JULY 2006 American Osteopathic College of Dermatology

Home , Eccrine nevus, Epidermal nevus syndrome, Foreign body reaction, Lymphangiosarcoma, Schimmelpenning syndrome, White sponge nevus

The Journal of the American PRSRT STD Osteopathic College of Dermatology U.S. POSTAGE PAID 3700 North 32nd Terrace MASON CITY, IA Hollywood, Fl 33201 PERMIT NO. 429

Address Correction Requested T HE J UNLO THE OF OURNAL

A JOURNAL SPECIFICALLY FOR AND BY RESIDENTS IN DERMATOLOGY A MERICAN O STEOPATHIC C LEEOF OLLEGE D ERMATOLOGY

Accepting Manuscripts from Dermatology Residents in AOA and ACGME Approved Residency Programs J ULY 2006

FOUNDING SPONSORS:ALLERGAN SKIN CARE • CONNETICS CORPORATION • GLOBAL PATHOLOGY LABORATORY • MEDICIS • STIEFEL LABORATORIES Journal of the AMERICAN OSTEOPATHIC COLLEGE OF DERMATOLOGY Journal of the 2005-2006 Officers President: Richard A. Miller, DO President-Elect: Bill V. Way, DO American First Vice-President: Jay S. Gottlieb, DO Second Vice-President:Donald K. Tillman, DO Osteopathic Third Vice-President: Marc I. Epstein, DO Secretary-Treasurer: Jere J. Mammino, DO Immediate Past President: Ronald C. Miller, DO College Trustees: David W. Dorton, DO Bradley P. Glick, DO Daniel S. Hurd, DO of Dermatology Jeffrey N. Martin, DO Executive Director: Rebecca Mansfield, MA

Editors Jay S. Gottlieb, D.O., F.O.C.O.O. Stanley E. Skopit, D.O., F.A.O.C.D. Founding Sponsors: James Q. Del Rosso, D.O., F.A.O.C.D. Allergan Skin Care Connetics Corporation Global Pathology Laboratory Medicis Stiefel Laboratories Editorial Review Board Ronald Miller, D.O. Eugene Conte, D.O. Evangelos Poulos, M.D. Stephen Purcell, D.O. AOCD • 1501 E. Illinois • Kirksville, MO 63501 Darrel Rigel, M.D. 800-449-2623 • FAX: 660-627-2623 www.aocd.org Robert Schwarze, D.O. Andrew Hanly, M.D. COPYRIGHT AND PERMISSION: written permission must be Michael Scott, D.O. obtained from the Journal of the American Osteopathic College of Dermatology for copying or reprinting text of more than half page, Cindy Hoffman, D.O. tables or figures. Permissions are normally granted contingent upon Charles Hughes, D.O. similar permission from the author(s), inclusion of acknowledgement Bill Way, D.O. of the original source, and a payment of $15 per page, table or figure of reproduced material. Permission fees are waived for authors Daniel Hurd, D.O. wishing to reproduce their own articles. Request for permission Mark Lebwohl, M.D. should be directed to JAOCD c/o AOCD PO Box 7525 Kirksville, MO 63501 Edward Yob, D.O. Copyright 2003 by the Journal of the American Osteopathic Jere Mammino, D.O. College of Dermatology Schield M. Wikas, D.O. Printed by: Stoyles Graphics Services, Mason City, IA 50401 Journal of the American Osteopathic College of Dermatology Journal of the VOLUME 6 , NUMBER 1 JULY 2006 American Osteopathic College of Dermatology

CONTENTS

Letter from the JAOCD Editors...... 4 Letter from the President...... 7 Uncombable Hair Syndrome: A Case Report...... 8 Scott A. Smith, D.O., Lisa N. Gelles, M.D. Fabry Disease: A Case Report of a Heterozygous Female Carrier...... 10 Scott A. Smith, D.O., Anita C. Gilliam, M.D., Ph.D., Paradi Mirmirani, M.D. Treatment with Tacrolimus 0.1% Ointment in En Coup de Sabre: A Case Report...... 12 Theresa Ng Mah, D.O., Charmaine Jensen, D.O., Schield Wikas Cutaneous Angiosarcoma: Classic Case Presentation and Review of the Literature...... 17 Shannon M. Campbell, MSIV, Jenifer R. Lloyd, D.O. Cutaneous Metastases of Prostate Adenocarcinoma: A Case Report and Literature Review...... 20 Jon Keeling, D.O., Brad Glick, D.O., M.P.H. , Les Rosen, M.D. Inflammatory Linear Verrucous Epidermal Nevus (ILVEN): A case report and review of the literature ...... 22 William Kirby, DO, Francisca Kartono, BS, Andrea Passalacqua, DO, Tejas Desai DO, David C. Horowitz, DO Collision Tumor: A Case Report...... 24 Jon Keeling, D.O., Harold Rabinovitz, M.D., Margaret Olivario, ARNP Epidermal Nevus Syndrome: A Case Report and Review of the Literature ...... 26 David M. Bracciano, D.O., F.AO.C.O., Kimball Silverton, D.O., F.A.O.C.D. Cutaneous Vasculitis...... 28 Carissa Summa, D.O., Cindy Hoffman, D.O. Pityriasis Versicolor During Infancy ...... 33 Iqbal A. Bukhari, MBBS, FD (KFU), Salha AlShehab, MBBS Darier’s Disease...... 35 Norma Montiel, D.O., Marvin S. Watsky, D.O. Paraneoplastic Pemphigus Associated With Breast Adenocarcinoma...... 39 Iqbal A. Bukhari, MBBS, FD (KFU) Effectiveness of Topical Pimecrolimus in the Treatment of Vitiligo ...... 41 Iqbal A. Bukhari, MBBS, FD (KFU) A Review of Mohs Micrographic Surgery: Common Indications...... 43 Thi T. Tran, D.O., F.A.O.C.D., Keoni Nguyen, D.O., Eugene T. Conte, D.O.,F.A.O.C.D. Eruptive Vellus Hair Cysts: A Case Report and Literature Review...... 51 Amy M. Broomer, D.O., Stanley E. Skopit, D.O., FAOCD A Case Study of ANA Negative Minocycline-induced Lupus ...... 54 Reagan B. Anderson, DO, MCS, Margaret T. Dupree, MD, CDR(sel), MC, USN Cholesterol Embolization Syndrome: Case Report and Review of the Literature ...... 56 Brian S. Walther, D.O., Stephen M. Purcell, D.O. Management of Epidermal Nevi in the Setting of Epidermal Nevus Syndrome: A Case Report and Literature Review ...... 58 Mark Levenberg, D.O., Tanya Ermolovich, D.O., Stephen M. Purcell, D.O. Observational Case Report: Acanthosis Nigricans Regression with Rosiglitazone after Previous Treatment with Pioglitazone...... 63 Derrick Adams, Captain, D.O., USAF, MC L ETTER F ROM T HE JAOCD EDITORS

JAY S. GOTTLIEB, D.O. STANLEY E. SKOPIT, D.O. JAMES Q. DELROSSO, D.O.

The medical field and the medical industry are in a state of never-ending change. We are disappointed that both Novartis Pharmaceuticals and 3M can no longer be sponsors of the JAOCD. Both of these companies have had major internal issues that will prevent them from their continued sponsorship of the JAOCD. Novartis and 3M have been friends and supporters of the AOCD and the JAOCD. As editors of the JAOCD, we thank them for giving freely, allowing us to bring the JAOCD to the level where we are today.

We also recognize the companies that have been and continue to be, our Founding Sponsors. Allergan Skin Care, with all of there innovative products, stepped up to the plate 4 years ago and have continued to support the JAOCD. Connet- ics Corporation, with their continuing unique line of foam-based topical medications, also was there from the beginning and continues to give their unrelenting support for this journal. Global Pathology Laboratory, providing national 24 hour expert dermatopathology evaluation, has always been there when we requested support. Medicis-The Dermatology Company, has been committed to the JAOCD from the beginning as a Founding Sponsor, providing the dermatology community with on-going science and new and innovative products. We thank all of our Sponsors for their continued support and for their confidence in our efforts to provide dermatologists with a unique journal that has been created and designed specifically as a journal by and for residents in dermatology.

Stiefel Laboratory, committed to dermatology, has been a long time supporter of the AOCD. Recently Stiefel has made the decision to be a Sponsor of the JAOCD. Dorothy Germino at Stiefel Laboratories did not hesitate when asked to sponsor our journal. We welcome Stiefel to our family at the JAOCD and look forward to a long and mutually beneficial relationship.

We have outsourced the grammar and spelling proofing responsibility of the JAOCD to Julie Layton at Freelance Proofreading and Editing. Working with Julie has been easy and a pleasure. We are committed to improving the JAOCD in every way possible.

As a reminder to the AOCD residents in dermatology, the Education Evaluation Committee (EEC) has made it mandatory for each resident to submit their annual paper for publication to a medical jour- JAOCD Founding Sponsor nal. As the editors of the JAOCD, we hope that the residents will consider the JAOCD when the time comes for them to consider where they will submit their annual papers. It is a relatively easy process to submit a paper to the JAOCD. Simply go to www.aocd.org and click on the JAOCD icon at the bottom of the screen. It is our hope that every resident in the AOCD will be encouraged by their Program Directors to submit their annual and other papers to the JAOCD throughout their three years of residency program.

Again we extend our sincere appreciation for the continued support to our Founding Sponsors: Allergan Skin Care, Con- netics Corporation, Global Pathology Laboratory Services and Medicis-The Dermatology Company. We again welcome Stiefel Laboratory as a new sponsor of the JAOCD!

Jay S. Gottlieb, D.O., F.O.C.O.O. (Editor) Stanley E. Skopit, D.O., F.A.O.C.D. (Editor) James Q. Del Rosso, D.O., F.A.O.C.D. (Editor)

4 “I have less itching Pow!Pow! and aking!”1 WWowow! “Who“Who sayssays yyouou ccan’tan’t havehave elegantelegant hairhair usingusing a prescription shampoo?”

Ef"cacy and Elegance Together. Pleaseseefullprescribinginformationonreverseside. Safety Information: LOPROX® Shampoo is indicated for the topical treatment of seborrheic dermatitis ofthescalpinadults.If noclinicalimprovementisshownafter4weeksoftreatment,thediagnosisshould be reviewed. LOPROX Shampooiscontraindicatedinindividualswhohaveshownhypersensitivitytoanyofitscomponents.Themost common adverse reactions are pruritus, burning, erythema, seborrhea, andrash.Ifareactionsuggesting sensitivityorirritationshouldoccur,treatmentshouldbediscontinued and appropriate therapy instituted. Avoidcontactwitheyes;ifcontactoccurs,rinsethoroughlywithwater.Seborrheic dermatitis may appear at puberty,however,noclinicalstudieshavebeendoneinpatientsyoungerthan 16 years. There is no relevant clinical experience in patients who have a history of immunosuppression, who are immunocompromised, or whohavediabeticneuropathy.

References: 1. LOPROX Shampoo [package insert]. Scottsdale, Ariz: Medicis Pharmaceutical Corporation; 2003. © 2006 Medicis Pharmaceutical Corporation LPX 06-005 04/30/07 JAOCD There is no relevant clinical experience with patients who have a history of immunosuppression (e.g., extensive, persistent, or unusual distribution of dermatomycoses, recent or recurring herpes zoster, or persistent herpes simplex), who are immunocompromised (e.g., HIV-infected patients and transplant patients), or who have a diabetic neuropathy. Information for Patients The patient should be instructed to: 1. Use LOPROX Shampoo as directed by the physician. Avoid contact with the eyes and mucous membranes. If contact occurs, rinse thoroughly with water. LOPROX Shampoo is for external use on the scalp only. Do not swallow. 2. Use the medication for seborrheic dermatitis for the full treatment time even though symptoms may have improved. Notify the physician if there is no improvement after 4 weeks. 3. Inform the physician if the area of application shows signs of increased irritation (redness, itching, burning, Rx Only blistering, swelling, or oozing) indicative of possible allergic reaction. FOR TOPICAL USE ONLY 4. Not use the medication for any disorder other than that for which it is prescribed. NOT FOR OPHTHALMIC, ORAL OR INTRAVAGINAL USE KEEP OUT OF REACH OF CHILDREN Carcinogenesis, Mutagenesis, and Impairment of Fertility: Long-term animal studies have not been performed to evaluate the carcinogenic potential of LOPROX DESCRIPTION Shampoo or ciclopirox. The following in vitro genotoxicity tests have been conducted with ciclopirox: evaluation of gene LOPROX® (ciclopirox) Shampoo 1% contains the synthetic antifungal agent, ciclopirox. mutation in the Ames Salmonella and E. coli assays (negative); chromosome aberration assays in V79 Each gram (equivalent to 0.96 mL) of LOPROX Shampoo contains 10 mg ciclopirox in a shampoo base Chinese hamster lung fibroblast cells, with and without metabolic activation (positive); chromosome consisting of Purified Water USP, Sodium Laureth Sulfate, Disodium Laureth Sulfosuccinate, Sodium aberration assays in V79 Chinese hamster lung fibroblast cells in the presence of supplemental Fe3+, Chloride USP, and Laureth-2. with and without metabolic activation (negative); gene mutation assays in the HGPRT-test with V79 Chinese hamster lung fibroblast cells (negative); and a primary DNA damage assay (i.e., unscheduled LOPROX Shampoo is a colorless, translucent solution. The chemical name for ciclopirox is 6-cyclohexyl- DNA synthesis assay in A549 human cells) (negative). An in vitro cell transformation assay in BALB/c 1-hydroxy-4-methyl-2(1H)-pyridone, with the empirical formula C12H17NO2 and a molecular weight of 3T3 cells was negative for cell transformation. In an in vivo Chinese hamster bone marrow cytogenetic 207.27. The CAS Registry Number is [29342-05-0]. The chemical structure is: assay, ciclopirox was negative for chromosome aberrations at a dosage of 5000 mg/kg body weight. A combined oral fertility and embryofetal developmental study was conducted in rats with ciclopirox olamine. No effect on fertility or reproductive performance was noted at the highest dose tested of 3.85 mg/kg/day ciclopirox (approximately 1.3 times the maximum recommended human dose based on body surface area comparisons). Pregnancy: Teratogenic effects: Pregnancy Category B Oral embryofetal developmental studies were conducted in mice, rats, rabbits and monkeys. Ciclopirox or CLINICAL PHARMACOLOGY ciclopirox olamine was orally administered during the period of organogenesis. No maternal toxicity, embryotoxicity or teratogenicity were noted at the highest doses of 77, 125, 80 and 38.5 mg/kg/day Mechanism of Action ciclopirox in mice, rats, rabbits and monkeys, respectively (approximately 13, 42, 54 and 26 times the Ciclopirox is a hydroxypyridone antifungal agent although the relevance of this property for the maximum recommended human dose based on body surface area comparisons, respectively). indication of seborrheic dermatitis is not known. Ciclopirox acts by chelation of polyvalent cations (Fe3+ Dermal embryofetal developmental studies were conducted in rats and rabbits with ciclopirox olamine or Al3+), resulting in the inhibition of the metal-dependent enzymes that are responsible for the degrada- dissolved in PEG 400. Ciclopirox olamine was topically administered during the period of organogenesis. tion of peroxides within the fungal cell. No maternal toxicity, embryotoxicity or teratogenicity were noted at the highest doses of 92 mg/kg/day and 77 mg/kg/day ciclopirox in rats and rabbits, respectively (approximately 31 and 54 times the Pharmacokinetics and Pharmacodynamics maximum recommended human dose based on body surface area comparisons, respectively). In a study in patients with seborrheic dermatitis of the scalp, application of 5 mL ciclopirox shampoo 1% twice weekly for 4 weeks, with an exposure time of 3 minutes per application, resulted in detect- There are no adequate or well-controlled studies of topically applied ciclopirox in pregnant women. able serum concentrations of ciclopirox in 6 out of 18 patients. The serum concentrations measured Because animal reproduction studies are not always predictive of human response, LOPROX Shampoo throughout the dosing interval on Days 1 and 29 ranged from 10.3 ng/mL to 13.2 ng/mL. Total should be used during pregnancy only if clearly needed. urinary excretion of ciclopirox was less than 0.5% of the administered dose. Nursing Mothers: CLINICAL STUDIES It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when LOPROX Shampoo is administered to a nursing woman. In two randomized, double-blind clinical trials, patients 16 years and older with seborrheic dermatitis of the scalp applied LOPROX Shampoo or its vehicle two times per week for 4 weeks. Patients who Pediatric Use: were immunocompromised, those with psoriasis or atopic dermatitis, women of childbearing potential Seborrheic dermatitis may appear at puberty, however, no clinical studies have been done in patients not using adequate contraception, and pregnant or lactating women were excluded from the clinical younger than 16 years. studies. An evaluation of the overall status of the seborrheic dermatitis, and the presence and severity Geriatric Use: of erythema or inflammation, and scaling, was made at week 4, using a scale of 0 = none, 1 = slight, In clinical studies, the safety and tolerability of LOPROX Shampoo in the population 65 years and older 2 = mild, 3 = moderate, 4 = pronounced, and 5 = severe. Effective treatment was defined as achieving was comparable to that of younger subjects. Results of the efficacy analysis in those patients 65 years * a score of 0 (or a score of 1 if the baseline score was 3) simultaneously for status of the seborrheic and older showed effectiveness in 25 of 85 (29%) patients treated with LOPROX Shampoo, and in 15 dermatitis, erythema or inflammation, and scaling at Week 4. Ciclopirox shampoo was shown to be of 61 (25%) patients treated with the vehicle; due to the small sample size, a statistically significant statistically significantly more effective than vehicle in both studies. Efficacy results for the two studies difference was not demonstrated. Other reported clinical experience has not identified differences in are presented in the following table. responses between the elderly and younger subjects, but greater sensitivity to adverse effects in some older individuals cannot be ruled out. Effective Treatment Rates at Week 4 in Studies 1 and 2 ADVERSE REACTIONS Ciclopirox Shampoo Vehicle In 626 patients treated with LOPROX Shampoo twice weekly in the two pivotal clinical studies, the most Study 1 220/380 (58%) 60/192 (31%) frequent adverse events were increased itching in 1% of patients, and application site reactions, such Study 2 65/250 (26%) 32/249 (13%) as burning, erythema, and itching, also in 1% of patients. Other adverse events occurred in individual patients only. Efficacy for black patients was not demonstrated, although only 53 black patients were enrolled in Adverse events that led to early study medication termination in clinical trials occurred in 1.5% the two pivotal studies. (26/1738) of patients treated with Loprox Shampoo and 2.0% (12/661) of patients treated with Microbiology shampoo vehicle. The most common adverse events leading to termination of study medication in either group was seborrhea. In the LOPROX Shampoo group, other adverse events included rash, pruritus, Ciclopirox is fungicidal in vitro against Malassezia furfur (Pityrosporum spp.), P. ovale, and P. orbicu- headache, ventricular tachycardia, and skin disorder. In the shampoo vehicle group, other adverse lare. Ciclopirox acts by chelation of polyvalent cations (Fe3+ or Al3+), resulting in the inhibition of the events included skin disorder and rash. metal-dependent enzymes that are responsible for the degradation of peroxides within the fungal cell. The clinical significance of antifungal activity in the treatment of seborrheic dermatitis is not known. DOSAGE AND ADMINISTRATION Wet hair and apply approximately 1 teaspoon (5 mL) of LOPROX Shampoo to the scalp. Up to 2 INDICATIONS AND USAGE teaspoons (10 mL) may be used for long hair. Lather and leave on hair and scalp for 3 minutes. A timer LOPROX Shampoo is indicated for the topical treatment of seborrheic may be used. Avoid contact with eyes. Rinse off. Treatment should be repeated twice per week for 4 dermatitis of the scalp in adults. weeks, with a minimum of 3 days between applications. If a patient with seborrheic dermatitis shows no clinical improvement after 4 weeks of treatment with CONTRAINDICATIONS LOPROX Shampoo, the diagnosis should be reviewed. LOPROX Shampoo is contraindicated in individuals who have shown hypersensitivity to any of its components. HOW SUPPLIED LOPROX‚® (ciclopirox) Shampoo 1% is supplied in 120 mL plastic bottles (NDC 99207-010-10).Dis- WARNINGS card unused product after initial treatment duration. Store between 15oC and 30oC (59oF and 86oF). LOPROX Shampoo is not for ophthalmic, oral, or intravaginal use. Keep out of reach of children. Manufactured for: MEDICIS® Pharmaceutical Corp. PRECAUTIONS Scottsdale, AZ 85258 General by: Patheon, Inc. If a reaction suggesting sensitivity or irritation should occur with the use of LOPROX Shampoo, treat- Mississauga, Ontario L5N 7K9 ment should be discontinued and appropriate therapy instituted. CANADA Contact of LOPROX Shampoo with the eyes should be avoided. If contact occurs, rinse thoroughly with water. PRESCRIBING INFORMATION AS OF FEBRUARY 2003 Seborrheic dermatitis may appear at puberty, however, no clinical studies have been done in patients younger than 16 years. LETTER FROM THE PRESIDENT OF THE AOCD

RICHARD MILLER, PRESIDENT

Dear fellow AOCD members, trainers to improve the learning experience we offer It has been my pleasure representing you thus far our residents. Our residents this year. We have made a great deal of progress in have traveled to the finest many areas. One of my major goals has been to programs in the country for unify our members and reinforce the benefits of elective rotations and have returned with exemplary maintaining membership in our college. I have had evaluations. Their performances have enhanced excellent feedback regarding my solicitation of our reputation in the greater world of dermatology. potential new members -- osteopathic dermatolo- They present posters and or papers yearly at the gists that for whatever reason have not realized the AAD as well as at our AOCD meetings. They have value of having or maintaining AOCD membership. been frequently published in international journals With the growth of our training programs and the as well as our excellent JAOCD. I am proud of the new or returning members, we may see our numbers osteopathic dermatologists that we have graduated increase dramatically in the next five years. These from all of our programs. To honor our residents, I increasing numbers will allow us the assurance that have developed a new award of academic excel- our training programs maintain the high quality that lence. This will be sponsored by the Medicis Corpo- we all want and expect. This will also allow us to ration. The goal is to recognize the resident from consider other services for our members and main- each class that is deemed to be most worthy in tain the excellent didactic sessions that we customize regard to a set of criteria developed by our awards to our members’ wants and needs. committee. I challenge all of our current residents to strive to achieve their greatest potential and take Our coordinator for corporate development, Shirley advantage of the unique opportunities that every Gottlieb, has been working diligently in her continu- program offers. The education evaluating committee ing attempt to maintain and attract corporate sponsors endeavors to improve all of our programs and give of our college. The funds that she acquires allow us every resident the opportunity to excel. We are to develop new educational opportunities for our open to any feedback you may have, both positive residents, such as the Intendis dermatology mentoring and negative. grant. With this grant, the resident will have the opportunity to work with experts in our field and Finally, I would like to publicly recognize the have the financial support of the AOCD. exemplary work done by our executive director, Becky Mansfield, and her husband, Rick, in main- As president, another of my personal areas of inter- taining the integrity of our AOCD office despite the est has been our residency training programs. We illness of their daughter. We all hope and pray for a are constantly reviewing our programs and attempting speedy recovery. to improve and address weaknesses. New programs are being developed to meet the demand for our specialty training and give our graduating osteopathic medical students an opportunity to achieve their goal of a career in dermatology. With the addition of new programs, it is our challenge to maintain the quality that we expect. As a program director myself, I constantly challenge myself and my co-

7 Uncombable Hair Syndrome: A Case Report

Scott A. Smith, D.O.*, Lisa N. Gelles, M.D.** * 3rd year Dermatology Resident, University Hospitals of Cleveland, Case Western Reserve, Cleveland, Ohio ** Assistant Professor, Case Western Reserve University, MetroHealth Medical Center, Cleveland, Ohio

ABSTRACT

Uncombable hair syndrome is a rare hair shaft disorder that typically presents in the first year of life with hair that is light in color, coarse, wiry, stands away from the scalp, and is difficult to manage. Uncombable hair is diagnosed by scanning electron microscope, which on cross sectioning reveals triangular shaped hairs with longitudinal indentation, giving the hairs a reniform- to-heart shape. We are presenting an infant girl who presented at the age of 11 months with a 4-month history of a significant change in hair color and texture.

Case Presentation An 11-month-old infant girl presented with a 4-month history of a change in color and texture of her hair. Per the patient’s mother, her hair has gradually gotten lighter, kinkier, more difficult to comb, and seems to stand up on end. There has not been any noticeable increase in hair loss or breakage. The patient’s growth and development have been normal. She has no significant past medical history and takes no medicines. On examination, the infant is well developed, well nourished, and well appearing. Involving the entire scalp, there are coarse, blonde hairs that have a spangled appear- Figure 1 ance and stand away from the scalp. The coarse, wiry, stands away from the scalp, been suggested to be autosomal dominant patient’s eyebrows, eyelashes, fingernails and is difficult to manage. The hair may with variable penetrance and expression or and toenails all appear normal. There are have a glistening or spangled appearance autosomal recessive. 8,9,10,11 no dental abnormalities. secondary to the reflection of light off the The cause of the structural defect has Figure 1 was taken of the patient at 2 surface of the irregularly shaped hairs. In yet to be elucidated. Stroud et al. proposed years of age. The patient’s sister began most cases of uncombable hair syndrome, that premature keratinization caused an having comparable findings at the age of only the scalp hairs are affected and typi- error in complementation of the inner root 10 months. The patient’s great aunt had cally in a generalized distribution. A local- sheath.12 In 1987, Stone et al. reported a similar hair complaints as a child, which ized variant has been reported as well in a Japanese girl with uncombable hair syn- subsequently improved with age. 5-year-old girl with involvement of her eye- drome, who on biopsy had one hair with Light microscopy shows normal appear- brows, eyelashes, and scalp hairs.4,5 asymmetrical atrophy of the hair bulb, sug- ing hair shafts, without signs of abnormal- Under scanning electron microscopy, gesting that the defect of the matrix ity. Scanning electron microscope on cross these hairs have a canal-like groove run- resulted in the characteristic longitudinal sectioning reveals triangular shaped hairs ning longitudinally along the length of the groove.13 Amino acid analysis, X-ray diffrac- with longitudinal indentation, giving the hair. The hairs may be reniform, heart tion analysis, and stress-strain analysis hairs a reniform-to-heart shape. These shaped or triangular, thus the name pili tri- showed no abnormalities compared to nor- findings are consistent with the diagnosis anguli et canaliculi. Salinas proposed that mal hair. However, the spun glass hair was of uncombable hair syndrome. the name be changed to pili canaliculi in shown to have decreased solubility in TUM 1988. 6 Camacho et al. had a patient with buffer.14 The significance of this is unclear Background the Rapp-Hodgkin variant whose hair at this time. shafts had two longitudinal grooves, pili This disorder was first described in 1973 bicanaliculi, and had a quadrangular Associated Disorders in the French literature by Dupré as shape. Therefore, Camacho et al. also felt “cheveux incoiffables,” that is, “uncombable that the name pili canaliculi should be Longitudinal grooves along the hair hair,” and the same year described by used, as pili trianguli et canaliculi was too shaft, although characteristic of, are not Stroud as “spunglass” hair. 1,2 The term pili limiting.7 exclusive to uncombable hair syndrome. trianguli et canaliculi was first used by Pili trianguli et canaliculi most commonly 3 Dupré and Bonafé in 1978. The monikers Etiology has no other associated somatic disorders. “uncombable hair” and “spunglass” come However, when another condition is pre- from characteristic clinical appearance. It has been proposed that uncombable sent the most frequent one is ectodermal The disorder typically presents in the first hair presents in both a sporadic and an dysplasia including the Rapp-Hodgkin and year of life with hair that is light in color, inherited pattern. The inherited cases have the Witkop variants. 6,7,15,16

8 UNCOMBABLE HAIR SYNDROME: A CASE REPORT Other disorders that have been reported 5. Chanwichitrtana S, Timpatanapong P, Sriurairatana S. Pili trianguli et canaliculi: a nonfamilial case with eyebrow and to be associated with longitudinal grooving eyelash involvement [letter]. Arch Dermatol 1986;122:977-8. include progeria, hypohidrotic ectodermal 6. Salinas C, Montes GM. Rapp-Hodgkin syndrome. Obser- vations on 10 cases and characteristic hair changes (pili dysplasia, retinal dysplasia, crystalline canaliculi). Birth Defects 1988;24:149-168. cataract, digit abnormalities, dental anom- 7. Camancho F, Ferrando J, Pichardo A, Sotillo I, Jorquera E. alies, phalangoepiphyseal dysplasias, Rapp-Hodgkin syndrome with pili canaliculi. Pediatr Der- matol 1993;10:54-7. wooly hair nevus, ichthyosis vulgaris, 8. Garty B, Metzker A, Mimouni M, Varsano I. Uncombable Marie-Unna hypotrichosis, acquired pro- hair: a condition with autosomal dominant inheritance. Arch Dis Child 1982;57:710-12. gressive hair kinking, drug-induced kinking, 9. de Luna MM, Rubinson R, de Kohan ZB. Pili trianguli uremia, pili torti, atopic dermatitis, progres- canaliculi: Uncombable hair syndrome in a family with apparent autosomal dominant inheritance. Pediatr Der- sive alopecia areata, hamartomas, nail matol 1985;2:324-27. abnormalities, lichen sclerosis, and 10. Van Neste D, Baden Hp. Abnormal fibrous protein patterns monilethrix.18,19,20 Uncombable hair syn- in the uncombable hair syndrome. Arch Dermatol Res 1985;277:151-52. drome by itself is not associated with any 11. Herbert AA, Charrow J, Esterly NB, Fretzin DF. Uncom- physical, neurologic, mental or develop- bable hair (pili trianguli et canaliculi): evidence for domi- 19 nant inheritance with complete penetrance based on mental abnormalities. scanning electron microscopy. Am J Med Genet Rest and Fretzin showed that the char- 1987;28:185-193. 12. Stroud JD. Complementation of the inner root sheath of acteristic longitudinal grooves could also be human hair. In Brown Ac, Crounse RG (eds): “Hair. Trace found in normal volunteers, although less elements and human illness.” New York: Medcom Press, 20 1980:163-68. than 10% of the hairs were affected. 13. Stone JL, Reizner GT, Muller A, Elpern DJ. Hair bulb Those with uncombable hair syndrome anomaly in a Japanese girl with uncombable hair. J Am Acad Dermatol 1987;17:842-3. were shown to have involvement of at least 14. Baden HP, Schoenfeld RJ, Stroud JD et al. Cheveux 20,21,22 50% of their hairs. incoiffables-diagnostic, clinical, and hair microscopic findings, and pathogenic studies. Br J Dermatol 1994;131:608. Treatment 15. Shelley WB, Shelley ED. Uncombable hair syndrome- occurrence in siblings with ectodermal dysplasia. J Am Acad Dermatol 1985;13:97-102. There are four reported cases of suc- 16. Micali G, Cook B, Blekys I, Solomon LM. Structural hair cessful treatment with the use of oral abnormalities in ectodermal dysplasia. Pediatr Dermatol 23,24,25 1990;7:27-32. biotin. One of the patients was evalu- 17. Powell J, Wojnarowska F, Dawber R, Slavotinek A, Huson ated by scanning electron microscopy, and S. Childhood vulval sclerosis in a patient with ectodermal no changes in the hairs’ structural morphol- dysplasia and uncombable hair. Pediatric Dermatology 1998;15(6):446-9. ogy were shown even though there was 18. Fleischmajer R, Nedwich A. Progeria (Hutchinson-Guil- increased manageability of the hair.25 Man- ford). Arch Dermatol 1973;107:253-258. 19. Hicks J. Uncombable hair (cheveux incoiffable, pili trianguli ageability may be increased with hair et canaliculi) syndrome: Brief review and role of scanning length. Hair quality may improve with age, electron microscopy in diagnosis. Ultrastructural Pathology 2001;25:99-103. and spontaneous remission is not uncom- 20. Rest EB, Fretzin DF. Quantitative assessment of scanning mon. electron microscope defects in uncombable hair syndrome. Pediatr Dermatol 1990;7:93-96. 21. Ferrando J, Fontarnau R, Gratacos R, Mascaro JM. Pili Discussion canaliculi (“cheveux incoiffables”): a specific hair shaft abnormality. J Cutan Pathol 1980;7:205-206. 22. Van Neste D, Armijo-Subieta F, Tennestedt D et al. The This syndrome is rare disorder with a uncombable hair syndrome: Four non-familial cases of pili characteristic clinical presentation. It has trianguli et canaliculi. Arch Dermatol Res 1981;271:223. been reported in both inherited and spo- 23. Shelley WB, Shelley ED. Uncombable hair syndrome: observations on response to biotin and occurrence in sib- radic forms. Subjects are usually affected lings with ectodermal dysplasia. J Am Acad Dermatol within the first year of life. The hair is char- 1985;13:97-102. 24. McCullum N, Sperling LC, Vidmar D. The uncombable hair acterized by bundles of hair arranged in all syndrome. Cutis 1990;46:479-83. different directions that resist being 25. Boccaleti V, Zendri E, Morrone P, Giordano G, Gnetti L, DePanfilis G. Abstracts for the 10th world congress on brushed or combed. The hair is often a sil- pediatric dermatology. Pediatric Dermatology 2004;21(3): very-blonde color with a spangled or glis- 326. tening appearance. Uncombable hair syndrome by itself is not associated with any physical, neurologic, mental or developmental abnormalities.19 The diagnosis is made by scanning electron microscopy. Hair quality may improve with oral biotin, increased length, and with age (as with the proband’s great aunt).

References 1. Dupré A, Richiccidi P, Bonafé JL. "Cheveux incoiffables" anomalie congénitale des cheveux. Bull Soc Franc Der- matol Syphil 1973;80:111-112. 2. Stroud JD, Mehregan AW. "Spunglass" hair: a clinicopathologic study of an unusual hair defect. In: Brown A, eds. First human hair symposium. New York: Medcom Press, 1973. 3. Dupré A, Bonafé JL. A new type of pilar dysplasia: the uncombable hair syndrome with pili trianguli et canaliculi. Arch Dermatol Res 1978;261:217-218. 4. Ravella A, Pujol RM, Noguera X, de Moragas JM. Local- ized pili canaliculi and trianguli. J Am Acad Dermatol 1987;17:377-80.

SMITH, GELLES 9 Fabry Disease: A Case Report of a Heterozygous Female Carrier

Nanda Channaiah, DO*, Frank Armstrong, DO, FAOCD**, Richard A. Miller, DO, FAOCD*** * Second-year dermatology resident,NOVA Southeastern University/Sun Coast Hospital, Largo, Florida. **Board-certified in dermatology and internal medicine, Bay Dermatology and Cosmetic Surgery, Port Richey, Florida. ***Program director of NOVA Southeastern University/Sun Coast Hospital.

