Topical Diphenylcyclopropenone Immunotherapy in Lymphomatoid Papulosis

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1 319 Case Report Topical Diphenylcyclopropenone Immunotherapy in Lymphomatoid Papulosis Supanida Kwangsukstid, M.D. Chontavat Suvanpiyasiri, M.D. Prayoon Erpaiboon, M.D. Niramol Vasharangsi, M.D. Walaiorn Pratchyapruit, M.D. Institute of Dermatology, Department of Medical Services ËÕß àõ â diphenylcyclopropenone π lymphomatoid papulosis ÿ «â ß ÿ µ å, «ÿ«ªî», ª Ÿ Õ ÈÕ æ Ÿ å, π «ß, «Õ ª æƒ Ï π º «Àπ ß æ å «æ å ÚıÙ ; Ú :ÛÒ -ÚÛ. Lymphomatoid papulosis (LyP) ªìπ º «Àπ ß ÈÕ ß π ÿà lymphoproliferative disorder ß π Õ ªìπµÿà πÿπ ß Èπ ªìπÊ À Ê À Õ Õ º ªìπ À «Ë Àâ Èπ àπ ª π metrotrexate, ßÕ µ «Õ µ À Õ Ë å àπ mechlorethamine, carmustine µà à«π À à Àâ Èπ Ë««ªìπ È Õß â À ÿ «Ÿâ πªí ÿ πæ «à Lymphomatoid papulosis ªìπ Ë À Ëß cytokine π Th2 à«π Diphenylcyclopropenone µÿâπ À Ëß cytokine π Th1 µ Èß µ π«à â Àâ π Ÿà «ÿ Õß Th1 Th2 π π È πà ÀâÕ Õß Èπ ß ππ È ªìπ ß π Õß â«diphenylcyclopropenone π π â Lymphomatoid papulosis Ëß À⺠ªìπ Ëπà æõ à º â ß ß Ë ÿπ ß à ªìπ È Õß π À«à ß Ú ªï ˵ µ Abstract : º «Àπ ß ÈÕ ß, Lymphomatoid papulosis is a chronic lymphoproliferative disorder of the skin. Characterized by recurrent crops of papules or nodules that may ulcerate. Various therapies such as oral methotrexate, photochemotherapy (PUVA) or UVB phototherapy topical chemotherapy with mechlorethamine or carmustine are effective however improvement is temporary with relapse within months after cessation of treatment. It is recently known that there is increase in Th2 cytokine secretion in lymphomatoid papulosis and topical diphenylcyclopropenone may systemically stimulate Th1 response. We hypothesized that restoration of Th1/ Th2 imbalance by the treatment of topical diphenylcyclopropenone may improve the clinical symptoms of lymphomatoid papulosis. This is the first case report of lymphomatoid papulosis patient treated with topical diphenylcyclopropenone. There was a favorable result, no significant side effect and no relapsed after the 2- year follow up. Key words: lymphomatoid papulosis, diphenylcyclopropenone, immunotherapy

2 320 «æ å ªï Ë Ú Ë ı æƒ ÚıÙ Introduction Since some patients with lymphomatoid papulosis (LyP) have the tendency to undergo spontaneous remission, we propose that the immunity may take an important role in determination of the course of the disease. There ts an incease of Th2 cytokine secretion in Lyp and topical diphenylcyclopropenone (DCP) which is an immunomodulating therapy stimulate Th1 response may restore Th1/Th2 imbalance. This is the first case report of LyP that was successfully treated with topical DCP. Case report A 4-year-old girl presented with 8-month history of remitting and relapsing multiple erythematous papules on her face, trunk, and extremities. Most lesions were associated with central necrosis, ulceration, crusting, healed with scar and hyperpigmentation. Physical examination revealed multiple erythematous papules, 5-25 mm. in diameter distribute on her face, trunk and extremities. Some of these papules were with superficial erosion or covered with crust. Neither lymphadenopathy nor hepatosplenomegaly was noted. She was first diagnosed clinically as PLEVA and was treated with oral erythromycin and topical 0.1% triamcinolone cream for 6 months. There was no improvement. She continued to develop new lesions that usually leave hyperpigmented or atrophic scar. Skin biopsy was done and histopathology showed superficial interface, deep perivascular infiltration with lymphocyte and histiocyte with mitosis and atypia in some of them. The infiltrative cells were positive for CD3, CD8 and CD45RO, and negative for CD20 and CD30. Complete blood counts, blood chemistry studies, and chest x-ray were unremarkable. On the basis of clinical, histologic and immunohistochemical findings, we diagnosed the patient as having LyP type B. Due to the severity of the disease, the patient should be treated in an attempt to prevent and limit scarring. Treatment with MTX or PUVA is probably not appropriate for this patient because of their invasive nature and potential serious side effect for children. Topical steroid and antibiotics have been tried without success, so we decided to start treatment with topical DCP. After informed consent, the patient's immune status was evaluated by checking anti HIV, blood for CD4, CD8, C3 level and CH50, which were in normal limits. The tuberculin skin test was not reactive. The patient was sensitized with 0.5% DCP on normal appearing skin on her left forearm. After achieving sensitization, DCP solution was applied weekly to four selected severe skin lesions. The concentration of DCP was started at 0.01% and weekly stepped up as 0.025, 0.05, 0.075, 0.1, 0.2, 0.3, 0.4 and 0.5% depending on skin reaction (If there was no reaction, the concentration would be increased one step above; if there was an appropriate reaction such as erythema, the same concentration would be continued; and if there was a blister, the application would be stopped for 1 week and restarted with DCP concentration 1-step lower than the previous

