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

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

2009-2010 AOCD Officers President: Leslie Kramer, DO, FAOCD President-Elect: Bradley Glick, DO, FAOCD First Vice-President: James Towry, DO, FAOCD Second Vice-President: Karen Neubauer, DO, FAOCD Third Vice-President: David Grice, DO, FAOCD Secretary-Treasurer: Jere Mammino, DO, FAOCD Immediate Past President: Marc Epstein, DO, FAOCD Trustees: Celeste Angel, DO, FAOCD Alpesh Desai, DO, FAOCD Mark Kuriata, DO, FAOCD Editors Rick Lin, DO, FAOCD Jay S. Gottlieb, DO Andrew Racette, DO, FAOCD Jon Keeling, DO Suzanne Rozenberg, DO, FAOCD Editorial Review Board Kevin Belasco, DO Rich Bernert, M.D. Sponsors: Iqbal Bukhari, MD Global Pathology Laboratory

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

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Mark Lebwohl, MD AOCD • 1501 E. Illinois • Kirksville, MO 63501 Rick Lin, DO 800-449-2623 • FAX: 660-627-2623 www.aocd.org Megan Machuzak, D.O. Jere Mammino, DO, FAOCD COPYRIGHT AND PERMISSION: written permission must be obtained from the Journal of the American Osteopathic College of Dermatology John Minni, DO for copying or reprinting text of more than half page, tables or figures. Navid Nami, DO Permissions are normally granted contingent upon similar permission from the author(s), inclusion of acknowledgement of the original source, Shaheen Oshtory, 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 John Perrotto, DO articles. Request for permission should be directed to JAOCD c/o AOCD Stephen Purcell, DO, FAOCD PO Box 7525 Kirksville, MO 63501 Copyright 2003 by the Journal of the American Osteopathic College of Michael Scott, DO, FAOCD Dermatology Kevin Spohr, DO Printed by: The Dimensional Group, Mason City, IA 50401 Proofreading: Julia Layton, Freelance Proofreading and Editing Journal of the American Osteopathic College of Dermatology Volume 19, Number 1 February 2011 aocdJournal of the Contents Letter from the JAOCD Editors...... 4 Irritant Contact Vasculitis with Systemic Symptoms After Exposure to the Agave Americana Plant...... 6 Joseph Del Priore, DO,* Helia Eragi, DO,** David C. Horowitz, DO, FACD*** Muir-Torre Syndrome: A Case Report...... 8 Krina K. Chavda, DO,* Sanjosh Singh, DO, MPH,** Marvin Watsky, DO*** A Case Report: Adult-Onset Still’s Disease...... 10 Garrett R. Bohrnstedt, D.O.,* Chad Johnston, D.O.,** Roxann Powers, M.D., F.A.A.D.,*** Rodney Kovach, MD**** Behçet’s Disease with MAGIC Syndrome in a Caucasian Female: A Case Report and Clinical Update...... 12 Brooke Walls, DO,* Jamie Hale-Hollenbeck, MS-III,** Frank Armstrong, DO, FAOCD,*** Keith Kappeler, DO, FACOFP**** Bilateral Idiopathic Auricular Ossificans:A Case Report and Review of the Literature...... 17. Wade R. Keller, D.O.,* Ellecia Cook, D.O.,** Don A. Anderson, D.O., F.A.O.C.D., F.A.S.M.S. *** Keratitis-Ichthyosis-Deafness Syndrome...... 20 Amanda Beehler, DO,* Michelle Jeffries, DO,** Stephen Kessler, DO,*** Ronald Hansen, MD**** Lobular Capillary Hemangioma...... 22 Cynthia L. Chen, BA,* Scott Deckelbaum, DO,** Mark Horowitz, DO,*** David Horowitz, DO, FAOCD, FAAD**** Cutaneous Metastatic Breast Carcinoma: Case Report and Review of the Literature...... 24 Jacqueline Thomas, DO,* Shawna Flanagan, MD,** Les Rosen, MD,*** Janet Allenby, DO**** Large Polypoid Dermatofibroma in a Young Boy: A Case Report...... 29 Kurt Grelck, DO,* Janet Allenby, DO, FAOCD** Lichen Planus Pigmentosus-Inversus...... 32 Zaina Rashid, D.O.,* Michael Land, MSIV,** Sarah Shuker, MSI,*** Don Anderson, D.O., FAOCD, FASMS**** Multinucleate-cell Angiohistiocytoma: A Unique Case and Literature Review...... 34 Julie Malchiodi, DO, FAOCD,* Jonathan D. Richey, DO, MHA,** Brian N. Parks, DO, PGY1,*** Cory D. Nelson, DO, PGY1,**** Annette LaCasse, DO, FAOCD***** A Case of Calciphylaxis and Review of the Literature...... 38 Christine Brooks, MSIV,* Brandon Miner, DO,** Peter Saitta, DO,*** Steven Grekin, DO, FAOCD**** Multiple Juvenile Xanthogranuloma: An Uncommon Presentation of the Most Common Histiocytosis...... 43 Andrea Baratta, DO,* Sourab Choudery, DO,** Suzanne Sirota Rozenberg, DO, FAOCD,*** Marvin S. Watsky, DO, FAOCD**** Use of Etanercept for patients with severe plaque psoriasis in the setting of advanced solid malignancies...... 46 Luis Dehesa, MD,* Magalys Vitiello, MD,** Francisco A. Kerdel, BSc, MBBS*** Papular-Purpuric Gloves and Socks Syndrome: A Case Report and Literature Review...... 48 Monica Nafsou, DO,* Patrick Keehan, DO** A Case of Kaposi’s Sarcoma...... 43 Amara Sayed, D.O., FACOFP,* Janet Allenby, D.O., FAOCD** Ashy Dermatosis with Novel Homeopathic Treatment Using Enoxaparin: A Case Report and Literature Review...... 47. Thomas Singer, D.O.,* Brad Glick, D.O.** Spitzoid Blue Nevus with Dysplasia: Case Study and Review...... 49 Robert A. Norman, DO, MPH, MBA,* Trupal Patel, B.S.** Central Centrifugal Cicatricial Alopecia: A Case Presentation and Literature Review ...... 53 Joanna I. Sadowska, D.O., M.H.S.,* Robert A. Norman, D.O., M.P.H., M.B.A.** Letter From The Editors

Jay Gottlieb, DO, FAOCD Jon Keeling, DO, FAOCD Senior Editor Co-Editor Help the JAOCD to grow…

The editors of the JAOCD want to take this opportunity to wish the entire AOCD a very happy and healthy New Year. We hope that your holiday season was exciting and spent with your family.

The JAOCD continues to grow, and we are expanding our editorial board. The expanded board will ensure that we are able to review manuscripts in a timely and efficient way. The manuscripts continue to improve in both content and writing style. All residents are required by the EEC to have their annual papers reviewed, proofed and approved by their program directors. This has made the review process on our end much more efficient.

Because of professional and personal obligations, Andrew Racette, D.O., has decided to step down as a co- editor of the JAOCD. We would like to thank Dr. Racette for his time and effort in helping the JAOCD grow.

The JAOCD has hired our proofreader, Julia Layton, to become the copy editor of the journal. She will be in direct contact with the authors to make sure that their manuscripts are complete and in the proper format to be published in the JAOCD. We are very excited about having Julia step up into this new position. We are confident that this will serve to improve the quality of our journal and also make the journal more uniform and consistent in format and content.

As always, we would like to increase the number of members that sit on our editorial board. Beginning with the next issue, all editorial-board members will have their photos in the front of the journal.

We extend our thanks to all of the members of the AOCD who help to improve the quality of our journal.

Special thanks are in order for Global Pathology, Galderma Pharmaceuticals, Medicis-The Dermatology Company and Ranbaxy Pharmaceuticals for their sponsorship of the JAOCD. The JAOCD would remain just an idea and a dream if we did not have their support.

Sincerely,

Jay Gottlieb, DO, FAOCD Senior Editor

Jon Keeling, DO, FAOCD Co-Editor

4 Letter From the Editors NOTICE TO READERS

The JAOCD staff is small and the budget is limited for the production of the JAOCD. The AOCD Education and Evaluating Committee (EEC) has made it a requirement, that every resident in the AOCD must submit their annual paper for consideration for publication to a scientific journal each year of their residency. We appreciate the number of residents that elect to submit their annual papers to the JAOCD for consideration to be published.

The EEC has also made it mandatory that every resident’s annual paper must be reviewed, proofed and approved by their residency program director. Each manuscript must be co-authored by the resident’s program director.

The JAOCD provides the best possible peer review based on the number of AOCD members that are able to review these manuscripts. The JAOCD recently has employed a Copy Editor to assure that our journal is proofed for grammar, spelling and format.

If any reader has questions or issues with any of the manuscript that appears in this issue, they should contact the author and/or their program chairman directly. The staff of the JAOCD will continue to do our best to keep the quality of the JAOCD at the highest level possible based on the resources at our disposal.

Jay S. Gottlieb, DO. FAOCD, FOCOO Senior Editor

Jon Keeling, DO, FAOCD Co-Editor

5 Irritant Contact Vasculitis with Systemic Symptoms After Exposure to the Agave Americana Plant

Joseph Del Priore, DO,* Helia Eragi, DO,** David C. Horowitz, DO, FACD*** *Dermatology Resident, Second Year, Western University/Pacific Hospital of Long Beach, Long Beach, CA **Intern, Pacific Hospital of Long Beach, Long Beach, CA ***Program Chairman/Dermatology Residency Director, Western University/Pacific Hospital of Long Beach, Long Beach, CA

Abstract Agave Americana, also known as the Century plant, is a low-growing plant that is prevalent in tropical, subtropical, and temperate climates and is mostly an ornamental plant in the United States; however, in Mexico it is fermented into a “pulque,” an alcoholic beverage. The sap of this plant consists of calcium oxalate crystals, acrid oils, saponins, and other compounds. Previous case reports have demonstrated a contact reaction to this plant sap with both skin and systemic symptoms. A vesiculopapular and purpuric variant has been described with and without systemic manifestations. Clinical purpuric lesions were also shown to have a leukocytoclastic vasculitis upon histologic exam. A toxin within the A. americana causes an immediate irritant reaction to the skin, but the cause of a systemic reaction has yet to be elucidated. This case report provides clinical demonstration of a purpuric variant with concomitant systemic symptoms soon after exposure to the sap of this plant. Key words: agave americana; century plant; vasculitis; contact dermatitis; irritant contact dermatitis; systemic symptoms

Case Report Discussion another purpuric variant with systemic symptoms, it has been speculated that A 63-year-old male presented with Agave Americana, also known as the the oxalic acid crystals lead to localized a three-day history of a pruritic rash on Century plant, is a low-growing plant and systemic vascular damage.8 Systemic his legs and arms that was unresponsive to that is prevalent in tropical, subtropical, toxicities along with lab abnormalities self treatment with topical hydrocortisone and temperate climates (Figure 3). It is a were apparent in 10 of 12 patients found and Eucerin calming moisturizer. He also member of the Agaveceae family that forms to have a contact dermatitis provoked by complained of concomitant mild shortness rosettes of tough, sword-shaped leaves with Agave americana.9 of breath, subtle blurry vision, decreased thorny margins. It gets the name “Century This case represents another appetite, myalgia, eyelid swelling, and an plant” from its infrequent, exuberant vesiculopapular vasculitic variant with overall feeling of malaise. Severe burning flowering, consisting of a spike with a cyme systemic symptoms. A toxin within the A. and itching of the skin started 10 to 20 of big yellow flowers that arises from a americana causes an immediate irritant minutes after cutting down a Century plant central stem that may reach up to 8 meters reaction to the skin; however, the systemic (Agave Americana) with a chainsaw. Soon in height. It was once believed to flower reaction has yet to be elucidated. As in the afterward, the patient went into his pool once every 100 years, but in reality the purpuric variants described, a chainsaw and then took a shower with soap in an plant flowers after 25 years and then dies. was used in this case, which appears to attempt to alleviate the discomfort, without Therefore, the name Century plant is a either cause deeper penetration into the success. No lesions were immediately misnomer. Agavaceae plants are used for a skin or to cause more of the toxin to be present. The next day, red papules variety of commercial (rope, fibers, mescal, transmitted to the skin. This author and vesicles began to appear, and then tequila), medicinal (steroid extraction, agrees that the oxalic acid crystals may excoriations began to appear secondary to pre-Columbian antibacterial salves), and be a culprit in causing localized and the scratching. A review of his symptoms was ornamental purposes.1-2 A. americana is systemic manifestation in the form of a negative for gastrointestinal involvement, mostly an ornamental plant in the U.S., but transient vasculitis. renal involvement, connective-tissue disease, in Mexico it is fermented into a “pulque,” hematological disorders, and malignancy. an alcoholic beverage.2-3 References The patient’s only other health issue The sap of this plant consists of was high cholesterol, controlled with Zetia calcium oxalate crystals, acrid oils, 1. Davidson JR, Ortiz de Montellano BR. The antibacterial properties of an Aztec wound remedy. J Ethnopharmacol and Crestor. He had no known drug saponins, and other compounds. It has 1983;8:149-61. allergies. He related a past systemic reaction been presumed by various authors that 2. High WA. Agave Contact Dermatitis. American Journal of Contact Dermatitis 2003; 14:213-4. after eating eggplant. His surgical and social the calcium oxalate crystals and saponins 3. Brazzelli V, Romano E, Balduzzi A, Borroni G. Acute irri- history was insignificant. (precursors of synthetic steroidal tant contact dermatitis from Agave americana L. Contact Physical exam revealed excoriated hormones) are the source of the marked Dermatitis 1995; 33:60-1. 4. Kerner J, Mitchell J, Maibach HI. Irritant contact dermati- erythematous papules and vesicles on pruritus and stinging associated with tis from Agave americana L. Incorrect use of sap as “hair both legs and arms sparing the clothing- exposure to the sap of the Agave plant.3-5 restorer.” Archives of Dermatology 1973:108:102-3. 5. Ricks MR, Vogel PS, Elston DM, Hivnor C. Purpuric covered area. There were scattered, bright Oxalic acid poisoning may lead to acidosis, agave dermatitis. J Am Acad Dermatol 1999:40:356-8. red, petechial papules with some purpura vascular damage, and obstruction of renal 6. Ellenhorn MJ. Ellenhorn’s Medical Toxicology: Diagnosis (Figure 1 & 2). There were neither vision- tubules.6 Systemic manifestations, such as and Treatment of Human Poisoning. Baltimore, Md: Williams and Williams; 1997: 1091-2. acuity impairments nor eyelid-swelling fever and leukocytosis, have been reported 7. Brenner S, Friedman J. Phytophotodermatitis induced by present on examination. Vital signs were in cases of contact with Ruta chalepensis, Ruta chalepensis. Contact Dermatitis 1985:12:230-2. 8. Cherpelis BS, Fenske NA. Purpuric Irritant Contact stable. No biopsy was performed. attributed to herbal chemicals (sapogenins) Dermatitis Induced by Agave americana. Cutis 2000:66: Our clinical diagnosis was a vasculitic or mediators of inflammation released 287-8. 7. 9. Brenner S, Landau M, Goldberg I. Contact Dermati- type of contact dermatitis. The patient was from the damaged skin. tis with Systemic Symptoms from Agave americana. treated with 10mg of prednisone twice a There have been previous reports Dermatology – Clinical and Laboratory Investigations. day along with a topical clobetasol spray. that describe a vesiculopapular eruption 1998:196:408-11. The patient returned two days later with upon exposure to the sap of the plant.3- dramatic relief of symptoms and a visual 4 In addition, a purpuric variant, with fading of lesions. A follow-up visit at seven evidence of leukocytoclastic vasculitis days revealed a complete resolution of the and a lack of systemic symptoms, has lesions with only a slight superficial scaling demonstrated a localized cutaneous 5 with desquamation remaining. vasculitis on histologic exam. In

6 irritant Contact Vasculitis with Systemic Symptoms After Exposure to the Agave Americana Plant Figure 1: Excoriated erythematous petechial papules with purpura sparing clothing-covered areas. Figure 4: Agave Americana: Example of exuberant flowering that consists of a spike with cyme of big yellow flowers that arises from a central stem. It may reach up to 8 meters in height.

Figure 2: Close-up of lesions showing bright-red petechial papules with purpura.

Figure 3: Agave americana, also known as the Century plant, in non-flowering state.

Priore, Eragi, Horowitz 7 Muir-Torre Syndrome: A Case Report

Krina K. Chavda, DO,* Sanjosh Singh, DO, MPH,** Marvin Watsky, DO*** *Dermatology Resident, 1st year, St. John’s Episcopal Hospital, Far Rockaway, NY **Family Practice Resident, 3rd year, St. John’s Episcopal Hospital, Far Rockaway, NY ***Program Director, Dermatology, St. John’s Episcopal Hospital, Far Rockaway, NY

Abstract Muir-Torre syndrome (MTS) is a rare genodermatosis characterized by sebaceous-gland neoplasm and at least one internal malignancy caused by germline mutations within two DNA mismatch repair (MMR) genes, MSH1 (8% of cases) and MLH2 (92% of cases). We present a unique case of Muir-Torre syndrome with angiosarcoma in addition to colon and renal carcinoma.

Case Report been proposed that two unique subtypes review of sebaceous neoplasms from the of SA are highly specific markers for MTS: Mayo Clinic Department of Dermatology A 62-year-old Russian man presented to cystic sebaceous adenoma and sebaceous from 1923 to 1983. This study revealed the dermatology office for evaluation of a adenoma with an architectural pattern or that 42 percent of patients with one or few flesh-colored papules in the head and combined features of keratoacanthoma. more sebaceous neoplasms had at least one Cystic sebaceous neoplasms have only been associated visceral malignancy, consistent back region (Fig. 1). Biopsy result returned 10 as sebaceous epithelioma (Fig. 2). The observed in patients with MTS, strongly with diagnostic criteria for MTS. Skin suggesting they are highly specific markers manifestations of MTS appear to precede patient had been treated numerous times 7. in the past for similar lesions. In 2004, the for MTS. the diagnosis of visceral malignancy in 22 biopsy diagnosis was BCC with sebaceous Sebaceous epitheliomas (SEs) percent of cases, to present concurrently are benign, sebaceous proliferations in 6 percent of cases, and to present differentiation (Fig. 3). The patient was 11 treated with Moh’s surgery. Later in 2004, clinically described as solitary, yellowish afterwards in 56 percent of cases. Hence, another lesion along the right nasal crease papules with rolled borders and the skin lesion might be a harbinger for an was biopsied and revealed sebaceous measuring <1 cm in diameter, but larger internal malignancy. carcinoma. This was also treated with lesions have been reported. Much is being discovered about MTS Moh’s surgery. In 2005, he returned with and its associated causes and health risks. Sebaceous carcinomas (SCs) are rare, MTS is thought to be a phenotypic yet another lesion, for which biopsy malignant neoplasms associated with MTS. diagnosis was sebaceous adenoma. He was subset of the more commonly known SCs most commonly occur on the hereditary nonpolyposis colorectal cancer referred to a GI specialist for colonoscopy, eyelids, where they generally arise from the which revealed transverse colon cancer syndrome (HNPCC). A high percentage meibomian glands and the glands of Zeiss. of MTS patients have germline mutations proximal to the splenic flexure, and he They may also appear on the ears, the feet, was treated with colon resection. He later within two DNA mismatch repair (MMR) the penis, and the labia. Unlike SAs, SCs are genes, MSH1 (8% of cases) and MLH2 developed left-sided renal carcinoma, aggressive in nature, with the tendency for 12 which was treated by nephrectomy. When (92% of cases). These two MMR angiolymphatic invasion and subsequent genes are also a characteristic feature the patient returned to the dermatology 8 15 office in 2009, he was being treated for metastatic disease. of HNPCC. This may explain why angiosarcoma of the right gluteal region. A keratoacanthoma (KA) may also gastrointestinal cancers develop in 61% of be a valid marker for MTS if it shows those with MTS and tend to be proximal sebaceous differentiation histologically to the splenic flexure.2 In contrast, the Discussion or if the patient fulfills the following majority of individuals without MTS three criteria: multiple keratoacanthomas who develop colorectal cancer have distal Muir-Torre syndrome (MTS) is a rare present, history of two or more low-grade lesions.2 The second most common site is genodermatosis consisting of sebaceous visceral malignancies, and a family history the urogenital tract, representing 22% of neoplasms (sebaceous adenoma, sebaceous of MTS.1 Common sites of involvement cases. A wide variety of other cases have epithelioma, sebaceous carcinoma, include the face and the dorsum of the been reported, including breast cancer, keratoacanthoma or BCC with sebaceous hands, but KAs can occur anywhere on lymphoma, leukemia, salivary gland differentiation) and at least one low-grade tumors, lower and upper respiratory visceral malignancy. The syndrome is the body. Sebaceous hyperplasia is not tract tumors and chondrosarcoma. characterized by an autosomal-dominant There have been a few reported cases of inheritance pattern with variable included in the diagnostic criteria of MTS, but there have been reports of patients the carcinoma of the ampulla of Vater in penetrance and expression, although association of MTS.13 Recently, there has sporadic cases may also occur.1 A recent with sebaceous hyperplasia exhibiting microsatellite instability and a visceral been one unique reported case of pancreas review cited just over 200 documented 14 malignancy, warranting an investigation and colon cancer in MTS. Surprisingly, cases. The median age of onset is 55 years, the internal malignancies associated with with a male-to-female ratio of 3:2. for cancer in the family history for a patient with sebaceous hyperplasia.9 MTS generally metastasize but are less Sebaceous adenomas (SAs) are aggressive than their sporadic counterparts. the most common sebaceous neoplasm SAs and SEs can be excised or treated with cryosurgery. SCs should be excised The median survival even in the setting associated with MTS, appearing in of metastatic disease appears to be at least 68% of patients.2,3 SAs are with wide margin of resection along with removal of involved lymph nodes. significantly longer for those patients with benign, multilobular tumors with 1 Radiotherapy may also be effective. malignancies associated with MTS. sebaceous differentiation. The lesions Immunohistochemistry (IHC) are characterized by smooth, well- Excision is adequate therapy for a single KA, but cryotherapy can be tried for analysis of tumor specimens for expression circumscribed, speckled yellow papules of MMR genes is a useful screening/ usually <0.5 cm in diameter, although multiple KAs. Oral isoretinoin may 4 prevent the cutaneous neoplasms in this diagnostic method. Studies have shown lesions >9 cm have been documented. The that IHC staining using antibodies against lesions occur on the trunk more often than syndrome. Furthermore, all patients with established diagnosis of sebaceous tumors MSH2 and MLH1 proteins in MTS- on the head and neck in MTS compared associated skin tumors is an extremely to sporadic cases.5 Lesions on the oral should undergo a thorough evaluation 6 for the presence of underlying MTS. This practical approach to diagnosis of the mucosa have also been reported. It has 15 recommendation is based on retrospective MMR-defective subtype of MTS. Before

8 muir-Torre Syndrome: A Case Report 2007., MSH1 and MSH2 were thought to Patients with suspicious cutaneous tumors and keratoacanthomas. Cancer 2005;103:1018- be the only MMR genes associated with lesions should undergo screening for any 1025. MTS, but recent cases of MTS caused by internal malignancy. It has been thought MSH6 have also been reported. MSH6 is a that the strong association of colorectal germline mutation also found in HNPCC. cancer with MTS mandates annual Therefore, it is recommended to include colonoscopy beginning between the MSH6 along with MLH1 and MLH2 in ages of 20 and 25 (or five years younger IHC screening.16 than the earliest age at diagnosis in the One disadvantage of IHC analysis family, whichever is earlier). Periodic is that the presence of MSH2 and MSH1 upper endoscopy, yearly urinalysis and proteins does not exclude the possibility dermatologic screening at least once a of an underlying DNA repair defect, such year are also recommended screening as a missense mutation, that may lead tools. Furthermore, screening for women to an altered amino-acid sequence and a between the ages of 25 and 30 should false-negative result. Therefore, it might include a yearly pelvis examination, Figure 1 be helpful to confirm an MTS diagnosis pap smear, transvaginal ultrasound by performing microsatellite instability and endometrial biopsy. All patients (MSI) testing. with typical cutaneous lesions of MTS Testing sebaceous lesions for MSI and positive family history should is another way of evaluating a patient be referred for genetic risk assessment for MTS. Microsatellites are repeated and consideration of genetic testing. sequences of DNA found in everyone’s Evaluation of an extended pedigree to genome. They may vary in size but identify other affected family members is are typically the same length within also recommended. individuals. Microsatellites are susceptible to mutations, and when the mutations are not repaired they can become abnormally References short or long. This variation in length is 1. Schwartz RA, Torre DP. The Muir-Torre Syndrome: a 25 year retrospect. J Am Acad Dermatol 1995; 33:90-104. termed MSI and is a marker for defects 2. 17. Cohen PR, Kohn SR, Kurzrock R. Association of in DNA MMR. MTS- and HNPCC- sebaceous gland tumors and internal malignancy: the Muir-Torre syndrome. Am J Med 1991;90:606-13. Figure 2 associated tumors exhibit high MSI, 3. Akhtar S, Oza KK, Khan SA, Wright J. Muir-Torre further suggesting MTS as a phenotypic syndrome: case report of a patient with concurrent 18 jejunal and ureteral cancer and a review of the literature. variant of HNPCC. J Am Acad Dermatol 1999;41:681-6. The advantage of performing 4. Eisen DB, Michael DJ. Sebaceous lesions and the associated syndromes: Part I. J Am Acad Dermatol MSI testing over IHC analysis remains 2009;61:549-60. 5. Singh RS, Grayson W, Redston M, Diwan AH, Warneke controversial. Some studies have shown CL, McKee PH, et al. Site and tumor type predicts MSI testing to be more sensitive at DNA mismatch repair status in cutaneous sebaceous neoplasia. Am J Surg Pathol, 2008;32:936-42. detecting patients with germline MMR 6. Orlian Al, Salman L, Reddi T, Yamane GM, Chaudry AP. defects than IHC.19,20 However, most Sebaceous adenoma of the oral mucosa. J Oral Med 1987;42:38-9. of those studies were done using fewer 7. Misago N, Narisawa Y. Sebaceous neoplasms in Muir- antibodies (MLH1 and MSH2). Two Torre syndrome. Am J Dermatopathol. 2000 Apr;22(2): 155-61. studies done with four antibodies (MLH1, 8. Harrington CR, Egbert BM, Swetter SM. Extraocular Figure 3 sebaceous carcinoma in a patient with Muir-Torre MSH2, MSH6 and PMS2) showed syndrome. Dermatol Surg. 2004 May;30(5):817-9. sensitivity equal to or greater than MSI, 9. Cesinaro Am, Ubiali A, Sighinolfi P, et al. Mismatch repair proteins expression and microsatellite instability in skin although these included a smaller number lesions with sebaceous differentiation: a study in different of patients.19 MSI testing is only available clinical subgroups with and without extracutaneous cancer. Am J Dermatopathol 2007; 29:351-358. in specialized laboratories and is more 10. Finan MC, Connolly SM. Sebaceous gland tumors and systemic disease: a clinicopathologic analysis. Medicine costly than IHC. Because IHC analysis is (Baltimore). 1984 Jul;63(4):232-42. less time-consuming and less expensive 11. Lucci-Cordisco E, Zito I, Gensini F, Genuardi M. Hereditary nonpolyposis colorectal cancer and related than MSI testing, many recent studies are conditions. Am J Med Genet A. 2003 Nov;122(4):325-34. recommending the use of IHC screening 12. Kruse R, Ruzicka T. DNA mismatch repair and significance of a sebaceous skin tumor for visceral for MTS in all diagnosed sebaceous cancer prevention. Trend Mol Med 2004;10:136-41. neoplasms. However, it must be noted that 13. Matthews JJ, Roberts R, O’Reilly DA, Schick S, Kingsnorth AN. Muir Torre syndrome: a case for 0-32% of spontaneous sebaceous lesions surveillance of the ampulla of Vater. Dig Surg 2002;19(1):65-6. tested with IHC have been negative for 14. Tanyi M, Olasz J, Lukacs G, et al. A new MMR gene protein expression.9 This mutation in Muir-Torre syndrome associated with familiar transmission of different gastrointestinal may suggest another subset of MTS not adenocarcinomas. J Can Surg 2009;35:1128-30. diagnosed by MSI or IHC, associated 15. Mathiak M, Rutten A, Mangold E, Fischer HP, Ruzicka T, Friedl W, Propping P, Kruse R. Loss of DNA mismatch with a different genetic or pathological repair proteins in skin tumors from the patients with Muir 21 Torre syndrome and MSH2 or MLH1 germline mutations: mechanism yet to be discovered. establishment of an immunohistochemical analysis as a screening test. Am J Surg Pathol. 2002 Mar;26(3):338- 43. 16. Mangold E, Rahner N, Friedrichs N, Buettner R, Summary Pagenstecher C, Aretz S, et al. MSH6 mutation in Muir-Torre syndrome: could this be a rare finding? Br J Dermatol 2007;156:158-62. The unique feature of our case is the 17. De la Chapelle A. Microsatellite Instability. N Engl J Med presence of angiosarcoma in addition to 2003;349:209-10. 18. Mathiak M, Rutten A, Mangold E, Fischer HP, Ruzicka T, colon and renal cancers in a patient with Friedl W, Propping P, Kruse R. Loss of DNA mismatch repair proteins in skin tumors from patients with Muir Muir-Torre syndrome. There have been Torre syndrome and MSH2 or MLH1 germline mutations: no documented cases of angiosarcoma establishment of an immunohistochemical analysis as a screening test. Am J Surg Pathol. 2002 Mar; 26(3): 338- associated with MTS published yet in 43. the literature. Unfortunately, a family 19. Hampel H, Frankel WL, Martin E, Arnold M, Khanduja K, Kuebler P, et al. Screening for Lynch syndrome history, which would have been helpful (hereditary nonpolyposis colorectal cancer). N Engl J Med 2005;352:1851-60. in early diagnosis and treatment, was 20. Pinol V, Castells A, Andreu M, Castellvi-Bel S, Alenda C, unobtainable. Genetic testing may Llor X, et al. Accuracy of revised Bethesda guidelines, microsatellite instability and immunohistochemistry for be useful in this case to identify a new, the identification of patients with hereditary nonpolyposis unknown MMR germline mutation colorectal cancer. JAMA 2005;293:1986-94. 21. Ponti G, Losi L, Di Gregorio C, et al. Identification of responsible for angiosarcoma in MTS. Muir-Torre syndrome among patients with sebaceous

chavda, singh, watsky 9 A Case Report: Adult-Onset Still’s Disease

Garrett R. Bohrnstedt, D.O.,* Chad Johnston, D.O.,** Roxann Powers, M.D., F.A.A.D.,*** Rodney Kovach, MD**** *Traditional Rotating Intern, 2009, Montgomery Regional Hospital, Blacksburg, VA **Dermatology Resident, West Virginia University, Morgantown, WV ***West Virginia University, Morgantown, WV ****Program Director, Dermatology, WVU Department of Medicine, Morgantown, WV

Abstract Adult-onset Still’s disease (AOSD) is a systemic inflammatory condition originally described by Bywaters in 1971.1,3,6 The disease is difficult to diagnose, and other conditions, including infections, malignancies, and vasculitides, must be ruled out before making the diagnosis.2,3,5 Typical presenting symptoms include a triad of spiking fever (often accompanied by pharyngitis), salmon-colored macular rash, and arthralgias.1,3,5 Characteristic lab findings include markedly elevated serum ferritin levels, leukocytosis, and increases in erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), lactate dehydrogenase, and liver function tests.1,3,5 Rheumatoid factor (RF) and antinuclear antibody (ANA) tests are typically negative.2 Finding an effective treatment option can be challenging due to the infrequency of the condition, unknown etiology, and lack of large-scale studies assessing the therapeutic efficacy.5 We are reporting a case of AOSD resistant to treatment and exhibiting a chronic articular course.

