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Journal of the American Osteopathic College of Dermatology

Volume 10, Number 1 SPONSORS: ',/"!,0!4(/,/'9,!"/2!4/29s-%$)#)3 March 2008 34)%&%,,!"/2!4/2)%3s#/,,!'%.%8 www.aocd.org Journal of the American Osteopathic College of Dermatology 2007-2008 Officers President: Jay Gottlieb, DO President Elect: Donald Tillman, DO Journal of the First Vice President: Marc Epstein, DO Second Vice President: Leslie Kramer, DO Third Vice President: Bradley Glick, DO American Secretary-Treasurer: Jere Mammino, DO (2007-2010) Immediate Past President: Bill Way, DO Trustees: James Towry, DO (2006-2008) Osteopathic Mark Kuriata, DO (2007-2010) Karen Neubauer, DO (2006-2008) College of David Grice, DO (2007-2010) Dermatology Sponsors: Global Pathology Laboratory Stiefel Laboratories Editors +BZ4(PUUMJFC %0 '0$00 Medicis 4UBOMFZ&4LPQJU %0 '"0$% CollaGenex +BNFT2%FM3PTTP %0 '"0$%

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CONTENTS

Letter from the JAOCD Editors ...... 4 Letter from the President ...... 5 Dissecting of the Scalp Treated Successfully with Adalimumab ...... 6 Kristen Marie Aloupis, DO, MPH, Stanley Skopit, DO, FAOCD, Francisco Kerdel, BSc, MBBS Acrodermatitis Continua Following Surgical Trauma: A Case Report ...... 9 Heather Higgins, DO, Steven Grekin, DO, FAOCD, Michael W. Whitworth, DO, FAOCD Eruption of Lymphocyte Recovery: A Case Presentation and Review of the Literature ...... 11 Lisa A. Zaleski, DO, LT, MC, USN, Peter R. Shumaker, MD, LCDR, MC, USN Oral : A Case Report and Review of Literature ...... 15 Julie Malchiodi, DO, Michelle Bruner, DO, Melissa Hintz, Jean Holland, MD Giant-cell Tumor of the Tendon Sheath: A Case Presentation and Review of the Literature ...... 18 Chris Buckley, DO, Stanley Skopit, DO, FAOCD Recurrent : Underlying Immunodeficiency? ...... 20 Brian S. Walther, DO, and Stephen M. Purcell, DO Idiopathic Thrombocytopenic Purpura: A case report and discussion ...... 22 Kevin DeHart, DO, Kristin Witfill, DO, Richard Miller, DO MRSA—Case and Review ...... 24 Robert A. Norman, DO, MPH, Steven Nodine, OMS III Porphyria Cutanea Tarda: Case Presentation and Literature Review ...... 27 Tracy Favreau, DO, Stanley Skopit, DO, FAOCD A Case of Curious Axillary “Freckling” ...... 29 Kevin Spohr, DO, Robert Berg, MD, Brad Glick, DO, MPH, FAOCD, Les Rosen, MD A Woman With Gradually Spreading ...... 31 Daniel Hansen, DO, MBA, Steven Grekin, DO, FAOCD, Don Collier, DO, FAOCD, Jonathan D. Richey, OMS IV Griseofulvin-induced Photoallergic Reaction: A Case Report in a 10-year-old Hispanic Male ...... 33 David R. Bonney, DO, Stanley Skopit, DO, FAOCD Accessory Tragus ...... 35 Robert A. Norman, DO, MPH, Veronica Cabigas Davis, OMS IV Treatment of with a Vascular Endothelial Growth Factor Inhibitor ...... 36 Stephen C. Verral, DO, MPH, Steven K. Grekin, DO, FAOCD : Mast Cell Burden and Symptomatology ...... 41 Aaron Bruce, DO, David Esguerra, DO Linear focal elastosis in a young Hispanic male: a new presentation ...... 43 Brian Feinstein, DO, Stanley Skopit, DO, FAOCD Amyopathic Associated with Myelodysplastic Syndrome ...... 46 David B. Roy DO, Don A. Anderson DO, FAOCD, F.A.S.M.S Perianal Basal Cell Carcinoma: A Case Report ...... 51 Andrea Passalacqua, DO, Ronald Liskanich, DO, Gloria Stevens, M.D., David Horowitz, DO Dermoscopy for Non-melanocytic Lesions ...... 53 Lynora Curtis Bassett, DO, Brad P. Glick, DO, MPH, FAOCD Sentinel Lymph Node Biopsy for Cutaneous Malignant Melanoma: A Review of the Rationale, Criteria, Procedure, and Controversies ...... 56 Raymond Ramirez, DO, Cindy Hoffman, DO, FAOCD, Charles Gropper, MD Making Sense of the Perforating Disorders: A Review ...... 62 Brett B. Bender, DO, Michael J. Mahon, DO, FAOCD Treatment of Lymphangioma Circumscriptum with Imiquimod 5% Cream ...... 66 Shaheen Oshtory, DO, Charles Gropper, MD, Cindy Hoffman, DO, FAOCD Cutaneous Metastasis of Adenocarcinoma ...... 68 Adam D. Wray, DO, Lloyd J. Cleaver, DO, FAOCD, Jonathan Cleaver, MSIV L ETTER FROM THE EDITORS

JAY S. GOTTLIEB, D.O. STANLEY E. SKOPIT, D.O. JAMES Q. DELROSSO, D.O.

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We are thankful to have Global Pathology Laboratory, Medicis-The Dermatology Company, Stiefel Laboratory and our most recent sponsor, CollaGenex BTTQPOTPSTPGUIF+"0$%5IFZ continue their commitment to the dermatology profession and support the AOCD in all of its FOEFBWPST

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4 LETTER FROM THE EDITORS LETTER FROM THE PRESIDENT of the AOCD JAY GOTTLIEB, D.O., F.A.O.C.D., F.O.C.O.O., PRESIDENT

Dear Fellow & Resident AOCD members,

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#FJOHUIFFEJUPSPGUIF+"0$%JTBMTPWFSZFYDJUJOH5IFNBOVTDSJQUTDPOUJOVFUPJNQSPWFJORVBMJUZ BOERVBOUJUZ0VSTQPOTPSTDPOUJOVFUPLFFQUIF+"0$%BSFBMJUZ(MPCBM1BUIPMPHZ-BCPSBUPSZ 4UJFGFM Laboratories, Medicis and CollaGenex have been providing the support that we need to keep a quality QSPEVDUJOUIFQJQFMJOF

*BNFOKPZJOHNZZFBSBTQSFTJEFOUPGUIF"0$%*UJTBMFBSOJOHFYQFSJFODFBOERVJUFFYDJUJOH*XJTIZPVBMM a great year, and I will see you in Monterey!

Fraternally Yours,

Jay

Jay Gottlieb, DO, FAOCD, FOCOO

LETTER FROM THE PRESIDENT 5 DISSECTING CELLULITIS OF THE SCALP TREATED SUCCESSFULLY WITH ADALIMUMAB

Kristen Marie Aloupis, DO, MPH,* Stanley Skopit, DO, FAOCD,** Francisco Kerdel, BSc, MBBS*** *3rd year resident, Nova Southeastern University/BGMC **Program Director, Nova Southeastern University/BGMC ***Dermatologist, Cedars Medical Center, Miami, FL

ABSTRACT

Dissecting cellulitis of the scalp is an uncommon, chronic, progressive, suppurative and inflammatory scalp disease. Its pathogen- esis and etiology are not completely understood. The disease is characterized by painful, fluctuant scalp nodules, abscesses and inter- connecting sinus tracts, and it can lead to a scarring alopecia. Treatment of this condition is often difficult and includes medical as well as destructive therapies. We report the successful treatment of one patient with dissecting cellulitis of the scalp using adalimumab.

Case Report Discussion A 24-year-old male presented with a Dissecting cellulitis (DC) of the scalp, several-month history of tender, fluctuant also known as perifolliculitis capitis nodules on his scalp associated with a abscedens et suffodiens, is an uncommon, patchy alopecia. In general, the patient was chronic, inflammatory disease of the in good health with a past medical history scalp characterized by painful fluctuant of guttate psoriasis. He had no known drug abscesses, sinus tract formation, and a allergies and no family history of similar resultant scarring alopecia. The vertex and disorders. He had previously been treated occipital scalp are sites of predilection. The with oral and topical corticos- etiology of this disease remains unclear. It teroids with minimal improvement. At has been associated with conglobata, initial consultation, physical exam revealed hidradenitis suppurativa, and a pilonidal Figure 1 a well-developed, well-nourished young cyst in the follicular occlusion tetrad.1 The man with multiple erythematous, tender, disease is most commonly found in adult boggy nodules and abscesses of the occip- black men; it is rarely seen in white males ital and parietal scalp (Figures 1 and 2). No as presented in our case. The course of this other lesions were noted, and there disease does not differ between races.2,3 DC was no cervical or occipital lymphade- follows a relapsing course and is usually nopathy. Most recent treatment included considered progressive. Moreover, metas- oral levofloxacin and clobetasol foam. tasizing squamous cell carcinoma arising Wound cultures were found to be nega- in a chronically inflamed lesion has been tive, and a punch biopsy of the scalp was reported by Curry et al.4 obtained. The skin biopsy specimen from Diagnosis is based on the presence of the posterior scalp showed histopatho- fluctuant nodules and abscesses on the logical features consistent with dissecting scalp, sometimes with sinus tract formation cellulitis (Figures 3 and 4). Pathologically, and seropurulent discharge. The course there was a significant decrease of folli- is often protracted, and marked scarring culo-sebaceous units with a dense cicatri- alopecia may ensue. The histopathology of cial fibrosis and a chronic mononuclear DC is well described, although the features perivascular interstitial and perifollicular are not diagnostic and depend on the stage infiltrate. One week later, the patient flared of the disease.5 There is an acneiform dila- with increased pain, fever, and malaise, tion of the follicular infundibulum with and required hospitalization. During his intrafollicular and perifollicular accumula- stay, the patient was treated with IV vanco- tion of neutrophils and subsequent folli- Figure 2 mycin, levofloxacin, and methylprednisone. cular perforation in the acute suppurative He improved clinically over the next few phase. Later, keratogenous debris incites a days. A PPD and chest X-ray were negative, granulomatous response with sinus tracts and the patient was discharged with the surrounded by a dermal fibrosis.5 instruction to initiate adulimumab injec- The treatment is often difficult and tions the following day. disappointing. Acute flares are best treated After one month of treatment with adal- with antibiotics, and oral zinc has occasion- imumab 40 mg given every other week, the ally produced improvement.6 Systemic or patient reported to be greatly improved. intralesional steroids offer partial relief.7,8 At follow-up, approximately six weeks Oral is effective, although it after initiation of treatment, there was a needs to be continued for four months marked reduction in the inflammatory after clinical improvement to prevent component of his disease, with resolution relapse.6,9-12 Surgical approaches have also of the abscesses (Figures 5 and 6). Also, the been employed. Intercommunicating Figure 3 patient’s psoriasis was notably improved. sinuses can be marsupialized, and cauter-

6 DISSECTING CELLULITIS OF THE SCALP TREATED SUCCESSFULLY WITH ADALIMUMA toid arthritis, psoriatic arthritis, and, more 17. Sullivan TP, Welsh E, Kerdel FA, Burdick AE, Kirsner RS. Infliximab for hidradenitis suppurativa. Br J Dermatol. recently, Crohn’s disease. Serious infec- 2003;149:1046-1049. tions have occurred in patients receiving 18. Lebwohl B, Sapadin AN. Infliximab for the treatment of hidradenitis suppuritiva. J Am Acad Dermatol. 22 adalimumab therapy. It additionally has 2003;49:S275-S276. a black box warning recommending evalu- 19. Martinez F, Nos P, Benlloch S, Ponce J. Hidradenitis suppurativa and Crohn’s disease: response to infliximab. ation and treatment for latent tubercu- Inflamm Bowel Dis. 2001;7:323-326. losis.22 There is a lack of long-term data 20. Moul DK, Korman NJ. Severe Hidradenitis Suppura- tiva Treated With Adalimumab. Arch Dermatol. regarding potential increased malig- 2006;142:1110-1112. nancy risk due to TNF-α inhibition with 21. Kelly P. and the follicular occlusion tetrad. Dermatology. St. Louis, Mo: Mosby-Year Book Inc; the use of adalimumab. Since there is a 2003:564-566. lack of long-term data and the potential 22. Humira (package insert). Abbott Park, III: Abbott Labora- tories; 2005. increased risk of malignancy, the Food and Figure 4 Drug Administration has recommended continued safety monitoring in patients being treated with anti-TNF agents. Other possible adverse effects of anti-TNF agents such as adalimumab include demyelinating disorders, congestive failure, and autoimmunity.22 Practitioners must discern appropriate candidates for anti-TNF treat- ment on a case-by-case basis. To the best of our knowledge, this is the first English-language case report of dissecting cellulitis treated successfully with adalimumab. Given its convenient subcutaneous dosing regimen, along with Figure 5 its strong anti-inflammatory properties, adalimumab may represent a therapeutic option for this often frustrating disease. Additional research is needed before adali- mumab’s true therapeutic benefit for treat- ment of dissecting cellulitis of the scalp can be elucidated.

References: 1. Plewig G, Kligman AM. Acne: Morphogenesis and Treat- ment. New York: Springer Verlag; 1975:192. 2. Richard BO, William DJ, Timothy GB. Andrews’ Diseases of the Skin. Clinical Dermatology. 9th ed. Philadelphia: W.B. Saunders; 2000:284-306. 3. Olsen EA. Hair. In: Freedberg IM, Eisen A, Wolff K, et al., Figure 6 eds. Fitzpatrick’s Dermatology in General Medicine. 5th ed. New York: McGraw-Hill; 1999:729-751. 4. Curry SS, Gaither DH, King LE Jr. Squamous cell carci- ization is utilized to destroy the epithelium noma arising in dissecting perifolliculitis of the scalp: A lining the sinuses.13 case report and review of secondary squamous cell carci- nomas. J Am Acad Dermatol. 1981;4:673-678. Our patient had severe DC of the scalp, 5. Lever WF, Schaumburg-Lever G. Histopathology of the Skin. 7th ed. Philadelphia: JB Lippincott; 1990. for which several treatments had failed. 6. Schewach-Millet M, Ziv R, Shapira D. Perifolliculitis capitis Given the recently reported cases of patients abscedens et suffodiens treated with isotretinoin. J Am Acad Dermatol. 1986;6:1291-2. with hidradenitis suppurativa successfully 7. Berne B, Venge P, Ohman S. Perifolliculitis capi- responding to anti-TNF-α therapies,14-20 we tis abscedens et suffodiens (Hoffman). Arch Dermatol. 1985;121:1028-30. attempted a trial of adalimumab, a fully 8. Shaffer N, Billick RC, Srolovitz H. Perifolliculitis capitis human monoclonal antibody directed abscedens et suffodiens. Resolution with combination therapy. Arch Dermatol. 1992;12:1329-31. against TNF-α. He had a prompt and 9. Bjellerup M, Wallengren J. Familial perifolliculitis capi- dramatic response to his initial injection tis abscedens et suffodiens in two brothers success- fully treated with isotretinoin. J Am Acad Dermatol. and continues to show improvement on 1990;23:752-3. his current every-other-week treatment 10. Taylor AEM. Dissecting cellulites of the scalp: Response to isotretinoin. Lencet. 1987; 25:225. regimen. 11. Dyall-Smith D. Signs, syndromes and diagnoses in Der- Though the pathogenesis of DC is not matology: Dissecting cellulites of the scalp. Austral J Der- matol. 1993;34:81-2. well understood, case reports of hidraden- 12. Scerri L, Williams HC, Allen BR. Dissecting cellulites itis suppurativa, which is believed to have of the scalp: response to isotretinoin. Br J Dermatol. 1996;134:1105-8. similar pathogenicity, responding to inflix- 13. Glass IF, Berman B, Laud D. Treatment of perifolliculitis imab and adalimumab suggest there is abscedens et suffodiens with the carbon dioxide laser. J Dermatol Surg Onc. 1989;15:673-6. an important role for the inflammatory 14. Adams DR, Gordon KB, Devenyi AG, Loffreda MD. Severe component. These findings are supported hidradenitis suppurativa treated with infliximab infusion. Arch Dermatol. 2003;139:1540-1542. by the fact that treatment with systemic 15. Roussomoustakaki M, Dimoulios P, Chatzicostas C, et al. corticosteroids usually leads to rapid Hidradentitis suppurativa associated with Crohn’s disease 21 and spondyloarthropathy: response to anti-TNF therapy. J improvement in disease activity. Gastroenterol. 2003;38:1000-1004. 16. Katsanos KH, Christodoulou DK, Tsianos EV. Axillary Adalimumab is not without associated hidradenitis suppurativa successfully treated with inflix- risk. Its safety profile is based on trials for imab in a Crohn’s disease patient. Am J Gastroenterol. its approved indications, namely rheuma- 2002;97:2155-2156.

ALOUPIS, SKOPIT, KERDEL 7 Members of the AOCD may advertise "position available"

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These ads must be submitted as an e-mail attachment and sent to [email protected]. Any photos to be included in an active member's ad, must be in a .pdf format. ACRODERMATITIS CONTINUA FOLLOWING SURGICAL TRAUMA: A CASE REPORT

Heather Higgins, DO,* Steven Grekin, DO, FAOCD**, Michael W. Whitworth, DO, FAOCD*** *First-year Dermatology Resident, Oakwood Southshore Medical Center **Program Director, Oakwood Southshore Medical Center ***Attending Physician, Oakwood Southshore Medical Center.

ABSTRACT

Acrodermatitis continua is a rare, painful form of palmoplantar psoriasis that is notoriously difficult to treat. The following is a report of an unusual case of treatment-resistant acrodermatitis continua following surgical trauma.

Clinical Presentation of oral cephalexin (Keflex®) and levofloxacin (Levaquin®). He failed to improve and was A 50-year-old male presented with bilat- then treated with terbinafine (Lamisil®). eral thickened toenails and painful, hyperk- On presentation to dermatology, the eratotic erythematous plaques on his distal patient was treated with oral cephalexin toes. The patient reported that the lesions 500 mg tid and topical silver sulfadiazine initially developed within one month (Silvadene®) compounded with gentamicin following laser matrixectomy of his bilateral for two weeks. Following a month-long great toes, performed by podiatry to treat course of sulfamethoxazole/trimethoprim his chronic onychocryptosis. Following (Bactrim DS®) po bid, the pustular lesions the surgery, his distal great toes devel- resolved, but the painful hyperkeratotic oped pustules with foul-smelling drainage plaques persisted. He was then treated with and thickening. The pustular areas a prednisone 60 mg taper and fluconazole Acrodermatitis Continua Photo 1 progressed to hyperkeratotic, tender scaly ® (Diflucan ) 100 mg qd for two weeks. The – Acrodermatitis continua patient at plaques, and subsequently most of his toes patient subsequently developed tenderness presentation. The patient is noted and several fingers were affected. In addi- and over his bilateral distal inter- to have edematous, erythematous tion, he later developed two erythematous phalangeal joints and was found to have toes with hyperkeratotic plaques and plaques with white scale on his dorsal penis new-onset arthritis. He completed a three- dystrophic nails. and a scaly lesion on his left heel. month course of acitretin (Soriatane®) 50 The patient denied any pruritus, eye mg daily and showed improvement but not irritation, oral lesions, or genitourinary clearance. The patient is currently being symptoms. His medical history was unre- treated with acitretin 25 mg daily and topical markable except for squamous-cell carci- betamethasone/calcipotriene (Taclonex®). noma of the scalp. The patient denied any The penile lesions have resolved, but the family or personal history of psoriasis. He toe and finger lesions remain refractory to was self-employed as a long-haul truck treatment. The patient’s treatment options driver, and his social history included are complicated by his continued regular frequent alcohol consumption. alcohol consumption despite repeated Physical examination revealed markedly recommendations to abstain. In addition, hyperkeratotic toenails. The periungual his occupation as a self-employed long-haul area and distal toes were edematous, tender, truck driver requires almost constant travel, Acrodermatitis Continua Photo 2 – and covered in a thick scale on an erythema- which precludes him from regularly sched- Section of shave biopsy taken from tous base. Several of the patient’s fingernails uled in-office light therapy. were similarly affected. The patient was penile lesion showing psoriasiform hyperplasia. also noted to have two small non-healing Discussion erythematous plaques on the dorsum of Nail destruction is characteristic, and his glans penis and an erythematous scaly Acrodermatitis continua, also known as involvement of the nail bed and matrix plaque on his left heel. dermatitis repens, was first described by leads to loss of the nail-plate or severe 1 Laboratory studies revealed elevated liver- Crocker in 1888 and further elucidated by onychodystrophy. The process begins at function tests and triglyceride levels. All Hallopeau in 1890.2 It is a rare, chronic, the tips of fingers or toes and slowly extends other tests were unremarkable. Culture extremely painful form of palmoplantar proximally as well as to the dorsum of the of the toe lesions was positive for strepto- pustular psoriasis. The exact etiology of hands or feet.3 Over time, some patients coccus and staphylococcus species. Fungal the condition remains unknown. The develop arthritic changes that may lead cultures were negative. Radiographic condition typically begins following minor, to osteolysis of the distal phalanx that lies studies revealed periarticular edema and incidental trauma and presents as either beneath the lesion. In 2005, Kirkup and arthritic changes in his distal interphalan- a sterile pustular eruption of the toes or Lovell reported a case of acrodermatitis geal joints. A shave biopsy of the dorsal fingers or as a . Pustules typi- continua of more than 20 years’ duration glans penis showed a psoriasiform hyper- cally progress and coalesce to form lakes that led to syndactyly.4 plasia consistent with psoriasis. A PAS stain of . Erythema, keratotic changes and Histologic features of pustular lesions was negative for fungal hyphae. fissures are usually present. Eventually the include subcorneal neutrophilic pustules The patient was initially treated by podi- pustular lesions are replaced by markedly with psoriasiform hyperplasia. Neutrophils atry with gentamicin cream and ketocon- hyperkeratotic plaques with erythematous accumulate between the stratum corneum azole (Nizoral®) cream, followed by courses bases.3

HIGGINS, GREKIN, WHITWORTH 9 and stratum spinosum, between degener- acrodermatitis continua of Hallopeau. Cutis 2002; 70: 106-108. ated and thinned , to form 7. Emtestam L, Weden U. Successful treatment for acroder- the “spongiform pustules of Kogoj.” These matitis continua of Hallopeau using topical calcipotriol. Br J Dermatol 1996; 135(4): 644-646. lesions are later replaced by scale crust with 8. Tsuji T, Nushimura M. Topically administered fluorouracil collections of neutrophils trapped between in acrodermatitis continua of Hallopeau. Arch Dermatol 1991; 127(1): 27-28. 5 parakeratotic layers. 9. Wilsmann-Theis D, Hagemann T, Dederer H, Wenzel J, Bieber T, Novak N. Successful treatment of acrodermati- Acrodermatitis continua is often resistant tis continua suppurativa with topical tacrolimus 0.1% oint- to treatment, and no straightforward treat- ment. Br J Dermatol 2004; 150: 1194-1197. 10. Slawsky LD, Libow LF. Successful treatment of acroder- ment guidelines exist. Topical treatments matitis continua of Hallopeau with etretinate. J Am Acad include corticosteroids,6 calcipotriene7 and Dermatol. 1990; 23: 1176-1178. 8 11. Van Dooren-Greebe RJ, van de Kerkhof PC, Chang 5-fluorouracil. In 2004, Wilsmann-Theis A, Happle R. Acitretin monotherapy in acrodermatitis et al. reported two cases of acrodermatitis continua Hallopeau. Acta Derm Venereol 1989; 69(4): 344-346. continua treated with tacrolimus 0.1% 12. Harland CC, Kilby PE, Dalziel KL. Acrodermatitis continua ointment under occlusion that produced responding to cyclosporine therapy. Clin Exp Dermatol 9 1992; 17(5): 376-378. marked improvement in the lesions. 13. James WD, Berger TG, Elston DM. Andrews’ Diseases Systemic treatments include retin- of the Skin: Clinical Dermatology 10th Edition. Saunders 10, 11 12 13 Elsevier. 2006: 195-204. oids, cyclosporine, methotrexate and 14. Nikkels AF, Nikkels-Tassoudji N, Pierard GE. Breaking PUVA.13 Recently, Nikkels et al. reported the relentless course of Hallopeau’s acrodermatitis by dapsone. Eur J Dermatol 1999; 126-128. a case of acrodermatitis continua of four 15. Nikkels AF, Pierard GE. Etanercept and recalcitrant years’ duration that cleared when treated for acrodermatitis continua of Hallopeau. Journal of Drugs in Dermatology 2006; 705. three months with dapsone (4-4’-diamino- 16. Bonish B, Rashid RM, Swan J. Etanercept responsive diphenyl sulfone, DDS).14 Several recent acrodermatitis continua of Hallopeau: is a pattern develop- ing? Journal of Drugs in Dermatology 2006; 903. reports of acrodermatitis continua treated 17. Sahin MT, Oztürkcan S, Türel A, Kandiloglu A. Acroder- with etanercept also show promising matitis continua of Hallopeau: Was it an outcome of a sur- 15,16 gical trauma or initially misdiagnosed as onychomycosis? results. Despite these reports of moderate J Eur Acad Dermatol Venereol 2003; 17: 236-238. success using biologic and novel systemic 18. Thomachot B, Lafforgue P, Acquaviva PC. Rhumatisme psoriasique post-traumatique: deux observations. La treatments, all treatment modalities show Presse Médicale 1996; 25: 21-24. variable efficacy. There is no clear consensus on treatment protocol for acrodermatitis continua. Therapeutic results last as long as treatment is continued, with relapses common after treatment withdrawal. Conclusion There have been very few cases reported of acrodermatitis continua following a surgical procedure. Sahin et al. reported a case of a man who developed acrodermatitis continua after undergoing a nail avulsion procedure.17 Thomachot et al. also reported a case of acrodermatitis continua following an open reduction with internal fixation (ORIF) orthopedic procedure to repair a fractured calcaneus.18 This case illustrates an unusual example of acrodermatitis continua secondary to surgical trauma. The treatment of acro- dermatitis continua is notoriously difficult, and the disease is a source of significant morbidity with adverse effects on quality of life. It is important to consider this rare but potentially devastating complication of surgical procedures.

References 1. H. Radcliff-Crocker, Diseases of the Skin, London: H.K. Lewis, 1888. 2. Hallopeau MH, Sur une asphyxie locale des extrémités avec polydactilite suppurative chronique et poussées éphémères de dermatite pustuleuse disséminée et symé- trique. Bull Soc Fr Derm Syph 1890; 1: 39-45. 3. Mengesha YM, Bennett ML. Pustular Skin Disorders Diagnosis and Treatment. Am J Clin Dermatol 2002; 3 (6): 389-400. 4. Kirkup ME, Lovell CR. Acquired syndactyly secondary to acrodermatitis continua of Hallopeau. Br J Dermatol 2005; 152: 1083-1084. 5. Weedon D. Skin Pathology, 2nd Edition. Churchill Living- stone, Elsevier Limited. 2005: 82-83. 6. Piquero-Casals J, Fonseca de Mello AP, Dal Coleto C, Fonseca Takahashi MD, Simonsen Nico MM. Using oral tetracycline and topical betamethasone valerate to treat

10 ACRODERMATITIS CONTINUA FOLLOWING SURGICAL TRAUMA: A CASE REPORT ERUPTION OF LYMPHOCYTE RECOVERY: A CASE PRESENTATION AND REVIEW OF THE LITERATURE

Lisa A. Zaleski, DO, LT, MC, USN,* Peter R. Shumaker, MD, LCDR, MC, USN* *Medical Department Head onboard the USS Gunston Hall (LSD44), Little Creek Amphibious Base, Virginia Beach, VA **Dermatology Department of the Naval Medical Center, San Diego

ABSTRACT

Eruption of Lymphocyte Recovery (ELR) is an uncommon eruption that develops 14 to 21 days after a period of bone-marrow aplasia, when immunocompetent lymphocytes return to the skin and peripheral circulation. The differential diagnosis for ELR is exten- sive, making history, physical examination, and laboratory data essential in differentiating these entities. Presented here is a case of eruption of lymphocyte recovery involving sun-exposed areas mimicking actinic keratoses, a finding not previously reported to our knowledge. The differential diagnosis for the eruption of lymphocyte recovery is discussed, along with why this case is believed to be unique.

Clinical Presentation keratinocytes. A diagnosis of eruption of lymphocyte recovery was made based on A 64-year-old Caucasian female presented the history, clinical appearance, and labora- with a five-day history of a mildly pruritic tory data. In light of her need for additional eruption primarily on the upper chest, cycles of chemotherapy, the increasing upper back, dorsal hands, and central nature of the symptoms, and the patient’s that began approximately 14 days after her distress, anticipatory treatment with predni- first session of chemotherapy for stage III sone was coordinated with her oncologist to large-cell non-Hodgkin’s lymphoma. Other coincide with the peak in her WBC counts. past medical history included hypothy- The patient was treated with oral predni- roidism, Sjogren’s syndrome, and hyper- sone 40mg daily for three to four days, with tension. Chemotherapy with etoposide, a marked reduction in symptoms. Figure 1 prednisone, oncovin, cyclophosphamide, hydroxydoxorubicin, and rituximab Discussion: began on day one and continued over a five-day period. Her initial eruption ELR was first reported in the literature began approximately two weeks later and in 1989 by Horn et al. and may be more resolved abruptly at the beginning of her common than once believed. Classically, second cycle on day 24. A similar but more ELR has been associated with chemotherapy intense eruption appeared approximately in leukemia patients and can be easily distin- 15 days after the conclusion of her second guished from a leukemia-induced eruption chemotherapy cycle, and she presented to due to the differences in the morphologic the dermatology clinic for evaluation. She features of the .1,2 ELR tends to be a denied fever, malaise, diarrhea, joint pain, diagnosis of exclusion with history, physical or other symptoms. examination, and lesion histology, all essen- Figure 2 Physical examination revealed a fatigued tial in establishing the correct diagnosis. that ELR could reflect a common clinical Caucasian female with an eruption of The typical clinical appearance of ELR is pathway in the manifestation of acute coalescing, erythematous and mildly symptomatic, erythematous papules allogenic GvHD, acute autologous (spon- plaques with scant scale and focal erosions. and plaques that can be variably confluent taneous) GvHD, eruptions associated with The lesions were primarily in sun-exposed and focal or more widespread. Typically, the administration of cyclosporin A, and areas including the face, , chest, upper the eruption develops 14 to 21 days after a human recombinant cytokines in pharma- back, and (Figures 1 and 2). The period of bone-marrow aplasia upon the cologic doses. All of these erythematous differential diagnosis included a drug reac- recovery of peripheral lymphocytes, indi- eruptions are thought to be caused either tion, eruption of lymphocyte recovery, Graft cating bone-marrow recovery. There are no by an increase in the release of cytokines by versus Host Disease (GvHD), subacute common medications or combination of infiltrating lymphocytes or to the admin- , viral exanthem, and medications that have been identified. ELR istration of cytokines in pharmacologic bacterial or fungal sepsis. is associated with a transient increase in doses.1,5-6 Laboratory examination revealed no temperature with negative urine and blood Histopathology of ELR is almost iden- liver enzyme abnormalities, negative blood cultures. Transfusion of blood products has tical to GvHD, revealing a T-cell infiltrate and urine cultures, and a close correla- not been correlated with ELR.3,4 in the upper with exocytosis, basal tion between the onset of her rash and the Although it is not well understood, the vacuolization, spongiosis, and dyskeratotic return of her peripheral white-blood-cell impetus for the cutaneous infiltration of keratinocytes. Satellite cell necrosis can (WBC) and lymphocyte counts to normal lymphocytes is believed to be either a defect also be seen on rare occasions in both ELR levels. Histopathology from a punch biopsy in the suppression of returning lympho- and GvHD. However, there may be a subtle specimen revealed a lymphocytic infiltrate cytes and/or the specific cytokine- and increase in the number of upper dermal in the upper dermis with exocytosis, basal ligand-mediated recruitment of lympho- lymphocytes in ELR compared to GvHD.7 vacuolization, spongiosis, and dyskeratotic cytes. More recently, it has been postulated The rash associated with GvHD involves

ZALESKI, SHUMAKER 11 the introduction of autologous or syngeneic therapy cessation in concert with the return bone-marrow elements. Similarly, the rash of lymphocytes to the peripheral circulation of lymphocyte recovery involves the reap- in predisposed individuals.4 The patient pearance of lymphocytes to the peripheral presented differs from the classic presenta- blood and tissues after a period of immu- tion of ELR in that the eruption occurred nosuppression.2 ELR occurs earlier than in sun-exposed areas, mimicking actinic GvHD and does not develop diarrhea or keratoses. In addition, our experience in liver abnormalities.7 Clinical information this case suggests that certain patients may is essential to distinguish between these two benefit from anticipatory treatment with entities. steroids in coordination with oncology. Infectious complications or manifes- tations of the underlying cause of bone- References: marrow aplasia must be ruled out through 1. Horn TD. Acute cutaneous eruptions after marrow ablation: roses by other names? J Cutan Pathol 1994;21:385-392. examination and laboratory investigations. 2. Horn TD, Redd JV, Karp JE et al. Cutaneous eruptions of Certain viruses have been known to cause lymphocyte recovery. Arch Dermatol 1989;125:1512-1517. 3. Ginarte M, Peteiro C, Toribio J. Eruption of lymphocyte a transient eruption, such as the maculo- recovery. Eur J Dermatol 1999;9(4):323-324. 4. Bonifazi E, Garofalo L, Mazzotta F, Gelmetti C. Off-che- papular rash that can develop 14 days after motherapy dermatitis. A new entity? Eur J Pediat Dermatol exposure to measles. This rash is related to 1996;6:73-76. 5. Horn T, Lehmkuhle MA, Fore S, Hood A, Burke P. Sys- the recovery from the immunosuppression temic cytokine administration alters the histology of 2,4 the eruption of lymphocyte recovery. J Cutan Pathol caused by the measles virus. 1996;23(3):242-246. Exacerbation of pre-existing dermatologic 6. Su LD, Duncan LM. Lymphoma- and leukemia-associated cutaneous atypical CD30+ T-cell reactions. J Cutan Pathol conditions can result in a similar presenta- 2000;27:249-254. 7. Bauer DJ, Hood AF, Horn TD. Histologic comparison of tion. Hossein et al. reported an inflamma- autologous graft-vs-host reaction and cutaneous eruption tory effect on actinic with the use of lymphocyte recovery. Arch Dermatol 1993;129:855-858. 8. Fitzpatrick JE. New histopathologic findings in drug erup- of systemic fluorouracil. The inflamma- tions. Dermatol Clin 1992;10(1):19-36. 9. Hossein N, Mohindra R, Mehregan D. Selective inflam- tion occurred one to two weeks after each matory effect of fluorouracil in actinic keratosis. Cutis chemotherapy cycle, producing a mildly 1999;64:43-44. 10. Gibne MD, Penneys NS, Nelson-Adesokan P. Cutane- pruritic rash on the midface and dorsal ous eruption of lymphocyte recovery mimicking mycosis aspect of both forearms.9,10 Information fungoides in a patient with acute myelocytic leukemia. J Cutan Pathol 1995;22:472-475. involving the form of chemotherapy, the type of malignancy, white-blood-cell count, preparation regimen, and timing of rash relative to chemotherapy or bone-marrow transplant are significant facts to obtain when attempting to differentiate ELR from other causes of similar eruptions. ELR most often resolves spontaneously, and generally no treatment is required.1 The lesions of the patient described in this case study were primarily in sun-exposed areas including the face, neck, chest, upper back, and forearms. The morphology of the lesions was not the distinctive scaling, erythematous papules of actinic keratoses, making ELR a more likely diagnosis. In addition, the timing of lesion onset with lymphocyte recovery, the rapid resolution with chemotherapy-induced cytopenia, and the lack of prior history of similar eruptions all were consistent with ELR. Though treat- ment is often not required, in this case brief courses of moderate doses of oral predni- sone were used successfully to attenuate the patient’s symptoms prior to subsequent chemotherapy cycles, as they were a source of great distress to this patient. Conclusion: The presenting lesions and laboratory evidence support the diagnosis of ELR in this case. This transient, self-healing erythematous eruption occurs after chemo-

