Hepatocellular carcinoma development in renal allograft recipients

Hepatocellular Carcinoma Development in Renal Allograft Recipients M. Ołdakowska-Jedynak, M. Durlik, L. Pa˛czek, B. Zielecka, J. Juskowa, J. Pawlak, K. Zieniewicz, M. Krawczyk, L. Gradowska, and M. Lao

O

RGAN transplant recipients are known to have a higher incidence of malignancies compared to expected cancers in age-matched control populations.1,2 Both the pattern and the incidence of malignancy depend on many factors and vary by geographic area.6,8 Skin cancer and lymphoma are reported as the most common malignancies.2,3 Development of hepatocellular carcinoma (HCC) after renal transplantation is a common complication in a large part of Asia and Africa.5,6 According to a review article from the Cincinnati Transplant Tumor Registry, hepatic malignancy was the most common type of tumor. The incidence of HCC was 2%.7 The aims of our retrospective study were to evaluate the incidence of HCC in cadaveric kidney allograft recipients, determine the correlation between HCC and type and duration of immunosuppression, and estimate the impact of tumor (HCC) on clinical results. PATIENTS AND METHODS Between January 1966 and December 1998, a total of 2654 patients (1648 men and 1006 women) received renal allotransplantation in our center. Grafts were allocated following the Eurotransplant exchange criteria. From 1966 to January 1985, the standard immunosuppression protocol consisted of prednisone and azathioprine (P ⫹ AZA). From 1985, three protocols were used: prednisone ⫹ azathioprine, prednisone ⫹ cyclosporine (P ⫹ CyA), and prednisone ⫹ azathioprine ⫹ cyclosporine (P ⫹ AZA ⫹ CyA). Acute rejection episodes were treated with high doses of steroids. In addition, patients received ALG, ATG, OKT3, and TFX. The diagnosis of HCC was based on abdominal ultrasound, CT scan, and liver biopsy (in 3 cases, autopsy). Serum alpha-fetoprotein levels were also estimated. Hepatitis B surface antigen

(HbsAg), HCV-RNA (detected by polymerase chain reaction) and anti-hepatitis C virus antibody (anti-HCV, detected by enzymelinked immunosorbent assay) were estimated.

RESULTS

Hepatoma (HCC) developed in 9 patients: 5 men and 4 women and it represented 10.8% of all malignancies in our renal allograft recipients. All cases of HCC were associated with HBV infection, and most of them with underlying cirrhosis. Two patients were found to have chronic hepatitis B virus (HBV) as well as HCV infection. The average time of diagnosis of HCC was 135.1 months following transplantation (range, 50 to 247 months). Mean age of patients with HCC after kidney transplantation was 32.4 years (range 26 to 46 years). Two patients underwent segmental liver resection. In two other patients, chemoembolization was performed. They were managed by a reduction in the immunosuppression. Immunosuppressive therapy was discontinued in one patient and dialysis therapy was started. Seven patients died; only two of them are still alive. DISCUSSION

Hepatoma (HCC) develops in patients with chronic liver disease from many causes. This is especially true of cirrhosis From the Transplantation Institute, Medical University of Warsaw, Department of General and Liver Surgery, Warsaw, Poland. Address reprint requests to U. Ołdakowska-Jedynak, Transplantation Institute, Department of Immunotherapy and Internal Medicine, Nowogrodzka 59, 02-006 Warsaw, Poland.

Table 1. Characteristics of Patients With HCC Case No.

Age at Transplantation

1 2 3 4 5 6 7 8 9

23.7 23 29.1 33.9 29.4 21.1 24.5 33.5 21.7

Sex

Hepatoma Diagnosed (Months After Transplantation)

HbsAg

Anti-HCV/HCV-RNA

Outcome

M M M F M M F F F

247 100 123 138 75 180 168 102 50

P P P P P P P P P

P N N N UKN N N N P

Died 4 months after diagnosis Alive Died 10 months after diagnosis Alive Died (autopsy-HCC) Died 6 months after diagnosis Died 1 month after diagnosis Died 4 months after diagnosis Died 1 month after diagnosis

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due to viral hepatitis. Serological research suggests that hepatitis B virus and hepatitis C virus are associated with the development of HCC. As stated previously, HCC developed in 9 patients, representing 10.8% of all malignancies in our renal allograft recipients. This distribution is different from that in other reports.2,6,8 Our study confirms that immunosuppressed renal transplant recipients are at increased risk of developing HCC. It also confirms that the cancer risk increases with time after allotransplantation. In our series, HCC was observed in patients receiving various types of immunosuppression regimens. No clear relationship between the type of immunosuppression and the incidence of hepatoma was found, but the time of diagnosis was shorter in patients treated with the combination of P ⫹ AZA ⫹ CyA and with P ⫹ CyA. Most of the reported cases of HCC in kidney transplant recipients were associated with hepatitis B virus infection.8 In our series, all cases of HCC were associated with HBV infection and most of them with the underlying cirrhosis. Two patients were found to have both HBV and HCV infection. We conclude that hepatoma is a late complication in renal allograft recipients with chronic HBV and HCV infection. Both immunosuppression and HBV or HCV infection are strong hepatocellular carcinogenesis factors. The course and the prognosis are generally poor, and most patients died within 6 months following diagnosis. The important concern is also the reduction or cessation

OŁDAKOWSKI-JEDYNAK, DURLIK, PA˛CZEL ET AL

of immunosuppression in risk patients for HCC development and after the diagnosis of HCC. In the case of aggressive tumors, cessation of immunosuppression seems to be the best decision. The fatal prognosis and disappointing treatment effects are partly the results of the high rate of recurrence that is caused either by intrahepatic metastasis or independent multicentric occurrence. The unresected cirrhotic liver is a premalignant condition.9 In summary, this group of patients might benefit from aggressive surveillance for HCC during their lifetime. Intensive screening programs for this risk group may increase the number of HCC cases detected early, allowing better patient selection and choice of adequate treatment. REFERENCES 1. Penn I: Clin Transpl 99, xx, 1994 2. Behrend M, Kolditz M, Kliem V, et al: Transplant Proc 29:834, 1997 3. Gruber SA, Skjei KL, Sothern RB, et al: Transplant Proc 23:1104, 1991 4. Ikeda K, Saitoh S, Arase Y, et al: Hepatology 4:1124, 1999 5. Chen CS, Jeng LB, Chen TC, et al: Transplant Proc 28:1607, 1996 6. Ochai T, Asano T, Isono K: Transplant Proc 19:2967, 1987 7. Penn I: Surg Clin North Am 74:1247, 1994 8. Lai MK, Huang CC, Chu SH, et al: Transplant Proc 26:1979, 1994 9. Bruix J: Hepatology 2:259, 1997