechanisms of oral reactions to drug administration are similar to those that cause adverse drug reactions in the skin. To diagnose such a condition, the clinical interview is a helpful aid in the diagnosis of adverse drug reactions affecting the mouth and a careful drug history, including identification of any prescription or herbal medicines used, is needed.63 Several drugs are known to cause OMLs and are shown in Table III.64

Drugs

Angiotensin-converting enzyme inhibitors

Captopril

β-Blockers

Propranolol

Centrally acting antihypertensive

Methyldopa

Loop diuretics

Furosemide

Potassium-sparing diuretics

Spironolactone

Thiazide diuretics

Hydrochlorothiazide

Antibiotics

Amphotericin B Dapsone Quinine Streptomycin Tetracycline

Anti-inflammatory

Anonymous

Oral hypoglygemic

Tolbutamide

First-generation potassium channel blocker

Sulfonylurea

Psychotropic agents

Carbamazepine

Tricyclic antidepressants

Phenothiazine

Histamine type 2 receptor blockers

Cimetidine

Cytotoxic drugs

Methotrexate Doxorubicin

Nonsteroidal anti-inflammatory drugs

Anonymous

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41 Mercahnt HW, Hayes LE, Ellison LT. Soft-palate pigmentation in lung disease, including cancer. Oral Surg Oral Med Oral Pathol. 1976;41:726–733.

42 Redman RS. Prevalence of geographic tongue, fissured tongue, median rhomboid glossitis, and hairy tongue among 3,611 Minnesota schoolchildren. Oral Surg Oral Med Oral Pathol. 1970;30:390–395.

43 Dawson TA. Tongue lesions in generalized pustular psoriasis. Br J Dermatol. 1974;91:419–424.

44 Banoczy J, Szabo L, Csiba A. Migratory Glossitis. A clinical-histologic review of seventy cases. Oral Surg Oral Med Oral Pathol. 1975;39:113–121.

45 Alderson DJ, Lannigan FJ. Lingual thyroid presenting after previous thyroglossal cyst excision. J Laryngol Otol.

1994;108:341–343.

46 McNally MA, Langlais RP. Conditions peculiar to the tongue. Dermatol Clin. 1996;14:257–272.

47 Rogers RS 3rd, Hutton KP. Screening for haematinic deficiencies in patients with recurrent apthous stomatties.

Australas J Dermatol. 1986;27:98–103.

48 Bruce AJ, Rogers RS 3rd. Acute oral ulcers. Dermatol Clin. 2003;21:1–15.

49 Zelickson BD, Rogers RS 3rd. Oral drug reactions. Dermatol Clin. 1987;5:695–708.

50 Cohen DM, Bhattacharyya I, Lydatt WM. Recalcitrant oral ulcers caused by calcium channel blockers: diagnosis and treatment considerations. J Am Dent Assoc.

1999;130:1611–1618.

51 Carpenter WM, Silverman S Jr. Over-the-counter products for oral ulcerations. J Calif Dent Assoc. 1998;26:199– 201.

52 Ghate JV, Jorizzo JL. Behçet’s disease and complex aphthosis. J Am Acad Dermatol. 1994;40:1–20.

53 Matfin G, Durand D, D’Agostino A, Wallach P, Adelman HM. An uncommon cause of oral ulcers. Hosp Pract (1995). 1998;33:11–14.

54 Parks ET, Lancaster H. Oral manifestations of systemic disease. Dermatol Clin. 2003;21:171–182.

55 Biel K, Böhm M, Luger TA, Bonsmann G. Long-standing oral aphthae–a clue to the diagnosis of coeliac disease.

Dermatology. 2000;200:340.

56 Zucker J, Mascrès C, Charland R. Oral manifestations of skin diseases. J Can Dent Assoc. 1990;56:867–871.

57 Williams DM. Non-infectious diseases of the oral soft tissue: a new approach. Adv Dent Res. 1993;7:213–219.

Oral Mucosal Lesions: Miscellaneous––Part III

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core curriculum

58 Vaillant L. Bullous autoimmune diseases of the oral mucosa. Rev Stomatol Chir Maxillofac. 1999;100:230– 239.

59 Wolff A, Ship JA, Tylenda CA, Fox PC, Baum BJ. Oral mucosal appearance is unchanged in health, different-aged persons. Oral Surg Oral Med Oral Pathol. 1991;71:569– 572.

60 Corbet EF, Holmgren CJ, Philipsen HP. Oral mucosal lesions in 65-74-year-old Hong Kong Chinese. Community Dent Oral Epidemiol. 1994;22:392–395.

61 MacEntee MI, Glick N, Stolar E. Age, gender, dentures and oral mucosal disorders. Oral Dis. 1998;4:32–36.

62 da Silva SR, Valsecki Júnior A. Evaluation of oral health conditions among the elderly in a Brazilian city. Rev Panam Salud Publica. 2000;8:268–271.

63 Scutariu MM, Voroneanu M. Oral effects of systemic medication in elderly. Rev Med Chir Soc Med Nat Iasi.

2009;113:885–891.

64 Parks ET. Lesions associated with drug reactions. Dermatol Clin. 1996;14:327–337.

Pogonology

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Volume 14 • Issue 3

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

A Leopard Can’t Change Its Spots, but a Melanocyte Can! False-Negative MART-1 Staining Parmvir Singh, BS;1 Hee Jin Kim, BS;1 Ann M. John, BA;1 Marc Z. Handler, MD;2 W. Clark Lambert, MD, PhD2 “In theory there is no difference between theory and practice; in practice there is.” ––Yogi Berra

M

elanin is produced within the melanosomes of pigment cells.1 The process involves conversion from tyrosine. Although melanin is an inert molecule, the precursors are toxic. Apparently, for this reason, melanocytes may cease production of melanin under stressful conditions.

Loss of skin pigment can be caused by a variety of processes.

Conditions associated with pigment loss include vitiligo, lichen sclerosus et atrophicans (LSA), and amelanotic melanoma. Vitiligo and LSA have been hypothesized to occur as a result of an autoimmune process. Amelanotic melanoma is caused by malignant proliferation of melanocytes that do not produce pigment. Vitiligo is characterized by inhibition/destruction of melanocytes in the epidermis.2 LSA demonstrates decreased, but otherwise normal melanogenesis.2 Stains, such as Melan-A, which identify melanocytes, can produce false-negative results in LSA and amelanotic melanoma, leading to delay in diagnosis and treatment.

Staining Monoclonal antibodies to Melan-A, S100, and HMB-45 antigens are the most commonly used immunostaining methods to identify melanocytes. In identification of melanoma, MelanA/MART-1 antibody has demonstrated a sensitivity of 75% to 92% and a specificity of 95% to 100%. S100 belongs to a group of calcium-binding proteins. S100 has very high sensitivity (97%–100%) but poor specificity (75%–87%).3 S100 is also positive in gliomas, schwannomas, and neurofibromas. HMB45 is a pre-immature melanosome protein that has low sensitivity (69%–93%) but high specificity (56%–100%). HMB-45 is minimally useful in children but is helpful in adults. When

staining for melanoma, it is advisable to first stain with Melan-A. If that is not informative, then staining with S100 is appropriate.

Vitiligo Vitiligo is an acquired, idiopathic disorder of cutaneous melanocyte loss characterized by hypomelanotic macules. The following antibodies have been detected in the sera of patients with vitiligo: melanocyte-specific tyrosinase, tyrosinase-related proteins 1 and 2, Pmel17, transcription factor SOX10, and melaninconcentrating hormone receptor 1. Autoantibodies to Melan-A (MART-1) are not detected in the sera of patients with vitiligo.

It is hypothesized that the autoimmune response to Melan-A in vitiligo is cytotoxic, not humoral.

Lichen sclerosus et atrophicans The Latin term “atrophicans” is in the ablative case. The ablative case expresses motion toward or away from something. In this case, it means toward (progressive) atrophy; hence, the commonly used term atrophicus is a misnomer. LSA is a chronically progressive, inflammatory, mucocutaneous skin disorder characterized by atrophic and sclerotic lesions.4 LSA presents as hypopigmented papules that coalesce to form atrophic plaques.4 It is a debilitating, female-predominant disorder that causes intense pruritus, burning, dysuria, and dyspareunia.5 The most commonly affected area is the anogenital region.6 Extragenital sites include the neck and shoulders, inner thighs, submammary area, wrist, and oral mucosa.4 The origin of LSA is not clear, but genetic, environmental, and infective causes have been hypothesized to play a role. It may be precipitated by trauma and a moist, occlusive environment. Autoimmunity, including cir-

From Rutgers-New Jersey Medical School, Newark, NJ,1 and the Departments of Pathology and Laboratory Medicine and of Dermatology, Rutgers-New Jersey Medical School, Newark, NJ2 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. False-negative results from MART-1 in a patient with a 20-year history of lichen sclerosus et atrophicans (original magnification ×540).

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

gery may be used when scarring leads to functional impairment.5 Circumcision is effective in men.5 We recently saw a patient with LSA with negative findings on staining for MART-1, but positive findings on staining for S100 (Figures 1 and 2). The area immediately adjacent to the LSA stained positively for MART-1. The patient, a 64-year-old woman, was labeled as having vitiligo for 20 years due to negative MART-1 staining. As noted above, MART-1 is not 100% sensitive for melanocytes. Melanocytes are still present in areas of LSA. The incidence of false-negative findings cannot be ignored.

S100 immunostaining, although producing more false-positive results, should be performed as a rule-out test because of its higher sensitivity. Treatment initiated during the 20-year delay period could have slowed the progression of this debilitating disease and decreased the risk of progression to squamous cell carcinoma.

Figure 2. Positive result from S100 in the same patient as Figure 1 (original magnification ×540).

Amelanotic melanoma culating antibodies to extracellular matrix protein 1, has been reported as a cause of LSA.7 It occurs comorbidly with other autoimmune diseases. Several studies have shown an association with Borrelia infection.4 Anogenital LSA is associated with a 4% to 5% risk of squamous cell carcinoma.4 The diagnosis of LSA is mainly clinical, but it does have some characteristic histologic features.5 Subepithelial, sclerotic collagen, with or without a lymphocytic infiltrate, is present. Early LSA is characterized by a lichenoid lymphoid infiltrate. This feature, if found alone, makes this a difficult diagnosis because it is common to many dermatoses.5 The mainstays of treatment for LSA are potent topical corticosteroids and phototherapy. SurSKINmed. 2016;14:203–205

Amelanotic melanoma is a type of melanoma without pigment (Figure 3). It presents clinically as an erythematous, asymmetric macule with irregular borders outlined by light brown or grey shade. Hypomelanotic melanomas with a small amount of pigment are more common than completely amelanotic melanomas.

Approximately 2% to 8% of cases of melanomas are amelanotic.8,9 The incidence is difficult to estimate as a result of misdiagnosis and delay in diagnosis.10 Amelanotic melanoma rarely presents with clinically recognizable, typical diagnostic features of melanoma such as asymmetry, border irregularity, and color variegation. The most common sites are the limbs in women and the trunk in men.10 A polymorphous pattern with no particular

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PERILS OF DERMATOPATHOLOGY cases, a more sensitive melanocyte stain, such as S100, can be used to avoid delay in initiation of treatment. Negative findings on MART-1 staining can lead to fatal consequences if it results in failure to diagnose an amelanotic melanoma.

References 1 Lerner AB. Behavior of pigment cells. J Invest Dermatol.

1980;75:121.

2 Carlson JA, Grabowski R, Mu XC, et al. Possible mechanisms of hypopigmentation in lichen sclerosus. Am J Dermatopathol. 2002;24:97–107.

3 Jing X, Michael CW, Theoharis CG. The use of immunocytochemical study in the cytologic diagnosis of melanoma: evaluation of three antibodies. Diagn Cytopathol.

2013;41:126–130.

4 Gubertini N, Bonin S, Trevisan G. Lichen sclerosus et atrophicans, scleroderma en coup de sabre and Lyme borreliosis. Dermatol Reports. 2011;3:e27.

Figure 4. False-negative results from MART-1 in the same patient as Figure 3 (original magnification ×270).

arrangement of vessels is characteristic on dermatoscopy.8,9 Similar to pigmented melanomas, the prognosis of amelanotic melanoma is mostly dependent on tumor thickness. False-negative MART-1 staining in amelanotic melanoma can lead to misdiagnosis (Figure 4). Amelanotic melanoma can mimic inflammatory disorders such as sarcoidosis, benign neoplasms, or malignant neoplasms such as basal cell carcinoma.

Conclusions Melanocytes can lose their melanin. A negative finding on MART-1 stain does not definitively rule out the presence of melanocytes. This results in confusion when considering depigmenting disorders, which can be caused by both melanocyte destruction and decreased melanin production/transport. In such

5 Fistarol SK, Itin PH. Diagnosis and treatment of lichen sclerosus: an update. Am J Clin Dermatol. 2013;14:27– 47.

6 Powell JJ, Wojnarowska F. Lichen sclerosus. Lancet.

1999;353:1777–1783.

7 Oyama N, Chan I, Neill SM, et al. Autoantibodies to extracellular matrix protein 1 in lichen sclerosus. Lancet.

2003;36:118–123.

8 Jaimes N, Braun RP, Thomas L, Marghoob AA. Clinical and dermoscopic characteristics of amelanotic melanomas that are not of the nodular subtype. J Eur Acad Dermtol Venereol. 2012;26:591–596.

9 Stojkovic-Filipovic J, Kittler H. Dermatoscopy of amelanotic and hypomelanotic melanoma. J Dtsch Dermatol Ges. 2014;12:467–472.

10 Cheung WL, Patel RR, Leonard A, Firoz B, Meehan SA. Amelanotic melanoma: a detailed morphologic analysis with clinicopathologic correlation of 75 cases. J Cutan Pathol. 2012;39:33–39.

“Shingles.” Moulage No. 15-16HZV, made by Lotte Volger in 1925 in the Clinic for Dermatology Zurich. Museum of Wax Moulages Zurich, www.moulagen.ch Courtesy of Michael Geiges, MD

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Edward L. Keyes Resident Contest for Outstanding Case Reports 12th World Congress of the International Academy of Cosmetic Dermatology May 4-6, 2017, Bengaluru, India Abstract deadline: January 10, 2017 To be awarded for the best Case Report submitted by a physician in training (resident, fellow, or registrar) for presentation at the 12th World Congress of the International Academy of Cosmetic Dermatology in Bengaluru, India, May 4-6, 2017.

