American Osteopathic College of Dermatology Journal of the American Osteopathic College of Dermatology

Journal of the American Osteopathic College of Dermatology Journal of the American Osteopathic College of Dermatology

2009-2010 AOCD Officers President: Marc I. Epstein, D.O., FAOCD President-Elect: Leslie Kramer, D.O., FAOCD First Vice-President: Bradley P. Glick, D.O., FAOCD Second Vice-President: James B. Towry, D.O., FAOCD Third Vice-President: Karen E. Neubauer, D.O., FAOCD Secretary - Treasurer: Jere J. Mammino, D.O., FAOCD Immediate Past-President: Donald K. Tillman, Jr., D.O., FAOCD Trustees: David L. Grice, D.O., FAOCD Mark A. Kuriata, D.O., FAOCD Rick Lin, D.O., FAOCD Editors Suzanne Rozenberg, D.O., FAOCD Jay S. Gottlieb, DO Andrew Racette, D.O., FAOCD Jon Keeling, DO Celeste Angel, D.O., FAOCD Andrew Racette, DO Executive Director: Rebecca Mansfield

Editorial Review Board Kevin Belasco, DO Sponsors: Rich Bernert, M.D. Global Pathology Laboratory

JAOCD Iqbal Bukhari, MD Medicis Founding Sponsor Ryan Carlson, DO JAOCD Founding Sponsor Igor Chaplik, DO Galderma Michael Conroy, M.D. Ranbaxy Brad Glick, DO, FAOCD Melinda Greenfield, DO Andrew J Hanly, MD

JAOCD David Horowitz, DO, FAOCD Founding Sponsor

Matt Leavitt, DO, FAOCD AOCD • 1501 E. Illinois • Kirksville, MO 63501 Mark Lebwohl, MD 800-449-2623 • FAX: 660-627-2623 www.aocd.org Rick Lin, DO Megan Machuzak, D.O. COPYRIGHT AND PERMISSION: written permission must be obtained from the Journal of the American Osteopathic College of Dermatology Jere Mammino, DO, FAOCD for copying or reprinting text of more than half page, tables or figures. John Minni, DO Permissions are normally granted contingent upon similar permission from the author(s), inclusion of acknowledgement of the original source, Navid Nami, DO and a payment of $15 per page, table or figure of reproduced material. Permission fees are waived for authors wishing to reproduce their own Shaheen Oshtory, DO articles. Request for permission should be directed to JAOCD c/o AOCD John Perrotto, DO PO Box 7525 Kirksville, MO 63501 Copyright 2003 by the Journal of the American Osteopathic College of Stephen Purcell, DO, FAOCD Dermatology Michael Scott, DO, FAOCD Printed by: The Dimensional Group, Mason City, IA 50401 Kevin Spohr, DO Proofreading: Julia Layton, Freelance Proofreading and Editing Journal of the American Osteopathic College of Dermatology Vo l u m e 15, Nu m b e r 1 Ja n u a r y 2010 Journal of the

Americaocdan Osteopathic College of Dermatology

Co n t e n t s

Letter from the JAOCD Editors...... 4 Letter from the President...... 5 Fluoroscopy-induced Radiation Dermatitis...... 6 Patrick Keehan, D.O., Peter Morrell, D.O., Joseph Susa, D.O., Bill V. Way, D.O. Betamethasone Dipropionate and Calcipotriene as a Treatment for Erythema Annulare Centrifugum...... 8 Marcus Goodman, D.O., Chris Buckley, D.O., Matthew Elias, D.O., Stanley Skopit, D.O., FAOCD Bullous pemphigoid of the penis...... 10 Lawrence A. Schiffman, D.O. Cutaneous Manifestation of a Primary Lung Cancer...... 13 Aleksandra Glisic, OMS IV, Vijay Subramaniam, MD, FCCP Dermatology without Borders...... 17 Babar Rao, M.D.; Hamza D Bhatti, OMSII Off-label Uses of Topical Pimecrolimus...... 19 Iqbal Bukhari, MD Refractory Subacute Cutaneous Lupus Erythematosus...... 22 Danica Leigh Alexander, D.O., Francisco A. Kerdel, M.D., Janet D. Allenby, D.O., FAOCD Acrokeratoelastoidosis with Overlapping Features of Degenerative Collagenous Plaques of the Hands...... 25 Leilani Townsend, MSIV, Patrick Keehan, D.O., Bill Way, D.O., F.A.O.C.D. Erythema Multiforme and Toxic Epidermal Necrolysis...... 29 Lisa A. Mainier, PhD, PA-C*; Jenifer R. Lloyd, D.O.** Successful Use of a Full Thickness Skin Graft to Repair a Large Defect on the Dorsal Hand and Wrist...... 32 Travis Hamblin, MSII, Adam Wray, D.O., F.A.O.C.D. Recalcitrant Pyoderma Gangrenosum...... 34 Michelle W. Foley, DO, Brett Bender, DO, Maureen Cliffel, DO, Michael Mahon, DO Granulomatous Slack Skin...... 36 Brooke L. Renner, D.O., Michelle Foley, D.O., Wendy L. McFalda, D.O., Michael Mahon, D.O., F.A.O.C.D. Pseudoepitheliomatous Hyperplasia and Necrobiotic Palisading Granulomatous Reaction to Tattoo Pigment...... 38 Mary Jo Robinson, DO, Shweta Patel, OMS IV A Case of Cutaneous Rosai-Dorfman Disease...... 39 Olga Globosky, D.O., Janese Trimaldi, M.D., Michael B. Morgan, M.D. A Case of Minocycline Induced Hyperpigmentation...... 42 Amara Sayed, D.O., FACOFP, Janet Allenby, D.O., FAOCD Recurrent Merkel Cell Carcinoma in a Transplant Patient...... 47 Melissa Voutsalath, DO, Anna Babayan, BS, Reza Sazgari, MD, Indira Misra-Higgins, DO, FAOCD Cutaneous Angiosarcoma: Case Report and Review of the Literature...... 50 Holly Kanavy, DO, David Kessler, DO Environmental Methicillin-resistant Staphylococcus Aureus on Public Toilet Seats – New Findings...... 55 Robert Norman, DO, MPH, MBA, Daniel R Johnson, OMS-IV Epithelioid Angiosarcoma: A Case Report and Review...... 59 Jami Reaves, D.O.,* Don A. Anderson, D.O., F.A.O.C.D., F.A.S.M.S.** A Case Report: Hailey-Hailey Disease...... 61 Krina K. Chavda, DO,* Marvin Watsky, DO** Elephantiasis Nostras Verrucosa...... 63 Carlos Gomez-Meade, D.O.*, Jerry Obed, D.O.**, Angela Combs, D.O.***, Stanley Skopit, D.O., FAOCD**** Elephantiasic Pretibial Myxedema: A Rare Form of Thyroid Dermopathy...... 65 David Judy, D.O.,* Claude S. Burton, M.D.,** Richard Miller, D.O.*** Le t t e r Fr o m Th e Ed i t o r s

Ja y Go t t l i e b , DO, Jo n Ke e l i n g , DO, An d r e w Ra c e t t e , DO, FAOCD Senior Editor FAOCD Editor FAOCD Editor Help the JAOCD to grow…

We are extremely enthusiastic about this issue of the JAOCD. It is our fifteenth issue of the JAOCD and the very first one that has been produced utilizing Editorial Manager, a fully on-line submission, review and production tool. Editorial Manager is used in production by thousands of scientific journals around the world. The AAD has utilized this tool for the past several years. The AOCD is now listed on Editorial Manager’s web site as one of thousands of distinguished scientific journals using its service.

We now have an international presence and flare. We have gone from a black-and-white journal to a full-color publication, and we are now ready to be a fully peer-reviewed journal. The JAOCD cover has evolved and is even more esthetically pleasing. We take great pride in all of these accomplishments, which seem to have happened so quickly.

As your editors, we continue to strive for improvement and growth. What is the next step? Without question, the next milestone is to be able to publish the JAOCD four times a year. When this happens, we will be able to have our journal listed in the Library of Congress as well as have it listed in Index Medicus. We therefore turn to the general, resident and student membership of the AOCD to assist us in making this happen as soon as possible.

We solicit your contribution in the way of presenting interesting cases or even a pearl on office management. We require consistency. Become a consistent contributor, always looking out for what would be of interest to the readers of our journal. Also, our resident members are required to prepare and submit one paper each year to the AOCD that is suitable for publication. We have petitioned the education and evaluation committee, and we were successful in making it mandatory that each resident submit a yearly paper for consideration for publication to a scientific journal. We hope that all residents will consider the JAOCD when deciding where to submit their manuscripts.

We will continue to cover topics that will be academically challenging. We will include such areas as dermatologic therapeutic modalities, original presentation of research, brief opinions, a review of dermatology-affili- ated clinical studies, brief individual case reports of unusual interest, basic science as it relates to dermatology, articles emphasizing cutaneous surgery, dermatopathology, cosmetic dermatology and pharmaceutical dermatology, editorials, letters to the editors, and finally pearls and anecdotes about dermatology.

We extend our sincere appreciation for continued support to our Founding Sponsors. Our deepest thank you goes to Global Pathology Laboratory Services, Galderma Pharmaceuticals, Ranbaxy Pharmaceuticals and to Medicis - The Dermatology Company, who have made their financial commitment known to the JAOCD and to the members and resident members of the American Osteopathic College of Dermatology.

Sincerely,

Jay S. Gottlieb, DO, FAOCD (Senior Editor) Jon Keeling, DO, FAOCD (Editor) Andrew Racette, DO, FAOCD (Editor)

4 Letter From the Editors Le t t e r f r o m t h e Pr e s i d e n t o f t h e AOCD

Ma r c (I. Ep s t e i n , DO)

Pr e s i d e n t Dear AOCD colleagues,

I want to extend warm holiday greetings to the AOCD membership, the executive staff and all your families. I hope the new year brings health and prosperity to all of us. I am honored to be serving as your 53rd president this coming year. It is also my hope you will take time out from your busy lives to help support our college and our board of trustees as we plan for our college’s future.

I believe it is time for the entire membership to support and strengthen our college in achieving the goals set forth in our mission statement. We need to share in the responsibility of the college to educate new health care providers and the general public about osteopathic dermatology. In today’s ever-changing world, your involvement is essential to maintain our position as viable specialists in the health care system. Each of us has hectic schedules, but if we all pitched in it would only require a small amount of time for each of us to help secure our college’s future.

In many ways, our future is tied to being DOs rather than MDs. We have to try harder, like Avis against Hertz, undergoing constant scrutiny by our MD colleagues and uninformed patients who are ignorant about what DO represents. We have continued to prove that we are, at the very least, head to head with our MD counterparts. As osteopathic dermatologists, it is our obligation to inform our patients, the general public and other healthcare professionals about the osteopathic philosophy and its advantages compared to the allopathic.

This journal, our journal, helps to define our accomplishments as osteopathic dermatologists. It has been nurtured over the years, as a labor of love, by our all-volunteer editorial staff. With your increased help and support, the staff can continue the journal’s professional evolution. It is a perfect vehicle to showcase the education and research being undertaken by osteopathic dermatology, from our residency programs to our private practices. This research is a key component in advancing our presence and equality within global dermatology. It is imperative for us to continue to support the journal. A small but significant new observation from a patient’s history, clinical exam, skin biopsy and/or treatment response, to a prepared mind, can lead to a journal contribution. It may become a letter to the editor, a new case study or a small, pivotal clinical trail that advances dermatology as well as osteopathic dermatology. But if you do not consider putting forth the effort, it is our journal and osteopathic dermatology that will be deprived of a contribution.

I’ve always wrestled with how osteopathic dermatologists can provide a holistic approach to patient care when we specialize in one organ system. In contemplating my acceptance speech, which is appearing in the upcoming issue of the DermLine, I came to understand how we accomplish this task. We do evaluate and treat our patients with a holistic approach when we view them as persons with skin problems and not just address their skin diseases. We should examine a patient’s skin in its entirety. Since the skin is the mirror to the rest of the patient’s health, we are indirectly evaluating the patient as a whole. If we see jaundice, we know there is hepatobiliary malfunction. If we see pallor, we know there is hematopoietic malfunction. If we see pitting edema, we know there is either a vascular, hepatic or nephrogenic malfunction. These are but a few examples of the external manifestations we use to help diagnose patients with internal dysfunction. So within our specialty, we actually fulfill our obligation as osteopathic physicians to evaluate and treat our patients holistically.

I hope you agree that we should be using this holistic approach of osteopathic medicine as we embark on a new year as a college. Throughout this year, we, as individual college members, should strive to help our college and this journal grow and prosper to better serve our membership as a whole, now and for our future generations.

Take care and be well,

Marc (I. Epstein, DO) 53rd President of the AOCD letter from the president 5 Fl u o r o s c o p y -i n d u c e d Ra d i at i o n De r m a t i t i s : A Ca s e Re p o r t a n d Li t e r a t u r e Re v i e w

Patrick Keehan, D.O.,* Peter Morrell, D.O.,** Joseph Susa, D.O.,*** Bill V. Way, D.O.**** *3rd-year Dermatology Resident, Northeast Regional Medical Center/Kirksville College of Osteopathic Medicine, Department of Dermatology, Texas Division, Duncanville, Texas **2nd-year Dermatology Resident, Northeast Regional Medical Center/Kirksville College of Osteopathic Medicine, Department of Dermatology, Texas Division, Duncanville, Texas ***UT Southwestern Medical Center at Dallas, Department of Dermatology, Division of Dermatopathology, Dallas, Texas ****Program Director, Northeast Regional Medical Center/Kirksville College of Osteopathic Medicine, Department of Dermatology, Texas Division, Duncanville, Texas

Abstract

Background: Radiation dermatitis was originally associated with traditional X-ray radiation. There have now been a few reported cases associated with fluoroscopy

Case Presentation: mately six cardiac catheterizations in the described.1,2,3,4,6,9,10,11,12 In a recent review of past seven years. His second cardiac cathe- 73 patients, initial diagnoses as disparate We report the case of a 63-year-old white terization, in November 1998, was complex as fixed-drug eruption, morphea, contact male who was first seen in June 2006 for and required over four hours to complete. dermatitis, infection and spider-bite were an eight-year-old lesion on the back. Prior After further discussion, he recalled that made.4 Lesions have appeared anywhere treatment consisted of various topical the lesion on the back began approximately from less than one day to 10 years after the steroids. A biopsy was performed in 2005 two to three weeks after his second cardiac causative procedure.3,4,6,7,13,14 Treatment for that revealed dermal sclerosis consistent catheterization. After again conferring and earlier lesions are topical and intralesional with morphea. This biopsy site had never reviewing the case with the dermatopathol- steroids. However, treatment for sclerotic healed. During the initial visit, the patient ogist, the diagnosis of fluoroscopy-induced lesions remains difficult. If mobility is explicitly denied a history of radiation radiation dermatitis was at last established. limited, surgical excision with musculosk- 15 exposure and felt that the inciting incident Narrow-band UVB and tacrolimus were eletal flap repair can be attempted. may have been a spider bite. discontinued. Treatment was switched to In spite of the difficulty in diagnosing Physical examination revealed a well- Biafine topical emulsion. The areas where this condition, improved physician educa- demarcated, sclerotic, indurated, hypop- the biopsies were taken have healed with tion and awareness have led to both higher igmented area with epidermal atrophy, this treatment, but the remainder of the rates of diagnosis as well as better preven- telangiectasias and a central area of crust. lesion has remained stable. tion. Frazier et al.3 in 2007 most recently This lesion measured approximately 85 mm x 55 mm in diameter and was located on the patient’s mid-back, just to the left of Discussion: midline (Figures 1 and 2). A 4-mm punch biopsy was repeated and Since the first X-ray was taken by submitted with a differential diagnosis Roentgen in 1895, the number of radio- of morphea vs. radiation dermatitis vs. graphic procedures performed worldwide necrobiosis lipoidica. Results confirmed has increased practically every year.1,2 In the previous diagnosis of morphea. Due the United States alone, there were over to lack of efficacy, topical steroids were 700,000 interventional fluoroscopic proce- discontinued, and the patient was placed dures performed in 1996 versus over 4.21 3,4,5 Figure 2. on tacrolimus ointment and narrow-band million in 2006. Consequently, the inci- Click here toFigure download high resolution image 1 UVB therapy three times weekly. dence of radiation dermatitis has increased At the three-month follow-up visit, as well.1 Paradoxically, however, the further specific questioning uncovered the number of reported cases appears much patient’s extensive cardiac history. It was smaller than might be expected.4 While the revealed that he had undergone approxi- first reported presentation of chronic radiation dermatitis was seen just four years after the original X-ray, there have been fewer than 100 fluoroscopically-induced cases reported in the literature to date.2,3,6,7,8 This phenomenon is most likely due to the difficulty in diagnosing this condition. Figure 2 The cutaneous morphology alone has spanned an impressively wide spectrum. Lesions ranging from simple erythema to summarized the known changes to skin transient alopecia, telangiectasia, atrophy, observed with increasing levels of radiation hyperpigmentation, hypopigmenta- (Figure 3). To prevent radiation-induced tion, necrosis, chronic ulceration and injury, the radiation dose to affected areas Figure 3 squamous cell carcinoma have all been of skin should be monitored in real-

6 Fluoroscopy-induced Radiation Dermatitis: A Case Report and Literature Review Figure 4. Click here to download high resolution image correlation. Some authors discourage biopsies in these cases altogether due to poor wound healing.4 It is only with a high index of suspicion and specific questioning that many of these mysterious cases with a long latent period can be solved. Hopefully, with improved physician awareness, fluoroscopy-induced radiation dermatitis will be correctly diagnosed more frequently.

Figure 5. Figure 4 Click here to download high resolution image

REFERENCES: 1. Barnea, Y., Amir, A., Shafir, R., Weiss, J., Gur, E. (2002). Chronic Radiodermatitis Injury After Cardiac Catheteriza- tion. Annals of Plastic Surgery, 49(6), 668-672. 2. Sajben, F., Schoelch, S., Barnette, D. (1999). Fluoro- scopic-Induced Radiation Dermatitis. Cutis, 64, 57-59. 3. Frazier, T., Richardson, J., Fabre, V., Callen, J. (2007). Fluoroscopy-Induced Chronic Radiation Skin Injury. Archives of Dermatology, 143, 637-640. 4. Koenig, T., Wolff, D., Mettler, F., Wagner, L. (2001). Skin Injuries from Fluoroscopically Guided Procedures: Part 1, Figure 6. Figure 5 Click here to download high resolution image Characteristics of Radiation Injury. American Journal of Radiology, 177, 3-11. 5. Market Research Cardiac Catheterization Products Over- view. Retrieved October 30, 2007, from http://www.imvinfo. com/index.aspx?sec=ccath&sub=def 6. Dehen, L., Vilmer, C., Humiliere, C., Corcos, T., Pentou- sis, D., Ollivaud, L., Chatelain, D., Dubertret, L. (1999). Chronic radiodermatitis following cardiac catheterisation: a report of two cases and a brief review of the literature. Heart, 81, 308-312. 7. Schecter, A., Lewis, M., Robinson-Boston, L., Pan, T. (2003). Cardiac catheterization-induced acute radiation dermatitis presenting as a fixed drug eruption - Case Reports. Journal of Drugs in Dermatology, 2(4), 425-427. 8. Wagner, L., Mcneese, M., Marx, M., Siegel, E. (1999). Severe Skin Reactions from Fluoroscopy: Case Report Figure 6 and Review of the Literature. Radiology, 213, 773-776. 9. Aerts, A., Decraene, T., Van Den Oord, J., Dens, J., Jans- sens, S., Guelinckx, P., Flour, M., Degreef, H., Garmyn, M. 9,10,12,13,14,16-19 (2003). Chronic radiodermatitis following percutaneous time and kept below these levels. coronary interventions: a report of two cases. Journal of the European Academy of Dermatology and Venereology, 17, 340-343. 10. Hivnor, C., Junkins-Hopkins, J., Kantor, J., Margolis, D., Naik, N., Nousari, C., Seykora, J., Van Voorhees, A. Dermatopathology: (2004). Subacute Radiation Dermatitis. American Journal of Dermatopathology, 26(3), 210-212. Histologically, the main findings of 11. Vano, E., Goicolea, J., Galvan, C., Gonzalez, L., Meiggs, L., Ten, J., Macaya, C. (2001). Skin radiation injuries in radiation dermatitis are dermal sclerosis, patients following repeated coronary angioplasty proce- telangiectasias, and scattered and atypical dures. British Journal of Radiology, 74, 1023-1031. 12. Lee, J., Hoss, D., Phillips, T. (2003). Fluoroscopy-Induced fibroblasts. The histological differential Skin Necrosis. Archives of Dermatology, 139, 140-142. diagnosis includes morphea, lichen scle- 13. Koenig, T., Wagner, L., Mettler, F., Wolff, D. Radiation Injury to the Skin Caused by Fluoroscopic Procedures: rosus et atrophicus, and sclerodermoid Lessons on Radiation Management. Scientific Exhibit graft-versus-host disease. Clinical history Cum Laude: Annual Meeting of the Radiological Society of North America. 2000. of radiation exposure is helpful to the 14. Mcfadden, S., Mooney, R., Shepherd, P. (2002). X-ray dermatopathologist in directing attention dose and associated risks from radiofrequency catheter ablation procedures. British Journal of Radiology, 75, 253- to the sometimes sparse or subtle atypical 265. fibroblasts. In our case, only after clinical 15. Henry M., Maender J., Shen Y., Tschen J., Subrt P., Schmidt J., Hsu S. Fluoroscopy-induced chronic radiation dermati- correlation was made did dermatopathology tis: A report of three cases. Dermatology Online Journal. note the findings of atypical fibroblasts and 15(1):3. 16. Stone, M., Robson, K., Leboit, P. (1998). Subacute radia- telangiectasias within a sclerotic dermis tion dermatitis from fluoroscopy during coronary artery (Figure 4-6). stenting: Evidence for cytotoxic lymphocyte mediated apoptosis. Journal of the American Academy of Dermatol- ogy, 38, 333-6. 17. Miller, D., Balter, S., Noonan, P., Georgia, J. (2002). Mini- mizing Radiation-induced Skin Injury in Interventional Conclusion: Radiology Procedures. Radiology, 225, 329-336. 18. Koenig, T., Mettler, F., Wagner, L. (2001). Skin Injuries from Fluoroscopically Guided Procedures: Part 2, Review From the perspective of the dermatologist, of 73 Cases and Recommendations for Minimizing Dose the emphasis has always been on enhanced Delivered to Patient. American Journal of Radiology, 177, 13-20. detection. Taking a detailed history, above 19. Cusma, J., Bell, M., Wondrow, M., Taubel, J., Holmes, Jr., all, is essential. As in our case, most patients D. (1999). Real-time Measurement of Radiation Exposure to Patients During Diagnostic Coronary Angiography and do not remember a prior history of fluo- Percutaneous Interventional Procedures. Journal of the roscopy, either because they assume it to be American College of Cardiology, 33(2), 427-434. irrelevant or have forgotten it completely.2,3,4 Even the histopathology may be of limited utility, as specimens are often non-diagnostic without proper history and clinical

Keehan, Morrell, Susa, Way 7 Ca s e Re p o r t : Betamethasone Di p r o p i o n a t e a n d Ca lc i p ot r i e n e a s a Tr e a t m e n t f o r Er y t h e m a An n u l a r e Ce n t r i f u g u m

Marcus Goodman, D.O.,* Chris Buckley, D.O.,* Matthew Elias, D.O.,** Stanley Skopit, D.O., FAOCD*** *3rd year Dermatology Resident, NSU-COM/BGMC **2nd year Dermatology Resident, NSU-COM/BGMC ***Program Director, NSU-COM/ BGMC

Abstract

Presented is a case of Erythema Annulare Centrifigum, a very uncommon figurate reactive erythema, with successful treatment using a novel combination approach. The treatment regimen included the unique use of combined calcipotriene 0.005% and betamethasone dipropionate 0.064% combination ointment (Taclonex®).

Introduction: in its effects on reducing proliferation and bilateral upper extremities. Each lesion differentiation of both keratinocytes and possessed a trailing scale with a very mild, Erythema annulare centrifugum (EAC) is on the cytokine environment.6 ill-defined, brown hyperpigmentation an uncommon reactive figurate erythema. In order to maximize treatment efficacy, centrally. No significant lymphadenopathy, It was first described by Darier in 1916, vitamin D derivatives such as calcipot- nail changes, or thyromegaly were noted. and it is estimated that the prevalence of riene are often combined with a second Initial laboratories included normal EAC is 1/100,000 population per year.1 therapeutic agent, such as a topical corti- complete blood count, complete metabolic Although the etiology of EAC is unknown, costeroid. This combination approach panel, thyroid stimulating hormone, and this unique entity has been related to a enhances the efficacy of the vitamin D PPD. wide variety of factors including drugs, analogue and limits corticosteroid toxicity.5 A shave biopsy was performed at the foods, pregnancy, infections, immunolog- This concept allowed for the described case advancing border of an active lesion on ical disorders, malignant neoplasms, and of EAC, which had been resistant to topical the right inner elbow. H&E revealed a 2 other systemic diseases. Dermatophytosis corticosteroid used alone, to be successfully superficial perivascular lymphohistiocytic has been implicated in up to 48% of EAC treated with a combination product. infiltrate, parakeratosis, hyperkeratosis, patients.3 Definitive diagnostic studies mild spongiosis and a slight vacuolar can be extensive due to the wide variety of degeneration. potential underlying etiologies. In addi- Case Report: At our initial meeting, the patient had tion to a complete history and physical, a been prescribed desonide 0.05% cream systemic workup, which includes complete A 27-year-old, healthy, African American to be applied twice daily to the affected blood count, liver function tests, urinalysis, female presented to our clinic with a areas until biopsy results returned. After chest radiography, antinuclear antibody, history of a scaly, itchy rash of two months the diagnosis of EAC had been confirmed, Ro and La antibodies, and thyroid stim- duration on her arms. She denied ever and the patient did not respond to the ulating hormone, is indicated. In most experiencing a similar rash prior to this cases, however, no underlying cause can be event, and admitted trying an over-the- found. counter anti-fungal preperation for 10 days Once the underlying condition is treated, without success. The patient denied any EAC usually resolves. If the investigational systemic symptoms as well as any rash in workup is negative, and there is no identifi- the axillary vaults, inframammary regions, able related condition, first-line therapy groin, and hand or feet areas. She had not is primarily topical corticosteroids. Some been taking any medications by mouth authors have investigated a wide variety within the previous several months and of other potentially effective therapeutic options, but little has been reported in denied being pregnant. the literature. Systemically administered Physical examination revealed several corticosteroid has shown short-term effi- areas of distinct erythematous papules cacy, but relapse is common after treat- coalescing into polycyclic plaques on the Figure 2 ment cessation. One case report provided evidence of clearance of EAC with once- daily dosing of topical calcipotriene (calcipotriol) 50 µg/g after three months, with no reports of flare for up to six months following treatment cessation.4 In humans, the natural supply of vitamin D depends primarily on exposure to ultraviolet rays from the sun for conversion of 7-dehydrocholesterol to vitamin D3 (chole- calciferol) in the skin. Calcipotriene is a synthetic analog of vitamin D3.5 Scientific evidence suggests that calcipotriene is Figure 1 Figure 3 roughly equipotent to the natural vitamin 8 Betamethasone Dipropionate and Calcipotriene as a Treatment for Erythema Annulare Centrifugum initial trial of desonide cream, she was REFERENCES: then switched to calcipotriene 0.005% 1. Rapini R, et.al. Dermatology. St. Louis: Mosby, 2003. 303. and betamethasone dipropionate 0.064% 2. González-Vela MC, González-López MA, Val-Bernal JF, et al. (2006). Erythema annulare centrifugum in a HIV-positive combination ointment (Taclonex®). The patient. International Journal of Dermatology. 45(12);1423– patient was instructed to use this oint- 1425. 3. Lebwohl G, et.al. Treatment of Skin Disease. Saint Louis: ment once daily for the next four weeks. C.V. Mosby, 2005. 194-195. Upon follow-up at our clinic, the patient 4. Gniadecki R. Calcipotriol for erythema annulare centrifugum. Br J Dermatol (2002) 146:317-319. reported complete clearance of her EAC 5. Dovonex® Cream [package insert]. Thornhill. Ontario: LEO after three weeks of use. There was some Pharma Inc.; 2005. 6. Del Rosso Do JQ. Combination topical therapy for the treat- residual brown hyperpigmentation noted ment of psoriasis. J Drugs Dermatol. 2006 Mar;5(3):232-4. in the prior EAC areas. On follow-up at six months, the patient denied any recurrence of her EAC, with additional clearance of the post-inflammatory hyperpigmentation.

Figure 4

Conclusion: Presented is a case of erythema annulare centrifigum, a very uncommon figurate reactive erythema, with successful treatment using a novel combination approach. As stated previously, EAC is a disease of unknown etiology that has been linked to a wide variety of potential causative factors. First-line treatment for idiopathic EAC has traditionally been topical corticosteroids. Treatment efficacy has also been recently reported with topical calcipotriene. We have reviewed the literature regarding treatment of EAC, and to our knowledge this is the first case report describing the unique use of combined calcipotriene 0.005% and betamethasone dipropionate 0.064% combination ointment (Taclonex®). The outcome of this novel approach has been positive and may lead to further investigation of Taclonex® use as a first-line treatment for idiopathic EAC.

Goodman, Buckley, Elias, Skopit 9 Bu l l o u s p e m p h i g o i d o f t h e p e n i s

Lawrence A. Schiffman, D.O. PGY-3 Dermatology St. John’s Episcopal Hospital, Far Rockaway, NY Program Director: Marvin Watsky, D.O.

Abstract

This interesting case report describes a patient with a chronic bullous eruption of the penis. Biopsy indicated bullous pemphigoid, albeit in an unusual location and distribution. Treatment necessitated combination treatment with both topical steroids and oral tetracycline to achieve complete resolution.

Case Report: was initially diagnosed, and the patient on the penis. Upon further questioning, he was given a prescription for valacyclovir reported a history of cold sores on his lips A 67-year-old male from the Balkans that would come and go. Examination of was referred to the clinic for evaluation the lips and oral mucosa again revealed no of a rash on his penis and scrotum. He active lesions, whereas the genital examina- complained of itchy blisters that lasted tion revealed new bullae and crusts. He approximately 10 days and then crusted was apprehensive about a biopsy, so he over. He reported a similar outbreak one was given a prescription for mupirocin 2% month prior. The man denied any sexual (Bactroban) ointment to be applied twice activity within the previous 10 years. He daily and told to return in one week. lived in an adult home. Past medical The next physical exam revealed addi- history included mild schizophrenia, hypo- tional bullae, erosions and crusts on the thyroidism following thyroidectomy, and penis. A bacterial culture was obtained, benign prostatic hypertrophy. Medications and a shave biopsy of perilesional skin listed were aspirin 325mg, furosemide was performed to confirm a diagnosis 20mg, L-thyroxin 0.075mg, olanzapine of bullous pemphigoid. He was given a Image 2: Tense and flaccid bullae, prescription for hydrocortisone butyrate 5mg, Flomax 0.4mg, and fluoxetine 10mg. erosions, and crusts of the right 0.1% cream (Locoid) and instructed to He had applied bacitracin ointment to the side of the penile shaft and scrotum. lesions for the previous few days. Lichenification is present. apply it to the lesions twice daily. The patient was groomed and in good Two weeks later, the patient returned to health. Physical examination revealed clinic and reported decreased pruritus, but grouped erosions, crusts and bullae on new blister formation. The culture grew the right scrotum and right penile shaft Staphylococcus aureus that was sensitive and prepuce. Some blisters were tense, to multiple medications, including tetra- while others were flaccid. The surrounding cycline. Histopathological evaluation of skin exhibited mild lichenification and the biopsy specimen showed subepidermal erythema, indicative of his complaint bullae associated with eosinophils and of pruritus (Images 1, 2, 3). There were underlying mild-to-moderate lymphocytic no lesions noted on the glans penis or infiltration admixed with eosinophils. PAS beneath the prepuce, nor were there any staining was negative for fungal organisms lesions on the oral/nasal mucosa, conjunc- (Images 4, 5, 6, 7). tiva, or perianal region. The remainder These findings favored a diagnosis of of the skin physical examination was Image 3: Grouped bullae and crusts bullous pemphigoid of the penis and non-contributory. with lichenification of the penis scrotum. The man was given a prescrip- An unusual case of herpes simplex tion for tetracycline capsules 500mg BID and fluocinonide 0.05% ointment BID. (Valtrex) 1 gram QD for 7 days and He was also sent for laboratory evalua- acyclovir 5% (Zovirax) ointment applied tion including indirect immunofluorescent QID. A viral culture was obtained from antibody titers (not performed), thyroid one of the bullae. The patient was sent profile and anti-thyroid antibodies, as well for laboratory work including HerpeSelect as complete blood count and comprehen- antibody titers for HSV-1 and HSV-2, RPR, sive metabolic profile. Labs were non- and HIV. contributory. Over the next few months, the condition stabilized and improved with Laboratory results revealed a negative a dosage taper of tetracycline from 1 gram viral culture. HSV-1 IgG antibody titers daily to 250 mg daily. The strength of the were HSV-1 positive and HSV-2 negative. RPR and HIV were both negative. The topical steroid was gradually decreased patient returned to clinic the following overtime. Throughout the course of Image 1: Bullae, erosions, and crusts week complaining of new blister formation treatment, the patient developed a mild of the prepuce balanitis probably related to both the oral 10 Bullous pemphigoid of the penis antibiotic and topical steroid. This was ally anywhere. The lesions of BP can be controlled with ciclopirox 0.77% (Loprox) extremely pruritic, resulting in significant cream twice daily. The patient was disease morbidity for the patient. Lesions on the free at five months. mucous membranes can cause pain and burning. Urination, defection, eating and breathing can become very uncomfortable Discussion: for the patient. The patho-mechanism of bullous Bullous pemphigoid represents a group pemphigoid is still not fully understood. of immunobullous disorders with a shared Humoral and cellular immune mecha- autoimmune etiology. Autoantibodies are nisms may play an important role, and formed against, and activated T lympho- BP may be associated with other autoim- Image 4: H&E 4x cytes target, the NC16A extracellular mune diseases such as diabetes mellitus, domain of the 180kD transmembrane rheumatoid arthritis, dermatomyositis, hemidesmosomal protein known as the ulcerative colitis, myasthenia gravis, and bullous pemphigoid antigen 180 (Bp180; thymoma. Drugs that have been associ- BpAg2) or collagen XVII (Col17). These ated with bullous pemphigoid include autoantibodies also target the 230kD intra- phenytoin, furosemide (a medication in cellular hemidesmosomal protein known this patient), penicillin, sulfa, captopril, as BP230 (BpAg1), as well as other proteins and enalapril. The disease can be chronic of the basement membrane zone such as and mild, or acute and severe. It can result laminin 5 and 6, B4-integrin and uncein.1 in a chronic, debilitating and mutilating The attack creates fragility at the dermo- disease, and treatment, although very diffi- epidermal junction as the hemidesmo- cult, should be initiated once the diagnosis some is unable to maintain its tight bonds is confirmed.6 The differential diagnosis within the basement membrane zone. As of erosive genital diseases is broad and Image 5: H&E 10x Subepidermal bullae immunoglobulin and complement deposit includes other bullous disorders such as with eosinophils along the BMZ, the basal keratinocytes of pemphigus, linear IgA bullous dermatosis, the epidermis lose their firm adhesion to epidermolysis bullosa acquisita, erythema the BMZ and begin to separate from the multiforme, Stevens-Johnson syndrome, dermis. This split occurs at the level of bullous lichen planus, bullous drug erup- the lamina lucida, which characteristically tion, bullous systemic lupus erythematosus forms subepidermal bullae when viewed and Hailey-Hailey disease.7 In addition, microscopically and clinically produces one must always rule out viral, fungal, and firm, tense bullae at affected sites. The bacterial diseases, especially when lesions lesions tend to be pruritic and may arise present on the genitalia. Finally, malignan- from an urticarial zone of erythema. cies such as squamous-cell carcinoma and When viewed under H&E, the charac- extramammary Paget’s disease may present teristic infiltrate is eosinophil rich. Direct with genital erosions.8, 9 immunofluorescence of perilesional skin Once the diagnosis of bullous pemphi- Image 6: H&E 10x will highlight linear IgG, C3, and to a lesser goid is confirmed by biopsy, as well as extent IgA deposits along the BMZ. This direct and indirect immunofluorescence, test can be positive in greater than 80% of treatment should be initiated. The choice patients with mucous membrane involve- of treatment is usually based on the sites of ment. IgG deposits map to the epidermal involvement, severity, and disease progres- side of salt-split skin. In addition, indirect sion. A combination of both topical and immunofluorescence can detect circu- systemic medications is often needed to lating autoantibodies in the serum. The manage patients. A multidisciplinary percentage of positive results in indirect approach utilizing primary care, ophthal- immunofluorescence studies varies from mologists, urologists, gynecologist, dentists, approximately 80% positive in mucous otorhinolaryngologists, immunologists and membrane pemphigoid to only 7% in dermatologists may be necessary when ocular-only pemphigoid.2 bullous pemphigoid affects these mucous Image 7: H&E 40x BP can affect both the skin and membrane sites as well as the skin. An mucous membranes. When only mucous international consensus conference on membranes are involved, the term mucous membrane pemphigoid (MMP) “cicatricial pemphigoid” is often used formulated evidence-based recommenda- to describe the condition. As the term tions for its management.10 suggests, the disease can produce scar- Corticosteroids, both topically and ring and disfigurement depending on its orally, remain the first-line treatment for severity and chronicity.3 BP, and especially bullous pemphigoid, especially for acute cicatricial BP, is most commonly a disease exacerbations of the disease. But, because affecting those in the 5th and 6th decades of their long-term adverse effects, these are and is more common in women.4 The typically combined with steroid-sparing most dreaded complication of mucous medications that are usually immuno- membrane pemphigoid is vision impair- suppressive and/or anti-inflammatory. ment due to conjunctival scarring.5 When Patients can be categorized as high-risk Image 8 only skin involvement occurs, sites favor if they have ocular, genital, laryngeal, the skin folds, but BP can appear virtu- esophageal, or nasopharyngeal involve- Schiffman 11 ment. These patients usually require high to a more chronic, debilitating and much dosages of systemic corticosteroids (pred- more difficult-to-treat illness. The differ- nisone 1-1.5mg/kg/day) in combination ence in immunological mechanisms, which with cyclophosphamide (1-2mg/kg/day), have yet to be elucidated, that determine or alternatively azathioprine (1-2mg/kg/ this discrepancy is so small, yet the clinical day). Dapsone and mycophenolate mofetil implications of this difference are so great. are other alternative treatments options Treatment must be tailored toward each used in combination with systemic corti- unique individual as well as to each unique costeroids.1 Tetracyclines (500-200mg/ presentation of the disease. day) are a very inexpensive and successful therapeutic option which exerts both anti-inflammatory and immunosuppressive effects.11 Nicotinamide (niacinamide, REFERENCES: 1. Sacher C, Hunzelmann N. Cicatricial Pemphigoid 200-2500mg/day) is commonly used in (Mucous Membrane Pemphigoid): Current and Emerging combination, as they act synergistically.12 Therapeutic Approaches. Am J Clin Dermatol 2005; 6 (2): 93-103. Finally, cyclosporine, tacrolimus, lefluno- 2. Fleming TE, Korman NJ. Cicatricial pemphigoid. J Am mide, methotrexate, sulfones, thalidomide, Acad Dermatol 2000 Oct; 43: 571-91. 3. Lever WF. Pemphigus and Pemphigoid. Springfield, IL: intravenous immunoglobulin, and plas- Charles C Thomas, 1965. mapheresis have been used with variable 4. Hardy KM, Perry HO, Pingree GC, Kirby TJ Jr. Benign mucous membrane pemphigoid. Arch Dermatol 1971; results. In the future, biologicals, such as 104(5): 467-75. TNF-alpha blockers and monoclonal anti- 5. Ramlogan D, Coulsom IH, McGeorge A. Cicatricial Pem- phigoid: A diagnostic problem for the Urologist. J.R. Coll. bodies like rituximab, may be studied as Surg. Edinb. 45, February 2000, 62-3. potential treatments.1 Duration of treat- 6. Axt M, Wever S, Baier G, et al. Cicatricial Pemphigoid: A therapeutic Problem. Hautarzt 1995 Sep; 46: 620-7. ments and their respective success depends 7. Ahmed AR, Kurgis BS, Rogers RS III. Cicatricial pemphi- on many factors. For low-risk patients, goid. J Am Acad Dermatol 1991 Jun; 24: 987-1001. 8. Kalajian A, Callen JP. Atypical herpes simplex infection topical treatments may suffice, but usually masquerading as recalcitrant pemphigus vulgaris. Aus- systemic corticosteroids and/or tetracy- tralasian Journal of Dermatology (2007). 48, 242-247. 9. Wojnarowska F, Cooper SM. Anogenital (nonvenereal) clines are necessary to curb acute exacerba- disease. In: Bolognia JL, Jorizzo JL, Rapini RP (eds). tions of the disease. As long-term topical Dermatology. St Louis, MO: Mosby, 2003; 1099-113 (1111-13). steroid use in and around the ocular, nasal, 10. Chan LS, Ahmed AR, Anhalt GJ, et al. The First Inter- oral, and genital skin may lead to adverse national Consensus on Mucous membrane Pemphigoid. Arch Dermatol 2002 Mar; 138: 370-9. effects, other topical treatment possibilities 11. Humbert P, Treffel P, Chapuis JF, et al. The tetracyclines now include tacrolimus or pimecrolimus. in dermatology. J Am Acad Dermatol 1991 Oct; 25: 691-7. 12. Fivenson DP, Breneman DL, Rosen GB, et al. Nicotin- The recent approval of topical dapsone 5% amide and tetracycline therapy of bullous pemphigoid. gel may be another potential topical treat- Arch Dermatol 1994 Jun; 130: 753-8. ment in our armamentarium. Our patient responded to treatment with a high-to-mid-potency topical steroid taper in addition to systemic tetracycline. Fortunately, the disease resolved quickly, and the risk of steroid atrophy on the affected sites was minimal. If there had been a prolonged course, topical agents such as tacrolimus or pimecrolimus may have been utilized as steroid-sparing agents. Within six months, the patient was clear, and fortunately there was no evidence of scarring. I believe this patient suffered from a localized variant of bullous pemphigoid limited to the skin, albeit an unusual location. A literature search of BP confined to the penis did not reveal any prior case reports. There have been reports of a localized genital subtype, but this is usually encountered in young females on the vulva. As BP tends to favor the intertriginous regions of the skin, genital and perineal involvement is commonly encountered and tends to be localized to those sites. In this case, the lesions were strictly confined to the penis and scrotum without mucous-membrane involvement. The course could have been much more severe and chronic if there were urethral or perianal lesions, as would be seen in true cicatricial or mucous-membrane pemphigoid. Complications may include urethral stricture, dysuria, sexual dysfunction, and disfigurement, ultimately leading

