Journal of the

American Osteopathic College

of Dermatology

Journal of the American Osteopathic College of Dermatology

Editors

Jay S. Gottlieb, D.O., F.O.C.O.O.Stanley E. Skopit, D.O., F.A.O.C.D.

Associate Editor

James Q. Del Rosso, D.O., F.A.O.C.D.

Editorial Review Board

Earl U. Bachenberg, D.O. Richard Miller, D.O.Lloyd Cleaver, D.O. Ronald Miller, D.O.Eugene Conte, D.O. Evangelos Poulos, M.D.Monte Fox, D.O. Stephen Purcell, D.O.Sandy Goldman, D.O. Darrel Rigel, M.D.Gene Graff, D.O. Robert Schwarze, D.O.Andrew Hanly, M.D. Michael Scott, D.O.Cindy Hoffman, D.O. Eric Seiger, D..ODavid Horowitz, D.O. Brooks Walker, D.OCharles Hughes, D.O. Bill Way, D.O.Daniel Hurd, D.O. Schield Wikas, D.O.Mark Lebwohl, M.D. Edward Yob, D.O.Jere Mammino, D.O.

2003-2004 OFFICERS

President: Stanley E. Skopit, DO President-Elect: Ronald C. Miller, DO

First Vice-President: Richard A. Miller, DO Second Vice-President: Bill V. Way, DO

Third Vice-President: Jay S. Gottlieb, DO Secretary-Treasurer: James D. Bernard, DO

Assistant Secretary-Treasurer: Jere J. Mammino, DOImmediate Past President: Robert F. Schwarze, DO

Trustees: Daniel S. Hurd, DOJeffrey N. Martin, DOBrian S. Portnoy, DODonald K. Tillman, DO

Executive Director: Rebecca Mansfield, MA

COPYRIGHT AND PERMISSION: written permission must be obtained from the Journal of the American Osteopathic College of Der-matology for copying or reprinting text of more than half page, tables or figures. Permissions are normally granted contingent upon sim-ilar permission from the author(s), inclusion of acknowledgement of the original source, and a payment of $15 per page, table or figureof reproduced material. Permission fees are waived for authors wishing to reproduce their own articles. Request for permission should

be directed to JAOCD c/o AOCD PO Box 7525 Kirksville, MO 63501Copyright 2003 by the Journal of the American Osteopathic College of Dermatology

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Journal of the American Osteopathic

2

AOCD1501 E Illinois Kirksville, MO 63501800-449-2623 FAX: 660-627-2623www.aocd.org

College of Dermatology

Journal of the American OsteopathicCollege of Dermatology

Volume 1, Issue 2 April 2004CONTENTS

Letter From The JAOCD Editors ....................................................................................................................................................................................4

Letter from the President of the AOCD............................................................................................................................................................................5

Osteopathic Medicine and Dermatology: The role of the D.O. in the prevention and treatment of skin disease ..........................................................6Robert A. Norman, D.O., MPH

Disorders of Cornification: The Multiplex Presentation of Ichthyosis ............................................................................................................................8Angela L. Phipps, D.O., B.S.N., R.N.

Disseminated Cryptococcosis in AIDS ..........................................................................................................................................................................12Igor Chaplik, D.O., Dr. Charles Gropper, M.D., Dr. Cindy Hoffman, D.O. , Dr. Richard Hwang, M.D.

Necrolytic Migratory Erythema in a Patient with Glucagonoma - A Case Report ........................................................................................................17Lynn M Sikorski, D.O., Michael Eyre, D.O., Ryan J Seaman, D.O.

Mastocytosis ..................................................................................................................................................................................................................20Robert A. Norman, D.O., MPH, FAAD.

Removable dirt and debris may be mistaken for true hyperpigmented skin lesions ......................................................................................................22Matthew T. Smetanick, Scott J.M. Lim, D.O.

Erythema Nodosum Caused by Celebrex ......................................................................................................................................................................24Steven L.Harlan M.D., Mary Evers D.O.

Treatment of Granuloma Annulare with Topical Tacrolimus 0.!% Ointment: A Phase IV Clinical Trial. ....................................................................25Paul M. Bedocs, D.O., Thomas E. Fleming, M.D., Mandi R. Motter R.N., Paul M. Bedocs, D.O.

Hailey-Hailey The Great Imitator ................................................................................................................................................................................29Robert A. Norman, DO, MPH, Joshua Dawalt, DO

Optimal Treatment of Onychomycosis: A Status Report on Oral Antifungal Therapy ................................................................................................33Marcus Goodman, B.S., MS-IV, James Q. Del Rosso, D.O., FAOCD

Observational Use of Pimecrolimus 1 % Cream: Clinical Results and Applications Based on a Large Private Practice Experience ..........................39Richard Diskin, D.O., James Q. Del Rosso, D.O., FAOCD, Saul Schreiber, D.O.

Local Reaction to Black Ink in a multi-colored Permanent Tattoo ................................................................................................................................42Scott J.M. Lim, DO, Joseph Nellis, BS

Tips For a Smooth Running Dermatology Practice........................................................................................................................................................44Jay S. Gottlieb, D.O., F.O.C.O.O.

Porokeratosis of Mibelli Occurring After Allogeneic Bone Marrow Transplant: A Case Report and Review of the Literature ................................49Risa Gorin, DO, Charles A Gropper, MD, Cindy F Hoffman, DO

Pharmacotherapy Review: Topical Tazarotene A Composite Review of Clinical & Research Experience With Focus on Optimal Use and Safety ..55James Q. Del Rosso, D.O., FAOCD

Segmental Variant of an Unusual Tumor: Case Presentation and Review of the Literature . ........................................................................................60Dan Ladd, D.O., Rick Lin, DO, MPH, Dermatology Residents, KCOM/Texas Division, Program Director: Bill V. Way, D.O.

Neonatal Lupus Erythematosus: Case Report and Review ............................................................................................................................................62Raymond A. Schwab, D.O.

3

Letter From The JAOCD Editors

Jay S. Gottlieb, D.O. Stanley E. Skopit, D.O. James Q. DelRosso, D.O.

As editors of the JAOCD it gives us great pride to say that this is our second issue of theJAOCD. From the feedback that we have received, the first issue was met with a warmwelcome and was considered a success by all. We want to thank the contributing authors andour inaugural corporate sponsors who have helped launch both the inaugural issue as well asthis current issue. We anticipate that all our readers will enjoy this second issue of the JAOCD.

The mission of the Journal of the American Osteopathic College of Dermatology remains tobetter serve the continuing educational needs of the AOCD members, residents and thedermatology community at large. The JAOCD will remain a vehicle for our residents to havethe opportunity for their required papers to be published during their residency program.

We will continue to include the following areas in the JAOCD: Dermatologic therapeutic modal-ities; Original presentation of research; Brief opinions; Clinical studies; Case reports; Basicscience as it relates to dermatology; Cutaneous surgery; Dermatopathology; Cosmetic derma-tology; Pharmaceutical dermatology; Editorials; Letters to the editors; Pearls and anecdotes indermatology.

Again, we extend our sincere appreciation to our Founding Sponsors:Allergan Skin Care, Connetics Corporation, Global Pathology LaboratoryServices, Novartis Pharmaceuticals Corporation, Medicis-The DermatologyCompany and 3M Pharmaceuticals. Without their continued support we wouldnot be able to have a journal to serve the AOCD.

The JAOCD is now online! Readers and authors may visit us at www.aocd.orgor e-mail us at jaocd@aol.com.

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. (Associate Editor)

4

JAOCD Founding Sponsor

5

Stanley Skopit, D.O., F.A.O.C.D.President

We have come along way since the inception of our college in 1957 when the AmericanOsteopathic College of Dermatology was recognized as a separate specialty within theAmerican Osteopathic Association. There are now over 300 members, 16 residencyprograms throughout the United States, training 62 residents. The AOCD is the organi-zation responsible for residencies and Continuing Medical Education nationwide.

The college organizes two national CME programs yearly. This year the annual meeting& scientific seminar of the AOCD took place October 2003 at the AOA convention inNew Orleans and the midyear program is scheduled for April 2004 in Tucson, Arizonaunder the Program Chair of Bill Way, D.O. at the host hotel, Hilton Tucson El Conquista-dor.

As President of the AOCD over the next year, my goals & objectives will revolve aroundthe current AOCD five year plan which serves as the College’s mission statement:1) Education & Awareness Programs lead to higher quality residency programs, CMEprograms & Public Awareness Programs through the public service awareness postercampaign; 2) Increasing membership opportunities for current & future meetings inorder to maintain unity with “strength in numbers” within the AOCD; 3) Dealing withchallenges that face our college & profession of Dermatology with regard to changes inour medical practice in the 21st century; 4) Diplomacy through efforts to gain the Ameri-can Academy of Dermatology as our ally in economic unity; 5) Maintaining & securingcorporate membership relations to help support our College financially; 6) Updating &maintaining the Administrative Policy Manual; 7) Establishing the AOCD foundation; 8)Pursuing of Fellowship by AOCD members are encouraged; and 9) Promoting the Jour-nal, JAOCD.

Stanley Skopit, D.O., F.A.O.C.D.

Osteopathic Medicine and DermatologyThe role of the D.O. in the prevention and treatment of skin disease

by Robert A. Norman, D.O., MPH

The role of osteopathy and osteopathictreatments in dermatology has receivedlittle attention. I will focus on a few keyareas and will provide the results of myexperience with using osteopathic tech-niques to improve care and save costs formy patients. Osteopathic techniques inthe general osteopathic exam, includingthe skin exam, and diagnosis, prevention,and treatment of wounds will bereviewed. By carefully studying andimplementing these findings, the practic-ing clinician can not only save his or herpatients much discomfort and costs butalso adhere to the practice and principleswhich form the basis of osteopathic medi-cine.

It is unfortunate when the pace andpressures of modern medicine discour-ages the practicing osteopathic specialistto incorporate the wonderful techniquesof osteopathy in his or her practice.Within dermatology, for example, it is pos-sible to simply prescribe one medicationafter another (dermatologists write moreprescriptions than any other practitioner)without looking into the skin signs of sys-temic disease or the powerful inherenttools we have to heal naturally. The tech-niques originally put in motion by Dr.Andrew Taylor Stil l can consistentlyinform the lives of all practitioners, nomatter how much one specializes.

Many of the basic skills of the osteo-pathic exam can truly shine in the derma-tological evaluation. Why is a patient’spsoriasis so flared at this point in time?Why now? Is there a particular stressgoing on in the patient’s life? All of thesequestions and more are essential for thegood dermatological history.

General Dermatology

The skin houses an enormous varietyof roadmarks for systemic disease. Thefirst clue of HIV infection is often theemergence of a skin disease. If the practi-tioner pays attention to the skin, earlydiagnosis and aggressive therapy arepossible.(1)

I have noted underlying osteopathicdysfunction in many patients complaining

of dermatological manifestations.

The definition of tissue texture abnor-mality (TTA) includes many of the signsfound in skin abnormalities, includingvasodilation, edema, fibrosis and thesymptoms of itching, pain, tenderness,and paresthesias (2). Types of TTA includethickening, stringiness, ropiness, firm-ness, and changes in temperature andmoisture. When examining the lowerextremities of patient, for example, manyof the signs and symptoms taught inosteopathy become apparent. A patientwith stasis dermatitis may complain ofitch and examination may reveal colorchanges, fibrosis, xerosis, increased tem-perature, and other symptoms of compro-mised circulation. Prime considerationsare improving blood flow including usingosteopathic techniques.

As Kelso et al have shown in their ther-mographic measurement research, warmskin areas of somatic dysfunction can bechanged by OMT (3). Adams et al exploredthe regional differences in palpatory char-acteristics of the skin when exploringabnormalities of tissue texture (4).

In 1938, SE Stanley wrote the article“General considerations of cutaneoustherapeutics: underlying causes shouldbe studied to insure greater success intreating skin conditions” in the journal TheOsteopathic Profession. In the article, Dr.Stanley points out that physicians tend toneglect seeking an etiology for skin dis-eases and skin manifestations and thatcorrect diagnosis involves not only nam-ing the disease but also seeking the etiol-ogy and developing a treatment plan onits basis. Dr. Stanley stated that osteo-pathic manipulation is the most valuabletreatment mode because it deals directlywith the circulation and nervous systemwhich is involved with skin disorders(5).Dr. AE Scardino noted in the article “Der-matology: discussion of common lesions:chemophysical therapy and manipulationefficacious for refractory skin diseases” inthe April 1942 The Osteopathic Profes-sion that osteopathic manipulation is rec-ommended for skin diseases since itdeals with motor and sensory nerve sup-ply and trophism (6).

Stasis dermatitis occurs with venousinsufficiency, pedal edema, and varicoseveins. The brownish color results fromhemosiderin deposition. The disease canlead to increased susceptibility to ulcera-tion or cellulitis. Acute exacerbation ofstasis dermatitis can result in “id” reactionor autosensitization dermatitis, producingsecondary, acute, papulovesicular, oftensymmetrical distribution on the extremi-ties.

Chronic venous insufficiency is due tovenous hypertension secondary to valvu-lar incompetence. Factors include heredi-tary, prolonged standing, venousthrombosis and may manifest as edema,varicosities, brown discoloration, superfi-cial neovascularization, dermatitis, andvenous ulcers. Therapy includes elevat-ing the legs, exercise, supportive stock-ings, surgery, mild to moderatecorticosteroids and oral antibiotics if sec-ondary infection is present.

Stasis dermatitis and chronic venousinsufficiency are two common dermato-logical conditions which can be improvedwith osteopathic evaluation and treat-ment. In a similar fashion to primary care,the task of the dermatologist and otherswho treat dermatological disease is oftenfilled with treating the external manifesta-tions of stress. Almost all skin diseaseappears to flare during exacerbations ofstress. Therefore, techniques acquiredduring osteopathic training of stressreduction, including OMT, and in manyinstitutions acupuncture, meditation, andother modalities, all can be used to treatour patients.

A holistic approach is crucial to achiev-ing comprehensive results. A skin spe-cialist can remove a skin cancer, butwould not being doing a complete job ifhe or she ignored the overall behaviorthat provokes unhealthy skin. Smokingcessation education in appropriatepatients, for example, is an integral partof patient care for all practitioners. We arefinding more and more evidence thatsmoking increases the incidence of skincancers, ulcers, and other skin abnormali-ties.

6 OSTEOPATHIC MEDICINE AND DERMATOLOGY

Education has always been a key com-ponent in the osteopathic physicians’armamentarium. Sun protection, such asusing sun block and wearing protectiveclothing, along with avoiding high inten-sity mid-day sun is crucial for our patients’wellness.

Wound Care Overview

A pressure ulcer is a localized area oftrauma resulting from lack of blood supplyto the involved tissues. Although manyfactors contribute to the development ofpressure ulcers, the four most critical arepressure, shearing forces, friction, andmoisture. Pressure results in ischemiaand tissue damage. Shearing forcesoccur when layers of tissue slide on eachother and twisting and stretching of bloodvessels results in subsequent ischemiaand damage. Friction is the force createdwhen two surfaces in contact moveacross each other, such as when apatient is pulled across the bed sheets,thus eliminating the outer protective stra-tum corneum and accelerating the ulcera-tive process. Moisture from urine, feces,wound exudate, or perspiration leads toskin maceration and increased risk ofulceration.

The vast majority of pressure ulcersoccur on bony prominences in the lowerpart of the body, with the sacral and coc-cygeal areas, ischial tuberosities, andgreater trochanters accounting for themajority of sites. Other frequentlyinvolved areas include the fibular head,malleolus, heel, and the medial condyleof the tibia.

The consequences of pressure ulcersare multiple and life-threatening. Ulcerscan be a source of sepsis andosteomyelitis, pyarthrosis, joint disarticu-lation, and systemic amyloidosis.

Chronic vs. Acute wounds

A chronic wound is defined as a loss intissue integrity produced by insult orinjury that is of extended duration or fre-quent recurrence. An acute wound is onein which simple medical or surgical inter-vention produces a resolution.

In homo sapiens, wound healing occursby repair vs. regeneration. Only hepaticand epithelial tissues are capable ofregeneration in man. In the toad, oblitera-tion of a limb can result in regenerating anew one identical to the original. In man,wounding that injures the dermis signalsthe body to restore the structural integrityvia the synthesis of new tissue differentthan the originally present. The type ofwound and mechanism by which thewound is closed depends on the extent of

injury and the type of tissue injured. Inchronic wounds, the healing time islonger and can be phased using markerssuch as the Clark model. Clark catego-rized healing into three phases--inflam-mation (from the moment of injury toapproximately four to six days postinjury), granulation tissue production (day4 to 21 and matrix formation and remod-eling (3 weeks up to 2 years). Key cellsin phase one include platelets, neu-trophils, lymphocytes, and epithelial cells.Macrophages play a crucial role in allthree phases. Fibroblasts are important inphase 2 and 3.

With superficial wounds, where only theepidermis or dermis is injured (partialthickness wound) may heal rapidly via theprocess of re-epithelialization. Epithelialcells migrate toward one another from theedges of the wound, from the hair folli-cles, sebaceous glands, and sweatglands and eventually close the wound.

Wound Recurrence factors

Chronic wounds often result from surgi-cal procedures, traumatic insults, ormetabolic, infectious, or neoplastic disor-ders. Pressure ulcers, diabetic ulcers,lower leg ulcers, vascular ulcers, post-operative open wounds, and enterocuta-neous fistulae are frequently occurringchronic wounds. Non-healing woundsgenerally occur in older individuals withmulti-system problems, poor medicalcare, and inadequate health habits.Chronic wounds often arise as a result ofdiabetes, cancer, liver, renal, or gastroin-testinal illness. Radiation trauma victims,transplant patients, and burn patientsoften suffer with chronic wounds. Drugtherapy such as steroids can make a per-son more prone to wound development.Obesity, smoking, poor nutrition, andimmobility can delay wound repair.

Given the many factors that predisposeour patients to chronic wound develop-ment, it is obviously crucial for any physi-cian or caregiver to carefully assess theirpatients and work on preventive strate-gies such as weight control, smoking ces-sation, proper nutrition, and appropriatedrug usage. Wounds represent an enor-mous burden to our patients’ economicand psychological well-being. The preva-lence of chronic non-healing wounds canonly be estimated. In 1989 in the UnitedStates, approximately 2,100,000 peoplehad pressure ulcers, 3,000,000 had dia-betic ulcers, 500,000 had vascular ulcers,6500 had open wounds or fistulae, for atotal of 5,606,500. The cost to heal a sin-gle pressure ulcer can range between$400 and $40,000 (7,8).

As an osteopathic practitioner, we canhelp in cost-saving efforts by practicing

good osteopathic skills in wound care.Evaluating areas of skin congestion withour palpatory skills can signal the clinicianto write orders to make sure the patient isturned off the congestion area, thus pre-venting further pressure and ulcers.

As part of my clinical investigationwhen writing this article, I examinedtwenty patients with previous documentedulcers for signs of osteopathic lesions,particularly in the sacroiliiac and lumbarareas. Of these twenty patients, twelvehad areas consistent with stage one ulcerformation.

By using osteopathic palpatory skills, Iwas able to document pre-ulcer condi-tions and review preventive findings withthe nurses on duty. Included were recom-mendations on proper nutrition, ambula-tion when possible, and circulationenhancing suggestions. In follow-ups sixand 12 months later, the results were dra-matic. Although one of the patients suc-cumbed to conditions unrelated to hisprevious wound problems, none of theremaining 11 patients had developed fur-ther ulcer formation. Two of the remainingpatients had stage two ulcer formation,and with osteopathic evaluation werereduced to stage one, and eventually alsocleared up. In addition, the nurse com-mented that the introduction of palpatoryskills into their caretaking regimen helpedimprove the condition of all their patients.

In summary, osteopathy and osteo-pathic treatments play a crucial role indermatology. I hope this article triggersother specialists to examine the funda-mental importance of osteopathic princi-ples in helping their patients achievemaximum benefits.

References1. Kurgis BS Skin Manifestations of human immunodeficiency

virus (HIV) Part 2 Noninfectious skin manifestations Jour-nal of the American Osteopathic Association 93 (2):223-9,1993 Feb

2. Foundations for Osteopathic Medicine P.1139 Ward RC et al Williams and Wilkins

3. Kelso AF Grant RG Johnston WL Use of thermograms tosupport assessment of somatic dysfunction or effects ofosteopathic manipulative treatment: preliminary reportJournal of the American Osteopathic Association 82 (3):182-188, 1982 Nov

4. Adams T Steinmetz MA Heisey SR Holmes KR Green-man PE Physiological basis for skin properties in palpa-tory physical diagnosis Journal of the AmericanOsteopathic Association 1982 March; 81 (7): 441.

5. Stanley SE General considerations of cutaneous therapeu-tics: underlying causes should be studied to insure greatersuccess in treating skin conditions The Osteopathic Pro-fession 1938 Jan; Vol 5 issue 4 pages 22-27, 46, 48.

6. Scardino AE Dermatology: discussion of common lesions:chemophysical therapy and manipulation efficacious forrefractory skin diseases. The Osteopathic Profession 1942Apr Vol 9 issue 7 18-21, 42

7. Norman, R How to Manage Wounds in Long-Term CarePatients Skin and Aging (The Journal of Geriatric Derma-tology) October 1999 pp 50-56

8. Norman, R Handling Chronic and Acute Wounds in AgingSkin (Panel Discussion) Skin And Aging (The Journal ofGeriatric Dermatology) November 1999 pp 65-69

NORMAN 7

8 DISORDERS OF CORNIFICATION: THE MULTIPLEX PRESENTATION OF ICHTHYOSIS

Ichthyosis Vulgaris

Description and Epidemiology:

Ichthyosis Vulgaris (IV) is a disorder ofcornification that presents with a veryfine, “collaret” scale that appears “pasted-on” over the entire cutaneous surface. Ithas an autosomal dominant inheritancepattern and is characterized by onset inearly childhood, usually between 3 and12 months of age.4, 5, 6

This common condition occurs inapproximately 1:250 to 1:500 persons.3, 4

Pathogenesis:

IV is a retention hyperkeratosis withnormal epidermal proliferation. The ker-atinocytes are unstable due to the defectin the keratohyaline granule’s major pro-tein- profillagrin.3 Standard skin biopsiesstained with hematoxylin and eosin ofpatients with IV show a granular layer thatis diminished to absent.2 ,3, 7 The kerato-hyalin granules appear spongy or frag-mented on electron microscope (EM).5, 6

This correlates with reduced profilag-grin expression. Filaggrin is notdetectable in the involved epidermis.5, 8 Nogene defect for reduced profilaggrin hasbeen found to date.2

Clinical Aspects:

Children with full-blown IV have finewhite scales from the neck to the ankles,sparing the axillary and gluteal folds(where humidity is higher). The face isalso usually spared (where the seba-ceous glands help to control scaling).3

The extensor surfaces of the extremitiesare most prominently involved.4, 5 Varyingdegrees of dryness of the skin may beevident. The scales are coarser on the

lower extremities having a lizard-likeappearance. Finer scales are seen on thetrunk that resembles small bran flakes.The palms often are dry and show hyper-keratosis and accentuated skin markingsreferred to as “hyperlinear palms.”3, 5 Ker-atotic lesions (keratosis punctata) may befound on the palmar creases.9 The scalpis involved with only slight scaling.5

The hair, teeth, and nails are normal.3

IV is frequently seen in association withatopic dermatitis and keratosis pilaris.Although the antecubital and poplitealfossae are usually spared by IV, atopicchanges may be present. Atopy mani-fested as hay fever, eczema, asthma, orurticaria is frequently present.2, 5

Laboratory:

A skin biopsy from a patient with IV willdisplay an absent granular layer. The EMfinding of abnormal keratohyalin granulesis the gold standard in making the diagno-sis.6

Prognosis:

The course of IV is favorable. It usuallyimproves in the summer and in warm,moist environments. It tends to improvewith age and has limited findings by thetime the patient is an adult.6

Therapy/Management:

IV can be controlled but not cured. Theinitial step is to hydrate the stratumcorneum and seal in the moisture. Simplesoaking in warm water followed quickly byapplication of a thick, greasy moisturizingcream or ointment is sufficient for mostpatients. Soaking twice daily is prefer-able, as long as sufficient moisturizingcream or ointment is applied immediatelyafter the bath.

Moisturizers that are available in jarsand scooped out with the fingers workbest. This includes petroleum jelly andeven vegetable shortening. More elegantsolutions include mild keratolytic agents(salicylic acid), alpha hydroxyl acids orpropylene glycol.3 Keratolytics helploosen the upper layer of scales and pro-mote shedding. Alpha hydroxy acids (lac-tic, citric, and glycolic) are simple,organic, hydroscopic acids that bothhydrate the skin and cause the skin cellsto detach. It is important to note thatalpha hydroxy acids sting and that mostchildren do not tolerate them. Whenapplied to the entire cutaneous surface,any acid preparation can cause acidosisin neonates and, therefore, should not beused.3

X-linked Ichthyosis

Description and Epidemiology:

X-linked Ichthyosis (XLI) is anotherdisorder of cornification that can clinicallybe difficult to distinguish from IV depend-ing on the severity. However, XLI typicallypresents with a larger, coarser, dirtyappearing, brown scale. It is more promi-nent on the anterior neck, extensor sur-facesof the extremities, and the trunk.This is an uncommon form of ichthyosisthat occurs only in males.3-6 The inci-dence ranges from 1:2000 to 1:6000births with onset usually before 3 monthsof age.2, 3, 6 The mother is an obligateheterozygote. Spontaneous partuition hasoften failed to occur when these patientswere born, owing to a placental sulfatasedeficiency.5, 10

Pathogenesis:

XLI is due to a deletion error of the X

Disorders of Cornification: The Multiplex Presentation of Ichthyosis

Angela L. Phipps, D.O., B.S.N., R.N.

Abstract

The term ichthyosis is derived from the Greek word icthys meaning fish.1 The ichthyoses are a heterogeneous group of diseasesthat share one presentation: scaly skin. The outermost layer of the skin that is contiguous with the environment is the epidermis.The cell kinetics of the epidermis are altered with the ichthyosiform disorders and results in the clinical appearance of skin thatresembles the scales of a fish. The keratinocyte is the principle cell of the epidermis.2 The ichthyoses represent abnormalities inthe formation and desquamation of these keratinocytes. The keratinocyte has a specialized function to produce filamentous pro-teins called keratins that form the structural framework inside the cell. To understand the ichthyoses, one must be familiar with theinternal to external progression of normal skin.3 In this progression, the keratinocytes progress through the epidermal layers (stra-tum basalis, stratum spinosum, stratum granulosum, stratum corneum) manufacturing proteins in a predictable sequence. Errors inthis manufacturing process will result in mutations that alter the skin’s physical appearance and function.

PHIPPS 9

chromosome at Xp22.3.2-6, 11, 12 This dele-tion resultsin a deficiency of the enzymesteroid sulfatase in the patient’s fibrob-lasts, leukocytes, and keratinocytes.Without the presence of the enzymesteroid sulfatase, cholesterol sulfateaccumulates causing the abnormal corni-fication.5

Clinical Aspects:

In patients with XLI, desquamation ofthe skin is seen within a few weeks ormonths after birth.

Dark brown scaling of the extensorsurfaces of the arms and legs, trunk, andespecially the sides of the neck areobserved. The scales are tightly adherentto the skin. The parents will report anunwashed look to the child’s skin and willoften vigorously scrub these regions to tryand remove the “dirt.” The elbow andknee flexures are relatively spared, as arethe central face and scalp.

Scaling can be seen around the earsand lateral cheeks. The palms and solesare nearly always spared. Hair, nails,teeth, and mucous mucosa are notaffected. The classic areas of involve-ment are the lower abdomen and sides ofthe neck. Marked seasonal variation isseen and warm weather ameliorates thescale. Placental sulfatase is needed forlabor to progress. Some mother’s reportprolonged labor or failure to initiate laborwhen carrying children afflicted with XLI.2-

6, 10

In contrast to IV, keratosis pilaris is notseen and the incidence of atopy is notabnormally high.5

Punctate corneal opacities and cryp-torchidism are the hallmark extra cuta-neous manifestations associated withXLI. Slit lamp examination will revealpunctate corneal opacities on the poste-rior capsule or Descent’s membrane inapproximately 50% of affected males andfemale carrier mothers.1 3 , 1 4 Cryp-torchidism is noted with a 12-15% inci-dence and an independently increasedrisk of testicular cancer.5, 15, 16 Patientsaffected by XLI also have a reduction ofsweat glands and a decrease in sweatproduction.17

Laboratory:

With XLI, the clinical differentiationfrom Ichthyosis Vulgaris (IV) at times maybe difficult. The diagnosis of XLI can bemade or confirmed by lipoprotein elec-trophoresis. The increase in cholesterolsulfate makes the LDL migrate muchmore rapidly. However, this test is difficultto obtain.5 The decrease in steroid sulfa-tase can be measured by three methods:(1) enzyme assays, (2) cholesterol sulfate

accumulation in various tissues, and (3)fluorescent in situ hybridization (FISH)test.3 The reduced enzyme activity canbe assessed in fibroblasts, keratinocytes,leukocytes, and prenatally in amniocytes.5

If the gene deletion is known, the FISHtest is useful for prenatal diagnosis.3, 18

The blood test for excess cholesterol sul-fate is the most reliable method foraffected males.2

Prognosis:

X-linked ichthyosis is a lifelong condi-tion that does not improve with age.Unlike IV, it can gradually worsen in bothextent and severity. However, it is notdebilitating and should not adverselyaffect normal life activities.3, 5

Therapy/Management:

Patients with XLI should have a thor-ough examination by a pediatrician.Referral to a dermatologist is indicated fortopical emollient treatment. The besttreatment, if tolerated, is to wear a plasticspacesuit as a pajama to bed after appli-cation of propylene glycol (40-60%) inwater to the entire body. The patientshould do this very night until the excessscales come off (usually 5-7 nights) andthen as needed. Once-a-week use of thesuit can keep skin clear.

If the patient is symptomatic or cryp-torchidism is present, a pediatric urologyreferral is indicated.6

Lamellar Ichthyosis

Description and Epidemiology:

Lamellar means arranged in multiplelayers or plate-like.3 This ichthyosiformdisorder is characterized by large (5 to15mm), grayish brown scales that arequadrilateral in shape. They are adherentin the center and free at the edges.5

Lamellar Ichthyosis (LI) is inherited as anautosomal recessive trait. It is a rareoccurrence with an incidence of approxi-mately 1:200,000 to 300,000 live births.The onset of LI is at birth.2- 6

Pathogenesis:

LI is due to mutations in the transgluta-minase 1 gene.2-4, 19, 20 Transglutaminasesare a large group of enzymes that cat-alyze transamination of glutamineresidues. This is necessary in a variety ofprocesses including blood clotting, cyto-plasmic destruction of the skin cells(apoptosis), formation of hair follicles, fer-tilization, and keratinization of skin.3

Transglutaminase controls the cross- link-ing of cell envelope precursor proteins.3, 4,

21 The LI phenotype is proposed to resultfrom the incomplete cross-linking of theseprecursor proteins, producing an abnor-

mal cell envelope.

Ultrastructurally, this is supported bythe fact that LI displays a thin or absentcell envelope.4, 22

At least three gene loci have beenfound for transglutaminase.3 The specifictransglutaminase 1 genes are heteroge-neous chromosomes 14q11 and 2q33-35.4, 5, 6, 20

Clinical Aspects:

Children who have LI usually presentwith a collodion-like membrane thatencases the baby at birth. This mem-brane usually desquamates over the first2 to 3 weeks of life. The scales with LI arelarge, thick, grayish-brown in color, andaffect the entire cutaneous surface. Insevere cases, the scales may be so thickthat they are like armor plates.2- 6 Moder-ate hyperkeratosis of the palms and solesis frequently present. The follicles in mostinstances have a crateriformappearance.5

Ectropion (turning out of the lower eye-lid) is almost always present with LI andis a helpful diagnostic sign. The red rim ofthe ectropion along the lower eyelid isdistinctive and gives the eyes a constant“rheumy” look. Facial tautness isaccented by eyelids and lips that arepulled out, corneal drying and attendantproblems. The hair becomes matteddown and sparse, and the nails can bedystrophic Sweat ducts are obstructedand can lead to hyperpyrexia in hot cli-mates or during exercise. Patients oftenhave profound hypohidrosis and theirpotential for heat shock can be high.23

Because the skin is inelastic, fissuresdevelop over the joints causing painfulopening and superficial skin infections. Insome cases, contracture deformities ofthe joints occur.2

Laboratory:

The histopathology of LI shows hyper-keratosis and a markedly thickened gran-ular layer, in contrast to the diminishedgranular layer of IV. Research laborato-ries have in vitro assays for transglutami-nase 1 on fresh skin sections. Electronmicroscopy is useful in detecting thepresence or absence of the marginalband.3

Prognosis:

LI is a lifelong condition with littlechange. It does not affect intellect or lifes-pan. Once the psychological effects ofaltered body image are overcome, thereis no reason that patients cannot be con-tributing members of society.3

Therapy/Management:

Topical therapy with aggressive mois-turization to keep the skin plasticized isthe mainstay of treatment. Alpha hydroxyacids, urea-based creams, and propyleneglycol can be used.

Applications are needed several timesdaily. Remember that the neonate has ahigh surface area to volume ration andabsorption of total body application ofacid-based creams can cause systemicacidosis. In systemic treatment, oralretinoids provide marked relief for LI.They help relieve the thick scale, but theydo not change the underlying pathology.Side effects of long-term retinoid use andissues of teratogenicity prohibit unre-stricted use. Only physicians who are wellacquainted with their risks and benefitsshould prescribe oral retinoids.3, 6

Congenital Ichtyosiform Erythroderma

Description and Epidemiology:

Congenital Ichthyosiform Erthroderma(CIE) is also known as Nonbullous CIE.2-6

It has a presentation of fine white scalesover the entire body with widespread ery-throderm of variable intensity.4 Patientswith CIE are often born as collodionbabies and may initially be indistinguish-able from infants with lamellar ichythosis(LI).1 CIE is an autosomal recessiveichthyosis with an unknown gene locus. Ithas an incidence of 1:180,000 live births.It ismore common than LI, and there is anequal male to female ratio. The onset ofCIE is at birth.4, 6

Pathogenesis:

The exact pathogenesis of CIE isunknown. There is an accelerated epider-mal turnover rate with increased n-alka-nes. This was previously thought to play arole, but has been found to be secondaryto exogenous emolliation.6

Clinical Aspects:

Most infants with CIE are bornenclosed in a constricting parchment-likeor collodion-like membrane that limitsmotion. Within 24 hours the skin begins tofissure and peel with large keratinouslamellae being cast off in 10 to 14 days.The underlying skin reveals redness andscales.5 During infancy these patientsdevelop generalized erythroderma withfine, white scales over the entire body.Generalized involvement is the rule,including face, palms, soles, and flexures.The legs may show large plate-likescales, but the rest of the body displaysthe characteristic fine, white scales. Thehair has cicatricial alopecia and nail dys-

trophy may also be present.4, 5, 6 Theeyes, like LI, often show ectropion andeclabion.

Laboratory:

When compared to LI, CIE has a morestriking parakeratosis. Radioactive label-ing indices of >15% clearly delineate CIEas a hyperproliferative keratosis and sep-arate it from LI, which displays normalkinetics.24 Ultrastructurally, CIE displaysmany distinctive features.

The epidermis has numerous lipiddroplets in the corneocytes with largenumbers of small lamellar bodies thathave abnormal dimensions and basic unitpatterns. The increased lamellar bodiesof CIE are characteristic of hyperprolifera-tive disorders and are another distin-guishing feature.4

Prognosis:

CIE usually has an unremitting coursebut it may improve at puberty.6

Therapy/Management:

The newborn with CIE needs to betransferred to the neonatal intensive careunit. They need to be monitored for fluidstatus, electrolyte stability, and sepsis. Ahigh-humidity chamber or maintaining ahumid environment in the isolette is nec-essary. Simple emollients are safest dur-ing the exfoliative stage for the newbornand the use of keratolytics should beavoided.

