Aquagenic Syringeal Acrokeratoderma

Home , Cherubism, Ectodermal dysplasia, Keratoderma, Lymphedema, Mastocytoma, Mastocytosis

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

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

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

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

JAOCD David Horowitz, DO, FAOCD Founding Sponsor

Matt Leavitt, DO, FAOCD AOCD • 1501 E. Illinois • Kirksville, MO 63501 Mark Lebwohl, MD 800-449-2623 • FAX: 660-627-2623 www.aocd.org Rick Lin, DO Megan Machuzak, D.O. COPYRIGHT AND PERMISSION: written permission must be obtained from the Journal of the American Osteopathic College of Dermatology Jere Mammino, DO, FAOCD for copying or reprinting text of more than half page, tables or figures. John Minni, DO Permissions are normally granted contingent upon similar permission from the author(s), inclusion of acknowledgement of the original source, Navid Nami, DO and a payment of $15 per page, table or figure of reproduced material. Permission fees are waived for authors wishing to reproduce their own Shaheen Oshtory, DO articles. Request for permission should be directed to JAOCD c/o AOCD John Perrotto, DO PO Box 7525 Kirksville, MO 63501 Copyright 2003 by the Journal of the American Osteopathic College of Stephen Purcell, DO, FAOCD Dermatology Michael Scott, DO, FAOCD Printed by: The Dimensional Group, Mason City, IA 50401 Kevin Spohr, DO Proofreading: Julia Layton, Freelance Proofreading and Editing Journal of the American Osteopathic College of Dermatology Volume 16, number 1 April 2010 Journal of the

AmericAnAOCD OsteOpAthic cOllege Of DermAtOlOgy

Contents

Letter from the JAOCD Editors ...... 4 Letter from the President ...... 5 What Syndrome Is This? Hidrotic Ectodermal Dysplasia: A Case Report and Discussion ...... 6 Paul Aanderud, DO; Chris Buatti, DO; Kimball Silverton, DO Dermatofibrosarcoma Protuberans and Multiple Angiolipomas: A Case Report and Discussion ...... 8 Ali Banki, D.O.; Cindy Hoffman, D.O.; Charles Gropper, MD Scleredema Adultorum of Buschke: A Case Presentation and Literature Review ...... 10 Nicholas A Benner, B.S.; Ramona Sarsama Nixon, D.O.; Mary Beth Luca, D.O., F.A.O.C.D A Sporadic Case of Steatocystoma Multiplex ...... 12 Chris N Buatti, D.O. Carcinoma Ex Pilomatrixoma: a unique histologic presentation and review of the literature ...... 14 Michael R Centilli, M.S., OMS-2; Patricia Moody McNab, M.D.; Michael B Morgan, M.D. Plexiform fibrohistiocytoma in a 13-year-old female: Case report and brief review ...... 16 Helia Eragi, OMS IV; Basile L Amy, DO, MPH; Chris Weyer, DO; Lloyd Cleaver, DO; Michael Morgan, MD To Urticate or Not to Urticate: A Case of TMEP and Review of Cutaneous Mastocytoses ...... 19 Gwyn E Frambach, DO; Charles Gropper, MD; Cindy Hoffman, DO, FAOCD The vexing nature of confluent and reticulated papillomatosis: Two case reports ...... 25 John Hibler, D.O.; John Thomas Hibler, D.O. Aquagenic Syringeal Acrokeratoderma ...... 27 Michelle L Jeffries, D.O.; Justin T Sawyer, M.D.; Stephen E Kessler, D.O. How much dermatology is being taught in our osteopathic medical schools? ...... 31 Aleksandra Glisic, OMS IV; Brent Loftis, D.O.; Bill Way, D.O. Lymphangioma Circumscriptum: A Case Report ...... 35 Andrea Baratta, DO; Andrea Baratta, DO; Lawrence Schiffman, DO; Suzanne Sirota Rozenberg, DO; Marvin Watsky, DO Acute Febrile Neutrophilic Dermatosis Induced by Coccidioidomycosis: A Case Report and Brief Review ...... 39 Joseph Machuzak, DO; Stephen Kessler, DO ...... Spindle Cell Malignant Melanoma Mimicking Dermatofibrosarcoma Protuberans: A Case Report ...... 41 Peter J Morrell, D.O.; Peter John Morrell, D.O.; Christopher Conner, M.D.; Carlos Cerruto, M.D.; Clay J Cockerell, M.D. Impetigo Herpetiformis: An Unusual Psoriatic Presentation ...... 43 Nathan Peterson, DO,; Chad Peterson, DO; Michael W Peterson, DO A rare case: Nephrogenic fibrosing dermopathy ...... 46 Zaina Rashid, D.O.; Don Anderson , D.O. FAOCD FASMS Cutaneous leishmaniasis: Case report and review of treatment options ...... 49 Rupa Reddy, D.O.; Jag C Reddy, M.D.; Stanley Skopit, D.O., FAOCD Noonan-like/Multiple Giant-cell Lesion Syndrome with Multiple Granular-cell Tumors: A Case Report and Literature Review ...... 52 Thomas J Singer, D.O.; Hamza Bhatti, OMS II; Brad P Glick, D.O. Case Report and Literature Review: Metastatic Nodular Melanoma of the Foot ...... 54 Jacqueline Thomas, D.O.; Scott M Greenberg, DO; David Thomas, MD, JD; Janet Allenby, DO An Unusual Presentation of Darier’s Disease ...... 56 Janese Trimaldi, M.D.; Olga Globosky, D.O.; Bradley Abrams, D.O; Michael B Morgan, M.D. Nephrogenic Systemic Fibrosis – A Current Look ...... 59 Madeline Turner, D.O.; Angela McKinney, D.O.; Elina Terushkin, D.O. Stevens-Johnson Syndrome - Toxic Epidermal Necrolysis Overlap ...... 63 Alice Do, D.O.; Kimball Silverton, DO, FAOCD Marjolin’s Ulcer in an Ipsilateral Lymphedematous Lower Extremity Overlap ...... 68 Jacqueline A Thomas, DO; David L Thomas, MD; Janet Allenby, DO letter From the editors

JAy gottlieb, do Jon Keeling, do Andrew rACette, do FAOCD Senior Editor FAOCD Editor FAOCD Editor

We would like to extend a warm welcome and congratulations to all of the new Fellows of the American Osteopathic College of Dermatology. The college continues to grow and evolve, as does the journal it created. The AOCD recently welcomed several new members who passed their board examinations this past fall. We welcome these new members and hope they will take an active role in the AOCD as well as in the journal of the AOCD.

Being involved with the journal is one of the easiest ways to give back to your college. We encourage you to take the time to continue to write new and interesting articles that will contribute to the knowledge of the students, residents, and other Fellows reading the JAOCD. Working with students and residents is a great way to keep your skills and knowledge at the forefront of the dermatology field. All students and residents need a board-certified dermatologist as one of the authors in order to submit their paper.

In addition, we hope the new Fellows of the AOCD will not only contribute in writing journal articles, but will also help in the review process. Since the AOCD has expanded, the number of dermatology programs and therefore the number of residents and articles submitted to the JAOCD have increased dramatically. We are always in need of more board-certified dermatologists willing to be part of our peer-review process. This is very important to the goal of having our journal indexed in the near future. The time commitment is small, one paper every two to three months, and the more reviewers we have the smaller the commitment will be. If you are interested in becoming a peer-reviewer for the JAOCD, please email us at [email protected].

Sincerely,

Jay S. Gottlieb, DO, FAOCD (Senior Editor)

Jon Keeling, DO, FAOCD (Editor)

Andrew Racette, DO, FAOCD (Editor)

4 Letter From the editors letter From the president of the AoCD

mArC (i. epstein, do)

president Greetings from Tucson, AZ,

By the time this message goes to print and you are reading it, for many of us the shorter, colder, dreary winter days will have yielded to the longer, warmer, inviting spring ones. I want to strongly encourage those of you who are looking for a combination business education and vacation trip this spring to consider attending this year’s mid-year meeting in Sedona, AZ, from April 14th through the 17th. Do not miss out on this enchanting Red Rock country offering breathtaking vistas, both spiritual and mystical, of our nation’s natural beauty. Our second vice president, Jim Towry, has been very busy planning an outstand- ing clinical education program for you during your stay. You should have received the meeting brochure in the mail. I hope to see you there.

While we’re on the subject of combining business education and vacation, I also want to remind everyone that this year’s annual meeting is in charming San Francisco, CA, from October 24th through the 28th. Our President Elect, Leslie Kramer, has also been working very hard to make it a memorable educational and social event for you. You should be pleased to know that Leslie has planned our opening reception at the MOMA, the Museum of Modern Art, just a half block down the street from the convention center. So please mark the dates on your calendar and make your plans now to attend.

I am hopeful that by the time this message reaches you, we will have earned the status of full membership in the AAD as osteopathic dermatologists. Unfortunately, since it takes a two-thirds majority vote to make the change, just like in other forms of politics apathy and ignorance can prevent needed and justified change. Some misconceptions about osteopathy and osteopathic dermatology were dispelled first hand by your first vice president, Brad Glick, at the January board meeting of the South Florida Dermatology Society. Those misconceptions are widespread. It is our burden to bear and to dispel them.

We cannot assume that our allopathic colleagues with whom we cordially interact professionally and socially on a daily, weekly or monthly basis are not also unintentionally harboring similar misconceptions. The only way to know and to dispel them is to make the somewhat uncomfortable effort to bring them up in conversation. The sooner we all have these conversations the better. Following my message in Derm Line is a copy of the letter your BOT sent to the AAD membership, with a synopsis of our training and credentialing, that was subsequently incorporated into the AAD website. You can distribute cop- ies of the letter to your MD colleagues or refer them to the AAD website during your conversations.

Ruth Carol is helping me to try and put together The History of Osteopathic Dermatology. Unfortunately, many of our historic documents were lost during the firing of our previous executive secretary. If you have any old relevant photographs, convention brochures or syllabi, meeting minutes, recollections, etc., please e-mail Ruth and me. They will be put to good use.

Toward this end, is there anyone willing to lead or be part of an ad hoc committee to research the history of osteopathic medicine and dermatology? This would include its origins, evolution, interaction with and incorporation of its principals into allopathic medicine, along with other topics. One of the goals of the committee would be to present the findings as a plenary lecture at an upcoming annual meeting of both the AOCD and the AAD as well as in an article for submission to both the JOACD and the JAAD. I think that the AOA may be helpful in part in accomplishing this endeavor. I have already broached the subject of a plenary lecture at an upcoming annual AAD meeting with the outgoing AAD president, Dr. David Pariser. He liked the idea and suggested I contact the AAD meeting committee.

Sincerely and fraternally yours,

Marc I. Epstein, DO Your 2009-2010 AOCD President

Letter From the president 5 whAt syndrome is this? hidrotiC eCtodermAl dysplAsiA: A CAse report And disCussion

Paul Aanderud, DO,* Chris Buatti, DO,** Kimball Silverton, DO*** *Intern, Oakwood Southshore Medical Center, Trenton, Michigan **Resident, Department of Dermatology, Genesys / Michigan State University, Grand Blanc, Michigan ***Program Director, Department of Dermatology, Genesys/ Michigan State University, Grand Blanc, Michigan

ABSTRACT

Hidrotic ectodermal dysplasia, or Clouston syndrome, is a rare, autosomal-dominant skin disorder characterized by general alopecia, nail dystrophy, and palmoplantar hyperkeratosis. Unlike other ectodermal dysplasias, the patient experiences normal sweat patterns and average dentition. This diagnosis is difficult to make because of the rare nature of the disorder and the odd presenting symptoms. A case of a 10-year-old female with the syndrome is given, along with a discussion of common findings in the disorder, genetic mapping, and treatment.

Case Report A 10-year-old girl of mixed Canadian origin presented with the chief complaint of alopecia since birth. She reported seeing many dermatologists in the past, but her condition persisted despite various conventional treatments. She also complained of thickened, painful palms and soles with nail dystrophy since childhood. The patient has two male siblings, but they remain free from the disease. She was born of an uncomplicated pregnancy and continued to develop mentally and reach her developmental milestones. Figure 1: A 10-year-old girl with Figure 4: Hyperkeratosis of the After discussion with the mother, a sparse hair on her scalp and absent soles. eyebrows. The teeth are normal. family history of similar physical find- frequency of dental caries or dental abnor- ings among extended relatives was real- malities. All other aspects of the physical ized. The patient’s mother is currently exam were normal. dealing with a mild form of the disease, The working diagnosis of hidrotic ecto- and her grandmother has near total dermal dysplasia was then given, and the alopecia with nail dystrophy. Among the patient was referred to a pediatric derma- patient’s many aunts, all of them but one tologist for further workup. had signs of alopecia, nail dystrophy, and thickened palms and soles. The patient believed that the other female relatives in the family had not received a diagnosis of Discussion hidrotic ectodermal dysplasia in the past. Hidrotic ectodermal dysplasia, other- Surprisingly, the male side of the family wise known as Clouston syndrome, is a has not shown any symptoms despite rare, autosomal-dominant disorder char- the autosomal-dominant nature of the Figure 2 : A closer view of the acterized by the triad of severe dystrophy syndrome. Included in the family history diffuse alopecia. of the nails, hyperkeratosis of the palms is a propensity toward miscarriages. Her and soles, and alopecia. While primarily mother experienced one, and her great found in French-Canadian descent grandmother had 10 total miscarriages. (1), it has been reported among a large The number of miscarriages experienced Chinese family (2) and a kindred of by the various aunts was not available. British ancestry (3). Our case demon- Clinical exam showed sparse, wispy hair strates a family that can trace its ancestry on the scalp and absent eyebrows (Figures through French, Dutch, Irish, Indian, 1 and 2). Her nails were hyperconvex, and German roots, and falls within the thickened, brittle, and grew slowly (Figure expected genetic connection with those 3). Also noticed were tufted terminal studied by Clouston (4). The affected phalanges and absent axillary and pubic females in the family experienced balding hair. She had diffuse keratoderma of both and hyperkeratosis, but the males were the palms and the soles (Figure 4). The devoid of symptoms. This inheritance patient was noted to have normal sweat pattern is strange and is unexplained at glands. There was no evidence of increased Figure 3 Nail dystrophy with thickened, this time. Variable expression is expected hardened nails.

6 hidrotic ectodermaL dyspLasia: a case report and discussion with autosomal-dominant disorders, but References as to why the females alone would share in 1. Clouston HR. A hereditary ectodermal dystrophy. Can. the disorder is not known. Med. Assoc. J. 1929: 21:18-31. 2. Tan E, Tay YK. What syndrome is this? Hereditary Ectoder- In hidrotic ectodermal dysplasia, there mal Dysplasia. Pediatric Dermatology. 2000: 17(1):65-67. 3. Bixler D, Patel RA. Clouston syndrome: a rare autosomal domi- are variable degrees of alopecia. Scalp hair nant trait with palmoplantar hyperkeratosis and alopecia. Am. J. is typically normal during infancy, but Hum. Genet.1990; 47:A49 4. Clouston HR. The major forms of hereditary ectodermal dyspla- can progress to complete alopecia during sia. Canad. Med. Assoc. J. 1939; 40:1-7. puberty. The scalp hair is wire-like, brittle, 5. Hassed SJ, Kincannon JM, Arnold GL. Clouston syndrome: an ectodermal dysplasia without significant dental findings. Am. J. and pale. The eyebrows and body hair are Hum. Genet. 1996; 61:274-276. usually absent. In contrast to hypohidrotic 6. Hazen PG, Zamora I, Bruner WE, et al. Premature cataracts in a family with hidrotic ectodermal dysplasia. Arch. Dermatol. 1980; ectodermal dysplasia, there is no abnor- 116:1385-1387. mality with sweating or sebaceous gland 7. Kibar Z, Der Kaloustian VM, Brais B, et al. The gene responsible for Clouston hidrotic ectodermal dysplasia maps to pericen- function. The nails are thick and hyper- tromeric region of chromosome 13q. Hum. Molec. Genet. 1996; convex with onycholysis, and paronychia is 5:543-547. 8. Lamartine J. Essenfelder G, Kibar Z, et al. Mutations in GJB6 common (5). Other reported abnormali- cause hidrotic ectodermal dysplasia. Nature Genet. 2000; ties include those of ophthalmologic origin 26:142-144. 9. Baris HN, et al. A novel GJB6 missense in hidrotic ectodermal including cataracts, strabismus, conjunc- dysplasia broadens its genotype basis. British J. of Der. 2008; tivitis, and pterygium. Other abnormali- 159:1373-1376. 10. Scriver CR, Solomons CC, Davies E, et al. A molecular abnor- ties found are sensorineural hearing loss, mality of keratin in ectodermal dysplasia. J. Pediatr. 1965; polydactylism, syndactylism, and multiple 67:946. eccrine poromas (6). There has been one account in the literature of mental retardation associated with Clouston syndrome, but the case was most likely the result of a new mutation (2). Life expectancy is not affected. Among other ectodermal dysplasias, abnormal dentition is often noted. This has not been the case with families affected by Clouston syndrome (5). The causative gene for Clouston syndrome was identified on chromosome 13q12 with positional cloning (7). It is thought that a missense mutation of GJB6 results in a non-synonymous amino acid substitution. This in turn disrupts GJB6 function to encode for connexin 30, a cell membrane protein that forms gap junctions (8). Gap junctions allow for tissue homeostasis by providing a pathway for metabolic transfer between conjoined cells. Recent work in the genetic commu- nity with DNA markers has unearthed common haplotypes among certain populations, indicating a common disorder (9). Among other populations not expressing the common genetic marker, it is thought that a new mutation, probably of different origin, is responsible. DNA testing on our patient was not done, but the key features present should have led us to test for the GJB6 gene. A biopsy of the patient’s hair and skin was not performed, but past studies suggest a molecular abnormality of keratin. The hair is light and wispy with decreased tensile strength, decreased fibrillar struc- ture, and increased number of reactive SH groups (10). Typically, treatment focuses on palmoplantar keratoderma and the use of kerato- lytic agents like urea and salicylic acid. Wigs are frequently used for cosmetic benefit. There has been little benefit seen with scalp Kenalog injections as the hair loss is not inflammatory in nature. Occasionally, abla- tion of the nail matrix is necessary for relief.

aanderud, Buatti, siLVerton 7 dermAtoFibrosArComA protuberAns And multiple AngiolipomAs: A CAse report And disCussion

Ali Banki, D.O.,* Cindy Hoffman, D.O.,** Charles Gropper, MD*** Fig. 1 *2nd-year dermatology resident, St. Barnabas Hospital, Bronx, NY **Program Director, St. Barnabas Hospital, Bronx, NY ***Chairman of department of Dermatology, St. Barnabas Hospital, Bronx, NY***

ABSTRACT Fig. 1 Dermatofibrosarcoma protuberans (DFSP) is characterized by bulky, protuberant neoplasms which are slowly progressive with little tendency to metastasize. They are CD34-positive. Lipomas are benign tumors composed of matures lipocytes. There are multiple histological subtypes of lipomas, including spindle-cell lipomas and angiolipomas, which are both CD34+. The CD34+, spindle- shaped cells in normal skin may represent interstitial dendritic cells. The occurrence of multiple spindle-cell lipomas and DFSP has been reported in the literature only once, suggesting a common origin from interstitial dendritic cells. We report the first case of angiolipomas occurring with DFSP, helping to further associate DFSP and lipomas under the Fig.same neoplastic 1 proliferation.

Introduction: able number of small vessels. Occasional vessels are occluded by fibrin thrombi.³ Dermatofibrosarcoma protuberans Spindle-cell lipomas are asymptomatic, (DFSP) is characterized by bulky, protu- slow-growing, subcutaneous tumors that berant neoplasms that slowly progress with have a predilection for the back, poste- Fig. 2 little tendency to metastasize. Fifty to 60% rior neck and shoulders of older men.¹ occur on the trunk, with less common The neoplasms consist of lobulated masses involvement of the proximal extremi- of mature adipose tissue with areas of ties and the head and neck.¹ Initially, it spindle-cell proliferation. Pathology shows presents as a slow-growing, asymptom- mature fat cells, small uniform spindleFig. 2 atic, skin-colored, indurated plaque. It cells, and strands of dense eosinophilic eventually develops into violaceous-to- “ropey” collagen. The spindle cells are red-brown nodules expanding in size. CD34+.³ Figure 1 Pathology usually reveals epidermis that The occurrence of multiple spindle-cell is normal, atrophic, or ulcerated. Cellular lipomas and DFSP has been reported in proliferation of thin, spindled fibroblasts the literature only once.5 Both DFSP and and collagen in the dermis extending multiple spindle-cell lipomas are char- to subcutaneous fat can be seen.² These acterized by a proliferation of CD34+, neoplasms are usually CD34+ and factor spindle-shaped cells, which may representFig. 2 XIII negative. Mohs surgical excision is interstitial dendritic cells. the treatment of choice. In a series of 50 patients, the recurrence rate was 2% with Case report: Mohs surgery, and 11% to 50% with wide local excision.¹ A 42-year-old Hispanic male presented Fig. 3 Lipomas are subcutaneous tumors to the St. Barnabas dermatology clinic for composed of mature lipocytes. They may the evaluation of multiple subcutaneous occur as solitary, sporadic lesions or as nodules present on his trunk and extremi- Figure 2 multiple lesions, with or without familial ties for one to two years. The patient stated history. They are most commonly found that some of the nodules were painful andFig. 3 on the neck, trunk, arms, proximal extrem- some were not. He had been seen previ- ities, and buttocks.¹ They are character- ously in the dermatology clinic, and some ized by slow growth. Once they achieve a of the nodules had been excised; pain was certain size, they tend to remain stable and relieved with excision. Histopathology of show no tendency to involute. There are lesions revealed both lipomas and angio- multiple histological subtypes of lipomas, lipomas. His past medical history was including spindle-cell lipomas, angioli- notable for DFSP on his anterior chest pomas, chondroid lipomas, pleomorphic wall in 2006, and the tumor was excised lipomas, hibernomas, lipoblastomas and with adjuvant external radiation therapy. liposarcomas.³ The patient had no prior surgical history, Angiolipomas are benign, subcuta- was not on any medications, and had no Figure 3 neous tumors composed of mature fat known drug allergies. and have a vascular component. They are On physical examination, the patientFig. wall, 3 there was an 8 x 4 cm, hypertrophic often more painful than ordinary lipomas. had multiple, rubbery, mobile, subcu- scar, which was the site of his previously Multiple subcutaneous angiolipomas taneous nodules on his upper extremi- excised DFSP (Figure 3). have no invasive or metastatic poten- ties bilaterally and the trunk (Figure 1). tial. Immunohistochemistry may reveal He had several linear surgical scars on Discussion: CD34 positivity.4 Pathology usually reveals his trunk from previous lipoma exci- mature adipose tissue admixed with a vari- sions (Figure 2). On his anterior chest Differentiation of DFSP has remained 8 dermatoFiBrosarcoma protuBerans and muLtipLe angioLipomas: a case report and discussion controversial since its first description. The differentiation of DFSP has been linked to a variety of neoplasms including neural, fibrohistiocytic, and even vascular. Cytogenetic and immunohistochemical studies have also linked this neoplasm to giant-cell fibroblastoma (juvenile variant of DFSP), Bednar tumor (the pigmented histologic variant of DFSP) and spindle-cell lipomas, which are all CD34+.5 Thus, it has only been recently that some experts have considered it as a neoplasm of interstitial dendritic cells.6 Similarly, spindle-cell lipomas have long been viewed as “lipogenic” tumors, and in recent literature Suster and Fisher characterized this entity as an interstitial dendritic neoplasm.4 Interstitial dendritic cells represent a resident CD34+ population of spindle cells in normal skin and subcutaneous tissue. They are specifically localized between dermal collagen bundles and individual adipocytes and surround hair follicles, eccrine glands, smooth muscles, blood vessels, and nerves. The exact function of these dendritic cells is not clearly understood, but it may include antigen processing and providing support to sweat glands and blood vessels.5 DFSP associated with spindle-cell lipomas has been previously established. Spindle-cell lipomas and DFSP share a common feature: proliferation of CD34+ spindle-shaped cells. Thus, common ancestry may explain their concurrence. The CD34+ spindle cells found in these tumors may represent interstitial dendritic cells.5 Additionally, with immunohistochemistry, angiolipomas show CD34 positivity.4 Thus, angiolipomas in association with DFSP in our patient may represent a relationship via the same common ancestry observed between spindle-cell lipomas and DFSP. In conclusion, we report the first case of angiolipomas occurring with DFSP, both CD34+ tumors. This case, along with a previously reported case of occurrence of DFSP with spindle-cell lipomas, may help further associate DFSP and lipomas under the same neoplastic proliferation.

References: 1. James W, Berger, T, Elston, D. Andrews’ Diseases of th Skin, Clinical Dermatology. Elsevier; 2006. 2. Rapini R. Practical Dermatopathology. Elsevier. 2005. 3. Bolognia J, Jorizzo J, Rapini R. Dermatology. Elsevier. Second edition; 2008. 4. Suster S, Fisher C. Immunoreactivity for the human hematopoietic progenitor cell antigen (CD34) in lipomatous tumors. Am J Surg Pathol 1997; 21: 195-200. 5. Harvell JD. Multiple spindle cell lipomas and dermatofibrosarcoma protuberans within a single patient: evidence for a common neoplastic process of interstitial dendritic cells? J AM Acad Dermatology 2003; 48 (1): 82-85. 6. Kempson R, Fletcher CDM, Evans HL, et al. Atlas of Tumor Pathology: Tumors of Soft Tissues. Washing (DC): Armed Forces Institute of Pathology; 2001.

Banki, hoFFman, gropper 9 sCleredemA Adultorum oF busChKe: A CAse presentAtion And literAture reView

Nicholas Benner, OMS IV,* Ramona Sarsama Nixon, D.O.,** Mary Beth Luca, D.O., F.A.O.C.D.*** OU-COM/O’Bleness Memorial Hospital, Athens, Ohio *4th-year medical student at OU-COM, Athens, Ohio **3rd-year dermatology resident at O’Bleness Memorial Hospital, Athens, Ohio ***Co-director of O’Bleness Memorial Hospital Dermatology Program, Athens, Ohio

ABSTRACT

Scleredema adultorum of Buschke is a rare primary cutaneous condition characterized by dermal mucinosis and mild sclerosis.1 This is a case presentation of a male diagnosed with scleredema adultorum of Buschke. Histological and clinical findings from this case are discussed, as well as the typical presentation and reported associated conditions.

CASE PRESENTATION to involve the arms, shoulders, back and chest.4 Onset is usually sudden and A 75-year-old man presented with a symmetric, but can be insidious, and the 10-year history of a nonpruritic, nontender disease can be slowly progressive.2,4,5 The thickening of his forehead. He previously upper body is most commonly involved. had been diagnosed as having rosacea Palms and soles are never involved, but and treated with minocycline and topical dorsal hands may be. Young persons are azelaic acid without benefit. His past classically affected, with 50% of cases medical history consisted of only hyperten- occurring in children. Females are twice sion and one basal-cell carcinoma on his as likely to develop non-diabetic scler- ear. The patient denied having diabetes edema. Diabetic scleredema is more likely and had recently been tested for it by his in males.6 family doctor. His current medications There are three main types of scler- included verapamil, minocycline, topical edema: (1) preceded by fever, malaise and Figure 1 azelaic acid and doxazosin. He denied a streptococcal infection of the respiratory having constitutional symptoms, and his tract (classic presentation); (2) without a review of systems was unremarkable. preceding illness, some association with Physical exam revealed a thickened, an underlying gammopathy; and (3) asso- erythematous, nonpitting induration on ciated with insulin-dependent diabetes his central forehead (Figures 1 and 2). The (scleredema diabeticorum).7 Typically, results of his cutaneous examination were patients in the second group (no diabetes normal. A punch biopsy specimen was or preceding infections) are the largest obtained from the right side of his fore- group affected.2 In the first group, there head (Figures 3 and 4 [hematoxylin-eosin] is often an asymptomatic period between and Figure 5 [Alcian blue]). resolution of infection and onset of skin changes, so taking a good history is very MICROSCOPIC important.6 FINDINGS AND Other associated findings include dysphagia, dysarthria, myositis, parotitis, Figure 2 CLINICAL COURSE ocular and cardiac abnormalities and an Hematoxylin-eosin (H&E) stained associated paraproteinemia (usually IgG). sections of the specimen demonstrated a Patients with dysphagia present with thickened and fibrotic reticular dermis. esophageal dysmotility and confirma- A mild, predominately perivascular and tory manometry that mimics scleroderma perifollicular chronic infiltrate was present esophagus. Esophageal manometry may in the dermis. No increase in fibroblasts be warranted in patients with sugges- 4,7,8,9 was noted. The Alcian blue stain revealed tive symptoms. One reported cardiac mucin between collagen bundles. A diag- association is pericarditis with pericardial 10 nosis of scleredema was made. The patient effusion. In more chronic forms, asso- had no systemic symptoms and declined ciations with other systemic conditions further testing and treatment. such as rheumatoid arthritis, hyperpara- thyroidism, Sjögren’s syndrome, malignant insulinoma, myeloma and HIV have also DISCUSSION Figure 3 been reported.4,8 Scleredema adultorum is considered It is important to identify and treat an uncommon condition of unknown any underlying associated disease. Initial clonal gammopathy (serum protein elec- etiology characterized by nonpitting indu- testing should be done to rule out diabetes trophoresis and immunoelectrophoresis).11 ration and diffuse swelling, thickening or (fasting blood sugar, glucose tolerance test, Histopathologically, scleredema char- tightening of the skin.1,2,3 Skin induration HgbA1c), recent infections (ASO, bacterial acteristically shows thickened collagen usually begins on the neck or face, moving cultures, ESR) and an underlying mono- bundles within the reticular dermis that

10 scLeredema aduLtorum oF Buschke: a case presentation and Literature reView collagen and mucin production.15 With treatment of infection, many cases of post-streptococcal scleredema resolve spontaneously.6

References 1 Basarab T, Burrows NP, Munn SE, Russell JR. Sys- temic involvement in scleredema of Buschke associated with IgG-kappa paraproteinaemia. Br J Dermatol. 1997;136(6):939-42. 2 Ioannidou DI, Krasagakis K, Stefanidou MP, Karampekios S, Panayiotidis J, Tosca AD. Scleredema adultorum of Buschke presenting as periorbital edema: A diagnostic challenge. J Am Acad Dermatol. 2003;52:S41-S44. 3 Bowen AR, Smith L, Zone JJ. Scleredema Adultorum Figure 4 of Buschke Treated with Radiation. Arch Dermatol. 2003;193:780-4. 4 James WD, Berger TG, Elston DM. Andrews’ Diseases of the Skin: Clinical Dermatology. 10th ed. Philadelphia, Pa: Saunders; 2006:186-7. 5 Rosenbach MA, Werth VP, Strachan DD, (2006, May 24). Scleredema. emedicine website: http://www.emedicine. com/derm/TOPIC385.HTM. 6 Alp H, Orbak Z, Aktas A. Scleredema adultorum due to streptococcal infection. Pediatrics International. 2003 Feb; 45 (1):101-3. 7 Bolognia JL, Jorizzo JL, Rapini RP, eds. Dermatology. St Louis, Mo: Mosby-Year Book Inc; 2003:653-4. 8 Meguerditchian C, Jacquet P, Béliard S, Benderitter T, Valéro R, Carsuzza F, Vialettes B. Scleredema adultorum of Buschke: an under recognized skin complication of diabetes. Diabetes Metabolism. 2006 Nov;32(5 Pt 1): 481-4. 9 Notar-Francesco V, Beatrice B, Cerulli MA, Bharathan T, Sohn W, Krishnaiah M. A Figure 5 rare presentation of scleredema adultorum of buschke with esophageal dysmotility. Amer J of Gastroenterol. Supplement 2002 Sept; 97 (9):S217. 10 Roussounis SH, Smith M. Scleredema of Buschke with are separated by mucin-containing fenes- pericarditis. Proc R Soc Med. 1976 Nov, 69 (11):844-5. trations. The mucin is thought to be 11 Lebwohl MG, Heymann WR, Berth-Jones J, Coulson I. Treatment of Skin Disease: Comprehensive therapeutic nonsulfated acid mucopolysaccharides. strategies. 2nd ed. St Louis, Mo: Mosby-Year Book Inc; The thickened collagen bundles are often 2005:598-600. 12 Tamburin LM, Pena JR, Meredith R, Soong VY. Scler- found in the deeper dermis. These find- edema of Buschke Successfully Treated With Electron ings can extend into the subcutaneous fatty Beam Therapy. Arch Dermatol. 1998; 134:419-22. 12 13 Singal A, Gandhi V, Bhattacharya SN, Kha. Scleredema tissue. On routine hematoxylin and eosin adultorum of buschke associated with non-scarring alo- staining, the mucin stains with colloidal pecia of scalp. Indian J Dermatol Venereol Leprol 1999; 65:38-9. iron. It is Alcian blue positive at pH 2.5 14 Stables GI, Taylor PC, Highet, AS. Scleredema associ- but negative at pH 0.5, and metachromasia ated with paraproteinemia treated by extracorporeal photophoresis. Br J of Dermatol, 2000 Apr; 142 (4):781-3. is present with toluidine blue at pH 7.0 and 15 Xiao T, Yang ZH, He CD, Chen HD. Scleredema adulto- 4.0.13 rum treated with narrow-band ultraviolet B phototherapy. J Dermatol. 2007 Apr; 34 (4):270-2. Management of scleredema is difficult because no therapeutic option has proved to be consistently effective.3,11 Many treatment options have been proposed, including thyroid hormone, pituitary extract, systemic corticosteroids (commonly used), hyaluronidase, and immunosuppressants.14 In patients with moderately severe disease, PUVA is recommended. For patients with severe disease (not responding to topical, intralesional, or systemic corticosteroid therapy or other regimens), electron-beam therapy is recommended.3,11,12 Alternative therapies include cyclosporine, high-dose IV penicillin, extracorporeal photophoresis (for those with a paraproteinemia) and chemotherapy (for those with myeloma).11 Many of the treatments have proven effective in recent case reports. Paraproteinemia- associated scleredema has been successfully treated with extracorporeal photophoresis (ECP) with PUVA in one case.14 Xiao et al. reported that narrow-band UVB (NB-UVB) monotherapy showed significant improvement in mobility and soft- ening of the lesions in a case of scleredema in a diabetic. This regimen is believed to induce apoptosis in fibroblasts, decreasing

Benner, nixon, Luca 11 A sporAdiC CAse oF steAtoCystomA multiplex

Chris Buatti, D.O., M.B.A. Genesys Regional Medical Center Program Director: Dr. Kimball Silverton

ABSTRACT

Abstract: 49 year old African American with a 24 year history of multiple yellow nodules from 3mm to 2.0cm in size. These cysts are widely scattered on the truck, proximal extremities, and inguinal region. They appeared in late adolescence which began to spread to his arms and neck in the last several years. This is a sporadic case of steatocystoma multiplex is considered to be a nevoid or harmartomatous condition that is either inherited in an autosomal dominant pattern or is nonhereditary. Patients typically exhibit numerous cutaneous cystic nodules of variable size, commonly on the anterior trunk and upper extremities. Cysts are concentrated in areas where high numbers of sebaceous glands are found (upper torso, proximal extremities). The involved areas becomes studded with deep, flesh-to-yellow, colored, dermal papules and lack a punctum.

History: the cysts and wanted them all removed. tion was localized.4 This mutation also has He had not tried oral isotretinoin or any been reported in steatocystoma multiplex A 49-year-old African American other medications. We excised some lesions cases without the features of pachyonychia presented with a 24-year history of through a 4.0mm punch on the truck congenital type 2.4 In steatocystoma multi- multiple yellow nodules ranging from and neck. The patient did have suppura- plex associated with vellus hair cysts, no 3mm to 2cm in size. These cysts were tive lesions from his axillae removed by a K17 mutation has been found. Keratins widely scattered on the truck, proximal general surgeon several years prior with are the major structural proteins of the extremities, and inguinal region. They some success. epidermis and its appendages and form appeared in late adolescence and began to the type I (K9-K20) and type II (K1-K8) 4 spread to his arms and neck in the previous Discussion: groups of intermediate filaments. several years. The patient denied that any Pachyonychia congenital (PC) is a rare, of his family members had similar lesions. Steatocystoma multiplex is considered to autosomal-dominant keratin disorder that be a nevoid or harmartomatous condition that is either inherited in an autosomal- Examination: dominant pattern or is nonhereditary.1 There were multiple (greater than Patients typically exhibit numerous cuta- a hundred) nodules on the chest, back, neous, cystic nodules of variable size, axillae and groin. These lesions were a commonly on the anterior trunk and few millimeters to a couple of centimeters upper extremities. Cysts are concentrated in diameter and appeared as cysts in the in areas where high numbers of sebaceous dermis that drained oily fluid if punctured. glands are found (upper torso, proximal They were asymptomatic to the patient. extremities). The involved areas become There was no acral involvement. No nail studded with deep, flesh-to-yellow colored, dermal papules and lack a punctum.3 dystrophy, focal keratoderma or mucosal When a cyst spontaneously ruptures to leukokeratoses were present. the skin surface or is incised and drained intentionally, the contents appear as a Figure 1 Laboratory values: syrup-like, yellowish, odorless oily mate- Liver function transaminase levels, total rial. The relationship of steatocystoma bilirubin, alkaline phosphatase and CBC multiplex to the development of sebaceous were normal. glands and its presentation at puberty suggest a hormonal trigger for the lesions’ Dermatohistopathology: growth.2 The main histologic features are the Biopsy specimens showed a dermal cyst absence of a granular layer with a wrinkled, lined by a thin, stratified squamous epithe- eosinophilic refractile cuticle of keratin, lium, with a granular layer surmounted and sebaceous elements within or adjacent by an irregular, corrugated, eosinophilic to the cyst wall. A relationship with erup- cuticle. Small sebaceous lobules were found tive vellus hair cysts has been suggested adjacent to the cyst wall. because of similar clinical appearance, Figure 2 time of onset, and overlapping histo- Diagnosis: logical features. It has been proposed that these clinical entities are a spectrum of can be divided into two main subtypes: Steatocystoma multiplex the same disease process and should be PC-1 Jadassohn-Lewandowsky syndrome classified as multiple pilosebacious cysts. and PC-2 Jackson-Lawler syndrome. Course and Treatment: Steatocystoma multiplex also has been seen Characteristics common to both forms are in patients with pachyonychia congenital hypertrophic nail dystrophy, focal palmo- The patient was very concerned about type 2, in which keratin 17 (K17) muta- plantar keratoderma, follicular keratoses

12 a sporadic case oF steatocystoma muLtipLex and oral leukokeratoses. Hyerpertrophic nail dystrophy of the hands and feet usually develops soon after birth and presents as thickened nails that grow to full lengths or nails that terminate prematurely. Oral leukokeratosis is normally present soon after birth and can be one of the earliest clinical observations. This is generally more pronounced in PC-1 than PC-2. Focal plantar keratoderma tends to develop later in life as children begin to walk, exerting pressure on the soles of the feet. Follicular keratoses are often found in areas of friction such as the elbows and knees. Epidermal inclusion cysts can be found in both PC subtypes. Pilosebacious cysts such as steatocystomas and vellus hair cysts are PC-2 specific and are the major clinical features distinguishing PC-2 from PC-1.2 Specifically, PC-1 is the result of mutations of keratin K6a and K16. In contrast, PC-2 results from mutations in K6b and K17.4 Steatocystoma multiplex is a benign disorder. In some patients, it may have psychological implications resulting from disfigurement of widespread lesions or from scarring seen in the inflammatory variant, steatocystoma suppurativa.6 No racial predilection has been found, and both sexes are equally affected. Various treatment options for steatocystoma multiplex have been published and include oral antibiotics, isotretinoin, and surgical removal. Local destructive methods such as cryotherapy and CO2 laser have been reported to be efficacious for localized variants of steatocystoma multiplex. The possibility for scarring and dyspigmentation in darker skin types limits the usefulness of these modalities.5

References 1. Setoyama M, Mizoguchi S, Usuki k. Kanzaki: Steato- cystoma multiplex: A case with unusual clinical and histological manifestation. Am J. Dermatopathology. 1997; 19:89-92. 2. Kiene P, Hauschild A, Christophers E: Eruptive vellus hair cysts and steatocystoma multiplex. Variants of one entity? Br. J. Dermatology. 1996; 134:365-367. 3. Apaydin R, Bilen N, Bayramguler D, et al. Steatocystoma Multiplex suppurativum: oral isotretinoin treatment with cryotherapy. Australas J Dermatology. 2000; 98-100. 4. Covella SP, Smith FJ, Sillevia Smitt JH, et al. Keratin 17 mutations cause either steatocystoma multiplex of pachyonychia congenital type 2. Br J Dermatology. 1998; 139:475-480. 5. Shwayder T, Adams B: Steatocystoma multiplex suppurativum. International Journal of Dermatology. 2008; 47:1155-1156. 6. Brownstein MH, Helwig EB: Subcutaneous dermoid cysts. Arch Dermatology. 1973; 107:237-239.

