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Heart transplant recipients have an increased risk of posttransplantation lymphoproliferative disorders (PTLD) associated with monoclonal antilymphocyte (OKT3) immunosuppression and Epstein-Barr viral (EBV) infections. We reviewed our experience with polyclonal inducation therapy to assess the risk of malignant neoplasms in 223 recipients between April 1985 and September 1998. Posttransplant immunosuppression therapy employed either polyclonal antilymphocyte or anithymocyte globulin given as 10mg/k per day in divided doses for three days followed by Cyclosporin, Azothioprine and steroids. OKT3 was used in only two patients for persistent rejection. Twenty-nine patients developed invasive malignant neoplasms (a mean of 57.9 months posttransplant; range 7 to 125). Invasive malignancies included carcinoma of the lung (7 patients), colon (3), kidney (3), bladder (2), prostate (1), squamous cell CA of the tongue (1), malignant melanoma (2), Kaposi's sarcoma (1) and squamous cell CA of anus (1). Five patients devolped lymphoma - 3 patients had PTLD, 2 patients had Hodgkin's and non-Hodgkin's lymphoma. EBV IgG titers (>4:1) were positive in 3 patients, but only one of these developed PTLD and none of these patients received OKT3. Forty-five percent (13/29) of patients with invasive malignancy died secondary to their malignancy; 5 patients died of unrelated causes (sepsis, myocardial infarction and organ failure) : 11 patients are alive after surgical excision and/or chemotherapy. The age adjusted incidence of invasive neoplasm was 7.33 (95% CI 5.95 - 8.09) fold greater then rates for the general population in the State of Michigan between 1988-1995. While induction polyclonal antilymphocyte therapy may reduce the risk of PTLD, the incidence of posttransplant malignancy remains high. A vigilant cancer surveillance protocol is mandatory in these high risk patients.