Extrahepatic malignancy following long‐term immunosuppressive therapy of severe hepatitis B surface antigen‐negative chronic active hepatitis

To determine the frequency, predisposing factors and consequences of extrahepatic malignancy following long‐term immunosuppressive therapy of severe HBsAg‐negative chronic active hepatitis, 149 patients who had received prednisone (20 mg daily) or prednisone (10 mg daily) in combination with azathioprine (50 mg daily) for at least 6 months were evaluated systematically for 109 ± 5 months (range: 7 to 223 months). Seven neoplasms involving cervix (2), lymphatic tissue (1), breast (1), bladder (1), soft tissue (1) and unknown site (1) developed in seven patients after 116 ± 23 months (range: 18 to 164 months). The incidence of extrahepatic neoplasm was 1 per 194 patient–years of surveillance, and the probability of tumor occurrence was 3% after 10 years. Tumor frequency was similar in men and women and the risk was 1.4‐fold greater than that in an age‐and sex‐matched normal population (95% confidence interval, 0.6‐ to 2.9‐fold normal). Patients with extrahepatic malignancy were not distinguished by age, sex, treatment regimen, cumulative duration of treatment (42 ± 9 vs. 60 ± 4 months, p = 0.7) or individual features of the liver disease. Five of the seven patients survived during 48 ± 25 months of follow‐up, including two patients who have lived for at least 5 years after the diagnosis of malignancy. We conclude that extrahepatic malignancy develops infrequently during long‐term immunosuppressive therapy. Its occurrence is not related to the type or duration of treatment, and long‐term survival after tumor detection is possible. The low but probably increased risk of extrahepatic neoplasm does not militate against the use of immunosuppressive therapy in these patients.