Ischemia/Reperfusion Injury and Hepatocellular Carcinoma Recurrence After Liver Transplantation: Cancer at WIT's End?

Hepatocellular carcinoma (HCC) is the second most common cause of cancer deaths worldwide, with hepatitis B representing its major risk factor. In the Western world, the risk factors have included infection with the more prevalent hepatitis C virus and alcoholic cirrhosis. With effective therapy for hepatitis C now available and with the obesity epidemic on the rise, the relative contribution of nonalcoholic steatohepatitis (NASH) to the incidence of HCC will undoubtedly increase. Management of HCC is challenging and complex, particularly in the setting of advanced liver disease. Liver transplantation has emerged as the treatment of choice for select patients with HCC and cirrhosis. Mazzaferro et al. [1] reported excellent survival in patients with cirrhosis complicated by HCC who were considered to be transplant candidates according to what is now known as the Milan criteria, ‘‘a tumor 5 cm or less in diameter in patients with single hepatocellular carcinomas and no more than three tumor nodules, each 3 cm or less in diameter, in patients with multiple tumors.’’ Still, despite careful patient selection and the use of multimodality ablative therapy prior to transplantation, *12 % of patients deemed suitable candidates according to the Milan criteria at the time of transplantation will experience recurrence of HCC within 5 years [2]. In this issue of Digestive Diseases and Sciences, Kornberg et al. [3] in an article entitled ‘‘Extended ischemia times promote risk of HCC recurrence in liver transplant patients’’ provide evidence that a prolonged warm ischemic time (WIT), the time taken to implant the liver allograft after its removal from cold storage, is an independent risk factor for recurrence of HCC after liver transplantation. In a retrospective analysis of 103 patients who underwent liver transplantation for HCC associated primarily with alcoholic and hepatitis C and B cirrhosis, the authors reported a recurrence rate of 12.7 % for patients within the Milan criteria as opposed to 39 % for those outside the criteria. In addition to the Milan criteria, Cox regression analysis identified serum a-fetoprotein concentration[400 IU/ml (a marker of tumor burden) [4], F-fluorodeoxyglucose positron emission tomography (FDG PET)-positive tumors (signifying the presence of microvascular invasion and lack of tumor differentiation) [5], and WIT[ 50 min as independent predictors of HCC recurrence. Of these, elevated serum afetoprotein and PET-positive tumors are established risk factors for recurrence, as is HCC that exceeds the Milan criteria, whereas WIT[ 50 min is a less well-documented risk factor for HCC recurrence in the setting of clinical liver transplantation. In the subset of patients who met Milan criteria, tumor recurred in 42.2 % with WIT[ 50 min as opposed to 0 % recurrence in patients with shorter WIT. In the subset of patients not meeting Milan criteria, 76.9 % of patients with WIT[ 50 min developed recurrence compared with 22.5 % of patients with WIT\ 50 min. In the subset of patients with PET-positive tumors, only WIT[ 50 min was identified as an independent risk factor for HCC recurrence according to multivariate Cox regression analysis. & Adrian H. Cotterell acotterell@mcvh-vcu.edu