ABSTRACT

Fabry disease (FD) is a rare, X-linked, recessive lysosomal storage disorder caused by a deficiency of the alpha-galactosidase A enzyme. This abnormality leads to an accumulation of neutral glycosphingolipids in the vascular endothelium and visceral tissues. Due to its inheritance pattern, males are more commonly affected than females. This case report presents a unique case of FD presenting itself in a heterozygous female carrier. In general, patients with FD have an increased risk of death from renal, cardiovascular, and cerebrovascular complications. By discussing the signs and symptoms, diagnostic testing, and novel treatment options, the dermatologist may be aided in the diagnosis and treatment of Fabry disease.

reflect the extent of enzyme Case Report activity, as well as the damage A 57-year-old female presented with a to involved organ systems. five-year history of “blood blisters” located The eyes, skin, and kidneys, on her chest, abdomen, and proximal as well as the cardiovascular, extremities. She reported intermittent, cerebrovascular, and periph- spontaneous bleeding of these lesions. eral nervous systems are pri- The patient denied any associated pruritus, marily affected. paresthesias, or tenderness. No symp- Neuropathic pain and toms of hemoptysis, hematuria, or melena episodic “crises” or acropares- were elicited. Her family history revealed thesias are generally the earli- similar skin lesions on her brother, who has est and most debilitating since died in his fifties secondary to a car- symptoms of Fabry disease. diac cause. Physical examination demon- Fortunately, these symptoms strated linear, violaceous petechiae and improve over time. Roughly papules following the relaxed skin tension 70% of affected males and lines, as well as scattered papules on her 10% of affected females have torso (Fig 1). There were no lesions in the paraesthesias.1,2 oral mucosa, distal extremities, or genital The characteristic cuta- region. Ophthalmologic, cardiac, and renal neous manifestation of Fabry exams revealed no abnormalities. Basic disease is diffuse angioker- blood work was within normal limits. An atomas located in the “bathing alpha-galactosidase A enzyme level trunk” distribution of approxi- revealed a low normal level. The skin mately 70% of affected males biopsy demonstrated ectatic, thin-walled and 30% of female carriers.1 vascular channels in the papillary dermis These lesions present as along with encased epidermal vascular small, dark-red to blue-black Figure 1 spaces (Fig 2). The patient was subse- papules found in clusters with Violaceous petechiae and papules in mid trunk quently diagnosed with Anderson-Fabry the propensity of becoming region disease, also known as Fabry disease or hyperkeratotic. Mucosal angiokeratoma corporis diffusum. involvement is common. Angiokeratomas increase in size, number, nonspecific polyuria4 to proteinuria,1,4 ure- Discussion and distribution over time. Hypohidrosis, mia, and eventually isothenuria if there is and less commonly anhidrosis, can also not early diagnosis and prompt treatment. Fabry disease (FD) is a rare, X-linked, occur, causing heat intolerance.3 Female carriers are usually asymptomatic, recessive disorder caused by a defect in or have minimal symptoms, while 90% of The most common extracutaneous man- 1 the lysosomal enzyme, alpha-galactosi- ifestation of Fabry disease is corneal opaci- affected males have proteinuria. Polariza- dase A. This results in progressive deposi- ties, which are whorl-like configurations tion microscopy of the urine reveals bire- tion of neutral glycosphingolipids fringent lipid globules often demonstrating found on slit-lamp examination. Most 1 throughout the vascular endothelium and affected males and 70 to 80% of female the characteristic Maltese crosses. visceral tissues. While FD primarily affects carriers are affected.1 This finding is the Cardiac manifestations of Fabry disease males, heterozygous female carriers, with most common presenting sign of Fabry dis- include but are not limited to angina, con- random X-chromosome inactivation, have ease in female carriers. Other ocular gestive heart failure, mitral valve insuffi- been identified with varying degrees of dis- abnormalities include subcapsular ciency, cardiomyopathy, hypertension, and 1,2 ease expression. cataracts and tortuous vascular lesions of arrythmias.1,4 While less than 1% of female The clinical signs and symptoms of the retina and conjunctiva.3 carriers have cardiac symptoms, affected Fabry disease are heterogeneous and Renal involvement can progress from males can die prematurely from a myocar-

10 FABRY DISEASE: A CASE REPORT OF A HETEROZYGOUS FEMALE CARRIER be implemented immediately to prevent further renal damage. Combination therapy with angiotensin-receptor blockers may be superior to either drug alone.9 If end-stage renal disease occurs, hemodialysis and/or renal transplantation are then required. Masson et al. comments on the importance of the transplant because of the renal pro- tection imparted by its own ·-galactosidase A enzyme, which fails to protect other organs. Research on gene therapy is on the horizon and may also aid in altering the natural history of this disease. Our patient, who is a heterozygous female carrier of Fabry disease, represents the minority of patients inflicted by this condition. She is doing well and returns for yearly exams to monitor disease progression. Periodically, symptomatic angiokeratomas are treated with electrodessication. The purpose of this case report is to present a unique case of Fabry disease in Figure 2 which an X-linked, recessive inherited con- Ectatic vessels in papillary dermis dition presented itself in a female patient. Although uncommon, it is important to con- dial infarction.1 ridges signifies the lesion to be specifically sider such a diagnosis in a female patient, Cerebrovascular involvement also por- associated with angiokeratoma corporis when the signs and symptoms and a his- tends a grave prognosis not only for hem- diffusum or Fabry disease.8 tory of a similar familial presentation are izygotes but also for heterozygotes.4 Management of Fabry disease is multi- demonstrated, in order to halt the progres- Therefore, careful monitoring is crucial to faceted, ranging from symptomatic and pal- sion of a potentially debilitating disease. prevent any secondary complications. liative treatment to prevention of secondary Mild, late-onset disease may occur in het- In general, without a positive family his- complications. Most important, correcting erozygous females as a result of uneven tory, Fabry disease has been a diagnostic the enzyme deficiency through enzyme- inactivation of the X chromosome that does 7 challenge due to its varied clinical manifes- replacement therapy (ERT) is optimal. To not carry the mutation. By presenting the tations and the potential involvement of var- prevent the relentless accumulation of gly- signs and symptoms, diagnostic testing ious organ systems. No distinct set of cosphingolipids, ERT is an option since the procedures, and treatment options of Fabry guidelines has been established thus far. advent and approval of two recombinant disease, one may feel more comfortable Therefore, a multidisciplinary approach can enzyme preparations, agalsidase-alpha diagnosing and treating this condition. assist in the early diagnosis of Fabry dis- (Replagal®) and agalsidase-beta‚ (Fab- ease. In addition to a high index of suspi- razyme®). Fabrazyme is the only form References cion through clinical signs and symptoms, approved in the United States and is dosed 1. Chang A, Kahn T. What syndrome is this? Pediatric Der- urine polarization microscopy demonstrat- at 1mg/kg for intravenous administration.9 matology 2002;19:85-87. 2. MacDermot KD, Holmes A, Miners AH. Anderson-Fabry ing lipid globules and Maltese crosses can Warnock reports that the phase IV random- disease: clinical manifest-ations and impact of disease in contribute to a diagnosis of FD. Further- ized, placebo-controlled study of ERT is a cohort of 60 obligate carrier females. J Med Genet promising, indicating that the incidence of 2001;38:769-775. more, plasma, peripheral leukocytes, or 3. Mehta A. New developments in the management of cultured skin fibroblasts revealing reduced renal, cardiovascular, and cerebrovascular Anderson-Fabry disease. Q J Med 2002;95:647-653. or absent alpha-galactosidase A enzyme events and death were decreased by 43% 4. Larralde M, Boggio P, Amartino H, Chamoles N. Fabry Disease: A study of 6 hemizygous men and 5 heterozy- 5,6 activity is helpful toward the diagnosis. with agalsidase-‚ at 1mg/kg every two gous women with emphasis on dermatologic manifest- However, in heterozygous females, the weeks as compared to the placebo group. ations. Arch Dermatol 2004;140:1440-1446. 7 5. Desnick R, Brady R, Barranger J, Collins A, Germain D, enzyme level may be near normal. Test- However, it is controversial as to when to Goldman M, Grabowski G, Packman S, Wilcox W. Fabry ing for alpha-galactosidase A enzyme gene institute ERT. Desnick et al. recommends Disease, an under-recognized multisystem disorder: initiating therapy as soon as signs and Expert recommendations for diagnosis, management, and mutations can confirm the diagnosis. enzyme replacement therapy. Ann Intern Med Imaging studies including MRI of the brain symptoms first appear. Breunig and col- 2003;138:338-346. to locate ischemic changes, echocardio- leagues advocate for earlier intervention, 6. Fuller M, Sharp P, Rozaklis T, Whitefield P, Blacklock D, Hopwood J, Miekle P. Urinary lipid profiling for the identifi- gram to rule out cardiac abnormalities, and prior to end-organ manifestations such as cation of fabry hemizygotes and heterozygotes. Clin Chem nuclear scan of the kidneys to evaluate the proteinuria and left ventricular hypertrophy. 2005;51:688-694. 7. Masson C, Cisse I, Simon V, Insalaco P, Audran M. Fabry glomerular filtration rate may also assist in In either case, the benefits of ERT are disease: A review. Joint Bone Spine;71:381-383. the diagnosis. Finally, angiokeratomas are undeniable, and ongoing studies will con- 8. Calonje and Wilson-Jones. Vascular tumors: Tumors and tinue to shed more light on this promising tumor-like conditions of blood vessels and lymphatics. classically found in five disease entities, Lever’s Histopathology of the Skin Philadelphia (PA) Lip- including angiokeratoma of Mibelli, angiok- treatment option. As discussed earlier, pincott Williams & Wilkins; 2005. p.1015-1059. eratoma circumscriptum, angiokeratoma of neuropathic pain is a major cause of mor- 9. Warnock D. Fabry disease: Diagnosis and management, with emphasis on the renal manifestations. Curr Opin Fordyce, solitary angiokeratoma, and bidity that can be controlled with anticon- Nephrol Hypertens 2005;14:87-95. angiokeratoma corporis diffusum. A skin vulsants including phenytoin, 10. Breunig F, Weidemann F, Beer M, Eggert A, Krane V, Spindler M, Sandstrede J, Strotmann J, Wanner C. Kidney biopsy demonstrating numerous, dilated, carbamazepine, and gabapentin. In addi- Int 2003;63:S181-S185. thin-walled, congested capillaries located tion, antiplatelet and anticoagulant therapy mainly in the papillary dermis with overlying may be necessary for stroke prevention. epidermal changes including acanthosis, With worsening proteinuria, angiotensin- hyperkeratosis, and elongation of the rete converting enzyme inhibitor therapy should

CHANNAIAH, ARMSTRONG, MILLER 11 Treatment with Tacrolimus 0.1% Ointment in En Coup de Sabre: A Case Report

Theresa Ng Mah, D.O.*, Charmaine Jensen, D.O.**, Schield Wikas*** *3rd year dermatology resident Tricounty Dermatology, Summa Health System: Cuyahoga Falls General Hospital, Cuyahoga Falls, OH **Charmaine Jensen, DO, Maine Dermatology, Rockport, ME ***Schield Wikas, D.O., Program Director, Tricounty Dermatology, Summa Health System: Cuyahoga Falls General Hospital, Cuyahoga Falls, OH

ABSTRACT

En coup de sabre is a rare variant of linear scleroderma. It is characterized by ivory-colored to hyperpigmented, band-like, firm, sclerotic plaques predominantly involving the frontoparietal scalp and paramedial facial regions. These lesions can extend to involve underlying structures. Various topical, systemic, and surgical therapeutic modalities have been used in the past; however, none have been shown to be consistently effective. Moreover, some of these treatment modalities do carry significant risks. Herein we report a case of an 11-year-old male with en coup de sabre who responded to treatment with topical tacrolimus 0.1% ointment. Topical tacrolimus 0.1% ointment may be a safe treatment option for patients with en coup de sabre. However, further studies are needed to prove the long-term efficacy of this medication.

En coup de sabre is a rare variant of linear scleroderma. It is characterized by band-like, ivory-colored to hyperpigmented, firm, sclerotic patches and plaques prefer- entially occurring in the frontoparietal scalp and face in the paramedian regions.1-5 It almost always presents in a unilateral distribution; however, bilateral distributions have been reported.6-8 These atrophic patches and plaques can extend to involve underlying subcutis, muscle, and osseous structures resulting in obvious deformities and eventual cicatricial alopecia. Treat- ment modalities have overall been unsatis- factory. Various topical, systemic, ultraviolet, and surgical therapies have been used, but none have been shown to work consistently, and some of these treatment modalities can carry significant risks of potential adverse effects. Herein we report a case of an 11-year-old male with en coup de sabre who responded to treatment with topical tacrolimus 0.1% ointment. Case Report An 11-year-old, Caucasian male pre- Figure 1 sented with a one-year history of two An 11 year old male with 2 slightly hyperpigmented atrophic band-like patches on patches located on the forehead region. the right forehead and glabellar region extending down to the nasal dorsum. There was reported associated irritation, pruritus, and scaling. He had no other associated symptomatology. The patient’s tissue disorder or epilepsy. laboratory studies were unremarkable, mother reported that the onset occurred On physical examination, patient had two including complete blood count with differ- approximately one month after applying firm, atrophic, hyperpigmented, slightly yel- ential, lyme titers, ANA on Hep2 substrate, sunscreen. There was a question whether lowish patches with no overlying scales. anti-Scl70 and anti-centromere antibodies. this could be due to underlying contact der- These linear, band-like patches were Radiologic brain studies were not done. matitis. Self treatment with multiple over- located on the right paramedian forehead, The patient was initially treated with topi- the-counter emollients, scar gel and central forehead, and the glabellar region cal desonide 0.05% ointment twice daily patches resulted in minimal improvement. extending from the frontal hair line to the and cefadroxil monohydrate 500 mg twice Patient was seen and evaluated by primary nasal dorsum, measuring 2.0 cm x 1.0 cm daily for one month with some improve- care physician and was given topical and 4.0 cm x 1.0 cm, respectively (Figure ment. Because of the possible adverse terbinafine ointment for presumed der- 1). A 4-mm punch biopsy was completed effects with long-term use of topical corti- matophytosis; however, patient had mini- on the right upper forehead. Histologically, costeroids, the patient was switched to a mal response and lesions persisted. there was a sclerosing dermatitis with non-steroidal alternative. Topical cal- Patient was a healthy child with no signifi- noted septal panniculitis (Figure 2-3). Over- cipotriene 0.005% ointment was pre- cant past medical or surgical history. all, histologic features were consistent with scribed; however, the patient’s insurance There was no family history of connective- linear scleroderma en coup de sabre. All company did not cover the medication.

12 TREATMENT WITH TACROLIMUS 0.1% OINTMENT IN EN COUP DE SABRE: A CASE REPORT Figure 2 tion and confirmed with a skin biopsy Medium Power Magnifica- including subcutis. Characteristic histo- tion: There is thickening logic features include thickening and scle- and sclerosis of reticular rosis of reticular dermis and subcutis, dermis and a superficial superficial and deep perivascular lympho- and deep perivascular cytic infiltrate with plasma cells and occa- infiltrate. sional eosinophils that can extend downward to involve the dermal-subcutaneous and septal-lobular junctions, and the presence of atrophic eccrine glands. Fur- thermore, small blood vessels may develop thickened walls and lumen narrowing.1, 32 The diagnosis of localized scleroderma including en coup de sabre can not be reliably confirmed by specific laboratory tests. However, it can be further supported by the presence of eosinophilia, hypergamma- Figure 3 globulinemia, and ANA.33 These laboratory Higher magnification: findings have been reported to be common There is predominantly a in all forms of localized scleroderma.1,4 lymphoplasmocytic infil- Blood eosinophilia and hypergammaglobu- trate extending to the deep linemia with polyclonal elevation of serum dermis and sub-cutis junc- IgG and IgM occurs in approximately 50 tion. percent of patients with linear scleroderma and usually corresponds to those with clinically active disease and clinical progression.1,4 The presence of serum autoantibodies have also been reported in children with linear scleroderma. When present, the most commonly detected autoantibodies are ANA, anti-ssDNA, and rheumatoid factor. In addition, antihistone and anticentromere antibodies have been reported but were less common.1,4 Previous The patient was subsequently placed on sequent pseudo-oculomotor palsy.17-19 reports suggest that the presence of these topical tacrolimus 0.01% ointment twice serum autoantibodies may correlate with Neurological abnormalities have also 1,5 daily. At the patient’s six-month follow-up, disease activity. However, it does not nec- been reported to be associated with en 4 he had clinical improvement with the noted coup de sabre, most notably seizures.20-22 essarily correlate with systemic disease. epidermal change; however, the depressed When present, these neurological manifes- The etiology and pathogenesis of en atrophy, although subtle, remained tations have been related to underlying coup de sabre are unknown. Implicated unchanged. The patient had no new symp- neuroimaging findings, i.e. skull abnormali- causes include infection, namely borrelia tomatology and remains healthy with no ties, intracerebral calcifications, focal atro- burgdorferi, environmental factors, i.e. reported or obvious neurological or ocular phy, white matter changes, and anomalous trauma, surgery, biological stress, vaccina- abnormalities. ecstatic vessels.23-26 Some authors have tions, and exogenous toxins, and autoim- 1 reported that these brain lesions can mune phenomenon. Previous reports have Discussion: progress.20-21 The underlying pathogenesis shown that some cases have presented of these brain lesions remains unclear. along the lines of Blaschko, which sug- En coup de sabre was first described by Some have postulated an inflammatory gests that the predisposition for en coup de Addison in 1854.9 Its name derives from process20-21, 23, while others propose a the- sabre may begin during early embryogene- the pattern it creates, resembling a scar ory of underlying vascular dysgenesis of sis secondary to underlying genetic cuta- 34-37 resulting from a cut of a sabre sword. En the brain.24-25 Nevertheless, brain MRI stud- neous mosaicism. Despite the many coup de sabre commonly occurs in chil- ies should be performed in en coup de theories, the underlying etiology and patho- dren more than adults and usually devel- sabre patients exhibiting neurological mani- genesis of en coup de sabre remain to be ops in the first and second decades of life.5 festations. However, the routine use of CT elucidated. It has an even sex distribution in contrast to and MRI studies in clinically asymptomatic Parry-Romberg syndrome is almost the female preponderance seen in other patients is still in question. always considered in the differential diag- 10-11 forms of morphea. Although rare, there In addition to ocular and neurological nosis of en coup de sabre. Parry-Romberg have been reports of familial cases of en findings, there have also been reports of syndrome is a rare, distinct variant of linear 12 coup de sabre. associated dental abnormalities, malocclu- morphea. It is characterized by progres- The active phase of the disease can sion, and tongue changes.27 Furthermore, sive facial hemiatrophy sclerosis and ocular progress for two to five years.1-2 The there have been a few isolated case changes including heterochromia, enoph- 38-39 course of the disease can be complicated reports of rare association and coexistence thalmos, and uveitis. There is a consid- by extracutaneous changes, most notably of en coup de sabre with aortic regurgita- erable overlap with regard to features ophthalmologic and neurological abnormal- tion28, hereditary deficiency of C229, sys- between Parry-Romberg syndrome and en ities. Ocular findings, although uncommon, temic lupus erythromatosus30, and lichen coup de sabre, but the latter can be distin- include retinal vascular anomalies13-14, planopilaris.31 guished clinically by more prominent cuta- 15-16 17 uveitis , ptosis , and ocular muscle dys- The diagnosis of en coup de sabre can neous sclerosis with associated function and motility disturbance with sub- be made on the basis of clinical presenta- hyperpigmentation and alopecia, while the

MAH, JENSEN, WIKAS 13 former typically has more extensive dict at this time whether topical tacrolimus 26. Liu P, Uziel Y, Chuang S, Silverman E, Krafchik B, Laxer R: Localized scleroderma: imaging features. Pediatr involvement of the lower face and minimal will have any effect on the cutaneous atro- Radiol. 1994;24(3):207-9 to no cutaneous sclerosis.39 Histologically, phy or halt the disease progression. Fur- 27. Marzano AV, Menni S, Parodi A, Borghi A, Fuligni A, Fab- bri P, Caputo R: Localized scleroderma in adults and chil- they can share similar features; however, ther studies are needed to prove clinical dren: Clinical and laboratory investigations on 239 cases. patients with en coup de sabre often have efficacy of topical tacrolimus in the treat- Eur J Dermatol. 2003 Mar-Apr;13(2):171-6 a more significant connective-tissue fibro- ment of en coup de sabre. 28. Sharma YK, Sawhney PS, Srivastava S: Systemic sclerosis, localized morphea, en coup de sabre and aortic regur- sis, adnexal atrophy, and mononuclear infil- Nevertheless, we propose that topical gitation: A rare association. Indian J Dermatol Venereol trate.39 The relationship between Leprol. 2004 Mar-Apr;70(2):99-101 tacrolimus is a reasonably safe therapeutic 29. Hulsmans RF, Asghar SS, Siddiqui AH, Cormane RH: Parry-Romberg syndrome and en coup de modality that clinicians can add to their Hereditary deficiency of C2 in association with linear scle- sabre remains unclear. Some authors treatment armamentarium when managing roderma ‘en coup de sabre’. Arch Dermatol. 1986 Jan;122(1):76-9 believe that they are distinct entities, while patients with en coup de sabre. 30. Mackel SE, Kozin F, Ryan LM, Sheth KJ, Jordon RE: Con- others believe that they are overlapping current linear scleroderma and systemic lupus erythro- conditions within the spectrum of the same matosus: a report of two cases. J Invest Dermatol. 1979 Nov;73(5):368-72 1, 39-41 References: disease process. 31. Munoz-Perez MA, Camacho F: Lichen planopilaris and 1. Vierra E, Cunningham BB: Morhphea and localized sclero- scleroderma en coup de sabre. J Eur Acad Dermatol The long-term prognosis of patients with derma in children. Semin Cutan Med Surg. 1999 Venereol. 2002 Sep;16(5):542-4 en coup de sabre and linear scleroderma is Sep;18(3): 210-25 32. Barnhill RL et al. Textbook of Dermatopathology. 2nd Edi- 2. Emery H: Pediatric scleroderma. Semin Cutan Med Surg. no different from the general population.5 tion. New York: McGraw-Hill Professional; 2004;pp405-6 1998 Mar;17(1): 41-7 33. Soma Y, Kawakami T, Yamasaki E, Sasaki R, Mizoguchi However, they can be associated with a 3. Eubanks LE, McBurney EI, Galen W, Reed R: Linear scle- M: Linear scleroderma along Blaschko’s lines in a patient varying degree of morbidity, often necessi- roderma in children. Int J Dermatol. 1996 May; 35(5):330- with systematized morphea. Acta Derm Venereol. 6 2003;83(5):362-4. tating treatment. Currently, there is no con- 4. Tuffanelli DL: Localized scleroderma. Semin Cutan Med 34. McKenna DB, Benton EC: A tri-linear pattern of sclero- sistently effective treatment for en coup de Surg. 1998 Mar;17(1): 27-33 derma ‘en coup de sabre’ following Blaschko’s lines. Clin 5. Hawk A, English JC 3rd: Localized and systemic sclero- Exp Dermatol. 1999 Nov;24(6):467-8 sabre. Treatments have been directed at derma. Semin Cutan Med Surg. 2001 Mar;20(1): 27-37 35. Soma Y, Fujimoto M: Frontoparietal scleroderma (en coup immunosuppression and at measures cor- 6. Gambichler T, Kreuter A, Hoffman K, Bechara FG, Alt- de sabre) following Blaschko’s lines. J Am Acad Dermatol. recting disease-related deformity. Various meyer P, Jansen T: Bilateral linear scleroderma “en coup 1998;38:366-8 de sabre” associated with facial atrophy and neurological 36. Itin PH, Schiller P: Double-lined Frontoparietal sclero- therapeutic modalities have been used, complications. BMC Dermatology. 2001;1:9 derma en coup de sabre. Dermatology. 1999;199(2):185-6 including topical therapies with corticos- 7. Rai R, Handa S, Gupta S, Kumar B: Bilateral en coup de 37. Stone J: Parry-Romberg syndrome: a global survey of 205 sabre-a rare entity. Pediatr Dermatol. 2000 May-Jun;17(3) patients using Internet. Neurology. 2003 Sept;61(5):674-6 teroids, calcipotriene 0.005% ointment, and 222-4 38. Sahin MT, Baris S, Karaman A: Parry-Romberg syndrome: topical capsaicin; systemic therapies with 8. Dilley JJ, Perry HO: Bilateral linear scleroderma en coup a possible association with borreliosis. J Eur Acad Derma- de sabre. Arch Dermatol. 1968 Jun;97(6):688-9 tol Venereol. 2004 Mar;18(2):204-7 corticosteroids, retinoids, vitamin E, vitamin 9. Behm AM, Blyumin M, Khachemoune A: En coup de 39. Orozco-Covarrunias L, Guzman-Meza A, Ridaura-Sanz C, D3 (oral calcitriol), penicillin, interferon sabre. Skin and Aging. 2004 Aug;pp64-65 Carrasco Daza D, Sosade-Martinez C, Ruiz-Maldonado R: gamma, and immunosuppressants i.e. 10. Mayes MD: Classification and epidemiology of sclero- Scleroderma ‘en coup de sabre’ and progressive facial derma. Semin Cutan Med Surg. 1998 Mar;17(1): 22-6 hemiatrophy: Is it possible to differentiate them? J Eur hydroxychloroquine, methotrexate, sala- 11. Peterson LS, Nelson WP, Su D, Mason T, O’Fallon WM, Acad Dermatol Venereol. 2002 Jul;16(4):361-6 zopyrine, cyclosporine, cyclophosphamide, Gabriel SE: The Epidemiology of Morphea (localized scle- 40. Lehman TJ: The Parry Romberg syndrome of progressive roderma) in Olmsted County 1960-1993. J Rheumatol. facial hemiatrophy and linear scleroderma en coup de D-penicillamine, and azathioprine; and 2003 Sep;30(9):1997-2004 sabre: Mistaken diagnosis or overlapping conditions? J ultraviolet phototherapy, namely oral or 12. Patrizi A, Marzaduri S, Marini R: A familial case of sclero- Rheumatol. 1992 Jun;19(6):844-5. derma en coup de sabre. Acta Derm Venereol. 2000 1-2, 5, 33, 41-43 41. Hunzelmann N, Scharffetter-Kochanek K, Hager C, Krieg bath PUVA. In addition, surgical May;80(3):237 T: Management of localized scleroderma. Semin Cutan procedures including autologous tissue 13. Neki AS, Sharma A: Ipsilateral Coat’s reaction in the eye Med Surg. 1998 Mar;17(1):34-40 injection and dermal fat graft have been of a child with en coup de sabre morphoea—a case 42. Gambichler T, Kreuter A, Rotterdam S, Altmeyer P, Hoff- report. Indian J Opthalmol. 1992 Oct-Dec;40(4): 115-116 man K: Linear scleroderma ‘en coup de sabre’ treated reported to provide some success in cor- 14. Taylor P, Talbot EM: Perilimbal vascular anomaly associ- with topical calcipotriol and cream psoralen plus ultraviolet ated with ipsilateral en coup de sabre morphoea. Br J A. J Eur Acad Dermatol Venereol. 2003;17:601-619 rection of the depressed atrophy in en coup Opthalmol. 1985 Jan;69(1):60-2 44-46 43. Cunningham BB, Landells IDR, Langman C, Sailer DE, de sabre. However, some of these treat- 15. David J, Wilson J, Woo P: Scleroderma ‘en coup de Paller AS: Topical calcipotriene for morphea/linear sclero- ments do carry a certain degree of risk for sabre’. Ann Rheum Dis. 1991 Apr;50(4):260-2 derma. J Am Acad Dermatol. 1998 Aug;39(2):211-215 16. Goldstein-Schainberg C, Pereira RM, Gusukuma MC, 44. Oh Ck, Lee, J, Jang BS, Kang YS, Bae YC, Kwon KS, major adverse events. Because of the Messina WC, Cossermelli W: Childhood linear sclero- Jang HS: Treatment of atrophies secondary to trilinears often observed self-limiting nature of this derma “en coup de sabre” with uveitis. J Pediatr. 1990 45. Scleroderma en coup de sabre by autologous tissue cock- disease, it is imperative that the clinician Oct;117(4):581-4 tail injection. Dermatol Surg. 2003 Oct; 29(10):1073-5 17. Suttorp-Schulten MS, Koornneef L: Linear scleroderma 46. Lapiere JC, Aasi S, Cook B, Montalvo A: Successful cor- consider the risks and benefits, especially associated with ptosis and motility disorders. Br J Opthal- rection of depressed scars of the forehead secondary to in the pediatric patient, before instituting mol. 1990 Nov;74(11)694-5 trauma and morphea en coup de sabre by en bloc autolo- 18. Scrup J, Serup L, Sjo O: Localized scleroderma “en coup gous dermal fat graft. Dermatol Surg. 2000 Aug; any aggressive treatment. According to an de sabre” with external eye muscle involvement at the 26(8):793-7 epidemiology study by Peterson et al., 50 same line. Clin Exp Dermatol. 1984 Mar;9(2):196-200 47. Milan MF, Bennett JE: Scleroderma en coup de sabre. 19. Obermoser G, Pfausler BE, Linder DM, Sepp NT: Sclero- Ann Plast Surg. 1983 May;10(5):364-70 percent of the patients with localized scle- derma en coup de sabre with central nervous system and roderma experienced cutaneous softening ophthalmologic involvement: Treatment of ocular symptoms with interferon gamma. J Am Acad Dermatol. or some evidence of disease resolution 2003;49:543-6 after 3.8 years.11 Although there is no stan- 20. Appenzeller S, Montenegro MA, Dertkigil SS, Sampaio- Barros PD, Marques-Neto JF, Samara AM, Andermann F, dard guideline for the treatment of en coup Cendes F: Neuroimaging findings in scleroderma en coup de sabre, the majority of the patients are de sabre. Neurology. 2004 May;62(9):1585-9 generally managed with non-aggressive 21. Grosso S, Fioravanti A, Biasi G, Conversano E, Marco- longo R, Morgese G, Balestri P: Linear scleroderma asso- approaches, namely topical therapies. ciated with progressive brain atrophy. Brain Dev. 2003 Jan;25(1):57-61 Herein, we report a case of an 11-year- 22. Flores-Alvarado DE, Esquivel-Valerio JA, Garza-Elizondo old male with en coup de sabre who M, Espinoza LR: Linear scleroderma en coup de sabre responded to topical tacrolimus 0.1% oint- and brain calcification: is there a pathogenic relationship? J Rheumatol. 2003 Jan;30(1):193-5 ment. The validity of our observation is lim- 23. Stone J, Franks AJ, Guthrie JA, Johnson MH: Sclero- ited since our patient has only been treated derma “en coup de sabre”: pathological evidence of intracerebral inflammation. J Neurol Neurosurg Psychiatry. for a short period of five months. The 2001;70:382-5 patient did have apparent clinical improve- 24. Higashi Y, Kanekura T, Fukumaru K, Kanzaki T: Sclero- derma en coup de sabre with central nervous system ment with cutaneous pigmentation and dis- involvement. J Dermatol. 2000 Jul;27(7):486-8 coloration; however, the cutaneous 25. Chung, MH, Sum J, Morrell MJ, Horoupian DS: Intracere- depressed atrophy, although subtle, bral involvement in scleroderma en coup de sabre: report of a case with neuropathologic findings. Ann Neurol. 1995 remained unchanged. It is difficult to pre- May;37(5):679-81

14 TREATMENT WITH TACROLIMUS 0.1% OINTMENT IN EN COUP DE SABRE: A CASE REPORT Impressive results. Less irritation.

Whether used alone 1,2 or with a retinoid,3 Duac® Topical Gel provides proven efficacy with superior tolerability.

For topical BPO/antibiotic acne therapy, Your Choice is Clear TM

Make the Clear ChoiceTM

IMPORTANT SAFETY INFORMATION Duac Topical Gel is indicated for the topical treatment of inflammatory acne. Duac Topical Gel is contraindicated in patients who have shown hypersensitivity to any of its components or lincomycin, and in those with a history of regional enteritis, ulcerative colitis, or antibiotic-associated colitis. Diarrhea, bloody diarrhea, and colitis have been reported with the use of topical clindamycin. Discontinuation is recommended if significant diarrhea develops. Please see accompanying Brief Summary of Prescribing Information.

©2006, Stiefel Laboratories, Inc DTG-04-2006-USA US Patent Nos. 5,466,446, 5,446,028, 5,767,098, and 6,013,637 Patents Pending www.stiefel.com Carcinogenesis, Mutagenesis, Impairment of Fertility: Benzoyl peroxide has been shown to be a tumor promoter and progression agent in a number of animal Duac® Topical Gel studies. The clinical significance of this is unknown. Benzoyl peroxide in acetone at doses of 5 and 10 mg administered twice per week (clindamycin, 1% - benzoyl peroxide, 5%) induced squamous cell skin tumors in transgenic TgAC mice in a study using For Dermatological Use Only. 20 weeks of topical treatment. Not for Ophthalmic Use. Genotoxicity studies were not conducted with Duac Topical Gel. Clindamycin Rx Only phosphate was not genotoxic in Salmonella typhimurium or in a rat micronucleus test. Benzoyl peroxide has been found to cause DNA strand breaks in a variety of INDICATIONS AND USAGE mammalian cell types, to be mutagenic in Salmonella typhimurium tests by some Duac Topical Gel is indicated for the topical treatment of inflammatory acne but not all investigators, and to cause sister chromatid exchanges in Chinese vulgaris. hamster ovary cells. Studies have not been performed with Duac Topical Gel or benzoyl peroxide to evaluate the effect on fertility. Fertility studies in rats treated Duac Topical Gel has not been demonstrated to have any additional benefit when orally with up to 300 mg/kg/day of clindamycin (approximately 120 times the compared to benzoyl peroxide alone in the same vehicle when used for the amount of clindamycin in the highest recommended adult human dose of 2.5 g treatment of non-inflammatory acne. Duac Topical Gel, based on mg/m2) revealed no effects on fertility or mating ability.

CONTRAINDICATIONS Pregnancy: Teratogenic Effects: Pregnancy Category C: Animal reproduction Duac Topical Gel is contraindicated in those individuals who have shown studies have not been conducted with Duac Topical Gel or benzoyl peroxide. It is hypersensitivity to any of its components or to lincomycin. It is also contraindicated also not known whether Duac Topical Gel can cause fetal harm when administered in those having a history of regional enteritis, ulcerative colitis, to a pregnant woman or can affect reproduction capacity. Duac Topical Gel should pseudomembranous colitis, or antibiotic-associated colitis. be given to a pregnant woman only if clearly needed. WARNINGS Developmental toxicity studies performed in rats and mice using oral doses of ORALLY AND PARENTERALLY ADMINISTERED CLINDAMYCIN HAS BEEN clindamycin up to 600 mg/kg/day (240 and 120 times the amount of clindamycin in ASSOCIATED WITH SEVERE COLITIS WHICH MAY RESULT IN PATIENT DEATH. the highest recommended adult human dose based on mg/m2, respectively) or USE OF THE TOPICAL FORMULATION OF CLINDAMYCIN RESULTS IN subcutaneous doses of clindamycin up to 250 mg/kg/day (100 and 50 times the ABSORPTION OF THE ANTIBIOTIC FROM THE SKIN SURFACE. DIARRHEA, amount of clindamycin in the highest recommended adult human dose based on BLOODY DIARRHEA, AND COLITIS (INCLUDING PSEUDOMEMBRANOUS COLITIS) mg/m2, respectively) revealed no evidence of teratogenicity. HAVE BEEN REPORTED WITH THE USE OF TOPICAL AND SYSTEMIC CLINDAMYCIN. STUDIES INDICATE A TOXIN(S) PRODUCED BY CLOSTRIDIA IS Nursing Women: It is not known whether Duac Topical Gel is secreted into human ONE PRIMARY CAUSE OF ANTIBIOTIC-ASSOCIATED COLITIS. THE COLITIS IS milk after topical application. However, orally and parenterally administered USUALLY CHARACTERIZED BY SEVERE PERSISTENT DIARRHEA AND SEVERE clindamycin has been reported to appear in breast milk. Because of the potential for ABDOMINAL CRAMPS AND MAY BE ASSOCIATED WITH THE PASSAGE OF BLOOD serious adverse reactions in nursing infants, a decision should be made whether to AND MUCUS. ENDOSCOPIC EXAMINATION MAY REVEAL PSEUDOMEMBRANOUS discontinue nursing or to discontinue the drug, taking into account the importance COLITIS. STOOL CULTURE FOR Clostridium difficile AND STOOL ASSAY FOR of the drug to the mother. Clostridium difficile TOXIN MAY BE HELPFUL DIAGNOSTICALLY. WHEN SIGNIFICANT DIARRHEA OCCURS, THE DRUG SHOULD BE DISCONTINUED. Pediatric Use: Safety and effectiveness of this product in pediatric patients below LARGE BOWEL ENDOSCOPY SHOULD BE CONSIDERED TO ESTABLISH A the age of 12 have not been established. DEFINITIVE DIAGNOSIS IN CASES OF SEVERE DIARRHEA. ANTIPERISTALTIC AGENTS SUCH AS OPIATES AND DIPHENOXYLATE WITH ATROPINE MAY ADVERSE REACTIONS PROLONG AND/OR WORSEN THE CONDITION. DIARRHEA, COLITIS AND During clinical trials, all patients were graded for facial erythema, peeling, burning, PSEUDOMEMBRANOUS COLITIS HAVE BEEN OBSERVED TO BEGIN UP TO and dryness on the following scale: 0 = absent, 1 = mild, 2 = moderate, and SEVERAL WEEKS FOLLOWING CESSATION OF ORAL AND PARENTERAL THERAPY 3 = severe. The percentage of patients that had symptoms present before treatment WITH CLINDAMYCIN. (at baseline) and during treatment were as follows: Mild cases of pseudomembranous colitis usually respond to drug discontinuation alone. In moderate to severe cases, consideration should be given to management Local reactions with use of Duac Topical Gel with fluids and electrolytes, protein supplementation and treatment with an % of patients using Duac Topical Gel with symptom present antibacterial drug clinically effective against Clostridium difficile colitis. Combined results from 5 studies (n = 397)

PRECAUTIONS Before Treatment (Baseline) During Treatment General: For dermatological use only; not for ophthalmic use. Concomitant topical acne therapy should be used with caution because a possible cumulative irritancy Mild ModerateSevere Mild Moderate Severe effect may occur, especially with the use of peeling, desquamating, or abrasive Erythema 28% 3% 0 26% 5% 0 agents. Peeling 6% <1% 0 17% 2% 0 The use of antibiotic agents may be associated with the overgrowth of nonsusceptible organisms, including fungi. If this occurs, discontinue use of this Burning 3% <1% 0 5% <1% 0 medication and take appropriate measures. Dryness 6% <1% 01%15% 0 Avoid contact with eyes and mucous membranes. (Percentages derived by # subjects with symptom score/# enrolled Duac subjects, Clindamycin and erythromycin containing products should not be used in n = 397). combination. In vitro studies have shown antagonism between these two antimicrobials. The clinical significance of this in vitro antagonism is not known. HOW SUPPLIED Information for Patients: Patients using Duac Topical Gel should receive the Duac® (clindamycin, 1% - benzoyl peroxide, 5%) Topical Gel is available in a following information and instructions: 45 gram tube - NDC 0145-2371-05. 1. Duac Topical Gel is to be used as directed by the physician. It is for external Prior to Dispensing: Store in a cold place, preferably in a refrigerator, between 2°C use only. Avoid contact with eyes, and inside the nose, mouth, and all mucous and 8°C (36°F and 46°F). Do not freeze. membranes, as this product may be irritating. Dispensing Instructions for the Pharmacist: Dispense Duac Topical Gel with a 2. This medication should not be used for any disorder other than that for which it 60 day expiration date and specify “Store at room temperature up to 25°C (77°F). was prescribed. Do not freeze.” 3. Patients should not use any other topical acne preparation unless otherwise Keep tube tightly closed. Keep out of the reach of small children. directed by their physician. U.S. Patent Nos. 5,466,446, 5,446,028, 5,767,098, and 6,013,637 4. Patients should report any signs of local adverse reactions to their physician. Patent Pending 5. Duac Topical Gel may bleach hair or colored fabric.