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 12th World Congress of the International Academy of Cosmetic Dermatology in Bengaluru, India, May 4-6, 2017.

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, January 10, 2017, 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, 2017. 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 Committeeâ&#x20AC;&#x2122;s decision by February 5, 2017.

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

May/June 2016

Volume 14 • Issue 3

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

JUBLIA (Efinaconazole): An Update Aditya K. Gupta, MD, PhD, FRCPC;1,2 Maria Cernea, PhD;2 William Abramovits, MD3,4,5

O

nychomycosis is a persistent fungal nail infection largely caused by dermatophytes; however, nondermatophyte molds and yeasts can also be the source of infection.1 The estimated prevalence of onychomycosis increases from 10% in the general population to 50% in those older than 70 years.1 Onychomycosis can affect patient quality of life, often causing discomfort and pain and, in severe cases, leading to more serious conditions such as cellulitis and foot ulcers.1

In spite of numerous therapeutic options, onychomycosis remains difficult to treat.2 Oral antifungals demonstrate the greatest efficacy rates; however, oral treatment poses the potential risks for systemic adverse effects, hepatotoxicity, drug reactions, and negative drug-drug interactions, especially in older, diabetic, and the immunocompromised patients.2 Topical antifungal therapies are not associated with drug interactions or treatment-related hepatotoxicity; however, the major challenge stems from the ability of the drug to effectively penetrate the nail, while maintaining sufficient concentrations to eradicate the fungus.3 The recently Food and Drug Administration–approved topical onychomycosis drug, efinaconazole,4 has broad-spectrum antifungal activity against dermatophytes, nondermatophyte molds, and yeasts in vitro and has demonstrated good results in onychomycosis patients.3 Efinaconazole has low surface tension, low keratin binding, and rapid release from keratin, which aids in its enhanced nail penetration and dispersal to the infection site.5 Efinaconazole accesses the site of infection by both transungual and subungual delivery,6,7 and possibly via the air gap that develops in more severe cases of onychomycosis.7 Phase III Studies Two identical, multicenter, randomized, double-blind, vehiclecontrolled studies were conducted in patients with mild to mod-

erate toenail onychomycosis (study 1: n=870; study 2: n=785).8 Participants received efinaconazole or vehicle once daily for 48 weeks. At 52 weeks, complete cure was achieved by 17.8% and 15.2% of efinaconazole-treated patients in studies 1 and 2, compared with 3.3% and 5.5% of vehicle-treated patients, respectively (P<.001). Mycologic cure was achieved by 55.2% and 53.4% of efinaconazole-treated patients compared with 16.8% and 16.9% of vehicle-treated patients (P<.001). Adverse events associated with efinaconazole were generally mild to moderate and clinically similar to vehicle (Figure). Additional analyses were carried out using data from phase III trials to determine the effects of predisposing factors on the efficacy of efinaconazole (Table).9,11,12,15 Patients With Tinea Pedis At the beginning of the studies, 21.3% of onychomycosis patients were also diagnosed with interdigital tinea pedis.9 In patients receiving concurrent treatment for tinea pedis and onychomycosis, complete cure rates with efinaconazole were 29.4% (vehicle 7.7%; P=.003) and mycologic cure rates were 56.2% (vehicle 26.6%; P<.001). In patients receiving treatment for onychomycosis only, complete cure rates with efinaconazole were 16.1% (vehicle 0%; P=.045) and mycologic cure rates were 45.2% (vehicle 12.5%; P=.007).

Patients With Diabetes The efficacy of efinaconazole was assessed in onychomycosis patients, who were also diabetic (n=112).10 At 52 weeks, 13% of diabetics and 18.8% of nondiabetics treated with efinaconazole achieved complete cure compared with 3.7% of diabetics treated with vehicle (P<.001). Mycologic cure was achieved in 56.5% of diabetic and 56.3% of nondiabetic patients compared with 14.8% of diabetics treated with vehicle (P=.016). No significant difference was found between the efficacy of efinaconazole (complete or my-

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, MD, 645 Windermere Road, London, Ontario, Canada N5X 2P1 • E-mail: agupta@execulink.com

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Table. Criteria Indicating a Positive Responder With Efinaconazole Cure Rates With Efinaconazole Patient/Infection Characteristics

Complete Cure

Mycologic Cure

25.8% vs 15.9%

58.2% vs 55.5%

42.6% vs 17.1% vs 16.2%

66% vs 59% vs 53.8%

Concurrent treatment of tinea pedis vs treatment of onychomycosis without treating tinea pedis9

29.4% vs 16.1%

56.2% vs 45.2%

Women vs men15

27.1% vs 15.8%

–

Patient age (≤65 vs >65 years)15

18.9% vs 15.7%

–

Patient weight (<84 kg vs ≥84 kg)15

21% vs 15.9%

–

Mild vs moderate onychomycosis12 Early (<1 year) vs baseline (1–5 years) vs advanced (>5 years)

11

Complete cure was defined as 0% clinical involvement of the target toenail plus negative results on potassium hydroxide (KOH) preparation and fungal culture.

Mycologic cure was defined as negative results on KOH microscopy and culture.

Mild onychomycosis was defined as ≤25% nail involvement and moderate onychomycosis was defined as 26% to 74% nail involvement.

Mild vs Moderate Onychomycosis At week 52, 25.8% of patients with mild (≤25% nail involvement) and 15.9% of patients with moderate (26% to 50% nail involvement) onychomycosis achieved complete cure, compared with 11.3% and 2.7% in the vehicle groups, respectively (P=.006 and P<.001).12 Mycologic cure was achieved by 58.2% of the patients in the mild group and 55.5% of the patients in the moderate group, compared with 25.0% and 14.1% in the vehicle groups, respectively (P<.001).

Figure. Common adverse events reported in efinaconazole phase III trials.

Patients Showing Early Clinical Improvement cologic cure) in the diabetic and nondiabetic groups. Adverse events with efinaconazole were comparable to vehicle (64.2% vs 66.7%).

Early vs Advanced Duration of Onychomycosis At week 52, patients receiving efinaconazole treatment achieved higher complete cure rates, compared with vehicle-treated patients, irrespective of disease duration (<1 year: 42.6% vs 16.7%, not significant; 1 to 5 years: 17.1% vs 4.4%, P<.001; >5 years: 16.2% vs 2.5%, P<.001).11 Similarly, mycologic cure rates in efinaconazole-treated patients were higher compared with vehicle-treated patients (<1 year: 66% vs 27.8%, not significant; 1 to 5 years: 59% vs 14.7%, P<.001; >5 years: 53.8% vs 14.4%, P<.001); moreover, the probability of onychomycosis spreading to surrounding toenails was greater in the vehicle groups compared with the efinaconazole groups, irrespective of the number of affected nontarget toenails at baseline.

SKINmed. 2016;14:207–209

Approximately 25% of patients showing early clinical improvement with efinaconazole treatment (at least 10% improvement in affected nail involvement by week 12) progressed to complete cures at week 52 (P<.001 vs vehicle);13 moreover, 22% of patients, who achieved mycologic cure at week 24, achieved complete cure at week 52. Finally, 34.7% of patients, with at least 10% clinical improvement in the affected toenail at week 12, achieved complete or almost complete cure at week 52 (P<.001 vs vehicle).

Quality of Life In order to determine changes in quality of life, phase III efinaconazole trial participants were asked to complete a self-administered questionnaire at the time of enrollment and at weeks 24 and 52.14 Based on the questionnaire, efinaconazole was significantly more effective in improving quality of life compared with vehicle; moreover, there was a significant difference in the treatment satisfaction scores between participants demonstrating clinical improvement compared with participants showing no progress.

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Conclusions Efinaconazole is effective in treating mild to moderate toenail onychomycosis.8,15 Efinaconazole is also safe, with no risk of hepatotoxicity or negative drug interactions.4 Treatment with efinaconazole significantly improves patient quality of life.14 Efinaconazole is also a safe and effective treatment option in diabetic and immunocompromised patients or in patients in whom oral antifungal therapy may not be an option. Due to its minimal adverse effects, efinaconazole may be an off-label option for children. Twice-weekly application of efinaconazole may also be beneficial as prophylaxis treatment in patients who are at high risk for relapse or reinfection. Efinaconazole drug levels plateau in the nail after 2 weeks of daily application and levels remain stable for up to 2 weeks following cessation of treatment.6 Efinaconazole could be used in conjunction with an oral antifungal or device in patients, who are classified as poor responders to classic onychomycosis treatments (Table). Use in conjunction with topical therapy for interdigital tinea pedis (diagnosed or suspected) may increase its success rate. Overall, efinaconazole is an effective and safe, broad-range topical antifungal that offers promising results in the treatment of onychomycosis. Head-tohead comparative studies vs other topical onychomycosis, as well as combination studies with them, are pending.

References 1 Thomas J, Jacobson GA, Narkowicz CK, et al. Toenail onychomycosis: an important global disease burden. J Clin Pharm Ther. 2010;35:497–519.

2 Gupta AK, Paquet M. Management of onychomycosis in Canada in 2014. J Cutan Med Surg. 2015;19:260–273.

3 Gupta AK, Cernea M. How effective is efinaconazole in the management of onychomycosis? Expert Opin Pharmacother. 2016;17:611–618.

4 LLC VPNA. Jublia (Efinaconazole) package insert [Internet]. 2014. http://www.accessdata.fda.gov/drugsatfda_ docs/label/2014/203567s000lbl.pdf. Accessed April 8, 2016.

5 Sugiura K, Sugimoto N, Hosaka S, et al. The low keratin affinity of efinaconazole contributes to its nail penetration and fungicidal activity in topical onychomycosis treatment. Antimicrob Agents Chemother. 2014;58:3837– 3842.

6 Sakamoto M, Sugimoto N, Kawabata H, et al. Transungual delivery of efinaconazole: its deposition in the nail of onychomycosis patients and in vitro fungicidal activity in human nails. J Drugs Dermatol. 2014;13:1388–1392.

7 Gupta AK, Pillai R. The presence of an air gap between the nail plate and nail bed in onychomycosis patients: treatment implications for topical therapy. J Drugs Dermatol. 2015;14:859–863.

8 Elewski BE, Rich P, Pollak R, et al. Efinaconazole 10% solution in the treatment of toenail onychomycosis: Two phase III multicenter, randomized, double-blind studies.

J Am Acad Dermatol. 2013;68:600–608.

9 Markinson B, Caldwell B. Efinaconazole topical solution, 10% efficacy in patients with onychomycosis and coexisting tinea pedis. J Am Podiatr Med Assoc. 2015;105:407– 411.

10 Vlahovic TC, Joseph WS. Efinaconazole topical, 10% for the treatment of toenail onychomycosis in patients with diabetes. J Drugs Dermatol. 2014;13:1186–1190.

11 Rich P. Efinaconazole topical solution, 10%: the benefits of treating onychomycosis early. J Drugs Dermatol.

2015;14:58–62.

12 Rodriguez DA. Efinaconazole topical solution, 10%, for the treatment of mild and moderate toenail onychomycosis. J Clin Aesthetic Dermatol. 2015;8:24–29.

13 Jellinek NJ, Korotzer A. Prognostic factors for complete cure following treatment of mild and moderate toenail onychomycosis with efinaconazole topical solution 10. J Drugs Dermatol. 2015;14:871–875.

14 Tosti A, Elewski BE. Treatment of onychomycosis with efinaconazole 10% topical solution and quality of life. J Clin Aesthetic Dermatol. 2014;7:25–30.

15 Gupta AK, Elewski BE, Sugarman JL, et al. The efficacy and safety of efinaconazole 10% solution for treatment of mild to moderate onychomycosis: a pooled analysis of two phase 3 randomized trials. J Drugs Dermatol.

2014;13:815–820.

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May/June 2016

Volume 14 • Issue 3

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

Adult-Onset Still Disease Is on the Move Warren R. Heymann, MD

G

eorge Frederic Still (1868–1941) described chronic polyarthritis in children in 1897, but it was not until 1971 that Eric George Bywaters (1910–2003) confirmed that adults can develop an indistinguishable malady, which is now known as adult-onset Still disease (AOSD). Fourteen women with seronegative polyarthritis, fever, dermatitis, and elevated erythrocyte sedimentation rate were described.1 Recently, there have been advances in the understanding of the pathophysiology and changing perceptions of the clinical presentation, histology, and therapeutic approach of AOSD. Diagnosing AOSD AOSD is a rare disease, with an incidence of less than 1 case per 100,000 people. The diagnosis is one of exclusion, ruling out other diseases that may present similarly including infections (such as infective endocarditis), malignancies (notably lymphomas), or autoimmune disorders (including vasculitis).

The most commonly used scheme for establishing the diagnosis of AOSD is the Yamaguchi criteria, which includes major criteria: (1) arthralgia >2 weeks, (2) fever >39oC intermittent for >1 week, (3) typical rash (macular to papular, nonpruritic), and (4) white blood cell count >10,000 with >80% granulocytes; and minor criteria: (1) sore throat, (2) lymphadenopathy and/or splenomegaly, (3) abnormal liver function tests, and (4) negative rheumatoid factor and alanine aminotransferase.