12 Bullous pemphigoid of the penis Cu t a n e o u s Ma n i f e s t a t i o n o f a Pr i m a r y Lu n g Ca n c e r – Ca s e Re p o r t a n d Re v i e w o f t h e Li t e r a t u r e

Aleksandra Glisic, OMS IV,* Vijay Subramaniam, MD, FCCP** *Des Moines University, Des Moines, Iowa **Pulmonologist, Respiratory and Critical Care Associates, Cedar Rapids, Iowa

Abstract

Cutaneous, subcutaneous, or superficial lymph node metastases are relatively uncommon events of lung cancer. We present a case of primary lung cancer with diffuse metastases diagnosed by a fine needle aspiration of a subcutaneous nodule.

Case Report cell lung cancer. The patient was referred adenocarcinoma.3 to oncology for treatment. The oncologist In one study of over 2,000 cases of lung- A 60-year-old Caucasian female determined that the patient was not a good cancer, 32 instances of cutaneous metas- presented to the office for consultation candidate for radiation and planned to treat tasis were noted, and skin was ranked as the regarding an abnormal chest X-ray and her with Cisplatin-based chemotherapy. thirteenth most common site of metastasis.4 possible lung cancer. She had a past The patient refused hospital admission and The identification of cutaneous metastases medical history of recurrent bronchitis and preferred to do outpatient chemotherapy. is often of great significance for both the hypertension. She had a long smoking Cisplatin chemotherapy was started on the patient and the physician. The cutaneous history and had recently been treated for first visit to the oncologist and continued nodules can in some instances provide a acute tracheobronchitis. She complained every day for another four days, at which of shortness of breath and musculoskeletal time the patient deteriorated and subse- chest discomfort. The patient also reported quently passed away. multiple skin lesions on her body which she noticed over the course of the previous three weeks. Discussion Pertinent positive findings on physical exam were multiple cutaneous and subcu- Lung cancer is the leading cause of taneous nodules on abdomen, chest, back, cancer death for both men and women left posterior neck and scalp. Nodules were in the United States. Lung cancer metas- erythematous, hard, and non-tender to tasizes to almost every organ. Frequent palpation and varied in size from 10mm extrathoracic sites include liver, adrenals, to 30mm. Bilateral cervical adenopathy bones, brain and kidney.1,4 Dermatological was also present. Pulmonary and cardiac manifestations of lung cancer as a part of exams were normal. Abdomen was non- the paraneoplastic syndrome are seen in Figure 1 tender. No other musculoskeletal or skin less than 1% of cases.1 Various neoplastic abnormalities were noted. and paraneoplastic dermatological mani- Work-up consisted of a chest X-ray, festations are described in Table 1. The chest/abdomen/pelvis CT and a fine-needle reported incidence of skin metastasis from 1 aspiration of a nodule. Chest X-ray showed lung cancer varies from 2.8% to 7.5%. hilar adenopathy with a questionable lytic Skin metastases are most common on the lesion. Chest, abdomen and pelvis CT scan head and neck, with nodular lesions being findings were consistent with a primary the most common, and adenocarcinoma is 1 lung carcinoma with diffuse metastases the most frequent histology. Lung cancer noted in multiple vertebral bodies, liver, metastases to skin usually present as cuta- spleen and skin (Figures 1, 2 and 3). Fine- neous nodules, and their recognition is needle aspiration of subcutaneous nodule important. New lesions in a patient who on the left posterior scalp indicated meta- is a smoker should lead to suspicion of Figure 2 static non-small-cell neoplasm. bronchogenic carcinoma, most commonly adenocarcinoma. Pathology revealed scattered groups of atypical, cohesive epithelioid cells with Of patients treated for lung cancer at scattered occasional intracytoplasmic a large referral center, 17% were noted to vacuolization (Figures 4-5). Many cells either have a skin metastasis or involve 2 had a slight plasmacytoid appearance or a superficial lymph node. But, only in an eccentrically placed nucleus. No large rare instances did the skin nodule lead to 2 glandular formation, squamous differentia- the diagnosis of lung cancer. In our case tion or pigmentation was noted. According report, the primary lung carcinoma was to the pathology report, these findings were diagnosed by the fine-needle aspiration most consistent with metastatic non-small- of a subcutaneous nodule. Cutaneous cell carcinoma, probably adenocarcinoma. manifestations are a sign of aggressive, poorly differentiated, malignant tumor Final diagnosis was a stage IV non-small- and are most commonly consistent with Figure 3

Glisic, Subramaniam 13 Conclusion Skin metastases, though uncommon, can be the sole manifestation of lung cancer. In the study by Lookingbill et al. (1990), the incidence of cutaneous metastasis as the presenting feature of lung carcinoma was only 0.6%.9,10 Cutaneous metastatic lesions due to lung cancer should always be considered in the differential diagnosis of patients with nodular skin lesions.5 An index of suspicion should be maintained Figure 4 and biopsy performed, particularly for non-healing ulcers, persistent indurated erythema, and unexplained skin nodules.8 The skin metastasis of lung cancer is usually seen in patients with advanced disease11 and indicates poor prognosis. Sometimes, however, as in our case, it may be the initial manifestation.

References: 1. Kamble R, Kumar L, Kochupillai V, et al. Cutaneous metastases of lung cancer. Postgrad Med J 1995; 71:741- 743. 2. Cornia PB, Raugi G. Dermatologic manifestations of pulmonary disease. eMedicine Dermatology. St. Petersburg: Figure 5 eMedicine, Corporation, 2000. 3. Dreizen S, Dhingra HM, Chiuten DF, et al. Cutaneous and subcutaneous metastases of lung cancer. Clinical tool for evaluating response to chemo- characteristics. Postgrad Med J 1986; 80:111-6. 4. Gupta KB, Tandon S, Kalra R, Arora B. Lung cancer with therapy. This response, however, may not skin metastasis - case report. Indian J Med Sci 2000; be related to the primary tumor, since the 54:398-9. 5. Coslett LM, Katlic MR. Lung cancer with skin metastasis. blood supply to the skin is relatively poor Chest 1990; 97:757–759. and skin nodules may be less sensitive to 6. Lookingbill DP, Spangler N, Helm KF. Cutaneous metas- 1 tases in patients with metastatic carcinoma: a retrospec- the chemotherapy. The development of tive study of 4020 patients. J Am Acad Dermatol 1993; these lesions may indicate the failure of 29:228-36. 7. Terashima T, Kanazawa M. Lung cancer with skin metas- ongoing therapy or the recurrence of a tasis. Chest 1994; 106:1448-1450. carcinoma that was previously eradicated. 8. Lookingbill DP, Spangler N, Sexton FM. Skin involvement as the presenting sign of internal carcinoma. A retrospec- In some instances, however, cutaneous tive study of 7316 cancer patients. J Am Acad Derma- metastases may be the first manifestation tol 1990; 22:19-26. 9. Inamadar AC, Palit A, Athanikar SB, et al. Inflammatory of unsuspected, asymptomatic, occult cutaneous metastasis as a presenting feature of bron- neoplasm.4 Cutaneous metastases of chogenic carcinoma. Indian J Dermatol Venereol Leprol 2003; 69:347-9. pulmonary origin are neither uniform nor 10. Lookingbill DP, Spangler N, Sexton FM. Skin involvement have a pathognomonic gross appearance. as the presenting sign of internal carcinoma. J Am Acad Dermatol 1990; 22:19-26. They may be mistaken for a variety of 11. Sariya D, Ruth K, Adams-McDonnell R, Cusack C, et al. benign dermal or subcutaneous growths, Clinicopathologic correlation of cutaneous metastases: experience from a cancer center. Arch of Dermatol 2007; and are generally painless and freely 143:613-620. movable. 3,4 Biopsy specimens must be 12. Hunstein W, Trimper LH, Dummer R, Schwechheimer K. Glucagonoma syndrome and bronchial carcinoma. Ann taken from all new skin lesions, particularly Intern Med 1988; 109:920. in patients who smoke or who already have 13. Cohen PR, Grossman MC, Almeida L, Kurzrock R. Triple a history of lung cancer.5 palm and malignancy. J Clin Oncol 1989; 7:669. In another study of 4,020 patients with metastatic disease, 420 (10%) had cutaneous metastases, and in 306 of them the skin metastases were the first sign of extranodal metastatis.6 This study also indicated nodular appearance of skin metastases and non-small-cell neoplasm pathology, most commonly adenocarcinoma. After recognition of skin metastases, mean patient survival ranged from one to 34 months depending on tumor type.6 In one study, mean survival of metastatic-lung-cancer patients from time of diagnosis of skin metastases was 4.9 months.7

14 cutaneous Manifestation of a Primary Lung Cancer

De r m a t o l o g y w i t h o u t Bo r d e r s

Babar Rao, M.D.; Hamza D Bhatti, OMSII

Abstract

Dermatology is an extremely adaptive field in which doctors will soon be able to treat patients on a national and possibly global level. Current technology has given patients the ability to receive consults from anywhere in the world, even in such a visual field as dermatology. Patients can conveniently use a myriad of methods including digital cameras, webcams or even their mobile phones to transfer images to the dermatologist and discuss their concerns in real-time over the Internet.

Introduction: throughout the day or night, consulting with patients who have also logged on. This Global dermatology is the beginning of a can be extremely beneficial for people in new era within the field of medicine. With developing countries who face a lack of the advancements in technology today, it is healthcare services. Basically, a patient logs possible to advise patients anywhere in the on to the website and verbally discusses world. The doctor-patient relationship will his or her chief complaint with the derma- soon be redefined.8 No longer will patients tologist online, talking “face to face” via be limited to seeing doctors based on avail- webcam. Thanks to advancements in tech- ability, location, and standard of healthcare, nology, the patient can take a picture of a especially relevant in underserved areas of mole, rash, or any other visible lesion with the world. a cell phone or digital camera. This image can be instantly transmitted to the doctor, Figure 1 Discussion: who can review the picture for a proper diagnosis (Fig. 2). The patient is then given Physicians have already set up online additional instructions to ensure sufficient consultation services in which they discuss treatment (Fig. 1). For patients who have difficult diagnoses and treatments with used this system before, the doctor already other doctors of the same specialty.1,7 has their history on record. This service Doctors in Australia have set up small could be extremely useful when people clinics all over China in more than 40 travel abroad as well. If a patient were to different specialties. Patients can come in get sick while traveling, he could easily log and receive a routine check-up and, if need on to the website and see a doctor in real- be, schedule an appointment to meet with a time. specialist, all done via telemedicine.2 These It is useful to note that telemedicine is clinics employ specially trained nurses who a new and rapidly developing field. Many perform exams that play a critical role for laws governing the legality of telemedi- Figure 2 the doctor in making the correct diagnosis. cine in the United States have not yet been New technology is used that can transmit formalized. Each state has different tests telemedicine were implemented in hospi- information normally heard by the digital for accreditations, and each has different tals, doctors’ offices, prisons and nursing stethoscope or seen by a digital otoscope malpractice rates. But in technical terms, homes. This study was funded partly through the Internet so the doctor can doctors are not practicing in areas out of by AT&T and released in November by actually hear the heart beats clearly, or their own jurisdiction.9 It is still unclear Boston-based Partners Healthcare System.3 see the tympanic membrane for himself.2 how doctors will be able to treat patients Further evidence of the rise of telemedicine Furthermore, a recent web-based survey beyond their jurisdictions, but new laws comes from Wall Street, which reports that showed that patients responded positively regarding this technology will soon be Cigna will begin to reimburse doctors for to their telemedicine experience both in discussed and implemented. The same telemedicine visits in January 2009.5 As terms of service and answers they received.4 would have to go for malpractice, HIPPA, insurance companies start to accept the In the age of telemedicine, patients can and liability. idea of telemedicine, reimbursements will go online and submit their chief complaint Though licensure and legal problems surely follow. with pictures, and receive a reply within are big obstacles to overcome, convincing 24 to 48 hours (the store-and-forward insurance companies to reimburse for tele- method). In order to eliminate the turn- medicine may be even bigger. Insurance Conclusion: around time, real-time telemedicine should companies in some states, like Texas, started be enacted. Imagine a diverse online to reimburse doctors for telemedicine visits Telemedicine may prove to be extremely medical network of board-certified derma- after legislation had been passed to do so. A beneficial to many people because it allows tologists from all over the world who are 2007 study showed that an average of $4.28 patients access to medical care anywhere in logged on to a website at different times billion dollars could be saved annually if the world. This service would offer a supe- Rao, Bhatti 17 rior level of medical care to many under- developed nations. Though there are many obstacles along the way, telemedicine will soon redefine the doctor-patient relationship as we know it.

References: 1. Telederm. The community for Teledermatology. Available at: www.Telederm.org. Accessed July 10, 2008. 2. Global Doctors. Available at: www.globaldoctors.com.au. Accessed July 12, 2008. 3. Collette, Mark. Telemedicine has a Global Reach. Available at http://galvestondailynews.com/story. lasso?ewcd=ff64fc16574709e0&-session=TheDailyNews :42F94251080f00a12DATJL3F8BA33. Accessed July 15, 2008. 4. The use of an Internet-based Ask the Doctor Service involving family physicians: evaluation by a web survey. Available at: http://fampra.oxfordjournals.org/cgi/content/ abstract/23/2/159. Accessed June 30, 2008. 5. Goldstein, Jacob. Big Insurers Pay for Online Doctor Visits. Wall Street Journal. 31 March 2008. Available at: http://blogs.wsj.com/health/2008/03/31/big-insurers-pay- for-online-doctor-visits/?mod=WSJBlog. Accessed July 20, 2008. 6. Doctors, Web Cams, and Online Consultations. Available at: http://scienceroll.com/2008/06/23/doctors-webcams- and-online-consultation/. Accessed July 13, 2008. 7. Soyer, H Peter M.D. Global Dermatology: A specific Web Application for Dermatological Consultation. Avail- able at: http://www.internet-health.org/ih200431e03.html. Accessed July 19th, 2008. 8. Remote Consultations. Available at: http://www.con- nected-health.org/programs/remote-consultations.aspx. Accessed July 12,2008 9. Watson, Alice J. “Teledermatology.” 27 Feb 2007. http:// www.emedicine.com/derm/topic527.htm. Accessed July 15,2008.

18 dermatology without Borders Off -l a b e l Us e s o f To p i c a l Pi m e c r o l i m u s

Iqbal Bukhari, MD* *King Fahad Hospital of the University, Al Khobar, Saudi Arabia

Abstract

Pimecrolimus is an immunomodulator that targets T-cells. It is mainly used in atopic dermatitis, but recently many reports have proved its effectiveness in other cutaneous conditions. In this report, we are suggesting new off-label uses of topical pimecrolimus.

Introduction: of the newly opened pustule were negative. The patient refused skin biopsy. She Pimecrolimus is a macrolactam immu- was diagnosed clinically as having palmo- nomodulator with calcineurin inhibition plantar pustulosis. Since the patient had as its mode of action. It selectively targets not responded to topical steroids in the T cells and mast cells. It inhibits T-cell past and was not in favor of taking systemic proliferation, production and release of therapy, she was started on pimecrolimus. interleukin-2 (IL), IL-4, interferon-gamma, She applied pimecrolimus 1% cream and a and tumor necrosis factor-alpha as well topical steroid of moderate potency twice 1,2 as decreasing mast-cell degranulation. daily for one week. Then the steroid was Pimecrolimus does not easily penetrate discontinued and the patient continued through the skin, so it has a very low risk using pimecrolimus cream twice daily. Figure 1: 40-year-old female with palmo- of systemic side effects. It has been shown After four weeks, the eruption had cleared plantar pustulosis to be effective in both adults and children 90% with residual postinflammatory a. before treatment with topical pime- with mild to moderate atopic dermatitis, hyperpigmentation, but no new lesions crolimus 1% cream intertriginous psoriasis, seborrheic dermatitis, chronic hand dermatitis, oral lichen had appeared. By the end of the twelfth planus and cutaneous lupus erythema- week, the condition had cleared completely, tosus.3-9 Case reports of clinical success and the patient was advised to discontinue have been reported for cutaneous lichen using pimecrolimus regularly and use it on planus, vitiligo and chronic graft-vs.-host an as-needed basis for new lesions only. disease.10-12 As opposed to corticosteroids, She was followed up for three years, during pimecrolimus and tacrolimus do not affect which she reported having only a few endothelial cells and fibroblasts; therefore, lesions that disappeared immediately after telangiectasia and skin atrophy do not the use of topical pimecrolimus. occur.13 In this article, we are reporting additional off-label uses of topical pime- Discussion: crolimus in dermatology. Palmoplantar pustulosis is a chronic, b. after 12 weeks of treatment, showing Case 1: persistent, localized form of pustular complete resolution psoriasis that usually occurs on the palms A 48-year-old Arabic female presented and soles of middle-aged women. It is to our dermatology clinic with a two-year usually treated by topical steroids, topical Case 2: history of a persistent, non-itchy pustular calcipotriol, psoralen and ultraviolet A 50-year-old Arabic female was referred eruption affecting the palms and soles. radiation (PUVA), acitretin, methotrexate to our dermatology clinic with painful According to the patient, the eruption had or cyclosporine.14-17 Combination treat- erosions of the buccal mucosa for the past never resolved completely. At a private ment with PUVA and acitretin, topical 10 years (Figures 2a, 2b). The condition clinic, she was treated with topical steroids calcitriol and tacrolimus, calcipotriol and of different potencies, tar-containing would wax and wane, but never completely betamethasone dipropionate or topical resolved. She was treated with topical and creams, and local psoralen with ultraviolet betamethasone valerate and oral tetracy- radiation, all with no response. There oral steroids prescribed by other derma- cline are reported to be effective.18-21 The was no history of arthralgia. The patient’s tologists, with no improvement. These efficacy of pimecrolimus in the therapy medical, family, allergy, and drug histories lesions interfered with eating and drinking, of inverse psoriasis has been documented were negative. She was a non-smoker. On which led to gradual weight loss. There examination of the hands and feet, there in a randomized, double-blind, placebo- were no other lesions on skin examina- were several small (<5 mm in diameter) controlled clinical trial involving 57 adult tion. Baseline laboratory investigations, pustules studded over an erythematous patients that showed clearance in almost including complete blood count, liver func- base (Figures 1a, 1b). The rest of the body 71% of the patients after therapy with tion and renal function tests, were normal, 22 was free of similar lesions. No axillary or pimecrolimus for eight weeks. In our case, and a hepatitis profile was negative. Biopsy inguinal lymphadenopathy was palpated topical pimecrolimus 1% was also shown to from the affected buccal mucosa revealed on examination. Baseline laboratory inves- be effective in localized pustular psoriasis. a diagnosis of erosive oral lichen planus. tigations revealed borderline hypercho- The patient requested not to be started on lesteremia only. Gram stain and culture topical or oral steroids due to her past Bukhari 19 population with long-term follow-up and pimecrolimus 1% cream twice daily for monitoring of the blood level of pime- 12 weeks. Initially, the lesion repigmented crolimus are required to better evaluate its with a diffuse perifollicular pattern, and usefulness and safety compared with other by the end of the twelfth week the area was therapeutic modalities. completely repigmented with no evidence of side effects such as redness or atrophy. Case 3: Follow-up of the patient for five years after discontinuation of topical pimecrolimus A 6-year-old Arabic female presented did not reveal any recurrence of vitiligo in to our dermatology clinic with a two- the treated area. month history of hypopigmented patches affecting the face, chest, arms and legs. Discussion: Figure 2: 40-year-old female with erosive She was prescribed hydrocortisone cream oral lichen planus applied twice daily for two months with no Vitiligo is a chronic, depigmenting a. before treatment with topical pime- response. The patient was asthmatic, and cutaneous disorder which has an autoim- crolimus 1% cream family history was negative for similar skin mune basis. Many treatment modalities condition. On examination of the skin, are available, but results are inconsistent there were hypopigmented patches with and variable. Several clinical studies have indistinct borders and fine whitish scaling been conducted involving the use of topical in some of the lesions. Woods light and tacrolimus in the treatment of vitiligo, and KOH scrapings were negative. Systemic all have proved its effectiveness in treating examination was normal. She was diag- this disorder.26-30 In this report, topical nosed as having extensive pityriasis alba. pimecrolimus, which has similar action Topical pimecrolimus 1% cream applied to tacrolimus, was used in a patient with twice daily was initiated. After 12 weeks, persistent vitiligo. Initially, our patient the condition resolved completely with no responded with a diffuse perifollicular recurrence. repigmentation pattern; by the end of the 12-week period, affected areas became Discussion: completely pigmented with no reported side effects. This diffuse pattern of pigmen- b. after eight weeks of treatment, showing Pityriasis alba is a type of endogenous tation was reported previously by Lepe and complete healing of the buccal mucosa eczema which usually affects children under colleagues in their study of tacrolimus in 12 years old. It is characterized by hypopig- childhood vitiligo.26 Adding to this favor- mented patches with indistinct borders able effect, pimecrolimus lacks the atro- experience, and therefore she was started affecting the face, neck, upper chest, and phogenic potential seen with prolonged use on pimecrolimus 1% cream twice daily. arms. Sometimes, fine scales can be seen of topical steroids, making it safer for the Clinical evaluation with photographs was in these patches. The cause of pityriasis patient. These findings suggest that pime- performed weekly, and all adverse events alba is unknown, but it is more notice- crolimus is a viable option in the treatment were documented. After two weeks, the able in summertime. The condition should of chronic, persistent vitiligo. patient reported gradual improvement be differentiated from pityriasis versicolor of her symptoms with transient burning and vitiligo. Usually, it is self resolving, but Conclusion: sensations. Complete resolution of the moisturizers or hydrocortisone cream can condition occurred after eight weeks, which be used. In our patient, pimecrolimus was In this report, topical pimecrolimus 1% allowed the patient to resume her normal used since it has proven its success in other cream has shown a therapeutic benefit diet. At a later follow-up, the patient types of endogenous eczema such as atopic in various dermatoses including local- reported bouts of a few lesions which dermatitis and seborrheic dermatitis.3,5 ized pustular psoriasis, erosive oral lichen immediately subsided with the application Interestingly, in our patient, the condition planus, pityriasis alba and vitiligo. However, of pimecrolimus cream for one week. The resolved almost completely by the tenth future double-blind, placebo-controlled patient was free of any active lesions after week of treatment, which adds a further studies are needed to confirm its efficacy. one year of follow-up. indication for topical pimecrolimus cream. Discussion: References: Case 4: 1 Marsland AM, Griffiths CE. The macrolide immunosup- pressants in dermatology: mechanisms of action. Eur J Erosive oral lichen planus (EOLP) A 19-year-old male of skin type IV with Dermatol 2002; 12: 618–22. is an intensely painful form of mucosal known vitiligo since the age of 10 years had 2 Grassberger M, Steinhoff M, Schneider D, et al. Pime- lichen planus with periods of remission crolimus – an anti-inflammatory drug targeting the skin. been regularly followed in our dermatology Exp Dermatol 2004; 13: 721–30. and relapses. It is usually treated by topical clinic for many years. The patient used to 3 Gisondi P, Ellis CN, Girolomoni G. Pimecrolimus in der- steroids, antimalarial agents, oral retin- matology: atopic dermatitis and beyond. have bilateral, symmetrical disease of the Int J Clin Pract. 2005 Aug;59(8):969-74. oids, systemic steroids, immunosuppressive knees and the periorbital areas. He was 4 Gribetz C, Ling M, Lebwohl M, et al. Pimecrolimus cream drugs, and extracorporeal photochemo- 1% in the treatment of intertriginous psoriasis: a double- treated intermittently over four years using blind, randomized study. J Am Acad Dermatol 2004; 51: therapy. The effectiveness of pimecrolimus topical psoralen with sun exposure and 731–8. 1% cream in EOLP has been suggested 5 Rigopoulos D, Ioannides D, Kalogeromitros D, et al. medium-potency topical steroids, which Pimecrolimus cream 1% vs. betamethasone 17-valerate in a few case reports and in one recent gradually resolved his lesions except over 0.1% cream in the treatment of seborrhoeic dermatitis. A randomized open-label clinical trial. Br J Dermatol 2004; comparative study in France that proved its the left knee, which was resistant to treat- 23-25 151: 1071–5. effectiveness with few mild side effects. ment and remained stationary until the 6 Belsito DV, Fowler JF Jr, Marks JG Jr, et al. Pimecrolimus However, topical steroids are much less cream 1%: a potential new treatment for chronic hand age of 17 years. The patient had a posi- dermatitis. Cutis 2004; 73: 31–8. expensive and more available than topical tive family history for vitiligo, as his uncle 7 Esquivel-Pedraza L, Fernandez-Cuevas L, Ortiz-Pedroza calcineurin inhibitors, which makes G, et al. Treatment of oral lichen planus with topical pime- and niece were affected. His autoantibodies crolimus 1% cream. Br J Dermatol 2004; 150: 771–3. topical calcineurin inhibitors a second- profile for thyroid and adrenal glands 8 Dissemond J, Schroter S, Franckson T, et al. Pimecroli- line therapy. Further studies on a larger mus in an adhesive ointment as a new treatment option were negative. He was started on topical for oral lichen planus. Br J Dermatol 2004; 150: 782–4. 20 oFF-label Uses of Topical Pimecrolimus 9 Kreuter A, Gambichler T, Breuckmann F, et al. Pimecroli- mus 1% cream for cutaneous lupus erythematosus. J Am Acad Dermatol 2004; 51: 407–10. 10 Lim SJ, Love EW. Steroid-free pimecrolimus (Elidel) for mono-therapy of lichen planus. J Drugs Dermatol 2004; 3: 563–4. 11 Mayoral FA, Gonzalez C, Shah NS, et al. Repigmentation of vitiligo with pimecrolimus cream: a case report. Derma- tology 2003; 207: 322–3. 12 Ziemer M, Gruhn B, Thiele JJ, et al. Treatment of extensive chronic cutaneous graft-versus-host disease in an infant with topical pimecrolimus. J Am Acad Dermatol 2004; 50: 946–8. 13 Queille-Roussel C, Paul C, Duteil L, et al. The new topical ascomycin derivative SDZ ASM 981 does not induce skin atrophy when applied to normal skin for 4 weeks: a randomized, double-blind controlled study. Br J Dermatol 2001; 144: 507–13. 14 Behrens S, von Kobyletzki G, Hoffmann K, et al. PUVA- bath photochemotherapy in Hallopeau’s acrodermatitis continua suppurativa. Hautarzt. 1997 Nov;48(11):824-7.. 15 Chowdhury MM, Motley RJ. Treatment of acrodermatitis continua of Hallopeau with oral propylthiouracil and methotrexate. Clin Exp Dermatol. 2001 Nov;26(8):657-60. 16 Reitamo S, Erkko P, Remitz A, et al. Cyclosporine in the treatment of palmoplantar pustulosis. A randomized, double-blind, placebo-controlled study. Arch Dermatol. 1993 Oct;129(10):1273-9. 17 Emtestam L, Wedén U. Successful treatment for acrodermatitis continua of Hallopeau using topical calcipotriol. Br J Dermatol. 1996 Oct;135(4):644-6. 18 Kuijpers AL, van Dooren-Greebe RJ, van de Kerkhof PC. Acrodermatitis continua of Hallopeau: response to combined treatment with acitretin and calcipotriol ointment. Dermatology 1996;192(4):357-9. 19 Brunasso AM, Lo Scocco G, Massone C. Recalcitrant acrodermatitis continua of hallopeau treated with calcitriol and tacrolimus 0.1% topical treatment. J Eur Acad Derma- tol Venereol. 2008 Apr 14. 20 Sotiriadis D, Patsatsi A, Sotiriou E, et al. Acrodermatitis continua of Hallopeau on toes successfully treated with a two-compound product containing calcipotriol and betamethasone dipropionate. J Dermatolog Treat. 2007;18(5):315- 8. 21 Piquero-Casals J, Fonseca de Mello AP, Dal Coleto C, et al. Using oral tetracycline and topical betamethasone valerate to treat acrodermatitis continua of hallopeau. Cutis. 2002 Aug;70(2):106-8. 22 Gribetz C, Ling M, Lebwohl M, et al. Pimecrolimus cream 1% in the treatment of intertriginous psoriasis: a double-blind, randomized study. J Am Acad Dermatol. 2004 Nov;51(5):731-8. 23 Dissemond J, Schroter S, Franckson T, et al. Pimecrolimus in an adhesive ointment as a new treatment option for oral lichen planus. Br J Dermatol. 2004;150:782-784. 24 Esquivel-Pedraza L, Fernandez-Cuevas L, Ortiz-Pedroza G, et al. Treatment of oral lichen planus with topical pimecrolimus 1% cream. Br J Dermatol. 2004;150:771-773. 25 Passeron T, Lacour JP, Fontas E, et al. Treatment of oral erosive lichen planus with 1% pimecrolimus cream: a double-blind, randomized, prospective trial with measurement of pimecrolimus levels in the blood. Arch Dermatol. 2007 Apr;143(4):472-6. 26 Lepe V, Moncada B, Castanedo-Cazares JP, et al. A double-blind randomized trial of 0.1% tacrolimus vs 0.05% clobetasol for the treatment of childhood vitiligo. Arch Der- matol 2003; 139: 581-5. 27 Travis LB, Weinberg JM, Silverberg NB. Successful treatment of vitiligo with 0.1% tacrolimus ointment. Arch Derma- tol 2003; 139: 571-4. 28 Grimes PE, Soriano T, Dytoc MT. Topical tacrolimus for repigmentation of vitiligo. J Am Acad Dermatol 2002; 47: 789-91. 29 Smith DA, Tofte SJ, Hanifin JM. Repigmentation of vitiligo with topical tacrolimus. Dermatology 2002; 205: 301-3. 30 Tanghetti EA. Tacrolimus ointment 0.1% produces repigmentation in patients with vitiligo: results of a prospective patient series. Cutis 2003; 71: 158-62.

