Journal of the American Osteopathic College of Dermatology

Volume 13, Number 1 SPONSORS: ',/"!,0!4(/,/'9,!"/2!4/29s-%$)#)3 January 2009 '!,$%2-!s2!."!89 www.aocd.org Journal of the American Osteopathic College of Dermatology Journal of the American Osteopathic College of Dermatology

2008-2009 Officers President: Donald K. Tillman, Jr., D.O., FAOCD President Elect: Marc I. Epstein, D.O., FAOCD First Vice President: Leslie Kramer, D.O., FAOCD Second Vice President: Bradley P. Glick, D.O., FAOCD Third Vice President: James B. Towry, D.O., FAOCD Secretary-Treasurer: Jere J. Mammino, D.O., FAOCD Immediate Past President: Jay S. Gottlieb, D.O., FAOCD Trustees: David L. Grice, D.O., FAOCD Mark A. Kuriata, D.O., FAOCD Karen E. Neubauer, D.O., FAOCD Editors Rick Lin, D.O., FAOCD Jay S. Gottlieb, DO Suzanne Rozenberg, D.O., FAOCD Jon Keeling, DO David Geiss, D.O., FAOCD Andrew Racette, DO Executive Director: Rebecca (Becky) Mansfield

Editorial Review Board Kevin Belasco, DO Sponsors: Iqbal Bukhari, MD Global Pathology Laboratory Daniel Buscaglia, DO Medicis Igor Chaplik, DO Tejas Desai, DO Galderma Brad Glick, DO Ranbaxy Melinda Greenfield, DO Andrew Hanley, MD David Horowitz, DO

JAOCD Rachel Kushner, DO Founding Sponsor

Mark Lebwohl, MD !/#$s%)LLINOISs+IRKSVILLE -/ Matt Leavitt, DO   s&!8   WWWAOCDORG Cindy Li, DO Rick Lin, DO #/092)'(4!.$0%2-)33)/.WRITTENPERMISSIONMUSTBEOBTAINED FROMTHE*OURNALOFTHE!MERICAN/STEOPATHIC#OLLEGEOF$ERMATOLOGY Jere Mammino, DO FORCOPYINGORREPRINTINGTEXTOFMORETHANHALFPAGE TABLESORlGURES John Minni, DO 0ERMISSIONSARENORMALLYGRANTEDCONTINGENTUPONSIMILARPERMISSION FROMTHEAUTHORS INCLUSIONOFACKNOWLEDGEMENTOFTHEORIGINALSOURCE Navid Nami, DO ANDAPAYMENTOFPERPAGE TABLEORlGUREOFREPRODUCEDMATERIAL 0ERMISSIONFEESAREWAIVEDFORAUTHORSWISHINGTOREPRODUCETHEIROWN Carlos Nousari, MD ARTICLES2EQUESTFORPERMISSIONSHOULDBEDIRECTEDTO*!/#$CO!/#$ John Perrotto, DO 0/"OX+IRKSVILLE -/ #OPYRIGHTBYTHE*OURNALOFTHE!MERICAN/STEOPATHIC#OLLEGEOF Stephen Purcell, DO $ERMATOLOGY Marta Rendon, MD Printed by: The Dimensional Group, Mason City, IA 50401 Michael Scott, DO Proofreading: Julia Layton, Freelance Proofreading and Editing Kevin Spohr, DO Journal of the American Osteopathic College of Dermatology VOLUME 13, NUMBER 1 JANUARY 2009 AOCDJOURNAL OF THE AMERICAN OSTEOPATHIC COLLEGE OF DERMATOLOGY

CONTENTS

Letter from the JAOCD Editors ...... 4 Letter from the President ...... 5 Follicular Mucinosis: A Case Report in a Teenage Girl ...... 6 Billie Casse, DO, Barry Auster, MD, Daniel Stewart, DO, FAOCD Eruptive Collagenoma in a 50-year-old White Female ...... 8 Michelle Legacy, DO, Reagan Anderson, DO, MPH, MCS, Christopher J Schwimer, DO, Steven Grekin, DO, FAOCD Cutaneous Leishmaniasis: A Case and Review ...... 10 Dawn L Sammons, DO, Joel Bain Herron, MD, John Hibler, DO Case Report and Review of Behcet’s Disease ...... 15 Shaheen Oshtory, DO, Charles Gropper, MD, Cindy Hoffman, DO, FAOCD Cutaneous Neonatal Lupus Erythematosus: A Case Report and Brief Review ...... 18 Michelle W Foley, DO, Lynn M Sikorski, DO, Michael J Mahon, DO A Sore Thumb ...... 20 Allison Schwedelson, DO, Stanley Skopit, DO, FAOCD Formaldehyde and Formaldehyde-releasing Preservative Induced Allergic Contact Dermatitis ...... 22 Kevin DeHart, DO, Richard Miller, DO Kawasaki Disease: Case Report and Review of Literature ...... 24 Yvette A Tivoli, DO, Bradley P Glick, DO, FAOCD Subcutaneous Sarcoidosis: A Case Report ...... 29 Andrea Passalacqua, DO, Ronald Liskanich, DO, David Horowitz, DO Pigmented Squamous Cell Carcinoma of the Skin: A Case Report and Review of the Literature ...... 31 Wade R Keller, DO, Don A Anderson, DO, FAOCD, FASMS Staphylococcal Scalded Skin Syndrome in a Patient with Hidradenitis Suppurativa: A Case Report ...... 35 Christopher Buckley, DO, Marcus B Goodman, DO, Stanley Skopit, DO, FAOCD Treatment of Recalcitrant Vulvar Lichen Sclerosus with Cyclosporine: A Case Report ...... 37 Jami Reaves, DO, Don A Anderson, DO, FAOCD, FASMS Primary Cutaneous B-cell Lymphoma: Indolent Follicular Center Cell Lymphoma Transforming Into Aggressive Diffuse Large B-cell Lymphoma ...... 39 Alice N Do, DO, Kimball Silverton, DO An Update and Review of Androgenic Alopecia ...... 44 Brian Feinstein, DO, Stanley Skopit, DO, FAOCD Perniosis: A Cold Weather Barometer ...... 46 Chad Peterson, DO, Nathan Peterson, DO, Don A Anderson, DO, FAOCD, FASMS Graft-versus-host Disease in a Liver Transplant Patient with Graft Dysfunction ...... 51 Angela Combs, DO, Emily Rubenstein, DO, Marcus Goodman, DO, Chris Buckley, DO, Stanley Skopit, DO, FAOCD Axillary Granular Parakeratosis - A Case Report ...... 53 Andleeb Usmani, DO, John Minni, DO, Layne Nisenbaum, DO, FAOCD Merkel Cell Carcinoma Mimicking A Cyst ...... 54 Danica L Alexander, DO, John P Minni, DO, Elaine Smith-Marchant, MD, Layne D Nisenbaum, DO, FAOCD Verrucous Psoriasis: A Clinicohistopathologic Variant of Psoriasis ...... 57 Anita Osmundson, DO, Mary McGonagle, DO, Tanya Ermolovich, DO Siblings with X-Linked Recessive Ichthyosis: A Case Report and Brief Review ...... 59 David R Bonney, DO, Matthew Elias, DO, and Stanley E Skopit, DO, FAOCD Case Report of Extragenital Lichen Sclerosis et Atrophicus in an Adolescent Female ...... 61 Derrick H Adams, DO, and Michael Mahon, DO, FAOCD Systemic Sclerosis: Case Report and Review of the Literature ...... 65 Adriana Ros, DO, Marvin Watsky, DO An Interesting Case of Leukoderma Associated with Systemic Disease ...... 68 Jack W Griffith, DO, Tony Nakhla, DO, Paul Shitabata, MD, David Horowitz, DO, FAOCD, FAAD LETTER FROM THE EDITORS

JAY GOTTLIEB, DO, JON KEELING, DO, ANDREW RACETTE, DO, FAOCD Senior Editor FAOCD Editor FAOCD Editor

We are pleased to bring you the 13th edition of the Journal of the Osteopathic College of Dermatology. The journal has consistently been published on a quarterly basis, and we believe that the content continues to improve with every issue. In an effort to keep up this trend, there have been several recent and exciting changes in our journal.

We would like to introduce two new editors for the JAOCD: Jon Keeling, DO, and Andrew Racette, DO. Both recently completed their dermatology residency programs and have come on board with new ideas to improve and expand our journal. Jon Keeling trained at Wellington Regional Medical Center/LECOM, and has joined Advanced Dermatology in Brandon, FL. Andrew Racette trained at Midwestern University Phoenix Dermatology and has opened his own practice, Omni Dermatology in Phoenix, AZ.

The journal has recently made a critical move to using Editorial Manager, a program that is used by other respected peer reviewed journals across the country. Editorial Manager streamlines the editorial process, making it much easier for authors, reviewers, and editors to communicate throughout the publishing process.

The JAOCD has expanded the peer review process by establishing an editorial review committee. The committee consists of both D.O. and M.D. board-certified dermatologists from across the country. This committee will bring the JAOCD one step closer to achieving our goal of being a PubMed indexed journal.

We would like to thank the sponsors of the JAOCD: Global Pathology Laboratory, Medicis-The Dermatology Company, Stiefel Laboratory, Galderma, and our most recent sponsor, Ranbaxy Pharmaceuticals. These companies have shown their support for the AOCD, the JAOCD and the dermatology community through this educational resource. We also thank you for continuing to share your interesting cases with the JAOCD. To all readers, please consider joining us in our goals of expanding and improving our journal by submitting your manuscripts for publication in the JAOCD.

Sincerely,

Jay S. Gottlieb, DO

Jon Keeling, DO

Andrew Racette, DO

4 LETTER FROM THE EDITORS LETTER FROM THE PRESIDENT OF THE AOCD

DONALD TILLMAN, DO, FAOCD

PRESIDENT

It is said that time passes quickly, and that certainly is true of this year being president of the AOCD. I I want to acknowledge Dr. Jay Gottlieb and the editorial review board for their hard work on this journal. I also want to congratulate and thank both Dr. Jon Keeling and Dr. Andrew Racette for taking on the role of co-editors of the JAOCD. Compiling, editing and producing the JAOCD are truly labors of love. It requires time and dedication to publish such an outstanding journal. I applaud their efforts, and congratulate them on their commitment to publish the JAOCD on a quarterly basis, allowing it to be indexed with Medline. I do not know of any other osteopathic specialty or sub-specialty that has a journal like the JAOCD to represent its members.

As the newly elected President, I want to thank Jay for his hard work last year as President of the AOCD. I would like to continue what he started by opening up better communication between residents, members, and the organization. The AOCD is OUR organization, and it only gets better as our members become involved.

This year, I will strive to improve communication. I invite all members and resident members to contact me, other members of the Executive Committee or the AOCD office via email or phone with any questions or if you would like to serve on AOCD committees. Email is certainly a very efficient tool and allows us to communicate on a more rapid and concise basis. I am dedicated to serving you this year, and although I may not have the answers or the solutions to all issues immediately, I will work hard to resolve them.

I invite you to attend the midyear meeting in Steamboat Springs, Colorado. Dr. Glick has planned an outstanding meeting with a wide variety of speakers. Steamboat promises to be a great vacation site, so I encourage you to bring your family. Air transportation in and out of Steamboat is currently inexpensive and easily accessible. I encourage you to mark this event on your calendar.

I do look forward to a good year. I hope you and yours have a happy holiday and a blessed New Year.

Donald Tillman, DO, FAOCD

AOCD President, 2008-2009

LETTER FROM THE PRESIDENT 5 FOLLICULAR MUCINOSIS: A CASE REPORT IN A TEENAGE GIRL

Billie Casse, DO,* Barry Auster, MD,** Daniel Stewart, DO, FAOCD*** *Dermatology Resident, 2nd year, St. Joseph Mercy Health System, Michigan State University **Clinical Associate, Private Practice, Farmington Hills, Michigan ***Program Director, St. Joseph Mercy Health System, Michigan State University

ABSTRACT

Follicular mucinosis (FM) was first described by Pinkus in 1957,1 characterized histologically by the presence of mucin in the follicular epithelium and the sebaceous glands. Since then, three clinical types have been delineated. The first and most common type occurs as an idiopathic, benign condition typically seen in young patients. The second clinical type is a more chronic disorder affecting people 40 to 70 years of age. And the third type is secondary FM, or malignancy-associated FM, which usually occurs in the elderly and presents with widespread lesions. Despite the various studies conducted, recent reports have demonstrated no reliable clinical or histopathologic features that differentiate benign and malignancy-associated FM. We present a case of FM with unknown etiology presenting in a 14-year-old female.

Case Presentation When this condition affects hair-bearing skin, a non-scarring alopecia termed A 14-year-old white female presented alopecia mucinosa can result.1 The exact with a two-month history of an asymp- pathogenesis is unknown, although the tomatic red, scaly plaque on the right cheek role of cell-mediated immunity and/or that had enlarged in diameter. She denied circulating immune complexes has been contact with a new animal, and the family considered. pets were free of skin disease. There was no Emmerson and Coskey further divided history of photosensitivity, recent illness, FM patients into three clinical types.2 The recent travel or trauma. Review of systems first and most common type occurs as an was negative, and the patient was other- idiopathic, benign condition typically seen wise healthy. She had previously applied a in young patients.3 It presents as a solitary, topical steroid without improvement. erythematous, indurated patch or plaque Figure 1 On physical examination, a 4cm, mildly on the face, neck, or scalp. This type typi- indurated, erythematous plaque with cally resolves spontaneously in two months fine scale was located on the mid-right to two years, although a study done by cheek (Figure 1). Remainder of the skin Brown et al. found this timeframe to be less exam was unremarkable. There was no reliable than once thought.2 In his series of lymphadenopathy. seven young patients, early resolution was Laboratory analysis including CBC, not demonstrated.2 The second clinical fungal culture and KOH were all negative. type is a more chronic disorder affecting A 3mm punch biopsy was performed, people 40 to 70 years of age. These patients and a hematoxylin-eosin stain revealed present with a widespread eruption that extensive mucinous deposition within can persist indefinitely but is not associated 2 follicles and sebaceous glands. There was with malignancy. a perivascular lymphocytic infiltrate with The third type is secondary FM, or occasional eosinophils. There was no malignancy-associated FM, which usually Figure 2 lymphocytosis or other atypical lymphoid occurs in the elderly and presents with infiltrate (Figure 2, 3). widespread lesions. The most common 40 did not develop a malignancy, while The diagnosis of follicular mucinosis malignancy associated with FM is cuta- 23% of the patients aged 30 to 40 years prompted treatment with Tazorac (tazaro- neous T-cell lymphoma. This occurs in did eventually develop mycosis fungoides. tene) and intermittent topical steroids. The approximately 15% to 30% of patients with Another small study was done by Gibson et FM.2 Cutaneous T-cell lymphoma can patient was sent for a chest X-ray and an al.4 following nine children who were under coincide with FM, precede FM, or develop abdominal ultrasound, which were both the age of 21 at the time of diagnosis. Five negative. Six months after the diagnosis months to years after FM. Other associated malignancies include leukemia, renal-cell patients had clearing of lesions, two did not was made, the lesion had a slight decrease have clearing of lesions, and two patients in erythema but was still present. carcinoma, Hodgkin’s disease, cutaneous B-cell lymphoma, and squamous-cell carci- developed Hodgkin’s disease. Discussion noma of the tongue.4 The unpredictability of FM has led to the The above three clinical types are not all use of molecular genetic analysis, targeting Follicular mucinosis (FM) is a rare inclusive and may give a false sense of secu- patients with a clonal T-cell receptor gene disorder first described by Pinkus in 1957.1 rity. Many patients do not fit the proto- rearrangement. It has been suggested that It is characterized histologically by mucin typical classifications stated above. In one patients with a clonal T-cell receptor rear- deposits within the hair follicles and the study quoted by Brown et al.,2 a group of rangement are at a higher risk for devel- sebaceous glands. The accumulation of patients diagnosed with FM were followed oping lymphoma.2 However, although mucin creates an inflammatory condition for a period of 10 years. Sixty-two percent the character of the lymphocytic infiltrate and a subsequent degenerative process.1 of the patients that were over the age of may be in question, there are numerous 6 FOLLICULAR MUCINOSIS: A CASE REPORT IN A TEENAGE GIRL may suggest the progression to mycosis References: fungoides. The latter group analyzed the 1. Pinkus H. Alopecia Mucinosa: Inflammatory Plaques with Alopecia Characterized by Root-Sheath Mucinosis. Arch histopathologic specimens of 44 patients Dermatol. 1957; 76:419-424. with and without lymphoma, and found 2. Brown HA, Gibson LE, Pujol RM, Lust JA, Pittelkow MR Primary follicular mucinosis: long-term follow-up of that in the group of lymphoma-associated patients younger than 40 years with and without clonal FM, nine of the 28 patients showed histo- T-cell receptor gene rearrangement JAAD. 2002 Dec;47(6):856-62. logic features that were more suggestive 3. Lockshin BN, Khachemoune A, Cohen C. Follicu- of benign FM. These findings included lar Mucinosis in a 4-year-old boy. Int J Dermatol. Dec 2004;43(12):950-2. mild lymphocytic infiltrate, lack of epider- 4. Gibson LE, SA Muller, MS Peters. Follicular Mucinosis motropism and the presence of eosino- of Childhood and Adolescence. Pediatric Dermatology. 1988;5 No. 4 November 1988 TABLE 1. phils. In fact, the initial diagnosis of these 5. Cerroni L, MD; Fink-Puches R, MD; Bäck B; Kerl individuals was idiopathic FM, and it was H, MD. Follicular Mucinosis, A Critical Reappraisal of Clinicopathologic Features and Association With Mycosis Figure 3 not until repeated biopsies were analyzed Fungoides and Sézary over a period of time that the diagnosis of Syndrome. Archives of Dermatology. Feb 2002; Vol 138, CTCL was made.5 No 2. reports of patients with and without this 6. Mehregan D, Gibson L, Muller S. Follicular Mucinosis: Despite the various studies conducted, Histopathologic review of 33 cases. Mayo Clin. Proc entity who have or have not progressed to 1991; 66: 387–90. 9. a malignant state. A long-term follow-up recent reports have demonstrated no reli- 7. Rupnik H, Podrumac B, Zgavec B, Lunder T. Follicular able clinical or histopathologic features that Mucinosis in a Teenage Girl. Acta Dermatoven APA study was conducted on seven patients with 2005; Vol 14, No 3 clonal T-cell gene rearrangement and were differentiate benign and malignancy-asso- younger than 40 years old.2 This study ciated FM. Therefore, in cases of benign concluded with no evidence of progression or idiopathic FM, long-term follow-up and to CTCL in that population, and there- multiple biopsies are recommended for a fore clonality did not appear to predict the minimum period of five years.7 development of the disease. Treatment has generally been ineffective, The uncertain clinical course of the but it includes topical, intralesional, and disease has also prompted histopathological systemic steroids. There has been little reviews by Mereghan et al.6 and Cerroni et success with PUVA and isolated success al.5 to try and ascertain features that would with dapsone, indomethacin, and inter- distinguish idiopathic FM from malig- feron. Other treatment options such as nancy-associated FM. The former group excision, localized radiation, and nitrogen performed a slide review of 33 cases of FM mustard have also been tried. If FM is and proposed the absence of eosinophils associated with a malignancy, the under- lying malignancy should be treated.7

CASSE. AUSTER, STEWART 7 ERUPTIVE COLLAGENOMA IN A 50-YEAR-OLD WHITE FEMALE

Michelle Legacy, D.O.,* Reagan Anderson, D.O., M.P.H., M.C.S.,** Christopher J. Schwimer, D.O.,*** Steven Grekin, D.O., F.A.O.C.D.**** *Oakwood Southshore Medical Center, Intern **Oakwood Southshore Medical Center, PGY3 Dermatology ***Hilbrich Dermatopathology Laboratory, Dermatopathologist ****Oakwood Southshore Medical Center, Program Director, Dermatology Program

ABSTRACT

Eruptive collagenoma is a hamartomous connective-tissue nevus primarily composed of dense, thickened collagen. It usually presents with the sudden appearance of several firm, white-to-flesh-colored papules symmetrically distributed on the trunk and lower extremities. Eruptive collagenoma is a rare disease for which definitive associations are not currently known. We present a case of a healthy 50-year-old white female with eruptive collagenomas of uncertain etiology.

Case Report various sizes, usually less than 1 centi- meter in diameter. Papules may coalesce A 50-year-old healthy white female to form large plaques.1-4 There are rarely reported to the clinic with an approximate epidermal changes, but occasionally lesions two-year history of multiple “bumps” grad- may have a peau de orange appearance.1 ually forming on her back. She was other- Lesions usually appear symmetrically on wise healthy and had no other complaints. the lower trunk and extremities,1-2 but ROS was negative, and there was no perti- have been reported on the face as well as nent family history. Patient had never been other body parts4-5 (see Table 1). Based pregnant, had no significant past medical on our literature review, the mean age for history, was not taking any prescription EC is 21, however other authors suggest or herbal medications, did not recall any that EC usually appears within the first illness before or during the onset of the two decades.1,5-7 There does not appear Figure 1 eruption, and did not recall any of the to be a predilection for a particular race. lesions developing after an inflammatory Histologic examination of the papules cutaneous process. reveals an accumulation of thickened, Physical examination revealed over homogenous collagen within the dermis 50 flesh-colored firm cutaneous papules with a diminished amount of elastin. A covering her back. No other similar lesions thorough and reliable family history were noted on other body parts, and no must be obtained in order to differentiate other significant dermatologic findings EC from other collagenous connective- were present on physical examination. tissue nevi. Also, it is of importance to Punch biopsy revealed hypocellular scle- rule out other syndromes that have been rosing process without identifiable mucin. associated with collagenomas or multiple Nodular dermal sclerosis with marked connective-tissue nevi, such as multiple attenuation of the elastic fibers was present. endocrine neoplasia type 1 (MEN-1), The diagnosis was eruptive collagenoma Buschke-Ollendorff syndrome, tuberous Figure 2 based on of history, physical examination, sclerosis, Hunters syndrome, Cowden 3,8 and histology. syndrome and Proteus syndrome. FCC may have a predilection for the upper Diagnosis of eruptive collagenoma is two thirds of the back and proximal arms, Discussion dependent on the appropriate clinical while EC has been commonly reported on manifestations and histologic features, other body parts such as lower extremi- Connective-tissue nevi of the skin are as well as a negative family history and ties, face and trunk.1,4,12 Based on the classified based on clinical, histopathologic absence of extracutaneous manifestations. limited number of reports, though, this and genetic features. Uitto et al. defined The lesions of EC are benign. Pathogenesis distribution pattern should not be used to and classified connective-tissue nevi as is unknown, and no treatment option has differentiate between EC and FCC. The those tumors formed by the proliferation been proven effective. distinguishing feature between the two of a single component of the extracellular The differential diagnosis for the collag- entities is the presence of an autosomal- matrix: collagen, elastin, or proteoglycan. enous connective-tissue nevi includes dominant inheritance pattern in those with Connective-tissue nevi are further catego- familial cutaneous collagenoma (FCC), FCC.1 As McClung et al.2 discusses, this rized as either acquired or inherited, and the shagreen patch of tuberous scle- familial pattern has been demonstrated in the presence or absence of extracutaneous rosis, isolated collagenoma, and papular previously. FCC appears within the first features distinguishes them further.1 elastorrhexis.1,9 two decades of life and may be influenced Eruptive collagenoma (EC) is a hamar- FCC resembles eruptive collagenoma by hormonal changes such as pregnancy tomous connective-tissue nevus primarily both clinically and histologically. Patients and puberty. Extracutaneous manifesta- composed of dense, thickened collagen. present with multiple, asymptomatic tions such as cardiac abnormalities have Usually, this entity presents with the papules and nodules distributed on the been suggested by some authors to be asso- sudden appearance of several firm, white- trunk and extremities which show identical ciated with FCC.1,2 Because our patient to-flesh-colored papules and nodules of histologic features when compared to EC. denies any family history of similar lesions, 8 ERUPTIVE COLLAGENOMA IN A 50-YEAR-OLD WHITE FEMALE Table 1 Resource Age at onset gender race Distribution Size Associated Findings Smith 35 M ? arms, back, abdomen Berberian 12 F ? back, abdomen 0.5-3 cm DePadova 43 M AA back, arms 2-4mm Mukhi 27 M ? Indian back, abdomen, Beckers nevus upper arms Lee 5 M ? trunk, ext 2-5mm Ryder 13 F C upper back 5-10mm Yahya 2 F AA face, extremities 7 x 3 cm, 1 x 1 cm McCLung 22 F AA trunk, shoulders 3-10mm Figure 3 Xia 32 M C neck, trunk, lower ext MEN-I, Beckers nevus been described as those isolated collag- secreting tumor (VIPoma). The various enomas on the plantar surface of the foot papules were indeed collagenomas, but it is that may occur in Proteus syndrome or unclear how the VIPoma may have contrib- as a separate entity.4,8 There have been uted to the growth of these collagenomas. two reported cases of isolated collagenoma Although no spontaneous resolution of EC that seem to follow Blaschko’s lines, and lesions has been reported, lesions have been as Girard10 suggests, these should be clas- reported to decrease in size after hormonal sified as papulolinear collagenoma. While influences were removed.2 Because our isolated collagenomas are asymmetrically previously healthy 50-year-old patient was distributed and localized to a body part, asymptomatic, and a work-up revealed no FCC and EC are commonly symmetric abnormalities, it is possible that hormonal and on several areas of the body. Isolated mechanisms are not necessary for EC’s Figure 4 collagenomas can be clearly separated from evolution. Homogenized, uniform and relatively FCC or EC based on appearance and distri- thin collagen bundles in the center bution; however, it is important to exclude References: of this lesion stand in contrast to the tuberous sclerosis in those presenting with normally thick and heterogeneously 1. Uitto J, Santa Cruz DJ, Eisen AZ. Connective tissue nevi an isolated collagenoma.1 of the skin: clinical, genetic and histopathologic classifica- distributed fibers typical of the back, tion of hamartomas of the collagen, elastin and proteogly- as seen in the lower right corner. Black Papular elastorrhexis (PE) is a rare can type. J Am Acad Dermatol 1980;3:441-461. condition that has been suggested to be 2. McClung A, Blumberg M, Huttenbach Y, Colome-Grim- staining elastic fibers are also markedly mer MI, Raimer SS. Development of collagenomas dur- diminished (Verhoff Van-Gieson stain, of the same entity as EC due to clinical ing pregnancy. J Am Acad Dermatol 2005;53: S150-3. and histological similarities. Papular elas- 3. Lee MW, Choi JH, Sung KJ, Moon KC, Koh JK. A case original magnification 100X) of eruptive collagenoma. Pediatr Dermatol 2002;19:565- torrhexis is a term that describes multiple, 567. 2 mm to 5 mm, flat, firm papules over 4. Yahya H, Rafindadi AH. Eruptive collagenoma in a Nige- and any obvious extracutaneous manifesta- rian girl. Int J Dermatol 2006;45:1344-1346. tions are absent, we believe FCC is not a the trunk and extremities with reduction 5. Mukhi SV, Kumar P, Yuvarajkumar D, Raghuveer CV. 9 Eruptive collagenoma. Indian J Dermatol Venereol Leprol likely diagnosis. and fragmentation of elastic fibers. It is this reduction in elastic fibers, along with 2002;68:98-99. The shagreen patch is a characteristic 6. DePadova-Elder S, Mols-Kowalczewski BL, Lambert WC. a similar clinical appearance, that make Multiple connective tissue nevi. Cutis 1988;42;222-4. cutaneous finding in those with tuberous 7. Smith LR, Bernstein, BD. Eruptive collagenoma. Arch papular elastorrhexis and EC hard to sclerosis (TS). Tuberous sclerosis is a Dermatol 1978;114:1710-1. distinguish. Amongst reported cases of 8. Xia Y, Darling TN. Rapidly growing collagenomas in rare genetic disease that affects multiple multiple endocrine neoplasia type I. J Am Acad Derm PE, histologic descriptions of the collagen organs and manifests commonly as mental 2007;56:877-80. component vary from normal collagen to 9. Ryder HF, Antaya RJ. Nevus anelasticus, papular elas- retardation and epilepsy along with torrhexis, and eruptive collagenoma: clinically similar condensed and thickened collagen, and other cutaneous and systemic abnor- entities with focal absence of elastic fibers in childhood. some descriptions make no mention of Pediatr Dermatol 2005;22:153- 157. malities. Unlike FCC and EC, the 10. Girard C, Bessis D. Papulolinear collagenoma. J Am the appearance of collagen.9 Like EC, the collagenous shagreen patch most Acad Dermatol 2006; **:S240. lesions of PE also appear during the first or 11. Berberian BB, Wood C. Asymptomatic nodules on the commonly appears within the first back and abdomen. Connective tissue nevi, eruption col- second decade, show no heritable pattern, decade of life as one or several lagenoma type. Arch Dermatol 1987;123:811-2,815. and occur without the presence of inflam- 12. Uitto J, Santa Cruz DJ, Eisen AZ. Familial cutaneous solitary plaque lesions which are asymmet- collagenoma: genetic studies on a family. Br J Dermatol mation or trauma. Nevus anelasticus is rically distributed on the lower back, with 1979; 40:255-7. another term in the medical literature 13. Amjadi M, Khorrami-Arani N, Mashman G, Allen PW. an occasional pig-skin or pebbly appear- Zosteriform connective tissue nevus: A case report. Am that describes perifollicular papules with ance.1,2 Adenoma sebaceum, subungual J Dermatopathol 2007;29:303-305. decreased elastic fibers, and this has been fibroma and “ash leaf” macules are among suggested to represent a variant of PE. Due the other cutaneous findings in TS. TS was to the limited number of case reports, it is ruled out in our patient based on the clin- uncertain whether these entities are part ical appearance, distribution of hundreds of the same disease process, or rather are of papules, and a lack of extracutaneous separate disease states.3,9 manifestations. It has been demonstrated that FCC may Isolated collagenoma includes those be influenced by hormonal mechanisms cases of collagenous hamartomas which such as pregnancy or puberty,2 and EC fail to show a heritable pattern and are may be influenced in a similar fashion. separate from EC.1 These collagenomas Xia et al.8 report a case of a 32-year-old have been reported to occur in a zosteri- man with MEN-I syndrome who noticed a form pattern.1,13 Also, paving stone nevi, sudden eruption of cutaneous papules on or plantar fibromatosis, shows histologic his trunk after having surgical resection of features consistent with collagenoma.1 a pancreatic vasoactive intestinal peptide- Cerebriform plantar collagenoma has LEGACY, ANDERSON, SCHWIMER, GREKIN 9 CUTANEOUS LEISHMANIASIS: A CASE AND REVIEW

Dawn L. Sammons, DO,* Joel Bain Herron, MD,** John Hibler, DO*** *3rd Year resident, O’Bleness Memorial Hospital Dermatology **Northeast Dermatology & Cosmetic Center ***Program Director, O’Bleness Memorial Hospital Dermatology Residency Program

ABSTRACT

The likelihood of a dermatologist encountering cutaneous leishmaniasis here in the United States used to be exceptionally low. However, with thousands of American troops now serving in the Middle East, that likelihood could change: There are reports that up to 1% of these young people will return home to the United States infected with this obligate intracellular parasite. Improved clinical ability to recognize the cutaneous manifestations of this disease will be needed to aid in early diagnosis and appropriate treatment. To aid in this understanding, a case of cutaneous leishmaniasis in a traveler is presented, and a review of the relevant literature is discussed.