Five criteria are necessary to diagnose AOSD, and at least two must be major criteria. Regarding laboratory tests, hyperferritinemia is most characteristic and is noted in up to 70% of patients. Ferritin levels are higher than in other autoimmune or inflammatory diseases (>3000 ng/mL being most commonly observed), with attendant glycosylated ferritin levels dropping to ≤20% in patients with AOSD.2

Pathophysiology AOSD is now considered a multigenic (or complex) autoinflammatory disorder, putting it “at the crossroads of autoinflammatory and autoimmune diseases.” Although no familial, ethnic, or geographic trend has been reported, and there have been no consistent human leukocyte antigen studies, polymorphisms in the interleukin (IL) 18 gene are significantly higher in AOSD patients compared with controls. Innate immunity activation, as noted by Toll-like receptor 7 ligation, promoting recruitment of neutrophils and the amplification of Th17-driven inflammatory responses has been noted. This correlates with AOSD activity and serum levels of cytokines IL-1β, IL-6, IL-18, and interferon γ. Adapative immunity may also be involved in the pathogenesis, as increased serum concentrations of the α-soluble receptor of IL-2 (CD25) are observed in AOSD patients, reflecting T-cell activation and proliferation.3 Rashes of AOSD The classic rash of AOSD is an evanescent eruption of lightpink papules, characterized histologically by a sparse superficial infiltrate including neutrophils.4 Recently, there have been multiple reports describing atypical rashes in AOSD that have been polymorphous, persistent, and pruritic—they have been called persistent pruritic papules and plaques (PPPPs)5,6 or persistent pruritic eruptions.7 PPPPs may appear clinically as urticarial erythema, flagellate erythema, or erythematous, slightly scaly, or crusted papules on the trunk and extremities.6 Lesions may also be described as lichenoid, dermatomyositis-like, and prurigo pigmentosa-like7 eruptions.

Reports vary with the frequency of concurrence of the typical rash with PPPP, ranging from 0%6 to 81%.4 Although the clini-

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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cal appearance may vary, all of the clinical variants share a unique histology that can be diagnostic (in the clinical context of other features of AOSD defined by the Yamaguchi criteria)—the presence of necrotic keratinocytes in the mid and upper epidermis, including the stratum corneum.8 Although there may be minor histologic variability including dermal mucin, a perivascular infiltrate with some neutrophils, or rare mild vacuolar alteration at the dermal-epidermal junction, it is the necrotic keratinocytes in the upper epidermis and cornified layer that are striking and may be considered pathognomonic for AOSD. Malignancies Associated With AOSD While debatable as to whether AOSD is a classic paraneoplastic disease, there is no question that there are an increasing number of reports linking an AOSD-like disease (if not AOSD itself ) to cancer. Malignancies may precede, appear concurrently, or present months or years after the symptoms and signs of AOSD. In a review of 31 cases of cancer associated with AOSD, 13 (42%) were diagnosed after the diagnosis of AOSD had been rendered.

Eight of the 31 (26%) were linked to lymphoma and six patients (19%) had breast cancer. Other cancers that have been reported include lung cancer, papillary thyroid cancer, melanoma,3 and ovarian cancer.9

er newer treatments are advocated (eg, anti–IL-1, anti–IL-6, and anti–IL-17 agents and tumor necrosis factor blockers).2 It is anticipated that targeted therapies will become increasingly refined with advances in deciphering the pathomechanisms of AOSD. Conclusions Concepts of AOSD have progressed from the classic transient rash associated with seronegative arthritis. Dermatologists should recognize PPPP with its pathognomonic histology, recall the association of AOSD with malignancy, and be cognizant of advances in therapy to allow our Still patients to move forward in good health.

References 1 Bywaters EG. Still’s disease in the adult. Ann Rheum Dis. 1971;30:121–133.

2 Senthilvel E, Papadakis A, McNamara M, Adebambo I. Adult-onset Still disease (AOSD). J Am Board Fam Med. 2010;23:418–422.

3 Gerfaud-Valentin M, Jamilloux Y, Iwaz J, Sève P. Adultonset Still’s disease. Autoimmun Rev. 2014;13:708–722.

4 Sun N, Brezinski EA, Berliner J, et al. Updates in adultonset Still disease: atypical cutaneous manifestations and associations with delayed malignancy. J Am Acad Dermatol. 2015;73:294–303.

Paraneoplastic syndromes arise from tumor secretion of hormones, peptides, or cytokines, or from immune cross-reactivity between malignant and normal tissues.10 An “ideal” paraneoplastic syndrome “should be a conspicuous and unmistakable sign, preferably not found otherwise in clinical dermatology—a sign specific for individual tumors or groups of tumors which arises early in the neoplastic process thus allowing timely diagnosis and treatment.” Key features of this ideal include concurrent onset, parallel course, and uniqueness of the clinical appearance.11 Based on these considerations, I would not classify AOSD as a classic paraneoplastic disease; however, it is important to recognize that cancers may be associated with AOSD (or an AOSDlike illness) and that an appropriate workup be considered, with emphasis on ruling out a lymphoproliferative malignancy or breast cancer.

5 Fortna RR, Gudjonsson JE, Seidel G, et al. Persistent pruritic papules and plaques: a characteristic histopathologic presentation seen in a subset of patients with adult-onset and juvenile Still’s disease. J Cutan Pathol.

2010;37:932–937.

Therapeutic Advances of AOSD

10 Pelosof LC, Gerber DE. Paraneoplastic syndrome: an approach to diagnosis and treatment. Mayo Clin Proc.

2010;85:838–854.

Treatment of AOSD is based on the presentation of either systemic or articular disease. Advances in the understanding of the pathogenesis of AOSD have allowed the introduction of newer targeted biotherapies.12 A proposed algorithm utilizes standard therapies first (nonsteroidal anti-inflammatory drug, prednisone, methotrexate). Should patients not respond to these agents, oth-

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6 Kikuchi N, Satoh M, Ohtsuka M, Yamamato T. Persistent pruritic papules and plaques associated with adultonset Still’s disease: report of six cases. J Dermatol.

2014;41:407–410.

7 Lee JY, Hsu CK, Liu MF, Chao SC. Evanescent and persistent pruritic eruptions of adult-onset Still disease: a clinical and pathologic study of 36 patients. Semin Arthritis Rheum. 2012;42:317–326.

8 Wolgamot G, Yoo J, Hurst S, et al. Unique histopathologic findings in a patient with adult-onset Still disease.

Am J Dermatopathol. 2007;49:194–196.

9 Schade L, Fritsch S, Gentili AC, et al. Adult Still’s disease associated with ovarian cancer: case report. Rev Bras Reumatol. 2013;53:532–534.

11 Fritsch P. Paraneoplastic syndromes of the skin. In: Hertl M, ed. Autoimmune Diseases of the Skin. New York, NY: Springer; 2011:517–536.

12 Jamilloux Y, Gerfaud-Valentin M, Henry T, Sève P. Treatment of adult-onset Still’s disease: a review. Ther Clin Risk Manag. 2014;11:33–43.

Adult-Onset Still Disease Is on the Move

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Volume 14 • Issue 3

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

Dermatology in a Bygone Era: Part II Eve J. Lowenstein, MD, PhD

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he 2016 meeting of the History of Dermatology Society was held on March 3 in Washington, DC. The topic was Dermatology in a Bygone Era, being a continuation of last year’s foray into diagnoses and treatments no longer in vogue.1

tion affecting the chin and upper lip, with perioral sparing, in middle-aged women.4 This pattern seems to have disappeared from the clinical landscape, implicating some exposure that no longer occurs.

Etiologies—Discarded Concepts

Introductory Presentation Mauricio Goihman-Yahr (Caracas, Venezuela) discussed three factors that contribute to the flourishing of medicine and dermatology: economics, freedom of information, and women. He postulated that since the early civilizations of Egypt and Greece, the influence of women, the least obvious of these factors, played pivotal roles in the progress of medicine and dermatology.

Diagnoses—No Longer Made Anya Serap Karadag (Istanbul, Turkey) presented on the topic of acnitis, a tuberculid disease first described in 1898 by Mortiz Kaposi (1837–1902). Subsequent entities identified and possibly eponymous include Barthelemy’s acnitis, acne agminata, acne scrofulosorum, granulomatous rosacea, lupus miliaris disseminatus fasciei, facial idiopathic granulomas with regressive evolution, and papulonecrotic tuberculid.2 Unlike papulonecrotic tuberculid, acnitis and its analogs are not associated with tuberculosis.

Noma was the subject presented by Eve J. Lowenstein (Brooklyn, NY). Still very much extant, noma, known since antiquity, is a noncommunicable acute, rapidly progressive and ravaging polymicrobial infection of the mouth. It can be fatal but survivors are left with severe disfigurement, trismus, and oral incontinence.3 Mohamed Amer (Cairo, Egypt) spoke next about Melanosis perioralis et peribuccale of Brocq. First described in 1923, the condition was associated with perioral red-brown pigmenta-

Heather Wickless (Dallas, TX) chose balneology as her topic. To combat dirt and disease, cleanliness was seen as a way to improve the lot of the poor. Repeal of a soap tax in 1853 allowed soap production to increase 500% through the end of the century.

Establishment of public bathhouses addressed these issues.

Natalie Cursio (Nashville, TN) presented Vincent’s angina, a term from World War I that is also known as trench mouth, and acute necrotizing gingivostomatitis. First described by Xenophon in 4th-century Greece, Jean Hyacinthe Vincent (1862–1950), a professor of bacteriology and epidemiologist in the early 20th century, delineated the disease as caused by the combination of Bacillus fusiformis and Borrelia vincentii.

Larry Millikan (Cumming, GA) reviewed the etiologic theories of sarcoidosis. The etiology has been attributed to pine pollen, wood-burning stoves, mold, insecticides, infections (acid-fast organisms or viruses), and foreign bodies (talc or zirconium).

Comorbid erythema nodosum has immunologic and other implicit associations.

Treatment No Longer Used Mark Bernhardt (Fort Lauderdale, FL) presented on the topic of chaulmoogra oil, an ancient Ayurvedic treatment used for centuries in different cultures to treat leprosy and other skin diseases.5 He called attention to Alice Augusta Ball, an African American woman and missionary who discovered its biochemical basis.

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

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history of dermatology

John Hall (Kansas City, MO) spoke about homeopathic therapy for herpes simplex. Focusing on the dangers and downsides, he described the failed use of echinacea, eleuthero, L-lysine, monolaurin bee products (derived from coconut oil), aloe vera, aspirin, lemon balm, topical zinc, and licorice root cream. Photodynamic therapy was the rage in 1970s but not effective, as was the case with smallpox vaccination.

Douglas Altchek (New York City, NY) discussed ice water bath therapy, used at various times since antiquity. There is a current fad with cryosaunas for weight reduction and psoriatic therapy.

Michael Lavery (Philadelphia, PA) spoke about scabies. Treatments have ranged from bloodletting in the 16th century to sulfur ointments, with regimens such as the Danish rapid cure treatment and Oppenheim’s rapid cure treatment involving a hot bath followed by sulfur ointment.

Daniel Wallach (Paris, France) presented on the topic of syphilis vaccination and syphilization. Joseph-Alexandre Auzias-Turenne (1812–1870) devised syphilization to eradicate syphilis between 1844–1870. He based his autoinoculation with soft chancre on the successful work done with smallpox, but his idea was not well received and ultimately failed. Confident in his discovery, Auzias-Turenne syphilized himself (confirmed by his autopsy with evidence of many chancres) and an unknown number of people.

came more evident such as with the 40- to 50-year latency before the appearance of numerous iatrogenic basal cell carcinomas.6 Gerd Plewig (Munich, Germany) presented on tobacco smoking and inflation. Derived from night shadow/solanum plants 500 years ago, tobacco was well known in the New World but unknown in the Old World until Columbus introduced the leaf.

Native Americans were first observed drinking and licking the extract but they also smoked it in a pipe, chewed the leaf, and sometimes used anal inflation. Johann Gottlieb Janitsch (1708– 1763) wrote an 18th-century book recommending anal tobacco inflation for parasites, colic, genitourinary, and gastrointestinal disorders.

Vaccine comes from the word “vaca” (Latin for cow), according to Robert Norman, who spoke about vaccines. Rabies was the first virus attenuated for a vaccine, while smallpox vaccination represented early preventative medicine.7 Reference

Robert Thomsen (Los Alamos, NM) discussed thorium X. Thorium-90, discovered in 1828 by a Swedish chemist, is a radioactive compound named for the Norse god Thor. Thorium is an α emitter, eventually decaying into thorium X, which was used in the early 20th century for a variety of skin disorders. Enthusiasm in the 1950s waned as the hazards of radioactive substances be-

1 Lowenstein EJ. Dermatology in a bygone era. SKINmed.

2015;13:389–391.

2 Forman L. Acnitis. Proc R Soc Med. 1930;10:1486–1487.

3 Enwonwu CO, Falkler WA, Phillips RS. Noma (cancrum oris). Lancet. 2006;368:147–156.

4 Ormsby O, Ebert M. Erythrose peribuccale pigmentaire de Brocq. Arch Dermatol Syphilol. 1931;13:429–438.

5 Parascandola J. Chaulmoogra oil in the treatment of leprosy. Pharm Hist. 2003;45:47–57.

6 Natkunarajah J, Cliff S. Thorium X treatment: multiple basal cell carcinomas within a port-wine stain. Clin Exp Dermatol. 2009;34:e189–e191.

7 Allen A. Vaccine: The Controversial Story of Medicine’s Greatest Lifesaver. New York, NY: W. W. Norton & Company; 2007.

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PHOTO CAPSULE

Lymphangioma Circumscriptum of the Vulva Virendra N. Sehgal, MD; Pullabatla V. S. Prasad, MD; Jangid B. Lal, MD; Pichai Kaliaperumal Kaviarasan, MD; Sonal Sharma, MD

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20-year-old married woman presented with progressive enlargement of the external genitalia for the past 10 years. The vulva was studded with several reddish, raised eruptions that had multiplied in the past 3 months. Right and left vulval involvement was prominent, accompanied by intense itching. There were areas of recurrent localized infection and oozing of clear fluid. She has had difficulty during coitus.

During pregnancy she had an enlargement of vulval lesions, with no regression during the postpartum period.

Examination revealed multiple translucent, papulovesicular lesions measuring 2 to 8 mm, confined to the labia majora occupying a 4×8-cm area and resembling a “frogspawn” (Figure 1). There was vulval edema with tenderness and no lymphadenopathy. Vaginal examination was unremarkable. Hematologic investigations including venereal disease research laboratory and enzyme-linked immunosorbent assay for human immunodeficiency virus I and II were unremarkable.

Histopathologic sections revealed multiple, large dilated lymphatics in the papillary and superficial dermis along with eosinophilic fluid (Figure 2). Lymphatics were lined by a single endothelial layer. The epidermis showed hyperkeratosis, acanthosis, and elongation of rete ridges.

