Mar/Apr, 2015 by jo-ann kalaka-Adams

March/April 2015 • Volume 13 • Issue 2 EDITORIAL Dermatopathology for Fun and Profit: “Updiagnosing” Distresses and Endangers Patients and Abuses Their Trust Lambert, Lambert, and Parish

case studies An Unusual Case of Darier Disease Complicated With a Parasitic Infestation Escandón-Vargas, Cabezas, and Díaz

COMMENTARY Acne Therapeutics: A Closer Look at Benzoyl Peroxide

Cutaneous Hyperneury: A New Entity or an Atypical Cutaneous Manifestation of MEN 2B?

ORIGINAL CONTRIBUTIONS Trichoscan Findings in Patients With Effluvium Capillorum

Generalized Eruptive Keratoacanthoma of Grzybowski

Bhatt and Mimesh

Mohammad and Burkhart

Kasumagic-Halilovic, Ovcina-Kurtovic, and Begovic

Chondroid Syringoma: Report of Four Cases

Limaiem, Bouslama, Haddad, Ben Slama, Bouraoui, Lahmar, and Mzabi-Regaya

Chowdhury, Bandyopadhyay, and Mondal

CORRESPONDENCE Use of Blogging in Telemedicine: Introduction to an Internet-Based Teledermatology Application Senel

Fixed-Drug Reaction Secondary to Cocaine Use Boyd

A Practical Method to Detect Mycoses of the Nails Goihman-Yahr, Franco-Arcia, and Maldonado

REVIEW Staphylococcus aureus and the Skin: A Longstanding and Complex Interaction Becker and Wardenburg

Subungual Black Onychomycosis and Melanonychia Striata Caused by Aspergillus niger Garcia, Arenas, and Vasquez del Mercado

BOOK REVIEW Atopic Dermatitis and Eczematous Disorders Pariser

Self-Assessment Examination Lambert

CORE CURRICULUM Alopecia Areata––Part II: Diagnosis and Pathology Estefan, Ribeiro, Abad, Saintive, and Ramos-e-Silva,

DEPARTMENTS PERILS OF DERMATOPATHOLOGY Scabies: Too Late? No, Checkmate Kim and Lambert

THE HEYMANN FILE BRAF Inhibitor–Induced Neutrophilic Dermatoses: A Bitter-“Sweet” Scenario

Lebanese Dermatological Society

Heymann

CONTACT DERMATITIS CAPSULE Pitfalls in Diagnosing Fragrance Allergy Bonchak and Zirwas

NORTH AMERICAN CLINICAL DERMATOLOGIC SOCIETY NEWSLETTER North American Clinical Dermatologic Society 55th Annual Meeting: Panama City, Panama and Havana, Cuba Benedetto

Belarusian Society of Dermatovenereologists and Cosmetologists

North American Clinical Dermatologic Society

African Association for Dermatology

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TABLE OF CONTENTS March/April 2015 • Volume 13 • Issue 2

EDITORIAL

Dermatopathology for Fun and Profit: “Updiagnosing” Distresses and Endangers Patients and Abuses Their Trust.................................................................................................................. 87

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

COMMENTARY

Acne Therapeutics: A Closer Look at Benzoyl Peroxide................................................................................ 94

Tasneem F. Mohammad, MD; Craig G. Burkhart, MD, MPH

ORIGINAL CONTRIBUTIONS

Trichoscan Findings in Patients With Effluvium Capillorum ......................................................................... 98

Emina Kasumagic-Halilovic, MD, PhD; Nermina Ovcina-Kurtovic, MD, MS; Begler Begovic, MD, MS

Chondroid Syringoma: Report of Four Cases ............................................................................................. 104

Faten Limaiem, MD; Sirine Bouslama, MD; Inès Haddad, MD; Sana Ben Slama, MD; Saâdia Bouraoui, PhD; Ahlem Lahmar, MD; Sabeh Mzabi-Regaya, PhD

A Practical Method to Detect Mycoses of the Nails ................................................................................... 108

Mauricio Goihman-Yahr, MD, PhD; Francisco Franco-Arcia, MD; Carlota Maldonado, RN, BSc

REVIEW

Staphylococcus aureus and the Skin: A Longstanding and Complex Interaction......................................... 111

Russell E. N. Becker, PhD; Juliane Bubeck Wardenburg, MD, PhD

Self Assessment Examination ................................................................................................................... 120

W. Clark Lambert, MD, PhD

CORE CURRICULUM Virendra N. Sehgal, MD, Section Editor

Alopecia Areata––Part II: Diagnosis and Pathology.................................................................................... 121

Juliany Estefan, MD; Marcia Ribeiro, MD, PhD; Eliane Abad, MD; Simone Saintive, MD; Marcia Ramos-e-Silva, MD, PhD

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

Scabies: Too Late? No, Checkmate ............................................................................................................ 127

Hee Jin Kim, BS; W. Clark Lambert, MD, PhD

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

BRAF Inhibitor–Induced Neutrophilic Dermatoses: A Bitter-“Sweet” Scenario .......................................... 132

Warren R. Heymann, MD

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

Pitfalls in Diagnosing Fragrance Allergy ................................................................................................... 136

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

North American Clinical Dermatologic Society Newsletter

North American Clinical Dermatologic Society 55th Annual Meeting: Panama City, Panama and Havana, Cuba......................................................................................................................... 139

Anthony V. Benedetto, DO

case studies Vesna Petronic-Rosic, MD, MSc, Section Editor

An Unusual Case of Darier Disease Complicated With a Parasitic Infestation............................................ 142

Kevin Escandón-Vargas, MD; Fausto Cabezas, MD; Claudia Juliana Díaz, MD

TABLE OF CONTENTS March/April 2015 2015 •• Volume Volume 13 13 •• Issue Issue 22 March/April

Cutaneous Hyperneury: A New Entity or an Atypical Cutaneous Manifestation of MEN 2B? ....................... 145

Taseer Ahmed Bhatt, MD; Samara Mimesh, MD, FCRPC

Generalized Eruptive Keratoacanthoma of Grzybowski .............................................................................. 148

Satyendranath Chowdhury, MD; Debabrata Bandyopadhyay, MD; Ashim Kumar Mondal, MD

CORRESPONDENCE Snejina Vassileva, MD, PhD, Section Editor

Use of Blogging in Telemedicine: Introduction to an Internet-Based Teledermatology Application............ 152

Engin Senel, MD

Fixed-Drug Reaction Secondary to Cocaine Use......................................................................................... 153

Alan S. Boyd, MD

Subungual Black Onychomycosis and Melanonychia Striata Caused by Aspergillus niger........................... 154

Carlos Garcia, MD; Roberto Arenas, MD; Elsa Vasquez del Mercado, MD

Erratum..................................................................................................................................................... 156

Book Review Jennifer L. Parish, MD, Section Editor

Atopic Dermatitis and Eczematous Disorders ............................................................................................ 158

Robert J. Pariser, MD

Editorial

ABOUT OUR JOURNAL SKINmed: Dermatology for the Clinician®, print ISSN 1540-9740, online ISSN 1751-7125, is published bimonthly by Pulse Marketing & Communications, LLC, located at 4 Peninsula Avenue, Sea Bright, NJ 07760. Printed in the USA. Disclaimer: The Publisher, Editors, and Editorial Board cannot be held responsible for errors or any consequences arising from the use of information contained in this journal; the views and opinions expressed herein do not necessarily reflect those of the Publisher, Editors, and Editorial Board, neither does the publication of advertisements constitute any endorsement by the Publisher, Editors, and Editorial Board of the products or services advertised. The Publisher, Editors, Editorial Board, Reviewers, Authors, and Affiliated Agents shall not be held responsible or in any way liable for the continued accuracy of the information or for any errors, inaccuracies, or omissions of any kind in this publication, whether arising from negligence or otherwise, or for any consequences arising thereafter.

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Lebanese Dermatological Society

Belarusian Society of Dermatovenereologists and Cosmetologists

North American Clinical Dermatologic Society

African Association for Dermatology

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INDICATION AND USAGE Taclonex® Topical Suspension is indicated for the topical treatment of plaque psoriasis of the scalp and body in patients 18 years and older and for plaque psoriasis of the scalp in patients 12 to 17 years. Patients 18 years and older should not use more than 100 g per week and patients 12 to 17 years should not use more than 60 g per week. IMPORTANT SAFETY INFORMATION Taclonex® Topical Suspension is not for oral, ophthalmic, or intravaginal use and should not be applied to the face, axillae, or groin. Do not use if atrophy is present at the treatment site. Do not use with occlusive dressings unless directed by a physician. If hypercalcemia or hypercalciuria develop, discontinue until parameters of calcium metabolism normalize. Taclonex® can cause reversible hypothalamic-pituitary-adrenal (HPA) axis suppression with the potential for clinical glucocorticosteroid insufficiency. If HPA axis suppression is documented, gradually withdraw the drug, reduce the frequency of application, or substitute with a less potent steroid. Cushing’s syndrome and hyperglycemia may also occur in adults. Pediatric patients are at a greater risk than adults of systemic toxicity, HPA axis suppression and adrenal insufficiency. The most common adverse reactions (≥1%) are folliculitis and burning sensation of skin. Patients who apply Taclonex® to exposed skin should avoid excessive exposure to either natural or artificial sunlight. There are no adequate and well-controlled studies of Taclonex® Topical Suspension in pregnant women. Safety and effectiveness of the use of Taclonex® Topical Suspension in pediatric patients under the age of 12 years have not been established. Please see Brief Summary of Prescribing Information on the following page. References: 1. Taclonex® Topical Suspension [package insert]. Parsippany, NJ: LEO Pharma Inc.; August 2014. 2. Segaert S, Ropke M. The biological rationale for use of vitamin D analogs in combination with corticosteroids for the topical treatment of plaque psoriasis. J Drugs Dermatol. 2013;12(8):e129-e137.

Rx Only BRIEF SUMMARY (See Package Insert for full Prescribing Information). INDICATIONS AND USAGE: Taclonex® Topical Suspension is indicated for the topical treatment of: • Plaque psoriasis of the scalp and body in patients 18 years and older • Plaque psoriasis of the scalp in patients 12 to 17 years WARNINGS AND PRECAUTIONS: Hypercalcemia and Hypercalciuria: Hypercalcemia and hypercalciuria have been observed with use of Taclonex® Topical Suspension. If hypercalcemia or hypercalciuria develop, discontinue treatment until parameters of calcium metabolism have normalized. The incidence of hypercalcemia and hypercalciuria following Taclonex® Topical Suspension treatment of more than 8 weeks has not been evaluated. Effects on Endocrine System: Taclonex® Topical Suspension can cause reversible hypothalamic-pituitaryadrenal (HPA) axis suppression with the potential for clinical glucocorticosteroid insufficiency. This may occur during treatment or upon withdrawal of treatment. Factors that predispose a patient to HPA axis suppression include the use of high-potency steroids, large treatment surface areas, prolonged use, use of occlusive dressings, altered skin barrier, liver failure, and young age. Evaluation for HPA axis suppression may be done by using the adrenocorticotropic hormone (ACTH) stimulation test. In a trial evaluating the effects of Taclonex® Topical Suspension and Taclonex® Ointment on the HPA axis, 32 adult subjects were treated with both Taclonex® Topical Suspension on the scalp and Taclonex® Ointment on the body. Adrenal suppression was identified in 5 of 32 subjects (16%) after 4 weeks of treatment and in 2 of 11 subjects (18%) who continued treatment for 8 weeks. In another trial of 43 subjects treated with Taclonex® Topical Suspension on body (including the scalp in 36 out of 43 subjects) adrenal suppression was identified in 3 out of 43 subjects (7%) after 4 weeks of treatment and in none of the 36 subjects who continued treatment for 8 weeks. In a trial evaluating the effects of Taclonex® Topical Suspension on the HPA axis, 31 subjects aged 12 to 17 years were treated with Taclonex® Topical Suspension on the scalp. Adrenal suppression was identified in 1 of 30 evaluable subjects (3.3%) after 4 weeks of treatment. If HPA axis suppression is documented, gradually withdraw the drug, reduce the frequency of application, or substitute with a less potent corticosteroid. Cushing’s syndrome and hyperglycemia may also occur due to the systemic effects of the topical corticosteroid. These complications are rare and generally occur after prolonged exposure to excessively large doses, especially of high-potency topical corticosteroids. Pediatric patients may be more susceptible to systemic toxicity due to their larger skin surface to body mass ratios. Use of more than one corticosteroid-containing product at the same time may increase the total systemic corticosteroid exposure. Allergic Contact Dermatitis with Topical Corticosteroids: Allergic contact dermatitis to a topical corticosteroid is usually diagnosed by observing a failure to heal rather than a clinical exacerbation. Such an observation should be corroborated with appropriate diagnostic patch testing. Allergic Contact Dermatitis with Topical Calcipotriene: Allergic contact dermatitis has been observed with use of topical calcipotriene. Such an observation should be corroborated with appropriate diagnostic patch testing. Eye Irritation: Avoid eye exposures. Taclonex® Topical Suspension may cause eye irritation. Risks of Ultraviolet Light Exposures: Patients who apply Taclonex® Topical Suspension to exposed skin should avoid excessive exposure to either natural or artificial sunlight, including tanning booths, sun lamps, etc. Physicians may wish to limit or avoid use of phototherapy in patients who use Taclonex® Topical Suspension. CONTRAINDICATIONS: None. ADVERSE REACTIONS: Clinical Trials Experience: Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directed compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Clinical Trials Conducted in Subjects 18 years and older with Scalp Psoriasis: The rates of adverse reactions given below were derived from randomized, multicenter, prospective vehicle- and/or active controlled clinical trials in adult subjects with scalp psoriasis. Subjects applied study product once daily for 8 weeks, and the median weekly dose was 12.6 g. Adverse reactions that occurred in ≥1% of subjects treated with Taclonex® Topical Suspension and at a rate higher than in subjects treated with vehicle are presented in Table 1: Table 1 Number and Percentage with Adverse Reactions in Scalp Psoriasis Trials (Events Reported by ≥1% of Subjects and for Which a Relationship is Possible) Betamethasone Calcipotriene Vehicle Taclonex® Topical Suspension dipropionate in vehicle in vehicle N=1,953 N=1,214 N=979 N=173 Event

# of subjects (%)

Folliculitis

16 (1%)

12 (1%)

5 (1%)

0 (0%)

Burning sensation of skin

13 (1%)

10 (1%)

29 (3%)

0 (0%)

Other less common adverse reactions (<1% but >0.1%) were, in decreasing order of incidence: acne, exacerbation of psoriasis, eye irritation, and pustular rash. In a 52-week trial, adverse reactions that were reported by >1% of subjects treated with Taclonex® Topical Suspension were pruritus (3.6%), psoriasis (2.4%), erythema (2.1%), skin irritation (1.4%), and folliculitis (1.2%). Clinical Trials Conducted in Subjects 18 years and older with Psoriasis on the Body: In randomized, multicenter, prospective vehicle- and/or active controlled clinical trials in adult subjects with plaque psoriasis on non-scalp areas, subjects applied study product once daily for 8 weeks. A total of 824 subjects were treated with Taclonex® Topical Suspension and the median weekly dose was 22.6 g. There were no adverse reactions that occurred in ≥1% of subjects treated with Taclonex® Topical Suspension and at a rate higher than in subjects treated with vehicle. Other less common adverse reactions (<1% but >0.1%) were, in decreasing order of incidence: rash and folliculitis. Clinical Trials Conducted in Subjects 12 to 17 years with Scalp Psoriasis: In two uncontrolled prospective clinical trials, a total of 109 subjects aged 12-17 years with plaque psoriasis of the scalp were treated with Taclonex® Topical Suspension once daily for up to 8 weeks. The median weekly dose

was 40 g. Adverse reactions included acne, acneiform dermatitis and application site pruritus (0.9% each). USE IN SPECIFIC POPULATIONS: Pregnancy: Teratogenic Effects: Pregnancy Category C: Animal reproduction studies have not been conducted with Taclonex® Topical Suspension. Taclonex® Topical Suspension contains calcipotriene that has been shown to be fetotoxic and betamethasone dipropionate that has been shown to be teratogenic in animals when given systemically. There are no adequate and well-controlled studies in pregnant women. Taclonex® Topical Suspension should be used during pregnancy only if the potential benefit to the patient justifies the potential risk to the fetus. Nursing Mothers: Systemically administered corticosteroids appear in human milk and can suppress growth, interfere with endogenous corticosteroid production, or cause other untoward effects. It is not known whether topically administered calcipotriene or corticosteroids could result in sufficient systemic absorption to produce detectable quantities in human milk. Because many drugs are excreted in human milk, caution should be exercised when Taclonex® Topical Suspension is administered to a nursing woman. The patient should be instructed not to use Taclonex® Topical Suspension on the breast when nursing. Pediatric use: Safety and effectiveness of the use of Taclonex® Topical Suspension in pediatric patients under the age of 12 years have not been established. The safety and effectiveness of Taclonex® Topical Suspension for the treatment of plaque psoriasis of the scalp have been established in the age group 12 to 17 years. Two prospective, uncontrolled trials (N=109) were conducted in pediatric subjects age 12 to 17 years with scalp psoriasis, including assessment of HPA axis suppression in 30 subjects. Because of a higher ratio of skin surface area to body mass, pediatric patients are at a greater risk than adults of systemic toxicity when treated with topical drugs. They are, therefore, also at greater risk of HPA axis suppression and adrenal insufficiency upon the use of topical corticosteroids. Rare systemic toxicities such as Cushing’s syndrome, linear growth retardation, delayed weight gain, and intracranial hypertension have been reported in pediatric patients, especially those with prolonged exposure to large doses of high potency topical corticosteroids. Local adverse reactions including striae have also been reported with use of topical corticosteroids in pediatric patients. Geriatric use: Clinical studies of Taclonex® Topical Suspension in plaque psoriasis on non-scalp areas included 124 subjects who were 65 years of age or over, and 36 were 75 years of age or over. Clinical studies of Taclonex® Topical Suspension in scalp psoriasis included 334 subjects who were 65 years or over and 84 subjects who were 75 years or over. No overall differences in safety or effectiveness of Taclonex® Topical Suspension were observed between these subjects and younger subjects, and other reported clinical experience has not identified any differences in response between elderly and younger patients. However, greater sensitivity of some older individuals cannot be ruled out. DOSAGE AND ADMINISTRATION: Instruct patients to shake bottle prior to using Taclonex® Topical Suspension and to wash their hands after applying the product. Apply Taclonex® Topical Suspension to affected areas once daily for up to 8 weeks. Therapy should be discontinued when control is achieved. Patients 18 years and older should not use more than 100 g per week and patients 12 to 17 years should not use more than 60 g per week. Taclonex® Topical Suspension should not be used with occlusive dressings unless directed by a physician. Taclonex® Topical Suspension is not for oral, ophthalmic, or intravaginal use. Avoid use on the face, groin, or axillae, or if skin atrophy is present at the treatment site. NONCLINICAL TOXICOLOGY: Calcipotriene may enhance the effect of UVR to induce skin tumors. Long-term animal studies have not been performed to evaluate the carcinogenic potential of betamethasone dipropionate. PATIENT COUNSELING INFORMATION: See FDA-approved patient labeling (Patient Information and Instructions for Use) Inform patients of the following: • Instruct adult patients (18 years and older) not to use more than 100 g per week. • Instruct pediatric patients (12 to 17 years) not to use more than 60 g per week. • Discontinue therapy when control is achieved unless directed otherwise by the physician. • Do not apply Taclonex® Topical Suspension to the scalp in the 12 hours before or after any chemical treatments to the hair. Since hair treatments may involve strong chemicals, talk with physician first. • If applied to the scalp, do not wash hair or take a bath or shower right after application. • Avoid use of Taclonex® Topical Suspension on the face, underarms, groin or eyes. If this medicine gets on face or in eyes, wash area right away. • Do not occlude the treatment area with a bandage or other covering unless directed by the physician. • Note that local reactions and skin atrophy are more likely to occur with occlusive use, prolonged use or use of higher potency corticosteroids. • Wash hands after application. • Instruct patients not to use other products containing calcipotriene or a corticosteroid with Taclonex® Topical Suspension without first talking to the physician. • Instruct patients who use Taclonex® Topical Suspension to avoid excessive exposure to either natural or artificial sunlight (including tanning booths, sun lamps, etc.). MANUFACTURED BY: LEO Laboratories Ltd. (LEO Pharma) 285 Cashel Road Dublin 12, Ireland

DISTRIBUTED BY: LEO Pharma Inc. 1 Sylvan Way, Parsippany, NJ 07054, USA

March/April 2015

Volume 13 • Issue 2

EDITOR IN CHIEF

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

DEPUTY EDITORS William Abramovits, MD

W. Clark Lambert, MD, PhD

Larry E. Millikan, MD

Jennifer L. Parish, MD

Dallas, TX

Newark, NJ Vesna Petronic-Rosic, MD, MSc

Meridian, MS Marcia Ramos-e-Silva, MD, PhD

Philadelphia, PA

Chicago, IL

Rio de Janeiro, Brazil

EDITORIAL BOARD Mohamed Amer, MD Cairo, Egypt

Howard A. Epstein, PhD Philadelphia, PA

Andrew P. Lazar, MD Washington, DC

Virendra N. Sehgal, MD Delhi, India

Robert L. Baran, MD Cannes, France

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

Jasna Lipozencic, MD, PhD Zagreb, Croatia

Riccarda Serri, MD Milan, Italy

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 I. Cohen, MD Engelwood, CO Noah Craft, MD, PhD, DTMH Torrance, CA Natalie M. Curcio, MD, MPH Nashville, TN Ncoza C. Dlova, MBChB, FCDerm Durban, South Africa Richard L. Dobson, MD Mt Pleasant, SC William H. Eaglstein, MD Menlo Park, CA Charles N. Ellis, MD Ann Arbor, MI

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

Julian Trevino, MD Dayton, OH

Oumeish Youssef Oumeish, MD, FRCP Amman, Jordan

Graham Turner, PhD, CBiol, FSB Port Sunlight, UK

Joseph L. Pace, MD, FRCP Naxxar, Malta

Snejina Vassileva, MD, PhD Sofia, Bulgaria

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

Art Papier, MD Rochester, NY

Daniel Wallach, MD Paris, France

Johannes Ring, MD, DPhil Munich, Germany

Michael A. Waugh, MB, FRCP Leeds, UK

María Daniela Hermida, MD Buenos Aires, Argentina

Roy S. Rogers III, MD Rochester, MN

Wm. Philip Werschler, MD Spokane, WA

Warren R. Heymann, MD Camden, NJ

Donald Rudikoff, MD New York, NY

Joseph A. Witkowski, MD Philadelphia, PA

Tanya R. Humphreys, MD Bala-Cynwyd, PA

Robert I. Rudolph, MD Wyomissing, PA

Ronni Wolf, MD Rechovot, Israel

Camila K. Janniger, MD Englewood, NJ

Vincenzo Ruocco, MD Naples, Italy

Matthew J. Zirwas, MD Columbus, Ohio

Abdul-Ghani Kibbi, MD Beirut, Lebanon

Noah Scheinfeld, MD, JD New York, NY

Lowell A. Goldsmith, MD, MPH Chapel Hill, NC Aditya K. Gupta, MD, PhD, FRCPC London, Ontario, Canada Seung-Kyung Hann, MD, PhD Seoul, Korea

SKINmed. 2015;13:85

2015

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March/April 2015

Volume 13 • Issue 2

Editorial

Dermatopathology for Fun and Profit: “Updiagnosing” Distresses and Endangers Patients and Abuses Their Trust W. Clark Lambert, MD, PhD;1 Peter C. Lambert, MA;2 Lawrence Charles Parish, MD, MD(HON)3 “He who pays the piper calls the tune.”—Proverb “I’m not upset that you lied to me, I’m upset that from now on I can’t believe you.”—Friedrich Nietzsche

rasmus Wilson (1809–1884), the noted 19th-century dermatologist from London, famously claimed that a number of dermatoses were caused by “worms.”1 Perusal of his 1857 textbook, On Diseases of the Skin (Figure 1), explains this quote. It contains numerous figures that could only have been drawn with the aid of a microscope, such as a near-perfect image of Sarcoptes scabei, the cause of scabies (Figure 2). Because the role of filamentous organisms, particularly dermatophytes, as cutaneous pathogens was still being defined in the mid-19th century, it becomes clear that Wilson was referring to dermatophytes, as he saw them under the microscope, and that both it and the discussion of scabies, as well as other parts of this textbook, give evidence that dermatologists were studying specimens under light microscopy, ie, practicing dermatopathology, at least as early as the mid-19th century. Dermatologists and Dermatopathology: An Endangered Association? Based on this and abundant other evidence, a convincing case may be made that dermatopathology is an integral part of dermatology, and thus dermatologists are allowed to read their own histopathologic slides, as well as those of specimens generated by other dermatologists. Dermatologists are permitted to refer cases to their own laboratories, an exception granted from the so-called Stark laws, which generally proscribe physicians from referring cases to diagnostic facilities in which they or their family members have a financial stake. The American Academy of

Dermatology Association has defended and continues to defend this carve out.2 We do not argue with this special exception, but we have other issues with this arrangement, even when the dermatopathology laboratory is owned and operated by others not associated directly with any dermatologist. Dermatopathology for Fun When diagnoses are rendered by a dermatopathology laboratory, regardless of its ownership, they would appear to be impartial with each diagnosis regardless of whether it is designated as an excision or as a biopsy, coded identically under the code “88305.” Some entities, such as acrochordans or cysts, are coded even lower, as an “88304,” but none higher. Thus, dermatopathologists would appear to be disinterested players, with the possible exception that they may be reluctant to process specimens as excisions rather than as biopsies because this requires significantly more work, technician time, and effort, with no financial reward rendered. The diagnosis does not affect the financial reward to the dermatopathologist; however, the total picture has become significantly more complex. Dermatopathology for Profit Dermatopathology has become a competitive business, with significant financial rewards gleaned by those to whom specimens are sent. While the dermatopathologist does not have a financial interest in the diagnosis that is rendered in each case, the dermatologist may have a significant interest. For example, cases of

From the Departments of Dermatology and of Pathology and Laboratory Medicine, Rutgers University – New Jersey Medical School, Newark, NJ;1 St. George’s University School of Medicine, Grenada, WI;2 and the Department of Dermatology and Cutaneous Biology and Jefferson Center for International Dermatology, Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia, PA3 Address for Correspondence: W. Clark Lambert, MD, PhD, Rutgers University – New Jersey Medical School, Departments of Dermatology and of Pathology and Laboratory Medicine, Room C576 Medical Science Building, 185 South Orange Avenue, Newark, NJ 07103 • E-mail: lamberwc@njms.rutgers.edu

SKINmed. 2015;13:87–90

March/April 2015

Editorial

Figure 2. Erasmus Wilson’s On Diseases of the Skin showing accurate drawing of Sarcoptes scabei.

Figure 1. Erasmus Wilson’s On Diseases of the Skin. 1857: Frontispiece.

nevocellular nevi that are not designated as “dysplastic” or “with atypia” by the dermatopathologist usually do not require a follow-up visit to the dermatology clinic/office, whereas those that are designated as dysplastic or with atypia often require such a follow-up, perhaps even more than one such visit. The dermatologist is paid for these visits, whether by the patient or by a third-party payer. If the original lesion is designated as “severely dysplastic” or even “moderately dysplastic” by the dermatopathologist, further surgery, such as excision of the lesion, may be warranted. The dermatologist is also paid for these follow-up visits and/or procedures. Because the dermatologist, whether or not there is a financial interest in the laboratory, often has a voice in the decision as to which dermatopathology laboratory the specimens are sent, a conflict of interest emerges. It becomes in the interest of the dermatopathology laboratory to “updiagnose” lesions. There are other financial benefits as well: the chances of a lesion with malignant potential being missed are arguably diminished and the dermatopathologist who updiagnoses a lesion may receive a subsequent excision of the same lesion, for which he or she is paid. The dermatologist may not even be involved in the process; the decision may be up to a business person or manager who simply notes that income is up if certain laboratories are used vs others. A similar observation may be made by administrators of the dermatopathology laboratory who may encourage dermatopatholoSKINmed. 2015;13:87–90

gists to make such calls or select those who do. As a result, there is also a conflict of interest for and within the dermatopathology laboratory. Endangering Patients and Betraying Their Trust Whereas “upcoding” for certain procedures may be readily detected by an auditor, updiagnosing is more subtle. Discrepancies between diagnoses rendered and codes generated are much less likely to emerge. In addition, the damage done to the patient may be much more severe. Upcoding results in higher bills to the patient or to the insurance company, and unweary patients may not even notice the difference. In fact, patients whose bills are paid by a third-party payer may be unaware that they have been overbilled. Even if the insurance bill is increased, the patient’s concern only occurs when there is an out-of-pocket expense as a result of a deductible or co-pay. In any case, only the patient’s or the taxpayer’s pocketbook is affected. Updiagnosing, on the other hand, is usually followed by additional office visits and or surgeries; otherwise, there would be little point in doing it. Whereas follow-up visits may not be difficult to arrange, such visits may require significant sacrifices for patients with travel or unpaid time off from work. Despite laws to the contrary, their jobs may even be threatened as a result. If additional surgery is performed, it usually has a good outcome,

Dermatopathology for Fun and Profit

March/April 2015 but bad outcomes, such as infections and drug eruptions, may occur. These situations are more likely in procedures performed by poorly supervised or even unsupervised physician assistants. All of this results in additional unnecessary risks, including accidental injury emerging from the clinic/office. Distressing Patients and Their Families Despite all of this, the greatest insult to the patient is likely by the physical burden imposed by these unnecessary office/clinic visits and surgeries but by the psychologic burden. For example, the patient is told by a practitioner who they trust and backed by a diagnostic laboratory that there is a risk for development of a melanoma, a particularly deadly type of cancer. The fear and anxiety that this generates in many patients is not unwarranted. The patient may then make major decisions, such as whether to get married, start a family or business, or pursue a graduate or professional career, influenced by this fear. Trust in the doctor, and, indeed, in the entire medical system has then been betrayed. To pretend that this does not have a profoundly negative impact on the patient’s health and well-being is to ignore reality. Surviving as an Honest Doctor Updiagnosing has become such a common practice that it is now not only adversely affecting health economics and driving up the cost of medical care, but it is also making it more difficult to practice medicine, even if one does so honestly. What is one to do with a diagnosis of “dysplastic nevus” from a dermatopathology laboratory? This is especially an issue if the laboratory is not well known to the dermatologist, perhaps, as is increasingly the case, having been chosen not by the dermatologist but by a third party. Even if the laboratory has been known in the past to be an honest entity by the dermatologist, it may have evolved its practices to be less so, perhaps in response to market pressures. All of this may be significantly exacerbated by the circumstances of the individual patient, which may involve, for example, comorbidities, difficulty in paying, challenging anatomic location of the lesion, significant morbidity from additional surgery, fear of arrest or deportation, or difficulty in taking time off from work. What can be done if the patient has joined the Peace Corps for a 4-year term and is booked on a plane to Mali leaving tonight at midnight? The dermatologist can ask to see the slide and refer it to a different laboratory, but this involves time and expense, even if the original laboratory chooses to be cooperative, which all too often it does not. Similarly, dermatopathologists who render “honest” reads may find themselves inexplicably out of work. Laboratories rarely advertise that they practice SKINmed. 2015;13:87–90

Editorial updiagnosing, lest they run afoul of regulators, confounding this issue. The “Solution” The solution that is likely to emerge from this mess is one that probably will frustrate dermatologists without solving the problem: removing the right of dermatologists to read (and to bill and be paid for reading) their own and others’ dermatopathology slides. This outcome would be worse than useless, because it would create the impression that the problem has been solved, when, in fact, it has not. As reviewed above, as long as dermatologists, or worse, business managers and/or practice owners, choose the dermatopathology laboratory and remain free to do so on purely economic grounds, this problem is likely to remain unsolved and even worsen. We suspect that there may even be dermatopathology laboratories in which every nevus is read as “with atypia,” justifying further office/clinic visits and/or surgery. Such laboratories appear to be rapidly growing, largely at the expense of other, honest laboratories, whose numbers are dwindling as a result. We propose an alternate solution, one that has been used in other contexts: When dermatopathology laboratories are inspected, the proportion of nevocellular nevi that are read as “dysplastic,” “severely dysplastic,” or “Spitzoid,” or synonyms of these terms, should be considered as a criterion for approval. Quantitative Review of Cases To initiate this process, one of us (WCL) has randomly chosen 500 consecutive cases read as “nevus” reported from his dermatopathology practice at University Hospital in Newark, New Jersey. Reports of lesions with prior surgery were excluded; otherwise the 500 cases were consecutive. Of these 500 cases, 78 in which the word “nevus” was part of the diagnosis but were not routine melanocytic nevi were also excluded. These included 14 cases of blue nevi, 4 cases of cellular blue nevi, 6 cases of giant hairy nevi, 44 cases of epidermal nevi (including nevus sebaceous of Jadassohn), and 10 cases of connective tissue nevi. None of these 78 cases showed any cytologic or structural atypia or dysplasia. All of these 500 cases were generated from the dermatology clinics at University Hospital. The results are shown in Table I and Table II. In our randomly selected series, less than 20% of the nevi showed any dysplasia. Less than 2% showed severe dysplasia. Five percent of the nevi showed Spitzoid features, which were once confounded with dysplastic features but are now distinguished from them by well-defined criteria.3 Even if one combines these two populations, the fraction of nevi that are dysplastic or Spitzoid is approximately 25%. Note again that

Dermatopathology for Fun and Profit

March/April 2015

Editorial

Table I. Subtypes of Nevocellular Nevi in a Random Sample of Cases Junctional

Compound

Intradermal

Total

257

320

Mild dysplasia

Moderate dysplasia

32b

Severe dysplasia

Total dysplastic nevi

Spitz nevi

Total Spitz and dysplastic nevi

102

Total nevi

108

269

422

Non-Spitz, non-dysplastic nevi

Dysplastic nevi

Values are expressed in percentages. Three lesions were combined with a blue nevus. None were dysplastic. These cases were counted as intradermal nevi. b Four lesions with moderate dysplasia also showed Spitzoid features. All were counted as moderately dysplastic nevi. a

Table 2. Subtypes of Nevocellular Nevi Junctional

Compound

Intradermal

Total

10.7

60.9

75.8

Mild dysplasia

0.2

2.6

2.8

Moderate dysplasia

5.7

7.6

1.4

14.7

Severe dysplasia

0.7

0.9

1.6

Total dysplastic nevi

6.6

11.1

1.4

19.2

Spitz nevi

3.6

1.4

Subtotal Spitz and dysplastic nevi

6.6

14.7

2.8

24.2

Total nevi

10.7

25.6

63.7

100

Non-Spitz, non-dysplastic nevi Dysplastic nevi

Values are expressed in percentages.

these lesions were biopsied or excised in a teaching hospital setting under the supervision of experienced, highly qualified dermatologists. We would, therefore, expect this to be a relatively high value, as less experienced practitioners would be expected to biopsy more nondysplastic lesions, being less certain of their clinical diagnoses. As a result, the true percentages of dysplastic and Spitz nevi in an average dermatopathology practice would be expected to be lower than these values. Our Proposal

nevocellular nevi should not exceed 40%, and the proportion of severely dysplastic nevi should not exceed 10%. Routine dermatopathology laboratories reporting in excess of these values should be called on the proverbial carpet.

While there may be valid exceptions, such as dermatopathology practices at referral pigmented lesion clinics or clinics that care for a high proportion of children or patients with certain genetic diseases, we believe that the percentage of dysplastic plus Spitz nevocellular nevi reported in a routine dermatopathology practice should not exceed 50%, the proportion of dysplastic SKINmed. 2015;13:87–90

References 1 Wilson E. On Diseases of the Skin. 7th American ed. Philadelphia, PA: Henry C. Lea; 1868:714–716. 2 American Academy of Dermatology Association: American Academy of Dermatology Association: 2014 Issues Guide. Washington, DC: American Academy of Dermatology Association; 2005:5. 3 Elder DE, Elenitsas R, Johnson BI, Jr, Murphy GF, eds. Lever’s Histopathology of the Skin. 9th ed. Philadelphia, PA: Lippincott Williams and Wilkins; 2005:375– 379.

Dermatopathology for Fun and Profit

AdvertoriAl

CleAn lAundry & Gentle on Skin Educate Patients: Who believe they must sacrifice cleaning power for a detergent that is non-irritating Sponsored by Procter & Gamble Researchers have found that nearly 45 percent of people report having “sensitive” or “very sensitive” skin.1 Many dermatologists recommend sensitive-skin patients use a dye- and perfume-free laundry detergent because dyes and fragrances are considered to be one of the most common causes of detergent skin allergies. Each one of us approaches our laundry with the same goal: to clean it. However, to those with sensitive skin, achieving “clean” has not always been a straightforward task. “A lot of my patients feel they are sacrificing cleaning power when using some dye-free and perfume-free laundry products,” said Dr. Marnie Nussbaum. “As a result, many of my patients compensate by using scented stain removers or even abandon dye-free and perfumefree products in order to get their clothes truly clean.” In fact, surveys of patients with sensitive skin show:

Marnie nussbaum, MD Dr. Nussbaum specializes in general and cosmetic dermatology. She is also Clinical Instructor of Dermatology at Weill Cornell Medical Center. Among her numerous awards are the Outstanding House Staff Award and the Women in Science Award. Dr. Nussbaum is a member of the American Academy of Dermatology, the American Society of Dermatologic Surgery and the Women’s Dermatologic Society.

• 80 percent say they are dissatisfied with their current fragrance-free laundry products and believe they must sacrifice cleaning power for a detergent that is non-irritating. • More than four out of five use a pre-treatment to compensate for a lack of cleaning power.2 More and more dermatologists are now recommending Tide Free & Gentle. New data show it provides a better clean while being mild on sensitive skin in multiple dermatologist supervised studies or tests.

How Does Tide Free & Gentle Clean Better?

In tests, Tide Free & Gentle removes more residue from stains than the leading free detergent. In fact, Tide Pods Free & Gentle outperform the leading free detergent on 10 different stains, including blood, coffee and grass stains, and is mild on sensitive skin. Tide Free & Gentle’s unique “Lift and Block” technology removes stains and soils to keep clothes clean while being gentle to skin.

Fig. 1 The fabric washed in Tide Free & Gentle is clean down to the fiber level, demonstrating superior clean ability; not only removing or lifting stains, dirt and odor particles, but preventing them from reattaching or redepositing to the fabrics, wash after wash. Original image in B&W. Soil has been colorized to show contrast.

Step 1: Lift

• Deep Clean System: Enzymes break up hard-to-remove stains and surfactants lift out stains, dirt and odor particles down to the fiber level. See Fig. 1.

Fig. 2 Soil residues left on fibers attract dirt from the wash water.

Step 2: Block

• Anti-Redeposition Technology: Concentrated polymers sweep in to trap the dirt in the wash water, to prevent it from reattaching to the fabric fibers. Our bodies produce up to 50 grams of body soil per day, including mucus, dead skin, sweat, sebum and bacteria. Clothing may look clean, but in a given laundry load, all that soil combines in the water to create a very dirty environment. This is important because even if a stain appears to have been removed from clothing the first trip through the washing machine, dirt attracts dirt, so any soil residues left on clothing fibers will cause dirt in the wash water to redeposit on clothes over time. See Fig. 2. Dirt redeposition is a primary reason why whites tend to appear dingy after numerous washings – not just dye transfer as is commonly believed. As larger high eﬃciency washers continue to become the norm in American households, this issue becomes more pronounced. High eﬃciency washers use three times less water so soil is more concentrated in the wash water, increasing the likelihood of redeposition of dirt on clothing. However, Tide Free & Gentle’s unique “Lift and Block” technology provides a superior clean from wash to wash. Patients benefit from the gentleness of a dye- and perfume-free detergent without having to sacrifice superior cleaning power.

The Importance of Patient Compliance in a Laundry Regimen

“I recommend Tide Free & Gentle to my patients because it drives compliance since it is not only gentle, but provides a better clean,” says Dr. Nussbaum.

Fig. 3 Eighty seven percent of those who use free detergent use scented fabric softeners or dryer sheets. But it’s also very important to remind patients with sensitive skin issues that the entire laundry regimen needs to be free of dyes and perfumes. Eighty seven percent of those who use free detergent use scented fabric softeners or dryer sheets. See Fig. 3. For this reason, it is critical to remind patients that caring for sensitive skin doesn’t stop with detergent; the entire laundry regimen needs to be dye-free and perfumefree. In fact, fabric softeners that do not contain dyes or fragrance, such as Downy Free & Gentle, may have sensitive skin benefits, such as reducing friction between clothes and skin and, therefore, skin irritation.

Dermatologists Play an Important Role

Dermatologists can help patients ensure they are achieving the best results for their laundry and their skin. Talk with your patients, particularly those with sensitive skin, about their current laundry detergent choices and help them understand the benefits of following a Free & Gentle regimen. Be sure to recommend products that complement your patient’s skin health needs while also helping them achieve the optimal result of clean laundry.

References

1 Misery, L., Sibaud, V., Merial-Kieny, C., & Taieb, C. Sensitive skin in the American population: Prevalence, clinical data, and role of the dermatologist. Int J Dermatol. 2011;50:961–967. 2 2010 Habits, Practices and Attitudes conducted by P&G.

CMY

March/April 2015

Volume 13 • Issue 2

COMMENTARY

Acne Therapeutics: A Closer Look at Benzoyl Peroxide Tasneem F. Mohammad, MD;1 Craig G. Burkhart, MD, MPH2

enzoyl peroxide is one of the most widely used treatments for acne, both alone and in conjunction with other medications. This review highlights benzoyl peroxide’s mechanism of action and its effects when combined with other agents, specifically tertiary amines. Recent presentations on benzoyl peroxide in the literature have stressed various aspects of its usage in treatment. Some have highlighted its anti-inflammatory effects1 and bacterial resistance,1,2 while others have discussed its tolerability3; however, little information is available discussing the drug’s chemistry, and, thereby, the ability to maximize the product in clinical usage is greatly diminished. Pathogenesis of Acne Acne, a chronic inflammatory disease of the pilosebaceous follicle, is the most common cutaneous disorder. The etiology of acne is multifactorial, with four main causes identified. The first is hyperproliferation and abnormal desquamation of the intrafollicular epithelium. Hyperkeratinization of the follicle contributes to microcomedo formation, which is the precursor lesion of acne. As keratinocytes and sebum accumulate within the follicle, the microcomedo expands. Androgenic hormones, such as testosterone, also contribute to acne by stimulating sebum production. The proliferation of Propionibacterium acnes within the sebaceous follicle is another mechanism of acne formation.4 This anaerobic bacterium is capable of forming biofilm, which is when bacteria form a community and encase themselves in a polysaccharide capsule after adhering to the surface. Biofilm formation is associated with increased antibiotic resistance and the adhesive elements may contribute to microcomedo formation by mixing with sebum and forming keratinaceous plugs.5 Cytokine release by P. acnes as well as microcomedo rupture leads to involvement of the immune system, including complement, cell-mediated immunity, and humoral factors. The ensuing in-

flammatory response promotes the formation of papules and pustules. Currently, several therapies for acne exist, each targeting different causal factors. Benzoyl peroxide is a compound that has been successful in treating acne. In recent years, the efficacy of combining benzoyl peroxide with tertiary amines has been studied, with promising results. Action of Benzoyl Peroxide Benzoyl peroxide is a lipophilic molecule that acts by entering the pilosebaceous follicle, breaking down into benzoyl radicals and benzoic acid. These byproducts are responsible for the efficacy of benzoyl peroxide, which has many mechanisms of action. Not only is it comedolytic by causing uncoiling and loosening of the comedo through decreased cellular adhesion, but it is sebosuppressive as well.6 Benzoic acid promotes mild desquamation of the skin without increasing mitotic activity, while benzoyl radicals have antibacterial activity. The mechanisms of its antibacterial properties include alteration of protein synthesis, inhibition of metabolic cooperation and DNA synthesis, as well as increased double-stranded breaks.7 Although benzoyl peroxide is an effective agent in combating acne, it does have some adverse effects. In addition to bleaching hair and clothing, it can also cause allergic and irritant contact dermatitis. Formation of Benzoyl Peroxide Free Radicals Free radicals are chemical compounds containing an extra electron that is available for bond formation. They are created by the interaction of a molecule, or initiator, with an activator, which can be in the form of heat, light, x-rays, or chemicals such as tertiary amines. Once exposed to an activator, a chemical bond within the molecule is split, causing each resulting segment to retain a single free electron from the broken bond. When benzoyl peroxide, C6H6-C(O)-O-O-C(O)-C6H6, is exposed to an activa-

From the Department of Internal Medicine, Section of Dermatology, University of Toledo College of Medicine, Toledo, OH Address for Correspondence: Craig G. Burkhart, MD, MPH, Clinical Professor, University of Toledo College of Medicine, 5600 Monroe Street, Suite 106B, Sylvania, Ohio 43560 • E-mail: cgbakb@aol.com

SKINmed. 2015;13:94–96

March/April 2015

COMMENTARY tains a tertiary amine. Here, both the benzoyl peroxide and tertiary amine contribute to energy transfer and catalysis of radical formation through an SN2 mechanism, creating benzoyloxyl and amine radicals. For clinical purposes, the stimulant must be combined with the benzoyl peroxide immediately before use because of the transient nature of the radicals.9

Benzoyl peroxide

Synergism of Benzoyl Peroxide Benzoyl peroxide has long been used in combination therapy because of its synergistic activity; however, now benzoyl peroxide is being used with antibiotics and antifungals containing tertiary amines to promote benzoyl radical formation. Because the bulky substituents present in certain antibiotics cause decreased activity of the tertiary amine through steric hindrance, the antibiotic structure must be taken into account.7 Erythromycin and clindamycin are two antibiotics that have been combined with benzoyl peroxide with success.

Benzoyl free radical

N,N-Dimethyl-p-toluidine (tertiary amine) Figure. Benzoyl peroxide is shown in its stable state first. The radical benzoyl peroxide molecule is its active functioning state. An example of a tertiary amine is demonstrated as this structure allows benzoyl peroxide to be activated to its radical state.

tor, it decomposes into two C6H6-C-O* units, where * represents an electron. Each unit represents a new free radical. Formation of benzoyl radicals, which are the most active state of benzoyl peroxide, can be promoted by three mechanisms. The first is by environmental modifications. Decreasing water content, increasing polyethylene glycol content, and adding heat are all methods that increase benzoyl radical formation8; however, these environmental changes must be balanced with the need for stability of the original benzoyl peroxide compound because radicals only exist for a few seconds. Another mechanism of radical formation is through an accelerator, which decreases the energy level required for benzoyl radical production. Trace metals, such as zinc, copper, and iron, are often used. The final method of creating benzoyl radicals is by using a stimulant, which conSKINmed. 2015;13:94â&#x20AC;&#x201C;96

When used apart, erythromycin and benzoyl peroxide are both equally effective in decreasing the severity of acne and the number of small inflammatory lesions. Using erythromycin alone, however, causes increased antibiotic resistance to erythromycin, clindamycin, and tetracycline. The combination of benzoyl peroxide and erythromycin is more effective in reducing papules and pustules than either alone. Erythromycin kills susceptible colonies, while benzoyl peroxide eradicates the antibiotic-resistant colonies through its antibacterial effects. In addition, the tertiary amine in erythromycin catalyzes benzoyl radical formation. When erythromycin was crushed into tetraethylene glycol dimethacrylate with benzoyl peroxide and heated, faster gelling was noticed compared with benzoyl peroxide or erythromycin alone. Gelling is an indicator of radical activity. At room temperature in a dark environment or when refrigerated, gelling of the combination occurred within an hour. The combination was unstable at higher temperatures, however, so it must be compounded at the time of dispensation and then refrigerated.7 The adverse effect profile of benzoyl peroxide and erythromycin is similar to benzoyl peroxide used alone. Clindamycin is another antibiotic used with benzoyl peroxide. Although it is better tolerated, it is less effective than benzoyl peroxide when used alone. The side effects of clindamycin are generally mild, with occasional reports of diarrhea and pseudomembranous colitis being noted. When combined with benzoyl peroxide, decreased bacterial count, resistant bacteria, and total acne lesion counts have been reported. In fact, the clindamycinbenzoyl peroxide combination is comparable to the erythromycin-benzoyl peroxide combination4; however, clindamycin and benzoyl peroxide together is stable at room temperature.4

Acne Therapeutics: A Closer Look at Benzoyl Peroxide

March/April 2015

Volume 13 • Issue 2

The use of benzoyl peroxide and antifungals, specifically allylamines containing tertiary amines, has also had some positive results. This combination avoids prolonged antibiotic use, which has been associated with breast cancer and the formation of resistance in nontarget bacteria, such as Staphylococcus aureus.12 These bacteria can then exchange resistance elements, creating even more antibiotic resistance.10 Another benefit of allylamines is that their substituents are less bulky than those of antibiotics, so their amine is more potent.11 When a combination of butenifine and benzoyl peroxide was compared with benzoyl peroxide alone, selfassessment questionnaires and treatment diaries showed that the combination product was superior. Not only was there higher satisfaction with the combination, but there was also greater treatment satisfaction as well. Participants reported a greater decrease in the number of comedones, facial oiliness, and inflamed lesions with the butenifine-benzoyl peroxide as well.12 Conclusions Benzoyl peroxide is one of the most effective medications available for the treatment of acne, largely as a result of the activity of benzoyl radicals. By combining benzoyl peroxide with other compounds containing tertiary amines, such as certain antibiotics and antifungals, benzoyl radical activity can be increased. This has resulted in combination products that are even more effective in treating acne than benzoyl peroxide alone. References 1 Newman M, Bowe W, Heughebaert, C, Shalita A. Therapeutic considerations for severe nodular acne. Am J Clin Dermatol. 2011:12:7–14.

2 Williams HC, Dellavalle RP, Garner S. Acne vulgaris. The Lancet. 2012:379:361–372. 3 Gonzalez P, Vila, R, Cirigliano M. The tolerability profile of clindamycin 1%/benzoyl peroxide 5% gel vs. adapalene 0.1%/benzoyl peroxide 2.5% gel for facial acne: results of a randomized, single-blind, split-face study. J Cosmet Dermatol. 2012;11:251–260. 4 Taylor G, Shalita A. Benzoyl peroxide-based combination therapies for acne vulgaris: a comparative review. Am J Clin Dermatol. 2004;5:261–265. 5 Burkhart CN, Burkhart CG. Microbiology’s principle of biofilms as a major factor in the pathogenesis of acne vulgaris. Int J Dermatol. 2003;42:925–927. 6 Burkhart CG. A reexamination of the function of benzoyl peroxide in acne. J Dermatol Allergy. 1982;5:23–26. 7 Burkhart CN, Specht K, Neckers D. Synergistic activity of benzoyl peroxide and erythromycin. Skin Pharmacol App Skin Physiol. 2000;13:292–296. 8 Chellquist E, Gorman G. Benzoyl peroxide solubility and stability in hydric solvents. Pharm Res. 1992;9:1341– 1346. 9 Burkhart CG, Burkhart CN. The chemistry and synergy of benzoyl peroxide with clindamycin. Br J Derm 2008;159:480–481. 10 Coates T, Eady A, Cove J. Propionibacterial biofilms cannot explain antibiotic resistance but might contribute to some cases of antibiotic recalcitrant acne. Br J Dermatol. 2003;148:366–367. 11 Burkhart CG, Burkhart CN, Isham N. Synergistic antimicrobial activity by combining an allylamine with benzoyl peroxide with expanded coverage against yeast and bacterial species. Br J Dermatol. 2006;154:341–344. 12 Burkhart CG, Burkhart CN. Treatment of acne vulgaris without antibiotics: tertiary amine-benzoyl peroxide combination vs. benzoyl peroxide alone (Proactiv Solution). Int J Dermatol. 2007;46:89–93.

VINTAGE LABEL

Courtesy of BuyEnlarge, Philadelphia, PA SKINmed. 2015;13:94–96

Acne Therapeutics: A Closer Look at Benzoyl Peroxide

ndd 121 d dd 396 60

IACD Goes to Vancouver

GREAT EXPECTATIONS

The Good vs. The Bad, and The Ugly Monday Morning, 8 am–12 noon, June 8th 2015 Vancouver Convention Centre – Room # West 210 Jennifer L Parish, MD, Director Philadelphia, Pennsylvania, USA The Good will focus on what new treatments and techniques that are available and also on new ideas with old treatments and techniques. Co-chairs:

Mohamed Amer, MD Ibrahim Galadari, MD Paula Karam, MD Joseph Pace, MD, FRCP Marcia Ramos-e-Silva, MD, PhD 8:00-8:09 Introduction Jennifer L Parish, MD 8:10-8:34 Scars The Good 1 Esperanza Welsh, MD: Monterey, Mexico Scars: Treatment with Lasers, Fillers, Cryotherapy, and Beyond The Bad and The Ugly 2 Oliverio Welsh, MD: Monterey, Mexico Scars: Cryochemopeeling in Acne and its Sequelae 8:35-8:59 Hair Transplantation

The Good 3 Walter Unger, MD, FRCPC: Toronto, Ontario, Canada Hair Transplantation 2015: The Good News The Bad and The Ugly 4 Robin Unger, MD: Toronto, Ontario, Canada Hair Transplantation: New

Innovations and their Potential Pitfalls 9:00-9:24 Drugs The Good 5 Zoe Draelos, MD: High Point, North Carolina, USA Beneficial Skin Cosmetics The Bad and The Ugly 6 Larry Millikan, MD: Meridian, Mississippi, USA Drugs and their Reactions 28/03/12 12:19 9:56 PM AM 24/12/11 19/01/12 2:01

9:25-9:49 Injections The Good 7 Hassan Galadari, MD: Dubai, United Arab Emirates Mid Face Augmentation with New Innovations for Treating the Tear Trough The Bad and The Ugly 8 Doris Hexsel, MD: Porto Alegre, Brazil Complications of Fillers in the Mid and Lower Face 9:50-10:14 Pigmentary Disorders The Good 9 Almond Derla, MD: Manila, the Philippines Pigmentation Disorders: New Treatments and Techniques

The Bad and The Ugly will focus on complications and procedures that do not provide significant results. The Bad and The Ugly 10 Mysore Venkataram, MD: Bangalore, India Complications of Vitiligo Treatment and other Pigmentary Disorders

The Bad and The Ugly 14 Vesna Petronic-Rosic, MD, MSc: Chicago, Illinois, USA Myths and Facts about Sensitive Skin

Health Break 10:15-10:29

11:20-11:44 Mohs Surgery

10:30-10:54 Beautiful Inside and Out The Good 11 Marina Landau, MD: Holon, Israel The Science and Art of Chemical Peels The Bad and The Ugly 12 Uwe Wollina, MD: Dresden, Germany Adverse Events with Fillers and Tattoos – the Bad and Ugly Side 10:55-11:19 Promises and Myths of Beauty Treatments The Good 13 Kyle Coleman, MD: Austin, Texas, USA New Treatments and Techniques for Body Sculpting

The Good 15 Paul Benedetto, MD: Philadelphia, Pennsylvania, USA What is New in Mohs Surgery? The Bad and The Ugly 16 Anthony Benedetto, DO: Philadelphia, Pennsylvania, USA Mohs: What Went Wrong? 11:45-12:00 Discussion and Awards for the most persuasive speakers The Good vs. The Bad and The Ugly

MEDIA PARTNER

March/April 2015

Volume 13 • Issue 2

Original contribution

Trichoscan Findings in Patients With Effluvium Capillorum Emina Kasumagic-Halilovic, MD, PhD;1 Nermina Ovcina-Kurtovic, MD, MS;1 Begler Begovic, MD, MS2 Abstract Effluvium capillorum is a form of nonscarring alopecia characterized by diffuse hair shedding. This condition occurs when the normal balance of hairs in growth and rest phases is disrupted. Trichoscan is a computerized program used for digital measurement of hair growth and hair loss. This study was performed to describe the TrichoScan as a method, which combines standard epiluminiscence microscopy with automatic digital image analysis for the measurement of human hair. The study included 30 patients with effluvium capillorum (16 women and 14 men). A control group consisted of 30 generally healthy patients (14 women and 16 men). For the measurement of hair density and anagen/telogen ratio, a commercially available software (TrichoScan) was used. The results of digital image analysis from the patients showed a highly increased proportion of telogen hair roots. The authors’ results indicate that TrichoScan represents a very useful tool in the evaluation of hair loss. (SKINmed. 2015;13:98–101)

ffluvium capillorum (EC) is a form of nonscarring alopecia characterized by diffuse hair shedding. In a healthy individual, up to 90% of hair follicles are in a growing phase (anagen) and only 10% are in a telogen, resting phase.1 EC occurs when the normal balance of hairs in growth and rest phases is disrupted, and the telogen phase predominantes. The disproportionate shedding leads to a decrease in the total number of hairs. Numerous methods have been described to asses the rate of hair growth. The technique can be classified as either invasive (biopsies), semi-invasive (trichogram), or noninvasive (phototrichogram) methods. A useful method must be able to analyze the biologic parameters of hair growth, which include hair density (n/cm2), hair diameter (μm), hair growth rate (mm/d), and anagen/telogen ratio.2 The manual identification of the hairs is a tedious process prone to human error.3 This study was performed to describe the TrichoScan (Tricholog GmbH, Freiburg, Germany) as a method, which combines standard epiluminiscence microscopy (ELM) with automatic digital image analysis for the measurement of human hair. For that reason, we investigated the findings of TrichoScan in patients with EC and compared them with those of healthy patients.