6. Duac Topical Gel can be stored at room temperature up to 25°C (77°F) for ® up to 2 months. Do not freeze. Keep tube tightly closed. Keep out of the reach of small children. Discard any unused product after 2 months. Stiefel Laboratories, Inc. Coral Gables, FL 33134 7. Before applying Duac Topical Gel to affected areas, wash the skin gently, rinse with warm water, and pat dry. 833185 Rev. 0504 8. Excessive or prolonged exposure to sunlight should be limited. To minimize exposure to sunlight, a hat or other clothing should be worn.

REFERENCES: 1. Lookingbill DP, Chalker DK, Lindholm JS, et al. Treatment of acne with a combination clindamycin/benzoyl peroxide gel compared with clindamycin gel, benzoyl peroxide gel and vehicle gel: combined results of two double-blind investigations. Am Acad Derm. 1997;37:590-595. 2. Tanghetti EA, Gold MH. A Two-center patient preference study comparing two benzoyl peroxide/clindamycin gels in acne vulgaris patients. Presented at: 63rd Annual Meeting of the American Academy of Dermatology; February 18-22, 2005; New Orleans, LA. Poster 108. 3. Tanghetti EA, Abramovits W, Solomon B. et al. Tazarotene versus tazarotene plus clindamycin/benzoyl peroxide in the treatment of acne vulgaris: a multicenter, double-blind, randomized parallel group trial. Presented at: 63rd Annual Meeting of the American Academy of Dermatology; February 18-22, 2005; New Orleans, LA. Poster 147. Duac is a registered trademark of Stiefel Laboratories, Inc. Your Choice is Clear, Make the Clear Choice, and Research in Dermatology are trademarks of Stiefel Laboratories, Inc. Cutaneous Angiosarcoma: Classic Case Presentation and Review of the Literature

Shannon M. Campbell, MSIV*, Jenifer R. Lloyd, D.O.** * Ohio University College of Osteopathic Medicine ** Co-Director, Residency Program, University Hospitals Health System - Richmond Heights Hospital, Department of Dermatology, Case Western Reserve Univer- sity School of Medicine, Cleveland, Ohio

ABSTRACT

Angiosarcoma, an uncommon and highly aggressive tumor, can present in an array of clinical forms. Diagnosis is based on histological findings and immunohistochemical markers but is complicated by the fact that classic histology may not always be present. Diagnostic delay remains a problem in treating angiosarcoma and contributes to its dismal prognosis. Treatment options include excision, radiation and chemotherapy. The clinician must possess a high index of suspicion and be aware of the variations in the clinical presentation of angiosarcoma.

Case Report A 75-year-old white male presented in April 2005 with a complaint of bleeding from a violaceous, 5-mm papule over his right temple when he shaved over it. The lesion clinically resembled a traumatized venous lake and was removed via excision with electrodessication and submitted for pathological evaluation. The report showed a collection of histiocytes in the superficial dermis, inflammatory or reactive in nature. Approximately two months later, the patient presented with an erythematous Figure 1: ecchymotic area looking almost traumatic Vascular lesions in nature on his right temple, which the excised for diagno- patient felt was a bruise because he was sis on 10/3/05 (A-D) on Coumadin. By mid August the "bruise" was noted to have worsened, and new nodular areas had developed. Due to the patient’s age, the clinical presentation, and a high index of suspicion for cutaneous angiosarcoma, the area was surgically excised and submitted for pathological evaluation. The findings revealed a malignant mesenchymal neoplasm, which was most consistent with superficial malignant fibrous histiocytoma; however, there were some focal areas that stained positive for factor VIII, which could not completely rule Figure 2: out angiosarcoma. Clinically, the presenta- Post surgical sites tion was behaving like an angiosarcoma, (A-D) on 10/21/05 and a consultation was made with an with new, evolving oncologist. A two-week follow-up visit vascular lesions revealed a recurrence along the midline incision as well as several new vascular rently undergoing radiation treatments. angiosarcoma accounts for approximately lesions (Figure 1). Excisional biopsies 50% of cutaneous angiosarcoma cases. were taken of all new areas, and the Most occur in Caucasian individuals, pathology revealed endothelial cells that Review of the Literature although there have been reports in Afro- stained positive for factor VIII. A definitive Accounting for less than 1-2% of soft tis- Americans and Asians.4 Cutaneous diagnosis of cutaneous angiosarcoma was sue neoplasms, angiosarcoma is a rare but angiosarcoma can also develop in the made. highly aggressive tumor that can occur at presence of chronic lymphedema (Stewart- Of interest, two weeks following suture any site, including visceral organs, breast Treves Syndrome) and post-irradiation. removal, several new areas of angiosar- and bone.1,2 However, the most common The majority of angiosarcoma cases aris- coma had developed (Figure 2). site affected is the skin. Classically, cuta- ing in the presence of chronic lymphedema Due to the patient’s negative PET scan, neous angiosarcoma presents on the head are secondary to mastectomy and consti- the oncologist felt there was no role for and neck of elderly individuals with a male tute 10-20% of cutaneous cases of adjuvant chemotherapy. The patient is cur- preponderance of 2:1.2,3 Head and neck angiosarcoma.1 Post-irradiation angiosar-

CAMPBELL, LLOYD 17 coma is uncommon and occurs in women are the most documented locations, take on a polygonal or spindle-cell shape. who have undergone subsequent radiation angiosarcoma can arise anywhere on the Consequently, the diagnosis of these therapy after breast-sparing surgery with skin3, including the plantar aspect of the tumors can be quite challenging and mis- lymphadenectomy.5,6 In addition to chronic foot, as documented in a case report by taken for carcinoma, melanoma or high- lymphedema and irradiation-induced Wolf and Pasquino.10 Angiosarcoma can grade fibrosarcoma. The presence of angiosarcoma, environmental toxins such present with a variety of features, which cytotoplasmic vacuoles within neoplastic as vinyl chloride, thorotrast and arsenic often causes delay in diagnosis and subse- cells helps to distinguish poorly differenti- have been linked to angiosarcoma.1 There quent treatment. The most “classic” pre- ated angiosarcoma from other potential has also been some suggestion that actinic sentation of angiosarcoma is diagnoses. Moreover, reticulin staining can damage and trauma might play a role in asymptomatic, bruise-like macules on the aid in identifying vascular channels.18 In causing angiosarcoma, but there is no head and scalp of elderly men.1,9 Bruising addition to vascular abnormalities, some direct evidence to support this.1,4 may also be associated with a suspected angiosarcomas are associated with lym- The exact etiology of cutaneous traumatic event or use of anticoagulant or phedema and possess lymphangiomatous angiosarcoma remains unclear. While antiplatelet therapy.11 Angiosarcoma can characteristics with an absence of erythro- there is a general agreement that angiosar- also present as nodules with or without cytes in irregular vascular channels.17 coma is of endothelial origin, it has not ulceration or possess features that mimic There may also be a lymphocytic infiltrate been determined if there is a malignant an infectious process.4 Cases of angiosar- surrounding the tumor as well as destruc- change in existing endothelial cells or if an coma have also been documented as tion of adnexal structures.18 Other histolog- endothelial malignant change occurs in chronic edematous plaques, recurrent ical variants of angiosarcoma have been pluripotential mesenchymal cells.1,3 Further- angioedema2, angioneurotic edema12, and documented, including granular cell more, the focus of the controversy lies in scarring alopecia.3 Other unusual presen- angiosarcoma, where an eosinophilic infil- whether the primary malignant change is of tations include rosacea-like clinical charac- trate dominates the majority of cells found vascular or lymphatic derivation. Evidence teristics, such as an erythematous infiltrate in the tumor,18,19 and angiosarcoma with in favor of a vascular origin include CD31 or a rhinophyma-like appearance of the foamy cells.18 Immunohistochemical stains, (platelet-endothelial cell adhesion molecule nose,8,13 and yellowish plaques above the such as CD31, CD34, factor VIII-related type I) expression, presence of blood in eyelid resembling xanthelasma and caus- antigen, and Ulex europaeus I lectin can be vascular channels, and factor VIII-related ing ptosis.14 Chapas et al also reported a helpful in diagnosing angiosarcoma.17,18 antigen.1 The ability of vascular endothe- case of well-differentiated angiosarcoma CD34 and factor VIII-related antigen help lial-derived growth factor (VEGF) to pro- arising in a seroma of a post-craniotomy identify angiosarcoma but also stain posi- duce well-differentiated angiosarcoma in a patient,15 and there has been a docu- tive in non-vascular tumors. CD31 stain murine model also favors a vascular origin.7 mented case of sclerodermic telangiectasia offers an advantage in that it is the most Conversely, the presence of discontinuous transforming into angiosarcoma.16 sensitive and specific of the immunohisto- basal lamina and absence of dendritic peri- While clinical manifestations may vary, it chemical markers for endothelial tissue.1,18 cytes lend support to a possible lymphatic does appear that there is a correlation However, the problem remains that the origin.1 Mentzel et al argued in favor of a between clinical presentation and immunohistochemical markers are nega- lymphatic origin, pointing out that only 14% histopathological findings. Ecchymotic-like tive in many cases of angiosarcoma and of cutaneous angiosarcomas stain posi- macules or plaques corresponded to well- are therefore unreliable as a sole means of tively for CD34 (human hematopoietic to-moderately differentiated angiosarcoma, diagnosis. progenitor cell antigen).8 while nodular lesions were consistent with Since angiosarcoma typically has dif- The controversy surrounding the etiology poorly differentiated tumors.1,4 Due to its fuse, ill-defined margins and tends to have of angiosarcoma has resulted in the usage spectrum of clinical presentation, the differ- multifocal involvement, treatment is difficult of varying terms to describe the disease.3 ential diagnosis of cutaneous angiosar- and recurrence is common.20 Metastasis In 1926, Livingston and Klemperer offered coma is great and dependent on the occurs via hematogenous or lymphatic the first description of the clinical and specific clinical variant present. For spread with the most common site being histopathological characteristics of instance, pigmented nodular lesions might the lymph nodes followed by the lungs, angiosarcoma. Almost 40 years later, in suggest melanoma, or edematous plaques liver, and bone.1,2,13 Treatment modalities 1964, E.W. Jones distinguished scalp could also be a presenting sign of sar- include wide excision, radiation, angiosarcoma as its own entity and coined coidosis, lymphoma, or granuloma faciale.13 chemotherapy or a combination thereof. the term “malignant angioendothelioma.”3,4,9 Other potential diagnoses include Kaposi’s Surgery is typically reserved for smaller, Several other documented cases of sarcoma, hemangiomas, lupus pernio, der- focal lesions usually less than 5 cm in angiosarcoma surfaced in between these matomyositis, and fixed drug eruptions.11 diameter, but a cure is often unattainable two events and were categorized as The vast array of possible differentials since the tumor has a tendency to spread hemangiosarcoma, hemangioendothe- makes histological diagnosis imperative, beyond clinical margins.21 There has been lioma, and lymphangiosarcoma.1,3 While but the histopathologic findings in angiosar- a case of Mohs chemosurgical microscopic there appears to be an issue of semantics coma can vary depending on the degree of technique used to successfully treat regarding a correct description, Knight et al differentiation. In well-differentiated angiosarcoma.22 Radiation is an effective asserts that angiosarcoma be used to col- tumors, diagnosis relies upon the presence treatment, especially when used post-sur- lectively refer to this tumor.3 The fact that of irregular, anastomosing vascular chan- gically, and may also be beneficial to con- well-differentiated cutaneous angiosar- nels that dissect through the dermis. trol subclinical disease.21 coma of the head and neck cannot be his- These channels are lined by atypical Chemotherapeutic agents have shown tologically distinguished from endothelial neoplastic cells which may mixed success in treating angiosarcoma. lymphangiosarcoma or angioendothelioma demonstrate hyperchromatism and pleo- Doxorubicin used in combination with other gives credence to the usage of angiosar- morphism. Some endothelial cells may agents and paclitaxel are among the most coma as an encompassing term.3,4,8 even protrude into the vascular lumen and promising drugs.1,20 Spieth et al reported Not only does the aggressive nature of form papillations.17,18 Poorly differentiated therapeutic efficacy of interferon alpha-2a 23 angiosarcoma offer a clinical challenge, but tumors may display ill-defined vascular and 13-cis-retinoic acid. Because so does its variation in clinical spaces with a proliferation of endothelial angiosarcoma is an endothelially derived presentation.9 Though the head and neck cells that show marked mitotic activity and tumor, there is also some speculation that

18 CUTANEOUS ANGIOSARCOMA: CLASSIC CASE PRESENTATION AND REVIEW OF THE LITERATURE utilizing antiangiogenic therapies, such as of angiosarcoma and possess a high index 12. Mackenzie, I.J. Angiosarcoma of the face. Arch Dermatol 1985;121:549-550. thalidomide, could be effective in the treat- of suspicion in order to make an accurate 13. Aguila, L.I. Sanchez, J.L. Angiosarcoma of the face ment of angiosarcoma.1,20 and opportune diagnosis. Concurrently, we resembling rhinophyma. J Am Acad Dermatol 2003; (49): 530-531. In spite of treatment, the prognosis for must also face the poor prognosis associ- 14. Lapidus, C.S. Sutula, F.C. Stadecker, M.J. et al. Angiosar- angiosarcoma is poor, with a five-year sur- ated with angiosarcoma and investigate the coma of the eyelid: yellow plaques causing ptosis. J Am 13 available and appropriate treatment options Acad Dermatol 1996;34:308-310. vival rate estimated at 10-35%. Holden et 15. Chapas, A.M. Askarian, F. Demierre, M.F. et al. Well-differ- al reported a five-year survival rate of 12%, for our patients while hoping for more ther- entiated angiosarcoma of the scalp: an unusual clinical apeutic advances in the near future. presentation. J Am Acad Dermatol 2005;52:S58-S59. with a median time of survival of 15 16. Puizina-Ivic, N., Bezic, J. and Marasovic, D. et al. 4 months. Complete surgical excision and Angiosarcoma arising in sclerodermatous skin. Acta Der- tumor size serve as two significant factors References matoven 2005;14:20-25. 8 17. Hunt, A.J. and Santa Cruz, D.J. Vascular tumors of the influencing prognosis. Maddox and Evans 1. Abrahamson, T.G., Stone, M.S. and Piette, W.W. Cuta- skin: a selective review. Semin Diagn Pathol 2004;21:166- noted that a tumor size of < 5 cm was neous angiosarcoma. Adv Dermatol 2001; (17): 270-298. 218. 24 2. Tay, Y.K and Ong, B.H. Cutaneous angiosarcoma present- 18. Requena, L. ans Sangueza, O.P. Continuous vascular associated with a favorable prognosis. A ing as recurrent angioedema of the face. Br J Dermatol proliferations. Part III. Malignant neoplasms, other cuta- study performed by Holden et al supported 2000;143:1346-1348. neous neoplasms with significant vascular component, this, demonstrating that tumors < 10 cm in 3. Knight, T.E. Robinson, H.M. and Sina, B. Angiosarcoma and disorders erroneously considered as vascular neo- (angioendothelioma) of the scalp. Arch Dermatol plasms. J Am Acad Dermatol 1998;38:143-175. diameter had a significantly increased 1980;(116): 683-686. 19. Hitchcock, M.G., Hurt, M.A. and Santa Cruz, D.J. Cuta- chance of survival than larger tumors.4 4. Holden, C.A., Spittle, M.F. Jones, E.W. Angiosarcoma of neous granular cell angiosarcoma. J Cutan Pathol the face and scalp, prognosis and treatment. Cancer 1994:256-262. Other prognostic indicators, such as sex, 1987;59:1046-1057. 20. Budd, G.T. Management of angiosarcoma. Curr Oncol age of the patient, and clinical appearance, 5. Tomasini, C., Grassi, M. and Pippione, M. Cutaneous Rep 2002;4:515-519. angiosarcoma arising in an irradiated breast. Dermatology 21. Morrison, W.H. Byers, R.M. Garden, A.S. et al. Cutaneous were not statistically significant in affecting 2004;209:208-214. angiosarcoma of the head and neck: a therapeutic 24 prognostic outcome. Moreover, histologi- 6. Rao, J., DeKoven, J.G., Beatty, J.D. and Jones, G. Cuta- dilemma. Cancer 1995;76:319-327. neous angiosarcoma as a delayed complication of radia- 22. Mikhail,G.R. and Kelly, A.P. Malignant angioendothelioma cal differentiation appears to offer little of the face. J Dermatol Surg Oncol 1977;3:181-183. 9 tion therapy for carcinoma of the breast. J Am Acad prognostic value. Interestingly, the pres- Dermatol 2003;49:532-538. 23. Spieth, K., Gille, J. Kaufmann, R. et al. Therapeutic effi- ence of a lymphocytic infiltrate and a lack 7. Arbiser, J. Larsson, H. Claesson-Welsh, L et al. Overex- cacy of interferon alfa-2a and 13-cis-retinoic acid in recur- pression of VEGF 121 in immortalized endothelial cells rent angiosarcoma of the head. Arch Dermatol of appendageal involvement are associ- causes conversion to slowly growing angiosarcoma and 1999;135:1035-1037.\ ated with a better prognosis.25 There is high level expression of the VEGF receptors VEGFR-1 24. Maddox, J.C., Evans, H.L. Angiosarcoma of skin and soft and VEGFR-2 in vivo. Am J Pathol 2000;156:1469-1476. tissue: a study of forty-four cases. Cancer 1981;48:1907- also some suggestion that low mitotic 8. Mentzel, T. Heinz, K. and Wollina, U. Cutaneous angiosar- 1921. 4,26 counts favor a better prognosis. Despite coma of the face: clinicopathologic and immunohisto- 25. Jones, E.W., Holden, C.A. a clinicopathological study of these positive prognostic factors, angiosar- chemical study of a case resembling rosacea clinically. J angiosarcoma of the face and scalp. Arch Dermatol Am Acad Dermatol 1998;38:837-840. 1984;120:1611-1612.\ coma remains a therapeutic challenge and 9. Jones, E.W. Angioendothelioma of the skin. Br J Derma- 26. Naka, N, Ohsawa, M. Tomita, Y. et al. Prognostic Factors has a high mortality rate. tol1964; 76:21-39. in Angiosarcoma: a multivariate analysis of 55 cases. J 10. Wolf, K. and Pasquino, J. Cutaneous angiosarcoma: a lit- Surg Oncol 1996;61:170-176. Angiosarcoma is both a diagnostic and a erature review and case report. J Am Podiatr Med Assoc therapeutic challenge for clinicians. We 1990;80:501-504. 11. Rich, A.L. and Berman, P. Cutaneous angiosarcoma pre- must be aware of the varying presentations senting as an unusual facial bruise. Age and Ageing 2004;33:512-514.

CAMPBELL, LLOYD 19 Cutaneous Metastases of Prostate Adenocarcinoma: A Case Report and Literature Review

Jon Keeling, D.O.*, Brad Glick, D.O., M.P.H. **, Les Rosen, M.D. *** * 1st year dermatology resident. Wellington Regional Medical Center ** Dermatology Residency Program Director, Wellington Regional Medical Center *** AmeriPath, Dermpath Diagnostics South Florida

ABSTRACT

An 85-year-old man presented to the office with a four-month history of several slowly enlarging, red-brown nodules on the face and arm. The patient had been diagnosed one year earlier with invasive prostate cancer. Biopsy proved the lesions to be metastatic prostate cancer to the skin. Prostate cancer is the second most common cancer in men, with frequent metastases, but only rarely to the skin. Metastatic prostate cancer tends to be aggressive, with a patient life expectancy of six months after diagnosis.1 Although rare, skin lesions can be the initial presentation of metastatic prostate cancer.2 This diagnosis should be considered in any elderly man presenting with an enlarging or unusual cutaneous or subcutaneous lesion.3

History: An 85-year-old man presented to our office with a four-month history of slowly enlarging lesions on his left temple and left arm. He also complained of asymptomatic “lumps” at the base of the right neck. The patient’s past dematologic history was positive for multiple actinic keratoses and a basal cell carcinoma. He missed his last dermatology visit and had not been evaluated for greater than six months. His pertinent medical history revealed an electively, non-treated form of Figure 1 A Figure 1 C invasive prostate cancer, which was diag- Violaceous to red-brown subcuta- Violaceous to red-brown subcuta- nosed twelve month prior to his presenta- neous nodules on the left temple neous nodule on the left arm tion to the dermatology office. Because of the patient’s age and his multiple health issues, he declined any aggressive treatment. He agreed only to palliative care. Upon presentation, the patient was primarily concerned about his skin lesions, as they had increased in size and became more symptomatic. Physical Exam: The patient appeared well nourished and of stated age. There were two firm, well circumscribed, violaceous to red- brown nodules on the left temple (Fig 1 Figure 1 B Figure 1 D A-B), and an identical, slightly smaller Close-up view: Violaceous to red- Bound-down skin with underlying coa- nodule on the left upper arm (Fig C). brown subcutaneous nodules on the lescent, subcutaneous nodules left temple There were several bound-down, palpa- same section at 40X and 63X magnifica- ble, non-painful and matted nodules in the panniculitis, deep tissue sarcoma, tion illustrated neoplastic cells with right supraclavicular region (Fig D). No angiosarcoma, sarcoidosis, and infectious eosinophilic cytoplasm and large, hyper- lymphadenopathy was appreciated. The granulomatous disorders. chromatic nuclei (Fig 2 B). Neoplastic remainder of the exam, with the exception cells with extensive mitotic figures were of actinically damaged skin, was unre- Histopathology: noted to be attempting to form glandular markable. structures and extensive mitotic figures Three 3-mm punch biopsies were per- were noted (Fig 2 C). Several immuno- Differential Diagnoses: formed to the two temporal and one left histochemical stains were performed, extremity nodule. A hematoxylin-eosin including leukocyte common antigen, The differential diagnosis of these cuta- (H&E) stained section of the medial tem- Melan A, S100 protein, Keratin, Prostate neous nodules includes: lymphocytoma poral lesion at 10X magnification revealed Specific Antigen (PSA), and Prostatic cutis, other B / T cell lymphomas, cuta- extensive replacement of the dermis by Acid Phosphatase (PAP). PSA at 40X neous metastases, lupus profundus, sub- anastamosing cords and aggregates of (Fig 3 A) and PAP at 63X magnification cutaneous granuloma annulare, neoplastic epithelial cells (Fig 2 A). The (Fig 3 B) illustrated diffuse and strong

20 CUTANEOUS METASTASES OF PROSTATE ADENOCARCINOMA: A CASE REPORT AND LITERATURE REVIEW Figure 2 A Figure 2 B Figure 2 C H&E stain at 10X magnification H&E stain at 40X magnification H&E stain at 63X magnification presenting with enlarging or unusual cutaneous or subcutaneous lesions.3

References: 1. Pique-Duran E, Paradela A, Farina MC, et al: Cutaneous metastasis from prostatic carcinoma. J Surg Oncol. 1996;62:144-147. 2. Davis, Mark D. P., M.D., Boswell, John S. Violaceous plaque on the forehead clinically resembling angiosarcoma: Cutaneous metastasis in a patient with prostatic adenocarcinoma. J Am Acad Dermatol. 2005;53(4):744- 745. 3. Agarwal Vikesh, Agarwal Pawan, Baghel Kishan. Subcuta- neous metastasis as first evidence of prostatic cancer. Indian Journal of Surgery. 2003;65(4):368-370. 4. Mueller TJ, Wu H, Greenberg RE, Hudes G, Topham N, Lessin SR, Uzzo RG. Cutaneous metastases from genitourinary malignancies. Urology. 2004; 63(6):1021-6. 5. Arita K, Kawashima T, Shimizu H. Cutaneous metastasis Figure 3 A Figure 3 B of prostate carcinoma. Clin Exp Dermatol. 2002;27(1):64-5. PSA stain at 40X magnification PAP stain at 63X magnification 6. Steinkraus, V., Lange, T., Abeck, D., Mensig, H., Ring, J., Cutaneous metastasis from carcinoma of the prostate. J Am Acad Dermatol. 1995;31:665. positive staining, confirming the diagnosis ules. The most common cutaneous sites 7. Venable, D, Hastings, D. Mistra, R., Unusual metastatic of metastatic prostate adenocarcinoma. include the lower abdomen, genitals, patterns of prostate adenocarcinoma. J Urol. groin, anterior thighs, nipples, periareolar 1983;130:980-5 8. Stahl, D., Veien, N., Cutaneous metastasis simulating 6 Discussion: skin, and head. Lesions of metastatic another dermatoses. Cutis. 1980;26:399-401. adenocarcinoma of the prostate 9. Webster WS, Small EJ, Rini BI, Kwon ED. Prostate cancer immunology: biology, therapeutics, and challenges. J Prostate adenocarcinoma is the second described in the literature have mimicked Clin Oncol. 2005;23(32):8262-9. most common type of cancer in men, sec- trichoepitheliomas, pyoderma gangreno- 10. Timme TL, et al. Therapeutic targets for metastatic prostate cancer. ond only to adenocarcinoma of the lung. sum, erysipeloides, cylindromas, mor- 11. Curr Drug Targets. 2003;4(3):251-61. There are 200,000 new cases of prostate phea, acanthosis nigricans, and 12. Armstrong AJ, Carducci MA. Novel therapeutic cancer diagnosed each year, and 30,000 angiosarcoma.2, 7, 8 approaches to advanced prostate cancer. Clin Adv Hema- tol Oncol. 2005;3(4):271-82. of these patients die of the disease. It is The diagnosis of cutaneous metastasis 13. Jeffrey Hunek, MD, Alice C. Watson, MD. Cutaneous estimated that 10% of cancer-related metastases from prostate carcinoma in a zosteriform pat- from prostate cancer is a grave finding. tern. Journal of the American Academy of Dermatology. deaths in men in the United States are The majority of patients die within six 2005;52(3):49. 4 secondary to prostate cancer. Prostate months of this diagnosis.1 Cutaneous 14. Wu JJ, Pang KR, Huang DB, Tyring SK. Cutaneous metastasis to the chest wall from prostate cancer. Journal cancer most frequently metastasizes to metastasis is therefore associated with of the American Academy of Dermatology. bone, liver, lungs, and adrenal glands, but advanced disease and no therapy is 2004;50(3):128. rarely to the skin. Cutaneous lesions are 6 15. Rossetti, R., Cassio M., Paschoal L., Burnier M. Cuta- described as being currative. Several neous metastasis originating from prostate adenocarci- an extremely rare finding in invasive treatments including hormonal therapy, noma. Int J Dermatol. 1991;30(5):363. prostate cancer, accounting for less than chemotherapy, androgen blockade, and 16. Metastasis of prostate gland adenocarcinoma to penile 5 and scrotal cutaneous tissues. J Am Osteopath Assoc. 0.5% of all metastatic cases. This is local radiation therapy have been 1989;89(3):349-52. notable when compared to a 5% cuta- reported as satisfactory for slowing pro- 17. Spencer, P., Helm, T., Skin metastasis in cancer patients. Cutis.1987;39:119-21. neous metastasis rate from most other gression of metastases and growth of 18. Lookingbill, D., Spangler, N., Sexton, F., Skin involvement 4 internal malignancies. There have been metastatic lesions, as well as aiding in as the presenting sign of internal carcinoma. J Am Acad approximately 70 cases of cutaneous 9, 10, 11 Dermatol. 1990;22:19-26. relief of uncomfortable symptoms. 19. Jones, C., Rosen, T., Multiple red nodules on the lower lesions secondary to metastatic prostate The patient in our care was prepared abdomen. Arch Dermatol. 1992;128:1533-8. cancer reported in the literature.5 Subcu- 20. Ng, C., Carcinoma Erysipeloides from Prostate Cancer for the diagnosis of cutaneous metas- presenting as Cellulitis. Cutis. 2000;65:215-216. taneous metastatic lesions appear to be tases from his prostate cancer. He did 21. Katske FA, Waisman J. Cutaneous and subcutaneous even more uncommon, with less than 50 metastases from carcinoma of prostate. Urology. 1 not want further therapy, and followed up 1982;19:373-6. cases reported. with his oncologist for palliative care. It The characteristic, relatively non-spe- should be stressed that metastatic cific lesions of metastatic prostate adeno- prostate cancer should be included in the carcinoma are multiple, asymptomatic, differential diagnosis in any elderly male violaceous to red-brown papules or nod-

KEELING, GLICK, ROSEN 21 Inflammatory Linear Verrucous Epidermal Nevus (ILVEN): A case report and review of the literature

William Kirby, DO*, Francisca Kartono, BS**, Andrea Passalacqua, DO***, Tejas Desai DO****, David C. Horowitz, DO***** * Co-Chief Dermatology Resident at Western University / Pacific Hospital of Long Beach, Long Beach, CA ** Francisa Kartono is a Medical Student at Western University of Health Sciences in Pomona, CA. *** first year Dermatology Resident at Western University / Pacific Hospital of Long Beach, Long Beach, CA **** Co-Chief Dermatology Resident at Western University / Pacific Hospital of Long Beach, Long Beach, CA ***** Dermatology Residency Program Director at Western University / Pacific Hospital of Long Beach, Long Beach, C

ABSTRACT

Appearing as a series of linear, scaly patches and papules, Inflammatory Linear Verrucous Epidermal Nevus (ILVEN) is most often observed in female pediatric patients. Complete epidemiology of this condition has yet to be clearly elucidated. ILVEN usually clears by adolescence but may occasionally remain into adulthood. This paper describes a case of ILVEN with exacerbation of symptoms in association with pregnancy along with a review of the literature regarding this condition. We also provide a tear- out, easy-to-duplicate section of frequently asked questions as a patient education sheet that would be useful for patients and the parents of affected children.

Case Report A pregnant 29-year-old female at 34 weeks of gestation presented with a slightly erythematous, serpiginous lesion on the posterior portion of her left thigh that had been present since approximately one year of age. She noted that the lesion had become thickened, more irritated, and more pruritic in the past few months (Fig- ure 1). Physical exam revealed that the lesion was palpable with a verrucous character. At the time of presentation she gave a history of topical treatment of the lesion with topical steroids of varying potency. Histopathologic Findings Figure 1 A 4mm-punch biopsy was performed Infammatory verrucous epidermal nevus. A slightly erythematous, serpiginous and regular alteration of parakeratotic plaque with a verrucous surface on the posterior of left thigh. areas of agranulosis and slightly depressed, cup-like, areas of orthokeratotic sion of the affected site yields the highest hyperkeratosis with a distinct granular layer Treatment success and surgical removal has proven were appreciated (Figure 2a,b). Elonga- Because the vast majority of ILVEN to be effective in some cases.2-5 This is of tions of the rete ridges are also noted. treatments have been presented as case course with limitations, including potential These characteristic findings confirmed a reports, there are no side-by-side compari- for scarring and increased potential for suspicion of Inflammatory Linear Verrucous son studies to illustrate which treatment adverse effects that come with surgery.4 A Epidermal Nevus (ILVEN). modality is most effective. In the dermato- surgical approach is obviously impractical if logical community it is well known that the lesion is extensive or located in an Inflammatory Linear treatment of ILVEN is often very challeng- anatomical site where procedures can be Verrucous Epidermal ing; only anecdotal therapeutic effective- difficult to perform. ness has been described. Additionally, Laser therapy has been recently used in Nevus most ILVEN treatments are currently used the form of pulsed dye laser and carbon to provide relief of the symptoms that dioxide.2-3, 5 Superpulsed carbon dioxide ILVEN, is a skin disease of childhood. It accompany ILVEN as opposed to complete laser was first used in 2001 in a French is usually seen in children less than five cure of the condition. study with satisfactory cosmetic result with years of age, and for unknown reasons is no recurrence at two-year follow-up.6 In a more observed in female patients. Appear- Traditional therapies for ILVEN include 1 recent study from Turkey in 20042, ILVEN ing as a series of verrucous, linear, scaly cryotherapy , dermabrasion, electrofulgura- was successfully treated with carbon diox- patches and papules, ILVEN may appear tion, and chemical peels with trichloroacetic ide laser. In this case, all symptoms asso- erythematous to brown in color. The most acid or phenol. These treatments however ciated to ILVEN resolved including redness, common sites of involvement include the have fallen out of favor in recent years as excoriations, scarring and itching. The only arm, trunk, and leg. Complete and concise they are uncomfortable, leave the patient notable side effect was a pale discoloration epidemiology of ILVEN has yet to be eluci- with scarring, and often result in incomplete limited to the treatment site. dated. ILVEN usually clears by adulthood resolution of the lesion with recurrence as but may occasionally remain into adult- a common late finding. A number of topical medications have hood. Many dermatologists contend that exci- been used to treat ILVEN: Calcipotriol oint-

22 INFLAMMATORY LINEAR VERRUCOUS EPIDERMAL NEVUS (ILVEN) ILVEN. In most cases however, only the Supplement: superficial portions of the lesions are removed. Surgical excision offers better ILVEN-RELATED QUESTIONS success in regard to symptomatic relief but FREQUENTLY ASKED BY PARENTS it may result in scarring. Q: CAN ILVEN BE TREATED? Q: WHAT IS ILVEN? A: Treatments for ILVEN are usually not A: Very simply put, Inflammatory Linear very effective. Different topical creams, Verrucous Epidermal Nevus (ILVEN) is a such as prescription-strength topical rare type of mole. These moles are due to steroids or calcipotriol may be helpful. an overgrowth of the upper layers of the Combination therapy with topical Tretinoin skin (the epidermis). and Fluorouracil cream has had beneficial Q: WHAT DOES ILVEN LOOK LIKE? results, but long-term success requires continued use. (see “Treatment”) A: ILVEN is a scaly, reddish, bumpy growth on the skin that may be very itchy. Q: WHERE CAN I FIND OUT MORE As the name suggests, it usually presents INFORMATION ON ILVEN linearly, as in “like a line”. It is almost A: www.ILVEN.org always limited to one side of the body, usually on an arm or leg. For reasons unknown, the left leg is more often affected References: than the right. 1. Fox BJ, Lapins NA. Comparison of treatment modalities for epidermal nevus: a case report and review. J Dermatol Q: WHO GETS LIVEN? Surg Oncol 1983;9:879-885 2. Ulkur E, Celikoz B, Yuksel F, Karagoz H. Carbon dioxide A: ILVEN is most often a condition of therapy for an inflammatory linear verrucous epidermal Figure 2 (a,b) nevus: a case report. Aesthetic Plast Surg 2004;28:428- Elongated rete ridges with alteration childhood. 75% of people that get ILVEN 430 of parakeratotic areas of agranulosis are under 5 years old. Girls are affected 3. Alster TS. Inflammatory linear verrucous epidermal nevus: successful treatment with the 585nm flashlamp- and slightly depressed, cup-like, areas four times more often than boys. Rarely, pumped pulsed dye laser. J Am Acad Dermatol 1994;31 of orthokeratotic hyperkeratosis with a ILVEN may appear during adulthood. The (3 Pt 1):513-514 4. Lee BJ, Mancini AJ, Renucci J, Paller AS, Bauer BS. Full- distinct granular layer. exact cause of the condition is unknown. thickness surgical excision for the treatment of inflammatory linear verrucous epidermal nevus. Ann Plast Surg Q: WHAT CAUSES ILVEN? 2001;47:285-292 ment has been used in a German study for 5. Sidwell RU, Syed S, Harper JI. Pulsed dye laser treat- ILVEN after corticosteroids and antibiotics A: Although familial cases have been ment for inflammatory linear verrucous epidermal naevus. 7 Br J Dermatol 2001;144:1267-1269 had failed. In addition, Calcipotriol also described, ILVEN usually arises sponta- 6. Michel JL, Has C, Has V. Resurfacing CO2 laser treat- has been shown to be efficacious in other neously. ment of linear verrucous epidermal nevus. Eur J Dermatol studies.9-12 Anthralins and retinoids have 2001;11:436-439 Q: HOW IS IT DIAGNOSED? 7. Bohm I, Bieber T, Bauer R. Successful therapy of an been used with fair results.8 It has also ILVEN in a 7-year-old girl with calcipotriol. Hautarzt been noted that combination therapy with A: ILVEN may be diagnosed clinically, 1999;50:812-814 8. De Mare S, van de Kerkhof PC, Happle R. Dithranol in topical Tretinoin and Fluorouracil cream but a skin biopsy may be performed to con- the treatment of inflammatory linear verrucous epidermal has had beneficial results, but long-term firm the diagnosis and rule out other condi- nevus. Acta Derm Venereol 1989;69:77-80 13 9. Bohm M, Luger TA, Traupe H. Successful treatment of success requires continued use. Topical tions. inflammatory linear verrucous epidermal naevus with topi- treatments with Podophyllin and alpha- cal natural vitamin D3 (calcitriol). Br J Dermatol Q: WILL ILVEN SPREAD? 2003;148:824-825 hydroxy acids are relatively ineffective. 10. Zvulunov A, Grunwald MH, Halvy S. Topical calcipotriol Lastly, systemic retinoids can produce a A: ILVEN may increase in size after its for treatment of inflammatory linear verrucous epidermal temporary response in some patients with nevus. Arch Dermatol 1997;133:567-568 initial presentation. It usually does not 11. Mitsuhashi Y, Katagiri Y, Kondo S. Treatment of inflamma- extensive disease. move to other parts of the body. tory linear verrucous epidermal naevus with topical Vita- min D3. Br J Dermatol 1997;136:134-135 Q: WHAT ARE THE SIDE EFFECTS OF 12. Micali G, Nasca MR, Musumeci ML. Effect of topical cal- Conclusion cipotriol on inflammatory linear verrucous epidermal ILVEN? nevus. Pediatr Dermatol 1995;12:386-387 Currently, there are no large-scale clini- 13. Kim JJ, Chang MW, Schwayder T. Topical tretinoin and 5- A: Intense itching is the most common fluorouracil in the treatment of linear verrucous epidermal cal trials comparing the different treatment nevus. J Am Acad Dermatol 2000;43 (1 Pt 1):129-132 complaint of patients who suffer from methods given that ILVEN is a rare condi- ILVEN. Parents and patients also report tion. Most of the research is limited based Other References: concerns regarding cosmetic appearance. on the age of the individuals affected. 14. Schwartz RA, Jozwiak S. Epidermal Nevus Syndrome. Rarely, arthritis, or joint pain, may be asso- Emedicine: Because there is no gold standard for the ciated. It is important to recognize this http://www.emedicine.com/DERM/topic732.htm Accessed treatment of ILVEN, each presentation March 1, 2006 early and have it treated appropriately. 15. Lee IW, Ahn SK, Choi EH. Inflammatory linear verrucous should have a custom tailored treatment epidermal naevus arising on a burn scar. Acta Derm regimen. Additionally, because epidermal Q: CAN ILVEN BE CURED? Venereol 1999;79:164-165 nevi are associated with a small risk for 16. Surve TY, Muranjan MN, Deshmukh CT, et al: Inflamma- A: The good news is that ILVEN usually tory linear verrucous epidermal nevus syndrome with bilat- malignant transformation, any suspicious eral vertebral artery occlusion. Indian Pediatr. 1999;36: areas should be biopsied. In the near goes away on its own by adulthood. Unfor- 820-823. tunate is the fact that no one therapy has 17. Vissers WH, Muys L, Erp PE, de Jong EM, van de Kerkhof future, therapy will most likely be guided by PC. Immunohistochemical differentiation between inflam- a combined approach with ablative laser been consistently successful in the perma- matory linear verrucous epidermal nevus (ILVEN) and therapy being a probable cornerstone of nent resolution of ILVEN. Laser therapy, psoriasis. Eur J Dermatol 2004;14:216-220 treatment. The patient in this presentation electrofulguration, liquid nitrogen cryother- elected to defer treatment until after preg- apy, dermabrasion, and chemical peels are nancy. all methods that have been used to treat

KIRBY, KARTONO, PASSALACQUA, DESAI, HOROWITZ 23 Collision Tumor: A Case Report

Jon Keeling, D.O.*, Harold Rabinovitz, M.D.**, Margaret Olivario, ARNP*** *Dermatology Resident, Wellington Regional Medical Center/LECOM **Associate Clinical Professor of Dermatology, University of Miami, Miller School of Medicine. Private Practice, Plantation, FL ***Registered Nurse Practitioner. Plantation, FL

ABSTRACT

Collision tumors are defined as two or more benign or malignant neoplasms arising in a single lesion. This case report describes a collision tumor of a melanoma with a seborrheic keratosis. The clinical, dermoscopic, and histological features of this lesion are described below. Collision tumors with a malignant component can be difficult to diagnose, secondary to certain features suggesting a benign neoplasm. Biopsies are recommended for lesions with unusual clinical and dermoscopic features.