Case individuals worldwide are affected by this disease, with a wide range of clinical A 45-year-old female presented with outcomes and varying levels of morbidity.1 complaints of non-pruritic “bumps” to the The infection occurs with a spectrum of posterior aspect of her upper arm and to clinical presentations, including localized her lateral neck. The lesions had devel- cutaneous Leishmaniasis (LCL), diffuse oped while the patient was vacationing cutaneous Leishmaniasis (DCL) and in Central America, spending time in mucocutaneous Leishmaniasis (MCL). both Costa Rica and on the west coast of The variable clinical features are due to a Mexico. Although the lesions did not itch complex interaction between the species of at any time and there was no recollection Leishmania involved, the particular vector, of an insect bite/sting, the patient initially environmental factors and the immune dismissed the lesions as mosquito bites. status and response of the host. Figure 1 When the lesions persisted after returning We will review the most recent data on home and the passage of several weeks the epidemiology of this disease, the asso- time, the patient decided to present for ciated vectors and reservoirs, the clinical further investigation. presentations, the current methods of Physical examination of the patient diagnosis and the most common forms revealed three 1.5 cm to 2 cm, edematous of treatment. Additionally, we will take a and erythematous nodules with crusted look at the increasing burden of disease surfaces and violaceous borders on the in the United States due to the elevated posterior right upper arm (Fig.1). There numbers of U.S. military forces stationed were also similar lesions on the right lateral in the Middle East and other areas endemic neck. On palpation, numerous 2 mm to to this disease. 3 mm subcutaneous nodules could be felt extending cephalad along lymphatic Epidemiology channels of the right upper arm. There Figure 2 was no palpable axillary or cervical Currently, cutaneous Leishmaniasis lymphadenopathy. is endemic to more than 88 countries A 4 mm punch biopsy was obtained worldwide, with 90% of cases occurring from the periphery of one of the nodules in Afghanistan, Algeria, Brazil, Pakistan, on the right arm. Histologic examination Peru, Saudi Arabia and Syria.1,2 Each year revealed hyperkeratosis and pseudoepithe- more than 1.5 million individuals are liomatous hyperplasia overlying a marked infected with this parasite, contributing dermal infiltrate of chronic inflammatory to an increasing burden of disease.2 In cells (Fig. 2). Within the dermis, numerous addition to those people who are native histiocytes were present which contained to endemic areas, infection also occurs in intracellular, nonencapsulated organisms military personnel stationed in endemic with a round nucleus and a smaller, rod- areas, and in civilian workers and travelers who journey into endemic areas. Prior to shaped paranucleus (Fig. 3). A diagnosis of Figure 3 cutaneous Leishmaniasis was made. the Gulf War in the early 1990s, there were only isolated reports within the United Introduction States of CL, usually occurring in travelers have been reported by the Department who had visited endemic areas.3,4,5 During of Defense amongst military personnel Cutaneous Leishmaniasis is an infection the Gulf War, however, 12 cases of CL were serving in Southwest and Central Asia caused by species of Leishmania, protozoa diagnosed in U.S. troops who had been between 2002 and 2004 alone.7 The that are obligate intracellular parasites in deployed to the region.6 Most recently majority of those persons were infected the human host. Currently over 12 million and more staggering, at least 522 cases in urban areas of Iraq after a median 10 CUTANEOUS LEISHMANIASIS: A CASE AND REVIEW period of deployment of only 60 days.7 (Old World) are the major causes of DCL.1 sporotrichosis, syphilis and sarcoidosis.11 Currently, it is believed that up to 1% of The localized form is the most common Therefore, whenever feasible, a laboratory U.S. troops serving in Iraq and the Middle presentation, and clinically is made up of diagnosis should be made. Additionally, the East may be infected by one of the species one to several lesions developing in locally identity of the implicated species should of Leishmania.8 contiguous areas. The diffuse form is the be sought so that appropriate treatment For those native to endemic areas, the rarest and most severe manifestation of planning may occur. Skin punch biopsy prevalence of CL tends to increase with age cutaneous disease. In this form, parasite- is an ideal method of obtaining tissue for up to the age of 15, and then the prevalence laden, non-ulcerated nodules dissemi- various diagnostic techniques, including declines.2 This drop-off in prevalence is nate both locally and hematogenously to histology, microscopy of smears, poly- believed to be due to the acquisition of other areas of the body, sometimes almost merase chain reaction (PCR) testing and species-specific immunity. Disease risk covering a patient’s body surface.1,2 DCL culture. Demonstration of Leishmania in factors in endemic areas have been found presents an anergic response to infec- skin smears or biopsy specimens is highly to be related to housing construction and tion, with a marked predominant Th2 sensitive; however, it does not allow for design, presence of domestic animals, male lymphocyte response. Not only is this species identification.12 Leishmania species, sex and age.2 form cosmetically deforming, but it is also especially those from the New World, are exceptionally difficult to treat, with some also notoriously difficult to culture, so Pathogenesis cases persisting indefinitely. The last form, having other options available is impera- mucocutaneous disease, has a distinctive tive.10 PCR is currently the diagnostic test There are 11 species of Leishmania that late secondary phase in which metastatic of choice, as it is highly sensitive and allows commonly cause cutaneous Leishmaniasis lesions develop at mucocutaneous junctions for species identification. This is especially in humans, and the species varies based days to years after the primary lesion(s). important when L. braziliensis may be the upon geographic region (Table 1). The The nose and mouth are most commonly etiologic agent, as prompt treatment may protozoa are transmitted by the bite of affected, but lesions can also involve the allow prevention of complications. the sandfly -- Phlebotomus spp in the Old larynx, conjunctiva, and external genitalia. Another test to confirm a clinical World (Europe, North Africa, Middle East Crusting and polyp formation occurs first, diagnosis, which is mostly of historical and Asia) and Lutzomyia spp in the New followed by ulceration and perforation of significance, is the Montenegro skin test. World (from southern Texas to northern affected tissue. The lesions heal slowly if It measures delayed hypersensitivity to the Argentina). Although somewhat simpli- at all, and secondary sepsis is a common parasite and is useful after a granulomatous fied, the ecological environment associated occurrence. This type of Leishmaniasis is response has occurred, typically several with Old World CL tends to be dry, semi- particularly resistant to treatment and may months after inoculation. A suspension arid or desert conditions. New World CL be fatal. of antigen from the promastigote form is is more associated with forest conditions. Regardless of the clinical spectrum, the injected into the forearm, and a positive These environments have an impact on most common initial presentation is a test occurs when a palpable nodule, 10 mm the species of sandfly and on the reser- small, sometimes pruritic, erythematous or more in diameter, is seen after 48 to 72 voirs that are involved. The arid habitats of papule, which appears anywhere from a hours. The test is of diagnostic value only the Old World translate into dogs, gerbils few days to many months after the bite of in patients who do not live in endemic and desert rodents being the main reser- the sandfly. Often the individual is not areas, as it is unable to distinguish between voirs; whereas the forest habitats of the even aware of the initial sandfly bite, so past and present infection. It will also New World are more conducive to sloths, a lack of recall regarding the bite prob- give false negative results in patients with monkeys and forest rodents being the main ably has no clinical significance. As time diffuse anergic cutaneous Leishmaniasis, reservoirs. passes, the papule may grow in size and as these patients do not develop a type IV The lifecycle of the Leishmania organism ulcerate at the center, producing a “wet” immunologic response to the organism. begins as an extracellular promastigote in sore common to New World species. Old The test is not species-specific and does not the gut of the sandfly. When the sandfly World species are more likely to produce necessarily reflect immunity to Leishmania. takes a blood-meal from either a human “dry” sores that become hyperkeratotic It is, however, simple to use and highly or a reservoir, the promastigote is released or smooth nodules. In all forms, the edge sensitive and specific. Currently, it is no into the skin, where it is phagocytized of the lesion takes on the characteristic longer available in the United States and is by macrophages and transformed into thickened, often hyperplastic, violaceous used mostly for epidemiological surveys.2 amastigotes by binary fission. It is in this border. More than 90% of lesions occur amastigote form that it is later taken up by on exposed skin, correlating with the areas Pathology another sandfly during feeding, allowing most susceptible to the bite of the sandfly.10 the cycle to start again. According to Lesions may grow to be large (2.5 cm – 5 In human tissue, the organisms are in studies done by the CDC and Department cm) but rarely grow beyond 10 cm in diam- the amastigote form and are small, round, of Defense, the infection rate in sandflies eter.1 Even in LCL, satellite nodules may non-flagellated forms 2.0 microns to 4.0 in endemic areas such as Iraq ranges from develop along draining lymphatic channels microns in diameter that usually stain with 0.06% to 2.78%.9 in a sporotrichoid fashion. The lesion(s) hematoxylin and eosin. They replicate typically remains for a few months and within macrophages and are then released Clinical Presentation then heals gradually with scarring. Healing to infect other cells; therefore, they may be is followed by species-specific immunity. found within macrophages or free in the There are three main spectrums of tissue. They typically have a large nucleus clinical presentation: localized cutaneous Diagnosis and a characteristic intracytoplasmic Leishmaniasis (LCL), diffuse cutaneous kinetoplast that may require accentuation Leishmaniasis (DCL) and mucocutaneous When there is a history of obvious travel with special stains such as Giemsa stain or Leishmaniasis (MCL). The spectrum of or past residence in an endemic area, a clin- Brown-Hopps gram stain. There tends disease seen is determined by the species ical diagnosis may be possible. However, to be hyperkeratosis, acanthosis and pseu- involved and by host immunity. L. there is a relatively extensive differential doepitheliomatous hyperplasia overlying braziliensis is known to be a major cause diagnosis for the clinical cutaneous presen- a marked dermal infiltrate of chronic of mucocutaneous disease, whereas L. tation, including cutaneous tuberculosis, inflammatory cells. Necrosis may develop amazonensis (New World) and L. aethiopica dermatophyte skin infections, myiasis, and be visible within a biopsied lesion.

SAMMONS, HERRON, HIBLER 11 Table 1 Most common Leishmania species causing cutaneous disease New World LCL, DCL L. mexicana L. amazonensis LCL L. venezuelensis LCL, MCL L. braziliensis L. panamensis L. peruviana L. colombiensis L. guyanensis Old World LCL, DCL L. aethiopica LCL L. major L. tropica LCL = Localized Cutaneous Leishmaniasis, DCL = Diffuse Cutaneous Leishmaniasis, MCL= Mucocutaneous Leishmaniasis

As immunity develops, parasite numbers that must be monitored for, including EKG References decrease and a shift from a histiocytic changes (T-wave abnormalities); abdominal 1) Bailey, M. & Lockwood, D. Cutaneous Leishmaniasis. Clinics in Dermatology. (2007)25, 203-211. reaction to a granulomatous reaction with pain; nausea and vomiting; fever; eleva- 2) Reithinger, R., et al. Cutaneous Leishmaniasis. Lancet lymphocytes, plasma cells, epithelioid tions of liver enzymes, amylase and lipase; Infectious Disease (2007)7, 581-596. 11,13 3) Reed, B., et al. Cutaneous leishmaniasis in an infant. cells, and Langerhans’ giant cells occur. leucopenia; and anemia. Fortunately, Pediatr Dermatol (1983) 1:2:142-5. Mucocutaneous lesions characteristically most abnormalities return to normal with 4) Centers for Disease Control. Cutaneous leishmaniasis – Ohio. MMWR Morb Mortal Wkly Rep (1985)34:33:515-6. display a necrotizing granulomatous reac- only a short interruption of treatment and 5) Clark, D & Anderson, P. Cutaneous Leishmaniasis in a tion with few organisms present. often remain normal even on reinstitution native of Missouri. Mo Med (1986) 83:5:269-70. 6) Centers for Disease Control and Prevention. Update: of the drug. cutaneous leishmaniasis in US military personnel – south- Treatment Other treatments that have been west/central Asia, 2002-2003. MMWR Morb Mortal Wkly Rep (2003); 52:42:1009-12. employed for LCL include intralesional 7) Centers for Disease Control and Prevention. Update: In the Old World version, most lesions injections of pentavalent antimony, paro- cutaneous leishmaniasis in US military personnel – south- will heal spontaneously and do not require west/central Asia, 2002-2004. MMWR Morb Mortal Wkly momycin ointments, imiquimod, topical Rep (2004); 53:264-5. systemic treatment. Typically, lesions will amphotericin B, cryotherapy, localized 8) WHO. The world health report 2004. Changing history. resolve within 12 months. Pharmacologic Geneva: WHO, 2004. http://www.who.int/whr/2004/en/ controlled heat therapy, carbon dioxide index.html. intervention, however, can be important laser and photodynamic therapy.11-14 9) Weina, P, et al. Old World Leishmaniasis: An emerging and is indicated when lesions are large and/ infection among deployed US military and civilian work- Additional systemic treatments for those ers. Clinical Infectious Diseases (2004), 39, 1674-1680. or potentially disfiguring, when there are in which systemic antimonials have either 10) Scarisbrick, J., et al. Clinical features and diagnosis of multiple lesions present and when lesions failed or are contraindicated include oral 42 travelers with cutaneous leishmaniasis. Travel Medi- 10,11 cine and Infectious Disease (2006), 4, 14-21. occur in immunosuppressed patients. amphotericin B, azithromycin, miltefosine, 11) Markle, W. & Makhoul, K. Cutaneous leishmaniasis: In the New World, the broad spectrum 14 Recognition and treatment. Journal of the American and pentamindine. If systemic treat- Academy of Family Physicians (2004) of clinical presentations, from benign to ment is warranted, referral to an infectious 12) Herwaldt, B. Leishmaniasis. Lancet (1999) 354, 1191-9. severe, makes species-specific treatment 13) Blum, J., et al. Treatment of cutaneous leishmaniasis disease expert or other specialist familiar among travelers. Journal of Antimicrobial Chemotherapy planning important. This is particu- with the systemic medications and their (2004) 53, 158-166. larly important when infection with L. 14) Minodier, P. & Parola, P. Cutaneous leishmaniasis treat- side effects is likely warranted. ment. Travel Medicine and Infectious Disease (2007) 5, braziliensis is suspected, as 2% to 10% of 150-158. untreated cases will progress to mucosal 15) Kenner, J.R., Aronson, N.E., & Benson, P.M. The United Conclusion States Military and leishmaniasis. Dermatol Clin (1999) involvement, making systemic pharmaco- 17, 77-92. logic treatment mandatory.13 Although cutaneous leishmaniasis is 16) Scope, A., et al. Experience with New World cutaneous leishmaniasis in travelers. J Am Acad Dermatol (2003) Pentavalent antimonials remain the gold not endemic in the United States, with the 49:4, 672-678. standard for the treatment of New World exception of Southern Texas, it is more 17) Wright, N, et al. Cutaneous Leishmaniasis in Texas: a northern spread of endemic areas. J Am Acad Dermatol cutaneous leishmaniasis. The recommen- likely than ever that dermatologists may (2008) 58:4, 650-653. dation is for 10-20mg/kg/day of sodium encounter a case in their own office. The stibogluconate (available through the increasing incidence in military personnel Centers for Disease Control and Prevention returning from the Middle East and the within the United States) for a period of 20 increasing ease of international travel mean to 30 days.14 The efficacy var ies with that more U.S. citizens may be infected the species involved, ranging from a 26% with this obligate intracellular parasite than to 51% cure rate, regardless of other host ever before. It is important for each of us variables.14 Unfortunately, administration to have a good clinical understanding of can be difficult; it must be given either the clinical presentations, the methods of intravenously or intramuscularly as there is diagnosis and the basics of effective treat- no oral form available. Additionally, there ment for this disease. are numerous side effects and toxicities

12 CUTANEOUS LEISHMANIASIS: A CASE AND REVIEW

CASE REPORT AND REVIEW OF BEHCET’S DISEASE

Shaheen Oshtory, D.O.,* Charles Gropper, M.D.,** Cindy Hoffman, D.O., F.A.O.C.D.*** *3rd-year resident, Saint Barnabas Hospital, Bronx, New York, USA **Chief of Dermatology, Saint Barnabas Hospital, Dermatology Program, Bronx, New York, USA ***Program Director, Saint Barnabas Hospital, Dermatology Program, Bronx, New York, USA

ABSTRACT

Behcet’s disease (BD) is a multi-system inflammatory disorder characterized clinically by recurrent oral and genital ulcers, uveitis, and erythema nodosum. It runs a chronic course with unpredictable exacerbations and remissions. The disease can affect both genders, typically young adults, and has a worldwide distribution, although it is more prevalent in countries of the ancient Silk Route. The cause of Behcet’s disease remains unknown. The treatment of BD is symptomatic, but generally specific to the clinical features of each patient. The majority of affected individuals do not have life-threatening disease.

Case Report Diagnostic Criteria However, the trend is reversed in people of other ethnic origins, with more women The agreed diagnostic criteria for History than men being affected. The disease Behcet’s disease requires the presence of can develop at any age, but mean age of A 26-year-old, Middle Eastern female recurrent oral ulceration (three times in onset ranges from the mid to late 20s to presented with a five-day history of painful one year) plus two of the following in the the fourth decade.5 It is relatively rare in ulcers around her cheeks, tongue, palate absence of other systemic disease: recurrent children and the elderly. Behcet’s disease and vulva. She stated that these lesions genital ulceration, eye lesions (uveitis or is also uncommon among black Africans, had recurred three times this year and four retinal vasculitis), skin lesions (erythema who tend to have more mucocutaneous times in the past year. She also reported nodosum, pseudofolliculitis, papulopus- features when affected.6 tular lesions, or acneiform nodules), or a a history of erythema nodosum. Upon Pathogenesis further questioning and the use of a trans- positive pathergy test (Table I). lator, the patient reported a history of Epidemiology The etiology of BD is unknown, but an Behcet’s disease, diagnosed in Saudi Arabia autoimmune reaction triggered by an infec- when she was 18 years old. She reported no Behcet’s disease is most common and tious or environmental agent in a geneti- other past medical history. She had been more serious in people with Silk Road cally predisposed individual seems most previously treated with prednisone, colchi- bloodlines. Silk Road countries include likely. In the eastern Mediterranean and cine, and topical and viscous lidocaine. To those in the Mediterranean basin, Middle East Asia, HLA-B5 and HLA-B51 antigens East and Far East, where the incidence have been associated with BD; however, in date she has had no eye findings, but did 1 report a history of ulcers after blood draws. is around 1 in 10,000 people. Behcet’s the United States and Europe, no consistent disease is seen worldwide even in those 7 She also noticed she had lost a significant HLA association has been reported. The with other ethnic heritage; in the United amount of weight in the last year. lesions could be the result of a combination States, the incidence is reported to be 1 in of factors involving immune dysregulation, Physical exam 20,000.1 inflammatory mediators, and infectious In people with Silk Road ancestry, BD agents such as herpes simplex virus and Cutaneous examination revealed multiple 5 2 to 12 millimeter, discrete, painful, round, is more common in men than in women. Streptococcus spp. The major immuno- red-rimmed lesions on the mucosa of her cheeks, tongue, palate, and pharynx. She Table 1 had similar lesions on her vulva. International Study Group Criteria for Behcet’s Disease (1990) Discussion Recurrent oral ulceration Minor aphthous, major aphthous, or herpetiform ulceration observed by physician or patient that recurred Introduction at least 3 times in one 12-month period Behcet’s disease (BD) is a chronic multi- Plus 2 of the following criteria: system inflammatory disorder character- Recurrent genital ulceration ized clinically by recurrent oral and genital Aphthous ulcerations or scarring observed by ulcers, uveitis, and erythema nodosum.1 physician or patient BD was first described by the Turkish dermatologist Hulusi Behcet in 1937 as Eye lesions Anterior uveitis, posterior uveitis, or cells in vitreous on “recurrent oral aphthous ulcers, genital slit lamp examination; or retinal vasculitis observed ulcers, and ‘hypopyon-uveitis.’”2 The by ophthalmologist disease has a variable course with exacerba- Skin lesions Erythema nodosum observed by physician or patient, tions being unpredictable. BD is a vascu- pseudofolliculitis or papulopustular lesions; or acneiform litis, affecting vessels of different types, nodules observed by physician in post-adolescent patients 1 sizes, and locations. The diagnosis of not receiving corticosteroid treatment Behcet’s disease is based on clinical criteria 3 as established by O’Duffy and Goldstein Positive pathergy test Read by physician at 24-48 hours and the International Study Group.4 OSHTORY, GROPPER, HOFFMAN 15 Table 2 Table 3 Clinical Features of Behcet’s Disease Therapies for Behcet’s Disease

Gastrointestinal Aphthous mouth ulcers Topical corticosteroids Isolated multifocal ulcer Systemic corticosteroids Commonly in ileocecal region Corticosteroid-sparing immunosuppressants: Urogenital Scrotal and/or penile ulcers Colchicine Vulval and/or vaginal ulcers Azathioprine Peri-anal ulcers Thalidomide Epididymo-orchitis in men Cyclosporine Tacrolimus Dermatologic Papules and pustules Methotrexate Erythema nodosum Antimicrobials: Ulcers Antibacterials Cutaneous pathergy response Antivirals

Ocular Anterior or posterior uveitis Retinoids Retinal vasculitis Dapsone

Musculoskeletal Arthralgias Anticoagulants Arthritis Non-steroidal anti-inflammatory agents Fatigue Biologic agents: Interferon alpha-2a Neural Headache Anti-TNF alpha Dural sinus thrombosis Parnchymal inflammatory lesions Meningo-encephalitis Cardiac manifestations of Behcet’s disease include myocardial infarction, Cardiac Myocardial infarction pericarditis, endocarditis, and valvular Pericarditis abnormalities including aortic and mitral Endocarditis regurgitation.5 Valvular abnormalities Several renal disorders have been associ- ated with BD and can be divided into five logical features of BD consist of increased eventually lead to vision loss if not treated.1 groups: (1) glomerulonephritis, (2) amyloi- T- and B-cell responses to heat-shock A variety of cutaneous lesions dosis, (3) renal vascular involvement, (4) proteins, increased neutrophil activity, and have been observed in BD, including interstitial nephritis, and (5) other prob- alterations in cytokine levels, although the lems such as complications of drug therapy erythema-nodosum-like lesions, papulo- 1 interrelationships between and among pustular eruptions, abscesses, pyoderma- or genito-urinary system abnormalities. these features are not clear.1 gangrenosum-like lesions, palpable Management Clinical Features purpuric lesions of necrotizing vascu- litis, and reactivity of skin to injections Currently there is no cure for Behcet’s Behcet’s disease presents with a wide (pathergy).8 disease. The main goal is to treat and manage the symptoms so that compli- spectrum of clinical features characterized The neurologic complications of BD cations do not develop. The treatment by unpredictable exacerbations and remis- mainly involve the central nervous system. of BD is generally specific to the clinical sions (Table II). Oral and genital aphthae Neurologic features include headaches, features of each patient. Treatment is occur in all patients diagnosed with BD. meningoencephalitis, seizures, cerebral usually multi-disciplinary, and is chal- Oral ulceration is the initial clinical feature venous thrombosis, cranial nerve palsies, in up to 86.5% of adults and children lenging given the variable clinical course cerebellar ataxia, hemiplegia, and benign 1,5 1 and lack of sufficient studies. Table III with BD. The most common sites of oral intracranial hypertension. These may summarizes therapies for Behcet’s disease. ulceration are the buccal mucosae, gums, occur from one to 10 years after initial Patients are initially treated with topical or tongue, lips, and pharynx. Oral ulcers in presentation of BD.7 intralesional corticosteroids and colchicine BD are typically painful, 1 to 3 cm in diam- Musculoskeletal symptoms in BD usually eter, shallow or deep, and have a yellow with the subsequent addition of dapsone. manifest as arthralgias or arthritis, with If conservative management fails, thali- fibrinous base. Patients may have single or mono-arthritis being the most frequent multiple ulcers lasting one to four weeks domide, methotrexate, or oral prednisone pattern of involvement. The knees and tapers may be required.5 that heal without scarring. Genital aphthae ankles are the most commonly affected are usually found on the scrotum or vulva joints.1 Prognosis and have a similar appearance and clinical Gastrointestinal (GI) involvement in course as oral aphthae.7 Behcet’s disease is a chronic disease BD is characterized by ulceration along Ocular manifestations in BD patients in which the acute phases come and go the GI tract including the esophagus and, with varying degrees of intensity. In the include panuveitis, anterior uveitis, poste- most commonly, in the terminal ileum rior uveitis, bilateral swelling of the optic early stages of the disease, attacks may be and cecum. Mucosal ulcers are the most frequent and last for several weeks. As time nerve head, retinal vasculitis, and bilateral common GI feature. Depending on the site lamellar macular holes. Ocular symptoms progresses, the intervals between attacks of involvement, the ulceration can give rise may become longer, and in some cases the vary from gritty sensation and blurring to dysphagia, abdominal pain, diarrhea, of vision to severe pain and blindness. attacks cease altogether. The disease is intestinal perforation, and peri-anal fistula then considered to be in remission but may Ocular disease is the most common cause formation.1 of significant morbidity in BD, since it may strike up again at any time. Death occurs 16 CASE REPORT AND REVIEW OF BEHCET’S DISEASE in about 4% of Behcet’s cases. Causes of mortality are attributed to gastrointes- tinal perforation, central nervous system involvement and vascular aneurysms. Most Behcet’s patients live a full life, although they will most likely deal with some level of symptoms throughout this time.9 Conclusion Behcet’s disease is a condition that remains difficult to diagnose and manage, having various clinical presentations and an unknown etiology. It therefore remains a significant challenge for clinicians of many specialties to manage and treat. Our patient was started on topical steroids and colchicine and improved with treatment. She was then lost to follow-up.

References 1. Al-Otaibi LM, Porter SR, Poate TWJ. Behcet’s Disease: A Review. Crit Rev in Oral Bio and Med 2005;3:209-222. 2. Behcet H. Uber rezidivivierende apthose, durch ein virus verursachte geschwure am mund, am auge und an den genitalien. Dermatol Wochenschr 1937;105:1152-7. 3. O’Duffy JD, Goldstein NP. Neurologic involvement in seven patients with Behcet’s disease. Am J Med 1976;61:17-8. 4. International Study Group for Behcet’s disease. Criteria for diagnosis of Behcet’s disease. Lancet 1990;335:1078- 80. 5. Jayashri GV, Jorizzo JL. Behcet’s disease and complex aphthosis. J Am Acad Dermatol 1990;40:1-18. 6. Jacyk WK. Behcet’s disease in South African blacks: report of five cases. J Am Acad Dermatol 1994;30:869- 73. 7. Yazici H, Chamberlain et al. HLA antigens in Behcet’s disease: a reappraisal by a comparative study of Turkish and British patients. Ann Rheum Dis 1980;39:344-8. 8. Chajek T, Fainaru M. Behcet’s disease: report of 41 cases and a review of the literature. Medicine 1975;54:179-96. 9. Kural-Seyahi E, Fresco I, Seyahi N et al. The long-term mortality and morbidity of Behcet’s syndrome: a 2-decade outcome survey of 387 patients followed at a dedicated center. Medicine 2003;82:60-76.