12 ERUPTION OF LYMPHOCYTE RECOVERY: A CASE PRESENTATION AND REVIEW OF THE LITERATURE "#"$""!&# " #



                                                                 

          

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AKHTAR, SKOPIT 13     Keep out of reach of children. MICROBIOLOGY The plasma concentrations of 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 fl ora 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 infl ammatory lesions (papules and pustules) of 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 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 Pharmacokinetics mice. However, data from an in vitro assay with CHO cells for potential to cause chromosomal aberrations ORACEA capsules are not bioequivalent to other doxycycline products. suggest that doxycycline is a weak clastogen. Oral administration of doxycycline to male and female Sprague-Dawley rats adversely affected fertility and CONTRAINDICATIONS reproductive performance, as evidenced by increased time for mating to occur, reduced sperm motility, velocity, This drug is contraindicated in persons who have shown hypersensitivity to doxycycline or any of the other and concentration, abnormal sperm morphology, and increased pre-and post-implantation losses. Doxycycline tetracyclines. induced reproductive toxicity at all dosages that were examined in this study, as even the lowest dosage WARNINGS tested (50 mg/kg/day) induced a statistically signifi cant reduction in sperm velocity. Note that 50 mg/kg/day is 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 suffi cient 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 observed following repeated short-term courses. Enamel hypoplasia has also been reported. Tetracycline Nursing Mothers: Tetracyclines are excreted in human milk. Because of the potential for serious adverse reactions drugs, therefore, should not be used during tooth development unless other drugs are not likely to in from doxycycline, ORACEA should not be used in mothers who breastfeed. (see WARNINGS section). be effective or are contraindicated. Pediatric Use: ORACEA should not be used in infants and children less than 8 years of age (see WARNINGS 3) All tetracyclines form a stable calcium complex in any bone-forming tissue. A decrease in fi bula growth rate section). ORACEA has not been studied in children of any age with regard to safety or effi cacy, therefore use has been observed in premature human infants given oral tetracycline in doses of 25 mg/kg every 6 hours. in children is not recommended. This reaction was shown to be reversible when the drug was discontinued. ADVERSE REACTIONS Results of animal studies indicate that tetracyclines cross the placenta, are found in fetal tissues, and can Adverse Reactions in Clinical Trials of ORACEA: In controlled clinical trials of adult patients with mild to cause retardation of skeletal development on the developing fetus. Evidence of embryotoxicity has been noted moderate rosacea, 537 patients received ORACEA or placebo over a 16-week period. The most frequent in animals treated early in pregnancy (see PRECAUTIONS: Pregnancy section). adverse reactions occurring in these studies are listed in the table below. Gastrointestinal effects: Pseudomembranous colitis has been reported with nearly all antibacterial Incidence (%) of Selected Adverse Reactions in Clinical Trials of ORACEA (n=269) vs. Placebo (n=268) agents and may range from mild to life-threatening. Therefore, it is important to consider this diagnosis in patients who present with diarrhea subsequent to the administration of antibacterial agents. ORACEA Placebo Treatment with antibacterial agents alters the normal fl ora of the colon and may permit overgrowth of clostridia. Nasopharyngitis 13 (4.8) 9 (3.4) Studies indicate that a toxin produced by diffi cile is a primary cause of “-associated colitis”. Pharyngolaryngeal Pain 3 (1.1) 2 (0.7) If a diagnosis of pseudomembranous colitis has been established, therapeutic measures should be initiated. Mild Sinusitis 7 (2.6) 2 (0.7) cases of pseudomembranous colitis usually respond to discontinuation of the drug alone. In moderate to severe Nasal Congestion 4 (1.5) 2 (0.7) cases, consideration should be given to management with fl uids and electrolytes, protein supplementation, and treatment with an antibacterial drug clinically effective against Clostridium diffi cile colitis. Fungal Infection 5 (1.9) 1 (0.4) Metabolic effects: The anti-anabolic action of the tetracyclines may cause an increase in BUN. While this Infl uenza 5 (1.9) 3 (1.1) is not a problem in those with normal renal function, in patients with signifi cantly impaired function, higher Diarrhea 12 (4.5) 7 (2.6) serum levels of tetracycline-class antibiotics may lead to azotemia, hyperphosphatemia, and acidosis. If renal Abdominal Pain Upper 5 (1.9) 1 (0.4) impairment exists, even usual oral or parenteral doses may lead to excessive systemic accumulations of the Abdominal Distention 3 (1.1) 1 (0.4) drug and possible liver toxicity. Under such conditions, lower than usual total doses are indicated, and if therapy 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 Note: Percentages based on total number of study participants in each treatment group. with ORACEA, patients should minimize or avoid exposure to natural or artifi cial sunlight (tanning beds or UVA/B treatment) while using ORACEA. If patients need to be outdoors while using ORACEA, they should Adverse Reactions for Tetracyclines: The following adverse reactions have been observed in patients wear loose-fi tting clothes that protect skin from sun exposure and discuss other sun protection measures receiving tetracyclines at higher, antimicrobial doses: with their physician. Gastrointestinal: anorexia, nausea, vomiting, diarrhea, glossitis, dysphagia, enterocolitis, and infl ammatory PRECAUTIONS lesions (with vaginal candidiasis) in the anogenital region. Hepatotoxicity has been reported rarely. Rare instances of esophagitis and esophageal ulcerations have been reported in patients receiving the capsule forms of the General: Safety of ORACEA beyond 9 months has not been established. drugs in the tetracycline class. Most of the patients experiencing esophagitis and/or esophageal ulceration took As with other antibiotic preparations, use of ORACEA may result in overgrowth of non-susceptible micro- their medication immediately before lying down. (see DOSAGE AND ADMINISTRATION section). organisms, including fungi. If superinfection occurs, ORACEA should be discontinued and appropriate therapy Skin: maculopapular and erythematous . Exfoliative dermatitis has been reported but is uncommon. instituted. Although not observed in clinical trials with ORACEA, the use of tetracyclines may increase the Photosensitivity is discussed above. (see WARNINGS section). incidence of vaginal candidiasis. 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, OVERDOSAGE liver function tests, ANA, CBC, and other appropriate tests should be performed to evaluate the patients. Use In case of overdosage, discontinue medication, treat symptomatically, and institute supportive measures. of all tetracycline-class drugs should be discontinued immediately. Dialysis does not alter serum half-life and thus would not be of benefi t in treating cases of overdose. Tissue : Tetracycline class antibiotics are known to cause hyperpigmentation. Tetracycline DOSAGE AND ADMINISTRATION therapy may induce hyperpigmentation in many organs, including nails, bone, skin, eyes, thyroid, visceral THE DOSAGE OF ORACEA DIFFERS FROM THAT OF DOXYCYCLINE USED TO TREAT INFECTIONS. tissue, oral cavity (teeth, mucosa, alveolar bone), sclerae and heart valves. Skin and oral pigmentation has EXCEEDING THE RECOMMENDED DOSAGE MAY RESULT IN AN INCREASED INCIDENCE OF SIDE been reported to occur independently of time or amount of drug administration, whereas other pigmentation EFFECTS INCLUDING THE DEVELOPMENT OF RESISTANT MICROORGANISMS. has been reported to occur upon prolonged administration. Skin pigmentation includes diffuse pigmentation as well as over sites of or injury. One ORACEA Capsule (40 mg) should be taken once daily in the morning on an empty stomach, preferably at least one hour prior to or two hours after meals. Pseudotumor cerebri: Bulging fontanels in infants and benign intracranial hypertension in adults have been reported in individuals receiving tetracyclines. These conditions disappeared when the drug was Effi cacy beyond 16 weeks and safety beyond 9 months have not been established. discontinued. Administration of adequate amounts of fl uid along with the capsules is recommended to wash down the Laboratory Tests: Periodic laboratory evaluations of organ systems, including hematopoietic, renal and hepatic capsule to reduce the risk of esophageal irritation and ulceration. (see ADVERSE REACTIONS section). studies should be performed. Appropriate tests for autoimmune syndromes should be performed as indicated. HOW SUPPLIED Drug Interactions: 1. Because tetracyclines have been shown to depress plasma prothrombin activity, ORACEA (beige opaque capsule printed with CGPI 40) containing doxycycline, USP in an amount equivalent to patients who are on anticoagulant therapy may require downward adjustment of their anticoagulant dosage. 40 mg of anhydrous doxycycline. Bottle of 30 (NDC 64682-009-01). 2. Since bacteriostatic drugs may interfere with the bactericidal action of penicillin, it is advisable to avoid Storage: All products are to be stored at controlled room temperatures of 15°C-30°C (59°F-86°F) and giving tetracycline-class drugs in conjunction with penicillin. 3. The concurrent use of tetracycline and dispensed in tight, light-resistant containers (USP). Keep out of reach of children. methoxyfl urane has been reported to result in fatal renal toxicity. 4. Absorption of tetracyclines is impaired by 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., Newtown, PA, 18940 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 , including isotretinoin CardinalHealth CollaGenex Pharmaceuticals, Inc. and acitretin, and the tetracyclines, primarily minocycline, can cause increased intracranial pressure, the Winchester, KY 40391 Newtown, PA, 18940 concurrent use of an oral and a tetracycline should be avoided. 7961-01 BPI 06/07 ORAL LICHEN PLANUS: A CASE REPORT AND REVIEW OF LITERATURE

Julie Malchiodi, DO,* Michelle Bruner, DO,** Melissa Hintz,*** Jean Holland, MD**** *2nd-year Dermatology Resident, Oakwood Healthcare System, Oakwood Southshore Medical Center, Trenton, Michigan **Intern, Oakwood Healthcare System, Oakwood Southshore Medical Center, Trenton, Michigan ***3rd-year Medical Student, Des Moines, IA ****Assistant Clinical Professor, Oakwood Healthcare System, Oakwood Southshore Medical Center, Trenton, Michigan

ABSTRACT

Oral lichen planus (OLP) is a relatively common, often asymptomatic chronic inflammatory condition of the oral mucosa. The three main types of OLP include reticular, erosive and atrophic. OLP shares a differential diagnosis with several conditions that are difficult to distinguish clinically and histologically. Diseases that resemble OLP are referred to as lichenoid reactions and include allergic contact reactions to dental materials, lichenoid drug reactions, graft vs. host disease, erythema multiforme and lupus erythematosus. Controversy surrounds the possibility that OLP is a premalignant lesion. Because OLP has no cure, treatment is mostly palliative, focusing on decreasing lesion size, alleviating symptoms and decreasing the risk of possible malignant transformation. We present a patient with oral lichen planus of the erosive type and a review of literature.

Case Report to rule out a contact allergy. It was found to be negative. A 62 year old white female presented with The patient was seen for a follow-up a 3 month history of painful mouth sores visit approximately three weeks later and on her buccal mucosa. She reported having reported some improvement with the treat- recent dental work with crowns placed and ment given. However, she had an emergency the oral symptoms began about one month root canal about three days prior to the later. She initially experienced ulcerations visit and complained that her mouth had on the lower gingiva in proximity to the become very sore again with the develop- dental crowns, which subsequently devel- ment of more erosive lesions on her buccal oped on the bilateral buccal mucosa and mucosa. tongue. Since the lesions were very painful Various therapies were tried over several she was only able to tolerate ice cream. She months with little improvement in the Figure 1 denied having any vulvar symptoms, skin patient’s symptoms. These included pred- rashes or pruritis and she had no history of nisone, acitretin, isotretinoin, retin-A skin conditions. Medical history included mixed with fluocinonide gel, a mixture of asthma and hypothyroidism and no aller- tetracycline, celestone, benadryl swish and gies to medications were reported. spit, triamcinolone ointment, and steroid A physical exam of the oral mucosa injections. The patient was also treated for revealed multiple scattered erosions and oral candidiasis with diflucan and mycelex hyperkeratotic papules with surrounding troches. The patient was recently started on erythema on the bilateral buccal mucosa a trial of methotrexate and will continue to (Figure 1). The erosions were not directly be followed periodically. associated with the dental crowns and there were no erosions on the gingivae. Upon Discussion examination of the skin there was only Figure 2 diffuse xerosis, without evidence of plaques Oral lichen planus (OLP) is a relatively or papules. common, usually asymptomatic, undi- have coexisting cutaneous lesions. When an A punch biopsy obtained from buccal agnosed and often misdiagnosed chronic oral lesion has a questionable diagnosis, the mucosa showed squamous mucosa with inflammatory condition of the oral mucosa. presence of skin findings can be a valuable focal erosion and fibrin deposition. Within It is notorious for having a persistent course tool in the identification of OLP.4 Twenty- the submucosa, there was a lichenoid infil- with cycles of activity and remission. OLP five percent of oral lesions occur as isolated trate of lymphocytes with some plasma is estimated to exist in 0.9% to 2% of the findings without concurrent cutaneous cells. Neutrophils were present at the base general population, but the true prevalence lesions and 35% of cutaneous lesions occur of the erosion as well as within the adja- is unknown.1 This uncertainty is attrib- in the absence of coexisting oral lesions.5 cent squamous epithelium. A PAS stain was uted to a vast under diagnosis since many In contrast to cutaneous lichen planus, negative for fungal hyphae (Figure 2). These patients only seek medical attention if they for which the spontaneous remission rate findings are consistent with erosive oral experience pain from their lesions.2 Due is 70% after one year, OLP is much more lichen planus. to its asymptomatic nature and location, chronic. The reported mean duration of Complete blood count, blood urea OLP is most often diagnosed as a result OLP is 5 years, but the erosive form may last 3 nitrogen, creatinine, AST, ALT were all of an incidental finding by dentists.3 The up to 20 years. within normal range. Her cholesterol and disease occurs most frequently in women Oral lichen planus is an autoimmune triglycerides were elevated, which were and affects a broad spectrum of ages, with condition in which the body generates an attributed to her diet of mostly ice cream. the mean being 50-55 years.1 Oral lichen abnormal immune response against basal Due to the timing of gold-containing dental planus can, but does not always coexist with cells in the oral mucosa. The stimulus of crown placement and the appearance of her cutaneous lichen planus. It is estimated that the initial autoimmune damage to the oral lesions, a gold patch test was performed 30% to 50% of patients with oral lesions basal keratinocytes is unknown, however

MALCHIODI, BRUNER, HINTZ, HOLLAND 15 it is postulated that the immune response fundamental in their diagnosis.3 The shared sized that they experience a fair degree of is triggered by numerous factors in indi- features include a hyperparakeratosis, uncertainty in their ability to distinguish viduals with a genetic susceptibility or often with acanthosis or a widening of the between the two. Although the differen- predisposition.6,7 The immune response spinous cell layer, occasional areas of thin tiation is difficult, pathologists were able takes place when basal keratinocytes are epithelium showing rete ridges with a short to agree on four features that are present recognized by the immune system as foreign and pointed saw-tooth-like morphology in amalgam related contact lesions and due to changes in the antigenicity of the and necrosis of the basal cell layer defined absent in OLP. These features include an cell surface. An intense hypersensitivity- as liquefaction degeneration with apoptosis infiltration of inflammatory cells located like T cell mediated response occurs at the of the keratinocytes. Also, there is a broad deep in relation to a superficial infiltrate, interface between the epithelium and the infiltration of T lymphocytes at the junc- perivascular infiltrates, and plasma cells and connective tissue.1 The release of cytokines tion of the epithelium and connective tissue. neutrophils in the connective tissue.6 Just as and other inflammatory mediators results These inflammatory T-lymphocytes may histological differences exist, certain clinical in injury to the basal keratinocytes.6 extend beyond the basement membrane. findings and elements of the patient history This autoimmune process manifests itself The microscopically visible thickened areas may provide clues to differentiate OLP from clinically as bilateral, symmetrical lesions of of rete ridges results in the clinical appear- a contact reaction. Oral lichenoid contact the oral cavity.8 They are most commonly ance of Wickham’s striae in reticular OLP.3,4 reactions to dental amalgam occur on located on the posterior buccal mucosa Despite the established shared features, the mucosal surfaces in direct contact with the but may be found anywhere, including the different types of OLP also exhibit unique dental material.4,8,10 Clinically lesions usually gingivae, tongue, palate and .1 They begin histological characteristics. The epithelium display erosions or fissures among thick as small papules that eventually migrate in erosive OLP is thin and ulcerated with white lines or plaques but the thin white together and fuse into a larger area with a total loss of the rete ridges. There is a striae characteristic of OLP are usually patterns specific to a particular type of OLP. thick infiltration of T-cells that extends absent.9 Contrary to OLP, these lichenoid The three main clinical types described are into middle and upper levels of epithelium. contact lesions do not migrate. Lichenoid reticular (the most common), erosive and Basement membrane liquefaction and basal contact lesions resolve when the amalgam atrophic. Patients may display more than cell destruction is present throughout most restoration is removed.4 one type of lesion at a time.8 Reticular OLP affected areas and the epithelium may be There is no straightforward clinical or may demonstrate a variety of presentations completely obliterated revealing connective histological characteristic that distinguishes and morphologies, however its identifying tissue.3 an oral lichenoid drug reaction from oral characteristic is keratotic formations.2 These OLP is difficult to diagnose due to its lichen planus or the other lichenoid lesions.8 formations display thin, white and lacy clinical and microscopic similarity to other It has been demonstrated that drug related keratotic lines, which appear reticular or diseases and its asymptomatic nature. A lichenoid reactions sometimes display annular, referred to as Wickham’s striae.1,3,4 large spectrum of diseases resemble lichen unique microscopic characteristics. These Reticular OLP has a plaque-like variant planus both histologically and on physical include a deep and superficial perivascular that can resemble and be misdiagnosed as exam and they are referred to as lichenoid infiltration of lymphocytes and eosinophils, leukoplakia. Erosive OLP is the second most reactions.6,8 In order to categorize a lesion as plasma cells and neutrophils.3 A careful drug frequent type of OLP. Erosive OLP presents lichenoid it must meet specific histological history in a patient with a lichenoid lesion is as a combination of shallow ulcerations and criteria, including basal injury helpful in obtaining a diagnosis. The list erythema surrounded by radiating kera- or apoptosis, an inflammatory cell response of drugs that cause lichenoid reactions is totic lines.4 The erosions are typically well in the connective tissue, and keratosis or extensive, however, drugs most likely to demarcated and ulcers may be covered with .6 Conditions that present be implicated include antibiotics, antihy- a pseudomembrane.1 Lesions can migrate with oral lichenoid lesions according to pertensives, gold diuretics, antimalarials and evolve into a multifocal distribution.4 these criteria include OLP, contact allergies and nonsteroidal antiinflammatories.3,4 This is the most symptomatic type of OLP to dental restoration materials, drug reac- Clinically, an established temporal relation- and the severity of symptoms can range tions, graft versus host disease, erythema ship between the onset and resolution of greatly from one person to the next.7 Some multiforme and lupus erythematosus.6,8 a lesion that correlates with drug use may patients suffer mild episodic pain, while An oral lichenoid lesion can be the result serve as a diagnostic tool. A temporal rela- others may experience symptoms so severe of a contact allergy to dental restorative tionship is not always obvious since drugs that daily activities such as mastication and materials in amalgam fillings.9 Allergic may cause lichenoid reactions even years oral hygiene are compromised.4 Atrophic type IV delayed hypersensitivity reactions after their introduction.8 The resolution of a OLP presents as large areas of erythema to products from dental amalgam cause lesion when a drug is discontinued can also among keratoses or thin, fine white lines tissue injury. This injury is manifested aid in the diagnosis of a drug reaction.8 or striae.2,4 Atrophic OLP is found most locally as oral contact mucositis. Oral Although many studies have shown commonly on the gingiva. This form of contact mucositis has been reported in OLP should be classified as a precancerous OLP can be extremely sensitive to envi- response to mercury, nickel and chromium lesion, this still remains controversial.11 ronmental irritants such as ingestion of in dental material. Overwhelming data in Scientific literature claims a wide range spicy food.5 Irritation may lead to avoidance the literature states that it is both clinically of frequency of malignancy. Some studies of tooth brushing and an eventual decline and histologically difficult to distinguish a report a rate of malignant transformation in oral hygiene, adding a variable of peri- lesion caused by contact hypersensitivity of 0.04% to 1.74% while other research odontal disease to the existing problem.1 In from OLP.10 Thornhill published a study reports a transformation rate as high as contrast to the other forms of OLP, litera- confirming the difficulty in distinguishing 10%.3,7,12 Many theories exist for the discrep- ture has documented that atrophic lesions OLP from lichenoid lesions caused by ancy of reported frequency in the litera- are more likely to undergo spontaneous hypersensitivity to amalgam fillings based ture concerning malignant transformation. resolution, with some studies reporting on histological examination alone. The Discrepancies in inclusion and diagnostic resolution rates as high as 12%.5 study reported that based on microscopic criteria may contribute to the seemingly Although the different types of OLP evaluation, pathologists were only able to elevated level of malignant transforma- have variations in histological presenta- make a correct distinction between OLP tion.11 Patients entered into studies diag- tion, several specific features have been and dental lichenoid reactions 33% of the nosed strictly in a clinical manner may be identified as shared by the three types and time. In addition, the pathologists empha- misdiagnosed with OLP and may actually

16 ORAL LICHEN PLANUS: A CASE REPORT AND REVIEW OF LITERATURE have premalignant dysplastic mucosa with 0.1% cream can be used for erosive lichen 1994;102:172-179. 11. Tizeira H, Aguas S, Sano S. Malignant transformation 7,11 15 lichenoid characteristics. The transforma- planus with few side effects. According of atypical oral lichen planus: a review of 32 cases. Med tion of OLP into squamous cell carcinoma to Passeron, all but one patient treated Oral. 2003;8:2-9. 12. Scully C, Beyli M, Ferreiro M. Update on oral lichen seems to be dependent upon the type of with pimecrolimus had at least a moderate planus: etiopathogenesis and management. Crit Rev Oral OLP. Little to no data has reported the improvement in their condition. However, Biol Med. 1998;9:86-122. 13. Eisen D, Carrozzo M, Sebastian JV, et al. Oral lichen development of squamous cell carcinoma one study showed the benefits were not planus: clinical features and management. Oral Diseases. from reticular LP. Malignant transforma- long-lasting, as those who improved subse- 2005;11: 338–49. 14. Trehan M, Taylor C. Low-dose excimer 308-nm laser tion occurs more frequently in atrophic, quently relapsed when assessed 1 month for the treatment of oral lichen planus. Arch Dermatol. erosive and ulcerative forms of OLP. The after treatment.15 Methotrexate has been 2004;140:415-20. 15. Passeron T, Lacour J, Fontas E, et al. Treatment of oral predisposition of malignant transformation shown to provide excellent control of erosive lichen planus with 1% pimecrolimus cream. Arch in specific types of OLP has created theories OLP in patients with the most refractory Dermatol. 2007;143:472-76. 16. Torti D, Jorizzo J, McCarty M. Oral lichen planus: A 16 14 about the etiology of the transformation of and aggressive disease. Trehan reports case series with emphasis on therapy. Arch Derma- OLP to squamous cell carcinoma. Possible improvement of symptomatic lesions, espe- tol. 2007;143:511-15.17. 17. Byrd J, Davis M, Bruce A, et al. Response of oral lichen explanations describe the damaged mucosa cially erosive lesions, with low-dose 308-nm planus to topical tacrolimus in 37 patients. Arch Dermatol. in these types of OLP makes the tissue more excimer laser radiation. Remission times 2004;140:1508-1512. 18. Laeijendecker R, Dekker S, Burger P, et al. Oral lichen susceptible to the affects of carcinogens in for patients who demonstrated a significant planus and allergy to dental amalgam restorations. Arch the oral cavity. Immunomodulating thera- response to treatment ranged from 2-17 Dermatol. 2004;140:1434-38. 19. Koch P, Bahmer F. Oral lesions and symptoms related pies have been considered in the etiology months. to metals used in dental restorations: a clinical, aller- of malignant transformation due to their gological, and histologic study. J Am Acad Dermatol. Patients with oral lichen planus, found 1999;41:422-30. ability to suppress the local immune system to have an allergy to mercury compounds, 20. Yiannias J, el-Azhary R, Hand J, et al. Relevant contact and possibly allow malignancy to progress.3 sensitivities in patients with the diagnosis of oral lichen may have significant improvement with planus. J Am Acad Dermatol. 2000;42:177-82. Candida albicans has also been implicated partial or complete replacement of amalgam by many studies in the malignant potential dental fillings.18,19,20 Whether patients of OLP. The immunomodulatory agents without mercury allergies should have fill- and corticosteroids frequently administered ings replaced remains controversial. Some to patients with OLP may predispose them authors suggest the removal of amalgam to candidal infection. These individuals fillings should only be performed in patients have a higher rate of candida coloniza- with known sensitivities.18,19 tion and infection than the general popu- Due to the risk of malignant transforma- lation. Candida can form the carcinogen tion to squamous cell carcinoma, patients N-nitrosobenzylmethylamine, which has with oral lichen planus should have periodic been related to malignant transforma- follow-up.7, 14 Promoting good oral hygiene 7 tion in leukoplakia. Even researchers who in patients with OLP is also very important. conclude that they do not consider OLP to In summary, we reported a case of oral be a premalignant condition acknowledge erosive lichen planus. OLP may be difficult there is a small increase in the risk of oral to distinguish from other lichenoid reac- squamous cell carcinoma in individuals who tions that may resemble it both clinically have OLP, when compared to individuals 2 and microscopically. Although the criteria without OLP. used to diagnose OLP are still debated, a Oral lichen planus is an idiopathic biopsy is often helpful. Treatment is mostly chronic inflammatory condition for which palliative, focused on decreasing the length 6 there is no cure. Treatment is mostly of episodes and severity of symptoms. In palliative, aiming to decrease lesion size, addition, since OLP may represent a prema- eliminate atrophic and ulcerative lesions, lignant lesion, patients should be followed alleviate symptoms and decrease the risk regularly. of malignant transformation.6,13 First line treatment of localized lesions includes the use of topical steroids and intralesional References 1. Lozada-Nur F, Miranda C. Oral Lichen Planus: Epidemiol- injections, while systemic corticosteroids ogy, clinical characteristics, and associated diseases. are often used for severe flares of wide- Semin Cutan Med Surg.1997;16:273-277. 14 2. Chainani-Wu N, Silverman S, Lozada-Nur F, et al. Oral spread lesions. Studies have shown corti- lichen planus patient profile, disease progression and treat- costeroids provided complete remission ment responses. J Am Dent Assoc. 2001;132:901-909. 3. DeRossi S, Ciarrocca K. Lichen planus, lichenoid drug in some patients. However, corticosteroids reactions, and lichenoid mucositis. Dent Clin N Am. are known to induce various side effects 2005;49:77-89. 4. Edwards P, Kelsch P. Oral lichen planus: clini- including atrophy, fragility, and higher cal presentation and management. J Can Dent Assoc. infection rates.15 2002;68:494-499. 5. Bricker S. Oral lichen planus: a review. Semin Dermatol. Other treatments include topical 1994;13(2):87-90. Review. immunosuppressants, topical or systemic 6. Thornhill M, Sankar V, Xu XJ. The role of histopathological characteristics in distinguishing amalgam-associated oral retinoids, thalidomide, methotrexate and lichenoid reactions and oral lichen planus. J Oral Pathol PUVA.14, 16 Topical tacrolimus treatment is Med. 2006;35:233-240. 7. Eisen D. The clinical features, malignant potential and safe and effective treatment for both erosive systemic associations of oral lichen planus: A study of 723 and reticulated forms of oral lichen planus. patients. J Am Acad Dermatol. 2002;46:207-214. 8. Al-Hashimi I, Schifter M, Lockhart P, et al. Oral lichen Byrd reported symptomatic response in 89% planus and oral lichenoid lesions: diagnostic and thera- and lesion clearance in 84% of participants. peutic considerations. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2007;103:S25-S31. Lesions responded to treatment within 6 9. Camisa C, Taylor J, Bernat J, et al. Contact hypersensitiv- months (mean 1 month). All participants ity to mercury in amalgam restorations may mimic oral lichen planus. Cutis. 1999;63:189-192or3?. with both oral and genital lesions had 10. Ostman P, Anneroth G, Skoglund A. Oral lichen planus symptomatic improvement.17 Pimecrolimus lesions in contact with amalgam fillings: a clinical, histo- logic, and immunohistochemical study. Scand J Dent Res.

MALCHIODI, BRUNER, HINTZ, HOLLAND 17 GIANT-CELL TUMOR OF THE TENDON SHEATH: A CASE PRESENTATION AND REVIEW OF THE LITERATURE

Chris Buckley, D.O.,* Stanley Skopit, D.O., FAOCD** **1st-year resident - Nova Southeastern University/BGMC **Program Director - Nova Southeastern University/BGMC

Introduction tive for the immunohistochemical markers CD68 and factor XIIIa, but negative for Giant-cell tumor of the tendon sheath is cytokeratins 5/6 and AE1/AE3 as well as a relatively rare, benign tumor that occurs melanocytic markers S-100 and Melan-A. most often on the hands. This is a case These findings confirmed the diagnosis of presentation of a 14-year-old female who giant-cell tumor of the tendon sheath. After developed a progressively enlarging, soli- evaluation and consideration of the parent's tary, non-tender nodule on the extensor concerns, the patient was referred to a hand surface of her right thumb. Additionally, a surgeon for surgical excision of the lesion. review of the literature and discussion of the common causes, cutaneous and histologic Comment findings, differential diagnoses, diagnostic techniques, and various treatment options Giant-cell tumor of the tendon sheath, Figure 1. Right thumb for this disease will be presented. also known as localized nodular tenosyno- vitis, is a relatively rare, benign growth, but Case Report is the most common primary tumor of the hand.1 In spite of this, it appears to be rarely An otherwise healthy 14-year-old mentioned in dermatological literature.2 It Caucasian female presented to the derma- was first described in 1852 by Chassaignac, tology clinic with her mother for evalua- who referred to these lesions as cancers of tion of a growth on her right thumb. The the tendon sheath; but malignant potential patient recalled that the growth was first in these lesions has since been disproven. noticed approximately three months prior There is growing consensus that these to presentation as a large bump on her tumors actually represent a localized form thumb, and it had grown slightly in size of pigmented villonodular synovitis.3 since that time. Neither she nor her family Giant-cell tumors of the tendon sheath could recall any history of similar prob- are typically painless, asymptomatic lems and denied any known trauma to the masses. They occur most commonly on the area or occupation that involved repetitive hand (80% of cases), with the next most motion. Furthermore, the patient denied common predilection being for the foot- Figure 2. Right thumb any pain, tenderness, difficulty with joint ankle complex. Most cases arise along the mobility or range-of-motion limitations. volar aspect of the long fingers, typically (Figures 3 and 4). Upon further questioning of the patient, adjacent to the DIP joint. There is a 3:2 For accurate diagnosis, incisional biopsy she denied painful joints, fever, or any other female-to-male sex predominance, with the with intraoperative frozen section and systemic symptoms. Although the patient lesions arising most commonly in the third histological analysis is the gold-standard. appeared relatively asymptomatic, her to fifth decades of life, and more rarely in Plain radiographs and MRI evaluations can mother was concerned about the appear- 4,5 children. be conducted preoperatively to evaluate ance of the lesion and the possibility of The true etiology of giant-cell tumors of clinically confusing lesions, and are recom- malignancy or infection. the tendon sheath is unknown. Although mended for soft-tissue tumors in children On physical examination, the patient was controversy exists as to whether these when giant-cell tumor of the tendon sheath found to have an approximately 1.0 cm x 0.9 tumors are neoplastic or localized reactive is being considered. Plain radiographs cm solitary, well-circumscribed nodule on responses, the most commonly accepted display a benign-appearing, circumscribed the extensor aspect of the first digit of the theory is that they arise as a reactive or soft-tissue swelling in approximately 50% right hand, just distal to the interphalangeal regenerative hyperplasia secondary to an of cases. Cortical erosion of the bone adja- joint. The nodule was non-tender, firm, inflammatory process. An association with cent to the mass is found in 10%-20% of non-fluctuant, fixed, and did not appear to rheumatoid arthritis or antecedent trauma cases and can be differentiated from osseous migrate with digit flexion or extension. No has been occasionally reported, but no lesions by MRI. True bone invasion is not cutaneous erythema or edema was appreci- evidence of this causal or pathogenic rela- typical and suggests an aggressive . 5-7 ated, and the overlying skin of the nodule tionship has been proven. On MRI evaluation, giant-cell tumor of the was freely mobile (Figures 1 and 2). Histologically, giant cell tumors of the tendon sheath presents as a solid mass with Two separate 2mm punch biopsies were tendon sheath have a lobular outline and areas of hypointense signal on both T1- and performed on the lesion for diagnostic are typically attached to the tendon sheath. T2-weighted images, with mild to moderate purposes. The histological findings of the They display a polymorphic population enhancement on gadolinium administra- biopsies were characterized as a prolifera- composed of mononuclear histiocytes with tion. Common differential diagnosis tion of mononuclear epithelioid cells with abundant pale foamy or vacuolated cyto- includes foreign-body , tendi- scattered xanthomatized cells, rare multi- plasm and hemosiderin deposits, and char- nous xanthoma, necrobiotic granuloma, nucleated giant cells, and a small amount acteristic multinucleated giant cells scattered ganglion cyst, rheumatoid nodule, lipoma, of focal hemosiderin. The lesion was posi- throughout the tumor in variable densities8,9 and epermoid cyst, among others.3,5,10

18 GIANT-CELL TUMOR OF THE TENDON SHEATH: A CASE PRESENTATION AND REVIEW OF THE LITERATURE 6. KC Booth MD et al. Giant cell tumor of tendon sheath with intraosseous invasion: a case report. J Hand Surg. Vol 20-A. No 6. 1995 Nov; p1000. 7. Vogrincic GS, O'Connell JX, Gilks CB. Giant cell tumor of tendon sheath is a polyclonal cellular proliferation. Hum Pathol. 1997 July; p815-9. 8. Ushijima M, et al. Giant cell tumor of tendon sheath (nodu- lar tenosynovitis). A study of 207 cases to compare the large joint group with the common digit group. Cancer. 1986 Feb; 57. p875-84. 9. Gupta K, Dey P, Goldsmith R, Vasishta RK. Comparison of cytological features of giant-cell tumor and Giant-cell tumor of tendon sheath. Diagn Cytopathol. 2004 Jan; 30. p14-8 10. De Schepper AM, Hogendoorn PC, Bloem JL. Giant cell tumors of tendon sheath may present radiologically as intrinsic osseous lesions. Eur Radiol. 2007 Feb; 17. p499-502. 11. Monaghan H, Salter DM, Al-Nafussi A. Giant cell tumor of tendon sheath (localized nodular tenosynovitis): clinico- pathological features of 71 cases. J Clin Pathol. 2001 May; 54. p404-7.

Figure 3

Figure 4

Surgical excision is the treatment of choice for giant-cell tumors of the tendon sheath.11 Recurrence rates of 10%-44% are reported, and risk factors for recurrence include incomplete excision, the presence of adjacent degenerative joint disease, and radiographic evidence of osseous erosion. Therefore, meticulous surgical excision with adequate exposure and use of surgical magnifying loupes is recommended. 3-5 In conclusion, giant-cell tumor of the tendon sheath is a relatively rare entity and one not commonly encountered in the dermatological setting. It has a predilec- tion for the hand and is the most common primary tumor of the hand. In spite of its benign nature, surgical excision is usually recommended to prevent progression as well as bony deterioration. Treatment is often curative, but local recurrence is common.