History and Clinical Findings A 76-year-old woman presented with a 5-mm by 7-mm papule on the back (Figure 1). The lesion was asymmetric with ill-defined borders and the colors of light brown, dark brown, and black. The left half of the lesion was smooth, whereas the right half had a crusted, scaly surface.

Dermoscopic Findings Figure 3 Dermoscopic examination revealed a Figure 1 melanocytic lesion with a heterogenic pattern, biaxial asymmetry, three colors, and overall disorganization (Figure 2). There were comedone-like openings within the lesion, short lines at the periphery, and a moth-eaten border. There were also gray areas noted. This was an unusual pattern, and an excisional biopsy was performed. Histopathological Findings The global view of the biopsy specimen on low power demonstrates two distinct lesions (Figure 3). The left side of the biopsy specimen (Figure 4) at 10X magnification illustrates an increased Figure 4 Figure 2 number of solitary melanocytes asym- scopic evaluation of the lesion pointed to metrically along the dermal-epidermal features of a solar lentigo or seborrheic junction with evident nuclear hyperchro- Diagnosis keratosis, but several characteristics matism and pleomorphism. There is The diagnosis is a collision tumor of a suggested consideration of a malignant exocytosis of melanocytes throughout melanoma and a seborrheic keratosis. neoplasm. The benign features the epidermis. Large, atypical included short lines running together at melanocytes are located in the papillary Discussion the periphery and a moth-eaten border, dermis forming nests, cords, and which are generally noted in solar lentig- strands. The right side of the biopsy The definition of a collision tumor is ines. The comedone-like openings are a finding of seborrheic keratoses. The specimen (Figure 5) at 10X magnifica- two or more benign or malignant neoplasms arising in a single lesion. In the malignant features included biaxial tion illustrates acanthosis with hyper- article by Cascajo et al., only two of 54 asymmetry, disorganization of the orthokeratosis and horn pseudocysts. collision tumors involved a seborrheic lesion, and gray areas suggesting keratosis and a melanoma.1 Dermo- regression.

24 COLLISION TUMOR: A CASE REPORT Figure 5 Conclusion Cutaneous collision tumors are extremely difficult to diagnose even with the help of dermoscopy. Biopsies are recommended for lesions with unusual clinical and dermoscopic features.

References 1. Cascajo CD, Reichel M, Sanchez JL. Malignant neoplasms associated with seborrheic keratoses. An analysis of 54 cases. Am J Dermatopathol. 1996 Jun;18(3):278-82. 2. Zaballos P, Llambrich A, Puig S, Malvehy J. Dermoscopy is useful for the recognition of benign-malignant compound tumours. Br J Dermatol. 2005 Sep;153(3):653-6. de Giorgi V, Massi D, Sestini S, Alfaioli B, Carelli G, Carli P. 3. Cutaneous collision tumour (melanocytic naevus, basal cell carcinoma, seborrhoeic keratosis): a clinical, dermoscopic and pathological case report. Br J Dermatol. 2005 Apr;152(4):787-90.

25 Epidermal Nevus Syndrome: A Case Report and Review of the Literature Genesys Regional Medical Center Grand Blanc, Michigan

David M. Bracciano, D.O., F.AO.C.O.*, Kimball Silverton, D.O., F.A.O.C.D.** *3rd Year Resident, Department of Dermatology Genesys Regional Medical Center, Grand Blanc, Michigan **Program Director, Department of Dermatology Genesys Regional Medical Center, Grand Blanc, Michigan

ABSTRACT

Epidermal nevus syndrome is a relatively rare neurocutaneous disorder that highlights the need for dermatologists to approach patients with a “holistic” manner and not focus solely on a patient’s cutaneous disease.1 In this paper, we will present an 11- year-old female whose systemic involvement required the expertise of multiple medical specialists to improve her quality of life. We will review both the cutaneous and systemic findings in patients with epidermal nevus syndrome and discuss the complex treatment options available.

Case Report Classification of Clinical An 11-year-old African-American female Manifestations presented to the Dermatology Clinic with a Epidermal nevus syndrome (ENS) is a chief complaint of “skin lesions.” According poorly defined entity that includes multiple to her mother, these multiple lesions had organ systems.2 Associated disorders been present since birth and were gradu- most often include bone, central nervous ally increasing in size. The patients past system, ocular, renal, vasculature, hor- medical history was positive for autism, monal, and biochemical abnormalities3. In seizure disorder, and amlyloplia. The addition, multiple types of nevi have been patient taking oxcarbanzepine. The described in this syndrome. Nevi associ- patient’s past surgical history was only sig- ated with the syndrome include: seba- nificant for a skin biopsy at a nearby univer- ceous nevus, nevus comedonicus, Figure 1 sity dermatology clinic. The patient had no pigmented hairy epidermal nevus (Becker Epidermal nevus syndrome patient: drug allergies. The family history was neg- nevus), and the flat, velvety, nonorganoid lesion extended from neck to oral cavity. ative for similar lesions and there wasno nevus seen in Proteus syndrome.3 family history of neurologic disorders. These epidermal nevi are hamartoma- Physical examination revealed a healthy tous lesions originating from mutations of appearing 11-year-old African-American pluripotential epidermal cells during early female with multiple hyperpigmented veru- embryonic development.4 Therefore, they ciform nevi on the neck, face, and lower lip. tend to follow Blascho’s lines, and the There were verruciform nevi involving the associated abnormalities often present on left gingival-buccal sulcus as well as the the ipsilateral side of the body. The com- soft palate. The cutaneous and oral plex and varied non-cutaneous abnormali- lesions only involved the right side of the ties seen in these syndromes are due to body and a portion of the forehead. The genetic mosaicism in the mesodermal forehead lesion did cross the midline. embryanal dervivatives.5 The majority of There was mild strabismus of her left eye. cases are likely due to spontaneous muta- There were no vascular malformations, tions; however, patients classified as hav- lipomas, or hemangiomas. The musculo- ing Proteus and CHILD syndromes are Figure 2 skeletal exam did not reveal any significant found to have a predominant and X-linked Note verrucous nature of lesion. abnormalities. 6 inheritance respectively. addition, in a recent review by Ruiz-Mal- According to the patient’s mother, the Schimmelpenning first described the cutaneous epidermal nevi wererelatively donado et. al., a seventh category of “ker- association of linear epidermal nevi and atinocytic nevus syndrome” is proposed.9 asymptomatic. The patient complained of CNS disorders in 1957. In 1975, Solomon mild dysphagia to while eating solid food. and Esterly proposed a classification The patient subsequently underwent direct scheme grouping many different variants of Management laryngoscopy and esophagoscopy, which nevi and systemic abnormalities under the Understanding that congenital nevi may revealed no evidence of laryngeal or term “epidermal nevus syndrome”.7 With esophageal pathology. Carbon dioxide be associated with multiple diverse and the newer genetic testing techniques, these severe somatic abnormalities is the first laser ablation of the intraoral nevi was then syndromes are now shown to represent six performed under general anesthetic with step in managing the care of these chil- discrete subtypes of epidermal nevus syn- dren. Mucosal examination may reveal complete resolution of the patients’ dys- drome, each with distinguishing clinical and phagia. Her parents considered carbon intraoral or ano-genital involvement. After genetic features. These include: seba- a thorough cutaneous exam has been per- dioxide laser treatment for her cutaneous ceous nevus syndrome, nevus come- lesions. She continued to have regular formed, cardiac, CNS, skeletal, and renal donicus syndrome, Becker nevus systems must be investigated. Nevi involv- neurology, ophthalmology, otolaryngology, syndrome, Phacomatosis pigmentokeratot- and dermatology evaluations. ing the head, neck and spinal area are indi- ica, Proteus syndrome, and congenital cations for neurology consultation, as well hemidysplasia with ichthyosiform nevus at CT or MRI imaging. Children with CNS and limb defects (CHILD) syndrome.8 In

26 EPIDERMAL NEVUS SYNDROME: A CASE REPORT AND REVIEW OF THE LITERATURE involvement often exhibit seizure activity References early in life. 1. Happle, R. Epidermal Nevus Syndromes. Seminars in Dermatology, Vol 14, No2, pp 111-121. Removal of congenital epidermal nevi 2. Vujevich, JJ, Mancini, AJ. The Epidermal Nevus Syn- needs to be individualized. Biopsy of dromes: Multisystem disorders. J Am Acad Dermatol, Vol changing lesions to rule out malignancy is 50, No 6, 20004; pp 957-961. 3. Booth, TN, Rollin, NK. MR Imaging of the Spine in Epi- always indicated. Tumors affecting vital dermal Nevus Syndrome. Am J Neuroradiol 22: 1607- structures may also require removal, i.e. 1610, October 2002. 4. Gorlin, RJ. Nevoid Basal Cell Carcinoma Syndrome. Der- oral, mucosal, and ocular lesions. Superfi- matologic Clinics, Vol 13, No 1, January 1995: 113-125. cial epidermal nevi may be removed with a 5. Tadini, G., Happle, R. , Phacomatosis Pigmentokeratotica. Arch Dermatol, Vol 134, 333-337. March 1998 Q-switched ruby laser, CO2 Laser, or elec- 6. Kishida, ES, Nacagami Sotto, M. Epidermal Nevus Syn- trodessication. However, involvement of drome Associated with Adnexal Tumors, Spitz Nevus, and the epidermal appendages may necessi- Hypophosphatemic Vitamin D-Resistant Rickets. Pediatric Dermatology, Vol 22, No 1: 48-54, 2005. tate more invasive removal techniques. 7. Sugarman, JL. Epidermal Nevus Syndromes. Seminars in Cutaneous Medicine and Surgery, Vol 28, No 2, 2004; pp145-157. Summary 8. Ruiz-Maldonado, R. Epidermal Nevus Syndromes: Clini- cal Findings in 35 Patients. Pediatric Dermatology, Vol 21, Children with epidermal nevus syndrome No 4, pp 432-439, 2004. present a diagnostic and therapeutic challenge to the dermatologist. Like most gen- odermatoses, our understanding of the molecular and genetic basis of this diverse group of disorders has allowed for more accurate classification of patients. This syndrome requires the dermatologist to work closely with many different colleges to maximize the appropriate treatment of these children. Often, the dermatologist will be called upon to make the initial diagnosis. Therefore, it behooves us to provide our patients, their families, and our colleagues with an accurate diagnosis that will guide the future treatment plan for these children.

BRACCIANO, SILVERTON 27 Cutaneous Vasculitis

Carissa Summa, D.O.*, Cindy Hoffman, D.O.** *Chief Resident, Lutheran Medical Center, Brooklyn, N.Y. **Program Director, Lutheran Medical Center, Brooklyn, N.Y.

of 1990 includes clinical, histologic, and Introduction disease history.1 The Chapel Hill Consen- Vasculitis is the inflammation and necro- sus Conference convened in 1992 and sis of blood vessel walls that presents with developed criteria for vasculitis based a wide range of clinical manifestations. The solely on histopathology.2 When approach- disease can range in severity from a self- ing a patient in dermatology, we often focus limited, single-organ disorder to a life- on acute causes such as hypersensitivity threatening disease with the prospect of or infection and chronic causes such as multiple-organ failure. The challenge is to malignancy, collagen vascular disease, or not only recognize vasculitis, but also pro- cryoglobulinemia. vide a specific diagnosis and treat the underlying etiologic condition. Common Etiologies of Clinically, there is a broad range of cuta- Figure 1 neous manifestations. Lesions may appear Cutaneous Vasculitis: Leukocytoclasis and extravasated erythrocytes. as petechiae or as erythematous-to-viola- Current data shows that cutaneous vas- ceous patches on the lower extremities. culitis is associated with numerous condi- They may progress upward on the body tions such as idiopathic (45-55%), infection and become palpable purpura or urticarial- (15-20%), inflammatory disease (15-20%), like plaques. Erosions, ulcerations and drug intake (10-15%), and malignancy necrosis may develop if left untreated. (<5%).3 Although the causes are diverse, there are limited histopathologic manifestations Infection of vasculitis. A necrotizing vasculitis mani- Infections can cause lesions that mimic fests as segmental areas of transmural vasculitis as well as directly cause septic infiltration and disruption of the vessel vasculitis. Infection occurs via any route, architecture by neutrophils with fibrinoid triggers an immune complex formation, the necrosis, and it is termed leukocytoclastic organism proliferates in a vessel wall, and vasculitis (LCV). Endothelial swelling, gran- vasculitis occurs. Occlusion of vessels ulocyte debris (leukocytoclasis), and causes necrosis. Bacteria, viruses, para- Figure 2 extravasated erythrocytes are also com- sites, and fungi can all cause vasculitis, but Necrotic papule. monly seen, but are not required for the not all can be discussed in the scope of diagnosis (Figure 1). The biopsy of any this article.4 type of vasculitis is both site and time The hepatitis B virus is estimated to dependent. In lesions earlier than 12 hours cause 5% to 7% of polyarteritis nodosa or greater than 48 hours of age, a largely cases. A known cause of cryoglobulinemic lymphocytic infiltrate can be seen. Some vasculitis includes infections, the vast conditions are characterized by a solely majority represented by the hepatitis C lymphocytic vasculitis. This article will only virus (HCV).2 Up to 54% of patients with discuss vasculitic conditions that have spe- HCV have cryoglobulinemia. HIV infection cific dermatologic signs secondary to ves- is also associated with cryoglobulinemia sel inflammation and small- and and leads to vasculitis.5 medium-vessel vasculitides. Several uncommon infections may cause vasculitis and should be noted. Ecthyma Classification gangrenosum can be caused by pseudomonas, aeromonas, e.coli, candida, There continues to be confusion regard- or aspergillus and is a known cause of ing the use of classification criteria, defini- necrotizing vasculitis in immunocompro- tions, and diagnostic criteria. This is due to mised and neutropenic patients. Mycobac- multiple factors, including paucity of knowl- terium induces nodular vasculitis. edge regarding etiologies and overlapping Erythema induratum is a specific form of clinical features. Several criteria have been vasculitis associated with M. tuberculosis. used to classify vasculitis. These criteria Disseminated gonorrhea triggers thrombi Figure 3 include vessel size, severity of disease formation, occlusion of vessels, and subse- Palpable purpura. (cutaneous versus systemic), clinical signs quent septic vasculitis. Other infections Mucormycosis and candida are common and symptoms, histopathologic features, include chlamydia, rickettsial pox, Rocky causes in diabetic patients. In all instances, and primary or secondary disease. The Mountain spotted fever, and lepromatous the underlying infection must be treated earliest classification was based on vessel leprosy. Aspergillosis is associated with IV accordingly.6 size and is still the most widely used. The catheter-site infection leading to vasculitis. American College of Rheumatology criteria

28 CUTANEOUS VASCULITIS Inflammatory Disorders laboratory studies. Eosinophilia is com- typically have purpuric or urticarial mon in systemic drug-induced vasculitis lesions.12 Vasculitis can be associated with a (79%), but is only seen in 22% of skin-lim- Many serologic abnormalities exist in broad range of inflammatory disorders ited disease. To establish causality, a tem- CV. Serum cryoglobulin levels do not cor- including systemic lupus erythematosus poral relation of drug intake to eruption relate with disease severity. Hypocomple- (SLE), rheumatoid arthritis (RA), Sjo- and effect of drug withdrawal and rechal- mentemia may be found in up to 90% of gren’s syndrome (SS), Behcet’s disease, lenge should be noted. patients, and C4 levels are low. Rheuma- and inflammatory bowel disease. toid factor is positive in more than 70% of Rheumatoid vasculitis affects 5% - 15% Malignancy patients, and antinuclear antibody is posi- of patients with RA and is associated with Malignancy causes cutaneous vasculi- tive in 20% of patients. Type II exhibits a increased morbidity and mortality. The tis in 2% to 5% of cases. Paraproteinemia monoclonal spike on serum electrophore- most common presentation includes pur- or a lymphoproliferative disorder most sis.12 puric lesions, but palpable purpura, often induces vasculitis. A classic associ- Short-term corticosteroid treatment is petechiae, digital infarcts, ulcers, nodules, ation exists between PAN and hairy cell sometimes effective for the purpura and livedo reticularis, and papulonecrotic leukemia. Vasculitis associated with solid arthralgias. For severe disease, IV corti- lesions may also be seen (Figure 2).7 tumors resolves with removal of the costeroids may be used, but they do not Vascular injury in SLE can be a result malignancy.11 affect the course of the disease. Steroids of atherosclerotic, thrombotic, or inflam- may be used in combination with cyto- matory processes. Small arterioles and toxic agents and Interferon.12 venules of the skin are the most com- Small-vessel Vasculitis: monly affected. Vasculitis occurs in asso- Urticarial Vasculitis ciation with a flare of the disease and has Cutaneous Small-vessel Approximately 5% to 10% of patients a poor prognosis.8 Vasculitis in SS com- Vasculitis who present with chronic urticaria have monly affects the skin and CNS. It affects Several causes of vasculitis are catego- urticarial vasculitis. Urticarial vasculitis is 20% to 30% of patients, usually present- rized by vessel size. An entity termed differentiated from urticaria by the dura- ing as palpable purpura, urticaria, or cutaneous small-vessel vasculitis (CSVV) tion of lesions longer than 24 hours, the ecchymosis of lower extremities. Symp- is characterized by crops of lesions that presence of purpura and post-inflamma- toms are more frequent and severe in resolve spontaneously in several weeks. tory pigmentation, and symptoms of burn- patients with associated cryoglobulinemia Only small vessels are affected, thus ing. The lesions favor the trunk and or positive SSA/SSB antigens. One form lesions consist of purpura, papules, vesi- proximal extremities and may last for up of SS is termed hypergammaglobulinemia cles, and urticarial plaques. Lesions occur to three years. of Waldenstrom. These patients are usu- in dependent areas or at sites of trauma.8 ally young females with recurrent leg Urticarial vasculitis is seen in 32% of Treatment is to remove any offending patients with SS and 20% of SLE petechial hemorrhages, polyclonal hyper- agent or to treat the underlying disease. gammaglobulinemia, and HCV infection.9 patients. Less common etiologies include Anectdotal therapy with colchicine has infection (HCV), drug ingestion, and IgM Vasculitis can be seen in patients with 8 cleared several patients. or IgG gammopathies. Schnitzler’s syn- localized or systemic scleroderma. drome is urticarial vasculitis associated Smaller vessels are primarily involved, Cryoglobulinemic Vasculitis with monoclonal IgM, fever, arthralgia, causing ulceration and scarring of finger- (CV) bone pain, and hepatomegaly. Other tips and toes.10 Treatment is warranted in forms of urticarial vasculitis are defined cases of infarctions, dermatologic lesions, A cryoglobulin is a monoclonal or poly- by complement levels.13 neuropathy or organ failure. Treatment clonal immunoglobulin that precipitates in includes oral corticosteroids for mild dis- cold. Type I consists of monoclonal IgM Laboratory evaluation may reveal high ease and cyclophosphamide, azathio- and is always associated with a malignant ESR, hypocomplementemia, positive prine, chlorambucil, or methotrexate for hematologic disorder such as multiple ANA, and hematuria. There are no ran- severe disease. Patients are treated for myeloma. Type II is a monoclonal IgM domized trials of treatments for urticarial three to six months and tapered to main- directed against IgG. Type III consists of vasculitis, and no effective therapy cur- tain remission.5 polyclonal IgM against IgG. Types II and rently exists. III are mixed cryoglobulins (MC). Cryo- globulins lead to vasculitis through inflam- Henoch-Schonlein Purpura Medications mation of vessel walls by deposition of Henoch-Schonlein purpura (HSP) is Medications are associated with 10% to IgM-IgG complexes and complement acti- defined by the tetrad of palpable purpura, 15% of all vasculitic lesions. Common vation. Type I disease is often associated arthritis, GI involvement, and nephritis. It offending drugs include the penicillins, with ischemic vasculopathy from direct is associated with IgA immune complexes sulfonamides, quinolones, insulin, tamox- obstruction of vessels by cryoglobulins. in the circulation and vessel walls. HSP is ifen, oral contraceptives, phenothiazines, Known causes of CV include infection, the most common systemic vasculitis in allopurinol, thiazides, retinoids, and anti- autoimmune disease, and lymphoprolifer- children. The disease usually follows an influenza vaccines. Newer drugs have ative disorders. The most common clinical upper respiratory infection and takes an been implicated as well, including Inter- manifestations of CV are purpura, arthral- acute course. Cutaneous manifestations feron (IFN) and leukotriene inhibitors. Vit- gias, or arthritis. Peripheral neuropathy begin as symmetric macular erythema or amins and nutritional supplements have and nephritic or nephrotic syndromes are urticaria and eventually manifest as pur- been reported to cause LCV. Among illicit also commonly seen. Palpable purpura of puric, inflammatory petechiae (Figure 3). drugs, sympathomimetics are most com- the lower extremities are the clinical hall- The lower extremities are commonly monly implicated. Chemicals such as mark of CV, with cold enhancing these involved, and there is regression in 10 to insecticides and foods such as milk and lesions. The face and trunk are generally 14 days. Renal involvement is associated gluten have induced vasculitis.5 spared. Type I CV is associated with with the spread of purpura above the Drug-induced vasculitis is a diagnosis mucosal involvement, livedoid vasculitis, waist with fever and an elevated ESR. In of exclusion, as there are no diagnostic gangrene, Raynaud’s phenomenon, and the absence of GI and renal involvement, cold-induced acrocyanosis. MC patients the treatment of HSP is supportive.14

SUMMA, HOFFMAN 29 Medium-vessel Vasculitis: laboratory findings include elevated ESR References and C-reactive protein, anemia, leukocyto- 1. Stegeman CA, Kallenberg CG. Clinical aspects of primary sis, and positive RF.15 vasculitis. Springer Semin Polyarteritis Nodosa Immunopathol.2001;23:231-251. 2. Jennette JC, Falk RJ, Andrassy K, Bacon PA, Churg J, Classic PAN is a multisystem disorder Churg-Strauss Syndrome Gross WL, et al. Nomenclature of systemic vasculitides. Proposal of an international consensus conference. Arthri- that often presents with a range of sys- Churg-Strauss syndrome courses tis Rheum 1994;37:187-92. temic signs and symptoms. It affects men through three distinct phases. The first 3. Gibson LE. Cutaneous vasculitis update. Dermatol clinic 2001;19:603-15. more than women and can occur at any phase is characterized by allergic rhinitis, 4. Somer T, Finegold SM. Vasculitides associated with infec- age. The patient presents with fever, weight nasal polyps, and asthma. The second tions, immunization, and antimicrobial drugs. Clin Infect loss, arthralgias, and malaise. It is esti- Dis 1995;20:1010-36. phase consists of eosinophilic pneumonia, 5. Fiorentino DF. Cutaneous Vasculitis. J Am Acad Dermatol. mated that approximately 5% to 7% of gastroenteritis, and peripheral eosinophilia. 2003;48:311-40. cases are due to HBV infection.14 The most The final stage is systemic vasculitis with 6. Bolognia JL, Jorizzo JL, Rapini RP. Dermatology, 1st ed: Mosby.2003;1:382-90. common cutaneous sign is palpable pur- granulomatous inflammation, which may 7. Sais G, Vidaller A, Jucgla A, Servitje O, Condom E, Peyri pura and occurs in approximately 20% to occur up to 30 years after initial presenta- J. Prognostic factors in leukocytoclastic vasculitis: a clini- 16 copathologic study of 160 patients. Arch Dermatol 50% of patients. Signs of medium-vessel tion. Palpable purpura is seen in nearly 1998:134:309-15. vasculitis are common, including livedo half of all patients. Subcutaneous nodules, 8. Hautmann G, Campanile G, Lotti TM. The many faces of reticularis, punched-out ulcers, and subcu- cutaneous vasculitis. Clin Dermatol 1999:17:515-31. urticaria, and papulonecrotic lesions occur 9. Stone JH, Calabrese LH, Hoffman GS, Pusey CD, Hunder taneous nodules. Patients are treated with frequently. Laboratory findings are similar GG, Hellmann DB. Vasculitis. A collection of pearls and corticosteroids, which improve the five-year to Wegener’s.17 myths. Rheum Dis Clin North Am 2001;27:677-728. 14 10. Lotti T, Ghersetich I, Commachi C, Jorizzo JL. Cutaneous survival. small-vessel vasculitis. J Am Acad Dermatol 1998;39:667- Cutaneous PAN is limited to the skin and 87. Physical Examination 11. Gyselbrecht L, DeKeyser F, Ongenae K, Naeyaert J, Praet occurs in 10% of PAN cases. It is the most M, Veys E. Etiological factors and underlying conditions in common form of PAN in children. Cuta- Physical examination helps to identify patients with leukocytoclastic vasculitis. Clin Exp Rheuma- both the size of vessel involvement and a tol 1996;14:665-8. neous lesions are painful dermal nodules, 12. Trejo O, Ramos-Casals M, Garcia-Carrasco M, Yague J, usually located on the lower extremities specific diagnosis. Palpable purpura, pin- Jiminez S, de la Red G, et al. Cryoglobulinemia:study of point papules, vesicles, petechiae, splinter etiologic factors and clinical and immunologic features in near malleoli. These nodules may ulcerate, 443 patients from a single center. Medicine 2001;80:252- creating a “starburst” pattern of livedo retic- hemorrhages, pustules, and urticaria are 62. ularis. Lesions may heal with atrophic indicative of small-vessel vasculitis. Subcu- 13. Sanchez NP, Van Hale HM, Su WP. Clinical and histopathologic spectrum of necrotizing vasculitis. Report scars of atrophie blanche. This form of PAN taneous nodules, livedo reticularis, ulcers, of findings in 101 cases. Arch Dermatol 1985:121:220. is associated with streptococcal, parvovius papulonecrotic lesions, and digital infarcts 14. Stone JH, Nousari HG. “Essential” cutaneous vasculitis: indicate medium-sized vessel involvement. what every rheumatologist should know about vasculitis of B19, HIV, and HBV. NSAIDS and aspirin the skin. Curr Opin Rheumatol 2001;13:23-34. may be used in treatment, but often high- 15. Davson J, Ball J, Platt R. The kidney in periarteritis 14 nodosa. Q J Med 1948;17:175-202. dose corticosteroids are needed. Laboratory Evaluation 16. Fauci AS, Haynes B, Katz P. The spectrum of vasculitis: clinical, pathologic, immunologic and therapeutic consider- Patients with suspected vasculitis should ations. Ann Intern Med 1978:89:660-76. Combined Small- and 17. Hunder GG, Arend WP, Bloch DA, Calabrese LH, Fauci have the following studies: complete blood AS, Freis Jf, et al. The American College of Rheumatology Medium-sized Vessel Vas- count, blood/urea nitrogen and creatinine, 1990 criteria for the classification of vasculitis. Arthritis culitis: liver functions, urinalysis, stool guaiac, Rheum 1990;33:1065-7. HBV/HCV serology, cryoglobulins, comple- Wegener’s Granulomatosis ment levels (C4, C3), and RF. If connective- tissue disease is suspected, an ANA is Wegener’s consists of a triad of necrotiz- warranted. If symptoms of malignancy are ing granulomatous inflammation of the present, a work-up to find the primary site upper and lower airways, systemic necro- should be done. tizing small-vessel vasculitis, and pauci- immune glomerulonephritis. The majority of Treatment cases occurs in Caucasians and equally affects males and females. The skin is The first step is to rule out any obvious involved in up to 66% of cases and may be infection, inflammatory disease, or malig- the presenting symptom. Palpable purpura nancy. Any offending medications should is most common, followed by ulcers. Papu- be discontinued. Underlying diseases must lonecrotic lesions, subcutaneous nodules, be treated in an attempt to eliminate the and ulcers are also found. Ulcers resemble vasculitis. those of pyoderma gangrenosum. Typical

30 CUTANEOUS VASCULITIS

TOPICS: 2006 AOCD Annual Convention: Malpractice and Dermatology, Carlos Nousari, MD Sex in the City: Las Vegas Update in STD, Ted Rosen, MD Coding in Dermatology, Inga Ellzey Great Cases from Osteopathic Dermatology Programs, Program Directors Update on Management of Eczema, Joe Fowler, MD Cutaneous Oncology Update, Peter Vitulli, DO Dermatology Therapeutic Update, James Q. Del Rosso, DO Skin Cancer below the Knee, Anthony Dixon, MD Psoriasis, Steve Feldman, MD Indoor Tanning Issues, Steve Feldman, MD Tropical Dermatology, Lloyd Cleaver, DO Dermatology in Iraq, Come join in the fun in Las Vegas. Regan Anderson, DO, US Marine Corp Dermatology Review of Multiple Topics The 2006 AOCD Annual Convention is being our Dermatology Residents held at the Las Vegas Hilton along with the AOA Convention October 17-20, 2006. Welcome Reception: Mark your calendar, and make your plans to October 16, 2006 at 6:00pm join us for a great meeting. AOCD Business Meeting: October 17, 2006 at 3:00pm Get up to 16 hours of Dermatology CME. Presidential Reception and Banquet: October 17, 2006 at 6:00pm

Again, make your plans to join us for this great meeting.

Bill V. Way, DO, FAOCD President Elect of the AOCD Program Chair for the 2006 AOCD Convention

AOA Convention: October 16-20, 2006 AOCD Business Meeting: October 17, 2006 at 3:00 pm Pityriasis Versicolor During Infancy

Iqbal A. Bukhari, MD, Salha AlShehab, MD Dermatology Department, College of Medicine, King Faisal University and King Fahad Hospital of the University, Dammam, Saudi Arabia

ABSTRACT

Pityriasis versicolor is a dermatophyte infection that rarely afflicts infants. Here we report two unrelated infants who were affected with tinea versicolor infection on the forehead and the trunk.

posing factors that have been suggested Introduction Discussion are genetic, pregnancy and malnutrition, Pityriasis versicolor is a common Pityriasis versicolor is a chronic, mild but evidence for these is not conclusive. superficial cutaneous infection caused by and usually asymptomatic infection of the Clinically, pityriasis versicolor presents as Malassezia furfur, a hyphal form of Pity- stratum corneum caused by the lipophilic asymptomatic, scaly hypo- or hyperpig- rosporum orbiculare. The disease is more yeast, Malassezia furfur. The disease is mented macular lesions that mainly occur prevalent in tropical areas and most com- more prevalent in tropical areas. It can on the upper trunk and arms. The mac- monly seen in young adults.1 It is rarely occur at any age but is most commonly ules frequently coalesce, producing reported under the age of one year.2,3,4 In seen in young adults and is comparatively patches of varying shapes and sizes. this paper, we report two separate cases rare in children, with an almost equal sex These pigmentary changes are thought to of pityriasis versicolor occurring during distribution.1 It is rarely reported under the be due to the inhibition of melanin forma- early infancy, which alerted us to consider age of one year. 2,3,4 Malassezia furfur is tion by substances, such as azelaic acid, this diagnosis in pigmentary changes part of the normal flora of the skin where produced by the enzyme activity of the occurring during the infancy period. it exists in a yeast phase. It has been yeasts.1 Examination of lesions under found that 97% of clinically normal people Wood's light reveals a golden yellow fluo- Case 1: may carry the yeast on the scalp and rescence, and it is easily diagnosed by A 4-month-old healthy baby boy born 92% on the trunk.5,6 The oval form was microscopic examination of skin scales by normal spontaneous vaginal delivery more common on the scalp (Pityrosporum mounted in 20% KOH to demonstrate the presented to the dermatology clinic with ovale), whereas the spherical form was yeast and hyphal forms of Malassezia fur- hypopigmented scaly macules located on more common on the trunk (Pityrosporum fur. Culture is not helpful because the forehead, the frontal part of the scalp orbiculare). The incidence of Malassezia Malassezia furfur is part of the normal and the upper chest since four weeks. furfur on clinically normal skin from the skin flora. The differential diagnosis of Family history was positive for pityriasis back of newborn infants and those aged pityriasis versicolor should include vitiligo, versicolor in relatives of the child. Wood's six months, one year, five years, 10 years seborrheic dermatitis, and pinta. Pityria- light examination showed golden yellow and 15 years was investigated by Faerge- sis versicolor can be treated effectively fluorescence, and direct microscopic mann and Fredriksson.7 In their study, with 2.5% selenium sulphide suspension examination with KOH 20% showed the they failed to demonstrate Malassezia fur- or topical imidazole creams or ketocona- hyphae and spores of Malassezia furfur. fur in children less than one year old and zole shampoo. It should be noted that So a diagnosis of pityriasis versicolor was found the highest prevalence (93%) was since Malassezia furfur is part of the nor- established. The infant and affected fam- in the 15-year old children. On the con- mal flora of the skin, relapses frequently 1 ily members were started on topical anti- trary, in other reports, Malassezia furfur occur. Our two cases clearly demon- fungal for two weeks. On follow up, the was isolated from the normal skin of 47% strate the importance of considering the hypopigmented macules were still pre- of 150 1-to-5-day-old infants8 and 37% of diagnosis of pityriasis versicolor in infants sent, but Wood's light and direct micro- infants hospitalized in intensive care units presenting with pigmentary changes and scopic examinations were negative. in the United States.9 The pathogenesis the need for screening of affected family of pityriasis versicolor is not clearly members so the condition could be Case 2: defined, but it is postulated that under treated effectively. A 6-month-old healthy baby girl pre- certain circumstances, the normal skin sented with hypopigmented scaly mac- organism converts from the yeast to the References: ules located on the back since two weeks. mycelial phase, leading to pityriasis versi- 1. Claton YM. Superficial Fungal Infections. In: Harper J, The family did not have any cutaneous color. Factors that were suggested to Oranje A, Prose N, editors. Textbook of Pediatric Derma- tology; Vol 1, sect. 5. United Kingdom: Blackwell Science, manifestations of Pityriasis versicolor. precipitate the condition include: persis- 2000: 465-7. Wood's light examination showed golden tence of maternal androgen during the 2. Michalowski R, Rodziewics H. Pityriasis versicolor in chil- first few months of life,10 prematurity and dren. Br J Dermatol 1963;75:397-400. yellow fluorescence, and direct micro- 3. Wyre HW, Johnston WT. Neonatal pityriasis versicolor. scopic examination with KOH 20% hospitalization in neonatal intensive care Arch dsermatol 1981; 117:752-3. 9 showed typical hyphae and spores of units, high humidity and excessive sweat- 4. Aractingi S, Cadranel S, Reygange P, Wallach D. Pustu- 1,11 lose neonatale induite par Malassezia furfur. Ann Derma- Malassezia furfur. The condition was ing, close contact with an affected par- tol Venereol 1991;118:856-8. 11 diagnosed as a case of pityriasis versi- ent, systemic corticosteroid therapy,5 5. Roberts S0B. Pityriasis: a clinical and mycological investi- 12 gation. Br J Dermatol 1969;81:315-26 color, and the patient was started on topi- Cushing's syndrome, immunosuppres- 6. Roberts SOB. Pityrosporum orbiculare incidence and dis- cal antifungal treatment, which cleared sion associated with transplantation but tribution on clinically normal skin. Br J Dermatol not with AIDS, and physiological changes 1969;81:246-9. the infection. 7. Faergemann J, Fredriksson T. Age incidence of Pityrospo- in skin lipids during puberty enhancing rum orbiculare on human skin. Acta Derm Venereol the fungal pathogenicity.5 Other predis- (Stockh) 1980;60:531-3.