Buatti 13 CArCinomA ex pilomAtrixomA: A unique histologiC presentAtion And reView oF the literAture

Michael Centilli, OMS-II,* Patricia Moody McNab, M.D.,** Michael B. Morgan, M.D.*** *Second-year medical student, MSUCOM, East Lansing, MI **Department of Pathology and Cell Biology, PGY II, University of South Florida College of Medicine, Tampa, FL ***Dermatopathologist, professor, Pathology USFCOM, Tampa, FL, Dermatology UFCOM, Gainesville, FL

ABSTRACT

We present a unique case of carcinoma arising within pilomatrixoma biopsied from a rapidly growing, 2 cm nodule located on the arm of a 46-year-old Caucasian male. Histology showed a non-keratinizing, infiltrative carcinoma without matricial differentiation, arising directly off the periphery of a histologically typical pilomatrixoma. These histologic features merit distinction from the histologic pattern documented in conventional malignant pilomatrixoma or pilomatrix carcinoma, to be discussed herein.

Case Presentation: matrix cells.1,2,3,4 This dermal or subcuta- contrast to benign pilomatrixoma, older neous lesion typically presents as a firm, males have a greater susceptibility, with A 46-year-old Caucasian male presented slow-growing mass ranging in size from 1 a male to female ratio of 2.9 to 1, and to the office with a 2 cm nodule on the to 60 mm, with an average size of 12 mm.2 a mean age of 46.3.8 These malignant posterior superior aspect of the left arm. Approximately 68% of cases arise in the tumors exhibit an increase in mitotic The lesion had been present for several head and neck region, and less frequently activity and prominent cytologic atypia, years and had undergone rapid growth, in the trunk and extremities.5,2 Although including high nucleocytoplasmic ratios, doubling in size over the previous month. most commonly found in females under prominent nucleoli, and vesicular nuclear It was non-pruritic and caused significant the age of 10, there have been reports in chromatin.12 These tumors usually present pain upon palpation. The patient had a patients as young as four months and as as asymptomatic dermal or subcutaneous 6,2 history of idiopathic urticaria, which was old as 86 years. The female to male ratio 13 2 tissue masses. They are characterized by being treated symptomatically. There was is 1.75:1. Pilomatrixomas are relatively matrical cells arranged in lobules, central common, accounting for 1 out of every a positive family history of melanoma and areas of necrosis and occasional dystro- 500 biopsies submitted for evaluation by leukemia in the patient’s mother. phic calcification within the tumor lobules. dermatologists.2,7 Physical examination revealed a well- Like its benign counterpart, basaloid and nourished but ill-appearing middle-aged Histologically, pilomatrixomas shadow cells are the dominant cell types. male. A 3 x 3 x 3 cm nodular lesion was are composed of coherent basophilic Varying levels of anaplasia are noted in epithelial cells and keratinized eosino- noted on the left arm, with pain upon the basaloid cells in addition to increased palpation. Initial clinical impression was philic “shadow” cells.6,2 These basaloid nuclear hyperchromasia. These cells are an epidermal inclusion cyst, and a 4 mm cells are generally uniform in size, with arranged in sheets, bands, cords, or nests. punch biopsy was taken during the office small circular nuclei and subtle nuclear In addition, lymphocytes, plasma cells visit. The biopsy, measuring .4 X .4 X .7 membranes. Centrally located shadow cells cm, was submitted entirely. The pathology are present in higher concentrations than and histiocytes are dispersed among a yielded a keratinizing squamous carcinoma the basaloid cells and arrange themselves arising in conjunction with pilomatrixoma in masses, whorls, or stacks.6,2 They derive (Figure 1, H&E 100X). Microscopy of the their name from the loss of their nuclei, squamous malignancy showed irregular which is characterized by the central infiltrative nests of pleomorphic keratin- unstained area of the cell.2 The shadow izing cells with prominent intercellular cells have a distinct, pale eosinophilic junctions connecting with a disparate basa- cytoplasm and faint, degenerated nuclear loid non-palisaded neoplasm comprised outline.8 Mineralization of the keratin- of smaller, darkly stained cells with scanty ized cells can also occur, accompanied cytoplasm that showed central abrupt kera- by surrounding granulomatous inflamma- tinization into typical foci of shadow/ghost tion.2 Grossly, bluish discoloration and cells (Figure 2, H&E 400X). The lesional ulceration of the overlying skin may be cells were CK-903 positive and S-100 nega- observed and indicates the possible pres- Figure 1 tive, consistent with the diagnosis. ence of pilomatrixoma in underlying Treatment entailed wide local exci- tissue.2,9 This entity must be differenti- sion, with the final pathology yielding no ated from epidermoid cysts, dermoid residual neoplasm and clear margins. No cysts, parotid-gland tumors, calcified other lesions were noted on the patient’s lymph nodes, calcified hematomas, and body, and there has been no recurrence. hemangiomas.2,10 Misdiagnosis is frequent, The patient is pleased with the outcome with a preoperative accuracy rate of only of the excision and will continue regular 21-28%.6,2 Treatment is excision or curet- dermatology screenings. tage, with rare recurrence given proper excision techniques.6 Discussion: Malignant pilomatrixoma or pilomatrical carcinoma, the malignant counterpart Pilomatrixoma is a benign, calcifying of pilomatrixoma, was first reported by neoplasm originating from hair-follicle Lopansri and Mihm in 1980.8,11 In sharp Figure 2 14 carcinoma ex piLomatrixoma dense, fibrous desmoplastic stroma lining oma and other benign cutaneous lesions of pilar origin. J the periphery of the tumor nests.8 Similar Cutan Pathol. 1986 Feb;13(1):22-9. 13. Sau P, Lupton GP, Graham JH. Pilomatrix carcinoma. to the benign form, the differential diag- Cancer. 1993 Apr 15;71(8):2491-8. Review. nosis includes pilomatrixoma, aggressive pilomatrixoma, proliferative pilomatrixoma, epidermal cyst, and basal-cell carcinoma.8,13 Pilomatrix carcinomas are locally aggressive with a high propensity to recur following incomplete excision. The likelihood of recurrence further increases in the presence of worsening anaplasia and extensive soft-tissue invasion.13 The preferred treatment is wide excision, including the adherent skin. Adjuvant radiation therapy is at the discretion of the treating physician.8,13,5 Perineural, vascular, lung, lymph node, and bone metastases have been reported, resulting in a survival range of three months to three years. This imparts a poorer prognosis than those successfully excised without evidence of metastasis.8,13,1 To date, there have been 75 well-documented cases of pilomatrix carcinoma discussed in the literature. A variant of carcinoma pilomatrixoma not yet recognized in the literature was recently discovered in a 46-year-old Caucasian male. Histology revealed a non- keratinizing infiltrative carcinoma without matricial differentiation, arising directly off the periphery of a histologically typical pilomatrixoma. These histologic features merit distinction from the histologic pattern documented in conventional malignant pilomatrixoma or pilomatrix carcinoma. There has not been a documented case of carcinoma arising from an adjacent pilomatrixoma, therefore a distinction of carcinoma ex pilomatrixoma was specified for the variant.

References 1. Mikhaeel NG, Spittle MF. Malignant pilomatrixoma with multiple local recurrences and distant metastases: a case report and review of the literature. Clin Oncol (R Coll Radiol). 2001;13(5):386-9. Review. 2. Pirouzmanesh A, Reinisch JF, Gonzalez-Gomez I, Smith EM, Meara JG. Pilomatrixoma: a review of 346 cases. Plast Reconstr Surg. 2003 Dec;112(7):1784-9. 3. Knight PJ, Reiner CB. Superficial lumps in children: what, when, and why? Pediatrics. 1983 Aug;72(2):147-53. 4. Yencha MW. Head and neck pilomatricoma in the pediatric age group: a retrospective study and literature review. Int J Pediatr Otorhinolaryngol. 2001 Feb;57(2):123-8. Review. 5. Yoshimura Y, Obara S, Mikami T, Matsuda S. Calcify- ing epithelioma (pilomatrixoma) of the head and neck: analysis of 37 cases. Br J Oral Maxillofac Surg. 1997 Dec;35(6):429-32. Review. 6. Julian CG, Bowers PW. A clinical review of 209 pilomatri- comas. J Am Acad Dermatol. 1998 Aug;39(2 Pt 1):191-5. 7. Marrogi AJ, Wick MR, Dehner LP. Pilomatrical neoplasms in children and young adults. Am J Dermatopathol. 1992 Apr;14(2):87-94. 8. Hardisson D, Linares MD, Cuevas-Santos J, Contreras F. Pilomatrix carcinoma: a clinicopathologic study of six cases and review of the literature. Am J Dermatopathol. 2001 Oct;23(5):394-401. Review. 9. Duflo S, Nicollas R, Roman S, Magalon G, Triglia JM. Pilomatrixoma of the head and neck in children: a study of 38 cases and a review of the literature. Arch Otolaryn- gol Head Neck Surg. 1998 Nov;124(11):1239-42. 10. Wells NJ, Blair GK, Magee JF, Whiteman DM. Piloma- trixoma: a common, benign childhood skin tumour. Can J Surg. 1994 Dec;37(6):483-6. 11. Lopansri S, Mihm MC Jr. Pilomatrix carcinoma or calcifying epitheliocarcinoma of Malherbe: a case report and review of literature. Cancer. 1980 May 1;45(9):2368-73. 12. Manivel C, Wick MR, Mukai K. Pilomatrix carcinoma: an immunohistochemical comparison with benign pilomatrix-

centiLLi, mcnaB, morgan 15 plexiForm FibrohistioCytomA in A 13-yeAr-old FemAle: CAse report And brieF reView

Helia Eragi,1 Amy L. Basile, DO, MPH,2 Chris Weyer, DO,3 Lloyd Cleaver, DO,4 Michael Morgan, MD5 1 MSIV, Western University of Health Sciences, Pomona, CA 2 Dermatology Resident, St. Joseph Mercy Hospital, Ypsilanti, MI 3 Dermatology Resident, Northeast Regional Medical Center Dermatology Program, Kirksville, MO 4 Program Director, Northeast Regional Medical Center Dermatology Program, Kirksville, MO 5 Associate Professor, Dept. of Pathology, University of Southern Florida, Tampa, FL

ABSTRACT

Plexiform fibrohistiocytoma (PFH) is a rare, intermediate-grade soft-tissue tumor, most often diagnosed in children and young adults (1). Approximately 200 cases have been reported in the literature. Here, we describe a case of PFH which presented as a tender, darkly pigmented nodule on the left shoulder of a 13-year-old girl. PFH is described as a slow- growing, asymptomatic mass located in the dermis and subcutaneous tissue. This tumor is commonly observed on the upper extremities and is more common in females (1). Histologically, the tumor can demonstrate plexiform proliferation of histiocyte- and fibroblast-like cells, fascicles of spindle cells and surrounding multinuclear giant cells (1,5). PFH has a tendency to recur and, rarely, to metastasize; therefore, aggressive removal and follow-up should be the standard treatment plan. A review of previous case series, including treatment options and prognosis, is incorporated into the discussion.

INTRODUCTION: CASE REPORT: 2). Tumor metastasis, vascular invasion or perineural extension were not identified Plexiform fibrohistiocytic tumor (PFH) A 13-year-old female with no significant (Figure 2). The lesion stained positive for is a rare, intermediate-grade mesen- past medical history presented to the clinic SMA and CD-68 histological markers and chymal tumor first described by Enzinger with a mildly tender, hyperpigmented was negative for S-100 (Figures 3 and 4). and Zhang in 1988 (1). Since the publi- nodule on her left posterior shoulder that In light of the histological features and cation of this sentinel paper, there have had recently turned “black.” According to immunohistochemical profile, the diag- been approximately 200 cases reported in the patient’s mother, the nodule was previ- nosis of PFH was rendered. the English literature. The majority of ously non-pigmented, had been present Following confirmation of the diag- PFH cases present in children and young for approximately one year and was diagnosis, the patient returned for complete adults under the age of 20, with mean age nosed as an epidermal inclusion cyst by her excision of the nodule. Five-millimeter of 14.5 years old and female prevalence primary care doctor. The patient denied margins were used to excise any remaining (>3:1) (1,6,10). There have been a handful pruritus, discharge, tendency to bleed, or tumor, and upon histological evaluation of cases reported in infants as young as an increase in size of the nodule. Complete all margins were clear. In addition to exci- 2.5 and 8 months old (4,5). The tumor review of systems was done, and of note, sion, a chest X-ray was obtained secondary generally presents as a slow-growing, pain- the patient denied recent trauma, weight to the risk of pulmonary metastasis. The less nodule, usually measuring less than loss, night sweats, fatigue or myalgia. patient was asked to follow up in the clinic 3cm, but this number can vary widely (0.3- The patient’s family history was nega- every three months for the first year, every 8cm) (1,5). PFH most commonly affects tive for skin cancer or connective-tissue six months the second year, and annually the upper extremities (~60%) including disease, and the patient denied taking any thereafter. the shoulders, forearm, fingers and wrist medication. (1,3,5,10). Less commonly, PFH has been On physical exam, a blue-black, DISCUSSION: reported on the lower extremities (10) and well-circumscribed nodule measuring rarely on the chest, trunk, head and neck 10x12mm was observed on the left The pathogenesis of PFH is unknown; region (1,6). posterior shoulder. Mild tenderness of however, trauma has been reported to be Histopathologically, the tumor is char- the nodule was elicited upon palpation; a predisposing factor in a few documented acterized by a plexiform proliferation (i.e. however, no erythema, discharge or cases (1). Additionally, two cases of interweaving network) of histiocyte- and blanching was observed. No supracla- congenital PFH have been reported (3,5). fibroblast-like cells, fascicles of spindle vicular, bilateral axillary or cervical lymph Cytogenetic evaluation has been completed cells and surrounding multinuclear giant nodes were palpated. The family and on two cases, but the usefulness of these cells (1,5). These tumor cells can infiltrate patient agreed to removal of the lesion karyotypes in the diagnosis and pathogen- the subcutaneous tissue as well as extend in the office, and an elliptical excision esis of disease remains to be seen (9,12). into the dermis or skeletal muscle (5,6,10). was performed. The clinical differen- Unique to this tumor is the lack of PFH is now categorized with a group of tial diagnosis included pilomatricoma, specific correlations between pathological childhood fibrohistiocytic soft-tissue vascular tumor and atypical melanocytic findings and the clinical behavior of the tumors that have intermediate malig- proliferation. tumor (1,5,10). For example, even though nancy, including giant-cell fibroblastoma Following routine histopathologic the tumor is known to be slow-growing, and angiomatoid fibrous histiocytoma (8). preparation, the skin yielded a well- systemic metastasis could be present at the PFH has a tendency to recur locally and circumscribed, dermal-based spindle cell time of diagnosis, although it is usually can metastasize to distant lymph nodes and neoplasm arranged in nests and sweeping observed late in the history of disease (10). the lungs (10,11). Therefore, it should be fascicles (Figure 1). The cells showed Predicting recurrence and metastasis is also treated aggressively, including wide local epithelioid proliferation that spilled into difficult as patients with metastasis may excision, and observed carefully over time other areas and an increased number of not have local recurrence, and recurrence for potential recurrence and metastasis. atypical mitosis was also observed (Figure does not always predict metastasis (10). 16 PLEXIFORM FIBROHISTIOCYTOMA IN A 13-YEAR-OLD FEMALE conditions (some of which are pigmented): blue rubber bleb nevus (B), eccrine spirad- enoma (E), neuroma (N), glomus tumor (G), angiolipoma (A), and leiomyoma (L). Additional differentials for a blue nodule include benign aneurysmal fibrous histiocytoma, angiosarcoma, hemangioma and metastatic melanoma. Given the unusual presentation of the current case (tender and darkly pigmented), the previous differentials would not typically characterize a classic PFH lesion. However, the above information is worth mentioning given the Figure 1. On physical exam, a blue- Figure 5. CD68 marker positive for presentation of disease and utility of the black, well circumscribed nodule macrophages/histiocyte-like cells. measuring 10x12mm was observed on available mnemonic. the left posterior shoulder. These clinical correlations are difficult to Given the distinct histopathological make given the small number of avail- features of classic PFH, additional differ- able cases. However, it remains critical to ential diagnoses may include the following: obtain a chest X-ray upon diagnosis and to cellular neurothekeoma, plexiform schedule frequent follow-up visits in order schwannoma, plexiform neurofibroma, to detect recurrence and metastasis (4). dermatofibroma, dermatofibrosarcoma Histologically, PFH is characterized by protuberans (DFSP), fibrous hamartoma a plexiform (network-like), infiltrative of infancy, soft-tissue giant-cell tumors, proliferation of three distinctive cell types: angiomatoid fibrous histiocytoma, malig- mononuclear histiocyte-like cells, multi- nant fibrous histiocytoma (MFH) and nucleated osteoclast-like cells and spindle myofibromatosis (1,3,4,15). fibroblastic-like cells (1,6,10). Depending Neurothekeomas are neural sheath on the predominant cell type present, myxomas described as asymptomatic three main growth patterns are recognized nodules often found on the upper extremi- Figure 2. Low magnification and named accordingly: the fibrohistio- ties of young female adults, similar to PFH (superficial dermis): The skin yielded cytic subtype, which is composed mainly (7). However, neurothekeomas can appear a well-circumscribed, dermal-based, of mononuclear histiocytic-like cells and lobulated and myxoid as opposed to the spindled-cell neoplasm arranged in multinucleated giant cells; the fibroblastic plexiform pattern of PFH (14). Typically, nests and sweeping fascicles. type, which is composed of elongated clus- neurothekeomas stain positive for S-100 ters and short fascicles of spindled fibro- (14). blast-like cells; and the mixed type, which Schwannomas are tumors of Schwann is composed of both patterns in equal cells, are generally seen in patients over 30 amounts (1,6,10). Pleomorphism or atypia and are often associated with neurofibro- is usually absent or minimal (1,6), and matosis type 2 (14). Similar to PFH, they generally, low mitotic activity is observed are asymptomatic nodules often on the (1,10). Finally, perineural growth, head and neck, but they can often affect hemorrhage, hyalinized collagen, chronic cranial nerves. Plexiform schwannomas inflammation and vascular invasion have are a histologic variant of Schwann-cell infrequently been reported (1,6,10). tumors and are known to grow within The immunohistochemical profile for the nerve (14). Schwannomas in general PFH is distinctive and can assist in estab- have spindle cells similar to PFH, but their lishing a diagnosis. Histiocyte- and osteo- myxoid appearance and palisading nuclei Figure 3. High magnification: Fascicles clast-like cells, as well as multinuclear giant forming Verocay bodies set it apart from of spindle cells and multinucleated cells, often demonstrate positive CD68 PFH (14). Additionally, schwannomas are giant cells. Increased number of (3,5,10). Smooth-muscle actin is a marker generally S-100 positive and SMA negative atypical mitosis was seen. Tumor of myofibroblastic differentiation, and (14). metastasis, vascular invasion and spindle cells demonstrate positivity in this Neurofibromas are pedunculated perineural extension were not tumor (3,5). In contrast, lesions are gener- identified. papules or nodules of the skin often associ- ally negative for S-100 protein, keratin, ated with neurofibromatosis type 1. They desmin, HMB45, CD34, lysozyme, NK1/C3 are essentially an overgrowth of all parts (CD57) and factor XIIIa (1,2,6). of a nerve but are usually asymptomatic (14). Plexiform neurofibromas are a larger DIFFERENTIAL variant of neurofibroma, involving the DIAGNOSIS: entire nerve in addition to its branches and forming a distinct “bag of worms” feel Upon evaluation of a tender, darkly under the skin (14). It can grow so large pigmented nodule in a child, many differ- that daily living is impaired (14), setting it ential diagnoses should come to mind. apart from the generally small size of PFH. Both clinical and histological features will Dermatofibromas or benign fibrous help to eliminate many of the differentials. histiocytomas are very common mesen- Tender nodules carry a very distinct clinical chymal tumors, often the result of trauma Figure 4. SMA marker positive differential diagnosis, which is summa- or arthropod bite in adults (14). They for smooth-muscle cells and rized by the widely used term “BENGAL.” usually present in women and demonstrate myofibroblasts. This mnemonic represents the following a “buttonhole” dimpling upon squeezing eragi, BasiLe, weyer, cLeaVer, morgan 17 (14). Histologically, they are characterized In one case report, Mohs micrographic of PFH presenting in a 13-year-old female by a spindly, storiform (spiral or cartwheel) surgery was used for complete resection on the left shoulder; tenderness and a blue- pattern without atypia and stain positive of an incompletely excised PFH in a right black pigmentation are unique features for factor XIIIa (14). axilla of an 11-year-old girl (8). A two- to the current case. Wide excision with Malignant fibrous histiocytoma (MFH) stage excision with 2mm margins was 5mm margins was used to extirpate the is a common soft-tissue sarcoma often initially performed. However, paraffin tumor, and a CXR was completed upon affecting the lower extremities (14). sections of the tumor demonstrated initial evaluation. Although very limited Histologically, the spindle cells of MFH residual tumor near the deep margin, recommendations are available in the liter- organize in a storiform pattern, and and re-excision with an additional 5mm ature, aggressive treatment with adequate mitotic figures are common, unlike what margin was performed. Repeat histo- surgical margins for excision is standard. is seen in PFH (14). Additionally, MFH logical evaluation indicated no residual The benefit of chemotherapy and radiation stains positive with CD68, but laminin and tumor. The patient was subsequently has not been elucidated, but each diagnosis collagen IV stains are also positive (14). followed for four years without evidence should be approached on a case-by-case Angiomatoid fibrous histiocytoma was of recurrence (8). basis. Long-term follow-up is necessary considered a variant of MFH but is now Despite surgical removal, PFH has to detect any local recurrence or systemic a distinct entity that shares many clinical frequently been reported to recur locally. metastasis, and the patient will be seen features with PFH. However, pathologi- According to Enzinger and Zhang, 37.5% frequently for evaluation. cally there are often many blood-filled (12 of 32 cases) recurred after surgical cystic spaces with a fibrous pseudocapsule removal (1). Additionally, two of the 12 REFERENCES and dense lymphoplasmacytic infiltrate recurrences reported developed regional 1. Enzinger FM, Zhang RY. Plexiform fibrohistiocytic tumor (13). This tumor is often negative for skel- lymph node metastasis (1). Local recur- presenting in children and young adults. An analysis of 65 cases. Am J Surg Pathol 12 (11): 818-26, 1988. etal muscle markers, although half of these rence rates range from 12.5% (10) to 40% 2. Giard F, Bonneau R, Raymond GP. Plexiform fibrohistio- tumors have been shown to be desmin (3), although the authors of the former cite cytic tumor. Dermatologica 183 (4): 290-3, 1991. 3. Hollowood K, Holley MP, Fletcher CD. Plexiform fibrohis- positive; CD68 is also frequently negative a short follow-up period and early aggres- tiocytic tumour: clinicopathological, immunohistochemical as opposed to in PFH (13). sive treatment as reasons for the low recur- and ultrastructural analysis in favour of a myofibroblastic lesion. Histopathology 19 (6): 503-13, 1991. Fibrous hamartomas of infancy are rence rate (10). 4. Jafarian F, McCuaig C, Kokta V, Hatami A, Savard P. In the case of pulmonary metas- Plexiform fibrohistiocytic tumor in three children. Pediatr rapidly growing nodules often presenting Dermatol 23 (1): 7-12, 2006. at birth or within the first year of life (14). tasis, thoracotomy with resection of the 5. Leclerc S, Hamel-Teillac D, Oger P, Brousse N, Fraitag pulmonary nodes was used to control two S. Plexiform fibrohistiocytic tumor: three unusual cases They are characterized by fibroblasts, occurring in infancy. J Cutan Pathol 32 (8): 572-6, 2005. primitive mesenchymal cells and mature of three reported cases with no evidence 6. Moosavi C, Jha P, Fanburg-Smith JC. An update on plexi- of recurrence years after treatment (10). form fibrohistiocytic tumor and addition of 66 new cases adipose tissue (14) as opposed to the from the Armed Forces Institute of Pathology, in honor of distinct components found in PFH. Radiation of large or inoperable tumors Franz M. Enzinger, MD. Ann Diagn Pathol 11 (5): 313-9, may have some benefit, but pulmonary 2007. Myofibromatosis is a benign prolif- 7. Papadopoulos EJ, Cohen PR, Hebert AA. Neurotheke- eration of fibroblasts and myofibroblasts radiation has been reported to cause signif- oma: report of a case in an infant and review of the litera- icant toxicity (pulmonary fibrosis) (10). ture. J Am Acad Dermatol 50 (1): 129-34, 2004. and can be found as solitary or multiple 8. Rahimi AD, Shelton R, Dumas A, DiConstanzo D, Phelps nodules in the skin, bone or muscle (14). Further data supporting the use of radia- R. Mohs micrographic surgery of a plexiform fibrohistio- tion in PFH is needed before suggesting cytic tumor. Dermatol Surg 27 (8): 768-71, 2001. Histologically, myofibromatosis demon- 9. Redlich GC, Montgomery KD, Allgood GA, Joste NE. strates a central hemangiopericytoma-like this treatment modality. No definitive Plexiform fibrohistiocytic tumor with a clonal cytogenetic statement can be made regarding the role anomaly. Cancer Genet Cytogenet 108 (2): 141-3, 1999. area (14), distinguishing it from PFH. 10. Remstein ED, Arndt CA, Nascimento AG. Plexiform fibro- Dermatofibrosarcoma protuberans of chemotherapy in treating PFH. histiocytic tumor: clinicopathologic analysis of 22 cases. Am J Surg Pathol 23 (6): 662-70, 1999. (DFSP) is an aggressive mesenchymal Although recurrence rates are high, 11. Salomao DR, Nascimento AG. Plexiform fibrohistiocytic tumor often described as slow-growing overall prognosis of local disease is fairly tumor with systemic metastases: a case report. Am J Surg Pathol 21 (4): 469-76, 1997. and occasionally pigmented (red-brown good. Remstein et al. reported three-year 12. Smith S, Fletcher CD, Smith MA, Gusterson BA. Cytoge- or violaceous) (14). DFSP is often found follow-up data for 16 patients diagnosed netic analysis of a plexiform fibrohistiocytic tumor. Cancer Genet Cytogenet 48 (1): 31-4, 1990. in adults, although the age range is varied and treated for PFH (10). Overall, 13 of 13. Thway K. Angiomatoid fibrous histiocytoma: a review with (14). The lesion usually stains positive 16 (82%) were alive with no evidence of recent genetic findings. Arch Pathol Lab Med 132 (2): 273-7, 2008. with CD34, and the proliferation of spindle disease (average, 3.6 years), 1 (6%) was 14. Wolff K, Goldsmith L, Katz S, Gilchrest B, AS P, DJ L, cells in the dermis is usually of a storiform alive with metastatic disease (follow-up, eds. Fitzpatrick’s Dermatology in General Medicine, 7th edition: McGraw-Hill Companies, Inc, 2008. pattern (14). 2.3 years), and 1 (6%) was alive with a 15. Zelger B, Weinlich G, Steiner H, Zelger BG, Egarter-Vigl stable pulmonary nodule of unknown E. Dermal and subcutaneous variants of plexiform fibro- Soft-tissue giant-cell tumors are asymp- histiocytic tumor. Am J Surg Pathol 21 (2): 235-41, 1997. tomatic, slow-growing tumors often found nature (follow-up, 1.75 years). Of the in adults on the lower extremities (14). three patients who developed pulmonary Histologically, this tumor is characterized metastasis, one patient died of disease by mononuclear and multinuclear osteo- three years after local recurrence and clastic giant cells (14). Soft-tissue giant- pulmonary metastases developed (6%, 1 cell tumors stain positive for CD68 but also of 16 patients) (10). This patient also had for vimentin (14), unlike PFH. evidence of vascular invasion upon initial evaluation. TREATMENT AND CONCLUSION: PROGNOSIS: Plexiform fibrohistiocytic tumor (PFH) Surgical resection with wide margins is is a mesenchymal neoplasm of interme- the principal treatment for patients with diate malignancy found mostly in children primary and recurrent lesions (1,5,10). and young adults. Although rare, PFH Specific margin recommendations have can display aggressive behavior with local not been well documented in the literature. recurrence or systemic metastasis, and the However, wide excision with large margins death rate has been reported around 6% of safety has been suggested (5). (1,10). Here, we report a fairly typical case

18 PLEXIFORM FIBROHISTIOCYTOMA IN A 13-YEAR-OLD FEMALE to urtiCAte or not to urtiCAte: A CAse oF tmep And reView oF CutAneous mAstoCytoses

Gwyn Frambach, DO,* Charles Gropper, MD,** Cindy Hoffman, DO, FAOCD*** *Dermatology Resident, PGY2, NYCOM/St. Barnabas Hospital, Bronx, NY **Director of Dermatology, St. Barnabas Hospital, Bronx, NY; Clinical Associate Professor of Dermatology, Mt. Sinai School of Medicine, New York, NY ***Program Director; Assistant Clinical Professor in Dermatology, NYCOM/St. Barnabas Hospital, Bronx, NY

ABSTRACT

Mast cells play an important immunologic role in host allergic response, most notably through the release of preformed mediators into the surrounding tissues and bloodstream when activated. In mastocytosis, these cells undergo a pathologic expansion either systemically or localized to the skin. Cutaneous mastocytosis can occur at any age, though it is more common in children. Childhood cases run a benign course and often undergo spontaneous resolution before puberty. Pathologic mast cell proliferation in adulthood is typically associated with an acquired c-kit mutation and systemic involvement, which may be indolent or life threatening. We present a case of telangiectasia macularis eruptiva perstans, a rare form of indolent mastocytosis seen in adults, as well as a review of the cutaneous mastocytoses.

Case Report marrow that function throughout the spec- children.5 The pathogenesis of cutaneous trum of allergic response, from immediate disease is unknown but may be related to In 2008, a 39-year-old Hispanic male hypersensitivity to chronic allergic reac- cytokine dysregulation, a new mutation, or presented to the St. Barnabas dermatology tions. The role of these cells involves the other abnormalities.6 In contrast, systemic clinic with a seven-year history of redness exocytosis of intracytoplasmic granules mastocytosis is characterized by a clonal of the skin on his chest, arms, and back. containing preformed mediators, avail- proliferation of bone-marrow derived Although the lesions were asymptomatic able for immediate release when triggered cells. This clonal hyperplasia is most often and not evolving, the patient sought a by a stimulus. This release occurs rapidly due to an activating somatic mutation diagnosis. Past medical history included after classical activation through IgE in the proto-oncogene c-kit, coding the hypertension, chronic hepatitis C, and a receptor cross-linking after surface receptor SCF receptor KIT.3 Interestingly, a loss- hemorrhagic stroke of the brainstem binding of an allergen, as well as by non- of-function mutation in c-kit is respon- with mild residual right-sided weakness. immunologic mechanisms.1,2 Mechanical sible for some cases of piebaldism.7 This Medications included hydralazine, amlo- stimulation of cutaneous lesions initiate mutation, most often, is a single base pair dipine, clonidine patch, hydrochlorothia- degranulation. This is well demonstrated substitution of aspartic acid with valine zide, and methadone. The patient was a in Darier’s sign, a non-generalized wheal- at codon 816 (D816V).8 It is thought smoker with a 12 pack-year history. Now and-flare reaction restricted to lesional that this mutation leads to constitutive sober, he also had a history of IV drug skin, elicited by rubbing or scratching the autoactivation of downstream pathways abuse. affected area.2 in the absence of ligand binding, and the Physical exam revealed large patches of Mast cells can be identified histologi- prevention of apoptosis.1,6 Patients with blanchable erythema with telangiectasia cally with special staining, often detecting this mutation present with adult-onset symmetrically involving the chest but the mediators contained within the gran- disease. Due to the potentially serious sparing the central chest, the upper back, ules. The stains for granular components systemic nature of these diseases, the WHO and bilateral upper arms (Fig. 1, Fig. 2). include but are not limited to the basic categorizes systemic mastocytoses under Darier’s sign was negative. A punch biopsy dyes toluidine blue and Giemsa, which myeloproliferative disorders.8,9 This clas- of the right arm revealed telangiectasia are metachromatic stains that bind acid sification scheme of systemic disease has with several perivascular mast cells (Fig. mucopolysaccharides, particularly been included in Table 1, and will not be 3). A Giemsa stain was then performed, heparin; Alcian blue, staining mucin; and discussed. showing a paucicellular mast cell infil- Leder, staining chloroacetate esterase. Symptoms found in patients with masto- trate (Fig. 4) consistent with telangiectasia Immunostaining for mast cells is more cytosis are due to the release of preformed macularis eruptiva perstans. Serology accurate and reliable. These include mediators normally housed in these cells. revealed a normal serum tryptase (9 ng/ CD117, which is more sensitive, and Mediators are stored in intracytoplasmic mL), complete blood count with differ- tryptase, which is the most specific immu- granules until released into the blood- ential (CBC), and liver function tests nomarker for mast cells.3,4 Mast cell devel- stream, leading to a varied response that (LFTs). Education was provided regarding opment relies heavily upon the binding of may include flushing, pruritus, urticaria, the disease process and treatment options. stem cell factor (SCF) to KIT (CD117), a abdominal pain, nausea, vomiting, diar- Because of the asymptomatic nature of surface receptor tyrosine kinase. Normal rhea, vascular instability, and headache.3 his condition on presentation, the patient receptor activation leads to downstream Granular components of significant did not require pharmacologic interven- phosphorylation and activation of proteins importance are histamine, responsible tion; he also declined laser therapy for the involved in cellular proliferation, growth, for acute clinical symptoms, and tryptase, cosmetic improvement of his telangiec- and differentiation.1 which becomes important in diagnosis. tasia. The patient will be monitored with Mastocytosis is characterized by the Other mediators housed within the gran- annual measurements of serum tryptase, pathologic accumulation of mast cells. ules include leukotrienes, prostaglandins, CBC with differential, and LFTs. Mastocytosis is divided into cutaneous and platelet-activating factor, cytokines, and systemic forms, and further categorized proteases.3,4,7,8 Discussion by adult or childhood onset. Childhood- Cutaneous mastocytoses, as previously onset disease comprises at least 65% of noted, are the more common, frequently Mast cells are immunologic cells derived all cases and is predominantly limited to banal form and are often diagnosed in from myeloid precursors in the bone the skin. Systemic involvement is rare in childhood. Childhood disease frequently FramBach, gropper, hoFFman 19 undergoes spontaneous resolution before puberty. When diagnosed in adulthood, more than 25% will develop systemic disease.3 According to the WHO classification, cutaneous mastocytoses have been subdivided into three sub-types: solitary mastocytoma, diffuse cutaneous mastocytosis, and the maculopapular forms, which include urticaria pigmentosa (UP) and telangiectasia macularis eruptiva perstans (TMEP) (Table 1).9 Urticaria pigmentosa Figure 1: Erythematous, telangiectatic, blanchable patches, most prominently on the chest. On the right is a close-up view of a lesional area on the right chest. Urticaria pigmentosa is the most common cutaneous mastocytosis in both children and adults, representing 80-90% of cases.3 Patients develop a generalized eruption of few to hundreds of yellow to brown macules, papules, and plaques on the trunk and extremities.5,10 Bullae formation may occur following the release of chymase from mast cell granules, a protease capable of cleaving the dermal- epidermal junction.5 Patients may provide a history of degranulation-related symptoms, especially pruritus. Lesions of UP are exacerbated by degranulating triggers, including temperature changes, stress and Figure 2: Erythematous telangiectatic patches are less pronounced on the arms emotional upset, vigorous exercise, hot and back. or spicy foods, cheese, shellfish, IV dye, ethanol, anesthetics, opiates, and aspirin. Darier’s sign may or may not develop when the skin is rubbed or scratched.5 UP tends to occur later in childhood and has a greater tendency to persist compared with other forms of cutaneous mastocytosis, resolving by adulthood in only 50% of cases.3 Unfortunately, most cases of adult- onset disease are associated with systemic involvement and do not auto-involute.11 Telangiectasia macularis eruptiva perstans Occurring in adults, telangiectasia macularis eruptiva perstans is the least common of the cutaneous mastocytoses, representing less than 1% of all forms.12 Patients develop red-brown telangiectatic macules that are non-pruritic and do not elicit a Darier’s sign.10 Histopathologically, patients have only a slight increase in the Figure 3: H&E staining reveals an increase in superficial vessels with a sparse number of perivascular mast cells of the perivascular infiltrate, prompting further stain. superficial vascular plexus. This paucicel- lularity explains the limited and asymptomatic nature, the lack of Darier’s sign, as well as the relative difficulty in histologic diagnosis.10 This adult-onset form tends to remain limited to cutaneous involvement without progression to systemic disease. Patients requesting treatment for reduction in telangiectasias may benefit from the use of 585nm flashlamp-pumped pulsed dye laser (PDL).12 Mastocytoma Figure 4 Low- and high-power images after Giemsa staining demonstrate a Nodular cutaneous mastocytosis, more paucicellular, perivascular mast cell infiltrate 20 TO URTICATE OR NOT TO URTICATE: A CASE OF TMEP AND REVIEW OF CUTANEOUS MASTOCYTOSES Table 1 and CD25. The D816V mutation in c-kit is identified in over 90% of patients with WHO Classification of Mastocytosis9 systemic mastocytosis.8 Children without symptoms suggesting systemic involve- CUTANEOUS SYSTEMIC ment, including abnormalities in CBC, findings of hepatomegaly, splenomegaly, Maculopapular: Indolent systemic mastocytosis (ISM) or LAD, do not require a bone marrow 8,11 Typical urticaria pigmentosa Aggressive systemic mastocytosis (ASM) biopsy. Recent investigations in the evalu- Systemic mastocytosis w/ associated clonal, ation and management of patients with Telangiectasia macularis hematological, non-mast cell lineage disease cutaneous mastocytosis are promising. eruptiva perstans (SM-AHNMD) The utility of tryptase levels in bone marrow blood was recently evaluated. Because mast cells tend to aggregate in Plaque form Mast cell leukemia (MCL) the bone marrow, there is a potential for Nodular form Mast cell sarcoma (MCS) sampling error during a needle biopsy. Data suggests concurrent measurement Diffuse cutaneous mastocytosis Extracutaneous mastocytoma of marrow tryptase may be more sensi- Solitary mastocytoma tive than marrow histologic evaluation alone, and may circumvent random error.14 The development of a scoring system for commonly referred to as a mastocytoma, so may induce systemic symptoms.13 disease severity, SCORMA (SCORing may be present at birth or develop within A lesional biopsy should be performed MAstocytosis), was shown to correlate the first few months of life.3 The typical and examined with special stains, which clinically with serum tryptase levels. This presentation is a brown to orange, soli- may include Giemsa, Leder, and immu- SCORMA index shows promise in moni- tary nodule with a predilection for the nohistochemical staining for tryptase. toring disease progression and improve- trunk and wrist. Lesions may also appear Histologically, mast cells are spherical ment, potentially decreasing the number of 11 on the face, scalp, or extremities, and may or spindle-shaped with a central round blood draws needed by affected patients. occur as a plaque, or as several lesions.5,9 nucleus. Mast cell infiltrates may be peri- Patients may provide a history of flushing vascular, interstitial, sheet-like, nodular, or Treatment but typically have no systemic involve- paucicellular.4,9 This histopathologic data ment. When rubbed, Darier’s sign or bullae must be combined with the clinical presen- Treatment of patients with cutaneous formation may occur along with systemic tation when determining the diagnosis. mastocytosis includes symptomatic relief 3,5 and trigger avoidance. Degranulation symptoms of degranulation. Most masto- Laboratory evaluation should promptly cytomas involute within several years of avoidance may involve bathing in tepid follow any skin biopsy that confirms the water, use of an air conditioner, and avoid- onset. These lesions are extremely rare in clinical diagnosis of mastocytosis. Testing adulthood.13 ance of the following: temperature changes, should begin with serum tryptase levels, stress and emotional upset, vigorous exer- a complete blood count with differential Diffuse cutaneous cise, hot or spicy foods, cheese, shellfish, (CBC), and liver function tests (LFTs). In IV dye, ethanol, anesthetics, opiates, and mastocytosis cutaneous mastocytosis, these levels should 13 8 aspirin. Patients with mastocytomas expe- be within normal limits. Tryptase levels riencing generalized symptoms may benefit Diffuse cutaneous mastocytosis is an indicate total body mast cell content, and extremely rare condition of infancy in from topical steroids under occlusion and in normal patients should measure less oral antihistamines.11 Individual nodules which the entire skin presents as yellow- than 11 ng/mL.14 Patients with systemic brown to erythroderma and is edematous, may be surgically removed, although most mastocytosis will have tryptase levels involute within several years. Patients thickened and doughy.3,5 Patients have a greater than 20 ng/mL.8 This information strongly positive Darier’s sign with bullae should protect the mastocytoma, avoiding should be used cautiously and in conjunc- physical manipulation of the lesion.13 formation and hemorrhage. There is an tion with clinical findings and history, as enormous mast cell burden throughout the Children with diffuse cutaneous disease these levels will also be elevated acutely and adults with UP may benefit from oral skin, which may result in severe systemic during a severe allergic reaction, as well symptoms of mediator release and a higher antihistamines for pruritus and flushing. as in other non-mast cell myelodysplastic A trial of topical cromolyn, a mast cell risk for severe complications.3,10 Clinical diseases.8 Patients with systemic disease manifestations often decrease or resolve stabilizing agent, may be indicated for may have elevated urinary histamine and pruritus.10,13 Other agents studied for cuta- over several years. However, children with histamine metabolites; these levels are not this form may have associated indolent neous mastocytosis show either limited as clinically relevant as and do not replace efficacy or potential for adverse effects and systemic disease and require long-term 14 the serum tryptase. include PUVA therapy and topical corti- monitoring for progression to systemic The next step in excluding or confirming mastocytosis.5 costeroids. Oral glucocorticoids are not systemic involvement is a bone marrow effective in cutaneous disease.13 All patients 8,11 biopsy. This should be performed on any should have an annual physical exam with Evaluation adult with UP, any patient with systemic repeat serum tryptase levels and CBC with signs or symptoms including organo- differential.5,10,11,13 Future pharmacologic Clinical evaluation of suspected cuta- megaly or lymphadenopathy, or following neous mastocytosis should begin with a interventions may include tyrosine kinase abnormal lab values, especially elevated inhibitors such as imatinib mesylate, which skin exam. An assessment for Darier’s sign 5,8,11 serum tryptase. Patients with normal may reduce downstream effects of SCF will reflect the relative quantity of mast tryptase levels who meet the above criteria cells in lesional skin. Lesions of urticaria activation, or omalizumab, which inhibits should be referred for flow cytometric IgE binding to mast cells.13 These medi- pigmentosa will often exhibit Darier’s sign. analysis for CD2 and CD25 and gene A mastocytoma should not be rubbed or cations show therapeutic potential in mutation analysis of c-kit in bone marrow systemic disease, though they may have a scratched for diagnostic purposes, as doing mast cells. Normal mast cells lack CD2

FramBach, gropper, hoFFman 21 limited role in cutaneous disease. Dec;5(6):300-2. 13. Castellas M, et al. Treatment and prognosis of mastocytosis All patients diagnosed with mastocytosis (cutaneous and systematic) In: UpToDate, Basow, DS (Ed), UpToDate, Waltham, MA, 2009. should carry an epinephrine autoinjector 14. Castellas M, et al. Evaluation and diagnosis of mastocytosis (EpiPen).10 In fact, unexplained anaphy- (cutaneous and systematic) In: UpToDate, Basow, DS (Ed), laxis or severe allergic reaction, especially UpToDate, Waltham, MA, 2009. after hymenoptera sting, warrants the measurement of serum tryptase levels, which may unmask an underlying mastocytosis. As with any anaphylactic or allergic reaction, tryptase levels may be acutely elevated and should be repeated along with basic labs two to three weeks following the event.8 As mentioned previously, patients with elevated tryptase levels should undergo bone marrow biopsy. Conclusion Most patients with cutaneous mastocytosis have an excellent prognosis.13 Patients are often diagnosed in childhood and have disease regression before puberty. Despite this limited nature, parents often experience anxiety and frustration over the health of their child. Adults may be fearful of disease progression and dislike the cosmetic appearance of their lesions. Ongoing research has been directed at optimizing diagnosis and treatment. In the absence of systemic involvement, patients with cutaneous mastocytosis have a favorable prognosis. An annual physical exam and labs including tryptase, CBC, and LFTs, particularly in adults without evidence of systemic disease, are useful in monitoring disease progression. The Mastocytosis Society provides an online resource for clinicians and patients. Acknowledgements The authors would like to thank Claudia Vidal, MD, for preparation of the histologic photographs.