References: 1. Walsh EF, Mechrefe A, Akelman E, Schiller AL. Giant cell tumor of tendon sheath. Am J Orthop. 2005 Mar; p116-21. 2. Rustin MH, Robinson TW. Giant cell tumor of the tendon sheath-an uncommon tumor presenting to dermatologists. Clin Exp Dermatol. 1989 Nov; p466-8. 3. Gholve, PA MD, et al. Giant cell tumor of tendon sheath: largest single series in children. J Pediatr Orthop. Vol 27. 2007; p67-74. 4. Messoudi A, Fnini S et al. Giant cell tumor of tendon sheath of the hand: 32 cases. Chir Main. 2007 April 24. 5. James Verheydon, MD. Giant cell tumor of tendon sheath: article by James R Verheydon, eMedicine. http://www. emedicine.com/orthoped/topic121.htm.

BUCKLEY, SKOPIT 19 RECURRENT ABSCESSES: UNDERLYING IMMUNODEFICIENCY?

Brian S. Walther, DO,* and Stephen M. Purcell, DO** *3rd-year resident, Department of Dermatology, Frankford Hospitals/Philadelphia College of Osteopathic Medicine **Associate Program Director, Dermatology Residency, Frankford Hospitals/Philadelphia College of Osteopathic Medicine

Case Report abscesses despite appropriate antibiotics, and have a history of non-specific derma- A 30-year-old Caucasian male presented titides and systemic abnormalities, careful with a 15-year history of mild hidradenitis consideration should be given to a primary suppurativa and acne conglobata, in addi- immunodeficiency. A search of the Online tion to multiple painful, draining abscesses Mendelian Inheritance in Man yielded affecting his face, neck, back, axillae, several of these primary immunodeficien- , and feet. These abscesses tended cies.1 Although it is beyond the scope of this to be recurrent and recalcitrant to many paper to review this exhaustive list, hyper- therapeutic regimens, and had required immunoglobulin E syndrome seems to be multiple incision and drainages to relieve the most prevalent and well-represented in his symptoms. Prior therapies have included the literature. prednisone, cephalexin, azithromycin, According to the Book of Job, “So went levofloxacin, , amoxicillin/ Satan forth from the presence of the Lord, clavulanate, dapsone, minocycline, tetra- and smote Job with sore from the cycline, trimethoprim-sulfamethoxazole, sole of his foot unto his crown.” Davis, clindamycin lotion, wash, Schaller and Wedgewood paid homage sodium sulfacetamide wash, tretinoin cream, to this biblical reference when they first intralesional triamcinolone acetonide, described two young girls with red hair, finasteride, and isotretinoin. Patient denied chronic dermatitis, and recurrent staphylo- any childhood history of atopy, recurrent coccal abscesses and pneumonias in 1966.2 lung infections, or musculoskeletal/dental Although several eponyms have been given difficulties, although he reported his father to this condition, including both Job’s and Figure 1. Severe scarring and had similar abscesses at “an early age.” On Buckley syndrome, they currently fall under inflammatory sinus tracts of the face physical examination, multiple cicatrices, the heading of hyperimmunoglobulin E and chest open/closed comedones, and draining sinus Syndrome (HIES). tracts of his face, neck, chest and back were HIES represents a rare, multisystem observed, with predominant scarring of his disease with only 250 cases reported in the axillae bilaterally (Figures 1, 2). literature.3 Both AD and AR variants have Laboratory evaluation included a been reported, each with its own unique, complete blood cell count, complete meta- albeit variable phenotypic expressivity. bolic panel, quantitative immunoglobulin Chromosome 4q has been suggested to be levels, nitroblue tetrazolium assay (NBT), the defective locus in patients with HIES. and several wound cultures. Studies revealed The underlying pathophysiology of HIES slightly decreased hemoglobin at 12.8 g/dL involves abnormal neutrophil chemotaxis (13.2-17.1), hematocrit 38.0 % (38.5-50.0), and altered immunoglobulin profiles. and IgM 17 mg/dL (948-271), as well as Analyses of cytokine profiles have shown elevated IgG at 2,363 mg/dL (694-1,618) that patients with HIES have functional and IgE 301 kU/L (≤114). Results of the and quantitative deficiencies in interferon NBT assay were negative. Wound cultures (IFN) gamma, which is a major activator of taken from the patient’s chest and left dorsal neutrophils. Moreover, studies have eluci- foot grew coagulase-negative staphylococci dated an upstream signaling error in inter- and beta-hemolytic streptococci, respec- leukin (IL) 12 production, whose function Figure 2. Purulent drainage from an tively. In addition, a 4-mm punch biopsy includes increasing IFN gamma production inflamed taken from the left dorsal foot demonstrated and suppressing IgE production. suppuration, necrosis, and granulation HIES represents a constellation of clinical morbidity secondary to recurrent pneu- tissue consistent with an abscess. findings, both dermatologic and extracuta- monia, usually due to S. aureus and neous. Perhaps the most common is recur- Haemophilus influenzae, although rare cases Discussion rent “cold” abscesses, typically associated of Pseudomonas aeruginosa and Aspergillus 4 with . The pathogno- fumigatus have also been reported. Certain Given the increasing prevalence of monic lack of calor signifies the underlying structural anomalies have also been char- community-acquired methicillin-resistant abrogated neutrophil response. Moreover, acterized as being suggestive for HIES. Staphylococcus aureus (MRSA) and sub- patients may demonstrate chronic candidi- Grimbacher et al. studied 30 patients with clinical colonization, patients presenting asis of the oral mucosa and nails, as well HIES and found that many shared similar with recurrent abscesses may reflect inad- as atopic-like dermatitides affecting the facial features, including facial asymmetry, equate treatment or failure to eradicate retroauricular and intertriginous spaces. prominent , deep-set eyes, broad- their carriage status. On the other hand, Patients with HIES also have an increased ened nasal ridge, increased canthal distance, when patients present with refractory and generalized “coarse” facies.5 In conjunc-

20 RECURRENT ABSCESSES: UNDERLYING IMMUNODEFICIENCY? tion with characteristic facies, delayed randomized studies are lacking, numerous primary tooth shedding is an additional case reports endorse the use of immuno- feature seen in HIES. Furthermore, other modulating agents such as cyclosporine. skeletal anomalies, including osteopenia, Considering the severity of our patient’s scoliosis, joint hypermobility and history clinical findings, as well as his lack of thera- of frequent fractures have been described. peutic response, we suspected our patient It has been postulated that patients with may have an underlying immunodefi- HIES have mononuclear cells that produce ciency, specifically HIES. However, after an increased levels of prostaglandin E2, which extensive workup, his clinical findings and in animal studies has been shown to miti- laboratory evaluation failed to support this gate demineralization and cortical bone diagnosis. Given his history of acne conglo- loss.6,7 bata and hidradenitis suppurativa, we spec- Although there is no consensus on the ulated that a “follicular occlusion” diathesis diagnostic criteria for HIES, many rely on could be blamed for this patient’s severe the laboratory evaluation for confirmation. clinical phenotype. Nonetheless, clinicians As the name implies, patients with HIES must be cognizant of hereditary immuno- have elevated IgE levels usually exceeding deficiencies when evaluating patients with 2,000 IU, which is 10 times normal level. unusual or recalcitrant infectious processes. Also, 93% of affected individuals have evidence of peripheral eosinophilia up to References 8 two standard deviations from the mean. 1. Recurrent abscesses. OMIM website. Available at http:// An important caveat is that disease activity www.ncbi.nlm.nih.gov/entrez/. Accessed July 2007. 2. Davis SD, Schaller J, Wedgewood RJ. Job’s syndrome is not proportionate to the extent of labo- with recurrent infection: a review of current opinion and ratory findings, and children younger treatment. Lancet 1966; 1:1013-1015. 3. Dewitt CA, Bishop AB, Buescher LS, Stone SP. Hyperim- than 6 months of age may have little or no munoglobulin E syndrome: two cases and a review of the elevation of their IgE levels despite clinical literature. J Am Acad Dermatol 2006; 54: 855-865. 4. Grimbacher B, Holland S, Gallin J, Greenberg F, Hill S, et disease. Management of HIES often requires al. Hyper IgE syndrome with recurrent infections-an auto- judicious use of antibiotics with anti- somal dominant multisystem disorder. N Engl J Med 1999; 340: 692-702. MRSA properties. Prophylactic antifungal 5. Grimbacher B, Holland S, Puck J. Hyper-IgE syndromes. therapy has also been suggested. Several Immunological Reviews 2005; 203: 244-250. 6. Cohan-Solal M, Prieur AM, Prin L, Denne MA, Launay clinicians advocate the use of cyclosporine, JM, et al. Cytokine-mediated bone resorption in patients as it has been shown to decrease IgE levels with the hyperimmunoglobulin E syndrome. Clin Immunol Immunopathol 1995; 76: 75-81. and modulate neutrophil chemotactic 7. Leung DY, Key L, Steinberg JJ, Young MC, Von Deck M, activity.8,9 Anecdotal reports describe the et al. Increased in vitro bone resorption by monocytes in the hyper-immunoglobulin E syndrome. J Immunol 1988; successful use of ascorbic acid, cimetidine, 140: 84-88. intravenous immunoglobulin G (IVIG) and 8. Kitai E, Wolach B. A case of Job’s syndrome. Harefuah 1996; 130: 239-41. recombinant IFN gamma, all of which have 9. Wolach B, Eliakim A, Pomeranz A, Cohen AH, Nusbacher immunomodulatory and anti-inflammatory J, et al. Cyclosporin treatment of hyperimmunoglobulin E 10-12 syndrome. Lancet 1996; 347: 67. properties. A thorough history and phys- 10. Sanal O, Gocmen A, Tezcan I, Ersoy F, Alalioglu G. ical, as well as review of systems, are impera- Hyper-IgE syndrome: a case report. Turk J Pediatr 1990; 32: 273-278. tive in patients with HIES, as numerous case 11. De La Torre Morin F, Garcia Robaina JC, Bonnet Moreno reports have suggested an increased risk of C, Fonta GL. Hyper-IgE syndrome. Presentation of three cases. Allergol Immunopathol 1997; 31: 177-179. lymphoma and autoimmune disease in this 12. Mawhinney H, Killen M, Fleming WA, Roy AD. The hyper- population.3 immunoglobulin E syndrome-a neutrophil chemotactic defect reversible by histamine H2 receptor blockade? Clin Careful consideration should be given Immunol Immunopathol 1980; 17: 483-491. to other primary immunodeficiencies that share similar cutaneous and laboratory abnormalities, including Wiskott-Aldrich syndrome, Chédiak-Higashi syndrome, and chronic granulomatous disease (CGD). Although specific genetic markers exist for many of these entities, the diagnosis of these diseases is presumptive and based upon the abnormal labs in addition to the charac- teristic clinical findings. In particular, NBT assay, which was normal in our patient, examines neutrophil oxidative capacity. Leukocytes in normal patients have approx- imately 80%-90% capacity to reduce NBT during the phagocytic process, compared to about 10% in patients with CGD. In conclusion, HIES represents a multi- system disease characterized by recurrent skin and pulmonary infections, distinctive musculoskeletal findings, and elevated IgE levels. There is no known cure for HIES, and treatment consists of prophylactic antibiotics and antifungals. Although large,

WALTHER, PURCELL 21 IDIOPATHIC THROMBOCYTOPENIC PURPURA: A CASE REPORT AND DISCUSSION

Kevin DeHart, DO,* Kristin Witfill, DO,** Richard Miller, DO*** *Sun Coast Hospital/NOVA Southeastern University, Resident, Department of Dermatology, Largo, FL **Sun Coast Hospital/NOVA Southeastern University, Associate Faculty, Department of Dermatology, Largo, FL ***Sun Coast Hospital/NOVA Southeastern University, Program Director, Department of Dermatology, Largo, FL

ABSTRACT

Idiopathic thrombocytopenic purpura (ITP) is a common cause of thrombocytopenia and should be considered in the differential diagnosis of those patients with petechiae, purpura or clinically significant bleeding. Laboratory studies show only an isolated throm- bocytopenia in most cases, and an extensive workup is usually not warranted. Treatments are numerous and not always satisfactory, and multiple modalities are often indicated for the treatment of ITP. We present a case of ITP and discuss its pathogenesis, clinical presentation, diagnostic tests and treatment options.

Case Presentation thrombocytopenia and must be excluded.1 Certain medications may also have a A 43-year-old female presented to the propensity to cause thrombocytopenia, and outpatient dermatology clinic with a two- a detailed medication timeline is essential. month history of asymptomatic, easy Drug-induced thrombocytopenia can be bruisability that progressively involved her caused by quinine, heparin, abciximab, epti- entire body surface area, including the oral fibatide, tirofiban, or vancomycin.2 The mucosa. Her past medical and dermato- underlying pathophysiology of ITP is not logic history was unremarkable. There was fully understood, but it most likely involves no personal or family history of bleeding premature destruction of autoantibody- disorders. A review of systems was negative covered platelets by the reticuloendothelial for weight loss, fatigue, fever, menorrhagia, system. hematemesis, epistaxis, and hematochezia. Idiopathic thrombocytopenic purpura Physical exam revealed a well-appearing presents with a wide range of clinical female in no acute distress. Skin exam manifestations, from isolated cutaneous Figure 1: Petechiae and purpura of the demonstrated diffuse, non-blanchable pete- petechiae or purpura to life-threatening left cheek chiae and purpura of the face, oral mucosa, hemorrhage. Morbidity and mortality are trunk, and upper and lower extremities increased with both recalcitrant and recur- (Figure 1, 2). Workup was unremarkable rent ITP.3 Intracranial hemorrhage remains except for a thrombocytopenia of approxi- the leading cause of death from ITP, with mately 1000/μL. Given the physical exam, advanced age being an important risk factor clinical history and isolated thrombocy- for serious complications. Interestingly, topenia, the patient was diagnosed with thrombocytopenia in females is most often idiopathic thrombocytopenic purpura. She seen with pregnancy and is rarely related to proceeded to a full recovery and avoided ITP. Infants born to ITP-affected mothers splenectomy. may be at an increased risk of thrombocy- topenia and bleeding diatheses compared Discussion to infants born to mothers with gestational thrombocytopenia.1 Idiopathic thrombocytopenic purpura A detailed history and physical examina- (ITP) is a common condition affecting both Figure 2: Petechiae and purpura of the tion are important in the diagnostic workup oral mucosa children and adults. Prevalence is estimated of idiopathic thrombocytopenic purpura. at one to 13 cases per 100,000 persons,1 Extensive laboratory workup is still contro- with most cases presenting in the third to versial, but a complete blood count with marrow biopsy in those older than sixty. fourth decades of life. Children often have peripheral smear is mandatory to rule out Bone-marrow biopsy is also indicated in an acute but benign, self-limited course other causes of thrombocytopenia. HIV, those individuals who are candidates for requiring minimal intervention. However, thyroid disorders, and systemic lupus splenectomy.3 adults with ITP tend to have persistent erythematosus, to name a few, are often Treatment protocols are not always satis- disease with frequent relapses and usually complicated by thrombocytopenia, and factory for patients with ITP. Splenectomy, require some form of treatment. in the appropriate clinical setting they intravenous anti-RhD, intravenous immu- ITP is a diagnosis of exclusion and is should be considered in the workup. Bone- noglobulin and glucocorticoids and are a defined by an isolated thrombocytopenia. A marrow biopsy, imaging studies and tests few of the well known, albeit not perfect, normal complete blood count and periph- for immunoglobulins, platelet antibodies treatments. Oral prednisone remains the eral smear are mandatory. Other condi- and lupus anticoagulant are other consid- mainstay of initial treatment for those tions such as HIV, SLE, lymphoproliferative erations, but are usually not indicated for a requiring intervention.4 Duration, dosage disorders, agammaglobulinemia, alloium- routine ITP workup.1 Myelodysplasia is one and length of taper are not well defined mune thrombocytopenia, and congenital important cause of thrombocytopenia in in the literature and therefore must be or hereditary thrombocytopenia may cause the elderly and must be excluded by bone- individualized. Patients are considered

22 IDIOPATHIC THROMBOCYTOPENIC PURPURA: A CASE REPORT AND DISCUSSION non-responsive if there is no improvement within three weeks. Intravenous immu- noglobulin is often second-line therapy and generally reserved for those patients with contraindications to corticoster- oids or who have failed initial treatment. Anti-RhD immunoglobulin is only effec- tive in RhD-positive, non-splenectomized patients and can be considered in children with acute ITP.4 Responses to treatment with splenectomy are good, but this is considered second-line therapy by most experts. Platelet counts often improve in just a few days after the procedure, and in some patients no further treatment is required. An accessory spleen is seen in approximately 11% of refractory, post-splenectomy cases, and further workup is required if thrombocytopenia persists.4 Sepsis is a possible life-threatening compli- cation after splenectomy, and appropriate vaccines should be administered. Conclusion Generally, ITP is acute and self-limiting, and no treatment is required. Treatment is usually reserved for those patients with clinically significant bleeding, patients with the potential for life-threatening hemor- rhage or for those requiring a procedure. Hospitalization may be necessary in symp- tomatic patients or those experiencing bleeding complications. ITP is a common cause of thrombocy- topenia and should be considered in the differential diagnosis of those patients with petechiae, purpura or clinically significant bleeding. Laboratory studies only show an isolated thrombocytopenia in most cases, and an extensive workup is usually not warranted. Treatments are numerous and not always satisfactory, and multiple modalities are often indicated for the treat- ment of ITP.

References 1. The American Society of Hematology ITP Practice Guideline Panel. Diagnosis and treatment of Idiopathic Thrombocytopenic Purpura: Recommendations of the American Society of Hematology. Ann Intern Med. 1997; 126:319-326. 2. Warkentin, T.E. Drug-induced immune-mediated thrombo- cytopenia — From purpura to thrombosis. N Engl J Med. 2007; 356:891-3. 3. Portielje JE, Westendorp RG, Kluin-Nelemans HC, Brand A. Morbidity and mortality in adults with idiopathic throm- bocytopenic purpura. Blood. 2001; 97:2549-54. 4. Stevens, W., Koene, H., Zwaginga, J.J., Vreugdenhil, G., Chronic idiopathic thrombocytopenic purpura: present strategy, guidelines and new insights. Neth J Med. 2006; 64:356-363.

DEHART, WITFILL, MILLER 23 MRSA—CASE AND REVIEW

Robert A. Norman, DO, MPH, Steven Nodine, OMS III Lake Erie College of Osteopathic Medicine, Bradenton, FL

Report of a Case: in 1880. Staphylococcus aureus literally Resources: translates to "Golden Cluster Seed." When 1. Braunwald, Eugene, Anthony S. Fauci, J. L. Jameson, Stephen L. Hauser, Dennis L. Kasper, and Dan L. Longo, A 60-year-old Caucasian male presented S. aureus is grown on blood agar, it takes eds. Harrison's Manual of Medicine. 16th Ed. New York: to our office for a follow-up visit to discuss on a yellow-gold appearance. It is catalase McGraw-Hill, 2005. 448-455. 2. Dockrell, Hazel M., Richard V. Goering, Cedric Mims, Ivan the results of abscess cultures from the left positive (the enzyme catalase causes H2O2 Roitt, Derek Wakelin, and Mark Zuckerman, eds. Medical jaw line and left upper thigh. The patient to break down into oxygen and water). S. Microbiology. 3rd Ed. New York: Elsevier Limited, 2004. 479. arrived for the appointment stating that a aureus is also coagulase positive (coagu- 3. Katzung, Bertram G., Susan B. Masters, and Anthony J. week earlier, he’d gone to the urgent care lase converts fibrinogen to fibrin, forming Trevor. Katzung & Trevor's Pharmacology. 7th Ed. New center concerned about acutely tender a clot). These two enzymes, catalase and York: Lange Medical Books/McGraw-Hill, 2005. 362-389. abscesses that had developed on his left jaw coagulase, are both used to identify the line and left upper thigh. The pus-filled bacteria. abscesses had been lanced, cleaned, and Antibiotics such as penicillin, which are packed to prevent re-infection of the wound used to kill gram-positive bacteria, bind area. Cultures of the areas had then been to the enzyme transpeptidase to prevent sent to a reference lab for identification and the bacteria from synthesizing their cell sensitivity. The physician at the urgent care walls. S. aureus produces an enzyme called center had prescribed cephalexin. penicillinase (a beta-lactamase), which is The cultures of the abscesses revealed the secreted from the bacterium. It also hydro- presence of colonies of Methicillin-resistant lyzes the beta-lactam ring on the penicillin, Staphylococcus aureus (MRSA). The sensi- thus inactivating penicillin. tivity demonstrated ≤0.5/9.5 sensitivity Methicillin is used to treat bacteria that to Trimethoprim-sulfamethoxazole. The produce penicillinase. This drug is peni- patient was instructed to return at a later cillinase-resistant. There are an increasing date to determine the efficiency of the anti- number of strains of S. aureus that are biotics and to monitor the healing process. resistant to methicillin. These methicillin- An infection with MRSA is a very serious resistant staphylococci (MRSA) synthesize matter, and prompt treatment saved him an additional penicillin-binding protein that potentially harsh physical discomfort and has a much lower affinity for beta-lactam disfigurement. antibiotics than the normal penicillin- binding proteins. This enables cell-wall Diagnosis: synthesis when its other penicillin-binding proteins are inhibited. MRSA strains of S. Methicillin-resistant Staphylococcus aureus usually develop around hospitals, aureus where there is extensive use of broad-spec- trum antibiotics. Discussion: MRSA is resistant to many antibiotics, and intravenous vancomycin is one of the Gram-positive bacteria are bacteria that few antibiotics useful in treatment. Since stain purple under the microscope due to this patient came to our clinical office and their thick outer cell walls, which is made not to a hospital, intravenous medications of peptidoglycan. The thick peptidoglycan would not be practical. Trimethoprim- cell wall is constructed by the enzyme sulfamethoxazole (TMP-SMX) was found to transpeptidase (penicillin-binding protein). be effective against this particular patient’s Transpeptidase enzyme cross-links the MRSA strain. TMP-SMX is a two-drug peptidoglycan chains, forming the bacterial combination that results in the sequen- cell wall. This is the last step in the cell-wall tial blockade of folate synthesis. Since synthesis. Staphylococcus aureus has this TMP-SMX can be taken orally, it was a more thick cell wall and thus is classified as gram practical antibiotic to prescribe. The patient positive. It has a round shape, forming cocci returned in two weeks, and his healing that grow in grape-like clusters. This is due reflected that the antibiotic had worked to the bacterial cell dividing in more than effectively with his immune system. one plane. S. aureus is the most virulent of all 33 staphylococcal species. It causes both toxin-mediated and non-toxin mediated Differential Diagnosis: disease. Fungal infection; bacterial infection other S. aureus was first discovered in pus than MRSA from surgical abscesses by the surgeon Sir Alexander Ogston in Aberdeen, Scotland,

24 MRSA—CASE AND REVIEW CLINDAMYCIN & TRETINOIN COME TOGETHER TO CREATE…

See reverse side for brief summary of Full Prescribing Information.

© 2007 Medicis Pharmaceutical Corporation ZNA 06-005R 09/30/08 JOACD BRIEF SUMMARY Table 1: Adverse Reactions Reported in at Least 1% of Patients (approximately 12 times the recom- (see package insert for Full Prescribing Information) Treated with ZIANA Gel: 12-Week Studies mended clinical dose assuming 100% ZIANA Gel Clindamycin Tretinoin Vehicle absorption and based on body surface N=1853 N=1428 N=846 N=423 area comparison) was considered to be the no-observed-adverse-effect level N (%) N (%) N (%) N (%) ZIANA™ (NOAEL) for maternal and developmental (clindamycin phosphate 1.2% and tretinoin 0.025%) Gel PATIENTS WITH AT toxicity following dermal administration Rx only LEAST ONE AR 497 (27) 342 (24) 225 (27) 91 (22) of ZIANA Gel for two weeks prior to artificial insemination and continuing until For topical use only Nasopharyngitis 65 (4) 64 (5) 16 (2) 5 (1) gestation day 18, inclusive. For purposes INDICATIONS AND USAGE Pharyngolaryngeal pain 29 (2) 18 (1) 5 (1) 7 (2) of comparisons of the animal exposure to human exposure, the recommended clini- ZIANA Gel is indicated for the topical treatment of acne Dry skin 23 (1) 7 (1) 3 (<1) 0 (0) cal dose is defined as 1 g of ZIANA Gel vulgaris in patients 12 years or older. Cough 19 (1) 21 (2) 9 (1) 2 (1) applied daily to a 60 kg person. CONTRAINDICATIONS Sinusitis 19 (1) 19 (1) 15 (2) 4 (1) Clindamycin ZIANA Gel is contraindicated in patients with regional Teratology (Segment II) studies using enteritis, ulcerative colitis, or history of antibiotic-associ- Note: Formulations used in all treatment arms were in the ZIANA vehicle gel. clindamycin were performed orally in ated colitis. Cutaneous safety and tolerance evaluations were rats (up to 600 mg/kg/day) and mice (up conducted at each study visit in all of the clinical trials to 100 mg/kg/day) (583 and 49 times amount of clinda- WARNINGS AND PRECAUTIONS by assessment of erythema, scaling, itching, burning, mycin in the recommended clinical dose based on a body surface area comparison, respectively) or with subcutane- Colitis and stinging: Systemic absorption of clindamycin has been demonstrated ous doses of clindamycin up to 180 mg/kg/day (175 and following topical use of this product. Diarrhea, bloody Table 2: ZIANA Gel-Treated Patients with 88 times the amount of clindamycin in the recommended diarrhea, and colitis (including pseudomembranous colitis) Local Skin Reactions clinical dose based on a body surface area comparison, have been reported with the use of topical clindamycin. respectively) revealed no evidence of teratogenicity. Local Reaction Baseline End of Treatment When significant diarrhea occurs, ZIANA Gel should be Tretinoin N=1835 N=1614 discontinued. In oral Segment III studies in rats with tretinoin, decreased N (%) N (%) Severe colitis has occurred following oral or parenteral survival of neonates and growth retardation were observed administration of clindamycin with an onset of up to several Erythema 636 (35) 416 (26) at doses in excess of 2 mg/kg/day (~ 78 times the recom- weeks following cessation of therapy. Antiperistaltic agents mended clinical dose assuming 100% absorption and such as opiates and diphenoxylate with atropine may Scaling 237 (13) 280 (17) based on body surface area comparison). prolong and/or worsen severe colitis. Severe colitis may Itching 189 (10) 70 (4) With widespread use of any drug, a small number of result in death. reports associated temporally with the Studies indicate a toxin(s) produced by clostridia is one Burning 38 (2) 56 (4) administration of the drug would be expected by chance alone. Thirty cases of temporally associated congenital primary cause of antibiotic-associated colitis. The colitis Stinging 33 (2) 27 (2) is usually characterized by severe persistent diarrhea and malformations have been reported during two decades severe abdominal cramps and may be associated with the At each study visit, application site reactions on a scale of of clinical use of another formulation of topical tretinoin. passage of blood and mucus. Stool cultures for Clostridium 0 (none), 1 (mild), 2 (moderate), and 3 (severe), and the Although no definite pattern of teratogenicity and no causal difficile and stool assay for C. difficile toxin may be helpful mean scores were calculated for each of the local skin association have been established from these cases, 5 diagnostically. reactions. In Studies 1 and 2, 1277 subjects enrolled with of the reports describe the rare birth defect category, moderate to severe acne, 854 subjects treated with ZIANA holoprosencephaly (defects associated with incomplete Light and Environmental Exposure midline development of the forebrain). The significance of Exposure to sunlight, including sunlamps, should be avoid- Gel and 423 treated with vehicle. Analysis over the twelve week period demonstrated that cutaneous irritation scores these spontaneous reports in terms of risk to the fetus is ed during the use of ZIANA Gel, and patients with sunburn not known. should be advised not to use the product until fully recov- for erythema, scaling, itching, burning, and stinging peaked ered because of heightened susceptibility to sunlight as a at two weeks of therapy, and were slightly higher for the Dermal tretinoin has been shown to be fetotoxic in rabbits result of the use of tretinoin. Patients who may be required ZIANA-treated group, decreasing thereafter. when administered in doses 40 times the recommended to have considerable sun exposure due to occupation and One open-label 12-month safety study for ZIANA Gel human clinical dose based on a body surface area compar- those with inherent sensitivity to the sun should exercise showed a similar adverse reaction profile as seen in the ison. Oral tretinoin has been shown to be fetotoxic in rats particular caution. Daily use of sunscreen products and 12-week studies. Eighteen out of 442 subjects (4%) when administered in doses 78 times the recommended protective apparel (e.g., a hat) are recommended. Weather reported gastrointestinal symptoms. clinical dose based on a body surface area comparison. extremes, such as wind or cold, also may be irritating to Nursing Mothers patients under treatment with ZIANA Gel. DRUG INTERACTIONS It is not known whether clindamycin is excreted in human Concomitant Topical Medication milk following use of ZIANA Gel. However, orally and ADVERSE REACTIONS Concomitant topical medication, medicated or abrasive parenterally administered clindamycin has been reported to Clinical Studies Experience soaps and cleansers, soaps and cosmetics that have a appear in breast milk. Because of the potential for serious Because clinical trials are conducted under prescribed con- strong drying effect, and products with high concentra- adverse reactions in nursing infants, a decision should be ditions, adverse reaction rates observed in the clinical trial tions of alcohol, astringents, spices or lime should be made whether to discontinue nursing or to discontinue the may not reflect the rates observed in practice. The adverse used with caution. When used with ZIANA Gel, there may drug, taking into account the importance of the drug to reaction information from clinical trials does, however, be increased skin irritation. the mother. It is not known whether tretinoin is excreted in provide a basis for identifying the adverse reactions that human milk. Because many drugs are excreted in human milk, caution should be exercised when ZIANA Gel is appear to be related to drug use for approximating rates. ZIANA Gel should not be used in combination with administered to a nursing woman. The safety data presented in Table 1 (below) reflects ex- erythromycin-containing products due to its clindamycin posure to ZIANA Gel in 1,853 patients with acne vulgaris. component. In vitro studies have shown antagonism Pediatric Use Patients were 12 years and older and were treated once between these two antimicrobials. The clinical significance Safety and effectiveness of ZIANA Gel in pediatric patients daily for 12 weeks. Adverse reactions that were reported of this in vitro antagonism is not known. under the age of 12 have not been established. in r 1% of patients treated with ZIANA Gel were compared Neuromuscular Blocking Agents Clinical trials of ZIANA Gel included patients 12–17 years to adverse reactions in patients treated with clindamycin Clindamycin has been shown to have neuromuscular of age. phosphate 1.2% in vehicle gel, tretinoin 0.025% in vehicle blocking properties that may enhance the action of Geriatric Use gel, and the vehicle gel alone: other neuromuscular blocking agents. Therefore, ZIANA Clinical studies of ZIANA Gel did not include sufficient Gel should be used with caution in patients receiving numbers of subjects aged 65 and over to determine such agents. whether they respond differently from younger subjects. USE IN SPECIFIC POPULATIONS Manufactured for: ® Pregnancy Medicis, The Dermatology Company Pregnancy Category C. There are no well-controlled trials Scottsdale, AZ 85258 in pregnant women treated with ZIANA Gel. ZIANA Gel Revised: 11/2006 should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. ZIANA Gel 300-13A was tested for maternal and developmental toxicity in New Zealand White Rabbits with topical doses of 60, 180 and 600 mg/kg/day. ZIANA Gel at 600 mg/kg/day 030507 PORPHYRIA CUTANEA TARDA: CASE PRESENTATION AND LITERATURE REVIEW

Tracy Favreau, D.O.,* Stanley Skopit, D.O., F.A.O.C.D.** *3rd-year dermatology resident, Nova Southeastern University, Ft. Lauderdale, FL **Program Director, Nova Southeastern University, Ft. Lauderdale, FL

ABSTRACT

It has been well established that porphyria cutanea tarda (PCT) is a porphyria that has both acquired and familial types. The acquired form of PCT is caused by a heterozygous inheritance of a gene mutation encoding partial deficiency of the activity of the enzyme uroporphyrinogen decarboxylase. This disorder presents most often in adults. The familial type of PCT is more common in children. This results in an excess of phophyrins within the lamina lucida of the .1 This manifestation causes cutaneous photosensitivity when exposed to sunlight, leading to fragility of the skin, thus inducing a bulla.2 A higher prevalence of PCT in patients with hepatitis C has been recently correlated in the literature.4 The case presented in this paper is an example of this relationship. This paper focuses on the acquired type of PCT.