Figure 1. Lymphangioma circumscriptum of the vulva depicting multiple translucent, papulovesicular lesions.

Discussion A lymphangioma/lymphatic malformation is a proliferation of lymphatic vessels accounting for around 4% of vascular tumors.1 Lymphatic malformation is either congenital (lymphangioma circumscriptum) or acquired (lymphangiectasia).2 Its initial name was “lymphangiectodes.”3 Lymphangioma circumscriptum4 was later coined. There are classic and localized variants,5 with the former typically seen at or soon after birth, while the latter may be seen at any age, appearing anywhere on the body.

Acquired lymphangiomas arise about 7 to 15 years after lymph node dissection and radiotherapy of the genitalia.6,7

Lymphangioma circumscriptum of the vulva is rare. Its clinical findings consist of multiple, thick-walled clear vesicles, owing to the serosanguinous fluid. The vesicles contain lymphatic fluid and resemble frogspawn caused by abnormal dilation of the lymph vessels.8 Excessive drainage and recurrent cellulitis are known complications in longstanding and untreated cases.

From the Dermato-Venereology (Skin/VD Centre), Sehgal Nursing Home, Delhi, Department of Dermatology, Venereology and Leprosy, Rajah Muthiah Medical College Hospital, Annamalai University, Chidambaram, Department of Pathology, University College of Medical Sciences and Associated GTB Hospital, Shahdara, 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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PHOTO CAPSULE References 1 Schwartz RA, Fernández G. Lymphangioma. http:// emedicine.medscape.com/article/1086806-overview.

Accessed November 13, 2009.

2 Verma SB. Lymphangiectasias of the skin: victims of confusing nomenclature. Clin Exp Dermatol. 2009;34:566– 569.

3 Fox T, Fox TC. On a case of lymphangiectodes with an account of the histology of the growth. Trans Pathol Soc London. 1878;30:470–476.

4 Morris M. Lymphangioma circumscriptum. In: Unna PG, Morris M, Duhring LA, LeLoir H, eds. International Atlas of Rare Skin Diseases. Vol. 2. Hamburg, Germany: Leopold Voss; 1889:1–4.

5 Peachey RD, Lim CC, Whimster IW. Lymphangioma of skin. A review of 65 cases. Br J Dermatol. 1970;83:519– 527.

Figure 2. Lymphangioma circumscriptum of the vulva showing multiple dilated channels in papillary and superficial dermis containing eosinophilic fluid with acanthotic epidermis (hematoxylin and eosin stain, original magnification ×100).

6 LaPolla, J, Foucar E, Leshin B, et al. Vulvar lymphangioma circumscriptum: a rare complication of therapy for squamous cell carcinoma of the cervix. Gynecol Oncol.

1985;22:363–366.

7 Virgili, A, Corazza M. Lymphangioma and lymphangiectasis of the vulva. J Eur Acad Dermatol Venerol.

1997;8:229–232.

Histopathologic features are well-described9 and are composed of numerous dilated lymphatics in the papillary dermis, containing clear fluid and occasionally red blood cells. The overlying epidermis may show mild acanthosis and hyperkeratosis.

8 Aggarwal K, Gupta S, Jain VK, et al. Congenital lymphangioma circumscriptum of the vulva. Indian Pediatr.

2009;46:428–429.

Treatment

10 Vignes S, Arrault M, Trevidic P. Surgical resection of vulva lymphoedema circumscriptum. J Plast Reconstr Aesthet Surg. 2010;63:1883–1885.

Surgical excision10 and carbon dioxide11,12 laser are the two main treatment modalities. Excisional surgery eliminates the abnormal subcutaneous lymph vessels and corrects the aesthetic appearance of the edematous vulva. Carbon dioxide laser is useful for treating superficial lesions, as are electrocoagulation, cryotherapy, and sclerosing therapy.

9 Whimster IW. The pathology of lymphangioma circumscriptum. Br J Dermatol. 1976;94:473–486.

11 Bailin PL, Kantor GR, Wheeland RG. Carbon dioxide laser vaporization of lymphangioma circumscriptum. J Am Acad Dermatol. 1986;14:257–262.

12 Huilgol SC, Neill S, Barlow RJ. CO(2) laser therapy of vulval lymphangiectasia and lymphangioma circumscriptum. Dermatol Surg. 2002;28:575–577.

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Volume 14 • Issue 3

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

A Souvenir From France: Acrodermatitis Chronica Atrophicans Presenting in the United States Lilia M. Correa-Selm, MD;1 Tara Bronsnick, BA;1 Babar K. Rao, MD;1 A. Yasmine Kirkorian, MD;1 Alan Marcus, MD;2 Jisun Cha, MD1

A 70-year-old man was referred by his rheumatologist to our dermatology clinic for evaluation of dermatitis on his right arm that appeared 3 months earlier. The skin lesion was asymptomatic and the patient denied current systemic symptoms, including fever, chills, and joint pain; however, 10 months prior to this presentation he experienced arthritis in the left knee. At that time, Borrelia serology revealed positive IgG (6.07; <0.8 negative, 0.8 to 0.99 borderline, ≥1 positive) and negative IgM titers. The patient had not received treatment for Lyme disease in the past. He was referred to rheumatology for evaluation of possible Lyme disease but did not follow up until 10 months later. The arthritis has since resolved. He travels frequently to France and recalls multiple tick bites during these trips. (SKINmed. 2016;14:217–219)

O

n physical examination, there was a 10×9 cm erythematous, edematous, centrally atrophic, annular plaque with fine wrinkling of the overlying skin on the right antecubital fossa (Figure 1A). The remainder of the skin and musculoskeletal examination was within normal limits.

A biopsy was performed. Histopathology revealed spongiosis and exocytosis in the epidermis with prominent myxoid changes in the dermis as well as superficial perivascular lymphocytic infiltrate admixed with mast cells (Figure 2).

A complete blood cell count and complete metabolic panel were within normal limits. Borrelia serology (enzyme-linked immunosorbent assay [ELISA]) 10 months prior to presentation revealed positive IgG and negative IgM titers, which is consistent with untreated chronic borrelial infection. As noted above, the patient was not previously treated for Lyme disease at the time of testing. A routine confirmatory Western blot was performed with bands that correlated with borrelial antigens p93, p66, p58, p45, p41, p39, p30, p28, p23, and p18. This Western blot pattern is consistent with Borrelia afzelii infection.1–3 The clinical findings in combination with the serologic and histologic evidence support a diagnosis of acrodermatitis chronica atrophicans (ACA) in the context of chronic B afzelii infection.

It is likely that the patient contracted this infection during earlier trips to France. For 2 weeks prior to evaluation in our clinic, the patient was treated with amoxicillin 400 mg three times a day.

The treatment was switched to doxycycline 100 mg twice daily for 2 months. At the end of this treatment, the lesion was significantly improved, with decreased redness and swelling (Figure 1B). On his most recent visit to the clinic, 4 months after completing treatment, the lesion had almost disappeared (Figure 1C) and the IgG titer decreased to 4.04 from an initial value of 6.07.

Discussion ACA is a late cutaneous manifestation of Lyme borreliosis that presents with one or multiple ill-defined inflammatory plaques with bluish red discoloration on the extensor surface of the extremities with doughy swelling. These evolve into chronic lesions in which there is a loss of dermal and epidermal structures, giving the skin a wrinkled and thinned appearance with a violaceous color, which is characteristically referred to as atrophic change of the skin. Some patients present with concomitant central and peripheral nervous system involvement including polyneuropathy and chronic joint involvement.4 ACA has been associated with one of the genospecies of Borrelia burgdorferi sensu lato, B afzelii in nearly all reports to date.5,6 Large case series of this cutaneous manifestation of Lyme borreliosis have been reported

From the Department of Dermatology1 and Pathology,2 Robert Wood Johnson Medical School, Rutgers University, New Brunswick, NJ Address for Correspondence: Jisun Cha, MD, 1 Worlds Fair Drive, Somerset, NJ 08873 • E-mail: chaji@rutgers.edu

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Figure 2. Findings from punch biopsy of the lesion demonstrating epidermal spongiosis and dermal myxoid change with perivascular lymphocytic infiltration (hematoxylin and eosin stain, original magnification ×2).

A

in Europe but only few cases have been reported in the United States.5,7 Given the scarcity of cases encountered in the United States, a review of diagnostic findings, including Western blot serotyping and histopathology, is likely to be helpful for clinicians in their diagnosis, management, and follow-up of patients with similar clinical situations.

B

C Figure 1. At initial presentation, there was a 10×9 cm erythematous, edematous, atrophic plaque with fine wrinkling of the skin located in the right antecubital fossa (A). Two months post-treatment, there was diminished erythema and atrophy of the plaque (B). Four months post-treatment, the lesion was barely noticeable (C).

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Serology requires a two-step diagnosis in which an initial ELISA is performed and, if positive, is followed by a confirmatory Western blot assay. ELISA identifies IgM and IgG antibodies to B burgdorferi antigens in the patient’s serum. Western blot detects specific serum proteins using gel electrophoresis to separate proteins by molecular weight. In this case, the proteins identified are antibodies to specific B burgdorferi antigens, which are bacterial structural components (ie, membrane proteins). Analysis of Western blot pattern can aide in identification of the etiologic Borrelia genospecies.3,8,9 The diagnostic Western blot pattern for B afzelii has bands that correlate with Borrelia antigens p93, p66, p58, p45, p41, p39, p30, p28, p23, and p18. As mentioned earlier, for this patient, the Western blot pattern was consistent with B afzelii infection and together with his history and clinical presentation confirm the diagnosis of ACA. The finding of positive IgG and negative IgM titers in this patient is caused by the chronicity of his disease. It is important to note that this titer pattern is possible in a patient with ACA. The typical histopathologic findings of ACA include an atrophic epidermis with dermal inflammatory infiltrate composed mainly of lymphocytes and plasma cells in the background of myxoid

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and edematous stroma. The pathophysiology underlying this picture is a T-cell–mediated inflammatory response to bacterial antigens. Down-regulation of major histocompatibility complex class II on Langerhans cells leads to defective immune response and persistence of the Borrelia antigen. Subsequently, chronic inflammation with associated angiopathy, myositis, and macrophage-mediated degradation of elastic tissue gradually results in the atrophy that is characteristic of ACA. In more advanced lesions, therefore, dermal edema and atrophy are seen.10,11 For our patient, histopathology revealed spongiosis and exocytosis in the epidermis with prominent myxoid changes as a result of the chronic inflammation in the dermis as well as superficial perivascular lymphocytic infiltrate admixed with mast cells. The histopathologic findings presented here add to the small number of available references for the cutaneous pathology seen in ACA. The treatment of choice for ACA is doxycycline (100 mg twice daily for 2 to 6 weeks) if no extracutaneous manifestations are present. If the patient is pregnant or younger than 8 years, amoxicillin should be used for a month-long course instead of doxycycline. If neurologic symptoms are present or if the patient presents with refractory arthritis, longer treatment duration or parenteral treatment with ceftriaxone, cefotaxime, or penicillin G is indicated.6,10 Positive antibody titers may occur for years despite treatment; therefore, persistent seropositive titers are not an indication of treatment failure. Currently, there is no test available to confirm successful clearance of the organism post-treatment.10 It is worth noting that our patient’s Lyme IgG titer decreased 4 months after treatment; however, previous studies have shown no correlation between serology and clinical improvement,12–14 and normalization of elevated titers did not occur.15 Conclusions

2 Norman GL, Antig JM, Bigaignon G, Hogrefe WR. Serodiagnosis of Lyme borreliosis by Borrelia burgdorferi sensu stricto, B garinii, and B afzelii western blots (immunoblots). J Clin Microbiol. 1996;34:1732–1738.

3 Zajkowska J, Czupryna P, Pancewicz SA, Kondrusik M, Moniuszko A. Acrodermatitis chronica atrophicans. Lancet Infect Dis. 2011;11:800.

4 Müllegger RR, Glatz M. Skin manifestations of lyme borreliosis: diagnosis and management. Am J Clin Dermatol.

2008;9:355–368 5 Smetanick MT, Zellis SL, Ermolovich T. Acrodermatitis chronica atrophicans: a case report and review of the literature. Cutis. 2010;85:247–252.

6 Asbrink E, Hovmark A, Olsson I. Clinical manifestations of acrodermatitis chronica atrophicans in 50 Swedish patients. Zentralbl Bakteriol Mikrobiol Hyg A. 1986;263:253–261.

7 Weber K, Neubert U. Clinical features of early erythema migrans disease and related disorders. Zentralbl Bakteriol Mikrobiol Hyg A. 1986;263(1-2):209-228.

8 Garbe C, Stein H, Dienemann D, Orfanos CE. Borrelia burgdorferi-associated cutaneous B cell lymphoma: clinical and immunohistologic characterization of four cases. J Am Acad Dermatol. 1991;24:584–590.

9 Aberer E, Koszik F, Silberer M. Why is chronic Lyme borreliosis chronic? Clin Infect Dis. 1997;25 suppl 1:S64– S70.

10 Mahalingam M, Bhawan J, Chomat AM, Hu L. Lyme borreliosis. In: Wolff K, Goldsmith LA, Katz SI, et al.

Fitzpatrick´s Dermatology in General Medicine. 7th ed.

New York, NY: McGraw-Hill; 2008:1797–1806.

11 Brehmer-Andersson E, Hovmark A, Asbrink E. Acrodermatitis chronica atrophicans: histopathologic findings and clinical correlations in 111 cases. Acta Derm Venereol. 1998;78:207–213.

12 Hulshof MM, Vandenbroucke JP, Nohlmans LM, et al.

Long-term prognosis in patients treated for erythema chronicum migrans and acrodermatitis chronica atrophicans. Arch Dermatol. 1997;133:33–37.

We present a case of ACA caused by B afzelii in the context of a tick bite that presumably occurred in France. Diagnostic findings for this rare condition, including histopathology and Western blot analysis as a means to identify Borrelia genospecies, are described. This presentation is likely to be helpful to clinicians who may encounter this rare, but treatable, manifestation of Lyme disease.