3 321 dose). After 10 treatments, we stepped the concentration to 0.5%, there was no reaction, so we stopped the treatment because higher concentration may cause irritant reaction. The clinical symptoms seem to improve. There was no eruption of new lesion during treatment and the existing lesions gradually regressed. Histopathological finding of the regressing lesion after 10 treatments revealed only superficial lymphohistiocytic perivascular infiltration. The treatment was well tolerated with mild pruritus. Three months after treatment, there were discrete hyperpigmented macules. The patient was otherwise healthy. Six months after treatment the lesions were completely resolved with hyperpigmentation and scar. There was no relapsed of the disease during 2-year follow up. Discussion Lymphomatoid papulosis (LyP) is a chronic lymphoproliferative disease of the skin characterized by recurrent crops of papules or nodules that may ulcerate. 1-3 The papules heal spontaneously over a period of 1-2 months, usually leaving slightly depressed scars. LyP is part of a spectrum of CD30 (Ki-1) positive lymphoproliferative diseases. 4,5 The clinical criteria currently used to diagnose LyP are (1) multiple papules or nodules; (2) spontaneous regression that often heal with a scar; (3) no evidence that skin lesions progressively grew to a diameter larger than 3 cm during 3 months of observation without treatment; (4) absence of lymphadenopathy. 6 The histopathologic of LyP demonstrates scattered CD30+ cells among abundant inflammatory cell, whereas CD30+ LCL has a predominance (>75%) of CD30+ cells with moderate or fewer inflammatory cells and has tendency to involve into the subcutis 6. The atypical lymphocyte is predominantly a CD4+ helper/inducer T cell with human leukocyte antigen DR(HLA-DR) and interleukin 2 receptor (CD25) expression and variable loss of CD5 and/or CD 7 antigen expression. CD30(Ki-1) expression is characteristic. Many patients will not require therapy as long as their lesions remain asymptomatic and heal without scarring or other cosmetic concerns. For patient with symptomatic severe involvement, oral methotrexate, 7 photochemotherapy (PUVA) or UVB phototherapy, 8 topical chemotherapy with mechlorethamine or carmustine 9 are effective but improvement is usually only temporary and the disease generally relapses within months after cessation of treatment. Topical steroid and antibiotic therapy has not been shown to alter the course of LyP. 4 On the basis of distinct pattern of cytokine secretion, Th1 cell subset secreting IL-2 and IFN-γ, and the Th2 subset producing IL-4, IL-5, IL-6 and IL-10. Recent studies indicate that the skin infiltrating cells, atypical cells in primary cutaneous CD30+ lymphoproliferative disorder and LyP have the cytokine secretion profile of Th2 cell. 10,11 The local or intravenous injection of recombinant IFN-γ improved the conditions and simultaneously down regulated Th2 cytokine mrna transcription in skin infiltrating cells. Recently favorable responses of

