Use of sirolimus for Epstein-Barr virus-positive smooth-muscle tumour

A 55-year-old Chinese woman was diagnosed in 1987 with end-stage renal failure secondary to chronic glomerulonephritis. She was given sirolimus and had complete remission of the disease. She received a cadaveric kidney transplantation in May, 1990. A routine abdominal ultrasound done in September, 2003, showed a liver nodule in each of segments six, seven, and eight. The largest nodule, in segment six, measured 1·9 cm (fi gure 1); those in segments seven and eight measured 1·1 cm each. At the time of this initial ultrasound, the patient was asymptomatic and her immunosuppresion regimen consisted of 75 mg ciclosporin twice a day, 8 mg prednisolone once a day, and 500 mg mycophenolate mofetil twice a day. She subsequently underwent an ultrasound-guided biopsy of the tumour in segment six in November, 2003. Pathological examination of the biopsy sample showed fascicles of elongated and rounded cells with scattered lymphocytes (fi gure 2). Histological analysis showed spindle-cell proliferation with nuclei staining positive for: Epstein-Barr virus (EBV)-encoded RNA (fi gure 2), which is characteristic of an EBV-associated smooth-muscle tumour; smoothmuscle actin, and Epstein-Barr virus nuclear antigen 2 (EBNA2). Total mammalian target of rapamycin (mTOR) and total protein kinase B (AKT) showed moderate staining for at least 60% of cells (fi gure 2). AKT phosphorylated at serine 473 was also positive, but phosphorylated mTOR (residue serine 2448) intensity was weak. EBV receptor CD21, proto-oncogene BCL2, and EBV protein latent membrane protein were negative, and Ki-67 expression (proliferating index) was also low. These fi ndings are consistent with other reports of EBV-positive smooth muscle tumour after organ transplantation. Because of a previous report of a poor response to chemotherapy in EBV-postive smooth-muscle tumour, we did not give her cytotoxic chemotherapy. To induce an immune-mediated host response against the tumour, we reduced her immunosuppression regimen to 60 mg ciclosporin twice a day and 7 mg prednisolone once a day, with complete withdrawal of mycophenolate mofetil. Despite a reduction in immunosuppression, a follow-up ultrasound in December, 2003, showed that the tumour in segment six had increased to 2·3 cm (fi gure 1). Because of the tumour progression and concomitant ciclosporin-induced arteriopathy detected on allograft biopsy, ciclosporin was gradually tapered off from March to April, 2004. She was simultaneously started on sirolimus in March, 2004. After a loading dose of 10 mg sirolimus, she received sirolimus once a day; sirolimus doses were titrated to a trough sirolimus concentration of 500–12 000 ng/L, attaining a fi nal maintenance dose of 2 mg once a day starting in May, 2004. An abdominal ultrasound in April, 2004, showed resolution of the lesions in segments seven and eight, with the lesion in segment six measuring 1·5 cm. Two subsequent ultrasound scans in August, 2004 (fi gure 1) and March, 2005, showed complete resolution of the nodule in segment six. An MRI scan of the liver in September, 2005, confi rmed sustained complete resolution of all lesions. Thus, complete tumour resolution was achieved within 5 months of sirolimus treatment and was sustained for more than 13 months, with no adverse eff ects from this drug. Lancet Oncol 2006; 7: 955–57