13 Hammers-Berggren S, Lebech AM, Karlsson M, et al. Serological follow-up after treatment of Borrelia arthritis and acrodermatitis chronica atrophicans. Scand J Infect Dis. 1994;26:339–347.

References

15 Olsson I, Asbrink E, von Stedingk M, von Stedingk LV. Changes in Borrelia burgdorferi-specific serum IgG antibody levels in patients treated for acrodermatitis chronica atrophicans. Acta Derm Venereol.

1994;74:424–428.

1 Robertson J, Guy E, Andrews N, et al. A European multicenter study of immunoblotting in serodiagnosis of lyme borreliosis. J Clin Microbiol. 2000;38:2097–2102.

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14 Plörer A, Sepp N, Schmutzhard E, et al. Effects of adequate versus inadequate treatment of cutaneous manifestations of Lyme borreliosis on the incidence of late complications and late serologic status. J Invest Dermatol. 1993;100:103–109.

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Volume 14 • Issue 3

CASE STUDY

Porokeratotic Adnexal Ostial Nevus—Report of a Case With Unusual Clinical and Histologic Features Julien Lanoue, BA;1 Karen B. Jacobson, MPH;1 Kohtaro Ooka, MD;1 Chanpreet Singh;2 Olga Camacho-Vanegas, PhD;2 John A. Martignetti, MD, PhD;2 Jacob Levitt, MD;1 Robert G. Phelps, MD1

An 11-year-old Tanzanian girl presented with diffuse verrucous lesions of varying morphology, scarring alopecia, and keloid scars over the face with a predilection for the ears. Physical examination revealed dark keratoderma and patches of hypopigmentation near the midline of the dorsal trunk (Figure 1a). Her forearms were densely covered by verrucous lesions with the exception of a clear linear patch on the dorsal aspect of the left forearm (Figure 1b). The perioral area was notable for white spires projecting from verrucous papules (Figure 1c) while the oral mucosa and teeth appeared normal on visual examination. The rest of her body, including the palms and soles, was covered by patchy, scaly lesions of varying severity. (SKINmed. 2016;14:221–224)

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he patient demonstrated partial hearing loss and language delay. No physical disabilities were appreciated. The girl’s uncle, and acting guardian, reported that the girl was born following a normal gestation and delivery and that her skin condition was present at birth.

of the connexin 26 gene (also known as GJB2, MIM 121011) was amplified by polymerase chain reaction using five overlapping amplicons (Figure 3). The resultant amplicons were sequenced in both directions by Sanger sequencing. No coding mutations were identified.

An incisional biopsy was obtained from the right forearm. Histologic examination revealed sharply circumscribed cornoid lamella within the lumina of the hair follicle and overlying the acrosyringium of the eccrine glands, while the adjacent epidermis showed papillomatosis but no acanthosis (Figure 2). There were scattered epidermoid and trichilemmal cysts and apocrine glands within the dermis. These findings were sufficient to make a diagnosis of porokeratotic eccrine ostial and dermal duct nevus (PEODDN).

Our patient had reported using a cream that successfully cleared some of the lesions on her forearm. We suspect the cream was a retinoid or anthralin. Unfortunately, our patient was lost to follow-up after biopsy as she was seen in the context of an overseas medical mission in Tanzania.

Genomic sequencing of the GJB2 gene was performed given its association with PEODDN and related disorders. Genomic DNA was isolated from biopsy tissue of the affected lesions that had been preserved in paraffin blocks. The entire coding region

Discussion PEODDN is a rare type of porokeratotic dermatosis, or clonal disorder of keratinization, classified as a hamartoma or adnexal tumor with eccrine differentiation.1 This dermatologic disorder is characterized histologically by cornoid lamella involving the acrosyringium. Severity can range from localized cutaneous lesions to systemic involvement, with an age of onset ranging from birth to adulthood.2–4 These lesions may diminish, progress, or

From the Departments of Dermatology1 and Genetics and Genomic Sciences,2 Icahn School of Medicine at Mount Sinai, New York, NY Address for Correspondence: Robert G. Phelps, MD, Annenberg Building Room 308, 1468 Madison Avenue, New York, NY 10029 • E-mail: robert.phelps@mountsinai.org

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(c)

Figure 1. Our patient’s forearms were densely covered by verrucous lesions (a), diffuse keratotic lesions of the trunk, (b) and extensive keloid scarring of the head (c). White spires projected from perioral verrucous lesions.

(a)

(b)

(c)

(d)

Figure 2. Hematoxylin and eosin stain of incisional biopsy specimen from the right forearm. Hematoxylin and eosin stain showing papillomatosis of the epidermis (original magnification ×40) (a), cornoid lamella in dilated ostia (×40) (b), and small trichilemmal cyst in the dermis (×100) (c), with higher power showing cornoid lamella above pale-staining ostia (×200) (d).

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Figure 3. Map of the GJB2 coding region and relative position of the five amplicons spanning the region. Primer sequences and polymerase chain reaction amplification conditions are available upon request.

remain stable over time. To date, only a few dozen cases have been reported, of which very few have been diffuse in presentation.5 Although there is little evidence that the disorder is hereditary, one case of familial PEODDN has been observed.1 In some cases, the affected areas have been observed to follow the lines of Blaschko.4,6,7

exon, which would be difficult to detect by the most frequently used sequencing technologies; epigenetic changes that would affect transcription of the gene; and a disease-causing mutation in another related gene. One such possibility is a mutation in connexin 30 (GJB6), which has also been reported to occur in association with KID syndrome.13

Porokeratotic eccrine and hair follicle nevus (PEHFN) is a similar entity in which there are cornoid lamellae in both eccrine and follicular ostia. Only five cases of PEHFN have been reported.6 Some authors have proposed the name porokeratotic adnexal ostial nevus (PAON) as a unifying name for PEODDN and PEHFN, and we believe this is a more accurate term for describing this entity.8

Although in some cases of PEODDN the lesions can improve or flatten over time, they are often persistent and resistant to treatment. Treatment with topical retinoids, steroids, or urea ointment have been successful to varying degrees in some patients.8 Results with psoriasis medications have similarly been mixed; one case found no improvement with calcipotriene, while another experienced short-term improvement with anthralin before relapse 6 months later.14

The exact etiology of PEODDN is unknown but it is postulated to be a form of genetic mosaicism due to reported occurrences along the lines of Blaschko and recent reports that have cited mosaic somatic mutations occurring in the coding portion (exon 2) of the connexin 26 (GJB2) gene.8,9 Two related disorders, known as keratitis ichthyosis and deafness (KID) syndrome and hystrix-like ichthyosis deafness (HID) syndrome, have been reported to be caused by mutations to the same portion of the GJB2 gene.10,11 KID syndrome, which manifests with deafness, follicular keratoses, alopecia, and nonscaling verrucous or hyperkeratotic erythrokeratodermic plaque, has also been reported to occur concurrently with PEODDN.9,10,12 Given the deafness and alopecia seen in our patient, we postulated that our patient may have exhibited an overlap syndrome with KID, or less likely HID, secondary to a mutation in GJB2. The results of our sequencing analysis of genomic DNA extracted from an affected lesion, however, found no mutations within the coding region of GJB2 where the majority of the previous mutations have been reported.13 Given this finding, a number of hypotheses regarding the genetic basis of our patient’s disorder are therefore possible.

These include mutations within the GJB2 gene that are present outside of the coding region; insertions or deletions of the SKINmed. 2016;14:221–224

Conclusions To our knowledge, systemic retinoids have not been attempted in the treatment of this condition, but we postulate that a trial of oral retinoids would have been a reasonable choice for therapy in our patient given its successful use in other hyperkeratotic conditions and the widespread distribution of lesions seen in our case. Carbon dioxide laser treatment has shown some evidence for efficacy in cosmetic improvement of lesions in patients with PEODDN, but treatment is reported to be painful and lesions often recur.15 Surgical excision may be an option for small, localized lesions.

References

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1 Masferrer E, Vicente MA, Bassas-Vila J, Rovira C, Gonzalez-Ensenat MA. Porokeratotic eccrine ostial and dermal duct naevus: report of 10 cases. J Eur Acad Dermatol Venereol. 2010;24:847–851.

2 Sassmannshausen J, Bogomilsky J, Chaffins M. Porokeratotic eccrine ostial and dermal duct nevus: a case report and review of the literature. J Am Acad Dermatol.

2000;43:364–367.

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3 Warren RB, Verbov JL, Kokai GK. Porokeratotic eccrine ostial and dermal duct nevus. Pediatr Dermatol.

2006;23:465–466.

4 Wang NS, Meola T, Orlow SJ, Kamino H. Porokeratotic eccrine ostial and dermal duct nevus: a report of 2 cases and review of the literature. Am J Dermatopathol.

2009;31:582–586.

5 Jamora MJ, Celis MA. Generalized porokeratotic eccrine ostial and dermal duct nevus associated with deafness.

J Am Acad Dermatol. 2008;59:S43–S45.

6 Criscione V, Lachiewicz A, Robinson-Bostom L, Grenier N, Dill SW. Porokeratotic eccrine duct and hair follicle nevus (PEHFN) associated with keratitis-ichthyosis-deafness (KID) syndrome. Pediatr Dermatol. 2010;27:514–517.

7 Cambiaghi S, Gianotti R, Caputo R. Widespread porokeratotic eccrine ostial and dermal duct nevus along Blaschko lines. Pediatr Dermatol. 2007;24:162–167.

8 Goddard DS, Rogers M, Frieden IJ, et al. Widespread porokeratotic adnexal ostial nevus: clinical features and proposal of a new name unifying porokeratotic eccrine ostial and dermal duct nevus and porokeratotic eccrine and hair follicle nevus. J Am Acad Dermatol.

2009;61:1060.e1–1060.e14.

9 Easton JA, Donnelly S, Kamps MA, et al. Porokeratotic eccrine nevus may be caused by somatic connexin26 mutations. J Invest Dermatol. 2012;132:2184–2191.

10 Lazic T, Li Q, Frank M, Uitto J, Zhou LH. Extending the phenotypic spectrum of keratitis-ichthyosis-deafness syndrome: report of a patient with GJB2 (G12R) Connexin 26 mutation and unusual clinical findings. Pediatr Dermatol. 2012;29:349–357.

11 van Geel M, van Steensel MA, Kuster W, et al. HID and KID syndromes are associated with the same connexin 26 mutation. Br J Dermatol. 2002;146:938–942.

12 Caceres-Rios H, Tamayo-Sanchez L, Duran-Mckinster C, et al. Keratitis, ichthyosis, and deafness (KID syndrome): review of the literature and proposal of a new terminology. Pediatr Dermatol. 1996;13:105–113.

13 Jan AY, Amin S, Ratajczak P, Richard G, Sybert VP. Genetic heterogeneity of KID syndrome: identification of a Cx30 Gene (GJB6) mutation in a patient with KID syndrome and congenital atrichia. J Invest Dermatol.

2004;122:1108–1113.

14 van de Kerkhof PC, Steijlen PM, Happle R. Co-occurrence of linear psoriasis and porokeratotic eccrine ostial and dermal duct naevus. Acta Derm Venereol. 1993;73:311– 312.

15 Wong JW, Summers EM, Taylor MB, Harris RM. Porokeratotic eccrine ostial and dermal duct nevus treated with a combination erbium/CO2 laser: a case and brief review. Dermatol Online J. 2011;17:10.

Historical Diagnosis and treatment: epithelioma

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Volume 14 • Issue 3

CASE STUDY

Four Diseases, Two Associations, One Patient: A Case of Frontal Fibrosing Alopecia, Lichen Planus Pigmentosus, Acne Rosacea, and Morbihan Disease Joanna L. Walker, MD;1 Leslie Robinson-Bostom, MD;1 Shoshana Landow, MD1,2

A 77-year-old woman born in the Dominican Republic presented with fullness of the glabella and medial eyebrows for 1 year followed by alopecia of the lateral eyebrows and frontal hairline. She stated that although she had a high hairline at baseline, it had receded in the past year. She had also noted central scalp hair thinning that started 6 years earlier. She denied all styling practices that used traction or chemical processes, although she admitted to hair dye and blow dryer use. She reported “acne” in the central face for decades and darkening of the skin on the lateral face for several years. Her medical history included hypertension, hyperlipidemia, hypothyroidism, benign paroxysmal positional vertigo, and treated breast ductal hyperplasia. Her medications were metoprolol, amlodipine, aspirin, levothyroxine, omeprazole, pravastatin, and meclizine; she denied starting any new medications within the past 2 years. Her family history was notable for androgenic pattern alopecia in a brother and a high hairline in her father. Review of systems was negative except for knee arthralgias and seasonal allergic rhinitis. (SKINmed.

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n physical examination, she had Fitzpatrick skin type IV skin and a 20-mm band of scarring alopecia of the frontal-temporal hairline with perifollicular keratotic papules and the “lonely hair” sign. Alopecia with loss of the follicle ostea affected the lateral half of both eyebrows. There was Sinclair grade 3 alopecia of the central scalp. On the bilateral medial brows were infiltrated plaques; subtle glabellar and periocular edema were also noted. On the nose, malar cheeks, and chin were inflammatory pink papules; the nose also had erythema and mild edema. On the lateral aspects of the cheeks and temples were coalescing dark brown macules. There were no other skin, hair, or nail abnormalities (Figures 1–3).

Biopsy results from the left frontal part of the scalp showed periinfundibular and peri-isthmic lichenoid interface dermatitis consistent with lichen planopilaris. There were also several naked hair shafts with surrounding histiocytic inflammation with multinucleated giant cells suggestive of pulling or traction (Figure 4). Biopsy results from the midle of the left eyebrow dem-

onstrated mild follicular and scant epidermal vacuolar interface dermatitis with rare necrotic keratinocytes, pigment incontinence, and dermal fibrosis (Figures 5 and 6). Colloidal iron stain highlighted mildly increased dermal mucin. Laboratory workup revealed normal complete blood cell count, thyroid-stimulating hormone, blood urea nitrogen, creatinine, aspartate aminotransferase, alanine aminotransferase (ALT), C-reactive protein, antinuclear antibody, anti-SCL-70 antibody, histone, creatinine kinase, and aldolase. Results from hepatitis C serologic testing were negative.

