Fludarabine: risk factor for aggressive behaviour of squamous cell carcinoma of the skin?

Fludarabine, a purine analogue, is effective in the therapy of low-grade non-Hodgkin's lymphomas. Side-effects include fever, peripheral neuropathy, pulmonary toxicity and significant depletion of T-lymphocyte populations. In addition, flare up and aggressive behaviour of squamous cell carcinoma (SCC) during fludarabine therapy has been observed [1Go].

We report on a 65-year-old patient with a lymphocytic B-cell lymphoma (stage IVA) diagnosed in 1997. Owing to an excess of blasts he was treated according to the German consensus protocol for aggressive non-Hodgkin's lymphoma. However, three cycles of CHOEP (cyclophosphamide, doxorubicin, vincristine, etoposide and prednisone) chemotherapy and two cycles of salvage therapy with holoxane, cytosar and vepeside did not produce a response, and led to complications such as Candida esophagitis and generalised herpes zoster infection. Owing to progressive lymphadenopathy and lymphocytosis, the patient was treated with four cycles of chlorambucil and prednisone, showing again minimal response. In 2001, six cycles of fludarabine led to a near complete remission with reduction of all lymph node manifestations and normalisation of peripheral lymphocyte counts. Since the patient's disease progressed again, a combined immunochemotherapy with rituximab and fludarabine was initiated in autumn 2002. Again, a near complete clinical remission was achieved. However, within 2 weeks of the fourth therapy cycle, the patient developed a well-circumscribed nodule on the right cheek. The tumour impressed with a diameter of 1 cm and a centrally located horn plug.

Histology showed a well demarcated invasive proliferation of epithelial cells with squamous differentiation, extending into the dermis, a perineural invasion by tumour cells and lymphohistiocytic infiltration at the margins of the neoplasm. Immunohistochemistry revealed that the majority of the infiltrating lymphocytes were CD3+ CD4+ T-helper cells, whereas a few cells expressed CD8 antigen. Complete excision of the lesion was conducted and confirmed by micrographic work-up of the specimen. Two months later the patient presented with regrowth of the tumour. Again, total excision was performed resulting in two further recurrences within the following 3 months. Nine months after local consolidating radiotherapy (51 Gy) no further recurrence had occurred.

Although differential diagnosis of keratoacanthoma was considered initially, the histological features of perineural invasion and infiltrative tumour strands, as well as repeated tumour recurrence, strongly suggested the diagnosis of SCC [2Go, 3Go]. However, aggressive behaviour of the tumour led to the question of whether in this immunocompromised patient human papilloma viruses (HPV), especially HPV 5 and 8, might be involved in the development and unusual clinical course of skin cancer [4Go]. Accordingly, we performed a nested PCR, but did not detect the suspected HPV-specific sequences in the biopsy tissue. Non-Hodgkin's lymphomas on their own or fludarabine may be responsible for the increased incidence and aggressive behaviour of SCC in these patients [5Go]. Thus, we assume that the altered immune status in this patient was aggravated by concomitant fludarabine-induced T-lymphocyte depletion, which thereby facilitated the growth and aggressive behaviour of this secondary malignancy [6Go]. Careful examination of patients at risk will be warranted in order to detect secondary malignancies early and to treat them extensively.

D. Herr1, S. Borelli2, W. Kempf3 and A. Trojan1,*

1 Department of Oncology and 3 Clinic of Dermatology, University Hospital, Rämistrasse 100, 8091 Zurich 2 Clinic of Dermatology, Triemli Hosital, Zurich, Switzerland

* Email: andreas.trojan{at}usz.ch

References

1. Davidovitz Y, Ballin A, Meytes D. Flare-up of squamous cell carcinoma of the skin following fludarabine therapy for chronic lymphocytic leukemia. Acta Haematol 1997; 98: 44–46.[ISI][Medline]

2. Schwartz RA. Keratoacanthoma. J Am Acad Dermatol 1994; 30: 1–19.[ISI][Medline]

3. Cherpelis BS, Marcusen C, Lang PG. Prognostic factors for metastasis in squamous cell carcinoma of skin. Deramtol Surg 2002; 28: 268–273.[CrossRef]

4. Meyer T, Arndt R, Nindl I et al. Association of human papillomavirus infections with cutaneous tumors in immunosuppressed patients. Transpl Int 2003; 16: 146–153.[ISI][Medline]

5. Hartley BE, Searle AE, Breach NM et al. Aggressive cutaneous squamous cell carcinoma of the head and neck in patients with chronic lymphocytic leukaemia. J Laryngol Otol 1996; 110: 694–695.[ISI][Medline]

6. Larsen CR, Hansen PB, Clausen NT. Aggressive growth of epithelial carcinomas following treatment with nucleoside analogues. Am J Hematol 2002; 70: 48–50.[CrossRef][ISI][Medline]





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