References: 1. Okayama Y, et al. Development, Migration, and Survival of Mast Cells. Immunologic Research 2006;34(2):97-115. 2. Despoina K, et al. Darier’s sign: A model for studying dermatographism. Indian Journal of Dermatology, Vene- reology and Leprology, Vol. 74, No. 3, May-June, 2008, pp. 271-272. 3. Wolff K, et al. Clinical and histopathological aspects of cutaneous mastocytosis. Leukemia Research 2001;25:519-528. 4. Krishnaswamy G, Chi DS, editors. Mast cells: methods and protocols. Totowa NJ: Humana Press; 2005. p. 63-67. 5. Briley L, et al. Cutaneous mastocytosis: a review focus- ing on the pediatric population. Clin Pediatr. 2008 Oct;47(8):757-61. 6. Hartmann K, et al. Evidence for altered mast cell proliferation and apoptosis in cutaneous mastocytosis. Br J Dermatol. 2003 Sep; 149(3):554-9. 7. Metcalfe D. Mast cells and mastocytosis. Blood 2008;112:946-956. 8. Valent P, et al. Diagnosis and classification of mast cell proliferative disorders: Delineation from immunologic diseases and non-mast cell hematopoietic neoplasms. J Allergy Clin Immunol 2004; 114:3-11. 9. Jaffe ES, Harris NL, Stein H, Vardiman JW, editors. Pathol- ogy and Genetics: Tumours of Haematopoietic and Lymphoid Tissues (WHO Classification of Tumours). Washington, DC: IARC; 2001. p. 293-301. 10. Longley J, et al. The mast cell and mast cell disease. JAAD. 1995 Apr;32(4):545-61. 11. Heide R, et al. Mastocytosis in Children: A Protocol for Man- agement. Pediatric Dermatology, 25(4), 493-500. 12. Rishpon A, et al. Telangiectasia macularis eruptiva perstans: unusual presentation and treatment. Skinmed. 2006 Nov-

22 TO URTICATE OR NOT TO URTICATE: A CASE OF TMEP AND REVIEW OF CUTANEOUS MASTOCYTOSES

the Vexing nAture oF ConFluent And retiCulAted pApillomAtosis: two CAse reports

J. Hibler, D.O. John Hibler, D.O. *Osteopathic Intern, Kalamazoo Center for Medical Studies, Kalamazoo, Michigan **FAOCD, Dermatology of Southeastern Ohio, Zanesville, Ohio

ABSTRACT

Confluent and reticulated papillomatosis is a relatively rare skin disease that is characterized by scaly reddish-brown plaques that are usually reticulated and located on the chest, trunk, and neck. It is often misdiagnosed, even by dermatologists because of its resemblance clinically and histopathologically to tinea versicolor and acanthosis nigricans. After correct diagnosis, often patients are recalcitrant to therapy, the mainstay being minocycline 100mg twice daily. Several different classes of medicines have been used, all with varying success. We report on two such patients that have been tried on numerous medicines, both being recalcitrant to common therapies.

Introduction eczematous dermatitis, seborrheic dermatitis, photodermatitis, cutaneous amyloi- Confluent and reticulated papillomatosis dosis, Dowling-Degos disease, and other (CARP) of Gougerot and Carteaud is a keratinization disorders.1 relatively uncommon skin condition that is The mainstay of treatment in the past characterized by confluent, scaly, reddish- has been systemic antibiotics (i.e. tetra- brown patches and plaques. It is more cycline, doxycycline, and minocycline). common in women than in men. It seems Doxycycline and minocycline remain the to affect dark-skinned individuals more most commonly recommended agents, than Caucasians. It is reported to be aggra- but increasing in popularity is the use of vated in the spring and summer seasons. azithromycin, due to its smaller side effect The most common sites affected are the profile. There are also several published chest, upper arms, back, and neck. This cases reporting the successful use of topical Figure 1. Patient described in Case 2, condition is frequently misdiagnosed as and systemic retinoids, as well as photo- with confluent yet reticulated patches tinea versicolor or acanthosis nigricans therapy, radiotherapy, and dermabrasion.2 of reddish-brown, scaly skin extending because the affected sites may have a very from the neck to the lower abdomen. similar presentation. The lesions on the Case 1 nape of the neck and the axilla are slightly more verrucous. Over time, the eruption A 16-year-old Caucasian female becomes much more confluent in the presented with an irritation to her upper midline, expands in a reticulated pattern trunk that had been present for approxi- and extends peripherally. The majority of mately 1.5 years. During that time, the patients with this condition are asymptom- patient had tried a number of over-the- atic, but cosmetic concerns may arise as the counter medicines and emollients with lesions become more pronounced. It does only limited success. The lesions were rela- not appear to affect mucous membranes. tively asymptomatic, but were cosmetically The histologic features are characteristic unacceptable to the patient. The reddish, but not diagnostic. There is hyperkera- scaly rash was increasing in distribution tosis with parakeratosis and papillomatosis. and thickness. The rash was character- Figure 2. Punch biopsy at 10x Occasionally there is follicular plugging ized by reticulated, confluent, yellow-tan to magnification. The histopathology reddish-brown, shiny, scaly patches to the with laminated hyperkeratin. The gran- shows compact hyperkeratosis, mild ular layer is usually slightly increased, and upper trunk, flank, and upper back. There orthokeratosis, papillomatosis, and occasionally there is perivascular infiltra- was a somewhat asymmetrical appear- focal acanthosis. tion. The histologic changes are similar ance. KOH after superficial scraping was to but milder than those of acanthosis performed and read as negative. Initially, nigricans. The clinical and histologic the patient was placed on ketoconazole Case 2 similarity between these two different oral tablets once daily for five days, then A 15-year-old Caucasian male presented entities has caused some discussion as two tablets monthly for three months. to the clinic with an irritating, some- to their exact relationship, some authors Topically, the patient was given ZNP soap what drying rash to the chest, back, and suggesting CARP as a variation of acan- weekly to affected areas, and monthly thosis nigricans. application of zinc pyrithione shampoo. lower abdomen (Figure 1). KOH stain The main differential diagnosis of CARP Subsequently, the patient had no signifi- was negative. A tentative diagnosis of includes tinea versicolor and acanthosis cant response, and the diagnosis of tinea CARP was made. The patient was placed nigricans. These three conditions share versicolor was unlikely. After consulting on minocycline 100mg twice daily. There similar lesions clinically, as well as having with other dermatologists, a diagnosis was significant clearing for approximately the same distribution. Other possible of CARP was made, and the patient was two months, but then the rash recurred. entities include pseudoacanthosis nigri- placed on minocycline 100mg daily. Her On initial follow-up at six months, the cans, Darier’s disease, prurigo pigmentosa, response after four months was limited. rash was stated as getting more irritating hiBLer,author hiBLer 2525 and itchy. The patient and mother both will help in timely and correct identifica- confirmed being completely compliant tion of the condition. From our experi- with the treatment. Biopsy was then ence, CARP can be challenging to diagnose performed, and the results were consistent and in the long-term is often recalcitrant to with the clinical diagnosis (Figure 2). A treatment. The highly variable presenta- PAS stain was not performed. Antibiotic tion and course of the disease may cause therapy was changed from minocycline grief for the patient, as well as for the to doxycycline 100mg twice daily, with physician. Nizoral cream to be applied two times a day. Lac-Hydrin cream was also added. Reference: The next follow-up showed only mild 1. Sau P, Lupton GP. Reticulate truncal pigmentation; Con- improvement, and benzyl peroxide 2.5% fluent and reticulate papillomatosis of Gougerot and wash was added to the regimen. At the Carteaud. Arch Dematol 1988:1272-5. 2. Jang HS, et al. Six cases of confluent and reticulate pap- last office visit, three months later, he illomatosis alleviated by various antibiotics. J Am Acad stated his rash and symptoms were only Dematol 2001:652-5. 3. Scheinfeld N. Confluent and reticulated papilloma- 5% improved. We decided to place him tosis: a review of the literature. Am J Clin Dermatol. on ketoconazole 200mg daily and await 2006;7(5):305-13. 4. Wu J., et al. Confluent and Reticulate Papillomatosis. further follow-up. Dermatology Online Journal 14 (3): 10 5. Schwartzberg JB, Schwartzberg HA. Response of conflu- Discussion ent and reticulate papillomatosis of Gougerot and Carte- Two French physicians, Gougerot and aud to topical tretinoin. Cutis. 2000 Oct;66(4):291-3. 6. Bowman PH, Davis LS. Confluent and reticulated papil- Carteaud, were the first to recognize and lomatosis: response to tazarotene.J Am Acad Dermatol. describe CARP in 1927. The pathogen- 003 May;48(5 Suppl):S80-1. esis is unknown but thought to be related to the overgrowth of Dietza spp., a type of corynebacterium, as well as a defect in keratinization.3 Because of the close resemblance to acanthosis nigricans, it is thought that CARP might also be caused by endocrine abnormalities. Other possible causes include Pityrosporum, reaction to UV light, and a variation of cutaneous amyloidosis. Frequently, the diagnosis is delayed and the disorder is not recognized by physicians, including dermatologists. There are anecdotal reports of patients being treated for tinea versicolor for years and being understandably recalcitrant to anti-fungal therapy. What complicates CARP cases even more is that even after correct diagnosis, patients often become recalcitrant regardless of which medicines are taken. Over the years, minocycline 100mg twice daily has been noted to be most effective, but despite the long list of possible treatments for CARP, both published and anecdotal, successful permanent allevia- tion of the lesions is rarely reported.4 The patient in Case 1 showed only minimal improvement on minocycline, while the second case showed good response and then an exacerbation of symptoms while on minocycline. Several antibiotics such as erythromycin and azithromycin have been used with limited success. As stated in the cases, our patients were also tried on other antibiotics as well as anti-fungals. There is some published evidence that systemic and topical retinoids have been used with moderate success.5,6 After discussions with other dermatologists and reviewing the current literature, CARP seems an uncommon disease that is difficult to diagnose as well as manage. The two patients presented here reinforce the suggestion that we may not completely understand CARP and its relation to other diseases and infectious agents. Experience and competence in interpreting KOH slides 26 titLeTHE VEXING NATURE OF CONFLUENT AND RETICULATED PAPILLOMATOSIS: AquAgeniC syringeAl ACroKerAtodermA

Michelle L. Jeffries, D.O.,* Justin T. Sawyer, M.D.,** Stephen E. Kessler, D.O.*** *Dermatology resident, 3rd year, MWU Alta Dermatology Residency Program, Mesa, AZ **Alta Dermatology, Mesa, AZ ***Program director, MWU Alta Dermatology Residency Program, Mesa, AZ

ABSTRACT

Abstract: Aquagenic syringeal acrokeratoderma is one of many terms that have been used to describe exaggerated palmar wrinkling after immersion in water. Approximately 30 cases of aquagenic syringeal acrokeratoderma have been reported in the literature. We present a case of an 11-year-old female with a one month history of exaggerated swelling and wrinkling of the palms with exposure to water who responded to treatment with 20% aluminum chloride hexahydrate.

Case Report to describe exaggerated palmar wrinkling the palms after immersion in water, and it after immersion in water. Approximately rarely occurs on plantar surfaces. In addi- An 11-year-old female presented with 30 cases of this condition have been tion, unlike the hereditary variant, patients a one-month history of dry skin on her reported in the literature on aquagenic tend to have minimal cutaneous findings palms that persisted despite over-the- syringeal acrokeratoderma as of December between episodes. The episodes may be counter lotions. In addition, exaggerated 2007. The first case report was by English asymptomatic or associated with symp- swelling and wrinkling of the palms was and McCollough in 1996.6 They described tomatic pain, burning or a sensation of noted with exposure to water. These find- two sisters with symmetric, skin-colored- skin tightening. It may also be associated ings have been asymptomatic, and no to-white papules on their palms that with hyperhidrosis. Orthokeratosis with family members have had a similar condi- developed a translucent white color after dilated eccrine ducts is visible on histology. tion. Past medical, surgical, and family exposure to water. They termed this Hypergranulosis and acanthosis may history includes a clinically benign ventric- phenomenon “transient reactive papulo- be seen in the epidermis, but no dermal ular septal defect that has been present translucent acrokeratoderma.” Since this changes are observed. since birth. She had a tonsillectomy in initial report in 1996, there have been Aquagenic syringeal acrokeratoderma 2002 and denies history of cystic fibrosis, multiple names provided for similar condi- can also be associated with cystic fibrosis atopic dermatitis, ectodermal disease, or tions, which makes it difficult to track as well as some medications. Generalized hyperhidrosis. cases. The term aquagenic syringeal acro- wrinkling of the skin after immersion On examination, there was a glazed keratoderma was chosen to describe our in water is a well-known observation in appearance of the palmar surfaces without patient as it was the term that incorporated patients with cystic fibrosis.5,8,10,11,15 Cystic scaling, erythema, or edema (see Figure the syringeal involvement that we observed. fibrosis is an autosomal-recessive disorder 1). After exposure of the left hand to tap Despite the multiple names given for with a cystic-fibrosis transmembrane water for two minutes, the palmar surface this condition, this entity can be divided conductance regulator gene defect. This developed diffuse, white, keratotic, pebbly into two distinct variants: hereditary gene encodes for a protein that functions plaques with punctate pitting (see Figures papulotranslucent acrokeratoderma and as a chloride channel and is regulated by 2 & 3). The remaining cutaneous exam transient reactive papulotranslucent cyclic AMP. The defect results in abnor- displayed no other abnormalities. acrokeratoderma (commonly known as malities in the cyclic AMP-regulated Based on these clinical findings a aquagenic syringeal acrokeratoderma). chloride transport across epithelial cells diagnosis of aquagenic syringeal acro- Hereditary papulotranslucent acrokerato- on mucosal surfaces, leading to decreased keratoderma was made. No biopsy was derma was initially described by Onwukwe secretion of chloride and increased reab- performed at family’s request. As a in 197319 in a case report of a 58-year- sorption of sodium and water across therapeutic trial, 20% aluminum chlo- old female who presented with bilateral, epithelial cells. There is decreased ride hexahydrate was applied twice symmetric, palmar and plantar, translu- epithelial lining fluid and less hydration daily to one hand. At one-week follow- cent, yellow-to-white papules that were of mucus. It is theorized that the exag- up, the treated hand was dry, chapped, exacerbated with immersion in water. He gerated aquagenic wrinkling is due to the and red. Also, there was an attenuated proposed an autosomal-dominant inheri- increased salt content of skin, which leads response to immersion. Treatment was tance based on the pedigree of this one to an increased water-binding capacity of temporarily discontinued, and hydrocor- patient. He also noted an association with keratin. tisone ointment was applied 3-4 times atopy and sparse scalp hair. On histopa- Aquagenic syringeal acrokerato- per day until irritation subsided. Twenty thology, he noted focal hyperkeratosis, derma has also been associated with the percent aluminum chloride hexahydrate acanthosis with normal eccrine ducts use of rofecoxib. Carder and Weston2 was resumed once nightly until the kera- and normal dermis. Treatments of this described an 18-year-old female with a totic papules no longer occurred with hereditary variant have not been successful. mixed connective-tissue disease who was immersion. These treatments include topical tretinoin, begun on rofecoxib one month prior to alpha hydroxy acids, salicylic acid and the onset of exaggerated palmar wrinkling Discussion cryotherapy.8 and swelling after exposure to water. The In contrast, aquagenic syringeal acroker- cutaneous problem resolved three weeks Aquagenic syringeal acrokeratoderma atoderma presents with translucent white after the discontinuation of rofecoxib. is one of many terms that have been used papules and plaques that are visible on Rofecoxib is a selective COX2 inhibitor that

JeFFries, sawyer,author kessLer 27

leads to increased sodium reabsorption derma. Data on the effectiveness of these in the kidneys. The authors speculate that treatment options is sparse and based on this may also occur in the skin, leading to case reports. Adding to the dilemma, at SOLODYN INNOVATION increased binding capacity. times this condition shows spontaneous Khuu et al.12 also described a case of an resolution.9, 12,16 association of aquagenic syringeal acro- Besides our treatment of 20% aluminum keratoderma in association with aspirin chloride hexahydrate,18,26 other treatment use. They describe a 16-year-old female options include 12% ammonium lactate with a history of excessive wrinkling of her cream,14 20% salicylic acid and 10% urea left palm with exposure to water two weeks cream,22 mometasone furoate ointment,7 after she began a regimen of 81 milligrams and botulinum toxin injections.4 of aspirin per day. She had no personal or family history of cystic fibrosis and nega- Figure 1 References tive genetic testing. The lesions resolved 1. Baldwin BT, Prakash A, Fenske NA, Messina JL. Aqua- spontaneously four months after theFigure initial 1: Glazed appearance of left palmar surface prior to water submersion. genic syringeal acrokeratoderma: Report of a case with presentation, despite continuation of histologic findings. J Am Acad Dermatol 2006; 54;5:899- 902. aspirin. Aspirin inhibits COX1 and COX2, 2. Carder KR, Weston WL. Rofecoxib-induced instant which are both expressed on keratinocytes. aquagenic wrinkling of the palms. Pediatr Dermatol 2002;19:353-5. The authors speculate that aspirin leads to 3. Davis LS, Woody CM. Idiopathic aquagenic wrinkling of increased epidermal sodium retention due the palms. Pediatr Dermatol 2004; 21;2:180. 4. Diba VC, Cormack GC, Burrows, NP. Botulinum toxin to the COX2 component. is helpful in aquagenic palmoplantar keratoderma. Br J Dermatol 2005;152:394-5. The associations of cystic fibrosis and 5. Elliott RB. Wrinkling of skin in cystic fibrosis. Lancet COX2 inhibitors have shed some light 1974; ii:108 (Letter). 6. English JC, McCollough ML. Transient reactive papu- on the pathophysiology of aquagenic lotranslucent acrokeratoderma. J Am Acad Dermatol syringeal acrokeratoderma. However, it 1996;34:686-7. may be helpful to understand the physi- 7. Erkek E. Unilateral transient reactive papulotranslu- Figure 2 cent acrokeratoderma in a child. Pediatr Dermatol 2007; ologic response of the exaggerated palmarFigure 2: White pebbly hyperkeratotic papules on left palmar surface immediately following24;5:564-6. 8. Heymann WR. Hereditary papulotranslucent acrokerato- wrinkling by reviewing what happensimmersion in for two minutes in room temperature tap water. derma Cutis 1998;61:29-30. physiologic wrinkling. As we know, palmar 9. Itin PH, Lautenschlager S. Aquagenic syringeal acrokeratoderma(transient reactive papulotranslucent and plantar wrinkling is normal after acrokeratoderma). Dermatology 2002;204:8-11. prolonged water exposure. This normal 10. Johns MK. Skin wrinkling in cystic fibrosis. Med Biol Illustr 1975;25:205-10. physiologic response has actually been used 11. Katz KA, Yan AC, Turner ML. Aquagenic wrinkling of the to evaluate sympathetic nerve injury. The palms in patients with cystic fibrosis homozygous for the delta F508 CFTR mutation. Arch Dermatol 2005;141:621- relationship between palmar wrinkling 4. and nerve injury was first discussed in a 12. Khuu PT, Duncan KO, Kwan A, Hoyme HE, Bruckner AL. 20 Unilateral Aquagenic Wrinkling of the palms associated case series report by O’Riain in 1973. He with aspirin intake Arch Dermatol 2006; 142;1661-2. noted that patients with hand injuries that 13. Kirnyai-Asadi A, Kotcher LB, Jih MH. The molecular basis of hereditary palmoplantar keratodermas. J Am Acad impacted the ulnar nerve lacked physi- Dermatol 2002;47:327-43. ologic wrinkling after prolonged immer- 14. Kocaturk E, Kavala M, Buyukbabani N, Turkoglu Z. Whitish papules on the palm. Internat J of Dermatol sion in water in the areas of innervation Figure 3 2007;46:736-7. of the ulnar nerve. He found this to be a 15. Lowes MA, Khaira GS, Holt D. Transient reactive papu- Figure 3: Close-up image of white papules on left palmar surface following water immersion.lotranslucent acrokeratoderma associated with cystic quick and easy test of nerve injury and increased vasomotor firing and subsequent fibrosis. Australas J Dermatol 2000;41:172-4. named it the “wrinkle test.” It is now used vasoconstriction, which in turn triggers 16. MacCormack MA, Wiss K, Malhotra R. Aquagenic syringeal acrokeratoderma: report of two teenage cases. J to evaluate sympathetic response after small muscle fiber contractions. The vaso- Am Acad Dermatol 2001;45:124-6. upper-limb neurologic injury or surgery. 17. Marcus D, Shwayder T. Aquagenic wrinkling of the constriction also results in a loss of volume SOLODYN is indicated to treat only infl ammatory lesions of non-nodular moderate to severe The wrinkle test has also been used in palms in an 11-year-old girl J Am Acad Dermatol 2007; on the palmar surface, leading to a negative 56:AB160. acne vulgaris in patients 12 years of age and older. SOLODYN did not demonstrate any effect dermatology. Sheskin and colleagues23 eval- pressure, which pulls down the skin. The 18. Neri I, Bianchi F, Patrizi A. Transient Aquagenic Palmar hyperwrinkling: The first instance reported in a young on non-infl ammatory lesions. Safety of SOLODYN has not been established beyond 12 weeks uated nerve injury by comparing patients contraction of the fine muscles also pulls boy. Pediatric Dermat 2006;23:39-42. of use. This formulation of minocycline has not been evaluated in the treatment of infections. with leprosy to controls using the wrinkle down the skin and results in a wrinkled 19. Onwukwe MF, Mihm MC Jr, Toda K. Hereditary papulotranslucent acrokeratoderma. A new variant of familial To reduce the development of drug-resistant bacteria as well as to maintain the effectiveness of test. They found that all 20 of the control and distorted appearance to the palmar punctate keratoderma? Arch Dermatol 1973;108:108-110. other antibacterial drugs, SOLODYN should be used only as indicated. subjects without nerve injury had physi- surface. 20. O’Riain S. New and Simple test of nerve function in hand. Br Med J 1973;3:615-6. SOLODYN Tablets Important Safety Information ologic wrinkling after immersion in water, Aquagenic syringeal acrokeratoderma 21. Yalcin B, Artuz F, Toy GG, et al. Acquired aquagenic whereas 32 of the 38 patients with leprosy appears to be an accelerated and exag- papulotranslucent acrokeratoderma. J Eur Acad Dermatol • The most commonly reported side effects were to the administration of antibacterial agents. Venereol 2005;19:654-6. headache, fatigue, dizziness, and pruritus. did not. gerated response to immersion in water. 22. Saray Y, Seckin D. Familial aquagenic acrokeratoderma: • Central nervous system side effects, including Further research on physiologic wrin- case reports and review of the literature. Int J Dermatol • Minocycline, like other tetracyclines, can cause light-headedness, dizziness, or vertigo, have The dermatology literature has provided 2005;44:604-9. kling revealed the role of vasoconstriction. several explanations for this phenomenon, 23. Sheskin J, Saatto S, Yosipovitz Z, Ilukevich A. Lack of fetal harm when administered to a been reported with minocycline therapy. Wilder-Smith and Chow25 measured the wrinkle formation in the fingertips of patients with Han- pregnant woman. • In rare cases, photosensitivity has been including dilation of the eccrine ducts sen’s disease. Confirmation of previous observations. velocity of ulnar and digital artery blood secondary to occlusion or friction,16 weak- Hansenol Int. 1983;8:54-60. • Tetracycline drugs should not be used during reported. flow before and after immersion in water. 15 24. Wilder-Smith EP. Water immersion wrinkling-physiology tooth development (last half of pregnancy and • Should not be used during pregnancy nor by ness in the eccrine duct wall, eccrine and use as an indicator of sympathetic function. Clin 1 up to 8 years of age) as they may cause They found significantly less blood flow glandular hyperplasia and possibly a Autonon Res 2004;14:125-31. individuals of either gender who are with palmar wrinkling after immersion 25. Wilder-Smith EP, Chow A. Water immersion wrinkling is permanent discoloration of teeth. attempting to conceive a child; concurrent use pathologic barrier in the stratum corneum due to vasoconstriction. Muscle Nerve 2003;27:307-11. 24 9, • Pseudomembranous colitis has been reported of tetracyclines with oral contraceptives may in water. A year later, Wilder-Smith leading to increased water absorbance. 26. Yan AC, Aasi SZ, Alms WJ, et al. Aquagenic palmoplantar proposed the following theory regarding 13 This might be secondary to an altered keratoderma. J Am Acad Dermatol 2001;44: 696-9. with nearly all antibacterial agents and may render oral contraceptives less effective. physiologic wrinkling: First, water diffuses cornified envelope that may lead to the range from mild to life-threatening; therefore, it • This drug is contraindicated in persons who into eccrine sweat ducts and the epidermal is important to consider this diagnosis in have shown hypersensitivity to any of the impaired barrier function of the palmar patients who present with diarrhea subsequent electrolyte homeostasis is altered. There surface, which results in the altered perme- tetracyclines. is then a subsequent change in membrane ability and increased water absorption. stability of the network of surrounding Multiple therapies have been advanced See reverse side for brief summary of Full Prescribing Information. nerve fibers. This instability triggers to treat aquagenic syringeal acrokerato- SOLODYN and Benefi ts built in are trademarks of Medicis Pharmaceutical Corporation. © 2009 Medicis, The Dermatology Company SOL 09-028 10/30/10 28 titLeAQUAGENIC SYRINGEAL ACROKERATODERMA

Medicis Creative Services Job number: Flat Trim Size: 8.5" x 11" Colors: 4CP Contact: SOL 09-028 10/30/10 Bleed Size: 8.75" x 11.25" Lisa Cherry SOLODYN New Strengths Journal Ad— Live Area: 7.5" x 10" Spot(s): None 480-291-5820 JAOCD [email protected]

Additional Info: SOLODYN INNOVATION

SOLODYN is indicated to treat only inﬂ ammatory lesions of non-nodular moderate to severe acne vulgaris in patients 12 years of age and older. SOLODYN did not demonstrate any effect on non-inﬂ ammatory lesions. Safety of SOLODYN has not been established beyond 12 weeks of use. This formulation of minocycline has not been evaluated in the treatment of infections. To reduce the development of drug-resistant bacteria as well as to maintain the effectiveness of other antibacterial drugs, SOLODYN should be used only as indicated. SOLODYN Tablets Important Safety Information • The most commonly reported side effects were to the administration of antibacterial agents. headache, fatigue, dizziness, and pruritus. • Central nervous system side effects, including • Minocycline, like other tetracyclines, can cause light-headedness, dizziness, or vertigo, have fetal harm when administered to a been reported with minocycline therapy. pregnant woman. • In rare cases, photosensitivity has been • Tetracycline drugs should not be used during reported. tooth development (last half of pregnancy and • Should not be used during pregnancy nor by up to 8 years of age) as they may cause individuals of either gender who are permanent discoloration of teeth. attempting to conceive a child; concurrent use • Pseudomembranous colitis has been reported of tetracyclines with oral contraceptives may with nearly all antibacterial agents and may render oral contraceptives less effective. range from mild to life-threatening; therefore, it • This drug is contraindicated in persons who is important to consider this diagnosis in have shown hypersensitivity to any of the patients who present with diarrhea subsequent tetracyclines.

See reverse side for brief summary of Full Prescribing Information.

author 29

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

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

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

Clostridium difficile colitis. occur independently of time or amount of activation.Minocycline was not clastogenic in Trial Subjects July 2009 drug administration, whereas other tissue vitro using human peripheral blood lymphocytes ® 17110103 2. Hepatotoxicity – Post-marketing cases pigmentation has been reported to occur upon or in vivo in a mouse micronucleus test. Adverse Event SOLODYN PLACEBO of serious liver injury, including irreversible prolonged administration. Skin pigmentation (1 mg/kg) N=364 drug-induced hepatitis and fulminant hepatic Impairment of Fertility—Male and female N=674 (%) (%) includes diffuse pigmentation as well as over reproductive performance in rats was unaffected failure (sometimes fatal) have been reported with sites of scars or injury. At least one treatment- 379 (56) 197 (54) minocycline use in the treatment of acne. by oral doses of minocycline of up to 300 mg/ emergent event Information for Patients kg/day (which resulted in up to approximately Headache 152 (23) 83 (23) Metabolic effects (See Patient Package Insert for additional 40 times the level of systemic exposure to Fatigue 62 (9) 24 (7) The anti-anabolic action of the tetracyclines minocycline observed in patients as a result of Dizziness 59 (9) 17 (5) information to give patients) may cause an increase in BUN.While this 1. Photosensitivity manifested by an exaggerated use of SOLODYN®). However, oral administration Pruritus 31 (5) 16 (4) is not a problem in those with normal sunburn reaction has been observed in some of 100 or 300 mg/kg/day of minocycline to male Malaise 26 (4) 9 (3) renal function, in patients with significantly individuals taking tetracyclines, including rats (resulting in approximately 15 to 40 times Mood alteration 17 (3) 9 (3) impaired function, higher serum levels of minocycline. Patients should minimize or the level of systemic exposure to minocycline Somnolence 13 (2) 3 (1) tetracycline-class antibiotics may lead to observed in patients as a result of use of Urticaria 10 (2) 1 (0) avoid exposure to natural or artificial sunlight azotemia, hyperphosphatemia, and acidosis. (tanning beds or UVA/B treatment) while using SOLODYN®) adversely affected spermatogenesis. Tinnitus 10 (2) 5 (1) If renal impairment exists, even usual oral or minocycline. If patients need to be outdoors Effects observed at 300 mg/kg/day included Arthralgia 9 (1) 2 (0) parenteral doses may lead to excessive systemic while using minocycline, they should wear a reduced number of sperm cells per gram Vertigo 8 (1) 3 (1) accumulations of the drug and possible liver of epididymis, an apparent reduction in the Dry mouth 7 (1) 5 (1) loose-fitting clothes that protect skin from sun toxicity.Under such conditions, lower than exposure and discuss other sun protection percentage of sperm that were motile, and (at Myalgia 7 (1) 4 (1) 30 titLe

