Stress and Inflammatory Skin Disorders: A Review of Non-Pharmacologic TreatmentsAlso in this issue:

JAOCDJournal Of The American Osteopathic College Of Dermatology

Volume 26

pg. 12

Journal of the american osteopathic college of Dermatology page 1

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page 2 Journal of the american osteopathic college of Dermatology

AOCD • 2902 N. Baltimore St. • Kirksville, MO 63501800-449-2623 • FAX: 660-627-2623www.aocd.org

COPYRIGHT AND PERMISSION: Written permission must be obtained from the Journal of the American Osteopathic College of Dermatology for copying or reprinting text of more than half a page, tables or figures. Permissions are normally granted contingent upon similar permission from the author(s), inclusion of acknowledgement of the original source, and a payment of $15 per page, table or figure of 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 63501.

Copyright © 2003 by the Journal of the American Osteopathic College of Dermatology

Print and layout by: S&S Printing and Graphics LLC, 401 N. Marion St., Kirksville, MO 63501Copy editing by: Julia Layton, Freelance Writing and EditingCover image by: Vikram Krishnamurthy, MD, Chicago, IL

2012-2013 officers

PRESIDENTDavid L. Grice, DO, FAOCD

PRESIDENT-ELECTSuzanne Sirota-Rozenberg, DO, FAOCD

FIRST VICE-PRESIDENTRick J. Lin, DO, FAOCD

SECOND VICE-PRESIDENTAlpesh Desai, DO, FAOCD

THIRD VICE-PRESIDENTKarthik Krishnamurthy, DO, FAOCD

IMMEDIATE PAST-PRESIDENTBradley Glick, DO, FAOCD

TRUSTEESDanica Alexander, DO, FAOCDReagan Anderson, DO, FAOCDMark A. Kuriata, DO, FAOCDDaniel Ladd, DO, FAOCDJohn P. Minni, DO, FAOCDBryan Sands, DO, FAOCD

SECRETARY-TREASURERJere J. Mammino, DO, FAOCD

EXECUTIVE DIRECTORMarsha A. Wise, B.S.

Editor-in-ChiefKarthik Krishnamurthy, DO

Sponsors:BayerAuroraDx Medicis Ranbaxy

JAOCDFounding Sponsor

Journal of the american osteopathic college of Dermatology

Journal of the american osteopathic

college of Dermatology

Journal of the american osteopathic college of Dermatology page 3

Table of Contents Volume 26

JAOCD Editors ............................................................................................................................................................................................ 4Letter from the Editor-in-Chief ................................................................................................................................................................... 5Letter from the Executive Director ............................................................................................................................................................... 6Letter from the President .............................................................................................................................................................................. 7

FeAture ArtICLe:Stress and Inflammatory Skin Disorders: A Review of Non-Pharmacologic Treatment Options Monica Huynh, BA, John Koo, MD ........................................................................................................................................................ 12

eDItOr’S PICkS:Old World meets New World Leishmaniasis: Leishmania tropica in Florida Ann Mazor-Reed, DO, Jacqueline A. Thomas, DO, FAOCD .................................................................................................................... 15Use of Acitretin in a Patient with Multiple Squamous Cell Carcinomas: A Case Report and Literature Review Dorene Niv, BS, Patrick Keehan, DO, FAOCD ....................................................................................................................................... 18Cutaneous Manifestation of Churg-Strauss Syndrome Holly Kanavy, DO, Cindy Hoffman, DO ................................................................................................................................................ 21

OrIgInAL ArtICLeS AnD CASe rePOrtSScalp Metastasis Heralding a Diagnosis of Breast Cancer: A Case Report and Discussion Mounir Wassef, DO, Robin Shecter, DO, FAOCD ................................................................................................................................... 24Case Report: Diffuse Bullous Eruption Following Antibiotic Use Capt. Shannon Buck, DO, Lt. Col. Erika Hill, MD, Col. (Ret) Wayne Sumpter, MD ................................................................................ 26Atypical Fibroxanthoma with Osteoclast-like Giant Cells: Report of Two Cases Viktoryia Kazlouskaya, MD, PhD, Vladyslava Doktor, MA, Elen Blochin, MD, PhD, Dirk Elston, MD ................................................... 28Primary Cutaneous Adenosquamous Carcinoma Treated with Mohs Donna D. Tran, DO, Brooke Walls, DO, Richard Miller, DO, FAOCD ................................................................................................... 30Lupus Panniculitis of the Lower Extremities: A Case Report and Review of the Literature Dustin Portela, H-BS, Paul M. Bedocs, DO, Melissa Piliang, MD ........................................................................................................... 31Oral and Cutaneous Lichenoid Drug Eruption Secondary to Imatinib Mesylate: A Case Report and Review of the Literature Kristen Suchniak, MD, Gregg Severs, DO ............................................................................................................................................... 33Dercum’s Disease Treated by Coolsculpting: A Case Report Jonathan S. Crane, DO, FAOCD, J. Kate Jackson, PA-C, Louis I. Padgett, BS .......................................................................................... 35The Companion: A Desmoplastic Trichoepithelioma Arising within a Melanocytic Nevus Peter Knabel, DO, Lloyd Cleaver, DO, FAOCD ...................................................................................................................................... 36Atypical Adult-onset Pityriasis Rubra Pilaris and Recurrent Corneal Ulcerations Natalie Edgar, BS, David Eslicker, DO, FAOCD, Henry Haskell, MD .................................................................................................... 38Granular Parakeratosis Treatment with Tacrolimus 0.1% Ointment: A Case Presentation and Discussion Bertha Baum, DO, Stanley Skopit, DO, MSE, FAOCD .......................................................................................................................... 40Hyperpigmentation in a 51-year-old Caucasian Female William Bethea, DO, Bryce Desmond, BS, Steven K. Grekin, DO ............................................................................................................ 42

page 4 JaocD eDitors

Associate Editors

Sami Abbasi, DOBrownstown, MI

Brad Abrams, DOSarasota, FL

Derrick Adams, DORed Bluff, CA

Brooke Bair, DOJacksonville, FL

Kevin Belasco, DOMilwaukee, WI

Brett Bender, DOFarmington Hills, MI

Richard Bernert, MDScottsdale, AZ

Ryan Carlson, DOHilliard, OH

Michael P. Conroy, MDColumbus, OH

Matther Elias, DOLighthouse Point, FL

Merrick Elias, DODelray Beach, FL

Brad Glick, DOMargate, FL

Marcus Goodman, DORoswell, GA

Melinda Greenfield, DOAlbany. GA

Denise Guevara, DOWeston, FL

Andrew Hanly, MDMiami, FL

Joel Harris, DOMadison Heights, MI

Heather Higgins, DOTroy, MI

David Horowitz, DOTorrence, CA

Jocelyn LaRocque, DOCharlotte, NC

Matt Leavitt, DOMaitland, FL

Mark Lebwohl, MDNew York, NY

Angela Leo, DONew York, NY

Scott Lim, DOErie, PA

Rick Lin, DOMcAllen, TX

Chava Lustig, DOWeston, FL

Jere Mammino, DOWinter Springs, FL

Chris Manlio, DOLoxahatchee, FL

John Minni, DOPort St. Lucie, FL

Tony Nakhla, DOOrange County, CA

Navid Nami, DONewport Beach, CA

Jon Keeling, DOLexington, KY

Dimitria Papadopoulos, DOBellmore, NY

John Perrotto, DOWest Palm Beach, FL

Stephen Purcell, DOAllentown, PA

Andrew Racette, DOPhoenix, AZ

Adriana Ros, DOClifton, NJ

Richard Rudnicki, DOMesquite, TX

Amara Sayed, DOSan Marcos, TX

Joseph Brant Schneider, DOShawnee Mission, KS

Gregg Severs, DOScranton, PA

Sean Stephenson, DOTroy, MI

Jacqueline Thomas, DOFort Lauderdale, FL

Jim Towry, DOOcala, FL

Not pictured: Iqbal Bukhari, MDAlkhobar, Saudi Arabia

editor-In-Chiefkarthik krishnamurthy, DO

Founding editorJay gottleib, DO

Assistant editorJulia Layton, BA, MFA

Editorial Board

Aaron Bruce, DOLoveland, CO

Michelle Foley, DOOrmond Beach, FL

Michael Scott, DOSeattle, WA

Scott Wickless, DODurango, CO

letter from the eDitor-in-chief

Karthik Krishnamurthy, DO, FAOCDEditor-in-Chief

letter from the eDitor-in-chief page 5

Dear JAOCD Readership,

On August 1, 2013, under the Physician Payment Sunshine Act (PPSA), “industry” must begin collating information regarding its relationships with physicians.  Starting in March 2014, “industry” will begin reporting “payment or other transfer of value” to the Department of Health and Human Resources.  What does this mean?

Begotten by the Patient Protection and Affordable Health Care Act of 2010, the intention of PPSA is to ensure transparency.  Reporting will be facilitated through CMS.gov (Centers for Medicare and Medicaid Services), and it is imperative that all physicians register with the service in order to receive notifications and track and verify “transactions,” as there will be a 45-day window to review or challenge individual entries.

“Industry” includes pharmaceutical, medical-device, biological and medical-supply companies. The definition of “payment or other transfer of value” is quite sweeping and includes gifts, entertainment, food/drink, travel, accommodations, consulting, honoraria, royalties, grants, facility fees, ownership interest, investments, charitable contributions, and more. Anything greater than $10 in value will be reported; and if greater than $100 is received, items less than $10 in value become eligible for reporting.  So, those donuts could influence how your patients perceive your professionalism.

Which brings us to the most important aspect: How will this affect our daily interactions with our patients?   We must be prepared to explain our relationships with industry to our patients.  I urge each of you to evaluate and manage your relationships (and identify colleagues who may need your friendly guidance).   Considering the recent cancellation of ACGME merger negotiations, we must stand together as a community to protect the integrity and reputation of osteopathic dermatology.  Each of us must be able impress upon our patients that any relationships in which we participate are ethical and do not negatively impact their care.

This will not be the only adjustment we face as a result of the Patient Protection and Affordable Health Care Act over the next several years, but this is the most acute.  We should remember that the PPSA does not prevent industry relationships. Industry needs physician input to create cutting-edge therapeutic products and modalities for our patients.  Vice-versa, this educational journal could not exist without grants from our loyal industry sponsors.  I believe that the benefits of continued relationships far outweigh any burdens created by the Act.  Each of us must formulate an individual strategy for our practices to manage interactions in an “above board” manner while demonstrating ethical behavior to our patients.  The best course of action is to be prepared.

Warm Regards,Karthik Krishnamurthy, DO, FAOCD

*I would like to recognize the editorial pieces from the July issue of Practical Dermatology and Modern Aesthetics as resources used for this column.

letter from the executive Director

Marsha WiseExecutive Director, AOCD

Greetings, everyone!

Summer is winding down, and soon it will be time for OMED 2013! Our lecture schedule is complete, so be sure to check out www.aocd.org for more information. Also, our 2014 Midyear Meeting will be held February 20th through 23rd in Dallas, Texas, and we hope to have that schedule released soon. (While you are saving dates, be sure to mark off April 23rd through 26th, 2015, for our 2015 Midyear Meeting in Charlotte, NC.)

The AOA’s Annual Business Meeting was held in July 2013 in Chicago, IL. Dr. Lloyd Cleaver and Dr. David Grice represented the AOCD as Delegates. In addition, three other AOCD members attended, representing their states: Dr. Richard Johnson for Pennsylvania; Dr. Shield Wikas for Ohio; and Dr. Cindy Hoffman for New York. These five members represent a combined total of more than 115 years of dermatologic practice.

ACGME Update

The AOA and AACOM announced during the AOA’s Annual Business Meeting that to date they have been unsuccessful in reaching an agreement with ACGME on a Memorandum of Understanding (MOU) for a unified graduate medical education accreditation system. However, the AOA and AACOM remain open to continued discussions with the ACGME. Visit the AOA’s website for detailed information (www.osteopathic.org).

Finally, July 1st was the launch date for the updated AOCD.ORG! We encourage everyone to log in and review your profiles. A calendar of events has been added to the website, so please alert us if you know of a meeting that may be of interest to others. The new AOCD site contains an enormous amount of information pertaining to residency training, meetings, and other AOCD news as well as archives of both the JAOCD and Dermline.  Likewise, the American Osteopathic Board of Dermatology has a new site, www.aobd.org, which also contains the information residents need for obtaining Board certification and meeting OCC requirements after they are certified. With the amount of information available at the click of a mouse, there is no reason to be uninformed!

Sincerely,Marsha A. Wise

page 6 letter from the executive Director

letter from the presiDent

David L. Grice, DO, FAOCDPresident, AOCD

letter from the presiDent page 7

In July, I had the honor of representing the AOCD as an alternate delegate to the AOA House of Delegates (HOD) meeting in Chicago. Lloyd Cleaver, DO, FAOCD, is our AOA representative, and I want to give a big thanks to Dr. Cleaver for helping me understand the issues and politics that go on at the AOA level.

The main topic of discussion was the possibility of a new, unified graduate medical education accreditation system with the Accreditation Council for Graduate Medical Education (ACGME). Discussions between AOA and ACGME leaders have been ongoing for more than 18 months. The ACGME presented the AOA with a Memorandum of Understanding, which was basically the ACGME’s terms of the deal. The AOA Board of Trustees was given a “take it or leave it” stance with no room for compromise.

So it was announced at the HOD meeting that the AOA and ACGME have been unsuccessful in reaching an agreement. This news was actually met with great approval and a standing ovation by the delegates! President Ray Stowers, DO, stated that it is important for the AOA to stay committed to “protecting the distinctiveness and identity of the osteopathic medical profession.” The AOA has pledged to keep dialog open for further discussion and still believes the American public can benefit from a unified graduate medical education accreditation system.

What does this mean to our residents? First of all, if a DO resident participates in an osteopathic residency program (e.g., internal medicine), he or she will not be able to participate in an allopathic fellowship (e.g., cardiology, gastroenterology, etc.). This may also apply to our dermatology residents who want to apply to an allopathic Mohs micrographic surgery or dermatopathology fellowship.

It is important for our osteopathic specialty colleges to continue to develop more residency slots for our graduating DO students. There were roughly 4,900 graduating DO students in 2013 and only 2,900 osteopathic residency slots available, so many of our graduates are forced to find allopathic residencies. We members of the AOCD want to continue to expand our residency programs and fellowships while maintaining our emphasis on quality over quantity.

David L. Grice, DO, FAOCD

Think of me

Specifically DesignedTolerability in Mind1with

ZIANA is a registered trademark of Medicis Pharmaceutical Corporation. ZNA 12-024 06/30/13

See reverse side for a Brief Summary of the Full Prescribing Information.

Important Safety Information for ZIANA Gel• The most commonly reported adverse events were nasopharyngitis, pharyngolaryngeal pain, dry skin, cough, and sinusitis.• Diarrhea, bloody diarrhea, and colitis (including pseudomembranous colitis) have been reported with the use of topical

clindamycin. ZIANA Gel should be discontinued if significant diarrhea occurs. Systemic absorption of clindamycin has been demonstrated following topical use of this product.

• If a reaction suggesting sensitivity or chemical irritation occurs, use of the medication should be discontinued.• Avoid exposure to sunlight and sunlamps. Patients with sunburn should not use the product. Use with caution in patients

who require considerable sun exposure due to occupation or who are inherently sensitive to the sun. Avoid excessive exposure to the sun, cold, and wind, which can irritate skin. Daily use of sunscreen and protective clothing are recommended.

• Keep away from eyes, mouth, angles of nose, and mucous membranes.• This drug is contraindicated in patients with regional enteritis, ulcerative colitis, or history of antibiotic-associated colitis.• Concomitant use of topical medications with a strong drying effect can increase skin irritation. Use with caution.

To learn more, contact your Medicis, The Dermatology Company representative.

•Indicatedforthetopicaltreatmentofacnevulgarisinpatients12yearsorolder.•Suspendedcrystallinetretinoininvehicledesignedtodelivertheactiveingredientstotheskin.2

•Hydrogelalcohol-freeaqueousbase.1

References: 1. ZIANA Gel Package Insert. Scottsdale, AZ: Medicis, The Dermatology Company; October 2008. 2. NDA 50-802 for ZIANA Gel; Sections 4.4.4.1 & 4.2.5. 2006. Data on file, Medicis Pharmaceutical Corporation.

Journal of the american osteopathic college of Dermatology page 8

Letter from the President

BRIEF SUMMARY (see package insert for Full Prescribing Information)

Rx onlY

For topical use only

InDICATIonS AnD USAGEZiana® Gel is indicated for the topical treatment of acne vulgaris in patients 12 years or older.

ConTRAInDICATIonSZiana® Gel is contraindicated in patients with regional enteritis, ulcerative colitis, or history of antibiotic-associated colitis.

WARnInGS AnD PRECAUTIonSColitissystemic absorption of clindamycin has been demonstrated following topical use of this product. Diarrhea, bloody diarrhea, and colitis (including pseudomembranous colitis) have been reported with the use of topical clindamycin. When significant diarrhea occurs, Ziana® Gel should be discontinued.

severe colitis has occurred following oral or parenteral administration of clindamycin with an onset of up to several weeks following cessation of therapy. antiperistaltic agents such as opiates and diphenoxylate with atropine may prolong and/or worsen severe colitis. severe colitis may result in death.

studies indicate a toxin(s) produced by clostridia is one primary cause of antibiotic-associated colitis. the colitis is usually characterized by severe persistent diarrhea and severe abdominal cramps and may be associated with the passage of blood and mucus. stool cultures for Clostridium difficile and stool assay for C. difficile toxin may be helpful diagnostically.

Ultraviolet light and Environmental Exposure exposure to sunlight, including sunlamps, should be avoided during the use of Ziana® Gel, and patients with sunburn should be advised not to use the product until fully recovered because of heightened susceptibility to sunlight as a result of the use of tretinoin. patients who may be required to have considerable sun exposure due to occupation and those with inherent sensitivity to the sun should exercise particular caution. Daily use of sunscreen products and protective apparel (e.g., a hat) are recommended. Weather extremes, such as wind or cold, also may be irritating to patients under treatment with Ziana® Gel.

ADVERSE REACTIonSClinical Studies Experience Because clinical trials are conducted under prescribed conditions, adverse reaction rates observed in the clinical trial may not reflect the rates observed in practice. the adverse reaction information from clinical trials does, however, provide a basis for identifying the adverse reactions that appear to be related to drug use for approximating rates.

the safety data presented in table 1 (below) reflects exposure to Ziana® Gel in 1,853 patients with acne vulgaris. patients were 12 years and older and were treated once daily for 12 weeks. adverse reactions that were reported in ≥ 1% of patients treated with Ziana® Gel were compared to adverse reactions in patients treated with clindamycin phosphate 1.2% in vehicle gel, tretinoin 0.025% in vehicle gel, and the vehicle gel alone:

Table 1: Adverse Reactions Reported in at least 1% of Patients Treated with ZIAnA® Gel: 12-Week Studies

ZIAnA® Geln=1853n (%)

Clindamycinn=1428n (%)

Tretinoinn=846n (%)

Vehiclen=423n (%)

patients WitH at least one ar 497 (27) 342 (24) 225 (27) 91 (22)nasopharyngitis 65 (4) 64 (5) 16 (2) 5 (1)pharyngolaryngeal pain 29 (2) 18 (1) 5 (1) 7 (2)Dry skin 23 (1) 7 (1) 3 (<1) 0 (0)cough 19 (1) 21 (2) 9 (1) 2 (1)sinusitis 19 (1) 19 (1) 15 (2) 4 (1)

note: Formulations used in all treatment arms were in the Ziana® vehicle gel.

cutaneous safety and tolerance evaluations were conducted at each study visit in all of the clinical trials by assessment of erythema, scaling, itching, burning, and stinging:

Table 2: ZIAnA® Gel-Treated Patients with local Skin Reactions local Reaction Baseline

n=1835n (%)

End of Treatmentn=1614n (%)

erythema 636 (35) 416 (26)scaling 237 (13) 280 (17)itching 189 (10) 70 (4)Burning 38 (2) 56 (4)stinging 33 (2) 27 (2)

at each study visit, application site reactions on a scale of 0 (none), 1 (mild), 2 (moderate), and 3 (severe), and the mean scores were calculated for each of the local skin reactions. in studies 1 and 2, 1277 subjects enrolled with moderate to severe acne, 854 subjects treated with Ziana® Gel and 423 treated with vehicle. analysis over the twelve week period demonstrated that cutaneous irritation scores for erythema, scaling, itching, burning, and stinging peaked at two weeks of therapy, and were slightly higher for the Ziana®-treated group, decreasing thereafter.

one open-label 12-month safety study for Ziana® Gel showed a similar adverse reaction profile as seen in the 12-week studies. eighteen out of 442 subjects (4%) reported gastrointestinal symptoms.

DRUG InTERACTIonSConcomitant Topical Medicationconcomitant topical medication, medicated or abrasive soaps and cleansers, soaps and cosmetics that have a strong drying effect, and products with high concentrations of alcohol, astringents, spices or lime should be used with caution. When used with Ziana® Gel, there may be increased skin irritation.

ErythromycinZiana® Gel should not be used in combination with erythromycin-containing products due to its clindamycin component. In vitro studies have shown antagonism between these two antimicrobials. the clinical significance of this in vitro antagonism is not known.

neuromuscular Blocking Agentsclindamycin has been shown to have neuromuscular blocking properties that may enhance the action of other neuromuscular blocking agents. therefore, Ziana® Gel should be used with caution in patients receiving such agents.

USE In SPECIFIC PoPUlATIonSPregnancypregnancy category c. there are no well-controlled trials in pregnant women treated with Ziana® Gel. Ziana® Gel should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Ziana® Gel was tested for maternal and developmental toxicity in new Zealand White rabbits with topical doses of 60, 180 and 600 mg/kg/day. Ziana® Gel at 600 mg/kg/day (approximately 12 times the recommended clinical dose assuming 100% absorption and based on body surface area comparison) was considered to be the no-observed-adverse-effect level (noael) for maternal and developmental toxicity following dermal administration of Ziana® Gel for two weeks prior to artificial insemination and continuing until gestation day 18, inclusive. For purposes of comparisons of the animal exposure to human exposure, the recommended clinical dose is defined as 1 g of Ziana® Gel applied daily to a 60 kg person.

Clindamycin teratology (segment ii) studies using clindamycin were performed orally in rats (up to 600 mg/kg/day) and mice (up to 100 mg/kg/day) (583 and 49 times amount of clindamycin in the recommended clinical dose based on a body surface area comparison, respectively) or with subcutaneous doses of clindamycin up to 180 mg/kg/day (175 and 88 times the amount of clindamycin in the recommended clinical dose based on a body surface area comparison, respectively) revealed no evidence of teratogenicity.

Tretinoinin oral segment iii studies in rats with tretinoin, decreased survival of neonates and growth retardation were observed at doses in excess of 2 mg/kg/day (~ 78 times the recommended clinical dose assuming 100% absorption and based on body surface area comparison).

With widespread use of any drug, a small number of birth defect reports associated temporally with the administration of the drug would be expected by chance alone. thirty cases of temporally associated congenital malformations have been reported during two decades of clinical use of another formulation of topical tretinoin. although no definite pattern of teratogenicity and no causal association have been established from these cases, 5 of the reports describe the rare birth defect category, holoprosencephaly (defects associated with incomplete midline development of the forebrain). the significance of these spontaneous reports in terms of risk to the fetus is not known.

Dermal tretinoin has been shown to be fetotoxic in rabbits when administered in doses 40 times the recommended human clinical dose based on a body surface area comparison. oral tretinoin has been shown to be fetotoxic in rats when administered in doses 78 times the recommended clinical dose based on a body surface area comparison.

nursing Mothersit is not known whether clindamycin is excreted in human milk following use of Ziana® Gel. However, orally and parenterally administered clindamycin has been reported to appear in breast milk. Because of the potential for serious adverse reactions in nursing infants, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. it is not known whether tretinoin is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Ziana® Gel is administered to a nursing woman.

Pediatric Usesafety and effectiveness of Ziana® Gel in pediatric patients under the age of 12 have not been established.

clinical trials of Ziana® Gel included patients 12–17 years of age.

Geriatric Use clinical studies of Ziana® Gel did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.

Manufactured for: Medicis, the Dermatology company scottsdale, aZ 85256

u.s. patents 5,721,275 and 6,387,383

Ziana is a registered trademark of Medicis pharmaceutical corporation.

prescribing information as of october 2008.

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page 12 stress anD inflammatory skin DisorDers: a review of non-pharmacologic treatment options

Stress and Inflammatory Skin Disorders: A Review of Non-Pharmacologic Treatment Options

Monica Huynh, BA,* John Koo, MD**

*Medical Student, Chicago College of Osteopathic Medicine at Midwestern University, Downers Grove, IL**Professor and Vice Chairman, Department of Dermatology, University of California, San Francisco, CA

AbstractDermatologic disorders account for 15% to 20% of complaints seen in general practice, and inflammatory skin disorders like psoriasis, acne, and atopic dermatitis are commonly encountered. Inadequate treatment of skin disorders often has a negative impact on the patient, not only physically but also psychologically, socially, and occupationally. One of the most common triggers for several inflammatory skin disorders including psoriasis is emotional stress. Despite the accumulated data on how the psychological states of dermatology patients can have profoundly negative effects on skin disorders, the idea of incorporating psychological treatment in dermatology is a barely discussed topic in our specialty, and no guidelines have yet been proposed. However, dermatologists and their patients are likely to benefit from such treatment options as long as they can be feasibly adopted in clinical practice. Non-pharmacological treatments are particularly appealing since they lack the side effects of pharmacological options. This article provides an overview of common non-pharmacological therapeutic options.