Bukhari 21 Re f r a c t o r y Su b a c u t e Cu t a n e o u s Lu p u s Erythematosus : A Ca s e Re p o r t

Danica Leigh Alexander, D.O. 3rd Year Dermatology Resident, Columbia Hospital, W. Palm Beach, FL Francisco A. Kerdel, M.D. Director of Inpatient Dermatology and President of Medical Staff University of Miami, Miami, FL Janet D. Allenby, D.O., FAOCD Program Director, Columbia Hospital, W. Palm Beach, FL Allenby Dermatology, Delray Beach, FL

Abstract

Subacute cutaneous lupus erythematosus (SCLE) is more common in women and presents as a papulosquamous or annular/ polycyclic eruption in sun exposed areas. It is generally thought SCLE has a less severe course than systemic lupus erythematosus, although this is debated. The pathogenesis is multifactorial and is likely a combination of genetic predisposition and environmental factors. First line therapy is sun protection, in addition to various topical and systemic treatments. We report a case of a 49 year old woman who is refractory to multiple therapies. A literature review of the pathogenesis and therapies for SCLE is discussed.

Case Report: have required twice-a-day dosing and more ration, atrophy or scar but can heal with frequent laboratory monitoring. prolonged dyspigmentation, especially A 49-year-old Caucasian female with a hypopigmentation. In addition, lesions history of discoid lupus presented to the of ACLE or DLE may occur in 10-35% of office with a rash on her face and chest Discussion: for three months. Examination revealed multiple erythematous annular plaques Lupus erythematosus is a multisystem on the sides of her face and neck, chest, disorder characterized by autoimmunity and upper back (Figures 1, 2). Review to nucleosomes and ribonucleoproteins. of systems was positive for photosensi- The course is quite varied from mild to tivity and arthralgias of her fingers, knees, very severe disease. James Gillman is cred- and ankles. Pertinent laboratory values ited with dividing the cutaneous mani- included: ANA 1:80 (speckled pattern), festations of lupus into three categories: elevated SS-A antibody (5.4), and normal acute, subacute, and chronic. On one end complete blood count, comprehensive of the spectrum is acute cutaneous lupus metabolic panel, dsDNA antibody, Smith erythematosus (ACLE), which has transient and RNP antibody and SS-B antibody. erythema. This is contrasted to discoid KOH of lesions on chest and face were lupus erythematosus (DLE), which has Figure 1 negative for fungi. Histology examina- chronic, inflamed, indurated papules and tion of the left sideburn revealed cell-poor plaques that lead to scarring and atrophy. interface dermatitis, superficial and deep The skin changes of SCLE are more persis- perivascular and perifollicular lympho- tent than those of ACLE, but unlike DLE histiocytic infiltrate, increased dermal are not associated with scarring. mucin, and necrotic keratinocytes without SCLE was recognized in 1979 by follicular plugging or epidermal atrophy Sontheimer, Thomas, and Gilman. The consistent with subacute cutaneous lupus patients with SCLE typically have a rash erythematosus (SCLE) (Figure 3,4). PAS on sun-exposed areas, involving the V of stain showed very early focal thickening of neck, upper back, shoulders and extensor the epidermal basement membrane (Figure aspects of upper extremities. Contrary 5). At the time of diagnosis, the patient was to other subtypes of lupus, in SCLE, the taking hydroxychloroquine 200 mg BID, mid-face is usually spared, and the sides of Figure 2 etanercept 50 mg/wk, methotrexate 15 mg/ the face are affected. It is more common in wk, prednisone 10 mg/day, and clobetasol women and typically presents in the third lotion. No evidence of discoid lesions or fourth decade of life, although there was present at examination; however, the are a few rare reports of SCLE presenting patient had developed lesions consistent in pediatric patients.1 The lesions are with SCLE. The patient did note that while categorized into two different subtypes but she had had improvement of the arthral- can occur concomitantly. Patients may gias with the current therapy, she desired present with annular/polycyclic plaques to simplify her regimen along with treating or a papulosquamous eruption (eczema- the current rash. It was decided to discon- tous or psoriasiform). Other variants that tinue the etanercept and start adalimumab have been described are: poikiloderma,2,3 due to the every-other-week dosing. erythema multiforme like, erythroderma,4,5 Mycophenolate mofetil was also considered pityriasiform, exanthematous, and neonatal for treatment of SCLE; however, this would lupus erythematosus.6 Lesions lack indu- Figure 3 22 refractory Subacute Cutaneous Lupus Erythematosus patients with SCLE. reports of efalizumab and leflunomide have quine or combined antimalarial therapy Along with the distinctive rash, many shown both success in the treatment of with quinacrine, are beneficial. The patients with SCLE have positive anti- SCLE and an association with drug-induced mechanism of action is multifactorial, Ro/SSA antibodies, although this is not SCLE.13,14,15 In cases of drug-induced SCLE, affecting light filtration as well as working required for diagnosis. Various reports it may take up to four to eight weeks for as an immunosuppressant and anti- have shown a positive anti-Ro/SS-A anti- the cutaneous lesions to resolve after stop- inflammatory agent. Patients who smoke body in 49-90% of patients and a positive ping the medication. There are cases where may be less response to antimalarials.20 anti-La/SS-B in 30-50%.6,7,8 As SCLE is the lesions persist, suggesting that in some Some patients may need a short course fairly recently described, the characteris- patients medications may precipitate SCLE. of oral corticosteroids, but long-term use tics of this entity continue to evolve, with There a few reports of patients with SCLE is discouraged because of the many side current studies often conflicting in regards developing a malignancy. A few authors effects. Methotrexate may be considered to laboratory values, prognosis and severity suggest SCLE could be a paraneoplastic for refractory disease; one case report of disease. Half of the patients fulfill dermatosis; however, this view is not widely showed clinical improvement within four the American College of Rheumatology accepted and is probably coincidental.16-18 weeks without significant side effects. The Criteria for diagnosis for SLE. Whether Histopathology of SCLE is consistent mechanism of action in SCLE is unclear but SCLE has a less severe course compared to with cell-poor interface dermatitis, very may be related to impairment in neutrophil SLE is debatable. In a study by Chlebus often a mild vacuolarization. The epidermis function or regulation of cytokine secre- et al., SCLE patients had significantly less is atrophic with satellite-cell necrosis and tion.21 Mycophenolate mofetil may also be renal involvement, serositis and arthritis little or no hyperkeratosis, follicular plug- considered for resistant disease and may and were less likely to have positive ging, or basement membrane thickening as work by inhibiting cytotoxic T cells. In one anti-dsDNA, anti-Sm, and anti-U1RNP compared to discoid lupus erythematosus. open pilot study, the first signs of improve- compared to SLE patients.9 A more recent The dermis shows edema, mucin deposi- ment were after four weeks, suggesting that report by Black et al., comparing patients tion, and a sparse mononuclear infiltrate patients may also need short-term therapy with SCLE to patients with SLE, showed an around blood vessels and periadnexa, but such as topical or systemic corticosteroids.22 increased frequency of serositis, hemato- occasionally can be lichenoid. It is not Thalidomide appears to decrease inflam- logic disorders, anti-dsDNA, anti-Sm and possible to differentiate between annular matory markers such as TNF-alfa and Fas anti-U1RNP in patients with SLE versus an and papulosquamous lesions histologically. ligand and inhibit UVB-induced apoptosis. increased photosensitivity in patients with Direct immunofluorescence may show a Side effects include drowsiness, dizziness, SCLE. Renal disease was similar between “dust-like particle” pattern of IgG deposi- teratogenicity, peripheral neuropathy, both groups, and central nervous system tion around epidermal basal keratinocytes. and thrombosis. Other therapies to be involvement was rare in both groups.7 The First-line treatment for SCLE is sun considered for treatment of SCLE include percentage of patients who will develop protection with sun protective clothing, azathioprine, retinoids, dapsone, cyclo- 6,23 active SLE including lupus nephritis is hats, sun block, and UV tinted windows. phosphamide, clofazimine, and IVIG. unclear, but the current literature suggests Topical corticosteroids are beneficial for Reports of biologic therapies such as 10-15%.10 Cohen and Crosby noted that localized areas. In one study, there was no TNF-α inhibitors or efalizumab have shown men with papulosquamous SCLE may significant difference in efficacy between success in treating SCLE; however, they have a more severe extracutaneous disease; topical clobetasol and topical tacrolimus. have also been reported to induce SCLE. however, more recently Black et al. noted Therefore, topical calcineurin inhibitors In one article, leflunomide was associated that patients with annular SCLE had more may be considered in the physician’s arma- with remission of SCLE in one patient frequent photosensitivity, arthritis, positive mentarium as steroid-sparing agents.19 and exacerbation of the disease in another 13,14,15 ANA and anti-Ro/SS-A.7,11 Some patients Antimalarials, especially hydroxychloro- patient. with SCLE have an overlap with Sjogren’s SCLE as a distinct entity has only been syndrome and are at an increased risk for defined in the past two decades, therefore other complications including vasculitis, the pathogenesis, clinical associations and peripheral neuropathy, and lymphoma. management will likely continue to evolve. The pathogenesis of SCLE is multifacto- As certain medications can potentially rial and is likely a combination of a genetic cause SCLE, the clinician may consider predisposition and environmental factors. discontinuing likely culprits. First-line Genetic associations include: HLA1, B8, therapies are sun protection, topical thera- DR3, DQ2, DRw52 and C4 null, deficien- pies, and antimalarials. Other treatments cies of C1q, C2 and C4 components of for recalcitrant disease include metho- complement, and TNFα 308 polymor- trexate, mycophenolate mofetil, thalido- phism. Ultraviolet light (especially UVB) mide, and biologic therapy. induces apoptosis and likely exposes self antigens that initiate and perpetuate 8 Figure 4 a state of autoimmunity. Recently, case REFERENCES: reports and reviews have focused atten- 1. Amato L, Coronella G, Berti S, Moretti, Fabbri P. Sub- tion toward drug-induced SCLE. The acute cutaneous lupus erythematosus. Pediatr Dermatol most common drugs implicated include 2003;20:31-4 2. Pramatarov K, Vassileva S, Miteva L. Subacute cutane- hydrochlorothiazide, calcium-channel ous lupus erythematosus presenting with generalized blockers, angiotensin-converting enzyme poikiloderma. JAAD 2000;42:286-288 3. Marzano AV, Facchetti M, Alessi E. Poikilodermatous inhibitors, terbinafine, griseofulvin, and subacute cutaneous lupus erythematosus. Dermatology statins. Other reported cases of drug- 2003;207:285-90 4. Mutasim D. Severe subacute cutaneous lupus erythe- induced Ro/SSA-positive lupus erythema- matosus presenting with generalized erythroderma and tosus include interferon alpha and beta, bullae. JAAD 2003;48:947-949 5. Kalavala M, Shah V, Blackford S. Subacute cutaneous rifampicin, nonsteroidal anti-inflammatory lupus erythematosus presenting as erythroderma. Clin drugs, Aldactone, cinnarizine/thiethylp- Exp Dermatol 2007;32:388-90 6. Wolff K, et al. Fitzpatrick’s Dermatology in General Medi- erazine, psoralen-UV-A, D-penicillamine, cine. 7th ed. The McGraw-Hill Companies, Inc. 2008 and glyburide.12 Interestingly, recent case Figure 5 7. Black DR, Hornung CA, Schneider PD, Callen JP. Fre- quency and severity of systemic disease in patients with Alexander, Kerdel, Allenby 23 subacute cutaneous lupus erythematosus. Arch Derma- tol 2002;138:1175-1178 8. Stavropoulos PG, Goules AV, Avgerinou G, Katsambas AD. Pathogenesis of subacute cutaneous lupus erythematosus. JEADV 2008;22:1281-1289 9. Chlebus E, Wolska H, Blaszczyk M, Jablonska S. Sub- acute cutaneous lupus erythematosus versus systemic lupus erythematosus: Diagnostic criteria and therapeutic implications. JAAD 1998;38:405-412 10. Bolognia JL, Jorizzo JL, Rapini R. Dermatology. 2nd ed. Mosby. 2007 11. Cohen MR, Crosby D. Systemic disease in subacute cutaneous lupus erythematosus: a controlled comparison with systemic lupus erythematosus. J Rheumatol 1994;21:1665-9 12. Srivastava M, et al. Drug-induced, Ro/SSA-Positive Cutaneous Lupus Erythematosus. Arch Dermatol 2003;139:45-49 13. Clayton TH, Ogden S, Goodfield M. Treatment of refractory subacute cutaneous lupus erythematosus with efalizumab. JAAD 2006;54:892-895 14. Bentley D, et al. Efalizumab-induced subacute cutaneous lupus erythematosus. JAAD 2006;54:S242-3 15. Suess A, Sticherling M. Leflunomide in subacute cutaneous lupus erythematosus- two side of the coin. Int J Dermatol 2008;47:83-86 16. Renner R, Sticherling M. Incidental cases of subacute cutaneous lupus erythematosus in association with malignancy. Eur J Dermatol 2008 17. Chaudhry SI, Murphy LA, White IR. Subacute cutaneous lupus erythematosus: a paraneoplastic dermatosis? Clin Exp Dermatol 2005;30:655-8 18. Covan H, Shumak SP, Morris D. Subacute cutaneous lupus erythematosus associated with hepatocellular carcinoma. Austral J Dermatol 2001;42:110-113 19. Tzellos TG, Kouvelas D. Topical tacrolimus and pimecrolimus in the treatment of cutaneous lupus erythematosus: an evidence-based evaluation. Eur J Clin Pharmacol 2008;64:337-41 20. Wolverton SE. Comprehensive Dermatologic Drug Ther- apy. 2nd ed. Saunders Elsevier 2007. 21. Kuhn A, Specker C, Ruzicka T, Lehmann P. Methotrexate treatment for refractory subacute cutaneous lupus erythematosus. JAAD 2002;46:600-603 22. Kreuter A, Tomi NS, Weiner SM, Huger M, Altmeyer P, Gambichler T. Mycophenolate sodium for subacute cutaneous lupus erythematosus resistant to standard therapy. Br J Dermatol 2007;156:1321-1327 23. Lampropoulos CE, Hughes GR, D’Cruz DP. Intravenous immunoglobulin in the treatment of resistant subacute cutaneous lupus erythematosus: a possible alternative. Clin Rheumatol 2007;26:981-3

24 refractory Subacute Cutaneous Lupus Erythematosus Ac r o k eratoelastoidosis w i t h Ov e r l a pp i n g Fe a t u r e s o f De g e n e r a t i v e Co l l a g e n o u s Pl a q u e s o f t h e Ha n d s : A Ca s e Re p o r t & Li t e r a t u r e Re v i e w

Leilani Townsend, D.O. Intern,* Patrick Keehan, D.O.,** Bill Way, D.O., F.A.O.C.D.*** *4th-year medical student, O’Bleness Memorial Hospital, Athens, Ohio **3rd-year dermatology resident, Northeast Regional Medical Center/Kirksville College of Osteopathic Medicine, Department of Dermatology, Texas Division, Duncanville, Texas ***Program Director, Northeast Regional Medical Center/Kirksville College of Osteopathic Medicine, Department of Dermatology, Texas Division, Duncanville, Texas

Abstract

Acrokeratoelastoidosis (AKE) and degenerative collagenous plaques of the hands (DCPH) are two conditions that fall under a group of disorders known as marginal papular acrokeratodermas. Each has been described as a separate entity; however, there is occasional overlap between the conditions. We report a case of a 78-year-old Caucasian woman who has features of both acrokeratoelastoidosis and degenerative collagenous plaques of the hands. Case Presentation: Discussion: plaques on the medial and lateral aspects of the hands, with no foot involvement.4,6 We report the case of a 78-year-old Acrokeratoelastoidosis and degenerative Histopathology reveals a dense zone of Caucasian woman with a one-year history collagenous plaques of the hands are two of mildly pruritic lesions on her hands. of the seven disorders known as marginal She denied any trauma to the lesions. Her papular acrokeratodermas. The remaining family history revealed that her mother, two five conditions that fall into this classifica- brothers, and a sister had similar-appearing tion are focal acral hyperkeratosis, mosaic lesions on their hands. Her past medical acral keratosis, digital papular calcific elas- history was significant for extensive sun tosis, keratoelastoidosis marginalis of the exposure to the area. She also had a history hands, palmoplantar keratoderma of the of renal failure secondary to hypertension punctate type, and hereditary papulotrans- and had been on dialysis for the previous lucent keratoderma. All essentially present four years. with crateriform keratotic papules along On physical examination, flesh-colored the borders of the hands and feet, which plaques on the lateral aspect of the thumbs may coalesce into plaques.1 Marginal and index fingers and the first web space papular acrokeratodermas have a great deal Figure 1 were seen (Figures 1 and 2). Her feet were of clinical and histopathologic overlap, with spared. Additionally, she had solar lentig- one classification system by Rongioletti et ines and actinic damage on the dorsum al. dividing them as hereditary or acquired of her hands. Our differential diagnosis and with or without elastorrhexis (Table included: acrokeratoelastoidosis, degen- 1).2 Several other authors propose that erative collagenous plaques of the hands, they are all relative variations of AKE verrucae planae, acrokeratosis verruci- attributable to variable gene expressions.3,4 formis of Hopf, palmar xanthomas, poro- Focal acral hyperkeratosis is clinically keratosis, and scleroderma. She was treated identical to acrokeratoelastoidosis; however, with topical urea 40% for a suspected kera- elastorrhexis is not present histopatho- toderma. Weeks later, the lesions remained logically. Mosaic acral keratosis is nearly unchanged. identical to focal acral hyperkeratosis A 4-millimeter punch biopsy was except this condition predominantly affects performed with a suspected diagnosis of females and African-American patients and linear keratoderma. The pathology revealed presents with keratotic papules in a jigsaw Figure 2 hyperkeratosis and acanthosis with elastor- pattern on the dorsal aspect of the feet and rhexis, or dermal elastic fiber fragmenta- adjacent lower legs.1 Keratoelastoidosis tion (Figures 3 and 4). A Verhoeff-Van Gieson stain (Figures 5 and 6) gave more marginalis of the hands was first described evidence of fragmentation of elastic fibers. in Australians and has keratotic papules at No solar elastosis or other actinic changes sites of trauma along the index finger and were appreciated. These findings were thumb. There may be a history of chronic consistent with a condition known as acro- sun exposure with this condition.1,5 keratoelastoidosis. Additional treatment DCPH primarily affects sun-damaged with topical 0.05% clobetasol foam was and chronically traumatized skin of the used without any improvement. elderly. There is no known genetic predis- The late presentation in our patient’s life position, although familial cases have been and, clinically, the linear array on her hands reported.4 Patients have symmetrical, also indicated features of a condition called yellowish, keratotic or smooth papules degenerative collagenous plaques of the and plaques affecting the thumb, first web Figure 3 hands (DCPH). Our patient appeared to space, and side of the index finger. These have an overlap of the two conditions. lesions often present as bandlike, linear Townsend, Keehan, Way 25 and soles. Later, he noted 14 Brazilians filaggrin that accumulates in a dense band who developed similar lesions during above the granular layer.9 their adolescence and early twenties. The Studies that have biopsied normal adja- plaques were located on the lower two- cent skin show a normal epidermis with thirds of the anterior legs, upper one-third dermal elastorrhexis, which is sugges- of the dorsal feet, and medial malleoli.8,9 tive of a defect of elastic tissue limited to Occasional keratosis or umbilication of the dermis.8.9 Further studies involving the lesions was seen.10 Since it was first electron microscopy have found rarified, described, several cases of acrokeratoelas- abnormal, damaged elastic tissue and toidosis have been reported. fibroblasts containing dense granules at Typical findings seen in acrokera- the periphery of the cytoplasm without toelastoidosis are 2-4 mm, small, discrete, extracellular fibers. These findings imply Figure 4 grouped, skin-colored papules. Lesions abnormal secretion of elastic material.8,13 are usually seen on the edge of the palms There are few effective reported treat- thickened and distorted collagen with and soles at the line of transgradience, ments for AKE. A topical combination of the boundary between dorsal and either salicylic acid and corticosteroid was tried palmar or plantar skin. Other sites where by one author without success.14 Nelson- lesions can occur are the anterior lower Adesokan et al. reported that etretinate legs, wrists, and fingers.9 Some sources 50 mg daily led to a clinical flattening of state that the lesions coalesce into plaques, the lesions, but the lesions recurred after while others refute this claim.10,11 The discontinuation of the drug.15 Erbil et al. condition is usually asymptomatic.8 attempted to resolve the lesions with an Acrokeratoelastoidosis usually pres- erbium:YAG laser. Only minor clinical ents in childhood or adolescence, but improvement was achieved; however, the cases presenting in adulthood have been lesions did not recur after six months.16 reported as well.1,10 There is no racial predilection, and both sexes are affected Conclusion: equally.1 Although the exact cause of Figure 5 acrokeratoelastoidosis is not fully under- Marginal papular keratodermas are a stood, cases described in the literature group of confusing and overlapping disor- have occurred sporadically or in an ders (summarized in Table 2).5 We present autosomal-dominant pattern.1,10-12 The a case of a woman who has features of autosomal-dominant inheritance pattern both acrokeratoelastoidosis and degen- is characterized by variable incomplete erative collagenous plaques of the hands. penetrance with a proposed link to chro- Her features that are consistent with mosome 2, yet conformational studies have acrokeratoelastoidosis include an auto- not been performed.1,4, 9 There is a reported somal-dominant inheritance pattern and association of AKE with hyperhidrosis, and histopathologic findings. Her age of onset rapid progression of the condition has been and the location of her lesions, however, noted during pregnancy.1,8-10 Repeated favor a diagnosis of DCPH. There are only trauma may have etiological importance, a few reported treatments for these condi- and no malignant changes of the condition tions. Unfortunately, none of the treat- have been reported.1 A possible association ments have resulted in complete resolution. between AKE and nodular scleroderma, With a better understanding of the disease Figure 6 as well as one between an acrokeratoelas- pathogenesis and with further research, toidosis variant and systemic scleroderma, there will hopefully be more treatment fragmentation of elastic fibers. There is have been proposed.6,9-11 Seven of 26 modalities in the future. also overlying hyperkeratosis and acan- patients with systemic scleroderma were thosis. Tajima et al. distinguishes DCPH found to have various AKE variants, from acrokeratoelastoidosis by the pres- leading Tajima et al. to hypothesize that ence of actinic changes and a relative the unique skin lesions may be related to lack of epidermal changes in DCPH.6 the altered connective-tissue metabolism However, there is controversy about exact seen in systemic scleroderma.6 The prog- distinguishing properties, as Abulafia et nosis of AKE is good, as the condition is al. reports that senile, actinic, and solar often asymptomatic with slow progression. elastosis may coexist with collagen degen- However, lesions have a high rate of recur- eration but may not be a critical factor for rence and can be aesthetically undesirable diagnosis.4 There have been reports of to patients.8,11 DCPH with bilateral symmetric nicking of Classical histopathological features of the nail plates.7 Telangiectatic vessels and AKE include: massive orthohyperkeratosis calcifications are other entities often seen overlying a crateriform dell lined by an in DCPH. When calcification is seen, the acanthotic epidermis;1,9 a prominent gran- condition is referred to as digital papular ular layer;10 and reduced numbers of elastic calcific elastosis.1 fibers, with the remaining fibers exhibiting Acrokeratoelastoidosis is a condition fragmentation or elastorrhexis.9 The alter- first described by Oswaldo Costa in 1953. ations of the elastic fibers are prominently Costa observed an 18-year-old Brazilian seen in the reticular dermis, with sparing woman who had a three-year history of of the papillary dermis.10 Keratotic papules small, asymptomatic papules on her palms may be the result of an overproduction of 26 acrokeratoelastoidosis with Overlapping Features of Degenerative Collagenous Plaques of the Hands Table 1

Table 2

Townsend, Keehan, Way 27 REFERENCES: 1 McKee P, Calonje E, Granter S. Pathology of the Skin with Clinical Correlation. China: Elsevier Mosby, 2005. 64-65. 2 Rongioletti F, Betti R, Crosti C, Rebora A. (1994). Mar- ginal popular acrokeratodermas: a unified nosography for focal acral hyperkeratosis, acrokeratosis, acrokeratoelastoidosis and related disorders. Dermatol. 88:28-31. 3 De Boer EM, Van Dijk E. (1985) Acrokeratoelastoidosis: a spectrum of diseases. Dermatol. 171:8-11. 4 Abulafia J, Vignale RA. (2000). Degenerative collagenous plaques of the hands and acrokeratoelastoidosis: pathogenesis and relationship with knuckle pads. Int J Derma- tol. 39:424-32. 5 Zhai Z, Yang X, Hao F. (2006). Acrokeratoelastoidosis. Eur J Dermatol. 162(2): 201-2. 6 Tajima S. Tanaka N, Ishibashi A, Suzuki K. (2002). A variant of acrokeratoelastoidosis in systemic scleroderma: Report of 7 cases. J Am Acad Dermatol. 46(5): 767-70. 7 Jeevankumar B, Thappa DM, Jayanthi S. (2003). Nail involvement in degenerative collagenous plaques of the hands. Indian J Dermatol Venereol Leprol. 69:309-10. 8 Tsai S, Kageyama N, Wartham M, Cockerell C. (2005). Acrokeratoelastoidosis. Int J Dermatol. 44: 406-7. 9 Bogle M., Hwang L, Tschen J. (2002). Acrokeratoelastoi- dosis. J Am Acad Dermatol. 47(3): 448-51. 10 Lewis K, Bercovitch L, Dill S, Robinson-Bostom L. (2004). Acquired disorders of elastic tissue: Part II. Decreased elastic tissue. J Am Acad Dermatol. 51(2): 179-81. 11 Ceccolini E. (2000). Acrokeratoelastoidosis viewed 9 August 2008, 12 Martinez-Mir A, Christiano A. (2003). Basic Principles of Genetics. In: Bolognia J, Jorizzo J, Rapini R. Dermatol- ogy. Edinburgh: Mosby. 819-20. 13 Shea C. (2003). Fibrous Lesions of Dermis and Soft Tissue. In: Freedberg I, Eisen A, Wolff K, Austen K, Gold- smith L, Katz S. Fitzpatrick’s Dermatology in General Medicine. New York: McGraw Hill. 993. 14 Kaya H, Bilgic O, Canpolat F, Eskioglu F, Ustun H. (2006). Acrokeratoelastoidosis of Costa: A Case Report. Turkiye Klinikleri J Dermatol 16: 26-30. 15 Nelson-Adesokan P, Mallory S, Leonardi C, Lund R. (1995). Acrokeratoelastoidosis of Costa. Int J Dermatol. 34(6):431-3. 16 Erbil A, Sezer E, Koc E, Tunca M, Tastan H, Dermi- riz M. (2008). Acrokeratoelastoidosis treated with the erbium:YAG laser. Clin Exp Dermatol. 33(1): 30-1.

28 acrokeratoelastoidosis with Overlapping Features of Degenerative Collagenous Plaques of the Hands Er y t h e m a Mu l t i f o r m e a n d To x i c Ep i d e r m a l Ne c r o l y s i s

Lisa A. Mainier, PhD, PA-C*; Jenifer R. Lloyd, D.O.** *MSIV, Lake Erie College of Medicine ** Co-Director, Residency Program, University Hospitals Health System - Richmond Heights Hospital, Department of Dermatology, Case Western Reserve University School of Medicine, Cleveland, Ohio

Abstract

Erythema multiforme minor (EM), erythema multiforme major (Stevens-Johnson syndrome, or SJS), and toxic epidermal necrolysis 3 (TEN) are cutaneous disorders that represent a continuum of blistering hypersensitivity reactions ranging from mild to severe. While EM minor is a distinct entity with an identifiable cause, SJS and TEN may overlap somewhat in etiology, presentation, and treatment. The differential diagnoses are varied. Diagnosis is made based on clinical presentation and history, but may be confirmed with a skin biopsy. Laboratory studies are nonspecific but necessary for management and prognosis. Treatment mainly consists of supportive care. Supplemental therapies are currently under study and remain controversial. Prognosis depends on etiology, age and previous health of the patient, as well as complications that arise from the disorder itself. This article reviews the clinical characteristics, diagnosis, differentials, and treatment of each of the entities. 4 Case Presentation: spread in a centripetal direction. Typically, (epidermal detachment that occurs after SJS begins with fever, malaise, sore throat lateral pressure to lesion) is a key feature Erythema multiforme minor, erythema and flu-like symptoms anywhere from 1-14 that differentiates TEN from erythema multiforme major, and toxic epidermal days prior to the cutaneous manifestations. multiforme. Although there is an overlap necrolysis are blistering hypersensitivity SJS lesions may be flat, bizarre target of between 10% and 30% epidermal- reactions that range from mild to severe. lesions or purpuric macules that are more detachment body surface area (BSA) in SJS Erythema multiforme minor is a local- extensive and located mostly on the trunk. and TEN, the latter is can also be charac- ized blistering eruption with rare mucosal Usually, there is no skin tenderness, but terized by greater than 30% detachment of involvement. Erythema multiforme major, mild burning and pruritis accompanies BSA. The mucosal and systemic manifesta- also known as Stevens Johnson syndrome the lesions. One mucosal surface may be tions of TEN are more pronounced and (SJS), includes more mucosal and skin evident in EM minor, but may be more may comprise oral pain severe enough to involvement and a moderate prodrome. prominent in SJS. SJS also involves hemor- lead to difficulty swallowing or opening Toxic epidermal necrolysis is similar to rhagic erosions and crusting of the lips, oral the mouth. Severe conjunctivitis causes 2 SJS, involving even more mucosal and skin mucosa, conjunctivae, and urogenital areas. eye pain, extensive swelling and drainage. surfaces and a more severe, acute onset Although the skin lesions of both entities Urogenital mucosal pain may be severe of prodromal symptoms. The incidence are similar, those of SJS are more gener- has been estimated to be 0.01% to 1% for alized, confluent, erythematous lesions Table 3 erythema multiforme. Combined, the inci- involving no less than 10% but no more Risk Factor 0 1 dence of SJS and TEN is approximately two than 30% of the body surface area with the Age (yrs) <40 >40 cases per million people per year, although 1 corresponding mucosal involvement.1,2,3 Associated malignancy - + SJS occurs more frequently than TEN. SJS Toxic epidermal necrolysis is a more Heart rate (bpm) <120 >120 affects younger people, ages 25 to 47, than BUN (mmol/L) <10 >10 TEN, which affects people between the ages severe and widespread reaction that BSA skin detachment (%) <10 >10 of 46 and 63 years.1 always involves the mucous membranes, Serum bicarbonate (mmol/L) >20 <20 begins with a more extensive prodrome of Serum glucose (mmol/L) <14 >14 rapid onset high fever, and has systemic symptoms similar to sepsis followed by Background generalized, widely distributed erythema- Table 4 Both erythema multiforme minor and tous macules that eventually coalesce to No. of Risk Factors Mortality Rate % SJS begin with “target” lesions, which are confluent erythema with more pronounced 0-1 3.2 erythematous macules with purpuric skin pain. The skin then develops large 2 12.1 centers and edematous papules with vesic- blisters that eventually break and slough, 3 35.3 ular centers that may become dusky violet. leaving denuded skin that becomes 4 58.3 The lesions of EM are located mostly on profoundly erythematous and may be 5+ >90 the extensor surfaces of the extremities, covered by gray, pseudomembranous exudates. A positive Nikolsky’s sign

Table 1 Differential Diagnoses for EM minor, SJS, and TEN Table 2 Fixed drug reactions Drug eruptions: erythematous, pustular, and phototoxic Treatment of Erythema Multiforme Minor Necrotizing vasculitis No treatment – resolution in 2-3 weeks without complications Toxic shock syndrome and staphylococcal scalded skin syndrome Symptomatic treatment – oral diphenhydramine elixer, local skin care with Burrow solution, viscous Septicemia Pemphigoid lidocaine, topical steroids, saline mouthwash, analgesics Pemphigus vulgaris IV/Oral acyclovir, famciclovir, or valacyclovir in cases of Herpes-induced EM minor, i.e.: acyclovir IV Recurrent aphthous ulcers Serum sickness 10mg/kg over 1hr q 8 hr x 5 days OR acyclovir 600-800mg PO BID x 10 days; famciclovir 125 mg PO q12 Urticaria hr x 5 days Secondary syphilis May require 6 to 12 months treatment with antiviral if > 5 recurrences per year: valacyclovir 500 mg PO Behcet syndrome Viral exanthems BID

Mainier, Lloyd 29 enough to cause urinary retention and presented in Table 1. symptoms are recognized. As mentioned phimosis.2,4 previously, long-term antiviral agents for recurrent herpes simplex infections are Treatment beneficial for those with recurrent herpes Etiology and Pathology simplex-associated EM minor. The treatment for EM minor is Very commonly, erythema multiforme supportive, as the condition is self limited minor may be idiopathic or may follow and will resolve in 2-3 weeks without Prognosis & Complications a herpes simplex virus infection, but it complications. Symptomatic treatment may may also follow mycoplasma infections. include oral antihistamines, analgesics, and EM minor is a self-limited process that SJS, more than TEN, on the other hand, is local skin and mucosal care. Systemic corti- resolves within 2-3 weeks, during which more frequently associated with exogenous costeroids are controversial; however, less time re-epithelialization occurs. The time agents, mainly medications including potent topical steroids are often employed for SJS and TEN to resolve is at least 3 to 6 sulfonamides, allopurinol, NSAIDs, and for symptomatic relief of skin lesions. If weeks depending on concurrent complica- anticonvulsants. TEN is almost exclusively EM minor is HSV-induced, patients may tions of fluid and electrolyte imbalances, associated with drug reactions,3 especially benefit from oral antiviral medications. secondary infection, age of patient, and noted in patients who are “slow acetyla- Low-dose, long-term antiviral medications extent of skin sloughing. Younger patients, tors,” those with low N-acetylation func- are also useful for recurrent HSV outbreaks notably children, rarely have complication and those with demonstrated HLA (greater than five per year) to avoid the tions and have a better prognosis than the subtypes, particularly HLA-B. It appears recurrence of EM minor (Table 2). elderly. SJS has a better prognosis than that the prolonged existence of the drug Treatment measures for SJS and TEN TEN. The mortality rate for SJS is 1-3 metabolites cause an immunologically require extensive supportive care tanta- percent, whereas mortality rates for TEN 14 induced reaction to keratinocytes, causing mount to thermal burn management, are as high as 25% in some studies. 5 mass apoptosis. Some viral infections, especially in more severe cases when more Long-term cutaneous effects that may including HIV, have shown some corre- than 30% of body surface area is involved. occur following SJS and TEN are scar- lation, as the immune system is already Treating the underlying process, including ring, hypo- or hyperpigmentation, nail impaired. Some physical stimuli, such as cessation of the causative agent, usually dystrophy, alopecia, and eruptive nevi, UV light and radiation therapy, may be a medication, is the initial management, all of which may be permanent.10 Other 6 co-factors as well. followed by electrolyte and fluid resusci- complications are related to systemic and tation, respiratory support, antibiotics if non-cutaneous involvement. For instance, necessary, and pain control. Cutaneous mucosal lesions may heal with scarring Diagnosis & Differentials lesions require fastidious wound care, with rare but possible strictures of the accompanied by the use of Burrows esophagus, bronchi, urethra, vagina, and Diagnosis is made from clinical picture solution or Domeboro, saline rinse and anus. Ocular complications may consist of and histopathological studies, as there are viscous lidocaine for oral lesions. The corneal erosions, synechiae, corneal opaci- no laboratory findings that are specific for use of systemic corticosteroids is thought ties, anterior uveitis, panophthalmitis, and SJS and TEN. Routine studies will demon- not to improve prognosis and may actu- even blindness. In severe cases, GI hemor- strate moderate leukocytosis with atypical ally increase the risk of complications, rhage, renal failure, or respiratory failure lymphocytes, mild anemia, and possible according to some studies, which are may result in permanent organ damage or eosinophilia. A markedly elevated WBC ongoing.9 death.15 indicates co-infection. Electrolytes may be Outside of supportive care, supple- The SCORTEN scale, a more statistical abnormal from mucosal and cutaneous mentary therapies have been studied. approach to determining prognosis, has fluid loss. BUN and creatinine abnormali- Intravenous immunoglobulin (IVIG) been studied and instituted. It is a scale of ties indicate a need for hospitalization. has been studied, with various results seven independent risk factors, systemi- Hepatic transaminases may be abnormal depending on dose. It appears that cally applied, that closely predict patient if there is liver involvement. Sedimentation high-dose, early use of IVIG may reduce mortality. The independent risk factors rate, although elevated, is non-specific. mucosal detachment and decrease days of include age greater than 40, presence of Other labs may be indicated to deter- symptoms.10 Other studies show possible malignancy (including evolving cancer and mine etiology of reaction based on clinical positive benefits of systemic corticoster- hematological malignancies), tachycardia history or to assess concominent and oids, and the debate continues as further 120 bpm or greater, initial percentage of subsequent complications. Additional studies report conflicting results.11 Another epidermal detachment greater than 10%, studies may include CXR, blood and tissue adjunct is the use of plasmapheresis to BUN above 10 mmol/L, serum glucose cultures, HSV antigens and other tests to levels above 14 mmol/L, and bicarbonate 7 remove toxins, drugs, metabolites or cyto- rule out any underlying pathology. toxic mediators, but conclusive evidence below 20 mmol/L (Table 3). The mortality Although the diagnosis is mostly based of decreased morbidity and increased rates are then adjusted according to the on clinical signs and symptoms, a definitive prognosis does not exist at this time.12 number of risk factors present (Table 4). diagnosis may also be derived by adjunctive Thalidomide, an antitumor necrosis factor, The easily measured laboratory and clin- cutaneous biopsy for routine and immu- has been discounted as a possible treat- ical variables make the SCORTEN scale nohistochemical studies. Histologically, ment option due to significant increased straightforward, easy to implement in burn moderate amounts of lymphocytic mortality during studies.13 units and ICUs, and is a relatively accurate 16,17 infiltrate both perivascularly and at the Preventive measures should be under- predictor of death from TEN. dermo-epidermal junction are noted. As taken for all patients who have experienced the reaction continues, there will be dermal EM minor, SJS, or TEN, especially avoid- edema and keratinocyte necrosis in the ance of causative agents, medications, and Conclusion epidermal layer with subsequent subepi- 8 other triggers. Recurrence is more common dermal bullae formation. in EM minor and less so with SJS and TEN. SJS and TEN are cutaneous blistering Some other cutaneous problems may Patients should be informed of potential disorders characterized by extensive patho- present in a similar fashion to SJS or TEN. triggers and symptoms of EM and advised logic, exfoliative lesions of the skin and Other differentials to be considered are to seek medical treatment as soon as mucous membranes. The etiology of these 30 erythema Multiforme and Toxic Epidermal Necrolysis disorders in some cases may be uncertain, but TEN is almost always associated with adverse drug reactions. SJS may be idiopathic or associated with infections, drugs, immunologic disorders, malignancy, or even physical triggers. Although supportive therapies are the mainstay of treatment, it is imperative for clinicians to promptly identify the clinical presentation and search for the underlying cause of the hypersensitivity reaction. Expeditious withdrawal of the offending agent or treatment of the underlying trigger is key to improving prognosis and is the initial step in treatment. For SJS and TEN with 30% or greater BSA involvement, treatment in a burn unit has been shown to improve outcome. Medical history and attention to clinical signs and symptoms of the disorders will guide appropriate treatment.

