September/October 2010 • Volume 8 • Issue 5skinmedjournal.com/skinmed_v8i5_l.pdf · otrichosis:...

September/October 2010 • Volume 8 • Issue 5

EDITORIALGranuloma Annulare: Not as Simple as It Seems

Parish and Witkowski

ORIGINAL CONTRIBUTIONSAllergic Contact Dermatitis:

Patch Testing Results at Mount Sinai Medical CenterYoo, Naami, Markowitz, and Hadi

The Frequency of Skin Diseases Among Students in a University Clinic

Ertam, Babur, Unal, and Alper

REVIEWSDermatoscopy: An Overview—Part I:

Nonmelanocytic LesionsLee and Hirokawa

Sporotrichosis: Part IISchechtman

COMMENTARYTraditional/Ayurvedic Pharmacotherapy

for Skin DiseasesSehgal and Srivastava

DEPARTMENTSPeRILS OF DeRMATOPAThOLOGy

Pseudomelanomas, Pseudo-pseudomelanomas, and Pseudometastasizing Pseudomelanomas

Sarkissian, Maghari, Rojas, and Lambert

SURGICAL CAPSULeSSurgical Management of Cylindromatosis

Humphreys

INFeCTIOUS DISeASe CAPSULeSA Fungus Among Us

Siddiqui, Bernstein, and Polenakovik

hISTORICAL VIGNeTTeDavid Gruby 1810–1898:

Unveiling of a Portrait Bust in his BirthplaceHolubar and Wikonkál

PhOTO CAPSULeSLupus Vulgaris in an hIV-Positive Patient

Dlova

CASE STUDIESKeloid Formation Occurring in the Distribution

of a Congenital Vascular MalformationMandrell, Youker, Allen, Hurley, and Obadiah

Psoriasis Triggered by MefloquinePace

Tropical Aquarium Aquatic Dermatoses: Bristle Worm envenomation

Kay, Bak, and Kay

Purpuric Nodules and Macules on the Scalp of an 18-Month-Old Boy

Malbora, Senel, Avci, and Ozbek

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TABLE OF CONTENTSSeptember/October 2010 • Volume 8 • Issue 5

eDITORIAL

Granuloma Annulare: Not as Simple as It Seems .......................................................................................... 255 Lawrence Charles Parish, MD, MD (Hon); Joseph A. Witkowski, MD

ORIGINAL CONTRIBUTIONS

Allergic Contact Dermatitis: Patch Testing Results at Mount Sinai Medical Center ......................................... 257 Jane Y. Yoo, MD, MPP; Munera Al Naami, MD; Orit Markowitz, MD; Suhail M. Hadi, MD, MPhil

The Frequency of Skin Diseases Among Students in a University Clinic ......................................................... 261 Ilgen Ertam, MD; Yesim Babur, MD; Idil Unal, MD; Sibel Alper, MD

ReVIeWS

Dermatoscopy: An Overview—Part I: Nonmelanocytic Lesions ...................................................................... 265 Jason B. Lee, MD; Dawn Hirokawa, MD, MPH Self-Test Review Questions (p. 273)

Sporotrichosis: Part II.................................................................................................................................. 275 Regina Casz Schechtman, MD, PhD

COMMeNTARy

Traditional/Ayurvedic Pharmacotherapy for Skin Diseases ........................................................................... 282 Virendra N. Sehgal, MD; Govind Srivastava, MD

DePARTMeNTS

Perils of DermatoPathologyW. Clark Lambert, MD, PhD, Section Editor

Pseudomelanomas, Pseudo-pseudomelanomas, and Pseudometastasizing Pseudomelanomas ...................... 285 Navér Sarkissian, MD, PhD; Amin Maghari, MD; Javier Rojas, MD; W. Clark Lambert, MD, PhD

surgical caPsulesTanya Humphreys, MD, Section Editor

Surgical Management of Cylindromatosis .................................................................................................... 289 Tanya Humphreys, MD

infectious Disease caPsulesJack M. Bernstein, MD, Section Editor

A Fungus Among Us .................................................................................................................................... 291 Abdul R. Siddiqui, MD; Jack M. Bernstein, MD; Hari Polenakovik, MD

September/October 2010 TABLE OF CONTENTS

250

DePARTMeNTS (continued)

historical VignetteCharles Steffen, MD, Section Editor

David Gruby 1810–1898: Unveiling of a Portrait Bust in His Birthplace ......................................................... 294 Karl Holubar, MD, FRCP, FRSM, GSE; Norbert Wikonkál, MD

Photo caPsulesNcoza C. Dlova, MBChB, FCDerm, Section Editor

Lupus Vulgaris in an HIV-Positive Patient ...................................................................................................... 296 Ncoza C. Dlova, MBChB, FCDerm

CASe STUDIeSVesna Petronic-Rosic, MD, MSc, Section Editor

Keloid Formation Occurring in the Distribution of a Congenital Vascular Malformation................................... 298 Joshua Mandrell, MD; Summer Youker, MD; Erin J. Allen, MD; Maria Yadira Hurley, MD; Joseph Obadiah, MD

Psoriasis Triggered by Mefloquine ............................................................................................................... 301 Joseph L. Pace, MD, FRCPEdin, FRCPLond

Tropical Aquarium Aquatic Dermatoses: Bristle Worm Envenomation ............................................................ 303 Martin H. Kay, MD, PhD; Rachel D. Bak, MD; David N. Kay, BA

Purpuric Nodules and Macules on the Scalp of an 18-Month-Old Boy ............................................................ 305 Baris Malbora, MD; Engin Senel, MD; Zekai Avci, MD; Namik Ozbek, MD

BOOK ReVIeWNoah S. Scheinfeld, MD, JD, Section Editor

The New Ideal in Skin Health: Separating Fact From Fiction .......................................................................... 307

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September/October 2010 Volume 8 • Issue 5

252

Mohamed Amer, MDCairo, Egypt

Robert L. Baran, MDCannes, France

Anthony V. Benedetto, DOPhiladelphia, PA

Brian Berman, MD, PhDMiami, FL

Jack M. Bernstein, MDDayton, OH

Sarah Brenner, MDTel Aviv, Israel

Joaquin Calap Calatayud, MDCadiz, Spain

Henry H.L. Chan, MB, MD, PhD, FRCPHong Kong, China

Noah Craft, MD, PhD, DTMHTorrance, CA

Ncoza C. Dlova, MBChB, FCDermDurban, South Africa

Richard L. Dobson, MDMt Pleasant, SC

William H. Eaglstein, MDPalo Alto, CA

Boni E. Elewski, MDBirmingham, AL

Charles N. Ellis, MDAnn Arbor, MI

Howard A. Epstein, PhDGibbstown, NJ

Ibrahim Hassan Galadari, MD, PhD, FRCPDubai, United Arab Emirates

Anthony A. Gaspari, MDBaltimore, MD

Michael Geiges, MD Zurich, Switzerland

Michael H. Gold, MDNashville, TN

Orin M. Goldblum, MDAbbott Park, IL

Lowell A. Goldsmith, MD, MPHChapel Hill, NC

Aditya K. Gupta, MD, PhD, FRCP(C)London, Ontario

Seung-Kyung Hann, MD, PhDSeoul, Korea

Roderick J. Hay, BCh, DM, FRCP, FRCPathLondon, UK

Tanya R. Humphreys, MDPhiladelphia, PA

Camila K. Janniger, MDEnglewood, NJ

Abdul-Ghani Kibbi, MDBeirut, Lebanon

Andrew P. Lazar, MDHighland Park, IL

Jasna Lipozencic, MD, PhDZagreb, Croatia

George M. Martin, MDKihei, HI

David I. McLean, MDVancouver, British Columbia

Marc S. Micozzi, MD, PhDBethesda, MD

George F. Murphy, MDBoston, MA

Oumeish Youssef Oumeish, MD, FRCPAmman, Jordan

Joseph L. Pace, MD, FRCPNaxxar, Malta

Art Papier, MDRochester, NY

Vesna Petronic-Rosic, MD, MScChicago, IL

Johannes Ring, MD, DPhilMunich, Germany

Roy S. Rogers III, MDRochester, MN

Donald Rudikoff, MDNew York, NY

Robert I. Rudolph, MDWyomissing, PA

Vincenzo Ruocco, MDNaples, Italy

Noah S. Scheinfeld, MD, JDNew York, NY

Virendra N. Sehgal, MDDelhi, India

Charles Steffen, MDOceanside, CA

Alexander J. Stratigos, MDAthens, Greece

James S. Studdiford III, MDPhiladelphia, PA

Robert J. Thomsen, MDLos Alamos, NM

Julian Trevino, MDDayton, OH

Snejina Vassileva, MD, PhDSofia, Bulgaria

Daniel Wallach, MDParis, France

Michael A. Waugh, MB, FRCPLeeds, UK

Wm. Philip Werschler, MDSpokane, WA

Joseph A. Witkowski, MDPhiladelphia, PA

Ronni Wolf, MDRechovot, Israel

eDITOR IN ChIeF

eDITORIAL BOARD

DePUTy eDITORS

William Abramovits, MDDallas, TX

W. Clark Lambert, MD, PhDNewark, NJ

Larry e. Millikan, MDMeridian, MS

Jennifer L. Parish, MDPhiladelphia, PA

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

Marcia Ramos-e-Silva, MD, PhDRio de Janeiro, Brazil

Power made personal©2010 Merz Pharmaceuticals All rights reserved. 5/10

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Naftin® Cream and Gel are contraindicated in individuals who have shown hypersensitivity to any of their components and are for topical use only.

During clinical trials with Naftin® Cream and Gel, the following side effects were most commonly reported: burning/stinging, dryness, erythema, itching, local irritation, skin tenderness and rash.

Please see brief summary on the following page.

For the fungicidal power you trust, turn to Naftin® (naftifi ne HCl 1%).Designed to suit a range of patients and preferences, Naftin® delivers power against tinea pedis, cruris and corporis. Choose Naftin® Gel, Naftin® Cream, or the innovative Naftin® Cream Pump and give your patients the customized care they deserve.

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SkinMed7-10.indd 1 6/3/10 3:20 PM


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

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INDICATIONS AND USAGE: Naftin® Cream, 1% is indicated for the topical treatment of tinea pedis, tinea cruris, and tinea corporis caused by the organisms Trichophyton rubrum, Trichophyton mentagrophytes, and Epidermophyton floccosum. Naftin® Gel, 1% is indicated for the topical treatment of tinea pedis, tinea cruris, and tinea corporis caused by the organisms Trichophyton rubrum, Trichophyton mentagrophytes, Trichophyton tonsurans*, Epidermophyton floccosum*. *Efficacy for this organism in this organ system was studied in fewer than 10 infections. CONTRAINDICATIONS: Naftin® Cream and Gel, 1% are contraindicated in individuals who have shown hypersensitivity to any of their components.

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255SKINmed. 2010;8:255–256 © 2010 Pulse Marketing & Communications, LLC

From the Department of Dermatology and Cutaneous Biology, Jefferson Center for International Dermatology, Jefferson Medical College of Thomas Jefferson University;1 and the Department of Dermatology, University of Pennsylvania School of Medicine,2 Philadelphia, PAAddress for Correspondence: Lawrence Charles Parish, MD, MD (Hon), 1760 Market Street, Suite 301, Philadelphia, PA 19103 • E-mail: [email protected]

Granuloma annulare (GA), the ringed eruption, has also been termed lichen annularis and heloderma simplex et annularis, just to recount a few of the names for this

“deeply seated nodule or a ring of closely grouped nodules of firm consistency, elevated, sharply circumscribed, whitish, pinkish, red-dish, purplish or bluish red in color.” This is a description, presented by Ormsby and Montgomery in their definitive text of more than a half century ago.1 When first delineated in 1895 by T. Colcott Fox in London as a ringed eruption, GA was considered either of unknown cause or due to a tubercular infection.2 Despite decades of investigations, its etiology continues to remain obscure, even today.

Our reasons for discussing this morphologically distinct entity with vague etiology and pathogenesis are due to some recent un-usual findings. A discussion of the traditional differential diag-noses of erythema elevatum diutinum and necrobiosis lipoidica diabeticorum would add little to our knowledge; however, a middle-aged man with stasis dermatitis and even elephantiasis raised our curiosity, when a cutaneous biopsy demonstrated GA among the areas, manifesting diffuse redness and thickening. Was this a coincidence or part of a dermatitis (Figure 1)? Could the diffuse presentation represent a Koebner phenomenon?

GA AND OTheR DISeASeS

GA has been linked with a number of diseases. For example, there are case reports of its association with prostate carcinoma, breast malignancies, pulmonary adenocarcinoma, and cervical adenocar-cinoma.3 GA has been found in patients with lymphomas, includ-ing Hodgkin’s disease, mycosis fungoides, and lymphoepithelioid cell lymphoma (Lennert’s lymphoma). Concerning Lennert’s lymphoma, the similarities with GA were raised due to the initial granulomatous presentation. Twenty percent of patients with lym-phomas other than mycosis fungoides have been found to have a number of cutaneous signs, ranging from erythema nodosum to urticaria, so that a granulomatous picture might not be so strange.4

There are patients with morphea and systemic scleroderma who have coexisting GA. Both diseases have vascular injuries, altered collagen, and lymphohistiocytic infiltrates. Whereas GA has fragmented col-

lagen bundles and inflammation, characterized by necrobiosis and granulomatous formation, morphea has dermal fibroblasts in excess.5

GA has been found following trauma, UV light exposure, insect bites, herpes zoster infection, mycobacterial infection, and even pressure ap-plied to the hands. The list goes on and on with little documentation to prove a cause and effect.6 GA has been found in infants as young as 68 days,7 while senior citizens infrequently are afflicted.

ADDITIONAL CONSIDeRATIONS

What is the pathogenesis of GA? No infectious origin has ever been confirmed. Periodically, the question of its being an

eDITORIAL

Granuloma Annulare: Not as Simple as It SeemsLawrence Charles Parish, MD, MD (Hon);1 Joseph A. Witkowski, MD2

Figure 1. A 47-year-old man developed dermatitis on both legs. While the stasis dermatitis diagnosis seemed a reasonable clinical diagnosis, the dermatopathology revealed granuloma annulare.

September/October 2010 EDITORIAL

256SKINmed. 2010;8:255–256 Granuloma Annulare: Not as Simple as It Seems

inherited disease is raised. Some have suggested that allergic con-tact dermatitis reactions might precipitate GA.8 Fortunately, GA seems to have escaped the strange fables of etiology that have plagued sarcoidosis—pine tree pollen.

Categorizing GA into various types: localized (Figure 2), general-ized (Figure 3), papular, subcutaneous, or even granuloma mul-tiforme contributes little to the understanding of this condition. There are no internal manifestations, and rarely does it involve the face. A review of the histopathologic picture of pallisading granulomas and necrobiosis does not make the background of this ringed eruption any clearer.9

Various treatments have been suggested but none can give posi-tive results for a pharmacologic proof. These might be consid-ered in the eras in which they were proposed: arsenic adminis-tered by mouth, salicylic acid ointment, tuberculin injections, carbon dioxide snow, and radiation. A more contemporary ap-proach would include topical corticosteroids, intralesional cor-ticosteroids, oral antihistamines, psoralen–UV-A, cyclosporine, pentoxifylline, isotretinoin, fumaric acid, and topical immuno-modulators. To add to the muddle, performing a biopsy some-times results in clearing of the lesions.

CONCLUSIONS

GA continues to remain an enigma with revelations lacking about its cause and, more importantly, effective treatment. The patient can be reassured that the disease is self-limiting, but GA has been known to last at least 34 years.

As to its association with stasis dermatitis, it is most likely a co-incidence. The facts remain that patients with GA usually do not have other strange diseases.6

ReFeReNCeS

1 Ormsby OS, Montgomery H. Diseases of the Skin. 8th ed. Phila-delphia, PA: Lea & Febiger: 1954.

2 Pringle J. Thomas Colcott Fox. Br J Dermatol. 1916;28:93–101.3 Vassileva S, Krasteva M, Marina S, et al. Widespread granu-

loma annulare and cervical adenocarcinoma. Int J Dermatol. 1992;31:819.

4 Bhushan M, Craven NM, Armstrong GR, et al. Lymphoepitheli-oid cell lymphoma (Lennert’s lymphoma) presenting as atypical granuloma annulare. Br J Dermatol. 2000;142:776–780.

5 Ben-Amitai D, Hodak E, Lapidoth M, et al. Coexisting morphoea and granuloma annulare —are the conditions related? Clin Exp Dermatol. 1999;24:86–89.

6 Dahl MV. Speculations on the pathogenesis of granuloma an-nulare. Australas J Dermatol. 1985;26:49–57.

7 Choi JC, Bae JY, Cho S, et al. Generalized perforating granulo-ma annulare in an infant. Pediatr Dermatol. 2003;20:131–133.

8 Stransky L. Contact granuloma anulare. Dermat Beruf Umwelt. 1990;38:162–163.

9 Magro CM, Crowson AN, Regauer S. Granuloma annulare and necrobiosis lipoidica tissue reactions as a manifestation of sys-temic disease. Hum Pathol. 1996;27:50–56.

Figure 2. The erythematous ringed lesion of granuloma an-nulare can appear alone.

Figure 3. Generalized granuloma annulare of several years’ duration in a middle-aged woman.



From the Department of Dermatology, Mount Sinai Medical Center, New York, NYAddress for Correspondence: Suhail Hadi, MD, MPhil, Department of Dermatology, Mount Sinai Medical Center, 5 East 98th Street, Fifth Floor, Box 1048, New York, NY 10029-6574 • E-mail: [email protected]

Patch testing remains a valuable technique in the diagno-sis of allergic contact dermatitis. Ongoing analysis of our patch testing reaction rates allows for the surveillance of

emerging trends in our patch test population.

As a cell-mediated hypersensitivity reaction occurring in the skin, allergic contact dermatitis (ACD) is mediated by antigen-specific T lymphocytes. To develop ACD, an individual must first be sen-sitized by an allergen of low molecular weight (<1000 Da) that can readily penetrate the stratum corneum.1 Since these chemicals are often too small to elicit an immunologic response on their own, they associate themselves with other proteins in the skin, thus for-mulating a hapten-protein antigen complex that may be recog-nized by certain immune cells. Langerhans cells, the professional antigen-presenting dendritic cells residing in the epidermis, pro-cess and uptake the antigen and present it to naïve T cells, which, in turn, produce two clonal populations of cells: antigen-specific effector and memory T cells. Upon an individual’s re-exposure to the specific allergen, Langerhans cells bearing the antigen interact with antigen-specific T lymphocytes circulating in the skin. This elicits an inflammatory response through the release of cytokines and other potent mediators, ultimately resulting in varying de-grees of erythema, edema, and vesiculation in patients.

Patch testing is an important diagnostic tool commonly used to identify allergens responsible for ACD. It is useful when ACD is clinically suspected and when the diagnosis is not readily ap-parent.2,3 Once the suspected allergen is identified, appropriate

measures can be taken, such as avoidance or eradication from the patient’s immediate environment. In addition, patch testing is indicated in cases where inflammation persists, despite avoid-ance of the offending allergen and topical treatment.4 Here we present an updated report on the most common allergens pres-ent in our patient population who underwent patch testing be-tween the period of 2004–2008.

MeThODS

We report patch testing results conducted at Mount Sinai’s De-partment of Dermatology between 2004 and 2008. Four hun-dred thirty-four patients (86 men, 348 women) with suspected ACD were evaluated and patch tested with a screening series of 50 baseline allergens from the NAC-80 North American Com-prehensive Series from Dormer Laboratories (Toronto, ON). Pa-tients’ ages ranged from 25 to 75 years. Patients were patch test-ed using standard patch testing technique with Finn Chambers (Epitest Ltd Oy; Tuusula, Finland) on Scanpor tape (Norges-plaster Alpharma A/S, Vennesla, Norway).5–7 The patches were left in place for 48 hours, and readings were performed at 48 and 96 hours. A positive patch test reaction was reported as 1+, 2+, or 3+ based on the manifestation of erythematous papules, vesicles, or spreading reaction with crust and ulceration.

ReSULTS

Our results, along with results from the North American Contact Dermatitis Group (NACDG) and the Mayo Clinic, are presented

ORIGINAL CONTRIBUTION

Allergic Contact Dermatitis: Patch Testing Results at Mount Sinai Medical Center

Jane Y. Yoo, MD, MPP; Munera Al Naami, MD; Orit Markowitz, MD; Suhail M. Hadi, MD, MPhil

ABSTRACT

Patch testing is an important diagnostic tool commonly used to identify allergens responsible for allergic contact dermatitis, especially in cases where the diagnosis is not clearly apparent. The authors report the patch test results from 2004–2008 and compare the results with the North American Contact Dermatitis Group and Mayo Clinic. Four hundred thirty-four patients with suspected allergic contact dermatitis underwent standardized patch testing with a tray consisting of 50 allergens at Mount Sinai Medical Center. Two hundred ninety patients (66.8%) had posi-tive reactions to at least one allergen. The most frequent contact allergens included nickel sulfate (13%), fragrance mix (9.6%), propylene glycol (7.8%), neomycin sulfate (6.6%), thimerosal (6.4%), bacitracin (6.2%), and sodium gold thiosulfate (5.8%). (SKINmed. 2010;8:257–260)

September/October 2010 ORIGINAL CONTRIBUTION

258SKINmed. 2010;8:257–260 Allergic Contact Dermatitis

in the Table. In our sample, 290 patients (66.8%) had a positive reaction to at least one allergen. The most frequent contact aller-gens included nickel sulfate (13%), fragrance mix (9.6%), propyl-ene glycol (7.8%), neomycin sulfate (6.6%), thimerosal (6.4%), bacitracin (6.2%), and sodium gold thiosulfate (5.8%).

DISCUSSION

We compared our results with that of the most recent study con-ducted by the NACDG and the Mayo Clinic. The NACDG conducted a study in 2005–2006 of 4454 patients in which they found 2907 (65.3%) of patients had at least one allergic patch test reaction.8 The most frequent contact allergens were nickel sulfate (19%), balsam of peru (myroxylon pereirae) (11.9%), fragrance mix (11.5%), neomycin sulfate (10%), quaternium-15 (10.3%), bacitracin (9.2%), and cobalt (II) chloride hexahydrate (8.4%). The Mayo Clinic conducted a retrospective review of 3854 pa-tients from 2001–2005 in which 2664 (69.1%) patients were found to have at least one positive reaction.9 The most frequent contact allergens were dermatophagoides mix 20% (27.4%), nick-el sulfate (17.1%), balsam of peru (myroxylon pereirae) (13.7%), gold sodium thiosulfate (13.5%), neomycin sulfate (11.8%), fra-grance mix (11.3%), and thimerosal (10.5%).