Case Report B and C, RPR, RF, and ANA. Her other lab rash is usually macular, salmon pink, and values included: WBC 12.6, Hgb 10.5, Hct intensifies with fever spikes.1,2 The rash A 19-year-old Caucasian female 32.1, ESR 118, ferritin 157.1, total iron 16, is most commonly found on the trunk presented to the clinic with a three- TIBC 216, albumin 2.1, and LDH 26.8. She but can appear anywhere, including the month history of a recurrent rash and also had negative blood and strep cultures. palms and soles.1 It may present at sites of fever. Her rash was more pronounced She was positive for DNase and had an pressure and has been shown to exhibit the with fever spikes that reached 103oF. ASO titer of 115. Her chest X-ray, EKG, Koebner phenomenon.1,5 Arthralgias are The fevers occurred almost daily and and echocardiogram were normal. At this symmetrical in nature and most commonly most often in the evening. She also point, a diagnosis of adult-onset Still’s affect the knees, wrists, and ankles.1,5 complained of sore throat, wrist pain, disease was made, and she was admitted to Arthritis with wrist involvement may abdominal pain with nausea and vomiting, the inpatient medical service. evolve into carpal ankylosis, which begins and fatigue. On multiple visits to the around six months after onset of the emergency department, she had received Discussion disease.5 It may reach its full intensity at intramuscular triamcinolone, with relief 1.5-3 years, leading to a marked decrease in of symptoms lasting approximately one Adult-onset Still’s disease (AOSD) carpal range of motion.1,5 Ankylosis has also week at a time. Previous workup had not is a rare systemic disorder of unknown been reported with the proximal and distal revealed any infectious process. etiology.1 AOSD has been speculated to interphalangeal joints, metacarpophalangeal Her past medical history included be caused by multiple environmental and and metatarsophalangeal joints, 6 temporomandibular joints, hips, post-partum depression (P1G 1) and genetic factors. Studies have shown it to contact dermatitis one year prior. She had be associated with multiple HLA antigens.1 and cervical spine.1 Other signs and no previous surgeries and reported no The condition mimics infectious (viral or symptoms include myalgias, sore throat, medication allergies. Her family history bacterial) diseases and rheumatological lymphadenopathy, splenomegaly, pleuritis, included type 2 diabetes mellitus, heart conditions, and may present similar pericarditis, and abdominal pain (maybe disease, and cancer. She admitted to to malignancies such as leukemia and due to mesenteric lymphadenitis).1,5 smoking 3-4 cigarettes per day. She was lymphoma.2,5 It is considered by many As mentioned above, the condition currently taking fluoxetine for depression as a reactive arthritis exhibiting a Th1- has been associated with increased and naproxen as needed for pain. dominant immune response.2,5,6 This is levels of acute phase reactants. This is On exam, she was febrile with a evident with increased levels of pro- evident with elevations in ESR and CRP, temperature of 103oF. She was in mild inflammatory cytokines such as IL-1, IL-6, along with a marked increase in ferritin distress, but otherwise appeared to be IL-18, and TNF α.2,5,6 Increases in the levels.3,5,6 Furthermore, ferritin levels in good health. She had a generalized, erythrocyte sedimentation rate, C-reactive may be used to monitor disease activity macular and papular rash showing protein, and serum ferritin levels have also and assess treatment efficacy (levels fall as koebnerization on the abdomen and been found.2 symptoms are relieved).3 There is also a legs (Figures 1 and 2). She displayed AOSD most commonly occurs in the decreased percentage of glycosylated serum palpable cervical lymphadenopathy and 3rd and 4th decades of life.2 Three different ferritin.5 The glycosylation mechanisms synovitis of the wrists bilaterally. The disease courses have been identified.3,5 become saturated due to the high serum differential diagnosis included rheumatic First, it may be self-limited, with remission ferritin levels.5 Glycosylated ferritin fever, rheumatoid arthritis, adult-onset in less than a year.3,5 Second, it may be is considered a more specific marker for Still’s disease, lymphoma, subacute intermittent or recurrent, which can be AOSD than ferritin levels alone, but its bacterial endocarditis, systemic lupus with or without joint complaints.3,5 Last, use is limited by availability and cannot be erythematosus, hepatitis, syphilis, familial it may exhibit a chronic articular pattern used to monitor disease activity.5 Other Mediterranean fever, and TNF-receptor- with more severe joint involvement labs include leukocytosis, increased associated periodic syndrome, or TRAPS. including ankylosis.3,5 Most common hepatic enzymes, increased LDH, and A punch biopsy was taken from the findings include spiking fever, typical hypergammaglobulinemia, and some upper extremity (Figure 3) and showed rash, and arthralgias.1 The patient’s fever patients show a reactive thrombocytosis.1,2,3,5 interstitial and perivascular neutrophilic- may be greater than 104oF with spikes Patients are reported negative for dominant infiltrate without any vasculitis once or twice a day, particularly in the antinuclear antibodies and rheumatoid (Figure 4). She tested negative for hepatitis late afternoon and early evening.1,5 The factor.6 Histological examination of 10 A Case Report: Adult-Onset Still’s Disease the rash shows interstitial, dermal, and to control her symptoms, slow progression, perivascular infiltrate with a predominance and prevent joint destruction and other of neutrophils.1,4 These findings are usually complications of the disease. present without any associated vasculitis.1 Before a diagnosis of AOSD can be References made, other more common infections, rheumatological diseases, and malignancies 1. Bolognia JL, Jorizzo JL, Rapini RP, editors. Adult-onset 5 Still’s disease. Dermatology. Edinburgh: Mosby, Inc; must be ruled out. Most viral infections 2003. p. 634-635. can be ruled out if symptoms persist 2. Firestein GS, Budd RC, Harris ED, McInnes IB, Ruddy 3,5 S, Sergent JS. Adult-onset Still’s disease (uncommon). for more than three months. Use of Firestein: Kelley’s Textbook of Rheumatology, 8th Edition. hematological studies can help differentiate W. B. Saunders Company. 2008. 3. Slovis B, Eyler A. A 32 year old man with pharyngitis, AOSD from malignancies such as leukemia transient rash, and multisystem failure. Chest. Sept. and lymphoma, but a bone marrow and/ 2007;132(3). 4. Bachmeyer C, et al. Vesiculopustules in Adult- Figure 1 or lymph node biopsy may be needed in Onset Still’s Disease. J Am Acad Dermatol. May difficult cases.5 Negative ANA and 2006;54(5):S247-S248. 5. Efthimiou P, Paik PK, Bielory L. Diagnosis and Manage- rheumatoid factor can help rule out ment of Adult-Onset Still’s Disease. Ann Rheum Dis. autoimmune disease.3,5 2006;65:564-572. 6. Wung PK, Pipeling MR, Wigley FM. Still Ill. The Amer Several physicians have formulated Journ of Med. June 2008;121(6):491-493. diagnostic criteria that may aid in a more confident diagnosis.3 The most frequently used, published by Yamaguchi et al., yields a sensitivity as high as 96.2%.3 The major criteria include a temperature greater than 39oC for greater than one week, leukocytosis, typical rash, and arthralgias for greater than two weeks. The minor criteria include sore throat, lymph node enlargement, Figure 2 splenomegaly, liver dysfunction, and a negative ANA and RF.2,5 Not included in the Yamaguchi criteria are ferritin and glycosylated ferritin.3,5 These values are included in more recent criteria by Fautrel, which increases the specificity of making a diagnosis to as high as 98.5% but decreases the sensitivity.3,5 Treatment for AOSD is usually empiric and based on small-scale retrospective studies and case reports.5 High doses of salicylates/ NSAIDs are the mainstay of treatment for mild disease, but systemic steroids may be needed as well.1,6 In fact, some sources say Figure 3 that most patients are given systemic steroids at some point in their treatment.5 Steroids are required in more severe disease or when there is internal organ involvement.3,6 It is recommended, with NSAID-resistant disease, that large doses of steroids be limited to six months duration.5 For patients who are resistant to both NSAIDs and steroids, disease-modifying anti-rheumatic drugs (DMARDs) and biologics have been used.5,6 DMARDs that have been used with some success include methotrexate and sulfasalazine.6 Biologics used with success include TNF antagonists and IL-1 antagonists.6 IVIG has been used, Figure 4 and an experimental IL-6 antagonist may prove to be beneficial in the future.5 In our case, the patient originally responded to high-dose aspirin and was discharged. However, within two months, prednisone was required to control her symptoms. Her disease has now progressed, and she has required treatment with methotrexate and adalimumab (Humira). Her disease course is consistent with the chronic articular pattern described above. Her response to the current treatment regimen will be monitored with the hope

Bohrnstedt, johnston, powers, Kovach 11 Behçet’s Disease with MAGIC Syndrome in a Caucasian Female: A Case Report and Clinical Update

Brooke Walls, DO,* Jamie Hale-Hollenbeck, MS-III,** Frank Armstrong, DO, FAOCD,*** Keith Kappeler, DO, FACOFP**** *Intern, Largo Medical Center, Largo, FL **NOVA Southeastern University, Ft. Lauderdale, FL ***Board-certified Dermatologist and Clinical Instructor at LECOM, Bradenton, FL; Armstrong Dermatology and Skin Cancer Center, Seminole, FL ****Family Practice, Largo, FL Teaching institution: HCA Largo Medical Center, Largo, FL

Case Report located in the posterior pharynx. Her metaplasia, and focal mild inflammation, abdomen was tender to palpation in the but no Helicobacter were seen by A 43-year-old Caucasian female mid-epigastric region. No abdominal immunocytochemistry. was admitted to the hospital for severe distention was appreciated. She had A colonoscopy with biopsies had been abdominal pain associated with anorexia, synovitis in the ankles and bilateral performed six months earlier. The left constipation, and bloating of one-month swelling of the hands with joint colon was significant for numerous isolated duration. She also complained of swelling enlargement. Multiple papillary lesions ulcerations with areas of inflammation and pain in her ankles, hands, and lower with scabs less than 1 centimeter were with edema, and multiple ulcerations were back. The patient is well known to us, noted on her chin, and hypopigmented noted as the scope was advanced (Images). with numerous hospital admissions in the macules were present on her left deltoid. The ileocecal valve appeared to be normal. past six months for similar GI and arthritis Laboratory results were significant for an The clinical impression was universal complaints. She reported having flares elevated erythrocyte sedimentation rate patchy colitis with multiple ulcerations of her typically abdominal symptoms of 7.7., C-reactive protein of 11.5, and that may represent gastrointestinal several times a year for the past 13 years. positivity for HLA-B27.. CBC revealed a manifestations of Behçet’s syndrome. In addition to the pain and bloating, normocytic, normochromic anemia with Colon-biopsy reports revealed she also sometimes experienced severe a hemoglobin level of 9.0. CT imaging multiple fragments of colonic mucosa odynophagia, oral and genital ulcers, of the abdomen showed mild mesenteric and muscularis mucosa with focal, arthritis in her ankles, and various skin lymphadenopathy and periaortic discrete, well-demarcated areas of acute lesions. She was first seen eight months lymphadenopathy with mild hepatomegaly. inflammation with surface erosion and prior with severe left ear pain initially ANA, rheumatoid factor, and dsDNA were with eosinophils and neutrophils. In one diagnosed as cellulitis. The patient within normal range. area there appeared to be some changes in reported the development of multiple An EGD with esophageal biopsies and the small vessels suggestive of vasculitis. irritating lesions on various areas of her gastric biopsies from a prior admission There were no granulomas. No features of skin with no particular distribution and revealed linear, mid and distal ulcer of ulcerative colitis, Crohn’s disease, dysplasia genital ulcers that flare with her other the esophagus approximately 2 mm or malignancy were noted. symptoms. Since first becoming a patient x 15 mm. Examination of the stomach The patient was originally treated with of ours, she has had an extensive work-up revealed proximal gastric inflammation prednisone and then colchicine for the joint including two EGDs, a colonoscopy, and with erosions and erosions of the distal pain and inflammation, both of which she extensive blood work. stomach. There were three discrete ulcers claimed to have adverse reactions to. She Her past medical history includes of the antrum, two of which were circular, was then started on IM methotrexate of 6 esophageal and gastric ulcers, anorexia measuring 3 to 4 mm in diameter, and mg weekly, which controlled the ulcers and nervosa, anxiety, partial liver gangrene, one that was linear, measuring 2 mm joint pain; however, the patient discontinued and chronic joint pain and swelling. x 4 mm. The duodenum showed mild the medication secondary to financial Her past surgical history includes inflammation, but no ulceration. The difficulties three months prior to her most liver biopsy with partial resection, second and third portions of the recent admission. Upon discontinuation of cholecystectomy, lymph node biopsy, duodenum as well as papilla were the methotrexate, the patient experienced a three cesarean sections, lysis of pelvic and otherwise normal. severe flare with abdominal pain, bloating, abdominal adhesions, colonoscopy, and Histological examination of the oral ulcers, various skin lesions and esophagogastroduodenoscopy. Her father esophageal biopsies revealed fragments swelling in her ankles. While an inpatient is deceased at age 53 secondary to leukemia. of squamous epithelium with some she re-started the methotrexate at 6 mg Her mother is alive and well at age 68. She erosion and acute inflammation and intramuscular injection. has three children who are all alive and well. what appeared to be some collections The patient is allergic to cephalexin and of bacteria, thought to be cocci. The Discussion penicillin, and she has an adverse reaction PAS stain was negative for fungal spores or hyphae, but some of the to prednisone. She is of American Indian Behçet’s disease is a chronic, relapsing, and Irish decent and has smoked a pack and nuclei in the stratified squamous epithelium were markedly enlarged and multi-vessel vasculitis that can affect many a half a day for the past 12 years. Her home organ systems. Behçet’s was first described medications include Protonix 40 mg BID, suspicious, although not diagnostic for herpes inclusions. The CDX-2 by Turkish dermatologist Hulusi Behçet in methotrexate 6 mg IM weekly, and Percocet 1937. as a clinical triad of recurrent buccal 10/650 mg Q 6 prn. marker was negative. Specimen 2 sections of the stomach demonstrated aphthosis, genital ulcer, and uveitis with Physical exam was significant for hypopyon. Since the original description, punched-out, white, oval, oral ulcerations epithelial hyperplasia, mild intestinal 12 Behçet’s Disease with MAGIC Syndrome in a Caucasian Female: A Case Report and Clinical Update other systemic features, including skin Patients present with a variety of one-half of patients, and is especially severe lesions, arthritis, and neurological and symptoms, and diagnosis is one of exclusion during exacerbations. gastrointestinal complications, have based on clinical signs and symptoms. The Another interesting association become associated with this disease. International Study Group for Behcet’s with this disease spectrum is that of While relatively rare in the United States disease proposed diagnostic criteria in polychondritis. MAGIC syndrome was and among northern Europeans, it has a 1990 (Table 1). According to the criteria, first described in 1985 by Firestein et al. higher prevalence along the ancient Silk recurrent oral ulceration must be present MAGIC is an acronym that stands for Road, extending from eastern Asia to the along with at least two of the following: Mouth and Genital ulcers with Inflamed Mediterranean basin. Turkey has the recurrent genital ulceration, eye lesions, skin Cartilage. Inflamed cartilage is a rare highest prevalence, with 80 to 37.0 cases per lesions or a positive pathergy test.4 manifestation of Behçet’s and is considered 100,000. Turkish men and Japanese women While oral ulcers are one of the earliest an overlap of Behçet’s disease with relapsing have the highest prevalence worldwide. In and most common manifestations of polychondritis. Very few cases have been the United States, the prevalence of Behcet’s Behçet’s disease, extensive gastrointestinal reported in the literature. A literature search is 0.12 to 0.33 per 100,000. Interestingly, ulcerations are rare and found in less revealed only nine. The inflammation can Behçet’s disease is rare among Japanese than 1% of patients.5 Clinically, GI be destructive at times and is best controlled immigrants in Hawaii and California.1 manifestations of Behçet’s are characterized with immunosuppression therapy.13 Age of onset is in the third and fourth by crampy abdominal pain, nausea, The lesions of Behçet’s disease decades. While the repeated flares of anorexia, odynophagia, dysphagia, diarrhea, are characterized histologically by inflammation can be painful, they are self- melena, and perforation. Esophageal leukocytoclastic and lymphocytic limited. However, repeated uveitis can ulcers may be linear, oval or round lesions vasculitis. Neutrophils from patients lead to blindness, which is more common primarily found in the mid to distal portion with Behçet’s have increased superoxide in Mediterranean men. Cases of GI ulcer of the esophagus.7. Unfortunately, gastric production, enhanced chemotaxis, perforation have also been reported, with ulcers may be complicated by perforation. and excessive production of lysosomal significant mortality. Small and large intestines may be involved, enzymes, indicating that the neutrophils The etiology of Behçet’s disease is and lesions include mucosal inflammation, are overactive, leading to increased tissue unknown but is likely to be a multifactorial ulcerations, and ischemia secondary to injury.1 Elevated levels of cytokines, combination of genetic, infectious vasculitis. The ileocecal region is reported including IL-8, TNF-alpha, and IL-1B, susceptibility, and autoimmune factors. to be the most commonly involved area. have been recorded in lesions, which are The prevalence of the HLA-B51 allele is Intestinal ulcers can be classified into three known to recruit neutrophils. Lymphocyte high among patients with Behcet’s disease groups based on appearance: volcano, function is abnormal in patients with who live in areas along the Silk Road but not geographic, and aphthous ulcers. Volcano Behçet’s, resulting in an expansion of auto- among white patients who live in Western ulcers are deep with discrete margins and reactive T cells. Countries.1 Infection has been implicated may extend into the serosa, with perforation The differential diagnosis includes as an initiating factor in developing Behçet’s. as a major concern. They may be difficult chronic oral aphthosis, herpes simplex, Herpes simplex, hepatitis C virus, parvovirus to distinguish from Crohn’s disease, but are Crohn’s disease, rheumatoid arthritis, and B19, and Streptococcus sanguis have all been typically deeper ulcers with more distinct Sweet’s syndrome. Because the disease has implicated; however, research has failed to boarders.7. Aphthous ulcers are small and such diverse clinical presentations, and a prove any specific infectious agent. In fact, usually found in clusters near the ileocecal pathognomonic laboratory test is lacking, it the results of a series of studies led to the region with surrounding erythema. can be a challenging diagnosis to make. hypothesis that ubiquitous antigens, including Skin lesions are common, occurring While there is no cure for Behçet’s heat shock protein of microorganisms, may in over 7.5% of patients with Behçet’s. The disease, there are many treatment options trigger cross-reactive autoimmune responses skin manifestations vary significantly from for the various manifestations. The focus in patients with Behçet’s disease.1 It has been patient to patient, ranging from acneiform of treatment is on reduction of symptoms noted that herpes simplex virus DNA and lesions to erythema nodosum. Acneiform and prevention of the progression of the serum antibodies against the virus have been lesions may be more common in association disease. For severe disease, corticosteroids found in a higher proportion of patients with with arthritis.8 Arthritis tends to be non- are used most often. Colchicine is used Behçet’s disease than in controls. erosive and asymmetric, occurs in about for mucocutaneous lesions, erythema

Table 1. Criteria for the Diagnosis of Behcet’s Disease* Finding Definition Recurrent oral ulceration Minor aphthous (< 1 cm), major aphthous (> 1 cm), or herpetiform ulcers observed by the physician or patient which have recurred at least three times over a 12-month period Recurrent genital ulceration Aphthous ulceration or scarring observed by the physician or patient Eye lesions Anterior uveitis, posterior uveitis, or cells in the vitreous on slit-lamp examination; or retinal vasculitis detected by an ophthalmologist

Skin lesions Erythema nodosum observed by the physician or patient, pseu- dofolliculitis, or papulopustular lesions; or acneiform nodules observed by the physician in a post-adolescent patient who is not receiving corticosteroids Positive pathergy test Test consists of pricking a sterile needle into the patient’s forearm. The results are judged to be positive when the puncture causes an aseptic erythematous nodule or pustule that is more than 2 mm in diameter at 24-48 hours. *The criteria were drawn up by the International Study Group for Behcet’s Disease.4 Walls, Hale-hollenbeck, armstrong, kappeler 13 nodosum, genital ulcers, and arthritis. Rheumatism. May 2009; 61(5):600-604. 4. International Study Group for Behçet’s Disease. “Criteria Thalidomide is utilized mainly in men due for diagnosis of Behçet’s disease.” Lancet. 1990; 335:1078-80. to its teratogenic side effects when used 5. Dowling, Catherine M, Arnold DK Hill, Carmel Malone, in women. Studies are proving it to be John J Sheehan, Shona Tormey, Kieran Sheahan, Enda McDermott, Niall J O’Higgins. “Case Report: Colonic effective for mucocutaneous lesions. Perforation in Behçet’s syndrome.” World J Gastroenterol. Immunosuppressants such as 2008; 14(42):6578-6580. 6. Wolff, Klaus, Richard Allen Johnson, Dick Suurmond. cyclophosphamide, cyclosporine, “Behçet’s Syndrome.” Fitzpatrick’s Color Atlas and azathioprine, and methotrexate are effective Synopsis of Clinical Dermatology. 5th ed. 2005; Section 14:368-371. and the cornerstone of treatment for 7. Johnston A, Gudjonsson JE, Sigmundsdottir H, Ludviksson BR, Valdimarsson H. “The anti-inflammatory action of MAGIC syndrome. However, the use of methotrexate is not mediated by lymphocyte apoptosis but these drugs is limited by their side effects, by the suppression of activation and adhesion molecules.” Clinical Immunology. 2005; 114 (2): 154-163 including risk of infection, hypertension, 8. Kotter I, Zierhut M, Eckstein AK, Vonthein R, Ness T, decreased blood counts, and liver and Gunaydin I, Grimbacher B, Blaschke S, Meyer-Riemann W, Peter HH, Stubiger N. “Human recombinant interferon kidney disease. Azathioprine improves alfa-2a for the treatment of Behcet’s disease with sight threatening posterior or panuveitis.” British Journal of prognosis and helps prevent ulcerations Ophthalmology. 2003; 87:423-431 and ocular disease when started early. 9. Smith Ellison MD, Schur Peter MD. “Treatment of Behcet’s Figure 1 disease.” UpToDate. 2009; May Version 17.2. Accessed Cyclophosphamide has limited proven September 23, 2009. effects but is used in neurologic and 10. “Questions and answers about Behcet’s disease.” National Institute of Arthritis and Musculoskeletal and Skin vascular manifestations. Methotrexate Diseases. www.niams.nih.gov/hi/topics/behcets/behcets. works as a DNA synthesis inhibitor and htm. Accessed October 5, 2009. 11. Schneider, Alison, M.D., Afkhamossada Merikhi, M.D., is S-phase specific. Methotrexate is a Barbara B. Frank, M.D. “Autoimmune Disorders: Gastrointestinal Manifestations and Endoscopic Findings.” folate antimetabolite, irreversibly binding Gastrointest Endoscopy Clin N Am. 2006;16:133-151. to dihydrofolate reductase.7. It is thought 12. Smith, Ellison L, M.D., John H Stone, M.D., MPH, and Paul L. Romain, M.D. “Clinical manifestation and diagnosis of that this is not the mechanism of action Behcet’s Disease.” UpToDate. May 1, 2009. responsible for its efficacy in the treatment 13. James, William D, M.D., Timothy Berger, M.D., Dirk MD Elston, M.D. Andrews’ Diseases of the Skin: Clinical of Behçet’s and other diseases such as Dermatology. 2005; ed. 10. rheumatoid arthritis, Crohn’s disease, and psoriasis. Instead, there are two other effects of low-dose methotrexate treatment: It inhibits the enzymes of purine metabolism and causes adenosine to accumulate; and it inhibits T-cell activation and suppresses T-cell expression of intracellular adhesion molecules. The anti-inflammatory effect of Figure 2 methotrexate was found to be a direct result of these actions.7. Immunomodulators are on the frontline of research for treating systemic disease. Interferon alpha-2alpha treats mucocutaneous, ocular, articular, and neurologic manifestations. Anti-TNF agents such as infliximab and etanercept are being used for ocular disease and mucocutaneous lesions.8 Conclusion Our patient presented with abdominal pain and bloating for 13 years and with the recent development of arthritis, mouth and genital ulcers and polychondritis of Figure 3 the pinna. Her diagnosis was delayed for multiple reasons, including possibly the dramatic nature of the patient. However, it is important to constantly review patient complaints and validate their concerns and continue to search for answers. Due to the rare occurrence of Behçet’s disease and MAGIC syndrome, there are no specific treatment guidelines. Therefore, clinical judgment and patient involvement are necessary to choose the right treatment option for each individual. Our patient will continue to take methotrexate to control her symptoms and will be followed clinically. References

1. Sakane, Tsuyoshi, M.D., Ph.D., Mitsuhiro Takeno, M.D., Ph.D., Noboru Suzuki, M.D., Ph.D., and Goro Inaba, M.D., Ph.D. “Behçet’s Disease.” NEJM. Oct. 1999;341(17):1284-91. 2. Welsh, John Patrick, M.D., Christopher B. Skvarka, M.D., Christine Ko, M.D., Carrie Ann Cusack, M.D. “Mystery of the Silk Road.” The American Journal of Medicine. 2007;120:322-324. 3. Calamia, Kenneth T., M.D., Floranne C. Wilson, M.D., Murat Icen, M.D., Cynthia S. Crowson, M.S., Sherine E. Gabriel, M.D., MSc, and Hilal Maradit Kremers, M.D., MSc. “Epidemiology and Clinical Characteristics of Behçet’s Disease in the US: A Population-Based Study.” Arthritis & 14 Behçet’s Disease with MAGIC Syndrome in a Caucasian Female: A Case Report and Clinical Update Quick, Accurate, Dependable — Your Global Pathology Diagnosis.

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Wade R. Keller, D.O.,* Ellecia Cook, 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, Kingman, AZ **Intern, Nova Southeastern University College of Osteopathic Medicine, Largo Medical Center, Largo, FL ***Program Director, Arizona College of Osteopathic Medicine, Midwestern University, Kingman, AZ