OSHTORY, GROPPER, HOFFMAN 17 CUTANEOUS NEONATAL LUPUS ERYTHEMATOSUS: A CASE REPORT AND BRIEF REVIEW

Michelle W Foley, DO,* Lynn M Sikorski, DO,** Michael J Mahon, DO*** *First-year Dermatology Resident – Michigan State University, Pontiac Osteopathic Hospital, Pontiac, Michigan **Sikorski Dermatology and Vein Clinic, Bloomfield Hills, Michigan ***Program Director POH/Botsford Hospital Consortium- Michigan State University; Middlebelt Dermatology, Farmington Hills, Michigan

ABSTRACT

Neonatal lupus erythematous (NLE) is an uncommon syndrome classically characterized by the presence of permanent congenital heart block and/or transient cutaneous rash. Less frequently, affected infants may demonstrate hematologic abnormalities in the form of cytopenias and cholestatic hepatitis.1-5 Children born to mothers with anti-SSA/Ro, anti-SSB/La or anti-U1RNP antibodies present in their sera are at well-documented risk for developing NLE secondary to the cross-placental transfer of these IgG1 autoantibodies.4,5 The precise incidence of NLE is unknown; however, it has become increasingly recognized with the emergence of diagnostic serologic markers.4,6

Case Report A 16-week-old male presented to our clinic in the presence of both parents for evaluation of a progressive skin rash that reportedly began at eight weeks of age. The patient continued to develop new lesions despite twice daily application of triam- cinolone 0.025 % cream. The patient’s mother reported an uneventful pregnancy and birth, and denied any recent illness in the patient. The patient’s immunizations were up to date, and he was growing and Figure 1 Figure 3 developing at an appropriate rate. The patient’s diet consisted only of breast milk, and the mother reported using allergy- free soap and unscented laundry deter- gent at home. The parents denied any family history of psoriasis, and the father admitted to a personal history of eczema. The patient’s physical exam revealed scat- tered, well circumscribed, polymorphic, erythematous, slightly atrophic macules, patches, and plaques, some with fine loose scale, on both the upper and lower extremi- ties (Fig. 1, 2). Similar lesions were noted on the patient’s trunk (Fig. 3) and face, Figure 2 Figure 4 including distinct periorbital involvement (Fig. 4). Upon further questioning, the was confirmed, and pediatric rheumato- The rash of NLE may be present at birth, patient’s mother admitted to a personal logic follow-up was recommended. but usually develops within the first six history of SLE, a recent diagnosis just weeks of life and resolves by seven months prior to her pregnancy. She reported that Discussion of age.4,5 Tissue injury and resulting the patient had in fact had a normal EKG rash is presumed to be dependent on in the hospital, shortly after birth. The The first case reports of NLE described the transplacental passage of maternal patient’s parents declined skin biopsy, but the cutaneous lesions as discoid-like; IgG autoantibodies. The target antigens were agreeable to laboratory examina- however, more recent literature stresses of these antibodies have been identified tions. A tentative diagnosis of neonatal the transient, mostly non-scarring nature as two separate SSA/Ro proteins, 52 Kd lupus erythematosus was discussed with of these erythematous macules, patches the patient’s parents. Laboratory examina- and papulosquamous eruptions.4,5,7 There and 60 Kd, as well as the 48 Kd SSB/La tion revealed an ANA titer of 1:640, with a are several case reports of residual telangi- protein. These proteins are expressed on speckled pattern. Anti-SSA/Ro antibodies ectases, postinflammatory dyspigmenta- keratinocytes, red blood cells, and fetal were also positive at 39.26 U/mL. Of note, tion, and atrophy present in children with cardiomyocytes, thus accounting for some the patient’s labs also demonstrated a mild a history of NLE.5,8-10 The characteristic of the clinical manifestations of NLE.5,6 anemia, mild hypoproteinemia, hypertrig- “eye mask” or “owl-eye” appearance of the Because the half-life of IgG antibodies is lyceridemia, and slight elevation of ALT periorbital eruption has been reported in a approximately 21-25 days, the resolution of (SGPT) liver enzyme. Given the patient’s majority of patients with cutaneous lesions the rash generally coincides with the disap- clinical presentation and laboratory data, a of NLE, and should be strongly emphasized pearance of the transplacental acquired diagnosis of neonatal lupus erythematosus as a diagnostic clue.4 maternal autoantibodies.11 18 CUTANEOUS NEONATAL LUPUS ERYTHEMATOSUS: A CASE REPORT AND BRIEF REVIEW In a prospective study of infants born to dyspigmentation in a preteen girl with neonatal lupus erythematosus. J Am Acad Dermatol 2003; 48: 626-8. mothers with anti-SSA/Ro antibodies, 16 9. Thornton CM, Eichenfield LF, Shinall EA, Siegfried E, percent of children demonstrated a skin Rabinowitz LG, Esterly NB, et al. Cutaneous telangi- ectases in neonatal lupus erythematosus. J Am Acad rash characteristic of NLE. The study also Dermatol 1995; 33: 19-25. noted that anti-SSB/La occurring with 10. Crowley E, Frieden IJ. Neonatal lupus erythematosus: an unusual congenital presentation with cutaneous atrophy, anti-SSA/Ro antibody seemed to increase erosions, alopecia, and pancytopenia. Pediatr Dermatol the risk for development of cutaneous 1998; 15: 38-42. 11. Lee LA. Neonatal lupus: clinical features, therapy, and NLE, when compared to anti-SSA/Ro pathogenesis. Curr Rheumatol Rep 2001; 3: 391. alone.6 Genetic factors in the infant are 12. Clancy RM, Backer CB, Yin X, Chang MW, Cohen SR, Lee LA, Buyon JP. Genetic association of cutaneous also believed to play a large role in the neonatal lupus with HLA class II and tumor necrosis development of cutaneous lesions. In one factor[alpha]: Implications and pathogenesis. Arthritis Rheum 2004; 50: 2598-2603. study, the -308A allele, HLA-DRQB1*02, 13. Gray K. Neonatal lupus erythematosus associated with and HLA-DRB1*03 were detected in a breast milk autoantibodies. J Am Acad Dermatol 2007; 56: AB155. majority of NLE infants with rash. Also, prominent tumor necrosis factor[alpha] staining was observed in the epidermis of lesional skin, thus supporting the notion that this inflammatory cytokine plays a role in the pathogenesis of cutaneous neonatal lupus, and providing evidence of a biologic link between NLE and subacute cutaneous lupus erythematosus (SCLE).12 Treatment of the cutaneous lesions of NLE is usually not required given the self- limiting nature of the rash, and no signifi- cant difference in outcome between treated and untreated children has been observed. For those children whose rash was treated, only low-to-mid-potency topical steroids were used.5 Ultraviolet protection and avoidance should be stressed, as many patients’ rashes were reported as exacer- bated after exposure to UV light.4,5,12 In one case report, delayed resolution of the cutaneous eruption was attributed to the high levels of IgA and IgG anti-nuclear and anti-Ro antibodies detected in the patient’s mother’s breast milk.13 In one retrospective review, by Neiman et al., of cutaneous-only NLE patients enrolled in a national registry, four of 57 affected children later developed signs or symptoms of autoimmune disease. Because the development of a rheumatic disease later in childhood or adolescence can occur, NLE patients warrant long-term follow-up. Mothers of children with cuta- neous NLE should undergo serial echocar- diographic monitoring of the fetus during subsequent pregnancies, as the crossover from rash to congenital heart block has been well documented.5

References: 1. Draznin TH, Esterly NB, Furey NL, DeBofsky H. Neo- natal lupus erythematosus. J Am Acad Dermatol 1979; 1:437. 2. Watson R, Kang JE, May M, Hudak M, Kickler T, Provost T. Thrombocytopenia in the neonatal lupus syndrome. Arch Dermatol 1988; 124:560-3. 3. Laxer RM, Roberts EA, Gross KR, Britton JR, Cutz E, Dimmick J, et al. Liver disease in neonatal lupus erythe- matosus. J Pediatr 1990; 116: 238-42. 4. Weston WL, Morelli JG, Lee LA. The clinical spectrum of anti-Ro-positive cutaneous neonatal Lupus erythemato- sus. J Am Acad Dermatol 1999; 40: 675-81. 5. Neiman AR, Lee LA, Weston WL, Buyon JP. Cutaneous manifestations of neonatal lupus without heart block: Characteristics of mothers and children enrolled in a national registry. J Pediatr 2000; 137: 674-80. 6. Cimaz R, Spence DL, Hornberger L, Silverman, E. Inci- dence and spectrum of neonatal lupus erythematosus: A prospective study of infants born to mothers with anti-Ro autoantibodies. J Pediatr 2003; 142: 678-83. 7. McCuiston CH, Schoch EP. Possible discoid lupus ery- thematosus in a newborn infant. Arch Dermatol 1964; 70: 782-5. 8. High WA, Costner MI. Persistent scarring, atrophy, and FOLEY, SIKORSKI, MAHON 19 A SORE THUMB

Allison Schwedelson, D.O.,* Stanley Skopit, D.O., F.A.O.C.D.** *Dermatology Resident, 2nd year, NSU/Broward General Medical Center **Program Director, NSU/Broward General Medical Center

ABSTRACT

Chilblains, also called pernio or perniosis, are localized inflammatory lesions caused by continued exposure to cold above the freezing point.1 There is an erythrocyanotic discoloration of acral skin accompanied by itching or burning.2 Chilblains need to be distinguished from chilblains lupus erythematosus and cold-sensitive blood dyscrasias.2 Preventive measures are important in the management of patients with this condition.

Case Presentation be due to underlying myelomonocytic leukemia, dysproteinemias, anorexia An 82-year-old female living in Florida nervosa, macroglobulinemia, cryo- presented with redness and mild pain of globulinemia, cryofibrinogenemia, cold her right thumb for two months duration. agglutinins, antiphospholipid antibody The patient denied trauma or history of syndrome, Raynaud’s disease, and drug similar symptoms. The other fingers were reactions.3 Sulindac-induced cases have not affected. The patient had an X-ray of been reported.3 the right thumb that showed osteoarthritis Pernio presents with single or multiple and no foreign body. Past medical and erythematous or violaceous papules or family history was non-contributory. nodules. Blistering or ulceration may be Physical examination revealed a well- present. The most common locations are developed, well-nourished elderly female. the distal fingers and toes; less common Figure 1 Examination of the patient’s hands revealed locations are the nose, ears, and heels. a distal right thumb with erythema, edema, Lesions may be accompanied by pruritus and induration that was mildly tender to and a burning sensation.2 Purpuric lesions palpation (Images 1, 2 and 3). There was are not uncommon. Lesions will typically no fluctuance or discharge present. During resolve in one to three weeks. In some, the exam, several of the patient’s fingertips lesions may persist and become chronic, turned white and then returned to their especially in the elderly with venous stasis. natural color. This condition should be distinguished Histopathology of a representative biopsy from other cold-induced syndromes, demonstrated focal interface dermatitis, including chilblains lupus erythematosus intravascular thrombus and a very promi- and cold-sensitive blood dyscrasias.2 The nent superficial and deep infiltrate with latter can be assessed by laboratory evalu- ation: CBC to rule out hemolytic anemia chronic hidradenitis. There were areas of Figure 2 fibrin deposition and a thrombus in one and leukemia; cryoglobulin, cold agglu- of the superficial blood vessels. There were tinin, and cryofibrinogen to rule out diffuse changes of venous vasculopathy. cold-sensitive dysproteinemia; and serum Acid-fast bacillus was negative. Findings protein electrophoresis and quantitative were consistent with chilblains (chronic immunoglobulins to rule out a monoclonal pernio). gammopathy causing an increase in serum 2 The following laboratory studies were viscosity. A false negative cryoprecipitate ordered and found to be within normal may occur, and therefore evaluating the patient for hepatitis C antibody or rheuma- limits: Factor V Leiden, cryoglobulin, plate- toid factor may be prudent in select cases. lets, ESR, ANA, homocysteine, RPR, cryo- fibrinogen, factor IX, protein C, protein S, Depending on the history and physical lupus anticoagulant, and PTT. The diag- presentation, other differentials may nosis of chronic chilblains associated with include: septic or atheromatous embolism, Raynaud’s phenomenon was determined. erythrocyanosis, erythromelagia, erythema Figure 3 multiforme, granuloma annulare, acro- cyanosis, polycythemia vera, hypersen- best prevents pernio. There is anecdotal Discussion sitivity vasculitis, sarcoidosis, and cold evidence in the literature of treatment with Chilblains are an abnormal inflamma- panniculitis.4 systemic and topical steroids, vasodilators, tory and vascular response to cold or damp Chilblains have a nonspecific histology 3 consisting of papillary dermal edema and a IV calcium followed by IM vitamin K, and conditions. It shows a genetic predisposi- 6 tion and has been described most often superficial or superficial and deep perivas- ultraviolet B radiation. The treatment of in temperate regions, where winters are cular infiltrate comprised primarily of choice for symptomatic chilblains is nife- occasionally cold and damp.1 It is more lymphocytes.2 Necrotic keratinocytes and dipine 10mg to 20mg three times daily for common in women, children, and people lymphocytic vasculitis have been noted.5 adults.7 Common side effects are head- with a low body mass.1 Chilblains can Keeping affected areas warm and dry ache, nausea, and facial flushing, which can 20 A SORE THUMB be troubling to some patients.1. In cases of crippling severity, thyrocalcitonin and hemodilution may be helpful.1 In summary, our patient’s case exempli- fies chronic chilblains due to abnormal microvascular disease as evidenced by Raynaud’s phenomenon, which presented itself on physical exam. A patient who resides in Florida, and is not exposed to damp, cold environments where this condi- tion is most commonly seen, should arouse suspicion for other possible causal factors. In typical chilblains, the most impor- tant point in management is prophylaxis with adequate, loose, insulating clothing and appropriately warm housing and workplace.1

References:

1. Freedberg IM, Eisen AZ, Wolff K, Austen KF, Goldsmith LA, Katz SI. Fitzpatrick’s Dermatology in General Medi- cine 2003;1216-7. 2. Bolognia, J., Jorizzo, J., Rapini. Dermatology 2003;1392. 3. McKee, Philip H., Calonje, Eduardo, Granter, Scott. (2005) Pathology of the Skin with Clinical Correlation. 274-275. 4. Cribier B, Djeridi N, Peltre B, Grosshans, E. A histologic and immunohistochemical study of chilblains. J Am Acad Dermatol 2001;45:924-9 5. Page EH, Shear NH. Temperature-dependent skin disor- ders. Journal of the American Academy of Dermatology. 1988; 18:1003-19. 6. Jacob JR, Weisman MH, Rosenblatt SI, Bookstein JJ. Chronic pernio. A historical perspective of cold induced vascular disease. Arch Inter Med 1986;146:1589-92. 7. Rustin MH, Newton JA, Smith NP, Dowd PM. The treatment of chilblains with nifedipine: The results of a pilot study, a double blind placebo-controlled random- ized study and a long term open trial. Br J Dermatol 1989;120:267-75.

SCHWEDELSON, SKOPIT 21 FORMALDEHYDE AND FORMALDEHYDE-RELEASING PRESERVATIVE INDUCED ALLERGIC CONTACT DERMATITIS

Kevin DeHart, D.O.,* Richard Miller, D.O.** *Dermatology Resident, PGY-4, Sun Coast Hospital/NOVA Southeastern University **Program Director, Dermatology Residency, Sun Coast Hospital/NOVA Southeastern University

ABSTRACT

Allergic contact dermatitis (ACD) is a frequently encountered skin condition and is secondary to innumerable exogenous allergens. While the inciting allergen is not always revealed, some allergens demonstrate classic skin reactions, and pertinent patient history is often helpful to the clinician. Formaldehyde and formaldehyde-releasing preservatives (FRPs) are common, albeit under-diagnosed, causes of allergic contact dermatitis. We present a case of allergic contact dermatitis in a patient sensitive to her formaldehyde- and FRP-treated wrinkle-resistant clothing. Allergen avoidance resulted in complete resolution of her skin condition. We will discuss pertinent facts related to ACD secondary to formaldehyde and FRPs, specifically quaternium-15, as well as diagnosis and prevention of this skin condition. Case Report Table 1 An 83-year-old female presented to the Common Formaldehyde Uses dermatology office complaining of pruritus (Adapted from Contact and Occupational of a three-month duration involving both Dermatology, 3rd edition, pg 92.) her upper and lower extremities. Five t
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22 FORMALDEHYDE AND FORMALDEHYDE RELEASING PRESERVATIVE INDUCED ALLERGIC CONTACT DERMATITIS Dermatitis Group study of cosmetic reac- over-the-counter topical medications, as Table 2 tions. Allergic reactions to quaternium-15 well as in cosmetics and household prod- Common Quaternium-15 Uses are quite common in the United States ucts. Formaldehyde- and FRP-treated (Adapted from Contact and Occupational and the United Kingdom but infrequent in fabrics can pose a problem in any sensi- Dermatology, 3rd edition, pg 92.) parts of Europe because it is not often used tive patient, as in the case we presented. in cosmetic products.3 Quaternium-15 has Pertinent clinical history, physical exam, t
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DEHART, MILLER 23 KAWASAKI DISEASE: CASE REPORT AND REVIEW OF LITERATURE

Yvette A. Tivoli, DO,* Bradley P. Glick, DO, FAOCD** *Traditional Rotating Intern, Palmetto General Hospital, Hialeah, FL **Program Director, Wellington Regional Medical Center Dermatology Residency Program, Wellington, FL

ABSTRACT

Kawasaki disease (KD) is an uncommon syndrome characterized by polymorphous rash involving mucous membranes, high fever, and lymphadenopathy. Early recognition and treatment in the acute phase of this condition is essential to minimize risk of coronary sequelae. A 10-year-old Hispanic male was referred to the emergency department by his pediatrician for evaluation of a generalized rash including palms and soles to rule out suspected Stevens-Johnson syndrome. Complete medical work-up, including history, physical evaluation and laboratory data, resulted in the rendering of a diagnosis of Kawasaki’s Disease. This article will encompass a detailed case report of KD and review of the literature including etiology, epidemiology, diagnostic criteria, differential diagnoses, therapy, prognosis and current outcome of the patient. Case Report The patient was hospitalized for six days. On day one, gallbladder and liver ultra- A 10-year-old Hispanic male was referred sounds were normal. On day two, fever to the emergency department by his pedia- persisted with a maximum temperature of trician the evening of October 30, 2006, 101.9° F, and the patient’s lips were begin- to rule out Stevens-Johnson syndrome. ning to peel. Azithromycin and ibuprofen He presented with persistently high fever were discontinued. The patient was started and a diffuse, generalized rash with bilat- on oral aspirin 650 mg every six hours eral involvement of palms and soles. The and IVIG therapy in titrated fashion. The patient admitted to a burning sensation patient received a total infusion of 170 over affected areas with light touch. Past mg over a 10 to 12 hour period. On day medical history was significant for obesity, four, status post IVIG infusion, the rash reactive airway disease and fatty liver was beginning to clear and the patient Figure 1: Admitting clinical disease. The patient reported no allergies. was afebrile. The patient reported two presentation of palms Review of systems was otherwise unre- episodes of emesis, one episode of diar- markable. Patient medications included rhea, epistaxis of the left nostril probably Singulair and Advair. The only over-the- secondary to nose picking, and anorexia. counter medication, ibuprofen, was given Labs had improved, with CRP 15.93, subsequent to commencement of the rash. ESR 13, WBC 11.4. Echocardiogram was On physical examination, his vital signs negative for evidence of coronary artery showed: blood pressure 138/84 mmHg, HR disease. Aspirin was decreased to 325 mg, 125 beats/min, RR 22 breaths/min, temper- and discharge was postponed for 24 hours ature 102.7°F. Physical findings were posi- pending further observation. On day five, tive for non-purulent bilateral conjunctival the patient remained afebrile with improve- hyperemia, mild pharyngeal erythema ment in rash. The patient continued on and exudates, an erythematous and aspirin 81 mg daily. On day six, he was Figure 2: Admitting clinical edematous tongue, widely disseminated, discharged in the care of his parents and presentation of plantar surface blanchable targetoid lesions, and bilateral told to take the following oral medications palmoplantar macules and papules. The daily: aspirin 81 mg, lansoprazole 30 mg, patient had no cervical lymphadenopathy. and loratadine 10 mg. Palms and soles were sensitive and tender The patient was seen by his pediatrician to touch. 16 days post admission. His hands and Laboratory data demonstrated feet were beginning to peel, but all other elevated WBC 17,000 microliters with symptoms had improved. Labs showed a predominance of neutrophils, slightly improvement: AST 41, ALT 75, ESR 21, elevated prothrombin time 14.8 seconds, WBC 7.7, platelets 465, CRP 0.17. The elevated total bilirubin 2.4, elevated AST patient was told to continue aspirin 81 mg 103 and ALT 145, and elevated ESR 37. daily for one more month. Upon follow-up, Mycoplasma titers were negative. Rapid he had no symptoms. strep test was negative, ruling out Scarlet Figure 3: Admitting clinical Fever. The patient was admitted with a Discussion presentation of anterior lower presumptive diagnosis of viral exanthem vs. extremities Kawasaki disease. Consults were ordered Kawasaki disease (KD), also referred to with cardiology, infectious disease and as mucocutaneous lymph node syndrome, gastroenterology. A dermatology consult is an acute systemic vasculitis that was not ordered. The patient was started predominantly affects children.1 In 1967, on Azithromycin 900 mg IV and ibuprofen Dr. Tomisaku Kawasaki first developed 600 mg every six hours. clinical diagnostic criteria, prior to which

24 KAWASAKI DISEASE: CASE REPORT AND REVIEW OF LITERATURE pathogens include staphylococci, strepto- cocci, bacterial rickettsiae, Epstein-Barr virus, parvovirus, retrovirus, Candida albi- cans, herpes virus-6, and even mycoplasma pneumoniae10, which has been cited in French literature. Review of the literature demonstrates no conclusive putative agent. There has also been speculation of an association with house dust mites, deter- gents, or chemicals.11 An article published in the British Journal of Medical Science reported possible association between Figure 4: Admitting clinical anionic detergents in carpet shampoo after presentation of posterior lower the 1982 outbreak of KD in Colorado. It extremities suggested that the anionic detergents in the shampoo provoked a hypersensitive reaction ultimately manifesting as KD. The other possibility was that a causative agent underwent aerosolization and subse- quent inhalation upon the carpet cleaning process. A subsequent study published by Rogers et al. in 198512 was unable to Figure 7: Clinical presentation at establish a similar link, and thus these admission (upper photo) and clinical proposed theories remain in doubt. The presentation after IVIG therapy (lower same article [Lloyd, A.J. et al, Kawaski photo) Disease: is it caused by an infectious agent?, Figure 5: Admitting clinical British Journal of Biomedical Science, presentation of the posterior torso Systemic vasculitides tend to affect the 2001, 58:122-128.] also noted the house elderly and the young. In the elderly, mite as a proposed allergen, suggesting large-vessel disease will occur, as seen in it may be a vector for potentially infec- giant-cell arteritis and primary systemic tious agents (e.g. Propionibacterium vasculitis, whereas in children there is a acnes) implicated in KD, although this predilection for coronary vessels.3 These too remains undetermined. The same vasculitic changes subsequently lead to was concluded for proposed links between formation of coronary artery aneurysms chemicals in standing bodies of water and and possibly myocardial infarction and mercury poisoning. None of these associa- death. tions has been irrefutably established in the literature.13 Acute symptoms of KD are considered self limited, but because of the aforemen- One immune-mediated mechanism that Figure 6: Clinical improvement after tioned pathogenesis it is important to has been examined is that of the superan- IVIG therapy diagnose and treat patients early in the tigen theory. Strains of Staphylococcus acute phase of the disease. KD has become aureus that express toxic shock syndrome toxin-1 (TSST-1) have been isolated in this disorder was typically diagnosed post the leading cause of acquired heart disease Kawasaki disease. These superantigens mortem. The criteria include a fever for a in children in North America and Japan, activate large numbers of T cells, specifi- minimum of five days along with four out and is increasingly recognized as a world- cally T-cell receptor V beta segments. of five of the following signs: bilateral non- wide problem.4 Eighty percent of children These TCR V beta segments demonstrate purulent conjunctivitis, oral or pharyngeal affected are less than five years old, with T-cell expansion consistent with superan- erythema (e.g. cheilitis, strawberry tongue), peak incidence seen in children approxi- tigen-driven T-cell proliferation.14,15 A case acute hand and foot edema, generalized mately one year old. However, there have 5 report of guttate psoriasis after Kawasaki polymorphous skin rash, and cervical been reports in older children and adults. disease reported in the British Journal of lymphadenopathy. It is important to note Incidence of KD is highest in Japan, at Dermatology is just one incidence that may there is no specific diagnostic test for KD, >100/100,000 children less than five years corroborate this theory. Guttate psoriasis and therefore the emphasis remains on the of age. Reported incidence rates are lower has been suggested partly to result from clinical presentation and combination of in the USA at 9.2, in South Korea at >45, toxin-mediated T-cell activation. the constellation of previously described Australia at 3.7 and the UK at 3.4 per Another interesting development has symptoms. Skin biopsy for histopatho- 100, 000, according to a recent Australian been the isolation of New Haven coro- logical findings is often not performed, Pediatric Surveillance Unit study.6 These navirus (HcoV-NH) in respiratory secre- as KD is diagnosed clinically. Typically, rates do not include any atypical cases tions of KD patients. A study conducted the histopathology of KD is nonspecific without cardiac complications. Prevalence by Esper et al. established a positive asso- and demonstrates small dermal vessels is higher among boys than girls, with a ciation between this virus and KD.16 This with perivascular mononuclear infiltrates, ratio of 1.3-1.7:1. While children from all study suggested that patients with certain edema and dilatation.2 ethnic backgrounds can develop this condi- genetic backgrounds may be predisposed All systemic vasculitides cause inflamma- tion, incidence remains highest among to such a viral infection and development tion and necrosis of blood vessel walls. The those of Asian descent. of KD. More research is needed, however, key difference in clinical manifestations The etiology of KD has not been eluci- to confirm the presence of the virus in will depend on the size of the blood vessel dated; however, several sources suggest Kawasaki disease. affected, the number of blood vessels, and genetic predisposition, infectious causes7,8 The incidence of KD among siblings is more importantly the site of the vessels. or immunogenic causes.9 Postulated high and thus suggests a genetic component TIVOLI, GLICK 25 that makes individuals susceptible to devel- KD patients (non-responsive to two IVIG 16. Esper F, Shapiro ED, Weibel C, et al. Association between a novel human coronavirus and Kawasaki dis- opment of the condition. Atopic disease infusions). Results were not in favor of ease. Journal of Infectious Disease, 2005;191;499-502. has also been studied because it shares this therapy, as one patient had a satisfac- 17. Wang, Chih-Lu, et al. Kawasaki disease Infection, Immu- nity and Genetics. The Pediatrician Infectious Disease immunoregulatory abnormalities with KD. tory outcome while the other developed Journal, Volume 24, Number 11, p.1002, November The following studies reveal specific abnor- giant coronary aneurysms and suffered a 2005. 18. Furukawa, S. et al, Increased Expression of FceR2/CD23 malities associated with atopy: A study by myocardial infarction two months after on Peripheral Blood B Lymphocytes and Serum IgE Lev- Matsuoka et al. demonstrated that positive onset of illness. Studies were performed els in Kawasaki disease. Int Arch Allergy Appl Immunol. 1991;95:7-12. family history of allergy was more common on 73 patients with mixed results, but still 19. Tang, RB et al. The significance of mite antigens in in children with KD than in the control showed that corticosteroid therapy should Kawasaki disease. Zhonghua Min Guo Wei Sheng Wu Ji 17 Mian Yi Xue Za Zhi. 1987,;20:29-36. patients ; Furukawa et al. demonstrated be considered a feasible alternative in 20. Matsubara, T et al, Decrease Interferon gamma produc- that there were increased levels of CD23+ patients who have refractory KD and have ing T cells in patients with acute Kawasaki disease. Clin 26 Exp Immunol 1999;116:554-557. B lymphocytes and serum IgE during the failed two infusions of IVIG of 2g/kg. 21. Tulloh, RM, Wood LE. Coronary artery changes in latter part of the acute stage of KD18; a patients with Kawasaki disease. [Review] Acta Paediat- If a clinician has a high index of suspi- rica Supplement 93(446):76, 2004, Dec. study by Tang et al. showed a correlation cion for Kawasaki disease, even in the 22. Royle, J, et al. The diagnosis and management of Kawa- between an anti-Dermatophagoides ptero- absence of all the previously ascribed saki disease. [Review] Journal of Paediatrics & Child 19 Health. 41(3):87-93, 2005 Mar. nyssinus specific IgE ; and Matsubara et features of this condition (e.g. in the setting 23. Dong Soo, Kim. Kawaski Disease [Review]. Yonsei al. indicated a decrease in the number of Medical Journal, Vol.47, p.767, No.6, 2006. of a child with high fever, polymorphous 24. Freeman, A. and Shulman, S., Recent developments in interferon-gamma producing T cells but rash, and elevated CRP and ESR levels), Kawasaki disease. Current Opinion in Infectious Dis- not the interleukin-4 producing cells in treatment should be instituted immedi- eases, 14:357-361, 2001. 20 25. Royle, J, et al. The diagnosis and management of Kawa- acute stages of KD. ately. An initial echocardiogram should be saki disease.[Review] J. Paediatr. Child Health 41, 87-93, 2005. Kawasaki disease is typically a diag- performed and then redone at six to eight 26. Hung, JJ, Chiu, CH. Pulse methylprednisolone therapy nosis of exclusion once differentials have weeks at follow-up. It has also been recom- in the treatment of immune globulin-resistant Kawasaki disease: case report and review of the literature [Review]. been ruled out. This will often require a mended that the patients undergo annual Annals of Tropical Paediatrics. 24(1):89-93, 2004 Mar. battery of tests to eliminate the possibility echocardiogram at one and two years after 27. Freeman, Alexandra, et al. Kawasaki disease: summary 27 of the American Heart Association guidelines.[Review]. of Scarlet Fever, Staphylococcal scalded initial onset of illness. Further infor- American Family Physician 74(7):1149-50, 2006 Oct 1. skin syndrome, Stevens-Johnson syndrome, mation can be provided to the families of toxic shock syndrome, measles, juvenile these patients via the Kawasaki Foundation rheumatoid arthritis, and drug reactions. on the Internet. The website is www. Untreated cases of KD or those treated KDfoundation.org. with aspirin alone can lead to coronary In summary, we have presented a patient lesions in as many as 20-40% of patients.21, manifesting the acute phase of KD, treated 22, 23, 24 These percentages vary depending with intravenous immunoglobulin and on the literature. Given this potential prog- high-dose aspirin, discharged from the nosis, it is paramount to treat patients early hospital, and following up with his pedia- and possibly avoid the coronary sequelae. trician. One year later he continues to do KD is treated with high-dose aspirin for well. His labs to date have normalized, and its anti-inflammatory properties. Aspirin his most recent echocardiogram has been is administered at levels of 80-100 mg/ negative for coronary artery aneurysm kg/day, and subsequently reduced once formation. fever has abated. Reduced levels of aspirin are given for its anti-platelet properties References at levels of 3-5mg/kg/day once daily and 1. Bolognia, Rappini, et al Dermatology. Vasculitis. Elsevier continued for six to eight weeks until a Publishing ; 2003 p.395- 396 2. Bolognia, Rappini, et al Dermatology. Vasculitis. Elsevier follow-up echocardiogram is performed. Publishing ; 2003 p.395- 396. Concurrent administration of intravenous 3. Lane, SE, et al. Epidemiology of systemic vasculitis. [Review] Current Rheumatology Reports. 74(4):270-5, immunoglobulin (IVIG) is given at 2g/kg 2005 Aug. infused over a 10-hour period. The role 4. Freeman, Alexandra and Shulman, Stanford, Recent Developments in Kawaski Disease. Current Opinion in of IVIG is unclear, but it is suggested that Infectious Diseases 14:357-361, 2001. it may provide passive immunity to the 5. Bolognia, Rappini, et al Dermatology. Vasculitis. Elsevier Publishing ; 2003 p.395- 396 causative antigen(s) and have non-specific 6. Royle, J, et al. The diagnosis and management of Kawa- immunomodulatory effects.25 Opinions saki disease.[Review] J. Paediatr. Child Health 41, 87-93, 2005. vary on response to therapeutic preven- 7. Lloyd, AJ, Walker C. Wilkinson M. Kawasaki disease tion of coronary artery aneurysms. Data is it caused by an infectious agent? British Journal of Biomed Science 58:122-128, 2001 reported in the current literature indicates 8. Bolognia, Rappini, et al Dermatology. Vasculitis. Elsevier that treatment usually reduces the forma- Publishing ; 2003 p.395- 396. 9. Wang, Chih-Lu, et al. Kawasaki disease Infection, Immu- tion of coronary artery aneurysms to nity and Genetics. The Pediatrician Infectious Disease 4-8%.21, 22, 23, 24 Journal, Volume 24, Number 11, November 2005. 10. Merlin, E. Al Fatuhi, H. Crost, P. Kawasaki Syndrome and Corticosteroids have long been used Mycoplasma Pneumoniae infection. Arch Pediatr 11:972- to treat systemic vasculitides, yet their 973, 2004. 11. Lane, SE, et al. Epidemiology of systemic vasculitis. use in the treatment of KD remains a [Review] Current Rheumatology Reports. 74(4):270-5, subject of debate. Use of corticosteroids 2005 Aug. 12. Rogers, MF et al, Kawasaki Syndrome: is exposure to rug as therapeutic agents in the management shampoo important? Am J Dis Child, 139:777-9, 1985. of KD compared to the management of 13. Lloyd, AJ, Walker, C and Wilkinson, M., Kawasaki dis- ease: is it caused by an infectious agent?, British Journal other systemic vasculitides is contro- of Biomedical Science, 58:122-128, 2001. versial. Corticosteroids may adversely 14. Wang, Chih-Lu, et al. Kawasaki disease Infection, Immu- nity and Genetics. The Pediatrician Infectious Disease affect outcome by causing progression of Journal, Volume 24, Number 11, p.1000, November coronary lesions. A case report in 2004 2005. 15. Rodriguez-Pla, Alicia, Stone, John H. Vasculitis and studied the use of pulse methylpredniso- systemic infections. [ Review] Current Opinion in lone (30mg/kg) in two refractory cases of Rheumatology. 18(1):39-47, 2006 Jan.

26 KAWASAKI DISEASE: CASE REPORT AND REVIEW OF LITERATURE The 2009 South Beach Symposium Faculty to include: Join us in Miami Beach... (Partial List) Symposium Chair Mark S. Nestor, MD, PhD

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WEB Any questions regarding this meeting please call 904-309-6262 SUBCUTANEOUS SARCOIDOSIS: A CASE REPORT

Andrea Passalacqua, D.O.,* Ronald Liskanich, D.O.,** David Horowitz, D.O.*** *3rd-year Dermatology Resident, Western University/Pacific Hospital of Long Beach, Long Beach, CA **Dermatology Residency Co-Program Director at Western University/Pacific Hospital of Long Beach, Long Beach, CA ***Dermatology Residency Program Director at Western University/Pacific Hospital of Long Beach, Long Beach, CA

ABSTRACT

Subcutaneous sarcoidosis, previously known as Darier-Roussy sarcoid, is rarely reported. Lesions are commonly found on the trunk or the extremities and present as non-tender, firm, flesh-colored or violaceous nodules that are 0.5-2 cm in diameter. These patients often do not have any systemic involvement. Subcutaneous sarcoidosis is a diagnosis of exclusion; therefore, tests and special stains must be performed to rule out other granulomatous diseases. Oral corticosteroids are the mainstay of therapy. We present a case of subcutaneous sarcoidosis and discuss its clinical presentation, recommended diagnostic tests and treatment options.