References: 1. Schopf E, Stuhmer A, Rzany B, Victor N, Zentgraf R, Kapp JF. Toxic epidermal necrolysis and Stevens-John- son syndrome. An epidemiologic study from West Ger- many. Arch Dermatol. 1991; 127:6. 2. Bastuji-Garin S, Rzany B, Stern RS, Shear NH, Naldi L, Roujeau JC. Clinical classification of cases of toxic epidermal necrolysis, Stevens-Johnson syndrome and erythema multiforme. Arch Dermatol. 1993; 129: 92-96. 3. Assier H, Bastuji-Garin S, Revuz, J, Roujeau JC. Ery- thema multiforme with mucous membrane involvement and Stevens-Johnson syndrome are clinically different disorders with distinct causes. Arch Dermatol. 1995; 131:539. 4. Roujeau JC. The spectrum of Steven-Johnson syndrome and toxic epidermal necrolysis; a clinical classification. J Invest Dermatol. 1994; 102:285. 5. Dietrich A, Kawakubo Y, Rzany B, et al. Low N-acetylating capacity in patients with Stevens-Johnson syndrome and toxic epidermal necrolysis. Exp Dermatol. 1995; 4:313. 6. Sommers KR, Kong KM, Bui DT, et al. Stevens-Johnson syndrome/toxic epidermal necrolysis in a patient receiving concurrent radiation and gemcitabine. Anticancer Drugs. 2003: 14:659. 7. Huff JC Weston WL, Tonnesen MG. Erythema multiforme: a critical review of characteristics, diagnostic criteria and causes. J Am Acad Dermatol. 1983; 8:763. 8. Cote, B, Wechsler J, Bastuji-Garin S, Assier H, et al. Clinicopathologic correlation in erythema multiforme and Stevens-Johnson syndrome. Arch Dermatol. 1995; 131:1268. 9. Chave TA, Mortimer NJ, Sladden MJ, et al. Toxic epidermal necrolysis: current evidence, practical management and future direction. Br J Dermatol. 2005; 153:241. 10. French LE, Trent JT, Kerdel FA. Use of intravenous immunoglobulin in toxic epidermal necrolysis and Ste- vens-Johnson syndrome; Our current understanding. Int Immunopharmacol. 2006; 6:543. 11. Halebian PH, Corder VJ, Madden MR, Finkelstein JL, Shires GT. Improved burn center survival of patients with toxic epidermal necrolysis managed without corticosteroids. Ann Surg. 1986; 204:503. 12. Egan CA, Grant WJ, Morris SE, et al. Plasmapharesis as adjunct treatment in toxic epidermal necrolysis. J Am Acad Dermatol. 1999; 40:458. 13. Wolkstein P, Latarjet J, Roujeau JC, et al. Randomized comparison of thalidomide versus placebo in toxic epidermal necrolysis. Lancet. 1998; 352:1586. 14. Letko E, Papaliodis DN, Papaliodis GN, et al. Stevens- Johnson syndrome and toxic epidermal necrolysis: a review of the literature. Ann Allergy Asthma Immunol. 2005; 94:419. 15. Sheridan RL, Schulz JT, Ryan CM, et al. Long-term consequences of toxic epidermal necrolysis in children. Pediatrics. 2002; 109:74. 16. Trent JT, Kirsner RS, Romanelli P, Kerdel FA. Use of SCORTEN to accurately predict mortality in patients with toxic epidermal necrolysis in the United States. Arch Der- matol. 2004; 140:890. 17. Bastuji-Garin S, Fouchard N, Bertocchi M, Roujeau JC, Revuz J, Wolkenstein P. SCORTEN: a severity-of-illness score for toxic epidermal necrolysis. J Invest Dermatol. 2000; 115:149. 18. Roujeau JC, Stern RS. Severe adverse cutaneous reactions to drugs. N Engl J Med. 1994; 331:1272.

Mainier, Lloyd 31 Su cc e s s f u l Us e o f a Fu l l Th i ck n e s s Sk i n Gr a f t t o Re p a i r a La r g e De f e c t o n t h e Do r s a l Ha n d a n d Wr i s t

Travis Hamblin, MSII,* Adam Wray, D.O., F.A.O.C.D.** *MSII, AZCOM at Midwestern University, Glendale, Arizona **Bingham Memorial Hospital, Blackfoot, Idaho

Abstract

Surgical repair of defects using Full Thickness Skin Grafts (FTSG) has been well documented and researched. We present a unique case of successful closure of a large defect on the dorsal hand and wrist following Mohs surgery to remove a Basosquamous cell carcinoma. A FTSG was harvested and utilized from the medial arm which is a nonstandard harvest site for the dorsal wrist. The size of the defect, 7.5 X 5.5 cm, was also relatively large for the conventional use of a FTSG.

Case Report: dure will maintain normal function of the wrist and hand as well as provide adequate An 83-year-old Caucasian male cosmesis. Normally, second intention presented to the dermatology clinic as a healing and primary closure are not suit- referral from his primary care physician able options due to contraction or tension, for a lesion on his right wrist. The patient which limit flexion of the hand. Local flaps stated that the lesion had been an open are also a poor choice due to the adjacent sore for approximately six years and had skin often being tight, thin, and fragile.1 started bleeding more than usual, which Skin grafts provide an alternative that prompted his visit. Physical exam revealed allows for the maintaining of function as a 4.0 x 2.5 cm tumor of the right dorso- well as a cosmetically acceptable outcome. lateral wrist with central ulceration and a The first report of a successful human rolled, pearly border. A punch biopsy of skin graft was by Bünger, a German physi- 2 days Post Operation the right dorsolateral wrist revealed a baso- cian, in 1823. Bünger successfully grafted philic tumor with deep invasion as well skin from a patient’s buttock onto his as eosinophilic nests of tumor cells with nose.2 Since then, much advancement has keratin pearls demonstrating features of been made in the procedure. Two primary basosquamous cell carcinoma. Treatment types of skin grafts are full-thickness skin options were discussed with the patient, grafts (FTSG), consisting of the entire and Mohs surgery was agreed upon. epidermis and dermis, and split-thickness The patient was brought back to the skin grafts (STSG), consisting of epidermis clinic, and Mohs surgery was performed and a varying thickness of dermis. Both on his wrist. The lesion was removed in have their advantages and disadvantages, two stages in the standard fashion. The which will be discussed herein. final defect measured 7.5 x 5.5 cm with STSGs are usually harvested from some bone and tendon exposed at the base. the buttock, thigh, or abdomen and are Closure options were discussed with the effective in covering large defects. They 8 days Post Operation patient, and it was decided that the lesion are also suitable in treating wounds that would be closed with a full-thickness skin lack adequate vascularization, which graft using his left medial arm as donor is one of their main advantages.3 Due to tissue. The patient returned two days later their reduced nutritional requirements, for follow-up and was also seen eight days, they offer a better chance of survival than 20 days, and 3.5 months postoperatively. FTSGs.3 Their transparent nature makes The graft took well, without necrosis and STSGs an ideal selection when covering with adequate cosmesis. The donor site the bed of an aggressive tumor, since they had also healed well, without deformity provide a “window” for skin cancer inspec- or impairment of function. The patient tion.4 The STSG is usually not the most had a favorable outcome using his left cosmetically viable option due to poor medial arm to close a rather large defect of color matching with the recipient site as the right dorsolateral wrist with minimal well as its propensity for contraction, which 20 days Post Operation exposed tendon and bone. has been estimated to be as much as 70%.5 For this reason, caution should be taken anatomical locations that would other- when using this graft near free margins.6,7 Discussion FTSGs, on the other hand, contract less and wise have their function compromised by provide adequate color as well as tissue- contraction of the graft. They appear to When confronted with repairing a texture match when a suitable donor site be much easier to harvest and secure to surgical defect on the dorsal hand or wrist, is selected. This allows them to be used their recipient site than STSGs.3 Due to it is important to determine which proce- to repair defects on the face as well as in their increased nutritional requirements, 32 successful Use of a Full Thickness Skin Graft to Repair a Large Defect on the Dorsal Hand and Wrist provide more suitable pigment or hair- bearing qualities than the upper extremity sites, making them less ideal in most situ- ations involving the dorsal hand and wrist. The medial arm provided a suitable option for closure of our patient’s defect and resulted in adequate range of motion and cosmesis.

References: 1. Gloster H, Daoud M, Roenigk R. The Use of Full-Thick- 3.5 Months Post Operation ness Skin Grafts for the Repair of Defects on the Dorsal Hand and Digits. Dermatol Surg. 1995;21:953-959. 2. Bünger C. Gelungener Versuch einer Nasenbildung. J Chir Augenk. 1823;4:569. 3. Adams D, Ramsey M. Grafts in Dermatological Surgery: Review and Update on Full-and Split –Thickness Skin Grafts, Free Cartilage Grafts, and Composite Grafts. Der- matol Surg. 2005;31:1055-1067. 4. Hurwitz DJ, White WL. Application of glove designs in resurfacing the dorsum of the hand. Plast Reconstr Surg. 1976;62:385-389 5. Skouge JW. Techniques for split-thickness skin grafting. J Dermatol Surg. 1987;13:841-849 6. Small RG, Sahl WJ. The use of split-thickness skin grafts for eyelid and facial reconstruction after Mohs’ fresh tissue surgery. Ophthal Plast Reconstr Surg. 1989;5:266- 270 7. Pitkanen JM, Al-Qattan MM, Russel NA. Immediate coverage of exposed, denuded cranial bone with split- thickness skin grafts. Ann Plast Surg. 2000;45:118-121 8. Mack GR. Superficial anatomy and cutaneous surgery of Intraoperative the hand. Adv Dermatol. 1992;7:315-351 9. Wheeland RG. Skin Grafts. In: Roenigk RK, Roenigk HH, Jr. eds. Dermatologic Surgery: Principles and Practice. FTSGs are more prone to necrosis. They New York: Marcel Dekker, 1989;26:323-345 are also limited in size due to the secondary defect created at the donor site. Gloster et al. suggest the FTSG for repair of defects larger than 1.0 cm on the dorsal hand since dorsal laxity in the hand is approximately 1.0 cm in almost all functional positions.8 FTSGs also resist wound contraction in up to 80% of cases, making them ideal for preserving function.9 The FTSG was the choice of closure for this particular patient even though the size of the defect would suggest caution be taken when considering an FTSG. It was felt that with the proper donor site, this option would provide the most favorable outcome. Selecting a donor site for a particular defect requires evaluation of the characteristics of the skin surrounding the defect. These include texture, color, and thickness as well as depth and size of the defect. An ideal match would include all of the above, and the physician should utilize all anatomical locations to ensure a suitable match is found. Another factor to consider when choosing a donor site is the secondary wound created by the harvesting of the donor tissue. Ease of closure, cosmesis, and scarring are all aspects that must be discussed with the patient. Typical donor sites for the dorsal hand and wrist include the anterior axillary fold, the antecubital fossa, the volar wrist, and the inguinal fold. However, when harvesting grafts from the volar wrist, care should be taken not to damage the palmar sensory branch of the median nerve. The consequences of a scar on the wrist, which could be perceived as a “suicide scar,” must also be discussed with the patient when considering the volar wrist as a donor site.1 Inguinal grafts rarely

Hamblin, Wray 33 Re c a l c i t r a n t Py o d e r m a Ga n g r e n o s u m

Michelle W. Foley, DO,* Brett Bender, DO,** Maureen Cliffel, DO,***, Michael Mahon, DO**** *Dermatology Resident, 2nd year, Michigan State University, POH Regional Medical Center **Middlebelt Dermatology Center, Farmington Hills, Michigan ***Brighton Dermatology, Brighton, Michigan; Director of POH/Baybrooke Dermatology Clinic, Pontiac, Michigan ****Program Director, POH/Botsford Hospital Consortium – Michigan State University; Middlebelt Dermatology Center, Farmington Hills, Michigan

Abstract

Pyoderma gangrenosum (PG) is an uncommon, chronic, ulcerative disease with a distinct morphology and systemic associations. The pathogenesis of PG is largely unknown, however, autoimmune mechanisms have been suggested. PG is often difficult to manage because of its recurrent nature and poor responsiveness to therapy. Although local wound care and topical agents may be sufficient to control the disease process in mild cases, a combination with systemic therapy is usually necessary.

Case Report lipid antibodies, urinalysis, and heme occult were all unremarkable. Her trig- A 28-year-old Caucasian female lycerides were elevated at 380 mg/dl. Her presented with a 3.5-year history of total cholesterol was 318 mg/dl and LDL non-healing leg ulcers that began with a was 200 mg/dl, both elevated. The patient “cat-scratch” in 2003. She had undergone did not obtain HLA-B51 and HLA-B27 as multiple antibiotic therapies and wound requested. debridements without successful resolution of her wounds. She was placed on oral Histopathology prednisone by Ophthalmology following an episode of diffuse anterior scleritis Skin biopsy of a new lesion revealed and uveitis, and began to notice improve- epidermal ulceration with a base of granu- Figure 1 ment in her leg wounds. Ophthalmology lation tissue and infiltrate of extravasated referred her to our clinic. erythrocytes, neutrophils, lymphocytes, The patient had a past medical history and siderophages. Intraepidermal and significant for morbid obesity, GERD, subepidermal pustular vesiculation were and hypertension. Her family history was seen (Fig 1), as well as dermal fibrosis and significant for Type 2 diabetes. Her medi- scar. Gram stain, Fite stain, and PAS stain cations at presentation included lisinopril, were all negative. Lasix, Pepcid, and prednisone 80 mg daily. She denied any personal or family history Course and Therapy of inflammatory bowel disease, rheuma- The patient’s clinical and histological toid arthritis, or blood disorders. She evaluations were consistent with the diag- denied fever, chills, weight loss, diarrhea, nosis of pyoderma gangrenosum. Her or fatigue. The patient was not following condition flared with attempts to wean Figure 2 up with a physician regularly because she is oral prednisone and appeared to exhibit uninsured. pathergy to intralesional injections. Tetracycline and topical tacrolimus also Physical Exam failed. She developed bilateral pulmonary Examination revealed a morbidly obese emboli while taking dapsone. Her hyper- female with three lower-extremity ulcers coagulable work-up was negative. Some on a mildly erythematous base with raised success was achieved with cyclosporine over violaceous boarders. The ulcers varied 1.5 years; however, the patient’s elevating from 4 mm to 1 cm in size. Several small blood pressure and creatinine called for areas of “bound-down” scar tissue without discontinuation of the drug. Methotrexate ulceration were also present. She had caused the patient severe ringing in the palpable pedal pulses bilaterally and 2+ ears, and was also discontinued. A two- pitting edema. Her oral mucosa was clear. month trial of subcutaneous adalimumab Figure 3 She refused a genital exam but reported no yielded some improvement but ulti- genital symptoms. mately resulted in discontinuation after currently awaiting judgment of award of recurrent wound infections with multi- state monetary and medical aid. She is also Laboratory resistant Gram-negative coliforms. Her seeking county assistance for obtaining a wounds continue to wax and wane (Fig 2, colonoscopy and bone-marrow biopsy to The patient’s CBC with smear, CMP, 3), and her wound infections are treated definitively rule out any underlying, associ- ANA, RA, VDRL, HIV, p-ANCA, c-ANCA, on a case-by-case basis. Because of her ated conditions. hepatitis panel, ACE level, antiphospho- uninsured and unemployed status, she is

34 recalcitrant Pyoderma Gangrenosum Discussion are numerous other reported successful treatment modalities including, but not Pyoderma gangrenosum (PG) is an limited to, thalidomide, methotrexate, uncommon, chronic, recurrent, ulcerative azathioprine, mycophenolate mofetil, disease with a distinctive morphologic cyclophosphamide, TNF-alpha inhibitors, presentation. It was first described by IVIg, and plasmapheresis.1,2,3,6,7 Brocq in 1916, and in 1930, Brunsting, Goeckerman, and O’Leary coined the term “pyoderma gangrenosum.”1 PG was REFERENCES: once considered pathognomonic of idio- 1. Bolognia J, Jorizzo JL, Rapini R. Dermatology. Vol 1, 2nd pathic ulcerative colitis, but has since been edn. Spain: Elsevier, 2008:383-86. described in association with a wide variety 2. Reichrath J, Bens G, Bonowitz A, Tilgen W. Treatment recommendations for pyoderma gangrenosum: An evi- of disorders including Crohn’s disease, dence-based review of the literature based on more than arthritis, rheumatologic and hematologic 350 patients. J Am Acad Dermatol. 2005;53:273-83. 3. Crowson AN, Magro C, Mihm MC. Pyoderma gangreno- conditions, sarcoidosis, HIV infection, sum: a review. J Cutan Pathol. 2003;30:97–107. iatrogenic immune suppression, PAPA 4. Brown TS, Marshall GS, Callen JP. Cavitating pulmonary infiltrate in an adolescent with pyoderma gangrenosum: a syndrome, and malignancy. Reports of rarely recognized extracutaneous manifestation of a neu- drug-induced PG include PTU, granulocyte trophilic dermatosis. J Am Acad Dermatol. 2000;43:108– 112. colony-stimulating factor, interferons, and 5. Jorizzo JL, Solomon AR, Zanolli MD, Leshin B. Neu- anti-psychotic medications as offending trophilic vascular reactions. J Am Acad Dermatol. 1988;19:983–1005. agents. Despite its associations, pyoderma 6. Lyon CC, Kirby B, Griffiths CE. Recalcitrant pyoderma gangrenosum is idiopathic in 25-50 percent gangrenosum. Br J Dermatol. 1999;140:562–564. 2 7. Ljung T, Staun M, Grove O, Fausa O, Vatn MH, Hell- of patients affected. strom PM. Pyoderma gangrenosum associated with Crohn disease: effect of TNF-alpha blockade with inflix- The pathogenesis of PG is largely imab. Scand J Gastroenterol. 2002;37:1108–1110. unknown, but autoimmune mechanisms such as immune complex-mediated neutrophilic vascular reactions, defects in cell-mediated and/or humoral immunity, and defects in neutrophil and monocyte function have all been proposed.1,2,3,4 The disease occurs most commonly in females 20-50 years old. PG can occur in infants and children, but this only accounts for approximately 4 percent of cases.1 Extracutaneous sites of PG have been reported, including involvement of bones, lungs, liver, pancreas, spleen, kidneys, and CNS.4 The classic morphology of pyoderma gangrenosum is an ulcer. The lesions usually begin as a tender papulopustule with surrounding erythematous or violaceous induration, an erythematous nodule, or a bulla on a violaceous base.1 The lesions typically undergo necrosis, leading to a central shallow or deep ulcer. Once fully developed, the ulcer has a purulent base with an irregular, undermined and overhanging, gunmetal-colored border that extends centrifugally. The lesions most commonly occur on the lower extremities but can occur anywhere.1,3,5 The histopathology of PG can be nonspecific, especially when the disease is partially treated or minimally inflamed. Sampling of chronic lesions may result in a non-diagnostic biopsy and is not recommended.1,3 There are no established guidelines for the treatment of pyoderma gangrenosum. Local or combined local and systemic corticosteroid therapy with or without adjunctive systemic therapy is generally standard. Mild disease may only require topical treatment with the possible addition of dapsone and oral antibiotics, such as tetracycline. First-line systemic treatment for more involved cases usually includes corticosteroids and/or cyclosporine. There Foley, Bender, Cliffel, Mahon 35 Granulomatous Sl a ck Sk i n

Brooke L. Renner, D.O.,* Michelle Foley, D.O.,** Wendy L. McFalda, D.O.,*** Michael Mahon, D.O., F.A.O.C.D.**** *Dermatology Resident, PGY II, Michigan State University-Botsford/ Pontiac Osteopathic Hospital Dermatology Residency **Dermatology Resident, PGY III, Michigan State University-Botsford/ Pontiac Osteopathic Hospital Dermatology Residency ***Clarkston Dermatology, Clarkston, Michigan ****Program Director, Michigan State University-Botsford/ Pontiac Osteopathic Hospital Dermatology Residency

Abstract

Granulomatous slack skin (GSS) is a rare cutaneous t-cell lymphoma which is currently categorized as a subtype of mycosis fungoides. It has an interesting clinical presentation in which indurated patches and plaques slowly evolve into pendulous hyperpigmented folds of skin. It has an indolent course, but is often associated with the development of lymphoproliferative malignancies, such as acute myeloid leukemia and Hodgkin’s disease. Here we present a case of GSS and discuss its clinical presentation, histology, relevant associations with systemic disease, and treatment options.

GRANULOMATOUS lower extremities. The rest of her physical exam was within normal limits. The SLACK SKIN patient experienced mild pruritus in the lesion, but it was otherwise asymptomatic. A 50-year-old Caucasian female She denied any nausea, vomiting, fever, presented to our office with an eight-year or chills, but admitted to occasional night history of a persistent skin eruption on her sweats and intentional recent weight loss. abdomen. It had previously been biopsied several times by other physicians, but A skin biopsy was taken from her left never definitively diagnosed. Clinically, lower abdomen, revealing an atypical her diagnoses over the years included lymphoid infiltrate with epidermotropism, lichen simplex chronicus, contact derma- granulomatous inflammation, and several titis, tinea, morphea, and lichen amyloi- large, multinucleated histiocytes suggestive dosis. Her first biopsy was taken from of granulomatous slack skin (Figures 2 Figure 1 her left lower abdomen in 2004, following and 3). A subsequent full-body CAT scan a prolonged course of topical steroids. was within normal limits. Blood work, It revealed spongiotic lichenoid derma- including routine chemistries, electrolytes, titis suggestive of parapsoriasis or early iron studies, and hepatitis antibodies, was patch-stage mycosis fungoides, but a repeat within normal limits. Immunostains were biopsy was recommended to substantiate performed on the sample, and the atyp- these findings. She was re-biopsied that ical lymphoid infiltrate was positive for month, just medial to the original site, expression of CD2, CD3, CD4 and CD5, and the sample was sent to a different but negative for CD30. CD7 and CD8 pathologist. That second biopsy, along expression was only present on a small with a review of her clinical photographs, subset of lymphocytes in the dermis. A led to a diagnosis of contact dermatitis T-cell PCR analysis of the sample did not or early inflammatory granuloma annu- show any evidence of a monoclonal T-cell Figure 2 lare. The patient was subsequently population. The patient was referred to an instructed to avoid nickel and to continue academic multidisciplinary dermatology mid-potency topical steroids three times center that initiated treatment with subcu- daily. Occasional intra-lesional steroid taneous interferon beta 1-α, topical bexaro- injections were administered as needed for tene, and narrowband UVB phototherapy. control of flares. In 2006, the condition Granulomatous slack skin (GSS) is an still had not resolved, and a DTM-culture extremely rare dermatologic disorder, with for fungus was performed with negative less than 50 cases reported to date in the results. A third skin biopsy was taken, literature. The most current World Health from the right side of the abdomen, which Organization-European Organization showed subacute spongiotic and lichenoid for Research and Treatment of Cancer dermatitis. She was instructed to continue (WHO-EORTC) classification of cutaneous lymphomas designates GSS as a treatment with topical steroids. Figure 3 In 2008, the patient presented to our subtype of mycosis fungoides. Due to the lack of strong supporting cytogenetic practice for the first time. Physical exam in other sites of the body.2 The first lesions showed a healthy-appearing female in evidence, it remains unclear whether GSS may actually be its own distinct type of are usually indurated patches and plaques, no apparent distress. Over her lower 1 which then evolve into hyperpigmented, abdomen there was a large, indurated and primary cutaneous T-cell lymphoma. GSS clinically presents with large, pendulous redundant skin folds. Atrophy and ulcer- erythematous plaque with foci of crinkling 2,3 and hyperpigmented folds of skin most ation may ensue. and atrophy (Figure1). Satellite macules The histology consists of non-case- were present over her groin, buttocks, and commonly seen in the axilla, groin and abdomen. It has, however, been reported ating granulomas and an upper dermal

36 granulomatous Slack Skin lymphohistiocytic band-like infiltrate of small- to medium-sized cells. There is a characteristic dermal elastolysis with loss of both papillary and reticular dermal elastic tissue seen clearly with Verhoeff-van Gieson staining. Occasional multinucleated giant cells containing phagocytosed elastic fibers are also present.4 The course of GSS is slow and indolent, and it seldom demonstrates extracutaneous involvement. Only in rare cases have granulomatous involvement of the lymph nodes, pulmonary system, bone marrow, and spleen been reported.4 Interestingly, about half of reported cases have been described to precede, be concurrent with, or follow the development of a lymphoproliferative disorder. The most frequently reported lymphoproliferative disorders include Hodgkin and non- Hodgkin lymphoma, mycosis fungoides, acute myeloid leukemia, and Langerhans cell histiocytosis. Because of this association, long-term follow-up is warranted in all patients.2 Due to the paucity of reported cases, the indolent course of this disorder, and failure of most attempted treatments, no standardized therapy has been widely accepted. PUVA, UVB, poly-chemotherapy, interferon, systemic steroids, radiotherapy, immune modulators, and surgery have all been tried alone or in combination, with only two complete remissions currently reported.5 It seems that a combination of modalities is most appropriate. Surgery can be utilized for functional or cosmetic concerns, topical treatments can slow disease progression, and systemic therapy can be used to treat severe or extracutaneous involvement. 2 Until more is known about this interesting disorder, therapy should be tailored based on the stage of the disease, patient goals, compliance, geographic limitations, and tolerability of side effects.

References: 1. Ikonomou IM, Aamot HV, Heim S, Fosså A, Delabie J. Granulomatous slack skin with a translocation t(3;9) (q12;p24). Am J Surg Pathol. 2007 May;31(5):803-6. 2. Van Haselen CW, Toonstra J, van der Putte SJ, van Dongen JJ, van Hees CL, van Vloten WA. Granuloma- tous slack skin. Report of three patients with an updated review of the literature. Dermatology. 1998;196(4):382- 91. 3. Kavusi S, Nazemi MJ, Ghiasi M, Sedaghat Y, Nasertork A. Granulomatous slack skin. Dermatol Online J. 2006 Dec 10;12(7):20. 4. Teixeira M, Alves R, Lima M, Canelhas A, Rosário C, Sel- ores M. Granulomatous slack skin. Eur J Dermatol. 2007 Sep-Oct;17(5):435-8. 5. Osuji N, Fearfield L, Matutes E, Wotherspoon AC, Bunker C, Catovsky D. Granulomatous slack skin disease-- disease features and response to pentostatin. Br J Hae- matol. 2003 Oct;123(2):297-304.

Renner, Foley, McFalda, Mahon 37 Ps e u d o e p itheliomatous Hy p e r p l a s i a a n d Ne c ro b i ot i c Pa l i s a d i n g Granulomatous Re a c t i o n t o Ta t t o o Pi g m e n t

Mary Jo Robinson, DO,* Shweta Patel, OMS IV** *Assistant Professor, Department of Pathology, University of Medicine and Dentistry of New Jersey – School of Osteopathic Medicine **University of Medicine and Dentistry of New Jersey – School of Osteopathic Medicine

Abstract

Tattoos have been increasing in popularity in recent years. The study of dye elements and their adverse reactions to skin has become imperative in dermatopathology. In this case study we examined a granulomatous reaction to black tattoo pigment, possibly attributed to mercury sulfide. Our patient presented with a new onset palpable lesion at the tattoo site. The history indicated that the tattoo had been present for many years, and had no prior problems with this or other tattoo sites. The entire lesion was gray-tan on punch biopsy and demonstrated prominent pseudoepitheliomatous hyperplasia and numerous necrobiotic granulomas.

the red tattoo (1,3). Mercury is also most commonly associated with granulomatous Clinical: tattoo reaction with epithelioid aggregates and lymphocytes. Cobalt in blue dye has A 35-year-old male presented with a been reported to cause localized hyper- raised lesion on the right lateral lower leg sensitivity reactions. Reaction to purple located within a tattoo. The tattoo had tattoo pigment can present as verrucous been present for several years. The clinical plaques with keratin-filled cystic dilations differential was dermatitis and granuloma and mild keratinocytic atypia as well as annulare. On a punch biopsy, the entire pseudoepitheliomatous hyperplasia and lesion was gray-tan and measured 0.8 x 0.7 palisading granulomas (2). In this report, x 0.8 cm. The subcutaneous surface was we describe one the few unusual cases of colored gray-red-white, with the pigmented pseudoepitheliomatous hyperplasia and Figure 1 region measuring 0.3 cm in thickness. necrobiotic palisading granulomatous reaction to black tattoo pigment. It is not clear which element in the black dye, carbon, Histology: iron oxide or logwood, is responsible for such a reaction. The epidermis was markedly hyperplastic, with prominent pseudoepitheliomatous hyperplasia and compact References: 1. Ball N, Silver S, Zhou Y. Photoallergic Lichenoid and orthohyperkeratosis (Fig 1: Scan view of Granulomatous Reaction to a Red Tattoo. Pacific Derma- punch biopsy of lesion from leg). There tologic Association: January 2004. www.pacificderm.org 2. Balfour E, Olhoffer I, Leffell D, Henderson T. Massive was both superficial and deep lympho- Pseudoepitheliomatous Hyperplasia: An Unusual Reac- cytic infiltrate with palisading histiocytes tion to a Tattoo. American Journal of Dermatology 2003; 25: 338-340. surrounding numerous large necrobiotic 3. Mortimer NJ, Chave TA, Johnston GA. Red Tattoo Reac- granulomas (Fig 2: Pseudoepitheliomatous tions. Clinical and Experimental Dermatology 2003; 28: Figure 2 hyperplasia and granuloma). Abundant 508-510. black and golden tattoo pigment was found within these granulomas and diffusely throughout the dermis (Fig 3: Necrobiotic granuloma with tattoo pigment). The necrobiotic granulomas also showed increased dermal mucin using colloidal iron stain. The stains for acid-fast bacilli and fungal organisms were negative.

Discussion: Figure 3 As tattoos are becoming increasingly popular, the reactions to various pigments can sometimes be puzzling. The most common allergic reaction to tattoo pigment is to red dye, usually containing mercury sulfide. Palisaded necrobiotic granuloma can be found on histology on this lichenoid-type inflammation from

38 pseudoepitheliomatous Hyperplasia and Necrobiotic Palisading Granulomatous Reaction to Tattoo Pigment A Ca s e o f Cu t a n e o u s Ro s a i -Do r f m a n Di s e a s e

Olga Globosky, D.O.,* Janese Trimaldi, M.D.,** Michael B. Morgan, M.D.*** *Clinical Associate, Internal Medicine, St. Petersburg General Hospital **Clinical Associate, Pathology, University of South Florida College of Medicine ***Professor of Pathology, University of South Florida College of Medicine; Clinical Professor of Dermatology, University of Florida College of Medicine; Managing Director, Bay Area Dermatopathology

Abstract

We report a case of a rapidly enlarging neck nodule in a 69 year old female. Subsequent biopsy showed a histologic diagnosis of cutaneous Rosai-Dorfman disease (RDD). Systemic workup including complete blood count was negative and imaging studies of the neck and lymph nodes were negative. Herein, we present the pertinent clinical and pathological differential diagnosis and review the literature on this unusual neoplasm.