After the first visit, doxycycline 100 mg was prescribed twice daily. At 1 month, there was less acne on the face, but the patient discontinued use due to gastrointestinal intolerance, at which point topical metronidazole was started. At this time, the patient was also treated with clobetasol foam to the scalp and intralesional triamcinolone to the eyebrows. The patient continued to experience recession of the frontal hairline and firm plaques of the medial eyebrows, therefore 300 mg of hydroxychloroquine

From the Department of Dermatology, The Warren Alpert Medical School of Brown University;1 and Center for Dermatoepidemiology, Veterans Affairs Medical Center,2 Providence, RI Address for Correspondence: Joanna Walker, MD, Department of Dermatology, University Dermatology, Inc, 593 Eddy Street, APC 10, Providence, RI 02903 • E-mail: joanna_walker@brown.edu

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Figure 1. Indurated plaques of the medial eyebrows, eyebrow alopecia, and inflammatory papules of the middle of the face and nose.

Figure 3. Hyperpigmented macules of the lateral aspects of the cheeks and forehead, and frontotemporal and eyebrow alopecia.

Figure 2. Scarring alopecia of the frontotemporal hairline with perifollicular erythema and the “lonely hair sign.”

daily was started. No appreciable improvement or worsening of the alopecia was noted 1 month after beginning hydroxychloroquine so it was continued. Isotretinoin will be considered for treatment of her rosacea and alopecia if there are unsatisfactory results with hydroxychloroquine.

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Figure 4. Biopsy results from the scalp revealing periinfundibular and peri-isthmic lichenoid interface dermatitis (hematoxylin and eosin stain, original magnification ×20).

Four Diseases, Two Associations, One Patient

May/June 2016

CASE STUDY eyebrow biopsy, which was taken at the lateral border of the indurated eyebrow plaques, did not show any features of sarcoidosis, cutaneous T-cell lymphoma, scleromyxedema, amyloidosis, lepromatous leprosy, or leishmaniasis. It did show vacuolar interface dermatitis and pigment incontinence, which, in light of the lateral facial dyschromia, are consistent with lichen planus pigmentosus (LPP). We believe that the lack of any infiltrating disease on pathology, the clinical appearance of upper face nonpitting edema, and acne rosacea together support a diagnosis of Morbihan disease, or solid facial edema.

FFA is a subtype of LPP that most commonly presents in postmenopausal women. It is characterized by frontoparietal or frontotemporal patterned cicatricial alopecia, eyebrow hair loss, and, at times, androgenic alopecia.1 Clinical signs of FFA include perifollicular erythema and keratotic spines at areas of active hair loss.2 Histopathology shows perifollicular lichenoid lymphocytic inflammation, fibrosis, and decreased hair follicles.3 A review of 60 cases of FFA in the United Kingdom indicated a 10-fold increasing incidence since 1999 and a significant correlation between FFA and autoimmune disease, in particular thyroid disease, which is present in our patient.2 A case series of 20 cases in South Africa reported preceding traction alopecia in 17 cases, leading them to hypothesize that traumatic hairstyling practices may trigger onset of FFA.4 Notably, our patient’s biopsy findings showed signs of traction; she denied harsh hair care practices, but did admit to blow-drying, which can subject the hair to heavy traction if it is used to straighten the hair. To date, seven familial cases of FFA have been reported. Our patient reported a high hairline in her father, but we were not able to further pursue this potential connection.5

Figure 5. Histology from eyebrow biopsy results showing mild follicular and scant epidermal vacuolar interface dermatitis and dermal fibrosis (hematoxylin and eosin stain, original magnification ×20).

Figure 6. Biopsy results from eyebrow showing epidermal vacuolar interface dermatitis with rare necrotic keratinocytes and pigment incontinence (hematoxylin and eosin stain, original magnification ×10).

Discussion This patient’s classic distribution of band-like frontotemporal and lateral eyebrow scarring alopecia, confirmed by biopsy, is characteristic of frontal fibrosing alopecia (FFA). The dermal fibrosis and pigment incontinence seen on the eyebrow biopsy are also consistent with late-stage scarring alopecia. Notably, the SKINmed. 2016;14:225–228

LPP is an uncommon variant of lichen planus (LP) that presents with coalescing and reticulated hyperpigmented macules in sun-exposed areas and flexures, but most commonly starting on the preauricular cheeks and forehead.6 Histopathologic findings include hyperkeratosis, epidermal atrophy, vacuolar basal cell degeneration, pigment incontinence with melanophages, and perivascular lymphocytic infiltrate.7 While FFA is rarely associated with classic LP, there have been 25 reported cases of concomitant FFA and LPP within at least recent years.8,9 A case series of African and Indian patients showed that 54% of patients with both FFA and LPP presented with LPP a mean of 14 months earlier, leading the authors to suggest that LPP may herald FFA. LPP classically affects patients with darker skin.6,7 To date, the literature has not described any Latinas, like our patient, with both FFA and LPP. Morbihan disease, or lymphedematous rosacea, is a rare complication of rosacea that presents with nonpitting solid edema of the

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upper two-thirds of the face, particularly the eyelids, forehead, glabella, and cheeks and can lead to distorted facial features and obstructed vision.10 There are reports of the condition associated with mild rosacea and as preceding other signs of rosacea, although it is generally considered a late-stage complication of episodic inflammation from rosacea.11 While patients typically present with bilateral diffuse solid edema and erythema of the upper face, variants include unilateral edema that generalizes, isolated eyelid edema, and a localized edematous plaque over the middle of the face.10,12 Histologic features vary and the precise etiology is unclear.

References

Various pharmacologic and surgical treatments have been tried for Morbihan disease without consistent success, although a recent case series showed promising results with long-term isotretinoin.10 FFA also tends to be refractory to treatment; however, a review of 40 patients with both LPP and FFA treated with hydroxychloroquine showed significant response in 83% of patients after 12 months according to a standardized scoring system.13 Another case review of 19 patients suggested stabilization of disease in the majority of those treated with 5-alpha-reductase inhibitors.14 We could find no pathogenic associations between LP and rosacea, or more specifically between FFA/LPP and Morbihan disease/rosacea in the literature. We believe they most likely represent two rare distinct disease processes presenting concurrently in our patient.

Conclusions We report a case of three rare disorders, FFA, LPP, and Morbihan disease, that presented simultaneously in a single patient with rosacea. Recent literature indicates an association between the first two, FFA and LPP, as uncommon variants of LP, but previously in persons with darker skin types and different ethnic backgrounds than our patient. As we could find no mention in the literature of an association between rosacea with Morbihan disease and LP variants, and we could not uncover a pathophysiologic mechanism that underlies all four diseases, we conclude that our patient has two distinct dermatologic categories of disease, each with two subtypes of linked disease but with no link to each other.

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1 Zinkernagel MS, Trueb RM. Fribrosing alopecia in a pattern distribution: pattterned lichen planopilaris or androgenetic alopecia with a lichenoid tissue reaction pattern? Arch Dermatol. 2000;136:205–211.

2 MacDonald A, Clark C, Holmes S. Frontal fibrosing alopecia: a review of 60 cases. J Am Acad Dermatol.

2012;67:955–961.

3 Chew A, Bashir SJ, Wain EM, Fenton DA, Stefanato CM. Expanding the spectrum of frontal fibrosing alopecia: a unifying concept. J Am Acad Dermatol. 2010;63:653–660.

4 Dlova NC, Jordaan HF, Skenjane A, Khoza N, Tosti A. Frontal fibrosing alopecia: a clinical review of 20 black patients from south africa. Br J Dermatol. 2013:169:939–941.

5 Dlova N, Goh C, Tosti A. Familial frontal fibrosing alopecia. Br J Dermatol. 2013;168:220–222.

6 Kanwar AJ, Dogra S, Handa S, Parsad D, Radotra BD. A study of 124 Indian patients with lichen planus pigmentosus. Clin Exp Dermatol. 2003;28:481–485.

7 Al-Mutairi N, El-Khalawany M. Clinicopathological characteristics of lichen planus pigmentosus and its response to tacrolimus ointment: an open label, nonrandomized, prospective study. J Eur Acad Dermatol Venereol. 2010;24:535–540.

8 Rao M, Sarda A, Khanna R, Balachandran C. Coexistence of frontal fibrosing alopecia with lichen planus pigmentosus. Int J Dermatol. 2014;53:622–624.

9 Dlova NC. Frontal fibrosing alopecia and lichen planus pigmentosus: is there a link? Br J Dermatol.

2013;168:439–442.

10 Smith LA, Cohen DE. Successful long-term use of oral isotretinoin for the management of Morbihan disease: a case series report and review of the literature. Arch Dermatol. 2012;148:1395–1398.

11 Nagasaka T, Koyama T, Matsumura K, Chen KR. Persistent lymphoedema in morbihan disease: formation of perilymphatic epithelioid cell granulomas as a possible pathogenesis. Clin Exp Dermatol. 2008;33:764–767.

12 Morales-Burgos A, Alvarez Del Manzano G, Sanchez J. Persistent eyelid swelling in a patient with rosacea. P R Health Sci J. 2009;28:80–82.

13 Chiang C, Sah D, Cho BK, Ochoa BE, Price VH. Hydroxychloroquine and lichen planopilaris: efficacy and introduction of lichen planopilaris activity index scoring system. J Am Acad of Dermatol. 2010;62:387–392.

14 Ladizinski B, Bazakas A, Selim MA, Olsen EA. Frontal fibrosing alopecia: a retrospective review of 19 patients seen at duke university. J Am Acad Dermatol.

2013;68:749–755.

Four Diseases, Two Associations, One Patient

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Volume 14 • Issue 3

CASE STUDY

Epidermal Nevus Presenting in a Pediatric Patient With Pallister-Killian Syndrome Garrett Nelson, MD;1 Sanjana Iyengar, BA;2 Philip Shenefelt, MD1 A six-year-old boy with Pallister-Killian syndrome (PKS) presented to the clinic with extensive lesions on his body (Figure 1). The patient was not born with the lesions but began developing them on the head and neck, extending to his lower extremities, at 2 years of age. These lesions had been evaluated by his primary care physician and were previously treated with desonide and ketoconazole cream with little improvement. (SKINmed. 2016;14:230–231)

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ur patient was diagnosed with PKS prenatally by amniocentesis, which revealed 47,XY+mar(10)/46,XY(6) karyotype. Fluorescence in situ hybridization (FISH) further demonstrated isochromosome 12p. Other features in our patient included facial features of PKS, cleft palate, congenital diaphragmatic hernia, aortopulmonary window, abnormal electroencephalographic findings, and mental retardation.

specific for chromosome 12p are applied to skin biopsies and reveal tetrasomy of chromosome 12p.2,6,7 Of note, blood lymphocytes usually carry a normal karyotype when cytogenetically analyzed.5 Using buccal smears for FISH analysis8 and microarray-based comparative genomic hybridization of whole blood has also been reported.9 Finally, the diagnosis can also be made in utero by amniocentesis,6 as was the case in our patient.

On examination, the patient had hyperpigmented and hyperkeratotic coalescing plaques with cobblestoning on his lower extremities, scalp, and forehead (Figure 2). There was relative sparing of his trunk and upper extremities. We performed a shave biopsy on his left knee that showed hyperkeratotic and papillomatus epidermal changes consistent with an epidermal nevus (Figure 3).

The phenotypic expression of PKS is variable and can appear in stages throughout childhood. One study reports a 14-year-old girl who developed hypertelorism, macrocephaly, and epicanthus during her first year of life. She was born at term with no complications. At the age of 12, she developed pigmentary changes.

Hypopigmented strips on her left calf, right shoulder, and upper arm were seen along with hyperpigmented streaks on her back.

Multicolor FISH (MFISH) and multibanding (MBAND) of chromosome 12 were performed on skin biopsies from normal and hyperpigmented skin. Both specimens revealed an isochromosome 12p in skin fibroblasts. This study illustrates the usefulness of skin biopsy in diagnosing PKS regardless of whether pigment changes are evident. While the use of MBAND and MFISH may be utilized to diagnose PKS, FISH analysis with a DNA probe is more commonly performed.5

Discussion We report an interesting case of PKS from a dermatologic perspective. This patient was referred to our center for extensive skin lesions with which the patient’s primary care providers were unfamiliar. We felt the lesions clinically resembled epidermal nevi, which was confirmed by biopsy.

Patients with streaks of hypopigmentation or hyperpigmentation with accompanying mental retardation should be carefully evaluated for PKS. Hypopigmented patches can be found in 40% of these patients and are visible under Wood’s lamp.1 The mosaicism is tissue specific and is often present in skin fibroblasts. There are multiple diagnostic modalities, including the most common method using FISH. Using FISH, DNA probes

While hyperpigmented streaks are suggestive of PKS in the context of mental retardation and facial structure abnormalities, the range of phenotypic expression involves many organ systems including cardiovascular, neurological, and skeletal. Additional dermatologic findings more recently described in patients with

From the Department of Dermatology, University of South Florida College of Medicine, Tampa, FL;1 and Florida State University College of Medicine, Tallahassee, FL2 Address for Correspondence: Garrett Nelson, MD, 12901 Bruce B. Downs, MDC 79, Tampa, FL 33612 • E-mail: gnelson1@health.usf.edu

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Figure 1. Photograph of verrucous hyperkeratotic lesions coalescing into plaques.

CASE STUDY

Figure 2. Close-up view of verrucous hyperkeratotic lesions.

PKS include an accessory nipple and sacral and postauricular pits.10,11 For dermatologists, in patients with dyspigmentation, mental retardation, and “coarse” facial features, it is important to exclude the diagnosis of PKS with chromosomal analysis of skin fibroblasts, preferably in areas of pigmentary alteration.4,11 There has been no reported association of epidermal nevus and PKS in the literature. Interestingly, the epidermal nevus syndrome is also a mosaic condition, similar to PKS. In addition, it has been suggested that PKS is on the Hypomelanosis of Ito spectrum.12 This may be a new dermatologic feature of the syndrome that may prompt the physician to consider PKS in a patient with epidermal nevi, dyspigmentation, characteristic facial features, and mental retardation.