The prevalence of positive patch test reactions (66.8%) is consis-tent with the findings from the NACDG (65.3%) and the Mayo Clinic (69.1%). While the percentage of positive reactions for each allergen was consistently lower as compared with the NACDG and Mayo Clinic, this may have been a result of our small sample size. The patients who underwent patch testing between 2004 and 2008 underwent testing with a tray of 50 chemicals as opposed to the 65 chemicals tested by the NACDG and Mayo Clinic. The additional 15 allergens that were tested by the two groups were found to produce positive reactions in less than 2% of the speci-fied populations. While increasing the number of antigens in a tray has been known to yield more positive reactions,10 it is important to determine the clinical relevance of these positive reactions. In one study, a standard tray with 65 allergens failed to detect ACD in 50.2% of patients.10 Therefore, testing for additional allergens beyond a standard series may be of great benefit when taking into consideration a patient’s history and environmental exposures.

Prior studies have consistently reported nickel sulfate hexahy-drate, neomycin sulfate, fragrance mix, and balsam of Peru as common sensitizers.8,11–14 According to the NACDG, the fre-quency of positive patch test reactions to nickel continues to rise with time and persists to be the most frequently positive antigen.8 In this small study, nickel was reported to have the highest number of positive reactions, although the percentage of individuals with a positive reaction to this allergen was less com-pared with the NACDG and Mayo Clinic. As the most common

allergen detected by patch test patients in the United States and as a major contact allergen in the world, there is strong evidence that its prevalence is rising.15 According to a recent report, nickel allergy is highest among women and patients younger than 18, affecting 35.8% of patch-tested patients in this demographic.16 Some countries in Europe, such as Denmark, have sought to regulate the release of nickel in consumer products, thus result-ing in a decrease in prevalence of this allergy.17

Fragrance allergy was the second common sensitizer. Fragrance allergy is consistently one of the most frequent patch test re-actions reported by the NACDG, and there is some evidence that fragrance sensitization increases with age.18–20 Fragrances are widely found in perfumes, cosmetics, and other skin care products. The 8 constituents of fragrance mix I (all at 1%) in-clude Evernia prunastri (oak moss) extract, isoeugenol, eugenol, cinnamal, hydroxcitronellal, geraniol, cinnamyl alcohol, and amyl cinnamal. In 2005, a new fragrance mix was presented. The constituents of fragrance mix II include citronellol 0.5%, hydroxyisohexyl 3-cyclohexne carboxaldhyde (Lyral) 2.5%, hex-yl cinnamal 5%, citral 1%, coumarin 2.5%, and farnsol 2.5%. One study found that 35% of individuals had positive reactions to fragrance mix II and negative reactions to fragrance mix I.21

Neomycin sulfate and bacitracin were also common allergens in our patient population. While bacitracin was reported as a fre-quently positive allergen by the NACDG, neomycin sulfate was a common allergen presented by the Mayo Clinic. Neomycin sulfate and bacitracin are antibacterial agents that may be found in topical creams, ointments, and lotions and are used to treat a variety of skin, eye, and external ear infections. These two anti-biotics are often paired in over-the-counter preparations because together they provide coverage against gram-positive cocci and aerobic gram-negative bacteria. There is evidence that ACD as-sociated with these agents is becoming an increasing problem in postoperative wound care.22 As a result, white petrolatum may be a preferable alternative topical agent.

Thimerosal elicited a frequently positive reaction in our popula-tion and in the Mayo Clinic population. Thimerosal is a mercuric derivative used as a preservative in vaccines, ophthalmic and nasal products, and even tattoo inks. While 6.4% of our patients were positive for thimerosal, 10.5% of patients at the Mayo Clinic were positive for this allergen. There have been some reports that the reaction with thimerosal may lack relevance, as this allergen may not be responsible for contact allergy. Therefore, thimerosal has been removed from many standard screening series.23,24

Likewise, gold sodium thiosulfate elicited a positive reaction in both our population and the Mayo Clinic. Gold is often found in jewelry, dental implants, and even intracoronary stents. A recent



investigation reported a correlation between contact allergy to gold and a gold concentration in the blood of patients with stents.25 As an increasing number of people with cardiovascular disease un-dergo stent procedures, it is important to note that metals such as gold can elicit a contact allergy in this population.

Propylene glycol was a frequent sensitizer unique to our patient population. Propylene glycol acts as a solvent, moisturizer, and emulsification agent for medicines, food, cosmetics, and other products. One retrospective study using the NACDG data iden-tified the most common sources of this allergen: 53.8% were

Table. Allergic Reactions to Tested Substances

allergen

mssm (2004–2008), % (no.)

nacDg (2005–2006), %

mayo clinic (2001–2005), %

2.5% Nickel sulfate 13 (57) 19 17.1

8% Fragrance mix 9.6 (42) 11.5 11.3

30% Propylene glycol 7.8 (34) 2.9 Not tested

20% Neomycin sulfate 6.6 (29) 10 11.8

0.1% Thimerosol 6.4 (28) Not tested 10.5

20% Bacitracin 6.2 (27) 9.2 8.1

0.5% Sodium gold thiosulfate 5.8 (25) Not tested 13.5

1% Cobalt chloride 5 (22) 8.4 10.3

2.5% 12 Methyldibromo-glutaronitrile/phenoxyethanol (Euxyl K-400) 4.6 (20) 5.8 6.1

25% Balsam of Peru 4.6 (20) 11.9 13.7

1% Formaldehyde 3.6 (16) 9 9.0

3% Carba mix 3.4 (15) 3.9 4.6

0.25% Potassium dichromate 3.2 (14) 4.8 6.7

2% Quaternium-15 2.8 (12) 10.3 8.1

1% Paraphenylendiamine 2.5 (11) 5 4.5

2% Methyl methacrylate 2.3 (10) 1 1.4

0.1% Sesquiterpene lactone mix 1.8 (8) 0.7 0.9

0.5% 2-Bromo-2-nitropropane-1,3-diol (Bronopol) 1.8 (8) 3.4 2.1

0.01% 5-Chloro-methyl-4-isothiazolin-3-one (KathonCG) 1.8 (8) 2.8 3

1% Thiuram mix 1.8 (8) 3.9 3.3

20% Colophony 1.6 (7) 2.2 2.6

12% Paraben mix 1.4 (6) 1.2 1.7

1% Cinnamic aldehyde 0.9 (4) 3.1 2

1% 4-Chloro-3,5-xylenol (PCMX) 0.9 (4) 0.5 0.7

1% 4-tert-Butylphenolformaldehyde resin 0.9 (4) 1.3 2

1% 2, 5 Diazolidinylurea (Germall II) 0.9 (4) 3.7 3.5

2% Imidazolidinyl urea (Germall 115) 0.9 (4) 2.9 2.8

0.01% Budesonide 0.9 (4) 1.5 1.5

0.1% Tixocortal-21-pivalate 0.6 (3) 2.7 3

5% Benzocaine 0.6 (3) 1.9 1.5

Abbreviations: MSSM, Mount Sinai School of Medicine; NACDG, North American Contact Dermatitis Group.



found in personal care products (creams, lotions, and cosmetics), 18.3% in topical corticosteroids, and 10.1% were found in other topical medications.26

Although most studies reported balsam of Peru as a common sensitizer, it elicited a reaction in only 4.6% of our patients. This was unusual, especially given the fact that this allergen is known to have some cross-reactivity to fragrance mix due to the overlap in chemicals.27

CONCLUSIONS

Patch testing remains a valuable tool in the identification of al-lergens contributing to dermatitis. While our study was limited with regard to sample size, our results were consistent with prior large-scale studies. Regional variation and changes in exposure patterns over time, however, may contribute toward shifts in positive allergen frequency. Identifying these changing trends will serve to better guide the treatment and care of patients with suspected ACD.

ReFeReNCeS

1 Karlberg AT, Bergstrom MA, Borge A, et al. Allergic contact der-matitis—formation, structural requirements, and reactivity of skin sensitizers. Chem Res Toxicol. 2008;21:53–69.

2 Albert MR, Gonzalez S, Gonzalez E. Patch testing reactions to a standard series in 608 patients tested from 1990 to 1997 at Massachusetts General Hospital. Am J Contact Dermat. 1998;9:207–211.

3 Belsito DV. The diagnostic evaluation, treatment and prevention of allergic contact dermatitis in the new millennium. J Allergy Clin Immunol. 2000;105:409–420.

4 Habif TP. Allergic contact dermatitis. In: Clinical Dermatology: A Color Guide to Diagnosis and Therapy. Beijing, China: Mosby; 2004:84–103.

5 Marks JG, Belsito DV, DeLeo VA, at al. North American Con-tact Dermatitis Group standard tray patch test results (1992 to 1994). Am J Contact Dermat. 1995;6:160–165.

6 Marks JG, Belsito DV, DeLeo VA, et al. North American Contact Dermatitis Group patch test results for the detection of delayed-type hypersensitivity to topical allergens. J Am Acad Dermatol. 1998;38:911–918.

7 Marks JG, Belsito DV, DeLeo VA, et al. North American Contact Dermatitis Group Patch-Test Results, 1996–1998. Arch Derma-tol. 2000;136:272–273.

8 Zug KA, Warshaw M, Fowler JF, et al. Patch-test results of the North American Contact Dermatitis Group 2005–2006. Derma-titis. 2009;20:149–160.

9 Davis M, Scalf LA, Yiannias JA, et al. Changing trends and allergens in the patch test standard series. Arch Dermtol. 2008;144:67–72.

10 Saripalli YV, Achen F, Belsito DV. The detection of clinically relevant contact allergens using a standard screening tray of twenty-three allergens. J Am Acad Dermtol. 2003;49:65–69.

11 Landeck L, Schalock PC, Baden L, et al. Patch-testing with the standard series at the Massachusetts General Hospital, 1998 to 2006. Dermatitis. 2009;20:89–94.

12 Wetter DA, Davis M, Yiannias JA, et al. Patch test results from the Mayo Clinic Contact Dermatitis Group, 1998–2000. J Am Acad Dermatol. 2005;53:416–421.

13 Mohammad AH, Cohen S, Hadi S. Patch testing: a retrospective analysis of 103 patients with emphasis on practical aspects for the clinician. Skinmed. 2005;4:340–344.

14 Zug KA, Rietschel RL, Warshaw EM, et al. The value of patch testing patients with a scattered generalized distribution of der-matitis: retrospective cross-sectional analyses of North Ameri-can Contact Dermatitis Group data, 2001 to 2004. J Am Acad Dermatol. 2008;59:426–431.

15 Rietschel RL, Fowler JF, Warshaw EM, et al. Detection of nickel sensitivity has increased in North American patch-tested pa-tients. Dermatitis. 2008;19:16–19.

16 Lu LK, Warshaw EM, Dunnick CA. Prevention of nickel allergy: the case for regulation? Dermatol Clin. 2009;27:155–161.

17 Thyssen JP, Nielsen NH, Linneberg A. Nickel allergy in Dan-ish women before and after nickel regulation. N Engl J Med. 2009;360:2259–2260.

18 Schafer T, Bohler E, Ruhdorfer S, et al. Epidemiology of contact allergy in adults. Allergy. 2001;56:1192–1196.

19 Buckley DA, Rycroft RJ, White IR, et al. The frequency of fra-grance allergy in patch-tested patients increases with their age. Br J Dermatol. 2003;149:986–989.

20 Buckley DA, Rycroft RJ, White IR, et al. Fragrance as an occupa-tional allergen. Occup Med (Lond). 2002;52:13–16.

21 Frosch PJ, Rastogi SC, Pirker C, et al. Patch testing with a new fragrance mix-reactivity to the individual constituents and chemi-cal detection in relevant cosmetic products. Contact Dermatitis. 2005;52:216–225.

22 Sheth VM, Weitzul S. Postoperative topical antimicrobial use. Dermatitis. 2008;19:181–189.

23 Suneja T, Belsito DV. Thimerosal in the detection of clini-cally relevant allergic contact reactions. J Am Acad Dermatol. 2001;45:23–27.

24 Breithaupt A, Jacob SE. Thimerosal and the relevance of patch-test reactions in children. Dermatitis. 2008;19:275–277.

25 Ekqvist S, Lundh T, Svedman C. Does gold concentration in the blood influence the result of patch testing to gold? Br J Derma-tol. 2009;160:1016–1021.

26 Warshaw EM, Botto NC, Maibach HI. Positive patch test reac-tions to propylene glycol: a retrospective cross-sectional analy-sis from the North American Contact Dermatitis Group, 1996–2006. Dermatitis. 2009;20:14–20.

27 Albert MR, Chang Y, Gonzalez E. Concomitant positive reactions to allergens in a patch testing standard series from 1988–1997. Am J Contact Dermat. 1999;10:219–223.



From the Department of Dermatology, Ege University Health, Culture and Sports Office, Izmir, TurkeyAddress for Correspondence: Ilgen Ertam, MD, Ege University Medical Faculty, Department of Dermatology, 35040 Bornova-Izmir, Turkey • E-mail: [email protected]

Due to the importance of personal appearance in the university years, skin has a significant importance among the younger population. Therefore, even a slight

change on the skin in this age group directs them to seek prompt medical advice. In this case, the physician is almost always a der-matologist. Our main objective in this research was to establish the reasons why students seek medical assistance at dermatology polyclinics and determine the most frequent diagnoses.

MeThODS

University students who visited two dermatology polyclinics within the Ege University Health, Culture and Sports Office between April 2003 and March 2004 were included in the de-scriptive study. Each student was examined by two dermatolo-gists. All dermatoses were recorded. Questions about demo-graphic data and frequency of using the swimming pool were directed to the patients. Patients were asked to assess and give a score for the state of their mental wellness using the visual analog scale (0–100) during the past month. The diagnosis of fungal infection was made by direct microscopic evaluation and mycological culture.

statistical analysis

SPSS version 11.0 (SPSS Inc, Chicago, IL) was used for data analy-sis. Chi-square and Student t tests were used for statistical analyses.

ReSULTS

A total of 1733 individuals were included in the study. Of these patients, 750 (43.3%) were men and 983 (56.7%) were women. The mean age was 21.14±2.52 years (median: 21.00; minimum–maximum: 16–45 years). A total of 33.7% of the students were living with their families, 30.9% shared an apart-ment with friends, and 29.9% lived in a dormitory. The most frequently seen diseases were acne vulgaris and related diseases (40.1%), followed by fungal diseases (17.08%). Parasitic skin diseases (0.46%) and vascular diseases (0.51%) were rarely de-tected (Table). The most frequently prescribed medicines were topical antifungals (17.8%), followed by acne vulgaris–related medicines (isotretinoin and other acne medicines) (15.7%). Of all the patients visiting dermatology outpatient clinics, the number of participants who used the swimming pool was 866 (41.5%) and the number of those who never used the pool was 1220 (58.5%).

Patients assessed their state of mental wellness during the past month on a scale of 100. The mean mental wellness score was 61.03±21.34 (0–100, median: 65.00). A total of 32.6% of the students stated that they needed psychological support in the past, whereas 17.6% said that they actually received such support. The relationship of occurrence of an allergic skin dis-ease to need for receiving psychological support and actually

ORIGINAL CONTRIBUTION

The Frequency of Skin Diseases Among Students in a University Clinic

Ilgen Ertam, MD; Yesim Babur, MD; Idil Unal, MD; Sibel Alper, MD

ABSTRACT

This study was conducted to assess the frequency of dermatologic diseases in Turkish university students. University students who visited two dermatology outpatient clinics within the Ege University Health, Culture and Sports Office were included in the study. Each student was exam-ined by two dermatologists. Questions about demographic data and information about the frequency of using the swimming pool were directed to the patients. All dermatological diseases were recorded. Patients were asked to assess and give a score for the state of their mental wellness using the visual analog scale (0–100) during the past month. Chi-square and Student t tests were used for statistical analyses. A total of 1733 individu-als, 750 (43.3%) men and 983 (56.7%) women, were included in the study. The most frequently seen diseases were acne vulgaris (40.1%) and fungal diseases (17.08%), whereas the least frequently seen were parasitic skin diseases (0.46%) and vascular diseases (0.51%). The mean mental wellness score was found to be 61.03±21.34 (0–100, median: 65.00). It can be concluded that students visit university dermatology outpatient clinics frequently and the most common complaints are acne vulgaris and fungal diseases. (SKINmed. 2010;8:261–262)


262SKINmed. 2010;8:261–263 Skin Diseases Among Students in a University Clinic

receiving such psychological assistance was insignificant (P=.507 and P=.727, respectively). No statistically significant association was determined between acne and factors such as need for psychological support (P=.30) and receiving psycho-logical support (P=.24).

The relationship between fungal diseases and where students reside (such as a dormitory) was found to have no statistical significance (P=.77). Similarly, the relationship between using the swimming pool and fungal diseases was also found to be insignificant (P=.48).

DISCUSSION

We found that acne vulgaris was the most frequent complaint of the university students (40.1%). The prevalence of acne vul-garis is quite high in this age group. Because acne vulgaris leads to psychosocial problems, students in this particular age group frequently go to a physician.1–7 The second most frequently seen diseases were fungal diseases (eg, Pityriasis versicolor and Tinea pedis). The least frequently seen were parasitic skin dis-eases (0.46%) (eg, scabies and pediculosis) and vascular diseases (0.51%) (eg, cherry angiomas and telangiectasia).

Prevalence of acne vulgaris can be as high as 80% during ado-lescence. It has been reported that the frequency of acne vulgaris increased with industrialization.1 In one study,2 the frequency of acne vulgaris was reported to be 23% to 50% in adolescence, com-patible with our results. There are a lot of factors associated with acne. The relationship between acne and diet is controversial.8–11

In the present study, students were asked to score their state of mental wellness (61.03±21.34). A total of 32.6% of the patients stated that they needed help, while 17.6% said they were al-ready getting psychiatric therapy. This shows that almost half of the university students (50.2%) have anxiety and psychiatric problems. Investigators have reported that stress intensifies issues associated with acne vulgaris.5 In fact, there was no correlation between acne vulgaris and those who need psychological sup-port (P=.30) and those who were getting such assistance (P=.24). Whether stress intensifies acne vulgaris–related issues or whether acne vulgaris actually causes stress remains controversial. In gen-eral, it is believed that acne vulgaris issues lead to stress.12–14

Fungal diseases (P versicolor and T pedis) were the second most frequently encountered diseases in this study. Fungal infections were seen more frequently among male students (18.1%). The relationship between presence of a fungal disease in the family and the occurrence of fungal infections in the students them-selves was found to be significant (P=.01). This finding shows that fungal diseases can be contagious within the family.

CONCLUSIONS

Students frequently visit dermatology outpatient clinics. Acne vulgaris and fungal disorders are the most common complaints of the students. Parasitic skin diseases and vascular diseases were found to be rare in our study. Results of the present study re-vealed that almost half of the university students (50.2%) need-ed psychological support. Interestingly, there was no statistical relationship between the dermatologic diseases and psychologi-cal condition. It can be concluded that during the significant period of personal development in the college years, university students benefit from psychiatric assistance while undergoing medical therapy.

ReFeReNCeS

1 Galobardes B, Davey Smith G, Jeffreys M, McCarron P. Has acne increased? Prevalence of acne history among university students between 1948 and 1968. The Glasgow Alumni Cohort Study. Br J Dermatol. 2005;152:803–829.

2 Smithard A, Glazebrook C, Williams HC. Acne prevalence, knowl-edge about acne and psychological morbidity in mid-adolescence: a community based study. Br J Dermatol. 2001;145:274–279.

3 Kilkenny M, Merlin K, Plunkett A, Marks R. The prevalence of common skin conditions in Australian school students: 3. Acne vulgaris. Br J Dermatol. 1998;139:840–845.

4 White GM. Recent findings in the epidemiologic evidence, clas-sification, and subtypes of acne vulgaris. J Am Acad Dermatol. 1998;39:34–37.

5 Green J, Sinclair RD. Perceptions of acne vulgaris in final year medical student written examination answers. Australas J Der-matol. 2001;42:98–101.

Table: Skin Diseases of University Students

Diagnosis no. %

Acne vulgaris and related diseases 696 40.1

Fungal diseases 296 17.08

Bacterial diseases 303 17.48

Viral diseases 113 6.5

Traumatic lesions 65 3.75

Nevi 29 1.67

Allergic diseases 135 7.78

Hair diseases 41 2.36

Pigmentary diseases 18 1.03

Parasitic skin diseases 8 0.46

Vascular diseases 9 0.51

Drug reactions 20 1.15

Total 1733 100


263SKINmed. 2010;8:261–263 Skin Diseases Among Students in a University Clinic

6 Rzany B, Kahl C. Epidemiology of acne vulgaris. J Dtsch Derma-tol Ges. 2006;4:8–9.

7 Borgia F, Cannavo S, Guarneri F, et al. Correlation between en-docrinological parameters and acne severity in adult women. Acta Derm Venereol. 2004;84:201–204.

8 Wolf R, Matz H, Orion E. Acne and diet. Clin Dermatol. 2004;22:387–393.

9 Danby EW. Acne and milk, the diet myth, and beyond. J Am Acad Dermatol. 2005;52:360–362.

10 Cordain L. Implications for the role of diet in acne. Semin Cutan Med Surg. 2005;24:84–91.

11 Adebamowo CA, Spiegel D, Danby FW, et al. High school dietary in-take and teenage acne. J Am Acad Dermatol. 2005;52:207–214.

12 Smithard A, Glazerbrook C, Williams H. Acne prevalence, knowl-edge about acne and psychological morbidity in mid-adolescence: a community-based study. Br J Dermatol. 2001;145:274–279.

13 Chiu A, Chon SY, Kimball AB. The response of skin disease to stress: changes in the severity of acne vulgaris as affected by examination stress. Arch Dermatol. 2003;139:897–900.

14 Mohrenschlager M, Henkel V, Moller HJ, et al. Disturbance in the well-being of a patient with acne: suggestions for anticipation and detection. Acta Derm Venereol. 2005;85:182–183.