IntroductionDermatologic disorders make up 15% to 20% of complaints seen in general practice, many of which are related to common inflammatory skin disorders such as psoriasis, acne, and atopic dermatitis.1 Psoriasis alone affects 2% to 3% of the U.S. population.2 Atopic dermatitis affects 15% to 20% of children and constitutes approximately 15% of the skin-related concerns in general practice.2 Acne affects 30% to 100% of school-age children, if one were to include the condition in all its severities.2,3,4 Since dermatology is a visually oriented specialty, dermatologists are accustomed to using observable modalities from diagnosis to treatment to address skin disorders. For example, assessment tools include psoriasis area and severity index (PASI) or eczema area and severity index (EASI), and treatments include topical medications and phototherapy.5 Patients are also visually oriented and may not be fully aware of the relationship between cutaneous disorders and psychological state and the impact it may have on the manifestation of disease. However, clinical practice involving an exclusively visual-based approach is oftentimes insufficient to manage skin disorders and may leave patients inadequately treated.6 Physical symptoms and visual aspects of skin diseases are not the only factors that negatively impact the patient’s health; depression, anxiety, stress, fatigue, perceived helplessness, and decreased social supports contribute as well.5 Therefore, inadequate treatment of skin disorders due to lack of attention to non-visible psychological aspects may result in negative outcome to the patient, not only physically but also psychologically, socially, and occupationally. Since dermatologic complaints comprise up to one-fifth of those encountered in general practice, the negative impact on quality of life from treatment failure may produce a significant social burden.1

Stress and the Psychological Impact on Common Inflammatory Skin DisordersIt has been established that approximately 30% to 40% of dermatology outpatients present with a psychological component associated with their skin complaint.7 Dermatology inpatients were also found to have a higher prevalence of psychiatric morbidity than general medical inpatients.7,8 Of note, one of the most common triggers for common inflammatory disorders is emotional stress. In 1998, Fortune et al. conducted a survey of 162 psoriasis patients, and 60% reported that emotional stress was strongly associated as an exacerbating factor for their psoriasis.9 In 2001, Lammintausta et al. prospectively studied 801 atopic dermatitis subjects, and psychic stress was the most commonly cited trigger factor.10 Also in 2001, Green et al. conducted a survey with 215 medical students, and 67% identified stress as a trigger for acne flares.11 Similarly, in another study 74% of patients with acne reported that anxiety was an exacerbating factor in their disease.12 Chiu et al. observed 20 subjects and found those with the greatest increase in perceived stress also displayed the greatest exacerbation of acne severity in a proportional and predictable manner.13 The particular type of stress may not be so critical as stress in its entire spectrum, which has been implicated as a precipitating or exacerbating factor for a variety of inflammatory skin conditions such as psoriasis, acne, and atopic dermatitis.3,13,14

Despite the above data on the importance of psychological state in skin disorders, the incorporation of psychological treatment in dermatology continues to be an unknown topic to most dermatologists. Therefore, dermatologists and their patients may benefit from psychological intervention that may be feasibly integrated in clinical practice. Non-pharmacological treatments are particularly

appealing since they lack the side effects of pharmacological options. The combination of non-pharmacological therapy and conventional therapy would offer more comprehensive care for patients who may need this dual approach to “turn the table around” on their skin disorders.15 This article will provide an overview of common non-pharmacological therapeutic options available.

Indications for Psychological EvaluationIndications for psychological evaluation of patients include a history of stress as a trigger or aggravating factor to their skin disorders, psychiatric comorbidities, or significantly decreased quality of life.29 Other alerting factors include patients who repeatedly seek dermatology consultation and yet are either not responding at all or relapsing more often than expected, or when the explanations or presentations of skin disorders seem strange or implausible.8

An effective and simple start would be to inquire whether the patient has experienced stress as the frequent worsening factor for the severity of their skin disease. Further inquiry may be made about stressful life events, depression, anxiety, or social support (or lack of it) to guide the physician toward diagnosis and appropriate treatment. Validated psychometric instruments such as Dermatology Life Quality Index (DLQI) and Skindex-29 are used to quantify the physical, psychological, and social impact of dermatologic disorders on patients’ well-being and quality of life.16,17 The clinical significance of the scores varies based on the scoring system used, and it is important to realize that emotional effects from skin diseases cannot always be adequately quantified or understood by simple, objective assessments. However, these instruments have the role of helping direct the patient-physician interaction to be more patient-centered by highlighting psychosocial

huynh, koo page 13

influences on the individual patient’s well-being. It may be worthwhile to routinely be on the alert for underlying psychiatric disorders such as major depression or generalized anxiety as described by Diagnostic Statistical Manual of Mental Disorders (4th edition) published by the American Psychiatric Association.20 Patients with diagnosable psychiatric disorders should be advised to obtain an appropriate mental health provider for management.

Management with Non-Pharmacologic ApproachesClinical trials and anecdotal reports support the use of psychotherapy in patients with recalcitrant inflammatory dermatologic disease who remain unresponsive to dermatologic treatment and in whom an underlying emotional cause is identified or suspected. For example, Waxman described a woman with a 20-year history of unresolved psoriasis who responded to 15 weeks of multi-modal psychiatric treatment. At a 10-month follow-up, she remained clear.21

In a different report, Brown et al. examined 72 patients with eczema. The patients with emotional disturbance had improved outcomes with the addition of psychological treatment, whereas those without additional psychological treatment did not have improved outcomes.22 Stewart et al. studied 18 atopic dermatitis subjects who were resistant to conventional topical therapies and antihistamines and were treated with the addition of psychological treatment such as relaxation and stress management. There was statistically significant improvement of itching and scratching, sleep disturbance, and mood as compared to therapy without psychological treatment.23

Children and adolescents, in particular, may benefit from psychiatric or psychological intervention. Psychological symptoms and comorbidities may impair growth during the developmental period. In cases where psychological causes have yet to be discovered, psychological intervention may still be beneficial in guiding behavioral development in children and demonstrating appropriate parental attitudes and educational techniques to parents.24 Research has also linked positive emotional functioning with good treatment adherence, especially for children with more chronic diseases.25,26

Specific Non-Pharmacological TechniquesNon-pharmacologic psychocutaneous therapies are rarely utilized as monotherapy and are typically incorporated into conventional dermatological treatments. The following sections will review some of the non-pharmacologic therapies for psychocutaneous disorders described in the medical literature.

Cognitive-behavioral therapy (CBT) addresses dysfunctional thought patterns and repetitive behaviors that harm the skin or interfere with dermatologic therapy.27 Shenefelt et al. outlined the steps of CBT: 1) identify specific maladaptive cognitive pattern through the patient’s verbalization of thoughts and feelings or direct observation of behavior; 2) determine goals of therapy; 3) develop hypothesis for underlying beliefs or triggers that provoke maladaptive thought patterns and behavior; 4) test hypothesis by deliberately altering cognition, behavior, or environment and observe effects; and 5) revise hypothesis if desired results are not obtained and repeat this process until the responsible maladaptive thoughts are correctly identified and countered or eliminated through alternative thought patterns. A few techniques include exposure therapy and cognitive processing therapy. Exposure therapy entails exposure to the feared object or context without any danger in order to overcome the associated anxiety. Cognitive processing therapy involves education on thoughts and emotions, formal processing of past trauma, and teaching cognitive skills necessary to identify, evaluate, and modify patients’ beliefs about the trauma.

The purpose of this method is to overcome negative thoughts, establish positive thoughts, and reorient patient perspective toward an optimistic outlook. For example, atopic dermatitis patients may enter an itch-scratch cycle where they feel compelled to scratch their itch. Through CBT, atopic dermatitis patients may learn constructive activities to distract thoughts of scratching, such as listening to music, and also substitute the scratching behavior with interests like sports or art. Fortune et al. demonstrated in 40 psoriasis patients that a 6-week course of adjunctive CBT improved anxiety, depression, stress, and psoriatic lesions compared to 53 controls who received standard treatment alone.28

Biofeedback is a technique that provides feedback of the biologic response. Patients are provided information regarding vital functions, such as heartbeat, muscle tone, skin temperature and resistance, and/or electric potential of the brain registered by electroencephalogram. This information is provided as evidence of the subject’s physiologic response to their emotional state.29 Though no one method of controlling physiology has consistently demonstrated superior efficacy, the availability of various methods (i.e. electromyography, feedback thermometer, electrocardiograph, a n d electroencephalograph) to assess biologic response allow individual patients the opportunity to figure out the most suitable choice for his or her case. Patients are taught

simple techniques, such as structured breathing or rhythmic breathing techniques, to modify and control physiologic activity. Individuals learn how to alter their autonomic response and, with enough repetition, work toward remodeling of behavior and establishment of new habits. For example, biofeedback of muscle tension via electromyography can enhance the mastering of relaxation techniques.27 Shenefelt regards dermatologic disorders with an autonomic nervous system component as improvable by biofeedback.27 Biofeedback has been studied for the treatment of acne, eczema, urticarial, pain syndromes, and psoriasis, and the results from these studies demonstrate biofeedback as a worthwhile option.7,30,31

Relaxation techniques include guided imagery, progressive relaxation, and deep breathing. The aim of these techniques is to reduce muscle and psychic tension. Guided imagery is typically facilitated with the clinician, a third-party facilitator, tapes, or scripts to direct thoughts toward a relaxed but focused state. Progressive relaxation involves the physical alternation of tensing and relaxing muscle while mentally focusing on the feelings of the tension and relaxation. Deep breathing demands concentration on breathing and allowing the rest of the body to relax. These techniques produce a relaxed state and result in reducing sympathetic reactivity and enhancing parasympathetic activity.5 Bae et al. studied 25 subjects with atopic dermatitis treated with either conventional treatment only or conventional treatments with progressive muscle relaxation (PMR). The degree of pruritus and loss of sleep was significantly decreased in the PMR group (p <0.001) but not among controls. However, there were no significant changes in serological parameters of NGF, NPY, IL-4, IL-5, and IL-13 in either group, or reduction of eczema. Area and Severity Index (EASI) scores were similar in both groups.3 Zachariae et al. compared 26 psoriasis patients treated with 12 weeks of cognitive-behavioral therapy, guided imagery, and relaxation therapy in addition to conventional therapy to 25 patients treated with conventional therapy only. Results showed slight but significant beneficial effect of psychological intervention on psoriasis severity according to Psoriasis Area Severity Index (PASI), Total Sign Score (TSS), and Laser Doppler Skin Blood Flow (LDBF).33

Hypnosis has been used since ancient times in the form of trance induction to assist healing. The precise definition varies, but Marmer defined hypnosis as a psychophysiological tetrad of altered consciousness consisting of narrowed awareness, restricted and focused attentiveness, selective wakefulness, and heightened

suggestibility.34 Hypnosis is not a therapy in and of itself but rather a tool to facilitate therapies including support (ego strengthening), direct suggestion, symptom substitution, and hypnoanalysis.35 Advantages include nontoxicity, cost-effectiveness, and ability of patients to self-treat and gain a sense of control with self-hypnosis. A wide spectrum of dermatologic disorders has been reported to have been improved or cured using hypnosis as an alternative or complementary therapy.35 However, hypnosis is currently hardly used in dermatologic practice, even though time requirements for screening, educating, and performing hypnosis is generally no greater than screening, preparing, educating, and performing cutaneous surgery. Those who prefer to refer patients to hypnotherapists or who desire further training in hypnotherapy can obtain referrals and information from the American Society of Clinical Hypnosis or similar organizations.

When to ReferDermatologists may feel comfortable treating patients with psychotherapeutic techniques. Many patients are motivated, and dermatology patients tend to have less-severe psychological elements often amendable to non-pharmacological approach. For a percentage of very disturbed patients, psychiatric or psychologic referral is recommended.

Some examples of patients who may be more appropriately referred include patients expressing ideation of harm to self or others and those who are clearly suffering from serious anxiety, depression, and agitation. Patients may display hesitation due to stigmatization by referral for psychological care.

Utilization of validated psychometric instruments, such as DLQI or Skindex-29, may help identify potential stress and justify the referral.

ConclusionMany clinical studies document the significance of psychological state on the onset and exacerbation of common inflammatory skin disorders such as psoriasis, eczema, and acne. Management of these skin disorders may be optimized by combining non-pharmacological therapies with the conventional dermatological treatment. Also, for patients in whom pharmacologic treatment is not tolerated, non-pharmacologic treatments can be a nontoxic alternative. Clinicians may master for themselves the techniques to provide mind-based therapy but also have the option to refer to mental health professionals. Patients may benefit greatly if provided with options to improve the psychological component of their skin disorder.

references1. Julian CG. Dermatology in general practice. Br J Dermatol 1999;141(3):518-520.

2. Barankin B, DeKoven J. Psychosocial effect of common skin diseases. Can Fam Physician 2002;48:712-716.

3. Heller, MM, Lee ES, et al. Stress as an influencing factor in psoriasis. Skin Therapy Lett 2011;16(5):1-4.

4. Kilkenny M, Merlin K, et al. The prevalence of common skin conditions in Australian school students: 3. acne vulgaris. Br J Dermatol 1998;139(5):840-845.

5. Fried RG, Hussain SH. Nonpharmacologic management of common skin and psychocutaneous disorders. Dermatol Ther 2008;21(1):60-68.

6. Poot F, Sampogna F, et al. Basic knowledge in psychodermatology. J Eur Acad Dermatol Venereol 2007;21(2):227-234.

7. Hughes JE, Barraclough BM, et al. Psychiatric symptoms in dermatology patients. Br J Psychiatry 1983;143:51-54.

8. Sambhi R, Lepping P. Psychiatric treatments in dermatology: an update. Clin Exp Dermatol 2010;35(2):120-125.

9. Fortune DG, Richards HL, et al. What patients with psoriasis believe about their condition. J Am Acad Dermatol 1998;39(2 Pt 1):196-201.

10. Lammintausta K, Kalimo K, et al. Prognosis of atopic dermatitis. A prospective study in early adulthood. Int J Dermatol 1991;30(8):563-568.

11. Green J, Sinclair RD. Perceptions of acne vulgaris in final year medical student written examination answers. Australas J Dermatol 2001;42(2):98-101.

12. Rasmussen JE, Smith SB. Patient concepts and misconceptions about acne. Arch Dermatol 1983;119(7):570-572.

13. Chiu A, Chon SY, et al. The response of skin disease to stress: changes in the severity of acne vulgaris as affected by examination stress. Arch Dermatol 2003;139(7):897-900.

14. Arndt J, Smith N, et al. Stress and atopic dermatitis. Curr Allergy Asthma Rep 2008;8(4):312-317.

15. Fried RG. Nonpharmacologic treatments in psychodermatology. Dermatol Clin 2002;20(1):177-185.

16. Finlay AY, Khan GK. Dermatology Life Quality Index (DLQI)--a simple practical measure for routine clinical use. Clin Exp Dermatol 1994;19(3):210-216.

17. Lewis V, Finlay AY. 10 years experience of the Dermatology Life Quality Index (DLQI). J Investig Dermatol Symp Proc 2004;9(2):169-180.

18. Hongbo Y, Thomas CL, et al. Translating the science of quality of life into practice: What do dermatology life quality index scores mean? J Invest Dermatol 2005;125(4):659-664.

19. Evers AW, Duller WP, et al. The Impact of Chronic Skin Disease on Daily Life (ISDL): a generic and dermatology-specific health instrument. Br J Dermatol 2008;158(1):101-108.

20. Diagnostic and Statistical Manual of Mental Disorders, 4th Ed, Text Revision (DSM-IV-TR).  Washington, DC: American Psychiatric Association; c2000. 943 p.

21. Waxman D. Behaviour therapy of psoriasis--a

hypnoanalytic and counter- conditioning technique. Postgrad Med J 1973;49(574):591-595.

22. Brown DG, Bettley FR. Psychiatric treatment of eczema: a controlled trial. Br Med J 1971;2(5764):729-734.

23. Stewart AC, Thomas SE. Hypnotherapy as a treatment for atopic dermatitis in adults and children. Br J Dermatol 1995;132(5):778-783.

24. Janowski, K, Pietrzak A. Indications for psychological intervention in patients with psoriasis. Dermatol Ther 2008;21(5):409-411.

25. Reid GJ, Dubow EF, et al. Contribution of coping to medical adjustment and treatment responsibility among children and adolescents with diabetes. J Dev Behav Pediatr 1994;15(5):327-335.

26. Mallin K, Lazarus MC. “Treating children is different.” Dermatol Clin 2005;23(2):171-180.

27. Shenefelt PD. Biofeedback, cognitive-behavioral methods, and hypnosis in dermatology: is it all in your mind? Dermatol Ther 2003;16(2):114-122.

28. Fortune DG, Richards HL, et al. Psychological stress, distress and disability in patients with psoriasis: consensus and variation in the contribution of illness perceptions, coping and alexithymia. Br J Clin Psychol 2002;41(Pt 2):157-174.

29. Sarti MG. Biofeedback in dermatology. Clin Dermatol 1998;16(6):711-714.

30. Haynes SN, Wilson CC, et al. Biofeedback treatment of atopic dermatitis: controlled case studies of eight cases. Biofeedback Self Regul 1979;4(3):195-209.

31. Hughes, HH, England R, et al. “Biofeedback and psychotherapeutic treatment of psoriasis: a brief report.” Psychol Rep 1981;48(1):99-102.

32. Bae BG, Oh SH, et al. Progressive muscle relaxation therapy for atopic dermatitis: objective assessment of efficacy. Acta Derm Venereol 2012;92(1):57-61.

33. Zachariae R, Oster H, et al. Effects of psychologic intervention on psoriasis: a preliminary report. J Am Acad Dermatol 1996;34(6):1008-1015.

34. Marmer MJ. Hypnosis in anesthesiology. Springfield, Ill: Thomas, 1959.

35. Shenefelt PD. “Hypnosis in dermatology.” Arch Dermatol 2000;136(3):393-399.

Correspondence: Monica Huynh, BA, 515 Spruce St., San Francisco, CA, 94118. Phone: 408-242-7618. E-mail: monicahuynh@gmail.com.

page 14 stress anD inflammatory skin DisorDers: a review of non-pharmacologic treatment options

Old World meets New World Leishmaniasis: Leishmania tropica in Florida

Ann Mazor-Reed, DO,* Jacqueline A. Thomas, DO, FAOCD**

*PGY-1, Larkin Community Hospital - Nova Southeastern University, Ft. Lauderdale, FL**Assistant Professor of Dermatology, Nova Southeastern University, Ft. Lauderdale, FL

IntroductionCutaneous leishmaniasis (CL) is one of the 10 most frequent causes of skin diseases in returning travelers from subtropical countries.1 In addition, between 2002 and 2004 the United States Department of Defense identified 522 confirmed cases of CL in military personnel deployed to Afghanistan, Iraq and Kuwait.2 According to the Center for Disease Control (CDC), there are approximately 1.5 million new cases of CL each year worldwide.3

Leishmaniasis is most often found within specific regions in nearly 88 countries, accounting for most of the world’s cases.4 Leishmaniasis is classified into Old World and New World based on the geographic location. Over 90 percent of

CL cases occur in Brazil and Peru (New World) and in parts of Afghanistan, Algeria, Iran, Iraq, Saudi Arabia, and Syria (Old World).4 Leishmaniasis is a vector-borne disease transmitted to humans by the bite of female Phlebotomine sand flies. The genus is named based on its geographic location: Lutzomyia in the New World and Phlebotomus in the Old World.1 The species predominance and host response vary by geographic distribution (Table 1).5,6

There are three main types of clinical manifestations caused by leishmaniasis: cutaneous leishmaniasis (CL), mucocutaneous leishmaniasis (ML), and visceral leishmaniasis (VL). The most common form, cutaneous

(CL), begins as multiple small papules at the sites of sand-fly bites that develop into ulcerative skin lesions over time. The second type, mucocutaneous leishmaniasis (ML), is a destructive mucosal inflammation that can often be disfiguring.7 It can occur months to years after the healing of a cutaneous ulcer.8 Lastly, visceral leishmaniasis (VL), also known as kala-azar, is a disseminated visceral infection characterized by fever, weight loss, anemia, and hepatosplenomegaly. If left untreated, VL is almost always fatal.8 Leishmania donovani from the Old World, ordinarily a visceral species, may manifest cutaneously in tandem with visceral disease, or cutaneous lesions may develop months to years after the visceral disease has resolved. This is termed post-kala-azar dermal leishmaniasis (PKDL).9

Case reportA 20-year-old male presented with a one-month history of “bites” on the trunk and extremities. The patient recounted recent travel to Israel and, while there, occupational contact with zoo animals. He was treated unsuccessfully with cefadroxil 500 mg BID for eight days and betamethasone cream. Past medical and surgical histories were negative, the patient was not on any other medications, and he had no allergies. When the lesions persisted despite antibiotic and topical corticosteroid treatment, the patient presented for further investigation. The physical exam revealed multiple pink, erythematous, 3 mm to 5 mm, dome-shaped papules in groups of two on the right forearm,

AbstractLeishmania tropica is typically found in the Middle East; however, we present a case of Leishmania tropica diagnosed in South Florida. Leishmaniasis is becoming more prevalent in the United States due to the increase in rural travel and the return of military personnel from the Middle East. This disease should be included in the dermatologist’s differential diagnosis when encountering a patient with pertinent occupational or travel history and treated with methods that are convenient and easily accessible. The traditional treatment utilizes pentavalent antimony; however, oral fluconazole was found to be successful in the treatment of this patient with Leishmania tropica.

Table 1: Clinical forms of Old World and New World leishmania species

Old World Clinical Form New World Clinical Form

L. tropica CL L. mexicana CL

L. major CL L. peruviana CL

L. aethopica CL L. guyanensis CL

L. infantum VL, PKDL L. venezuelensis CL

L. donovani VL, PKDL L. panamensis CL, ML

L. braziliensis CL, ML

L. chagasi CL, VL

L. amazonensis CL, VL

CL: Cutaneous leishmaniasisML: Mucocutaneous leishmaniasisVL: Visceral leishmaniasisPKDL: Post Kala-Azar leishmaniasis

mazor-reeD, thomas page 15

Figure 1 Figure 2 Figure 3

left postero-lateral neck, and left medial aspect of the upper arm (Figures 1-3). Palpable lymph nodes were absent, and the patient was afebrile. A 3 mm punch biopsy was obtained from a papule on the right arm. Histologic examination of the biopsy revealed granulomatous inflammation with intracytoplasmic leishmania organisms confirmed with direct examination of Giemsa-stained tissue (Figures 4, 5). The presumptive diagnosis of cutaneous leishmaniasis consistent with leishmania tropica was established based on clinical findings, travel history, and geographic distribution for the natural habitat of the species and organismal confirmation with Giemsa. The patient was treated with fluconazole 200 mg daily for six weeks. The patient responded to antifungal therapy with complete resolution of skin lesions.

DiscussionSince the patient presented herein sought medical care in the United States, uncovering a subtype of New World leishmania is expected. The key component of this case’s diagnosis is the recent travel history to an endemic region, uncovering an Old World variety of leishmania.19 This case illustrates not only the importance of a thorough history, but also that infectious diseases do not remain in isolated areas of the world and can be found in geographically distant regions. The most common diagnostic approach includes microscopic examination of a Giemsa-stained tissue biopsy because more sophisticated techniques are less cost effective and rarely available.7 Culture methods with isoenzyme or monoclonal antibody analysis are time consuming, expensive and require specialized technical expertise.7,19

Through its web site, the CDC provides resources for health professionals in laboratory diagnosis for lesions suspicious for leishmaniasis.8 The CDC guidelines recommend treatment for leishmaniasis with pentavalent antimonials such as sodium stibugluconate or meglumine antimoniate. These medications are time consuming and difficult to obtain. They are currently not FDA-approved and must be obtained through the CDC under investigational new drug (IND) protocol.8 Alternatively, fluconazole has been found to have successful results and is easily obtained in the United States.10

treatmentAlthough most cases of CL resolve over time, many patients seek treatment due to cosmetic concerns. Following confirmatory biopsy results, several treatments have been described in the literature. It is of utmost importance to obtain a biopsy and confirm the infecting parasite strain, as each species may manifest various complications over time. Leishmania tropica, for example, can evolve to a relapsing lesion known as leishmaniasis recidiva cutis or leishmaniasis recidivans, or ML in some cases.9 In 2001, a case of leishmaniasis recidivans in the United States was reported to have arisen 43 years after the patient’s initial lesion resolved.11

According to Magill et al., after confirming the case of CL, the treating physician must consider specific criteria when deciding whether or not to treat. Specifically, treatable criteria include: lesions that are not improving over the course of a few weeks; multiple lesions; “complicated” lesions, including ones that restrict joint mobility or inhibit the wearing of shoes or clothing; mucosal involvement; immunocompromised patients; lesions on exposed areas; lesions over 5 cm; or lesions in cosmetically undesirable areas. Patients with proven or suspected New World CL should always be offered systemic treatment, as the concern for mucocutaneous complications is high.12

There is no worldwide agreement on which drug is superior, and treatment is chosen on an individual basis. The most widely used treatment worldwide is pentavalent antimonial drugs, sodium stibugluconate, and meglumine antimoniate IV or IM for 20 days. These drugs are quickly being replaced by newer, less-toxic medical treatments.

Systemic Therapy: Oral AdministrationThe FDA has not approved any oral agents for the treatment of CL in the United States. Oral antifungal azoles are easily accessible in the U.S. and are found to have anti-leishmanial activity.12 The mechanism of action is through inhibition of P450-mediated 14α-demethylation of lanosterol, which blocks ergosterol synthesis and causes a corresponding build-up of 14α-methyl steroids.16 It is generally well tolerated; the most common

adverse effects include gastrointestinal-related symptoms and headache.