For the older child or adult, the treat-ment of CIE is the same as LI. It consistsof emollients, retinoids, and keratolytics.Additionally, calcipotriol has been shownto enhance differentiation, but does notreduce proliferation.3, 4, 6 In a high turnoverichthyosis like CIE, one should monitorforanemia and treat with iron supplements ifiron deficient. In kids that are failing tothrive and erythrodermic, the protein intheir diet should be increased.6

Epdermolytic Hyperkeratosis

Description and Epidemiology:

Epidermolytic Hyperkeratosis (EH) isalso known as bullous congenitalichthyosiform erythroderma.2- 6 Onset isevident at birth or soon thereafter withblistering and erythroderma.

When ruptured, the blisters leave ten-der denuded skin that is commonlyinfected with streptococcus or Staphylo-coccus aureus. EH is an autosomal domi-nant disorder of cornification.

It has a prevalence of 1:100,000-300,000. At least 50% of cases of EH are

sporadic and are thought to representnew mutations.4 There is linkage to chro-mosome 12q and 17q, along with KeratinK1 and K10 gene mutations. There is anequal male to female ratio.6

Pathogenesis:

EH is due to an error in synthesis ofthe epidermal keratins 1 and 10 which arefound in the upper spinous to granularlayers. The phenotypes differ slightlydepending on the defect, with keratin 1defects causing palm and sole bullae.The intraepidermal blistering seen in EHis due to abnormal keratin filament forma-tion that leads to an abnormal cytoskele-ton, resulting in mechanical fragility. Inaddition, the desmosomal attachmentsare imperfect, which leads to blister for-mation.4

Clinical Aspects:

Newborns present with red, scalylesions, widespread bullae, erythroderma,and areas of denuded skin. The blistersare superficial (in the upper epidermis)and, therefore, do not scar. Neonatalhyperkeratosis may be present, but it canbe subtle. After the neonatal period, theblistering lessens (but does not disap-pear), and the hyperkeratosis becomemore obvious. The scale in EH is a dis-tinctive porcupine-like quill that is thick-ened, horny, warty and ridged involvingtheentire body. These thick, grayishbrown, sometimes verruciform scalesprominently involve the flexures and theintertriginous areas. These areas areespecially prone to excessive moistureand maceration, which lead to chronicbacterial overgrowth. This colonizationproduces a foul odor that is often quitedistressing to the patient. Other parts ofthe skin may be involved, but to a lesserextent. There is remarkable heterogene-ity, particularly in regard to extent of bodysurface involvement, presence orabsence of erythroderma, and palm andsole involvement. Nails may be dys-trophic and hair is normal.3, 4, 5

There are several variants of EH: bul-lous ichthyosiform erythroderma of Frocq,ichthyosis hystrix Curth-Macklin type, andichthyosis bullosa of Siemens. Bullousichthyosiform erythroderma of Brocq isthe classic form of EH described above.Ichthyosis hystrix Curth-Macklin type mayresemble EH both clinically and histologi-cally, but it does not display blistering.4

Several advances have been made indefining ichthyosis bullosa of Siemens asa distinct entity. Clinically, it resemblesEH, but the hyperkeratosis is milder andgenerally confined to the extremitites.4

This condition is characterized by a lackof erythema, the “masering phenomenon”

10 DISORDERS OF CORNIFICATION: THE MULTIPLEX PRESENTATION OF ICHTHYOSIS

(a superficial molting or peeling of theskin), and confinement of the epider-molytic change to the superficial layers ofthe epidermis.5

Laboratory:

The histologic picture of EH is distinc-tive, but not pathognomonic. Hyperker-atosis is marked.

The granular layer is markedly thick-ened and contains coarse keratohyalinegranules. Epidermal cells detach in thegranular cell layer. EM reveals the forma-tion of perinuclear haloes. These findingsallow prenatal diagnosis by fetal skinbiopsy.5, 25

Prognosis:

EH is a lifelong condition with a normallife expectancy. Generalized involvementmay improve to localized disease afterpuberty.3,6

Therapy/Management:

Newborns who exhibit bullae can haveproblems with fluid and electrolyte imbal-ances as well as sepsis. They should bemanaged in the intensive care unit with IVbroad-spectrum antibiotics until culturesare negative, gentle handling to preventfurther blistering, and protective isolation.Beyond the neonatal period, hyperkerato-sis and foul odor are the two primaryproblems. Simple soaking in water, scrub-bing, and after-bath greasing can soften

and remove many quills. Topical retinoicacids and/or alpha-hydroxy acids (10%glycolic acid lotions) are helpful, but thelarge body surface areas that must betreated and expense make these thera-pies prohibitive. Topical propylene glycolic(10% to 50% in water) is a less expensivealternative. It is applied under occlusion ifpossible, and the saturated scales fall offin the next bath. Use of oral retinoids isassociated with mixed results; sometimesblistering is increased while scale isdecreased. Avoid chronic oral antibioticsto prevent growth of resistant organisms.Emolliation and control of odor withantibacterial medication are the main-stays of therapy.3, 6

References:1. Schwayder T, Ott F. All about ichthyosis. Pediatr Clin North

Am 1991; 38:835-8572. Odom RB, James WD, Berger TG. The Skin: Basic Struc-

ture and Function. Andrews’Diseases of the Skin 9th ed. Philadelphia: WB Sanders; 2000.pp 1-6 3. Schwayer T. Ichthyosis in a nutshell. Pediatrics in Review

1999; 20:5-124. Ammirati CT, Mallory SB. The Major Inherited Disorders ofCornification Dermatol Clin 1998; 16(3):497-5065. Odom RB, James WD, Berger TG. Some Genodermatoses

and Acquired Syndromes.Andrews’ Diseases of the Skin 9th ed. Philadel-

phia: WB Sanders; 2000. pp 701-7066. Spitz JL, editor. Genodermatoses Baltimore: Williams &

Wilkins; 19967. Fleckman P. Absence of the granular layer and kerato-

hyalin define a morphologically distinct subset of individualswith ichthyosis vulgaris. Exp Dermatol 2002; 11(4):327-3368. Presland RB. Loss of normal profilaggrin and filaggrin in

flaky tail mice: an animal model for the filaggrin-deficient skindisease ichthyosis vulgaris. J Invest Dermatol 2000;115(6):1072-10819. Just M, Ribera M, Bielsa I, Calatrava A, Ferrandiz C. Ker-

atosis punctata of the palmar creases: report of two casesassociated with ichthyosis vulgaris. Br J Dermatol 1999;141(3):551-55310. Lykkesfeldt G, Neilsen MD, Lykkesfeldt AE. Placentalsteroid sulfatase deficiency-biochemical diagnosis and clinicalreview. Obstet Gynecol 1984; 64:49-5411. Gohlke BC. Interstitial deletion in Xp22.3 is associated withX linked ichthyosis, mental retardation, and epilepsy. J MedGenet 2000; 37(8):600-60212. BallabioA, Parenti G, Carollo R, et al. Isolation and charac-terization of a steroid sulfatase cDNA clone: genomic deletionsin patients with X-chromosome linked ichthyosis. Proc NatlAcad Sci USA 1987; 84:4519-452313. Haritoglou C, Ugele B, Kenyon KR, Kampik A. Cornealmanifestations of X-linked ichthyosis in two brothers. Cornea2000; 19(6):861-86314. Kempster RC, Hirst LW, de la Cruz Z, et al. Clinicopatho-logic study of the cornea in X-linked ichthyosis. Arch Ophthal-mol 1997; 115:409-41515. Al Jasmi F. X-linked ichthyosis and undescended testes.Int J Dermatol 2002; 41(9):614-61616. Lykkesfeldt G, Hoyer H, Lykkesfeldt AE, et al. Steroid sul-fatase deficiency associated with testes cancer. Lancet 1983;2:145617. Delfino M, De Ritis G, Fabbrocini G, Procaccini EM, IllianoGM, Piccirillo A. Sweat gland function in patients with X-linkedichthyosis. Recenti Prog Med 1991; 82(12):677-67818. Valdes-Flores M, Kofman-Alfaro SH, Jimenez-Vaca AL,Cuevas-Covarrubias SA. Carrier identification by FISH analy-sis in isolated cases of X-linked ichthyosis. Am J Med Genet2001; 102(2):146-14819. Cserhalmi-Friedman PB, Milstone LM, Christiano AM.Diagnosis of autosomal recessive lamellar ichthyosis withmutations in the TGM1 gene. Br J Dermatol 2001; 144(4):726-73020. Russel LJ, Digiovanna JJ, Hashem N, et al. Mutations inthe gene for transglutaminase 1 in autosomal recessive lamel-lar ichthyosis. Nat Genet 1995; 9:279-28321. Jeon S, Djian P, Green H. Inability of keratinocytes lackingtheir specific transglutaminase to form cross-linked envelopes:absence of envelopes as a simple diagnostic test for lamellarichthyosis. Proc Natl Acad Sci USA 1998; 95(2):687-69022. Hohl D, Huber M, Grenk E. Analysis of the cornified cellenvelope in lamellar ichthyosis. Arch Dermatol 1993; 129:222-22723. Baden H. Keratinizing Disorders. Genetic Disorders of theSkin St. Louis: Mosby; 1991. pp 170-19424. Hazell M, Marks R. Clinical, histologic and cell kinetic dis-criminates between lamellar ichthyosis and nonbullous con-genital ichthyosis erythroderma. Arch Dermatol 1985;121:489-49325. Ackerman AB. Histopathologic concepts of epidermolytichyperkeratosis. Arch Dermatol 1970; 102:253-259

PHIPPS 11

Cryptococcus neoformans is an encap-sulated yeast like fungus. Strains aregrouped into two varieties that includefive serotypes known as C. neoformansvariety neoformans (serotypes A, D, andAD) and C. neoformans variety gattii(serotypes B and C). The serotype differ-ences reflect antigenic differences in thestructure of the capsular polysaccharide.C. neoformans var. neoformans is foundthroughout the world in association withexcreta from certain birds includingpigeons, chickens, canaries, and cocka-toos, as well as contaminated soil, fruits,and milk1. C. neoformans var. gattii isfound primarily in tropical and subtropicalregions and has been associated withseveral species of eucalyptus trees. Inorder to cause disease in humans, thefungus must be inhaled into the lungs,although a small percentage of patientscan develop primary cutaneous crypto-coccus after direct implantation.2,3

Case Report

A forty one year old African Americanmale was admitted to the hospital forfever, cough, groin swelling, and anasymptomatic skin rash for the last threemonths. He is an intravenous heroin drugabuser and is presently homeless. Hisimmune status and past medical history isunknown, he denies allergies to medicine,and is presently not taking medication.He has received cryotherapy for his rashat a local clinic. Upon further questioning,the patient admits to intermittentheadaches, weakness, shortness ofbreath, and a twenty-pound weight lossover the last month.

The physical exam revealed a cachec-tic, febrile patient with a temperature of102.4ºF. He was breathing rapidly at 22breaths per minute, and his heart ratewas 76. His blood pressure was 90/66.His skin exam revealed several, discrete,dome-shaped, some umbilicated, papuleson the abdomen and chest. Also presentwere several, hyperpigmented, scalyplaques on his abdomen and chest. (Fig.1 and 2). Bilateral inguinal and axillarylymph nodes were palpable. Auscultation

of the lungs revealed bilateral rales andrhonchi.

Due to the constellation of findings, anHIV test was performed, a PPD placed, afull sepsis work-up initiated, and a skinbiopsy performed. The working differen-tial diagnosis was that this patient wasimmunocompromised and that a commu-nity acquired pneumonia, tuberculosis, oran opportunistic pathogen were causinghis symptoms. The dermatological pre-sentation coupled with systemic findingsadds to the possibility that an organismthat causes molluscum-like lesions suchas Histoplasma capsulatum, Coccidioidesimitis, Penicillium marneffei, or Cryt-pococcus neoformans had disseminatedto the skin and possibly other organs.

Subsequently, the patient was placedon empiric treatment with intravenous flu-conazole, ceftriaxone, azithromycin, andfluid replacement. The patient’s completeblood count revealed a white count of8600, with 84.9% neutrophils. His hemo-globin was low at 10.2 g/dl and his hema-tocrit low at 31.1%. The patient wasfound to be HIV positive, with a CD4 < 20cells/microliter and an RNA by PCR of69965 copies/ml. His skin biopsyrevealed numerous organisms of varioussizes surrounded by capsules, whichstained positive with mucicarmine in thesuperficial and deep dermis, with very lit-tle inflammatory response. (Fig 3,4) HisChest X-ray and CT scan revealed bilat-eral pulmonary infiltrates suggestive ofseptic emboli vs. malignancy and medi-astinal and hilar adenopathy. His bloodculture grew out a fungus, which waslater identified to be Cryptococcus neo-formans. Also, the patient’s serum waspositive for cryptococcal antigen at a titerof 1 to 4096. Furthermore, a CT scan ofthe brain with contrast showed nonen-hancing hypodensities in the right thala-mic nuclei, corpus collosum, and rightoccipital lobe. A CSF analysis was sub-sequently obtained and revealed an ele-vated protein of 53 mg/dl, no WBC’s, and19 RBC/mm3. The CSF fluid was posi-tive for an India ink preparation and theCSF culture also grew Cryptococcus neo-

formans. A lymph node biopsy revealedmassive amounts of organisms thatexpand nodal sinuses and stain positivewith mucicarmine. (Fig 5) During thecourse of his hospitalization, the patientbecame hypoxic and a bronchoscopy withalveolar lavage was performed. Thepatient’s lavage specimen containednumerous organism that stained positivewith mucicarmine, and grew out Crypto-coccus neoformans and Aspergilllusfumigatus. (Fig. 6) Despite the additionof intravenous amphotericin B and venti-latory support, the patient succumbeddue to respiratory failure and overwhelm-ing cryptococcal infection.

Comment

When Cryptococcus is inhaled throughthe lungs, the infection is either entirelycleared by the host, becomes dormant, orbecomes an acute infection that may sys-tematize. The direction and outcome ofthe infection depends on the complexinterplay between the immune system,the virulence of the fungus, and the sizeof inoculum. The host’s immune statusappears to be the most important factor indetermining outcome and a healthy hostis usually able to contain the fungi with abrisk and effective immune response.This response relies mostly on T-cellmediated immunity and granulomas areformed to wall of the infection, similar tothe primary complex seen Mycobac-terium tuberculosis.4,5 Because HIV pre-dominantly infects T cells, fungemia andsubsequent dissemination is strikinglycommon in the compromised host, partic-ularly when the T helper count falls below100 cells/micrometer.5 In fact, severalstudies show that even those who aredirectly exposed to C. neoformans, suchas healthy lab workers in cryptococcusresearch facilities, rarely develop sympto-matic infection despite testing positive ondelayed hypersensitivity skin tests.6 Animmunocompromised host, as in thiscase, is much more likely to developacute and chronic infection. Rates ofcryptococcosis in non-HIV patientsapproach 1 in 100,0007, whereas cases inHIV infected patients approaches as high

12 DISSEMINATED CRYPTOCOCCOSIS IN AIDS

Disseminated Cryptococcosis in AIDS

Igor Chaplik, D.O. St. Barnabas Hospital. Chief Resident DermatologyDr. Charles Gropper, M.D. St Barnabas Hospital. Chief of Dermatology

Dr. Cindy Hoffman, D.O. St Barnabas Hospital. Dermatology Program DirectorDr. Richard Hwang, M.D. St. Barnabas Hospital. Staff Pathologist.

Cryptococcus Neoformans is an opportunistic pathogen that frequently presents with skin findings. Pulmonary complaints coupledwith signs of disseminated disease, such as skin or CNS findings should alert the physician to the possibility of cryptococcosis. Onesuch patient is presented, along with the diagnostic, therapeutic, and prognosticating factors that influence decision making in suchpatients.

as 13.3%8 in some large U.S. cities.Patients with cancer9, organ transplants10,chronic steroid therapy11 systemic lupuserythematosus12, and multiple myeloma12

are also at an increased risk of develop-ing disease. Co-infection with otherpathogens is not uncommon and was afactor in the patient presented. Althoughthere is no characteristic x-ray finding,single or multiple nodules are the mostcommonly encountered and are oftenconfused with tumor.13 Radiographic find-ings of single or multiple nodules, mass-like infiltrates, pleural effusions,cavitation, and hilar adenopathy have allbeen reported.13

From the lungs the fungus can infectany organ system via the bloodstream,the skin being the second most commonsite.5 Cryptococcal dissemination to theskin occurs in 10-20% of patients and isoften the presenting sign of disease.14

Cutaneous manifestations of dissemi-nated disease are protean and most com-monly occur on the head and neck.15

Although molluscum-like lesions are themost common; acneiform lesions, pur-pura, vesicles, tumors, abscesses, oraland genital ulcers, granulomas, plaques,sinus tracts, cellulitis, subcutaenous nod-ules, and HSV-like lesions have all beenreported.14,16,17,18,19 Direct cutaneous crypto-coccosis caused by traumatic implanta-tion is rare and produces solitary nodulesthat ultimately break down or ulcerate.3,6

Lymphadenopathy may or not be present.Biopsy specimens will often show twotypes of histological patterns: gelatinousand granulomatous. This patient’s biopsyconsisted of the gelatinous type, whichproduces little inflammatory reaction andnumerous organisms (4 to 12 mum) withlarge polysaccharide capsules.20 The cap-sule stains purple with methylene blue,blue with alcian blue, and red with muci-carmine.20 The granulomatous type pro-duces more of an inflammatory reactionwith giant cells and a small number oforganisms. The organisms are 2 to 4mum, have thin or no capsules, and arefound within giant or mononuclear cells.The fungi stain red with PAS, black withmethanamine silver, and dark brown withFontana-Masson.20 A large majority ofpatients who have confirmed cutaneouscryptococcal disease do so as a result ofdissemination. As such, a thorough work-up for organ involvement, particularly theCNS, is indicated.

The CNS is the most common site ofdissemination and any immunocompro-mised patient that has evidence of lung orskin cryptococcosis should have a lumbarpuncture to rule out CNS disease.5

According to one series, 90% of AIDSpatients with cryptococcal pneumoniahave concomitant CNS dissemination at

time of presentation.12 A culture of CSFfluid, fluid analysis, and opening pressureare imperative to the diagnosis, manage-ment, and prognosis of disease.Because high CSF pressures are discov-ered in over 50% of AIDS patients andmay lead to a worse prognosis, someauthors recommend serial lumbar tapsand shunts to both monitor and maintainnormal pressure.21 Also, the direct exami-nation of CSF using an India ink prepara-tion can yield a rapid diagnosis and waspositive in this patient. CT scans and

MRI can also be used to diagnose andmanage CNS disease. On radiographythere is no pathgnomonic finding, buthydrocephalus, gyral enhancement, andsingle or multiple enhancing and nonen-hancing nodules (as in this case) have allbeen reported.22

Because opportunistic cryptococcalfungemia spreads in a characteristic wayto organ systems, diagnostic tests shouldbe tailored based on signs and symp-toms. Hemotogenous seeding is particu-

CHAPLIK, GROPPER, HOFFMAN, HWANG 13

Fig. 1 showing numerous, discrete,dome-shaped, some umbilicatedpapules and several, fairly well-defined, hyperpigmented, scalyplaques on abdomen and chest.

Fig 3. H & E stain of 3mm punchbiopsy at 10X showing numerousencapsulated organisms in the super-ficial and deep dermis with very littleinflammatory response.

Fig 5. Mucicarmine stain showing a40X of lymph node revealing largeamounts of red staining organismsthat expand nodal sinuses.

Fig. 2 Close-up of umbilicated papule.

Fig. 4. Mucicarmine stain of 3mmpunch biopsy at 40X showing thecharacteristic red staining capsule inthe superficial dermis.

Fig 6. Muciarmine stain of alveolarlavage showing 40 X organism stainedred with mucicarmine in proximity toalveolar macrophage.

larly high in the immunocompromised anda blood culture is essential in determiningcryptococcemia, turning positive in 3-7days.5 A more rapid approach, that is bothspecific and sensitive, is the serologicdetection of cryptococcal polysaccharidecapsule using either latex agglutination orenzyme immunoassay. In fact, the anti-gen can be detected in urine and CSFfluid as well. A urine culture is necessaryto rule out prostatic involvement. Theprostate has been described as a reser-voir for relapse of infection even duringantifungal treatment.23 An ophthalmologicconsult is warranted because eye involve-ment can lead to loss of vision, retinalinvolvement, cranial palsies, and endoph-thalmitis. Presenting signs in organ sys-tems such as skin and lymph nodes oftenprompt biopsies and can lead to the diag-nosis before cultures become positive.Furthermore, a KOH preparation, Tzancksmear, and India ink preparation of anytissue suspected of harboring fungi mayalso be used as a rapid, direct test fordiagnosis

The treatment approach after the diag-nosis is established in a patient with AIDSrelies on Amphotericin B. Althoughamphotericin B monotherapy for the treat-ment of cryptococcal meningitis is provento improve survival, combination therapywith flucytosine allowed for lower Ampho-tericin doses at shorter courses and lesstoxicity.25,26,27 Among patients with HIVinfection and cryptococcal meningitis,induction therapy with amphotericin B(0.7-1 mg/kg/d) plus flucytosine (100mg/kg/d for 2 weeks) followed by flucona-zole (400 mg/d) for a minimum of 10weeks is the treatment of choice.28 Flu-conazole should be continued for life.Lipid formulations of amphotericin B canbe substituted for amphotericin B forpatients whose renal function is impaired.Ambisone at 4 mg/kg/day has beenshown to perform similar to AmphotericinB.29 For those patients with HIV who pre-sent with isolated pulmonary, cutaneous,

or urinary tract disease, fluconazole (200-400 mg/d) is indicated and itraconazole(200-400 mg/d) is an acceptable alterna-tive.29 For immunocompetent hosts withpulmonary disease, non-CNS-isolatedcryptococcemia, urinary tract or cuta-neous disease, fluconazole for 3-6months is the drug of choice.28 Itracona-zole (200-400 mg/day) for 6-12 months isan acceptable alternative.

The treatment of disseminated diseasein AIDS has been clearly delineated andshown to improve morbibity and mortality.Prognosis, however, depends most oncontrol of the patient’s underlying diseaseand may be poor despite adequate treat-ment. Patients with high polysaccharideantigen titers (>1:1024), heavily positiveIndia ink examination, weak CNSresponse to infection (<20 leukocytes/microliter), and altered mental statusshow a high fungal burden and tend to dopoorly.5 Rapid diagnosis leading to propertreatment will improve survival in mostpatients with cryptococcosis. Becausecryptococcosis often manifests with skinfindings coupled to systemic disease inthe immunocompromised patient, a highindex of suspicion for this opportunisticpathogen must be maintained.

References1. Krywonis N, Kaye V, Lynch P. Cryptococcal cellulitis in con-genital lymphedema. Int J Dermatol. 1990;29:41-44.2. Casadevall AJ, Mukherjee J, Ruong R, Perfect JR. Manage-ment of Cryptococcus neoformans contaminated needleinjuries. Clin Infect Dis. 1994;19:951-3.3. Glaser JB, Garden A. Inoculation of cryptococcosis withouttransmission of the acquired immunodeficiency syndrome. NEngl J Med. 1985;313:264.4. Baker RD. The primary pulmonary lymph node complex ofcryptococcosis. Am J Clin Pathol. 1976;65:83-92.5. Perfect JR. Cryptococcosis. Infect Dis Clin North Am. 2002;16(4): 837-746. Newberry Jr. WM, Walter JE, Chandler Jr. JW, Tosh FE. Epi-demiologic study of Cryptococcus neoformans. Ann InternMed. 1967;67:724-32.7. Hajjeh RA, Brandt ME, Pinner RW. Emergency of cryptococ-cal disease: epidemiologic perspective 100 years after its dis-covery. Epidemiol Rev. 1995;17:303-20. 8. Sorvillo F, Beall G, Turner PA. Incidence and factors associ-ated with extrapulmonary cryptococcosis among persons withHIV infection in Los Angeles County. AIDS. 1997;11:673-9. 9. Zimmerman LE, Rappaport H. Occurrence of cryptococcosisin patients with malignant disease of reticuloendothelial sys-tem. Am J Clin Pathol. 1954;24:1050.

10. Gallis HA, Berman RA, Cate TR. Fungal infection followingrenal transplantation. Arch Intern Med. 1975;135:1163-7211. Goldstein E, Rombo ON. Cryptococcal infection followingsteroid therapy. Ann Intern Med. 1962;56:114. 12. Schupbach DW, Wheeler CE, Briggaman RA, et al.Cuta-neous manifestations of disseminated Cryptococcus. ArchDermatol. 1976;112:1734-40.13. Feigin DS. Pulmonary cryptococcosis: radiologic-patho-logic correlates of its three forms. AJR Am J Roentgenol.1983;141:1263-72.14. Dimino-Emme L. Cutaneous manifestations of diseemi-nated Cryptococcus. J Am Acad Dermatol. 1995; 32(5 Pt 2):844-5015. Hernandez AD. Cutaneous cryptococcosis. Dermatol Clin.1989;7:269-73.16. Brown JW III, Seabury JH. Cryptococcosis. In: Demis DJ,Crounse RG, Dobson RL, et al., eds. Clinical dermatology.Philadelphia: JB Lippincott, 1992;(3)17-17:1-9.17. Chu AC, Hay RJ, MacDonald DM. Cutaneous cryptococco-sis. Br J Dermatol. 1980;103:95-9.18. Borton LK, Wintroub BU. Disseminated cryptococcosis pre-senting as herpetiform lesions in a homosexual man withacquired immunodeficiency syndrome. J Am Acad Dermatol.1984;10:387-90.19. Rico MJ, Penneys NS. Cutaneous cryptococcosis resem-bling molluscum contagiosum in a patient with AIDS. Arch Der-matol. 1985;121:901-2.20. Lever WF, Schaumberg-Lever G. Histopathology of theskin. Philadelphia: JB Lippincott, 1990:379-81.21. Graybill JR, Sobel J, Saag M, et al, Cerebrospinal fluidhypertension patients with AIDS and cryptococcal meningitis[abstract I-153]. In: Program and abstracts of the 37th Inter-science Conference on Antimicrobial Agents and Chemother-apy (Toronto, ON, Canada). Washington, DC: AmericanSociety for Microbiology, 199722. Cornell SH, Jacoby CG. The varied computed tomo-graphic appearance of intracranial cryptococcosis. Radiology.1982;143:703-7.23. Braman RT. Cryptococcosis (Torulopsis) of prostate. Urol-ogy. 1981;17:284-6. 24. Denning DW, Armstrong RW, Fishman M, Stevens DA.Endophthalmitis in a patient with disseminated cryptococcosisand AIDS who was treated with itraconazole. Rev Infect Dis.1991;13:1126-30. 25. Bennett JE, Dismukes W, Duma RJ, Medoff G, Sande MA,Gallis H, et al. A comparison of amphotericin B alone and com-bined with flucytosine in the treatment of cryptococcal meningi-tis. N Engl J Med. 1979;301:126-31.26. Utz JP, Garrigues IL, Sande MA, Warner JF, Mandell GL,McGhee RF, et al. Therapy of cryptococcosis with a combina-tion of flucytosine and amphotericin B. J Infect Dis.1975;132:368-73.27. Dismukes WE, Cloud G, Gallis HA, Kerkering TM, MedoffG, Craven PL, et al. Nat'l Institute of Allergy and Infectious Dis-eases Mycoses Study Group. Treatment of cryptococcalmeningitis with combination amphotericin B and flucytosine forfour as compared with six weeks. N Engl J Med.1987;317:334-41.28. Saag MS.Practice guidelines for the management of cryop-tococcal disease:Infectious Disease Society of America. ClinInfect Dis. 2000; 30(4): 710-829. Hamil RJ, Sobel J, El-Sadr W, Johnson P, Graybill JR,Javaly K, et al. Randodmized double-blind trial of ambisomeand amphotericin B in acute cryptococcal meningitis in AIDSpatients [abstract 1161]. Presented at the Interscience Confer-ence on Antimicrobial Agents and Chemotherapy, San Fran-cisco, CA, September 26–29, 1999.

14 DISSEMINATED CRYPTOCOCCOSIS IN AIDS

15

16

Case ReportHistory of Present Illness

A 34-year-old Caucasian male pre-sented to the dermatology departmentwith a six-week history of a painful, pru-ritic groin rash. The rash began on theupper, inner thighs and then slowly pro-gressed to include the scrotum and baseof the penis. He described the rash asbeing initially pruritic, but recently becom-ing painful as to make daily washingpainful and walking difficult.

The patient also complained of redpatches on his face and scalp with asso-ciated scale. He denied any dysuria,hematuria or penile discharge. Otherthan occasional diarrhea, he denied anyconstitutional symptoms. He could notrecall any history of a similar rash. Previ-ous trials of antifungal and corticosteroidcreams proved unhelpful.

Upon further questioning, the patientstated he had previously been treatedwith somatostatin infusions for a tumor ofthe pancreas. He independently stoppedinfusions three months prior to presenta-tion at our clinic. He also reported takingseveral anti-depressant medications(Remeron, Wellbutrin and Zyprexa) forthe past eight weeks. Recently,Trazadone had been added to his psychi-atric regimen.

Physical ExamPhysical exam revealed a 34-year-old

cachectic white male with a flat affect.Diffuse and patchy erythema with scalewas noted on the scalp, face and bilateralpalms. The scalp hair appeared thinnedand brittle. Erythema and fissuring werenoted at the oral commisures. Thetongue was erythematous and enlargedwith lateral imprints of dentition (Fig. 1-4).Sclera were anicteric and nohepatosplenomegaly was appreciated.Beefy red, erosive patches with surround-ing erythema were noted on the scrotum,base of the penis and upper medial thighs(Fig. 5-6).

LaboratoryLaboratory investigation showed a nor-

mochromic/ normocytic anemia (hemo-

globin 13.0 G/DL, normal 14-18). ALTwas elevated (74 IU/L, normal 7-40)along with alkaline phosphatase (195 U/L,normal 37-107). PTH, intact PTH, serumcalcium, total protein and zinc were allwithin normal limits. Elevated hormonesincluded insulin (27.5 UU/L, normal 1-18),gastrin (112 PG/L, normal 0-90) andglucagon (1650 NG/L, normal 40-130). Apathological specimen was not obtained.Computed tomography (CT) of theabdomen revealed calcification of the tailof the pancreas (Fig. 7) with multiplemetastatic lesions in the liver (Fig. 8).

ManagementWith the diagnosis of necrolytic migra-

tory erythema in association withglucagonoma syndrome, the patient wasreferred to oncology. A regimen of alter-nating streptozocin and adriamycin wasstarted. Repeat imaging, performed afterthree cycles of chemotherapy, revealedstabilization of the pancreatic and livermasses. Laboratory testing revealednear normalization of serum glucagonlevels. Resolution of skin findings wasachieved with a mixture of nystatin,hydrocortisone and zinc oxide. Thepatient showed an increase of thirty-fivepounds over three months of chemother-apy. Psychiatric medications were contin-ued as before.

Discussion- GlucagonomaNecrolytic Migratory Erythema (NME)

is seen in paraneoplastic syndromesresulting from grastroenteropancreatic(GEP) tumors. The most common tumorassociated with NME is a glucagonoma.Glucagonomas make up approximately2% of all malignancies of the gastroin-testinal system, with an increasing inci-dence in the United States over the pasttwo decades (12). Tumors of the gastroen-teropancreatic system may present with amixture of hormone overproduction in30% of cases, usually with a dominanthormone (14). Characteristic dominant-hor-mone tumors are seen in several syn-dromes such as Carcinoid (serotonin),Zollinger-Ellison (gastrin), Insulinoma(insulin), Verner-Morrison (vasointestinalpeptide), Somatostatinoma (somato-statin), and Glucagonoma (glucagon).

Accounting for 4% of all GEP tumors,

the estimated incidence of glucagonomasis 1 in 20 million per year with only 200published cases to date (3)(4). It is usuallyseen in the 4th and 5th decades with anequal female to male preponderance.

SIKORSKI, EYRE, SEAMAN 17

Necrolytic Migratory Erythema in a Patient with Glucagonoma - A Case Report

Lynn M Sikorski, D.O., Michael Eyre, D.O., Ryan J Seaman, D.O.

Fig. 1

Fig. 2

Fig. 3

Occasionally, it may be part of multipleendocrine neoplasia (MEN) syndromes,especially MEN1 where 13% of suchpatients may be affected (13). In suchcases, the patient is usually less than 40years old and there are associatedparathyroid tumors and pituitary hyperpla-sia.

PresentationThe clinical presentation of the

glucagonoma syndrome is varied.Weight loss is the most common present-ing sign, seen in 73% of patients. Follow-ing weight loss is the characteristic rashtermed necrolytic migratory erythema (15).Diabetes mellitus may also be present. In

most cases, there are factors beyond theincreased glucagon leading to diabetes.These include pre-existing insulin resis-tance, secondary hormones, metabolicchanges due to the primary tumor burdenor metastases and side effects ofchemotherapy (4). Other than cheilosis orstomatitis, gastrointestinal complaints areusually limited to diarrhea (5). Rarely,abdominal pain may be present.

Patients may also be anemic. This isusually a normochromic/ normocytic ane-mia, but it may be macrocytic in some.Neurological changes, a characteristicfeature of all GEP tumors, are present in20% of patients (14). The changes arevaried and include depression, dementia,psychosis, optic atrophy, incontinenceand muscle weakness. In contrast to theneurological changes seen in many of theGEP tumors, thromboembolic phenom-ena are unique to glucagonoma syn-drome. Seen in nearly 30% of patients,thrombosis accounts for more than 50%of deaths reported (4).

DiagnosisDiagnosis of the glucagonoma syn-

drome relies on several sources. No testor symptom is individually diagnostic. Inaddition to the classical clinical presenta-tion of NME along with diabetes mellitusand weight loss, elevated serumglucagon and radiologic evidence of pan-creatic tumor are helpful for diagnosis. Aserum glucagon greater than 1,000 NG/Lis highly suggestive of existingglucagonoma. However, a normalresponse cannot rule out the presence ofan islet cell tumor of the pancreas. Onthe other hand, one may see anincreased glucagon without an associatedrash of NME. Secondary hyper-glucagonemia usually presents with lev-els less than 500 NG/L ( 1 4 ). Thedifferential of such cases is large andincludes liver disease, pancreatic dis-ease, chronic renal failure, myocardialinfarction, fasting or starvation, diabetesmellitus, bacteremia or sepsis, celiac dis-ease, trauma, burns, surgery, Cushing’ssyndrome and danazol therapy.

Diagnosis of glucagonomas has beenaided by several advancements in radio-logic imaging. Most of the tumors arefound in the pancreas, 50% being foundin the tail. Rarely, they may be found inextra-pancreatic tissues such as the duo-denal wall and kidney (12). Computedtomography is the most common methodof imaging, but selective visceral angiog-raphy may be the gold standard. Angiog-raphy allows better visualization of thesehypervascular tumors and will showhepatic metastases despite a normal liverscan.

TherapyOnce diagnosed, therapy consists of

medical and, at times, surgical interven-tion. Surgery is the optimal treatmentmodality; however, because of the multi-centricity of primary tumors, the high rateof co-morbidities and usual delay in diag-nosis, surgical extirpation is usually onlypalliative. Glucagonomas are slow grow-ing and often encapsulated, allowing forsurgical debulking. Palliative surgerieshave shown a considerable decrease inmorbidity in some cases. Perioperativemanagement is complicated by theincreased risk of thrombosis, poor controlof blood glucose levels, need for transfu-sions and delayed wound healing sec-ondary to a relative decrease in aminoacids. Survival rates are not enhancedby surgical therapy (4).