Case Presentation: were elevated to 237 μg24/h. Thus the total porphyrins was elevated to 2266.8 μg/24h. A 56-year-old Caucasian male presented The patient was subsequently sent to a with the chief complaint of an outbreak of hepatologist and started on interferon-alfa blisters on both hands. Onset was approxi- 2b/ribavirin for treatment of his hepatitis C. mately one week prior to this visit. The Current consideration is to start the patient patient stated that the blisters on his hands on chloroquine 125mg twice weekly or a low developed after a weekend fishing trip and dosage of hydroxychloroquine if approved binge drinking of alcohol. Subsequently, by his hepatologist. Until approval, phle- he noted that exposure to sunlight caused botomy will be the treatment. The patient an exacerbation of blistering followed by a abstained from alcohol and was placed on gradual rupturing in stages. This resulted in topical steroid cream and sunblock. scarring as well as a darkening of the skin Figure 1 in involved areas. Occasionally, he noticed Comments: while urinating that the color of his urine appeared dark brown. The only significant A review of the literature establishes past history obtained from the patient was that PCT is the most common of all the a previous diagnosis of hepatitis C approxi- porphyrias, though it only occurs in about mately 40 years ago. He was scheduled for a 1 in 25,000 people. This sporadic condition liver biopsy five years ago, but due to finan- appears to be more frequent than the inher- cial difficulty and a lack of health insurance, ited type. In the sporadic type, the enzyme it was never scheduled. Review of all systems deficiency is noted in the liver.4 Recently, was positive for fatigue only. The patient hereditary hemochromatosis (HH) has denied nausea, vomiting or loss of weight. been noted as an underlying condition for Social history was positive for alcohol and PCT.5 Many authors have published articles drug abuse. There were no allergies to showing the high incidence of PCT associ- medications. ated with hepatitis C.2 What has been very On physical examination, the patient interesting is the discovery of geographic appeared well nourished and well devel- preponderance. Of note is its prevalence oped. The patient’s bilateral hands, dorsal increasing from northern Europe (8%-10%) 6,7 aspects, revealed multiple bullae with to southern Europe (71%-91%). At this Figure 2 erythematous bases. The erupted bullae time, no studies have been performed formed small erosions with a significant in the United States to demonstrate any have also triggered PCT.10 The literature amount of erythema in the periphery. There geographical relationship. There are several also reports that renal dialysis for renal were large amounts of post inflammatory studies that establish a definite relation- insufficiency may create the same triggering hyperpigmentation, and atrophy was noted ship between hepatitis C and PCT in North mechanism.10 within older healed lesions. America. In these studies, the prevalence The pathophysiological mechanism that 8 In order to establish a diagnosis of is reported as being as high as 94%. A creates the skin lesions in PCT is somewhat porphyria cutanea tarda, biopsies and labo- similar relationship with the familial PCT dependant on the etiology, although most ratory analyses were performed. The diag- has not been established at this point in theories attribute the problem to accumula- 9 nosis was confirmed with positive tissue time. In addition to the high association tion of water-soluble porphyrins within pathologic findings and specific laboratory between PCT and hepatitis C, there are the skin, which are light sensitive. The light results. The uroporphyrins were elevated to many articles in the literature that show an is the triggering mechanism, causing the 1190.8 μg/24h, the heptacarboxylporphyrin association with hemochromatosis, Wilson blister secondary to the release of prote- 11 was elevated to 735.5 μg/24h, the hexacar- disease, diabetes mellitus, renal failure, HIV, olytic enzymes into the cell cytoplasm. boxylporphyrin was elevated to 11.3 g/24h, Sjogren’s syndrome, rheumatoid arthritis As this complement activation takes place, μ 5 the pentacarboxylporphyrin was elevated and systemic lupus erythematosis. Alcohol, the complement can be found at the to 91.5 μg/24h, and the coproporphyrins estrogens and some tuberculostatic drugs dermal-epidermal junction on microscopic

27 evaluation. Analysis of the bullous lesions shows complement-degradation products.12 Scarlett et al. demonstrated immunoglobu- lins G and M around the dermal vessels. This was established using immunofluores- cence, showing their presence at the dermal- epidermal junction.13 The most frequent sites for blistering are usually the dorsum of the hands and the upper extremities, because they are precipitated by a combina- tion of sunlight and trauma.1 The current approach to therapy is three-prong. The basic aspect is to avoid the triggering mechanism, whether that is light, alcohol or systemic drugs. Iron deple- tion and porphyrin elimination are the other two aspects of therapy. This can be achieved through phlebotomy, to reduce iron, and low-dose chloroquine therapy.10 Interferon-alfa 2b/ribavirin is the current therapy for treatment of hepatitis C. This has been shown to be most effective after phlebotomy.14

1. Mehta S, Levey JM, Bonkovshy HL. Extrahepatic mani- festations of infection with hepatitis C virus. Clin Liver Dis. 2001;5:979-1008. 2. Brudieux E et al. J Viral Hepat. 2001: 8(1):41-7 3. Gisbert JP; Garcia-BUEY l; Pajares JM; Moreno-Otero R. Prevalence of hepatitis C virus infection in Porphyria Cuta- nea Tarda systemic review and meta-analysis. J Hepatol. 2003; 39 (4):620-7 4. Bleasel NR. Porphyria Cutanea Tarda. Australas J Derma- tol. 2000;41:197-206 5. Sams H, Kiripolsky MG, Bhat L, Stricklin GP. Porphyria Cutanea Tarda, hepatitis, alcoholism and hemochromato- sis: a case report and review of the literature. Cutis. 2004; 73(3):188-90 6. Teubner A, et al. Hepatitis C, hemochromatosis and porphyria cutanea tarda. Dtsch Med Wochenschr. 2006; 131(13)691-5. 7. Navas S; Bosch O; Castillo I; et al. Porphyria cutanea tarda and hepatitis C and B viruses infection: a retrospec- tive study. Hepatology. 1995;21:279-284. 8. Chuang TY. Porphyria cutanea tarda and hepatitis C virus: a case-controlled study and meta-analysis of the literature. J Am Acad Dermatol. 1999;41:31-36. 9. Herrero C, Vincente A, Bruguera M, et al. Is hepatitis C virus infection a trigger of porphyria cutanea tarda? Lan- cet. 1993;341:788-789. 10. Kostler E, Wollina U. Therapy of porphyria cutanea tarda. Expert Opin Pharmacother. 2005; 6(3):377-83 11. Volden G, Thume P. Photosensitivity and Cutaneous acid hydrolase in porphyria cutanea tarda. Ann Clin Res. 1979;11:129-132. 12. Lim HW, Gigli I. Role of complement in porphyrin-induced photosensitivity. J Invest Dermatol. 1981;76:4-9 13. Scarlett YV, Brenner DA. Bloomer JR. Hepatic porphyrias. Clin Liver Dis. 1998;2:77-102 14. Wilson RA, Kirby P, Hart J. Association of chronic hepatitis C and porphyria cutanea tarda. Hepatology. 1992;16:225A

28 PORPHYRIA CUTANEA TARDA: CASE PRESENTATION AND LITERATURE REVIEW A CASE OF CURIOUS AXILLARY “FRECKLING”

Kevin Spohr, DO,* Robert Berg, MD,** Brad Glick, DO, MPH, FAOCD,*** Les Rosen, MD**** *2nd-year resident, Wellington Regional Medical Center/LECOM **Clinical Associate, Private practice, Stuart, Florida ***Program director, Wellington Regional Medical Center/LECOM ****Clinical professor, dermatopathology

ABSTRACT

Poikiloderma vasculare atrophicans (PVA) is a nonspecific histological finding that can clinically be confused with Crowe’s sign of 1 (NF-1). The differential diagnosis must also include mycoses fungoides, poikiloderma congenitale of Rothmund- Thompson, Bloom’s syndrome and , as well as dermatomyositis and, less commonly, systemic lupus erythe- matosus (SLE). A good history and clinical suspicion are essential in making the correct diagnosis. This report will briefly review these etiologies and comment on the treatment of mycosis fungoides.

Case Presentation: Oncology was consulted for further work-up, which initially included blood A 71-year-old white male seen in our chemistries -- CBC, electrolytes, ANA, alka- office for total cutaneous exam presented line phosphatase, albumin, BUN, creatinine, with a complaint of curious bilateral axil- total protein, calcium, glucose, chloride, lary "freckling," which had been present LDH and serum for quantitative immu- asymptomatically for more than 10 years. noglobulins. These studies were all within The patient's past medical history was normal limits. Further studies included significant for , hypertension, CT of the chest, abdomen and pelvis, PET gastric reflux, arthritis and environmental scan and bone-marrow examination. These allergies. Surgical history revealed in-situ studies, as well, proved to be normal. squamous-cell and basal-cell carcinomas of the skin that had been treated successfully. Discussion Figure 1 Family history was negative for any chronic cutaneous and genetic diseases, neurofi- True axillary freckling is typically asso- bromatosis or other genodermatoses. The ciated with NF-1. Our patient's "curious remainder of the pertinent review of systems freckling" was clinically consistent with further excluded any ocular disorders. PVA. A review of the literature revealed Physical exam revealed purple-to-brown, no other disorders directly associated with reticulated atrophic patches with telangi- this entity (Pub Med search words "axillary ectasias in both axillae without scale (Fig. freckling"). 1). There was no cervical, submandibular, Poikiloderma vasculare atrophicans (PVA) parotid, supraclavicular or axillary lymph- is a non-specific finding that clinically, adenopathy. As well, there were no papules, in its early stage, presents with erythema, nodules, hyper- or hypopigmented macules slight superficial scaling, telangiectases and or patches appreciated (Fig. 2). mottled pigmentation. In the later stage, the The differential diagnosis at time of erythema resolves and the lesions present Figure 2 examination included poikiloderma vascu- with the "classic triad" of epidermal atrophy, 1,2,3 lare atrophicans associated with mycoses telangiectases and mottled pigmentation, fungoides, dermatomyositis, SLE and neuro- as in our patient. fibromatosis type 1. PVA is most commonly observed in three Biopsy was performed, and pathology settings: mycosis fungoides; three geno- revealed moderate thinning of the stratum dermatoses -- poikiloderma congenitale of malpighii, effacement of the rete ridges and Rothmund-Thompson, Bloom's syndrome hydropic degeneration of the basal cells. The and dyskeratosis congenital; and two rheu- upper dermis had a band-like infiltrate of matologic diseases -- dermatomyositis and, mainly lymphoid cells and a few histiocytes, less commonly, systemic lupus erythema- 1,2,3 edema of the upper dermis and superficial tosus (SLE). capillary dilation and pigment incontinence In mycosis fungoides, poikiloderma-like that invaded the epidermis in some places lesions appear in either the large plaque- Figure 3 (Fig. 3). These findings were consistent with type parapsoriasis en plaques or the parap- Poikiloderma 20X magnification (H&E) a diagnosis of poikiloderma vasculare atro- soriasis variegata form.1 Poikiloderma phicans. The specimen was then subjected congenitale of Rothmund-Thompson to immunostaining techniques with CD20 demonstrates poikiloderma mainly on the (B-cell marker) and CD3 (T-cell marker), face, hands and feet, with arms, legs and which further diagnosed this lesion as buttock less commonly affected. Bloom's patch-stage mycoses fungoides (Fig. 4, 5). syndrome usually presents with poikilo-

SPOHR, BERG, GLICK, ROSEN 29 case. Hopefully this review has expanded the reader's differential diagnostic consid- erations and stressed the continued significance of careful history and physical examination.

References: 1. Bolognia, Dermatology 2nd edition 2. Levers Histopathology of the Skin, 9th edition 3. Fitzpatrick Dermatology in General Medicine, 6th edition 4. Spitz Genodermatoses, 2nd Edition 5. National Institutes of Health: Neurofibromatosis. Confer- ence statement. National Institutes of Health Consensus Development Conference. Figure 4 Arch Neurol 1988 May; 45(5): 575-8. 6. Hoppe RT, Abel EA, Deneau DG, et al. Mycosis fungoides: Poikiloderma CD20 positive (B-cell management with topical nitrogen mustard. J Clin Oncol 5 marker) (11): 1796-803, 1987. 7. Duvic M, Cather JC. Emerging new therapies for cutane- ous T-cell lymphoma. Dermatol Clin. 2000; 18 147-56. 8. Querfield C, Rosen S, Kuzel T, et al. Long-term Follow Up of Patients With Early-Stage Cutaneous T-Cell Lymphoma Who Achieved Complete Remission With Psoralen Plus UV-A Monotherapy. Archives of Dermatology. 2005; 141: 305-311. 9. Hoppe RT, Cox RS, Fuks Z, et al.: Electron-beam therapy for mycosis fungoides: the Stanford University experience. Cancer Treat Rep 63 (4): 691-700, 1979. 10. QuirÛs PA, Jones GW, Kacinski BM, et al. Total skin electron beam therapy followed by adjuvant psoralen/ ultraviolet-A light in the management of patients with T1 and T2 cutaneous T-cell lymphoma (mycosis fungoides). Int J Radiat Oncol Biol Phys 38 (5): 1027-35, 1997.† 11. Olsen EA, Bunn PA. Interferon in the treatment of cutane- ous T-cell lymphoma. Hematol Oncol Clin North Am. 1995; 9:1089-97 12. Duvic M, Hymes K, Heald P, et al. Bexarotene is effec- tive and safe for treatment of refractory advanced-stage Figure 5 cutaneous T-cell lymphoma: multinational phase II-III trial Poikiloderma CD3 positive (T-cell results. J Clin Oncol 19 (9): 2456-71, 2001. marker) derma on the face, forearms and hands. Dyskeratosis congenita presents with widely distributed, net-like pigmentation sugges- tive of PVA.4 PVA can also be seen in dermatomyo- sitis (poikilodermatomyositis) and systemic lupus erythematosus, but this is usually in the late phase of these diseases. Finally, PVA can be clinically confused with the so called "Crowe's" sign seen in neurofibromatosis 1; however, a good history and physical exam will rule out this entity.5 Treatment of mycoses fungoides can be classified in three groups. First, there are the skin-targeted therapies, including topical Class 1 high-potency corticosteroids; cyto- toxic agents such as topical mechlorethamine6 (nitrogen mustard); topical retinoids such as bexarotene (Targretin®);7 phototherapy (PUVA);8 and radiotherapy (total-skin elec- tron-beam irradiation, or TSEB).9,10 Next, there is systemic chemotherapy such as CHOP (cyclophosphamide, hydroxydauno- mycin [doxorubicin], Oncovin® [vincristine] and prednisone).7 The final treatment class is biological response modifiers -- inter- feron alpha (IFN α)11 and oral retinoids such as the above-mentioned bexarotene (Targretin®).12 Conclusion Axillary freckling is a clinical sign that may be confused with presentations of other dermatologic disorders, as in our

30 A CASE OF CURIOUS AXILLARY “FRECKLING” A WOMAN WITH GRADUALLY SPREADING TELANGIECTASIAS

Daniel Hansen, DO, MBA,* Steven Grekin, DO, FAOCD,** Don Collier, DO, FAOCD,*** Jonathan D. Richey, OMS IV**** *1stYear Resident, Oakwood Southshore Program, Michigan State University, Allen Park, MI **Program Director, Oakwood Southshore Program, Michigan State University, Wyandotte, MI ***Clinical Faculty, Oakwood Southshore Program, Michigan State University, Warren, MI ****4th Year Medical Student, Henry Ford Wyandotte Hospital, ATSU-KCOM, Trenton, M

ABSTRACT

Generalized essential (GET) is a rare, progressive, vascular condition. The cause of the widespread telangiectasias that is characteristic of this disease, without hereditary or systemic explanation, is unknown. We present a case of a 48-year-old female patient who demonstrated widespread telangiectasias spreading from her legs to her trunk, arms, face, and conjunctiva over the period of 10 years with consistently positive ANA laboratory findings. In addition, we discuss GET and review the sparse literature on the subject.

Case Presentation: a comment stating that while the biopsy lacked the interface alteration typical of A 48-year-old female presented with a mixed connective-tissue disease, the vascu- complaint of the progressive development lopathic alterations described in the report of small, superficial blood vessels beginning have been described in patients with mixed on the medial thighs 10 years ago. They connective-tissue disease.1 have since spread to the lower legs, trunk, The patient has seen two rheumatolo- arms, and face, including the conjunctiva. gists, who both dismissed the diagnosis of Over the same time span, laboratory tests connective-tissue disease and dismissed consistently demonstrated an elevated ANA the laboratory results as incidental find- titer with a centromere pattern. She denied ings. Without an identifiable cause of the pain, pruritus, or bleeding of the lesions. telangiectasias, she was given the diagnosis She reported frequent pain in both elbows of generalized essential telangiectasia, and Figure 1 and the posterior aspect of the . She therapy was initiated. A five-month course Reticulated telangiectasias of the gave a history of Raynaud’s phenomenon of tetracycline was attempted unsuccessfully. lower extremity primarily in the right index finger. Over The patient was then started on a course of the last year, intermittent dysphagia with a acyclovir 200mg taken five times daily. To sensation of globus had developed that did date, none of the attempted therapies have not improve using a proton pump inhib- yielded meaningful results. Laser therapies itor. Also significant was a long history of have been discussed but not yet attempted. smoking, one pack per day, and frequent alcohol consumption, one to two beers per Discussion day. The family history was negative for similar lesions and for connective tissue Generalized essential telangiectasia disease. Her mother had varicose veins. (GET) is a slowly progressing and persis- On examination, there was a reticulated tent condition in which primary telangi- pattern of dark blue, violaceous, and red ectasias first appear on the legs and then telangiectasias over the upper and lower spread to the trunk, arms, and face.2,3,4 It is a diagnosis of exclusion, as there are no Figure 2 extremities, abdomen, lower back, chin, Fine telangiectasias of upper . nose, and conjunctiva of the eyes (Figures associated causes. Conjunctival telangi- 1 and 2). These areas blanched with dias- ectases have been described, but they are copy. There was no periungual erythema or rare.5,6,7 In the largest study of GET to date, telangiectasias. The hair, nails, and mucous the average onset was 38 years, and 72% membranes appeared unaffected. of those affected were women.8 GET has Laboratory analysis showed a borderline been reported more commonly in whites, positive ANA screen, with an ANA titer of perhaps because of the marked contrast of 1:1280. The anti-centromere antibodies the vessels on light-complexioned skin. This were 1:1280 and had a centromere pattern. type of telangiectatic disorder is not gener- All other labs were within normal ranges ally associated with bleeding or systemic (Table 1). disease. A similar condition seen in families with an autosomal-dominant inheritance A punch biopsy (right upper thigh), pattern has been termed hereditary benign performed in an outside office, was telangiectasia.9 A factor identifying GET described as having a slight superficial from hereditary hemorrhagic telangiectasia Figure 3 perivascular lymphoid infiltrate with (HHT) is the rarity of systemic involvement. Underlying a normal epidermis, there is vascular ectasia and hyalinization of vascular ectasia with thickening of the HHT often causes recurrent epistaxis, liver vascular basement membranes (Figure vessel walls and a sparse perivascular enlargement and cirrhosis, and aneurysm 3). The pathology report also included lymphoid infiltrate.

HANSEN, GREKIN, COLLIER, RICHEY 31 Br J Dermatol. 1981;84:93-94. 11. Dowd PM, Champion RH. Disorders of blood vessels. In: Champion RH, Burton JL, Burns DA, Breathnach SM Table 1 (eds). Textbook of Dermatology, Vol. 3, 6th edn. Oxford: Blackwell Science, 1998, 2073-97. Laboratory Test Finding 12. Buckley R, Smith KJ, Skelton HG. Generalized essential telangiectasia in a patient with Graves' disease: should the spectrum of autoimmune diseases associated with ANA Screen Borderline generalized telangiectasia be expanded? Cutis 2000 Mar;65(3):175-7. ANA Titer 1:1280 (normal <1:160) 13. Weedon D, Skin Pathology, 2nd edn, Churchill Living- stone, 2002, 1006 14. Shelley WB. Essential progressive telangiectasia: Suc- ANA Pattern Centromere cessful treatment with tetracycline. JAMA 1971 May 24;216(8):1343-4. Centromere Ab 1:1280 (normal <1:40) 15. Shelley WB, Shelley ED. Essential progressive telangi- ectasia in an autoimmune setting: successful treatment with acyclovir. J Am Acad Dermatol. 1989 Nov;21(5 Pt Anti-dsDNA Normal 2):1094-6. 16. Gambichler T, Avermaete A, Wilmert M, Altmeyer P, Hoff- Anti-RNP Ab Normal mann K. Generalized essential telangiectasia successfully treated with high-energy, long-pulse, frequency-doubled Nd:YAG laser. Dermatol Surg. 2001 Apr;27(4):355-7. Anti-Sm Ab Normal 17. Buscaglia DA, Conte ET. Successful treatment of general- ized essential telangiectasia with the 585-nm flashlamp- Anti-SSA Normal pumped pulsed dye laser. Cutis 2001 Feb;67(2):107-8. 18. Jacobe HT, Sontheimer RD, Autoantibodies encountered in patients with autoimmune connective tissue diseases, Anti-SSB Normal Dermatology, Vol. 1, 1st edn. Mosby, 2003, 592. 19. Lee SL, Tsay GJ, Tsai RT. Anticentromere antibodies in subjects with no apparent connective tissue disease. Ann IgG Normal Rheum Dis. 1993 Aug; 52(8): 586–9. Rheumatoid Factor Normal Urinalysis Normal of blood vessels.10,11 The literature does not documented in such conditions as primary support a direct association between GET biliary cirrhosis, pulmonary hypertension, and connective-tissue diseases. There is, and primary Raynaud's phenomenon.19 This however, growing evidence of an underlying patient had consistently elevated ANA and autoimmune process.12 ACA. She also had arthralgias, intermittent The histopathology typically shows dysphagia, Raynaud’s phenomenon, and a thin-walled vascular channels found in the skin biopsy reported as connective-tissue upper dermis with minimal mononuclear disease. The significance of this patient’s inflammatory infiltrate. These channels elevated ANA and anti-centromere anti- are produced by dilation of postcapillary bodies with regard to the generalized essen- venules of the upper horizontal plexus.13 tial telangiectasias is yet to be determined. Telangiectatic vessels in GET reportedly lack alkaline phosphatase activity in the Conclusion of both the terminal arterial and the arterial portion of the capillary The diagnosis of GET has a good prog- loops.13 This may be a method of differenti- nosis, and those affected with the disorder ating GET from the telangiectasia associated have a normal lifespan; however, the with systemic disease, in which the walls lesions have a tremendous negative impact of normal terminal arterioles and capil- emotionally. Our patient is very self lary loops and the telangiectases associated conscious about her appearance to the point with dermatomyositis are all alkaline-phos- that it alters her normal daily activities. We phatase positive. plan to refer this patient for laser therapy, as In individual reports, tetracycline, keto- reports have shown good results. conazole, and the treatment of chronic sinus infection have led to resolution by References involution of the vessels.14 Successful treat- 1. Magro et al. Mixed connective tissue disease. Am J Derm Path. 1997, 19(3):206-213. ment with acyclovir has been reported in 2. Long D, Marshman G. Generalized essential telangiecta- an autoimmune setting.15 Laser ablation sia. Australas J Dermatol. 2004 Feb;45(1):67-9. 3. Blume JE. Generalized essential telangiectasia: using a high-energy, high-frequency, long- a case report and review of the literature. Cutis. 2005 pulse Nd:YAG laser or a 585 nm flash- Apr;75(4):223-4. 4. Abrahamian LD, Rothe MJ. Primary telangiectasia of child- lamp-pumped pulsed dye laser have both hood. Int J Dermatol. 1992;31:307-13. produced good results.16,17 5. Mannis M, Bindi C, Huntley A. Ocular manifesta- tions of generalized essential telangiectasia. Cornea With regard to this patient’s serology, 1999;18:731-733. ANA titers have been shown to be elevated 6. Seiter S, Gantenbein C, Ugurel S et al. An oculocutaneous presentation of essential progressive telangiectasia. Br J as a consequence of aging and without Dermatol. 1999;140:969-971. any signs of disease.18 In fact, up to 15% 7. Ali MM, Teimory M, Sarhan M. Generalized essential telangiectasia with conjunctival involvement. Clin Exp Der- of otherwise healthy individuals over the matol. 2006 Nov;31(6):781-2. age of 55 can have a significantly elevated 8. McGrae JD, Winkelmann RK. Generalized essential telangiectasia: a report of a clinical and histochemical 18 ANA titer of no clinical consequence. study of 13 patients with acquired cutaneous lesions. In addition, anti-centromere antibodies JAMA 1963;185:909-913. 9. Abrahamian LD, Rothe MJ. Primary telangiectasia of child- (ACA) do not always indicate the presence hood. Int J Dermatol 1992;31:307-13. of connective-tissue disease and have been 10. Wells RS, Dowling GB. Hereditary benign telangiectasia.

32 A WOMAN WITH GRADUALLY SPREADING TELANGIECTASIAS GRISEOFULVIN-INDUCED PHOTOALLERGIC REACTION: A CASE REPORT IN A 10-YEAR-OLD HISPANIC MALE

David R. Bonney, D.O.,* Stanley Skopit, D.O., FAOCD** *NOVA Southeastern University/BGMC 2nd-year resident **Program Director, NOVA Southeastern University/BGMC

Introduction significantly improved by dietary fat intake. The medication is considered very safe, with Photosensitive reactions are unwanted reported use for over 40 years. Its most adverse effects that are recognized following common side effects include headache and the administration of topical and systemic gastrointestinal disturbances, but may also medications, and subsequent exposure cause a fixed-drug eruption, photosensi- to either artificial or natural UV rays. tivity, petechiae, pruritus, urticaria, and may These drug-induced photodermatoses exacerbate lupus or porphyria.2,5 are commonly divided into photoallergic Adverse reactions secondary to photo- reactions and phototoxic reactions. Tissue sensitization induced by griseofulvin is well damage is a direct result in phototoxic known and documented, but only a few reactions, and most clinically resembles an cases have been reported with detailed infor- exaggerated sunburn. Eruptions develop mation on clinical appearance, histological shortly after exposure to light, with inten- exam and outcomes. One such report sity increasing in a dose-dependent manner. details six Japanese patients on griseofulvin In photoallergic reactions, the damage is for variable lengths of time in treatment of immunologically mediated.1,3 There can tinea unguium.1 The following case report be an immediate (humoral-mediated) details the particulars of a 10-year-old hypersensitivity, delayed (cell-mediated) Hispanic male growing up in south Florida hypersensitivity, or both, developing with histological evidence of a photoallergic into a photoactivated compound that is reaction secondary to griseofulvin. transformed into an antigen during radia- Determining the mechanism of a Figure 1 tion. In contrast to phototoxic reactions, photosensitivity reaction can be impor- photoallergy is usually elicited by the longer tant because the phototoxic and photo- UVA wavelengths, only occurs in sensi- allergic types can be managed differently. tized persons, and are not dose dependent. Phototoxins can be manipulated and even Clinically, drug-induced photoallergic reac- tolerated by decreasing the dose of a medi- tions can appear as solar urticaria or as cation or the amount of radiation exposure. eczematous dermatitis on predominantly In photoallergic reactions, however, altering light-exposed areas.3,5 these parameters does not significantly Photosensitive reactions have been change the outcome. Drug-induced photo- studied for a number of topical antibiotics, allergic reactions usually disappear sponta- systemic antibiotics (especially sulfon- neously once the offending photosensitizer amides, tetracyclines and quinolones), and has been removed. Rarely, a persistent antifungals such as griseofulvin. The precise light reaction can occur, remain longer and mechanism of photosensitivity reactions relapse with minimal UV radiation.3 Figure 2 caused by griseofulvin are not completely understood, but is commonly listed as a Case Report griseofulvin according to the father. Family systemic photosensitizing drug. UVA radia- history was noncontributory as well. tion is known to be responsible for eliciting A 10-year-old Hispanic male presented to On physical examination, the 10-year-old griseofulvin photoreactions. Griseofulvin the clinic along with his father for evalua- male did not appear acutely ill and was has also been shown to exacerbate preex- tion of a rash that developed two days prior afebrile. The patient's scalp revealed three isting systemic lupus erythematosus and to to this visit. The patient's father reported erythematous, boggy nodules with matting induce subacute cutaneous lupus erythema- that his son was placed on griseofulvin of the scalp hair in these areas. Examination tosus in reported cases.3,5 solution based on his weight for a fungal of his face and ears revealed erythematous, Griseofulvin is fungistatic against infection on his scalp five days prior at an follicular lesions on the bilateral cheeks, Trichophyton, Microsporum and emergency room. Three days after initiating nose, and pinnae. There was a similar erup- Epidermophyton. It is not active the medication, the patient developed an tion noted on the patient's anterior and against Pityrosporum dimorphic fungi, itchy rash on his face, neck, ears, forearms posterior neck, anterior chest, forearms and Cryptococcus or the fungi that cause chro- and legs. The father does report spending tibial regions of both legs. The abdomen, momycosis. The indications for systemic time outside with his son on a football field lower back, thighs, buttocks, palms and griseofulvin include tinea capitis, onycho- in bright sunlight without sunscreen the day soles were spared. There was no perior- mycosis, and widespread superficial fungal before the rash began. There were no other bital or perioral erythema or edema noted. infections. Dosages of griseofulvin are reported issues, including no fevers, chills, No targetoid lesions were observed. There based on weight in the pediatric population sweats, abdominal pain, nausea, vomiting, was mild, palpable, slightly tender cervical and do require a long duration of therapy or changes in urination. There were no adenopathy appreciated (Figures 1, 2). in most cases. Absorption of griseofulvin is known drug allergies or prior exposure to After discussion with the patient's father,

BONNEY, SKOPIT 33 weight of 78 pounds. Eight weeks later, the cillin allergy.1 As with any known potential father reported complete resolution of the photosensitive medications, recommenda- scalp infection with evidence of new hair tions for diligent photoprotection must be growth and no residua of the rash on his conveyed to patients. face, ears, trunk or extremities. References: Discussion 1. Kojima, T, Hasegawa, T, Ishida, H, Fujita, M, and Oka- moto, S. Griseofulvin- induced Photodermatitis - Report The antimycotic medication griseof- of Six Cases. J Dermatol. 1988 Feb;15(1):76-82. 2. Ljunggren, B, and Bjellerup, M. Systemic Drug Photosen- ulvin has been reported to cause photo- sitivity. Photodermatol. 1986 Feb;3(1):26-35. sensitivity reactions. In a survey on side 3. Vassileva, SG, Mateev G, and Parish, LC. Antimicrobial Photosensitive Reactions. Arch Intern Med. 1998 Oct effects of griseofulvin, it was reported in 12;158(18):1993-2000. Figure 3 about 2% of patients.2 Clinical reports on 4. Kawabe Y, Mizuno N, Miwa, N, and Sakakibara, S. Pho- tosensitivity induced by Griseofulvin. Photodermatol. 1988 these photoreactions to griseofulvin are Dec;5(6):272-4 few, and the precise mechanisms of the 5. Bolognia, J, Jorizzo, J, and Rapini, R. Dermatology Vol. 2. various photosensitivity reactions it causes 2003; 1376-1379. are not completely clarified. UVA radia- tion is known to be responsible for eliciting griseofulvin photosensitivity.3 In humans, griseofulvin has been shown to inhibit heme synthesis, which results in increased urinary porphyrin excretion. Mouse studies have shown porphyrin-metabolism disturbances after griseofulvin ingestion resulting in phototoxin reactions. After single doses of Figure 4 200mg/kg in mice, griseofulvin was clearly phototoxic. However, this has not been a 3mm punch biopsy was performed on conclusively demonstrated in humans, and the right posterior neck. The patient was thus griseofulvin-induced photosensitivity instructed to stop the griseofulvin at that in humans may not depend on porphyrin- time and to continue with Claritin and metabolism disturbances.2,3 Benadryl as needed for itching as prescribed Histologically, this patient demonstrated by the pediatrician. Cutivate cream was a spongiotic dermatitis with dermal eosino- prescribed for symptomatic relief, with phils consistent with an eczematoid drug directions to apply it twice daily to the trunk eruption (Fig. 3, 4). This appears to be most and extremities for no more than two weeks. consistent with a photoallergic reaction. Serology was ordered, including a CBC, IgE Clinically, there was oral administration level, ASO titers, urinalysis and Epstein-Barr of griseofulvin followed by significant UV virus IgM and IgG antibodies. exposure according to history by the father. The patient followed up in the office The patient developed a pruritic eruption two days later with his parents, with mild on sun-exposed areas of the body about 48 improvement of symptoms. On exami- hours later. In a Japanese study by Kojima nation, the scalp was clinically unchanged et al. of six reported cases of griseofulvin- except for a new purulent discharge and induced photodermatitis, all showed acute some serosanguinous fluid noted in the to subacute dermatitis histologically.1 The area. Examination of the face, trunk and authors also reported variable results in extremities revealed improvement of the photocross-linking reactions to penicillin, follicular eruption, with drying and less positive photopatch tests in some patients, erythema noted. No new lesions were iden- distant flare-up phenomena and persistent tified. The biopsy revealed a spongiotic light reactions, suggesting that the patho- dermatitis with dermal eosinophils consis- genesis is photoallergic in these patients.1 tent with eczematoid drug eruption. Biopsy The term photoallergy for systemically results were discussed with the patient's administered drugs is confusing in the liter- parents in detail, and the patient was placed ature, however, and whether systemically on Azithromycin suspension 200mg per 5cc administered drug photosensitization is based on weight. caused by photoallergy has not been clearly Two weeks after initial presentation to the proven. office, the patient returned with his father This case study suggests that, based on for other treatment considerations for scalp histology, the mechanism of griseofulvin- fungal infection. They reported tenderness induced photodermatitis is most likely of the scalp with hair loss, but no fevers, photoallergic. However, due to the sample chills or sweats. The patient also reported size of one and the lack of supporting that the rash on his face, ears, neck, chest, evidence with photopatch testing and arms and legs had resolved significantly photocross reactions to penicillin, the exact with no residual pruritus. Liver function mechanism remains unclear. Kojima et al. tests were within normal limits, and the recommend checking for penicillin allergy patient was placed on Lamisil 125mg one before administering griseofulvin based on tablet daily for four weeks based on his their data of a 33% overlap with a peni-

34 GRISEOFULVIN-INDUCED PHOTOALLERGIC REACTION: A CASE REPORT IN A 10-YEAR-OLD HISPANIC MALE ACCESSORY TRAGUS

Robert A. Norman, DO, MPH, Veronica Cabigas Davis, OMS IV Lake Erie College of Osteopathic Medicine, Bradenton, FL

Case Report Each pharyngeal arch is covered on the outside by surface ectoderm and on the A 2-year-old African American female inside by endoderm. cells presented with her foster father to our office migrate into the arches to comprise the with a small growth in front of her left ear. skeletal components of the face. The meso- She’d had it since birth. The foster father derm is important in the formation of denied any associated symptoms such as blood vessels and in the formation of the erythema, tenderness, pruritus, infection, musculature of the face and neck. or drainage. It had not recently grown in The first pharyngeal arch is made by size or changed in shape or color. Her past the maxillary process and the mandibular medical history was noncontributory, and process, which involves Meckel’s cartilage. her family history was mostly unknown as This cartilage subsequently disappears she was in the foster care system. Her birth except for portions that form the incus and Figure 1 mother was a known methamphetamine malleus. The premaxilla, maxilla, zygomatic addict, and her foster father attributed the bone, and part of the temporal bone from abnormal growth to be a birth defect related the mesenchyme (a loose kind of connective to drug use in utero. tissue), all part of the maxillary process, The patient was otherwise healthy, was undergo membranous ossification. The not currently taking any medications, and formation of the bones of the middle ear had no known drug allergies. She was to takes place here as well. be placed in daycare soon, and her foster The second pharyngeal or hyoid arch father feared she would get made fun of by (Reichert’s cartilage) gives rise to the stapes, other children and was here to discuss treat- the styloid process of the temporal bone, ment options. On physical examination, the the stylohyoid ligament and, ventrally, the patient was a well-appearing 2-year-old who lesser horn and upper part of the body of was in the appropriate growth percentile for the hyoid bone. The facial supplies her age. Upon inspection, her left ear was the muscles of this arch. Those muscles are normal in appearance, except for the pres- the stapedius, the stylohyoid, the posterior ence of a single, unilateral, raised, peduncu- belly of the digastric, the auricular and the lated nodule approximately 1.5 cm in length muscles of facial expression. and 0.5 cm in width, which protruded from Early on in development, an accessory the preauricular area (Figure 1). It was soft, tragus may develop anywhere along the line non-tender and skin-colored. There were of migration from the angle of the mouth to no other craniofacial abnormalities, and the the anterior border of the sternocleidomas- rest of the physical exam was unremark- toid muscle. Five percent of patients with able. The patient’s foster father was told the accessory tragi also have associated devel- diagnosis and the treatment options, which opmental abnormalities of the pharyngeal included surgery. He was told to think arch. Accessory tragus is a consistent feature about it and returned two weeks later to seen in Goldenhar's syndrome, also known have the child’s growth surgically removed, as oculo-auricular-vertebral syndrome, and which yielded excellent results. is less consistently seen in Townes-Brocks, Treacher-Collins, VACTERL, and Wolf- Diagnosis: Hirschhorn syndromes. Accessory Tragus Differential Diagnosis Discussion Differential diagnosis includes fibroepi- thelial polyp, soft fibroma, chondroma and The tragus is the part of the external ear . projecting posteriorly over the external auditory meatus. An accessory tragus is one of the most common congenital defects of Resources the external ear in the absence of any other 1. Sadler, T.W. Langman’s Medical Embryology, 9th ed. Bal- timore: Lippincott Williams & Wilkins, 2004: 363-383. abnormality. It is believed to arise from an 2. Junkins-Hopkins, J. Textbook of Dermatopathology, 2nd embryological defect in the development of ed. McGraw-Hill Professional, 2004: 427 the first and second brachial arches as they move dorsally to form the auricle. These arches appear in the fourth and fifth weeks of development.

NORMAN, DAVIS 35 TREATMENT OF PSORIASIS WITH A VASCULAR ENDOTHELIAL GROWTH FACTOR INHIBITOR

Stephen C. Verral, DO, MPH,* Steven K. Grekin, DO, FAOCD** *Oakwood Southshore Medical Center, Trenton, MI **Michigan State University Osteopathic Consortium, Dermatology Program Chairman, Grekin Skin Institute, Wyandotte, MI

ABSTRACT

Psoriasis has received increased attention with the success of the biologic therapies currently available. We report a case of pso- riasis treated with a shark-lipid-derived vascular endothelial growth factor inhibitor. The patient presented with large plaque psoriasis covering approximately 60% of his body surface area, and he had almost complete clearing of psoriatic plaques after three months of therapy.