Patients and Methods

Patients Thirty patients with effluvium (16 women and 14 men, aged 12–63, median age, 35 years) and the same number of clinically healthy individuals (14 women and 16 men, aged 15–62, median age, 35 years) were included in the study. The diagnosis of EC was made on clinical grounds. Patients with alopecia areata, trichotillomania, or cicatrial alopecia were excluded from the study. All participants gave their informed consent in accordance with the requirements of the institutional ethics committee.

Methods For the measurement of hair density (n/cm2) and anagen/telogen ratio, we used the TrichoScan as a method that combines standard ELM with automatic digital image analysis. The use of the TrichoScan initially involves shaving a scalp area (approximately 1.8 cm2). The area to be shaved is chosen using the same criteria as for epilation with the classic trichogram technique. After 3 days, the hairs in the shaven area are dyed and a digital photograph is taken at 20-fold magnification (Figure 1). The recorded photographs were loaded into the TrichoScan software (TrichoScan Professional Version 3.0; Tricholog GmbH 79117

From the Department of Dermatology and Venereology1 and Clinical Pharmacology,2 Sarajevo University Clinical Center, Bolnicka 25, 71 000 Sarajevo, Bosnia and Herzegovina Address for Correspondence: Emina Kasumagic-Halilovic, MD, PhD, Department of Dermatology and Venereology, Sarajevo University Clinical Center, Bolnicka 25, 71 000 Sarajevo, Bosnia and Herzegovina • E-mail: kasumagicemina@yahoo.com

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ORIGINAL CONTRIBUTION

Freiburg, Germany), which automatically proceeded with the analysis. Figure 2 illustrates a digital image taken at 20-fold magnification and shows the area of 0.57 cm analyzed with the TrichoScan software. Red hairs are nongrowing hairs (telogen) and green hairs are growing (anagen). In the definition of the TrichoScan procedure, an anagen hair is a hair that is detectable 3 days after complete hair clipping. Within this time, only anagen hairs should grow significantly. A telogen hair is a hair that has not grown in the 3 days after hair clipping.

Statistics Analysis was carried out by calculating 95% confidence interval (CI) for median values of hair density, anagen/telogen ratio, and median proportions for anagen and telogen proportions. The distribution of TrichoScan values (hair density, anagen proportion, telogen proportion, anagen/telogen ratio, number of vellus, and terminal hairs) were compared between the groups using MannWhitney test. Values with P<.05 were accepted as statistically significant. We used the point biserial correlation coefficient (rpb) for analysis of the relationship between dichotomous variable (effluvium or control) and continuous variable (proportion of anagen hairs, ratio of anagen/telogen hairs, hair density (n/cm2), and density of vellus hairs (n/cm2). Statistical significance was set at P<.05.

Figure 1. Trichoscan procedure.

Statistical analyses were performed using MedCalc for Windows, version 11.6.1.0 (MedCalc Software, Mariakerke, Belgium). Results We performed a cross-sectional study in 30 consecutive outpatients with scalp effluvium and 30 age- and sex-matched controls. Demographic data of patients and controls are shown in Table I. The mean (±standard deviation) age of the patients and control group (CG) was 35.00±14.47 years and 35.37±13.74 years, respectively (P=.9205). Results from Mann-Whitney test showed a significant difference in hair density (n/cm2) between the effluvium group (EG) (median, 87.00; n=30; 95% CI, 63.94–104.63) and CG (median, 104.25; n=30; 95% CI, 92.70–118.56) (z=2.432, P=.015) (Table II, Figure 3). A statistically significant difference was found in anagen proportion between EG (median, 56.50; n=30; 95% CI, 48.00–64.48) and CG (median, 79.50; n=30; 95% CI, 76.00–81.38) (z=5.789, P<.01) (Table II, Figure 4). The same statistically significant differences were found in telogen proportion and anagen/telogen ratio (Table II and Figures 5 and 6). Between-group difference in the number of vellus hairs per cm2 was significantly different: EG (median, 4.75; n=30; SKINmed. 2015;13:98–101

Figure 2. Example of trychoscan analysis.

95% CI, 3.50–10.10) and CG (median, 3.50; n=30; 95% CI, 1.70– 4.16) (z=2.644, P=.0082) (Table II). There was no significant difference in the number of terminal hairs (n/cm2) between EG (median, 138.70; n=30; 95% CI, 107.37–166.26) and CG (median, 167.70; n=30; 95% CI, 146.21–194.19) (z=1.952, P=.051) (Table II). Test point biserial coefficient of correlation showed that a smaller proportion of anagen hairs correlated strongly (r=–0.754, P<.0001) with effluvium. The same result was recorded for the ratio of anagen/telogen hairs (r=–0.754, P<.0001). The same test showed that both more vellus hairs (r=0.345, P=.0069) and high density of hairs (r=–0.317, P=.0137) correlated weakly with effluvium.

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ORIGINAL CONTRIBUTION

Table I. Demographic Data of Patients (Effluvium Group) and Volunteers (Control Group) Effluvium Group, No. (%)

Control Group, No. (%)

P Value

Men

14 (47)

16 (53)

>.05

Women

16 (53)

14 (47)

>.05

Age range, y

12–63

15–62

Age, mean (SD), y

35.00 (14.47)

35.37 (13.74)

>.05

Figure 3. Hair density.

Figure 5. Telogen proportion.

Figure 4. Anagen proportion.

Figure 6. Anagen/telogen ratio.

Discussion For many years, dermatologists have been searching for a simple, noninvasive method to quantitatively evaluate hair loss and hair growth. In the 1960s, a compound measurement of the major biological parameters of hair growth was first described.4 This technique was to be known later as the trichogram. The trichogram, so-called classical hair-root examination, is a standardized SKINmed. 2015;13:98–101

light-microscopic investigation of the hair roots from the epilated hair. This method enables the investigator to decide on the activity of the hair loss. The traditional trichogram is a semiinvasive technique of great help to the clinician but poorly tolerated by the patients. First introduced by Saitoh in 1970, the photrichogram is a noninvasive technique that is simpler and more reproducible and sensitive than a trichogram.5 It allows the in vivo study of the hair growth cycle.

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Table II. Results of Digital Image Analysis Hair Parameter

Effluvium Group

Control Group

Median

95% Confidence Interval

Median

95% Confidence Interval

Z Statistic

P Value for Mann-Whitney Test

Hair density, n/cm2

87.00

63.94–104.63

104.25

92.70–118.56

2.432

.0150

Anagen proportion, %

56.50

48.00–64.48

79.50

76.00–81.83

5.789

<.0001

Telogen proportion, %

43.50

35.53–52.00

20.50

18.18–24.00

5.789

<.0001

Anagen/telogen ratio

1.30

0.92–1.82

3.88

3.17–4.51

5.789

<.0001

Velus hairs, n/cm2

4.75

3.50–10.10

3.50

1.70–4.16

2.644

.0082

Terminal hairs, n/cm2

138.70

107.37–166.26

167.70

146.21–194.19

1.952

.0510

The information technology revolution has resulted in advances throughout medicine, including hair measurement. In 2001, a step forward was taken with the development of a new phototrichogram technique called the Trichoscan.2 Epiluminiscence microscopy is a clinical tool that was originally refined for the diagnosis of pigmented skin lesions.6 In recent years, ELM has been adapted to quantify hair growth. Specially developed computer software enables assessment of the 4 basic biological parameters of hair growth. This software system is able to recognize individual hair fibers. According to the inventor, the TrichoScan is investigator independent, very precise, reproducible, time-saving, and easy to handle.2 In recent years, some authors have validated the TrichoScan technology7–9 and concluded that there is an excellent correlation between evaluation of hair parameters using manual identification of hairs and the fully automated Trichoscan method. It was further proposed that the Trichoscan is particularly suitable for clinical studies with treatment comparisons.10,11

References

On the contrary, some limitations of the TrichoScan are reported in the literature. Our results show that the technique is able to automatically analyze all parameters: scalp hair density of the patients were detected to be significantly lower than those of the controls. The results of digital image analysis from the EC patients showed a highly increased proportion of telogen hair roots.

1 Abell E. Embriology and anatomy of the hair follicle. In: Olsen EA, ed. Disorders of Hair Growth: Diagnosis and Treatment. New York, NY: McGraw-Hill; 1994:1–19. 2 Hoffmann R. TrichoScan: combining epiluminiscence microscopy with digital image analysis for the measurement of hair growth in vivo. Eur J Dermatol. 2001;11:362– 368. 3 Van Neste D, Trueb RM. Critical study of hair growth analysis with computer-assisted methods. J Eur Acad Dermatol Venereol. 2006;20:578–583. 4 Barman JM, Pecoraro V, Astore I. Method, technique and computations in the study of the trophic state of human scalp hair. J Invest Dermatol.1964;42:421–426. 5 Dhurat R. Phototrichogram. Indian J Dermatol Venereol Leprol. 2006;72:242–244. 6 Chamberlain AJ, Dawber RP. Methods of evaluating hair growth. Australas J Dermatol. 2003;44:10–18. 7 Aktan S, Akarsu S, Ilknur T, Demirtasoglu M, Ozkan S. Quantification of female pattern hair loss: a study in a Turkish population. Eur J Dermatol. 2007;17:321– 324. 8 Riedel-Baima B, Riedel A. Use of the TrichoScan to assess female pattern hair loss. Dermatol Surg. 2009;35:651–655.

Conclusions

9 Lopez V, Martin JM, Sanchez R, Ortega C, Richart JM. Usefulness of TrichoScan professional in the evaluation of hair loss in females. Report of 180 cases. J Eur Acad Dermatol Venereol. 2011;25:1068–1072.

The TrichoScan represents a noninvasive technique with simple interpretation that may be helpful in the clinical diagnosis and control the effect of treatment for diffuse hair loss. The advantages of this method lie in its simple and speedy photographic processing, the painlessness of the procedure, and the reproducibility of the results.

11 Hoffmann R. A 4-month, open-label study evaluating the efficacy of eflornithine 11.5% cream in the treatment of unwanthed facial hair in womenusing TrichoScan. Eur J Dermatol. 2008;18:65–70.

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10 Gassmueller J, Rowold E, Frase T, Huges-Formella B. Validation of TrichoScan technology as a fully-automated tool for evaluation of hair growth parameters. Eur J Dermatol. 2009;19:224–231.

Trichoscan Findings in Patients With Effluvium Capillorum

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Michael H. Gold, Md • Lawrence Charles Parish, Md • Wm. Phillip Werschler, Md Joel Cohen, Md • dr. Erin Gilbert, Md, Phd • dr. Miles Graivier, Md • Michael Kane, Md Mukta Sachdev, Md • dr. Julie Woodward, Md, Phd TRIALS INCLUDED:

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IntroductIon and HIstory of BotulInum toxIns BotulInum toxIns – suBtypes BotulInum toxIns In use In aestHetIc medIcIne Botox Cosmetic Dysport Xeomin PurTox Neuronox ChinaTox Other Toxins InjectIon tecHnIques for cosmetIc IndIcatIons Glabella Crow’s Feet and Lower Eyelid Forehead Brow Lift Bunny Lines Nose Nasolabial Folds Gummy Smile Upper and Lower Lip Lines Marionette Lines Cobblestone Chin Neck and Platysmal Bands BotulInum toxIn for HyperHIdrosIs BotulInum toxIn–otHer IndIcatIons used for aestHetIc medIcIne BotulInum toxIn–comBInatIon tHerapy wItH otHer modalItIes With Fillers With Lasers and Light Sources With Chemical Peels With Surgical Procedures adverse events of BotulInum toxIn topIcal BotulInum toxIns future devIces and tHeIr role In muscle relaxtIon Index

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March/April 2015

Volume 13 • Issue 2

Original contribution

Chondroid Syringoma: Report of Four Cases Faten Limaiem, MD; Sirine Bouslama, MD; Inès Haddad, MD; Sana Ben Slama, MD; Saâdia Bouraoui, PhD; Ahlem Lahmar, MD; Sabeh Mzabi-Regaya, PhD Abstract Chondroid syringomas or mixed tumors of the skin are relatively rare adnexal tumors constituting 0.01% to 0.1% of all primary skin tumors. The majority of chondroid syringomas occur at the head and neck region (80%). Their clinical presentation is not specific and the final diagnosis is based on histopathologic examination. The authors report four cases of benign chondroid syringoma in three women and one man aged 26, 45, 50, and 38 years, respectively. They presented with a slow-growing, painless and firm subcutaneous nodule measuring between 1 and 3 cm involving the lower eyelid, the nasogenien groove, the nose, and the chin, respectively. All patients underwent uneventful surgical excision of the nodules. Histologic examination of the surgical specimen was compatible with benign chondroid syringoma in all cases. Chondroid syringomas must be considered in the differential diagnosis of any small subcutaneous nodule in the head and neck region in middle-aged patients. The treatment of choice is total excision, with wide disease-free margins, to rule out malignancy and reduce the risk of recurrence and malignancy in the future. (SKINmed. 2015;13:104–106)

hondroid syringomas (CS), or mixed tumors of the skin, are relatively rare cutaneous tumors of sweat gland origin that usually arise in middle age with a predilection for the head and neck region (80%).1 The hallmark of these biphasic tumors is the spectrum of histologic changes, which is manifested by both epithelial and mesenchymal components. In this paper, we report four cases of CS involving the lower eyelid, the chin, the nasogenien groove, and the nose. Our aim was to highlight the clinicopathologic features of this relatively uncommon neoplasm with review of the current literature.

Clinical Findings Clinical data and histologic findings of the four patients are summarized in Table I and Table II. There were three women and one man aged between 26 and 50 years (mean, 39.75 years). The lesions occurred as solitary firm and painless subcutaneous nodules located on the lower eyelid, the chin, the nasogenien groove, and the nose, respectively. They measured between 1 and 3 cm in diameter (mean, 1.65 cm). Surgical excision of the tumor was performed in all cases with no evidence of recurrence postoperatively.

Table I. Clinical Data in Four Patients With Chondroid Syringoma Case 1

Case 2

Case 3

Case 4

Age/sex

26/women

38/men

45/women

50/women

Location

Lower eyelid

Chin

Nasogenien groove

Nose

Diameter

1 cm

1.5 cm

3 cm

1.1 cm

Clinical presentation

Slow-growing, painless, firm nodule

Nontender, firm, subcutaneous nodule

Treatment

Surgical excision of the nodule

Evolution

No recurrence

From the Department of Pathology, Mongi Slim Hospital, La Marsa, Tunisia and the Faculty of Medicine, Université de Tunis El Manar, Tunisia Address for Correspondence: Faten Limaiem, MD, Mongi Slim Hospital, Department of Pathology, 4, Impasse Tark Ibn Zied, Mutuelleville, Tunis 1082 • E-mail: fatenlimaiem@yahoo.fr

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Table II. Histological Findings in Four Patients With Chondroid Syringoma Case 1

Case 3

Case 4

Epithelial component

Nonbranching tubules Branching ducts lined by lined by 2-cell–thick 2-cell–thick epithelium epithelium

Nonbranching tubules lined by 2-cell–thick epithelium

Branching ducts lined by 2-cell–thick epithelium Apical snouts with decapitation secretions Follicular differentiation

Mesenchymal component

Myxochondroid matrix

Chondroid matrix

Fibrous, hyaline, and chondroid matrix Adipose tissue

Myxochondroid matrix Adipose tissue

Histologic type

Apocrine chondroid syringoma

Case 2

Figure 1. (a) Nonbranching tubules lined by a two-cellthick epithelium. The tubules were surrounded by plasmacytoid epithelial cells within a myxoid matrix (hematoxylin and eosin, original magnification ×40). (b) Apical snouts with decapitation secretions were focally noted in some ductular structures (hematoxylin and eosin, original magnification ×40).

Figure 2. Follicular differentiation determined by presence of hair follicular germ and mesenchymal cells of follicular papillae. Note the aggregates of adipocytes surrounded by myxoid areas (hematoxylin and eosin, original magnification ×20).

Histologic Findings Histologic examination of the surgical specimen established the diagnosis of CS in all cases. All lesions showed a nodular growth pattern involving the dermis. The epithelial component of the tumor was composed of nests, cords, or scattered epithelial cells (n=4) as well as branching (n=2) and nonbranching (n=2) ductular structures lined by two rows of epithelial cells (Figure 1a). Apical snouts with decapitation secretions were evident in only one case (Figure 1b) and follicular differentiation was noted in only one case (Figure 2). The mesenchymal component of the tumor comprised a myxochondroid matrix in two cases, an exclusively chondroid matrix in one case (Figure 3), and a hyalineSKINmed. 2015;13:104–106

chondroid stroma in one case. Adipose tissue was identified in only two cases. Nuclear atypia and mitosis were absent in all cases. Discussion The frequency of CS among primary skin tumors varies from 0.01% to 0.1% in reported series.2,3 Patients with CS range in age from 22 to 73 years (mean age, 50 years) with a male predominance.4,5 Clinically, CS presents as a slow-growing, nontender, firm, dermal, or subcutaneous nodule or papule measuring 0.5 to 3 cm in diameter. It is usually adherent to the overlying epidermis with no fixation to the underlying fascia. Common sites

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ORIGINAL CONTRIBUTION epithelial markers such as cytokeratin, whereas the outer layers express mesenchymal markers such as vimentin, S-100 protein, neuron-specific enolase, and glial fibrillary acidic protein.6,7,9 Malignant CS is extremely rare.6,8 Most malignancies develop de novo, and few cases arise in the preexisting benign CS.6,10 The optimal management of CS is total excision with wide disease-free margins without destroying the aesthetic and functional structures.6,8 Regular follow-up is required to monitor for recurrence and malignancy.3,6–8 Conclusions CS must be considered in the differential diagnosis of any small subcutaneous nodule in the head and neck region in middle-aged patients. The treatment of choice is total excision to rule out malignancy and reduce the risk of recurrence and malignancy in the future. Definitive diagnosis relies on histopathologic examination of the excised tissue.

Figure 3. Mesenchymal components of apocrine chondroid syringoma: chondroid stroma (hematoxylin and eosin, original magnification ×40).

are the cheek, nose, or the skin above the lip.6–9 It often presents as a single entity, but multiple CS have also been reported.8 CS are often mistaken for other types of skin lesions, such as dermoid or sebaceous cyst, neurofibroma, dermatofibroma, lipoma, basal cell carcinoma, pilomatricoma, histiocytoma, and seborrheic keratosis.3,8 Because CS are uncommon and rarely undergo aspiration, preoperative diagnoses of many cases are incorrect.3,7 Very few cases describing the cytologic features of CS are available in the literature.6,8 If the typical biphasic epithelial and mesenchymal elements are not represented on the aspirate, with one component predominating, it may lead to diagnostic difficulties and misdiagnoses.6 Histologic examination of the excised tissue is the most reliable tool in establishing a definitive diagnosis.6,7 Histopathologically, CS has epithelial and mesenchymal stromal components. The tumor stroma may be myxoid, chondroid, adipocytic, or fibrous. CS has been classified into apocrine and eccrine types based on the histopathologic appearance of the sweat gland lumina in the tumor. The apocrine type is more common and is characterized by tubular and cystic branching lumina lined by two layers of cuboidal or flattened epithelial cells. The inner epithelial layer exhibits apocrine features. The eccrine type is characterized by small tubular lumina lined by a single layer of cuboidal epithelial cells. Some tumors may exhibit both apocrine and eccrine features.3,7,8 The inner layer expresses

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References

106

1 Sungur N, Uysal A, Gumus M, Kocer U. An unusual chondroid syringoma. Dermatol Surg. 2003;29:977–979. 2 Kitazawa T, Hataya Y, Matsuo K. Chondroid syringoma of the orbit. Ann Plast Surg. 1999;42:100–102. 3 Yavuzer R, Basterzi Y, Sari A, Bir F, Sezer C. Chondroid syringoma: a diagnosis more frequent than expected. Dermatol Surg. 2003;29:179–181. 4 Mandeville JT, Roh JH, Woog JJ, et al. Ophthal Plast Reconstr Surg. 2004;20:110–116. 5 Vangveeravong S, Katz SE, Rootman J, White V. Tumors arising in the palpebral lobe of the lacrimal gland. Ophthalmology. 1996;103:1606–1612. 6 Dubb M, Michelow P. Cytologic features of chondroid syringoma in fine needle aspiration biopsies: a report of 3 cases. Acta Cytol. 2010;54:183–186. 7 Tokyol C, Aktepe F, Yavas BD, Yildiz H, Aycicek A. Chondroid syringoma: a case report. Acta Cytol. 2010;54:973– 976. 8 Skoro M, Ostović KT, Cikara I, et al. Fine needle aspiration cytology of chondroid syringoma. Coll Antropol. 2010;34:687–690. 9 Mishra K, Agarwal S. Fine needle aspiration cytology of malignant chondroid syringoma: a case report. Acta Cytol. 1998;42:1155–1158. 10 Sun TB, Chien HF, Huang SF, Shih TT, Chen MT. Malignant chondroid syringoma. J Formos Med Assoc. 1996;95:575– 578.

Chondroid Syringoma: Report of Four Cases

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March/April 2015

Volume 13 • Issue 2

Original contribution

A Practical Method to Detect Mycoses of the Nails Mauricio Goihman-Yahr, MD, PhD;1,2 Francisco Franco-Arcia, MD;1 Carlota Maldonado, RN, BSc1 Abstract The authors present a method that allows for reliable identification of fungal structures in nails with suspected colonization by fungi. The method is based on the well-known technique of heating nail fragments in 20% potassium hydroxide, but its details allow for reliable and quick processing of samples, when convenient. The method requires simple equipment and is designed for individual practices but might be employed as is or with minor technical improvements by a dermatology department. Minor changes will make it feasible to simultaneously process several samples. The results that were obtained show that while experienced clinicians achieve positive clinical diagnoses in the majority of instances, inaccuracies occur in a sizable proportion of cases. In addition, the varied combination of yeasts and hyphae that were found, bolster the view that microscopic examination is necessary to justify and optimize systemic treatment of mycoses of the nails. Our technique permits the processing and observation of the totality of samples obtained from a single nail or several nails. (SKINmed. 2015;13:108–110)

ycoses of the nails (particularly of the toenails) have always existed but have gained notoriety because of current fashions that favor leaving toes in plain sight, particularly among women. Current effective treatment for this pathology rests on systemic long-term administration of antifungals. This is expensive, rather inconvenient, and might produce side effects, which can be serious although uncommon. Proper monitoring requires initial and consecutive laboratory tests, with the latter increasing expense and inconvenience. It is clear that systemic antifungal therapy for onychomycoses can be justified only if clinical suspicions are confirmed by objective evidence. The latter include visualization of fungal structures and culture. Mycologic cultures of nail material are expensive, might take weeks to obtain results, have low sensitivity (albeit high specificity), and require special training and laboratory facilities. Fortunately, cultures are not necessary to choose appropriate therapy for nail mycoses; however, they are still valuable for scientific and epidemiological studies.

A practical, highly sensitive method to detect fungi in nails by direct microscopy would be useful in clinical practice, and here we discuss a procedure based on the well-known fact that hot 20% potassium hydroxide (KOH) is able to digest proteins of nails and other cornified structures, while polysaccharidic fungal cell walls are left intact or at least identifiable. Our method requires only simple, easily available equipment and is highly sensitive and convenient. We have used it in fingernails and toenails although the latter seem to be more frequently involved. We do not aim at presenting conceptual advances in knowledge; but rather a method that is practical and reliable. This technique could be adapted for processing many more samples. Materials and Methods Nail material was processed from either the toenails or fingernails of men and women. The nails had features of onychomycosis, namely subungual hyperkeratosis, onycholysis, thickening and discoloring of nail plates, and onychogryphosis. No enamel was allowed when samples were taken, and patients had to go at least 2 weeks and preferably a month without systemic or topical treat-

From the Unidad Clinica Esmeralda, Los Proceres San Bernardino, Caracas, Venezuela;1 Department of Dermatology, Vargas School of Medicine, Central University of Venezuela, Caracas Venezuela (retired)2 Address for Correspondence: Mauricio Goihman-Yahr, MD, PhD, Chair of Dermatology, Vargas School of Medicine, Central University of Venezuela, Caracas, Venezuela • E-mail: mgoihmanyahr@yahoo.com

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ORIGINAL CONTRIBUTION a. Mechanical tool (Dremel) b. Kidney-shaped basin c. Scalpel and blade d. Glass Petri dish e. Nail clipper f. Needle holder g. Curette h. Beaker holding glass carpule in a water bath i. Burner (alcohol or Bunsen burner) j. Matches k. Alcohol for disinfection

Figure. Schematic depiction of the method employed for microscopic examination of digested nail samples.

ment. They were also told to stop “cleaning” the undersurface of the nails. If many nails were affected, samples could be taken from several of them, and such samples were usually pooled. The surface of the nails was cleaned with alcohol, using gloves, sterile instruments, and protective goggles. Samples were taken with nail clippers of varying sizes and the nail bed (usually hyperkeratotic) was scraped with a 15 scalpel blade and/or a sterile glass slide. A size 3 curette was also used occasionally. Samples of thick nails were obtained by using a motor tool (Dremel). The business end of the tool was sterilized by flaming before and after the procedure. All material was collected in a 10.5-cm D sterile glass Petri dish. The dish was held obliquely if necessary to catch particles. At the end of the sampling, the particles were pushed together in a margin of the dish by gently tapping the exterior of the closed dish with a scalpel handle. The particles were collected with a scalpel blade and transferred carefully and totally into a small 63×8-mm glass tube (empty carpule). The tube was held vertically, taped inside a 50-mL glass beaker. After transfer, the carpule was capped with a plastic 30-gauge needle cover. The material was then processed by one of two different methods. Up until 2005, we added 20% KOH in distilled water, exSKINmed. 2015;13:108–110

actly five drops per glass container, and left at room temperature for 2 days before observation. Starting in 2005, we simply kept the dry sample at room temperature until we were ready to process one or several samples. Then we added the five drops of 20% KOH and put the capped tubes in a boiling water bath for 30 minutes. They were held in place by means of two taped wooden tongue depressors. In both methods we poured the heated processed sample over a standard glass slide and covered it with a 50×24-mm coverslip. This latter size secured that there would be no overflow or empty spaces. If thick fragments of nails were processed, the consistency of the sample would be gel-like after digestion (either in the cold or in the water bath). The gel was extruded from the tube by tapping or by fishing it out with a bent needle and the mass was transformed into a thin layer by gently pressing over the coverslip. The slides rested in a standard microscope for at least 5 minutes and were then examined with low dry and/or high dry objectives. No ink or penetrating substances were needed. The whole slide was examined in a systematic way either in a stepwise fashion or horizontally throughout the length of the slide and then vertically (Figure).