BUKHARI, ALSHEHAB 33 8. Thiaprasit M, Thagerngpol K. Pityriasis versicolor. In: Gatti F, de Vroey C, eds. Human Mycoses in Tropical Countries. Bolognia: Quaderni di Cooperazione Sanitaria 1991:63-9. 9. Powell DA, Hyes J, Durrell DE, Miller M, Marcon MJ. Malassezia furfur skin colonization of infants hospitalised in Intensive care units. J Pediatr 1987;111: 217-20. 10. Terragni L, Lasagni A, Oriani A, Gelmetti G. Pityriasis versicolor in pediatric age. Pediatr Dermatol 1991;8:9-12. 11. DiSilverio A, Zeccara C, Serra F, Ubezio S, Mosca M. Pityriasis versicolor in a newborn. Mycoses 1995;38:227-8 12. Canizares O, Shat H, Kellert AJ. Cushing's syndrome and dermatomycosis. Arch Dermatol 1959;80: 701-12.

34 PITYRIASIS VERSICOLOR DURING INFANCY Darier’s Disease

Norma Montiel, D.O.*, Marvin S. Watsky, D.O.** *Dermatology Resident, 3rd Year, St. John’s Episcopal Hospital ** Director of Dermatology Residency Program Director, St. John’s Episcopal Hospital

ABSTRACT

Darier’s disease is a rare, autosomal-dominant genodermatosis of the ATP2A2 gene. Both males and females are affected at the same rate between the ages of six and 20 years old. First described by Darier and White in 1889, it is characterized by loss of intercellular adhesion and disordered keratinization. Cutaneous lesions manifest as greasy, hyperkeratotic, firm papules that range in color from flesh to brown. Secondary infection with Staphylococcus aureus and viral infection may occur. Pathognomonic nail changes include V-shaped notching of the free edge of the nail with longitudinal red and white sandwich streaks. Treatment should start with simple life changes and progress to both oral and topical retinoids depending on the severity of the disease. Surgery should be considered the last resort.

A 47-year-old man presents with multi- lar adhesion and disordered keratinization.3 ple, greasy, crusted papules over his neck, Dermatologic skin changes manifest chest, arms and shoulders (Figure 1). between the ages of six and 20 years old There was a negative family history for sim- and are often misdiagnosed as seborrheic ilar skin lesions. The patient admitted to dermatitis or acne until topical agents, sun, suffering with Darier’s disease since ado- heat, stress or sweating aggravates the lescence. A skin biopsy was performed, lesions.2,3,4 Incidence in men and women which was diagnosed as Darier’s disease. are about equal. Peak incidence occurs The patient was prescribed a topical between 11 and 15 years of age.2 Severity retinoid that cleared his skin lesions. is unpredictable and fluctuates.4 There There are two types of Darier’s disease, have been reports of peri-menstrual exac- Type I and Type II. Type I segmental devel- erbation of this disease.4 Typically, lesions ops from new mutations occurring in an appear on the central trunk, the supraclav- Figure 1 otherwise healthy embryo. Type II seg- icular fossa, the sides of the neck, the fore- 4 Darier’s disease of the right shoulder mental originates in a heterozygous head, the ears and the scalp. embryo from post zygotic loss of the corre- Characteristic features include greasy, sponding normal allele. This results in a hyperkeratotic, firm papules that range in clone that is either homozygous or hemizy- color from flesh to brown.5 Up to 80% of gous for the mutation.1 Others have patients experience pruritus, which may be described a variant called localized Dari- intractable.4,5 Pain is unusual. Patients may er’s.2 This variant affects people between also experience eczematization (inflamma- 20 and 30 years old with localized or unilat- tion).4,5 Discrete papules found in flexures eral disease.3 It is identical to Darier’s dis- may coalesce into plaques and may ease histologically, however clinically there become exophytic, malodorous and difficult are no mucosal or nail changes.2 In addi- to control.4 Rarely, the patient may experi- tion, this variant has no familial history, and ence skin fragility with painful erosions and some would prefer to use the term “acan- fissuring. Greater than 95% of patients Figure 2 tholytic dyskeratosis epidermal nevus”.2 have acral involvement.4 Secondary skin Red streaking of the thumb nail Darier’s disease is an autosomal-domi- infection is a common complication. nant genodermatosis with high penetrance Staphylococcus aureus and viral infection coarse ‘pebbly’ appearance of the palate. but variable expression.2,3 Abnormal kera- (both herpes and varicella viruses) may Fifteen to 50% of Darier’s disease patients tinization rarely skips a generation but may occur. V-shaped notching of the free edge may have oral lesions, which are asympto- 3 be so mild as to go unnoticed. The gene is of the nail with longitudinal red and white matic and require no treatment. There localized to the 2-cM region on the gene sandwich streaks are pathongnomonic nail have been case reports of vulvar manifes- 6 ATP2A2, found on chromosome 12.12q23- manifestations of Darier’s disease (Figure tations and parotid swelling. 24.1.1,2,4 This chromosome encodes a 2).5 Other nail manifestations include sub- Darier’s disease has been associated sarco/endoplasmic reticulum calcium ungal hyperkeratosis and splinter hemor- with neuropsychiatric disorders including ATPase pump (SERCA 2).4 Other dis- rhages.4 In addition, patients may have pits bipolar affective disorder, mental retarda- eases caused by a defect of the calcium or punctuate keratotic papules on the tion, schizophrenia and epilepsy. Studies ATPases include Hailey-Hailey and Brody’s palms and soles.4 Keratotic papules, indis- indicate, however, that Darier’s patients disease (a rare musculoskeletal wasting tinguishable from plane warts, are a sign of experience less psychological distress than disease).3 disease in infancy.3 Acrokeratosis verruci- atopic patients. Most problems stem from Darier’s-White disease, or keratosis fol- formis-like lesions on the dorsal aspect of symptoms and feelings, while social rela- 3 licularis, was first described independently the hands and feet is also an early sign of tionships were relatively unaffected. 5 by Darier and White in 1889.3 It is a rare Darier’s disease. Histologically, Darier’s disease has a loss disease characterized by loss of intercellu- Oral lesions range from fine granular to of cohesion between suprabasal epidermal

MONTIEL, WATSKY 35 cells (acantholysis). This results in erides and cholesterol may be elevated, treated with oral essential fatty acids suprabasilar clefting with papillomatosis and abnormal renal function was reported. improved after six to nine months.4 and dyskeratosis with abnormal ker- All oral retinoids should be discontinued In conclusion, Darier’s disease is a rare, atinocytes (corps ronds).3,6 There is hyper- during pregnancy. Isotretinoin is preferred autosomal-dominant genodermatosis keratosis with some degree of over etretinate or acitretin in women of affecting people between six and 20 years parakeratosis. Electron microscopy shows childbearing age because its effects are old. First described by Darier and White in loss of the desmosomal protein attach- negligible at one month post-treatment 1889, it is characterized by loss of intercel- ments that normally link keratinocytes and instead of three years. Once on the oral lular adhesion and disordered keratiniza- perinuclear aggregation of keratin fila- retinoid, 70% of patients respond within tion. Cutaneous lesions manifest as greasy, ments.7 one month. Studies indicate that hyperkeratotic, firm papules that range in Treatment should be initiated with simple isotretinoin should be started at 0.5 color from flesh to brown. Secondary infec- life changes. Irritation, the most common mg/kg/day and then adjusted accordingly. tion with Staphylococcus aureus and viral symptom, is best treated with simple emol- Initial treatment with acetretin is 10-25 infection may occur. Pathognomonic nail lients, containing urea and lactic acid, as mg/day and etretinate 30 mg/day.4 changes include V-shaped notching of the soap substitutes. Keeping the skin cool by Fluorouracil inhibits DNA synthesis, free edge of the nail with longitudinal red wearing cotton clothing will improve symp- resulting in cell death, and therefore is and white sandwich streaks. Treatment toms of irritation.3,4 Topical steroids are effective in the hyperproliferative state of should start with simple life changes and helpful for some patients.4 Sunblock should Darier’s Disease, yet no trials have been progress to both oral and topical retinoids be used in patients with a history of pho- performed. Treatment response is two depending on the severity of the disease. toaggravation. Lithium carbonate has been weeks. Calcipotriol in early studies indi- Surgery should be last resort in treating reported to cause exacerbations and if cated it was an extreme irritant and in this disease process. medically possible should be discontinued.3 some patients worsened their disease.3 Finally, DARDIS is a support group Although studies using isotretinoin gel Secondary infections may manifest with started in the UK. Further information may 0.05% and 0.1% have proven to be effec- exudates and painful blisters. Manage- be obtained from the British Association of tive, irritation was a constant limiting factor. ment is the standard of care for whatever Dermatologists (www.bad.org.uk/about).3 In Darier’s disease patients with acne, ada- the infectious agent is. palene has been proven to be more effec- Surgery is the last resort in the treatment References tive than isotretinoin. Adapalene gel is a for hypertrophic skin lesions. Surgical pro- 1. Happle R, Itin PH, Brun AM. Type 2 segmental Darier dis- modulator of cellular differentiation, kera- cedures are often used in conjunction with ease. Eur J Dermatol. 1999 Sep;9(6):449-51. tinization and inflammation.2 The use of 2. English JC 3rd, Brown J, Halbach DP. Effective treatment medical treatment. Surgical approaches of localized Darier’s disease with adapalene 0.1% gel. topical retinoids may result in flattening of include electrosurgical, dermabrasion, Cutis. 1999 Apr;63(4):227-30 the papules in the mild generalized or lin- sharp debridement, split-thickness skin 3. Cooper SM, Burge SM. Darier’s disease: epidemiology, pathophysiology, and management. Am J Clin Dermatol. ear disease. Retinoids should be started grafting, surgical excision and laser abla- 2003:4(2):97-105. every other day, then every day as toler- tion. Dermabrasion has been reported to 4. Burge S. Management of Darier’s disease. Clin Exp Der- ated. Alternating days of topical corticos- matol. 1999 Mar;24(2):53-6. last as long as two and one-fifth years. 5. Hulatt L, Burge S. Darier’s disease: hopes and chal- teroid will help alleviate the erythema and Carbon-dioxide laser (Er:Yag) treatment lenges. J R Soc Med. 2003 Sep;96(9):439-41. pruritis.4 6. Bell HK, Farrar CW, Curley RK. Papular acantholytic has been shown to be successful for up to dyskeratosis of the vulva. Clin Exp Dermatol. 2001 Extensive disease may require oral two years. Surprisingly, sufficiently deep Jul;26(5):386-8. retinoids, including etretinate, acitretin and (papillary dermis ablation) surgical inter- 7. Burge S. Darier’s disease – the clinical features and pathogenesis. Clin and Exp Dermatol. 1994;19:193-205. isotretinoin.4 Ninety percent of patients with vention does not seem to cause scarring, hyperkeratosis respond to oral retinoids. as might be expected from the isomorphic Although effective, these medications phenomenon seen in response to trauma.3 cause severe irritation, pruritus, drying and One study demonstrated that 13 of 16 soreness of mucosal membranes. Triglyc- patients with Darier’s disease that were

36 DARIER’S DISEASE For the temporary treatment of moderate to severe glabellar lines in patients 18 to 65 years of age

Trusted tool of aesthetic artistry

BOTOX® Cosmetic is indicated for the temporary improvement in the appearance of moderate to severe glabellar lines associated with corrugator and/or procerus muscle activity in patients 18 to 65 years of age.

Important Safety Information: BOTOX® Cosmetic is contraindicated in the presence of infection at the proposed injection site(s) and in individuals with known hypersensitivity to any ingredient in the formulation. There have been rare reports of adverse events involving the cardiovascular system. Serious and/or immediate hypersensitivity reactions have been reported rarely. These reactions include anaphylaxis, urticaria, soft-tissue edema, and dyspnea. The most common adverse events following injection include blepharoptosis and nausea. Less frequently occurring (<3%) adverse reactions include facial pain, erythema at the injection site, paresthesia, and muscle weakness. Patients with neuromuscular disorders By prescription only such as ALS, myasthenia gravis, or Lambert-Eaton syndrome may be at increased risk of serious adverse events. Please see brief summary of full prescribing information on following page.

©2006 Allergan, Inc., Irvine, CA 92612 ® Marks owned by Allergan, Inc. BotoxCosmetic.com Re-order: 4960049 603280 BOTOX® COSMETIC viability of the embryos. (Botulinum Toxin Type A) Nursing mothers: It is not known whether this drug is excreted in human milk. Because many Purified Neurotoxin Complex drugs are excreted in human milk, caution should be exercised when BOTOX® COSMETIC is administered to a nursing woman. INDICATIONS AND USAGE Pediatric use: Use of BOTOX® COSMETIC is not recommended in children. ® BOTOX COSMETIC is indicated for the temporary improvement in the appearance of moderate Geriatric use to severe glabellar lines associated with corrugator and/or procerus muscle activity in adult The two clinical studies of BOTOX® COSMETIC did not include sufficient numbers of subjects patients < 65 years of age. aged 65 and over to determine whether they respond differently from younger subjects. However, CONTRAINDICATIONS the responder rates appeared to be higher for patients younger than age 65 than for patients 65 BOTOX® COSMETIC is contraindicated in the presence of infection at the proposed injection years or older. (See: CLINICAL STUDIES) site(s) and in individuals with known hypersensitivity to any ingredient in the formulation. There were too few patients (N=3) over the age of 75 to allow any meaningful comparisons. WARNINGS ADVERSE REACTIONS BOTOX® and BOTOX® COSMETIC contain the same active ingredient in the same formulation. General: Therefore, adverse events observed with the use of BOTOX® also have the potential to be BOTOX® and BOTOX® COSMETIC contain the same active ingredient in the same formulation. associated with the use of BOTOX® COSMETIC. Therefore, adverse events observed with the use of BOTOX® also have the potential to be ® Do not exceed the recommended dosage and frequency of administration of BOTOX® associated with the use of BOTOX COSMETIC. COSMETIC. Risks resulting from administration at higher dosages are not known. The most serious adverse events reported after treatment with botulinum toxin include rare Hypersensitivity Reactions spontaneous reports of death, sometimes associated with anaphylaxis, dysphagia, pneumonia, Serious and/or immediate hypersensitivity reactions have been rarely reported. These reactions and/or other significant debility. There have also been rare reports of adverse events involving the include anaphylaxis, urticaria, soft tissue edema, and dyspnea. One fatal case of anaphylaxis has cardiovascular system, including arrhythmia and myocardial infarction, some with fatal outcomes. been reported in which lidocaine was used as the diluent, and consequently the causal agent Some of these patients had risk factors including pre-existing cardiovascular disease. (See: cannot be reliably determined. If such a reaction occurs further injection of BOTOX® COSMETIC WARNINGS). New onset or recurrent seizures have also been reported, typically in patients who are should be discontinued and appropriate medical therapy immediately instituted. predisposed to experiencing these events. The exact relationship of these events to the botulinum toxin injection has not been established. Additionally, a report of acute angle closure glaucoma one Pre-Existing Neuromuscular Disorders ® day after receiving an injection of botulinum toxin for blepharospasm was received, with recovery Caution should be exercised when administering BOTOX COSMETIC to individuals with four months later after laser iridotomy and trabeculectomy. Focal facial paralysis, syncope and peripheral motor neuropathic diseases (e.g., amyotrophic lateral sclerosis, or motor neuropathy) exacerbation of myasthenia gravis have also been reported after treatment of blepharospasm. or neuromuscular junctional disorders (e.g., myasthenia gravis or Lambert-Eaton syndrome). ® Patients with neuromuscular disorders may be at increased risk of clinically significant systemic In general, adverse events occur within the first week following injection of BOTOX COSMETIC effects including severe dysphagia and respiratory compromise from typical doses of BOTOX® and while generally transient may have a duration of several months or longer. Localized pain, COSMETIC. Published medical literature has reported rare cases of administration of a botulinum infection, inflammation, tenderness, swelling, erythema and/or bleeding/bruising may be toxin to patients with known or unrecognized neuromuscular disorders where the patients have associated with the injection. shown extreme sensitivity to the systemic effects of typical clinical doses. In some of these cases, Glabellar Lines dysphagia has lasted several months and required placement of a gastric feeding tube. In clinical trials of BOTOX® COSMETIC the most frequently reported adverse events following Dysphagia injection of BOTOX® COSMETIC were headache*, respiratory infection*, flu syndrome*, Dysphagia is a commonly reported adverse event following treatment of cervical dystonia patients blepharoptosis and nausea. with all botulinum toxins. In these patients, there are reports of rare cases of dysphagia severe Less frequently occurring (<3%) adverse reactions included pain in the face, erythema at the enough to warrant the insertion of a gastric feeding tube. There is also a case report where a patient injection site*, paresthesia* and muscle weakness. While local weakness of the injected muscle(s) is developed aspiration pneumonia and died subsequent to the finding of dysphagia. representative of the expected pharmacological action of botulinum toxin, weakness of adjacent Cardiovascular System muscles may occur as a result of the spread of toxin. These events are thought to be associated with There have also been rare reports following administration of BOTOX® of adverse events the injection and occurred within the first week. The events were generally transient but may last involving the cardiovascular system, including arrhythmia and myocardial infarction, some with several months or longer. fatal outcomes. Some of these patients had risk factors including pre-existing cardiovascular (* incidence not different from Placebo) disease. The data described in Table 4 reflect exposure to BOTOX® COSMETIC in 405 subjects aged 18 Human Albumin to 75 who were evaluated in the randomized, placebo-controlled clinical studies to assess the This product contains albumin, a derivative of human blood. Based on effective donor screening use of BOTOX® COSMETIC in the improvement of the appearance of glabellar lines (See: and product manufacturing processes, it carries an extremely remote risk for transmission of viral CLINICAL STUDIES). Adverse events of any cause were reported for 44% of the BOTOX® diseases. A theoretical risk for transmission of Creutzfeldt-Jakob disease (CJD) also is COSMETIC treated subjects and 42% of the placebo treated subjects. The incidence of considered extremely remote. No cases of transmission of viral diseases or CJD have ever been blepharoptosis was higher in the BOTOX® COSMETIC treated arm than in placebo (3% vs. 0). identified for albumin. In the open-label, repeat injection study, blepharoptosis was reported for 2% (8/373) of subjects PRECAUTIONS in the first treatment cycle and 1% (4/343) of subjects in the second treatment cycle. Adverse events of any type were reported for 49% (183/373) of subjects overall. The most frequently General: ® reported of these adverse events in the open-label study included respiratory infection, The safe and effective use of BOTOX COSMETIC depends upon proper storage of the product, headache, flu syndrome, blepharoptosis, pain and nausea. selection of the correct dose, and proper reconstitution and administration techniques. Physicians administering BOTOX® COSMETIC must understand the relevant neuromuscular Because clinical trials are conducted under widely varying conditions, adverse reaction rates and/or orbital anatomy of the area involved, as well as any alterations to the anatomy due to prior observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials surgical procedures and avoid injection into vulnerable anatomic areas. Caution should be used of another drug and may not be predictive of rates observed in practice. when BOTOX® COSMETIC treatment is used in the presence of inflammation at the proposed TABLE 4. injection site(s) or when excessive weakness or atrophy is present in the target muscle(s). Reduced blinking from BOTOX® COSMETIC injection of the orbicularis muscle can lead to corneal Percent of Patients Reporting Adverse Events exposure, persistent epithelial defect and corneal ulceration, especially in patients with VII nerve disorders. In the use of BOTOX® for in the treatment of blepharospasm, one case of corneal perforation in an aphakic eye requiring corneal grafting has occurred because of this effect. Careful BOTOX® Cosmetic Placebo Adverse Events by Body testing of corneal sensation in eyes previously operated upon, avoidance of injection into the (N=405) (N=130) System lower lid area to avoid ectropion, and vigorous treatment of any epithelial defect should be % % employed. This may require protective drops, ointment, therapeutic soft contact lenses, or closure of the eye by patching or other means. Inducing paralysis in one or more extraocular muscles may produce spatial disorientation, Overall 44 42 double vision or past pointing. Covering the affected eye may alleviate these symptoms. ® Body as a Whole Caution should be used when BOTOX COSMETIC treatment is used in patients who have an 2 1 inflammatory skin problem at the injection site, marked facial asymmetry, ptosis, excessive Pain in Face dermatochalasis, deep dermal scarring, thick sebaceous skin or the inability to substantially Skin and Appendages lessen glabellar lines by physically spreading them apart as these patients were excluded from 1 0 the Phase 3 safety and efficacy trials. Skin Tightness Needle-related pain and/or anxiety may result in vasovagal responses, (including e.g., syncope, Digestive System hypotension) which may require appropriate medical therapy. Nausea 3 2 Injection intervals of BOTOX® COSMETIC should be no more frequent than every three months Dyspepsia 1 0 and should be performed using the lowest effective dose (See Adverse Reactions, 1 0 Immunogenicity). Tooth Disorder Information for Patients Special Senses Patients or caregivers should be advised to seek immediate medical attention if swallowing, 3 0 speech or respiratory disorders arise. Blepharoptosis Drug Interactions Musculoskeletal System ® 1 2 0 Co-administration of BOTOX COSMETIC and aminoglycosides or other agents interfering with Muscle Weakness neuromuscular transmission (e.g., curare-like nondepolarizing blockers, lincosamides, polymyxins, quinidine, magnesium sulfate, anticholinesterases, succinylcholine chloride ) should Cardiovascular 1 0 only be performed with caution as the effect of the toxin may be potentiated. Hypertension

The effect of administering different botulinum neurotoxin serotypes at the same time or within ® several months of each other is unknown. Excessive neuromuscular weakness may be Adverse Events Reported at Higher Frequency (>1%) in the BOTOX COSMETIC Group exacerbated by administration of another botulinum toxin prior to the resolution of the effects of Compared to the Placebo Group a previously administered botulinum toxin. Immunogenicity Pregnancy: Pregnancy Category C Treatment with BOTOX® COSMETIC may result in the formation of neutralizing antibodies that Administration of BOTOX® COSMETIC is not recommended during pregnancy. There are no may reduce the effectiveness of subsequent treatments with BOTOX® COSMETIC by adequate and well-controlled studies of BOTOX® COSMETIC in pregnant women. When inactivating the biological activity of the toxin. The rate of formation of neutralizing antibodies in pregnant mice and rats were injected intramuscularly during the period of organogenesis, the patients receiving BOTOX® COSMETIC has not been well studied. ® developmental NOEL (No Observed Effect Level) of BOTOX COSMETIC was 4 U/kg. Higher The critical factors for neutralizing antibody formation have not been well characterized. The doses (8 or 16 U/kg) were associated with reductions in fetal body weights and/or delayed results from some studies suggest that botulinum toxin injections at more frequent intervals or at ossification. higher doses may lead to greater incidence of antibody formation. The potential for antibody In a range finding study in rabbits, daily injection of 0.125 U/kg/day (days 6 to 18 of gestation) formation may be minimized by injecting the lowest effective dose given at the longest feasible and 2 U/kg (days 6 and 13 of gestation) produced severe maternal toxicity, abortions and/or fetal intervals between injections. malformations. Higher doses resulted in death of the dams. The rabbit appears to be a very sensitive species to BOTOX® COSMETIC. Rx Only If the patient becomes pregnant after the administration of this drug, the patient should be ® Marks owned by Allergan, Inc. apprised of the potential risks, including abortion or fetal malformations that have been observed in rabbits. Based on package insert 71711US13S revised January 2005 Carcinogenesis, Mutagenesis, Impairment of fertility Manufactured by: Allergan Pharmaceuticals Ireland Long term studies in animals have not been performed to evaluate carcinogenic potential of a subsidiary of: Allergan, Inc., 2525 Dupont Dr., Irvine, CA 92612 BOTOX® COSMETIC. Reference: The reproductive NOEL following intramuscular injection of 0, 4, 8, and 16 U/kg was 4 U/kg in male rats and 8 U/kg in female rats. Higher doses were associated with dose-dependent 1. Wang YC, Burr DH, Korthals GJ, Sugiyama H. Acute toxicity of aminoglycoside antibiotics Appl Environ Microbiol reductions in fertility in male rats (where limb weakness resulted in the inability to mate), and as an aid in detecting botulism. 1984; 48:951-955. testicular atrophy or an altered estrous cycle in female rats. There were no adverse effects on the Paraneoplastic Pemphigus Associated With Breast Adenocarcinoma

Iqbal A. Bukhari, MD* *Dermatology Department, College of Medicine, King Faisal University, Dammam, Saudi Arabia

ABSTRACT

Paraneoplastic pemphigus (PNP) is a blistering, mucocutaneous disease occurring in patients with malignant neoplasms of different origins. Here we are reporting the third case in the literature of PNP occurring simultaneously with breast adenocarcinoma. Key words: Adenocarcinoma, bullous disease, autoimmune, malignancy

Introduction chest and the upper back. In the oral cavity, membrane zone there were similar, superficial, slightly 4. Serum antibodies detected by IIF Paraneoplastic pemphigus (PNP) is an painful ulcers affecting the gingiva, the floor that bind cell surfaces of stratified autoimmune, blistering, mucocutaneous of the mouth, the tongue, the hard palate squamous epithelia, as well as sim- disease associated with neoplasia. Char- and the soft palate. No occular or vaginal ple, columnar and transitional acteristically, it manifests with erosions and involvement was observed. Two skin punch epithelia shallow ulcerations of the oral mucosa and biopsies were taken at six-month intervals. 5. Serum immunoprecipitation with a polymorphic cutaneous lesions that can be There were non-specific findings in the first complex of five proteins (desmo- pemphigus-like, pemphigoid-like, erythema one, which initially biased our diagnosis, plakin I-250 kDa, BP Ag-230 kDa, multiforme-like, graft versus host disease- but significant findings in the second biopsy envoplakin and desmoplakin II-210 like and lichen planus-like.1 Interestingly, revealed acantholysis and mild, superficial, kDa and periplakin-190 kDa and different morphologic patterns of skin dermal perivascular lymphohistiocytic infil- 170-kDa)2 lesions may be present concomitantly in a trate. A biopsy from oral mucosa showed These were later revised by Camisa and nonspecific ulceration and lymphohistio- patient or may vary during the disease Helm,4 who divided them into major and 2 course. Most PNP cases are associated cytic infiltrate with no intraepithelial lesion minor signs: The major signs include poly- with a hematologic malignancy, but cases or malignancy. Direct immunofluorescence morphic mucocutaneous eruption, concur- of solid, non-hematologic neoplasms of dif- (DIF) from skin, repeated twice, was posi- rent internal neoplasia and serum 2 ferent origins can also occur. In this report, tive at the epidermal intercellular zone and antibodies with a specific immunoprecipita- we present the third case in the literature of basement membrane zone. Those clinical tion pattern. The minor signs include histo- PNP occurring simultaneously with breast and histopathological findings combined logic evidence of acantholysis, DIF adenocarcinoma. with DIF results were suggestive of a diag- showing intercellular and basement mem- nosis of PNP. The patient was kept on brane staining, and IIF staining with rat Case Report potassium permanganate soaks three bladder epithelium. Either three major or times a day for the weeping lesions, clobe- two major and two minor signs are required tasol dipropionate cream for skin lesions A 46-year-old Arabic female, a known for the diagnosis of PNP.2 The existence of case of completely resected bilateral breast and triamcinolone acetonide in oral paste a neoplasm is recognized prior to the erup- adenocarcinoma, diabetes mellitus and for oral lesions, both twice daily. After three tion of PNP in about two-thirds of the weeks, the lesions were in the healing hypothyroidism, presented to our dermatol- cases.5 Clinically. paraneoplastic pemphi- ogy clinic with recurrent, slightly painful, phase; but after three months the same gus (PNP) manifests with erosions and shallow, ulcerated, mucocutaneous lesions bullous lesions recurred, and treatment ulcerations of the oral mucosa plus poly- for the past year. According to the patient, was repeated. morphic bullous cutaneous lesions which the condition started as recurrent, fluid- can be pemphigus-like, pemphigoid-like, filled bullae that ruptured easily, leaving Discussion erythema multiforme-like, graft versus host macerated and ulcerated lesions that disease-like and lichen planus-like.1 Iso- healed completely. They were mainly Paraneoplastic pemphigus (PNP) was lated oral lesions, as the first sign, are pre- first defined as a separate blistering dis- located in the mouth, scalp and upper sent in 45% of cases,6 while oral ease in 1990 by Anhalt et al.3 Since then, trunk. The patient underwent bilateral radi- involvement is reported in 100% of cases.2 cal mastectomy six years prior, oophorec- almost 150 cases have been reported in Conjunctival lesions, which can resemble tomy and hysterectomy two years prior and the literature. Initially, the diagnostic criteria those seen in cicatricial pemphigoid, are included the following clinical, histologic, had received multiple courses of present in about two-thirds of the patients.5 chemotherapy for her breast adenocarci- DIF, indirect immunofluorescent (IIF) and Of all reported PNP cases, 84% were noma, of which the last course was four immunoprecipitation tests: associated with hematologic-related neo- months prior to her presentation. She 1. Painful mucosal erosions and poly- plasms.2 The non-hematologic neoplasms never received radiotherapy. Since then, morphous skin eruptions associated with PNP comprised 16% of all she was kept on Fucidin cream and clobe- 2. Histopathologic features of intraepi- cases, of which 8.6% were epithelial-origin tasol dipropionate twice daily for her skin dermal acantholysis, dyskeratosis carcinoma,1,7-14 and 6.2% were mesenchy- lesions and triamcinolone acetonide in oral and vacuolar interface dermatitis mal-origin sarcoma.3,15-21 Of the reported paste twice daily for her mouth lesions. On 3. DIF findings of intercellular epider- carcinomas, there were adenocarcinoma of examination, there were multiple ruptured mal IgG and complement, with or the pancreas,11,19 colon,12,22 breast2,8 and bullae with a few irregularly shaped, ery- without granular linear complement prostate;5,9 squamous cell carcinoma of the thematous, superficial ulcers affecting the deposition along the basement tongue14 and vagina;11 and one case of

BUKHARI 39 multiple skin tumors.23 In the presented associated with follicular dendritic cell sarcoma arising from Castleman’s tumor. J Am Acad Dermatol 1999;40(2 case, the patient was initially undiagnosed, Pt 2):294–7. but repeated skin biopsies and DIF sup- 17. Mimouni D, Anhalt GJ, Lazarova Z, et al. Paraneoplastic pemphigus in children and adolescents. Br J Dermatol ported our clinical impression of PNP. She 2002;147:725–32. was also a known case of breast adeno- 18. Berg WA, Fishman EK, Anhalt GJ. Retroperitoneal reticu- carcinoma and was having recurrent muco- lum cell sarcoma: a cause of paraneoplastic pemphigus. South Med J 1993;86(2):215–7. cutaneous bullous ulcerated lesions, 19. Krunic AL, Kokai D, Bacetic B, et al. Retroperitoneal making up two major and two minor PNP round-cell liposarcoma associated with paraneoplastic 4 pemphigus presenting as lichen planus pemphigoides-like diagnostic criteria. Treatment of PNP is dif- eruption. Int J Dermatol 1997;36(7):526–9. ficult, with options including resection of the 20. van der Waal RI, Pas HH, Nousari HC, et al. Paraneoplas- tic pemphigus caused by an epithelioid leiomyosarcoma initial tumor and corticosteroids, sometimes and associated with fatal respiratory failure. Oral Oncol in combination with cyclosporine or 2001;36(4):390–3. cyclophosphamides, azathioprine, 21. Beele H, Claerhout I, Kestelyn P, et al. Bilateral corneal melting in a patient with paraneoplastic pemphigus. Der- mycophenolate mofetil, rituximab and matology 2001;202(2):147–50. plasmapheresis or immunoapheresis.2 22. Joly P, Thomine E, Gilbert D, et al. Overlapping distribution of autoantibody specificities in paraneoplastic pemphi- Generally, prognosis is poor, with a mean gus and pemphigus vulgaris. J Invest Dermatol 1994; survival time after initial diagnosis of three 103(1):65–72. 5 23. Perniciaro C, Kuechle MK, Colon-Otero G, Raymond MG, months, although occasional patients sur- Spear KL, Pittelkow MR. Paraneoplastic pemphigus: a vived longer.17,23,24 Death usually occurs as a case of prolonged survival. Mayo Clin Proc result of respiratory failure or infections.2 In 1994;69(9):851–5. 24. Helm TN, Camisa C, Valenzuela R, et al. Paraneoplastic conclusion, this is the third reported case of pemphigus. A distinct autoimmune vesiculobullous disor- PNP occurring in a patient with a preexist- der associated with neoplasia. Oral Surg Oral Med Oral ing breast adenocarcinoma, which signifies Pathol 1993;75(2):209–13. that clinicians should be highly suspicious when signs and symptoms of bullous der- matosis are present in cancer patients of both hematologic and non-hematologic origin.

References 1. Nguyen VT, Ndoye A, Bassler KD, et al. Classification, clinical manifestations, and immunopathological mechanisms of the epithelial variant of paraneoplastic autoimmune multiorgan syndrome: a reappraisal of paraneoplastic pemphigus. Arch Dermatol 2001;137(2):193–206. 2. Kaplan I, Hodak E, Ackerman L, et al. Neoplasms associated with paraneoplastic pemphigus: a review with emphasis on non-hematologic malignancy and oral mucosal manifestations. Oral Oncol 2004;40(6):553-62. 3. Anhalt GJ, Kim SC, Stanley JR, et al. Paraneoplastic pemphigus. An autoimmune mucocutaneous disease associated with neoplasia. N Engl J Med 1990;323(25):1729–35. 4. Camisa C, Helm TN. Paraneoplastic pemphigus is a distinct neoplasia-induced autoimmune disease. Arch Der- matol 1993;129(7):883–6. 5. Kimyai-Asadi A, Jih MH. Paraneoplastic pemphigus. Int J Dermatol 2001;40(6):367–72. 6. Joly P, Richard C, Gilbert D, et al. Sensitivity and speci- ficity of clinical, histologic, and immunologic features in the diagnosis of paraneoplastic pemphigus. J Am Acad Der- matol 2000;43(4):619–26. 7. Fullerton SH, Woodley DT, Smoller BR, et al. Paraneo- plastic pemphigus with autoantibody deposition in bronchial epithelium after autologous bone marrow transplantation. JAMA 1992;267(11):1500–2. 8. Bowen GM, Peters NT, Fivenson DP, et al. Lichenoid dermatitis in paraneoplastic pemphigus: a pathogenic trigger of epitope spreading? Arch Dermatol 2000; 136(5):652–6. 9. Martel P, Gilbert D, Labeille B, et al. A case of paraneoplastic pemphigus with antidesmoglein 1 antibodies as determined by immunoblotting. Br J Dermatol 2000;142(4):812–3. 10. Lam S, Stone MS, Goeken JA, et al. Paraneoplastic pemphigus, cicatricial conjunctivitis, and acanthosis nigricans with pachydermatoglyphy in a patient with bronchogenic squamous cell carcinoma. Ophthalmology 1992;99(1):108–13. 11. Rongioletti F, Truchetet F, Rebora A. Paraneoplastic pemphigoid–pemphigus? Subepidermal bullous disease with pemphigus-like direct immunofluorescence. Int J Dermatol 1993;32(1):48–51. 12. Chamberland M. Pemphigus paraneoplastique et adenocarcinoma du colon. Union Med Can 1993;122(3):201–13. 13. Matz H, Milner Y, Frusic-Zlotkin M, et al. Paraneoplastic pemphigus associated with pancreatic carcinoma. Acta Derm Venereol 1997;77(4):289–91. 14. Wong KC, Ho KK. Pemphigus with pemphigoid-like presentation, associated with squamous cell carcinoma of the tongue. Australas J Dermatol 2000;41(3):178–80. 15. Oursler JR, Labib RS, Arris-Abdo L, et al. Human antibodies against desmoplakins in paraneoplastic pemphigus. J Clin Invest 1992;89(6):775–82. 16. Lee IJ, Kim SC, Kim HS, et al. Paraneoplastic pemphigus

40 PARANEOPLASTIC PEMPHIGUS ASSOCIATED WITH BREAST ADENOCARCINOMA Effectiveness of Topical Pimecrolimus in the Treatment of Vitiligo

Iqbal A. Bukhari, MD* *Dermatology Department, College of Medicine, King Faisal University, Dammam, Saudi Arabia

ABSTRACT

Background: different therapeutic options are available for the treatment of vitiligo and topical immunomodulators are one of the newly suggested treatment for that disease. Objective: to evaluate the effect of pimecrolimus 1% cream in the treatment of stable vitiligo. Methods: a total of 10 patients with stable vitiligo of whom 7 were on narrow band ultraviolet B phototherapy three times weekly and 3 were not on any treatment. All the patients were instructed to apply pimecrolimus 1% cream twice daily at facial and knee vitiliginous lesions. The patients were followed up every 12 weeks for a total period of 12 months. Results: by the end of the 12-months period, 5 patients showed 100% repigmentation of the areas treated with pimecrolimus, 4 patients showed 50-90% improvement while one patient showed 25% improvement. Conclusion: this study shows the potential effectiveness of topical pimecrolimus in the treatment of vitiligo.

Key words: immunomodulators, vitiligo, autoimmune, pimecrolimus.