Case Report and abdomen were within normal limits. A Gallium scan performed on the whole A 65-year-old Hispanic female presented body showed no focal abnormal activity. with a seven-year history of having a large, Two separate venous Doppler exams of erythematous plaque on her right leg the right lower extremity demonstrated no measuring 4 cm in diameter. She denied evidence of deep venous thrombosis. An any history of ulcers or any discharge. Her ophthalmologic examination only showed primary care physician previously treated early cataract and presbyopia. her with antibiotics for cellulitis without Various therapies were instituted over improvement. As the plaque continued several months including terbinafine, to expand, the erythema intensified to a clobetasol 0.05 percent ointment, rifampin, wine-colored, slightly raised lesion that doxycycline, minocycline, and injections was tender, swollen, and warm to the of triamcinolone 5mg/cc to the subcuta- Figure 1: Erythematous to violaceous, touch. Imaging was done to rule out a neous nodules. The erythema on her right slightly elevated plaque with some DVT after her right leg was noted to be leg fluctuated in intensity, but never fully nodularity on the right leg larger in circumference. Past medical resolved. Because of her history of border- history included hypertension, arthritis, line diabetes, she was placed on plaquenil, and borderline diabetes. She was a retired which demonstrated significant improve- window-factory worker who handled ment initially. Prednisone was then aluminum and other metals for 20 years. added at a low dose. The combination of The patient had no significant family Plaquenil and prednisone seem to keep the history of skin disease. erythema, nodularity, and thickness of the On physical examination, the patient was plaque under relative control. The patient found to have an erythematous to viola- will continue to be monitored with serum ceous, slightly elevated plaque with some ACE levels periodically. nodularity measuring 16 cm x 10 cm on the right lower leg (Figure 1). She had +1 Disucssion pitting edema on the right leg and minimal edema on the left leg. Her right leg was Sarcoidosis is a systemic granulomatous slightly tender to the touch. disease that affects the skin in approxi- A 3mm punch biopsy showed sections mately 25% of cases. Internal organs may sparing the upper dermis; epithelioid be involved as well, including the lungs, tubercles incompletely surrounded mediastinal and peripheral lymph nodes, by lymphocytes; and fibroplasias of the eyes, phalangeal bones, myocardium, subcutis consistent with a granulomatous central nervous system, kidneys, spleen, inflammation (Figure 2, 3). Acid-fast liver and parotid gland. Sarcoidosis cultures, as well as fungal cultures, were occurs worldwide and affects both men negative. The patient was diagnosed with and women. However, it seems to be subcutaneous sarcoidosis. most prevalent among African American Figure 2: Biopsy at 5x magnification showing the upper dermis spared Complete blood count, complete meta- women.1 A bimodal age distribution is bolic panel, and rheumatoid factor were seen, with peaks between ages 25-35 within normal limits. Her cholesterol, trig- and 45-65 years. The exact etiology of lycerides, antinuclear antibody (ANA) titer, sarcoidosis is unknown; however, the cell- angiotensin-converting enzyme (ACE) level mediated immune system appears to be and erythrocyte sedimentation rate (ESR) involved.2 Genetics and environmental were slightly elevated. factors are also thought to contribute in Chest X-rays showed cardiomegaly but the disease process.3 Since the cutaneous no acute pulmonary disease. CT of chest manifestations are so varied and it can have PASSALACQUA, LISKANICH, HOROWITZ 29 almost any morphology, sarcoidosis is often costeroids can also be useful in treating known as the “great imitator.” Variants cutaneous lesions. Therapy is guided by the include subcutaneous, lupus pernio, and severity of the disease and its progression. ulcerative.4 Hydroxychloroquine and chloroquine can Subcutaneous sarcoidosis was first be effective in controlling chronic disease. described in 1906 by Darier-Roussy and Other treatment options include: metho- is considered a rare, specific subtype of trexate, thalidomide, isotretinoin, mino- nodular cutaneous sarcoidosis. The cycline, and allopurinol.4 Radiation has nodules were often referred to as Darier- also been used to treat resistant cutaneous Roussy sarcoid, but the eponym is consid- lesions.3 Since subcutaneous sarcoidosis ered nonspecific because it was used to is rare, many of the treatment options are describe many subcutaneous inflammatory based upon few reported cases.5 Consults disorders.5 The lesions of subcutaneous from other specialists, such as an ophthal- sarcoidosis are typically non-tender, firm, mologist, an internist, and a pulmonologist, mobile, flesh-colored or violaceous nodules are recommended to rule out and monitor that range in size from 0.5-2 cm in diam- other organ involvement.3 eter, usually on the trunk or extremities.3 It represents sarcoidosis limited to the subcu- REFERENCES: taneous tissue, since it does not involve the 1. James, WD, et al. Sarcoidosis. Andrews’ Diseases of the epidermis.4 In order to make the diagnosis Skin, Clinical Dermatology Tenth edition. Canada. Saun- ders; 2006. pp.708-713. of subcutaneous sarcoidosis, a biopsy is 2. Braverman IM. Sarcoidosis. In Freedberg IM et al editors. required.1 Fitzpatrick’s Dermatology in General Medicine 6th edition. New York. McGraw-Hill; 2003. pp. 1777-1783. Histopathologically, subcutaneous 3. Gould, KP. eMedicine: http://www.emedicine.com/derm/ topic381.htm, Accessed May 12, 2008. sarcoidosis is demonstrated by epithelioid 4. Bolognia JL, et al. Sarcoidosis. Dermatology 1st edition. cell tubercles in the subcutaneous fat. The London. Mosby; 2003. pp.1455-1460. 5. Heller M, Soldano AC. Sarcoidosis with subcutaneous epithelioid granulomas have minimal or lesions. Dermatology Online Journal 2007; 14(5):1. absent lymphocyte or plasma cells associ- 6. Marcoval J, et al. Subcutaneous sarcoidosis-clinico- pathological study of 10 cases. Br J Dermatol 2005; ated with them and are known as “naked” 153(4):790-794. tubercles. Central caseation is usually absent, and multinucleated histiocytes are usually present.4 Biopsy specimens may need special stains to rule out infectious causes of granuloma formation, including mycobacterial and deep fungal infections.3 The diagnosis of subcutaneous sarcoi- dosis is a diagnosis of exclusion, both clinically and histologically. In order to make the diagnosis, the clinical history should be supported by the presence of non-caseating granulomas in at least one organ system.4 Subcutaneous sarcoidosis usually indicates a form of sarcoidosis with non-severe systemic involvement and is not associated with chronic fibrotic disease.6 Recommended laboratory studies include complete blood count with differential, serum calcium and 24-hour urine calcium levels, serum ACE level, serum chemis- tries, ESR, and ANA titers. Imaging studies recommended include chest radiography, CT of thorax, and whole body gallium Ga 67 scanning. ACE level can be used to monitor the progression of the disease.3 The differential diagnosis for sarcoidosis is extensive and includes multiple infectious causes that lead to granulomatous inflam- mation. Since sarcoidosis is a diagnosis of exclusion, other dermatologic condi- tions that need to be considered include: granuloma annulare, necrobiosis lipoidica, annular elastocytic giant-cell granuloma, rheumatoid nodules, Crohn’s disease, gran- ulomatous mycosis fungoides, granuloma- tous rosacea, tuberculoid leprosy, and lupus vulgaris. Other histiologic mimics include foreign-body reactions to zirconium, beryl- lium, silica, and tattoo ink.4 The mainstay of therapy is oral corticos- teroids.5 Topical and intralesional corti- 30 SUBCUTANEOUS SARCOIDOSIS: A CASE REPORT PIGMENTED SQUAMOUS CELL CARCINOMA OF THE SKIN: A CASE REPORT AND REVIEW OF THE LITERATURE

R. Keller, D.O.,* Don A. Anderson, D.O., F.A.O.C.D., F.A.S.M.S.** *Second-year Resident, Arizona College of Osteopathic Medicine, Midwestern University of Health Sciences, Kingman, AZ **Program Director, Arizona College of Osteopathic Medicine, Midwestern University of Health Sciences, Kingman, AZ

ABSTRACT

Pigmented squamous cell carcinoma is a rare neoplastic entity that is easy to confuse both clinically and histologically with malignant melanoma. Misdiagnosis as melanoma portends a more severe prognosis and leads to unnecessary treatment and work-up. We describe what appears to be first case in the literature of a poorly differentiated, pigmented squamous cell carcinoma with basaloid features, as well as a review of the English literature. Recommendations are made for future characterization and understanding of why melanocytes colonize squamous cell carcinomas.

Case Report plump dendritic melanocytes on histology. The specimen from the Mohs case demon- A 78-year-old Caucasian male presented strated infiltrative and expansile nests and with a 30 mm erythematous and centrally cords of atypical and poorly differenti- ulcerated plaque to his left temple with ated basal-squamoid cells with focal single an overlying dried hemorrhagic crust. cell necrosis and a background desmo- The patient’s primary care physician had plastic response. Numerous melanophages performed cryosurgery to the area “many and pigmented dendritic melanocytes times” prior to its evaluation by a derma- were associated with the proliferation. tologist. A shave biopsy was performed, Sub-optimal fixation of the original biopsy and upon lifting the lesion off the temple a was questioned, and the immunohis- black nodule was noted within the dermis. tochemistries were repeated. Anti-S-100 A punch biopsy was performed on the and anti-MART-1 confirmed the presence Figure 1 Clinical PSCC at Mohs underlying black nodule. of innumerable, focally enlarged dendritic Biopsy sections revealed a nodular melanocytes diffusely spread throughout and reticulated, sheet-like dermal prolif- the cellular proliferation. A few cords eration of neoplastic cells with basaloid and nodules of the tumor cells show rela- morphology, extracellular keratin forma- tive lack of proliferation of the dendritic tion and mucin production. Some of the melanocytes. tumor cells contained brown pigment Similar to the initial biopsy, anti- within their cytoplasm, suggestive of pancytokeratin (AE1/AE3) did not reveal melanin pigment. Scattered mitotic figures significant immunoreactivity within the were seen as well as epidermal ulceration. tumor cells. Anti-cytokeratin 5/6 revealed Immunohistochemical staining was nega- focal cytoplasmic immunoreactivity within tive with S-100, ruling out melanoma. The a few cords of malignant cells, scattered findings were consistent with an invasive single cells and areas of keratinization. carcinoma with features of both basal and Anti-Ber-EP4 demonstrated a weak but squamous cell carcinoma. Additional relatively diffuse membranous immunore- immunohistochemistries demonstrated activity within the tumor cells. The immu- focal positivity with BCL-2, cytokeratin nohistochemistries support the diagnosis Figure 2 Dendritic Melanocytes 5/6 and Ber-EP4, and negative EMA. The of a baso-squamous infiltrative and poorly- added immunohistochemistries and the differentiated carcinoma with numerous morphogy are most consistent with a basal intralesional dendritic melanocytes. No recognize melanin, Becker reported three cell carcinoma. evidence of melanoma was present, and of 43 cases (7%) as pigmented squamous 13 The patient was referred for Mohs micro- the final diagnosis was that of a pigmented cell carcinomas. Reports as high as 25% 3,11 graphic surgery, but was lost to follow-up squamous cell carcinoma with basaloid exist in the non-English literature. The for 59 days due to his having suffered a features. At the patient’s four-month frequency range of pigmented squamous stroke. At the time of Mohs surgery, the follow-up, he was clinically disease free. cell carcinoma commonly reported in lesion clinically resembled a malignant the literature is 0.01% to 7%.6,11 Of the melanoma, and histologically demonstrated Discussion reported cases of PSCC of the skin, 89% poorly differentiated malignant cells with involve the head.1,3-7,9-12 The other case basaloid and spindloid features. It was Pigmented squamous cell carcinoma reports involve the scrotum8 and chest;2 cleared by Mohs with a final postoperative (PSCC) of the skin is a rare tumor. To however, Becker’s series did not address the defect of 61 mm. The defect was repaired date in the English literature, 21 cases location of the lesions.13 with a full thickness skin graft. affecting the skin have been reported.1-13 The clinical differential diagnosis of The specimen was sent for repeat immu- Morgan et al. calculated the relative pigmented skin lesions include melanoma, nohistochemical analysis due to the lesion’s frequency at 0.01%.6 Seventy-four years pigmented basal cell carcinoma, pigmented clinical appearance and the presence of ago in a small series using a silver stain to Bowen’s disease, capillary thrombosis,

KELLER, ANDERSON 31 from a pigmented basal cell carcinoma by dermoscopy.4 The recommendation of Zalaudek et al. is to include PSCC in the differential diagnosis of pigmented skin lesions with homogenous blue pigmentation.2 Conclusion We describe the case of a pigmented squamous cell carcinoma with basaloid features. This neoplasm appears to follow a similar course to classical SCC with no reported recurrences; however, the reported number of cases is quite small.3,5,6 Future research needs to focus on ultrastruc- Figure 3 Dendritic Melanocytes Figure 5 Pigmented SCC at 10X tural and immunohistochemical analysis of those squamous cell carcinomas with pigmentation to determine the stimulus for melanocytic colonization and pigmentary transfer to the neoplasm.

References 1. Chang CY, Chapman WE, Furdyna JA. Differentiat- ing between squamous cell carcinoma and pigmented squamous cell carcinoma. Ear Nose Throat J. 2005; 84(12): 766-7. 2. Zalaudek I, et al. Dermoscopy Features of Pigmented Squamous Cell Carcinoma: A Case Report. Dermatol Surg. 2004; 30(4 pt 1): 539-40. 3. Jurado I, Saez A, Luelmo J, et al. Pigmented Squamous Cell Carcinoma of the Skin: Report of Two Cases and Review of the Literature. Am J Dermatopathol. 1998; 20(6): 578-81. 4. Ohnishi T, Nakai K, Nagayama T, et al. Pigmented squamous cell carcinoma of the skin. Report of a case with epiluminescence microscopic observation. Br J Der- matol. 2003; 149(6): 1292-3. 5. Kamiya M, Maehara R, Lizuka S, et al. Pigmented Figure 4 Pigmented SCC 4X Figure 6 Pigmented SCC at 40X squamous cell carcinoma with dendritic melanocyte colo- nization in the external auditory canal. Pathol Int. 1999; 49(10): 909-12. dermal hemorrhage, angiokeratoma, cytose melanin granules from the tips of 6. Morgan MB, Lima-Maribona J, Miller RA, et al. Pig- 15 mented squamous cell carcinoma of the skin: morpho- lentigo, melanocytic nevi, seborrheic dendritic melanocytes. [missing a verb logic and immunohistochemical study of five cases. J keratosis and tattoo.6,11 The histologic here, and I don’t know what it’s supposed Cutan Pathol. 2000; 27(8): 381-6. 7. Chapman MS, Quitadamo MJ, Perry AE. Pigmented differential diagnosis includes piloma- to be) Kuwabara et al. described the inti- squamous cell carcinoma. J Cutan Pathol. 2000; 27(2): tricoma, melanoacanthoma, pigmented mate relationship between the neoplasm 93-5. 8. Matsumoto M, Sonobe H, Takeuchi T, et al. Pigmented in-situ SCC, pigmented BCC, melanoma and melanocytic dendritic processes as well squamous cell carcinoma of the scrotum associated with with pseudoepitheliomatous hyperplasia, as the presence of mature melanosomes in a lentigo. Br J Dermatol. 1999; 141(1): 132-6. 9. Mathews A, Abraham EK, Amman S, Nair MK. Pig- squamomelanocytic tumor and pigmented the carcinoma cells with very few premel- mented squamous cell carcinoma of nasal cavity. Histo- porocarcinoma, keratinizing pigmented anosomes.16 Speculation exists as to the pathology. 1998; 33(2): 184-5. 6,11 10. Kossard S, Cook D. Pigmented squamous cell carcino- BCC. mechanism of pigment induction within mas with dendritic melanocytes. Australas J Dermatol. the neoplasm. The possibility of pigment 1997; 38(3). 145-7. Histologically, pigmented squamous 11. Satter EK. Pigmented Squamous Cell Carcinoma. Am J cell carcinoma evolves in broad sheets and induction due to collision with a lentigo Dermatopathol. 2007; 29(5): 486-9. or melanocytic nevus has been proposed.3,8 12. Terada T, Yamagami J, Fugimoto A, et al. Pigmented nodules with abundant eosinophilic cyto- squamous cell carcinoma of the cheek skin probably aris- 6 plasm and prominent intercellular bridges. Other hypotheses include divergent deriva- ing from solar keratosis. Pathol Int. 2003; 53: 468-72. tion of melanocytes from matrix stem cells 13. Becker SW. Melanocytic neoplasms of the skin. Am J It extends into the dermis with cytologic Cancer. 1934; 22: 17-40. atypia, mitotic figures and dyskeratosis and and neoplastic production of a yet-to-be 14. Satomura K, Tokuyama R, Yamasaki Y, et al. Possible produces keratin horn pearls.6,7 Finally, discovered factor inducing migration and involvement of stem cell factor and endothelin-1 in the 5,6 emergence of pigmented squamous cell carcinoma in PSCC is defined by intratumoral melanin proliferation of melanocytes. Satomura oral mucosa. J Oral Pathol Med. 2007; 36: 621-4. et al. demonstrated the increased produc- 15. Jauregui HO, Klintworth GK. Pigmented squamous cell pigment and colonization by dendritic carcinoma of cornea and conjunctiva: A light microscopic, melanocytes with benign cytologic tion of stem cell factor and endothelin-1 histochemical and ultrastructural study. Cancer. 1976; features.4,6,7,11 Immunohistochemistry of in PSCC versus the nonpigmented SCC 38: 778-88. 14 16. Kuwabara H, Uda H, Miyaguchi M, et al. Pigmented pigmented squamous cell carcinoma stain is control. squamous cell carcinoma of the alveolar ridge in the oral mucosa. Oral Surg Oral Med Oral Pathol. 1994; 77: positive for low and high molecular weight Dermoscopy is a useful tool to determine 61-5. cytokeratins and epithelial membrane the characteristics of a pigmented skin 17. Braun RP, Rabinovitz HS, Oliviero M, et al. Dermoscopy 6,7 17 of pigmented skin lesions. J Am Acad Dermatol. 2005; antigen and negative for S-100. Jurado et lesion. Three of the PSCC case reports 52: 109-21. al. noted that some neoplastic cells stained include results from dermoscopic analysis. focally positive for S-100 and HMB-45, Diffuse blue to grey-blue pigmentation is which was speculated to be due to anti- noted, with either blue-grey granular or genic transference or release of soluble grey-brown to slate-blue nodular struc- protein from the cytoplasm of the dendritic tures without peripheral pigment network, melanocytes.3 milia-like cysts, dots, globules, or truncated Jauregui and Klintworh demonstrated vessels.2,4,10 Ohnishi appreciated that the that the squamous carcinoma cells phago- pigmented lesion was indistinguishable

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Keep out of reach of children. MICROBIOLOGY The plasma concentrations of doxycycline achieved with ORACEA during administration (see DOSAGE AND ¥ 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 flora of the oral cavity, skin, intestinal tract, and vagina. 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 inflammatory 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/ 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. 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 significant reduction in sperm velocity. Note that 50 mg/kg/day is Teratogenic effects: 1) Doxycycline, like other tetracycline-class antibiotics, can cause fetal harm approximately 3.6 times the amount of doxycycline contained in the recommended daily dose of ORACEA for a when administered to a pregnant woman. If any tetracycline is used during pregnancy or if the 60-kg human when compared on the basis of AUC estimates. Although doxycycline impairs the fertility of rats patient becomes pregnant while taking these drugs, the patient should be informed of the potential when administered at sufficient dosage, the effect of ORACEA on human fertility is unknown. 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 fibula growth rate section). ORACEA has not been studied in children of any age with regard to safety or efficacy, 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 flora of the colon and may permit overgrowth of clostridia. Nasopharyngitis 13 (4.8) 9 (3.4) Studies indicate that a toxin produced by Clostridium difficile 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 cases, consideration should be given to management with fluids and electrolytes, protein supplementation, and Nasal Congestion 4 (1.5) 2 (0.7) treatment with an antibacterial drug clinically effective against Clostridium difficile 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 Influenza 5 (1.9) 3 (1.1) is not a problem in those with normal renal function, in patients with significantly 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 artificial 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-fitting 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 inflammatory 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 benefit 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 Efficacy beyond 16 weeks and safety beyond 9 months have not been established. discontinued. Administration of adequate amounts of fluid 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 methoxyflurane 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 STAPHYLOCOCCAL SCALDED SKIN SYNDROME IN A PATIENT WITH HIDRADENITIS SUPPURATIVA: A CASE REPORT

Christopher Buckley, D.O.,* Marcus B. Goodman, D.O.,* Stanley Skopit, D.O., FAOCD** *2nd-year dermatology resident, Nova Southeastern University-COM/BGMC, Ft. Lauderdale, FL **Program Director, Nova Southeastern University-COM/BGMC, Ft. Lauderdale, FL

ABSTRACT

Staphylococcal scalded skin syndrome (SSSS) is a rare disease that is part of a spectrum of illnesses precipitated by Staphylococcal infections. It is clinically manifested by a toxin-mediated severe exfoliative dermatitis, which is preceded by an erythematous cellulitis. SSSS typically occurs in infants and children but rarely can occur in adults.1,2 This is a case presentation of SSSS in an adult patient, presumptively secondary to an infectious nidus in underlying chronic hidradenitis suppurativa.

Case Presentation: A 26-year-old African American female presented to the emergency room with a three-day history of progressively wors- ening fever, irritability, and malaise. The patient also complained of recent onset suprapubic pain and swelling with severe tenderness and redness along the abdomen at the site of longstanding hidradenitis suppurativa. She denied any recent medi- cations and reported feeling well until the abrupt onset of the above symptoms. Figure 1 Figure 3 The patient’s past medical history was significant only for longstanding, refrac- tory hidradenitis suppurativa of the axillae and suprapubic area. She had received numerous prolonged antibiotic courses in the past, but she denied any recent treatment for this disease. Family history was negative for any associated diseases or similar reactions. The patient had no known drug allergies, and although she admitted to multiple courses of antibi- otics in the past, she denied any recent medications. Figure 2 Figure 4 Within 24 hours of admission, a general- ized eruption of flaccid bullae occurred intact flaccid bullae present, and the Cutaneous therapy with topical steroids with an abrupt onset of severe hemody- epidermis of intact skin was able to be and emollient-impregnated dressings was namic instability. The patient was trans- easily sheared with slight pressure (positive instituted, with continuation of hemody- ferred to ICU care and subsequently was Nikolsky’s sign). Minimal facial edema was namic and airway support. intubated secondary to declining menta- tion and respiratory compromise. Empiric present, with mild perioral crusting and Histological evaluation of the biopsies antibiotics were initiated, but dermatologic fissuring, but no oral lesions were present. revealed a sharply demarcated zone of consultation was not obtained until gener- Examination of the lower abdomen and cleavage at the stratum granulosum. A few alized desquamation began on day three of groin revealed several erythematous, acantholytic keratinocytes were present hospital admission. eroded nodules with tracting and oozing of with mild dermal edema. Additionally, Physical examination upon dermato- purulent material in the suprapubic area, there was a minimal inflammatory infil- logical consultation revealed an obese, medial buttocks, and gluteal fold. trate with no epidermal necrosis present. dark-skinned female who was being main- Blood cultures obtained at the time of The findings were consistent with the diag- tained with ventilator assistance. She was admission returned positive for methicillin- nosis of SSSS. No organisms were seen, and unresponsive to verbal or physical stimuli resistant Staphylococcal aureus. Cutaneous deep fungal cultures were also negative. and was hemodynamically stabilized with bacterial swab cultures taken at the time Viral swab cultures and repeated bacte- pressor and fluid support. Cutaneously, of admission to unspecified locations were rial cultures of suprapubic, groin, and there was diffuse erythema to the entire negative. Empiric antibiotics were discon- buttocks areas revealed negative findings. body with sparing only of the palms and tinued and replaced with intravenous Due to the above clinical, laboratory, soles, and there was scattered plate-like vancomycin. Two separate 4mm punch and histological findings, a diagnosis of desquamation with a proclivity toward biopsies were obtained from the right arm SSSS was given. The patient was continued intertriginous areas. There were a few and buttocks area for histological analysis. on antibiotic and wound therapy as well BUCKLEY, GOODMAN, SKOPIT 35 as ICU support. Her condition stabilized granular layer. There is bullae formation and then slowly began improving. She was but with the absence of inflammatory infil- eventually weaned off support systems and trate. There is no occurrence of epidermal was discharged approximately two weeks or keratinocyte necrosis or alteration, and after admission without obvious perma- no organisms are present.4,5 nent sequelae. Diagnosis is usually based on typical clinical-presentation characteristics Discussion: supported by histopathological features consistent with SSSS. Bacterial cultures SSSS was first described in 1956 and obtained from the bullae are negative but is part of a spectrum of infectious toxin- may be found positive if taken from the mediated disorders that also includes toxic initiating infectious nidus. Hematologic 3 shock syndrome and bullous impetigo. infection does not usually occur in chil- It is a rare disease that occurs primarily dren, but blood cultures may be positive in infants and children less than six years in adults. Diagnostic confirmation can be of age, but can occur even more rarely in obtained through examination of frozen adults. Underlying chronic renal insuffi- tissue sections or identification of serum ciency and immunosuppression are predis- exfoliative exotoxins through either slide 4 posing factors. latex agglutination or ELISA testing.4 SSSS is typically initiated by a local- Management of patients with SSSS varies ized infection of Staphylococcus aureus, depending on the severity of the illness most commonly at a remote site such as but typically requires hospitalization for the nasopharynx or mucosal cavities. The supportive care, observation, and insti- cutaneous manifestations are incited by tution of oral or parenteral ß-lactamase- the release of exfoliative exotoxins and resistant antibiotics (or sensitive agents epidermolysins, which are produced by of MRSA). Mild pediatric cases can be various strains of both methicillin-resistant successfully treated with admission to and methicillin-sensitive S. aureus but general pediatric units. More severe cases, 4,5,6 mainly by strains from phage group II. though, and especially adult cases, should There are two human types of S. aureus- be maintained in an ICU or burn-unit derived exfoliative toxins, ETA and ETB, environment where close supervision, and S. aureus uses these exfoliative toxins intensive skin care, and ventilator as well to proliferate by disrupting the epidermal as hemodynamic support can be offered. 7 barrier. Specifically, these exfoliative toxins Bland emollients should be applied to the bind directly with desmoglein-1, causing denuded areas of the skin for lubrication a conformational change that inspires a and to decrease tenderness and pruritus. cleavage of the extracellular domain of Affected newborns should be isolated from desmoglein-1. This interaction results other neonates. Finally, it is important to in the development of a split and sterile identify S. aureus carriers so that treatment bullae formation at the granular layer of can be instituted.12 the epidermis.4 Clinically, SSSS characteristically mani- References: fests as an acute, generalized exfoliative 1. King, Randall W, et al. Staphylococcal Scalded Skin Syn- dermatitis. There may be an associated drome. eMedicine from WebMD. prodromal phase of fever, malaise, irrita- 2. Nso Roca, AP, et al. Staphylococcal Scalded Skin Syn- drome. An Pediatr (Barc) 2008 Feb;68(2):124-7. bility or tenderness of the skin, as well as 3. Lyell A. Toxic Epidermal Necrolysis: an Eruption Resem- signs of a localized bacterial infection such bling Scalding of the Skin. Br. J Dermatology 1956; 68:355-61. as rhinorrhea, conjunctivitis, or abscess.8 4. Bolognia, JL, Jorizzo, JL, Rapini, RP. Dermatology 2nd Erythema often first begins on the head Edition (Mosby) 2008. p. 1079. 5. Lina, Gerard, et al. Toxin Involvement in Staphylococcal and progresses to incorporate the entire Scalded Skin Syndrome. Clinical Infectious Diseases body within 48 hours. The skin then takes 1997;25:1369-73 6. Melish, ME, Glasgow, LA. The Staphylococcal Scalded- on a wrinkled, sandpaper-like appearance Skin Syndrome. Development of an Experimental Model. with the development of flaccid bullae. The N Engl J Med 1970;282:1114-9 7. Kondo, I, et al. Two Serotypes of Exoliatin and their Dis- Nikolsky sign is positive, and within one to tribution in Staphylococcal Strains Isolated from Patients two days a sheet-like desquamation occurs, with Scalded Skin Syndrome. J Clin Microbiol 1975; 1:397-400. leaving behind areas of shallow denudation 8. Todd, JK. Staphylococcal Toxin Syndromes. Annu Rev and thin crust.4,9 Facial edema and perioral Med 1985;36:337-47. 9. King, R. Staphylococcal Scalded Skin Syndrome. Emedi- crusting can occur, and although most cine. July 13, 2006. Topic 782. pediatric patients do not appear severely ill, 10. Mockenhaupt, Maja, et al. Epidemiology of Staphylo- coccal Scalded Skin Syndrome in Germany. Journal of dehydration and hypothermia can ensue, Investigative Dermatology (2005) 124, 700–703 and affected individuals (especially adults) 11. Longo, Raffaele, et al. Journal of Clinical Oncology. Vol 21, Issue 19 (October), 2003: 3702-3703. can rapidly progress to the need for ICU 12. Resnick S. Staphylococcal Toxin Mediated Syndromes in supportive care.10 The mortality rate for Children. Semin Dermatol. 1992; 11:11-18. pediatric patients is approximately 3% but approaches 50% for adults and can be much higher in patients with comorbid disease states.11 Histologically, there is a sharply demar- cated zone of intraepidermal cleavage at the

36 STAPHYLOCOCCAL SCALDED SKIN SYNDROME IN A PATIENT WITH HIDRADENITIS SUPPURATIVA: A CASE REPORT TREATMENT OF RECALCITRANT VULVAR LICHEN SCLEROSUS WITH CYCLOSPORINE: A CASE REPORT

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

ABSTRACT

Lichen sclerosus (LS) is a relatively uncommon, chronic, inflammatory mucocutaneous disorder of unknown etiology that can lead to vulvar atrophy and scarring. Various hormonal, infectious, autoimmune, genetic and cell-mediated immune responses have been associated with the disorder; however, the exact origin of LS is unknown.1,2,3,4,5,6 It is most commonly treated with topical corticosteroids and calcineurin inhibitors.7,8,9,10 There are few well-studied alternatives for those patients failing these treatment modalities. Baskan et al. reported five patients with refractory vulvar LS treated successfully with oral cyclosporine.1 To date, there has been no other similar study. We present a case that supports cyclosporine therapy in recalcitrant vulvar lichen sclerosus.