Clinical trials have shown efficacy of the following regimens: ketoconazole 600 mg daily for 28-30 days due to L. mexicana, L. panamensis and L. major, and fluconazole 200 mg daily for six weeks due to uncomplicated L. major.10,13-15 Limited data suggests there may be an effect against L. braziliensis with higher doses of fluconazole (8 mg/kg for 4-6 weeks).17 The patient presented herein with L. tropica was successfully treated with oral fluconazole 200 mg for six weeks.

Miltefosine is a newer oral anti-Leishmania medication. This oral anti-tumor agent inhibits phospholipid and sterol biosynthesis in addition to interfering with cell signal-transduction pathways.19 Most reported side effects are mild and gastrointestinal in nature.19 When compared to sodium stibogluconate, it was shown to be superior in patients older than 12 years in the treatment of CL.18 Miltefosine has a low-to-mild toxicity, which may increase patient adherence and is an advantage over other more-toxic treatments.19

Systemic Therapy: Intravenous and Intramuscular AdministrationPentavalent antimonials were used against leishmania as early as 1912.20 Over the last two decades, these drugs were studied in over 1,600 patients with acute Old World CL.17 There are two pentavalent antimonial (SbV) preparations: sodium stibogluconate and meglumine antimoniate. Although the exact mechanism of action is unknown, it involves inhibition of DNA topoisomerase I, glycolysis and beta-oxidation of fatty acids resulting in decreased synthesis of adenosine triphosphate (ATP), which is the energy required in the survival of the parasite.17 These drugs have serious but usually reversible adverse effects such as gastrointestinal and musculoskeletal disturbances, renal failure, hepatotoxicity, and cardiotoxicity, and no systemic toxic side-effects with local or intralesional use as compared with parenteral, IM, or IV use.7 They are administered systemically via intravenous or intramuscular route. They are most commonly used for complicated Old World CL, L. panamensis, L. braziliensis, and other New World CL. The recommended dosage in the U.S. is 20 mg of antimony/kg/day IV or IM for 20 days. A longer treatment (28 days) of 20 mg of antimony/kg/day IV or IM can be used to treat ML. Sodium stibogluconate is available under investigational new drug protocol from the CDC.8

Local Therapy: Intralesional Injections

Intralesional injection with sodium stibogluconate or meglumine antimoniate is used as a therapy for Old World CL, specifically L.

page 16 olD worlD meerts new worlD leishmaniasis: leishmania tropica in floriDa

Figure 4 Figure 5

major and L. tropica. This method is especially useful in patients who cannot tolerate systemic antimonials. It is generally considered a rapidly effective, safe, and less-expensive technique of treating uncomplicated Old World CL.21 There is no current SbV intralesional treatment protocol in the U.S., and experience is limited.12

Local Therapy: Topical TreatmentParamomycin phosphate (PP) is commonly used to treat Old World CL, specifically for uncomplicated L. major. The mechanism of action is through inhibition of protein biosynthesis in sensitive organisms.17 Side effects are rare and include itching, erythema, edema, and tenderness.17 It has also been used for ulcerative lesions from uncomplicated L. mexicana.12 It is formulated as either 15% PP with 12% methylbenzethonium chloride in white soft paraffin, known as “P-ointment,” or 15% PP formulated with 10% urea in white soft paraffin. A study by El-On et al. showed after 10 days of twice daily treatment, 72% of treated patients were clear of parasites.21 Neither formulation is available in the U.S. but can be compounded by a specialized pharmacy on request. If improvements in lesions are not seen within two to four weeks, an alternative treatment should be considered.12

Physical Treatment: Photodynamic Therapy (PDT)Two separate studies showed photodynamic therapy (PDT) as a superior treatment modality when compared to topical paramomycin.23,24 The literature reveals cases of successful treatment of CL with PDT. Enk et al. treated 32 lesions on 11 Israeli patients with topical 5-aminolevulinic acid (ALA) – PDT, showing clinical improvement in lesion size after one week.25 In 2011, Song et al. successfully treated one patient with CL using PDT, methylene blue, and low-dose SbV (5 mg/kg/day for 20 days).26

Physical Treatment: Radiofrequency-induced heat (RFH) Therapy This modality is best used for uncomplicated Old World CL and uncomplicated L. mexicana.12 It generates heat using localized delivery of radiofrequencies under local anesthesia into lesions for 30 seconds to 60 seconds at a time using a current-field radiofrequency generator.27 In 2002, the FDA approved the use of the ThermoMed device, a radiofrequency generator, for the treatment of CL.12 A study in Afghanistan found 69% of patients with L. tropica to be disease-free at 100 days after treatment with RFH.28 Short-term follow-up studies are promising, showing RFH therapy to be comparable to antimonials.29

Physical Treatment: Cryotherapy (Liquid nitrogen)This is best used for small cutaneous lesions acquired in the Old World. Apply liquid

nitrogen with a cotton-tipped applicator for a 15- to 20-second freeze with a 2 mm to 3 mm surrounding margin followed by a one-minute thaw cycle. Two freeze-thaw cycles are generally adequate. Re-evaluate after two weeks, and repeat treatment as needed.12

Physical Treatment: Surgical Excision Surgical excision is not recommended due to the potential risk of recurrence.23

Future Therapies: Hyperbaric Oxygen (HBO) + Meglumine Antimoniate (glucantime)Ayres et al. studied the effect of HBO alone, glucantime alone and HBO plus glucantime on mice with CL. The mice were exposed to 100% oxygen at a pressure of 2.5 atmospheres for one hour per day in an animal hyperbaric chamber. In addition, they were injected with 27 mg Sb+5/kg/day for 20 days. The combination group showed lesions smaller than those of mice treated with glucantime or HBO alone.30

Future Therapies: VaccineAccording to the WHO, there is no effective vaccine to prevent leishmaniasis to date. Recently, however, a vaccine has been studied in human and animal models. Phase I trials are promising and are still being studied in the United States and Latin America.31

ConclusionIt is vital that dermatologists keep this disease in mind as it is becoming more and more prevalent outside endemic regions due to increased travel to and from tropical and sub-tropical countries. With the increase in rural travel and the return of military personnel from the Middle East, we can conclude that leishmaniasis must be on our list of differential diagnoses when encountering a patient with a pertinent travel history. It is important to understand how this disease presents clinically as well as how to treat it on an outpatient basis with convenient, easily accessible methods.

AcknowledgmentThe authors would like to thank Eduardo Weiss, MD, for his support in this manuscript.

references1. Zeegelaar JE. Imported tropical infectious ulcers in travelers. Am J Clin Dermatol. 2008;9(4):219-232.

2. Aronson M. (2004). Update: Cutaneous leishmaniasis in U.S. military personnel - southwest/central Asia, 2002-2004. MMWR. 2004;53(12):264-265.

3. U.S. Centers for Disease Control and Prevention (US). Parasites A-Z Index [Internet]. Atlanta (GA): U.S. Centers for Disease Control and Prevention; [updated 2013 Apr 19]. Parasites - leishmaniasis: epidemiology and risk factors; [reviewed 2013 Jan 10; cited 2012 Jan 10]. Available from: http://www.cdc.gov/parasites/leishmaniasis/epi.html

4. Desjeux P. Leishmaniasis: current situation and new perspectives. Comp Immunol Microbiol Infect Dis. 2004;27:305–318.

5. Bern C, Maguire JH, Alvar J. Complexities of assessing the disease burden attributable to leishmaniasis. PLoS Negl Trop Dis. 2008;2(10):e313.

6. Barral A, Pedral-Sampaio D, Grimaldi Junior G, Momen H, et al. Leishmaniasis in Bahia, Brazil: evidence that Leishmania amazonensis produces a wide spectrum of clinical disease. The American Journal of Tropical Medicine and Hygiene. 1991;44(5):536-546.

7. Reithinger R, Dujardin JC, Louzir H, Pirmez C, et al. Cutaneous leishmaniasis. Lancet Infect Dis. 2007;7:581–596.

8. U.S. Centers for Disease Control and Prevention (US). Parasites A-Z Index [Internet]. Atlanta (GA): U.S. Centers for Disease Control and Prevention; [updated 2013 Apr 19]. Parasites – leishmaniasis: Resources for Health Professionals; [2013 Jan 10; cited 2012 Jan 15]. Available from http://www.cdc.gov/parasites/leishmaniasis/health_professionals/index.html

9. Goto H. Current diagnosis and treatment of cutaneous and mucocutaneous leishmaniasis. Expert Rev Anti Infect Ther. 2010;8(4):419-433.

10. Alrajhi AA, Ibrahim EA, De Vol EB, Khairat M, et al. Fluconazole for the treatment of cutaneous leishmaniasis caused by Leishmania major. N Engl J Med. 2002;346: 891–895.

11. Marovich M, Lira R, Shepard M, Fuchs G, et al. Leishmaniasis recidivans recurrence after 43 years: A clinical and immunologic report after successful treatment. Clinical Infectious Disease. 2001;33:1076-1079.

12. Magill A. Cutaneous leishmaniasis in the returning traveler. Infect Dis Clin N Am. 2005;19:241-266.

13. Navin TR, Arana BA, Arana FE, et al. Placebo-controlled clinical trial of sodium stibogluconate (Pentostam) versus ketoconazole for treating cutaneous leishmaniasis in Guatemala. J Infect Dis. 1992;165(3):528–534.

14. Saenz RE, Paz H, Berman JD. Efficacy of ketoconazole against Leishmania braziliensis panamensis cutaneous leishmaniasis. Am J Med. 1990;89(2):147–155.

15. Salmanpour R, Handjani F, Nouhpisheh MK. Comparative study of the efficacy of oral ketoconazole with intra-lesional meglumine antimoniate (Glucantime) for the treatment of cutaneous leishmaniasis. J Dermatolog Treat. 2001;12:159–162.

16. Minodier P, Philippe P. Cutaneous leishmaniasis treatment. Travel Med Infect Dis. 2007;5(3):150-158.

17. Khatami A, Firooz A, Gorouhi F, Dowlati Y.

mazor-reeD, thomas page 17

Treatment of acute old world cutaneous leishmaniasis: A systematic review of the randomized controlled trials. J Am Acad Dermatol. 2007 Aug;57(2):335.e1-e29.

18. Machado P, Ampuero J, Guimaraes L, Villasboas L, et al. Miltefosine in the treatment of cutaneous leishmaniasis caused by leishmania braziliensis in Brazil: A randomized and controlled trial. PLoS Neglected Tropical Disease. 2010;4(12):e912.

19. Machado P, Penna G. Miltefosine and cutaneous leishmaniasis. Curr Opin Infect Dis. 2012;25(2):141-144.

20. Alrajhi A. Cutaneous leishmaniasis of the old world. Skin Therapy Letter. 2003;8(2):1-4.

21. Alkhawajah AM, Larbi E, al-Gindan Y, Abahussein A, et al. Treatment of cutaneous leishmaniasis with anti- mony: intramuscular versus intralesional administration. Ann Trop Med Parasitol. 1997;91(8):899-905.

22. El-On J. E., Livshin R., Even-Paz Z., Hamburger D., et al. Topical treatment of cutaneous leishmaniasis. J Invest Dermatol. 1986;87(2):284-288.

23. Gardlo K, Horska Z, Enk CD, et al. Treatment of cutaneous leishmaniasis by photodynamic therapy. J Am Acad Dermatol. 2003;48:893-896.

24. Asilian A, Davami M. Comparison between the efficacy of photodynamic therapy and topical paromomycin in the treatment of Old World cutaneous leishmaniasis: A placebo-controlled, randomized clinical trial. Clin Exp Dermatol. 2006;31:634-637.

25. Enk CD, Fritsch C, Jonas F, et al. Treatment of cutaneous leishmaniasis with photodynamic therapy. Arch Dermatol. 2003;139:432–434.

26. Song D, Lindoso J, Oyafuso L, Kanashiro E, et al. Photodynamic therapy using methylene blue to treat cutaneous leishmaniasis. Photomedicine and Laser Surgery. 2011;29(10):711-715.

27. Bumb R, Satoskar A. Radiofrequency-induced heat therapy as first-line treatment for cutaneous leishmaniasis. Expert Rev. Anti Infect. Ther. 2011;9(6):623-625.

28. Reithinger R, Mohsen M, Wahid M, Bismullah M, et al. Efficacy of thermotherapy to treat cutaneous leishmaniasis caused by Leishmania tropica in Kabul, Afghanistan: a randomized, controlled trial. Clin Infect Dis. 2005;40(8):1148-55.

29. Lobo IM, Soares MB, Correia TM, et al. Heat therapy for cutaneous leishmaniasis elicits a systemic cytokine response similar to that of antimonial (Glucantime) therapy. Trans. R. Soc. Trop. Med. Hyg. 2006;100:642–649.

30. Ayres D, Fedele T, Marcucci M, Giorgio S. Potential utility of hyperbaric oxygen therapy and propolis in enhancing the leishmanicidal activity of glucantime. Rev. Inst. Med. Trop. Sao Paulo. 2011;53(6):329-334.

31. World Health Organization. Initiative for Vaccine Research (IVF): Selection of Diseases from IVF Portfolio [Internet]. Geneva (Switzerland): Parasitic diseases: leishmaniasis; [cited 2012 Jan 15]. Available from http://www.who.int/vaccine_research/diseases/soa_parasitic/en/index3.html

Correspondence: Ann Mazor-Reed, DO, 2766 W. Atlantic Blvd., Pompano Beach, FL 33069, Phone: (954) 977-0270, Email: amazorreed@larkinhospital.com

Use of Acitretin in a Patient with Multiple Squamous Cell Carcinomas:A Case Report and Literature Review

Dorene Niv, BS,* Patrick Keehan, DO, FAOCD**

*Medical Student, 3rd year, University of North Texas Health Science Center, Fort Worth, TX**Board-certified Dermatologist, Premier Dermatology, Fort Worth, TX

IntroductionThe appearance of squamous cell carcinomas (SCC) of the skin in patients is often attributed to DNA damage, gene mutations, and various chemicals. Epidemiologic research has found multiple risk factors for SCC, including older age, fair skin phenotype, tendency toward sunburn, chronic sun exposure, and previous history of SCC.1

Current treatment regimens involve use of retinoids. As derivatives of vitamin A, retinoids have been shown to affect SCC by 1) inhibiting skin cell growth and 2) inducing cell apoptosis. However, research has been primarily carried out with patients with high risk factors, such as solid organ transplant recipients or patients with previous history of skin cancer.

Case reportAn 83-year-old-woman initially presented with multiple purple polygonal papules and plaques located in her mouth and on bilateral upper and lower extremities. With a mucosal biopsy diagnosis of lichen planus, the patient began treatment with systemic and topical steroids.

Twelve weeks into follow-up, the patient complained of worsening pruritus and spreading of lesions. Physical exam revealed hyperkeratotic, irregularly bordered papules and large tender nodules with central crateriform eruptions on bilateral upper and lower extremities (Figures 1-3).

Biopsies were performed, revealing both SCC and keratoacanthomas (KA). The patient began treatment with acitretin 25 mg daily and saw improvement within eight weeks (Figure 4). Adverse effects included initial pruritus, which subsided with hydroxyzine HCl 10 mg, and increasing bone pain reported eight weeks into treatment, likely secondary to her Paget’s disease. Significant post-inflammatory

hyperpigmentation was noted as KA-SCC-type lesions resolved (Figure 5). New appearances of KA-SCC-type lesions occurred within four weeks of beginning treatment with acitretin, with regression promptly following. The patient remained on a maintenance dose of 25 mg once daily throughout her treatment, and she continues to report success of initial and prophylactic prevention of SCC.

DiscussionThe mainstay of treatment involves retinoids for carcinoma suppression, inhibiting cell growth and inducing apoptosis. The manner in which retinoids inhibit cell line growth includes retinoid X receptors (RXR). RXR function as transcription factors in skin cell lines that serve to alter gene expression. These receptors were found to be suppressed 75% in SCC tissues when compared to normal skin, and 68% when compared to actinic keratosis.2 The suppression of RXR found in premalignant and malignant tissues supports the administration of systemic retinoids to inhibit growth of SCC cell lines.2

Acitretin’s primary mechanism in suppressing SCC involves inducing cell apoptosis via the extrinsic death receptor pathway. This pathway is activated by the binding of Fas ligand to the Fas receptor, which in turn activates caspase-8. This specific caspase is implicated in the final steps of apoptosis and has been found to be activated by acitretin in SCC SCL-1 cells.3 Lin et al. demonstrated acitretin’s inhibition of cell growth in SCC in both a dose- and time-dependent manner. Following application of acitretin, transmission electron microscopy was used to visualize the nucleus of SCL-1 cells, revealing nucleus shrinkage with dense aggregation and margination of chromatin. The nuclei in control groups displayed normal nuclear shape with evenly distributed chromatin.3

AbstractSquamous cell carcinoma is a common skin cancer often presenting on skin exposed to sunlight. It is described as an ulcerative red lesion with histologically visible keratin pearls. Recurrent cases have been reported in high-risk patients, including recipients of organ transplants on immunosuppressant therapy and following photochemotherapy for common skin disorders. Research has indicated high-dose retinoids can serve as treatment in high-risk patients for initial therapy, as well as provide prophylactic suppression of malignant occurrence. This case report describes the efficacy and safety of low-dose acitretin in treating an 83-year-old female with multiple SCC tumors. The results were considered excellent by both investigators and the patient.

page 18 use of acitretin in a patient with multiple squamous cell carcinomas:a case report anD literature review

The induction of apoptosis was confirmed by the Cell Death Detection ELISA. Inhibitors of caspases-8 and -9 were applied to SCL-1 cells, alone and after acitretin application. With no previous acitretin, the caspase inhibitors produced no effect on apoptosis. When the caspase-8

inhibitor was combined with acitretin, the apoptosis was blocked. Following the caspase-9 inhibitor with acitretin produced no effect on apoptosis. The significance of failed apoptosis with acitretin and caspase-8 inhibitor strengthens the theory that acitretin-induced apoptosis relies

on caspase-8’s activation.3

Prior to caspase-8 activation, the extrinsic pathway requires binding of Fas and Fas ligand. Increased levels of both proteins were found in a time-dependent manner, after 12 hours of acitretin administration. Such demonstration strengthens the mechanism of acitretin in suppressing human cutaneous SCC in patients, regardless of previous risk-factor classification. The possibility of retinoids in preventing development of SCC involves their effect on tumor invasiveness. In order for tumors to spread and reach deeper tissues, matrix metalloproteinases are needed to cross basement membranes and interstitial stroma. The synthesis of such proteinases has been shown to be inhibited by retinoids.2 Therefore, retinoids may function in both suppressing the growth of SCC and preventing associated metastasis.

The adverse side effects associated with acitretin are characteristic of hypervitaminosis A, and are generally preventable or manageable through routine monitoring and dose adjustments. The earliest and most frequent symptom described is cheilitis, seen in over 75% of patients on a high dose of 75 mg/day.4 Other dose-related mucous-membrane adverse effects include dryness of the mouth and nasal mucosa, with epistaxis being a frequent occurrence.5 Symptomatic relief may be provided with use of emollients for dry skin or lips.

Hyperlipidemia may occur in some patients with elevations in triglyceride levels and total cholesterol. Baseline serum lipids should be obtained prior to initiating treatment and followed one to two weeks thereafter. Dietary changes and drug therapy may be needed to prevent hypertriglyceridemia-induced pancreatitis in patients with high risk factors, such as those with diabetes mellitus, obesity, increased alcohol intake, or a family history.4 Routine monitoring of liver function should be performed, as increases in AST, ALT, or LDH have been reported to occur. Fortunately, these increases may be reversible upon lowering the dose or discontinuing therapy.4 Acitretin may have an associated effect on hyperostosis, as prospective studies have shown worsening of pre-existing skeletal overgrowth in patients treated with retinoids on high doses and after long-term therapy.5 A screening radiograph of an ankle has been suggested for baseline radiography.

Specific precautions must be taken when beginning treatment with acitretin. Due to its teratogenicity, which is not strictly dose-related, patients should begin contraception one month before, during, and for three years after treatment.4 Patients should be advised to avoid vitamin A supplements to prevent hypervitaminosis A.

Within the past decade, occurrences of SCC have been reported in patients after receiving a variety of treatments for common skin conditions. SCC cases were reported as complications secondary

niv, keehan page 19

Figure 1

Figure 3

Figure 4

Figure 2

Figure 5

to psoralen and ultraviolet A (PUVA) therapy in patients treated for psoriasis.2 Evidence of SCC has been found in solid organ transplant recipients, likely attributed to their long-term immunosuppressant therapy.3

Multiple recurrent tumors that histologically resemble SCC and KAs have occurred after radiotherapy treatment for KA. These tumors, while similar to SCC, have been found to follow an autosomal-dominant inheritance pattern, and regress spontaneously. These tumors exhibit no evidence of mismatch repair gene defect, and chromosomal analysis reveals a normal karyotype. As a result, these multiple self-healing squamous epithelioma (MSSE) are no longer classified as SCC, but rather referred to as Ferguson-Smith disease.6

Prior history of SCC remains a significant risk factor for future occurrences. In 2011, nonmelanoma skin cancers (NMSC) accounted for 3.5 million new cancer diagnoses. Basal cell carcinomas (BCC) and SCC compose the majority of NMSC, occurring at a ratio of approximately 4:1. The rate of new primary NMSC in patients with a history of over 10 NMSC is nearly 100%.1

The incidence of SCC in solid organ transplant patients may be secondary to their defect in immunity post immune-suppression therapy. Langerhans cells function as antigen-presenting immune cells in the skin and mucosa. A significant reduction of these cells was found in skin tumors of renal transplant patients. After treatment with retinoids, both oral and systemic, an increase in Langerhans cells occurred.7 The response to retinoid therapy strengthens the theory that retinoids may prevent development of SCC in organ transplant recipients.

Much success has been reported with acitretin in clinically suppressing pre-malignant actinic keratosis, SCC, and the SCC imposter Ferguson-Smith. A second generation retinoid, acitretin originally was tested in preventing NMSC in renal transplant (RT) patients. Over a period of two years, acitretin 25 mg daily was shown to significantly reduce the number of SCC when compared to placebo.8 In a second study of RT patients, 30 mg acitretin daily was tested for the prevention of SCC. Results indicated a statistically significant success in preventing new SCC in these patients when compared to placebo.9 These trials indicate the potential of systemic retinoids in reducing the rate of NMSC occurrence in high-risk populations like transplant patients.

As for pre-malignant conditions, acitretin has been shown to decrease the rate of new actinic keratosis in patients with no significant risk factors, as well as in high-risk organ transplant recipients.1,10 In Ferguson-Smith disease, a trial of 60 mg daily for 12 weeks led to clearance of MSSE. The patient continued on acitretin therapy at a lower dose

of 10 mg for maintenance suppression. After 12 months, treatment was discontinued, and within weeks, facial keratotic papules returned. Acitretin treatment was restarted a second time for 18 months, and the patient remained free of MSSE return.6 The histologic resemblance of MSSE to SCC strengthens the use of acitretin in tumor suppression, despite the absence of a mismatch repair gene defect. In patients considered high-risk due to previous history of NMSC, systemic retinol or isotretinoin provided no difference in the incidence of SCC when compared with placebo. As for moderate-risk patients with a history of fewer than four occurrences of NMSC, systemic retinol did significantly reduce the risk of a new SCC. Neither study indicated a significant difference in the time to first SCC.6

In 2011, Kadakia et al. revisited retinoid treatment in SCC by use of acitretin. Patients in this trial had a history of more than two NMSC, and were treated for two years with either daily 25 mg acitretin or a placebo. While no statistically significant difference was found in the rate of new NMSC cases, the trial did reveal numerically lower rates in existing NMSC in those on acitretin. The total number of NMSC in patients receiving acitretin therefore was significantly less over the two-year trial.1 The suppression of recurrent SCC observed in these patients after treatment with a second-generation retinoid warrants further research.

ConclusionThe success with use of retinoids in the suppression of skin cancers is confirmed with cellular mechanism and clinical patient improvement. Regardless of risk classification, acitretin is on the leading edge for treatment of recurring SCC. Previously utilized in only high-risk patients, this second-generation retinoid has proved to suppress the development of SCC in patients with moderate to low risk factors. Despite the lack of significant evidence in decreasing time to new first cancer, acitretin has been shown to decrease numerically the occurrence of a new NMSC.

The most significant drawback is the consistent return of SCC with discontinuation of these retinoids. The requirement for maintenance therapy thus results in significant associated side effects with treatment. Physicians must evaluate the risks and benefits in treating their patients, and come to a conclusion with their patients regarding their use of retinoid therapy.

references1. Kadakia KC, Barton DL, Loprinzi CL, Sloan JA, Otley CC, Diekmann BB, Novotny PJ, Alberts SR, Limburg PJ, Pittelkow MR.  Randomized Controlled Trial of Acitretin Versus Placebo in Patients at High Risk for Basal Cell or Squamous Cell Carcinoma of the Skin (North Central Cancer Treatment Group Study 969251). Cancer [Internet]. 2012 Apr [cited May 2013];118(8):2128-2137. Available from: http://onlinelibrary.wiley.com/doi/10.1002/cncr.26374/full.

2. Lebwohl M, Tannis C, Carrasco D. Acitretin suppression of squamous cell carcinoma: Case report and literature review. J Dermatol Treat 2003;14:3-6.

3. Lin, XY, He, CD, Xiao, T, Jin, X, et al. Acitretin induces apoptosis through CD95 signaling pathway in human cutaneous squamous cell carcinoma cell line SCL-1. J Cell Mol Med 2009;13:2888-2898.