Conclusions Although rare, PKS has several important cutaneous features. An additional cutaneous feature that may present in these patients is epidermal nevi. Further cases will need to be evaluated to determine whether epidermal nevus is a characteristic feature of PKS. References 1 Guareschi E, Garavelli L, Pedori S, et al. Dermatologic features in Pallister-Killian syndrome and their importance to the diagnosis. Pediatr Dermatol. 2007;24:426–428.

2 Yeung A, Francis D, Giouzeppos O, Amor DJ. PallisterKillian syndrome caused by mosaicism for a supernumerary ring chromosome 12p. Am J Med Genet A. 2009;149A:505–509.

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Figure 3. Papillomatous and hyperkeratotic epidermal changes (hematoxylin and eosin stain, original magnification ×5).

3 Pallister PD, Meisner LF, Elejalde BR, et al. The pallister mosaic syndrome. Birth Defects Orig Artic Ser. 1977;13:103–110.

4 Genevieve D, Cormier-Daire V, Sanlaville D, et al. Mild phenotype in a 15-year-old boy with pallister-killian syndrome. Am J Med Genet A. 2003;116A:90–93.

5 Gerdes AM, Hansen LK, Brandrup F, et al. Pallister-Killian syndrome: multiband FISH of tetrasomy 12p. Pediatr Dermatol. 2006;23:378–381.

6 Soukup S, Neidich K. Prenatal diagnosis of PallisterKillian syndrome. Am J Med Genet. 1990;35:526–528.

7 Speleman F, Leroy JG, Van Roy N, et al. Pallister-Killian syndrome: characterization of the isochromosome 12p by fluorescent in situ hybridization. Am J Med Genet.

1991;41:381–387.

8 Ohashi H, Ishikiriyama S, Fukushima Y. New diagnostic method for Pallister-Killian syndrome: detection of i(12p) in interphase nuclei of buccal mucosa by fluorescence in situ hybridization. Am J Med Genet.

1993;45:123–128.

9 Theisen A, Rosenfeld JA, Farrell SA, et al. aCGH detects partial tetrasomy of 12p in blood from pallister-killian syndrome cases without invasive skin biopsy. Am J Med Genet A. 2009;149A:914–918.

10 Wilkens A, Liu H, Park K, et al. Novel clinical manifestations in Pallister-Killian syndrome: comprehensive evaluation of 59 affected individuals and review of previously reported cases. Am J Med Genet A. 2012;158A:3002–3017.

11 Shah K, George R, Balla ES, et al. An Indian boy with additional features in Pallister-Killian syndrome. Indian J Pediatr. 2012;79:1238–1240.

12 Freedberg IM, ed. Fitzpatrick’s Dermatology in General Medicine. 6th ed. New York, NY: McGraw-Hill; 2003.

Epidermal Nevus Presenting in a Pediatric Patient

4thâ&#x20AC;&#x201C;7th May 2017, Bengaluru, India

MEDIA PARTNER

May/June 2016

Volume 14 • Issue 3

CASE STUDY

Penile Granuloma Annulare Liam Mercieca, MD, MRCP(UK);1 Philip Carabot, MD, Dip Ven, FRCP(Lond);2 Michael J. Boffa, MD, FRCP(Lond), MSc(Lond)1

A 50-year-old man presented to the genitourinary medicine clinic with a 3-year history of skin-colored circular papules over the shaft and glans of the penis. There were multiple lesions that were initially small, around 0.3 cm in diameter, and gradually enlarged. Physical examination revealed five nodules over the glans and shaft of the penis, with the largest lesion measuring 3×1 cm over the lateral aspect of the shaft (Figure 1). There were no similar lesions elsewhere. There was no lymphadenopathy and the rest of the examination was unremarkable. The patient complained of discomfort during sexual intercourse but the lesions were otherwise asymptomatic and nontender. There was no history of trauma to the area and no dermatological history. He had had the same sexual partner for the past 22 years, no significant medical history, and was not taking any medication. He was a smoker with a 32-pack-year history. His family history did not include any dermatological diseases. His father was diagnosed with type II diabetes at 65 years of age and his mother had hypertension since age 60 years. He had consulted his general practitioner regarding the penile eruption a year earlier and was treated for a presumed fungal infection with clotrimazole cream for 1 month with no effect. Results from genitourinary investigations for sexually transmitted diseases including syphilis were all negative.

(SKINmed. 2016;14:233–236)

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e was referred to the dermatology department, and a punch biopsy confirmed the clinical impression of granuloma annulare (GA), showing geographic areas of eosinophilic necrobiosis in the superficial and mid-dermis, surrounded by palisaded epithelioid histiocytes and lymphocytes. The overlying epidermis was mildly acanthotic but otherwise unremarkable (Figures 2a and 2b). This was consistent with subcutaneous GA. Results from laboratory tests including complete blood cell count; liver, renal, and thyroid function; fasting glucose; and rheumatoid factor were normal or negative. He was prescribed 0.1% mometasone furoate ointment twice daily for 1 month then once daily for another month. The patient reported that there was nearly complete resolution after 1 month. At 2 months his physical examination showed only a small single residual papule over the biopsy site with complete resolution of the other lesions (Figure 3). There was no sign of recurrence on further review 6 months later.

Discussion GA occurring on and limited to the penis is a rare presentation of the disease, with only 17 cases published to date. A summary of the characteristics of published cases of penile GA (together with our case) is shown in the Table. The median age of presentation was 24.5 years, ranging from 7 to 80 years (average age, 27.6 years). The duration before presentation varied from 3 weeks to 3 years, and patients presented to different specialties including urology (five), genitourinary medicine (four), dermatology (two), and pediatric surgery (two) in order of frequency.

The number of lesions varied from solitary to multiple nodules and the size ranged from 3 mm up to 5.4 cm. All cases were confined to the penis, with no lesions elsewhere, and were usually located on the shaft of the penis. Only two reported cases located the lesions on the glans. Lesions were asymptomatic in nearly all cases.

From the Department of Dermatology, Sir Paul Boffa Hospital,1 and the Genitourinary Medicine Clinic, Mater Dei Hospital,2 Malta Address for Correspondence: Liam Mercieca, Department of Dermatology, Sir Paul Boffa Hospital, Harper Lane, Floriana FRN 1940, Malta • E-mail: liam.mercieca@gov.mt

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Figure 1. Granuloma annulare on the glans and shaft of the patient’s penis at presentation.

Figure 3. Complete resolution 2 months after treatment with a topical steroid.

ferent time intervals, with eight of the cases persisting or recurring and six showing complete resolution. It is worth noting that the only two cases treated with a topical steroid both resolved, while most of those treated surgically recurred. Subcutaneous GA was the most common variant reported. There were no particular triggering factors identified. Three patients reported a history of asthma, but there does not seem to be any association between the two or any other conditions.

Our case is the third in the literature of penile GA reporting lesions on the glans and improvement with a topical steroid. This highlights the importance of including GA in the differential diagnosis of nodules on the glans and shaft of the penis and of reaching a correct histological diagnosis to avoid unnecessary surgery.

A

Conclusions GA is a relatively common condition that can very rarely present on the shaft and glans of the penis as solitary or multiple nodules with varying sizes at any age. It is usually asymptomatic, and there are no known triggering factors or associated conditions. Lesions can resolve spontaneously and may recur. Different treatment options have been tried and we recommend a conservative approach with a trial of a topical steroid to avoid unnecessary surgery.

B Figure 2. Histology showing geographic areas of eosinophilic necrobiosis in the superficial and mid-dermis, surrounded by palisaded epithelioid histiocytes and lymphocytes. (Hematoxylin and eosin stain, original magnification ×20 (A) and ×40 (B).)

Acknowledgments

Treatments varied from surgical excision, circumcision, oral pentoxifylline, topical steroids, and triamcinolone injection to no treatment. Fourteen of the 17 cases reported follow-up at difSKINmed. 2016;14:233–236

Alexandra Betts, MD, BChD, MPhil, FRCPath, FMCPath (Consultant Histopathologist, Mater Dei Hospital, Malta) provided the histology report and made the slides available, and Joseph Pace, MD, FRCP (Consultant Dermatologist, President of the Malta Association of Dermatology & Venereology) reviewed the manuscript.

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Table. Summary of Characteristics of All Reported Cases of Penile GA Case No.

Age,

Tender

Presenting Clinic

Treatment

Resolved/ Recurred

Reference

1

3×0.5

No

N/S

Circumcision

No recurrence after 2 y

Kossard et al3

5

N/S

No

N/S

No treatment

N/S

Kossard et al3

2y

Multiple

N/S (small)

No

GP

Surgical excision

Recurred

Kossard et al3

Shaft

1y

1

2×1

No

GUM

No treatment

Reduction in size 6 wk after biopsy

Hillman et al4

20

Shaft

18 mo

2

0.5×0.5

No

Urology

Surgical excision

Recurred 3 mo later

Trap et al5

6

23

Dorsal shaft

1 mo

1

Peasized

No

GUM

Surgical excision

Resolved no recurrence after 12 mo

Narouz et al6

7

41

Shaft/ glans

N/S

4

0.4

No

GUM

No treatment

Resolved spontaneously after 2 y

Lucas et al7

Urology

Excision of seven nodules, triamcinolone injection of four other lesions

Recurred

Sidwell et al8

Recurred then most resolved after circumcision after 6 mo

Sidwell et al8

Location

Duration

Number

24

Shaft

N/S

Multiple

2

26

Shaft

6 mo

3

25

Shaft

4

61

5

8

y

16

Shaft

18 mo

Multiple

Size, cm

0.5–1

N/S

9

13

Dorsal shaft

2y

5

Peasized

No

N/S

Excision of two nodules, then circumcision

10

29

Shaft

2 mo

Multiple

N/S

No

Dermatology

Excisional biopsy

N/S

Kim et al9

11

80

Glans

1 mo

Multiple

0.7

No

N/S

Clobetasol cream daily

Resolved after 1 mo

Foroozan et al10

12

7

Base of penis

1 mo

1

1

No

Pediatric urology

Excision under GA

Resolved, no recurrence after 6 mo

Floyd et al11

Resolved, no recurrence after 6 mo

PintoAlmeida et al12

13

34

Foreskin

4 mo

3

0.8–2

No

Dermatology

Topical clobetasol propionate 0.5 mg/g ointment daily

14

13

Shaft

1y

5

0.5

No

Pediatric surgery

No treatment

Same after 1y

Suarez et al13

15

24

Dorsal shaft

3 wk

7

Small

No

Urology

Lost to follow-up

Lost to follow-up

Toepfer et al14 Continued

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Table. Summary of Characteristics of All Reported Cases of Penile GA (Continued) Case No.

Age,

16

26

17

18

y

Location

Duration

Number

Shaft

6 mo

Multiple

13

Shaft

50

Shaft and glans

1y

3y

Multiple

6

Size, cm

0.3–0.4

5.4× 2.8× 1.5

3×1

Tender

Presenting Clinic

Treatment

Resolved/ Recurred

Reference

Tender

Urology

Oral pentoxifylline 400 mg tds

Recurred after stopping medication

Toepfer et al14

Urology

Surgical excision under GA, triamcinolone injection of remaining nodules

Recurred

Toepfer et al14 and Forman et al15

GUM

Topical 0.1% mometasone furoate ointment

Nearly complete resolution after 2 mo

Current case

No

No

Abbreviations: GA, granuloma annulare; GP, general practitioner; GUM, genitourinary medicine; N/S, not specified.

References 1 Muhlbauer JE. Granuloma annulare. J Am Acad Dermatol.

1980;217–230.

2 Smith MD, Downie JB, DiCostanzo D. Granuloma annulare. Int J Dermatol. 1997;326–333.

3 Kossard S, Collins AG, Wegman A, et al. Necrobiotic granulomas localised to the penis: a possible variant of subcutaneous granuloma annulare. J Cutan Pathol.

1990;17:101–104.

4 Hillman RJ, Waldron S, Walker MM, et al. Granuloma annulare of the penis. Genitourin Med. 1992;68:47–49.

5 Trap R, Wiebe B. Granuloma annulare localized to the shaft of the penis. Scand J Urol Nephrol. 1993;27:549–551.

6 Narouz N, Allan PS, Wade AH. Penile granuloma annulare. Sex Transm Infect. 1999;75:186–187.

7 Lucas F, Viraben R. Palisading granuloma of the penis: a variant of subcutaneous granuloma annulare. Ann Dermatol Venereol. 2002;129:1046–1048.

8 Sidwell RU, Green JS, Agnew K, et al. Subcutaneous granuloma annulare of the penis in 2 adolescents. J Pediatr Surg. 2005;40:1329–1331.

9 Kim do Y, Park CO, Park YK, et al. A case of penile subcutaneous granuloma annulare. J Am Acad Dermatol.

2007;57(2 suppl):S45–S46.

10 Foroozan M, Cuny JF, Schmutz JL. Papular eruption of male genitalia. Eur J Dermatol. 2010;20:846–847.

11 Floyd MS Jr, Kokai G, McAndrew HF. Granuloma annulare of the penis in a seven-year-old boy. Scand J Urol Nephrol.

2011;45:77–79.

12 Pinto-Almeida T, Torres T, Sanches M, et al. Granuloma annulare of the penis––subcutaneous presentation. Eur J Dermatol. 2011;21:448–449.

13 Suarez Peñaranda JM, Aliste C. Granuloma annulare of the penis: an uncommon location for an usual disease.

Am J Dermatopathol. 2011;33:e44–e46.

14 Toepfer NJ, Wessner SR, Elston DM, et al. Three cases of subcutaneous granuloma annulare of the penis: a rare presentation of a common disease. Urology.

2011;78:508–510.

15 Forman SB, Sumfest JM, Pride HB, et al. Penile granuloma annulare of an adolescent male-case report and review of the literature. Pediatr Dermatol. 2008;25:260262.

