Therapy

Risa TAMAGAWA1 Norito KATOH1 Chihiro SHIMAZAKI2 Akira OKANO2 Shinya YAMADA2 Kaori ICHIHASHI1 Koji MASUDA1 Saburo KISHIMOTO1
1 Department of Dermatology, Department of Medicine, Kyoto Prefectural University of Medicine Graduate School of Medical Science. 465, Kajii-cho, KawaramachiHirokoji, Kamigyo-ku, Kyoto, Japan 2 Division of Hematology and Oncology, Department of Medicine, Kyoto Prefectural University of Medicine Graduate School of Medical Science. 465, Kajii-cho, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto, Japan

Eur J Dermatol 2005; 15 (4): 265-7

Lymphoma with large-plaque parapsoriasis treated with PUVA

We report on a 78-year-old Japanese woman with a 50-year history of large-plaque parapsoriasis that had evolved into cutaneous T-cell lymphoma. Her large-plaque parapsoriasis had been treated with psoralen plus ultraviolet A for 10 years. Subsequently an isolated nodule appeared on her right lower leg. Prior or concurrent patches or plaques were absent. Histology revealed a diffuse nonepidermotropic inltrate of large lymphocytes in the dermis, which had enlarged nuclei and prominent nucleoli. A diagnosis of CD30 cutaneous large T-cell lymphoma was made. Following systemic chemotherapy, there was clinical improvement. No evidence of recurrence or systemic lymphoma has subsequently been found. Key words: carcinogenesis, CD30 cutaneous large T-cell lymphoma, large-plaque parapsoriasis, non-mycosis fungoides T-cell lymphoma, psoralen plus ultraviolet A

Reprints: Risa Tamagawa. Fax: (+81) 75 251 5586. <risat@koto.kpu-m.ac.jp>

Article accepted on 8/8/2004

arapsoriasis is a group of disorders characterized by a persistent, scaling, inammatory eruption, and was rst named by Brocq in 1902 [1]. It consists of three types: large-plaque parapsoriasis (LPP), small-plaque parapsoriasis, and pityriasis lichenoides. LPP is considered to have the potential to evolve into mycosis fungoides. We describe a patient with LPP with long-term exposure to PUVA who presented with cutaneous T-cell lymphoma (CTCL), and discuss the possibility that the use of PUVA may have predisposed the patient to the development of lymphoma.

Case report
A 78-year-old Japanese woman presented with a rapidly enlarging nodule, of one months duration, on her right lower leg. Shortly afterwards an enlargement of the right inguinal lymph nodes was detected. There was no evidence of any prior patches or plaques on the same spot as the nodule. A physical examination identied a reddish and non-tender nodule with partial ulceration on her right lower leg (gure 1) and palpable lymphadenopathy in the right inguinal area. No other peripheral lymphadenopathy was found. She had a 50-year history of LPP, during which period she had experienced irregularly shaped, pruritic patches on her extremities and trunk. These patches were pinkish red and slightly scaly, and could exceed 5 cm in diameter. Some were transitory and disappeared spontaneously; others required treatment with topical PUVA. There had been a red patch on the same spot as the nodule six months previously, which had disappeared after 1 month, following treatment
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with PUVA. The patient had been exposed to PUVA therapy over a ten-year period since 1993; it was discontinued after 350 treatments and a cumulative UVA dose of 105.4 joules/cm2. A skin biopsy with a histological examination of the nodule showed a diffuse nonepidermotropic inltrate of atypical lymphocytes in the dermis. The lymphocytes were large in size with enlarged nuclei and prominent nucleoli. Atypical mitotic gures were often seen (gures 2A and 2B). Immunophenotyping of lymphocytes in the tissues revealed expression of CD3+, CD5+, CD7+, CD30, with CD4/CD8 ratio of 19, suggestive of a T-helper cell lymphoproliferative disorder. A right inguinal lymph node biopsy showed an inltrate of atypical lymphocytes. T-cell beta gene receptor analysis of the lymph node by Southern blot analysis demonstrated the presence of monoclonal beta gene rearrangements. Laboratory ndings showed a white cell count of 4.1 109 cells/L, with 34.2% lymphocytes, 55.8% neutrophils, and 5.6% monocytes. Hemoglobin and platelet counts were within normal limits. Peripheral blood examination detected no atypical lymphocytes. Computerised tomography scans of the chest and abdomen were unremarkable. Absence of prior or concurrent patches or plaques, and lack of epidermotropism excluded the diagnosis of mycosis fungoides and results of an extensive examination for systemic lymphoma were negative. Thus, a diagnosis of CD30 cutaneous large T-cell lymphoma was made according to the European Organization for Research and Treatment of Cancer classication for primary cutaneous lymphomas [2]. Chemotherapy was started with THP-COP (pirarubicin 30 mg, cyclophosphamide 550 mg, vincristine 1 mg and prednisolone 60 mg). It was given over ve days,