4. Katz, HI, Waalen, J, Leach, EE. Acitretin in psoriasis: An overview of adverse effects. J Am Acad Derm 1999 Sep;41(3):S7-S12.

5. Saurat, JH. Side effects of systemic retinoids and their clinical management. J Am Acad Dermatol 1992;27:S23-S28.

6. Robertson, SJ, Bashir, SJ, Pichert, G, et al. Severe exacerbation of multiple self-healing squamous epithelioma (Ferguson-Smith disease) with radiotherapy, which was successfully treated with acitretin. Clin Exp Dermatol 2009;35:e100-e102.

7. Rook AH, Jaworsky C, Nguyen T et al. Beneficial effect of low-dose systemic retinoid in combination with topical tretinoin for the treatment and prophylaxis of premalignant and malignant skin lesions in renal transplant recipients. Transplantation 1995;59(5):714-19.

8. George R, Weightman W, Russ GR, et al. Acitretin for chemoprevention of non-melanoma skin cancers in renal transplant recipients: Australas J Dermatol 2002;43(4):269-73.

9. Bouwes Bavinck JN, Tieben LM, Van der Woude FJ et al. Prevention of skin cancer and reduction of keratotic skin lesions during acitretin therapy in renal transplant recipients: a double-blind, placebo-controlled study: J Clin Oncol 1995;13(8):1933-8.

10. Carneiro RV, Sotto MN, Azevedo LS, et al. Acitretin and skin cancer in kidney transplanted patients. Clinical and histological evaluation and immunohistochemical analysis of lymphocytes, natural killer cells and Langerhans cells in sun exposed and sun protected skin. Clin Transplant 2005;19:115-121.

Correspondence: Dorene Niv, BS, University of North Texas Health Science Center / Texas College of Osteopathic Medicine, 855 Montgomery St., Fort Worth, TX, 76107. E-mail: Doreneniv@gmail.com.

page 20 use of acitretin in a patient with multiple squamous cell carcinomas:a case report anD literature review

kanavy, hoffman page 21

Cutaneous Manifestation of Churg-Strauss Syndrome

Holly Kanavy, DO,* Cindy Hoffman, DO**

*PGY-2 Resident, St. Barnabas Hospital, Bronx, NY **Residency Program Director, Dermatology, St. Barnabas Hospital, Bronx, NY

IntroductionChurg-Strauss syndrome (CSS) is a rare, necrotizing granulomatous vasculitis involving small- and medium-sized vessels. It is characterized by blood and tissue eosinophilia and has a broad range of clinical manifestations. Patients typically present with allergic rhinitis, asthma, and respiratory tract infections. Cutaneous, neural, gastrointestinal, and cardiac involvement may also be seen. Skin lesions are observed in the majority of patients and may be the initial manifestation of disease. Herein, we describe a case of Churg-Strauss syndrome presenting with palpable purpura of bilateral lower extremities.

Case PresentationA 39-year-old Caucasian male presented to our clinic with a rash of both lower legs that he believed started after a bug bite on his right ankle eight weeks prior. The rash was initially slightly pruritic, but was otherwise asymptomatic. Review of systems revealed a recent history of fatigue and shortness of breath. The patient reported being in good overall health, aside from mild childhood asthma, until six months prior, when he was hospitalized for pneumonia complicated by a pleural effusion. Shortly after his hospitalization, the patient developed a deep vein thrombosis in his left leg. He was taking warfarin daily and had recently completed a prednisone taper prescribed by his pulmonologist.

Upon physical examination, bilateral lower extremities contained purpuric papules

measuring from 4 mm to 2 cm, some with superficial crust (Figures 1a, 1b). A 6 mm punch biopsy of lesional skin revealed superficial dermal capillaries partially occluded by platelet-fibrin thrombi and fragmented neutrophils with minimal dermal inflammation (Figures 2a, 2b). Laboratory testing revealed elevated levels of antineutrophilic cytoplasmic antibodies directed against myeloperoxidase with a perinuclear staining pattern on indirect

immunofluorescence (P-ANCA) at 1:40; the presence of myeloperoxidase autoantibodies (12.5 U/mL); positive antinuclear antibodies (ANA) at 1:320 with a homogeneous pattern on indirect immunofluorescence; and anti-double-stranded DNA antibodies (26.9 IU/mL). Urinalysis revealed the presence of amorphous sediment. Report of a lung biopsy performed during the patient’s hospitalization revealed eosinophilic pneumonia.

Reinstatement of oral corticosteroids provided significant relief of the patient’s pulmonary and cutaneous symptoms.

DiscussionIn 1951, Churg and Strauss described 13 patients with fever, severe asthma, eosinophilia and necrotizing vasculitis involving multiple organs. The disease was differentiated from classic polyarteritis nodosa based on the presence of granulomatous inflammation within vessel walls. They named the disease “allergic angiitis and granulomatosis.” The syndrome has subsequently been named after the pathologists who first described it.1

Churg-Strauss syndrome is classified as one of the ANCA-associated vasculitides along with microscopic polyangiitis and granulomatosis with polyangiitis (formerly Wegener’s granulomatosis). The reported incidence of CSS ranges from 0.5 to 6.8 cases per million per year in the general population and 35 to 67 cases per million in those with asthma. The age of onset ranges from 30 to 60 years, with a mean age of 35 years. There is no gender or racial predilection.2,3

The clinical course of Churg-Strauss syndrome is divided into three phases.4 The first phase is the allergic, or prodromal, phase, in which patients suffer from rhinitis, nasal and sinus polyposis, and late-onset asthma (mean age 30 yrs). The second phase is the eosinophilic phase, which consists of peripheral eosinophilia and end-organ eosinophilic infiltration, particularly of the lung, heart, and gastrointestinal tract. The third phase is the vasculitic phase and presents with manifestations of systemic small-vessel vasculitis with widespread eosinophilic infiltration and granulomatous inflammation. This phase tends to occur several years to decades after initial symptoms and is often life-threatening. Significant overlap tends to occur among these 1a, 1b: Palpable purpura of bilateral lower extremities

2a: Minimal dermal inflammation

2b. Superficial dermal capillaries partially occluded by platelet-fibrin thrombi and fragmented neutrophils.

three phases in most patients.5

All major organ systems may be affected in CSS. Incidence of the various systemic manifestations of the disease was reported in a review of the literature by Bosco et al. in 2011 and Pagnoux et al. in 2007.2,6 Up to 80% of patients report constitutional symptoms, including fatigue, weight loss, fever, and myalgias or arthralgias. Respiratory-tract involvement is universal in CSS patients. Upper respiratory-tract involvement manifests with allergic rhinitis, paranasal sinusitis, and nasal and sinus polyposis. Lower respiratory involvement includes asthma, pneumonitis, and hemoptysis secondary to pulmonary alveolar hemorrhage (alveolar capillaritis). Migratory infiltrates consistent with eosinophilic pneumonia may be seen. Cardiovascular involvement occurs in up to half of patients and consists of pericarditis, endomyocarditis, and myocardial infarction secondary to coronary vasculitis. The most common neural manifestation of CSS is mononeuritis multiplex, a painful, asymmetric, asynchronous sensory and motor peripheral neuropathy involving multiple nerves in random areas of the body. The gastrointestinal system is affected in 10% to 40% of patients and may present as GI bleeding, bowel ischemia and perforation, and colitis. Glomerulonephritis is reported in 5% to 30% of patients.2,6

Cutaneous involvement is seen in 40% to 81% of patients and has been reported as the initial disease manifestation in 14% of cases. Lesions include palpable purpura (50%), retiform purpura, livedo reticularis, urticarial lesions, ulcerations, bullous lesions, digital ischemia or infarcts, and subcutaneous nodules.2,6 The association of venous thromboembolism with CSS, as seen with this patient, is well-recognized. A meta-analysis performed on all cases reported from 1951 to 2010 reported an association of 8.1%.7

PathogenesisThe onset of disease has been associated with several exogenous triggering factors including inhaled allergens, vaccinations, desensitization therapy, infections, and medications including macrolides, carbamazepine, and quinine.6 Treatment of asthma with leukotriene receptor antagonists has been recently implicated, although it is more likely the concomitant rapid discontinuation of corticosteroids that unmasks the symptoms of CSS.9 HLA-DRB4 has been identified as a genetic risk factor for CSS and may increase the likelihood of vasculitic manifestations of the disease.10

CSS is considered to be primarily a Th2- mediated disease due to its prominent allergic component. CD4+ T cells expressing Th2 markers have been demonstrated in CSS lesions, and peripheral CD4+ T-cell lines produce large amounts of

Th2 cytokines. Interleukin-4, -5, and -13 serum levels are elevated in CSS patients. IL-4, IL-5 and IL-13 promote allergy, and IL-5 induces bone marrow mobilization, activation and tissue recruitment of eosinophils. CD4+ T-cell lines from CSS patients also secrete significantly high amounts of interferon-gamma (IFN-α), a potent Th1 cytokine involved in vasculitis and granuloma formation. Recent studies have also suggested a possible role of Th17 cells, as their levels and the levels of IL-17A were higher in CSS patients. Th17 cells can induce autoimmunity and have been implicated in the pathogenesis of other autoimmune vasculitides as well. Therefore, Th2 responses probably predominate in CSS, but Th1 and Th17 immunity may also contribute to the disease pathogenesis. The balance between these T-helper arms likely differs throughout the various stages of disease and ultimately shapes the disease phenotype.11

The pathogenesis of venous thromboembolism in CSS is thought to be attributable to the fact that eosinophils store and release tissue factor, which initiates the coagulation cascade, as well as cationic proteins major basic protein (MBP), eosinophilic cationic protein (ECP), and eosinophil peroxidase (EPOx), which inhibit natural anticoagulant activity and activate platelets. Antineutrophilic cytoplasmic antibodies are also implicated in shifting the endothelial lining to a proadhesive and prothrombotic surface.7

The work-up for patients with suspected disease

includes CBC with differential, in which eosinophilia of greater than 10% (>1,500 cells/mm3) is typically seen, along with anemia of chronic disease. Antineutrophilic cytoplasmic antibodies directed against myeloperoxidase with a perinuclear staining pattern on indirect immunofluorescence (P-ANCA) are detected in 40% to 65% of patients. The test has high sensitivity (~ 99%) and good specificity (~ 70%).12 Positive status is associated with renal involvement, peripheral neuropathy, and vasculitis. Acute phase reactants such as C-reactive protein and erythrocyte sedimentation rate are frequently elevated. Antineutrophilic antibody and rheumatoid-factor testing may be positive in up to 70% of patients. To test for renal involvement, serum BUN and creatinine levels should be obtained. Urinalysis may reveal abnormal urine sediment, proteinuria,

microscopic hematuria, and RBC casts. Levels of markers for eosinophilic activation, including eosinophil cationic protein (ECP), soluble interleukin-2 receptor (sIL-2R), and soluble thrombomodulin (sTM) may be tested. Other tests that may be considered include ECG, GI endoscopy, EMG and nerve-conduction studies.

Primary therapy of CSS is systemic glucocorticoids. Certain patients, such as those with cardiac or central-nervous-system involvement, will require addition of immunosuppressants such as cyclophosphamide. Following induction of remission with steroids +/- cyclophosphamide, maintenance therapy may be employed for 12 to 18 months or longer, azathioprine being the preferred agent along with steroids.13 Most patients respond rapidly to systemic glucocorticoids, with a survival rate of 70% at five years.14 Other treatment options include rituximab, IVIG, and methotrexate, which has been used successfully for both remission induction and as a maintenance regimen.15-17 There has also been one report of successful use of combined dapsone and low-dose corticosteroids, which resulted in complete resolution of the cutaneous disease.18

Poor prognostic factors have been identified and include renal insufficiency, cardiomyopathy, gastrointestinal involvement, and CNS involvement. Left untreated, CSS has a dismal prognosis.14

ConclusionsThis case demonstrates a typical presentation of a rare disease entity. In patients who present with palpable purpura, the differential diagnosis is broad and includes immune-complex–mediated diseases, connective-tissue diseases, autoimmune diseases, drug-induced and infectious etiologies, as well as the ANCA-associated vasculitides, such as microscopic polyangiitis, granulomatosis with polyangiitis, and Churg-Strauss syndrome. Also of interest is the associated thromboembolic event that occurred in our patient, which has been reported to occur in association with Churg-Strauss syndrome.

page 22 cutaneous manifestation of churg-strauss synDrome

American College of Rheumatology diagnostic criteria for CSS8*Asthma (a history of wheezing or the finding of diffuse high-pitched wheezes on expiration) Eosinophilia >10% on differential white-blood-cell countMononeuropathy (including multiplex) or polyneuropathyMigratory or transient pulmonary opacities detected radiographicallyParanasal sinus abnormalityBiopsy containing a blood vessel showing the accumulation of eosinophils in extravascular areas*Four of the six criteria and biopsy evidence of vasculitis required for diagnosis.

references1. Churg J, Strauss L. Allergic granulomatosis, allergic angiitis, and periarteritis nodosa. Am J Pathol. Mar-Apr 1951;27(2):277-301.

2. Bosco L, Peroni A, Schena D, Colato, C, Girolomoni G. Cutaneous manifestations of Churg-Strauss syndrome: report of two cases and review of the literature. Clin Rheumatol. 2011;30:573-580.

3. Harrold LR, Andrade SE, Go AS, et al. Incidence of Churg-Strauss syndrome in asthma drug users: a population-based perspective. J Rheumatol 2005;32(6):1076–80.

4. Lanham JG, Elkon KB, Pusey CD, Hughes GR. Systemic vasculitis with asthma and eosinophilia: A clinical approach to the Churg–Strauss syndrome. Medicine 1984; 63:65–81.

5. Guillevin L, Cohen P, Gayraud M, et al. Churg-Strauss syndrome. Clinical study and long-term follow-up of 96 patients. Medicine 1999;78(1):26-37.

6. Pagnoux C, Guilpain P, Guillevin L. Churg-Strauss syndrome. Curr Opin Rheumatol 2007;19(1):25-32.

7. Ames PR, Margaglione M, Mackie S, Alves JD. Eosinophilia and thrombophilia in Churg-Strauss syndrome: a clinical and pathogenetic overview. Clin Appl Thromb Hemost. 2010;16(6):628-36.

8. Masi AT, Hunder GG, Lie JT, Michel BA, Bloch DA, Arend WP, et al. The American College of Rheumatology 1990 criteria for the classification of Churg-Strauss syndrome. Arthritis Rheum. 1990; 33:1094-1100.

9. Bibby S, Healy B, Steele R, Kumareswaran K, Nelson H, Beasley R. Association between leukotriene receptor antagonist therapy and Churg-Strauss syndrome: an analysis of the FDA AERS database. Thorax. 2010;65(2):132-8.

10. Vaglio A, Martorana D, Maggiore U, Grasselli C, Zanetti A, Pesci A, et al. HLA-DRB4 as a genetic risk factor for Churg-Strauss syndrome. Arthritis Rheum. Sep 2007;56(9):3159-66

11. Hellmich B, Csernok E, Gross WL. Proinflammatory cytokines and autoimmunity in Churg–Strauss syndrome. Ann NY Acad Sci 2005; 1051: 121–131.

12. Savige J, Davies D, Falk RJ, Jennette JC, Wiik A. Antineutrophil cytoplasmic antibodies and associated diseases: a review of the clinical and laboratory features. Kidney Int. 2000;57(3):846-62.

13. Grau R. Churg-Strauss Syndrome: 2005-2008 Update. Curr Rheum Rep. 2008;10:453-458.

14. Keogh KA, Specks U. Churg–Strauss syndrome. Semin Respir Crit Care Med. 2006;27:148.

15. Reinhold-Keller E. Use of methotrexate in ANCA-associated vasculitides. Clin Exp Rheumatol. 2010-09;28:S178-82.

16. Cartin-Ceba R. Treatment of antineutrophil cytoplasmic antibody-associated vasculitis with rituximab. Curr Opin Rheumatol. 2012-01;24:15-23.

17. Svetlicky N. The beneficial effects of intravenous immunoglobulin for antineutrophil cytoplasmic antibody-positive vasculitis. Isr Med Assoc J. 2012-09;14:568-9.

18. Bolotin D. Cutaneous Churg-Strauss syndrome: response to dapsone therapy. J Am Acad Derm. 2011-07;65:244-6.

Correspondence: Holly Kanavy, DO, 26 Brockmeyer Dr., Massapequa, NY, 11758. Phone: 516-996-0741. E-mail: hollykanavy@yahoo.com.

kanavy, hoffman page 23

page 24 scalp metastasis heralDing a Diagnosis of Breast cancer: a case report anD Discussion

Scalp Metastasis Heralding a Diagnosis of Breast Cancer: A Case Report and Discussion

Mounir Wassef, DO,* Robin Shecter, DO, FAOCD**

*PGY-6 Resident, Columbia Hospital (PBCGME), West Palm Beach, FL**Program Director, Dermatology Residency, Columbia Hospital (PBCGME), West Palm Beach, FL

Case reportA 64-year-old woman with history of hemochromatosis and recent falls presented to the dermatology clinic complaining of a tender scalp lesion of three weeks duration. There was a 2 cm x 1.5 cm, erythematous plaque devoid of hair with central ulceration on the right occipital scalp (Fig. 1). Biopsy revealed an atypical glandular neoplasm in the dermis (Fig. 2). This neoplasm, which had prominent glandular differentiation (Fig. 3a, 3b) was strongly positive for CK-7 (Fig. 4) and negative for CK-20. The immunohistochemical stains and the glandular nature of the tumor noted on H&E suggested a primary breast adenocarcinoma, which is the most common cause of cutaneous metastasis in women. The patient’s left breast had a palpable mass; her last mammogram was years ago and was negative. Due to the clinical finding of a palpable mass and the biopsy report that suggested a metastatic breast carcinoma, an ultrasound-guided needle core biopsy of the left breast was performed and revealed an invasive ductal carcinoma. Since the patient was complaining of loss of balance and had a recent history of falls, a brain MRI was performed and revealed small, right temporal lobe metastasis. The patient and her family

decided not to pursue any further testing, and she was admitted to hospice.

DiscussionMalignant tumors are able to grow at sites distant from the primary site of origin; thus, dissemination to the skin may occur with any malignant neoplasm. Five percent to 10% of patients with cancer develop skin metastases. The reported incidence figures vary widely according to the type of study undertaken and the site of primary tumor studied. The frequency of involvement of the skin is low when other sites are considered, such as the lung, liver, lymph nodes, and brain. Usually, metastases occur as numerous firm, hard, or rubbery masses, with a predilection for the chest, abdomen, or scalp, in an adult over the age of 40 who has had a previously diagnosed carcinoma. Many variations in morphology, number of lesions, site of growth, age at onset, and timing of metastases exist, however. They are most commonly intradermal papules, nodules, or tumors that are firm, skin-colored to reddish,

purplish, black or brown, and may be fixed to underlying tissues. The so-called Sister Mary Joseph nodule is formed by localization of metastatic tumors to the umbilicus. The most common primary sites are the stomach, large bowel, ovary, and pancreas. The primary tumor is usually diagnosed

before the appearance of metastases, and dissemination to the skin is often a late finding. Metastases to other more commonly involved organs, such as the lung and liver, have usually occurred. A poor prognosis is thus the rule. Skin infiltrates may, however, be the first harbinger of a malignant visceral neoplasm and are often the first clinically apparent metastatic site. The principal anatomic sites to which metastases localize are the chest, abdomen, and scalp, with the back and extremities being relatively uncommon areas. Involvement of the skin is likely to be near the area of the primary tumor. Thus, chest lesions are usually caused by breast carcinoma in women and lung carcinoma in men, abdominal or perineal lesions by colonic carcinoma, and the face by squamous cell carcinoma of the oral cavity. Extremity lesions, when they occur, are most commonly caused by melanoma.3

Of all the carcinomas metastatic to the skin, breast cancer may be the one with the widest

Cutaneous metastases are either the initial presentation of an undiagnosed neoplasm or appear in established oncology patients with relapsing or progressive disease. Through hematogenous spread, lymphatic spread, or by direct extension, malignant cells from the primary tumor invade the skin. In a retrospective study of 7,316 cancer patients, Lookingbill et al. reported that skin involvement was the first sign of cancer in 0.8% of cases.1 Abrams et al. reported that 18.6% of deceased patients with breast cancer exhibited evidence of cutaneous metastasis at autopsy.2

Figure 1

Figure 2 Figure 3a Figure 3b

Figure 4

wassef, shecter page 25

range of clinical presentations. Several unusual morphologic patterns occur. Carcinoma en cuirasse is a diffuse infiltration of the skin that imparts an indurated and hidebound leathery quality to it. This sclerodermoid change, also referred to as scirrhous carcinoma, is produced by fibrosis and single rows of tumor cells. Carcinoma telangiectaticum is another unusual type of cutaneous metastasis from breast carcinoma that presents as small, pink to purplish papules, pseudo-vesicles, and telangiectases. Inflammatory carcinoma (carcinoma erysipelatoides) is characterized by erythema, edema, warmth, and a well-defined leading edge, similar to erysipelas in appearance. Histologically, there is little to no inflammation, but rather neoplastic cells within dilated superficial dermal vessels.

Alopecia neoplastica is defined as hair loss secondary to a visceral malignancy that has metastasized to the scalp.4 Although cancers that primarily present in the skin, such as basal cell carcinoma, squamous cell carcinoma, and angiosarcoma, can morphologically appear as alopecia, this presentation does not fulfill the established definition of alopecia neoplastica.5 Visceral malignancies that metastasize to hair-baring areas such as eyelids, causing alopecia in these locations, also do not fulfill the established definition of alopecia neoplastica, which specifies the scalp as the location of metastasis. Alopecia neoplastica may present as a scarring alopecia, appearing anywhere on the scalp, and it has been described with cutaneous metastasis from breast, gastric, lung, renal and pancreatic carcinomas.6

A review of 724 patients with cutaneous metastases in 1972 by Brownstein and Helwig showed that in women, commensurate with the greater frequency of carcinoma of the breast, 69% of all cutaneous metastases originated in the breast.7 Cutaneous metastases that occur predominantly by lymphatic dissemination include inflammatory carcinoma, carcinoma en cuirasse, telangiectatic and nodular carcinoma, and carcinoma of the inframammary crease. Alopecia neoplastica and mammary carcinoma of the eyelid are probably caused by hematogenous spread.8

Therapy can be tailored to treat any combination of primary cancer and cutaneous metastasis. Treatment of the latter includes chemotherapy, immunotherapy, radiotherapy, excision, heat and observation. Occasionally, intralesional and topical (e.g. imiquimod) agents are employed. Tumor burden, maintaining daily function, cosmesis, and the possibility of pain, bleeding and infection are factored into the treatment algorithm. Although the disease course depends on the underlying malignancy and its therapeutic response, cutaneous metastasis is a marker of advanced disease; historically, life expectancy has been short.

ConclusionCutaneous metastasis may present as the initial symptom of an undiagnosed malignancy or may occur in oncology patients with an established cancer history. Clinicians should be aware of this clinical entity and have a low threshold to biopsy newly acquired or persistent cutaneous lesions, especially in cancer patients. Timely identification of this cutaneous manifestation of underlying tumor can potentially lead to earlier detection of primary neoplasms and more accurate staging in those individuals who already have a cancer diagnosis. The diagnosis of a cutaneous metastasis should result in a multidisciplinary approach that includes the primary care physician, the oncologist, and, depending on the situation, possibly a surgeon and a radiation oncologist.

references1. Lookingbill DP, Spangler N, Sexton FM. Skin involvement as the presenting sign of internal carcinoma. A retrospective study of 7316 cancer patients. J Am Acad Dermatol 1990;22:19-26.

2. Abrams HL, Spiro R, Goldstein N. Metastases in carcinoma; analysis of 1000 autopsied cases. Cancer 1950;3:74-85.

3. James WD, Berger T, Elston D.  Andrews Diseases of the Skin. 11th ed. Philadelphia: Saunders; c2011. Chapter 28, Dermal and Subcutaneous Tumors, p. 574-619.

4. Rolz-Cruz G, Kim CC. Tumor invasion of the skin. Dermatol Clin 2008;26:89-102.

5. Murray S, Simmons I, James C. Cutaneous angiosarcoma of the face and scalp presenting as alopecia. Australas J Dermatol 2003;44:273-276.