4 322 «æ å ªï Ë Ú Ë ı æƒ ÚıÙ patient with LyP to IFN-α 12,13 and IFN-γ 14 support the idea that restoration of the Th1/Th2 imbalance may improve LyP. Topical diphenylcyclopropenone (DCP) is a potent contact sensitizer and nonmutagenic. 15,16 It has been proposed as a systemic immunotherapy on the basis of its ability to stimulate Th1 responses, such as those for systemic lupus erythematosus, in which the ability of Th2 response is upregulated 17 and for HIV infection, in which Th1 response is deficient. 18,19 There was a report about the efficacy of topical dinitrochlorobenzene (DNCB) therapy as a systemic immunotherapy in chronic prurigo, in which participation of Th2 cells in the pathogenesis is suggested. 20 In atopic dermatitis, topical DNCB may systemically stimulate Th1 responses of patient with atopic dermatitis, resulting in restoration of the Th1/Th2 imbalance and possible clinical improvement. 21 According to this basic knowledge, we expect that topical DCP may improve LyP. In this patient, although spontaneous regression occasionally occurred, recurrence was also observed. The majority of the lesions were large and healed with scar that caused disfiguration. After 10 treatments with DCP, it was clinically improved. The existing lesions gradually regreessed with no new lesion. After 3 months of thrapy most of the lesions subsided and completely cleared after 6 months with hyperpigmentation and scar. There was no relapse after 2-year follow up. Although the follow up period in our patient was short and later recurrence could not be excluded, but compare with the course of the disease before treatment, it was proven effective in controlling the disease. The advantage of topical DCP is that there was no systemic administration and side effect, does not require continuation, caused long term remission. However further control study in more patients, mechanisms of action and appropriate regimens of topical DCP treatment in LyP should be studied. References 1. Macaulay WL. Lymphomatoid papulosis. a continuing self-healing eruption, clinically benign-histologically malignant. Arch Dermatol 1968; 97: Macaulay WL. Lymphomatoid papulosis update. a historcal perspective. Arch Dermatol 1989; 125: Karp DL, Horn TD. Lymphomatoid papulosis. J Am Acad Dermatol 1994; 30: Willemze R, Beljaards RC. Spectrum of primary cutaneous CD30 (Ki-1)-positive lymphoproliferative disorders. a proposal for classification and guidelines for management and treatment. J Am Acad Dermatol 1993; 28: Drews R, Samel A, Kadin ME. Lymphomatoid papulosis and anaplastic large cell lymphoma of the skin. Semin Cutan Med Surg 2000; 19: Demierre MF, Goldberg LJ, Kadin ME, Koh HK. Is it lymphoma or lymphomatoid papulosis? J Am Acad Dermatol 1997; 36: Vonderheid EC, Sajjadian A, Kadin ME. Methotrexate is effective therapy for lymphomatoid papulosis and other primary cutaneous CD30-positive lymphoproliferative disorders. J Am Acad Dermatol 1996; 34: Wantzin GL, Thomsen K. PUVA-treatment in lymphomatoid papulosis. Br J Dermatol 1982; 107: Zackheim HS, Epstein EH Jr., Crain WR. Topical carmustine therapy for lymphomatoid papulosis. Arch Dermatol 1985; 121: Vowels BR, Lessin SR, Cassin M, Jaworsk C, Benoit B, Wolfe JT, et al. Th2 cytokine mrna expression in skin in cutaneous T-cell lymphoma. J Invest Dermatol 1994; 103: Dummer R, Willers J, Kamarashev J, Uroservic M, Dobbeling U, Burg G. Pathogenesis of cutaneous

5 323 lymphomas. Semin Cutan Med Surg 2000; 19: Wyss M, Dummer R, Dommann SN, Joller-Jemelka HI, Dours-Zimmermann MT, Giliet F, et al. Lymphomatoid papulosis-treatment with recombinant interferon alfa-2a and etretinate. Dermatology 1995; 190: Schmuth M, Topar G, Illersperger B, Kowald E, Fritsch PO, Sepp NT. Therapeutic use of interferon-alpha for lymphomatoid papulosis. Cancer 2000; 89: Yagi H, Tokura Y, Furukawa F, Takigawa M. Th2 cytokine mrna expression in primary cutaneous CD30-positive lymphoproliferative disorders: successful treatment with recombinant interferon-gamma. J Invest Dermatol 1996; 107: Wilkerson MG, Henkin J, Wilkin JK. Diphenylcyclopropenone: examination for potential contaminants, mechanisms of sensitization, and photochemical stability. J Am Acad Dermatol 1984; 11: Vonderhoid EC, Ekbote SK, Kerrigan K, Kalmanson JD, Van Scott EJ, Rook AH, et al. The prognostic significance of delayed hypersensitivity to dinitrochlorobenzene and mechlorethamine hypochloride in cutaneous T cell lymphoma. J Invest Dermatol 1998; 110: Stricker RB, Goldberg B, Epstein WL. Immunological changes in patient with systemic lupus erythematosus treated with topical dinitrochlorobenzene. Lancet 1995; 345: Stricker RB, Elswood BF, Goldberg B, Dumlao C, Van Elk J, Henry J, et al. Clinical and immunologic evaluation of HIV-infected patients treated with dinitrochlorobenzene. J Am Acad Dermatol 1994; 31: Stricker RB, Elswood BF. Topical dinitrochlorobenzene in HIV disease. J Am Acad Dermatol 1993; 28: Yoshizawa Y, Kitamura K, Maibach HI. Successful immunotherapy of chronic nodular prurigo with topical dinitrochlorobenzene. Br J Dermatol 1999; 141: Yoshizawa Y, Matsui H, Izaki S, Kitamura K, Maibach H. Topical dinitrochlorobenzene therapy in the treatment of refractory atopic dermatitis: systemic immunotherapy. J Am Acad Dermatol 2000; 42: