SkinMed: July/Aug 2017 by jo-ann kalaka-Adams

Chinese Society of Dermatology

Metin and Parish

COMMENTARY Emperipolesis, Proposed Mechanism for a Unique Intercellular Interaction: The Defective Phagocytosis Hypothesis

Lambert, Handler, Wang, Galen, and Lambert

Belarusian Society of Dermatovenereologists and Cosmetologists

Lebanese Dermatological Society

Belarusian Society of Dermatovenereologists and Cosmetologists

EDITORIAL Acne Keloidalis Nuchae—Is the Barber Really to Blame?

Lebanese Dermatological Society

North American Clinical Dermatologic Society

The Dermatologic & Aesthetic Surgery International League

Sehgal, Sehgal, and Sehgal

Analysis of Sebaceous Neoplasms for DNA Mismatch Repair Proteins in Muir-Torre Syndrome

Pollinger, Kieliszak, Logemann, and Gratrix

REVIEW Molecular Variations in Histologic Subtypes of Basal Cell Carcinoma Deng, Marsch, and Petronic-Rosic

Self Assessment Examination Lambert

CORE CURRICULUM Techniques for Optimizing Surgical Scars, Part 1: Wound Healing and Depressed/Atrophic Scars Konda, Potter, Ren, Wang, Srinivasan, and Chilukuri

The Dermatologic & Aesthetic Surgery International League

African Association for Dermatology

July/AugustDEPARTMENTS 2017 • Volume 15• Issue 4 PERILS OF DERMATOPATHOLOGY Fading Signals: How Long Does Antigenicity in Immunohistochemical Staining Last? John, Holahan, Singh, Handler, Chung, and Lambert

NEW THERAPY UPDATE Brodalumab (Siliq®): A Treatment for Plaque Psoriasis Gupta, Versteeg, Abramovits, and Vincent

ORIGINAL CONTRIBUTIONS Hidradenitis Suppurativa and Concomitant Down Syndrome: Literature Review of Other Associated Mucocutaneous Manifestations in Adults

North American Clinical Dermatologic Society

THE HEYMANN FILE Telangiectasia Macularis Eruptiva Perstans Revisited Heymann

CONTACT DERMATITIS CAPSULE On Lanolin Allergy and the Approach to Its Diagnosis Bonchak and Zirwas

case studies Diffuse Papular Eruption of the Face and Eyelids Frisch, Kozel, Jensen, and Vidal

Demodicosis Treatment with Systemic Ivermectin

July/August 2017 • Volume 15• Issue 4

Oxalosis in a Patient with Livedo Reticularis

Triki, Ksentini, Kallel, Bahloul, Jarraya, Masmoudi, and Boudawara

Auricular Hemosiderosis in a Diabetic Patient Larson and Russell

Isotretinoin and Surgical Extraction for Adult-Onset Nevus Comedonicus Dong, Phelps, and Levitt

Transient Reactive Eruptive Lymphangiectasia Following Partial Vulvectomy for Chronic Acquired Lymphangioma Wirth and Lin

Acquired Idiopathic True Transverse Leukonychia Hadi and Stern

CORRESPONDENCE Tuberous Sclerosis Complex: Unusual Presentation in an Adult Patient Kansal

Anticoagulation in Patients with Pseudoxanthoma Elasticum Liaqat and Heymann

Coelho da Rocha, Travassos, Uva, Sequeira, and Filipe

Neutrophilic Eccrine Hidradenitis in an HIV-Infected Patient

Ruiz-López, Martínez-Luna, Toussaint-Caire, Fuentes-Suárez, and Vega-Memije

Cutaneous Rosai-Dorfman Disease

Keeling, LaPresto Thelin, Gavino, and Ahmed Scan this QR code with your QR reader

Otezla® (apremilast) is indicated for the treatment of patients with moderate to severe plaque psoriasis who are candidates for phototherapy or systemic therapy.

Otezla was evaluated in 2 multicenter, double-blind, placebocontrolled trials of similar design. Patients with moderate to severe plaque psoriasis (N = 1257) were randomized 2:1 to Otezla 30 mg or placebo twice daily for 16 weeks, after a 5-day titration1,3 ◆ Inclusion criteria: Age ≥18 years, BSA involvement ≥10%, sPGA ≥3, PASI score ≥12, candidates for phototherapy or systemic therapy1,3 ◆ PASI-75 response at week 16 (primary endpoint) – ESTEEM 1: Otezla 33% vs placebo 5% (P < 0.0001)1-3 ◆

– Similar PASI-75 response was achieved in ESTEEM 21,2 BSA, body surface area; PASI, Psoriasis Area and Severity Index; sPGA, static Physician Global Assessment.

INDICATIONS Otezla® (apremilast) is indicated for the treatment of patients with moderate to severe plaque psoriasis who are candidates for phototherapy or systemic therapy. Otezla is indicated for the treatment of adult patients with active psoriatic arthritis.

IMPORTANT SAFETY INFORMATION Contraindications ◆ Otezla® (apremilast) is contraindicated in patients with a known hypersensitivity to apremilast or to any of the excipients in the formulation Warnings and Precautions ◆ Diarrhea, Nausea and Vomiting: Cases of severe diarrhea, nausea, and vomiting have been reported with the use of Otezla. Most events occurred within the first few weeks of treatment. In some cases patients were hospitalized. Patients 65 years of age or older and patients taking medications that can lead to volume depletion or hypotension may be at a higher risk of complications from severe diarrhea, nausea, or vomiting. Monitor patients who are more susceptible to complications of diarrhea or vomiting; advise patients to contact their healthcare provider. Consider Otezla dose reduction or suspension if patients develop severe diarrhea, nausea, or vomiting ◆ Depression: Treatment with Otezla is associated with an increase in depression. During clinical trials 1.3% (12/920) of patients reported depression, compared to 0.4% (2/506) on placebo. Suicidal behavior was observed in 0.1% (1/1308) of patients on Otezla, compared to 0.2% (1/506) on placebo. Carefully weigh the risks and benefits of treatment with Otezla for patients with a history of depression and/or suicidal thoughts/behavior, or in patients who develop such symptoms while on Otezla. Patients, caregivers, and families should be advised of the need to be alert for the emergence or worsening of depression, suicidal

thoughts or other mood changes, and they should contact their healthcare provider if such changes occur ◆ Weight Decrease: Body weight loss of 5-10% occurred in

12% (96/784) of patients treated with Otezla and in 5% (19/382) of patients treated with placebo. Monitor body weight regularly; evaluate unexplained or clinically significant weight loss, and consider discontinuation of Otezla ◆ Drug Interactions: Apremilast exposure was decreased when Otezla was co-administered with rifampin, a strong CYP450 enzyme inducer; loss of Otezla efficacy may occur. Concomitant use of Otezla with CYP450 enzyme inducers (e.g., rifampin, phenobarbital, carbamazepine, phenytoin) is not recommended Adverse Reactions ◆ Adverse reactions reported in ≥5% of patients were (Otezla%, placebo%): diarrhea (17, 6), nausea (17, 7), upper respiratory tract infection (9, 6), tension headache (8, 4), and headache (6, 4) Use in Specific Populations ◆ Pregnancy and Nursing Mothers: Otezla is Pregnancy Category C; it has not been studied in pregnant women. Use during pregnancy only if the potential benefit justifies the potential risk to the fetus. It is not known whether apremilast or its metabolites are present in human milk. Caution should be exercised when Otezla is administered to a nursing woman ◆ Renal Impairment: Otezla dosage should be reduced in patients with severe renal impairment (creatinine clearance less than 30 mL/min); for details, see Dosage and Administration, Section 2, in the Full Prescribing Information Please turn the page for Brief Summary of Full Prescribing Information. References: 1. Otezla [package insert]. Summit, NJ: Celgene Corporation. 2. Data on file, Celgene Corporation. 3. Papp K, Reich K, Leonardi CL, et al. J Am Acad Dermatol. 2015;73(1):37-49. 4. Information derived from Symphony Health Solutions PrescriberSource PatientFocus data, Celgene proprietary methodology. April 2014 through June 2017. * Data includes healthcare professionals (dermatologists, rheumatologists, nurse practitioners, and physician assistants) and their Otezla prescriptions (including refills) from April 2014 through June 2017 for patients with plaque psoriasis or psoriatic arthritis. Source: Data on file, Celgene Corporation.

Get the latest news at otezlapro.com

Rx Only OTEZLA® (apremilast) tablets, for oral use The following is a Brief Summary; refer to Full Prescribing Information for complete product information. INDICATIONS AND USAGE OTEZLA® (apremilast) is indicated for the treatment of patients with moderate to severe plaque psoriasis who are candidates for phototherapy or systemic therapy. CONTRAINDICATIONS OTEZLA is contraindicated in patients with a known hypersensitivity to apremilast or to any of the excipients in the formulation [see Adverse Reactions (6.1)]. WARNINGS AND PRECAUTIONS Diarrhea, Nausea, and Vomiting: There have been postmarketing reports of severe diarrhea, nausea, and vomiting associated with the use of OTEZLA. Most events occurred within the first few weeks of treatment. In some cases patients were hospitalized. Patients 65 years of age or older and patients taking medications that can lead to volume depletion or hypotension may be at a higher risk of complications from severe diarrhea, nausea, or vomiting. Monitor patients who are more susceptible to complications of diarrhea or vomiting. Patients who reduced dosage or discontinued OTEZLA generally improved quickly. Consider OTEZLA dose reduction or suspension if patients develop severe diarrhea, nausea, or vomiting. Depression: Treatment with OTEZLA is associated with an increase in adverse reactions of depression. Before using OTEZLA in patients with a history of depression and/or suicidal thoughts or behavior prescribers should carefully weigh the risks and benefits of treatment with OTEZLA in such patients. Patients, their caregivers, and families should be advised of the need to be alert for the emergence or worsening of depression, suicidal thoughts or other mood changes, and if such changes occur to contact their healthcare provider. Prescribers should carefully evaluate the risks and benefits of continuing treatment with OTEZLA if such events occur. During the 0 to 16 week placebocontrolled period of the 3 controlled clinical trials, 1.3% (12/920) of patients treated with OTEZLA reported depression compared to 0.4% (2/506) treated with placebo. During the clinical trials, 0.1% (1/1308) of patients treated with OTEZLA discontinued treatment due to depression compared with none in placebo-treated patients (0/506). Depression was reported as serious in 0.1% (1/1308) of patients exposed to OTEZLA, compared to none in placebo-treated patients (0/506). Instances of suicidal behavior have been observed in 0.1% (1/1308) of patients while receiving OTEZLA, compared to 0.2% (1/506) in placebo-treated patients. In the clinical trials, one patient treated with OTEZLA attempted suicide while one who received placebo committed suicide. Weight Decrease: During the controlled period of the trials in psoriasis, weight decrease between 5%-10% of body weight occurred in 12% (96/784) of patients treated with OTEZLA compared to 5% (19/382) treated with placebo. Weight decrease of ≥10% of body weight occurred in 2% (16/784) of patients treated with OTEZLA 30 mg twice daily compared to 1% (3/382) patients treated with placebo. Patients treated with OTEZLA should have their weight monitored regularly. If unexplained or clinically significant weight loss occurs, weight loss should be evaluated, and discontinuation of OTEZLA should be considered. Drug Interactions: Co-administration of strong cytochrome P450 enzyme inducer, rifampin, resulted in a reduction of systemic exposure of apremilast, which may result in a loss of efficacy of OTEZLA. Therefore, the use of cytochrome P450 enzyme inducers (e.g., rifampin, phenobarbital, carbamazepine, phenytoin) with OTEZLA is not recommended [see Drug Interactions (7.1) and Clinical Pharmacology (12.3)]. ADVERSE REACTIONS Clinical Trials Experience in Psoriasis: Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trial of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. Diarrhea, nausea, and upper respiratory tract infection were the most commonly reported adverse reactions. The most common adverse reactions leading to discontinuation for patients taking OTEZLA were nausea (1.6%), diarrhea (1.0%), and headache (0.8%). The proportion of patients with psoriasis who discontinued treatment due to any adverse reaction was 6.1% for patients treated with OTEZLA 30 mg twice daily and 4.1% for placebo-treated patients.

Table 3: Adverse Reactions Reported in ≥1% of Patients on OTEZLA and With Greater Frequency Than in Patients on Placebo; up to Day 112 (Week 16) Placebo OTEZLA 30 mg BID Preferred Term (N=506) (N=920) n (%) n (%) Diarrhea 32 (6) 160 (17) (17(17) (17) Nausea 35(6) (7) 155 (17) (7)(7) ((17) Upper respiratory tract infection 31 (6) 84 (9) Tension headache 21(6) (4) 75 (8) Headache 19(4) (4) 55 (6) ((4) Abdominal pain* 11 (2) 39 (4) Vomiting 8(2) (2) 35 (4) Fatigue 9 (2) 29 (3) Decrease appetite 5 (1) 26 (3) Insomnia 4 (1) 21 (2) Back pain 4 (1) 20 (2) Migraine 5 (1) 19 (2) Frequent bowel movements 1 (0) 17 (2) Depression 2 (0) 12 (1) Bronchitis 2 (0) 12 (1) Tooth abscess 0 (0) 10 (1) Folliculitis 0 (0) 9 (1) Sinus headache 0 (0) 9 (1) *Two subjects treated with OTEZLA experienced serious adverse reaction of abdominal pain. Severe worsening of psoriasis (rebound) occurred in 0.3% (4/1184) patients following discontinuation of treatment with OTEZLA (apremilast). DRUG INTERACTIONS Strong CYP 450 Inducers: Apremilast exposure is decreased when OTEZLA is co-administered with strong CYP450 inducers (such as rifampin) and may result in loss of efficacy [see Warnings and Precautions (5.3) and Clinical Pharmacology (12.3)]. USE IN SPECIFIC POPULATIONS Pregnancy: Pregnancy Category C: OTEZLA should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Pregnancy Exposure Registry: There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to OTEZLA during pregnancy. Information about the registry can be obtained by calling 1-877-311-8972. Nursing Mothers: It is not known whether OTEZLA or its metabolites are present in human milk. Because many drugs are present in human milk, caution should be exercised when OTEZLA is administered to a nursing woman. Pediatric use: The safety and effectiveness of OTEZLA in pediatric patients less than 18 years of age have not been established. Geriatric use: Of the 1257 patients who enrolled in two placebo-controlled psoriasis trials (PSOR 1 and PSOR 2), a total of 108 psoriasis patients were 65 years of age and older, including 9 patients who were 75 years of age and older. No overall differences were observed in the efficacy and safety in elderly patients ≥65 years of age and younger adult patients <65 years of age in the clinical trials. Renal Impairment: Apremilast pharmacokinetics were characterized in subjects with mild, moderate, and severe renal impairment as defined by a creatinine clearance of 60-89, 30-59, and less than 30 mL per minute, respectively, by the Cockcroft–Gault equation. While no dose adjustment is needed in patients with mild or moderate renal impairment, the dose of OTEZLA should be reduced to 30 mg once daily in patients with severe renal impairment [see Dosage and Administration (2.2) and Clinical Pharmacology (12.3)]. Hepatic Impairment: Apremilast pharmacokinetics were characterized in patients with moderate (Child Pugh B) and severe (Child Pugh C) hepatic impairment. No dose adjustment is necessary in these patients. OVERDOSAGE In case of overdose, patients should seek immediate medical help. Patients should be managed by symptomatic and supportive care should there be an overdose. Manufactured for: Celgene Corporation, Summit, NJ 07901 OTEZLA® is a registered trademark of Celgene Corporation. Pat. http://www.celgene.com/therapies ©2014-2017 Celgene Corporation, All Rights Reserved. Based on APRPI.006

OTZ_PsO_HCP_BSv.006 06_2017

TABLE OF CONTENTS July/August 2017 • Volume 15 • Issue 4

EDITORIAL

Acne Keloidalis Nuchae—Is the Barber Really to Blame? .......................................................................... 247

Simon Arda Metin, MA (Cantab), MB BChir; Lawrence Charles Parish, MD, MD (Hon)

COMMENTARy

Emperipolesis, Proposed Mechanism for a Unique Intercellular Interaction: The Defective Phagocytosis Hypothesis .......................................................................................................................... 251

Muriel W. Lambert, PhD; Marc Z. Handler, MD; Qing Wang, MD, PhD; Mark A. Galen, MD; W. Clark Lambert, MD, PhD

ORIGINAL CONTRIBUTIONS

Hidradenitis Suppurativa and Concomitant Down Syndrome: Literature Review of Other Associated Mucocutaneous Manifestations in Adults ................................................................................ 253

Virendra N. Sehgal, MD, FNASc, FAMS, FRAS (Lond.); Naresh Sehgal, MD, DGO; Ruchi Sehgal, DNB, DGO

Analysis of Sebaceous Neoplasms for DNA Mismatch Repair Proteins in Muir-Torre Syndrome ................ 259

Tess H. Pollinger, DO; Christopher R. Kieliszak, DO; Nicholas Logemann, DO; Max L. Gratrix, MD

REVIEW

Molecular Variations in Histologic Subtypes of Basal Cell Carcinoma ....................................................... 265

Min Deng, MD; Amanda F. Marsch, MD; Vesna Petronic-Rosic, MD, MSc

Self Assessment Examination ................................................................................................................... 269

W. Clark Lambert, MD, PhD

CORE CURRICULUM

Virendra N. Sehgal, MD, FNASc, FAMS, Section Editor

Techniques for Optimizing Surgical Scars, Part 1: Wound Healing and Depressed/Atrophic Scars ........... 271

Sailesh Konda, MD; Kathryn Potter, MD; Vicky Zhen Ren, MD; Apphia Lihan Wang, MD; Aditya Srinivasan, MS; Suneel Chilukuri, MD

Departments Perils of Dermatopathology

W. Clark Lambert, MD, PhD, Section Editor

Fading Signals: How Long Does Antigenicity in Immunohistochemical Staining Last? ............................... 277

Ann M. John, BA; Heather M. Holahan, MD; Parmvir Singh, BS; Marc Z. Handler, MD; Stella Chung, MS; W. Clark Lambert, MD, PhD

New Therapy Update

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

Brodalumab (Siliq®): A Treatment for Plaque Psoriasis ............................................................................ 281

Aditya K. Gupta, MD, PhD, FRCPC; Sarah G. Versteeg, MSc; William Abramovits, MD; Kimberly D. Vincent, MD

The Heymann File

Warren R. Heymann, MD, Section Editor

Telangiectasia Macularis Eruptiva Perstans Revisited ............................................................................... 287

Warren R. Heymann, MD

242

TABLE OF CONTENTS July/August 2017 • Volume 15 • Issue 43

Contact Dermatitis Capule Matthew J. Zirwas, MD, Section Editor

On Lanolin Allergy and the Approach to Its Diagnosis ............................................................................... 289

Jonathan G. Bonchak, MD; Matthew J. Zirwas, MD

case studies

Vesna Petronic-Rosic, MD, MSc, Section Editor

Diffuse Papular Eruption of the Face and Eyelids ...................................................................................... 291

Stephanie Frisch, MD; Jessica Kozel, MD; Sarah Jensen, MD; Claudia I. Vidal, MD, PhD

Demodicosis Treatment with Systemic Ivermectin .................................................................................... 293

Manuel Coelho da Rocha, MD; Ana Rita Travassos, MD; Luís Uva, MD; Hortênsia Sequeira, BHSc; Paulo Filipe, MD, PhD

Neutrophilic Eccrine Hidradenitis in an HIV-Infected Patient .................................................................... 297

Patricia Ruiz-López, MD; Eduwiges Martínez-Luna, MD; Sonia Toussaint-Caire, MD; Adán Fuentes-Suárez, MD; Elisa Vega-Memije, MD

Cutaneous Rosai-Dorfman Disease ........................................................................................................... 301

Brett H. Keeling, MD; Lindsay LaPresto Thelin, MD; A. Carlo Gavino, MD; Ammar M. Ahmed, MD

Oxalosis in a Patient with Livedo Reticularis ............................................................................................. 303

Meriam Triki, MD; Meriem Ksentini, MD; Rim Kallel, MD; Emna Bahloul, MD; Faiçal Jarraya, MD; Abderrahmen Masmoudi, MD; Tahya Boudawara, MD

Auricular Hemosiderosis in a Diabetic Patient .......................................................................................... 307

Krista N. Larson, MD; Mark A. Russell, MD

Isotretinoin and Surgical Extraction for Adult-Onset Nevus Comedonicus ................................................. 309

Joanna Dong, BA; Robert G. Phelps, MD; Jacob Levitt, MD

Transient Reactive Eruptive Lymphangiectasia Following Partial Vulvectomy for Chronic Acquired Lymphangioma ........................................................................................................................... 311

Paul J. Wirth, MD; Lin Lin, MD, PhD

Acquired Idiopathic True Transverse Leukonychia ..................................................................................... 315

Ali Hadi, MD; Dana Stern, MD

correspondence

Snejina Vassileva, MD, PhD, Section Editor

Tuberous Sclerosis Complex: Unusual Presentation in an Adult Patient .................................................... 318

Naveen Kansal Kansal, MD

Anticoagulation in Patients with Pseudoxanthoma Elasticum .................................................................. 319

Maryam Liaqat, MD; Warren R. Heymann, MD

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July/August 2017

Volume 15 • Issue 4

Editorial

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

MANAGING EDITOR Marla Kipp marla@skinmedjournal.com

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Authors interested in submitting a paper should refer to the instructions located online at: http://www.skinmedjournal.com/author-info.html. Submissions should be e-mailed to the Editor at: larryderm@yahoo.com

Publishing PUBLISHER Art Kalaka

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Chinese Society of Dermatology

Lebanese Dermatological Society

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244

Belarusian Society of Dermatovenereologists and Cosmetologists

North American Clinical Dermatologic Society

African Association for Dermatology

The Dermatologic & Aesthetic Surgery International League

Volume 15 • Issue 4

July/August 2017

EDITOR IN CHIEF

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

DEPUTY EDITORS William Abramovits, MD

Aditya K. Gupta, MD, PhD, FRCPC

W. Clark Lambert, MD, PhD

Vesna Petronic-Rosic, MD, MSc

Dallas, TX

London, Ontario, Canada

Newark, NJ

Chicago, IL

Larry E. Millikan, MD

Marcia Ramos-e-Silva, MD, PhD

Jennifer L. Parish, MD

Meridian, MS

Rio de Janeiro, Brazil

Philadelphia, PA

EDITORIAL BOARD Mohamed Amer, MD Cairo, Egypt

Howard A. Epstein, PhD Philadelphia, PA

Jasna Lipozencic, MD, PhD Zagreb, Croatia

Todd E. Schlesinger, MD Charleston SC

Robert L. Baran, MD Cannes, France

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

Ada Lo Schiavo, MD Naples, Italy

Virendra N. Sehgal, MD Delhi, India

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

Charles Steffen, MD Oceanside, CA

George M. Martin, MD Kihei, HI

Alexander J. Stratigos, MD Athens, Greece

Marc S. Micozzi, MD, PhD Rockport, MA

James S. Studdiford III, MD Philadelphia, PA

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

Robert J. Thomsen, MD Los Alamos, NM

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

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

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

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

Oumeish Youssef Oumeish, MD, FRCP Amman, Jordan

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

Joseph L. Pace, MD, FRCP Naxxar, Malta

María Daniela Hermida, MD Buenos Aires, Argentina

Art Papier, MD Rochester, NY

Warren R. Heymann, MD Camden, NJ

Johannes Ring, MD, DPhil Munich, Germany

Tanya R. Humphreys, MD Bala-Cynwyd, PA

Roy S. Rogers III, MD Scottsdale, AZ

Camila K. Janniger, MD Englewood, NJ

Donald Rudikoff, MD New York, NY

Abdul-Ghani Kibbi, MD Beirut, Lebanon

Robert I. Rudolph, MD Wyomissing, PA

Andrew P. Lazar, MD Washington, DC

Noah Scheinfeld, MD, JD New York, NY

SKINmed. 2017;15:246

246

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

July/August 2017

Volume 15 • Issue 4

Editorial

Acne Keloidalis Nuchae—Is the Barber Really to Blame? Simon Arda Metin, MA (Cantab), MB BChir;1 Lawrence Charles Parish, MD, MD (Hon)2

ffective management of acne keloidalis nuchae (AKN), also known as folliculitis keloidalis nuchae, is challenging, given our incomplete understanding of its pathogenesis. Mechanical irritation has been suggested to precipitate inflammation that progresses to scarring and alopecia, with fingers pointed at the barber. But what if it were merely a catalyst for an already established process? Research has suggested potential candidates as inflammatory triggers, whose involvement could revolutionize our understanding of AKN. MECHANICAL IRRITATION

Being most prevalent in people of African origin, the curvature of their hair follicles and tendency for ingrown hairs has been linked to AKN, as it has been for pseudofolliculitis barbae. Although these conditions are similar, no association has been made between these histologically distinct diseases.1,2 Such hair is also coarser, requiring more force to groom and cut. There seems also to be an association between onset and a recent haircut. Additionally, AKN patients often have more frequent haircuts that are close-cut and may even cause bleeding.3,4 These observations have led to the hypothesis that mechanical irritation could trigger inflammation, being a forerunner of AKN. Unfortunately, this cannot completely explain the demography of disease, being more common in postpubertal African men. An alternative explanation could be that inflammatory papules (Figure 1) arise independently of irritation but form an irregular surface prone to injury. Trauma evoked by a close haircut could exacerbate inflammation and accelerate progression to scarring and alopecia (Figures 2 and 3). Given their increased likelihood to undergo such trauma, it could explain the predominance in African individuals. If this were true, we must identify the cause for early disease. Histologic studies show that inflammation is pivotal in the pathogenesis of AKN, and it has been suggested that epithelial and/or intrafollicular antigens attract inflammatory cells.2,5

HORMONES

Androgens AKN peaks at 25 to 34 years of age, but it is not found in children or in adults more than 55 years of age, which could suggest a hormonal causation.6 Given its 20:1 male/female ratio and the fact that AKN patients are known to have significantly higher fasting testosterone levels than unaffected patients, androgens may be potential candidates.7,8 Because testosterone increases sebaceous secretions, it may be that sebum attracts the inflammatory cells. This is supported by the observation that sebaceous glands are destroyed in AKN lesions.2,5 AKN has also been described in women, which seemingly conflicts with this hypothesis;9,10 however, the women described were noted to have an oily complexion, suggesting an elevated androgen level and/or sensitivity. Caucasian patients who were immunosuppressed with cyclosporine have developed histologically proven AKN.11 Because androgens and cyclosporine are known to increase hair growth, it could be that hair and/or excess hair growth attracts inflammatory cells. Another patient was noted to develop AKN-like lesions while on carbamazepine and diphenylhydantoin, which diminished upon cessation and failed to return with subsequent carbamazepine monotherapy.12 The observation that diphenylhydantoin also causes hypertrichosis supports this hypothesis.

Metabolic syndrome The occasional occurrence of AKN in women could suggest another hypothesis. Aside from an oily complexion, women in one study had an elevated body mass index and insulin level, and reduced insulin sensitivity.10 Additionally, the 0.5% prevalence among African-American men increases to 13.6% in AfricanAmerican football players, who are known to have a higher body mass index.13 These observations suggest that the metabolic syndrome may also be involved in development of AKN.

From Cambridge University School of Clinical Medicine, Cambridge, UK;1 and the Department of Dermatology and Cutaneous Biology, Jefferson Center for International Dermatology, Kimmel Medical College of Thomas Jefferson University, Philadelphia, PA2 Address for Correspondence: Lawrence Charles Parish, MD, MD (Hon), 1845 Walnut Street, Suite 301, Philadelphia, PA 19103 • E-mail: larryderm@yahoo.com

SKINmed. 2017;15:247–249

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EDITORIAL

Figure 1. Papules of varying size in the occipital and nuchal areas, with slight tenderness.

Figure 3. Extensive acne keloidalis nuchae with severe scarring.

FLORA Bacterial infection of AKN lesions is common and thought to be secondary to excoriations. Conversely, it could also be that the skin flora, their metabolic by-products, and/or low-grade chronic infection attract inflammatory cells in early disease. Although it is difficult to distinguish between cause and effect, there is no evidence to prove that flora are on either side, making it worthwhile to investigate.

Figure 2. Acne keloidalis nuchae with scarring and alopecia.

LOCATION OF LESIONS

A possible genetic candidate is the peroxisomal proliferator-activated receptor-γ (PPAR-γ), whose dysfunction is established in the metabolic syndrome. Laboratory studies show that PPAR-γ knockout mice develop skin inflammation and eventual primary cicatricial alopecia whose histology is similar to AKN.2,14 There is also evidence to suggest PPAR-γ activation inhibits production of inflammatory cytokines, providing a possible explanation for this observation.15 Taken together, PPAR-γ dysfunction in the metabolic syndrome could promote inflammation that predisposes individuals to AKN. SKINmed. 2017;15:247–249

The hypotheses suggested above could, at least in part, account for AKN’s demography, but they fail to explain its predilection for the occiput/nuchal areas. Although it has been observed that the occipital mast cell density is almost double that of the anterior scalp, it is difficult to envisage any causal relation.8 Androgen involvement could explain scalp involvement, because this area has an increased density of sebaceous glands. An increased androgen sensitivity of occipital sebaceous glands could then account for the regional selectivity. This has shown to be true for affected sebaceous glands in androgenic alopecia, which has been associated with AKN.16

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CONCLUSIONS Although the barber was once held responsible for AKN, antigens derived from hormone imbalance and/or infection may be the real culprits. Additional involvement of the metabolic syndrome, especially PPAR-γ dysfunction, is equally promising. Understanding the pathogenesis of AKN underpins its management, which is currently non-specific and focused on the downstream effects of inflammation. If confirmed, androgen involvement and/or PPAR-γ dysfunction could enable the development of specific therapies that target the upstream cause of disease. Such intervention could revolutionize the treatment of AKN and make this refractory disease a thing of the past. References 1 Smith JD, Odom RB. Pseudofolliculitis capitus. Arch Dermatol. 1977;113:328–329. 2 Sperling LC, Homoky C, Pratt L, Sau P. Acne keloidalis is a form of primary scarring alopecia. Arch Dermatol. 2000;136:479–484. 3 Salami T, Omeife H, Samuel S. Prevalence of acne keloidalis nuchae in Nigerians. Int J Dermatol. 2007;46:482– 484. 4 Khumalo NP, Jessop S, Gumedze F, et al. Hairdressing is associated with scalp disease in African schoolchildren. Br J Dermatol 2007;157:106–110. 5 Herzberg AJ, Dinehart SM, Kerns BJ, Pollack SV. Acne keloidalis. Transverse microscopy, immunohistochemistry, and electron microscopy. Am J Dermatopathol. 1990;12:109–121.

6 Ogunbiyi AO, Adedokun B. Perceived etiological factors of folliculitis keloidalis nuchae and treatment options amongst Nigerian men. Br J Dermatol. 2015;173:22–25. 7 Dinehart SM, Tanner L, Mallory SB, Herzberg AJ. Acne keloidalis in women. Cutis. 1989;44:250–252. 8 George AO, Akanji AO, Nduka EU, Olasode O. Clinical, biochemical and morphological features of acne keloidalis in a black population. Int J Dermatol. 1993;32:714– 716. 9 Ogunbiyi A, George A. Acne keloidalis in females: Case report and review of literature. J Natl Med Assoc. 2005;97:736–738. 10 Loayza E, Cazar T, Uraga V, et al. Acne keloidalis nuchae in Latin American women. Int J Dermatol. 2015;54:e183–e185. 11 Azurdia RM, Graham RM, Wesmann K, Guerin DM. Acne keloidalis in Caucasian patients on cyclosporine following organ transplantation. Br J Dermatol. 2000;143:465–467. 12 Grunwals MH, Ben-Dor D, Livini E, Halevy S. Acne keloidalis-like lesions n the scalp associated with antiepileptic drugs. Int J Dermatol. 1990;29:559–561. 13 Knable AL Jr, Hanke CW, Gonin R. Prevalence of acne keloidalis nuchae in football players. J Am Acad Dermatol. 1997;37:570–574. 14. Karnik P and Stenn K. Cicatricial alopecia symposium 2011: Lipids, inflammation and stem cells. J Invest Dermatol. 2012;132:1529–1531. 15 Jiang C, Ting AT, Seed B. PPAR-γ agonists inhibit production of monocyte inflammatory cytokines. Nature 1998;391:82–86. 16 Sawaya ME, Honig LS, Hsia SL. Increased androgen binding capacity in sebaceous glands in scalp of malepattern baldness. J Invest Dermatol. 1989;92:91–95.

VINTAGE LABEL

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Commentary

Emperipolesis, Proposed Mechanism for a Unique Intercellular Interaction: The Defective Phagocytosis Hypothesis Muriel W. Lambert, PhD;1,2 Marc Z. Handler, MD;1 Qing Wang, MD, PhD;2 Mark A. Galen, MD;2 W. Clark Lambert, MD, PhD1,2 “Just because we can assign a name to something does not mean we understand it.”—Rudolph Virchow

mperipolesis is a phenomenon, observed histologically, in which an intact cell is surrounded by the cytoplasm of another cell (Figures 1 and 2). Although not part of the definition, the latter cell tends to be a large foamy histiocyte. Emperipolesis is related to the term peripolesis, which refers to a cell being attached to, but not encased within, another (usually larger) cell. PHAGOCYTOSIS Neither term should be confused with phagocytosis, in which a (usually smaller) entity is engulfed within, and destroyed by, a cell, or with pinocytosis, in which a smaller entity is engulfed within, and digested by, a cell. One striking example of phagocytosis is engulfment of necrotic lymphocyte nuclei by polymorphonuclear cells after opsinization by circulating anti-DNA antibodies in systemic lupus erythematosus, forming the characteristic “LE cell.” Phagocytosis of some cell types by others is also a feature of some diseases; for example, phagocytosis of erythrocytes by lesional endothelial cells is characteristic of Kaposi hemorrhagic sarcoma. Notably, phagocytosis is also associated with profound metabolic changes in the phagocytosing cell, including activation of the “pentose shunt” pathway of glycolysis, and with it abrupt and marked increased oxygen consumption.

SINUS HISTIOCYTOSIS WITH MASSIVE LYMPHADENOPATHY More than 40 years ago, Juan Rosai (1940– ) and Ronald Dorfman (1923–2012) described a benign proliferation of histiocytes and lymphocytes that they designated as a new entity: sinus histiocytosis with massive lymphadenopathy.1 A striking feature of this new entity was emperipolesis, particularly of lymphocytes and plasma cells within large, foamy histiocytes. Through subsequent decades, a number of cases of this rare disorder have been described, with cutaneous and lymph nodal variants reported. More often, both types occur together. In this issue, Keeling et al report a facial cutaneous case of this entity.2 Only a handful of such cases have been previously reported, with about 3% of this already rare disease reported limited to the skin, and an even smaller percentage exclusively on the face.3 EMPERIOPOLESIS Although emperipolesis has been, and continues to be, associated with what has come to be known as Rosai-Dorfman disease, the association is not absolute, and instances have been reported of one without the other. Indeed, emperipolesis has also been found to be associated with and to be a sign of hepatitis B infection.4 In fact, based on heterogeneity of case reports, it has been

See also Keeling et al, page 301 in this issue. From the Department of Dermatology1 and the Department of Pathology and Laboratory Medicine,2 Rutgers – New Jersey Medical School, Newark, NJ Address for Correspondence: W. Clark Lambert, MD, PhD, Departments of Dermatology and Pathology and Laboratory Medicine, Room H576 Medical Science Building, Rutgers – New Jersey Medical School, 185 South Orange Avenue, Newark, NJ 07103 • Email: lamberwc@njms.rutgers.edu

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Figure 2. Emperipolesis (same case as in Figure 1). The phenomenon is seen to better advantage using an immunohistiochemical stain that stains macrophages but not the phagocytosed cells (S-100 immunostain, magnification ×960).

Figure 1. Emperipolesis (Rosai-Dorfman disease). Within the cytoplasm of large, foamy histiocytes are trapped intact lymphocytes, plasma cells, and other inflammatory cells (hematoxylin and eosin stain, magnification ×960).

questioned whether Rosai-Dorfman disease is an entity at all, but rather a histopathological phenomenon related to a variety of disorders.

underlying mechanism, emperipolesis results when phagocytosis is simply defective. The cell engulfing the emperipolesed cell is simply incapable of completing the task of destroying it.

Because the characteristic foamy histiocyte is approximately 100 μm in diameter, whereas the standard histological section is only 4 μm in thickness, it is not difficult to see where an instance of emperipolesis might be missed due simply to tissue sectioning. In addition, there is a report of serial biopsies of the same case of Rosai-Dorfman disease that showed emperipolesis in some biopsies, but not in others, either due to this cause or because emperipolesis simply was not present throughout the lesion.5

References

CONCLUSIONS The underlying mechanism(s) for emperipolesis have been extensively debated, with a large number of cytokines and even primordial relationships with single-celled ancestors invoked.6 We offer a simpler hypothesis: We have seen similar large foamy histiocytes in cases of lysosomal storage disease in which defective phagocytosis was evident. We propose that, whatever the

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1 Rosai J, Dorfman RF. Sinus histiocytosis with massive lymphadenopathy: A newly recognized benign clinicopathological entity. Arch Pathol. 1969;87:63–70. 2 Keeling BH, LaPresto Thelin L, Gavino AC, Ahmed AM. Cutaneous Rosai-Dorfman disease. SKINmed 2017;15:301–302. 3 Fang S, Chen AJ. Facial Rosai-Dorfman disease: A case report and literature review. Exptl Therapeut Med. 2015;9:1389–1392. 4 Hu Y, Jiang L, Zhou G, et al. Emperipolesis is a potential histological hallmark associated with chronic hepatitis B. Curr Mol Med. 2015;15:873–871. 5 Ilyer VK, Handa KK, Sharma MC. Variable extent of emperipolesis in the evolution of Rosai-Dorfman disease: Diagnostic and pathologic implications. J Cytol. 2009;26:111–116. 6 Lozupone F, Fais S. Cancer cell cannibalism: A primeval mechanism to survive. Curr Mol Med. 2015;15:836–841.

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original contribution

Hidradenitis Suppurativa and Concomitant Down Syndrome: Literature Review of Other Associated Mucocutaneous Manifestations in Adults Virendra N. Sehgal, MD, FNASc, FAMS, FRAS (Lond.); Naresh Sehgal, MD, DGO; Ruchi Sehgal, DNB, DGO

This contribution describes hidradenitis suppurativa (HS) occurring in Down disease that presented with morphology conforming to an overlap of stages 1 and 2 of the Hurley staging system, namely the formation of solitary or multiple isolated abscesses without scarring or sinus tracts, recurrent abscesses, and single or multiple widely separated lesions with sinus tract formation, occupying apocrine sweat gland–bearing areas: the inner thighs, groin, and buttocks. The lesions were bilateral and symmetrical, of rare occurrence. In addition, the clinical and pathognomonic features of several other concomitant diseases are defined and reviewed; these include elastosis perforans serpiginosa, fissured tongue/ macroglossia, syringomas, palmoplantar keratodermas, cheilitis, xerosis, atopic dermatitis, seborrheic dermatitis, vitiligo, cutis marmorata, and alopecia areata. (SKINmed. 2017;15:253–258)

S is an infrequently diagnosed, chronic skin disorder identified by clusters of abscesses or subcutaneous boillike infections affecting apocrine sweat gland–bearing areas: the underarms, under the breasts in women, and the inner aspects of the thighs, groin, and buttocks.1,2 It seems to be hereditary among certain ethnic groups and autoimmune in nature.3 The concomitant occurrence of HS in Down syndrome is very rare and has so far been very sparingly reported;4 hence, the focus on the current case. In addition, a succinct review of other concomitant cutaneous manifestations is given for reference. CLINICAL ILLUSTRATION A 21-year-old man with Down syndrome was brought to the outpatient department with painful, multiple, red, raised eruptions the size of a pea that were affecting the whole of the groin area, including the inguinal medial aspect of the thigh and part of the perineal region. This was accompanied by mild fever, which waxed and waned with the periodic exacerbation of the eruptions. Some of the lesions burst open, emitting a blood-stained purulent discharge. The episode had had its onset 5 years before,

since when remissions and exacerbations had been its hallmark. A couple of months previously, the man’s parents had noticed the appearance of similar (initial) eruptions in both axillae, without any clinical manifestations Skin surface examination revealed erythematous papulovesicular pustules and/or abscesses. The abscesses were solitary or multiple isolated abscesses without scarring or sinus tracts. The abscesses were recurrent and attended by inflammation that restricted the movement of the legs (Figure 1), conspicuous lesions on the face, macroglossia, obstructive sleep apnea, and a fissured tongue (Figure 2). The lesions were confined largely to apocrine sweat gland–bearing areas: the inner aspect of the thighs, groin, and buttocks. The severity and extent of the lesions were evaluated according to the Hurley staging system (see below),5 which indicated an overlap of stages 1 and 2. The initial acneiform (Figure 3) lesions were also seen on the underarms, and the axillae. The lesions were bilaterally symmetrical.

From the DermatoVenereology (Skin/VD) Centre, Sehgal Nursing Home, Panchwati, Delhi, India Address for Correspondence: Virendra N. Sehgal, MD, FNASc, FAMS, FRAS (Lond.), DermatoVenerology (Skin/VD) Center, Sehgal Nursing Home, A/6 Panchwati, Delhi 110 033, India • E-mail: drsehgal@ndf.vsnl.net.in

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Figure 2. Hidradenitis suppurativa in Down syndrome, showing a characteristic facial appearance, macroglossia, and fissured tongue.

Figure 1. Hidradenitis suppurativa in Down syndrome, showing erythematous papulovesicular pustules and/or abscesses, either solitary or multiple, on the inner aspect of the thighs, groin, and buttocks.

Conventional culture, automated identification, and sensitivity were carried out. Purulent discharge from a lesion was taken using a cotton swab for culture on MacConkey agar, blood agar, and enrichment media (brain-heart infusion broth) for culture of the pus. No aerobic pyogenic organism could be grown (the sample was sterile) after 48 hours of incubation at 37Â°C. Liver function studies and lipid profiles were normal. Ultrasonography of the upper abdominal organs and posteroanterior and lateral chest radiology were normal. Echocardiographic evaluation of the heart showed largely normal echocardiographic parameters except for a poor (suboptimal) window and a ventricular septal defect measuring 0.9 to 1.0 cm wide with a leftto-right shunt across it. The maximum pressure gradient across the ventricular septal defect was 20 mmHg. SKINmed. 2017;15:253â&#x20AC;&#x201C;258

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Figure 3. Hidradenitis suppurativa in Down syndrome, illustrating the initial acneiform lesions. Hidradenitis Suppurativa and Concomitant Down Syndrome

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DISCUSSION HS, also known as acne inversa, is a well-recognized inflammatory skin disease characterized by recurrent boil-like lumps (nodules and abscesses) that culminate in pus-like discharge, difficult-to-heal open wounds (sinuses), and scarring. It commonly occurs on apocrine sweat gland–bearing areas: the groins, the underarms (axillae), and under the breasts. Immunodeficiency in Down syndrome seems plausible as leading to susceptibility to infections,6 including HS. The term hidradenitis suppurativa is derived from the Greek words hidros, sweat and aden, a gland. Credit for describing it is given to the French physician Valpeau,7 who in 1839 described a strange inflammation of the skin with superficial abscesses in the axillary, perianal, and mammary areas.4 Subsequently, the condition was named hidrosade´nite phlegmoneuse, emphasizing the association between HS and sweat glands, which had been identified by Purkinje in 1833. The incidence of HS may be as high as 1 in 300,8 and it is two to five times more common in women than men. The peak age of onset is the second and third decades of life, and the condition is uncommon before puberty.7,9 Onset is infrequent after menopause. Genitofemoral lesions are more common in women, but there seems to be no difference in axillary involvement between the sexes.1

Figure 4. Down syndrome: alopecia areata (localized hair loss).

The morphology, severity, and extent of lesions in this patient conformed to stages 1 and 2 of the Hurley staging system:10 • Stage 1: solitary or multiple isolated abscess without scarring or sinus tracts. • Stage 2: recurrent abscesses and single or multiple widely separated lesions, with sinus tract formation.

• Longest distance between two relevant lesions (ie, nodules and fistulas, in each region, or size if only one lesion): less than 5 cm, 2 points; 5 to 10 cm, 4 points; more than 10 cm, 8 points.

• Stage 3: diffuse or broad involvement, with multiple interconnected sinus tracts and abscesses. The most commonly used option, the Sartorius hidradenitis suppurativa score,11 involves counting regions, nodules, and sinus tracts: • Anatomic region involved (axillary, groin, genital, gluteal, or other inflammatory region, left and/or right): 3 points per region involved. • Number and scores of lesions (abscesses, nodules, fistulas, scars): 2 points for each nodule, 4 points for each fistula, 1 point for each scar, and 1 point each for “other” lesion. SKINmed. 2017;15:253–258

• Lesions clearly separated by normal skin in each region: yes, 0 points; no, 6 points. Mucocutaneous manifestations HS is one of the pre-eminent cutaneous manifestations of Down syndrome, the others being elastosis perforans serpiginosa,12,13 fissured tongue,14–16 macroglossia,17 syringomas,18–23 palmoplantar keratodermas,24–26 cheilitis,27–29 xerosis,30–33 atopic dermatitis,34,35 seborrheic dermatitis,36,37 vitiligo,38,39 cutis mamorata,40–42 and alopecia areata (Figure 4).43-47 The salient clinical and histopathologic features are outlined in the Table.

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Table. Mucocutaneous manifestations of Down syndrome other than hidradenitis suppurativa Diagnosis

Clinical Features

Pathognomonic Features

Elastosis perforans serpiginosa12,13

Characterized by: • Transepidermal elimination of elastic fibers • Distinctive clinical lesions • Serpiginous distribution

• Demonstrates a column of keratotic debris forming a focal invagination through a hyperplastic epidermis • Closer inspection identifies material undergoing transepidermal elimination, brightly eosinophilic fibers seen within the extruded material, mixed with keratinous debris and an inflammatory cell infiltrate

Fissured tongue,14–16 scrotal tongue, lingua plicata/plicated tongue, furrowed tongue, macroglossia17

Characterized by: • Multiple deep grooves (fissures) 2 to 6 mm in depth on the dorsum of the tongue • Benign condition • Enlarged tongue, tracheal hysteresis in sleep, apnea

• Tissue exhibits characteristic noncaseating granulomatous inflammation

Syringomas18–23

• About 2 mm skin-colored to yellow round and/or flat papules or vesicles • Near the eyelids, axillae, chest, and vulva • Friedman and Butler’s classification scheme Four variants of syringoma are recognized: 1 Localized 2 Associated with Down syndrome 3 Generalized, which encompasses multiple and eruptive syringomas 4 Familial eruptive and giant syringe syringomas usually occur in clusters and are bilaterally symmetrical, especially over the lower eyelids

• Hematoxylin and eosin stain shows the presence of multiple small ducts and epithelial cords within the dermis. The ducts are lined by two rows of flattened epithelial cells, the outer layer bulging outward to create a comma-like tail. Ductal lumina are filled with amorphous, periodic acid–Schiff-positive material • Histologically, syringomas react strongly with S-100, carcinoembryonic antigen, epithelial membrane antigen, lysozymes, and antibodies to breast cystic fluid protein GCDFP-15 and GCDFP-24. Eccrine gland enzymes, eg, succinic dehydrogenase, phosphorylase, and leucine aminopeptidase predominate in syringoma cells

Palmoplantar keratodermas24–26 Autosomal recessive and dominant, X-linked

Variants: • Diffuse, characterized by an even, thick, symmetrical hyperkeratosis, evident at birth or in the first few months of life • Focal, large, compact masses of keratin at sites of recurrent friction, in a discoid (nummular) or linear pattern • Puncuated

• Conspicuous epidermis; orthokeratosis, parakeratosis, perinuclear vacuolization, and keratohyalin granules of varying size and shape in the cell periphery. Electron microscopy shows a perinuclear region containing many ribosomes and vacuoles surrounded by a tonofibril shell

Cheilitis27–29

Characterized by: • Angular stomatitis (fissures and red, scaly skin at the corners of the oral cavity and lips) • Complicated by either bacterial infection or candida (oral candidosis)

• Noncaseating granulomatous inflammation

Xerosis,30–33 xeroderma or xerodermia, dry skin

• Skin becomes abnormally dry, rough, and inelastic in children of 5 to 10 years of age • Mild to moderate generalized xerosis of by 15 years of age

Atopic dermatitis34,35

• Occurs in more than 50% of patients in childhood • Red, scaly, itchy skin • Affects the cheeks, areas behind the ears, and popliteal and antecubital fossae

• A thin, confluent parakeratotic horn over compact orthokeratosis • Hypergranulosis • Normal rete ridge pattern • Minimal dermal inflammation • Sequential histopathologic undertones • Begins with a perivascular interstitial spongiotic dermatitis • Evolves into a psoriasiform microvesicular spongiotic dermatitis • Results in psoriasiform dermatitis Continued

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Table. Mucocutaneous manifestations of Down syndrome other than hidradenitis suppurativa (continued) Diagnosis

Clinical Features

Pathognomonic Features

Seborrheic dermatitis,36,37 seborrhea, sebopsoriasis, seborrheic eczema, dandruff, pityriasis capitis

• Growth of very thick skin on the palms and soles, palmoplantar keratoderma

• Seborrheic dermatitis/eczema resembles atopic dermatitis and palmoplantar keratoderma

Vitiligo38,39

Characterized by: • Loss of pigmentation of the skin • Occurrence anywhere on the body and at any age

Cutis mamorata,40–42 cutis mamorata telangiectatica congenita

Characterized by: • An evanescent, lacy, reticulated red and/or blue mottled or marbled cutaneous vascular pattern, affecting most of the body surface in a newborn child exposed to low environmental temperature • An accentuated physiologic vasomotor response, sometimes discernible in older children, that disappears with increasing age • Lesions are more intense, segmental, and persistent; epidermal atrophy and ulceration occur

• Proliferation of vasculature in addition to dilated capillaries in the dermis

Alopecia areata43–47

Characterized by: • Patchy hair loss occurring in 6% to 9% of patients (compared to 1% to 2% of the general population) • Alopecia is unpredictable, with patients experiencing several episodes of hair loss and regrowth during their lifetime

• The duration of the current episode is the major factor affecting histopathology • Acute stage: bulbar lymphocytes surrounding terminal hairs in early episodes, and miniaturized hairs in repeated episodes • Subacute stage: decreased anagen, and increased catagen and telogen, hairs are characteristic • Chronic stage: decreased terminal and increased miniaturized hairs, with variable inflammation • During recovery, increasing numbers of terminal anagen hairs from regrowth of miniaturized hairs and lack of inflammation

References 1 Alikhan A, Lynch E. Hidradenitis suppurativa: a comprehensive review. J Am Acad Derm. 2009;60:539–561. 2 Sehgal VN, Verma P, Sawant S, et al. Contemporary surgical treatment of hidradenitis suppurativa (HS) with a focus on the use of the diode hair laser in a case. J Cosmet Laser Ther. 2011;13:180–190. 3 Fimmel S, Zouboulis CC. Comorbidities of hidradenitis suppurativa (acne inversa). Dermatoendocrinol. 2010;2:9– 16. 4 Blok J, Jonkman M, Horváth B. The possible association of hidradenitis suppurativa and Down syndrome: Is increased amyloid precursor protein expression resulting in impaired Notch signalling the missing link? Br J Dermatol. 2014;170:1375–1377.

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• Fontana-Masson–stained tissue sections of vitiligo lesions depict more basal hypopigmentation and dermal inflammation than perilesional normal skin • Hematoxylin and eosin– stained sections show basal inflammation in papillary dermis, in contrast to perilesional skin; this is confirmed by FontanaMasson staining

5 Balik E, Eren T, Bulut T, et al. Surgical approach to extensive hidradenitis suppurativa in the perineal/perianal and gluteal regions. World J Surg. 2009;33:481–487. 6 Ram G, Chinen J. Infections and immunodeficiency in Down syndrome. Clin Exp Immunol. 2011;164:9–16. 7 Ather S, Chan DSY, Leaper DJ, et al. Surgical treatment of hidradenitis suppurativa: case series and review of the literature. Int Wound J. 2006;3:159–169. 8 Bernard JH, Mudge M, Hughes L. Recurrence after surgical treatment of hidradenitis suppurativa. Br Med J(Clin Res Ed). 1987;294:487–489. 9 Palo Alto Medical Foundation. Teenage Growth & Development: 15 to 17 Years. http://www.pamf.org. Accessed November 9, 2013. 10 Hurley HJ. Axillary hyperhidrosis, apocrine bromhidrosis,

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hidradenitis suppurativa, and familial benign pemphigus: Surgical approach. In: Roenigk RK, Roenigk Jr. H.H., eds. Dermatologic Surgery: Principles and Practice. New York, NY: Marcel Dekker; 1989:729–739.

30 Coyle MB, Leonard RB, Nowowiejski DJ, Malekniazi A, and Finn DJ. Evidence of multiple taxa within commercially available reference strains of Corynebacterium xerosis. J Clin Microbiol. 1993;31:1788–1793.

11 Sartorius K, Lapins J, Emtestam L, et al. Suggestions for uniform outcome variables when reporting treatment effects in hidradenitis suppurativa. Br J Dermatol. 2003;149:211–213.

31 Thyssen JP, Elias PM. Xerosis is latitude dependent and affects the propensity to develop atopic disease. J Allergy Clin Immunol. 2012;130:820–82; author reply 821–822.

12 Wilms A, Dummer R. Elastosis perforans serpiginosa in Down syndrome. Hautarzt. 1997;48:923–925. 13 Pereira AC, Baeta IG, Costa Júnior SR, Gontijo Júnior OM, Vale EC. Elastosis perforans serpiginosa in a patient with Down’s syndrome. An Bras Dermatol. 2010;85:691–694. 14 Rapini RP, Bolognia JL, Jorizzo JL. Progeria. Dermatology. St. Louis, MO: Mosby; 2007. 15 Elston D, Berger T, James WD. Andrews’ Diseases of the Skin: Clinical Dermatology. 10th edn. Philadelphia, PA: Saunders Elsevier; 2006. 16 Scully C. Oral and Maxillofacial Medicine: The Basis of Diagnosis and Treatment. 2nd edn. Edinburgh: Churchill Livingstone; 2008. 17 Guimaraes CV, Donnelly LF, Shott SR, et al. Relative rather than absolute macroglossia in patients with Down syndrome: Implications for treatment of obstructive sleep apnea. Pediatr Radiol. 2008;38:1062–1067. 18 Jacobs S, Grussendorf-Conen EI. Disseminated eruptive syringomas in Down syndrome. Hautarzt. 2004;55:70–72. 19 Urban CD, Cannon JR, Cole RD. Eruptive syringomas in Down’s syndrome. Arch Dermatol. 1981;117:374–375. 20 Schepis C, Siragusa M, Palazzo R, et al. Palpebral syringomas and Down’s syndrome. Dermatology. 1994;189:248–250. 21 Kanzaki T, Nakajima M. Milialike idiopathic calcinosis cutis and syringoma in Down’s syndrome. J Dermatol. 1991;18:616–618. 22 Friedman SJ, Butler DF. Syringoma presenting as milia. J Am Acad Dermatol. 1987;16:310–314. 23 Patrizi A, Neri I, Marzaduri S, et al. Syringoma: A review of twenty nine cases. Acta Derm Venereol. 1998;78:460–462. 24 Patel S, Zirwas M, English JC. Acquired palmoplantar keratoderma. Am J Clin Dermatol. 2007;8:1–11. 25 Abdul-Wahab A, Takeichi T, Liu L, et al. Autosomal dominant diffuse nonepidermolytic palmoplantar keratoderma due to a recurrent mutation in aquaporin-5. Br J Dermatol. 2016;174:430–432. 26 Dereure O. Palmoplantar keratoderma syndromes: New findings. Ann Dermatol Venereol. 2015;142:305–306. 27 Daneshpazhooh M, Nazemi TM, Bigdeloo L, Yoosefi M. Mucocutaneous findings in 100 children with Down syndrome. Pediatr Dermatol. 2007;24:317–320. 28 Elston D, Berger T, James WD (2006). Disorders of the Mucous Membranes. In: Andrews’ Diseases of the Skin: Clinical Dermatology. 10th edn. Philadelphia, PA: Saunders Elsevier; 2006:795–797. 29 Hoede N, Korting GW, Burgdorf WHC, Young SK. The Mouth, Tongue and Teeth. In: Bork K, ed. Diseases of the Oral Mucosa and the Lips. Philadelphia, PA: Saunders, 1996:10.

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32 Engelke M, Jensen J-M, Ekanayake-Mudiyanselage S, Proksch E. Effects of xerosis and ageing on epidermal proliferation and differentiation. Br J Dermatol. 1997;137:219– 225. 33 Bernacchi E, Bianchi B, Amato L, et al. Xerosis in primary Sjögren syndrome: Immunohistochemical and functional investigations. J Dermatol Sci. 2005;39:53–55. 34 Schepis C, Barone C, Siragusa M, Romano C. Prevalence of atopic dermatitis in patients with Down syndrome: A clinical survey. J Am Acad Dermatol. 1997;36:1019–1021. 35 Sehgal VN, Khurana A, Mendiratta V, et al. Atopic dermatitis: clinical connotations, especially a focus on concomitant atopic undertones in immunocompromised/susceptible genetic and metabolic disorders. Indian J Dermatol. 2016;61:241–250. 36 Berk T, Scheninfeld N. Seborrheic dermatitis. P T. 2010;35:348–352. 37 Bilgili SG, Akdeniz N, Karadag AS, et al. Mucocutaneous disorders in children with Down syndrome: Case-controlled study. Genet Couns. 2011;22:385–392. 38 Sehgal VN, Srivastava G. Vitiligo: Compendium of clinicoepidemiological features. Indian J Dermatol Venereol Leprol. 2007;73:149–156. 39 Brown AC, Olkowski ZL, McLaren JR, et al. Alopecia areata and vitiligo associated with Down’s syndrome. Arch Dermatol. 1977;113:1296. 40 Zagne V, Fernandes NC. Dermatoses in the first 72 h of life: A clinical and statistical survey. Indian J Dermatol Venereol Leprol. 2011;77:470–476. 41 Thiele P, Runge E. Conservative therapy of acral circulatory disorders and cutaneous microangiopathies [in German]. Z Gesamte Inn Med. 1983;38:200–207. 42 Jansson H. [Side-phenomena of the human skin. I. Cutis marmorata, acrocyanosis, erythrocyanosis]. Z Haut Geschlechtskr. 1957;23:188–192 contd. 43 Khare KC, Khare S, Jindal KC. Alopecia areata and xerosis in Down’s syndrome. Indian J Dermatol Venereol Leprol. 1996;62:129. 44 Du Vivier A, Munro DD Alopecia areata, autoimmunity, and Down’s syndrome. Br Med J. 1975;1:191–192. 45 Estefan JL, Oliveira JC, Abad ED, et al. HLA antigens in individuals with Down syndrome and alopecia areata. World J Clin Cases. 2014;2:541–545. 46 Brown AC, Olkowski ZL, McLaren JR, et al. Alopecia areata and vitiligo associated with Down’s syndrome. Arch Dermatol. 1977;113:1296. 47 Elias PM, Hatano Y, Williams ML. Basis for the barrier abnormality in atopic dermatitis: Outside-insideoutside pathogenic mechanisms. J Allergy Clin Immunol. 2008;121:1337–1343.

Hidradenitis Suppurativa and Concomitant Down Syndrome

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Volume 15 • Issue 4

ORIGINAL CONTRIBUTION

Analysis of Sebaceous Neoplasms for DNA Mismatch Repair Proteins in Muir-Torre Syndrome Tess H. Pollinger, DO;1 Christopher R. Kieliszak, DO;2 Nicholas Logemann, DO;3 Max L. Gratrix, MD1 Abstract Muir-Torre syndrome is a rare genodermatosis inherited most frequently in an autosomal dominant fashion. Current criteria for its diagnosis include at least one sebaceous tumor and an underlying visceral malignancy. Muir-Torre syndrome is strongly associated with a germline mutation in DNA mismatch repair genes. We report two patients with a history of colorectal carcinoma who presented with sebaceous neoplasms on the face and trunk. Immunohistochemical staining of the sebaceous neoplasms demonstrated absence of mismatch repair proteins MSH2 and MSH6. Genetic studies confirmed deletions in the MSH2 gene, and a diagnosis of Lynch syndrome was made. Immunohistochemical staining for mismatch repair genes MLH1, MSH2, MSH6 and PMS2 may aid in the diagnosis of Muir-Torre syndrome in cases where there is high suspicion. Genetic testing is an important final step in the confirmation of Muir-Torre syndrome. (SKINmed. 2017;15:259–264)

irst described by Edward G. Muir (1906–1973) et al in 19671 and then by Douglas P. Torre (1919–1996) in 1968,2 Muir-Torre Syndrome (MTS) is characterized by the presence of at least one cutaneous tumor, either of sebaceous glands (sebaceous adenoma, sebaceoma, sebaceous carcinoma) or keratoacanthoma, and at least one visceral malignancy, most commonly large bowel, endometrium, gastrourinary tract, breast, or ovary.3,4 MTS displays a high degree of penetrance with a wide range of clinical presentations due to variable expressivity.5 It has been proposed that MTS is a phenotypic variant of hereditary nonpolyposis colorectal carcinoma, as the same mutations involved in the pathogenesis of hereditary nonpolyposis colorectal carcinoma are also seen in many patients with MTS.4 Fifty-six percent of skin lesions in MTS occur after diagnosis of the first malignancy, 6% occur concomitantly, and 22% occur as the first malignancy of the syndrome.6 Sebaceous neoplasms can arise from any sebaceous gland, most occurring on the eyelids or the nose due an abundance of sebaceous glands in these areas. However, in MTS, sebaceous neoplasms occur most commonly

below the head and neck.7 Most internal malignancies occur in the gastrointestinal tract, but they can also occur in the genitourinary tract, breast, endometrium, and ovaries.4 Microsatellite instability and mismatch repair (MMR) are core concepts in the development of MTS. Microsatellites are short repetitive DNA sequences normally scattered throughout the genome.8 MMR is a mechanism by which DNA coding errors are repaired. Loss of expression of the MMR gene by way of germline mutation on one allele and a “second hit” somatic mutation on the opposite allele prevent an essential component of normal DNA repair; this results in an accumulation of microsatellites mutations, leading to microsatellite instability. microsatellite instability is said to be found in 46% to 100% of the tumors associated with MTS,5 and 95% of hereditary nonpolyposis colorectal carcinoma–associated neoplasms.4 A clinical diagnosis of MTS due to inherited MMR gene defects may be confirmed by immunohistochemical (IHC) staining for

From the Department of Dermatology, Walter Reed National Military Medical Center, Bethesda MD;1 Department of Otolaryngology Head and Neck Surgery, OhioHealth Doctors Hospital, Columbus, OH;2 and 3Department of Dermatopathology, Walter Reed National Military Medical Center Bethesda, MD Address for Correspondence: Christopher R. Kieliszak, DO, OhioHealth Doctors Hospital, 5100 W Broad Street, Columbus, OH 43228 • E-mail: ckieliszak@gmail.com

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ORIGINAL CONTRIBUTION MLH1 and MSH2,5 followed by genetic testing. Two interesting cases of MTS are presented, followed by a discussion of the laboratory tests used to confirm the diagnosis. The establishment of an accurate diagnosis of MTS can guide the patient and the patientâ&#x20AC;&#x2122;s close relatives in making informed decisions about genetic testing. CASE REPORT

Patient 1 Figure 1. Right nasal ala revealing a multilobular, skincolored nodule with prominent telangiectasias.

Figure 2. Right nasolabial crease revealing keratoacanthoma.

A 52-year-old woman with a history of colorectal carcinoma, endometrial carcinoma, and squamous cell carcinoma of the forehead presented with a rapidly growing lesion on the right nasal ala. The patient reported a small papule in that location, which had been biopsied 2 years earlier, and was consistent with a fibrous papule. She denied any other new lesions. Her family history was notable for a father who had died of colorectal carcinoma in his 20s, and a brother who had also been diagnosed with colorectal carcinoma. Physical examination revealed a firm, nontender, 1.5cm, multilobular, skin-colored nodule with prominent telangiectasias on the right nasal ala (Figure 1), and a 6-mm, skin-colored papule with central, friable umbilication at the right nasolabial crease (Figure 2). Histology revealed the alar lesion to be sebaceous carcinoma (Figure 3), and the nasolabial crease lesion to be a keratoacanthoma. Suspicion of MTS was raised due to a family history suggestive of hereditary nonpolyposis colorectal carcinoma. This prompted IHC analysis and subsequent genetic testing, which confirmed a diagnosis of MTS.

(b)

(a)

Figure 3. Hematoxylin and eosinâ&#x20AC;&#x201C;stained low-power (a) and high-power (b) sections of a right nasal ala shave biopsy demonstrating basaloid tumor lobules in the dermis with multifocal sebaceous differentiation. There is moderate pleomorphism and atypia of the tumor cells, and numerous mitotic figures. Two foci of tumor appeared to be contiguous with the overlying epidermis, associated with superficial ulceration. The tumor also contains foci of squamous differentiation, random variably sized cysts, focal mucin, and occasional ductal structures. Clefting of tumor lobules away from surrounding stroma and well-developed peripheral palisading of basaloid cells was not appreciated. SKINmed. 2017;15:259â&#x20AC;&#x201C;264

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Patient 2 A 63-year-old male with a history of colorectal carcinoma and squamous cell carcinoma on the scalp presented with a 3-mm pink, friable papule on the central forehead (Figure 4) and a 5-mm violaceous firm papule on the left buttock (Figure 5). Biopsies were performed and histology demonstrated both lesions to be sebaceomas (Figure 6). IHC analysis of the sebaceomas and subsequent genetic testing confirmed MTS. MATERIALS AND METHODS Figure 4. Pink, friable 3-mm papule on the central forehead.

IHC staining IHC staining of the sebaceous neoplasms in both patients was performed using antibodies to MLH1, MSH2, MSH6, and PMS2 in order to assess for expressivity or absence of MMR proteins. Results for patient 1 demonstrated absent expression of the MMR proteins MSH2 and MSH6, suggestive of a deficient MMR function (Figure 7). Results for patient 2 also demonstrated absent expression of MSH2 and MSH6 (Figure 8). These findings warranted referral to the genetics service.

Genetic testing

Figure 5. Violaceous, firm 5-mm papule on the left buttock.

Quantitative polymerase chain reaction analysis and multiplex ligation-dependent probe amplification analysis were performed for sequencing of all exons and immediately adjacent intron regions of the MSH2 gene and comprehensive rearrangement testing of the MLH1 and MSH2 genes. The results from patient 1

(a)

(b)

Figure 6. Hematoxylin and eosin stain of central forehead lesion. Low power (a) reveals an attenuated epidermis with islands and trabeculae of a basaloid proliferation centered in the mid-dermis, with no overlying epidermal connection. On higher magnification (b), foci of sebaceous differentiation can be noted in the central portions of the basaloid islands. The predominance of basaloid cells is in keeping with a sebaceoma. Significant necrosis, atypia, and mitoses are not found. SKINmed. 2017;15:259â&#x20AC;&#x201C;264

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(a)

Figure 7. Patient 1: Immunohistochemical staining shows retained expression of the mismatch repair gene MLH1 (a), with loss of MSH2 (b).

(b)

(a)

Figure 8. Patient 2: Immunohistochemical staining shows retained expression of the mismatch repair gene MLH1 (a), with loss of MSH2 (b).

were consistent with a germline MSH2 mutation with deletions of exons 1–6, resulting in premature truncation of the MSH2 protein. The results for patient 2 also demonstrated a germline MSH2 mutation, with deletions of exons 8–15. These results are consistent with a diagnosis of MTS. DISCUSSION MTS is a rare, cancer-associated genodermatosis that is inherited in an autosomal dominant fashion and is often caused by germSKINmed. 2017;15:259–264

line mutations in the DNA MMR genes MLH1 and MSH2.9,10 The MMR proteins most intimately tied to MTS are MSH2, MLH1, and MHS6, although PMS2 and MLH3 are currently being investigated.11 Germline mutations are primarily found in the MMR genes MSH2 (on chromosome 2) and MLH1 (on chromosome 3).12 Deleterious mutations in MSH2 can confer as much as an 82% risk of colorectal carcinoma and 60% risk of endometrial carcinoma by age 70 years.13 First-degree relatives have a 50% chance of having this mutation. Although no isolated mutation in the MSH6 (on chromosome 2) gene has been

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demonstrated, mutation in the MSH2 gene can produce a lack of expression of the MSH6 protein, since MSH2 and MSH6 form a heterodimer.4

accordingly. The authors recommend that first-degree relatives should be evaluated, monitored, and counseled for early, routine cancer screening and genetic testing.

Laboratory investigations of patients suspected of having MTS include IHC staining of biopsy specimens for MMR gene proteins MLH1 and MSH2, and genetic testing by polymerase chain reaction analysis of DNA for microsatellite instability. Both IHC and polymerase chain reaction were performed in our patients.

CONCLUSIONs

The utility of immunohistochemistry is presently the subject of debate. Some authors believe that it should be universally used as a tool to examine sebaceomas, sebaceous adenomas, and carcinomas, and basal cell carcinomas with sebaceous differentiation and seboacanthomas.5 Additionally, some hospital protocols perform IHC testing for MSH2, MSH6, MLH1, and PMS2 on all suspected cases of MTS.11 Currently at our facility, reflex IHC testing for MMR genes is performed on all cases of sebaceous neoplasms as well as colorectal carcinomas.

The presence of sebaceous tumors should raise suspicion for an underlying visceral malignancy. Immunohistochemical staining of sebaceous neoplasms for MLH1, MSH2, MSH6, and PMS2 continue to aid in the diagnosis of MTS and should not be overlooked. Once the diagnosis of MTS has been established, patients should continue to have regular dermatologic examinations as well as appropriate cancer surveillance by specialists familiar with the management of these patients. In addition, genetic counseling should be offered to patients and their firstdegree relatives. References

Other investigators have found high false-positive rates of MMR IHC when performed on sebaceous neoplasms.3 As a result, they recommend that MMR IHC analysis be performed on visceral malignancies rather than sebaceous neoplasms. This recommendation is based on the fact that the specificity of MMR IHC with these tumor types is much higher than that of MMR IHC with sebaceous neoplasms.3 The Mayo Muir-Torre syndrome risk scoring system has recently been proposed for use in identification of high-risk patients presenting with sebaceous neoplasms that should prompt further evaluation for Lynch syndrome (hereditary nonpolyposis colorectal carcinoma).3 The risk scoring system uses clinical factors such as age, number of sebaceous neoplasms, personal history of any Lynch-related cancer, and family history of any Lynch-related cancer.3 The scoring system also discusses why MMR IHC of sebaceous neoplasms should not occur. Immunohistochemistry is a relatively inexpensive investigation14 that can be reliably used as a screening tool to dictate the necessity of further workup of MTS. Germline mutation analyses of MLH1, MSH2, MSH6, and PMS2 may then be performed to confirm the MMR mutation identified from IHC. Since cutaneous and visceral neoplasms can occur many years apart,7 early identification of patients with MTS allows for diagnosis and management of new primary malignancies. Appropriate preventive cancer screening programs can be implemented. The diagnosis of MTS in patient 1 raised clinical suspicion for additional primary malignancies, gynecological surveillance was able to identify an endometrial carcinoma, and the patient was treated SKINmed. 2017;15:259–264

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1 Muir EG, Bell AJ, Barlow KA. Multiple primary carcinomata of the colon, duodenum, and larynx associated with kerato-acanthomata of the face. Br J Surg. 1967;54:191–195. 2 Torre D. Multiple sebaceous tumors. Arch Dermatol. 1968;98:549–551. 3 Roberts ME, Riegert-Johnson DL, Thomas BC, et al. A clinical scoring system to identify patients with sebaceous neoplasms at risk for the Muir-Torre variant of Lynch syndrome. Genet Med. 2014;16:711–716. 4 Ponti G, Ponz de Leon M, Losi L, et al. Different phenotypes in Muir-Torre syndrome: Clinical and biomolecular characterization in two Italian families. Br J Dermatol. 2005;152:1335–1338. 5 Fernandez-Flores A. Considerations on the performance of immunohistochemistry for mismatch repair gene proteins in cases of sebaceous neoplasms and keratoacanthomas with reference to Muir-Torre syndrome. Am J Dermatopathol. 2012;34:416–422. 6 Esche C, Kruse R, Lamberti C, et al. Muir-Torre syndrome: Clinical features and molecular genetic analysis. Br J Dermatol. 1997;136:913–917. 7 Cohen PR, Kohn SR, Kurzrock R. Association of sebaceous gland tumors and internal malignancy: The MuirTorre syndrome. Am J Med. 1991;90:606–613. 8 Zhang L. Immunohistochemistry versus microsatellite instability testing for screening colorectal cancer patients at risk for hereditary nonpolyposis colorectal cancer syndrome. II. The utility of microsatellite instability testing. J Mol Diagn. 2008;10:301–307. 9 Schwartz RA, Torre DP. The Muir-Torre syndrome: A 25-year retrospect. J Am Acad Dermatol. 1995;33:90– 104. 10 Rajan Kd A, Burris C, Iliff N, Grant M, Eshleman JR, Eberhart CG. DNA mismatch repair defects and microsatellite instability status in periocular sebaceous carcinoma. Am J Ophthalmol. 2014;157:640-647.e1–e2.

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11 Lorente-Lavirgen AI, Morillo-Andujar M, Zulueta-Dorado T, Conejo-Mir J. Microsatellite and genetic instability in patients with Muir-Torre syndrome. Actas Dermosifiliogr. 2013;104:643–644. 12 de la Chapelle A. Genetic predisposition to colorectal cancer. Nat Rev Cancer. 2004;4:769–780.

13 Aarnio M, Sankila R, Pukkala E, et al. Cancer risk in mutation carriers of DNA-mismatch-repair genes. Int J Cancer. 1999;81:214–218. 14 Gould-Suarez M, El-Serag HB, Musher B, Franco LM, Chen GJ. Cost-effectiveness and diagnostic effectiveness analyses of multiple algorithms for the diagnosis of Lynch syndrome. Dig Dis Sci. 2014;59:2913–2926.

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Molecular Variations in Histologic Subtypes of Basal Cell Carcinoma Min Deng, MD;1 Amanda F. Marsch, MD;2 Vesna Petronic-Rosic, MD, MSc1 Abstract There are many molecular variations in the histologic subtypes of basal cell carcinoma (BCC); Ki67 and Bcl-2 expression differs among them and might relate to their prognostic features. The clinically notable friability and its histologic counterpart, retraction, are dependent on cell-cell adhesion and basement membrane characteristics, which may be altered in different ways depending on the tumor morphology and phenotype. Finally, we discuss the pathogenesis of BCCs and recent molecular advances with a review of new and upcoming molecular-based therapeutics. (SKINmed. 2017;15:265–268)

hy are morpheaform, infiltrative, and micronodular basal cell carcinomas (BCCs) more extensive at surgical excision than superficial and nodular subtypes? Are there molecular differences that lead to a greater proliferative rate? Are there differences in the cytokine and protein milieu that might allow greater invasion and spread in soft tissue? Or is the clinical appearance of these subtypes more subtle than their counterparts, leading to a delay in diagnosis?

loproteinase capable of breaking down extracellular matrix.4 Morpheaform BCCs also have significantly higher expression of αvβ6, an epithelium-specific integrin crucial for activation of transforming growth factor β1 (TGF-β1) and subsequent transformation of fibroblasts to myofibroblasts.5

In a retrospective study comparing primary BCCs with recurrence to nonrecurrent tumors, the percentage of cells expressing Ki67, a proliferative marker, was significantly higher in the former (25%) compared with the latter (12%).1 The biologic implication of this difference is unclear. The subtype in both groups was predominantly nodular; therefore, no statistical correlation could be made between histologic subtype and Ki67 expression. Other studies have found variable differences in Bcl-2 expression between BCC subtypes.2–4

Clinically, BCCs are friable and this relates to the histologic presence of retraction spaces around tumor islands. These changes are likely caused by impaired cell-cell and basement membrane attachments compared with normal keratinocytes. Cell-cell adhesion is mediated by adherens junctions, as well as desmosomes, both of which are significantly decreased in BCCs.6 The expression of E-cadherin, a calcium-dependent cell-cell adhesion molecule, was assessed in BCCs, and although the study found no association with patient age, sex, or tumor size, E-cadherin was found to be preserved in all superficial and nodular BCCs but significantly reduced in most infiltrative BCCs.7,8

Multiple studies have evaluated differences in stromal tissue between aggressive and nonaggressive BCCs. α-Smooth muscle actin (αSMA) staining in aggressive subtypes is significantly more intense and diffuse in the stromal cells surrounding aggressive BCCs.4,5 αSMA is typically expressed in myofibroblasts, which, when activated, can also produce stromelysin, a matrix metal-

Another study demonstrated noteworthy differences in desmosomal proteins with significantly reduced expression of both desmoglein I and plakoglobin in BCCs compared with controls. All 11 solid BCCs showed reduced expression whereas all three morpheaform BCCs and two superficial BCCs showed no expression, demonstrating possible microstructural differ-

From the Section of Dermatology, The University of Chicago Pritzker School of Medicine,1 and the Department of Dermatology, University of Illinois at Chicago College of Medicine,2 Chicago, IL Address for Correspondence: Vesna Petronic-Rosic, MD, MSc, The University of Chicago Section of Dermatology, 5841 S Maryland Avenue, MC 5067, Chicago, IL 60637 • E-mail: vrosic@medicine.bsd.uchicago.edu

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ences that may account for their varying phenotypes.9 Microscopically, BCCs also appear to have impaired basement membranes and hemidesmosomes. Compared with nodular BCC islands, which have a continuous basement membrane, the basement membrane surrounding morpheaform and basosquamous BCCs appears significantly reduced and focally absent.6 Within the basement membrane, hemidesmosomes are also significantly reduced, comprising only 7% of the basal area in tumor cells compared with 45% in normal keratinocytes, likely accounting for the classic retraction spaces surrounding tumor islands.6 Could these or other structural and cellular differences in BCCs account for the difference in tumor morphology and phenotype? Molecular Advances In the past 30 years, significant developments in molecular biology and genomics have allowed scientists to identify the crucial role of the hedgehog signaling pathway in the induction of BCCs. PTCH1 encodes Patched, a 12-pass transmembrane hedgehog receptor, which normally inhibits Smoothened (Smo), another transmembrane protein. When hedgehog, most commonly sonic hedgehog (Shh), is bound to Patched, however, this inhibition on Smo is removed and an intracellular signaling cascade is able to proceed with the activation of Gli1, transcription of TGF-β1, WNT, and PTCH1, and subsequent cell proliferation and BCC formation.10 Multiple linkage studies in families with basal cell nevus syndrome (Gorlin syndrome), where individuals develop BCCs among other phenotypic abnormalities starting at an early age, have mapped the genetic defects to 9q where PTCH1 resides.11–13 Up to 70% of sporadic BCCs now appear to have a similar defect in PTCH1 with no variation between BCC subtypes.14–16 Mutations in other proteins in the hedgehog pathway have also been reported in BCCs, including up to 20.6% of sporadic BCCs with activating mutations in Smo.17,18 Molecular-Based Therapeutics With the recent advances in our understanding of the hedgehog signaling pathway in the induction of BCCs,19 vismodegib, an Smo inhibitor, has been a new and promising molecularly targeted therapeutic agent in the treatment of advanced and aggressive BCCs. In a cohort of patients with metastatic BCC, 73% of patients treated with vismodegib 150 mg daily experienced tumor shrinkage with a median progression-free survival of 9.5 months.20 In a group of patients with locally advanced BCC, SKINmed. 2017;15:265–268

treatment with vismodegib 150 mg daily resulted in 43% of patients with >30% tumor shrinkage and 21% with complete response. Again, the median progression-free survival was 9.5 months.20 In a separate study assessing response rates in a cohort of patients with basal cell nevus syndrome, treatment with vismodegib 150 mg daily resulted in significant reduction in the number of new surgically eligible BCCs (mean, 2 vs 29 per year), reduction in size of existing BCCs, and decrease in palmoplantar pits, with differences evident within 1 month of treatment.21 The clinical response correlated both histologically and molecularly with reduction in residual BCC in biopsy specimens, a 90% decrease in GLI1 mRNA, and decreased proliferation as assessed by Ki67.21 Based on the results of these and many other clinical trials, vismodegib was approved by the Food and Drug Administration (FDA) on January 30, 2012, for the treatment of adults with metastatic or locally advanced BCC that recurred following surgery or who were not candidates for surgery, and who were not candidates for radiation.22 While promising as a therapeutic agent for advanced and difficult-to-treat cases, vismodegib is not without side effects. The most common adverse events include muscle spasms, alopecia, dysgeusia, decrease in weight, fatigue, nausea, decrease in appetite, and diarrhea, which can be severe and likely contributes to the high discontinuation rate in clinical trials.20,21,23 Other molecularly targeted therapies beyond vismodegib are now being actively researched for their therapeutic potential for BCCs. Despite the promising response to vismodegib, there are still many patients who do not respond and, even among patients who initially respond, many eventually develop clinical resistance.24 Possible explanations include novel mutations in Smo distinct from the inhibitory binding of vismodegib, novel mutations downstream of Smo signaling, other compensatory tumor mutations, and baseline molecular heterogeneity in tumor cells.22,24,25 While there are many additional compounds currently being tested for the treatment of advanced BCC, itraconazole, a common antifungal agent, and arsenic trioxide (ATO), a treatment for acute promyelocytic leukemia, are of particular clinical interest. Of a screening library of approximately 2400 FDA-approved and post–phase I drugs evaluated, itraconazole was relatively well-tolerated, with a mechanism that involves inhibition of Smo at a site distinct from vismodegib.26 In vitro studies are promising and show a synergistic effect on hedgehog signaling when used in conjunction with vismodegib as well as inhibitory activity on cells with acquired vismodegib-resistant SmoD477G mutations.25,26

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Although effective against cells with the SmoD477G mutation, treatment with itraconazole alone at maximum concentration nevertheless leaves residual activity (~30%); however, when used in conjunction with KAAD-cyclopamine, another Smo inhibitor, doses that are partially inhibitory for each individual agent result in complete inhibition of the signaling pathway.25 These results were also replicated in vivo. In a mouse model of SmoWT, treatment with itraconazole resulted in 96% tumor inhibition compared with controls on day 9 of treatment. Results were even more substantial when used in conjunction with ATO, which acts downstream of Smo in inhibiting the hedgehog signaling pathway, with inhibition of tumor growth and reduction of tumor volume by 72%.25,26 In contrast to vismodegib, which was ineffective in treating mouse models expressing SmoD477G, both itraconazole and ATO retained similar potency compared with SmoWT.25

References

A proof-of-concept phase 2 clinical trial of itraconazole treatment for BCC showed a 24% average decrease in tumor size, 45% decrease in Gli1 mRNA, and 45% decrease in Ki67 expression after treatment with 200 mg twice daily for 1 month. While the number of patients was small in this study, there were no cases of complete response. The clinical response rate was similar in patients treated with a lower dose of itraconazole (100 mg twice daily) for 2 months.27 The results are difficult to compare with those of vismodegib, because only once BCC within this cohort qualified as an advanced tumor; however, three of the patients had previously failed therapy with vismodegib, and all three had no clinical response or change in Ki67 expression to itraconazole. The number of patients was limited and the mechanism of vismodegib resistance was not evaluated in these cases. A pilot clinical trial evaluating the effect of ATO in treating patients with BCC was recently completed (NCT01791894). Because ATO acts downstream of Smo signaling in the hedgehog pathway, this may prove effective as a standalone therapy or as an adjunctive treatment with vismodegib for patients with advanced BCC. Conclusions Significant understanding of the pathophysiology of BCC has fueled the recent advancement of molecularly targeted therapies. In the next few years, further research involving the mechanisms of drug resistance, as well as any correlation with underlying histologic patterns, will allow better tailoring of these therapeutic targets. SKINmed. 2017;15:265–268

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1 Healy E, Angus B, Lawrence CM, Rees JL. Prognostic value of Ki67 antigen expression in basal cell carcinomas. Br J Dermatol. 1995;133:737–741. 2 Crowson AN, Magro CM, Kadin ME, Stranc M. Differential expression of the bcl-2 oncogene in human basal cell carcinoma. Hum Pathol. 1996;27:355–359. 3 Ramdial PK, Madaree A, Reddy R, Chetty R. bcl-2 protein expression in aggressive and non-aggressive basal cell carcinomas. J Cutan Pathol. 2000;27:283–291. 4 Adegboyega PA, Rodriguez S, McLarty J. Stromal expression of actin is a marker of aggressiveness in basal cell carcinoma. Hum Pathol. 2010;41:1128–1137. 5 Marsh D, Dickinson S, Neill GW, et al. alpha vbeta 6 Integrin promotes the invasion of morphoeic basal cell carcinoma through stromal modulation. Cancer Res. 2008;68:3295–3303. 6 Miller SJ. Biology of basal cell carcinoma (Part I). J Am Acad Dermatol. 1991;24:1-13. 7 Pizarro A, Benito N, Navarro P, et al. E-cadherin expression in basal cell carcinoma. Br J Cancer. 1994;69:157– 162. 8 Pizarro A. E-cadherin expression in basal cell carcinoma: association with local invasiveness but not with metastatic inefficiency. J Cutan Pathol. 2000;27:479–480. 9 Tada H, Hatoko M, Tanaka A, Kuwahara M, Muramatsu T. Expression of desmoglein I and plakoglobin in skin carcinomas. J Cutan Pathol. 2000;27:24–29. 10 Holíková Z, Massi D, Lotti T, Hercogová J. Insight into the pathogenesis of sporadic basal cell carcinoma. Int J Dermatol. 2004;43:865–869. 11 Gailani MR, Bale SJ, Leffell DJ, et al. Developmental defects in Gorlin syndrome related to a putative tumor suppressor gene on chromosome 9. Cell. 1992;69:111–117. 12 Compton JG, Goldstein AM, Turner M, et al. Fine mapping of the locus for nevoid basal cell carcinoma syndrome on chromosome 9q. J Invest Dermatol. 1994;103:178–181. 13 Johnson RL, Rothman AL, Xie J, et al. Human homolog of patched, a candidate gene for the basal cell nevus syndrome. Science. 1996;272:1668–1671. 14 Gailani MR, Ståhle-Bäckdahl M, Leffell DJ, et al. The role of the human homologue of Drosophila patched in sporadic basal cell carcinomas. Nat Genet. 1996;14:78–81. 15 Undén AB, Zaphiropoulos PG, Bruce K, Toftgård R, Ståhle-Bäckdahl M. Human patched (PTCH) mRNA is overexpressed consistently in tumor cells of both familial and sporadic basal cell carcinoma. Cancer Res. 1997;57:2336–2340. 16 de Zwaan SE, Haass NK. Genetics of basal cell carcinoma. Australas J Dermatol. 2010;51:81–92; quiz 93–84. 17 Reifenberger J, Wolter M, Weber RG, et al. Missense mutations in SMOH in sporadic basal cell carcinomas of the skin and primitive neuroectodermal tumors of the central nervous system. Cancer Res. 1998;58:1798–1803. 18 Lacour JP. Carcinogenesis of basal cell carcinomas: genetics and molecular mechanisms. Br J Dermatol. 2002;146 suppl 61:17–19.

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19 Gupta AK, Daigle D, Martin G. Basal cell carcinoma. Skinmed. 2014;12:33–38; quiz 38. 20 Sekulic A, Migden MR, Oro AE, et al. Efficacy and safety of vismodegib in advanced basal-cell carcinoma. N Engl J Med. 2012;366:2171–2179.

24 Chang AL, Oro AE. Initial assessment of tumor regrowth after vismodegib in advanced Basal cell carcinoma. Arch Dermatol. 2012;148:1324–1325.

21 Tang JY, Mackay-Wiggan JM, Aszterbaum M, et al. Inhibiting the hedgehog pathway in patients with the basal-cell nevus syndrome. N Engl J Med. 2012;366:2180–2188.

25 Kim J, Aftab BT, Tang JY, et al. Itraconazole and arsenic trioxide inhibit Hedgehog pathway activation and tumor growth associated with acquired resistance to smoothened antagonists. Cancer Cell. 2013;23:23– 34.

22 Cowey CL. Targeted therapy for advanced basal-cell carcinoma: vismodegib and beyond. Dermatol Ther (Heidelb). 2013;3:17–31.

26 Kim J, Tang JY, Gong R, et al. Itraconazole, a commonly used antifungal that inhibits Hedgehog pathway activity and cancer growth. Cancer Cell. 2010;17:388–399.

23 Axelson M, Liu K, Jiang X, et al. U.S. Food and Drug Administration approval: vismodegib for recurrent, locally advanced, or metastatic basal cell carcinoma. Clin Cancer Res. 2013;19:2289–2293.

27 Kim DJ, Kim J, Spaunhurst K, et al. Open-label, exploratory phase II trial of oral itraconazole for the treatment of basal cell carcinoma. J Clin Oncol. 2014;32:745– 751.

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 288)

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SELF ASSESSMENT EXAMINATION W. Clark Lambert, MD, PhD 1. Of the following, which histologic subtype of basal cell carcinoma tends to be less extensive on surgical excision than the others? a. Infiltrative. b. Micronodular. c. Morpheaform. d. Nodular. e. All of these histologic subtypes of basal cell carcinoma tend to be equally extensive on surgical excision. 2. Which of the following histologic characteristics of basal cell carcinoma appear to be related to increased friability of tumor tissue? a. Peripheral palisading of basaloid cell nuclei in tumor nests. b. Retraction (clefting) of tumor parenchyma away from tumor stroma. c. Both. d. Neither.

5. The PTCH-1 gene product, Patched, is a 12 pass transmembrane protein (ie, protein that passes through the cell membrane 12 times), which: a. Activates Smoothened so as to inhibit activation of Gli 1. b. Binds to Smoothened, another transmembrane protein. c. Serves as a receptor for Sonic Hedgehog. d. All of these. e. None of these.

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

3. Which of the following histologic subtypes of basal cell carcinoma tends to have a higher incidence of mutations in the PTCH-1 gene? a. Infiltrative. b. Micronodular. c. Morpheaform. d. Nodular. e. All of these histologic subtypes of basal cell carcinoma tend to be equally likely to have a mutation in the PTCH-1 gene.

4. Immunostaining for which of the following is significantly more diffuse and intense in the tumor and/or stroma of aggressive, vs nonaggressive, basal cell carcinomas? a. Adherens junctions. b. α-Smooth muscle actin. c. Basement membrane surrounding tumor islands. d. Desmosomes. e. Hemidesmosomes.

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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Breast & Body Practice Management Facial Rejuvenation Aesthetic Dermatology Cybersecurity Update New Technology Update Hot Topic Sessions

SAVE THE DATE

THE 2ND GLOBAL AESTHETICS CONFERENCE Miami Beach

November 2nd - 5th, 2017

Co-Chairs Renato Saltz, MD FACS and S. Randolph Waldman, MD www.globalaestheticsconference.com Up to 33 CME Credits Available

MEDIA PARTNER

July/August 2017

Volume 15 • Issue 4

Core curriculum Virendra N. Sehgal, MD, FNASc, FAMS, Section Editor

Techniques for Optimizing Surgical Scars, Part 1: Wound Healing and Depressed/Atrophic Scars Sailesh Konda, MD;1,2 Kathryn Potter, MD;1 Vicky Zhen Ren, MD;3 Apphia Lihan Wang, MD;4 Aditya Srinivasan, MS;3 Suneel Chilukuri, MD5

Surgical management of benign or malignant cutaneous tumors may result in noticeable scars that are of great concern to patients, regardless of sex, age, or ethnicity. Techniques to optimize surgical scars are discussed in this three-part review. In part 1, an overview of the importance of preoperative planning, intraoperative technique, and pathophysiology of wound healing is followed by a discussion of scar revision options for depressed/atrophic scars. Scar revision options for these scars include dermabrasion, needling and subcision, punch excision and grafts, fillers, nonablative fractional lasers, ablative and fractional ablative lasers, and platelet-rich plasma (PRP). This review examines the scar revision outcomes for each technique, discusses potential adverse effects, and highlights the importance of further studies to optimize postsurgical scar revision. (SKINmed. 2017;15:271–276)

any treatment options are available for surgical scars; however, efforts to minimize cutaneous scarring should begin with proper surgical technique, which allows for optimal wound healing. Relaxed skin tension lines are formed by the perpendicular pull of underlying muscles and naturally divide the face into cosmetic units. Within each cosmetic unit, skin texture and color is generally consistent, whereas greater variations occur between different cosmetic units.1 To increase the likelihood of producing a well-camouflaged, inconspicuous scar, incisions should be positioned along, rather than across, relaxed skin tension lines and confined within single cosmetic subunits. During surgery, the skin should be handled delicately with skin hooks to minimize trauma to wound edges. If toothed forceps are used, care should be taken to grab the dermis or fascia rather than the relatively cellular epidermis, to avoid permanent scarring. Overcoagulation along the wound edge should also be avoided, as this could adversely affect the appearance of a scar as well as increase the risk of infection and abnormal wound healing.1 Proper closure at the conclusion of surgery should yield a

well-approximated and everted wound edge with minimal, uniformly distributed tension. Although the use of tissue adhesives for closure has increased, a Cochrane review found that sutures are faster to use and more effective at minimizing dehiscence.2 Ideally, suturing should provide enough strength to avoid dehiscence and enough flexibility to allow for wound edema.3 Interrupted vertical and horizontal mattress sutures promote eversion and are beneficial when skin edges have to be brought together over a distance and closed under tension. If these sutures are removed early, “railroad” scars can be minimized.4 Intradermal buried sutures without additional skin suturing are also safe and produce good cosmetic results.5 No significant differences in the long-term cosmetic outcome between nonabsorbable and absorbable sutures have been found.6 Interestingly, injection of botulinum toxin into facial surgical wounds has allowed for improved cosmetic outcomes by decreasing tension and movement, and allowing for the use of finer sutures.7–9 However, despite excellent surgical technique, poor healing may sometimes contribute to obvious scars that are candidates for scar revision.

From the Department of Dermatology, University of Florida College of Medicine, Gainesville, FL;1 the Department of Dermatology, Loma Linda University Medical Center, Loma Linda, CA;2 the Department of Dermatology, Baylor College of Medicine, Houston, TX;3 the Department of Dermatology, University of Alabama at Birmingham School of Medicine, Birmingham, AL;4 and Refresh Dermatology, Houston, TX5 Address for Correspondence: Suneel Chilukuri, MD, Refresh Dermatology, 4914 Bissonnet Street, #100A, Houston, TX 77401 • Email: dermsurg@gmail.com

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PATHOPHYSIOLOGY OF WOUND HEALING Wound healing is characterized by three predictable and overlapping phases: inflammation, proliferation, and remodeling. The inflammatory phase begins within minutes of induction of a cutaneous wound and lasts for days. The first step is hemostasis, which involves the formation of a fibrin plug and coagulation. Activated platelets adhere and aggregate at the site of vessel damage, eventually forming a platelet plug. Platelet aggregation also triggers the intrinsic coagulation cascade, which aids in the formation of a fibrin plug to control bleeding. The cellular response of the inflammatory phase is characterized by the recruitment of neutrophils and monocytes by chemotactic factors generated during hemostasis and released by mast cells. Initially, neutrophils cleanse the wound of bacteria and debris via phagocytosis and protease secretion. Within a few days, however, circulating monocytes invade the wound site, transform into activated tissue macrophages, and become the predominant cell type. In addition to phagocytosing bacteria, cells, and tissue, macrophages secrete growth factors and cytokines that coordinate granulation tissue formation in the proliferative phase.10 The proliferative phase begins within days and lasts for weeks. It is characterized by reepithelialization, fibroplasia, and angiogenesis. During reepithelialization, epidermal keratinocytes from the wound margin or residual skin appendages migrate into the wound area and proliferate to cover the wound. This is followed by reconstitution of the basement membrane, differentiation into a well-stratified epidermis, and formation of an intact basement zone between the epidermis and dermis. Reconstitution of the dermis begins within 3 to 4 days of cutaneous injury, and is characterized by replacement of the fibrin plug with granulation tissue composed of macrophages, fibroblasts, and endothelial cells.10 Macrophages, via the secretion of platelet-derived growth factor and transforming growth factor-beta 1, induce fibroblasts to proliferate in the wound, where they lay down a type III collagen-rich matrix. This provides a framework for endothelial cells to proliferate and lay down new vessels during angiogenesis.11 The remodeling phase occurs throughout the wound healing process as the early fibrin clot is replaced by loose type III collagen-rich granulation tissue, which is then replaced by a dense type I collagen-dominant scar. Remodeling occurs over a period of 1 year or longer. However, a maximum of 70% to 80% of baseline tensile strength is generally reached by 3 months.12 Wound contraction begins soon after wound induction and peaks at 2 weeks, serving to reduce the surface area of the scar.11 The end result is structurally and functionally similarâ&#x20AC;&#x201D;but not identicalâ&#x20AC;&#x201D;to intact skin.10 SKINmed. 2017;15:271â&#x20AC;&#x201C;276

This cascade of wound healing can lead to increased or decreased tissue formation and ultimately scar formation. Hypertrophic scars and keloids are secondary to increased collagen deposition, which, in the latter, can expand beyond the borders of the original wound. Atrophic scars are the results of a loss or damage of tissue. Scars may also undergo color changes, such as erythema, hyperpigmentation, or hypopigmentation. These changes may make scars more prominent, which may prompt patients to seek treatment. The choice of treatment depends largely on the type of scar, with the ultimate goal of improving texture and color homogeneity. Notably, most of the literature on the treatment of atrophic scars has focused on acne scarring, an endogenous nonsurgical insult, which may be extrapolated to the treatment of postsurgical atrophic scars. DEPRESSED/ATROPHIC SCARS

Dermabrasion Dermabrasion was established as a treatment for scarring in the 1950s.13,14 During dermabrasion, a high-speed brush, diamond cylinder, fraise, or silicone carbide sandpaper is used to manually remove tissue in a controlled and operator-dependent manner to the level of the dermis without any thermal injury. After treatment, reepithelialization occurs via migration of stem cells from adnexal structures, including hair follicles, sebaceous glands, and sudoriferous glands. Hypertrophic scars and keloids have a poor response to dermabrasion due to their lack of adnexal structures. Forty-eight patients with acne scarring were treated with dermabrasion, and the cosmetic result was excellent (>60% improvement) in 15, good (35% to 60% improvement) in 20, and poor (<35% improvement) in 13.15 Seven patients with atrophic acne scars taking isotretinoin underwent dermabrasion, and all patients had excellent scar revision at their 6-month follow-up.16 Additionally, a series of 192 full-thickness skin grafts of the nose, periorbital area, and ear, using age- and site-matched controls, were treated with dermabrasion 6 to 8 months after grafting. Dermabrasion of elevated grafts in all locations was more likely to result in resolution of the elevation compared to control participants, with the nose having the greatest improvement. Interestingly, grafts that were depressed 6 months after the grafting procedure remained depressed regardless of whether dermabrasion had been performed.17 Electron microscopic and immunohistochemical studies have revealed an increase in collagen bundle density and size with a reorientation of fibers parallel to the epidermal surface, which can contribute to improved scar texture. There is also an upregulation of tenascin expression throughout the papillary dermis and

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alpha-6/beta-4 integrin subunit on the keratinocytes throughout the stratum spinosum.18 Reepithelialization is usually complete within 7 to 10 days, and erythema can last for up to 4 weeks. Other side effects include milia, bacterial or viral infections, hypertrophic or keloidal scarring, telangiectasias, photosensitivity, treatment demarcation lines, and dyspigmentation.19 Dermabrasion remains an important treatment modality due to its predictable results and minimal morbidity.

Needling and subcision Skin needling, also termed needle dermabrasion or collagen induction therapy, can be used to treat atrophic scars. During skin needling, a device comprised of a barrel with many small needles is rolled along areas of scarring. This results in many micropunctures of the skin, which is thought to induce platelet-derived growth factor, transforming growth factor-alpha, transforming growth factor-beta, and fibroblast growth factor, which stimulate collagen production.20 In an early study, a 10-mm barrel with 96 needles (1.5 mm in length) in four rows was rolled across the area of acne scarred skin four times in four different directions. All 32 patients in the study were treated with two sessions and showed an improvement in acne scarring.20 In contrast to needling, subcision is a technique in which a needle is inserted into the dermis, resulting in the release of fibrotic strands under atrophic scars. A tri-beveled hypodermic needle is maneuvered under the scar to release the base of the scar, resulting in the base elevation. In addition to allowing for scar elevation, this technique also induces wound healing and formation of connective tissue.21 Subcision can also be used in combination with suctioning. Re-depression of scars after subcision can occur up to 10 days after the procedure. Forty-six patients completely followed a protocol in which suction sessions were started the third day after subcision and continued every other day for 2 weeks. The patients had a 60% to 90% improvement in the depth and size of their scars. Potential complications of this procedure included discoloration, which resolved after 2 months, and hypertrophic scars, which occurred in 1.7% of the scars treated in this study.22

Punch excision and grafts Punch excision is a suitable option for atrophic acne scars, such as ice pick or deep boxcar scars.23 After local anesthesia, a punch biopsy with a diameter ranging from 1.5 to 4 mm is used to excise the entire scar, and is followed by a sutured closure of the new defect.23 With punch grafting, the atrophic scar is removed with a punch biopsy, a donor graft is obtained from postauricular skin, and the graft is placed in the recipient site so that it will SKINmed. 2017;15:271â&#x20AC;&#x201C;276

be level or slightly elevated.24,25 After 3 to 4 weeks, dermabrasion can be used to treat any surface texture irregularities. A variation of this procedure involves superficial dermabrasion of the surrounding scar area and the graft itself before correction of the defect to give a better aesthetic appearance.26 These techniques may be expanded to include the revision of larger atrophic scars secondary to excisional and flap surgery.27 If a scar falls near a hairline or in hair-bearing skin, follicular unit micrografting techniques may be used to camouflage the scar. Two or three follicular units can be prepared from a harvested donor strip and placed in recipient sites, taking care to match the direction and density of the surrounding hair follicles.28

Fillers Over the past decade, the use of dermal fillers has grown rapidly due to their effectiveness, versatility, and favorable safety profile. Dermal fillers have the ability to quickly replace lost volume in atrophic scars. While injectable collagens and hyaluronic acid preparations are viable options for mild atrophic scars, they tend to last only in the short term, for 3 to 6 months. Longer acting dermal fillers, such as calcium hydroxyapatite and injectable poly-l-lactic acid, can stimulate collagen production and are used off-label for larger areas of atrophic scarring. Calcium hydroxyapatite is a semi-permanent filler that lasts approximately 9 to 12 months. Ten patients with saucerized acne scars were treated with calcium hydroxyapatite, and, after 12 months, three patients had greater than 75% improvement, with six patients showing 50% to 75% improvement.29 Poly-l-lactic acid was initially approved for the treatment of HIV-associated lipodystrophy. The favorable results obtained in this subset of patients led to its use in use in immunocompetent individuals for larger areas of acne scarring, with clinical benefits persisting for up to 2 years. Twenty patients with moderate to severe acne or varicella scars were treated with poly-l-lactic acid and noted significant reductions in acne scar size and severity over the course of seven treatment sessions, with a maximum reduction of 46.4%.30 More recently, polymethylmethacrylate was used off-label to treat atrophic acne scars after subcision in 14 patients, and investigator ratings showed that 96% of the atrophic acne scars had some degree of improvement, with most patients noting a moderate improvement.31 A skin test must be performed before administration of polymethylmethacrylate. A case series evaluated fillers for postsurgical depressed scars after four patients underwent Mohs micrographic surgery for basal cell carcinomas and presented with depressed scars at their 3-month follow-up. Their scars were reshaped with either hyaluronic acid or calcium hydroxyapatite, and all four patients were

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extremely satisfied with the aesthetic improvement.32 Side effects of fillers include discomfort, bruising, bleeding, swelling, infection, Tyndall effect (more common with hyaluronic acid), rare allergic reactions, skin necrosis, and a rare risk of blindness.33 More studies on a larger scale are needed to further evaluate fillers in the treatment of postsurgical depressed scars.

Nonablative fractional lasers Nonablative fractional lasers are commonly employed in the treatment of atrophic scars, and have been become an attractive alternative to ablative lasers due to less downtime and a lower incidence of side effects. Nonablative fractional lasers create hundreds of microthermal treatment zones (MTZs) as far down as the reticular dermis. These microthermal treatment zones are in regularly spaced arrays and separated by islands of untreated skin. This allows for rapid migration and proliferation to repair the damaged areas within 1 day, and postoperative erythema usually resolves in 3 to 4 days. A retrospective analysis of 82 patients (Fitzpatrick skin types III to V) with acne scars treated with either the nonablative fractional 1550-nm or ablative fractional CO2 lasers found that 35% of patients treated with the nonablative fractional 1550nm laser and 37% of patients treated with ablative fractional CO2 laser attained more than 50% improvement. These results prove that both are effective treatment options with similar outcomes.34 An erbium-doped 1550-nm fractional photothermolysis laser was used to treat acne scars in 29 patients (Fitzpatrick skin types I to V) with two to six treatments at 1-month intervals. Five patients had an improvement of greater than 75% in acne scarring, five patients had a 25% to 50% improvement, and one patient had less than 25% improvement.35 Another study involved 30 Chinese patients with atrophic acne scars undergoing split-face treatment with the 1550-nm fractional Er:Glass laser at 20-day intervals for a total of four treatments. The treated side of the face showed significant improvement at 12 weeks posttreatment follow-up compared to the control side. Side effects noted in this study were temporary irritation and erythema.36 Additionally, a case report described a 49-year-old woman with a depressed right nasal alar scar resulting from Mohs micrographic surgery followed by secondary intention healing. Starting at 2 months postoperatively, she was treated a total of five times at 1-month intervals, resulting in a nearly imperceptible scar.37 Side effects of fractional laser photothermolysis include acneiform eruptions (1.87%), herpes simplex infection (1.77%), erosions SKINmed. 2017;15:271â&#x20AC;&#x201C;276

(1.35%), and rarely, post-inflammatory hyperpigmentation, erythema, edema, and dermatitis.38

Ablative and fractional ablative lasers The CO2 laser emits light at a wavelength of 10,600 nm, which targets extracellular and intracellular water, and can penetrate to depths of 20 to 30 Îźm with thermal damage of 50 to 150 Îźm. This allows for the removal of the epidermis and partial-thickness dermis, which are composed of nearly 90% water. Skin reepithelialization is usually apparent after 2 weeks, although continued improvement may be seen for up to 18 months. While greater penetration depths are more efficacious in removing scars, care must be taken to not destroy the base of hair follicles, as this can impede skin regeneration. Sixty patients with moderate to severe atrophic facial acne scars were treated with a single-pass CO2 laser treatment, with an average improvement of 69% at 1 month, 67% at 6 months, 73% at 12 months, and 75% at 18 months, with continued neocollagenesis and remodeling evident on histologic examination.39 The forehead, perioral, and medial cheek regions have been found to produce superior results in comparison to the temple and lateral area of the cheek.40 Complete healing occurs between 10 and 21 days posttreatment. Side effects include protracted healing, prolonged erythema lasting up to 4.5 months, dyspigmentation, dermatitis, milia, and acne.41 The Er:YAG laser emits light at a shorter wavelength of 2936 nm, which corresponds to the peak absorption coefficient of water. This limits the zone of thermal injury and allows for a gentler form of ablation than the CO2 laser. This produces faster postoperative recovery and a mitigated side effect profile; however, there is less intraoperative hemostasis and less dermal remodeling. This has led to the development of the dual-mode Er:YAG laser, which combines ablative and coagulative pulses to produce greater collagen contracture and improved hemostasis. Twentyfive patients with moderate to severe atrophic facial acne scars were treated with a dual-mode Er:YAG laser, and the average clinical grading score reflected good to excellent results.42 Complete healing occurs between 5 and 7 days post-treatment. Side effects include erythema, transient hyperpigmentation, and rare delayed hypopigmentation. Recently, fractional ablative lasers, which use Er:YAG or CO2 as a medium, have emerged as an alternative to ablative lasers due to the reduced recovery time and more favorable side effect profile. Similar to nonablative fractional lasers, ablative fractional lasers also create microthermal treatment zones with islands of untreated skin; however, these microthermal treatment zones

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July/August 2017 also vaporize the stratum corneum and are full thickness. Sixty patients (Fitzpatrick skin types II to IV) were treated with a fractional CO2 laser every 6 weeks for a total of three to four sessions. When scars were assessed at 6 months posttreatment, 26 patients (43.3%) had an excellent response, 15 patients (25%) a good response, and 19 patients (31.7%) a poor response, with the best response seen with rolling and superficial boxcar scars.43 Fractional CO2 lasers have an abated side effect profile with decreased thermal injury and recovery time and less risk of dyspigmentation, scars, and persistent erythema. Reactivation of herpes simplex infection is a risk after treatment using any of the ablative and fractional ablative lasers, and perioperative prophylaxis should be considered.

discuss scar revision options for erythema, hyperpigmentation, and hypopigmentation. References

Platelet-rich plasma PRP contains various growth factors and cytokines that may assist in wound healing and reduce the duration of transient side effects. PRP has been proven to reduce erythema and hasten wound healing after autologous application of PRP to fractional CO2 laser–treated sites. Twenty-five patients were treated with fractional ablative CO2 on the upper inner areas of the arms bilaterally. A randomly allocated side subsequently received treatment with PRP prepared from 10 mL of whole blood, and the contralateral side received normal saline as a control. The PRP-treated side recovered faster, with a lower erythema and melanin index.44 Another study extrapolated this and compared the efficacy of topical versus intradermal PRP after fractional ablative CO2 in 30 patients undergoing split-face therapy. Assessment at 6 months showed that PRP and fractional ablative CO2 produced a significantly better response, fewer side effects, and quicker recovery than fractional ablative CO2 laser-treated alone.45 CONCLUSIONS Preoperative planning and intraoperative technique are paramount to minimizing surgical scars, which are a result of a complex wound healing process. When a scar’s visibility is of concern to a patient, we have an armamentarium of scar revision techniques to diminish its visibility and improve patient satisfaction. Part 1 of this three-part review has focused on scar revision for depressed or atrophic scars. Although a significant portion of the reviewed literature has revolved around the treatment of acne scarring, these techniques may be extrapolated to atrophic postsurgical scars. Techniques employed included dermabrasion, needling and subcision, punch excision and grafts, fillers, nonablative fractional lasers, ablative and fractional ablative lasers, and PRP. Part 2 will discuss scar revision options for hypertrophic scars and keloids, and part 3 will SKINmed. 2017;15:271–276

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1 Poblete-Lopez C. Basic excisional surgery. In: Vidimos AT, Ammirati CT, Poblete-Lopez C, eds. Requisites in Dermatology: Dermatologic Surgery. Philadelphia, PA: Elsevier; 2009:123–137. 2 Coulthard P, Esposito M, Worthington HV, et al. Tissue adhesives for closure of surgical incisions. Cochrane Database Syst Rev. 2010;(5):CD004287. 3 Moy RL, Waldman B, Hein DW. A review of sutures and suturing techniques. J Dermatol Surg Oncol. 1992;18:785– 795. 4 Zuber TJ. The mattress sutures: Vertical, horizontal, and corner stitch. Am Fam Physician. 2002;66:2231–2236. 5 Hohenleutner U, Egner N, Hohenleutner S, Landthaler M. Intradermal buried vertical mattress suture as sole skin closure: Evaluation of 149 cases. Acta Derm Venereol. 2000;80:344–347. 6 Al-Abdullah T, Plint AC, Fergusson D. Absorbable versus nonabsorbable sutures in the management of traumatic lacerations and surgical wounds: A meta-analysis. Pediatr Emerg Care. 2007;23:339–344. 7 Gassner HG, Sherris DA, Otley CC. Treatment of facial wounds with botulinum toxin A improves cosmetic outcome in primates. Plast Reconstr Surg. 2000;105:1948– 1953; discussion 1954–1955. 8 Gassner HG, Brissett AE, Otley CC, et al. Botulinum toxin to improve facial wound healing: A prospective, blinded, placebo-controlled study. Mayo Clin Proc. 2006;81:1023– 1028. 9 Wilson AM. Use of botulinum toxin type A to prevent widening of facial scars. Plast Reconstr Surg. 2006;117:1758–1766; discussion 1767–1768. 10 Li J, Chen J, Kirsner R. Pathophysiology of acute wound healing. Clin Dermatol. 2007;25:9–18. 11 Profyris C, Tziotzios C, Do Vale I. Cutaneous scarring: Pathophysiology, molecular mechanisms, and scar reduction therapeutics. Part I. The molecular basis of scar formation. J Am Acad Dermatol. 2012;66:1–10; quiz 11–12. 12 Ebner JA, Maytin EV. Cutaneous wound healing. In: Vidimos AT, Ammirati CT, Poblete-Lopez C, eds. Requisites in Dermatology: Dermatologic Surgery. Philadelphia, PA: Elsevier; 2009:85. 13 Gold MH. Dermabrasion in dermatology. Am J Clin Dermatol. 2003;4:467–471. 14 Lawrence N, Mandy S, Yarborough J, Alt T. History of dermabrasion. Dermatol Surg. 2000;26:95–101. 15 Savant SS. Facial dermabrasion in acne scars and genodermatoses – a study of 65 patients. Indian J Dermatol Venereol Leprol. 2000;66:79–84. 16 Bagatin E, dos Santos Guadanhim LR, Yarak S, Kamamoto CS, de Almeida FA. Dermabrasion for acne scars during treatment with oral isotretinoin. Dermatol Surg. 2010;36:483–489.

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17 Robinson JK. Improvement of the appearance of fullthickness skin grafts with dermabrasion. Arch Dermatol. 1987;123:1340–1345.

33 Cohen JL. Understanding, avoiding, and managing dermal filler complications. Dermatol Surg. 2008;34(suppl 1):S92–S99.

18 Harmon CB, Zelickson BD, Roenigk RK, et al. Dermabrasive scar revision. Immunohistochemical and ultrastructural evaluation. Dermatol Surg. 1995;21:503–508.

34 Alajlan AM, Alsuwaidan SN. Acne scars in ethnic skin treated with both nonablative fractional 1,550 nm and ablative fractional CO2 lasers: Comparative retrospective analysis with recommended guidelines. Lasers Surg Med. 2011;43:787–791.

19 Rivera AE. Acne scarring: A review and current treatment modalities. J Am Acad Dermatol. 2008;59:659–676. 20 Fabbrocini G, Fardella N, Monfrecola A, Proietti I, Innocenzi D. Acne scarring treatment using skin needling. Clin Exp Dermatol. 2009;34:874–879. 21 Orentreich DS, Orentreich N. Subcutaneous incisionless (subcision) surgery for the correction of depressed scars and wrinkles. Dermatol Surg. 1995;21:543–549. 22 Aalami Harandi S, Balighi K, Lajevardi V, Akbari E. Subcision-suction method: A new successful combination therapy in treatment of atrophic acne scars and other depressed scars. J Eur Acad Dermatol Venereol. 2011;25:92–99. 23 Batra RS. Surgical techniques for scar revision. Skin Therapy Lett. 2005;10:4–7. 24 Johnson WC. Treatment of pitted scars: punch transplant technique. J Dermatol Surg Oncol. 1986;12:260– 265. 25 Solotoff SA. Treatment for pitted acne scarring—postauricular punch grafts followed by dermabrasion. J Dermatol Surg Oncol. 1986;12:1079–1084. 26 Mancuso A, Farber GA. The abraded punch graft for pitted facial scars. J Dermatol Surg Oncol. 1991;17:32–34. 27 Dzubow LM. Scar revision by punch-graft transplants. J Dermatol Surg Oncol. 1985;11:1200–1202. 28 Reed ML, Grayson BH. Single-follicular-unit hair transplantation to correct cleft lip moustache alopecia. Cleft Palate Craniofac J. 2001;38:538–540. 29 Goldberg DJ, Amin S, Hussain M. Acne scar correction using calcium hydroxylapatite in a carrier-based gel. J Cosmet Laser Ther. 2006;8:134–136. 30 Beer K. A single-center, open-label study on the use of injectable poly-l-lactic acid for the treatment of moderate to severe scarring from acne or varicella. Dermatol Surg. 2007;33(suppl 2):S159–S167. 31 Epstein RE, Spencer JM. Correction of atrophic scars with ArteFill: An open-label pilot study. J Drugs Dermatol. 2010;9:1062–1064. 32 Kasper DA, Cohen JL, Saxena A, Morganroth GS. Fillers for postsurgical depressed scars after skin cancer reconstruction. J Drugs Dermatol. 2008;7:486–487.

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35 Chrastil B, Glaich AS, Goldberg LH, Friedman PM. Second-generation 1,550-nm fractional photothermolysis for the treatment of acne scars. Dermatol Surg. 2008;34:1327–1332. 36 Yang Q, Huang W, Qian H, et al. Efficacy and safety of 1550-nm fractional laser in the treatment of acne scars in Chinese patients: A split-face comparative study. J Cosmet Laser Ther. 2016;18:312–316. 37 Schulz KK, Walling HW. Fractional photothermolysis improves a depressed alar scar following Mohs micrographic surgery. J Drugs Dermatol. 2010;9:66–67. 38 Graber EM, Tanzi EL, Alster TS. Side effects and complications of fractional laser photothermolysis: Experience with 961 treatments. Dermatol Surg. 2008;34:301–305; discussion 305–307. 39 Walia S, Alster TS. Prolonged clinical and histologic effects from CO2 laser resurfacing of atrophic acne scars. Dermatol Surg. 1999;25:926–930. 40 Trimas SJ, Boudreaux CE, Metz RD. Carbon dioxide laser abrasion. Is it appropriate for all regions of the face? Arch Facial Plast Surg. 2000;2:137–140. 41 Nanni CA, Alster TS. Complications of carbon dioxide laser resurfacing. An evaluation of 500 patients. Dermatol Surg. 1998;24:315–320. 42 Tanzi EL, Alster TS. Treatment of atrophic facial acne scars with a dual-mode Er:YAG laser. Dermatol Surg. 2002;28:551–555. 43 Majid I, Imran S. Fractional CO2 laser resurfacing as monotherapy in the treatment of atrophic facial acne scars. J Cutan Aesthet Surg. 2014;7:87–92. 44 Na JI, Choi JW, Choi HR, et al. Rapid healing and reduced erythema after ablative fractional carbon dioxide laser resurfacing combined with the application of autologous platelet-rich plasma. Dermatol Surg. 2011;37:463–468. 45 Gawdat HI, Hegazy RA, Fawzy MM, Fathy M. Autologous platelet rich plasma: Topical versus intradermal after fractional ablative carbon dioxide laser treatment of atrophic acne scars. Dermatol Surg. 2014;40:152–161.

Techniques for Optimizing Surgical Scars, Part 1

July/August 2017

Volume 15 • Issue 4

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

Fading Signals: How Long Does Antigenicity in Immunohistochemical Staining Last? Ann M. John, BA; Heather M. Holahan, MD; Parmvir Singh, BS; Marc Z. Handler, MD; Stella Chung, MS; W. Clark Lambert, MD, PhD “The truth will set you free, but first it will make you miserable.”—James A. Garfield

mmunohistochemistry is a pivotal tool in pathology, allowing determination of diagnosis, prognosis, therapeutic options, and probable treatment response by directly observing protein expression. Standardized methods of fixing, processing, and storing slides are essential to determine the validity of a stain. While methods for short-term use of sections are well established, pathologists may need to store immunostained slides and revisit them after several months or years. Long-term storage supports continuity of patient care and provides a resource for retrospective research; however, the longevity of immunohistochemistry signals is unclear, with reports of diminished quantity and quality of signals over time.1–3

Various factors have been implicated in the deterioration of signals. Antigens located in the nucleus, endoplasmic reticulum, cytoplasm, and cell membrane are all subject to diminished antigenicity over time;4 moreover, each stain is subject to a different degree of diminution. For instance, epithelial membrane antigen, smooth muscle antigen, S-100, CD45, CD20, and CD30 maintain their antigenicity for at least a year, while p53, estrogen receptor, progesterone receptor, and HER-2/neu demonstrate decreased staining intensity and quantity of positive cells within the same time frame.2,4–7 Ki-67 shows decreased antigenicity in as little as 3 months.3 The type of antibody, polyclonal versus monoclonal, has not been shown to affect antigenicity.8

AN ILLUSTRATIVE CASE A 67-year-old woman developed an asymptomatic, enlarging nodule on her left lower eyelid over a 3-month interval. On physical examination, the lesion was soft, flesh colored, and nonulcerated. Pathologic examination revealed a highly cellular lesion composed of small cells with large nuclei (Figures 1 and 2). The lesion was excised with no definitive pathologic diagnosis rendered. Five years afterwards, the patient developed metastatic lesions in her lungs with the origin unknown. The case was then referred to a consulting dermatopathologist (WCL), who rendered a diagnosis of trabecular (Merkel cell) carcinoma, based on the presence of cloudy (“murky”) cells within the lesion, trabeculae within the lesion, and areas of necrosis, cytological atypia, and numerous mitoses (Figures 1 and 2). This was not supported, however, by a CK20 immunostain of the lesion, carried out on sections cut from the 5-year-old paraffin block, which were negative. COMMENT Regarding cytokeratin 20, nitrogen storage and paraffin coating of slides together may result in a 4% loss of cytokeratin 20 antigenicity after 3 months. Storage under ambient oxygen conditions results in 88% signal loss during this interval.9

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

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PERILS OF DERMATOPATHOLOGY Storage of sections at low temperatures allows for longer preservation of signals, with reports of significantly reduced loss of staining in slides stored at 4°C, compared to slides stored at room temperature.5,7 Light exposure, in addition to heat from light sources, also results in antigen degradation.10 Shorter slide processing time results in loss of antigenicity, most likely because it allows for the retention of endogenous water in tissue sections. This causes antigen degradation through hydrolysis. 7 The composition of tissue fixative affects antigen deterioration, with reports of decreased antigenicity in slides fixed in 10% formalin with 70% alcohol and in 10% formalin and after fixation with Bouin solution. 4,5 Newer fixatives, including the Hepes-glutamic acid buffer mediated Organic solvent Protection Effect (HOPE) fixative, zinc fixation, ethanol fixation, and Universal Molecular Fixative (UMFix), are currently being investigated as ways to preserve antigenicity.9 Prolonged fixation time can also lead to diffusion artifacts and may damage antigenicity,3 while vacuum packaging of slides with dessicant has been shown to preserve antigenicity. 6,7

Figure 1. Trabecular (Merkel cell) carcinoma. Note trabeculae within the lesion and cloudy “murky” cells with foci of necrosis (hematoxylin and eosin stain, ×270).

Coating sections with paraffin has been proposed to decrease oxidation and thus antigenicity deterioration. The use of paraffin coating and nitrogen storage will help to preserve staining, although this is not as useful for ki67 staining.9 Other reports suggest that paraffin coating does not significantly protect slides from antigen degradation. Additionally, because paraffin is difficult to remove, variable staining results lead to false-positive and false-negative results.5 CONCLUSIONS Lack of proper storage has several implications for research and patient care. Large cohort and collaborative studies rely on storage of slides for future studies. Tissue microarrays, as a research tool for stains of large cohorts of specimens and long-term tissue banking, rely on storage of slides. The risk of false-negative and false-positive results can adversely impact the success of research. Pathologists may need to perform additional studies for routine care as well as during clinical trials.

Figure 2. Same case as in Figure 1. Again note trabeculae within the lesion (center left) and necrosis (right). Note also cytological atypia and high mitotic rate (hematoxylin and eosin stain, ×540).

Several factors facilitate the loss of antigenicity. Unstained slides demonstrate a faster rate of antigen degradation than does tissue fixed and stored in paraffin blocks, with disappearance of antigen positivity in as few as 3 months.7 Section exposure to air causing oxidation plays a role in loss of antigenicity.7,8 Paradoxically, coating slides with antioxidants, including butylated hydroxytoluene and butylated hydroxyanisole, may cause further diminishment of signals.5,9 SKINmed. 2017;15:277–279

Most studies suggest that storage of sections in cool, dry environments with no light exposure and little air contact is the most appropriate method to preserve antigenicity. Further insight into a standardized protocol should be performed to ensure research success and improve patient care. References

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1 Prioleau J, Schnitt SJ. p53 antigen loss in stored paraffin slides. N Engl J Med. 1995;332:1521–1522.

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2 Fergenbaum JH, Garcia-Closas M, Hewitt SM, et al. Loss of antigenicity in stored sections of breast cancer tissue microarrays. Cancer Epidemiol Biomarkers Prev. 2004;13:667–672. 3 Economou M, Schoni L, Hammer C, et al. Proper paraffin slide storage is crucial for translational research projects involving immunohistochemistry stains. Clin Transl Med. 2014;3:4. 4 Bertheau P, Cazals-Hatem D, Meignin V, et al. Variability of immunohistochemical reactivity on stored paraffin slides. J Clin Pathol. 1998;51:370–374. 5 Jacobs TW, Prioleau JE, Stillman IE, Schnitt SJ. Loss of tumor marker-immunostaining intensity on stored paraffin slides of breast cancer. J Natl Cancer Inst. 1996;88:1054–1059. 6 Wester K, Wahlund E, Sundstrom C, et al. Paraffin section storage and immunohistochemistry. Effects of time,

temperature, fixation, and retrieval protocol with emphasis on p53 protein and MIB1 antigen. Appl Immunohistochem Mol Morphol. 2000;8:61–70. 7 Xie R, Chung JY, Ylaya K, et al. Factors influencing the degradation of archival formalin-fixed paraffinembedded tissue sections. J Histochem Cytochem. 2011;59:356–365. 8 Blind C, Koepenik A, Pacyna-Gengelbach M, et al. Antigenicity testing by immunohistochemistry after tissue oxidation. J Clin Pathol. 2008;61:79–83. 9 DiVito KA, Charette LA, Rimm DL, Camp RL. Long-term preservation of antigenicity on tissue microarrays. Lab Invest. 2004;84:1071–1078. 10 Ramos-Vara JA, Webster JD, DuSold D, Miller MA. Immunohistochemical evaluation of the effects of paraffin section storage on biomarker stability. Vet Pathol. 2014;51:102–109.

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Edward L. Keyes Resident Contest for Outstanding Case Reports 13th World Congress of the International Academy of Cosmetic Dermatology Dubrovnik, Croatia June 28–July 1, 2018 Abstract deadline: March 31, 2018 To be awarded for the best Case Report submitted by a physician in training (resident, fellow, or registrar) for presentation at the 13th World Congress of the International Academy of Cosmetic Dermatology in Dubrovnik, Croatia from June 28–July 1, 2018. We invite you to submit original Case Reports that reflect the presentation of new ideas and original observations to the Academy membership and other attendees of the Congress. The case may be medical, surgical, and cosmetic (or combined) in nature. The author whose abstract obtains the highest score during the review process will receive a scholarship by the IACD to present the full paper at the 13th World Congress of the International Academy of Cosmetic Dermatology in Dubrovnik, Croatia from June 28-July 1, 2018. The scholarship will provide reasonable travel expenses, lodging for 3 nights, the Congress registration fee, and a basic spending stipend. Please submit your case report abstract via email to vrosic@medicine.bsd.uchicago.edu before noon, CDT, March 31, 2018. The abstract should be no longer than 2,500 characters including spacing. Material that was previously presented, published, or submitted for publication should not be offered. Applications will be graded based upon the educational value of the abstract and the extent to which it presents new and significant work. The Review Committee strongly recommends that abstracts have an organized, coherent, well-thoughtout, and complete presentation. Please note that no paper submitted for consideration will be eligible if it has already been, or is in consideration for, publication elsewhere at any time prior to the meeting. The winner(s) agree to publish their outstanding case report(s) in SKINmed: Dermatology for the Clinician, an official publication of the International Academy of Cosmetic Dermatology. By submitting your paper for consideration, you give SKINmed: Dermatology for the Clinician first-rights of refusal for publication through December 31, 2018. The applicant must be in training at the time of the Congress presentation. All applicants will receive e-mail notice of the Resident Case Report Review Committee’s decision by May 1, 2018. Vesna Petronic-Rosic, MD, MSc Chair, Resident Contest Committee Professor and Chief The University of Chicago Pritzker School of Medicine Section of Dermatology Tel: +1.773.702.6559 vrosic@medicine.bsd.uchicago.edu

July/August 2017

Volume 15 • Issue 4

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

Brodalumab (Siliq®): A Treatment for Plaque Psoriasis Aditya K. Gupta, MD, PhD, FRCPC;1,2 Sarah G. Versteeg, MSc;2 William Abramovits, MD;3,4,5 Kimberly D. Vincent, MD6

soriasis is a chronic T-cell–mediated inflammatory autoimmune disease characterized by erythematous and scaly plaques, lesional pruritus, and atypical histology. Successful treatment of this disease is important as associated inflammatory mediators increase the risk of cardiovascular disease, metabolic syndrome, and diabetes.1 Environmental factors, genetics, and immune dysregulation have been suggested as its pathogenesis. New therapies, including brodalumab (Siliq®, Valeant Pharmaceuticals Luxembourg, Grand Duchy of Luxembourg, Luxembourg), have been developed due to the side effects (eg, liver toxicity, infusion reactions), loss of efficacy, and dissatisfaction with traditional treatments.2,3 MECHANISM OF ACTION

The inflammation in psoriasis has been linked to the production of interleukin-17 (IL-17) by a subset of helper T cells (Th17).4,5 Patients have elevated levels of IL-17A, IL-17C, and IL-17F mRNA, cytokines that can induce the expression of proinflammatory genes.4,5 Brodalumab, a human anti–IL-17 monoclonal antibody could effectively address the clinical manifestations and signs of psoriasis by normalizing this altered transcriptional expression (Figure).6 By competitively inhibiting IL-17 receptor signaling, brodalumab can suppress the expression of disease-related genes, decreasing the biologic activity of IL-17A, IL-17C, and IL-17F.3 Other psoriasis treatments such as secukinumab (Cosentyx®, Novartis Pharmaceuticals Corporation, East Hanover, New Jersey) and ixekizumab (Taltz®, Eli Lilly and Company, Indianapolis, Indiana) bind to the IL-17A cytokine rather than antagonizing the IL-17 receptor.7,8

PHASE I STUDIES In a randomized, placebo-controlled, single-dose trial, brodalumab was evaluated in patients with moderate to severe plaque psoriasis (n=25).9 An improvement in the Psoriasis Area and Severity Index (PASI) occurred for all brodalumab concentrations tested (140 mg, 350 mg, 700 mg) within 2 weeks of treatment versus placebo (no P value reported; Table I). Higher concentrations of brodalumab significantly reduced epidermal thickening, keratin 16 levels, and the number of Ki67-expressing cells compared with baseline. Brodalumab treatment also reduced mRNA levels of IL-17–modulated keratinocyte-derived factors (IL-17A, IL-17C, IL-17F), achieving nonlesional mRNA levels over 6 weeks. Non-neutralizing anti-brodalumab antibodies were found in two patients taking brodalumab. The administration of brodalumab 140 mg every 2 weeks can maintain interleukin-17 receptor A (IL-17RA) occupancy (>1 µg/mL), enabling improvement.10 PHASE II STUDIES In a randomized, double-blind, placebo-controlled, 10-week dose-ranging study, brodalumab- treated patients (n=198) showed a significant improvement in PASI score at week 12 when compared to placebo-treated patients (P<.001).11 At week 16 (4 weeks after the last dose), PASI (mean percentage) improvement still favored brodalumab (P<.001 for all concentrations; Table I), and the affected surface area in brodalumabtreated patients was significantly lower than in placebo-treated patients (70 mg, P<.01; all other concentrations, P<.001). The proportion of patients with a Physician Global Assessment

From the Department of Medicine, University of Toronto School of Medicine, Toronto,1 and Mediprobe Research Inc., London,2 Ontario, Canada; 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; and Private Practice, Belle Meade Dermatology, Nashville, TN6 Address for Correspondence: Aditya K. Gupta, MD, 645 Windermere Road, London, Ontario, Canada N5X 2P1 • E-mail: agupta@execulink.com

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Figure. The antagonistic interaction of brodalumab on the interleukin-17 (IL-17) pathway. IL-17RA, interleukin-17 receptor A; IL-17RC, interleukin-17 receptor C.

score of 0 (clear) or 1 (minimal disease) was higher with brodalumab than placebo (70 mg, P<.01; all other concentrations, P<.001). For brodalumab-treated patients, psoriasis had a lesser effect on their quality of life and well-being as evidenced by a significantly lower Dermatology Life Quality Index score (70 mg, P<.01; all other concentrations, P<.001) and significantly higher 36-Item Short Form Survey scores (physical component 140 mg, P<.01; mental component 140 mg, P<.05; 210 mg, P<.01). At least one adverse event (AE) occurred in all treatment groups, with nasopharyngitis, upper respiratory tract infections, and erythema at the injection site being most commonly reported. Three serious AEs occurred: one (ectopic pregnancy) in the placebo group, and two (renal colic, grade 3 asymptomatic neutropenia) in the brodalumab group. Brodalumab (210 mg, 410 mg) also reduced PASI scores in moderate to severe psoriasis patients in an open-label, 52-week study (n=145); nasopharyngitis and upper respiratory tract inflammations were common AEs.12 PHASE III STUDIES Brodalumab was compared to ustekinumab in two phase III, multicenter, randomized, double-blind, placebo-controlled studies of patients with moderate to severe psoriasis.3 These inSKINmed. 2017;15:281â&#x20AC;&#x201C;285

cluded a 12-week induction phase (brodalumab, ustekinumab or placebo) and 40-week maintenance phase (brodalumab given to ustekinumab- and placebo-treated patients). At the end of the induction phase, brodalumab significantly improved PASI scores (a reduction of >75% from baseline) compared to placebo (P<.001 for both studies) and ustekinumab (210 mg, P=.007 study 2) (Table I). More patients had Physician Global Assessment scores of 0 (clear) or 1 (minimal disease) with brodalumab than placebo (140 mg, P<.001, 210 mg P<.001) or ustekinumab (210 mg, P<.001). A similar trend was found when ustekinumab- and placebo-treated patients were given 210 mg of brodalumab (Table I). Significantly more patients treated with brodalumab and ustekinumab had at least one AE compared to those given placebo. Nasopharyngitis, upper respiratory tract infections, headaches, and arthralgia were the most common AEs. Non-neutralizing anti-brodalumab antibodies were detected in 65 brodalumab-treated patients across studies, in four patients at baseline, and in six ustekinumab-treated patients (StelaraÂŽ, Cilag AG, Schaffhausen, Switzerland). Patients treated with brodalumab (210 mg, 140 mg) showed a significant decrease in Hospital Anxiety and Depression Scale scores after 12 weeks of treatment compared to patients given placebo (P<.001 and P<.001, respectively).13

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Table 1. The Impact of Brodalumab on Psoriasis Area and Severity Index (PASI) Scores Study Papp et al, 2012

Papp et al, 2012b11

Lebwohl et al, 20153

Treatment

PASI 75

PASI 100

140 mg

0/4=0%

—

350 mg

3/8=38%

—

700 mg

7/8=88%

—

Placebo

0/5=0%

—

70 mg

13/39=33%*

4/39=10%***

140 mg

30/39=77%*

15/39=38%*

210 mg

30/40=82%*

25/40=62%*

280 mg

28/42=67%*

12/42=29%*

Placebo

0/38=0%

140 mg

S1: 406/610=67%* S2: 435/629=69%*

S1: 157/610=26%* S2: 170/629=27%*⁰

210 mg

S1: 528/612=86%* S2: 531/624=85%*⁰

S1: 272/612=44%*⁰ S2: 229/624=37%*⁰

Ustekinumab

S1: 210/300=70% S2: 217/313=69%

S1: 65/300=22% S2: 58/313=19%

Placebo

S1: 25/309=8% S2: 19/315=6%

S1: 2/309=1% S2: 1/315=0.3%

210 mg after ustekinumab treatment

S1: 40/44=91% S2: 49/60=82%

S1: 20/44=46% S2: 24/60=40%

210 mg after placebo treatment

S1: 233/248=94% S2: 240/257=93%

S1: 153/248=62% S2: 174/257=68%

Induction phase

Maintenance phase

Abbreviations: S1, AMAGINE-2; S2, AMAGINE-3; PASI 75, percentage of patients that achieved a 75% improvement in Psoriasis Area and Severity index (PASI) scores; PASI 100, percentage of patients that achieved a 100% improvement in PASI scores. *P<.001 compared to placebo. ***P<.05 compared to placebo. ⁰P<.001 compared to comparator.

Historical comparisons between brodalumab and secukinumab and ixekizumab show comparable reductions in PASI 75, 90, and 100 (Table II).14 A phase III study suggested that brodalumab could be more effective than secukinumab as a higher proportion of patients achieved PASI 90 and 100 (Table II), suggesting that brodalumab and secukinumab may not work as fast as ixekizumab in reducing severity of psoriasis. A 25% to 55% improvement in PASI scores can occur as early as 2 weeks with brodalumab (70 mg and 210 mg, respectively).11 Secukinumab-treated patients showed an improvement of ~25% to 35% in their PASI scores by week 2, and ~40% to 50% by week 4 (150 mg and 300 mg, respectively).7 Patients treated with ixekizumab (150 mg) had a 75% or greater reduction in PASI scores, from approximately 20% by week 2 to approximately 65% by week 4.8 SKINmed. 2017;15:281–285

ADVERSE EFFECTS Across studies of brodalumab, one case of Crohn’s disease (1/503=0.2%) has been reported, occurring during the maintenance phase of one study.3 Exacerbations of ulcerative colitis and Crohn’s disease are among the warnings listed for ixekizumab (prevalence rate 0.1% for Crohn’s disease and 0.2% for ulcerative colitis) and secukinumab (reported prevalence rate of >1% for inflammatory bowel disease and three cases of Crohn’s disease).15,16 Brodalumab’s package insert does have restrictive labeling because of the following AEs: depression (reported in 12 patients), suicidal ideation (reported in 4 patients) and suicidal behavior (reported in 7 patients).3,17 In a news release, Amgen stated, “suicidal ideation and behavior in the brodalumab program …

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Table II. Historical Comparison Between Brodalumab and Other Interleukin-17 (IL-17) RA-Blocking/IL-17A-Neutralizing Agents Treatmenta

Brodalumab3

Secukinumab7

Ixekizumab19

Placebo

S1: 25/309=8% S2: 19/315=6%

S1: 11/246=5% S2: 16/324=5%

—

Low dose

S1: 406/610=67%* S2: 435/629=69%*

S1: 174/243=72%* S2: 219/327=67%*⁰

N: 484/590=82%⁰ E: 109/143=76%⁰

High dose

S1: 528/612=86%* S2: 531/624=85%*⁰

S1: 200/245=82%* S2: 249/323=77%*⁰

N: 522/594=88%⁰ E: 130/142=92%⁰

Comparator

S1: 210/300=70% S2: 217/313=69%

S1: N/A S2: 142/323=44%

N: 306/604=51% E: 47/136=35%

Placebo

S1:9/309=3% S2: 6/315=2%

S1: 3/246=1% S2: 5/324=2%

—

Low dose

S1: 299/610=49% S2: 327/629=52%

S1: 95/243=39%* S2: 137/327=42%*⁰

N: 378/590=64%⁰ E: 79/143=55%⁰

High dose

S1: 428/612=70% S2: 431/624=69%

S1: 145/245=59%* S2: 175/323=54%*⁰

N: 403/594=68%⁰ E: 108/142=76%⁰

Comparator

S1: 141/300=47% S2: 150/313=48%

S1: N/A S2: 67/323=21%

N: 147/604=24% E: 18/136=13%

Placebo

S1: 2/309=1% S2: 1/315=0.3%

S1: 2/246=1% S2: 0/324=0%

—

Low dose

S1: 157/610=26%* S2: 170/629=27%*⁰

S1: 31/243=13%* S2: 47/327=14%⁰

N: 206/590=35%⁰ E: 36/143=25%⁰

High dose

S1: 272/612=44%*⁰ S2: 229/624=37%*⁰

S1: 70/245=29%* S2: 78/323=24%⁰

N: 220/594=37%⁰ E: 67/142=47%⁰

Comparator

S1: 65/300=22% S2: 58/313=19%

S1: N/A S2: 14/323=4%

N: 42/604=7% E: 5/136=4%

PASI 75

PASI 90

PASI 100

Abbreviations: E (experienced): prior exposure to biologics; N (naive): no previous exposure to biologics; PASI 75, percentage of patients that achieved a 75% improvement in Psoriasis Area and Severity Index (PASI) scores; PASI 90, percentage of patients that achieved a 90% improvement in PASI scores; PASI 100, percentage of patients that achieved a 100% improvement in PASI scores; S1: study 1; S2: study 2. aEndpoints evaluated after 12 weeks of treatment. *P<.001 compared to placebo. ⁰P<.001 compared to comparator.

would necessitate restrictive labeling.”18 Amgen withdrew its interest in brodalumab in 2015. Later that year, Valeant agreed to help commercialize brodalumab and continue its development. CONCLUSIONS Significantly more patients achieve PASI 90 and 100 with IL17 inhibitors (eg, brodalumab, secukinumab, ixekizumab) than with other available biologic agents.14 Brodalumab has also shown superiority over ustekinumab.3 From historical comparisons, the effectiveness of brodalumab in reducing PASI scores may exceed that of secukinumab. Caution is advised as nasoSKINmed. 2017;15:281–285

pharyngitis and upper respiratory tract inflammation are commonly associated with brodalumab treatment, and Crohn’s disease and ulcerative colitis may develop or be aggravated.3,11,12 The possibility of depression, suicidal ideation, and suicidal behavior has led to restrictive labeling. Brodalumab (210 mg) has recently been approved by the US Food and Drug Administration to treat moderate to severe plaque psoriasis. As brodalumab is late joining other IL-17 inhibitors that have been approved for the treatment of psoriasis, its likelihood of surviving will depend on marketing. As head-

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to-head studies or historic comparisons show comparable effectiveness between brodalumab, secukinumab, and ixekizumab, differences in safety profiles between them may play the critical role in their success.14 Other psoriasis treatments in development, such as the anti-IL-23 drugs tildrakizumab and recently approved guselkumab, might also influence the staying power of anti-IL-17 drugs as the former may prove to be more efficacious and may not require restrictive labeling. References 1 Davidovici BB, Sattar N, Prinz JC, et al. Psoriasis and systemic inflammatory diseases: Potential mechanistic links between skin disease and co-morbid conditions. J Invest Dermatol. 2010;130:1785–1796. 2 Lebwohl MG, Kavanaugh A, Armstrong AW, et al. US Perspectives in the management of psoriasis and psoriatic arthritis: Patient and physician results from the population-based Multinational Assessment of Psoriasis and Psoriatic Arthritis (MAPP) Survey. Am J Clin Dermatol. 2016;17:87–97. 3 Lebwohl M, Strober B, Menter A, et al. Phase 3 studies comparing brodalumab with ustekinumab in psoriasis. N Engl J Med. 2015;373:1318–1328. 4 Johnston A, Fritz Y, Dawes SM, et al. Keratinocyte overexpression of IL-17C promotes psoriasiform skin inflammation. J Immunol Baltim Md. 2013;190:2252–2262. 5 Johansen C, Usher PA, Kjellerup RB, et al. Characterization of the interleukin-17 isoforms and receptors in lesional psoriatic skin. Br J Dermatol. 2009;160:319–324. 6 Russell CB, Rand H, Bigler J, et al. Gene expression profiles normalized in psoriatic skin by treatment with brodalumab, a human anti-IL-17 receptor monoclonal antibody. J Immunol Baltim Md. 2014;192:3828–3836. 7 Langley RG, Elewski BE, Lebwohl M, et al. Secukinumab in plaque psoriasis—results of two phase 3 trials. N Engl J Med. 2014;371:326–338. 8 Leonardi C, Matheson R, Zachariae C, et al. Anti-interleukin-17 monoclonal antibody ixekizumab in chronic plaque psoriasis. N Engl J Med. 2012;366:1190–1199. 9 Papp KA, Reid C, Foley P, et al. Anti-IL-17 receptor antibody AMG 827 leads to rapid clinical response in subjects with moderate to severe psoriasis: Results from a phase I, randomized, placebo-controlled trial. J Invest Dermatol. 2012;132:2466–2469.