6. Rapini RP, Bolognia JL, Jorizzo JL. Dermatology: 2-Volume Set. 2nd ed. St. Louis: Mosby; c2008. 2584 p.

7. Brownstein MH, Helwig EB. Metastatic tumors of the skin. Cancer 1972;29:1298.

8. Schwartz RA. Cutaneous metastatic disease. J Am Acad Dermatol 1995;33:161.

Correspondence: Mounir Wassef, DO, Columbia Hospital/Palm Beach Centre for Graduate Medical Education, 2201 45th St., West Palm Beach, FL, 33407. Phone: 561-863-2315. Fax: 561-881-4365. E-mail: Mounir_Wassef15@Hotmail.com.

page 26 case report: Diffuse Bullous eruption following antiBiotic use

Case Report: Diffuse Bullous Eruption Following Antibiotic Use

Capt. Shannon Buck, DO,* Lt. Col. Erika Hill, MD,** Col. (Ret) Wayne Sumpter, MD***

*Flight Surgeon, Offutt Air Force Base, Nebraska**Staff Dermatologist, Offutt Air Force Base, Nebraska***Command Flight Surgeon, Offutt Air Force Base, Nebraska

Case reportA 39-year-old female presented to the clinic for evaluation of a diffuse, blistering, pruritic rash. She reported having a sore throat for about two weeks and took one of her husband’s doses of azithromycin, which was prescribed to him for a streptococcus infection. Three days after taking the azithromycin, she developed diffuse itching followed by pustules, blisters and oral ulcers. The skin rash began on her legs and spread to her arms, back, and chest. She also had a few lesions on the palms of her hands. At the onset of the rash, she was seen in the ER and given a shot of penicillin and a triamcinolone injection. She returned to the ER three days later with a severe sore throat and no improvement of her rash. At that time she was diagnosed with pharyngitis and released with a prescription for amoxicillin and prednisone (40 mg/d for four days). She was also given a prescription for magic mouthwash (lidocaine, maalox, and nystatin) to use for the oral lesions. She was seen by her family physician two days later with concerns of new skin lesions. Her oral lesions, however, had largely resolved. Physical examination revealed diffuse, small (3 mm to 1.5 cm), discrete, tense bullae on an erythematous base covering her back, arms and the extensor surfaces of her thighs and lower legs (Figures 1-3). Many of the bullae had a central crust with a ring of surrounding vesicles. There were a few superficial vesicles on her palms as well as several pustules scattered over the remainder of her body. She also had a small erosion present on

her hard palate.Her past medical history was unremarkable, with no prior history of skin problems. She had no significant family history, and no family members with similar skin manifestations. The patient denied any fevers, chills, changes in weight, and chronic use of any medications. She denied any recent outdoor exposures, contact with irritants or chemicals, and any dietary changes.The differential diagnosis based on the history and physical included linear IgA bullous dermatosis (LABD), erythema multiforme, acute generalized exanthematous pustulosis (AGEP), and bullous pemphigoid. Due to the distribution and morphology of bullae, a diagnosis of LABD was favored but not confirmed. Punch biopsies were done of one of the intact vesicles and a pustule (Figures 4-6). The patient was given topical triamcinolone and hydroxyzine for symptomatic relief.

DiscussionLinear IgA bullous dermatosis is an immune-mediated subepidermal bullous disease characterized by vesicles, ulcers, and bullae. The lesions may appear as annular plaques or in a herpetiform arrangement on an erythematous base.1 The affected areas can be very pruritic. There are many different causes of LABD including drug-induced, malignancy, and inflammatory bowel disease. The most common offending drug is vancomycin.2 The disease can affect both adults and children. Adults usually present after the age

of 60, while the average age in children is 4.5 years.3 Childhood LABD is typically self-limited, while the adult form follows a chronic course with relapsing symptoms.4 Mucosal involvement is a common occurrence and affects both adults and children. Mucosal disease can be present in up to 80% of adults, with oral and ocular mucosal surfaces being the most commonly affected sites.3

Diagnosis of LABD can be difficult as it resembles other diseases both clinically and histologically. The pathology will show collections of neutrophils in dermal papillae and neutrophils present in subepidermal blisters.5 Clinically, the disease can resemble both dermatitis herpetiformis and bullous pemphigoid, but direct immunofluorescence (DIF) for LABD will show homogenous linear deposits of IgA at the dermal-epidermal basement membrane, which is pathognomonic.6 The treatment for this condition typically utilizes dapsone, which can be initiated following the evaluation of glucose-6-phosphate dehydrogenase level, liver function tests, and a complete blood cell count (CBC). Subsequent CBCs should be followed during the treatment course to screen for hemolytic anemia and agranulocytosis. Topical steroids may be added to control pruritus. Counseling patients on avoiding sun exposure is also key, as UV radiation can aggravate bullous diseases.7 It is important to educate patients that lesions may continue after therapy is started but eventually will regress.8 Sulfonamides and colchicine are alternative treatments, and systemic steroids may be needed for additional symptomatic control. Erythema multiforme, AGEP, and bullous pemphigoid are a few of the diseases in the differential that are discussed below (see Table 1). There are many other skin conditions that could also be included in the differential but are not discussed here.Erythema multiforme classically presents as target-like lesions that have a symmetric

Figure 3Figure2Figure 1

Buck, hill, sumpter page 27

distribution commonly involving the extensor surfaces of the extremities. It usually affects young adults, with a slightly higher distribution in males. Infections are the most common cause of erythema multiforme, with HSV being the most common associated infection.9 Diagnosis is based on history and clinical exam, with biopsy confirming the diagnosis.Acute generalized exanthematous pustulosis is characterized by superficial pustules that present acutely after infection or medication use. The pustules often appear on the face and quickly spread to other parts of the body, causing severe pruritus. Antibiotics are implicated in most of the cases of AGEP, while viral infections also play a small role.10 Affected areas should resolve after the offending drug is stopped.Bullous pemphigoid is an autoimmune disease that presents as diffuse, large bullae affecting the elderly population. Skin biopsy with direct immunofluorescence will show deposits of C3 along the basement membrane, which is key to diagnosis.11 Treatment is largely focused on using high-dose oral glucocorticoids (typically 1 mg/kg daily), but topical glucocorticoids are also effective. Mortality rates vary widely, from 20% to 40% of reported cases.12

ConclusionGlucose-6-phosphate dehydrogenase level, liver function tests, and a CBC were ordered at presentation and were all unremarkable. Pathology findings were consistent with several possible diagnoses, which included LABD, dermatitis herpetiformis, and bullous pemphigoid. DIF was not accomplished due to limitations of the laboratory. The patient was seen two weeks later and noted that the bullae

on her extremities had resolved but there were new lesions on her neck and face. She was also complaining of pruritus in the corner of her left eye. The patient was started on dapsone 25 mg/day orally for one week, given desonide topically for her face, referred to ophthalmology, and asked to follow up in one week.Her eye exam was unremarkable except for a mild allergic conjunctivitis. At her follow-up one week later, the patient stated that her blisters had resolved and she had not developed any new lesions. Her CBC showed a normal white blood cell count, normal hemoglobin, and normal hematocrit. Her platelets had dropped from 201 (x109/L) to 162 (x109/L); segmented neutrophils that were previously within the normal range had decreased to 32.3%; and an eosinophilia of 29.9% was now present. She was advised to stop the dapsone due to it potentially being the cause of her CBC abnormalities. The patient was started on a four-week-long prednisone taper starting at 40 mg/day and was asked to repeat her CBC in one month.After one month, her CBC had returned to normal, and her skin symptoms had completely resolved. We contacted the patient six months later, and she reported she continued to be symptom free.

references1. Bolognia JL, et al. Dermatology. 2nd Edition. Elsevier Limited. 2008.

2. Kocyigit P, Akay BN, Karaosmanoolu N. Linear IgA bullous dermatosis induced by interferon-alpha 2a. Clin Exp Dermatol. 2009;34:e123-e124.

3. Wojnarowska F, Marsden RA, Bhogal B, Black MM. Chronic bullous disease of childhood, childhood cicatricial pemphigoid, and linear IgA disease of adults. A comparative study demonstrating clinical and immunopathologic overlap. J Am Acad Dermatology 1988;19:1972.

4. Marzano AV, et al. Refractory linear IgA bullous dermatosis successfully treated with mycophenolate sodium. J Dermatol Treat. 2008;19:364-367.

5. Serwin AB, et al. Linear IgA bullous dermatosis in a diabetic patient with chronic renal failure. Int J Dermatol. 2002;41:778-780.

6. Jones DH, et al. Early diagnosis is key in vancomycin-induced linear IgA bullous dermatosis and Stevens-Johnson syndrome. J Am Osteopath Assoc. 2004;104:157-162.

7. Panasiti V, et al. Amoxicillin-clavulanic acid-induced linear immunoglobulin A bullous dermatosis: case report and review of the literature. Int J Dermatol. 2009;48:1006-1010.

8. Takagi Y, et al. Coexistence of psoriasis and linear IgA bullous dermatosis. Br J Dermatol. 2000;142:513-516.

9. Huff JC, Weston WL, Tonnesen MG. Erythema multiforme: a critical review of characteristics, diagnostic criteria, and causes. J Am Acad Dermatol. 1983; 8:763.

10. Roujeau JC, Bioulac-Sage P, Bourseau C, et al. Acute generalized exanthematous pustulosis. Analysis of 63 cases. Arch Dermatol. 1991;127:1333.

11. Wu H, Schapiro B, Harrist TJ. Noninfectious vesiculobullous and vesiculopustular diseases. In: Elder DE, Elenitsas R, Johnson BL, Murphy GF (Eds). Lever’s Histopathology of the Skin. 9th ed. Philadelphia (PA): Lippincott Williams and Wilkins; 2005;p.243

12. Khumalo N, Kirtschig G, Middleton P, et al. Interventions for bullous pemphigoid. Cochrane Database Syst Rev. 2003;(3):CD002292.

Correspondence: Shannon Buck, DO, 14202C Tregaron Ridge Ave., Bellevue, NE, 68123. Phone: 719-660-8405. E-mail: buckshan@gmail.com.

Table 1

Selected Differential Diagnosis of Linear IgA Bullous Dermatosis

Condition Characteristics

Erythema multiforme A common reaction of erythematous, iris-shaped or target lesions typically involving the extremities and mucous membranes; commonly associated with herpes simplex.

Linear IgA bullous dermatosis An extremely pruritic disease with heterogeneous groups of vesicles and bullae with a symmetric distribution; presence of linear deposits of IgA at the cutaneous basement membrane zone.

Acute generalized exanthematous pustulosis

Febrile eruption that may follow viral infection or taking a medication; presents as sterile pustules with a background of diffuse erythema.

Bullous pemphigoid Autoimmune disease consisting of large, tense bullae usually affecting the elderly population; anti-basement membrane zone IgG autoantibodies.

Figure 4Figure 5 Figure 6

Atypical Fibroxanthoma with Osteoclast-like Giant Cells: Report of Two Cases

Viktoryia Kazlouskaya, MD, PhD,* Vladyslava Doktor, MA,** Elen Blochin, MD, PhD,*** Dirk Elston, MD****

*International visiting fellow, Ackerman Academy of Dermatopathology, New York City, New York**Medical Student, 3rd-year, Touro College of Osteopathic Medicine, New York City, New York***Associate, Ackerman Academy of Dermatopathology, New York City, New York****Director, Ackerman Academy of Dermatopathology, New York City, New York

IntroductionThe term “atypical fibroxanthoma” (AFX) was first coined by Helwig in 1963 to describe an anaplastic tumor on the sun-damaged skin of elderly patients. The tumor demonstrated paradoxically indolent behavior despite its bizarre histologic appearance.1 Clinically, AFX presents as a nodule or papule, often on the ear and sometimes ulcerated. It rarely metastasizes but is capable of recurring locally if excision is inadequate. The histogenesis of AFX is undetermined. Most evidence favors fibrohistiocytic differentiation, although some examples may represent de-differentiated squamous-cell carcinoma (SCC). Histopathologic sections of AFX usually demonstrate a well-circumscribed tumor composed of anaplastic cells located in the superficial parts of the dermis. Marked pleomorphism and atypical mitotic figures are common. The pure spindle-cell variant of AFX is less common and demonstrates hyperchromatic spindle cells immediately beneath the epidermis with no intervening grenz zone. Spindle-cell AFX must be differentiated from spindle-cell squamous carcinoma, spindle-cell melanoma and leiomyosarcoma. Rare histopathological variants include foci of osteoid or chondroid formation.2 Cellular abnormalities may include presence of clear and multinucleated cells including osteoclast-like giant cells.3-6 We describe two cases of AFX with osteoclast-like giant (OCG) cells, review the literature, and discuss possible differential diagnoses.

Materials and MethodsExcisional biopsies from two patients with AFX were studied. The first case was diagnosed in an 85-year-old Caucasian male presenting with a right upper anterior arm lesion. The second lesion was excised in a 60-year-old woman from the vertex of the scalp. For the immunohistochemistry, formalin-fixed paraffin-embedded tissue was cut on charged slides at 5 µm and baked at 60 C for 30 minutes. Staining with CD68, CD10, Melan-A, S100, pan-cytokeratin (CK), CK903, low- and high-

weight CK, CAM5.2-CK, and p63 was carried out on the Ventana BenchMark XT. Visualization was done with Ventana’s iView DAB Detection Kit and counterstained with Harris hematoxylin (Surgipath). Appropriate positive and negative controls were used.

resultsBoth cases presented as relatively well-circumscribed polypoid tumors. On hematoxylin-eosin stains (H&E), both lesions were characterized by numerous multinucleated cells including OCG cells. Mitotic figures were numerous, and each tumor demonstrated marked nuclear pleomorphism. Some cells in each tumor showed a spindle, oval or round morphology (Figure 1: A1-B2). Both tumors were strongly positive for CD68. CD10 positivity was seen in the tumor cells with round, oval or spindle morphology, but not in OCG cells (Figure 1: C1-D2). Melan-A and S100 stains were negative in both cases. High- and low-molecular-weight cytokeratins (CK) were used to exclude squamous-cell carcinoma. A polyclonal pan-keratin cocktail and a cocktail of monoclonal low- and high-molecular with CKs were used in the first case. CAM5.2-CK, polyclonal pan-keratin, and CK903 were used in the second case. P63 staining performed on the second tumor was also negative.

Discussion The diagnosis of AFX is mainly based on the exclusion of other neoplasms. The histopathology of AFX is variable. The lesion is commonly colonized by S100-positive Langerhans cells, and interpretation of immunostains must be done carefully. Luzar and Calonje reported that an admixture of spindle and epithelioid cells was the most frequent pattern (60%) among 66 AFX cases they studied.7 Rare findings in AFX include granular cell change, pigmented change, clear cell change, keloid-like areas, myxoid degeneration, and presence of osteoid or chondroid foci.8-11

The frequency of osteoclast-like giant cells has varied in different series. We noted only two examples among all cases diagnosed between 2005 and 2011 at the Ackerman Academy of

Dermatopathology, NY, NY, USA. The percentage of osteoclast-like giant cells in AFX may be variable, ranging from several cells to being a predominant pattern in the neoplasm. In the majority of the reported cases, OCG cells expressed CD68. We were unable to find prior reports of CD10 staining in AFX cases with OCG cells. In our cases, while the majority of AFX cells were positive with CD10, the osteoclast-like giant cells did not express this marker. The origin of the giant cells has been a matter of debate, with some authors suggesting different lines of differentiation of tumor cells, and others suggesting the cells are not innate to the tumor at all but instead represent a reactive phenomenon.14 The lack of CD10 staining in our cases supports a reactive etiology for the giant cells. Familiarity with the presence of OCG cells within AFX is important to prevent misdiagnosis, as other tumors including melanoma, squamous carcinoma and dermatofibroma can present with similar cells.15-17

references 1. Helwig E. Atypical fibroxanthoma. Tex J Med 1963;59:664-7.

2. Wilson PR, Strutton GM, Stewart MR. Atypical fibroxanthoma: two unusual variants. J Cutan Pathol 1989;16(2):93-8.

3. Val-Bernal JF, Corral J, Fernandez F, Gomez-Bellvert C. Atypical fibroxanthoma with osteoclast-like giant cells. Acta Derm Venereol 1994;74(6):467-70.

4. Khan ZM, Cockerell CJ. Atypical fibroxanthoma with osteoclast-like multinucleated giant cells. Am J Dermatopathol 1997;19(2):174-9.

5. Tomaszewski MM, Lupton GP. Atypical fibroxanthoma. An unusual variant with osteoclast-like giant cells. Am J Surg Pathol 1997 Apr;21(2):213-8.

6. Ferrara N, Baldi G, Di Marino MP, Bellucci G, Baldi A. Atypical fibroxanthoma with osteoclast-like multinucleated giant cells. In Vivo 2000;14(1):105-7.

7. Luzar B, Calonje E. Morphological and immunohistochemical characteristics of atypical fibroxanthoma with a special emphasis on potential diagnostic pitfalls: a review. J Cutan Pathol 2010;37(3):301-9.

AbstractAtypical fibroxanthoma (AFX) is a tumor of presumably fibrohistiocytic origin, usually seen on the sun-damaged skin of elderly patients. One of the rare cellular abnormalities observed in AFX is the presence of osteoclast-like giant (OCG) cells. The origin of OCG cells remains unknown. We present two cases of AFX with OCG cells in an 85-year-old male and a 60-year old female and discuss the differential diagnosis. CD10 was found to be negative in OCG cells but positive in the remainder of the tumor cells, suggesting that the giant cells may represent a reactive phenomenon.

page 28 at ypical fiBroxanthoma with osteoclast-like giant cells: report of two cases

kazlouskaya, Doktor, Blochin, elston page 29

8. Wright NA, Thomas CG, Calame A, Cockerell CJ. Granular cell atypical fibroxanthoma: case report and review of the literature. J Cutan Pathol 2010;37(3):380-5.

9. Rios-Martin JJ, Delgado MD, Moreno-Ramirez D,

Garcia-Escudero A, Gonzalez-Campora R. Granular

cell atypical fibroxanthoma: report of two cases. Am J

Dermatopathol 2007;29(1):84-7.

10. Diaz-Cascajo C, Weyers W, Borghi S. Pigmented

atypical fibroxanthoma: a tumor that may be

easily mistaken for malignant melanoma. Am J

Dermatopathol 2003;25(1):1-5.

11. Murali R, Palfreeman S. Clear cell atypical

fibroxanthoma - report of a case with review of the

literature. J Cutan Pathol 2006;33(5):343-8.

12. Longacre TA, Smoller BR, Rouse RV. Atypical

fibroxanthoma. Multiple immunohistologic profiles.

Am J Surg Pathol 1993;17(12):1199-209.

13. Beer TW, Drury P, Heenan PJ. Atypical

fibroxanthoma: a histological and immunohistochemical

review of 171 cases. Am J Dermatopathol

2010;32(6):533-40.

14. Orlandi A, Bianchi L, Ferlosio A, Innocenzi

I, Spagnoli LG. The origin of osteoclast-like giant

cells in atypical fibroxanthoma. Histopathology

2003;42(4):407-10.

15. Al-Brahim N, Salama S. Malignant melanoma with

osteoclast-like giant cells: an unusual host response:

immunohistochemical and ultrastructural study of

three cases and literature review. Am J Dermatopathol

2005;27(2):126-9.

16. Wooff J, Werner D, Murphy J, Walsh N. Osteoclast-

like giant cell reaction associated with cutaneous

squamous cell carcinoma: a report of 2 cases and review

of the literature. Am J Dermatopathol 2009;31(3):282-

7.

17. Papalas JA, Balmer NN, Wallace C, Sangueza

OP. Ossifying dermatofibroma with osteoclast-like

giant cells: report of a case and literature review. Am J

Dermatopathol 2009;31(4):379-83.

Correspondence: Dirk Elston, MD, Ackerman

Academy of Dermatopathology, 145 E32 street, 10th

floor, New York, NY, 10016. Tel: (800) 553-6621. Fax:

(212) 889-8268. E-mail: DElston@ameripath.com.

Figure 1. Atypical fibroxanthoma

Case 1: A1/B1/C1/D1 ; Case 2: A2/B2/C2/D2

A1/A2 – H&E stained sections, 200x.B1/B2 - Multinucleated osteoclast-like giant cells, H&E-stained sections, 600x. C1/C2 - CD68-positivity in tumor cells and osteoclast-like giant cells, CD68-stained sections, 600x. D1/D2 – CD10-positive tumor cells and CD10-negative osteoclast-like giant cells, CD10-stained sections, 600x.

page 30 primary cutaneous aDenosquamous carcinoma treateD with mohs

Primary Cutaneous Adenosquamous Carcinoma Treated with Mohs

Donna D. Tran, DO,* Brooke Walls, DO,** Richard Miller, DO, FAOCD***

*Traditional Intern, Botsford Hospital, Farmington Hills, Michigan**Dermatology Resident, PGY3, Largo Medical Center/Nova Southeastern University College of Osteopathic Medicine, Largo Medical Center, Largo, Florida***Program Director, Bay Dermatology/Largo Medical Center/Nova Southeastern University College of Osteopathic Medicine, Largo, Florida

Case reportA 73-year-old man presented for an annual skin examination. His only complaint was a new, itchy spot on his scalp. There were no other symptoms associated with the lesion, and the patient was unsure of the duration of its presence. Physical examination revealed an erythematous, hyperkeratotic papule located on the right scalp. A shave biopsy of the lesion was performed. Histopathological examination revealed nests and cords of malignant epithelial cells with keratin pearls and intercellular bridges with signs of a glandular component. The epidermis had no relevant changes. Immunohistochemical stains confirmed a diagnosis of primary infiltrative adenosquamous carcinoma (Figures 1-3). The squamous component was strongly positive for cytokeratin (CK) 5/6 and CK 34 (Figure 4). The glandular component was strongly positive for CAM 5.2, CK 7 and BER-EP4.The patient underwent Mohs micrographic surgery with clearance after four stages. The primary defect was then closed with a skin graft. Due to the potential recurrence of the tumor,

localized radiation treatment was initiated after the graft healed. No recurrence or metastases were present at three-month follow-up.

DiscussionPrimary ASC of the skin is a rare neoplasm with an unusually aggressive course as documented by multiple recurrences and metastasis. Weidner and Foucar originally described it in 1985 as a high-grade variant of cutaneous squamous cell carcinoma, rather than mucoepidermoid carcinoma, an entity with which ASC is often confused in the literature.1 Clinically, most reported cases develop in elderly patients, with a male predominance, and they tend to involve the head and neck region.2-4,5 Lesions have been described as an indurated, erythematous, hyperkeratotic papule or plaque, indistinguishable from squamous cell carcinoma or basal cell carcinoma.4 Of note, most of the reported cases have been associated with sun-damaged skin, as was evident in our case.1,2,4 Histopathologic examination reveals the tumors consist of nests of epithelial cells

with intercellular bridges and keratin pearls, demonstrating squamous differentiation. There is often an epidermal connection separated by areas of uninvolved epidermis. The glandular differentiation ranges from focal to diffuse, and deep extension into the dermis is not uncommon, with tubular structures lined by atypical cuboidal cells and infiltrative features.3

Immunohistochemical stains reveal cytokeratin positivity in both squamous and glandular components.3 Glandular differentiation may be confirmed by carcinoembryonic antigen positivity and cytokeratin 7 positivity or staining with mucicarmine and/or Alcian blue pH 2.5.3,4 The squamous differentiation may be confirmed by cytokeratins. Cytokeratin 34, also known as high molecular weight keratin (HMK) 903, stains positive in a variety of carcinomas, including squamous cell carcinoma.4,7 The histologic differential diagnosis consists of other primary cutaneous squamous cell carcinomas, as well as metastatic carcinomas. Of note, mucoepidermoid carcinoma (MEC) is often a topic of confusion in the literature, as some authors have defined MEC as equitable to ASC.6 However, as Riedlinger et al. describes, the two can be differentiated microscopically. ASC is a well-differentiated adenocarcinoma that may exhibit high-grade nuclear morphologic features often with an epidermal component. MEC, on the other hand, is a dermal-based solid or cystic tumor, with mucogenic cells, papillary features, and peritumoral fibrosis, lacking an intraepidermal component and high-grade nuclear features.6 Fu et al. suggest that MEC is best reserved for tumors in extracutaneous sites such as salivary and submucosal glands of the head and neck.4

Although rare, adenosquamous carcinoma of the skin is a distinct clinicopathological entity. It has an unusually aggressive clinical behavior, such as high rate of local invasion, recurrence, and metastasis. Lesion thickness, microscopic perineural invasion, and immunosuppression have been found to be associated with extensive local disease and recurrence.4 Of the six patients reported by Fu et al., three were treated with Mohs microscopic surgery (MMS), three had locoregional recurrences, and one developed in-

AbstractAdenosquamous carcinoma (ASC) of the skin is a rare malignant neoplasm characterized by mixed squamous and glandular differentiation and a propensity for aggressive clinical behavior. Clinical presentation is non-diagnostic, and histopathology and immunochemistry are necessary for diagnosis and appropriate therapy. Herein, we report a case of primary ASC arising on the right scalp of a 73-year-old man.

Figure 3

Figure 1 Figure 2

Figure 4

portella, BeDocs, piliang page 31

transit metastasis as well as involvement of the primary nodal basin.4 None of their patients had evidence of distant metastasis after a mean of 2.3 years follow-up. Of the 10 patients reported by Banks and Cooper, five died of their disease, and two were alive with extensive disease and clinical evidence of regional lymph node involvement.2 Unfortunately, other reported cases have documented a similarly poor prognosis in these patients. ASC is best initially treated with MMS and close monitoring for locoregional recurrence. Adjuvant radiotherapy may be indicated for patients with high risk factors, particularly in cases with locally advanced lesions or in patients who are immunosuppressed.4 The use of epidermal growth factor receptor antagonist as adjuvant therapy has been reported.4

In conclusion, primary cutaneous ASC is a rare malignant neoplasm with mixed squamous and glandular differentiation and an unusually aggressive behavior. Clinical diagnosis is difficult, as ASC often presents as a hyperkeratotic papule or plaque. Histopathology and immunochemistry are necessary for diagnosis, and early detection and superficial location are associated with a better prognosis. Our patient underwent MMS with complete removal after four stages, graft placement, and subsequent radiation therapy. No recurrence or metastases were present at 12-month follow-up.

references1. Weidner N, Foucar E. Adenosquamous carcinoma of the skin. An aggressive mucin- and gland-forming squamous carcinoma. Arch Dermatol.1985;121(6): 75-779

2. Azorin D, Lopez-Rios F, Ballestin C, Barrientos N, Rodriguez-Peralto JL. Primary cutaneous adenosquamous carcinoma: a case report and review of the literature. J Cutan Pathol. 2001;28(10):542-545

3. Banks ER, Cooper PH. Adenosquamous carcinoma of the skin: a report of 10 cases. J Cutan Pathol. 1991;18(4):227-234

4. Fu JM, McCalmont T, Yu SS. Adenosquamous carcinoma of the skin a case series. Arch Dermatol. 2009; 145(10): 1152-1158

5. Cassarino DS, Derienzo DP, Barr RJ. Cutaneous squamous cell carcinoma: a comprehensive clinicopathologic classification—part two. J Cutan Pathol. 2006;33(4):261-279

6. Riedlinger WFJ, Hurley MY, Dehner LP, Lind AC. Mucoepidermoid Carcinoma of the Skin: A Distinct Entity From Adenosquamous Carcinoma. A Case Study with a Review of the Literature. Am J Surg Pathology. 2005;29:131-135

7. Pernick N. Stains; cytokeratin 34betaE12. Pathology outlines. http://www.pathologyoutlines.com/topic/stainsck34be12.html Updated Jan 5, 2013. Accessed 6/15/2013

Correspondence: Brooke Walls, DO, Largo Medical Center/NOVA Southeastern University, 201 14th St., Largo, FL, 33770. Phone: 727-588-5200. E-mail: blissy79@gmail.com.