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From the Department of Dermatology and Cutaneous Biology, Jefferson Medical College of Thomas Jefferson University, Philadelphia, PAAddress for Correspondence: Jason B. Lee, MD, Associate Professor of Dermatology, Department of Dermatology and Cutaneous Biology, Jefferson Medical College, 833 Chestnut Street, Suite 740, Philadelphia, PA 19107 • E-mail: [email protected]

Although Paul Gerson Unna used principles of derma-toscopy as early as 1893, it was Johann Saphier, another German dermatologist, who coined the term dermatos-

kopie in 1920 while employing a binocular device with a built-in light source to study the vessels of the skin.1 In the United States, Leonard Goldman was the early pioneer who reported the use of this diagnostic technique, which he referred to as surface micros-copy, to evaluate melanocytic lesions in 1951.2 It was not until the 1980s, however, when dermatoscopy caught the attention of a broader audience. Since that time, the field of dermatology has witnessed an explosive number of publications regarding derma-toscopy, especially during the recent decade in which more than 1060 articles have been published on the subject. In Europe and Australia, the continents in which the major studies of derma-toscopy have originated during the past 2 decades, it has become the standard of care in evaluating pigmented skin lesions due in part to the wide availability of portable handheld dermatoscopes. In the United States, however, dermatoscopy is slowly gaining popularity. In 2010, approximately 50% of surveyed dermatolo-gists used a dermatoscope on a regular basis,3 a noticeable increase from only 25% in 2002.4

A dermatoscope renders the cornified layer translucent, reveal-ing subsurface structures within the epidermis and superficial dermis, providing additional morphologic criteria in diagnosing skin diseases. The widely available handheld pocket-size derma-toscopes have a light source with usually a 10-time magnifica-tion, some requiring contact with the skin while others offer-ing the option of contact and noncontact. Immersion contact dermatoscopes usually employ a halogen light bulb as a light

source, whereas polarized light dermatoscopes, which provide the option of contact and noncontact, are equipped with mul-tiple light-emitting diode (LED) light bulbs. Immersion contact dermatoscopy allows slightly better visualization of superficial structures such as milia-like structures, comedo-like openings, and blue-white veils, while polarized light dermatoscopy, either contact or noncontact, allows slightly better visualization of deeper structures such as fibrosis and vascular structures.5,6 No study exists that demonstrates a difference in diagnostic accuracy between the two different methods of dermatoscopy in the clini-cal setting; thus, a dermatoscope should be chosen based on the user’s preferences.

The initial interest in dermatoscopy in the modern era focused on its ability to improve the diagnostic accuracy of melanoma, although, of late, it has been promoted to be useful in diagnos-ing a wide range of skin diseases that includes infections, infesta-tions, and inflammatory diseases. Accordingly, there are two key objectives of dermatoscopy: (1) to decrease unnecessary harvest-ing of benign skin lesions, and (2) to increase the diagnostic ac-curacy of melanomas, especially early melanomas.7–9

Evaluation of a skin lesion with a dermatoscope involves a 2-step process (Figure 1). The first step is to determine whether the lesion is melanocytic. If the lesion is determined to be melanocytic, then the second step is to determine whether the melanocytic lesion is benign, malignant, or indeterminate using any one of the avail-able algorithms. Expert dermatoscopists have developed simpli-fied algorithms for the nonexperts, including primary care physi-cians and dermatologists, to facilitate the use of the dermatoscope.

ReVIeW

Dermatoscopy: An Overview—Part I: Nonmelanocytic Lesions

Jason B. Lee, MD; Dawn Hirokawa, MD, MPH

ABSTRACT

The practice of dermatoscopy continues to gain popularity among clinical dermatologists as well as nondermatologists, and therefore an increasing number of publications in the literature are targeted toward providing education on using a dermatoscope with success. Part 1 of this overview on dermatoscopy will focus on a detailed description of dermatoscopic findings of nonmelanocytic simulators of melanoma. (SKINmed. 2010;8:265–272)

September/October 2010 REVIEW

266SKINmed. 2010;8:265–272 Dermatoscopy: Nonmelanocytic Lesions

Simplified algorithms, however, do not allow an in-depth critical understanding of the dermatoscopic structures that are required to avoid some of the pitfalls and limitations of dermatoscopy.

An alternative to the simplified algorithms is the comprehen-sive analysis referred to as pattern analysis, a method that may

be superior in learning and practicing dermatoscopy.10 Pattern analysis requires a methodical and sequential analysis of all of the observed dermatoscopic structures, requiring not only the correct recognition but also the understanding of the diagnostic significance of the observed dermatoscopic structures. In con-trast to simplified algorithms, meaningful clinical application of pattern analysis requires more time in training and experience.

For the novice who is weighing the decision to use a dermatoscope, the sheer amount of available information and knowledge on der-matoscopy may be daunting. Just trying to make sense of the no-menclature of dermatoscopy is challenging. With experience, one learns to focus on the more relevant dermatoscopic structures in arriving at a diagnosis for the various entities. Indeed, the correct recognition of the relevant dermatoscopic structures is the key to becoming proficient in dermatoscopy no matter which method is employed, either a simplified algorithm or more comprehensive pattern analysis. In this review, the major dermatoscopic struc-tures observed in a variety of entities are highlighted, especially concerning those entities that may simulate melanoma and/or en-tities in which application of dermatoscopy is particularly useful.

NONMeLANOCyTIC LeSIONS

Step one of the 2-step process of dermatoscopy consists of de-termining whether the lesion is melanocytic or nonmelanocytic. This initial triaging step may have a greater clinical impact than the second step of dermatoscopy. The additional morphologic criteria provided by dermatoscopy have the potential to increase the diagnostic accuracy of a variety of benign lesions such as the hemangioma, dermatofibroma, solar lentigo, and seborrheic ker-atosis that may simulate melanoma, thereby obviating the need for a biopsy confirmation of these benign lesions. Malignant le-sions, especially basal cell carcinoma (BCC), can be diagnosed with more accuracy using a dermatoscope as well.

heMORRhAGe

Dermatoscopic criteria of hemorrhage (Figure 2):

• “Blood spots”: oval to round islands of pigment that range from yellow, red, maroon, brown, purple, to black

• Concomitant presence of the color spectrum of blood spots

• Separate small islands of pigment with a red hue that have no connection to the main body of the pigment serve as a good clue

Hemorrhage within the cornified layer of skin and mucous mem-branes, as well as that within the nail apparatus, can be a deceitful simulator of a melanocytic lesion. Dermatoscopy can be helpful in discriminating true hemorrhage from a melanocytic lesion, espe-cially on volar skin and nail apparatus, thus avoiding unnecessary biopsies. In hemorrhage, present are discrete sharply delineated

2-Step Process of Dermatoscopy

Skin Lesion

Nonmelanocytic Melanocytic

Indeterminate Malignant Benign

Step 1

Step 2

Algorithms 1. Pattern analysis2. CASH method 3. ABCD rule 4. Menzies method 5. 3-Point checklist6. 7-Point checklist

Figure 1. Two-step process of dermatoscopy. CASH indicates color, architecture, symmetry, and homogeneity; ABCD, asym-metry, border, color, differential structure.

Figure 2. Hemorrhage. (A) Brown-black hemorrhage; (B) dermatoscopic image of A showing islands of pigment with red hue (blood spots) and discrete islands of pigment sepa-rated from the main body of pigment; (C) linear irregularly pigmented band; (D) dermatoscopic image of C showing mul-ticolored blood spots that are brown, red, and dark gray; (E) brown-black pigment; (F) dermatoscopic image of E showing islands of red-brown pigment separated from the main body of pigment and signs of trauma (cracks of the nail plate).



round pigmented bodies, referred to as “blood spots” that range in hue from yellow, red, maroon, brown, purple, to black. Sepa-rate small islands of pigment with a yellow or red hue that have no connection to the main body of the pigment serve as a good clue that the pigmentation is due to blood and not aggregations of melanocytes. Since the presence of hemorrhage within the nail apparatus does not explicitly exclude an underlying neoplasm, a biopsy may still be necessary depending on the clinical context and the index of suspicion of an underlying neoplasm.

heMANGIOMA

Dermatoscopic criteria of hemangioma (Figure 3):

• Multiple closely set lacunae (lagoons) that range in color from red, maroon, blue-red, to blue-black with or without subtle gray-white outline

• Dermatoscopic findings vary depending on the presence of:

o Epidermal changes (eg, hyperkeratosis, acanthosis)

o Location of the vessels

o Presence of thrombosis

With the naked eye, vascular lesions, especially thrombosed ones, may simulate a melanocytic lesion. The dermatoscopic structures in vascular lesions are relatively distinctive, enabling the clini-cian to readily distinguish them from other entities. Dermato-scopically, there are closely grouped round to oval pigmented structures, referred to as lagoons or lacunae, that are yellow, red, maroon, purple, blue-red, or blue-black.12,13

The presence of a subtle gray-white peripheral outline surround-ing each of the lacunae provides an additional clue. These lacu-nae or lagoons histologically correspond to dilated dermal blood vessels14 and therefore can appear more red when the offending vessels are more superficial or more purple or bluish if the vessels are located deeper within the dermis. The peripheral gray-white outline represents thin fibrous septae between the dilated vessels. Acanthosis and hyperkeratosis of the epidermis further accentuate the gray-white color. A frequent clinical finding is that of a throm-bosed hemangioma, which can be a diagnostic challenge due to its jet-black clinical appearance. The concomitant presence of the color spectrum of lacunae, especially the presence of yellow and red hue in addition to the jet-black hue, is a good clue that the lesion is vascular in nature. A homogenous jet-black thrombosed vascular lesion with no discrete lacunae may not be dermatoscopi-cally distinguishable from other pigmented lesions. When the ves-sels are present in the deep dermis, the dermatoscopic findings minimally contribute in the diagnostic evaluation.

SeBACeOUS GLAND hyPeRPLASIA

Dermatoscopic criteria of sebaceous gland hyperplasia (Figure 4):

• White to yellow lobulation (“cumulus sign”) with a central umbilication

• Prominent vessels that surround the lesion (“crown vessels”)

Sebaceous gland hyperplasia usually does not pose a diagnostic difficulty for clinicians, owing to its characteristic size, distri-bution, color, and surface attributes. At times, however, the color and surface features are not readily visible with the na-ked eye, resulting in the need for biopsies to exclude, most frequently, BCCs. A view through a dermatoscope frequently reveals the white to yellowish lobulation (“cumulus sign”) with surrounding vessels (“crown vessels”) and central umbilication characteristic of a sebaceous gland hyperplasia,15,16 providing clinicians with a diagnostic confidence superior to that of the naked-eye examination alone, and thus potentially resulting in fewer biopsies.

Figure 3. Hemangioma. (A) Dark red hemangioma; (B) derma-toscopic image of A showing discrete lacunae surrounded by a gray-white rim; (C) brown-black hemangioma; (D) dermato-scopic image of C showing multiple lacunae surrounded by a gray-white rim and concomitant presence of different colored lacunae (red, purple, black).

Figure 4. Sebaceous gland hyperplasia. (A) Yellowish skin-col-ored sebaceous gland hyperplasia; (B) dermatoscopic image of A showing white lobulation (“cumulus sign”) with prominent vessels at the periphery (“crown vessels”).



DeRMATOFIBROMA

Dermatoscopic criteria of dermatofibroma (Figure 5):

• White scar-like area or white network, often central

• Peripheral pigment network

Dermatofibromas are very common benign cutaneous lesions that are clinically firm papules, plaques, or nodules that vary in color from light brown, dark brown, reddish purple, to yellow. In many cases, the history, clinical context, and clinical examination readily differentiate these lesions from other entities, ie, the firmness on palpation can consistently suggest the diagnosis of a dermatofi-broma. In lesions that remain problematic despite clinical exami-nation, dermatoscopy can be of value. The central white scar-like area with a peripheral pigment network comprises the most fre-quent dermatoscopic structures found in a dermatofibroma.17–19

The varying degree of fibrosis in the superficial dermis and the elongated pigmented thin rete-ridges represent the histopatho-logic correlate of the dermatoscopic structures. Sometimes the scar-like area may show a central white “pigment network” rath-er than a homogeneous white area, corresponding to the uneven fibrosis in the superficial dermis.19,20 Since the histopathologic findings vary widely in dermatofibromas, the dermatoscopic findings will mirror those dominant histopathologic findings that are present. For example, if foamy histiocytes predominate, the yellow hue becomes the dominant background color; if nu-merous erythrocytes and siderophages predominate, blue-gray becomes the background color, proving it difficult to differenti-ate from a blue nevus or nodular melanoma; if follicular induc-

tion is prominent, discrete foci of translucency may be present; and if sebaceous gland induction is prominent, small white to yellow globular structures may be present.17

BASAL CeLL CARCINOMA

Dermatoscopy of BCC (Figure 6):

Nonpigmented

• Telangiectasia

• Arborizing vessels

• Short fine telangiectasias

• Arborizing microvessels

• white streaks/white areas (“chrysalis structures”)

• Translucency

• Milky-pink to red background

• Erosion/ulceration

Pigmented

In addition to the criteria above:

• Islands of pigment

o Blue-gray globules

o Blue-gray ovoid nests

• Pigment distribution pattern

o Maple-leaf

o Spoke-wheel

Initially, dermatoscopy had been enthusiastically promoted to be use-ful in detecting pigmented BCCs, but, more recently, the application of the diagnostic technique has been expanded to include detecting nonpigmented ones.21,22 Indeed, rather than attempting to under-stand the dermatoscopic criteria for pigmented BCCs, understanding the dermatoscopic criteria that are common to both pigmented and nonpigmented BCCs offers a more fundamental and compelling ap-proach in differentiating BCCs from entities that may simulate them, such as solar keratosis, lichen planus-like keratosis, Bowen’s disease, and both benign and malignant melanocytic lesions. Published der-matoscopic criteria for BCC, for the most part, apply to superficial and nodular BCC,21,23 although dermatoscopic findings of rare sub-types such as fibroepithelial tumor of Pinkus have been described.24 By understanding the repeatable histopathologic findings of BCCs, whether pigmented or not, one can predict the dermatoscopic find-ings. Prominent vasculature situated parallel to the surface, varying amounts and degree of fibromucinous stroma, and epithelial ag-gregations that vary in size are the usual histopathologic findings. The telangiectasias, white areas or streaks (“chrysalis” structures), and semi-translucency represent the corresponding dermatoscopic findings. The combination of histopathologic findings provides the

Figure 5. Dermatofibroma. (A) Dermatofibroma; (B) dermato-scopic image of A showing central white area accompanied by a peripheral pigment network; (C) hemosiderotic hemangioma (sclerosing hemangioma); (D) dermatoscopic image of C showing an irregular white network centrally and a gray-blue background color with foci of reddish hues.



background milky-pink to reddish hue that is frequently present on dermatoscopy. Depending on the size and configuration, the telangi-ectatic vessels have been described as short fine telangiectasias, arboriz-ing microvessels, and arborizing vessels.25

Larger caliber arborizing vessels are more frequently found in nodular BCCs, while short fine telangiectasias are more frequently found in superficial BCCs. Translucency on dermatoscopy may be subtle to obvious depending on the size and location of the neo-plastic epithelial aggregations. Hence, translucency is more preva-lent in nodular BCCs compared with the flatter superficial BCCs in which the translucency may be subtle to absent.

Islands of pigment varying in size are present in addition to the aforementioned dermatoscopic findings in clinically pigmented BCCs. Pigment ranges from tan to brown to blue-gray. Small islands of blue-gray pigment have been referred to as blue-gray globules, while the large islands of blue-gray pigment have been referred to as blue-gray ovoid nests.26 Rarely, the pigment may be distributed in a “maple leaf–” or “spoke-wheel”–like pattern.26 For the pigmented BCCs, the challenge for the clinician is to differentiate pigmented structures of epithelial aggregations from pigmented structures of melanocytic aggregations, which may be difficult and at times im-possible if other dermatoscopic features of BCC are subtle to absent.

Most of the dermatoscopic findings of BCC (eg, prominent ves-sels, white streaks, blue-gray globules) are not specific, but these findings in concert with clinical examination and context lead to a more accurate diagnosis or, at least, narrow the diagnostic possibilities. For the experienced dermatologist, dermatoscopy has limited utility in diagnosing typical superficial and nodular BCCs. For clinically subtle or atypical-appearing lesions, how-ever, even the most seasoned dermatologist will appreciate some of the advantages that a dermatoscope offers, as it often reveals the characteristic BCC subsurface structures that were not ap-parent with the naked-eye examination.

SeBORRheIC KeRATOSIS

Dermatoscopic criteria of seborrheic keratoses (Figure 7):

• Comedo-like openings and milia-like cysts

• Sulci and gyri (fissures)

o Cerebriform or brain-like structures

o “Fat fingers”

o Network-like structures

• Hairpin vessels

• Sharply demarcated

Seborrheic keratoses are common benign keratinocytic growths that typically present as waxy brown lesions, predominantly on the

trunk but also on the face and extremities. Because these lesions are so widespread among the population, their clinical appearance can vary greatly, especially depending on the age of the lesion. While

Figure 6. Basal cell carcinoma (BCC). (A) Nodular BCC; (B) dermatoscopic image of A showing semi-translucency, arborizing vessels, white streaks, ulceration, and a milky pink background; (C) nodular BCC; (D) dermatoscopic image of C showing semi-translucency, arborizing vessels, and white streaks; (E) pigmented nodular BCC; (F) dermatoscopic image of E showing semi-translucency, white streaks, telangiecta-sias, and islands of brown pigment; (G) pigmented superficial BCC; (H) dermatoscopic image of G showing semi-translucen-cy, white streaks, and “maple leaf” like pigment (arrow); (I) superficial BCC; (J) dermatoscopic image of I showing white streaks, short fine telangiectasias, small islands of pigment, and a milky pink background.



some seborrheic keratoses appear as benign “stuck-on” keratotic papules, others can present as asymmetric papules or plaques with a multitude of colors and even whitish areas within, often raising suspicion of a melanoma. The use of a dermatoscope may reveal the characteristic subsurface structures leading to a more appropriate management of this very common benign epithelial lesion.

The classic dermatoscopic features of seborrheic keratoses in-clude a sharply demarcated lesion with comedo-like openings, milia-like cysts, hairpin vessels, and sulci and gyri within a back-ground color that usually ranges from tan to brown-black.27–29

Comedo-like openings refer to well-defined brown or black circu-lar areas within the lesion,27 and milia-like cysts are whitish circular

areas that are less well-demarcated.27 These structures histological-ly correspond to widened infundibulae and infundibular tunnels, respectively.30 Hairpin blood vessels refer to superficial telangiecta-sias arranged in loops that present in some seborrheic keratoses.28 The sulci and gyri or fissures represent the epithelial undulation that is frequently present in seborrheic keratoses. The widths of the sulci and gyri may significantly vary. Narrow-width sulci and gyri may appear as thick grids of pigment network, referred to as network-like structures, while the thicker sulci and gyri at the pe-riphery of some seborrheic keratoses may resemble “fat fingers.”31 Because milia-like cysts, comedo-like openings, hairpin vessels, and fissures may be observed in melanocytic lesions, absence of major melanocytic dermatoscopic structures should be confirmed.

Additional dermatoscopic features, namely signs, have been de-scribed, but their relevance and contribution in making the di-agnosis seborrheic keratoses are unclear. The “wobble sign” has been described in reference to seborrheic keratoses, as these le-sions do not wobble from side to side when the dermatoscope is moved (in contrast to papillomatous melanocytic nevi).29 The “jelly sign,” or jelly-like border, has been defined as peripher-al subtle pigment appearing on the skin surface much as jelly would be spread over a piece of bread.32 Consistent reproducible descriptions and images of a jelly sign and the histologic cor-relate are lacking, and thus the reproducibility and utility of the sign requires further validation.

SOLAR LeNTIGO

Dermatoscopic criteria of solar lentigo (Figure 8):

• Sharp demarcation

• Scalloped border (“moth-eaten”)

• Hypopigmented areas

• Light brown structureless areas

• Faint pigment network

• Linearly striated pigment network (“fingerprint” appearance)

• Pigment “psuedonetwork” (head and neck area only)

Dermatologists frequently encounter solar lentigines in the daily practice owing to their high prevalence and clinical variability in appearance. Solar lentigines are not infrequently biopsied by dermatologists because melanoma cannot be excluded with con-fidence by naked-eye examination. The diagnostic difficulty arises when solar lentigines are inflamed, heavily pigmented, or un-evenly pigmented. The diagnostic difficulty may be compounded when the lesion occurs on the face and is accompanied by any of these atypical features. Sharply marginated scalloped borders, hypopigmented areas, and light brown areas, characteristic of a solar lentigo, are better delineated through a dermatoscope.29,33,34

Figure 7. Seborrheic keratosis. (A) Seborrheic keratosis; (B) dermatoscopic image of A showing prominent sulci and gyri; (C) seborrheic keratosis; (D) dermatoscopic image of C show-ing comedo-like openings, milia-like cysts, and hairpin vessels; (E) unevenly pigmented seborrheic keratosis; (F) dermatoscop-ic image of E showing milia-like cysts and “fat fingers” (arrow); (G) dark brown seborrheic keratosis; (H) dermatoscopic image of G showing “network-like” structures (black arrow) and comedo-like openings (blue arrow).



When pigment network is present in solar lentigines, it is regu-larly meshed, but faint and patchy. A more characteristic pig-ment network pattern may be present, namely linearly striated pigment network that has been likened to a “fingerprint” pat-tern.34 Histopathologically, this characteristic pigment network represents thin elongated rete-ridges (likened to “hockey sticks”) that are heavily pigmented at the basal layer. As there is some relationship between solar lentigo and seborrheic keratoses, the linearly striated pigment network can also be found in flat or “macular” seborrheic keratoses.

On the face, especially on a severely sun-damaged one, a different kind of pigment network may be observed. A network of pigment may be formed when closely set follicular openings that are spared of pigment are found within a background of an interfollicular in-terconnecting epidermis that is pigmented. The resulting pigment network has been referred to as pigment “pseudonetwork” of the face, since the network is not a manifestation of hyperpigmented ridges as in a conventional pigment network. One caveat is that if the follicles are sufficiently apart, a conventional pigment network may also be present. Pigmented solar (actinic) keratoses, flat sebor-rheic keratoses, lichen planus–like keratoses, and solar lentigines occurring on the face may exhibit this particular pigment network pattern. While these lesions usually have symmetric pigmenta-tion around the follicular openings with a relatively even pigment pattern between them, early melanomas may have perifollicular asymmetric pigmentation and gray to brown granules within the interfollicular epithelium (annular-granular pattern).35 In ad-vanced melanomas, sparing of the pigment around the follicular openings is no longer preserved, resulting in foci of homogenous black areas. Diagnostic difficulties arise when the nonmelanocytic pigmented lesions present with asymmetric pigmentation around the follicular openings surrounded by brown granules, making the differentiation from melanoma difficult and therefore necessitat-ing a histologic confirmation if other dermatoscopic features of the benign lesion are not present.