Additional Info: BRIEF SUMMARY usual total doses are indicated, and if therapy measures with their physician. Treatment 100 and 300 mg/kg/day) increased numbers Adverse reactions not observed in the clinical (see package insert for Full Prescribing is prolonged, serum level determinations of the should be discontinued at the first evidence of of morphologically abnormal sperm cells. trials, but that have been reported with ow muCh dermAtology is being tAught in our osteopAthiC Information) drug may be advisable. skin erythema. Morphological abnormalities observed in sperm minocycline hydrochloride use in a variety of h samples included absent heads, misshapen indications include: ® Central nervous system effects 2. Patients who experience central nervous SOLODYN heads, and abnormal flagella. 1. Central nervous system side effects including system symptoms (see WARNINGS) should Skin and hypersensitivity reactions: fixed drug mediCAl sChools (MINOCYCLINE HCl, USP) EXTENDED RELEASE be cautioned about driving vehicles or using Limited human studies suggest that eruptions, balanitis, erythema multiforme, ? TABLETS light-headedness, dizziness or vertigo have been reported with minocycline therapy. Patients who hazardous machinery while on minocycline minocycline may have a deleterious effect on Stevens-Johnson syndrome, anaphylactoid Rx Only experience these symptoms should be cautioned therapy. Patients should also be cautioned spermatogenesis. purpura, photosensitivity, pigmentation of skin KEEP OUT OF REACH OF CHILDREN about driving vehicles or using hazardous about seeking medical help for headaches or SOLODYN® should not be used by individuals of and mucous membranes, hypersensitivity Brent Loftis, D.O.,* Aleksandra Glisic, OMS IV,** Bill Way, D.O., FAOCD*** blurred vision. reactions, angioneurotic edema, anaphylaxis. INDICATIONS AND USAGE machinery while on minocycline therapy.These either gender who are attempting to conceive *1st-year Resident, Dermatology Institute, Texas Division of A.T. Still University, Kirksville College of Osteopathic Medicine, Duncanville, TX symptoms may disappear during therapy and ® 3. Concurrent use of tetracycline may render a child. Autoimmune conditions: polyarthralgia, SOLODYN is indicated to treat only usually rapidly disappear when the drug is oral contraceptives less effective (See Drug pericarditis, exacerbation of systemic lupus, **OMS IV, Des Moines University, Des Moines, IA inflammatory lesions of non-nodular moderate Pregnancy—Teratogenic Effects: Pregnancy discontinued. Interactions). category D (See WARNINGS) pulmonary infiltrates with eosinophilia, transient ***Dermatology Residency Program Director, Dermatology Institute, Texas Division of A.T. Still University, Kirksville College of Osteopathic Medicine, to severe acne vulgaris in patients 12 years of lupus-like syndrome. age and older. SOLODYN® did not demonstrate 2. Pseudotumor cerebri (benign intracranial 4. Autoimmune syndromes, including drug- All pregnancies have a background risk of Duncanville, TX hypertension) in adults and adolescents has induced lupus-like syndrome, autoimmune Central nervous system: pseudotumor cerebri, any effect on non-inflammatory lesions.Safety birth defects, loss, or other adverse outcome of SOLODYN® has not been established beyond been associated with the use of tetracyclines. hepatitis, vasculitis and serum sickness regardless of drug exposure. There are no bulging fontanels in infants, decreased hearing. Minocycline has been reported to cause or have been observed with tetracycline-class adequate and well-controlled studies on the use thyroid discoloration, abnormal 12 weeks of use. Endocrine: precipitate pseudotumor cerebri, the hallmark antibiotics, including minocycline.Symptoms of minocycline in pregnant women. Minocycline, thyroid function. This formulation of minocycline has not been ABSTRACT of which is papilledema.Clinical manifestations may be manifested by arthralgia, fever, rash like other tetracycline-class antibiotics, crosses evaluated in the treatment of infections. include headache and blurred vision. Bulging and malaise. Patients who experience such Oncology: papillary thyroid cancer. the placenta and may cause fetal harm when To reduce the development of drug-resistant fontanels have been associated with the use symptoms should be cautioned to stop the Oral: glossitis, dysphagia, tooth discoloration. administered to a pregnant woman.Rare bacteria as well as to maintain the effectiveness of tetracyclines in infants.Although signs and drug immediately and seek medical help. Gastrointestinal: enterocolitis, pancreatitis, Background: Dermatologic diseases are commonly encountered in primary care settings, yet training in dermatology is limited for ® spontaneous reports of congenital anomalies of other antibacterial drugs, SOLODYN should symptoms of pseudotumor cerebri resolve after 5. Patients should be counseled about including limb reduction have been reported with hepatitis, liver failure. be used only as indicated. discontinuation of treatment, the possibility for osteopathic medical students. discoloration of skin, scars, teeth or gums that minocycline use in pregnancy in post-marketing Renal: reversible acute renal failure. permanent sequelae such as visual loss that can arise from minocycline therapy. experience. Only limited information is available Objective: The purpose of our study was to determine the amount of dermatology being taught in osteopathic medical schools in CONTRAINDICATIONS may be permanent or severe exists. Patients Hematology: hemolytic anemia, This drug is contraindicated in persons who 6. Take SOLODYN® exactly as directed. Skipping regarding these reports; therefore, no conclusion thrombocytopenia, eosinophilia. number of hours during 1st and 2nd years and the number of weeks of clinical rotations during 3rd and 4th years. should be questioned for visual disturbances on causal association can be established. have shown hypersensitivity to any of the prior to initiation of treatment with tetracyclines doses or not completing the full course of Preliminary studies suggest that use of Methods: All 28 osteopathic medical schools were contacted and asked about the amount of dermatology being taught in their tetracyclines. and should be routinely checked for papilledema therapy may decrease the effectiveness of Minocycline induced skeletal malformations minocycline may have deleterious effects on the current treatment course and increase the (bent limb bones) in fetuses when administered WARNINGS while on treatment. human spermatogenesis (see Carcinogenesis, medical school. likelihood that bacteria will develop resistance to pregnant rats and rabbits in doses of 30 Mutagenesis, Impairment of Fertility Concomitant use of isotretinoin and minocycline and will not be treatable by other antibacterial mg/kg/day and 100 mg/kg/day, respectively, Results: The amount of dermatology hours taught during 1st and 2nd years of medical school varied among schools from 0 Teratogenic effects should be avoided because isotretinoin, a section). 1) MINOCYCLINE, LIKE OTHER TETRACYCLINE- drugs in the future. (resulting in approximately 3 times and 2 systemic retinoid, is also known to cause hours to 52 hours. Dermatology rotations were not required during 3rd and 4th clinical years but could be taken electively. Weeks of CLASS ANTIBIOTICS, CAN CAUSE FETAL ® times, respectively, the systemic exposure to OVERDOSAGE pseudotumor cerebri. 7. SOLODYN should not be used by pregnant HARM WHEN ADMINISTERED TO A PREGNANT women or women attempting to conceive a minocycline observed in patients as a result In case of overdosage, discontinue medication, electives for any specialty varied between the osteopathic medical schools from four weeks to 32 weeks. Average number of weeks ® WOMAN. IF ANY TETRACYCLINE IS USED Photosensitivity child (See Pregnancy, Carcinogenesis and of use of SOLODYN ).Reduced mean fetal treat symptomatically and institute supportive for any electives, including dermatology, for all schools was 16.4 weeks during 3rd and 4th year. DURING PREGNANCY OR IF THE PATIENT Photosensitivity manifested by an exaggerated Mutagenesis sections). body weight was observed in studies in which measures. Minocycline is not removed in minocycline was administered to pregnant rats BECOMES PREGNANT WHILE TAKING THESE sunburn reaction has been observed in some 8. It is recommended that SOLODYN® not be significant quantities by hemodialysis or at a dose of 10 mg/kg/day (which resulted DRUGS, THE PATIENT SHOULD BE APPRISED OF individuals taking tetracyclines.This has been used by men who are attempting to father a peritoneal dialysis. THE POTENTIAL HAZARD TO THE FETUS. reported rarely with minocycline. Patients should in approximately the same level of systemic child (See Impairment of Fertility section). HOW SUPPLIED ® minimize or avoid exposure to natural or artificial exposure to minocycline as that observed in SOLODYN should not be used during ® ® pregnancy nor by individuals of either gender sunlight (tanning beds or UVA/B treatment) Laboratory Tests patients who use SOLODYN ). SOLODYN (MINOCYCLINE HCl, USP) Extended care doctor for a specific dermatologic ® Background Results who are attempting to conceive a child (see while using minocycline.If patients need to be Periodic laboratory evaluations of organ systems, SOLODYN should not be used during Release Tablets are supplied as aqueous 1 complaint. In a 1982 study, Branch, PRECAUTIONS: Impairment of Fertility & outdoors while using minocycline, they should including hematopoietic, renal and hepatic pregnancy.If the patient becomes pregnant while film coated tablets containing minocycline 15 Pregnancy). wear loose-fitting clothes that protect skin from studies should be performed.Appropriate tests taking this drug, the patient should be apprised hydrochloride equivalent to 45 mg, 65 mg, 90 Health care delivery has changed Collins, and Wintroub found that more Table 1 shows all the data collected from sun exposure and discuss other sun protection for autoimmune syndromes should be performed of the potential hazard to the fetus and stop mg, 115 mg or 135 mg minocycline. 2) THE USE OF DRUGS OF THE TETRACYCLINE measures with their physician. as indicated. CLASS DURING TOOTH DEVELOPMENT treatment immediately. The 45 mg extended release tablets are gray, dramatically in the past couple of decades. than 22% of patients (111/495) encoun- the osteopathic medical schools. It includes unscored, coated, and debossed with “DYN-045” (LAST HALF OF PREGNANCY, INFANCY, AND PRECAUTIONS Drug Interactions Nursing Mothers on one side. Each tablet contains minocycline From 1975 through 2000, there has been tered in a primary care setting during a number of hours taught during 1st and CHILDHOOD UP TO THE AGE OF 8 YEARS) MAY 1. Because tetracyclines have been shown to Tetracycline-class antibiotics are excreted in General hydrochloride equivalent to 45 mg minocycline, CAUSE PERMANENT DISCOLORATION OF THE ® depress plasma prothrombin activity, patients human milk. Because of the potential for serious a dramatic shift from fee-for-service to one-year period had at least one derma- 2nd years of medical school as well as Safety of SOLODYN beyond 12 weeks of use supplied as follows: TEETH (YELLOW-GRAY-BROWN). has not been established. who are on anticoagulant therapy may require adverse effects on bone and tooth development managed health care.1,2 Managed care tologic problem.1 Fien et al. found that number of elective weeks during the 3rd This adverse reaction is more common during downward adjustment of their anticoagulant in nursing infants from the tetracycline-class NDC 99207-460-30 Bottle of 30 As with other antibiotic preparations, use dosage. NDC 99207-460-10 Bottle of 100 long-term use of the drug but has been of SOLODYN® may result in overgrowth of antibiotics, a decision should be made whether plans attempt to reduce costs by restricting 21% (50/239) of patients who presented and 4th clerkship years. observed following repeated short-term courses. nonsusceptible organisms, including fungi. If 2. Since bacteriostatic drugs may interfere with to discontinue nursing or discontinue the drug, The 65 mg extended release tablets are blue, to their family medicine physician had at Enamel hypoplasia has also been reported. superinfection occurs, the antibiotic should be the bactericidal action of penicillin, it is advisable taking into account the importance of the drug unscored, coated, and debossed with “DYN-065” patient access to specialists, who are We found that the amount of derma- 1,3 4 TETRACYCLINE DRUGS, THEREFORE, SHOULD discontinued and appropriate therapy instituted. to avoid giving tetracycline-class drugs in to the mother (see WARNINGS). on one side.Each tablet contains minocycline assumed to be more costly. Patients least one skin problem. Therefore, derma- conjunction with penicillin. hydrochloride equivalent to 65 mg minocycline, tology taught during 1st and 2nd years NOT BE USED DURING TOOTH DEVELOPMENT. Bacterial resistance to the tetracyclines may Pediatric Use 3. The concurrent use of tetracycline and ® supplied as follows: are encouraged to use their primary care tologic conditions present to primary care 3) All tetracyclines form a stable calcium develop in patients using SOLODYN,® therefore SOLODYN is indicated to treat only of osteopathic medical school varied methoxyflurane has been reported to result in NDC 99207-463-30 Bottle of 30 complex in any bone-forming tissue.A decrease the susceptibility of bacteria associated with inflammatory lesions of non-nodular fatal renal toxicity. physicians for most of their needs. Primary physicians quite often, yet most primary among schools from 0 hours to 52 hours. in fibula growth rate has been observed in infection should be considered in selecting moderate to severe acne vulgaris in The 90 mg extended release tablets are yellow, premature human infants given oral tetracycline antimicrobial therapy. Because of the potential 4. Absorption of tetracyclines is impaired by patients 12 years and older. Safety and unscored, coated, and debossed with “DYN-090” care physicians are encouraged to provide a care physicians have limited training in One school out of 28, or 3.5%, did not in doses of 25 mg/kg every 6 hours. This effectiveness in pediatric patients below 4,10-13 for drug-resistant bacteria to develop during antacids containing aluminum, calcium or on one side.Each tablet contains minocycline wider spectrum of services to their patients dermatology. reaction was shown to be reversible when the ® magnesium and iron-containing preparations. the age of 12 has not been established. hydrochloride equivalent to 90 mg minocycline, have any dermatology incorporated into drug was discontinued. the use of SOLODYN, it should be used only as indicated. 5. In a multi-center study to evaluate the effect Use of tetracycline-class antibiotics below supplied as follows: in an attempt to save resources. According Knowing that due to changes in health the required curriculum. Twelve schools Results of animal studies indicate that of SOLODYN® on low dose oral contraceptives, the age of 8 is not recommended due to NDC 99207-461-30 Bottle of 30 tetracyclines cross the placenta, are found Autoimmune Syndromes hormone levels over one menstrual cycle with the potential for tooth discoloration (see NDC 99207-461-10 Bottle of 100 to the American Osteopathic Association, care, primary care physicians are seeing taught four to 15 hours of dermatology, in fetal tissues, and can cause retardation of Tetracyclines have been associated with the and without SOLODYN® 1 mg/kg once-daily WARNINGS). The 115 mg extended release tablets are green, approximately 65% of practicing osteo- skeletal development on the developing fetus. development of autoimmune syndromes.The more dermatological cases, we posed the 11 schools taught 16 to 30 hours, and were measured. Geriatric Use unscored, coated, and debossed with “DYN-115” Evidence of embryotoxicity has been noted long-term use of minocycline in the treatment Based on the results of this trial, minocycline- Clinical studies of SOLODYN® did not include on one side. Each tablet contains minocycline pathic physicians specializes in primary question of whether primary care physi- four schools taught more than 30 hours in animals treated early in pregnancy (see of acne has been associated with drug-induced related changes in estradiol, progestinic sufficient numbers of subjects aged 65 and over hydrochloride equivalent to 115 mg minocycline, PRECAUTIONS: Pregnancy section). lupus-like syndrome, autoimmune hepatitis and care areas including family practice. cians are trained adequately to handle of dermatology. This data is also repre- vasculitis. Sporadic cases of serum sickness hormone, FSH and LH plasma levels, of to determine whether they respond differently supplied as follows: Gastro-intestinal effects breakthrough bleeding, or of contraceptive from younger subjects. Other reported clinical NDC 99207-464-30 Bottle of 30 Implementation of managed health care have presented shortly after minocycline these dermatological cases. The purpose sented in percentage form in Figure 2. 1. Pseudomembranous colitis has been failure, can not be ruled out.To avoid experience has not identified differences in use.Symptoms may be manifested by fever, The 135 mg extended release tablets are pink reported with nearly all antibacterial contraceptive failure, female patients are advised responses between the elderly and younger has increased the number of dermatology of our study is to determine how much Fourteen schools provided this derma- rash, arthralgia, and malaise.In symptomatic (orange-brown), unscored, coated, and debossed agents and may range from mild to life- to use a second form of contraceptive during patients. In general, dose selection for an elderly patients, liver function tests, ANA, CBC, and with “DYN-135” on one side. Each tablet cases primary care physicians encounter threatening. Therefore, it is important to treatment with minocycline. patient should be cautious, usually starting at dermatology is being taught in osteopathic tology education during both 1st and 2nd other appropriate tests should be performed to contains minocycline hydrochloride equivalent to consider this diagnosis in patients who the low end of the dosing range, reflecting the evaluate the patients.Use of all tetracycline-class Drug/Laboratory Test Interactions 135 mg minocycline, supplied as follows: and treat. medical schools. We hypothesize that the years of medical school, 10 schools taught present with diarrhea subsequent to the drugs should be discontinued immediately. False elevations of urinary catecholamine greater frequency of decreased hepatic, renal, administration of antibacterial agents. or cardiac function, and concomitant disease or NDC 99207-462-30 Bottle of 30 Dermatologic diseases are prevalent in amount of dermatology currently taught in dermatology during the 2nd year, and four Serious Skin/Hypersensitivity Reaction levels may occur due to interference with the Treatment with antibacterial agents alters other drug therapy. NDC 99207-462-10 Bottle of 100 Post-marketing cases of anaphylaxis and fluorescence test. the United States. Some reports say that osteopathic medical schools is not enough schools taught dermatology during the 1st the normal flora of the colon and may permit Store at 25ºC (77ºF); excursions are permitted to serious skin reactions such as Stevens Johnson ADVERSE REACTIONS overgrowth of clostridia. Studies indicate that Carcinogenesis, Mutagenesis & 15º-30ºC (59º-86ºF) [See USP Controlled Room syndrome and erythema multiforme have been Because clinical trials are conducted under 5.3% of all annual office visits are related to prepare primary care physicians for the year. This data is represented in Table 2. a toxin produced by Clostridium difficile is a Impairment of Fertility Temperature]. reported with minocycline use in treatment prescribed conditions, adverse reaction rates primary cause of “antibiotic-associated colitis”. Carcinogenesis—Long-term animal studies Protect from light, moisture, and excessive heat. to symptoms attributed to the skin, hair growing number of dermatology cases they The average number of hours of derma- of acne. have not been performed to evaluate the observed in the clinical trial may not reflect the 4,5 After the diagnosis of pseudomembranous rates observed in practice. However, adverse Dispense in tight, light-resistant container with and nails. Other studies have indicated will encounter and treat in their practice. tology taught during 1st and 2nd years in Tissue Hyperpigmentation carcinogenic potential of minocycline.A colitis has been established, therapeutic reaction information from clinical trials provides child-resistant closure. Tetracycline class antibiotics are known to structurally related compound, oxytetracycline, measures should be initiated.Mild cases of a basis for identifying the adverse events that 6% to 7% of all outpatient visits are for all osteopathic medical schools was 17.9 cause hyperpigmentation. Tetracycline therapy was found to produce adrenal and pituitary U.S. Patent 5,908,838* and Patents Pending 1,6-8 Methods pseudomembranous colitis usually respond to tumors in rats. appear to be related to drug use. *90 mg is also covered by U.S. Patents discontinuation of the drug alone. In moderate may induce hyperpigmentation in many organs, skin complaints. Of these visits, only hours. Adverse events reported in clinical trials for 7,541,347 and 7,544,373 to severe cases, consideration should be given including nails, bone, skin, eyes, thyroid, Mutagenesis—Minocycline was not mutagenic A geographic map with locations of SOLODYN® are described below in Table 2. about 33% of patients are treated by a Lectures were taught from either hand- to management with fluids and electrolytes, visceral tissue, oral cavity (teeth, mucosa, in vitro in a bacterial reverse mutation assay Manufactured for: all osteopathic medical schools is shown protein supplementation, and treatment with alveolar bone), sclerae and heart valves.Skin (Ames test) or CHO/HGPRT mammalian cell Table 2 – Selected Treatment-Emergent Medicis, The Dermatology Company dermatologist, while 22.7% of patients outs provided by the school or a required an antibacterial drug clinically effective against and oral pigmentation has been reported to assay in the presence or absence of metabolic Adverse Events in at least 1% of Clinical Scottsdale, AZ 85256 in Figure 1. We contacted each of the 28

Clostridium difficile colitis. occur independently of time or amount of activation.Minocycline was not clastogenic in Trial Subjects July 2009 with skin disease are treated by family book, or else students were given a list drug administration, whereas other tissue vitro using human peripheral blood lymphocytes 4,9 osteopathic medical schools inquiring ® 17110103 2. Hepatotoxicity – Post-marketing cases pigmentation has been reported to occur upon or in vivo in a mouse micronucleus test. Adverse Event SOLODYN PLACEBO medicine physicians. This means that of recommended books they could use. of serious liver injury, including irreversible prolonged administration. Skin pigmentation (1 mg/kg) N=364 about how much dermatology was being drug-induced hepatitis and fulminant hepatic Impairment of Fertility—Male and female N=674 (%) (%) family medicine physicians are second only Fifteen schools provided a handout for includes diffuse pigmentation as well as over reproductive performance in rats was unaffected taught during the four years of training failure (sometimes fatal) have been reported with sites of scars or injury. At least one treatment- 379 (56) 197 (54) to dermatologists in the treatment of skin their dermatology lectures either as sole minocycline use in the treatment of acne. by oral doses of minocycline of up to 300 mg/ emergent event 4 at their school. Information was gathered Information for Patients kg/day (which resulted in up to approximately Headache 152 (23) 83 (23) disease. resource for the lectures, in combination Metabolic effects (See Patient Package Insert for additional 40 times the level of systemic exposure to Fatigue 62 (9) 24 (7) from the department chairs of academic The anti-anabolic action of the tetracyclines minocycline observed in patients as a result of Dizziness 59 (9) 17 (5) information to give patients) Several studies have been done to deter- with an online tutorial, or in combination may cause an increase in BUN.While this 1. Photosensitivity manifested by an exaggerated use of SOLODYN®). However, oral administration Pruritus 31 (5) 16 (4) and clinical years. This provided us with is not a problem in those with normal mine the prevalence of patients seen in with a textbook. Seven schools required sunburn reaction has been observed in some of 100 or 300 mg/kg/day of minocycline to male Malaise 26 (4) 9 (3) information on how many hours of derma- renal function, in patients with significantly individuals taking tetracyclines, including rats (resulting in approximately 15 to 40 times Mood alteration 17 (3) 9 (3) primary care who presented with skin Fitzpatrick textbook, and two schools impaired function, higher serum levels of minocycline. Patients should minimize or the level of systemic exposure to minocycline Somnolence 13 (2) 3 (1) tology were taught during 1st and 2nd tetracycline-class antibiotics may lead to observed in patients as a result of use of Urticaria 10 (2) 1 (0) avoid exposure to natural or artificial sunlight disease. Brooke et al. found that during required Habif textbook. Two schools did azotemia, hyperphosphatemia, and acidosis. (tanning beds or UVA/B treatment) while using SOLODYN®) adversely affected spermatogenesis. Tinnitus 10 (2) 5 (1) years as well as how many weeks of elec- If renal impairment exists, even usual oral or Arthralgia 9 (1) 2 (0) not have required books or handouts but minocycline.If patients need to be outdoors Effects observed at 300 mg/kg/day included a two-year period, 26.5% of patients tives students were allowed during their parenteral doses may lead to excessive systemic while using minocycline, they should wear a reduced number of sperm cells per gram Vertigo 8 (1) 3 (1) accumulations of the drug and possible liver of epididymis, an apparent reduction in the Dry mouth 7 (1) 5 (1) (151/570) presented to their primary instead provided students with a list of loose-fitting clothes that protect skin from sun 3rd and 4th years. toxicity.Under such conditions, lower than exposure and discuss other sun protection percentage of sperm that were motile, and (at Myalgia 7 (1) 4 (1) LoFtis, gLisic,author way 3131

Additional Info:

weeks of electives were allowed during 3rd A Geographic Map of Colleges of Osteopathic Medicine and 4th years of osteopathic medical educa- (for entering class 2008) tion. Six schools offered 0 to 8 weeks of electives, 10 schools offered nine to 16 weeks of electives, 11 schools offered 17 to 24 weeks of electives and only one school offered more than 24 weeks of electives. Discussion This is the first study done to show how much dermatology is being offered in osteopathic medical schools. We found that the number of dermatology hours taught during 1st and 2nd years in osteopathic medical schools varied significantly from school to school, with mean of 17.9 hours in 1st and 2nd years combined. Additionally, none of the 28 osteopathic medical schools required a rotation in dermatology during 3rd or 4th years. Number of elective weeks among schools also varied, from four weeks to 32 weeks during 3rd and 4th years combined. 11 In 1985, Ramsay and Mayer surveyed 1. A.T. Still University Kirksville 14. Oklahoma State University Center for Health dermatology departments or section chair- College of Osteopathic Medicine Sciences College of Osteopathic Medicine 2. A.T. Still University 15. Ohio University College of Osteopathic Medicine persons to determine the extent of derma- School of Osteopathic Medicine in Arizona 16. Philadelphia College of Osteopathic Medicine tology training in U.S. allopathic medical 3. Arizona College of Osteopathic Medicine 17. Pikeville College School of Osteopathic Medicine of Midwestern University 18. Pacific Northwest University of Health Sciences schools. They found the median number of 4. Arizona College of Osteopathic Medicine College of Osteopathic Medicine required hours of dermatologic training to of Midwestern University 19. Rocky Vista University College of Osteopathic be 14 hours, which they calculated to repre- 5. Des Moines University College of Osteopathic Medicine Medicine 20. Touro College of Osteopathic Medicine - New York sent 0.24% of the overall medical school 6. Georgia Campus 21. Touro University - California curriculum time.10 They also reported that Philadelphia College of Osteopathic Medicine Touro University College of Osteopathic Medicine 7. Kansas City University of Medicine and Biosciences 22. Touro University - Nevada 28% of students participated in a derma- College of Osteopathic Medicine Touro University College of Osteopathic Medicine tology clerkship, raising their dermatology 8. Lake Erie College of Osteopathic Medicine 23. University of Medicine and Dentistry of New Jersey 9. Lake Erie College of Osteopathic Medicine School of Osteopathic Medicine exposure time to 2.9% of their medical Bradenton Campus 24. University of New England education hours.10 Ramsay and Mayer 10. Lincoln Memorial University College of Osteopathic Medicine DeBusk College of Osteopathic Medicine 25. University of North Texas Health Science Center at concluded that (1) there was no obvious 11. Michigan State University Fort Worth Texas College of Osteopathic Medicine national standard of appropriate curric- College of Osteopathic Medicine 26. Edward Via Virginia College of Osteopathic Medicine 12. New York College of Osteopathic Medicine 27. Western University of Health Sciences ulum time for cutaneous disease, and (2) Of The New York Institute of Technology College of Osteopathic Medicine of the Pacific the existing allotted time for dermatologic 13. Nova Southeastern University 28. West Virginia School of Osteopathic Medicine education was inadequate given the amount College of Osteopathic Medicine Figure 2: Percentage of schools with number of hours of dermatology of cutaneous disease likely to be encoun- 10 taught during 1st and 2nd years of medical school tered in the ambulatory care setting. 10 In 1995, Knable, Hood and Pearson 50.0% found an average of 18 hours of required

45.0% 42.9% dermatologic contact per medical student. 39.3% Using the same calculations as Ramsay and 40.0% Mayer, they calculated that this equates to 35.0% 0.3% of a typical medical student’s four-year 10 30.0% education. They also found that 34% of students participated in dermatology clerk- 25.0% ships, raising their dermatology exposure 20.0% time to 3.0% of the total curriculum.10 14.3% 15.0% Neither of the studies above mentioned Percent of schools 10.0% dermatology education in osteopathic 3.6% medical schools. Osteopathic physicians are 5.0% encouraged to enter the field of primary 0.0% care, and with the new shift in health care 0 4 to 15 16 to 30 > 30 toward managed care, primary care physi- Hours of dermatology taught during 1st and 2nd years cians are bound to encounter and treat Figure 2 - Percentage of schools with number of hours of dermatology taught more dermatology cases in their practice. during 1st and 2nd years of medical school. According to recent statistics, family medicine physicians are second only to dermatologists in the treatment of skin disease.4 recommended books. One school had a during clinical years. Weeks of electives Does dermatology training of 17.9 hours specific textbook requirement indicated by * varied between the schools from four weeks on average and maybe a few weeks of elec- in Table 1 and listed below Table 1. Only one to 32 weeks. Average number of weeks of tives prepare these physicians to treat their school had not chosen lecture material yet. electives for all schools was 16.4 weeks. patients appropriately? Considering the Dermatology rotations were not required Table 3 shows a breakdown of how many increasing morbidity and mortality asso-

32 titLehow much dermatoLogy is Being taught in our osteopathic medicaL schooLs? Table 1 28 Osteopathic medical schools’ dermatology didactict itlecurriculum

Weeks of Authors Hours of electives, • credentials dermatology dermatology School taught Book or handout Year taught not required

A.T. Still University KCOM MO 21 * 1st and 2nd 16

A.T. Still University ABSTRACT SOMA AZ 21 * 1st and 2nd 16 abstract AZCOM AZ 4 handout and online tutorial 1st and 2nd 16

CCOM IL 4 handout and online tutorial 1st and 2nd 8

DMU-COM IA 15 Fitzpatrick 2nd 12

GA-PCOM GA 12 Fitzpatrick 2nd 32

KCUMB-COM MO 18 no required book, lecture handout 1st and 2nd 20 article LECOM PA 5 no required book, lecture handout 2nd 24

LECOM-Bradenton FL 0 (PBL) no required book, lecture handout 1st and 2nd 24

LMU-DCOM TN 26 Fitzpatrick 2nd 20

MSUCOM MI 21 handout 1st and 2nd 8

NSU-COM FL 29 Habif 1st and 2nd 8

NYCOM NY 52 Fitzpatrick 1st 4

OSUCOM OK 8 no required book, lecture handout 1st and 2nd 24

OU-COM OH 4 handout and online tutorial 1Figurest and 2 nd1 12

PCOM PA 12 Fitzpatrick 2nd 20

PCSOM KY 10 Habif 2nd 12

PNWU-COM WA 18-20 no book chosen, lecture handout 1st and 2nd 8

RVUCOM CO 43 ** 1st 12

TOUROCOM-NY 18 no book chosen, new school 1st and 2nd 24

TUCOM-CA 18 no required book, lecture handout 1st and 2nd 16

TUNCOM NV 12 no required book, lecture handout 2nd 20

UMDNJ-SOM NJ 16 no required book, lecture handout 1st and 2nd 8

UNECOM ME 26 Fitzpatrick 2nd 18

UNTHSC/TCOM TX 4 no book chosen, lecture handout 1st 24

VCOM VA 35 handout and Habif 2nd 20

Western U/COMP CA 36 handout 2nd 16

WVSOM WV 12 Fitzpatrick 1st 16

*Text - one required for the course A) Andrews’ Diseases of the Skin, Clinical Dermatology. 10th edition. Arnold, ed. W.B. Saunders (2006). B) Clinical Dermatology. 4th edition. Habif T, ed. Mosby (2003). C) Color Atlas & Synopsis of Clinical Dermatology. 5th edition. Fitzpatrick, ed. McGraw Hill (2005). D) Dermatology, Bolognia JL, Jorizzo JL, Rapini RP, eds. Mosby (2007).

**Text - one required for the course Robbins Basic Pathology, 8th Ed., Kumar, Abbas, et al. Saunders (2007). Interactive Case Study Companion to Robbins Pathologic Basis of Disease, CD-ROM. Kumar and Hagler. Saunders. Basic Histology Text and Atlas. 10th edition. Junquiera. Lange (2002). Cecil Medicine. 23rd edition. Goldman, Ausiello. Saunders (2008) (with online Expert Consult). Basic and Clinical Pharmacology. 10th edition. Katzung. McGraw Hill (2007).

LoFtis, gLisic,author way 3333 Table 3:

Number of elective weeks in 3rd and 4th years of osteopathic medical school

Weeks of elective rotations, Number of Percent of dermatology not required schools schools 0-8 6 21.4% 9-16 10 35.7% 17-24 11 39.3% 25-32 1 3.6%

ciated with cutaneous cancers as well as 3. Weary PE. Behold, the gatekeeper cometh. Int J Dermatol. the growing number of dermatology cases 1984; 23:33-34. 4. Fien S, Berman B, Magrane B. Skin disease in a primary encountered in primary care, this appears to care practice. SKINmed: Dermatology for the Clinician. be an inadequate amount of time devoted 2007; 4:350-353. 5. Cherry DK, Burt CW, Woodwell DA. National ambulatory to dermatology in our osteopathic medical medical care survey: 2001 summary. Adv Data. 2003; schools. 337:1-44. 6. Stern RS, Johnson M, DeLozier J. Utilization of physi- A limitation of our study is that we did cian services for dermatologic complaints. Arch Dermatol. 1977;113:1062–1066. not take into account how much derma- 7. Schappert SM. National ambulatory medical care sur- tology is being taught as a part of other vey: 1990 summary. National Center for Health Statistics. Advance Data. 1992; 213:. systems. Some schools do not have a set 8. Stern RS. Managed care and the treatment of skin dis- dermatology curriculum but their derma- eases: dermatologists do it less often. Arch Dermatol. tology lectures are integrated in the appro- 1996;132:776–780. 9. Thompson TT, Feldman SR, Fleischer AB Jr. Only 33% of priate systems taught during 2nd year of visits for skin disease in the US in 1995 were to derma- osteopathic medical education. A question tologists: is decreasing the number of dermatologists the appropriate response? Dermatol Online J. 1998; 4:3. that also may be posed, and can even be 10. Knable A, Hood AF, Pearson TG. Undergraduate medical considered another limitation of the study, education in dermatology: report from the AAD Interdis- ciplinary Education Committee, Subcommittee on Under- is “who is teaching these lectures?” Some graduate Medical Education. J Am Acad Dermatol. 1997; schools have board-certified dermatologists 36:467-470. 11. Ramsay DL, Mayer F. National survey of undergraduate teaching the lectures, whereas others may medical education. Arch Dermatol. 1985; 121:1529–1530. have family practice physicians with limited 12. Pariser RJ, Pariser DM. Primary care physicians’ errors in handling cutaneous disorders: a prospective survey. J Am dermatology training teaching the same Acad Dermatol. 1987; 17:239–245. lectures. 13. Ramsay DL, Weary P. Primary care in dermatology: whose role should it be?. J Am Acad Dermatol. 1996; 35:1005– 1008. 14. Finlay AY, Coles EC. The effect of severe psoriasis on Conclusion the quality of life of 369 patients. Br J Dermatol. 1995; 132:236-244. Medical education in the United States today continues to emphasize the importance of producing primary care physicians to serve the needs of the population.10 Primary care physicians encounter and treat a significant number of dermatology cases in their practice. Current dermatology education provided by osteopathic medical schools is not sufficient to provide appropriate training for the primary care physicians who will encounter a growing population of dermatology patients in their practice. We recommend that at least 24 lecture hours of dermatology and four weeks of dermatology rotations be required of osteopathic medical students at our colleges during their four-year curriculum.

References 1. Lowell BA, Froelich CW, Federman DG, Kirsner RS. Der- matology in primary care: prevalence and patient disposi- tion. J Am Acad Dermatol. 2001; 45:250-255. 2. Graham FE. A glossary of terms. Medical Group Manage- ment J. 1993; 40:96-102.

34 htitLeow much dermatoLogy is Being taught in our osteopathic medicaL schooLs? lymphAngiomA CirCumsCriptum: A CAse report

Andrea Baratta, DO; Lawrence Schiffman, DO; Suzanne Sirota Rozenberg, DO; Marvin Watsky, DO *Second-year Dermatology *1st-year Dermatology Resident, St. John’s Episcopal Hospital (SJEH), Far Rockaway, NY, **3rd-year Dermatology Resident, SJEH, Far Rockaway, NY ***Assistant Program Director, SJEH, Far Rockaway, NY, ****Program Director, SJEH, Far Rockaway, NY

ABSTRACT

Lymphangiomas are rare, benign proliferations of the lymphatic system. Lymphangioma circumscriptum (LC) is the most common cutaneous form of lymphangioma. It typically presents early in life and, in general does not interfere with a patients well-being. LC may be confused with other more common skin conditions and confirmation by biopsy is usually necessary. Interference of vital function, secondary complications and preservation of cosmesis are the major concerns in LC. Treatment options are varied and depend on locations and depth of lesions. Here we describe a case of a 16 year-old with congenital LC of the lower extremity.

Introduction ital disorders include Turner’s syndrome, allergies. On physical exam, the patient Noonan’s syndrome, chromosomal aneu- demonstrated grouped, flesh-colored and Lymphangioma circumscriptum (LC) is ploidy, Down syndrome and other trisomy hyperpigmented, well-circumscribed, a rare, hamartomatous lymphatic anomaly disorders.1 CH may also be associated with discreet papules and vesicles on the right that may be congenital or acquired.11 It fetal alcohol syndrome and hydrops fetalis.1 buttocks and right upper and lateral thigh may present at any time; however, it usually Here we present a case report of LC, (Fig. 1). Some lesions were coalescing presents at birth or during childhood.2,7 a microcystic lymphatic anomaly. It and resembling frogspawn (Fig. 2). Based It is due to hyperplasia of the lymphatic represents aggregations of poorly defined, on the history and physical examination, network.5 abnormal, microscopic, dilated lymphatic the diagnosis of lymphangioma circum- Lymphatic anomalies may be classified channels.5,11 This most commonly pres- scriptum was suspected. A shave biopsy as microcystic or macrocystic.1,5 If the ents clinically on the skin as a plaque with was performed in the clinic, and the hyperplastic lymphatics lie within loose a crop of clear or hemorrhagic vesicles histopathology demonstrated several thin- areolar tissue, then a macrocystic anomaly distributed on its surface, resembling walled lymphatic channels with luminal will predominate; if the lymphatics lie frogspawn.1,5 The lesions on the plaque valves in the papillary dermis, lined by a beneath dense muscle and fibrous tissue, surface tend to increase in number and single row of endothelial cells4 (Fig. 3, 4). then a microcystic anomaly is more size as time progresses.11 Lesions tend to be This was indeed consistent with lymphan- likely to ensue.12 The two most common much more extensive than what is seen on gioma circumscriptum. At that time, we macrocystic anomalies are cystic hygroma the surface of the skin, and imaging studies advised that the patient undergo an ultra- (CH) and cavernous lymphangioma (CL), are important to determine the extent of sound and MRI to determine the extent whereas the most common microcystic a lesion.5,11 Lymphatic anomalies are best and depth of the lesions and to rule out anomaly is LC.1,5 visualized by MRI.5 LC can be complicated any other congenital lymphatic anoma- Macrocystic lymphatic anomalies are by intermittent leakage of lymphatic fluid lies. At the follow-up visit, our patient had collections of large lymphatic cisterns with and secondary infections but in general is not completed the recommended imaging a thin endothelial lining.5 Clinically, they a benign process and usually requires no studies. appear as skin-colored, red, blue and some- treatment.1,5 Antibiotics may be necessary times transparent swellings under the skin.1 when a secondary infection occurs. LC Discussion There are no visible surface skin changes, may need to be removed surgically if it but they are in general readily detected due is in an inconvenient location that inter- Lymphangioma circumscriptum (LC) is to their large size.1,12 Macrocystic anoma- feres with a vital function.1,11 Patients may rare, accounting for only 4% of all vascular lies found at birth or early in infancy on also wish to have LC removed in order to tumors in children.6,14 It is due to hyper- 5,6 the neck, axilla, groin or lateral chest wall improve cosmetic appearance.2 proliferation of the lymphatic vessels. It are termed CH. Due to their location and usually presents at birth or during child- size, CH may be diagnosed prenatally via Case Report hood as a cluster of small, firm blisters ultrasound.5 filled with fluid that can range from clear CL can affect any part of the body.1 The This is a case report of a 16-year-old to pink to black, representing hemor- most common locations are the head, neck Caucasian male who presented to the rhage.1,2,5,6 The blisters may have a verru- and extremities. Their clinical appearance dermatology clinic at St. John’s Episcopal cous appearance on the surface.1,8,12 The is similar to CH with no involvement of Hospital with his mother for evaluation lesions visible on the skin’s surface repre- the overlying skin; however, they are not of some growths on his right leg that sent saccular dilations from underlying detected as easily on superficial examina- had been present since birth. This was lymphatic vessels in the papillary dermis tion due to their smaller size and greater his first time seeking evaluation. The that are pushing upward on the overlying depth.1 CL also tend to have a more lesions present had begun to increase epidermis.6,11 There is no reported racial rubbery consistency. Some authors regard in size and number, would occasionally predominance, and there is an equal sex CH as a distinct entity, whereas others bleed and had become mildly pruritic. distribution.11 It is most commonly found regard it as a subset of CL.1,12 One special The patient’s past medical history was on the shoulders, neck, axillae, limbs and note of concern is that CH may be associ- significant for severe autism and perva- the oral cavity.1,5 The lesions of LC can ated with many congenital disorders; there- sive developmental disorder. He had no become more prominent at puberty, may fore, prenatal diagnosis should be followed significant past surgical history, was not ooze or bleed and can occasionally become by karyotyping.1,5 The associated congen- on any medications and had no known infected.1,5 Baratta, schiFFman, rozenBerg,author watsky 35 both its cosmetic appearance and prevention of complications such as cellulitis.2,6 Treatment options for LC are varied. Definitive treatment for superficial and small LC lesions is surgical excision and is 91-100% curative; however, larger lesions treated surgically have a tendency to recur due to the inability to completely excise the deeper components.2,6,11 If the LC occurs in a surgically inaccessible site, other treatment modalities such as cautery, cryotherapy, radiotherapy and carbon-dioxide Figure 1 laser vaporization can be employed.2,6,13,14 Two new therapeutic options that have been reported in the literature are 23.4% hypertonic saline sclerotherapy and intralesional OK432 (picibanil).8 Our patient and his mother declined any treatment of his lesions as they were not concerned with the cosmetic appearance and he was not experiencing any secondary complications. We present this case to educate others about this rare entity and to demonstrate the importance of timely referral if necessary.

Figure 2 References 1. Ed. Rook A, Wilkinson DS, Ebling FJB, Champion RH, Burton JL. Textbook of Dermatology. Fourth edition. Blackwell Scientific Publications. 2. Goble RR, Frangoulis MA. British Journal of Ophthalmol- ogy, 1990, 74, 574-575. 3. Amini S, et al. Dermoscopic-Histopathologic Correlation of Cutaneous Lymphangioma Circumscriptum. Arch Der- matol, Vol 144 (12), Dec, 2008. 4. Rapini R P. Practical Dermatopathology, Elsevier Mosby, 2005. 5. Bolognia JL, Jorizzo JL, Rapini RP. Dermatology, second edition, pgs 1589-1590. 6. Heller M, Mengden S. Lymphangioma Circumscriptum. Dermatology Online Journal, Volume 14 (No. 5): 27. 7. Amouri A, Ali IB, et al. Acquired Lymphangioma Circum- scriptum of the Vulva. Dermatology Online Journal, Volume 14 (No.4): 10. 8. Horn LC, Kuhndel K, Pawlowitsch T, Leo C, Einenkel J. Acquired lymphangioma circumscriptum of the vulva mimicking genital warts. Eur J Obstet Gynecol Reprod Biol. Nov 1 2005; 123 (1): 118-20. Figure 3 9. Bikowski JB, Dumont AM. Lymphangioma circumscriptum: treatment with hypertonic saline sclerotherapy. J Am Acad Dermatol. Sep 2005; 53 (3): 442-4. 10. Ahn SJ, Chang SE, Choi JH, Moon KC, Koh JK, Kim DY. A case of unresectable lymphangioma circumscriptum of the vulva successfully treated with OK-432 in childhood. J Am Acad Dermatol. Nov 2006; 55 (5 suppl): S106-7. 11. Blum EJ. Lymphangioma Circumscriptum. J Dermatol Surg Oncol. Sep 1988; 14 (9): 1033. 12. Darmstadt GL. Perianal lymphangioma circumscriptum mistaken for genital warts. Pediatrics. Sep 1996; 98 (3 Pt 1): 461-3. 13. Haas AF, Narukar VA. Recalcitrant breast lymphangioma circumscriptum treated by UltraPulse carbon dioxide laser. Dermatol Surg. Aug 1998; 24 (8): 893-5. 14. Okazaki T, Iwatani S, Yanai T, Kobayashi H, Kato Y, Marusasa T, et al. Treatment of lymphangioma in children: our experience of 128 cases. J Pediatr Surg. Feb 2007; 42 (2): 386-9.

Figure 4 Fortunately, LC seldom interferes with a patient’s well-being and has nearly no risk of malignant transformation; however, it may present a diagnostic challenge.1,8,12 It is important to distinguish it from other vascular and lymphatic lesions as well as from lesions with a similar appearance such as verrucae, molloscum contagiosum, condyloma accuminata and hidrocystoma. This is why a biopsy is usually necessary to confirm the diagnosis.3,8,11,12 Indications for treating LC include

36 LYMPHANGIOMA CIRCUMSCRIPTUM: A CASE REPORT Authors • credentials

ACute Febrile neutrophiliC dermAtosis induCed by CoCCidioidomyCosis: A CAse report And brieF reView

Joseph Machuzak, DO,* Stephen Kessler, DO** *3rd-year dermatology resident, Midwestern University/Alta Dermatology, Mesa, AZ **Program director, Dermatology, Midwestern University/Alta Dermatology, Mesa, AZ

ABSTRACT

Acute febrile neutrophilic dermatosis or Sweet’s syndrome is a reactive process caused by an underlying illness or other disease process. Classic Sweet’s usually occurs in middle aged females and is characterized by the abrupt onset of painful, tender, red to purple papules, nodules and plaques. The eruption usually affects the upper extremities, face and neck. We describe a case of Sweet’s syndrome induced by coccioidomycosis and discuss the importance of a clinician to be knowledgeable of certain illnesses that may be endemic to a certain geographical area.

Case Report Discussion with the onset of the eruption, and the face, neck and extremities are the most A 42-year-old, otherwise healthy Acute febrile neutrophilic dermatosis, common sites, affected in an asymmetric Caucasian female presented to our also termed Sweet’s syndrome, was initially distribution. Oral lesions can also occur office with a complaint of “red bumps” described by Robert Sweet in 1964.1 It is a in Sweet’s syndrome, and these lesions that began approximately 16 days prior reactive process to many different under- most commonly appear in patients with to being evaluated by us. The eruption lying causes ranging from a mild respira- an underlying hematologic malignancy. initially affected her chest and shoulders tory illness to other inflammatory illness or Extracutaneous involvement can lead to but had since spread to her back and malignancy. The eruption usually involves substantial morbidity if not treated early in arms. She stated that the eruption eventu- the upper extremities, face and neck, can the course of the disease. ally became fixed and extremely painful. be associated with fever and a peripheral A set of diagnostic criteria has been She had been treated with a course of neutrophilia, and can range from a more proposed and includes the presence of Keflex, Bactrim DS, and a Medrol dose mild form of the disease to an aggressive two major and two minor clinical find- pack from an urgent care physician for an neutrophilic process. It usually presents ings. Major criteria include the abrupt upper respiratory infection, which resulted with an abrupt onset of red-to-purple onset of tender or painful erythematous in some reduction of the pain and erup- papules and nodules that usually coalesce plaques or nodules and a predominantly tion. She also stated the eruption would into plaques. neutrophilic infiltration in the dermis flare when not on the above-mentioned The cutaneous manifestation of Sweet’s without a leukocytoclastic vasculitis. medications. She denied any recent illness, syndrome can be the initial sign of an Minor criteria include a prior nonspecific change in medications, or travel to oather underlying inflammatory process or malig- respiratory or gastrointestinal infection, countries. Her past medical history was nancy and should warrant further inves- history of inflammatory disease or malig- non-contributory. tigation. The potential causes are many nancy, malaise and fever, elevated erythro- Physical exam revealed multiple crops and include hematologic malignancy, most cyte sedimentation rate, positive C-reactive of 1-2cm, moderately well demarcated, commonly acute myeloid leukemia, solid protein, >70% bands in peripheral blood erythematous, infiltrated, edematous tumors, inflammatory and infectious etiol- smears and a leukocytosis.5 papules, pustules and plaques affecting ogies, and drugs, and there is a pregnancy- The diagnosis is primarily made by her upper chest, neck, back, shoulders and induced variant.2 histopathologic evaluation with clinical thighs. There was no evidence of vesicles, As previously mentioned, acute febrile correlation. Laboratory and imaging scaling or scarring associated with these neutrophilic dermatosis is a reactive studies should be ordered to help confirm lesions. The rest of her skin examination process, or a hypersensitivity reaction, diagnosis and to identify the underlying appeared normal. A 4mm punch biopsy mediated by neutrophils. Although the process responsible for the hypersensi- was performed on her left anterior thigh pathophysiology remains unknown, there tivity reaction. This would include age- which demonstrated a wedge-shaped, appears to be a dysregulation of several appropriate screening for an underlying superficial and deep dermal infiltrate with cytokines. Among those implicated are malignancy. neutrophils, nuclear dust and few histio- interleukin-1, granulocyte colony stimu- Treatment would include the identifi- cytes. Based on the clinico-histopatho- lating factor, granulocyte-macrophage cation and appropriate treatment of an logical findings, acute febrile neutrophilic stimulating factor and interferon-γ.3,4 underlying cause. If no cause can be iden- dermatosis, or Sweet’s syndrome, was The skin is the primary organ affected tified, prednisone is rapidly effective, but suspected, and the patient was sent for by Sweet’s syndrome, but almost any recurrences are common with steroid taper. further work-up of underlying causes. extracutaneous site can be affected, Other treatments include high-potency Upon further analysis, the patient had most commonly the lungs and kidneys. topical steroids, dapsone, indomethacin, positive serum titers for Coccidioides Typically, patients will complain of a fever colchicine, doxycycline, and methotrexate, immitis, and chest X-ray showed a primary that may have preceded the eruption. The among others.6 Pharmacotherapy is pulmonary infection. These findings crops or nodules often appear abruptly and used to reduce morbidity and to prevent proved a diagnosis of Sweet’s syndrome are reddish-blue or violet in color. Some complications. secondary to coccidiomycosis. She was lesions may be studded with pustules or subsequently started on fluconazole, have a vesicular appearance due to massive Conclusion and the eruption began to resolve with subepidermal edema. Patients may continued treatment. complain of associated pain and burning In our patient, acute febrile neutro-

machurzak, kessLer 39 C. An immunohistochemical study of the dermal infiltrate and epidermal staining for interleukin 1 in 12 cases of sweet’s syndrome. British Journal of Dermatology 1996, vol. 134, n4, pp. 705-709. 4. Giasuddin AS, El-Orfi AH, Ziu MM, El-Barnawi NY. Sweet’s syndrome: is the pathogenesis mediated by helper T cell type 1 cytokines? J Am Acad Dermatol. 1998;39:940-3. 5. Su WP, Liu HN. Diagnostic criteria for sweet’s syndrome. Cutis. Mar 1986;37(3):167-74. 6. Bolognia JL, Jorizzo JL, Rapini RP. Neutrophilic dermatosis. Dermatology. 2008:27:382-3.