Introduction: Vitiligo is an acquired cutaneous disorder characterised by circumscribed depigmented lesions due to loss of melanocytes within the epidermis. It affects people of all races, with an incidence of 1–2%.1 and approximately one-half of those patients are below the age of 20 years.2 Epidemio- logical studies have shown that one quarter to one third of patients with vitiligo have family members affected with the disease.2 There are several hypotheses on the pathogenesis of the disease. Autoimmune Hypothesis is the most important and popular which suggests that abnormalities of the immune system result in destruction of a b melanocytes. Other hypotheses include neural hypothesis, melanocyte self- Figure1 destruction hypothesis and biochemical Vitiligo lesion one month after the start of treatment with topical pimecrolimus hypothesis. Immunohistochemical studies showing perifollicular and diffuse repigmentation (a) and at the end of 5 months indicated that T cells are abundant in showing complete repigmenation (b) actively progressing lesions which are Seven patients were on NBUVB for more mainly CD4+ and CD8+ which express Objective: than one year while three were not on any activation molecules such as interleukin-2 treatment due to either the condition was receptor (IL-2R). Topical tacrolimus (FK This study was done to evaluate the newly diagnosed or past failure of topical 506) and pimecrolimus (SDZ ASM 981) are effect of pimecrolimus 1% cream with or steroids and phototherapy. None of our known topical immunomodulators (TIMs) without narrow band ultraviolet B pho- patients had thyroid or parathyroid disease, which inhibit the activation and maturation totherapy (NBUVB) in the treatment of sta- cardiovascular disease, malignancy, of T cells by inhibiting calcineurin func- ble vitiligo. impaired renal or liver function, pregnancy, tion.3,4 In addition, pimecrolimus inhibits or lactation. Seven Patients were instructed transcription and production of IL-4, IL-5, Methods: to apply pimecrolimus 1% cream twice IL-10, IFN delta, TNF alpha and the daily on the facial lesions and 3 patients on release of inflammatory mediators from Ten patients with stable vitiligo and who the knee lesions. Patients who were on mast cells and basophils.5,6,7,8 Studies on were followed up regularly in our dermatol- NBUVB phototherapy were allowed to con- the use of tacrolimus in vitiligo have been ogy clinic at King Fahad Hospital of the tinue their scheduled sessions. Response published 9,10,11,12,113,14 but two reports on the University in Alkhobar, Saudi Arabia to treatment was recorded by taking pho- use of pimecrolimus in vitiligo have been enrolled in this study during the period of tographs of the lesions before and after the published so far.15,16 In this trial we explored December 2004 to November 2005. Their start of treatment. Improvement was further the effectiveness of topical pime- ages ranged between 5-55 years. Nine recorded as minimal (25-50%), moderate crolimus in the treatement of vitiligo. were females and one was male. Their vitiligo had been present for a duration (50-75%), marked (75-90%) or complete ranging between 4 months to 15 years. (90-100%). The cream was stopped if all

BUKHARI 41 the depigmented areas regained the pig- types of vitiligo and in patients with exten- ment or there was no pigmentation sive lesions. observed for the first 3 months. Side effects related to treatment were reported includ- References: ing burning sensation and atrophy. Patients 1. Kostovic K, Nola I, Bucan Z, et al. Treatment of vitiligo: were followed up at 12-week interval for 12 current methods and new approaches. Acta Dermatoven- months. erol Croat 2003; 11 (3): 163-70 2. Kovacs SO. Vitiligo. J Am Acad Dermatol 1998 ; 38 (5 Pt 1): 647-66 3. Marsland AM, Griffiths CE. The macrolide immunosup- Results: pressants in dermatology: mechanisms of action. Eur J Dermatol 2002; 12 (6): 618-22 All of our patients completed the study. 4. Bornhovd EC, Burgdorf WH, Wollenberg A. Immunomodu- Their ages ranged between 5 to 55 years latory macrolactams for topical treatment of inflammatory diseases. Curr Opin Investig Drugs 2002; 3 (5): 708-12 (mean 26 years). The duration of vitiligo 5. Cheer SM, Plosker GL. Tacrolimus ointment: a review of varied from 4 months to 15 years (mean its therapeutic potential as a topical therapy in atopic dermatitis. Am J Clin Dermatol 2001; 2 (6): 389-406 4.9 years). The face and neck were 6. Gupta AK, Chow M. Pimecrolimus: a review. J Eur Acad affected in 8 patients, the acral regions in 2 Dermatol Venereol 2003; 17 (5): 493-503 7. Zuberbier T, Chong SU, Grunow K, et al. The ascomycin patients, trunk in one patient, and extremi- macrolactam pimecrolimus (Elidel, SDZ ASM 981) is a ties in 6 patients. At the end of the 12 potent inhibitor of mediator release from human dermal months period, 5 patients (50%) showed mast cells and peripheral blood basophils. J Allergy Clin Immunol 2001; 108 (2 Pt 1): 275-80 complete repigmentation, one patients 8. de Paulis A, Stellato C, Cirillo R, et al. Anti-inflammatory (10%) showed marked improvement, 3 effect of FK-506 on human skin mast cells. J Invest Der- matol 1992; 99 (6): 723-8 patients (30%) showed moderate improve- 9. Lepe V, Moncada B, Castanedo-Cazares JP, Torres- ment while one patient (10%) showed mini- Alvarez MB, et al. A double-blind randomized trial of 0.1% tacrolimus vs 0.05% clobetasol for the treatment of child- mal improvement. In more than 80% of hood vitiligo. Arch Dermatol 2003; 139: 581-5. patients, the onset of the repigmentation 10. Travis LB, Weinberg JM, Silverberg NB. Successful treat- was observed within the first 12 weeks. ment of vitiligo with 0.1% tacrolimus ointment. Arch Der- matol 2003; 139: 571-4. The pattern of repigmentation was diffuse 11. Grimes PE, Soriano T, Dytoc MT. Topical tacrolimus for and perifollicular which subsequently pro- repigmentation of vitiligo. J Am Acad Dermatol 2002; 47: 789-91. gressed to full repigmentation. Other areas 12. Smith DA, Tofte SJ, Hanifin JM. Repigmentation of vitiligo which were treated with only NBUVB were with topical tacrolimus. Dermatology 2002; 205: 301-3. 13. Tanghetti EA. Tacrolimus ointment 0.1% produces repig- responding at a slower rate than the areas mentation in patients with vitiligo: results of a prospective treated with both topical pimecrolimus and patient series. Cutis 2003; 71: 158-62. NBUVB. No patients reported any adverse 14. Silverberg N, Lin P, Travis L, et al. Tacrolimus ointment promotes repigmentation of vitiligo in children: A review of reactions. 57 cases. J Am Acad Dermatol 2004;51:760-6. 15. Mayoral FA, Gonzalez C, Shah NS, et al. Repigmentation of vitiligo with pimecrolimus cream: a case report. Derma- Discussion: tology 2003; 207(3): 322-3. 16. Coskun B, Saral Y, Turgut D. Topical 0.05% clobetasol pro- pionate versus 1% pimecrolimus ointment in vitiligo. Eur J There has been a substantial interest in Dermatol 2005;15(2):88-91. topical pimecrolimus because of its significant anti-inflammatory and immunomodulatory activities and low systemic immunosuppressive potential. Several studies were conducted on patients with vitiligo who responded to treatment with tacrolimus ointment9,10,11,12,13,14 and concluded that tacrolimus ointment may be an efficacious and safe treatment option for vitiligo while others reported similar response with pimecrolimus cream.15,16 In this study we have provided evidence that application of pimecrolimus 1% cream is effective in the induction of repigmentation in vitiligo either used alone or with NBUVB. Additionally, it may promote faster repigmentation of vitiligo with NBUVB making it a good addition to the treatment regime with NBUVB. The most logical explanation for this clinical response is the immunomodulatory effect of pimecrolimus exerted locally at the vitiliginous lesions. Besides, considering the lack of atrophogenic potential and ocular cataracts or glaucoma with pimecrolimus cream makes this agent suitable for treating vitiligo of the face. In conclusion, this study showed that topical pimecrolimus is an effective and safe treatment option for stable vitiligo and we recommend larger prospective studies to explore further the efficacy of pimecrolimus cream in different

42 EFFECTIVENESS OF TOPICAL PIMECROLIMUS IN THE TREATMENT OF VITILIGO A Review of Mohs Micrographic Surgery: Common Indications

Thi T. Tran, D.O., F.A.O.C.D.*, Keoni Nguyen, D.O.**, Eugene T. Conte, D.O.,F.A.O.C.D.*** * Private practice, Village Dermatology & Cosmetic Surgery, LLC, The Villages, Florida ** Intern, Kalamazoo Center for Medical Studies, Michigan State University, Kalamazoo, Michigan *** Private practice, Advanced Dermatology, Dayton, Ohio

ABSTRACT

Background: Mohs micrographic surgery (MMS) is a highly effective surgical modality for removal of aggressive tumors, recurrent tumors, or tumors located in the high-risk anatomic locations. MMS is founded on the idea of excision with minimal margins and immediate histologic examination where the dermatologist acts as a surgeon and pathologist. Method: We reviewed the literature regarding clinical and pathological considerations for MMS. We also explored the most common tumors, basal cell carcinoma (BCC) and squamous cell carcinoma (SCC), treated with MMS with respect to their cure rates and cost effectiveness compared to non-Mohs modalities. Results: The results showed the five-year cure rates for primary BCC treated with MMS compared to non-Mohs modalities to be 99% verses 93%, respectively. Recurrent BCC treated with MMS had a 94.4% cure rate compared to non-Mohs at 80.1%. MMS cure rates for primary SCC were found to be 96.6% as opposed to non-Mohs modalities at 92.1%. The recurrent SCC cure rates were 90-93.3% for MMS verses 76.8% with non-Mohs modalities. Cost analysis illustrated MMS charges were comparable to non- Mohs modalities. The results showed the average cost of MMS to be $1,243 verses $1,167 for excision with permanent section margin control, $1,400 for excision in the office with frozen section margin control, and $1,973 for excision with frozen section margin control in an ambulatory surgical facility. Conclusions: MMS is a meticulous modality that can effectively excise high-risk basal cell carcinoma and squamous cell carcinoma tumors. It relies on horizontal sectioning to visualize all peripheral and deep tumor margins. MMS is a cost-effective technique that ensures maximal tissue preservation while producing the highest cure rates of primary and recurrent cutaneous tumors.

treatment of cancer of the face” in a derma- through Dr. Mohs’ Chemosurgery Clinic Historical Perspective tology journal, the technique received great and through his trainees. Currently, there Frederick E. Mohs, a general surgeon, popularity among dermatologists. are several pathways to receive Mohs first introduced the Mohs micrographic Although the original fixed-tissue tech- micrographic surgery training. The first surgery (MMS) technique in the 1930s at nique was reliable, it was very time con- pathway is through the American College the University of Wisconsin. Mohs micro- suming, laborious, uncomfortable, and of Mohs Micrographic Surgery and Cuta- graphic surgery was originally described as oftentimes painful. Thus, in the 1970s, neous Oncology (ACMMSCO), established Mohs chemosurgery due to the application doctors Theodore Tromovitch and Samuel in 1967.14 There are approximately 60 of 20% zinc chloride paste fixed to the can- Stegman modified the popular Mohs tech- approved programs. The second pathway cerous skin to adhere it in-situ prior to sur- nique with the utilization of horizontal is through the American Society for Mohs gical removal of the tissue.1 In 1941, Dr. frozen sections rather than fixed tissue.4 Surgery (ASMS), established in 1990. Mohs was able to show the efficacy of this The fresh-tissue technique utilizes local The ASMS was established to provide pro- revolutionary fixed-tissue technique on eye- anesthesia for controlled excision of the fessional and educational support for non- lid cancer. He reported a high five-year tumor within a single day. Except for the ACMMSCO trained Mohs surgeons.15 The cure rate of 98% and 98.1% for basal cell application of the 20% zinc chloride fixa- third pathway is through the Accreditation carcinoma and squamous cell carcinoma, tive, the fresh-tissue technique follows the Council for Graduate Medical Education respectively. same processes as the original Mohs tech- (ACGME) Procedural Dermatology Fellow- The fixed-tissue technique begins with nique. Advantages of the fresh-tissue ship training program, established in 16 delineating the tumor outline and debulking technique include elimination of the periop- 2003. This fellowship program consists of the tumor with a curette or scalpel. erative pain produced by the fixative, the 12 months of advanced dermatologic train- Dichloroacetic acid is applied to the ability to perform multiple excisions in one ing that provides surgical training beyond debulked area to promote penetration of day, and elimination of the post-fixation the scope that is expected in a dermatol- zinc chloride paste. The paste is applied to slough, which had precluded immediate ogy residency training program, including the tissue for six to 24 hours to enhance reconstruction.5 Summary of the Mohs training is Mohs micrographic surgery, tissue fixation in-situ. A thin, pie-shaped micrographic surgery using the fresh-tissue cutaneous reconstruction of surgical layer of tissue can then be excised in an technique is illustrated in table 1.6-13 defects, sclerotherapy, chemical peel, hair outpatient setting for processing and micro- Since the inception of Mohs micro- transplantation, dermabrasion, small-vol- scopic examination.2, 3 If the histological graphic surgery was introduced over seven ume liposuction, cutaneous soft tissue aug- margins are positive, then the above decades ago, it has developed into a sub- mentation with injectable filler material, process would be repeated. Because the specialty of dermatology. Although there laser surgery, and rhinophyma correction 16 Mohs fixed-tissue technique was a surgical are other subspecialists who practice cutaneous oncology. All of the above procedure, Dr. Mohs published his first five MMS, dermatologists are uniquely suited MMS programs are considered training or reports in surgical journals; however, few for this procedure given their training in der- fellowship without certification through the surgeons elected to utilize this novel tech- matopathology, cutaneous oncology, and American Board of Dermatology. However, nique. Conversely, after Dr. Mohs pub- cutaneous surgery. Initially, training was the American Osteopathic Board of Der- lished an article on “Chemosurgical informal, lasting from days to months matology (AOBD) offers a Certificate of

TRAN, NGUYEN, CONTE 43 Added Certification in MMS for eligible AOBD boarded dermatologists. 17 Clinical Considerations for MMS The most compelling indication for MMS is recurrent tumors, due to their unpredictable growth patterns along surgical scars and through low-resistance planes such as subcutaneous and muscle tissues. These unstable growth patterns are harbin- gers for subclinical extension. The high peril zone for recurrence and metastases is skin overlying cartilage and bony structures especially in the preauricular area, retroau- ricular sulcus, nasolabial fold, inner can- thus, philtrum, temple, upper lip, nose, and eyelid. Because recurrent tumors possess aggressive growth patterns, they have higher risk of recurrence and metastases; therefore, conventional excisional methods are not recommended, for they are unreliable. Hence, MMS is the treatment of choice for recurrent tumors located in these high-risk areas. Additionally, an important location for MMS indication is where tumor growth is in a cosmetically or functionally important area such as the genitals, fingers, and toes. 8, 9, 18, 19 Other common clinical considerations for MMS are tumor size, poorly defined tumors, and tumors with positive margins after conventional excision. A large primary skin cancer lesion is defined as greater than 2 cm on the trunk or the extremities and greater than 1 cm on the face. Due to the direct correlation of tumor size and location with high risk of recurrence and metastases, MMS is the treatment of choice for these tumors.7, 8, 11, 18 - 20 Poorly defined tumors imply subclinical spread and risk of recurrence. Thus, if conventional excision were used, wide margins would be required to prevent recurrence, which would sacrifice normal skin. For these reasons, poorly defined tumors are treated with MMS in order to provide complete evaluation of the specimen and spare healthy tissue.8, 11, 18, 19 Finally, tumors with positive margins are indicated for MMS because scar from the previous treatment creates a low-resistance pathway for deep-tissue infiltration of malignant cells, which exhibits unrecognized spread 20 8, 9, 11, 18 cutaneous perineural invasion has been rate of 47.2% and 0%, respectively. (Table 2). widely recognized, its prevalence is rare.26 - Patients with tumors of the face who exhibit 30 Perineural invasion carries a high risk of perineural invasion may never experience Pathological recurrence and metastases and is more symptoms of pain, numbness, paresthesia, Considerations for MMS common in squamous cell carcinoma facial paralysis, diplopia, blurring vision, or (SCC) than basal cell carcinoma (BCC), decreased corneal reflexes.26 - 31 In fact, 60 In 1835, Jean Cruveilhier, a French with reported incidence of 2.5 to 14%26, 27 to 70% of patients with perineural invasion pathologist, described the first perineural and 0.178%31, respectively. Rowe et al.20 are asymptomatic.26, 29, 32, 33 It is important to spread of tumor cells in a mammary carci- reported that SCC with perineural spread recognize that adjuvant radiation therapy is noma that spread along the facial nerve.22 elicited a local recurrence rate of 47.2% recommended for post-surgical excision of Since then, perineural spread has been and a metastatic rate of 47.3%. Further- perineural tumors due to their unpre- well-documented in a wide variety of malig- more, he compared conventional excision dictable surgical margins and high possibil- nant neoplasms such as carcinomas of the verses MMS in the treatment of neurotropic ity of recurrence and metastases (Figures prostate,23 rectum,24 and parotid.25 Although SCC, which displayed a local recurrence 1 – 2).8, 9, 20

44 A REVIEW OF MOHS MICROGRAPHIC SURGERY: COMMON INDICATIONS Table 3. Pathological Considerations for MMS

1. Perineural invasion 2. Depth of lesion 3. Degree of differentiation for SCCs 4. BCC subtypes: infiltrative, morpheaform, micronodular, and metatypical

Figure 1 Squamous cell carcinoma, infiltrative type, left scalp pre-operative MMS Table 4. Five-year Recurrence Rates of Primary BCCs

Procedures Percent 1. Mohs Micrographic Surgery 1 2. Cryosurgery 7.5 3. Currettage and Electrodessication 7.7 4. Radiation Therapy 8.7 5. Traditional Surgical Excision 10.1

tumor. Although BCCs rarely have tal sectioning technique as compared to metastatic potential to effectuate the death the random examination of inferior and lat- of the patient;36 certain subtypes of BCCs eral margins when the pathology lab possess unpredictable spread beyond clini- “bread loaves” the sections after surgical cal margins with high risk for recurrence excision.20 and metastases, such as infiltrative, mor- Basal cell carcinomas that are indicated pheaform, and micronodular types.37, 38 for MMS have the aggressive subtypes, Figure 2 Currently, BCCs are the most common such as infiltrative, morpheaform, and A microscopic section of final Mohs skin cancer in the United States, with an micronodular. The term infiltrative was first stages from the patient in Figure 1 estimated frequency of over 900,000 cases described by Thackray in 1951 as a histo- 39 showed clearance of per year. Because BCCs are the most logical subtype of BCC that he felt was aggressive SCC with perineural common cutaneous tumors, they constitute more difficult to eradicate than nodular 41 involvement (H&E, original magnifica- the highest number of cases for MMS. BCC. Years later, Sexton et al.’s study tion x 600). Studies have revealed the five-year cure illustrated that infiltrative BCC was more (Photographed by Andrew J. Hanly, rate of primary tumors to be 99% with likely to have positive margins after simple M.D., Global Pathology) MMS compared with a 96% cure rate with surgical excision than nodular BCC, 26.5% recurrent BCCs.8, 9, 19 Additionally, according versus 6.4%, respectively.42 Clinically, infil- In addition to perineural invasion, depth to Rowe et al.,20 the five-year recurrence trative BCC’s tumor masses are usually of the lesion should also be considered rate for non-Mohs procedures was 8.7 small with irregular, spiky, or jagged bor- when deciding to treat SCC. That is, risk of times higher than recurrence rates for ders.43 Histologically, the infiltrative subtype metastases increases when the tumor MMS when treating primary BCCs. Com- is made up of small cords and nests that invades the dermis to a depth of 4 mm or paring MMS with other non-Mohs proce- disperse by small, finger-like extensions, more.19, 20, 21 Furthermore, a degree of differ- dures, the five-year recurrence rate of which can permeate through tissue without entiation for SCCs and tumor histologic primary BCCs treated by MMS was 1%, much displacement.44 Thus, positive mar- subtypes should also be considered in 7.5% for cryosurgery, 7.7% for curettage gins and recurrence are more likely to selecting appropriate treatment. SCCs that and electrodessication, 8.7% for radiation occur. are moderately or poorly differentiated are therapy, and 10.1% for surgical excision The morpheaform subtype BCC has defined as high risk for recurrence and (Table 4).20 Rowe’s study of the five-year been clinically described as solitary, flat, ill metastases; thus, these tumors should be recurrence rate for primary BCCs treated defined, smooth, yellowish plaque, or treated with MMS. As for BCCs, the sub- with surgical excision corroborated Silver- slightly depressed indurated plaque (Fig- types of micronodular, infiltrative, metatypi- man et al.’s study, which had a recurrence ures 3 - 4).45, 46, 47 Morpheaform’s clinical cal, and morpheaform are considered rate of 10.6%.40 extension is indistinctive, thus making it aggressive and carry a high risk of recur- As for the treatment of recurrent BCCs, extremely difficult to assess its true margin rence and hence need to be managed with the recurrence rate was 5.6% with MMS as with simple surgical excision. Histologically, MMS (Table 3).8, 11, 18 - 21, 34 compared to the average 19.9% when morpheaform has been referred to as the treated with non-Mohs modalities.20 For “iceberg epithelioma” due to its infiltrating Most Common Tumors BCCs less than 3 cm, the cure rate was ribbons and tentacles of neoplastic cells over 99%; however, if the tumor was that vary from small aggregations to one or Treated With MMS greater than 3 cm, the cure rate dropped to two cells embedded in dense, concentri- 93%.8 The lower recurrence rates for MMS cally arranged fibrous stroma that tend to Basal Cell Carcinoma: as compared to surgical excision were best grow laterally and deeply away from the 46, 47, 48 Basal cell carcinoma was originally justified by the Mohs surgeon’s meticulous main clinical neoplastic mass. described by Jacob in 182735 as a locally examination of all of the lateral and inferior Salasche et al.’s 49 study of 51 mor- invasive and slowly spreading cutaneous margins of the resected tissue via horizon- pheaform cases found the average exten-

TRAN, NGUYEN, CONTE 45 atosis.51 As for clinical features of erythroplasia of Queyrat, it usually presents with a sharply demarcated, velvety, erythematous, moist, and shiny patch on the inner surface of the prepuce and glans penis. Histologically, the epidermis of SCC in-situ shows hyperkeratosis, parakeratosis, and broad acanthosis or anastamosis of adjacent rete ridges. The atypical epidermal layer may produce the “flip sign,” whereby the epidermis has lost its polarity to the point that the superficial epidermis resem- Figure 3 bles the deeper epidermis; thus, if you flip Figure 5 Morpheaform basal cell carcinoma of the tissue upside down and microscopically Squamous cell carcinoma on right the left lower lip margin, pre-operative examine it, you would barely notice the dif- temple with MMS, preoperative size size of 1.7 x 1.5 cm ference between the superficial epidermis 2.2 x 1.6 cm and the deeper epidermis.21, 52 SCC in-situ may be treated with cryotherapy or topical 5-fluorouracil; however, there is a high rate of recurrence. Imiquimod 5% cream has been an effective therapeutic option, with an efficacy rate as high as 90%. MMS is usually the treatment of choice when preservation of normal tissue is critical, such as with lesions located on the face, digits or penis or when lesions are greater than 2 cm on the trunk.51 Figure 4 Squamous Cell Carcinoma: Figure 6 Status post five stages of MMS for Squamous cell carcinoma on right morpheaform basal cell carcinoma of Squamous cell carcinoma (SCC) is cur- temple status post two stages of MMS, the left lower lip margin, defect 4.6 x rently the second most common type of defect size of 2.5 x 2.2cm 3.0 cm nonmelanoma skin cancer.52 For the past two decades, the incidence of SCC has proliferation with sparse keratin pearls and sion to be 7.2 mm beyond clinically esti- steadily risen due to the increase in sun more severe atypical cells.52 mated borders. Similarly, Burg et al.’s exposure of the general population. Sun- Primary SCC is the second most com- group had comparable results with an aver- exposed SCCs metastasize in less than age subclinical extension of 9.3 mm, but mon skin cancer treated with MMS, which 1% of the cases; however, the incidence is has a five-year local cure rate of 96.9% with a smaller group of morpheaform sub- higher on the lip, in sun-covered areas, and 50 compared to the five-year local cure rate of types. These examples of subclinical 52 in neoplasms greater than 1.0 cm thick. 20 extensions illustrate the fact that MMS is 92.1% with non-Mohs modalities. For Additionally, SCCs’ risk of metastases recurrent SCCs, MMS is associated with a the treatment of choice for aggressive BCC depends on the size, depth of invasion, dif- subtypes and that a greater number of five-year cure rate of 90 - 93.3% as com- ferentiation, anatomical location, neurotro- 20 stages of excisions are required to extir- pared to 76.8% for non-Mohs modalities. pism, host immunosuppression, and Other than MMS, conventional excision has pate these elusive tumors. As for the recurrence after previous treatment.20 The micronodular subtype BCC, these tumors been the long-time standard of care for risk of metastases in primary SCC has SCC, with a 91.9% cure rate;20 however, as are not clinically distinctive and show histo- been reported to range from 2.5% to 5%, logical features of smooth, palisading previously discussed, this technique sacri- whereas recurrent tumors are reported to fices more normal skin to obtain clear mar- tumor nests no larger than follicular struc- have a metastatic rate of 30%.19, 20 tures,38, 43 so MMS is highly recommended. gins. For well-differentiated SCC, the cure In the United States, the annual SCC rate for non-Mohs modalities is 81% verses Squamous Cell Carcinoma incidence is estimated to be 1 case per 97% with MMS. Poorly-differentiated In-Situ: 1,000 individuals, which approximates to SCCs significantly decrease the cure rate, about 250,000 cases per year.53 Clinically, with MMS at 67.4% verses non-Mohs Squamous cell carcinoma in-situ (SCC SCC frequently arises at the site of actinic modalities at 46.4% (Table 5).20 Another in-situ) is also known as Bowen’s disease keratosis on sun-exposed areas such as non-Mohs modality in the treatment of or erythroplasia of Queyrat depending on the face and back of hands (Figures 5 - 6). SCCs is radiation therapy. Adjuvant radia- the clinical location of the lesion. SCC in- Well-differentiated SCCs may present with tion therapy has been utilized in the treat- situ on the penis is erythroplasia of indurated hyperkeratotic nodules or ment of both superficially invasive and Queyrat; otherwise, it is considered plaques that may also become eroded or moderate-to-high-risk SCCs in the geriatric Bowen’s disease. Clinically, Bowen’s dis- ulcerated. However, undifferentiated population that is not eligible for surgery. ease presents with a sharply demarcated, SCCs appear as red, soft, fleshy, granulat- Additionally, it is also used as adjuvant erythematous and slightly scaly plaque or ing, friable papules or nodules. Histologi- therapy for neurotropic SCCs and for papule, which may be mistaken for psoria- cally, a well-differentiated SCC shows pale patients with a high risk of recurrence after sis, tinea corporis, nummular eczema, seb- epithelial proliferation with a greater num- surgery.54, 55 As for cryotherapy in the treat- 51 orrheic keratosis, or actinic keratosis. ber of keratin pearls or squamous eddies ment of SCCs, it should only be utilized for Squamous cell carcinoma that evolves and is less atypical.52 A poorly-differentiated superficially invasive SCCs or SCCs in-situ from Bowen’s disease tends to be more SCC shows more aggressive and infiltra- that are less than 2.0 cm, because it offers aggressive than SCC arising in actinic ker- tive behavior. It shows less pale epithelial no histologic margin control.35, 54, 55

46 A REVIEW OF MOHS MICROGRAPHIC SURGERY: COMMON INDICATIONS mation, wound infection, wound dehis- cence, and flap/graft necrosis) with Mohs Table 5. Summary Comparison of Five-year Cure Rates micrographic surgery. Their results con- for BCCs & SCCs cluded that the overall complication rate in 1,343 MMS cases was 1.64%.67 These surgical complications were due to hemo- Tumors Mohs (% Non-Mohs (%) stasis difficulties, for which no assistance 1. Primary BCCs 99 93 from other specialists was required and 2. Recurrent BCCs 94.4 80.1 there was no hospitalization of the patient. Dermatologic surgeons are now per- 3. Primary SCCs 96.6 92.1 forming more-invasive surgical procedures 4. Recurrent SCCs 90 – 93.3 76.8 in the office setting using the Mohs micro- 5. Well-differentiated SCCs 97 81 graphic technique. A retrospective review of over 1,100 MMS cases preformed in the 6. Poorly-differentiated SCCs 67.4 46.4 office setting resulted in no lasting damage to the peripheral nerves of the head and neck.68 In these cases, meticulous surgical planning was necessary for a successful outcome while treating aggressive skin Table 6. Average Cost Analysis Summary of malignancies. 400 Consecutive Patients Summary Procedures Cost The subspecialty of Mohs micrographic 1. Mohs Micrographic Surgery $1,243 surgery has flourished since its inception 2. Excision with Permanent Section $1,167 over seven decades ago. Dermatologists 3. Excision in Office with Frozen Section $1,400 are uniquely suited for this procedure due to their specialized training in der- 4. Excision in Ambulatory Facility with Frozen Section $1,973 matopathology, cutaneous oncology, and cutaneous surgery. MMS is considered the treatment of choice for the removal of basal conducted a cost-effectiveness study of cell carcinoma, squamous cell carcinoma Cost Analysis of MMS 400 consecutive tumors treated with MMS and their clinical and pathological indica- Nonmelanoma skin cancers (NMSCs) versus traditional surgical excision and the tions as mentioned previously. MMS is a are the most common type of cancer in the supplemental fee for re-excising the recur- meticulous modality that can effectively United States, with approximately 1.3 mil- rent tumors. Their results showed the aver- excise high-risk cutatneous tumors, relying lion cases diagnosed annually. 56 In the age cost of MMS was $1,243 versus on horizontal sectioning to visualize all United States, one in two men and one in $1,167 for excision with permanent section peripheral and deep tumor margins. In three women will develop NMSC in their life margin control, $1,400 for excision in the addition to complete microscopic control of time.56 Although there are only about 2,000 office with frozen section margin control, surgical margins, MMS preserves normal to 2,500 deaths annually, due to NMSCs’ and $1,973 for excision with frozen section tissue, which decreases operative defect sheer numbers they represent about 5% of margin control in an ambulatory surgical size and hence decreases reconstructive all Medicare cancer expenditures.57 For this facility (Table 6).64 Cook et al.’s study vali- cost and minimizes anatomic functional reason, in today’s cost-conscious medical dates the cost-effectiveness of MMS com- defects. MMS is a safe and cost-effective system, there is increasing pressure on pared to traditional surgical excision. Thus, technique that produces the highest cure physicians to deliver the best medical care MMS should be considered a cost-effective rates for primary and recurrent basal cell with scrupulous attention to cost. Conse- treatment with inherent value compared to and squamous cell carcinomas. quently, dermatologists are faced with a traditional surgical excision of selected dilemma in choosing the best, most cost- cutaneous tumors. References: effective treatment for NMSCs because 1. Mohs FE. Mohs Micrographic Surgery. A historical per- there are many modalities, such as elec- spective. Dermatol Clin.1989; 7:609-611. Safety Data of MMS 2. Phelan JT, Milgron H. The use of the Mohs chemosurgery trodessication and curettage, cryosurgery, technique of the treatment of skin cancers. Surg Gynecol surgical excision, radiation therapy, photo- The field of dermatologic surgery has Obstet 1967; 125:549-560. flourished over the past several decades.65 3. Tromovitch TA., Beirne GA, Beirne CG. Cancer chemo- dynamic therapy, and Mohs micrographic surgery. Cutis. 1982; 1:523- 529. surgery. A survey by the American Society for Der- 4. Tromovitch TA, Stegman SJ. Microscopic – Controlled exi- matologic Surgery predicated that its mem- cion of cutaneous tumors: Chemosurgery, fresh tissue Mohs micrographic surgery has been technique. Cancer. 1978;41:653-658. lauded to provide the highest cure rates for bers performed approximately 3.9 million 5. Swanson NA. Mohs surgery: Techniques, Indications, both primary and recurrent cutaneous procedures, of which 1.4 million were out- Applications and the Future. Arch Dermatol. 66 1983;119:761-773. 20, 58-60 malignancies. Furthermore, the tissue patient cutaneous surgeries. Thus, due to 6. Jaffe AT, Proper SA. An Alternate Approach for Harvesting preservation from MMS spares greater nor- the increased trend toward outpatient cuta- Mohs Specimens with a Flexible Scalpel. Dermatol Surg. neous surgeries, it is important for derma- 2001; 27(10):851. mal tissue and decreases the operative 7. Nouri K. What you need to know about Mohs micrographic defect size; therefore, it decreases the cost tologists and dermatologic surgeons to surgery. Skin Aging. 2000;8:68-70. scrupulously characterize the safety of 8. Shriner D, McCoy DK, Goldberg DJ, et al. Mohs micro- of reconstruction. Despite these advan- graphic surgery. J Am Acad Dermatol. 1998;39:79-97. tages, many investigators have questioned office-based surgery. Cook and Perone 9. Tulli A. Mohs micrographic surgery. In: Chu T, Chu AC, 61-63 have shown the safety associated with out- Edelson RL, eds. Malignant Tumors of the skin. London, the utilization of MMS due to its cost. England: Arnold. 1999;381-395. 64 However, Cook et al. believe that MMS is patient surgery in their prospective evalua- 10. Telfer NR. Mohs micrographic surgery for nonmelanoma a cost-effective modality for the treatment tion of the incidence of complications skin cancer. Clin Dermatol. 1995;13:593-600. (postoperative hemorrhage, hematoma for- 11. Drake LA, Dinehart SM, Goltz RW, et al. Guidelines of of cutaneous malignancies; therefore, they care for Mohs micrographic surgery. J Am Acad Dermatol.