Introduction: of a biopsy specimen showed uninvolved epidermis separated from a diffuse dermal Sinus histiocytosis with massive lymph- infiltrate. The infiltrate extended from adenopathy (SHML), or Rosai-Dorfman the papillary dermis to the deep reticular disease (RDD), is a distinct clinicopatho- dermis. It was composed of aggregates of logical entity involving the neoplastic large histiocytic cells with small, round- proliferation of non-Langerhans cell histio- to-oval nuclei and abundant foamy to cytes. It was initially described by Rosai and lightly eosinophilic cytoplasm (Fig. 1, 2). Dorfman in 1969. At first, the disease was Some cells contained intact lymphocytes thought to be confined to the lymph nodes, (emperipolesis) (Fig. 3). These cells were and was thus termed sinus histiocytosis admixed with a large number of lympho- with massive lymphadenopathy. Later it cytes and scattered plasma cells. The histo- become evident that the disease can involve logic features, including the presence of Figure 1 - There is a diffuse mixed-cell both nodal and extranodal sites, including emperipolesis, supported the diagnosis of infiltrate of histiocytes, lymphocytes, and the skin. Cutaneous involvement in RDD cutaneous Rosai-Dorfman disease. A Fite plasma cells with epidermal effacement. is commonly seen, but cases of purely cuta- stain for acid-fast bacilli, a Steiner stain for neous disease are rare. spirochetes, and a periodic acid-Schiff stain for fungi were negative. Polarization failed Case Report: to show foreign material. The entire neck nodule was excised. Since A 69-year-old woman was referred to excision of the nodule there has been no the dermatology clinic for evaluation of recurrence. Systemic evaluation, including a progressively enlarging skin lesion on imaging and bone-marrow biopsy, was the neck. She claimed the lesion had been negative. present for several months and had been slowly expanding. She complained of mild Discussion: pruritus but was otherwise asymptomatic. She denied fevers, chills, myalgias or other RDD is a rare, benign, non-Langerhans Figure 2 - The enlarged histiocytes with associated symptoms. The patient’s past histiocytic proliferative disorder. The clear to foamy cytoplasm. medical history included essential hyper- disease is prevalent in African Americans tension. Medications included atenolol. and rare in Asian Americans. It is more On physical examination, a single red- common in children and adolescents, brown nodule measuring 3 cm x 3 cm with although it can be seen in all age groups. a translucent yellow center was present on Mean age of onset is 20 years, and it is the right neck. The patient was afebrile. observed in females and males equally. There was no cervical, supraclavicular, Patients with cutaneous RDD may have an axillary or inguinal lymphadenopathy. older age of onset, female predominance,1 Complete blood count was within normal and significant Asian and Caucasian limits. The erythrocyte sedimentation rate predominance.2 The etiology is unknown. was elevated to 22 mm/hr. Liver func- It is believed to be a reactive disorder, tion tests and basic metabolic panel were and the possibility of an immunological normal. Serum protein electrophoresis response to an infectious agent has been Figure 3 - The large histiocytic cells demonstrated no gammopathy. Results of considered, including herpes virus 63 and contain lymphocytes (emperipolesis). autoimmune screening for lupus erythe- parvovirus B19.4 See arrow. matosus were negative. A computed Clinically, there is massive painless tomography scan of chest, abdomen, lymphadenopathy. Cervical lymph nodes ment.5 Almost every organ system may and pelvis in January 2009 did not show are most commonly involved. About be affected by the disease, with the skin as lymphadenopathy. Histologic examination 40% of patients have extranodal involve- the most common site.5 Approximately 38 pseudoepitheliomatous Hyperplasia and Necrobiotic Palisading Granulomatous Reaction to Tattoo Pigment Globosky, Trimaldi, Morgan 39 27% of patients with lymph-node involve- indistinguishable from lesions seen in or dendritic in appearance can be positive ment have cutaneous lesions. However, RDD.14 Considering the nonspecific presen- for S100.15 purely cutaneous disease is very rare, with tation of this entity clinically, we want to Progressive nodular histiocytosis shows about 3 percent of patients having disease emphasize that the diagnosis is incumbent nodules with cellular and fibrous patterns confined to the skin.5 Cutaneous RDD is upon the histopathologic findings. similar to those seen in dermatofibromas. usually a non-progressive and self-limited The histological attributes of this Histiocytes, foam cells, and spindle-shaped disorder with a chronic, indolent course. neoplasm engender a discussion of the cells are sometimes seen arranged in a Leukocytosis, fever, elevated sedimentation histologic differential diagnosis of histi- storiform pattern and embedded in a deli- rate, and polyclonal hypergammaglobu- ocytic neoplasms capable of presenting cate fibrocollagenous matrix. Touton cells linemia may be present.5 If laboratory find- in the skin. Histiocytic infiltrates can be can be present. There is a lack of other ings are normal, systemic complaints are broadly subcategorized into Langerhans inflammatory cells. Special stains can be usually absent.6 Cutaneous lesions in RDD cell histiocytosis and non-Langerhans cell used to demonstrate that fat and hemosid- are nonspecific. They may appear as single histiocytosis. Langerhans cell histiocytosis erin are present. The cells are positive for: or multiple macules, papules, plaques, is characterized by clusters and sheets of CD68, HAM-56, and factor XIIIa. They are or nodules. The color varies from red- large, ovoid cells with abundant eosino- negative for: CD34, CD1a, and S100. There brown to orange and yellow.1,7 Sometimes philic cytoplasm and reniform or (some- is variable staining for Mac387, lysozyme, the lesions are indurated and might have times eccentrically placed) coffee-bean α1-antitrypsin, and smooth muscle actin.15 central atrophy or ulceration.7 In one large nuclei. In adult cases, these cells are often In the early stages of xanthoma dissemi- study, the skin lesions were divided into in periappendageal locations. They can natum, histiocytes are predominant. In three main categories: papulonodular also focally invade the epidermis, showing older lesions, histiocytes, foam cells, (79.5%), indurated plaque (12.8%), and small foci in the upper epidermis. There spindle cells, Touton cells and a moderate tumor (7.7%).2 Cutaneous RDD may be are occasional binucleate cells and scattered number of inflammatory cells are seen. found on any anatomic location.5 It appears mitoses seen. An admixture of inflamma- Macrophages demonstrating phagocytosis that the extremities are involved the most. tion is present, including polymorphonu- of elastic fibers and sometimes collagen Trunk and face are also very common clear leukocytes and eosinophils. These can be seen. Siderosis is often seen, and is a sites.2 Some studies suggest that there is a lesions show positivity for S100, HLA-DR, prominent feature of the very rare xantho- process of clinicopathological evolution of and CD1a, and show negativity for Mac387, siderohistiocytosis variant. Cells are posi- the lesions in cutaneous RDD. It consists CD34, and MS-1.15 tive for: HLA-DR, CD68, CD14, CD11b, of three phases: growth, static phase and In juvenile xanthogranuloma, a dense CD11c, and factor XII1. They are negative regression. Growth phase lasts for 0.5-1 infiltrate of small histiocytes involves the for: S100, CD4, and CD1a. There is variable year and presents as erythematous patches dermis and subcutaneous fat in a poorly staining for Mac387.15 or plaques. It further progresses to the full- demarcated, nodular infiltrate. There can Reticulohistiocytoma consists of a blown static phase as nodules with satellite be extension into skeletal muscle, although circumscribed dermal nodule lying papules. After one to two years, regression this is a rare finding. The cells are spindle beneath an area of epidermal thinning. begins as lesions involute into patches with shaped and plump, or polygonal with An irregular admixture of multinucleate 8 a yellowish hue that eventually scar. indistinct cytoplasmic borders. Mitoses are giant cells with a ground glass appear- Histologically, cutaneous RDD presents rare. Early lesions are fairly monomor- ance, inflammatory cells, and oncocytic as a dense dermal infiltrate consisting of phous with inconspicuous foam cells, while mononuclear histiocytes are present. typical polygonal histiocytes. Scattered older lesions possess foamy histiocytes and There can be phagocytosis of leukocytes. lymphocytes, plasma cells, and neutrophils varying numbers of Touton cells (wreath- A few Touton giant cells containing lipid might be present. The histiocytes have like multinucleated histiocytes). These cells may be present. An abundance of reticulin large vesicular nuclei and abundant foamy have a less foamy periphery than seen in fibers surround individual cells. An infil- eosinophilic cytoplasm. Emperipolesis (the other xanthomatous conditions. There trate of PMNs is present, and the stroma presence of intact lymphocytes and other can be small aggregates of foam cells, but is comprised of many spindle-shaped cells circulating cells within histiocytes) is very fully xanthomatized variants also occur. and xanthomatized cells. Cells are positive characteristic. Typical histiocytes of RDD Scattered lymphocytes, PMNs, eosinophils for: factor XIIIa, CD68, HAM-56, lysozyme, are usually positive for S-100, negative for and rare plasma cells can be seen. Older α1-antitrypsin, CD11b, and CD14. Cells are CD1a, and variably positive for CD68.1 lesions will show interstitial fibrosis and negative for: CD1a, CD34, and smooth However, the S-100 protein positivity is not proliferating fibroblasts. The spindle-cell muscle actin. While usually negative, posi- specific to RDD, as it might be found in xanthogranuloma is a variant of the adult tivity for S-100 has been reported in a few other histiocytoses. form of xanthogranuloma, and is char- cases. Remote consideration should also In the case of purely cutaneous RDD acterized by spindle-shaped histiocytes be given to infectious etiologies in which when massive lymphadenopathy is absent, in a storiform arrangement, with other histiocytes are characteristically seen.15 the diagnosis may be difficult due to the mononuclear and multinucleate (Touton) Cutaneous tuberculosis and other myco- rare nature of the disease, broad histo- cells accompanying them. In the scalloped- bacterial infections show a mixed dermal pathological differential diagnosis of this cell variant, more than 75% of the lesion infiltrate of PMNs, lymphocytes, and disorder and non-specific clinical presenta- is usually comprised of scalloped histio- plasma cells. This is then followed by super- tion of skin lesions. It is essential for the cytes. These cells possess an angulated or ficial necrosis and ulceration. After weeks, physician to have a high index of suspi- scalloped border, with a homogenous and tuberculoid granulomas form, which may cion. Cutaneous RDD has been clinically slightly eosinophilic cytoplasm surrounding be accompanied by caseation necrosis. The mistaken for other dermatologic disor- a large, round to oval nucleus. They are granulomas consist of giant cells of the ders, including: vasculitis,9 acne vulgaris,10 set apart from one another by a delicate Langerhans and foreign-body type, with a hidradenitis suppurativa,11 granuloma fibrous matrix. These histiocytes show substantial rim of lymphocytes and plasma annulare,12 lupus vulgaris,10 malignant positivity for: CD68, HAM-56, HHF35, cells, and often show a tendency to become breast neoplasm,13 sarcoidosis,10 and other cathepsin B, vimentin, factor XIIIa, fascin, confluent. Acid-fast bacilli are easy to see histiocytoses.10 The other non-Langerhans CD4, lysozyme and α1-antitrypsin. They are in the early form of this lesion, but once cell histiocytoses such as xanthogranuloma, negative for: Mac387, smooth muscle actin, granulomas form, very few bacilli can be reticulohistiocytosis, generalized eruptive CD34, CD1a and S100. About 1-10% of the present. Similarly, deep fungal infections histiocytosis, and xanthoma are clinically other cells in the lesion that are elongated may show predominance of epithelioid 40 a Case of Cutaneous Rosai-Dorfman Disease granulomata and giant cells with an associ- References: ated PMN infiltrate. Special stains for fungi 1. Brenn T, et al. Cutaneous Rosai-Dorfman disease is a including PAS and GMS should be positive distinct clinical entity. Am J Dermatopathol 2002; 24:385 15 2. Kong YY, et al. Cutaneous Rosai-Dorfman Disease: a in most instances. clinical and histopathologic study of 25 cases in China. Am J Surg Pathol 2007; 31:341 Treatment is not always necessary 3. Levine PH, et al. Detection of human herpesvirus 6 in tis- for cutaneous RDD. The disorder is sues involved by sinus histiocytosis with massive lymphadenopathy (Rosai-Dorfman disease). J Infect Dis 1992; often asymptomatic and self-limiting. 166:291 Spontaneous regression has been observed 4. Mehraein Y, et al. Parvovirus B19 detected in Rosai- 16 Dorfman disease in nodal and extranodal manifestations. over months to years in many cases. J Clin Pathol 2006; 59:1320 Treatment may be indicated in the case 5. Foucar E, Rosai J, Dorfman R. Sinus histiocytosis with massive lymphadenopathy (Rosai-Dorfman disease): of cosmetically unacceptable skin lesions, review of the entity. Semin Diagn Pathol. 1990; 7:19-73. 16 presence of symptoms or progressive 6. Merola, JF, Pulitzer M, Rosenman K, Brownell I. Cutane- 17 ous Rosai-Dorfman disease. Dermatology Online Journal. disease. Surgical intervention, such as 2008 May 15; 14 (5): 8. 17 excisional biopsy or resection, is thought 7. Lu C, Kuo T, Wong W, Hong H. Clinical and histopathologic spectrum of cutaneous Rosai-Dorfman disease in to be the most effective treatment, although Taiwan. J Am Acad Dermatol 2004; 51:931-9. in certain patients there has been recur- 8. Wang KH, Chen WY, Liu HN, Huang CC, Lee WR, Hu 6 CH. Cutaneous Rosai–Dorfman disease: clinicopatho- rence of the disease. In cases where exten- logical profiles, spectrum and evolution of 21 lesions in sive or multiple lesions are present, other six patients. British Journal of Dermatology 2006 154, 17 pp277–286 therapeutic regimens may be used. This is 9. Stefanato CM, Ellerin PS, Bhawan J. Cutaneous sinus especially important since extensive cuta- histiocytosis (Rosai-Dorfman disease) presenting clinically as vasculitis. J Am Acad Dermatol. 2002; 46:775- neous involvement may engender unaccept- 778 able cosmetic disfigurement and/or severe 10. Ang P, Tan SH, Ong BH. Cutaneous Rosai-Dorfman disease presenting as pustular and acneiform lesions. J Am emotional distress. However, it is difficult Acad Dermatol. 1999; 41:335-337. to assess the efficacy of each treatment due 11. Lazar AP, Esterly NB, Gonzalez-Crussi F. Sinus histiocytosis clinically limited to the skin. Pediatr Dermatol. 1987; to rarity of the disease and limited thera- 4:247-53. peutic options reported. Isolated patients 12. Scheel MM, Rady PL, Tyring SK, Pandya AG. Sinus histiocytosis with massive lymphadenopathy: presenta- have responded favorably to superficial tion as giant granuloma annulare and detection of human 1 10 2 radiotherapy, cryotherapy, isotretinoin herpesvirus 6. J Am Acad Dermatol. 1997; 37:643-646. 1,16 13. Mac-Moune Lai F, Lam WY, Chin CW, Ng WL. Cutaneous and oral corticosteroids. In one case, Rosai-Dorfman disease presenting as a suspicious breast oral steroids were used for six weeks with mass. J Cutan Pathol. 1994; 21:377-382. 16 14. Choon SE, Moktar Z, Ghani GA. Delayed Diagnosis of complete resolution of the lesion. In a Cutaneous Rosai-Dorfman Disease With Distinctive His- different clinical trial, prednisolone and tologic Features in a Malayan Man. Arch Dermatol. 2008; 144(1):120-121. hydroxychloroquin were used with partial 15. Weedon D. Histiocytic infiltrates. In Weedon D (ed: Skin 17 response. Serial injections of intralesional Pathology 2nd Edition, 2002 London, Churchill Living- stone) pp. 1079-1082, 1067-1078, 625-629. steroids may be effective for nodular areas, 16. Rubenstein MA, Farnsworth NN, Pielop JA, Orengo IF, and topical steroids and retinoids for thin, Curry JL, Drucker CR, Hsu S. Cutaneous Rosai-Dorfman disease. Dermatology Online Journal. 2006 Jan 27; cutaneous lesions. Adequate results were 12(1):8. achieved with triamcinolon acetonide 17. Hsiao CH, Tsai TF, Yang TH, Liu CM. Clinicopathologic Characteristics of Rosai–Dorfman Disease in a Medical injections and clobetasol propionate 0.05% Center in Northern Taiwan. J Formos Med Assoc. 2006; 18 ointment and 0.1% adapalene gel. Liquid Vol 105; No 9 18. Satter EK, Graham BS, Steger JW. Response of cutane- nitrogen applied two or three times with ous Rosai-Dorfman disease to topical and intralesional two-week interval may accelerate regression steroids. British journal of Dermatology. 2003; 149, 655- 8 680 of lesions. Carbon-dioxide laser therapy 19. Tjiu JW, Hsiao CH, Tsai TF. Cutaneous Rosai-Dorfman has been utilized successfully on the face disease: remission with thalidomide treatment. Br J Der- 14 matol. 2003 May; 148(5):1060-1. with no recurrence of the disease. High- 20. Chan CC, Chu CY. Dapsone as a Potential Treatment dose thalidomide has been used for the for Cutaneous Rosai-Dorfman Disease With Neutrophilic control of extensive cutaneous disease. A Predominance. Arch. Dermatol. 2006; 142:428-430. dose of 300 mg daily was given to a patient during a five-month period.19 In one case report, after unsuccessful treatment with several different therapeutic modalities, oral dapsone was administered, 100 mg daily for three months. It resulted in significant regression of the lesion with residual scar formation and no recurrence.20

Globosky, Trimaldi, Morgan 41 A Ca s e o f Mi n o c y c l i n e In d u c e d Hy p e r p igmentation

Amara Sayed, D.O., FACOFP,* Janet Allenby, D.O., FAOCD** *Second-year Dermatology Resident, Columbia Hospital, West Palm Beach, FL **Program Director, Columbia Hospital, West Palm Beach, FL; Allenby Dermatology, Delray Beach, FL

Abstract

Minocycline is known to cause three types of hyperpigmentation. The first is a blue-black discoloration in previous scars or sites of inflammation. The second is a blue-gray discoloration most commonly on the anterior aspect of the lower extremity; and the third is a generalized muddy brown discoloration.³ We present a case of a patient with drug induced extensive lower extremity hyperpigmentation initially thought to be bruising.

Case The patient’s history and histopathology A 58-year-old Caucasian female, indicated drug-induced hyperpigmenta- Fitzpatrick skin type III, presents for a tion. The patient’s antibiotic was switched routine office visit in January 2009 and to spironolactone, and improvement was describes discoloration which she describes seen within a few months after the minocy- as “bruising” on the posterior aspect of her cline was discontinued. lower extremity. She denies any history of trauma. The discoloration was present for Discussion over six months. The patient did present a history of bilateral hip replacement surgery Minocycline is a commonly used anti- related to congenital hip disease; however, biotic of the tetracycline family often used Figure 1: Blue-black patches on the posterior aspects of both thighs the discoloration did not present for several to treat acne vulgaris.V Minocycline is Figure 1: Blue-black patches on the months post surgery. associated with side effects including drug- posterior aspects of both thighs. She had a vascular work-up, ordered by induced lupus, hyperpigmentation of the her primary care physician, including lower skin, sclera and teeth, serum sickness-like extremity Doppler ultrasound to rule out reactions and DRESS (drug reaction and deep vein thrombosis. On physical exam, eosinophilia with systemic symptoms).II,III extensive blue-black patches are noted on There are three types of hyperpigmentation the posterior aspects of both thighs with described with minocycline use. The first is discoloration present in scars (resulting a blue-black discoloration in previous scars from hip surgery) on the buttocks as well as or sites of inflammation. The second is a the ankles and dorsum of her feet (Figures blue-grey discoloration most commonly on 1 and 2). The discoloration is painless, the anterior aspect of the lower extremity. and no discoloration is noted on the The third is a generalized muddy brown sclera or oral mucosa. No discoloration is discoloration.III Figure 2: Pigment deposit in surgical scar, left buttock present on the anterior aspect of the lower Figure 2: Pigment deposit in surgical extremity or in acne scars on her face. The scar, left buttock. patient has a history of acne vulgaris for Histology: which she is taking minocycline 100mg daily. Type I pigmentation is thought to be PMX: congenital hip disease; acne due to hemosiderin and so will stain with vulgaris PSHX: bilateral hip replacement in PERLS Prussian blue for hemosiderin or 2008 All: NKDA iron. Type II will stain for both melanin and iron and can be stained using PERLS and Fontana-Masson, a silver stain.X The Histopathology third type of pigmentation is thought to be due to melanin only and can be A 3mm punch biopsy was taken from stained with Fontana-Masson.III,VIII The a representative area of the left lower pigment is known to deposit in elastic extremity. fibers in the dermis as well as be taken up Figure 3: H&E at 40x magnification H&E showed pigment deposits in the by macrophages near vessels and eccrine Figure 3: H&E at 40x magnification showing pigment deposits in the dermis dermis and extending into the subcuta- structures.IV showing pigment deposits in the dermis. neous fat (Figures 3 and 4). Fontana- Minocycline pigmentation can also Masson was also positive in both the dermis occur in other areas besides the skin, and report a case of isolated subcutaneous fat and the fat (Figures 5 and 6). Staining with Pepine et al. describe a case of generalized pigmentation due to minocycline.X The PERLS showed positivity in the dermis pigmentation of the skin as well as the pigment usually deposits in the dermis (Figure 7). nail beds, sclera and teeth.IX Rahman et al. or in both the dermis and the subcuta- 42 a Case of Minocycline Induced Hyperpigmentation the patient presented with pigmentation on layer (Figure 9). the posterior aspect alone. On histology, our patient showed pigment deposition in the dermis and Treatment subcutaneous fat, which stained positive for Fontana-Masson, a silver stain There have been reported cases of the used to stain melanin pigment, as well as pigmentation resolving or slowly improving PERLS, a stain used to identify iron. This once the drug has been discontinued over pattern is consistent with type II deposi- months to years.X The Q-switched ruby tion. Interestingly, our patient also showed and alexandrite (755nm) laser have also increased melanin deposition in the basal shown to be effective in some cases.VI, X layer of the epidermis, which can be seen Alster et al. report six cases of minocycline- FigureFigure 4: H&E 4:at 63x H&E magnification at showing 63x pigment magnification in the subcutaneous fat sho- with type III pigment deposition (Figure induced hyperpigmentation on the face wing pigment in the subcutaneous fat 8). Pigment deposition in Caucasian or legs successfully treated with a 755nm skin type does not typically present with Q-switched alexandrite laser.I Izikson et al. increased basal layer melanin deposition. report a case of a patient with minocycline- The pigmentation may be a normal variant induced hyperpigmentation of the face that if our patient had increased sun exposure. resolved using fractional photothermolysis. She was not known to be on any other VII Soung et al. report a case that resolved medication to explain this finding. The after use of oral isotretinoin therapy.XI pigment in the basal layer did stain posi- Although prolonged use may increase tively with Fontana-Masson but was nega- the chance of minocycline hyperpigmenta- tive for PERLS, confirming the presence of tion, it can occur irrespective of dosage or melanin but not hemosiderin in the basal duration.X Our patient was on minocycline for many months, and her pigmentation improved once the medication was discontinued. The pigmentation may not fully Figure 5: 63x magnification showing positive staining with Fontana-Masson in the Figuredermis and along 5: eccrine 63x units magnification showing resolve, and she may need further treat- positive staining with Fontana-Masson ment if desired in the future to improve in the dermis and along eccrine units. her cosmetic appearance.

Summary The tetracycline family of antibiotics is often prescribed in dermatology to treat infections, for their anti-inflamma- Figure 7: 63x magnification showing PERLS positive staining of the pigment in the Figuredermis 7: 63x magnification showing tory effects, or in the treatment of acne. PERLS positive staining of the pigment While many patients tolerate the medi- in the dermis. cation well, there are known side effects. Minocycline, in addition to causing headache, vertigo, and even drug-induced lupus-like syndrome, is a known cause of FigureFigure 6: 63x magnification 6: 63x showing magnification positive staining with Fontana-Masson showing in the positivesubcutaneous fat staining with Fontana-Masson hyperpigmentation of the skin. Patients in the subcutaneous fat. should be cautioned of the possible side effects, and the medication should be neous fat, as was the case with our patient. discontinued if darkening of the skin is Isolated pigmentation in the subcutaneous noted. Our patient’s hyperpigmentation, fat alone is an unusual presentation. although improved, has not fully resolved. Our patient had been on minocycline Treatment options include watchful waiting for over a year to treat her acne, and at the or the use of laser treatment. time she developed the hyperpigmenta- Figure 8: H&E at 63x magnification showing pigmentation in the basal layer tion her acne was under control and she Figure 8: H&E at 63x magnification was not presenting with new scars on her showing pigmentation in the basal layer Minocycline Clinical Presentation Histological Staining face. We believe our patient did not fit Hyperpigmentation Pattern Type I Blue-black discoloration PERLS for hemosiderin any one category of minocycline hyper- in scars or sites of or iron; pigmentation can inflammation be intracellular and pigmentation but had overlap of features extracellular and found in the dermis clinically (see Table 1). Her discoloration Type II Blue-grey discoloration PERLS and Fontana- typically on anterior Masson for both melanin occurred on her lower extremities and aspects of lower extremity and iron containing pigment in the dermis and was visible in the scars on her buttocks subcutis Type III Generalized muddy- Fontana-Masson for brown discoloration melanin (often increased from her hip-replacement surgery. There in the basal layer of the epidermis and in was no pigmentation evident, however, melanophages in the dermis) in the acne scars on her face. If she had Table 1: Clinical and Histological Presentation of Minocycline-induced type 1 hyperpigmentation alone we would HyperpigmentationIII,VII,X expect her acne scars to be affected also. Although minocycline pigmentation is Figure 9: 63x magnification showing positive staining of the basal layer with Fontana- Table 1: Clinical and Histological more typical on the anterior aspects of the FigureMasson only 9: 63x magnification showing Presentation of Minocycline-induced lower extremity, as is expected with type II positive staining of the basal layer with Hyperpigmentation pigmentation, our case was unusual in that Fontana-Masson only.

Sayed, Allenby 43 References: 1. Alster TS, Gupta SN. Minocycline-induced hyperpigmentation treated with a 755-nm Q-switched alexandrite laser. Dermatol Surg. 2004 Sep;30(9):1201-4. 2. Bettge AM, Gross GN. A serum sickness-like reaction to a commonly used acne drug. JAAPA. 2008 Mar;21(3):33- 4. 3. Bolognia J, Jorizzo J. Dermatology e-dition, 2nd edition. Mosby Elsevier, 2008 4. Bowen AR, McCalmont TH. The histopathology of subcutaneous minocycline pigmentation. J Am Acad Dermatol. 2007 Nov;57(5):836-9. 5. Del Rosso JQ, Kim G. Optimizing use of oral antibiotics in acne vulgaris. Dermatol Clin. 2009 Jan;27(1):33-42. 6. Green D, Friedman KJ. Treatment of minocycline- induced cutaneous pigmentation with the Q-switched Alexandrite laser and a review of the literature. J Am Acad Dermatol. 2001 Feb;44(2 Suppl):342-7. 7. Izikson L, Anderson RR. Resolution of blue minocycline pigmentation of the face after fractional photothermolysis. Lasers Surg Med. 2008 Aug;40(6):399-401. 8. Patterson JW, Wilson B, Wick MR, Heath C. Hyperpig- mented scar due to minocycline therapy. Cutis. 2004 Nov;74(5):293-8. 9. Pepine M, Flowers FP, Ramos-Caro FA. Extensive cutaneous hyperpigmentation caused by minocycline. JAAD. 1993 Feb;28:292-295. 10. Rahman Z, Lazova R, Antaya RJ. Minocycline hyperpigmentation isolated to the subcutaneous fat. J Cutan Pathol. 2005 Aug;32(7):516-9. 11. Soung J, Cohen J, Phelps R, Cohen SR. Case reports: minocycline-induced hyperpigmentation resolves during oral isotretinoin therapy. J Drugs Dermatol. 2007 Dec;6(12):1232-6.

44 a Case of Minocycline Induced Hyperpigmentation

Re c u r r e n t Me r k e l Ce l l Ca r c i n o m a i n a Tr a n s p l a n t Pa t i e n t

Melissa Voutsalath, DO,* Anna Babayan, BS,** Reza Sazgari, MD,*** Indira Misra-Higgins, DO, FAOCD**** *Intern, Oakwood Healthcare System, Oakwood Southshore Medical Center, Trenton, Michigan **Third-year medical student, Michigan State University College of Osteopathic Medicine, East Lansing, Michigan ***Board-certified radiologist, Beverly Hills, Michigan ****Board-certified dermatologist, Beverly Hills Skin Care Institute, Beverly Hills, Michigan

Abstract

Merkel cell carcinoma (MCC) is an uncommon and potentially aggressive cutaneous neuroendocrine malignancy. Though the etiology remains controversial, it most often develops in elderly with a history of long-term sun exposure, and may appear even earlier in immunocompromised patients. Here we present a case of recurrent MCC in a patient undergoing chronic immunosuppressive therapy after organ transplantation. Histologic analyses of MCC as well as current treatment options are reviewed and the importance of diligent follow-up emphasized. Figure 1. Patient with 3-cm right pre-auricular mass.

Abstract Merkel cell carcinoma (MCC) is an uncommon and potentially aggressive cutaneous neuroendocrine malignancy. Though the etiology remains controversial, it most often develops in elderly patients with a history of long-term sun exposure, and may appear even earlier in immunocompromised patients. Here we present a case of recurrent MCC in a patient undergoing chronic immunosuppressive therapy after organ transplantation. Histologic Figure 1: Patient with 3-cm right Figure 2: Axial post-contrast CT analyses of MCC as well as current treat- Figurepre-auricular 1. Patient mass. with 3-cm right pre-auricularscan mass.Figure of the 2. neckAxial demonstratespost-contrast CT scana of the neck demonstrates a poorly-defined, infiltrative, ment options are reviewed, and the impor- poorly-defined,right-sided periauricular infiltrative, mass. right-sided This is an image of the patient’s first mass, not the tumor in tance of diligent follow-up emphasized. 1). No other nodules were appreciated. periauricular mass. This is an image Figure 1. Excision of the pre-auricular mass was of the patient’s first mass, not the Case Report performed. Gross evaluation of the spec- tumor in Figure 1. imen revealed an oval-shaped portion of A 64-year-old Caucasian female skin with underlying soft tissue encom- presented with a 3-cm right pre-auricular passing a central nodule with smooth soft tissue mass. This was the sixth mass surface. Overlying skin appeared to be presenting on the right side of her head normal, without ulceration or telangiecta- and neck in the course of a year. Each mass sias. Cut sections revealed a soft, grayish- presented as a non-tender, flesh-colored tan tumor involving the dermis. A thin bump increasing in size over time. Three membranous tissue lined the base of the masses were surgically excised without nodule. Histologic evaluation revealed a adjuvant therapy, while the remaining two high-grade malignant neoplasm involving were treated with radiation. She under- dermal and subcutaneous tissue without went three cycles of chemotherapy with epidermal involvement. Sheets of etoposide and carboplatin, which were Figureneoplastic 2. Axial cells post-contrastwere present, CT containing scan of the neck demonstrates a poorly-defined, infiltrative, discontinued due to intolerance. basophilic nuclei with fine, dispersed FigureFigure 3. 3: Coronal Coronal reformatted reformatted image image of the post-IV contrast CT scan of the neck. It demonstrates right-sided periauricular mass. This is an image of the patient’s first mass, not the tumor in Past medical history was significant for chromatin and scant cytoplasm (Figure 4). ofextension the post-IV of the contrastperiauricular CT mass scan to ofinvolve the the parotid gland, extending partially into the right neck. It demonstrates extension of primary biliary cirrhosis, for which the FigureChromogranin 1. (Figure 5), synaptophysin, carotid space. Again, this is an image of the patient’s first mass, not the tumor in Figure 1. patient underwent a liver transplant in the periauricular mass to involve the and CK-20 (Figure 6) immunohistochem- parotid glad, extending partially into 2001. She was placed on immunosuppres- ical stains were positive, while leukocyte sant therapy consisting of methylpredni- the right carotid space. Again, this is common antigen and epithelial membrane an image of the patient’s first mass, solone, tacrolimus, and azathioprine for antigen stains were negative. CT images not the tumor in Figure 1. five years post transplant. Medical history of the first mass found in our patient were was also significant for Coombs-negative obtained and are shown in Figures 2 and 3. hemolytic anemia, hypertension and Merkel cell tumor, primary small cell chronic obstructive pulmonary disease. Discussion carcinoma of the skin, neuroendocrine Past surgical history includes liver trans- carcinoma, primary undifferentiated carci- plant, removal of multiple head/neck Merkel cell carcinoma (MCC) is an noma of the skin, malignant Merkel cell tumor, primary small cell carcinoma of the masses and MediPort placement. She had uncommon and aggressive malignancy skin with endocrine differentiation, and a 45-pack-per-year smoking history but of the skin that carries a poor prognosis. anaplastic carcinoma of the skin.1-11 denied alcohol use. There was no signifi- It was first described in 1972 by Toker. cant family history of head or neck cancer. MCC has been called many different names MCC most often occurs in the seventh and eighth decades of life. Individuals who Physical exam revealed a 3-cm, flesh- including cutaneous APUDoma (amine Figure 4. Hematoxylin and eosin magnification 400x. Sheets of small basophilic cells with scant colored, right pre-auricular nodule (Figure precursor uptake and decarboxylation), are immunocompromised have been found cytoplasm, fine chromatin, few nucleoli, and focal tumor necrosis are seen. Voutsalath, Babayan, Sazgari, Misra-Higgins 47 Figure 3. Coronal reformatted image of the post-IV contrast CT scan of the neck. It demonstrates extension of the periauricular mass to involve the parotid gland, extending partially into the right carotid space. Again, this is an image of the patient’s first mass, not the tumor in Figure 1.