Figure 1

Figure 2

Figure 3 philic dermatosis was the reactive process to a pulmonary infection by Coccidioides immitis. This dimorphic fungus is endemic in the southwestern United States and underscores the importance of a clinician being knowledgeable of the various conditions which may be native to a particular area. Another possible confounding problem is the high travel rate of “winter visitors” to this particular location. These habits may cause the presentation of a certain condition that another clinician may not be particularly familiar with, leading to a delay in diagnosis. Our patient was started on fluconazole, which resulted in resolution of her cutaneous eruption. This result also identifies the importance of detecting an underlying cause so appropriate therapies can be started in a timely fashion.

References: 1. Von den Dreisch P. Sweet’s syndrome (acute febrile neutrophilic dermatosis). J Am Acad Dermatol. 1994Oct;31(4):535-56. 2. Cohen PR, Kurzrock R. Sweet’s syndrome: A review of current treatment options.Am J Clin Dermatol. 2002; 3(2):117-31. 3. Bourke JF, Jones JL. Fletcher A. ; Graham-Brown R. A.

40 acute FeBriLe neutrophiLic dermatosis induced By coccidioidomycosis Spindle Cell Malignant MelanoMa MiMiCking derMatofibroSarCoMa protuberanS: a CaSe report

Pete Morrell, DO1, Carlos Cerruto, MD2, Christopher Conner, MD3 , Clay J. Cockerell, MD4 , Bill V. Way, DO5 1Dermatology Resident, 1st Year, Northeast Regional Medical Center-Texas Division, Duncanville, TX, 2Dermatopathologist, Dermpath Diagnostics - Central Florida, Altamonte Springs, FL 3Plastic Surgeon/Mohs-Micrographic Surgeon, Woodlands, TX 4Dermatologist/Dermatopathologist, UT Southwestern Medical Center, Dallas, TX; Managing Director, Dermpath Diagnostics – Cock- erell and Associates, Dallas, TX 5Program Director, Dermatology, Northeast Regional Medical Center-Texas Division, Duncanville, TX

ABSTRACT

Malignant melanoma is remarkable for its ability to histologically simulate other soft-tissue tumors.1,2 This is especially the case for spindle-cell malignant melanoma, which can mimic dermatofibrosarcoma protuberans (DFSP), atypical fibroxanthoma, storiform- pleomorphic malignant fibrous histiocytoma, myxofibrosarcoma, hemangiopericytoma, xanthogranulomas, epidermotrophic xanthomas, and malignant schwannomas.1,3-6 The differentiation of these malignant neoplasms is dependant on the use of immunohistochemical staining. The case presented is one of an atypical spindle-cell melanoma mimicking dermatofibrosarcoma protuberans. Immunoperoxidase stains were strongly positive for S-100 protein as well as pan-melanoma antigen, but were negative for CD-34.

Introduction Spindle-cell malignant melanoma is one of the most challenging diagnoses in dermatopathology.1,2 Non-pigmented forms of malignant melanoma are often clinically misdiagnosed as soft-tissue neoplasms.3,4,7 Though these generally occur on sun-exposed areas of the body, they can occur elsewhere. These melanocytic neoplasms are generally composed of cells with elongated, narrow, tapering cytoplasmic processes.7,10 When viewed with routine H&E stain, Figure 1a Figure 1b atypical forms may appear to simu- Figure 1 A&B: Spindle cell melanoma, composed of elongated spindle malignant late other soft-tissue tumors.1,2 These melanocytes, arranged in short fascicles. include: DFSP, atypical fibroxanthomas, storiform-pleomorphic malignant fibrous histiocytomas, myxofibrosarcomas, xanthogranulomas, hemangiopericytomas, epidermotrophic xanthomas, and malignant schwannomas.1,3-6 Differentiation of these various entities is dependant on immunohistochemical staining. DFSP is a fibrohistiocytic neoplasm of intermediate malignant potential composed predominantly of mononuclear spindle cells in a storiform cartwheel pattern8,9 (Figure 2). Clinically, it appears most commonly as a large cutaneous Figure 2a Figure 2b nodule or an indurated plaque on the Figure 2 A&B: DFSP, composed of spindle cells arranged in a storiform pattern trunk or proximal extremities of middle- extending to the subcutaneous fat with focal entrapment. aged adults.10 While recurrence is common after resection, metastases are unusual.8,9 On H&E examination, this lesion pan-melanoma antigens but were negative demonstrated a spindle-cell proliferation for CD-34 (Figure 5). Final diagnosis was Case Report with cartwheel arrangement of the cells malignant spindle-cell melanoma, 7.5 mm extending into the deep subcutaneous in thickness, Clark’s level V, histologically An 83-year-old female presented with a tissue encasing fat (Figures 3, 4). There resembling DFSP. 15 mm, black nodule on the vertex of the was no epidermal involvement or melanin scalp. It had been slowly enlarging over noted (Figures 1, 2). At the base of the Discussion the previous two years. The patient had specimen, malignant cells were present a history of a pilar cyst removed from the between collagen bundles. Mitotic activity Malignant spindle-cell melanoma simu- same area two years prior. Preoperative was seen. Immunoperoxidase stains were lating DFSP and other benign and malig- diagnosis was recurrent cyst versus malig- strongly positive for S-100 protein and nant soft-tissue neoplasms is a known nant melanoma.

morreLL, cerruto, conner, cockereLL, way 41 S-100, pan-melanoma antigen and cytokeratin), the various possibilities can be differentiated. Ultimately, the care and outcome will depend on the correct diagnosis being made.

References: 1. Zelger BG, Steiner H, Wambacher B, Zelger B. Malig- nant melanomas simulating various types of soft tissue tumors. Dermatologic Surgery 1997; 23(11), 1047-1054. 2. Walker AN, Morton D. Immunohistochemistry: a useful adjunct in the evaluation of malignant cutaneous spindle cell tumors. Southern Medical Journal 1998; 81(12), 1505-1508. 3. Volpe R, Carbone A. Dermatofibrosarcoma protuberans metastatic to lymph nodes and showing a dominant histiocytic component. The American Journal of Dermato- pathology 1983; 5(4), 327-334. 4. Weiss SW. Dermatofibrosarcoma protuberans or spindled Figure 3 Figure 4 melanoma? The American Journal of Dermatopathology Figure 3 & 4: Spindle cell MM, composed of malignant spindle melanocytes arranged in 1984 6(3), 309-310. 5. Busam KJ, Rosai J, Iversen K, Jungbluth AA. Xantho- a storiform pattern extending to the subcutaneous fat with focal entrapment. granulomas with inconspicuous foam cells and giant cells mimicking malignant melanoma. The American Journal of Surgical Pathology, 2000; 24(6), 864-869. 6. Northcutt AD. Epidermotropic xanthoma mimicking bal- loon cell melanoma. The American Journal of Dermato- pathology 2000; 22(2), 176-178. 7. McKee P, Calonje E, Granter S. Pathology of the skin with clinical correlations. 3rd ed.: Mosby, 2005. 8. Filho JS, Milanezi F, Ferro J, Schmitt FC. Pediatric pigmented dermatofibrosarcoma protuberans (Bednar tumor): case report and review of the literature with emphasis on the differential diagnosis. Pathology Research and Practice 2002; 198, 621-626. Intraoperative 9. Ma CK, Zarbo RJ, Gown AM. Immunohistochemical characterization of atypical fibroxanthoma and dermatofibrosarcoma protuberans. Anatomic Pathology 1992; 97(4), 478-483. 10. Kumar V, Abbas A, Fausto N. Pathologic Basis of Dis- ease. 7th ed. Philadelphia: Elsevier Saunders, 2005. 11. Ma CK, Zarbo RJ, Gown AM. Immunohistochemical Characterization of Atypical Fibroxanthoma and Derma- tofibrosarcoma Protuberans. Am J Clin Pathology 1992; 478-483 Figure 5 th 12. Elder D, editor, Lever’s Histopathology of the Skin, 8 ed., Figure 5: Spindle cell MM, showing immunoreactivity to melanoma markers Philadelphia: Lippincott Williams and Wilkins 1997.

Table 1.

(Modified from Lever’s Histopathology of the Skin) Suggested immunohistochemical reactions as an aid to the differential diagnosis of cutaneous spindle-cell tumors Epithelial Atypical DFS SCC Desmoplastic Leiomyo- Sarcoma Fibroxan. Melanoma sarcoma Cytokeratin + - - + - - Vimentin + + + - + + S-100 - + - - + - Desmin - rare - - - + CD-34 variable variable + - - - diagnostic pitfall on clinical as well as path- are required procedures.” They do warn ological exam.1 Clinically, most amelanotic that “melanoma and leiomyosarcoma melanomas, desmoplastic melanomas and can express cytokeratin and leiomyosar- spindle-cell melanomas present as soft- comas can demonstrate immunoreactivity tissue lesions. These are most common for S-100 protein.”(11) A summary of the on the sun-exposed areas of the body.7 use of these stains is included (Table 1).12 Pathologically, these types of melanomas This is modified from a table from Lever’s may morphologically resemble several textbook.12 soft-tissue neoplasms. In cases where an Important clinical factors such as age epithelial component or melanin can not (older individuals), special site (head, neck be identified, special stains are necessary to and abdomen), and recurrent “benign” differentiate the possible cell type of origin. lesions increase the suspicion of malignant Chan et al. reviewed the use of special melanoma. A deeply located neoplasm stains in spindle-cell tumors. In their with spindle-cell morphology and high experience, “in daily practice only cytoker- mitotic activity should alert the dermato- atin, vimentin and S-100 protein staining pathologist. With special stains (CD-34,

42 titLespindLe ceLL maLignant meLanoma mimicking dermatoFiBrosarcoma protuBerans impetigo herpetiFormis: An unusuAl psoriAtiC presentAtion

Nathan Peterson, D.O.,* Michael Peterson, D.O.,** Chad Peterson, D.O.*** *Flight Surgeon, U.S. Naval Academy **Board Certified Dermatologist, US Army ***Board Certified Dermatologist, F.A.O.C.D

ABSTRACT

Impetigo herpetiformis is classified as a pustular dermatosis of pregnancy, characterized histopathologically by a massive infiltration of neutrophils resulting in the clinical formation of numerous sterile pustules. There is debate regarding impetigo herpetiformis as a subclassification of pustular psoriasis or as a stand-alone clinical entity. Regardless of the academic classification of impetigo herpetiformis, dermatologists should understand that it is a systemic illness associated with pregnancy and delivery. As such, dermatologists should be expected to provide an accurate diagnosis with an aggressive treatment plan to avoid complications, which include: placental insufficiency, fetal intrauterine growth retardation and stillbirth, hypotension, hypocalcemia, tetany, seizure delirium, and even death. In our case report, we discuss impetigo herpetiformis and its implications regarding diagnosis and treatment in pregnant and postpartum patients.

CASE REPORT from representative lesions, one of which arranged in groups or rings. was sent in Michelle’s solution for DIF In the intertriginous areas, the lesions A 24-year-old G1P1 female with no studies. become condyloma-like. prior history of psoriasis presented to our Histopathologic analysis showed hyper- Itching is mild. outpatient clinic complaining of numerous keratosis with neutrophilic crusting. Fever is present along with signs and erythematous plaques of varying sizes. Superficial pustules consisting predomi- symptoms of severe systemic toxicity that Within the plaques were randomly distrib- nantly of neutrophils were evident. There can lead to death of the patient. uted pustules, too numerous to count in was irregular psoriasiform hyperplasia with The disease is usually not recurrent. aggregate. a generally decreased granular layer. The disease occurs in both sexes. Such lesions were also accompanied by Additionally, there were findings of a systemic symptoms of generalized myalgias superficial perivascular lymphohistiocytic The cause is unknown. and arthralgias causing significant pain, infiltrate including neutrophils as well as Marked hyperpigmentation follows but the patient lacked a detectable fever. interstitial neutrophils and mononuclear healing of the lesions. A thorough medical history revealed cells. Histologic section of a skin lesion the initial presentation to be an isolated Mild to moderate spongiosis and papil- reveals an intraepidermal pustule. plaque appearing at the left breast approxi- lary dermal edema, along with exocytosis The historical background of impetigo mately one week prior to an uncomplicated of neutrophils and occasional mononu- herpetiformis provides a framework for spontaneous vaginal delivery of a normal- clear cells were identified. a clinical diagnosis for today’s practicing weight infant at 40 weeks estimated gesta- Direct immunoflourescence was essen- dermatologists. However, the recent liter- tional age. tially negative with respect to IgG, IgM, ature, as referenced in the next section, During the last week of her pregnancy, IgA, C3 and fibrinogen. favors the segregation of impetigo herpeti- the pustular rash was slowly progressive With respect to the above findings, formis as a pregnancy-specific diagnosis, over her left chest and back. However, the histologic sample is compatible with with supporting histiopathologic evidence delivery precipitated a dramatic flare, pustular psoriasis. that it is a disease sui generis.7 as numerous plaques with associated pustules rapidly encompassed 40% of HISTORICAL PERSPECTIVE DISCUSSION her body surface area over the next seven days. Additionally, she stated that epidural Impetigo herpetiformis was first Impetigo herpetiformis is a rare anesthesia with accompanying bandaging described as a separate clinical entity by dermatosis classified as an inflammatory 3 1 caused a dramatic increase in lesions to her Hebra in 1872. The first reported cases disorder of pregnancy. Clinically, it pres- mid-back, suggestive of Koebnerization of were in pregnant women, and almost ents as pustular psoriasis with general- 3 lesions. all patients had died. It was originally ized erythematous patches and plaques thought that impetigo herpetiformis was a accompanied by pustules. Impetigo A broad differential diagnosis was more serious variant of “dermatitis herpet- herpetiformis classically begins in the entertained, including: pustular psoriasis, iformis of pregnancy” (herpes gestationis).3 flexural regions such as the inner thigh impetigo herpetiformis, bullous impetigo, However, later male patients were given and continues to spread in a generalized disseminated HSV, pemphigus vulgaris, the diagnosis of impetigo herpetiformis, pattern commonly sparing the hands, feet acute generalized exanthematous pustu- apparently dissociating impetigo herpeti- and face. losis (AGEP) and Stevens-Johnson formis from pregnancy.3 syndrome. Impetigo herpetiformis presents in In 1961 the diagnostic criteria was modi- a pregnant patient usually in the third PATHOLOGY fied to include:3 trimester. Patients generally have no prior The primary lesion is a pustule, not a history of psoriasis.1 In order to obtain a prompt diagnosis, vesicle. Although an updated diagnostic crite- two 4.0 mm punch biopsies were obtained The pustules and resultant crusts are rion is lacking, impetigo herpetiformis peterson, perterson, peterson 43

CASE REPORT

A 24-year-old G1P1 female with no prior history of psoriasis presented to our outpatient clinic complaining of numerous erythematous plaques of varying sizes. Within the plaques were randomly distributed pustules, too numerous to count in aggregate. Such lesions were also accompanied by systemic symptoms of generalized myalgias and arthralgias causing significant pain, but the patient lacked a detectable fever. A thorough medical history revealed the initial presentation to be an isolated plaque appearing at the left breast approximately one week prior to an uncomplicated spontaneous vaginal delivery of a normal-weight infant at 40 weeks estimated gestational age. During the last week of her pregnancy, the pustular rash was slowly progressive over her left chest and back. However, delivery precipitated a dramatic flare, as numerous plaques with associated pustules rapidly encompassed 40% of her body surface area over the next seven days. Additionally, she stated that epidural anesthesia with accompanying bandaging caused a dramatic increase in lesions to her mid-back, suggestive of Koebnerization of lesions. A broad differential diagnosis was entertained, including: pustular psoriasis, impetigo herpetiformis, bullous impetigo, disseminated HSV, pemphigus vulgaris, acute generalized exanthematous pustulosis (AGEP) and Stevens-Johnson syndrome.

mise. Complications such as placental insufficiency, premature rupture of the membranes, intrauterine growth retardation and stillbirth have all been reported.6 Impetigo herpetiformis has been documented to occur in subsequent pregnancies.5,12 It is now generally accepted to occur specifically with pregnancy and to not occur in male patients.2 The current debate revolves around the classification scheme:

whether impetigo herpetiformis is a sepa- Figure 1 – Numerous erythematous plaques of varying sizes with randomlySlide distributed 1 – Tissue section of lesion at 10x. Mild to moderate spongiosis and papillary Figure 1 – Numerous erythematous plaques of varying sizes with randomlySlide 1 distributed– Tissue section of lesion at 10x. Mild to moderate spongiosis and papillaryrate clinical entity or a variant of pustular pustules. Figure 1 – Numerous erythematousdermal dermal edema.Slide edema. 1 – Tissue section of lesion at pustules. plaques of varying sizes with randomly 10x. Mild to moderate spongiosis and psoriasis during pregnancy.

distributed pustules. papillary dermal edema. In 1983, Pierard et al. attempted to make a histopathologic distinction between impetigo herpetiformis and pustular psoriasis of pregnancy. He illustrated that in pustular psoriasis of pregnancy, there is a perivascular mixed cellular infiltrate of lymphocytes, histiocytes and neutrophils around the blood vessels of the superficial plexus. Small lymphocytes or monocytes are sometimes present in the dermis.7 He noted that in impetigo herpetiformis, “there are many large mononuclear cells in the dermis. Proliferation of these mononuclear cells

SlideSlide 2 – Tissue2 – Tissue section section at 20x. at 20x. Hyperkeratosis Hyperkeratosis with with neutrophilic neutrophilic crusting crusting and andpustulein pustulethe dermis is intense.” Additionally, he

formation,formation, irregular irregular psoriasiform psoriasiform hyperplasia hyperplasia with with a decreased a decreased granular granular laye layer. r. Figure 2 – Plaques with associated noted that the pustules of impetigo herpeti- Figure 2 – Ppustuleslaques with associated rapidly pustules encompassed rapidly encompassed 40% 40% of of the patientSlide’s 2 – Tissue section at 20x. formis do not show any tendency toward bodyFigure surface 2 – Parealaques. with associated pustules rapidly encompassed 40% of theHyperkeratosis patient’s with neutrophilic body surfacethe area patient’s. body surface area. confluence, and they contain both neutro- crusting and pustule formation, phils and mononuclear cells with abundant irregular psoriasiform hyperplasia with cytoplasm.7 a decreased granular layer. In 2003, Chang et al. contributed to the debate by describing a patient as having impetigo herpetiformis during pregnancy. One year later, the patient experienced another similar pustular outbreak while not pregnant. She exhibited systemic symptoms on both occasions. As such, she was given an updated diagnosis of generalized pustular psoriasis, rather than true impetigo herpetiformis.9

Figure 3 – Plaques with associated pustules rapidly encompassed 40% of the patient’s Figure 3 – Plaques with associated body surface area. TREATMENT pustules rapidly encompassed 40% of

the patient’s body surface area. Slide 3 – Tissue section at 40x. Hyperkeratosis with neutrophilic infiltration andRecognition, pustule diagnosis and treatment formation, irregular psoriasiform hyperplasia with a decreased granular layer. Slide 3 – Tissue section at 40x. of impetigo herpetiformis are particularly

Slide 3Hyperkeratosis – Tissue section at 40x. Hyperkeratosis with neutrophilic with neutrophilic infiltration important and pustule in the pregnant patient because formation,infiltration irregular psoriasiform and hyperplasia pustule with formation,a decreased granular layer.of known complications threatening irregular psoriasiform hyperplasia with maternal and fetal wellbeing. a decreased granular layer. Systemic corticosteroids are the initial treatment, and symptoms are typically controlled with a relatively low dose of 15-30 mg daily.1,3 While corticosteroids may be sufficient to control systemic and cutaneous symptoms, they are not efficacious in prevention of

placental insufficiency resulting in IUGR or death of the fetus. Figure 4 – FigurePlaques with 4 associated – Plaques pustules rapidly with encompassed associated 40% of the patient’s body surface area. Slide 4 – Tissue section at 100x. Interstitial neutrophils and mononuclear cells. Interval monitoring with a biophysical pustules rapidly encompassed 40% of

the patient’s body surface area. profile and umbilical-artery Doppler studies have been recommended to assure

PATHOLOGYis usually associated with some systemic the wellbeing of the fetus and to prevent symptoms of malaise, fever, delirium, diar- severe complications, including stillbirth.12 In order to obtain a prompt diagnosis, two 4.0 mm punch biopsiesSlide were 4 obtained– Tissue section at 100x. Interstitial neutrophils and mononuclearAvoidance cells. of other severe complications from representativerhea, vomiting, lesions, one ofhypocalcaemia which was sent in Michelle’s and tetany. solution for DIFSlide studies. 4 – Tissue section at 100x. HistopathologicThere isanalysis evidence showed thathyperkeratosis impetigo with neutrophilicherpeti- crusting.Interstitial neutrophils and requires proper maintenance of fluid and Superficial pustules consisting predominantly of neutrophils were evident. There was electrolyte imbalances specifically related to irregular psoriasiformformis can hyperplasia lead withto maternal/fetala generally decreased compro granular layer. - mononuclear cells. Additionally, there were findings of a superficial perivascular lymphohistiocytic infiltrate including neutrophils as well as interstitial neutrophils and mononuclear cells. Mild44 to moderateimpetigo spongiosisherpetiFormis: and papillary dermal edema an, alongunusuaL with exocytosispsoriatic presentation of neutrophils and occasional mononuclear cells were identified. Direct immunoflourescence was essentially negative with respect to IgG, IgM, IgA, C3 and fibrinogen. With respect to the above findings, the histologic sample is compatible with pustular psoriasis. hypocalcaemia and treatment for potential 8. Mak RHK, et al. Generalized pustulosis in pregnancy: 11 psoriasis or impetigo herpetiformis? British journal of Der- sepsis. matology 2005;153:72. Combination therapy may be warranted 9. Chang SE. Impetigo herpetiformis followed by generalized pustular psoriasis: more evidence for same disease for patients who have difficulty clearing entity. International Journal of Dermatology 2003;42:754. lesions with systemic corticosteroids alone. 10. Reich A, et al. Severe Acute Generalized Exanthem- atous Pustulosis in a Pregnant Woman. SKINmed Treatment with 4 mg/kg daily cyclospo- 2006;5(4):197-199. rine in addition to prednisone in a third 11. Heymann WR. Dermatoses in Preganacy Update. J Am Acad Dermatology. 2005;52:888-889. trimester pregnancy was shown to be effec- 12. Ekuma-Nkama EN, et al. Impetigo Herpetiformis: tive without complication to mother or An Obstetric Concern. Annals of Saudi Medicine 1998;18:537-538. fetus.4 A case report demonstrated the efficacy of 70 mg/day of prednisone combined with 35 mg/day of etretinate in a postpartum patient, providing a marked reduction in symptoms after one week of treatment and complete clearance after three weeks.5 Although etretinate is no longer available, similar results may be seen with use of its active metabolite acitretin. Similarly, methotrexate 7.5 mg weekly in addition to 0.5 mg/kg oral prednisone resulted in improvement of symptoms and cessation of new pustules within the first week of combination treatment in a postpartum patient.6 Treatments using psoralens, retinoids and PUVA have been cited as alternative options to be included in combination or as single agents for the treatment of impetigo herpetiformis.6 When considering the treatment options for impetigo herpetiformis, systemic corticosteroids and cyclosporin provide the safer options as FDA class C medications for pregnancy. The use of psoralens, PUVA, retinoids, methotrexate and etrinate are not recommended during pregnancy, and caution must be exercised in the postpartum patient. CONCLUSION Impetigo herpetiformis is a rare disease with systemic symptoms affecting pregnant and peripeural patients and carrying the potential for severe complications. While debate persists regarding the classification of impetigo herpetiformis, a presentation of pustular psoriasis in a gravid patient requires early recognition and an appropriate treatment plan. Prompt, coordi- nated medical care is mandated to provide relief of symptoms and prevention of the aforementioned complications.

REFERENCES 1. Kroumpouzos G, Cohen LM. Dermatoses of Pregnancy. J Am Acad Dermatology 2001;45:1-22. 2. Jones SAV, Black MM. Pregnancy Dermatoses. J Am Acad Dermatology 1999;45:233-241. 3. Sauer G, Geha B. Impetigo Herpetiformis: Report of a Case Treated with Corticosteroid – review of the Litera- ture. Archives of Dermatology 1961;83:173-180. 4. Brighman L, et al. Third-trimester impetigo herpetiformis treated with cyclosporine. J Am Acad Dermatology 2007;56:S62-S64. 5. Bukhari I. Impetigo herpetiformis in a primigravida: successful treatment with etrinate. Journal of Drugs in Der- matology 2004; July-Aug. 6. Lim KS, et al. Impetigo Herptiformis – A Rare Dermatosis of Pregnancy associated with Prenatal Complications. 2005;34:565-568. 7. Pierard GE, et al. Impetigo herpetiformis and pustular psoriasis during pregnancy. The American Journal of Dermatopathology 1983;5:215-220. peterson, perterson, petersonauthor 45 A rAre CAse: nephrogeniC Fibrosing dermopAthy

Zaina Rashid, D.O.,* Don Anderson, D.O., FAOCD, FASMS** *Dermatology Resident, First Year, Arizona Desert Dermatology/Midwestern University, Kingman, AZ **Program Director, Arizona Desert Dermatology/Midwestern University, Kingman, AZ

ABSTRACT

Nephrogenic fibrosing dermopathy (NFD) is a rare new entity occurring in patients with a history of renal disease. Here, we present a case of a caucasian male with end-stage renal disease who had biopsy-proven diagnosis of NFD.

A 56-year-old Caucasian male with Discussion: a slight male preponderance is observed.1,2 hypertension, emphysema, rheuma- Patients of all ages may suffer from this toid arthritis and end-stage renal disease Nephrogenic fibrosing dermopathy skin disorder, with a mean age of diag- presented with a seven-month history (NFD) is a rare, idiopathic fibrotic disorder nosis of 49.8 years and a range between of erythematous, non-tender, indurated that occurs in patients with a history 8 and 81.1-4 Jan et al. and Jain et al. have plaques on the trunk and upper and lower of renal failure. The condition of NFD reported cases of NFD in the pediatric extremities associated with some pitting appears as scleromyxedema clinically and population.14,15 edema. His hands had multiple fissures histologically and was first described by The etiology of NFD is unknown. and erosions with some joint deformities. Cowper et al. in 2000 as a “scleromyx- The only common denominator is renal Flexion contracture was noted due to skin edema-like illness of renal disease,” as it failure, which is a factor present in all tightness, and multiple large areas of hard- was observed in hemodialysis and renal cases described.8 No infectious cause or ened skin were found on his lower extremi- transplant patients.1 Since the first report, medication has been identified, although ties. No lesions were noted on the face or many cases have been identified, and in some theories have been postulated as neck. Mucosal membranes were spared. 2001 Cowper et al. renamed the entity to a possible cause.3,4,8 Cowper et al. and Lesions started a month after the patient “nephrogenic fibrosing dermopathy.”2 Quan et al. have implicated the pres- began hemodialysis for acute renal failure Patients typically develop symmetric, ence of circulating, fibroblast-like cells, secondary to malakoplakia. He denies any indurated plaques with brawny hyper- described as circulating fibrocytes (CF), prior thromboembolic events or vascular pigmentation confined to the extremities derived from the bone marrow.3,4,16 They surgery. His current medications include and trunk, sparing the head and neck.2 assume a spindled morphology and are Renagel and Norvasc. The patient was Ankles, shins and lower thighs are the immunohistochemically positive for CD34 being treated by a rheumatologist at the most commonly affected areas.1-5 Upper and procollagen I.2,3,4,8,16 The CFs migrate time of our consultation. extremities are the second most common to sites of tissue injury and participate in Laboratory evaluation revealed creati- area of involvement.2-4 The skin is often antigen presentation, wound repair and nine 8.2 mg/dl (0.8-1.5mg/dl), urea shiny and thickened and may feel “woody” tissue remodeling.3,4,16,24 These cells appear nitrogen 32 mg/dl (9-20mg/dl), eryth- with peau d’orange appearance.2,3,6 Edema to be the major constituent in the biopsy rocyte sedimentation rate 24 mm/hr may precede or occur with the cuta- samples of most patients with NFD. To (0-20mm/hr), rheumatoid factor 42 IU/ neous lesions, and severe pain, pruritus date, the etiologic factors that lead to infil- ml (<14 IU/ml), angio convert enzyme and burning sensation are common tration of CFs remain unknown. Macky- 98 U/L (8-52 U/L), ANA positive 1:160 complaints.2-5 Hand and foot swelling with Wiggan et al. noted in four patients the titer, C-reactive protein 1.21 mg/dl (<0.5 blister-like lesions has also been reported.2-7 presence of anticardiolipin and antiphos- mg/dl), and serum immunoglobulin IgG Streams et al. describes yellow papules or pholipid antibodies, postulating that a 2055 mg/dl (700-1600 mg/dl). Serum plaques on or near the eyes in two patients hypercoagulability disorder may feature electrophoresis revealed increase in the that do not seem to affect the vision.7 As in the pathogenesis of NFD.9 Swartz et al. gamma protein 1.50 g/dl (0.52-1.37 g/dl). the fibrosing process progresses, flexion suggests that transforming growth factor-β Anticardiolipin antibodies test was nega- contractures develop, limiting mobility. (TGF-β) may be involved in the disease tive. The remaining complete blood count, The patients may become wheelchair pathogenesis.10 Recent reports from Austria hepatitis profile, metabolic profile, anti- dependent in as little as two weeks. have strongly correlated the development scl-70 antibody (topoisomerase-1), anti-Jo More than 200 cases are identified in the of NFD with exposure to gadolinium, antibody, SSA (Ro) antibody, SSB(La) NFD registry.8 Most of the patients were an MRI contrast agent. Whether that is a antibody, complement C3 and C4 were being treated with hemodialysis at the time common denominator of all NFD cases is negative or within normal limits. Patient’s of presentation, although some reports, still under investigation.3,8,17 initial set of biopsies showed evidence of like Macky-Wiggan et al., Swartz et al. and A biopsy is required for diagnosis. significant proliferation of stellate-shaped Cassis et al., reported patients developing Histopathologic features include thickened fibroblasts and histiocytes in the papil- NFD who had renal failure not requiring collagen bundles in the dermis with infil- lary dermis, multiple multinucleated giant dialysis.2,9,10,11 Hauser et al. reports a case tration of numerous spindle-shaped and cells present in the dermis, and increased of NFD in a renal transplant recipient.12 elongated fibroblasts, most of which are focal disorganization of thickened collagen In contrast with the original description CD34-positive spindled fibrocytes.2,3,4,8,16 bundles. Colloidal iron stain showed an of a purely cutaneous disorder, in 2003, a Mucin is noted in the clefts between the increase in interstitial mucin. case reported by Ting et al. indicated that collagen bundles, detected by Alcian blue The second set of biopsies revealed this disorder displays evidence of systemic or colloidal iron stains.2,3,8,16 Multinucleated CD34-positive spindle cells. Alcian blue involvement.13 No racial predisposition or cells positive for CD68 and factor XIIIa, staining revealed increase in mucin. sexual predilection is recognized; however, and an increased expression of TGF-beta 46 a rare case: nephrogenic FiBrosing dermopathy improvement of renal function.19 Gilliet et al. reports success in three patients using extracorporeal photopheresis.20 Kafi et al. found that UVA phototherapy improved NFD in one case.21 Schmook et al. reported significant improvement of the skin using photodynamic therapy with the lipophilic agent methyl aminolevulinate (MAL).22 Topical Dovonex under occlusion has shown some improvement in localized skin lesions.3,6,8 Chung et al. reported usage of local interferon or IV IgG to be partially 23 Figure 1 Figure 6 effective. Other treatments such as corticosteroids local and systemic, cyclosporine, Cytoxan and methotrexate have failed to show improvement.3,6,8,16 We started our patient on Potaba (aminobenzoate potassium) 12gm/day divided into six doses taken with meals. The patient had reported moderate improvement in skin tightness and joint mobility. This medication was discontinued due to potential side effect: The medicine is excreted by the kidneys and his potassium levels increased. The patient’s renal function has shown improvement Figure 2 Figure 7 on dialysis twice a week, and his skin symptoms have showed mild improvement. The patient is currently on PUVA therapy starting at 10mJ and increasing by 5mJ every two days. Mild improvement has been reported. Physical therapy was recommended to prevent disability related to joint contractures. Since NFD is a rare, new entity, many studies are ongoing to investigate the cause of and find a treatment for this disease. The growing literature of NFD suggests systemic involvement, and therefore it is important to recognize patients with 4,13 Figure 8 systemic fibrosis. It is highly recom- Figure 3 mended to report any case to the NFD registry to accumulate information.

References 1. Cowper SE, Robin HS, Steinberg SM, Su LD, Gupta S, LeBoit PE. Scleromyxoedema-like cutaneous disease in renal-dialysis patients. Lancet. 2000;356:1000–01. 2. Cowper SE, Su LD, Bhawan J, Robin HS, LeBoit PE. Nephrogenic fibrosing dermopathy. Am J Dermatopathol. 2001;23:383–93. 3. Cowper SE, Boyer PJ. Nephrogenic systemic fibrosis: an update. Curr Rheum Reports 8(2):151-7. April 2006 4. Cowper SE, Bucala R, Leboit PE. Nephrogenic fibrosing dermopathy/nephrogenic systemic fibrosis-setting the record straight. Semin Arthritis Rheum. 2006;35(4):208- 10. 5. Tan AW, Tan SH, Lian TY, Ng SK. A case of nephrogenic Figure 9 fibrosing dermopathy. Ann Acad Med Singapore.2004; Figure 4 33(4):527-9. 6. George DE, Lu R, George SJ, Hsu S. Nephrogenic fibrosing dermopathy: case report and review. Dermatol 1, have also been observed.3,4,10,16,26 Ortonne Online J 12(3):7. March 2006 7. Streams BN, Liu V, Liegeois N, Moschella SM. Clinical et al. describes the presence of CD45RO+/ and pathological features of nephrogenic fibrosing der- CD34+ cells in early NFD skin lesions.18 mopathy. Jour Amer Acad Dermatol. 2003; 48(1): 42-7. 8. The International Center for Nephrogenic Fibrosing Der- The course of NFD remains largely mopathy Research (ICNFDR)- http://www.icnfdr.org/ unknown.2,3,16 There is currently no effec- 9. Mackay-Wiggan JM, Cohen DJ, Hardy MA, Knobler EH, Grossman ME. Nephrogenic fibrosing dermopathy tive treatment. Improving renal func- (scleromyxedema-like illness of renal disease). J Am tion seems to slow or arrest the fibrosing Acad Dermatol. 2003;48:55–60. 10. Swartz RD, Crofford LJ, Phan SH, Ike RW, Su LD. 3-9 process. Plasmapheresis has been used as Nephrogenic Fibrosing Dermopathy: A novel cutaneous a treatment; however, the results reported fibrosing disorder in patients with renal failure. Am J Med. 2003;114:563–72. 3,6,8,16 are inconsistent. Baron et al. reported 11. Cassis T, Jackson J, Sonnier G, Callen J. Nephrogenic improvement in three patients with fibrosing dermopathy in a patient with acute renal failure never requiring dialysis. Int J of Dermatol 2006;45:56-59 liver/kidney transplants and concurrent Figure 5 rashid, anderson 47 12. Hauser C, Kaya G, Chizzolini C. Nephrogenic fibrosing dermopathy in a renal transplant recipient with tubulointer- stitial nephritis and uveitis. Dermatol.2004; 209(1):50-2. 13. Ting WW, Stone MS, Madison KC, Kurtz K. Nephrogenic fibrosing dermopathy with systemic involvement. Arch Der- matol. 2003;139:903–06. 14. Jan F, Segal JM, Dyer J, LeBoit P, Siegfried E, Frieden IJ. Nephrogenic fibrosing dermopathy: two pediatric cases. J Pediatr. 2003;143:678–81. 15. Jain SM, Wesson S, Hassanein A, Canova E, Hoy M, Fen- nell RS, et al. Nephrogenic fibrosing dermopathy in pediatric patients. Pediatr Nephrol. 2004;19:467–70. 16. Quan TE, Cowper S, Wu SP, Bockenstedt LK, Bucala R. Circulating fibrocytes: Collagen-secreting cells of the peripheral blood. Int J Biochem Cell Biol. 36(4):598-606. April 2004 17. Grobner T. Gadolinium - a specific trigger for the development of nephrogenic fibrosing dermopathy and nephrogenic systemic fibrosis? Nephrol Dial Transplant. 2006;21(4):1104-8. 18. Ortonne N, Lipsker D, Chantrel F, Boehm N, Grosshans E, Cribier B. Presence of CD45RO+ CD34+ cells with collagen synthesis activity in nephrogenic fibrosing dermopathy: a new pathogenic hypothesis. Br J Dermatol. 2004;150:1050–52. 19. Baron PW, Cantos K, Hillebrand DJ, H KQ, Ojogho ON, Nehlsen-Cannarella S, Concepcion W. Nephrogenic Fibrosing Dermopathy After Liver Transplantation Success- fully Treated With Plasmapheresis. Amer J Dermatopathol 2003;25(3):204-209. 20. Gilliet M, Cozzio A, Burg G, Nestle FO: Successful treatment of three cases of nephrogenic fibrosing dermopathy with extracorporeal photopheresis. Br J Dermatol 152:531- 536,005. 21. Kafi R, Fisher GJ, Quan T, Shao Y, Wang R, Voorhees JJ, Kang S. UV-A1 phototherapy improves nephrogenic fibrosing dermopathy. Arch Derm.2004;140(11):1322-4. 22. Schmook T, Budde K, Ulrich C, Neumayer HH, Fritsche L, Stockfleth E. Successful treatment of nephrogenic fibrosing dermopathy in a kidney transplant recipient with photodynamic therapy. Nephrol Dial Transplant. 2005;20(1):220-2. 23. Chung HJ, Chung KY. Nephrogenic fibrosing dermopathy: response to high-dose intravenous immunoglobulin [Letter] Br J Dermatol. 2004; 150(3):596-7 24. Dehoratius DM, Cowper SE. Nephrogenic systemic fibrosis: an emerging threat among renal patients. Sem in Dialysis 19(3):191-4. May/June 2006 25. Hubbard V, Davenport A, Jarmulowicz M, Rustin M. Sclero- myxoedema-like changes in four renal dialysis patients. Br J Dermatol. 2003;148:563–68. 26. Jimenez SA, Artlett CM, Sandorfi N, et al. Dialysis-associated systemic fibrosis (nephrogenic fibrosing dermopathy): study of inflammatory cells and transforming growth factor beta 1 expression in affected skin. Arthritis Rheum. 2004;50:2660-2666. 27. Gibson SE, Farver CF, Prayson RA. Multiorgan involvement in nephrogenic fibrosing dermopathy: an autopsy case and review of the literature. Arch Pathol Lab Med.2006;130(2):209-12.

48 epitheLioid angiosarcoma: a case report and reView CutAneous leishmAniAsis: CAse report And reView oF treAtment options

Rupa Reddy, DO,* Jag Reddy, MD,** Stanley Skopit, DO, FAOCD*** *1st-year resident, NSUCOM/BGMC, Hollywood, FL **Infectious Disease Attending, Broward General Medical Center, Fort Lauderdale, FL ***Dermatology Residency Program Director, NSUCOM/BGMC, Hollywood, FL

ABSTRACT

Old World cutaneous leishmaniasis is a common disease primarily in the Middle East. It is characterized by asymptomatic ulcers that usually heal spontaneously over months with residual scarring. Treatment is not always necessary, however can hasten healing time as well as aid in better cosmetic outcomes. The clinical presentation, pathogenesis, pathological findings and treatment options are reviewed.