Case Report was gradually increased to 100 mg three responsive to topical agents.14 As in the times daily over the following month. case of our patient, there are those indi- A 54-year-old female presented to our Symptoms were markedly decreased, viduals with recalcitrant disease resistant to clinic in July 2003 with a 25-year history of and the patient remained stable for an all commonly used topical and oral immu- vulvar lichen sclerosus treated with betame- additional two months, at which time nosuppressive therapies. thasone and testosterone ointments. She cyclosporine was slowly tapered off. By Baskan et al. reported five patients reported intermittent control and partial February 2008, the patient reported with recalcitrant vulvar lichen sclerosus resolution of symptoms. While initially complete resolution of symptoms and treated with moderate doses of the oral controlled, she had begun to experience was completely weaned off cyclosporine, immunosuppressant cyclosporine (3-4 mg/ an increase in pruritus, dysuria and vulvo- requiring only occasional use of topical kg/day).1 Cyclosporine is an immuno- dynia in the three months preceding the corticosteroids. At the time of publication, suppressive agent used in the treatment initial office visit. Treatment options were the patient continued to remain symptom- of many inflammatory skin disorders. discussed, but the patient declined any new free, reporting the only “true” resolution of Cyclosporine binds to cyclophilin A, and therapies and was continued on topical her symptoms in 25 years and a return to the cyclosporine-cyclophilin complex binds betamethasone ointment. activities she had long ago abandoned. to calcineurin, thus blocking the dephos- She presented to the office six months phorylation of nuclear factor of activated later with continued symptoms. Treatment Discussion T cells (NFAT). This blockade inhibits options were again discussed, and the the up-regulation of the pro-inflammatory patient opted for more aggressive therapy. Lichen sclerosus is a relatively cytokines interleukin-2 and interferon- She was started on hydroxychloroquine uncommon, chronic, inflammatory muco- gamma, thus decreasing the number of 200 mg daily with increase to twice daily cutaneous disorder of unknown etiology T-helper cells and cytotoxic T cells in 16 dosing after two weeks of therapy. She that can lead to vulvar atrophy and scar- the epidermis. Baskan’s patients had was also given clobetasol 0.05% ointment, ring. Various hormonal, infectious, response to cyclosporine therapy as early tacrolimus 0.1% ointment and testosterone autoimmune, genetic and cell-mediated as one month, and all were symptom-free 2% cream for topical use twice daily. At immune responses have been associated at the time of discontinuation of therapy 1 one month follow-up, the patient reported with the disorder; however, the exact origin at three-month follow-up. There was no complete resolution of pruritus and dyses- of LS is unknown.1,2,3,4,5,6,11,12,13 It can cause clinical recurrence or rebound flare after 1 thesia. There were no objective signs of significant pruritus, burning, dyspareunia discontinuation of cyclosporine therapy. atrophy at that time. However, over the and pain during micturition and defeca- They concluded that moderate-dose next nine months the patient experienced tion, as well as positional discomfort while cyclosporine was an effective treatment only one symptom-free month. She was seated or ambulatory. alternative in severe and refractory lichen 1 subsequently lost to follow-up for 18 Various treatment modalities have sclerosus. Our case confirms the findings months. been reported for lichen sclerosus, the of Baskan et al.: Cyclosporine can be an effective and safe treatment alternative for She returned to the clinic in June 2007. most effective and well-studied being recalcitrant lichen sclerosus.1 Over time, the patient had experienced high-potency topical corticosteroids.8,14 repeated, more frequent flares despite However, there are significant concerns therapy with Plaquenil (hydroxychlo- about long-term toxicity of corticosteroids, REFERENCES roquine), class-I topical corticosteroids, and recurrence rates may be as high as 1. Baskan, Emel et al. Open-Label trial of cyclosporine for 10,15 vulvar lichen sclerosus. Journal of the American Acad- topical testosterone and topical tacrolimus. 82 percent following discontinuation. emy of Dermatology 2007; 57: 276-278 Her symptoms of pruritus and burning While topical calcineurin inhibitors offer 2. Heymann, Warren. Lichen sclerosus. Journal of the American Academy of Dermatology 2007; 56: 683-684 were so severe that the patient had to fewer long-term side effects, there appears 3. Kelly, S. et al. Lichen sclerosus of the lip. Pediatric Der- file for short-term disability as she was to be only a moderate increase in long- matology 2006; 23: 500-502 8,9,10 4. Oyama N. et al. Autoantibodies to extracellular matrix only comfortable at home in recumbent term remission of disease. In addition, protein 1 in lichen sclerosus. Lancet 2003; 362: 118-123 position. She was placed on cyclosporine well-controlled, randomized trials and 5. Fujiwara H. et al. Detection of Borrelia burgdorferi DNA (B garinii or B afzelii) in morphea and lichen sclerosus 100 mg daily and was slowly weaned off long-term safety and efficacy studies of et atrophicus tissues of German and Japanese but not calcineurin inhibitors are lacking. There of US patients. Archives of Dermatology 1997; 133(1): hydroxychloroquine. At two-week follow- 41-44 up the patient reported some improvement have been small case series and case 6. Breier, F. et al. Isolation and polymerase chain reaction typing of Borrelia afzelii from a skin lesion in a serone- in pruritus and dysesthesia, and atrophy reports of use of hydroxychloroquine in gative patient with generalized ulcerating bullous lichen was objectively improved. Cyclosporine the therapy of lichen sclerosus that is not sclerosus et atrophicus. British Journal of Dermatology REAVES, ANDERSON 37 2001;144(2): 387-392 7. Assmann, Till et al. Tacrolimus ointment for the treat- ment of vulvar lichen sclerosus. Journal of the American Academy of Dermatology 2003; 48: 935-937 8. Hengge, U. Multicenter, phase II trial on the safety and efficacy of topical tacrolimus ointment for the treatment of lichen sclerosus. British Journal of Dermatology 2006; 155(5): 1021-1028 9. Strittmatter, H. Calcineurin antagonists in vulvar lichen sclerosus. Archives of Gynecology and Obstetrics 2006; 274(5): 266-270 10. Luesley, D. Topical tacrolimus in the management of lichen sclerosus. British Journal of Obstetrics and Gynaecology 2006; 113(7): 832-834 11. Carlson, J. Comparative immunophenotypic study of lichen sclerosus: epidermotropic CD57+ lymphocytes are numerous – implications for pathogenesis. American Journal of Dermatopathology 2000; 22(1): 7-16 12. Farrell, A. Alterations in distribution of tenascin, fibronec- tin and fibrinogen in vulval lichen sclerosus. Dermatology 2000; 201(3): 223-229 13. Farrell, A. Cytokine alterations in lichen sclerosus: an immunohistochemical study. British Journal of Dermatol- ogy 2006; 155(5): 931-940 14. Bolognia, Jean, editor. Dermatology, Second Edition. Mosby; 2008 15. Smith, Y. Clobetasol propionate in the treatment of premenarchal vulvar lichen sclerosus. Obstetrics and Gynecology 2001; 98: 588-591 16. Wolverton, Stephen, editor. Comprehensive Dermato- logic Drug Therapy, Second Edition. Saunders; 2007

38 CASE REPORT OF EXTRAGENITAL LICHEN SCLEROSIS ET ATROPHICUS IN AN ADOLESCENT FEMALE PRIMARY CUTANEOUS B-CELL LYMPHOMA: INDOLENT FOLLICULAR CENTER CELL LYMPHOMA TRANSFORMING INTO AGGRESSIVE DIFFUSE LARGE B-CELL LYMPHOMA

Alice N. Do, DO,* Kimball Silverton, DO** * Dermatology resident, Genesys Regional Medical Center ** Dermatology residency director, Genesys Regional Medical Center

ABSTRACT

Primary cutaneous B-cell lymphoma is a relatively rare entity. Of the different types of B-cell lymphomas, follicular center cell lymphoma is the most common form. It typically has a chronic, indolent course. There have been reports of low-grade lymphomas that have transformed into higher grade, more aggressive lymphomas. We present a case of a chronic, indolent follicular center cell lymphoma that transformed into a diffuse large B-cell lymphoma, along with a review of the literature.

Case Report Abbreviations Key A 73-year-old Caucasian woman presented with a 20-year history of asymp- CBCL cutaneous B-cell lymphoma tomatic, violaceous nodules of the left CBCL-PI cutaneous B-cell lymphoma prognostic index periocular area and left chest that waxed CHOP cyclophosphamide, doxorubicin, vincristine, prednisone and waned. These lesions were previ- CHOP-R cyclophosphamide, doxorubicin, vincristine, prednisone and rituximab ously biopsied over 10 years ago, and DLBCL diffuse large B-cell lymphoma were diagnosed as a low-grade follicular center cell lymphoma without evidence of EORTC European organization for research and treatment of cancer systemic involvement. No chemotherapy FCC follicular center cell lymphoma was indicated at the time. Over the years, LDH lactate dehydrogenase the lesions continued to wax and wane. MALT mucosa-associated lymphoid tissue She denied fever, night sweats, weight loss, or fatigue. Over the last few months, the PCBCL primary cutaneous B-cell lymphoma lesions had gotten quickly larger. For the REAL revised European American lymphoma classification first time in 20 years, the patient presented WHO World Health Organization to dermatology. Medical History was not performed. A peripheral blood neoplastic cells. BCL-2 positivity was ques- smear was normal. Bone marrow aspirate tionable. Negative immunophenotypical The patient had a history of fibrocystic and bone marrow biopsy were normal. stains included: CD10, CD30, CD45RO, breast disease, with bilateral mastectomy Clonality studies revealed a restriction in factor VIII, CK20, synaptophysin, and and breast implants. The patient also had lambda light chain. No lymph node biopsy pancytokeratin. a history of atrial fibrillation. She denied was performed, as there was no lymphade- history of Lyme disease, cytomegalovirus, nopathy on exam. HIV, or Epstein-Barr virus. She had family Diagnosis history of breast cancer, but she denied Imaging Diffuse large B-cell non-Hodgkin’s family history of lymphoma. A PET scan showed uptake in the left lymphoma, high grade. Medications & Drug Allergies periorbital subcutaneous tissue, left upper Based on the patient’s workup, she anterior chest wall, and right axilla. These had primary, cutaneous disease without The patient was on metoprolol for atrial sites corresponded to cutaneous lesions. evidence of systemic involvement. fibrillation and she reported drug allergies to codeine, penicillin, and ibuprofen. Histopathology Differential Diagnosis Examination A close differential diagnosis included The hematoxylin and eosin (H & E) high-grade diffuse follicular center cell There were large, violaceous nodules biopsy showed expansion of the dermis and masses in the left periocular area (see by large, atypical lymphoid cells. A Grenz lymphoma (FCC). Figure 1). There were similar lesions on zone separated these lesional cells from the Other differential diagnoses included the left anterior chest (see Figure 2) and epidermis, which demonstrated an absence cutaneous T-cell lymphoma, CD30+ right posterior flank (see Figure 3), which of epidermotropism. These cells had anaplastic large cell lymphoma, lympho- presented as plaques, papules, and patches. prominent nucleoli and mitotic figures, matoid papulosis, Hodgkin’s lymphoma, No ulcerations were present. No other and were growing in a diffuse pattern. No Burkitt’s lymphoma, cutaneous lymphoid bodily sites were involved. There was no follicular centers were noted (see Figure 4). hyperplasia, angiosarcoma, and Merkel cell fever, lymphadenopathy, or hepatospleno- Immunophenotypical stains revealed carcinoma. megaly on exam. positive lymphoid markers, such as LCA, Staging Laboratory and positive markers for B-cell, such as CD20 and CD79a (see Figure 5). T-cell The patient was staged using the Ann Complete blood count (CBC) with markers, such as CD3 and CD5, were posi- Arbor staging system for non-Hodgkin’s differential and serum chemistries, tive along the periphery and represented lymphoma as stage IE, and her five-year including liver function tests (LFTs) and only reactive T lymphocytes to the lesional survival rate was estimated to be between creatinine, were within normal limits. LDH 51% and 73% (See Table 1). DO, SILVERTON 39 Table 1

The Ann Arbor staging system for non-Hodgkin’s lymphoma and the International Prognostic Index (IPI) have been used to predict prognosis. Each factor is assigned one point, and cumulative points predict the five-year survival rate. This system is used in systemic lymphomas. Staging systems for cutaneous lymphomas are in development.

Staging Classification

Stage Areas involved

I
Single lymph node region involved (I).
Single lymph node region and extranodal involvement (IE). Figure 1: Violaceous nodules and masses were present in the left II
2 lymph node regions involved on same side of diaphragm (II). periocular area.
2 lymph node regions on same side of diaphragm and extranodal involvement (IIE).

III
Lymph node regions on both sides of diaphragm involved (III).
Lymph node regions on both sides of diaphragm involved and extranodal involvement (IIIE).
Lymph node regions on both sides of diaphragm involved and spleen involvement (IIIS).
Lymph node regions on both sides of diaphragm involved and extranodal and spleen involvement (IIIES).

IV
Multiple/disseminated involvement of extra-lymphatic organs.

Staging Sub-classification

A Asymptomatic

B Symptomatic: unexplained weight loss, unexplained fever, night sweats, fatigue Figure 2: Similar lesions in the left anterior chest region presented as plaques, papules and patches. A Prognostic factors Risk International Prognostic 5-year survival

Index (IPI) score biopsy was taken from the upper Low 0-1 73% portion of the lesion.
Age > 60 years
Stage III or IV Low / intermediate 2 51%
> 1 extranodal site High / intermediate 3 43%
High LDH
Poor general health High >4 26%

suffered bilateral pulmonary emboli and a lymphomas differ greatly in their prog- deep vein thrombosis. Her CHOP chemo- nosis compared to primary cutaneous therapy was then discontinued. Currently, lymphomas.3,4 Staging systems for cuta- she is undergoing radiation treatment and neous lymphomas have been proposed and intravenous rituximab. include the Cutaneous B-cell Lymphoma 3 Discussion: Prognostic Index (CBCL-PI), which takes into account histology and bodily sites B-cell lymphoma and follicular center involved, and the International Society of Figure 3: The right posterior trunk cell lymphoma transforming into diffuse Cutaneous Lymphoma & Task Force of presented with an erythematous patch. large B-cell lymphoma the EORTC (European Organization for B-cell lymphomas are a type of non- Research and Treatment of Cancer). No Course & Treatment Hodgkin’s lymphoma. The majority of system has been universally accepted at this primary cutaneous lymphomas are T-cell in time, and staging systems for cutaneous The patient underwent her first course origin, with B-cell lymphomas comprising lymphomas continue develop. of chemotherapy, which included the a small minority. Primary cutaneous Classification schemes for cutaneous CHOP-R regimen consisting of cyclophos- B-cell lymphomas (PCBCL) are quite rare. lymphomas have been controversial and phamide, doxorubicin, vincristine, predni- There may be a slightly higher incidence of continue to be disputed. Multiple clas- sone and rituximab. After the first course PCBCL in Europe, associated with Borrelia sification schemes have been proposed, and of chemotherapy, the patient had dramatic burgdorferi infection.1 Previously, cuta- have led to confusion in terminology. The improvement of her cutaneous lesions, neous B-cell lymphomas were lumped with classifications that have been used in the with the large facial nodules flattening to the systemic forms. They were not recog- past include the REAL (Revised European patches. However, one week after starting nized as a distinct entity until the 1980s. American Lymphoma) classification, the chemotherapy, she suffered a cerebrovas- Therefore, they likely occurred more WHO (World Health Organization) clas- cular accident. She was hospitalized for frequently than previously believed.1 sification, and the EORTC (European three weeks and had motor and sensory The purpose of a staging workup is to Organization for Research and Treatment deficits of the left leg and left hand, which calculate prognosis using the International of Cancer) classification. The latest clas- improved with physical therapy. She was Prognostic Index (IPI)2 (See Table 1). sification scheme, the WHO-EORTC, re-evaluated by her oncologist, who felt However, the Ann Arbor staging system arose from consensus meetings in 2003 that the chemotherapy was not related to that is currently used for systemic non- and 2004 and lists the types of cutaneous her stroke. Therefore, she was continued Hodgkin’s lymphomas is less appropriate B-cell lymphoma currently recognized (see on chemotherapy, and subsequently to stage cutaneous lymphomas, as systemic Table 2).5 Gene studies have attempted to 40 PRIMARY CUTANEOUS B-CELL LYMPHOMA Figure 4: Scanning microscopic power revealed basophilic cells packing the dermis (25X magnification). A Grenz zone separated these cells from the epidermis, in which there was no epidermotropism present (100X magnification). Atypical lymphoid cells with prominent nucleoli were growing in a diffuse pattern (400X magnification).

or positron emission tomography (PET) scan, to rule out involvement of the lymph nodes and extracutaneous organs, and help to exclude systemic disease.4 Clonality studies are not diagnostic of lymphoma, nor can they accurately predict progression towards lymphoma. However, they may help to lean the diagnosis towards malignancy if all other workup is unclear. If clonality studies show a restriction in either lambda light chain or kappa light chain, this may indicate a clonal population of cells, suspicious for malignancy.1,6 Table 3 shows a summary of staging workup for Figure 5: Lesional lymphoid cells stained positively with B-cell markers, CD20 cutaneous lymphoma. (40X magnification) and CD79 (100X magnification). Differentiating between primary and secondary disease is important to direct treatment and predict mortality (see Table and upper trunk. Typically, there are no 4). Primary disease originates in the skin, lesions of the extremities. These indolent and is limited to skin involvement only. lymphomas may wax and wane and be Lymph nodes and organs are not involved. present for up to 20 years. Long-standing, Typically, patients present with upper body chronic disease can transform over time lesions. Secondary disease originates in the to higher grade lymphomas. Aggressive lymph nodes, and then metastasizes to the forms of lymphoma, such as DLBCL, have skin. Patients usually present with wide- a shorter course and exhibit more aggres- spread lesions. As expected, these patients sive growth patterns.2,3,6 DLBCL of the have a worse prognosis. leg arises on the legs of elderly women.2,7 Uncommon DLBCL that arises on the head Transformation or neck may be very difficult to distinguish There have been reports of indolent low- Figure 6: Follicular center cell 6 from high-grade FCCs. Patients may grade lymphomas transforming into high- lymphoma (FCC) and diffuse large complain of unexplained fever, weight loss, grade, more aggressive lymphomas. MALT B-cell lymphoma (DLBCL) have night sweats, and fatigue.4 different clinical presentations and marginal zone B-cell lymphomas and courses of progression. In a Examination may reveal cutaneous may transform to DLBCL, DLBCL of the patient whose lymphoma transforms erythematous-to-violaceous nodules, anaplastic variant, Hodgkin’s lymphoma, (red arrows) from indolent FCC plaques or patches. The number and loca- and high grade FCC. Mantle cell to aggressive DLBCL, clinical tion of the lesions are helpful in deter- lymphomas may transform to a blastic presentation is unclear. mining the type of cutaneous lymphoma. variant of mantle cell lymphoma. Small A lesional skin biopsy should be performed. lymphatic lymphoma/leukemia may trans- aid in classification, however results are In addition to a cutaneous exam, the lymph form to DLBCL, DLBCL of the anaplastic inconsistent. nodes, liver, and spleen should palpated to variant, and unclassifiable lymphoma examine if these areas may be involved. A resembling Burkitt’s lymphoma or The purpose of a staging workup for lymph node biopsy should be considered if lymphoma with blastic morphology, or cutaneous lymphoma is to evaluate for lymphadenopathy is present on exam. Hodgkin’s lymphoma.2,8,9 extracutanous involvement and to distin- Laboratory workup should include a Given the chronicity of our patient’s guish between primary and secondary CBC with differential, serum chemistries to lesions and the recent change in biological disease. A workup includes history, phys- evaluate liver and renal function, and LDH. behavior, we believe that transformation ical exam, laboratory workup, and imaging. Further systemic evaluation may include a occurred from a low-grade FCC to DLBCL. A history should elicit the chronicity of peripheral blood smear and bone marrow The risk of transforming to DLBCL can lesions and their biological behavior. FCCs evaluation.6 Workup should also include exceed 20% in five years and 30% in 20 present as erythematous-to-violaceous imaging, such as computed tomography years.9 Overall, transformation in cuta- nodules and masses on the head, neck, (CT) of the chest, abdomen, and pelvis neous lymphoma can occur in up to 40% DO, SILVERTON 41 Table 2

Various classification schemes have been proposed for cutaneous B-cell lymphoma. The latest classification scheme, the WHO-EORTC consensus, lists the types of cutaneous B-cell lymphoma currently recognized.

Cutaneous B-cell lymphoma classification schemes

WHO-EORTC consensus
REAL classification - Primary cutaneous marginal zone B-cell lymphoma
WHO classification - Primary cutaneous follicular center lymphoma - Primary cutaneous diffuse large B-cell lymphoma, leg type
EORTC classification - Primary cutaneous diffuse large B-cell lymphoma, other - Intravascular large B-cell lymphoma

of cases.4 Histological appearance and diagnosis towards DLBCL, particularly of immunophenotypical stains may aid in the leg type.2,7,11 FCCs are typically BCL2 References 6,10,11 diagnosing transformation, therefore negative. 1. Pandolfino TL et al. Primary Cutaneous B-Cell Lym- any rapid change in lesion size or change phoma: Review and Current Concepts. Journal of Clinical Oncology 2000;18(10):2152-2168. in biological behavior should prompt Treatment 2. Fatovic-Ferencic S, Plewig G, Holubar K, editors. An re-biopsy to evaluate for transformation. Illustrated Guide to Skin Lymphoma, 2nd edition Malden, Massachusetts: Blackwell Publishing; 2004. According to the WHO-EORTC clas- Low-grade, indolent B-cell lymphomas 3. Smith BD et al. The Cutaneous B-Cell Lymphoma Prog- do not require aggressive chemotherapy, nostic Index: A Novel Prognostic Index Derived From a sification scheme, diffuse-pattern FCCs Population-Based Registry. Journal of Clinical Oncology are not classified as FCCs, but instead as and may be observed for malignant trans- 2005;23(15):3390-3395. 5 formation. Localized lesions may benefit 4. Gajra A, Vajpayee, N, Grethlein, S. Lymphoma, B-Cell. DLBCL, and therefore we favor DLBCL Emedicine 2007. as a final diagnosis. FCCs and DLBCL from radiation therapy. Generalized or 5. Willemze, R et al. WHO-EORTC classification for cuta- of the leg are two distinct entities that multiple-site lesions may make radia- neous lymphomas. Blood 2005;105(10):3768-3785. 4 6. Fung MA et al. Practical evaluation and management of present very differently. There has been tion treatment more impractical. cutaneous lymphoma. Journal of the American Academy Rituximab, an anti-CD20 antibody that of Dermatology 2002;46(3):325-357. little discussion in the literature of the 7. Grange F et al. Primary cutaneous diffuse large B-cell clinical appearance of patients who are targets the CD20 receptor on B cells, is lymphoma, leg type: clinicopathologic features and prog- transforming from indolent to aggressive generally used for low- or high-grade nostic analysis in 60 cases. Archives of Dermatology 12,13 2007;143(9):1144-50. lymphomas. This “transition zone” of clin- B-cell lymphomas. Because aggres- 8. Freeman AA, Friedberg JW. Diffuse large B-cell lym- sive, multi-agent chemotherapy does not phoma in adults. Up-to-Date 2008. ical appearance, histology, etc. that exists 9. Said J. Transformation to aggressive B-cell lymphoma. can further muddle the clinical picture improve patient survival or prevent relapse Applied Immunohistochemistry & Molecular Morphology and can present a challenge to diagnosis of disease, it is not indicated for indolent 2003,11(3):199-205. 1 10. Greene FL, Page DL, Fleming ID, editors. Skin Pathology (see figure 6). Our patient did not have cutaneous B-cell lymphomas. by David Weedon, 2nd edition New York, NY, Churchill The standard treatment for aggressive, Livingstone Publishing; 2003. leg lesions. But given the unclear clinical 11. Geelen FA et al. BCL-2 protein expression in primary presentation of a transforming lymphoma, high-grade B-cell lymphomas includes cutaneous large B-cell lymphoma is site-related. Journal 7 multiple-agent chemotherapy. The of Clinical Oncology 1998;16:2080-2085. perhaps she does not have leg lesions yet. 12. Fink-Puches R et al. Treatment of primary cutaneous agents that are typically employed are B-cell lymphoma with rituximab. Journal of the American cyclophosphamide, doxorubicin, vincris- Academy of Dermatology 2005; 52:847-853. Histology 14 13. Heinzerling LM et al. Reduction of tumor burden and sta- tine, and prednisone (CHOP regimen). bilization of disease by systemic therapy with anti-CD20 Histologically, lymphoid cells are atypical Chemotherapy is often combined with antibody (rituximab) in patients with primary cutaneous B-cell lymphoma. Cancer 2000;89(8):1835-44. with prominent nucleoli. If the lymphoma rituximab, which has shown to improve 14. Halleck Neto AE et al. Results of CHOP chemotherapy is aggressive, multiple mitoses may be survival.4,12,13 This may be followed with for diffuse large B-cell lymphoma. Brazilian Journal of easily seen. FCCs resemble the follicular radiation treatment. Other systemic treat- Medical and Biological Research 2006;39:1315-1322. center of a lymph node, and therefore have ments for aggressive cutaneous lymphoma a nodular pattern of growth of small-to- include interferon alfa.4 medium-sized cells.2,10 Over time, this nodular pattern is lost, and FCCs take on Conclusion a more diffuse pattern of growth. The cells also tend to get larger. Once this occurs, Primary cutaneous B-cell lymphomas are diffuse-pattern FCC may closely resemble quite rare. Occasionally, and particularly DLBCL, and distinguishing between these in chronic lesions, they may transform into two entities on histology may be impos- more aggressive forms of lymphoma. There sible, even with immunophenotypical has been little in the literature about how markers.1 these transformed cutaneous lymphomas Immunophenotype will stain posi- present clinically. We have presented a case tively for lymphoid markers, such as LCA of FCC that transformed to DLBCL. More (CD45), and B lymphocyte markers, such attention should be directed towards how as CD20 and CD79a. these transforming, cutaneous lymphomas The patient had a questionable BCL2- present to recognize transformation, and positivity, which may slightly lean the to correctly diagnose and manage these patients.

42 PRIMARY CUTANEOUS B-CELL LYMPHOMA Table 3

The workup for cutaneous lymphoma assesses possible systemic involvement. Referral to an oncologist may aid in the workup.

Cutaneous lymphoma workup

History (duration of lesions, biological activity of lesions, fever, weight loss, night sweats, fatigue)

Exam (skin exam: number and location of lesions; palpate lymph nodes, liver, and spleen)

Labs (CBC, LFTs, creatinine, LDH)

Peripheral blood smear

Skin biopsy

Lymph node Bx (if lymphadenopathy on exam)

CT scan of chest, abdomen, pelvis; or PET scan

Bone marrow aspirate / bone marrow biopsy

Clonality studies

Table 4

Differentiation between primary and secondary cutaneous B-cell lymphoma includes history, examination, labs, and imaging.

Primary cutaneous B-cell lymphoma Secondary cutaneous B-cell lymphoma

Originates in the skin Originates in the lymph nodes Limited to skin involvement only Metastasizes to the skin No lymph node or distal organ involvement Lesions typically above the waist Widespread lesions CBC, LFTs, and Cr normal CBC, LFTs, or Cr abnormal and may show liver or kidney involvement Peripheral blood smear normal Peripheral blood smear abnormal, indicating circulating lymphoma cells No lymphadenopathy Lymphadenopathy may be present and lymph node Bx may show lymphoma CT or PET scan normal CT or PET scan shows extracutaneous involvement Asymptomatic Symptomatic, such as unexplained fever, unexplained weight loss, night sweats, or fatigue No hepatomegaly or splenomegaly Hepatomegaly and/or splenomegaly present, which may represent involvement of these organs Bone marrow aspirate / bone marrow Bone marrow aspirate or bone marrow biopsy biopsy normal abnormal, indicating involvement

DO, SILVERTON 43 AN UPDATE AND REVIEW OF ANDROGENIC ALOPECIA

Brian Feinstein, D.O.,* Stanley Skopit, D.O., F.A.O.C.D.** *3rd-year Dermatology Resident, Nova Southeastern University-COM/BGMC **Director, Dermatology Residency Training Program, Nova Southeastern University-COM/BGMC

ABSTRACT

Androgenic alopecia (AGA) is an extremely common disorder affecting more than 90% of all men over the course of their lifetime. It is a progressive condition in which almost all patients will have onset prior to the age of 40. The progression of AGA is the gradual transformation of pigmented terminal hair to fine, colorless, almost invisible vellus-like hair follicles. The roles of androgens have been identified in the pathogenesis of AGA. Thus, primary pharmacologic therapy has been aimed at targeting the formation of those androgens. Surgical treatment options are also available, but proper patient selection and surgical technique are critical in order to obtain a successful outcome. Recent advancements in the understanding of AGA have allowed physicians to provide patients with accurate counseling and effective treatments. Background Androgenic Alopecia down midline. By comparing the width of the patient’s part to one of the eight Throughout history, hair has played an examples, the system could be adapted to important role in human self expression clinical trials and serve as a method by and communication. Hair is a feature an which practitioners could quantify their individual can uniquely tailor according patient’s hair loss and growth. The flaw in to style and/or religious or cultural beliefs. the Savin scale is that it does not depict the The loss of hair limits this self expression typical pattern of hair loss experienced by and can result in a poor self image, a loss most patients, and it has not been widely of self confidence and a feeling of being accepted by hair-restoration surgeons.1, 2, 4 older. Cultures have long recognized the Role of Androgens in Pattern psychological sequela of this condition and Hair Loss have worked to develop various treatments. In 2000 BC, the Egyptians recorded treat- The role of androgens in AGA was ment recipes for hair loss. In the days of first identified in eunuchs who did not Aristotle (384-322 BC), scholars recognized receive hormone replacement therapy. The and noted that eunuchs did not suffer from androgen most closely associated with hair loss, nor did it occur in individuals AGA is dihydrotestosterone (DHT). This prior to sexual development.1-3 was studied in a group of males from the In 1942, the modern understanding Dominican Republic who genetically lacked of male pattern hair loss or androgenic Type II 5α-reductase (5AR), the enzyme alopecia (AGA) was theorized by Hamilton. required to convert testosterone to DHT, and who consequently never developed It was established that AGA is a physiologic typical AGA. The medication finasteride process induced in genetically predisposed targets the conversion of testosterone to hair follicles and is influenced by andro- DHT. It works by competitively inhibiting gens.1 It was noted that below the normal Type II 5AR and thus decreasing the levels level of androgens, genetically determined of DHT, resulting in the effective treatment individuals would manifest the clinical of AGA.4 characteristics of AGA. In 1951, Hamilton Androgens affect the hair by a pathway developed the first grading scale for AGA. of testicular and adrenal gland testosterone This scale was modeled after Caucasian Figure 1 Norwood-Hamilton that diffuses passively into the skin cells. men and women, with a range from type Classification4 Once in the cells, it is converted to DHT I to type VIII. Type I represents the prepu- by 5AR. Two types of 5AR exist in the cells. bertal scalp, with terminal hair growth on Type I is found on sebaceous glands and in the forehead and all over the scalp, and AGA is far and away more common in the pilosebaceous unit, whereas Type II is type VII and VIII represent progressive found in the outer root sheath of the scalp balding, with hair only present on the back Caucasian males. However, some sources have estimated the incidence of AGA to hair follicles, prostate, and dermal papillae. and sides of the head. The classification A cytosol androgen receptor protein then system was later modified by Norwood to be greater than 80% in all races and as high as 96% in Caucasians. Sixty-two forms a complex with DHT, allowing include variations of the middle grades. access into the cell nucleus. Once inside These were labeled IIIa, IVa, and Va, and percent of Caucasian men aged 20 to 40 years have bitemporal recession, and the nucleus, DHT causes conformational they show a more prominent recession of change to lead to the inactivation of the 1,4 54% of Caucasian men over the age of 30 the middle and frontal hairline. 4 years are affected with AGA.4 In the mid hair follicle. Figure 1 shows the Norwood-Hamilton 1990s, Savin designed a system of eight Treatment Overview classification. The Norwood-Hamilton computer-engineered pictures of hair loss scale is used for the assessment of effi- with progressive severity. The pictures were Only two classes of medications have ciency of medication for hair restoration in top views of the scalp with the hair parted been proved to be effective in the treatment clinical trials. of AGA. The first is a direct hypertrichotic 44 AN UPDATE AND REVIEW OF ANDROGENIC ALOPECIA agent, and the second affects the androgen treatment, the progression can be arrested pathway. In each of the two categories, only and partly reversed in the majority of one medication has gained approval by patients who have mild to moderate AGA. the U.S. Food and Drug Administration Despite many years of research and (FDA) for the treatment of pattern investigation into the pathogenesis of alopecia.5 Minoxidil is a potassium channel AGA, very little is actually known about opener and vasodilator, initially approved the entirety of this condition. It is crucial for use as an antihypertensive agent, with for practitioners to fully understand the the notable side effect of hypertrichosis. known elements of this process in order The FDA originally approved a 2% topical to recommend and prescribe appropriate solution and later a 5% topical solution, therapeutic treatment options. In the past, both of which were prescription prod- few treatments, if any, were effective in the ucts.4 It was first speculated that minoxidil treatment of AGA. In the future, through produced hair growth by way of vasodila- continued scientific research, more effec- tion, but this was found to be incorrect. tive and better-tolerated therapies may Minoxidil enhances hair survival in tissue become available. Physicians who specialize cultures even in the absence of a blood in male health issues should be familiar supply. Topical minoxidil is considered with this common condition and all avail- to be a nonspecific biologic modifier with able approved treatment options. an unknown mechanism of action in hair 1 growth. References: The second approved medication, 1. Oterberg N. Androgenic Alopecia. Endocrinology and finasteride, is a competitive inhibitor of Metabolism Clinics of North Am 2007; 36(2): 379-98. 2. Feinstein R. Androgenic Alopecia. Emedicine; 2007. Type II 5AR. Finasteride is administered 3. Hamilton JB. Male Hormone stimulation is prerequi- as a pill taken orally at 1mg/day. Multiple site and an incident in common baldness. Am J Anat 1942;71(3):451-80 studies have determined that finasteride 4. Haber R. Hair Transplantation: Pathogenesis and Medical has proven clinical efficacy over placebo Therapy of Male and Female Pattern Hair Loss. Philadel- phia: Elsevier; 2006. P. 1-8. alone. Because finasteride has been known 5. D’Amico A. Effect of 1mg/day finasteride on concentra- to reduce serum prostate-specific antigen tions of serum prostate-specific antigen in men with androgenic alopecia: a random controlled trial. Lancet (PSA) levels by 30-50%, men over the 2007; 8:21-25. age of 40 are advised to have their PSA levels doubled for interpretation; however, because this correction might not adjust PSA accurately, a potentially unnecessary or missed diagnostic procedure may occur.1 Finasteride works best to prevent ongoing hair loss. Patients are therefore encouraged to begin treatment as soon as hair thinning is noted.5 Diagnostics The diagnosis of AGA in men is usually not difficult. The hair loss is non-scarring and shows a preservation of the follicular ostia. Basic qualitative tests, such as a hair- pull test, contrast paper, and dermoscopy, can easily be used as a tool during a hair consultation. A hair-pull test is usually used as a quick assessment of the activity of the telogen count in the involved area. A scalp biopsy allows a definitive diagnosis, as it provides information on histological features, the number of terminal and vellus hairs per area, and the number of anagen and telogen hairs; but for routine diagnos- tics, a scalp biopsy is usually not necessary. Summary AGA, or male pattern hair loss, affects approximately 50% of the male popula- tion. AGA is an androgen-related condi- tion in genetically predisposed individuals. DHT has been identified as the unregulated mediator, but its exact mode of action on the dermal papilla is not fully understood. There is no treatment to completely reverse AGA in advanced stages, but with medical