Lupus Panniculitis of the Lower Extremities:A Case Report and Review of the Literature

Dustin Portela, H-BS,* Paul M Bedocs, DO,** Melissa Piliang, MD***

*Osteopathic Medical Student, 4th year, Des Moines University College of Osteopathic Medicine, Des Moines, IA**Associate Professor of Dermatology, Michigan State University, East Lansing, MI and Ohio University, Athens, OH***Dermatopathologist, Associate Residency Program Director, The Cleveland Clinic, Cleveland, OH

AbstractLupus panniculitis, or lupus erythematosus profundus (LEP), is a lobular panniculitis that presents as firm nodules that heal with atrophy of the subcutaneous fat. It is most commonly found on the trunk and upper extremities. We present the case of a patient with a two-year history of painful erythematous nodules on her bilateral lower extremities. Clinical considerations were narrowed to morphea and panniculitis. Biopsy of an active lesion revealed histology consistent with lupus panniculitis. This case illustrates the clinical variability of LEP and demonstrates that it may manifest outside the commonly described pattern of distribution.

Case reportA 50-year-old Caucasian female presented to her dermatologist with a two-year history of erythematous, tender subcutaneous nodules over her anterior tibias bilaterally. The nodules developed gradually and had become increasingly painful. The patient denied any previous trauma to the area or nodules elsewhere on the body. The overlying epidermis showed only mild erythema. Initial clinical considerations were panniculitis or morphea. A biopsy was taken of a clinically active lesion. Histology revealed a lobular panniculitis with a brisk lymphoplasmacytic infiltrate. Additional histologic features demonstrated diffuse adipocyte necrosis with hyalinization and pseudocyst formation. Within the dermis, a mild perivascular and periadnexal lymphohistiocytic infiltrate were seen along with excess mucin deposition. The epidermis and stratum corneum were unaffected.

Given the clinical and histologic findings, the patient was diagnosed with lupus panniculitis. Laboratory evaluations were within normal limits at the time of diagnosis. The patient was placed on hydroxychloroquine, leading to resolution of her lesions, leaving only significant atrophy. Four years following her initial diagnosis, the patient presented to rheumatology complaining of increasing fatigue and formation of a new nodule. Serum analysis revealed a mildly elevated CRP but was negative for complement deficiency, antinuclear antibody by immunofluorescence, dsDNA, SSA, SSB, Sm, Cent B, Histone, RF, or anti-CCP. Dermatologic follow-up revealed skin findings again consistent with active and inactive areas of lupus panniculitis (Figure 1). The patient has never met criteria for systemic lupus erythematosus, nor has she developed stigmata elsewhere on her body.

DiscussionKaposi first described the presence of subcutaneous nodules in the setting of lupus erythematosus in 1883.1 The first American case was reported in 1940 by Irgang, who described a patient with an infiltrated plaque on the back and a discoid lesion on the face. He named this clinical entity “lupus erythematosus panniculitis” (LEP).2 It was not until Arnold published a review of four cases, which included LEP in the absence of discoid lesions, that this became understood as a distinct clinical entity.3

LEP most commonly occurs in women between the ages of 30 to 60.4 It typically presents as deep subcutaneous nodules or plaques that are frequently tender. The most common location for LEP lesions are the forehead, upper extremities, trunk, and buttocks.5 Cases involving the breast,

Figure 1. Depressed area of lipoatrophy from a resolving lesion on the left lower extremity. Although difficult to visualize, there is a newly forming nodule on the right lower extremity.

page 32 lupus panniculitis of the lower extremities: a case report anD review of the literature

salivary glands, and peri-orbital area have been described as well.6,7,8 LEP involving the lower extremities may occur as a single manifestation or in the setting of a more classic distribution, but it remains a rare presentation.9 Panniculitis may be the sole manifestation of disease or may occur in the presence of other clinical signs. Discoid lupus or systemic lupus erythematosus (SLE) may occur before, during, or after the onset of LEP.10,11 Discoid lesions have been described in 20% to 70% of patients.12 SLE develops in 10% to 42% of patients.4 Conversely, only 2% to 7% of patients with SLE will eventually develop LEP.13 Patients can expect that their disease will follow a chronic relapsing course. When lesions heal, they tend to cause considerable atrophy and residual scarring (Figure 2).4 Histopathologic analysis of LEP reveals a primarily lobular panniculitis; however, septal involvement has been documented.14 Many authors agree that lymphocytic infiltrate of the fat lobules and hyaline necrosis of the fat lobule are important defining characteristics.4 Hyaline fat necrosis is observed in 45% to 69% of cases, while lymphoid follicles are observed in 45% to 78% of cases.12,14 Due to the variability that may be seen, Peters et al. have proposed several major (important for diagnosis) and minor (not necessary for diagnosis) histopathological criteria to aid in diagnosis (Table 1).15,16 It is important

to note that these criteria are not universally agreed upon, and it would be rare to see even all four of the major criteria in any single histological sample. Treatment of LEP often involves the use of antimalarial agents such as hydroxychloroquine (200 to 400 mg/day), which commonly provides a clinical response in six to eight weeks.17 Patients who are uncontrolled or experience relapse may require combination therapy. Other therapies reported include quinacrine, dapsone, thalidomide, mycophenolate mofetil and oral corticosteroids.4,18,19 Caution should be used with topical or intralesional steroids as these may exacerbate the potential for atrophy.4

ConclusionIn summary, lupus erythematosus profundus is a primarily lobular panniculitis that predominately affects middle-aged females. It may occur in the presence or absence of discoid lupus or systemic lupus erythematosus. Although LEP most commonly occurs on the head, trunk, and upper extremities, this case illustrates further variability of its clinical presentation.

references1. Kaposi M. Pathologie und Therapie der Hautkrankheiten in Vorlesungen. 2nd ed. Vienna: Urban & Schwarzenberg; 1883. Chapter 30, Lupus; p. 642.

2. Irgang S. Lupus erythematosus profundus: Report of an example with clinical resemblance to darier-roussy sarcoid. Arch of Dermatol Syph. 1940;42:97-108.

3. Arnold HLJ. Lupus erythematosus profundus; commentary and report of four more cases. AMA Arch Derm. 1956 Jan;73(1):15-33.

4. Fraga J, García-Díez A. Lupus erythematosus panniculitis. Dermatol Clin. 2008 Oct;26(4):453-63.

5. Watanabe T, Tsuchida T. Lupus erythematosus profundus: A cutaneous marker for a distinct clinical subset? Br J Dermatol. 1996 Jan;134(1):123-5.

6. Holland NW, McKnight K, Challa VR, Agudelo CA. Lupus panniculitis (profundus) involving the breast: Report of 2 cases and review of the literature. J Rheumatol. 1995 Feb;22(2):344-6.

7. White WL, Sherertz EF, Berg D, Clark RE. Periparotid lupus erythematosus panniculitis. clinicopathologic correlation of two cases presenting as primary parotid disease. Arch Pathol Lab Med. 1993 May;117(5):535-9.

8. Nowinski T, Bernardino V, Naidoff M, Parrish R. Ocular involvement in lupus erythematosus profundus (panniculitis). Ophthalmology. 1982 Oct;89(10):1149-54.

9. Strober BE. Lupus panniculitis (lupus profundus). Dermatol Online J [Internet]. 2001 Dec;7(2):20.

10. Patel RM, Marfatia YS. Lupus panniculitis as an initial manifestation of systemic lupus erythematosus. Indian J Dermatol. 2010;55(1):99-101.

11. Winkelmann R, Peters M. Lupus Panniculitis. In: Moschella, SL, editor. Dermatology Update; New York: Elsevier; 1982. p. 135-52.

12. Sánchez NP, Peters MS, Winkelmann RK. The histopathology of lupus erythematosus panniculitis. J Am Acad Dermatol. 1981 Dec;5(6):673-80.

13. Ogura N, Fujisaku A, Jodo S, Ichikawa K, Tsutsumi A, Mukai M, Koike T. Lupus erythematosus profundus around the salivary glands: A case resembling submandibular salivary gland disease. Lupus. 1997;6(5):477-9.

14. Massone C, Kodama K, Salmhofer W, Abe R, Shimizu H, Parodi A, Kerl H, Cerroni L. Lupus erythematosus panniculitis (lupus profundus): Clinical, histopathological, and molecular analysis of nine cases. J Cutan Pathol. 2005 July;32(6):396-404.

15. Peters MS, Su WP. Lupus erythematosus panniculitis. Med Clin North Am. 1989 Sept;73(5):1113-26

16. Peters MS, Su WP. Eosinophils in lupus panniculitis and morphea profunda. J Cutan Pathol. 1991 June;18(3):189-92.

17. Izumi AK, Takiguchi P. Lupus erythematosus panniculitis. Arch Dermatol. 1983 Jan;119(1):61-4.

18. Ujiie H, Shimizu T, Ito M, Arita K, Shimizu H. Lupus erythematosus profundus successfully treated with dapsone: Review of the literature. Arch Dermatol. 2006 Mar;142(3):399-401.

19. Housman TS, Jorizzo JL, McCarty MA, Grummer SE, Fleischer AB Jr, Sutej PG. Low-dose thalidomide therapy for refractory cutaneous lesions of lupus erythematosus. Arch Dermatol. 2003 Jan;139(1):50-4.

Correspondence: Dustin Portela, H-BS, Des Moines University, 3200 Grand Ave., Des Moines, IA, 50312. Phone: 800-240-2767. E-mail: porteladr@gmail.com.

Figure 2. A resolved lesion on the medial side of the left lower extremity demonstrating the significant atrophy that can occur.

Major Criteria (important for diagnosis) Hyaline necrosis of fat Lymphocytic aggregates / lymphoid follicle formation Periseptal or lobular lymphocytic panniculitis Calcification

Minor Criteria (not necessary for diagnosis) DLE changes in the skin overlying panniculitis Lymphocytic vascular inflammation Hyalinization of subepidermal zone Mucin deposition Histiocytes and small granulomas Presence of plasma cells or eosinophils

Table 1. Proposed criteria to aid in the histopathological diagnosis of lupus panniculitis15,16

suchniak, severs page 33

Oral and Cutaneous Lichenoid Drug Eruption Secondary to Imatinib Mesylate: A Case Report and Review of the Literature

Kristen Suchniak, MD,* Gregg Severs, DO**

*PGY-1, Internal Medicine, Penn State Milton S. Hershey Medical Center, Hershey, PA**Assistant professor, The Commonwealth Medical College, Scranton, PA

Case reportA 78-year-old Caucasian man with chronic myelogenous leukemia (CML) presented in June 2011 with a one-month history of worsening pruritic skin eruption resembling lichen planus and asymptomatic, white patches on his buccal mucosa that began four months after initiating treatment with imatinib mesylate. He had been diagnosed with CML in February 2011 and had begun treatment with 400 mg/day imatinib mesylate shortly thereafter. The skin lesions consisted of erythematous, violaceous papules and plaques dispersed on his forehead, arms, legs (Figure 1b), trunk, and buttocks (Figure 1a), and the oral patches were composed of white streaks resembling Wickham striae, characteristic of lichen planus (Figure 2). The patient’s concurrent medical conditions included hypertension, hyperlipidemia, hypothyroidism, and heart disease. His dermatologic history prior to this case was unremarkable, and he reported no known drug allergies. His past surgical history included coronary-artery bypass surgery, cataract surgery, appendectomy, and hemorrhoidectomy. His additional medications included levothyroxine, metoprolol succinate, isosorbide dinitrate, and simvastatin. A skin biopsy of the right hip was performed. Histopathologic findings revealed a lichenoid pattern, with compact orthokeratosis and thin focal parakeratotic scale with follicular plugging in the stratum corneum (Figure 3a). The epidermis demonstrated irregular acanthosis,

wedge-shaped hypergranulosis, and mild spongiosis with exocytosis of a few lymphocytes and eosinophils. Some individual necrotic keratinocytes were apparent, predominantly localized to the lower levels of the epidermis. The dermis showed a band-like lymphocytic infiltrate with many eosinophils (Figure 3b). A PAS stain demonstrated no evidence of any pathologic fungal organisms in the stratum corneum. A diagnosis of lichenoid drug eruption secondary to imatinib was suspected.Due to the patient’s treatment preference, he was instructed to apply clobetasol propionate cream 0.05% to affected areas on the skin twice daily as needed and triamcinolone 0.1% in dental paste to lesions inside the mouth twice per day. The cutaneous lichenoid eruption worsened (Figure 4) despite the topical steroids and, five months later, had spread extensively across the scalp with the appearance of a lichen planopilaris-like eruption with areas of cicatricial alopecia (Figure 5). The treatment was altered to oral prednisone, and the lesions improved.

DiscussionImatinib mesylate is a tyrosine-kinase inhibitor that was designed to target the platelet-derived growth factor receptor (PDGF). It was determined to also inhibit BCR-ABL, the fusion protein resulting from the Philadelphia chromosome implicated in chronic myelogenous leukemia, as well as c-kit (CD117), which is overexpressed in gastrointestinal stromal tumors.3 In addition, imatinib mesylate has been approved

for the treatment of dermatofibrosarcoma protuberans, aggressive systemic mastocytosis, hypereosinophilic syndrome, and refractory Philadelphia-chromosome-positive acute lymphocytic leukemia.1

Adverse reactions to imatinib are commonly mild and include nausea, muscle cramps, myalgia, edema, and skin reaction, with serious non-hematological reactions occurring in less than 10% of patients.2 Various skin eruptions secondary to imatinib have been described including, but not limited to, Stevens-Johnson syndrome, pityriasis rosea-like eruption, mycosis fungoides-like reaction, Sweet syndrome, purpuric vasculitis, follicular mucinosis, and lichenoid eruption.4-10 Cutaneous reactions to imatinib have been reported in 9.5 percent to 69 percent of patients.11 Although some skin eruptions related to imatinib use are serious, lichenoid eruptions are often self-limiting and resolve with continued use or concomitant oral steroid or acitretin therapy. 3,12

Clinical manifestations of lichenoid eruptions are heterogenous and include cutaneous lupus erythematosus and lichen planus. The pathogenesis of lichenoid reactions involves damage to the epidermal basal-cell layer with subsequent sub-epithelial inflammatory infiltrate.13 Histopathology in the epidermis characteristically shows degeneration of basal

cells, maintenance or proliferation of the granular layer, orthokeratosis, and damage to melanocytes. The dermis typically displays a

Figure 2. Lichenoid lesion on buccal mucosa with Wickham striae.Figure 1. Lichenoid eruption on the buttock (a) and leg (b).

AbstractImatinib mesylate is a tyrosine-kinase inhibitor approved as the first-line therapy for chronic myelogenous leukemia and gastrointestinal stromal tumor (GIST). It is also used in the treatment of dermatofibrosarcoma protuberans, hypereosinophilic syndrome, aggressive systemic mastocytosis, and refractory Philadelphia-chromosome-positive acute lymphocytic leukemia.1 Therapy with imatinib is generally well-tolerated, with common adverse effects including nausea, myalgia, edema, and skin reactions.2 Skin eruption due to imatinib mesylate is common, and several types of skin reactions to imatinib have been previously reported. We report a case of a 78-year-old man who presented with lichen planus-like lesions on his arms, legs, and trunk secondary to the use of imatinib mesylate for chronic myeloid leukemia and review the literature on lichenoid drug eruption secondary to imatinib therapy.

lymphocytic infiltrate along with invasion of the lower epidermal layers, capillary propagation, and involvement of histiocytes in production of pigmented macrophages.14 Common causes of lichenoid eruption include medications such as anti-inflammatories, antihypertensive agents, antimalarials, tetracyclines, thiazide diuretics, and many others.15 Numerous lichenoid drug eruptions secondary to imatinib mesylate therapy have been previously described, but only several have described oral and cutaneous lesions occurring simultaneously.11,12,16-18 In addition, one of these cases occurred during the treatment of GIST rather than CML.11 Other cases of lichenoid drug eruption that have been described were observed two or three months after initiation of treatment with imatinib.12,16,18 However, in our particular case, the lichenoid drug eruption did not present until four months after the onset of imatinib therapy. One of the previously described simultaneous oral and cutaneous eruptions resolved after treatment with acitretin 25mg, but the others are similar to our case in that they

resolved after treatment with oral prednisone in combination with topical steroids.12,16 However, our case is different in that the eruption also involved a lichen planopilaris-like component. To our knowledge, this is the first reported case of lichenoid drug eruption secondary to imatinib mesylate that manifested with cutaneous and oral lesions as well as a lichen planopilaris-like eruption.

ConclusionIn summary, imatinib mesylate is an essential drug for treating CML and numerous other disorders. Although it is generally well-tolerated, skin

reactions are common. Such reactions are often self-limiting and resolve with continued use or with concomitant oral steroid or acitretin therapy, but it is nonetheless important for dermatologists to recognize such reactions due to the importance of continuation of imatinib mesylate in the treatment of CML and other diseases.

references1 Heidary N, Naik H, Burgin S. Chemotherapeutic agents and the skin: an update. J Am Acad Dermatol. 2008;58:545-5702 Druker BJ, Sawyers CL, Kantarjian H, et al. Activity of a specific inhibitor of the BCR-ABL tyrosine kinase in the blast crisis of chronic myeloid leukemia and acute lymphoblastic leukemia with the Philadelphia chromosome. N Engl J Med. 2001;344:1038-1042 3 Savage DG, Antman KH. Imatinib mesylate – a new oral targeted therapy. N Engl J Med. 2002;346:683-93 4 Hsiao LT, Chung HM, Lin JT, et al. Stevens-Johnson syndrome after treatment with STI571: a case report. Br J Haematol. 2002;117:620-6225 Brazzelli V, Prestinari F, Roveda E, et al. Pityriasis rosea-like eruption during treatment with imatinib mesylate: description of 3 cases. J Am Acad Dermatol. 2005;53:S240-S2436 Clark SH, Duvic M, Prieto VG. Mycosis fungoides-like reaction in a patient treated with Gleevec. J Cutan Pathol. 2003;30:279-281

7 Ayirookuzhi SJ, Ma L, Ramshesh P, Mills G. Imatinib-induced Sweet syndrome in a patient with chronic myeloid leukemia. Arch Dermatol. 2005;141:368-3708 Hamm M, Touraud JP, Mannone L, et al. Imatinib-induced purpuric vasculitis. Ann Dermatol Venereol. 2003;130:765-7679 Yanagi T, Sawamura D, Shimizu H. Follicular mucinosis associated with imatinib (STI571). Br J Dermatol. 2004;151:1276-127810 Guilhot F. Indications for imatinib mesylate therapy and clinical management. The Oncologist. 2004;9:271-28111 Sendagorta E, Herranz P, Feito M, et al. Lichenoid drug eruption related to imatinib: report of a new case and review of the literature. Clin Exp Dermatol. 2009:1812 Dalmau J, Peramiquel L, Puig L, et al. Imatinib-associated lichenoid eruption: acitretin treatment allows maintained antineoplastic effect. Br J Dermatol. 2006;154:1213-121613 Meller, S, Gilliet M, Homey B. Chemokines in the pathogenesis of lichenoid tissue reactions. Journal of Investigative Dermatology. 2009;129:315-31914 Pinkus H. Lichenoid tissue reactions: a speculative review of the clinical spectrum of epidermal basal cell damage with special reference to erythema dyschromicum perstans. Arch Dermatol. 1973;107(6):840-84615 Scully C, Bagan JV. Adverse drug reactions in the orofacial region. CROBM. 2004;15:221-23916 Pascual, JC, Matarredona J, Miralles J, et al. Oral and cutaneous lichenoid reaction secondary to imatinib: report of two cases. Int J Dermatol. 2006;45:1471-147317 Wahiduzzaman M, Pubalan M. Oral and cutaneous lichenoid reaction with nail changes secondary to imatinib: report of a case and literature review. Dermatol Online. J 2008;15:1418 Kuraishi N, Nagai Y, Hasegawa M, Ishikawa O. Lichenoid drug eruption with palmoplantar hyperkeratosis due to imatinib mesylate: a case report and a review of the literature. Acta Derm Venereol. 2010;90:73-76 Correspondence: Kristen Suchniak, BS, The Commonwealth Medical College, 525 Pine St., Scranton, PA, 18509. Phone: (570) 504-7000. Fax: (570) 504-9660. E-mail: ksuchniak@tcmedc.org.

Figure 3. Histopathology showing a lichenoid pattern with compact orthokeratosis and thin focal parakeratotic scale with follicular plugging in the stratum corneum. Left (a): H&E, original magnification x40.Right (b): Band-like lymphocytic infiltrate with many eosinophils in the dermis, H&E, original magnification x10.

Figure 4. Progressed lichenoid reaction on buttock and leg five weeks after initial presentation.

Figure 5. Lichen planopilaris-like eruption with areas of cicatricial alopecia on the scalp.

page 34 oral anD cutaneous lichenoiD Drug eruption seconDary to imatiniB mesylate: a case report anD review of the literature

Dercum’s Disease Treated by Coolsculpting: A Case Report

Jonathan S. Crane, DO, FAOCD,* J. Kate Jackson, PA-C,** Louis I. Padgett, BS***

*Dermatologist, Atlantic Dermatology Associates, Wilmington, NC; Dermatology professor, Campbell University School of Osteopathic Medicine, Buies Creek, NC**Dermatology physician assistant, Atlantic Dermatology Associates, Wilmington, NC***Medical student, 4th year, University of Pikeville- Kentucky College of Osteopathic Medicine, Pikeville, Kentucky

IntroductionDercum’s disease is a rare disorder that was first described in medical literature in 1882 by a neurologist by the name of Francis Xavier Dercum.1 Dercum’s disease, also known as adiposis dorsa, is characterized by the formation of multiple painful lipomas and generalized obesity.1,2 The lipomas are typically found on the trunk and extremities, and the pain can range from mild to severe. Dercum’s disease has a strong female predominance, affecting females 30 times more commonly than males, and a typical initial presentation between the ages of 45 and 60.1 Dercum’s disease is believed to be inherited as an autosomal-dominant trait; however, many cases occur sporadically.3,4 Although many theories have been proposed, the exact pathophysiology of Dercum’s disease remains unknown.5 Associated manifestations in Dercum’s disease include: generalized weakness, fatigue, emotional instability, depression, confusion and dementia.2,5 Treatment has been challenging and mainly relies on weight loss and surgical intervention. Here we present a case of a patient with Dercum’s disease that was successfully treated using the Coolsculpting procedure. To date, there have been no reports in literature of Dercum’s disease being treated by Coolsculpting. We propose the Coolsculpting procedure as a new, non-invasive treatment approach in patients with Dercum’s disease.

Case reportAn 80-year-old white female with a medical history of Dercum’s disease, stroke, seizures, diabetes, hypertension, hypercholesterolemia, and atrial fibrillation presented to our office complaining of painful lipomas on her abdomen. The patient described her pain as severe and said that these particular lesions on her abdomen had been growing for 13 years. Her painful lipomas had been treated medically by various analgesics without relief. Her lipomas were also treated surgically by excision; however, the patient developed significant post-operative bleeding complications. On two different occasions she had a 15 cm lipoma removed from her abdomen and a 13 cm lipoma removed from her flank. The pathology report from both of the excised lesions

was consistent with lipomas. The patient had post-operative bleeding that continued for over a month, causing her hemoglobin to drop down to 6g/dL, requiring blood transfusions. The patient was in a difficult position, as the lipomas were extremely painful and she had developed more of them, but she was afraid to undergo surgical excision due to the severe bleeding complications she had experienced in the past.

We decided to treat the patient’s abdominal lipomas using Coolsculpting. Three lipomas were noted in the 8 cm to 10 cm range along her upper abdomen. A large (8.0) applicator was applied to the upper abdomen and pulled the large lipomas into a vacuum applicator. The applicator draw was 10 mm above the standard silver bar, and the areas were treated with cooling for 60 minutes at suction settings of 65/80/65. Suction was then turned off, and the applicator was removed. After the procedure was completed, a five-minute massage was performed on the treated area.

At the two-month follow-up appointment, the patient reported that she had minimal discomfort during the procedure, and within 24 hours following the procedure the patient’s abdominal pain had completely resolved. The painful lipomas were completely resolved within 24 hours and remained so at the two-month follow-up. The patient was ecstatic and felt as if this was a life-changing event.