TRAN, NGUYEN, CONTE 47 1995;33:271-278. 49. Salasche SJ and Amonette RA. Morpheaform Basal-Cell 12. Fazio MJ, Zitelli JA. Principles of reconstruction following Epitheliomas. J Dermato Surg Oncol. 1981;7:5:387-394. excision of nonmelanoma skin cancer. Clin Dermatol. 50. Burg G, Hirsch RD, Kontz B, et al. Histographic surgery: 1995;13:601-616. Accuracy of visual assessment of the margins of basal- 13. Becker GD, Adams LA. Management of large Mohs cell epithelioma. J Dermatol Surg. 1975;1(3):21- 24. defects. Ann Otol Rhinol Laryngol. 2000;109:863-870. 51. James WD, Berger TG, Elston DM. Andrew’s Disease of 14. http://www.mohscollege.org. Mar 2006. the Skin: Clinical Dermatology. 10th ed. Canada; Saun- 15. http://www.mohssurgery.org. Mar 2006. ders. 2006. 16. http://www.acgme.org. Mar 2006. 52. Rapini RP. Practical Dermatopathology. China; Elsevier 17. http://www.aoa.org. Mar 2006. Mosby. 2005. 18. Steinman HK. Indications for Mohs surgery. In:Gross KG, 53. Scheinfeld NS and Spann CT. Skin malignancies, Squa- Steinman HK, Rapini RP, eds. Mohs Surgery Fundamen- mous Cell Carcinoma. e medicine. www.emedicine.com. tals and Techniques. St. Louis, MO: Mosby Inc; 1999:9-14. Mar 2006. 19. Martinez JC, Otley CC. The management of melanoma 54. Geisse JK. Comparison of treatment modalities for squa- and nonmelanoma skin cancer: a review for the primary mous cell carcinoma. Clin Dermatol. 1995;13:621-626. care physician. Mayo Clin Proc. 2001;76:1253-1265. 55. Parker RG. Radiation therapy for skin neoplasms. Clin 20. Rowe DE, Carroll RJ, Day CL. Prognostic factors for local Dermatol. 1995;13:579-588. recurrence, metastasis, and survival rates in squamous 56. Diepgen TL, Mahler V. The epidemiology of skin cancer. cell carcinoma of the skin, ear, and lip. J Am Acad Derma- Br J Dermatol. 2002;146:1. tol. 1992;26:976-990. 57. Housman TS, et al. Skin cancer is among the most costly 21. Maguire B, Smith MP. Histopathology of cutaneous squa- of all cancers to treat for the Medicare population. J Am mous cell carcinoma. Clin Dermatol. 1995;13:559-568. Acad Dermatol. 2003;48:425. 22. Cruveilhier J. Maladies des nerfs. In: Cruveilhier J. 58. Zitelli JZ, Brown C, Hanusa B. Mohs micrographic surgery Anatomie pathologique du corps humain. 2nd edition, Part for the treatment of primary cutaneous melanoma. J Am 35. Paris: Bailliere, 1835:3. Acad Dermatol. 1997;37:236-245. 23. Hassan MO, Maksem J. The prostatic perineural space 59. Davis JL, Randle HW, Zalla MJ, et al. A comparison of and its relation to tumor spread. Am J Surg Pathol. Mohs micrographic surgery and wide excision for the 1980;4:43-8. treatment of atypical Fibroxanthoma. Dermatol Surg. 24. Seefeld PH, Bargen JA. The spread of carcinoma of the 1997;23:105-110. rectum: invasion of lymphatics, veins, and nerves. Ann 60. Dawes KW, Hanke CW. Dermatofibrosarcoma Protuber- Surg. 1943;118:76-90. ans treated with Mohs micrographic surgery. Dermatol 25. Quattlebaum FW. Adenocarcinoma cylindroma type of the Surg. 1996;22:530-534. parotid gland. Surg Gynecol Obstet. 1946;82:342-7. 61. Arnaud EJ, Perrault M, Revol M, et al. Surgical treatment 26. Mohs FE, Lathrop TG. Modes of spread of cancer of skin. of Dermatofibrosarcoma Protuberans. Plast Reconstr Arch Dermatol Syph. 1952;66:427-39. Surg. 1997;00:884-8895. 27. Goepfert H, Dichtel WJ, Medina JE, et al. Perineural inva- 62. Poller D. Mohs surgery. Lancet. 1994;343:924-925. sion in squamous cell carcinoma of the head and neck. 63. Abide JM, Nahai F, Bennett R. The meaning of surgical Am J Surg. 1984;148:542-7. margins. Plast Reconstr Surg. 1984;73:492-496. 28. Terashi H, Kurata S, Tadokora T, et al. Perineural and 64. Cook J, Zitelli JA. Mohs micrographic surgery: A cost anal- neural involvement in skin cancers. J Dermatol Surg sysis. J Am Acad Dermatol. 1998;39(5):698-703. Oncol. 1997;23:259-65. 65. Tuleya S. A status report: dermatological surgery. Skin 29. Cottel WE. Perineural invasion by squamous cell carci- Aging. 2002;10(5):10. noma. J Dermatol Surg Oncol. 1982;8:589-600. 66. Aasi SZ, Leffell DJ. Complications in Dermatologic 30. Nelson BR, Goldberg LH,. Facial nerve palsy as a result of Surgery: How Safe is Safe? Arch Dermatol. 2003; squamous cell carcinomao of the skin. J Dermatol Surg 139:213-214. Oncol. 1989;15:510-3. 67. Cook JL, Perone JB. A prospective evaluation of the inci- 31. Niazi ZBM, Lamberti BGH. Perineural infiltration in basal dence of complications associated with Mohs micro- cell carcinomas. Br J Plast Surg. 1993;46:156-7. graphic surgery. Arch Dermatol. 2003;139:143-152. 32. Mendenhall WM, Parsons JT, Mendenhall NP, Brant TA. 68 Tran TT, Muellenhoff M, Nguyen, K. Avoiding nerve injury Carcinoma of the skin of the head and neck with per- in the head and neck during Mohs micrographic surgery. J ineural invasion. Head Neck. 1989;11:301-8. Acad Dermatol Supp. 2004;50:3. 33. Barrett TL, Greenway HT, Massullo V, Carlson C. Treat- ment of basal cell carcinoma and squamous cell carcinoma with perineural invasion. Adv Dermatol. 1993;8:277- 305. 34. Motley R, Kersey P, Lawrence C. Multiprofessional guidelines for the treatment of the patient with primary cutatneous squamous cell carcinoma. Br J Dermatol. 2002;46:18-25. 35. Jacob A. Observations respecting an ulcer of peculiar character, which attacks the eyelids and other parts of the face. Dublin Hospital Reports and Communications in Medicine and Surgery. 1827;4:232-9. 36. Lo SJ, Snow SN, Reizner GT, et al. Metastatic basal cell carcinoma: Report of twelve cases with a review of the literature. J Am Acad Dermatol. 1991;24:715-9. 37. Leffell DJ, Fitzgerald DA. Basal cell carcinoma. In: Freed- berg I, Eisen AZ, Wolff K, et al. eds. Dermatology in Gen- eral Medicine. New York, NY: McGraw-Hill; 1999:857-864. 38. Maloney ME. Histology of basal cell carcinoma. Clin Der- matol. 1995;13:545-549. 39. Jiang SB, Szyfelbein K. Pathology: Basal Cell Carcinoma. e-medicine. Sep 2, 2005. 40. Silverman MK, Kopf AW, Grin CM, et al. Recurrence Rates of Treated Basal Cell Carcinomas: Part 1 Overview. Dermatol Surg Oncol. 1991;17:713-718. 41. Thackray AC. Histologic classification of rodent ulcers and its bearing on their prognosis. Br J Cancer. 1951;5:213-6. 42. Sexton M, Jones GB, Maloney ME. Histologic pattern analysis of basal cell carcinoma. J Am Acad Dermatol. 1990;23:1118-26. 43. Leffell DJ, Fitzgerald DA. Basal cell carcinoma. In: Freed- berg IM, Eisen AZ, WolffK, et al., eds. Dermatology in General Medicine. New York, NY: McGraw-Hill. 1999;857- 864. 44. Hendrix JD, Parlette HL. Duplicitous Growth of Infiltrative Basal Cell Carcinoma. Analysis of Clinically Undetected Tumor Extent in a Paired Case-Control Study. Dermatol Surg. 1996;22:535-539. 45. Litzow TJ, Perry HO, and Soderstrom CW. Morpheaform basal-cell carcinoma. Am J Surg. 1968;116:499-505. 46. Caro MR and Howell JB. Morphea-like epithelioma. Arch Dermatol Syphilogr. 1951;63:53. 47. Howell JB and Caro MR. Morphra-like epithelioma. Arch Dermatol. 1957;75:517- 524. 48. Elder D, Elenitsas R, Johnson B, et al. Synopsis and Atlas of Lever’s Histopathology of the Skin. Lippincott Williams & Wilkins. 1999;56-58.

48 A REVIEW OF MOHS MICROGRAPHIC SURGERY: COMMON INDICATIONS For anywhere there’s acne, there’s EVOCLIN.

Finally, an acne formulation that’s easy to apply over multiple body areas.1 EVOCLIN comes in a patient- preferred foam vehicle, with minimal residue.1,2 It’s effective in reducing inflammatory and noninflammatory lesions. Plus it’s safe and well tolerated.3 Looking for a treatment that works anywhere there’s acne? EVOCLIN is here. EVOCLIN is a once-a-day topical clindamycin foam for the treatment of acne vulgaris. The most common adverse events were headache (3%) and application-site reactions including burning (6%), itching (1%), and dryness (1%). EVOCLIN is contraindicated in individuals with a history of hypersensitivity to preparations containing clindamycin or lincomycin, or a history of regional enteritis, ulcerative colitis, or antibiotic-associated colitis. Diarrhea, bloody diarrhea, and pseudomembranous colitis have been reported with systemic and rarely with topical clindamycin. Discontinuation is recommended if diarrhea develops. Please see following page for full prescribing information. For further details, visit www.evoclin.com. Genotoxicity tests performed included a rat micronucleus test and an Ames Salmonella reversion test. Both tests were negative. Reproduction studies in rats using oral doses of clindamycin hydrochloride and clindamycin palmitate hydrochloride have revealed no evidence of impaired fertility. (clindamycin phosphate) Foam, 1% Pregnancy: Teratogenic effects - Pregnancy Category B Reproduction studies have been performed in rats and mice using subcutaneous and Rx Only oral doses of clindamycin phosphate, clindamycin hydrochloride and clindamycin palmitate hydrochloride. These studies revealed no evidence of fetal harm. The highest FOR TOPICAL USE ONLY. NOT FOR OPHTHALMIC, ORAL, OR INTRAVAGINAL USE. dose used in the rat and mouse teratogenicity studies was equivalent to a clindamycin DESCRIPTION phosphate dose of 432 mg/kg. For a rat, this dose is 84 fold higher, and for a mouse 42 fold Evoclin (clindamycin phosphate) Foam, 1%, a topical antibiotic in a foam vehicle, contains higher, than the anticipated human dose of clindamycin phosphat e from Evoclin based on clindamycin phosphate, USP, at a concentration equivalent to 10 mg clindamycin per a mg/m2 comparison. There are, however, no adequate and well-controlled studies in gram in a vehicle consisting of cetyl alcohol, dehydrated alcohol (ethanol 58%), pregnant women. Because animal reproduction studies are not always predictive of polysorbate 60, potassium hydroxide, propylene glycol, purified water, and stearyl human response, this drug should be used during pregnancy only if clearly needed. alcohol, pressurized with a hydrocarbon (propane/butane) propellant. Nursing Mothers: It is not known whether clindamycin is excreted in human milk Chemically, clindamycin phosphate is a water-soluble ester of t he semi-synthetic following use of Evoclin. However, orally and parenterally administered clindamycin has antibiotic produced by a 7 (S)-chloro-substitution of the 7 (R)-hydroxyl group of the parent been reported to appear in breast milk. Because of the potential for serious adverse antibiotic, lincomycin, and has the structural formula represented below: reactions in nursing infants, a decision should be made whether to discontinue nursing Figure 1: Structural Formula or to discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use: Safety and effectiveness of Evoclin in children under the age of 12 have

CH3 not been studied. H3C N Geriatric Use: The clinical study with Evoclin did not include sufﬁcient numbers of H H Cl patients aged 65 and over to determine if they respond differently than younger patients. H ADVERSE REACTIONS N CH H 3 ≥ H The incidence of adverse events occurring in 1% of the patients in clinical studies comparing Evoclin and its vehicle is presented below: O Selected Adverse Events Occurring in ≥1% of Subjects HO O Adverse Event Number (%) of Subjects OH Evoclin Foam Vehicle Foam N = 439 N = 154

SCH3 Headache 12 (3%) 1 (1%) Application site burning 27 (6%) 14 (9%) OPO3H2 Application site pruritus 5 (1%) 5 (3%) Application site dryness 4 (1%) 5 (3%) The chemical name for clindamycin phosphate is methyl 7-chloro-6,7,8-trideoxy-6-(1- methyl-trans-4-propyl-L-2-pyrrolidinecarboxamido)-1-thio-L-threo-␣-D-galacto- Application site reaction, 3 (1%) 4 (3%) octopyranoside 2-(dihydrogen phosphate). not otherwise specified CLINICAL PHARMACOLOGY Pharmacokinetics: In an open label, parallel group study in 24 patients with acne In a contact sensitization study, none of the 203 subjects developed evidence of allergic vulgaris, 12 patients (3 male and 9 female) applied 4 grams of Evoclin Foam once-daily for contact sensitization to Evoclin. five days, and 12 patients (7 male and 5 female) applied 4 grams of Clindagel® Orally and parenterally administered clindamycin has been associated with severe (clindamycin phosphate) Topical Gel, 1%, once daily for five days. On Day 5, the mean Cmax colitis, which may end fatally. and AUC(0-12) were 23% and 9% lower, respectively, for Evoclin Foam than for Cases of diarrhea, bloody diarrhea, and colitis (including pseudomembranous colitis) Clindagel®. have been reported as adverse reactions in patients treated with oral and parenteral Following multiple applications of Evoclin Foam less than 0.024% of the total dose was formulations of clindamycin and rarely with topical clindamycin (see WARNINGS). excreted unchanged in the urine over 12 hours on Day 5. Abdominal pain and gastrointestinal disturbances, as well as gram-negative folliculitis, References: 1. Feldman SR, Sangha N, Setaluri V. Topical Microbiology: The clindamycin component has been shown to have in vitro activity have also been reported in association with the use of topical formulations of corticosteroid in foam vehicle offers comparable coverage against Propionibacterium acnes, an organism which is associated with acne vulgaris; clindamycin. compared with traditional vehicles. J Am Acad Dermatol. however, the clinical significance of this activity against P. acnes was not examined in OVERDOSAGE 2. clinical trials with this product. Cross-resistance between clindamycin and erythromycin Topically applied Evoclin may be absorbed in sufficient amounts to produce systemic 2000;42:1017-1020. Data on file [001], Connetics has been demonstrated. Corporation. 3. EVOCLIN™ prescribing information. effects (see WARNINGS). CLINICAL STUDIES DOSAGE AND ADMINISTRATION In one multicenter, randomized, double-blind, vehicle-controlled clinical trial patients Apply Evoclin once daily to affected areas after the skin is washed with mild soap and Evoclin, the “wisp” logo, and the foam dollop are trademarks, with mild to moderate acne vulgaris used Evoclin (clindamycin phosphate) Foam, 1% or allowed to fully dry. Use enough to cover the entire affected area. and VersaFoam and Connetics are registered trademarks of the vehicle foam once daily for twelve weeks. Treatment response, defined as the Connetics Corporation. proportion of patients clear or almost clear, based on the Investigator Static Global Assessment (ISGA), and the mean percent reductions in lesion counts at the end of treatment in this study are shown in the following table: To Use Evoclin: © 2005 Connetics Corporation 1. Do not dispense Evoclin directly onto your PRM-CLF-030 Evoclin Foam Vehicle Foam hands or face, because the foam will begin 2/05 Efficacy Parameters N=386 N=127 to melt on contact with warm skin. Printed in USA Treatment response (ISGA) 31% 18%* 2. Remove the clear cap. Align the black mark with the nozzle of the actuator. Percent reduction in lesion counts 3. Hold the can at an upright angle and then Inflammatory Lesions 49% 35%* press firmly to dispense. Dispense an amount directly into the cap or onto a cool Noninflammatory Lesions 38% 27%* surface. Dispense an amount of Evoclin that will cover the affected area(s). If the Total Lesions 43% 31%* can seems warm or the foam seems runny, *P< 0.05 run the can under cold water. 4. Pick up small amounts of Evoclin with your INDICATIONS AND USAGE fingertips and gently massage into the Evoclin is indicated for topical application in the treatment of acne vulgaris. In view of the affected areas until the foam disappears. potential for diarrhea, bloody diarrhea and pseudomembranous colitis, the physician should consider whether other agents are more appropriate. (See CONTRAINDICATIONS, WARNINGS, and ADVERSE REACTIONS.) CONTRAINDICATIONS Throw away any of the unused medicine that you dispensed out of the can. Evoclin is contraindicated in individuals with a history of hypersensitivity to preparations Avoid contact of Evoclin with eyes. If contact occurs, rinse eyes thoroughly with water. containing clindamycin or lincomycin, a history of regional enteritis or ulcerative colitis, or a history of antibiotic-associated colitis. WARNINGS HOW SUPPLIED Orally and parenterally administered clindamycin has been associated with severe Evoclin containing clindamycin phosphate equivalent to 10 mg clindamycin per gram, is colitis, which may result in patient death. Use of the topical formulation of available in the following sizes: 100 gram can - NDC 63032-061-00 and 50 gram can - NDC clindamycin results in absorption of the antibiotic from the skin surface. Diarrhea, 63032-061-50 bloody diarrhea, and colitis (including pseudomembranous colitis) have been reported with the use of topical and systemic clindamycin. STORAGE AND HANDLING Studies indicate a toxin(s) produced by Clostridia is one primary cause of Store at controlled room temperature 20°- 25°C (68°- 77°F). antibiotic-associated colitis. The colitis is usually characterized by severe FLAMMABLE. AVOID FIRE, FLAME OR SMOKING DURING AND IMMEDIATELY persistent diarrhea and severe abdominal cramps and may be associated with the FOLLOWING APPLICATION. passage of blood and mucus. Endoscopic examination may reveal Contents under pressure. Do not puncture or incinerate. Do not expose to heat or store pseudomembranous colitis. Stool culture for Clostridium difficile and stool assay at temperature above 120°F (49°C). for C. difficile toxin may be helpful diagnostically. Keep out of reach of children. When significant diarrhea occurs, the drug should be discontinued. Large bowel endoscopy should be considered to establish a definitive diagnosis in cases of Manufactured for Printed in USA severe diarrhea. Antiperistaltic agents, such as opiates and diphenoxylate with Connetics Corporation October 2004 atropine, may prolong and/or worsen the condition. Palo Alto, CA 94304 USA Diarrhea, colitis, and pseudomembranous colitis have been observed to begin up to several weeks following cessation of oral and parenteral therapy with For additional information: clindamycin. 1-888-500-DERM or visit Mild cases of pseudomembranous colitis usually respond to drug discontinuation alone. www.evoclin.com In moderate to severe cases, consideration should be given to management with fluids AW No: AW-0317-r3 and electrolytes, protein supplementation and treatment with an antibacterial drug clinically effective against C. difficile colitis. U.S. Patent Pending Avoid contact of Evoclin with eyes. If contact occurs, rinse eyes thoroughly with water. PRECAUTIONS General: Evoclin should be prescribed with caution in atopic individuals. Drug Interactions: Clindamycin has been shown to have neuromuscular blocking properties that may enhance the action of other neuromuscular blocking agents. Therefore, it should be used with caution in patients receiving such agents. Evoclin is a trademark, and VersaFoam, the V logo, the interlocking C logo, and Connetics are registered trademarks of Connetics Corporation. Carcinogenesis, Mutagenesis, Impairment of Fertility The carcinogenicity of a 1% clindamycin phosphate gel similar to Evoclin was evaluated © 2004 Connetics Corporation by daily application to mice for two years. The daily doses used in this study were approximately 3 and 15 times higher than the human dose of clindamycin phosphate from 5 milliliters of Evoclin, assuming complete absorption and based on a body surface area comparison. No significant increase in tumors was noted in the treated animals. A 1% clindamycin phosphate gel similar to Evoclin caused a statistically significant shortening of the median time to tumor onset in a study in hairless mice in which tumors were induced by exposure to simulated sunlight. Eruptive Vellus Hair Cysts: A Case Report and Literature Review

Amy M. Broomer, D.O.*, Stanley E. Skopit, D.O., FAOCD** *3rd Year Resident, NOVA Southeastern University/BGMC **Program Director, NOVA Southeastern University/BGMC

ABSTRACT

Eruptive vellus hair cysts is a rare condition that presents in children and young adults. These small papules usually appear on the chest. Treatment options include keratolytics, and rarely, the lesions spontaneously regress. This paper will review the clinical presentation, histology, and pathophysiology of eruptive vellus hair cysts.

Overview Eruptive vellus hair cysts (EVHC) were first described by Easterly et al in 1977.1 Understanding of this entity has greatly increased over the years. Multiple lesions are referred to as “eruptive” vellus hair cysts, although solitary cysts are occasionally seen. Lesions are most commonly seen on the chest; however, they can be present on the face, neck, extremities, abdomen, back, buttocks, and groin.2 Clinically, these lesions can present with Figure 1 Figure 2 a variety of colors and shapes. Color variations include skin color, yellow, red, with the numerous characteristic vellus brown, gray, and black.3 These small hairs were seen within the cyst. Rarely, lesions, usually 1 to 3 mm, may appear other structures can be observed in the as papules (with or without inflammation), cyst wall, such as melanocytes, langer- umbilicated lesions, or open, comedone- han cells, and small arrector pili muscles like lesions.4 attached to the outer cyst wall.5 Some cysts connect with the surface of the epi- Case Report dermis, forming an open pore containing keratin and vellus hairs.6 It is unclear A 14-year-old Indian female presented whether these open pores are the initiat- with a one-year history of papular erup- ing process in cyst formation or the end tion on the legs and abdomen. Multiple stage with extrusion of the contents and follicular papules, as well as open come- resolution. In specimens where the cysts dones, were seen on the lower extremi- Figure 3 had almost disappeared, foreign-body ties and the abdomen (Figs 1 and 2). granuloma with giant cells containing vel- Numerous erythematous papules were EVHC. lus hairs were observed.7 noted, as well as the occasional gray Although EVHC has presented from papule; lesions were 1 to 2 mm in size. There are many reports in the literature birth to those in the sixth decade of life, it of EVHC seen in conjunction with steato- The patient’s medical history was unre- 8,9 10 most commonly appears in children or markable; however, the family history was cystoma multiplex and pachyonychia . young adults.15 There does not appear to positive in the father for keratosis pilaris Both of these conditions have been asso- be any racial predilection or gender bias. ciated with mutations that encode keratin on the posterior aspect of the upper 11 These lesions are not associated with any extremities. The patient was taking no 17, as does EVHC. Some individuals subjective symptoms.16 Clinically, EVHC express a dominant inheritance,12 while medications except for salicylic acid 6%, 13 should be differentiated from acneiform started one week prior to being seen in others appear to be more congenital. eruptions, folliculitis, perforating disorders, the clinic. Mild improvement was The exact progression of this entity is and keratosis pilaris. Treatment is symp- reported by the patient with the salicylic poorly understood. Easterly et al. postu- tomatic. Rarely, some individuals have acid. The biopsy that was performed was lated that the development of the cyst complete remission of their lesions.17 stained with hematoxylin and eosin (Fig was initiated by the loss of epidermal con- Therapeutic modalities include retinoids, tact, allowing for the retention of the ker- 3). Histology revealed an infudibular cyst 14 lactic acid, incision and drainage, needle with vellus hairs, hyperkaratosis and atinous material and hairs. They also evacuations, and CO2 or erbium:YAG inflammation. postulated that a keratotic plug at the fol- laser ablation.18 licular infundibulum deflected hairs to the Vellus hair cysts are usually located in deeper part of the follicle, which caused the middle-to-upper dermis. Histologi- the dilation in which several hair roots of a Conclusion cally, these lesions are lined by stratified compound follicle unit have a common squamous epithelium with an attenuated Eruptive vellus hair cysts is an uncom- infundibulum. There is much to be granular layer. Loose, laminated keratin mon disease that usually manifests in learned to complete our understanding of

BROOMER, SKOPIT 51 childhood and can spontaneously clear without sequelae. Many patients do not seek medical evaluation because of its innocuous nature, and it is probably under-diagnosed. Additionally, its asymptomatic nature reduces the number of biopsies that are performed, and its clinical similarity to other benign entities increases the risk of misdiagnosis. Acknowledgements I would like to thank Dr. Raymond Barn- hill, Dr. Andrew Hanly, and Dr. Evangelos Poulos at Global Pathology Laboratory Services for providing the histological images in this case report.

References: 1. Easterly NB, Fretzin DF, Pinkus H. Eruptive vellus hair cysts. Arch Dermatol 1977;113:500-503. 2. Grimalt R, Gelmetti C. Eruptive Vellus hair cysts: Case Report and Review of the Literature. Pediatric Dermatol- ogy 1992;9(2)98-102. 3. Barnhill RL, Crowson, AN. Textbook of Dermatopathol- ogy. 2nd Ed. New York. McGraw-Hill. 2004: 565. 4. Lee S, Kim J, Kang, JS. Eruptive Vellus Hair Cysts. Arch Dermatol 1984; 120;1191-1195. 5. Barnhill RL, Crowson, AN. Textbook of Dermatopathol- ogy. 2nd Ed. New York. McGraw-Hill. 2004: 565. 6. Lee S, Kim J, Kang, JS. Eruptive Vellus Hair Cysts. Arch Dermatol 1984; 120;1191-1195. 7. Lee S, Kim J, Kang, JS. Eruptive Vellus Hair Cysts. Arch Dermatol 1984; 120;1191-1195. 8. Cho S, Chang SE, Choi JH, Sung KJ, Moon KC, Koh JK. Clinical and histologic features of 64 cases of steatocystoma multiplex. Journal of Dermatology. 2002; 129(3);152-156 9. Hurlimann AF, Panizzon RG, Burg G. Eruptive vellus hair cyst and steatocystoma multiplex: hybrid cysts. Dermatol- ogy. 1996; 192(1):64-66. 10. Takeshita T. Takeshita H. Irie K. Eruptive vellus hair cyst and epidermoid cyst in a patient with pachyonychia con- genita. Journal of Dermatology. 2000; 27(10):655-657. 11. Tomkova H, Fujimoto W, Arata J. Expression of Keratins K10 and K17 in Steatocystoma Multiplex, Eruptive Vellus Hair Cysts, and Epidermoid and Trichilemmal cyst. Am J Dermatopathol. 1997; 19;250-253. 12. Stiefler RE, Bergfeld WF. Eruptive Vellus Hair Cysts: An Inherited Disorder. J Am Acad Dermatol 1980; 3:425-529. 13. Piepkorn MW, Clark L, Lombardi DL. A Kindred with Con- genital Vellus Hair Cysts. J Am Acad Dermatol 1981;5:661-665. 14. Easterly NB, Fretzin DF, Pinkus H. Eruptive vellus hair cysts. Arch Dermatol 1977;113:500-503. 15. Lee S, Kim J, Kang, JS. Eruptive Vellus Hair Cysts. Arch Dermatol 1984; 120;1191-1195. 16. Stiefler RE, Bergfeld WF. Eruptive Vellus Hair Cysts: An Inherited Disorder. J Am Acad Dermatol 1980; 3:425- 529.17 Lee S, Kim J, Kang, JS. Eruptive Vellus Hair Cysts. Arch Dermatol 1984; 120;1191-1195. 18. Kageyama N, Tope WD. Treatment of Multiple Eruptive Hair Cysts with Erbium:YAG Laser. Dermatol Surg. 1999; 25;819-822. Please send correspondence to Amy Broomer 1501 NE Miami Gardens Dr. #C339 Miami, FL 33179

(305)610-6675 fax: (954)894-5425 email: [email protected]

52 ERUPTIVE VELLUS HAIR CYSTS: A CASE REPORT AND LITERATURE REVIEW

A Case Study of ANA Negative Minocycline-induced Lupus

Reagan B. Anderson, DO, MCS, LT, MC, USNR,* Margaret T. Dupree, MD, CDR(sel), MC, USN** * First Reconnaissance Battalion, Camp Pendleton, CA **Staff Dermatologist Branch Medical Clinic Miramar, San Diego, CA

*The views expressed in this article are those of the author and do not necessarily reflect the official policy or position of the Department of the Navy, Department of Defense, nor the U.S. Government.

ABSTRACT

Minocycline-induced lupus is an uncommon condition marked by articular complaints, malaise, fever, weight loss, and positive laboratory findings. This is a case study where the classic presentation of minocycline-induced lupus was present without the supportive laboratory findings.

started to complain of mild arthritic symp- developed. Introduction toms in bilateral elbows. Treatment was Minocycline is a semi-synthetic deriva- continued with follow-up in two weeks. Follow-up and Revision of tive of tetracycline used in the treatment of After two weeks, most of the arthritic symp- Diagnosis numerous diseases. Minocycline is very toms shifted from his elbows to bilateral Two weeks later, the patient returned to lipophilic, penetrates easily into most tis- wrists and hands. He also complained of the clinic with a 90% reduction in arthritic sues, binds to the 30S subunit of the bacte- fatigue and malaise to the point of and morning stiffness symptoms. He was rial ribosome, and is bacteriostatic, making decreased ability to perform any degree or still experiencing malaise and fatigue. it a good antibiotic to treat a variety of infec- amount of exercise. As an avid exerciser, Orthopedic evaluation was normal. Labo- tious diseases. Minocycline also has this is the first time in his life any of these ratory values and radiographs including numerous anti-inflammatory properties that symptoms had been present. A complete peripheral smear, ANA, ENA, TSH, LFT, P- make it a versatile drug for treating many history and physical examination was con- ANCA, ESR, RF, HIV, RPR, UA, Lyme anti- different inflammatory diseases such as ducted. body titers, and bilateral wrist and hand rheumatoid arthritis and bullous der- Complete review of systems was nega- radiographic series were all within normal matoses.1,2 It is a fairly non-toxic drug; but tive except for complaints of joint pain, limits. like any other pharmaceutical, it can pro- morning stiffness, fatigue, and malaise. The patient was instructed to restart the duce a number of side effects including a The joint pain would wake him up in the minocycline, although some sources rec- hypersensitivity reaction that mimics sys- middle of the night with 7 out of 10 pain ommend against re-challenging a patient temic lupus erythematosus, SLE. This and progressively decrease throughout the with the inciting drug.1 He was told to dis- syndrome is called drug-induced lupus day with a reported 4 out of 10 pain in the continue treatment if his symptoms reap- syndrome, DIL; when minocycline is the evening. peared. Within two days of restarting the cause, it has been referred to as minocy- minocycline, the arthritic symptoms 2 Differential Diagnosis cline-induced lupus, MIL. returned. The patient stopped the medica- The differential diagnosis for a migratory tion and all symptoms were completely Case Study polyarthopathy is extensive: rheumatic resolved two weeks later. The patient was fever, rheumatoid arthritis, primary amyloi- diagnosed with drug-induced lupus, DIL, History dosis, hypogammaglobulinemic arthritis, caused by minocycline. He has been hyperimmunoglobulin D, hemochromatosis, instructed not to take minocycline in the A 30-year-old Caucasian male presents hypothyroidism, hyperparathyroidism, HIV future. to the clinic with chronic, mild-to-moderate arthritis, syphilis, parvovirus arthritis, pan- nodulocystic acne covering approximately creatic cancer, hepatitis, primary biliary cir- 50% of his face and neck. Over the past rhosis, Lyme disease, SLE, DIL, and a host Definition of Drug-induced five years he has been treated with a vari- of other disease processes.3 Lupus ety of products and in a variety of combina- tions to include benzoyl peroxide gels, Physical Examination The definition of drug-induced lupus is topical clindamycin, metronidazole gel, still somewhat nebulous as there are still An objective examination revealed stable relatively few reported cases, 50 as of sum- localized steroid injections, and a variety of vital signs, stable weight from one year mer 2000.4 However, it is generally agreed topical retinoids. None of the treatments prior, and unremarkable heart, lung, produced greater than 50% improvement. upon that to diagnose DIL the patient must abdominal, neurological, musculoskeletal, have at least one lupus-like symptom, posi- Doxycycline 100mg PO BID was started and dermatological examinations. along with QAM benzoyl peroxide and tive QHS topical retinoids. After six months, Assessment and Plan ANA (usually greater than 1:1280), and doxycycline was discontinued due to inade- resolution of symptoms with discontinua- The patient was diagnosed with migra- quate results and moderate gastrointestinal tion of drug exposure.5,6,7,8 To more accu- tory polyarthropathy of unknown etiology. side effects. Minocycline 100mg PO BID rately diagnosis DIL, the patient must Minocycline was discontinued. The patient was then started. possess four of the 11 SLE-specific find- was given an orthopedic consultation, labo- ings while taking a medication which is After one month of treatment with ratory and radiologic studies were ordered minocycline, there was a dramatic reduc- known to cause ANA positively or DIL.5 and the patient was instructed to return in However, there is wide variation in the tion in number and size of nodulocystic two weeks or sooner if new problems lesions. However, after three months he degree and amount of positive laboratory

54 A CASE STUDY OF ANA NEGATIVE MINOCYCLINE-INDUCED LUPUS values in DIL, thus making the absolute DIL normally does not have life-threatening definition more complicated.9 consequences. DIL differs from SLE in two key areas: DIL is often less severe than SLE; and Conclusion DIL’s ANA antibodies are usually of the deoxyribonucleoproteins, or antihistones, Doubts may be raised whether our variety rather than against double-stranded patient had minocycline-induced lupus due DNA antibodies as in spontaneous SLE. to the lack of positive ANA that is almost After discontinuation of the inciting drug, always present in these cases. However, ANA titers can take as long as 12 months the patient’s return of symptoms within 48 to return to normal for DIL (typical time hours of restarting the minocycline and res- course is four months) but usually remain olution of symptoms after stopping the drug positive for spontaneous SLE.4,5 DIL also makes a compelling case in favor of this has no predilection for sex, whereas spon- diagnosis. Two weeks after cessation of taneous SLE affects nine times more the drug from the re-challenge, all symp- women than men.6 toms resolved and have not returned. It is Typically, DIL has been associated with our opinion that this is a case of ANA-neg- medications like procainamide and ative MIL and serves as a reminder to con- hydralazine. However, an increasing num- sider this diagnosis despite a negative ber of drugs are being associated with the ANA. syndrome. Minocycline is listed as a defi- nite cause in Cecil’s Textbook of Medicine, References while Habif lists it in the category of “drugs 1. Genovese MC, Harris, editor . Treatment of Rheumatoid recently reported to cause DIL.”6,8 Arthritis. Kelley’s Textbook of Rheumatology, 7th ed. St. Louis: W.B. Saunders; 2005. p. 1079-1088 When patients are considered to have 2. Tsanokov, N, Broshtilova, V, Kazandjieva, J. Tetracyclines DIL by drugs that are widely accepted as in Dermatology Clinics in Dermatology 2003;21:33-39. 3. Goldman L, Bennet, JC editors. Synthetic Diseases in causes, i.e. procainamide and hydralazine, which Arthritis is a Feature. Cecil Textbook of Medicine, the ANA is positive between 90-95% of the 21st ed. Philadelphia: W.B. Saunders Company; 2000. p. 1556-1558. time. In these situations, the clinician has 4. McHugh, NJ. Minocycline Induced Lupus Syndrome. to diagnose based on clinical course and Lupus UK News and Views, Spring 2000(60). Retrieved 6,8 June 11, 2005 from symptomatology, not on lab values. http://www.infotech.demon.co.uk/Mino.htm. 5. Quiceno, GA, Cush, JJ. Iatrogenic Rheumatologic Syn- dromes in the Elderly. Clin Geriatr Med 2005;21:577-588. Manifestations of 6. Schur, PH (2000). Systemic Lupus Erythematosus. In Goldman, L, Bennett JC, editors. Cecil Textbook of Medi- Drug-induced Lupus cine, 21st Ed. (1509-1517). Philadelphia: W.B. Saunders Company; 2000. p. 1509-1517. Articular complaints are present 80% of 7. Knights, SE, Leandro, MJ, Khamashta MA, Hughes GR. Minocycline-induced Arthritis. Clin Exp Rheumatol. the time, with arthalgias or myalgias being 1998;Sep-Oct 16(5):587-90. more prevalent than arthritis. Other com- 8. Habif, TP. Connective Tissue Diseases. Clinical Dermatol- ogy, 4th ed. St. Louis: Mosby Inc.; 2004. p.592-603. mon presenting symptoms are malaise, 9. Lawson, TM, Amos, N, Bulgen, D,Williams BD. Minocy- 4,5 fever, and weight loss. Usually, symp- cline-induced lupus: clinical features and response to chal- toms resolve rapidly with the discontinua- lenge. Rheumatology 2001;40:329-335. 10. Schlienger, RG, Bircher, AJ, Meier, CR. Minocycline- tion of therapy, although some case reports induced lupus. A systematic review. Dermatology have suggested the time line can be as 2000;200(3):223-31. long as two years. This small case study proposed that re-challenging patients with minocycline usually results in the return of original symptoms within 24-72 hours.9 A systematic review of 57 cases of minocycline-induced lupus found that all patients had polyarthralgia/polyarthritis and a positive ANA. Twelve of the 57 cases had a dermatologic manifestation (nonspecific rash, livedo reticularis, oral ulcerations, subcutaneous nodules, or alopecia).10 Habif states that between 25- 53% of patients will have dermatologic manifestations, although this usually does not include alopecia, a butterfly rash, dis- coid lesions, or mucosal ulcers.8 Treatment The offending drug must be removed. Treatment of DIL is supportive for symptomatic complaints. NSAIDS are most frequently used to control the arthralgias. Occasionally, corticosteroids are used if the side effects are severe.1 Note however that

ANDERSON, DUPREE 55 Cholesterol Embolization Syndrome: Case Report and Review of the Literature

Brian S. Walther, D.O.* and Stephen M. Purcell, D.O.** * Brian S. Walther, D.O., is a resident in dermatology at Lehigh Valley Hospital, Allentown, Pennsylvania ** Stephen M. Purcell, D.O., is the chairman and program director of the Lehigh Valley Hospital/PCOM Dermatology Residency Program, Allentown, Pennsylvania

ABSTRACT

Cholesterol embolization syndrome (CES) is a disseminated atherosclerotic disease with frequent cutaneous involvement. Risk factors include invasive vascular procedures as well as anticoagulant and thrombolytic therapies. Cutaneous manifestations are variable, but CES most commonly presents as livedo-reticularis. Diagnosis is predicated on clinical findings, laboratory evaluation and histopathology of cholesterol clefts within dermal vessels. Despite surgical and medical intervention, CES has an overall high morbidity and mortality rate.