acquiring neuroendocrine features during of immunoperoxidase stains.2 malignant transformation.13 While the Immunohistochemical markers cytok- etiology remains controversial, develop- eratin-20 (CK-20), synaptophysin, chro- ment of MCC is known to be linked to mogranin and neurofilaments (NF) are environmental exposure, genetic mutations positive in MCC.12,13,17 Figure 5 shows and immunosuppression. Environmental tissue stained positive with chromogranin. exposure to ultraviolet radiation is linked Thyroid transcription factor 1 (TTF1), to MCC.4,5,12,13 Structural abnormalities leukocyte common antigen, epithelial in chromosomes 1, 11 and 13 have been membrane antigen and S-100 stains are found in patients with MCC, a pattern negative.13,17 Neurofilament proteins similar to that in small cell lung carcinoma. (NF-L) are regularly expressed in most Structural abnormalities in chromosome MCC with a paranuclear dot-like or diffuse 1p, the location of tumor suppressor gene Figure 4. 4: Hematoxylin Hematoxylin and and eosin eosin magnification 400x. Sheets of small basophilic cells with scantpattern. CK-20 also has a characteristic magnification 400x. Sheets of small p73, have been noted in up to 40% of cases. paranuclear dot-like pattern as demon- cytoplasm,basophilic fine cells chromatin, with scant few cytoplasm, nucleoli, and focalCytogenetic tumor necrosis abnormalities are seen. have also been strated in Figure 6.17 fine chromatin, few nucleoli, and focal found in tumor suppressor gene p53.13 Initial staging workup should include: tumor necrosis are seen. Immunocompromised patients with HIV chest radiograph and computerized tomog- or those undergoing chronic immunosup- raphy (CT) scan of the chest, abdomen and pressive therapy after organ transplantation head if symptomatic.13 Staging of MCC are at risk. MCC occurs more frequently is often based on the AJCC system, which and earlier in this subset of patients.13 An incorporates tumor size, lymph-node status increased risk of MCC as a second primary and the presence or absence of distant malignancy has been identified among metastatic disease at the time of diagnosis. patients with multiple myeloma, chronic Stage I disease includes tumors that are less lymphocytic leukemia, non-Hodgkin than 2 cm in length or width (T1) without lymphoma, and melanoma.15 any nodal disease or distant tumor spread. Merkel cells are endocrine cells activated Stage II disease is defined as tumors that are by tactile stimulation due to their close between 2 and 5 cm (T2), or greater than 5 proximity to nerve endings involved in the cm (T3) but with no evidence of lymph- sensation of touch. Cells are found in the Figure 5: Chromogranin node spread or metastatic disease. Stage III Figure 5. Chromogranin immunoperoxidase stain magnification 200x. Dark brown signifies Figureimmunoperoxisase 5. Chromogranin stain immunoperoxidase magnification stainbasal magnification layer of the epidermis,200x. Dark mainly brown around signifies disease includes tumors that invade deep diffuse200x.diffuse Dark cytoplasmiccytoplasmic brown signifies positivitypositivity forfor neuroendocrineneuroendocrinehair differentiation,differentiation, follicles. These involvinginvolving neuroendocrine dermisdermis withoutwithout cells extra-dermal structures, such as cartilage, are derived from the neural crest and skeletal muscle or bone (T4), or any tumor, extensiondiffuseextension cytoplasmic toto epidermis.epidermis. positivity for neuroendocrine differentiation, differentiate as part of the amine precursor regardless of size, that has spread to the involving dermis without extension to uptake and decarboxylation system.1,2,6,13 regional lymph nodes. Stage IV tumors are epidermis. Tumors develop in the dermis and consist defined by the presence of distant meta- of small lymphocytoid cells that extend to static disease, regardless of primary size the epidermis.1,2,4,7,16 The high metastatic and node status.6,13 AJCC classification has potential of this tumor mandates that an been shown to correlate with survival.7 early and accurate diagnosis be made by MCC is a biologically aggressive tumor. the clinician and the pathologist.2 Clinical While distant metastases are uncommon appearance of Merkel cell carcinoma is of at presentation, one-third to one-half of non-tender, solitary or multiple, flesh or patients will eventually develop systemic red-violaceous intradermal nodules with disease. The most common site of indistinct margins and an intact epidermis. metastasis is the draining lymph-node Telangiectasias may be seen on or around basin (27-60%), followed by distant skin lesions.1,4,7,12,14 Although the majority of (9-30%), lung (10-23%), central nervous MCC cases are exclusively dermal, involve- system (18%), bone (10-15%), and liver ment of the epidermis has been reported (13%). Other reported metastatic sites Figure 6: Cytokeratin-20 magnification in up to 10% of cases. Most reported cases include testis, pancreas, heart, bone 200x, showing pathognomonic FigureFigure 6.6. Cytokeratin-20Cytokeratin-20 magnificationmagnification 200x,200x, showingshowingof MCC pathognomonicpathognomonic with epidermotropism perinuclearperinuclear have dotdot an perinuclear dot cytokeratin staining marrow, pleura, parotid, gastrointestinal cytokeratin staining pattern. 13,16 15 cytokeratinpattern. staining pattern. underlying dermal component. Three tract, prostate, and bladder. Distant histologic subtypes exist: trabecular, inter- metastatic failure is common in patients to develop disease earlier. Masses arise in mediate and small cell. Intermediate is the with MCC, and 30-40 percent of patients most common type, followed by small cell ultimately die of their disease.4 skin of the head and neck region (50%) or and trabecular.17 extremities (40%). Less than 10% affect There are currently no guidelines for the trunk and mucous membranes.4,5,12,13 Tumor cells appear as irregular collec- treatment. The recommended treatment tions of hyperchromatic, deeply basophilic, Merkel cell carcinoma carries an incidence for localized disease has been wide local pleomorphic cells with virtually no cyto- excision of the primary lesion with a 2-3 of 0.2-0.4 cases per 100,000, with a majority plasm. Cells have anastomosing trabeculae cm margin.4 Sentinel lymph-node biopsy being elderly caucasians.3,7,12-14 Surveillance and a rosette cell arrangement.1,11-14,17 It is (SLNB) should also be performed to stage Epidemiology and End Results (SEER) data often difficult to distinguish MCC from the lymph-node basin. This is the most in 2001 showed incidence rates were higher other small cell tumors such as small cell sensitive and specific test for selecting in males compared to females (0.65 and carcinoma of the lung, lymphoma, carci- appropriate patients for further treatment 13 0.26 cases per 100,000, respectively). noid, neuroblastoma, retinoblastoma and and direct regional therapy.15 Patients may The etiology of MCC is unknown. It rhabdomyosarcoma. Accurate diagnosis is elect to have a lymph-node dissection since is thought to be derived from either best derived from a combination of thor- about 75% of patients may develop regional Merkel cells located in the basal layer of ough clinical evaluation coupled with light lymph-node metastasis.4,7,8,12 Failure to the epidermis or totipotential stem cells or electron microscopy and a defined panel control the primary site has demonstrated 48 recurrent Merkel Cell Carcinoma in a Transplant Patient the strongest correlation with the develop- with a low survival rate.17 Truncal lesions, in people with a history of long-term sun ment of regional and distant metastasis.4 especially the vulva or perianal region, are exposure, those who are immunocompro- Merkel cell carcinoma is a highly radio- thought to have the worst prognosis.13 mised are at risk of developing the disease sensitive tumor, which implies that primary Mott et al.12 demonstrated that depth at an earlier age. radiation therapy has an integral role in of invasion and lymphocytic infiltration, treatment. Radiation can be utilized as when considered collectively, were supe- References: post-op adjuvant therapy, primary treat- rior prognostic predictors. Outcome in 1. Pan D, Narayan D, Ariyan S. Merkel cell carcinoma: ment of unresectable lesions or inoperable 86% of cases with a sensitivity of 100% five case reports using sentinel lymph node biopsy patients, or salvage treatment for recurrent and a specificity of 63% were correctly and a review of 110 new cases. Plast Reconstr Surg 2002;110(5):1259-1265. disease. Local control can be achieved in predicted. This study also found that 2. Hitchcock CL, Bland KI, Laney RG, Franzini D, Harris B, a high percentage of patients, and long- tumors made of small cells containing Copeland EM . Neuroendocrine (merkel cell) carcinoma of the skin: its natural history, diagnosis, and treatment. term disease-free survival may be provided scant cytoplasm growing in sheets with Ann Surg 1988;207(2):201-207. in some cases.4,11,13 There is increasing an absence of organoid arrangement (i.e. 3. Llombart B, Menteagudo C, Lopez-Guerrero JA, Carda C, Jorda E, Sanmartin O, Almenar S, Molina I, Martin JM, evidence supporting conservative resec- diffuse growth pattern) had the highest Llombart-Bosch A. Clinicopathological and immunohis- tion supplemented with radiotherapy as association with death. Authors reported tochemical analysis of 20 cases of merkel cell carcinoma in search of prognostic markers. Histopathology 2005;2- presenting a better balance between tumor metastasis of 78% of tumors extending 13. control and cosmesis. Bichakjian et al. beyond the dermis, compared to 29% of 4. Muller A, Keus R, Neumann N, Lammering G, Schnabel T. Management of merkel cell carcinoma: case series of suggest considering radiation as primary those confined to the dermis. However, 36 patients. Oncol Rep 2003;10:577-585. therapy for patients who are non-surgical overall attempts to correlate depth of inva- 5. Meeuwissen JA, Bourne RG, Kearsley JH. The importance of postoperative radiation therapy in the treatment candidates or in the case of minute tumor sion of primary lesions with outcome have of merkel cell carcinoma. Int J Rad Oncol Bio Phys burden in the sentinel lymph node. If yielded conflicting results, making it an 1995;31(2):325-331. 13 6. National Cancer Institute. Merkel cell carcinoma: Treat- extracapsular nodal extension is present, inconsistent parameter. ment. Available at: http://www.cancer.gov/cancertopics/ radiation following complete lymph-node According to Bichakjian et al., the pdq/treatment/merkelcell/patient/allpages. Accessed April 15 20, 2007. dissection should be considered. most consistent predictor of survival in 7. Goldberg SR, Neifeld JP, Frable WJ. Prognostic value of tumor thickness in patients with Merkel cell carcinoma. J Irradiation portals should encompass MCC to date is the presence or absence of Surg Oncol 2007;95:618-622. 15 the original tumor volume with a 5 cm lymph-node disease. This makes SLNB 8. Allen PJ, Bowne WB, Jaques DP, Brennan MF, Busam K, Coit DG. Merkel cell carcinoma: prognosis and treat- wide margin of normal tissue, as well as the an invaluable prognostic tool and allows ment of patients from a single institution. J Clin Oncol entire surgical bed and scar and primary for identifying nodal disease in patients 2005;23(10):2300-2309. 4,12 9. Gillenwater AM, Hessel AC, Morrison WH, Burgess MA, draining lymph nodes. Radiation who seem to have no nodal involvement Silva EG, Roberts D, Goepfert H. Merkel cell carcinoma 15,20 therapy is highly recommended for based on clinical examination findings. of the head and neck: effect of surgical excision and radiation on recurrence and survival. Arch Otol Head patients with any of the following high- Several studies report the use of SLNB for Neck Surg 2001;127:149-154. risk features: tumor size >2 cm, positive patients with clinically lymph-node nega- 10. Toker C. Trabecular carcinoma of the skin. Arch Dermatol 1972;105:107-110. resection margins or tumors that closely tive MCC and found a fairly consistent 11. Morrison WH, Peters LJ, Silva EG, Wendt CD, Ang KK, approximate surgical margins, angiolym- SLNB positivity rate of approximately 20% Goepfert H. The essential role of radiation therapy in securing locoregional control of merkel cell carcinoma. Int phatic invasion, documented regional to 30%. One study involving 251 patients J Rad Oncol Biol Phys 1990;19:583-591. lymph-node involvement or staging of reported a five-year survival rate of 97% 12. Mott RT, Smoller BR, Morgan MB. Merkel cell carcinoma: a clinicopathologic study with prognostic implications. J lymph nodes not performed, and severely versus 52% for pathologically staged Cutan Pathol 2004;31:217-223. 13 immunocompromised patients. lymph-node negative disease versus lymph- 13. Up to Date. Merkel cell (neuroendocrine) carcinoma of 15 the skin. Available at: http://utdol.com/utd/content/topic. The role of chemotherapy in the treat- node positive disease, respectively. do?topicKey=skin_can/7766&view. Accessed February ment of MCC, both in the adjuvant setting MCC requires frequent follow-up due to 15, 2008. 14. Gottschalk-Sabag S, Ne’eman Z, Glick T. Merkel cell and in treatment of metastatic disease, its aggressive nature. Frequency of follow- carcinoma diagnosed by fine needle aspiration. Am J remains controversial. According to Allen up should be individualized according to Dermatopathol 1996;18(3):269-272. 15. Bichakjian CK, Lowe L, Lao CD, Sandler HM, Bradford et al., once distant disease occurs, patients risk factors. Routine chest radiograph CR, Johnson TM, Wong SL. Merkel cell carcinoma: criti- do poorly whether or not they receive is indicated, while CT scans of the chest, cal review with guidelines for multidisciplinary manage- 18 ment. Cancer 2007;110(1):1-12. chemotherapy. One author reports that abdomen and head may be required in 16. Brown HA, Sawyer DM, Doug M, Woo T. Intraepidermal given the significant morbidity associ- patients with symptoms suggestive of merkel cell carcinoma with no dermal involvement. Am J Dermatopathol 2000;22(1):65-69. ated with chemotherapeutic regimens, recurrence. When recurrence is found, full 17. Bobos M, Hytiroglou P, Kostopoulos L, Karkavelas particularly in the elderly MCC popula- staging work-up should be performed.1 3 G, Papadimitriou C. Immunohistochemical distinction between Merkel cell carcinoma and Small cell carcinoma tion, adjuvant chemotherapy currently Almost all recurrences will occur within of the lung. Am J Dermatopathol 2006;28(2):99-104. has no established role in the treatment the first two years after initial treatment. 18. Allen PJ, Zhang ZF, Coit DG. Surgical management of merkel cell carcinoma. Ann Surg 1999;229(1):97-105. of localized or regional disease. However, Local recurrence has been seen in 20-75% 19. Tai PT, Yu E, Winquist E, Hammond A, Stitt L, Tonita J, combination chemotherapy is a reason- of patients, usually four months after Gilchrist J. Chemotherapy in neuroendocrine/merkel cell 1 3 carcinoma of the skin: case series and review of 204 ably effective and tolerable treatment excision. Llombart et al. reported an cases. J Clin Oncol 2000;18:2493-2499. that should be considered for all patients association between tumor size and local 20. Gupta SG, Wang LC, Penas PF, Gellenthin M, Lee SJ, Nghiem P. Sentinel lymph node biopsy for evaluation and who have inoperable tumors and a good recurrence, lymph-node involvement and treatment of patients with merkel cell carcinoma. Arch performance status.15 Other authors report distant metastasis. They found all cases Dermatol 2006;142:685-690. that chemotherapy has a well-defined role with distant metastases involved tumors in metastatic disease, but responses are >30mm.3 Leg lesions are associated with usually short-lived and all patients ulti- a high incidence of local recurrence, mately succumb to the disease.4 mainly because of poor lower extremity Prognosis of MCC depends on different blood supply in the elderly as well as poor factors. Male gender seems to be an adverse tolerance of high-dose irradiation in lower prognostic factor,19 as does stage at presen- extremities.13 tation. Five-year survival rates by pathologic stage is as follows: stage 1 - 81%, stage Conclusion 2 - 67%, stage 3 - 52% and stage 4 - 11%.13 Overall survival rates range between 30% MCC is an uncommon and potentially and 75%.7 Small cell size, high mitotic aggressive cutaneous neuroendocrine rate and large tumor size are all associated malignancy. Though it most often develops Voutsalath, Babayan, Sazgari, Misra-Higgins 49 Cu t a n e o u s An g i o s a r c o m a : Ca s e Re p o r t a n d Re v i e w o f t h e Li t e r a t u r e

Holly Kanavy, DO, David Kessler, DO Massapequa Dermatology, Massapequa, New York

Abstract

An Angiosarcoma is a relatively uncommon malignant neoplasm derived from vascular endothelial cells. These tumors may occur anywhere in the body, but they are most commonly seen in skin and soft tissue. They are characteristically quite aggressive, tending to metastasize and recur. Risk factors for cutaneous angiosarcoma include previous radiation therapy and chronic lymphedema. Prognosis is dismal, regardless of treatment, and has been found to correlate with the extent of the primary tumor. Here we present a case report of a 67 year old woman diagnosed with cutaneous angiosarcoma of the lower abdomen and perform a review of the literature.

Case Presentation cells forming irregular vascular channels dissecting through the dermal collagen. CK, a 67-year-old woman, presented to The majority of the cells contained large, the office with a rash of her lower abdomen hyperchromatic nuclei with mitotic figures. that had been slowly enlarging over the The cells reacted diffusely with immunos- previous three months. She reported that tain CD31 and CD34, and did not react the skin had become thickened and purple- with immunostains to HHV-8, cytokeratin, to-red in the area. She denied itching, pain, or LCA. The immunofluorescence study or trauma to her abdomen. She described was negative. some bleeding and scab formation within The CT studies revealed several small the lesion over the previous few weeks. CK pulmonary nodules which were described denied any changes in her usual state of as being indeterminate by CT criteria. Also health. She reported no recent illness, no noted on CT was diffuse dermal thickening Figure 1 travel, and no new medications. Her only of the ventral pelvic wall with infiltration pets were cats. She denied any history of of the deep subcutaneous fat, as well as skin rashes or lesions of this type. nodularity within the midline. CK’s past medical history was signifi- A PET scan was performed to further cant for type 2 diabetes and hypertension. qualify the nature of the pulmonary Family history was non-contributory. nodules. The scan demonstrated a lack The patient had a 15-pack-year history of of uptake in the lungs, but did reveal mild tobacco use; she quit in 1976. She denied uptake in the esophagus, suggestive of any alcohol or illicit drug use. Her medica- esophagitis. tions included metformin, fosinopril, and CK was sent for evaluation by an oncolo- hydrochlorothiazide. CK was otherwise gist. While the optimal treatment for cuta- healthy. neous angiosarcoma is surgical resection On physical exam, CK was a pleasant followed by adjuvant radiation therapy, Figure 2 woman in no distress, and did not appear systemic chemotherapy was initiated first acutely or chronically ill. She was centrally due to the extent of the lesion. The patient obese. A full skin examination revealed was started on weekly paclitaxel at a dose a 35cm by 15cm violaceous, indurated of 80mg/m2. After several weeks of this plaque of the lower abdomen, studded with therapy, the lesion reduced significantly in nodules and foci of erosions and crusts. size. The patient is now being evaluated for There were scattered satellite lesions surgical excision of the residual lesion. around the primary plaque. There was no temperature alteration in the area. Discussion Three punch biopsies were obtained from the lesion: one for H&E examination taken of the plaque itself, one for H&E Epidemiology of a nodule within the plaque, and one Soft tissue sarcomas account for less than for immunohistologic studies. Given the 1% of all malignancies. Angiosarcomas vascular appearance of the lesion and the make up 1% to 4% of these. While they Figure 3 likelihood of associated internal disease, can occur anywhere in the body, the most the patient’s primary care physician was common locations for angiosarcoma are great vessels, orbit, pharynx, oral cavity, contacted and the patient was sent for a CT the skin and superficial soft tissue, which salivary gland, gastrointestinal tract, larynx, scan of the chest, abdomen, and pelvis. comprise 60% of reported cases. Other nasal cavity, kidney, and prostate. The Microscopic examination was found to be sites include the retroperitoneum, breast, cutaneous variant of angiosarcoma most consistent with angiosarcoma. There was a liver, bone, and spleen. There also have commonly occurs in elderly Caucasian dermal infiltration of atypical endothelial been cases reported involving the heart and males, with a male-to-female ratio of 2:1. 50 cutaneous Angiosarcoma ated angiosarcoma; 3) post-irradiation bodies, bone wax, surgical sponges, and angiosarcoma; 4) miscellaneous soft-tissue adjacent to Dacron vascular prosthesis.7 angiosarcoma. They have occurred in pre-existing benign All cutaneous angiosarcomas have a vascular tumors including lymphangiomas typical clinical presentation: a 2 to 3 month and port wine stains, and malignant history of an enlarging, indurated purple peripheral nerve sheath tumors.8 Herein lesion or bruise-like area, varying from blue lies a second possibility to the etiology of to red in color. The tumor often becomes disease in our patient: There may have multicentric, and blue nodules may develop been a benign vascular tumor present on as the tumor progresses. Some patients the abdomen that went unnoticed by the report bleeding, edema, ulceration, and patient. Angiosarcomas have also been pain.1 Up to 40% of patients have multi- reported as a complication of renal trans- Figure 4 focal disease on presentation.3 plantation, arteriovenous fistulas, varicose The condition can easily be regarded ulceration, xeroderma pigmentoum, and as rosacea when it occurs on the face. It gouty tophus. Sun exposure has been might also be dismissed as a bruise-like implicated due to the low incidence of this lesion or as chronic edematous changes. tumor in dark-skinned individuals, and Some characteristic features that help the predilection for the head and neck. No distinguish angiosarcoma include the pres- studies have been able to demonstrate such ence of a peripheral erythematous ring, an association, however. satellite nodules, intramural hemorrhage, Pathogenesis tendency for spontaneous bleeding, and bleeding after minimal trauma.4 Angiosarcoma arises from vascular endothelial cells. Several factors appear Etiology to play a role in the pathogenesis The cause of cutaneous angiosarcoma and progression of these tumors. First Figure 5 is not known. There are some definitive is vascular endothelial growth factor-D correlations that have been drawn, however. (VEGF-D). Vascular endothelial growth Previous radiation exposure has a strong factors are involved in the regulation of association with the development of this endothelial-cell proliferation, angiogenesis, tumor. This has been described following and vascular permeability. VEGF-D is a radiotherapy for other malignancies, such member of this family that is upregulated as carcinoma of the breast, cervix, ovary, in tumor cells and in the serum of patients endometrium, and Hodgkin’s disease. The with angiosarcoma. A second potential overall estimated risk of radiation-induced player in the pathogenesis of these tumors sarcomas is 0.03% to 0.8%. The latency is angiopoietin 2. Angiopoietin 2 is known period from radiation exposure to diag- to promote increased capillary diameter, nosis ranges from four to 40 years. It may basal lamina remodeling, proliferation and occur up to 12 years later for a malignant migration of endothelial cells, and new condition, and up to 23 years later if the blood vessel growth. Levels of this factor Figure 6 condition for which the radiation therapy are increased in angiosarcoma patients as was administered was a benign one.5 well. Vascular endothelial cadherin may also be involved in the pathogenesis of Chronic lymphedema is a highly recog- these neoplasms. This protein is expressed nized risk factor for cutaneous angiosar- in normal vascular endothelial adherens coma. This typically occurs in the junctions. There is a lack of this molecule ipsilateral arm of women who have under- in angiosarcomas, which may lead to a gone radical mastectomy for breast cancer decrease in cell-cell adhesion, promoting (Stewart-Treves syndrome). There is a local spread and metastasis.2 5% risk of development of lymphedema- associated angiosarcoma (LAS) five years after mastectomy. The most common Diagnosis site is the medial aspect of the upper Physical examination and history are arm. LAS has also been reported after pivotal in the diagnosis of these lesions. axillary-node dissection for melanoma, Figure 7 Biopsy establishes the diagnosis. CT scans in the setting of congenital lymphedema, are used for evaluation of the local lymph filarial lymphedema, in chronic idiopathic nodes and lungs for metastatic disease. The average age of onset is in the seventh lymphedema, and in chronic lymphedema or eighth decade of life.1,2 At least half of associated with previous trauma. Of Histopathology all reported cases of cutaneous angiosar- particular interest are two reported cases comas involve the head and neck region, of cutaneous angiosarcoma that occurred Angiosarcomas are poorly circumscribed particularly the scalp.1 in the dependent portions of an abdom- dermal tumors. They may infiltrate into Clinical presentation inal panniculus in the setting of morbid subcutaneous fat or fascia, and even skel- obesity.6 This may be a potential factor in etal muscle and periosteum, in a variety There are four major clinicopatho- the development of the tumor in the case of patterns. Lesions with a dissecting logic types of cutaneous angiosarcoma of our patient, in which none of the known pattern display an anastomosis of irregular recognized in the literature: 1) idiopathic risk factors can be identified. vascular channels that dissect through angiosarcoma of the face, neck, and scalp There have also been cases of angiosar- dermal collagen and surrounding struc- (Wilson-Jones angiosarcoma, senile coma arising in the setting of retained tures. The channels are lined by endothe- angiosarcoma); 2) lymphedema-associ- foreign material such as shrapnel or metal lial cells with enlarged hyperchromatic Kanavy, Kessler 51 nuclei and condensed chromatin. These necrosis and epithelioid infiltration pattern cells may be spindled, epithelioid, or pleo- were associated with increased mortality.10 morphic. Highly differentiated tumors Unresectable lesions and metastatic disease contain more densely packed vessels and at diagnosis correlate with a dismal prog- vascular channels lined by multiple layers nosis. Death may occur either from local of atypical endothelial cells. Some tumors extension or metastatic disease. Delayed display an epithelioid pattern of infiltra- diagnosis and treatment is a major factor in tion whereby diffuse sheets of spindled the poor prognosis of cutaneous angiosar- and/or epithelioid cells with prominent comas, which is most likely due to the mitotic activity are seen, and few vascular highly variable clinical nature of the tumor. structures are present. This epithelioid The five-year local recurrence rate was variant is associated with an aggressive found by Morgan to be 84%. The reported course and death within two to three years five-year survival ranges from 12% to 34%. of diagnosis. Many cases show a combination of dissecting and epithelioid histologic patterns. References: 1. Mark RJ, et al. Angiosarcoma: A Report of 67 Patients CD31 (platelet-endothelial cell adhe- and a Review of the Literature. Cancer 1996; 77: 2400- sion molecule) is a marker for vascular 2406. 2. Mendenhall W, et al. Cutaneous Angiosarcoma. Am J endothelial cells and is useful in diagnosing Clin Oncol 2006; 29: 524-528. angiosarcoma, being both sensitive and 3. Pawlik TM, Paulino AF, et al. Cutaneous Angiosarcoma of the scalp: a multidisciplinary approach. Cancer 2003; specific. CD34 is also a marker for vascular 98: 1716-1726. tumors but is less specific. Factor VIII- 4. James, WD, et al., editor. Andrews’ Diseases of the Skin: Clinical Dermatology: Elsevier Publishing; 2006. related antigen (von Willebrand factor) is 5. Mark RJ, Tran LM, et al. Post-irradiation sarcomas: a also used to identify vascular tumors, but single institution study and review of the literature. Can- cer 1994; 73: 2653-62. is limited by a low sensitivity. Staining 6. Azam M, et al. Cutaneous Angiosarcoma Complicating for UEA-I (Ulex europaeus agglutinin I) Morbid Obesity. Arch Pathol Lab Med. 2001; 125:531- 533. may also be performed. This is a marker 7. Textbook of Dermatology. Ed Rook A, Wilkinson, DS, for vascular cells that is reported to have Ebling FJB, Champion RH, Burton JL. Forth Edition. 1 Blackwell Scientific Publications. greater sensitivity than factor VIII. 8. Claude G, et al. Cutaneous angiosarcoma. Cancer 1970; 26: 868-883 9. Morgan M, Swann BS, et al. Cutaneous Angiosarcoma: A Treatment case series with prognostic correlation. J Am Acad Der- matol 2004; 50:867-74. 10. Deyrup, AT, McKenney, JK, et al. Sporadic Cutaneous Optimal treatment of cutaneous Angiosarcoma. Am J Surg Path 2008; 32: 72-77. angiosarcoma is resection of gross disease with wide margins followed by postoperative radiotherapy to the primary site and regional lymphatics. This is often difficult due to the extensive nature of the lesion at the time of diagnosis, as well as the location, most commonly being on the face and scalp. Chemotherapy is of palliative use for incurable disease.2 Prognosis/prognostic factors Despite aggressive treatment, prognosis for cutaneous angiosarcoma is poor. In 2004, Dr. Morgan and his colleagues evaluated several demographic and histologic factors to determine their prognostic significance in 47 cases of cutaneous angiosarcoma. Features found to be associated with adverse outcome included an external tumor diameter greater than 5 cm, depth of invasion greater than 3 mm, positive surgical margins, tumor recurrence, and metastases. Morgan et al. did not discover any demographic features that altered prognosis.9 In January 2008, Deyrup et al. published a proposal for risk stratification of sporadic cutaneous angiosarcomas based on clinical and histological parameters in 69 cases. While these factors appeared to apply mainly to tumors less than 5 cm in dimen- sion, it was found that older age, the presence of primary lesions on the trunk and extremities, and the histologic findings of

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Central nervous system side effects including system symptoms (see WARNINGS) should Skin and hypersensitivity reactions: fixed drug (MINOCYCLINE HCl, USP) EXTENDED RELEASE be cautioned about driving vehicles or using Limited human studies suggest that eruptions, balanitis, erythema multiforme, TABLETS light-headedness, dizziness or vertigo have been reported with minocycline therapy. Patients who hazardous machinery while on minocycline minocycline may have a deleterious effect on Stevens-Johnson syndrome, anaphylactoid Rx Only experience these symptoms should be cautioned therapy. Patients should also be cautioned spermatogenesis. purpura, photosensitivity, pigmentation of skin KEEP OUT OF REACH OF CHILDREN about driving vehicles or using hazardous about seeking medical help for headaches or SOLODYN® should not be used by individuals of and mucous membranes, hypersensitivity blurred vision. reactions, angioneurotic edema, anaphylaxis. INDICATIONS AND USAGE machinery while on minocycline therapy.These either gender who are attempting to conceive symptoms may disappear during therapy and ® 3. Concurrent use of tetracycline may render a child. Autoimmune conditions: polyarthralgia, SOLODYN is indicated to treat only usually rapidly disappear when the drug is oral contraceptives less effective (See Drug pericarditis, exacerbation of systemic lupus, inflammatory lesions of non-nodular moderate Pregnancy—Teratogenic Effects: Pregnancy discontinued. Interactions). category D (See WARNINGS) pulmonary infiltrates with eosinophilia, transient to severe acne vulgaris in patients 12 years of lupus-like syndrome. age and older. SOLODYN® did not demonstrate 2. Pseudotumor cerebri (benign intracranial 4. Autoimmune syndromes, including drug- All pregnancies have a background risk of hypertension) in adults and adolescents has induced lupus-like syndrome, autoimmune Central nervous system: pseudotumor cerebri, any effect on non-inflammatory lesions.Safety birth defects, loss, or other adverse outcome of SOLODYN® has not been established beyond been associated with the use of tetracyclines. hepatitis, vasculitis and serum sickness regardless of drug exposure. There are no bulging fontanels in infants, decreased hearing. Minocycline has been reported to cause or have been observed with tetracycline-class adequate and well-controlled studies on the use thyroid discoloration, abnormal 12 weeks of use. Endocrine: precipitate pseudotumor cerebri, the hallmark antibiotics, including minocycline.Symptoms of minocycline in pregnant women. Minocycline, thyroid function. This formulation of minocycline has not been of which is papilledema.Clinical manifestations may be manifested by arthralgia, fever, rash like other tetracycline-class antibiotics, crosses evaluated in the treatment of infections. include headache and blurred vision. Bulging and malaise. Patients who experience such Oncology: papillary thyroid cancer. the placenta and may cause fetal harm when To reduce the development of drug-resistant fontanels have been associated with the use symptoms should be cautioned to stop the Oral: glossitis, dysphagia, tooth discoloration. administered to a pregnant woman.Rare bacteria as well as to maintain the effectiveness of tetracyclines in infants.Although signs and drug immediately and seek medical help. Gastrointestinal: enterocolitis, pancreatitis, ® spontaneous reports of congenital anomalies of other antibacterial drugs, SOLODYN should symptoms of pseudotumor cerebri resolve after 5. Patients should be counseled about including limb reduction have been reported with hepatitis, liver failure. be used only as indicated. discontinuation of treatment, the possibility for discoloration of skin, scars, teeth or gums that minocycline use in pregnancy in post-marketing Renal: reversible acute renal failure. permanent sequelae such as visual loss that can arise from minocycline therapy. experience. Only limited information is available CONTRAINDICATIONS may be permanent or severe exists. Patients Hematology: hemolytic anemia, This drug is contraindicated in persons who 6. Take SOLODYN® exactly as directed. Skipping regarding these reports; therefore, no conclusion thrombocytopenia, eosinophilia. should be questioned for visual disturbances on causal association can be established. have shown hypersensitivity to any of the prior to initiation of treatment with tetracyclines doses or not completing the full course of Preliminary studies suggest that use of tetracyclines. and should be routinely checked for papilledema therapy may decrease the effectiveness of Minocycline induced skeletal malformations minocycline may have deleterious effects on the current treatment course and increase the (bent limb bones) in fetuses when administered WARNINGS while on treatment. human spermatogenesis (see Carcinogenesis, likelihood that bacteria will develop resistance to pregnant rats and rabbits in doses of 30 Mutagenesis, Impairment of Fertility Concomitant use of isotretinoin and minocycline and will not be treatable by other antibacterial mg/kg/day and 100 mg/kg/day, respectively, Teratogenic effects should be avoided because isotretinoin, a section). 1) MINOCYCLINE, LIKE OTHER TETRACYCLINE- drugs in the future. (resulting in approximately 3 times and 2 systemic retinoid, is also known to cause CLASS ANTIBIOTICS, CAN CAUSE FETAL ® times, respectively, the systemic exposure to OVERDOSAGE pseudotumor cerebri. 7. SOLODYN should not be used by pregnant HARM WHEN ADMINISTERED TO A PREGNANT women or women attempting to conceive a minocycline observed in patients as a result In case of overdosage, discontinue medication, ® WOMAN. IF ANY TETRACYCLINE IS USED Photosensitivity child (See Pregnancy, Carcinogenesis and of use of SOLODYN ).Reduced mean fetal treat symptomatically and institute supportive DURING PREGNANCY OR IF THE PATIENT Photosensitivity manifested by an exaggerated Mutagenesis sections). body weight was observed in studies in which measures. Minocycline is not removed in minocycline was administered to pregnant rats BECOMES PREGNANT WHILE TAKING THESE sunburn reaction has been observed in some 8. It is recommended that SOLODYN® not be significant quantities by hemodialysis or at a dose of 10 mg/kg/day (which resulted DRUGS, THE PATIENT SHOULD BE APPRISED OF individuals taking tetracyclines.This has been used by men who are attempting to father a peritoneal dialysis. THE POTENTIAL HAZARD TO THE FETUS. reported rarely with minocycline. Patients should in approximately the same level of systemic child (See Impairment of Fertility section). HOW SUPPLIED ® minimize or avoid exposure to natural or artificial exposure to minocycline as that observed in SOLODYN should not be used during ® ® pregnancy nor by individuals of either gender sunlight (tanning beds or UVA/B treatment) Laboratory Tests patients who use SOLODYN ). SOLODYN (MINOCYCLINE HCl, USP) Extended

who are attempting to conceive a child (see while using minocycline.If patients need to be Periodic laboratory evaluations of organ systems, SOLODYN® should not be used during Release Tablets are supplied as aqueous outdoors while using minocycline, they should including hematopoietic, renal and hepatic pregnancy. If the patient becomes pregnant while film coated tablets containing minocycline PRECAUTIONS: Impairment of Fertility & Pregnancy). wear loose-fitting clothes that protect skin from studies should be performed.Appropriate tests taking this drug, the patient should be apprised hydrochloride equivalent to 45 mg, 65 mg, 90 sun exposure and discuss other sun protection for autoimmune syndromes should be performed of the potential hazard to the fetus and stop mg, 115 mg or 135 mg minocycline. 2) THE USE OF DRUGS OF THE TETRACYCLINE measures with their physician. as indicated. CLASS DURING TOOTH DEVELOPMENT treatment immediately. The 45 mg extended release tablets are gray, unscored, coated, and debossed with “DYN-045” (LAST HALF OF PREGNANCY, INFANCY, AND PRECAUTIONS Drug Interactions Nursing Mothers on one side. Each tablet contains minocycline CHILDHOOD UP TO THE AGE OF 8 YEARS) MAY 1. Because tetracyclines have been shown to Tetracycline-class antibiotics are excreted in General hydrochloride equivalent to 45 mg minocycline, CAUSE PERMANENT DISCOLORATION OF THE ® depress plasma prothrombin activity, patients human milk. Because of the potential for serious Safety of SOLODYN beyond 12 weeks of use supplied as follows: TEETH (YELLOW-GRAY-BROWN). has not been established. who are on anticoagulant therapy may require adverse effects on bone and tooth development This adverse reaction is more common during downward adjustment of their anticoagulant in nursing infants from the tetracycline-class NDC 99207-460-30 Bottle of 30 As with other antibiotic preparations, use dosage. NDC 99207-460-10 Bottle of 100 long-term use of the drug but has been of SOLODYN® may result in overgrowth of antibiotics, a decision should be made whether observed following repeated short-term courses. nonsusceptible organisms, including fungi. If 2. Since bacteriostatic drugs may interfere with to discontinue nursing or discontinue the drug, The 65 mg extended release tablets are blue, Enamel hypoplasia has also been reported. superinfection occurs, the antibiotic should be the bactericidal action of penicillin, it is advisable taking into account the importance of the drug unscored, coated, and debossed with “DYN-065”

TETRACYCLINE DRUGS, THEREFORE, SHOULD discontinued and appropriate therapy instituted. to avoid giving tetracycline-class drugs in to the mother (see WARNINGS). on one side.Each tablet contains minocycline conjunction with penicillin. hydrochloride equivalent to 65 mg minocycline, NOT BE USED DURING TOOTH DEVELOPMENT. Bacterial resistance to the tetracyclines may Pediatric Use 3. The concurrent use of tetracycline and ® supplied as follows: 3) All tetracyclines form a stable calcium develop in patients using SOLODYN,® therefore SOLODYN is indicated to treat only methoxyflurane has been reported to result in NDC 99207-463-30 Bottle of 30 complex in any bone-forming tissue.A decrease the susceptibility of bacteria associated with inflammatory lesions of non-nodular fatal renal toxicity. in fibula growth rate has been observed in infection should be considered in selecting moderate to severe acne vulgaris in The 90 mg extended release tablets are yellow, premature human infants given oral tetracycline 4. Absorption of tetracyclines is impaired by patients 12 years and older. Safety and unscored, coated, and debossed with “DYN-090” antimicrobial therapy.Because of the potential in doses of 25 mg/kg every 6 hours.This for drug-resistant bacteria to develop during antacids containing aluminum, calcium or effectiveness in pediatric patients below on one side. Each tablet contains minocycline reaction was shown to be reversible when the ® magnesium and iron-containing preparations. the age of 12 has not been established. hydrochloride equivalent to 90 mg minocycline, drug was discontinued. the use of SOLODYN, it should be used only as indicated. 5. In a multi-center study to evaluate the effect Use of tetracycline-class antibiotics below supplied as follows: Results of animal studies indicate that of SOLODYN® on low dose oral contraceptives, the age of 8 is not recommended due to NDC 99207-461-30 Bottle of 30 tetracyclines cross the placenta, are found Autoimmune Syndromes hormone levels over one menstrual cycle with the potential for tooth discoloration (see NDC 99207-461-10 Bottle of 100 in fetal tissues, and can cause retardation of Tetracyclines have been associated with the ® WARNINGS). and without SOLODYN 1 mg/kg once-daily The 115 mg extended release tablets are green, skeletal development on the developing fetus. development of autoimmune syndromes.The were measured. Geriatric Use unscored, coated, and debossed with “DYN-115” Evidence of embryotoxicity has been noted long-term use of minocycline in the treatment Based on the results of this trial, minocycline- Clinical studies of SOLODYN® did not include on one side. Each tablet contains minocycline in animals treated early in pregnancy (see of acne has been associated with drug-induced related changes in estradiol, progestinic sufficient numbers of subjects aged 65 and over hydrochloride equivalent to 115 mg minocycline, PRECAUTIONS: Pregnancy section). lupus-like syndrome, autoimmune hepatitis and vasculitis. Sporadic cases of serum sickness hormone, FSH and LH plasma levels, of to determine whether they respond differently supplied as follows: Gastro-intestinal effects breakthrough bleeding, or of contraceptive from younger subjects. Other reported clinical NDC 99207-464-30 Bottle of 30 have presented shortly after minocycline 1. Pseudomembranous colitis has been failure, can not be ruled out.To avoid experience has not identified differences in use.Symptoms may be manifested by fever, The 135 mg extended release tablets are pink reported with nearly all antibacterial contraceptive failure, female patients are advised responses between the elderly and younger rash, arthralgia, and malaise.In symptomatic (orange-brown), unscored, coated, and debossed agents and may range from mild to life- to use a second form of contraceptive during patients. In general, dose selection for an elderly patients, liver function tests, ANA, CBC, and with “DYN-135” on one side. Each tablet threatening. Therefore, it is important to treatment with minocycline. patient should be cautious, usually starting at other appropriate tests should be performed to contains minocycline hydrochloride equivalent to consider this diagnosis in patients who the low end of the dosing range, reflecting the evaluate the patients.Use of all tetracycline-class Drug/Laboratory Test Interactions 135 mg minocycline, supplied as follows: present with diarrhea subsequent to the drugs should be discontinued immediately. False elevations of urinary catecholamine greater frequency of decreased hepatic, renal, administration of antibacterial agents. or cardiac function, and concomitant disease or NDC 99207-462-30 Bottle of 30 Serious Skin/Hypersensitivity Reaction levels may occur due to interference with the Treatment with antibacterial agents alters other drug therapy. NDC 99207-462-10 Bottle of 100 Post-marketing cases of anaphylaxis and fluorescence test. the normal flora of the colon and may permit Store at 25ºC (77ºF); excursions are permitted to serious skin reactions such as Stevens Johnson ADVERSE REACTIONS overgrowth of clostridia. Studies indicate that Carcinogenesis, Mutagenesis & 15º-30ºC (59º-86ºF) [See USP Controlled Room syndrome and erythema multiforme have been Because clinical trials are conducted under a toxin produced by Clostridium difficile is a Impairment of Fertility Temperature]. reported with minocycline use in treatment prescribed conditions, adverse reaction rates primary cause of “antibiotic-associated colitis”. Carcinogenesis—Long-term animal studies Protect from light, moisture, and excessive heat. of acne. have not been performed to evaluate the observed in the clinical trial may not reflect the After the diagnosis of pseudomembranous rates observed in practice. However, adverse Dispense in tight, light-resistant container with Tissue Hyperpigmentation carcinogenic potential of minocycline.A colitis has been established, therapeutic reaction information from clinical trials provides child-resistant closure. Tetracycline class antibiotics are known to structurally related compound, oxytetracycline, measures should be initiated.Mild cases of a basis for identifying the adverse events that cause hyperpigmentation. Tetracycline therapy was found to produce adrenal and pituitary U.S. Patent 5,908,838* and Patents Pending pseudomembranous colitis usually respond to tumors in rats. appear to be related to drug use. *90 mg is also covered by U.S. Patents discontinuation of the drug alone. In moderate may induce hyperpigmentation in many organs, Adverse events reported in clinical trials for 7,541,347 and 7,544,373 to severe cases, consideration should be given including nails, bone, skin, eyes, thyroid, Mutagenesis—Minocycline was not mutagenic SOLODYN® are described below in Table 2. to management with fluids and electrolytes, visceral tissue, oral cavity (teeth, mucosa, in vitro in a bacterial reverse mutation assay Manufactured for:

protein supplementation, and treatment with alveolar bone), sclerae and heart valves.Skin (Ames test) or CHO/HGPRT mammalian cell Table 2 – Selected Treatment-Emergent Medicis, The Dermatology Company an antibacterial drug clinically effective against and oral pigmentation has been reported to assay in the presence or absence of metabolic Adverse Events in at least 1% of Clinical Scottsdale, AZ 85256