Medical therapy may be employed incombination with palliative tumor debulk-ing, or alone when surgery is not possi-ble. Options include pharmacologic andcytotoxic chemotherapy and supplemen-tation with amino acids, zinc and essen-tial fatty acids. Pharmacologic therapyconsists primarily of the synthetic analogof somatostatin called octreotide (Sando-statin). By inhibiting pituitary and gas-trointestinal hormones, octreotideincreases absorption of water and elec-

18 NECROLYTIC MIGRATORY ERYTHEMA

Fig. 4

Fig. 5

Fig. 6

Fig. 7

Fig. 8

trolytes, decreases pancreatic and gastricsecretions and delays intestinal transittime. Octreotide is limited, however, by ashort plasma half-life of 3 to 4 minutes.Newer somatostatin analogues such asLanreotide or Octreotide long actingrepeatable (LAR) may prove to be moreuseful. Lanreotide has a biological activ-ity of 10 to 14 days, allowing the suppres-sion of symptoms to last for 7 to 10 days(16), while Octreotide LAR was found in anItalian study to alleviate symptoms for 28days at a time (11). While it may improvesymptomatology, these somatostatin ana-logues do not, however, lead to suppres-sion of tumor growth.

Alternative therapies include hepaticartery embolization and transplantation.Embolization, while never curative, mayreduce tumor mass, control symptoms ofhormone excess and prolong life (15). Totalpancreatectomy with liver transplantationhas been reported. This may be anoption, but only in cases diagnosed earlyin patients with minimal co-morbid condi-tions.

PrognosisBecause of varied and insidious pre-

sentations, the morbidity and mortalityrates are rather high in cases ofglucagonoma syndrome. Metastatic dis-ease is present in 50-75% of patients.Liver metastases (80%) are seen mostcommonly, followed by the peripancreaticlymph nodes (38%) (9). Other areas ofmetastases include bone, lung, adrenals,kidney and chest wall. Tumor-relateddeath averages 3-7 years and is usually aresult of thromboembolism, sepsis or gas-trointestinal bleeding.

Discussion-NecrolyticMigratory Erythema

First described in 1942 by Becker,NME is the hallmark of glucagonoma syn-drome (3). The rash is seen in approxi-mately two-thirds of patients and usuallybegins as small, erythematous maculesand papules in the perineum, lowerextremities and periorificially. Lesionstend to coalesce and blister with centralerosions. Healing may leave anindurated bronze discoloration ( 4 ).Affected areas are regularly pruritic andoften intensely painful. Secondary infec-tions like candida and staphylococcusmay be present.

Most cases of NME secondary toglucagonoma follow Curth’s criteria fordiagnosing a paraneoplastic syndrome.First, both conditions begin simultane-

ously and follow a parallel course. Nei-ther symptom, nor their correlation isexplained by a genetic etiology. This spe-cific, uncommon dermatosis occurs withthis specific tumor, and the association ofthe two conditions occurs in a high per-centage. Along with the fact that symp-toms of NME are frequently relievedfollowing treatment of the tumor, NME ismost often considered to be a paraneo-plastic phenomenon (6).

Differential DiagnosisBecause of slow onset and varied pre-

sentation, NME may be difficult to diag-nose. Similar appearing rashes includeacrodermatitis enteropathica, Seborrheicdermatitis, subcorneal pustular dermato-sis, psoriasis, contact dermatitis, Hailey-Hailey disease, pemphigus foliaceous,paraneoplastic pemphigus, pellagra andmucocutaneous candidiasis (1).

PathophysiologyThe exact mechanism producing NME

is unknown, but several theories havebeen put forth. Some investigators pro-pose that, because of the excessglucagon, patients exist in a catabolicstate. This leads to prolonged gluconeo-genesis and glycogenolysis with subse-quent depletion of epidermal proteins.Ultimately, epidermal necrosis develops(2). Other possible mechanisms that maybe responsible for NME have to do withthe liver. Because of frequent hepaticinvolvement, there may be decreasedamino acids, zinc and essential fattyacids (7). Each of these may indepen-dently lead to keratinocyte toxicity (14).Striking similarities exist between thecutaneous findings in NME and acroder-matitis enteropathica, though serum zinclevels are inconsistently low in NME.Deficiencies in mononuclear and poly-morphonuclear cell chemotaxis havebeen noted, which may be related toinappropriate zinc uptake, thus contribut-ing to the dermatitis (3).

HistologyAlthough several different patterns

may be seen, key features of NMEinclude confluent parakeratosis, variableacanthosis, necrosis of the upper epider-mis, edema of the papillary dermis withvascular dilation and a lympho-histiocyticinfiltrate (7). Immunofluorescent studiesare negative.

TherapyMany therapies have been used to

alleviate the symptoms of NME. Cer-tainly, the best therapy is to cure or

lessen the effects of the underlyingglucagonoma and accompanying bio-chemical abnormalities. Topical antifun-gals and antibiotics are useful in cases ofsecondary infections. Infusions of aminoacids, essential fatty acids and zinc haveproved to be beneficial in some cases;however, such therapy tends to be expen-sive (4). Diet may be modified with caloricsupplementation and high protein intaketo offset the negative nitrogen balancebrought about by the prolonged catabolicstate. Other therapies that have beenused include oral steroids, UV light,methotrexate and Dapsone (14).

Overall management should includecareful screening and monitoring for otherendocrinopathies. Elevations in otherhormones are common in GEP syn-dromes. In fact, elevated gastrin levelsare seen in 50% of glucagonoma cases.Increased insulin is the next most com-mon hormone abnormality (14). Because ofthe near certainty of developing insulin-dependent diabetes mellitus, patientsshould be offered comprehensive diabeticcounseling and education. Prompt refer-ral should be made to oncology, neurol-ogy, endocrinology and psychiatryservices.

References1. Alkemade JA, van Tongeren JH et al. Delayed diagnosis ofglucagonoma syndrome. Clin Exp Dermatol. 1999Nov;24(6):455-7.2. Bewley AP, Ross JS et al. Successful treatment of a patientwith octreotide-resistant necrolytic migratory erythema. Br JDerm. 1996 Jun;134(6):1101-4.3. Boyce S, Harper J. Paraneoplastic Dermatoses. DermatolClin. 2002 Jul;20(3):523-324. Chastain MA. The glucagonoma syndrome: a review of itsfeatures. Am J Med Sci. 2001 May;321(5):306-20.5. Chao S, Lee J. Brittle nails and dyspareunia as first clues torecurrences of malignant glucagonoma. Br J Derm. 2002Jun;146(6):1071-4.6.Johnson S, Smoller B et al. Necrolytic Migratory Erythemaas the only presenting sign of a glucagonoma. J Am Acad Der-matol. 2003 Aug;49(2 Pt 1):325-87.Kheir SM, Omura EF, Grizzle WE et al. Histologic variation inthe skin lesions of the glucagonoma syndrome. Am J SurgPathol 1986; 10: 445-453.8. Pech O, Lingenfelser T et al. Pancreatic glucagonoma as arare cause of chronic obstructive pancreatitis. GastrointestEndosc. 2000 Oct;52(4):562-49. Povoski S, Zaman S et al. Dermatitis, Glossitis, Stomatitis,Cheilits, Anemia and Weight Loss: A Classic Presentation ofPancreatic Glucagonoma. W V Med J. 2002 Jan-Feb;98(1):12-4.10. Sinclair SA, Reynolds NJ. Necrolytic migratory erythemaand zinc deficiency. Br J Derm. 1997 May; 136(5):783-5.11. Tomassetti P, Migliori M et al. Treatment of gastroenteropancreatic neuroendocrine tumourswith octreotide LAR. Ailment Pharmacol Ther. 2000May;14(5):557-6012. Tomassetti P, Migliori M et al. Epidemiolog, clinical fea-tures and diagnosis of gastroenteropancreatic endocrinetumors. Ann Oncol. 2001; 12 Suppl 2:S95-9.13. Tsao H. Update on familial cancer syndromes and the skin.J Am Acad Dermatol. 2000 Jun;42(6):939-6914. Wermers RA, Fatourechi V, Kvols LK. Clinical spectrum of hyperglucagonemia associated with malignant neuroendocrinetumors. Mayo Clin Proc. 1996 Nov;71(11):1030-8.15. Wermers RA, Fatourechi V et al. The glucagonoma syn-drome: Clinical and pathological features in 21 patients. Medi-cine. 1996 Mar; 75(2):53-63.16. Zeng J, Wang B et al. Glucagonoma Syndrome: Diagnosisand Treatment. J Am Acad Dermatol. 2003 Feb;48(2):557-60

SIKORSKI, EYRE, SEAMAN 19

BackgroundMastocytosis is due to the excess of

normal-appearing mast cells in the skin.The three forms include urticaria pigmen-tosa, solitary mastocytomas, and diffusecutaneous mastocytosis. The pediatriccutaneous form is the most common.

HistoryThe incidence is 1 in 1000 to 1 in 8000

live births. It is usually confined to theskin in young children, and adults aremore likely to develop systemic forms.The cause is unknown. Familial occur-rence is rare. The onset is between birthand 2 years in 55% of cases, an addi-tional 10% of cases occur before age 15.The condition gradually improves andusually clears spontaneously by puberty.If the diseases begins after age 10, it usu-ally persists for the patient's life. If thedisease is systemic, the gastrointestinaltract and the skeletal system are mostcommonly involved. Although itching isminimal with localized disease, it can bevery bothersome with large numbers oflesions present.(1)

Urticaria Pigmentosa is the most com-mon form of mastocytosis. It is character-ized by small, reddish-brown macules orpapules that occur mainly on the trunk ofthe body. They may range in numberfrom a few to thousands (2). These tend tourtication with mild mechanical trauma orchemical irritation. The lesions may thenbecome pruritic, edematous and erythe-matous. This is referred to as Darier'ssign. It is probably a result of mast celldegranulation induced by physical stimu-lation (3).

The macules or papules in urticariapigmentosa contain a large number ofmast cells. Mastocytosis is characterizedby mast cell proliferation and accumula-tion within various organs, most com-monly the skin. Types of cutaneousmastocytosis include mastocytoma, dif-fuse erythrodermic mastocytosis, telang-iectasia macularis eruptiva perstans(TMEP) and urticaria pigmentosa.(4)

PathophysilogyMastocytosis is probably a hyperplasic

response to an unknown stimulus and nota neoplastic condition. There are rarecases recorded of familial urticaria pig-mentosa (4). Local concentrations of mastcell growth factor in skin lesions are pos-tulated to stimulate mast cell proliferation,melanocyte proliferation, and melanin pig-ment production This induction ofmelanocyte production explains thehyperpigmentation that is commonlyassociated with skin mast cell lesions (5).Some forms of mastocytosis produce sys-temic manifestations. These are thoughtto be associated with the release of sev-eral mast cell derived mediators includ-ing: histamine, prostaglandins, heparin,neutral proteases, and acid hydrolases.These mediators can induce symptomsthat may include: headache, flushing,dizziness, tachycardia, hypotension, syn-cope, anorexia, nausea, vomiting,abdominal pain, and diarrhea (6).

Mastocytosis presents with a highlyvariable clinical picture. In urticaria pig-mentosa lesions are multiple and widelydistributed. The lesions are round tooval, red-brown, non-scaling papules andsmall plaques. In systemic mastocytosis,skin lesions similar to those seen inurticaria pigmentosa are accompanied bymast cell infiltration of bone marrow, liver,spleen, and lymph nodes (6).

The histology of mastocytosis usuallyvaries from a small increase in the num-bers of spindle-shaped and stellate mastcells around superficial dermal blood ves-sels, to large number of tightly packed,round to oval mast cells in the upper tomid-dermis. This may also be accompa-nied by variable fibrosis, edema, andsmall numbers of eosinophils. Becauseof extensive mast cell degranulation, it issometimes difficult to detect these cellswith light microscopy without specialmetachromatic stains (5).

Factors Associated with Urticaria Pig-mentosa

Mortality/Morbidity: Most cases ofurticaria pigmentosa in children resolvespontaneously. However, acute exten-sive mast cell degranulation can on rareoccasions cause life-threatening shock.

Urticaria pigmentosa with onset occurringin adolescence or adulthood is more likelyto produce a persistent condition andthere is a greater risk of systemic involve-ment. Juvenile onset systemic mastocy-tosis has around a 7% malignancytransformation rate, while adult onsetmastocytosis has up to a 30% malignanttransformation rate (4).

Race/Nationality: Most reported casesare in Caucasians. This may be becausethe cutaneous lesions characteristic ofmost type of mastocytosis are less visiblein more pigmented skin. The incidence ofmastocytosis does not appear to be dif-ferent in other countries than in theUnited States (5).

Gender/Age: Mastocytosis affectsmales and females equally. With regardto age, most affected patients are chil-dren. About 75% of all cases occur dur-ing infancy or early childhood. There is asecond incidence peak in the 30's and40's (4).

History and PhysicalPatients commonly present with pru-

ritic cutaneous lesions which may beextensive. Pruritus and flushing may betriggered by certain foods, temperaturechanges, alcohol and drugs such as mor-phine, codeine, and aspirin (5).

Besides the skin manifestations,patients may experience flushing,headache, dyspnea, wheezing, rhinor-rhea, nausea, vomiting, diarrhea, andsyncope. It also possible for patients tohave chronic systemic complaints involv-ing various organ systems. These couldinclude:

Skeletal system-bone pain or newonset of fracture

CNS-neuropsychiatric symptoms aswell as malaise and irritability

GI-weight loss, diarrhea, nausea/vom-iting and abdominal cramps

Cardiovascular-shock, syncope(fromvascular dilation) or angina (3).

Findings upon physical examinationcould possibly be variable and would

20 MASTOCYTOSIS

MastocytosisRobert A. Norman, D.O., MPH, FAAD, Cynthia Futral-Eason, DO

Abstract

A literature review was performed to determine recent medical practices concerning the pathophysiology, diagnosis and treatment ofmastocytosis. Literature was reviewed concerning the following conditions: urticaria pigmentosa, mastocytoma, diffuse erythroder-mic mastocytosis, and telangiectasia macularis eruptiva perstans (TMEP). A representative sample of scientific papers includedresearch from 1980 to the present time.

include one or some of the following:

Skin- lesion types--Macules, papules,nodules, plaques, blisters and bullae inchildren

Skin- distribution Widespread sym-metric distribution, trunk more thanextremities, usually not on face, scalp,palms, and soles. (a large solitary collec-tion is called a mastocytoma)

Skin-color, number, size

Usually number from 1-1000, size1mm-several cm., color yellow-tan toRed-brown, slightly elevated plaques, typ-ically form in small groups on the trunk.Erythema and blisters (often afterscratching) are common in the first twoyears of life.

Skin-special characteristics--Darier'ssign, and dermatographism in uninvolvedskin, flushing from stroking or afteringesting a mast cell degranulating agent

Liver- possible hepatomegaly(40% ofadults with systemic mastocytosis)

Spleen- possible splenomegaly(50% ofpatients with systemic mastocytosis)

Cardiovascular- hypotension (5)

Lab StudiesSkin Biopsy

In many cases urticaria pigmentosacan be diagnosed by a history and physi-cal examination revealing the characteris-tic lesions that demonstrate Darier's sign(3). The most common confirmatory test isa skin biopsy. In the skin biopsy, ananesthetic agent without epinephrineshould be injected adjacent but notdirectly into the lesion to be biopsied, sothat mast cell degranulation can beavoided. It may be necessary to stain thebiopsy with Giemsa stain in order to visu-alize the mast cell granules (5).

Blood/Urine Tests

In patients with systemic mastocytosisa CBC exam may demonstrate anemia,thrombocytopenia, leukocytosis andeosinophilia. With regard to urinalysispatients with extensive skin lesions mayhave a two to three time normal elevationin urine histamine excretion(based on 24hour urine test) (4).

Imaging Studies

If a pediatric patient's CBC is abnor-mal then a bone scan and radiologic sur-vey is normally done. The same is true ofnon-pediatric cases of systemic mastocy-tosis. Any patient who complains of prob-lems with the skeletal system should alsohave a bone scan and radiologic surveyto identify any bone lesions, osteoporosis,or osteosclerosis (3). If a patient complainsof GI problems then a GI workup shouldbe ordered to identify peptic ulcers,abnormal mucosal patterns or motility dis-turbances.(6)

Other Tests Useful in Diagnosing Mas-tocytosis

Serum Tryptase--Tryptase levels areelevated in mastocytosis. These levelsmay be more useful than histamine lev-els, because histamine can be elevated inhypereosinophilic states.(3)

NMH (Urinary N-methylhistamine)-NMH levels are more specific and sensi-tive than urinary histamine levels. NMHlevels correlate directly with the extent ofskin lesions. NMH levels decrease withage, so age must be taken into consider-ation when interpreting results.(5)

Urinary PGD2 Metabolite Level-Although this test is not widely available itis useful. Even during asymptomatic peri-ods urinary PGD2 metabolites may rangefrom 1.5-150 times above normal (6)

Treatment

Medical therapy is conservative andfocuses on symptomatic relief. The prog-nosis for most mastocytosis patients isvery good, and none of the medicinescurrently available induce permanentinvolution of skin lesions or systemicinvolvement. Patients should beinstructed to avoid medications that pre-cipitate mast cell mediator release.These agents include: aspirin, NSAIDs,codeine, morphine, alcohol, thiamine, qui-nine, opiates, gallamine, decamethanon-ium, procaine, radiographic dyes,dextran, polymyxin B, scopalamine, andD-turbocurarine. Dietary substances thatshould be avoided are salicylates, craw-fish, lobster, alcohol, spicy foods, hot bev-erages, and cheese.

Recognition and explanation of the dis-ease helps parents limit unintentional

scratching and trauma of the lesions.

In addition patients should avoid stim-uli such as high emotional stress, temper-ature extremes, physical exertion,bacterial toxins, and insect bites (7,8,9).

Medications Useful in Mastocytosis

H1 and H2 antihistamines are some-times used to decrease pruritus, flushing,and GI symptoms. Oral disodium cromo-glycate is useful in ameliorate cutaneoussymptoms like pruritus, whealing andflushing, as well as systemic symptomslike diarrhea, abdominal pain, bone pain,and cognitive function disorders.(10)

If a patient does not respond well toH1 and H2 antagonist therapy then a verycautious administration aspirin is indi-cated. The aspirin can be slowly titratedto a plasma level 20-30mg/100mL. Thistreatment should be done with cautionbecause aspirin can induce mast cellmediator release and subsequent cardio-vascular collapse.(10)

Skin lesions that involve a limited bodyarea may be treated with potent Class 1topical corticosteroids. It is also possibleto do intralesional injections of dilute corti-costeroids. Skin atrophy and adrenocorti-cal suppression can be minimized bytreating limited body areas during a singletreatment session. Generally, systemiccorticosteroids are not useful for mastocy-tosis except where there is the occur-rence of ascites and/or malabsorption.(3)

Oral PUVA therapy can result in gen-eral and cosmetic benefits in cutaneousmastocytosis, especially telangiectasiamacularis eruptiva perstans. There arerisks involved in this treatment includingskin cancer if over 200 treatments arerequired. PUVA therapy is consequentlyusually reserved for severe unresponsivecases in adults, and is rarely used in chil-dren. (3)

References:1. Habif TP et al Skin Disease Diagnosis and TreatmentMosby copyright 20012. Urticaria Pigmentosa (Website Article), www.skinsite.com3. Mastocytosis (Website Article), www.emedicine.com4. Clinical Allergy 1984 March; 14(2): 147-1525. Pathologic Basis of Disease. Robins et al, 1994, W.B.Saunders Co.6. American Journal of Medicine 1985 Jan;78(1) 9-147. Journal of Investigative Dermatology 1991 March;96(3): 15-188. British Journal of Dermatology 1981 Nov; 105 (5): 563-5679. Dermatologica 1983; 166 (1): 44-4710. Sanford Guide to Antimicrobial Therapy. Gilbert et al, 1999

NORMAN, FUTRAL-EASON 21

Concentrated build-up of dirt anddebris on certain anatomical areas maysometimes mimic pigmented lesions suchas melanocytic nevi and acanthosis nigri-cans. Patients will sometimes presentwith concern over the development ofthese pigmented ‘lesions.’ By recognizingsuch phenomena and using a simple

alcohol prep, the clinician may easily wipeaway these ‘lesions,’ alleviating thepatient’s fears and avoiding unnecessarytreatments and even surgical excisions.

We present a case of a 15 year-oldwhite male who was referred to the der-matology clinic for evaluation of recurrent“moles” on the left side of his neck. Thepatient initially presented to his familyphysician almost two years prior with con-cern that these hyperpigmented lesionswere cancerous. The patient was assuredthat the lesions were clinically benignjunctional nevi. At the patient’s request,the lesions were removed via shave exci-sion without biopsy confirmation of thediagnosis. The lesions later returned inthe same general location. The patientdenied any irritation, pruritus, or bleedingrelated to the lesions.

On dermatologic exam, three distinctovoid, hyperpigmented patches wereobserved measuring approximately 1x1cm2 on the left side of his neck, appear-

ing to be concentrated areas of dirt anddebris (Figure 1). The dermatologic examwas also remarkable for cutaneous thick-ening and hyperpigmentation in the axil-lary and posterior cervical regions,characteristic of acanthosis nigricans.Based on previous clinical experiencesinvolving grime-based lesions, the markswere removed by rubbing them with analcohol prep (Figures 2-3). The patientwas reassured that the lesions were nei-ther benign nor dysplastic nevi. He wassubsequently counseled on the need forbetter hygiene to prevent such lesionsand recurrences. In addition, the patientwas counseled on the potential signifi-cance of acanthosis nigricans and wasadvised to follow up with his family physi-cian for appropriate monitoring and test-ing for diabetes and other endocrinedisorders.

Additionally, we present a case of an 8year-old white male, seen in consultationfor evaluation of a “rash” involving the

Removable dirt and debris may be mistaken for true hyperpigmented skin lesions

Primary Author: Matthew T. Smetanick, Corresponding Author: Scott J.M. Lim, D.O.

Figure. 1. Hyperpigmented patch onleft side of neck. The other two‘lesions’ have already been wipedaway. Acanthosis nigricans is evidentin posterior cervical region.

Figure 4. Hyperpigmented papules onanterior neck.

Figure 6. Removal of the lesions onanterior neck after wiping with analcohol prep.

Figure 7. Removal of the lesions onleft post-auricular region after wipingwith an alcohol prep.

22 REMOVABLE DIRT AND DEBRIS MAY BE MISTAKEN FOR TRUE HYPERPIGMENTED SKIN LESIONS

Figure 5. Hyperpigmented papules onleft post-auricular region.

Figure. 2. Left side of neck after wip-ing area with an alcohol prep. The dirthas not been completely removedfrom the patch seen in Figure 1.

Figure. 3. Alcohol prep demonstratingremoval of superficial dirt and debrisfrom the hyperpigmented patch on leftneck.

anterior neck and bilateral post-auricularregions, which had been present for sixmonths. The patient was initially evalu-ated by his primary care physician, whoclinically reached a diagnosis of acantho-sis nigricans. Work-up was ordered,including a fasting glucose level that wasnormal. The “rash” was asymptomaticand characterized as speckled hyperpig-mented papules, grouped into ovoidpatches and oriented along the skin lines(Figures 4-5). The possibility of an accu-mulation of dirt and grime was consid-ered. After wiping the lesions with analcohol prep, the pigment was removed(Figures 6-7).

Prior to these cases, one author(S.J.M.L.) encountered a 50 year-old baldmale who was concerned about a distinct

hyperpigmented plaque-like lesion on hisscalp. Interestingly, the mark was wipedaway with an alcohol prep, proving to benothing more than a localized accumula-tion of dirt and sebaceous material. Suchlesions can evidently develop in a pro-gressive and chronic manner when notadequately scrubbed during bathing. Pro-longed anxiety and/or treatment regimenscan be avoided if one anticipates ques-tionable lesions in body locations such asthe scalp and body folds. The cliniciancan diagnose the problem and reassurethe patient with a simple alcohol wipe.

Corresponding Author: Scott J.M. Lim, D.O.

Correspondence and reprint requestsshould be sent to:Scott J.M. Lim, D.O.5100 Peach Street, Erie, PA, 16509Office phone: 814-864-2625Fax: 814-868-9339E-mail: slimderm@adelphia.net.

No outside or institutional funding wasrequired for this manuscript. The authorshave no conflict of interest to disclose.We warrant that the article is original,does not infringe upon any copyright orother proprietary right of any third party, isnot under consideration by another jour-nal, and has not been published previ-ously.

SMETANICK, LIM 23

Erythema nodosum is a hypersensitiv-ity reaction that presents as a nodularerythematous eruption usually limited tothe anterior and lateral aspects of thelower extremities. Other symptoms witherythema nodosum include low-gradefever, malaise, arthralgias, and lowerextremity edema.1 Many causes havebeen reported including infections, sar-coidosis, malignancies, Behcet’s andSweet’s syndrome.2-4 Medications thathave been implicated include oral contra-ceptives, omeprazole, antibiotics, bro-mides, barbiturates, and sulfonamides.1,5,6

We report a case of erythema nodosumcaused by Celebrex (celecoxib), acyclooxygenase-2 (COX-2) inhibitor. Thisside effect of Celebrex has never beenreported.

Case ReportA 63-year-old white female with a 20-

year history of osteoarthritis was treatedwith multiple trials of nonsteroidals, whichresulted in GI upset. She was placed onCelebrex 200mg po QD with a resolutionof symptoms. Other medications takensimultaneously were Cholestyramine,Prempro, Pepcid, Lipitor, Zoloft, andAccupril. She is not allergic to sulfon-amides.

Approximately 2 months after initiationof Celebrex, the patient presented withright lower leg patchy erythema, pedaledema, and slight pruritis. In addition,there was some purplish discolorationcombined with the edema suggestive ofHenoch-Schonlein purpura. TSH, ANA,and Rheumatoid Factor were negative.Over the next two days the erythema andedema worsened and the left leg becameinvolved. Bilateral lower leg nodoselesions evolved on the extensor surfacesof her legs. Chest X-Ray, ASO titer, ACEtiter, ANCA, and ESR were all negative.Punch biopsy from the left leg revealed areactive epidermis with benign hyperker-atosis. A perivascular mixed lymphocyticand polymorphonuclear (PMN) light infil-trate was noted around the superficialdermal vessels. In the subcutaneous fat,a heavy granulomatous mixed infiltrationof giant cells, monocytes, and PMN’s withtoxic fibrinoid changes to small veins wasnoted in a septal panniculitis pattern (Fig-

ure 1). These findings are consistent witherythema nodosum. All of her medica-tions were stopped and Indocin 25 mgTID was initiated.

The patient responded to treatmentand no new lesions were noted within aweek. Both legs remained edematouswith nodose lesions slowly resolving onthe extensor surfaces. In addition, Lymetest, tuberculin skin test, and venousDoppler of her legs were negative. Overa period of 4-6 weeks the nodules andedema resolved. The patient wasrestarted on all prior medications with theexception of Celebrex. There was norelapse of the erythema nodosum.

DiscussionThere is a strong association between

treatment with sulfonamides and ery-thema nodosum. Celebrex is a sulfon-amide-containing 1,5-diarylpyrazolederivative that selectively inhibits COX-2.COX-2 is one of two isoforms of the ratelimiting enzyme cyclooxygenase that syn-thesizes prostaglandins- mediators ofinflammation, renal blood flow, and gas-tric “cytoprotection”. By selectivelyinhibiting only COX-2 Celebrex hasshown to possess anti-inflammatory activ-ity with little or no gastric effects. Cur-rently it is recommended for the treatmentof rheumatoid and osteoarthritis.7 Cuta-neous reactions involving Celebrex thathave been reported include erythematousrash, maculopapular rash, pruritis,urticaria, exfoliative dermatitis, Erythemamultiforme and toxic epidermal necroly-sis.8 No report of erythema nodosumlinked to Celebrex has ever beenreported. We propose that the sulfon-amide-containing moiety of Celebrex isresponsible for the erythema nodosum.

ConclusionThe patient’s history, physical exami-

nation, laboratory examinations, and X-ray findings failed to reveal another causefor erythema nodosum. The results of thebiopsy are characteristic for erythemanodosum. There was no relapse of theerythema nodosum following Celebrexwithdrawal and reintroduction of all priormedications. We conclude that Celebrex

should be added to the drugs known tocause erythema nodosum.

References:1. Habif TP, editor. Clinical Dermatology 3rd ed. St. Louis:

Mosby; 1996.2. Garcia-Porrua C, Gonzalez-Gay MA, Vazquez-Caruncho M,

et al. Erythema Nodosum. Arthritis & Rheumatism 2000;43:584-592.

3. Mana J, Marcoval J, Craells J, et al. Cutaneous involve-ment in sarcoidosis. Archives of Dermatology 1997;133:882-888.

4. Ginarte M, Toribio J. Association of sweet syndrome anderythema nodosum. Archives of Dermatology 2000;136:673-674.

5.Salvatore MA, Lynch PJ. Erythema nodosum, estrogens,and pregnancy. Archives of Dermatology 1980; 116:557-558.

6. Ricci RM, Deering KC. Erythema nodosum caused byomeprazole. Cutis 1996; 57:434.

7. Penning TD, Talley JJ, Bertenshaw Sr, et al. Synthesis andbiological evaluation of the 1,5-diarylpyrazole class ofcyclooxygenase-2 inhibitors: identification of 4-[5- (4-methylphenyl)-3-(trifluoromethyl)-1h-pyrazol-1-yl] benzene-sulfonamide (sc-58635, celecoxib). American ChemicalSociety 1997; 40:1347-1365.

8. Sifton DW, editor. Physicians’ Desk Reference 56th ed.Montvale: Medical Economics Company; 2002.

Corresponding Author: Steven L.Harlan M.D.Dermatology and Dermatologic Surgery Center PC8131 University Boulevard, Des Moines, Iowa 50325Adjunct Professor Des Moines University-Osteopathic MedicalCenterPhone: (515) 225-8180, Fax: (515) 225-2041E-mail: HARLAN8131@aol.com

24 ERYTHEMA NODOSUM CAUSED BY CELEBREX

Erythema Nodosum Caused by CelebrexSteven L.Harlan M.D., Mary Evers D.O.

Abstract

We report a case of erythema nodosum caused by Celebrex (celecoxib). This adverse reaction has not been pre-viously reported. A 63-year-old white female developed symptoms consistent with erythema nodosum. A thoroughhistory, physical examination, laboratory evaluation, and radiologic studies failed to reveal another cause for ery-thema nodosum. Her symptoms resolved following cessation of Celebrex. We conclude that Celebrex should beadded to the list of medications known to cause erythema nodosum.

Figure1A

Figure1B

Figure 1 (A), Low and (B) high magnifi-cation views consistent with erythemanodosum. Note a heavy granuloma-tous mixed infiltration of giant cells,monocytes, and PMN’s in a septalpanniculitis pattern. (Hematoxylin-eosin stain; original magnifications: A,x40; B, x100.)

Introduction:Granuloma annulare (GA) is a benign,

idiopathic, granulomatous dermatosis ofthe integument that is recalcitrant to manytreatments. Clinically, GA may have oneof several presentations but is most com-monly characterized by asymptomatic,erythematous to violaceous, smooth,annular and arcuate plaques with accen-tuated, indurated borders. Plaques of GAtypically affect dorsal surfaces of theextremities but may affect any area. GAdevelops slowly and may remainunchanged for months or years beforedisappearing spontaneously without scar-ring or other residua. The diagnosis ofGA can usually be made clinically, how-ever, a biopsy is occasionally used toconfirm clinical suspicion. Histologicevaluation classically demonstratesdegraded collagen fibrils and mucin infil-trates surrounded by palisading granulo-matous inflammation in the dermis.

Tacrolimus ointment is a nonsteroidaltopical macrolide immunomodulator pro-duced by Streptomyces tsukabaensis. Ithas been demonstrated that tacrolimusinhibits T-lymphocytes activation, leadingto decreased production of IL2, IL3, IL4,IL5, GM-CSF, TNF-alfa and gamma-inter-feron, many of which are hypothesized toplay a role in the pathogenesis of GA.1,2

This study assessed the theraputic effectof treating GA with topical 0.1%tacrolimus ointment.

Patients and Methods:The study was a phase IV, open label,

single center, clinical trial to evaluate theefficacy and safety of topically appliedtacrolimus 0.1% ointment in 10 evaluableadult patients with GA. The diagnosis ofthe patient’s GA was made clinically.Biopsy was not taken due to reports inthe literature of spontaneous involution oflesions after biopsy.

Subject eligibility was determined atthe pre-study screening visit and upon

confirmation of a negative, in-house KOHtest. All eligible subjects returned to theclinic following any applicable concomi-tant medication washout for the treatmentinitiation visit. Of the ten patientsenrolled, all were women. The durationof the patients’ diseases ranged from 2months to 3 years. Baseline safety andseverity data was collected and the sub-ject was provided with the study medica-tion and instructions for use. Subjectsapplied tacrolimus 0.1% ointment bid as athin coat covering the affected areas forup to 24 weeks. Dosing schedules wereincreased to a tid application if a 50% orgreater improvement was not appreciatedat the week 4 visit.

The subjects were evaluated every 4weeks in the clinic throughout the treat-ment period. Efficacy was assessed usinga calculated score that combined multipleclinical parameters including: erythema,discoloration, induration, presence ofpapules or nodules, prutitus and annularconfigurations. The primary efficacy end-point was the Physician’s Global Evalua-tion of Clinical Response in the GATreatment Regions at the Week 24/ End-of-Study visit.

Results:All 8 patients who completed the study

demonstrated a decrease in diseaseseverity. The efficacy of tacrolimus oint-ment was apparent in the 8 individualsafter the first week of treatment, yet theycontinued to improve throughout the 24-week course. Six of the 10 subjects whoapplied tacrolimus ointment demonstrated50% or greater clearing by the end-of-study visit (Figure 1). Of the remaining 4subjects, 2 obtained 25% clearing and 2showed no improvement. The 2 patientswho did not improve did not complete thestudy.

Initially, mild localized irritation consist-ing of primarily erythema was experi-enced by 9 of the subjects. However,

with continued use, irritation subsidedand dosing was not interrupted. No otheradverse effects were observed.

Discussion:Many speculative hypotheses have

been rendered to explain the pathogene-sis of GA.3 The literature reports possibleassociations with diabetes mellitus,mycobacterial infections, trauma, viralinfections, insect bites, UV exposure,HLA antigens, contact dermatitis, immunecomplex vasculitis and circulatingimmunocomplexes.4-12 Recent data sug-gests a delayed-type IV hypersensitivityreaction as the pathogenesis of GA. Thismechanism is supported by the regularpresence of activated T-helper 1 (Th-1)lymphocytes in the GA lesions.13

BEDOCS, FLEMING, MOTTER 25

Treatment of Granuloma Annulare with Topical Tacrolimus 0.1%Ointment: A Phase IV Clinical Trial

Paul M. Bedocs, D.O., Thomas Fleming, M.D., Mandi R. Motter, R.N.

Abstract

Granuloma annulare (GA) is a common idiopathic granulomatous condition that responds poorly to many treat-ments. Our objective was to study the effects of topically applied tacrolimus 0.1% ointment on ten patients with GA.In an open label clinical trial, 10 female patients applied tacrolimus 0.1% ointment two times daily to the affectedareas. The frequency of application was increased to three times daily for slow responders.

Results demonstrated that in this subset of patients with localized GA, tacrolimus ointment effectively reduced thesize and symptoms of the lesions in all 8 patients who completed the study. Transient localized irritation occurred in 9patients. Topical tacrolimus 0.1% ointment appears to be safe and effective in a subset of patients with localized GA.A larger study is needed to determine with greater confidence the percentage of patients likely to respond.

Figure 1A, pre-treatment: Distinctannular plaques of GA.

Figure 1B, post-treatment: Markedimprovement after 24 weeks of treat-ment with tacrolimus.