Abstract Petrified auricles are an uncommon phenomenon. Of the over 160 cases in the literature to date only 19 demonstrate histologically proven auricular ossification. This review exemplifies the etiologies of auricular petrifaction with an emphasis on true ossification of the auricles. The case discussed is one of bilateral idiopathic auricular ossificans, noted by the incidental finding of asymptomatic stone hard, immalleable pinnae. Under consideration is whether this is a truly rare condition or just rarely reported. It also emphasizes the importance of auricular evaluation beyond visual inspection. Case Report parathyroid hormone, ionized calcium tion is due to either dystrophic (primary) and vitamin D levels were not evaluated. or metastatic (secondary) processes.5,6 Dys- A 45-year-old white male presented to Radiography of the left auricle demon- trophic calcification occurs with normal the clinic for an annual skin cancer screen strated increased parallel opacities in the calcium and phosphorus levels. Calcium shape of the auricular cartilage consistent deposition is due to the increased alkalinity with complaint of a lesion to the scaph- 5,6 oid fossa of the left auricle. The tender with auricular petrifaction (Figure 3). of nonviable tissue. The most common lesion was clinically suspicious for non- The patient consented to another ear causes of dystrophic calcification are frost- biopsy to further evaluate his petrified pin- bite and mechanical trauma (e.g. wrestling melanoma skin cancer. However, on closer 5,8 examination, both auricles were stone hard nae. A disposable 3 mm punch biopsy of or boxing). Systemic conditions associ- the antihelix of the left auricle provided a ated with dystrophic calcification include and immalleable, each moving painlessly 9 8,10,11,13 as a solid unit and unable to fold over as small but full-thickness specimen for evalu- hypertension, diabetes mellitus, ation. However, during the procedure, a alkaptonuria,13 hypopituitarism,14,15 hypo- expected. Palpation of the auricles dem- 16 8,17. onstrated more extensive hardening of second 3 mm punch was required to obtain thyroidism, acromegaly, Addison’s dis- the specimen because the first punch ease,11,18,19 systemic chondromalacia (Von the left auricular cartilage (Figure 1) than 11 the right (Figure 2), without involvement became imbedded in the stone hard auricle, Meyenburg’s disease), familial cold hyper- and while attempting to remove the stuck sensitivity,11 polyarteritis nodosa,8 and of the lobules. Visually, both auricles 8 appeared normal with the exception of the instrument, the plastic handle slid off the scleroderma. Further, radiation therapy back end of the circular punch blade. The was reported as a cause of auricular calcifi- chief complaint. Other than actinic dam- 20 age to the patient’s head, arms and torso, blade was extracted with forceps, and a sec- cation. Metastatic calcification occurs in the remainder of his cutaneous examina- ond 3 mm punch successfully completed the presence of elevated calcium levels and tion was unremarkable. The lesion on the the procedure. Histologic evaluation of is seen in primary and secondary elevations left scaphoid fossa was biopsied and found the specimen at low magnification demon- of parathyroid hormone, pseudopseudohy- strated trabecular bone formation (Figure poparathyroidism,21 hypervitaminosis D, to be a squamous cell carcinoma, which 22 was subsequently successfully treated with 4). On higher magnification, osteocytes in milk-alkali syndrome, and sarcoidosis. Mohs micrographic surgery. The patient’s lacunae with Haversian canals and cement Sherrer attempted epidemiologic skin cancer did not appear to contribute to lines had replaced the normal auricular evaluation of petrified auricles in 1932. He the incidental finding of inflexible auricles. cartilage (Figure 5). examined 800 auricular pairs in an outpa- On follow-up, the patient was re-eval- tient setting during routine ear, nose and throat exams and was unable to find any uated regarding his ears. The patient denied Discussion 23 otalgia, hearing loss, tinnitus or other audi- hardness or immobility. However, in a tory symptoms related to his auricles. He Bilateral or unilateral petrifaction of specific population with Addison’s disease, reported “stiffening” of his ears as a teen- the auricles is an uncommon phenom- Jarvis found six out of 120 cases with auricular calcification based on radiographic ager with progressive rigidity ever since. He enon. In 1866, Bochdalek, a professor of 18 denied prior injury or trauma to the auricles anatomy in Prague, documented the first findings. And in 1964, Gordon examined including frostbite, persistent cold expo- case of bilaterally petrified pinnae in a 65- 300 patients for nodularity, thickness, or sure, wrestling, or boxing. At the time of or 7.0-year-old male cadaver.1 Wassmund inflexibility of the auricle without regard to initial exam, he noted no use of prescrip- described the radiographic characteris- diagnosis. He found 11 patients (3%) with tion medications and reported no allergies tics of this process in 1899.2 In the early auricular calcification based upon radio- to medications. He denied any history of 1930s, both Higbee and Childrey referred graphic evidence, as well as 12 patients hypertension, diabetes mellitus, thyroid dis- to hardening of the auricles as “calciger- (25%) without the aforementioned clinical ease, Addison’s disease, scleroderma or other ous metaplasia,” which does not differenti- criteria but with a history of primary dis- 3,4 ease associated with ectopic calcification/ collagen vascular disease. His family history ate between ossification and calcification. 8 was unremarkable, and neither his parents Finally, in 1985, DiBartolomeo coined the ossification. To date, more than 160 cases of petrified auricular cartilage have been nor his siblings reported stone hard ears. term “petrified auricle,” referring to auricu- 5,24 He is a native of Arizona, reporting the rare lar cartilage that has become stone hard and reported in the literature. consumption of alcohol and denying use of inflexible on palpation, moves as a solid, Lister asserted in 1969 that histo- tobacco products and illicit substances. fixed unit if at all, and clinically appears logic evaluation of the tissue is “irrefutable 5 proof” of the transformation of the elastic On auditory physical exam, the Weber normal. The patient is most commonly 25 test showed no lateralization, and the asymptomatic but may experience otalgia, cartilage of the ear into bone. DiBartolo- Rinne test was positive bilaterally. As such, ulceration, aural fullness, stenosis of the meo concurred, stating that ossification of auricular cartilage can only be substanti- audiometry was not performed. Labo- external auditory canal, hearing loss, and 5 ratory evaluation demonstrated normal pain with pressure with insomnia second- ated by histologic evaluation. The histol- indices for complete blood count, elec- ary to pain.5,6,7. ogy of auricular ossification includes the trolytes, calcium, phosphorus, and glu- Petrified auricles due to calcification presence of osteocytes within lacunae, cose as well as hepatic and renal function are more common than those due to ossi- Haversian canals, and trabeculae within a panels. Thyroid stimulating hormone was fication, the former defined as deposition marrow space. In cases of histologically in the normal range, and an antinuclear of insoluble calcium salts into cartilaginous proven auricular ossification, the pattern of antibody screen was negative. Cortisol, auricular tissue.5,6 This ectopic calcifica- radiographic defraction is identical to that Keller, Cook, Anderson 17 of normal bone.26,27. As such, of the more tomatic.6 But in patients with otalgia, sur- 1982;55:354-357. 16. Thomson MA, Biggs P, Berth-Jones J. Familial petrified than 160 cases of petrified auricles in the gery may be required. Knapp performed ears associated with endocrinopathy. J Am Acad Dermatol 2007;57:S121-S122. literature, 19 (inclusive of the current case) the first reported surgical removal of ectopic 17. Nathanson L, Losner S. Ossification of the Auricles of include histologic confirmation of auricular bone from the pinna in 1889, with improve- the External Ears Associated with Acromegaly. Radiology 5,6,8,23-25,27.-37. 28 1947;48:66-68. ossification (Table I). The current ment of the prior deformity. Insomnia 18. Jarvis JL, Jenkins D, Sosman MC, Thorn GW. case is the sixth case of idiopathic bilateral secondary to pain while lying on the ossi- Roentgenologic Observations in Addison’s Disease. 5,6 Radiology 1954;62:16-29. auricular ossificans. fied pinna was cured, according to Lister, by 19. Novick WH. Calcification of Auricular Cartilage in Addison’s Disease. Arch Otolaryng 1960;72:448-449. Ossification is defined as formation wedge resection, which also improved the 20. 25 Williams JP, et al. Calcification of the Auricular Cartilage of true bone with deposition of calcium auricular flexibility. In the patient with and Basal Ganglia Secondary to Radiation Therapy. Bull Los Angeles Neurol Soc 1973;38:33-36. and phosphate in a proteinaceous matrix acrobatic ears, a conchal reduction improved 21. Strauss RM. Petrified ears associated with as hydroxyapatite crystals concomitant the deformity satisfactorily.30 Similarly, pseudohypoparathyroidism. British J of Dermatol 5 2008;158:409-410. to osteoblastic activity. Ectopic ossifica- Sterneberg-Vos et al. report a case in which 22. Batson J. Calcification of the ear cartilage associated tion may be considered either primary (de decreased pain while sleeping was noted with the hypercalcemia of sarcoidosis. N Engl J Med 36 1961;265:876-877. novo) or secondary when developing within after excisional biopsy. They recommend 23. Scherrer F. Calcification and ossification of the external ears. Ann Otol 1932; 41:867-885. a pre-existing lesion. Reports of primary a wedge excision rather than a punch biopsy 24. Mastronikolis NS, Zampakis P, Kalogeropoulou C, Stathas ectopic ossification include fibrodysplasia in those patients with complaints of discom- T, Siabi V, Geropoulou E, Goumas PD. Bilateral ossification 30 of the auricles: an unusual entity and review of the ossificans progressiva, congenital plaque-like fort. Manni et al. reported the surgical literature. Head Face Med 2009; 5:17(1-7). osteomatosis, Albright hereditary osteodys- removal of the ossified external ear canal, 25. Lister G. Ossification in the elastic cartilage of the ear. Br J 5,6,24 Surg 1969;56:399-400. trophy, and osseous heteroplasia. Col- medial concha to the antitragus, the isth- 26. Kewlarmani L. Ectopic Ossification. Am J Phys Med lagen vascular diseases including CREST mus, and tragus with return of hearing and 1977;56:99-121. 27. Cohen AM, Talmi YP, Floru S, Tsigelman R, et al. X-ray syndrome and childhood dermatomyositis the ability to visualize the tympanic mem- microanalysis of ossified auricles in Addison’s disease. 34 Calcif Tissue Int 1991;48:88-92. may be associated with ossification. Rela- brane. A patient with complaint of aural 28. Knapp H. Ossification of the auricle in consequence of tively newer syndrome complexes described fullness and conductive hearing loss due to perichondritis seropurulenta. Arch Otol 1890;19:45-50. 29. Cohen A, Talmi Y, Floru S, Bar Ziv J, Zohar Y, Djaldetti by Keutel in 197.2 and Primrose in 1982 may stenosis of the external auditory canal expe- M. View from within-radiology in focus: ossification of the be considered primary ossification condi- rienced improvement of his hearing loss auricle in Addison’s disease. J Lryngol Otol 1989, 103:885- 38,39 37. 886. tions. Primrose syndrome is extremely after meatoplasty. With the exception of 30. Lari AA, al-Rabah N, Dashti H. Acrobatic ears: a cause of petrified auricles. Br J Plast Surg 1989, 42:719-721 rare and includes ossified ear cartilage with the aforementioned case reports and due to 31. Lautenschlager S, Itim P, Rufli T. The petrified ear. mental deficiency, muscle wasting, and the rarely symptomatic nature of this condi- Dermatology 1994, 189:435-436. 39 32. Yeatman JM, Varigos GA. Auricular ossification. Australas J bony changes. Keutel syndrome is a rare tion, minimal information is available per- Dermatol 1998, 39:268-270. autosomal-recessive condition that includes taining to treatment.6 33. High WA, Larson MJ, Hoang MP. Idiopathic bilateral auricular ossificans: a case report and review of the diffuse cartilage calcification/ossification, literature. Arch Pathol Lab Med 2004, 128: 1432-1434. brachytelephalangism (short terminal pha- 34. Manni JJ, Berenos-Riley LC. Ossification of the external Conclusion ear: a case report and review of the literature. Eur Arch langes), peripheral pulmonary artery ste- Otorhinolaryngol 2005, 262: 961-964. 35. Gonzalez-Sixton B, Garcia-Doval I, Conde A, Mayo E, nosis, hearing loss, dysmorphic facies, and The petrified auricle is an uncommonly Pardavila R, de la Torre C, et al. Bilateral ossification of the mental retardation.38 auricular cartilage. Actas Dermosifiliogr 2006, 97(2): 134- encountered entity. However, considering 135. Secondary ectopic ossification of the the often asymptomatic nature of this con- 36. Sterneberg-Vos H, Winnepenninckx V, Frank J, Kelleners- auricular cartilage is most commonly due Smeets NW. Ossification of the auricle. Int J of Dermatol 5,6,31,32,35,36 dition, it is likely that it is underreported. 2007;46(Sup.3):42-44. to frostbite/recurrent cold injury. Gordon asserted that the low number of 37. Carfrae MJ, Foyt D. Auricular ossification resulting in Neoplasms associated with ossification external auditory canal stenosis. Ear Nose Throat J. 2008, encounters is due to a failure to seek the 87(3):148-149. include basal cell carcinoma, osteo-naevus 8 38. Keutel J, Jorgensen G, Gabriel P. A New Autosomal lesion rather than to its extreme rarity. Cli- Recessive Syndrome: Peripheral Pulmonary Stenosis, of Nanta, pilomatrixoma, and chondroid nicians are encouraged to examine the pin- Brachytelephalangism, Neural Hearing Loss, and Abnormal syringoma. Other etiologies of auricu- Cartilage Calcifications/Ossifications. Birth Defects nae by palpation and visualization, because 1972;8:60-68. lar ossification include endocrinopathies, evaluation of the auricles may lead to the 39. Primrose DA. A Slowly Progressive Degenerative Condition inflammation, repetitive trauma, and idio- Characterized by Mental Deficiency, Wasting of Limb discovery of an undiagnosed systemic condi- Musculature and Bone Abnormalities, Including Ossification pathic. The endocrinopathy most often of the Pinnae. J Ment Defic Res 1982;26:101-106. tion that is amenable to treatment 40. Wang CY, Chang TC, Chen FW. Ossification of the Auricles: associated with auricular ossification is A Forgotten Sign in Adrenal Insufficiency. J Otolaryngol Addison’s disease, but diabetes mellitus was 2002; 31(1):52-54. 22,27.,29,40 41. Silva LGE, Martins O, Picoto ADS, Verde SF, Oliveira ADS. also noted in a single case. Inflamma- Acknowledgement Bone Formation in Chondrodermatitis Nodularis Helicis. J tory conditions include chondrodermatitis Dermatol Surg Oncol 1980;6:582-585. 41 42. Urist MR. Bone: Formation by autoinduction. Science nodularis helicis (CNH) and perichondri- Keliegh Culpepper, M.D. 1965;150:893-899. 8,28 43. Friedman N, Kritzler R. The pathology of high altitude tis. The four cases described by Silva et frostbite. Am J Pathol 1946;23:173-187. al. note the presence of bone with the CNH References 44. Urist MR, Strates BS. Bone Morphogenetic Protein. J Dent lesion but do not mention auricular petrifac- Res 1971;50:1392-1406. tion.41 Lari et al. describe a case of repetitive 1. Bochdalek G. Physiologische Verknöcherung der Auricula. Prag Vierteljahrschr 1866;89:33-46. trauma in a male teenager who repeatedly 2. Wassmund L. Verknocherung der Ohrmuschel und curled his prominent pinna and inserted it Roentgenographie. Deutsche Med Wchnschr 1899;4:439- 30 440. into his external auditory meatus. This 3. Higbee DR. Calcigerous Metaplasia of the Auricular Cartilage. Arch Otolaryngol 1931;14:70-79. manipulation is referred to as acrobatic 4. Childrey JH. Calcigerous Metaplasia in the Auricle. Arch ears.30 Finally, the etiology of auricular ossi- Otolaryng 1932;15:883-885. 30,33,34,37. 5. DiBartolomeo JR. The petrified auricle: comments on fication may be undetermined. ossification, calcification and exostoses of the external ear. Ectopic ossification begins with a tissue Laryngoscope 1985;95:566-576. 6. Stites PC, Boyd AS, Zic J. Auricular ossificans (ectopic insult that leads to a cascade of mediators ossification of the auricle). J Am Acad Dermatol 2003, 42 49:142-144. resulting in bone formation. Considering 7. Clarke JT, Clarke LE, Miller JJ. Petrified ears: Calcification frostbite as an etiology, this type of hypo- of the auricular cartilage. J Am Acad Dermatol 2004;51:799- 800. thermia leads to thrombosis and ischemia 8. Gordon D. Calcification of auricular cartilage. Arch Intern within an inflammatory microenviron- Med 1964, 112:73-77. 43 9. Childrey JH. Ossification in Auricle; Seven Cases. ment. Within this inflammatory micro- Laryngoscope 1938;48:339-345. environment, postfetal osteogenesis occurs 10. Laskiewiez A. Ein Fall von Verkalkung beider Ohrmuscheln. Nowinglekareki 1924, no. 2 (cited by Scherrer) through autoinduction via bone morpho- 11. McKusick VA, Goodman RM. Pinnal calcification: observations in systemic diseases not associated with genetic protein, which acts upon the mes- disordered calcium metabolism. JAMA 1962;179:230-232. enchyme to stimulate new bone formation 12. Strumia R, Lombardi AR, Altieri E. The Petrified ear – a 42,44 manifestation of dystrophic calcification. Dermatology in nonosseous structures. It is proposed 1997;194:371-373. but not confirmed that auricular ossification 13. Pomeranz MM, Friedman LJ, Tunick IS. Roentgen Findings 5,6 in Alkaptonuric Ochronosis. Radiology 1941;37:295-303. follows a similar mechanism. 14. Randall RE, Spong FW. Calcification of the auricular cartilage in a patient with hypopituitarism. N Engl J Med Treatment of auricular ossificans is not 1963;269:1135-1137. usually necessary, because it is often asymp- 15. Barkan A, Glantz I. Calcification of Auricular Cartilages in Patients with Hypopituitarism. J Clin Endocrinol Metab

18 Bilateral Idiopathic Auricular Ossificans: A Case Report and Review of the Literature Figure 3. Radiography of the left auri- Figure 2. The right auricle appears nor- cle demonstrates parallel densities in the Figure 1. The left auricle appears normal but moves as a solid, fixed unit with shape of the auricular cartilage consistent mal but moves as a unit and does not pressure from a cotton-tipped applicator. with a petrified auricle. flex forward with pressure from a cotton- tipped applicator. A scar is notable in the scaphoid fossa from resection of the squamous-cell carcinoma by Mohs micrographic surgery.

Figure 4. Low-power (2X) view of the Figure 5. High-power (40X) view of the biopsy from the left auricle demonstrates biopsy from the left auricle demonstrates trabecular bone formation. osteocytes in lacunae with Haversian canals and cement lines.

Table I. Data for 19 documented cases of histologically proven ossification within a petrified auricle No. Author (year) Age (years)/Sex* Unilateral/Bilateral Etiology 19. Current Case (2010) 45/M Bilateral Idiopathic 18. Mastronikolis (2009)24 73/M Bilateral Addison’s disease and diabetes mellitus 17. Carfrae and Foyt (2008)37 49/M Left Idiopathic 16 Sterneberg-Vos et al. (2007)36 70/M Unilateral Frostbite 15. Gonzalez-Sixton et al. (2006)35 65/M Bilateral Hypothermia 14. Manni et al. (2005)34 63/F Bilateral Idiopathic 13. High et al. (2004)33 60/M Bilateral Idiopathic 12. Stites et al. (2003)6 65/M Left Cold injury 11. Yeatman and Varigos (1998)32 66/M Right Cold injury 10. Lautenschlager et al. (1994)31 66/M Bilateral Recurrent cold injury 9. Cohen et al. (1991)27 46/M Bilateral Addison’s disease 8. Lari et al. (1989)30 17/M Bilateral Trauma 7. Cohen et al. (1989)29 70/M Bilateral Addison’s disease 6. DiBartolomeo (1985)5 77/M Bilateral Cold injury 5. DiBartolomeo (1985)5 72/M Bilateral Cold injury 4. Lister (1969)25 58/M Bilateral Idiopathic 3. Gordon (1964)8 34/F Bilateral Perichondritis 2. Scherrer (1932)23 53/F Bilateral Toxic adenoma 1. Knapp (1890)28 24/M Unilateral Perichondritis *M: Male, F: Female Keller, Cook, Anderson 19 Keratitis-Ichthyosis-Deafness Syndrome

Amanda Beehler, DO,* Michelle Jeffries, DO,** Stephen Kessler, DO,*** Ronald Hansen, MD**** *Dermatology Resident, 1st year, Midwestern University/Alta Dermatology, Mesa, AZ; Scottsdale Healthcare System – Osbourn Campus, Scottsdale, AZ **Dermatology Resident, 3rd year, Midwestern University/Alta Dermatology, Mesa, AZ ***Program Director, Midwestern University/Alta Dermatology, Mesa, AZ; Scottsdale Healthcare System – Osbourn Campus, Scottsdale, AZ ****Pediatric Dermatologist, Phoenix Children’s Hospital, Phoenix, AZ

Abstract Keratitis-ichthyosis-deafness (KID) syndrome is a rare, autosomal-dominant ectodermal dysplasia. Mutations in a component of the gap junction connexin 26 are responsible for the clinical aspect of this disorder. KID syndrome is characterized by localized, erythematous, hyperkeratotic plaques, progressive keratitis and sensorineural deafness. This paper presents a young boy with skin involvement at birth and later development of hearing loss as well as severe myopia. Case Report connexin-26 mutation after evaluation by a geneticist. At two years of age, he was diag- A six-month-old Hispanic boy pre- nosed with severe myopia requiring eye sented to the dermatology office with a glasses and mild keratitis that was treated complaint of itchy ears, scalp and forehead with eye drops by the ophthalmologist. He that had not been treated with medica- did not have photophobia. At two years of tion. The patient also had complete hear- age he also developed difficulty sweating. ing loss in his right ear and 90% hearing loss in his left ear. He was initially evalu- Discussion ated in the NICU shortly after birth for rough, red skin, near-absent finger and toe Keratitis-ichthyosis-deafness (KID) nails, and absence of hair. The pregnancy syndrome was first described in 1915 was complicated with maternal depres- and was finally named in 1981, although sion, hypothyroidism and group B strep most agree that the ichthyosis is actually infection that were treated with Zoloft, Figure 2 - Fine, patchy hair on the scalp. an erythrokeratoderma.1 KID syndrome is Synthroid and clindamycin, respectively. The patient was given triamcinolone representative of an overlap between disor- He was born via spontaneous vaginal deliv- ders of cornification and ectodermal dys- ery with APGAR scores of 6 and 6, with 0.1% ointment to be applied twice a day to the body. He was also given hydrocortisone plasias. It is very rare, with only 100 cases delayed breathing that initially required reported. KID is autosomal-dominant, but bag mask ventilation; however, he subse- 2.5% ointment for his face and advised 1,6 to occlude with Vaseline twice a day. After around 90% of the cases are sporadic. quently recovered with no sequela. The The disease is caused by mutations in two patient had been seen by an ophthalmolo- one month, there was minimal improvement of his presenting skin condition. The connexin genes on chromosome 13q12.11, gist shortly after birth and was found to and a majority of patients have muta- have no ocular abnormalities. No devel- patient’s cheeks and left antecubital fossa showed small, scaling, reddish-brown pap- tions in gap-junction protein GJB2, which opmental delays had been noted by the encodes for connexin-26 (Cx26).2 Cx26 is mother or the pediatrician. There had been ules coalescing into plaques. He continued to have a diffuse follicular prominence of part of gap junctions in the epidermis, the no genetic evaluation of the patient. inner and outer root sheaths of the hair On physical exam, there was wide- his skin. In addition, he now had bilateral 6,7. hearing aids in his ears. and the stria vascularis in the cochlea. So spread, generalized, rough, reddish-colored far, all mutations recognized for KID have skin. Dermoscopy of the extremities, trunk been heterozygous missense mutations.1 and head showed 2mm perifollicular, flat- Patients with KID typically present topped papules with mild scaling. Licheni- with a transient erythroderma at birth or fication and fissuring was seen on both during infancy.3 Later on, well-demarcated, ears. There was fine, patchy hair on the hyperkeratotic plaques with erythematous scalp. His eyebrows consisted of sparse, bases develop symmetrically. These plaques vertically oriented hairs. His eyelashes are commonly seen on the knees, elbows, were intact. On the palms and soles there face, outer ears, and scalp.2,3 Prominent were 1mm coalescent, hyperkeratotic, flat- follicular keratosis and perlèche are com- topped papules. mon.1 Patients’ nails can be dystrophic and can also show leukonychia. Lusterless hair and alopecia of scalp, eyebrows and eyelashes have been described in patients with KID.3 Dental abnormalities can include Figure 3 - Left antecubital fossa with small or absent teeth. Rarely, heat intoler- reddish-brown scaling papules. ance has been noted. The patient returned for follow-up All patients have congenital sensori- in another two months. There was still neural hearing impairment, which is gener- near-complete absence of hair on his scalp ally severe and bilateral, although unilateral or moderate hearing loss has been noted.1 and complete absence of body hair. The 5 bilateral cheeks still had scaling and ery- Deafness is usually apparent by age seven. thema. The patient’s mother was advised to In 95% of patients, there have been ocular symptoms that are progressive, includ- continue the topical steroids as previously 1 prescribed as well as Protopic 0.1% twice a ing photophobia and chronic blepharitis. day to his face and antecubital fossae. Vascularizing keratitis and conjunctivitis occurs, with scarring and neovasculariza- At 11 months of age, the patient was 1 hospitalized for multiple MRSA-positive tion that eventually leads to blindness. Figure 1 - Near-absence of scalp hair, The anterior portion of the cornea is along with sparse eyebrows. abscesses. He was later confirmed to have a 20 keratitis-Ichthyosis-Deafness Syndrome derived from ectoderm, which explains Questions: the corneal involvement.4 KID patients also have susceptibility to bacterial, viral What is the most common and fungal infections, especially C. albi- cans, S. aureus, E. coli, P. aeruginosa, and T. type of skin cancer associated rubrum.5 Squamous cell carcinoma of the with KID syndrome? skin and oral mucosa has been observed in a. BCC 11% of patients and is a serious morbidity SCC that can shorten life expectancy.6 Malignant b. proliferative pilar tumors of the scalp have c. Cutaneous lymphoma been reported in two patients with KID syn- d. Kaposi’s sarcoma drome.7. Otherwise, patients have a normal life span. See reference #6 Treatment is usually limited to supportive care. Basic skin care consists of Correct answer: B emollients and keratolytics for hyperkeratosis.1 Topical retinoids have also been used Which connexin is affected in with some benefit.8 Oral retinoids, on the other hand, can actually aggravate the kera- KID syndrome? titis and have only shown mixed success for a. 21 the skin lesions.1,2 Topical cyclosporine has b. 26 2 been shown to help the keratitis. Corneal c. 31 transplants are the only known treatment for improving vision, but these are generally d. 32 not successful because of revascularization.1 Hearing aids and cochlear implants are used See reference #2 4 successfully for hearing loss. Correct answer: B Conclusion Keratitis-ichthyosis-deafness syndrome results from a mutation in connexin-26, a gap-junction protein. This mutation leads to erythematous, hyperkeratotic plaques, keratitis and sensorineural deafness. The patient presented here had all three of these main findings along with the often reported bacterial infection. The patient’s skin lesions have been managed with topical steroids and Protopic for supportive care. Topical retinoids have not been tried yet. His eye manifestations are currently managed simply with eye glasses, and his hearing deficit is addressed with hearing aids. He will continue to be managed at the outpatient dermatology clinic.

References

1. Bolognia J, Jorizzo J. Dermatology 2nd edition. Mosby 2008. 2. Spitz, J. Genodermatoses: A Clinical Guide to Genetic Skin Disorders. Lippincott Williams & Wilkins, 2005. 3. Schachner L, Hansen R. Pediatric Dermatology. 3rd edition. Mosby 2003. 4. Choung Y, Shin Y, Kim H, et al. Cochlear implantation and connexin expression in the child with keratitis-ichthyosis-deafness syndrome. Int J Pediatr Otorhinolaryngol 2008;72:911-915. 5. Conrado L, Marques S, Lastoria J, et al. Keratitis-ichthyosis-deafness (KID) syndrome with squamous cell carcinoma. Int J Dermatol 2007;46:403-406. 6. Terrinoni A, Codispoti A, Serra V, et al. Connexin 26 (GJB2) mutations as a cause of the KID syndrome with hearing loss. Biochem Biophys Res Commun 2010;395:25-30. 7. Nyquist G, Mumm C, Grau R, et al. Malignant Proliferating Pilar Tumors Arising in KID Syndrome: A Report of Two Patients. Am J Med Genet A 2007;143A:734-741. 8. Gonzalez M, Tlougan B, Price H, et al. Keratitis-ichthyosis- deafness (KID) syndrome. Dermatol Online J 2009;15:8.

Beehler, Jeffries, kessler, hansen 21 Lobular Capillary Hemangioma

Cynthia L. Chen, BA,* Scott Deckelbaum, DO,** Mark Horowitz, DO,*** David Horowitz, DO, FAOCD, FAAD**** *Osteopathic Medical Student, Year 3, Western University - College of Osteopathic Medicine of the Pacific, Pomona, CA **Dermatology Resident, PGY-1, Western University - Pacific Hospital, Torrance, CA ***Dermatology Attending Physician, Western University - Pacific Hospital, Torrance, CA ****Dermatology Residency Program Director, Western University - Pacific Hospital, Torrance, CA

Abstract Lobular capillary hemangioma (pyogenic granuloma) is a benign, vascular lesion, appearing as a protuberant red papule on cutaneous or mucosal surfaces. They are rapidly growing and can bleed spontaneously or with minor trauma. We report the case of a 38 year old Caucasian female who presented with an impressively large mass on the pad of her finger. The lesion was surgically removed and sent to histology which revealed a lobular capillary hemangioma. Three months after excision, the lesion has not recurred.

Case Report They can occur on any skin surface but are reported adequate response to systemic most common on the head, neck, upper steroid treatment.4 Imiquimod may prove trunk, and extremities. an alternative to surgical or destructive A 38-year-old Caucasian female 13,14 presented with an enlarging mass on her Lobular capillary hemangiomas are removal. Holbe et al. reported success characterized as a reactive, hyperprolif- with simple ligation of a pedunculated right finger. She reported the mass had 15 begun as a small red dot two months prior erative vascular response to a variety of pyogenic granuloma. The pregnancy to her presentation. She complained of stimuli, including a history of trauma or variant of pyogenic granuloma usually mild discomfort and reported recurrent irritation, preceding the onset of the lesion. regresses following parturition. bleeding both spontaneously and with They may also develop in patients being treated with antiretroviral therapies and mild trauma. There was no preceding 5,6 References trauma or inciting event she could recall. chemotherapeutic agents. Additionally, Her past medical history, including they have been reported in two cases of 1. Grosshans E. “Pyogenic granuloma: Who are you?” medications, was unremarkable. acne patients within two to three weeks European Academy of Dermatology and Venereology. of topical tretinoin application.7. There 2001. 15, 106-7. Physical exam was significant for a 2. Patrice SJ, Wiss K, Mulliken JB. “Pyogenic granuloma large, protuberant polypoid mass emanat- is also one report of a lobular capillary (lobular capillary hemangioma): a clinicopathologic study ing from the pad of her right fourth digit hemangioma that developed secondarily of 178 cases. Pediatric Dermatology. 1991:8:267-76. on an inflamed dermatofibroma following 3. Harris MN, Desai R, Chuang T-Y, Hood AF, Mirowski GW. measuring over 2 centimeters in diameter 7. “Lobular capillary hemangiomas: an epidemiologic report, (Figures 1 and 2). The lesion had an ery- application of topical tretinoin. There with emphasis on cutaneous lesions.” Journal of the is another form of pyogenic granuloma American Academy of Dermatology. June 2000, Vol 42, thematous base and some mild to moder- Number 6 ate tenderness with manipulation. (granuloma gravidarum or epulis gravi- 4. Tursen U, Demirkan F, Ikizoglu G.”Giant recurrent pyo- A tourniquet was applied, and the darum) that occurs in pregnant women, genic granuloma on the face with satellitosis responsive found primarily in the mucosa and gingiva, to systemic steroids.” Clinical and Experimental Derma- mass was removed with simple scissor dis- tology. 2004. 29, 40-41. and is associated with exposure to estrogen 5. Ward HA, Russo GG, Shrum J. “Cutaneous manifesta- section. The base of the lesion was cau- 8 terized; however, this failed to provide and other hormones. tions of antiretroviral therapy.” Journal of the American This lesion can usually be diagnosed Academy of Dermatology. February 2002 (Vol. 46, Issue adequate hemostasis. The defect was sub- 2, Pages 284-293) sequently closed with simple interrupted based on clinical presentation and history, 6. Heidary N, Naik H, Burgin S. “Chemotherapeutic agents 4.0 nylon sutures. but histopathological examination may and the skin: An update.” Journal of the American Acad- be indicated to distinguish it from similar emy of Dermatology. April 2008 (Vol. 58, Issue 4, Pages Histopathology showed a lobular 545-570) proliferation of capillaries surrounded by pigmented and vascular-like growths that 7. Teknetzis A, Ioannides D, Vakali G, Lefaki I, Minas A. an epithelial collarette (Figures 3 and 4). may have malignant potential. Mimick- Pyogenic granulomas following topical application of treti- ing lesions include hemangiomas, amela- noin. European Academy of Dermatology and Venereol- Bands of connective tissue separated the 9 ogy. 2004. 18, 337-339. lobules. Three months after removal, there notic melanoma, irritated nevi and warts. 8. Choudhary S, MacKinnon CA, Morrissey GP, Tan ST. “A In immunosuppressed patients, bacillary Case of Giant Nasal Pyogenic Granuloma Gravidarum.” was no recurrence of the lesion. Journal of Craniofacial Surgery. 2005. 16(2). angiomatosis and Kaposi’s sarcoma can 9. 10 Zaballos P, Rodero J, Serrano P, Cuellar F, Guionnet N, also appear similar. Vives JM. “Pyogenic granuloma clinically and dermo- Lobular Capillary The histopathological pattern of scopically mimicking pigmented melanoma.” Dermatol- pyogenic granuloma appears as active ogy Online Journal. 2009.15(10):10. Hemangioma 10. Nthumba PM. “Giant pyogenic granuloma of the thigh: endothelial proliferation resulting in a case report.” Journal of Medical Case Reports. 2008. masses or lobules of capillaries separated 2:95 Lobular capillary hemangioma (pyo- 1,4 11. Elder DE, Elenitsas R, Johnson BL, Murphy GF. Lever’s genic granuloma) is an acquired, benign by fibrous connective tissue. There is Histopathology of the Skin. Lippincott Williams and a collarette of epidermis demarcating Wilkins; Ninth Edition. 2004. vascular lesion occurring on both cutane- 12. Raulin C, Greve B, Hammes S. “The Combined Con- 1 the lesion, and a sparse or prominent ous and mucosal surfaces. It is most com- tinuous-Wave/Pulsed Carbon Dioxide Laser for Treat- mon in young children and adolescents but inflammatory infiltrate may be noted. ment of Pyogenic Granuloma.” Archives of Dermatology. can manifest in all age groups.2,3 Its preva- They are also surrounded by myxoid 2002;138:33-37. stroma containing scattered spindle-and 13. Marra DE, Haynes HA, Li VW. “Antiangiogenic treatment lence is likely equal in men and women; of pyogenic granuloma with imiquimod.” Journal of the stellate-shaped connective-tissue cells and American Academy of Dermatology. March 2004 (Vol. 50, however, mucosal lesions are more com- 11 mon in women.3 Lobular capillary hem- occasional mast cells. Issue 3, Supplement, Page P57) Treatment of pyogenic granulomas 14. Ezzell TI, Fromowitz JS, Ramos-Caro FA. “Recurrent angiomas are rapidly growing and appear pyogenic granuloma treated with topical imiquimod.” as a protuberant red papule or nodule with includes removal of the lesion by shave Journal of the American Academy of Dermatology. May a moist to scaly surface, often surrounded or curettage followed by destruction of 2006 (Vol. 54, Issue 5, Supplement, Pages S244-S245) the base by electrocautery or chemical 15. Holbe HC, Frosch PJ, Herbst RA. “Surgical pearl: liga- by a collarette of scale. They are friable and tion of the base of pyogenic granuloma—an atraumatic, can bleed spontaneously or with minor means. Smaller pyogenic granulomas are simple, and cost-effective procedure.” Journal of the trauma, frequently leading to ulceration. usually treated with electrocoagulation American Academy of Dermatology. September 2003 or lasers.12 Surgical excision is usually (Vol. 49, Issue 3, Pages 509-510) They are usually small (less than 1 cm) and 8 solitary, but multiple satellite lesions and preferred for larger lesions. For recurrent giant-sized lesions have been reported.4 giant pyogenic granulomas, one case

22 LOBULAR CAPILLARY HEMANGIOMA Figure 1

Figure 2

Figure 3

Figure 4

Chen, deckelbaum, horowitz, horowitz 23 Cutaneous Metastatic Breast Carcinoma: Case Report and Review of the Literature

Jacqueline Thomas, DO,* Shawna Flanagan, MD,** Les Rosen, MD,*** Janet Allenby, DO**** *Dermatology Resident, Second Year, Columbia Hospital Palm Beach Centre for Graduate Medical Education, West Palm Beach, FL **Clinical Faculty, Columbia Hospital Palm Beach Centre for Graduate Medical Education, West Palm Beach, FL ***Dermpath Diagnostics, Pompano Beach, FL ****Program Director, Columbia Hospital Palm Beach Centre for Graduate Medical Education, West Palm Beach, FL

Abstract Breast carcinoma has been known to metastasize. This is a devastating condition that may present years or decades after suspected remission. Although the incidence of cutaneous manifestations is low, the morbidity is quite high. We report a case of cutaneous metastases found to be of breast carcinoma origin.

