Granulomatous mycosis fungoides responsive to gemcitabine

ARTICLE

We report a 61-year-old woman with a 1-year-history of widespread erythematous scaly patches and plaques as well as red/purplish to brownish confluent plaques. Ulcerated lesions with a purulent, hemorrhagic exudate and sharp elevated borders were located on the lower extremities. Diagnosis of granulomatous mycosis fungoides was supported by histopathologic findings showing an inflammatory reaction with epithelioid and large giant cells associated with features characteristic of mycosis fungoides. Immunohistochemical studies showed a T-helper phenotype of neoplastic cells (CD3⁺, CD4⁺, CD45RO⁺) with expression of the cytotoxic protein TIA-1. Molecular analysis of TCRgamma gene demonstrated a monoclonal rearrangement in the lesional skin. After failure of conventional therapies, 6 cycles of gemcitabine treatment produced partial remission of cutaneous lesions and stable disease throughout a 12-month follow-up period, suggesting that gemcitabine is a promising chemotherapeutic agent for refractory mycosis fungoides.

Key words: cutaneous lymphoma, chemotherapy, cytotoxic proteins, gemcitabine, granulomatous mycosis fungoides.

Granulomatous mycosis fungoides (MF) is an unusual histopathologic variant of MF first described in 1970 by Ackerman and Flaxman [1], that shows the typical histopathologic features of MF admixed with multinucleated giant cells and collections of epithelioid histiocytes. Distinct clinical characteristics are lacking since a variable appearance with papules, patches, plaques and/or nodules, sometimes ulcerated, has been reported [2]. The histopathogenesis and prognosis of granulomatous MF are still controversial. Treatment modalities of granulomatous MF do not differ from those usually recommended for "classical" MF. Interferon-alpha, PUVA therapy, retinoids, total-skin electron beam irradiation, photopheresis or systemic chemotherapy are commonly used for treatment of widespread plaque and tumor stage MF [2, 3].

Gemcitabine (2',2'-difluorodeoxycytidine) is a novel cytosine arabinoside analogue that exerts its antitumor activity by both inhibiting DNA replication and repair and increasing apoptosis [4]. A significant clinical activity of gemcitabine has been shown in previously treated patients with solid tumors including pancreatic, ovarian, breast, lung and bladder cancer, as well as hematologic malignancies [5, 6] and cutaneous T-cell lymphomas [7].

We report a patient with disseminated skin lesions of granulomatous MF unresponsive to conventional therapies. Six cycles of gemcitabine treatment resulted in partial remission. No systemic adverse effects were observed, and the ulcerated plaques showed almost complete healing. The disease remained stable throughout a 12-month follow-up period.

Case report

A 61-year-old woman presented with a 1-year-history of erythematous scaly patches and plaques that initially developed on the lower extremities and gradually spread to the entire skin surface. In addition to the erythematous scaly patches and plaques, physical examination revealed generalized, red/purplish to brownish confluent plaques (Fig. 1A). Most of the lesions located on the lower extremities discharged a purulent and hemorrhagic exudate and presented sharp and slightly elevated borders surrounded by a purplish halo. No lymphadenopathy nor hepatosplenomegaly was detected.

A skin biopsy specimen from a plaque on her thigh showed a dense lymphohistiocytic infiltrate throughout the whole dermis and subcutaneous tissue with focal epidermotropism. Numerous small to medium-sized atypical lymphocytes with hyperchromatic and convoluted nuclei were admixed with a pronounced granulomatous infiltrate consisting of epithelioid histiocytes and multinucleated giant cells (Fig. 2A, B). Immunohistochemical studies showed a T-helper (memory) phenotype of neoplastic cells (CD3⁺, CD4⁺, CD45RO⁺) with expression of the cytotoxic protein TIA-1. Scattered small cells without nuclear atypia were stained by CD8, and were interpreted as reactive T lymphocytes. Histiocytes and giant cells showed positive staining for CD68. Molecular analysis by PCR demonstrated a monoclonal rearrangement of the TCRgamma in the lesional skin.