10 Osamu N, Hirotaka N, Koji S, et al. Clinical pharmacology of the anti-IL-17 receptor antibody brodalumab (KHK4827) in Japanese normal healthy volunteers and Japanese subjects with moderate to severe psoriasis: A randomized, dose-escalation, placebo-controlled study. J Dermatol Sci. 2014;75:201–204. 11 Papp KA, Leonardi C, Menter A, et al. Brodalumab, an anti-interleukin-17-receptor antibody for psoriasis. N Engl J Med. 2012;366:1181–1189. 12 Umezawa Y, Nakagawa H, Niiro H, et al. Long-term clinical safety and efficacy of brodalumab in the treatment of Japanese patients with moderate-to-severe plaque psoriasis. J Eur Acad Dermatol Venereol. 2016;30:1957– 1960. 13 Papp KA, Reich K, Paul C, et al. A prospective phase III, randomized, double-blind, placebo-controlled study of brodalumab in patients with moderate-to-severe plaque psoriasis. Br J Dermatol. 2016;175:273–286. 14 Farahnik B, Beroukhim K, Nakamura M, et al. Anti-IL-17 agents for psoriasis: A review of phase III data. J Drugs Dermatol. 2016;15:311–316. 15 US Food and Drug Administration. TALTZ (ixekizumab) injection, for subcutaneous use. 2016. http://www.accessdata.fda.gov/drugsatfda_docs/ label/2016/125521s000lbl.pdf. Accessed January 24, 2017. 16 US Food and Drug Administration. COSENTYXTM (secukinumab) injection, for subcutaneous use COSENTYXTM (secukinumab) for injection, for subcutaneous use. 2015. http://www.accessdata.fda.gov/drugsatfda_ docs/label/2015/125504s000lbl.pdf. Accessed January 24, 2017. 17 Chiricozzi A, Romanelli M, Saraceno R, et al. No meaningful association between suicidal behavior and the use of IL-17A-neutralizing or IL-17RA-blocking agents. Expert Opin Drug Saf. 2016;15:1653–1659. 18 Danesh MJ, Kimball AB. Brodalumab and suicidal ideation in the context of a recent economic crisis in the United States. J Am Acad Dermatol. 2016;74:190– 192. 19 Gottlieb AB, Lacour J-P, Korman N, et al. Treatment outcomes with ixekizumab in patients with moderate-tosevere psoriasis who have or have not received prior biological therapies: An integrated analysis of two Phase III randomized studies. J Eur Acad Dermatol Venereol. 2017;31:679–685.

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Brodalumab (Siliq®): A Treatment for Plaque Psoriasis

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July/August 2017

Volume 15 • Issue 4

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

Telangiectasia Macularis Eruptiva Perstans Revisited Warren R. Heymann, MD

have always struggled with the diagnosis of telangiectasia macularis eruptiva perstans (TMEP). Aside from taking the first 6 months of my residency to remember how to say it, I have never been confident in securing the diagnosis. It would always enter the differential diagnosis, once telangiectasias were observed, especially on the trunk, when associated with hyperpigmented macules and papules. Classically, the Darier sign is negative in TMEP. Recently reported variants of TMEP include those presenting with an island of sparing,1 linearity,2 or unilaterality.3 Upon considering the diagnosis of TMEP, many questions abound: How many perivascular mast cells are necessary to define the entity? What diagnostic studies should be obtained? What is the likelihood of systemic involvement? SYSTEMIC INVOLVEMENT OF TMEP In a survey of 243 patients with cutaneous mastocytosis, 34 (14%) were classified as having TMEP. Sixteen of the 34 (47%) had systemic mastocytosis, with three (9%) having “aggressive” mastocytosis (manifested by bone fractures and/or gastrointestinal injury, resulting in malabsorption and weight loss). Patients were diagnosed by skin biopsies for routine microscopy, immunohistochemical stains using anti-CD 117, and detection of a KIT point mutation at codon 816. The authors noted that the low number of mast cells in dermal tissue, the low frequency of KIT point mutations, and the low serum tryptase levels in patients with TMEP suggested a smaller mast cell burden than in other forms of mastocytosis. What is hard to grasp, therefore, was the high frequency of systemic manifestations in TMEP. What was especially disconcerting was that the tryptase levels were normal in many TMEP patients

with systemic clinical manifestations, with only 9 (26.5%) having levels of more than 20 μg/L. I have been relying on the serum tryptase level of more than 20 μg/L as the threshold to consider referring patients with mastocytosis for systemic evaluation by a hematologist. Perhaps I have been relying too much on a number and not enough on a review of systems inquiring about fatigue, diarrhea, flushing, dyspnea, etc. While the authors acknowledged that their study might have been subject to referral bias, it is hard to argue with their conclusion that more work is needed to better define the diagnostic criteria of TMEP. 4 In a retrospective review of 299 cases of mastocytosis using the National Institutes of Health Biomedical Translational Research Information System, 24 cases of TMEP were identified. The majority of these patients had systemic manifestations, including nine with anaphylaxis and four with syncope. The Darier sign was positive in 40% of these TMEP patients, and the median serum tryptase level was 24.2 ng/mL. Twenty-one patients underwent bone marrow biopsy for evaluation of possible systemic mastocytosis. Sixteen patients (67%) met the World Health Organization diagnostic criteria for indolent systemic mastocytosis, 7 (29%) had mastocytosis limited to the skin (all urticaria pigmentosa), and 1 did not meet the criteria for mastocytosis limited to the skin or systemic disease (4%). The authors concluded by stating “the diagnosis of TMEP appears to be over-used, has little clinical utility and is confusing to physicians and patients.” They contend that highly vascularized urticaria pigmentosa more accurately describes these pigmented macular lesions that localize with observable telangiectasia, suggesting that in the majority of instances, where the diagnosis

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

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of TMEP is used, the lesions are more accurately described as urticaria pigmentosa.5

References

Although systemic involvement in TMEP has been described since its initial description in 1930, it has been considered that TMEP has little tendency to progress to systemic disease.6 The aforementioned studies clearly challenge that assumption. Additionally, a recent consensus paper did not include TMEP as a unique subset of mastocytosis. The recommendation was to classify cutaneous mastocyosis as either urticaria pigmentosa (subdivided into the monomorphic variant seen in adults or the polymorphic variant observed in children), diffuse cutaneous mastocytosis, or cutaneous mastocytoma.7 CONCLUSIONS Personally, I do not think that the term TMEP will be expunged from the dermatologic lexicon, for the same reason that we still say that patients with cutaneous T-cell lymphoma may have mycosis fungoides—the terms are entrenched in our vocabulary. Future generations will be proud to make the diagnosis. What will be different, however, is that more consistent diagnostic criteria will be forthcoming, and there will be an appreciation that TMEP may imply far greater systemic involvement that previously perceived.

1 Ragi J, Lazzara DR, Harvell JD, Milgraum SS. Telangiectasia macularis eruptiva perstans as island sparing. J Clin Aesthet Dermatol. 2013;6:41–42. 2 Kagimoto Y, Mizaushi M, Iazawa O, Aiba S. Linear telangiectasia macularis eruptiva perstans mimicking acquired nevoid telangiectasia in a 5-year-old girl. Int J Dermatol. 2012;51:61–79. 3 Patel N, Stranahan D, Fenske NA. Unilateral telangiectasia macularis eruptiva perstans of the breast. Cutis. 2012;90:262–268. 4 Severino M, Chandesris MO, Barete S, et al. Telangiectasia macularis eruptiva perstans (TMEP): A form of cutaneous mastocytosis with potential systemic involvement. J Am Acad Dermatol. 2016;74:885–891. 5 Williams KW, Metcalfe DD, Prussin C, Carter MC, Komarow HD. Telangiectasia macularis eruptiva perstans or highly vascularized urticaria pigmentosa? J Allergy Clin Immunol Pract. 2014;2:813–815. 6 Marrouche N, Grattan C. TMEP or not TMEP: That is the question. J Am Acad Dermatol. 2014;70:581–582. 7 Hartmann K, Escribano L, Grattan C, et al. Cutaneous manifestations in patients with mastocytosis: Consensus report of the European Competence Network on Mastocytosis; the American Academy of Allergy, Asthma & Immunology; and the European Academy of Allergology and Clinical Immunology. J Allergy Clin Immunol. 2016;137:35–45.

Historical Diagnosis and treatment

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Telangiectasia Macularis Eruptiva Perstans Revisited

July/August 2017

Volume 15 • Issue 4

Contact Dermatitis Capsule Matthew J. Zirwas, MD, Section Editor

On Lanolin Allergy and the Approach to Its Diagnosis Jonathan G. Bonchak, MD; Matthew J. Zirwas, MD

14-year-old boy with no significant past medical history presented with a chief complaint of a diffusely pruritic eruption for the previous several months that had begun shortly after moving to a new home on a large wooded lot (Figure). He could identify no exacerbating factors, but oral corticosteroids did provide temporary relief. The dermatitis was disabling enough that he was being bullied at school. On physical examination, there were pink-red macules, patches, and plaques with scale and excoriations, involving the face, neck, trunk, and extremities. Patch testing with the North American Contact Dermatitis Group standard series (65 allergens in total) showed a 2+ reaction to Amerchol L-101. Further questioning revealed that his parents had started a petting zoo with sheep on their new property. Avoidance of the sheep led to resolution of the previously recalcitrant dermatitis. DISCUSSION Taking a thorough history is generally considered a cornerstone in the evaluation of contact dermatitis patients. We agree; however, the time at which it is most useful to take a “thorough history” is frequently not specified. When our patch test center was established almost a decade ago, our assumption was that the history needed to be taken before patch testing to determine what allergens to use for testing. Over the ensuing years and with the experience gained through testing many thousands of patients, we eventually realized that this was not the case. The number of questions one could ask “pre-patch testing” is almost infinite, making the likelihood of asking the “right” question, even in a 40-minute visit, quite low. For instance, in this case, asking if there were exposure to a petting zoo was definitely not part of our pre-patch test history. Once we knew the patient was allergic to lanolin, inquiring about exposure to sheep

quickly led to the relevant history. The key point is that the results of patch testing allow the clinician to focus on the history and to explore the relevant exposures to the detected allergens. It is, of course, crucial that an adequate screening series, such as the American Contact Dermatitis Society Core Series, is used. Amerchol L-101 is a combination of concentrated lanolin alcohols and mineral oil used as a marker for lanolin allergy in patch testing. Lanolin, also known as wool alcohol, is a wool wax with emollient and emulsifying properties derived from the sebaceous gland secretions of sheep. It has been used by humans for centuries and functions as a vehicle in cosmetic products and medicaments applied to the skin, lips, nails, and hair.1 These products serve as the primary source of exposure in most cases of allergic contact dermatitis, although wool clothing has also been implicated.2 Lanolin is composed primarily of aliphatic alcohols and sterols. The alcohol portion has been identified as the primary sensitizing component.3 Although the composition of lanolin has been described generally, it is quite a complex substance. There are subtle component variations owing to breed and location of sheep, methods of extraction, and levels of purification.2 The variable chemical character of lanolin lends some obfuscation to its allergenic properties and our ability to reliably detect them in a clinical setting. The prevalence of positive patch test reactions to lanolin ranges from 1.6% to 4.1% based on data from large, multicenter studies.4–6 Intuitively, the prevalence is higher for subgroups in which cosmetic allergy is suspected.2,4 Counterintuitively, in the general population, men are significantly more likely to be allergic than women.2 This seems to indicate that lanolin-containing medicaments are more important sensitizers than traditional cosmetic

From the Division of Dermatology, The Ohio State University College of Medicine, Columbus, OH Address for Correspondence: Matthew J. Zirwas, MD, 540 Officenter Place, Suite 240, Gahanna, OH 43230 • E-mail: matt.zirwas@osumc.edu

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Contact Dermatitis CAPSULE products. Patients with leg ulcers, venous stasis dermatitis, or dermatitis confined to the leg are more likely to be lanolin-sensitive.7,8

(a)

CONCLUSIONS The index patient had daily and prolonged exposure to wool alcohols in the form of Aquaphor® Healing Ointment, which he had been applying to his dermatitis, and the sheep with which he interacted daily. Although lanolin is not commonly thought of as causing severe contact dermatitis, the clinical scenario matched perfectly enough to encourage avoidance of the sheep and discontinuation of any products containing the allergen. There was near-complete resolution of his eruption and pruritus 3 months after the family sold their sheep and changed moisturizers. References 1 Cosmetic Ingredient Expert Review Panel. Final Report on the Safety Assessment for Acetylated Lanolin, Lanolin Alcohol, and Related Compounds. Int J Toxicol. 1980;4:63–92. 2 Lee B, Warshaw E. Lanolin allergy: History, epidemiology, responsible allergens, and management. Dermatitis. 2008;19:63–72.

(b)

3 Giorgini S, Melli MC, Sertoli A. Comments on the allergenic activity of lanolin. Contact Dermatitis. 1983;9:425– 426. 4 Dinkloh a, Worm M, Geier J, Schnuch A, Wollenberg A. Contact sensitization in patients with suspected cosmetic intolerance: Results of the IVDK 2006-2011. J Eur Acad Dermatol Venereol. 2014:1–11. 5 Warshaw EM, Nelsen DD, Maibach HI, et al. Positive patch test reactions to lanolin: Cross-sectional data from the North American Contact Dermatitis Group, 1994 to 2006. Dermatitis. 2009;20:79–88. 6 Wakelin SH, Smith H, White IR, Rycroft RJ, McFadden JP. A retrospective analysis of contact allergy to lanolin. Br J Dermatol. 2001;145:28–31. 7 Trummer M, Aberer W, Kränke B. Clinical relevance of + patch test reactions to lanolin alcohol. Contact Dermatitis. 2002;46:118. 8 Nguyen JC, Chesnut G, James WD, Saruk M. Allergic contact dermatitis caused by lanolin (wool) alcohol contained in an emollient in three postsurgical patients. J Am Acad Dermatol. 2010;62:1064–1065.

Figure. (a) A 14-year-old boy with a diffuse pruritic eruption most severe on the face, neck, chest, and arms. (b) Patch testing showed a 2+ reaction to Amerchol L-101 (patch number 7). The eruption resolved completely 3 months after avoidance of Aquaphor® and sheep. SKINmed. 2017;15:289–290

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Volume 15 • Issue 4

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

Diffuse Papular Eruption of the Face and Eyelids Stephanie Frisch, MD;1 Jessica Kozel, MD;1 Sarah Jensen, MD;2 Claudia I. Vidal, MD, PhD1

A 68-year-old Caucasian woman presented with a 1-month history of a facial and neck eruption (Figure 1A). Her face was covered with 3-mm monomorphic, pink, shiny, papules and rare pustules on an erythematous background. The eruption extended down the neck, her conjunctivae were injected, and her lid margins were inflamed. She had no history of rosacea. (SKINmed. 2017;15:291–292)

he was initially treated with a 2-day course of cephalexin and daily topical metronidazole gel but failed to respond. A prednisone taper provided only initial and temporary improvement. Biopsy of an affected area was, therefore, performed and showed a collection of neutrophils, histiocytes, and multinucleated giant cells surrounding a portion of a dislocated Demodex mite within the dermis, consistent with nodular demodicosis (granulomatous demodicidosis) (Figure 2). Special stains to exclude fungal elements and bacteria were performed on the biopsy specimen, including Grocott methenamine silver stain, tissue Gram stain, and acid-fast bacteria stain; these failed to highlight fungal elements, bacteria, and mycobacteria, respectively. After the biopsy results had been obtained, the patient was treated with oral ivermectin weekly for 4 weeks, nightly permethrin application to the face and neck for 1 week, and baby shampoo wash with erythromycin 2% ointment to the lid margins. An infectious disease specialist added oral doxycycline for 2 weeks. The lesions started to clear after the ivermectin and doxycycline treatment (Figure 1B). DISCUSSION

Demodex folliculorum and Demodex brevis are the only two species of mites known to infect human pilosebaceous units. Demodex folliculorum mites home to the infundibular portion of the

Figure 1. Nodular demodicosis with a papular eruption on an erythematous background on the face extending down the neck. (A) Initial presentation of the patient. (B) Clearance following treatment.

hair and eyelash follicles, whereas Demodex brevis inhabits the sebaceous and meibomian glands, using sebum as nourishment. The prevalence of nodular demodicosis increases significantly in middle-aged and older adults.1 In 1961, Samuel Ayres, Jr. (18931987) was one of the first authors to describe Demodex infestation in humans, namely pityriasis folliculorum and rosacea-like demodicidosis.2 Additional dermatologic conditions including pustular folliculitis, papulopustular scalp eruptions, and perioral

From the Department of Dermatology, Saint Louis University, St. Louis, MO;1 and Private Practice, Festus, MO

Address for Correspondence: Claudia I. Vidal MD, PhD, Department of Dermatology, Saint Louis University, 1755 South Grand Boulevard, Anheuser Busch Institute, 4th Floor, Room 402, St. Louis, MO 63104 • E-mail: cvidal1@slu.edu

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Figure 2. Histology of nodular demodicosis shows a granulomatous infiltrate surrounding a Demodex mite, shown by the arrow. Hematoxylin and eosin, original magnification ×40 (A) and 100 (B).

dermatitis have been associated with a high-density Demodex infestation (>5/cm2).1 High-density Demodex colonization can also contribute to ocular clinical manifestations, usually manifested as blepharitis.3 Diagnosis of the demodicidosis can be confirmed by direct microscopic examination of a biopsy, as in our patient, or from skin scrapings.4 Mites are seen within the dilated ostium of hair follicles, with a surrounding inflammatory cell infiltrate. A causal relationship between Demodex infestation and other dermatologic conditions has been a controversial subject among dermatologists. Many agree that it exacerbates rosacea, but doubt whether there is enough evidence to suggest causality. Many theories attempt to explain a pathogenic role for Demodex. The blockage of follicles and sebaceous ducts by the mites perhaps incites reactive hyperkeratinization and epithelial hyperplasia. An unknown antigen of follicular or mite origin may provoke a delayed hypersensitivity. Others have proposed that the mite functions as a vector for bacteria, or that its chitinous skeleton causes a foreign body granulomatous reaction.5 A recent meta-analysis reviewed 48 case-control studies in the literature and concluded that there was a significant association between a Demodex density of greater than 5/cm2 and rosacea.6,7

ing, persistent erythema or photosensitivity, sebostatic skin type, burning and itching sensations, the absence of significant telangiectasias with an asymmetrical distribution, involvement of the eyelids, previous steroid use, and poor general health. Several effective therapies are available, including salicylic acid, selenium sulfide, metronidazole, crotamitone, lindane, sublimed sulfur, oral ivermectin with topical permethrin, and oral or topical retinoids. For Demodex blepharoconjunctivitis, yellow mercury ointment 1% or topical metronidazole gel 2% is recommended.1 We believe that awareness of demodicidosis is important as it can clinically resemble other processes such as folliculitis, papulopustular erythema, blepharoconjunctivitis, and granulomatous dermatitis. Cases recalcitrant to first-line medications should warrant a search for Demodex infestation. References

Conclusions Certain clinical features may favor a demodicidosis flare, for example sudden onset, rapid progression, lack of history of flush-

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1 Baima B, Sticherling M. Demodicidosis revisited. Acta Derm Venereol. 2002;82:3–6. 2 Ayres S. Demodectic eruptions (demodicidosis) in the human. 30 years’ experience with 2 commonly unrecognized entities: pityriasis folliculorum (Demodex) and acne rosacea (Demodex type). Arch Dermatol. 1961;83:816–827. 3 Morgan RJ, Coston TO. Demodex blepharitis. South Med J. 1964;57:694–699.

Diffuse Papular Eruption of the Face and Eyelids

July/August 2017

Volume 15 • Issue 4

CASE STUDY

Demodicosis Treatment with Systemic Ivermectin Manuel Coelho da Rocha, MD;1 Ana Rita Travassos, MD;2 Luís Uva, MD;2 Hortênsia Sequeira, BHSc;3 Paulo Filipe, MD, PhD2

A 23-year-old white man presented to our dermatology department complaining of pruriginous and erythematous papulopustules on the right cheek that had developed 6 months previously. He had a history of chronic blepharitis, complicated by a recurrent hordeolum that had been treated with warm compresses and topical antibiotic ointment (chloramphenicol) for approximately 2 years. The patient had oily skin and atopy (allergic rhinitis) and did not experience photosensitivity or flushing or have previous exposure to immunosuppressants or topical/systemic corticosteroids. (SKINmed. 2017;15:293–295)

dermatologic examination showed erythematous, nonsquamous papulopustules of 4 to 6 mm diameter on the right cheek. There were also signs of bilateral blepharitis, which were more prominent on the right lower eyelid, corresponding to rosacea subtype 4 (Figure 1A). The patient was tested for HIV infection and antinuclear antibodies, both of which were negative. Skin was scraped from the lesions on the right cheek, and some eyelashes and eyebrow hairs were epilated. The samples were prepared with 20% KOH, and microscopy showed multiple Demodex mites and eggs (Figure 2). The patient was prescribed 0.75% metronidazole topical cream and 100 mg minocycline once daily. After 1 month of treatment, there was minimal improvement of the lesions, and 10% crotamiton topical cream once daily was added to the regimen. One month later, the lesions were remaining unresponsive, and another round of skin scraping was performed, the samples of which still contained Demodex mites. Based on his resistance to topical treatments, the patient was administered a single oral dose of 12 mg ivermectin (200 μg/kg). After 4 weeks of systemic treatment, the lesions had nearly disappeared (Figure 1B); thus, we repeated this cycle, and the patient recovered fully. The patient remains free of lesions without additional treatment or preventive measures at the 1-year follow-up (Figure 3); furthermore, the skin scrapings harbor 0 to 1 mites/cm2.

DISCUSSION Demodex mites—Demodex folliculorum and Demodex brevis— are the most common permanent parasites in humans.1 They inhabit the pilosebaceous unit and use sebum as nourishment. This parasite prefers areas with high sebum production, such as the forehead, cheek, nose, nasolabial folds, chin, and eyelids.2 The function of Demodex in skin disease is debated. Certain authors consider these mites as merely passengers in normal adult skin,3,4 whereas others have demonstrated that Demodex has an aversion for skin lesions of the face.5 Several pathogenic mechanisms of demodicosis have been proposed, including: (1) blockage of hair follicles and sebaceous ducts by mites or reactive hyperkeratosis; (2) stimulation of a host’s humoral and cell-mediated immune reactions by mites and their waste products; (3) a granulomatous reaction to a mite’s chitinous skeleton; and (4) acting as a vector for bacteria.2,6 Demodex mites have been implicated as a causative agent in rosacea2,6 and blepharitis.7 There are three evidence-based risk factors for contracting Demodex: age (the rate at which Demodex is detected increases with age), skin type (people with oily or mixed skin are more likely to be infested with Demodex mites), and previous skin disease.5 Men are often more heavily infested than women, likely because they have more sebaceous glands and thus produce more food

From the Faculdade de Medicina de Lisboa,1 Clínica Universitária de Dermatologia, Faculdade de Medicina de Lisboa,2 and Laboratório de Micologia,3 Clínica Universitária de Dermatologia, Faculdade de Medicina de Lisboa, Lisboa, Portugal Address for Correspondence: Manuel Coelho da Rocha, Clínica Universitária de Dermatologia, Faculdade de Medicina de Lisboa, Avenida Prof. Egas Moniz, Hospital de Santa Maria, 1649-035 Lisboa, Portugal • E-mail: manel.rocha@gmail.com

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Figure 1. (A) Photograph before treatment showing nonsquamous papulopustules on the cheek and signs of blepharitis. (B) After 4 weeks of systemic ivermectin, the lesions almost disappeared.

Figure 2. Demodex mites and eggs on a microscopic view of an eyelash.

for the mites.8 Immunosuppressed patients (eg, HIV infection or long-term corticosteroid therapy) also have a greater incidence of demodicosis.9 The diagnosis of demodicosis requires an appropriate clinical picture—erythematous papulopustules that are associated with itching in susceptible areas2—and the presence of more than 5 mites/cm² on histopathology.7 Agents that are used to eradicate infestation with Demodex mites include topical metronidazole, permethrin, lindane, sulfur, crotamiton, retinoids, selenium sulfide, salicylic acid, and benzyl benzoate. With resistant or diffuse lesions, systemic treatment with metronidazole, retinoids, and ivermectin is preferred.2,10 In our case, we administered two indicated topical agents, metronidazole and crotamiton, which were unsuccessful. Topical metronidazole is anti-inflammatory, possibly acting through antioxidant effects rather than antimicrobial activity. The mechanism of action of crotamiton is unknown, but it is suspected of being toxic to Demodex mites; however, crotamiton is associated with frequent treatment failure, even in Sarcoptes scabiei infestation. Based on our patient’s resistance to topical treatments and the relatively diffuse involvement of the face, we began systemic ivermectin, and after 4 weeks the lesions were nearly absent. Conclusions The diagnosis of demodicosis is based on a high index of clinical suspicion; this hypothesis must always be considered when a localized occurrence of papulopustules and recurrent eyelid SKINmed. 2017;15:293–295

Figure 3. Photograph taken at one-year follow-up. The patient is free of lesions without additional treatment or preventive measures.

infection is encountered. In addition, Forton et al noted that demodicosis is the ninth most frequent diagnosis in a dermatologic consultation.11 Systemic ivermectin should be considered in the treatment of resistant or diffuse lesions of demodicosis, as given in other cases.12

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References 1 Desch C, Nutting WB. Demodex folliculorum (Simon) and D. brevis akbulatova of man: Redescription and reevaluation. J Parasitol. 1972;58:169–177. 2 Baima B, Sticherling M. Demodicosis revisited. Acta Derm Venereol. 2002;82:3–6. 3 Kemal M, Sümer Z, Toker MI, et al. The prevalence of Demodex folliculorum in blepharitis patients and the normal population. Ophtalmic Epidemiol. 2005;12:287–290. 4 Okyay P, Ertabaklar H, Savk E, et al. Prevalence of Demodex folliculorum in young adults: Relation with sociodemographic/hygienic factors and acne vulgaris. J Eur Acad Dermatol Venereol. 2006;20:474–476. 5 Zhao YE, Guo N, Xun M, et al. Sociodemographic characteristics and risk factor analysis of Demodex infestation (Acari: Demodicidae). J Zhejiang Univ Sci B. 2011;12:998–1007. 6 Bonnar E, Eustace P, Powell FC. The Demodex mite population in rosacea. J Am Acad Dermatol. 1993;28:443–448.

7 Czepita D, Kuzna-Grygiel W, Czepita M, et al. Demodex folliculorum and Demodex brevis as a cause of chronic marginal blepharitis. Ann Acad Med Stetin. 2007;53:63– 67. 8 Elston DM. Demodex mites: Facts and controversies. Clin Dermatol. 2010;28:502–504. 9 Eismann R, Bramsiepe I, Danz B, et al. Abscessing nodular demodicosis-therapy with ivermectin and permethrin. J Eur Acad Dermatol Venereol. 2010;24:79–81. 10 Dourmishev AL, Dourmishev LA, Schwartz RA. Ivermectin: Pharmacology and application in dermatology. Int J Dermatol. 2005;44:981–988. 11 Forton F, Germaux MA, Brasseur T, et al. Demodicosis and rosacea: Epidemiology and significance in daily dermatologic practice. J Am Acad Dermatol. 2005;52:74–87. 12 Karincaoglu Y, Miman O, Kalayci B, et al. A demodicosis case which responded to systemic ivermectin. Eur J Dermatol. 2009;19:189–190.