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ORIGINAL CONTRIBUTION 7. Positive for hyphae and yeasts

Table. Results of Direct Microscopy of Nail Material (N=584) Negative

19.35% (n=113)

Only hyphae

29.11% (n=170)

Only yeasts

3.60% (n=21)

Only “hourglass structures” (HGS)

5.14% (n=30)

Hyphae + yeasts + HGS

15.41% (n=90)

Hyphae + HGS

12.33% (n=72)

Hyphae + yeasts

7.02% (n=41)

Yeasts + HGS

8.05% (n=47)

8. Positive for yeasts and HGS. Results A paired comparison of 10 successive samples performed in 2005 showed that both methods that had been employed gave identical results. Thus, the latter were pooled for analysis. A total of 584 specimens from patients were consecutively analyzed during July 1991 to August 2014. All patients were presented to the private practice of one of the authors (MGY). The Table shows the results. Hyphae were found in nearly 64% of patients. Only slightly more than 19% of samples were negative. Yeasts were present alone or in combination in slightly more than 34% of samples. The enigmatic HGS were present alone in slightly more than 5% of samples.

The following structures could be easily identified: 1. Hyphae. We were able to determine comparative diameter and length, presence of arthrospores, wall thickness, and in some cases colored hyphae. The state of preservation of hyphae was also noted. (One might determine exact diameter of hyphae and length by means of a micrometric rule, but we did not do so). 2. Small yeast-like structures. 3. Bigger yeast structures with or without germinating tubes or pseudohyphae. 4. Peculiar structures that had a yeast-like shape with a double contour. They had an hourglass shape but also showed lateral longitudinal prolongations. The interior was optically empty. We called them “hourglass-shaped structures (HGS).” In addition to the above we could detect bacteria (bacilli or cocci), blood, and other pigmentary matter. These were not specifically noted for this paper. Results were recorded as: 1. Negative (no yeasts, hyphae, or HGS) 2. Positive for hyphae alone 3. Positive for yeasts alone 4. Positive for HGS alone 5. Positive for hyphae, yeasts, and HGS 6. Positive for hyphae and HGS

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It is clear that while clinical diagnosis was accurate in the majority of cases, a considerable proportion of samples yielded negative results. If these patients were to be treated with systemic antifungals they would in all likelihood receive unwarranted, ineffective therapy. In addition, the high proportion of samples containing yeasts suggests that systemic treatment with agents effective only or mainly against filamentous fungi might be ineffective in cases such as these. This underlines the need for microscopic examination before embarking on long-term oral treatment. Conclusions The method presented is relatively easy to perform and requires only simple and easily available instruments. It was designed for a private referral practice, in which the number of weekly cases was relatively small. One can easily foresee minor changes (eg, designing a heat-resistant holder that would permit simultaneous processing of samples or incorporate stains that would facilitate scanning) that would allow simultaneous processing of several samples. This would make this method suitable for busy laboratories or hospital departments of dermatology. We stress the importance of detailed microscopic examination to apply optimal systemic treatment, as permitted by currently available therapies. The method that we present can be performed at a convenient time for the performer. It provides reliable results and permits a glimpse into the varied mycoflora of nails and nail beds that go beyond the simple negative/positive approach. This is made possible by the fact that the totality of the sample obtained from a nail or several nails can be processed and observed.

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Staphylococcus aureus and the Skin: A Longstanding and Complex Interaction Russell E. N. Becker, PhD;1 Juliane Bubeck Wardenburg, MD, PhD1,2 Abstract Staphylococcus aureus is a leading cause of human bacterial infection, most notable for its ability to infect any tissue in the human host. Among the most common sites of S aureus infection is the skin, predicated by the existence of this organism as a part of the commensal flora in up to half of the population. While the molecular mechanisms by which S aureus adapts to the ecologic niche of the skin and transitions to cause both skin infection and more severe invasive disease are incompletely defined, these represent an exciting and rapidly moving area of research. The ultimate goal of these investigations is to understand human disease pathogenesis, define host susceptibility factors that predispose to colonization and infection, and utilize this knowledge to inform the strategic development of novel preventive and therapeutic strategies. (SKINmed. 2015;12:111–119)

taphylococcus aureus is a prominent bacterial pathogen capable of causing a broad spectrum of human pathology, ranging from superficial infections to life-threatening invasive disease.1 The most common forms of S aureus disease are skin and soft tissue infections (SSTIs), accounting for more than 11 million outpatient visits and 500,000 hospitalizations per year in the United States alone.2 S aureus is responsible for the majority of SSTIs worldwide, and is the nearly universal cause of furuncles, carbuncles, and skin abscesses.2–5 Among the SSTIs, S aureus has also been identified as a causative agent of folliculitis, impetigo, erysipelas, cellulitis, necrotizing fasciitis, pyomyositis, and Fournier gangrene.6 Secreted toxins also cause severe desquamating eruptions in infants (staphylococcal scalded skin syndrome) and adults (staphylococcal toxic shock syndrome).7 Several excellent reviews detailing clinical management strategies for skin and soft tissue infections have been published recently.3,5,6,8,9 SSTIs can precede more serious invasive infection with the organism, including endocarditis, pneumonia, sepsis, and osteomyelitis. S aureus is adept at colonizing foreign materials and implanted devices, and thus is a leading cause of nosocomial infections, including ventilator-associated pneumonia and infections of the urinary tract, bloodstream, and surgical wounds.1,10–12 The direct medical costs of outpatient S aureus SSTIs in the United States are estimated to exceed $340 million annually.13

These figures encompass only methicillin-resistant infections, which account for approximately 60% to 90% of outpatient SSTIs.4,5,14 The total economic burden of inpatient S aureus infection in the United States exceeded $14.5 billion in 2003.15 Epidemiologic and economic data for other countries are more difficult to compare but it is clear that S aureus and the rise of antibiotic-resistant strains pose a significant and growing challenge throughout the world.8,10,16–18 Transmission and Elevated-Risk Populations S aureus is transmitted by direct contact. As the organism can survive on inorganic fomites for hours to days,19 strict hand hygiene practices and contact precautions have proven effective in lowering hospital transmission rates.20 All people appear to harbor susceptibility to infection by this pathogen, and uncomplicated S aureus SSTIs frequently occur in previously healthy individuals. Populations with increased risk for S aureus SSTI include those in close-contact settings such as daycare attendees, military recruits, prisoners, and competitive athletes, as well as immunocompromised individuals, diabetics, and those with healthcare exposure.4,5,21 Several immunologic disorders are uniquely associated with S aureus infection. A comprehensive review of these was recently published,22 and here we will highlight three syndromes of

From the Departments of Microbiology1 and Pediatrics,2 The University of Chicago, Chicago, IL Address for Correspondence: Juliane Bubeck Wardenburg, MD, PhD, University of Chicago, Departments of Pediatrics and Microbiology, Chicago, IL 60637 • E-mail: jbubeckw@peds.bsd.uchicago.edu

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particular interest. Chronic granulomatous disease (CGD) is a rare genetic primary immunodeficiency involving defects in the NADPH oxidase enzyme, which plays a critical role in phagocytic killing of certain bacteria and fungi.23 S aureus is the most common bacterial pathogen identified in CGD patient infections, and is the predominant cause of SSTI.24,25 Continuous antibiotic and antifungal prophylaxis is commonly prescribed to decrease the risk of infectious morbidity and mortality.23–25 Atopic dermatitis (AD), a chronic inflammatory skin condition, is also associated with elevated rates of S aureus colonization and infection. More than 90% of patients with AD are colonized by S aureus, and acute flares of AD often involve secondary infection of the lesion by S aureus.26 Although the molecular mechanisms of pathogenesis in this complex disease remain unclear, both host and microbiologic variables have been shown to correlate with the severity of AD. Hyper-IgE syndrome (HIES) is a primary immunodeficiency caused by defects in STAT3, an intracellular signaling molecule important in epithelial immunity.27 HIES patients classically have atopic dermatitis-like skin lesions with eosinophilia and increased susceptibility to staphylococcal infections starting in early infancy. Unlike the superficial skin infections commonly seen in AD, HIES patients experience recurrent deep-seated S aureus skin abscesses that may lack the typical signs of inflammation, instead forming “cold abscesses.” The original description of HIES was based on the curious presentation of two patients,28 and recurrent skin abscesses remain one of the major criteria in the clinical diagnosis of HIES. Colonization and Recurrent Infection S aureus colonizes the skin and anterior nares in 30% to 50% of US adults, with 10% to 20% persistently harboring the organism.1,3,29 Although colonized individuals are at higher risk for infection, the relationship between these two distinct states, as well as the mechanisms responsible for transitions between them, remain poorly understood.3,19 Decolonization regimens of intranasal mupirocin and topical chlorhexidine have been used to prevent infection in high-risk populations and to control outbreaks, particularly in the healthcare setting.1,3,8,29,30 A recent trial conducted in 43 US hospitals found that universal decolonization of patients in adult intensive care unites significantly reduced the rates of overall bloodstream infections31; however, the applicability of such measures to control S aureus in the general population is not well established.3,8,12,19,32 Approximately 30% to 50% of S aureus SSTIs are recurrent over a period of months to years.22,33 These episodes may represent SKINmed. 2015;13:111–119

repeated autoinfection from benign sites of colonization, or repeated infections from external sources. The household environment and close personal contacts are important sources of repeated inoculation, and attempts at eradication should include consideration of these reservoirs.19,32 Although they are a characteristic feature of immune disorders noted above, recurrent SSTIs often occur in otherwise healthy individuals, highlighting the fact that S aureus primary infection does not confer protective immunity.4,33 Historical Perspectives

Early Studies on S aureus Disease The initial descriptions of S aureus as an etiologic infectious agent of skin abscesses and wound infections were reported by Alexander Ogston in 1880.34 Ogston utilized the methods of his contemporary Robert Koch to examine S aureus in the purulent exudate of newly opened human skin abscesses. By injecting small amounts of this exudate into animals, Ogston found that he could elicit similar lesions in the new host, from which the proliferating bacteria could again be obtained. Nearly half a century later in 1928, S aureus captured attention when a partially used vial of diphtheria toxin-antitoxin preparation became contaminated with the organism. Twenty-one young children in the town of Bundaberg, Australia, were immunized with this contaminated stock on the next clinic day. Twelve children died of systemic infection within hours, while survivors developed injection-site abscesses.35 This tragic series of events set in motion the decades of rigorous investigation into the basic biology and pathogenesis of S aureus that followed. Studies borne out of the Bundaberg tragedy highlighted the importance of the secreted staphylococcal α-toxin, and provided the basis for some of the earliest attempts at targeted interventions.36 By 1930, the widely used Wright’s vaccine, containing whole killed staphylococci, had proven to be ineffective at preventing recurrent furuncles.37 Preparations of formaldehyde-inactivated, purified S aureus α-toxin were injected into patients with recurrent SSTI, with encouraging results.37,38 Passive immunization by infusion of horse antitoxic serum into patients with acute infection also showed efficacy against SSTIs.39 These initial efforts to induce human immunity to S aureus infection spearheaded years of study that still remain the center of the field to date.

Antibiotic Resistance and the Rise of MRSA Although uncomplicated SSTIs can be treated by incision and drainage, invasive and complicated infections require more aggressive management. Perhaps the most daunting clinical chal-

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lenge posed by S aureus is its remarkable antimicrobial resistance. Soon after the introduction of penicillin in the 1940s, penicillinase-expressing S aureus isolates were described.40 By the 1950s, these strains were pandemic in hospitals and spurred the development of the penicillinase-resistant–related compound, methicillin. Just a year after its introduction in 1959, however, resistance again emerged.12 For 2 decades, methicillin-resistant S aureus (MRSA) was strictly a nosocomial infection. The first cases of MRSA infection in patients without prior exposure to the healthcare setting were seen in a local outbreak among intravenous drug users in 1980,41 followed by reports of severe pediatric infections.42 The current global epidemic of community-associated MRSA (CA-MRSA) began in the mid to late 1990s. CAMRSA strains were recognized to be genetically distinct from the typical healthcare-associated MRSA (HA-MRSA) strains, being generally more susceptible to non–β-lactam antimicrobials. This distinction has become blurred in recent years, as CA-MRSA strains increasingly also cause hospital-acquired infections, and vice versa.3,43 MRSA now accounts for the majority of S aureus isolates in the United States,14,21,44 including approximately 60% to 80% of community-acquired SSTIs.5,14 Interestingly, these numbers are highly variable worldwide, and in some regions <1% of S aureus isolates are MRSA.4,8,12,16,18 This is a noteworthy distinction, since MRSA infection carries the added burden of significantly longer hospital stays, higher mortality, and increased costs compared with methicillin-susceptible S aureus (MSSA) infection.8,43 Further, the therapeutic options available to treat severe and life-threatening S aureus infections are becoming more limited—by 1997, 56.2% of MRSA isolates in US ICUs were sensitive only to vancomycin.1 Reports of disease caused by vancomycin-resistant strains of S aureus began to appear in Japan by 1996 and in the United States in 2002.12 More recently, linezolid, daptomycin, and ceftaroline have been utilized for S aureus infection; however, drug resistance has been reported for these agents as well.45,46

Development of Animal Models of S aureus SSTI Researchers began to develop animal models of S aureus skin abscesses in the late 1980s, starting with immunocompromised mice and a complex surface inoculation method that involved scraping off the superficial layers of the skin and covering the surface with an impermeable film.47 Subsequent studies expanded to immunocompetent mice but required subcutaneous foreign bodies to serve as a harbor for the infection.48 Later, it was found that the inclusion of dextran microbeads49 or direct subcutaneous injection of larger inocula of S aureus could produce consistent abscesses in mice50 or rabbits.51 Abscess histopatholSKINmed. 2015;13:111–119

ogy demonstrated large numbers of staphylococci and infiltrated immune cells in a circumscribed central abscess lesion, also revealing the ability of the organism to cause direct toxic injury to the overlying epidermis (Figure). This now widely used technique minimizes tissue trauma and experimental variability induced by the inoculation approach, offering the advantage that lesions can be easily monitored noninvasively over time in the same animal. An epicutaneous inoculation model, which may better mimic the acquisition of S aureus on healthy skin, has recently been developed.52 An appraisal of existing animal data and clinical disease readily highlights key unanswered questions in the field, which collectively center around our need to better understand the host-pathogen interaction. The Figure illustrates these central questions. Ongoing Research Efforts to Understand S Aureus Biology and Disease Pathogenesis

Key Virulence Factors in S Aureus Disease S aureus stands out among bacterial pathogens for its vast and diverse arsenal of virulence factors. The discovery and mechanistic characterization of these has relied heavily on the use of bacterial mutants in animal models of disease. To give a few examples, secreted exotoxins directly injure host cells and tissues and disrupt anatomical barriers to facilitate invasion; surface proteins aid in adhesion to tissues and foreign materials, promote blood coagulation, and prevent immune recognition; the staphylococcal capsule inhibits phagocytosis; and superantigens cause aberrant and dysfunctional activation of lymphocytes.7,12,33 The organism can also seek shelter from antibiotics and the host immune system by forming drug-impermeant biofilms, invading epithelial cells and persisting in the intracellular environment, or altering bacterial metabolism to induce a small-colony variant state that temporarily evades detection.33

Determinants of CA-MRSA Virulence The simple trait of resistance to methicillin does not in itself alter the pathogenesis of S aureus infection.1,12 In fact, the additional genetic material necessary for methicillin resistance is thought to confer a fitness cost to the bacteria in the absence of antibiotic treatment12,19; however, the clonal strains of CAMRSA now rampant in the United States and much of the world harbor pathogenic characteristics that distinguish them from the historical nosocomial strains of MSSA that predominated in the first half of the 20th century and from the HA-MRSA strains that remain largely confined to the healthcare setting. Perhaps the most obvious of these is their extensive transmission and pathogenesis among otherwise healthy individuals in the community. Recurrence of S aureus SSTI is also more common

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Figure. Key features of Staphylococcus aureus skin infection and challenges to understanding disease. Experimental S aureus skin infection recapitulates features of human disease evidenced by histopathologic analysis of lesions following infection of mice with the widespread community-associated methicillin-resistant S aureus strain USA300 (center images). Lesions reveal large accumulations of staphyloccci and invading immune cells in the abscess site. The adjacent epidermis also demonstrates hallmarks of cellular and tissue injury. A number of current areas of investigation in the field are being pursued (noted around the center images), and these represent the areas of greatest opportunity to increase our understanding of disease and develop novel interventional strategies.

among CA-MRSA strains.19 In addition, CA-MRSA strains have been noted to cause a variety of infectious syndromes not historically associated with S aureus, including necrotizing fasciitis, pyomyositis, purpura fulminans, and Waterhouse-Friderichsen syndrome.12,19,50,51,53

element in the absence of antibiotics.19 Recently, the role of antecedent nasal colonization in CA-MRSA infection has been called into question, with colonization of other body sites and environmental sources thought to play more prominent roles in transmission of these strains.19,63

The mechanisms responsible for these differences between strains remain poorly understood. Several groups have proposed that the expression of various staphylococcal exotoxins, including α-toxin, Panton-Valentine Leukocidin, or phenolsoluble modulins may play a key role.12,19,51,54–61 Others have used whole-genome sequence comparisons to identify genes encoding bacteriocins, antibacterial agents that could eliminate competing microorganisms and facilitate niche establishment, as well as a novel gene cluster involved in arginine metabolism, in CA-MRSA strains.19,62 The genetic methicillin resistance element in CA-MRSA strains is smaller than in HA-MRSA strains, which may minimize the fitness cost of this

Immune Responses to S Aureus Infection

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Another area of intense interest is the host immune response to staphylococcal infection. Current knowledge of this hostpathogen interaction stems from studies of immunodeficiency syndromes, including those described above, displaying exquisite susceptibility to S aureus infection.22,64 Recent research efforts have elucidated several key features of the host immune response to S aureus and the pathogen’s strategies for immune evasion. Several thorough reviews on these topics have recently been published, and we recommend these for more detailed discussion.22,33,64–66

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The skin serves as a critical anatomic barrier and first line of defense against microbial pathogens. The commensal microbiota, low temperature and pH of the skin surface, hydrophobic physical barrier of the stratum corneum, and constitutive secretion of antimicrobial compounds all aid in limiting the pathogenic capacity of potentially infectious microbes. When S aureus is able to breach this first line of defense, the host immune response is rapidly activated. Cellular injury initiates inflammatory signals that recruit neutrophils from the circulation to the site of infection. Upon arrival at the site, these first responders play several important roles, including further proinflammatory signaling, direct antimicrobial activity by phagocytosis and bacterial killing, and damage control by forming a contained abscess to effectively prevent local and systemic spread of the infection. Both animals and patients with defects in neutrophil function display profound susceptibility to S aureus infection. Resident and recruited T-cells have also been discovered to participate in early immune responses to S aureus SSTI.22,64 Other recent studies have demonstrated critical roles for a number of host cytokines and signaling molecules, including STAT3, MyD88, the NLRP3 inflammasome, and interleukins 1α, 1β, and 17.22,64–67 Immune Evasion and Immunomodulation By S Aureus S aureus is particularly adept at thwarting host immune responses. Immune evasion strategies by the pathogen include both secreted and surface-associated virulence factors with a wide variety of molecular mechanisms. This important area of study has received detailed attention in recent reviews.33,65,68 A broad notion of the unique and diverse immune-evasive strategies employed by S aureus will be described with a few key examples. S aureus displays an antiphagocytic capsule and surface proteins that prevent the binding of antibodies and complement peptides.69 Clumping factors A and B bind host fibrinogen, possibly forming a protective coat that inhibits opsonization and phagocytosis.65 Protein A binds to the Fc and Fab regions of host antibodies on the bacterial surface, preventing opsonophagocytosis by immune cells.70 The surface of the bacteria also contains proteins that directly inhibit complement binding and activation, and others that recruit and activate host plasminogen, leading to the degradation of surface-bound complement.71,72 The formation of biofilms and intracellular growth are also thought to help limit exposure of S aureus to the host’s pathogen-sensing mechanisms.73,74 The pathogen resists killing by antimicrobial peptides by reducing their binding affinity, sequestering or degrading them.65 When immune recognition and activation do occur, S aureus elaborates numerous factors that facilitate its survival SKINmed. 2015;13:111–119

against the respiratory oxidative burst and degradative enzymes that normally kill bacteria within the lysosome.68 The organism also employs numerous mechanisms to actively confound the host immune system. S aureus secretes several toxins with lytic activity directed against host leukocytes.75 Many strains also produce a chemotaxis inhibitory protein that interferes with neutrophil recruitment.76,77 Staphylococcal protein A and toxic shock syndrome toxin act as superantigens to cause nonspecific activation of B- and T-cell populations, preventing the generation of productive, specific adaptive immune responses.70,78 Updates on Vaccine Development As the emergence of antibiotic resistance in S aureus continues to drastically outpace the development of new drugs, we face the imminent possibility of returning to the pre-antibiotic era. At present, we have only a marginal advantage over this organism, and only in the setting of infection caused by drug-susceptible strains. Therefore, it is also crucial to develop preventive measures against S aureus disease, including hygiene, surveillance, and public health measures to limit transmission, as well as immunization strategies. Currently, a Food and Drug Administration–approved vaccine for S aureus is not available, and the focus on vaccine and therapeutic development has been one of the foremost goals in the field for more than a decade. Since the 1930s, researchers have sought to develop effective vaccines capable of generating protective immunity against S aureus in the human host. These efforts have been extensively reviewed in recent years.79–82 Most immunization strategies thus far have focused on the stimulation of humoral antibody responses against secreted toxins or surface proteins. Recently examined subunit vaccines have shown varying degrees of protection in animal models of disease,80,82 and this has prompted the progression of a number of candidate vaccines into human clinical trials. Two S aureus active vaccine candidates have been subjected to human randomized clinical trials. StaphVax (Nabi Pharmaceuticals), a CP5/CP8-PEA conjugate induced capsular polysaccharide-specific antibodies in healthy volunteers and was documented to meet safety/tolerability criteria in hemodialysis recipients.83 Anti-capsular polysaccharide antibodies were elicited upon vaccination among 80% of 892 phase III study enrollees (NCT00071214); however, 27 vaccine recipients developed S aureus bacteremia in comparison to 37 of 906 controls over a 1-year period, failing to achieve the primary study endpoint.84 More recently, Merck/Intercell conducted a phase II/III clinical trial examining an IsdB-targeting vaccine (V710, NCT00518687), delivered as a single preoperative dose to cardiothoracic surgery patients. The multi-site phase III study

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enrolled 8032 patients prior to termination owing to a safety concern superimposed on a lack of clinical efficacy.85 Several additional active vaccine programs are currently in early clinical trials. The failures of recent clinical trials highlight several points that will help shape future efforts. Investigators have questioned the applicability of strategies focused solely on eliciting a protective antibody response, as many individuals develop natural antibodies to S aureus early in life yet remain susceptible to disease.22 Further, the complex mechanisms of immunomodulation by the pathogen likely obscure the path to effective vaccine approaches. Of note, correlates of protective immunity in humans remain elusive, although one recent study demonstrated a link between natural antibodies to α-toxin and protection against S aureus in the context of recurrent infection in pediatric patients,86 supporting passive and active immunization studies that demonstrated antibodies against α-toxin to be protective in animal models of skin infection.57,87 There is now general agreement in the field that effective vaccines: (1) will incorporate multiple targets of various types in a polyvalent immunization, and (2) will be developed based on knowledge of the correlates of human immunity to S aureus infection. While S aureus skin infection has neither been a target of recent vaccine development nor served as a primary endpoint in large-scale clinical trials, the burden of disease coupled with an increasing knowledge of pathogenesis and features that govern susceptibility highlight this as perhaps one of the most promising paths for exploration. Remaining Challenges Since the 1960s and the emergence of widespread antimicrobial resistance, S aureus has become one of the most important, prevalent, and devastating infectious disease challenges. A number of scientific and clinical efforts have contributed greatly to our understanding of S aureus basic biology and pathogenesis. Yet, more than a century after Ogston’s initial descriptions of the etiologic agent of skin abscesses, disease caused by S aureus remains a prominent clinical problem, with limited strategies for prevention and therapy. Hygiene, surveillance, and public health measures can play important roles in limiting the transmission of S aureus, particularly in the healthcare setting, but these interventions are clearly insufficient in the face of the massive disease burden. Novel preventive and therapeutic approaches are desperately needed to combat this important global pathogen.

following areas: (1) understanding the specific role of individual virulence factors in disease, defining both their unique functions and appreciating their spatiotemporal action in the context of the tissue microenvironment; (2) defining bacterial factors that establish and maintain the commensal state; (3) understanding the genetic and environmental factors that govern host susceptibility; and (4) delineating the correlates of human protective immunity. Fortuitously, skin and soft tissue infection caused by S aureus is amenable to additional study in experimental model systems and in the human population. Given the numbers of individuals of all ages affected by S aureus skin infection, there is considerable opportunity to support robust clinical investigations as well as large-scale clinical trials of novel disease-modifying strategies. In this light, skin infection may pave a path for successful design and implementation of strategies to combat human S aureus infection. Acknowledgments We apologize to the authors of many excellent papers and reviews that were not incorporated into this paper owing to space limitations. We thank members of our laboratory for discussion and comments on the manuscript. R.E.N.B. is a trainee of the National Institutes of Health Medical Scientist Training Program at the University of Chicago (grant GM007281). This work was supported by a grant from the National Institute of Allergy and Infectious Diseases (NIAID), Infectious Disease Branch (AI097434 to J.B.W.). J.B.W. acknowledges membership within and support from the Region V Great Lakes Regional Center of Excellence in Biodefense and Emerging Infectious Diseases Consortium (NIAID Award 1-U54-AI-057153) and support from the Burroughs Wellcome Foundation through the Investigators in the Pathogenesis of Infectious Disease Program. Financial Disclosure J.B.W. has the potential to receive royalties from Novartis Vaccines and Diagnostics in relation to patents owned by the University of Chicago. References

Conclusions The development of these approaches will require continued advances in our understanding of the pathogenic mechanisms of S aureus disease in the human host, which must focus on the SKINmed. 2015;13:111–119

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17 Gould IM, Reilly J, Bunyan D, Walker A. Costs of healthcare-associated methicillin-resistant Staphylococcus aureus and its control. Clin Microbiol Infect. 2010;16:1721– 1728.

33 Kim HK, Thammavongsa V, Schneewind O, Missiakas D. Recurrent infections and immune evasion strategies of Staphylococcus aureus. Curr Opin Microbiol. 2012;15:92– 99.

18 Sader HS, Flamm RK, Jones RN. Antimicrobial activity of daptomycin tested against Gram-positive pathogens

34 Ogston A, Witte W. On abscesses. Rev Infect Dis. 1984;6:122–128.

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32 Fritz SA, Hogan PG, Camins BC, et al. Mupirocin and chlorhexidine resistance in Staphylococcus aureus in patients with community-onset skin and soft tissue infections. Antimicrob Agents Chemother. 2013;57:559–568.

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35 Kellaway CH, Tebbutt AH. Royal commission of inquiry into fatalities at Bundaberg. Report of the Royal Commission of Inquiry into Fatalities at Bundaberg. 1928.

52 Prabhakara R, Foreman O, De Pascalis R, et al. Epicutaneous model of community-acquired Staphylococcus aureus skin infections. Infect Immun. 2013;81:1306–1315.

36 Burnet FM. The exotoxins of staphylococcus pyogenes aureus. J Pathol Bacteriol. 1929;32:717–734.

53 Adem PV, Montgomery CP, Husain AN, et al. Staphylococcus aureus sepsis and the Waterhouse-Friderichsen syndrome in children. N Engl J Med. 2005;353:1245–1251.