CONCLUSIONS

Diagnostic evaluation of a skin lesion depends on multiple con-siderations that include history, context, naked-eye examination, and now dermatoscopic examination. Each of these factors may have a different impact depending on the clinical situation. In addition, the extent to which the dermatoscopic findings play a role in the diagnostic evaluation also depend on the user’s clinical experience as well as the entities to which they are be-ing applied. For the novice, recognition of the more relevant and reproducible dermatoscopic structures and the limitation of their specificity offers a more fundamental approach to learning dermatoscopy. Attempting to simply memorize the colorful and

metaphorical signs and names of the dermatoscopic structures may lead to inappropriate application of the diagnostic tech-nique, as many of the dermatoscopic structures have not been fully validated, even the major ones, which have limitations on interobserver reproducibility.

Every dermatologist strives to become proficient in recognizing melanomas, but to become proficient, it is equally important to recognize all the simulators of melanoma and not only the

Figure 8. Solar lentigo. (A) Solar lentigo; (B) dermatoscopic image of A showing a scalloped (“moth-eaten”) border, hypopigmented areas, and light brown structureless areas; (C) solar lentigo; (D) dermatoscopic image of C showing hypopig-mented follicular openings, pigment “pseudonetwork,” and lin-ear striated pigment network (insert); (E) unevenly pigmented solar lentigo; (F) dermatoscopic image of E showing hypopig-mented follicular openings, pigment “pseudonetwork,” and linear striated pigment network (“fingerprint”); (G) ill-defined solar lentigo; (H) dermatoscopic image of G showing asym-metric pigment around the follicular openings, and annular granular pattern around the follicular openings (such pattern usually requires a biopsy confirmation).



melanomas themselves. Dermatoscopy has the potential to in-crease the diagnostic accuracy of melanomas by increasing the diagnostic accuracy of pigmented and nonpigmented skin le-sions that simulate melanoma. In other words, dermatoscopy has the potential to increase the specificity in diagnosing mela-nomas. Hence, step one of dermatoscopy may well have just as much of a clinically relevant role as the second step of dermatos-copy, a subject of the next issue. The importance and relevance of the first step are being recognized as additional algorithms in reference to step one are being formulated.36

ReFeReNCeS

1 Saphier J. Die dermatoskopie. I. mittelung. Arch f Dermatol u Syphilol. 1920;128:1–19.

2 Goldman L. Some investigative studies of pigmented nevi with cutaneous microscopy. J Invest Dermatol. 1951;16:407–427.

3 Engasser HC, Warshaw EM. Dermatoscopy use by US der-matologists: a cross-sectional survey. J Am Acad Dermatol. 2010;63:412–419.

4 Tripp JM, Kopf AW, Marghoob AA, et al. Management of dys-plastic nevi: a survey of fellows of the American Academy of Dermatology. J Am Acad Dermatol. 2002;46:674–682.

5 Benvenuto-Andrade C, Dusza SW, Agero AL, et al. Differences between polarized light dermoscopy and immersion contact dermoscopy for the evaluation of skin lesions. Arch Dermatol. 2007;143:329–338.

6 Pan Y, Gareau DS, Scope A, et al. Polarized and nonpolarized dermoscopy: the explanation for the observed differences. Arch Dermatol. 2008;144:828–829.

7 Menzies SW, Zalaudek I. Why perform dermoscopy? The evi-dence for its role in the routine management of pigmented skin lesions. Arch Dermatol. 2006;142:1211–1212.

8 Kittler H. Early recognition at last. Arch Dermatol. 2008;144:533–534.

9 Argenziano G, Ferrara G, Francione S, et al. Dermoscopy —the ultimate tool for melanoma diagnosis. Semin Cutan Med Surg. 2009;28:142–148.

10 Carli P, Quercioli E, Sestini S, et al. Pattern analysis, not simpli-fied algorithms, is the most reliable method for teaching der-moscopy for melanoma diagnosis to residents in dermatology. Br J Dermatol. 2003;148:981–984.

11 Thomas L, Ronger-Savle S. Dermoscopic examination of melano-nychia striata. In: Marghoob AA, Braun RP, Kopf AW, eds. Atlas of Dermoscopy. London & New York: Taylor & Francis; 2006:289.

12 Katz B, Rao B, Marghoob AA. Vascular lesions, hemangiomas/angiokeratomas. In: Marghoob AA, Braun RP, Kopf AW, eds. Atlas of Dermoscopy. London & New York: Taylor & Francis; 2006:72.

13 Sgambato A, Zalaudek I, Ferrara G, et al. Nodules with a promi-nent vascular component. Arch Dermatol. 2008;144:702.

14 Wang SQ, Katz B, Rabinovitz H, et al. Lessons on dermoscopy #7. The diagnosis was thrombosed hemangioma. Dermatol Surg. 2000;26:891–892.

15 Bryden AM, Dawe RS, Fleming C. Dermatoscopic features of benign

sebaceous proliferation. Clin Exp Dermatol. 2004;29:676–677.16 Zaballos P, Ara M, Puig S, et al. Dermoscopy of sebaceous hy-

perplasia. Arch Dermatol. 2005;141:808.17 Zaballos P, Puig S, Llambrich A, et al. Dermoscopy of dermatofi-

bromas: a prospective morphological study of 412 cases. Arch Dermatol. 2008;144:75–83.

18 Arpaia N, Cassano N, Vena GA. Dermoscopic patterns of derma-tofibroma. Dermatol Surg. 2005;31:1336–1339.

19 Agero AL, Taliercio S, Dusza SW, et al. Conventional and polar-ized dermoscopy features of dermatofibroma. Arch Dermatol. 2006;142:1431–1437.

20 Zaballos P, Puig S, Malvehy J. Dermoscopy of atypical dermato-fibroma: central white network. Arch Dermatol. 2006;142:126.

21 Scalvenzi M, Lembo S, Francia MG, et al. Dermoscopic pat-terns of superficial basal cell carcinoma. Int J Dermatol. 2008;47:1015–1018.

22 Altamura D, Menzies SW, Argenziano G, et al. Dermatoscopy of bas-al cell carcinoma: morphologic variability of global and local features and accuracy of diagnosis. J Am Acad Dermatol. 2010:62:67–75.

23 Giacomel J, Zalaudek I. Dermoscopy of superficial basal cell carcinoma. Dermatol Surg. 2005;31:1710–1713.

24 Zalaudek I, Ferrara G, Broganelli P, et al. Dermoscopy patterns of fibroepithelioma of pinkus. Arch Dermatol. 2006;142:1318–1322.

25 Pan Y, Chamberlain AJ, Bailey M, et al. Dermatoscopy aids in the diagnosis of the solitary red scaly patch or plaque-features distinguishing superficial basal cell carcinoma, intraepidermal car-cinoma, and psoriasis. J Am Acad Dermatol. 2008;59:268–274.

26 Menzies SW. Dermoscopy of pigmented basal cell carcinoma. Clin Dermatol. 2002;20:268–269.

27 Grichnik JM. Dermoscopy of keratinocytic neoplasms: subpat-terns of seborrheic keratoses. Arch Dermatol. 2004;140:260.

28 Elgart GW. Seborrheic keratoses, solar lentigines, and lichenoid keratoses. Dermatoscopic features and correlation to histology and clinical signs. Dermatol Clin. 2001;19:347–357.

29 Stolz W, Braun-Falco O, Bilek P. Color Atlas of Dermatoscopy. 2nd ed. Hoboken, NJ: Wiley-Blackwell; 2002.

30 Provost N, Kopf AW, Rabinovitz HS, et al. Globulelike dermo-scopic structures in pigmented seborrheic keratosis. Arch Der-matol. 1997;133:540–541.

31 Kopf AW, Rabinovitz H, Marghoob A, et al. “Fat fingers:” a clue in the dermoscopic diagnosis of seborrheic keratoses. J Am Acad Dermatol. 2006;55:1089–1091.

32 Paech V, Schulz H, Argenyi Z, et al. Compendium of Surface Mi-croscopic and Dermoscopic Features. Berlin, Germany: Spring-er Berlin Heidelberg; 2008.

33 Wang SQ, Katz B, Rabinovitz H, et al. Lessons on dermoscopy #11. Solar lentigo. Dermatol Surg. 2000;26:1173–1174.

34 Elgart GW. Seborrheic keratoses, solar lentigines, and lichenoid keratoses. Dermatoscopic features and correlation to histology and clinical signs. Dermatol Clin. 2001;19:347–357.

35 Stolz W, Schiffner R, Burgdorf WH. Dermatoscopy for facial pig-mented skin lesions. Clin Dermatol. 2002;20:276–278.

36 Marghoob AA, Braun R. Proposal for a revised 2-step algorithm for the classification of lesions of the skin using dermoscopy. Arch Dermatol. 2010;146:426–428.


273

1) Compared to immersion contact dermatoscopy, polarized light dermatoscopy, either contact or noncontact, allows slightly better:a. diagnostic accuracyb. visualization of milia-like structures and comedo-like openingsc. visualization of blue-white veilsd. visualization of fibrosis and vascular structurese. All of the abovef. None of the above

2) Which of the following layers is rendered translucent by derma-toscopy?a. Stratum corneumb. Stratum granulosumc. Stratum spinosumd. Stratum basalee. Stratum malpighii

3) Which of the following is (are) found on dermatoscopic examina-tion in seborrheic keratoses but not in melanocytic lesions? a. Milia-like cystsb. Comedo-like openingsc. Hairpin vesselsd. Fissurese. All of the abovef. None of the above

4) Which of the following findings on dermatoscopic examination is (are) specific for basal cell carcinoma?a. Prominent vesselsb. White streaksc. Blue-gray lobulesd. All of the abovee. None of the above

5) Which of the following patterns, seen on dermatoscopic exami-nation of solar lentigos and some seborrheic keratoses, cor-responds to thin elongated rete ridges heavily pigmented at the basal layer likened to “hockey sticks” seen on histopathologic examination?a. “Fingerprint” patternb. “Moth-eaten” patternc. “Wobble sign” d. “Jelly sign”e. “Maple-leaf” patternf. “Spoke-wheel” patterng. “Chrysalis structures”h. “Blood spots”

SELF-TEST REVIEW QUESTIONSW. Clark Lambert, MD, PhD, Section Editor

Instructions: For each of the following numbered questions, choose the single most appropriate lettered response.

1) d, 2) a, 3) f, 4) e, 5) a

ANSWeRS TO SeLF-TeST ReVIeW QUeSTIONS:

From the Departments of Pathology and Dermatology, UMDNJ-New Jersey Medical School, Newark, NJAddress for Correspondence: W. Clark Lambert, MD, PhD, Room C520 MSB, UMDNJ-NJMS, 185 South Orange Avenue, Newark, NJ 07101 • E-mail: [email protected]

FORMULARy OF DR GeORGe C. ANDReWSBleach

Sodium perborate compound

• Soda perborate – 50

• Bismuth oxychloride – 40

• Talc powder – 10

M & S: Mix quantity of this powder with sufficient amount of peroxide, to which a few drops of ammonia have been added, to make a thick paste. Apply and leave on for 20 minutes. Remove grease from hairs first.

Submitted by Douglas D. Altchek, MD, New York, NY



From the Instituto de Dermatologia Prof Rubem David Azulay (IDPRDA), Santa Casa da Misericórdia do Rio de Janeiro, Rio de Janeiro, BrazilAddress for Correspondence: Regina Casz Schechtman, MD, PhD, rua Ribeiro de Almeida 44 Apt 102, Rio de Janeiro, Brazil, CEP 22240-060 • E-mail: [email protected]

Sporotrichosis is the only subcutaneous mycosis for which direct examination or histology is of little or no value for diagnosis. The diagnosis solely rests on the isolation of Spo-

rothrix schenckii in culture. This is best achieved by inoculation of pus on Sabouraud glucose agar containing chloramphenicol and cycloheximide.1

IDeNTIFICATION OF S Schenckii

Direct examination/Biological samPles

Examination is through aspirate with purulent and seropuru-lent contents from gummy lesions. Pus need not be collected by painful aspiration from subcutaneous nodules, but can be ob-tained from the ulcerated lesions. After removal of the dry, crusty surface, a small drop of milky pus can readily be recovered. A swab can be used from exudative and/or ulcerated lesions with draining tracts.1

Skin biopsy must be obtained from the border of active lesions and divided into 2 fragments: one fragment should be fixed in 10% buffered formalin for histopathologic examination and stained for hematoxylin and eosin, Wade, periodic acid-Schiff, and Grocott staining; and the other fragment should be kept in sterile saline for mycologic examination. Direct microscopic examination is with a wet-mount preparation of 4% sodium hy-droxide or 10% potassium hydroxide. Organisms are rarely seen, except in immunocompromised hosts. In this case, we could ob-

serve, in special colorations such as periodic acid-Schiff or silver stain, various budding yeasts to cigar-shaped organisms.1

In specimens taken from skin biopsy, few organisms are seldom observed and are difficult to identify. On hematoxylin and eosin preparations, granulomas with giant body cells are visualized and isolated oval yeast cells surrounded by an eosinophilic substance could be seen (called asteroid bodies).2

macroscoPic morPhology

Since organisms are not typically seen by potassium hydroxide or histopathologic examination, culture (of pus or tissue) is usually required to definitively diagnosis sporotrichosis.

Growth is rapid at 25ºC, revealing raised moist colonies with a membranous aspect and a wrinkled or folded surface. In principle, the colonies are white to cream-colored, later turning brown to dark gray and black (Figure 1). During subculture, the colonies may irreversibly lose their dark color, becoming creamy white.2

microscoPic morPhology

This fungus is dimorphic with a mycelial phase and a yeast phase. The mycelial saprophytic phase is characterized by slen-der, hyaline, septated, and branched hyphae containing thin conidiophores whose apex forms a small vesicle with sympodi-ally arranged denticles. Each denticle produces one conidium, each measuring approximately 2 to 4 mm, and these conidia are

ReVIeW

Sporotrichosis: Part IIRegina Casz Schechtman, MD, PhD

ABSTRACT

Sporotrichosis is a subcutaneous mycosis of implantation. It is the only subcutaneous mycosis for which direct examination or histology is of little or no value for diagnosis. The diagnosis solely rests on the isolation of Sporothrix schenckii in culture. On pathologic examination, causative organisms are rarely seen. Staining with fluorescent-labeled antibodies may aid in visualizing the cigar-shaped yeast forms; however, the organisms are still difficult to identify. Topical therapy is not effective. Potassium iodide is an effective treatment for sporotrichosis, but this agent has not been subjected to specific treatment trials comparing its efficacy against azoles or allylamine alternatives. Itraconazole is generally safe and well tolerated, and the relapse rate is low. Terbinafine could be another therapeutic alternative to treat the disease. Since 1998, research-ers from Brazil suggested that feline transmission of sporotrichosis in Rio de Janeiro city was associated with a large and long-lasting outbreak of the disease. To understand the outbreak, there have been studies on the epidemiology and antifungal susceptibility of the S schenckii strains through molecular diagnosis. Data suggest that all isolated strains were genetically related. (SKINmed. 2010;8:275–280)


276SKINmed. 2010;8:275–280 Sporotrichosis: Part II

arranged in flower-like groups (Figure 2). The conidia become detached from the conidiophores, sometimes being arranged side by side in a row bilaterally to the hyphae. The yeast parasitic phase is pleomorphic, showing spindle-shaped and/or oval cells measuring 2.5 to 5 mm in diameter and resembling a “cigar.”2

Pathology

Histologic, both suppurative and granulomatous, inflammation is seen in the dermis and subcutis. The causative organisms are rarely seen. Staining with fluorescent-labeled antibodies may aid in visualizing the cigar-shaped yeast forms; however, the organ-isms are still difficult to identify. Asteroid bodies are also seen. When numerous fungi are present, as in the immunocompro-mised host, budding yeast to cigar-shaped organisms are often identified by periodic acid-Schiff or silver stains.2

TReATMeNT

Topical therapy is not effective. Saturated solution of potassium iodide (SSKI) has been used with success. Although neither fun-gistatic nor fungicidal, SSKI is thought to affect the host’s im-mune reaction to the organism. Its cost is low, but it has a bitter taste as well as potential side effects (eg, iododerma, gastrointes-tinal upset, thyroid suppression). SSKI clearly is effective but has not been subjected to specific treatment trials comparing its ef-ficacy against azoles or allylamine alternatives. Many factors can contribute to the shortage of relevant literature. The duration of therapy in patients taking SSKI will also depend on drug com-pliance. Treatment is limited by side effects and the therapeutic dose should be maintained for up to 4 weeks beyond the time of total clinical cure.3–5 Itraconazole, for example, is quite effec-

tive against sporotrichosis, compared with ketoconazole, which is ineffective. In a study of 17 patients with lymphangitic and cutaneous sporotrichosis, all had significant clinical improve-ment and mycological cure when treated with 90 to 180 days of oral itraconazole (100 mg/d).6 The drug is generally safe and well tolerated, and the relapse rate is low. Amphotericin B may be indicated in severe or disseminated disease.7 Fluconazole is thought to be effective in fixed cutaneous sporotrichosis and dis-seminated disease with bone and joint involvement. Terbinafine may be another therapeutic alternative to treat the disease. Some investigators found that patients have demonstrated good re-sponse with terbinafine with few adverse reactions.8 The dosage of terbinafine to treat sporotrichosis can range from 250 mg/d to 1000 mg/d, according to different studies.9,10

The ePIDeMIC IN BRAzIL

In Rio de Janeiro city, Brazil, the first case of human sporotrichosis transmitted by cats was reported at the Clinical Research Institute Evandro Chagas, Fiocruz, between 1994 and 1997. From 1998 until today, the number of zoonotic sporotrichosis cases has ex-ponentially increased and investigators11,12 have characterized the beginning of an epidemic outbreak of zoonotic sporotrichosis transmitted by cats. This is the largest epidemic of sporotrichosis due to zoonotic transmission described in Rio de Janeiro.11,12

Between 1998 and 2004, at the Evandro Chagas Clinical Re-search Institute, 1503 cats, 64 dogs, and 759 humans have been diagnosed with sporotrichosis by isolation of S schenckii in cul-ture.11,13,14 As a rule, feline disease preceded human and canine diseases, and persons most frequently affected included house-wives taking care of cats with sporotrichosis.13,15 Domiciliary or professional contact with sick cats was observed in 84.1% of the canine cases and in 84.7% of the human cases. Among the lat-ter, 57.1% reported a history of a scratch or bite. In one study, women were most commonly affected (n=122, 68%) and the age range was 5 to 89 years, with a median of 39 years. Among a group of 178 patients, 156 reported domiciliary or professional contact with cats with a suspected or confirmed diagnosis of spo-rotrichosis and 97 reported a history of a scratch or bite. The most frequent occupations were domestic activities (30%) and students (18%). Five percent of the patients were veterinarians and veterinary assistants. The disease was frequent in women in-volved in domestic activities and animal care.

molecular Diagnosis

To understand the outbreak in Rio de Janeiro, Brazilian investiga-tors have been studying the epidemiology and antifungal suscep-tibility of the S schenckii strains cultivated from humans and cats involved in the sporotrichosis epidemic through fingerprinting

Figure 1. Sporotrichosis. Macroscopic morphology. Sab-ouraud agar at 25ºC. Colonies are wrinkled and folded with a brown to dark gray and black surface.



analysis. They found 9 subtypes of S schenckii, but none were associated with specific clinical forms. Their data suggest that all strains isolated from patients and cats with sporotrichosis origi-nated from a common source and were genetically related.16,17

clinical, histoPathologic, anD serologic features The lymphocutaneous form was the most frequent clinical form (n=95, 55.6%), followed by the fixed cutaneous form (n=45, 25.3%) and multiple cutaneous lesions (n=29, 16.3%).15,18 Mu-cosal involvement was observed in 5 patients (2.8%), affecting the nasal cavity in 1 and the conjunctiva in 4.15,19,20 The lesions varied in morphology, including nodules, tubercles, pustules, cysts, gummas, ulcers, vegetating lesions, verrucous lesions, and plaques accompanied or not by lymphangitis. The predominant sites affected were the upper limbs (65.2%), followed by the low-er limbs (12.9%) and the face (6.2%).13 Histopathologic exami-nation of 73 biopsy fragments revealed a granulomatous infil-trate in 66 (90.4%), and the fungus was detected in 21 (28.8%), corresponding to a high frequency.13

Arthralgia was a symptom reported by 53 (29.8%) patients, of whom 5 had signs of arthritis.13,21 According to investigators,13,15,18 in places with a large number of cases of the disease, reports of spontaneous regression are not rare, nor are the occurrence of hy-persensitivity reactions such as erythema nodosum/multiforme.

For the first time, erythema nodosum22 and erythema multi-forme23 were associated with sporotrichosis. These uncommon manifestations might be explained by different mechanisms, such as repeated inoculation during prolonged contact with sick animals, self-inoculation, dissemination of the fungus through the bloodstream, or aspiration of conidia and/or yeasts origi-nating from lesion exudates or respiratory particles released by sneezing of the infected cats.18,24 In addition, continuous expo-sure to large amounts of fungus-contaminated materials and subclinical reinfections may result in hypersensitivity.22

In 2004, investigators13 studied 52 patients with sporotrichosis confirmed by isolation of S schenckii and reactivity to Montenegro skin test during the ongoing outbreak of this mycosis in Rio de Janeiro. The authors emphasized the importance of parasitologic confirmation and the possibility of incorrect diagnosis based on the lesion’s appearance, epidemiologic information, and immu-nologic tests. The antigen used for the Montenegro skin test was conserved in either thimerosal 1:10.000 (group 1) or 0.4% phenol (group 2). Nineteen patients (39%) in group 1 and 7 (12%) in group 2 presented an induration >10 mm (P<.001). Sera from 3 patients (6.7%) reacted to indirect immunofluorescence for leish-maniasis, while sera from 10 patients (22%) reacted to enzyme-liked immunosorbent assay. Fifteen patients (28.8%) presented

with up to 2 lesions, with a predominance of ulcers. Forty-four patients (84.6%) were treated with itraconazole. The authors sug-gest that in the differential diagnosis between sporotrichosis and leishmaniasis, the possibility of coinfection, allergy to the reagent diluents, and cross-reactions should be investigated.