Case Report Epidemiology tions of cutaneous manifestations of breast cancer. These are inflammatory metastatic An 80-year-old female presented with Cutaneous involvement is seen in carcinoma, en cuirasse metastatic carci- a rash on her chest and abdomen for sev- approximately 30% of metastatic breast noma, telangectatic metastatic carcinoma, eral months. It was described as non-pain- carcinoma patients.6 Reports of delayed nodular metastatic carcinoma, alopecia neo- ful, raised, red bumps with irritation and cutaneous metastases beyond a decade or plastica, Paget’s disease of the breast (con- occasional pruritus. Her past medical and more after treatment of the primary tumor sidered direct extension of breast cancer surgical history was significant for a basal have been cited in the literature.2 Cutane- to the skin), breast carcinoma of the infra- cell carcinoma of the scalp diagnosed in ous metastases were an initial presenting mammary crease, metastatic mammary carcinoma of the eyelid with histiocytoid 2005 and treated with Mohs surgery in sign in 7..6% of patients with prior breast 2 2006, left breast carcinoma 20 years prior carcinoma.2 Cancer can involve cutane- histology, and the nose. Cutaneous metas- treated with mastectomy and lymph node ous surfaces by direct extension from the tases can be a presenting manifestation of internal malignancy and can manifest dissection, and right breast carcinoma primary tumor or by either local or dis- 5 seven years prior treated with breast con- tant metastases.2 The incidence of cutane- acutely with firm, painless papulonodules. serving surgery and lymph node dissec- ous metastases is 0.7.% to 9% of all cancer The clinical appearance of inflammation and radiation therapy. Medications patients.2,7.-8 Although cutaneous metasta- tory metastatic carcinoma is due to capillary congestion and tumor cells inside ectatic included alendronate, atenolol, paroxetine, ses can be the first sign of visceral cancer, 2 and topical tretinoin. The patient denied it is often a sign of recurrence in patients lymphatic channels. This gives rise to the having allergies or using tobacco or alco- with previously treated breast cancer.2 characteristic erythematous plaque or patch hol. Physical exam of the right breast and In one study, breast cancer was the most with an active spreading border. Several case chest showed a diffuse distribution of oval- common primary malignancy with skin reports noted that inflammatory metastatic carcinoma can resemble erysipelas or ery- round, pink-red and flesh-colored, ery- metastases in women, found in 69% of 2 thematous plaques and nodules from the patients.2,9 In the same study, 2% of men thema annulare centrifugum. right mid axillary line to the right side of with skin metastases were found to have Diffuse induration of the skin, her chest and abdomen (Figure 1). Several breast cancer as the primary malignancy.2,9 described as encasement in armor, is characteristic of en cuirasse metastatic carci- lesions on the right breast and nipple were In a retrospective study performed by 2 crusted (Figure 2). Dermatopathology of Lookingbill et al., 23.9% of 4,020 total noma. Clinical manifestations include the 4mm punch biopsies revealed meta- patients with breast cancer were found to firm, scattered lenticular papules and nod- 10 ules on a smooth, red-blue surface or an static carcinoma of the chest and abdomen have cutaneous metastases. The same 2 consistent with metastatic breast carci- authors in a different study looking at erythematous surface. Sclerodermatous noma (Figures 3-5). The CK7. immunoper- 7.,319 total patients found 6.3% of patients changes of en cuirasse metastatic carcinoma can occur when papules coalesce oxidase stain was positive (Figure 6). with breast cancer having skin involvement at the time of diagnosis, with 3.5% into a sclerodermoid plaque without of patients having skin involvement as the inflammation and are termed carcine Introduction 11 eburnée2 or scirrhous carcinoma with presenting clinical sign. 13 One study reviewing 7.8 biopsies morphea-like induration. One study Cutaneous metastases arising from divided carcinoma en cuirasse into pri- found the most frequent anatomical loca- 14 malignant tumors are rare but can herald tion for cutaneous metastases, without mary and secondary types. Symptoms a previously undiagnosed primary internal differentiating the type of primary carci- such as pruritus, foul-smelling discharge, malignancy or a recurrence of a previously noma, was the abdomen.12 Lookingbill edema, bleeding and pain are due to local known malignancy. Following the final et al. found that breast carcinoma was disease and are not usually associated with step in the therapeutic process in the treat- internal organ spread in primary carci- the most common cancer to invade the 14 ment of the original primary malignancy, skin at the time of diagnosis.11 The study, noma en cuirasse. The secondary type patients have a sense of completion. The reviewing 4,020 patients, found the most is more common than the primary type diagnosis of cutaneous metastases can be common anatomic location for cutaneous and presents following initial therapy for unexpected and discouraging for patients. metastatic breast carcinoma was the back, primary breast carcinoma including mas- This cutaneous manifestation can change tectomy, chemotherapy or radiotherapy.14 1,2 followed by the scalp, upper extremities, treatment plans. Most internal malignan- abdomen, neck, shoulders, lower extremi- Both pruritus and pain are caused by pros- cies are not outwardly visible to the patient. ties, flank, contralateral chest without ipsi- taglandin-like material from the tumor and Cutaneous metastases add a visible dimen- are controlled with prostaglandin synthe- lateral involvement, buttocks, and face, in 14 sion of cancer that can be psychologically descending order of frequency.10 tase inhibitors. disturbing for these patients.3,4 The discov- Pruritic, violaceous papulovesicles char- ery of an acute onset of firm, painless, pos- acterize telangiectatic metastatic carcinoma.2 sibly pruritic papulonodules on the chest Clinical Features Dilated vessels trap blood, giving rise to the of a female with a history of breast carci- violaceous hue.2 Case reports have described noma should raise the suspicion of cutane- There are traditionally eight distinct 2 this entity as clinically mimicking lymph- ous metastases.5 patterns of cutaneous involvement, with angioma circumscriptum, metastatic mela- a ninth type displaying unusual presenta- noma, and cutaneous vasculitis.2

24 Cutaneous Metastatic Breast Carcinoma: Case Report and Review of the Literature Multiple, firm papulonodules or nod- (ER), progesterone receptor (PR), and RXR-selective retinoids, termed rexinoids, ules, which may be solitary, ulcerated, pig- BRST-2 (a monoclonal antibody to gross such as bexarotene and LG100268, are mented or, less commonly, bullous, are cystic disease fluid protein-15) in surgical showing favorable results as monotherapy characteristic of nodular metastatic car- pathology to help determine invasive ductal and in combination with selective estrogen cinoma.2 Pigmented basal-cell carcinoma breast carcinoma and invasive lobular breast receptor modulators such as arzoxifene in and keratoacanthoma have been suggested carcinoma.6 One study found that BRST-2 both in vitro and in vivo models.21 This when, rarely, pigmented nodules with irreg- can enhance diagnostic sensitivity for novel use of rexinoids may ultimately prove ular borders or a dome-shaped nodule with ductal and lobular origins of breast cancer to be a useful means for breast cancer a central core have been clinical findings when used in conjunction with hormone prevention in high-risk populations. in nodular metastatic carcinoma.2 Rare receptor status but is unable to distinguish Cutaneous metastases can be a difficult reports of cutaneous metastases from breast primary cutaneous lesions from metastatic oncologic problem when patients are not carcinoma described as bullous in a zos- cutaneous breast carcinoma.6 candidates for standard therapies including teriform pattern of distribution have been An aspartic protease known as cathepsin surgery, radiation, or systemic chemother- described in the literature.10 D is an immunohistochemical marker apy.3 Chemotherapeutic agents can lead to Circular to oval, painless, nonpruritic, for metastatic breast carcinoma.16 Pan severe adverse reactions in patients. For this well-demarcated areas of alopecia with or cytokeratin markers, epithelial membrane reason and due to limited efficacy, they are without red-pink, smooth plaques character- antigen and carcinoembryonic antigen infrequently used as palliative therapy for ize alopecia neoplastica.2 One study describes usually stain positive in breast carcinoma.16 symptomatic relief.22 Several studies have scalp erythema without alopecia as a rare Podoplanin, or D2-40 antibody, stains published data indicating that exceptions to variant of alopecia neoplastica.15 Areas of completely negative in cutaneous breast the limited use of chemotherapeutic agents alopecia without plaques can be mistaken carcinomas and is therefore useful to in the palliation of cutaneous metastatic for alopecia areata, whereas cicatricial scalp distinguish primary cutaneous adnexal breast cancer exist and that it may be ben- plaques may resemble discoid lupus erythe- carcinomas from adnenocarcinomas eficial, particularly to enhance the quality matosus, morpheaform basal-cell carcinoma, metastatic to skin by labeling lymphatic of life for these patients. Kawaguchi et al. lichen planopilaris, or pseudopelade.2 endothelium, vascular tumors, and showed that oral capecitabine in low doses Paget’s disease of the breast commonly myoepithelial cells of the breast.20 (600mg/day) as monotherapy for three occurs on the nipple or areola as a sharply A non-invasive method of detection cycles in a patient with metastatic breast demarcated plaque or patch of erythema of cutaneous metastases from breast carci- cancer with cutaneous, pleural, and liver and scale, first described by Paget in 187.4.2 noma was reported using F-18 FDG PET/ metastases was found to result in significant Paget’s disease can occur simultaneously CT imaging.8 Multiple lesions were found improvement in quality of life, activities of with other types of cutaneous metasta- as cutaneous and subcutaneous nodules on daily living and resolution of the cutaneous ses from breast cancer.2 Paget described the posterior neck, bilateral arms, anterior metastases, without severe toxicities.22 this entity clinically as a “long–persistent chest wall and trunk in a 7.3-year-old female There have been several promising eczema” in women aged 40 to 60 years.2 with metastatic left breast carcinoma.8 studies in the literature using topical An exophytic nodule in the Biopsies revealed invasive ductal carcinoma chemotherapeutic treatments for inframammary crease in women with involving the deep dermis.8 cutaneous metastases from breast cancer. pendulous breasts appearing clinically Terwogt et al. published a phase II clinical similar to squamous-cell carcinoma, basal- Prognosis trial using a topically applied inhibitor cell carcinoma, or intertriginous dermatitis of protein kinase C, thereby stopping is characteristic for breast carcinoma of the cell differentiation, which interacts with 2 Cutaneous metastasis arising from inframammary crease. any primary carcinoma is a grave prognos- cell membrane components “linked to Unusual presentations and locations 5,19 phospholipid turnover and membrane tic sign. Survival time of patients with 3 of metastatic mammary carcinoma have cutaneous metastases from breast cancer is signal transduction.” This cytostatic been described on the eyelid, known as expected to be less than one year at the time alkylphosphocholine can penetrate the skin carcinomatous blepharitis, and as a red of diagnosis; however, the prognosis also without causing serious adverse reactions nodule on the nasal tip, known as clown at a systemic level.3 These authors used 2,5,16-17. depends on the type and behavior of the nose deformity. One case reports primary tumor.16 miltefosine or hexadecylphosphocholine, cutaneous metastatic breast cancer on the Lookingbill et al. found that the mean He-PC, in a 6% solution for eight weeks in right ear and right palm after three years 30 patients with verified breast carcinoma 18 survival, defined as the average time from of chemotherapy. diagnosis of skin metastasis to death, for with skin metastases and found it effective Metastases can be as small as a single in temporarily controlling breast cancer 19 7.07. patients with breast carcinoma was 31 milia cyst to as large as a “hen’s egg.” months.10 Another study found the five- skin metastases in patients pretreated Most cutaneous metastases appear as systemically or for use in postponing 10 year survival and 10-year survival rates for 3 multiple nodules. patients with a single cutaneous lesion was aggressive chemotherapy. Other phase Lymphatic spread is thought to be the 42% and 22%, respectively.18 However, the II clinical trials have tested the cytostatic cause of metastasis for inflammatory meta- topical treatment miltefosine, showing same study found that for patients with 4,23 static carcinoma, en cuirasse metastatic car- metastases in multiple organs and cutane- similar results. Topical 6% miltefosine cinoma, telangiectatic metastatic carcinoma, ous metastases, the five-year survival and is well tolerated and can be used effectively and nodular metastatic carcinoma, whereas 10-year survival rates dropped to 10% and as monotherapy or as adjuvant therapy alopecia neoplastica is thought to be caused 0%, respectively.18 in palliative treatment for cutaneous by hematogenous spread.2 metastases from breast cancer.3-4,23 Oncologists are not the only physi- Diagnostic Techniques Treatment cians with the ability to use new therapeutic modalities for the treatment of cutaneous The principle goal of treatment is to metastases from breast cancer. Dermatolo- Histologic features of breast carcinoma improve the quality of life.14 Metastatic include glandular formation, Indian fil- gists can utilize photodynamic therapy in skin cancer has been found to respond the palliation of metastatic breast carcinoma ing, lymphatic embolization, and fibrotic to systemic anticancer treatment, 2 and epidermotropic patterns.16 One study to the skin. Photodynamic therapy was intralesional chemotherapy, surgical found to decrease wound care difficulties divided the histologic classification of breast 2 excision, and radiotherapy. and aid in palliation of pain by using IV metastases into ductal origin, lobular origin, There are currently clinical trials mucinous and scirrhous, showing meta- Photofrin and 630nm diode laser, showing underway examining the use of retinoids an excellent clinical response.24-25 Rosta- static ductal adenocarcinoma of the breast against mammary carcinogenesis. to be the most common type.10 porfin is activated by red light at 664nm Alitretinoin and bexarotene have been to form free radicals that destroy cancer Several immunohistochemical found to inhibit growth of premalignant markers used to identify neoplasms of cells after being injected into patients and mammary epithelial cells, preventing the binding to plasma lipoproteins produced mammary origin are estrogen receptor progression of invasive breast cancer.21

Thomas, Flanagan, rosen, allenby 25 by those cancer cells.26 One of the original 19. Hussein MR. Skin metastasis: A pathologist’s perspec- tive. J Cutan Pathol 2009 Nov 17. Epub Accessed Feb 4, uses of rostaporfin was in the photody- 2009. namic treatment of cutaneous metastatic 20. Liang H, Wu H, Giorgadze TA, Sariya D, Bellucci KSW, breast cancer; however, the manufactur- et al. Podoplanin is a highly sensitive and specific marker to distinguish primary skin adnexal carcinomas from ers announced in 1998 that they were adenocarcinomas metastatic to skin. Am J Surg Pathol not going to pursue cutaneous metastatic 2007;31:304-310. breast cancer so their efforts could be 21. Zanardi S, Serrano D, Argusti A, et al. Clinical trials with retinoids for breast cancer chemoprevention. Endocrine- focused on the treatment of age-related Related Cancer 2006;13:51-68. macular degeneration.26 Photodynamic 22. Kawaguchi T, Iwase S, Takeuchi H, Ikeda A, Kuroda Y, et therapy targets dysplastic cells in specific al. Chemotherapy with low-dose capecitabine as palliative treatment in a patient with metastatic breast cancer: tumor destruction while leaving the sur- A case report. Cases Journal 2009;2:9081. rounding tissue intact, thereby maintaining 23. Clive S, Gardiner J, Leonard RC. Miltefosine as a topical treatment for cutaneous metastases in breast carcinoma. the cosmesis and leaving the function of Cancer Chemother Pharmacol 1999;44 Suppl:S29-30. the skin undisrupted.24 24. Taub AF. Photodynamic therapy: Other uses. Dermatol Clin 2007;25:101-109. Figure 4: Epithelioid islands with small 25. Cuenca RE, Allison RR, Sibata C, et al. Breast cancer glandular spaces at 10x magnification. with chest wall progression: Treatment with photody- Conclusion namic therapy. Ann Surg Oncol 2004;11(3):332-7. 26. Hunt DW. Rostaporfin (Miravant Medical Technologies). The acute onset of firm, painless nod- IDrugs 2002 Feb;5(2):180-186. ules in a patient with a history of breast carcinoma should arouse suspicion of the presence of cutaneous metastases from a previously treated carcinoma. The thresh- old to perform a biopsy on these lesions should be low. The prognosis is extremely poor when cutaneous metastases are present. Nonetheless, cutaneous metastatic breast carcinoma requires a multidisciplinary approach to care in order to maximize a patient’s quality of life. References Figure 5: Infiltrating tumor cells with pleomorphic, hyperchromatic nuclei and sin- 1. Vano-Galvan S, Moreno-Martin P, Salguero I, Jaen P. gle file atypical cells at 20x magnification. Cutaneous metastases of breast carcinoma: A case report. Cases Journal 2009; 2:71. 2. Schwartz RA. Cutaneous metastatic disease. J Am Acad Dermatol 1995; 33:161-82. 3. Terwogt JMM, Mandjes IAM, Sindermann H, Beijnen JH, Figure 1: Pink to red colored papules and ten Bokkel Huinink WW. Phase II trial of topically applied plaques diffusely on chest and abdomen. miltefosine solution in patients with skin-metastasized breast cancer. Br J Cancer 1999; 79 (7/8), 1158-1161. 4. Leonard R, Hardy J, von Tienhoven G, Houston S, Sim- monds P, David M, Mansi J. Randomized, double-blind, placebo-controlled, multicenter trial of 6% miltefosine solution, a topical chemotherapy in cutaneous metastases from breast cancer. J Clin Oncol 2001; 19:4150- 4159. 5. Santiago F, Saleiro S, Manuel-Brites M, Frutuoso C, Figueiredo A. A remarkable case of cutaneous metastatic breast carcinoma. Dermatology Online J 2009 Jul 15;15(7)10. Accessed Feb. 4, 2009. 6. Wallace ML, Smoller BR. Differential sensitivity of estrogen/progesterone receptors and BRST-2 markers in metastatic ductal and lobular breast carcinoma to the skin. Am J Dermatopathol 1996; 18(3): 241-247. Figure 6: CK7 positivity at 10x magnifica- 7. Whitaker-Worth DL, Carlone V, Susser WS, Phelan N, tion Grant-Kels JM. Dermatologic diseases of the breast and nipple. J Am Acad Dermatol 2000;43:733-51. 8. Borkar S, Pandit-Taskar N. F-18 FDG uptake in cutaneous metastases from breast cancer. Clin Nucl Med Figure 2: Crusted, scaling pink-red pap- 2008;33:488-489. ules and nodules on the right breast and 9. Brownstein MH, Helwig EB. Patterns of cutaneous nipple-areolar complex. metastasis. Arch Dermatol 1972;105(6):862-868. 10. Lookingbill DP, Spangler N, Helm KF. Cutaneous metastases in patients with metastatic carcinoma: A retrospective study of 4020 patients. J Am Acad Dermatol 1993;29:228-236. 11. Lookingbill DP, Spangler N, Sexton M. Skin involvement as the presenting sign of internal carcinoma: A retrospective study of 7316 cancer patients. J Am Acad Dermatol 1990;22:19-26. 12. Fernandez-Flores A. Cutaneous metastases: A study of 78 biopsies from 69 patients. Am J Dermatopathol 2010; 32(3):222-239. 13. Rapini RP. Metastatic neoplasms to skin. Practical Der- matopathology. Elsevier Mosby; 2005 p 360. 14. Siddiqui MA. Primary carcinoma en cuirasse. J Am Geriatr Soc 1996;44(2):221-222. [Letter] 15. Mallon E, Dawber RPR. Alopecia neoplastica without alopecia: A unique presentation of breast carcinoma scalp metastasis. J Am Acad Dermatol 1994;31:319-321. 16. Prabhu S, Pai SB, Handattu S, Kudur MH, Vasanth V. Cutaneous metastases from carcinoma breast: The common and the rare. Indian J Dermatol Venereol Leprol Figure 3: Tumor cells infiltrating the der- 2009;75:499-502. mis at 5x magnification. 17. Soyer HP, Cerroni L, Smolle J, Kerl H. Klown Nase. Hautmetastase eines Mammakarzinoms. Z Hautkr 1990; 65:929-31. [English Abstract] 18. Cil T, Altintas A, Pasa S, Isikdogan A. Atypical skin metastases from early tubular breast carcinoma. Int J Dermatol 2008;47:1311-1313.

26 Cutaneous Metastatic Breast Carcinoma: Case Report and Review of the Literature

Large Polypoid Dermatofibroma in a Young Boy: A Case Report

Kurt Grelck, DO,* Janet Allenby, DO, FAOCD** *First-year Dermatology Resident, Columbia Hospital, West Palm Beach, FL **Program Director, Columbia Hospital, West Palm Beach, FL

Abstract Polypoid dermatofibroma is a rare subtype of dermatofibroma characterized by its unusual clinical phenotype. The lesion’s sometimes rapid growth and overall size lead the clinician and patient alike to suspect malignant disease, but the histologic analysis reveals this entity to have a benign character. We present an uncommon case of an 8 year old boy with a pedunculated polypoid dermatofibroma on the upper extremity. Introduction course of action was excision with a Histopathology subcuticular closure. The patient tolerated Dermatofibroma, also known the procedure well, and the pathologic Grossly, the specimen was an irregular as benign fibrous histiocytoma, is specimen was returned to the United States pedunculated polypoid portion of skin a constituent of the heterogeneous for interpretation. measuring 2.0 x 1.2 x 1.7. cm in size. The conglomeration known as fibrohistiocytic epidermis showed mild acanthosis and tumors of the skin. Dermatofibromas are Table 1: Dermatofibroma widened rete ridges. A dermal spindle-cell the most common fibrohistiocytic tumor, proliferation with peripheral collagen trap- and these indolent tumors form classically Subtypes ping and focal storiform morphology was 1 on the lower extremities of young adults. 5,6,7. present (Figures 2 and 3). No atypia or The affected patient age distribution is Atrophic dermatofibroma mitotic figures were seen. There was a mild typically 20-60 years of age, but 20 percent Atypical polypoid dermatofibroma8,9,10 mixed infiltrate. Immunohistochemical of presentations are in patients younger Balloon cell11 staining for CD34 expression was negative than 17. years old.2,3 The etiology of this Clear cell12 proliferation is unknown; however, there Erosive dermatofibroma13 is some association with trauma and Generalized eruptive histiocytoma14 1 arthropod bites. Dermatofibromas are Giant dermatofibroma15 usually histologically characterized by a Granular cell16 proliferation of fibroblast-like spindle cells, 17. histiocytes, blood vessels, and potentially Intracytoplasmic eosinophilic globules Keloidal18 other mesenchymal components in 19 the dermis depending on the subtype Lichenoid described.4 Many subtypes have been Lipidized (ankle-type)20 previously reported (see Table 1), and the Multiple clustered dermatofibroma21 presentation of most dermatofibromas Multiple palmoplantar histiocytoma22 as asymptomatic, ≤ 5mm growths with Multinodular hemosiderotic dermatofi- indolent clinical character can be quite broma23 dissimilar from some of the more unusual Myxoid24 dermatofibroma subtypes, including the 25 Figure 1: An eight-year-old Haitian boy Osteoclast-like giant cells with enlarging pedunculated polypoid case described herein. This case presents 26 Palisading nodule. an eight-year-old boy with a large polypoid 27.,28 pedunculated dermatofibroma. Polypoid Prominent myofibroblastic proliferation29 Signet-ring cell30 Case Report Smooth-muscle proliferation31 32 An eight-year-old boy from Port-au- Subcutaneous fibrous histiocytoma Prince was seen at a mobile clinic following Subungual pleomorphic dermatofibroma33 the tragic earthquake that struck Haiti Ulcerated dermatofibroma34 on January 12, 2010, with a complaint of an enlarging mass on the right arm Table 2: Differential for the previous few months (Figure 1). Neither the patient nor his mother Diagnosis was able to provide any inciting event or trauma to the area, and the nodule had Acrochordon been asymptomatic apart from its fairly Acral fibrokeratoma Figure 2: H&E, 5x rapid increase in size. He had no medical Atypical polypoid dermatofibroma history apart from occasional asthma, and Basal-cell carcinoma he had a negative review of systems. He Dermatofibroma sarcoma protuberans was developmentally normal and did not (DFSP) have any family history of note. Dermatomyofibroma On exam, the patient had a 2 cm Epidermal nevus pedunculated flesh-colored nodule, which Giant dermatofibroma was non-tender and firm to palpation Keloid without any palpable signs of infiltration Lipidized dermatofibroma of the deeper tissues. He had no associated Malignant melanoma adenopathy, and the remainder of his Neurofibroma exam was unremarkable. Due to the lack Pleomorphic fibroma of available specialty physician follow-up Polypoid dermatofibroma and the deficiency of referable medical Spitz nevus facilities, it was felt the most beneficial Figure 3: H&E, 20x Grelck, allenby 29 (Figure 4). Factor 13a (Figure 5) and actin preexisting collagen fibers and cause (Figure 6) stains were positive throughout characteristic “entrapment.”3,35 The many the dermal component of the lesion. variants of dermatofibroma can make an accurate clinical diagnosis less feasible; correct diagnosis relies on the lesion’s Diagnosis histopathologic makeup. Polypoid dermatofibroma is a very Polypoid dermatofibroma with myofi- 28 broblastic differentiation rare variant. In a review by Black et al., 610 dermatofibromas from 57.9 patients were evaluated, and the most common Discussion and Comment lesion morphology was a slightly elevated, round nodule.38 In this series, polypoid Dermatofibroma is a frequently lesions were much less common at 3%.38 encountered dermatologic entity, the In another series, Katsumata analyzed 190 Figure 4: CD34 immunostain negativity, diagnosis of which is usually apparent dermatofibromas, none of which were clinically. However, due to the many types polypoid.39 Ohshima et al. studied a series 20x of dermatofibroma, there remains a subset of 101 patients with dermatofibromas and of rare variants that are often clinically found 16 cases of nodular polypoid lesions.40 misdiagnosed due to their atypical size, Few reports of polypoid location or clinical history.15 The typical dermatofibroma exist in the literature, and presentation of dermatofibroma is as a series by Hueso et al. presents 21 cases of a red-brown or yellow-brown papule on giant dermatofibroma characterized by a the leg measuring a few millimeters in size greater than 5 centimeters in diameter, diameter. Patients not uncommonly will polypoid/pedunculated appearance, benign have complaints of pruritus or tenderness.2 biological behavior despite their size, and Clinically, dermatofibromas can usually the same histopathologic characteristics as be recognized by their firm character on conventional dermatofibroma.15,41 Our case palpation and tendency to show the central does not fit the 5 cm diameter criteria for “dimple sign” when compressed laterally.35 giant dermatofibroma, although the original Larger and more infiltrative subtypes 41,42 report by Danckaert did not either. We Figure 5: Factor 13a immunostain lacking typical superficial changes are more suspect that due to our patient’s young difficult to diagnose clinically and need to age and the lesion’s rapid growth, the area positivity, 20x be approached more cautiously.35 Most would likely have continued to enlarge patients that are affected fall into a broad without intervention. This case is also age range from 20-60 years of age; however, unusual in that most giant dermatofibromas approximately 17.% are under the age of occur on the lower legs or, more rarely, the 20 when they present.3 Women are more back. In the review by Hueso et al., 20/21 prone to the development of these lesions, patients had lower leg or, more rarely, trunk for uncertain reasons.36,37. locations, with one patient presenting with The etiology of these lesions remains a shoulder lesion.15 Akagi et al. reported unknown, although they are thought a case of polypoid dermatofibroma 2 to arise from a reactive dermal process centimeters in diameter also located on the or response to injury.15 Typical inciting lower leg.43 Finally, a 1.5 x 1.4 centimeter events have been reported and include case of polypoid dermatofibroma reported arthropod assault, folliculitis, and local by Sogabe et al. was present on the patient’s infections, although cases of eruptive wrist; they theorized that the lesion’s dermatofibromas have been reported with polypoid morphology was a result of Figure 6: Actin immunostain positivity, 20x underlying inflammatory diseases such as anatomic location, which placed it over a lupus, HIV, and leukemia.35 Some consider demonstrate architectural features similar firm subcutaneous tissue such as tendon 44 dermatofibromas to be a neoplastic or or bone.28 They hypothesized that location to DFSP. DFSP is typically seen in adult clonal proliferation, but many think patients, but it has been reported in children above these structures led to the exophytic 35,45 dermatofibroma to be an initially reactive polypoid projection of the lesion. Our case as well. The typical storiform, invasive process with later autonomous growth and seems to defy this idea, as this lesion was pattern of spindle-cell growth was not customarily benign character.35 situated over the soft tissues of the arm. seen in our case. In order to distinguish Histologic findings in most cases The age of our patient was markedly outside between DFSP and benign dermatofibroma, demonstrate an acanthotic epidermis with the average age of presentation for these several reports have suggested using elongated rete ridges. Often accompanying 15,35,41 the immunohistochemical staining tumors, as well. 35,46,48 this finding is hyperpigmentation of the basal The clinical differential diagnosis characteristics of CD34 and factor 13a. keratinocytes.3 As this is a mesenchymal for a pedunculated polypoid nodule These stains are neither perfectly specific process, the papillary dermis is typically on the skin is sizable (see Table 2), and nor sensitive, as focal CD34 positivity not involved, and a tumor-free area (Grenz in our case the clinical suspicion was of can be seen in some dermatofibromas, zone) can been seen.3,35 The dermal tumor and some DFSPs uncharacteristically a malignant etiology due to the lesion’s 46,47. component consists of spindle cells, some of rapid growth, atypical location and express factor 13a. In our case, benign which are histoid, and other mesenchymally young age of the patient. Histologically, dermatofibroma was confirmed by derived cell types depending on the subtype however, the differential diagnosis was immunohistochemical staining with CD34 of dermatofibroma being characterized.35 In more limited, as our lesion had the negativity and factor 13a positivity. Other this case, smooth-muscle actin staining was appearance of a typical dermatofibroma investigators are now considering the use of indicative of a myofibroblastic differentiation. with a lack of atypical mitotic figures and other immunohistochemical stains such as Dermatofibromas often have spindle a benign appearance apart from its large stromelysin, tenascin, and D2-40 as possible cells that form short, intersecting fascicles, methods of differentiating dermatofibroma size. However, due to the atypical clinical 47.,49,50 occasionally in a well-formed storiform presentation, the diagnosis of DFSP had to from DFSP. pattern in focal areas. As a lesion be excluded. Although histopathological Treatment of large or giant polypoid matures, stromal capillary proliferation examination reveals conventional features dermatofibroma is complete excision, often increases with time.3 Hemosiderin of dermatofibroma in most cases of large which is curative. Despite the large size and deposition in macrophages as well as or giant dermatofibroma, an incisional sometimes rapid growth of these lesions, multinucleated giant cells can be seen. biopsy specimen from the tumor may many partially resected cases also had no Peripherally, tumor cells can encircle recurrences.41,51 It should be noted, however, 30 Large Polypoid Dermatofibroma in a Young Boy: A Case Report that certain subtypes of dermatofibroma Dermatologica. 1990;181:320-3. 24. Zelger BG, Zelger B. Myxoid dermatofibroma. do not have such benign behavior, and a Histopathology 1999; 34; 357–364. more aggressive clinical approach should be 25. Kutchemeshi M, Barr RJ, Henderson CD. Dermatofibroma undertaken in those cases.52,53 For multiple with osteoclast-like giant cells. Am. J. Dermatopathol. 1992; 14; 397–401. or diffuse lesions, some have advocated laser 26. Schwob VS, Santa Cruz DJ. Palisading cutaneous fibrous 54 treatment as well. histiocytoma. J. Cutan. Pathol. 1986; 13; 403–407. In summary, this young patient had 27. Cho JH, Yoon SY, Cho SH, Lee JD. A Case of Polypoid Dermatofibroma. The Korean Journal of Dermatology. the very unusual presentation of a large 2005, VOL 43; PART 5, pages 669-671. polypoid pedunculated dermatofibroma on 28. Sogabe Y, Takahashi A, Tamura A, Ryuzaki K, Ishikawa the arm. Although this lesion’s presentation O. A case of polypoid dermatofibroma. J Dermatol. 2002 Dec;29(12):786-9.7 was of concern to the patient and clinician 29. Zelger BW, Zelger BG, Rappersberger K. Prominent myofi- alike, the histopathologic diagnosis was broblastic differentiation. A pitfall in the diagnosis of dermatofibroma. Am. J. Dermatopathol. 1997; 19; 138–146. reassuring for a benign clinical course. 30. Garrido-Ruiz MC, Carrillo R, Enguita AB, Rodriguez Per- alto LJ. Signet-ring cell dermatofibroma. Am. J. Dermato- pathol. 2009; 31; 84–87. Acknowledgements 31. LeBoit PE, Barr RJ. Smoot-muscle proliferation in dermatofibromas. Am. J. Dermatopathol. 1994; 16; 155–160. 32. Chang SE, Choi JH, Sung KJ, Moon KC, Koh JK. Subcuta- The authors would like to gratefully neous dermatofibroma showing a depressed surface. Int J acknowledge Dr. Les Rosen, MD, and Dermatol. 2001;40:77-8. Dermpath Diagnostics for donating their 33. Hsieh Y, Lin Y, Wu Y, Su H, Billings SD, Hood AF. Subun- gual pleomorphic fibroma. J Cutan Pathol. 2003;30:569-71. expertise, time and services to the Haitian 34. Yus ES, Soria L, De Eurelio E, Requena L. Lichenoid, ero- relief effort. sive and ulcerated dermatofibroma. Three clinico-pathologic variants. J Cutan Pathol. 2000;27:112-7. 35. Hügel H. Fibrohistiocytic skin tumors. 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Zaina Rashid, D.O.,* Michael Land, MSIV,** Sarah Shuker, MSI,*** Don Anderson, D.O., FAOCD, FASMS**** *2nd Year Resident, Midwestern University/AZ Desert Dermatology, Kingman, AZ **Touro University, Vallejo, CA ***University of Guadalajara, Jalisco, Mexico ****Program Director, Arizona College of Osteopathic Medicine, Midwestern University of Health Sciences, Kingman, AZ

Abstract Lichen planus pigmentosus (LPP) is a rare disease process, possibly a clinical variant of lichen planus (LP), that presents as slate gray, brownish-black or brown macules, papules, patches, or reticulated hyperpigmentation classically found on areas of the face and neck and occasionally flexural folds. We present the case of a man with a variant of LPP, lichen planus pigmentosus-inversus, distinguished only by lesional anatomic location.