Tacrolimus inhibits T-lymphocyte activationand may therefore impact the progression orfacilitate the regression of GA lesions.Tacrolimus inhibits T-lymphocyte activation byfirst binding to the intracellular proteinFKBP.1,14 The complex of tacrolimus-FKBP-calcium-calmodulin, and calcineurin is thenformed and the phosphatase activity of cal-cineurin is inhibited. This effect has beenshown to prevent the dephosphorylation andsubsequent translocation of nuclear factors ofactivated T-cells, a nuclear componentthought to initiate gene transcription for theformation of pivotal lymphokines such asinterleukin-2 and gamma-interferon.Tacrolimus also inhibits the transcription forgenes that encode IL-3, IL-4, IL-5, GM-CSFand TNF-alfa, all of which are involved in theearly stages of T-cell activation.1,2 Given itsmechanism of action, and the role of T-lym-phocytes in the pathogenesis of GA, it is easyto hypothesize how tacrolimus may impactdisease progression.

The lack of clear understanding of thepathogenesis and the unpredictable naturalhistory of GA complicates the evaluation andtreatment of this common skin disorder. Thepresent study demonstrates that a subset ofpatients with GA responded positively to treat-ment with topical tacrolimus 0.1% ointment.A larger study is necessary to determine withbetter confidence the percentage of patientslikely to respond.

References:1. Nghiem P, Pearson G, Langley RG. Tacrolimus and pimecrolimus:from clever prokaryotes to inhibiting calcineurin and treating atopicdermatitis. J Am Acad Dermatol 2002 Feb; 46(2): 228-41. 2. Fayyazi A, Schweyer S, Eichmeyer B, Herms J, Hemmerlein B,Readzun HJ, Berger H. Expression of IFNgamma, coexpression ofTNFalfa and matrix metalloproteinases and apoptosis if T lympho-cytes and macrophages in granuloma annulare. Arch Dermatol Res2000 Aug;292(8):384-90. 3. Dahl MV. Speculations on the pathogenesis of granuloma annu-lare. Aust J Dermatol 1985;26:49-57.4. Muhlbauer JE. Granuloma annulare. J Am Acad Dermatol1980;3:217-30.5. Calista D, Landi G. Disseminated granuloma annulare in acquiredimmunodeficiency syndrome: case report and review of the literature.Cutis 1995;55:158-60.6. Curwen W. Granuloma annulare, multiple, suggesting insect bitereaction. Arch Dermatol 1963;88:355-6.7. Dabski K, Winkelmann RK. Generalized granuloma annulare: clini-cal and laboratory findings in 100 patients. J Am Acad Dermatol1989;20:39-47.8. Draheim JH, Johnson LC, Helwig EB. A clinicopathologic analysisof “rheumatoid” nodules occuring in 54 children [Abstract]. Am JPathol 1959;35:678.9. Guill MA, Goette DK. Granuloma annulare at sites of healing her-pes zoster. Arch Dermatol 1978;114:138310. Spencer SA, Fenske NA, Espinoza CG, Hamill JR, Cohen LE,Espinoza LR. Granuloma annulare-like eruption due to chronicEpstein-Barr virus infection. Arch Dermatol 1988;124:250-5.11. Perserico A, Ossi E, Salvador L, Ruffatti A, Fornasa CV, Rondi-none R, et al. Circulating immune complexes in granuloma annulare.Arch Dermatol Res 1988;280:325-6.12. Tolmach JA. Case 5: disseminated granuloma annulare (atypi-cal). Arch Dermatol 1961;85:167-8.13. Mempel M, Musette P, Flageul B, Schnopp C, Remling R, Gache-lin G, Kourilsky P, Ring J, Abeck D. T-cell receptor repertoire andcytokine pattern in granuloma annulare: defining a particular type ofcutaneous granulomatous inflammation. J Invest Dermatol. 2002Jun;118(6):957-66.14. Standaert RF, Galat A, Verdine GL, Schreiber SL. Molecularcloning and overexpression of the human FK506-binding proteinFKBP. Nature 1990;346:671-4.

26 TREATMENT OF GRANULOMA ANNULARE WITH TOPICAL TACROLIMUS 0.1% OINTMENT: A PHASE IV CLINICAL TRIAL

JAOCD Founding Sponsor

A 47 y/o female with a thirteen year ofdisease “everywhere there is a crease”reported her disease started with a sorered rash under her armpits, under herbreasts and around her groin and but-tocks. When she is placed in a stressfulsituation or in humid, moist conditions sheflares up with seeping crusted erosionscausing her great discomfort and embar-rassment. She also complains of pre-menstrual exacerbation. Her pastmedical history was significant forasthma, bronchitis and kidney stones.Her family history was negative for heartdisease, diabetes, and skin cancer. Shehad a positive history for Hailey-Hailey onthe paternal side of family (father andcousins). Her past treatment includedciprofloxin, triamcinolone acetonide, keto-conazole, ketoconazole shampoo, cyclop-sorine (oral solution topically once daily),white vinegar, fluconazole, and laser ther-apy. She states only diphenydramine 50mg three times per day and ciprofloxinhelp.

Hailey Hailey Disease (H-H Dz) is noteasily recognized, and in many cases ismistaken for something else. Because ofthe body regions where it is usuallyfound, high friction areas such as armpits,under breasts, genitals, and inner thighs,it is commonly first mistaken for bacterialinfection, chronic fungal infections, or insevere cases other bullous disorders likePemphigus Vulgaris. (2,3) An antimicrobialagent or topical corticosteroid (both ofwhich are often used) will many timescalm down a flare up. But, if a correctdiagnosis is not made and exacerbatingfactors are not recognized, recurrencesoccur. Therefore, it becomes extremelyimportant for the physician to at least rec-ognize the existence of this disorder in hisor her own differential diagnosis. Oncethis has been done, the family physicianwill become a vital participant in helpingto manage and control the disease,largely increasing the quality of life ofeach of these patients.

Certainly, H-H Dz is not a common dis-order, affecting only one person in a mil-lion. But because this is an autosomaldominant disease, when it does affect theperson it affects the entire family, oftenshowing up inter-generationally, includingsiblings and extended family members.Due to the autosomal dominance, each

child of an afflicted individual has a fiftypercent chance of obtaining the disorder,and both sexes are affected equally withsome evidence that there is partial pene-tration of the genetic disorder (3,4).

In trying to understand the geneticdefect that causes H-H Dz, it is importantto review the physiology of skin structure.There are three main layers of the skin.The three layers include the epidermis,which is the outermost layer; the dermis,which is the middle layer; and the subcu-taneous layer, which is the bottom layer.The epidermis is made up of primarilykeratinocytes, or epidermal cells, and isdivided into four layers. From bottom totop, it includes the basal cell layer (stra-tum basalis); the spiny cell layer (stratumspinosum); the granular layer (stratumgranulosum); and finally on the surfacesits the cornified layer (stratum corneum).Lying below the stratum basalis andabove the dermis layer sits the basementmembrane with the extremely importantfunction of maintaining strength andstructure to the skin, by attaching thebasal cell layer to the dermis. Maintain-ing strength and structure is also per-formed by small attachments between thekeratinocytes called desmosomal com-plexes. These complexes consist of thedesmosome and the tonofilaments, bothof which function to hold the keratinocytestogether (5). It is in these desmosomalcomplexes that the genetic defect of H-HDz produces its affect (4,6).

Unlike the Pemphigus disorders, forwhich H-H Dz is also often mistaken, thedefect to the desmosomal proteins is notdue to autoantibodies, but insteadbecause of genetic wiring which helps informing these proteins (7). It is this defectthat is responsible for causing loss of cel-lular attachment among the keratinocytesand, thus, skin breakdown and bullousformation similar to Pemphigus. Themutation is found in a gene on chromo-some 3, and interestingly, researchershave recently found that this gene isresponsible for making a calcium pump.It is thought that the calcium inside thecell signals the desmosomal complexes,or “sticky junctions”; to tell exactly how“sticky” they need to be. So in H-H Dz,where the pumps in many of the skin cellsdo not work, faulty signals are sent whichdecrease the cells’ ability to hold together,

called acantholysis. (6) The skin breaksand becomes raw, forms blisters, allowsfor ripe conditions of overlying infection,and presents as H-H Dz.

So, how does H-H Dz present, andhow would a family doctor be able to rec-ognize and treat the disorder? Usually,patients will present in the third or fourthdecade with erythematous, localizedpatches or plaques of minute vesicles orbullae with crusted erosions especially inareas of moisture and friction such as the

NORMAN, DEWALT 29

Hailey-Hailey The Great Imitator Robert A. Norman, DO, MPH, Joshua Dawalt, DO

.Abstract

Hailey Hailey Disease, also known as Benign Familial Pemphigus, is a chronic, recurrent, autosomal dominant,blistering disease that may significantly affect quality of life (1).

Figure 1

Figure 2

Figure 3

axilla, groin, or under breasts (2,8). Burn-ing, pain and itching accompany the erup-tions, and a malodorous seeping clear orpus-like fluid is many times present espe-cially in a flare up. In some patients, lon-gitudinal white bands are found on thefingernails, and unlike other familial bul-lous disorders, mucosal involvement isvery rare (2,4,9).

It usually starts out mild, and increasesin severity as time passes, reaching apeak in the so-called flare-ups, thought bymost to be a result of an overlying infec-tion, which is either bacterial or fungal (4).One of its other distinguishing character-istics is its recurrent nature. For much ofthe time it is either not present or mild,not causing the patient much discomfort;but, when external factors occur, such asseasonal changes, stress, or restrictiveclothing, the flare that then occurs can bedebilitating. The areas affected are inhighly frictional regions of the body, andwith the body in constant movement;these regions are especially emphasizedwhich in turn elicits pain. Finally, with theseeping of malodorous fluid occurring,great embarrassment afflicts many ofthese patients, which can significantlyaffect them socially (2,4,8). If a suspicion isestablished with a family history, a biopsyis standard for making the diagnosis.

As if recognizing the disorder is not dif-ficult enough, finding the right treatmentcan be as strenuous. There is no onespecific method or modality in doing so,and unfortunately, refractory cases occur,making it even more frustrating. But onthe other hand, many cases are manage-able on an outpatient basis, making theprimary care physician a vital aspect totheir management. Discussions with H-HDz patients show that it is important tofind the regime that works best for eachpatient (10). To help in making this easier, itis useful to break down each case intomaintenance therapy, therapy for flare-ups, and refractory therapy.

In maintenance therapy, improvingoverall quality of life and preventing flare-ups are the emphasis. First, and mostimportant, a healthy weight, which willhelp in minimizing friction and moistureon certain regions of the body, should beemphasized. Instructing patients to usecool compresses and dressings, as wellas keeping the body parts as dry as pos-sible by using a hair dryer following abath should also be stressed (7,10). Simplepreventive acts in general hygiene andtoiletry can make a lot of difference,which includes certain bathing acces-sories. Many over-the-counter remediesincluding Tea-Tree Oil, Oilatum Plus, andoatmeal products such as Aveeno Col-loidal Oatmeal have been recommendedby H-H Dz sufferers as being especially

soothing and important in keeping theskin supple (10).

It has also been recommended byother sufferers to use an astringent, adrying agent used in management ofhyperhidrosis (4,10). Again there are severalover-the-counter choices, including Alu-minum Chloride (Drysol) or MitchumClear Gel (that is sold as an antibacterialdeodorant) that may be applied toaffected regions each night for a weekand then on a whenever needed basisworks well. The latter uses a triple nozzletop and ejects the gel by a turn screw inthe base, thus minimizing any possiblecross infection from using a roll on top (10).Finally, recognizing that an overlying bac-terial or fungal infection is usually a causeof a flare up is important to all H-H Dzsufferers. If caught early enough, a flare-up can be prevented (2,4,8).

Flare-ups are common to all H-H Dzsufferers, and instructing the patient to beaware of this becomes necessary ( 4 ).When a flare up does occur, the physicianshould first question whether an externalfactor such as weather changes, stress,or restrictive clothing is the partial cause(2,4). Working on changing or at least try-ing to avoid these factors can helptremendously, and might allow othertreatments to be saved for later. Then,understanding that infection, maceration,and friction induce a cascade of inflam-mation responsible for the flare up is thenext step (11). It is in this understandingthat physicians have found that theseflare-ups often respond to antimicrobialsand corticosteroids.

For some cases, a topical antibioticcream such as clindamycin or ery-thromycin used twice a day will be a firstand only line of treatment. Combiningthis with intermittent use of a mild to mod-erate topical corticosteroid, also twice aday, may be just what is needed. Forsome widespread flares a systemic antibi-otic may be required. In this case ery-thromycin 500mg twice a day,clindamycin 300mg four times a day, ortetracycline 500mg four times a day areall options. A bacterial culture and sensi-tivity can then provide the much neededadditional information for gearing furthertreatment, and in many cases a fungalswab may be needed to determine ifthere is also an overlying fungal infectionwhich would then require an antifungalagent such as ketoconazole cream 2%applied once or twice a day for two to sixweeks. Once the flare up is diminishedwith the above protocols, maintenancetherapy with an oral antibiotic such aserythromycin 250mg once daily can bevery beneficial in helping to prevent thenext flare-up (1,2,4,8,10).

In refractory cases, the aim is at stop-ping the inflammatory response of T lym-phocytes and cytokine transcription, bothof which have recently been found to beincreased in severe H-H Dz. Suchmodalities able to do this includeimmunosuppresants, oral corticosteroids,and occasionally, a retinoid such asisotretinoin (2,4). Among the immunomodu-lators shown to have a strong effect inrefractory cases, topical Tacrolimus(FK506) 0.1% ointment applied twicedaily has been shown to have significantreduction in the extent of disease withminimal discernible side effects (11). Oralmethotrexate 5mg once per week hasalso been shown to improve refractorycases, but, with hepatic and renal func-tion being a concern in patients usingthis, it should only be used as one of thelast resorts (10).

Oral corticosteroids and isotretinoinuse are also last resorts. With oral corti-costeroids, rebound flare-ups are com-mon once the medication is discontinuedemphasizing that these should only beused in severe cases on a short-termbasis (4). With isotretinoin, used in thiscase for its ability to inhibit sebaceousgland function allowing for dryer skin, sideeffects such as liver toxicity and possibleteratogenicity not to mention the cost oftherapy also make it a last resort. Finally,other modalities such as carbon dioxidelaser therapy, dermabrasion, PUVA, oraland topical cyclosporine, oophorectomy,and photodynamic therapy with topical 5-aminolevulinic acid with subsequent irra-diation therapy have all been used in themost refractory cases. Definitive carehas been show by each of these, but withscarring to afflicted regions a potentialrisk, these are only reserved for the mostunmanageable cases (1,4,8, 12, 13, 14, 15, 16, 17).

As can be seen from above, the vari-ety of treatments and modalities are vast.It is important from a patient’s perspectiveto know both the type of treatment andthe etiology of their problem. To thosesuffering from H-H Dz, it is imperative thatphysicians, including family doctors, be atleast aware of its existence. For whenthe time comes that a patient with an oddrash, who has tried everything to make itbetter, comes to the office in much dis-tress, and not aware of their family his-tory, H-H Dz will be a possibility. Allowingfor an earlier diagnosis results in an ear-lier treatment regime greatly improves thepatient’s quality of life, which is the goalof every physician.

References(1) Rodriguez Ricardo Ruiz, Alvarez J.G., Jaen P., Acevedo A.,Cordoba S., “Photodynamic therapy with 5-aminolevulinic acidfor recalcitrant familial benign pemphigus (Hailey Hailey dis-ease)”, Journal of the American Academy of Dermatology,November 2002; 47(5). www.mdconsult.com(2) Gallager Thomas Casey, M.D. “Familial Benign Pemphi-

30 HAILEY-HAILEY: THE GREAT IMITATOR

gus”, Dermatology Online Journal, 2000; 6(1):7. http://derma-tology.cdlib.org/DOJvol6num1/NYUcases/hailey/Hailey.html (3) Smith N., Dr. “Things you should know about HHD”, HaileyHailey disease.com, updated September 10, 2000. www.hai-leyhaileydisease.com/thingsknow.html(4) Helm Thomas N., M.D., Lee Thomas C. “Familial BenignPemphigus (Hailey Hailey Disease), updated April 12, 2002;Sections 1-11. www.emedicine.com/derm/topic150.html(5) Bennion Scott D., M.S., M.D., FACP. “Structure and Func-tion of the Skin”, Dermatology Secrets in Color, Second Edi-tion. Hanley and Belfus, Inc. 2001; 1-4.(6) Burge Susan, DM, FRCP. :Completing the Jigsaw puzzle;an important piece is in place”, Hailey Hailey disease.com,August 2000; 1. www.haileyhaileydisease.com/jigsaw.html(7) “Hailey Hailey or Benign Familial Pemphigus”, InternationalPemphigus Foundation, updated April 1999; 1. www.pemphi-

gus.org/am_hailey.html(8) Leibold Ann M., M.D., “Disorders of Keratinization”, Derma-tology Secrets in Color, Second Edition. Henley and Belfus,Inc. 2001; 27-28.(9) Rebecca, “Can HHD lesions appear in the mouth or vulva”,Hailey Hailey disease.com, April 2002; 1. www.haileyhaileydis-ease.com/mucosal.html.(10) “Learning to Live with HHD”, Hailey Hailey disease.com;1. www.haileyhaileydisease.com/livewith.html(11) Rabeni Erika J., M.D., Cunningham Nancy M., M.D.“Effective treatment of Hailey Hailey disease with topicalTacrolimus”, Journal of the American Academy of Dermatol-ogy, November 2002; 47(5). www.mdconsult.com(12) Shelley W, Shelley E Advance Dermatologic Therapy IIWB Saunders 2001 p. 505.(13) Webster CG, Resnik KS, Webster GF: Axillary granular

parakeratosis: response to isotretinoin, J Am Acad Dermatol37:789-7900, 1997.(14) Omerod Ad, Duncan J, Stankler L: Benign familial pem-phigus responsive to cyclosporin, a possible role for cellularimmunity in pathogenesis. Br J Dermatol 124:299-300, 1991.(15) Hamm H, Metze D, Brocker E Hailey Hailey Disease.Eradication by dermabrasion. Arch Dermatol 130: 1143-1149,1994.(16)Jitaukawaa K, Ring J, Weyer U, et al: Topical cyclosporinein chronic benign familial pemphigus(Hailey-Hailey Disease) JAm Acad Dermatol 27: 625-626, 1992.(17) James MP, Williams RM: Benign familial pemphigus—premenstrual exacerbation suppressed by goserelin andoophorectomy. Clin Exp Dermatol 20: 54-55, 1995.

NORMAN, DEWALT 31

2004 AOCD MID-YEAR CONVENTION

Hilton Tucson El Conquistador Golf & Tennis Resort

Tucson, Arizona

March 31 - April 3, 2004Wednesday – Saturday

20 Hours CME

What’s New in DermatologyPsoriasis: Biologics

UrticariaContact Dermatitis

MelanomaPigmented Disorders of the Skin

AndSeveral other exciting topics

Program Chair: Bill V. Way, DO

Make plans to come and have fun with your whole familyplaying golf, tennis, swimming, horseback riding,

and visiting the many local attractions in the Tucson area.

For more information, go to http://www.aocd.organd also be looking for your

2004 AOCD Mid-Year Convention announcement coming soon in the mail.

32

Currently Available OralAntifungal Agents

Although itraconazole, fluconazole andterbinafine are commonly referred to as“newer” oral antifungal agents, this cate-gorization is based on the conspicuousabsence of additional agents, especiallyfor cutaneous indications, since 1996.With regard to treatment of onychomyco-sis and other cutaneous uses, itracona-zole and terbinafine are “time tested” interms of efficacy and safety, with a contin-uous accumulation of clinical experiencein several million patients.

Spectrum of AntimycoticCoverage for Onychomy-cosis

Dermatophytes. Over 90% of mycotictoenail infections are caused by dermato-phytes, with Trichophyton rubrumreported to be the most commonpathogen.1 , 2 Both itraconazole andterbinafine exhibit activity against der-matophytes, based on in vitro studies andevaluations of clinical efficacy.1-4 Themajority of study data collected on treat-ment of onychomycosis relates to der-matophyte-induced disease.

Yeasts. In immunocompetent patients,Candida onychomycosis of toenails isless common than dermatophyte infec-tion. Candida spp, especially C. albicans,are more likely to be a factor in fingernailinfection, including immune competentpatients, immunocompromised individu-als, and patients with peripheral vascular

disease affecting the fingers, such asRaynaud’s phenomenon.1,2 Itraconazole isactive against several Candida speciesincluding C. albicans and C. parapsilo-sis.2 , 4 Terbinafine exhibits a greaterdegree of variability in its activity againstpathogenic yeasts. C. parapsilosis hasbeen reported to be responsive withlesser activity noted against C. albicans.3,5

Non-Dermatophyte Molds. Due to

lower prevalence among patients withonychomycosis, data on treatment ofnon-dermatophyte mold infection is morelimited.6-8 Itraconazole has demonstratedefficacy for nondermatophyte mold infec-tions including Aspergillus spp, Scopular-iopsis brevicaulis and Fusarium spp.7,8

The latter organism tends to be the mostrefractory, with combination treatmentusing surgical debridement and topicaltherapy more likely to be effective.

GOODMAN, DEL ROSSO 33

Optimal Treatment of Onychomycosis: A Status Report on Oral Antifungal Therapy

Marcus Goodman, B.S., MS-IV, James Q. Del Rosso, D.O., FAOCD

The management of onychomycosis has been plagued with frustration for physicians and patients due to difficulty inachieving cure, especially with topical approaches. The availability of the “newer generation of oral agents” includes thetriazoles (itraconazole, fluconazole) and terbinafine (an allylamine compound), proven to achieve higher cure rates thanolder oral antifungal agents (griseolfulvin, ketoconazole) and topical therapies. The “newer generation agents” have sig-nificantly improved the treatment of onychomycosis due to higher cure rates; continued experience with the newer agentshas provided additional support of their favorable safety profiles.1

The following updates information on (a) the use of oral antifungal agents for the treatment of onychomycosis (b) rec-ommended monitoring guidelines and (c) safety profiles. The review emphasizes the “newer” oral agents approved by theFood and Drug Administration (FDA) for treatment of onychomycosis in the United States, itraconazole and terbinafine.As onychomycosis is rarely cleared utilizing topical agents or surgical approaches as monotherapy, appropriate utilizationof oral antifungal therapy provides the greatest chance of achieving mycologic cure and improving the appearance ofaffected nails.

Table 1: TIME LINE OF DEVELOPMENT OF ORAL ANTIFUNGAL AGENTSOral Initial FDA-ApprovedDrug Availability in US Indications (US Product Monographs)

Griseofulvin 1958 - Dermatophyte infections of skin, hair, nails

Ketoconazole 1981 - Treatment of severe recalcitrant dermatophyte infections unresponsive totopical therapy or griseofulvin or in patientsunable to take griseofulvin

- Candidiasis including chronic mucocutaneous candidiasis and oral thrush

- Several deep fungal mycoses

Fluconazole 1990 - Vaginal, oropharyngeal and esophageal candidiasis, cryptococcal meningitis

Itraconazole 1992 - Toenail and fingernail dermatophyte (capsules)* onychomycosis

- Systemic mycoses inclusive of aspergillosis,histoplasmosis and blastomycosis

Terbinafine 1996 -Toenail and fingernail dermatophyte onychomycosis

(*Oral solution of itraconazole available and approved for oropharyngeal and esophageal candidia-sis and empiric therapy in febrile neutropenic patients with suspected fungal infection)

Among the non-dermatophyte mold infec-tions treated with itraconazole, infectionwith Aspergillus spp appears to be themost responsive.7 In some cases of non-dermatophyte mold onychomycosis,longer durations of treatment than thosetypically required for dermatophyte ony-chomycosis may be needed to achieveclearance of infection and clinicalimprovement. Data on terbinafine use fornon-dermatophyte onychomycosis is alsolimited to relatively small case collectionsand isolated reports. Terbinafine hasbeen shown to be effective in some casesof S. brevicaulis nail infection; cure ratesappear to be lower than with dermato-phyte disease and a longer duration oftherapy is required.3,5 In some cases,however, itraconazole and terbinafinehave demonstrated efficacy for ony-chomycosis caused by S. brevicaulisusing the same regimens as those rec-ommended for dermatophyte disease.8

Currently available oral antifungalagents exhibit little to no clinical efficacyfor the treatment of onychomycosiscaused by Onychocola canadensis, Scy-talidium hyalinum and Scytalidiumdimidiatum.2,9

Reported Regimens andResponses in Dermato-phyte Onychomycosis

A myriad of trials have been completedevaluating both itraconazole andterbinafine for the treatment of dermato-phyte onychomycosis, especially toenaildisease.3,5,10,11 Both blinded and open-labeltrials have been completed using a vari-ety of parameters to evaluate the successof treatment. Evaluation after nail plateoutgrowth (12 months after start of ther-apy) has been commonly used as thestudy endpoint. Criteria evaluating dis-ease clearance in “target nails” has typi-cally included mycologic cure, defined asboth a negative direct microscopy (potas-sium hydroxide preparation) and fungalculture, clinical cure, defined as a com-pletely normally appearing nail, and clini-cal response (or success), usuallydefined as a combination of completelynormal appearing nails and those that aremarkedly improved in visible appearance.

Regimens. For toenail onychomycosisin adults, terbinafine has primarily beenevaluated using continuous therapy with250 mg daily for a duration of 12 or 16weeks.2,3,5,10 At present, studies evaluatingintermittent regimens with terbinafine arelimited with regard to the number ofpatients treated.10 Itraconazole has beenevaluated in adult patients with toenailonychomycosis using either intermitenttherapy with 200 mg twice daily for 1week per month (“pulse” therapy) over 3

or 4 cycles or continuous therapy with200 mg daily for 12 or 16 weeks.2,4,10,11 Asresponses have suggested either greateror comparable efficacy with the intermit-tent approach, pulse therapy has becomethe more common prescribing practicewhen using itraconazole.10,12 Both itra-conazole and terbinafine are capable ofachieving significantly higher cure rateswith shorter treatment courses, as com-pared to griseofulvin and ketoconazole,due to their more favorable pharmacoki-netics in the nail unit; persistent therapeu-tic drug levels are noted within the nail forseveral months after discontinuation oftherapy and clearance from the systemiccirculation (Figure 1).13

Treatment Responses. Complete dis-cussions of available onychomycosis tri-als, comparative trials and reported curerates are beyond the scope of this review.Although a range of cure rates have beenpublished, available data from a variety ofresearch sources clearly supports theneed for oral antifungal therapy when thedesired goal is to provide the best chanceof clearing onychomycosis.1,2,10 Overallmeta-averages and pooled data for der-matophyte toenail onychomycosis withitraconazole pulse therapy report a clini-cal cure rate of 58 + 10%, a clinicalresponse rate of 82 + 3 %, and mycologiccure rate of 77 + 5%.10,12 Similar meta-averages and pooled analysis withterbinafine report a clinical cure rate of 64+ 8%, a clinical response rate of 76 + 8%and a mycologic cure rate of 80 + 5%.3,10

Adjunctive Treatments andAdjustments in Therapy

Reasons For Treatment Failure. Poorcompliance and inadequately prescribedtreatment are obvious causes of treat-ment failure. Less obvious causes associ-ated with an increased risk of treatmentfailure with oral antifungal monotherapyrelate to specific clinical presentationsand physical factors. The use of adjunc-tive surgical debridement has beenshown to enhance response to treatment,especially in cases of dermatophytomasand spikes, lateral columns of disease,extensive onycholysis and marked nailplate thickening.14

Adjustments In Therapy. The use ofbooster therapy has been advocated inpatients demonstrating a slower thananticipated response.15 Using nail marking(grooving) techniques to assess plategrowth, if at least 4 mm of new clear prox-imal plate is not noted within 3 months offinishing the course of oral therapy, addi-tional treatment is probably warranted (ie.additional pulse of itraconazole, additionalmonth of terbinafine). If culture positivityfor the same organism (dermatophyte) isdocumented at 6 months from baseline (3

months after completion of oral therapy),this suggests significant persistence ofinfection and has been correlated with agreater likelihood of treatment failure; anadditional course of oral therapy is sug-gested.3 , 1 6 An extension study withterbinafine has also confirmed the valueof clinical examination at 18 months afterbaseline. Clearance at this point in timesuggests a reasonable likelihood of moreprolonged benefit; if disease persistenceor “relapse” is noted at this point, an addi-tional course of therapy is likely to inducea sustained response.16

Prevention of Recurrence. Withregard to onychomycosis, definitions ofrelapse versus reinfection have not beenwell-defined and are arbitrary. The rede-velopment of previously cleared ony-chomycosis may represent recurrence ofthe same infection or may be the result ofa new infection related to recolonizationof the foot with dermatophyte organisms.The longer the time period until the “new”infection develops, the greater is theassumption that reinfection with an inde-pendent organism has occurred. In anyevent, it is widely accepted that dermato-phyte onychomycosis starts first as tineapedis or pedal colonization, prior tomigration into the nail bed and undersur-face of the plate.2

In a study of patients with toenail ony-chomycosis who cleared with itracona-zole or terbinafine, patients were followedevery 3 months over a period of 3 years.17

Relapse rates increased over time,reported as 8.3% at 1 year 19.4% at 2years and 22.2 % at 3 years.

Considering the widespread presenceof dermatophyte organisms in the envi-ronment, and the tendency for many indi-viduals to harbor or become infected withdermatophytes (ie. T. rubrum) due to agenetic “immunologic blind spot”, suchrates of recurrent infection are not sur-prising. Although large scale studies arenot available, initiation of topical antifun-gal therapy applied to pedal skin aftercompletion of the course of oral antifungaltreatment is suggested to suppress der-matophyte recolonization of the foot andreduce the risk of reinfection.2

Safety ConsiderationsPatient Populations. Both agents have

been utilized in elderly patients, in dia-betic patients, and in immunocompro-mised patients with favorable efficacy andsafety documented.2,10,18

Although data is more limited withregard to the number of children treatedwith onychomycosis, both itraconazoleand terbinafine have been used effec-tively and safely in this population.19 Thisis not surprising as both agents have

34 OPTIMAL TREATMENT OF ONYCHOMYCOSIS: A STATUS REPORT ON ORAL ANTIFUNGAL THERAPY

been reported to be effective and safe inseveral reports of children treated fortinea capitis.20

Adverse Reactions. After 11 years ofitraconazole use and 7 years ofterbinafine use in the United States, andseveral additional years of usage world-wide, the adverse reaction profiles ofthese agents are well established. Theincidence of “nuisance” side effects suchas transient skin eruptions, headache andgastrointestinal upset are low (<1 – 5%)with both agents. Asymptomatic and tran-sient elevations of hepatic enzymes havealso been observed (< 4%).2 , 3 , 1 0

Terbinafine has been associated withreversible changes in taste in 0.4 % ofpatients, usually developing during thefirst few weeks treatment, and loss oftaste in 0.3 % of patients, associated witha more delayed onset of 4 to 8 weeks.3,5,21

Occasional cases of reversible cutaneousreactions have been reported includingsubacute cutaneous lupus withterbinafine and acute generalized exan-thematous pustulosis with both itracona-zole and terbinafine.22-24

Severe adverse reactions are rare withboth itraconazole and terbinafine.2-5,10

Rare cases of symptomatic hepatotoxi-city have been reported sporadically withboth agents.10 Sporadic reports of hema-tologic abnormalities have also been pub-lished in association with terbinafine use;the incidence of significant neutropenia isestimated to be 1 in 400,000 patients.3

Caution regarding the potential for exac-erbation of congestive heart failure byitraconazole has been reported based onadverse reaction reports; use of itracona-zole for the treatment of onychomycosisis contraindicated in this patient popula-tion.25 Overall, considering the large num-ber of patients treated with bothitraconazole and terbinafine, the safeyprofiles of both of these agents is veryfavorable. Most patients complete treat-ment without difficulty, with rationalpatient monitoring serving to detect thevast majority of rare adverse events.

Drug Interactions. Itraconazole, aninhibitor of cytochrome 3A4 (CYP 3A4),may be associated with potentially signifi-cant drug interactions with other drugsmetabolized by this same enzyme.26 Useof itraconazole is contraindicated withsome hypnotic agents (triazolam, midazo-lam), some HMG-CoA reductaseinhibitors (lovastatin, simvastatin, atorvas-tatin), cisapride, quinidine, dofetilide andpimozide.25 Cautious co-adminiistration oravoidance of concomitant use is sug-gested in patients treated with digoxinand some calcium channel blockers.25-27

As with other azole antifungal agents,cautious use is also suggested in patients

treated with cyclosporin.26,28 Itraconazolerequires an environment of gastric acidityfor dissolution of the capsule formulation,suggesting the need to avoid co-adminis-tration with antacids, H-2 blocker antihist-amines and proton pump inhibitors.26,29

Terbinafine utilizes several pathways forits own metabolism and is an inhibitor ofcytochrome 2D6 (CYP 2D6).30 Drug inter-actions with terbinafine have been mini-mal to absent with no contraindicationsnoted.21.30

Rifampin may significantly increase themetabolism of terbinafine and all azoleantifungal agents, including itraconazole,thereby enhancing the risk of antifungaltreatment failure.25,31 Phenytoin and carba-mazepine may decrease itraconazoleserum levels through enzyme induction.25

Evaluation and MonitoringGuidelines

Disease-Related. A method for tabulat-ing the baseline status of onychomycosisprior to treatment is recommended. Pho-tography may be utilized where available.It may be useful to place a groove withinthe nail plate at the proximal edge of visi-ble disease and at the base of the platejust distal to the proximal nail fold, espe-cially with larger nail plates such as thelarge toenail. This allows for an easierassessment of the extent of growth andprogression of disease-free nail over timewhich can also be demonstrated to thepatient. If response is lagging despiteallowance for a sufficient amount of timeto achieve a response (ie. 5 to 6 months),the clinician may then elect to “boost”therapy by initiating a short course ofadditional treatment.

Confirmation of diagnosis by labora-tory evaluation using potassium hydrox-ide preparation, fungal culture and/or nailplate “biopsy” with PAS staining prior toinitiation of treatment has been suggestedin updated product monographs with itra-conazole and terbinafine.25,31 This dog-matic stance has been a matter ofcontroversy; the most reasonable positionis probably somewhere in between. It isjustifiable to state that laboratory confir-mation of a mycotic nail infection is theideal scenario, precluding the inefficiency,risk and unwarranted cost of antifungaltreatment in patients with onychodystro-phies that are not onychomycosis.32 Evenin the case of topical therapy, such aswith ciclopirox nail lacquer, usage in apatient who does not have onychomyco-sis is an inefficient and unnecessaryexpense.

Laboratory confirmation of onychomy-cosis is very dependent on obtaining anappropriate nail specimen and utilizing a

quality laboratory; specimens for directmicroscopy and fungal culture achievethe greatest yield when subungual debrisis obtained after trimming of onycholyticplate, preferably with a small curette.33-35

Nail plate “biopsy” specimens are mosthelpful when then are full-thicknessthrough the plate and not limited to onlydistal slivers.35

Clinical. A detailed medical and drughistory is very important to detect a pre-exiting history of congestive heart failure,hepatic disease or potentially significantdrug interactions. After initiation of treat-ment, periodic clinical follow-up is recom-mended to monitor clinical efficacy,compliance and to observe for potentialadverse reactions. The use of itracona-zole or terbinafine for onychomycosis isgenerally not recommended in patientswith pre-existing hepatic abnormalities,especially active or chronic disease.25,31

The US product monograph also sug-gests that terbinafine is not recom-mended in patients with significant renalimpairment (< 50 mL/min).31

Laboratory Monitoring. Although therisk of significant toxicities such a hepato-toxicity are rare with itraconazole andterbinafine, suggested guidelines serve toprovide a comfortable and consistentbaseline for the clinician. Based on USproduct monographs, pre-treatment(baseline) evaluation of hepatic enzymesis recommended prior to initiation of treat-ment with itraconazole and terbinafine.25,31

This allows the clinican to screen forunknown pre-existing hepatic diseaseand possibly for findings suggestive ofundisclosed alcohol ingestion. The deci-sion regarding repetition of testing ismade on a case-by-case basis by theclinician, based on factors related to theindividual patient (ie. past medical history,use of other medications with hepatotoxi-city potential, etc).

There are no specific recommenda-tions regarding hematologic monitoring inpatients treated with itraconazole for ony-chomycosis.25 In patients with immnunedeficiency, the US product monographsuggests that a complete blood cell countshould be considered in patients treatedwith terbinafine for greater than 6weeks.31

References1) Elewski BE. Onychomycosis: Treatment, quality of life, andeconomic issues. Am J Clin Dermatol 2000;1(1):19-26.2) Del Rosso JQ. Advances in the treatment of superficial fun-gal infections: focus on onychomycosis and dry tinea pedis. JAm Osteopath Assoc 1997;97(6):339-346.3) Darkes MJM, Scott LJ, Goa KL. Terbinafine: a review of itsuse in onychomycosis in adults. Am J Clin Dermatol2003;4(1):39-65.4) Shemer A, Nathansohn N, Kaplan B, et al. Open random-ized comparison of different itraconazole regimens for thetreatment of onychomycosis. J Dermatol Treat 1999;10(4):245-249.5) Gupta AK, Shear NH. Terbinafine: an update. J Am AcadDermatol 1997;37:978-988.

GOODMAN, DEL ROSSO 35

6) Gupta AK, Ryder JE, Summerbell RC. The diagnosis ofnondermatophyte mold onychomycosis. Int J Dermatol2003;42(4):272-273.7) Tosti A, Piraccini BM, Lorenzi S. Onychomycosis caused bynondermatophytic molds: clinical features and response totreatment of 59 cases. J Am Acad Dermatol 2000;42:217-224.8) Gupta AK, Gregurek-Novak T. Efficacy of itraconazole,terbinafine, fluconazole, griseofulvin and ketoconazole in thetreatment of Scopulariopsis brevicaulis causing onychomyco-sis of the toes. Dermatology 2001;202:235-238.9) O’Donoghue NB, Moore MK, Creamer D. Onychomycosisdue to Onychocola canadensis. Clin Exp Dermatol2003;28:283-284.10) Jain S, Sehgal VN. Itaconazole versus terbinafine in themanagement of onychomycosis: an overview. J Dermatol Treat2003;14(1):30-4211) Gupta AK, Konnikov N, Lynde CW. Single-blind, random-ized, prospective study of terbinafine and itraconazole for thetreatment of dermatophyte toenail onychomycosis in theelderly. J Am Acad Dermatol 2001;44:479-484.12) Gupta AK, Maddin S, Arlette J, et al. Itraconazole pulsetherapy is effective in dermatophyte onychomycosis of the toe-nail: a double-blind placebo-controlled study. J Dermatol Treat2000;11(1):33-37.13) DeDoncker P. Pharmacokinetics of oral antifungal agents.Dermatologic Therapy 1997;3:46-57.14) Goodfield MJD, Evans EGV. Combined treatment withsurgery and short duration oral antifungal therapy in patientswith limited dermatophyte infection. J Dermatol Treat2000;11(4):259-262.15) Baran R, Gupta AK. Are boosters or supplementation ofanti-fungal drugs of any use for treating onychomycosis. J

Drugs Dermatol 2002;1:35-41.16) Sigurgeirsson B, Olafsson JH, Steinsson J, et al. Long-term effectiveness of treatment with terbinafine vs itraconazolein onychomycosis: a 5-year blinded prospective follow-upstudy. Arch Dermatol 2002;138:353-357.17) Tosti A, Piraccini BM, Stinchi C. et al. Relapses in ony-chomycosis after successful treatment with systemic antifungalagents: a three year follow-up. Dermatology 1998;197:162-166.18) Rich P. Onychomycosis and tinea pedis in patients withdiabetes. J Am Acad Dermatol 2000;43(5):S130-S134.19) Gupta AK, Chang P, Del Rosso JQ. Onychomycosis in chil-dren. Pediatr Dermatol 1998;15:464-471.20) Gupta AK, Adam P, Dlova N, et al. Therapeutic options forthe treatment of tinea capitis caused by Trichophyton ton-surans species: griseofulvin versus the new oral antifungalagents, terbinafine, itraconazole and fluconazole. Pediatr Der-matol 2001;18:433-438.21) Hall M, Monka C, Krupp P, et al. Safety of oral terbinafine:results of a postmarketing surveillance study in 25,884patients. Arch Dermatol 1997;133:1213-1219.22) Bonssmann G, Schiller M, Luger TA, et al. Terbinafine-induced subacute lupus erythematosus. J Am Acad Dermatol.2001;44:925-931.23) Dupin N, Gorin I, Djien V, et al. Acute generalized exanthe-matous pustulosis induced by terbinafine. Arch Dermatol1996;132:1253-1254.24) Park Y, Kim J, Kim C. Acute generalized exanthematouspustulosis induced by itraconazole. J Am Acad Dermatol1997;36:794-796.25) Physicians’ Desk Reference, Sporanox capsules US prod-

uct monograph, Montvale, NJ, 2003.26) Gupta AK, Katz I, Shear NH. Drug interactions with itra-conazole, fluconazole and terbinafine and their management. JAm Acad Dermatol 1999;41:237-248.27) Rex J. Itraconazole-digoxin interaction. Ann Intern Med1992;116:525.28) Kwan JT, Foxall PJD, Davidson DGC, et al. Interaction ofcyclosporin and itraconazole. 1987;ii:282.

29) Jaruratanasirikul S, Kleepkaew A. Influence of an acidicbeverage (Coca-Cola) on the absorption of itraconazole. Eur JClin Pharmacol 1997;52:235-237.30) Vickers AE, Sinclair JR, Zollinger M, et al. Multiplecytochrome P-450s involved in the metabolism of terbinafinesuggest a limited potential for drug-drug interactions. DrugMetab Dispos 1999;27:1029-1038.31) Physicians’ Desk Reference, Lamisil tablets US productmonograph, Montvale, NJ, 2003.32) Mehregan DR, Gee SL. The cost effectiveness of testingfor onychomycosis versus empiric treatment of onychodystro-phies with oral antifungal therapy. Cutis 1999;64:407-410.33) Hull PR, Gupta AK, Summerbell RC. Onychomycosis: anevaluation of three sampling methods. J Am Acad Dermatol1998;39:1015-1017.34) Lawry MA, Haneke E, Strobeck K, et al. Methods for diag-nosing onychomycosis: a comparative study and review of theliterature. Arch Dermatol 2000;136:1112-1116.Del Rosso JQ, Daniel CR III. Disorders of the nail. In: Dale DC,Federman DD (Eds). Scientific American Medicine WebMD,Vol 2, New York, 2003, pp 519-525

36 OPTIMAL TREATMENT OF ONYCHOMYCOSIS: A STATUS REPORT ON ORAL ANTIFUNGAL THERAPY

JAOCD Founding Sponsor

38

Pimecrolimus 1% cream is a non-steroidal calcineurin inhibitor approved inthe United States for treatment of atopicdermatitis. Available studies demonstrateanti-inflammatory activity through inhibi-tion of cytokine production and releasefrom activated T lymphocytes.1,2 As com-pared to cyclosporin and tacrolimus,based on various laboratory models,pimecrolimus has been reported todemonstrate greater skin selectivity, com-parable or superior anti-inflammatoryactivity and less immunosuppressiveactivity.1-3 Efficacy and safety have beendemonstrated in short (6 weeks) andlong-term (12 months) studies in adultand pediatric patients (age 3 months to17 years) with atopic dermatitis.1 ,2 ,4 -8

Although FDA-approved for the treatmentof mild to moderate atopic dermatitis, effi-cacy has also been demonstrated inpatients with severe disease.1,2,4-8 As sys-temic absorption is usually undetetectableor negligible with chronic administration,pimecrolimus use is continued until clear-ance of disease is achieved and restartedat the immediate onset of signs andsymptoms.3,6-8 Maintenance therapy withpimecrolimus 1% cream has been shownto be topical steroid-sparing.6-8

The rapid population growth of the LasVegas, Nevada community has resultedin an observed increase in allergic-relateddisorders, including atopic dermatitis, pre-senting to practicing clinicians. Diseaseflares are common throughout the year,due to construction-related airborne dustcirculation and intermittent wind storms,dry desert climate exacerbating xerosisand epidermal barrier disruption, intermit-tent abrupt temperature fluctuations andincreased foliage (ie. residential and com-mercial landscaping, golf courses)increasing release of airborne allergens.

A multicenter observational evaluationwas initiated in February 2002 examiningopen-label usage of pimecrolimus 1%cream for eczematous dermatitis includ-ing atopic dermatitis, and other applica-tions (“off label” uses) including handeczema, chronic intermittent eyelid der-matitis, psoriasis, vitiligo and seborrheicdermatitis. Tabulated results includeglobal evaluation of efficacy, patientassessment of timing of improvement insigns and symptoms of disease, definitionof usage as monotherapy or in combina-

tion with other therapies, adverse reac-tions and evaluation of previous thera-pies. The goal of the evaluation is toreport “real world” experience reflective ofprivate practice usage from three sepa-rate general dermatology offices, of pime-crolimus 1% cream in adults and childrenin order to (1) better define optimal clini-cal applications and limitations of therapyand to (2) evaluate consistencies and dif-ferences as compared to controlled, piv-otal trials. Reported results includeexperience documented between Febru-ary 2002 – January 2003.

Observational EvaluationAt the initial encounter, the following

information was documented:

• Patient name / date of birth

• Total duration of disease

• Duration of disease

• Past medical history

• Family history

• Previous therapies used

• Clinical presentation

• Anatomic sites affected

• Symptoms / severity (rated by patient asmild, moderate, severe)

• Overall disease severity (rated by physi-cian as mild, moderate, severe)

• Recommended skin care products (ie.cleansers, emollients)

• Recommended therapy (pimecrolimuscream + any other medications pre-scribed)

• Follow-up instructions

At follow-up visit(s), the following infor-mation was documented:

• Response to therapy

o visible eruption (improvement rated by physician as completely cleared, mod-erate, minimal or none)

o symptoms ie. pruritus (improvementrated by patient as completely resolved,moderate, minimal or none)

• Resistent anatomic sites

• Tolerability

• Adverse reactions

• Stoppage of any medications

• Changes in therapy

• Follow-up

In all patients, topical pimecrolimus 1%cream was applied twice daily. The term“combination therapy” refers to concomi-tant use of pimecrolimus 1% cream twicedaily and a specified topical corticosteroidagent applied twice daily after applicationof topical pimecrolimus or once daily atbedtime.

Patient follow-up was based oninstructions given at the discretion of thephysician at each encounter consistentwith what would be recommended in aprivate practice scenario. The pediatricage range was defined as 16 years ofage or less. Patients included in theanalysis were instructed to utilize specificbasic skin care products selected by thetreating dermatologist while undergoingtherapy. The choices included brandedcleansers and emollients recognized toexhibit a low risk of associated irritation.Follow-up therapy after the initial visit wasusually scheduled for 2 – 4 weeks.

ResultsA total of 300 patients were treated

with pimecrolimus 1% cream twice dailywith or without other concomitant thera-pies for a variety of dermatologic presen-tations. In previously treated patients, allwere off of any prescription therapyrelated to their skin condition for at leasttwo weeks prior to presentation. The dis-ease states treated were as follows:

- Atopic Dermatitis (children) 50%(34% mild / 56% moderate / 10% severe)

- Atopic Dermatitis (adults) 20%(91% moderate / 9% severe)

- Recurrent Hand Eczema (adults) 10%(subacute or chronic presentations)

- Idiopathic Scrotal Pruritus (adults) 2%(early lichen simplex)

- Recurrent Eyelid Dermatitis (adults)10% (subacute or chronic presentation)

- Seborrheic Dermatitis (adults) 5%

DISKIN, DEL ROSSO, SCHREIBER 39

Observational Use of Pimecrolimus 1% Cream: Clinical Results and Applications Based on a

Large Private Practice Experience

Richard Diskin, D.O., James Q. Del Rosso, D.O., FAOCD, Saul Schreiber, D.O.

(face, periauricular)

- Other Disease States 3%

Alopecia Areata 5 patients (discoid scalp patches)

Psoriasis (adults)2 patients (localized)

Vitiligo (adults)2 patients (localized)

Atopic DermatitisPediatric Group. One hundred-fifty

children (81 females / 69 males) withatopic dermatitis were treated with pime-crolimus 1% cream twice daily. Clinicalpresentation included involvement of theface (17%), neck (16%), extremities(96%) and trunk (67%).

Mild disease: In patients with mild dis-ease, pimecrolimus 1% cream was uti-lized as monotherapy in 73% of cases;the remainder were prescribed a low tomid potency topical corticosteroid to useonce or twice daily during the first 1 – 2weeks of treatment. In those receivingpimecrolimus 1% cream alone, 79%reported resolution of pruritus within 1week and 86 % reported marked or com-plete clearance of the eruption within thefirst 2 – 4 weeks. In those using initialcombination therapy, 94 % experiencedresolution of pruritus within in 1 week andmarked or complete clearance of theeruption within 2 – 4 weeks or less. Onereport of mild transient burning was notedafter application of topical pimecrolimusalone over the first few days of use; thisdid not result in discontinuation of ther-apy.

Moderate disease: Forty-four percentof patients with moderate disease usedpimecrolimus 1% cream twice daily asmonotherapy; the remainder used combi-nation therapy with a mid-potency topicalcorticosteroid once or twice daily duringthe first 1 – 2 weeks of treatment. Inthose receiving pimecrolimus 1% creamalone, 71% reported marked improve-ment or resolution of pruritus within 1 - 3weeks and 73% reported marked or com-plete clearance of the eruption within thefirst 2 – 4 weeks. In those using initialcombination therapy, 86% reportedmarked improvement or resolution of pru-ritus in 1 – 2 weeks and 87% demon-strated marked or complete clearance ofthe eruption within 2 – 4 weeks. Fivereports of mild transient stinging or burn-ing were noted after application of topicalpimecolimus therapy; therapy was contin-ued.

Severe disease: The patients present-ing with severe disease were all treatedwith pimecrolimus 1% cream in combina-tion with a mid or high potency topical

corticosteroid.

One patient also received a 7 daycourse of oral prednisolone. Markedimprovement or clearance of pruritus wasseen in 70% of patients within the first 1 –3 weeks and 60% demonstrated markedimprovement in the eruption within 2 – 4weeks. The remainder demonstrated aslower response and additional adjust-ments in therapy. Two cases of local intol-erability were noted, described as burningor stinging, that did not result in interrup-tion in treatment.

Maintenance therapy: In all groups,once control was achieved, pimecrolimus1% cream was used as monotherapy tomaintain remission with therapy initiatedat the immediate onset of disease signs(ie. erythema) or symptoms (pruritus).Topical corticosteroid therapy was used tocontrol flares, usually with a mid potencyagent.

Adult Group. Sixty adult patients (34males / 26 females) presented with atopicdermatitis and were treated; areas ofinvolvement included the neck (20%),extremities (85%) and trunk (70%).

Moderate disease: In patients withmoderate disease, pimecrolimus 1%cream was utilized as monotherapy in 50% of cases; the remainder were pre-scribed a mid potency topical corticos-teroid to use once or twice daily duringthe first 1 – 2 weeks of treatment. Inthose receiving pimecrolimus 1% creamalone, 65 % reported resolution of pruri-tus within 1 week and 75 % reportedmarked or complete clearance of theeruption within the first 2 – 4 weeks. Inthose using initial combination therapy, 80% experienced resolution of prurituswithin 1 week and marked or completeclearance of the eruption within 2 – 4weeks. Two patients treated with topicalpimecrolimus alone reported transientstinging after application that did notresult in discontinuation in treatment.

Severe disease: The patients present-ing with severe disease were all treatedwith pimecrolimus 1% cream in combina-tion with a high or ultra-high potency topi-cal corticosteroid. Marked improvementor clearance of pruritus was seen in 70 %of patients within the first 1 – 2 weeks and70% demonstrated marked improvementin the eruption within 2 – 4 weeks. Theremainder demonstrated a slowerresponse and required additional adjust-ments in therapy. No adverse reactionswere reported.

Maintenance therapy: Once controlwas achieved, pimecrolimus 1% creamwas used as monotherapy to maintainremission in 60% of patients. Therapywas initiated at the immediate onset of

disease signs (ie. erythema) or symptoms(pruritus). Mid-potency topical corticos-teroid therapy was used to control flares.The remainder maintained control ofatopic dermatitis using intermittent topicalcorticosteroid treatment alone, initiated atthe onset of a flare.

Recurrent Hand EczemaThirty adults (16 females / 14 males)

with recurrent subacute hand eczemawere treated. In all cases combinationtherapy with a mid-potency topical corti-costeroid was used. The topical corticos-teroid was used either after application ofpimecrolimus 1% cream twice daily orprior to bedtime. Forty percent of patientsreported improvement in visible eruptionand decrease in pruritus with combinationtherapy as compared to previous therapywith topical corticosteroid alone. Althoughdata was too limited to assess the role ofpimecrolimus therapy in combination withtopical coprticosteroid use in this patientgroup, reported responses suggestedbenefit in some patients. The role of topi-cal pimecrolimus as monotherapy in thispatient population requires further investi-gation. No adverse reactions werereported.

Idiopathic Scrotal PruritusSix adult males with idiopathic persis-

tent-recurrent scrotal pruritus present forat least 6 months were treated with topi-cal pimecrolimus 1% cream twice daily asmonotherapy. Three patients had previ-ously used low or mid potency topical cor-ticosteroid therapy with success followedby recurrence. The only clinical featureswere early lichen simplex without any evi-dence of other primary skin findings. Allsix patients demonstrated markedimprovement or resolution within 2 - 4weeks of therapy with pimecrolimus 1%cream. Due to the chronicity of diseaseand involvement at a naturally occludedanatomic site where topical corticos-teroids may be associated with cutaneousatrophy after prolonged use, pime-crolimus therapy was continued to main-tain disease control. No adversereactions were reported.

Recurrent Eyelid Dermatitis

Thirty adult patients (27 female / 3male) presenting with eyelid dermatitisrecurring intermittently over a period of atleast 1 – 2 years were treated with topicalpimecrolimus as monotherapy. In 90 % ofpatients, marked improvement or com-plete resolution of the visible eruption andpruritus were noted within 7 – 10 days orless. The remainder required the additionof a short course (< 1 week) of low to midpotency topical corticosteroid therapy for

40 OBSERVATIONAL USE OF PIMECROLIMUS 1% CREAM

control. No adverse reactions werereported.

Seborrheic Dermatitis Fifteen adult patients (13 males / 2

females) with recurrent seborrheic der-matitis involving the face and/or periauric-ular region were treated with topicalpimecrolimus alone. In 80% of patients,the visible eruption and pruritus resolvedwithin 7 – 10 days or less. The remaindercleared using either a short course ofmedium potency topical corticosteroidtherapy or topical sulfacetamide-sulfurtopical suspension. No adverse reactionswere reported.

Other Disease StatesAlopecia areata. Two adult females

and one female child with scatteredpatches of scalp alopecia areata weretreated with topical betamethasone valer-ate 0.12% foam followed by topical pime-crolimus twice daily. The two adultpatients developed significant regrowthrated as 75% and 60% within 4 – 6weeks. The female child exhibited partialregrowth (rated as 50% improvement)within 4 weeks. One male child demon-strated complete regrowth of hair withinan isolated patch of scalp alopecia areatawithin 8 weeks using topical pimecrolimusas monotherapy. One adult female patienttreated with a ultra-high potency topicalcorticosteroid in combination with topicalpimecrolimus demonstrated no responseto treatment after one month. None of thepatients exhibited an ophiasis pattern.Further study is needed to evaluate therole of topical pimecrolimus in alopecia

areata.

Psoriasis. Two patients with plaquepsoriasis localized to the extremities weretreated with topical pimecrolimus alone.One adult male with bilateral elbowinvolvement had developed a decreasedresponse to a high potency topical corti-costeroid that had been previously effec-tive. Tachyphylaxis was suspected. In thispatient, a frictional component (Koebner’sphenomenon) was also suspected. Topi-cal pimecrolimus as monotherapy with-out occlusion produced significantimprovement within 6 weeks. A secondmale patient with chronic plaque psoriasisinvolving the knees demonstrated little tono improvement with topical pimecrolimustherapy. The role of topical pimecrolimusin the treatment of various clinical presen-tations of psoriasis warrants further study.

Vitiligo. One adult female patient withsmall scattered patches of vitiligo on theupper extremities demonstrated signifi-cant partial repigmentation within 3months of topical pimecrolimus monother-apy. A second adult female patient withextensive vitiligo on the dorsum of thehands exhibited no improvement.

ConclusionsAn open evaluation in 3 private prac-

tice centers support the following conclu-sions:

• Topical pimecrolimus 1% cream appliedtwice daily was effective and well toler-ated when used as monotherapy inpatients with mild to moderate atopic der-matitis in adults and children.

• The use of combination therapy withtopical pimecrolimus and topical corticos-teroids demonstrated significant efficacyin patients with all severities of atopic der-matitis and was well tolerated. Whether ornot the combination therapy approachprovides additive or synergistic therapeu-tic benefit would require a properlydesigned, controlled evaluation.

• There was no apparent antagonisticeffect or associated local adverse reac-tions associated with a short term combi-nation therapy approach (less than 4weeks). Although case numbers are lim-ited, combination therapy may be of ben-efit in some patients with alopecia areata.

• Topical pimecrolimus therapy waseffective in the management of idiopathicscrotal pruritus, recurrent eyelid dermati-tis and seborrheic dermatitis.

Referencesi1. Wellington KW, Jarvis B. Spotlight on topical pimecrolimusin atopic dermatitis. Am J Clin Dermatol 2002;3:435-4382. Reitamo S. Topical macrolide immunomodulators for ther-apy of atopic dermatitis. In: Bieber T, Leung DYM, Eds. AtopicDermatitis, First Edition. Marcel Dekker Inc., New York, 2002,pp 541-5653. Stuetz A, Grassberger M, Meingassner JG. Pimecrolimus(SDZ ASM 981) – preclinical pharmacologic profile and skinselectivity. Sem Cutan Med Surg 2001;20:233-2414. Hebert AA, Warken KA, Cherill R. Pimecrolimus cream 1 %:a new development in nonsteroid topical treatment of inflam-matory skin diseases. Sem Cutan Med Surg 2001;20:260-2675. Eichenfield LF, Lucky AW, Boguniewicz M, et al. Safety andefficacy of pimecrolimus (ASM 981) cream 1% in the treatmentof mild and moderate atopic dermatitis in children and adoles-cents. J Am Acad Dermatol 2002;46:495-5046. Kapp A, Papp K, Bingham A, et al. Long-term managementof atopic dermatitis in infants with topical pimecrolimus, a non-steroid anti-inflammatory drug. J Allergy Clin Immunol2002;110:277-2847. Wahn U, Bas JD, Goodfield M, et al. Efficacy and safety ofpimecrolimus cream in the long-term management of atopicdermatitis in children. Pediatrics 2002;110:1-88. Meurer M, Folster-Holst R, Wozel G, et al. Pimecrolimuscream in the long-term management of atopic dermatitis inadults: a six-month study. Dermatology 2002;205:271-277

DISKIN, DEL ROSSO, SCHREIBER 41

Introduction:Tattooing is a common art in the west-

ern world. Many tattoo related reactionshave been reported, therefore, it is likelythat a physician or surgeon will encounterpatients having reactions of some fashionto a tattoo. The vast majority of reportedreactions to tattoos have been involvingtemporary tattoos and also permanenttattoos associated with colored inks suchas red, blue and green. Few reports arefound in literature involving black perma-nent ink reactions. We describe one suchreaction to black ink in a permanent tattooand discuss other reported black ink reac-tions in permanent tattoos as well astreatment options available.

Case Report: A 26 year old white female with no pre-

viously known allergies, and in good gen-eral health, reported to clinic complainingof discomfort and irritation at the site of apermanent tattoo which was placed threeweeks earlier. The tattoo was a circum-ferential band of blue, black and red ofabout two centimeters in width locatedaround her left upper arm.

Examination revealed erythema aswell as a yellow/green papular eruptiononly in black pigmented areas. Red andblue areas of the tattoo were unremark-able (Figure 1). Axillary lymph nodeswere not palpable.

Biopsy was not performed at this timedue to the patient’s wishes to preservethe tattoo and try conservational therapyfirst. The clinical diagnosis made con-sisted of allergic contact/foreign body der-matitis secondary to black pigment withpossible localized infectious component.

Treatment consisted of oral cephalexin500 milligrams twice daily for ten daysand 0.1% hydrocortisone butyrate creamapplied twice daily.

Upon follow-up nine days later, the

affected areas demonstrated completeresolution. Only minor hypopigmentationwithin the black pigmented areas (Figure2) remained. Topical steroid usage wasdiscontinued at that time. Patch testingwas offered upon follow-up, however, thepatient declined.

Comment:It has been estimated that 3-5% of the

western population have tattoos 1. Wecan intuitively assume that in certain sub-sets of the population, this percentagemay be higher. From data collected in1999, Dr. Stephens found that 27% ofU.S. Marine Corps and Air Force recruitshave tattoos 2. Data collected in 1995-1996 suggests that 4.5% of adolescentshad a tattoo 3. American Family Physicianreports a poll published in AmericanAcademy of Pediatrics News that foundone in ten adolescents had a tattoo and55% of the remaining were contemplatinggetting one 4. Therefore, we should expectto see tattoo allergies at a higher inci-dence in certain subsets of the popula-tion, such as in the military andadolescent groups.

Regardless of the exact numbers, it isclear that tattooing is common in our soci-ety yet there is surprisingly little publishedliterature found concerning reactions toblack permanent tattoos.

A literature search for reported casesof allergic reactions to permanent blacktattoo ink revealed a case of pruritic ery-thematous papules in and around anIndia Ink tattoo which was only partlyresponsive to topical steroid therapy 5.

A similar case to ours was reportedconsisting of a perilesional pruritis,edema and erythema with crusts andpapulovesicals, which resolved followingtreatment with topical 1% hydrocortisoneplus five days of oral clarithromycin 6.

Doctor Goldberg reported a general-ized lichenoid reaction (pruritic macular

rash) localized to a black, blue, green andred pigmented tattoo, which reoccurredfollowing steroidal treatments and wassurgically removed. The patient contin-ued to suffer from reduced intensity reoc-currences, which were controlled with oralsteroid therapy 7.

In another report, a foreign body gran-ulomatous type reaction occurred to theblack pigment of tattoos placed ten yearsearlier. In this case, the inflamed andpuritic reaction responded well to 0.05%diflorasone diacetate applied twice daily 8.

Some unique conditions have alsobeen described relating to permanent tat-too black dye. Doctor Jacob describes acase of guttate psoriasis erupting oneweek following placement of a permanentblack tattoo on the upper arm 9. A mor-phea-like reaction was reported involvinga green, purple and black tattoo 10. Sys-temic and pulmonary sarcoidosis present-

42 LOCAL REACTION TO BLACK INK IN A MULTI-COLORED PERMANENT TATTOO

Local Reaction to Black Ink in a multi-colored Permanent Tattoo

Scott J.M. Lim, DO, Joseph Nellis, BS

AbstractA 26 year old female presented to the clinic complaining of discomfort and irritation involving a recent tattoo on her upper arm.

A papular reaction on an erythematous base was noted involving the black colored areas of a circumferential blue, red and blackcolored permanent tattoo on her upper left arm. The clinical diagnosis made consisted of allergic contact/foreign body dermatitissecondary to black pigment with possible localized infectious component. A case report and literature review of reactions to blackpermanent tattoo ink follows. Literature reviewed utilizing the PubMed search engine with key words: tattoo, reaction, black ink,and laser in varied combinations.

Figure 1

Figure 2

ing via tattoo reactions has also beendescribed 11-12.

From the cases reviewed, we can seethat reactions to black permanent tattoodye do in fact occur. The reactions maybe self limiting or may be progressive.Some reactions may require more thanone treatment, may reoccur, or mayrequire removal via surgery or laser. Weinitiated conservative therapy in our case,which fortunately cleared.

Conclusion:Tattoo reactions may resolve sponta-

neously, clear with conservative treat-ment, reoccur or become chronic, or theymay become severe and/or systemic.This can pose a dilemma when trying todetermine the patient’s prognosis anddecide on management. Biopsies canassist in diagnosis, however, it wouldrequire some degree of destruction to theartwork which may not be desired by thepatient. Cultures of wounds may helpdiagnose or exclude infections, however,open wounds would expectedly grow nor-mal skin flora, therefore, may be lesshelpful. Patch testing can help identifythe causative agent, however, obtaininginformation from ink manufacturers con-cerning ingredients may be difficult, aswell as obtaining exact lot and manufac-turer samples from the tattoo artist. Inaddition, the patient may find patch test-ing economically and logistically cumber-some. These dilemmas can impedemeaningful patch testing and withoutknowledge of exact allergens, it can bedifficult to foresee future reactions withtattoos. Our patient was not deterredfrom pursuing additional tattoos despitebeing advised of the risk for future allergyreactions.

The physician confronting a tattooreaction may have to make treatmentdecisions based solely on clinical presen-tation, as in our case. We suggestedconservative management initially. Otherpossibly useful strategies might includeadding an antihistamine and/or utilizingoral steroids for more generalized or per-sistent reactions. One may also considerthe addition of an immunomodulator aswell, such as tacrolimus or pimecrolimus.Bacterial cultures and/or biopsy may beuseful to further direct treatment as well.We did neither culture nor biopsy, how-

ever, their utility is recognized. Biopsyrecommendations may be difficult to jus-tify for localized, less involved reactions,due to the destruction of the artwork,however, we recommend they be offeredin order to assist in diagnosis and excludeother pathology. Bacterial cultures wouldnaturally help adjust antimicrobial therapyif a causative organism was found.

Persistent, severe, atypical der-matoses and/or reoccurrences mayrequire removal. Tattoos can be removedvia surgical excision or via laser. Surgicalremoval would be the surest and quickestway for removal of a tattoo instigating areaction, but would result in surgical scarsand may not be feasible due to the sizeand location of the tattoo. Laser treat-ment may be a better approach if thearea to be excised is too large or anatom-ically not advisable to excise, however,multiple laser treatments may be requiredto remove the tattoo 13-14.

There are relatively few reports foundin our literature search concerning theability of lasers to resolve persistent tat-too allergies. Of those reported, the suc-cessful treatments involved reactions tored ink 15,16,20. Successful treatment of alichenoid reaction15 and a flaky pruriticreaction16 has been published with nocomplications noted. On the other hand,there has been a report of a localeczematous tattoo reaction involvinggreen and yellow dyes evolving into gen-eralized urticaria for three months follow-ing laser treatment17. Other reports ofreactions following laser treatment of tat-toos involve elective treatments of non-reactive tattoos. These dermatosesrange from localized reactions followingtreatment of a multicolored tattoo18 tomore generalized reactions such asurticaria and diffuse papular pruritis19.However, laser removal can be targetedto certain colors and does not leave ascar as would other removal methods. Ithas been published that re-tattooing of apreviously laser removed tattoo due toallergic reaction may be successfullyaccomplished with a different coloredink20. Therefore, laser removal may be amore desirable option for the reasonsalready stated, or for those who wish toretain as much of their artwork as possi-ble or simply refuse surgery as an option.Due to the risks and complications inher-

ent with both surgery and laser removal,we suggest that the patient be asinvolved and informed as possible aboutthe options available.

Given the popularity of tattoos and thelikelihood for tattoo reactions, we look for-ward to more reports regarding types ofreactions, possible prognostic indicators,treatment options and treatment out-comes in the future.

References1. McCormack Brown K, Perlmutter P, McDermott RJ. Youthand tattoos: what school health personnel should know. Jour-nal of School Health 2000; 70 (9): 355-60.2. Stephens, MB. Behavioral risks associated with tattooing.Fam Med. 2003 Jan;35(1):52-4.3. Roberts TA, Ryan SA.Tattooing and high-risk behavior inadolescents.Pediatrics. 2002 Dec;110(6):1058-63.4. Quantum Sufficit. American Family Physician; 1997 Jul;56(1).5. Gallo R, Parodi A, Cozzani E, Guarrera M. Allergic reactionto India ink in a black tattoo. Contact Dermatitis. 1998Jun;38(6):346-7.6. Treudler R, Tebbe B, Krengel S, Orfanos CE. Allergic con-tact dermatitis from black tattoo. Contact Dermatitis. 1997Dec;37(6):295.7. Goldberg HM. Tattoo allergy. Plast Reconstr Surg. 1996Dec;98(7):1315-6.8. Tope WD, Arbiser JL, Duncan LM. Black tattoo reaction: thepeacock's tale.J Am Acad Dermatol. 1996 Sep;35(3 Pt 1):477-9. 9. Jacob CI. Tattoo-associated dermatoses: a case report andreview of the literature.Dermatol Surg. 2002 Oct;28(10):962-5.10. Mahalingam M, Kim E, Bhawan J. Morphea-like tattooreaction.Am J Dermatopathol. 2002 Oct;24(5):392-5.11. Jones MS, Maloney ME, Helm KF. Systemic sarcoidosispresenting in the black dye of a tattoo. Cutis. 1997Mar;59(3):113-5.12. Collins P, Evans AT, Gray W, Levison DA. Pulmonary sar-coidosis presenting as a granulomatous tattoo reaction. Br JDermatol. 1994 May;130(5):658-62.13. Leuenberger ML, Mulas MW, Hata TR, Goldman MP, Fitz-patrick RE, Grevelink JM. Comparison of the Q-switchedalexandrite, Nd:YAG, and ruby lasers in treating blue-black tat-toos. Dermatol Surg. 1999 Jan;25(1):10-4.14. Kuperman-Beade M, Levine VJ, Ashinoff R. Laser removalof tattoos.Am J Clin Dermatol. 2001;2(1):21-5.15. Hindson C, Foulds I, Cotterill J. Laser therapy of lichenoidred tattoo reaction.Br J Dermatol. 1995 Oct;133(4):665-6.16. Dave R, Mahaffey PJ. Successful treatment of an allergicreaction in a red tattoo with the Nd-YAG laser. Br J Plast Surg.2002 Jul;55(5):456.17. Zemtsov A, Wilson L. CO2 laser treatment causes localtattoo allergic reaction to become generalized. Acta DermVenereol. 1997 Nov;77(6):497.18. England RW, Vogel P, Hagan L. Immediate cutaneoushypersensitivity after treatment of tattoo with Nd:YAG laser: acase report and review of the literature.Ann Allergy Asthma Immunol. 2002 Aug;89(2):215-7.19. Ashinoff R, Levine VJ, Soter NA. Allergic reactions to tattoopigment after laser treatment. Dermatol Surg. 1995Apr;21(4):291-4.20. Brodell RT. Retattooing after the treatment of a red tattooreaction with the CO2 laser. J Dermatol Surg Oncol. 1990Aug;16(8):771

LIM, NELLIS 43

TIP 1-Refer to a ‘reception area’ not a ‘wait-

ing room’. Nobody likes to wait.

TIP 2-Keep patients informed of approximate

time until they will be seen.

I realized how important this really wasone day at an airport. I arrived on time atmy departure gate and the sign said‘Delayed’. It did not say how long thedelay would be. When I asked the gatepersonnel how long the wait might be, allthey would say is the flight is delayed andthey didn’t know how long it might be. Iwas stuck! No options. If they wouldhave said 2 hours, I may have left the air-port and went home; if it was an hour Icould have gone to the airport restaurantand had lunch. I learned for this experi-ence. From that day on, I had my frontoffice staff walk into the reception area(not talk though the sliding glass win-dows) whenever I was more then 20 min-utes behind schedule. They wouldannounce to all of the patients that I wasrunning behind by whatever the period oftime that I was delayed. The patientswere then given 3 options: 1) they couldcontinue to wait, 2) they could go to thediner across the street for coffee and adoughnut on us and come back or 3) theycould reschedule their appointment. Itwas amazing how this improved ouroffice! We put the decision on the patientand they now had a choice. Less dis-gruntled patients. That’s a good thing!