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Volume 15 • Issue 4

CASE STUDY

Neutrophilic Eccrine Hidradenitis in an HIV-Infected Patient Patricia Ruiz-López, MD; Eduwiges Martínez-Luna, MD; Sonia Toussaint-Caire, MD; Adán Fuentes-Suárez, MD; Elisa Vega-Memije, MD

A 35-year-old man presented with a 2-day history of a maculopapular pruritic eruption that had affected his general state of health and was accompanied by chills. The patient had been diagnosed with HIV in 2008, and was undergoing treatment with a combination of emcitrabine/tenofovir plus nevirapine. He had a current viral load of 1,558,160 copies/mL and a lymphocyte count CD4+ count of 230/ mm3. Physical examination revealed an eruption involving the face, nape of the neck, chest, abdomen, extremities, palms, and soles. This was characterized by erythematous papules approximately 2 mm in diameter coalescing on the palms and soles, where they formed plaques (Figures 1 and 2). (SKINmed. 2017;15:297–299)

istopathologic examination showed an inflammatory infiltrate composed mainly of neutrophils, lymphocytes, and histiocytes, arranged around the eccrine ducts with epithelial vacuolization of the duct walls (Figure 3). Gram and PAS staining was carried out to exclude an infectious cause, and results were negative. The diagnosis of neutrophilic eccrine hidradenitis (NEH) was made. Treatment was initiated with ibuprofen and loratadine, with improvement and resolution after 3 weeks. DISCUSSION

NEH is a disease characterized by a neutrophilic infiltrate around the eccrine ducts. It is part of the spectrum of the neutrophilic dermatoses.1 There are few reports—only 51 to date—on this entity,1,2 perhaps because it has a benign course, or because the clinical lesions are not specific, leading to misdiagnosis. We report a case in an HIV-infected patient, which is, to our knowledge, the first one reported in Mexico. This disease was initially described in 1982 as a secondary complication of chemotherapy using cyratabine in patients with acute myeloid leukemia.3 Since then, it has been associated with other chemotherapeutic agents and drugs such as acetaminophen and antiretroviral agents;1,4 moreover, it has also been associated with infectious agents, HIV among others.1,4

Figure 1. An eruption characterized by erythematous papules involving the trunk and limbs.

From the Dermatology Division, Hospital General Dr. Manuel Gea González, Mexico City, Mexico Address for Correspondence: Eduwiges Martínez Luna, MD, Hospital General Dr. Manuel Gea González, Tlalpan # 4800 Col. Sección XVI, Mexico D.F. C.P 14080, Mexico • E-mail: eduwiges_ml@hotmail.com

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Figure 2. A close-up of the erythematous papules on the right forearm (a), which formed plaques on the palms (b).

Figure 3. (a) An inflammatory infiltrate arranged around the eccrine ducts (hematoxylin and eosin stain, ×10 magnification). (b) At higher magnification, an inflammatory infiltrate composed mainly of neutrophils is visible around and within dilated ducts of the eccrine glands (hematoxylin and eosin stain, ×40 magnification).

NEH occurs in 90% of cases in patients with any kind of malignancy, hematologic malignancies, especially acute myeloid leukemia, being the most frequent.1,4 Regarding its association with HIV, six cases have been reported to date,1,2,5–8 five of them associated with antiretroviral therapy,1,2,6,8 and one case occurred in a patient with pneumonia caused by Pneumocystis jiroveci without SKINmed. 2017;15:297–299

antiretroviral therapy.7 Another presented with concurrent nonHodgkin’s lymphoma.1 The pathogenesis still remains poorly understood. Because the first cases were observed in patients undergoing chemotherapeutic treatment, one hypothesis suggests that it originates from

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direct cytotoxicity of drugs excreted in sweat. However, as it has been observed in patients without previous pharmacologic treatment, the most widely accepted hypothesis is that it is part of the spectrum of neutrophilic dermatoses.1 A diversity of clinical lesions has been observed, the most common being erythematous papules and plaques that are infiltrated and edematous, scattered or grouped, and asymptomatic or painful.1 The differential diagnosis should include infectious forms of NEH, mainly caused by Serratia, Enterobacter, Staphylococcus aureus and Nocardia, as well as other neutrophilic dermatoses.1 NEH has a benign course, with spontaneous resolution after days or weeks without sequelae or scarring; therefore, the treatment is symptomatic with nonsteroidal anti-inflammatory drugs.1 Systemic corticosteroids have been given for painful lesions or fever; these seem to shorten the duration of lesions, lessen the fever, and relieve pain.9–11 In a recurrent case in an HIV-infected patient, dapsone was used.1 Colchicine was used in another patient with HIV as well as in patient with idiopathic NEH.2,12 References 1 Bachemeyer, C. Aractingi, S. Neutrophilic eccrine hidradenitis. Clin Dermatol. 2000;18:319–330. 2 Rouanet I, Jantac M, Lechiche C, Hope-Rapp E, Sotto A. Neutrophilic eccrine hidradenitis in an HIV-1 infected patient. AIDS. 2012;26:775–778. 3 Harrist TJ, Fine JD, Berman RS, Murphy GF, Mihm

MC, Jr. Neutrophilic eccrine hidradenitis. A distinctive type of neutrophilic dermatosis associated with myelogenous leukemia and chemotherapy. Arch Dermatol. 1982;118:263–266. 4 Srivastava M, Scharf S, Meehan S, Polsky D. Neutrophilic eccrine hidradenitis masquerading as facial cellulitis. J Am Acad Dermatol. 2007;56:693–696. 5 Bachmeyer C, Reygagne P, Aractingi S. Recurrent neutrophilic eccrine hidradenitis in an HIV-1-infected patient. Dermatology. 2000;200:328–330. 6 Krischer J, Rutschmann O, Roten SV, et al. Neutrophil eccrine hidradenitis in a patient with AIDS. J Dermatol. 1998;25:199–200. 7 Sevila A, Morell A, Bañuls J, Silvestre JF, Betlloch I. Neutrophilic eccrine hidradenitis in an HIV-infected patient. Int J Dermatol. 1996;35:651–652. 8 Smith KJ, Skelton HG 3rd, James WD, et al. Neutrophilic eccrine hidradenitis in HIV-infected patients. Armed Forces Retrovirus Research Group. J Am Acad Dermatol. 1990;23(5 Pt 1):945–947. 9 Bernstein EF, Spielvogel RL, Topolsky DL. Recurrent neutrophilic eccrine hidradenitis. Br J Dermatol. 1992;127:529–533. 10 Nikkels AF, Hansen I, Collignon J, et al. Neutrophilic eccrine hidradenitis: A case report. Acta Clin Belg. 1993;48:397–400. 11 Aractingi S, Mallet V, Pinquier L, et al. Neutrophilic dermatoses during granulocytopenia. Arch Dermatol. 1995;131:1141–1145. 12 Belot V, Perrinaud A, Corven C, et al. Adult idiopathic neutrophilic eccrine hidradenitis treated with colchicine. Presse Med. 2006;35:1475–1478.

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W W W. T N L A S E R S O C I E T Y. C O M

July/August 2017

Volume 15 • Issue 4

CASE STUDY

Cutaneous Rosai-Dorfman Disease Brett H. Keeling, MD; Lindsay LaPresto Thelin, MD; A. Carlo Gavino, MD; Ammar M. Ahmed, MD

A 48-year-old Hispanic man presented with a nodule on the right cheek. The lesion had started as a papule 4 months previously that had slowly enlarged and then plateaued at its present size. The nodule was asymptomatic, and the patient denied bleeding, draining, or preceding trauma. Review of systems was negative for fevers, weight loss, night sweats, lymphadenopathy, or other skin findings. Past medical history was significant only for type 2 diabetes mellitus, hyperlipidemia, and hypertension. (SKINmed. 2017;15:301–302)

hysical examination was significant for a 1.3-cm, pearly, pink, dome-shaped nodule with overlying telangiectasias (Figure 1). There were no other significant skin findings or lymphadenopathy. A shave biopsy was performed, and histopathologic evaluation revealed a dense dermal infiltrate of large polygonal histiocytes with admixed lymphocytes, plasma cells, and neutrophils (Figure 2). There was prominent emperipolesis, and histiocytes stained positive for S100. Laboratory evaluation was within normal limits, including complete blood count, comprehensive metabolic panel, and erythrocyte sedimentation rate. A diagnosis of cutaneous Rosai-Dorfman disease (RDD) was given. DISCUSSION

RDD is a non-Langerhans cell histiocytosis with two main subtypes: one form that affects the lymph nodes and occasionally extranodal organs, and another form that is exclusively cutaneous.1–3 While the skin is the most common extranodal site affected by RDD, pure cutaneous RDD (CRDD) is rare, occurring in only 3% of RDD patients.2–4 The etiology of this disease process remains to be elucidated, although viral and immune origins have been postulated.1 CRDD presents as single or multiple erythematous to brown papules, plaques, or nodules without site predilection.1–3 In contrast to RDD, CRDD lacks systemic signs and clinical manifestations including lymphadenopathy, fevers, leukocytosis, anemia, elevated erythrocyte sedimentation rate, and hypergammaglobulinemia.1–3,5 CRDD has a female predomi-

Figure 1. Right cheek with a smooth, pink, dome-shaped nodule.

nance and a median age of onset of 43 years of age, whereas RDD has a male predominance and median age of onset of 20 years of age.2, 3 Histologically, CRDD displays a normal epidermis and dense dermal lymphohistiocytic infiltrate, with or without subcutaneous involvement. Emperipolesis is the distinguishing finding in RDD and CRDD, and is defined as the presence of intact lymphocytes, or less often erythrocytes, neutrophils, or plasma cells, within histiocytes.1–3,5 Lymphoid follicles may also be observed. Immunohistochemical stains can be helpful for diagnosis; his-

From the Department of Dermatology, University of Texas – Austin School of Medicine, Austin, TX Address for Correspondence: Brett Keeling, MD, Department of Dermatology, University of Texas – Austin, 601 East 15th Street, CEC 2.470, Austin, TX 78701 • E-mail: bhkeeling@seton.org

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CASE STUDY a benign, indolent course, and treatment may not be necessary unless the extent or distribution of the disease causes distress to the patient. Spontaneous remission has been documented over the course of months to years.3–5 CONCLUSIONS Owing to the lack of distinguishing clinical characteristics, CRDD can be a difficult diagnosis to make; however, a high index of suspicion and histopathologic evaluation can facilitate accurate diagnosis and subsequent clinical management. References 1 Dalia S, Sagatys E, Sokol L, Kubal T. Rosai-Dorfman disease: Tumor biology, clinical features, pathology, and treatment. Cancer Control 2014;21:322–327.

Figure 2. Pathology demonstrates a dense dermal infiltrate of large polygonal histiocytes with admixed lymphocytes, plasma cells, and neutrophils. Emperipolesis can be seen.

2 Kutlubay Z, Bairamov O, Sevim A, Demirkesen C, Mat MC. Rosai-Dorfman disease: A case report with nodal and cutaneous involvement and review of the literature. Am J Dermatopathol. 2014;36:353–357.

tiocytes of CRDD stain positively for S100, variably for CD68, and negatively for CD1a.1–3,5 A variety of treatment options have been employed for CRDD, with variable success. For solitary tumors, excision is a great option. Other options include destructive modalities (cryotherapy, radiation therapy), corticosteroids (topical, intralesional, systemic), systemic retinoids, imatinib, dapsone, thalidomide, or vincristine.1–4,6 Due to its rarity, there is no consensus regarding treatment of CRDD. Fortunately, most cases of CRDD have

3 Rubenstein MA, Farnsworth NN, Pielop JA, et al. Cutaneous Rosai-Dorfman disease. Dermatol Online 2006;12:8. 4 Fang S, Chen AJ. Facial cutaneous Rosai-Dorfman disease: A case report and literature review. Exp Ther Med 2015;9:1389–1392. 5 Lin SK, Guralnick MP, Cassarino DS. Elusive diagnosis of left ear nodules. Cutaneous Rosai-Dorfman disease (RDD). JAMA Dermatol 2014;150:81–82. 6 Liu P, Wang P, Du J, Zhang J. Successful treatment of refractory cutaneous Rosai-Dorfman disease with vincristine. J Dermatol 2015;42:97–98.

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July/August 2017

Volume 15 • Issue 4

CASE STUDY

Oxalosis in a Patient with Livedo Reticularis Meriam Triki, MD;1 Meriem Ksentini, MD;1 Rim Kallel, MD;1 Emna Bahloul, MD;2 Faiçal Jarraya, MD;3 Abderrahmen Masmoudi, MD;2 Tahya Boudawara, MD1

A 27-year-old man with terminal renal failure requiring peritoneal dialysis for the past 2 years was referred to the dermatologist for evaluation of red violaceous macular skin lesions consistent with livedo reticularis. These lesions had appeared suddenly on his legs (Figure 1). He had first experienced recurrent nephrolithiasis at the age of 14. Results from urine analysis and abdominal ultrasound revealed chronic kidney failure. Because the patient had a sister with similar findings, primary hyperoxaluria (PH) was suspected and genetic testing was performed in all members of his family. The results confirmed PH type 1 (PH1) in both our patient and his sister, who had died 8 years after the establishment of the diagnosis. A biopsy of the livedo reticularis lesions revealed deposits of a yellowish brown crystalline material within the lumen and the media of medium vessels in the hypodermis associated with a histiocytic giant cell reaction (Figure 2a). There was no evidence of extravascular calcium deposition in the sections examined. The deposits were intensely birefringent under polarized light, and classic speculated crystals of oxalate salts were observed (Figure 2b). No focal epidermal or superficial dermal necrosis was seen. On the basis of the histopathologic findings, the diagnosis of oxalate crystal–induced vascular disease was established. The patient subsequently developed complications including pancreatitis and peritonitis. He underwent hemodialysis until a combined liver-kidney transplant could be performed. (SKINmed. 2017;15:303–305)

rimary hyperoxaluria is a rare group of autosomal-recessive inherited metabolic disorders. It is divided into various subtypes. Type 1 is the most common. It is associated with deficiency of alanine-glyoxylate aminotransferase (AGT), a pyridoxine-dependent hepatic peroxisomal enzyme responsible for the detoxification of glyoxylate.2 PH1 is further divided into three forms: infantile, juvenile, and adult. In the infantile form, there is no history of nephrolithiasis, and renal failure is rapidly progressive. The juvenile form is the most frequent and is characterized by recurrent nephrolithiasis prior to the development of renal failure. The rarest is the adult form. It is characterized by the development of renal failure before systemic complications related to oxalate deposition.3 All types of PH result in an increased endogenous production of oxalate leading to excessive urinary oxalate excretion. Secondary hyperoxaluria is caused by excess intake of oxalate or oxalate precursors.4 Because the main source of oxalate removal from the body is through urine excretion, renal failure of any origin requiring hemodialysis can lead to the deposition of oxalate salt in the body tissues, but with a much lower degree than that

from PH. This precipitation first occurs in the kidney and causes nephrolithiasis and nephrocalcinosis.5 Involvement of other tissue including the skin indicates late disease.2 Skin manifestations are extremely uncommon. Very few cases have been reported in the literature.4 In PH, skin lesions are caused by vascular complications resulting from oxalate deposition within arterial walls. The vascular insufficiency predisposes patients to livedo reticularis, acrocyanosis, and gangrene.6 In contrast to patients with PH, patients with systemic oxalosis caused by chronic renal failure are more likely to present with extravascular calcified deposits in the skin. The skin manifestations include dermal and subcutaneous nodules, macules, and papules, usually in an acral distribution or on the face.2,6 Patients with PH1 are usually diagnosed between 4 and 7 years of age in Europe and from birth to the sixth decade of life in Japan, with an average age at diagnosis of 13 years.5 At the time of diagnosis, a high proportion of patients (10%–40%) have already reached end-stage renal disease.5 Our patient was diagnosed with PH1 at the age of 14 years. Unfortunately, he had

From the Department of Pathology, Habib Bourguiba University Hospital,1 and the Department of Dermatology2 and Department of Nephrology,3 Hedi Chaker University Hospital, Sfax, Tunisia Address for Correspondence: Meriam Triki, MD, Department of Pathology, Habib Bourguiba University Hospital, El Ain Road Km 0.5, 3029 Sfax, Tunisia • E-mail: meriamtriki@yahoo.fr

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already developed chronic kidney disease at the time of the diagnosis. Eleven years later, he developed terminal renal failure and skin lesions 2 years later.

Figure 1. Red violaceous macular skin lesions of the lower limbs consistent with livedo reticularis.

The presence of renal failure with skin lesions in our patient suggested two main clinical differential diagnoses: calciphylaxis and nephrogenic systemic fibrosis (NSF). Both calciphylaxis and NSF develop in patients who are on long-term hemodialysis.7,8 Calciphylaxis is generally a fatal condition, usually observed in the setting of end-stage renal disease with secondary hyperparathyroidism.2,9 It manifests clinically with violaceous, reticulate areas of cutaneous necrosis and eschar, primarily of the extremities. NSF occurs in patients with advanced renal failure exposed to gadolinium contrast for radiologic evaluations. It presents with tender brawny indurated plaques or erythematous papules of the extremities and the trunk, sparing the face. The lesions are generally associated with pruritus and a burning sensation.8,10 A skin biopsy is necessary to establish the diagnosis. It shows, in patients with oxalosis, strongly birefringent yellow-brown crystals within vessel walls, usually unstained in hematoxylin and eosin sections.2 In contrast, a skin biopsy in calciphylaxis reveals basophilic calcium salt deposits within vessel walls and the interstitium.4 The elevation of calcium phosphorus product and parathyroid hormone levels further supports this diagnosis.7 Histopathologic evaluation of NSF skin biopsy shows fibrosis of the dermis, subcutis, and sometimes even fascia and muscle, associated with increased numbers of spindle cells and variable mucin deposition.10

Figure 2. (a) Yellowish brown crystalline material within the lumen and the media of medium vessels in the hypodermis (hematoxylin and eosin stain, original magnification ×400). (b) Birefringent crystals under polarized light (hematoxylin and eosin stain, original magnification ×400). SKINmed. 2017;15:303–305

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When oxalosis is suspected, plasma oxalate levels should be measured.11 If elevated and secondary hyperoxaluria is ruled out, genetic testing and liver biopsy should be performed to determine the disease subtype.1 In our case, the diagnosis of PH was prior to the development of livedo reticularis lesions. Histologic findings of the skin biopsy further supported the diagnosis.

References

Early treatment of hyperoxaluria consists in supportive therapy to keep the urine oxalate and calcium concentrations low. Oral pyridoxine, a cofactor for AGT, can be prescribed; however liver-kidney transplantation is considered to be the best therapeutic option for patients who have developed renal failure. Until transplantation is accomplished, hemodialysis is more effective than peritoneal dialysis in eliminating oxalate.4 In our case, livedo reticularis manifestations occurred when the patient was undergoing peritoneal dialysis. This further supports the fact that this type of dialysis is not suitable for patients with PH1. Without treatment, nearly one third of patients will die in 2 years, and death usually occurs before the age of 20 years2; however, after a liver-kidney transplant, patient survival rates can reach 86%, 80%, and 69% at 1 year, 5 years, and 10 years, respectively.5

1 Blackmon JA, Jeffy BG, Malone JC, Knable AL, Jr. Oxalosis involving the skin: case report and literature review. Arch Dermatol. 2011;147:1302–1305. 2 Rubenstein MC, Martinelli PT, Bayer-Garner IB, et al. Persistent cutaneous manifestations of hyperoxaluria after combined hepatorenal transplantation. Dermatol Online J. 2004;10:10. 3 Bogle MA, Teller CF, Tschen JA, Smith CA, Wang A. Primary hyperoxaluria in a 27-year-old woman. J Am Acad Dermatol. 2003;49:725–728. 4 Jorquera-Barquero E, Suarez-Marrero MC, Fernandez Giron F, Borrero Martin JJ. Oxalosis and livedo reticularis. Actas Dermosifiliogr. 2013;104:815–818. 5 Harambat J, Fargue S, Bacchetta J, Acquaviva C, Cochat P. Primary hyperoxaluria. Int J Nephrol. 2011;2011:864580. 6 Ohtake N, Uchiyama H, Furue M, Tamaki K. Secondary cutaneous oxalosis: cutaneous deposition of calcium oxalate dihydrate after long-term hemodialysis. J Am Acad Dermatol. 1994;31:368–372. 7 Dauden E, Onate MJ. Calciphylaxis. Dermatol Clin. 2008;26:557–568, ix. 8 Schieren G, Wirtz N, Altmeyer P, et al. Nephrogenic systemic fibrosis—a rapidly progressive disabling disease with limited therapeutic options. J Am Acad Dermatol. 2009;61:868–874. 9 Magro CM, Simman R, Jackson S. Calciphylaxis: a review. J Am Col Certif Wound Spec. 2010;2:66–72.

Conclusions Dermatologists should be aware of cutaneous vascular complications of PH, because early recognition of the disease may achieve long-term survival with the appropriate treatment.

10 Waikhom R, Taraphder A. Nephrogenic systemic fibrosis: a brief review. Indian J Dermatol. 2011;56:54–58. 11 Kemper MJ, Conrad S, Muller-Wiefel DE. Primary hyperoxaluria type 2. Eur J Pediatr. 1997;156:509–512.

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July/August 2017

Volume 15 • Issue 4

CASE STUDY

Auricular Hemosiderosis in a Diabetic Patient Krista N. Larson, MD; Mark A. Russell, MD

A 74-year-old Caucasian man with poorly controlled diabetes and hypertension was seen in the dermatology clinic for treatment of a nodular basal cell carcinoma on his right temple. He had poorly controlled diabetes for decades and had been insulin dependent for 20 to 25 years. He had not been on any anticoagulation therapy in the past or present and had no history of a hematologic disorder. He was retired and did woodworking as a hobby. During a routine presurgical head and neck skin examination, he was noted to have macular bluegray dyspigmentation of the central portion of the anterior portion of his ear lobes, bilaterally (Figure 1). He had first noticed this color change approximately 2 years ago and thought the pigmentation was darkening. It was not symptomatic. A punch biopsy was obtained. (SKINmed. 2017;15:307–308)

istologic examination of the punch biopsy specimen showed normal epidermis and diffuse deposition of granular brown pigmentation throughout the dermis. The pigmentation was located in the interstitial dermis and in macrophages. It was semi-refractile with polarization. Results from Fontana-Masson stain were negative for melanin while findings from Prussian blue stain highlighted the pigment, confirming the presence of hemosiderin (Figures 2 and 3). This anatomic location corresponded with the site of blood glucose checks performed by the patient. The patient had been performing blood glucose checks at this site for at least 7 years and for at least 5 years prior to the presentation of the skin lesions. Discussion

The phenomenon of localized pigmented skin is well studied and has multiple etiologies. Traumatic dermal depositions of heavy metals, through lead pencil injury or tattoos, have been reported.1,2 Endogenous ochronosis (alkaptonuria) can lead to blue-black pigmentation in the ears, nose, and sclera secondary to homogentisic acid collection in collagenous tissues.3,4 Exogenous ochronosis may also occur from topical use of high concentrations of hydroquinone and is typically localized to the skin.5 Endogenous melanin production can give the skin a blue hue as seen in blue nevi and other dermal melanocytoses. While the melanin itself is not blue, it absorbs red and green wavelengths, allowing reflection of blue wavelengths by the surrounding collagen.6

Figure 1. Clinical photographs of auricular cutaneous hemosiderosis present bilaterally––61×86 mm (300×300 DPI).

Additionally, various medications and substances of abuse have resulted in hyperpigmentation of a blue-gray hue in precise areas of skin. Most well known to dermatologists is the pigment change associated with minocycline use7; however, similar changes can be seen with use of antimalarials, antipsychotics,

From the Department of Dermatology at the University of Virginia School of Medicine, Charlottesville, VA Address for Correspondence: Krista Larson, MD, University of Virginia Department of Dermatology, 1221 Lee Street, #3, Charlottesville, VA 22908 • E-mail: knl4bm@virginia.edu

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CASE STUDY In our patient’s case, hemosiderin deposition was caused by repetitive blood glucose checks from the anterior portion of the earlobes, which he preferred to finger sticks because of his woodworking hobby. Using the earlobe as an alternative site for blood glucose checks has been researched as a potential site that causes less pain than the regular finger prick.14,15 This case illustrates a complication of using the ear as an alternative site for blood glucose monitoring. References 1 Granstein RD, Sober AJ. Drug- and heavy metal–induced hyperpigmentation. J Am Acad Dermatol. 1981;5:1–18. 2 Tsuji T. Experimental hemosiderosis: relationship between skin pigmentation and hemosiderin. Acta Derm Venereol. 1980;60:109–114.

Figure 2. Hematoxylin and eosin stain of punch biopsy from auricular cutaneous hemosiderosis site (Olympus microscope at 4× magnification).

3 Carlson DM, Helgeson MK, Hiett JA. Ocular ochronosis from alkaptonura. J Am Optom Assoc. 1991;62:854– 856. 4 Albers SE, Brozena SJ, Glass LF, et al. Alkaptonuria and ochronosis: case report and review. J Am Acad Dermatol. 1992;27:609–614. 5 Engasser PJ. Ochronosis caused by bleaching creams. J Am Acad Dermatol. 1984;10:1072–1073. 6 Findlay GH. Blue skin. Br J Dermatol. 1970;83:127–134. 7 Simons JJ, Morales A. Minocycline and generalized cutaneous pigmentation. J Am Acad Dermatol. 1980;3:244– 247. 8 Tuffanelli D, Abraham RK, Dubois EJ. Pigmentation from antimalarial therapy. Its possible relationship to the ocular lesions. Arch Dermatol. 1963;88:419–426. 9 Zelickson AS. Skin pigmentation chlorpromazine. JAMA. 1965;194:670–672. 10 Trimble JW, Mendelson DS, Fetter BF, et al. Cutaneous pigmentation secondary to amiodarone therapy. Arch Dermatol. 1983;119:914–918. 11 Resende RG, Teixeira RG, Vasconcelos Fde O, et al. Imatinib-associated hyperpigmentation of the palate in postHSCT patient. J Craniomaxillofac Surg. 2011;40:e140– e143.

Figure 3. Prussian blue stain of auricular hemosiderosis site confirming presence of hemosiderin (Olympus microscope at 4x magnification).

azidothymidine, and amiodarone.8–10 In these cases, cutaneous pigmentation may be diffuse or limited to sun-exposed skin. Another medication, imatinib, has been most noted to cause hypopigmentation, but a few case reports of hyperpigmentation have been reported.11 Levamisole-adulterated cocaine has also been seen to cause immune complex–mediated vasculitis of the ear lobe in addition to the findings of agranulocytosis, neutropenia, and retiform purpura on the trunk.12 Perniosis may also cause purple-blue discoloration of the earlobes that is transient, usually lasting 1 to 2 weeks.13

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12 Chung C, Tumeh PC, Birnbaum R, et al. Characteristic purpura of the ears, vasculitis, and neutropenia– –a potential public health epidemic associated with levamisole-adulterated cocaine. J Am Acad Dermatol. 2011;65:722–725. 13 Scurry JP, Cowen SJ. Necrobiotic pernio. Australas J Dermatol. 1989;30:29–31. 14 Anzalone P. Equivalence of earlobe site blood glucose testing with finger stick. Clin Nurs Res. 2008;17:251– 261. 15 Carley SD, Libetta C, Flavin B, et al. An open prospective randomised trial to reduce the pain of blood glucose testing: ear versus thumb. BMJ. 2000;321:20.