Introduction Psoriasis is a T-cell-mediated chronic inflammatory skin disorder affecting 2% of the population.1 Angiogenesis has been shown to be a necessary inflammatory response early in the pathogenesis of psori- asis.2 Vascular endothelial growth factor (VEGF) causes hyperpermeability of blood vessels as well as endothelial cell prolifera- tion, and its production is increased in the epidermis of psoriatic lesions.3,6 The over- production of VEGF plays an important role in the pathogenesis of psoriasis.4 Studies have shown the level of VEGF to be 50 times greater in psoriatic plaques when compared to normal stratum corneum.3,4,7 The plasma levels of VEGF in psoriatic patients have also been demonstrated to decrease with improvement of their psoriatic plaques.5 Shark lipids and other shark products have been studied significantly since the 1990s for their anti-angiogenesis effects and possibility in treating cancer.8,9 Some of the compounds studied in shark products seem to demonstrate the ability to inhibit angiogenesis.10,11,12,13 We report successful treatment of a patient with large plaque psoriasis with a VEGF inhibitor extracted from shark lipids. Case Report A 28-year-old Caucasian male presented with a 10-year history of plaque psoriasis on his chest, back, groin, buttock and upper and lower extremities, covering approxi- mately 70% of his body surface area. He had previously been treated with etanercept 50mg subcutaneously twice weekly as part of a clinical trial, with some success after 12 weeks of therapy; but he was unable to continue treatment at the end of the trial due to financial circumstances. He had last received etanercept six months prior to Figure 1 presenting at our office. He had previously tried topical corticosteroids, dovonex and narrow-band UVB without success, either due to lack of efficacy or lack of compli-

36 TREATMENT OF PSORIASIS WITH A VASCULAR ENDOTHELIAL GROWTH FACTOR INHIBITOR ance with treatment regimen. He was not taking any other medications and was otherwise healthy. His family history was unremarkable. Physical examination revealed large, well-defined erythematous plaques with thickened white scale on his chest, back, arms, legs, groin and buttocks (Figure 1). Palms and soles were clear of any lesions. All laboratory findings were within normal range, including complete blood count, liver function and basic chemistries. A diagnosis of psoriasis was made, and the patient was started on SupermacoTM, a shark-liver mucolipin extract, taken by mouth three times a day. Due to finan- cial constraints, the patient was unable to obtain any other prescription medication and was only taking the Supermaco pills. The patient was seen in the clinic monthly, and no adverse events occurred. At the end of three months of therapy, the patient was almost completely clear, with small plaques remaining on the elbows (Figure 2). The patient reported not only looking better but also feeling better than he had in years. Discussion The new biologic therapies for psoriasis offer more targeted treatment capabilities, but most also possess some potentially serious side effects, are cost prohibitive, and currently are only available as a subcuta- neous injection or intravenous infusion. Supermaco is an all-natural product with potent anti-angiogenesis effects that comes in a pill form and is a fraction of the cost of the new biologic therapies. There are several mechanisms thought to be involved in the anti-angiogenesis effects of Supermaco. A study conducted at the Wellington School of Medicine in New Zealand was able to demonstrate that shark lipids have Figure 2 the ability to inhibit vascular endothelial growth factors (VEGF), fibroblast growth demonstrated a decrease in plasmalogen not considered to be dangerous, although factor (FGF-2), and transforming growth and von Willebrand factor content in the there is some concern about accumula- 9 factor beta (TGF-Beta). VEGF are proteins tumors, affecting the ability to promote tion if taken in high doses for long periods shown to promote the formation of new angiogenesis.15 Shark products have also of time.17 One case of hepatitis has been blood vessels; FGF-2 is a protein shown to been shown to interfere with matrix metal- reported in a patient taking a shark-carti- promote proliferation of many different loproteases (MMPs), allowing the growth lage product; and in some clinical studies, cell types; and TGF-beta demonstrates of new blood vessels.9,16 MMPs are secreted some participants taking shark products suppression of cytokine production and by some tumors and are thought to break by mouth developed signs of liver dysfunc- major histocompatability complex (MHC) down surrounding tissue. tion such as dark urine, excessive fatigue, type II expression, suppressing the immune widespread pruritis, nausea, vomiting, pain 14 In this case study, our patient expe- system. or swelling in the right upper abdomen, The shark lipids also demonstrated minor rienced significant improvement in his and/or jaundice.18 Cases of hypercalcemia inhibitory effects against interleukin 2 psoriasis without any adverse events after have also been reported in some cancer (IL-2) and platelet-derived growth factor three months of therapy; however, some patients taking various dietary supplements (PDGF).9 In another study by Pedrono et adverse events have been reported in including shark products. Other less severe al., the alkylgycerols present in shark lipids other patients taking shark supplements. side effects also reported while taking oral were demonstrated to have a direct inhibi- Some shark products have been shown to shark products include constipation, dizzi- tory effect on tumor neovascularization contain heavy metal contaminants such ness, nausea, indigestion, bad taste in the and dissemination of Lewis lung carcinoma as mercury and cadmium. In these cases, mouth, diarrhea, low blood pressure, and in mouse models. Additionally, the lipids the levels of mercury and cadmium were weakness.18,19

VERRAL, GREKIN 37 This case report demonstrates the possibly potent effects that the anti-angiogenesis compound SupermacoTM can have on the treatment of psoriasis. We are currently undertaking a pilot study to investigate the use of Supermaco as a treatment for psori- asis. If this case report is any indication of the therapeutic effects of Supermaco, we believe it will be a safe, targeted, inexpensive treatment to add to the currently available regimens.

REFERENCES 1. Bowcock AM and Krugger, JG. Getting under the skin: the immunogenetics of psoriasis. Nat Rev Immunol. 2005 Oct;5(10):826. 2. Leong TT, Fearon U, Veale DJ. Angiogenesis in psoriasis and psoriatic arthritis: clues to disease pathogenesis. Curr Rheumatol Rep. 2005 Aug;7(4):325-9. 3. Zhang Y, Matsuo H, Morita E. Vascular endothelial growth factor 121 is the predominant isoform in psoriatic scales. Exp Dermatol. 2005 Oct:14(10):758-64. 4. Young HS, Summers AM, Bhushan M, Brenchley PE, Griffiths CE. Single-nucleotide polymorphisms of vascular endothelial growth factor in psoriasis of early onset. J Invest Dermatol. 2004 Jan;122(1):xiv-xv. 5. Nielsen HJ, Christensen IJ, Svendsen MN, Hansen U, Werther K, Brunner N, et al. Elevated plasma levels of vascular endothelial growth factor and plasminogen acti- vator inhibitor-1 decrease during improvement of psoriasis. Inflamm Res. 2002 Nov;51(11):563-7. 6. Detmar M. The role of VEGF and thrombospondins in skin angiogenesis. J Dermatol Sci. 2000 Dec;24 Suppl 1:S78-84. 7. Bhushan M, McLaughlin B, Weiss JB, Griffiths CE. Levels of endothelial cell stimulating angiogenesis factor and vas- cular endothelial growth factor are elevated in psoriasis. Br J Dermatol. 1999 Dec;141(6):1054-60. 8. Davis, Paul. Research, development and future prospects of bioactive preparations based on shark lipids. Bioacitiv- ity Investigation Group. Wellington School of Medicine in New Zealand. 2004. 9. Ratel D, Glazier G, Provencal M, Boivin D, Beaulieu E, Gingras D, Beliveau R. Direct-acting fibrinolytic enzymes in shark cartilage extract: potential therapeutic role in vas- cular disorders. Thromb Res. 2005;115(1-2):143-52. 10. Biovin D, Provencal M, Gendron S, Ratel D, Demeule M, Gingras D, Beliveau R. Purification and characterization of a stimulator of plasmin generation from the antiangio- genic agent Neovastat: identification as immunoglobulin kappa light chain. Arch Biochem Biophys. 2004 Nov. 15;431(2):197-206. 11. Cho J, Kim Y. Sharks: a potential source of antiangiogenic factors and tumor treatments. Mar Biotechnol (NY). 2002 Dec;4(6):521-5. 12. Skopinska-Rozewska E, Chorostowska-Wynimko J, Krot- kiewski M, Rogala E, Sommer E, Demkow U, Skurzak H. Inhibitory effect of Greenland shark liver oil combined with squalen and arctic birch ashes on angiogenesis and L-1 sarcoma growth in Balb/c mice. Pol J Vet Sci. 2003;6(3 Supple):54-6. 13. Berbari P, Thibodeau A, Germain L. Antiangio- genic effects of the oral administration of liquid carti- lage extract in humans. Journal of Surgical Research. 1999;87(2):108-113. 14. Dahl, Mark V. Clinical Immunodermatology. 3rd Edition. 1996;p87-97. Mosby-Year Book, Inc. St. Louis, Missouri. 15. Pedrono F, Martin B, Leduc C, Le Lan J, Saiag B, Legrand P, Moulinou JP, Legrand AB. Natural alkylglycerols restrain growth and metastasis of grafted tumors in mice. Nutr Cancer. 2004;48(1):64-9. 16. Bukowski RM. AE-941, a multifunctional antiangiogenic compound: trials in renal cell carcinoma. Expert Opin Investig Drugs. 2003 Aug;12(8):1403-11. 17. Kim M. Mercury, cadmium and arsenic contents of cal- cium dietary supplements. Food Addit Contam. 2004 Aug;21(8):763-7. 18. Ashar B, Vargo E. Shark cartilage-induced hepatitis. Annals of Internal Medicine. 1996;125(9):780-781. 19. Lagman R, Walsh D. Dangerous nutrition? Calcium, vitamin D, and shark cartilage nutritional supplements and cancer-related hypercalcemia. Support Care Cancer. 2003 Apr;11(4):232-5.

38 TREATMENT OF PSORIASIS WITH A VASCULAR ENDOTHELIAL GROWTH FACTOR INHIBITOR

MASTOCYTOSIS: MAST CELL BURDEN AND SYMPTOMATOLOGY

Aaron Bruce, D.O.,* David Esguerra, D.O.** *Second-year Resident, Sun Coast Hospital/NOVA Southeastern University, Largo, FL **Clinical Professor, Sun Coast Hospital/NOVA Southeastern University, Largo, FL; Bay Dermatology & Cosmetic Surgery, P.A., Largo, FL

ABSTRACT

Mastocytosis refers to a spectrum of diseases related to an accumulation of mast cells. The range of diseases caused by mast-cell aggregation and degranulation vary from relatively benign cutaneous forms to myelodysplastic disorders. The most common child- hood form of mastocytosis, (UP), represents 60%-90% of cases. Typically, UP resolves by ; however, rare cases have evolved into systemic disease in adulthood. We present a 25-year-old female with a history of adolescent-onset urticaria pigmentosa, who presented to us complaining of recurrent episodes of , pruritus, palpitations, wheezing, crampy abdominal pain, vomiting, syncope, and headache within the last year. Her skin lesions become raised, erythematous, and pruritic with exacerba- tions that coincided with “asthma attacks.” Exercise makes her symptoms worsen, and Naprosyn also reportedly induced an acute episode. Despite her severe symptoms, an extensive workup revealed no evidence of extracutaneous disease. This case demonstrates the unpredictable relationship between mast-cell burden and symptomatology. A review of the literature related to mast-cell burden and symptom severity is discussed.

Case Report exhaustive literature review found no corre- lation between PHA and mastocytosis. We A 25-year-old female with a history concluded that the PHA was a coincidental of adolescent-onset urticaria pigmen- finding. tosa presented as a new patient to estab- Biopsy report and slides from 2001 were lish care and have “moles” examined. obtained and confirmed with a dermato- Neurocardiogenic syncope was noted on pathologist. Histology revealed increased medical history. Upon further questioning, superficial dermal perivascular cells with she admitted to recurrent episodes of granular cytoplasm. The cells stained flushing, pruritus, palpitations, wheezing, metachromatically with Giemsa. These crampy abdominal pain, vomiting, syncope, findings are consistent with cutaneous and headache within the last year. Her skin mastocytosis.5 lesions become raised, erythematous, and Figure 1 pruritic with exacerbations that coincided Discussion: with “asthma attacks.” Exercise worsened her symptoms, and Naprosyn induced an Mastocytosis (MC) is a heterogeneous acute episode. Multiple therapies targeted group of disorders characterized by at the skin lesions had been tried in the past, abnormal proliferation and accumulation of including laser, intralesional and topical mast cells in the skin, bone marrow, gastro- corticosteroids. Medications upon presenta- intestinal tract, liver, spleen, and lymph tion included fluticasone propionate/salme- nodes. The spectrum of mast cell disease terol discus (Advair), ipratropium bromide/ has been classified based on type and extent albuterol sulfate inhaler (Combivent), of involvement as well as age of onset. levothyroxine (Synthroid), montelukast Cutaneous forms include solitary masto- sodium (Singulair), and drospirenone/ cytoma, urticaria pigmentosa, diffuse ethinyl estradiol (Yasmin). cutaneous mastocytosis, and telangiectasia Examination reveals a healthy-appearing, macularis eruptiva perstans. Urticaria 25-year-old female with numerous reddish- pigmentosa is the most common form brown, well-demarcated macules and of cutaneous MC. Urticaria pigmentosa papules less than 1 cm in diameter. These usually presents in childhood, and may lesions are symmetrically distributed and persist into adulthood. However, most cases most numerous on the trunk, buttocks and spontaneously improve. Cases have been proximal extremities. The face is spared. reported of UP progressing into aggressive An initial work-up, including CBC, such as mast-cell leukemia or 9 CMP, rheumatoid factor, ANA, and serum mast-cell sarcoma. Figure 2 protein electrophoresis, was normal. Serum A variety of laboratory tests are avail- tryptase was found to be normal at 12 ng/ able for evaluation of patients suspected and CD25 receptors are strongly associated ml. Karyotype and bone marrow biopsy to have or being followed for mastocy- with severity of bone marrow involvement.2 with flow cytometry were also negative. tosis. Elevated serum tryptase levels and Flow cytometric analysis of bone marrow Peripheral smear showed the Pelger-Huet 24-hour urine histamine metabolites both mast cells is also a sensitive method of diag- anomaly (PHA), a benign, inherited defect support a mastocytosis diagnosis. Serum nosing systemic mast-cell disease. However, of terminal neutrophil differentiation.6 tryptase is a mast-cell–specific marker and more than one bone marrow biopsy may Upon further questioning, her father also correlates closely with cumulative mast-cell be required, as patchy marrow involvement reportedly was diagnosed with PHA. An burden.2,7,10 High levels of soluble CD117 may be missed on a single specimen.4

BRUCE, ESGUERRA 41 An extensive Medline search dating back to ous involvement in children and adults with mastocyto- sis: relationship to symptomatology, tryptase levels, and 1966 reveals only one article that addresses bone marrow pathology. J Am Acad Dermatol 2003; 48: some of these issues.3 A few authors do 508-516 4. Butterfield JH, Li CY. Bone marrow biopsies for the diag- make generalizations, likely based on clinical nosis of systemic mastocytosis: is one biopsy sufficient? experience. Am J Clin Pathol 2004; 121(2): 264-7 5. Elders, David E, et al. Lever’s Histopathology of the Skin. Brockow et al. assessed the extent of cuta- Philadelphia: Lippincott Williams & Wilkins, 2005. (Chapter 6) neous disease as a predictor of systemic 6. Hoffman, R, et al. Hematology: Basic Principles and Prac- disease.3 They looked at both adults and tice, 4th ed. Philadelphia: Elsevier, 2005. (Chapter 46) 7. Longley J. The mast cell and mast cell disease. J Am children. In children, the extent of cuta- Acad Dermatol 1995; 32(4): 545-61 neous disease did not predict systemic 8. Noack F. Evolution of urticaria pigmentosa into indolent systemic mastocytosis: abnormal immunophenotype of disease. In adults, it was found that the mast cells without evidence of c-kit mutation ASP-816- absence of skin lesions and very dense VAL. Leuk Lymphoma 2003; 44(2): 313-9 (abstract) Figure 3 9. Shaffer HC. Recurrent syncope and anaphylaxis as pre- cutaneous involvement were more likely to sentation of systemic mastocytosis in a pediatric patient: predict extracutaneous disease and more case report and literature review. J Am Acad Dermatol 2006; 54(5 Suppl): S210-3 severe symptoms. However, the only symp- 10. Tharp MD, Mastocytosis. Dermatol Clin 2001; 19(4): toms discussed were flushing, pruritus, 679-96 nausea, fatigue and musculoskeletal pain. In light of this paper, our case becomes even more peculiar. Which factors may influence symptom severity can only be speculated. Ratios of the mast cell mediators could vary person to person, or some individuals may be more sensitive to the various mediators. Mast cells may have great variability in their propensity to degranulate, or some indi- Figure 4 viduals may release greater quantities of Patients with UP may also experi- mediators than others. Further research in ence various symptoms such as pruritus, this area would help elucidate some of the flushing, dizziness, palpitations, syncope, influencing factors and perhaps open new nausea, diarrhea, abdominal pain, and possibilities for treatment. It is clear by headache.2 Anaphylaxis has been reported the absence of literature on this topic that in both children and adults.9 Symptoms this spectrum of diseases remains poorly such as musculoskeletal pain, neuropsy- understood. chiatric disturbances, weight loss, night In conclusion, extensive workup has not sweats, fevers, and malaise are more revealed any evidence of systemic disease in likely indicators of systemic involvement. our patient. Follow-up visits reveal flares of Symptoms are thought to be caused by the nausea, dizziness, and palpitations despite mast-cell mediators, which are grouped aggressive medical management. Current into preformed granule-associated media- medical regimen includes fexofenadine tors, lipid mediators, and cytokines.2 The and ranitidine in the morning, loratadine preformed granule-associated mediators at lunch, and cetirizine, ranitidine and include histamine, serine proteases, heparin, montelukast sodium every evening. Her and chondroitin sulfate. Lipid mediators main triggers are reported to be heat, exer- include leukotrienes and prostaglandin D2, cise, emotional stress, sun exposure and among others. These mediators and many certain foods. She is followed closely by cytokines can be linked to the mast-cell dermatology, allergy/immunology, and her mediator release syndrome. primary care physician. Regular follow-up It has been reported that the mast cell visits and blood work, including tryptase, concentrations within mastocytomas are will be checked. If any evidence of change 150-fold greater than in normal skin, occurs, repeat bone marrow biopsy will 40-fold greater in childhood UP, and eight- be considered. This case demonstrates fold greater in adult mastocytosis lesions.10 that even a minimal increase in mast cell Considering these mast cell concentrations, burden can cause an unpredictable degree our patient appears to have very little mast of symptoms, and, as in our case, severely cell burden. This is supported by a negative disrupt a patient’s quality of life. The litera- bone marrow biopsy and flow cytometry. ture reveals a poor understanding of this In light of the normal serum tryptase level, spectrum of disease and calls for increased it is possible but unlikely that she has occult efforts in expanding our basic under- extracutaneous disease. standing and treatment options. This case raises several questions regarding the nature of the mast cell disease References and symptomatology. How can a seemingly 1. Brockow K, et al. Levels of mast-cell growth factors in plasma and in suction skin blister fluid in adults with mas- small mast cell burden be responsible for tocytosis: correlation with dermal mast-cell numbers and such severe symptoms? What factors influ- mast-cell tryptase. J Allergy Clin Immunol 2002; 109(1): 82-8 ence these symptoms? What implications 2. Brockow K, et al. Urticaria pigmentosa. Immunol Allergy would answers to these questions yield? Clin North Am 2004; 24(2): 287-316, vii 3. Brockow K, et al. Assessment of the extent of cutane-

42 MASTOCYTOSIS: MAST CELL BURDEN AND SYMPTOMATOLOGY LINEAR FOCAL ELASTOSIS IN A YOUNG HISPANIC MALE: A NEW PRESENTATION

Brian Feinstein, DO*, Stanley Skopit, DO, FAOCD** *2nd year resident, Nova Southeastern University/NBHD **Program Director, Nova Southeastern University/NBHD

ABSTRACT

Linear focal elastosis is an uncommon dermal elastosis that occurs predominately on the back. It was first described by Burket, Zelickson, and Pandilla in 1989 in three elderly white men. To date, only 27 cases have been reported in the literature. Case reports of linear focal elastosis have included Asian, Caucasian, black, Indian, and Turkish persons who range from 7 to 89 years of age. Reports of occurrence in men are more common than those in women. This is the first reported case of linear focal elastosis in a Hispanic male.

Introduction: scopic examination. The tissue sections were stained with hematoxylin-eosin, revealing Linear focal elastosis is an uncommon abnormal findings (Image 1). The epidermis disorder characterized by yellow, palpable was unremarkable. There was deposition of striae on the middle and lower back. It was abundant pale staining material separating originally reported in three patients by and fragmenting the larger, darker staining Burket et al. in 1989.1 In 1991, Hagari et bundles. Elastic tissue stain showed the pale al. was the second to report a case of linear staining material to be wavy, fragmented focal elastosis, this one in an 86-year-old elastic tissue (Images 2a-c). Japanese man. He concluded that it was characterized by an onset after 60 years of Discussion: age.2 Since then, 23 additional cases have been reported, including onset beginning Because the elastic changes found in Photo 1 in early childhood with facial, axillae, and these lesions were so localized, Burket et al. extremity involvement.3,4 found it reasonable to use the term focal The pathogenesis remains unclear. Some to distinguish it from other forms of elas- authors have suggested that linear focal totic change. Therefore, linear focal elastosis elastosis may be an unusual form of striae had been coined to describe this specific 1 distensae or that it may reflect a condition. repair of striae distensae.5 The location of The differential diagnosis of linear focal the dermatosis in sun-protected areas and elastosis includes striae distensae, pseudox- the lack of any sign of solar elastosis suggest anthoma elasticum, dermatofibrosis lentic- that it is not an actinically derived condi- ularis disseminate, and linear xanthomas. tion. Histologically, the clinically palpable Striae distensae are characterized by white, linear plaques correspond to an increase in red, or violaceous bands of atrophic, wrin- kled skin and are associated with topical abnormal elastic tissue in the subpapillary Photo 2 to lower reticular dermis.1 and systemic steroid use, pregnancy, and weight gain. Lesions usually occur on the lenticularis disseminate is also inherited axillae, abdomen, thighs, arms, or breasts, Case Report: in an autosomal-dominant fashion with a and histopathologic examination shows relatively high penetrance, making the pres- A 15-year-old Hispanic male presented a flattened epidermis, abnormal collagen ence of similar symptoms likely in family for consultative evaluation of palpable, fibers, and variable changes in elastic tissue. members.8 yellow linear plaques on the mid and lower In contrast, linear focal elastosis is char- back. The patient had noticed the slow acterized by palpable yellow plaques that The etiology of linear focal elastosis progression of theses lesions over the past show characteristic changes in elastic tissue; remains unknown. There may be a familial six months. The striae-like lesions were the epidermis and collagen fibers are not or genetic tendency for development of asymptomatic and were localized to either affected.6 the condition. Moiin reported a case in a 29-year-old black man who stated that his side of the vertebral column (Photographs may be differ- father, who was deceased at time of presen- 1, 2). He had no significant past medical entiated from linear focal elastosis by the tation, had similar symptoms for most of his history, no history of systemic or topical presence of calcified elastic-tissue fibers. adult life.11 Others have inferred an ethnic or medications, and no history of trauma to The presence of calcium can be ruled out geographic origin to this condition, as some that region. The patient and his mother with a negative Von Kossa stain. Clinically, clinicians practicing in relatively remote both stated no dramatic changes in height pseudoxanthoma elasticum is characterized areas have found multiple cases within a or weight in the past 12 months. Laboratory by soft yellow papules found on the neck, relatively short period of time.14 Yet, low studies revealed normal complete blood axillae, and groin. In theses areas, it has physician awareness and an asymptom- count, complete metabolic profile, thyroid- been described as having a cobblestone or atic nature may lead to underreporting, stimulating hormone, adrenocorticotropic plucked-chicken skin appearance.7 hormone, and serum cortisol. leading one to believe that the condition Dermatofibrosis lenticularis dissemi- may be much more common than currently The clinical diagnosis was confirmed nate is characterized by oval, skin-colored thought. In fact, many patients with linear with a 4mm punch biopsy taken from the papules rather than the linear plaques seen focal elastosis have reported having symp- patient's right mid back and sent for micro- in linear focal elastosis. Dermatofibrosis

FEINSTEIN, SKOPIT 43 Table 1 A chronological listing with age, sex, ethnicity, and location of every documented case of linear focal elastosis. Reference (year)citation Age Sex Ethnicity Location #VSLFUFUBM  1 69 M White Back   . 8IJUF #BDL 71 M White Back Image 1 Hagari et al (1991)2 86 M Asian Back Biopsy from right mid back stained White GM (1992)10 Elderly M Unknown Axillae with hematoxylin and eosin, 11 29 M Black Back demonstrating dermal edema and .PJOOFUBM  loosely bound collagen fibers with 5SVFCFUBM  12 21 F Unknown Back multiple focal areas of increased and 7PHFMFUBM   89 M White Back irregular pale-staining fibers in the upper/mid dermis. 69 M Unknown Back 1BMNFSFUBM  9 81 M Unknown Back 5BNBEBFUBM  14 17 M Asian Back 20 M Asian Back 29 M Asian Back )BHBSJFUBM  6  ' "TJBO #BDL #SJFSFUBM    ' "TJBO -FHT $IBOHFUBM  16 7 M Asian Back 14 M Asian Back 1BTBE%  4 19 M Indian Axillae

 Image 2a )BTIJNPUP,    . #MBDL #BDL $IPJFUBM  17 16 M Asian Back 18 F Unknown Legs Ramlogan (2001)18  ' 6OLOPXO #BDL 1VJ+  8  . 8IJUF #BDL *OBMP[FUBM    . 5VSLJTI 'BDF ,PTTBSE4  21  ' 8IJUF #BDL"YJMMBF 8IBMFOFUBM  20  . #MBDL #BDL-FHT   ' #MBDL #BDL"SNT $VSSFOU    . )JTQBOJD #BDL

Image 2b toms for as long as 40 years prior to seeking Citations 9 medical evaluation. To date, no reports of 1. Burket JM, Zelickson AS, Padilla RS. Linear focal elas- tosis (elastotic striae). J Am Acad Dermatol 1989 Apr; linear focal elastosis in a person of Spanish 20(4):633-6. or Hispanic ethnicity have been docu- 2. Hagari Y, Mihara M, Morimura T, Shimao S. Linear focal elastosis. An ultrastructural study. Arch Dermatol 1991 mented (see Table 1). All 27 case reports Sep; 127(9):1365-8. in the literature have described patients of 3. Inaloz HS, Kirtak N, Karakok M, Ozgoztasi O. Facial linear focal elastosis: a case report. Int J Dermatol 2003 Jul; either Asian, Caucasian, black, Indian or 42(7):558-60. Turkish ethnicity. 4. Pasad D. Linear focal elastosis. Indian J of Dermatol, Venereol, and Leprol 1998; 64(6):299-300. 5. Hashimoto K. Linear focal elastosis: Keloidal repair of Conclusion: striae distensae. J Am Acad Dermatol 1998 Aug; 39(2 Pt 2):309-13. 6. Hagari Y, Norimoto M, Mihara M. Linear focal elastosis The first known case of linear focal associated with striae distensae in an elderly woman. elastosis in a Hispanic is presented. The Cutis 1997 Nov; 60(5):246-8. 7. Lewis KG, Bercovitch L, Dill SW, Robinson-Bostom L. condition is relatively rare; however, certain Acquired disorders of elastic tissue: part 1. Increased Image 2c ethnicities appear to be more prone to elastic tissue and solar elastotic syndromes. J Am Acad Dermatol 2004 Jul; 51(1):1-21. Images 2a-c: A Verhoeff-van Gieson its development. Due to the asymptom- 8. Pui JC, Arroyo M, Heintz P. J Drugs Dermatol. 2003 Jan; stain confirms elastic origin of fibers, atic nature of linear focal elastosis, many 2(1):79-83. 9. Palmer J, Madison KC, Stone MS. Asymptomatic linear revealing long and short, haphazardly patients may not seek care and simply go bands across the back. Linear focal elastosis. Arch Der- arranged elastic fibers in the mid and undiagnosed. It is important to recognize matol 1995 Sep; 131(9):1070-4. 10. White GM. Linear focal elastosis: a degenerative or regen- lower dermis. this entity and distinguish if from other erative process of striae distensae? J Am Acad Dermatol forms of dermal elastosis for both clinical 1992 Sep; 27(3):468. 11. Moiin A, Hashimoto K. Linear focal elastosis in a young and patient reassurance. black man: a new presentation. J Am Acad Dermatol 1994 May; 30(5 Pt 2):874-7.

44 LINEAR FOCAL ELASTOSIS IN A YOUNG HISPANIC MALE: A NEW PRESENTATION 12. Trueb RM, Fellas AS. Linear focal elastosis (elastotic striae). Hautarzt 1995 May; 46(5):346-8. 13. Vogel PS, Cardenas A, Ross EV, Cobb MW, Sau P, James WD. Linear focal elastosis. Arch Dermatol 1995 Jul; 131(7):855-6. 14. Tamada Y, Yokochi K, Ikeya T, Nakagomi Y, Miyake T, Hara K. Linear focal elastosis: a review of three cases in young Japanese men. J Am Acad Dermatol 1997 Feb; 36(2 Pt 2):301-3. 15. Breier F, Trautinger F, Jurecka W, Honigsmann H. Linear focal elastosis (elastotic striae): increased number of elas- tic fibres determined by a video measuring system. Br J Dermatol 1997 Dec; 137(6):955-7. 16. Chang SE, Park IJ, Moon KC, Koh JK. Two cases of linear focal elastosis (elastotic striae). J Dermatol 1998 Jun; 25(6):395-9. 17. Choi SW, Lee JH, Woo HJ, Park CJ, Yi JY, Song KY, Kim HO. Two cases of linear focal elastosis: different histo- pathologic findings. Int J Dermatol. 2000 Mar; 39(3):207-9. 18. Ramlogan D, Tan BB, Garrido M. Linear focal elastosis. Br J Dermatol 2001 Jul; 145(1):188-90. 19. Pec J, Chromej I. Linear focal elastosis: what's new? J Eur Acad Dermatol Venereol 2004 May; 18(3):247-9. 20. Whalen JG, English JC. Case study on linear focal elasto- sis. Dermatol Nurs 2006 Oct; 18(5):246-8. 21. Kossard S. Pseudoxanthoma-like late-onset focal dermal elastosis. Aust J Dermatol 2005; 46:47-50.

FEINSTEIN, SKOPIT 45 AMYOPATHIC DERMATOMYOSITIS ASSOCIATED WITH MYELODYSPLASTIC SYNDROME

David B. Roy D.O.,* Don A. Anderson D.O., F.A.O.C.D., F.A.S.M.S** *Dermatology resident, 2nd year, Kingman Regional Medical Center, Midwestern University **Program Chairman, Kingman Regional Medical Center, Midwestern University

ABSTRACT

Amyopathic dermatomyositis (ADM) is a subset of dermatomyositis in which biopsy-proven cutaneous findings are demonstrated for six months or greater with no clinical or laboratory findings of muscle involvement. The association between classic dermatomyosi- tis and myelodysplastic syndrome (MDS) is rare. We report a case of ADM associated with myelodysplastic syndrome. To our knowl- edge, this is the first reported case of ADM associated with MDS. The identification of any autoimmune phenomenon is crucial to the management of patients with MDS, as they generally will have a poorer prognosis than those without an autoimmune component.