Thirteen (7.3%) of the 178 patients showed spontaneous regres-sion of the cutaneous lesions, whereas 165 (92.7%) required spe-cific treatment with itraconazole orally administered at 100 mg/d for 4 to 36 weeks (median = 12 weeks). Of these 165 patients, 49 (90.3%) were cured and 16 (9.7%) abandoned treatment. Five of the 9 diabetic patients required a longer treatment (16 to 24 weeks) and the itraconazole dose needed to be increased to 200 mg/d to 400 mg/d in 3 patients. Four other patients with chronic obstructive pulmonary disease and 9 with a history of alcohol abuse responded well to treatment of itraconazole 100 mg/d. All patients were followed up for 6 months to 1 year after the end of treatment and many remained in contact with cats with sporotrichosis. Lesion reactivation was observed in only 2 patients, who were successfully treated.

sPorotrichosis in cats anD Dogs

The first case of sporotrichosis disease in cats was described in 1956. The same investigators described other cases of sporotri-chosis in cats and dogs between 1963 and 1964.25

In 2002, researchers investigated the potential of cats as a pos-sible source of infection. A total of 148 cats with sporotricho-sis and 84 apparently healthy cats in domiciliary contact with the affected animals were studied regarding the presence of S

Figure 2. Sporotrichosis. Microscopic morphology (original magnification ×40). Mycelial saprophytic phase characterized by hyaline hyphae containing thin conidiophores with flower-like conidia.



schenckii in different biological materials.24 The fungus was iso-lated from 100% of cutaneous lesions, 47 (n=71, 66.2%) nasal cavity swabs, 33 (n=79, 41.8%) oral cavity swabs, and 15 (n=38, 39.5%) pools of nail fragments from cats with sporotrichosis. S schenckii was also isolated from oral swabs of 3 (n=84, 3.57%) apparently healthy cats in domiciliary contact with the affected animals (Figure 3).24 Isolation of the fungus from the nails and oral cavities of cats reinforces evidence indicating that transmis-sion can occur through a scratch or bite, whereas isolation from nasal fossae and cutaneous lesions, together with the wealth of yeast-like elements observed in histologic sections of skin biop-sies,11,26 demonstrates the possibility of contamination through secretions.11,27,28 The results of molecular typing of S schenckii isolated from humans and animals support this hypothesis.11

Until the 1990s, the largest series of cases involving dogs con-sisted of only 12 animals.25 Since 1998, a sporotrichosis epidemic affecting domestic pets and humans has been observed in Rio de Janeiro.11–13 In 2006, naturally acquired sporotrichosis resulting from an epidemic outbreak in the Metropolitan area of Rio de Janeiro was diagnosed in 44 dogs during a period of 5 years.14 Present knowledge about canine sporotrichosis is derived from a few reports of isolated cases. The large number of dogs with sporotrichosis observed in this epidemic might be attributed to cats acting as the main source of infection.11 In that study, spo-rotrichosis in cats preceded its occurrence among their owners and dogs with which they had contact. The majority of infected dogs probably did not have systemic manifestations, and cutane-ous lesions may have resolved without treatment. Although the cutaneous lymphatic form is the most frequent clinical presenta-tion in humans, the same does not apply to cats11 or, according to this study, to dogs. It is likely that the habit of dogs to sniff their environment is related to acquisition of the fungus through the nose. The presence of cats in the homes of humans and dogs with sporotrichosis was observed in 82.9% of cases.14 Findings suggest that sporotrichosis in dogs has a good prognosis and is easily treated, in contrast to cats in which the disease is usually severe, often systemic, and difficult to treat.11 According to inves-tigators, dogs are probably not directly involved in the transmis-sion of sporotrichosis in view of the scarcity of viable fungal ele-ments in lesions and the absence of S schenckii in the oral cavity. Apart from that, there were no reports of human cases associated with transmission from dogs in the epidemic in Rio de Janeiro.13 Other investigators12,13 have also suggested that cats are the most important vector in the transmission of sporotrichosis.28

At the Instituto de Dermatologia Prof Azulay, Rio de Janeiro, Brazil, there were 78 cases of sporotrichosis associated with cat scratch and/or contact with cats (Figure 4) from 2000 until 2006.29 They have accomplished an extensive bibliographic re-view from published cases based on journals included in Medline and Lilacs. All data included were collected from cases reported of cat-transmitted sporotrichosis (CTS) between the years of 1980 and 2006 in Brazil. The main objective of their study was to investigate the epidemiology of CTS and confirm the Rio de Janeiro epidemic outbreak of CTS as well as to compare it with data from other states of Brazil (Figure 5). While there were no cases described in the north, northeast, and central west regions of the country, there were a few cases in the south and other states of the southeast region, apart from the state of Rio de Ja-neiro. An epidemic outbreak in Rio de Janeiro was confirmed by Fiocruz researchers from the year of 1998 to the present. Ac-cording to these investigators, cases of CTS were revealed to be increasing with time. It is important to call public attention as

Figure 3. Sporotrichosis disease in a cat.

Figure 4. Sporotrichosis. Fixed cutaneous form. Infiltrated nodular eroded papule on the nose.



well as governmental authorities to improve the early diagno-sis and treatment of sporotrichosis. A multidisciplinary team of health workers, including physicians, social workers, and vet-erinary personnel, is necessary to properly control the sporotri-chosis outbreak. Moreover, Rio de Janeiro is a tourist town and therefore foreign travelers should be advised about this outbreak and physicians should learn to prevent and treat it properly.30

imPortant Questions, Discussion, anD conclusions There are still some very important questions to be answered: is it possible that the successive passages in those animals (cats) could have increased the virulence of the fungus? Has the organ-ism of the cats worked as a filtering system to naturally select the more aggressive strains of S schenckii? On the other hand, certain strains of a genotypic more aggressive S schenckii might have oc-curred and contributed to suppression of the immune response, leading to an increased number of widespread cutaneous cases. Does it explain the high percentage of cutaneous disseminated cutaneous lesions compared with the normal population? What makes the Brazilian outbreak different?

There are many possible explanations on this matter. First of all, it is not considered at the present time to be an outbreak. That is be-cause this outbreak has been going on since 1998. It can be char-acterized as an epidemic of sporotrichosis. The number of patients affected in addition to cats is steadily increasing each year without any focus from the authorities, despite the numerous notifications from the local health system. The cats affected with sporotrichosis carry a large number of parasites, and if the disease is not treated, it can be fatal. Humans and dogs behave differently. Both develop a localized form of the disease if there is no underlying immunosup-pression. They usually carry fewer parasites and their immune sys-tems can deal with them in a better way. Cats acquire the disease when they scratch themselves onto vegetation and when they fight with other street cats. Nevertheless, we still do not know why this epidemic is confined to Rio de Janeiro. Possibly it is because of the number of street cats in this city as well as the hygienic conditions of the population affected.11,12

There are important actions to be taken: to study the human and animal cases by an integrated team of physicians, veterinarians, and mycologists. Another step is to thoroughly investigate the environment, preferably by a team of biologists and ecologists, to examine the soil and vegetation conditions that propagate this infection and learn how to interrupt the chain of transmission of the disease to cats, dogs, and humans.

To control the outbreak in Rio de Janeiro, it is crucial to create a suitable system to notify public health authorities and iden-tify potential risk groups and areas of high prevalence of CTS.

The general population should learn through educational actions about the potential risks of the infection. Moreover, medical, health, and veterinary professionals need to be properly trained to diagnose and treat the disease.

ReFeReNCeS

1 De Vroey C. Identification of agents of subcutaneous myco-ses. In: Evans EG, Richardson MD, eds. Medical Mycology: A Practical Approach. London, England: Oxford University Press; 1989:134–137.

2 Lacaz CS. Sporothrix schenckii. In: Lacaz CS, Porto E, Heins-Vaccari EM, Melo NT, eds. Guia Para Identificação De Fungos, Actinomicetos E Algas De Interesse Médico. São Paulo, Brazil: Savier; 1998:326–331.

3 Kauffman CA, Hajjeh R, Chapman SW. Practice guidelines for the management of patients with sporotrichosis. Clin Infect Dis. 2000;30:684–687.

4 Sterling JB, Heymann WR. Potassium iodide in dermatol-ogy: a 19th century potassium iodide in dermatology: a 19th century drug for the 21st century—uses, pharmacology, ad-verse effects, and contraindications. J Am Acad Dermatol. 2000;43:691–697.

5 Ramos-e-Silva M, Vasconcelos C, Carneiro S, et al. Sporotricho-sis. Clin Dermatol. 2007;25:181–187.

Figure 5. Mapping the bibliographic review on reported cases of sporotrichosis in Brazil from 1998 to 2003. AM indicates Amazonas; PA, Pará; MA, Maranhão; RR, Roraima; RO, Rondo-nia; AC, Acre; AP, Amapa; MT, Mato Grosso; TO, Tocantins; PI, Piauí; CE, Ceará; RN, Rio Grande do Norte; PB, Paraíba; PE, Pernambuco; AL, Alagoas; SE, Sergipe; BA, Bahia; GO, Goias; MG, Minas Gerais; MS, Mato Grosso do Sul; SP, Sao Paulo; RJ, Rio de Janeiro; PR, Paraná; SC, Santa Catarina; RS, Rio Grande do Sul.



6 Restrepo A, Robledo J, Gomez I, et al. Itraconazole therapy in lymphangitic and cutaneous sporotrichosis. Arch Dermatol. 1986;122:413–417.

7 Sobera JO, Elewski BE. Infections, infestations and bites: fungal diseases. In: Bologna JL, Jorizzo JL, Rapini RP, eds. Dermatol-ogy. London, England: Mosby; 2003:1188–1190.

8 Hull PR, Vismer HF. Treatment of cutaneous sporotrichosis with terbinafine. Br J Dermatol. 1992;126(suppl 39):51–55.

9 Chapman SW, Pappas P, Kaufman C, et al. Comparative evalua-tion of the efficacy and safety of two doses of terbinafine (500 and 1000 mg day) in the treatment of cutaneous or lymphocuta-neous sporothricosis. Mycoses. 2004;47:62–68.

10 Francesconi G, Valle AC, Passos S, et al. Terbinafine (250 mg/day): an effective and safe treatment of cutaneous sporothrico-sis in patients in whom itraconazole use is not possible. J Eur Acad Dermatol Venereol. 2009;23:1273–1276.

11 Schubach TM, Schubach A, Okamoto T, et al. Evaluation of an epidemic of sporotrichosis in cats: 347 cases (1998–2001). J Am Vet Med Assoc. 2004;224:1623–1629.

12 de Lima Barros MB, Schubach TM, Gutierrez-Galhardo MC, et al. Sporotrichosis: an emergent zoonosis in Rio de Janeiro. Mem Inst Oswaldo Cruz. 2001;96:777–779.

13 Barros MB, Schubach AD, do Valle ACF, et al. Cat-transmitted sporotrichosis epidemic in Rio de Janeiro, Brazil: description of a series of cases. Clin Infect Dis. 2004;38:529–535.

14 Schubach TM, Schubach A, Okamoto T, et al. Canine sporotri-chosis in Rio de Janeiro, Brazil: clinical presentation, laboratory diagnosis and therapeutic response in 44 cases (1998–2003). Med Mycol. 2006;44:87–92.

15 Barros MB. Estudo de uma série de casos de esporotricose atendidos no instituto de pesquisa clínica evandro chagas, Rio de Janeiro. Universidade Federal do Rio de Janeiro Faculdade de Medicina. 2004.

16 Galhardo MC, De Oliveira RM, Valle AC, et al. Molecular epidemiol-ogy and antifungal susceptibility patterns of Sporothrix schenckii isolates from a cat-transmitted epidemic of sporotrichosis in Rio de Janeiro, Brazil. Medical Mycology. 2008;46:141–151.

17 Reis RS, Almeida-Paes R, Muniz MD, et al. Molecular characteri-sation of Sporothrix schenckii isolates from humans and cats involved in the sporotrichosis epidemic in Rio de Janeiro, Brazil.

Mem Inst Oswaldo Cruz. 2009;104:769–774.18 de Lima Barros MB, Schubach AO, Galhardo MC, et al. Spo-

rotrichosis with widespread cutaneous lesions—a report of 24 cases related to transmission by domestic cats in Rio de Ja-neiro, Brazil. Int J Dermatol. 2003;42:677–681.

19 Schubach A, de Lima Barros MB, Schubach TM, et al. Primary conjunctival sporotrichosis: two cases from a zoonotic epidem-ic in Rio de Janeiro, Brazil. Cornea. 2005;24:491–493.

20 Schubach AO. Esporotricose primária da mucosa nasal. Rev Soc Bras Med Trop. 2003;36:222.

21 Pereira AC, Levy RA, Barros MB, et al. Manifestações articula-res da esporotricose no Rio de Janeiro. Revista Brasileira de Reumatologia. 2002;42:44.

22 Gutierrez Galhardo MC, de Oliveira Schubach A, de Lima Barros MB, et al. Erythema nodosum associated with sporotrichosis. Int J Dermatol. 2002;41:114–116.

23 Gutierrez-Galhardo MC, Barros MB, Schubach AO, et al. Ery-thema multiforme associated with sporotrichosis. J Eur Acad Dermatol Venereol. 2005;19:507–509.

24 Schubach TM, de Oliveira Schubach A, dos Reis RS, et al. Sporothrix schenckii isolated from domestic cats with and with-out sporotrichosis in Rio de Janeiro, Brazil. Mycopathologia. 2002;153:83–86.

25 Freitas DC, Moreno G, Saliba AM, et al. Esporotricose em cães e gatos. Rev Fac Med Vet São Paulo. 1965;7:381–387.

26 Schubach TM, Schubach AO, Cuzzi-Maya T, et al. Pathol-ogy of sporotrichosis in 10 cats in Rio de Janeiro. Vet Rec. 2003;152:172–175.

27 Kauffman CA. Sporotrichosis. Clin Infect Dis. 1999;29:231–236; quiz 237.

28 Rosser E, Dunstan R. Sporotrichosis. In: Greene C, ed. Infec-tious Diseases of the Dog and Cat. Philadelphia, PA: Saunders; 1998:399–402.

29 Schechtman RC. Zoonotic sporotrichosis. Invited lecture at: 61st AAD meeting, February 2007; Washington, DC.

30 Duque-Estrada B, Meccia C, Aarão A, et al. Cat-transmitted spo-rotrichosis: an outbreak in Rio de Janeiro state. In: 21st World Congress of Dermatology. September 2007; Buenos Aires, Ar-gentina: 2007.

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From the Dermato Venereology (Skin/VD) Center, Sehgal Nursing Home, Panchwati, Azadpur, Delhi, and the Skin Institute, School of Der-matology, Greater Kailash, New Delhi, IndiaAddress for Correspondence: Virendra N. Sehgal, MD, A/6 Panchwati, Delhi, 110 033, India • E-mail: [email protected]

Modern physicians harbor the notion that scientific dermatology originated and developed in Western Europe from the 17th century onwards. It is not

true. In India, the therapeutics of dermatoses have been prac-ticed by physicians for centuries. Several ancient Indian texts have discussed traditional methods of treating skin diseases,1,2 including the Charaka Samhita3 (6th century BC), which con-tains detailed descriptions of the causes, symptoms, signs, and prognoses of skin diseases.

CLASSIFICATION

According to Atreya Punarvasu,4 there are 18 types of der-matoses: 7 of them are major (Kepala, Udumbara, Mandala, Rishiyajiva, Punderika, Sidhma, and Kakana), while 11 are

minor (Ekakushtha, Charamakushtha, Kitima, Vipadika, Alaa-saka, Dadru, Charmadala, Pama, Visuphota, Sataru, and Vi-charchika). The etiology of dermatoses, according to ancient Indian dermatologic literature,3,4 was related to 3 complexions (humors), whose morbidity vitiates the skin, blood, flesh, and the body fluids.

BODy hUMORS BALANCe AS SIGN OF heALTh

According to Ayurveda,5 the factors responsible for causing skin diseases can pollute all the humors (Vata, Pitta, and Kapha), thus resulting in affliction of the skin, blood, flesh, and body fluids (Table). By the diagnosis of a particular dermatosis, the underlying humoral morbidity can easily be identified and vice versa. Dryness, atrophy, pricking pain, aching pain, contraction, dilation, hardness, roughness, horripilation, and dusky red col-orations are the signs and symptoms of dermatoses of the Vata type (Figure 1 and Figure 2). Burning, redness, exudation, sup-puration, smell of raw meat, softening, and sloughing are the symptoms of dermatoses of the Pitta type. Discordance of the Kapha humor produces whiteness, coldness, pruritus, heaviness, sliminess, and softening. These concepts are still valid and form the basis of Ayurvedic treatment. Thus, the therapy of dermato-ses consists of purification of the whole body system, along with systemic and/or local medication.

CeRTAIN NOTeWORThy PRINCIPLeS

concePt of sense of heat

In dermatologic practice, heat in the blood, or sense of heat (SOH), is not an uncommon complaint. It may manifest as erup-tions, urticaria, toxoallergic dermatitis, reaction to medicine, erythroderma, genital eruptions, and acne. Discussing the origin of SOH, some experts6 maintain that temperament is the pattern of activity and reactivity of the body and is expressed in terms of elementary qualities: heat, cold, dryness, and moisture. Investiga-tors7 later limited the qualities to 2 types: parasympathomimetic and sympathomimetic. The scientific assessment of the SOH

COMMeNTARy

Traditional/Ayurvedic Pharmacotherapy for Skin Diseases

Virendra N. Sehgal, MD; Govind Srivastava, MD

Table. Factors Responsible for Causing Skin Diseases According to Ayurveda Medicine5

Constant use of mutually incompatible foods/drinks

Unctuous/heavy articles of diet

Suppressing the urge to vomit/answering other calls of nature

Overexertion, exposure to heat after excessive junk food

Irregular indulgence in cold or hot food, fasting or overeating

Using cold water suddenly after afflicted by heat

Fatigue/fear

Indulgence in predigested meals

Wrongful administration of the 5 purificatory processes

Habitual use of grain curds or fish

Excessive use of salt, acid articles, black-gram, radish, and stale food

Performing the sex act before food is digested

Sleeping during the day

Persecuting wise men and elders

Committing sinful acts

September/October 2010 COMMENTARY

283SKINmed. 2010;8:282–284 Traditional/Ayurvedic Pharmacotherapy for Skin Diseases

complex was studied in several skin diseases such as urticaria, drug-related dermatitis, and eczemas8; SOH covering the entire body was also observed in acne, seborrheic dermatitis, melanoder-matitis toxica, and rosacea. Certain Ayurvedic preparations such as khus (Vetiveria zizanioides) are particularly helpful in alleviating SOH and thus relieving the symptoms of dermatoses.

concePt of Phagocytic inDex moDification

Phagocytes (polymorphonuclear leucocytes) of blood play an im-portant role in the control and cure of skin infections. Swerita Chiraita, a bitter herb, was found to increase the phagocytic coef-ficients of the polymorphonuclear leucocytes, and may thus be invaluable in treatment of infective disorders such as chronic pyo-dermas, furunculosis, fungal, bacterial, and viral infections.9,10

role of trace elements

Essential trace elements such as zinc, copper, selenium, and mag-nesium have been found to be rich in certain herbs. They are often an integral part of the enzyme systems that regulate major metabolic events in the body. In a number of skin diseases, al-ternations of several trace elements are observed. During inflam-matory processes, a large number of free radicals are produced. The scavenger enzymes of free radicals, including superoxide dis-mutase and glutathione peroxidase, are dependent on these trace elements. Further, zinc plays an important role in the normal functioning of skin and hair. It has also been associated with a number of skin conditions, including acrodermatitis entero-pathica, acne vulgaris, wound healing of leg ulcers, and pustular psoriasis. Several herbs that are rich in zinc, such as Swertia chi-raita, are known to provide dramatic results in such disorders.9

BLOOD PURIFICATION CONCePT

Purification of blood is another important area that may help in amelioration of many skin and systemic disorders. Several Ay-urvedic preparations have been used as blood purifiers. In addi-tion, if properly selected and stored, they are believed to be less toxic and more useful in clearing dermatoses. Psychosomatic fac-tors are important in several skin disorders such as psoriasis, li-chen simplex chronicus, trichotillomania, neurotic excoriations, factitial dermatitis, parasitic delusions, and vulvodynia. Several herbal preparations such as Bacopa monniri, Nardostachys Jata-mansi, and Withania somnifera have distinct anti-stress and neuropharmacologic effects. Ashwagandha (Withania somnifera) can be an effective adjuvant therapy for the treatment and pre-vention of neurocutaneous disorders.9,10

ReFeReNCeS

1 Kirtikar KR, Basu B. Indian Medicinal Plants. Vol I–IV. New Delhi, India: Bishan Singh & M.P. Singh Publishers; 1975.

2 Behl PN. Ancient Indian dermatology. Probe. 1967;6:137–143.3 Charak Samhita. Vol I to VI. Jamnagar, India: Shri Gulab Kuna-

verta Ayurvedic Society; 1949.4 Behl PN, Arora RB, Srivastava G. Ancient Indian dermatology.

Figure 1. Dusky red coloration affecting the adjoining area of the lips.

Figure 2. Erythema, edema, vesiculations, and scaling affect-ing the chest.

September/October 2010 COMMENTARY

284SKINmed. 2010;8:282–284 Traditional/Ayurvedic Pharmacotherapy for Skin Diseases

Traditional Indian Dermatology. 1st ed. New Delhi, India: SISD Publication; 1992:7.

5 Dash B. Diagnosis and Treatment of Disease in Ayurveda Massers. Vol 7. New Delhi, India: Concept Publishing Com-pany; 1990.

6 Shah MH. The General Principles of Avicenna’s Canon of Medi-cine. Karachi, Pakistan: Naveed Clinical; 1966.

7 Udupa KN. Gynap Constitution Clinical Medicine. Historical Con-

sideration Advances in Research in Indian Medicines. Varanasi, India: Banaras Hindu University; 1970.