diagnosis of LPP is suspected or confirmed, 62(3): Supplement 1. Case Report 6. Kashima A, Tajiri A, Yamashita A, Asada Y, Setoyama conservative laboratory workup may M. Two Japanese cases of lichen planus pigmentosus- A 7.3-year-old man presented with include serological testing for HCV. inversus, Int J Dermatol. 2007 Jul;46(7):740-2. The differential diagnosis of 7. Cho S, Whang KK. Lichen planus pigmentosus asymptomatic, dark brown patches in the presenting in zosteriform pattern. J Dermatol. 1997 axillae for three months duration. There LPP includes EDP, CTCL, granular Mar;24(3):193-7. was no history of prolonged sun exposure parakeratosis, drug-induced dermatoses, 8. Chuang TY, Stitle L, Brashear R, Lewis C. Hepatitis C and contact and occupational dermatoses virus and lichen planus: A case-control study of 340 or trauma in the area of investigation. patients. J Am Acad Dermatol. Nov 1999;41(5 Pt 1):787- The patient denied any symptoms of with hyperpigmentation. LPP can be 9. pain or pruritus. Past medical history was distinguished from other disease processes 9. Shengyuan L, Songpo Y, Wen W, Wenjing T, Haitao clinically and histologically. Clinically, it is Z, Binyou W. Hepatitis C virus and lichen planus: remarkable for hypertension controlled a reciprocal association determined by a meta- with atenolol. essential to distinguish LPP from EDP. EDP analysis. Arch Deratol. Sep 2009;145(9):1040-7. On physical exam, there were well- has active borders and does not involve 10. Bigby M. The relationship between lichen mucosal surfaces, whereas LPP does not have planus and hepatitis C clarified. Arch demarcated, brown mottled patches in both Dermatol. Sep 2009;145(9):1048-50. axillae (Figure 1). There was no involvement active borders and can involve the mucosal 11. Raslan HM, Ezzat WM, Abd El Hamid MF, Emam H, of the extremities, nails, or oral mucosa. surfaces. Histopathological studies reveal Amre KS. Skin manifestations of chronic hepatitis C virus similarities between LPP and EDP, making it infection in Cairo, Egypt. East Mediterr Health J. May- Autoantibodies and complete blood workup Jun 2009;15(3):692-700. was performed, resulting in negative or difficult to distinguish between the two based 12. Black MM. Lichen planus and lichenoid disorders. In: on histopathology alone.4 LPP shows atrophy Champion RH, Burton JL, Burns DA, editors. Textbook within-normal-limits outcomes. of Dermatology. 6th ed. Oxford: Blackwell Science Ltd; Several biopsies were performed, of the epidermis with basal vacuolar changes 1988:1910. showing focal atrophy in the epidermis, a and the presence of a lymphohistiocytic or 13. Bhutani LK. Ashy dermatosis or lichen planus lichenoid infiltrate at the dermoepidermal pigmentosus. What is in a name? Arch Dermatol band-like lymphocytic infiltrate associated 1986;122:133. junction. The dermis shows melanophages 14. Naidorf KF, Cohen SR. Erythema dyschromicum perstans with pigmented macrophages, and 5 interface vacuolar change (Figure 2). A PAS with pigment incontinence. and lichen planus. Arch Dermatol 1982;118:683-5. There are no specific standard 15. Convit J, Kerdel-Vegas F, Rodriguez G. Erythema stain was negative for fungal elements. dyschromicum perstans. J Invest Dermatol 1961;36:457- treatments for LPP. Topical steroids, 62. keratolytics, prednisone, griseofulvin Discussion and chloroquine have been used with inconsistent results. Tacrolimus ointment In 197.4, Bhutani et al. first reported showed promising results in one study, LPP in Indian patients, describing a with improvement in seven out of 13 pigmentary disorder similar to erythema patients (53.8%) with LPP.3 dyschromicum perstans (EDP), or ashy 1 Since LPP is rare, many ongoing dermatosis. It differs from classic LP in treatments are still being tested for their that it exhibits dark brown macules ability to achieve some clearance. We began and or papules and has a longer clinical a new approach with our patient, using a course without pruritus or scalp, nail, trial of 10% hydroquinone cream with 1% and mucosal involvement. The lesions hydrocortisone cream (1:1 ratio, 100gm may be cosmetically unappealing to jar) applied to the axillae twice daily for the patient but are otherwise clinically three months. We report mild success in asymptomatic. Occasionally, LPP occurs decreasing the brown pigmentation in our on the intertriginous areas of the body, patient’s axillae (Figure 3). Currently, he is and in such cases has been dubbed lichen on an every-other-day regimen. planus pigmentosus-inversus, a variant of LPP.2 There have also been a few cases presenting as mottled hyperpigmentation, References zosteriform, arcuate and linear patterns. 1. Bhutani LK, Bedi TR, Pandhi RK, Nayak NC. Lichen The cause of LPP is currently Planus Pigmentosus. Dermatologica, 1974; 149: 43-50. unknown. It has been strongly suggested 2. Pock L, Jelinkova L, Drjik L, Abrhamova S, Vojtechovska that lichen planus may be associated with S, Sezemska D, Borodacova I, Hercogova J. Lichen planus pigmentosus-inversus. Journal of the European hepatitis C virus (HCV). In a 2009 study, Academy of Dermatology and Venereology, 2001; 15(5): Al-Mutairi et al. evaluated 33 LPP patients 452-454. in Kuwait.3 Of the patients, 20 (60%) were 3. Al-Mutairi N, El-Khalawany M. Clinicopathological characteristics of lichen planus pigmentosus and its seropositive for HCV, with significantly response to tacrolimus ointment: an open label, non- higher liver enzymes (AST and ALT). Since randomized, prospective study. Journal of the European LPP is considered to be in the spectrum Academy of Dermatology and Venereology, 2009; online publication. of lichenoid disorders and may be 4. Vega ME, Waxtein L, Arenas R, Hojyo T, Dominguez- a variant of LP, it is not surprising that Soto L. Ashy dermatosis and lichen planus pigmentosus: a clinicopathologic study of 31 cases. International this study supports a possible association Journal of Dermatology, 1992; 31(2): 90-94 between LPP and HCV. Therefore, when a 5. Lichen Planus Pigmentosus-Inversus: A Case Report. Journal of the American Academy of Dermatology, 2010; 32 Lichen Planus Pigmentosus-Inversus Figure 1 - Right armpit before.

Figure 2 - LPP-40X

Figure 3

Rashid, Land, shuker, anderson 33 Multinucleate-cell Angiohistiocytoma: A Unique Case and Literature Review

Julie Malchiodi, DO, FAOCD,* Jonathan D. Richey, DO, MHA,** Brian N. Parks, DO, PGY1,*** Cory D. Nelson, DO, PGY1,**** Annette LaCasse, DO, FAOCD***** *Dermatologist, Oakwood Southshore Hospital, Wyandotte, Michigan **2nd-year Resident, Pontiac Osteopathic Hospital, Pontiac, Michigan ***Genesys Regional Medical Center, Grand Blanc, Michigan ****St. Johns Hospital, Madison Heights, Michigan *****Program Director, Pontiac/Botsford Hospital, Pontiac, Michigan

Abstract We present the clinical, histologic, and immunologic features of one case of multinucleate-cell angiohistiocytoma (MCAH) on the face. Of the approximately 70 cases reported in the last 24 years, this is the first one documented on the cheek. MCAH typically occurs in middle-aged women and consists of reddish- purple, dome-shaped papules on the extremities. We summarize the significant findings of previous cases, present a table of immunohistochemical staining particular to MCAH, and make recommendations for documentation in future publications.

Case Report multinucleate-cell angiohistiocytoma. the face,3,18,20,21 eyelids,23 orbit,22 upper lip,17. The patient was given treatment options temple,21 oral mucosa,7. forehead,3,18 and 5,12,15,20,24 A 7.2-year-old female presented with of wide excision, laser treatment, or trunk. Lesions usually are unilateral, observation. She chose observation and but bilateral cases4,5,7.-9,16,20,21,23,24 and a progressive development of a small pre- 12 auricular lesion that had been present declined further excision. generalized case have also been reported. for three years. The lesion had gradually MCAH presents as red/pink to violet or grown in size and appeared to spread Discussion brown lesions. Lesions are typically domed down her cheek. She also had more or flat-topped papules that are smooth recently developed a bump within the Multinucleate-cell angiohistiocytoma and firm. Lesions often develop on acral lesion. The patient denied any other (MCAH) is a rare, benign soft-tissue surfaces and persist indefinitely without complaints. She denied pruritus or pain. lesion with distinctive histologic, intervention. There may be solitary lesions She denied history of travel, trauma, immunohistochemical, and ultrastructural or multiple groups of papules. Multiple or insect bites prior to the lesion onset. features that was first described by Smith lesions are more common and can coalesce A topical steroid had been applied to and Wilson-Jones in 1985.1,2 MCAH is linearly, annularly, or randomly to form the lesions with little to no change in an acquired disorder of unknown cause. patches or plaques. the presentation. The patient did not It is uncertain if these lesions represent a MCAH seems to be a benign demonstrate any sun sensitivity. Her benign fibrohistiocytic vascular neoplasm condition that progresses slowly over dermatologic history was benign except or a reactive/inflammatory process. It years without associated disease. for a distant basal-cell carcinoma that occurs predominantly on the extremities MCAH typically doesn’t regress, but there have been cases of spontaneous had been excised previously. She was of middle-aged and elderly women. So 5,21 under concurrent medical management far there have been no reported cases regression reported in the literature. for hypertension. of mortality or significant morbidity None of the cases described to date Physical examination revealed scattered associated with this disorder. have shown association with either violaceous patches and slightly indurated The differential diagnosis of malignancy or systemic symptoms. plaques on the left pre-auricular face, MCAH may include but is not limited to Lesions tend to be asymptomatic, but some cases have been reported to with involvement inferior to the mandible angiofibroma, annular sarcoid granuloma, 13,21,24 (Figure 1). The patches had superficial scale dermatofibroma, epithelioid angiomatosis, be pruritic. The occurrence of MCAH in non-Caucasian races has haphazardly arranged within the plaques giant-cell fibroblastoma, Kaposi’s sarcoma, 5,6,11,17. and outside the borders of the lesions. The lymphocytic infiltrates, nodular lichen only been reported in a few cases. lesions were negative for fungal elements via planus, progressive lymphangioma, light microscopy and potassium hydroxide pseudo-Kaposi’s sarcoma, spindle-cell Pathophysiology preparation. The plaques were blanchable hemangioma, and granuloma annulare.3-8 on diascopy. Full body exam revealed no It is important to differentiate MCAH from The pathogenesis of MCAH is other vascular lesions or lymphadenopathy. Kaposi’s sarcoma and other conditions that uncertain. It has been proposed that there The hair, nails, and mucous membranes require treatment.5,9 exists a relationship between mast cells were unaffected. A search of the English and Spanish and factor XIIIa-positive fibrohistiocytic The site was biopsied with a 4 language literature revealed 63 documented cells. The release of various pro-angiogenic mm punch. Differential diagnosis at cases of MCAH. Tables 1, 2 and 3 cytokines, such as IL-4, may add to the the time was vascular malformation, summarize the clinical characteristics of the vascular proliferation.20 Another theory discoid lupus erythematosus, Kaposi’s 63 documented cases of MCAH, plus our is that the condition may be associated sarcoma, histiocytoma, sarcoidosis, and case presented above.3-25 The data suggests with trauma, because it tends to occur lymphocytoma cutis. Histopathologic that most cases occur in middle-aged and on the dorsal aspects of the hands and examination revealed sections with elderly women. The lesions develop more around the knees.8 Most available evidence increased numbers of thin, ectatic blood frequently in women than in men (F:M strongly suggests that MCAH is reactive, vessels in the mid to upper dermis 3.85:1). The age range of these patients is not neoplastic. The lesions typically do (Figure 2). Angulated multinucleate cells 24 to 86 years old (mean 56.92, median not show an expansive growth pattern, surrounded the vessels (Figures 3 and 56). The lesions tend to range from 1 to and MCAH has not been correlated with 4). Patchy lymphocytic inflammation 120 mm in size, with 85% of the cases other comorbidities. There have been and solar elastosis were seen. CD31 being 1 to 10 mm in size. The lesions on the no reported cases of familial history, immunohistochemical stain was limbs were found on the arm/forearm,11,12 malignant degeneration, or association performed to highlight the vessels in the dorsal parts of the hands or wrists and with cancer. dermis. An HHV8 immunohistochemical fingers,3-5,8,13-14,18,20,23,24 thighs, 5,7.-10,12,16,19,21 stain was negative. These findings knees,5,22,23 and lower extremities.5,9,25 Other, are consistent with a diagnosis of less common lesions have been reported on

34 multinucleate-cell Angiohistiocytoma: A Unique Case and Literature Review Dendritic cells were positive for factor XIIIa, angiohistiocytoma of the upper lip. Oral Surg Oral Med Histopathology Oral Pathol. 1994 Dec;78(6):743-7. characteristic of fibrous histiocytes.20 18. Kopera D, Smolle J, Kerl H. Multinucleate cell angiohistiocytoma: treatment with argon laser. Br J The principle histopathologic findings in Dermatol. 1995 Aug;133(2):308-10. 19. Monteagudo B, Labandeira J, Ginarte M, Alvarez MCAH are the presence of multinucleate Treatment JC, de las Heras C, Cacharrón JM, García Rego cells and vascular proliferation. JA. [Multinucleate-cell angiohistiocytoma.] Actas Dermosifiliogr. 2005 May;96(4):272-3. Multinucleate cells found in MCAH are Due to the seemingly benign nature 20. Puig L, Fernández-Figueras MT, Bielsa I, Lloveras B, characteristic but not pathognomonic. Alomar A. Multinucleate cell angiohistiocytoma: of MCAH, a conservative approach a fibrohistiocytic proliferation with increased mast cell The multinucleate cells can also be seen in numbers and vascular hyperplasia. J Cutan Pathol. 2002 to the treatment and management is Apr;29(4):232-7. other inflammatory, neoplastic, or reactive 21. Pérez LP, Zulaica A, Rodríguez L, Campo MC, Peñaranda processes. The multinucleated cells resemble recommended. For cosmetic reasons, JM, Fernández-Redondo V, Toribio J. Multinucleate cell angiohistiocytoma. Report of five cases. J Cutan Pathol. cells that are in stages midway between surgical excision may be recommended, 2006 May;33(5):349-52. activated fibroblasts and fully developed and it appears to be curative.1,2,5,17.,23,16 As 22. Shields JA, Eagle RC Jr, Shields CL, Sohmer KK. 5 21 Multinucleate cell angiohistiocytoma of the orbit. Am J multinucleated giant cells. shown in Table 3, cryosurgery, argon Ophthalmol. 1995 Sep;120(3):402-3. 9,18 24 23. Smolle J, Auboeck L, Gogg-Retzer I, Soyer HP, Kerl H. The multinucleated giant cells have laser, and CO2 laser have shown clinical Multinucleate cell angiohistiocytoma: a clinicopathological, hyperchromatic nuclei that are closely immunohistochemical and ultrastructural study. Br J resolution of the lesions. Unsuccessful Dermatol. 1989 Jul;121(1):113-21. aggregated or arranged in the center of the 7. 24. Väkevä L, Saksela O, Kariniemi AL. Multinucleate cell 5,12,13,17.,20,22,23 treatments reported include radiotherapy, cytoplasm along the cytoplasmic 16 11 angiohistiocytoma: a report of four cases in Finland. Acta 5,6,8,20,21 topical steroids, and nitrogen mustard. Derm Venereol. 2003;83(3):222-3. membrane in a ring-like fashion. 25. Zelger BW, Steiner H, Kutzner H. Clear cell The multinucleate cells appear to have a MCAH is not known to be associated with dermatofibroma. Case report of an unusual fibrohistiocytic scalloped or angulated cytoplasm and are any systemic diseases and is thought to lesion. Am J Surg Pathol. 1996 Apr;20(4):483-91. scattered evenly throughout the lesion. be benign, with no cases of morbidity or The multinucleate cells usually show mortality. Therefore, further follow-up care abundant, rough endoplasmic reticulum, is not necessarily indicated unless the lesion nuclear membrane reinforcement (zonula grows or the patient desires its removal. nucleus occludens), pinocytic vesicles, and cytoplasmic protrusions. Numerous lysosomes have also been reported, Summary suggesting differentiation to a fibroblastic/ histiocytic phenotype.5,9,20,23 We believe that multinucleate-cell The vascular proliferation consists of angiohistiocytoma shows enough clinical, capillaries, venules, and small arterioles1,5,23 histopathologic, and ultrastructural that can involve the full thickness of the findings to be considered an independent dermis.5,7.,20 These vessels tend to have round entity. Due to the benign nature of MCAH, lumina and may be narrowed or dilated.6 it most likely is under-recognized and The region surrounding the vessels often under-reported. We recommend that contains a sparse inflammatory infiltrate future reported cases comment on the Figure 1. Scattered violaceous patches containing mostly lymphocytes, plasma demographics of each case as well as all and slightly indurated plaques on the left cells4,9,10,21 and, in some cases, an increased immunohistological studies. Through this, pre-auricular face, with involvement infe- number of mast cells.10,17.,20 The vascular we hope to better define and understand rior to the mandible. proliferation is embedded in a fibrous multinucleate-cell angiohistiocytoma. stroma rich in fibrohistiocytic cells. The endothelial cells lining these vessels have References been described as plump, prominent, and 1. Smith N, Wilson Jones E. Multinucleate cell luminally protruding.4,10,17. angiohistiocytoma: a new entity. Br. J Dermatol. 1985; 113:15. Other histopathologic characteristics 2. Smith N, Wilson Jones E. Multinucleate cell seen in MCAH include collagen bundles angiohistiocytoma: a new entity. J Cutan Pathol. 1986; 113:15 that seem to be thickened, coarse, and 3. Annessi G, Girolomoni G, Giannetti A. Multinucleate arranged haphazardly or slightly parallel cell angiohistiocytoma. Am J Dermatopathol. 1992 17. Aug;14(4):340-4. to the skin surface. The overlying 4. Blanco Barrios S, Rodríguez Díaz E, Alvarez Cuesta 8,24,13,9 C, Galache Osuna C, Requena Caballero C, Martínez epidermis is hyperplastic. Closer Merino A, Requena Caballero L, Kutzner H. Multinucleate examination reveals the presence of loosely cell angiohistiocytoma: a new case report. J Eur Acad Dermatol Venereol. 2005 spaced dendritic cells throughout the 5. Jones WE, Cerio R, Smith NP. Multinucleate cell lesion.4,6,9 An abundance of mononuclear angiohistiocytoma: an acquired vascular anomaly to be distinguished from Kaposi’s sarcoma. Br J Dermatol. 1990 cells in the interstitium has also been May;122(5):651-63. 9,20 6. Rawal YB, Anderson KM, Rawal SY. Multinucleate cell seen. The diagnosis of MCAH is based angiohistiocytoma: an uncommon mucosal tumour. Clin on histopathologic findings, although Exp Dermatol. 2008 Nov 24. Mar;19(2):208-11. 7. Romiti R, Perniciaro C, White JW Jr. Multinucleate cell immunohistochemical studies may be useful angiohistiocytoma. Cutis. 1997 Apr;59(4):190-2. 8. Shapiro PE, Nova MP, Rosmarin LA, Halperin AJ. in confirming the diagnosis. Multinucleate cell angiohistiocytoma: a distinct entity diagnosable by clinical and histologic features. J Am Acad Dermatol. 1994 Mar;30(3):417-22. Immunohistochemistry 9. Sass U, Noel JC, André J, Simonart T. Multinucleate cell angiohistiocytoma: report of two cases with no evidence of human herpesvirus-8 infection. J Cutan Pathol. 2000 Table 4 is a summary of the May;27(5):258-61. 10. Aloi F, Solaroli C, Tomasini C, Pippione M. Multinucleate immunohistochemical studies of MCAH cell angiohistiocytoma: a report of two cases. J Eur Acad reported in the literature. The multinucleated Dermatol Venereol. 1998 Jul;11(1):51-54. Figure 2. Increased numbers of thin, 11. Bader RS, Telang GH, Vonderheid EC. Multinucleate-cell ectatic blood vessels in the mid to upper cells were positive for vimentin5,6,7.,17.,20,21,23,24 angiohistiocytoma occurring in a patient with mycosis fungoides. Cutis. 1999 Mar;63(3):145-8. dermis. H&E original magnification 2x. and more variably positive for factor 12. Chang SN, Kim HS, Kim SC, Yang WI. Generalized XIIIa,3,5,9,13,23 CD689,12,20 and factor VIII,7.,23 multinucleate cell angiohistiocytoma. J Am Acad Dermatol. 7.,9 9,20,23 1996 Aug;35(2 Pt 2):320-2. but were negative for CD34, MAC 387., 13. Cribier B, Gambini C, Rainero M, Grosshans E. 23 7.,9,20 9 9 Multinucleate cell angiohistiocytoma. A review and report BMA 120, S100, CD31, and BCl-2. of four cases. Acta Derm Venereol. 1995 Sep;75(5):337-9. The endothelial cells stained positive 14. Duncan LM, Baden HP. Vascular papules on the dorsum of 20 24 20,24 the hands. Multinucleate cell angiohistiocytoma (MCAH). for vimentin, CD31, CD34, factor Arch Dermatol. 1996 Jun;132(6):703, 706. VIII,6,20,23 BMA 120,23 and occasionally factor 15. Issa AA, Lui H, Shapiro J, Trotter MJ. Plaque-type 5,17. 23 multinucleate cell angiohistiocytoma. J Cutan Med Surg. XIIIa, but were negative for lysozyme. 1998 Oct;3(2):112-4. Mononuclear interstitial cells were positive 16. Jaconelli L, Kanitakis J, Ktiouet S, Faure M. Multinucleate 20 20,24 20,24 Cell Angiohistiocytoma: Report of three new cases and for factor XIIIa, vimentin, CD68, and literature review. Dermatology Online Journal 2009, 15(2):4 MAC 387.,20 but were negative for S100.20 17. Jones AC, Mullins D, Jimenez F. Multinucleate cell malchiodi, richey, parks, nelson, LaCasse 35 Table 1. Reported Location of Individual Lesions (n=83) % of Total Lower Extremity (n=39) 46.99 Thigh (n=16) 19.28 Knee (n=11) 13.25 Calf/leg (n=12) 14.46 Upper Extremity (n=28) 33.73 Arm/forearm (n=2) 2.41 Hands/wrists (n=26) 31.32 Head (n=10) 12.05 Face (n=5) 6.02 Eyelid (n=2) 2.41 Upper lip (n=1) 1.20 Figure 3. Slightly thickened collagen bun- Orbit (n=1) 1.20 dles arranged haphazardly or parallel to the epidermis. H&E stain, magnification 10x. Oral mucosa (n=1) 1.20 Trunk (n=5) 6.02 Generalized (n=1) 1.20

Table 2. Reported Lesion Characteristics % of Group Total Size (n=54) 1-10 mm (n=46) 85.19 11-40 mm (n=5) 9.26 40-120 mm (n=3) 5.55 # of Lesions per Patient (n=45) Solitary (n=5) 11.11 Multiple (n=40) 88.89 Symmetry (n=43) Unilateral (n=26) 60.46 Bilateral (n=16) 37.21 Figure 4. Plump endothelial cells lining the vessels, lacking atypia. H&E stain, magni- Central (n=1) 2.33 fication 10x. Symptoms (n=27) Asymptomatic (n=22) 81.48 Pruritic (n=5) 18.51

Table 3. Resolution by Treatment Modality (n=24) % of treated group Excision (5/5) 100 CO2 Laser (2/2) 100 Cryosurgery (1/1) 100 Argon Laser (2/3) 66.67 Observation (1/11) 9.09 Nitrogen Mustard (0/1) 0 Radiotherapy (0/1) 0

36 multinucleate-cell Angiohistiocytoma: A Unique Case and Literature Review Table 4: Summary of Reported Immunohistochemical Markers

Mast Multinucleate Dendritic Infiltrative Marker Vessels Monocytes Cells Cells Cells Interstitium

CD34 8/8 (100%) 0/3 (0%) Factor VIII 15/15 (100%) 2/3 (67%) Vimentin 6/6 (100%) 11/11 (100%) 25/25 (100%) 1/1 (100%) Factor XIIIa 2/4 (50%) 12/14 (86%) 0/2 (0%) 2/15 (13%) 4/6 (67%) 0/2 (0%) MAC 387 4/4 (100%) 0/11 (0%) Lysozyme 0/2 (0%) 5/7 (71%) 0/2 (0%) 1/8 (13%) 0/2 (0%) 0/2 (0%) CD68 8/8 (100%) 6/16 (38%) 1/1 (100%) BMA 120 3/3 (100%) 0/2 (0%) S100 0/3 (0%) 0/8 (0%) 1/1 (100%) 1/1 (100%) CD31 5/5 (100%) 0/2 (0%) BCL-2 0/2 (0%) 0/2 (0%)

malchiodi, richey, parks, nelson, LaCasse 37 A Case of Calciphylaxis and Review of the Literature

Christine Brooks, MSIV,* Brandon Miner, DO,** Peter Saitta, DO,*** Steven Grekin, DO, FAOCD**** *Michigan State University College of Osteopathic Medicine, Lansing, Michigan **Dermatology Resident, PGY IV, Oakwood Southshore Medical Center, Trenton, Michigan ***Dermatology Resident, PGY II, Oakwood Southshore Medical Center, Trenton, Michigan ****Dermatology Residency Program Director, Oakwood Southshore Medical Center, Trenton, Michigan

Abstract Calciphylaxis is a rare, highly morbid condition characterized by metastatic calcification, thrombosis, and cutaneous ischemia. The syndrome is generally observed in patients with a history of chronic renal failure, renal transplantation, and/or secondary hyperparathyroidism; although cases of calciphylaxis have been described in the absence of such comorbidities. The pathogenesis is largely unknown, but is likely multifactorial, involving genetic, metabolic, and biomolecular factors. Meticulous wound care and effective pain management strategies play an essential role in attenuating the progression of calciphylaxis. We present a case of calciphylaxis cutis and review the literature pertaining to the pathogenesis, diagnostic features, and treatment options for the condition.