TIP 3-Answering the phone. I instituted this

phrase “Doctors office, this is Mary, howmay I direct your call?” No more “pleasehold” or “may I put you on hold”. Nobodylikes to wait and nobody likes to beplaced on hold. They don’t mind being

“directed”. So no matter what the patien-t’s reply is to “Doctors office, this is Mary,how may I direct your call?” your officestaff has the opportunity to place thatpatient on hold as they are ‘directed’.Think about it! What a simple idea.

TIP 4-Recall cards. Have 3 by 5 recall cards

to remind patients of their appointments.These cards can be used to remind thepatient to make an appointment (maybean annual exam appointment) or it mayactually have the time and date of anupcoming appointment. Have the patientaddress the card themselves at thecheckout window. Place them into anindex card file system under the monthyou wish to send out the reminder. Youwill have less no shows and morepatients calling to inform you that theyhave a conflict in their schedule. The netresult is less open slots in your schedule.

TIP 5-Flag system-For a one or two doctor

office the flag system works well. Theseare inexpensive plastic flags that flip outand are attached to the wall next to eachexam room door. You can get them withanywhere from 2 to10 colored plasticflags.

Interpretation of the flags:

* No flags protruding sig-nify a clean room

* Red flag means there is apatient is in the room

* Green flag means it’s anew patient (you may intro-duce yourself differently toa new patient!)

If you have 4 rooms thenthe blue flag could be the

first room to see, the yellow flag could bethe second room to see, etc. If there aretwo doctors in the office then each doctorcan get their own colored flag. It soundscomplex but there is no confusion as towhich patient is next. The system islearned by all very quickly. An examplewould be that a room with a red, greenand blue flag would easily tell you thatthat room has a patient in it, that thepatient is a new patient and that patient isthe next to be seen. When the doctorwalks into that room he or she flips all butexcept the red flag and that will signifythat there is a patient in that room.

TIP 6-Rack/Jot System-This works for a

practice with 2 or more doctors. Here,when a patient is placed in a room, theirchart is placed in a rack near thedoctor/nurse station or on the patient’sdoor. A blank sheet of paper is taped tothe counter at the doctor/nurse station.This paper is used for the entire day.When apatient isplaced in aroom, thatroom num-ber is thenwritten onthat pieceof paper. Ifthe patientneeds tosee a particular physician, then the initialof that physician is placed next to theroom number on that piece of paper.

When the doctor looks at the paper, heor she immediately knows which patientthey are to go to see next. If the patientagreed to see the first available doctor,then only the room number, with no doc-tor’s initials, is jotted down on the piece of

Tips For a Smooth Running Dermatology Practice

Jay S. Gottlieb, D.O., F.O.C.O.O.

AbstractPresented are some office tips that have been implemented to help the author run two busy offices over a 20 year career. Many

of these tips may help you better manage your practice.

I began my own practice in 1982. Previously, I had worked with some very smart physicians. Let me preface this article by stat-ing that I have not had an original idea or thought in my entire life. Everything is copied or borrowed. Many of these tips that I amabout to relay to you were copied from Dr. Warren Brandes, Dr. Henry Sonnenshein and Dr.Michael Sherbin, who were my oto-laryngology trainers. Other tips were taken from Dr. Art Lieberman and Dr. Terry Podolsky, with whom I worked part-time in a familypractice in Michigan. They taught me a lot of “business medicine”. Dr. Murray Zedeck gave me my post doctorate training in “busi-ness medicine” over many lunch dates here in south Florida. It gives me great pleasure sharing these tidbits of information with mycolleagues. Here we go….these are tips that have helped me manage my practice:

44 TIPS FOR A SMOOTH RUNNING DERMATOLOGY PRACTICE

paper. The next available doctor wouldsimply put his or her initial next to theroom number and circle it and then pro-ceed to that room. If office personnelneed to know where any particular doctoris at any given time, all they need to do islook at this piece of paper taped on thecounter at the doctor/nurse station andthey will see which room was last circledby any given physician. Too easy!

TIP 7-Office reflection policy- This is what

your office says about you! Assign spe-cific office personnel to these tasks. Per-sonnel can change tasks weekly. Onechecks the dates on the magazines in thereception area (patients may equate theaged reading material in your receptionarea with how well you keep up with yourown medical journals!) The same personchecks the reception area at least 3 timesduring the day for cleanliness. One per-son checks the restrooms for cleanlinessat least 3 times a day. All personnel(including doctors) pick up pieces ofpaper that may be on the floor in commonarea or in exam rooms. All personnelmust know that each exam room must beclean and no dirty instruments left in theexam room before a patient is escortedinto that room.

TIP 8- Evaluation cards. Don’t be afraid to

evaluate your practice. These cards canbe carried in your pocket. They arestamped and self addressed back to apost office box that you or your spouseshould pick up every week or so. Don’tallow your staff to pick these up! Theymay get tossed if they don’t like what theysee! The card should address:

• Did the physician take appropriate inter-est in them and their medical condition?

• Did they feel like the physician under-stood their concerns and what was theirperceived quality of care?

• What was their experience with thecheckout process?

• How would they rate their overall experi-ence in your office?

• Ask if they would feel comfortable refer-ring a friend or family member to youroffice ?

• How quickly was their call wasanswered when they called to make theappointment?

• How long were they placed on hold?

• How long it took to get an appointment?

• How clear the directions were to theoffice?

• Was parking adequate ?

• Were they greeted in a courteous fash-ion?

• Was the reception area clean and com-fortable?

• Were they informed of how long the waitwould be until seen by the physician?

• How long did they have to wait beforethey were seen by the physician?

These inquires can be scored on a 1to10 numeric basis. You, the physician,should hand the patient this survey cardwhen you complete your visit and person-ally ask them to please complete this cardhonestly and send it back. Explain thatthis is very important to you and will helpyou make your office better for yourpatients. I experienced over a 90%response rate when I surveyed mypatients in this manner. The alternative isto run your practice on the hope thatthings are going well. You can also utilize‘mystery shoppers’ to test your officesphone etiquette and how well your officeis doing with your initial contacts byphone. Your can judge the number ofrings until their call is answered, ifemployees identify themselves appropri-ately, the hold time, level of professional-ism and overall perception. There arecompanies that you can hire to do allsorts of office evaluations to help assurethat you, in fact, are running an efficientand courteous office.

TIP 9-Outsource! Various

tasks in your practice arecritical and need to be doneefficiently. If you find thatcertain areas continuouslyfall behind and they arehaving a negative impacton your practice, youshould consider outsourc-ing that task. This may bebilling, cleaning the facility or transcrip-tions. I have instituted outsourcing tran-scriptions. I found that I was runningfurther and further behind in my transcrip-tions. There were many times that Iwould either receive a call from a patientor see a patient back in the office and mytranscription was still not back on thechart. This was having a negative impacton patient care and also making me lookbad when I had to ask the patient whatmedications I (or my associates) hadplaced the patient on.

I interviewed several “overnight” tran-scriptions services. I eventually settledon a company called GL Transcriptions(561-998-1981). They guaranteed a 24hour turn around time. I now dictate intoa digital recorder. I am able to usemacros (say a phrase that can trigger aparagraph of dictated script!). I download

them via the internet at the end of theday. By the next morning an entry leveloffice staff member is able to print eachdictation and have it on the chart by noon!Boy do I look good now! Talk to Gary atGL Transcriptions, he got me off to a verysmooth transition with this new system.

TIP 10- Account for each and every patientencounter form (superbill). Have eachencounter form sequentially numbered. Ifa patient pays cash or sometimes evenwith a check (“that’s okay, I will just stampthe doctors name on your check!”) andthat superbill gets tossed then you will beout of a lot of money, or worse, out ofbusiness! Account for each superbill. Ihad an assigned staff member put thesuperbills in order at the end of each day.It would take this entry level person about45 minutes to perform this task. It madeaccounting for superbills quite easy. Itwas to clear to the entire office personnelthat this aspect of the practice was underclose scrutiny.

TIP 11- Hold office personnel meetings on a

regular basis. The doctors must attendthese meetings! If the meetings are to beseen as important to the office staff(which they are!), then the doctors mustbe present to listen and to have input.

TIP 12-Respect and thank your office staff.

Each member of the office staff is animportant link of the chain that makesyour practice work. Every link is impor-tant and must be appreciated and recog-nized fully for what they contribute to theoverall success of the practice. I came tounderstand this important concept in theoperating room. If an orderly did notproperly prepare the patient and bringthem to the operating room or if theemployees in the instrument room did notcare for the surgical instruments appropri-ately, then the operation about to be per-formed would not have a successfuloutcome. I was the surgeon, but I wasuseless without the other members of thesurgical team. It always amazed mewhen a surgeon was abusive with theoperating room personnel. The same istrue in our offices! Each member needsto be recognized for their contribution tothe practice in order to have an efficientand orderly practice.

TIP 13-Don’t do it for the money! Early in my

career, Dr. Barbara Ross Lee, one of mymentors, told me to always keep my prior-ities in order. She told me that I neededto look forward to going to work each day,but, more importantly, that I needed tolook with greater anticipation to leavingwork and going home at the end of each

GOTTLIEB 45

day. There was a lot of wisdom in thatsuggestion. In my first year of practice Idid about 12-15 facelifts. In my opinion (Iam usually my own worst critic) myresults were very good. But, I found theprocedure quite boring and that I reallydidn’t like working with that particularpatient mix. I decided that rhytidectomywas one procedure that I would discon-tinue performing. The bottom line is that Ireally didn’t enjoy the procedure or thatpatient mix. Design your practice so thatyou enjoy what you do. There will alwaysbe some things that we don’t enjoy doingand yet we need to do them (for me, in

otolaryngology it was cerumin impactionsand dermatology, it is the tearful femalepatient with diffuse hair loss at 4:45pm).Bottom line, limit what you don’t enjoydoing. The money just isn’t worth it!

Now that I have presented these 13tips to running a smooth operation, I feelmore at peace with myself. After all theseyears of impressing my friends, familyand colleagues with my ability to havecreated an enjoyable and smooth runningpractice, I have come clean! I haveopenly and publicly admitted that none ofmy success in practice was of my own

doing. I copied and borrowed as I wentalong. Shameful? Not really. Successdoes leave a trail. Talk to people that arehaving the type of success that you wantin your practice and in your life. It’samazing when you ask a successful per-son how they did it, they will be more thenhappy to talk to you about their success.As they say, “Just do it!”

Contact Information:Jay S. Gottlieb, D.O.3700 N. 32nd TerraceHollywood, FL 33021Jay1953@aol.com

46 TIPS FOR A SMOOTH RUNNING DERMATOLOGY PRACTICE

B A S E L I N E W E E K 1 2

Patient treated with TAZORAC ® Cream 0.1% q.d.

Because retinoids may cause fetal harm when administered to a pregnantwoman, TAZORAC® Cream is contraindicated in women who are or who may become pregnant. Women should use adequate birth controlmeasures when TAZORAC® Cream is used.

TAZORAC® Cream 0.1% is indicated for acne vulgaris. The most frequent adverse events reported during clinical trials for the treatment of acne vulgaris were seen in 10% to 30% of patients and included, in descending order, desquamation, dry skin, erythema, and burning sensation.

These unretouched photographs represent actual clinical experience withTAZORAC ® Cream 0.1%. However, as with all medications, results may vary.

By week 4, a significantly greater reduction in comedones, 21% vs 14% for vehicle (P ≤ .05)1

46% reduction in open and closed comedones by week 12 vs 27% for vehicle (P ≤ .001)1

41% reduction in inflammatory acne byweek 12 vs 27% for vehicle (P = .01) 1

Tolerability of TAZORAC ® Cream 0.1% proven to be comparable to Differin®gel 0.1%in a 4-week study of healthy volunteers 2

FAST

POTENT

ELEGANT

The differenceis in the

results.

1. Data on file, Allergan, Inc. [TAZORAC® Cream vs vehicle in acne.]2. Data on file, Allergan, Inc. [Leyden data, TAZORAC® Cream vs Differin®.]Please see adjacent page for brief summary of prescribing information.

©2003 Allergan, Inc., Irvine, CA 92612 4941391 Printed in USA 01/03

Think power. Think cream. TAZORAC is a registered trademark owned by Allergan, Inc.Differin is a registered trademark owned by Galderma Laboratories, L.P.

IN THE TREATMENT OF ACNE...

JAOCD Founding Sponsor

BRIEF SUMMARY (For full prescribing information, see package insert)INDICATIONS AND USAGE: TAZORAC® (tazarotene) Cream 0.1% is indicated for the topical treat-ment of patients with acne vulgaris. CONTRAINDICATIONS:Retinoids may cause fetal harm when administered to a pregnant woman.In rats, tazarotene 0.05% gel administered topically during gestation days 6 through 17 at 0.25 mg/kg/day resulted in reduced fetal body weights and reduced skeletal ossification. Rabbitsdosed topically with 0.25 mg/kg/day tazarotene gel during gestation days 6 through 18 were notedwith single incidences of known retinoid malformations, including spina bifida, hydrocephaly, andheart anomalies. Systemic exposure (AUC

0-24h) to tazarotenic acid at topical doses of 0.25 mg/kg/day

tazarotene in a gel formulation in rats and rabbits represented 4.0 and 44 times, respectively, the maxi-mum AUC

0-24hin acne patients treated with 0.1% tazarotene cream at 2 mg/cm2 over 15% body surface

area in a controlled pharmacokinetic study.As with other retinoids, when tazarotene was given orally to experimental animals, developmentaldelays were seen in rats; and teratogenic effects and post-implantation loss were observed in rats andrabbits at doses producing 3.5 and 85 times, respectively, the maximum exposure (AUC

0-24h) seen in

acne patients treated topically with 0.1% tazarotene cream at 2 mg/cm2 over 15% body surface area ina controlled pharmacokinetic study. In a study of the effect of oral tazarotene on fertility and early embryonic development in rats,decreased number of implantation sites, decreased litter size, decreased number of live fetuses, anddecreased fetal body weights, all classic developmental effects of retinoids, were observed whenfemale rats were administered 2 mg/kg/day from 15 days before mating through gestation day 7. A lowincidence of retinoid-related malformations at that dose were reported to be related to treatment. Thatdose produced an AUC

0-24hthat was 11 times that observed in acne patients treated with 0.1% tazarotene

cream at 2 mg/cm2 over 15% body surface area.Systemic exposure to tazarotenic acid is dependent upon the extent of the body surface area treated. INPATIENTS TREATED TOPICALLY OVER SUFFICIENT BODY SURFACE AREA, EXPOSURE COULD BEIN THE SAME ORDER OF MAGNITUDE AS IN THESE ORALLY TREATED ANIMALS. Although theremay be less systemic exposure in the treatment of acne of the face alone due to less surface area forapplication, tazarotene is a teratogenic substance, and it is not known what level of exposure isrequired for teratogenicity in humans.There were three reported pregnancies in patients who participated in the clinical trials on acne withtazarotene cream 0.1%. Two of the patients were found to have been treated with tazarotene cream andthe other had been treated with vehicle. One of the patients who was treated with tazarotene creamelected to terminate the pregnancy. The other gave birth to an apparently normal, healthy child at 36 weeks gestation. Seven pregnant women who were inadvertently exposed to topical tazarotene dur-ing other clinical trials subsequently delivered healthy babies. As the exact timing and extent of expo-sure in relation to the gestation times are not certain, the significance of these findings is unknown.TAZORAC® Cream is contraindicated in women who are or may become pregnant. If this drug is usedduring pregnancy, or if the patient becomes pregnant while taking this drug, treatment should be dis-continued and the patient apprised of the potential hazard to the fetus. Women of child-bearing poten-tial should be warned of the potential risk and use adequate birth-control measures when TAZORAC®

Cream is used. The possibility that a woman of child-bearing potential is pregnant at the time of insti-tution of therapy should be considered. A negative result for pregnancy test having a sensitivity downto at least 50 mIU/mL for human chorionic gonadotropin (hCG) should be obtained within 2 weeksprior to TAZORAC® Cream therapy, which should begin during a normal menstrual period. (see alsoPRECAUTIONS: Pregnancy: Teratogenic Effects).TAZORAC® Cream is contraindicated in individuals who have shown hypersensitivity to any of itscomponents.WARNINGS: Pregnancy Category X. See CONTRAINDICATIONS section. Women of child-bearing potentialshould be warned of the potential risk and use adequate birth-control measures when TAZORAC®

Cream is used. The possibility that a woman of child-bearing potential is pregnant at the time of insti-tution of therapy should be considered. A negative result for pregnancy test having a sensitivity downto at least 50 mIU/mL for hCG should be obtained within 2 weeks prior to TAZORAC® Cream therapy,which should begin during a normal menstrual period. PRECAUTIONS:General: TAZORAC® Cream should be applied only to the affected areas. For external use only. Avoidcontact with eyes, eyelids, and mouth. If contact with eyes occurs, rinse thoroughly with water. Retinoids should not be used on eczematous skin, as they may cause severe irritation.Because of heightened burning susceptibility, exposure to sunlight (including sunlamps) should beavoided unless deemed medically necessary, and in such cases, exposure should be minimized dur-ing the use of TAZORAC® Cream. Patients must be warned to use sunscreens (minimum SPF of 15)and protective clothing when using TAZORAC® Cream. Patients with sunburn should be advised not touse TAZORAC® Cream until fully recovered. Patients who may have considerable sun exposure due totheir occupation and those patients with inherent sensitivity to sunlight should exercise particular cau-tion when using TAZORAC® Cream and ensure that the precautions outlined in the Information forPatients subsection of the full package insert are observed.TAZORAC® Cream should be administered with caution if the patient is also taking drugs known to bephotosensitizers (e.g., thiazides, tetracyclines, fluoroquinolones, phenothiazines, sulfonamides)because of the increased possibility of augmented photosensitivity.Some individuals may experience excessive pruritus, burning, skin redness or peeling. If these effectsoccur, the medication should either be discontinued until the integrity of the skin is restored, or thedosing should be reduced to an interval the patient can tolerate. However, efficacy at reduced fre-quency of application has not been established. Weather extremes, such as wind or cold, may be moreirritating to patients using TAZORAC® Cream.Drug Interactions: Concomitant dermatologic medications and cosmetics that have a strong dryingeffect should be avoided. It is also advisable to “rest” a patient’s skin until the effects of such prepara-tions subside before use of TAZORAC® Cream is begun.Carcinogenesis, Mutagenesis, Impairment of Fertility: A long term study of tazarotene following oral administration of 0.025, 0.050, and 0.125 mg/kg/day to

rats showed no indications of increased carcinogenic risks. Based on pharmacokinetic data from ashorter term study in rats, the highest dose of 0.125 mg/kg/day was anticipated to give systemic expo-sure in the rat equivalent to 2.0 times the maximum AUC

0 -24hseen in acne patients treated with

0.1% tazarotene cream at 2 mg/kg/cm2 over 15% body surface area in a controlled pharmacokinetic study. In evaluation of photo co-carcinogenicity, median time to onset of tumors was decreased, and thenumber of tumors increased in hairless mice following chronic topical dosing with intercurrent expo-sure to ultraviolet radiation at tazarotene concentrations of 0.001%, 0.005%, and 0.01% in a gel for-mulation for up to 40 weeks. A long-term topical application study of up to 0.1% tazarotene in a gel formulation in mice terminatedat 88 weeks showed that dose levels of 0.05, 0.125, 0.25, and 1.0 mg/kg/day (reduced to 0.5 mg/kg/day for males after 41 weeks due to severe dermal irritation) revealed no apparent carcino-genic effects when compared to vehicle control animals; untreated control animals were not com-pletely evaluated. Systemic exposure (AUC

0-12h) at the highest dose was 13 times the maximum AUC

0-24h

seen in acne patients treated with 0.1% tazarotene cream at 2 mg/cm2 over 15% body surface area in acontrolled pharmacokinetic study.Tazarotene was found to be non-mutagenic in the Ames assays using Salmonella and E. coli and didnot produce structural chromosomal aberrations in a human lymphocyte assay. Tazarotene was alsonon-mutagenic in the CHO/HGPRT mammalian cell forward gene mutation assay and was non-clasto-genic in the in vivo mouse micronucleus test.No impairment of fertility occurred in rats when male animals were treated for 70 days prior to matingand female animals were treated for 14 days prior to mating and continuing through gestation and lac-tation with topical doses of tazarotene gel up to 0.125 mg/kg/day. Based on data from another study,the systemic drug exposure in the rat would be equivalent to 2.0 times the maximum AUC

0-24hobserved

in acne patients treated with 0.1% tazarotene cream at 2 mg/cm2 over 15% body surface area in a con-trolled pharmacokinetic study. No impairment of mating performance or fertility was observed in male rats treated for 70 days prior tomating with oral doses of up to 1.0 mg/kg/day tazarotene. That dose produced an AUC

0-24hthat was

6.3 times the maximum AUC0-24h

observed in acne patients treated with 0.1% tazarotene cream at2 mg/cm2 over 15% body surface area. No effect on parameters of mating performance or fertility was observed in female rats treated for 15 days prior to mating and continuing through day 7 of gestation with oral doses of tazarotene up to2.0 mg/kg/day. However, there was a significant decrease in the number of estrous stages and anincrease in developmental effects at that dose (see CONTRAINDICATIONS). That dose produced anAUC

0-24hthat was 11 times the maximum AUC

0-24hobserved in acne patients treated with

0.1% tazarotene cream at 2 mg/cm2 over 15% body surface area.Reproductive capabilities of F1 animals, including F2 survival and development, were not affected bytopical administration of tazarotene gel to female F0 parental rats from gestation day 16 through lacta-tion day 20 at the maximum tolerated dose of 0.125 mg/kg/day. Based on data from another study, thesystemic drug exposure in the rat would be equivalent to 2.0 times the maximum AUC

0-24hobserved in

acne patients treated with 0.1% tazarotene cream at 2 mg/cm2 over 15% body surface area.Pregnancy: Teratogenic Effects: Pregnancy Category X:See CONTRAINDICATIONS section. Women of child-bearing potential should use adequate birth-con-trol measures when TAZORAC® Cream is used. The possibility that a woman of childbearing potentialis pregnant at the time of institution of therapy should be considered. A negative result for pregnancytest having a sensitivity down to at least 50 mIU/mL for hCG should be obtained within 2 weeks prior to TAZORAC® Cream therapy, which should begin during a normal menstrual period.There are no adequate and well-controlled studies in pregnant women. Although there may be lesssystemic exposure in the treatment of acne of the face alone due to less surface area for application,tazarotene is a teratogenic substance , and it is not known what level of exposure is required for terato-genicity in humans.Nursing mothers:After single topical doses of 14C-tazarotene gel to the skin of lactating rats, radioactivity was detected inmilk, suggesting that there would be transfer of drug-related material to the offspring via milk. It is notknown whether this drug is excreted in human milk. Caution should be exercised when tazarotene isadministered to a nursing woman.Pediatric Use:The safety and efficacy of tazarotene cream have not been established in patients with acne under theage of 12 years. Geriatric Use: Tazarotene cream for the treatment of acne has not been clinically tested in persons 65 years of age or older.ADVERSE REACTIONS: In human dermal safety studies, tazarotene 0.05% and 0.1% creams did not induce allergic contactsensitization, phototoxicity, or photoallergy.The most frequent adverse reactions reported during clinical trials with TAZORAC® Cream 0.1% in thetreatment of acne, occurring in 10-30% of patients, in descending order included desquamation, dryskin, erythema, and burning sensation. Events occurring in 1 to 5% of patients included pruritus, irri-tation, face pain, and stinging.OVERDOSAGE:Excessive topical use of TAZORAC® Cream 0.1% may lead to marked redness, peeling, or discomfort(see PRECAUTIONS: General).TAZORAC® Cream 0.1% is not for oral use. Oral ingestion of the drug may lead to the same adverseeffects as those associated with excessive oral intake of Vitamin A (hypervitaminosis A) or otherretinoids. If oral ingestion occurs, the patient should be monitored and appropriate supportive mea-sures should be administered as necessary. Rx onlyU.S. Patent Number 5,089,509

® Registered trademarks of Allergan, Inc. ©2003 Allergan, Inc., Irvine, California 92612, USA Printed in USA

TAZORAC®

(tazarotene) Cream, 0.1%

Case ReportN.C. is a19 year-old African American

male who presented to our dermatologyclinic with a seven-year history of a per-sistent rash. The lesions began on hisproximal extremities and increased innumber and size over time. It was occa-sionally pruritic and unresponsive to treat-ment with super-high potency topicalsteroids. He stated that the rash beganapproximately one year after a bone mar-row transplant and that he was not takingany immunosuppressants when the rashstarted.

His past medical history was signifi-cant for an allogeneic bone marrow trans-plant at the age of 9 for acutemyelogenous leukemia. The patientreports that he also received chemother-apy and radiation therapy to the neck forhis leukemia prior to the bone marrowtransplant. He denied any other medicalproblems, was taking no medications,and denied drug allergies. His family his-tory was negative for chronic skin condi-tions. He was a student and deniedtobacco, illicit drugs, and alcohol.

A comprehensive cutaneous examina-tion revealed four discrete annularplaques with central clearing and aperipheral keratotic ridge, ranging in sizefrom 1.5 to 3.0 cm, on the extremities(Figure 1 and Figure 2). Four similar, butsmaller, lesions were identified on theshaft of the penis and two hyperpig-mented prurigo-like nodules were on hisabdomen and right hand. There were nooral lesions.

The clinical differential diagnosis atthat time included chronic graft versushost, lichen planus, porokeratosis ofMibelli, disseminated superficial poroker-atosis, and granuloma annulare. A 3-mmpunch biopsy was performed from his leftknee lesion. Histologically, within thecornified layer there was an elongatedcolumn of parakeratosis coming off theepidermis at a forty-five degree angle.Underneath the column of parakeratosis,

there was an absent granular layer and,focally, dyskeratotic and large ker-atinocytes with hyperchromatic nuclei.The epidermis showed uniform, mild pso-riasiform hyperplasia. Within the dermisthere was a superficial perivascular lym-phohistiocytic infiltrate. (Figures 3 to 5)These findings were considered charac-teristic for porokeratosis of Mibelli.

CommentPorokeratosis is a disorder of kera-

tinization, which is characterized histolog-ically by the presence of a cornoidlamella-a thin column of closely stacked,parakeratotic cells extending through thestratum corneum (1). Mibelli first describedPorokeratosis in 1893 (2). Today, five clini-cal variants are recognized: classic poro-keratosis of Mibelli, disseminatedsuperficial porokeratosis (DSP) and dis-

GORIN, GROPPER, HOFFMAN 49

Porokeratosis of Mibelli Occurring After Allogeneic Bone MarrowTransplant: A Case Report and Review of the Literature

Risa Gorin, DO, Charles A Gropper, MD, Cindy F Hoffman, DO

AbstractPorokeratosis is a disorder of keratinization characterized histologically by the presence of a cornoid lamella. While the associa-

tion of porokeratosis and immunosuppression has been reported, few cases have been documented after bone marrow transplant.A case of a 19 year-old African American male that developed Porokeratosis of Mibelli after an allogeneic bone marrow transplantfor acute myelogenous leukemia is presented. In addition, the salient clinical and histologic features of porokeratosis, its associa-tions with immunosuppression, premalignant potential, clinical course and treatment options are reviewed.

Figure 3 (H & E original magnificationx 20) and Figure 4 (H& E original mag-nification x 40) demonstrating theelongated column of parakeratosis,the cornoid lamella, coming off theepidermis at an angle.

Figure 5 (H&E original magnification x100). Underneath the column of parak-eratosis, there is an absent granularlayer and dyskeratotic and large ker-atinocytes with hyperchromaticnuclei.

Figure 1 and Figure 2. Well definedannular plaques with central clearingand a peripheral keratotic ridge on theright shoulder and left knee, respec-tively.

seminated superficial actinic porokerato-sis (DSAP), porokeratosis palmaris etplantaris disseminata (PPPD), linearporokeratosis, and punctate porokerato-sis. Different clinical variants have beenreported to coexist in an individual patient(3).

Classic lesions of porokeratosis ofMibelli start as small, brownish, keratoticpapules, which slowly enlarge formingirregular, annular plaques with a well-demarcated raised hyperkeratotic border.The center of the lesion is usuallyatrophic, hairless, hypo- or hyperpig-mented and can range in size from a fewmillimeters to several centimeters indiameter. Usually, only a few lesions arepresent and they can be present any-where, but are typically found on the acralareas of the extremities, thighs, and peri-genital region. Lesions can spread bykoebnerization (4).

The onset of porokeratosis of Mibelli isduring childhood and lesions slowlyenlarge over time. Lesions are usuallyasymptomatic. Family studies suggest anautosomal dominant mode of inheritance.Males are more often affected thanfemales (4).

The most common form of porokerato-sis, DSP, is a more generalized processinvolving mainly the extremities in a sym-metric, bilateral fashion. The palms,soles, mucous membranes, inguinalfolds, and axillae are spared. In half ofthe cases, lesions are restricted to sun-exposed areas (DSAP). Clinically,lesions of DSP and DSAP are small,superficial, numerous, and appear incrops. Early lesions are small, keratoticpapules, often with a central dell, measur-ing 1 to 3 mm in diameter. They may beerythematous, pigmented, or flesh col-ored. Lesions enlarge to form superficial,ring-like lesions with a slightly atrophiccenter surrounded by a very discreteridge topped by a barely visible furrow.Koebner phenomenon is not observed (5).

DSP and DSAP occur equally in bothsexes. They usually start in the third andfourth decades and are slowly progres-sive over years. Genetic studies showthat DSP and DSAP are inherited in anautosomal dominant mode with a reducedpenetrance at a young age (6). DSAP ismore often observed in geographic areaswith high sun exposure, and is extremelyrare in blacks (5,7,8). Prolonged exposureto artificial UV light (9), photochemotherapy(10), and phototherapy for psoriasis (11) canexacerbate lesions.

Lesions of PPPD are superficial, small,relatively uniform, and outlined by a dis-tinctive peripheral ridge of no more than 1mm in height. Palmar and plantar lesionsare generally more hyperkeratotic with a

more pronounced longitudinal furrow.Clinically, lesions first arise on the palmsand soles and spread in large numbersover the extremities and trunk, includingnon-sun exposed areas and mucousmembranes. Lesions may be pruritic.The onset of PPPD is usually during ado-lescence and early adulthood. It is inher-ited in an autosomal dominant mode andaffects males twice as often as females (4).

Linear porokeratosis presents in a dis-tinctly unilateral, linear manner. Clinically,the lesions are identical to those of theMibelli type, including lichenoid papules,small annular lesions, hyperkeratoticplaques with central atrophy, and thecharacteristic peripheral ridge. However,lesions are grouped and linearly arrangedon the extremities, more commonly onthe distal aspects. They may even be ina zosteriform distribution (12). Onset isusually in infancy and childhood, but nodefinite inheritance pattern has beenestablished (4). Lesions of linear poroker-atosis have been reported to have ahigher incidence of malignant transforma-tion compared to other types of poroker-atosis (13).

Punctate porokeratosis is usuallyassociated with either linear porokerato-sis or classic Mibelli. Multiple, minute,discrete, punctate, hyperkeratotic, lesionssurrounded by a thin, raised margin arepresent on the palms and soles. Lesionsmay coalesce to form plaques or may belinearly arranged.

The etiology of porokeratosis isunknown. Mibelli termed the disorderporokeratosis for its presumed origin inthe acrosyringeal portion of eccrine sweatducts, a belief supported by severalauthors (2). It is now well accepted thatcornoid lamellae emanate not only fromeccrine sweat ducts, but also frominfundibula of hair follicles, and from epi-dermis proper (1).

To some investigators, the cornoidlamella represents a defect in cornifica-tion. Reed and Leone proposed thatporokeratosis of Mibelli could be relatedto mutant cellular “clones” of epithelialcells in the epidermis, and the cornoidlamella was a marker for the boundarybetween the abnormal clonal populationand the normal epithelium (14). This the-ory assumes that changes in the dermisbeneath porokeratotoic lesions are sec-ondary to those in the epidermis and notpart of the causal mechanism (14,15). Addi-tionally, altered Langerhans cell surfacemarkers in lesional DSAP skin inimmunosuppressed subjects was foundby Manganoni, et al. suggesting thataltered immune surveillance by epidermalLangerhans cells may allow the develop-ment of an abnormal clone of epidermalkeratinocytes (16).

In contradiction to Reed and Leone’shypothesis, there are reports suggestingthat dermal injury could be an initiatingfactor in the pathogenesis of porokerato-sis (1). Wade and Ackerman have hypoth-esized that fibrotic scarring andinflammation in the papillary dermis areprobable causal mechanisms for lamella-tion and may disorder epithelial metabo-lism. Furthermore, they state that otherdiseases of the skin characterized byparakeratosis (e.g. solar keratosis, psori-asis, and pale cell acanthoma) result fromabnormalities of the papillary dermis thatare subsequently manifested in the epi-dermis (1).

Actinic damage may play a role in thedevelopment of porokeratosis. This hasbeen well studied in DSAP, and a numberof patients receiving topical (17) and sys-temic (10) PUVA therapy have developedDSAP. In addition, under experimentalconditions, UV light exposure hasinduced DSAP-like lesions (9).

A hypothetical infectious agent hasbeen suggested to be the etiology for thedevelopment of porokeratosis in trans-plant recipients (18,19). However, no reporton transmissibility of porokeratosis hasbeen published (7, 20).

Specimens for biopsy should be takenfrom the peripheral, raised, hyperkeratoticridge. On histologic examination, theridge then shows a keratin-filled invagina-tion of the epidermis. In the plaque typeof porokeratosis, the invagination extendsdeeply downward at an angle, the apex ofwhich points away from the central por-tion of the lesion. In the center of thiskeratin-filled invagination rises a paraker-atotic column, the so-called cornoidlamella, representing the most character-istic feature of porokeratosis of Mibelli.Within the parakeratotic column, thehorny cells appear homogeneous andpossess pyknotic nuclei. In the epidermisbeneath the parakeratotic column, thekeratinocytes are irregularly arranged andhave pyknotic nuclei with perinuclearedema. Usually an absent or decreasedgranular layer is found at the site at whichthe parakeratotic column arises.

The epidermis overlying the centralportion of a lesion of porokeratosis maybe either flattened or normal in thicknessor rarely, acanthotic. A nonspecificperivascular infiltrate of chronic inflamma-tory cells is present in the dermis.

The histologic changes in the otherforms of porokeratosis are similar tothose seen in the plaque type but lesspronounced, the central invaginationbeing rather shallow, especially in DSAP.Additionally, DSAP displays epidermalatrophy and solar elastosis.

50 POROKERATOSIS OF MIBELLI

Acquired immunodeficiency is fre-quently found as a prelude to the devel-opment of porokeratosis and can accountfor half of new cases (15,21). Organ trans-plantation is the most common immunedeficiency favoring the development ofporokeratosis (22). Many reports describeexacerbation of lesions associated withimmune depression (14), and others, thecomplete remission of porokeratosis afterwithdrawing immunosuppressants (14, 23).How immune suppression can induce thegenesis of porokeratosis is not known.However, clinical and histopathologic find-ings revealed that the nature of the dis-ease is essentially the same in both theimmunosuppressed and nonimmunosup-pressed patients (15).

The reported incidence of porokerato-sis occurring after organ transplantationin the different published series variesgreatly from 0.34% to 11% (23). Over 60patients with various clinical forms ofporokeratosis occurring after organ trans-plant have been reported including kid-ney, heart, bone marrow (~5), lung, and livergrafts. The majority, however, had the dis-seminated superficial form of porokerato-sis (7,20,22).