8 Behl PN. Modern Dermatology and Indian System of Medicine. New Delhi, India: IHMMER/Printing Press; 1986:29–41.

9 Behl PN, Arora RB, Srivastava G. Traditional Indian Dermatology. New Delhi, India: SISD Publication; 1992.

10 Behl PN, Srivastava G. Herbs Useful in Dermatological Therapy. 2nd ed. New Delhi, India: CBS Publishers & Distributors; 2004.

hISTORICAL DIAGNOSIS & TReATMeNTDiagnosis and treatments have advanced over the past century. This feature depicts conditions from a collection of steroptic cards published in 1910 by The Stereoscopic Skin Clinic, by Dr. S. I. Rainforth.

DIAGNOSIS: Erythema bullosum is to be differentiated by the presence of other lesions of erythema multiforme, the develop-ment of the bullae from erythematous macules, the distribution and comparatively acute course. In urticaria bullosa the blebs arise from wheals.

TREATMENT: Arsenic given to the limit of tolerance and long continued, often, but not invariably, produces good results. The greatest effort should be directed toward improving the patient’s general health. The bullae are to be evacuated, covered with pulvis talci salicylates N.F. and protected with dry compresses. Or a 2 per cent boric acid wet dressing may be employed. In severe, extensive cases the continuous warm bath gives the patient the most comfort.



From the Departments of Pathology, Divisions of Anatomic Pathology1 and Dermatopathology,2 and the Department of Dermatology,3 UMDNJ-New Jersey Medical School, Newark, NJAddress for Correspondence: W. Clark Lambert, MD, PhD, Room C520, Medical Science Building UMDNJ-New Jersey Medical School, Newark, NJ 07101 • E-mail: [email protected]

Pitfalls abound in the diagnosis of melanomas, especially in differentiating between them and benign melanocytic le-sions. One lesion in particular is diagnostically troublesome

and was therefore given the designation of “pseudomelanoma” by Kornberg and Ackerman in 19751; however, true melanomas may be misdiagnosed under this term. There are other ways in which nevi may mimic melanomas, as the following will demonstrate.

PSeUDOMeLANOMA

Pseudomelanoma consists of a recurrent nevocellular nevus in which, following incomplete surgical excision, most likely saucer-ization (ie, “scoop,” “scallop,” or “shave” excisional biopsy, or “shave excision”),2,3 or partial destruction by other means, such as laser,4 the lesion recurs due to proliferation and/or migration of remaining ne-vocellular cells into the cicatrix (scar) that resulted from the destruc-tive procedure.3 These melanocytic cells tend to grow irregularly in streaks of variable dimensions often accompanied by, in addition to scar tissue, inflammation and proliferation of blood vessels. In typi-cal lesions, an irregular pigmented lesion in the site of a previously treated nevocellular nevus is seen clinically. The clinical appearance is, therefore, disturbing and may be reinforced by dermatoscopic findings that also resemble a melanoma or a dysplastic nevus.

The diligent dermatologist may be unaware of the previous proce-dure and, in turn, sees a melanocytic lesion that indeed looks his-topathologically worrisome. The typical lesion shows an irregular proliferation of melanocytes in or adjacent to scar tissue (Figure 1). These often line the dermoepidermal interface, but may occur within the scar. The tendency to line the interface is apparently due to an epidermotropism inherent in cutaneous melanocytes.

The diagnosis is confirmed by recognition that the connective tissue fibrosis is due to the procedure and does not represent a stromal reaction to the melanocytic lesion, when finding one or more nests of typical nevus cells within or adjacent to the scar tissue (Figure 2). This may represent a significant pitfall.

PSeUDO-PSeUDOMeLANOMA

Wallace H. Clark, Jr, MD, renowned dermatopathologist who introduced both multivariate analysis and the variable of tumor thickness into the melanoma field, is said to have famously re-marked upon learning of the newly coined term pseudomela-noma, “Melanomas recur, too.” Indeed they do.

This may happen if the initial lesion was not recognized as a mel-anoma. We refer to this lesion as a “pseudo-pseudomelanoma” (Figure 3). Because melanomas may arise in nevi, the residual nevocellular tissue may appear benign, even though the recur-rent tissue is not (Figure 4). Simply recognizing that the lesion is recurring in a scar and identifying benign nevus tissue deep within the scar tissue is not sufficient to rule out a melanoma. This represents a situation where “a little knowledge is a danger-ous thing.” Either lesion may occur in scar tissue in which deep nests of bland nevus cells are not visible on the histopathologic sections examined, further complicating the diagnosis.

PSeUDOMeTASTASIzING PSeUDOMeLANOMA

Lesions other than recurrent nevi may resemble melanoma, both clin-ically (with or without dermatoscopy) and histologically. One such lesion is the cellular blue nevus. Cellular blue nevi are also prone to undergo a process known as benign metastasis, in which tissue from an otherwise benign lesion or even some normal tissue disseminates to a local lymph node and then does not proceed further.

Nevi are especially prone to undergo this phenomenon, as is thyroid tissue. One of us (WCL) has previously reported this process in a 20-year-old woman who developed a metastatic lesion from a cel-lular blue nevus of the dorsum of her foot.5 Unfortunately, she had been previously misdiagnosed as having metastatic melanoma, lead-ing to extensive surgery and morbidity with massive lymphedema of a lower extremity, when we first saw her. We coined the term pseudometastisizing pseudomelanoma to denote this type of lesion.5

PeRILS OF DeRMATOPAThOLOGyW. Clark Lambert, MD, PhD, Section Editor

Pseudomelanomas, Pseudo-pseudomelanomas, and Pseudometastasizing Pseudomelanomas

Navér Sarkissian, MD, PhD;1,2,3 Amin Maghari, MD;1,2,3 Javier Rojas, MD;1 W. Clark Lambert, MD, PhD1,2,3

September/October 2010 PERILS OF DERMATOPATHOLOGY

286SKINmed. 2010;8:285–287 Pseudomelanomas

Nevi may also occur in lymph nodes and other internal tissue because of an error in histogenesis, in which melanocytes migrating from the neural crest in embryogenesis fail to reach their target tissue and then

give rise to nevi. Most such lesions are simply never discovered. They may be found in a lymph node dissection or sentinel lymph node biopsy, following excision of a primary lesion, leading to confusion.

Figure 1. Case 1: Pseudomelanoma: Recurrent nevus cells in a “saucerization” excision cicatrix. (Hematoxylin and eosin stain, original magnification ×340).

Figure 2. Case 1: Pseudomelanoma: Nest of bland nevus cells deep within excision cicatrix. (Hematoxylin and eosin stain, original magnification ×340).

Figure 3. Case 2: Pseudo-pseudomelanoma: Melanoma cells within the epidermis following melanoma excision. (Hematoxy-lin and eosin stain, original magnification ×340).

Figure 4. Case 2: Pseudo-pseudomelanoma: Nest of bland nevus cells deep within excision cicatrix. (Hematoxylin and eosin stain, original magnification ×340).

September/October 2010 PERILS OF DERMATOPATHOLOGY

287SKINmed. 2010;8:285–287 Pseudomelanomas

ReFeReNCeS

1 Kornberg R, Ackerman AB. Pseudomelanoma: recurrent mela-nocytic nevus following partial surgical removal. Arch Dermatol. 1975;111:1588–1590.

2 Ho J, Brodell RT, Helms SE. Saucerization biopsy of pigmented lesions. Clin Dermatol. 2005;23:631–635.

3 Duray PH, Livolsi VA. Recurrent dysplastic nevus following shave

biopsy. J Dermatol Surg Oncol. 1984;10:811–815.4 Dummer R, Kempf W, Burg G. Pseudomelanoma after laser

treatment. Dermatology. 1998;197:71–73.5 Lambert WC, Brodkin RH. Nodal and subcutaneous cellular blue

nevus: a pseudometastasizing pseudomelanoma. Arch Derma-tol. 1984;120:367–370.

WAx MOULAGe

Lues II Kopie, Secondary Syphilis. Moulage No 463 made by Lotte Volger in the Dermatology Clinic in Zurich in 1924. Museum of Wax Moulages Zurich, www.moulagen.chCourtesy of Michael Geiges, MD



From the Department of Dermatology and Cutaneous Biology, Jefferson Medical College of Thomas Jefferson University, Philadelphia, PAAddress for Correspondence: Tanya Humphreys, MD, Department of Dermatology and Cutaneous Biology, Jefferson Medical College, 833 Chestnut Street, Suite 740, Philadelphia, PA 19107 • E-mail: [email protected]

Brooke Spiegler syndrome is an autosomal dominant genodermatosis that is characterized by the growth of multiple adnexal neoplasms including spiradenoma,

trichoblastoma, trichoepithelioma, and cylindroma. The syn-drome has been linked to a mutation in the tumor suppressor gene CYLD1, located on chromosome 16q12–13.1 The clinical phenotype is quite variable and may be characterized by the pres-ence of one or all of these neoplasms. Familial cylindromatosis can be particularly disfiguring since the so-called turban tumors can be numerous and grow quite large.

Because of the superficial nature of trichoepitheliomas, destruc-tion or ablation using CO2, Erb: YAG laser, or radiofrequency devices is often effective.2 Ablative therapies are generally not ef-fective for cylindromas, however, because of their depth. In addi-tion, because the growth of cylindromas generally spans the full thickness of the dermis, they cannot be shelled out like a cyst. Surgical management of cylindromas generally consists of deep ex-cision of large or painful tumors to deep fat. Incomplete excision and recurrence are typical due in part to the multifocal nature of tumor development. Malignant transformation of cylindromas is fortunately rare,3 but the progressive growth of tumors is nonethe-less a serious therapeutic and cosmetic problem for some patients. The presence of large confluent tumors can lead to complications such as infection, bleeding, and even chronic anemia.3

Agminated plaques of cylindromas tend to occur in the cen-tral portion of the forehead (Figure 1). The patient depicted in Figure 1 demonstrates cumulative tumor development on the forehead over the course of 35 years. Because of the wide area of involvement and the likelihood of recurrence, we chose to excise the problematic area in toto to the level of the frontalis muscle and graft with skin from an unaffected area of the body

SURGICAL CAPSULeSTanya Humphreys, MD, Section Editor

Surgical Management of CylindromatosisTanya Humphreys, MD

Figure 1. Preoperative view of a patient with familial cylindromato-sis. Note the common pattern of tumor clustering at the mid-fore-head along hairline. The bluish nodule represents a spiradenoma.

Figure 2. (A) Donor site for full thickness skin graft. (B) Forehead surgical site after excision of agminated cylindromas and place-ment of full thickness skin graft. (C) Tie over bolster dressing to secure graft.

September/October 2010 SURGICAL CAPSULES

290SKINmed. 2010;8:289–290 Surgical Management of Cylindromatosis

(posterior upper arm, Figure 2A). Since the patient was reluctant to undergo excision of the entire cosmetic unit of the forehead, a rectangular area of excision was designed to encompass the most concentrated area of tumor growth and allow placement of suture lines in preexisting horizontal skin lines of the fore-head for best cosmesis. A full thickness skin graft was sutured to

the recipient bed (Figure 2B) and a bolster dressing was applied (Figure 2C). The patient tolerated the procedure well, and the color and texture of the grafted skin is a satisfactory match to the uninvolved skin on the forehead after 2 months (Figure 3). There have been no new tumors within the grafted site to date (18 months post-operatively). The rectilinear design of the flap within the borders of the horizontal forehead lines allows for future subsequent excisions with grafting to be performed on adjacent tissue while respecting relaxed skin tension lines.

In summary, solitary cylindromas can be managed with conser-vative excision while large areas of recurrent agminated tumor may be best managed with full thickness skin grafting.

ReFeReNCeS

1 Bowen S, Gill M, Lee D, et al. Mutations in the CYLD gene in Brooke-Spiegler syndrome, familial cylindromatosis, and mul-tiple familial trichoepithelioma: lack of genotype-phenotype cor-relation. J Invest Dermatol. 2005;124:919–920.

2 Rallan D, Harland CC. Brooke-Spiegler syndrome: treatment with laser ablation. Clin Exp Dermatol. 2005;30:355–357.

3 De Francesco V, Frattasio A, Pillon B, et al. Carcinosarcoma arising in a patient with multiple cylindromas. Am J Dermatopa-thol. 2005;27:21–26.

Figure 3. Appearance 2 months postoperatively.

VINTAGe LABeL




From the Department of Medicine, Veterans Affairs Medical Center, Dayton, OH;1 and the Department of Internal Medicine, Division of Infectious Diseases, Wright State University School of Medicine, Dayton, OH2

Address for Correspondence: Hari Polenakovik, MD, Wright State University, Department of Internal Medicine, Weber CHE 2nd Floor, 128 E. Apple Street, Dayton, OH 45409 • E-mail: [email protected]

A 56-year-old diabetic woman underwent total abdomi-nal hysterectomy for stage IV clear cell endometrial car-cinoma 4 months before presentation. After receiving

the third cycle of chemotherapy (carboplatin, liposomal doxoru-bicin, and paclitaxel), she developed intestinal perforation that required emergent bowel resection and colostomy. Her hospital course was complicated by heparin-induced thrombocytope-nia and development of ischemic gangrene involving both feet. Conservative treatment with local wound care was recommend-ed. Three weeks later, the patient was readmitted for resumption of chemotherapy. On examination, both feet showed mummi-fied toes with dry gangrene with a mold-like coating over the plantar aspect of her foot (Figure 1). The patient underwent debridement followed by bilateral transmetatarsal amputations. Multiple tissue cultures grew the fungus shown in Figure 2.

CLINICAL COURSe

The fungus was identified as Paecilomyces lilacinus. The patient was treated with intravenous voriconazole and wound lavage with amphotericin B; however, her clinical condition rapidly de-teriorated with the development of intraabdominal sepsis, which was poorly responsive to conservative treatment. The decision was made to withhold aggressive measures and she was dis-charged to hospice care, where she died. No fungi were isolated from fungal blood cultures.

DISCUSSION

Paecilomyces species are saprophytic filamentous fungi that are found worldwide in soil and as air and water contaminants.1 Al-though Paecilomyces species are uncommon pathogens, they can produce serious infections in immunocompromised patients, and the incidence of infections in immunocompetent hosts has been increasing in recent years.2 The majority of cases described in the literature involve patients with identified predisposing fac-tors.3 The most common predisposing factors for cutaneous and subcutaneous infections are solid organ and bone marrow trans-plants, malignancy, and corticosteroid therapy.

P lilacinus and Paecilomyces variotii are the two species associated most frequently with human disease. The differentiation between these two species is clinically important, since there is a marked dif-ference in their in vitro susceptibilities to the antifungal agents. P lilacinus grows rapidly on Sabouraud’s dextrose agar and develops colonies with a violet appearance when mature. The identification of Paecilomyces is difficult for most clinical microbiological labora-tories because it can be morphologically confused with other fungi

INFeCTIOUS DISeASe CAPSULeSJack M. Bernstein, MD, Section Editor

A Fungus Among UsAbdul R. Siddiqui, MD;1,2 Jack M. Bernstein, MD;1,2 Hari Polenakovik, MD2

Figure 1. Mold-like coating over the plantar aspect of the patient’s right foot.

September/October 2010 INFECTIOUS DISEASE CAPSULES

292SKINmed. 2010;8:291–292 A Fungus Among Us

such as Penicillium. Assistance of a reference laboratory is often re-quired. The optimal treatment for P lilacinus infections has not yet been established. In localized infections, removal of the infected foci and elimination of any foreign body should be attempted, if feasible.4 Amphotericin B, itraconazole, and echinocandins have shown poor activity against P lilacinus, while the new triazoles are active against it. P variotii on the other hand has exhibited a dif-ferent susceptibility pattern, being susceptible to most antifungal

agents apart from voriconazole and ravuconazole.5 Optimal dura-tion of treatment is unknown, but a minimum of 3 months of potent antifungal treatment is suggested by some authors.6

ReFeReNCeS

1 Gutierrez F, Masia M, Ramos R, et al. Pulmonary mycetoma caused by an atypical isolate of Paecilomyces species in an immunocompetent individual: case report and literature review of Paecilomyces lung infections. Eur J Clin Microbiol Infect Dis. 2005;24:607–611.

2 Carey J, D’Amico R, Sutton DA, et al. Paecilomyces lilacinus vaginitis in an immunocompetent patient. Emerg Infect Dis. 2003;9:1155–1158.

3 Pastor FJ, Guarro J. Clinical manifestations, treatment and out-come of Paecilomyces lilacinus infections. Clin Microbiol Infect. 2006;12:948–960.

4 Walsh TJ, Groll A, Hiemenz J, et al. Infections due to emerging and uncommon medically important fungal pathogens. Clin Mi-crobiol Infect. 2004;10(suppl 1):48–66.

5 Castelli MV, Alastruey-Izquierdo A, Cuesta I, et al. Susceptibility testing and molecular classification of Paecilomyces spp. Anti-microb Agents Chemother. 2008;52:2926–2928.

6 Schooneveld TV, Freifeld A, Lesiak B, et al. Paecilomyces lilaci-nus infection in a liver transplant patient: case report and review of the literature. Transpl Infect Dis. 2008;10:117–122.

Figure 2. Lactophenol cotton blue stain of fungus growing in tissue fungal culture.

VINTAGe LABeL


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From the Departments of Dermatology and the History of Medicine, Medical University of Vienna, Vienna, Austria;1 and from the Department of Dermatology, Semmelweis University, Budapest, Hungary2

Address for Correspondence: Karl Holubar, MD, FRCP, FRSM, GSE, Emeritus Professor of Dermatology and the History of Medicine, Medical University of Vienna, Waehringer Str. 25, A-1090 Vienna, Austria • E-mail: [email protected]

Born in Bačko Dobro Polje (Kis Kér/Klein-Ker) in the then Kingdom of Hungary, Austrian Empire, David Gruby was schooled in Budapest, attended medical school in Vi-

enna, and received his medical degree in 1839. Shortly after, he moved to Paris and continued his microscopic research, started in Vienna. He would have been required to change his Mosaic denomination to pursue a career in Austria.1

BACKGROUND

He discovered many fungi, eg, Candida albicans and Trichophy-ton ectothrix. Gruby also described the propagation of puerperal infection via lymph and blood vessels, thereby anticipating Ignaz Philip Semmelweis’ clinical observation a few years later. As a practitioner, he counted among his patients Fréderic Chopin, Franz Liszt, Alexandre Dumas père, Heinrich Heine, Alphonse Lamartine, and other celebrities.

Heinrich Heine, Jewish-German poet in France, caustically joked that he has a doctor so small that somebody might think he has no doctor. Well, Gruby was short in stature but big in brain. When he died, he left a fortune of ₣300,000 to his kin-ship of several dozen persons in the Gruby mishpakhah. Sure, this was a bit less than the £200,000 Sir Erasmus Wilson had left a few years earlier, and more than the 51,000 fl. Salomon Stricker left to his widow (still a lordly sum) in the very same year. Wilson was of Scottish-Norwegian descent, while Gruby and Stricker were Hungarian Jews.

During the nineties of two centuries ago, another Serbian gentle-man Dr Milroad Obradović dedicated much time to investigate the background of the master and the Gruby clan. I knew of this en-

deavor through Professor Kovać, but, alas, before Obradović could finish and publish, he met his untimely death. Professor Nikola Gaćeša, together with a foreword by Professor Kovać, published part of it posthumously in Serbian in 2006. More details of the Gruby story will emerge in the history seminar at the Seoul World Con-gress of Dermatology in 2011 by Professor Sarolta Kárpáti, head and chairwoman of dermatology at the Semmelweis University in Budapest. Why then? There is some suspicion that Gruby was in fact born in 1811 and not in 1810.

On occasion of the forthcoming bicentennial of Gruby’s birth (Au-gust 20), a bronze portrait bust was unveiled in his birthplace, a small community on the right bank of the lower Danube about 200 km south of Budapest, in Serbia of today (Figure). This move was initiat-ed by Professor Teodor Kovać, erstwhile president of the Jewish Com-munity in Novi Sad (Úividék/Neusatz/Neoplanta), regional capital of the Vojvodina, and by the local administrative authorities.

hUMANITIeS AND SCIeNCe

Still another point to be emphasized: 200 years ago, the humani-ties and the sciences developed alongside education. The above-mentioned Agostino Bassi for instance, as much as his teacher Lazzaro Spallanzani (born 1729) (the portraits of both hung in Louis Pasteur’s laboratory), were both law graduates. Imagine the polyglot capabilities a man such as Gruby must have had: Yiddish and Hebrew as much as Hungarian were sung at his cradle; countless years of Latin, Greek, and German followed during the classes of gymnasium; then medical school; followed by 50 years of French (which he probably had to learn earlier since many at the time, including Kaposi, insisted that French

hISTORICAL VIGNeTTeCharles Steffen, MD, Section Editor

David Gruby 1810–1898: Unveiling of a Portrait Bust in His Birthplace

Karl Holubar, MD, FRCP, FRSM, GSE;1 Norbert Wikonkál, MD2

David Gruby (1810–1898) was an early mycologist, the most prominent between Agostino Bassi (1773–1856) who discovered the fungus on silk worms and Raymond Sabouraud (1864–1938) who wrote the first textbook in the field.

September/October 2010 HISTORICAL VIGNETTE

295SKINmed. 2010;8:294–295 David Gruby 1810–1898

be spoken at the table in the home regularly, as confided to me [KH] by his granddaughter Hildegard).

Admittedly, a PhD in medicine/biology today may be much more knowledgeable than Gruby was in this field. What immea-surable flexibility, however, the study of more than half a dozen languages (and cultures) must have conferred to his thinking, a far cry from the monolingual Anglo-Saxon of today.

Scientific thinking, including planning handwork, needs both the humanities and the sciences. This is neglected today, deplor-ably so. The late giant of our field, Darrel Wilkinson, and I [KH] discussed this topic time and again over the decades, eg, compar-ing the number of lines we had to learn by heart of one or the other classical poets, and the influence such background has on our present-day activities.

Gruby was an early hero of microscopy, before the developments of Ernst Abbé, Carl Zeiss, Carl Weigert, Ira van Gieson, Oskar Israel, and Robert Remak, to haphazardly name just a few. They facilitated the application of microscopic techniques, until the star in mycology appeared on the scene, Raymond Sabouraud, who was born in the year when Johann Lucas Schönlein died (1864).

DeDICATION

Being invited to remove the cloth from the memorial bust and place a wreath, together with the local dignitary in the name of

the Vienna and Budapest medical schools, was a signal honor for the authors. These lines may serve to stimulate our memory of the early microscopic researcher and enliven the overabundance of the medico-Judean heritage of Central Europe, the date, April 12, 2010 (28 Nissan), Holocaust Day, being conducive to this act.