Introduction posterior calf (Figure 1). Several painful, arteriolar calcification, vascular stenosis, indurated nodules were palpated both thrombosis, and consequent ischemic cuta- 5 Calciphylaxis is an uncommon condi- proximal and distal to this ulceration. neous necrosis. tion of systemic calcification that often There was no evidence of eczematous or Calcific uremic arteriopathy is consid- results in death secondary to wound infec- infectious changes on either lower extrem- ered the preferred nomenclature for calci- tion, septicemia, and resultant multior- ity. An incisional biopsy was performed, phylaxis that occurs in individuals with a gan failure. It has been purported that an and bacterial cultures were obtained at the history of chronic renal failure, renal trans- time of the visit. plantation, or secondary hyperparathy- elevated calcium-phosphorous product in 6-8 the circulation leads to aberrant deposition The incisional biopsy revealed epi- roidism. One accepted theory maintains of calcium in the vasculature, resulting in dermal ulceration with mild interstitial that in such patients, the dysregulation of severe cutaneous manifestations. Most dermal inflammation and focal deposition calcium homeostasis results in an elevated often, patients with end-stage renal dis- of calcium in the subcutaneous adipose tis- calcium-phosphorous product, leading to ease have a propensity for developing the sue as well as around small vessels (Figures microvascular occlusive phenomena and disease. Much has been written about the 2-4). The bacterial culture was positive for target organ damage. A calcium-phospho- effects of obesity, diabetes mellitus, and aerobic growth of normal skin flora but rous product >7.0 mg2/dL2 is considered excluded staphylococcus, streptococcus, highly predictive of metastatic calcification.2, anticoagulant usage on increasing the risk 9 of being diagnosed with calciphylaxis. In and pseudomonal agents. As many as 1% to 4% of patients with a the presence of these conditions, cutane- The constellation of clinical and path- history of peritoneal or hemodialysis are ous abnormalities should be viewed with a ological features confirmed the diagnosis affected by calcific uremic arteriopathy of calciphylaxis. The patient was initially owing to intravascular microcalcification high degree of suspicion. 10-12 Lesions of calciphylaxis are usually instructed to continue antibiotic and pain and other less-understood mechanisms. described as painful, rapidly progressive, management as prescribed by the emer- A number of studies have been pub- gency room. In addition, we started the lished in recent years that emphasize the ischemic plaques on the distal extremi- 13, 14 ties. It is not uncommon for the lesions patient on a compound of topical mometa- prevalence of non-uremic calciphylaxis. to evolve into ulcerative and gangrenous sone 0.1% ointment, Garamycin ointment, Patients in this subgroup often have a med- wounds over time. The diagnosis is made and Biafine topical emulsion to be used ical history significant for primary hyper- based on clinical suspicion, histopathologic twice daily. The patient was instructed parathyroidism, connective-tissue disease, to apply topical lidocaine 5% ointment liver cirrhosis, or malignancy.15 As many as evaluation of affected tissue, and corre- 16 lation with laboratory and radiographic nightly as needed for break-through pain, 61% report corticosteroid use. The mea- findings. The prognosis for patients diag- and to hold vitamin and calcium supple- sured calcium-phosphorous product in this nosed with calciphylaxis is generally poor, mentation. Renal and wound-care consul- patient population is within normal limits, notwithstanding aggressive medical and tations were requested. and the individuals do not show signs of deteriorating renal function. However, the surgical management. Discussion cutaneous manifestations are equivalent to those noted in calcific uremic arteriopathy. Case Report Although the clinical symptoms of A multitude of medical conditions are calciphylaxis have been reported since the known to increase the risk of developing A 59-year-old African American late 1800s, the pathogenesis of the disorder calciphylaxis, including obesity, diabetes woman presented with a three-week his- remains elusive.1-3 Selye and colleagues mellitus, malignancy, liver disease, hyper- tory of a non-healing, painful “bruise” on phosphatemia, hypercalcemia, and hypervi- utilized a rodent model to illustrate the 17.-19 her right calf. The pain was intensely sharp cutaneous manifestations of calciphylaxis taminosis D. Warfarin anticoagulation and remained localized to the area of the in 1962. They described a systemic hyper- and immunosuppressant-agent usage have “bruise.” The patient denied any previ- also been implicated in the pathogenesis sensitivity process in which subcutaneous 20 ous trauma to the area. A venous ultra- tissue calcification was the primary out- of calciphylaxis. It is also hypothesized sound of the leg, taken one day prior in the come. Rodents were injected with para- that protein C and S deficiencies, which emergency room, was negative for venous elicit thrombosis, play a role in the patho- thyroid hormone or vitamin D in order to 21,22 thromboses. Her past medical history was induce systemic hypercalcemia and were genesis of the condition. In most cases, significant for chronic renal failure. The then exposed to certain challenging agents increased risk is noted in patients with cir- patient was taking two tablets of acetamin- including egg albumin, metallic salt, or culatory disease or coagulopathy. ophen/hydrocodone 500/5 every 2 hours tissue trauma. The rats subsequently expe- Compelling evidence for increased and doxycycline 100mg twice daily, both of rienced extravascular calcinosis, inflam- risk of calcification by molecular mecha- which were given to her at the emergency matory sequela, and sclerosis.4 It was later nisms exists in the literature. The tran- room visit. postulated that the phenomenon observed scription factor NFκB, the receptor Physical examination revealed a 2.3 in rodents approximates systemic calcifica- activator of NFκB (RANK), RANK-ligand, cm, exquisitely tender stellate ulcer with tion in human disease. Salient features of and osteoprotegerin are critical regulatory a surrounding purpuric rim on the right calciphylaxis in human patients consist of factors in bone mineralization and reab- 38 a Case of Calciphylaxis and Review of the Literature sorption.2 Altered activity of these essential findings allow one to diagnose the condition 12. Coates T, Kirkland GS, Dymock RB, Murphy BF, Brealey JK, Mathew TH et al. Cutaneous necrosis from calcific mediators can result in systemic vascular with confidence. uremic arteriolopathy. Am J Kidney Dis 1998;32:384-91. 13. Pollock B, Cunliffe WJ , Merchant WJ. Calciphylaxis in the calcification. Additionally, fetuin-A has All patients presenting with a potential absence of renal failure. Clin Exp Dermatol 2000;25:389- been recognized as an inhibitor of systemic diagnosis of calciphylaxis must undergo an 92. 14. Zechlinski JJ , Angel JR. Calciphylaxis in the absence of calcification, and patients with chronic extensive work-up including laboratory and renal disease: secondary hyperparathyroidism and sys- inflammatory disease or a history of dialysis imaging studies. Elevated levels of parathy- temic lupus erythematosus. J Rheumatol 2009;36:2370-1. 15. Kalajian AH, Malhotra PS, Callen JP , Parker LP. Calci- have markedly decreased circulating lev- roid hormone, calcium, phosphate, calcium- phylaxis with normal renal and parathyroid function: not as els of the protein. This could lead one to phosphorous product, alkaline phosphatase, rare as previously believed. Arch Dermatol 2009;145:451- 8. believe that in the absence of functional lev- urea, and creatinine are consistent with cal- 16. Nigwekar SU, Wolf M, Sterns RH , Hix JK. Calciphylaxis from nonuremic causes: a systematic review. Clin J Am els of fetuin-A, the probability of developing ciphylaxis, but not specific for the diagno- Soc Nephrol 2008;3:1139-43. calciphylaxis may be elevated.23-25 sis.6,38,39 Leukocytosis and anemia may also 17. Ahmed S, O’Neill KD, Hood AF, Evan AP , Moe SM. Calciphylaxis is associated with hyperphosphatemia and It is likely that calciphylaxis is the result be detected. The most specific radiographic increased osteopontin expression by vascular smooth of a multifactorial process in predisposed finding found on soft-tissue X-ray and com- muscle cells. Am J Kidney Dis 2001;37:1267-76. 18. Mazhar AR, Johnson RJ, Gillen D, Stivelman JC, Ryan individuals in which cumulative insults lead puted tomography is small-vessel calcifica- MJ, Davis CL et al. Risk factors and mortality associated to clinical manifestations. Although any tion within the dermis and subcutaneous with calciphylaxis in end-stage renal disease. Kidney Int 40 2001;60:324-32. age group may be affected, the median age tissue. Digital mammography is a novel 19. Hussein MR, Ali HO, Abdulwahed SR, Argoby Y , Tobeigei FH. Calciphylaxis cutis: a case report and review of litera- at presentation is 48 years, and the disease technique being utilized in the diagnosis of ture. Exp Mol Pathol 2009;86:134-5. has a 3:1 prevalence in women.6, 26 Cauca- calciphylaxis, and studies show that arte- 20. Brewster U. Dermatological disease in patients with CKD. Am J Kidney Dis 2008;51:331-44 sians represent the majority of individuals riolar calcification can be determined with 21. Goli AK, Goli SA, Shah LS, Byrd RP, Jr. , Roy TM. Calci- affected by the disease. greater sensitivity on mammography than phylaxis: a rare association with alcoholic cirrhosis. Are 41 deficiencies in protein C and S the cause? South Med J Patients with calciphylaxis typically with plain films or CT. Bone scintigraphy 2005;98:736-9. 22. 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Lowry LR, Tschen JA, Wolf JE , Yen A. Calcifying pan- been reported in a large number of cases, with subtotal or total parathyroidectomy in the niculitis and systemic calciphylaxis in an end-stage renal exceedingly poor prognostic outcomes.31, 32 management of calciphylaxis is controver- patient. Cutis 1993;51:245-7. 48-50 37. Au S , Crawford RI. Three-dimensional analysis of a calci- Histopathologic evaluation of punch and sial. Therapeutic benefit following sur- phylaxis plaque: clues to pathogenesis. J Am Acad Derma- incisional biopsy specimens of affected tissue gery has been demonstrated in patients with tol 2002;47:53-7. 38. Senturk S, HoSnuter M, Tosun Z , Savaci N. Calciphylaxis: reveals several hallmark features of calciphy- calciphylaxis secondary to uremia or renal cutaneous necrosis in chronic renal failure. Ann Plast Surg 51 2002;48:104-5. laxis. Circumferential small- and medium- transplantation. Despite advances in the 39. Wang KL, Li SY, Huang CH , Chen JY. Calciphylaxis. Kid- vessel calcification, ischemic epidermolysis, management of calciphylaxis, the progno- ney Int 2006;70:1196. 40. Trent JT , Kirsner RS. Calciphylaxis: diagnosis and treat- and subintimal hyperplasia and fibrosis are sis for patients diagnosed with the disease ment. Adv Skin Wound Care 2001;14:309-12. classic findings.30,33 Microthrombi within the 41. Bleibel W, Hazar B , Herman R. A case report comparing remains poor. various radiological tests in the diagnosis of calcific uremic dermis and subcutis and inflammatory infil- arteriolopathy. Am J Kidney Dis 2006;48:659-61. trates are also often noted on histopathology. 42. Norris B, Vaysman V , Line BR. Bone scintigraphy of cal- References ciphylaxis: a syndrome of vascular calcification and skin Another predominant feature of calciphylaxis necrosis. Clin Nucl Med 2005;30:725-7. 34-36 43. Bardsley S, Coutts R , Wilson C. Calciphylaxis and its sur- is panniculitis of the septal or lobular type. 1. Fischer AH , Morris DJ. Pathogenesis of calciphylaxis: gical significance. ANZ J Surg 2005;75:356-9. Au and Crawford examined an intact plaque study of three cases with literature review. Hum Pathol 44. Dean SM , Werman H. Calciphylaxis: a favorable outcome 1995;26:1055-64. with hyperbaric oxygen. Vasc Med 1998;3:115-20. of calciphylaxis and found that medial-vessel 2. Weenig RH. Pathogenesis of calciphylaxis: Hans Selye to 45. Podymow T, Wherrett C , Burns KD. Hyperbaric oxygen in calcification was universal across the plaque nuclear factor kappa-B. J Am Acad Dermatol 2008;58:458- the treatment of calciphylaxis: a case series. Nephrol Dial 71. Transplant 2001;16:2176-80. and largely represents the earliest manifesta- 3. Dustagheer S , Khan K. Calciphylaxis - a multifaceted 46. Monney P, Nguyen QV, Perroud H , Descombes E. Rapid 37. entity. J Plast Reconstr Aesthet Surg 2007;60:1372. improvement of calciphylaxis after intravenous pamidro- tion of disease. 4. Selye H. Calciphylaxis. Chicago: The University of Chicago nate therapy in a patient with chronic renal failure. Nephrol A comprehensive list of differential Press; 1962. Dial Transplant 2004;19:2130-2. 5. Weenig RH, Sewell LD, Davis MD, McCarthy JT , Pittelkow 47. Min H, Morony S, Sarosi I, Dunstan CR, Capparelli C, diagnoses for calciphylaxis should include MR. Calciphylaxis: natural history, risk factor analysis, and Scully S et al. Osteoprotegerin reverses osteoporosis by bullous pemphigoid, lupus erythemato- outcome. J Am Acad Dermatol 2007;56:569-79. inhibiting endosteal osteoclasts and prevents vascular 6. Dauden E , Onate MJ. Calciphylaxis. Dermatol Clin calcification by blocking a process resembling osteoclasto- sus, pyoderma gangrenosum, erythema 2008;26:557-68, ix. genesis. J Exp Med 2000;192:463-74. nodosum, polyarteritis nodosa, mixed 7. Brewster UC , Perazella MA. Calcific uremic arteriolopathy 48. Kriskovich MD, Holman JM , Haller JR. Calciphylaxis: in a transplanted kidney. Am J Med Sci 2005;329:102-3. is there a role for parathyroidectomy? Laryngoscope connective-tissue disease, scleroderma, and 8. Hanvesakul R, Silva MA, Hejmadi R, Mellor S, Ready AR, 2000;110:603-7. 38 Cockwell P et al. Calciphylaxis following kidney transplan- 49. Khafif RA, DeLima C, Silverberg A , Frankel R. Calciphy- Wegener’s granulomatosis. The lesions of tation: a case report. J Med Case Reports 2009;3:9297. laxis and systemic calcinosis. Collective review. Arch Intern calciphylaxis may resemble the cutaneous 9. Levin NW , Hoenich NA. Consequences of hyperphos- Med 1990;150:956-9. phatemia and elevated levels of the calcium-phosphorus 50. Gipstein RM, Coburn JW, Adams DA, Lee DB, Parsa KP, manifestations of cold-agglutination, vessel product in dialysis patients. Curr Opin Nephrol Hypertens Sellers A et al. Calciphylaxis in man. A syndrome of tis- 2001;10:563-8. sue necrosis and vascular calcification in 11 patients with invasive disease, embolization, coagulopa- 10. Angelis M, Wong LL, Myers SA , Wong LM. Calciphylaxis 15 chronic renal failure. Arch Intern Med 1976;136:1273-80. thy, and Degos disease. Several differential in patients on hemodialysis: a prevalence study. Surgery 51. Bahar G, Mimouni D, Feinmesser M, David M, Pop- 1997;122:1083-9; discussion 9-90. ovzer A , Feinmesser R. Subtotal parathyroidectomy: a diagnoses have clinical heterogeneity with 11. Fine A , Zacharias J. Calciphylaxis is usually non-ulcer- possible treatment for calciphylaxis. Ear Nose Throat J calciphylaxis, but specific histopathologic ating: risk factors, outcome and therapy. Kidney Int 2003;82:390-3. 2002;61:2210-7.

Brooks, Miner, Saitta, Grekin 39 Figure 1 Figure 3

Figure 2 Figure 4

40 a Case of Calciphylaxis and Review of the Literature AD 3-1 Discoverthe ZIANA® E e cit t

ZIANA Gel is indicated for the topical treatment of acne vulgaris in patients 12 years or older. Important Safety Information for ZIANA Gel • Th e most commonly reported adverse events were nasopharyngitis, pharyngolaryngeal pain, dry skin, cough, and sinusitis. • Diarrhea, bloody diarrhea, and colitis (including pseudomembranous colitis) have been reported with the use of topical clindamycin. ZIANA Gel should be discontinued if signiﬁ cant diarrhea occurs. Systemic absorption of clindamycin has been demonstrated following topical use of this product. • If a reaction suggesting sensitivity or chemical irritation occurs, use of the medication should be discontinued. • Avoid exposure to sunlight and sunlamps. Patients with sunburn should not use the product. Use with caution in patients who require considerable sun exposure due to occupation or who are inherently sensitive to the sun. Avoid excessive exposure to the sun, cold, and wind, which can irritate skin. Daily use of sunscreen and protective clothing are recommended. • Keep away from eyes, mouth, angles of nose, and mucous membranes. • Th is drug is contraindicated in patients with regional enteritis, ulcerative colitis, or history of antibiotic-associated colitis. • Concomitant use of topical medications with a strong drying eﬀ ect can increase skin irritation. Use with caution.

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

ZIANA is a registered trademark of Medicis Pharmaceutical Corporation. ZNA 09-026AR 12/30/11 BRIEF SUMMARY DRUG InTERACTIonS (see package insert for Full Prescribing Information) Concomitant Topical Medication concomitant topical medication, medicated or abrasive soaps and cleansers, soaps and cosmetics that have a strong drying effect, and products with high concentrations of alcohol, astringents, spices or lime should be used with caution. When used with Ziana® Gel, there may be increased skin irritation. Erythromycin Ziana® Gel should not be used in combination with erythromycin-containing products due to its clindamycin component. In vitro studies have shown antagonism between these two antimicrobials. the clinical significance of this in vitro antagonism is not known. neuromuscular Blocking Agents clindamycin has been shown to have neuromuscular blocking properties that may enhance the action Rx onlY of other neuromuscular blocking agents. therefore, Ziana® Gel should be used with caution in patients For topical use only receiving such agents.

InDICATIonS AnD USAGE USE In SPECIFIC PoPUlATIonS Ziana® Gel is indicated for the topical treatment of acne vulgaris in patients 12 years or older. Pregnancy pregnancy category c. there are no well-controlled trials in pregnant women treated with Ziana® Gel. ConTRAInDICATIonS Ziana® Gel should be used during pregnancy only if the potential benefit justifies the potential risk to ® ® the fetus. Ziana Gel was tested for maternal and developmental toxicity in new Zealand White rabbits Ziana Gel is contraindicated in patients with regional enteritis, ulcerative colitis, or history of ® antibiotic-associated colitis. with topical doses of 60, 180 and 600 mg/kg/day. Ziana Gel at 600 mg/kg/day (approximately 12 times the recommended clinical dose assuming 100% absorption and based on body surface area WARnInGS AnD PRECAUTIonS comparison) was considered to be the no-observed-adverse-effect level (noael) for maternal and developmental toxicity following dermal administration of Ziana® Gel for two weeks prior to artificial Colitis insemination and continuing until gestation day 18, inclusive. For purposes of comparisons of the animal systemic absorption of clindamycin has been demonstrated following topical use of this product. exposure to human exposure, the recommended clinical dose is defined as 1 g of Ziana® Gel applied Diarrhea, bloody diarrhea, and colitis (including pseudomembranous colitis) have been reported with the daily to a 60 kg person. use of topical clindamycin. When significant diarrhea occurs, Ziana® Gel should be discontinued. Clindamycin severe colitis has occurred following oral or parenteral administration of clindamycin with an onset of up teratology (segment ii) studies using clindamycin were performed orally in rats (up to 600 mg/kg/ to several weeks following cessation of therapy. antiperistaltic agents such as opiates and diphenoxylate day) and mice (up to 100 mg/kg/day) (583 and 49 times amount of clindamycin in the recommended with atropine may prolong and/or worsen severe colitis. severe colitis may result in death. clinical dose based on a body surface area comparison, respectively) or with subcutaneous doses of studies indicate a toxin(s) produced by clostridia is one primary cause of antibiotic-associated colitis. clindamycin up to 180 mg/kg/day (175 and 88 times the amount of clindamycin in the recommended the colitis is usually characterized by severe persistent diarrhea and severe abdominal cramps and may clinical dose based on a body surface area comparison, respectively) revealed no evidence of be associated with the passage of blood and mucus. stool cultures for Clostridium difficile and stool teratogenicity. assay for C. difficile toxin may be helpful diagnostically. Tretinoin Ultraviolet light and Environmental Exposure in oral segment iii studies in rats with tretinoin, decreased survival of neonates and growth retardation exposure to sunlight, including sunlamps, should be avoided during the use of Ziana® Gel, and patients were observed at doses in excess of 2 mg/kg/day (~ 78 times the recommended clinical dose assuming with sunburn should be advised not to use the product until fully recovered because of heightened 100% absorption and based on body surface area comparison). susceptibility to sunlight as a result of the use of tretinoin. patients who may be required to have With widespread use of any drug, a small number of birth defect reports associated temporally considerable sun exposure due to occupation and those with inherent sensitivity to the sun should with the administration of the drug would be expected by chance alone. thirty cases of temporally exercise particular caution. Daily use of sunscreen products and protective apparel (e.g., a hat) are associated congenital malformations have been reported during two decades of clinical use of another recommended. Weather extremes, such as wind or cold, also may be irritating to patients under formulation of topical tretinoin. although no definite pattern of teratogenicity and no causal association treatment with Ziana® Gel. have been established from these cases, 5 of the reports describe the rare birth defect category, holoprosencephaly (defects associated with incomplete midline development of the forebrain). the ADVERSE REACTIonS significance of these spontaneous reports in terms of risk to the fetus is not known. Clinical Studies Experience Because clinical trials are conducted under prescribed conditions, adverse reaction rates observed in Dermal tretinoin has been shown to be fetotoxic in rabbits when administered in doses 40 times the the clinical trial may not reflect the rates observed in practice. the adverse reaction information from recommended human clinical dose based on a body surface area comparison. oral tretinoin has been clinical trials does, however, provide a basis for identifying the adverse reactions that appear to be shown to be fetotoxic in rats when administered in doses 78 times the recommended clinical dose based related to drug use for approximating rates. on a body surface area comparison. the safety data presented in table 1 (below) reflects exposure to Ziana® Gel in 1,853 patients with acne nursing Mothers vulgaris. patients were 12 years and older and were treated once daily for 12 weeks. adverse reactions it is not known whether clindamycin is excreted in human milk following use of Ziana® Gel. However, that were reported in ≥ 1% of patients treated with Ziana® Gel were compared to adverse reactions in orally and parenterally administered clindamycin has been reported to appear in breast milk. Because patients treated with clindamycin phosphate 1.2% in vehicle gel, tretinoin 0.025% in vehicle gel, and the of the potential for serious adverse reactions in nursing infants, a decision should be made whether to vehicle gel alone: discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. it is not known whether tretinoin is excreted in human milk. Because many drugs are excreted in Table 1: Adverse Reactions Reported in at least 1% of Patients Treated human milk, caution should be exercised when Ziana® Gel is administered to a nursing woman. with ZIAnA® Gel: 12-Week Studies ZIAnA® Gel Clindamycin Tretinoin Vehicle Pediatric Use ® n=1853 n=1428 n=846 n=423 safety and effectiveness of Ziana Gel in pediatric patients under the age of 12 have not been n (%) n (%) n (%) n (%) established. patients WitH at least one ar 497 (27) 342 (24) 225 (27) 91 (22) clinical trials of Ziana® Gel included patients 12–17 years of age. nasopharyngitis 65 (4) 64 (5) 16 (2) 5 (1) Geriatric Use pharyngolaryngeal pain 29 (2) 18 (1) 5 (1) 7 (2) clinical studies of Ziana® Gel did not include sufficient numbers of subjects aged 65 and over to Dry skin 23 (1) 7 (1) 3 (<1) 0 (0) determine whether they respond differently from younger subjects. cough 19 (1) 21 (2) 9 (1) 2 (1) Manufactured for: sinusitis 19 (1) 19 (1) 15 (2) 4 (1) Medicis, the Dermatology company note: Formulations used in all treatment arms were in the Ziana® vehicle gel. scottsdale, aZ 85256 cutaneous safety and tolerance evaluations were conducted at each study visit in all of the clinical trials u.s. patents 5,721,275 and 6,387,383 by assessment of erythema, scaling, itching, burning, and stinging: Ziana is a registered trademark of Medicis pharmaceutical corporation. Table 2: ZIAnA® Gel-Treated Patients with local Skin Reactions prescribing information as of october 2008. local Reaction Baseline End of Treatment 300-13B n=1835 n=1614 n (%) n (%) erythema 636 (35) 416 (26) scaling 237 (13) 280 (17) itching 189 (10) 70 (4) Burning 38 (2) 56 (4) stinging 33 (2) 27 (2) at each study visit, application site reactions on a scale of 0 (none), 1 (mild), 2 (moderate), and 3 (severe), and the mean scores were calculated for each of the local skin reactions. in studies 1 and 2, 1277 subjects enrolled with moderate to severe acne, 854 subjects treated with Ziana® Gel and 423 treated with vehicle. analysis over the twelve week period demonstrated that cutaneous irritation scores for erythema, scaling, itching, burning, and stinging peaked at two weeks of therapy, and were slightly higher for the Ziana®-treated group, decreasing thereafter. one open-label 12-month safety study for Ziana® Gel showed a similar adverse reaction profile as seen in the 12-week studies. eighteen out of 442 subjects (4%) reported gastrointestinal symptoms. Multiple Juvenile Xanthogranuloma: An Uncommon Presentation of the Most Common Histiocytosis

Andrea Baratta, DO,* Sourab Choudery, DO,** Suzanne Sirota Rozenberg, DO, FAOCD,*** Marvin S. Watsky, DO, FAOCD**** *2nd-year Dermatology Resident, St. John’s Episcopal Hospital (SJEH), Far Rockaway, NY **Pediatric Dermatology Attending and SJEH Dermatology Residency Faculty, Brooklyn, NY ***Assistant Program Director, SJEH Dermatology Residency, Far Rockaway, NY ****Program Director, SJEH Dermatology Residency, Far Rockaway, NY

Abstract The histiocytoses are a rare group of poorly understood proliferative disorders. After many classification schemes developed over the years, today they are most commonly divided into the Langerhan cell histiocytosis and the non-Langerhan cell histiocytosis, so named for their discovered cell of origin. The following case report is concerning the most common non-Langerhan cell histiocyte proliferation: Juvenile Xanthogranuloma (JXG). Herein we present an uncommon case of multiple JXG in a five month old female. Following the case report we will discuss the history of the disease, its pathophysiology with clinical manifestations and discuss the possible extracutaneous involvement that can occur and how to properly screen for these potential problems. Lastly, we will discuss the histology, differential diagnosis and treatment options when necessary as most cases of JXG are selfresolving.

Case Report Introduction favorable, and is mostly cutaneous and self-limiting except for the very rare 1,9,14 We report a case of a five-month-old The proliferative disorders known systemic JXG. The prevalence of JXG in normal, healthy children is between female, AL, referred to the pediatric der- as the histiocytoses are a group of 2 matologist for the presumed diagnosis of well-known but poorly understood 1% and 2%. One review by Janssen et al. revealed that the median age at diagnosis molloscum contagiosum. AL had no sig- disorders. The variety of names 9 nificant past medical or surgical history. given to these disorders over the years is five months. The first description She lived in Brooklyn, NY, and was born reflects the lack of understanding of JXG was in 1905 by Adamson, who coined the term congenital xanthoma full-term to parents of Italian descent, with regarding their origin. Today it is clear 1,7.,14 no reported prenatal, antenatal or post- that all the histiocytoses are closely multiplex. McDonagh was the first to natal complications. Her immunizations related entities, with Langerhans cell hypothesize on the cellular origin of JXG in 1912 and suggested that the endothelial were up to date. She had no known drug histiocytosis (LCH) representing 9 allergies and was not taking any medica- one group and non-Langerhans cell cell was the source of this lesion. The tions. Her parents reported that the lesions histiocytosis (non-LCH) representing term JXG was offered by Helwig and began to erupt approximately two months another. LCH is now synonymous Hackney in 1954 after discovering the histology of the lesion to be xanthomatous prior to her presenting to us. The first one with histiocytosis X and comprises the 1,9,11 was noted on the upper back, and then formerly known Letterer-Siwe disease, histiocytes and giant cells. Since gradually she developed more on the back, Hand-Schuller-Christian disease, then, it has been determined that JXG is a macrophage disorder with factor XIIIa scalp and flanks. Her parents said she did eosinophilic granuloma and congenital 9 not appear to be disturbed by the erup- self-healing reticulohistiocytosis + dermal dendrocytes. JXG has a male predominance in childhood of 1.5:1 and tion. She was not observed scratching the (Hashimoto-Pritzker disease). Non-LCH 1,9 lesions and did not appear to be bothered histiocytosis is synonymous with non-X has no sex predilection in adulthood. The male-to-female ratio is higher in those in any way. AL seemed happy and was histiocytosis and the primarily cutaneous 7. eating, sleeping and eliminating without and usually self-resolving entities with multiple cutaneous lesions. The majority of cases occur in Caucasians, with difficulty. She had no fever, chills, weight including juvenile xanthogranuloma 1,9,14 loss or other constitutional symptoms. On (JXG), benign cephalic histiocytosis 7.5% presenting in the first year of life. physical exam in our office, in general AL (BCH), giant-cell reticulohistiocytoma, JXG is rare in adults, but when it does was awake, alert and playful. She appeared generalized eruptive histiocytoma, and occur the peak incidence is in the late 20s 1 to early 30s, and adult JXG is less likely to well-developed and well-nourished. Her indeterminate cell histiocytosis. 1,11,14 skin exam revealed multiple discreet, pink- There are three histiocytes of cutane- resolve spontaneously. to-brown papules and nodules distributed ous importance: the Langerhans cell, the It is not known what causes over her posterior scalp, back and flanks. mononuclear cell (aka macrophage) and proliferation of a dermal dendrocyte to The lesions had a firm, rubbery consistency the dermal dendrocyte. All three function form a JXG; however, some authors believe and were non-tender (Figures 1 & 2). The as antigen-presenting cells (APCs) and/or it to be a histiocytic reactive process to an decision was made to do a shave biopsy to have phagocytic capabilities. These cells infectious or traumatic stimulus. There confirm our suspected diagnosis of juve- are hypothesized to arise from a common are two variants of JXG: the small and nile xanthogranuloma (JXG). The pathol- CD34+ progenitor cell within the bone large nodular forms. The small nodular ogy was indeed consistent with JXG and marrow and, depending upon the cytokine form is also known as micronodular demonstrated a diffuse dermal infiltrate milieu, differentiate along two major path- and is the least common of the two of lipid-laden histiocytes, Touton giant ways: CD14+ cells, which can differentiate variants. It presents with multiple pink- cells and an inflammatory infiltrate con- further into tissue macrophages or der- to-red-to-brown, dome-shaped papules sisting mainly of lymphocytes and occa- mal dendritic cells, and CD14- cells, which measuring 2-5mm in diameter that sional eosinophils. Immunohistochemistry become Langerhans cells. eventually turn yellow. The large nodular revealed histiocytes that stained positively form has only one to a few nodules, but for CD68 and factor XIIIa and were CD1a Pathophysiology, they measure 1-2cm in diameter. Some negative (Figures 3 & 4). This pattern con- sources cite a third variety, termed giant History and Clinical xanthogranuloma, which refers to JXG firmed the diagnosis of a non-Langerhans 11 cell histiocytosis and in combination with Manifestations greater than 20mm. One review of 129 the clinical scenario confirmed the diag- patients with JXG revealed that nearly 90% of those patients presented with a nosis of JXG. The patient was referred for JXG represents an abnormal an ophthalmologic exam, and a letter was solitary lesion, whereas multiple cutaneous proliferation of the dermal dendrocyte. 9 sent to her pediatrician recommending an lesions were present in only 1.9% of cases. It is the most common histiocytosis Multiple JXG is extremely rare in adults, evaluation for leukemia. and is fairly common among the non- 1,11,1314 and those reported have been associated LCH. It most often presents in with a hematological malignancy such as infants and children, is prognostically Baratta, Choudery, Rozenberg, watsky 43 leukemia or a monoclonal gammopathy.11 childhood hematologic malignancies Langerhans cells will be positive for CD1a JXG is found on the head, neck and trunk and has a poor prognosis, with a median and S-100, both of which are negative in more often than on the extremities.1,9 Ver y survival of four years.2,6 Suggestive features JXG, and the classic racquet-shaped Birbeck rarely, JXG can be found in the mouth, of JMML include lymphadenopathy, granules are found on electron microscopy typically on the hard palate or lateral aspect hepatosplenomegaly, pallor and skin in the cytoplasm of LCH cells only.1,9 JXG of the tongue.1 Lesions of cutaneous JXG rash.2 The cutaneous signs of JMML must also be distinguished from molloscum may arise at any anatomic site.9 may include JXG, a leukemic infiltrate, contagiosum, which can be excluded usually urticaria, petechiae and purpura reflecting on clinical appearance alone. JXG may also Extracutaneous JXG the underlying thrombocytopenia, or, less resemble a Spitz nevus, keloid, pyogenic commonly, a toxic exanthema consisting granuloma or fibrous histiocytoma, 2,3,6,15 The most common site of of erythematous macules. The all of which can be distinguished by extracutaneous involvement of JXG is the incidence of JMML in patients with NF1 histopathologic examination. 1,4,14 is exceedingly rare and reported to be eye. Ocular JXG is seen in only 0.4% 2 to 0.5% of patients with cutaneous JXG, 1:2,000 to 1:5,000. The incidence of the Treatment triple association of JXG, JMML and NF1 while 40% of patients with ocular JXG will 2 have multiple cutaneous lesions.1,4 The iris is unknown. JXG in the setting of JMML Generally, no treatment is required for is the most common site of involvement and has two features that differ from sporadic cutaneous JXG due to the self-limiting and can lead to hemorrhage into the anterior JXG: The first is that they are more often benign nature of the eruption.1,14 There is a chamber (termed a hyphema), glaucoma multiple, and the second is that the eruption case report of CO2 laser therapy being used 1,4,14 is more frequently papular and confluent on and ultimately blindness. Occasionally, 6 for multiple cutaneous JXG in an adolescent involvement of the iris is subtle and may the scalp and face. Although it is important female that did not spontaneously resolve. not be easily noted unless a slit-lamp to be aware of these associations, most cases This treatment was well tolerated, and five- examination is performed.4 Determining of JXG are confined to the skin and are self- year follow-up revealed no recurrent lesions; whether or not ocular involvement limiting and benign. Lesions usually regress there was, however, some residual scarring.10 will occur is difficult, but the number of within three to six years; however, some Referral to an ophthalmologist may be lesions appears to be an important risk post-inflammatory hyperpigmentation, important to rule out ocular involvement, factor, as all patients reported to have atrophy or anetoderma may remain. which, if present, may require intervention, ocular involvement have also had multiple such as topical corticosteroids for iris lesions cutaneous lesions.4 The second most Histology or excision for limbal lesions.1,14 It is unclear important risk factor is age, as 92% of whether or not routine ophthalmologic patients reported in the literature as having Histologically, there is a well- screening of children with cutaneous JXG ocular involvement with JXG were less than demarcated, dense histiocytic infiltrate in will result in earlier diagnosis and treatment or equal to two years of age.4 Some authors the dermis, the depth of which depends and decreased morbidity, but the consensus believe that ocular involvement occurs on the size of the lesion. Earlier lesions in the literature is that it is prudent to only with the micronodular form of JXG, can be more difficult to identify with their refer these children for a screening exam.4 while other involved viscera is seen more numerous monomorphic histiocytes and Evaluating patients for extracutaneous JXG commonly with the macronodular form.4,8 abundant eosinophilic cytoplasm.1,9 In (other than ocular) is not recommended The lung is the second most common site more mature lesions, the histiocytes begin unless the patient is exhibiting symptoms to of extracutaneous disease, followed by liver, to accumulate lipid in their cytoplasm, suggest its presence.11 In the case of patients CNS, pericardium, testes, ovaries, colon and imparting a foamy or “xanthomatous” with JXG and NF1, it is important to monitor bone, but according to the literature almost appearance, and this allows for easier for the development of JMML.1 Due to the any organ can be involved.10,14 Of the diagnsois.9 Touton giant cells, which have infrequent nature of systemic involvement, reported cases of systemic JXG, spontaneous a wreath-like arrangement of nuclei within there are only isolated case reports of regression occurred in most, and only two them, are a characteristic finding in JXG chemotherapeutic trials, radiation therapy, deaths have been reported to date.1,5 Both but are not diagnostic. Touton giant cells high-dose corticosteroids and cyclosporine, reported deaths due to systemic JXG had are either absent or present in reduced and no optimal treatment guidelines have CNS and hepatic involvement.5,8 numbers in extracutaneous JXG.7. The been established.1,5 Visceral involvement may inflammatory cells consist of lymphocytes, also be safely observed with no treatment Associated Diseases eosinophils and plasma cells scattered until spontaneous involution.1 throughout. Anti-stabilin-1 antibody If patients with JXG also display expression is highly specific for cutaneous References six or more café-au-lait macules (CAM) non-LCH, but the immunohistochemistry more than 5mm in diameter, it should specific to the dermal dendrocyte in JXG 1. Bolognia JL, et al. Dermatology, 2nd edition, Vol. 2, Mosby/ will reveal positivity for vimentin, HAM56, Elsevier, 2003, p 1402-1404. be determined whether they have a 2. Burgdorf W, et al. JXG, NF1 and JMML: Alphabet Soup CD68 and factor XIIIa, with CD1a being or a Clinical Issue? Pediatric Dermatology, Vol. 21, No. 2, family history of neurofibromatosis type 1,9,10,14 2004, p174-176. I (NF1) or if they display other stigmata consistently negative. 3. Cambiaghi S, et al. Juvenile Xanthogranuloma Associated 3 with Neurofibromatosis 1: 14 Patients without Evidence of that fulfill criteria for NF1. CAMs may Hematologic Malignancies. Pediatric Dermatology, Vol. 21 occur independently of NF1; however, (2), 2004, p97-101. Differential Diagnosis 4. Chang MW, et al. The risk of intraocular juvenile the presence of JXG and multiple CAMs xanthogranuloma: Survey of current practices and is considered an excellent marker for Dermoscopy may be a useful, non- assessment of risk. Journal of the American Academy of 3 Dermatology, Mar, 1996, p 445-449. NF1. The association between JXG and invasive tool to help aid in the diagnosis 5. Chantranuwat C. Systemic Form of Juvenile Xanthogranuloma: Report of a Case with Liver and Bone NF1 is well known. The earliest mention of JXG when it is not possible to obtain Marrow Involvement. Pediatric and Developmental in the literature of an association between histology, such as in a small, uncooperative Pathology 7, 2004, p646-648. 12 6. Cooper PH, et al. Association of Juvenile these two entities was in 1937.. It is also child. Dermoscopic characteristics of JXG Xanthogranuloma With Juvenile Myeloid Leukemia. known that patients with NF1 have a include an orange-yellow background Archives of Dermatology, Vol. 120, Mar, 1984, p371-375. 7. Dehner LP. Juvenile Xanthogranulomas in the First much higher risk of developing juvenile coloration with clouds of paler yellow Two Decades of Life. The American Journal of Surgical 13 Pathology, Vol. 27 (5), 2003, p 579-593 myelomonocytic leukemia (JMML), and deposits. Further studies of dermoscopic 8. Flach DB, et al. Juvenile xanthogranuloma with central a so-called “triple association” consisting features of JXG with histologic correlation nervous system lesions. Journal of the American Academy of Dermatology, Vol. 14 (3), Mar 1986, p 405-411. of JXG, NF1 and JMML has been reported are needed. JXG is often mistaken for other 9. Janssen D, et al. Juvenile Xanthogranuloma in Childhood in several patients.1,14 Patients with JXG diagnoses. The most common diagnoses and Adolescence, A Clinicopathologic Study of 129 Patients From the Kiel Pediatric Tumor Registry. American and NF1 should be observed closely for that JXG is mistaken for are LCH and the Journal of Surgical Pathology, Vol. 29, No. 1, January, 1,9 2005, p21-28 the development of JMML as they are non-LCHs. BCH and generalized eruptive 10. Klemke CD, et al. Multiple Juvenile Xanthogranulomas known to have a 20- to 32-fold increased histiocytoma can be distinguished from successfully treated with CO2 laser. JDDG, 2007, 5, p 30-33. risk of developing this type of leukemia JXG by the absence of Touton giant cells 11. Nayak S, et al. Multiple Xanthogranulomas in an compared to patients with NF1 who do on histopathology. LCH can be easily adult. Indian Journal of Dermatology, Venereology and 3,15 Leprology. Vol. 74 (1), 2008, p67-68. not have JXG. JMML makes up 2% of distinguished with immunostains, as 12. Newell GB, et al. Juvenile Xanthogranuloma and

44 multiple Juvenile Xanthogranuloma: An Uncommon Presentation of the Most Common Histiocytosis Neurofibromatosis. Archives of Dermatology, Vol. 107, Feb, 1973 13. Palmer A, Bowling J. Dermoscopic Appearance of Juvenile Xanthogranuloma. Dermatology, 2007; 215: p 256-259. 14. Redbord KP, et al. Multiple Juvenile Xanthogranulomas in a 13-Year-Old. Pediatric Dermatology, Vol. 24, No. 3, 2007, p 238-240. 15. Zvulunov A, et al. Juvenile Xanthogranuloma, Neurofibromatosis, and Juvenile Chronic Myelogenous Leukemia. Archives of Dermatology. Vol 131, Aug, 1995, p904-908.