Clostridium difficile colitis. occur independently of time or amount of activation.Minocycline was not clastogenic in Trial Subjects July 2009 drug administration, whereas other tissue vitro using human peripheral blood lymphocytes ® 17110103 2. Hepatotoxicity – Post-marketing cases pigmentation has been reported to occur upon or in vivo in a mouse micronucleus test. Adverse Event SOLODYN PLACEBO of serious liver injury, including irreversible prolonged administration. Skin pigmentation (1 mg/kg) N=364 drug-induced hepatitis and fulminant hepatic Impairment of Fertility—Male and female N=674 (%) (%) includes diffuse pigmentation as well as over reproductive performance in rats was unaffected failure (sometimes fatal) have been reported with sites of scars or injury. At least one treatment- 379 (56) 197 (54) minocycline use in the treatment of acne. by oral doses of minocycline of up to 300 mg/ emergent event Information for Patients kg/day (which resulted in up to approximately Headache 152 (23) 83 (23) Metabolic effects (See Patient Package Insert for additional 40 times the level of systemic exposure to Fatigue 62 (9) 24 (7) The anti-anabolic action of the tetracyclines minocycline observed in patients as a result of Dizziness 59 (9) 17 (5) information to give patients) may cause an increase in BUN.While this 1. Photosensitivity manifested by an exaggerated use of SOLODYN®). However, oral administration Pruritus 31 (5) 16 (4) is not a problem in those with normal sunburn reaction has been observed in some of 100 or 300 mg/kg/day of minocycline to male Malaise 26 (4) 9 (3) renal function, in patients with significantly individuals taking tetracyclines, including rats (resulting in approximately 15 to 40 times Mood alteration 17 (3) 9 (3) impaired function, higher serum levels of minocycline. Patients should minimize or the level of systemic exposure to minocycline Somnolence 13 (2) 3 (1) tetracycline-class antibiotics may lead to observed in patients as a result of use of Urticaria 10 (2) 1 (0) avoid exposure to natural or artificial sunlight azotemia, hyperphosphatemia, and acidosis. (tanning beds or UVA/B treatment) while using SOLODYN®) adversely affected spermatogenesis. Tinnitus 10 (2) 5 (1) If renal impairment exists, even usual oral or minocycline. If patients need to be outdoors Effects observed at 300 mg/kg/day included Arthralgia 9 (1) 2 (0) parenteral doses may lead to excessive systemic while using minocycline, they should wear a reduced number of sperm cells per gram Vertigo 8 (1) 3 (1) accumulations of the drug and possible liver of epididymis, an apparent reduction in the Dry mouth 7 (1) 5 (1) loose-fitting clothes that protect skin from sun toxicity.Under such conditions, lower than exposure and discuss other sun protection percentage of sperm that were motile, and (at Myalgia 7 (1) 4 (1)

Additional Info: JAOCD En v i r o n m e n t a l Me t h i c i l l i n -r e s i s t a n t St a p h y l o c o cc u s Au r e u s o n Pu b l i c To i l e t Se a t s – Ne w Fi n d i n g s

Robert Norman, DO, MPH, MBA Daniel R Johnson, OMS-IV

Abstract

Infections with MRSA have risen dramatically in recent years. We noted that the majority of the MRSA-positive cases cultured within a six-month timeline were located in the buttocks, prompting a search for a transmission source. Upon review of infectious- disease literature, we found that the majority of previous studies had involved patients with active MRSA. In several of the studies, S. aureus bacteria were found alone in environmental locations with high pedestrian traffic flow, prompting our search for a transmission vehicle. In a small study including 20 public restrooms around southern Florida, toilet seats were cultured for the most prevalent type of bacterial species in order to determine if public restrooms were contributing to the increasing incidence of anal-rectal methicillin- resistant Staphylococcus aureus (MRSA) soft-tissue abscesses seen in today’s population. The sites included gas stations, a convention center, restaurants, and multiple convenience stores. Although the most commonly cultured species were of the Staphylococcus family, none were of the methicillin-resistant S. aureus strain. In fact, all of the bacterial species identified were methicillin-sensitive. The second most common subtypes found were Gram-positive bacilli and rod species.

Introduction vating the antibiotic.3 Methicillin, a later- generation antibiotic from the penicillin Gram-positive bacteria are a class of class, is used to treat bacteria that secrete bacteria that stain purple-violet with hema- the penicillinase enzyme. Methicillin toxylin and eosin stain under microscopy withstands the effects of the penicillinase due to their thick outer cell wall made of enzyme. However, S. aureus is becoming peptidoglycan. This peptidoglycan layer is increasingly resistant to methicillin, forcing comprised of the enzyme transpeptidase the medical community to find new alter- (penicillin-binding protein), which effec- natives to treatment. tively cross-links the peptidoglycan chains Based on recent evidence, resistant S. to form the bulk of the cell wall. This is the aureus strains have been found to synthe- last step in the cell-wall synthesis of Gram- size an additional penicillin-binding positive bacteria.1 All Staphylococcus protein that carries a much lower affinity Figure 1 aureus strains possess this thick pepti- for beta-lactam antibiotics than in the doglycan cell wall, making them Gram- primitive S. aureus strains. This molecular contact. CA-MRSA can be identified by positive by bacterial classification. S. aureus resistance to deactivation enables cell-wall its biochemical differences as compared has a spherical shape (cocci), and repli- synthesis without antibiotic deactivation. to HA-MRSA. Interestingly, carriers of cates into grape-like clusters as it divides Methicillin-resistant strains are thought to CA-MRSA strains frequently develop active in multiple planes. The aureus strain is have originated in hospitals, where broad- infections, whereas medical personnel who the most virulent of all 33 Staphylococcal spectrum antibiotics are routinely admin- may be repeatedly exposed to HA-MRSA species, causing both toxin-mediated and istered. Resistance continues to grow both strains rarely develop acute skin infections non-toxin-mediated diseases. internationally and exponentially. despite commonly heavy colonization S. aureus was first discovered by the counts.4 The primary division between surgeon Sir Alexander Ogston in Aberdeen, Discussion CA and HA strains lies in their antibi- Scotland, in 1880. The bacteria were otic-sensitivity profiles. Comparatively cultured from the pus of a deep skin Methicillin-resistant Staphylococcus speaking, CA-MRSA strains tend to be abscess. “S. aureus” literally translates to aureus (MRSA) was first recognized during more responsive to antibiotic therapy but “Golden Cluster Seed.” When S. aureus the 1960s. Originally, infections presented are significantly more virulent than their is grown on blood agar, it takes on a exclusively in the hospital setting. Until the hospital-acquired counterpart. This can golden-yellow hue. All strains are positive early 1990s, it was considered a hospital- be explained by the presence of a panton- for catalase, an enzyme causing H2O2 to acquired disease associated with prolonged valentine-leukocidin (PVL) toxin that dissociate into oxygen and water mole- in-patient status and chronic antibiotic destroys local leukocyte functionality. PVL cules.2 S. aureus is also coagulase posi- therapy. Today, MRSA remains a leading toxin is not typically found in hospital- tive. Coagulase is an enzyme that rapidly cause of nosocomial infections in many acquired strains.5 converts fibrinogen to fibrin, inducing clot parts of the world and is becoming the In the United States of America, approxi- formation. Both catalase and coagulase are most common stimulus for acute derma- mately 97% of CA-MRSA cultures posi- used to identify the bacterial species. tologic infections treated in the emergency- tive as the USA300-subtype. Its virulence Penicillin antibiotics are used to kill room setting. appears to be genetic in origin. Moreover, Gram-positive bacteria. The penicillin It is critical that physicians identify the presence of lukS-PV and lukF-PV was molecule binds the transpeptidase enzyme, MRSA in the medical setting due to the detected in 67% of soldiers who cultured preventing the bacteria from synthesizing growing antibiotic resistance of CA-MRSA positive for CA-MRSA in a recent study its cell wall. S. aureus strains produce an strains. MRSA has become increasingly of military troops.6 This strain of MRSA enzyme called penicillinase (a beta lacta- prevalent throughout the world over has been classified as the Panton-Valentine mase), which hydrolyzes the β-lactam ring the past decade and has been theorized leukocidin (PVL)-positive CA-MRSA on the penicillin molecule, thereby deacti- to result from direct person-to-person genotype. PVL appears to thrive in the NORMAN 55 soft tissues, inducing the vast majority sanitation protocol in public restrooms Conclusion of tissue abscess and necrosis seen in this was targeted in the study, along with other type of bacterial infection. PVL-positive various criteria. In the study, the potential Patients who presented with localized MRSA has been cultured in antibiotic- for bacterial transmission was traced to abscess and cellulitis correlated directly refractory pneumonias as well as compli- toilet seats, door handles, paper dispenser with MRSA in the trial-based hospital sites cated skin infections on several continents handles, faucet knobs, toilet levers and with a 95% confidence interval. Although throughout the world. Geneticists theorize contact with other surfaces throughout antibiotic resistance was noted in some that CA-MRSA developed from an allelic public facilities. Night clubs and bars were instances, 90% were susceptible to clin- modification of the Methicillin-sensitive assessed to be at greatest risk for infection damycin, trimethoprim-sulfamethoxazole S. aureus (MSSA) strain. They have deter- transfer due to careless inebriation and (TMP-SMX), and doxycycline, while virtu- mined that MRSA strains are a result of tight spaces.10 Greed went on to discuss ally 100% of CA-MRSA infections tested the insertion of the mobile staphylococcal that, in spite of a “clean-appearing” rest- sensitive to rifampin. The best antibiotic cassette chromosome mec-gene (SCCmec) room, the bacteria are virulent and can therapy in spite of increasing resistance into a virulent, PVL-positive, MSSA strain.7 harbor anywhere where direct skin-to- appears to be a regimen of rifampin, The strains have thrived since their genetic surface then surface-to-skin contact occurs. TMP-SMX, or a combination of both.11 modification. Lack of infection control, inadequate Sulfa-allergic patients must be taken Patients will typically present with a decontamination, and sub-par restroom into consideration in all cases prior to pustular, indurated, poorly healing, and designs were among the identified factors TMP-SMX administration. mildly painful “spider bite” on examina- in the study. An expert in cleaning science Studies completed earlier this decade tion. The circumferential skin is character- stated, “Architects never think about indicated that the national S. aureus colo- istically pink and edematous with a central cleaning the buildings they design.” The nization prevalence was 32.4% in patients focus of necrosis. When left untreated, article went on to identify design strategies with a positive MRSA history, while MRSA lesions may rapidly progress into localized for public restrooms that would accom- colonization prevalence was approximately cellulitis.8 The diabetic population appears modate many of the recommendations and 0.8% in healthy individuals without active to be at greatest risk for infection secondary improve general sanitation. In short, legis- disease or history of the infection. On to poor wound healing and inadequate lation mandates were requested in order further assessment, the studies discovered circulation. According to culture data, to inspire immediate change and slow the nares colonization in patients with active CA-MRSA is one of the most commonly spread of the virulent bacteria. CA-MRSA to be around 41%. Notably, isolated bacterial strains in diabetic ulcers. Contrary to many claims, our analysis of this percentage was significantly higher Recent reports estimate that as many as southern Florida found that MRSA strains than that reported for the general popu- 50% of diabetic patients may be infected were not commonly isolated when cultured lation (0.8%) without active infection.12 with the MRSA strain. It is rare to find from contaminated public surfaces despite Community-acquired MRSA also tends HA-MRSA in diabetic wounds, suggesting heavy colonization rates of Staphylococcal to colonize the axillary and groin regions, an increased virulence of CA-MRSA in species. Our theory behind why MRSA contributing to an increased prevalence spite of frequent hospitalizations and abscess tends to present in the buttocks, in those areas of the body. The recom- multiple co-morbidities. The bacterial gluteal cleft, and perineum is yet unclear mendation stands that in otherwise healthy strain is not exclusive to diabetics, however, based on our findings. The sample under patients presenting with acute CA-MRSA as it afflicts young and healthy patients just study included 20 public restrooms around infections, a topical antibiotic should be as commonly. Improved hygiene and thor- southern Florida where we cultured toilet provided for treatment of the nares with ough decontamination of known sources seats for the most prevalent bacterial or without positive cultures. Mupirocin appears to enhance resistance to infection. species in order to determine if public rest- ointment is an antibiotic of choice for The New England Journal of Medicine rooms were contributing to the increasing both topical and nares application. New compared MRSA to other bacterial isolates incidence of anal-rectal MRSA soft-tissue investigations with trimethoprim-sulfame- in the urgent care setting and determined abscesses. The locations included gas thoxazole and rifampin have proven to be that infection was directly associated with stations, a convention center, restaurants, efficacious antibiotic regimens in the treat- one or more of the following conditions:9 and multiple convenience stores. Although ment of CA-MRSA. • Antibiotic use within one month prior the most commonly cultured species were The risk of toilet seats and public rest- to presentation to the emergency room of the Staphylococcus family, none were of rooms as a source of infection should be the methicillin-resistant strain. All of the recognized, and prevention that includes • Presentation labeled a “spider bite” at cultured S. aureus was methicillin-sensitive. thorough cleaning with proper disinfec- enrollment into the emergency room The second most common bacteria were tants must be initiated. Redesign of public • Positive history of MRSA infection Gram-positive bacilli and rod species. Our restrooms and tight social spaces may also • History of contact with an individual desire to determine a transmission source be a solution to the growing problem. with identical lesions or skin infections was inspired by the fact that within a six- Based upon our evidence, it appears that month timeline, the majority of anal-rectal the development of anal-rectal MRSA Black race was also correlated with an abscesses we saw in clinic were MRSA. abscess is more likely a result of direct increased likelihood of an acute CA-MRSA The antibiotic sensitivity profile in skin-to-skin transmission as opposed to infection. The findings of the study CA-MRSA continues to narrow as viru- surface-to-skin transmission. Why the supported evidence that non-Hispanic lence increases. However, vancomycin anal-rectal anatomy is preferred by the blacks followed by non-Hispanic whites (inpatient), clindamycin, linezolid, moxi- bacteria remains unknown. Nevertheless, were more likely than any other ethnicity floxacin, trimethoprim-sulfamethoxazole, contaminated surfaces can not be elimi- to present with MRSA to the emergency tetracycline, rifampin, levofloxacin, and nated as a potential vehicle for transmis- room. Although there is variability among gentamicin (mild potency) all appear to sion. Methicillin-resistant Staphylococcus studies, these are some major tendencies of have significant efficacy in the treatment aureus bacterial infections should be CA-MRSA. of the virulent SCCmec, PVL-positive, taken seriously, as appropriate treatment In a unique study performed by C. CA-MRSA bacterial strain. Nevertheless, and prevention can protect patients from Greed out of the UK, public toilets and diminishing antibiotic sensitivity to potentially severe tissue destruction and restrooms were identified as vehicles in the CA-MRSA has become a valid concern in systemic complications. rapid spread of MRSA. Lack of mandated hospitals and clinics around the world. 56 environmental Methicillin-resistant Staphylococcus Aureus on Public Toilet Seats References: 1. Braunwald, Eugene, Anthony S. Fauci, J. L. Jameson, Stephen L. Hauser, Dennis L. Kasper, and Dan L. Longo, eds. Harrison’s Manual of Medicine. 16th ed. New York: McGraw-Hill, 2005. 448-455. 2. Dockrell, Hazel M., Richard V. Goering, Cedric Mims, Ivan Roitt, Derek Wakelin, and Mark Zuckerman. Medical Microbiology. 3rd ed. New York: Elsevier Limited, 2004. 479. 3. Katzung, Bertram G., Susan B. Masters, and Anthony J. Trevor. Katzung & Trevor’s Pharmacology. 7th ed. New York: Lange Medical Books/McGraw-Hill, 2005. 362-389. 4. http://www.sportsozone.com/what-are-the-differences- between-ha-mrsa-and-ca-mrsa.html (matrix) 5. Susan Boyle-Vavra and Robert S. Daum; Dept of pediatrics-University of Chicago, IL. www.laboratoryinves- tigation.org. Community-acquired methicillin-resistant Staphylococcal Aureus: the role of Panton Valentine Leukocidin; © December 4, 2006. 6. Natural History of CA-MRSA in Soldiers; CID 2004:39; © (1 October); 977 7. Moroney, S.M. et al. Dept of pathology – Tampa General Hospital. Staphylococcal Cassette Chromosome mec and Panton-Valentine Leukocidin Characterization of Methicillin-Resistant Staphylococcus Aureus Clones., © December 15, 2006. 8. Demling, R.H., MD, Waterhouse, B, PhD. The Increasing problem of wound bacterial burden and infection in acute and chronic soft-tissue wounds caused by methicillin- resistant Staphylococcus aureus. Brigham and women’s hospital, burn and trauma center, Boston, MA, © Novem- ber 16, 2007. 9. Moran, G.J., et al. Dept of Emergency Medicine and the division of infectious diseases, Olive View-UCLA Medical Center, Sylmar, CA and Centers for Disease Control – Atlanta, GA. Methicillin-Resistant S. aureus Infections among Patients in the Emergency Department. N Engl J med © 2006 10. Greed, C, PhD. Faculty of the Built Environment. Univer- sity of the West of England, Bristol, UK. The Role of the Public Toilet: pathogen transmitter or health facilitator? p127-139. Building Serv. Eng. Res. Technol. 27,2. 2006. 11. Zafar, Uzma, MD, et al. Infection Control and Hospital Epidemiology. Prevalence of Nasal Colonization among Patients with Community-Associated Methicillin-Resistant Staphylococcus aureus Infection and there Household Contacts. vol 28, no. 8. August, 2007. 12. Zafar, Uzma, MD, et al. Infection Control and Hospital Epidemiology. Prevalence of Nasal Colonization among Patients with Community-Associated Methicillin-Resistant Staphylococcus aureus Infection and there Household Contacts. vol 28, no. 8. August, 2007.

56 environmental Methicillin-resistant Staphylococcus Aureus on Public Toilet Seats NORMAN 57 VOLUNTEERS NEEDED

JAOCD is doing quite well with the number of submissions that we receive. We are in constant lookout for energetic, board-certified dermatologists who would like to help us grow. We encourage our members to sign on as reviewers for articles in their areas of expertise or for general dermatology. You will be asked to review about three manuscripts each- year. Information on becoming a JAOCD reviewer can be obtained by e-mailing the editors at [email protected].

Existing reviewers should also take this opportunity to log on to Editorial Manager (www.editorialmanager.com/jaocd), click on the “Update My Information” tab at the top under the JAOCD logo, and make sure all of their personal information, especially e-mail address, is correct. Save all changes by clicking “Submit” at the bottom of the page.

Please remember that we welcome quality articles to JAOCD on any subject area within the vast scope of dermatology. Remember that all submissions must go through the usual review process. Visit www.editorialmanager.com/jaocd to submit your manuscript.

Sincerely,

Jay Gottlieb, DO Jon Keeling, DO Andrew Racette, DO JAOCD Editors

CONGRATULATIONS to Julia Layton (Our JAOCD Proofreader) & to TJ Mahlin (Julia’s Husband)

On the birth of their ﬁ rst child,

Wishing them all of the happiness in the world!

Editors of the JAOCD Jay Gottlieb, DO Jon Keeling, DO Andrew Racette, DO Ep i t h e l i o i d An g i o s a r c o m a : A Ca s e Re p o r t a n d Re v i e w

Jami Reaves, D.O.,* Don A. Anderson, D.O., F.A.O.C.D., F.A.S.M.S.** *Third-year Resident, Arizona College of Osteopathic Medicine, Midwestern University of Health Sciences **Program Director, Arizona College of Osteopathic Medicine, Midwestern University of Health Sciences

Abstract

Epithelioid angiosarcoma is a rare variant of cutaneous angiosarcoma that has only recently been described.1,2,3 Angiosarcomas are aggressive tumors with a tendency to recur locally and metastasize despite extensive therapy. Prognosis is poor.1,4,5 They have been reported following immunosuppression - as seen in post-transplant patients - as well as arising in extremities with chronic lymphedema or radiation dermatitis.6-11 We present a case of this very rare entity and a review of the current literature including histopathologic findings and therapeutic options. To our knowledge, this is the first case report of epithelioid angiosarcoma in a patient with rheumatoid arthritis treated with infliximab; whether a causal relationship exists has yet to be determined.

CASE REPORT count with differential; complete metabolic panel; lactate dehydrogenase level; chest A 51-year-old female patient presented to radiograph; CT of the chest, abdomen, and our clinic in February 2009 in consultation pelvis with and without contrast; as well as from her primary care physician. She had PET scans. developed a small red papule on her right shin in December 2008. The lesion was DIFFERENTIAL DIAGNOSIS rapidly enlarging and resembled a “blood 1.Malignant melanoma blister.” She denied history of trauma to the area and had noted no other lesions. 2.Angiosarcoma Her medical history was significant for 3.Kaposi’s sarcoma rheumatoid arthritis controlled with inflix- 4.Lymphoma imab infusions, bipolar disorder, schizo- 5.Pseudolymphoma Figure 2 phrenia, hypothyroidism and asthma. Her 6.Cutaneous metastasis, family history was unknown, as she was unknown primary was recommended upon initial consulta- adopted. She denied the use of tobacco 7.Organized hematoma tion. Histology of the wide local excision, products, alcohol or recreational drugs. however, revealed no residual malignancy, Review of systems was positive for cold and radiation therapy was deferred. It is Histology revealed a deep dermal sweats approximately one time monthly, uncertain whether immunosuppressive neoplasm that had multinodular and inter- shortness of breath with exertion, and one therapy with infliximab had any role in stitial components that extended to the episode of hematochezia in the month the development of this malignancy, and subcutaneous fat (see photos). The cells prior to presentation. as such it has not been discontinued at this were composed of pleomorphic epithe- Upon examination, the patient had a time. 15-millimeter, deeply violet-to-black lioid cells with numerous mitotic figures nodule without overlying ulceration on the and atypical forms. Immunohistochemical DISCUSSION right mid-anterior tibia. No edema of the staining was diffusely positive with CD31, extremity or lymphadenopathy was noted HMB45, S100, melan-A, cytokeratin 5/6, Angiosarcoma is a rare, aggressive, at this initial visit. There was a 3-centi- and desmin. Human herpesvirus-8 immu- malignant neoplasm that may present in meter, soft, compressible, freely mobile noperoxidase stains were negative. The multiple organs including the skin.1-3, 12 subcutaneous nodule in the right supra- final diagnosis was moderately to poorly Angiosarcomas are of endothelial deri- clavicular fossa. Skin and mucosal exam differentiated epithelioid angiosarcoma vation and account for less than 1% of was otherwise unremarkable. Excisional present at surgical margins. all sarcomas.4,13 Unlike most sarcomas, biopsy with 2.5-millimeter margins was The patient’s laboratory evaluation was angiosarcomas have a predilection for the obtained at that time from the leg lesion. within normal limits, as was the chest skin; 60 percent of cases occur within the Tests ordered included complete blood radiograph. The CT scans of the chest, skin or superficial soft tissue.1,3-5 They are abdomen and pelvis were also negative. aggressive tumors with a tendency to recur The PET scan revealed multiple areas of locally and metastasize in spite of extensive uptake in the nasopharynx, bilateral therapy. As such, prognosis is poor.1,3,4,5,14,15 tonsils and bilateral neck; this was felt to Angiosarcomas are most commonly found be inflammatory in nature with secondary on the face and scalp region of Caucasian reactive lymph nodes and not representa- men over the age of 40 years.1,5,12,13 Despite tive of metastases. The mass present upon their virulent behavior, they often initially initial exam at the right supraclavicular appear as innocuous. They often present fossa was non-reactive on PET scan. as a bruise-like patch. More advanced The patient was referred to a tertiary lesions are violaceous plaques that may center at that time for further treatment. even be ulcerated and are often clini- Wide local excision followed by skin cally misdiagnosed as melanomas. They grafting and adjuvant radiation therapy have been reported following immuno- Figure 1 Reaves, Anderson 59 suppression – as seen in post-transplant REFERENCES: patients – as well as arising in extremities 1. Requena L, et al. Cutaneous vascular proliferations: with chronic lymphedema or radiation Part III. Malignant neoplasms, other cutaneous neo- 1,3-13 plasms with significant vascular component and disorders dermatitis. erroneously considered as vascular neoplasms. Journal of the American Academy of Dermatology 1998; 38: 143- Epithelioid angiosarcoma is a very rare 175 variant of an uncommon malignancy, 2. Mobini N. Cutaneous epithelioid angiosarcoma: a neoplasm with potential pitfalls in diagnosis. Journal of Cuta- and cutaneous lesions have only recently neous Pathology 2009; 36(3): 362-369 1,3,4,5 been described. Clinically, lesions of 3. Marrogi A, et al. Cutaneous epithelioid angiosarcoma. American Journal of Dermatopathology 1990; 12: 350- epithelioid angiosarcoma are indistinguish- 356 able from conventional angiosarcoma but 4. Holden C, et al. Angiosarcoma of the face and scalp, prognosis and treatment. Cancer 1987; 59: 1046-1057 tend to have a predilection for the lower 5. Morgan M, et al. Cutaneous angiosarcoma: A case extremities. Lesions of the face and scalp series with prognostic correlation. Journal of the Ameri- can Academy of Dermatology 2004; 50: 867-874 have also been described. Radiation expo- 6. Stewart F, et al. Lymphangiosarcoma in postmastectomy sure has been implicated as a possible cause lymphedema. Cancer 1948; 1: 64-81 7. Cafiero F, et al. Radiation-associated angiosarcoma: of this neoplasm, though this is not seen diagnostic and therapeutic implications – two case reports as consistently as with standard angiosar- and a review of the literature. Cancer 1996; 77: 2496- 1,3,4,5 2502 coma. Epithelioid angiosarcoma is 8. Marchal C, et al. Nine breast angiosarcomas after con- often purported to have a better prognosis servative treatment for breast carcinoma: a survey from French comprehensive cancer centers. International than other cutaneous angiosarcomas, Journal of Radiation Oncology Biology and Physiology yet in most patients widespread meta- 1999; 44: 113-119 9. Bessis D, et al. Endothelin-secreting angiosarcoma static disease develops within one year of occurring at the site of an arteriovenous fistula for hae- 1,3,4,5 presentation. modialysis in a renal transplant recipient. British Journal of Dermatology 1998; 138: 361-363 Histopathologically, cutaneous epithe- 10. Ahmed I, et al. Angiosarcoma in a chronically immuno- lioid angiosarcoma mimics an epithelial suppressed renal transplant recipient: report of a case 1,16 and review of the literature. American Journal of Der- neoplasm. The tumor is composed of matopathology 2002; 24(4): 330-335 sheets of rounded epithelioid cells with 11. Mehta R, et al. Post-irradiation cutaneous angiosarcoma. Cases Journal 2008; 1(1): 241 abundant cytoplasm, vesicular nuclei and 12. Mendenhall W, et al. Cutaneous angiosarcoma. Ameri- prominent nucleoli. Irregular vascular can Journal of Clinical Oncology 2006; 29(5): 524-528 13. Wilson-Jones E. Malignant angioendothelioma of the channels lined by atypical endothelial skin. British Journal of Dermatology 1964; 76: 21-29 cells that dissect the collagen bundles are 14. Abraham J, et al. Treatment and outcome of 82 patients with angiosarcoma. Annals of Surgical Oncology 2007; not often prominent, but the finding of 14(6): 1953-1967 such areas has a high diagnostic value.1,16 15. Deyrup A, et al. Sporadic cutaneous angiosarcomas: a proposal for risk stratification based on 69 cases. Ameri- Immunohistochemical staining is also can Journal of Surgical Pathology 2008; 32(1): 72-77 helpful in the diagnosis of this unusual 16. Prescott R, et al. Cutaneous epithelioid angiosarcoma: a clinicopathological study of four cases. Histopathology neoplasm. Angiosarcomas often express 2007; 25(5): 421-429 markers of vascular differentiation such 17. McCluggage W, et al. Cutaneous epithelioid angiosarcoma exhibiting cytokeratin positivity. Histopathology as CD31, CD34 and factor VIII-related 1995; 27: 291-294 antigen.1,16 Cytokeratin positivity is present 18. Gray M, et al. Cytokeratin expression in epithelioid vascular neoplasms. Human Pathology 1990; 21: 179-181 in about one-third of epithelioid angiosar- 19. Fink-Puches R, et al. No detection of human herpesvirus comas, making distinction from carcinoma 8 in different types of cutaneous angiosarcoma. Archives problematic.17,18 Fortunately, this distinc- of Dermatology; 38: 131-132 tion can be accomplished by demonstra- tion of coexistent CD31 expression. Unlike Kaposi’s sarcoma, angiosarcomas do not stain positively with human herpesvirus-8 immunoperoxidase staining.19 Therapy of angiosarcoma is rarely cura- tive, with fewer than 15 percent of patients surviving five years after diagnosis.1,4,5,12,14-16 Surgical excision with wide margins is indicated, and most patients with long- term survival received early radical abla- tive surgery.1,4,5,12,14-16 Even with negative margins by histologic examination, the recurrence rate and chance of metastatic disease is high. This may in part reflect the tendency for multifocality.1,4.5.12.14-16 The addition of post-operative radiation for close margins or worrisome pathologic features can result in long-term survival in some patients.14-16 The role of adjuvant chemotherapy at this time is unclear.14

60 epithelioid Angiosarcoma: A Case Report and Review A Ca s e Re p o r t : Ha i l e y -Ha i l e y Di s e a s e

Krina K. Chavda, DO,* Marvin Watsky, DO** *Dermatology Resident, 2nd year, St. John’s Episcopal Hospital, Far Rockaway, NY, 11691 **Program Director, St. John’s Episcopal Hospital, Far Rockaway, NY, 11691

Abstract

Hailey-Hailey disease, also known as “familial benign chronic pemphigus,” is a rare, hereditary blistering skin disease first described in 1939 by the Hailey brothers.1 Hailey-Hailey disease is an inherited skin disorder, although occasionally, sporadic cases arise without a family history.1, 2 We report a case of a 52-year-old African American female with crusty skin lesions in the intertriginous area. The diagnosis of Hailey-Hailey disease was made based on her clinical and histopathological findings.

Case report: It is often described as “benign familial pemphigus” since it is not life-threatening A 52-year-old African American female the way pemphigus vulgaris is.1 It is a presented for evaluation of waxing and rare, autosomal-dominant disorder with waning rashes in her axillae, groin and incomplete penetrance. It is characterized under her breasts (Fig. 1, 2 and 3) for over by intraepidermal blistering resulting in a period of eight years. The condition was recurrent vesicular eruptions mainly local- worse in the summer season. Treatment ized to the flexural areas of the body, such with a variety of topical antifungal agents as the groin, axilla, and neck. Hailey-Hailey led to inconsistent responses. disease usually appears in the third or Physical examination revealed moist fourth decade of life, although it can occur erythema, scaling, and hyperpigmentation at any age.2 It typically begins as a painful with some honey-colored crusting in her erosive skin rash in the skin folds. The Figure 1 axillae (Fig 1) as well as in the deep folds lesions tend to come and go and leave no of her groin, neck and under her breasts scars. As the lesions get bigger, the center (Fig. 2 and 3). Her toe nails, palms, soles, clears, leaving a typical ring shape. If the and mucosa were uninvolved. There was lesions are present for some time, they may no evidence of any associated systemic become thickened. The skin then tends disorder or any other cutaneous disease, to macerate, leaving very painful fissures. including Darier’s disease. Secondary bacterial infection, which is not Careful family history revealed that her uncommon, can give rise to an unpleasant mother and her daughter had a similar smell. White bands on the fingernails and kind of cutaneous disease affecting both pits in the palms can also occur. axillae and groins with a history of exacer- Heat, sweating and friction often exac- bation in the summer months. Her mother erbate the disease, and most patients have had died a few years prior, and examina- worse symptoms during the summer Figure 2 tion of her daughter revealed erythematous months.2 scaly plaques in her axillae. Pathophysiology: Repeated skin scrapings for fungus were negative. Other investigations, including Keratinocytes are held together through complete blood counts, blood sugar, urinal- desmosomes and adherent junctions. ysis, liver function tests, and serological These junctions consist of calcium-binding tests for syphilis and HIV antibodies, were transmembrane glycoproteins, which 2, 3 negative. contribute to cellular adhesion. Many A 2 mm punch biopsy was performed, hypotheses exist concerning the pathogen- and histological examination revealed a esis of familial benign pemphigus, but the hyperplastic epidermis with foci of acan- cause remains uncertain. An overall defect tholytic cells. There were prominent supra- in keratinocyte adhesion appears to be basilar clefts, edema within the papillary secondary to a primary defect in a calcium 2 Figure 3 dermis and a superficial chronic perivas- pump protein, ATP2C1. cular inflammatory infiltrate (Fig. 4, 5, ATP2C1 encodes the secretory pathway tions of familial benign pemphigus.4 and 6). PAS stain was negative for fungal Ca2+/Mn2 ATPase (hSPCA1). Mutant organisms. proteins in familial benign pemphigus Treatment: create a loss of sensitivity to Ca2+ and Discussion: Mn2+ ion binding and transport. Low Familial benign pemphigus waxes and levels of Ca2+ within Golgi bodies impair wanes in intensity. Use of mild corti- Hailey-Hailey disease (HHD) is a chronic protein processing.3 Localized post-zygotic costeroid preparations (class V or class disease with exacerbations and remissions. mutation has caused segmental manifesta- VI corticosteroids) and topical antibi-

Chavda, Watsky 61 chronic involvement of intertriginous areas with sparing of mucous membranes, in the presence of significant family history led us to the diagnosis of Hailey-Hailey disease (benign familial chronic pemphigus), which was confirmed by skin biopsy.

References: 1. Jean Bolognia. Dermatology Volume I. 2007. p 823 – 832. 2. Hailey H, Hailey H. Familial benign chronic pemphigus. Arch Dermatol. 1939;39:679-85. 3. Fairclough RJ, Dode L, Vanoevelen J, Andersen JP, Mis- siaen L, Raeymaekers L, et al. Effect of Hailey-Hailey Dis- Figure 4 ease mutations on the function of a new variant of human secretory pathway Ca2+/Mn2+-ATPase (hSPCA1). J Biol Chem. Jul 4 2003;278(27):24721-30. 4. Cooley JE, Briggaman RA, Cronce DJ, Banes AJ, O’Keefe EJ. Hailey-Hailey disease keratinocytes: normal assembly of cell-cell junctions in vitro. J Invest Derma- tol. Dec 1996;107(6):877-81. 5. Rabeni EJ, Cunningham NM. Effective treatment of Hailey-Hailey disease with topical tacrolimus. J Am Acad Dermatol. Nov 2002;47(5):797-8. 6. Ruiz-Rodriguez R, Alvarez JG, Jaén P, Acevedo A, Cór- doba S. Photodynamic therapy with 5-aminolevulinic acid for recalcitrant familial benign pemphigus (Hailey-Hailey disease). J Am Acad Dermatol. Nov 2002;47(5):740-2. 7. Hurd DS, Johnston C, Bevins A. A case report of Hailey- Hailey disease treated with alefacept (Amevive). Br J Dermatol. Feb 2008;158(2):399-401.