Case Report oral therapy with fluconazole 200mg daily Diagnosis can be made via tissue biopsy for six weeks. with visualization of organisms within A 73-year-old Caucasian male with past macrophages, cutaneous scrapings stained medical history of coronary artery disease Discussion with Giemsa, and needle aspirate. Samples presented with an asymptomatic, non- obtained from the ulcer base will typically healing ulcer on the left upper thigh for Cutaneous leishmaniasis is a parasitic yield the most organisms. Media for tissue approximately two months duration. He disease that is transmitted by the bite culture can be obtained from the Centers denied any history of previous lesion in of a female sandfly. It is found world- for Disease Control and Prevention (CDC). that area or trauma. wide; however, 90% of cases occur in Parasite DNA may also be isolated by PCR Review of systems was negative Afghanistan, Algeria, Brazil, Iran, Peru, methods. 1,2 for fevers, chills, night sweats or weight Saudi Arabia, and Syria. As per the World Old World leishmaniasis lesions tend to changes. Past medical history was signifi- Health Organization, the annual incidence heal spontaneously over months, leaving cant for heart disease, hypertension, and of CL is 1 to 1.5 million cases, the majority an atrophic scar. However in immuno- 1-3 hypercholesterolemia. There was no of which occur in the Middle East. The compromised hosts, disseminated disease history of diabetes mellitus. Medications number of cases is increasing as there is may develop, and these lesions are not included Plavix, Benicar, amlodipine, greater international travel, wars, lack of likely to resolve on their own. Cutaneous Crestor and fish oil. There were no aller- vaccination, and the presence of the sandfly disease is usually treated to expedite cure, gies to medications, only to mangoes. in rural and urban areas. The clinical prevent dissemination in cases of relapse, Social history was negative for alcohol, presentation and causative organisms vary and to reduce scarring, especially as most tobacco or any drugs. He reported a travel by geographic location and can be broken lesions are located in cosmetic sites. As history to Israel three months prior to down into Old World (acquired in Africa, this is a self-limiting process, the decision presenting to the clinic. Asia, and Europe) and New World (Latin to treat must be weighed heavily against America) subtypes. As the vectors of Physical examination revealed an irreg- the possible adverse effects of the treat- disease transmission as well as the species ular, 4.5cm x 3cm, punched-out shallow ment itself. Treatment with pentavalent causing disease differ, so do the clinical ulcer with raised erythematous borders antimonials has been the treatment of presentations and natural history of Old on the left upper outer thigh (Figure 1). choice, however may be associated with World versus New World disease. This There was no associated inguinal lymph- severe side effects. The pentavalent anti- discussion will be limited to the treatment adenopathy. monies work by inhibition of glycolysis for Old World disease. Differential diagnosis of this lesion and beta-oxidation of fatty acids of the Old World cutaneous leishmaniasis (CL) includes atypical mycobacterial infec- parasite. In the United States, pentavalent usually presents as a localized process that tion, deep fungal infection, leishmaniasis, antimony comes in the form of sodium is characterized by a papule or nodule that tuberculosis, leprosy, syphilis, squamous stibogluconate (Pentosam: Glaxo-Smith- eventually ulcerates. It is transmitted by cell carcinoma, leukemia cutis, metastatic Kline, Research Triangle Park, NC USA); the bite of a sandfly and caused by three disease, and pyoderma gangrenosum. in Europe, the compound is meglumine Leishmania species: L major, L tropica, antimonite (Glucantime: Rhone-Polene, Biopsy of the lesion revealed an ulcer- 2 and L aethiopica. The promastigote form Paris, France). These medications must ated, dense dermal infiltrate of macro- develops in the sandfly vector, and after a be delivered parenterally via intravenous phages, lymphocytes, plasma cells, and bite the parasite enters the human host and or intramuscular injection for absorp- neutrophils (Figures 2 and 3). Giemsa 3,4 is engulfed by macrophages. The amas- tion; however, they are also commonly stain highlighted numerous organisms in tigote form develops, and this is the form administered as intralesional injections. the cytoplasm of macrophages. Additional that affects cellular immunity and causes The treatment dose is 20mg/kg/day for 20 histochemical stains (AFB, PAS, GRAM, disease. As the majority of affected body days. Reversible adverse effects include and GMS) were negative for pathogenic parts are exposed sites such as the head fatigue, arthralgias, gastrointestinal upset, microorganisms. and neck, hand, and foot, the small size of elevation in transaminases, pancreatitis, Tissue culture sent to the Centers the vector (2mm) allows it to go unnoticed pancytopenia, and electrocardiogram for Disease Control (CDC) yielded a on other body parts and inflict disease.4 abnormalities. As pentavalent antimonies moderate number of amastigotes with The incubation period is from two to eight are difficult to administer and have a risk nucleus and kinetoplast, and PCR detec- weeks; however, it can be longer. There of untoward side effects, several other tion isolated L major as the causative may be one or multiple lesions that are modalities have been studied in order to organism. The patient was initiated on usually painless. provide alternative treatment options for

reddy, reddy, skopit 49 after twice daily application for 10-20 England Journal of Medicine by Alrajhi days.5 In other studies, the effectiveness et al., the use of fluconazole for the treat- of topical paromomycin was proven to be ment of CL caused by Leishmania major superior to placebo and was also shown to was studied in a double-blind random- be less effective, therefore the efficacy of ized controlled design in Saudi Arabia.12 this treatment remains controversial. Side Azole antifungals inhibit the cytochrome effects were minimal and included pain, P-450-mediated 14 -demethylation of local inflammation, and itching. lanosterol, thereby inhibiting ergosterol In a study by Mosleh et al., the efficacy synthesis and causing accumulation of of weekly cryotherapy was studied in 14 -methyl sterols.6,12 In this study, oral patients with confirmed Leishmania major fluconazole 200mg daily was administered infections.8 Two freeze-thaw cycles were for six weeks. At three-month follow-up, performed weekly from one up to seven complete healing was noted in 79% of the Figure 1 sessions. Clinical improvement was seen in treated group versus 34% of the placebo lesions after one to four sessions. Cultures group, and healing occurred faster in the were also obtained to assess survival of the fluconazole-treated group. The medication parasite after cryotherapy. The parasite was well tolerated, and side effects were was obtained in cultures one week after similar in each group. Other azole medica- the first cryotherapy session in seven of tions such as ketoconazole and itraconazole 16 patients examined. In this study, 84% have also been studied but did not show of lesions were cured after up to 4-weekly statistically significant improvement in sessions. As this study was not a double- cure rates over placebo. blind random control design, the efficacy In a study performed in Iran, another of this modality is difficult to interpret. topical treatment, imiquimod, was studied However, the investigators did observe in comparison with intralesional meglu- patients who had multiple Leishmania mine antimoniate.10 Imiquimod is an Figure 2 lesions. In these patients, some lesions immune-response modifier that is capable were left untreated, and healing was of inducing the innate and adaptive observed alongside the lesions that were immune systems. This molecule works treated. They noted that the untreated by stimulating antigen-presenting cells by lesions remained the same, slightly binding to the transmembrane receptor, improved or even worsened in comparison toll-like receptor 7 (TLR-7). In this small to the treated lesions. Adverse effects were study, they appreciated that imiquimod noted to be mild, including pain, secondary alone, and in combination with meglu- infection, hypopigmentation and hyper- mine antimoniate, was more effective than pigmentation, and mild scarring. The meglumine antimoniate for treatment of cosmetic results of the scars were superior Old World CL. to the scarring achieved in self-healing Other treatment considerations include lesions. No relapses were noted in the oral allopurinol, which incorporates into patients that were assessed after three years. parasite RNA and causes death. Treatment Figure 3 Photodynamic therapy (PDT) has been with 300mg per day for three months was studied as an alternative treatment for noted to be effective for a patient in Israel cutaneous leishmaniasis. In vitro studies with L major infection that failed treat- have demonstrated antimicrobial proper- ment with intralesional antimony sodium ties of porphyrins as well as the ability to gluconate.11 There have been case reports destroy amastigotes in macrophages. In and randomized controlled trials demon- a study by Gardlo et al., 20% aminolevu- strating the effectiveness of zinc sulfate, linic acid ointment was applied to lesions administered intralesionally and orally, in and allowed to incubate for five hours.7 treatment of Old World CL.13 However, Red-light illumination (570-670 nm) with complete healing was noted in only a few a total energy of 75 J/cm2 was applied. PDT of the cases, and there were reports of was performed twice weekly for 12 weeks necrosis at the needle insertion site. In a and then once weekly for an additional study by Kochar et al., rifampin 1200mg/ four weeks. In the same patient, other day for four weeks demonstrated efficacy Figure 4 lesions were treated with topical 15% versus placebo, however lack of random- paromomycin sulfate with 5% urea in an ization between the two groups has been a disease that may spontaneously resolve ointment once daily; all lesions that did noted.14 over time. not respond by four months were treated As Old World CL is a self-limiting Treatment with topical paromomycin with PDT. All lesions treated by PDT were disease, the decision to initiate treat- has been studied in several random clinically healed after 20 PDT sessions. The ment must be carefully weighed against controlled trials. Paromomycin is an accumulation of porphyrins after red-light possible adverse effects of the treatments. aminoglycoside that inhibits protein irradiation drives peroxidase and oxidase Currently, there is no ideal therapy for Old synthesis. Ointments composed of 15% reactions that generate reactive oxygen World CL. Traditionally, treatment with paromomycin sulfate in combination species, permitting cell death.7 This study pentavalent antimonials have been stan- with other components, such as methyl- suggests PDT may be an effective treatment dard, but given the possibility of severe benzethonium, water, soft white paraffin, option for cutaneous leishmaniasis. Side side effects and difficulties in parenteral and urea have been studied. In a study effects included erythema, burning, and administration, other treatment modali- by El-On et al., clearance of parasites was hyperpigmentation. ties have been explored. The results reported to be 76% as compared to placebo In a recent study published in the New published in the literature are difficult to 50 cutaneous Leishmaniasis: case report and reView oF treatment options interpret because many of the studies are not double-blind randomized controlled trials, and it is a self-healing disease. Based on this review, treatment with oral fluconazole offers a safe and efficacious option with relative ease of administration. Our patient demonstrated re-epithelialization of the lesion after one month of fluconazole 200mg daily, as seen in Figure 4. Treatment with weekly cryotherapy is another modality that may become more favorable due to ease of administration and low cost, in particular for smaller lesions. Acknowledgements The authors wish to thank Evangelos Poulos, MD, and Eli Piatigorsky, MD, with Global Pathology Services, for aiding with the diagnosis.

References 1. Herwaldt, BL. Leishmaniasis. Lancet 1999; 354:1191-99. 2. Willard RJ, Jeffcoat AM, Benson PM, Walsh DS. Cutane- ous leishmaniasis in soldiers from Fort Campbell, Ken- tucky returning from Operation Iraqi Freedom highlights diagnostic and therapeutic options. J Am Acad Dermatol 2005; 52:977-87. 3. Murray HW, Berman JD, Davies CR, Saravia NG. Advances in leishmaniasis. Lancet 2005; 366:1561-77. 4. Markle WH, Makhoul K. Cutaneous leishmaniasis: recognition and treatment. Am Fam Physician 2004; 69:455-60. 5. El-On J, Halevy S, Grunwald MH, Weinrauch L. Topical treatment of Old World cutaneous leishmaniasis caused by Leishmania major: a double-blinded control study. J Am Acad Dermatol 1992; 27:227-31. 6. Khatami A, Firooz A, Gorouhi F, Dowlati Y. Treatment of acute Old World cutaneous leishmaniasis: a systematic review of the randomized controlled trials. J Am Acad Der- matol 2007; 335:e1-29. 7. Gardlo K, Horska Z, Enk CD, Rauch L, et al. Treatment of cutaneous leishmaniasis by photodynamic therapy. J Am Acad Dermatol 2003; 48:893-6. 8. Mosleh IM, Geith E, Natsheh L, Schonian G, et al. Effi- cacy of weekly cryotherapy regimen to treat Leishmania major cutaneous leishmaniasis. J Am Acad Dermatol 2008; 58:617-24. 9. Berman, J. Current treatment approaches to leishmaniasis. Curr Opin Infect Dis 2003; 16:397-401. 10. Arevalo I, Ward B, Miller R, et al. Successful treatment of drug-resistant cutaneous leishmaniasis in humans by use of imiquimod, and immunomodulator. Clin Infect Dis 2001; 33:1847-51. 11. Barzilai A, Friedman J, Trau H. Treatment of cutaneous leishmaniasis with allopurinol. J Am Acad Dermatol 1995; 32:518. 12. Alrajhi AA, Ibrahim EA, De Vol EB, Khairat M, et al. Flucon- azole for the treatment of cutaneous leishmaniasis caused by Leishmania major. N Engl J Med 2002; 346:891-5. 13. Sharique KE, Najim RA, Farjou IB, Al-Timimi DJ. Oral zinc sulphate in the treatment of acute cutaneous leishmaniasis. Clin Exp Dermatol 2001; 26:21-26. 14. Kochar DK, Aseri S, Sharma BV, et al. The role of rifam- picin in the management of cutaneous leishmaniasis. Q J Med 2000; 93:733-737.

reddy, reddy, skopit 51 noonAn-liKe/multiple giAnt-Cell lesion syndrome with multiple grAnulAr-Cell tumors: A CAse report And literAture reView

Thomas J Singer, D.O.; Hamza Bhatti, OMS II; Brad P Glick, D.O. *1st-year Dermatology Resident, NSU-COM/BGMC *1st-year Dermatology Resident, Wellington Regional Medical Center/LECOM **2nd-year Medical Student at Touro College of Osteopathic Medicine, NY, NY ***Program Director, Wellington Regional Medical Center/LECOM

ABSTRACT

Noonan-like/multiple giant cell lesion syndrome (NL/MGCLS) is a specific phenotype of Noonan’s syndrome that shares clinical features of both classic Noonan’s syndrome and cherubism. It is characterized by multiple giant cell lesions of the mandible and soft tissues in addition to many of the typical Noonan’s phenomena. Genetically, it has only been observed with the Noonan’s related mutations PTPN11 and SOS1, and not with the SH3BP2 defect that is found in cherubism. Herein, we present a case of Noonan-like/ multiple giant cell lesion syndrome to provide a basic understanding of the clinical features and management of this unique patient.

Case Report characteristics of NL/MGCLS and traditional for karyotyping and genetic counseling. NS NS are almost identical. This raises the ques- is associated with bleeding diatheses, most tion as to whether NL/MGCLS is indeed a notably factor XI deficiency. Thus, a referral A 12-year old male presented to the office true separate clinical entity or just part of to a hematologist is also recommended. for evaluation of multiple dermatologic the spectrum of disease for classic NS. The Numerous cardiovascular defects including issues. He had a history of Noonan-like/ consensus from authors is that NL/MGCLS pulmonic stenosis, ASD, and cardiac-cushion multiple giant-cell lesion syndrome (NL/ represents an extreme phenotype of NS defects require a full cardiac work-up by a MGCLS). Previously diagnosed phenomena (Table 1).1,12 Our patient had many classical pediatric cardiologist. High-frequency senso- included: prominent mandible (Fig. 1 and features of NS as well as a history of giant-cell rineural hearing loss occurs in up to 50% 2), multiple submandibular giant-cell lesions, lesions of the mandible and full facies, which of patients and should be addressed by an short stature, enlarged hyper-mobile joints, led to his diagnosis of NL/MGCLS. audiologist. Approximately 25% of Noonan’s facial hemangiomas, CAL macules, multiple 13 A gain-in-function missense mutation of patients have mental retardation. Therefore, nevi and granular-cell tumors. The child’s the PTPN11 gene located on chromosome assessment of developmental delays is neces- mother related that flesh-colored nodules 12q24 has been identified as the cause of sary to allow for proper intervention. Lastly, had been slowly enlarging on her son’s right Noonan’s syndrome (NS) in 45% of familial radiographic monitoring of the giant-cell knee, neck and elbows (Fig. 3) over the prior and sporadic cases.2,3 The PTPN11 gene lesions of the mandible and soft tissues months. She denied any change in color, encodes the non-receptor protein tyro- should be employed. Surgical intervention bleeding or drainage of the nodules. History sine phosphatase, SHP-2.4 SHP-2 is key to is not usually needed, as the tumors often of nevi was also unremarkable for growth, 14 multiple intracellular signal transduction regress with time. change in color, bleeding, or pruritus. After a pathways that affect but are not limited to complete skin examination, excisional biop- mesodermal patterning and limb develop- sies of the nodules were obtained utilizing a Granular-cell Tumor ment,5,6 epidermal growth factor signaling7 conservative margin. Histology of the two Discussion and cardiac semilunar valvulogenesis.8 A nodules revealed epidermal hyperplasia with review of published reports of 24 patients The multiple granular-cell tumors (GCT) infiltration of the dermis and subcutaneous with NL/MGCLS found 17 (70.8%) had found in our patient are not considered part tissue by large cells with granular cytoplasm pulmonic stenosis.1 In classic NS, over of the diagnostic criteria of NL/MGCLS, but and small, centrally located nuclei. This 80% of patients have a cardiovascular have been reported previously in this pheno- yielded a diagnosis of granular-cell tumors. abnormality, pulmonic stenosis being the type as well as in classic Noonan’s syndrome. A shave biopsy of an irregular 0.5 cm most common.9,10 The high prevalence of Clinically, GCT presents as an asymptom- black/brown papule was also obtained and pulmonic stenosis within the NL/MGCLS atic or occasionally tender, flesh-colored to was reported as a compound dysplastic subset of patients lends the notion that brownish-red, firm, dermal or subcutaneous nevus. Also of note were numerous 1-2 PTPN11 is likely the dominant gene muta- papulonodule. Occasionally, the surface mm folliculocentric papules on his cheeks tion. However, the first case report of can show ulceration or verrucous changes. bilaterally. The clinical diagnosis of keratosis a gain-in-function mutation of the SOS1 “Granular-cell tumor” is a descriptive term pilaris was made, and adapalene 0.1% cream gene in a family (father and sons) with NL/ for a heterogeneous group of neoplasms applied nightly with daily Cetaphil cream MGCLS has recently been described.11 The composed of cells with granular cytoplasm application was prescribed. SOS1 gene has been established as the second due to the accumulation of lysosomal gran- most common mutation found in classic NS. ules.15 The majority of cutaneous GCT are of Noonan-like/Multiple This new finding supports the idea that NL/ neural origin; however, granular-cell change Giant-cell Lesion MGCLS is part of the spectrum of disease occurs in a variety of neoplasms. GCT is a Syndrome Discussion in Noonan’s syndrome, and not a separate relatively rare tumor that occurs primarily disease. Furthermore, no reported cases of in adults, with a 1:3 male-to-female predilec- Noonan-like/multiple giant-cell lesion NL/MGCLS have been found to have the tion. The tumor is usually solitary, with 70% SH3BP2 gene defect that is known to cause located on the head and neck and 30% of syndrome (NL/MGCLS) has clinical 16 overlap with both Noonan’s syndrome (NS) cherubism.1 It is possible that NL/MGCLS these on the tongue. and cherubism. The primary phenotypic can be misdiagnosed as cherubism in less On H&E, the typical GCT will show a commonalities between cherubism and NL/ typical cases because of the variable expres- dermally located, poorly circumscribed MGCLS include giant-cell lesions of the sion of NS.12 This can result in a delayed nodule composed of polygonal, pale-stained bones and soft tissues, enlarged neck lymph work-up for systemic symptoms and can cells that may infiltrate the adjacent dermis. nodes, and full facies. In contrast, the shared lead to morbidity. If the clinical diagnosis is The tumor cells have abundant, granular, in question, a geneticist should be consulted faintly eosinophilic cytoplasm with round, 52 noonan-Like/muLtipLe giant-ceLL Lesion syndrome with muLtipLe granuLar-ceLL tumors Table 1

Comparison of NL/MGCLS, Noonan’s Syndrome and Cherubism (Table 1)1 System NL/MGCLS Noonan’s Syndrome Cherubism Head and Neck -Webbed neck -Webbed neck -Enlarged neck -Enlarged submandibular lymph -Cystic hygroma lymph nodes nodes -Hypertelorism -Hypertelorism -Hypertelorism -Triangular facies -Giant-cell -Giant-cell lesions in bone/soft -Micrognathia, malocclusion lesions tissue -Epicanthic folds -Full facies -Full facies -Ptosis -Prognathism, -Malocclusion -Downward palpebral fissures malocclusion -Ptosis -Arched palate Figure 1 -Downward palpebral fissures -Low-set posterior ears, -Arched palate deafness -Posterior ears -Deeply grooved philtrum -Bitemporal narrowing -Blue-green irides -Low hairline -Myopia

Growth -Short stature -Short stature ------Cardiovascular -Pulmonic stenosis -Pulmonic stenosis ------Septal defects -Aortic regurgitation -Patent ductus arteriosus

Genitourinary -Cryptorchidism -Hypogonadism ------Cryptorchidism Figure 2 Dermatologic -Multiple lentigines -Multiple lentigines ------CAL macules -Wooly hair -Involuted hemangioma -Lymphedema

Musculoskeletal -Pectus excavatum/carinatum -Vertebral anomalies ------Generalized osteopenia -Clinodactyly, brachydactyly -Clinodactyly -Pectus excavatum/carinatum -Cubitus valgus - Cubitus valgus Neurological -Developmental delay -Mental retardation ------Malignant schwannoma -Articulation difficulties

Hematologic -Mild, insignificant elevation in -von Willebrand’s ------Figure 3 PT/PTT -Thrombocytopenia -Partial deficiency of XI:C, XII:C, XII:C

type of peripheral nerve-sheath tumor. The the epidermal growth factor receptor in mammals. Proc Natl Acad Sci USA 1999;96:8528–33. treatment is complete excision. If incom- 8. Chen B, Bronson RT, Klaman LD, Hampton TG, Wang JF, pletely excised, this tumor has a high local Green PJ, Magnuson T, Douglas PS, Morgan JP, Neel BG. Mice mutant for Egfr and Shp2 have defective cardiac semi- recurrence rate due to the plexiform or lunar valvulogenesis. Nat Genet 2000;24:296–9. perineural growth pattern.15 Temporary 9. Sharland M, Burch M, McKenna WM, Paton MA. A clinical study of Noonan syndrome. Arch Dis Child 1992;67:178–83. regression after intralesional corticosteroid 10. Marino B, Digilio MC, Toscano A, Giannotti A, Dallapiccola injection has also been reported.20 B. Congenital heart diseases in children with Noonan syndrome: an expanded cardiac spectrum with high prevalence References of atrioventricular canal. J Pediatr 1999;135:703–6. Figure 4 11. Hanna N, Parfait B, Talaat IM, Vidaud M, Elsdefy HH. 1. Lee JS, Tartaglia M, Gelb BD, Fridrich K, Sachs S, Strata- SOS1: a new player in Noonan-like/multiple giant cell dark nuclei (Fig 4).17 Characteristic larger kis CA, Muenke M, Robey PG, Collins MT, Slavotinek A. lesions syndrome. Clin Genet 2009; 75:568-571. Phenotypic and Genotypic Characterization of Noonan-like/ 12. Reichenberger E. Noonan-like syndrome in PTPN11 in cytoplasmic granules are called pustulo- Multiple Giant Cell Lesion Syndrome. J. Med. Genet. patients diagnosed with cherubism. Clin Genet 2005; ovoid bodies. These granules are PAS 2005;42;e11 doi:10.1136/jmg.2004.024091 68:190-191. 2. Tartaglia M, Mehler EL, Goldberg R, Zampino G, Brunner 13. Ibrahim J, McGovern M. Noonan’s Syndrome Differential positive but diastase-resistant. Perineural HG, Kremer H, van der Burgt I, Crosby AH, Ion A, Jeffery S, Diagnosis and Work Up. Emedicine. 2009. http://emedicine. and plexiform growth patterns have been Kalidas K, Patton MA, Kucherlapati RS, Gelb BD. Mutations medscape.com/article/947504-diagnosis. in PTPN11, encoding the protein tyrosine phosphatase SHP- 14. Cancino C. Giant Cell Lesions with a Noonan-like Phe- described, as have increased numbers of 2, cause Noonan syndrome. Nat Genet 2001;29:465–8. notype. The Journal of Contemporary Dental Practice mast cells. In approximately 3% of cases, 3. Tartaglia M, Kalidas K, Shaw A, Song X, Musat 2007;4:1-6. DL, van der Burgt I, Brunner HG, Bertola DR, 15. Argenyi ZB. Neural and neuroendocrine neoplasms (other malignant behavior (local and metastatic) Crosby A, Ion A, Kucherlapati RS, Jeffery S, Pat- than neurofibromatosis). Dermatology. Elsevier Limited; is observed, usually when the tumor arises ton MA, Gelb BD. PTPN11 Mutations in Noonan 2008 pgs 1804-1805. 15 Syndrome: Molecular Spectrum, Genotype-Phe- 16. Stout AP. The peripheral manifestations of specific nerve from a visceral or deep location. The histo- notype Correlation, and Phenotypic Heterogeneity. sheath tumor. Am J Cancer 1935;24:751-96. logic criteria to identify the rare aggressive Amer J Hum Genet 2002;70:1555-63. 17. Mentzel T, Wadden C, Fletcher CD. Granular cell change in 4. Dechert U, Duncan AM, Bastien L, Duff C, Adam M, Jirik smooth muscle tumors of the skin and soft tissue. Histopa- GCT have not been defined. The presence of FR. Protein-tyrosine phosphatase SH-PTP2 (PTPN11) is thology 1994;24:223-31. necrosis, increased mitoses, and spindling of localized to 12q24.1–24.3. Hum Genet 1995;96:609–15. 18. Fanburg-Smith JC, Meis-Kindblom LG. Malignant granular 5. Saxton TM, Henkemeyer M, Gasca S, Shen R, Rossi DJ, cell tumor of soft tissue. Diagnostic criteria and clinico- the cells has been suggested as a predictor of Shalaby F, Feng GS, Pawson T. Abnormal mesoderm pathologic correlation. Am J Surg Path 1988;22:779-94. aggressive behavior.18 Immunohistochemical patterning in mouse embryos mutant for the SH2 tyrosine 19. Armin A, Connelly EM, Rowden G. An immunoperoxidase phosphatase Shp-2. Embo J 1997;16:2352–64. investigation of S-100 protein in granular cell myoblas- staining of GCT yields S100 protein and 6. Saxton TM, Ciruna BG, Holmyard D, Kulkarni S, Harpal K, tomas: evidence for Schwann cell derivation. Am J Clin CD57 positivity, which is also seen in many Rossant J, Pawson T. The SH2 tyrosine phosphatase shp2 Pathol 1983;79:37-44. 19 is required for mammalian limb development. Nat Genet 20. Noppakun N, Apisarnthanarx P. Multiple Cutaneous Granu- Schwann-cell tumors. However, the classic 2000;24:420–3. lar Cell Tumors Simulating Prurigo Nodularis. International form of GCT does not resemble any other 7. Qu CK, Yu WM, Azzarelli B, Feng GS. Genetic evidence Journal of Dermatology 2008;20:126-129 that Shp-2 tyrosine phosphatase is a signal enhancer of singer, Bhatti, gLick 53 CAse report And literAture reView: metAstAtiC nodulAr melAnomA oF the Foot

Jacqueline A. Thomas, DO,* Scott M. Greenberg, DO,** David L. Thomas, MD, JD,*** Janet Allenby, DO**** *Dermatology Resident, First Year, Columbia Hospital Palm Beach Centre for Graduate Medical Education, West Palm Beach, FL **Private Practice, Tampa, FL ***Professor and Chairman, Department of Surgery, Nova Southeastern University, Ft. Lauderdale, FL ****Program Director, Columbia Hospital Palm Beach Centre for Graduate Medical Education, West Palm Beach, FL

ABSTRACT

Clinicians should have a low threshold to biopsy melanotic nodules, papules, plaques, or ulcers located on the feet, expanding in size and present longer than one month. Amputation for advanced lower extremity melanoma is infrequently performed but is indicated for palliation of pain. We report a case of nodular-type metastatic melanoma on the sole presenting as a bleeding ulcer ultimately treated via below-the-knee amputation for palliation of intractable pain. Few reported cases of major palliative amputations for extremity melanoma exist in the literature.

Case Report Discussion Presented is a case of an obese 50-year- The incidence of melanomas of the old male complaining of right foot pain hands and feet in the United States is less and swelling for 18 months and a one- than 5% of all melanomas.1 Melanoma month history of a bleeding ulcer on the is the most common malignancy of the right medial foot and ankle (Figure 1). foot.2 Thirty percent of all melanomas are The right foot edema had progressively plantar melanomas.4 Melanomas arising worsened over a month and was signifi- on the plantar aspect of the foot are more cant when visually compared to the normal likely to be misdiagnosed than in other left foot as seen in Figure 2. There was a locations.2,3 Malignant melanoma of the two-month history of 20-pound weight foot has been misdiagnosed as a verruca, loss, decreased appetite, fatigue, weakness, onychomycosis, subungual or traumatic Figure 1 Metastatic Nodular Melanoma nausea, and inability to bear weight associ- hematoma, ischemic digits, benign nevus, ated with decreased range of motion of paronychia, pyogenic granuloma, ganglion the right foot. Past medical and surgical cyst, blister, eccrine poroma and derma- history included hypertension, obesity, tofibroma.2,3 Melanomas arising on the right knee arthroscopy performed in the plantar surface of the foot have a worse 1970s, and a 60 pack-year smoking history. prognosis than other sites.4 A reduced Multiple areas of lymphadenopathy existed five-year survival rate is associated with in the right cervical nodes, right axilla, melanoma on the plantar aspect of the foot right inguinal region, and right lower (56%) compared with melanoma on the extremity. The patient was diagnosed with dorsal aspect of the foot (80%).5 chronic lymphocytic leukemia and a right Nodular melanomas are the second lower extremity fungating tumor. Multiple most common subtype of melanomas, areas of metastases were found both above accounting for 10% to 15% of melanomas Figure 2 Metastatic Nodular Melanoma and below the diaphragm including the diagnosed in Caucasians.6 They have a lungs, chest wall, mediastinal lymph nodes, characteristic, rapidly advancing vertical pigment, expanding the differential diag- abdominal and pelvic lymph nodes. The growth phase common to thick mela- nosis to include vascular lesions.10 patient underwent a right below-the-knee nomas.7,8 Nodular melanomas are most amputation for palliation of pain from commonly found on the trunk in males Palliative surgical intervention has been the tumor. Intraoperatively, the tumor and the extremities in females; however, used to debulk a large tumor burden. The appeared to include the entire medial they can occur on any body surface.5 There column of the foot and ankle without is a 2:1 female-to-male ratio of lower largest primary melanoma reported in the bony involvement, thought to be soft extremity melanomas.1 The diagnosis of literature to date was found on the back tissue in nature. Also, an excisional biopsy pigmented lesions can be challenging for of a 29-year-old male, measured 22 x 25 10 of cervical lymph nodes was performed. the clinician, and nodular melanomas are x 7 cm, and weighed 7280 grams. The Pathologic diagnosis of the right foot tissue no exception. The commonly used ABCD management included palliative surgical revealed an ulcerated, verrucous, nodular criteria do not fit for nodular melanomas, intervention with the intention of reducing melanoma 13cm in length and 6cm in thereby contributing to the complexity the risk of superinfection and patient depth involving bone and extending to the in diagnosing the malignancy. Nodular discomfort.10 Surgery is the primary thera- margin of resection. Positive immunohis- melanomas are usually well circumscribed, peutic modality for localized cutaneous tochemical stains included Mart-1, S-100, symmetrical, of small diameter (frequently melanoma. Surgical therapy for melanoma and HMB-45. Neck lymph node biopsy less than 6mm), a uniform black or of the hands and feet is difficult as primary stains were also positive for HMB-45 and blue color, minimally elevated, and firm closure can be challenging in these areas, S-100, confirming metastatic spread. The to palpation, but can present as lower leading to the necessity for amputation patient expired prior to admission to extremity ulcers. 6,8,9 The color of these and skin grafts to achieve closure following hospice. pigmented lesions can be due to blood or resection of thicker lesions.1 Most studies 54 casetitLereport and Literature reView: metastatic noduLar meLanoma oF the Foot evaluating surgical margins are for mela- Dermatology Online Journal 2007; 13(2):7. Accessed Nov 11, 2008. nomas on the trunk, and the current 11 Swetter SM. Malignant Melanoma. Last updated Janu- recommendations are based on Breslow ary 23, 2008. www.emedicine.com/Derm/topic257.htm Accessed November 7, 2008 8:45pm. depth. The margin for melanoma in situ 12 Paz IB. Major palliative amputations. Surgical Oncoligic is 5mm; 1cm margins are recommended Clinics of North America 2004;13(3):543-7. 13 Kapma MR, Vrouenraets BC, Nieweg OE, van Geel AN, for melanomas up to 1mm deep, 1-2cm Noorda EM, Eggermont AAM, Kroon, BBR. Major ampu- margins are recommended for 1-4mm tation for intractable extremity melanoma after failure of isolated limb perfusion. European Journal of Surgical melanomas; and margins of 2cm are Oncology 2005;31:95-99. recommended for melanomas greater than 4mm.11 For lesions smaller than 1.5mm, a 1cm margin, and for lesions larger than 1.5mm a 2cm margin is recommended by Tseng and colleagues specifically for melanomas of the hands and feet.1 Major amputation for palliation of cancer patients is controversial. One author rarely recommends amputation for the palliation of cancer patients as risks of extremity amputation may result in loss of function, extended recovery, and morbidity. 12 Major amputation does serve a palliativearticle role for extremity melanoma for specific indications and offers a greater than 75% rate of successful treatment.10 These indications include uncontrol- lable pain, extensive loco-regional tumor progression, loss of ankle function due to local tumor growth, and ulcerating and fungating lesions unresponsive to other treatments.13 Conclusion Early detection of nodular melanoma is possible with education. Clinicians and patients should be encouraged to check the soles and web spaces between toes. Clinicians should have a low threshold to biopsy expanding, persistent, pigmented papules, plaques, and ulcers on the feet. Early detection is the best way to reduce potential morbidity such as amputation and worse, mortality. Further studies are needed to determine the best interventions.

References 1 Tseng JF, Tanabe KK, Gadd MA, Cosimi AB, Malt RA, et al. Surgical Management of Primary Cutaneous Melanomas of the Hands and Feet. Annals of Surgery 1997;225(5):544-553. 2 Greenway HT, Twersky JM, Meads SB, Kelley BF. Melanoma of the foot and ankle: a case series of an underrecognized entity. Archives of Dermatology 2007;143:543-544. 3 Fortin PT, Freiberg A, Rees R, Sondak VK, Johnson TM. Malignant Melanoma of the Foot and Ankle. Journal of Bone and Joint Surgery 1995;77-A(9):1396-1403. 4 Kato T, Suetake T, Tabata N, Takahashi K, Tagami H. Epide- miology and prognosis of plantar melanoma in 62 Japa- nese patients over a 28-year period. International Journal of Dermatology 1999;38:515-519. 5 Barnes BC. Seigler HF, Saxby TS, Terence S., Kocher MS, Harrelson JM. Melanoma of the Foot. Journal of Bone and Joint Surgery 1994;76-A(6):892-898. 6 Chamberlain AJ, Fritschi L, Kelly JW. Nodular melanoma: patients’ perceptions of presenting features and implications for earlier detection. Journal of the American Acad- emy of Dermatology 2003;48:694-701. 7 Richard MA. Melanoma and tumor thickness: the chal- lenges of early diagnosis. Archives of Dermatology 1999;135:269-274. 8 Liu W, Dowling JP, William MK, McArthur GA, Thompson JF, Wolfe R, Kelly JW. Rate of growth in melanomas characteristics and associations of rapidly growing melanomas. Archives of Dermatology 2006;142:1551-1558. 9 Perrotto J and Glick B. Lower extremity malignancies masquerading as ulcers. Ostomy Wound Management 2006;52(10):46-52. 10 Harting M, Tarrant W, Kovitz CA, Rosen T, Harting MT, Souchon E. Massive nodular melanoma: a case report.

thomas, greenBerg, thomas, aLLenByauthor 55 An unusuAl presentAtion oF dArier’s diseAse

Janese Trimaldi, M.D.1, Olga Globosky, D.O.2, Bradley Abrams, D.O.3, Michael B. Morgan, M.D.4 1 Clinical Associate in Pathology, University of South Florida College of Medicine, Tampa, FL 2 Clinical Associate, St. Petersburg General Hospital, St Petersburg, FL 3 Private Practice, Sarasota, Florida 4 Professor of Pathology, University of South Florida College of Medicine, Tampa, FL; Clinical Professor of Dermatology, University of Florida College of Medicine, Jacksonville, FL; Managing Director, Bay Area Dermatopathology, Tampa, FL

ABSTRACT

We present a case of Darier disease in a 77 year old male. The patient had a sixteen year history of a unilateral, pruritic eruption of the right hemithorax, which became increasingly raised and itchy in the six months prior to his biopsy. His past medical history was negative for any similar condition, and he denied a history of shingles or herpes. The biopsy showed changes of Darier’s disease, which in conjunction with the clinical history was consistent with localized Darier’s disease. The clinical and histologic differential diagnosis, as well as the unusual aspects of this case will be discussed herein.