Routine laboratory investigations were within normal limits except for a marked increase of LDH (817 U/l; n.v.: 220-450 U/l). Lymphocyte typing showed a higher proportion of CD4⁺ (67%; n.v. 39-53%) and a decrease of CD8⁺ T-cells (10%; n.v. 19-33%) with a T4/T8 ratio of 6.70 (n.v.: 1.12-2.78). There were no circulating Sézary cells. Serum electrophoresis and angiotensin-converting enzyme levels were within normal limits. Serological tests for human T-cell lymphotropic virus type 1 antibody and anti-nuclear antibody titers were negative. Clinicopathologic findings were consistent with the diagnosis of the granulomatous variant of MF. Staging procedures (chest X-ray, total body computed tomography scans and bone marrow biopsy) revealed no abnormalities. Stage of the disease was diagnosed as T₂N₀M₀.

The patient was treated initially with PUVA therapy for a total of 20 sessions and then with systemic recombinant interferon alpha-2b (6 x 10⁶ IU) three times a week in combination with daily oral etretinate (25 mg/day) for a period of 6 months. As no benefit was obtained, the patient received a total of 6 courses of gemcitabine by slow intravenous infusion on days 1, 8, 15 of a 28-day schedule at a dosage of 1,250 mg/m² of body surface. Partial remission of cutaneous lesions, rated as a reduction of greater than 50% of the overall skin involvement [7], was achieved after six cycles of gemcitabine treatment. Ulcerated plaques showed almost complete healing from the fourth cycle; however, most erythematous scaly lesions persisted at the end of all cycles (Fig. 1B). Modest hematological toxicity was observed; otherwise the treatment was well-tolerated. The patient has stable disease after 12 months of follow-up.

Discussion

Histopathologic evidence of granulomatous inflammation in MF is seen in less than 5% of cases but has been observed in all stages of the disease [8]. A variety of distinct granulomatous reaction patterns have been described with the most common pattern consisting of small histiocytic granulomas or single multinucleated giant cells scattered within the infiltrate in the upper dermis, as observed in our patient [8-11]. Less often, granulomas may mimic sarcoidosis [12, 13], granuloma annulare [8, 13], necrobiosis lipoidica [14], or rarely appear as tuberculoid granulomas [10]. Misdiagnosis with benign granulomatous dermatoses may occur if a few atypical T-cells are masked by an extensive granulomatous infiltrate or if epidermotropism is minimal [10, 12]. In our patient, clinical course, detection of typical histopathologic features of MF, immunohistochemical studies and TCR gene rearrangement analysis ruled out other benign causes of granulomatous reaction. Granulomatous MF shares histopathologic similarities with granulomatous slack skin (GSS). However, distinctive features of GSS that were not observed in our patient include the presence of prominent elastolysis, elastophagocytosis and atrophying features together with progressive occurrence of hanging bulky folds of lax skin in flexural areas [8].

The pathogenesis and prognosis of this MF variant remain unclear. Granulomatous reactions may represent a protective response of the host immune system against tumor progression [1]. A more benign clinical course has been initially claimed for granulomatous MF but aggressive biological behavior with occurrence of systemic spread or transformation to a high-grade lymphoma has been frequently reported [9, 14-16].

Gemcitabine has been recently shown to be a promising chemotherapeutic agent for stage T₃ or T₄N₀M₀ MF [7]. In a pivotal phase II trial, a 70% overall response rate was achieved after 3 courses of gemcitabine in 30 pretreated patients with refractory or relapsed MF, with a complete response observed in 3/30 (10%) patients and a partial response in 18/30 (60%). The treatment was well tolerated and hematologic toxicity was mild with no organ toxicity. In our patient, partial remission of cutaneous lesions with almost complete healing of ulcerated plaques was observed after 6 cycles of gemcitabine. Stable disease is still detected after 12 months of follow-up. Larger clinical trials will be necessary to further evaluate the efficacy of gemcitabine as a single agent or in combination chemotherapy regimens in unresponsive MF patients.

References

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Acknowledgements

The authors wish to thank Barbara J. Rutledge, for editing assistance.

Article accepted on 12/5/02