37 Weise EC. Staphylococcus toxin in the treatment of furunculosis: preliminary report. JAMA. 1930;95:324–326. 38 Farrell LN. The potency of staphylococcal toxoid. J Immunol. 1941;41:119–126. 39 Dolman CE. Staphylococcus antitoxic serum in the treatment of acute staphylococcal infections and tox ae mias. Can Med Assoc J. 1934;31:130–135. 40 Chambers HF, Deleo FR. Waves of resistance: Staphylococcus aureus in the antibiotic era. Nat Rev Microbiol. 2009;7:629–641. 41 Saravolatz LD, Markowitz N, Arking L, Pohlod D, Fisher E. Methicillin-resistant Staphylococcus aureus. Epidemiologic observations during a community-acquired outbreak. Ann Intern Med. 1982;96:11–16. 42 From the Centers for Disease Control and Prevention. Four pediatric deaths from community-acquired methicillin-resistant Staphylococcus aureus—Minnesota and North Dakota, 1997–1999. JAMA. 1999;282:1123– 1125.

54 Labandeira-Rey M, Couzon F, Boisset S, et al. Staphylococcus aureus Panton-Valentine leukocidin causes necrotizing pneumonia. Science. 2007;315:1130–1133. 55 Bubeck Wardenburg J, Bae T, Otto M, Deleo FR, Schneewind O. Poring over pores: alpha-hemolysin and PantonValentine leukocidin in Staphylococcus aureus pneumonia. Nature medicine. 2007;13:1405–1406. 56 Bubeck Wardenburg J, Patel RJ, Schneewind O. Surface proteins and exotoxins are required for the pathogenesis of Staphylococcus aureus pneumonia. Infect Immun. 2007;75:1040–1044. 57 Bubeck Wardenburg J, Schneewind O. Vaccine protection against Staphylococcus aureus pneumonia. J Exp Med. 2008;205:287–294. 58 Inoshima I, Inoshima N, Wilke GA, et al. A Staphylococcus aureus pore-forming toxin subverts the activity of ADAM10 to cause lethal infection in mice. Nat Med. 2011;17:1310–1314.

43 Klevens RM, Morrison MA, Nadle J, et al. Invasive methicillin-resistant Staphylococcus aureus infections in the United States. JAMA. 2007;298:1763–1771.

59 Inoshima N, Wang Y, Bubeck Wardenburg J. Genetic requirement for ADAM10 in severe Staphylococcus aureus skin infection. J Invest Dermatol. 2012;132:1513–1516.

44 Wisplinghoff H, Bischoff T, Tallent SM, et al. Nosocomial bloodstream infections in US hospitals: analysis of 24,179 cases from a prospective nationwide surveillance study. Clin Infect Dis. 2004;39:309–317.

60 Powers ME, Kim HK, Wang Y, Bubeck Wardenburg J. ADAM10 mediates vascular injury induced by Staphylococcus aureus alpha-hemolysin. J Infect Dis. 2012;206:352–356.

45 Bayer AS, Schneider T, Sahl HG. Mechanisms of daptomycin resistance in Staphylococcus aureus: role of the cell membrane and cell wall. Ann N Y Acad Sci. 2013;1277:139–158.

61 DeLeo FR, Kennedy AD, Chen L, et al. Molecular differentiation of historic phage-type 80/81 and contemporary epidemic Staphylococcus aureus. Proc Natl Acad Sci U S A. 2011;108:18091–18096.

46 Richter SS, Heilmann KP, Dohrn CL, et al. Activity of ceftaroline and epidemiologic trends in Staphylococcus aureus isolates collected from 43 medical centers in the United States in 2009. Antimicrob Agents Chemother. 2011;55:4154–4160.

62 Thurlow LR, Joshi GS, Richardson AR. Virulence strategies of the dominant USA300 lineage of communityassociated methicillin-resistant Staphylococcus aureus (CA-MRSA). FEMS Immunol Med Microbiol. 2012;65:5– 22.

47 Kraft WG, Johnson PT, David BC, Morgan DR. Cutaneous infection in normal and immunocompromised mice. Infect Immun. 1986;52:707–713.

63 Fritz SA, Hogan PG, Hayek G, et al. Staphylococcus aureus colonization in children with community-associated Staphylococcus aureus skin infections and their household contacts. Arch Pediatr Adolesc Med. 2012;166:551– 557.

48 Sherertz RJ, Forman DM, Solomon DD. Efficacy of dicloxacillin-coated polyurethane catheters in preventing subcutaneous Staphylococcus aureus infection in mice. Antimicrob Agents Chemother. 1989;33:1174–1178. 49 Bunce C, Wheeler L, Reed G, Musser J, Barg N. Murine model of cutaneous infection with gram-positive cocci. Infect Immun. 1992;60:2636–2640. 50 Voyich JM, Otto M, Mathema B, et al. Is Panton-Valentine leukocidin the major virulence determinant in community-associated methicillin-resistant Staphylococcus aureus disease? J Infect Dis. 2006;194:1761–1770. 51 Kobayashi SD, Malachowa N, Whitney AR, et al. Comparative analysis of USA300 virulence determinants in a rabbit model of skin and soft tissue infection. J Infect Dis. 2011;204:937–941.

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64 Krishna S, Miller LS. Innate and adaptive immune responses against Staphylococcus aureus skin infections. Semin Immunopathol. 2012;34:261–280. 65 Foster TJ. Immune evasion by staphylococci. Nat Rev Microbiol. 2005;3:948–958. 66 Krishna S, Miller LS. Host-pathogen interactions between the skin and Staphylococcus aureus. Curr Opin Microbiol. 2012;15:28–35. 67 Kebaier C, Chamberland RR, Allen IC, et al. Staphylococcus aureus alpha-hemolysin mediates virulence in a murine model of severe pneumonia through activation of the NLRP3 inflammasome. J Infect Dis. 2012;205:807– 817.

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68 Nizet V. Understanding how leading bacterial pathogens subvert innate immunity to reveal novel therapeutic targets. J Allergy Clin Immunol. 2007;120:13–22. 69 O’Riordan K, Lee JC. Staphylococcus aureus capsular polysaccharides. Clin Microbiol Rev. 2004;17:218–234. 70 Silverman GJ, Goodyear CS. Confounding B-cell defences: lessons from a staphylococcal superantigen. Nat Rev Immunol. 2006;6:465–475. 71 Rooijakkers SH, Ruyken M, Roos A, et al. Immune evasion by a staphylococcal complement inhibitor that acts on C3 convertases. Nat Immunol. 2005;6:920–927. 72 Rooijakkers SH, van Wamel WJ, Ruyken M, van Kessel KP, van Strijp JA. Anti-opsonic properties of staphylokinase. Microbes Infect. 2005;7:476–484. 73 Archer NK, Mazaitis MJ, Costerton JW, et al. Staphylococcus aureus biofilms: properties, regulation, and roles in human disease. Virulence. 2011;2:445–459. 74 Tuchscherr L, Medina E, Hussain M, et al. Staphylococcus aureus phenotype switching: an effective bacterial strategy to escape host immune response and establish a chronic infection. EMBO Mol Med. 2011;3:129–141. 75 Yoong P, Torres VJ. The effects of Staphylococcus aureus leukotoxins on the host: cell lysis and beyond. Curr Opin Microbiol. 2013;16:63–69. 76 Bestebroer J, De Haas CJ, Van Strijp JA. How microorganisms avoid phagocyte attraction. FEMS Microbiol Rev. 2010;34:395–414. 77 Otto M. Basis of virulence in community-associated methicillin-resistant Staphylococcus aureus. Ann Rev Microbiol. 2010;64:143–162. 78 McCormick JK, Yarwood JM, Schlievert PM. Toxic shock syndrome and bacterial superantigens: an update. Ann Rev Microbiol. 2001;55:77–104.

79 DeDent A, Kim HK, Missiakas D, Schneewind O. Exploring Staphylococcus aureus pathways to disease for vaccine development. Semin Immunopathol. 2012;34:317– 333. 80 Proctor RA. Challenges for a universal Staphylococcus aureus vaccine. Clin Infect Dis. 2012;54:1179–1186. 81 Spellberg B, Daum R. Development of a vaccine against Staphylococcus aureus. Semin Immunopathol. 2012;34:335–348. 82 Bagnoli F, Bertholet S, Grandi G. Inferring reasons for the failure of Staphylococcus aureus vaccines in clinical trials. Front Cell Infect Microbiol. 2012;2:16. 83 Robbins JB, Schneerson R, Horwith G, Naso R, Fattom A. Staphylococcus aureus types 5 and 8 capsular polysaccharide-protein conjugate vaccines. Am Heart J. 2004;147:593–598. 84 Shinefield H, Black S, Fattom A, et al. Use of a Staphylococcus aureus conjugate vaccine in patients receiving hemodialysis. N Engl J Med. 2002;346:491–496. 85 Intercell. Merck and Intercell AG announce termination of phase II/III clinical trial of investigational Staphylococcus aureus vaccine, V7102011. 86 Fritz SA, Tiemann KM, Hogan PG, et al. A serologic correlate of protective immunity against communityonset Staphylococcus aureus infection. Clin Infect Dis. 2013;56:1554–1561. 87 Kennedy AD, Bubeck Wardenburg J, Gardner DJ, et al. Targeting of alpha-hemolysin by active or passive immunization decreases severity of USA300 skin infection in a mouse model. J Infect Dis. 2010;202:1050– 1058.

Chickenpox: Courtesy of Museo delle Cere Anatomiche L. Cattaneo, University of Bologna, Italy. Photo by Alberto Martini. Submitted of Diana Garrisi, London, UK.. SKINmed. 2015;13:111–119

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SELF ASSESSMENT EXAMINATION W. Clark Lambert, MD, PhD For each of the following numbered questions, chose the single most appropriate lettered response. 1. The most common forms of disease due to Staphylococcus aureus (S. aureus) are skin infections and: a. Nephritis. b. Osteomyelitis. c. Peritonitis. d. Pneumonia. e. Soft tissue infections.

4. The current global epidemic of community associated–methicillin-resistant Staphylococcus aureus (CA–MRSA) infections began in: a. 1928. b. 1948. c. The late 1960s. d. The early 1980s e. The late 1990s. f. 2008.

2. What proportion of skin and soft tissue infections by S. aureus is due to methicillin-resistant Staphylococcus aureus (MRSA)? a. 5-10 percent. b. 10-20 percent. c. 20-40 percent. d. 40-60 percent. e. 60-90 percent.

5. Which of the following infectious syndromes, not historically associated with S. aureus, have been noted to be caused by CA–MRSA? a. Necrotizing fasciitis. b. Purpura fulminans. c. Pyomyositis. d. Waterhouse–Friderichsen syndrome. e. All of the above. f. None of the above.

3. Recurrent skin abscesses, especially “cold abscesses,” are one of the major criteria in the clinical diagnosis of: a. Atopic dermatitis (AD). b. Chronic granulomatous disease (CGD). c. Hyper-IgE syndrome (HIES). d. All of the above. e. None of the above.

ANSWERS TO EXAMINATION: 1. e 2.e 3. c 4. e 5. e

VINTAGE LABEL

Courtesy of BuyEnlarge, Philadelphia, PA

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

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Core curriculum Virendra N. Sehgal, MD, Section Editor

Alopecia Areata––Part II: Diagnosis and Pathology Juliany Estefan, MD;1,2 Marcia Ribeiro, MD, PhD;2 Eliane Abad, MD;3 Simone Saintive, MD;3 Marcia Ramos-e-Silva, MD, PhD1

Alopecia areata is characterized by the abrupt appearance of round or oval, non-scarring, flat, single or multiple areas of alopecia, which may coalesce forming large patches of alopecia. The diagnosis is usually clinical but there are important differentials and dermatopathology may help in this definition. (SKINmed. 2015;13:121–126)

he diagnosis of alopecia areata is usually easy to be defined but there are several conditions that may mimic this frequent hair disorder. A biopsy may be required and useful in some difficult to diagnose cases. Differential Diagnosis In children, tinea capitis and trichotillomania correspond to the main differential diagnosis.1

Tinea capitis Tinea capitis includes scalp dermatophytosis and the associated hair (Figure 1). It can be triggered by many pathogens, but the most common is Microsporum canis. Although the incidence rate is unknown, it is most commonly found in patients from 3 to 14 years of age and rarely affects adults.2 It can be differentiated from AA by the presence of desquamative inflammation and tonsured hair.1 Lymphadenopathy is found in nearly all cases.3

Trichotillomania Trichotillomania is a psychiatric disorder that is defined as the compulsive act of plucking hair from any area of the body, mainly in the parietal region (Figure 2) and vertex.4,5 The extraction

of anagen hair is more difficult and painful, which is why the telogen hairs are typically plucked first by patients.6 Many patients admit that they pluck their hair, but most deny any manipulation.7 Women are more affected than men,4 and the condition is more severe in adults. In children, it evolves with spontaneous improvement over the years.8 Trichotillomania is clinically featured with rarefaction areas and/ or irregular alopecia areas and with asymmetric or bizarre lesions. The presence of short vellus or broken hair of different lengths helps in the diagnosis, as these hairs provide a rough texture to the lesion, as opposed to the smooth surface seen in AA.1 Bruising, bleeding, and neurodermatitis can be found on the scalp.4 The criteria for diagnosis are described in the Table.9 In trichotillomania, the hair pull test is negative in the periphery of the lesion and dermatoscopy reveals changes by fracture of the hair shaft, at any height, producing decreased hair density, empty follicular ostia and black spots, “broom-” or “brush-” tipped hair and “V” or “split ends” (trichoptilosis), curled hair, yellow dots with and without inner black spots, and vellus short hair.4,10,11 Trichotillomania may be associated with trichophagia and in

From the Sector of Dermatology and Post-Graduation Course, University Hospital and School of Medicine;1 the Sector of Medical Genetics, Pediatric Institute Martagão Gesteira and School of Medicine;2 and the Sector of Dermatology, Pediatric Institute Martagão Gesteira and School of Medicine,3 Federal University of Rio de Janeiro, Rio de Janeiro, Brazil Address for Correspondence: Marcia Ramos-e-Silva, MD, PhD, University Hospital and School of Medicine, Federal University of Rio de Janeiro, Rua Dona Mariana 149/C-32, 22280-020 Rio de Janeiro, Brazil • E-mail: ramos.e.silva@dermato.med.br

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Table. Trichotillomania Diagnostic Criteria According to the American Psychiatric Association Recurrent hair plucking behavior resulting in areas of alopecia Increased tension preceding the act of pulling hair or when attempting to resist the behavior Pleasure, gratification, or relief when plucking the hair The disturbance is not caused by any mental, systemic, or local illness in the scalp The disorder causes distress or impairment in social, occupational, or other areas Modified from American Psychiatric Association.9

some cases there is presences of accumulated hair in the gastrointestinal tract,4 onychophagia, onychotillomania, and anxiety.10 Treatment should be multidisciplinary, with the aid of psychiatrists or psychologists,4 and the prognosis is usually benign and self-limited.10

Figure 1. Tinea capitis.

Traction alopecia Traction alopecia mainly affects individuals with Negroid hair, resulting from continuous traction of the hair that leads to chronic irritant folliculitis with progressive destruction of the follicles. It mainly affects the edge of the scalp.12,13 Early diagnosis is the best way to succeed in the regression of the picture. The interruption of the techniques that pull the hair and the treatment of folliculitis may reduce inflammation by preventing follicle atrophy. In severe cases, treatment consists of rotation of flaps or hair transplant.13

Loose anagen hair syndrome Loose anagen hair syndrome is a change caused by a defect in the keratinization of the hair that clinically develops with thin, short, and sparse hair.14 In this condition, the hair may be easily plucked without pain, upon light traction.15 It usually affects individuals of both sexes15 between the ages of 2 and 9 years.14 There is no specific treatment available for this condition.16

Figure 2.Trichotillomania.

Telogen effluvium Telogen effluvium is characterized by the sudden loss of hair that may reach 600 hairs per day.17 It is caused by the premature transformation of hair from the anagen stage to the catagen or telogen stage. It is related to several factors, including drug use; stress; hypothyroidism; iron, zinc, and vitamin B12 deficiency; restrictive diets, systemic diseases; surgery; and childbirth. It usually develops 3 to 4 months after the event.17 The differential diagnosis with SKINmed. 2015;13:121â&#x20AC;&#x201C;126

diffuse AA can be difficult. Anamnesis can help by showing a triggering factor that points to telogen effluvium.1 Biopsy and histopathology may be required for the correct diagnosis. Although not common in this age group, telogen effluvium may affect neonates, beginning in the first days of life, with sudden or gradual loss of hair.3

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The treatment for such cases consists of removing the underlying cause or treating the precipitating diseases18 with total repilation generally 2 to 3 months after the end of the process.17

Androgenetic alopecia The etiology of androgenetic alopecia is related to genetic (autosomal dominant inheritance), hormonal, and inflammatory factors, leading to the miniaturization of hair and transformation of terminal hair into vellus. The anagen stages become shorter and more telogen hairs are found.14 Female androgenetic alopecia pattern: Approximately 50% of women will present with female pattern alopecia during their lifetime.19 The clinical picture usually appears with hair loss along the central region of the scalp, midline expansion, and preservation of the front edge18 (known as the “Christmas tree” pattern).14 Some women may present with frontoparietal rarefaction characteristic of male pattern alopecia. The Ludwig classification for female pattern alopecia is the most widely used.14 Male androgenetic alopecia pattern: Male androgenetic alopecia affects approximately 50% of white men in their 50s.19 It clinically evolves with frontoparietal and vertex rarefaction (Figure 3). Hamilton ranked male alopecia pattern based on these characteristics.14 Dihydrotestosterone plays a key role in male pattern baldness and men with lower levels of dihydrotestosterone experience decreased loss of hair.20

Cicatricial alopecia Cicatricial alopecia corresponds to the end result of many pathological processes of the follicular unit and its surroundings, resulting in irreversible destruction of hair follicles and permanent alopecia. It may be caused by several changes, including some dermatoses (lichen planus, lupus erythematous, dissecting folliculitis, folliculitis decalvans, pseudopelade, central centrifugal scarring alopecia, keloid folliculitis, and follicular mucinosis), inflammatory changes by infections, defective development (aplasia cutis), physical trauma, and neoplasias. Additional tests, such as serology and/or scalp biopsy, may be required for confirmation.16

Secondary syphilis Syphilis is a chronic infectious disease caused by Treponemes pallidum, which can affect various organs. The main transmission route is sexual (acquired syphilis) in 95% of cases, but it can also be transmitted vertically (mother to fetus).21 SKINmed. 2015;13:121–126

Figure 3. Male androgenetic alopecia pattern.

It presents in three stages, although secondary syphilis may evolve with diffuse alopecia, called patchy alopecia, with emphasis on the parietal and occipital regions. In addition to scalp hair, the eyelashes and the eyebrows’ final portion may be affected (madarosis).21

Congenital atrichia with papules Congenital atrichia is a rare autosomal recessive form of nonscarring alopecia characterized by the loss of hair after birth and emergence of follicular cysts and whitish papules, similar to milium on the skin at a later stage.16,22 A similar picture can be detected in patients with vitamin D–resistant rachitism.16

Congenital triangular alopecia Congenital triangular alopecia is a form of nonscarring alopecia that evolves with an area of triangular alopecia in the temporal region. It can easily be seen in newborns with abundant hair or can be diagnosed around the age of 2.23 It may be evidenced by vellus or complete absence of hair. In most cases, a single lesion is seen that does not change throughout life.16 This condition does not respond to topical or intralesional steroids.24

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core curriculum In anamnesis, it is important to inquire patients about the duration and volume of hair loss, personal history, family history, medical history of anemia, collagen disease, thyroid disease, sleep disorders, psychological disorders, atopy, and use of medications, as well as assessing associated symptoms such as itching, irritation of lesions, and nail changes.27 The factor that triggers the hair loss (viral infection, general fatigue, lack of sleep) may occur 1 to 3 months prior to AA, but, in many cases, the exact causes are not determined.28 Although laboratory tests are not typically required in most AA patients, some cases are difficult and therefore require examinations to assist in the diagnosis. Tests include antinuclear antibodies, deoxyribonucleic antacid antibody, free T3, free T4, thyroid-stimulating hormone, antiperoxidase thyroid antibodies, antimicrosomal antibody, iron and zinc serum dosage, Venereal Disease Research Laboratory and fluorescent treponemal antibody absorption,27 and, sometimes, direct mycological culture and scalp biopsy.1

Figure 4. Dermatoscopy.

The traction test may be performed in all patients with a history of hair loss.29 It is observed in the acute phase in diffuse and plaque forms, especially in the periphery of active plaques.11 It can be evidenced in the chronic phase. Besides being found in AA, it can also be positive in telogen effluvium.26 Scalp and hair trichoscopy or dermatoscopy is a conservative method that is a low-cost, useful, painless, and easy to perform procedure with a device called dermatoscope. The most widely used is the portable dermatoscope, with a 10-fold magnifying capacity.30 Dermatoscopic images help in the diagnosis and evaluation of growth, caliber, and density of hair, often dispensing invasive examinations such as scalp biopsy, particularly in the pediatric population. There are several dermatoscopic criteria that help in the diagnosis of AA (Figures 4 and 5).26

Figure 5. Dermatoscopic images help in the diagnosis and evaluation of growth, caliber, and density of hair, often dispensing invasive examinations such as scalp biopsy, particularly in the pediatric population. There are several dermatoscopic criteria that help in the diagnosis of alopecia areata.

Marie-Unna hypotrichosis Marie-Unna hypotrichosis is a dominant autosomal alteration that evolves with progressive loss of hair that changes in hair quality and density. It begins in childhood and worsens during adolescence.25

An exclamation mark shape of the hair represents typical changes caused by AA and is observed mainly in the plaqueâ&#x20AC;&#x2122;s surrounding areas, with greater disease activity.31 These hairs are thinner and lighter at the point of emergence from the scalp and thicker and darker at the distal end.32 This change may also be observed in trichotillomania.33

Diagnosis

Black dots or cadaveric hair is fractured prior to its emergence on the scalp.31 The image displayed is similar to a comedone.32 They are indications of disease activity and are mainly observed in the area surrounding the lesion.31

Most AA manifestations are clinically diagnosed by anamnesis, clinical examination, and dermatoscopy.1,26

Yellow dots are not exclusive to AA. They are also observed in androgenetic alopecia.34 These dots may be deprived of hair or

In adults, a sparse portion at the edge of the scalp remains. Eyebrows, eyelashes, and body hair become sparse.16

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contain miniaturized or cadaveric hair.31 Black dots and exclamation mark hair are signs of active disease, whereas yellow dots are dominant in long-term AA.33,36 Brittle and bizarrely shaped shafts by keratinization changes, known as dystrophic shafts, are also observed in AA.26,32 Pseudomoniletrix is a dermatoscopic finding in AA, characterized by the alternance of areas of constriction (inflammatory activity in the hair follicle) and dilation of the shaft.10 The presence of vellus hair can also be demonstrated in AA lesions by dermatoscopy, usually found in areas of remission of the disease.35,36

the proportion changes to 1:1, while the normal ratio is 7:1.2 The inflammatory infiltrate, when present in this stage, is seen on the papillary dermis around the miniaturized follicles. Over time, there is a reduction of this infiltrate. In the recovery phase, there is mild or nonexistent infiltrate, the number of terminal hairs increases, and there is a tendency to return to normal. Conclusions AA is very common, greatly affects the quality of life and selfesteem of patients, and thus must be well known by all dermatologists, as well as clinicians and pediatricians. References

The elbow sign is caused by the alteration of keratinization and occurs when the hair folds are pushed along its own axis in the direction of the scalp.26,32 Pathology Biopsy is an invasive, slightly painful, and technically easy to achieve method used to help in the differential diagnosis of scalp diseases. The procedure is performed under local anesthesia, and the material should be obtained by incision using a scalpel blade or punch between 4 mm and 6 mm parallel to the hair.37 The area chosen for biopsy is important and trichotomy of the area should be performed, preferably with a blade.38 Alterations in AA’s histopathologic examination depends on the stage39 and duration of disease.40,41 AA is characterized by a peribulbar lymphocytic inflammatory infiltrate,42 although peribulbar inflammation may be absent in some cases.39 In the acute phase, there is an increase in the number of catagen and telogen follicles, dense or moderate peribulbar infiltrate by lymphocytes and Langerhans cells, and occasional eosinophils.40 The typical infiltrate is known as “bee swarms” and is present mainly in anagen follicles.39,43 It comprises CD4+ and CD8+ lymphocytes with CD4+/CD8+ ratio higher during disease activity.44 Edema, necrosis, and apoptosis occur as a result of inflammation.45,46 The greatest loss of anagen hairs and relative increase of telogen hairs occur in the acute phase of the disease. In the subacute phase, an increase in the number of hairs in the catagen phase is observed.39 After about 2 weeks in the catagen phase, the root of the hair grows.39 In the chronic phase, terminal hairs disappear by miniaturization and presence of peribulbar infiltrate of variable intensity.39 With the reduction of terminal hair and increase of vellus hair, SKINmed. 2015;13:121–126

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1 Alkhalifah A, Alsantali A, Wang E, McElwee KJ, Shapiro J. Alopecia areata update. Part I. Clinical picture, histopathology, and pathogenesis. J Am Acad Dermatol. 2010;62:177–188. 2 Nelson MM, Martin AG, Heffernan MP. Superficial fungal infections: dermatophytosis, onychomicosis, tinea nigra, piedra. In: Freedberg IM, Eisen AZ, Wolff K, et al, eds. Fitzpatrick’s Dermatology in General Medicine. 6th ed. New York, NY: McGraw-Hill; 2003:1989– 2005. 3 Lenane P, Pope E, Krafchik B. Congenital alopecia areata. J Am Acad Dermatol. 2005;52(2 suppl 1):S8–S11. 4 Pereira JM. Compulsive trichoses. An Bras Dermatol. 2004;79:609–618. 5 Bartels NG, Blume-Peytavi U. Hair loss in children. In: Blume-Peytavi U, Tosti A, Whiting D, Trueb R, eds. Hair Growth and Disorders. Leipzig, Germany: Springer. 2008:293–294. 6 Steck WD. The clinical evaluation of pathologic hair loss, with a diagnostic sign in trichotillomania. Cutis. 1979;24:293–301. 7 Elliott AJ, Fuqua WR. Acceptability of treatment for trichotillomania. Effects of age severity. Behav Modif. 2002;26:378–399. 8 Oranje AP, Peereboom-Wynia JD, De Raeymaecker DM. Trichotillomania in childhood. J Am Acad Dermatol. 1986;15(4 pt 1):614–619. 9 American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 4th ed. (DSM-IV). Washington, DC; 1994. 10 Abraham LS, Torres FN, Azulay-Abulafia L. Pistas dermatoscópicas para diferenciar a tricotilomania da alopecia areata em placa. An Bras Dermatol. 2010;85:723– 726. 11 Rivitti EA. Alopecia areata: revisão e atualização. An Bras Dermatol. 2005;80:57–68. 12 Slepyan AH. Traction 1958;78:395–398.

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13 Addor FAZ. Peles étnicas. In: Ramos-e-Silva M, Castro MCR. Fundamentos de Dermatologia. Rio de Janeiro: Atheneu; 2009:1925–1931.

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14 Steiner D. Cabelos. In: Ramos-e-Silva M, Castro MC. Fundamentos de Dermatologia. Rio de Janeiro, Brazil: Atheneu; 2009:1847–1861.

31 Tosti A. Alopecia areata. In: Tosti A, ed. Dermatoscopy of Hair and Scalp Disorders. London, England: Informa Healthcare; 2007:26–44.

15 Sato MT, Brennef M, Marzagão R, et al. Síndrome dos cabelos anágenos frouxos associada à distrofia macula: descrição de uma família. An Bras Dermatol. 2004;79:725–731.

32 Pereira JM. Doenças dos cabelos e do couro cabeludo. São Paulo, Brazil: Atheneu; 2001:163–175.

16 Hurwitz S. Alterações dos cabelos e das unhas. In: Hurwitz S. Dermatologia Pediátrica. 3rd ed. London, England: WB Saunders; 2009:145–183. 17 Pereira JM. Eflúvio telógeno após dermatite de contato no couro cabeludo. An Bras Dermatol. 2006;81(5 suppl 3):S288–S289. 18 Mounsey AL, Reed SW. Diagnosing and treating hair loss. Am Family Physician. 2009;80:357–362. 19 Price VH. Treatment of hair loss. N Engl J Med. 1999;341:964–973. 20 Bergfeld WF. Androgenetic alopecia: an autosomal dominant disorder. Am J Med. 1995;98(1A):95S–98S.