ReFeReNCe

1 Kovać T. Povodom 185-godišnice rođenja David Gruby 1810–1898 (on occasion of David Gruby´s 185th birth anniversary). Med Pregl. 1995;XLVIII:123–142.

Figure. Unveiling of Gruby´s bust, April 12, 2010, Bačko Dobro Polje, Serbia (©N. Wikonkál).

VINTAGe LABeL



296SKINmed. 2010;8:296 © 2010 Pulse Marketing & Communications, LLC

From the Department of Dermatology, Nelson R. Mandela School of Medicine, Durban, South Africa

A 35-year-old male prisoner presented with a 9-month history of an enlarging, asymptomatic plaque on the chin, which later ulcerated and became secondarily

infected. The patient was positive for the human immunodefi-ciency virus, with a CD4 cell count of 135.

The Mantoux test was positive and blistering, and findings on chest x-ray were normal.

Skin biopsy and tuberculosis culture confirmed Lupus vulgaris. The patient was commenced on antituberculosis treatment and responded very well.

PhOTO CAPSULeS Ncoza C. Dlova, MBChB, FCDerm, Section Editor

Lupus Vulgaris in an HIV-Positive PatientNcoza C. Dlova, MBChB, FCDerm

Figure 1. Lupus vulgaris.

Figure 2. Lupus vulgaris with blistering Mantoux test.

Figure 3. Lesion after more than 2 months of antituberculosis treatment.

STOMATOPyROSISAlso known as burning mouth/tongue syndrome (BMS), stomatodynia, glossopyrosis, or glossodynia, stomatopyrosis represents burning in the mouth and may be caused by the following medications:

Adapted from Litt, JZ. Curious, Odd, Rare, and Abnormal Reactions to Medications. Fort Lee, NJ: Barricade Books; 2009:165–168.

Angiotensin- converting enzyme inhibitors

Penicillin

Atacand

Prinivil

Cephalosporins

Sinequan

Chloroptic

Sustiva

Gold

Teveten

Klonopin

Vasotec

Mercury

Viramune

Neurontin

Zephrex

Pamelor

Zestril

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From the Division of Dermatology, Loyola University Medical Center, Maywood, IL;1 the Department of Dermatology, University of California, Davis, School of Medicine, Sacramento, CA;2 Providence Medical Group Dermatology Surgery, Portland, OR;3 the Department of Dermatology, Saint Louis University School of Medicine, Saint Louis, MO;4 and the Department of Dermatology, Oregon Health & Science University, Portland, OR5

*All authors were affiliated with Saint Louis University School of Medicine at the time this contribution was written.Address for Correspondence: Joshua Mandrell, MD, Division of Dermatology, Loyola University Medical Center, Building 54, Room 101, 2160 South First Avenue, Maywood, IL 60153 • E-mail: [email protected]

Klippel-Trenaunay syndrome (KTS or angio-osteohy-pertrophy) is a sporadic vascular malformation with no confirmed genotype that consists of a triad of superficial

vascular malformation of the skin in association with venous var-icosities and underlying bony and soft tissue hypertrophy.1 The distribution of the vascular stain in a mosaic pattern led Happle to postulate that the disorder would only occur in the setting of a somatic mutation. Genetic analysis has identified several cases of KTS associated with an upregulation of VG5Q, an angiogenic factor.2 Vascular birthmarks are classified into 2 major catego-ries, which include hemangiomas and the rarer vascular mal-formations. Hemangiomas are characterized by endothelial cell hyperplasia, a rapid proliferative phase, followed by a period of involution.3 In contrast, vascular malformations lack endothelial hyperplasia, do not involute, and are categorized according to the type of vessel involved and hemodynamic features.3

The condition acne keloidalis nuchae describes keloidal pap-ules often coalescing into plaques arising on the posterior scalp and neck. The lesions are thought to be secondary to chronic perifolliculitis and folliculitis that results in destruction of the follicle and liberation of hair shafts with ensuant fibrosis and ultimately keloid formation. Acne keloidalis nuchae typically occurs in men of African descent but also occurs in Hispan-ics, Asians, and less often in Caucasians. Patients present with suppurative inflammation of the follicular unit that heals with keloid papules which may coalesce into plaques over time.

We present a patient with KTS and a 10-year history of acne keloidalis nuchae with massive keloidal hypertrophy on the occipital scalp in the distribution of his congenital capillary malformation. Literature searches were performed to assess previous cases demonstrating a connection between keloid

CASe STUDyVesna Petronic-Rosic, MD, MSc, Section Editor

Keloid Formation Occurring in the Distribution of a Congenital Vascular Malformation

Joshua Mandrell, MD;1 Summer Youker, MD;2 Erin J. Allen, MD;3 Maria Yadira Hurley, MD;4 Joseph Obadiah, MD5

A 35-year-old African American man presented with complaints of malodorous drainage from hypertrophic lesions on his occipital scalp (Figure 1, inset). The patient had no family history of keloid formation and no other keloids on his body. The hypertrophic mass on his scalp had been present for 10 years and had not been a result of any type of mechanical, surgical, or laser treatment. It corresponded to the distribution of a large vascular malformation over the occiput (Figure 1). The vascular malformation extended from the occipital scalp to the right parietal scalp, the right side of the face, neck, upper chest, and right arm, with varicosities and hypertrophy of the right upper extremity (Figure 2). The vascular malformation over the right parietal scalp and ear was characterized by bleb formation and hypertrophy of the right ear. The patient reported that no manipulation, including laser treatment, of the vascular malformation had been previously performed. He did state that a previous dermatologist had attempted serial surgical excision of the cerebriform nodules but retired during the course of treatment. He stated that the appearance of his keloid formation and port-wine stain had not changed during the past 10 years. A previous biopsy of a hypertrophic lesion showed histologic findings consistent with folliculitis keloidalis nuchae. Cephalexin 500 mg 4 times daily for 14 days was prescribed for the purulent drainage. A Doppler ultrasound was ordered of the right upper extremity to evaluate for an arteriovenous malformation and showed no evidence of venous thrombosis or arteriovenous malformation. On a second visit 2 weeks later, the hypertrophic lesions continued to show drainage. Clindamycin gel to be applied twice daily to the scalp was added. The patient also had magnetic resonance imaging with and without gadolinium contrast (Figure 3) ordered, which showed a large hypertro-phic giant scalp keloid overlying the occipital and suboccipital region measuring 12×19 cm. There was soft tissue thickening involving the right external ear, extending inferior to the right ear, overlying an intact parotid gland. There was no evidence of muscular or skull invasion.

September/October 2010 CASE STUDY

299SKINmed. 2010;8:298–300 Keloid Formation

formation and underlying vascular malformations. Cross refer-ence of “Kippel-Trenaunay” and “keloid,” “vascular malforma-tion” and “keloid,” “port-wine stain” and “keloid,” and “Sturge Weber” and “keloid” in both OvidMedline and PubMed yield-ed no results. Similar growth factors and abnormal structural elements, however, are involved in the etiology of both vascular malformations and keloids.

One of the major hypotheses for the pathogenesis of keloids is the concept that there is enhanced growth factor activity. A key explanation behind the alterations in growth factor activ-ity in keloids is the relative hypoxia found in keloid tissue. The hypoxic microenvironment present in the early stages of wound healing triggers the release of angiogenic growth fac-tors, inducing endothelial proliferation, delaying wound heal-ing, and increasing collagen production.4 Some evidence also suggests that keloids are, to a degree, angiogenic lesions. His-tologically, keloids show increased blood vessel density com-pared with normal dermis or normal scars. In fact, many of the treatments for keloids such as pulsed dye laser, interferon, and imiquimod are believed to target keloid development by inhibiting angiogenesis.

In vitro and in vivo studies have demonstrated a significant-ly higher angiogenic activity of keloid fibroblasts compared with normal fibroblasts, and vascular endothelial growth fac-tor (VEGF) levels have been demonstrated to correlate with this activity.5 Hypoxic stress, an acute condition of the early wound, has been characterized as a powerful inducer of VEGF expression in vitro and in healing skin wounds.6,7 Recent works have demonstrated an accumulation of hypoxia-inducible fac-tor 1 a protein in freshly biopsied keloid tissue, thus providing first evidence that a local state of hypoxia exists in keloids.8 Hypoxia-inducible factor 1 a contributes to keloid formation by activating transcription of VEGF.7,9 Reports have also dem-onstrated a strong association between elevated tissue expres-sion of VEGF and vascular malformations.10 Nitric oxide is another molecule implicated in both the regulation of vascular endothelial cell proliferation11,12 by increasing VEGF expres-sion and in the genesis of keloids.

This is the first case report, to our knowledge, of massive keloid overgrowth corresponding to the distribution of an underlying vascular malformation. This interesting case highlights the idea that in a susceptible patient, common, underlying elements in-cluding growth factors, hypoxia, and nitric oxide may play a role in the development of both vascular malformations and keloids. The most common causes of keloid formation are mechanical. Although the clinical time line does not suggest it, this patient’s keloid could have resulted from surgical treatment of his vascular

formation, or, theoretically, from bleb formation, causing fol-licular occlusion and keloid formation. Although one would sus-pect keloid formation associated with a vascular malformation to be more common if the pathogenic mechanisms and etiologies were overlapping, as we theorize, it is nonetheless an interesting and valid idea. Because this is an isolated case, more research needs to be done in this area to truly link the pathogeneses of these two conditions.

ReFeReNCeS

1 Capraro P, Fisher J, Hammond D, et al. Klippel-Trenaunay syn-drome. Plast Reconstr Surg. 2002;109:2052–2062.

2 Garzon MC, Huang JT, Odile E, et al. Vascular malformations. J Am Acad Dermatol. 2007;56:541–564.

3 Powell J. Update on hemangiomas and vascular malformations. Curr Opin Pediatr. 1999;11:457–463.

4 Al-Attar A, Mess S, Thomassen JM, et al. Keloid pathogenesis and treatment. Plast Reconstr Surg. 2006;117:286–300.

5 Fujiwara M, Muragaki Y, Ooshima A. Upregulation of transform-ing growth factor–beta 1 and vascular endothelial growth factor in cultured keloid fibroblasts: relevance to angiogenic activity. Arch Dermatol Res. 2005;297:161–169.

6 Le AD, Zhang Q, Wu Y, et al. Elevated vascular endothelial growth factor in keloids: relevance to tissue fibrosis. Cells Tis-sues Organs. 2004;176:87–94.

Figure 1. Acne keloidalis nuchae in distribution of congenital vascular malformation. Soft compressible vascular plaques on parietal scalp with firm keloidal lesions on occiput (inset).


300SKINmed. 2010;8:298–300 Keloid Formation

7 Zagzag D, Zhong H, Scalzitti JM, et al. Expression of hypoxia-in-ducible factor 1-alpha in brain tumors: association with angiogen-esis, invasion, and progression. Cancer. 2000;88:2606–2618.

8 Krieg M, Haas R, Brauch H, et al. Up-regulation of hypoxia-induc-ible factors HIF-1-alpha and HIF-2-alpha under normoxic conditions in renal carcinoma cells by von Hippel-Lindau tumor suppressor

gene loss of function. Oncogene. 2000;19:5435–5443.9 Gira AK, Brown LF, Washington CV, et al. Keloids demonstrate

high-level epidermal expression of vascular endothelial growth factor. J Am Acad Dermatol. 2004;50:850–853.

10 Zhang L, Lin X, Wang W, et al. Circulating levels of vascular endo-thelial growth factor in differentiating hemangioma from vascular malformation patients. Plast Reconstr Surg. 2005;116:200–204.

11 Cobbold CA. The role of nitric oxide in the formation of keloid and hypertrophic lesions. Med Hypotheses. 2001;57:497–502.

12 Bussolati B, Dunk C, Grohman M, et al. Vascular endothelial growth factor receptor-1 modulates vascular endothelial growth factor-mediated angiogenesis via nitric oxide. Am J Pathol. 2001;159:993–1008.

Figure 2. Port-wine stain and limb hypertrophy of right side.

Figure 3. Magnetic resonance imaging of head showing hypertro-phic scalp keloid and soft tissue thickening of right external ear.

VINTAGe LABeL




From the University of Malta Medical School, MaltaAddress for Correspondence: Joseph L. Pace, MD, FRCPEdin, FRCPLond, 16 Marquis Scicluna Street, Naxxar NXR2069, Malta • E-mail: [email protected]

The drugs mainly involved in aggravating/triggering pso-riasis1–3 are the antimalarials, lithium, b-blockers,4 and a large miscellaneous group of drugs including 3,4-methyl-

enedioxymethamphetamine (ecstasy),5 losartan,6 terbinafine,7 and increasingly anti–tumor necrosis factor a medication.8 With the exception of antimalarials, these drugs can both induce and trigger psoriasis with almost equal frequency, namely they induce psoria-sis de novo or they exacerbate an already existing psoriasis in 30% to 50% of reported cases. In contrast, antimalarials do not induce psoriasis de novo, but only trigger already existing psoriasis.9

Psoriasis completely clears up after withdrawal of the drug in only 30% of patients taking antimalarials, as compared with more than 60% of those receiving lithium and nearly 50% of those receiving b-blockers. This is probably also why the “incu-bation period” of the cases induced by antimalarial drugs (1–2 months) is much shorter than that of lithium and b-blockers (often up to 12 months). It is postulated that in triggered pso-riasis (as with antimalarials), the drug only sets off with a chain of pathologic events previously programmed and ready to be set off, whereas in true drug-induced cases (as in some cases of lithium and b-blockers), the drug is supposed to cause more profound changes and therefore more time is needed for these changes to occur.9,10 It should be noted that a recent study sug-gests that there is no strong objective evidence to refute or sup-port the role of antimalarials in the exacerbation of psoriasis,11

but, in fact, the association is widely accepted, with a reported incidence of 18%.

MeFLOQUINe

Mefloquine was developed by the US Army and introduced for the treatment of malaria in the late 1970s. It was first used for prophylax-is in 1985. Mefloquine is commonly prescribed to prevent malaria in travelers and has replaced other drugs because Plasmodium falciparum is commonly resistant to them. Mefloquine may be associated with serious and occasionally permanent neuropsychiatric harmful effects that may occur in up to one third of persons taking it, thus consider-ably limiting its acceptability. There is evidence from nonrandomized studies that mefloquine has potentially harmful effects in tourists and business travelers, and its use needs to be carefully balanced against this risk.12 It has also been postulated that preceding thyroid and liver problems or concurrent medication may be significantly related to mefloquine toxicity. In addition, it was also suggested that in the ab-sence of alcohol intake, oral contraceptives, thyroid disease, and liver disease, the drug can safely be taken in most situations.13

MeFLOQUINe AND PSORIASIS

Mefloquine is chemically related to quinidine, which has also been known to aggravate psoriasis, but only one case linking a flare of psoriasis to mefloquine ingestion has appeared in the literature. Re-searchers14 point out that severe psychological stress preceded the

CASe STUDy

Psoriasis Triggered By MefloquineJoseph L. Pace, MD, FRCPEdin, FRCPLond

A 46-year-old Caucasian man living on the central Mediterranean island of Gozo (Malta) was started on mefloquine 250 mg once weekly before a trip to lower Egypt. He took his medication 1 week before starting his holiday and was advised to continue it for 4 weeks after returning. He did not take any other medication and enjoyed the holiday, which he initially intended to repeat in the near future. His medical history revealed a number of episodes of psoriasis for which he sought dermatologic advice. He had been given systemic therapy on at least one occasion, but the condition had been fairly quiescent for some time and he had not needed to consult a dermatologist for more than 4 years. Soon after the third tablet of mefloquine and effectively just after his return home to Gozo, the patient noticed that the psoriasis was “creeping back.” He noted progressive deterioration in his skin problem but nevertheless finished the recommended course of therapy considering that “being sure about not developing malaria was far more important than a touch of psoriasis.” The psoriasis worsened to the extent that he had taken off work for 2 weeks from his job as a self-employed carpenter at the time of referral. On examination, clearly there was a significant flare up of his psoriasis with severe involvement of the hands (Figure 1) and feet and less so over the rest of his body. He had been off work and matters were steadily getting worse in spite of topical treatment with a combination of calcipotriol-betamethasone ointment. Oral methotrexate 15 mg once weekly was commenced together with topical therapy with good results (Figure 2).


302SKINmed. 2010;8:301–302 Psoriasis Triggered By Mefloquine

development of psoriasis in their case finding and wonder whether this well recognized side effect of mefloquine may have influenced the subsequent flare of psoriasis. Stress was not apparent in the pa-tient reported here. Be that as it may, the association fails to find a mention in the manufacturer’s Food and Drug Administration–ap-proved extensive information leaflet15 or in the current online ad-vice to patients with psoriasis given by the UK’s Health Protection Agency,16 which categorically states that “Proguanil, atovaquone/proguanil (Malarone), doxycycline, and Mefloquine do not cause problems in those with psoriasis.”

CONCLUSIONS

While cutaneous side effects of mefloquine have been greatly overshadowed by the neuropsychiatric problems related to this

drug, it is important to remember that they can occur. It appears that in addition to cutaneousvasculitis,17 mefloquine may also, although rarely, cause an exacerbation of psoriasis. It nevertheless remains a choice in psoriatic patients who cannot avoid going to an area where malaria is endemic, but the possibility of a flare up needs to be kept in mind. Additionally, the very frequent psy-chological side effect encountered with this drug may constitute a potential further aggravating factor.

ReFeReNCeS

1 Tsankov N, Angelova I, Kazandjieva J. Drug-induced psoriasis: rec-ognition and management. Am J Clin Dermatol. 2000;1:159–165.

2 Wolf R, Ruocco V. Triggered psoriasis. Adv Exp Med Biol. 1999;455:221–225.

3 Rongioletti F, Fiorucci C, Parodi A. Psoriasis induced or aggra-vated by drugs. J Rheumatol Suppl. 2009;83:59–61.

4 Brauchli YB, Jick SS, Curtin F, et al. Association between beta-blockers, other antihypertensive drugs and psoriasis: population-based case-control study. Br J Dermatol. 2008;158:1299–1307.

5 Tan B, Foley P. Guttate psoriasis following ecstasy ingestion. Australas J Dermatol. 2004;45:167–169.

6 Lamba G, Palaniswamy C, Singh T, et al. Psoriasis induced by losartan therapy: a case report and review of the literature. Am J Ther. 2009 Dec 19. [Epub ahead of print]

7 Szepietowski JC. Terbinafine exacerbates psoriasis: case report with a literature review. Acta Dermatovenerol Croat. 2003;11:17–21.

8 Shale M, Ghosh S. Learning the lessons of antitumour necro-sis factor therapy-associated psoriasis. Can J Gastroenterol. 2009;23:674–676.

9 Wolf R, Lo Schiavo A, Lombardi, ML, de Angelis F, Ruocco V. The in vitro effect of hydroxychloroquine on skin morphology in psoriasis. Int J Dermatol. 1999;38:154.

10 Vine JE, Hymes SR, Warner NB, Cohen PR. Pustular psoriasis induced by hydroxychloroquine: a case report and review of the literature. J Dermatol. 1996;23:357–361.

11 Herman SM, Shin MH, Holbrook A, Rosenthal D. The role of anti-malarials in the exacerbation of psoriasis: a systematic review. Am J Clin Dermatol. 2006;7:249–257.

12 Croft AM, Garner P. Mefloquine for preventing malaria in non-immune adult travellers. Cochrane Database Syst Rev. 2008;23:CD000138.

13 Croft AM, Herxheimer A. Adverse effects of the antimalaria drug, mefloquine: due to primary liver damage with secondary thyroid involvement? BMC Public Health. 2002;2:6.

14 Potasman I, Seligmann H. A unique case of mefloquine-induced psoriasis. J Travel Med. 1998;5:156.

15 FDA-approved patient information leaflet on Lariam. http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHu-manMedicalProducts/ucm153319.htm. Accessed July 7, 2010.

16 Health Protection Agency Web site. http://www.hpa.org.uk/web/HPAweb&HPAwebStandard/HPAweb_C/1203496943315. Ac-cessed July 7, 2010.

17 Pace JL, Scerri L. Mefloquine-associated cutaneous vasculitis. Int J Dermatol. 1993;32:517–518.

Figure 1. Psoriasis of the hands following mefloquine ingestion.

Figure 2. Improvement after treatment and discontinuation of mefloquine.



From the Department of Dermatology, Keck School of Medicine, University of Southern California,1 and the Department of Family Practice, David Geffen School of Medicine at UCLA,2 Los Angeles, CAAddress for Correspondence: Martin H. Kay, MD, PhD, Assistant Professor, Departments of Dermatology, Western College of Medicine and Keck School of Medicine, University of Southern California, 201 South Buena Vista Street, Burbank, CA 91505 • E-mail: [email protected]

Aquatic dermatoses are being seen more often in derma-tology offices due to the increase in travel of patients to exotic locales. Although many of these conditions are

self-limiting and require only topical care and reassurance, oth-ers may need quick diagnoses and treatment with an appropriate antibiotic or antiparasitic medication. It is important to real-ize that these aquatic dermatoses can be acquired right here at home. Natural bodies of water, swimming pools, and aquariums contain many living organisms. Some of these aquatic species may cause traumatic or toxic skin reactions after contact, as well as life-threatening systemic reactions.1,2 Injuries may be com-plicated by secondary bacterial infections, Staphylococcus aureus being the most common. Vibrio vulnificus infections also occur with associated cirrhosis.3,4

Many people today have salt water tropical aquariums in their houses that have lionfish and other types of scorpion fish, which can envenomate and cause pain, bleeding, and systemic symp-toms.5 A relatively rarely seen aquatic dermatosis in America, caused by a marine worm (the “bristle worm,” from the Poly-chaeta class of annelid worms), is now being seen here due to home aquarium exposure. The polychaetes have a pair of fleshy protrusions (parapodia) on each body segment that have many

bristles (chaetae).6 Bristle worms are composed of many seg-ments and have bristles (setae) that extend from both sides of the body. They also have a head with eyes, antennae, and sensory palps. These worms are bottom dwellers often found on rocks, coral, and sponges.7 Of the many species of worms in the world, the bristle worm is one of the most dangerous.8 When touched or threatened, the bristle worm contracts, causing its parapodial chaetae to erect in a defensive position. These spines (chaetae) are sharp, needlelike, and very fragile, breaking off in the skin when coming into contact with it.9

Contact with a bristle worm produces a burning sensation ac-companied by moderate edema, a papular eruption, and oc-casional necrotic lesions.5 Itching develops soon afterward and may be quite severe. Multiple stings may lead to considerable edema and paraesthesia. The most severe itching and burning will usually subside within 10 days; however, some may expe-rience numbness, itching, and pain for several weeks follow-ing contact. Although it is not known what toxin the bristle worm produces, the intensity and persistence of symptoms helps support the concept of a toxin-associated injury. Because there is relief of pain in hot water, it is thought that the toxin is thermolabile.9

CASe STUDy

Tropical Aquarium Aquatic Dermatoses: Bristle Worm Envenomation

Martin H. Kay, MD, PhD;1 Rachel D. Bak, MD;2 David N. Kay, BA1

A 55-year-old high school science teacher with diabetes presented with severe pain and swelling of his left hand. He reported receiving a “shock” 2 days earlier while cleaning out his classroom’s aquarium with a bare left hand. Thinking it was a “short” in the electrical connections to the aquarium’s pump, he disconnected the electrical cord and continued to clean behind the pump mechanism. After a few more such shocks he put on a glove and retrieved 10 foot-long worms. Antibiotics were started. It took more than 2 weeks for the hand to return to its normal size. On presentation to our office, the patient’s left hand was moderately swollen, with blistering and purpura seen on his distal fingers. He reported pain, itching, and numbness in the hand, which was getting worse. No systemic symptoms were reported. The patient was a non–insulin-dependent diabetic who was also taking warfarin for a carotid vascular problem. He brought to our office a bucket with coiled aquatic worms at the bottom (Figure 1). When extended, they measured about 1 foot and their morphology could be better seen (Figure 2). No spicules could be seen in the patient’s hand on magnification, but taping was performed to remove any possible residual spicules. The patient was given oral antibiotics, a Medrol dose pack, oral antihistamines, and topical corticosteroids. Within 1 day of starting treatment his symptoms and hand swelling began to abate, by 1 week his hand skin peeled, and by 2 weeks the swelling and skin appearance was almost back to normal. Bacterial cultures of the hand’s wounds showed no growth.