Case Report An 82-year-old Caucasian female presented with a progressive onset of painful nodules and ulcerations of both her legs and lower back. Two weeks prior to her visit, she underwent angiography with stent placement after she developed ischemic colitis following identification of a high- grade stenosis of her superior mesenteric artery. Subsequently, she developed painful nodules on her inner thighs and lower back, some of which became necrotic. The patient denied any associ- Figure 1 Figure 2 ated constitutional symptoms or history of A 6-cm, indurated, ill-defined, subcuta- Punch biopsy demonstrating multiple, similar lesions. Clinical examination neous nodule with central necrosis needle-shaped clefts within the vessel revealed a 6-cm, indurated, ill-defined, sub- and surrounding erythema and ecchy- lumen, consistent with cholesterol cutaneous nodule with central necrosis and mosis on the lower back emboli surrounding erythema and ecchymosis on clear of any new lesions, and laboratory neous occurrences may also arise in the her lower back (Figure 1). Multiple, painful, values were all within normal limits. setting of hypertension, secondary to the poorly-circumscribed subcutaneous nod- shearing forces of turbulent blood flow.3 ules were noted on her inner thighs. Discussion Time to onset of cutaneous symptoms is The patient’s medical history included quite variable and is predicated on the incit- diabetes mellitus, hypertension, hypothy- Cholesterol embolization syndrome ing event.4 For example, vascular proce- roidism, and psoriasis, as well as a docu- (CES) represents a disseminated athero- dures and thrombolytic intervention act to mented allergy to penicillin. Patient denies sclerotic disease phenomenon initially physically destabilize the atheromatous any recent institution of new medications. described by Panum in 1862. According to plaque, causing clinical manifestations Two punch biopsies were obtained and some small case studies, its incidence is often within days to weeks. Conversely, ini- formalin-fixed and paraffin-embedded in estimated at 6.2 per million and most com- tiation of anticoagulant therapies inhibits standard fashion (Figure 2). Analysis of monly affecting Caucasian males at an the fibrin/coagulation cascade and typically both hematoxylin-eosin stained slides average age of 66.1 Some authorities has a more insidious onset over weeks to revealed a normal epidermis; however, believe that the true incidence of CES is months. As stated previously, the patho- vessel lumens within the deep reticular der- grossly underestimated, largely due to the physiology of CES is due to the disruption mis and subcutaneous tissue demon- high prevalence of subclinical disease or of an established thrombus, with showering strated several occlusive, needle-shaped misdiagnosis. Thurlbeck and Castleman of microemboli into the systemic circula- clefts with variable surrounding fat necro- examined autopsies of hypertensive tion. This cascade leads to tissue hypoxia, sis. These findings were consistent with the patients who had undergone aortic surgery, inflammatory response, and end-organ diagnosis of cholesterol embolization syn- specifically focusing on the incidence of damage, namely the gastrointestinal tract, drome. renal atheroemboli.2 Although 70% of the lungs, and kidneys. Interestingly, Franks Shortly after the patient’s initial office test group demonstrated evidence of kid- and colleagues demonstrated that adeno- visit, laboratory data revealed elevations of ney involvement, approximately 30% of the sine, a by-product of tissue ischemia and a both her blood urea nitrogen (BUN) and age-and-sex-matched control group also potent vasodilator, actually decreases creatinine levels, indicative of acute renal demonstrated subclinical renal emboli. glomerular filtration and leads to incipient failure. Patient underwent a brief hospital Risk factors for the development of CES renal failure, a significant cause of morbid- stay for temporary dialysis and manage- include vascular procedures such as angio- ity/mortality in this population.5 ment of her electrolyte imbalances and plasties and arteriograms,thrombolytic/anti- In a large case study by Falanga and was discharged in stable condition. At fol- coagulant therapies and other colleagues, cutaneous manifestations of low-up several months later, patient was hyperlipidemic disease processes. Sponta- CES were found in 35% of patients.6 It was

56 CHOLESTEROL EMBOLIZATION SYNDROME: CASE REPORT AND REVIEW OF THE LITERATURE determined that livedo reticularis (49%) Despite early detection and institution of was the most frequent presenting sign, fol- proper therapy, CES continues to have a lowed by gangrene (35%), acral cyanosis poor prognosis. Patients frequently have or the “blue toe syndrome” (28%), ulcera- recurrent embolization, and amputation tion (17%), nodules (10%) and purpura rates range between 15% and 32%.11-16 (9%). Cutaneous symptoms are typically Mortality rates have been quoted as high bilateral and typically affect the lower as 81%, often secondary to declining car- extremities, although unilateral variants diac and renal function.1 have been reported. In the appropriate In summary, CES remains a diagnostic clinical setting, the constellation of extrem- and therapeutic challenge, often requiring a ity pain and livedo reticularis in the pres- multidisciplinary approach. Fortunately, ence of palpable pulses is considered by our patient received prompt supportive some to be pathognomonic for CES4. In care and temporary dialysis, with complete our patient, catheterization of her superior resolution of her symptoms. Her favorable mesenteric artery may have resulted in clinical course re-emphasizes the need for embolization of an intercostal artery, caus- a high level of suspicion and early interven- ing her lumbar ulceration, a rare and infre- tion to avert potentially fatal outcomes. quently reported finding. Because the clinical findings overlap and References mimic a variety of dermatologic entities, 1. Fine MJ, Kappor W, Falanga V. Cholesterol crystal further laboratory studies are often needed embolization: a review of 221 cases in the English litera- to confirm the diagnosis. Albeit non-spe- ture. Angiology 1987;38: 769-84. 2. Thurlbeck, WM, Castleman B. Atheromatous emboli to the cific, complete blood count (CBC) with dif- kidneys after aortic surgery. N Engl J Med 1987; 257:442- ferential, BUN/creatinine, urinalysis, 7. 3. Donohue KG, Saap L, Falanga V. Cholesterol crystal erythrocyte sedimentation rate and crea- embolization: an atherosclerotic disease with frequent and tine phosphokinase are markers that reflect varied cutaneous manifestations. Acta Derm Venereol a systemic inflammatory response and 2003; 17:504-11. 4. Pennington M et al. Cholesterol embolization syndrome: 1 end-organ damage. Additional labs, cutaneous histopathological features and a variable onset including anti-neutrophilic cytoplasmic anti- of symptoms in patients with different risk factors. Br J Dermatol 2002;146:511-7. bodies (ANCA), cryoglobulins, and hepati- 5. Franks RS, Mohammed MM, Podrazik, RM. Renal vaso- tis screening panel, may be helpful to rule constriction and transient declamp hypotension after infrarenal aortic occlusion: role of plasma purine degrada- out other entities in the differential, includ- tion product. J Vasc Surg 1988;4: 515-22. ing polyarteritis nodosa and other vasculi- 6. Falanga V et al. The cutaneous manifestations of choles- tides.3 Systemic radiographic evaluation to terol crystal embolization. Arch Dermatol 1986;122:1194- 1198. identify the source of emboli is also of criti- 7. Chauvapun JP, Dryjski, M. Distal peripheral microem- cal importance.7 bolism. Vascular 2005;13:50-7. 8. Resnick, KS. Intravascular cholesterol clefts as an inciden- Many consider the histopathologic find- tal finding: cholesterol embolism or not? Am J Der- ings to be diagnostic for this condition. matopathol 2003; 25:497-99. 9. Elinav E, Chajek-Shaul T, Stern M. Improvement in cho- Biopsy reveals multiple biconvex, needle- lesterol embolization syndrome after iloprost therapy. Br shaped clefts within arteries and arterioles, Med J 2002; 324:268-9. 10. Cabili S, Hochman I, Goor Y. Reversal of gangrenous which are remnants of cholesterol washed lesions in blue toe syndrome with lovastatin: a case report. out during processing.4 Typically, vasculitis Angiology 1993; 44:821-5. 11. Shames ML, Rubin BG, Sanchez LA. Treatment of is not a histopathologic feature of CES, embolizing arterial lesions with endoluminally placed stent though acute and chronic inflammatory grafts. Ann Vasc Surg 2002; 16:608-12. infiltrates have been demonstrated. Hyper- 12. Friedman SG, Krishnasastry KV. External iliac ligation and axillary-bifemoral bypass for blue toe syndrome. Surgery plastic intimal proliferation is thought to be 1994; 115:27-30. an additional late finding, and older lesions 13. Brewer ML, Kinnison ML, Perler BA. Blue toe syndrome: treatment with anticoagulants and delayed percutaneous may show a foreign-body reaction. How- transluminal angioplasty. Radiology 1988; 166:31-36. ever, serial sections are often required to 14. Kumpe DA, Zwerdlinger S, Griffin DJ. Blue digit syndrome: treatment with percutaneous transluminal angioplasty. identify the segment involved. Incidental Radiology 1988; 166:37-44. findings of cholesterol clefts in the absence 15. Dolmatch BL et al. Blue toe syndrome: treatment with per- of cutaneous disease have been reported, cutaneous atherectomy. Radiology 1989; 173:799-804. 8 16. Matchett WJ et al. Blue toe syndrome: treatment with requiring clinicopathologic correlation. intra-arterial stents and review of therapies. J Vasc Interv Surgical intervention remains the gold Radiol 2000; 11:585-92. standard for therapy of CES in an attempt to preserve functional tissue. However, poor surgical candidates require medical management. Anecdotal reports of IV iloprost, a prostacyclin analogue, have shown vasodilatory and anti-platelet properties.9 Similarly, statins have been suggested to possess plaque-stabilization attributes.10 Pentoxifylline and corticosteroids have also been used to reduce inflammation and pain, with inconsistent results. In all of these patients, supportive care, including the correction of fluid and electrolyte imbalances, is crucial.

WALTHER, PURCELL 57 Management of Epidermal Nevi in the Setting of Epidermal Nevus Syndrome: A Case Report and Literature Review

Mark E. Levenberg, D.O.*, Tanya Ermolovich, D.O.** and Stephen M. Purcell, D.O.*** * 3rd year dermatology resident, Lehigh Valley Hospital-Philadelphia College of Osteopathic Medicine, Philadelphia, Pennsylvania ** Clinical Instructor in Dermatology, Philadelphia College of Osteopathic Medicine, Philadelphia, Pennsylvania *** FAOCD, Program Director, Philadelphia College of Osteopathic Medicine, Philadelphia, Pennsylvania

ABSTRACT

The epidermal nevus syndromes (ENS) are a group of congenital disorders characterized by the association of epidermal nevi with abnormalities of the skin, eyes, skeletal, central nervous, cardiovascular, and genitourinary systems, as well as with malignant conditions. Because of the wide spectrum of organ involvement, a multidisciplinary approach is advisable in the management of these cases. These conditions rarely present a diagnostic difficulty, but the epidermal nevi are particularly difficult to treat and patients require continued medical care for associated abnormalities. As an illustrative case, we describe a 23-year-old woman with a systematized epidermal nevus, nevus sebaceus of the scalp and unilateral palmoplantar keratoderma with associated musculoskeletal defects. Her epidermal nevus has been relatively recalcitrant to treatment, and herein, a summary of the literature discussing the classification and management of epidermal nevi is presented.

Case Report A 23-year-old female presented with extensive verrucous and hyperkeratotic lesions of the head and neck, trunk, genitalia and extremities. The lesions appeared focally on the chin at 6 months of age and slowly progressed in size, darkened color and distribution through adolescence. There was no history of erythroderma, vesicles, seizures or afflicted family members. A computed tomography scan of the brain was unremarkable. Past medical history includes early development of secondary sex characteristics, short stature Figure 2 and scoliosis. The lesions are largely Figure 1 Whorled and linear verrucous plaques asymptomatic, except for occasional pruri- Whorled plaques on right abdomen on chest and arms tus and discomfort associated with the absence of adnexal structures. Higher lesions in the anogenital and flexural areas. magnification reveals focal spongiosis and The patient is severely burdened by the moderate mixed cell infiltrate in the papil- cosmetic impairment caused by the lary dermis. There was no evidence of lesions. acantholysis, dyskeratosis or epidermolytic Physical examination revealed an obese hyperkeratosis. These features are non- female of short stature with normal intel- specific, essentially that of a benign papil- lect. Dermatologic examination revealed loma, but support a diagnosis of an numerous flesh colored to brown, verru- epidermal nevus.[Fig. 6] A shave biopsy cous, discrete and confluent papules taken from the large alopetic plaque on the arranged in grouped, linear and whorled scalp showed the features of hyperkerato- pattern, following the lines of Blaschko on sis, papillomatosis, and irregular acantho- the head and neck, torso, genitalia and sis of the epidermis. In the dermis there extremities. [Fig. 1,2,3] Brachydactyly and were increased numbers of mature seba- clinodactyly were noted on several fingers, ceous glands and small hair follicles and Figure 3 along with hyperkeratosis and keratoderma buds of basaloid cells, which may repre- Verrucous plaques on the face with transgrediens of the right palm and sent malformed hair germs. These features financial constraints. sole. [Fig. 4] A 15 cm alopetic, yellow- are consistent with a diagnosis of a nevus Treatment with isotretinoin at age 8 for orange, verrucous plaque was present on sebaceus (of Jadassohn). [Fig. 7] the right parietal/superior aspect of scalp. one year’s duration did not improve the To further evaluate the patient, the fol- [Fig. 5] Examination of the teeth, oral appearance or halt the progression of the lowing studies were requested: mucosa and nails was unremarkable. lesions. Carbon dioxide (CO2) laser treat- chest/skeletal radiographs, computed ment of the plantar surface of the feet, axil- Histologically, a shave biopsy of a verru- tomography scan(brain), abdominal ultra- lae and inner thighs did not produce cous papule taken from the right inguinal sound, cardiac echocardiogram, ophthal- significant clearing of the lesions and left region showed features of a polypoid lesion mologic and neurologic consultation and minor scarring. Additionally, treatment has with hyperkeratosis, papillomatosis and complete metabolic profile. The patient was included local surgical deplaning and scis- irregular acanthosis of the epidermis over- not able to complete this evaluation due to sor excision of large or symptomatic lying a hyperplastic fibrous stroma with an

58 MANAGEMENT OF EPIDERMAL NEVI IN THE SETTING OF EPIDERMAL NEVUS SYNDROME Figure 4 Hyperkeratotic plaques on the foot

Figure 5 Orange verrucous alopetic plaque on scalp

Figure 6 Scarring resulting from CO2 laser lesions, as well as cryotherapy to small or the pluripotent cells of the embryonic ecto- year of life, however, they may also develop individual lesions. The patient is applying derm. These nevi may be further classified later during childhood or adulthood.5,6 Clini- topical emollients to the skin daily and is into a number of distinct variants, which are cally, verrucous epidermal nevi are charac- using a topical 40% urea cream to her based on clinical morphology, extent of terized by verrucous papules often palms and soles. Consideration is being involvement, and the predominant epider- coalescing into well-demarcated plaques. given for future treatment of selected areas mal structure in the lesion. Variants include They may be skin-colored, brown, or gray- with topical retinoids, 5-fluorouracil, der- keratinocytic nevi, also called verrucous or brown. The linear arrangement of verru- mabrasion and CO2 laser, each as linear epidermal nevi, and organoid nevi, cous epidermal nevi typically follows the monotherapy or in combination. She con- such as, nevus sebaceus, nevus come- lines of Blaschko, reflecting the pattern of tinues to be followed at regular intervals for donicus, eccrine nevus, apocrine nevus, stem cell migration during embryonic surveillance. Becker's nevus and white sponge nevus. development. The distribution, surface Keratinocytic nevi are the most common of characteristics, and histology of the lesions Discussion the epidermal nevi. are variable.1 Histologically, verrucous epi- The incidence of all types of epidermal dermal nevi show features of hyperkerato- Epidermal nevi are benign hamartomas nevi is estimated to be 1 in 1000 live births, sis, acanthosis and papillomatosis. that result from hyperplasia of the epider- equally affecting males and females.1 Most Epidermolytic hyperkeratosis may be noted mis and/or adnexal structures in a localized cases arise sporadically during embryonic histologically in diffuse cases, and less area of skin as a result of somatic muta- development, but familial patterns of inheri- commonly, in localized epidermal nevi. tions or genetic mosaicism. Epidermal nevi tance have been observed for certain types Paller et al. identified a familial pattern of may be keratinocytic, follicular, sebaceous, of epidermal nevi.2-4 The majority of epider- disease, in which patients with large or sys- apocrine, or eccrine in origin arising from mal nevi appear at birth or within the first tematized verrucous epidermal nevi had an

LEVENBERG, ERMOLOVICH, PURCELL 59 Patients with large or widespread epider- tive. Systemic retinoids may be beneficial mal nevi and those with ENS, require a for the treatment of widespread system- careful history with particular attention atized epidermal nevi, but the requirement given to developmental history, attainment of life-long therapy may be inappropriate for of milestones, history of seizures, and smaller lesions.26,27 Retinoids, both systemic abnormalities of the bones, eyes, and uri- and topical, may be most effective in nary tract. Thorough mucocutaneous, neu- lesions with histologic features of epider- rologic, ophthalmologic, and orthopedic molytic hyperkeratosis. Nelson et al. have examinations are necessary, with special previously discussed the therapeutic ratio- attention paid to examination of the eyes, nale behind retinoid therapy of epidermal head circumference, spine, extremities, nevi.28 They described successful manage- R. Inguinal 2/12/03 and central and peripheral nervous sys- ment of one patient using a combination tems. Consultations with pediatric, ophthal- treatment of 0.1% tretinoin cream twice Figure 7 mologic, neurologic, and orthopedic daily and 5% 5-FU once daily for 6 months. Photomicrograph 5x services should be considered. Depending No occlusion was used and recurrence on the findings on history and physical was noted 3 to 4 weeks after cessation of examination, further investigations may be treatment. However, continuing the topical indicated. Establishing the diagnosis and combination 2 to 3 times a month was screening for associated abnormalities may effective as maintenance therapy. In one involve skin biopsies, blood chemistries, report, a patient with nevus comedonicus chest and skeletal radiographs, urinalysis, who failed multiple topical and systemic electroencephalograms, computed tomog- therapies was successfully treated with raphy scans or magnetic resonance imag- 12% ammonium lactate lotion applied twice ing, echocardiography, abdominal daily.29 ultrasonography, and serum and urine The treatment of linear verrucous epider- measurements of calcium and phosphorus mal nevus (LVEN) has also proven difficult. metabolism.1,10 A regular follow-up program A review by Fox and Lapins14 describes should be established for routine monitor- various approaches to treating verrucous Scalp 2/12/03 ing and surveillance because of the risk of epidermal nevi using intralesional steroids, primary and secondary tumors of the skin Figure 8 topical steroids with and without occlusion, and viscera, both benign and malignant.11 Photomicrograph 10x dithranol, phenol peeling, topical tretinoin Because the skin lesions only rarely under occlusion, podophyllin ointment increased risk of having offspring with Epi- become malignant, supported by observa- under occlusion, 5-FU under occlusion, dermolytic Hyperkeratosis (Bullous Con- tions of basal cell carcinoma arising within dermabrasion, and cryotherapy.15 They 36 genital Icthyosiform Erythroderma). a nevus sebaceus,12 the indication to treat found the surgical modalities were most The presence of multiple or extensive is most often for cosmetic improvement. effective at clearing the lesions, but epidermal nevi in an infant or child should Hence, the removal of these lesions is per- resulted in significant scarring. Other prompt consideration of other organ formed for the purpose of reducing disfig- agents used to treat LVEN have since been abnormalities. The diagnosis of epidermal urement and alleviating discomfort. reported, including a successful response nevus syndrome (ENS) is generally Localization to cosmetically sensitive with isotretinoin27 and anthralin17. Moreover, straightforward in a patient presenting areas, such as the head and neck or distal topical calcipotriol23 has been reported to with epidermal nevi in association with extremities, can be very embarrassing and be beneficial in treating the inflammatory other organ abnormalities.5 Happle7-9 has distressing for patients. Extensive epider- variant of LVEN, which has been argued to suggested that the “epidermal nevus syn- mal nevi can cover much of the body sur- represent true linear psoriasis or superim- drome” consists of a spectrum of clinical face and, if present in intertriginous areas, posed psoriasis.13 The literature is replete subtypes. Well-defined epidermal nevus can become tender, macerated plaques with case reports and anecdotal evidence syndromes include Nevus Comedonicus and a potential source of infection. of successful treatment with various syndrome, Pigmented Hairy Epidermal The treatment of epidermal nevi is chal- agents, but there have been only a few Nevus syndrome (Becker’s nevus syn- lenging. Epidermal nevi have been notori- large series of patients in randomized stud- drome), Congenital Hemidysplasia with ously difficult to treat due to their large size ies. Ichthyosiform Erythroderma and Limb and occasional conspicuous location. Mul- Removal of lesions is often technically Defects (CHILD), Proteus syndrome, tiple medical and surgical treatments for difficult.5,13-15 Superficial means of removal Phacomatosis Pigmentokeratotica and epidermal nevi have been attempted13-23, frequently result in recurrence. Aggressive Schimmelpenning syndrome. Each sub- but no ideal or universally acceptable treat- approaches may be more successful, but type is defined by particular phenotypic, ment has emerged. The treatment of also carry a higher risk of postoperative histopathologic, and genetic criteria. choice for small epidermal nevi is exci- scarring. Surgical excision, dermabrasion, These are summarized in Table 1. The sion.24 Lesions may enlarge slowly in child- cryosurgery, electrosurgery, and laser diagnosis can usually be made on the hood, become darker and thicker, and by surgery have each been used to treat epi- clinical appearance and distribution of the adolescence reach a stable size after dermal nevi. In particular, surgical excision lesions alone. However, a skin biopsy is which further growth is unlikely.25 Therefore, always causes scar formation and thus is required to not only aid in establishing the it is preferable to delay surgery until the reserved for the smallest lesions. Der- diagnosis, but also determine the pre- lesions have clinically reached final matura- mabrasion, if superficial, is associated with dominant cell type, presence of inflammation. Early excision may result in recur- a high rate of recurrence, and deep dermal tion, characteristics of keratinocytes (ie. rence. dermabrasion can result in hypertrophic acantholysis, dysplasia, epidermolytic Many medical treatments for epidermal scarring. Cryosurgery has similar limita- hyperkeratosis) and malignant potential nevi have been attempted.14 Corticos- tions, with the risks including slow healing, which may have implications on the teroids applied under occlusion or by injec- exudation, swelling, and not uncommonly, selection of appropriate therapies and tion, as well as tretinoin cream applied depigmentation. prognosis. topically, may sometimes be partially effec- Physicians have been performing laser

60 MANAGEMENT OF EPIDERMAL NEVI IN THE SETTING OF EPIDERMAL NEVUS SYNDROME treatment on epidermal nevi for decades.13 to reach the desired end point. Extremely tion vol1. New York. Mc Graw Hill, 1993:858-864. 12. Ichikawa T, Saiki M, Kaneko M, Saida T. Squamous cell Recent advances in laser technology have thick lesions can be debulked with electro- carcinoma arising in a verrucous epidermal nevus. Der- increased the ease, precision, and safety cautery or the laser on continuous wave matology 1996;193:135-8 13. Hohenleutner U, Landthaler M. Laser therapy of verrucous of such treatments. Several reliable and mode, and the setting can be changed to epidermal naevi. Clin Exp Dermatol 1993;18:124-7. effective methods for treating epidermal pulsed mode once the epidermal compo- 14. Fox BJ, Lapins NA. Comparison of treatment modalities nevi with lasers have been developed. Sev- nent is mostly removed.35 However, a limita- for epidermal nevus: a case report and review. J Dermatol Surg Oncol 1983;9:879-85. eral articles in the literature detail such tion of this technique is its slowness. 15. Ratz JL, Bailin PL, Wheeland RG. Carbon dioxide laser treatment, and different types of lasers Numerous laser passes to the same area treatment of epidermal nevi. J Dermatol Surg Oncol 1986;12:567-70. have been reported to be effective. Suc- are time-consuming, and extensive lesions 16. Happle R, Kastrup W, Macher E. Systemic retinoid ther- cessful eradication appears dependent on covering large parts of the body are not apy of systematized verrucous epidermal nevus. Dermato- logica 1977;155:200-5. the clinical characteristics of the nevus. amenable to such treatment. Also, recur- 17. de Mare S, van de Kerkhof PCM, Happle R. Dithranol in Softer, flat nevi were more responsive to rences can occur months or years after the treatment of inflammatory linear verrucous epidermal the argon laser and carbon dioxide laser removal of epidermal nevi by any method. nevus. Acta Dermatol Venereol 1989;69:77-80. 18. Rulo HFC, van de Kerkhof PCM. Treatment of inflamma- than were the harder, keratotic forms of Patients should be made aware of this, as tory linear verrucous epidermal nevus. Dermatologica LVEN.13,30 The pulsed ruby laser effectively well as the possibility of hypertrophic scar 1991;182:112-4. 19. Dellon AL, Luethke R, Wong L, Barnett N. Epidermal lightened dark-colored epidermal nevi, but formation. nevus: surgical treatment by partial-thickness skin exci- its efficacy has not been shown in nonpig- In summary, the diagnosis of epidermal sion. Ann Plast Surg 1992;28:292-6. 21 20. Alster TS. Inflammatory linear verrucous epidermal nevus: mented nevi. Long-pulsed ruby lasers nevi can usually be made on the clinical successful treatment with the 585 nm flashlamp-pumped have been used31 with 1 to 4 treatments appearance and distribution of the lesions pulsed dye laser. J Am Acad Dermatol 1994;31:513-4. resulting in good cosmetic improvement. 21. Baba T, Narumi H, Hanada K, Hashimoto I. Successful alone. In the context of ENS, a skin biopsy treatment of dark-colored epidermal nevus with ruby laser. The handful of patients treated did not will not only confirm the diagnosis, but may J Dermatol 1995;22:567-70. experience lesion recurrence during 2 to 3 22. Basex J, El Sayed F, Sans B, Belhaouari L, Larrègue M, also determine the predominant cell type, Marchac D. Shave excision and phenol peeling of general- years of follow up. Hypopigmentation, presence of inflammation, depth of lesion ized verrucous epidermal nevus. Dermatol Surg either transient or permanent, was noted in and characteristics of keratinocytes (ie. 1995;21:719-22. 23. Zvulunov A, Grunwald MH, Halvy S. Topical calcipotriol for some cases, as was decrease in hair acantholysis, dysplasia, epidermolytic treatment of inflammatory linear verrucous epidermal growth at the treated sites. hyperkeratosis) which may have implica- nevus. Arch Dermatol 1997;133:567-8. 24. Losee J, Serletti J, Pennino R. Epidermal nevus syn- Additionally, other lasers have been used tions in the prognosis and selection of drome: a review and case report. Ann Plast Surg to treat epidermal nevi. Targeted vascular appropriate therapies. Excision should be 1999;43:211-214. 25. Carpo B, Grevelink J, Grevelink S. Laser treatment of pig- lasers for the treatment of inflammatory lin- reserved for smaller nevi or lesions, such mented lesions in children. Semin Cutan Med Surg 32 ear verrucous epidermal nevus (ILVEN) as nevus sebaceus, which carry a low risk 1999;18:233-243. has been reported to be effective. In one of malignant transformation. The treatment 26. Happle R, Kastrup W, Macher E. Systemic retinoid therapy of systematized verrucous epidermal nevus. Dermato- report, the 585 nm flashlamp-pumped of extensive epidermal nevi should gener- logica 1977;155:200-205. pulsed dye laser was successful at reliev- ally be approached with a combination of 27. Herman AR, Scott RA. Systematized epidermal nevus treated with isotretinoin. J Drugs Dermatol. 2002 ing pruritus, but resulted in only partial medical and surgical methods. The man- Sep;1(2):195-6. clearing of the lesion.20 Erbium:YAG lasers agement of patients with ENS requires an 28. Nelson BR, Kolansky G, Gillard M, Ratner D, Johnson TM. Management of linear verrucous epidermal nevus with have been used to permit more precise interdisciplinary team approach because of topical 5-fluorouracil and tretinoin. J Am Acad Dermatol removal of epidermal nevus tissue, but diffi- the multiple organ systems involved. Fur- 1994;30:287-8. culty in achieving hemostasis with these thermore, the treatment of epidermal nevi 29. Milton GP, DiGiovanna JJ, Peck GL. Treatment of nevus 33,34 comedonicus with ammonium lactate lotion. J Am Acad devices can make treatment impractical. in this setting should be guided by the Dermatol. 1989 Feb;20(2 Pt 2):324-8. In deeper lesions, bleeding can complicate patient’s cosmetic desires and need for 30. Hohenleutner U, Wlotzke U, Konz B, Landthaler M. Car- bon dioxide laser therapy of a widespread epidermal the procedure, and scar formation may symptomatic relief. Realistic expectations nevus. Lasers Surg Med 1995;16:288-91. occur. Newer modified erbium lasers have should be established and long-term follow 31. Ohtsuka H, Nakaoka H, Watanabe T, Okayama N. Ruby laser treatment of pigmented skin lesions. Jpn J Plast greater coagulative capacity and may be up is necessary because of the potential Reconstr Surg 1991;34:615-23. used in a manner similar to that for the for multisystem involvement and the overall 32. Sidwell RU, Syed S, Harper JI. Pulsed dye laser treatment pulsed carbon dioxide laser. Continuous- increased risk of malignancy. for inflammatory linear verrucous epidermal naevus. Br J Dermatol. 2001 Jun;144(6):1267-9. wave carbon dioxide laser treatment of epi- 33. Kaufmann R, Hibst R. Pulsed erbium:YAG laser ablation in dermal nevi was reported by Ratz, Bailin cutaneous surgery. Lasers Surg Med 1996:19;324-30. 15 References: 34. Park, Jae-Hong, Hwang, Eul-Sang et al Er:YAG Laser and Wheeland, treating 15 patients over a Treatment of Verrucous Epidermal Nevi. Dermatologic 1. Solomon LM, Esterly NB Epidemal and other organoid Surgery. 2004:30(3);378-381. period of 5 years. Since then, others have nevi . Curr Probl Pediatr 1975;6:1-56. noted success with this approach. Hohen- 2. Alsaleh QA, Nanda A, Hassab-El-Naby HMM, Sakr MF. 35. Alam M, Arndt KA. A method for pulsed carbon dioxide 30 leutner et al found the continuous-wave Familial inflammatory linear verrucous epidermal nevus laser treatment of epidermal nevi. J Am Acad Dermatol. (ILVEN). Int J Dermatol 1994;33:52-4. carbon dioxide laser able to remove epider- 2002:46(4):554-6. 3. Hamm H, Happle R. Inflammatory linear verrucous epider- 36. Paller AS et al. Genetic and clinical mosaicism in a type of mal nevi of various types and textures. mal nevus (ILVEN) in a mother and her daughter. Am J epidermal nevus. NEJM 1994;331:1408-1415. Med Genet 1986;24:685-90. “Soft, flat, papillomatous” variants were 4. Goldman K, Don PC. Adult onset of inflammatory linear treated without scar formation even when verrucous epidermal nevus in a mother and her daughter. Dermatology 1984;189:170-2. they covered substantial body surfaces, 5. Rogers M, McCrosin I, Commens C. Epidermal nevi and and “hard, keratotic” lesions responded but the epidermal nevus syndrome. J Am Acad Dermatol with a tendency to hypertrophic scar forma- 1989;20:476-488. 13,30 6. Adams Brian B and Mutasim Diya F. Adult onset verru- tion. They speculated that removal of the cous epidermal nevus. J Am Acad Dermatol firmer lesions may require greater depth of 1999:41(5);824-26. 7. Happle R. How many epidermal nevus syndromes exist?. ablation of the dermis and hence increased J Am Acad Dermatol 1991;25:550-556. risk of damage to adnexal structures. 8. Happle R. Epidermal nevus syndromes. Semin Dermatol 1995;14:111-121. The pulsed carbon dioxide laser has sev- 9. Happle R, Hoffmann R, Restano L, Caputo R, Tadini G. eral advantages over continuous-wave Phacomatosis pigmentokeratotica: a melanocytic-epidermal twin nevus syndrome. Am J Med Genet 1996; 65: devices. Target lesions can be flattened in 363-5. a manner that permits precise control of 10. Oranje A, Pzyrembel H, Meradji M, Loonen M, de Klerk C. depth of ablation. Each laser pass vapor- Solomon's epidermal nevus syndrome (type: linear sebaceous) and hypophosphatemic vitamin D-resistant rickets. izes a limited amount of tissue, and a Arch Dermatol 1994;130:1167-1171. series of such thin slices can be removed 11. Fitzpatrick TB. Dermatology in general medicine. 4th edi-

LEVENBERG, ERMOLOVICH, PURCELL 61 Position available for a full time BCBE Dermatologist Jacksonville Florida. Good benefits, wonderful working environment, position available October 2006. For more information please call Mr. Jose Paredes Practice Adminis- trator 904-644-0204 or fax resume to 904-541-0316.

Members of the AOCD may advertise "position available."

This is a free service for all active members of the AOCD. A 3" column black and white ad will be provided in the journal as a free service. If members wish to use a larger space, they may do so. The cost for this advertising is:

Black and White - 1/4 page-$125, 1/2 page-$200, full page-$350 Full 4 color ad - 1/4 page-$275, 1/2 page-$350, full page-$500 Resident members may run a 3" column black and white ad stating their desired professional position.

These ads must be submitted as an e-mail attachment and sent to [email protected]. Any photos to be included in an active member's ad, must be in a .pdf format.

62 Observational Case Report: Acanthosis Nigricans Regression with Rosiglitazone after Previous Treatment with Pioglitazone

Derrick Adams, Captain, D.O., USAF, MC

ABSTRACT

After an institutional decision to delete pioglitazone from formulary and add rosiglitazone, near complete resolution of acanthosis nigricans was observed in three obese African American type 2 diabetics. This case report details the clinical presentations of the lesions and medical history of the patients.

Acanthosis nigricans (AN) is a non-spe- Upon physical examination, two of the References: cific, cutaneous pattern that may accom- patients demonstrated only trace papillo- 1. Habif T. Clinical Dermatology: A color guide to diagnosis pany obesity, diabetes, internal matotic hyperpigmentation to the dorsal and therapy. 4th edition. Philadelphia, Pa: Mosby, Inc; 2004 Page 900-901.2 malignancies, pineal tumors, multiple neck surfaces. Comparison through previ- 2. Kobaissi H, Weignesberg M, Ball G, Cruz M, Shaibi G, endocrinological abnormalities, and use of ous documentation revealed quite exten- Goran M. Relation between acanthosis nigricans and 1 insulin sensitivity in overweight Hispanic children at risk for nicotinic acid. AN is a clinically significant sive involvement of not only the dorsal neck type 2 diabetes. Diabetes Care. 27(6) Jun 2004:1412- lesion that may predict the early onset of but also of bilateral axillae in these individu- 1416.3 insulin-resistance syndromes or diabetes.2 als. The third patient was free of any 3. Hermanns-Le, T, Scheen A, Pierard G. Acanthosis nigricans associated with insulin resistance: pathophysiology The roles of insulin and insulin-like growth lesions at the time of examination, but her and management. American Journal of Clinical Dermatol- factor on keratinocytes are well-recognized chart had noted right axillary involvement ogy. 5(3) 2004:199-203. 4. Walling H, Messingham M, Myers L, Mason C, Strauss J. in the pathogenesis of this epidermal and right peri-areolar lesions. Improvement of acanthosis nigricans on isotretinoin and hyperplasia.3 AN is classified as either Clinical measurements and laboratory metformin. Journal of drugs in dermatology. 2(6) Dec 2003:677-681. malignant or benign, the latter including values of the three individuals changed obesity-related, hereditary and endocrine minimally after treatment was implemented syndromes. Although the lesions range in with rosiglitazone. The average BMI prior to severity of involvement, all are character- the transition was 34 and was unchanged ized by brownish thickening that is often when the lesions were first noted to be described as warty or leathery. Common absent. The hemoglobin A1c was noted to areas of involvement are the flexural sur- have increased an average of 0.35%, faces of the neck, axillae, groin and dorsal which was of no clinical significance. Blood surfaces of fingers, although lesions can pressures, liver function tests, creatine, and appear anywhere, including the oral cavity. urine microalbumin measurements were Lesions are usually asymptomatic and essentially unchanged throughout the require no treatment. Retinoic acids, 12% stated period (although one patient was lactic acid cream, oral isotretinoin and topi- changed from an angiotensin-receptor cal cholecalciferol are effective for reducing blocker to an angiotensin-converting lesions in areas of maceration or for cos- enzyme inhibitor). Collectively, there was metic appearances.4 no history of internal malignancy or poly- Three well-controlled African American cystic ovarian syndrome. The average type 2 diabetics managed on pioglitazone dose of the three patients was 5.3 mg and (Actos®, Takeda Chemical Industries, Ltd) the average length of rosiglitazone treat- and metformin were transitioned to rosigli- ment was 11 months when regression was tazone (Avandia®, GlaxoSmithKline) and first documented. continued on their previous metformin This clinical observation suggests that doses. The decision to alter the patients’ rosiglitazone may play a role in the treat- course of therapy was based solely upon ment of AN. There are three separate, doc- financial decisions made at the institutional umented case reports on improvement of level, as none were experiencing any side AN with metformin,5 but there have been effects or complications of pioglitazone no literature reports addressing the use of therapy. Each patient reported that the typi- thiazolidinedione antidiabetic agents. The cal acanthotic lesions had been present mechanism of action of both metformin and since young adulthood (the patients’ ages rosiglitazone remain only partially eluci- were 46, 44, and 69 years old). Only one of dated; however, it is reasonable to hypothe- the three patients had sought therapy for size that they may share similar effects on the asymptomatic lesions and had received keratinocytes and the complex regulations Retin-A 0.025% cream from a dermatolo- leading to AN formation. It is unclear why gist. This patient chose to discontinue use these particular patients had regression of after one month secondary to financial their AN lesions with rosiglitazone and not issues. The diagnosis of AN was annotated pioglitazone. This observation has led to a in each patient’s chart at least once within proposal for further study that is currently the previous four years by either a family before the facility’s Internal Review Board. practice physician or dermatologist.

ADAMS 63 Not Much of a Stretch to GETTING PUBLISHED!

The editors of the Journal of the American Osteopathic College of Dermatology (JAOCD) welcome all dermatology residents in AOA and ACGME residency programs to enjoy this issue of the JAOCD. The JAOCD was developed as a journal for and by residents in dermatology. The editors of the JAOCD welcome input from all dermatology residents, program chairman, program directors and practicing dermatologists. Our editorial review board is open to new members. Our goal is to become a quarterly publication within 1 year and then become a bimonthly publication soon thereafter.

We encourage all dermatologists to participate in this effort. Seasoned practitioners have time-tested wisdom to impart on dermatology residents. When residents are excited about specific cases, they like to share with their co-residents. Original research is the lifeblood of our profession and is always encouraged. Clinical, surgical as well as office management pearls have been topics covered in past issues.

For more information about becoming involved with the JAOCD or submitting manuscripts for consideration for publication, visit www.aocd.org and click on the JAOCD icon or feel free to contact the editors at [email protected] The Journal of the American PRSRT STD Osteopathic College of Dermatology U.S. POSTAGE PAID 3700 North 32nd Terrace MASON CITY, IA Hollywood, Fl 33201 PERMIT NO. 429

Address Correction Requested T HE J UNLO THE OF OURNAL

A JOURNAL SPECIFICALLY FOR AND BY RESIDENTS IN DERMATOLOGY A MERICAN O STEOPATHIC C LEEOF OLLEGE D ERMATOLOGY

Accepting Manuscripts from Dermatology Residents in AOA and ACGME Approved Residency Programs J ULY 2006

FOUNDING SPONSORS:ALLERGAN SKIN CARE • CONNETICS CORPORATION • GLOBAL PATHOLOGY LABORATORY • MEDICIS • STIEFEL LABORATORIES