33 Rudnicka L, Olszewska M, Rakowska A, Slowinska M. Trichoscopy update 2011. J Dermatol Case Rep. 2011;4:82–88. 34 Inui S, Nakajima T, Itami S. Coudability hairs: a revisited sign of alopecia areata assessed by trichoscopy. Clin Exp Dermatol. 2010;35:361–365. 35 Inui S, Nakajima T, Nakagawa K, Itami S. Clinical significance of dermoscopy in alopecia areata: analysis of 300 cases. Int J Dermatol. 2008;47:688–693. 36 Inui S, Nakajima T, Itami S. Significance of dermoscopy in acute diffuse and total alopecia of the female scalp: review of twenty cases. Dermatology. 2008;217:333– 336.

21 Avelleira JC, Bottino G. Sífilis: diagnóstico, tratamento e controle. An Bras Dermatol. 2006;81:111–126.

37 Frishberg D, Sperling LC, Guthrie VM. Transverse scalp sections: a proposed method for laboratory processing. J Am Acad Dermatol. 1996;35(2 pt 1):220–222.

22 John P, Aslam M, Rafiq MA, et al. Atrichia with papular lesions in two Pakistani consanguineous families resulting from mutations in the human hairless gene. Arch Dermatol Res. 2005;297:226–230.

38 Barcaui C, Maceira JP. Estudo de microanatomia transversal do couro cabeludo: técnica e indicações. An Bras Dermatol. 2001;76:141–167.

23 Trakimas C, Sperling LC, Skelton HG 3rd, Smith KJ, Buker JL. Clinical and histologic findings in temporal triangular alopecia. J Am Acad Dermatol. 1994;31(2 pt 1):205–209. 24 Elmer KB, George RM. Congenital triangular alopecia: a case report and review. Cutis. 2002;69:255–256. 25 Yan KL, He PP, Yang S, et al. Marie Unna hereditary hypotrichosis: report of a Chinese family and evidence for genetic heterogeneity. Clin Exp Dermatol. 2004;29:460– 463. 26 Silva AP, Sanchez APG, Pereira JM. The importance of trichological examination in the diagnosis of alopecia areata. An Bras Dermatol. 2011;86:1039–1041.

39 Whiting DA. Histopathologic features of alopecia areata: a new look. Arch Dermatol. 2003;139:1555–1559. 40 Elston DM, McCollough ML, Bergfeld WF, Liranzo MO, Heibel M. Eosinophils in fibrous tracts and near hair bulbs: a helpful diagnostic feature of alopecia areata. J Am Acad Dermatol. 1997;37:101–106. 41 El Darouti M, Marzouk SA, Sharawi E. Eosinophils in fibrous tracts and near hair bulbs: a helpful diagnostic feature of alopecia areata. J Am Acad Dermatol. 2000;42(2 pt 1):305–307. 42 Sperling LC, Lupton GP. Histopathology of nonscarring alopecia. J Cutan Pathol. 1995;22:97–114.

27 Ito T. Advances in the management of alopecia areata. J Dermatol. 2012;39:11–17.

43 Weedon D. Diseases of cutaneous appendages. In: Weedon D, ed. Weedon’s Skin Pathology. London, England: Churchill Livingstone; 2002:398–441.

28 Ito T, Tokura Y. Alopecia areata triggered or exacerbated by swine flu virus infection. J Dermatol. 2012;39:863– 864.

44 Todes-Taylor N, Turner R, Wood GS, Stratte PT, Morhenn VB. T cell subpopulations in alopecia areata. J Am Acad Dermatol. 1984;11(2 pt 1):216–223.

29 Olsen EA. Hair. In: Freedberg IM, Eisen AZ, Wolff K, et al. Fitzpatrick’s Dermatology in General Medicine. 6th ed. New York, NY: McGraw-Hill; 2003:633–655.

45 Tobin DJ, Fenton DA, Kendall MD. Cell degeneration in alopecia areata. Am J Dermatopathol. 1991;13:248–256.

30 Rezze GG, Sá BCS, Neves RI. Dermatoscopia: o metodo de analise de padrões. An Bras Dermatol. 2006;81:261– 268.

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46 Ghersetich I, Campanile G, Lotti T. Alopecia areata: immunohistochemistry and ultrastructure of infiltrate and identification of adhesion molecule receptors. Int J Dermatol. 1996;35:28–33.

Alopecia Areata—Part II

March/April 2015

Volume 13 • Issue 2

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

Scabies: Too Late? No, Checkmate Hee Jin Kim, BS; W. Clark Lambert, MD, PhD “Like a giant game of chess. Predicting your opponent’s next move to stay one step ahead.”––Unknown

cabies is a common skin disease caused by the obligate ectoparasitic mite Sarcoptes scabiei. Scabies mites were first identified by Aristotle in ancient times as “lice in the flesh” and subsequently have been described by many different writers.1–7 Scabies is common in populations with poor hygiene, poor nutritional status, homelessness, immigrant status, indiscriminate sexual contact, and overcrowded conditions.3 It is also endemic in urban and rural communities of the developing world, where its prevalence may approximate 10% in the general population and 50% in children of school and preschool age.6 Epidemiologic studies suggest an association between a higher prevalence of scabies in a younger age group with a higher likelihood of greater personal contact and socialization in that age group.3 The infestation of scabies begins with the female mite, which burrows in the lower stratum corneum/subcorneal area and lays two to three eggs per day, resulting in raised papules on the surface of the skin. After 2 weeks, adult mites emerge onto the surface and then reinfect the host at a different site or infect another host, explaining the contagiousness of scabies.7 Importantly, the clinical presentation is delayed, occurring 2 to 6 weeks after the initial infestation, at which point the female mite may have already migrated out of the burrow and infected another site, usually a few millimeters proximal to the burrow site.4 The most commonly used procedure for diagnosis of scabies is microscopic examination of skin scrapings from the burrow site3 (Figures 1 and 2). Unfortunately, most patients infected with scabies mites seek medical help only after they experience clinical symptoms of intense itching and have developed an eruption, by which time the female mite may have already left the burrow. Skin scrapings performed at the burrows at the time of presentation often do not reveal scabies mites on histology (Figure 3). One study reported that scabies mites were found in only two of

a total of 15 patients on histology of skin scrapings.9 Such findings suggest that the current practice of performing skin scrapings at the burrow site at the time of presentation may often be in vain. Rather than chasing after scabies mites’ tails, we suggest that it would be more efficient to predict their next move, just as in a game of chess, and stay one step ahead of them by performing skin scrapings a few millimeters proximal to the burrow site. Clinical Presentation The clinical appearance of scabies occurs over 4 to 6 weeks after primary infection. Patients typically present with generalized itching worse at night and a linear papular eruption localized to the webs of the fingers, the flexor aspects of the wrists, the extensor aspects of the elbows, ankles, periumbilical region, buttocks, and penis in men and periareolar region in women.7 Scabies can present clinically in many forms, but the two most common manifestations are categorized as ordinary scabies and crusted scabies. Ordinary scabies is described as a generalized, intensely pruritic allergic eruption, accompanied by papular or vesicular lesions at the burrow sites. Crusted scabies is a more severe type associated with a higher number of mites––into the thousands per gram of skin per patient––and a resulting hyperkeratosis that may affect the face, ears, and scalp. It is also associated with a higher frequency of recurrent hyperkeratosis and a possibility of subsequent depigmentation.1 Depending on the severity of the host’s inflammatory response, the clinical manifestation of scabies can vary greatly, but the classic pathognomonic signs for the diagnosis of scabies shared by all forms are skin burrows, erythematous papules, and generalized pruritus with nocturnal exacerbation.3,7,11 Burrows present as whitish wavy lines of several millimeters in length located in the epidermis. Secondary papules, pustules, and vesicles often

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

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Figure 1. Lateral view of scabies mite seen histopathologically in a burrow in the epidermis (hematoxylin and eosin, original magnification ×620).

Figure 2. Dorsal view of scabies mite seen histopathologically in a burrow in the epidermis (hematoxylin and eosin, original magnification ×310).

accompany the burrows. Intense itching results from a delayed type IV hypersensitivity reaction to the mite or its saliva, eggs, or excrement, thus the symptoms usually occur up to 3 weeks after initial infection.11 Scabies in either form should be recognized as soon as possible to prevent the spread of infestation.3 Immune Evasion The clinical manifestation of scabies appears 4 to 6 weeks after the primary infestation. One possible explanation for this delay in presentation is that scabies mites may be secreting immunomodulatory molecules that can suppress the early host immune response. Several studies have been conducted to test the effect of S scabiei extracts on the cytokine-secreting activity of many cell subsets.1 One study examined data from S scabiei cDNA libraries and identified several unique genes. The authors distinguished inactivated proteases called the scabies mite inactivated protease paralogues (SMIPPs), which are nonfunctional proteases that may behave as antagonists of active proteases by competing for the same substrates. The study reports that SMIPPs may also be able to bind to, but not activate, receptors on the surface of keratinocytes that are normally responsible for inducing cytokine release. In this way, SMIPPs may protect scabies mites from the host inflammatory response.11 Another study suggests similar actions of SMIPPs on all three pathways of the complement system and hypothesizes that such inhibitory mechanisms allow the scabies mite to survive by down-regulating host innate immune responses.1 A different paper discusses scabies mites as the source of substances that increase production of interleukin SKINmed. 2015;13:127–129

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Figure 3. Scabies seen histopathologically as a burrow in the epidermis; the organism is no longer present (hematoxylin and eosin, original magnification ×620). Scabies: Too Late? No, Checkmate

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perils of dermatopathology

1 (IL-1) receptor antagonist by skin cells, which can then inhibit the proinflammatory activity of IL-1. The study also discusses additional inhibitory effects on B- and T-cell costimulatory interactions that result in subsequent down-regulation of T-cell function.5 Collectively, these studies suggest a reason why scabies mites are often not seen in clinically apparent lesions: the host immune and, therefore, inflammatory response is subdued at the siteƒ where the organism is actually present. Diagnosis In the past, the diagnosis of scabies was possible with extraction of the mites out of their burrow. One investigator2 reported extraction of more than 9000 mites from more than 800 men infested with scabies. This is no longer recommended, because the pathognomonic burrow from which the author extracted the mite is rarely present today, at least not in developed countries, possibly as a result of improved lifestyle and soap use. Modern dermatologists are often not familiar with these ancient presentations.2

perform skin scrapings at appropriate sites to ensure an accurate diagnosis of scabies infection. Because of its course and that the skin lesions may not be readily recognizable, biopsy and/or scrapings should concentrate on sites a few millimeters proximal to those seen clinically. Scabies is a contagious disease and identifying a patient with scabies early in its course will benefit the patient and his or her close contacts with a high likelihood of sharing the infestation. In addition to improving the diagnostic technique of skin scrapings for scabies, a better understanding of the immunology and host-parasite interaction involving scabies mites, as well as the role of secretory factors produced by scabies mites on delaying the onset of clinical symptoms and evading host immune responses is necessary. References

Scabies today can mimic a variety of infectious and noninfectious diseases. The specificity of a diagnosis based solely on clinical findings is low. Even though the presence of the burrow is pathognomonic for scabies infection, the burrow is often not present or visible and is likely to be destroyed from scratching. In addition, much of the time, burrow sites are not inhabited by scabies mites, which make the diagnosis even more difficult.3,6 Because of insufficient clinical signs, the current recommendation is to make a definitive diagnosis based on the identification of the mite or mite products, such as eggs, eggshell fragments, or fecal pellets from skin scrapings or detection of the mite at the end of its burrow.2,6,8,10 We suggest, especially in developed countries such as the United States, that this be modified as follows: (1) biopsy/skin scraping sites should be a few millimeters proximal to where the lesions are observed clinically, and (2) when the characteristic subcorneal burrow is observed, especially if eosinophils are seen in the underlying dermis, a diagnosis of scabies should be presumed and treatment initiated.

1 Mounsey KE, McCarthy JS, Walton SF. Scratching the itch: new tools to advance understanding of scabies. Trends Parasitol. 2013;29:35–42. 2 Wolf R, Davidovici B. Treatment of scabies and pediculosis: facts and controversies. Clin Dermatol. 2010;28:511– 518. 3 Park JH, Kim CW, Kim SS. The diagnostic accuracy of dermoscopy for scabies. Ann Dermatol. 2012;24:194– 199. 4 Rosendahl C, Cameron A, Weedon D. Pre-emptive diagnosis of a case of scabies by dermatopathology. Dermatol Pract Concept. 2012;2:61–63. 5 Cote NM, Jaworski DC, Wasala NB, Morgan MS, Arlian LG. Identification and expression of macrophage migration inhibitory factor in Sarcoptes scabiei. Exp Parasitol. 2013;135:10. 6 Walter B, Heukelbach J, Fengler G, et al. Comparison of dermoscopy, skin scraping, and the adhesive tape test for the diagnosis of scabies in a resource-poor setting. Arch Dermatol. 2011;147:468–473. 7 Walton SF, Currie BJ. Problems in diagnosing scabies, a global disease in human and animal populations. Clin Microbiol Rev. 2007;20:268–279. 8 Falk ES, Eide TJ. Histologic and clinical findings in human scabies. Int J Dermatol. 1981;20:600–605. 9 Shahab RK, Loo DS. Bullous scabies. J Am Acad Dermatol. 2003;49:346–350.

Conclusions

10 Micali G, Lacarrubba F, Massimino D, Schwartz RA. Dermatoscopy: alternative uses in daily clinical practice. J Am Acad Dermatol. 2011;64:1135–1146.

Scabies is a common skin disease that affects health worldwide. It is of the utmost importance for the dermatologist to correctly

11 Hengge UR, Currie BJ, Jäger G, Lupi O, Schwartz RA. Scabies: a ubiquitous neglected skin disease. Lancet Infect Dis. 2006;6:769–779.

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March/April 2015

Volume 13 • Issue 2

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

BRAF Inhibitor–Induced Neutrophilic Dermatoses: A Bitter-“Sweet” Scenario Warren R. Heymann, MD

argeted therapy in oncology has revolutionized therapy for melanoma and other cancers. Targeting the mitogen-activated protein kinase signaling pathway, which regulates cell proliferation, differentiation, and survival, has been used to an advantage by inhibiting the signaling cascade of RASRAF-MEK-ERK. The RAF family members (ARAF, BRAF, and CRAF) are serine-threonine kinases. While mutations in ARAF and CRAF are rare, activating BRAF mutations are found in multiple cancers including melanoma, colorectal, papillary thyroid, ovarian, lung, brain, and in hairy cell leukemia cancers. The most common mutation is the substitution of valine for glutamic acid at codon 600 in exon 15 (V600E) with most other mutations being V600K. To date, two BRAF inhibitors have been approved for the treatment of advanced melanoma: vemurafenib and dabrafenib.1

have been reported.3 Severely atypical nevi and melanoma may develop in patients taking vemurafenib presumably by transactivation of wild-type BRAF.4 Recently, there have been an increasing number of reports of patients developing neutrophilic panniculitis and Sweet syndrome following the administration of BRAF inhibitors. Case Reports

Two other agents have been released for managing melanoma: ipilimumab, which augments the immune response by inhibiting cytotoxic T-lymphocyte antigen-4 (CTLA-4) and trametinib, a selective inhibitor of MEK1 and MEK2. While various combinations of these agents have been utilized, and newer targeted therapies are on the horizon, this commentary will focus on BRAF inhibitors exclusively, notably vemurafenib.

Two cases of women have been detailed with metastatic melanomas harboring BRAFV600E mutations that developed subcutaneous nodules accompanied by arthralgias at 16 days and 7 weeks after the administration of oral class I RAF inhibitors, respectively. C-reactive protein levels were elevated in both patients. A rheumatologic evaluation of the first patient was negative, except for an antinuclear antibody of 1:160. A biopsy of the former patient demonstrated a neutrophilic lobular panniculitis with vasculitis of the small vessels, while the latter had a septolobular neutrophilic panniculitis with focal noncaseating granuloma formation. Therapy with the inhibitors was continued in both patients (with a dose reduction in the first patient) following rapid resolution of the lesions with prednisolone and nonsteroidal inflammatory drugs (NSAIDs) in the former patient and NSAIDs in the latter. Joint and skin lesions did not recur despite continued therapy with the inhibitors.5

The most common systemic toxicities of single-agent BRAF inhibitors include fatigue, arthralgias, and fever. Squamous cell carcinomas (keratoacanthoma-type) develop in approximately 25% of patients with a median time of development of 8 weeks. Alopecia and photosensitivity may be noted.2 Keratosis pilaris– like eruptions, facial erythema, and hand-foot skin reactions

Similarly, another group reported the first two cases of neutrophilic panniculitis attributed to vemurafenib, both patients being women with metastatic melanoma demonstrating the BRAFV600E mutation. They developed tender subcutaneous nodules that displayed neutrophilic panniculitis without vasculitis. Rheumatologic and infectious etiologies were ruled out. Because

Additional Agents

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

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of the clinical and radiological response to vemurafenib, the drug was continued. Both patients’ panniculitic lesions spontaneously resolved, although one patient had recurrent lesions for about 6 days. Neither patient was treated for these lesions.6 Two additional cases of neutrophilic panniculitis induced by vemurafenib were subsequently reported. The presentations were similar to the previously described cases, although vemurafenib was discontinued in one patient because of a recurrence of lesions, despite lowering the dose of vemurafenib. A third case was described in which the patient developed nodules revealing leukocytoclastic vasculitis on biopsy, associated with squamous metaplasia of the eccrine glands, suggestive of a chemotherapy effect (the patient had previously been treated with radiation, temozolomide, and ipilimumab). These nodules resolved and did not recur with a lower dose of vemurafenib.7 Subsequent similar cases of vemurafenib-induced panniculitis have been reported.8,9,10 Interestingly, with the exception of one male patient,9 all patients were women. Additionally, although this group described the lesions of both patients as being consistent with erythema nodosum, I believe that these cases were clinically and histologically identical to the other patients reported as neutrophilic panniculitis. Others detailed the first case of vemurafenib-induced neutrophilic panniculitis in the pediatric literature. Their patient was a 15-year-old girl with a BRAFV600E brainstem glioma. Her cutaneous lesions developed after being on vemurafenib for 10 months; her skin lesions resolved slowly over months despite continuation of inhibitor therapy.11 Sweet Syndrome Classical Sweet syndrome is characterized histologically by dermal infiltration of neutrophils without vasculitis. Sweet syndrome may be associated with malignancies in up to 20% of cases (hematologic malignancies in 85% of patients, with the remainder being solid tumors of the genitourinary tract, breast, and gastrointestinal tract). Sweet syndrome may also be postinfectious (usually an upper respiratory infection caused by Streptococci), associated with autoinflammatory/autoimmune disorders (eg, inflammatory bowel disease, sarcoidosis, Behçet syndrome, and autoimmune thyroid disease), or drug-induced (classically granulocyte colony-stimulating factor).12 Neutrophilic panniculitis is not a specific diagnosis, but rather a reaction pattern that may be caused by infection (bacterial, mycobacterial, or fungal), factitial causes, pancreatic disease, α1-antitrypsin deficiency, bowel-bypass syndrome, Behçet disease, or subcutaneous Sweet syndrome.13 SKINmed. 2015;13:132–134

Sweet syndrome caused by vemurafenib has been reported in a 64-year-old man with a recurrent history of BRAFV600E mutant cholangiocarcinoma that responded to prednisone. After the skin lesions resolved, vemurafenib administration was reinstated.14 Researchers reported the case of an 83-year-old woman with melanoma and the classical BRAF mutation who developed Sweet syndrome after the administration of vemurafenib, accompanied by acute renal failure (possibly secondary to renal Sweet syndrome), which necessitated discontinuing the drug and administering systemic steroids.15 When the neutrophilic infiltrate of subcutaneous Sweet syndrome is robust, one could speculate that most of the cases reported as neutrophilic panniculitis caused by vemurafenib are consonant with a diagnosis of subcutaneous Sweet syndrome. The pathogenesis of Sweet syndrome is believed to be the result of immunodysregulation involving cytokines such as interleukins 1 and 6 and granulocyte colony-stimulating factor.14 The mechanism by which BRAF inhibitors affect neutrophilic migration remains unknown. Conclusions There is now sufficient literature to reach the following conclusions: (1) BRAF inhibitor–induced neutrophilic dermatoses (panniculitis or Sweet syndrome) is not rare; (2) cases occur predominantly in women with melanoma, but may be seen in children or in patients with other malignancies such as a brain stem glioma or cholangiocarcinoma; (3) in most cases, vemurafenib need not be discontinued; if symptomatic, administration of steroids or NSAIDs will usually suffice in controlling the lesions; and (4) much remains to be learned about the pathomechanism of this adverse reaction. Indeed, if the drug’s mechanism that affects neutrophilic function could be elucidated, perhaps novel therapies for conditions such as cyclic neutropenia or myelokathexis could be developed. Now that would be sweet! References

133

1 Hertzman Johansson C, Egyhazi Brage S. BRAF inhibitors in cancer therapy. Pharmacol Ther. 2014;142:176– 182. 2 Saranga-Perry V, Ambe C, Zager JS, Kudchadkar RR. Recent developments in the medical and surgical treatment of melanoma. CA Cancer J Clin. 2014;64:171–185. 3 Huang V, Hepper D, Anadkat M, Cornelius L. Cutaneous toxic effects associated with vemurafenib and inhibition of the BRAF pathway. Arch Dermatol. 2012;148:628– 623. 4 Gerami P, Sorrell J, Martini M. Dermatoscopic evolution of dysplastic nevi showing high-grade dysplasia in a metastatic melanoma patient on vemurafenib. J Am Acad Dermatol. 2012; 67:3275–3276.

BRAF Inhibitor–Induced Neutrophilic Dermatoses

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the heymann file

5 Zimmer L, Livingstone E, Hillen U, et al. Panniculitis with arthralgia in patients with melanoma treated with selective BRAF inhibitors and its management. Arch Dermatol. 2012;148;357–361.

10 Maldonado-Seral C, Berros-Fombella, Vivanco-Allende B, et al. Vemurafenib-associated neutrophilic panniculitis: an emergent adverse effect of variable severity. Dermatol Online J. 2013;19:16.

6 Monfort JB, Pagès C, Schneider P, et al. Vemurafenibinduced neutrophilic panniculitis. Melanoma Res. 2012;22:399–401.

11 West ES, Williams VL, Morelli JG. Vemurafemib-induced panniculitis in a child with a brainstem glioma. Pediatr Dermatol. 2014 Mar 6 [Epub ahead of print].

7 Novoa RA, Honda K, Koon HB, Gerstenblith MR. Vasculitis and panniculitis associated with vemurafenib. J Am Acad Dermatol. 2012;67:e271–e272.

12 Bonamigo RR, Razera F, Olm GS. Neutrophilic dermatoses––part I. An Bras Dermatol. 2011;86:195–209.

8 Kim GH, Levy A, Compoginis G. Neutrophilic panniculitis developing after treatment of metastatic melanoma with vemurafenib. J Cutan Pathol. 2013;40:667–669. 9 Sinha R, Edmonds K, Newton-Bishop J, Gore M, et al. Erythema nodosum-like panniculitis in patients with melanoma treated with vemurafenib. J Clin Oncol. 2013;31:e320–e321.

13 Guhl G, García-Díez A. Subcutaneous Sweet syndrome. Dermatol Clin. 2008;26:541–551. 14 Pattanprichakul P, Tetzlaff MT, Lapolla WJ, et al. Sweet syndrome following vemurafenib therapy for recurrent cholangiocarcinoma. J Cutan Pathol. 2014;326–328. 15 Yorio JT, Mays SR, Ciurea AM, et al. Case of vemurafenibinduced Sweet’s syndrome. J Dermatol. 2014;41:817– 820.

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 156)

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March/April 2015

Volume 13 • Issue 2

CONTACT DERMATITIS CAPSULE Matthew J. Zirwas, MD, Section Editor

Pitfalls in Diagnosing Fragrance Allergy Jonathan G. Bonchak, MD; Matthew J. Zirwas, MD

28-year-old nurse presented with itching and dermatitis confined to the eyelids and hands for 2 years. The dermatitis was exacerbated after wearing gloves at work, but topical and intramuscular corticosteroids provided her temporary relief. Results from allergen patch testing 1 year ago was negative. Physical examination revealed pink-red plaques with scaling and cracking at the dorsal hands and volar wrists (Figure 1), as well as pink patches with scaling at the eyelids that extended infraorbitally (Figure 2). Patch testing with the North American Contact Dermatitis Group’s standard series of 70 allergens showed a 2+ reaction to fragrance mix II (FM II). Discussion Fragrance is found in a myriad of products including perfumes, baby wipes, and household cleaning agents. Thousands of fragrance components are available, ranging from laboratory-synthesized chemicals to essential oils and natural extracts, with more than 100 known to cause allergic contact dermatitis.1 An individual product may contain more than 100 fragrance components.2 Even products labelled “fragrance-free” have been shown to contain fragrance components.1 These factors complicate the detection of fragrance allergy and highlight the importance of identifying the components that most commonly cause contact dermatitis. In prevalence studies of contact allergy, fragrance is consistently rated among the most common allergen along with nickel and thiomersal.3,4 Large studies have estimated that the prevalence of fragrance allergy is between 1.3% and 11.4% in the general population.5–7 Positive patch testing to fragrance is most often seen in older women presenting with hand or facial dermatitis.1,7 Common baseline series for patch test allergens, such as the European Standard patch test and the T.R.U.E. Test (SmartPractice, Phoenix, AZ) series, include fragrance mix I (FM I). First

introduced in 1977 by Walter Larsen,8 FM I contains eight of the 28 components that he found were responsible for almost all cases of allergic contact dermatitis caused by the original formulation of Mycolog cream: cinnamic alcohol, cinnamic aldehyde, hydroxycitronellal, amylcinnamaldehyde, geraniol, eugenol, isoeugenol, and oakmoss absolute.1,9 Studies have suggested that FM I is identified in 57% to 67% of patients with fragrance allergy, but its sensitivity has decreased over the past 2 decades, as manufacturers change the composition of their fragranced products in response to patterns of positive patch testing.10,11 Balsam of Peru, an indicator of fragrance allergy that is included in all standard patch test panels along with the fragrance mix, has been banned for use as a fragrance component in its pure form by the International Fragrance Association, illustrating industry responsiveness to trends in contact dermatitis.1 As ingredient lists evolve, new allergens must be added to standard patch test panels. A new fragrance mix, FM II, was introduced in 2005, containing the six most common sensitizers found in a large European multicenter trial: hydroxyisohexyl 3-cyclohexene carboxaldehyde (Lyral), citral, farnesol, citronellol, α-hexyl-cinnamic aldehyde, and coumarin.8 Positive reactions to this new fragrance mix in the general population have ranged from 1.8% to 5.5% in large multicenter European studies.8,12,13 By patch testing patients with both fragrance mixes, those studies showed that between 12.6% and 28.0% of fragrance allergies would have been missed without testing with FM II.12 Multiple large studies have concluded that FM II serves as an important screening tool for the detection of fragrance allergy and should be included in the standard series.8,11,12,14 Conclusions FM II is currently included in the North American Contact Dermatitis Group’s standard screening tray, but it is not included

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

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CONTACT DERMATITIS CAPSULE References 1 Johansen JD. Fragrance contact allergy. Am J Clin Dermatol. 2003;4:789–798. 2 Frosch PJ, Pirker C, Rastogi SC, et al. Patch testing with a new fragrance mix detects additional patients sensitive to perfumes and missed by the current fragrance mix. Contact Dermatitis. 2005;52:207–215. 3 Thyssen JP, Linneberg a, Menné T, Nielsen NH, Johansen JD. Contact allergy to allergens of the TRUE-test (panels 1 and 2) has decreased modestly in the general population. Br J Dermatol. 2009;161:1124–1129. 4 Thyssen JP, Linneberg A, Menné T, Johansen JD. The epidemiology of contact allergy in the general population--prevalence and main findings. Contact Dermatitis. 2007;57:287–299. 5 Dotterud LK, Smith-Sivertsen T. Allergic contact sensitization in the general adult population: a populationbased study from Northern Norway. Contact Dermatitis. 2007;56:10–15.