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Figure 1. A reddish nodule with partial ulceration on the right lower leg.

B
Figure 2. A) A diffuse inltrate of atypical lymphocytes in the dermis was seen in the biopsy from the nodule (Haematoxylin and Eosin, original magnication 40). B) Cytological details of the inltrate (Haematoxylin and Eosin, original magnication 400).

and repeated once every three weeks for six cycles. Initially the patients condition showed an improvement and the postchemotherapy skin biopsy showed no inltrate of atypical lymphocytes. However, after one month a new nodule appeared on the same spot. A punch biopsy showed an inltrate of large atypical lymphocytes in the dermis, which meant a recurrence of CTCL. She received radiotherapy over a three-week period and there was a reduction in the size of the tumor. Then she relapsed with right inguinal lymph node swelling, but it was controlled well with oral administration of etoposide 50 mg and prednisolone 10 mg for ten days per month.

Discussion
Parapsoriasis is considered a disease of unknown etiology, chronicity, failure to respond to treatment, and lack of symptoms. LPP, one of three sub-types of parapsoriasis, is a disease of middle-aged and old people, with peak incidence in the fth decade, and is probably more common in males [3]. It is known that most of the dermal inltrating lymphocytes in patients with parapsoriasis are CD4+ T-cells [4] and it has been shown that there are dominant clonal rearrangements of the inltrating T-cells [5]. This nding has led to the

hypothesis that parapsoriasis represents the early stages of CTCL. Parapsoriasis involves a process in which an initial DNA defect is followed by weak promotional stimuli leading to the generation of the T-cell clone, which exclusively migrates to the skin. This cell clone then undergoes further mutations leading to the development of overt CTCL [6]. Mycosis fungoides is the commonest type of CTCL. It displays the three classic phases of slow cutaneous progression in which the disease begins with erythematous macular eruption. Tumors can arise in areas of prior patches or in plaques, which suggests the development of a vertical growth phase. Histological ndings show epidermotropic lymphoma accompanying lymphocytes with hyperconvoluted cerebriform nuclei and Pautriers microabscesses. These clinical and histological features form the basis of a diagnosis of mycosis fungoides. In our case discussed here, the absence of the three phases of slow cutaneous progression, together with the presence of histological features that showed nonepidermotropism, excluded a diagnosis of mycosis fungoides. Approximately 10 to 20 percent of cases of
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LPP progress to overt mycosis fungoides [7]. To our knowledge, our report is the rst case of non-mycosis fungoides T-cell lymphoma to develop in a patient with LPP. Our patient had received PUVA therapy for ten years. The efcacy of PUVA in the treatment of various cutaneous diseases such as psoriasis, vitiligo, and mycosis fungoides has been repeatedly and convincingly demonstrated since its introduction in 1974 [8]. It has been shown that PUVA causes photoconjugation of psoralen to DNA, and a subsequent suppression of mitosis, DNA synthesis and cell proliferation [9]. On the other hand, many immunomodulating properties of PUVA have been demonstrated. These include causing an alteration in the number and proportion of circulating T-cells [10], and inhibition of lymphoid cell DNA synthesis [11]. Through these mechanisms PUVA may exert benecial effects on some cutaneous diseases. However, it is also known that PUVA is mutagenic and carcinogenic in animals. This risk is related to the damage it can cause to DNA, although PUVA-induced downregulation of the immune response plays an additional role. There is considerable evidence from experimental systems that this form of immunosuppression is a critical step in UV-associated carcinogenesis [12]. Another published case report has noted the occurrence of lymphoma in a PUVA-exposed patient with actinic reticuloid [13]. PUVA may sometimes allow for the expansion of an abnormal clone of cells in the skin and the subsequent development of lymphoma. We propose that long-term exposure to PUVA may be one of the causes of the development of overt CTCL in our patient. In some studies of carcinogenic risk associated with PUVA, investigators have documented that patients receiving more than 200 PUVA treatments had an increased risk compared to patients with fewer treatments [14]. Furthermore, it has been shown that an increased risk in the incidence of cutaneous cancer is associated with doses greater than 1500 joules/cm2 [15]. Based on this nding, the cumulative UVA dose (105.4 joules/cm2) in our case study would seem, therefore, to be too low to cause malignancy. This has led us to suggest that in premalignant conditions such as LPP, it might be possible to cause a lymphoma with a lower cumulative dose of UVA than might pertain when treating nonpremalignant conditions. If this is found to be correct, these ndings have important implications in the treatment of premalignant skin diseases with PUVA. j