Although the pathogenesis of poroker-atosis is unknown, it was for many yearsviewed as a benign entity. Despite sev-eral reports of malignancy arising inlesions of porokeratosis, it was not until1968 that serious consideration wasgiven to the premalignant nature of thisdisorder (25,26). The potential for malignancyhas not been well defined, and the risk ofmalignant transformation remainsunknown. Early reports of malignancyarising in lesions of porokeratosis stronglycorrelated with a history of radiation treat-ment (25).

In 1996, Sasson and Krain (25) reviewedthe English literature from 1964-1994 andidentified 281 cases of porokeratosis, 21(7.5%) of which had an associated malig-nancy that developed within a lesion ofporokeratosis. They found that olderpatients and those with longstanding dis-ease were found to be at increased riskfor the development of malignancy.Malignant lesions tended to occur on theextremities, with only 2 patients display-ing malignancies on the trunk. Theyfound that out of the 21 malignancies,eight arose in linear porokeratosis. Thiswas consistent with prior findings of anincreased malignant potential in the linearform (13). However, in contrast to previousreports, only 2 patients had a history ofirradiation. Additionally, no cases wereassociated with iatrogenic immune sup-pression.

Others have reported similar rates ofmalignant degeneration (27), with the most

commonly reported malignant lesionsbeing Bowen’s disease, squamous cellcarcinoma, and rarely, basal cell carci-noma (25,27). Rarely, however, do these neo-plasms metastasize. However, recently, acase of disseminated porokeratosis withfatal metastatic squamous cell carcinomahas been reported (28).

To support the belief that porokeratosisrepresents a premalignant condition,cytologic and ultrastructural studies wereperformed on lesional skin. Cytologically,it has been demonstrated that fibroblastsfrom lesional skin show chromosomalabnormalities as well as clonal popula-tions of cytogenetically abnormal cells (29).These changes were not present in unaf-fected skin. Ultrastructural studies oflesional keratinocytes reveal abnormalkeratinization patterns (30). Immunohisto-chemical staining patterns of ker-atinocytes below the cornoid lamella aresimilar to those observed in squamouscell carcinoma, while centrally locatedcells stain similar to actinic keratoses (31).This failure of normal keratinocyte differ-entiation may indicate a premalignantstate. In addition, overexpression of p53has been found in some biopsy samplesof DSAP with and without malignantdegeneration (32). However, this overex-pression of p53 and its potential relation-ship to the premalignant nature ofporokeratosis has yet to be elucidated.

When considering treatment options,the optimal procedure must be selecteddepending on the lesion’s size and loca-tion, functional and aesthetic require-ments, and the general condition of thepatient. Lesions can recur with manytherapeutic modalities. Circumscribedlesions of porokeratosis of Mibelli or lin-ear porokeratosis may be excised ordestroyed by cryotherapy, electrodessica-tion, dermabrasion, CO2 laser (33) or 585pulsed dye laser (34). Lubrication usuallyimproves the symptoms in superficialforms of porokeratosis, as does kera-tolytic treatment of hyperkeratotic lesions.Other topical therapies reported withvarying success include topical 5-fluo-rouracil (35), retinoids, and imiquimod (36).The use of oral retinoids has yielded con-flicting results (37). Cytologic atypia disap-peared with retinoid therapy, thus, theymight have an inhibitory effect on cuta-neous carcinogenesis in porokeratoticlesions (4). However, one must be awarethat relapses usually follow several weeksor months after discontinuation of retinoidtherapy.

Lastly, all therapeutic measures thatmight increase the malignant potential ofporokeratosis (radiation, immunosuppres-sion, and excessive UV exposure) shouldbe avoided. And, in spite of a poorlydefined pathogenesis, porokeratosis dis-

plays a potential for malignancy. There-fore, careful observation is warranted.

Acknowledgements:The authors would like to thank Craig

Austin, MD for his assistance with inter-preting the histopathology slides andMichael Miller, MD of Mount Sinai Depart-ment of Pathology, New York, NY, forphotographing the histological slides.

Bibliography1. Wade TR, Ackerman AB: Cornoid lamellation: A histologicreaction pattern. Am J Dermatopath, 2(1):5-15, 1980.2. Mibelli V: Contributo alla studio della ipercheratosi deicanalibusodriferi (porokeratosis). G Ital Mal Venereree Pelle,28:313, 1893.3. Kaur S, Thami GP, Mohan H, Kanway AJ: Co-Existence ofVariants of Porokeratosis: A Case Report and a Review of theLiterature. The Journal of Dermatology. 2001;29:305-309.4. Wolff-Schreiner EC: Porokeratosis, in Freedberg IM, EisenAZ, Wolff K, Austen KF, Goldsmith LA, Katz SI, Fitzpatrick TB(eds): Dermatology in General Medicine, vol. 1, 5th edMcGraw-Hill, New York, 1999:624-630.5. De Oliveira Filho J, Cutin SL, Cucu LC. DisseminatedSuperficial Actinic Porokeratosis in a Black Patient [Letter tothe Editor]. Arch Dermatol. 1986;122:852-8536. Anderson DE, Chernosky ME. Disseminated superficialactinic porokeratosis-genetic aspects. Arch Dermatol.1969;99:408-412.7. Rio B, Magana C, Le Tourneau A, Bachmeyer C, Levy V,Hamomt N, Diebold J, Zittoun R. Disseminated superficialporokeratosis after autologous bone marrow transplantation.Bone Marrow Transplantation. 1997;19:77-79. 8. Shumack, SP, Commens CA. Disseminated superficialactinic porokeratosis: A clinical study. J Am Acad Dermatol.1989;20:1015-1021.9. Chernosky ME, Anderson DE. Disseminated superficialactinic porokeratosis: Clinical studies and experimental pro-duction of skin lesions. J Am Acad Dermatol. 1969;99:40110. Hazen PG et al. Disseminated actinic porokeratosis:Appearance associated with photochemotherapy for psoriasis.J Am Acad Dermatol. 1985; 12:107711. Cockerell CJ. Induction of disseminated superficial actinicporokeratosis by phototherapy for psoriasis. J Am Acad Der-matol. 1991; 24:45.12. Goldner RM. Zosteriform porokeratosis of Mibelli. ArchDermatol. 1971;104:425.13. Murata Y, Kumano Y, Takai T. Type 2 segmental manifes-tation of disseminate superficial porokeratosis showing a sys-temized pattern of involvement and pronounced cancerproneness. Eur J Dermatol. 2001;11:191-194.14. Reed RJ, Leone P. Porokeratosis: A mutant clonal kerato-sis of the epidermis. I. Histiogenesis. Arch Dermatol.1970;101:340-347.15. Raychaudhuri SP, Smoller BR. Porokeratosis in immuno-suppressed and nonimmunosuppressed patients. Interna-tional Journal of Dermatology. 1992;31:781-782.16. Manganoni AM, Fachetti F, Gavazzoni, R. Involvement ofepidermal langerhans cells in porokeratosis of immunosup-pressed renal transplant recipients. [Brief Communications] JAm Acad Dermatol. 1989;21:799-801.17. Allen AL, Glaser DA. Disseminated superficial actinicporokeratosis associated with topical PUVA. J Am Acad Der-matol. 2000;43:720-722.18. Mizukawa Y, Shiohara T. Onset of porokeratosis of Mibelliin organ transplant recipients: Lack of a search for transmissi-ble agents in these patients. [Letter to the editor] J Am AcadDermatol. 2001;44. 19. Kono T, Kobayashi H, Ishii M, Nishiguchi S, Taniguchi S.Synchronous development of disseminated superficial poro-keraotsis and hepatitis C virus-related hapatocellular carci-noma. J Am Acad Dermatol. 2000;43:966-968.20. Macmillan AL, Roberts SOB. Porokeratosis after renaltransplant. Br J Dermatol 1974;90:45-51.21. Lederman JS, Sober AJ, Lederman GS. Immunosuppres-sion: a cause of porokeratosis? J Am Acad Dermatol.1985;13:75-79.22. Kanitakis J, Euvrard S, Claudy A. Porokeratosis in organtransplant recipients. J Am Acad Dermatol. [Letter to the edi-tor] 2001;44(1).23. Tsambaos D, Spiliopoulos T. Disseminated superficialporokeratosis: Complete remission subsequent to discontinua-tion of immunosuppression. J Am Acad Dermatol.1993;28:651-652.24. Kanitakis J. Porokeratosis. In:Euvrard S, Kanitakis J,Claudy A, editors. Skin diseases after organ transplantation.Paris: J. Libbey Eurotext; 1998. p183-194.25. Sasson M, Krain AD. Porokeratosis and cutaneous malig-nancy. A review. Dermatol Surg. 1996;22(4):339-342.26. Bazex A, Dupre¢ A. Porokeratose de Mibelli zoniformeavec degenerescence. Presentation de deux observations.Ann Derm Vener Paris 1968;95:361-374.

GORIN, GROPPER, HOFFMAN 51

27. Otsuka F, Someya T, Ishibashi Y. Porokeratosis and malig-nant skin tumors. J Cancer Res Clin Oncol 1991;117:55-60.28. Rongioletti F, Rebora A. Disseminated porokeratosis withfatal metastatic squamous cell carcinoma. The AmericanJournal of Dermatopathology. 2002;24(2):144-148. 29. Taylor AMR, Harden DG, Fairburn EA. Chromosomalinstability associated with susceptibility to malignant disease inpatients with porokeratosis of Mibelli. Br J Dermatol.1974;90:607-616.30. Ito M, Fujiwara H, Muruyama T, Oguro K, Ishiharo O, SatoY. Morphogenesis of the cornoid lamella: histochemical,immunohistochemical, and ultrastructural study of porokerato-

sis. J Cutan Pathol 1991;18:245-256.31. Gray MH, Smoller RS, Mcnutt MS. Carcinogenesis inporokeratosis: evidence for a role relating to chronic growthactivation of keratinocytes. Am J Dermatopathol.1991;13:438-444.32. Puig L, Alegre M, Costa I, Matias-Guiu X, de Maragus J.Overexpression of p53 in disseminated superficial actinic poro-keratosis with and without malignant degeneration. [correspon-dence]. Arch Dermatol. 1995;131:353-354.33. Barnett JH. Linear porokeratosis: treatment with the carbondioxide laser. J Am Acad Dermatol 1986;14:902-904.34. Alster TS, Nanni CA. Successful treatment of porokerato-

sis with 585 nm pulsed dye laser irradiation. Cutis.1999;63:265-266.35. McDonald SG, Peterka ES. Porokeratosis (Mibelli): treat-ment with topical 5-Fluorouracil. J Amer Acad Dermatol.1983;8:107-110.36. Agarwal S, Berth-Jones J. Porokeratosis of Mibelli: suc-cessful treatment with 5% imiquimod cream. [correspondence]British Journal of Dermatology. 2002;146:331-344.37. Scott OLS. Porokeratosis of Mibelli with squamous cell car-cinoma. Br J Dermatol. 1893;109:(suppl. 24):74.

52 POROKERATOSIS OF MIBELLI

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TOPICAL SUSPENSION(CICLOPIROX) 0.77% (W/W)FOR DERMATOLOGIC USE ONLY.NOT FOR USE IN EYES.Rx OnlyDESCRIPTION: Loprox® (ciclopirox) Topical Suspension 0.77% is for topical use.Each gram of LOPROX Topical Suspension contains 7.70 mg of Ciclopirox (asCiclopirox Olamine) in a water miscible suspension base consisting of Purified WaterUSP, Cocamide DEA, Octyldodecanol NF, Mineral Oil USP, Stearyl Alcohol NF, Cetyl Alcohol NF, Polysorbate 60 NF, Myristyl Alcohol NF, Lactic Acid USP, SorbitanMonostearate NF, and Benzyl Alcohol NF (1%) as preservative. LOPROX Topical Sus-pension contains a synthetic, broad-spectrum, antifungal agent ciclopirox (as ciclopirox olamine). The chemical name is 6-cyclohexyl-1-hydroxy-4-methyl-2(1H)-pyridone, 2-aminoethanol salt.The CAS Registry Number is 41621-49-2.The chemical structure is:

LOPROX Topical Suspension has a pH of 7.CLINICAL PHARMACOLOGY: Ciclopirox is a broad-spectrum, antifungal agent thatinhibits the growth of pathogenic dermatophytes, yeasts, and Malassezia furfur.Ciclopirox exhibits fungicidal activity in vitro against isolates of Trichophyton rubrum, Tri-chophyton mentagrophytes, Epidermophyton floccosum, Microsporum canis, and Can-dida albicans.Pharmacokinetic studies in men with radiolabeled ciclopirox solution in polyethyleneglycol 400 showed an average of 1.3% absorption of the dose when it was applied top-ically to 750 cm2 on the back followed by occlusion for 6 hours. The biological half-lifewas 1.7 hours and excretion occurred via the kidney. Two days after application only0.01% of the dose applied could be found in the urine. Fecal excretion was negligible.Autoradiographic studies with human cadaver skin showed that ciclopirox penetratesinto the hair and through the epidermis and hair follicles into the sebaceous glands anddermis, while a portion of the drug remains in the stratum corneum.In vitro penetration studies in frozen or fresh excised human cadaver and pig skin indi-cated that the penetration of LOPROX Topical Suspension is equivalent to that ofLoprox® (ciclopirox) Cream 0.77%. Therapeutic equivalence of cream and suspensionformulations also was indicated by studies of experimentally induced guinea pig andhuman trichophytosis.INDICATIONS AND USAGE: LOPROX Topical Suspension is indicated for the topicaltreatment of the following dermal infections: tinea pedis, tinea cruris and tinea corporisdue to Trichophyton rubrum, Trichophyton mentagrophytes, Epidermophyton flocco-sum, and Microsporum canis; cutaneous candidiasis (moniliasis) due to Candida albi-cans; and tinea (pityriasis) versicolor due to Malassezia furfur.CONTRAINDICATIONS: LOPROX Topical Suspension is contraindicated in individualswho have shown hypersensitivity to any of its components.WARNINGS: General: LOPROX Topical Suspension is not for ophthalmic use.PRECAUTIONS: If a reaction suggesting sensitivity or chemical irritation should occurwith the use of LOPROX Topical Suspension, treatment should be discontinued andappropriate therapy instituted.

Reference:1. Data on file, Medicis Pharmaceutical Corporation

Information for Patients: The patient should be told to:1. Use the medication for the full treatment time even though signs/symptoms may

have improved and notify the physician if there is no improvement after four weeks.2. Inform the physician if the area of application shows signs of increased irritation

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3. Avoid the use of occlusive wrappings or dressings.Carcinogenesis, Mutagenesis, Impairment of Fertility: A carcinogenicity study infemale mice dosed cutaneously twice per week for 50 weeks followed by a 6-monthdrug-free observation period prior to necropsy revealed no evidence of tumors at theapplication site. The following in vitro and in vivo genotoxicity tests have been con-ducted with ciclopirox olamine: studies to evaluate gene mutation in the Ames Salmo-nella/Mammalian Microsome Assay (negative) and Yeast Saccharomyces CerevisiaeAssay (negative) and studies to evaluate chromosome aberrations in vivo in the MouseDominant Lethal Assay and in the Mouse Micronucleus Assay at 500 mg/kg (negative).The following battery of in vitro genotoxicity tests were conducted with ciclopirox: achromosome aberration assay in V79 Chinese Hamster Cells, with and without meta-bolic activation (positive); a gene mutation assay in the HGPRT - test with V79 ChineseHamster Cells (negative) and a primary DNA damage assay (i.e., unscheduled DNASynthesis Assay in A549 Human Cells (negative)). An in vitro Cell Transformation Assayin BALB/C3T3 Cells was negative for cell transformation. In an in vivo Chinese Hamster Bone Marrow Cytogenetic Assay, ciclopirox was negative forchromosome aberrations at 5000 mg/kg.Pregnancy Category B: Reproduction studies have been performed in the mouse, rat,rabbit, and monkey, via various routes of administration, at doses 10 times or more thetopical human dose and have revealed no significant evidence of impaired fertility orharm to the fetus due to ciclopirox. There are, however, no adequate or well-controlledstudies in pregnant women. Because animal reproduction studies are not always pre-dictive of human response, this drug should be used during pregnancy only if clearlyneeded.Nursing Mothers: It is not known whether this drug is excreted in human milk. Cautionshould be exercised when LOPROX Topical Suspension is administered to a nursingwoman.Pediatric Use: Safety and effectiveness in pediatric patients below the age of 10 yearshave not been established.ADVERSE REACTIONS: In the controlled clinical trial with 89 patients using LOPROXTopical Suspension and 89 patients using the vehicle, the incidence of adverse reac-tions was low. Those considered possibly related to treatment or occurring in more thanone patient were pruritus, which occurred in two patients using ciclopirox suspensionand one patient using the suspension vehicle, and burning, which occurred in onepatient using ciclopirox suspension.DOSAGE AND ADMINISTRATION: Gently massage LOPROX Topical Suspension intothe affected and surrounding skin areas twice daily, in the morning and evening. Clinicalimprovement with relief of pruritus and other symptoms usually occurs within the firstweek of treatment. If a patient shows no clinical improvement after four weeks of treat-ment with LOPROX Topical Suspension the diagnosis should be redetermined. Patientswith tinea versicolor usually exhibit clinical and mycological clearing after two weeks oftreatment.HOW SUPPLIED: LOPROX® (ciclopirox) Topical Suspension 0.77% is supplied in 30mL bottles (NDC 99207-022-30), 60 mL bottles (NDC 99207-022-60).Bottle space provided to allow for vigorous shaking before each use.Store between 5˚ and 25˚C (41˚ and 77˚F).US Patent PendingPrescribing Information as of May 2002

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Cellular Mechanisms Modulated by Tazarotene

Topical tazarotene is a “precursor”compound, metabolized rapidly byesterase hydrolysis to its active retinoidmetabolite, tarazotenic acid, after cuta-neous application.1 With increased under-standing of cellular mechanisms involvedin differentiation and inflammation, theeffects of topical retinoids, includingtazarotene, extend beyond their long-established comedolytic activity.

Tazarotenic acid is believed to modu-late its therapeutic effects in skin predom-inantly via high affinity binding to retinoicacid receptor-gamma (RAR gamma);binding also occurs to RAR-beta andweakly to RAR-alpha, but not to retinoid Xreceptors (RXRs).1-3 The impact of RARbinding by tazarotenic acid correspondswith the modulation and expression ofretinoid- responsive genes regulating celldifferentiation, proliferation and inflamma-tory pathways.1,3 Several observed bio-logic effects appear to relate to themechanisms of action of tazarotene fortreatment of acne, psoriasis and/or photo-damage.1,3-8 These include:

• downregulated aberrant expression ofkeratinocyte transglutaminase I (Tgase I)

• downregulated expression of epidermalgrowth factor receptor

• decreased markers of inflammationsuch as migration inhibitory factor-relatedprotein (MRP-8)

• reduced expression of hyperproliferative

keratins (K6, K16) that are increased dur-ing early comedogenesis

• suppression of the AP-1 transcriptionfactor pathway

Topical retinoids have also beenshown to reduce expression and bindingof toll-like receptors (ie. TLR-2) involvedin the proinflammatory cytokine produc-tion and stimulation of inflammatory path-ways induced by Propionibacteriumacnes.9-11 In addition, by reducing come-dogenesis, topical retinoids such astazarotene, prevent the formation of a fol-licular microclimate required for prolifera-tion of P. acnes organisms.12 Topicalretinoids also suppress activation of theAP-1 transcription factor pathwayinvolved in the regulation of matrix metal-loproteinase genes.1,11,13 A rational modelbased on in vivo human studies supportsthis pathway as a component of acneinflammation and scarring.11 AP-1 proteinis also overexpressed in a variety ofhyperproliferative and inflammatory disor-ders.1

Pharmacokinetics,Pharmacology and Toxicology of Tazarotene

Pharmacokinetics. The systemicabsorption of tazarotene is minimal due torapid conversion to tazarotenic acid. Thehalf-life of tazarotene is 2 – 18 minutes.1

Maximum concentration of tazarotenicacid in systemic circulation is noted at 9hours after application with up to 5 % totalsystemic absorption of applied drugnoted after application to normal skin;

<1% of radiolabeled tarazotene isabsorbed within 10 hours of applicationon unoccluded psoriatic skin and <6 % isabsorbed within 10 hours on occludednormal skin.3,14,15,16,17 Tazarotenic acid (freeacid form) is rapidly deactivated to inac-tive sulfone and sulfoxides metabolitesthat are excreted in the urine; the elimina-tion half-life of tazarotenic acid is 1 – 2hours and the terminal half-life is approxi-mately 18 hours.1,3,14,18

Toxicology. During preclinical toxicol-ogy evaluation, a battery of tests revealedthat tazarotene was nonmutagenic, non-carcinogenic and without evidence ofchromosomal effects. As with otherretinoids, high dose oral administration oftazarotene induced teratrogenicity, how-ever, teratrogenicity was not observedafter high dose topical application oftazarotene in both rabbit and rat mod-els.1,3,7,15

No clinically significant systemic, oph-thalmologic, hematologic abnormalities orchanges in serum chemistry parameterswere observed in association with topicalapplication of tazarotene.3,15

Impact of Repeated Applica-tions of Tazarotene

Plasma Concentrations of TazarotenicAcid. Plasma concentration versus timeprofiles were evaluated following singleand repeated applications of tazarotene0.1% cream applied once daily for 28days in female patients with moderate-to-severe facial acne.19 Applications weremade to the face only or to an exagger-

DEL ROSSO 55

Pharmacotherapy Review: Topical TazaroteneA Composite Review of Clinical & Research Experience With

Focus on Optimal Use and Safety

James Q. Del Rosso, D.O., FAOCD

AbstractTazarotene is a synthetic retinoid compound with unique properties, approved as topical therapy for acne vulgaris, psoriasis and

photoaging. Efficacy and safety have been confirmed in multiple, well-designed controlled studies. Initial availability in a gel formula-tion proved to be clinically effective, but was limited by a high incidence of irritation. Additional blinded, controlled studies havedemonstrated high efficacy with every other night application of tazarotene 0.1% gel for facial acne vulgaris, with efficacy and toler-ance comparable to other topical retinoids applied nightly. Studies with a newer tazarotene 0.1% cream formulation applied dailyconfirm favorable efficacy and patient tolerance in both acne vulgaris and photoaging, including short term and long term trials forthe latter application. For therapy of plaque psoriasis, topical tazarotene has been shown to be effective, with optimal resultsachieved in combination with topical corticosteroids, including mid, high and super-potency agents; efficacy superior to other topicaltherapy approaches including calcipotriene has been documented. Steroid-enhancing and sparing effects with improved mainte-nance of disease control and a reduction of topical steroid-induced cutaneous atrophy have been documented with topicaltazarotene use. Topical tazarotene has also been used effectively and safely in patients of various ethnicities, including African-American patients. Pharmacokinetic studies have confirmed limited systemic absorption of tazarotene after topical application. Theefficacy, safety data and experience related to topical tazarotene use based on review of studied applications, with special empha-sis on acne treatment, are presented. Suggestions for optimal use of tazarotene are outlined.

ated body surface area (15% BSA)involving face, upper trunk, shouldersand/or neck. Multiple sequential plasmaconcentrations were completed through-out the study inclusive of the 72 hourperiod after the first and last applicationsand over 24 hours after dosing on days 8,15 and 22. In both study groups, maximalplasma concentration was noted on day15, suggesting that continued accumula-tion of drug within the plasma compart-ment does not occur with repeated topicalapplication of tazarotene. In studypatients completing only repeated facialapplications, tazarotenic acid plasma con-centrations were very low (~ 0.1 ng/ml). Inthe study group applying drug to theexpanded body surface area, plasmaconcentrations of tazarotenic acid were atthe low end of the range of concentratiosof endogenous tretinoin and its metabo-lites, oxoisotretinoin and isotretinoin (1 –4 ng/ml), with the total cumulative retinoidconcentration reported to be up to 8ng/ml. As a comparison, the plasma con-centration of isotretinoin that may bereached during a course of oral therapyfor severe nodulocystic is >1000 ng/ml.20

Other studies have evaluated plasmaconcentrations of tazarotenic acid afterapplication of tazarotene 0.05% and 0.1%gel, which range from 0.06 – 0.13 ng/ml;repeated application once daily over 28days in female patients with facial acnereported a plasma concentration range of0.136 + 0.107 ng/ml after the last drugapplication.21,22

These concentrations compare favor-ably to the reported plasma concentra-tions of endogenous tretinoin and itsmetabolites.23

Relationship to Tetatrogenicity Risk.Unlike other available prescription topicalretinoids which are FDA-approved fortreatment of photoaging and/or acne vul-garis and are classified as pregnancy cat-egory C, tazarotene is classified aspregnancy category X as it is the onlytopical retinoid also FDA-approved fortreatment of psoriasis.3 The categoriza-tion of tazarotene in pregnancy categoryX is based on precaution due to antici-pated application to an extensive bodysurface area in some psoriasis patientsand is not related to any cases of docu-mented teratrogenicity associated withtopical tazarotene use in humans.3,24-26

Pharmacosurveillance has not detectedcases of teratrogenicity associated withinadvertent use of topical tazarotene inpregnant female patients.3,25,26 Post treat-ment tazarotene/tazarotenic acid retinoidplasma levels are comparable to endoge-nous retinoid levels and levels achievedby tretinoin or adapalene after topicaluse, all of which are dramatically lowerthan plasma levels detected after use of

oral isotretinoin which produces 100-foldhigher plasma retinoid concentrationsthan topical retinoid application.25 It is rec-ommended that practitioners exercise acautious approach and avoid prescribingany topical retinoid to female patients dur-ing pregnancy.3

Use of Tazarotene and Combination Therapy forPsoriasis

As psoriasis therapies, such as topicalcorticosteroids, and topical tazarotene arecommonly used in combination for treat-ment of psoriasis, the impact of compati-bility with tazarotene and the effect oftazarotene on corticosteroid-inducedcutaneous atrophy are of clinical signifi-cance.

Topical Corticosteroid-Induced SkinAtrophy. A 4 week trial evaluated thecutaneous atrophogenic effect of diflo-rasone diacetate 0.05% ointment appliedalone daily on 6 days per week to forearmskin in 24 human adult volunteers versusthe effect of combination treatment withtazarotene 0.1% gel also applied daily on6 days per week.27 Tazarotene 0.1% gelalone increased mean epidermal thick-ness by 62% compared to 20% withplacebo vehicle. Application of diflo-rasone diacetate 0.05% ointment alonereduced mean epidermal thickness by43%. Statistically significant reduction incorticosteroid-induced atrophy was notedwith the combination regimen; topicaltazarotene reduced the epidermal atrophyassociated with diflorasone diacetate useby 37% as compared to application of thecorticosteroid alone.

Compatibility with Other PsoriasisTherapies. A two-week in vitro stabilityevaluation demonstrated good stability ofall compounds when tazarotene wascombined with equal quantities of severalcorticosteroid formulations includingmometasone furoate 0.1% cream, fluoci-nonide 0.05% ointment and cream,betamethasone 0.05% cream and lotion,clobetasol dipropionate 0.05% ointment,cream and scalp solution and diflorasonediacetate 0.05 % ointment.28 In a largetrial of 300 patients, combination therapyregimens with a mid- or high potency topi-cal corticosteroid applied in the morningand tazarotene gel applied in the eveninghave been shown to be effective, andalso minimize associated skin irritation.29,30

The parameters evaluating mean time toachieve >50% improvement, overall suc-cess at study end-point (12 weeks), clini-cal signs of psoriasis and local tolerabilityreactions responded more favorably inthe groups utilizing topical corticosteroid-tazarotene regimens than with tazarotenemonotherapy. Maintenance regimens uti-lizing topical tazarotene, evaluated over a

five month study phase to assess poten-tial “steroid rebound” and exacerbations,have also shown that topical tazaroteneenhances the ability to sustain control ofpsoriasis.31

Adjunctive use of fluticasone 0.05%ointment in the evening along withtazarotene 0.1% gel in the morning wasshown in 12 week study to provide supe-rior global improvement scores and agreater decrease in erythema and scalingthan tazarotene monotherapy; the use oftwice daily fluticasone offered little to noadditional benefit over once daily usage.32

Enhanced efficacy and favorable toler-ance were also confirmed in studies eval-uating the use of tazarotene gelformulations in combination with pho-totherapy using broad-band UVB, narrowband UVB and PUVA therapy.29 Topicaltazarotene has also been shown to bestable in the presence of calcipotriene.28

“Switch medication analysis” involvinga change in topical therapy for plaquepsoriasis from calcipotriene to tazarotenewas completed in 246 patients undergo-ing combination therapy with a topicalcorticosteroid agent.33 The study demon-strated significant improvement in efficacyand greater patient satisfaction correlatedwith the change from topical calcipotrieneto tazarotene for up to 12 weeks. Theseresults correlated with findings from aprevious study evaluating a switch in ther-apy from topical calcipotriene totazarotene with or without use of a topicalcorticosteroid.34

Use of Tazarotene in Combi-nation with Other Agents forAcne

A multicenter 12-week investigator-blinded trial of 440 patients (age > 12years) with mild-to-moderate facial acnevulgaris evaluated the efficacy and tolera-bility of once daily tazarotene 0.1% gelmonotherapy as compared to combina-tion with twice daily use of benzoyl per-oxide 4% gel, erythromycin 3%/benzoylperoxide 5% gel or clindamycin phos-phate 1% lotion.35 A comparator groupusing topical clindamycin alone was alsoincluded. For efficacy against inflamma-tory lesions, tazarotene plus the ery-thromycin/benzoyl peroxide combinationgel produced a 65% decrease in meanlesion counts compared to a range ofresponses approximating 40% with allother regimens, including tazaroteneused alone. The greatest levels of globalimprovement by study endpoint wasobserved with tazarotene plus clin-damycin lotion (77%) and tazarotene pluserythromycin/benzoyl peroxide gel (73%).Treatment success defined as 75 – 100%clearance of facial acne by week 12 was

56 PHARMACOTHERAPY REVIEW: TOPICAL TAZAROTENE

greatest in the study group using thetazarotene-clindamycin regimen (67%versus 38 – 49%). All combination regi-mens were associated with transientdevelopment of local tolerability reactionssuch as dryness and erythema which wasusually rated as mild. The range ofpatients reporting favorable overallimpressions regarding their treatment inthe combination therapy groups was 85 –92% as compared to 73% with tazarotenemonotherapy and 58% with clindamycinused alone. The percentage of patientsreporting that they would continue treat-ment with the same regimen after studycompletion was highest in the combina-tion therapy groups (86 – 93%). In thegroup treated with tazarotene alone, 76%indicated they would use the same treat-ment in the future and 65% foundtazarotene monotherapy to be at least aseffective or more effective than previouslyused acne medications.

A large open-label private practiceexperience trial was inclusive of 673patients (age > 12 years) with mild-to-moderate facial acne vulgaris treated withtazarotene 0.1% gel once daily for 12weeks in combination with at least oneother topical acne medication, with orwithout oral antibiotic therapy.36 Eightypercent used only one concomitant agent(clindamycin 27%, benzoyl peroxide 22%,erythromycin/benzoyl peroxide 14%). Byweek 12, mean percentage reduction ininflammatory lesion counts weredecreased by 66% and 64% in patientsusing clindamycin/tazarotene and ben-zoyl peroxide/tazarotene, respectively,and 58% in patients using tazarotene astheir sole topical agent. Tazarotene aloneproduced a 65% reduction in comedonallesion mean percentage which was com-parable to responses noted withtazarotene-containing combination regi-mens (56 – 67%). In 378 patients, theaddition of topical tazarotene to an exist-ing regimen was reported to provide anadditional mean percentage reduction of69% for comedonal lesions and 66% forinflammatory lesions, independent ofwhether or not patients were utilizing oralantibiotic therapy. Upon switching fromanother topical retinoid to tazarotenewithout any other changes in their regi-men, in patients changed from tretinoingel/cream or adapalene gel, an additional56% and 65% reduction in comedonallesions was observed, and an additional51% and 56% reduction in inflammatorylesions was observed, respectively. Alesser degree in lesion count reductionswere noted in patients changed fromtretinoin 0.1% microgel (microsphere),with an additional 39% reduction in come-donal lesions and 27% reduction ininflammatory lesions correlated with theswitch to tazarotene use.

DEL ROSSO 57

Leyden JJ, et al/Mild-Moderate Facial Acne Double-Blind Randomized 12-Week Trial/Age 12+ Years37

Tazarotene 0.1% Gel >50 % Global Improvement: 67%Once Daily (n = 84) Median Reduction Inflammatory Lesions: 56%*

Median Reduction NonInflammatory Lesions: 60%Tolerability: Most reactions mild Irritation 13% / Erythema 11% / Dryness 7% Scaling 4% / Peeling 5% / Burning 11%Discontinuations due to reactions 2%

Tretinoin 0.1% Microsphere Gel >50 % Global Improvement: 49 %Once Daily (n = 85) Median Reduction Inflammatory Lesions: 46 %*

Median Reduction NonInflammatory Lesions: 38 Tolerability: Most reactions mildIrritation 4 % / Erythema 6 % / Dryness 6 % /Scaling 2 % / Peeling 1% / Burning 9 %Discontinations due to reactions 2 %

Webster GF, et al/Mild-Moderate Facial Acne/Double-Blind Randomized 12-Week Trial/Age 12+ Years38

Tazarotene 0.1% Gel >50 % Global Improvement: 78 %Once Daily (n = 72) Median Reduction Inflammatory Lesions: 70 %

Median Reduction NonInflammatory Lesions: 71 %Tolerability: Most reactions mildIrritation 13 % / Erythema 3 % / Dryness 1% /Stinging 3 % / Peeling 6 % / Burning 8 %Discontinuations due to reactions 1%

Adapalene 0.1% Gel >50 % Global Improvement: 52 %Once Daily (n = 73) Median Reduction Inflammatory Lesions: 55 %

Median Reduction NonInflammatory Lesions: 48 %Tolerability: Most reactions mildIrritation 5 % / Erythema 0 % / Dryness 5 % /Stinging 0 % / Peeling 1% / Burning 3 %Discontinuations due to reactions 1%

Webster GF, et al/Mild-Moderate Facial Acne/Double-Blind Randomized 12-Week Trial/Age 12+ Years39

Tazarotene 0.1% Gel Mean Reduction Open Comedones: 65 % Once Daily (n = 72) Mean Reduction NonInflammatory Lesions: 55 %

Mean Reduction Inflammatory Lesions: 54 %*Tolerability: Most reactions mild / trace Irritation 6 % / Erythema 4 % / Dryness 6 % /Peeling 1% / Burning 7 %Discontinuations due to reactions 3 %

Tretinoin 0.025 % Gel Mean Reduction Open Comedones: 44 %Once Daily (n = 71) Mean Reduction NonInflammatory Lesions: 42 %

Mean Reduction Inflammatory Lesions: 44 %*Tolerability: Most reactions mild / traceIrritation 3 % / Dryness 3 % / Burning 3 %Discontinuations due to reactions 0 %

Leyden JJ, et al/Mild-Moderate Facial Acne Double-Blind Randomized 15-Week Trial/Age 12+ Years40

Tazarotene 0.1% Gel >50 % Global Improvement: 74 %*Once Every Other Day (n = 82) Mean Reduction NonInflammatory Lesions: 55 %*

Mean Reduction Inflammatory Lesions: 57 %*Tolerability: Most reactions mild / traceDiscontinuations due to reactions < 1%Total Drug Usage: 29.9 grams

Adapalene 0.1% Gel >50 % Global Improvement: 73 %*Once Daily (n = 82) Mean Reduction NonInflammatory Lesions: 58 %*

Mean Reduction Inflammatory Lesions: 54 %*Tolerability: Most reactions mild / traceDiscontinuations due to reactions < 1%Total Drug Usage: 87.2 grams

(*difference not statistically significant)

Summary of Comparative Studies with Topical TazaroteneTRIAL RESULTS

Cream Formulation ofTazarotene

Based on available data and clinicalexperience, the cream formulation oftazarotene appears to maintain efficacyand reduce the incidence of local tolera-bility reactions.