Figure 1. Pink-red plaques with scale and skin cracking are seen on examination of a 28-year-old nurse who complained of severe itching and discomfort in the hands for 2 years. She washed her hands more than 10 times daily.

6 Nielsen NH, Svendsen UG, Madsen F, Dirksen A. Allergen skin test reactivity in an unselected Danish population. The Glostrup Allergy Study, Denmark. Allergy. 1994;49:86–91. 7 Schäfer T, Böhler E, Ruhdorfer S, et al. Epidemiology of contact allergy in adults. Allergy. 2001;56:1192–1196. 8 Frosch PJ, Pirker C, Rastogi SC, et al. Patch testing with a new fragrance mix detects additional patients sensitive to perfumes and missed by the current fragrance mix. Contact Dermatitis. 2005;52:207–215. 9 Scheinman PL. Allergic contact dermatitis to fragrance: a review. Dermatitis. 1996;7:65–76. 10 Heisterberg MV, Andersen KE, Avnstorp C, Kristensen B, Kristensen O. Fragrance mix II in the baseline series contributes significantly to detection of fragrance allergy. Contact Dermatitis. 2010;63:270–276.

Figure 2. Patch testing revealing a 2+ reaction to fragrance mix II.

in the European Standard or T.R.U.E. Test series. Given the significant proportion of fragrance allergy missed by patch testing with FM I alone, it is important to expand our patch testing panels by using FM II. This should be especially considered for women with hand and facial dermatitis. The American Contact Dermatitis Society maintains the Contact Allergy Management Program (CAMP) database, a valuable tool for clinicians and patients that can generate lists of safe-to-use products based on patch test results. In the case of our patient, her dermatitis dramatically improved after 1 month by strictly using truly fragrance-free soap and moisturizer found on the CAMP database.

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11 Larsen W, Nakayama H, Fischer T, et al. A study of new fragrance mixtures. Am J Contact Dermat. 1998;9:202– 206. 12 Krautheim A, Uter W, Frosch P, Schnuch A, Geier J. Patch testing with fragrance mix II: results of the IVDK 20052008. Contact Dermatitis. 2010;63:262–269. 13 Uter W, Rämsch C, Aberer W, et al. The European baseline series in 10 European Countries, 2005/2006––results of the European Surveillance System on Contact Allergies (ESSCA). Contact Dermatitis. 2009;61:31–38. 14 Bruze M, Andersen KE, Goossens A. Recommendation to include fragrance mix 2 and hydroxyisohexyl 3-cyclohexene carboxaldehyde (Lyral) in the European baseline patch test series. Contact Dermatitis. 2008;58:129–133.

Pitfalls in Diagnosing Fragrance Allergy

March/April 2015

Volume 13 • Issue 2

North American Clinical DermatologIC Society Newsletter

North American Clinical Dermatologic Society 55th Annual Meeting: Panama City, Panama and Havana, Cuba Anthony V. Benedetto, DO

he North American Clinical Dermatologic Society (NACDS) convened at the Trump Hotel, Panama City, Panama, January 28 – February 2, 2014, and at the Melia Cohiba Hotel, Havana, Cuba February 2 – February 9, 2014. Highlights of the scientific sessions are presented. Panama City, Panama Catherine Ramsay, Berkeley, CA, reviewed current concepts about hidradenitis suppurativa (HS). While the chronic, painful nodules and abscesses in apocrine gland-bearing skin are well-known, HS can be associated with other follicular occlusive disorders. The inframammary area is the least involved, with atypical locations found more in men. Currently, the pathogenesis of HS includes follicular occlusion, defective follicular support, and keratin debris and bacteria in a biofilm configuration, which triggers an autoinflammatory response via the innate immune system. Treatment has traditionally involved topical and systemic antimicrobials but recently anakinra and ustekinumab have been shown to be effective, as well as Nd:YAG laser treatments, used for up to 4 months, carbon dioxide ablation surgery, and photodynamic therapy. Steven Kossard, Darlinghurst, Australia, presented a retrospective analysis on his 33 years of experience in defining rare and esoteric skin diseases in relation to dermatopathology. Necrobiotic xanthogranuloma, which appears as indurated violaceous and xanthomatous nodules and plaques, is concentrated around the periorbital area, face, trunk, and extremities. Lesions may have deep subcutaneous involvement, are prone to ulceration, and may resemble necrobiosis lipoidica or have plane xanthomatous components. Eight-five percent of cases present with elevated erythrocyte sedimentation rate, 80% with paraprotein, 58% with leukopenia, 45% with decreased

complement, 15% with abnormal lipids, and 25% with abnormal glucose. Frontal fibrosing alopecia, a variant of lichen planopilaris, is predominantly found in postmenopausal women and is rarely seen in men. There is a progressive recession of the frontal and temporal hairline. Pale, smooth skin is devoid of follicular openings and loss of the eyebrows is frequently seen. Current therapy does not appear to alter the course. The most common treatments include hydroxychlorquine, finasteride, topical and intralesional steroids, topical tacrolimus, doxycycline, and immunosuppressives, all with questionable efficacy. Lymphocytic thrombophilic arteritis is a distinctive form of vasculitis seen as a biopsy finding in livedo racemosa. The main complaint is persistent, slowly progressive, patchy discoloration on the extremities and lasting years. Nevoid lentigo maligna, a variant of small cell melanoma, is characterized by broad-based lentiginous melanocyte proliferation along the epidermal-dermal junction with confluence. Small cell melanoma is a cellular variant of malignant melanoma, composed of small melanocytes resembling benign nevus cells. Most small cell melanomas develop in individuals older than 50 years. They often have a lentiginous melanocytic precursor, develop in sun-damaged skin, and may represent a special nevoid variant of lentigo maligna melanoma. Norman Levine, Oklahoma City, OK, presented an outline of the most recent advances in melanoma diagnosis and surgical treatment. Emphasis was placed on the value and indications for sentinel lymph node dissection and appropriate patient selection. Stephen Stone, from Springfield, IL, discussed new diagnostic tests for scabies, including the delta wing sign, which corresponds to the brownish black anterior part of the embedded mite; the adhesive tape test as described by Katsumata and Kat-

Clinical Professor of Dermatology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA Address for Correspondence: Anthony V. Benedetto, DO, Medical Director, Dermatologic SurgiCenters, Philadelphia and Drexel Hill, PA • E-mail: avb@benedettoderm.com

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sumata; and the burrow ink test. He explained that clinicians should perform skin scrapings whenever possible to confirm the diagnosis microscopically in order to provide appropriate and timely treatment. This can be done using a dermatoscope or the superficial cyanoacrylate biopsy specimen approach, in which a drop of super glue is placed on the burrow, a microscope slide is placed over it and peeled off a few seconds later, taking with the slide the mite, which is then examined under the microscope. Anthony Benedetto, Philadelphia, PA, detailed his technique for injecting different absorbable fillers in various areas of the face. Understanding the elasticity, viscosity, and other physical and physiologic properties of the fillers should guide a physician-injector in choosing the best product for a desired outcome. Hyaluronic acid–based fillers are the only injectibles that should be used to enhance lips and the periorbital area. The mid-face is best treated with calcium hydroxylapatite. Lateral aspects of the face are conveniently enhanced with Poly L-lactic acid filler. A joint scientific session was held with the Panamanian Dermatologic Society and the Department of Dermatology of Panama City University, which permitted the NACDS members to observe rare cases and interact with their Panamanian colleagues. Dr Jose Manuel Rios-Yuil, Panama, highlighted the session by presenting updated findings on cutaneous parasitic infections in Panama and Latin America, and detailed the complex interactions between parasites and the immune system, which determines the clinical expression of the disease. Havana, Cuba Anthony Benedetto, in recalling the development of Mohs micrographic surgery, pointed out that originally the procedure involved applying zinc chloride fixative paste to the tumor prior to excision. Current Mohs micrographic surgery is now performed under local anesthesia (without zinc chloride paste), which allows for better wound reconstruction and quicker healing. A comparative table of different therapeutic modalities for treating skin cancer revealed that the cost of Mohs surgery is much less expensive than radiation therapy or surgical excisions performed in hospitals or ambulatory surgery centers with surgical pathology interpretation. Recurrences from any other therapeutic attempt automatically escalate costs for a therapeutic cure well beyond the basic cost of Mohs surgery, which has a 98% cure rate for primary lesions and 95% cure rate for recurrent lesions.

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Vera Price, San Francisco, CA, clarified that pattern hair loss in women includes three stages of hair miniaturization based on age of onset: androgenic alopecia, female pattern hair loss, and senescent alopecia. The histopathology of all three stages is similar, while the pathophysiology of the three stages presents diverse mechanisms for a common final pathway of follicular downsizing or miniaturization. The therapeutic goal is to prolong anagen and to reverse matrix reduction. Current medical management of miniaturization includes minoxidil, androgen blockade using 5α-reductase inhibitors, and androgen receptor inhibitors. The sexual dysfunction controversy regarding finasteride, as well as observations with finasteride and prostate cancer in men, were debated. C. Ralph Daniel, Jackson, MS, explained that there are countless drugs, chemicals, and biologic substances that can accumulate and remain in the hair and nails, making them useful for retrospective analysis. He then reexamined two criminal cases in which information ascertained from the analysis of the nails proved useful in solving unexplained illnesses and deaths. In each case, Mees’ lines found on the nails led to suspicion of heavy metal poisoning. In one case, the distance between the Mees’ lines on a victim’s fingernails corresponded to the days that he visited a particular restaurant. This information was ultimately used to arrest and convict one of the restaurant’s waitstaff of murder. At the joint scientific meeting with the Cuban Dermatology Society, presentations and discussions on the diagnosis and management of melanoma and nonmelanotic skin cancer in Cuba were led by Olaine Gray, Havana. The President of the Cuban Dermatology Society, Alfredo Abreu, highlighted his unique experiences of his many years in practicing dermatology in Cuba. Fernanda Pastrana and Maria del Carmen Seijas provided insights into dermatologic conditions, such as leprosy and linear dermatoses that affect local children. Moving Forward Members of the NACDS not only visited various historical sites but were also allowed a first-hand glimpse of the Cuban health-care delivery system by visiting local outpatient clinics, extended care facilities, and orphanages. The 2015 meeting will take place May 11 – 24, when members and guests will travel to Iceland, Holland, and Denmark. Dermatologists interested in joining the group should contact Judy Koperski (jakoperski@yahoo.com) or go to: www.nacds.com.

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March/April 2015

Volume 13 • Issue 2

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

An Unusual Case of Darier Disease Complicated With a Parasitic Infestation Kevin Escandón-Vargas, MD;1 Fausto Cabezas, MD;1 Claudia Juliana Díaz, MD2

A 40-year-old woman living in the countryside near Cali, Colombia, presented with exacerbation of papules located on her face and neck and an ulcer located on the left retroauricular area of 2 weeks’ duration. She stated that her skin lesions appeared erratically, beginning at 13 years of age and that her father and daughter had similar skin lesions. Physical examination revealed multiple erythematous, hyperkeratotic papules, and yellowish brown crusts that coalesced to plaques located on symmetrical areas of the forehead, neck, and periauricular areas with excoriation and malodor (Figure 1a and 1b). There were flat-topped papules on the dorsal aspect of her hands. The fingernails exhibited subungual hyperkeratotic fragments, V-shaped notches at the free edges of some nails, distal onycholysis, and white longitudinal bands (Figure 1c). We also discovered a foul-smelling left retroauricular cavity, approximately 3 cm in length and 3 cm in depth, with multiple fly larvae inside of it (Figure 2). We made the diagnosis of retroauricular myiasis and obtained skin biopsy specimens from her forehead and scalp, to confirm the presumptive diagnosis of Darier disease. (SKINmed. 2015;13:142–144)

uring surgical debridement, we removed approximately 30 larvae, which were later confirmed to be Cochliomyia hominivorax, characterized by their morphology. The medical group prescribed oral ivermectin 0.6% (200 μg/ kg), daily cleaning of the ulcer, and a 1-month course of oral doxycycline to control the bacterial overgrowth of the face and neck lesions. Laboratory workup revealed good immunologic status. The ulcer healed 1 month after hospital discharge (Figure 3). Darier disease was confirmed by the skin biopsy (Figure 4). We prescribed topical retinoids as the best therapeutic option to treat her dermatologic disease. Discussion Darier disease is a rare, autosomal dominant disease, caused by mutations in the gene ATP2A2, which encodes the sarco/endoplasmic reticulum Ca2+-ATPase isoform 2 (SERCA2).1,2 It is unclear how this genotype leads to the phenotypic characteristics of the disease; however, recent evidence suggests that the abnormal intracellular calcium signaling in the keratinocytes disrupts the biogenesis, transport, and union of desmosomes and other adhesion complexes, leading to premature and abnormal keratinization (dyskeratosis), loss of cohesion between epidermal

cells (acantholysis), suprabasal clefting, and the presence of corps ronds (rounded keratinocytes) and grains.3,4 Clinically, it presents as hyperkeratotic, yellowish brown and greasy papules and plaques, mainly in seborrheic areas of the skin and folds. Nail involvement includes red and white longitudinal bands, V-shaped notches at the free margin of the nails, subungual hyperkeratosis, and nail fragility.1,5 Symptoms are exacerbated with lithium intake,6 UV-B radiation,7 heat, friction, and infections. Topical palliative medical therapies such as emollients, steroids, and retinoids are used for relief of symptoms, reducing hyperkeratosis and papules. Physicians should advise all patients to wear cool cotton clothing and use high-SPF sunscreen.8 Darier disease typically runs a chronic relapsing course, but severe complications remain uncommon. Lesions caused by Darier disease often lead to epithelial disruption and, hence, predispose to infections, which are responsible for discomfort and malodor. Staphylococcus aureus, herpes simplex virus, and varicella zoster virus are pathogens associated with the disease.9 It has been described that dermatological conditions, especially ulcerative and hyperkeratotic lesions, predispose to myiasis.

From the School of Medicine, Faculty of Health,1 and the School of Dermatology and Dermatological Surgery, Hospital Universitario del Valle,2 Universidad del Valle, Cali, Colombia Address for Correspondence: Kevin Escandón-Vargas, MD, School of Medicine, Faculty of Health, Universidad del Valle, Calle 4B #36 - 00, Cali, Colombia • E-mail: kevin.escandon@correounivalle.edu.co

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(a)

(b)

Figure 2. Foul-smelling left retroauricular cavity with presence of approximately 30 fly larvae. Larvae were removed during surgical debridement and identified as Cochliomyia hominivorax (b).

(b)

Figure 3. Favorable outcome of wound myiasis 1 month after hospital discharge.

(c)

Figure 1. Greasy, hyperkeratotic, yellowish brown papules on the patient’s forehead, neck, and periauricular areas with excoriation and malodor (a and b). Flat-topped papules on the dorsal aspect of the patient’s hands and nails with subungual hyperkeratotic fragments, V-shaped notches at the free edges of some fingernails, distal onycholysis, and white longitudinal bands (c). SKINmed. 2015;13:142–144

Figure 4. Histologic image of epidermis with hyperkeratosis, acantholysis, suprabasal clefts, and dyskeratosis including corps ronds and grains, and linfoplasmocitary infiltrate in the superficial dermis (hematoxylin and eosin stain, original magnification x10).

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Myiasis is the tissue infestation with dipterous larvae. It occurs mainly in tropical and subtropical regions in people with inadequate hygiene and poor housing conditions. There are numerous reports in the literature describing the clinical manifestations and fly larvae species. Specifically, wound myiasis occurs when fly larvae infest necrotic, hemorrhaging, or purulent lesions. Cochliomyia species infestation commonly causes wound myiasis worldwide.10–12 Conclusions We report an unusual case of Darier disease complicated with a retroauricular myiasis caused by Cochliomyia hominivorax. The patient lives in a tropical area and has poor living conditions. We believe these factors might have contributed to the flare-up of her lesions, facilitating the parasitic infestation. The woman exhibited complete resolution of the myiasis with treatment and hygiene recommendations. She was advised to start topical retinoids. Acknowledgments Dr Ricardo Rueda (dermatopathologist) assisted in providing the histopathologic image. References 1 Burge SM, Wilkinson JD. Darier-White disease: a review of the clinical features in 163 patients. J Am Acad Dermatol. 1992;27:40–50.

2 Pani B, Singh BB. Darier’s disease: a calcium-signaling perspective. Cell Mol Life Sci. 2008;65:205–211. 3 Koch CB. Enfermedad de Darier-White clásica y lineal. Rev Argent Dermatol. 2009;90:142–151. 4 Hulatt L, Burge S. Darier’s disease: hopes and challenges. J R Soc Med. 2003;96:439–441. 5 Savignac M, Edir A, Simon M, Hovnanian A. Darier disease: a disease model of impaired calcium homeostasis in the skin. Biochimica et Biophysica Acta. 2011;1813:1111–1117. 6 Rubin MB. Lithium-induced Darier’s disease. J Am Acad Dermatol. 1995;32:674–675. 7 Otley CC, Momtaz K. Induction of Darier-White disease with UVB radiation in a clinically photo-insensitive patient. J Am Acad Dermatol. 1996;34:931–934. 8 Eimer L, Lagodin C, Bonavia P, et al. Enfermedad de Darier-White tratada con isotretinoína oral. Arch Argent Pediatr. 2011;109:e63–e66. 9 Zeglaoui F, Zaraa I, Fazaa B, et al. Dyskeratosis follicularis disease: case reports and review of the literature. J Eur Acad Dermatol Venereol. 2005;19:114–117. 10 Francesconi F, Lupi O. Myiasis. Clin Microbiol Rev. 2012;25:79–105. 11 Antunes AA, Santos T de S, Avelar RL, et al. Oral and maxillofacial myiasis: a case series and literature review. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2011;112:e81–e85. 12 Duque CS, Marrugo G, Valderrama R. Otolaryngic manifestations of myiasis. Ear Nose Throt J. 1990;69:619– 622.

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March/April 2015

Volume 13 • Issue 2

CASE STUDY

Cutaneous Hyperneury: A New Entity or an Atypical Cutaneous Manifestation of MEN 2B? Taseer Ahmed Bhatt, MD; Samara Mimesh, MD, FCRPC

A 33-year-old healthy woman with a family history of hyperlipidemia presented with asymptomatic skin-colored yellowish linear transverse plaques and papules on the trunk and forearms for a period of 6 months (Figure 1). She noticed that the lesions during this period have been gradually increasing in size and number. The initial clinical impression was eruptive xanthomas. A serum lipid profile showed a total serum cholesterol level of 406 mmol/L (high-density lipoprotein, 1.38 mmol/L; low-density lipoprotein, 2.73 mmol/L) and a triglyceride level of 1.1 mmol/L, which is within the normal range. A 4-mm punch biopsy was performed from the skin lesion on the patient’s forearm, and findings showed the presence of bundles of mature nerve fibers in the papillary dermis (Figure 2) with a normal overlying epidermis. No abnormalities were seen in the subcutaneous tissue. There was no evidence of lipid deposition. A diagnosis of cutaneous hyperneury was made. (SKINmed. 2015;13:145–146)

utaneous neuromas are a rare manifestation of multiple endocrine neoplasia type 2B (MEN 2B) and are seen mainly on the face. MEN 2b is a syndrome characterized by the triad of medullary thyroid carcinoma (MTC), pheochromocytoma, and mucosal neuromas. Mucosal neuromas are universal manifestation of MEN 2B and are seen on the tongue, lips, and oral mucosa. All these features appear in adolescence before the appearance of MTC and pheochromocytoma.1–3

revealed a mutation within exon 13 of the RET proto-oncogene by single-stranded conformational polymorphism analysis.5 In view of these findings, the patient was considered to have an atypical form of MEN 2B syndrome based on the location of the cutaneous neuromas on the trunk and absence of mucosal neuromas. The differential diagnosis of MTC with unusual cutaneous association and an overlap of MEN 2A and MEN 2B

Our patient was 33 years old and had cutaneous lesions on her trunk and forearms for 6 months. A literature search revealed 2 case reports describing a similar histolopathologic picture. The first case was a 60-year-old woman with linear red-brown parallel stripes on the trunk that had begun 10 years earlier. This patient had marfanoid features, abnormal electromyography, and corneal nerve hypertrophy, which were not seen in our patient. The authors considered it to be a mild and unusual form of MEN 2B, and the presentation was classified as linear cutaneous neuromas.4 In another case report, a 45-year-old Caucasian woman had a cutaneous presentation similar to our patient. She also had euthyroid nodular goiter. Her laboratory investigations revealed normal serum calcitonin, phosphate, and vanylmandelic acid levels. Total thyroidectomy was performed and histopathology revealed 2 foci of MTC. The DNA analysis of peripheral blood

Figure 1. Cutaneous hyperneury. Skin-colored yellowish transverse linear plaques and papules on the forearms.

From the Dermatology Division, Department of Internal Medicine, Main Hospital, King Fahad Medical City, Riyadh, Saudi Arabia-11525 Address for Correspondence: Taseer A. Bhatt, MD, Assistant Consultant Dermatologist, Dermatology Division, Department of Internal Medicine, Main Hospital, King Fahad Medical City, Riyadh, Saudi Arabia-11525 • E-mail: tbhatt@kfmc.med.sa

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Case Study were also considered. Given these case reports, we screened our patient for MEN syndrome, but the laboratory evaluation was normal (calcitonin, 4 pg/mL; serum calcium, 10 mg/dL; plasma phosphate, 1.05 mmol/L; plasma metanephrine, 0.20 nmol/L; and normetanephrine, 0.50 nmol/L). The DNA analysis of peripheral blood cells was performed and did not reveal any mutation of RET proto-oncogene. Conclusions The late appearance of isolated cutaneous lesions in our patient and the negative screening for MEN 2B suggests a new entity not reported previously in the literature. References 1 Bazex A, Boulard C, Delsol G, Bazex J, Louvet JL. [Hereditary Sipple syndrome (author transl)]. Ann Dermatol Venerol. 1977;104:103–114. 2 Kaufman FR, Roe TI, Isaacs H Jr, Weitzman J. Metastatic medullary thyroid carcinoma in young children with mucosal neuroma syndrome. Pediatrics. 1982;70:263–267. 3 Gorlin RJ, Sedano HO, Vickers RA, Cervenka J. Multiple mucosal neuromas, pheochromocytomas and medullary carcinoma of the thyroid—a syndrome. Cancer. 1968;22:293–299. 4 Guillet G, Gauthier Y, Tamisier JM, et al. Linear cutaneous neuromas (dermatoneurie en stries): limited phakomatosis with striated pigmentation corresponding to cutaneous hyperneury (featuring multiple endocrine neoplasia syndrome?). J Cutan Pathol. 1987;14:43–48.

Figure 2. Cutaneous hyperneury. Histologic examination showing mature nerve fiber bundles in the papillary dermis with no surrounding inflammatory infiltrate. The epidermis is normal (hematoxylin and eosin stain, original magnification ×100).

5 Baykal C, Buyukbabani N, Boztepe H, Barahmani N, Yazganoglu KD. Multiple cutaneous neuromas and macular amyloidosis associated with medullary thyroid carcinoma. J Am Acad Dermatol. 2007;56:S33–S37.

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March/April 2015

Volume 13 • Issue 2

CASE STUDY

Generalized Eruptive Keratoacanthoma of Grzybowski Satyendranath Chowdhury, MD; Debabrata Bandyopadhyay, MD; Ashim Kumar Mondal, MD

A 51-year-old otherwise healthy farmer presented with a 1-year history of numerous extremely itchy bumps on his skin. The lesions came in crops, were pinhead-sized, and subsequently enlarged to form nodules of varying sizes. There was no history of ocular or mucosal involvement or of spontaneous healing of any of the lesions. His medical history was unremarkable. There was neither any family history of similar illness nor any personal or family history of atopy or malignancy. He was previously treated with potent topical steroids and antihistamines without any appreciable benefit. (SKINmed. 2015;13:148–150)

eneral and systemic examination was noncontributory. Cutaneous examination revealed numerous domeshaped papules and nodules (2 to 20 mm in diameter) on the entire cutaneous surface sparing only the face, palms, and soles (Figure 1). No mucosal lesion was seen. The lesions were mostly discrete, but coalescence into plaques was seen over his legs, which were also the sites of most profound affection. Many of the larger lesions showed central craters filled with keratotic materials. Lichenification over some areas of the skin was evident. Results from routine laboratory tests and serum biochemistry panel was normal. Findings from abdominal ultrasonography, computed tomography of the abdomen and chest, and chest x-ray showed no abnormality. HIV testing was nonreactive. Estimation of arsenic in his hair and nails tested normal. Histopathologic examination of multiple biopsy specimens showed hyperplastic epidermis with glassy keratinocytes, dilated follicular infundibula filled with keratin plugs, and multiple horn pearls (Figure 2). Scattered mitotic figures were visible. After clinicopathologic correlation, a diagnosis of generalized eruptive keratoacanthoma (KA) of Grzybowsky was made. He was put on hydroxyzine (25 mg three times a day), emollients, and acitretin 50 mg/d. Since the response was unsatisfactory even after 3 months of treatment, acitretin was substituted with methotrexate 15 mg/wk for 8 weeks but that too was suspended as no appreciable benefit was noted. The patient was then treated with 100 mg/d cyclophosphamide. The patient is currently on

this regimen and over a period of 4 months most of the lesions on his trunk have disappeared (Figures 3 and 4) and the larger lesions significantly diminished in size with remarkable symptomatic relief. Discussion KA is an epithelial tumor of the skin characterized by fast initial growth followed by slow spontaneous healing and a histology that mimics squamous cell carcinoma. KAs are relatively common, with the usual variety presenting with a solitary lesion on sun-damaged skin. Several rare forms of multiple, eruptive KAs have also been described.1 Generalized eruptive KA was first reported by Grzybowski in 1950.2 Since then, fewer than 40 cases of this extremely rare sporadic form of KA have been reported. Generalized eruptive KA of Grzybowski is characterized by a rapid and progressive eruption of hundreds of small papules containing a central keratin-plugged umbilication. Sun-exposed sites are favored and there may be prominent facial involvement with ectropion. Similar lesions may also occur on the oral mucosa.3 Palmoplantar sparing is the rule and severe itching and Koebnerization are common. There is no sex predilection and the median age of onset is 57 years.4 Histopathology of generalized KA is similar to that of the solitary lesions.1,5 Features include epidermal hyperplasia, central keratin-filled crater, eosinophilic hyaline keratinocytes, and horn pearls with central

From the Department of Dermatology, Venereology, & Leprosy, Medical College, Calcutta, 88, College Street, Kolkata 700073, India Address for Correspondence: Debabrata Bandyopadhyay, Professor and Head, Department of Dermatology, Venereology, & Leprosy, Medical College, Calcutta, 88, College Street, Kolkata 700073, India • E-mail: dr_dban@yahoo.com

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Figure 1. Keratoacanthomas on the trunk, with the larger lesions showing central keratotic plugs.

Figure 3. Lesions on the back before cyclophosphamide therapy.

Figure 2. Hyperplastic epidermis with glassy keratinocytes and multiple horn pearls with central keratinization (hematoxylin and eosin stain, original magnification ×100).