Figure 5

Figure 6 otics result in transient improvement. In patients with refractory cases of familial benign pemphigus (Hailey-Hailey disease), systemic corticosteroids, methotrexate, and retinoids (isotretinoin or acitretin) have been tried and have been reported to be of value in some reports. Topical tacrolimus ointment has been found to be helpful in familial benign pemphigus, and photodynamic therapy with 5-aminolevulinic acid has been used for recalcitrant cases.5,6 Reports indicate that low-dose botulinum toxin type A injection may be of benefit for familial benign pemphigus. Control of hyperhidrosis, which aggravates the disease, may be the mechanism for this off-label, novel approach. Dermabrasion, carbon dioxide laser ablation, and pulsed dye laser therapy have been tried in the treatment of familial benign pemphigus, with variable success. Isolated reports of intramuscular alefacept leading to improvement in the condition warrant further study.7 Conclusion: In our 52-year-old African-American female, classic skin lesions, which included

62 hailey-Hailey Disease El e p h a n t i a s i s No s t r a s Ve r r u c o s a

Carlos Gomez-Meade, D.O.*, Jerry Obed, D.O.**, Angela Combs, D.O.***, Stanley Skopit, D.O., FAOCD**** *1st-year Dermatology Resident, NSU-COM/BGMC **Dermatology Fellowship, NSU-COM/BGMC ***2nd-year Dermatology Resident, NSU-COM/BGMC ****Dermatology Program Director, NSU-COM/BGMC

Abstract

Elephantiasis nostras verrucosa is a rare, chronically deforming multifactorial disease that presents as a non-filarial lymphedema. Causative factors include obesity, congestive heart failure, venous stasis, neoplastic obstruction and radiation injury, to name a few. Patients with this disease are susceptible to frequent episodes of cellulitis, which leads to worsening fibrotic changes and inflammation. This is represented clinically as chronic lichenification, non-pitting edema, limb deformation, cobblestone-like papules and nodules with a woody induration of the affected limbs. Histologically, dilated lymphatic channels are a classic finding in this disease. This debilitating condition requires close monitoring and appropriate management of both the edematous and infectious states. In the following case report, we present a case of a patient with a history of progressive, chronic, indurated lymphedema with frequent hospitalizations for cellulitis to the lower extremities.

Case Report tive for osteomyelitis, malignancy and deep vein thrombosis. An 82-year-old, obese, Caucasian male Multiple intralesional punch biopsy was admitted to the hospital for recurrent specimens were obtained along with bacte- cellulitis to bilateral lower extremities. Past rial and fungal cultures, which showed medical history was significant for conges- cellulitic changes with stasis dermatitis, tive heart failure, chronic lymphedema, a fibrotic dermis and dilated lymphatic venous stasis, diabetes mellitus and spaces (Figures 5 and 6). Biopsies were multiple hospital admissions for recurrent negative for PAS, Gram staining, AFB and cellulitis to his lower extremities. He had other pathogenic organisms. Blood and noticed progressive swelling and associated cutaneous cultures were also negative for pain to his legs six years prior, which had microfilariae. However, wound cultures worsened since the episodes of cellulitis were positive for methicillin-resistant Figure 1 began. The swelling began on the dorsum Staphylococcus aureus. Based on the of his feet and ascended to mid-calf during historical and clinical findings as well as this time. the confirmatory biopsy results, the diag- The patient denied multiple mosquito nosis of elephantiasis nostras verrucosa bites, recent travel outside of the country was made. The patient was treated with (particularly to equatorial Africa, Central systemic antibiotics, wound care, leg eleva- or South America) or family history of tion and compression. After a 21-day any similar lymphedema (Nonne-Milroy’s hospital stay, the patient was discharged to disease). a rehabilitation center and eventually for Physical exam revealed an obese male home health and wound care. presenting with poor hygiene and diffuse, exaggerated lichenification of his lower Discussion extremities extending from the mid-calf to Figure 2 the lower leg (Figures 1 and 2). There was First described by Castellani in 1934 as a generalized, brown, papular and nodular, a non-filarial lymphedematous disorder, edematous and verrucous cobblestoning “elephantiasis nostras verrucosa” was appearance (Figure 3). The legs were coined as a way to differentiate those forms malodorous and warm to palpation, with of elephantiasis traditionally seen in trop- diffuse, non-pitting edema. The dorsum ical lymphedema caused by Wuchereria of the feet appeared to have a fluctuant bancrofti, Wuchereria malayi or Wuchereria and layered consistency (Figure 4). The pacifica. The term nostras was added for toes of both feet showed thickened toenails its Latin description meaning “from our without intertriginous changes, but with region.” Castellani then formed four major evident fissuring between the toes. Pulses subtypes: elephantiasis tropica (filarial were unable to be appreciated at the form), elephantiasis nostras (due to bacte- dorsalis pedis or anterior tibias secondary rial infections), elephantiasis symptomatica to the edema, but sensation was intact (due to other causes such as tuberculosis, Figure 3 distally. Lymphatic palpation was negative fungi, syphilis and neoplasms) and elephan- i,ii for enlargement. tiasis congenita. Castellani believed that ring in the interdigital fissures. elephantiasis nostras was caused mostly by The patient’s cardiac status was Elephantiasis nostras verrucosa is a rare, streptococcal, and less often staphylococcal, confirmed with echocardiogram and heart deforming disease with a multifactorial infections, with minor trauma leading to catheterization. Imaging studies such as cascade of progression. Most important introduction of the bacteria, usually occur- MRI and Doppler ultrasound were nega- is the subsequent, chronic lymphatic

Gomez-Meade, Obed, Combs, Skopit, 63 Clinically, there are marked, non-pitting al. also proposed topical treatment with edema and disfiguring of the affected tazarotene for a similar case involving the limbs. The chronic changes usually present abdomen, but this has yet to be established. as malodorous and verrucoid, lichenified Other proposed treatments in the literature nodules on the affected areas. This may are lymphovenous anastomosis, microsur- be accompanied by superimposed bacte- gical lymphatic anastomosis and lymphatic rial and/or fungal infections with areas of transplantation as ways to improve fluctuance. lymphatic flow and reduce fluid retention. Differential diagnoses for elephantiasis xiv Severe and debilitating cases may also nostras verrucosa are lipedema, in which need surgical debulking or debridement, there is bilateral swelling of the lower which unfortunately does nothing for extremities but sparing of the feet, pretibial the cause but rather treats the cutaneous Figure 4 myxedema, filariasis, ichthyosis, venous appearance. Other keratolytics such as stasis dermatitis and other primary and topical urea may also be beneficial for this secondary causes of lymphedema.v purpose.xv,xvi Finally, amputation may be an Diagnosis of elephantiasis nostras is unfortunate consideration if both conser- usually made on the clinical and historical vative and surgical treatments fail and if grounds, but confirmatory skin biopsies the risk of persistent cellulitis and sepsis and supplementary imaging studies are become life-threatening. Frequent follow- helpful, especially when ruling out other up visits are paramount to improving etiologies and complications. Of note, outcomes with these patients. Many times, lymphoscintigraphy has replaced lymp- treatment involves a multi-specialty coop- hangiography, since it preserves the deli- erative effort, since poor patient compli- cate lymphatic channels and can identify ance and lack of follow-up care can become xvii anatomy, patency, flow dynamics and a trying burden. Figure 5 obstruction. However, CT and MRI are Acknowledgements: helpful when trying to rule out malignancy. The authors would like to thank In addition, the diagnosis of Evangelos Poulos, M.D., Director of lymphedema can be subdivided into Global Pathology Laboratory Services, Eli primary and secondary types. Classification Piatigorsky, M.D., and Patty Arias, also of primary lymphedema is based on age of of Global Pathology, for their kind and onset: Congenital form arises shortly after generous help with this case. birth; lymphedema praecox presents within the age range of 9 to 25 years, but usually REFERENCES: during puberty; and lymphedema tarda, or 1 Duckworth A, Husain J, DeHeer P. Elephantiasis Nos- tras Verrucosa or “Mossy Foot Lesion” in Lymphedema Meige’s disease, presenting after the age of Praecox. J American Pod Med Assoc 98: No 1, 66-69, 35 years. Primary lymphedema can also be 2008. 2 Castellani A. Researches on elephantiasis nostras and familial or inherited, as in Nonne-Milroy’s elephantiasis tropica with special regard to their initial disease. By far the most common form stage of recurring lymphangitis (lymphangitis recurrens Figure 6 elephantogenica). J Trop Med Hyg 72: 89, 1969. of primary lymphedema is lymphedema 3 Schissel DJ, Hivnor C, Elston DM. Elephantiasis nostras praecox, accounting for 65-80% of all cases verrucosa. Cutis. Aug; 62(2):77-80. 1998 obstruction that usually begins as an vi,vii,viii,ix,x 4 Vaccaro M, Borgia F, Guarneri F, et al. Elephantiasis nos- of primary lymphedema. tras verrucosa. Int J Dermatol 39:764, 2000. effect of obesity, congestive heart failure, Secondary lymphedema is caused by 5 Guarneri C, Vaccaro M. Cobblestone-like skin. Canadian venous stasis, inflammation, chronic infec- Med Assoc Journal. 179 (7):673-4. 2008 recurrent lymphangitis or cellulitis, para- 6 Harel L, Amir J, Nussinovitvh M, et al. Lymphedema tion and inflammation, tumor obstruc- sitic infections, lymph node dissection, praecox seen as isolated unilateral arm involvement: tion and radiation injury. The patient case report and review of the literature. J Pediatr 130: malignant obstruction, radiation injury, 492, 1997. had several of these factors. This obstruc- 7 Lewis JM, Wald ER. Lymphedema praecox. J Pedatr 104: obesity, surgical excisions and granuloma- 641, 1984 tion leads to a gross enlargement of the xi tous diseases. 8 Revis DR. Lymphedema. www.emedicine.com/med/ affected limbs, with thickening and fibro- topic2722.htm. sing changes to the skin and subcutaneous Detection and treatment of primary 9 Bauer T, Wechselberger G, Schoeller ZT, et al. Lym- causes should be the first step in addressing phedema praecox of the lower extremity. Surgery 132: tissue. Histologically, this is represented by 899, 2002. hyperkeratosis and papillomatosis of the any form of lymphedema. However, 10 Usta M, Dilek K, Ersoy A, et al. A family with IgA neph- restoring function and reducing physical ropathy and hereditary lymphedema praecox. J Int Med epidermis, with underlying woody fibrosis 251: 447, 2002 of the dermis and subcutaneous tissue.iii and psychological stress should be the ulti- 11 Bolognia JL, et al. Dermatology 2nd edition. Lym- mate goal. Edema control and prevention phedema. Vol 2, 1602-1603, 2008 Recurrent infections cause a worsening, 12 Sisto K, Khachemoune A. Elephantiasis nostras verru- protein-rich interstitial edema and an of recurrent infections are the basis of treat- cosa: a review. Am J Clin Dermatol; 9(3):141-6. 2008 ment for elephantiasis nostras, though this 13 Zouboulis CC, et al. Elephantiasis nostras verrucosa: increase in fibroblasts and scarring. This xii beneficial effect of oral etretinate therapy. Br J Dermatol. inflammatory stasis thereby catalyzes the often may be challenging. Compression Oct;127 (4):411-6. 1992 therapy with elastic bandages, pneumatic 14 Motegi S, et al. Successful treatment with lymphaticov- vicious cycle of infection, scarring and enular anastomosis for secondary skin lesions of chronic edema. stockings and mechanical massage, along lymphedema. Dermatology; 215 (2): 147-51. 2007 with elevation of the affected limbs, are 15 Iwao F, et al. Elephantiasis Nostras Verrucosa success- The early or first stage of the disease is fully treated by surgical debridement. Dermatol Surgery. essential, usually in combination with also known as the “soft” or “water bag” type Vol 30, Issue 6, 939-941. 2004. antimicrobials, diuretics and topical treat- 16 Ferrandiz L, et al. Elephantiasis Nostras Verrucosa and presents as smooth, moderately thick- treated with surgical debridement. Dermatol Surgery. Vol ments to minimize recurrent infections ened skin that is freely movable from the 31, Issue 6: 731. 2006 and further stasis damage. 4 17 Yoho RM, et al. Elephantiasis Nostras Verrucosa. J Amer underlying fascia. The late or second stage Podiatric Med Assoc. Vol 96, Number 5: 442-444. 2006 of the disease presents as the more indu- Zouboulis et al. found a beneficial effect rated and fibrotic form, with the typical from systemic etretinate therapy, which verrucous papules and nodules.iv reduced epidermal proliferation, collagen synthesis and inflammation.xiii Boyd et

64 eLephantiasis Nostras Verrucosa El e p h a n t i a s i c Pr e t i b i a l My x e d e m a : A Ra r e Fo r m o f Th y r o i d De r m o p a t h y

David Judy, D.O.,* Claude S. Burton, M.D.,** Richard Miller, D.O.*** *Lead Author, 1st-year Resident, Largo Medical Center/Sun Coast Hospital **Co-Author, Duke University Medical Center, Professor of Medicine, Division of Dermatology, Duke Clinic ***Program Director, Largo Medical Center/Sun Coast Hospital

Abstract

Thyroid dermopathy is a cutaneous manifestation most commonly associated with Graves’ disease. The most frequent location is over the pretibial area of the lower legs. Elephantiasic pretibial myxedema is a rare presentation of thyroid dermopathy. We present a case of elephantiasic pretibial myxedema in a patient with Grave’s disease that was initially treated with thyroidectomy. Symptomatic cases should be treated with topical glucocorticosteroids, compression therapy and possibly lymphatic-massage therapy to provide symptomatic comfort for the patient.

Introduction: started on thyroid replacement. In 2003, for unclear reasons, he stopped his thyroid Thyroid dermopathy, also known as replacement therapy and started taking the pretibial myxedema, is a known condition OTC Thyroid Support®, which has neither of Graves’ disease but may also manifest thyroxine nor triiodothyronine. Review of in other non-thyrotoxic thyroid patholo- systems included fatigue, cold intolerance gies such as Hashimoto’s thyroiditis.1 The and intermittent constipation. incidence of thyroid dermopathy is 0.5% Physical examination revealed non- to 4.3% in patients with Graves’ thyro- pitting edema, multiple flesh-colored to toxicosis and 15% in patients with Graves’ violaceous, indurated, confluent, polypoid ophthalmopathy.2 nodules, fissured plaques and verrucoid Thyroid dermopathy can occur in other changes extending from the knees to the areas of the body but most commonly proximal feet bilaterally (figure 2). There Figure 1 presents on the pretibial area.3 The lesions was also a large nodule on the dorsal aspect typically present as light-colored, waxy of the left great toe (figure 3). There was plaques and typically occur bilaterally on a surgical scar noted on the anterior neck. the lower extremities.3 The deep tendon reflexes were greatly Thyroid dermopathy of the lower diminished. Exophthalmosis was present, extremities is classified into four different with blurriness in the right eye and blind- clinical forms: edema accompanied by ness in the left eye. Laboratory evaluation typical skin-color changes, plaque, nodular, revealed a thyroid-stimulating hormone or elephantiasic form.4 In a study of 178 (TSH) with a markedly high titer of 94.02 patients, 77 patients had the non-pitting µIU/mL (normal: 0.34 to 5.66) and a mark- edema form of thyroid dermopathy with a edly low free thyroxine level of <0.15 µIU/ relative frequency of 43.3%.4 The second mL (normal: 0.52 to 1.21). most frequent, at 27%, was the plaque Based on a detailed dermatologic history Figure 2 type, and the nodular type was third most and clinical presentation, a diagnosis of common at 18.5%.4 The rarest form is the elephantiasic pretibial myxedema was elephantiasic form, with only five out of made. The various forms of pretibial myxe- 178 patients having it, a relative frequency dema are distinguished based on clinical of 2.8%.4 evaluation alone. Histological presentation of pretibial myxedema has large amounts Case: of mucin present in the dermis.5 The large amounts of mucin may result in splitting A 50-year-old male presented with a six- of the collagen bundles into fibers. There year history of swelling in his legs. He is typically an increase in number of mast stated that for the past several years, his cells when compared to normal skin and legs had been progressively more swollen a perivascular infiltrate of lymphocytes. and painful. In reviewing his medica- Unfortunately, there are no microscopic Figure 3 tion, he was taking an over-the-counter characteristics that distinguish between the (OTC) herbal supplement called Thyroid various clinical forms of dermopathy, and of thyrotoxicosis, but in a small portion Support® (Figure 1). When questioned Fatourechi showed this in his review of 80 of patients it can develop four to 12 years about the supplement, he stated he had 2 patients. later.3 Thyroid dermopathy tends to occur been taking it for his thyroid disease. He was diagnosed with Graves’s disease Discussion: within the first two years after the develop- in 2000 and was treated with antithyroid ment of Graves’ ophthalmopathy, with the drugs without improvement. Finally, he The onset of thyroid dermopathy is highest frequency in the first 12 months.2 underwent a total thyroidectomy and then usually 12 to 24 months after the diagnosis Thyroid dermopathy results from an Judy, Burton, Miller 65 accumulation of glycosaminoglycans in the References: reticular dermis, especially hyaluronic acid, 1. Cannavò SP, Borgia F, Vaccaro M, Guarneri F, Magliolo with it being six to 16 times higher in these E, Guarneri B. Pretibial myxoedema associated with 4 Hashimoto’s thyroiditis. J Eur Acad Dermatol Venereol. lesions as compared to normal skin. The 2002 Nov;16(6):625-627. cause of this localized pathology remains 2. Fatourechi V, Pajouhi M, Fransway AF. Dermopathy of Graves disease (pretibial myxedema). Review of 150 controversial. Some have implicated heat cases. Medicine (Baltimore). 1994 Jan;73(1):1-7. shock proteins, IL-1, TGF-B, and thyroid- 3. Fatourechi V. Pretibial myxedema: pathophysiology and 4 treatment options. Am J Clin Dermatol. 2005;6(5):295- stimulating hormone receptor antibodies. 309. Review. While some report a more cell-type site- 4. Schwartz KM, Fatourechi V, Ahmed DD, Pond GR. Dermopathy of Graves’ disease (pretibial myxedema): specific phenomenon, others report local- long-term outcome. J Clin Endocrinol Metab. 2002 ized physical and anatomical factors such Feb;87(2):438-446. 5. Somach SC, Helm TN, Lawlor KB, Bergfeld WF, Bass J. as edema and trauma. Rapoport et al. Pretibial mucin. Histologic patterns and clinical correla- hypothesize that dependent edema, with tion. Arch Dermatol. 1993 Sep;129(9):1152-6. 6. Rapoport B, Alsabeh R, Aftergood D, McLachlan SM. a slower return of lymphatic fluid to the Elephantiasic pretibial myxedema: insight into and a general circulation, may cause decreased hypothesis regarding the pathogenesis of the extrathy- roidal manifestations of Graves’ disease. Thyroid. 2000 clearance and prolonged half-life of fibro- Aug;10(8):685-692. blast-stimulating cytokines.6 Whether 7. Bull RH, Coburn PR, Mortimer PS. Pretibial myxoedema: a manifestation of lymphoedema? Lancet. 1993 Feb the cause of these changes are cell-specific 13;341(8842):403-404. or localized edema, these patients have 8. Susser WS, Heermans AG, Chapman MS, Baughman RD. Elephantiasic pretibial myxedema: a novel treatment damage to their lymphatics, especially in for an uncommon disorder. J Am Acad Dermatol. 2002 the elephantiasic form. Bull et al. report May;46(5):723-726. abnormalities of both the lymphatic struc- ture and function in patients with extensive pretibial myxedema.7 Pretibial myxedema is usually asymptomatic and does not require treatment. The lesions usually do not expand and may regress partially or completely over time.4 However, if the dermopathy causes discomfort, functional impairment, or is cosmetically disfiguring, topical glucocorticoids are the treatment of choice.2 The fluid accumulation is often forgotten in these patients because the edema is non-pitting. These patients may benefit from compression therapy to help with their lymphatic insufficiency, especially those with the more severe forms of pretibial myxedema. Although our patient was lost to follow- up, our clinical experience demonstrates that compression therapy combined with corticosteroids have shown improvements. Inelastic compression, such as an Unna boot, is favored initially over compression stockings because of its ability to maintain higher compression. Unna boots are impregnated with zinc oxide and calamine, which tend to be an added benefit for the skin changes such as xerosis. Susser et al. also demonstrated compression therapy along with manual lymphatic drainage providing a good outcome.8

66 eLephantiasic Pretibial Myxedema: A Rare Form of Thyroid Dermopathy B:9.25” T:8.5” S:7”

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Important Safety Information Oracea® is indicated for the treatment of only inflammatory lesions (papules and pustules) of rosacea in adult patients. In clinical trials, the most common adverse events reported were gastrointestinal upsets, nasopharyngitis/pain, and nasal congestion/sinusitis. Oracea® should not be used to treat microbial infections, and should be used only as indicated. This drug is contraindicated in people who have shown hypersensitivity to any of the tetracyclines, and, like other tetracycline drugs, may cause fetal harm when administered to a pregnant woman. Oracea® should not be used during pregnancy, by nursing mothers, or during tooth development (up to the age of 8 years). Although photosensitivity was not observed in clinical trials, Oracea® patients should minimize or avoid exposure to natural or artificial sunlight. All contraindications, warnings, and precautions associated with tetracyclines must be considered before prescribing Oracea®. The safety of Oracea® treatment beyond 9 months has not been established. Please see brief summary of Prescribing Information on next page. References: 1. Del Rosso JQ, Schlessinger J, Werschler P. Comparison of anti-inflammatory dose doxycycline versus doxycycline 100 mg in the treatment of rosacea. J Drugs Dermatol. 2008;7(6):573-576. 2. Fowler JF Jr. Combined effect of anti-inflammatory dose doxycycline (40-mg doxycycline, USP monohydrate controlled-release capsules) and metronidazole topical gel 1% in the treatment of rosacea. J Drugs Dermatol. 2007;6(6):641-645. 3. Preshaw PM, Novak MJ, * Mellonig J, et al. Modified-release subantimicrobial dose doxycycline enhances scaling and root planing in subjects with periodontal disease.J Periodontol. 2008;79(3):440-452. 4. Del Rosso JQ, Webster GF, Jackson M, et al. Two randomized phase III clinical trials evaluating anti-inflammatory dose doxycycline (40-mg doxycycline, USP capsules) administered once daily for treatment of rosacea. J Am Acad Dermatol. 2007;56(5):791-802.

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The plasma concentrations of doxycycline achieved with ORACEA during administration (see DOSAGE AND B/W Prints: Trim: PI_m11 #:Summary Job Brief ORA-0039 ADMINISTRATION) are less than the concentration required to treat bacterial diseases. In vivo microbiological studies utilizing a similar drug exposure for up to 18 months demonstrated no detectable long-term effects on

bacterial fl ora of the oral cavity, skin, intestinal tract, and vagina. 11"h x 8.5"w Carcinogenesis, Mutagenesis, Impairment of Fertility: Doxycycline was assessed for potential to induce carcinogenesis in a study in which the compound was administered to Sprague-Dawley rats by gavage at Brief Summary of Full Prescribing Information dosages of 20, 75, and 200 mg/kg/day for two years. An increased incidence of uterine polyps was observed INDICATIONS AND USAGE in female rats that received 200 mg/kg/day, a dosage that resulted in a systemic exposure to doxycycline ORACEA is indicated for the treatment of only infl ammatory lesions (papules and pustules) of rosacea in approximately 12.2 times that observed in female humans who use ORACEA (exposure comparison based upon adult patients. area under the curve (AUC) values). No impact upon tumor incidence was observed in male rats at 200 mg/kg/ Live Area:Live The dosage of ORACEA differs from that of doxycycline used to treat infections. To reduce the development day, or in either gender at the other dosages studied. Evidence of oncogenic activity was obtained in studies with of resistant bacteria as well as to maintain the effectiveness of other antibacterial drugs, ORACEA should be related compounds, i.e., oxytetracycline (adrenal and pituitary tumors) and minocycline (thyroid tumors). used only as indicated. Doxycycline demonstrated no potential to cause genetic toxicity in an in vitro point mutation study with CLINICAL PHARMACOLOGY mammalian cells (CHO/HGPRT forward mutation assay) or in an in vivo micronucleus assay conducted in CD-1 mice. However, data from an in vitro assay with CHO cells for potential to cause chromosomal aberrations Pharmacokinetics suggest that doxycycline is a weak clastogen. 9.875"h x 7"w ORACEA capsules are not bioequivalent to other doxycycline products. Oral administration of doxycycline to male and female Sprague-Dawley rats adversely affected fertility and CONTRAINDICATIONS reproductive performance, as evidenced by increased time for mating to occur, reduced sperm motility, velocity, This drug is contraindicated in persons who have shown hypersensitivity to doxycycline or any of the other and concentration, abnormal sperm morphology, and increased pre-and post-implantation losses. Doxycycline tetracyclines. induced reproductive toxicity at all dosages that were examined in this study, as even the lowest dosage WARNINGS tested (50 mg/kg/day) induced a statistically signifi cant reduction in sperm velocity. Note that 50 mg/kg/day is approximately 3.6 times the amount of doxycycline contained in the recommended daily dose of ORACEA for a Teratogenic effects: 1) Doxycycline, like other tetracycline-class antibiotics, can cause fetal harm 60-kg human when compared on the basis of AUC estimates. Although doxycycline impairs the fertility of rats when administered to a pregnant woman. If any tetracycline is used during pregnancy or if the when administered at suffi cient dosage, the effect of ORACEA on human fertility is unknown. patient becomes pregnant while taking these drugs, the patient should be informed of the potential hazard to the fetus and treatment stopped immediately. Pregnancy: Teratogenic Effects: Pregnancy Category D. (see WARNINGS section). Results from animal ORACEA should not be used during pregnancy (see PRECAUTIONS: Pregnancy). studies indicate that doxycycline crosses the placenta and is found in fetal tissues. 2) The use of drugs of the tetracycline class during tooth development (last half of pregnancy, Nonteratogenic effects: (see WARNINGS section). infancy, and childhood up to the age of 8 years) may cause permanent discoloration of the teeth Labor and Delivery: The effect of tetracyclines on labor and delivery is unknown. (yellow-gray-brown). This adverse reaction is more common during long-term use of the drug but has been Nursing Mothers: Tetracyclines are excreted in human milk. Because of the potential for serious adverse reactions observed following repeated short-term courses. Enamel hypoplasia has also been reported. Tetracycline drugs, therefore, should not be used during tooth development unless other drugs are not likely to in infants from doxycycline, ORACEA should not be used in mothers who breastfeed. (see WARNINGS section). be effective or are contraindicated. Pediatric Use: ORACEA should not be used in infants and children less than 8 years of age (see WARNINGS 3) All tetracyclines form a stable calcium complex in any bone-forming tissue. A decrease in fi bula growth rate section). ORACEA has not been studied in children of any age with regard to safety or effi cacy, therefore use has been observed in premature human infants given oral tetracycline in doses of 25 mg/kg every 6 hours. in children is not recommended. This reaction was shown to be reversible when the drug was discontinued. ADVERSE REACTIONS Results of animal studies indicate that tetracyclines cross the placenta, are found in fetal tissues, and can Adverse Reactions in Clinical Trials of ORACEA: In controlled clinical trials of adult patients with mild to cause retardation of skeletal development on the developing fetus. Evidence of embryotoxicity has been noted moderate rosacea, 537 patients received ORACEA or placebo over a 16-week period. The most frequent in animals treated early in pregnancy (see PRECAUTIONS: Pregnancy section). adverse reactions occurring in these studies are listed in the table below. Gastrointestinal effects: Pseudomembranous colitis has been reported with nearly all antibacterial agents and may range from mild to life-threatening. Therefore, it is important to consider this diagnosis Incidence (%) of Selected Adverse Reactions in Clinical Trials of ORACEA (n=269) vs. Placebo (n=268) in patients who present with diarrhea subsequent to the administration of antibacterial agents. ORACEA Placebo Treatment with antibacterial agents alters the normal fl ora of the colon and may permit overgrowth of clostridia. Nasopharyngitis 13 (4.8) 9 (3.4) Studies indicate that a toxin produced by Clostridium diffi cile is a primary cause of “antibiotic-associated colitis”. Pharyngolaryngeal Pain 3 (1.1) 2 (0.7) If a diagnosis of pseudomembranous colitis has been established, therapeutic measures should be initiated. Mild Sinusitis 7 (2.6) 2 (0.7) cases of pseudomembranous colitis usually respond to discontinuation of the drug alone. In moderate to severe

Nasal Congestion 4 (1.5) 2 (0.7) B:12.25”

cases, consideration should be given to management with fl uids and electrolytes, protein supplementation, and S:10” T:11” treatment with an antibacterial drug clinically effective against Clostridium diffi cile colitis. Fungal Infection 5 (1.9) 1 (0.4) Metabolic effects: The anti-anabolic action of the tetracyclines may cause an increase in BUN. While this Infl uenza 5 (1.9) 3 (1.1) is not a problem in those with normal renal function, in patients with signifi cantly impaired function, higher Diarrhea 12 (4.5) 7 (2.6) serum levels of tetracycline-class antibiotics may lead to azotemia, hyperphosphatemia, and acidosis. If renal impairment exists, even usual oral or parenteral doses may lead to excessive systemic accumulations of the Abdominal Pain Upper 5 (1.9) 1 (0.4) drug and possible liver toxicity. Under such conditions, lower than usual total doses are indicated, and if therapy Abdominal Distention 3 (1.1) 1 (0.4) is prolonged, serum level determinations of the drug may be advisable. Abdominal Pain 3 (1.1) 1 (0.4) Photosensitivity: Photosensitivity manifested by an exaggerated sunburn reaction has been observed in Stomach Discomfort 3 (1.1) 2 (0.7) some individuals taking tetracyclines. Although this was not observed during the duration of the clinical studies with ORACEA, patients should minimize or avoid exposure to natural or artifi cial sunlight (tanning beds or Note: Percentages based on total number of study participants in each treatment group. UVA/B treatment) while using ORACEA. If patients need to be outdoors while using ORACEA, they should Adverse Reactions for Tetracyclines: The following adverse reactions have been observed in patients wear loose-fi tting clothes that protect skin from sun exposure and discuss other sun protection measures receiving tetracyclines at higher, antimicrobial doses: with their physician. Gastrointestinal: anorexia, nausea, vomiting, diarrhea, glossitis, dysphagia, enterocolitis, and infl ammatory PRECAUTIONS lesions (with vaginal candidiasis) in the anogenital region. Hepatotoxicity has been reported rarely. Rare instances General: Safety of ORACEA beyond 9 months has not been established. of esophagitis and esophageal ulcerations have been reported in patients receiving the capsule forms of the As with other antibiotic preparations, use of ORACEA may result in overgrowth of non-susceptible micro- drugs in the tetracycline class. Most of the patients experiencing esophagitis and/or esophageal ulceration took organisms, including fungi. If superinfection occurs, ORACEA should be discontinued and appropriate therapy their medication immediately before lying down. (see DOSAGE AND ADMINISTRATION section). instituted. Although not observed in clinical trials with ORACEA, the use of tetracyclines may increase the Skin: maculopapular and erythematous rashes. Exfoliative dermatitis has been reported but is uncommon. incidence of vaginal candidiasis. Photosensitivity is discussed above. (see WARNINGS section). ORACEA should be used with caution in patients with a history of or predisposition to candidiasis overgrowth. Renal toxicity: Rise in BUN has been reported and is apparently dose-related.(see WARNINGS section). Bacterial resistance to tetracyclines may develop in patients using ORACEA. Because of the potential for drug- Hypersensitivity reactions: urticaria, angioneurotic edema, anaphylaxis, anaphylactoid purpura, serum sickness, resistant bacteria to develop during the use of ORACEA, it should be used only as indicated. pericarditis, and exacerbation of systemic lupus erythematosus. Autoimmune Syndromes: Tetracyclines have been associated with the development of autoimmune Blood: Hemolytic anemia, thrombocytopenia, neutropenia, and eosinophilia have been reported. syndromes. Symptoms may be manifested by fever, rash, arthralgia, and malaise. In symptomatic patients, liver function tests, ANA, CBC, and other appropriate tests should be performed to evaluate the patients. Use OVERDOSAGE of all tetracycline-class drugs should be discontinued immediately. In case of overdosage, discontinue medication, treat symptomatically, and institute supportive measures. Dialysis does not alter serum half-life and thus would not be of benefi t in treating cases of overdose. Tissue Hyperpigmentation: Tetracycline class antibiotics are known to cause hyperpigmentation. Tetracycline therapy may induce hyperpigmentation in many organs, including nails, bone, skin, eyes, thyroid, visceral DOSAGE AND ADMINISTRATION tissue, oral cavity (teeth, mucosa, alveolar bone), sclerae and heart valves. Skin and oral pigmentation has THE DOSAGE OF ORACEA DIFFERS FROM THAT OF DOXYCYCLINE USED TO TREAT INFECTIONS. been reported to occur independently of time or amount of drug administration, whereas other pigmentation EXCEEDING THE RECOMMENDED DOSAGE MAY RESULT IN AN INCREASED INCIDENCE OF SIDE has been reported to occur upon prolonged administration. Skin pigmentation includes diffuse pigmentation EFFECTS INCLUDING THE DEVELOPMENT OF RESISTANT MICROORGANISMS. as well as over sites of scars or injury. One ORACEA Capsule (40 mg) should be taken once daily in the morning on an empty stomach, preferably at Pseudotumor cerebri: Bulging fontanels in infants and benign intracranial hypertension in adults have least one hour prior to or two hours after meals. been reported in individuals receiving tetracyclines. These conditions disappeared when the drug was Effi cacy beyond 16 weeks and safety beyond 9 months have not been established. discontinued. Administration of adequate amounts of fl uid along with the capsules is recommended to wash down the Laboratory Tests: Periodic laboratory evaluations of organ systems, including hematopoietic, renal and hepatic capsule to reduce the risk of esophageal irritation and ulceration. (see ADVERSE REACTIONS section). studies should be performed. Appropriate tests for autoimmune syndromes should be performed as indicated. Drug Interactions: 1. Because tetracyclines have been shown to depress plasma prothrombin activity, HOW SUPPLIED patients who are on anticoagulant therapy may require downward adjustment of their anticoagulant dosage. ORACEA (beige opaque capsule printed with CGPI 40) containing doxycycline, USP in an amount equivalent to 2. Since bacteriostatic drugs may interfere with the bactericidal action of penicillin, it is advisable to avoid 40 mg of anhydrous doxycycline. Bottle of 30 (NDC 64682-009-01). giving tetracycline-class drugs in conjunction with penicillin. 3. The concurrent use of tetracycline and Storage: All products are to be stored at controlled room temperatures of 15°C-30°C (59°F-86°F) and methoxyfl urane has been reported to result in fatal renal toxicity. 4. Absorption of tetracyclines is impaired by dispensed in tight, light-resistant containers (USP). Keep out of reach of children. bismuth subsalicylate, proton pump inhibitors, antacids containing aluminum, calcium or magnesium and iron- Patent Information: U.S. Patents 5,789,395; 5,919,775; 7,232,572; 7,211,267 and patents pending. containing preparations. 5. Doxycycline may interfere with the effectiveness of low dose oral contraceptives. To ORACEA is a registered trademark of CollaGenex Pharmaceuticals, Inc. avoid contraceptive failure, females are advised to use a second form of contraceptive during treatment with doxycycline. 6. There have been reports of pseudotumor cerebri (benign intracranial hypertension) associated Manufactured by: Marketed by: with the concomitant use of isotretinoin and tetracyclines. Since both oral retinoids, including isotretinoin CardinalHealth Galderma Laboratories, L.P. and acitretin, and the tetracyclines, primarily minocycline, can cause increased intracranial pressure, the Winchester, KY 40391 Fort Worth, TX 76177 concurrent use of an oral retinoid and a tetracycline should be avoided. 7961-01 BPI 06/08

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