References

1. Brocq L. Les parapsoriasis. Ann Dematol Syphilol 1902; 3: 43368. 2. Willemze R, Kerl H, Sterry W, et al. EORTC classication for primary cutaneous lymphomas: a proposal from the cutaneous lymphoma study group of the European Organization for Research and Treatment of Cancer. Blood 1997; 90: 354-71. 3. Wood GS, Hu C-H. Parapsoriasis. In: Freedberg IM, Eisen AZ, Wolff K, Austen KF, Goldsmith LA, Katz SI, eds. Fitzpatricks Dermatology in General Medicine. 6th ed. New York: McGraw-Hill, 2003: 450-5. 4. Ralfkiaer E, Wantzin GL, Mason DY, et al. Phenotypic characterization of lymphocyte subsets in mycosis fungoides Comparison with large plaque parapsoriasis and benign chronic dermatoses. Am J Clin Pathol 1985; 84: 610-9. 5. Haeffner AC, Smoller BR, Zepter K, et al. Differentiation and clonality of lesional lymphocytes in small plaque parapsoriasis. Arch Dermatol 1995; 131: 321. 6. Burg G, Dummer R. Small plaque (digitate) parapsoriasis is an abortive cutaneous T-cell lymphoma and is not mycosis fungoides. Arch Dermatol 1995; 131: 336-8. 7. Lambert WC, Everett MA. The nosology of parapsoriasis. J Am Acad Dermatol 1981; 5: 373-95. 8. Parrish JA, Fitzpatrick TB, Tanenbaum L, et al. Photochemotherapy of psoriasis with oral methoxsaren and longwave ultraviolet light. N Engl J Med 1974; 291: 1207-11. 9. Hnigsmann H, Szeimies RM, Knobler R, Fitzpatrick TB, Pathak MA, Wolff K. Photochemotherapy and Photodynamic Therapy. In: Freedberg IM, Eisen AZ, Wolff K, Austen KF, Goldsmith LA, Katz SI, eds. Fitzpatrickss Dermatology in General Medicine. 6th ed. New York: McGraw-Hill, 2003: 2477-93. 10. Moscichi RA, Morison WL, Parrish JA, et al. Reduction of the fraction of circulating helper-induced T-cells identied by monoclonal antibodies in psoriatic patients treated with long-term psoralen/ ultraviolet-A radiation (PUVA). J Invert Dermatol 1982; 79: 205-8. 11. Kraemer KH, Waters HL, Cohen LI, et al. Effects of 8-methoxypsoralen and ultraviolet radiation on human lymphoid cells in vitro. J Invert Dermatol 1981; 76: 80-7. 12. Noonan FP, Muller HK, Fears TR, et al. Mice with genetically determined high susceptibility to ultraviolet (UV)-induced immunosuppression show enhanced UV carcinogenesis. J Invert Dermatol 2003; 121: 1175-81. 13. Ashinoff R, Buchness MR, Lim HW. Lymphoma in a black patient with actinic reticuloid treated with PUVA: Possible etiologic considerations. J Am Acad Dermatol 1989; 21: 1134-7. 14. Stern RS, Lange R, et al. Non-melanoma skin cancer occurring in patients treated with PUVA ve to ten years after rst treatment. J Invert Dermatol 1988; 91: 120-4. 15. Stern RS, Laird N, Melski J, et al. Cutaneous squamous cell carcinoma in patients treated with PUVA. N Engl J Med 1984; 310: 1156-61.

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