Case Report patient was referred to internal medicine for an occult malignancy workup which Table 1 A 73-year-old Caucasian male presented included a colonoscopy, bronchoscopy, to the clinic with a four-month history of upper endoscopy, and CT scans of head, Diagnostic criteria for ADM erythematous patches involving his face, neck, chest, and abdomen. The colonos- as proposed by Euwer and hands, chest, back, elbows, and knees. The copy revealed four hyperplastic polyps, Sontheimer onset of these patches was slow and asymp- all of which were removed at the time of tomatic. The patient denied any fatigue, the procedure. The remaining tests were $VUBOFPVTDIBOHFT muscle weakness, myalgias, arthralgias, unremarkable. pathognomonic of CDM fever, or other constitutional symptoms. He Due to the lack of symptoms, it was felt )JTUPQBUIPMPHJDBMDIBOHFT was an avid golfer and spent a great deal of that systemic immunosuppressive therapy consistent with CDM time outdoors. He reported a worsening of was not warranted, and the patient was /PDMJOJDBMGJOEJOHTTVHHFTUJWFPG the erythema with sun exposure. educated on the importance of sun avoid- proximal muscle weakness within Physical exam revealed a healthy male ance and regular follow-up visits. Topical two years of skin disease appearing younger than stated age. Of note corticosteroids were prescribed, and the were erythematous patches with subtle patient was monitored closely. At his /PSNBMTLFMFUBMFO[ZNFMFWFMTGPS areas of atrophy involving his forehead, three-month follow-up visit, the patient two years after development of skin neck, chest, and upper back. Erythematous complained of cosmetic concerns with disease patches with fine overlying scale were noted regards to the rash involving his face and on his elbows and knees. A heliotrope rash hands and stated that he desired more was noted, as were clinical Gottron’s papules aggressive treatment. After obtaining a Discussion and periungual telangiectasias. Mild tender- consult with ophthalmology, the patient was Due to the dynamic nature of the disease, ness to palpation was noted in the region of started on Plaquenil 200mg twice daily. amyopathic dermatomyositis (ADM) is the left deltoid; however, this was attrib- Minimal response was noted at three difficult to characterize. ADM, as defined by uted to a recent golf injury. The remaining months, and at six months a mild pancy- Sontheimer, is a subset of dermatomyositis physical exam was noncontributory. topenia was noted. The Plaquenil was in which biopsy-proven cutaneous-findings Laboratory evaluation revealed a mildly discontinued. Three months later, the are demonstrated for six months or greater decreased hematocrit at 39.3%. The pancytopenia continued to worsen. Iron with no clinical or laboratory findings of remainder of the CBC, as well as a CMP, levels, TIBC, folate, and B-12 were all muscle involvement. Exclusion criteria sedimentation rate, CPK, and aldolase within normal limits. However, his TSH was include the use of drugs that are known were all normal. His chest X-ray was elevated at 6.63 mU/L, and anti-thyroglob- to cause skin changes resembling classical unremarkable. ANA, SSA, SSB, anti-Jo-1, ulin and anti-microsomal antibodies were dermatomyositis (CDM) at the onset of skin anti-dsDNA, anti-Smith, anti-scl70, and positive at 287 IU/ml and 47 IU/ml, respec- findings, and the use of systemic immu- anti-RNP antibodies were all negative. A tively. The patient was referred to endocri- nosuppressives for two months or longer G6PD level was within normal limits. In nology for evaluation. There, a diagnosis within the first six months after the onset addition, two 4-millimeter punch biopsies of subclinical autoimmune thyroiditis was of skin findings.1 Euwer and Sontheimer revealed epidermal atrophy, a thickened made; however, this did not explain the suggested four criteria for the diagnosis of basement membrane with mild interface worsening pancytopenia. ADM (Table 1).2 Stonecipher et al. offered changes, and perivascular and perifollicular Upon referral to hematology, a bone- three group descriptions to distinguish infiltrate. Direct immunofluorescence marrow biopsy was performed and was patients with ADM, as did Kovacs and revealed linear IgG 1+ at the DE junction, consistent with myelodysplastic syndrome Kovacs.3-4 For the purposes of this article, linear IgA 1+ at the DE junction, and IgM (MDS). To our knowledge, this is the first Sontheimer’s definition and Euwer and 3+ colloidal bodies at the DE junction. reported case of ADM associated with MDS. Sontheimer’s diagnostic criteria have been Based on the clinical, laboratory, and It is important to note that the pancytopenia used. pathological findings, a diagnosis of amyo- developed approximately one year after the Sontheimer also offered definitions for pathic dermatomyositis was made. The onset of the cutaneous symptoms. other dermatomyopathies. While most

46 AMYOPATHIC DERMATOMYOSITIS ASSOCIATED WITH MYELODYSPLASTIC SYNDROME Targoff et al. reported that in 16 of 18 IU/I, while ANA, RF, and anti-Jo-1 were patients with amyopathic dermatomyositis, all reported as negative. Initially failing Table 2 autoantibodies to the Se protein and the to respond to systemic corticosteroids, Dermatologic manifestations 155-kd protein were identified. None were the addition of azathioprine resulted in a associated with MDS found to be positive for Jo-1 or Mi-2.6 reversal of her autoimmune symptoms.9 Gerami et al. reported that calcinosis is Approximately 10%-13% of patients with Leukocytoclastic vasculitis rare. Malignancy and lung-disease asso- MDS will display some form of autoim- gangrenosum ciations were similar to CDM, but, in mune phenomenon. Of these, systemic Bullous pemphigoid contrast, there was a low rate of positive vasculitis appears to be the most common. anti-Jo-1 antibody in ADM associated with Autoimmune manifestations associated Vitiligo lung disease. Lung disease was reported in with MDS have been classified into five Lupus erythematosus 13% of patients, and internal malignancy groups:1 acute systemic vasculitis or autoim- 4KPHSFOTTZOESPNF was reported in 14%.5 It is important to mune disorder,2 chronic or isolated auto- note that potentially fatal interstitial lung immune phenomena,3 classical connective 3BZOBVETQIFOPNFOPO disease has been reported in association tissue disorders,4 immune-mediated hema- Relapsing polychondritis with ADM.7 Hisopathological and immu- tological abnormalities, and5 asymptomatic Dermatomyositis nofluorescent findings currently do not serological immunologic abnormalities. Anaphylactoid purpura allow for a distinction between CDM and Several dermatologic manifestations have ADM. CPK is the best initial test for muscle been associated with MDS. These are Xerotic dermatitis involvement. EMG and MRI appear to summarized in Table 2.11-15 Thrombophlebitis have a higher sensitivity than muscle biopsy Shimamoto et al. analyzed, specifically, Erythema nodosum for identifying muscle involvement due to autoantibodies and dermatologic manifesta- ADM. In terms of muscle involvement, it is 4XFFUTTZOESPNF tions in 22 patients with MDS. Five patients recommended that if CK and physical exam were found to be positive for autoanti- vulgaris are negative for evidence of muscle involve- bodies and dermatoses. One demonstrated Microscopic polyangiitis ment, no further workup is warranted. a positive ANA, while four had a positive reticularis However, it is important to repeat enzymes rheumatoid factor. No other autoanti- and exams regularly.5 bodies were found to be present.12 Other Reports of the coexistence of dermato- autoantibodies that have been reported are beyond the scope of this paper, three myositis and myelodysplastic syndrome are in MDS include rheumatoid factor, ANA, are of importance. Confirmed amyo- limited. In 2003, Tsuji et al. described a alloantibodies, antiglobulins, ANCA, lupus pathic dermatomyositis is defined as the patient presenting with CDM and MDS/ anticoagulant, anti-mitochondrial anti- presence of amyopathic dermatomyositis myelofibrosis concurrently. The patient body, anti-microsomal antibody, and anti- for 24 months or longer. Hypomyopathic described had positive laboratory and smooth-muscle antibody. Cryoglobulins, dermatomyositis (HDM) is diagnosed in clinical findings of muscle involvement. cold agglutinins, hypogammaglobulinemia, patients with the classical findings of DM Laboratory evaluation revealed elevated hypergammaglobulinemia (polyclonal and with no clinical evidence of muscle involve- AST, LDH, CK, aldolase, CRP, and ferritin, monoclonal), positive Coombs test, and ment but with positive evidence of muscle and a positive ANA. Anti-RNP, anti-Scl decreased levels of C3 and C4 have also involvement on laboratory, electrophysi- 70, and anti-Jo-1 antibodies were nega- been reported.11-13 ological or radiologic evaluation. Finally, tive. Initially resistant to monotherapy clinically amyopathic dermatomyositis with systemic corticosteroids, the patient Conclusion (CADM) encompasses both AMD and responded well to the addition of metho- HDM, with the essential element being that trexate 5mg/week.7 The identification of any autoim- the predominant component of the disease In 2006, Muslimani et al. reported a mune phenomenon in patients with is skin involvement.1 case of a 62-year-old female with CDM MDS is crucial to their management, as The most comprehensive review of ADM and myelofibrosis. CPK, LDH, aldolase, these patients generally will have a poorer was reported by Gerami et al. in 2006. Two myoglobin, AST, and ALT were elevated, prognosis than those without an autoim- hundred and ninety-one patients were with evidence of anemia and thrombocy- mune component. The role of amyopathic identified as having CAMD. The average topenia. No comment was made on the dermatomyositis in MDS is unclear, and is age of these patients was 50, and there was patient’s ANA or other extractable nuclear rarely reported. At this time, the patient a female-to-male predominance of 3:1. antigens. An electroneuromyogram of reported herein has had an unremarkable The average duration of skin involvement the deltoid and tensor fascia lata revealed course; however, his prognosis remains without clinical muscle involvement was evidence of an inflammatory myopathy, guarded. 3.74 years. Seventy percent of the patients 5 polymyositis or CDM, and a muscle biopsy were Caucasian. demonstrated perivascular lymphocytes References With regard to laboratory evaluation 1. Euwer RL, Sontheimer RD. Amyopathic dermatomyositis: consistent with CDM. Treatment consisted a review. J Invest Dermatol 1993;100:S124-7. of these patients, 63% were ANA positive. of 40mg of oral prednisone daily, to which 2. Gerami P, Schope JM, McDonald L, et al. A systematic Only 3.5% of patients were aAnti-Jo-1 anti- 8 review of adult-onset clinically amyopathic dermatomyosi- the patient responded well. tis (dermatomyositis sine myositis): A missing link within body positive, but overall reporting was low, In 2006, Ito et al. reported a case of a the spectrum of the idiopathic inflammatory myopathies. J and as a whole, myositis specific antibodies Am Acad Dermatol 2006;54(4):597-613. 74-year-old female with CDM associated 3. Ito A, Umeda M, Koike T, Naruse S, Fujita N. A case of (Jo-1 and Mi-2) were typically negative. with chronic idiopathic myelofibrosis dermatomyositis associated with chronic idiopathic myelo- ESR was elevated in 25% of patients. Anti- fibrosis. Rinsho Shinkeigaku. 2006 Mar;46(3):210-3. (CIMF). Her skin disease developed three 4. Kovacs SO, Kovacs SC. Dermatomyositis. J Am Acad double-stranded DNA, anti-Smith, Ro and years after her diagnosis of CIMF. Muscle Dermatol 1998;39:899-922. La antibodies were negative in the majority 5. Modiano P, Riechert S, Barbaud A, et al. Bullous pem- involvement was apparent both clinically phigoid in association with cutaneous lesions specific to a of patients.5 myelodysplastic syndrome. Brit J Dermatol 1997;136(3): and serologically. CK was elevated at 1,757 402–5.

ROY, ANDERSON 47 6. Muslimani A, Ahluwalia MS, Palaparty P. Idiopathic myelo- fibrosis associated with dermatomyositis. Am J Hematol- ogy 2006 Jul;81(7):559-60. 7. Novaretti MCZ, Sopelete CR, Velloso ERP, et al. Immuno- hematological Findings in Myelodysplastic Syndrome. Acta Haematologica 2001;105:1-6. 8. Saif MW, Hopkins JL, Gore SD. Autoimmune phenomena in patients with myelodysplastic syndromes. Leukemia and Lymphoma 2002;43(11):2083-2092. 9. Shimamoto Y, Narisawa Y, Suga K, Yasutake T, Kohda H, Yamaguchi M. Relationship between autoantibody and dermatosis in myelodysplastic syndrome. Haematologia (Budap) 1993;25(4):253-61. 10. Shirota T, Hayashi O, Uchida H, et al. Myelodysplas- tic syndrome associated with relapsing polychondri- tis: Unusual transformation from refractory anemia to chronic myelomonocytic leukemia. Annals of Hematology 1993;67(1):45-47. 11. Sontheimer, RD. Would a new name hasten the accep- tance of amyopathic dermatomyositis (dermatomyositis sine myositis) as a distinctive subset within the idiopathic inflammatory dermatomyopathies spectrum of clinical ill- ness? J Am Acad Dermatol 2002;46:626-36. 12. Sontheimer RD, Miyagawa S. Potentially fatal interstitial lung disease can occur in clinically amyopathic dermato- myositis. J Am Acad Dermatol 2003;48:797-8. 13. Stonecipher MR, Jorizzo JL, White WL, et al. Cutane- ous changes of dermatomyositis in patients with normal muscle enzymes: dermatomyositis sine myositis? J Am Acad Dermatol 1993;28:951-6. 14. Targoff IN, Trieu EP, Sontheimer RD. Autoantibodies to 155 KD and Se antigens in patients with clinically-amyo- pathic dermatomyositis. Arthritis Rheum 2000;43(Suppl 9):S194. 15. Tsuji G, Maekawa S, Saigo K, et al. Dermatomyositis and Myelodysplastic Syndrome with Myelofibrosis Responding to Methotrexate Therapy. Am J Hematol 2003;74:175-178. Now you can treat acne wherever it pops up.

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50 ATYPICAL : A CASE REPORT PERIANAL BASAL CELL CARCINOMA: A CASE REPORT

Andrea Passalacqua, D.O.,* Ronald Liskanich, D.O.,** Gloria Stevens, M.D.,*** David Horowitz, D.O.**** **2nd-year 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 ***Clinical Assistant Professor at LAC-USC Medical Center, Los Angeles, CA ****Dermatology Residency Program Director at Western University/Pacific Hospital of Long Beach, Long Beach, CA

ABSTRACT

We report the case of an 80-year-old Caucasian male with a basal cell carcinoma (BCC) on the perianal region. BCC on the perianal region is extremely rare and is generally not an aggressive tumor. Clinical and histopathologic findings are described along with the differential diagnosis for such a lesion in the perianal region. The patient was treated with a trial of imiquimod, but ultimately required surgical excision to provide adequate treatment.

Case Report: nuclei, and fibrotic stroma with mucin deposition (Figures 2 and 3). A PAS stain An 80-year-old Caucasian male presented failed to demonstrate any fungal organisms. with a rash located in the perianal area The patient was diagnosed with having a of approximate six-month duration. He perianal basal cell carcinoma. Because of initially complained of a pimple-like lesion the location of the lesion, the slides were with intermittent bleeding and tender- sent out for an additional dermatopa- ness. The patient was unsure if he had thology consultation. That diagnosis was scratched the area at night while sleeping felt to be basal cell carcinoma with striking and admitted to excessive wiping after isthmic and superficial follicular differen- bowel movements. He denied any history tiation, with possible concurrent squamous of tanning-bed use or nude sunbathing. His cell carcinoma in situ. primary-care physician treated the area with The topical medicines already prescribed accuzyme (a debriding agent) and nystatin were discontinued immediately given the powder; however, there was no improve- histopathology. Options were discussed ment. Past medical history included pros- with the patient regarding surgical excision tate cancer, neurodermatitis, psoriasis, and versus a trial with topical imiquimod. Based Figure 1 eczema. The prostate cancer was staged at on his age and the extent of the surgical T2N0M0 and treated with Lupron injec- excision required to remove the lesion in tions. No radiation therapy was adminis- its entirety, the patient opted for a trial of tered. The patient had no significant family topical treatment first. history of skin disease. The patient was instructed to apply On physical examination, the patient imiquimod three to five times per week at was found to have a perianal, erythematous night to the lesion for approximately three plaque measuring 5cm x 7cm, with whitish, months. Due to the expected irritation serpiginous borders. Some nodularity was resulting from imiquimod, the medication also noted (Figure 1). was discontinued intermittently to minimize Initial treatment included desonide discomfort. The perianal lesion appeared to cream and ketoconazole cream twice daily be slightly receding, and a decrease in the to the perianal area. A bacterial culture nodularity was noted (Figure 4). The area was performed, which showed E. coli and was re-biopsied and still showed perianal basal cell carcinoma, extending to the Klebsiella pneumoniae, and the appropriate Figure 2 oral and topical antibiotics were given. peripheral margins. Since it was unclear if the erythematous Since there seemed to be no resolution with the hair follicle. Risk factors in the lesion extended into the rectum, and with of the basal cell carcinoma, the patient was development of basal cell carcinoma include his history of prostate cancer, he was sent to offered the option to undergo either Mohs ultraviolet radiation, radiation therapy, a a gastroenterologist for a colonoscopy. The micrographic surgery or radiation. He positive family history of BCC, immunosup- colonoscopy demonstrated severe perianal opted for Mohs surgery and is currently pression, skin types I and II, and a history dermatitis and internal hemorrhoids, and undergoing treatment. of blistering sunburns in childhood. BCC aggressive wound care was recommended. is a slow-growing skin cancer that locally The area was treated with desoximeta- Discussion invades, extending over time, and eventually sone 0.25% cream and vusion ointment can become ulcerative. Patients typically do (miconazole nitrate, zinc oxide, and white Basal cell carcinoma (BCC) is the most not feel any pain, but will often state that petrolatum). common cancer and accounts for more the lesion bleeds intermittently. As the BCC A punch biopsy was performed to rule than 75% of all non-melanoma skin cancers spreads, it may form serpiginous patches. out intertrigo (versus psoriasis). The biopsy diagnosed in the United States each year.1-2 Metastasis is extremely rare, but has been showed interconnecting thin cords of basa- The origin of the tumor is in the basal cell reported to occur.2 loid cells contiguous with the epidermis, layer of the epidermis and appears to arise Basal cell carcinoma occurs most often in prominent palisading of the peripheral from immature pluripotent cells associated the elderly population on the sun-exposed

PASSALACQUA, LISKANICH, STEVENS, HOROWITZ 51 chronic eczematous changes in the perianal region, it is important to differentiate them from benign processes. The differential diagnosis of chronic perianal dermatitis includes the following: anal intraepithe- lial neoplasia, verrucous carcinoma of the perianal region, extramammary Paget disease, Langerhans cell histiocytosis, and cutaneous T-cell lymphoma.6 In addi- tion, basal cell carcinoma must be distin- guished from basaloid carcinoma of the anus. Histologically, the two are similar; however, basaloid carcinoma of the anus is more aggressive, metastasizes early, can be fatal, and requires different therapy.7 The monoclonal antibody Ber-EP4 is a positive marker for perianal basal cell carcinoma and can be useful in differentiating it from Figure 3 basaloid carcinoma of the anus.3 BCC of the perianal region is approximately 15-fold less common than squamous cell carcinoma in the same area.8 Considering this differen- tial diagnosis, biopsies and histopathologic examination are recommended in order to avoid delays in the diagnosis and treatment of such lesions. Even though perianal basal cell carcinoma is a rare tumor, the diagnosis alone should prompt physicians to thoroughly examine the patient to ensure detection of other possible basal cell carcinomas on the body. Perianal BCC has not demonstrated to be Figure 4 an aggressive neoplasm compared to BCC on other areas of the body. Local excision areas, such as the head and neck. BCC of the lesion has proved to provide adequate occurring on non-sun-exposed areas is very therapy.9 Mohs micrographic surgery may rare. There have been fewer than 200 cases be preferred for treatment of this area for of BCC in the perianal and genital regions tissue preservation and if the histology is reported, accounting for less than 1% of more aggressive.1 Other therapy options all basal cell carcinomas.1 Perianal basal are localized radiation and electron therapy. cell carcinoma accounts for only 0.2% of Perianal basal cell carcinoma has a good the anorectal tumors.3 Perianal BCC can prognosis, but strict follow-up is recom- often be misdiagnosed as an inflammatory mended because of the possibility of local or infectious and incor- recurrence.10 rectly treated. Patients affected by perianal BCC tend to be middle-aged to elderly. References: There may be a delay in seeking treatment 1. Gibson GE, Ahmed, I. Perianal and genital basal cell car- because of the location of the lesion and the cinoma: A clinicopathologic review of 51 cases. J Am Acad thought that it may be temporary irritation. Dermatol 2001; 45(1):68-71. 2. James WD, et al. Basal cell carcinoma. Andrews’ Dis- Therefore, these lesions on average are large eases of the Skin, Clinical Dermatology, Tenth edition. in size and ulcerated. It is recommended Canada. Saunders; 2006. pp.646-650. 3. Alvarez-Canas C, et al. Perianal basal cell carcinoma: A 1 that a biopsy of the site be performed. comparative histologic, immunohistochemical, and flow cytometric study with basaloid carcinoma of the anus. Am Histologic subtypes of basal cell carci- J Dermatopathol 1996; 18(4): 434-443. nomas include nodular, superficial, 4. Bolognia JL, et al. Basal cell carcinoma. Dermatology, 1st edition. London. Mosby; 2003. pp.1687-1693. micronodular, infiltrating, morpheaform, 5. Soeprono FF. Basal cell carcinoma. A systemic approach and fibroepithelioma of Pinkus. Nodular to dermatopathology: A color atlas 1st edition. Soeprono; 2006. pp. 327. BCC is the most common subtype, 6. Wacker, J, Hartschuh W. Differential diagnosis of chronic comprising more than 60% of all tumors, perianal dermatitis. Premalignant and malignant disorders. Hautarzt 2004; 55:266-272. with superficial BCC being the second 7. Damin DC, et al. Perianal basal cell carcinoma. J Cutan most common type.4 Histologic features of Med Surg 2002; 6(1):26-28. 8. Augey F, et al. Perianal basal cell carcinoma. Apropos of 2 basal cell carcinoma include the presence of cases. Ann Dermatol Venereol 1994; 121:476-478. necrosis en masse, dyskeratosis, prominent 9. Paterson CA, Young-Fadok TM, Dozois RR. Basal cell carcinoma of the perianal region: 20-year experience. Dis palisading of peripheral nuclei, predomi- Colon Rectum 1999; 42(9):1200-1202. nance of basaloid lobules over stroma, and 10. Montagliani L, et al. Perianal basal cell carcinoma. Presse clefts between neoplastic aggregates and the Med 2004; 33(6):389-390. stroma.5 Since certain neoplasms, both premalig- nant and malignant, can clinically mimic

52 PERIANAL BASAL CELL CARCINOMA: A CASE REPORT DERMOSCOPY FOR NON-MELANOCYTIC LESIONS

Lynora Curtis Bassett, D.O.,* Brad P. Glick, D.O., M.P.H., F.A.O.C.D.** *3rd-year Resident, Wellington Regional Medical Center, Lake Erie College of Osteopathic Medicine, Dermatology Residency Program, Wellington, FL **Residency Director, Wellington Regional Medical Center, Lake Erie College of Osteopathic Medicine, Dermatology Residency Program, Wellington, FL

ABSTRACT

Dermoscopy is primarily used to evaluate pigmented skin lesions, to improve clinical differential diagnosis, and to aid in the early detection of melanoma in situ and malignant melanoma. Dermoscopy can also be used to evaluate non-melanocytic lesions and increase the accuracy of a clinical diagnosis. This paper will look at the history and principles of dermoscopy, describe the value of using a dermatoscope in daily patient care, and present the dermoscopic features of non-melanocytic lesions. The non-melanocytic lesions reviewed include: , solar lentigo, basal-cell carcinoma, squamous-cell carcinoma, dermatofibroma, and vascular lesions

Introduction uate skin capillaries, , , morphological basis of skin color, and study When assessing cutaneous lesions for melanocytic nevi. Saphier was the first to removal/biopsy, evaluation with the naked describe the globules that are still used in eye is limited to characteristics such as size, the modern classification.1 Dermoscopy shape, color, symmetry, elevation, and - was first applied in the United States in ation of the lesion. This limitation is due to 1922 by Michael, a Houston dermatolo- the reflection, refraction, and deflection of gist, and further developed by Goldman in light off the lesion’s stratum corneum. The the 1950s.1 In 1971, Rona MacKie differ- clinical evaluation and diagnosis of a lesion entiated for the first time between benign can be improved by using a tool called a and malignant pigmented skin lesions.1 In dermatoscope. This tool uses polarized 1990, Bahmer et al. described the features light to allow the observer to see additional in pigmented lesions and correlated them features inside the lesion and beyond what with underlying histology. That paper was Figure 1 is appreciated with the naked eye or simple the first to standardize terminology used in Dermoscopy of a seborrheic keratosis magnification. Dermoscopy is primarily dermoscopy.2 The work has continued over Sharp borders, -like openings, used for the evaluation of pigmented the years in Europe and in the United States. and milia-like cysts lesions to improve clinical differential diag- Dermoscopy, also known as epilumines- Courtesy of Harold Rabinovitz, M.D. nosis while looking for features of malig- cence microscopy (ELM), dermatoscopy, nant melanoma or early melanoma in situ. and amplified skin surface microscopy, is Dermoscopy can be used for non-melano- becoming more widely accepted. Although cytic lesions as well. Non-melanocytic there have been many terms used for lesions have characteristic features appreci- looking at the skin surface, currently ated with the dermatoscope that help to “dermoscopy” is the favored term in the differentiate benign from malignant. These United States. features aid the clinician in setting up a framework to determine which lesions to Principles of Dermoscopy biopsy, saving the patient from unnecessary biopsies and scars. When a lesion is examined with the naked eye, visible light is reflected by the The History of Dermoscopy stratum corneum, and only certain features such as size, shape, color, symmetry, eleva- The idea of looking “into” the skin tion, and ulceration can be appreciated. surface has been around for a long time. When an immersion liquid (mineral oil, Skin surface microscopy started with Peter alcohol, water, gel) is applied to the skin Borrelus in 1655 and Johan Kolhaus in 1663 surface, it reduces the air pockets in the Figure 2 to investigate the small vessels in the nail stratum corneum, which in turn reduces Dermoscopy of a solar lentigo bed and nail fold using a microscope.1 In the reflection, refraction, and diffraction of Faint, irregular, “finger-print” like 1893, Unna transferred the application of light.3 The immersion liquid with magni- network and “moth-eaten” borders immersion oil in microscopy to skin-surface fication allows the observer to evaluate the Courtesy of Harold Rabinovitz, M.D. microscopy, recognizing that the oil made structures and features of the lesion at the the upper layer of the epidermis more trans- dermal-epidermal junction and papillary lucent.1 Over the next 25 years, monocular dermis.4 In addition, a flat surface can be and binocular capillary microscopes were examined when the glass of the dermato- built that also allowed 10-172x magnifi- scope is used to compress the skin surface. cation of the skin. In Germany, Johann An alternative to direct-contact dermoscopy Saphier used the term “dermatoscopy” is to use a dermatoscope with polarized in 1920 for the first time.1 He applied a light. The cross-polarized lens absorbs all binocular microscope primarily to eval- the scattered incident light that is reflected

BASSETT, GLICK 53 quick, and convenient to use. A derma- toscope is useful to confirm a clinical diagnosis while examining a patient or to aid in the evaluation of a lesion that has clinical uncertainty. It can be looked at as the bridge between clinical inspection with the naked eye and histopathological interpretation with a microscope. After the reflection of visible light is removed from a lesion, the clinician is able to “look into the lesion.” The features within the lesion can help distinguish between benign lesions Figure 3 Figure 6 (seborrheic keratosis, lentigo, compound Dermoscopy of basal-cell carcinoma Dermoscopy of a dermatofibroma , blue nevus, hemangioma) and Blue-gray ovoid nest, congealed blood, Central depigmentation and peripheral malignant lesions (early melanoma in situ, arborizing telangiectasias, pink-white delicate network malignant melanoma, basal-cell carcinoma, areas, absence of pigment network Courtesy of Harold Rabinovitz, M.D. squamous-cell carcinoma). On the one Courtesy of Harold Rabinovitz, M.D. hand, it may save a patient an unneces- sary biopsy; and on the other hand it may save a patient’s life. It also has value in differentiating between melanocytic lesions, such as nevi, and non-melanocytic lesions such as solar lentigos, seborrheic keratoses, and even pigmented basal-cell carcinoma. Vascular lesions can be evaluated with the dermatoscope to confirm a clinical diag- nosis. In addition, capillary microscopy can aid in early detection of systemic connective-tissue disease when inspecting the nail folds for vascular changes such as telangiectasias.1 Inflammatory lesions such Figure 7 Dermoscopy of a vascular lesion as psoriasis can be seen more clearly. It has Multiple, well-demarcated, red-to-blue- even aided in the location of a foreign body, Figure 4 red lacunae throughout lesion such as a thorn, that can’t be visualized with Dermoscopy of basal-cell carcinoma Courtesy of Harold Rabinovitz, M.D. the naked eye. The dermatoscope is a useful Spoke-wheel pattern (“Rabinovitz tool for the clinician to have at his disposal sign”). to quickly give additional information when off the surface while allowing transmission Courtesy of Harold Rabinovitz, M.D. examining a patient. The application of of the light waves oscillating in one plane.3 such a tool requires training, and with expe- Although not required, it is often beneficial rience it becomes invaluable. to use immersion fluid with a polarized dermatoscope. Non-melanocytic Lesions The Dermatoscope The non-melanocytic lesions whose dermoscopic features will be discussed in The most popular type of dermatoscope is detail include the following: seborrheic the hand-held one. It is light-weight, conve- keratosis, solar lentigo, basal-cell carcinoma, nient, and easily fits into a clinician’s pocket. pigmented basal-cell carcinoma, squamous- It is equipped with a transilluminating light cell carcinoma, dermatofibroma, and source and standard magnifying optics.3 vascular lesions including hemangioma. Light sources tend to be halogen or LED (light emitting diode). It is battery powered, Seborrheic keratoses. Seborrheic kera- and the magnification is usually 10-fold.5 toses are benign lesions that tend to have a Several of the handheld units have a cross- “stuck-on” appearance. They can vary in polarization lens that eliminates the need size, shape, and color. The borders tend to Figure 5 for a liquid interface or direct contact with be sharply demarcated. Although the diag- Dermoscopy of squamous-cell the skin.6,7 Other types of dermoscopic nosis of these lesions tends to be straight- carcinoma. Glomeruli vessels and forward, clinical uncertainty can arise when erythema equipment include binocular stereomicro- scopes, as well as electronic dermatoscopes the lesion is heavily pigmented, simulating Courtesy of Harold Rabinovitz, M.D. a melanoma, or early in its evolution, with and without computer link and 8 analytic algorithms. Further advancement mimicking a solar lentigo. Dermoscopy is in the field of “algorithmic dermoscopy” valuable in confirming that the distinctive involves the use of multispectral dermos- features are those of a seborrheic keratosis copy imaging systems for computer analysis and not those of an atypical melanocytic of dermoscopic images.3 lesion. Early seborrheic keratoses are sharply demarcated with moth-eaten borders and a fingerprinting or network- The Value of Dermoscopy like pattern.8 Features include comedo-like Dermoscopy is a tool that is noninvasive, openings (crypts) -- ovoid craters that have

54 DERMOSCOPY FOR NON-MELANOCYTIC LESIONS black or brown comedo-like plugs. These dermoscopically, dots in a pigmented basal- When hemangiomas or angiokeratomas plugs correlate histologically to keratin-filled cell carcinoma are due to small amounts become thrombosed, they can have a dark invaginations of the skin surface.8 Milia- of pigment in the dermis. Globules and blue-black color and resemble a melanoma like cysts, whitish-yellow circular structures, ovoid nests are due to large deposits of (Figure 14).6,11 Dermoscopy will differen- correlate histologically to intraepidermal, pigment in the dermis. Blue-gray globules tiate these benign vascular lesions from keratin-filled cysts (Figure 1).8 Fissures are smaller than ovoid nests. Ulceration nodular melanoma and save the patient an (a.k.a. “valleys” or “sulci”), linear depres- appears as congealed blood with dermos- unnecessary biopsy. sions within the lesion, correlate with deep, copy, and there should be an inquiry about a keratin-filled invaginations of the epidermis. history of trauma to the lesion.9 Arborizing Conclusion These produce either a network or cribi- telangiectasias are multiple branching blood form pattern.8 They may also be seen vessels in a tree-like pattern9 resulting from In summary, the history, principles and in congenital melanocytic lesions. Ridges the dilated arterial circulation that feeds tools of dermoscopy were presented here. (“mountains”) on either side of a fissure the tumor.4 Arborizing vessels are 99% The value of dermoscopy for non-melano- and can be hypo- or hyperpigmented. specific4 and are seen in both pigmented cytic lesions was discussed, and the features These ridges or “gyri” have also been called and non-pigmented basal-cell carcinomas.9 of several non-melanocytic lesions that “fat fingers.” Multiple sulci and gyri give a Structureless, pink-white to white shiny can be appreciated using a dermatoscope seborrheic keratosis a “cribiform” or “brain- areas are another common feature in basal were reviewed. Dermoscopy adds valu- like” appearance.6 Hairpin blood vessels cell carcinomas (Figure 3).4 Other char- able additional information to the clinical tend to be clustered in seborrheic keratoses, acteristic findings of pigmented basal-cell picture of a lesion and increases the accu- with each one surrounded by a whitish carcinomas include the leaf-like pattern and racy of a clinical differential diagnosis in halo, mainly at the periphery of the lesion. spoke-wheel pattern.9 The leaf-like pattern the ultimate distinction from, or determina- They correspond to long capillary loops is usually brown or blue-gray in color and tion of, a malignant melanoma. Although commonly seen in keratinizing tumors.6 has the appearance of a maple leaf due to the dermoscopic features of melanocytic Although hairpin vessels may be associated discrete, bulbous extensions connected to lesions including melanoma are outside the with seborrheic keratoses, they can also be a base.9 The spoke-wheel pattern has a scope of this commentary, it must be said seen with some melanomas. Dermoscopy central point of dark brown, blue, or black, that there is great satisfaction in finding will aid in the important differentiation with well defined tan, blue, or gray radial melanoma in situ or malignant melanoma of uncertain seborrheic keratoses from projections (Figure 4).9 lesions by simply assessing the lesion with melanoma, especially when a patient may Squamous cell carcinoma. Squamous- the dermatoscope and having a firm belief have hundreds of seborrheic keratoses and cell carcinoma lacks all the features of or suspicion that a clinically benign lesion performing numerous biopsies is unrealistic melanocytic lesions. It has characteristic must be biopsied. and unappealing. glomeruli vessels and erythema (Figure 5). Solar lentigines. Solar lentigines are Dermatofibromas. Dermatofibromas Acknowledgment benign lesions found predominantly on are benign dermal nodules. Although the I wish to sincerely thank Dr. Harold sun-exposed areas. They are induced by UV exact etiology is unknown, a dermatofi- Rabinovitz for his review of this manuscript, exposure and persist indefinitely.8 They are broma is thought to arise from trauma to insight, and assistance with the dermoscopic formed from increased accumula- the skin, such as an arthropod bite. It tends images. I also sincerely thank Dr. David tion in hyperplastic keratinocytes and can to be a firm solitary nodule on the lower Alperstein for his review and support in the evolve into a seborrheic keratoses.8 The extremity that “dimples” when squeezed preparation of this manuscript. borders are sharply demarcated, curved, laterally.10 Patients come to the office irregular, and “moth-eaten.”8 There may be concerned about these benign lesions after the appearance of a network that is faint, noticing them. The dermoscopic features References: irregular, or “finger-print” like (Figure 2). include a central depigmented area due to 1 .Stolz W, Braun-Falco O, Semmelmayer U, Kopf AW. His- 10 tory of Skin Surface Microscopy and Dermoscopy. Atlas Many of these lesions have structureless fibrosis in the lesion. In the surrounding of Dermoscopy: Taylor & Francis. 2004. p. 1-2 areas that are light brown and void of a periphery, there may be a tan-to-dark- 2. www.rcsed.ac.uk/fellows/marcmoncrieff,logbook/thesis/ 6,8 ch2.pdf p.6 [THIS URL DOES NOT WORK] network or structure. In addition to the brown delicate network of pigmentation 3. Sanchez Negron FA, Kopf AW, Marghoob AA. Dermos- previous features, lentigines on the face and resulting from hyperpigmentation (rather copy and Beyond: The Instruments. The Evolution from 6,8 the Dermoscope to Computer Analysis of Dermoscopic scalp may also have a pseudonetwork. Ink than from melanocytic proliferation) of Images. Atlas of Dermoscopy: Taylor & Francis. 2004. p. spot lentigos have a black-pigmented, thick the basal layer (Figure 6).6,10 Although 13-14 4. Johr R, Soyer HP, Argenziano G, Hofmann-Wellenhof R, or thin network that ends abruptly at the usually structureless, brown globule-like Scalvenzi M. Dermoscopy The Essentials: Mosby. 2004. edge of the lesion.8 They exhibit an absence structures or blood vessels may be found p. 1 5. Binder M, Braun RP. Principles of Dermoscopy. Atlas of of other structures and melanoma-specific in the area. In melanocytic lesions, Dermoscopy: Taylor & Francis. 2004. p. 7-9 criteria and tend to be located on the upper globules are due to nests of , 6. Mulvehy J, Puig S, Braun RP, Margoob AA, Kopf AW. 4 Handbook of Dermoscopy: Taylor & Francis. 2004. p. viii trunk and extremities. but in dermatofibromas the globules are 7. DermLite Brand Dermatoscopes. Official Web site. www. Pigmented and non-pigmented due to flat, confluent, and hyperpigmented dermlite.com 10 8. Wang SQ, Rabinovitz H, Oliviero MC. Dermoscopic Pat- basal-cell carcinoma. Dermoscopy can rete ridges. terns of Solar Lentigines and Seborrheic Keratoses. Atlas help differentiate pigmented basal-cell Vascular Lesions. Vascular lesions, of Dermoscopy: Taylor & Francis. 2004. p. 60-61 9. Polsky D. Pigmented Basal Cell Carcinoma. Atlas of Der- carcinoma from other pigmented lesions, such as hemangiomas, have a character- moscopy: Taylor & Francis. 2004. p. 55-56 and non-pigmented basal-cell carcinoma istic dermoscopic pattern of multiple, 10. Katz B, Rao B, Marghoob AA. Dermatofibroma. Atlas of Dermoscopy: Taylor & Francis. 2004. p. 81-82 from nevi, sebaceous-gland hyperplasia, well demarcated, red-to-blue-red or blue- 11. Katz B, Rao B, Marghoob AA. Vascular Lesions, Heman- melanoma, fibrous papules, and seborrheic black-to-maroon, round-to-oval lacunae giomas/Angiokeratomas. Atlas of Dermoscopy: Taylor & Francis. 2004. p. 72-73 11 keratoses. In pigmented basal-cell carci- (Figure 7). These lacunae are diagnostic 12. Bolognia JL, Jorizzo JL, Rapini RP. Dermatology: Mosby. noma, the melanin pigmentation is irregu- when there is an absence of criteria for a 2003. Volume Two. p. 1799-1800 larly deposited in dermal melanophages, melanocytic lesion such as a pigmented tumor melanocytes, and tumor cells.9 Since network, globules and/or branched streaks.6 the pigment is deep in the dermis and not When the vascular lesion with lacunae is located in the rete ridges of the epidermis, accompanied by hyperkeratosis, the lesion there is no pigment network.9 Viewed is considered to be an angiokeratoma.

BASSETT, GLICK 55 SENTINEL LYMPH NODE BIOPSY FOR CUTANEOUS MALIGNANT MELANOMA: A REVIEW OF THE RATIONALE, CRITERIA, PROCEDURE, AND CONTROVERSIES

Raymond Ramirez, D.O.,* Cindy Hoffman, D.O., F.A.O.C.D.,** Charles Gropper, M.D.*** *PGY-4, Lutheran Medical Center, Department of Dermatology, Brooklyn, NY **Dermatology Residency Program Director, Lutheran Medical Center, Dept. of Dermatology, Brooklyn, NY ***Director - Department of Dermatology, Saint Barnabas Hospital, Bronx, NY

ABSTRACT

Cutaneous malignant melanoma remains a major public health threat worldwide. Nodal metastasis (Stage III disease) occurs in 15% to 20% of intermediate-thickness melanomas and, alongside tumor thickness and ulceration, has profound prognostic impact. Sentinel node biopsy has become the de facto standard of care, but it remains the topic of controversy and heated debate. The purpose of this article is to familiarize ourselves, as dermatologists, with the rationale, criteria, procedure, and controversies of the sentinel lymph node biopsy.