DiscussionDercum’s disease is a rare disorder comprised of multiple painful lipomas on the trunk and extremities. It is commonly associated with generalized obesity, weakness, fatigue, and emotional instability.5 The typical patient is an obese, postmenopausal female between the ages of 40 and 60. The pain may vary in severity and quality and is often out of proportion to physical findings. The etiology of Dercum’s disease is poorly understood, and a number of theories have been suggested. The pain associated with the lipomas is postulated to arise from mechanical pressure on nerves by growing lipomas.6 Other theories suggest endocrine abnormalities and adipose tissue dysfunction as the cause of these painful

lipomas.7,8 Having an unclear pathophysiology has made the treatment of Dercum’s disease very challenging. Current therapeutic options in the treatment of Dercum’s disease focus on symptomatic control and may be either medical or surgical. Medical therapy consists of a variety of agents including analgesics, IV and transdermal lidocaine, and corticosteroids.5,9,10 Current surgical options are invasive and include liposuction and lipoma resection. Liposuction provides some pain reduction; however, the minimal improvement level does not provide clear indication to warrant the operation and its associated risks.11 There have been no reports of laser liposuction as a treatment method. Lipoma excision is an effective surgical treatment in many individuals; however, our patient experienced significant post-operative bleeding complications with prior lipoma excisions.Coolsculpting is a non-invasive procedure that uses cryolipolysis technology to cool adipose tissue to induce lipolysis without damaging surrounding tissue. A cooling applicator is applied to the desired treatment area, and the vacuum pressure draws the tissue between the applicator cooling panels. The tissue is cooled for 60 minutes, and during this time the exposure to cooling causes fat-cell apoptosis. Inflammatory cells gradually digest the affected fat cells in the months following the procedure. Side effects are minimal and include transient discomfort, swelling, bruising and decreased sensation over the treated area. Coolsculpting technology has traditionally been used for fat reduction, but in our case we were able to use it to successfully treat painful abdominal lipomas in a patient with Dercum’s disease.12

ConclusionDercum’s disease (adiposis dolorosa) is a rare condition for which there has been no truly successful treatment to date. In this particular patient, excision was life-threatening, as it had previously resulted in prolonged bleeding post-operatively. We report the first case in which Coolsculpting has been used to treat Dercum’s disease.

AbstractDercum’s disease is a condition that involves slowly forming, painful lipomas. This pain can range in severity and is often disproportionate to what would normally be expected. The reason for the painful lipomas is unknown. To our knowledge, this case is the first time in which Dercum’s disease has been treated by Coolsculpting. We had an extremely successful outcome; the patient’s pain was completely resolved within 24 hours.

crane, Jackson, paDgett page 35

page 36 the companion: a Desmoplastic trichoepithelioma arising within a melanocystic nevus

references1. Dercum FX. Three cases of a hitherto unclassified affection resembling in its grosser aspects obesity, but associated with special symptoms: adiposis dolorosa. Am J Med Sci. 1892;104:521-35.

2. Hansson E, Svensson H, Brorson H. Depression in Dercum’s disease and in obesity: A case control study. BMC Psychiatry. 2012 Jul 3;12:74-74.

3. Lynch HTH, Harlan WLW. Hereditary factors in adiposis dolorosa (Dercum’s disease). Am J Hum Genet. 1963 Jun;15(2):184-190.

4. Cantu JM, Ruiz-Barquin E, Jimenez M, Castillo L, Macotela-Ruiz E. Autosomal dominant inheritance in adiposis dolorosa (Dercum’s disease). Humangenetik. 1973;18(1):89-91.

5. Hansson E, Svensson H, Brorson H. Review of Dercum’s disease and proposal of diagnostic criteria, diagnostic methods, classification and management. Orphanet J Rare Dis. 2012 Apr 30;7:23-23.

6. Mella BA. Adiposis dolorosa. J Univ Mich Med Cent. 1967 Mar-Apr; 33(2):79-81.

7. Dercum FX, McCarthy DJ. Autopsy in case of adiposis dolorsa. Am J Med Sci. 1902;124:994-1007.

8. Blomstrand R, Juhlin L, Nordenstam R, Ohlsson B, Engstrom J. Adiposis dolorosa associated with defects in lipid metabolism. Acta Derm Venereol. 1971;51(4):243-50.

9. Iwane T, Maruyama M, Matsuki M, Ito Y, Shimoji K. Management of intractable pain in adiposis dolorosa with intravenous administration of lidocaine. Anesth Analg. 1976 Mar-Apr;55(2):257-9.

10. Desai MJ, Siriki R, Wang D. Treatment of pain in Dercum’s disease with Lidoderm (lidocaine 5% patch): a case report. Pain Med. 2008 Nov;9(8):1224-6.

11. Hansson E, Manjer J, Svensson H, Brorson H. Quality-of-life in patients with Dercum’s disease: before and after liposuction. J Plast Surg Hand Surg. 2012 Sept;46(3-4):252-256.

12. Nelson A, Wasserman D, Avram M. Cryolipolysis for reduction of excess adipose tissue. Semin Cutan Med Surg. 2009 Dec;28(4):244-249.

Correspondence: Jonathan S. Crane, DO, Atlantic Dermatology Associates, PA,  1099 Medical Center Drive, Wilmington, NC, 28401. Phone: (910) 251-9944. E-mail: 1104@bizec.rr.com.

The Companion: A Desmoplastic Trichoepithelioma Arising within a Melanocytic Nevus

Peter Knabel, DO,* Lloyd Cleaver, DO, FAOCD**

*Dermatology Resident, 3rd year, Northeast Regional Medical Center/ATSU, Kirksville, Missouri**Program Director, Northeast Regional Medical Center/ATSU, Kirksville, Missouri

Case reportA 51-year-old Caucasian female presented by referral from her primary care physician for evaluation of a lesion on the right cheek. The patient stated that the lesion had been present for approximately 10 years and denied any significant change in pigmentation. She noted that the lesion had slightly increased in size within the last year but denied any pain, bleeding, erosions, or ulcerations. The patient denied any previous history of nonmelanoma skin cancer.

On physical examination, a 0.8 cm x 0.7 cm, annular, flesh-colored papule with a central depression and brown pigmentation was noted on the right cheek, just superior to the nasolabial fold (Figure 1). Telangiectasia without evidence of arborizing vessels was noted. A punch biopsy of the lesion was performed due to the central dyspigmentation and history of change in size. The lesion was submitted for histological examination, and the differential diagnosis included pigmented basal-cell carcinoma, melanocytic nevus, sebaceous hyperplasia, and adnexal neoplasm.

Hematoxylin and eosin sections showed nests of nevomelanocytes with no significant atypia. Deep to the nevus cells, irregular basaloid epithelial nests and cords were found within a fibrous

stroma (Figure 2). Suggestions of a connection with the epidermis were present as well as areas of calcification. The deep and lateral margins were involved, and no peripheral palisading or artifactual retraction was appreciated. The presence of the desmoplastic epithelial proliferation and nevomelanocytes likely represented a desmoplastic trichoepithelioma (DTE) arising within a melanocytic nevus, but the possibility of a basal-cell carcinoma (BCC) variant or, less likely, microcystic adnexal carcinoma could not be excluded. Due to this uncertainty, further surgical therapy was recommended.

The patient was scheduled for Mohs micrographic surgery due to the location of the lesion and the desire for tissue sparing and complete margin control. The DTE in association with

Figure 1

Figure 2

knaBel, cleaver page 37

a melanocytic nevus was cleared in two stages, and the defect was closed primarily, hiding it within the nasolabial fold. The patient has been followed routinely with no signs of recurrence for 20 months.

DiscussionDesmoplastic trichoepithelioma (DTE) has been described in the literature under several different names: Zeligman’s “solitary trichoepithelioma” in 1960, MacDonald and College’s “sclerosing epithelial hamartoma” in 1977, and in the same year Brownstein and Shapiro described an identical tumor.1,2,3 Brownstein and Shapiro noted a triad of microscopic findings consisting of narrow strands of basaloid tumor cells, keratinous cysts, and desmoplastic stroma.3 Due to its unique histologic features, Brownstein and Shapiro believed it was a distinct entity, different from trichoepitheliomas, syringomas, microcystic adnexal carcinoma, and morpheaform basal-cell carcinoma. They gave it the name “desmoplastic trichoepithelioma,” by which it is known today. Desmoplastic trichoepithelioma arising within a melanocytic nevus has been described in the literature but is probably under-reported. Frequently, these types of lesions are described as collision tumors.

Distinguishing between BCC and DTE can prove very difficult due to similar histologic features. This can be made even more difficult when only a portion of the lesion is available for interpretation. Punch biopsies and superficial shave biopsies at times provide only a small portion of the lesion, making it difficult to assess overall architecture, symmetry, and depth. Studies have evaluated the histologic and immunohistochemical differences between BCC and DTE to help aid in a more accurate diagnosis. DTE tends to be well-circumscribed and symmetric with a central depression, with narrow strands and nests and no ulceration.4 Follicular differentiation, horn cysts, epidermal hyperplasia, keratin granules, and calcification are frequently present.5 Morpheaform BCC tends to be asymmetric, have a connection to the surface epithelium with larger aggregations of cells, and lack a central depression. Frequently, ulceration can be appreciated.4,5 Basal-cell carcinoma demonstrates peripheral palisading and retraction artifact that is not present in DTE.5

Immunohistochemical markers are often sought to help identify or discriminate one diagnosis from another. Multiple stains have been evaluated (CD34, CD10, CK20, androgen receptor, Bcl-2, Ki-67, and p53) to identify if one could accurately and repeatedly differentiate between a DTE and morpheaform BCC. CK20 was found to stain the Merkel cells within the epithelial strands of a DTE and not those of morpheaform BCC; morpheaform BCC stained

for androgen receptors, and DTE did not.4 Fibroblast-activation protein has been reported to aid in the distinction via expression in the peritumoral stromal fibroblasts of morpheaform BCC and not those of DTE.6 The stain p75 neurotrophin receptor (p75NTR) has been shown to stain DTE and be non-immunoreactive in morpheaform BCC.7 It appears that there is no universal agreement on which one stain will correctly and consistently distinguish between DTE and morpheaform BCC. The overall clinical picture and histologic features need to be taken into consideration when interpreting the results of any stain.

Clinically, a typical DTE presents as an annular, firm, flesh-colored to yellow papule with a depressed center and raised periphery.3,8 It favors the face, occurring most commonly on the cheek of young to middle-aged females.3 This description and location fits the clinical presentation of the lesion we biopsied, though the addition of the central pigmentation in our case makes it unique from a typical DTE. In a study by Takei et al. differentiating between DTE and morpheaform BCC, 70% of the patients with DTE were female, ranging in age from 15 to 79. In that study, 45.8% were located on the cheek, with the nose, forehead, chin, lip, and eyelid being the next most common sites.5 The lesions are often asymptomatic and may slowly enlarge over time. Due to the location and appearance of these lesions, basal-cell carcinoma (BCC) and microcystic adnexal carcinoma are commonly in the differential diagnosis. In one study, BCC was listed as the main differential diagnosis in 41% of the biopsy reports.8 Because of the clinical and histologic appearance of DTE, they are often treated with complete surgical removal by electrodessication and curettage, wide excision, or with a more tissue-sparing technique such as Mohs micrographic surgery.

DTEs have been described to arise within other lesions. In our case, the patient presented with a slowly enlarging pigmented lesion, which was shown to be a benign melanocytic nevus within a surrounding DTE. Morpheaform BCC has not been known to commonly arise within melanocytic nevi.5 It has been proposed that melanocytic nevi, through production of cytokines or growth factors, are responsible for this epithelial proliferation (DTE) that arises within a previously existing nevus.5

Taking into consideration these previously described features of basal-cell carcinoma and desmoplastic trichoepithelioma will help allow for better distinction between these two similar entities. One should also keep in mind the under-reported association with previously existing melanocytic nevi. This association occurs in approximately 10% of DTE and can be a

friendly companion for the pathologist to aid in distinguishing this benign cutaneous neoplasm from a malignant neoplasm with comparable clinical and histologic features.5,9,10 Often, only portions of lesions are available for interpretation by the pathologist, but noting this association may help to prevent unwanted or unnecessary treatment. We as clinicians need to examine all the clinical and histologic information available. This allows us to provide our patients with the best recommendations so they can make a truly informed decision for their care.

references1. Zeligman I. Solitary trichoepithelioma. Arch Derm. 1960;82:89-94

2. MacDonald DM, Jones EW, Marks R. Sclerosing epithelial hamartoma. Clin Exp Dermatol. 1977;2:153-160.

3. Brownstein M, Shapiro L. Desmoplastic trichoepithelioma. Cancer. 1977;40:2979-86.

4. Costache M, Bresch M, Boer A. Desmoplastic trichoepithelioma versus morphoeic basal cell carcinoma: a critical reappraisal of histomorphological and immunohistochemical criteria for differentiation. Histopathology. 2008;52:865-876.

5. Takei Y, Fukushiro S, Ackerman BA. Criteria for histologic differentiation of desmoplastic trichoepithelioma (sclerosing epithelial hamaratoma) from morphea-like basal-cell carcinoma. Am J Dermatopathol. 1985;7(3):207-221.

6. Abbas O, Richards JE, Mahalingam M. Fibroblast-activation protein: a simple marker that confidently differentiates morpheaform/infiltrative basal cell carcinoma from Desmoplastic trichoepithelioma. Modern Pathol. 2010;23:1535-1543.

7. Krahl D, Sellheyer K. p75 neurotrophin receptor differentiates between morphoeic basal cell carcinoma and desmoplastic trichoepithelioma: Insights into the histogenesis of adnexal tumors based on embryology and hair follicle biology. Br J Dermatol. 2010;163:138-145.

8. Mamelak AJ, Goldberg LH, Katz TM, Graves JJ, Arnan O, Kimyai-Asudi A. Desmoplastic trichoepithelioma. Dermatol Surg. 2010;62:102-106.

9. Niimi Y, Kawana S. Desmoplastic trichoepithelioma: the association with compound nevus and ossification. Eur J Dermatol. 2002;12:90-92.

10. Wang SH, Tsai RY, Chi CC. Familial Desmoplastic Trichoepithelioma. Int J Dermatol. 2006;45:756-758.

Correspondence: Peter Mark Knabel, DO, Northeast Regional Medical Center,  800 W. Jefferson St., Kirksville, MO, 63501. Phone: 866.626.2878. E-mail: pknabel@atsu.edu.

page 38 at ypical aDult-onset pit yriasis ruBra pilaris anD recurrent corneal ulcerations

Atypical Adult-onset Pityriasis Rubra Pilaris and Recurrent Corneal Ulcerations

Natalie Edgar, BS,* David Eslicker, DO, FAOCD,** Henry Haskell, MD***

*Medical Student, OMS IV, Oklahoma State University Center for Health Sciences, Tulsa, OK**Dermatologist, Regional Dermatology, Bartlesville, OK***Dermatopathologist, Regional Medical Laboratory, Tulsa, OK

AbstractPityriasis rubra pilaris (PRP) is a rare papulosquamous disorder that may be acquired or inherited. The etiology is unknown, and prognosis depends upon disease type. Atypical adult-onset (type II) PRP is refractory to treatment and typically lasts for more than 20 years. It is characterized by generalized ichthyosiform scaling, follicular keratosis, and eczematous dermatitis. In this case report, we present a 57-year-old Caucasian male with type II PRP and associated recurrent corneal ulcerations.

IntroductionPityriasis rubra pilaris (PRP) is a chronic, idiopathic, papulosquamous disease of the skin. The incidence of PRP is bimodal with peaks in the first and sixth decades of life.1 It affects males and females equally. The majority of cases are acquired, but familial cases have been reported. Autosomal-dominant and autosomal-recessive inheritance patterns have both been documented. Prognosis and management of PRP depend upon disease extent, type, and age of onset. Griffiths Classification divides PRP into six subtypes: classical adult-onset (type I), atypical adult-onset (type II), classic juvenile (type III), circumscribed juvenile (type IV), atypical juvenile (type V), and HIV-associated (type VI).2-5 Piamphongsant and Akaraphant also proposed a classification system for PRP, but Griffiths Classification is more widely used.5

The etiology of PRP is unknown, though several mechanisms have been postulated. Abnormal vitamin A metabolism, including vitamin A deficiency and low retinol-binding protein levels, have been proposed as possible causes for acquired PRP. Synthetic vitamin A medications, like isotretinoin and acitretin, are used in lieu of high-dose vitamin A to avoid toxicity.1,4,6 Increased cellular p53 expression has also been suggested as a cause of PRP.1,7 Baran et al. reported elevated levels of P53 protein in lesional skin of those with PRP as compared to unaffected controls, suggesting a cell-cycle disturbance in PRP epidermis.7 P53 is elevated in other inflammatory skin conditions including psoriasis, lichen planus, and lupus erythematosus. P53, a phosphoprotein, protects from tumorogenesis by arresting the cell cycle and allowing for DNA repair. Mutations in genes encoding the p53 protein have been found in greater than half of all human tumor types.7,8 Interestingly, PRP has been associated with malignancies including leukemia, cutaneous squamous cell carcinoma, Merkel-cell carcinoma, bronchogenic carcinoma, hepatocellular carcinoma, and adenocarcinoma of the lung.1,9 Another suspected etiology of PRP is an alteration in the normal immune response, namely autoimmunity and superantigen response.1,4,10,11 PRP has been associated with rheumatoid arthritis, seronegative arthritis, and dermatomyositis.1,6,11,12 Superantigen immune

dysregulation of Th1-related cytokines, primarily TNF-alpha, may also be involved in PRP pathogenesis.1,4,10,14,15 The disease mechanism of PRP remains unclear, but abnormal vitamin A metabolism, increased cellular expression of p53, and immune dysregulation may be implicated. Differentiating between classic (type I) and atypical (type II) adult-onset PRP is based upon clinical presentation and disease course. Histopathologically, they are identical and are characterized by acantholysis, increased granular cell layer, follicular plugging, and absence of epidermal neutrophilic abscesses.11,15-17 Clinically, atypical adult-onset PRP (type II) has annular erythematous patches 0.5 cm to 1.5 cm in diameter with lamenant scale, follicular keratosis, eczematous dermatitis, ichthyosiform scaling on extremities, and alopecia.1,6,14 Unlike classic adult-onset PRP (type I), type II PRP is chronic and lacks the classic cephalocaudal progression and erythroderma with “islands of sparing” presentation. Nail involvement including nail thickening, yellow-brown discoloration, and splinter hemorrhages may also be present.2 Type II PRP accounts for about 5% of cases and has a chronic course, generally lasting for more than 20 years.1

Case reportA 57-year-old Caucasian male presented seven years ago with complaints of a scaly, salmon-colored rash that was present on sun-exposed areas, namely the arms, face, and scalp (Figure 1). The patient also had some involvement of the trunk and body folds. Initially, the rash would wane each winter and reappear during the summer months. After three years of waxing and waning with the seasons, it no longer disappeared during the winter. The patient experienced occasional pruritis and had nail involvement including longitudinal ridges, beading, and splinter hemorrhages (Figure 2). Consent was obtained, and a biopsy was taken. The histology was consistent with a diagnosis of PRP, showing psoriasiform acanthosis of the epidermis with a hyperkeratotic scale, mild dermal perivascular lymphohistiocytic inflammation (Figure 3), and small foci of parakeratosis with a subtle “checkerboard” pattern of horizontal and vertical alternation (Figure 4). The patient was diagnosed with atypical adult-onset (type II) PRP based upon the disease duration, localized disease distribution, lack of erythroderma with “islands of sparing,” and the absence of waxy palms and soles. Over several years, the patient failed treatment with broad-spectrum sunscreens, topical steroids, topical tazarotene, topical pimecrolimus, topical calcitriol, and narrow-band UVB.During a follow-up appointment, the patient

Figure 1

eDgar, eslicker, haskell page 39

reported seeing an ophthalmologist for eye symptoms that had developed two months prior to this appointment. The patient reported symptoms of dry eye, tearing, foreign body sensation, and a tearing sensation upon opening his eyes first thing in the morning. The eye discomfort worsened with sunshine and improved with lubrication. The patient denied history of trauma and did not have an ectropion on exam. The diagnosis of culture-negative corneal erosion was made by the ophthalmologist, and the patient was prescribed 5% hypertonic saline drops to instill in his eyes four times daily and 5% hypertonic saline ointment to use every evening. Despite compliance with treatment, the patient still had corneal erosions six weeks following the original ocular diagnosis. Considering the patient’s history of refractory type II PRP, we considered that PRP was causing his corneal erosions. The patient was placed on methotrexate 20 mg per week for 12 weeks. Unfortunately, he failed to show improvement and continues to experience corneal erosions on a weekly basis for the last 10 months.

DiscussionUpon review of the literature, there were very few reports of PRP and corneal complications. Paranjothy et al. reported a case of culture-negative corneal ulceration and perforation following minor corneal trauma.18 A PRP flare-up occurred directly following ulcerative keratitis at the graft-host junction of her tectonic keratoplasty. The ulcer healed with systemic infliximab treatment for concurrent PRP flare-up. Kitzmann et al. reported a case of bilateral HSV keratitis with unilateral polybacterial keratitis that progressed rapidly to stromal perforation in a patient with classic adult-onset PRP (type I).19 The patient had significant improvement following a penetrating keratoplasty, oral acyclovir, topical antibiotics, and continued PRP treatment with methotrexate and prednisone. PRP, especially the atypical adult-onset type, is often resistant to topical and systemic therapies. There are no randomized, controlled trials in the literature assessing treatment options for PRP, only case reports and case series. Systemic retinoids, like isotretinoin or acitretin, seem to be the most effective therapeutic agents to date.1,4,12,13 Our patient was not a candidate for a systemic retinoid, however, because of his ocular involvement. Xerophthalmia, caused by a systemic retinoid, could worsen his corneal erosions. Recently, TNF-alpha antagonists

(adalimumab, infliximab, or etanercept) have been used to successfully treat PRP.1,12,15 Our patient raises pigeons and is not a candidate for TNF-alpha inhibitors due to his increased risk for histoplasmosis infection. Kerr et al. reported a case of type II PRP that was substantially improved with monthly IVIg infusions, though this treatment may be cost prohibitive.20 Ocular involvement, lifestyle factors, and cost may limit therapeutic options in patients with PRP.

ConclusionClinicians should be aware that ocular involvement is possible with various types of PRP and must be considered when choosing a treatment plan. To the best of our knowledge, we are reporting the first case of recurrent corneal ulcerations in a patient with atypical adult-onset (type II) PRP.

references1. Klein A, Landthaler M, Karrer S. Pityriasis Rubra Pilaris: A Review of Diagnosis and Treatment. Am J Clin Dermatol 2010;11(3):157-170.

2. Habif TP. Clinical Dermatology: A Color Guide to Diagnosis and Therapy. 5th ed. Mosby Elsevier Inc.; c2010. Chapter 8, Pityriasis Rubra Pilaris; p. 309-11.

3. Sehgal VN, Srivastava G, Dogra S. Adult Onset Pityriasis Rubra Pilaris. Indian J Dermatol Venereol Leprol 2008;74:311-21.

4. Gemmeke A, Schonlebe J, Koch A, Wollina U. Pityriasis Rubra Pilaris - a Retrospective Single Center Analysis Over Eight Years. J Dtsch Dermatol Ges 2010;8:439-444.

5. Piamphongsant T, Akaraphant R. Pityriasis Rubra Pilaris: a New Proposed Classification. Clin Exp Dermatol 1994;19:134-138.

6. Chan H, Liu FT, Naguwa S. A Review of Pityriasis Rubra Pilaris and Rheumatologic Associations. Clin Dev Immunol 2004;11(1):57-60.

7. Baran W, Szepietowski JC, Szybejko-Machaj G. Enhanced Expression of p53 Protein in Pityriasis Rubra Pilaris. Acta Derm Venereol 2006;86(3):276-277.

8. Harris CC, Hollstein M. Clinical implications of the p53 tumor-suppressor gene. N Engl J Med 1993;329:1318–1327.

9. Garretson CB, Machan ML, Krejci-Manwaring J, Aires D, Tonkovic-Capin V. Letter: Adenocarcinoma of the Lung Associated with Pityriasis Rubra Pilaris. Dermatol Online J 17(11):14.

10. Sehgal VN, Srivastava G, Verma P. Pityriasis Rubra Pilaris: Evolution of Challenges in Promising Treatment Options. Skin Med 2012;10:18-23.

11. Magro CM, Crowson AN. The Clinical and Histomorphological Features of Pityriasis Rubra Pilaris. J Cut Pathol 1997;24:416-424.

12. Kim JH, Park M, Kim S. Etanercept-induced Clinical Remission of Type II Pityriasis Rubra Pilaris with Rheumatoid Arthritis. Acta Derm Venereol 2012;92(4):399-400.

13. Ahn S, Kim J, Ahn SK, Oh YS. Clinical Improvement of Pityriasis Rubra Pilaris with Antibiotic Therapy. Eur J Dermatol 2011;21(1):106-107.

14. Garcovich S, Di Giampetruzzi AR, Antonelli G, Garcovich A, Didona B. Treatment of Refractory Adult-onset Pityriasis Rubra Pilaris with TNF-alpha Antagonists: A Case Series. J Eur Acad Dermatol Venereol 2010;24:881-884.

15. Wassef C, Lombardi A, Rao BK. Adalimumab for the Treatment of Pityriasis Rubra Pilaris: A Case Report. Cutis 2012;90:244-247.

16. Ko CJ, Milstone LM, Choi J, McNiff JM. Pityriasis Rubra Pilaris: the Clinical Context of Acantholysis and Other Histologic Features. Int J Dermatol 2011;50:1480-1485.

17. Leger M, Newlove T, Robinson M, Patel R, Meehan S, Ramachandran S. Pityriasis Rubra Pilaris. Dermatol Online J 2012;18(12):14.

18. Paranjothy B, Shunmugam M, MacKenzie J, Azuara-Blanco A. Peripheral Ulcerative Keratitis in Pityriasis Rubra Pilaris. Eye 2007;21:1001-1002.

19. Kitzmann AS, Goins KM, Syed NA, Wagoner MD. Bilateral Herpes Simplex Keratitis with Unilateral Secondary Bacterial Keratitis and Corneal Perforation in a Patient with Pityriasis Rubra Pilaris. Cornea 2008;27(10):1212-1214.