FEINSTEIN, SKOPIT 45 PERNIOSIS: A COLD WEATHER BAROMETER

Chad Peterson, D.O.,* Nathan Peterson, D.O.,** Don A. Anderson, D.O., F.A.O.C.D., F.A.S.M.S.*** *Third-year Resident, Kingman Regional Medical Center, Kingman, AZ **Flight Surgeon, U.S. Naval Academy ***Program Director, Arizona College of Osteopathic Medicine Dermatology Residency, Midwestern University of Health Sciences

ABSTRACT

Perniosis is characterized by a localized, pruritic, sometimes painful, erythematous to violaceous rash with nodules (chilblains) that present in the acral skin as an abnormal response to repeated exposure to cold. A diagnosis of perniosis is made clinically and can be supported by dermatohistopathologic findings. This condition may be associated with systemic illnesses, and it can be difficult to distinguish idiopathic perniosis from secondary perniosis and similar cutaneous manifestations of lupus erythematosus. A review of literature supports an investigation and biopsy of lesions for confirmation of the underlying pathology.

Case Report #1 Pathology A 33-year-old Caucasian female Punch biopsies were taken from both presented to our clinic with a long- patients, exhibiting similar histology. standing history of recurrent, eruptive, Characteristically, they revealed: a dense, erythematous, tender papules on her toes. lichenoid, lymphocytic, inflammatory cell She reported having a similar outbreak infiltrate within the superficial dermis, yearly, coinciding with the first significant associated with scattered vacuolar inter- cold front of the fall season. This eruption face changes with occasional apoptotic had been occurring annually in October or keratinocytes; and a prominent superfi- November for more than 10 years. cial dermal edema with a tightly cuffed, Physical exam revealed multiple, tender, moderate, perivascular, lymphocytic, erythematous papules on all 10 digits inflammatory cell infiltrate in the mid-to- Case #1 (33-year-old female) dorsally. Mild edema was noted without deep reticular dermis. Multiple erythematous papules on the purpura, ulceration or bullae formation. Based on the characteristic histopa- toes. A biopsy suggested perniosis, thology and negative clinical work-up, and a negative systemic work-up Case Report #2 a diagnosis of perniosis (chilblains) was helped confirm the diagnosis. confidently rendered. A 25-year-old Caucasian male presented clothing in cold weather, and cases occur- to our dermatology clinic in mid-December Epidemiology ring on the thighs of individuals after with symptoms of recurrent, swollen, Perniosis is caused by exposure and inad- wading across cold mountain rivers.10 pruritic toes with subsequent sanguineous equate protection in a cold (non-freezing), There has been one case report linking blister formation. Pruritus was always the humid environment. Patients with perni- celiac disease with perniosis.14 initial symptom, followed by erythema osis typically present through the winter at his distal toes, progressing to his mid- Physicians’ unfamiliarity with perniosis months, and it is more common in areas foot. This was followed by an eruption of gives rise to unnecessary hospital admis- of moderate cold as opposed to areas of sions with expensive laboratory and radio- multiple, painful, erythematous papules, severe cold.1 which progressed to significant edema logic evaluations and, at times, hazardous In one study of a moderately cold area 11 and pain of all 10 digits. Symptoms lasted therapy. in Pakistan, the disease was found to have five to seven days, but never completely greater prevalence among outdoor workers Pathogenesis: resolved before another recurrence. No and young adolescent.2 The annual inci- prior history of similar findings was dence in the United States is not known, The abnormal response to cold expo- reported. but it is reported as high as 10% in sure is thought to induce vasospasm in the Initial physical exam revealed blanching, England. exposed tissue, producing a lymphocytic erythematous and violaceous skin with Perniosis most commonly occurs in vascular reaction and lymphocytic infiltra- marked edema confined exclusively to the young women, but it has been known to tion and exudation of fluid into the tissue.3 digits. Areas of bullae formation were also occur among older individuals and even Cold temperature has been described as a evident. The toes were tender to palpation, children. Some authors have noted an cause of arteriolar and venule constriction with limited motion. Sensation and capil- association with thin body habitus, BMI with subsequent edematous response.1 lary refill remained intact. 9 <25th percentile. A positive family history Acute perniosis may develop 12 to 24 The patient denied a personal history of has been noted in approximately 20% of hours after exposure to cold. Chronic 13 coronary artery disease, diabetes, vascu- cases. Up to 67% of cases have been asso- perniosis, with the persistence of lesions, 13 litis, rheumatoid arthritis, systemic lupus ciated with outdoor workers. occurs with repeated exposure to cold. erythematosus or autoimmune disease. He Lesions typically occur on the fingers had been on no recent medications and and toes, but can also occur on the ears and Diagnosis: denied use of tobacco, alcohol or other the face. recreational drugs. Exceptional case reports have included Perniosis is generally a clinical diagnosis. horse riding enthusiasts wearing tight A history of cold exposure with subsequent 46 PERNIOSIS: A COLD WEATHER BAROMETER development of localized pruritic or tender, erythematous to violaceous papules or nodules (chilblains) with associated edema is a classic presentation for perniosis. There are several systemic diseases whose initial symptoms and dermatologic manifes- tations present similarly to that of perniosis. These include systemic lupus erythematosus, antiphospholipid antibody syndrome, viral hepatitis, rheumatoid arthritis, cryofibrino- genemia, hypergammaglobulinemia, Crohn’s disease, Raynaud’s phenomenon4, small joint arthralgias, positive ANA, acrocya- nosis, emboli (septic or cholesterol), eryth- romelalgia, ischemia, polycythemia vera, and chronic myelogenous leukemia. Thus, in suspected cases, a baseline work-up has been recommended to include: CBC, ANA, anti- bodies to SSA (Ro), SSB (La), RF, cryoglobu- lins, cryofibrinogens and antiphospholipid, hepatitis screen and serum electrophoresis with quantitative immunoglobulins.4 Dermatohistopathology has also been helpful in distinguishing perniosis (idio- pathic chilblains) from lesions that are Case # 1 (33 year old female) similar in patients with lupus erythematosus. Scattered vacuolar interface Perniosis exhibits findings of necrotic kera- changes with occasional apoptotic tinocytes and spongiosis in the epidermis keratinocytes are noted with prominent with perieccrine infiltrate, and edema of the superficial dermal edema. dermis. These findings can be helpful to confirm a diagnosis of idiopathic perniosis.5 Treatment: Treatment of perniosis should first be directed toward prevention of exposure to cold. Education focused on limiting exposure to cold and adequate rewarming can prevent initial onset or recurrence of symptoms. The patient’s symptoms are self-limited, and relief can be hastened using nifedipine 10 mg TID or 20 mg BID-TID. Upon reso- lution, the patient can be maintained on a A tightly cuffed, moderate, sustained-release preparation of nifedipine perivascular, lymphocytic, 6 inflammatory cell infiltrate in the mid- 20 mg BID. This has been shown in limited to-deep reticular dermis is noted. clinical trials to significantly reduce the time to clearance of existing lesions and to prevent the development of new chilblains. Nifedipine also reduced the pain, soreness and irritation of the lesions.6 Case #2 (25-year-old male) Nifedipine is a calcium channel blocker Notable erythema and edema to all that induces vasodilation, causing increased toes. A laboratory work-up proved blood flow, and has antiplatelet effects. negative for systemic disease. Punch These qualities perhaps explain the resolu- biopsies helped to confirm the tion of signs and symptoms generally occur- diagnosis of perniosis. ring between eight to 28 days for lesions on the hands, thighs and feet.6,12 Aside from the above noted study, which is frequently cited throughout the published A tightly cuffed moderate perivascular literature on treatment for perniosis, it lymphocytic infloammatory cell should be noted that strong evidence with infiltrate in the mid to deep reticular placebo-controlled trials for the use of nife- dermis is noted. dipine is lacking. Other treatment options that have been suggested include: topical and systemic steroids, nicotinamide, hexyl nicotinate, amlodipine, and UVB. These suggestions are based primarily on anecdotal reports. PETERSON, PETERSON, ANDERSON 47 A tightly cuffed, moderate, perivascular lymphocytic inflammatory cell infiltrate without evidence of vasculitis.

Case #2 (25-year-old male) There is mild edema and a lichenoid A tightly cuffed, moderate, superficial infiltrate with extravasation of red and deep perivascular lymphocytic blood cells. inflammatory cell infiltrate is noted in addition to a lichenoid infiltrate with mild edema.

Pediatrics. 2005 Sep;116(3):e472-5. Conclusion: 10. Price RD, Murdoch DR Case Report: Perniosis (Chil- blains ) of the thigh: Report of five cases, including four Perniosis is a cold-induced abnormal following river crossings. High Altitude Medicine and Biology. Dec 1, 2001, 2(4): 535-538. response of the skin primarily in the acral 11. Goette DK Chilblains (perniosis). J Am Acad Dermatol. areas. A diagnosis can be made clinically 1990 Aug;23(2 Pt 1):257-62. 12. Palamaris I, Kyriakis K. Calcium antagonists in dermatol- and can be supported by histopathology. ogy: A review of the evidence and research-based stud- It is recommended to complete a base- ies. Dermatology Online Journal 11(2): 8. 13. Raza N, Sajid MD, Ejaz A. Chilblains at Abbottabad, a line work-up in patients with suspected moderately cold weather station. J Ayub Med Coll Abbot- perniosis (idiopathic chilblains) to iden- tabad. 2006 Jul-Sep;18(3):25-8. 14. St. Clari NE, et al. Celiac disease presenting with chil- tify possible systemic illnesses, particularly blains in an adolescent girl. Pediatric Dermatology. 2006 connective-tissue disorders. The mainstay Sep-Oct;23(5):451-4. of treatment is prevention. Nifedipine has been shown to reduce the duration of symptoms and is the most supported pharmacologic intervention. Increasing awareness in patients and physicians may prove to prevent future cases, unnecessary treatments and recurrence.

REFERENCES: 1. Jordaan HF. The diagnosis and management of perniosis (chilblains). SA Fam Pract. 2007:49(6). 2. Raza N, Sajid M, Ejaz A. Chilblains at Abbottabad, a moderately cold weather station. J Ayub Med Coll Abbot- tabad 2006;18(3). 3. Goette DK. Chilblains (perniosis). J Am Acad Dermatol. Aug 1990;23(2 Pt 1):257-62. 4. Crowson AN, Magro CM. Idiopathic perniosis and its mimics: a clinical and histological study of 38 cases. Hum Pathol. Apr 1997;28(4):478-84. 5. Cribier B, Djeridi N, Peltre B, Grosshans E. A histological and immunohistochemical study of chilblains. J Am Acad Dermatol. 2001 Dec;45(6):924-9. 6. Rustin MH, Newton JA, Smith NP, Dowd PM. The treat- ment of chilblains with nifedipine: the results of a pilot study, a double-blind placebo-controlled randomized study and a long-term open trial. Br J Dermatol. Feb 1989;120(2):267-75. 7. Langtry JA, Diffey BL. A double-blind study of ultraviolet phototherapy in the prophylaxis of chilblains. Acta Derm Venereol. 1989;69(4):320-2. 8. Maroon MS, Hensley D. In: Elmets CA, Vinson R, Libow L, Quirk C, James WD, eds. eMedicine World Medical Library, August 20, 2002. 9. Simon TD, Soep JB, Hollister JR. Pernio in pediatrics.

48 PERNIOSIS: A COLD WEATHER BAROMETER

GRAFT-VERSUS-HOST DISEASE IN A LIVER TRANSPLANT PATIENT WITH GRAFT DYSFUNCTION

Angela Combs, DO,* Emily Rubenstein, DO,* Marcus Goodman, DO,** Chris Buckley, DO,** Stanley Skopit, DO, FAOCD*** *1st-year dermatology resident, Nova Southeastern University, College of Osteopathic Medicine & Broward General Medical Center, Ft. Lauderdale, FL **2nd-year dermatology resident, Nova Southeastern University, College of Osteopathic Medicine & Broward General Medical Center, Ft. Lauderdale, FL ***Program Director, Nova Southeastern University, College of Osteopathic Medicine & Broward General Medical Center, Ft. Lauderdale, FL

ABSTRACT

Graft-versus-host disease (GVHD) is the result of lymphocytes from a donor that undergo clonal replication and mount an immune response against a recipient who cannot defend the attack. This complication usually presents with fever, skin rash, diarrhea, or pancytopenia occurring between two and six weeks after the transplant. A hallmark of GVHD in liver transplant patients is that the transplanted liver function is not impaired because it is the source rather than the target of immunologically active cells. This case report describes an unusual case of GVHD in a liver transplant patient after aggressive immunosuppressant therapy was initiated for graft dysfunction three months after transplant. The GVHD resolved after the patient underwent a second liver transplant for cholestatic liver disease.

Case Report very jaundiced. Skin biopsies performed revealed superfi- A 56-year-old, Caucasian, female liver cial lymphohistiocytic dermatitis with focal transplant patient was admitted into the satellite cell necrosis consistent with GVHD hospital for elevated liver function tests early stage (Fig. 2, A and B). Gram and PAS (LFTs) and neutropenia. The patient had stains were negative for pathogenic organ- undergone an orthotopic liver transplant isms. Tissue cultures were negative for CMV for Laennec’s cirrhosis approximately three and Epstein-Barr virus. Approximately 10 months prior to admission, without compli- days later, the skin eruption progressed to cations. She was noted to have an increasing become more generalized, involving the trend in liver function tests at routine trunk and extremities. There were also follow-up in outpatient clinic and was sent noted to be some areas of white hypopig- for hospital admission. The patient had a mentation. Repeat skin biopsies revealed Figure 1. Erythematous maculopapular past medical history of hepatitis C, alco- acute GVHD with a histological grade of eruption on right upper extremity. holic liver cirrhosis, hypertension, diabetes II (Fig. 2, A and B). Triamcinolone 0.1% Patients affected by GVHD typically mellitus, mitral valve prolapse, and bipolar cream and hydroxyzine were added to the present two to six weeks after transplanta- disorder. The patient had a history of patient’s treatment regimen. The patient’s tion with fever or skin rash that is maculo- alcohol abuse but had been sober for over a LFTs continued to be elevated, and there papular, starting distally on the palms and year. Once admitted, the patient was started was no improvement in her overall status. on aggressive immunosuppressant therapy soles and then spreading centrally to become The patient underwent another liver biopsy, 1-21 with Solu-Medrol©, mycophenolate mofetil generalized. Vesicles or bullae may form which revealed central venous conges- 1-21 © © as the eruption progresses. The patient (CellCept ), and tacrolimus (Prograf ). An tion and micro-hemorrhage. The patient may experience diarrhea as a result of donor endoscopic retrograde cholangiopancre- was then placed on the transplant list. lymphocytic infiltration and destruction of atography (ERCP) revealed a stricture of Approximately two weeks later, the patient intestinal mucosa.1-21 Marked pancytopenia the common bile duct at the anastomosis underwent transplant of another liver. Post- may present, leading to life-threatening site. The patient underwent a sphinctero- recovery was unremarkable. The GVHD infection and hemorrhage.1-21 Unlike classic tomy, and a stent was placed. The patient cutaneous findings resolved at the time of GVHD in bone-marrow transplantation, the continued to have elevated LFTs and started discharge, 10 days status post second liver liver is not involved and LFTs are normal.1-21 complaining of epigastric pain. A repeat transplant. ERCP revealed continued blockage, and a This is because the source of the activated stent revision was performed. The patient lymphocytes is the donor liver, and thus Discussion 1-21 continued to have fluctuating LFTs and they do not affect the liver epithelium. elevated bilirubin. A liver biopsy revealed Acute GVHD is a rare complication However, this case is unique in that the nonspecific inflammation. The patient then of liver transplantation that affects 1-2% patient had elevated LFTs and bilirubin underwent an exploratory laparotomy with of patients and has high morbidity and due to graph dysfunction from a common hepatic jejunostomy and Roux-en-Y recon- mortality.1-21 GVHD is more frequently seen bile duct stricture. The GVHD skin rash struction. Approximately 10 days post-op, as a complication of allogeneic bone-marrow developed after the initiation of aggressive the bilirubin levels remained elevated and transplantation and was only recently immunosuppressant therapy. the LFTs fluctuated. Another liver biopsy first described by Burdick et al. in 1988 as Consideration of GVHD requires a high revealed central venous congestion and a complication of liver transplantation.1-21 clinical suspicion correlated with skin biopsy micro-hemorrhage. The patient also started The inciting event of GVHD is thought to for evaluation of any patients presenting to develop a blanchable, erythematous be immunologically active T lymphocytes with an erythematous maculopapular maculopapular rash, predominantly over from the donor liver that engraft and mount rash and history of transplantation. Other the bilateral upper and lower extremities an immune response against the recipient considerations should include drug erup- involving the palms and soles. There were tissues.1-21 The devastating effects are multi- tions, viral infections and graft rejection.1-21 no ulcerations, vesicles or bullae present systemic, involving the skin, gastrointestinal The histological picture of acute GVHD (Fig. 1). The patient was also noted to be track and bone marrow.1-21 involves a superficial perivascular lympho- COMBS, RUBENSTEIN, GOODMAN, BUCKLEY, SKOPIT 51 prognosis of GVHD is poor. Two published 3. Whalen JG, Jukic DM, English JC III. Rash and pancy- topenia as initial manifestations of acute graft-versus-host case series of GVHD after liver transplanta- disease after liver transplantation. J Am Acad Dermatol tion report a high mortality rate of approxi- 2005; 52: 908-11. 4. Schmuth M, Vogel W, Weinlich G, Margreiter R, Fritsch P, 2,23-24 mately 85%. The most common cause Sepp N. Cutaneous lesions as the presenting sign of acute of death was overwhelming sepsis.2,23-24 graft-versus-host disease following liver transplantation. Br J Dermatol 1999;141:901-4. Patients who present with fever have the 5. Collins RH Jr, Cooper B, Nikaein A, Klintamalm G, Fay poorest outcome, with 97% mortality.2,23-24 JW. Graft-versus-host disease in a liver transplant recipi- ent. Ann Intern Med 1992;116:391-2. GVHD confined to the skin occurs in 6. Bhaduri BR, Tan KC, Humphreys S, Williams R, Donald- approximately 15% of reported cases and son P, Vergani D, et al. Graft-versus-host disease after 2,23-24 orthotopic liver transplantation in a child. Transplant Proc has a better prognosis. 1990;22:2378-80. 7. DePaoli AM, Bitran J. Graft-versus- host disease and liver Current treatment for GVHD after liver transplantation. Ann Intern Med 1992;117:170-1. transplantation is mostly empirical and 8. Soejima Y, Shimada M, Suehiro T, Hiroshige S, Gondo H, Takami A, et al. Graft-versus-host disease following living Figure 2 A: Focal vacuolar change based on treatment for GVHD after bone- donor liver transplantation. Liver Transpl 2004; 10: 460-4. with sparse superficial perivascular marrow transplantation.2 The first-line 9. Ghali MP, Talwalkar JA, Moore SB, Hogan WJ, Menon lymphohistiocytic infiltrate 2,23-24,28-30 KV, Rosen CB. Acute graft-versus-host disease after liver therapy is corticosteroids. However, transplantation. Transplantation 2007;83:365-6. corticosteroid therapy for GVHD after 10. Hassan G, Khalaf H, Mourad W. Dermatologic complica- tions after liver transplant: a single-center experience. liver transplantation is less effective than Transplant Proc 2007;39:1190-4. in GVHD after bone-marrow transplan- 11. Cattral MS, Langnas AN, Wisecarver JL, Harper JC, Rubocki RJ, Bynon JS, et al. Survival of graft-versus-host tation. Consequently, additional immu- disease in a liver transplant recipient. Transplantation nosuppression therapy is usually given.1-2 1994;57:1271-4. 12. Roberts JP, Ascher NL, Lake J, Capper J, Purohit S, However, this has not been shown to Garovoy M, et al. Graft vs host disease after liver trans- improve outcomes.1-2,23-24,28-30 Thus, reducing plantation in humans: a report of four cases. Hepatology 1991;14:274-81. or completely withdrawing immunosup- 13. Marubayashi S, Marsuzaka C, Takeda A, et al. Fatal gen- pression has been proposed, but it is not eralized acute graft-versus-host disease in a liver trans- 2,27 plant recipient. Transplantation 1990;50:709-11. currently recommended. Such therapy 14. Neumann U, Kaisers U, Langrehr JM, Muller AR, may lead to graft rejection or worsening Blumhardt G, Bechstein WO, et al. Fatal graft-versus-host disease: a grave complication after orthotopic liver trans- of GVHD by lifting any restraining effects plantation. Transplant Proc 1994;26:3616-7. of immunosuppression on donor lympho- 15. Neumann U, Knoop M, Langrehr JM, Kaisers U, Bechstein Figure 2 B: High power view vacuolar 2 WO, Blumhardt G, et al. Graft-versus-host reaction: a cytes. Even though withdrawal of immu- severe complication after orthotopic liver transplantation. change and satellite cell necrosis nosuppressant therapy is not recommended, Zentralbl Chir 1995;120:478-81. 16. Redondo P, Espana A, Herrero JI, Quiroga J, Cienfuegos our patient presented in this case was noted JA, Azanza JR, et al. Graft-versus-host disease after liver cytic infiltrate with epidermal involvement to have developed signs and symptoms of transplantation. J Am Acad Dermatol 1993;29:314-7. graded from I to IV, with grade I involving 17. Mazzaferro V, Andreola S, Regalia E, Poli F, Doci R, Boz- GVHD after initiation of aggressive immu- zetti F, et al. Confirmation of graft-versus-host disease focal vacuolar changes of the basal cell nosuppression. Thus, there is still much to after liver transplantation by PCR HLA-typing. Transplanta- layer.22 Grade II has vacuolar changes of tion 1993;50:423-5. elucidate about the role of immunosuppres- 18. Pageaux GP, Perrigault PF, Fabre JM, Portales P, Souche the basal cell layer associated with necrosis sant therapy. Besides immunosuppressant B, Dereure O, et al. Lethal acute graft-versus-host disease of keratinocytes that sometimes have adja- in a liver transplant recipient: relations with cell migration therapy, medical management should be and chimerism. Clin Transpl 1995;9:65-9. cent lymphocytes, a phenomenon known as directed toward the prevention of infec- 19. Alexandre G, Portman B. Graft-versus-host disease after “satellite cell necrosis” (Fig 2 B).22 Formation 2,23-24 liver transplantation. Hepatology 1990;11:144-5. tion. Broad-spectrum antibiotics and 20. Nikaein A, Collins RH, Klintmalm G, Poole T, Fay JW, of subepidermal clefts or microvesicles antifungal prophylaxis is recommended.2,23-24 Stone MJ. Immunologic monitoring of graft-versus-host is seen in Grade III.22 Finally, Grade IV disease following orthotopic liver transplantation. Trans- CMV prophylaxis should also be consid- plantation 1994;57:637-40. is the most severe, with bullae formation ered.2,23-24 Patients with severe neutropenia 21. Sanchez-Izquierdo JA, Lumbreras C, Colina F, Martinez- and massive necrosis with complete loss Laso J, Jiminez C, Gomez R, et al. Severe graft-versus- or pancytopenia may benefit from admin- host disease following liver transplantation confirmed by 22 of epidermis. The histopathology must istration of granulocyte colony stimulating PCR-HLA-B sequencing: report of a case and literature be correlated with the clinical picture. The 2,23-24 review. Hepatogastroenterology 1996;43:1057-61. factor. 22. Lerner KG, Kao GF, Storb R, Buckner CD, Clift RA, histological features of GVHD can be seen in In conclusion, GVHD after liver trans- Thomas ED. Histopathology of graft-vs-host reaction other disease entities such as drug eruption, (GvHR) in human recipients of marrow from HLA-matched plantation is an uncommon complication sibling donors. Transplant Proc 1974;6:367-71. erythema multiforme and toxic epidermal and requires a high clinical suspicion. The 23. Smith DM, Agura E, Netto G, Collins R, Levy M, Goldstein necrolysis.2-4 Thus, current studies have been R, Christensen L, et al. Liver transplant-associated graft- most common presenting signs include versus-host disease. Transplantation 2003;75:118-26. focused on alternative diagnostic tools that fever and rash. Typically, the transplanted 24. Taylor AL, Sudhindran S, Key T, et al. Monitoring systemic are more specific for GVHD. Chimerism donor lymphocyte macrochimerism to aid the differential liver is not affected. However, in this case the diagnosis of graft versus host disease following liver trans- is the presence of donor lymphocytes in graft was dysfunctional secondary to a CBD plantation. Transplantation 2004;77:441-46. the peripheral blood.1,2,18,24 This has meet 25. Domiati-Saad R, Klintmalm GB, Netto G, Aura ED, Chin- stricture. Most patients succumb to death nakotla S, Smith DM, et al. Acute graft versus host disease with mixed diagnostic value even when by infection and hemorrhage. The use of in after liver transplantation: patterns of lymphocyte chime- aided by polymerase chain reaction and rism. Am J Transplant 2005;5:2968-73. situ hybridization for the detection of donor 26. Meves A, El-Azhary RA, Talwalkar JA, Moore SB, Brewer flow cytometry techniques. More recently, lymphocytes in skin biopsies may aid in JD, Motsonelidze C, McNallan KT, Reed AM, Rosen CB, a published case report of the use of fluo- et al. Acute graft-versus-host disease after liver trans- making the diagnosis. Current therapy for plantation diagnosed by fluorescent in situ hybridization rescent in situ hybridization analysis was GVHD in liver transplant patients is largely testing of skin biopsy specimens. J Am Acad Dermatol able to confirm the presence of a significant 2006;55:642-6. empirical and based on management of 27. Lehner F, Becker T, Sybrecht L, Luck R, Schwinzer R, number of donor lymphocytes in biopsied GVHD after bone marrow transplantation. Slateva K, Blasczyk R, Hertenstein B, Klempnauer J, skin when a polymerase chain reaction- Nashan B, et al. Successful outcome of acute graft-versus- It includes immunosuppressant therapy and host disease in a liver allograft recipient by withdrawal of based chimerism assay failed to identify control of infection. immunosuppression. Transplantation 2002;73:307-10. donor DNA in peripheral blood.26 Detection 28. Vogelsang GB, Lee L, Bensen-Denndy DM, et al. Patho- genesis and treatment of graft-versus-host disease after of donor lymphocytes in skin biopsies via bone marrow transplant. Annu Rev Med 2003;54:29-52. in situ hybridization may serve as a routine References 29. Hings IM, Filipovich AH, Miller WJ, et al. Prednisolone therapy for acute graft-vs-host disease: short-vs longterm 1 Burdick JF, Vogelsang GB, Smith WJ, et al. Severe graft- diagnostic tool for GVHD in the future, treatment. A prospective randomized trial. Transplantation versus-host disease in a liver-transplant recipient. N Eng J 1993;56:577. which may help with earlier recognition and Med 1988; 318: 689-91. 30. Martin PJ, Schoch G, Fischer L, et al. A retrospective 2. Taylor AL, Gibbs P, Bradley JA. Acute graft versus host treatment. analysis of therapy for acute graft-versus-host disease: disease following liver transplantation: the enemy within. initial treatment. Blood 1990;76: Early diagnosis is essential because the Am J Transpl 2004; 4: 466-74.