Introduction Cutaneous malignant melanoma remains a major public health threat worldwide. According to CDC estimates, there will be an expected 59,940 new cases and 8,110 deaths due to melanoma in the United States in 2007.1 As dermatologists, we are on the front- line of efforts to contain this threat. Data has shown some positive effects of these efforts, with melanomas being detected earlier and thinner, and hence with greater rates of survival. The majority of cutaneous melanomas are curable with wide resection.2 Figure 1 Nodal metastasis (Stage III disease) does Stage III (nodal) Metastatic Disease: occur, however, in 15% to 20% of interme- Tumor cell emboli travel from the diate-thickness melanomas.3 The importance primary cutaneous tumor site (arrow of nodal metastatic involvement cannot be head) via cutaneous lymphatic vasculature to regional nodal basin overstated. Nodal metastatic involvement, (arrow). in addition to tumor thickness and ulcer- Tumor emboli may also form metastatic ation, has profound prognostic impact, with foci along the route of drainage WHICH Figure 2 a significant difference in five-year survival are defined as in-Transit metastasis. between patients with occult, microscopic Sappey’s line and Midline areas of ambiguous lymphatic drainage. nodal metastases (one node with microscopic ment of occult nodal metastatic (Stage III) Sappey’s line is described as a band metastasis: 52%) versus patients with clini- disease (Figure 1). In 1892, Snow put forth of ambiguous lymphatic drainage, cally palpable nodal metastasis (one node the theory that melanoma spreads from its 4 approximately 5cm in width at the with clinical metastasis: 29%). To address the primary site in the skin via the lymphatic level of the umbilicus and extending 5 risk of nodal metastasis, melanomas of suffi- vasculature to a draining nodal basin. In around the back at the level of L2. The cient thickness or displaying other so-called 1874, Sappey published a detailed descrip- midline of the trunk is another area high-risk features have been evaluated tion of the lymphatic vascular anatomy.6 The of ambiguous drainage approximately initially by elective lymph node dissection expectation that metastatic melanoma cells 5cm in width on the anterior and (ELND) and later by sentinel lymph node will follow an orderly progression of spread posterior midline trunk. Lesions biopsy (SLNBx). In its most current form, the via lymphatics, and that these lymphatic within Sappey’s line may drain in a sentinel-node biopsy has become the de facto channels can be accurately predicted, led cephalic, caudal, or both directions, standard of care in the medical community. to the practice of prophylactic dissection while midline lesions may drain to In spite of its widespread usage, the proce- of suspected nodal basins to detect occult the right, left, or both sides. Lesions dure remains the topic of controversy and disease. It was hoped that occult metastatic within the intersection of these two heated debate. The purpose of this article is to disease could not only be detected, but that zones (umbilical, mid-back at L2) have familiarize ourselves, as dermatologists, with a surgical cure might be achieved. In prac- the potential for drainage in all four the rationale, criteria, procedure, and contro- tice, this procedure is the elective lymph directions. versies of the sentinel lymph node biopsy. node dissection (ELND). With elective lymph node dissection demonstrate a survival benefit only in Rationale (ELND), primary cutaneous melanomas selected patient populations -- specifically, that are considered of sufficiently high males aged 60 years or less with primary enough risk are evaluated for occult nodal melanoma tumor thicknesses of 1.1mm Nodal metastasis and elective lymph to 2mm.7 The remainder of patients is node dissection spread via prophylactic dissection of the suspected draining nodal basin. While subjected to significant morbidity, such as The core concept behind both ELND intended to both detect and possibly cure chronic lymph edema, without a demon- and SLNBx is the detection and manage- occult metastatic disease, analyses of ELND strable survival benefit. In addition, ELND

56 SENTINEL LYMPH NODE BIOPSY FOR CUTANEOUS MALIGNANT MELANOMA Some institutions will also include features such as high mitotic rate, vertical growth phase, and vascular involvement in their inclusion criteria. Tumors with undeter- mined Breslow thickness due to extensive regression or involvement of the deep tumor margin may also be considered for SLNBx. The 2007 NCCN (National Compre- hensive Cancer Network) recommends the discussion of lymphatic mapping and SLNBx in patients with melanomas >1mm Breslow thickness or in patients with lesions <1mm Breslow thickness but with other adverse histologic findings such as Clark level IV or V, ulceration, or high mitotic rate.15 Procedure Once the initial diagnosis of malignant melanoma is made, our role as dermatolo- gists becomes more limited in scope. By Figure 3 the above criteria, our role for the treat- Watershed areas of lymphatic drainage Figure 4 Overview of the steps involved in ment of melanoma would be limited to a were found to be far more extensive wide re-excision of primary tumors that and unpredictable than Sappey’s line SLNBx are less than 1mm Breslow thickness and and the Midline would indicate. Within node(s), much less-invasive surgery is these areas of the mid-line, trunk, and lacking in adverse histologic features such required, with completion of dissection as ulceration, Clark level IV or V, deep the head and neck, lymphatic drainage only occurring if metastases are found on may be multi-directional. margin involvement, and extensive regres- histologic evaluation. SLNBx also has the sion. Beyond this, the surgical treatment of is not suitable for the evaluation of mela- advantage of identifying drainage patterns the melanoma falls under the purview of nomas that are located in areas of ambig- in ambiguous or so-called “watershed” areas surgeons and nuclear medicine physicians. of the body. Early descriptions of these areas uous or multiple draining patterns such as There are a number of in-depth articles of ambiguous drainage include Sappey’s the head and neck or midline trunk. These detailing the technique(s) for SLNBx.11,13,16-18 line and the midline (Figure 2). The limited areas of ambiguous drainage patterns will This section will summarize the key steps be discussed at length later in the article. predictability of lymphatic drainage leads to limitations regarding when and where of the procedure (Figure 4). ‘Sentinel node’ and sentinel lymph the ELND is the appropriate procedure. Lymphoscintigraphy node biopsy Studies of lymphatic mapping, however, have demonstrated even more variability At present, there is no FDA-approved The sentinel node is described as the first in lymphatic drainage than early lymphatic radiocolloid for use in SLNBx. In the United 99m 99m node to receive lymphatic drainage, and diagrams would suggest.12 The watershed States, Technetium-sulfur colloid ( Tc- thus tumor emboli, from the primary tumor areas of lymphatic drainage have been sulfur colloid) is generally the radiocolloid site. Studies have shown the presence or shown to be unpredictable to as far as 10 of choice. It has a particle size that varies absence of metastatic tumor cells within this cm away from the traditional Sappey’s and from 50nm to 2,000nm (mean: 300nm). sentinel node to be indicative of the status midline areas (Figure 3).13,14 Some authors advocate 0.2μm filtration 8 prior to injection, which decreases particle of the remainder of the basin’s nodes. Through intraoperative lymphatic size to below 200nm.19 Early research in lymphatic mapping mapping, the lymphatic drainage pattern of for solid tumors was carried out for penile melanomas can now be traced even within Injection of the radiocolloid is performed 9 carcinomas by Cabanas. Later studies, these ambiguous areas. There is improved preoperatively. Injections are performed however, failed to show improved survival. accuracy in defining and evaluating the intradermally to ensure entry into the The procedure of choice for malignant most likely involved lymph node(s) (i.e. draining lymphatic channels. A 25- to melanoma, meanwhile, remained ELND. the sentinel node). A completion of nodal 27-gauge needle is used to inject small Investigation of the sentinel lymph node in dissection is only performed for the approx- volumes (0.05 to 0.2mL) in the immediate relation to malignant melanoma was intro- imately 20% of cases where metastatic vicinity of melanoma tumor (if present) or 10 duced by Morton et al. in 1992. Initial involvement is detected. The remaining narrow excision scar. Enough radiocolloid 20 studies by Morton et al. using vital blue ~80%, meanwhile, will have undergone a is injected to raise a small wheal at the site. dye demonstrated an accuracy rate of 82% much less invasive procedure with minimal The number and exact location of the injec- 11 in identifying the sentinel lymph node. morbidity. tions depend on the location of the tumor. With the later addition of radiocolloid Once the radiocolloid is injected, and lymphoscintigraphy, nodal identifica- Criteria dynamic and static images are taken via a tion rates as high as 99% accuracy were high-resolution gamma camera (Figures obtained.8 Criteria for SLNBx vary among different 5 and 6). Dynamic images are taken over institutions. In general, SLNBx is offered for 20 to 30 minutes to demonstrate path of Sentinel node biopsy versus elective patients with a melanoma primary tumor lymphatic drainage and receiving nodal lymph node dissection >1mm in Breslow thickness, or less than basin. This is very useful in areas of ambig- SLNBx provides a number of advantages 1mm if there is involvement of Clark level uous drainage, as discussed earlier, in which over ELND. Since SLNBx allows for iden- IV or V (i.e. reticular dermal or subcuta- the lymphatics may drain to totally unex- tification of specific draining (sentinel) neous involvement) or tumor ulceration. pected sites. It is also useful for detecting

RAMIREZ, HOFFMAN, GROPPER 57 Figures 5&6: Conceptual illustrations: Dynamic and static images of the Figure 7 radiocolloid as it travels from the injection site (arrowhead) to the sentinel lymph Evaluation and Treatment algorithm node (arrow) in the regional nodal basin. following completion of SLNBx. drainage to so-called in-transit or interval additional confirmation of the appropriate Further treatment decisions lymph nodes, nodes that exist outside of node(s) to be dissected out. This section discusses the steps required regional basins. Static images are also taken In most cases, only one sentinel node is following the SLNBx (Figure 7). of all possible draining basins to detect identified, though in some cases, two or 20 Once a patient is found to have micro- possible radiotracer deposits. Once the more sentinel lymph nodes are revealed. scopic nodal metastases, the next step is the draining nodal basins have been identified The surgeon may also remove incidental complete dissection of the involved nodal on lymphoscintigraphy, surface markings lymph nodes that are encountered during are made on the patient’s skin, tracing the basin. The intent of complete lymphadenec- the dissection of the sentinel node. These lymphatic drainage route(s) to the receiving tomy is to determine whether there may be “non-sentinel” nodes are also examined for basin(s). These act as anatomic guides to further metastatic nodal involvement and help guide the surgeon. tumor involvement. to possibly affect a surgical cure (i.e. no As demonstrated earlier, nodal drainage Histopathologic examination evidence of further metastatic disease). In may be ambiguous, with multiple or unusual the majority of cases (~80%), no further Different sectioning techniques are sites of drainage. A number of studies have nodal involvement is discovered, while the used in different centers. In their multi- been performed, investigating the possible remaining 20% will have one or more addi- center trial, Morton et al. standardized the 24 discrepancies between the expected sites tional nodes with metastatic foci. sectioning technique in the participating of lymphatic drainage and sites of actual The patient will also require evaluation MSLT centers. Their technique advocates involvement. Discordant findings are most for possible distant metastatic involvement first bisecting the lymph node in the longest often observed in the head/neck region as (i.e. Stage IV disease). Different centers may dimension. Following fixation, 10 serial well as on the trunk. Doris et al. noted that have their own protocols for a metastatic sections are obtained. Sections 1, 3, 5, and 43% of preoperative head/neck lymphos- work-up, but should include imaging studies possibly section 10 are stained with hema- cintigraphy identified a sentinel node in a such as CT scans of the chest, abdomen, and toxylin-eosin (H&E). Section 2 is stained basin not clinically predicted.21 Leong et al. pelvis, an MRI scan of the brain, liver ultra- with S-100 protein, and section 4 is stained found an overall discordance of 19.5%, with sonography, and a whole body PET scan or with HMB-45 antigen. Sections 6 and 7 are the highest rate in the head/neck region the new CT-PET scan. Each modality has used as negative controls for immunoperox- (36.7%) and the trunk (25.3%).22 its advantages and idiosyncrasies, which are idase studies, while sections 8 and 9 are kept beyond the scope of this article. Laboratory 8 Blue-dye injection, wide re-excision, in reserve for possible additional staining. evaluation includes liver function studies and nodal dissection Histopathologic evaluation of the and LDH, as well as a complete blood count. resected lymph nodes is performed with Confirmed findings, indicating distant Vital blue dye is not used by all surgeons routine H&E staining as well as immunohis- metastatic disease, changes the treatment performing SLNBx. Its primary usefulness tochemical staining with HMB-45 antigen options for the patient yet again. is in allowing for an additional method of and S-100 protein. H&E staining has a If the metastatic work-up proves nega- visually identifying the receiving node(s). detection sensitivity of one melanoma cell tive, however, the patient may be considered Complication risks of using vital blue dye per 10,000 background cells, while S-100 for stage III (nodal) disease protocols. The include “tattooing” of the skin at the injec- protein has been shown to detect one mela- only FDA-approved treatment for stage III tion site and allergic reaction to the dye.23 noma cell per 100,000 background cells.16 disease is interferon α2b therapy for one The blue dye is injected approximately Immunohistochemistry techniques improve year. There are also experimental treatment five to 15 minutes prior to wide-re-excision detection over routine H&E staining, but protocols in multiple centers around the of the primary tumor site and nodal basin they have also led to some controversy. In country. A list of nearly 200 experimental some cases, H&E staining will be negative, exploration. This allows time for the dye to trials, their locations, and inclusion criteria while immunohistostaining may be positive. drain to the sentinel node.18 are listed on the National Cancer Institute This raises the question of what to do with An incision is performed over the area (NCI) Web site: http://www.cancer.gov/ a patient who is H&E negative and S-100 clinicaltrials. of nodal drainage as indicated by lympho- positive. Some centers consider this to be a Should the SLNBx findings demonstrate scintigraphy. A hand-held gamma probe is positive SLNBx, while others do not. used to detect the area of highest radioac- no microscopic metastatic involvement, Some centers also perform RT-PCR anal- the patient will be considered as having tivity (counts per second). If vital blue dye ysis for detection of so-called “submicro- has been used, the afferent lymphatics and only local involvement (Stages I and II), scopic” metastases. RT-PCR is not, however, with adequate treatment and requiring no lymph node may be stained blue, giving widely in use.

58 SENTINEL LYMPH NODE BIOPSY FOR CUTANEOUS MALIGNANT MELANOMA these tidings, we will be expected to explain Table 1 the diagnosis and advise our patients on what they should do next. It is this advice Adapted from Rousseau et al. stratification of SLNBx positive cases that brings the controversy over SLNBx into according to: Breslow thickness and AJCC tumor (T) staging criteria.27 sharp perspective. This section will attempt to address the Tumor Thickness % SLNBx Positive outstanding questions that both the patient and dermatologist may have: NN  What is the likelihood of the SLNBx oNN  being positive? oNN  s !NUMBEROFSTUDIES BOTHSINGLEAND NN  multi-institution, have been performed with varied database sizes and results. In the largest recent multi-institutional study AJCC T-staging % SLNBx Positive (Multicenter Selective Trial, or MSLT), sentinel node positivity 5B  was found to be 19.4% with the initial SLNBx for melanomas of 1.2mm to 5C  3.5mm thickness.26 Other studies have 5B  noted similar percentages. Rousseau et al. stratified 1,375 SLNBx patients according 5C  to the 2002 AJCC staging system. They found that 16.9% of patients had posi- 5B  tive SLNBx results. They further stratified 5C  these positive findings according to 2002 AJCC staging (Table 1).27 5B  What are the risks or side effects (i.e. 5C  morbidity) associated with SLNBx? s 4HEREPORTEDRATEOFSEQUELAEFROM3,."X Table 2 is significantly lower than the older ELND procedure. Sequelae include reactions to Adapted from Morton et al. evaluation of patients with at least 1 vital blue dye (as previously mentioned), complication in dissected nodal basins during SLNBx.28 , seroma, nerve injury, wound infection, and wound dehiscence. Complication Number and %Occurrence Morton et al. examined the rate opera- tive morbidity with SLNBx versus SLNBx 8PVOE4FQBSBUJPO   plus completion of lymph node dissec- 4FSPNB)FNBUPN   tion. The overall rate of morbidity in 937 SLNBx patients was 10.2%. A stratifica- *OGFDUJPO   tion of these complications is listed below (Table 2).28 5PUBM   What is the chance of the test being further surgery. These patients will require Questions and wrong and missing the melanoma? regular follow-up and observation to detect Controversies s &ALSENEGATIVEFINDINGS ASDEMONSTRATED future recurrences of melanoma. In a review by recurrence of metastases in the SLNBx- of 1,019 patients undergoing axillary or SLNBx has become widely available and is negative nodal basin, have been noted in inguinal lymphadenectomy for mela- the de facto modality of choice for the eval- various studies. The rate of false negative noma, 80% of recurrences occur within cases was also evaluated by Morton et al. 25 uation of possible microscopic nodal meta- two years of surgery. Late recurrences of static disease. Nevertheless, SLNBx remains in the MSLT-1 trial. They found 59 cases disease, however, may occur years later. For a topic of intense controversy. Opponents to of regional nodal recurrence out of 944 this reason, most centers and physicians SLNBx have voiced objection to subjecting SLNBx-negative patients, meaning a total have observation protocols that start with patients to a surgical procedure that has not, rate of 6.3%. Eighty-one percent of these frequent, regular follow-up examinations to date, demonstrated a benefit to overall recurrences (48 patients) occurred in the (every three to four months) and annual patient survival. Likewise, the literature (as sentinel node draining basin, while the studies such as a chest X-ray and laboratory well as any large discussion among derma- remaining 11 patients had recurrences in tests. Over the next several years, the follow- tologists) is replete with anecdotal accounts nodal basins that had not been sampled.28 up visits are spaced farther apart (every six of patients who underwent SLNBx only s %XPLANATIONS FOR THIS FALSE NEGATIVE months to one year). All melanoma patients to suffer melanoma recurrence and death. phenomenon are varied. One possible should, however, be seen on an annual basis This controversy is, of course, more than a explanation is related to the injection for the rest of their lives. This is not only for subject of statistical debate. As dermatolo- process. When the radiocolloid (and the detection of recurrent and metastatic gists, we are the physicians most likely to possibly vital blue dye) is injected at the disease, but also to detect future additional diagnose our patients’ melanoma and are primary melanoma site, care must be primary melanomas. likewise the ones who will have to break taken to ensure that the injectant is placed the news of their diagnosis. As the bearer of in the correct area to be picked up by the

RAMIREZ, HOFFMAN, GROPPER 59 correct draining lymphatic channels. This tions have examined the impact of SLNBx NCT00297895. It is hoped that this trial procedure, obviously, is operator depen- on disease-free survival, disease-specific may finally answer the outstanding ques- dant, requiring the requisite experience. survival, and of course overall survival. tion of whether SLNBx has a positive In the MSLT trial, Morton et al. noted a Findings in some institutions have shown prognostic impact. learning curve of 30 training cases before a positive prognostic impact,30,31 while operators were considered proficient others have not.32,33 Conclusion at performing SLNBx.26 As a practical s -ORTONETALRECENTLYPUBLISHEDTHETHIRD matter for us, the referring dermatolo- of five interim analyses for the MSLT. It has been repeatedly demonstrated that gists, we should be sure that the prospec- This multi-institution, international trial SLNBx is a reproducibly accurate modality tive surgeon has experience (>30 cases) examined 1,269 patients with melanomas for identifying microscopic nodal meta- with malignant melanoma. of 1.2mm to 3.5mm Breslow thickness. static melanoma. It is a procedure with a s 0ROPERPLACEMENTOFRADIOCOLLOIDAND Patients were randomly assigned to either low incidence of morbidity, yet it offers a vital blue dye is also affected by the a wide excision and sentinel node biopsy statistically significant survival advantage condition of the primary site. If the arm (60%) or wide excision and nodal to those patients for whom it really matters: tumor is still present, or if there has been observation arm (40%). Patients of the patients with nodal metastatic involvement. only minimal surgical alterations of the sentinel node arm with positive SLNBx Nevertheless, the debate over SLNBx will, no site, the lymphatic vasculature is less underwent immediate complete lymph- doubt, continue. It is hoped that this article likely to have been altered. If, however, adenectomy (CLND). Patients of the will help to clarify the issues surrounding a wide local excision with or without observation arm underwent CLND only SLNBx and help us, the dermatologists, to tissue transfer, such as a flap, has been if clinically palpable nodes were noted on educate our patients so they can make truly performed, the lymphatics may be altered follow-up examination. Findings in this informed decisions in their treatment. to the point that the dye may no longer interim analysis noted a five-year disease- be reliable for locating the “true” sentinel free survival of 78.3 ± 1.6% for the SLNBx References: lymph node. As such, it behooves us, the arm versus 73.1 ± 2.1% for the observa- 1. Jemal A, Siegel R, Ward E, Murray T, Xu J, Thun MJ. Can- cer Statistics, 2007. CA Cancer J Clin. 2007;57(1):43-66. dermatologists, to perform the minimal tion arm (95% CI, P = 0.0009). Overall 2. Essner, R. Surgical treatment of malignant melanoma. amount of surgery required to diagnose survival between the two study arms was Surg Clin N Am (2003)109-156. 26 3. Morton DL, Thompson JF, Cochran AJ., et al. Sentinel- the melanoma without significant tissue not statistically significant. One possible Node Biopsy or Nodal Observation in Melanoma. N Engl alteration. explanation for this finding, described J Med 2006;355:1307-17. 4. Balch CM, Soong SJ, Gershenwald JE, et al. Prognostic s !SSUMING THE PROPER NODES ARE by Balch, is the “dilutional” effect of the Factors Analysis of 17,600 Melanoma Patients: Validation dissected, there remains the possibility 84% of patients who never had nodal of the American Joint Committee on Cancer Melanoma Staging System. J Clin Oncol 2001;19:3622-3634. for metastases to be missed. In a perfect metastatic involvement, making it prob- 5. Snow H. Melanotic cancerous disease. Lancet 1892;2:872. world, pathologists would serially section lematical to demonstrate an overall 6. Thompson JF, Uren RF, Coventry BJ. Lymphoscintigra- phy, In: Balch Cm, Houghton AN, Sober AJ, eds. Cutane- and review the entire sentinel node spec- survival advantage in the remaining 16% ous Melanoma. 4th ed. St. Louis, Mo: Quality Medical imen. This is, however, impractical if not of patients with nodal metastases.34 In Publishing Inc; 2003:329-352. 7. Balch CM, Soong SJ, Bartolucci AA, et al. Efficacy of an impossible. Sectioning and staining tech- the patient subset with nodal metastatic elective regional lymph node dissection of 1 to 4 mm thick niques have been discussed previously. involvement, the sentinel node arm, with melanomas for patients 60 years of age and younger. Ann Surg 224:255-266, 1996. Even with such dramatic sensitivities, it is confirmed nodal metastasis and imme- 8. Morton DL, Thompson JF, Essner R. Validation of the still possible to simply “miss” the section diate CLND, had a significantly higher Accuracy of intraoperative Lymphatic Mapping and Sen- tinel Lymphadenectomy for Early-Stage Melanoma. Ann of the node that has the few metastatic survival rate (72.3 ± 4.6%) than those of Surg. 230:453-465, 1999. cells, thus leading to a falsely negative the observation arm with delayed CLND 9. Cabanas RM. An approach for the treatment of penile car- cinoma. Cancer 1977;39:456-66. report. (52.4 ± 5.9%). The survival difference 10. Morton DL, Wen DR, Wong JH, et al. Technical details may be related to amount of nodal tumor of intraoperative lymphatic mapping for early stage mela- s &INALLY THEQUESTIONOFhHEMATOGENOUS noma. Arch Surg 1992;127:392-9. spread” is often raised. If metastatic cells burden of each subgroup. In the SLNBx 11. Morton DL, Wen DR, Cochran AJ. Management of early- are able to penetrate lymphatic vascula- arm, the average burden was 1.4 lymph stage melanoma by intraoperative lymphatic Mapping and selective lymphadenectomy or “watch and wait.” Surg ture, then why might they not also be able nodes versus 3.4 lymph nodes in the Oncol Clin North Am 1992;1:247-59. to enter the capillary vasculature with observation arm.26 These findings are in 12. Norman J, Wells K, Kearney R, et al. Identification of lym- phatic basins in patients with cutaneous melanoma. Semin direct access to distant sites? Early studies keeping with survival statistics demon- Surg Oncol 1993;9:224-7. evaluating the spread of melanoma have strated by Balch et al. for the 2002 AJCC 13. Uren RF, Hoffman-Gile RB, Shaw HM, et al. Lymphos- cintigraphy in high-risk melanoma of the trunk: Predicting consistently demonstrated a predilection staging criteria, in which there was a draining node groups, defining lymphatic channels and for a stepwise spread from the primary significant survival decline in patients locating the sentinel node. J Nucl Med 34:1435, 1993. 14. Norman J, Cruse CW, Wells K, et al. A redefinition of skin cutaneous site to regional lymph nodes, with an increased number of involved lymphatic drainage by lymphoscintigraphy for malignant and then to distant sites. Cases of distant nodes or with macroscopic (i.e. clinical) melanoma. Am J Surg 162:432, 1991. 15. Houghton AN, Bichakjian CK, Coit DG, et al. NCCN Prac- spread without demonstrable nodal nodal metastases. tice Guidelines in Oncology: Melanoma, version 2.2007. involvement certainly occur, but only s 4HE-3,4))TRIALISCURRENTLYUNDERWAY Available at: http://www.nccn.org/professionals/physician_ gls/PDF/melanoma.pdf rarely. In a study of 243 SLNBx-negative The primary outcome measure for the 16. Glass FL, Cottam JA, Douglas S et al.: Lymphatic mapping patients with recurrence of their mela- trial is melanoma-specific survival, and sentinel node biopsy in the management of high-risk melanoma. Journal Amer Acad Derm Vol. 39 No. 4 part 1, nomas, nine patients (3.7%) developed defined as the time between the date of 603-610 distant metastases as their first site of randomization (or date of CLDN for 17. Mosca PJ, Tyler DS, Seigler HF, eds. Surgical manage- ment of cutaneous melanoma: current practice and impact 29 recurrence. One proposed explanation subjects in the CLDN arm) and the date on prognosis. Adv Surg 2004;38:85-119. for this is that shearing forces related to of death from melanoma. The follow-up 18. Edwards MJ, Martin KD, McMasters KM. Lymphatic map- ping and sentinel lymph node biopsy in the staging of entry and exit from the blood vasculature period extends to 10 years or the date of melanoma. Surg Oncol 1998;7:51-57. destroys metastatic cells before they have the subject’s death. Secondary outcome 19. Thompson JF, Uren RF, Coventry BJ. Lymphoscintigra- phy, In: Balch Cm, Houghton AN, Sober AJ, eds. Cutane- the chance to take hold. measures are disease-free survival and ous Melanoma. 4th ed. ST. Louis, Mo: Quality Medical recurrence during the 10-year follow-up Publishing Inc; 2003:329-352. 20. Mariani G, Gipponi M, Moresco L, et al. Radioguided What is the prognostic significance of period. Inclusion and exclusion criteria, Sentinel Lymph Node Biopsy in Malignant Cutaneous SLNBx? as well as participating centers, are listed Melanoma. J Nucl Med 43:811–827, 2002 on the National Institutes of Health Web 21. Doris L, Franc BL, Kashani-Sabet M, et al. Lymphatic s 4HISISPERHAPSTHEMOSTCONTENTIOUSISSUE drainage patterns of head and neck cutaneous melanoma site: http://www.clinicaltrials.gov/show/ observed on lymphoscintigraphy and sentinel lymph node concerning SLNBx. A number of institu- biopsy. Head & Neck Mar 2006:259-255

60 SENTINEL LYMPH NODE BIOPSY FOR CUTANEOUS MALIGNANT MELANOMA 22. Leong S, Achtem TA, Habib FA, et al. Discordancy between clinical predictions vs. lymphoscintigraphy and intraoperative mapping of sentinel lymph node drainage of primary melanoma. Arch Derm Vol 135(12):1472-1476, 1999 23. Leong, SP. Selective sentinel lymphadenectomy for malig- nant melanoma. Surg Clin N Am 83 (2003)157-185. 24. Gershenwald JE, Thompson W, Mansfield PF, et al. “Multi-Institutional Melanoma Lymphatic Mapping Experi- ence: The Prognostic Value of Sentinel Lymph Node Status in 612 Stage I or II Melanoma Patients.” J Clin Oncol.1999;17:976-983. 25. Gadd MA, Coit DG. Recurrence patterns and outcome in 1019 patients undergoing axillary or inguinal lymph- adenectomy for melanoma. Arch Surg 127:1412, 1992. 26. Morton DL, Thompson JF, Cochra AL, et al. Sentinel-Node Biopsy or Nodal Observation in Melanoma. N Engl J Med 2006;355:1307-17. 27. Rousseau DL, Ross MI, Johnson MM, et al. Revised American Joint Committee on Cancer Staging Criteria Accurately Predict Sentinel Lymph Node Positivity in Clini- cally Node-Negative Melanoma Patients. Ann Surg Oncol, Vol. 10, No. 5, 2003 28. Morton DL, Cochran AJ, Thompson JF, Et al. Sentinel node biopsy for early-stage melanoma: accuracy and morbidity in MSLT-I, an international multicenter trial. Ann Surg. 2005 Sep;242(3):302-11; discussion 311-3. 29. Gershenwald JE, Colome MI, Lee JE, et al. Patterns of recurrence following a negative sentinel lymph node biopsy in 243 patients with stage I or II melanoma. J Clin Oncol. 1998;16:2253–2260. 30. Yee VSK, Thompson JF, McKinnon JG, et al. Outcome in 846 cutaneous melanoma patients from a single center after a negative sentinel node biopsy. Ann Surg Oncol 12(6):1-11, 2005 31. Moehrle M, Schippert W, Rassner G, et al. Micrometas- tasis of a sentinel lymph node in cutaneous melanoma is a significant prognostic factor for disease-free survival, distant-metastasis-free survival, and overall survival. Der- matol Surg 2004;30:1319-1328. 32. Roka F, Kittler H, Cauzig P, et al. Sentinel node status is not predictive for overall survival upon multivariate analy- sis. Br J Cancer 92(4),662-667, 2005 33. Gutzmer R, Al Ghazal M, Geerlings H, et al. Sentinel node biopsy in melanoma delays recurrence but does not change melanoma-related survival: a retrospective analy- sis of 673 patients. Br J Dermatol 153,1137-1141, 2005 34. Balch CM, Cascinelli N. Sentinel-node biopsy in mela- noma. N Engl J Med 2006;355:1370-71. 35. Balch CM, Soong SJ, Gershenwald JE, et al. Prognostic Factors Analysis of 17,600 Melanoma Patients: Validation of the American Joint Committee on Cancer Melanoma Staging System. J Clin Oncol 19:3622-3634. 2001

RAMIREZ, HOFFMAN, GROPPER 61 MAKING SENSE OF THE PERFORATING DISORDERS: A REVIEW

Brett B. Bender, DO*, Michael J. Mahon, DO, FAOCD** *2nd-year Dermatology Resident, POH/BGH Consortium, Pontiac, MI **Program Director, POH/BGH Consortium, Pontiac, MI

ABSTRACT

The perforating disorders are classically grouped into four entities: Kyrle’s disease, perforating folliculitis, reactive perforating collagenosis and elastosis perforans serpiginosa. A thorough review of these entities is performed, including a historical review, epidemiology, etiology, clinical presentation, histopathologic features and treatment options.