304SKINmed. 2010;8:303–304 Bristle Worm Envenomation

The two most effective ways to remove the bristles are to use forceps or tape. The forceps method is usually too difficult because the very small bristles can be deeply embedded in the skin. One usually applies adhesive tape to the skin and a quick removal of the tape can pull out the bristles. To re-lieve pain, one can place the affected area in a hot water bath (110°F–115°F) with dilute vinegar or ammonia. Other topical remedies include meat tenderizer and 40% to 70% isopropyl alcohol. The pruritic and local urticarial component may be treated with cooling creams or lotions, topical corticosteroids, and antihistamines.9

CONCLUSIONS

We report a case of a middle-aged diabetic teacher who was stung repeatedly by a tropical sea worm, the bristle worm, when clean-ing out the classroom’s salt water aquarium. His hand significantly swelled and blistered, and, after treatment was initiated a few days post-envenomation, his recovery took approximately 2 weeks.

Sea worms of the family Amphinomidae can have chitinous bristles around their bodies. When touched, they raise their bristles in defense as the bodies of the worms contract. This presents to any enemy a continuous bristled surface. The bristles detach easily and can penetrate the skin in a similar fashion to cactus spines. They can be as difficult to remove as cactus spines as well.8,9 The worms found in our case had all the traditional markings of Hermodice carunculata Kinsberg, the most common bristle worm of the Gulf of Mexico. It most likely entered the school aquarium in porous rock bought at a local store.

Our case study highlights the increasingly more common occur-rence of aquatic skin injuries and the need to be vigilant even with our own aquariums. Our patient had a relatively uneventful recovery but he had other medical problems that could have led to serious complications.

ReFeReNCeS

1 Ulrich H, Landthaler M, Vogt T. Aquatic dermatoses. J Dtsch Dermatol Ges. 2008;6:133–147.

2 Schaper A, Desel H, Ebbecke M, et al. Bites and stings by exotic pets in Europe: an 11 year analysis of 404 cases from Northeastern Ger-many and Southeastern France. Clin Toxicol (Phila). 2009;47:39–43.

3 Haddad V Jr, Lupi O, Lonza JP, Tyring SK. Tropical dermatology: marine and aquatic dermatology. J Am Acad Dermatol. 2009;61:733–750.

4 Chan WL, Chan CH, Chan TY. Vibrio vulnificus septicaemia and necrotizing fasciitis after a prick from the dorsal fin of a tilapia. Trans R Soc Trop Med Hyg. 1999;93:174.

5 Phillips C, Brady WH. Sea Pests, Poisonous or Harmful Sea Life of Florida and the West Indies. University Miami Press; Miami, FL. 1953:247.

6 Polychaete. Wikipedia. http://en.wikipedia.org/wiki/Polychaete. Accessed August 15, 2008.

7 Chesapeake Bay Program-Bay Field Guide. http://www.chesa-peakebay.net/bfg_bristle_worms.aspx?menuitem=14416. Ac-cessed August 15, 2008.

8 eMedicineHealth. Bristle worm sting. http://www.emedicine-health.com/wilderness_bristleworm_sting/article_em.htm. Ac-cessed August 15, 2008.

9 Smith M. Cutaneous problems related to coastal and marine worms. Dermatol Ther. 2002;15:34–37.

Figure 1. Hermodice carunculata Kinsberg bristle worm.

Figure 2. Hermodice carunculata Kinsberg bristle worms uncoiling.



From the Department of Pediatric Hematology, Baskent University Faculty of Medicine, Ankara, Turkey;1 and the Clinic of Dermatology, Merzifon Military Hospital, Merzifon, Amasya, Turkey2

Address for Correspondence: Engin Senel, MD, Merzifon Military Hospital, Clinic of Dermatology, Merzifon-Amasya, Turkey • E-mail: [email protected]

Cutaneous involvement can be the presenting sign of hematologic malignancies in children. Leukemia cutis is the infiltration of neoplastic leukocytes into the skin

with clinically identifiable cutaneous lesions, and it is associated with poor prognosis of leukemia.

The incidence of AML is 4.8 to 6.6 per million in children younger than 15 years.2 There is no male or female preponder-ance. The incidence of leukemia cutis appears to be relatively higher in children than in adults. Skin involvement in leukemia has been observed in 25% to 30% of patients. Most of these patients have myelogenous leukemia. The pathogenesis of the migration of leukemic cells to the skin is not clear.

Skin lesions of leukemia cutis include specific lesions resulting from the infiltration of the skin by the leukemic cells and nonspecific lesions such as erythema, ecchymoses, or reactive dermatosis (eg, Sweet syndrome–like lesions and urticaria). The specific lesions of leukemia cutis are often asymptomatic and mostly seen in the nodu-lar morphology.3 Blueberry muffin is a term referred to the appear-ance of the specific nodular lesions in addition to purpuric lesions.

Although skin involvement may be the presenting feature of leukemia in a patient, as in our case, leukemia cutis is often a late involvement of leukemia and is associated with poorer prog-nosis. Investigators described 9 children with skin lesions as a presenting sign of leukemia and reported that these patients had unfavorable prognostic factors such as hepatosplenomegaly, ear-ly onset, and high leukocyte count.4 In a review of the medical literature on AML from 1965 to 2001, it was reported that the overall survival rate was 6% at 2 years in patients with leukemia cutis and 30% in those without leukemia cutis.5

The differential diagnosis of leukemia cutis in infancy includes metastatic neuroblastoma, urticaria pigmentosa, and Langer-hans cell histiocytosis. Histopathologic findings of leukemia cutis show different patterns of infiltration of leukemic cells de-pending on the subtype of leukemia. The most common pattern has been reported to be diffuse infiltration, which may separate collagen bundles.6 A bandlike or compact nodular infiltration pattern may also be seen in acute myeloid leukemia with the large cells. Immunophenotyping of the infiltration with specific markers is required for subtyping. Acute myeloid leukemia cells

CASe STUDy

Purpuric Nodules and Macules on the Scalp of an 18-Month-Old Boy

Baris Malbora, MD;1 Engin Senel, MD;2 Zekai Avci, MD;1 Namik Ozbek, MD1

An 18-month-old boy was consulted to a pediatric clinic with a 5-month history of purpuric macules and nodules on the scalp. He had a history of trauma (falling down from a chair) to the scalp about 6 months before the consultation. He had been brought to an emergency department after the trauma. Cranial computed tomography revealed a small crack on the temporal bone. Purpuric macules and nodules of the scalp had been noticed on the control 1 month later. Results of total blood tests had been within normal limits. Dermatologic examina-tion disclosed multiple pink to violaceous infiltrated cutaneous nodules and purpuric macules with diameters of 0.5 to 1.5 cm on his scalp (Figure 1). No petechiae or ecchymoses were seen. Cervical lymphadenopathy was detected during physical examination. There was no hepatosplenomeg-aly. A punch biopsy was obtained from one of the infiltrated nodules and was sent for histopathologic examination. Histopathologic examination revealed diffuse dermal and subcutaneous edema, erythrocyte extravasation and infiltration by monomorphic cells with large hyperchro-matic nuclei, and high mitotic activity (Figure 2). Histopathologic staining was positive for leukocyte common antigen and CD68 in these cells. Results of complete blood cell count of the patient were as follows: hemoglobin: 8.44 g/dL; white blood cell count: 29.2 × 109/L; and platelet count 55.6 × 109/L. Bone marrow aspirate results showed 68.4% blast cells and a biopsy specimen confirmed the diagnosis of acute myeloid leukemia, with flow cytometry findings positive for acute monoblastic leukemia (AML) French-American-British (FAB)-M5 phenotype. We initiated induction chemotherapy for AML (AML-M5) according to the AML Berlin–Frankfurt–Munster 2004 protocol.1 Complete resolution of the leukemia cutis lesions was attained with chemotherapy at the end of the first month of treatment.


306SKINmed. 2010;8:305–306 Purpuric Nodules and Macules on the Scalp

stain with lysozyme but not with chloracetate esterase. M4 and M5 types of acute myeloid leukemia express CD15, CD43, and CD45; CD68 is also expressed in the M4 and the M5 types.7

Treatment of childhood acute myeloid leukemia consists of remis-sion induction chemotherapy followed by post-remission chemo-therapy with or without bone marrow transplant; however, aggres-sive chemotherapy and bone marrow transplant have been known to add increased risk of morbidity and mortality. A few cases with spontaneous regression have been reported in the literature.8

Physicians should be aware of the clinical features of leukemia cutis because occurrence of the skin lesions may be the present-ing sign of leukemia and a skin biopsy may help in early diagno-sis of the hematologic malignancy.

ReFeReNCeS

1 Creutzig U, Zimmermann M, Ritter J, et al. Treatment strategies and long-term results in paediatric patients treated in four con-secutive AML-BFM trials. Leukemia. 2005;19:2030–2042.

2 Gurney JG, Severson RK, Davis S, et al. Incidence of cancer in

children in the United States. Sex-, race-, and 1-year age-specific rates by histologic type. Cancer. 1995;75:2186–2195.

3 Campbell DC, Grippaudo FR, Lewandowski R. Congenital leu-kemia cutis: an unusual manifestation of a rare disease. Plast Reconstr Surg. 1997;100:1809–1811.

4 Millot F, Robert A, Bertrand Y, et al. Cutaneous involvement in children with acute lymphoblastic leukemia or lymphoblastic lymphoma. The Children’s Leukemia Cooperative Group of the European Organization of Research and Treatment of Cancer (EORTC). Pediatrics. 1997;100:60–64.

5 Zweegman S, Vermeer MH, Bekkink MW, et al. Leukaemia cu-tis: clinical features and treatment strategies. Haematologica. 2002;87:ECR13.

6 Zhang IH, Zane LT, Braun BS, et al. Congenital leukemia cutis with subsequent development of leukemia. J Am Acad Dermatol. 2006;54:S22–S27.

7 Biondi A, Cimino G, Pieters R, et al. Biological and therapeutic aspects of infant leukemia. Blood. 2000;96:24–33.

8 Grundy RG, Martinez A, Kempski H, et al. Spontaneous remis-sion of congenital leukemia: a case for conservative treatment. J Pediatr Hematol Oncol. 2000;22:252–255.

Figure 1. Multiple pink to violaceous cutaneous nodules and purpuric macules on the scalp. Figure 2. Diffuse dermal and subcutaneous infiltration by

monomorphic cells (Hematoxylin-eosin stain, original magnifi-cation ×10).

VINTAGe LABeL



307SKINmed. 2010;8:307 © 2010 Pulse Marketing & Communications, LLC

For the esthetician, a most en-cyclopedic text. This book is so chock full of facts that its useful-ness will not only be for its in-tended audience of estheticians and physician extenders but also for dermatologists and cosmetic chemists.

The textbook begins aptly with a chapter concerned with defining the roles of the licensed estheti-cian—“a person who is profes-sionally interested in the health

and beauty of…the skin”—the nurse and medical assistant, the physician assistant, nurse practitioner, and most of all, the physi-cian, all of whom may be involved in the medical spa.

Major sections include basic physiology of the skin, reflecting the senior author’s excellent training at the University of Cali-fornia at San Francisco. This means good discussions of the skin barrier and contact dermatitis. There are additional snippets about commonly encountered skin diseases that could be useful for patient handouts about various diagnoses.

Additional sections are devoted to cosmeceuticals and “putting it into practice.”

In the chapter on botanical ingredients, there is straightforward information, as reflected by Table I and Table II.

The book seems carefully researched* and is well executed. —Lawrence Charles Parish, MD, MD (Hon), Jefferson Medical College of Thomas Jefferson University, Philadelphia, PA

*I checked some of the details and found the authors were correct in stating that dental education can be three or four years. The Univer-sity of the Pacific has the three-year curriculum.

BOOK ReVIeWNoah S. Scheinfeld, MD, JD, Section Editor

The New Ideal in Skin Health: Separating Fact From Fiction

By Carl Thornfeldt, MD and Krista Bourne, LE

505 pages. Carol Stream, IL; Allured Books; 2010 $89. ISBN 1932633693

Table I. Herbs triggering a fatal outcome

Aristocholia

Armica

Cayenne

Comfrey

Henna

Kava kava

Mistletoe

Rue

Senna

Yohimbine

Table II. Herbs leading to surgical complications

Echinacea

Garlic

Gingko

Ginseng

Kava kava

St John’s wort

Valerium

Locoid Lipocream® Cream, 0.1% Rx Only(hydrocortisone butyrate 0.1% cream)For Topical Use Only

BRIEF SUMMARY

INDICATIONS AND USAGELocoid Lipocream is a topical corticosteroid indicated for: relief of the inflammatoryand pruritic manifestations of corticosteroid-responsive dermatoses in adults andthe treatment of mild to moderate atopic dermatitis in patients 3 months to 18 yearsof age.

WARNINGS AND PRECAUTIONSReversible hypothalamic-pituitary-adrenal (HPA) axis suppression may occur, withthe potential for glucocorticosteroid insufficiency. Consider periodic evaluations forHPA axis suppression if Locoid Lipocream is applied to large surface areas or usedunder occlusion. If HPA axis suppression is noted, reduce the application frequency,discontinue use, or switch to a lower potency corticosteroid. Systemic effects of topical corticosteroids may also include manifestations ofCushing’s syndrome, hyperglycemia, and glucosuria. Pediatric patients may be more susceptible to systemic toxicity due to their largerskin surface-to-body-mass ratios. Initiate appropriate therapy if concomitant skin infections develop. Discontinue use if irritation develops.

ADVERSE REACTIONSThe most common adverse reactions (>1%) are HPA axis suppression andapplication site reactions.The following additional local adverse reactions have been reported infrequentlywith topical corticosteroids, and they may occur more frequently with the use ofocclusive dressings and higher potency corticosteroids. These reactions included:irritation, folliculitis, acneiform eruptions, hypopigmentation, perioral dermatitis,allergic contact dermatitis, secondary infection, skin atrophy, striae, miliaria andtelangiectasia.

USE IN SPECIFIC POPULATIONSPregnancyPregnancy Category C. Corticosteroids have been shown to be teratogenic inlaboratory animals when administered systemically at relatively low dosage levels.Some corticosteroids have been shown to be teratogenic after dermal applicationin laboratory animals.There are no adequate and well-controlled studies inpregnant women. Therefore, Locoid Lipocream should be used during pregnancyonly if the potential benefit justifies the potential risk to the fetus.Please refer to full prescribing information for detailed information regardingsystemic embryofetal development studies.Nursing MothersSystemically administered corticosteroids appear in human milk and couldsuppress growth, interfere with endogenous corticosteroid production, or causeother untoward effects. It is not known whether topical administration ofcorticosteroids could result in sufficient systemic absorption to produce detectablequantities in human milk. Because many drugs are excreted in human milk, cautionshould be exercised when Locoid Lipocream is administered to a nursing woman.Pediatric UseSafety and efficacy in pediatric patients below 3 months of age have not beenestablished. Because of higher skin surface-to-body-mass ratios, pediatric patients are at agreater risk than adults of HPA axis suppression when they are treated with topicalcorticosteroids. They are therefore also at a greater risk of glucocorticosteroidinsufficiency after withdrawal of treatment and of Cushing’s syndrome while ontreatment. Eighty-six (86) pediatric subjects (5 months to less than 18 years of age) withmoderate to severe atopic dermatitis affecting at least 25% of body surface area(BSA) treated with Locoid Lipocream three times daily for up to 4 weeks wereassessed for HPA axis suppression. The disease severity (moderate to severeatopic dermatitis) and the dosing regimen (three times daily) in this HPA axis studywere different from the subject population (mild to moderate atopic dermatitis) andthe dosing regimen (two times daily) for which Locoid Lipocream is indicated. Five of the 82 evaluable subjects (6.1%) demonstrated laboratory evidence ofsuppression, where the sole criterion for defining HPA axis suppression was aserum cortisol level of less than or equal to 18 micrograms per deciliter aftercosyntropin stimulation. Suppressed subjects ranged in age from 5 months to 16 years and, at the time of enrollment, had 25% to 95% BSA involvement. Thesesubjects did not develop any other signs or symptoms of HPA axis suppression. At the first follow up visit, approximately one month after the conclusion oftreatment, cosyntropin stimulation results of all subjects had returned to normal,with the exception of one subject. This last subject recovered adrenal function bythe second post treatment visit, 65 days post-treatment. Cushing’s syndrome, linear growth retardation, delayed weight gain, andintracranial hypertension have also been reported in pediatric patients receivingtopical corticosteroids. Manifestations of adrenal suppression in pediatric patientsinclude low plasma cortisol levels to an absence of response to ACTH stimulation.Manifestations of intracranial hypertension include bulging fontanelles, headaches,and bilateral papilledema.

Geriatric UseClinical studies of Locoid Lipocream did not include sufficient numbers of subjectsaged 65 and over to determine whether they respond differently from youngersubjects.Carcinogenesis, Mutagenesis, Impairment of FertilityNo studies were conducted to determine the photococarcinogenic or dermalcarcinogenic potential of Locoid Lipocream.Hydrocortisone butyrate revealed no evidence of mutagenic or clastogenicpotential based on the results of two in vitro genotoxicity tests (Ames test andL5178Y/TK+ mouse lymphoma assay) and one in vivo genotoxicity test (mousemicronucleus assay).No evidence of impairment of fertility or effect on mating performance wasobserved in a fertility and general reproductive performance study conducted inmale and female rats at subcutaneous doses up to and including 1.8 mg/kg/day(0.7X maximum topical human dose [MTHD]). Mild effects on maternal animals,such as reduced food consumption and a subsequent reduction in body weight gain,were seen at doses ≥0.6 mg/kg/day (0.2X MTHD).

PATIENT COUNSELING INFORMATIONPatients using Locoid Lipocream should receive the following information and instructions:Apply a thin layer to the affected skin two or three times daily for corticosteroid-responsive dermatoses in adults. Consult with your physician to determine iftreatment is needed beyond 2 weeks. Apply a thin film to the affected skin areastwo times daily for atopic dermatitis in patients 3 months of age and older. Safety of Locoid Lipocream in pediatric patients has not been established beyond 4weeks of use.Rub in gently.Avoid contact with the eyes. Do not bandage, otherwise cover, or wrap the affected skin area so as to beocclusive unless directed by your physician.Do not use Locoid Lipocream in the diaper area, as diapers or plastic pants mayconstitute occlusive dressings.Do not use Locoid Lipocream on the face, underarms, or groin areas unlessdirected by your physician.If no improvement is seen within 2 weeks, contact your physician.Do not use other corticosteroid-containing products while using Locoid Lipocreamwithout first consulting your physician.

Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP ControlledRoom Temperature]. Protect from freezing. Keep out of the reach of children.

Marketed and Distributed By:Triax Pharmaceuticals, LLCCranford NJ 07016www.Locoid.com

Manufactured for: Triax Pharmaceuticals, LLCCranford NJ 07016By: Ferndale Laboratories, Inc.Ferndale MI 48220

131B301Rev 11/09

Locoid Lipocream is a registered trademark of Astellas Pharma Europe BV licensed to Triax Pharmaceuticals, LLC.

LOC-321 Skin Med.qxd:8x10.75 4/12/10 4:48 PM Page 2

Now younger eczema patients have something

to smile about

Now approved for use in children down to 3 months of age

(hydrocortisone butyrate 0.1%) Cream

Locoid Lipocream is indicated for the relief of the inflammatory and pruritic manifestations of corticosteroid-responsive dermatoses, including the treatment of mild to moderate atopic dermatitis in patients 3 months of age and older.Safety and effectiveness in pediatric patients below 3 months of age have not been established.Reversible HPA axis suppression may occur, with the potential for corticosteroid insufficiency. Consider periodic evaluations for HPA axis suppression if applied to large surface areas or used under occlusion . Systemic effects of topical corticosteroids may also includemanifestations of Cushing’s syndrome, hyperglycemia, and glucosuria. Pediatric patients may be more susceptible to systemic toxicity due to their large skin surface-to-body-mass ratios. Initiate appropriate therapy if concomitant skin infection develops. Discontinue use if irritation develops. Please see full Prescribing Information on adjacent page. Visit us at www.locoid.com

©2010 Triax Pharmaceuticals, LLC. All rights reserved. Locoid is a registered trademark of Astellas Pharma Europe B.V. licensed to Triax Pharmaceuticals, LLC. LOC-0410-01

The power of an ointment with the elegance of a cream

LOC-321 Skin Med.qxd:8x10.75 4/12/10 4:48 PM Page 1

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