20. Kerr AC, Ferguson J. Type II Adult-onset Pityriasis Rubra Pilaris Successfully Treated with Intravenous Immunoglobulin. British Journal of Dermatology 2007;156:1055-1056.

Correspondence: Natalie Edgar, BS, 929 E. 37th Pl., Tulsa, OK, 74205. Phone: (303) 956-7662. E-mail: Natalie.Edgar@okstate.edu.

Figure 3Figure 2

Figure 4

page 40 granular parakeratosis treatment with tacrolimus 0.1% ointment:a case presentation anD Discussion

Granular Parakeratosis Treatment with Tacrolimus 0.1% Ointment:A Case Presentation and Discussion

Bertha Baum, DO,* Stanley Skopit, DO, MSE, FAOCD**

*Dermatology Resident, 1st year, Larkin Community Hospital / Nova Southeastern University College of Osteopathic Medicine, Miami, FL**Program Director, Larkin Community Hospital / Nova Southeastern University College of Osteopathic Medicine, Miami, FL

Case reportA 67-year-old Caucasian female presented to the clinic complaining of a rash on bilateral underarms of two-week duration. The rash was itchy and burning, and the patient history revealed no changes in products like deodorants. The patient denied any drug allergies and had a past medical history of hypothyroidism, breast cancer and hyperhidrosis. Synthroid was the only medication taken at the time of visit, and the hypothyroid condition was stable and under control. Also, the past surgical history revealed a total abdominal hysterectomy, lumpectomy, right knee surgery and sweat-duct removal surgery. A review of systems was otherwise normal.ExaminationOn physical exam, the patient presented with more involvement in the left axillae demonstrating small dark purple papules coalescing into patches and also some scattered satellite lesions. Mild erythema noted in the background. The right axillae although involved, less affected with small scattered purple papules and mild erythema. No lymphadenopathy notes on bilateral cervical,

axillary and inguinal examination. A KOH failed to reveal any signs of a fungal component, also a woods lamp examination showed no fluorescence.

HistopathologyA 3 mm punch biopsy was done at the right lower axillae (per patient location of the most recent lesions) and a rule-out of granular parakeratosis vs. contact dermatitis vs. breast cancer metastasis was sent to the lab. The histology (Figures 3 and 4) showed the classic features of parakeratosis, hypergranulosis, acanthosis and papillomatosis.

Course and treatment The treatment recommended for this case of granular parakeratosis was tacrolimus 0.1%

ointment twice daily for two to four weeks. Figures 5 and 6 show the patient two weeks after treatment was started, revealing almost complete resolution and mild hypopigmentation of the area. The latter resolved one month after (pictures not shown).

DiscussionGranular parakeratosis was first described in 1991 by Northcutt et al. as a benign, erythematous, hyperpigmented and hyperkeratotic disease.1 This uncommon entity may be pruritic but many times presents asymptomatically and without systemic impact. It does, however, represent a diagnostic challenge and must be differentiated. Some suggest that a basic defect exists in the processing of profilaggrin to filaggrin, which maintains the keratohyaline granules in the stratum corneum during cornification.2 Metze and Rutten came to the same conclusion as Northcutt et al., that the retention of keratohyalin granules within the stratum corneum could be due to a defect in filaggrin metabolism.3 Because

Figures 1-2: Clinical evaluation of bilateral axillae at time of suture removal, one week post punch-biopsy and prior to treatment.

Abstract A Caucasian female presented to the office with bilateral axillary plaques. Diagnosed with granular parakeratosis, a rare hyperkeratotic agent, she was successfully treated with tacrolimus 0.1% ointment. A discussion on granular parakeratosis and its different presentations follows.

Figures 3-4: Hematoxylin–eosin staining demonstrates the histopathology with psoriasiform hyperplasia, a thickened stratum corneum with retention of keratohyalin granules, and parakeratosis. Also, a well-developed granular layer is noted. All findings confirm the granular parakeratosis diagnosis.

Figures 5-6: Clinical evaluation of bilateral axillae after treatment with tacrolimus 0.1% ointment for two weeks

Baum, skopit page 41

granular parakeratosis has been associated with excessive use of topical preparations, an occlusive environment, increased sweating, and, sometimes, local irritation, some suggest that it is an allergic contact or irritant reaction.4 Many explanations have been given, but the causative agent remains unknown. Patients should be educated on avoiding occlusive compounds and should avoid excessive washing of axillary areas, groin, or other affected areas.Granular parakeratosis is quite rare, and only case reports have been published, most presenting in women around the 40 to 50 year age range. Most cases present with a one-month to 11-month history of axillary or intertriginous irritations with pruritus.5 There have been reports of patients with lesions in the abdomen, thighs, cheeks and scalp.6 Pediatric cases have also been reported, where the presentation of the lesions was divided into two clinical types: erythematous geometric plaques in diaper pressure sites, and bilateral linear plaques on inguinal folds.6 Granular parakeratosis manifests with intertriginous (e.g., axillary, groin, intermammary or submammary regions and abdominal folds), bilateral or unilateral, brown- or red-crusted patches, papules, or plaques. They can coalesce into larger, well-demarcated plaques with various degrees of maceration secondary to local occlusion. Granular parakeratosis can appear as slightly erythematous and lichenified plaques.8

Several reports have been made of different treatment options like topical steroids and oral and topical retinoids.9 Numerous treatment strategies have been described, with varying results. Among these, corticosteroids, topical retinoids, isotretinoin, botulinum toxin, cryosurgery and, more recently, calcitriol have been proposed as successful treatments.10,11 This case review suggests more studies for the possibility of tacrolimus 0.1% ointment as a treatment agent for granular parakeratosis.

references1. Northcutt AD, et al. Axillary granular parakeratosis. J Am Acad Dermatol. 1991;24:541.

2. Niesmann J, Bierhoff E, Dirschka T. Hyperkeratotic pruritic papules in the submammary area. Diagnose: Granular parakeratosis. J Dtsch Dermatol Ges. 2010 Aug;8(8):631-3.

3. Metze D, Rutten A. Granular parakeratosis-a unique acquired disorder of keratinization. J Cutan Pathol. 1999;26:339.

4. Mehregan DA, et al. Intertriginous granular parakeratosis. J Am Acad Dermatol. 1998;39:495.

5. English JC, et al. Axillary granular parakeratosis. J Cutan Med Surg. 2003;7:330.

6. Wallace CA, et al. Granular parakeratosis: a case report and literature review. J Cutan Pathol. 2003;30:332.

7. Chang MW, Kaufmann JM, Orlow SJ, Cohen DE, Mobini N, Kamino H. Infantile granular parakeratosis: recognition of two clinical patterns. J Am Acad Dermatol. May 2004;50(5 Suppl):S93-6.

8. Scheinfeld NS, Mones J. Granular parakeratosis: pathologic and clinical correlation of 18 cases of granular parakeratosis. J Am Acad Dermatol. 2005

May;52(5):863-7.

9. Webster CG, et al. Axillary granular parakeratosis: response to isotretinoin. J Am Acad Dermatol. 1997;37:789.

10. Brown SK, Heilman ER. Granular parakeratosis: resolution with topical tretinoin. J Am Acad Dermatol. 2002 Nov;47(5 Suppl):S279-80.

11. Contreras ME, Gottfried LC, Bang RH, Palmer CH. Axillary intertriginous granular parakeratosis responsive to topical calcipotriene and ammonium lactate. Int J Dermatol. May 2003;42(5):382-3.

Correspondence: Bertha Baum, DO, Larkin Community Hospital, 7031 S.W. 62nd Ave., South Miami, FL, 33143. Phone: 305-740-3353. E-mail: drberthabaum@yahoo.com.

page 42 hyperpigmentation in a 51-year-olD caucasian female

Hyperpigmentation in a 51-year-old Caucasian Female

William Bethea, DO,* Bryce Desmond, BS,** Steven K. Grekin, DO***

*PGY-III Dermatology Resident, Oakwood Southshore Medical Center, Trenton, MI**MSIV, Touro University Nevada College of Osteopathic Medicine, Henderson, NV ***Dermatology Program Director, Oakwood Southshore Medical Center, Trenton, MI

AbstractMinocycline is an antibiotic often used in acne vulgaris. It is a member of the tetracycline class and has potent bacteriostatic and anti-inflammatory benefits. In addition to a variety of gastrointestinal and neurological side effects, minocycline has been reported to cause blue-brown hyperpigmentation of skin in some patients, notably those who have been taking the drug for an extended period of time. We present a 51-year-old female with a history of intermittent minocycline use for 10 years. She presented to our clinic with multiple blue-brown hyperpigmented patches on the face, gingivae, nails, external auditory canal, and anterior chest. The hyperpigmentation was treated successfully by discontinuation of minocycline.

Case reportHistoryA 51-year-old Caucasian female presented with a two-year history of discoloration on her face. She reported that the skin changes had progressively spread and darkened over the two years. The patient believed the topical retinoid, which she was currently using, was the cause of the color change. Other medication history was significant for intermittent use of oral minocycline for 10 years. At the time of presentation, she was taking minocycline 100 mg three times daily. A review of systems was

negative for any other symptoms.

ExaminationPhysical examination revealed a well-appearing patient with blue-brown hyperpigmented patches localized to the face, gingivae, nails, external auditory canal, and anterior chest ranging in size from 0.5 cm to 1.5 cm (Figures 1-4). The majority of lesions were grouped symmetrically on the eyebrows and forehead bilaterally. The patches were non-tender and asymptomatic. The patient had no other areas involved.

HistopathologyMicroscopic examination revealed solar elastosis with normal-appearing epidermis (Figure 5). The dermis contained scant superficial perivascular lymphoid infiltrate with rare collections of brown pigment. This pigment was visible when stained for melanin with Schmorl’s stain (Figure 6). A Perls stain for iron was negative.

Course and therapyMinocycline was discontinued, and the hyperpigmentation resolved.

DiscussionMinocycline is a broad-spectrum antibiotic belonging to the tetracycline class of antibiotics. It is a highly lipid, soluble, yellow, crystalline material that turns black with oxidation.1 It has bacteriostatic activity along with anti-inflammatory properties that allow its application in a broad range of dermatological diseases, the most common of which is the treatment of acne vulgaris.1

The most commonly reported adverse reactions to this medication include gastrointestinal disturbance, vestibular dysfunction, headache, and photosensitivity reactions.2 Skin hyperpigmentation has also become a commonly reported reaction, with an incidence of 2.4% to 14.8% in some studies.2

While normal metabolism of iron by macrophages leads to storage of ferritin deposits in lysosomes, this process is interrupted during minocycline-induced hyperpigmentation. The pathogenic mechanism of this pigmentation proposes a chelate formation by the iron and minocycline, leading to lysosomal disruption and accumulation of iron in the macrophage. This stable and insoluble complex is resistant to degradation and thus cannot be easily removed, leading to persistence of hemosiderin pigment in the tissue.3

Figure 1

Figure 5

Figure 2

Figure 4Figure 3

Figure 6

Bethea, DesmonD, grekin page 43

Minocycline-induced hyperpigmentation can be classified into three distinct types, though overlap may also occur. Focal hyperpigmentation, or type I, is the most common type and is described as blue-black pigment at sites of inflammation or scarring. Relatively low doses are required for occurrence of the focal type. Diffuse pigmentation requires larger doses (>70 g) for pigmentation to occur and can be divided into type II and type III.4 Type II is characterized by blue-gray pigment on the anterior lower legs and dorsum of the hands and feet. Type III occurs on sun exposed areas and is described as a muddy brown color. This type is widely regarded as a phototoxic reaction, as an increase in melanization causes the pigmentation, as opposed to a chelate as in the other forms.5

Progression of the hyperpigmentation will stop once the patient is no longer taking the drug. Focal pigmentation can be expected to resolve completely after some time. Diffuse pigmentation, however, will improve but is unlikely to completely resolve. Laser treatment of the lesions has been successful in some studies and may be an effective alternative therapy, with resolution occurring within one month for most patients.6 It is paramount that risks of treatment are carefully explained to patients and expectations kept realistic. Careful monitoring of the patient is also essential to achieve the best possible results.

references1. Granstein RD, Sober AJ. Drug and heavy metal-induced hyperpigmentation. J Am Acad Dermatol. 1981;5:1-18.

2. Trentham DE, Dynesius-Grentham RA. Antibiotic therapy for rheumatoid arthritis: scientific and anecdotal appraisals. Rheum Dis Clin North Am. 1995; 828-30.

3. Fenske NA, Millns JL, Greer KE. Minocycline induced pigmentation at sites of cutaneous inflammation. J Am Med Assoc. 1980;244:1103.

4. Goulden V, Glass D, Cunliffe WJ. Safety of long term high-dose minocycline in the treatment of acne. Br J Dermatol. 1996;134:693-5.

5. Simmons JJ, Morales A. Minocycline and generalized cutaneous pigmentation. J Am Acad Dermatol. 1980;3:244-7.

6. Collins P, Cotterill JA. Minocycline-induced pigmentation resolves after treatment with the Q-switched ruby laser. Br J Dermatol. 1996;135:317-9.

Correspondence: Bryce Desmond, BS, 203 Oro Canyon St., Henderson, NV, 89074. Phone: 801-755-4523. E-mail: bryce.desmond@nv.touro.edu.

It’s true. Rosacea is complex and it’s with them for life. Finacea® treats the papules and pustules with associated erythema of mild to moderate rosacea. Although some reduction of erythema which was present in patients with papules and pustules of rosacea occurred in clinical studies, effi cacy for treatment of erythema in rosacea in the absence of papules and pustules has not been evaluated.

You have made Finacea® the #1 Dermatologist-prescribed topical brand.1

INDICATION & USAGEFinacea® (azelaic acid) Gel, 15% is indicated for topical treatment of infl ammatory papules and pustules of mild to moderate rosacea. Although some reduction of erythema which was present in patients with papules and pustules of rosacea occurred in clinical studies, effi cacy for treatment of erythema in rosacea in the absence of papules and pustules has not been evaluated.

IMPORTANT SAFETY INFORMATIONSkin irritation (e.g. pruritus, burning or stinging) may occur during use with Finacea®, usually during the fi rst few weeks of treatment. If sensitivity or severe irritation develops and persists during use with Finacea®, discontinue use and institute appropriate therapy. There have been isolated reports of hypopigmentation after use of azelaic acid. Since azelaic acid has not been well studied in patients with dark complexion, monitor these patients for early signs of hypopigmentation.

Avoid contact with the eyes, mouth, and other mucous membranes. In case of eye exposure, wash eyes with large amounts of water. Wash hands immediately following application of Finacea®. Avoid use of alcoholic cleansers, tinctures and astringents, abrasives and peeling agents. Avoid the use of occlusive dressings or wrappings.

In clinical trials with Finacea®, the most common treatment-related adverse events (AE’s) were: burning/stinging/tingling (29%), pruritus (11%), scaling/dry skin/xerosis (8%) and erythema/irritation (4%). Contact dermatitis, edema and acne were observed at frequencies of 1% or less.

Finacea® is for topical use only. It is not for ophthalmic, oral or intravaginal use. Patients should be reassessed if no improvement is observed upon completing 12 weeks of therapy.

Please see Brief Summary of full Prescribing Information on adjacent page.

You are encouraged to report negative side effects of prescription drugs to the FDA. Visit www.fda.gov/medwatch, or call 1-800-FDA-1088.1. According to IMS NPATM (National Prescription Audit) July 2010-August 2013© 2013 Bayer HealthCare Pharmaceuticals. Bayer, the Bayer Cross and Finacea® are registered trademarks of Bayer. All rights reserved. FIN-10-0001-13b | AUGUST 2013

Rosacea is with her wherever she goes.

So is Finacea®.

Finacea® (azelaic acid) Gel, 15% is a topical prescription medication used to treat infl ammatory papules and pustules of mild to moderate rosacea.

JAOCD8.5 X 11 in

For Dermatologic Use Only–Not for Ophthalmic, Oral, or Intravaginal Use Rx only

BRIEF SUMMARYCONSULT PACKAGE INSERT FOR FULL PRESCRIBING INFORMATION

1 INDICATIONS AND USAGEFINACEA® Gel is indicated for topical treatment of the inflammatory papules and pustules of mild tomoderate rosacea. Although some reduction of erythema which was present in patients with papulesand pustules of rosacea occurred in clinical studies, efficacy for treatment of erythema in rosacea inthe absence of papules and pustules has not been evaluated.

5 WARNINGS AND PRECAUTIONS5.1 Skin ReactionsSkin irritation (i.e. pruritus, burning or stinging) may occur during use of FINACEA Gel, usually duringthe first few weeks of treatment. If sensitivity or severe irritation develops and persists, discontinuetreatment and institute appropriate therapy. There have been isolated reports of hypopigmentation after use of azelaic acid. Since azelaic acid hasnot been well studied in patients with dark complexion, monitor these patients for early signs ofhypopigmentation.

5.2 Eye and Mucous Membranes IrritationAvoid contact with the eyes, mouth and other mucous membranes. If FINACEA Gel does come incontact with the eyes, wash the eyes with large amounts of water and consult a physician if eyeirritation persists [see Adverse Reactions (6.2)].

6 ADVERSE REACTIONS6.1 Clinical Trials ExperienceBecause clinical trials are conducted under widely varying conditions, adverse reaction rates observedin the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drugand may not reflect the rates observed in practice.In two vehicle-controlled and one active-controlled U.S. clinical trials, treatment safety was monitoredin 788 subjects who used twice-daily FINACEA Gel for 12 weeks (N=333) or 15 weeks (N=124), orthe gel vehicle (N=331) for 12 weeks. In all three trials, the most common treatment-related adverseevents were: burning/stinging/tingling (29%), pruritus (11%), scaling/dry skin/xerosis (8%) anderythema/irritation (4%). In the active-controlled trial, overall adverse reactions (including burning,stinging/tingling, dryness/tightness/ scaling, itching, and erythema/irritation/redness) were 19.4%(24/124) for FINACEA Gel compared to 7.1% (9/127) for the active comparator gel at 15 weeks.

Table 1: Adverse Events Occurring in ≥1% of Subjects in the Rosacea Trials by Treatment Groupand Maximum Intensity* FINACEA Gel, 15% Vehicle N=457 (100%) N=331 (100%) Mild Moderate Severe Mild Moderate Severe n=99 n=61 n=27 n=46 n=30 n=5 (22%) (13%) (6%) (14%) (9%) (2%) Burning/ 71 (16%) 42 (9%) 17 (4%) 8 (2%) 6 (2%) 2 (1%) stinging/ tingling Pruritus 29 (6%) 18 (4%) 5 (1%) 9 (3%) 6 (2%) 0 (0%) Scaling/ 21 (5%) 10 (2%) 5 (1%) 31 (9%) 14 (4%) 1 (<1%) dry skin/ xerosis Erythema/ 6 (1%) 7 (2%) 2 (<1%) 8 (2%) 4 (1%) 2 (1%) irritation Contact 2 (<1%) 3 (1%) 0 (0%) 1 (<1%) 0 (0%) 0 (0%) dermatitis Edema 3 (1%) 2 (<1%) 0 (0%) 3 (1%) 0 (0%) 0 (0%) Acne 3 (1%) 1 (<1%) 0 (0%) 1 (<1%) 0 (0%) 0 (0%)

* Subjects may have >1 cutaneous adverse event; thus, the sum of the frequencies of preferredterms may exceed the number of subjects with at least 1 cutaneous adverse event.

In patients using azelaic acid formulations, the following adverse events have been reported: worseningof asthma, vitiligo, depigmentation, small depigmented spots, hypertrichosis, reddening (signs ofkeratosis pilaris) and exacerbation of recurrent herpes labialis.Local Tolerability StudiesFINACEA Gel and its vehicle caused irritant reactions at the application site in human dermal safetystudies. FINACEA Gel caused significantly more irritation than its vehicle in a cumulative irritationstudy. Some improvement in irritation was demonstrated over the course of the clinical trials, but thisimprovement might be attributed to subject dropouts. No phototoxicity or photoallergenicity werereported in human dermal safety studies.

6.2 Post-Marketing ExperienceThe following adverse reactions have been identified post approval of FINACEA Gel. Because thesereactions are reported voluntarily from a population of uncertain size, it is not always possible toreliably estimate the frequency or establish a causal relationship to drug exposure: Eyes: iridocyclitis upon accidental exposure of the eyes to FINACEA Gel

7 DRUG INTERACTIONSThere have been no formal studies of the interaction of FINACEA Gel with other drugs.

8 USE IN SPECIFIC POPULATIONS8.1 PregnancyTeratogenic Effects: Pregnancy Category B There are no adequate and well-controlled studies in pregnant women. Therefore, FINACEA Gel shouldbe used during pregnancy only if the potential benefit justifies the potential risk to the fetus.Dermal embryofetal developmental toxicology studies have not been performed with azelaic acid,15% gel. Oral embryofetal developmental studies were conducted with azelaic acid in rats, rabbits,and cynomolgus monkeys. Azelaic acid was administered during the period of organogenesis in allthree animal species. Embryotoxicity was observed in rats, rabbits, and monkeys at oral doses ofazelaic acid that generated some maternal toxicity. Embryotoxicity was observed in rats given 2500mg/kg/day [162 times the maximum recommended human dose (MRHD) based on body surfacearea (BSA)], rabbits given 150 or 500 mg/kg/day (19 or 65 times the MRHD based on BSA) andcynomolgus monkeys given 500 mg/kg/day (65 times the MRHD based on BSA) azelaic acid. Noteratogenic effects were observed in the oral embryofetal developmental studies conducted in rats,rabbits and cynomolgus monkeys.An oral peri- and post-natal developmental study was conducted in rats. Azelaic acid was administeredfrom gestational day 15 through day 21 postpartum up to a dose level of 2500 mg/kg/day. Em-bryotoxicity was observed in rats at an oral dose of 2500 mg/kg/day (162 times the MRHD basedon BSA) that generated some maternal toxicity. In addition, slight disturbances in the post-nataldevelopment of fetuses was noted in rats at oral doses that generated some maternal toxicity(500 and 2500 mg/kg/day; 32 and 162 times the MRHD based on BSA). No effects on sexualmaturation of the fetuses were noted in this study.

8.3 Nursing MothersIt is not known whether azelaic acid is excreted in human milk; however, in vitro studies using equilibriumdialysis were conducted to assess the potential for human milk partitioning. The studies demonstratedthat, at an azelaic acid concentration of 25 µg/mL, the milk/plasma distribution coefficient was 0.7and the milk/buffer distribution was 1.0. These data indicate that passage of drug into maternal milkmay occur. Since less than 4% of a topically applied dose of 20% azelaic acid cream is systemicallyabsorbed, the uptake of azelaic acid into maternal milk is not expected to cause a significant changefrom baseline azelaic acid levels in the milk. Nevertheless, a decision should be made to discontinuenursing or to discontinue the drug, taking into account the importance of the drug to the mother.

8.4 Pediatric UseSafety and effectiveness of FINACEAGel in pediatric patients have not been established.

8.5 Geriatric UseClinical studies of FINACEA Gel did not include sufficient numbers of subjects aged 65 and over todetermine whether they respond differently from younger subjects.

17 PATIENT COUNSELING INFORMATIONInform patients using FINACEA Gel of the following information and instructions:

Use only as directed by your physician.•For external use only.•Before applying FINACEA Gel, cleanse affected area(s) with a very mild soap or a soapless cleansinglotion and pat dry with a soft towel.

•Avoid use of alcoholic cleansers, tinctures and astringents, abrasives and peeling agents.•Avoid contact with the eyes, mouth and other mucous membranes. If FINACEA Gel does come incontact with the eyes, wash the eyes with large amounts of water and consult your physician if eyeirritation persists.

•Wash hands immediately following application of FINACEA Gel.•Cosmetics may be applied after the application of FINACEA Gel has dried.•Avoid the use of occlusive dressings or wrappings.•Skin irritation (e.g., pruritus, burning, or stinging) may occur during use of FINACEA Gel, usuallyduring the first few weeks of treatment. If irritation is excessive or persists, discontinue use andconsult your physician.

•Report abnormal changes in skin color to your physician.•To help manage rosacea, avoid any triggers that may provoke erythema, flushing, and blushing.These triggers can include spicy and thermally hot food and drinks such as hot coffee, tea, or alcoholicbeverages.

© 2012, Bayer HealthCare Pharmaceuticals Inc. All rights reserved.

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Indication:Kenalog® Spray (triamcinolone acetonide topical aerosol, USP) is indicated for relief of the inflammatory and pruritic manifestations of corticosteroid-responsive dermatoses.Important Safety Information:Systemic absorption of topical corticosteroids has produced reversible hypothalamic-pituitary-adrenal (HPA) axis suppression, manifestations of Cushing’s syndrome, hyperglycemia, and glucosuria in some patients.Conditions which augment systemic absorption include the application of the more potent steroids, use over large surface areas, prolonged use, and the addition of occlusive dressings.Children may absorb proportionally larger amounts of topical corticosteroids and thus be more susceptible to systemic toxicity (see PRECAUTIONS, Pediatric Use).You are encouraged to report negative side effects of prescription drugs to the FDA at 1-800-FDA-1088 or www.fda.gov/medwatchFor topical use only. Please see adjacent page for full prescribing information.For more information, visit www.kenalogspray.comReference: 1. Data on file. Ranbaxy Laboratories, Inc. Princeton, NJ. * After spraying, the nonvolatile vehicle remaining on the skin contains approximately 0.2% triamcinolone acetonide. Each gram of spray provides 0.147 mg triamcinolone acetonide in a vehicle of isopropyl palmitate, dehydrated alcohol (10.3%), and isobutane propellant.

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