Auricular Hemosiderosis in a Diabetic Patient

July/August 2017

Volume 15 • Issue 4

CASE STUDY

Isotretinoin and Surgical Extraction for Adult-Onset Nevus Comedonicus Joanna Dong, BA;1 Robert G. Phelps, MD;1,2 Jacob Levitt, MD1

We present a case of postmenopausal-onset nevus comedonicus in a 58-year-old white woman with no relevant medical history. Two years before presentation, the patient had had a solitary red nodule, measuring 3.8 cm wide, on the mid lateral region of her left thigh. This progressed to a large area, 11.4 cm wide and 14 cm long, of multiple pruritic and painful red nodules, cysts, and deep open comedones extending across the lateral part of the left thigh, with less severe segmental extension to the lateral aspect of the left leg. (SKINmed. 2017;15:309–310)

he patient had previously been employed as a store associate but had not worked for years before the initial onset. She denied exposures to chemicals substances, organic solvents, or other caustic substances, and had never worked in a factory or in textiles. The patient had previously failed treatment with emollients, azelaic acid, intralesional triamcinolone, doxycycline, tazarotene, and topical tretinoin. She experienced intolerable facial retinoid dermatitis with isotretinoin 80 mg during her first month of treatment and discontinued therapy as a result. Punch biopsy of an inflamed epidermoid cyst showed an inflammatory cystic reaction and the presence of a perifollicular mononuclear infiltrate (Figure 1). A diagnosis of inflammatory nevus comedonicus with epidermoid cysts was made based on the histopathology and clinical presentation. We restarted oral isotretinoin at 20 mg once daily, increasing to 60 mg per day over the course of 2 months (40 mg in the morning and 20 mg at bedtime), with treatment for a total of 5 months. Importantly, we incised and drained comedones and inflamed cysts on a monthly basis until the process had been extinguished (Figure 2). The patient enjoys remission with retained areas of postinflammatory hyperpigmentation and scarring after treatment. DISCUSSION

Nevus comedonicus (NC) is a rare epidermal nevus characterized by the formation of hamartomas of the pilosebaceous unit.1 Thought to be due to defective embryonal development of follicular structures, soft keratin fills the adnexal space normally taken

up by terminal hair or sebaceous gland. Clinical presentation is a grouped or linear pattern of enlarged follicles filled with darkly pigmented keratin plugs, resembling large open comedones, typically on the face, trunk, abdomen, or proximal extremities. The spectrum of severity ranges from asymptomatic comedones to inflammatory cysts, fistulas, or abscesses that heal with scarring.2 NC lesions present shortly after birth or in childhood and, very uncommonly, after 10 years of age. We report a case of late-onset severe inflammatory NC with epidermoid cysts, distributed segmentally over the left lower extremity along broad bands of Blaschko lines, that was successfully treated with oral isotretinoin and incision and drainage.3 This case is striking for two reasons: its postmenopausal onset and the efficacy of isotretinoin in the setting of the inflammatory histopathological variant disease. To our knowledge, there are no reported cases in the literature of NC presenting later than the second decade of life.4–7 NC is benign and typically treated in a similar manner to acne. Conservative management includes moisturizers and emollients, keratolytics, topical steroids in inflammatory cases, topical retinoids, vitamin D analogues, and oral isotretinoin.5 More invasive and definitive approaches include extraction, curettage and dermabrasion, and surgical excision.8 Inflammatory NC lesions involving infected tissue may be drained if abscesses are present, and treated with antibiotics. Given the low incidence of disease, studies of comparative treatment strategies are not feasible, and there is no

From the Department of Dermatology,1 and the Department of Pathology,2 Icahn School of Medicine at Mount Sinai, New York, NY Address for Correspondence: Jacob Levitt, MD, 5 East 98th Street, 5th Floor, New York, NY 10029 • E-mail: jacob.levitt@mountsinai.org

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CASE STUDY efficacy in some patients.6,9 The molecular basis of NC pathogenesis is as yet unknown but perhaps is linked to upregulated FGFR2 signaling leading to increased interleukin-1α expression and follicular hyperkeratinization.1,5 Retinoids attenuate the downstream effects of FGFR2 in acne, including inflammation and follicular hyperkeratinization, suggesting a similar role in NC.10 Most recently, somatic mutations in NEK9 affecting follicular differentiation have been found in NC patients.11 It is thus tempting to speculate that retinoids have a role in treating cases of NC with particularly inflammatory and aberrantly hyperkeratotic characteristics, as may be seen on pathology specimens. CONCLUSIONS

Figure 1. H&E stain at ×20 magnification. Multiple intradermal small epithelial cysts lined by attenuated squamous epithelium and without any epithelial attachments or pilosebaceous glands. Some cysts are surrounded by prominent lymphohistocystic inflammatory infiltrate.

We have demonstrated the successful use of concurrent oral isotretinoin and regular surgical extraction in treating a case of late-onset inflammatory NC complicated by numerous cysts. Isotretinoin may have mitigating effects on the inflammatory and follicular processes underlying NC, thus suggesting its application specifically in inflammatory-type NC. Procedural draining of inflammatory material and cystic lesions may further facilitate treatment. References 1 Lefkowitz A, Schwartz RA, Lambert WC. Nevus comedonicus. Dermatology. 1999;199:204–207. 2 Kirtak N, Inaloz HS, Karakok M, et al. Extensive inflammatory nevus comedonicus involving half of the body. Int J Dermatol. 2004;43:434–436. 3 Happle R. Mosaicism in human skin. Understanding the patterns and mechanisms. Arch Dermatol. 1993;129:1460–1470. 4 Manola I, Ljubojevic S, Lipozencic J, et al. Nevus comedonicus—case report and review of therapeutical approach. Acta Dermatovenerol Croat. 2003;11:221–224. 5 Tchernev G, Ananiev J, Semkova K, et al. Nevus comedonicus: An updated review. Dermatol Ther (Heidelb). 2013;3:33–40. 6 Chhabra N, Pandhi D, Verma P, et al. Inflammatory nevus comedonicus with epidermoid cyst. Indian J Dermatol. 2014;59:422. 7 Boudhir H, Bouhllab J, Senouci K, et al. [Nevus comedonicus]. Presse Med. 2015;44:115–116. 8 Milburn S, Whallett E, Hancock K, et al. The treatment of naevus comedonicus. Br J Plast Surg. 2004;57:805–806.

Figure 2. Subsidence of deep comedones and cysts with scarring and postinflammatory hyperpigmentation of the lateral aspect of the left thigh.

9 Cestari TF, Rubim M, Valentini BC. Nevus comedonicus: Case report and brief review of the literature. Pediatr Dermatol. 1991;8:300–305.

compelling argument of the most efficacious course of treatments in the literature among case reports and series.

10 Melnik BC, Schmitz G, Zouboulis CC. Anti-acne agents attenuate FGFR2 signal transduction in acne. J Invest Dermatol. 2009;129:1868–1877.

Traditionally, oral isotretinoin has been considered an ineffectual treatment option for NC, but recent case reports suggest selective

11 Levinsohn JL, Sugarman JL, McNiff JM, et al. Somatic mutations in NEK9 cause nevus comedonicus. Am J Hum Genet. 2016;98:1030–1037.

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CASE STUDY

Transient Reactive Eruptive Lymphangiectasia Following Partial Vulvectomy for Chronic Acquired Lymphangioma Paul J. Wirth, MD;1 Lin Lin, MD, PhD2

A 64-year-old white woman was originally diagnosed with histiocytic lymphoma in 1977. She had bilateral lymph node biopsies of the groin, chemotherapy, and radiation therapy after her diagnosis had been confirmed pathologically. She was treated with prednisone and vincristine. (SKINmed. 2017;15:311–313)

he patient eventually developed gross lymphedema of the lower extremities. She had chronic, recurrent lymphangitis and had worn support hose for her lower extremities for many years. She had persistent enlarged left inguinal lymph nodes, which had been stable in size on routine computed tomography examinations. The patient, since the time of her initial lymph node biopsies, had had persistent vulvar edema with the development of multiple (50 to 80) 2- to 3-mm vesicles containing clear fluid. These vesicles were prone to constant rupture, lymphorrhea, and recurrence. The patient had to wear incontinence diapers. A cutaneous biopsy, early in the course of her condition, confirmed the vesicles to be lymphangioma. Over the next 20 years, the patient had many multiple cryosurgical and electrosurgical vaporization treatments in an effort to control the lymphangiomas. After many years of treatment, the patient decided to have a left-sided vulvectomy in hope of a more permanent solution to her lymphorrhea (Figure 1). Twenty-four hours after the excision of the vulvar lymphangioma, the patient developed an asymptomatic explosion of hundreds of minute, 1- to 3-mm hemorrhagic vesicles on her abdomen. The abdominal skin had been clinically normal before surgery, and no dressings had been applied to the involved area (Figures 2 and 3). A biopsy of the abdominal vesicles showed

dilated vascular channels consistent with lymphangioma (Figure 4). No treatment was given, and the vesicles resolved in 24 hours. A lymphoscintigraph was ordered, and there was no other complication of the vulvectomy procedure. Over the 5 years that have elapsed since the vulvectomy, the patient has had no lymphorrhea and no recurrence of the vesicles, and she no longer needs incontinence diaper protection. DISCUSSION Lymphangioma of the skin develops in a number of clinical scenarios depending on the size and location, and on whether lymphatic obstruction has occurred for any reason. Lymphangioma circumscriptum, the most common type of lymphangioma, usually appears at birth or during childhood. It can, however, appear at any time, usually on the axillary folds, proximal areas of the limbs, shoulders, and neck.1–4 Cavernous lymphangioma are large, soft swellings of the subcutaneous tissue that may be circumscribed or defined by their clinical presentation.5,6 Acquired lymphangioma develops secondary to obstruction and pressure elevation in the lymphatic system itself.7,8 Numerous types of obstructive phenomenon have been reported in the literature as resulting in elevated intralymphatic pressure. Our pa-

From the Department of Dermatology, Jacobs School of Medicine and Biomedical Sciences, Buffalo, NY;1 and the Division of Dermatologic Surgery and Dermatopathology, Department of Dermatology, Buffalo Medical Group, Buffalo, NY2 Address for Correspondence: Paul J. Wirth, MD, Buffalo Medical Group, 325 Essjay Road, Williamsville, NY 14221 • E-mail: paulwirt@buffalo.edu

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Figure 3. Close-up view of the eruptive lymphangiectasia.

Figure 1. Presurgical chronic lymphangioma of the vulvar skin. Note the multiple vesicles and scar tissue related to prior vaporization procedures.

Figure 4. The biopsy specimen reveals a dome-shaped lesion showing dilated vascular channels within the papillary dermis. The surrounding dermis shows extravasation of erythrocytes with marked lymphohistiocytic infiltrate. Scattered plasma cells and eosinophils are also noted.

Figure 2. The abdomen 24 hours after vulvectomy, showing eruptive lymphangiectasia.

tient demonstrates the results of elevated hydrostatic pressure of the lymphatic system, here caused by iatrogenic obstruction and leading to a common chronic form of acquired lymphangioma and an uncommon acute form of lymphangiectasia. SKINmed. 2017;15:311â&#x20AC;&#x201C;313

The pathogenesis of acquired chronic lymphangioma is related to obstruction of the lymphatic system with a secondary increase in intralymphatic hydrostatic pressure resulting in a retrograde bulging vesicular response by the tiny lymphatic channels in the skin.9 What is unique in this patient is the acute development of numerous transient lymphangiectasia lesions on the abdomen as a result of surgery on the original acquired lymphangioma of the vulva. Many cases of benign lymphangiomatous papules have been cited in the literature. Reported cases generally are of a single or

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several papules developing after years of latency. In this patient, these benign lymphangiomatous papular lesions developed in 24 hours and numbered in the hundreds.10 The response in the abdominal skin was likely related to transient edema and obstruction in the vulvar region. Once the edema had resolved and the lymphatic pressure had reduced, the abdominal lymphangiectasia resolved on its own. Surgical excision of chronic lymphangioma of the vulva may be adventitious for patients who have demonstrated recurrences from more commonly used ablative procedures. CONCLUSIONS Chronic lymphangiomas are a bothersome potential side effect of surgeries involving manipulation of lymph nodes that are necessary for drainage of the limbs. The uniqueness of this case lies in the number of lymphangiectasia lesions on the abdomen, which were likely a result of the iatrogenic obstruction in the vulvar region. References 1 Flanagan BP, Helwig EB. Cutaneous lymphangioma. Arch Dermatol 1977;113:24–30.

2 Palmer LC, Strauch WG, Welton WA. Lymphangioma circumscriptum. A case with deep lymphatic involvement. Arch Dermatol 1978;114:394–396. 3 Whimster IW. The pathology of lymphangioma circumscriptum. Br J Dermatol 1976;94:473–486. 4 Browse NL, Whimster I, Stewart G, et al. Surgical management of lymphangioma circumscriptum. Br J Surg 1996;73:585–588. 5 Sieber PR, Sharkey FE. Cystic hygroma of the breast. Arch Pathol 1986;110:353. 6 Mosca RC, Pereira GA, Mantesso A. Cystic hygroma: characterization by computerized tomography. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2008;105:e65– e69. 7 Watanabe M, Kishiyama K, Ohkawara A. Acquired progressive lymphangioma. J Am Acad Dernatol 1983;8:663– 667. 8 Moon SE, Youn JI, Lee YS. Acquired cutaneous lymphangiectasia. Br J Dermatol 1993;129:193–195. 9 Landthaler M, Hohenleutner U, Braun-Falco O. Acquired lymphangioma of the vulva: palliative treatment by means of laser vaporization carbon dioxide. Arch Dermatol 1990;126:967–968. 10 Requena L, Heinzkutzner, Mentzel T, Duran R. Vascular proliferations in irradiated skin. Am J Surg Pathol 2002;26:328–337.

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July/August 2017

Volume 15 • Issue 4

CASE STUDY

Acquired Idiopathic True Transverse Leukonychia Ali Hadi, MD;1 Dana Stern, MD2

A 34-year-old man from Djibouti presented with a 14-year history of relapsing and remitting transverse white bands on the fingernails with sparing of the toenails. Examination revealed several transverse, white bands following the contour of the lunula on seven of his fingernails that did not fade upon compression of the digits (Figure). There was no onycholysis. No other skin lesions were noted. The patient reported having lived for 4 years (2000–2004) in a house that had well water as its primary water supply. This 4-year period was a stressful point in our patient’s life. During that time, he had been a student at university. He had had no reported occupational exposure to arsenic. He reported being a cigarette smoker since 1996 but denied any illicit drug use or alcohol consumption. His past medical history was significant for hepatitis A infection, but he denied any history of systemic illness, including renal disease, heart disease, and lung disease. He denied any family history of leukonychia. He denied any trauma or participation in activities that require excessive use of his hands, and also denied manipulation of the cuticles. The patient’s liver function tests, lipid panel, complete blood count, and urinalysis were all within normal limits. A blood test revealed normal arsenic levels. Histologic examination of the nail plate showed segmental parakeratosis, with no evidence of fungal organisms upon PAS staining. (SKINmed. 2017;15:315–317)

eukonychia has historically been classified in multiple ways. One way is by the pattern of color, with the categories being leukonychia totalis, which involves the entire nail, leukonychia punctata, in which there are white spots on the nail, and transverse leukonychia, in which there are transverse white stripes across the nail. Another way is to consider where the pathology lies: within the nail plate itself (true leukonychia) or underneath it (apparent leukonychia). For example, transverse leukonychia can present either as Muerckhe lines, which are due to subungual vascular pathology, or as Mees lines, which are due to a defect of the nail plate, typically in the context of arsenic poisoning.1 Furthermore, leukonychia can be inherited or acquired. The inherited form has been determined to be a result of a mutation in genes for type II cytokeratins, located on chromosome 12q13.2

Acquired leukonychia is classically associated with drug exposure, specifically to arsenic, thallium, and chemotherapy agents, or internal disease, typically renal disease (Table).3 Idiopathic acquired leukonychia is rare. Mees lines are typi-

cally associated with stress of some sort, with arsenic poisoning being a common association, as mentioned above. The association with arsenic is so strong that it has been reported in multiple settings. A case of Mees lines after acute arsenic intoxication, with transverse white bands developing 10 weeks later, has been reported in the literature.4 Similarly, a case of iatrogenic arsenic-induced Mees lines developing only 7 days after treatment with arsenic trioxide for acute myeloid leukemia has been reported.5 In both cases, Mees lines were limited to the fingernails and not observed in the toenails, consistent with our patient’s presentation. Arsenic-induced Mees lines were initially in our differential diagnosis for this patient. The United States Environmental Protection Agency reports that ground water supplies have higher levels of arsenic than surface sources and recommends regular testing of well water arsenic levels; however, our patient had no other sequelae of arsenic intoxication, including alopecia, neuropathy, and hyperpigmentation, pointing away from arsenic exposure as the cause of our patient’s leukonychia.

From the Ronald O. Perelman Department of Dermatology, New York University School of Medicine, New York, NY;1 and the Department of Dermatology, Icahn School of Medicine at Mount Sinai, New York, NY2 Address for Correspondence: Ali Hadi, MD, New York University School of Medicine, 550 First Avenue, New York, NY 10016 • E-mail: alihadi91@gmail.com

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CASE STUDY Furthermore, chronic arsenic exposure can result in skin lesions such as arsenical keratosis, as well as a higher risk of development of basal cell carcinomas, also not observed in our patient. Our patient had normal serum arsenic levels at the time of presentation. Arsenic levels can be measured directly in nail samples.4 These levels normalize within 2 years of exposure, making them less likely to be abnormal in our patient whose exposure to arsenic would have occurred 10 years before presentation.4 Although arsenic-induced Mees lines are a possible diagnosis in our patient given his history of drinking well water, his normal serum arsenic level, remote and unconfirmed history of exposure, and lack of other clinical manifestations makes this diagnosis unlikely. A case of idiopathic acquired leukonychia sparing the toenails in a young African man, which also relapsed and remitted for years in a similar fashion to our patient, has been reported. The patient in that case also had normal laboratory tests, a non-contributory family history, and no confirmed history of exposure to agents that induce leukonychia.2 In this report, we describe the second known case of idiopathic acquired leukonychia in an individual of African descent, and the only known case of idiopathic true transverse leukonychia in any patient.

Figure 1. Transverse leukonychia or transverse white lines following the contour of the lunula of the right second, third, and fourth fingernails.

Table. Differential Diagnosis of Acquired Transverse Leukonychia Cause

Test

Our Patient

Renal disease3

Serum creatinine and protein/blood in urine

Asymptomatic, with normal creatinine and no proteinuria

Arsenic poisoning3

Serum arsenic, 24-hour urinary arsenic excretion, and nail sample

Patient had normal serum arsenic levels with no other signs of arsenic poisoning

Thallium poisoning3

At low doses, thallium causes hair loss and peripheral neuropathy

Patient did not exhibit clinical manifestations of thallium poisoning

Carbon monoxide poisoning

Measure carboxyhemoglobin in the blood

No reason to suspect carbon monoxide poisoning

Trauma

Patient history and physical examination

No history or evidence of trauma

Patient history

No history of chemotherapy

Heart disease3

ECG, physical examination, and patientâ&#x20AC;&#x2122;s medication history would indicate this

No history of heart disease

Severe infection

Leukocytosis, fever

Patientâ&#x20AC;&#x2122;s laboratory results were normal and there was no complaint of fever

Hodgkin lymphoma7

Diagnosed by pathology specimen

No B cell clinical manifestations or lymphadenopathy

Leprosy7

Skin lesions in an endemic area

No history or evidence

Malaria7

History of fever, anemia, joint pain, and nausea. Test by blood smear

Patient reports no history of malaria

Chemotherapy

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Conclusions Acquired transverse leukonychia has a broad differential diagnosis, with many systemic diseases and toxins being common associations. A thorough workup including a detailed history, examination, and laboratory investigations, especially in patients with clinical manifestations, is warranted to exclude more serious causes; however, acquired idiopathic true transverse leukonychia, although rare, is also a possibility and needs to be considered as a diagnosis in patients presenting in this manner. References

2 Dlova NC, Tosti A. Idiopathic acquired true total and subtotal leukonychia: report of two cases. Int J Dermatol. 2014;53:e261-e263. 3 Chauhan S, D’Cruz S, Singh R, Sachdev A. Mees’ lines. Lancet. 2008;372:1410. 4 Seavolt MB, Sarro RA, Levin K, Camisa C. Mees’ lines in a patient following acute arsenic intoxication. Int J Dermatol. 2002;41:399-401. 5 Bagic A, Lupu V, Kessler CM, Tornatore C. Iatrogenic arsenic induced Mees’ lines. Postgrad Med J. 2006;82:515. 6 Wu YY, Chao TY. Mees’ lines. Intern Med J. 2011;41:578.

1 Grossman M, Scher RK. Leukonychia. Review and classification. Int J Dermatol. 1990;29:535-541.

7 Mirfazaelian H, Namazi MR, Daneshbod Y. Mees’ lines. ScientificWorldJournal. 2011;11:267-268.

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Volume 15 • Issue 4

correspondence Snejina Vassileva, MD, PhD, Section Editor

Tuberous Sclerosis Complex: Unusual Presentation in an Adult Patient Naveen Kansal Kansal, MD To the Editor:

DISCUSSION

Inappropriate use of medications, in particular penicillin, may lead to antibiotic resistance and its consequences, and was accurately predicted by Sir Alexander Fleming (1881–1955) in his Nobel Lecture in 1945.1 Self-medication by patients, either on their own or on the advice of friends, relatives, or a pharmacist, has become a significant problem in India.2 Topical corticosteroid-induced, rosacea-like facial dermatosis, resulting from application of corticosteroid preparation(s) to facial skin, has reached “epidemic” proportions in India.2,3 Recently, in a rather bizarre example of self-medication, an adult patient with tuberous sclerosis presented to us, having applied a “mole-removal” paste to treat his angiofibromas.

The initial diagnosis of tuberous sclerosis is primarily a field for pediatricians or pediatric dermatologists, as approximately 50% of patients present with infantile spasms. Skin examination should be performed in infants with infantile spasms—an early diagnosis with proper follow-up may improve clinical outcome in this disease, as tuberous sclerosis has considerable morbidity and mortality.4,5 Not all cases present in infancy, and some patients are diagnosed later, usually due to dermatologic manifestations, epilepsy or learning difficulties, or systemic involvement (hamartomatous tumors), and so on; however, it is rare to see a presentation like that in our patient, in which there was no history of epilepsy, and the patient had not sought previous medical advice earlier. In fact, the first visual impression as the patient entered the outpatient department room was of xeroderma pigmentosum.

CASE STUDY A 42-year-old man presented to the dermatology outpatient department with multiple “moles” on his face that had been present since childhood. He had recently applied an over-thecounter mole-removing medication, resulting in many of the “moles” becoming erythematous with burning and pain. There was no history of epilepsy, mental retardation, or any systemic complaint. Examination revealed multiple angiofibromas, a few ulcerated, covering most of his face, along with considerable scarring (Figure 1). He also had a fibrous plaque on the forehead (Figure 1) and an ash-leaf macule on the back, as well as periungual fibromas (Koenen tumors) on the fingers (Figure 2) and toes. A diagnosis of tuberous sclerosis (fulfilling two major criteria of the updated diagnostic criteria)3 was made. The constituents of the mole-removal “medication” were not printed on the packet, but they are likely to be a caustic chemical agent. We prescribed cefixime 200 mg twice daily and a corticosteroid cream to be applied for 5 days.

Figure 1. Numerous angiofibromas (some ulcerated) and considerable scarring of the face, with a fibrous plaque near the left eyebrow.

From the Department of Dermatology and Venereology, All India Institute of Medical Sciences, Rishikesh, India Address for Correspondence: Naveen Kansal Kansal, MD, Department of Dermatology and Venereology, All India Institute of Medical Sciences, Rishikesh-249203, India • E-mail: kansalnaveen@gmail.com

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The facial scarring suggested prior unsuccessful attempts at treating angiofibromas, which brings us to the problem of unrestrict-

ed use or sale of medicines, whether it is a prescription topical corticosteroid cream, other medicaments, or a so-called medicine with unknown components. CONCLUSIONS This patient encounter highlights the social responsibility for the primary physician and even the dermatologist to counsel patients and the general public about the harmful effects that may occur with the irresponsible use of any medication,2 even an innocuous-looking cream. References 1 Fleming A. Penicillin: Nobel Lecture, Dec 11, 1945. http://www.nobelprize.org/nobel_prizes/medicine/ laureates/1945/fleming-lecture.pdf. Accessed April 29, 2017. 2 Porter G, Grills N. Medication misuse in India: A major public health issue in India. J Public Health (Oxf). 2016;38:e150–e157. 3 Verma SB. Topical corticosteroid misuse in India is harmful and out of control. BMJ. 2015;351:h6079. 4 Northrup H, Krueger DA, International Tuberous Sclerosis Complex Consensus Group. Tuberous sclerosis complex diagnostic criteria update: Recommendations of the 2012 International Tuberous Sclerosis Complex Consensus Conference. Pediatr Neurol. 2013;49:243–254. 5 Osborne JP, Green AJ. Tuberous sclerosis. In: Irvine AD, Hoeger PH, Yan AC, eds. Harper’s Textbook of Pediatric Dermatology. 3rd ed. Vol. 2. Oxford: Wiley-Blackwell; 2011:129.1–129.13.

Figure 2. Koenen tumors on the left index and ring fingers.

Anticoagulation in Patients with Pseudoxanthoma Elasticum Maryam Liaqat, MD; Warren R. Heymann, MD To the Editor: A cardiothoracic surgeon asked for our recommendation regarding anticoagulation in an 80-year-old Japanese woman with biopsy-proven pseudoxanthoma elasticum (PXE) who was scheduled for coronary artery bypass graft surgery. This request prompted us to review the literature regarding current best prac-

tices about anticoagulation for the thrombohemorrhagic complications of PXE. DISCUSSION PXE, also known as Grönblad-Strandberg syndrome, is an autosomal recessive condition.1 PXE is considered the prototypical multisystem ectopic mineralization disorder with

From the Division of Dermatology, Cooper Medical School of Rowan University, Camden, NJ Address for Correspondence: Maryam Liaqat, MD, Division of Dermatology, Cooper Medical School of Rowan University, 3 Cooper Plaza, Suite 504, Camden, NJ 08103 • E-mail: liaqat-maryam@cooperhealth.edu

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abnormal mineralization of soft connective tissue with degeneration of elastic fibers. PXE primarily involves the eyes, cardiovascular system, and skin. Vascular involvement is characterized by thrombotic and hemorrhagic complications including acute upper gastrointestinal hemorrhage, intestinal angina, coronary artery disease, transient ischemic attacks, and strokes.2 To address our query, data were collected from PubMed with search terms including: PXE + anticoagulation (AC); PXE + aspirin or/& warfarin or/& low molecular weight heparin (LMWH) or /& novel anticoagulants; thrombohemorrhagic disease (TH) + AC; TH + aspirin or/& warfarin or/& LMWH or/& novel anticoagulants; as well as ectopic mineralization (EM) + AC; EM+ aspirin or/& warfarin or/& LMWH or/& novel anticoagulants. The review revealed a paucity of data with some contradictory conclusions. Cardiac guidelines suggest that aspirin be used as a standard of care preoperatively and postoperatively. In one case report, percutaneous coronary angioplasty using a drug-eluting stent was performed in a patient with PXE. The authors chose a heparin-coated stent to reduce the risk of stent thrombosis, and the patient was discharged using antiplatelet monotherapy. The use of rapamycin or taxol drug-eluting stents was deferred to avoid double oral antiplatelet therapy.3 In contrast, a 100-patient cohort with PXE was followed in the Netherlands with a mean follow-up of 17.1 years. Within the cohort, seven patients had an ischemic stroke caused by small vessel occlusive disease. However, a larger group of 17 patients were noted to have gastrointestinal hemorrhage. One of the patients with a fatal gastrointestinal bleed was taking aspirin. The authors concluded this constitutes a contraindication for use of aspirin in PXE.4

Table. Summary of Anticoagulation in Patients with Pseudoxanthoma Exanthem Anticoagulant

Aspirin Warfarin Newer lowmolecular-weight heparins

Otherwise Healthy

Use

Perhaps avoid

Avoid

No data

There are no clear guidelines for anticoagulation in patients with PXE; however, the risk of thrombosis outweighs the risk of bleeding in patients with known arterial disease. In such patients, aspirin or other antiplatelet therapy as monotherapy would be acceptable (Table). Warfarin, however, should be avoided. No conclusions can be reached regarding use of the newer low-molecular-weight heparins, such as apixaban or rivaroxaban, as no data are available. CONCLUSIONS Our patient underwent successful coronary artery bypass surgery, and was discharged on aspirin (81 mg daily) and apixaban (2.5 mg twice daily) without complications. In conclusion, given the risk of gastrointestinal bleeding and thrombotic events in PXE, guidelines for appropriate anticoagulation must be developed. References

An animal model study was performed to assess the effect of warfarin on ectopic mineralization within a group of ABCC6-deficient mice. This demonstrated significantly increased serum levels of oxidized vitamin K.5 In addition, mice fed a warfarin-containing diet were found to have an abundant uncarboxylated form of matrix Gla protein; this has been shown to lead to progressive tissue mineralization. This study also surveyed patients with PXE on warfarin; of 539 patients, 2.6% reported either current or past warfarin use. These patients observed worsening of their clinical disease during anticoagulation. The authors theorized that because of the increased risk of mineralization, warfarin should be avoided in patients with PXE.

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1 Marconi B, Bobyr I, Campanati A, et al. Pseudoxanthoma elasticum and skin: Clinical manifestations, histopathology, pathomechanism, perspectives of treatment. Intractable Rare Dis Res. 2015;4:113–122. 2 Uitto J, Jiang Q, Váradi A, Bercovitch LG, Terry SF. Pseudoxanthoma elasticum: Diagnostic features, classification and treatment options. Expert Opin Orphan Drugs. 2014;2:567–577. 3 Baglini R, Sesana M, Capuano C, Danzi GB. Intracoronary ultrasound guided percutaneous coronary angioplasty using a drug eluting stent in a patient with pseudoxanthoma elasticum. Atherosclerosis. 2005;180:205–207. 4 Vandenberg J, Hennekam RC, Cruysberg JR, et al. Prevalence of symptomatic intracranial aneurysm and ischaemic stroke in pseudoxanthoma elasticum. Cerebrovasc Dis. 2000;10:315–319. 5 Li Q, Guo H, Chou DW, et al. Warfarin accelerates ectopic mineralization in Abcc6–/– mice. Am J Pathol. 2013;182:1139–1150.

Anticoagulation in Patients with Pseudoxanthoma Elasticum

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