Introduction Case Report Darier’s disease (DD), first described The patient was a 77-year-old Caucasian by Darier and White in 1989, is a rare, male with a 16-year history of unilateral, autosomal-dominant genodermatosis.1 pruritic eruptions over the right hemi- With an onset that usually occurs in thorax. Over a six-month time span, the adolescence, it is clinically characterized lesions had become increasingly itchy and by greasy, hyperkeratotic, erythema- raised. The patient denied any significant tous papules and papulovesicles located past medical history. He was taking no mainly in the seborrheic areas of the medications, denied allergies, and specifi- head, neck and trunk. Coalescence cally denied any history of herpes or shin- of papules produces plaques that can gles. He recalled an episode of chicken pox become papillomatous. The lesions when he was five years old. Physical exam often form hypertrophic, foul-smelling yielded a linear, erythematous papular masses. Palmar pits, nail dystrophy, and eruption. The lesions individually shared Figure 1 Unilateral linear eruption on mucosal-membrane involvement is also slight hyperkeratosis, and were irregularly the right hemithorax. seen. Both sexes are equally affected, and outlined with a tendency to agminate in this chronic condition is aggravated and plaques (Figure 1). The lesions didn’t cross can be initiated by sunlight. Rare clinical the midline. A 4-millimeter punch biopsy variants include bullous, comedonal, was performed, yielding changes confined hypertrophic (cornifying), leukodermic, to the epidermis, which consisted of slight and localized forms. epithelial acanthosis, focal dyskeratosis Microscopically, acantholysis and with corp ronds and grains, as well as asso- dyskeratosis are the two main features of ciated acantholysis (Figures 2, 3). Neither this entity. Suprabasal acantholysis is seen, ballooning and/or reticular degeneration with formation of small clefts (lacunae) of the epithelium nor herpes cytopathic that are penetrated by irregular projec- effects were identified. tions of the papillary dermis covered by a single layer of basal cells (villi). Two Discussion types of dyskeratotic cells, corps ronds The localized form of this disease is and grains, are present. Corps ronds repre- Figure 2 sent acantholytic cells and are seen in the rare, accounting for approximately 10% upper spinous and granular layer. These of all cases of Darier’s disease (DD). It cells harbor small, pyknotic nuclei with was first described in 1909 by Kreibich.4 clear perinuclear halos, and have a very Other names include: zosteriform, linear, bright eosinophilic cytoplasm. Grains segmental, and unilateral. Due to the fact are small, seed-shaped cells residing in that this form often lacks a family history, the stratum granulosum or higher. They as well as other signs typically associ- possess elongated nuclei that resemble ated with classical DD, in the past it was parakeratotic corneocytes, except they are postulated that localized DD was instead plumper. A thick, orthokeratotic keratin a form of epidermal nevus.5-8 One study plug with focal parakeratosis overlies each questioned this hypothesis, describing lesion. Acanthosis and mild papilloma- a unilateral acantholytic dyskeratotic tosis is often seen. The folliculosebaceous epidermal nevus (ADEN) that also had elements may show infundibular dilation features of DD.9 To explore this further, and plugging.2,3 in 1995, Cambiaghi presented yet another case of ADEN accompanied by ipsilateral Figure 3 56 antitLe unusuaL presentation oF darier’s disease nail dystrophy and palmar pits, and postu- disease differs from DD in that the lesions central groove, follows the lines of Blaschko lated that ADEN may in fact be a mosaic are smaller and less well-formed. Sometimes and can present at birth. Ulceration and form of DD.10 Interestingly, in noticing the corps ronds and grains are seen, as are small erosions may appear in the lesion and delay ability of focal acantholytic dyskeratosis villi. There is a superficial perivascular correct diagnosis. Therefore, linear poroker- (FAD) to distribute itself in either a wide- infiltrate of lymphocytes and occasional atosis should be considered in differential spread or circumscribed manner, Ackerman eosinophils, with spillover into the inter- diagnosis of ulcerative lesions during the likened FAD to epidermolytic hyperkera- stitium. This feature distinguishes it from neonatal period. This variety of porokeratosis.11 Epidermal hyperkeratosis, like DD, DD, in which eosinophils are usually absent. tosis is at highest risk for malignant trans- has both a generalized and systematized Lesions of Grover’s disease usually have a formation, which most commonly includes or linear form. Indeed, it is now thought much thinner keratin plug than those of squamous cell carcinoma, basal cell carci- that both entities may in fact reflect the DD. noma and Bowen’s disease.23 ability of autosomal-dominant skin disor- Although both DD and pemphigus Linear lichen planus appears spontane- ders to manifest mosaicism by involving vulgaris display dyskeratosis, DD displays ously as discrete lesions which follow the body in linear arrangements, with two significantly more. In pemphigus vulgaris, the Blaschko lines and should be distin- types manifested depending on whether there are suprabasal bullae with acanthol- guished from linear lesions of LP as a there is heterozygosity for the mutant allele ysis, and clefting that may extend down into result of Koebner phenomenon in sites of (Type 1), or a loss of heterozygosity for the adnexal structures. The basal cells lose intra- trauma. The characteristic lesion of LP is a mutant allele (Type 2).12-14 Goldberg et al. cellular bridges but remain attached to the polygonal- shaped, flat-topped, violaceous, emphasized the importance of determining dermis, giving a “tombstone” appearance. pruritic papule which may be umbilicated.24 whether or not past reports of linear, Similar to Hailey-Hailey, the initial patho- Linear lichen planus may manifest as simple localized or “zosteriform” DD-like lesions logical process is suprabasal acantholysis. hyperpigmentation or papules with a followed a dermatomal distribution, or if However, in pemphigus vulgaris, there is varying degree of overlying hyperkeratosis. they instead, as in this case, followed the less acantholysis overall, and the separa- Skip areas of normal skin between the indi- lines of Blaschko.15 Lines of Blaschko are the tions are often restricted to the cell layer vidual lesions are often seen. This entity has patterns assumed by many different naevoid immediately superficial to the basal kerati- been reported in less than 1% of patients.23 skin diseases that are thought to be caused nocytes, making them lack the “dilapidated Usual age of onset is late 20s or early 30s. It by a form of mosaicism.16 This distinction brick wall” appearance of Hailey-Hailey is believed that this pattern reflects somatic is important because it implicates genetic disease. Blister cavities usually contain some mosaicism.24 mosaicism as the cause of this entity, and acantholytic cells with degenerative changes Nevus comedonicus appears as groups therefore supports the theory that this local- and occasional eosinophils or neutrophils. of papules arranged in a linear distribu- ized form may in fact be a genetic mosaic of When present, the finding of eosinophils tion. The papules are slightly elevated and generalized DD. Recent work has discovered supports this diagnosis. The dermis usually typically have a keratinous plug in the the gene defect, showing that mosaicism for contains a mild, superficial mixed inflam- center which may resemble a comedone. In the ATP2A2 mutation causes segmental DD matory-cell infiltrate with some eosinophils. approximately 50% of cases, cysts, fistulas, by interfering with the sarco/endoplasmic Direct immunofluorescence shows IgG abscesses and scars may develop. This is reticulum Ca 2+ ATPase isoform 2 pump in the intercellular regions of the affected described as “inflammatory” nevus comedo- (SERCA2), which plays an important role in epidermis. nicus. Lesions, most commonly found on 17-20 Ca2+ signal transduction. Because there is prominent follicular the trunk, are unilateral or bilateral and may The main histological differential diag- involvement in warty dyskeratoma, the be localized or distributed over a large area. nosis for DD includes: Hailey-Hailey comedonal variant of DD can look similar The extensive form is associated with abnor- disease, transient acantholytic dermatosis to warty dyskeratoma.21,22 Typical lesions malities of bone, central nervous system and (Grover’s disease), pemphigus vulgaris and of DD do not display these features. The eyes. The most common age of onset is from warty dyskeratoma. fact that warty dyskeratoma usually pres- birth to 15 years old.23 Both Hailey-Hailey and DD show supra- ents as a solitary nodule or papule with Lichen striatus (LS) is a rare, asymptom- basal acantholysis with villi protruding a central keratotic plug helps in differen- atic disorder characterized by a distinctive into the separations caused by this process. tiating between these two entities. Warty linear distribution of papules. The papules Additionally, Hailey-Hailey shows wide- dyskeratomas consist of well-circumscribed, are flat topped, smooth or scaly, and pink, spread acantholysis of the spinous layer cup-shaped invaginating lesions with basal- tan or skin-colored. They are 2-4 mm in involving at least half the thickness of the layer downgrowths extending into the diameter. The linearity has been shown epidermis. Basal layer budding and villi are dermis. The central depression is filled with to correspond to the pattern of Blaschko’s usually less prominent in Hailey-Hailey. In a keratinous plug containing some grains. lines. Typically, there is a single streak, but DD, the separations consist of small lacunae, Hyperkeratosis is less prominent than in multiple bands or bilateral distribution whereas in Hailey-Hailey, there is forma- DD. There is an inflammatory infiltrate in is possible. LS most commonly is seen on tion of larger vesicles and bullae. Some of the underlying dermis. Clinically, one can extremities and can be associated with nail the acantholytic cells in Hailey-Hailey show see solitary papules or nodules with umbili- dystrophy. The eruption appears suddenly, dyskeratosis, but they have well-defined cated or pore-like centers which can bleed extends over the course of a week or more, nuclei and preserved cytoplasm. Thus, corps or discharge a grumous material. and after several months undergoes sponta- ronds and grains are infrequent or rare. In The main clinical differential diagnosis neous healing. Postinflammatory hypopig- Hailey-Hailey, intercellular edema leads to engendered by localized (segmental) DD mentation might be present. It generally the characteristic “dilapidated brick wall” includes: linear porokeratosis, linear lichen affects children between the ages of four appearance. Polymorphonuclear leuko- planus, nevus comedonicus, lichen striatus, months and 15 years but occasionally may cytes can be numerous within vesicles or in linear psoriasis, linear verrucous epidermal be seen in adults. The etiology is unknown.24 the surface of the parakeratotic crust. The nevus, inflammatory linear verrucous Linear psoriasis is an extremely rare dermis shows variable superficial chronic epidermal nevus (ILVEN), and herpes entity. It follows Blaschko’s lines. This may inflammatory infiltrate. zoster. be easily confused with Koebner phenom- There are four histological patterns of Linear porokeratosis is a rare variant enon caused by injury in the presence of Grover’s disease seen: Darier-like, Hailey- of porokeratosis. It occurs in a unilateral, generalized psoriasis or with inflammatory Hailey-like, pemphigus vulgaris-like, and linear form, has characteristic clinical epidermal nevus.24 spongiotic. The Darier pattern of Grover’s appearance of a keratotic ridge with a Linear verrucous epidermal nevus pres- trimaLdi, gLoBosky, aBrams, morganauthor 57 ents at birth or within the first 10 years of in the cutaneous and genital areas. Br J Dermatol 1998;138:875-878. life as pink, dirty gray or brown papules in 9. Munro CS, Cox NH. An acantholytic dyskeratotic epider- a linear distribution. Papules may coalesce mal naevus with other features of Darier’s disease on the same side of the body. Br J Dermatol 1992;127:168-171. and form a serpiginous plaque. It follows 10. Cambiaghi S, Brusasco A, Grimalt R, Caputo R. Acan- Blaschko’s lines and almost never extends tholytic dyskeratotic epidermal nevus as a mosaic form of Darier’s disease. J Am Acad Dermatol 1995;32:284-286. beyond the mid-sagittal line. Bilateral 11. Ackerman AB. Focal acantholytic dyskeratosis. Arch involvement might be present. Genetic Derm 1972;106:702-706. 12. Happle R. A rule concerning the segmental manifestation mosaicism is thought to be involved in of autosomal dominant skin disorders. Arch Dermatol the etiology. Histologically, epidermal 1997;133:1505-1509. 13. Happle R, Itin PH, Brun AM. Type 2 segmental Darier nevus exhibits hyperkeratosis, acanthosis disease. Eur J Dermatol 1999;9(6):449-451. and papillomatosis. There have been rare 14. Sakuntabhai A, Dhitavat J, Burge S, Hovnanian A. Mosa- icism for ATP2A2 mutations causes segmental Darier’s reports of malignancies developing within disease. J Invest Dermatol 2000;115:1144-1147. nevi.23 15. Goldberg EI, Lefkovits AM, Sapadin AN. Zosteriform Darier’s disease versus acantholytic dyskeratotic epider- Inflammatory linear verrucous mal nevus. Mt Sinai J Med 2001; Sept-Oct 68(4-5):339- epidermal nevus (ILVEN) is differenti- 341. 16. Jackson R. The lines of Blaschko: a review and reconsid- ated from linear epidermal nevus. There eration. Br J Dermatol 1976;95:349 is erythema and pruritis present clini- 17. Wada T, Shirakata Y, Takahashi H, Murakami S, IIzuka H, Suzuki H, Hashimoto K. A Japanese case of segmental cally as well as parakeratosis and inflam- Darier’s disease caused by mosaicism for the ATP2A2 mation histologically. The individual mutation. Br J Dermatol 2003;149:185-188. 18. Gilaberte M, Puig L, Vidal D, Alomar A. Acantholytic dys- lesions appear as erythematosus papules keratotic naevi following Blaschko’s lines: a mosaic form and plaques with fine scale and thus are of Darier’s disease. JEADV 2003;17:196-199. 19. Sanderson EA, Killoran CE, Anita PL, Wilkel CS. Local- morphologically nonspecific. It is therefore ized Darier’s disease in a Blaschkoid distribution: Two important to recognize the distribution of cases of phenotypic mosaicism and a review of mosaic Darier’s disease. J Dermatol 2007;34:761-764. this entity. Although it usually presents at 20. Itin PH, Buchner SA, Happle R. Segmental manifesta- birth or during the first few years of life, tion of Darier disease. What is the genetic background in type1 and type 2 mosaic phenotypes? Dermatology it may also appear as late as the forties or 2000;200:254-257. fifties. ILVEN may be unilateral or bilateral. 21. Aliagaoglu C, Atasoy M, Anadolu R, Engin RI . Com- edonal, cornifying and hypertrophic Darier’s disease Familial cases as well as systemic involve- in the same patient: A Darier combination. J Dermatol ment with musculoskeletal and neurologic 2006;33:477-480. 22. Lee MW, Choi JH, Sung KJ, Moon KC, Koh JK. Two 23 sequelae have been seen. cases of comedonal Darier’s disease. Clin Exp Dermatol. 2002 Nov;27(8):714-5. Herpes zoster is characterized by a 23. Odom R, James W, Berger T. Andrews’ Diseases of the unilateral eruption that is distinctly skin. 10th edition. 2003. pp. 219, 379-384, 633-636. 24. Bolognia J, Jorizzo J, Rapini R. Dermatology. Mosby; dermatomal, restricted to a distribution 2003. pp. 178-182, 184-186, 566-567. of a cranial or spinal sensory nerve. Pain in the affected area usually precedes the eruption by several days but may appear simultaneously. In some cases, pain may follow the eruption. The initial eruption typically presents as papules and plaques. Blisters typically follow the development of the papules. New lesions may continue to appear for one to five days and with time may become necrotic, bullous or hemorrhagic. In the typical case, the rash gradu- ally becomes pustular and then crusts and heals. The total duration of the eruption is two to six weeks. In younger patients, the total duration is shorter than in older patients. Scarring may occur. Herpes zoster is caused by reactivation of varicella zoster virus. Age and immounosupres- sion increase the risk of reactivation of the virus.23

References 1. White JC, Darier FJ. A case of keratosis (ichthyosis) follicularis. Journal of Cutaneous and Genitourinary Dis- eases. 1889; 7: 201-209. 2. Textbook of Dermatopathology. 2nd ed. Raymond L. Barn- hill, A. Neil Crowson. McGraw-Hill Professional. 2004 3. Skin Pathology. 2nd Ed. David Weedon. Churchill Livings- ton. 2002. 4. Kreibich K. Zum wesen der psorospermosis Darier. Arch Derm Syph (Wien) 1906;80:367. 5. Demetree JW, Lang PG, St.Clair JT. Unilateral, linear, zosteriform epidermal nevus with acantholytic dyskeratosis. Arch Dermatol 1979; 115:875-877. 6. Starink TH.M. Woerdeman MJ. Unilateral systematized keratosis follicularis. A variant of Darier’s disease or an epidermal naevus (acantholytic dyskeratotic epidermal naevus)? Br J Dermatol 1981;105:207-214. 7. Youn M, Hann S, Moon T, Lee M. Acantholytic dyskeratotic epidermal nevus induced by ultraviolet B radiation. J Am Acad Dermatol 1998;39:301-4. 8. Cottoni F, Masala MV, Cossu S. Acantholytic dyskeratotic epidermal naevus localized unilaterally

5858 antitLe unusuaL presentation oF darier’s disease nephrogeniC systemiC Fibrosis – A Current looK

Madeline Turner, D.O.*, Angela McKinney, D.O.**, Elina Terushkin, D.O.*** * Certified Dermatologist, Pontiac Osteopathic Hospital Medical Center; Rochester, MI **Traditional Intern Year 1, Oakwood Southshore Hospital; Trenton, Michigan *** Traditional Intern Year 1, St. Petersburg General Hospital; St. Petersburg, Florida

ABSTRACT

Nephrogenic systemic fibrosis is a rare cutaneous fibrosing disorder with potential for significant systemic involvement. While no solitary etiology has been established, the most promising evidence lies in the association between patients with renal failure and their exposure to gadolinium contrast agents during imaging studies. It is important for physicians to understand initiating causes and variable mechanisms of this disease. Knowledge and recognition of early clinical manifestations will allow for more appropriate treatment methods and system management. We present a literature review of Nephrogenic systemic fibrosis, discussing currently accepted clinical and histological criteria, as well as recent therapeutic options.

INTRODUCTION disease (ESRD).2,3 The notion of gadolinium agents do not develop NSF. This leads to the as a causative agent was reinforced after notion that other compounding variables Nephrogenic fibrosing dermopathy retained gadolinium was found in the skin are required for disease expression. It has (NFD) is a rare disease that was first and systemic lesions of NSF patients.4,5 been suggested that the timing of admin- identified in 1997. Initially, reported In healthy individuals, gadolinium is istration of contrast material in relation to cases portrayed this disease as a cuta- rapidly metabolized, with a half life of 1.5 predisposing events such as proinflamma- neous fibrosing disorder, marked by hours; however, this may increase to greater tory conditions may be a crucial component acute onset of induration involving the than 30 hours with impaired renal func- in the occurrence of disease. A predisposing upper and lower extremities in patients tion.6,7 Grobner hypothesized that prolonged inflammatory condition can lead to exces- with renal failure. Over 250 cases have excretion of gadolinium allows for sponta- sive cytokine activation, enzymatic activity been reported since the original publica- neous dissociation of gadolinium chelate and a lowered pH. In a cohort study, all 33 tion. This intriguing new disease entity complex into metal ion and ligand.1 There patients suffering from NSF were compli- sparked awareness and research worldwide. is increasing evidence that gadolinium cated by some degree of inflammatory When multiple reports of systemic fibrosis deposition is facilitated by ions such as zinc, insult such as recent surgery, sepsis or vascu- surfaced, increased investigation expanded copper, iron and calcium, which compete litis.13 The intravascular compartment is the clinical manifestations of NFD to for physiologic binding sites.8,9 It is through exposed to the highest concentrations of those beyond the skin. The recognition this competitive binding that gadolinium gadolinium-containing contrast agents and of extensive systemic involvement led to is thought to be released from its chelate. serves as the primary site for the recruit- NFD’s current name: nephrogenic systemic Free gadolinium is insoluble and may then ment of fibrocytes, monocytes, and various fibrosis (NSF). In 2006, a link between precipitate with tissue anions into various cytokines.14 It is reasonable to believe that the development of NSF and exposure to organs. This theory is supported by the location, timing and predisposing inflam- a gadolinium-containing contrast agent discovery of gadolinium, along with calcium matory conditions are relevant and neces- during imaging studies in the setting of and phosphate, in skin biopsies taken three sary in NSF development. Further research renal disease was established. Throughout years after exposure.10 Once deposited in is essential and highly warranted. the past decade, a vast amount of research the skin, gadolinium contrast agents have has been performed, leading to several not only shown to increase fibroblast Histopathological Findings theories for initiating causes and mecha- proliferation but also to stimulate collagen nisms of this disease as well as numerous turnover.11 Histologically, NSF is characterized by innovative treatment methods. We present Metabolic acidosis, a common finding dermal fibrosis, seen as a thickened dermis a literature review of NSF, including in renal failure, may play an additional with increased fibrocytes, collagen, mucin, currently accepted clinical and histological role in the development of NSF. Khurana and elastin. Fibrocytes and elastin tend criteria and recent therapeutic options. revealed a tendency toward anion gap, to align parallel to collagen strands, while which enhances transmetallation and liber- mucin and edema form clefts that sepa- Causes ation of free gadolinium from its chelate.12 rate the collagen bundles, a characteristic Another observation was made in hemo- finding distinguishing NSF from other With increased publicity and research dialysis patients receiving erythropoietin fibrosing disorders. This feature can be of NSF, a link between renal failure, expo- who have shown a significantly higher observed using mucin stains. Significant sure to gadolinium contrast agents during chance of developing NSF than individ- fibrosis of septa within the subcutaneous imaging studies, and the development of uals not receiving erythropoietin.10 This fat can also be appreciated. Higher disease has been established.1 It should be claim is controversial in that people with magnification of these lesions often shows noted that two forms of gadolinium exist: ESRD are more likely to receive erythro- a proliferation of spindle and epithe- macrocyclic and linear. These forms differ poietin therapy, perhaps indicating a false lioid cells that stain positively with CD in thermodynamic and kinetic stability. correlation. 34 and procollagen I. In more advanced All cases of NSF have thus far been associ- Most of the aforementioned possible disease, fibrocytes become more plump ated with linear forms, most commonly causes of NSF are secondary to common and intensely procollagen I positive.15 This gadodiamide (Omniscan). NSF is seen in manifestations of renal failure; however, dual staining is characteristic of circulating all stages of kidney failure, although it most most patients with kidney disease who fibrocytes derived from the bone marrow, commonly manifests with end-stage renal receive gadolinium-containing contrast suggesting a relocation of cells from the turner, mckinney, terushkinauthor 5959 bone marrow to the skin and other soft making an accurate diagnosis a challenge. pharyngitis.23 tissues.16 The differential most commonly includes: In eosinophilic fasciitis (EF), inflamma- Although many histologic findings are lipodermatosclerosis, scleroderma/deep tion and fibrosis of the fascia and tissue characteristic of NSF, a large amount of morphea, scleromyxedema, scleredema, surrounding muscles occur.16 Histologic variability can occur. Some histologic eosinophilia-myalgia syndrome, eosino- findings demonstrate a thick eosinophilic changes overlap with other fibrosing philic fasciitis (Shulman syndrome), and fascia due to fibrosis and hyalinization of diseases. For example, calcification and chronic graft versus host disease (cGVHD).16 collagen. A variable infiltrate of lympho- osteoclast-like giant cells with osseous Less commonly affiliated conditions include cytes, plasma cells, and occasional eosino- metaplasia have rarely been reported.17 Also, systemic lupus erythematosus, dermatomy- phils may be present.24 Unlike NSF, mucin despite recent associations of NSF with pro- ositis, systemic amyloidosis, hypothyroidism deposition and fibrocytes are absent in EF. inflammatory and hypercoagulable states, and stiff skin syndrome. 23 Similar to NSF, this condition may present lesions display varying degrees of vascular Lipodermatosclerosis (LDS) occurs most with cutaneous findings of deep indura- proliferation and inflammatory cellular commonly in patients with edema from tion and peau d’orange changes. Typically, infiltrates.18 In fact, Swartz and colleagues venous insufficiency and vascular stasis, these lesions involve the trunk and extremi- found NSF biopsies lacking neutrophils and usually presenting with painful induration ties, sparing the hands and feet.23 Systemic eosinophils unless otherwise present due of the distal lower extremities.16 Involvement involvement may also occur. to an imposing inflammatory condition. is rarely observed above the knee. Histology Eosinophilia–myalgia syndrome (EMS) is xix Other reports show different intensities typically shows necrosis of the fat lobule associated with the ingestion of the amino of CD68 and Factor XIIIa staining, which is and lipomembraneous change overlying acid l-tryptophan. EMS is characterized of unknown significance.18 A wide range of stasis changes.24 In patients with sclero- by edema, erythema, papules, and diffuse histologic findings can be observed in the derma/deep morphea, multiple internal thickened areas with a peau d’orange diagnosis of NSF, making the clinical picture organs may be affected along with the pres- appearance on the extremities that may ever so important in identifying this disease. ence of autoantibodies SCL-70 and ANA. spread to the face and trunk.16 EMS is Dyspigmentation of the trunk and forehead histologically similar to EF but often shows Clinical Manifestations may also be observed as a “salt and pepper” greater dermal involvement as well as a late pattern of pigment retention at the follicles. stage characterized by dermal mucinosis.24 The clinical and histological involvement Sclerodactyly may be seen, as well as foci Chronic graft versus host disease of both cutaneous and systemic compo- of vascular compromise in the fingertips (cGVHD) is characterized by findings nents of disease remains highly variable. related to Raynaud’s disease. Morphea similar to those of NSF in an entirely Classically, the earliest cutaneous findings (localized scleroderma) presents as indu- different clinical setting, most often related of NSF include edema, erythema, and rated plaques on the trunk or extremities to allogeneic stem cell transplantation.16 16 occasional palpable warmth. Diagnostic and is usually not associated with systemic Histologically, the dermis appears thickened 16 lesions present as papules and coalescing involvement. Histologic examination typi- and sclerotic, with features of basal vacuol- plaques that resemble peau d’orange, cally shows thick, closely packed, hyalinization and destroyed adnexal structures.24 most often concentrated along the trunk ized collagen in the deeper dermis, loss of Due to the lack of diagnostic criteria and and extremities.15 The skin involvement is adventitial fat which results in “trapped” confusion between disorders that manifest often symmetrical and bilateral.16 Typically, eccrine glands, and a sparse, deep lympho- skin lesions similar to those of NSF, it is brawny or woody induration develops, plasmacytic infiltrate. Although the histo- important to rely on discriminating features originating in the distal extremities and logic features of scleroderma and morphea to aid with diagnosis. Consideration of extending proximally with time. These are similar, morphea is usually more inflam- the morphology and distribution of skin lesions may also be accompanied by irreg- matory and lacks the intimal thickening lesions, their history, histologic tendencies, ular erythema and hyperpigmentation.17,20,21 and luminal obliteration of vessels seen in 24 and association with concurrent disease or Some patients may present with deep systemic scleroderma. serological parameters can significantly aid skin lesions relatively early and rapidly, Scleromyxedema (SCX), on the other in distinguishing NSF from other entities. whereas more superficial lesions may appear hand, is characterized by cutaneous on patients long after established, deep mucinosis and fibrosis of the face, neck, Treatment involvement has occurred. Contractures arms, hands and, less frequently, the legs of numerous joints may also occur, often and trunk. Patients may form widespread Identification of effective therapeutic proceeded by pain, muscle weakness, inflex- papules and plaques with areas of diffuse options for NSF remains a significant chal- ibility, and increased difficulty carrying out induration. Internal deposits of mucin can lenge due to the absence of a proven etio- activities of daily living. NSF progresses lead to a variety of systemic complaints pathogenesis for this devastating disorder. to marked physical disability character- such as cardiac and neurologic dysfunc- Although various methods and treatment ized by almost complete loss of range of tion.16 Histologically, SCX shows an increase regimens have been utilized and several have motion in all extremity joints.16 In addition, in dermal fibroblasts, fine collagen fibers, resulted in significant symptomatic relief for asymptomatic scleral involvement has been and interstitial mucin.24 An underlying patients, there is no evidence in the current observed in up to 75% of cases. Initially, gammopathy (IgG paraprotein) may often literature for a consistently effective mode these ocular findings appear similar to accompany this disorder. Unlike NSF, SCX of therapy. Experimental therapies have conjunctivitis, but often progress to yellow- has not been reported in children.23 included chemotoxic and immunosuppres- white scleral plaques.4 Not only does NSF Scleredema is a condition that demon- sive agents such as prednisone, thalidomide, present with many cutaneous findings, strates indurated skin lesions distributed mycophenolate mofetil, calcineurin inhibi- but may also be accompanied by various on the face, neck and back. Histologically, tors, and plasmapheresis.25 Used alone, systemic manifestations such as cardiomy- it is associated with dermal fibrosis, corticosteroids have failed to ameliorate or opathy, pulmonary fibrosis, pulmonary prominent mucin deposition along with benefit NSF symptoms.26 However, DiCarlo hypertension, and diaphragmatic paralysis.22 increased space between collagen fibers et al. report near complete resolution of in the deeper dermis, and the absence of NSF lesions in a pediatric patient treated Differential Diagnosis fibrocytes and inflammation.24 This disease with combination therapy of topical and selectively appears in the setting of three systemic corticosteroids along with a short Many other clinical conditions present conditions: poorly controlled diabetes, course of methotrexate and compression with substantial skin fibrosis similar to NSF, monoclonal gammopathy, and streptococcal therapy.27 Beneficial results have also been

6060 nephrogenictitLe systemic FiBrosis – a current Look observed with intravenous sodium thiosul- can help prevent formation or slow progres- cised when incorporating imaging tech- fate (STS), thought to be attributed to the sion of joint contractures that ultimately nology into the management of patients agent’s chelating and antioxidant proper- lead to significant disability and wheelchair with renal disease. ties.28 Most recently, several mechanisms dependence.21,34 Many attempts at inter- have been proposed for reduction of tissue vention have been made; however, success Conclusion fibrosis if treated with STS early.29 lies in the complete understanding of the Among the immunomodulators, imatinib underlying mechanisms for gadolinium- Nephrogenic systemic fibrosis is a rare mesylate (Gleevec) has been shown to induced fibrosis. Hopefully, the future will disease with significant disabling poten- decrease fibrosis by blocking signal trans- provide links to aid our recognition, under- tial. Although originally thought to present duction through the transforming growth standing, and treatment of NSF. with only cutaneous findings, recent studies factor β receptor (TGFβR) and the platelet- have established the presence of significant derived growth factor receptor (PDGF- What To Expect systemic involvement. While many theories BB), both of which mediate fibrosis. have been proposed regarding the patho- Unfortunately, once treatment is discon- Without an adequate and concrete treat- genesis of NSF, the most promising evidence tinued, skin fibrosis appears to resume.30 ment option for NSF, it is important for lies in the association between patients with Duration of treatment required for perma- physicians to be aware of serious adverse renal failure and their exposure to gado- nent reversal of fibrosis remains to be reactions when using gadolinium contrast linium contrast agents during imaging investigated. Although its mechanism is agents. In June 2006, the FDA mandated studies. Gadolinium has been shown to poorly understood, high-dose intravenous a black box warning highlighting the risk precipitate into soft tissues, including the immunoglobulin has also shown benefit. for NSF following exposure to gadolinium skin and various organs. One patient experienced increased range contrast agents in patients with severe acute Many etiologies for NSF have been of motion after just one cycle, although or chronic renal insufficiency (a glomerular proposed. However, despite the past decade subsequent cycles provided only minimal filtration rate <30 mL/min/1.73m2) and of research and many theories, no solitary improvement.31 These treatments are highly patients with acute renal insufficiency of any etiology has been established. Nevertheless, variable, expensive, and have a high poten- severity due to the hepato-renal syndrome physicians should be extra wary of early tial for adverse effects. Most important, or in the peri-operative liver transplanta- signs such as cutaneous erythema, edema, 38 they do not guarantee positive results. tion period. This awareness holds the palpable warmth of extremities, pruritus, NSF lesions have been reported to reverse physician accountable for risk stratifica- pain, and muscle weakness. Recognition of following return to normal renal function, tion and appropriate medical decision these symptoms may be the initial step in but only a small proportion of affected making when choosing a contrast agent. prevention of disabling joint contractures patients have reversible renal failure or are Gadolinium agents are amongst the safest and weakness observed with late onset NSF. imaging techniques for renal patients, and renal transplant candidates.17,20,32 Although Once NSF is diagnosed, the most optimal only a few patients have received renal only a small minority has serious complica- results occur with improvement of renal transplants, those observed in a recent trial tions. Following specific protocols may be function. In the meantime, while trying showed marked clinical improvement of beneficial in the prevention of NSF. Of to achieve optimal renal status, the most their symptoms as early as one week after course, avoidance of gadolinium-based important components of treatment include their transplant and up to six months post- contrast exposure is the best approach for pain control and aggressive physical therapy. high-risk patients. It becomes difficult, transplantation.33 Though transplantation Although gadolinium is considered to may be a reasonable option for a select however, when the severity or accurate be one of the safest contrast agents, it is handful of patients, most others must history cannot be obtained. When possible, imperative for physicians to follow strict depend on modalities and regimens yet to the physician should evaluate each patient’s guidelines to assess risks versus bene- be identified. medical history and risk of renal disease. fits among patients with renal disease. Information such as history of hyperten- Additional research will help determine Phototherapy, either in the form of sion, congestive heart failure, diabetes, psoralen plus ultraviolet light A (PUVA) alternative options for imaging as well as and use of nephrotoxic drugs may alert treatment interventions for this specific or extracorporeal photopheresis, although the physician to potential complications.39 variable in response and treatment length, patient population. While much remains If possible, renal function tests prior to to be understood, the current research has may also be safe and effective treatment imaging may assist in decision making as 34 provided clinicians with a sound foundation modalities for NSF patients. The proposed well. Although a history of renal disease mechanism involves the exertion of local or for recognition and potential prevention of may be present, gadolinium contrast agents NSF. systemic effects on fibrocytes, monocytes, may still be required to obtain optimal or T-lymphocytes, resulting in reduced images. In such instances, use of low cytokine production, reduced fibrocyte dosages of more stable macrocyclic agents is REFERENCES migration to the skin from peripheral safer and preferred.40 1. Grobner T: Gadolinium – a specific trigger for the develop- blood, or reduced fibrocyte maturation and ment of nephrogenic fibrosing dermopathy and nephro- proliferation in the skin.35 Photodynamic Failure of physicians to apply risk strati- genic fibrosing dermopathy and nephrogenic systemic fication protocols could result in litigation. fibrosis? Nephro Dial Transplant 2006; 21:1104-1108 therapy (PDT) with lipophilic agent methyl 2. Perez-Rodriguez J, Lai S, Ehst BD, Fine DM, Bluemke DA: aminolaevulinate (MAL) has also shown Thus far, legal action is mainly directed Nephrogenic systemic fibrosis: incidence, associations, toward the manufacturer for strict liability. and effect of risk factor assessment–report of 33 cases. promising results via induction of matrix Radiology. 2009 Feb;250(2):371-7 metalloproteinases in fibroblasts and reduc- Houck and colleagues explain strict liability 3. Grobner T, Prischl FC: Patient characteristics and risk fac- as a design, manufacturer or warning defect. tors for nephrogenic systemic fibrosis following gadolinium tion of collagen synthesis in the dermis.36 exposure. Semin Dial. 2008 Mar-Apr;21(2):135-9. Epub They also indicate that additional lawsuits 2008 Jan 23. Review. Lastly, improvement has also been observed 4. Boyd AS, Zic JA, Abraham JL: Gadolinium deposition in arise based on negligence and breach of nephrogenic fibrosing dermopathy. J Am Acad Dermatol. with UV-A1 irradiation in one case that 41 integrated three-times-weekly sessions for implied warranty. The current recipients 2007 Jan;56(1):27-30. Epub 2006 Nov 15. Review. of litigation appear to be manufacturers, 5. Kay J, Bazari H, Avery LL, Koreishi AF: Case records 12 weeks.37 of the Massachusetts General Hospital. Case 6-2008. A but with increased awareness of NSF patho- 46-year-old woman with renal failure and stiffness of the Although much progress has been made genesis, physicians may become the next joints and skin. N Engl J Med. 2008 Feb 21;358(8):827-38. since the discovery of this multisystem 6. Staks T, Schuhmann-Giampieri G, Frenzel T, Weinmann targeted population. Until an alternative HJ, Lange L, Platzek J: Pharmacokinetics, dose propor- fibrosing disorder, physical therapy and pain contrast agent with a higher safety profile tionality, and tolerability of gadobutrol after single intrave- management are the mainstays of treatment. nous injection in healthy volunteers. Invest Radiol. 1994 is derived, extreme caution should be exer- Jul;29(7):709-15. Pain relief enables physical activity, which 7. Tombach B, Bremer C, Reimer P, Schaefer RM, Ebert W, turner, mckinney, terushkinauthor 61 Geens V, Heindel W: Pharmacokinetics of 1M gadobutrol Semin Dial. 2008 Mar-Apr;21(2):155-9. Epub 2008 Jan 23. in patients with chronic renal failure. Invest Radiol. 2000 35. Wahba IM, Simpson EL, White K: Gadolinium is not the Jan;35(1):35-40 only trigger for nephrogenic systemic fibrosis: insights from 8. Idée JM, Port M, Raynal I, Schaefer M, Le Greneur S, two cases and review of the recent literature. Am J Trans- Corot C: Clinical and biological consequences of transplant 7:2425-2432,2007 metallation induced by contrast agents for magnetic reso- 36. Karrer S, Abels C, Weiderer P, Bosserhoff A, Ladthaler M, nance imaging: a review. Fundam Clin Pharmacol. 2006 Szeimies RM: Induction of collagenases in human dermal Dec;20(6):563-76 fibroblasts by 5-aminolevulinic acid and light. Med Laser 9. Kimura J, Ishiguchi T, Matsuda J, Ohno R, Nakamura A, Appl 16: 148, 2001 Kamei S, Ohno K, Kawamura T, Murata K: Human com- 37. Kafi R, Fisher GJ, Quan T, Shao Y, Wang R, Voorhees JJ, parative study of zinc and copper excretion via urine after Kang S: UV-A1 phototherapy improves nephrogenic fibros- administration of magnetic resonance imaging contrast ing dermopathy. Arch Dermatol 140:1322-1324, 2004 agents. Radiat Med. 2005 Aug;23(5):322-6 38. http://www.fda.gov/cder/drug/InfoSheets/HCP/ 10. 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Deng A, Bilu Martin D, Spillane A, Chwalek J, Surin-Lord S, Brooks S, Petrali J, Sina B, Gaspari A, Kao G: Nephro- genic systemic fibrosis with a spectrum of clinical and histopathological presentation: a disorder of aberrant dermal remodeling. J Cutan Pathol. 2009 Mar 31. 19. Swartz RD, Crofford LJ, Phan SH, Ike RW, Su LD: Neph- rogenic fibrosing dermopathy: a novel cutaneous fibrosing disorder in patients with renal failure. Am J Med. 2003 May;114(7):563-72. 20. Mackay-Wiggan JM, Cohen DJ, Hardy MA, Knobler EH, Grossman ME: Nephrogenic fibrosing dermopathy (scleromyxedema-like illness of renal disease). J Am Acad Der- matol 48:55-60, 2003 21. Knopp E, Cowper SE: Nephrogenic systemic fibrosis: early recognition and treatment. Semin Dial 21:123-138,2008 22. Nainani N, Panesar M. Nephrogenic Systemic Fibrosis: Am J Nephrol. 2009;29(1):1-9. Epub 2008 Jul 29. Review. 23. Boin F, Hummers LK: Scleroderma-like fibrosing disorders. Rheum Dis Clin North Am. 2008 Feb;34(1):199-220; ix. 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Clin J Am Soc Nephrol. 2007 Mar;2(2):258-63. Epub 2007 Feb 7. 29. Kadiyala D, Roer DA, Perazella MA: Nephrogenic systemic fibrosis associated with gadoversetamide exposure: treatment with sodium thiosulfate. Am J Kidney Dis. 2009 Jan;53(1):133-7. Epub 2008 Nov 20. 30. Kay J, High WA: Imatinib mesylate treatment of nephrogenic systemic fibrosis. Arthritis Rheum. 2008 Aug;58(8):2543-8. 31. Chung HJ, Chung KY: Nephrogenic fibrosing dermopathy: response to high-dose intravenous immunoglobulin. Br J Dermatol 150:596-597,2004 32. Mathur K, Morris S, Deighan C, Green R, Douglas KW: Extracorporeal photopheresis improves nephrogenic fibrosing dermopathy/nephrogenic systemic fibrosis: three case reports and review of literature. J Clin Apher. 2008;23(4):144-50. Review. 33. Panesar M, Banerjee S, Barone GW: Clinical improvement of nephrogenic systemic fibrosis after kidney transplantation. Clin Transplant. 2008 Nov-Dec;22(6):803-8. Epub 2008 Aug 18. 34. Linfert DR, Schell JO, Fine DM: Treatment of nephrogenic systemic fibrosis: limited options but hope for the future. 62 nephrogenic systemic FiBrosis – a current Look steVens-Johnson syndrome - toxiC epidermAl neCrolysis oVerlAp

Alice N. Do, DO,* Kimball Silverton, DO, FAOCD** *3rd-year resident, Genesys Regional Medical Center, Grand Blanc, MI **Program director, Genesys Regional Medical Center, Grand Blanc, MI