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Scrotodynia: Diagnostic and Therapeutic Challenge Abhineetha Hosthota, MD, MBBS;1 Swapna Bondade, MD, MBBS;2 Divya Monnappa, MD, MBBS;1 Vinay Basavaraja, MD, MBBS2 Case 1 A 35-year-old married man presented with diffuse burning of the scrotum for 6 months’ duration that was aggravated by sitting and wearing tight-fitting undergarments. He reported a history of sexual exposure 6 months prior, after which the complaint started.

Clinical examination of the scrotal skin, testis, epididymis, penis, and perianal area did not reveal any abnormality. Rectal examination was performed to rule out chronic proctitis. Investigations were performed to exclude sexually transmitted infections. Ultrasonography of the abdomen and pelvis was ordered to rule out organic cause. The patient experienced guilt from the exposure because he was married, and therefore was referred to the psychiatrist to rule out psychological problems. A diagnosis of major depressive disorder was made. He was started on amitriptyline 25 mg and was gradually increased to 50 mg. The patient showed gradual improvement in symptoms after 3 weeks of follow-up. (SKINmed. 2016;14:237–238)

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ase 2 A 33-year-old man presented to the dermatology department with complaints of burning sensation on the scrotal skin for 1 year. Examination did not reveal any abnormality of the skin, genitals, or surrounding area. Relevant investigations were performed to rule out organic cause and sexually transmitted infections. He was treated with nonsteroidal anti-inflammatory drugs for 2 weeks, which did not relieve his symptoms. A clinical interview by psychiatrist did not reveal any psychologic problem. The patient was started on amitriptyline 10 mg for 1 week, but little symptom relief was observed. Amitriptyline was then increased to 25 mg and there was gradual improvement in symptoms after 2 weeks.

Discussion

Scrotodynia is analogous to vulvodynia. The scrotal and penile skin is embryologically equivalent to the vulval and clitoral counterparts.1 Scrotodynia has received little attention because of scant reporting and paucity of literature, whereas vulvodynia has received more impetus from investigations by the International Society for the Study of Vulvo Vaginal Disease (ISSVD) through the interested members of the Society.2 Vulvodynia have been described as early as the 19th century,3 whereas it took an-

other hundred years to coin the term scrotodynia. There are currently two articles on scrotodynia. The first case was reported by Markos in 2002 who discussed two cases of scrotodynia, and the other article of scrotodynia with somatodynia was reported by Mancuso and Berdondini in 2005.1,4 Scrotodynia is a chronic genital pain syndrome, which may be confused with other chronic pain syndromes of adjacent structures. These include testicular pain syndrome, post-vasectomy pain syndrome, and epididymal pain syndrome. Other causes including bacterial/viral/fungal infections must be excluded by examination before the diagnosis can be made.5 The pathomechanisms involved in scrotodynia are poorly understood. The scrotum is a pain-prone area of the body because of the vulnerable anatomical site. It is also associated with high levels of anxiety, fear, and embarrassment. Chronic pain is a symptom complex of neurobiological phenomenon with a variety of factors contributing to peripheral and central pain-signaling mechanisms.6 Pain is mediated by three types of afferent fibers: the large myelinated type A beta fibers, the smaller myelinated type A nerve fibers, and the poorly myelinated or nonmyelinated type C fibers. These latter fibers are responsible for pain per-

From the Departments of Dermatology1 and Psychiatry,2 The Oxford Medical College, Hospital & Research Center, Yadavanahalli, Bangalore, India Address for Correspondence: Abhineetha Hosthota, MD, MBBS, The Oxford Medical College, Hospital and Research Centre, Hosur Road,Yadavanahalli, Attibele Hobli, Anekal Taluk, Bengaluru 562107, Karnataka, India • E-mail: abhineethahosthota@yahoo.com

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ception, and the pain mediated by C fibers often has a burning quality; however, type A fibers, responsible for touch sensation, can become involved in mediating pain. This explains why patients with scrotodynia often experience pain after wearing tight undergarments.7 When patients experience chronic pain, afferent nerve fibers appear to become “sensitized,” discharging more easily to lower levels of stimulation or spontaneously without apparent noxious stimulus.8,9 This basic concept explains that pain can occur even in the absence of an observable abnormality.

reported. The paucity of literature can be explained by lower patient reporting as a result of embarrassment, which is a major deterrent for seeking help and lack of recognition in the medical establishment. Delayed diagnosis significantly contributes to psychiatric morbidity. Early diagnosis and management is important to shorten the duration of symptoms. This scenario can be resolved by increased reporting in the medical literature.

References

The sources of symptoms in scrotodynia are reasonably complex and may include biologic, psychologic, and social factors. The psychologic factors associated with scrotodynia have been relatively ignored. In 1996, investigators recommended attention to three areas: (1) symptoms and their control, (2) role function and psychological factors, and (3) sexual function. Currently, our understanding of this condition is only superficial.10 In the present paper, the first case had a history of exposure 6 months prior, following symptom onset. The clinical interview of the patient by the psychiatrist revealed depression. The other case had no comorbid psychiatric illness. Both patients responded well to amitriptyline over a period of time.

Amitriptyline is a tricyclic antidepressant (TCA). TCAs are the most studied antidepressants for the treatment of pain and are a mainstay in the treatment armamentarium.1 These antidepressants exert their effects on serotonin and norepinephrine, particularly along the descending spinal pain pathways. Antidepressants may also exert adjunctive therapeutic influences through histamine receptors as well as modulation of sodium channels.11 It is generally accepted that a relationship exists between chronic pain and depression12; however, which factor is primary and which is secondary is controversial. Recently, several studies have demonstrated the analgesic efficacy of TCAs in the treatment of chronic pain that appears to be independent of any antidepressant effect. The antinociceptive activity of this class of drugs appears to be independent of any antidepressant effects.13

1 Markos AR. The male genital skin burning syndrome (dysaesthetic peno/scroto-dynia). Int J STD AIDS. 2002;13:271–272.

2 International Society for the Study of Vulvar Disease Taskforce. Burning vulvar syndrome: report of the ISSVD taskforce. J Reprod Med. 1984;29:457.

3 Gerber S, Witkin SS, Stucki D. Immunological and genetic characterization of women with vulvodynia. J Med Life. 2008;1:432–438.

4 Mancuso G, Berdondini RM. Simultaneous occurrence of dysaesthetic peno/scrota-dynia and stomatodynia.

Int J STD AIDS. 2005;16:830–831.

5 Cooper SM, Wojnarowska F. Anogenital (nonvenereal) disease. In: Bolognia JL, Jorizzo JL, Schaffer JV, eds. Dermatology. 3rd ed. London, England: Elsevier; 2012:1182.

6 Dharmshaktu P, Tayal V, Kalra BS. Efficacy of antidepressants as analgesics: a review. J Clin Pharmacol.

2012;52:6–17.

7 Cox JT. Deconstructing vulval pain. Lancet. 1995;345:53.

8 Coderre TJ, Katz J, Vaccarino AL, et al. Contribution of central neuroplasticity to pathological pain: review of clinical and experimental evidence. Pain. 1993;52:259– 285.

9 Gracely RH, Lynch SA, Bennett GJ. Painful neuropathy: altered central processing maintained dynamically by peripheral input. Pain. 1992:51:175–194.

10 Berghuis JP, Heiman JR, Rothman I, et al. Psychological and physical factors involved in chronic idiopathic prostatitis. J Psychosom Res. 1996;41:313–325.

11 Gallagher RM. Management of neuropathic pain: translating mechanistic advances and evidence-based research into clinical practice. Clin J Pain. 2006;22:S2–S8.

Conclusions

12 Bair MJ, Robinson RL, Katon W, Kroenke K. Depression and pain comorbidity: a literature review. Arch Intern Med. 2003;163:2433–2445.

More literature is needed to decode the etiopathogenesis and treatment aspect of this condition. Scrotodynia is not infrequent, but it is often underdiagnosed/misdiagnosed and seldom

13 Brown RS, Bottomley WK. Utilization and mechanism of action of tricyclic antidepressants in the treatment of chronic facial pain: a review of the literature. Anesth Prog. 1990;37:223–229.

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Facial Blanching After Cosmetic Botulinum Toxin Injection: Case Series Donald Warren, MD;1,* Meghan Woody, MPH;2 Jennifer Vickers, MD1

Case 1 A 32-year-old woman was treated for the first time with onabotulinumtoxinA (BoNT), receiving 10 units in her forehead and 20 units in her glabella. She reported no history of skin disease and had a very active lifestyle. She first noticed blanching while doing a group workout and a friend inquired if she had “hives” on her forehead (Figure 1). She continued to note the blanching during workouts 5 months after injection. Each episode lasted 30 minutes to 2 hours. There were no associated symptoms with the blanching other than minor embarrassment. Given her active lifestyle and frequent blanching, she has elected not to receive further injections. (SKINmed.

2016;14:239–240)

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ase 2 A 27-year-old woman without history of skin disease or allergies to BoNT received 10 units of BoNT in her forehead and 20 units in her glabella. She noted blanching 2 weeks after injection while out for a long run. It lasted for 10 to 15 minutes after running and was not associated with any symptoms. She stopped running for several months afterwards and did not notice a recurrence when she resumed running. She is open to using BoNT again.

Case 3 A 32-year-old woman without history of skin disease or allergies to BoNT received previous injections with BoNT without any problems. She received 10 units BoNT in her forehead and 12 units in her glabella. She had worked out daily without any side effects until she participated in a much longer run where she noticed blanched areas on her forehead (Figure 2). The episode occurred 1 month after injection and lasted 45 minutes to 1 hour. No other symptoms were noted. Because the blanching occurred only with high-intensity exercise, she is open to more injections in the future.

For all three cases in this report, 100 units of BoNT were diluted in 1.0 mL bacteriostatic sodium chloride solution prior to injection. All of the patients received BoNT from different lot numbers and none of them experienced blanching or side effects immediately after injection.

Discussion Cosmetic use of BoNT injections has increased dramatically to become the most popular nonsurgical cosmetic procedure in the United States. Its use continues to climb in all female demographics and has increased over 800% since 2000.2,6 In 2014, women 39 years and younger made up over 20% of BoNT injection recipients in the United States, and women aged 30 to 39 years showed the sharpest percentage increase of BoNT use compared with the previous year among all demographics.6 This likely represents increased awareness of the procedure and the belief that it may delay or prevent rhytides.

As demonstrated in our patients, skin sites injected with BoNT may affect cutaneous vasodilation seen during exercise, leading to this potential undesirable cosmetic effect. Botulinum toxin works by inhibiting the presynaptic release of acetylcholine.1,2 Cutaneous injection of BoNT blocks the vasodilatory effect of acetylcholine, inhibiting the expected facial flushing associated with physical activity and leading to potential blanching at injection sites.3 Given that this adverse effect has been reported in only one other patient despite millions of patients receiving BoNT annually, it appears to be a rare side effect. It may, however, be underreported or not seen as commonly as would be expected for the following reasons.

From the Department of Dermatology, University of Texas at Austin, Dell Medical School, Austin, TX;1 and Texas A&M Health Science Center College of Medicine, Bryan, TX2 Address for Correspondence: Meghan Woody, MPH, 601 E 15th St, Austin TX 78701 • E-mail: mgmwoody@gmail.com * Dr Warren was the recipient of the Edward L. Keyes Award for this case study presented at the 10th World Congress of the International Academy of Cosmetic Dermatology, Rio de Janeiro, Brazil, November 14, 2015.

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Figure 1. Forehead blanching after exercise. Circular blanched areas of skin on the forehead at previous injection sites of onabotulinumtoxinA.

Figure 2. Forehead blanching after exercise. Circular blanched areas of skin on the forehead at previous injection sites of onabotulinumtoxinA.

First, its effects are transient and completely asymptomatic. Patient 1 had the most exuberant flushing of the three cases but was unaware of any blanching until a friend pointed it out to her. Other patients may notice the blanching and realize it is related to BoNT, but many may not tell their providers because it is self-limited and asymptomatic.

would still have less flushing, and any blanching they experienced would be less noticeable.

Second, although acetylcholine is the primary mediator of the sweating response, it is not the sole mediator of cutaneous vasodilation.3 Other molecules such as nitrous oxide, prostaglandins, and endothelium-derived hyperpolarizing factors seem to play a role in this process as well.2–4 It is possible that in some individuals, these other modulators compensate for the acetylcholine blockade.

As younger women receive BoNT injections, this side effect may become more salient and prevalent. This effect likely occurs in men as well but currently men constitute only 6% of BoNT recipients in the United States.

Conclusions Young women using BoNT should be warned of this cosmetic adverse event, particularly if they are known to exercise regularly, have a history of flushing, or perform group workouts.

References

Third, vasoconstriction through noradrenergic pathways predominates at the onset of exercise and only after a certain threshold of increased body temperature are acetylcholine and other mediators activated to produce cutaneous vasodilation.3 Considering that 80% of patients who receive BoNT are older than 40 years, they may not be as involved in the type of strenuous exercise necessary to produce flushing compared with younger patients. This is illustrated with patient 3 who performed several workouts in the same week that did not produce blanching until she performed her most strenuous and difficult exercise on the weekend.

Finally, age itself is a risk factor for endothelial dysfunction.5 Endothelial cells and vascular smooth muscle cells are less responsive to vasodilatory molecules as we age. Therefore, older patients who perform high-intensity and longer-lasting exercise SKINmed. 2016;14:239–240

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1 Yuraitis M, Jacob CI. Botulinum toxin for the treatment of facial flushing. Dermatol Surg. 2004;30:102–104.

2 Carruthers JD, Carruthers JA. Treatment of glabellar frown lines with C. botulinum-A exotoxin. J Dermatol Surg Oncol. 1992;18:17–21.

3 Khan TT, Herne K, Dayan SH, Woodward JA. Facial blanching due to neurotoxins: proposed mechanisms.

Dermatol Surg. 2013;39:24–29.

4 Johnson JM, Minson CT, Kellogg DL Jr. Cutaneous vasodilator and vasoconstrictor mechanisms in temperature regulation. Compr Physiol. 2014;4:33–89.

5 Holowatz LA, Thompson CS, Minson CT, Kenney WL. Mechanisms of acetylcholine-mediated vasodilatation in young and aged human skin. J Physiol. 2005;563:965–973.

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Facial Blanching After Cosmetic Botulinum Toxin Injection

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