Figure 1

Figure 2

Figure 3: JXG medium magnification

Figure 4: JXG high magnification

Baratta, Choudery, Rozenberg, watsky 45 Use of Etanercept for patients with severe plaque psoriasis in the setting of advanced solid malignancies

Luis Dehesa, MD,* Magalys Vitiello, MD,** Francisco A. Kerdel, BSc, MBBS*** *Dermatology Resident, University of Miami Hospital/Florida Academic Dermatology Center, Miami, FL **Clinical Dermatology Research Fellow, University of Miami Hospital/Florida Academic Dermatology Center, Miami, FL ***Director of Dermatology Inpatient Service, University of Miami Hospital/Florida Academic Dermatology Center, Miami, FL

Abstract Etanercept is a recombinant human chimeric protein obtained from the fusion of two soluble human TNF receptors (p75) and the constant fraction of human IgG11. It inhibits the activity of TNF by competitively binding to both TNF α and TNF β showing efficacy in the treatment of several inflammatory diseases. It is currently FDA approved for treatment of moderate to severe plaque psoriasis in adults, psoriatic arthritis, rheumatoid arthritis, juvenile idiopathic arthritis, and ankylosing spondylitis. Etanercept as others TNF inhibitor agents had been related to the development of lymphomas and solid malignancies, however, the impact of treatment with Etanercept on the development and course of these malignancies is not fully understood. We report our experience using etanercept safely in two patients with severe psoriasis and advanced solid malignancies. While this approach is not generally recommended, patients with advanced malignancies and severe psoriasis/psoriatic arthritis can be treated with Etanercept with caution.

Introduction week in April of 2006, and in September rheumatoid arthritis, with more than 1.5 of 2007., while on treatment with Enbrel, million patients treated.2 In recent years, Tumor necrosis factor (TNF) is a she developed a hepatocarcinoma, which the indications for use of TNF inhibitors cytokine involved in normal inflammatory required treatment with right hepatic have expanded to include psoriasis and and immune responses. Elevated levels lobectomy. The treatment with etanercept psoriatic arthritis, among other diseases. of TNF are found in involved tissues was stopped, but after six months of only Nevertheless, the current knowledge about and fluids of patients with rheumatoid topical corticosteroids, she developed a the long-term safety of TNF inhibitors is arthritis, psoriatic arthritis, ankylosing severe flare-up of her psoriatic arthritis, mainly derived from observations made spondylitis and plaque psoriasis. which required the restarting of etanercept. in their use in rheumatoid arthritis and Etanercept binds specifically to TNF and Now, after two years of treatment with inflammatory bowel disease. Patients blocks its interaction with cell-surface etanercept, the psoriasis remains stable and with both rheumatoid arthritis and TNF receptors, showing efficacy in the the hepatocarcinoma is in remission. inflammatory bowel disease are often treatment of several inflammatory diseases. treated with a combination of TNF Since tumor necrosis factor (TNF) Case 2 inhibitors and an immunosuppressive agent plays an important role in host defense A 7.1-year-old female with personal (methotrexate, 6 MP, or azathioprine), and tumor-growth control, etanercept, like medical history of psoriasis for 50 years whereas patients with psoriasis are most other TNF inhibitors, has been associated and psoriatic arthritis for 15 years had often treated with TNF inhibitors as with the development of lymphomas and been treated with several drugs including monotherapy. It therefore seems possible solid malignancies as well as an increased methotrexate, cyclosporine, acitretin, that extrapolations regarding the safety risk of serious infections. In several clinical PUVA, narrow-band UVB and topical of TNF inhibitors derived from this trials, compared to control patients, more corticosteroids. A diagnosis of colon combination therapy data may overestimate cases of lymphoma were observed among cancer was made in 1996. At the time, the potential risk of these agents when used patients receiving TNF blockers; however, her psoriasis was being treated with as monotherapy in psoriasis. patients with rheumatoid arthritis and other methotrexate 15 mg weekly. She was The potential risk of lymphoma inflammatory disorders, particularly those treated by surgery (left hemicolectomy) induction by TNF inhibitors is a much- with highly active disease, may be at a higher and chemotherapy. Six years later, debated issue. Existing data from clinical risk for the development of lymphoma. etanercept 50 mg twice a week was trials suggest that patients treated with Therefore, the potential role or impact of prescribed for a severe psoriasis flare-up. etanercept are at an increased risk of She was treated for 18 months, but then developing lymphomas when compared TNF-blocking therapy on the development 3 and course of malignancies is not fully she developed liver metastases. At that to the general population. However, it is understood. We report our experience point, etanercept was stopped and a also known that patients with rheumatoid using etanercept on two patients with severe right hepatic lobectomy was performed, arthritis, inflammatory bowel disease and psoriasis in the setting of advanced solid followed by six cycles of chemotherapy psoriasis are at increased risk of developing (oxaliplatin). However, two months after lymphomas when compared to the general malignancies. The drug did not appear 4,5 to have had any effect on the progression surgery she developed a severe flare-up population. Consequently, the role of of the malignancies, and therefore it may of pustular psoriasis that required etanercept in the possible development prove to be free of complications in this systemic therapy with cyclosporine of lymphomas is still not clear. However, setting. More cases like these are needed to and etanercept to gain control. She had there have been numerous anecdotal cases consider etanercept a safe drug in patients remained on etanercept for three years of lymphomas reported in patients being treated with TNF inhibitors, and some of with underlying malignancies. when she developed new primary colon cancer, which was treated by complete these have resolved after discontinuation colectomy. Three months after surgery she of the drug.6 Therefore, one should Case Report was re-started on etanercept, and after 18 carefully consider the decision to use TNF months of therapy she has good control antagonists in patients with a history of Case 1 of her cutaneous and articular signs malignancy, particularly lymphoma. A 61-year-old female patient with a and symptoms without any evidence of There have also been descriptions 34-year history of psoriasis and psoriatic malignancy recurrence. of melanoma and non-melanoma arthritis had undergone several treatments, skin cancer,7.-11 although it is not clear including methotrexate, PUVA, NBUVB, whether these lesions can be attributed to cyclosporine and infliximab. She also had Discussion psoriasis itself or to treatments received previous history of hypothyroidism and previously, such as phototherapy, TNF inhibitors have been available cyclosporine, or methotrexate.11 chronic hepatitis C. She started treatment for more than 12 years, mostly for with etanercept (Enbrel) 50 mg twice a It is not known whether etanercept inflammatory bowel disease and can influence the development of solid 46 Use of Etanercept for patients with severe plaque psoriasis in the setting of advanced solid malignancies tumors. Prostate, lung, and breast tumors lymphomas in patients with rheumatoid arthritis and in their first-degree relatives. Arthritis Rheum 2003; 48: 963-70. have been described in clinical trials and 5. Gelfand JM, Berlin J, Van Voorhees A, et al. Lymphoma rates are low but increased in patients with psoriasis: post-marketing reports of the use of results from a population-based cohort study in the United etanercept.11,12 However, an important, Kingdom. Arch Dermatol 2003; 139: 1425-9. 6. Brown SL, Greene MH, Gershon SK, et al. Tumor necrosis large observational study of patients with factor antagonist therapy and lymphoma development: rheumatoid arthritis demonstrated no twenty-six cases reported to the Food and Drug Adminis- tration. Arthritis Rheum 2002; 46:3151-8. increased risk of solid cancers in patients 7. Fulchiero GJ Jr, Salvaggio H, Drabick JJ, et al. Eruptive 9 latent metastatic melanomas after initiation of antitumor treated with biologic agents. These findings necrosis factor therapies. J Am Acad Dermatol 2007; contrast with the results of a meta-analysis 56(Suppl):S65-7. 8. Smith KJ, Skelton HG. Rapid onset of cutaneous squa- of rheumatoid arthritis studies examining mous cell carcinoma in patients with rheumatoid arthritis patients treated with adalimumab and alters starting tumor necrosis factor alpha receptor IgG1- Fc fusion complex therapy. J Am Acad Dermatol 2001; infliximab, which revealed an increased risk 45:953-6. of solid cancers.13 9. Wolfe F, Michaud K. Biologic treatment of rheumatoid arthritis and the risk of malignancy: analyses from a large On the other hand, in recent US observational study. Arthritis Rheum 2007; 56:2886-95. 10. Fryrear RS II, Wiggins AK, Sangueza O, et al. Rapid onset clinical trials involving 16 patients with of cutaneous squamous cell carcinoma of the penis in a advanced breast cancer refractory to patient with psoriasis on etanercept therapy [letter]. J Am Acad Dermatol 2004; 51 (6): 1026. conventional therapy and nine patients 11. Gottlieb AB, Leonardi CL, Goffe BS, et al. Etanercept with advanced carcinomas, in which monotherapy in with psoriasis: a summary of safety, based on an integrated multistudy database. J Am Acad Dermatol patients with haematological malignancies 2006 Mar; 54 (3 Suppl. 2): S92-100. 12. Sanchez Carazo JL, Santos LM, Martinez VO. Safety of were excluded, etanercept showed safety etanercept in psoriasis: a critical review. Drug Saf 2006; and biological activity in the treatment 29 (8): 675-85. 13. Bongartz T, Sutton AJ, Sweeting MJ, et al. Anti-TNF anti- of solid malignancies when used as body therapy in rheumatoid arthritis and the risk of serious monotherapy or in combination with other infections and malignancies: systematic review and meta- analysis of rare harmful effects in randomized controlled chemotherapeutic agents on the theoretical trials. JAMA 2006; 295:2275-85. basis that treatment with etanercept reduces 14. Madhusudan S, Foster M, Muthuramalingam SR, et al. A phase II study of etanercept (Enbrel), a tumor necrosis fac- multiple proinflammatory cytokines and tor alpha inhibitor in patients with metastatic breast cancer. Clin Cancer Res. 2004 Oct. 1; 10(19):6528-34. adhesion molecules and decreases cell 15. Nemunaitis J, Senzer N, Sarmiento S, et al. A phase I trial trafficking and angiogenesis.14,15 of intravenous infusion of ONYX-015 and Enbrel in solid tumor patients. Cancer Gene Ther. 2007 Nov.; 14(11):885- In our cases, we used etanercept at a 93. standard dosage for the treatment of severe plaque psoriasis (50 mg twice weekly),2 and it demonstrated efficacy in controlling the signs and symptoms of severe plaque psoriasis and psoriatic arthritis in both patients. No remarkable side effects were shown in our patients apart from mildly pruritic injection site reactions. At this time, cutaneous and articular signs and symptoms are very well controlled in both patients (PASI 2.4 and 3.3, respectively), and their malignancies appear to be in remission. One could argue that patient 2 developed metastases after etanercept. However, the short evolution and successful intervention without recurrence argues against this. The other patient also developed her malignancy while on etanercept. She was, however, hepatitis C positive, which implies an increased risk of liver cancer. In our opinion, taking into account the risk-benefit of the treatment, biologic therapies represent an interesting therapeutic option for patients with severe psoriasis associated with advanced solid malignancies, allowing an improvement in the patients’ quality of life without negative influence in the neoplastic process. In summary, we report our experience using etanercept in two patients with severe psoriasis in the setting of advanced solid malignancies. Etanercept showed efficacy in our cases and, given that both patients are in remission, also safety. More and larger case series are necessary in order to confirm our findings. References

1. Gottlieb AB, Matheson RT, Lowe N, et al. A randomized trial of etanercept as monotherapy for psoriasis. Arch Der- matol 2003; 139:1627-32. 2. Menter A, Gottlieb A, Feldman SR, et al. Guidelines of care for the management of psoriasis and psoriatic arthritis: Section 1. Overview of psoriasis and guidelines of care for the treatment of psoriasis with biologics. J Am Acad Der- matol. 2008 May; 58(5):826-50. 3. Keystone EC. Safety of biological therapies: an update. J Rheumatol 2005; 32 Suppl. 74:8-12. 4. Ekstrom K, Hjalgrim H, Brandt L, et al. Risk of malignant

dehesa, vitiello, kerdel 47 Papular-Purpuric Gloves and Socks Syndrome:

A Case Report and Literature Review

Monica Nafsou, DO,* Patrick Keehan, DO** *Intern, St. Joseph Mercy-Oakland Hospital, Pontiac, MI **Dermatologist, Fort Worth, TX

Abstract Papular Purpuric Gloves and Socks Syndrome (PPGSS) is a self-limited exanthem that appears typically in young adults. The rash is characterized by a painful and pruritic symmetric erythema and edema with papular-purpuric lesions of the hands and feet. A hallmark of the syndrome is a sharp demarcation at the wrists and ankles in a gloves-and-socks distribution. The condition progresses to petechiae and purpura and may develop into vesicles and bullae with skin sloughing. Although there are many infectious causes two-thirds of the cases are due to Parvovirus B19. It is important to recognize this syndrome in order to reassure patients that it is benign and treatment is based on symptomatic relief.

Case Report acanthotic and papillomatous. There Discussion were hypergranulosis and overlying We report the case of a 42-year-old orthokeratotic hyperkeratosis with no focal Papular-purpuric gloves and socks African-American female who initially hyperkeratosis. Within the epidermis, syndrome (PPGSS) is a characteristic presented with “bumps” for two weeks on there were mild spongiosis and foci exanthem, originally described in 1990 by her hands and one week on her feet. The with exocytosis of lymphocytes. In the Harms, Feldmann, and Saurat.1 It is a self- patient described the bumps as tender to superficial dermis, at low power there was limited febrile illness of mostly infectious the touch but non-pruritic. The patient a mild superficial perivascular infiltrate origin that preferentially appears in young also stated that she had been experiencing consisting of lymphocytes (Figure 3). adults, although pediatric and adult cases bilateral hip pain that started at the same The right medial foot biopsy was read as have also been described.1,4,7.,8 Cases of time, as well as feeling very fatigued. Upon mild superficial perivascular lymphocytic PPGSS occur mostly in the late spring further questioning, the patient stated that dermatitis. The epidermis was acanthotic and summer months.1,5,6,8 Two-thirds her symptoms had started shortly after with orthokeratotic hyperkeratosis. Within of the PPGSS cases have been associated visiting her niece who was hospitalized the dermis, there were prominent vessels. with acute parvovirus B19 infection, with mononucleosis. During review of A mild lymphocytic infiltrate was present and the others have been associated with systems, the patient stated that she had in the superficial dermis, around vessels, hepatitis B, cytomegalovirus, Epstein- recently had an upper respiratory infection with focal extension into the epidermis. Barr virus, measles, coxsackievirus B, with sore throat and enlarged lymph A 200x magnification showed some rubella, human herpes virus types 6 and nodes for which she’d been prescribed extravasated red blood cells, corresponding 7., and drug-induced by sulfamethoxazole Augmentin, and the infection had resolved. to petechiae, and subtle interface (Figure and trimethoprim.1,2,3, 6,7.,8 Patients with Physical exam showed a healthy- 4). A PAS stain for fungus was negative for PPGSS are considered infectious when appearing female in no acute distress. both specimens. presenting with the rash.5 The syndrome There was an ovoid papulosquamous New papules continued to erupt on is self-limited and resolves within seven eruption and psoriasiform dermatitis on the patient’s palms and feet for two weeks to 14 days under symptomatic therapy, the patient’s bilateral wrists and ankles after her initial visit (Figure 5). At that accompanied by desquamation and (Figure 1). Furthermore, there were time, additional laboratory evaluation usually without relapse.1,4,7.,8 In cases of purpuric subcutaneous nodules and included HIV-antibody screen, HSV-1 and immunosuppression, however, the illness papules present on the palmar and plantar -2, CMV, parvovirus B19, Rickettsia, and may lead to persistent anemia and pruritus surfaces (Figure 2). VDRL. Laboratory results showed positive and a prolonged duration of skin lesions.5 Our differential diagnosis included IgG antibodies for CMV IgG, parvovirus The rash is clinically characterized by diseases with acral and/or petechial B19, and HSV-1. The rickettsial antibody a painful and pruritic, symmetric erythema skin lesions, including Rocky Mountain and typhus-fever antibody tests were IgG and edema with papular-purpuric lesions spotted fever, meningococcemia, erythema positive, which is suggestive of infection of the hands and feet extending proximally multiforme, syphilis, palmoplantar at some undetermined time or of past with less severity.3,7.,8 A hallmark of the psoriasis, drug-induced exanthems, and infection or early recurrent response to syndrome is a sharp demarcation at the contact dermatitis. Furthermore, we infection. Most significant, the Epstein wrists and ankles in a gloves-and-socks contemplated whether this was a unique Barr virus IgG and IgM antibodies were distribution. The condition gradually presentation of an eruption typically positive, suggesting a recent infection. progresses to petechiae and purpura and associated with adolescents such as When the patient presented may develop into vesicles and bullae with Gianotti–Crosti syndrome, Kawasaki for follow-up to the office, her skin sloughing.3 Involvement of additional syndrome, and hand-foot-mouth disease. papulosquamous eruption was sites, including the cheeks, elbows, knees, Our initial plan was to obtain a CBC desquamating further, but no new papules inner thighs, buttocks, or genitalia and oral with differential, ANA titer, sedimentation were present. Due to the test results and mucosa, has been reported.1,2,3 Normally, rate, and RPR. On follow-up, the blood the patient’s disease history of purpuric the purpuric lesions of PPGSS spare the test results were all within normal papular palmoplantar lesions, her face.6 There have been reports of a PPGSS- limits. At this time it was decided to do diagnosis was consistent with papular- like presentation in patients who also had a 4 mm punch biopsy of the left dorsal purpuric gloves and socks syndrome involvement of the perioral region and the hand and the right medial foot, areas (PPGSS). Her infection with the Epstein chin, known as “acropetechial syndrome.”5,6 where the lesions were active. The Barr virus was responsible for not only The various oral manifestations, which patient was asked to return in 10 days the PPGSS but also the mononucleosis. have been described for more than half to remove the sutures and review the Another component contributing to her of PPGSS patients, include petechiae, pathology reports. The pathology report papulosquamous eruption was the use of erythema and swelling, vesicles, aphthous described the left dorsal hand specimen Augmentin to treat her mononucleosis. ulcers and Koplik spots on the hard and as benign, a mild subacute spongiotic The rash is a common reaction that occurs soft palates and the labial and buccal dermatitis most consistent with a mild when a beta-lactam antibiotic is prescribed mucosa.1,2, 3,4,7. The genital mucosa may be eczematous dermatitis. The microscopic to treat pharyngitis, which was a symptom affected with painful edema, erythema, description stated that the epidermis was masking the mononucleosis diagnosis. and small ulcers, sometimes accompanied

48 papular-Purpuric Gloves and Socks Syndrome: A Case Report and Literature Review by dysuria.1,3,5 Extracutaneous signs syndrome in a mother and daughter. J Am Acad Dermatol. 2003 Jun;48(6):941-4. and symptoms may precede or occur 4. Fruhauf J, et al. Bullous papular-purpuric gloves and socks simultaneously with the skin lesions and syndrome in a 42-year-old female: molecular detection of 3 parvovirus B19 DNA in lesional skin. J Am Acad Dermatol. are usually mild and transient. Systemic 2009 Apr;60(4):691-5. 5. Harel L, et al. Papular purpuric rash due to parvovirus B19 symptoms, such as asthenia, anorexia, low- with distribution on the distal extremities and the face. Clin grade fever, lymphadenopathy, myalgias, Infect Dis. 2002 Dec 15;35(12):1558-61. 6. McNeely M, et al. Generalized petechial eruption induced and arthralgias may accompany the skin by parvovirus B19 infection. J Am Acad Dermatol. 2005 eruption but are generally only mild to May;52:109-13. 4,5 7. James W, et al., eds. Andrews’ Diseases of the Skin: moderate. During the course of infection, Clinical Dermatology: Elsevier Publishing; 2006. laboratory findings include leukopenia, 8. Bolognia J, et al. Dermatology: Mosby; 2003. anemia, thrombocytopenia and elevated liver enzyme levels.2,3,4,7. The erythrocyte sedimentation rate and C-reactive protein level are infrequently increased.5 The pathogenetic pattern and Figure 4 subsequent clinical presentation may be the result of a complex interplay of the host’s humoral and/or cellular response, viral load, and even co-infection with another virus.6 Direct immunofluorescence analysis of skin biopsy specimens reveals granular deposition of IgM antibody and C3 in the walls of the papillary dermal vessels, suggesting a vascular reaction to an antigenic stimulus.5,6 The Figure 1 histopathologic findings include slight acanthosis, predominantly CD3/CD30 lymphocytic perivascular and interstitial inflammatory infiltrate of lymphocytes with Figure 5 some neutrophils and eosinophils in the papillary dermis, edema in the papillary and reticular dermis, extravasation of erythrocytes, lymphocytic exocytosis with necrosis of basal keratinocytes, and vacuolar degeneration of the basal layer of the epidermis with a lichenoid inflammatory infiltrate.1,3,4,5,7.,8 Focal vasculitic changes with fibrin deposition in the vessel walls, thrombi, nuclear dust, and hemorrhages can also be observed.4 Although not Figure 2 pathognomonic for PPGSS, these findings are consistent with a virus-induced rash.4 The causative agent can be confirmed by serologic analysis. It may also be confirmed by ELISA or PCR analysis for DNA in the serum and in cutaneous biopsy specimens.1,2,4 Many patients have immunoglobulin M and immunoglobulin G antibodies to the causative agent, which can be detected from lesional skin with the use of PCR. The observation of seroconversion from negative for antibodies on admission analysis to positive for both immunoglobulin M and immunoglobulin G antibodies later in the disease process has been reported in several cases.1,3 Figure 3 PPGSS is a benign eruption that can mimic other acral skin lesions. PPGSS is distinguishable by a sharp demarcation at the wrists and ankles of a painful and pruritic, symmetric erythema and edema with papular-purpuric lesions. The information gleaned from clinical laboratory data in coordination with molecular techniques can help identify the causative agent. It is important to reassure patients that the rash is self-limiting, and treatment is solely based on symptomatic relief. Referecnces

1. Grilli R, et al. Papular-purpuric “gloves and socks” syndrome: polymerase chain reaction demonstration of parvovirus B19 DNA in cutaneous lesions and sera. J Am Acad Dermatol. 1999 Nov;41:793-6. 2. Toyoshima M, et al. Papular-purpuric “gloves and socks” syndrome caused by parvovirus B19 infection in Brazil: a case report. Braz J Infect Dis. 2006 Feb;10(1):62-4. 3. Alfadley A, et al. Papular-purpuric “gloves and socks”

Nafsou, keehan 49 A Case of Kaposi’s Sarcoma

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

Abstract Kaposi’s sarcoma is a vascular neoplasm likely related to a viral infection with human herpes virus 8. Four subtypes exist: classic, African-endemic, AIDS-associated, and iatrogenically induced in immunocompromised individuals. Cutaneous lesions can present as pink to blue-purple patches, plaques or nodules. We present a case of classic Kaposi’s sarcoma in a 70-year-old Caucasian Jewish male.

Case Report developing this form after the age of 50.2 underlying pathology, a watchful waiting The lower extremity is the most common approach may be undertaken, as in the case location, and it can present as red to purple of our patient. A 7.0-year-old white male presented 7. for a routine skin exam without any chief to brown patches, plaques or nodules. complaints. A patch of blue-red discol- Endemic Kaposi’s in Africa is more References oration was noted on the plantar aspect common in males. Seroepidemiological studies have shown horizontal transmis- 1. Alamartine E. Up-to-Date Epidemiological Data and of the right foot extending to the dorsum Better Treatment for Kaposi’s Sarcoma. Transplantation. of the toes. A small focus of similar dis- sion, suggestive of transmission routes 80(12):1656-1657, December 27, 2005. other than sexual.8 Passage from mom 2. Bolognia J, Jorizzo J. Dermatology e-dition, 2nd edition. coloration was also noted on the left foot Mosby Elsevier, 2008. (Figures 1-2). When questioned further, to baby may occur via infected saliva in 3. Iscovich J, Boffetta P. Classic Kaposi’s sarcoma in Jews 2 living in Israel, 1961-1989: a population-based incidence the patient denied any history of trauma masticated food. Subtypes of the endemic study. AIDS. 12(15):2067-2072, October 1998. form include nodular, florid, infiltrative 4. Kennedy M, Cooper K. Identification of HHV8 in early or the use of blood thinners. He stated 2 Kaposi’s sarcoma: implications for Kaposi’s sarcoma he was previously evaluated by podiatry and lymphadenopathic. The lymphade- pathogenesis. Molecular Pathology.51(1):14-20, February nopathic type is more common in children 1998. for the discoloration, but he required no 5. Mendez J, Procop G. Relationship Of HHV8 Replication further treatment at that time. The dis- and carries a worse prognosis. and Kaposi’s Sarcoma After Solid Organ Transplantation. Transplantation. 67(8):1200-1201, April 27, 1999. coloration was present for several months The incidence of HIV-associated 6. Monini P, Sgadari C. Clinical course of classic Kaposi’s Kaposi’s has decreased with the advent sarcoma in HIV-negative patients treated with the HIV and was asymptomatic. His medical his- protease inhibitor indinavir. AIDS. 23(4):534-538, Febru- tory was significant for Parkinson’s disease, of HAART therapy; however, it remains ary 20, 2009. one of the most common tumors in HIV- 7. Rapini R. Textbook of Practical Dermatopathology. Mosby hypertension, and non-insulin-dependent 6,8 Elsevier, 2005 diabetes. A punch biopsy of a representa- infected patients. 8. Stebbing J, Portsmouth S. Insights into the molecular In immunosuppressed patients, such as biology and sero-epidemiology of Kaposi’s sarcoma. Cur- tive area was sent to pathology. The differ- rent Opinion in Infectious Diseases. 16(1):25-31, Febru- ential diagnosis included Kaposi’s sarcoma, organ-transplant patients, it has been shown ary 2003. pseudo-Kaposi’s, trauma-induced bruising, that HHV-8 can reactivate after transplanta- and senile purpura. tion, and replication of the virus increases significantly.5 The lesions have also been shown to regress after discontinuation of Histopathology the immunosuppressive agent.3 H and E staining revealed slit-like vascular spaces lined with spindled endothe- Histopathology lial cells in the dermis and extravasated red blood cells (Figures 3-5). A diagnosis of On histology, lesions of Kaposi’s sar- Kaposi’s sarcoma was made. coma display slit-like vascular spaces with The patient was tested and found to be spindled epithelial cells in early patch lesions. HIV negative. He was referred to oncology In older lesions, dilated blood vessels may for further treatment and elected to be fol- predominate with extravasated red blood lowed closely by observation. The possible cells. Promontory sign, the stroma of blood use of sirolimus was discussed if he devel- vessels projecting into the vascular space, oped progressive disease. may be present. Stains for CD31, CD34 and HHV-8 can be used for confirmation.7. Discussion Treatment Kaposi’s sarcoma (KS) is a chronic disease primarily affecting elderly men of Several treatment options exist and Jewish, Eastern European or Mediterra- should be based on the etiology and stage nean descent.2 Four subtypes have been of the disease. Kaposi’s can be treated described: classic, African-endemic, AIDS- with local destruction with cryotherapy or associated, and iatrogenically induced in topical alitretinoin gel. Other anti-HHV8 immunocompromised individuals. All agents include pegylated liposomal doxo- types are thought to be virally induced by rubicin, paclitaxel or interferon alpha.1 In human herpes virus 8 (HHV8).2, 5 Kennedy some AIDS-related cases, HAART ther- et. al evaluated 16 cases of early Kaposi’s apy may cause regression.2 Treatment in sarcoma for the presence of HHV8 using transplant patients is less well established. PCR. They found 87.% of the cases were Immunosuppressive drugs need to be positive, suggesting HHV8 is the etiological tapered; however, this increases the risk of factor in the pathogenesis of the disease.4 graft rejection.1 The use of sirolimus has Classic KS is more prevalent in men of been shown to be effective in some of these Jewish or Mediterranean descent, with many patients.1 In limited disease without other

50 a Case of Kaposi’s Sarcoma

Figure 1: Sharply demarcated blue-red Figure 4. Medium-power H&E: Slit-like patch vascular spaces and extravasated red blood cells

Figure 2: Blue patches on dorsum of foot Figure 5. High-power H&E: Spindle cells, slit-like vascular spaces and extravasated red blood cells

Figure 3. Low-power H&E

sayed, aleenby 51 Ashy Dermatosis with Novel Homeopathic Treatment Using Enoxaparin: A Case Report and Literature Review

Thomas Singer, D.O.,* Brad Glick, D.O.** *2nd-year Dermatology Resident, Wellington Regional Medical Center/LECOM, West Palm Beach, FL **Program Director, Wellington Regional Medical Center/LECOM, West Palm Beach, FL

Abstract The debate between lichen planus pigmentosus (LPP) and ashy dermatosis (AD) has gone on for decades. Previous authors have made valid points for and against these entities being the same disease. Clinically, LPP and AD present with different morphologies. However, histologically they can be interchangeable on both hematoxylin and eosin (H&E) and direct immunofluorescence (DIF). Factors such as ethnicity, geographic distribution, and effective medications have led to convincing arguments on both sides. Multiple studies and case reports have shown efficacy of low-dose enoxaparin for treating traditional lichen planus. Does the efficacy of enoxaparin for treating AD equate to its inclusion into the disease spectrum of traditional lichen planus? Herein, we present a case of ashy dermatosis effectively treated using homeopathic doses of subcutaneous enoxaparin.

