Temporary Regression of Merkel Cell Carcinoma Metastases After Cessation of Cyclosporine

A 46-year-old male received two preemptive living-donor kidney transplants in 1989 and in 1998 and was treated with prednisone, cyclosporine (CsA), and azathioprine. Pulse methylprednisolone and ATG therapy were given in 1992 for acute cellular rejection. In September 1999, a cervical swelling was removed and recurred 3 months later. Histology of the removed tissue showed Merkel cell carcinoma (MCC) (sheets of closely packed small cells with round nuclei containing finely dispersed chromatin, scant cytoplasm, and mitotic figures and immunohistochemistry showing scattered staining with chromogranin and prominent paranuclear dot-like staining with cytokeratin, epithelial membrane antigen moderately to intensely positive and negative for leukocyte common antigen, desmin and S-100). Azathioprine therapy was stopped. Five courses of cyclophosphamide, adriamycin, vincristine, and etoposide had no effect on the neck swelling, which increased in size during therapy. Local radiotherapy to a total dose of 50 Gy caused reduction in the swelling. Oral prednisone 7.5 mg and CsA 100 mg twice daily were continued. The patient remained in good general condition without local tumor recurrence for over 6 months. In October 2000 the patient returned with recent onset of anorexia, weight loss, and diffuse bone pains that were unresponsive to analgesics. He was unable to walk. There was a painful swelling in his neck at the site of the previously resected tumor. Multiple new growths protruding from his skull had appeared. One of these was excised and confirmed the metastatic spread of the MCC. Immunohistochemistry performed on this biopsy material showed positive staining for transforming growth factor (TGF)-β (Fig. 1). Tc-99 M-MDP bone scan showed multiple areas of increased uptake including in the skull, right acromion, several ribs, and left sacroiliac joint. Biochemistry showed normal renal function and no change in mildly elevated liver enzymes (chronic biopsy verified hepatitis C). The patient received further palliative radiotherapy to his left shoulder region and to his sacrum. CsA was stopped and only 5 mg of prednisone was continued. Carboplatin therapy was advised but the patient opted not to receive this because, soon after stopping CsA, he became free of pain. All visible signs of his MCC metastases disappeared, he was freely mobile, and gained weight. External examination of his cranium revealed no signs of the previous multiple metastatic growths. His kidney function was excellent. The whole blood-specific CsA levels before cessation of therapy were 96–130 ng/ml.Figure 1: Immunohistochemical stain of cranial metastatic lesion showing reddish positive staining for TGF-beta (magnification ×40).The patient remained in excellent condition for 8 months after withdrawal of CsA therapy. In May 2001 sudden paraparesis occurred. CT scan showed thoracic spinal compression by a soft tissue lesion and several hypodense liver lesions. Palliative radiotherapy did not prevent total paraplegia and the patient died at home 1 month later. His renal function remained normal until his death. MCC is a rare skin cancer arising from cells of neuroendocrine origin and seems to be especially aggressive after organ transplantation (1). The value of reduction in immunosuppressive therapy, especially cessation of azathioprine, has been shown mostly in tumors associated with oncogenic viruses such as Kaposi’s sarcoma and posttransplantation lymphoproliferative disease (2,3), but there are very few reports of regression of solid tumors. CsA therapy has been associated with more rapid growth of hepatic tumors (4) and stimulates tissue expression of TGF-β (5). A nonimmunologic mechanism whereby CsA promoted phenotypic changes in several types of malignant cells in vitro and increased tumor growth and metastatic spread of malignant cells in vivo has recently been described (6). Treatment with anti-TGF-β monoclonal antibodies prevented these effects of CsA. The MCC metastases in our patient showed positive staining for TGF-β, and it is thus possible that the dramatic regression of the MCC metastases in our patient were via such a CsA-induced TGF-β mechanism. Withdrawal of CsA therapy enabled a terminally ill patient to return to good health for an 8-month period until a new spinal metastasis caused a rapid fatal outcome. Michael M. Friedlaender1 Dvora Rubinger Eli Rosenbaum Gail Amir Edgar Siguencia