Introduction and Coskey described PF, distinguishing end products in the dermis from elevated it from KD by the follicular unit being blood glucose levels, or the over-expres- The perforating disorders are a hetero- the primary focus of inflammation and sion of TGF-β3.1,15,19,20 4 geneous group of cutaneous dermatoses perforation. To muddy the waters even Clinical Presentation that share the transepithelial elimination further, another entity, called acquired of a dermal product. These disorders reactive perforating collagenosis (ARPC), Lesions of APD present as 2mm-8mm have been classically categorized into was suggested by Faver et al. in the JAAD hyperkeratotic papules with a central, four distinct entities: Kyrle’s disease in 1994 with a diagnostic criteria of: 1) cone-shaped plug. The lower extremities (KD), perforating folliculitis (PF), reac- eliminated necrotic collagen through a are the most common site of involvement, tive perforating collagenosis (RPC), and cup-shaped epidermis on histology; 2) followed by the upper extremities, trunk, elastosis perforans serpiginosa (EPS).1 umbilicated papules or nodules with a head and neck. The mucosal surfaces, This classification system, though, is not central keratotic plug clinically; and 3) palms and soles are typically spared. The without flaws. Specifically, Kyrle’s disease, age of onset after 18 years.5 Since the lesions can occur as a group of single folli- perforating folliculitis and acquired RPC naming of these entities, multiple authors cular or extra-follicular papules/nodules show overlapping clinical and histologic have concluded that each of these diseases or can coalesce into verrucous-appearing features as well as treatment options. most likely represents a variation of a plaques. Pruritus is variable, although To address this issue, the term acquired similar causative event and thus should excoriations are commonly appreciated, perforating dermatosis (APD) was all fall under the designation of APD. and the Koebner effect can be seen.1 2 suggested in the early 1990s. Epidemiology/Etiology Histopathology The goal of this manuscript is to provide a review of the perforating disor- APD is not an uncommon disorder. The classic finding is a keratotic plug, ders, including a brief historical review, It is typically seen in middle-aged with the apical portion of the plug epidemiology, clinical presentation, histo- individuals, with no gender or racial pointing toward the dermis, imbedded pathologic features and current treatment predominance. APD is not a primary in a cup-shaped epidermal invagination. options. Other cutaneous disorders that disorder, but instead is seen in asso- The keratotic plug contains parakeratosis may show transepithelial elimination of ciation with a systemic disease or prior and variable cellular debris, and occasion- dermal products will also be reviewed. pruritic cutaneous eruption. The most ally includes degenerated collagen and common association is with patients with elastin fibers. The presence of collagen Acquired Perforating diabetes mellitus and/or chronic renal and elastin fibers within the plug is not Dermatosis failure. Approximately 10% of patients a diagnostic criterion for APD, as most on hemodialysis for chronic renal failure lesions do not show evidence of elimi- 6 1 History are affected. Other associations include nation of this material. The presence sclerosing cholangitis and other hepatic of this material in the proper clinical The term acquired perforating diseases including hepatocellular carci- context should not dissuade the clinician dermatosis (APD) was coined in 1989 noma and hepatitis C, as well as HIV, in making the diagnosis of APD. to describe the findings previously seen hypothyroidism, hyperparathyroidism, A mixed inflammatory infiltrate of in PF, KD and the acquired version of healed lesions of herpes zoster, post lymphocytes, neutrophils and foreign RPC.2 All of these entities show similar laser hair removal, Hodgkin’s disease, body giant cells are seen at the base of clinical lesions, respond to similar treat- IgA nephropathy, pulmonary fibrosis, the disruption. If follicular structures ments and thus probably represent myelodysplastic syndrome, cutaneous are involved, the disruption normally variations of a similar etiology. Kyrle CMV infection and .1,7-18 The occurs at the infundibulum, and a coiled first described these lesions in 1919 in underlying etiology of this disease is still hair is often seen. Dyskeratotic keratino- a young diabetic female and dubbed unknown. Possible reasons why lesions cytes and vacuolization of the basal layer this entity “hyperkeratosis follicularis occur include: a reaction from chronic around the epidermal invagination can et parafollicularis en cutem penetrans,” pruritus/scratching, dermal microangiop- occur.1 which describes the clinical and histologic athy from diabetes leading to necrosis, features fairly accurately: hyperkeratosis, abnormal action of fibronectin within the Treatment follicular and peri-follicular inflamma- dermis, increased levels of matrix metal- Treatment for APD is frustrating for tion, and the perforation (penetration) of loproteinases, immature keratinization, the patient and for the physician. Topical a dermal substance.3 In 1968, Mehregan accumulation of advanced glycosylation therapies such as ultra potent corticos-

62 MAKING SENSE OF THE PERFORATING DISORDERS: A REVIEW teroids, the “soak and smear” method study with two patients diagnosed with elastin receptor that could result in the with mid-potency ointments, retinoids RPC.21 clinical findings.30 As with the other and bland emollients are first-line treat- Clinical Presentation perforating diseases, the role of focal irri- ments, but they rarely control all but tation of the skin cannot be discounted. the mildest forms of disease. Systemic The lesions of RPC present as small, EPS has been divided into three general options are varied, with no one treatment 1mm-10mm flesh-colored papules with categories. Type 1 EPS is the idiopathic considered effective in all patients. Oral a central umbilication and a keratin plug. type, with no associated systemic disease. antihistamines, oral retinoids, PUVA and The most frequent sites of involvement Type 2 is referred to as reactive EPS, with thalidomide have shown some success. are areas of high incidence of trauma: associated connective-tissue disease. A small study by Ohe et al. showed near dorsal hands, forearms, elbows and These associated diseases include: Down complete clearing of all lesions in five knees. Lesions classically occur after a syndrome (the most frequently associated patients after 10-15 treatments with superficial injury to the skin and then disease, with 1% of these patients showing NB-UVB at a starting dose of 400mJ/cm2 resolve spontaneously within six to eight EPS lesions), Ehlers-Danlos, osteogen- and a maximum dose of 1500 mJ/cm2.22 weeks, leaving behind a hypopigmented esis imperfecta, Marfan’s, Rothmund- Another option is allopurinol at a dose of scar. Koebnerization of lesions can be Thompson, acrogeria, systemic sclerosis, 100mg daily, which has shown, in multiple observed, although pruritus is often not , XYY karyotype, renal disease, separate case studies, marked improve- present.27 diabetes mellitus and .36,37,39 The ment in lesions within two weeks.23,24,41 Histopathology final category is type 3, which is associ- Doxycycline, at a dose of 100mg daily ated with penicillamine use for the treat- for 14 days, was shown in a case study Histopathology reveals a cup-shaped ment of Wilson’s disease, cystinuria or by Brinkmeier et al. to stop formation depression in an acanthotic epidermis, juvenile rheumatoid arthritis.31 of new lesions within five days and to filled with parakeratotic debris, degen- affect complete clearance of lesions by erated collagen and inflammatory cells, Clinical Presentation five months with the addition of a urea- similar to APD. What differentiates RPC Typically, EPS presents as 2mm-5mm, based cream.25 In patients with end-stage from APD is the presence of a thinned, flesh-colored-to-red papules with a central renal disease, skin lesions have cleared disrupted epidermis underlying the invagination, arranged in an arcuate-to- post renal transplant.2 In summary, only depression with thin, vertically oriented serpiginous manner and located on one small case reports exist that show agents streaks of basophilic collagen streaming region of the body. The most common beneficial in the treatment of this disease. into the depression.20 These vertically location is the nape of the neck, followed oriented collagen fibers are essential in by the face, upper extremities, lower Reactive Perforating making an RPC diagnosis. extremities and, rarely, the trunk. Lesions Collagenosis Treatment are often asymptomatic and run a vari- able course, lasting anywhere from six History Treatment options for RPC and APD months to five years and often resolving are quite similar. For most cases of RPC, spontaneously with scarring.31 Mehregan et al. first described the lesions are transient and asymptom- RPC in their article in the Archives of atic and may not require treatment at all. Histopathology Dermatology in 1967.26 Some authors In more resistant cases, topical retinoids The epidermis in EPD is acanthotic divide RPC into a rare genoderma- have shown some success. with hyperkeratosis. A central, narrow tosis with childhood onset and a more channel can be seen coursing through the common acquired form in adults associ- Elastosis Perforans epidermis in a follicular or parafollicular ated with renal disease and diabetes. As Serpiginosa location, giving a funnel or corkscrew-like previously discussed, the acquired form appearance. Parakeratosis, degenerated “fits” better under the label of APD, and History keratinocytes, inflammatory cells and, therefore the term RPC should refer to most important, elastic fibers are found the childhood-onset disease. EPS was first described in 1953 by within this channel. Chronic inflamma- Lutz, who dubbed the entity keratosis tion is seen at the base of the perforation Epidemiology/Etiology follicularis serpiginosa due to its clinical 28 with the presence of multinucleated giant RPC is a rare genetic disorder that appearance. In 1955, Meischer identi- cells, and increased amounts of elastic has shown autosomal-dominant, auto- fied elastin fibers penetrating into the fibers within the papillary dermis are seen somal-recessive and sporadic modes epidermis along with other degenerated with elastic stains.31 of inheritance.27 Onset of disease is in dermal material in these lesions, and early childhood, often before the age of suggested the name elastoma intrapapil- Treatment 29 five, and males and females are equally lare perforans verruciforme. Since then, Treatment options for EPS are varied. affected. Systemic disease is not known the name has been abbreviated to its Topical medications include potent corti- to be associated with the skin lesions, current form. costeroids, calcipotriene ointment, and although a case report of RPC in a child Epidemiology/Etiology glycolic and salicylic acids.31 A case report with the Treacher Collins syndrome was by Kelly and Purcell showed complete noted.42 One thought on the etiology of Young adults are the most common clearing of a chin lesion with daily use of this disease is that it is a reaction to super- portion of the population to be affected, imiquimod for six weeks and then three ficial trauma to the skin, as lesions often with a male-to-female ratio of 4:1. The times weekly for four weeks.32 Another appear in cold weather, after an insect bite etiology is unknown, but an autosomal- case study of two patients with EPS or in areas of folliculitis.27 Herzinger et al. dominant mode of inheritance has been 34 showed moderate improvement with suggest an alternate theory involving anti- suggested by one author. Fujimoto et nightly use of tazarotene 0.1% gel for bodies to type IV collagen, as shown via al., in the British Journal of Dermatology eight weeks, although the disease relapsed immunohistochemical staining in their in 2002, described a defect in the 67 kD

63 shortly after discontinuing the medicine.33 1989;125:1074-8. 36. Rosen LB, Muellenhoff M, Tran TT, Muhart M. Elasto- 3. Kyrle J. Hyperkeratosis follicularis et parafollicularis in sis perforans serpiginosa secondary to D-penicillamine Systemic treatments with oral isotretinoin cutem penetrans. Arch Dermatol Syphilol 1916;123:466. therapy with coexisting cutis laxa. Cutis 2005;76:49-53. 4. Mehregan AH, Coskey RJ. Perforating folliculitis. Arch 37. Mehta R, Burrows N, Payne C, Mendelsohn S, Pope F, and narrow-band UVB have shown some Dermatol 1968;97:394-9. Rytina E. Elastosis perforans serpiginosa and associated success. Destructive methods include 5. Faver IR, Daoud MS, Su WP. Acquired reactive perforat- disorders. Clin Exp Dermatol 2001;26:521-24. ing collagenosis. Report of six cases and review of the 38. Kaufman AJ. Treatment of elastosis perforans serpigi- cryotherapy, cellophane tape stripping, literature. J Am Acad Dermatol 1994; 30:575-580. nosa with the flashlamp pulsed dye laser. Derm Surg electrodessication and curettage and 6 .Hurwitz RM, Melton ME, Creech FT, Weiss J, Handt A. 2000;26:1060-2. 31 Perforating folliculitis in association with hemodialysis. Am 39. Barr RJ, Siegel JM, Graham JH. Elastosis perforans ser- laser therapy. The flashlamp pulsed dye J Dermatopathol 1982;4:101-8. piginosa associated with morphea. J Am Acad Dermatol laser seems to be the most effective laser 7. Briggs PL, Fraga S. Reactive perforating collagenosis of 1980;3:19-22. diabetes mellitus. J Am Acad Dermatol 1995;32:521-23. 40. Vearrier D, Buka RL, Roberts B, Cunnigham BB, Eichen- modality, according to two studies, while 8. Doshi SN, Levy ML, Markus R. Koebnerization of reactive feld LF, Friedlander SF. What is the standard of care in the perforating collagenosis induced by laser hair removal. evaluation of elastosis perforans serpiginosa? A survey of the Erbium:YAG and pulsed CO2 lasers Lasers in Surgery and Medicine 2003;32:177-79. pediatric dermatologists. Ped Dermatol 2006;23:219-24. have shown minimal benefit.35, 38 9. Yamashita N, Watanabe D, Ozawa H, Takama H, Tamada 41. Hoque SR, Ameen M, Holden CA. Acquired reactive Y, Hara K, Matsumoto Y. Reactive perforating collagenosis perforating collagenosis: four patients with a giant variant An important part of treating patients with cutaneous cytomegalovirus infection. Euro J Dermatol treated with allopurinol. Brit J Dermatol 2006;154:759-62. 2006;16:696-7. 42. Tay YK, Weston WL, Aeling JL. Reactive perforating with EPS is to recognize the possible asso- 10. Kilic A, Gonul M, Cakmak SK, Gul U, Demiriz M. Acquired collagenosis in Treacher Collins syndrome. J Am Acad ciation of a coexistent systemic disease. reactive perforating collagenosis as a presenting sign of Dermatol 1996;35:982-3. hepatocellular carcinoma. Euro J Dermatol 2006;16:447. 43. Sapadin AN, Lebwohl MG, Teich SA, Phelps RG, DiCon- Vearrier et al. performed a survey of pedi- 11. Karpouzis A, Tsatalas C, Sivridis E, Kotsianidis I, Mar- stanzo D, Cohen SR. Periumbilical pseudoxanthoma atric dermatologists in order to deter- garitis D, Kouskoukis C, Bourikas G. Acquired reactive elasticum associated with chronic renal failure and angioid perforating collagenosis associated with myelodysplastic streaks: apparent regression with hemodialysis. J Am mine the standard of care in evaluating syndrome evolving into acute myelogenous leukaemia. Acad Dermatol 1998;39:338-40. pediatric patients with lesions of EPS.40 Aus J Dermatol 2004;45:78-9. 44. Ratnavel RC, Norris PG. Perforating : 12. Bong JL, Fleming CJ, Kemmett D. Reactive perforating Response to treatment with isotretinoin. J Am Acad Der- The results of the study indicate that the collagenosis associated with underlying malignancy. Brit J matol 1995;32:126-7. Dermatol 2000; 142:390-1. 45. Ohnishi T, Nakamura Y, Watanabe S. Perforating pilo- history and physical exam of the entire 13. Rubio FA, Herranz P, Robayna G, Pena J, Contreras F, matricoma in a process of total elimination. J Am Acad patient should guide the clinician on Casado M. Perforating folliculitis: Report of a case in an Dermatol 2003;49:S146-7. HIV-infected man. J Am Acad Dermatol 1999;40:300-2. whether further workup, i.e. imaging or 14. Sehgal V, Jain S, Thappa DM, Bhattacharya SN, Logani K. blood work, should be obtained. The Perforating dermatoses: A review and report of four cases. J Dermatol 1993;20:329-40. routine ordering of lab tests in patients 15. Yanagihara M, Fujita T, Shirasaki A, Ishiguro K, Kawa- with EPS and no other stigmata is not hara K, Ueda K. The pathogenesis of the transepithelial elimination of the collagen bundles in acquired reactive warranted. perforating collagenosis. J Cutan Pathol 1996;23:398-403. 16. Tsuboi H, Mukuno A, Sato N, Katsuoka K, Yanasc N. Other Perforating Dermatoses Acquired reactive perforating collagenosis in a patient with lung fibrosis. J Dermatol 2004;31:916-19. 17. Hinrichs W, Breuckmann F, Altmeyer P, Kreuter A. There are myriad dermatologic entities Acquired perforating dermatosis: A report on four cases that on histology may show evidence of associated with scabies infection. J Am Acad Dermatol 2004;51:665-7. transepidermal elimination of a dermal 18. Eingentler TK, Metzler G, Brossart P, Fierlbeck G. product. One of the better documented Acquired perforating collagenosis in Hodgkin’s disease. J Am Acad Dermatol 2005;52:922. conditions is periumbilical perforating 19. Kawakami T, Soma Y, Mizoguchi M, Saito R. Immuno- pseudoxanthoma elasticum. This histochemical analysis of transforming growth factor- 3 expression in acquired reactive perforating collagenosis. is an entity usually seen in multipa- Brit J Dermatol 2001;144:197-9. 20. Morgan MB, Truitt CA, Taira J, Somach S, Pitha JV, rous, middle-aged, obese females, and Everett MA. Fibronectin and the extracellular matrix in it presents with hyperpigmented, firm the perforating disorders of the skin. Am J Dermpath 1998;20:147-54. papules surrounding the umbilicus. 21. Herzinger T, Schirren CG, Sander CA, Jansen T, Kind P. Microscopically, the elimination of calci- Reactive perforating collagenosis—transepidermal elimina- 43 tion of type IV collagen. Clin Ex Dermatol 1996;21:279-82. fied elastic fibers is seen. 22. Ohe S, Danno K, Sasaki H, Isei T, Okamoto H, Horio T. Treatment of acquired perforating dermatosis with narrow- Various other case reports exist for band ultraviolet B. J Am Acad Dermatol 2004;50:892-4. commonly seen dermatologic disorders 23. Iyoda M, Hayashi F, Kuroki A, Shibata T, Kitazawa K, Sugisaki T, Sakai O. Acquired reactive perforating collag- that show perforation on histology. Some enosis in a nondiabetic hemodialysis patient: Successful of these entities include granuloma annu- treatment with allopurinol. Am J Kid Dis 2003;42:1-3. 24. Querings K, Balda BR, Bachter D. Treatment of acquired lare, lichen nitidus, morphea, piloma- reactive perforating collagenosis with allopurinol. Brit J Dermatol 2001;145:174-6. tricoma, chondrodermatitis nodularis 25. Brinkmeier T, Schaller J, Herbst RA, Frosch PJ. Success- chronica helicis and perforating verruci- ful treatment of acquired reactive perforating collagenosis 44,45 with doxycycline. Acta Derm Venereol 2002;82:393-5. form collagenoma. 26. Mehregan AH, Schwartz OD, Livingood CS. Reactive per- forating collagenosis. Arch Dermatol1967;96:277-82. 27. Kumar V, Mehndiratta V, Sharma RC, Narayan S, Koranne Conclusion RV, Kakar N. Familial reactive perforating collagenosis: A case report. J Dermatol 1998;25:54-6. In conclusion, the three primary perfo- 28. Lutz W. Keratosis follicularis serpiginosa. Dermatologica 1953;106:318-20. rating disorders have been presented 29. Meischer G. Elastoma intrapillare perforans verruciforme. Dermatologica 1955;110:254. in detail. Making sense of this often- 30. Fujimoto N, Akagi A, Tajima S, Ishibashi A, Nomura K, confusing topic will enable the clinician Matsushita A, Nagai Y, Shishiba K. Expression of the 67-kDa elastin receptor in perforating skin disorders. Brit J to render a correct diagnosis, give the Dermatol 2002;146:74-9. patient an accurate prognosis and provide 31. Lewis KG, Bercovitch L, Dill SW, Robinson-Botsom L. Acquired disorders of elastic tissue: Part I. Increased rational treatment options for these often elastic tissue and solar elastotic syndromes. J Am Acad difficult-to-treat entities. Dermatol 2004;51:1-21. 32 .Kelly SC, Purcell SM. Imiquimod therapy for elastosis perforans serpiginosa. Arch Dermatol 2006;142:829-30. 33. Outland JD, Brown TS, Callen JP. Tazarotene is an effec- References: tive therapy for elastosis perforans serpiginosa. Arch Der- 1. Saray Y, Seckin D, Bilezikci B. Acquired perforating der- matol 2002;138:169-71. matosis: clinicopathological features in twenty-two cases. 34. Langeveld-Wildschut EG, Toonstra J, van Vloten WA, J Eur Acad Dermatol Venereol 2006;20:679-88. Beemer FA. Familial Elastosis Perforans Serpiginosa. 2. Rapini RP, Hebert AA, Drucker CR. Acquired perforating Arch Derm 1993;129:205-7. dermatosis: evidence for combined transepidermal elimi- 35. Saxena M, Tope W. Response of elastosis perforans ser- nation of both collagen and elastic fibers. Arch Dermatol piginosa to pulsed CO2, Er:YAG and dye lasers. Dermatol Surg 2003;29:677-8.

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65 TREATMENT OF LYMPHANGIOMA CIRCUMSCRIPTUM WITH IMIQUIMOD 5% CREAM

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

Lymphangiomas are common benign vascular tumors often found in children. The treatment of choice for lymphangiomas has tra- ditionally been complete surgical excision. However, incomplete resections are frequent, with a high rate of recurrence. Several non- surgical interventions have been proposed, all with unsatisfactory results. In this case, we sought to examine the role for imiquimod (Aldara™) in the treatment of lymphangioma circumscriptum. Imiquimod 5% cream was prescribed nightly, as a therapeutic trial, due to its ability to induce antiangiogenic cytokines. Resolution of superficial vesicles was noted, but more studies need to be done to investigate the role for imiquimod in the treatment of lymphangiomas.

Introduction tion was never sought, as the lesion was thought to be a birthmark. Physical exam Lymphangiomas, resulting from an revealed small clusters of pink vesicles and abnormal proliferation of lymphatic vessels papules, approximately 2 to 4 millimeters involving the skin and subcutaneous tissues, in size, on the left lower abdomen (Fig. 1). are common benign vascular tumors in chil- Hematoxylin and eosin staining of a skin dren.1 The term “lymphangioma” is used specimen revealed dilated vessels filling the when lymphatics are distended to tumor- papillary dermis (Fig. 2) with thick walls like proportions, and “lymphangioma that contain lined by a single circumscriptum” (LC) for lymphatic layer of endothelial cells (Fig. 3), consis- malformations that are localized to an area tent with the diagnosis of lymphangioma of skin, subcutaneous tissue or even muscle. circumscriptum. LC may present at any age, but is usually Figure 1. Small clusters of pink noted at birth or appears during childhood. Materials and Methods vesicles and papules, approximately Common sites include the axillary folds, 2 to 4 millimeters in size, on left lower , flanks, proximal extremities Imiquimod 5% cream was applied topi- abdomen. and perineum. LC manifests with fluid- cally, at night, to the right side of the skin filled vesicles, which are mostly translucent lesion. Cryotherapy using liquid nitrogen but may vary in color from red to blue- (temperature -196°C) was used on the left black. Vesicles are well defined, discrete side of the skin lesion. The patient was or grouped, resembling frogspawn.2 The evaluated at baseline, at six weeks and at 12 treatment of choice for lymphangiomas weeks. She used imiquimod 5% cream for has traditionally been complete surgical a total of 12 weeks, had three cryotherapy excision to ensure removal of the superficial treatments (baseline, six, and 12 weeks), and as well the deep components. However, was then lost to follow-up. Physical exami- incomplete resections are frequent, with nation was performed by the dermatology a high rate of recurrence.1 Several non- residents and attending faculty, and pictures Figure 2. At low power, dilated vessels surgical interventions have been proposed, were taken at each visit to assess improve- filling the papillary dermis. such as electrocautery, carbon-dioxide laser ment and resolution of skin lesions. ablation, superficial X-ray therapy, cryo- of superficial lesions and may require more therapy, and injection sclerotherapy,3-7 all Results treatments when compared to treatment with unsatisfactory results. In this case, we with cryotherapy. Side effects included local sought to examine the role for imiquimod Topical application of imiquimod cream nightly for six weeks resulted in pain and irritation immediately after treat- (AldaraTM) in the treatment of lymp- ment with cryotherapy. Imiquimod cream hangioma circumscriptum. Imiquimod 5% minimal improvement of skin lesions when compared to baseline evaluation, and was tolerated well, with no side effects cream was prescribed nightly, as a thera- reported. peutic trial, due to its ability to induce anti- initial treatment with cryotherapy caused angiogenic cytokines.8 only mild erythema with no resolution of superficial vesicles (Fig. 4). At 12 weeks, Discussion a reduction in the number of superficial Lymphatic malformations are due to a Case Report vesicles and erythematous macules were hyperproliferation of the lymphatic vessels. observed at the imiquimod treatment site, A previously healthy 14-year-old Hispanic Lymphangiomas constitute approximately while slightly atrophic, erythematous and female presented to our dermatology clinic 4% of all vascular tumors and approximately hyperpigmented macules were observed with a chief complaint of bumps on her 26% of all benign vascular tumors in chil- at the cryotherapy treatment site (Fig. 5). left abdomen that recently started draining dren.9 Lymphangiomas can occur anywhere Standard treatment with cryotherapy did clear fluid. According to both the patient in the skin and the mucous membranes. provide superior results when compared and her mother, the rash started in infancy They may be localized or generalized, and to treatment with imiquimod. However, and slowly enlarged. Medical atten- the most common sites are the head and imiquimod did reduce the number and size

66 TREATMENT OF LYMPHANGIOMA CIRCUMSCRIPTUM WITH IMIQUIMOD 5% CREAM Imiquimod (imidazoquinoline 5%) is a topical immune-response-modifier agent that inhibits angiogenesis. Previous studies have shown imiquimod to be a strong inhibitor of tumor-cell-induced angiogen- esis through the production of a wide range of immunomodulatory and antiangiogenic cytokines.11,12 Additionally, imiquimod down-regulates several pro-angiogenic factors, increases endogenous angiogenesis inhibitors, and induces endothelial apop- tosis.12 Imiquimod specifically induces interferons (IFN) α, β, and γ, which inhibit angiogenesis independently of their immu- Figure 3. At high power, vessels 1,11,12 have thick walls that contain smooth nomodulatory functions. Imiquimod muscle and are lined by a single layer is used clinically for its antiangiogenesis of endothelial cells. activity to treat and regress vascular prolif- erative lesions such as hemangiomas of infancy, pyogenic granuloma, hemangiosar- coma, and Kaposi’s sarcoma.12 Since lymp- hangiomas are due to hyperproliferation of lymphatic vessels, imiquimod may promise a non-invasive treatment option for the condition.

References: 1 Reinhardt MA, Nelson SC, Sencer SF, et al. Treatment of Childhood Lymphangiomas with Interferon-α. J Pediatr Hematol Oncol, Vol. 19, No. 3, 1997. 2 Agarwal SK, Oberoi S. Lymphangioma Circumscriptum. Indian Pediatrics, Vol. 41, No. 12, 2004. 3 Giguere CM, Bauman NM, Smith RJ. New treatment options for lymphangioma in infants and children. Ann Otol Rhinol Laryngol, Vol. 111, No. 12, 2002. 4 Treharne LJ, Murison MS. CO2 laser ablation of lymp- hangioma circumscriptum of the scrotum. Lymphat Res Biol, Vol. 4, No. 2, 2006. 5 Johnson DW, Klazynski PT, Gordon WH, et al. Mediasti- Figure 4. Six-week follow-up visit after nal lymphangioma and chylothrax: the role of radiotherapy. imiquimod and cryotherapy treatment. Ann Thorac Surg, Vol. 41, 1986. 6 Kafil-Hussain N, Khooshabeh R, Graham C. Superficial adnexal lymphangioma. Orbit, Vol. 24, No. 2, 2005. 7 Herbreteau D, Riche MC, Enjolras O, et al. Percutaneous embolization with Ethibloc of lymphatic cystic malforma- tions with a review of the experience of 70 patients. Int Angiol, Vol. 12, 1993. 8 Diego ME, Haynes HA, Li VW. Antiangiogenic treatment of pyogenic [poster abstract 217]. J Am Acad Dermatol, Vol. 50(Suppl):S57, 2004. 9 Bikowski J, Dumont AM. Lymphangioma circumscriptum: Treatment with hypertonic saline sclerotherapy. J Am Acad Dermatol, Vol. 53, No. 3, 2005. 10 Ezekowitz RA, Mulliken JB, Folkman J. Interferon alfa-2a therapy for life-threatening hemangiomas of infancy. N Engl J Med, Vol. 326, 1992. 11 Majewski S, Marczak M, Mlynarczyk B, et al. Imiquimod is a strong inhibitor of tumor cell-induced angiogenesis. International J of Derm, Vol. 44, 2005. Figure 5. Twelve-week follow-up visit 12 Li V, Li W, Talcott K, et al. Imiquimod as an Antiangio- after imiquimod and cryotherapy genic Agent. J Drugs Dermatol, Vol 4, No. 6, 2005. treatment. the neck, followed by the proximal extremi- ties, the buttocks, and the trunk. These tumors rarely regress spontaneously, and if untreated they persist and often expand.1 For the treatment of lymphangioma circumscriptum, the main indications are usually cosmetic but can also be to control complications such as infection, hemor- rhage, and pain. The only cure is to remove the superficial component as well as the deeper lymphatic cisterns through surgical destruction or laser ablation of lesions. All other treatments are palliative to control symptoms. Electrocautery, cryotherapy, carbon-dioxide laser, and sclerotherapy can also be used to reduce the risk of infection and to reduce lymphorrhea.10

OSHTORY, GROPPER, HOFFMAN 67 CUTANEOUS METASTASIS OF ADENOCARCINOMA

Adam D. Wray, DO,* Lloyd J. Cleaver, DO, FAOCD,** Jonathan Cleaver, MSIV*** *Dermatology Resident, 3rd year, Northeast Regional Medical Center **Program Chairman, Northeast Regional Medical Center; Clinical Professor, A.T. Still University at KCOM ***MSIV, A.T. Still University at KCOM

ABSTRACT

Cutaneous metastasis in patients with an internal malignancy is an anomaly that occurs anywhere from 0.7% to 9% of cancers.1 Cutaneous manifestations that take place at the time of diagnosis of an internal malignancy occur in only 1.3% of the cases.2 Malignancies of the breast and lung are the most common to metastasize to the skin.3 Presentation varies greatly but usually presents as a painless, firm, skin-colored pink or nodule. The peak incidence is in patients in the fifth to seventh decades of life. The site of cutaneous metastasis depends on the source of the primary cancer. When cutaneous metastases are present at the time of diagnosis, the patient’s outcome is much grimmer. The average patient survives only three months after the diagnosis is made.4 This study describes a case of cutaneous metastasis, likely from a bronchoalveolar primary malignancy.

Introduction PCP, the patient noticed two more "knots" along the left side of his throat, which were Skin metastases of internal malignancies tender to palpation. The internist ordered are rare at the time of diagnosis. These a chest X-ray, computed axial tomography cancers carry a significant prognostic (CT), and a positron emission tomography importance. Because of the varied presen- (PET) scan. The patient's chest X-ray tation of these tumors, they must be diag- showed a lobular infiltrate in the mid left nosed histologically. Clinical suspicions for lung. The CT and PET scan were recom- these tumors are low, and they are usually mended, but the results were not obtained thought to be basal-cell carcinomas as at the time of presentation to the derma- opposed to squamous-cell carcinomas. We tology clinic. observed this rare occurrence in a 68-year- The patient had a family history of Figure 1 old Caucasian male who presented with non-melanoma skin cancer and a brother Lesion of the left occipital region three cutaneous growths, lymphadenopathy, who died of throat cancer. He also had a of scalp, measuring 0.8cm x 1.0cm. syncopal spells, and malaise. The patient history of hypertension, hyperlipidemia, The lesion represents cutaneous metastasis of adenocarcinoma. was referred by the primary care physi- and stomach disease. He quit smoking cian (PCP) to the dermatology clinic for tobacco in 1978; prior to that he had a evaluation. history of 40 to 50 packs per year. The patient drank two alcoholic beverages per Presentation of Case day. He was a divorced, retired construction worker who never wore a shirt, hat, or skin A 68-year-old white male presented with protection. Current medications included "knots" on the back of his scalp. He was Accupril, Lipitor, Aciphex, fish oil, Bayer, referred by his PCP to the dermatology garlic, niacin, and Centany (2% mupirocin clinic for evaluation of the suspicious ointment). areas. Three lesions had developed on his The patient had experienced a 3-pound scalp within a few weeks of each other. weight loss over the previous two to three The patient did not remember the exact months, and he had chills and hot flashes Figure 2 onset, but thought the nodules occurred periodically. He denied any chest pain, Lesion measuring 1.3cm x 1.3cm at approximately four to six weeks prior to discomfort or shortness of breath. His the mid-occipital area. The lesion presentation to the dermatology clinic. appetite and bowel and bladder functions represents cutaneous metastasis of adenocarcinoma. The lesions were originally asymptomatic were unchanged, although reports of a but then progressed and changed in their stone were identified on the CT scan. appearance. Upon presentation to the The patient denied dysuria and hematuria. dermatology clinic, the lesions had recently The patient denied an artificial heart valve, become warm and started bleeding when mitral valve prolapse, artificial joint replace- palpated. The patient admitted to having ment or past history of endocarditis. scratched these areas at times. The lesions On initial evaluation the patient was weak also bled when towel drying his hair. but in no acute distress. Three lesions were The patient, two weeks prior to presenta- found on the scalp. They were erythema- tion at the dermatology clinic, had felt a tous-based papules with scale and crust. Site "knot" on his left clavicle and went to see A was on the left occipital region of the scalp, his PCP. The PCP asked the patient about measuring 0.8cm x 1.0cm (Fig. 1). Site B was the cutaneous lesions on his scalp and the located at the mid-occipital area, measuring Figure 3 enlarged supraclavicular lymph node. He 1.3cm x 1.3cm (Fig. 2). Site C was located referred the patient to the dermatology Lesion on the mid-parietal area, in the mid-parietal area measuring 0.5cm x measuring 0.5cm x 0.4cm. The lesion clinic and to an internal medicine clinic. 0.4cm (Fig. 3). Hyperkeratotic scaly lesions, Approximately two weeks after seeing his represents cutaneous metastasis of with erythematous bases consistent with adenocarcinoma.

68 CUTANEOUS METASTASIS OF ADENOCARCINOMA melanoma, metastatic carcinoma, dermato- cancer in men, followed by melanoma.1-3 fibroma, dermatofibrosarcoma protuberans, They can occur at anytime of life, but the cutaneous lymphoma, sarcoidosis, and greatest incidence is the fifth through the foreign body granuloma. The etiology of seventh decades. the lymphadenopathy was unknown. Tumors most likely to metastasize to the The treatment plan for the neoplasms scalp are from the breast, lung, stomach, of the skin was to be determined by shave pancreas, and kidneys.1,6 The tumors biopsy of the three lesions on the scalp. The usually appear as firm, asymptomatic, actinic keratoses were treated with liquid erythematous, skin-colored nodules, but nitrogen. The patient was given informa- they have been known to appear in many tion and was encouraged to use sunscreen different manners. At the time of diagnosis and protective clothing. The patient was of internal cancers, only 1.3% of patients also advised to do self-exams from head to have a skin metastasis present.2 Diagnosis Figure 4 toe. The patient was to follow up with his with cutaneous metastases leads to a much Low-power view of nests of tumor primary care physician and internist for bleaker outcome. Reingold reported that cells with cystic structures, follow-up diagnostic, lab, and additional his patients only survived an average of representing cutaneous metastasis of testing. The pathologist was consulted, three months after the development of cuta- adenocarcinoma. and stains were ordered based upon her neous metastasis.4 discretion. Immunohistochemistry can be used to The three lesions on the scalp were posi- help differentiate between carcinomas from tive for CK7 and CK20. The CEA stain different origins. Cytokeratin 7 is found in showed some background staining and tumors of the lung, ovary, endometrium, and positive-rimming tumor cells, but the tumor breast, but not in tumors of the gastrointes- cells themselves were not positive. PSA and tinal tract. Cytokeratin 20 is detected in 68% TTf1 stains were negative. The pathology of the gastrointestinal tumors, but in none report from all three lesions revealed of the metastatic lung carcinomas. Thyroid nests of metastatic adenocarcinoma from transcription factor 1 (TTF-1) is typically an unknown origin (Fig. 4-6). Possible positive for lung and thyroid cancers. PSA primary sites include gastric, pancreatic, is positive in prostatic pathology. A posi- urothelial and salivary gland. tive CK20+/CK7+ and TTF-1- have been The patient followed up with an oncol- reported in colorectal adenocarcinoma and ogist. The CT scan showed mediastinal mucinous bronchoalveolar carcinoma.7-9 Figure 5 lymphadenopathy or a possible left perihilar Given the lung mass found on chest X-ray Medium-power view showing mass. There were two well defined pleural- and the immunohistochemistry of the biopsy aggregates and nests of basophilic based lesions involving the superior left specimens, our patient most likely had a rare tumor cells with cystic structures, upper lobe. PET scan was recommended mucinous bronchoalveolar carcinoma with representing cutaneous metastasis of subsequent cutaneous metastasis to the scalp. adenocarcinoma. and revealed extensive subcutaneous meta- static nodules, hilar lymphadenopathy, and a Skin metastases are rare and can be very large hepatic metastatic deposit. There were difficult to diagnose. Histological evalua- retroperitoneal, pericaval and periaortic tion is very important in determining the lymph nodes, pelvic lymphadenopathy, and diagnosis and treatment. Diagnosing skin rib metastases. After the patient's visit to metastasis as early as possible is crucial to the dermatology office, he progressively got the treatment and overall outcome of an weaker and experienced a greater decrease internal malignancy. in appetite and weight loss and extreme right hip pain. The oncologist ordered a References: magnetic resonance imaging (MRI) of the 1. Spencer PS, Helm TN. Skin metastases in cancer brain as well as an X-ray of the right hip. patients. Cutis. 1987;39:119-21. 2. Lookingbill DP, Spangler N, Sexton F. Skin involvement He suggested starting the patient on chemo- as the presenting sign of therapy for the metastatic disease. The internal carcinoma. A retrospective study of 7316 cancer patients. J Am Acad Dermatol. 1990:22; 19-26. therapy would most likely consist of Avastin, 3. Lookingbill DP, Spangler N, Helm KF. Cutaneous metas- Figure 6 Taxol, and Carboplatin. Based upon the tases in patients with metastatic carcinoma: a retro- High-power view showing basophilic spective study of 4020 patients. J Am Acad Dermatol. results of the X-ray, he would possibly add 1993;29:228-36. tumor nests with marked cellular radiation therapy. The patient was unable 4. Reingold IM. Cutaneous metastases from internal carc- pleomorphism, mitotic figures, noma. Cancer. 1966;19:162- 8. to decide whether he wanted therapy. He 5. Brodland DG, Zitelli JA. Mechanisms of metastasis. J Am prominent nucleoli, and nuclear atypia. passed away before starting any of the treat- Acad Dermatol. 1992;27:1-8. This represents cutaneous metastasis ment options. 6. Mehregan AH. Metastatic carcinoma in the skin. Derma- of adenocarcinoma. tologica. 1961;123:311-25. 7. Ikeda S, Fujimori M, Shibata S, et al. Combined immuno- histochemistry of ß-catenin, cytokeritan 7, and cytokeratin Discussion 20 is useful in discriminating primary lung adenocarci- actinic keratoses, were noted on all sun- nomas from metastatic colorectal cancer. BMC Cancer. Cutaneous metastases are a rare phenom- 2006;6:31. exposed areas. Lymphadenopathy was found 8. Wang NP, Zee S, Zarbo RJ, et al. Coordinate expression in the neck, supraclavicular space, axillae, enon that occurs in approximately 0.7% to of cytokeratins 7 and 20 defines unique subset of carcino- 10% of internal malignancies.1-3 Carcinoma mas. Appl Immunohistochem. 1995;3:99-107. and upper arm chain on the left side. These 9. Saad R, Cho P, Silverman J, Liu Y. Usefulness of Cdx2 in locations were tender to palpation. The can spread through vascular or lymphatic Separating Mucinous Bronchioloalveolar Adenocarcinoma embolization, contiguous spread, or direct of the Lung from Metastatic Mucinous Colorectal Adeno- remainder of the physical exam was normal. carcinoma. Am J Clin Pathol. 2004;122:421-427. The differential diagnosis for the three implantation through surgical procedures.5,6 neoplasms of the skin was basal-cell Cutaneous metastases most commonly carcinoma, squamous-cell carcinoma, occur with breast cancer in women and lung

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