ABSTRACT

Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are a spectrum of the same disease, best described as a rare, life-threatening allergic reaction to medications that results in rapid keratinocyte apoptosis and is associated with high mortality. The exact pathophysiology of SJS and TEN has not been clarified, and there is no consensus on how to manage this disorder. The number of medications that trigger SJS/TEN continues to grow. We present a case of a patient with SJS/TEN overlap and a review of the literature. Case Report Exam was more consistent with a diagnosis SJS/ TEN than an allergic drug reaction (see We present a case of a 52-year-old The patient was afebrile and nontoxic Figure 5). Caucasian woman with a history of breast on initial evaluation, although she was cancer and ulcerative colitis. The patient uncomfortable. She had an erythematous Diagnosis had recently undergone a bilateral mastec- morbilliform eruption on her face, neck, tomy, and had a MediPort placement in chest, abdomen, upper back, buttocks, A diagnosis of SJS/TEN overlap was preparation for chemotherapy. She also upper extremities and lower extremities made based on clinical appearance of had a history of childhood tuberculosis, (see Figure 1). She also had erythematous skin lesions, extent of TBSA involved, and was therefore placed on prophylactic macules and patches on her palms and number of mucosal surfaces involved, and histopathology. isoniazid (INH) in preparation for her soles (see Figure 2). Atypical targets were immunosuppression. After the port place- noted on the upper extremity (see Figure ment, she developed a minor skin infection 3). Initially, these lesions covered approxi- Course of Treatment mately 15% of her total body surface and was placed on cephalexin. The patient’s medication list was Two and a half weeks after starting area (TBSA). There were no cutaneous reviewed to find possible culprits (see Table INH and five and a half weeks after vesicles, bullae, or areas of desquamation; 11). The patient had already discontinued starting cephalexin, the patient devel- however, tender erosions were present on INH, cephalexin, and acetaminophen/ oped a pruritic eruption on her upper the oral labial mucosa, buccal mucosa, hydrocodone. Other medications were less extremities and experienced diarrhea and and tongue (see Figure 4). A nasopha- likely to be implicated. Her colitis was abdominal cramping. An allergic drug ryngoscopic exam revealed multiple ulcer- still being managed with 6-MP. We felt eruption was suspected, and both medi- ations, mucosal sloughing, and crusts on that this was the main culprit in driving cations were discontinued. However, the lips, pharynx, nasal vaults, and supra- the cutaneous eruption, given the patient’s over the next two days, both the cuta- glottic region of the larynx. There were continued decline while on this medica- no urogenital mucosal lesions. Despite neous eruption and gastrointestinal tion, and it was discontinued. symptomology, there was no conjunctivitis symptoms worsened. Given her history We strongly considered immediate on exam. of ulcerative colitis, she was hospitalized transfer to a burn unit, since the patient for a colitis workup. was quickly deteriorating. Intravenous The patient’s cutaneous eruption spread Course of illness to her lower extremities and trunk. On the The patient was being managed for Silverton day of hospital admission, she had onset ulcerative colitis with 6-MP. She had low- of painful mouth sores and complained of grade fevers and a mild leukocytosis, but dysphagia. Upon inquiry, she reported that her blood and stool cultures were negative, her eyes were burning slightly. She denied and the patient appeared nontoxic. burning upon urination or other urinary The next day, the patient’s cutaneous tract symptoms or genital symptoms. She eruption worsened to involve 25% TBSA. denied a recent herpes outbreak. Her eruption still appeared morbilliform, Her past medical history was signifi- without desquamation. She reported wors- cant for the above-mentioned conditions, ening dysphagia, and her oral intake was as well as hypertension and depression. poor. She continued to be mildly febrile, She reported a history of drug allergies but now appeared toxic and lethargic. A 3 to oxicodone/aspirin (Percodan) and mm punch biopsy was performed on the hydromorphone (Dilaudid), both of which trunk for frozen section. Her colitis was caused rashes, and erythromycin, which still being managed with 6-MP. caused shortness of breath. Histopathology Prior to the patient’s cutaneous erup- The frozen section showed necrotic tion, her medications included INH, keratinocytes scattered throughout the cephalexin, 6-mercaptopurine (6-MP), epidermis. A lymphocytic infiltrate with hydrocodone/acetaminophen (Vicodin) spongiosis and a vacuolar-interface change Figure 1: Generalized morbilliform taken only as needed, sertraline, atenolol, were present at the dermoepidermal junc- eruption on the face, neck, trunk, and hydrochlorothiazide, and mesalamine. tion. No eosinophils were visualized. This the lower extremities. do, siLVerton 63 immunoglobulin (IVIG) was initiated at a dose of 1 gram/kg/day for three days. The patient experienced shaking chills and spiking fevers during the first infusion, but this resolved when the infusion rate was slowed to administer the drug over a six- hour period. She tolerated subsequent infu- sions well, and received a total dose of 3 gram/kg of IVIG. The patient was treated with topical steroids and intravenous diphenhydramine for her pruritic rash. A 2% viscous lidocaine mouthwash with sulcrafate and diphenhydramine was used to alleviate oropharyngeal symptoms. Intravenous fluids and nutrition were maintained, and Figure 2: Palms and soles are often involved in SJS/TEN. Erythematous macules electrolyte imbalances were corrected. and patches were present bilaterally. In less than 12 hours after discontinuation of 6-MP and initiation of IVIG, the patient’s condition quickly improved. She no longer appeared toxic or lethargic. Over the next few days, the patient’s cutaneous lesions decreased in erythema, becoming dusky and resolved with hyperpigmentation (see Figure 6). There was subsequent, slight, superficial desquamation, involving 1-2% of her TBSA, which slowly resolved over the next several weeks (see Figure 7). Her burning eye symptoms resolved, and her oral lesions healed slowly over the course of Figure 3: Atypical targets were Figure 6: Erythema of the lower two weeks. She was tolerating greater oral present on the upper extremities. extremities resolved, becoming intake (see Figure 8). dusky and hyperpigmented after We briefly contemplated whether her discontinuation of 6-MP and treatment colitis was due to SJS/TEN or her ulcerative with IVIG. colitis. Because her skin and oral mucosa markedly improved, while her ulcerative colitis lingered, and because she had a history of colitis attacks not associated with skin manifestations of SJS/TEN, we felt these were two separate processes. The patient was discharged from the hospital when both conditions were controlled. Differential Diagnosis Our patient’s differential diagnosis included allergic drug reaction including Figure 4: Erosions on the oral labial drug-hypersensitivity syndrome, drug rash mucosa. The patient also had erosions with eosinophilia and systemic symptoms on the buccal mucosa, nasal mucosa, (DRESS syndrome), Behcet’s syndrome, and tongue, pharynx, and larynx. paraneoplastic pemphigus. Figure 7: Very slight, superficial desquamation involved 1-2% TBSA. Discussion SJS/TEN overlap is a rare, life-threatening condition, triggered by an allergic reaction to medications. It occurs in two in one million per year; however, the incidence continues to grow.2,3 It is part of a spectrum of diseases that includes bullous erythema multiforme (EM), SJS, and TEN, with TEN being the most severe of these disorders. Five categories of this spectrum are Figure 5: On histopathology, necrotic recognized:2 keratinocytes were scattered throughout the epidermis. Spongiosis and vacuolar 1. Bullous EM. This involves <10% TBSA interface changes were present as a and presents with cutaneous typical and result of a lymphocytic infiltrate at the Figure 8: The patient’s oral labial atypical target lesions. If there is mucosal dermoepidermal junction. Few to no erosions resolved after discontinuation involvement, it is usually limited to the eosinophils were present. of 6-MP and treatment with IVIG. oral mucosa. 64 steVens-Johnson syndrome - toxic epidermaL necroLysis oVerLap allowing for interaction between Fas and FasL. This interaction sets off a cascade of events leading to intracellular activation of caspases, which degrade DNA, leading to apoptosis and rapid keratinocyte death.2 The other model explaining TEN apoptosis recognizes the perforin/granzyme pathway (see Figure 10).2 Once a cytotoxic T cell recognizes a target, it releases perforin, which creates a hole in the target’s Figure 9: One theory of the pathophysiology of SJS/TEN is the Fas-FasL cell membrane, by which granzyme B can pathway. Under normal conditions, Fas (the death receptor) is on the surface enter and activate caspases, leading to of the keratinocytes, and the Fas ligand (FasL) is kept intracellularly. During apoptosis of the keratinocyte. TEN, FasL moves extracellularly, allowing Fas and FasL to interact, leading to Pereira et al. and Faye et al. consider keratinocyte apoptosis. IVIG binds Fas, preventing the interaction between Fas TEN a T cell-mediated disorder, involving and FasL, thereby inhibiting this pathway. TNF alpha, leading to apoptosis.2,10 However, TNF alpha also has anti-apop- acral surfaces and is triggered by infection, totic effects. Whether a pro-apoptotic or such as herpes, and patients are younger anti-apoptotic process predominates in and healthier. SJS and TEN include wide- TEN is not clear, and therefore it is unclear spread skin lesions and are triggered by if the use of anti-TNF alpha therapies medications, and patients are older and would be helpful or harmful. Several other more ill.4 pathways that may be involved in TEN SJS and TEN are characterized by rapid are being investigated.2 Most likely, TEN keratinocyte apoptosis,5 which may result involves more than just one pathway. in massive sloughing of large sheets of Symptoms start with fever, sore throat, skin. This compromise of skin barrier burning eyes, painful, burning skin, and leaves patients vulnerable to infection and mucosal sloughing, leading to painful fluid loss through denuded skin. Death erosions, leading to conjunctivitis and is secondary to sepsis or multiorgan dysphagia. This can make swallowing failure.6 Multiple sources report mortality and oral intake of nutrition challenging. varying from 15% to 60%, but on average, Tracheal and bronchial involvement can Figure 10: A competing theory of SJS/ mortality is 30%.2 lead to shortness of breath, tachypnea, TEN pathophysiology is the granzyme/ Medications commonly associated and hypoxemia.2,5,11 Gastrointestinal and perforin pathway. Perforin creates a with SJS and TEN include sulfonamide genitourinary mucosal surfaces can be perforation through the keratinocyte antibiotics, beta-lactam, tetracycline, and involved.5,11 There have been reports of cell membrane, allowing granzyme to quinolone antibiotics. Anticonvulsants, colitis associated with SJS.3,12 In our case, enter and trigger apoptosis. allopurinol, non-steroidal anti-inflam- the patient’s colitis was felt to be a separate matory drugs (NSAIDs), acetaminophen, process from SJS/TEN. 2. SJS. This involves <10% TBSA and pres- and antivirals are also implicated.2,4,5 The Patients are often febrile and ill. The ents with widespread erythematous or number of medications that trigger SJS/ skin lesions are generalized, dusky, purpuric macules or target lesions. At TEN is growing. erythematous macules or papules, typical least two mucosal surfaces are involved. SJS/TEN mortality can be predicted or atypical target lesions, vesicles or bullae, 3. SJS/TEN overlap. This involves 10-30% using SCORTEN, which adds the risk erosions, or sheets of desquamation.2,5 This TBSA and presents with widespread factors to calculate mortality (see Tables fragile skin demonstrates Nikolsky sign. erythematous or purpuric macules or 2 & 3).7 Our patient’s mortality was Purulent conjunctivitis, oral or genital target lesions. At least two mucosal predicted to be 35.3%. erosions may also be seen on exam. surfaces are involved. The exact pathophysiology of SJS/ Diagnosis is made based on skin lesions, 4. TEN with spots. This involves >30% TEN is still under debate. Medications TBSA, and involvement of at least two TBSA and presents with widespread may activate T cells by acting as haptens, mucosal surfaces. Biopsy is confirmatory.5 erythematous or purpuric macules or prohaptens, or directly activating the T A 3 mm punch biopsy of skin that includes target lesions. At least two mucosal cells. Nassif et al. mention the possibility epidermis should be obtained for frozen surfaces are involved. of a sulfonamide drug cross-sensitivity section, which can offer an immediate 5. TEN without spots. This involves >10% triggering TEN.8 The end result of SJS/ diagnosis for this emergent condition.2,3 TBSA and presents with large sheets of TEN is keratinocyte apoptosis. There are The sooner TEN is diagnosed, the sooner epidermal detachment without erythem- at least two models suggesting how apop- it can be property treated. It may also be atous or purpuric macules or target tosis occurs. prudent to obtain a specimen for immu- lesions. At least two mucosal surfaces are One model recognizes the Fas-Fas nofluorescent studies to rule out immu- involved. ligand pathway (Fas-FasL). Under normal nobullous disorders if they are suspected. conditions, keratinocytes express Fas on Our patient lacked any cutaneous vesicles Our patient was diagnosed with SJS/ the surface. Fas is a cell surface death or bullae that would favor the diagnosis TEN overlap, given the type of cutaneous receptor, which responds to the need for of immunobullous disease, therefore lesions, TBSA, and mucosal surfaces quick apoptosis.9 It only responds when no immunofluorescence samples were involved. it interacts with its ligand, FasL, which is obtained. EM major, previously thought to be normally intracellular (see Figure 9). In Differential diagnosis for SJS/TEN a part of the spectrum of SJS and TEN, TEN, there is an upregulation of FasL, and overlap include EM major, Behcet’s is now considered a separate entity. It it goes from its intracellular location to syndrome, drug hypersensitivity / DRESS includes target lesions typically limited to the surface of the keratinocyte membrane, syndrome, paraneoplastic pemphigus do, siLVerton 65 Table 1

Various cutaneous eruptions are associated with the patient’s medications. The top culprits for SJS/TEN in our patient were 6-MP, hydrocodone/acetaminophen, INH, and cephalexin1.

Drug Reported cutaneous eruptions 6-mercaptopurine 1-10% rash reported; TEN reported, 1-10% stomatitis reported; 1-5% oral (6-MP) lesions reported EM reported; 1-10% pruritus reported; >10% rash reported; SJS reported; TEN hydrocodone reported acetaminophen EM reported; <1% rash reported; SJS reported; TEN reported. isoniazid <1% EM reported; <1% rash reported; SJS reported; <1% TEN reported (INH) cephalexin <1% EM reported; <1% rash reported; <1% SJS reported; <1% TEN reported

sertraline allergic reaction reported; <1% EM reported; 2.1% rash reported; SJS reported

atenolol 1-5% pruritus reported; rash reported; EM reported; TEN reported

hydrochlorothiazide <1% EM reported; rash reported; SJS reported; TEN reported

mesalamine <1% allergic reaction reported; 3% rash reported Table 2

SCORTEN is used to predict mortality associated with SJS and TEN. It should be calculated within the first 24 hours of admission5,6. Each risk factor is assigned one point.

Risk Factor Point score

Age > 40 years 1

History of malignancy 1

>10% TBSA of epidermal detachment (blisters or desquamation) 1

Serum urea nitrogen > 28 mg/dL 1

Serum glucose > 252 mg/dL 1

Serum bicarbonate < 20 mEq/L 1

Heart rate > 120 beats/minute 1 Table 3

Risk factor points are added to predict TEN mortality5. Histologically, necrotic keratinocytes are syndrome and allergic drug reaction, which Total points Mortality seen throughout the epidermis. Later on, show an abundance of eosinophils. full-thickness keratinocyte necrosis may Management of SJS and TEN can be 0 - 1 3.2% be appreciated. The infiltrate is predomi- extremely challenging. Once the process 2 12.2% nantly lymphocytic, located at the dermo- starts, if allowed to spin out of control it is 3 35.3% epidermal junction, causing spongiosis, very difficult to control later. The impor- papillary edema, and vacuolar interface 4 58.3% tance of attempting to halt the disease changes which may lead to subepidermal process as early as possible cannot be 5-7 90% separation.13 This accounts for the bullae emphasized enough. Much emphasis must and desquamation associated with SJS/TEN. be placed on identifying and discontinuing (PNP), acute generalized exanthamous Rarely are eosinophils seen. Histologically, the offending drug. The sooner the drug is pustulosis (AGEP), staphylococcal scalded SJS/TEN must be differentiated from stopped, the more keratinocyte apoptosis skin syndrome, and linear IgA dermatosis.2 DRESS syndrome / hypersensitivity and epidermal necrosis can be avoided, and

66 steVens-Johnson syndrome - toxic epidermaL necroLysis oVerLap the lower the mortality.5 with a dose of IVIG that was too low.6 In Conclusions Managing patients with TEN with large studies where the dose of IVIG was even denuded areas of skin is similar to treating lower (1.6 g/kg total), IVIG had greater We presented a case of SJS/TEN overlap burn victims, so transfer to a burn unit mortality than SCORTEN expected. These and a review of the literature. As derma- must always be considered. The faster a studies demonstrate that if instituted, IVIG tologists, we can expect to see an increasing patient is transferred to a burn unit, the must be administered early in the disease number of cases of SJS and TEN. It is of greater the chance of survival.2 We strongly process and at high enough doses to be utmost importance to be able to recognize considered transferring our patient to a effective. Currently, the recommended dose and manage this life-threatening disease. burn unit, but fortunately, she responded of IVIG is 1 g/kg/day for three days, for a More studies are needed to elucidate the quickly to treatment, rendering transfer total of 3 g/kg. exact mechanism of SJS/TEN and to guide unnecessary. The reason for inconsistent IVIG effect treatment strategies. Supportive therapy maintains a on TEN is unknown. Bachot et al., French skin barrier to prevent large fluid losses. et al., and Prins et al. all speculate that the References Denuded skin can be treated with nonstick different outcomes with IVIG treatment 1. Litt JZ, editor. Litt’s drug eruption reference manual. New dressings soaked with normal saline or may be due to different batches of IVIG York, NY, Pantheon Publishing Group, 2007. 2,11 6,9,11 2. Pereira FA et al. Toxic epidermal necrolysis. Journal of silver nitrate. Fluid replacement is impor- used. Different batches of IVIG were the American Academy of Dermatology 2007;56(2):181- tant, with intravenous fluids, and electro- demonstated to have different anti-Fas 200. 9 3. James WD, Berger TG, Elston DM, editors. Andrew’s Dis- lytes should be monitored and corrected. activity. Other non-Fas mechanisms, such eases of the Skin. Philadelphia, PA, Elsevier publishing Denuded skin also places the patient at risk as the granzyme/perforin pathway that 2006, p. 129-130. 4. Auquierr-Dunant A, et al. Correlations between clinical for infection. Pan-cultures and complete may be involved in TEN, may explain why patterns and causes of erythema multiforme majus, Ste- blood counts should be performed to detect IVIG is not effective in all patients.2 With vens-Johnson syndrome, and toxic epidermal necrolysis. Archives of Dermatology 2006; 138(8):1019-1024. infection. Antibiotics should be instituted so many different variables present in TEN, 5. Trent JT, et al. Analysis of intravenous immunoglobulin only if there is evidence of infection, as separating them could be challenging, as for the treatment of toxic epidermal necrolysis using SCORTEN. Archives of Dermatology 2003;139:39-43. prophylactic use leads to antibiotic resis- controlled studies cannot be performed for 6. Bachot N et al. Intravenous immunoglobulin treatment for tance and greater mortality.2 Oral lesions TEN due to its emergent condition. Stevens-Johnson syndrome and toxic epidermal necrolysis. Archives of Dermatology 2003;139:33-36. should be managed to maintain nutrition, The use of systemic steroids to treat 7. Trent, et al. Use of SCORTEN to accurately in patients as this encourages skin healing. Various SJS/TEN is controversial. Although some with toxic epidermal necrolysis in the United States. Archives of Dermatology 2004;140:890-892. viscous lidocaine preparations may make studies show that high doses of pulse 8. Nassif A et al. Toxic epidermal necrolysis: effector cells oral intake more comfortable. If conjunc- corticosteroids given early in the disease are drug-specific cytotoxic T cells. J Allergy Clin Immunol 2004;114:1209-15. tival mucosa is involved, an ophthalmology course may be helpful, once the disease 9. French LE et al. Use of intravenous immunoglobulin in evaluation may be prudent to prevent process is under way steroids do not help toxic epidermal necrolysis and Stevens-Johnson syndrome: our current understanding. Int Immunopharma- sequela, including scarring and blindness. and contribute to greater mortality by col 2006;6(4): 543-9. Primary treatment of SJS/TEN includes increasing the risk of infection. Steroids 10. Faye, O et al. Cell-mediated immunologic mecha- 2 nism and severity of TEN. Archives of Dermatology discontinuing the suspected medication, are best avoided. Schneck et al. performed 2005;141:775-776. transfer to a burn unit, and supportive a retrospective study that compared the 11. Prins C, et al. Treatment of toxic epidermal necrolysis with high-dose intravenous immunoglobulins. Archives of therapy mentioned above. Beyond that, mortality of 281 patients with SJS and Dermatology 2003;139:26-32. there is no consensus for adjuvant drug TEN treated with supportive care only, 12. Powell N, et al. Colonic involvement in Stevens-Johnson syndrome. Postgraduate Medical Journal 2006;82e10. 14 regimens to manage SJS and TEN. IVIG only, systemic corticosteroids only, 13. Rapini RP, editor. Practical Dermatopathology. New and a combination of IVIG and systemic York, NY, Pantheon publishing, 2005, p. 62-63. Intravenous immunoglobulin (IVIG) 14. Wolff, K, Tappeiner, G. Treatment of toxic epidermal comes from a pool of healthy blood donors. corticosteroids. The results of their study necrolysis. Archives of Dermatology 2003;139:85-86. showed no benefit from any treatment and 15. Mittmann N, et al. Intravenous immunoglobulin use in It contains primarily IgG, but also has small patients with toxic epidermal necolysis and Steven-John- amounts of other immunoglobulins.15 One concluded that there is no specific treat- son syndrome. American Journal of Clinical Dermatology ment for SJS/TEN.16 2006;7(6):359-368. mechanism by which IVIG may help with 16. Schneck J, et al. Effects of treatment on the mortal- TEN is by binding Fas, blocking the signal Many other treatment modalities have ity of Stevens-Johnson syndrome and toxic epidermal been used for the management of TEN, necrolysis: a retrospective study on patients included in for keratinocyte apoptosis, which is the prospective EuroSCAR study. Journal of the American rationale for its use in the management of yet none have been universally adopted Academy of Dermatology 2008;58(1):33-40. SJS and TEN (see Figure 9).5,9 However, as standard treatment. Cyclosporine 3 results using this medication are inconsis- mg/kg/day may have promise in treating tent, and studies show mixed results with TEN.2 Plasmapheresis has shown prom- IVIG. Trent et al. studied patients with TEN ising results, and is relatively safe.2,11 treated with IVIG 1 g/kg/day for four days, N-acetylcysteine has also shown prom- for a total dose of 4 g/kg. Actual mortality ising results.2 Cyclophosphamide is not was lower than predicted with SCORTEN. generally used for TEN.2,11 Thalidomide The authors concluded that IVIG signifi- is not recommended.2 Anti-TNF therapy cantly reduced mortality in patients with is controversial, since it is unknown if TEN. Lower doses of IVIG were associated TNF alpha plays a pro-apoptotic or anti- with greater mortality.5 Prins et al. noted apoptotic role in SJS/TEN and whether its that survivors of TEN had been treated blockade would improve or worsen this with IVIG at a high dose of 1 g/kg/day for condition.2 It may be best to await further three days, for total dose of 3 g/kg, and were studies to elucidate if it is a useful adjuvant treated early in the disease course. They also to TEN treatment. showed deaths occurred in patients who had SJS and TEN are triggered by medica- received a lower dose of IVIG (2 g/kg total). tions. Our patient’s case was triggered They recommend administering IVIG early by 6-MP, which is not a medication and in adequate doses.11 Likewise, Bachot commonly implicated in the disease, et al. studied a dose of IVIG 2 g/kg total and although it has been previously reported found increased mortality with this lower to be associated.1 This case illustrates the dose of IVIG, and they also contemplated growing number of medications that may the increased mortality may be associated trigger SJS and TEN, despite its rarity.3 do, siLVerton 67 CAse report And literAture reView: mArJolin’s ulCer in An ipsilAterAl lymphedemAtous lower extremity

Jacqueline A Thomas, DO; David L Thomas, MD; Janet Allenby, DO *Dermatology Resident, First Year, Columbia Hospital Palm Beach Centre for Graduate Medical Education, West Palm Beach, FL **Professor and Chairman, Department of Surgery, Nova Southeastern University, Ft. Lauderdale, FL ***Program Director, Columbia Hospital Palm Beach Centre for Graduate Medical Education, West Palm Beach, FL

ABSTRACT

Marjolin’s ulcers are rare, aggressive epidermoid carcinomas arising in previously traumatized skin, chronic wounds, ulcers, fistulas, burns, and scars. We report a case of a Marjolin’s ulcer arising in a non-healing wound in an ipsilateral lymphedematous lower extremity. In this case, there were no other carcinogenic factors for the development of squamous cell carcinoma in this wound. Lymphedema may be an independent risk factor in the development of these aggressive carcinomas.

Case Report posterior lower extremity donor site and placed over the right lower extremity The patient is a morbidly obese, African wound. The postoperative clinical American, 69-year-old female with severe course was uneventful. Currently, the lower extremity lymphedema complaining wound measures 13 cm x 8 cm x 2 mm, of a chronic, non-healing wound on her and wound treatment includes use of a right lower leg for six years (Figure 1). The petrolatum impregnated dressing, a silver wound appeared as a small “pimple” that impregnated dressing, and a two-layer self- grew larger and more uncomfortable. It adherent elastic compression wrap system. started draining serosanguinous fluid and later became malodorous. The patient had Discussion a much smaller but similar wound on the posterior left lower extremity years ago Although lymphangiosarcoma, Figure 1 that spontaneously resolved without recur- described first in 1948 by Stewart rence. Previous treatments included an and Treves, is a recognized complica- Unna boot and topical medication, the tion of chronic lymphedema arising details of which are unknown. The patient in post-mastectomy upper extremities,1 initially ambulated with a cane due to squamous cell carcinoma arising in chroni- lower extremity degenerative joint disease, cally lymphedematous tissue is rare. To but currently ambulates with a walker our knowledge, there are 13 previously due to worsening lower extremity edema, reported cases of Marjolin’s ulcers found discomfort, and arthritis. Past medical in ipsilateral lymphedematous lower and surgical history include hypertension, extremity sites unrelated to burn scars.2,3,4,5,6 obesity, dyspnea, degenerative joint disease, There have been two reports of epidermo- hernia repair and hysterectomy due to dysplasia verruciformis-like patients with fibroids. There is no history of diabetes lymphedema and wart-like lesions trans- Figure 2 mellitus. The right lower extremity wound forming into squamous cell carcinoma.7,8 initially measured 7 cm in length, 1.4 cm in One case of penile squamous cell carci- type of ulcer termed ulcère verruqueux width, and 1 mm in depth. It progressed noma arising in idiopathic chronic penile in the Dictionnaire de Medecine.13 One to 25 cm in length, 19 cm in width, and 5 lymphedema was reported.9 There has medical historian notes Marjolin used the mm in depth. The wound color appeared been one case of a Marjolin’s ulcer occur- term ulcères cancroids, describing it as a pink, with an exophytic, nodular, verru- 10 ring in an amputation stump. Furukawa non-malignant variety of an ulcer.14 The cous texture, and the periwound area was et al. reported a case of a Marjolin’s ulcer concepts of malignancy and the association slightly macerated and spongy inferiorly in a lymphedematous lower extremity with scars or chronic ulcers were absent with diffuse cornification (Figure 2). in an 82-year-old female patient with a 13 Biopsies of the wound revealed a verrucous from Marjolin’s published entry. In 1850, history of “uterectomy” due to carcinoma the Irish surgeon Robert William Smith and invaginated epidermal proliferation, without additional carcinogenic factors.6 noted locally destructive “ulcers that some- focal ulceration, both chronic and acute Lymphedema may be an independent risk times developed in the scars left by burns, inflammatory infiltrate, edema, and well- factor for the development of ipsilateral floggings and severe lacerations, with differentiated squamous cell carcinoma. squamous cell carcinoma, as the Furukawa the ‘warty ulcers’ of Marjolin.”13 Smith Immunostaining for HPV6/11, 16/18 and case and our case support. 31/33 were negative. described pathological fractures and lymph The patient was treated regularly with History of the Eponym node metastases that were caused by such edema compression therapy while awaiting ulcers.13 In 1902, the Philadelphia surgeon definitive operative management. The Aurelius Cornelius Celsus, in the first John Chalmers DaCosta presented to the patient was then taken to the operative century A.D., described malignancy Philadelphia Academy of Surgery two cases suite for complete resection of the right in burn scars.10,11,12 In 1828, the French of chronic lower extremity ulcers that lower extremity tumor. A split-thickness surgeon Jean-Nicolas Marjolin wrote underwent surface carcinomatous changes, skin graft was harvested from the left a section on ulcers, and in it he listed a crediting the description to Marjolin.15

68 marJoLin’s uLcer in an ipsiLateraL Lymphedematous Lower extremity Today, a Marjolin’s ulcer is a rare, aggres- locally, but can also metastasize.17 The light-skinned Caucasians, in whom 80% of sive epidermoid carcinoma 2,3,12,18,20,24 found rate of metastasis ranges between 30% lesions are basal cell carcinoma and 20% are to arise within a scar, chronic ulcerated and 40% in Marjolin’s ulcers.12,18 The squamous cell carcinoma.25 wound, previously traumatized skin, burn, incidence of chronic wounds undergoing chronic inflammatory process, sinus tracts, malignant degeneration varies, with an Diagnosis or fistulas.9, 10,12,14,16,17,18,19,21 There have also estimated range between 0.23% and been reports of the malignant changes 1.7%.18,20,21 Marjolin’s ulcers are most Multiple biopsies at various depths and of Marjolin’s ulcers in osteomyelitis,18 common in men between the ages of 40 various locations within the margin and hidradenitis suppurativa, lupus vulgaris, and 70 years. They are more likely to the base of the Marjolin’s ulcer should be perifolliculitis,10,19,20 radiotherapy,21 dystro- occur in the lower extremities in those performed. Indications for biopsy include phic epidermolysis bullosa,22 and a kerato- with burn scars, a history of osteomyelitis, wounds unresponsive to standard therapy, acanthoma arising in a vaccination scar.14 and chronic wounds.21,23 The average wounds present for longer than three to Squamous cell carcinoma is the most latency is 30 years.17,22 However, Thio et four months, and wounds that are suspi- common carcinomatous change found in al. reported a case with development of cious for potential malignancy.21 The a Marjolin’s ulcer;10,20 however, basal cell malignant changes after 18 months.19 A clinician should be suspicious for such carcinomas have been reported.11,12,23 In Nigerian study found 18.5 years to be malignant potential in any wound demon- addition, several other malignancies have the average latency period, with a range strating increase in size, foul odor, pain, been reported within the wound beds of of 6 to 40 years found in 6 patients with abundant granulation tissue that extends chronic venous ulcers including sarcomas, Marjolin’s ulcers.23 Treves, in 1930, defined beyond the borders of the wound, sudden lymphomas, and melanomas.10,21 Burn scars, Marjolin’s ulcers as scars undergoing crusting or ulceration of scar tissue, genital lichen sclerosis et atrophicus, oral malignant change and classified them into bleeding, purulent malodorous mate- lichen planus, and erythema ab igne have two groups based on latency.19 Scars that rial, increase in discharge, or irregular been linked to the development of squa- undergo malignant transformation in less edges.15,19,21,23 Cytology using touch or scrape mous cell carcinoma.18 than one year following the inciting injury smears is 98.7% accurate, 98% sensitive, are considered acute compared to scars and 100% specific, providing a fast and Pathogenesis that degenerate after one year. The average reliable alternative to frozen section for latency of acute Marjolin’s ulcers was evaluation of excised margins in the intra- Many theories exist describing the reported to be 0.3 years;19 however, this fast operative diagnosis of Marjolin’s ulcers.26 malignant degeneration of these wounds, latency period has been absent in reviews Due to the focal nature of malignant change although the exact mechanism is unknown. of the current literature. The recurrence in Marjolin’s ulcers, incisional or excisional DaCosta explained his observation rate of Marjolin’s ulcers is reported to biopsy is recommended. One study found that cancer may arise in areas of chronic be between 20% and 50%.23 Marjolin’s that multiple punch biopsies were negative, inflammation due to the proliferation of ulcers have been reported in pediatric, while complete excision revealed the diag- benign and malignant epithelial cells.15 He adult, and geriatric age populations. The nosis of squamous cell carcinoma.16 cautioned that one should be suspicious ages of the patients previously reported The mucinous glycoprotein podoplanin of any induration, pain, profuse discharge, with Marjolin’s ulcers in ipsilateral lymph- may prove to be a lymphatic marker associ- malodorous discharge, bloody discharge, edematous lower extremities without addi- ated with squamous cell carcinoma and a irregular base, or a warty appearance.15 He tional carcinogenic factors ranged from 52 possible adjunct to diagnosis and progres- further observed the malignant changes are to 82 years.2,3,4,5,6 Metastatic spread has been sion of Marjolin’s ulcers in patients with most likely to appear at the wound edges, found to invade lymph nodes, brain, liver, lymphedema in the future. Podoplanin- where a portion should be removed for lung and kidney.23 Lower extremity lesions deficiency is found in congenital lymph- histopathologic evaluation.15 Chronic irri- have a 53.8% risk of metastasis.12 Overall edema and impaired lymphatic vascular tation, repeated damage and attempts to five-year survival is 60%, and involvement patterns.27 Podoplanin, as recognized by repair such damage may be the stimulus of regional lymph nodes yields a 35% D2-40 antibody, is generally absent in for a prolonged inflammatory condition survival rate.23 normal human epidermis but is strongly leading to more production of malignant Squamous cell carcinoma is the second induced in squamous cell carcinomas.27 cells and less production of normal cells most common skin cancer in the United 2,21 through malignant clones. Several States; however, it appears to be a more Prognosis other theories include inducing dormant common dermatologic malignancy than neoplastic cells, damaged tissues releasing basal cell carcinoma in African popula- Prognosis is based on histologic tumor toxins that lead to cell mutation and malig- tions.24,25 Skin-cancer frequency in people grade. Marjolin’s ulcers of squamous cell nancy, traumatic implantation of epidermal of African descent with Fitzpatrick skin carcinoma origin are classified into three cells into the dermis leading to a foreign types V and VI is lower than in people of grades: Grade I involves well-differentiated body reaction that results in cancer, and the European descent with Fitzpatrick skin squamous cell carcinoma; grade II shows decreased organizational pattern of scars types I and II. A small African study found moderately differentiated squamous cell that are thus more likely to ulcerate and that the primary risk factor for development carcinoma; and grade III shows poorly 21 transform into a tumor. Further theories of melanoma, epidermoid carcinoma, or differentiated squamous cell carcinoma. describe immunologic isolation whereby basocellular carcinoma was albinism.24 The The lesion grade indicates the rapidity of an antigen is unable to reach lymph-node most common dark-skinned African carci- spread. Grade I lesions are least likely to sites due to lymphatic channel oblitera- noma in a Nigerian study was squamous spread, and if spread to lymph nodes does 19 tion, the random selection of a genetic cell carcinoma found in the lower limbs occur, the rate is slower than with grade II 12 mutation in the hyperplastic tissue of an of patients with Marjolin’s ulcers (37%), lesions. Some believe treatment of lymph 5 immunologically privileged site, and viral whereas the incidence of basal cell carci- node involvement is based on histologic 5,15 oncogenesis. noma was reported to be significantly lower grade. Grade I lesions require lymph node (8%) in the same study.25 These African dissection only if lymph nodes are palpable, Epidemiology studies support that dark-skinned Africans whereas grade II and grade III lesions generally require lymph node dissection.21 Some Marjolin’s ulcers are more aggres- and African-Americans are less likely to develop skin cancer than Caucasian popu- authors base treatment on the histologic sive than other epidermoid carcinomas. tumor grade, advocating amputation in These carcinomas can not only recur lations. These findings are in contrast to

thomas, thomas, aLLenBy 69 B:9.25” T:8.5” S:7”

grade II and grade III carcinomas12 and Report and Review of the Literature. Dermatologic Sur- 20 gery 2002;28(10):951-953. wide local excision in grade I carcinomas. 7 Ostrow RS, Manias D, Mitchell A, Stawowy L, Faras A. Epidermodysplasia Verruciformis: A case associated with primary lymphatic dysplasia, depressed cell- Treatment mediated immunity, and bowen’s disease containing human papillomavirus 16 DNA. Archives of Dermatology Historically, amputation was the only 1987;123:1511-1516. 8 Kreuter A, Hochdorfer B, Brockmeyer NH, Altmeyer P, recommended treatment for Marjolin’s Pfister H, Wieland U, Competence Network HIV/AIDS. A ulcers.15 Wide local excision with 1 human papillomavirus-associated disease with disseminated warts, depressed cell-mediated immunity, primary centimeter margins and skin grafting if lymphedema, and anogenital dysplasia WILD Syndrome. necessary, Mohs micrographic surgery, Archives of Dermatology 2008;144(3):366-372. 9 Hadway P, Lynch M, Corbishley CM, Mortimer PS, Watkin and amputation are the contemporary NA. Squamous cell carcinoma of the penis in a patient treatments of choice for Marjolin’s ulcers with chronic isolated penile lymphoedema. Urologica Internationalis 2006;76(1):87-88. demonstrating squamous cell carci- 10 Bloemsma GC and Lapid O. Marjolin’s Ulcer in an Ampu- noma.18,28 Radiotherapy and chemotherapy tation Stump. Journal of Burn Care Research 2008; 29:1001-1003. have also been used in combination with 11 Love RL and Breidahl AF. Acute Squamous Cell Carci- surgical modalities.10 Early skin grafting noma Arising within a Recent Burn Scar in a 14-year- old Boy. Plastic & Reconstructive Surgery 2000; 106 has been used to prevent Marjolin’s ulcers (5):1069-1071. in patients with burn scars.11 Amputation 12 Sabin SR, Goldstein G, Rosenthat HG, Haynes KK. Aggressive Squamous Cell Carcinoma Originating as a is generally reserved for instances when Marjolin’s Ulcer. Dermatologic Surgery 2004;30(2):229- negative margins cannot be obtained.29 230. 13 Cruickshank AH and Gaskell E. Jean-Nicolas Marjolin: Amputation proximal to the tumor is Destined to be forgotten? Med Hist 1963;7(4):383-384. also indicated in cases associated with 14 Steffen C. Marjolin’s ulcer. Report of two cases and evidence that Marjolin did not describe cancer arising in 20,21 chronic osteomyelitis. Patients treated scars of burns. American Journal of Dermatopathology with amputation have a metastatic rate 1984;6(2):187-193. 15 Da Costa JC. Carcinomatous changes in an area of 20 ranging from 20% to 35%. Cure rates for chronic ulceration, or Marjolin’s Ulcer. Annals of Surgery Mohs micrographic surgery have not been 1903;37:496-502. 16 Phillips TJ, Salman SM, Bhawan J, Rogers GS. Burn scar 20 compared to amputation. Mohs surgery carcinoma. Diagnosis and management. Dermatologic should be avoided if regional lymph nodes Surgery 1998;24(5):561-565. 17 Esther RJ, Lamps L, Schwartz HS. Marjolin ulcers: sec- 21 or distant metastases are present. Barr ondary carcinomas in chronic wounds. J South Orthop et al. found that recurrences following Assoc 1999;8(3):181-187. 18 Menendez M and Warriner RA. Marjolin’s Ulcer: Report of local excision tend to be local and can be Two Cases. Wounds 2006;18(3):65-70. managed by re-excision or amputation; 19 Thio D, Clarkson JHW, Misra A, Srivastava S. Malignant change after 18 months in a lower limb ulcer: acute they discouraged prophylactic lymph node Marjolin’s revisited. British Journal of Plastic Surgery dissection.30 2003;56:825-828. 20 Ogawa B, Chen M, Margolis J, Schiller FJ. Marjolin’s B:12.25”

Ulcer Arising at the Elbow: A Case Report and Literature S:10” Prophylactic lymph node irradiation T:11” Review. Hand 2006;1:89-93. is controversial. Ninety-five percent of 21 Trent JT and Kirsner RS. Wounds and Malignancy. patients with metastasis present within the Advances in Skin & Wound Care 2003;16(1):31-34. 20 22 Hess S D, Schmults CD, Goldman G. Squamous Cell first year. Many authors advocate prophy- Carcinoma. Last updated June 1, 2006. www.emedicine. lactic lymph node irradiation12,20,29 because com/DERM/topic401.htm accessed Nov. 7, 2008 8:30pm. 23 Asuquo M, Ugare G, Ebughe G, Jibril P. Marjolin’s ulcer: there is a 24% risk of developing metastasis the importance of surgical management of chronic cuta- without lymph node irradiation.20 neous ulcers. Internaltional Journal of Dermatology 2007;46 (Suppl. 2):29-32. • 24 Adegbidi H, Yedomon H, Atadokpede F, Balley-Pognon MC, do Ango-Padonou F. Skin cancers at the National • Conclusion University Hospital of Cotonou from 1985 to 2004. Inter- national Journal of Dermatology 2007; 46 (Suppl. 1):26- Lymphedema may be an independent 29. • risk factor for Marjolin’s ulcers demon- 25 Asuquo ME, Ngim O, Ugare G, Omotoso J, Ebughe G. Major dermatologic malignancies encountered in a teach- strating squamous cell carcinoma. ing hospital surgical department in South Nigeria. Ameri- • Marjolin’s ulcers are rare; but due to their can Journal of Clinical Dermatology 2008;9(6):383-387. 26 Kakagia D, Tamiolakis D, Grekou A, Vavetsis S, Lambro- aggressive nature, these patients should poulou M, Papadopoulos N. Intraoperative cytological be observed carefully. Early diagnosis of evaluation of Marjolin ulcers. Onkologie 2006;29(1-2):21- 24. wounds in African American populations 27 Schacht V, Dadras SS, Johnson LA, Jackson DG, Hong and suspicious nonhealing wounds in any YK, Detmar M. Up-regulation of the lymphatic marker podoplanin, a mucin-type transmembrane glycoprotein, in Important Safety Information population is encouraged. Early surgical human squamous cell carcinomas and germ cell tumors. treatment is warranted in Marjolin’s ulcers. American Journal of Pathology 2005;166:913-921. 28 Lenz O, Plogmeier K, Fansa H, Schneider W. Surgical Special thanks to Thomas Rosen, DPM. treatment of cicatricial carcinoma—methods and results. Chirug 2001;72(6):690-696. 29 Wysocki WM, Komorowski AL, Mitus J. Re: Epidermoid carcinoma arising in chronic lymphedema, Bilen et al. References European Journal of Surgical Oncology 2004; 30:88. 1 Stewart FW and Treves N. Lymphangiosarcoma in post 30 Barr LH and Menard JW. Marjolin’s ulcer The LSU experi- mastectomy lymphoedema. Cancer 1948;1:64-81. ence. Cancer 1983;52(1):173-175. 2 Bilen BT, Gurlek A, Alaybeyoglu N, Celik M, Aydin NE. Epidermoid carcinoma arising in chronic lymphedema. European Journal of Surgical Oncology 2003;29:697-698.

3 Echenique-Elizondo M, and Elorza J. Squamous-cell car- * cinoma on long-lasting lymphoedema. Lancet Oncology 2002;3:319. 4 Lister RK, Black MM, Calonie E, Burnand KG. Squamous cell carcinoma arising in chronic lymphoedema. British Journal of Dermatology 1997;136:384-387. * 5 Epstein JI and Mendelsohn G. Squamous carcinoma of the foot arising in association with long standing verrucous hyperplasia in a patient with congenital lymphedema. Cancer 1984;54(5):943-947. 6 Furukawa H, Yamamoto Y, Minakawa H, Sugihara T. Squa- mous Cell Carcinoma in Chronic Lymphedema: Case www.oracea.com/HCP 70 marJoLin’s uLcer in an ipsiLateraL Lymphedematous Lower extremity B:9.25” T:8.5” S:7”

In the management of rosacea, the direction is clear . . . Powerful Change for the Journey Ahead B:12.25” S:10” T:11”

Early efficacy1,2 with safety for the long term3

• Reduction in inflammatory lesion count seen as early as week 1,24 • Similar efficacy to doxycycline 100 mg in reducing inflammatory lesions1 • No evidence of bacterial resistance4 and no increase in side effects over the long term (9 months)3 • Patients pay no more than $25* for each Oracea® prescription

* For a 30-day/30-capsule prescription of Oracea® (excludes Medicaid, Medicare, or federal or state programs).

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

Oracea and Galderma are registered trademarks of Galderma Laboratories, L.P. ©2010 Galderma Laboratories, L.P. Galderma Laboratories, L.P. 14501 N. Freeway Fort Worth, TX 76177 ORA-365F Printed in USA 01/10 www.oracea.com/HCP B:9.25” T:8.5” S:7”

Rx Only Keep out of reach of children. MICROBIOLOGY

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

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

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

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

43355ETL_0039_PI_v1 1 12/16/08 7:33:23 PM