Figure 4. Marked improvement after 2 months of cyclophosphamide therapy.

keratinization. The relationship of KA with squamous cell carcinoma remains controversial and the conditions may be histopathologically indistinguishable. Grzybowski’s original case, despite having widespread involvement, did not show any signs of malignancy within 16 years of onset of the disease, lending support to the view that this variety of KA does not show invasive growth or progress to squamous cell carcinoma.6 SKINmed. 2015;13:148–150

Grzybowski’s variant of multiple KA needs to be differentiated from multiple self-healing KAs of Ferguson Smith type and multiple KA of Witten and Jak type. The Ferguson Smith type of KA is characterized by autosomal dominant inheritance, fewer lesions, occurrence on sun-exposed skin during childhood or adolescence, and spontaneous involution with depressed scars.5 In the Witten and Zak type of multiple KA, large self-healing

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lesions occur in association with multiple small miliary lesions.7 Nodulo-ulcerative destructive lesions and oral KAs also occur in this variety.

patient is the first reported case of generalized eruptive KA of Grzybowski from the Indian subcontinent. References

The etiology of multiple KA is unknown. Human papillomavirus was not detected in lesions of multiple or eruptive KAs.3,8 UV exposure, chemical carcinogens, and immunosuppression have been proposed as possible predisposing factors, but these associations have not been proved.9 Treatment with sorafenib, a multikinase inhibitor antiproliferative agent used in the treatment of solid tumors, has been associated with multiple KAs.10 Grzybowski’s multiple KA has been associated with cancer in some cases, but this association appears to be coincidental.3 Our patient has more lesions on the covered parts of his skin, with facial sparing, and he has no immunosuppression or associated malignancy. Treatment of Grzybowski’s variant of KA is largely unsatisfactory. Oral retinoids have reportedly given good results in some cases.11,12 Remission of disease has been reported with cyclophosphamide therapy in retinoid-resistant cases.13 Variable results have been obtained with other treatment options including methotrexate, ranitidine, interferons, and intralesional injection with bleomycin, triamcinolone, and 5-fluorouracil.5 Our patient showed poor response to prolonged retinoid and methotrexate therapy but has been showing favorable response to cyclophosphamide. Conclusions Generalized eruptive KA of Grzybowski is an extremely rare sporadic variety of multiple KA that presents with innumerable KAs in a widespread distribution. Treatment of this condition is problematic. Retinoids may provide good results and cyclophosphamide therapy may benefit retinoid-resistant cases, as was demonstrated by our patient. To the best of our knowledge, our

1 Schwartz RA. Keratoacanthoma. J Am Acad Dermatol. 1994:30:1–19. 2 Grzybowski M. A case of peculiar generalized epithelial tumors of the skin. Br J Dermatol Syphilol. 1950;62:310–313. 3 Gjersvik PJ, Egass E, Clausen OP. Grzybowski’s generalized eruptive keratoacanthomas: a case report. Eur J Dermatol. 2000;10:135–138. 4 Jaber PW, Cooper PH, Greer KE. Generalized eruptive keratoacanthoma of Grzybowski. J Am Acad Dermatol. 1993;29:299–304. 5 Consigli JE, Gonzalez ME, Morsino R, et al. Generalized eruptive keratoacanthoma (Grzybowski variant). Br J Dermatol. 2000;142:800–803. 6 Schwartz RA, Blaszczyk M, Jablonska S. Generalized eruptive keratoacanthoma of Grzybowski: follow-up of the original description and 50-year retrospect. Dermatology. 2002;205:348–352. 7 Witten VH, Zak FG. Multiple, primary, self healing, prickle cell epithelioma of the skin. Cancer. 1952;5:539–550. 8 Haas N, Schadendorf D, Henz BM, Fuchs PG. Nine-year follow-up of a case of Grzybowski type multiple keratoacanthomas and failure to demonstrate human papillomavirus. Br J Dermatol. 2002;147:793–796. 9 Chu DH, Hale EK, Robins P. Generalized eruptive keratoacanthoma. Dermatol Online J. 2003;9:36 10 Lynch MC, Straub R, Adams DR. Eruptive squamous cell carcinomas with keratoacanthoma-like features in a patient treated with sorafenib. J Drugs Dermatol. 2011:10:308–310. 11 Yell JA. Grzybowski’s generalized eruptive keratoacanthoma. J R Soc Med. 1991;84:170–171. 12 Vandergriff R, Nakamura K, High WA. Generalized eruptive keratoacanthomas of Grzybowski treated with isotretinoin. J Drugs Dermatol. 2008;7:1069–1070. 13 Oakley A, Ng S. Grzybowski’s generalized eruptive keratoacanthoma: remission with cyclophosphamide. Australas J Dermatol. 2005;46:118–123.

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March/April 2015

Volume 13 • Issue 2

correspondence Snejina Vassileva, MD, PhD, Section Editor

Use of Blogging in Telemedicine: Introduction to an Internet-Based Teledermatology Application Engin Senel, MD To the Editor: Teledermatology may be performed through three major techniques: store-and-forward (SF), real-time (videoconferencing), and hybrid (combination of SF and real-time). SF is the most frequently used teledermatology technique because it provides more affordable communication and higher image quality.1 Patient information and images are stored offline and can be uploaded when necessary. Synchronized evaluation is not required in the SF method. Consultants can evaluate the prerecorded materials at a later time even with a simple computer system. The SF method may also be performed via e-mail. Although there are many free and advanced e-mail services on the World Wide Web, it may be complicated to perform teledermatology research via e-mail. There may be hundreds of images and patient information documents in even only one teledermatology study, making it extremely difficult to extract required data from all the daily mail in the inbox. It is also difficult to organize images and information of patients and to create a case-hierarchy in an e-mail account. As a bias problem, in a two-step study, teleconsultants or teledermatologists may see their previous comments or responses. In the digital era, new technologies provide more advanced imaging, storage, and publication possibilities. New Options We would like to introduce a novel feasible option for SF applications: World Wide Web blogging platforms. Blogging is an easy and popular way of sharing information and reflecting daily experiences on the Internet. Regarding a recent estimate, there are more than 152 million blogs on the Internet, with 172,800 blogs being added to daily.2 There are many free blogging platforms including WordPress, Blogger, Tumblr, Google+, Quora, Svbtle, and Typepad. WordPress is one of the most popular free Web blogging services for creating a Web site or a blog. It is an open-source blogging

tool and a content management system (CMS) containing PHP and MySQL support. A user can create as many blogs as he/she wants in a hosting area via this CMS. There are two options for using this blogging system. First, WordPress.com provides a free hosting service but limited customization. Second, users can set the software freely and easily on their own hosting area. In 2012, we initiated a Web blog for our teledermatology workgroup with a domain name www.teledermatoloji.com (Turkish equivalent of teledermatology). We preferred to run WordPress on our own Web hosting area that we had obtained before for our personal Websites. So far, we have carried out three teledermatology studies on this Web site. We installed WordPress software on our hosting root directory for creating the main Web site and then we constituted subdomains for each teledermatologist. WordPress was also installed on the subdomains. We use the main Web site for the introduction of previous studies of our workgroup. We upload patients’ data and teledermatology images onto the subdomains of teledermatologists in our studies. A teledermatologist can enter his/her own subdomain just by clicking the link on the main Web site. We delete or close the previous subdomain of a teledermatologist after obtaining his/her responds/comments regarding the patient to prevent them from seeing the previous response/comments. One of the most significant problems in an SF study is the protection of privacy of personal information and images. WordPress, as a CMS, provided us with a very simple solution to this problem. It is so customizable and open-sourced that it has thousands of plug-ins and themes. We install one of the privacy plug-ins named “Private Only” onto the subdomains of teledermatologists in our studies. This plug-in makes the blog a private Web site and redirects all users who are not logged into the blog to the login page.3 As a result, only a teledermatologist may enter the subdomain with his/her password.

From the Department of Dermatology, Hitit University Faculty of Medicine, Çorum, Turkey Address for Correspondence: Engin Senel, MD, Hitit University Faculty of Medicine, Department of Dermatology, Çorum, Turkey 19030 • E-mail: enginsenel@enginsenel.com

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Conclusions

References 1 Senel E. History of teledermatology: a technique of the future in dermatology. Skinmed. 2010;8:167-70.

Teledermatology is fast-developing branch of telemedicine. Developments in imaging and storage opportunities will be able to affect teledermatologic applications positively in the near future. Physicians should be aware of advances in technology and eager to perform new studies by means of new developments.

2 How many blogs are on the Internet. http://www.wpvirtuoso.com/how-many-blogs-are-on-the-internet/. Accessed April 12, 2014 3 Private Only WordPress Plugin. http://wordpress.org/ plugins/private-only/. Accessed April 13, 2014.

Fixed-Drug Reaction Secondary to Cocaine Use Alan S. Boyd, MD

A 36-year-old white woman presented to the Vanderbilt University Dermatology Clinic with a 3-day history of painful cutaneous lesions, some of which were beginning to blister. She took no medications on a regular basis and denied any recent ingestion of analgesics, vitamins, health supplements, or herbal therapies. She was employed in a business office without any known exposure to industrial chemicals. On physical examination, there were a dozen erythematous to dusky lesions on her torso and extremities (Figure 1). Some appeared hemorrhagic and focally bullous.

They were exquisitely tender to palpation. A biopsy of her left arm showed an interface inflammatory infiltrate with numerous dyskeratotic keratinocytes, pigment incontinence, and scattered eosinophils (Figure 2), consistent with a fixed-drug reaction (FDE). At follow-up 1 week later, she admitted to having used crack cocaine 24 hours before the lesions began. Additionally, she revealed that the FDE had occurred three times previously, always following use of crack cocaine with the lesions arising in exactly the same place each time and leaving residual pigmentation. She was advised that she was experiencing an FDE, almost certainly caused by the cocaine and that subsequent exposures

Figure 1. Clinical image of the patient taken at 1 week exhibiting a resolving bullae and mild hyperpigmentation.

Figure 2. Histologic images from the patient’s biopsy exhibiting dermal-epidermal separation, dyskeratotic keratinocytes, vacuolar basal layer changes, and eosinophils (hematoxylin and eosin stain, original magnification ×40).

To the Editor:

From the Departments of Medicine (Dermatology) and Pathology, Vanderbilt University School of Medicine, Nashville, TN Address for Correspondence: Alan S. Boyd, MD, 719 Thompson Lane, Suite 26300, Nashville, TN 37204 • E-mail: alan.boyd@vanderbilt.edu

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would elicit future outbreaks. Topical steroids were prescribed, which resolved the erythema and discomfort within a few days. Discussion Sulfonamides are responsible for most FDRs; however, nonsteroidal anti-inflammatory drugs (NSAIDs), tetracyclines, barbiturates, and carbamazepine are also commonly implicated. These reactions usually present 1 to 2 weeks after the initial exposure as erythematous to violaceous well-demarcated plaques with edema and central darkening. Bullae may also be seen. Any site may be affected, but the acral areas and genitalia are favored. Hyperpigmentation is often noted as the lesions resolve. Subsequent bouts can commence within 24 hours and affect the exact sites of the previous lesions. Histologically, an interface inflammatory infiltrate with abundant dyskeratotic keratinocytes, dermal eosinophils, and pigment incontinence are noted.

pathic/vasculitic condition with a predilection to involve acral sites has been attributed to the use of levamisole-contaminated cocaine.4 The one reported case of an FDR secondary to cocaine use involved a middle-aged man, also with an FDR to procaine.5 Use of cocaine for nasal mucosa shrinkage caused a slight flare of the disease suggesting cross-reactivity. Conclusions Patients are often hesitant to admit to illicit drug use; regardless, it is important to ask about exposure to drugs, both legal and illegal. References 1 Vagi SJ, Sheikh S, Brackney M, et al. Passive multistate surveillance for neutropenia after of cocaine or heroin possibly contaminated with levamisole. Ann Emerg Med. 2013;61:468–474. 2 Hennings C, Miller J. Illicit drugs: what dermatologists need to know. J Am Acad Dermatol. 2013;69:135–142.

Cocaine is derived from the leaves of the Erythroxylum coca plant. Nearly 2 million US residents use cocaine with some degree of regularity.1 Cocaine can be snorted (insufflated), ingested, injected (either subcutaneously or intravenously), or smoked and is associated with feelings of enhanced confidence, wellbeing, and euphoria.2 Physiologic manifestations include hypertension, altered mental status, and tachycardia.2 Cutaneous conditions associated with cocaine use are primarily vascular, including pseudovasculitis, Churg-Strauss vasculitis, HenochSchonlein purpura, palpable purpura, urticarial vasculitis, Raynaud’s phenomenon, and Buerger’s disease.3 Recently, a vasculo-

3 Brewer JD, Meves A, Bostwick JM, Hamacher KL, Pittelkow MR. Cocaine abuse: dermatologic manifestations and therapeutic approaches. J Am Acad Dermatol. 2008;59:483–487. 4 Bradford M, Rosenberg B, Moreno J, Dumyati G. Bilateral necrosis of earlobes and cheeks: another complication of cocaine contaminated with levamisole. Ann Int Med. 2010;152:758–759. 5 Nelson LM. Fixed drug eruptions: a report of two cases, one caused by niacin, the other by cocaine. Calif Med. 1955;82:127–128.

Subungual Black Onychomycosis and Melanonychia Striata Caused by Aspergillus niger Carlos Garcia, MD;1 Roberto Arenas, MD;2 Elsa Vasquez del Mercado, MD3 To the Editor: We present the case of a 21-year-old Hispanic man with a 3-month history of black discoloration of his left toenails. There was no history of trauma, medications, or personal or family history of melanoma. Physical examination revealed a thick band of melanonychia involving the medial half of the left great

toenail and two longitudinal bands on the left second toenail with onychoschizia, fissuring, mild hyperkeratosis, and proximal leukonychia (Figure 1). Dermatoscopic examination showed irregularly spaced, thick, and parallel black to brown pigmentation. Direct microscopy with Black Chlorazol stain revealed abundant dichotomously branched septate hyphae and large, thick-walled spores. Also seen were conidiophores with typical

From Dawson Medical Group, Oklahoma City, OK;1 the Department of Dermatology, Section of Mycology, Manuel Gea Gonzalez General Hospital, Mexico City, Mexico;2 and the Department of Dermatology, Manuel Gea Gonzalez General Hospital, Mexico City, Mexico3 Address for Correspondence: Carlos Garcia, MD, Dawson Medical Group, 4805 South Western Avenue, Oklahoma City, OK 73109 • E-mail: cg.derm@yahoo.com

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radiating black conidial heads (Figure 2). Fungal culture on Sabouraud dextrose agar grew distinct black colonies of Aspergillus niger with no growth of dermatophytes (Figure 3). Nail biopsy findings from periodic acid–Schiff stain showed spores and horizontal filaments involving full nail plate thickness. The patient was subsequently treated for A. niger onychomycosis with 2 months of oral terbinafine 250 mg daily, topical bifonazol 1%, and urea cream 40%. Marked clinical improvement was seen at 1-month follow-up. Discussion Subungual black onychomycosis and fungal melanonychia1 may simulate melanonychia striata caused by melanocyte activation seen in darkly pigmented individuals, nail matrix nevus, or subungual melanoma, as well as other causes such as trauma, chemotherapy drugs, pregnancy, post-inflammatory changes, Bowen’s disease, verrucae, basal cell carcinoma, and myxoid cysts. In contrast with subungual melanoma, nonsuperficial fungal melanonychia always starts from beneath the free edge of the nail plate.

Figure 1. Aspergillus niger onychomycosis. Black onychomycosis with fissuring and onychoschizia of the left great toenail and longitudinal melanonychia of the left second toenail.

Our literature review revealed that A. niger onychomycosis presenting as diffuse melanonychia is rare.2 We have described a case that was clinically similar to a subungual melanoma, in that the lesion was black and located on the toenails. Black superficial onychomycosis is commonly caused by Trichophyton rubrum and Scytalidium spp.3 Aspergillus onychomycosis typically involves a superficial white pattern but can appear as proximal subungual onychomycosis,2 striated deep leukonychia or dark spots,4 and diffuse melanonychia. The black discoloration, as in our case, is likely from A. niger’s darkly colored pigment aspergillin. It could be postulated that A. niger was a contaminant in our case; nevertheless, the lack of growth of any dermatophyte, the isolation of A. niger on culture, and the findings on direct microscopy adhere to English’s criteria for the diagnosis of pathogenic molds.5 This is an interesting and rare case presentation. Approximately 90% of onychomycosis cases are caused by dermatophytes and less than 10% by yeasts or nondermatophyte molds (Aspergillus spp., Fusarium spp., Acremonium spp., Scopulariopsis brevicaulis, Scytalidium spp.).6 The striking clinical presentation prompted us to consider subungual melanoma in the differential diagnosis. Clinical features suggestive of melanoma of the nail unit include Hutchinson’s sign, patient age older than 60, brown or black band greater than 3 mm width, band changes, and family history of melanoma. Our patient lacked all of these features, except a longitudinal black band greater than 3 mm involving the left big toenail. SKINmed. 2015;13:152–156

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Figure 2. Aspergillus niger onychomycosis. Conidiophores with characteristic radiating conidial heads.

Figure 3. Aspergillus niger onychomycosis. Black colonies of A. niger. Subungual Black Onychomycosis and Melanonychia Striata

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Conclusions The combination of nail biopsy findings and culture plus findings from thendermatoscopic and microscopic examination were consistent with a definitive diagnosis of A. niger onychomycosis. Although rare, A. niger should be considered in the differential diagnosis of melanonychia striata. References 1 Lee SW, Kim YC, Kim DK, et al. Fungal melanonychia. J Dermatol. 2004;31:904–909.

2 Tosti A, Piraccini BM. Proximal subungual onychomycosis due to Aspergillus niger: report of 2 cases. Br J Dermatol. 1998;139:156–157. 3 Finch J, Arenas R, Baran R. Fungal melanonychia. J Am Acad Dermatol. 2012;66:830–841. 4 Onsberg P, Stahl D, Veien NK. Onychomycosis caused by Aspergillus terreus. Sabouradia. 1978;16:39–46. 5 English MP. Nails and fungi. Br J Dermatol. 1976;94:697– 701. 6 Hilmioglu-Polat S, Metin DY, Inci R, et al. Non-dermatophytic molds as agents of onychomycosis in Izmir Turkey––a prospective study. Mycopathologia. 2005;160:125–128.

Historical Diagnosis and treatment: H ERPES ZOSTER (Continued from page 134)

ERRATUM SKINmed. 2014;12:310. Condyloma Acuminata and Mollusca Contagiosa: A Giant Manifestation in a Patient With Lupus Severino Persechino, MD; Claudia Abruzzese, MD; Cristiano Caperchi, MD; Flavia Persechino, MD; Antonella Tammaro, MD Dr. Tammaro’s name was incorrect in the author line of this contribution. The corrected author line appears above. SKINmed. 2015;13:152–156

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March/April 2015

Volume 13 • Issue 2

Book Review Jennifer L. Parish, MD, Section Editor

Atopic Dermatitis and Eczematous Disorders Reviewed by Robert J. Pariser, MD

onald Rudikoff, Stephen Cohen, and Noah Scheinfeld take on the considerable task of approaching the complex subject of atopic dermatitis from as many angles as possible. The book’s 45 contributors bring their perspectives from dermatology, allergy, and pediatrics to bear on the subject. The result is admirable. The dermatologist, the pediatrician, the allergist, and the generalist will find this work a useful guide. The book contains, as expected, detailed information to aid the clinician in diagnosis and management of atopic dermatitis, supported by excellent clinical photography. Particularly useful are chapters on the subsets and variants of atopic dermatitis, such as eyelid dermatitis, hand dermatitis, nummular dermatitis, and ichthyosis vulgaris. Conditions apart from classic atopic dermatitis, namely stasis dermatitis, seborrheic dermatitis, and immunodeficiency disorders with atopic-like features, also get similar comprehensive discussions. For those who enjoy a deeper look “under the hood,” there are chapters on histopathology, pathophysiology, mechanisms of itch, and skin barrier dysfunction. The relationship of atopic dermatitis to asthma and the clinical implications of the “atopic march” are discussed in detail. I can think of only a few aspects of the atopic diathesis that might have been included in this book. I would have appreciated some discussion of the apparently mutually exclusive nature of atopic dermatitis and psoriasis. How about some guidance for the clinician in managing patients with both atopic dermatitis and acne vulgaris? Are we really seeing an increased incidence of adultonset atopic dermatitis or is this a situation of diagnostic confusion? Finally, my daughter (who is a veterinary dermatologist) would never forgive me if I failed to mention the omission of any discussion of atopic dermatitis in animals. She spends a considerable portion of her professional time trying to reduce the suffering of atopic dogs. Interestingly, the veterinary approach to atopy more closely resembles that of human allergists than of human dermatologists; perhaps we human dermatologists could pick up some useful pointers from these two disciplines.

In contrast to these “omissions,” the first and the last chapters of the book are unexpected treats. Chapter 1, “The History of Eczema and Atopic Dermatitis,” provides an extensive overview of how medical thinking about this disorder evolved and chronicles the all-too-common terminological confusion it engendered. Figure 1.5, which shows a one-sided response in an atopic infant to unilateral application of hydroEdited by Rudikoff D, cortisone, from the 1954 publiCohen SR, Scheinfeld N cation by Witten and colleagues,1 Boca Raton, FL: CRC Press; 2014: 456 pages. brought back some fond personal $159.96 memories of spending time in Dr Victor Witten’s (1916–2007) clinic as a lowly dermatology resident and of the numerous dermatologic admissions to Jackson Memorial Hospital in Miami, which resulted in paired comparison topical treatments. Chapter 24, “Legal Aspects of Atopic Dermatitis,” presents material of very practical importance to clinicians handling these cases. I would hope to see similar chapters become the norm in clinical treatises. Kudos to Drs Rudikoff, Cohen, and Scheinfeld for pulling together the considerable talent and experience of the contributors to this work. Although some aspects of its subject (eg, etiology and pathogenesis) may need occasional updating, and, hopefully, treatment options will evolve and improve, the book represents the high water mark of our current understanding of this complex and sometimes frustrating condition. If you provide care to individuals who are atopic, you will want this volume at your side. Reference 1 Witten VH, Amler AB, Sulzberger MB, Desanctis AG. Hydrocortisone ointment in the treatment of infantile eczema. AMA Am J Dis Child. 1954;87:298–304.

Reviewed by Robert J. Pariser, MD, Professor of Dermatology, Eastern Virginia Medical School, 700 West Olney Road, Norfolk, VA 23507 • E-mail: rpariser@gmail.com

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IMPORTANT INFORMATION ABOUT

SOOLANTRA®

(ivermectin) Cream, 1% BRIEF SUMMARY This summary contains important information about SOOLANTRA (soo lan’ trah) Cream. Read this information carefully before you prescribe SOOLANTRA Cream. For full Prescribing Information and Patient Information please see the package insert. WHAT IS SOOLANTRA CREAM? SOOLANTRA Cream is a topical prescription medicine indicated for the treatment of the inflammatory lesions of rosacea. WHO IS SOOLANTRA CREAM FOR? SOOLANTRA Cream is indicated for people with inflammatory lesions of rosacea. It is not known if SOOLANTRA Cream is safe and effective for children. Advise your patients to not use SOOLANTRA Cream for a condition for which it was not prescribed and remind them to not give SOOLANTRA Cream to other people, even if they have the same symptoms as it may harm them. WHAT SHOULD I ASK MY PATIENTS BEFORE PRESCRIBING SOOLANTRA CREAM? Before you prescribe SOOLANTRA Cream, ask your patients if they: • have any other medical conditions. • are pregnant or planning to become pregnant. It is not known if SOOLANTRA Cream can harm an unborn baby. • are breastfeeding or plan to breastfeed. It is not known if SOOLANTRA Cream passes into breast milk and if it can harm a baby.

SOOLANTRA Cream is supplied in a child-resistant capped tube. • To open, gently press down on the child resistant cap and twist counterclockwise. To avoid spilling, do not squeeze the tube while opening or closing. • To close, gently press down on the child resistant cap and twist clockwise. WHAT ARE THE INGREDIENTS IN SOOLANTRA CREAM? Active ingredient: ivermectin. Inactive ingredients: carbomer copolymer type B, cetyl alcohol, citric acid monohydrate, dimethicone, edetate disodium, glycerin, isopropyl palmitate, methylparaben, oleyl alcohol, phenoxyethanol, polyoxyl 20 cetostearyl ether, propylene glycol, propylparaben, purified water, sodium hydroxide, sorbitan monostearate, and stearyl alcohol. WHERE SHOULD I GO FOR MORE INFORMATION ABOUT SOOLANTRA CREAM? • This Brief Summary summarizes the most important information about SOOLANTRA Cream. For full Prescribing Information and Patient Information please see the package insert. • Go to www.soolantra.com or call 1-866-735-4137

Trademarks are the property of their respective owners. GALDERMA LABORATORIES, L.P., Fort Worth, Texas 76177 USA Revised: December 2014

WHAT ARE THE MOST COMMON SIDE EFFECTS OF SOOLANTRA CREAM? The most commonly reported side effects when using SOOLANTRA Cream include skin burning sensation and skin irritation. Remind your patients to tell you if they have any side effect that bothers them or that does not go away. These are not all of the possible side effects of SOOLANTRA Cream. For more information, see the full Prescribing Information. You are encouraged to report negative side effects of prescription drugs to the FDA at www.fda.gov/medwatch or call 1-800-FDA-1088. You may also contact GALDERMA LABORATORIES, L.P. AT 1-866-735-4137. HOW SHOULD PATIENTS USE SOOLANTRA CREAM? • SOOLANTRA Cream is for use on the face only and should not be used in the eyes, mouth, or vagina. • SOOLANTRA Cream should be applied to the affected areas of the face once a day. APPLYING SOOLANTRA CREAM: • A pea-sized amount of SOOLANTRA Cream should be applied to each area of the face (forehead, chin, nose, each cheek) that is affected. Avoid contact with the lips and eyes.

References: 1. Stein Gold L, Kircik L, Fowler J, et al; Ivermectin Phase III Study Group. Efficacy and safety of ivermectin 1% cream in treatment of papulopustular rosacea: results of two randomized, double-blind, vehicle-controlled pivotal studies. J Drugs Dermatol. 2014;13(3):316-323. 2. Data on file. Galderma Laboratories, L.P. 3. Taieb A, Ortonne JP, Ruzicka T, et al; Ivermectin Phase III Study Group. Superiority of ivermectin 1% cream over metronidazole 0.75% cream in treating inflammatory lesions of rosacea: a randomized, investigator-blinded trial. Br J Dermatol. In press.

TREATING INFLAMMATORY LESIONS OF ROSACEA CAN BE TOUGH…

INTRODUCING

A TOUGH TOPICAL NEW SOOLANTRA® (ivermectin) CREAM, 1%—POWERFUL AND RAPID RESULTS FROM A ONCE-DAILY TOPICAL1,2*† • –20.5 (–64.9%) mean inflammatory lesion count reduction at week 122*† • Better efficacy from once-daily Soolantra Cream, 1% vs twice-daily metronidazole 0.75% cream as early as 3 weeks3‡ • Specifically formulated for patients with inflammatory lesions of rosacea—Cetaphil® Moisturizing Cream was the basis for the vehicle2

www.soola n t ra .com/h cp Important Safety Information Indication: SOOLANTRA® (ivermectin) Cream, 1% is indicated for the treatment of inflammatory lesions of rosacea. Adverse Events: In clinical trials with SOOLANTRA® Cream, 1% the most common adverse reactions (incidence ≤1%) included skin-burning sensation and skin irritation. Warnings/Precautions: Not for oral, ophthalmic, or intravaginal use. You are encouraged to report negative side effects of prescription drugs to the FDA. Visit www.fda.gov/medwatch or call 1-800-FDA-1088. Please see brief summary of Prescribing Information on adjacent page. * The efficacy and safety of SOOLANTRA® Cream, 1% once daily was evaluated in subjects aged ≥18 years in 2 identically designed phase 3 clinical trials (N=1371). Final results were comparable between the 2 studies, with the least favorable results presented here. † A phase 3, multicenter, randomized, double-blind, 12-week, vehicle-controlled, parallel-group study assessing the efficacy and safety of SOOLANTRA® Cream, 1% once daily in 683 subjects with moderate to severe papulopustular rosacea (Investigator Global Assessment [IGA] score of 3 or 4). ‡ An investigator-blinded, multicenter, randomized, parallel-group study comparing the efficacy and safety of SOOLANTRA® Cream, 1% once daily with metronidazole 0.75% cream twice daily in 962 subjects with moderate to severe papulopustular rosacea (IGA score of 3 or 4) over a 16-week treatment period.