Case Report Discussion of Ashy and other Asians. A retrospective study of 124 patients with LPP also found We present a case of a 48-year- Dermatosis vs. Lichen concomitant traditional lichen planus in 19 patients, further supporting LPP’s old, Columbian-born male with a Planus Pigmentosus 9 one-year history of advancing, slate inclusion into the disease spectrum. grey-blue colored patches with a slightly Ashy dermatosis is characterized In multiple small studies, low-dose erythematous border on his back clinically by blue-grey to ashy colored enoxaparin has been shown to be effective and extremities (Fig. 1&2). Previous patches, sometimes with an active red in treating traditional lichen planus. In treatments included topical tacrolimus border. AD is usually disseminated and T-cell-mediated diseases such as lichen 0.1% ointment BID and clofazimine, is characteristically located on the upper planus, these lymphocytes must traverse without improvement. Upon our initial extremities, trunk and face.1 In contrast, the extracellular matrix. The ability of visit, we obtained two biopsies of the lichen planus pigmentosus lesions are these cells to express heparinase, which leading edge of a patch and sent them typically well-circumscribed, brown- degrades the heparin-sulfate moiety black pruritic patches on the sun-exposed of the proteoglycan matrix, is essential for H&E and DIF. The patient was also 10 treated for acne on his back using benzoyl and flexural areas and can be seen with to this process. Both in vivo and in peroxide 5% wash and clindamycin 1% an erythematous border. On histology, vitro studies have shown that low-dose lotion. Further noted were macules of AD and LPP are both known to have heparin suppressed the expression of post-inflammatory hyperpigmentation at vacuolar change, colloid bodies, melanin T-lymphocyte heparinase activity, leading previous sites of acneiform lesions, as well incontinence, and perivascular or interface to inhibition of T-cell migration and 2 delayed-type hypersensitivity reactions.11 as a Becker’s nevus on the right upper back. lymphocytes. In a clinicopathologic study of 31 patients by Vega et al., it was noted Low-dose, low-molecular-weight heparin H&E: Revealed abundant pigment that in a portion of LPP patients there were administered to mice has shown to inhibit incontinence in the papillary dermis hyperkeratosis/hypergranulosis and/or a experimental T-lymphocyte-mediated with subtle interface changes, lichenoid infiltrate observed on histology,1 disease and allograft rejection.12 Low- focal basal vacuolopathy and few both of which are found in traditional molecular-weight heparin was found to dyskeratotic keratinocytes. lichen planus and supports the theory that inhibit allergic contact dermatitis in DIF: Showed dense linear and shaggy LPP is a related condition. humans, as well.13 fibrin deposits, IgM+ cytoid bodies, and The AD direct immunofluorescence Our effective treatment of ashy was negative for IgG, IgA, C3 and C5-9. is not always positive and does not yield dermatosis with homeopathic enoxaparin Both biopsy findings are consistent information that allows for definitive likely recapitulates its effectiveness in with ashy dermatosis/lichen planus diagnosis. The following phenomena have other T-cell-mediated processes. The lack pigmentosus. Clinically, the lesions were been observed: fibrin deposition at the of pruritus while receiving therapy could most consistent with ashy dermatosis. We dermoepidermal junction, a mixture of correlate to the lack of infiltration by commenced treatment with weekly 30 mg IgM, IgG, IgA and, rarely, complement- lymphocytes and disease activity. The return subcutaneous injections and monitored the positive colloid bodies, thought to be of pruritus when our patient missed his patient every six weeks. due to basal cell apoptosis.3,4,5 The DIF dose also supports this theory. Certainly, At his first follow-up, the AD patches findings of LPP do not allow for definitive it appears that lichen planus pigmentosus, had not progressed, and the erythema diagnosis, either. Convit et al. report that ashy dermatosis, and lichen planus are of the leading edge had faded (Fig the lichenoid variant has similar structural related based upon their histology and the 3&4). In addition, the slate grey-blue and immunofluorescence patterns to AD.6 latter two’s response to low-dose enoxaparin. pigmented patches appeared to have faded However, there is a paucity of exact DIF However, these diseases may only share a into his normal skin tone. The patient results reported for confirmed cases of LPP. T-cell-mediated process that manifests actually missed his 12-week follow-up Similar to both AD and LPP, traditional differently in certain genotypes. Clearly, a and was rescheduled for one week later. lichen planus has a mixed DIF pattern with double-blind, placebo-controlled study Consequently, he missed one injection, possible IgM, IgG, IgA, and C3-positive would help to realize the full potential of and he remarked that he could feel the colloid bodies and fibrin deposition.7. this treatment. In our opinion, low-dose lesions becoming moderately pruritic. The geographic and ethnic enoxaparin represents a safe alternative when Upon examination, there was mild distributions of these diseases also support conventional therapies prove to be ineffective. erythema at the border, but the patches the notion that they are separate entities. remained faded. The patient did not AD has a high incidence in Mexico and References report any bleeding complications or have Latin America, occurring mainly in dark- visible purpuric lesions. He is ultimately 1. Vega M, Waxstein L. Ashy Dermatosis and Lichen skinned people, slightly predominantly Planus Pigmentosus: A Clinicopathologic Study of 31 satisfied with the treatment and continues in women, and favoring development in Cases. Internation Journ of Dermatol. Feb; 21(2)90-4. 8 2. Rapini R. Practical Dermatopathology. China: Mosby, on enoxaparin therapy. the first to third decades. LPP is a fairly 2005. Print. Pg 80 common pigmentation disorder in Indians 3. Person JR, Rogers RS. Ashy Dermatosis. An Apoptotic Disease. Arch of Dermatol. 1981 Nov;117(11):701-4.

52 ashy Dermatosis with Novel Homeopathic Treatment Using Enoxaparin: A Case Report and Literature Review 4. Roustan G, Hospital M, Villegas C, et al. Lichen Planus with Predominant Plasma Cell Infiltrate. Arch of Dermatopathol. 1994;16:311-14. 5. Kontochristopoulos, et al. Erythema Dyschromicum Perstans and Hepatitis C. International Journal of Dermatology. 2008; 40:346-348. 6. Convit J, Piquer-Martin J. Erythema dyschromicum perstans. Int J Dermatol 1989; 28:168-169. 7. Bolognia J. Dermatology. Spain: Mosby, 2008. Print. 159- 170. 8. Navarro Jiminez BR, Sanchez Navarro LM. Dermatosis Cenicienta. Estudio prospective de 23 pacientes, Med Cutan Ibero Lat Am 1988; 16:407-12. 9. Kanwar AJ, et al. A study of 124 patients with Lichen Planus Pigmentosum. Clin Exp Dermatol. 2003 Sep; 28 (5);481-5. 10. Hodak E, et al. Low-dose low molecular weight heparin (enoxaparin) is beneficial in lichen planus: a preliminary report. J Am Acad Dermatol 1998;38:564-8. 11. Naparstek Y, Cohen IR, Fuks Z, Vlodavsky I. Activated T lymphocytes produce a matrix degrading heparin sulfate endoglycosidase. Nature 1984;310:241-3. 12. Lider O, et al. Suppression of experimental autoimmune diseases and prolongation of allograft survival by treatment of animals with low molecular weight heparin. J Clin Invest 1989;83:752-6.

Figure 3 - 12 Weeks

Figure 1 - Before Starting Enoxaparin

Figure 4 - 12 Weeks

Figure 2 - Before Starting Enoxaparin

singer, glick 53 Spitzoid Blue Nevus with Dysplasia: Case Study and Review

Robert A. Norman, DO, MPH, MBA,* Trupal Patel, B.S.** *Associate Professor of Dermatology, Nova Southeastern University, Tampa, FL **Associate, Dermatology Healthcare, Tampa, FL

Abstract A 23-year-old woman presented to our office with a 3mm diameter lesion of 8 months duration on her right chin. There was no history of trauma to the site. She had very fair skin and further inspection of her face and scalp showed no other locations of nevi. Patient had a family history of melanoma (mother). A biopsy of the chin lesion was taken for microscopic diagnosis. She was diagnosed with a Spitzoid Blue Nevus with Dysplasia. Conservative excision of the blue nevus was performed.

Case Report tions, where the prevalence is estimated to rare cases of persistent blue nevi, satellite be 3-5% in adults. They are found in 1-2% lesions may manifest around the original A 23-year-old woman presented to our of Caucasians and are rarely found in dark- excision site. These must be distinguished office with a 3mm-diameter lesion of eight skinned individuals. Blue nevi are uncom- from malignant blue nevus, and re-excision months duration on her right chin. There mon at birth or in the first few years of life, is recommended. with an estimated prevalence of less than 1 was no history of trauma to the site. She had 1 very fair skin, and further inspection of her case per 1,000 population. face and scalp showed no other locations The homogeneous blue pigmentation of nevi. The patient had a family history of is caused by the Tyndall effect, resulting from a dense dermal infiltrate of heav- melanoma (mother). A biopsy of the chin 2 lesion was taken for microscopic diagnosis. ily pigmented dendritic melanocytes. Pathological examination showed a sin- Although the homogeneous blue color is gle combined nevus with unusual features the most classic pattern, peculiar dermo- favoring compound spitzoid blue nevus, with scopic-histopathologic variants of blue moderate dysplastic margins involved. Con- nevi have been described recently, namely servative excision was recommended. blue-blue nevi, black-blue nevi, brown- The patient was counseled on the blue nevi, white-blue nevi and polychro- matic blue nevi.3 Blue color per se is a diagnosis and treatment plan and started on clobetasol propionate ointment 0.05% highly unspecific dermoscopic feature that for psoriatic plaques. On return visit, the can be found in a series of skin tumors, Figure 1 abnormal chin lesion was removed by sur- including nodular melanoma, melanoma metastases or pigmented basal cell car- gical excision. The patient was counseled 4 about melanoma and genetic inheritance cinoma. Blue nevi should be diagnosed patterns and was told to be seen every six upon seeing that there is no history of changes. Nodular melanoma and mela- months for checkup. noma metastases show a history of changes and history of previous melanoma, respec- Discussion tively. The pigmented basal cell carcinoma shows a history of progressive growth. The common blue nevus was first There have been several rare cases of described by Tièche in 1906; before that, cellular blue nevi being associated with similar lesions had been described as chro- malignant melanoma.5 Dr. Rudolf Roth matophoroma and melanofibroma. The notes that malignant change in cellular blue two variants of the blue nevus that are nevi may be heralded by a sudden increase currently diagnosed are the common blue in size and occasionally ulceration.1 This key nevus and cellular blue nevus. feature of malignant growth can be used to Figure 2 The common blue nevus can be seen distinguish common blue nevi from dif- as a macule, plaque, or papule with a flat ferent types of melanoma. However, many References surface that is slightly elevated. It usually melanocytic lesions have been shown to dis- 1. Roth RR, Acker SM. (2009) Blue Nevi. Retrieved from has a gray to bluish-black pigmentation. play various types of coloration and features http://emedicine.medscape.com/article/1056397-over- These lesions commonly occur on the that may be difficult to diagnose. A recent view. 2. Argenziano G, Soyer HP, Ferrara G, et al. Superficial head, pelvis, and upper surfaces of hands study identified differences in the dermo- black network: an additional dermoscopic clue for the diagnosis of pigmented spindle and/or epithelioid cell and feet. The patient described here has an scopic pattern of nevi between individuals nevus. Dermatology 203, 333-335 (2001). uncommon blue nevus on the surface of with a personal history of melanoma and 3. Ferrara G, Soyer HP, Malvehy J, et al. The many faces of 6 blue nevus: a clinicopathologic study. J. Cutan. Pathol.34, her right chin with an irregular shape. a healthy control group. The majority of 543-551 (2007). Nevi are atypical moles. The term patients in this study exhibiting mixed pat- 4. Zalaudek I, Manzo M, Ferrara G, Argenziano G. 10/01/2008; Expert Rev Dermatol. 2008;3(4):477-489. “dysplastic” characterizes nevi that tend to terns of nevi had melanoma, compared to Expert Reviews Ltd. be larger than regular atypical moles. They 5. Lambert WC, Brodkin RH. Nodal and subcutaneous the healthy patients who had simple, uni- cellular blue nevi. A pseudometastasizing pseudomela- also have the features of irregular borders form nevi patterns. Therefore, individuals noma. Arch Dermatol. Mar 1984;120(3):367-70. 6. Lipoff JB, Scope A, Dusza SW, Marghoob AA, Oliveria and mixed colors and may be present in harboring nevi with a complex pattern seem SA, Halpern AC. Complex dermoscopic pattern: a poten- larger numbers. Regular nevi tend to be to be at higher risk of melanoma develop- tial risk marker for melanoma. Br. J. Dermatol. 158, 821- benign, while dysplastic nevi can give rise ment and may require closer surveillance 824 (2008). to malignant melanoma. than individuals with nevi in a uniform The cellular blue nevus has similar pattern.4 Although there is no medical ther- characteristics to the common blue nevus apy for common or cellular nevi, a biopsy but tends to be larger. It can measure any- should be performed on any changing, pig- where from 1cm to 3cm in diameter. Blue mented lesion, and in many cases simple nevi are most common in Asian popula- excision is curative in solitary lesions. In the

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Joanna I. Sadowska, D.O., M.H.S.,* Robert A. Norman, D.O., M.P.H., M.B.A.** *Intern, Largo Medical Center, Largo, Florida **Dermatology Healthcare, LLC, Tampa, Florida

Abstract Etiology of central centrifugal cicatricial alopecia is thought to be multifactorial, ultimately resulting in injury to hair follicles and fibrous restructuring of tissue. Mechanical, chemical, and thermal insults applied chronically to scalp hair may lead to irreversible destruction of pilosebaceous units. Inflammatory damage to both the hair matrix and the follicular stem cells results in progressive scar formation. The environmental impact, personal grooming and hairstyling practices, as well as yet to be elucidated genetic predispositions may play a role in the pathogenesis of this formidable condition.

4.5 cm x 3.2 cm shiny patch of cicatricial and progressively. Patches or tufts of Case Report alopecia to the vertex (crown) region of the normal hair may be evident within the head (Figure 1). zone of atrichia, but once the follicles are History and Clinical Some stranded hairs in an otherwise destroyed, scar tissue develops and hair Presentation denuded vertex of the scalp were does not grow back. CCCA may be the appreciated. No other scalp, cutaneous or most common type of alopecia seen in A 35-year-old African-American oral lesions were discovered. the United States, and although it impacts female presented for a follow-up visit black women primarily, African-American regarding an ongoing case of parietal scalp Histopathology men as well as Caucasians can be affected.1,2 alopecia. Her hair loss had started one Early in the course of the disease, year prior as a “sore” and ulcerating lesion A parietal-scalp tangential patients may experience pruritus, tingling, on the vertex of the scalp. Her condition shave biopsy sample was obtained, tenderness, tightness, and scalp paresthesia. had initially seemed to improve, but and it demonstrated hyperkeratosis, The alopecia occasionally extends to subsequently deteriorated and expanded hypergranulosis, and irregular epidermal the frontal hairline, but the lateral and in the involved area. The patient was now hyperplasia with vertically oriented fibrosis occipital scalp are generally spared.3 complaining of scalp “flaking,” tenderness, in some areas of the papillary dermis. Alopecia can be emotionally and pruritus, which upon further Presence of a perivascular inflammatory devastating, as it bears strongly on self- questioning were linked to her recent hair- infiltrate of lymphocytes and occasional esteem, social interactions and personal styling practices. She was initially treated eosinophils was noted. The lesion was relationships. Correct diagnosis, prevention, with Luxiq 0.12% foam, ketoconazole 2% eroded, and subepidermal fibrosis was and choosing the appropriate line of shampoo, and oral cephalexin. prominent. GMS stain was negative for treatment affects the wellbeing of the patient, Upon her return to the office after regardless of what caused the disorder.1 two weeks, the patient had sustained some fungal organisms. degree of improvement. She felt her scalp was Diagnosis Dermatohistopathology “healing well” and that the medications were effective. At that time, her scalp showed an Central centrifugal cicatricial alopecia (CCCA) Even though CCCA overtly looks almost completely healed site of ulceration, non-inflammatory, dermatohistopathology with no signs of infection noted and some Differential Diagnoses characteristically exposes mononuclear cell infiltration and replacement of hair return of hair growth. The patient was • Alopecia mucinosa instructed to discontinue ketoconazole 2% follicles by fibrosing concentric lamellar • Classic pseudopelade of Brocq columns.3 Additionally, lichenoid shampoo but continue with the Luxiq 0.12% • Dissecting folliculitis (cellulitis) foam applications as prescribed. perifolliculitis with progressive fibrosis and • Erosive pustular dermatosis presence of lymphocytic reactions may The patient returned to the office one • Folliculitis decalvans 2 year later with continued complaints of be evident. Another striking feature of • Folliculitis necrotica CCCA is a premature disintegration of the parietal scalp alopecia. She reported • Lichen planopilaris that during a hairdressing session several the inner portion of follicular infundibula • Neurodermatitis and corresponding sebaceous glands, days prior she had “tight braids taken out” • Prurigo nodularis and hair-relaxing chemicals administered followed by scar tissue formation. Since • Traction alopecia the inflammatory attack commences on the to her hair. At that time, she noticed a • Trichotillomania large amount of hair coming out in upper part of hair follicle, containing stem patches from the crown area of the head, • Tufted folliculitis cells and sebaceous units, the possibility as well as profuse scalp bleeding, which was of hair regeneration is forfeited and Course and Treatment 4,5 somehow curtailed by the hairdresser. The permanent hair loss results. In end-stages patient admitted to itching and drainage Following a discussion of possible of the disease, foreign-body granulomatous reactions occur in the dermis as giant cells following the procedure, resulting in crusty treatment options, Kenalog 10 mg/cc was 1 exudates over the lesion. She also indicated injected intralesionally. The patient was encircle hair infundibula. “rubbing” the area often, but denied any also started on clobetasol 0.05% solution Some studies suggest both scratching. Inspection of the parietal scalp to be applied to the affected scalp area as histopathologic and direct revealed a circular area of hair loss and directed. The treatment plan was reviewed immunofluorescence (DIF) examination limited muco-purulent drainage with good with the patient, and she was instructed to for incontrovertible diagnosis. Nonetheless, traditional histopathology granulation tissue. The patient was given return to the office for follow-up visits. prescriptions consisting of hydroxyzine, evaluation seems to be sufficient in the cephalexin, triamcinolone 0.1% cream, and majority of cases, with increasing utility Discussion of DIF in inconclusive or ambiguous mupirocin 2% cream. instances.6 Furthermore, the combination Clinical Features of CCCA of vertical and transverse tissue segments Physical Examination has optimal diagnostic value. With a The patient came back for a follow-up Central centrifugal cicatricial alopecia single biopsy specimen available, it may visit two weeks later, at which time she (CCCA) occurs predominantly in women be cut either vertically or transversely at reported some improvement with of African descent and begins at the the discretion of the dermatopathologist. treatment. Scalp inspection revealed a vertex of the head, spreading centrifugally Regardless of the directionality chosen Sadowska, Norman 57 by the pathologist, serial step sections are prudent practitioners.11 Even with excellent appealing future frontiers for immuno- needed in order to diminish the danger of tissue sampling and expert interpretation, protective therapies aimed at follicular missing critical histological findings.7.,8 primary cicatricial alopecia variants are stem cells as well as re-establishment of exceedingly difficult to classify, further desired immunosuppresion.16 Differential Diagnosis magnifying the importance of collecting Hair-specific keratins may play 12 Distinguishing CCCA from other forms meticulous patient history. High index of a role in CCCA via disturbing effects of hair loss presents a unique challenge, suspicion should initiate a biopsy at the site on follicular architecture. Structural as all primary cicatricial alopecias share of erythema to establish causative factors, integrity of hair varies with keratin genetic overlapping characteristics.9 An irrefutable often followed by a second biopsy of the polymorphisms or various gene expressions, balding zone, which should demonstrate predisposing certain individuals to hair diagnosis may be elusive both clinically and 10 histologically. CCCA is classified under focal follicular scarring. Otherwise-inevitable breakdown, follicular demise, spillage of hair-loss progression may be curtailed with epithelial debris into the dermal layer, and (patchy or localized) and cicatricial—or 17. scarring—hair loss.2 Diagnostic hallmarks early recognition and treatment of this consequent inflammatory response. A of CCCA at its onset include perifollicular insidious ailment. defective inner root sheath structure that lymphocytic infiltration, inflammatory leads to premature desquamation may pustules, and focal atrichia in the shape of a Pathogenetic Hypotheses be responsible for the pathobiology of circle at the crown. Follicular ostia may be CCCA is a variant of primary cicatricial CCCA. On the molecular level, premature loss of cytokeratin 7.5 (K7.5) is observed diminished or missing in the bald spot. As alopecia, synonymous with follicular 18 the disorder gradually advances, epidermis degeneration syndrome (FDS), sometimes within the follicles. It is evident that atrophies, and follicles are reconstituted by described in the literature under such terms even in the absence of traumatic hair- fibrous scarring.10 In general, other scarring as “hot comb alopecia” and “ethnic variant care practices, some people will be more alopecias also tend to demolish hair follicles, of cicatricial alopecia.” The pathogenesis prone to hair damage and loss simply remodeling them with fibrous scar tissue and of CCCA is not fully understood, but due to the inherently weaker follicular producing permanent deficits in hair density. physically and chemically traumatic hair structures supported by their genetically Selected causes of hair loss may styling techniques are cited as common pre-programmed keratins. CCCA appears be excluded more easily. Androgenetic denominators in the instigation of the to be a complex polygenic affliction shaped alopecia, for example, features a non- condition in most patients.2 Still, it is by an as-of-yet undetermined combination scarring and diffuse hair loss principally uncertain whether the incipient follicular of nature and elusive exogenous factors. affecting the frontal scalp. Moreover, family disruption is intrinsically or extrinsically history of androgenetic alopecia and/ mediated, and whether the progressive Personal Grooming Practices or male-pattern baldness can frequently fibrosis of the reticular dermis is primary or It is clinically relevant to underscore be elicited, and the condition can be secondary to the underlying inflammation. that with alopecias, hair grooming treated with topical minoxidil solution.9 Since the malady is chiefly seen in history is exceedingly more important Similarly, patchy hair loss can be attributed blacks, we will briefly describe some with African-American than with to infections by fungal organisms (tinea pertinent characteristics specific to ethnic Caucasian or Asian patients.13 The capitis) or bacteria, which should be ruled hair. African-American hair is elliptical in American Academy of Dermatology out by culturing any present exudates, shape, tightly coiled, and features spiral— reported in 2004 that alopecia was an examining scalp scrapings, or performing but less dense—hair follicles, which impede epidemic among women of color owing histopathological stains. sebaceous secretions from nourishing hair to tight hairstyles and unforgiving Drug-induced alopecia is quite shafts. Additionally, its low water content chemicals injuring hair shafts and common and mostly associated with and poor tensile strength translate into follicles.19 Approximately 80% of abnormal hair cycling or excessive shedding. dryness, fragility, difficulty in combing, and African-American women in the U.S.A. Telogen effluvium—or temporary increase relative vulnerability to thermal injury.13 use chemical hair relaxing, risking in hair loss—has been attributed to Review of animal models sheds new contact or chemical burns, damaging ACE inhibitors (enalapril), antimitotics light on the etiology of hair loss, particularly tensile strength of hair, and ultimately (colchicine), oral contraceptives, interferon, from the genetic and molecular points leading to CCCA.13,20 Other aggressive anticoagulants, antiparkinsonian agents of view. Mice with sebaceous gland hair-care practices include methods such (levodopa), beta blockers (metoprolol, abnormalities display histopathology as hot comb styling (using heated metal propranolol), psychiatric drugs (lithium, reminiscent of human cicatricial alopecias. and petrolatum), persistent hair tension valproic acid), H2 blockers (cimetidine), Mutated genes code for the stearoyl CoA (tight braids or cornrows, weighty hair and retinoids. Other disturbances may be desaturase-1 (Scd1), a rate-limiting enzyme styles), chemical straighteners with contributory, including endocrine (hypo- in conversion from saturated to mono- alkali-containing compounds, and or hyperthyroidism), nutritional (calorie, unsaturated fatty acids. The absence of chemical color processing.21 One study mineral, or vitamin deprivation), and a gene crucial to lipid reactions leads to reported a solid association between physical or psychological stress (anemia, sebaceous gland ablation, prolonged anagen the use of hair weaving (sewn-in and surgery, illness). Anagen effluvium—or phase, and gradual follicular replacement glued-in hair), cornrows, artificial hair diffuse scalp balding—has been reported by scarring. If sebaceous glands are not extensions, or braided hairstyles and with antineoplastic agents, radiation working properly, the hair follicles are CCCA. Women with this disorder tended therapy, systemic chemotherapy, heavy- obliterated and fibrosed.14 Hypoplastic to relay a history of scalp tenderness metals poisoning (mercury, thallium, boric sebaceous glands under-produce the sebum following hair dressing appointments.22 acid), and severe protein deficiency or that is required for optimal pilosebaceous Trauma to hair follicles leading to malnutrition. Certain autoimmune diseases unit functioning.15 Sebaceous glands chronic dermal inflammation seems to have cutaneous manifestations, notably may prove to be the initial as well as the be paramount in the etiology of CCCA. lupus erythematosus and alopecia areata.2 propagating injury site in the pathogenesis Sufferers frequently remember pain or In solving the diagnostic dilemma of of CCCA. burning of the scalp during or immediately scarring alopecias, a thorough evaluation Cutaneous autoimmunity can after hair styling procedures.1 Nevertheless, and follow-up of the patient must be also be implicated in scarring alopecia even with a cessation of the habitual undertaken. A scalp biopsy is vital, but even pathoetiology. It is postulated that damage, scalp hair loss is slowly progressive more significant is the exact area chosen potent pro-inflammatory triggers destroy in the majority of patients.21 Some for sampling, since it has to be undergoing epithelial hair-follicle stem cells via authors contend that this clinical entity is active disease process rather than in the immune dysregulation. Whether these really a permutation of traction alopecia, final “burnout” stages.1 Histopathological events happen secondary to interferon- or end-stage traction alopecia, caused by results need clinical corroboration; detailed mediated cytotoxicity or loss of follicular irreversible processes related to hair-styling patient demographics as well as descriptions immune privilege remains to be techniques.23 CCCA could be feasibly of the hair loss pattern and surrounding elucidated. Although the veracity of this explained as a final common pathway circumstances should be supplied by theory still hangs in the balance, it offers reciprocating myriad pathologies.

58 Central Centrifugal Cicatricial Alopecia: A Case Presentation and Literature Review confer that abrasive hair grooming practices practices and central centrifugal cicatricial alopecia. J Am Course, Treatment, and Prognosis Acad Dermatol. 2009;60:574-8. are detrimental to hair cells and should 23. Ackerman AB, Walton NW, Jones RE, Charissi C. Hot The course of CCCA is typically 1 be stopped by patients exhibiting CCCA. comb alopecia/follicular degeneration syndrome in African prolonged, and baldness is classically Theoretically, if the rapidly progressive American women is traction alopecia! Dermatopathology: irreversible. The affected individuals may Practical and Conceptual. 2000;6. situation is thwarted in its infancy, the 24. Rook A, et al. Textbook of Dermatology. Edition 4. Oxford: go through periods of relative clinical inflammatory changes could subside, and Blackwell Scientific Publications; 1986:49-50. remission, followed by reactivation and the scalp may be allowed sufficient time and 25. Scott DA. Disorders of the hair and scalp in blacks. exacerbation of the alopecia. Since Dermatologic Clinics. 1988;6:387-395. milieu to self-heal. 26. Whiting DA, Olsen EA. Central centrifugal cicatricial the exact causative agent has yet to be alopecia. Dermatol Ther. 2008;21:268-78. elucidated, management of CCCA is 27. Ross EK, Tan E, Shapiro J. Update on primary cicatricial controversial. Treatment options, anecdotal Conclusion alopecias. Journal of the American Academy of and experimental at best, mainly target Dermatology. 2005;53:1-37. No standardized treatment methods 28. Hassan AS. Surgical treatment of secondary cicatricial inflammatory changes with intralesional alopecia of scalp and eyebrow. Indian J Plast Surg. 2 exist for CCCA, but the use of anti- 2009;42:63-7. as well as topical corticosteroids. When inflammatory and immunomodulating treating with intralesional steroids, central agents is the first line of defense. vertex as well as peripheral injections are Practitioners must advocate non-aggressive advised for several months with hopes hair-care routines among their patients, of stimulating new hair growth once the 19 including minimal use of heat, chemical inflammation has subsided. processing, and decreased hair traction. Anti-inflammatory properties of Hereditary contributors to the oral antibiotics have been exploited with condition remain to be ascertained, but positive results, using a regimen of oral congenital follicular defects, sebaceous tetracycline with topical corticosteroids. gland polymorphisms, and various hair Innovative approaches include topical keratins are all theoretical contenders. immunomodulators such as tacrolimus Further clinical and basic science research (Protopic) and pimecrolimus (Elidel) and should aim to extrapolate causes of the may be especially effective in combating 24 disease as well as define novel directions for early signs of irritation. Antimalarial drug hydroxychloroquine has been tried improved therapeutic modalities. Figure 1. The scalp is shiny, smooth, and on account of its anti-inflammatory flesh-colored, with decreased hair density effects,25 along with oral mycophenolate References at the vertex (crown) region. mofetil and cyclosporine, a calcineurin 1. Scarring Alopecia Index. Scarring alopecia - central inhibitor exerting its action by suppressing centrifugal cicatricial alopecia. Available at: http://www. gene transcription. Topical minoxidil can keratin.com/at/at011.shtml. Accessed July 20, 2009. 2. Johnson RA, Suurmond D, Wolff K. Fitzpatrick’s Color foster hair re-growth as well as nourish Atlas & Synopsis of Clinical Dermatology. 5th ed. New any remaining non-scarred follicles.26 York: McGraw-Hill, 2005:952-1015. Additionally, the Cicatricial Alopecia 3. Sperling LC, Sau P. The follicular degeneration syndrome in black patients: ‘Hot Comb Alopecia’ revisited and Research Foundation describes topical revised. Arch Dermatol. 1992;128:68-74. applications of Derma-Smoothe scalp oil 4. Sullivan JR, Kossard S. Acquired scalp alopecia. Part II. A to the affected areas in the repertoire of review. Australas J Dermatol. 1999;40:61. 21 5. Sperling LC, Solomon AR, Whiting DA. A new look at therapeutic measures. scarring alopecia. Arch Dermatol. 2000;136:235-242. Although termination of chronic 6. Trachsler S, Trueb RM. Value of direct immunofluorescence for differential diagnosis of cicatricial hair trauma may not reverse or even alopecia. Dermatology. 2005;211:98-102. curtail the progression of the underlying 7. Elston DM, Ferringer T, Dalton S, Fillman E, Tyler W. disease process, the use of strong heat, A comparison of vertical versus transverse sections in the evaluation of alopecia biopsy specimens. J Am Acad chemicals, and excessive traction should Dermatol. 2005;53:267-72. 27. be discouraged. Patients may be advised 8. Elston DM, McCollough ML, Angeloni VL. Vertical and to wear hairstyles designed to camouflage transverse sections of alopecia biopsy specimens: combining the two to maximize diagnostic yield. J Am Acad parietal hair loss. Wigs, hair pieces, hats, Dermatol. 1995;32:454-7. and scarves offer useful disguises.9 Hair 9. Woolery-Lloyd H. Central Centrifugal Scarring Alopecia. transplantation or grafting may be Skin & Aging. 2003;11. 10. Olsen EA. The Many Faces of Cicatricial Alopecia. contemplated for purely cosmetic and Dermatology Focus. 2006;25:6. psychological benefits. Surgical excision 11. Sperling LC. Scarring alopecia and the dermatopathologist. J Cutan Pathol. 2001;28:333-42. of the scarred dermis is considered as a 12. Mirmirani P, Willey A, Headington JT, Stenn K, McCalmont last resort, and only if the disease has been TH, Price VH. Primary cicatricial alopecia: histopathologic inactive for a number of years.21 Another findings do not distinguish clinical variants. J Am Acad Dermatol. 2005;52:637-43 surgical procedure that is sometimes feasible 13. Baldwin HE. Ethnic Hair. Dermatology Focus. 2007;26:3-6. is scalp reduction for hair restoration, 14. Sundberg JP, Boggess D, Sundberg BA, Eilertsen K, which involves removal of the hairless Parimoo S, Filippi M, Stenn K. Asebia-2J (Scd1ab2J): A New Allele and a Model for Scarring Alopecia. Am J Pathol. area and direct closure of the defect 2000;156:2067-2075. with hair-bearing scalp. Healthy hair- 15. Stenn KS. Insights from the asebia mouse: a molecular containing scalp can be surgically folded sebaceous gland defect leading to cicatricial alopecia. J Cutan Pathol. 2001;28:445-7. over a bald spot using a technique called an 16. Harries MJ, Meyer KC, Paus R. Hair loss as a advancement flap. Atrichia correction can result of cutaneous autoimmunity: frontiers in the also be accomplished with scalp expanders, immunopathogenesis of primary cicatricial alopecia. Autoimmun Rev. 2009;8:478-83. reduction through serial excisions, and 17. Schweizer J, Langbein L, Rogers MA, Winter H. Hair reconstruction by composite hair-covered follicle-specific keratins and their diseases. Experimental 28 Cell Research. 2007;313:2010-20. scalp grafts. 18. Sperling LC, Hussey S, Sorrells T, Wang JA, Darling T. Recommended hair care products Cytokeratin 75 expression in central, centrifugal, cicatricial and shampoos need to be gentle and non- alopecia - new observations in normal and diseased hair follicles. J Cutan Pathol. 2009 Jul 10. [Epub ahead of irritating to the scalp, with some options print]. 21 available by prescription only. Infrequent 19. Lohr E. Alopecia Nearly Epidemic Among Black Women. shampooing, styling hair with emollient Clinical Psychiatry News. 2004:96. 20. Nicholson AG, Harland CC, Bull RH, Mortimer PS, Cook pomades, air drying rather than blow MG. Chemically induced cosmetic alopecia. Br J Dermatol. drying, and regular removal of split ends 1993;128:537-41. are also advocated to minimize hair damage 21. Cicatricial Alopecia Research Foundation. Available at: 13 http://www.carfintl.org/index.html. Accessed July 20, 2009. and optimize recovery. Some experts 22. Gathers RC, Jankowski M, Eide M, Lim HW. Hair grooming Sadowska, Norman 59 Members of the AOCD may advertise "position available"

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