52 GRAFT-VERSUS-HOST DISEASE IN A LIVER TRANSPLANT PATIENT WITH GRAFT DYSFUNCTION AXILLARY GRANULAR PARAKERATOSIS - A CASE REPORT

Andleeb Usmani, DO,* John Minni, DO,** Layne Nisenbaum, DO, FAOCD*** *1st-year Resident - Columbia Hospital, West Palm Beach, FL **3rd-year Resident - Columbia Hospital, West Palm Beach, FL ***Program Director - Columbia Hospital, West Palm Beach, FL

ABSTRACT

A 52-year-old woman developed a pruritic, erythematous eruption in the axilla on her right side. Histopathologic examination showed orthokeratosis, parakeratosis and hypergranulosis, which is consistent with the diagnosis of axillary granular parakeratosis, also known as granular parakeratosis. Granular parakeratosis is a benign, idiopathic disorder of the intertriginous areas that manifests as red or brown, scaly or hyperkaratotic papules or plaques. Histopathology is characterized by parakeratosis with retention of keratohyaline granules. The cause is thought to be a defect in the conversion of profilaggrin to filaggrin and hence a defect in the keratinization process. Treatment with corticosteroids, retinoids, Vitamin D analogs, and cryotherapy have been employed but still need more evidence- based data.

the processing of profilaggrin to filaggrin 5. Mehregan DA, Vandersteen P, Sikorski L, Mehregan DR. Case Report Axillary granular parakeratosis. J Am Acad Dermatol. Aug and retention of keratohyaline granules, 1995;33(2 Pt 2):373-5 A 52-year-old woman presented with is the cause. This hypothesis of retention 6. Mehregan DA, Thomas JE, Mehregan DR. Intertrigi- nous granular parakeratosis. J Am Acad Dermatol. Sep a two-week history of unilateral, pruritic, hyperkeratosis is supported by Metze and 1998;39(3):495 erythematous rash in the right axilla. Other Rutten2 and Webster et al.3 Also, reports of 7. Wohlrab J, Lüftl M, Wolter M, Marsch WC. Submam- 3,9 mary granular parakeratosis: an acquired punctate intertriginous areas were not involved. The cases with response to retinoids suggest hyperkeratosis of exogenic origin. J Am Acad Dermatol. patient’s past medical history was consis- that granular parakeratosis is a disorder of 1999;40:813-814 8. Wallace CA, Pichardo RO, Yosipovitch G, Hancox J, tent with right-sided breast cancer that was keratinization. Even though the primary Sangueza OP. Granular parakeratosis: a case report and treated successfully five years prior, with no triggers for this condition are unknown, literature review. J Cutan Pathol. May 2003;30(5):332-5. 9. Brown SK, Heilman ER. Granular parakeratosis: resolu- evidence of recurrence. antiperspirant and deodorants1 have been tion with topical tretinoin. J Am Acad Dermatol. Nov suggested as a causative agent. However, 2002;47(5 Suppl):S279-80. Histological examination showed 10. Mar Blanes Martínez et al. Scaling Lesions on the Axillary orthokeratosis, parakeratosis, hypergran- other intertriginous areas besides the axilla, Skin of a 52-Year-Old Man—Quiz Case. Arch Dermatol. ulosis and mild acanthosis. A periodic- where these products are not applied, have 2004;140: 2,6-8 11. Rodriguez G. [Axillary granular parakeratosis]. Biomed- Schiff exam was negative for fungi. A been involved. Occlusion and macera- ica. Dec 2002;22(4):519-23. diagnosis of axillary granular parakeratosis tion has been suggested as the cause. was made. The patient was treated with Microbiologic cultures have not found a 2.0% hydrocortisone and 1.0% iodoquinol known pathogen, but the role of unrecov- cream (Alcortin) and was advised to avoid ered microorganisms cannot be excluded.10 deodorant. The eruption cleared up in a There has been no association with any few weeks, and there was no recurrence systemic diseases, but in 2002, Rodriguez three months later. reported three cases in obese women.11 The optimal treatment of granular Discussion parakeratosis is not known. In various reports, patients have shown response to Axillary granular parakeratosis is a rare, topical corticosteroids, oral and topical benign, acquired dermatitis of intertrigi- retinoids, topical antifungals and antibi- nous skin first described by Northcutt, otics and vitamin D analogues. Physical Nelson, and TechNet in 1991 in four destruction with cryotherapy has been patients with a maxillary eruption similar reported, as well as spontaneous resolu- to Hailey-Hailey.1 Metze and Rutten tion.2 In our case, the patient responded to suggested the term granular parakeratosis 2.0% hydrocortisone and 1.0% iodoquinol since the eruption can occur in other inter- (Alcortin). 2 triginous areas besides the axilla. In conclusion, granular parakeratosis is a Granular parakeratosis can occur rare, benign disorder of the intertriginous in either sex, but it is more common in areas most likely caused by a defect in the women in their fifth or sixth decade. It keratinization process. presents as erythematous or hyperpig- 3-5 mented papules and plaques in the axilla References or other intertriginous areas,2,6-8 unilater- 1. Northcutt AD, Nelson DM, Tschen JA. Axillary granular ally or bilaterally. Secondary lesions with parakeratosis. J Am Acad Dermatol. Apr 1991;24(4):541- crusts and scales can be present. Patients 4. 2. Metze D, Rütten A. Granular parakeratosis - a unique can have associated pruritus and burning. acquired disorder of keratinization. J Cutan Pathol. Aug 1999;26(7):339-52. The etiology of granular parakera- 3. Webster CG, Resnik KS, Webster GF. Axillary granular tosis is unknown. Northcutt et al.1 first parakeratosis: response to isotretinoin. J Am Acad Der- matol. Nov 1997;37(5 Pt 1):789-90. proposed the hypothesis that a defect in 4. Kossard S, White A. Axillary granular parakeratosis. Aus- the cornification process, specifically in tralas J Dermatol. 1998;39:186-187.

USMANI, MINNI, NISENBAUM 53 MERKEL CELL CARCINOMA MIMICKING A CYST

Danica L. Alexander, DO,* John P. Minni, DO,** Elaine Smith-Marchant, MD,*** Layne D. Nisenbaum, DO, FAOCD**** *2nd Year Dermatology Resident, Columbia Hospital, West Palm Beach, FL **3rd Year Dermatology Resident, Columbia Hospital, West Palm Beach, FL ***West Palm Beach VA Medical Center, West Palm Beach, FL ****Program Director, Columbia Hospital, W. Palm Beach, FL

ABSTRACT

Merkel cell carcinoma (MCC) is an uncommon but aggressive tumor usually occurring in sun-exposed areas of elderly men. The clinical presentations of this tumor are varied. We present an 81-year-old man with a rapidly growing cyst, treated locally without resolution. Subsequent biopsy revealed MCC, and the patient was treated with Mohs surgery and radiation. A review of the literature for diagnosis and management of MCC is also discussed. Clinicians should have a high clinical suspicion when evaluating a cyst in sun-exposed areas of the elderly.

Case Report Discussion An 81-year-old white male with The median age of MCC is 69 years, but Parkinson’s disease and nonmelanoma it may occur earlier in immunocompro- skin carcinoma presented to the derma- mised patients. It predominantly affects tology clinic with a 1 cm, firm but freely elderly Caucasian men. Synonyms include movable cyst on his right mandibular trabecular cell carcinoma, neuroendocrine angle. The patient returned to the clinic or primary small cell carcinoma of the skin, two months later, and the cyst had doubled and anaplastic cell carcinoma. MCC is in size (Figure 1). Incision and drainage most commonly seen in sun-exposed areas, of the cyst was attempted, but no contents especially the head and neck, although were expressed; because of this, a 3 mm there are cases on genitalia and perianal 1 punch biopsy was performed. There was locations. Figure 1 no appreciable lymphadenopathy or oral Overall incidence of MCC has increased lesions. Histopathology revealed Merkel from 0.15 to 0.44 cases per 100,000 popula- cell carcinoma (Figures 2,3). Confirmatory tion between 1986 and 2001, according to immunohistochemical stains were positive the Surveillance Epidemiology and End 2 for cytokeratin 20 (Figure 4), chromogr- Results data. While there are no definitive anin, and synaptophysin. Stains were nega- causes of MCC, there may be possible asso- tive for cytokeratin 7, thyroid transcription ciations with ultraviolet radiation, immu- nosuppression (renal cell transplantation, factor 1 (TTF-1), leukocyte common 2,3 antigen (CD45), S100, and HMB45. He HIV, CLL) and chronic arsenic exposure. There are no clear cytogenetic abnormali- was sent for CT scans of head, neck, and ties, but some reports indicate structural thorax. CT of the head was normal. CT of abnormalities in chromosomes 1, 11 and 13 the neck revealed a 1.9 x 2.1 cm right upper and mutations in tumor suppressor genes neck lesion infiltrating the skin and subcu- Figure 2 p73 and p53.4,5 There are also ongoing taneous fat with questionable infiltration debates as to whether MCC is derived to the parotid gland, and an enlarged 1.1 from Merkel cells, mechanoreceptors in cm left supraclavicular lymph node. A 6 the basal layer, or from pluripotent dermal x 6 mm speculated lesion was found at stem cells.2 Although not confirmed, a the anterior aspect of the left upper lobe, recent research study suggests an associa- suggesting primary versus metastatic tion between polyomavirus and MCC.6 lesion. PET scan was normal. The patient Merkel cell carcinoma is most commonly was scheduled for Mohs surgery, followed found on the head and neck region, by plastic surgery one week later (Figure 5). followed by extremities, trunk, and geni- He subsequently received radiation therapy talia. The typical presentation is a rapidly for six weeks. In addition to dermatology, growing firm, nontender, shiny, pink-red to the patient was followed by hematology/ violaceous, dome-shaped solitary nodule. Figure 3 oncology. A repeat PET scan to assess At the time of diagnosis, there were few therapy was done six months later. It reports describing MCC mimicking a revealed numerous confluent focal areas cyst as seen in this case report. Recently, 56% were presumed benign, and mean 3 of intensely increased tracer uptake in liver, however, in a study of 195 patients, a cyst tumor diameter was 1.8 cm. There are ribs, spine, pelvis, proximal femur and left or acneiform lesion was the most common other reports of Merkel cell carcinoma gluteal muscles. Diffuse metastatic disease presumptive diagnosis. Other tumor presenting as or within a cyst. Two cases was seen on MRI of the spine. Patient was characteristics in that report include: 88% discuss Merkel cell tumors associated with admitted to the hospital for lethargy, and asymptomatic, 63% were rapidly growing trichilemmal cysts.7,8 One report describes soon after expired. (≤ 3 months), 56% were pink or red, a 58-year-old man with Merkel cell carci- 54 MERKEL CELL CARCINOMA MIMICKING A CYST The most commonly used staging system unknown. It is generally not recom- is from Memorial Sloan-Kettering Cancer mended for node negative MCC with good Center (MSKCC): prognosis considering the lack of survival Stage I (T1, N0, M0, primary tumor benefit and side effects. It may be consid- <2cm) ered for distant metastases or advanced Stage II (T2 N0 M0, primary tumor >2 local or regional disease in a palliative cm) manner. Stage III (any T, N1, M0) Favorable prognostic factors are: small Stage IV (any T, any N, M1) size of the primary lesion, initial localized disease, primary tumor in head and neck, Five-year mortality data is12: female sex, age less than 65 year old, and Stage I - 81% absence of nodal disease. In one report, Figure 4 Stage II - 67% 43% of patients with local or regional Stage III - 52% disease developed recurrence, and the Stage IV - 11% median time was nine months. Recurrence Visceral metastasis occurs in liver, bone, typically occurred at the draining lymph lung, and skin. Work-up may include chest node basin. Eight percent of patients with X-ray (to exclude small cell lung carci- a margin-negative excision developed local noma), CT chest, abdomen and pelvis, PET, recurrence.12 Although a time period has and CT head. Sentinel node lymph node not been established, frequent follow-ups biopsy is helpful in establishing staging and with physical examination and chest radio- prognosis; however, more studies need to graph to rule out recurrences or metastases be done to assess benefit in survival.2 are recommended. CT scans of chest, Treatment is varied due to the lack of abdomen and head may also be performed, defined guidelines for this rare tumor. especially in symptomatic patients. In conclusion, this case report empha- Figure 5 Surgery remains the hallmark of treat- ment of MCC. Wide local surgical excision sizes the need for the clinician to have a has been the mainstay of treatment, with high index of suspicion when evaluating a noma arising in the wall of an epidermal cyst, especially in a patient who describes a cyst.9 There are two other cases of Merkel recommended margins of 1-3 cm. Recent studies have shown that Mohs micrographic cyst with a rapid increase in size or who has cell masquerading as an eyelid cyst and risk factors including elderly age, immu- chalazion.10,11 surgery is at least comparable to wide local excision especially in head, neck and distal nosuppression and cyst location in sun- The tumor is found in the dermis and extremities.13,14,15 One study showed 4% exposed areas. subcutaneous tissue, but may be also in the marginal recurrence and 16% overall recur- epidermis in up to 10% cases. There are rence (marginal recurrence plus in-transit References three histologic subtypes: trabecular, inter- 16 metastases) in small stage I disease. 1. Swann MH, Yoon, J. Merkel cell carcinoma. Semin mediate and small cell variants. The inter- MCC is considered to be radiosensitive, Oncol 2007; 34:51-6 mediate variant is the most common and 2. Bichakjian C et al. Merkel Cell Carcinoma: Critical consists of nodules and sheets of basophilic but there are no strict guidelines on when Review With Guidelines for Multidisciplinary Manage- to use adjuvant radiation therapy (RT), or ment. Cancer 2007;110:1-12 cells with vesicular nuclei. The second 3. Heath M, et al. Clinical characteristics of Merkel cell car- most common is the small cell variant when to radiate only the primary site, or cinoma at diagnosis in 195 patients: the AEIOU features. to include the lymph node basin. A recent JAAD 2008;58:375-81 described as cells with hyperchromatic 4. Leonard, JH, Leonard P, Kearsley, JH. Chromosomes nuclei, arranged in sheets and clusters, review of the literature showed that surgery 1, 11, and 13 are frequently involved in karyotypic abnor- plus local adjuvant irradiation was associ- malities in metastatic Merkel cell carcinoma. Cancer and associated with crushed nuclei debris. Genet Cytogenet 1993; 67:65 ated with significantly lower rates of local 5. Van Gele M, et al. Mutation analysis of P73 and TP53 in The trabecular, the least common subtype, Merkel cell carcinoma. Br J Cancer 2000; 82:823 and regional recurrence of MCC than 6. Feng H. Clonal Integration of a polyomavirus in human is characterized by ribbons of uniform 17 cells. Mitotic figures and lymphatic and surgery alone. However, treatments did Merkel cell carcinoma. Science 2008;319:1049-50 not vary significantly in a study comparing 7. Collina G, Bagni A, Fano RA. Combined neuroendocrine vascular invasion are common. The cells carcinoma of the skin (Merkel cell tumor) and trichilemmal contain neuropeptides including chro- Mohs with or without adjuvant radiation, cyst. 1997;19:545-8 and the authors suggested radiation for 8. Perse RM, Klappenbach RS, Ragsdale BD. Trabecular mogranin, calcitonin, vasoactive intestinal (Merkel cell) carcinoma arising in the wall of an epidermal peptide, metenkephalin, somatostatin, and patients unable to have complete excision or cyst. Am J Dermatopathol 1987;9:423-7 for large or recurrent tumors.16 Additional 9. Ivan D, et al. Merkel cell tumor in a trichilemmal cyst: col- synaptophysin. Immunohistochemistry lision or association? Am J Dermatopathol;29:180-3 is frequently positive for cytokeratin 20, studies are needed to determine if this affects 10. Rawlings NG, Brownstein S, Jordan DR. Merkel cell overall survival. Radiation may be beneficial carcinoma masquerading as a chalazion. Can J Ophthal- neurofilament, neuron-specific enolase, mol. 2007;42:469-70 and epithelial membrane antigen, but nega- for larger primary tumors, close or positive 11. Kirkham N, Cole MD. Merkel cell carcinoma: a malignant surgical margins, or inoperable patients. neuroendocrine tumour of the eyelid. 1983:67:600-3 tive for cytokeratin 7, thyroid transcription 12. Allen P, et al. Merkel Cell Carcinoma: Prognosis and Controversy exists as to the manage- Treatment of Patients From a Single Institution. J Clin factor 1, vimentin, and S-100. The histo- Oncol 2005;23:2300-2309 logic differential diagnosis includes: small ment of micrometastatic disease found 13. O’Connor WJ, Roenigk, Brodland DG. Merkel cell car- with sentinel lymph node biopsy. Limited cinoma. Comparison of Mohs micrographic surgery cell lung carcinoma (SCLC), lymphoma, and wide excision in eighty-six patients. Dermatol Surg small cell melanoma, and primitive data suggests that complete lymph node 1997;23:929-33 neuroectodermal tumor (PNET)/Ewing’s dissection (CLND) is the first line of treat- 14. Gollard R, et al. Merkel Cell Carcinoma: Review of 22 2 Cases with Surgical, Pathologic, and Therapeutic Con- sarcoma. Cytokeratin 20, a low molecular ment. RT to the lymph node basin may be siderations. Cancer 2000;88:1842-51 another option or an addition to CLND in 15. Senchenkov A, Barnes SA, Moran SL. Predictors of weight intermediate filament, is helpful in survival and recurrence in the surgical treatment of differentiating MCC from SCLC. It stains patients with extensive lymph node disease. merkel cell carcinoma of the extremities. J Surg Oncol In patients who have not had a sentinel 2007;95:229 as brown paranuclear dots and is positive 16. Boyer JD, et al. Local control of primary Merkel cell in 89% to 100% of MCC compared to up lymph node biopsy, adjuvant nodal therapy carcinoma: Review of 45 cases treated with Mohs micro- may be warranted.11 graphic surgery with and without adjuvant radiation. Der- to 33% of small cell lung carcinoma. TTF1 matol Surg 2002;47:885-92 is positive in 83%-100% of SCLC but nega- Chemotherapy is the least studied 17. Lewis KG, et al. Adjuvant Local Irradiation for Merkel Cell tive in MCC.2 therapy, and the optimal regimen is Carcinoma. Arch Dermatol 2006;142:693-700

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Anita Osmundson, D.O.,* Mary McGonagle, D.O.,** Tanya Ermolovich, D.O.*** *Dermatology Resident, Third Year, Philadelphia College of Osteopathic Medicine/Frankford Hospitals, Philadelphia, Pennsylvania **Philadelphia Institute of Dermatology, Fort Washington, Pennsylvania ***Residency Program Director, Philadelphia College of Osteopathic Medicine/Frankford Hospitals, Philadelphia, Pennsylvania

ABSTRACT

Verrucous psoriasis is a rare, clinico-histopathological variant of psoriasis that may clinically and histopathologically resemble verruca vulgaris. This variant of psoriasis is thought to result from repeated trauma or irritation to pre-existing psoriatic lesions. We present a case of verrucous psoriasis occurring in a 47-year-old African American male with no history of psoriasis.

Introduction acin. A fungal culture was negative. been implicated. Scavo et al. report a case of Histopathologic examination of a skin verrucous psoriasis developing after inter- Psoriasis is a common, chronic, biopsy performed on his right lateral neck feron (IFN-α) therapy in a patient with a immune-mediated disorder of the skin demonstrated parakeratosis, papilloma- history of common psoriasis and a six-year that has various clinical features. There tosis, numerous neutrophils within finger- history of chronic hepatitis C.7 are several clinico-histopathologic vari- like epidermal hyperplasia (particularly in Histopathologically, verrucous psoriasis ants that include classic psoriasis vulgaris, the parakeratotic horn), an absent granular shows overlapping features of both psoriasis erythrodermic, guttate and pustular.1 A layer and a superficial perivascular mixed- and verruca vulgaris.2 Some areas show the rare, under-recognized variant given the cell infiltrate (Figures 4, 5, 6). Periodic acid typical psoriatic histopathology of parak- name verrucous or hypertrophic psori- Schiff staining for fungi was negative. eratosis, Munro’s microabscesses, regular asis produces lesions that may clinically Currently, he is being treated with halo- elongation of the rete ridges, decreased and histopathologically resemble verruca betasol 0.05% ointment to lesions on the or absent granular layer, suprapapillary vulgaris. The lesions typically occur in trunk and considering systemic treatment thinning, dermal vascular dilatation patients with a history of psoriasis and with methotrexate. and perivascular lymphocytic infiltrate. present as wart-like growths on the extrem- In addition, histopathologic features of ities. Histopathologically, the lesions have Discussion verruca vulgaris are common, including overlapping features of both psoriasis and epidermal papillomatosis, creating finger- verruca vulgaris.2 We report a case of new- Psoriasis is a chronic, common derma- like projections and bowing of the periph- onset verrucous psoriasis developing in a tosis characterized by well-demarcated, eral rete ridges toward the center of the patient with no history of psoriasis. erythematous papules and plaques with an lesion (buttressing).2,4,5 Hypergranulosis adherent silver-white scale. The lesions are and koilocytic changes observed in verruca Case distributed symmetrically with a predilec- vulgaris are not present.2 tion for the scalp, elbows, knees, low back 3 Treatment options specific for this A 47-year-old African American male and genitals. Nail involvement characteris- variant of psoriasis are not well reviewed presented to the office with a five-month tically presents as pitting and onycholysis. in the literature. Treatment with topical history of an asymptomatic rash, which Histopathologically, psoriasis typically corticosteroids, coal tar, PUVA and cryo- started on his abdomen. Initially, he was shows parakeratosis, Munro’s microab- therapy have been reported in the litera- treated with a three-month course of scesses, regular elongation of the rete ture.4,6 Kuan et al. reported a patient with terbinafine by his primary care physician, ridges, decreased or absent granular layer, multiple verrucous carcinomas who was who suspected a fungal infection as well suprapapillary thinning, dermal vascular successfully treated with acitretin.8 In an as onychomycosis of several toenails. His dilatation and perivascular lymphocytic editorial to this case by Larsen et al., the 1 toenails and several skin lesions cleared; infiltrate. authors believed the patient actually had however, a few lesions persisted. The erup- Verrucous or hypertrophic psoriasis is verrucous psoriasis, which would explain tion then worsened. The lesions spread an under-recognized and seldom-reported the rapid response to acitretin.9 to involve the head, neck and extremities clinico-histopathologic variant of psori- and became thicker and more wart-like in asis.2 It clinically presents with mammil- Conclusion appearance. The patient had no history of lated, tan-white, hyperkeratotic papules psoriasis or joint pain, and his past medical and plaques in patients with a history of Verrucous psoriasis is a distinct, clinico- history included hypertension, which was psoriasis vulgaris. A symmetrical distribu- histopathologic variant of psoriasis that controlled by valsartan. He had a question- tion may be observed. These lesions tend may clinically and histopathologically able family history of psoriasis. to favor the dorsal hands and extensor resemble verruca vulgaris. The lesions Physical examination revealed multiple surfaces of the extremities.2,4-6 An annular are thought to be a cutaneous response pink, tan, mammillated and hyperkera- variant of verrucous psoriasis occurring to repeated trauma in patients with pre- totic papules and plaques on the head, on the back of a 22-year-old female with existing psoriasis. Clinically, the lesions neck, trunk, axillae, groin, and extremities a 10-year history of psoriasis has also been are reminiscent of verruca vulgaris and (Figures 1, 2, 3). No pitting, thickening described.6 tend to occur on the dorsal extremities, or discoloration of nails was observed. A The pathogenesis is unknown; however, it sites with a higher predilection for trauma. bacterial culture grew Enterobacter cloacae is postulated by Khalil et al. to be a patterned Histopathologically, epidermal papillo- and Staphylococcus aureus, and he was response of the epithelium to repeated matosis and epidermal buttressing seen treated with a 10-day course of ciproflox- trauma or irritation.2 Medications have also in these lesions is suggestive of verruca OSMUNDSON, MCGONAGLE, ERMOLOVICH, 57 vulgaris. Our patient is unique because he developed a majority of his lesions on the head, neck and trunk and has no history of pre-existing psoriasis.

References: 1. Spongiotic, psoriasiform and pustular dermatoses. In: McKee PH, Calonje E, Granter SR, editors. Pathology of the skin with clinical correlation. Philadelphia: Elsevier Mosby; 2005. p195-206. 2. Khalil FK, Keehn CA, Saeed S, Morgan MB. Verrucous pso- riasis: a distinctive clinicopathologic variant of psoriasis. Am J Dermatopathol 2005;27:204-7. 3. Gudjonsson JE, Elder JT. Psoriasis. In: Wolff K, Goldsmith LA, Katz SI, Gilchrest BA, Paller AS Leffell DJ, editors. Fitzpatrick’s dermatology in general medicine. New York: Figure 1. Pink, mammillated papules McGraw-Hill; 2008. p169-193. and plaques on the scalp, face and 4. Nakamura S, Mihara M, Hagari Y, Shimao S. Psoriasis ver- neck. rucosa showing peculiar histologic features. J Int Dermatol 1994;21:102-5. 5. Rajendran SS, Premalatha S, Yesudian P, Zahra A. Psoriasis verruciformis. Int J Dermatol 1984;23:552-3. Figure 4. Punch biopsy from the right 6. Erkek E, Bozdogan O. Annular verrucous psoriasis with exag- gerated papillomatosis. Am J Dermatopathol 2001;23:133-5. lateral neck demonstrating features 7. Scavo S, Gurrera A, Mazzaglia C, Magro G, Pulvirenti of psoriasis, including parakeratosis, D, Gozzo E et al. Verrucous psoriasis in a patient with chronic C hepatitis treated with interferon. Clin Drug Invest regular elongation of the rete ridges 2004;24:427-9. and a perivascular infiltrate. Verrucous 8. Kuan Y, Hsu H, Kuo T, Huang YH, Ho HC. Multiple verru- cous carcinomas treated with acitretin. J Am Acad Dermatol features include hyperkeratosis and 2007;56:S29-32. papillomatosis. (Hematoxylin-eosin 9. Larsen F, Susa JS, Cockerell CJ, Abramovits W. Case of stain; 4x magnification) multiple verrucous carcinomas responding to treatment with acitretin more likely to have been a case of verrucous psoria- sis. J Am Acad Dermatol 2007;57:534-5.

Figure 2. Tan, verrucous papules and plaques on the trunk.

Figure 5. Parakeratosis; Munro’s microabscesses; epidermal papillomatosis creating finger- like projections; absent granular layer; dermal vascular dilatation. (Hematoxylin-eosin stain; 10x magnification)

Figure 3. Verrucous plaque on the lower back.

Figure 6. Higher magnification showing a column of parakeratosis, Munro’s microabscesses and epidermal finger- like projections. (Hematoxylin-eosin stain; 20x magnification)

58 VERRUCOUS PSORIASIS: A CLINICOHISTOPATHOLOGIC VARIANT OF PSORIASIS SIBLINGS WITH X-LINKED RECESSIVE ICHTHYOSIS: A CASE REPORT AND BRIEF REVIEW

David R. Bonney, D.O.,* Matthew Elias, D.O.,* and Stanley E. Skopit, D.O., FAOCD** *Dermatology Resident, NSU/Broward General Medical Center **Program Director, NSU/Broward General Medical Center

ABSTRACT

X-linked recessive ichthyosis is an inherited disorder of keratinization that affects approximately one in 6,000 boys and men. It is due to steroid sulfatase deficiency, and most cases are caused by deletions of the steroid sulfatase (STS) gene found on the distal portion of the short arm of the X chromosome (Xp22.3). Two first-degree siblings presented with a lifelong history of diffuse, brown, thickened scales that mostly covered their extensor surfaces of the extremities, trunk and face. They reported having biopsy-proven X-linked recessive ichthyosis diagnosed while in the Dominican Republic. This case report outlines the details of their clinical presentation and medical management, and reviews publications of similar findings

Case Presentation 25mg orally starting every other day, tazar- otene cream 0.1% to the hands at bedtime, Two brothers, F.A. and A.A., aged 13 and ammonium lactate 12% lotion twice and 14 years, respectively, presented to our daily to the rest of the body. In addition, office with a lifelong history of very dry general instructions regarding treatment skin with thick scales and some itching. for xerosis were advised, including mild The boys were accompanied by their soaps and the liberal use of moisturizers. grandmother, who reported a biopsy being Copies of their most recent blood work done in the Dominican Republic six years were ordered, and both patients were sent prior to this visit. She reported that they for a testicular ultrasound and ophthalmo- were given the diagnosis of X-linked reces- logic examination if warranted. A copy of sive ichthyosis. They were treated with the biopsy performed in the Dominican multiple topical medications, including Republic could not be obtained. Figure 1 tazarotene, ammonium lactate 12% lotion, The two first-degree siblings returned and urea lotion, with marked improve- for a follow-up approximately one month ment. They also reported taking acitretin later, with minimal improvement. They with significant improvement. The dosage were only using the 12% ammonium and length of time were unknown. Our lactate because of difficulties obtaining the patients reported not being on any medica- other medications through their insurance. tion for several months due to medical Again, they reported no other symptoms or insurance issues, and presented for treat- problems at that time. Blood work results ment for exacerbation of their skin rash. were reviewed, and were all within normal F.A. and A.A. denied any other limits. Eye exams showed mild ectropion of complaints at that time, including no eye both lower lids in F.A., and mild ectropion difficulties, smelling problems, or any with corneal scarring in A.A. Testicular abnormalities with the testicles. There was ultrasound in A.A. revealed a small left Figure 2 no report of intellectual impairment or hydrocele and no testicular masses. The other problems with their health. They did report on F.A. was still pending at that with chorionic villus sampling (CVS) by report recently having blood work and an time. a steroid sulfatase assay and by increased ophthalmologic examination ordered by The patients were continued on the dehydroepiandrosterone sulfate (DHEAS) their primary care physician. The grand- 12% ammonium lactate lotion twice daily, levels. The worldwide birth incidence mother denied any known family history and prior authorization for the acitretin ranges between 1 in 2,000 to 1 in 9,500 of similar skin conditions in male or female and tazarotene were initiated. Again, both members. males, and the age of presentation is from patients were advised to continue with two to six weeks old. On physical examination of both general dry skin care. Yearly eye exams and An STS gene deletion leads to decreased patients, there was generalized symmetrical, self testicular exams with periodic testicular steroid sulfatase activity in the stratum thickened, hyperpigmented and translu- ultrasounds were also recommended. No corneum. This leads to increased choles- cent scaling of the face, neck, extremities biopsies or genetic testing were performed, and trunk. Both the extensor and flexor and the patients were due for follow-up at terol sulfate and DHEAS with subsequent surfaces were affected, and large areas of the time of this documentation. accumulation of cholesterol-3-sulfate in desquamation were noted as well. There the epidermis. This process is believed were no significant differences in severity Discussion to play a role in retention hyperkeratosis. or location on the two brothers. No Failure of labor to begin or progress in a signs of secondary infection were noted. X-linked recessive ichthyosis, also known mother carrying an affected fetus occurs Otherwise, both patients were pleasant, well as steroid sulfatase (STS) deficiency, has because of decreased placental sulfatase and nourished, well developed and in general been reported to occur after complete gene estrogen, as well as increased fetal DHEAS. good health. No gross eye, ear, nose or deletion on the Xp22.32 location in 90% This leads to insufficient dilation of the testicular abnormalities were found. of patients and inactivating mutations in cervix. This can be partially overcome by F.A. and A.A. were placed on acitretin others. A prenatal diagnosis can be made oxytocin administration, but often requires BONNEY, ELIAS, SKOPIT 59 cations improve the scaling. Emollients, in particular propylene glycol, topical kera- tolytics and retinoids, are effective alone or in combination. The administration of systemic retinoids is rarely necessary.

REFERENCES: 1. Hazan C, Orlow SJ, Schaffer JV. X-linked recessive ich- thyosis. Dermatol Online J. 2005 Dec 30; 11(4): 12. 2. Liao H, Waters AJ, Goudie DR, Aitken DA, Graham G, Smith FJ, Lewis-Jones S, McLean WH. Filaggrin muta- tions are genetic modifying factors exacerbating X-linked ichthyosis. J Invest Dermatol. 2007 Dec;127(12):2795-8. 3. Lesca G, Sinilnikova O, Theuil G, Blanc J, Edery P, Till Figure 3 M. Xp22.3 microdeletion including VCX-A and VCX-B1 genes in an X-linked ichthyosis family: no difference in deletion size for patients with and without mental retarda- tion. Clin Genet. 2005 Apr;67(4):367-8. 4. Abe K, Matsuda I, Matsuura N, Murayama T, Uzuki K, Okuno A. X-linked ichthyosis, bilateral cryptorchidism, hypogenitalism and mental retardation in two siblings. Clin Genet. 1976 Mar:9(3):341-5 5. Spitz, JL. Genodermatoses. A Clinical Guide to Genetic Skin Disorders. Second Edition. 2005. Lippincott Wil- liams & Wilkins. P.4-5. 6. Bolognia JL, Jorizzo JL, Rapini RP. Dermatology. 2003. Mosby. P.781-2.

Figure 4 a Cesarean section for delivery. The key features of X-linked recessive ichthyosis are the brown, firmly adherent, large polygonal scales predominantly on the extensors, posterior neck and trunk, with relative sparing of the flexures. Sparing of the palms, soles and face is common, with the exception of the preauricular area. This last finding is thought to be pathog- nomonic by some clinicians. Other find- ings include asymptomatic, comma-shaped corneal opacities occurring in 50% of adult males and some female carriers. There also is cryptorchidism in approximately 20% of affected males, with an increased risk of testicular cancer. The cutaneous involvement waxes and wanes throughout the patient’s life, with seasonal variation. It does not significantly subside with age, in contrast to ichthyosis vulgaris. The histopathologic findings include hyperkeratosis or parakeratosis overlying a normal or slightly thickened granular layer. Follicular hyperkeratosis may also be present. On electron microscopy there are an increased number and size of kera- tohyalin granules. In the stratum corneum, the cells contain a large number of melano- somes, and the desmosomes are retained. Clinically, ichthyosis vulgaris is distin- guished from X-linked recessive ichthyosis by sparing of the flexural areas, especially the neck, and an association with hyper- linear palms and soles as well as keratosis pilaris. Other conditions to be considered in the differential diagnosis of STS defi- ciency are Kallmann syndrome and Rud syndrome. It is important to maintain good hydra- tion in these patients, and multiple medi- 60 SIBLINGS WITH X-LINKED RECESSIVE ICHTHYOSIS: A CASE REPORT AND BRIEF REVIEW CASE REPORT OF EXTRAGENITAL LICHEN SCLEROSIS ET ATROPHICUS IN AN ADOLESCENT FEMALE

Derrick H. Adams, DO,* and Michael Mahon, DO, FAOCD** *Resident of Dermatology, Botsford Hospital, Farmington Hills, MI **Program Director, Pontiac Osteopathic Hospital, Pontiac, MI

ABSTRACT

Lichen sclerosis et atrophicus (LSetA) is an uncommon cutaneous disease of unknown cause that manifests itself as white plaques with epidermal atrophy. Extragenital LSetA is quite rare in children, with the majority of cases favoring females.1 We describe a case of a 6-year-old female with LSetA involving her abdomen, and we discuss the available literature regarding the emerging pathophysiology and treatment of extragenital LSetA.

Case Report have been seen on both female and male genitalia, approximately 15%-20% of A 6-year-old white female in a usual cases do not involve the genitals. On the state of good health was referred to the non-genital skin, the disease may manifest dermatology clinic for “white patches” on itself as atrophic, porcelain-white patches her abdomen of four-month duration. She and can appear as discrete plugs inside the had been previously treated by her family orifices of follicles or sweat glands. Atrophy physician with over-the-counter moistur- of the skin also commonly occurs. Typical izers without any benefit. On exam, two extragenital distribution is seen in the atrophic, well-demarcated hypopigmented body folds, inframammary areas, shoul- patches with “cigarette-paper” appearance ders and neck. While rare, oral cases have were noted on her right lower abdomen. been reported. Extragenital cases are typi- Figure 1 The remainder of her exam was unremark- cally asymptomatic except for pruritis and able. The patient had no systemic symp- associated cosmetic concerns. Both genital previous examples support the numerous toms and no family history of autoimmune and extragenital cases are characterized observational reports of familial cases of diseases. There were no other family by cycles of remission and exacerbations, LSetA.5 Additionally, it has been observed members with LSetA. Desoximetasone often independent of treatment efforts. that the condition is likely to spontane- cream 0.25% was prescribed twice daily, While the exact cause of LSetA is still ously resolve during puberty, leading to the and the benign nature and course of LSetA unknown, several autoimmune mecha- hypothesis that unknown developmental was discussed with the parents. On follow- nisms have recently been elucidated. factors may be implicated.6 The Koebner up a month later, the father stated the size Inflammation and altered fibroblast phenomenon has also been reported in of the patches was slightly improving, but activity results in fibrosis in the upper areas of repeated trauma, sunburn, and they were still present. The desoximetasone dermis. Associations in the abnormal old surgical scars. Extragenital LSetA along was tapered to daily application during the ratios of interleukin-1 (IL-1) and inter- the distribution of Blaschko’s lines has also week and twice daily on weekends. The leukin-1 receptor antagonist (IL-1ra) have been described.1 patient continues to do well, is monitored been observed.3 IL-1ra is a naturally occur- Except for the occasional associated with monthly appointments, and remains ring cytokine that inhibits interleukin-1 pruritis, extragenital LSetA rarely requires free of corticosteroid-induced side effects. (IL-1) by binding to IL-1 receptors, halting any therapeutic intervention. High-potency Close follow-up with the patient and intracellular signal transduction; thus, topical steroids are the most accepted parents is maintained to ensure treatment IL-1ra acts as a powerful endogenous anti- treatment, but they have been associated utilization is consistent with their under- inflammatory molecule. A genetic repeat with a greater than 50% relapse rate at 16 standing and expectations. resulting in the decreased production of months in one study.7 Therefore, it must IL-1ra has been isolated in patients with be stressed that any potential cosmetic Discussion LSetA, cutaneous lupus, and inflammatory benefits of treatment must be carefully bowel diseases3 and has been hypothesized weighed against development of steroid- LSetA is a benign, but chronic inflamma- to play a partial role in this disease state. induced complications or contact derma- tory cutaneous disease of unknown cause Other recent investigations have centered titis. Pimecrolimus cream 1%, topical that appears as hypopigmented patches on the development of ELISA methods to retinoids, metronidazole (250mg three with epidermal atrophy, rendering a clas- quantitatively measure circulating autoan- times a day), and erythromycin (250mg sical “cigarette paper” or parchment-like tibodies to the glycoprotein extracellular a day) have been successfully utilized in appearance. LSetA of the vulva and penis matrix protein 1 (ECM1) in patients with genital LSetA and would likely be well- in children is more common, and females LSetA. Higher anti-ECM1 titers correlated tolerated in our patient; however, no litera- are usually afflicted more than males, at with more longstanding and refractory ture supporting the effectiveness of these ratios as high as 10:1.2 There have been lesions and cases complicated by squamous- treatments could be located specifically in numerous case reports discussing LSetA cell carcinoma.4 Demonstration of passive regard to extragenital cases.8,9 There have having been mistaken for child abuse by transfer, with anti-ECM1 IgG inducing been sporadic reports in the literature of practitioners unfamiliar with this entity. histopathic changes of LSetA in the murine vulvar LSetA progressing to squamous- While the majority of cases described model, has also been achieved.4 These two cell carcinoma, but the precise risk and

ADAMS, MAHON 61 which cofactors are involved remain under investigation.1 While there is a paucity of data regarding the malignant transforma- tion potential of extragenital lesions, that potential is widely believed to be low.10 In summary, we describe a case of extragenital LSetA and briefly review the pathophysiology and treatments of this uncommon inflammatory entity.

References: 1 Meffert J. Lichen sclerosis et atrophicus. Dec 2006. http:// www.emedicine.com/DERM/topic234.htm 2 Powell J, et al. Childhood vulvar lichen sclerosus: An increasingly common problem. J Am Acad Dermatol 2001;44:803-6 3 Clay F, et al. Interleukin 1 receptor antagonist gene poly- morphism association with lichen sclerosis. Hum. Genet. 1994: 407-410 4. Oyama N, et al. Autoantibodies to extracellular matrix protein 1 in lichen sclerosis. Lancet 362: 118-123, 2003. 5. Shirer J, et al. Familial occurrence of lichen sclerosus et atrophicus: case reports of a mother and daughter. Arch. Derm. 1987; 485-488 6 Thomas M, et al. Lichen sclerosus et atrophicus and autoimmunity—a study of 350 women. British Journal of Dermatology 1988;118(1):41–46 7 Renaud-Vilmer C, et al. Vulvar lichen sclerosus effect of long-term topical Application of a potent steroid on the course of the disease. Arch Dermatol. 2004;140:709-712. 8. Shelley W, Shelley E. Lichen sclerosus et atrophicus. Advanced Dermatologic Therapy. 2001; 647-49 9 Eriksen N, et al. Pimecrolimus cream 1% in the treatment of lichen sclerosis. Gynecologic & Obstetric Investigation. 2007; 63(3):151-4 10 Van Rossum M, et al. Lichen sclerosus: review. Neder- lands Tijdschrift voor Geneeskunde. 2007 Jun; 151(22):1225-31

62 CASE REPORT OF EXTRAGENITAL LICHEN SCLEROSIS ET ATROPHICUS IN AN ADOLESCENT FEMALE The 2009 South Beach Symposium Faculty to include: Join us in Miami Beach... (Partial List) Symposium Chair Mark S. Nestor, MD, PhD

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WEB Any questions regarding this meeting please call 904-309-6262 SYSTEMIC SCLEROSIS: CASE REPORT AND REVIEW OF THE LITERATURE

Adriana Ros, D.O.,* Marvin Watsky, D.O.** *3rd-year resident, St. John’s Episcopal Hospital, South Shore, Department of Dermatology – Far Rockaway, NY **Program Director, St. John’s Episcopal Hospital, South Shore, Department of Dermatology – Far Rockaway, NY

ABSTRACT

Systemic sclerosis is a chronic autoimmune disorder characterized by thickening of the skin and accumulation of connective tissue in various organs, causing varying degrees of organ dysfunction. The symptoms result from inflammation and progressive tissue fibrosis and occlusion of the microvasculature by excessive production and deposition of types I and III collagens. In this case report, we describe a Hispanic female with new dermatologic and systemic findings consistent with systemic sclerosis and review the literature.

Case Report: She was started on Claritin 10mg daily, Kenalog cream 0.1% twice a day, and over- A 44-year-old Hispanic woman presents the-counter moisturizers for her pruritus. with pain in her hands and feet for the past She was given prednisone 5mg twice a six months. The patient states both her day and Cuprimine 250mg three times a hands and feet are pruritic and swollen. day by her rheumatologist. She was also She also complains of cold hands for which prescribed Flexeril 10mg at bedtime as she needs to wear gloves despite the warm needed. The patient was encouraged to temperature. This is her first occurrence. wear double gloves for her hands to keep She denies any history of dermatological them warm and well circulated. She was disorders. Her past medical history is instructed to avoid skin trauma and cold significant for carpal tunnel syndrome. exposure. Physical therapy of the hands She denies a family history of skin or and feet were recommended to prevent Figure 1 rheumatologic disease. She does not take contractures. She was instructed to follow- any medications. On review of systems, up with cardiology, rheumatology, gastro- she complains of dysphagia, chest pain, enterology, and nephrology. frequent urination, xerostomia, arthralgia, and diffuse pruritus. On physical exami- Discussion: nation, there is skin tightness along with Scleroderma is derived from the Greek induration of both her dorsal hands and word “sklerosis,” meaning hardness of the feet. There is a salt-and-pepper appearance skin. The group of diseases called scle- to the skin, with areas of hyperpigmenta- roderma fall into two main classes: local- tion alternating with hypopigmentation ized scleroderma and systemic sclerosis. (Figures 1 and 2). Areas of her skin appear Localized scleroderma can be further shiny with loss of hair, mostly on the fore- categorized into morphea and linear scle- arms. The fingertips appear well perfused. roderma. Systemic sclerosis is divided into Figure 2 There are no telangiectasias on the face, limited cutaneous and diffuse cutaneous. hands, or chest. There is no perioral or Limited cutaneous scleroderma typically facial involvement. She has atrophic comes on gradually and affects the skin plaques on both knees with tenderness only in certain areas: the fingers, hands, (Figure 3). Examination of the heart, face, lower arms, and legs. Most people lungs, and abdomen are unremarkable. with limited disease have Raynaud’s There are no neurologic deficits. phenomenon for years before skin thick- The laboratory values were assessed ening starts. Telangiectasias and calcinosis at this time. Her complete blood count, often follow. People with limited disease comprehensive metabolic panel, and often have all or some of the symptoms thyroid function test were within normal called CREST, which includes calcinosis, limits. Sjogren’s anti-SS A and B were Raynaud’s phenomena, esophageal dysfunc- within normal limits. RNP antibodies, tion, sclerodactyly, and telangiectasias. anti-myeloperoxidase antibodies, and anti- Systemic sclerosis is an autoimmune Figure 3 proteinase 3 were negative. C-ANCA and disorder of the connective tissue and is P-ANCA had normal titers. C-reactive characterized by skin induration and thick- Raynaud’s phenomena, healed pitting protein was high at 6.2. ANA was positive ening. This condition typically comes on ulcers in the fingertips, and cutaneous and with a ratio of 1:80. ACE, RF, and ESR were suddenly. Skin thickening begins in the mucosal telangiectasis. The skin of the face normal. Antiscleroderma-70 antibodies hands and spreads quickly over much of were negative. Due to the limited outside the body in a symmetrical fashion. Skin becomes masklike and expressionless, with clinical facility, the patient did not have a changes can cause the skin to become loss of the normal facial lines and then skin biopsy done. She did not follow-up in edematous, shiny, tight and pruritic. Other thinning of the lips and constriction of our hospital clinic for a skin biopsy. associated cutaneous symptoms include the opening of the mouth (microstomia).2 ROS, WATSKY 65 Radial furrowing around the mouth is with a peak onset at 30-50 years of age. In have been used to treat pulmonary issues. seen.2 There may also be a small, sharp general, the survival rate lies between 34% Proton pump inhibitors and H2 blockers appearance to the nose. and 73%.4 The age-adjusted death rate for can help control gastroesophageal reflux Systemic sclerosis is also accompanied systemic sclerosis is 6.8 cases per million symptoms. Surgery for esophageal stric- by various degrees of tissue fibrosis and in women, 2.1 cases per million in men, tures can be utilized. Antifibrotic treat- chronic inflammatory infiltration in and 4.7 cases per million for the whole ment options include D-penicillamine, numerous visceral organs. People with population.7 Death rates peaked a decade interferon alpha and gamma, corticos- diffuse disease often are lethargic, lose earlier in the African American population teroids, methotrexate, thalidomide, and weight, and have joint swelling and/or when compared with those in the white cyclosporine. Early and continuous phys- pain. Patients can have gastroesopha- population (65-74 years vs. 75-84 years of ical therapy is crucial to maintain joint geal reflux, dyspepsia, constipation, age).7 Age-adjusted mortality was highest mobility. Smoking cessation should be chest pain, and dyspnea. They may also in African American women at 9.5 cases encouraged to decrease the morbidity asso- suffer from arthralgia, loss of joint range per million. ciated with Raynaud’s phenomena. of motion, and palpable tendon friction A logistic regression model identified In this case report, we describe a middle- rubs. Sclerodactyly causes the fingers to three factors: proteinuria, elevated ESR and aged Hispanic woman with systemic scle- become tapered. Trigeminal neuralgia low carbon monoxide diffusing capacity, rosis. Our patient has the major criteria and carpal tunnel symptoms may result which in combination had an accuracy of of sudden onset of skin thickening and from peripheral entrapment neuropathies. 80% in predicting mortality.7 The absence induration of her hands and feet. She Cardiac manifestations may include palpi- of these three factors was associated with has also developed dysphagia, dyspnea, tations, conduction abnormalities, conges- 93% survival. Pulmonary fibrosis is the Raynaud’s phenomena, and arthralgia. tive heart failure, pericardial effusion, and major predictor of poor hospitalization D-penicillamine (Cuprimine) has been myocardial fibrosis. Patients may develop outcomes in SSc patients in recent years. recently discontinued and azathioprine erectile dysfunction, dyspareunia, hypo- The diagnosis of systemic sclerosis is (Imuran) has been substituted. She is thyroidism, hypertension, renal crisis, or generally made from the patient’s history currently stable and able to function at chronic renal insufficiency. Xerostomia and the findings on examination of the work. To date, our patient is undergoing a and xerophthalmia may be part of the skin and other organs. A skin biopsy is multi-specialty approach to her condition. examination findings. The patient may not usually necessary but characteristically also have poor dentition. Oropharyngeal shows a squared-off biopsy with fibrosis, References: 6 and esophageal cancers can occur. edema, and sclerosis in the dermis. 1 Bolognia L, Jean, Jorizzo JL, et al. Dermatology Mosby; The American College of Rheumatology Lymphoplasmacytic inflammatory infil- 2003; Volume 2 [pages?]. 2 Freedberg IM, et al. Fitzpatrick’s Dermatology in General (ACR) criteria for the classification of trates separate collagen strands, surround Medicine. Sixth edition. McGraw-Hill Professional 2003. systemic sclerosis require one major eccrine coils in the deep dermis, and are Volume 2 1709-1717. 3 Hasegawa, M, et al. Elevated serum levels of interleukin criterion or two minor criteria, as associated with loss of adipocytes around 4, IL-10, and IL-13 in patients with systemic sclerosis. follows. Major criteria include proximal the eccrine apparatus.6 Journal of Rheumatology 24:328, 1997. 4 Haustein UF, et al. Systemic sclerosis-scleroderma. scleroderma characterized by symmetric Specific circulating antibodies are useful Dermatology Online Journal Volume 8 number 1. thickening, tightening, and induration of in establishing the diagnosis. Antinuclear 5 LeRoy, EC et al. Scleroderma (systemic sclerosis): Clas- sification, subsets, and pathogenesis. Journal of Rheu- the skin of the fingers and the skin that antibodies can be detected. Centromere matology 15:202, 1988. is proximal to the metacarpophalangeal antibody is common with limited disease 6 Lever E. David, et al. Lever’s Histopathology of the Skin. 5 Lippincott Williams and Williams; 2005: 693-694. or metatarsophalangeal joint. Minor and CREST. A nucleolar pattern, although 7 Mendoza, Fabian, MD. Systemic Sclerosis Mortality in criteria include sclerodactyly of the fingers, less common, is more specific for systemic the United States: 1999-2002: Implications for Patient Care. Journal of Clinical Rheumatology. 13(4):187-192, digital pitting scars or depressed areas of sclerosis. Topoisomerase I antibodies August 2007. the fingertips, and bibasilar pulmonary (formerly Scl-70) are present in approxi- 8 Odum, Richard B, et al. Andrews’ Diseases of the Skin: Clinical Dermatology fibrosis.5 mately 30% - 40% of patients with diffuse Systemic sclerosis is the result of promi- disease (absent in limited disease) and are nent fibroproliferative vasculopathy and associated with pulmonary fibrosis.2 Other humoral and cellular immune alterations. studies include ESR and hypergammaglob- The symptoms result from inflammation ulinemia. Imaging studies can include CT and progressive tissue fibrosis and occlu- scan, chest X-ray, echocardiography, and sion of the microvasculature by excessive esophagraphy. Pulmonary function testing, production and deposition of types I and 24-hr Holter monitoring, and brochoscopy III collagen. Endothelial damage leads to may be necessary as well. the release of proinflammatory cytokines, There is no cure for systemic sclerosis, such as TNF alpha, interleukin-1, IL-6 and and treatment is aimed at controlling IL-8, that shift the endothelium to a proin- symptoms and preventing complications. flammatory, procoagulant, vasoconstric- Corticosteroids, emollients, and PUVA tive-activated phenotype.2 IL-2 is found are used for pruritus. Avoidance of cold in abundance in patients with scleroderma temperatures and the use of gloves and due to its role in endothelial damage.2 socks to prevent Raynaud’s phenomena Other causes include environmental factors should be encouraged. Calcinosis is such as plastics, solvents, paraffin, silica, treated with calcium channel blockers, or radiation exposure. It has also been intralesional steroids, or anticoagulants. thought that there may be a relationship Hydroxychloroquine sulfate 200mg twice between scleroderma and human cyto- a day can be considered for patients who megalovirus or human herpes 5. Drugs show active inflammatory stage.1 In such as bleomycin and pentazocine may patients with kidney involvement, ACE also be implicated. inhibitor therapy is indicated. Blood The estimated incidence of systemic scle- pressure monitoring should be routinely rosis is 19 cases per million. The risk of performed. Calcium-channel blockers, systemic sclerosis is higher in black women, prostaglandins, and cyclophosphamide 66 SYSTEMIC SCLEROSIS: CASE REPORT AND REVIEW OF THE LITERATURE © 2008 Medicis, The Dermatology Company ZNA 08-029 07/30/09 JAOCD AN INTERESTING CASE OF LEUKODERMA ASSOCIATED WITH SYSTEMIC DISEASE

Jack W. Griffith, DO,* Tony Nakhla, DO,** Paul Shitabata, MD,*** David Horowitz, DO, FAOCD, FAAD**** *First-year Dermatology Resident, Western University - Pacific Hospital **Second-year Dermatology Resident, Western University - Pacific Hospital ***Director Dermatopathology, Harbor-UCLA Dermatology ****Dermatology Residency Program Director, Western University - Pacific Hospital

Case Report: Weissenbach syndrome (also referred to as CREST syndrome). As the name implies, A 40-year-old woman presented with a PSS is a progressive multi-organ disease. It two-year history of diffuse spotty hypop- is characterized by thickening and fibrosis igmentation. The patient stated that her of the skin. Systemically, this disease can hypopigmentation gradually progressed involve many internal organs including over two years to its current state. She the heart, lungs, kidney, and gastrointes- denied any repigmentation of her lesions. tinal tract. Extensive disease can lead to She stated that the lesions had not changed death as a result of complications with for many months. The patient denied any these organ systems. Classic criteria for medications or any medical issues except PSS are proximal sclerosis or two or more that her primary care physician had recently of the following: sclerodactly, digital pitting told her she might have lupus based on scars, and bilateral pulmonary fibrosis. The Figure 1 a series of blood tests that she could not earliest sign of disease in the majority of recall. Upon further review of systems, our patients is Raynaud’s phenomenon. patient admitted to shortness of breath, CREST syndrome (calcinosis cutis, stating that she often found it difficult Raynaud’s phenomenon, esophageal to catch her breath even at rest. She also dismotility, sclerodactyly, and telangi- noted that her fingertips had often become ectasias) is considered a limited form of blue and cold at room temperature. systemic sclerosis. CREST syndrome rarely Physical exam revealed patches of hypop- progresses to involve the lungs or kidneys igmentation with areas of retained pigment and portends a more favorable prognosis around the follicular orifices (Figures 1-2). when compared to PSS. The anticen- These lesions covered her face, chest, back, tromere antibody is relatively sensitive and upper extremities, and upper thighs. In specific for CREST syndrome, while Scl-70 addition to these skin findings, the patient’s and ANA correlate to PSS. Figure 2 exam revealed signs of resolving finger Limited cutaneous scleroderma is tip ulcerations and mild digital clubbing referred to as morphea, which is charac- (Figures 3-4). terized by circumscribed ivory, leather- Recent outside labs included an ANA appearing patches or lesions. Morphea titer of 1:640 and an ESR of 23. Complete seldom progresses to systemic disease. blood count, serum chemistry, and liver Initial skin findings in systemic sclero- function tests were all within normal limits. derma are usually acral and facial, with swelling and induration of the hands, digits Histopathology: and around facial orifices. The effect on the face is that the skin becomes drawn A biopsy of the right upper extremity tight and expressionless, while the lips revealed a square punch biopsy on low power (Figure 5). On high power, are pursed and the nose appears pinched. The hands become contracted and claw- the dermal collagen bundles appeared Figure 3 thickened, and there was a relative lack like, ultimately impairing function. of skin appendages within the reticular Additionally, pterygium inversum unguis dermis. The dermis appeared hypocel- (fusion of the hyponychium to the under- uncommonly associated with other auto- lular, with few vessels. MART-1 (Melan-A) surface of the distal nail plate) can occur, as immune disorders such as thyroid disease stain was performed on the sample, and well as hypopigmentation of the skin. This and diabetes mellitus. it was found that the part of the basal might exist in a large patch or with perifol- Strong evidence that vitiligo is an auto- layer of the epidermis corresponding to licular pigment retention, mimicking the immune disorder derives from several the leukodermic skin did not stain, while pattern of perifollicular pigmentation that factors. One example is Vogt-Koyanagi- the pigmented portion stained positively one sees when a patch of vitiligo undergoes Harada syndrome, wherein aseptic menin- (Figure 6). These findings were consistent repigmentation. gitis triggers an autoimmune reaction with scleroderma superimposed on vitiligo. Vitiligo is characterized by stark, causing the disease to manifest in the tissue white, depigmented patches of skin with derived from neural crest origin. This is Background: well-defined borders that histologically characterized by vitiligo, iritis, retinitis, and correlates with the epidermal loss of central nervous system manifestations.1 Systemic scleroderma is commonly cate- melanocytes. Though vitiligo is believed to Vitiligo has been seen in association with gorized into two disease states: progressive be an autoimmune disorder, little is known multiple autoimmune syndrome (MAS), systemic sclerosis (PSS) and Thibierge- about the pathogenesis. However, it is not defined as three or more concurrent auto- 68 AN INTERESTING CASE OF LEUKODERMA ASSOCIATED WITH SYSTEMIC DISEASE findings of scleroderma.8 by similar methods. Both types of lesions Scleroderma and vitiligo have not only may occur secondarily to similar insults been observed together, but they have in predisposed humans, and both diseases also been experimentally induced. In the respond to the same standard therapies. process of attempting to devise a therapy It is therefore intuitive that we begin to for malignant melanoma, Lacour et al. explore the possibility that these diseases extracted lymphocytes from a melanoma are different manifestations of the same lesion of a patient. These lymphocytes pathologic mechanism at work. This could were irradiated and injected back into the entail the reconsideration of common same patient. The result was the develop- auto-antibodies and their predictive factor ment of limited lesions of both scleroderma on these diseases. Additionally, as more and vitiligo.9 Sanchez has argued that, patients with diverse diseases are treated Figure 4 while the hypopigmentation associated with biologics, and as a result of direct with some cases of scleroderma has many clinical trials, the role these medications overlapping characteristics with vitiligo, will have for these diseases will become they are not the same entity.7 However, clear. our patient’s pathologic specimen clearly showed the characteristics of both vitiligo References: and scleroderma in the same pathology 1. James WM, et al. Andrews Diseases of the Skin Clinical specimen. This provides evidence that viti- Dermatology. 2006; 10th ed: 863-4 2. Kilsick A, et al. Vitiligo in multiple autoimmune syndrome: ligo not only occurs with scleroderma but a retrospective review of eleven cases and review of the also that the underlying pathologic disease literature. Rev Med Interne 1998 May; 19(5): 348-52 3. Maleto, et al. Association of localized morphea and mechanism may overlap. This could also vitiligo of the lip in a patient with Lichen Planus. Minerva explain the limited efficacy of common Stomatol 2000 Nov; 49(11-12): 549-54 4. Finkelstein, et al. Coexistence of vitiligo and morphea a therapies used to treat both conditions. case report and review of the literature. J Dermatol 1995 Likewise, potential for new treatments of May; 22(5): 351-3 Figure 5. Bonifati C, et al. Simultaneous occurrence of linear scle- both conditions have recently become real- roderma and homolateral segmental vitiligo. J Eur Acad ized in the form of T-cell-directed anti Dermatol Veneral 2006 Jan; 20(1): 63-65 6. Rai VM, et al. Pseudo vitiligo in systemic sclerosis. Der- tumor necrosis factor alpha biologics. matol Online J. 2005 Dec 1;11(3):41 Increasing case reports of patients 7. Sanchez JL, et al. Vitiligo like macules in systemic sclero- derma. Arch Dermatol 1983; (2):129-33 having improvement of scleroderma and 8. De Villers WJ, et al. Systemic sclerosis sine scleroderma vitiligo while receiving biologic therapy presenting with vitiligo-like depigmentation and intersti- tial pulmonary fibrosis. Clin Exp Dermatol 1992 Mar; for other diseases have recently made 17(2):127-31 their way into the literature. One such 9. Lacour, et al. Vitiligo-like depigmentation and morphea after specific intralymphocytic immunotherapy for malig- report involves a patient being treated for nant melanoma. Dermatology 1992; 18(4): 283-5 ankylosing spondylitis with infliximab, a 10. Simon JA, et al. Vitiligo improvement in a patient with ankylosing spondylitis treated with infliximab. Dermatol- biologic. While infliximab helped resolve ogy 2008; 216(3): 234-5 the patient’s ankylosing spondylitis, resolu- 11. Regopoulos, et al. Etanercept in the treatment of vitiligo. Dermatology 2007; 215(1): 84-5 tion of long-standing vitiligo lesions was 12. Koca SS, et al. Effectiveness of etanercept in bleomycin also observed.10 induced scleroderma. Rheumatology 2008 Feb; 47(2): Figure 6 172-5 In scleroderma, the evidence of efficacy 13. Antoniou KM, et al. Infliximab treatment in pulmonary of biologics is even stronger. Regopoulos fibrosis associated with collagen vascular disease. Clin 2 Exp Rheumatol 2007 Jan-Feb; 25(1): 23-8 immune diseases in the same patient. conducted a study that described the Also, multiple sources describe similar successful treatment of vitiligo with etan- inflammatory infiltrates of T-lymphocytes ercept.11 In a randomized trial, bleomycin in the early lesions of vitiligo, scleroderma, 3 was used to induce sclerodermatous lesions and other autoimmune disorders. While in mice. The experimental group was given specific autoantibody associations in viti- etanercept to clear the lesions, while the ligo are not defined as in scleroderma, control group was given a placebo. The evidence is strong for an auto-self etiology. result was a more extensive and persistent disease burden to the control group that Discussion: did not receive treatment with etanercept.12 While the association of systemic sclero- A study analyzed a large series of patients derma and vitiligo is very rare, some case having both collagen vascular disease and reports describe leukoderma or “vitiligo- pulmonary fibrosis in respect to progres- like macules” in association with either sion of pulmonary fibrosis while treated limited or systemic scleroderma. Cases with infliximab. A percentage of these describing both morphea and linear scle- patients had progressive systemic sclerosis. roderma have been reported to be associ- It was found that in treated patients, disease ated with vitiligo. These reports include remained more stable than in patients not 13 cases with overlap of onset as well as treated with biologics. distribution of the lesions.4-5 There are several case reports that describe sclero- Conclusion: derma along with “vitiligo-like macules,” It is evident that scleroderma and viti- “pseudo-vitiligo” or “salt and pepper depig- ligo not only occur concurrently in the mentation.”6-7 One case details a patient same patients, but also have overlapping presenting with systemic sclerosis and lesions. Moreover, both types of lesions vitiligo but lacking the characteristic skin have been induced in laboratory animals

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