Acne Vulgaris. Two parallel-group,multicenter double-blind, vehicle con-trolled studies inclusive of 847 patientswith facial acne vulgaris, compared tara-zotene 0.1% cream applied once daily for12 weeks versus placebo vehicle.4 1

Tazarotene 0.1% cream was significantlysuperior than vehicle in reducing totalnumber of acne lesions, number ofinflammatory lesions and number of non-inflammatory lesions. Tazarotene 0.1%cream was associated with a lower inci-dence of most signs and symptoms oflocal tolerability reactions as compared toincidence rates reported in studies evalu-ating tazarotene 0.1% gel, including sting-ing, burning, irritation and pruritus. Onefemale patient discontinued tazaroteneuse at week 8 due to a postive pregnancytest and subsequently delivered a healthychild. Multiple sample evaluations ofplasma tarazotenic acid levels were com-pleted at weeks 4 and 8; the meanplasma level was 0.1 + 0.1 mg/ml, signifi-cantly lower than reported endogenousconcentrations of tretinoin and itsmetabolites. Over the 8 week period ofpharmacokinetic analysis, based on atotal of eighty-nine samples, plasma tara-zotenic acid levels did not increase overtime with repeated daily tarazotene creamapplication.

Photoaging. A dose-response multi-center, investigator-blinded, vehicle con-trolled, parallel-group study comparedtazarotene 0.01 %, 0.025 %, 0.05 % and0.1% creams and tretinoin 0.05 % emol-lient cream applied over 24 weeks fortreatment of facial photodamage.42 Treat-ment success rates based on globalassessment at the end of treatment werehighest for tazarotene 0.1% cream (67 %,n = 58), tretinoin 0.05 % emollient cream(55 %, n = 58) and tazarotene 0.05 %cream (52 %, n = 58) as compared tovehicle (22 %, n = 58). Tarazotene 0.1%cream demonstrated a trend towardquicker response than tretinoin. Histologicevaluations of tazarotene-treated skindemonstrated favorable changes in pho-todamaged skin including increased epi-dermal thickness and decreased melanincontent. Consistent with other studiesevaluating topical tazarotene in both geland cream formulations, systemic expo-sure to tarazotenic acid was minimal withuse of the tarazotene creams (0.02 – 0.1ng/ml). Local irritation was seen most fre-quently in patients treated with higher

concentrations of topical tazarotenereported in most cases as mild to moder-ate in severity; in each treatment group,three subjects or less discontinued partic-ipation in the trial due to adverse effects.

In a 52-week multicenter vehicle-con-trolled trial inclusive of a 24-four weekdouble-blind phase (n = 511) and a 28-week open phase (n = 482), tazarotene0.1% cream achieved significantly greatertreatment success (>50% global improve-ment), and a minumum of 1-gradeimprovement in tactile roughness, finewrinkling, coarse wrinkling, mottled andirregular dyschromia, lentigines, elastosisand pore size.43 Continued improvementwas observed throughout both phases ofthe study with no plateau effect notedover 52 weeks of therapy. Plasma levelsof tarazotenic acid were based on 60actively treatred patients from the firststudy phase and 48 patients from thesecond study phase. There was no evi-dence of drug accumulation or increasedplasma concentrations with repeateddaily tazarotene application over 52weeks of therapy; mean plasma levelswere consistently below 0.13 ng/ml anddid not exceed 0.71 ng/ml.

Use of Topical Tazarotene forAcne in Skin Types V or VI

A pilot study evaluated the use oftazarotene 0.05 % gel once daily for 8weeks in ten African-American and fourHispanic patients treated for mild-to-mod-erate facial acne vulgaris.44 The first two-weeks, a small quantity of tazarotene gelwas applied along with an equal quantityof moisturizer. If no signs of intolerancewere noted after two weeks, thetazarotene gel was then apply withoutmoisturizer dilution. No adverse reactionsor changes in pigmentary skin intensitywere noted. At study endpoint, the meaninflammatory and noninflammatory lesioncounts decreased by 52 % and 77%,respectively.

Reducing Local TolerabilityReactions Associated withTopical Reinoids

All currently available topical retinoids,including tretinoin, tazarotene, adapaleneand retinol, are associated with a signifi-cant risk for the development of local tol-erability reactions, referred to as “retinoiddermatitis”. Such reactions may berelated to the vehicle properties, inherentproperties of the specific retinoid, con-comitant skin care practices or use ofadjunctive skin care products thatenhance the development of irritation.The role of vehicle in development ofretinoid associated irritation has beendefined by the “irritation history” of topical

tretinoin; the more recent availability ofemollient, microsponge and polymer vehi-cles for tretinoin have at least partlyreduced the potential for irritation. Of theavailable prescription-only topicalretinoids, the adapalene 0.1% formula-tions have generally been associatedwith the lowest reported incidence of localtolerability reactions.

The availablility of tazarotene in twostrengths (0.05%, 0.1%), the addition ofthe newer cream formulation and theidentification of appropriate applicationtechnique allows for adjustments in treat-ment and a lowered risk of applicationsite reactions. Split-face evaluations of“sensitive skin” patients (history ofrosacea or atopy) treated with tazarotene0.1% gel, tretinoin 0.025% gel or adapa-lene 0.1% gel for up to 29 days demon-strated comparable increases in facialdryness and erythema.45 Use of moisturiz-ers were excluded. The authors con-cluded that the need to adjust or modifytopical retinoid therapy is more depen-dent on individual patient tendency thanon the inherent differences in the irritationpotential of specific topical retinoids. Ablinded analysis specifically evaluatingonce versus twice daily application oftazarotene 0.1% gel demonstrated supe-rior tolerability with the use of an alternateday (every other day) regimen at the initi-ation of therapy for the first two weeks.45

In later studies evaluating once dailyuse of topical tazarotene 0.1% or 0.05%gel, lower reported rates of local tolerabil-ity reactions were correlated with the useof specified skin care instructions.39 Whenusing topical tazarotene, irritation may beavoided by instructing patients to:

• Cleanse with a gentle skin cleanser

• Apply no more than a pea-sized amountof medication

• Use a noncomedogenic, nonfragrancedmoisturizer

• Initiate therapy every other day for thefirst two weeks then progress to dailyapplication if no significant local applica-tion site reactions are noted

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Dermatol 1998;39:S129-S133.9. Vowels BR, Yang S, Leyden JJ. Induction of proinflamma-tory cytokines by a soluble factor of Propionibacterium acnes:implications for chronic inflammatory acne. Infection Immunity1995;63:3158-3165.10. Wolf JE. Potential anti-inflammatory effects of topicalretinoids and retinoid analogues. Adv Therapy 2002;19:109-117.11. Kang S. A new concept of acne scarring. presented at Win-ter Skin Seminar,Snowmass, Colorado, February 2003.12. Cunliffe WJ, Gollnick HPM. Acne – Diagnosis and Manage-ment. Martin Dunitz, London, 2001, pp. 15-37, 107-115.13. Nagpal S, Athanikar J, Chandraratna RAS. Separation oftransactivation and AP1 antagonism functions of retinoic acidreceptor alpha. J Biol Chem 1995;270:923-927.14. Marks R. Pharmacokinetics and safety review oftazarotene. J Am Acad Dermatol 1998;39:S134-S138.15. Marks R. Clinical safety of tazarotene in the treatment ofplaque psoriasis. J Am Acad Dermatol 1997;37:S25-S32.16. Tang-Liu DDS, Matsumoto RM, Usansky JI. Clinical phar-macokinetics and drug metabolism of tazarotene. Clin Phar-macokinetics 1999;37:273-287.17. Franz TJ, Lehman PA, Franz S, et al.Percutaneousabsorption of AGN 190168 0.1 % gel, a new synthetic retinoid, through human skin mod-els in vivo (abstract). J Invest Dermatol 1992;98:650.18. Matsumoto RM, Sun H, Tang-Liu D, et al. Species correla-tion of AGN 190168 disposition in mouse, hamster, rat, rabbit,monkey and man. Pharmaceut Res 1992(S):9:274.19. Zhiling Yu, Kopper SC, Walker PS, et al. Pharmacokineticsof tazarotenic acid after single and repeat applications oftazarotene cream 0.1 % to either the face or an exaggeratedbody surface area in female patients with acne vulgaris. Posterpresentation.20. Nulman I, Berkovitch M, Klein J, et al. Steady-state phar-macokinetics of isotretinoin and its 4-oxo metabolite: implica-tions for fetal safety. J Clin Pharmacol 1998;38:926-930.21. Shalita AR, Chalker DK, Griffith RF, et al. Tazarotene gel issafe and effective in the treatment of acne vulgaris: a multicen-ter, double-blind, vehicle-controlled study. Cutis 1999;63:349-354.22. Yu Z, Matsumoto RM, Sefton J, et al. Pharmacokinetics of

tazarotene in female patients with facial acne following facialapplication of tazarotene gel 0.1 % for 28 days. Poster presen-tation. American Academy of Dermatology Annual Meeting,San Francisco, California, 2000 23. Buchan P, Eckhoff C, Caron D, et al. Repeated topicaladministration of all-trans-retinoic acid and plasma levels ofretinoic acids in humans. J Am Acad Dermatol 1994;30:428-434.24. Tauscher AE, Fleischer AB, Phelps KC, et al. Psoriasis andpregnancy. Sem Cutan Med Surg 2002;6:561-57025. Menter A. Pharmacokinetics and safety of tazarotene. JAm Acad Dermatol 2000;43:S31-S35.26. Weinstein GD, Krueger GG, Lowe NJ, et al. Tazaraotenegel, a new retinoid, for topical therapy of psoriasis: vehicle-controlled study of safety, efficacy, and duration of therapeuticeffect. J Am Acad Dermatol 1997;37:85-92.27. Kays K, Kopper SC, Sefton J, et al. A pilot study to deter-mine the effect of tazarotene gel 0.1 % on steroid-induced epi-dermal atrophy. Int J Dermatol 2001;40:468-471.28. Hecker D, Worsley J, Yueh G, et al. In vitro compatibility oftazarotene with other topical treatments of psoriasis. J AmAcad Dermatol 2000;42:1008-1011.29. Guenther L. Tazarotene combination treatments in psoria-sis. J Am Acad Dermatol 2000;43:S36-S42.30. Lebwohl MG, Breneman DL, Goffe BS, et al. Tazarotene0.1 % gel plus corticosteroid cream in the treatment of plaquepsoriasis. J Am Acad Dermatol 1998;39:590-596.31. Lebwohl M. Strategies to optimize efficacy, duration, ofremission, and safety in the treatment of plaque psoriasis byusing tazarotene in combination with a corticosteroid. J AmAcad Dermatol 2000;43:S43-S46.32. Guenther LC, Poulin YP. Adjunctive use of fluticasone pro-pionate ointment (q.d. or b.i.d.) with tazarotene gel in the treat-ment of plaque psoriasis. . Poster Presentation. AmericanAcademy of Dermatology. Washington DC, 200133. Coynik D. Clinical effects of switching from calcipotriene totazarotene in the treatment of plaque psoriasis. Poster Presen-tation. American Academy of Dermatology Annual Meeting.Washington DC, 2001 34. Tanghetti EA. An observation study evaluating the efficacyof tazarotene plus corticosteroid in treating plaque psoriasis inpatients switched form treatment with calcipotriene + cortocos-teroid. Cutis 2000;66(suppl 6S):12-18.35. Draelos ZD, Tanghetti EA. Optimizing the use of

tazarotene for the treatment of facial acne vulgaris throughcombination therapy. Cutis 2002;69:20-2936. Sabean J, Eisen D. The TOPS trial: tazarotene 0.1 % gelas monotherapy and in combination therapy in the treatment offacial acne vulgaris. American Academy of Dermatology Sum-mer Meeting, Nashville, Tennessee, 200037. Leyden JJ, Tanghetti EA, Miller B, et al. Once-dailytazarotene 0.1 % gel versus once-daily tretinoin 0.1 %microsponge gel for the treatment of facial acne vulgaris: adouble-blind randomized trial. Cutis 2002;69:12-1938. Webster GF, Guenther L, Poulin YP, et al. A multicenter,double-blind, randomized comparison study of the efficacy andtolerability of once-daily tazarotene 0.1 % gel and adapalene0.1 % gel for the treatment of acne vulgaris. Cutis 2002;69:4-1139. Webster GF, Berson D, Stein LF, et al. Efficacy and tolera-bility of once-daily tazarotene 0.1 % gel versus once-dailytretinoin 0.025 % gel in the treatment of facial acne vulgaris: arandomized trial. Cutis 2001;67:4-940. Leyden JJ, Lowe N, Kakita L, et al. Comparison of treat-ment of acne with alternate-day applications of tazarptene 0.1% gel and once-daily applications of adapalene 0.1 % gel: arandomized trial. Cutis 2001;67:10-1641. Shalita AR, Berson DS, Thiboutot DM, et al. Tarazotenecream in the treatment of acne: two multicenter, double-blind,randomized, vehicle-controlled, parallel-group studies of thesafety and efficacy of tazarotene 0.1 % cream applied oncedaily for 12 weeks in patients with acne vulgaris. Poster pre-sentation. American Academy of Dermatology.42. Kang S, Leyden JJ, Lowe NJ, et al. Tazarotene cream fortreatment of facial photodamage. Arch Dermatol2001;137:1597-160443. Philips TJ, Gottlieb AB, Leyden JJ, et al. Efficacy of 0.1 %tazarotene cream for the treatment of photodamage: a 12-month, multicenter, randomized trial. Arch Dermatol2002;138:1486-149344. Grimes P. Using tazarotene to treat acne in patients withskin type V or VI. Poster presentation. American Academy ofDermatology Annual Meeting, New Orleans, Louisiana, 200245. Leyden JJ, Grove GL. Randomized facial tolerability stud-ies comparing gel formulations of retinoids used to treat acnevulgaris. Cutis 2001;67:17-27

DEL ROSSO 59

Case Presentation:A 43 yo African-American female pre-

sented to our clinic with a complaint of“knots” on the buttocks, asymptomatic,which seemed to be spreading for 25years. Most recently the lesions hadstarted to ulcerate. Clinical examinationrevealed smooth dome shaped viola-ceous to black nodules clustered in a lin-ear array in various sizes. The largestnodules were approximately 20 x 15mmin diameter. Mild ulceration was seen insome of the lesions. The digital photo-graph below depicts these lesions in thegluteal cleft.

Background:TAA is an uncommon cystic lesion which

is benign. While the lesions are typicallysolitary, there have been reports of multi-ple lesions. Presentation varies, but usu-ally TAA presents as a solitary papule, upto 1.5 cm, dome shaped, translucent orbluish/black. It may be clinically misdiag-nosed as cystic basal cell carcinoma, pig-mented basal cell carcinoma, and evenmelanoma resulting at times to inappro-priately aggressive surgical intervention.This highlights the importance of obtain-ing biopsy results before planning surgi-cal intervention.

Histologically TAA is characterized bynumerous irregularly shaped tubularstructures, some with dilated lumens withpapillary projections. At times thesestructures project so excessively into thelumen that they form bridging type intralu-minal hyperplasia. TAA may have verru-cous architecture resemblingsyringocystadenoma papilliferum, but itlacks the plasma cell rich stromal inflam-matory infiltrate seen in syringocystade-noma papilliferum. In fact, the stromasurrounding TAA is markedly fibrous andhas very few inflammatory cells. The cys-tic structures in TAA typically have a dou-ble layer of cells. The luminal cells tendto be cuboidal whereas the peripheralcells tend to be flat. Decapitation secre-tion of the luminal cells is characteristic ofapocrine differentiation. The cystic tubu-lar structures are not continuous with the

epidermis. The treatment is simple exci-sion. H&E histology from this case is pre-sented in the digital photomicrographsbelow.

Literature Review:Jadassohn in 1914 defined “Adenoma”

as having atypical glandular structures incontrast to simple enlargement or morenumerous typical glands found in thenevus sebaceous of Jadassohn.

Tappener in 1947 and Civatte et al in1964 all noted that TAA is microscopicallydistinct from apocrine hidrocystoma,nevus sebaceous of Jadassohn, hidrade-noma papilliferum, syringocystadenomapapilliferum, apocrine mixed tumor orpapillary apocrine hidrocystoma. Theynoted that Hidradenoma papilliferum hasa more arborizing and trabeculated pat-tern than TAA. Syringocystadenomapapilliferum has an inflammatory infiltraterather than the fibrous stroma seen inTAA.

In the paper by Landry et al. entitled “AnUnusual Tubular Apocrine Adenoma” a66 yo woman with a 7 x 4 cm peduncu-lated, exuberant tumor with cerebriformsurface on the scalp was presented. Thiscase was unusual because the TAAarose in a pre-existing nevus sebaceousof Jadassohn she had since birth. Thetumor was excised with no recurrenceafter 1 year. A histochemical analysis ofthe specimen revealed evidence for apoc-rine differentiation including decapitationsecretion and positive staining for indoxylesterase and acid phosphatase. Thepossibility of eccrine differentiation wascast into doubt as the specimen failed tostain with phosphorylase.

Umbert et al. in their paper entitled“Tubular Apocrine Adenoma” repeatedthe findings from Landry’s case andadded a second newer case. This timethe patient was a 23 year old white malewho presented with a 2 x 1 cm nodulevertex scalp that had been present forseveral years. This was an interestingcase because the original histologic diag-nosis was metastatic adenocarcinoma.This patient had no evidence of cancer in

the GI tract. The lesion was treated withwide excision, and no recurrence wasseen at 1 year. Histologically this tumorrevealed decapitation sccretion andstained positively for markers of apocrinedifferentiation such as indoxyl esterase,acid phosphatase and leucine aminopep-tidase. Apocrine tubules were well differ-entiated in some areas and poorlydifferentiated in others. The articledetailed a number of parameters thatmight help the pathologist to favor a diag-nosis of TAA over metastatic adenocarci-noma as follows: organoid differentiation,high degree of cellular differentiation,connection to epidermis, absence ofmitotic figures and absence of cellularanaplasia.

“Apocrine Gland Adenoma and Adeno-carcinoma of the Axilla” by Warkel et al.reviewed 12 patients with axillary apoc-rine tumors. Two of those patients werediagnosed with TAA and were alive at 3and 4 years after excision. Eight werediagnosed with adenocarcinoma, and ofthose 2 died of unrelated causes (heartattack and stroke), 3 died of adenocarci-noma, 1 was alive with skeletal metasta-sis. The remaining 4 diagnosed withadenocarcinoma were alive and well at 3year follow ups and one was found to bealive at a 15 year follow up. In comparingthe histologic features of TAA to those ofapocrine adenocarcinoma, the followingfeatures of apocrine adenocarcinomawere highlighted: poor cellular differentia-tion, linearly infiltrating pleomorphic tumor

60 SEGMENTAL VARIANT OF AN UNUSUAL TUMOR: CASE PRESENTATION AND REVIEW OF THE LITERATURE

Segmental Variant of an Unusual Tumor: Case Presentation andReview of the Literature

By Dan Ladd, D.O., Rick Lin, DO, MPH, Dermatology Residents, KCOM/Texas Division, Program Director: Bill V. Way, D.O.

AbstractTubular apocrine adenoma (TAA) is a rare cystic tumor that is easily treated with excision. Because atypical variants of this

tumor share many features with apocrine adenocarcinoma, precise guidelines for appropriate management may be elusive. Thispaper presents a case of TAA and review of the literature to better elucidate this rare entity.

Figure 1

cells with stromal desmoplasia and hyper-plasia with frank neoplasia.

Okun et al reported in their article enti-tled “Apocrine Adenoma versus ApocrineCarcinoma” 2 cases of TAA. One wasclearly benign but the other had moderatenuclear pleomorphism, which led 3 of 8

pathologists to diagnose apocrine adeno-carcinoma rather than TAA. Graham,Johnson & Helwig believe recurrent TAAof the axilla is frequently misdiagnosed asadenocarcinoma.

In the article entitled “Perianal ApocrineGland Adenoma” Weigand et al describeda 59 year old with a perianal pedunculatetumor, originally misdiagnosed as condy-loma acuminata, which had failed treat-ment with topical podophyllum resin.Histology was consistent with TAA andtreatment was simple excision with norecurrence.

In the article by Burket et al entitled“Tubular apocrine adenoma with per-ineural invasion” a tumor on the scalpwith features of TAA and syringoideccrine carcinoma was described. Per-ineural invasion was present. Perineuralinvasion is common in syringoid eccrinecarcinoma but had never been reported intubular apocrine adenoma at the time thisarticle was printed. Burket et al. felt theinfiltrative and invasive features seen intheir case broadened the category of TAAso that it would no longer be consideredcompletely benign. The recommendationwas to manage TAA as you would otherlocally aggressive malignancies.

Zulaica et al in their paper entitled“Tubular Apocrine Adenoma” described a33 yo woman with foul smelling tumor onposterior scalp x 6 months. Histopathol-ogy revealed features of syringoscystade-noma papill iferum, includingpapillomatous surface changes and aninflammatory infiltrate rather than a purelyfibrous stroma. Again treatment was sim-ple excision.

DiscussionA review of the literature reveals that

tubular apocrine adenoma is a rare tumorthat has histological features that mayoverlap with a number of entities includ-ing apocrine adenocarcinoma, hidrade-noma papill iferum, apocrinehidrocystoma, mixed apocrine tumor,syringoid eccrine carcinoma and syringo-cystadenoma papilliferum. Given thisconfusing multitude of diagnostic dilem-mas, the bottom line in patient carebecomes the age old decision of “benignv. malignant”.

Several of the articles mentioned abovesite cytologic features as the best way torule out malignancy in these lesionsincluding pleomorphism, degree of cellu-lar differentiation, stromal desmoplasia,degree of infiltration of tumor, hyperplasiaand of course frank neoplasia. Specialstains may be used to differentiateeccrine from apocrine origin, but are of lit-tle use in settling the question of malig-nancy.

Our patient remains tumor free 3 yearsafter excision and histologically her tumorlacked features that would suggest malig-nancy. Our case was unusual becausethe presentation was that of a linear orsegmental grouping of nodular lesionsrather than a single nodule or tumor. Toour knowledge this is the first reportedcase of segmental or linear variant oftubular apocrine adenoma. Review of theliterature reveals that pathologists andclinicians should be vigilant for cytologicfeatures of malignancy in these unusualtumors and that follow up should be per-formed at regular intervals.

Bibliography1. An Unusual Tubular Apocrine Adenoma, Landry et al, ArchDermatol, 15: 869. June 1972.2. Tubular Apocrine Adenoma, Umbert et al, J. Cutan. Path, 3:75-87, 1976. 3. Apocrine Gland Adenoma and Adenocarcinoma of theAxilla, Warkel et al, Arch Dermatol, 1978, 114: 1978.4. Apocrine Adenoma versus Apocrine Carcinoma, Okun et al,J Am Acad Dermatol 2: 322-326, 1980.5. Perianal Apocrine Gland Adenoma, Weigand et al, ArchDermatol, 116: 1051-1053, 1980.6. Tubular Apocrine Adenoma with Perineural Invasion, Burketet al, J Am Acad Dermatol, 11: 639-642, 1984.7. Tubular Apocrine Adenoma, Zulaica et al, J Cutan Pathol14: 114-117, 1987. Okun et al, JAAD, April 1980, Vol. 2: 4.

LADD, LIN, DERMATOLOGY RESIDENTS, WAY 61

Figure 2

Figure 3

Figure 4

Figure 5

Report of CaseA 7- week- old male infant was

referred for dermatologic evaluation of arash present since three weeks of age.The rash was widespread and located onthe head, neck, chest, abdomen, arms,and in the diaper region. Prior treatmentwith topical moisturizers and hydrocorti-sone cream were not helpful. Previousskin scrapings for fungal culture werenegative. The infant was born at term andin a normal state of health. He wasafebrile and had no known associated ill-nesses. Prior to delivery, the infant’smother was being followed for an unde-termined autoimmune disorder associ-ated with intermittent facial rash, andserlogies positive for antibodies toSSA/Ro and SSB/La.

Examination of the infants skin revealedscattered annular erythematous maculesand patches ranging from 2mm to 20mmin size. Areas of annular erythema werepresent on the scalp, forehead, eyelids,neck, trunk, arms, and in the suprapubicarea (Figures 1 and 2). There was no evi-dence of scale or other cutaneouschanges. A mild erythema was noted onthe cheeks bilaterally. The palms andsoles were clear. Repeat skin scrapingsfor potassium hydroxide evaluation werenegative for fungal elements.

Laboratory evaluation of the infant wassignificant for a positive antinuclear anti-body (ANA) at a titer of 1:2,560 in aspeckled pattern. Additional antibodystudies were positive for both SSA/Roand SSB/La antibodies. All other labora-tory tests to include a complete bloodcount with platelets, liver and renal func-tion tests were within normal parameters.A rapid plasma reagin test was non-reac-tive. Cardiac evaluation by an electrocar-diogram was significant for a normalsinus cardiac rhythm without evidence ofheart block. A diagnosis of NeonatalLupus Erythematosus was made basedon clinical and laboratory findings. Treat-ment was started with topical desonidecream twice daily. Photoprotective mea-

sures were also instituted. Complete res-olution of all areas of annular erythemaoccurred within five weeks. Repeat labo-ratory testing for ANA, SSA/Ro andSSB/La antibodies turned negative by sixmonths of age. The child remains healthyto date and free from cutaneous, cardiac,or autoimmune disease.

DiscussionNeonatal Lupus Erythematosus (NLE)

is an uncommon disorder that mayrequire dermatologic evaluation for diag-nosis. The incidence of NLE is 1 in12,500 live births. (1,2) The accepted causeof NLE is from transplacental passage ofmaternal autoantibodies to the fetus fromwomen with either Systemic Lupus Ery-thematosus, Sjogrens Syndrome or anundifferentiated autoimmune disease. (1-13)

A reported 50% of women are asympto-matic at the time of delivery. However, thevast majority of these women developsome form of connective tissue diseaseover time. (1-3,7,9-15) Specific autoantibodiesinvolved in NLE include SSA/Ro and/orSSB/La antibodies. (1-18) SSA/Ro is consid-ered the antibody marker in NLE andfound in over 90% of cases.(1,7,9,11,14,16-18)

Less commonly reported autoantibodiesinclude ANA, dsDNA , U1RNP and Scl-70. (1-3,6,8,11,16,19) These maternally acquiredautoantibodies are transient in the infantand clear from the infant’s circulation bysix months of age. (1-3,7,8,12,14,18) The majorclinical features of NLE involve the skinand heart.

Cutaneous features of NLE occur in50% of patients and consist of a charac-teristic annular erythema. (1-3,6,7,9-11,13,14,16)

Annular erythematous macules andpatches appear at birth or within the firstfew weeks of life. The annular erythemahas a predilection for the head and neckbut may involve other skin areas as seenin this case. The pathogenesis of skin dis-ease in NLE involves the binding ofSSA/Ro, SSB/La and other autoantibod-ies to the basal keratinocytes. (3) Skin dis-ease is exacerbated by ultraviolet light;therefore, photoprotection is helpful in thetreatment of the cutaneous manifesta-

tions of NLE. (2,3,5,7,10,11,14,16) Other treatmentoptions for the cutaneous features of NLEinclude the use of nonfluorinated topicalcorticosteroids. (3,5,14,16) Regardless of treat-ment, the skin lesions of NLE are selflim-ited. Resolution of skin lesions correlateswith the clearance of maternal autoanti-bodies from the infant’s circulation at sixmonths of age. (1-3,5,7,10-14,16,18) Scarring is anunusual sequelae of cutaneous disease.However, hypopigmentation, epidermalatrophy and persistent telangiectasesmay follow the rash of NLE. (1,2,7,11,14,16) Skinbiopsy of the annular erythema in NLEdisplays epidermal atrophy with hydropicdegeneration of the basal layer. A superfi-cial mononuclear cell infiltrate predomi-nates. Biopsy findings mimic those ofsubacute cutaneous lupus erythemato-sus. (2,3,6,10,11,14,16)

Cardiac involvement in NLE occurs in50% of patients and represents the mostserious manifestation of the disease. (1-3,7,19)

Complete congenital heart block (CCHB)is the major cardiac finding. CCHB is anirreversible, third degree, atrioventricular(AV) block. Significant morbidity andmortality is associated with CCHB due to

62 NEONATAL LUPUS ERYTHEMATOSUS: CASE REPORT AND REVIEW

Neonatal Lupus Erythematosus: Case Report and Review

Raymond A. Schwab, D.O., Lieutenant Colonel, US Air Force, Medical Corps, Wright-Patterson Air Force Base, Ohio

AbstractNeonatal Lupus Erythematosus is a multisystem disorder with cutaneous, cardiac, hematologic and hepatobiliary manisfesta-

tions. Transplacental passage of maternal autoantibodies to the fetus from women with either Systemic Lupus Erythematosus, Sjo-grens Syndrome or an undifferentiated autoimmune disease is the accepted cause. A case report of Neonatal LupusErythematosus and literature review is presented.

Figure 1

Figure 2

the development of congestive heart fail-ure. (1-4,6-16,19) Placement of a permanentpacemaker is required in two-thirds ofinfants with CCHB in NLE. Regardless oftherapy, a reported 15-30% mortality rateoccurs in infants with CCHB in NLE.(1,3,7,10,13,14) CCHB can be detected as earlyas 16-18 weeks gestation by fetalechocardiogram. Fetal echocardiogramwill reveal evidence of either a bradycar-dia or an arrhythmia. (1-4,6,11-14) The patho-genesis of CCHB in NLE is due to fibrosisand calcification in the area of the AVnode. The fetal cardiac conduction sys-tem appears vulnerable to SSA/Ro andSSB/La autoantibodies during cardiacembryogenesis. (6,13,14,18) After birth, CCHBcan be detected by an electrocardiogram.The maternal risk for delivering an infantwith CCHB in primagravida women withSLE is 1-2%. However, this risk increasesto 25% with subsequent pregnancies.(1,4,10,11) Therefore, appropriate counselingof these women and serial fetal echocar-diograms are warranted in all pregnan-cies. Case reports have described theuse of systemic corticosteroids such asdexamethasone and prednisolone inpregnant women with fetal echocardio-graphic evidence of complete AV block.The systemic corticosteroids completelyor partially diminished the AV block in theinfants at the time of birth. (6,13) Unfortu-nately, these results have not beenproven universally effective. Infants pre-senting with both the cutaneous and car-diac features of NLE are seen in only 9%of cases. (3)

Hematologic abnormalities are foundin 10-20% of patients with NLE. (1-3,5,7,10,14,18)

These include anemia, thrombocytopenia,and leukopenia. Appropriate supportivemeasures are helpful for these transientfeatures of NLE. Hepatobiliary involve-ment may develop in 20%- 40% ofpatients with NLE. Manisfestations mayrange from mild transaminasemia andhyperbilirubinemia to rarely reported liverfailure. (1-3,6,7,10,14,18,20) Children with a historyof NLE do not have an increased risk ofdeveloping SLE. However, the develop-ment of some form of autoimmune dis-ease in early childhood may occur.Examples include juvenile rheumatoidarthritis, Hashimoto’s thyroiditis, psoriasis,diabetes mellitus and hypothyroidism. (19)

This risk necessitates continued medicalsurveillance of these patients throughoutchildhood.

NLE is an uncommon disorder with acharacteristic presentation. The first clueto NLE maybe the finding of a bradycar-dia or an arrhythmia on fetal echocardio-gram. Infants present with either the skinrash of annular erythema, complete con-genital heart block or both. Associatedfeatures of NLE may include hematologicand hepatobiliary abnormalities. The der-

matologist plays a vital role in the earlyrecognition and diagnosis of NLE. Earlydiagnosis may improve the morbidity andmortality of NLE.

References1. Liu J, Yang YH, Lin YT, Chiang BL. Clinical characteristics ofneonatal lupus erythematosus. Journal of Microbiology,Immunology & Infection 2001; 34(4): 265-268.2. Corona R, Angelo C, Cacciaguerra MG, et al. Neonatallupus erythematosus. Cutis 2000; 65 (6): 379-381. 3. McCauliffe DP. Neonatal lupus erythematosus: a tran-spacentally acquired autoimmune disorder. Seminars in Der-matology 1995; 14(1): 47-53.4. Gladman G, Silverman ED, Yuk-Law, et al. Fetal echocar-diographic screening of pregnancies of mothers with anti-Roand/or anti-La antibodies. American Journal of Perinatology2002; 19(2): 73-79. 5. Yazici Y, Onel K, Sammaritano L. Neonatal lupus erythen-atosus in triplets. The Journal of Rheumatology 2000; 27(3):807-809.6. Ishimaru S, Izaki S, Kitamura K, Morita Y. Neonatal lupuserythematosus: dissolution of atrioventricular block afteradministration of corticosteroid to the pregnant mother. Derma-tology 1994; 189(1): 92-94.7. McCune AB, Weston WL, Lee LA. Maternal and fetal out-come in neonatal lupus erythematosus. Annals of InternalMedicine 1987; 106(4): 518-523.8. Shimizu T, Toshihiro I, Nishimoto K, et al. Advanced atri-oventricular block in a neonate with lupus erythematosus andanti-SS-A antibodies. Pediatric Cardiology 1988; 9(2): 121-124.9. Lawrence S, Luy L, Laxer R, et al. The health of mothers ofchildren with cutaneous neonatal lupus erythematosus differsfrom that of mothers of children with congenital heart block.American Journal of Medicine 2000; 108(9): 705-709.10. Neiman A, Lee L, Weston W, Buyon J. Cutaneous manis-festations of neonatal lupus without heart block: characteristicsof mothers and children enrolled in a national registry. Journalof Pediatrics 2000; 137(5): 674-680.11. Topper SF, Agha A, Hashimoto K. Annular scaly plaques inan infant. Archives of Dermatology 1994; 130(1): 105-106.12. Lockshin MD, Gibofsky A, Peebles CL, et al. Neonatallupus erythematosus with heart block: family study of a patientwith anti-SS-A and SS-B antibodies. Arthritis & Rheumatism1983; 26(2) 210-213.13. Buyon JP. Neonatal lupus. Current Opinion in Rheumatol-ogy 1996; 8(5): 485-490.14. Lee LA, Weston WL. Neonatal lupus erythematosus. Semi-nars in Dermatology 1988; 7(1): 66-72. 15. Callen JP. Neonatal lupus erythematosus. Pediatric Der-matology 2000; 17(1): 82.16. Hetem MB, Takada MH, Llorach Velludo MA, Foss NT.Neonatal lupus erythematosus. International Journal of Derma-tology 1996; 35(1): 42-44.17. Garcia S, Nascimento JH, Bonfa E, et al. Cellular mecha-nism of the conduction abnormalities induced by serum fromanti-Ro/SSA- positive patients in rabbit hearts. Journal of Clini-cal Investigation 1994; 93(2): 718-724. 18. Houssiau FA, Lebacq EG. Neonatal lupus erythematosuswith congenital heartblock associated with maternal systemiclupus erythematosus. Clinical Rheumatology 1986; 5(4): 505-508.19. Martin V, Lee LA, Ankanase AD, et al. Long-term followupof children with neonatal lupus and their unaffected siblings.Arthritis & Rheumatism 2002; 46(9): 2377-2383.20. Bolognia JL. Dermatology. 1st Ed. Philadelphia: Mosby,2003: 606.

Figure LegendsFigure 1 and Figure 2: annular erythematous macules andpatches of Neonatal Lupus Erythematosus.

Correspondence:Raymond A. Schwab, D.O.Lt. Col, USAF, MCDermatology Element4881 Sugar Maple DriveWright-Patterson AFB, Ohio 45433Phone: 937-257-1574Fax: 937-257-4119E-mail: Raymond.Schwab@WPAFB.AF.MILNo funding sources

Disclaimer: The opinions and assertions contained herein arethose of the author and are not to be construed as reflectingthe views of the United States Air Force or the Department ofDefense.

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