Recurrence of hepatocellular carcinoma after liver transplantation: Is immunosuppression a factor?

Hepatocellular carcinoma (HCC) is a malignancy, with the inherent potential for vascular invasion and distant metastasis. Untreated, it usually leads to death, as the result of local progression. However, when the natural history is modified by surgical intervention, metastatic disease figures more prominently in the outcome. In cases where at presentation the disease appears confined to the liver and is potentially resectable by either partial hepatectomy or transplantation, the risk of subsequent appearance of metastatic disease may be predicted preoperatively using imaging-based criteria (presence of macroscopic vascular invasion and size/number of tumors, which are surrogates for microscopic invasion), and the prediction may be refined based on information gained on pathologic study of the resected specimen (microscopic invasion, satellites, histologic grade).1 HCC, hepatocellular carcinoma; EBV, Epstein-Barr virus; CsA, cyclosporine; VEGF, vascular endothelial growth factor. Further characterization of the metastatic potential of a particular HCC may be gained by analysis of genetic alterations within the tumor. By combining conventional and molecular criteria, the likelihood of posttransplantation recurrence can be predicted with a high degree of reliability.2 Because of the scarcity of donor livers, there is low tolerance within the organ allocation system for posttransplantation HCC recurrence. The Milan criteria (one nodule ≤5 cm or 2-3 nodules all ≤3 cm, without macroscopic vascular invasion)3 provide a simple means of selecting patients with HCC for transplantation who are at low risk (≈10%) for recurrence. By definition, posttransplantation tumor recurrence is the result of metastasis prior to or during surgery. What role, then, might posttransplantation immunosuppression play in its occurrence? There is an undisputable relationship between transplant-related immunosuppression and the development of skin and virally mediated cancers (e.g., lymphoma related to Epstein-Barr virus [EBV]).4 It is by no means clear, however, that the incidence of common nonvirally-mediated solid tumors (e.g., breast and colon cancer) is affected by immune suppression. More relevant to the issue at hand is whether tumor progression is more rapid in immunosuppressed patients, but here again reports are mixed.5 HCC, while often the result of virally induced cirrhosis, is not driven by viral replication à la EBV-related lymphoproliferative disease; its behavior in this regard is similar to that of other solid tumors. An early report from Pittsburgh suggested that progression of recurrent HCC was more rapid after transplantation than after hepatic resection.6 The rate of progression of recurrent tumor, however, is related to the stage of disease prior to surgery,7 and the Pittsburgh findings likely relate to the fact that in their early experience, patients who underwent transplantation for HCC had very advanced tumors; their findings have not been substantiated subsequently.8 As documented in a series of 66 patients from our center, posttransplantation HCC recurrence often presents late and runs an indolent course, with 20% of patients with recurrence remaining alive 5 years after transplantation.7 The paper by Vivarelli et al. published in this issue is the second from the group in Bologna making a case for cyclosporine's playing a key role in posttransplantation recurrence of HCC.9, 10 They analyzed 70 patients with HCC who underwent transplantation, 7 of whom developed recurrence. In this study, alpha-fetoprotein, microscopic vascular invasion, and cyclosporine (CsA) exposure (defined as the area under the curve of CsA levels plotted against time, divided by the time to recurrence or latest follow-up) were associated with recurrence on univariate analysis; on multivariate analysis only CsA exposure was significantly associated with recurrence. Further, using a receiver operating characteristic curve, a level of CsA exposure (189.6 ng/mL) was identified that perfectly differentiated patients with and without recurrence. How are we to take these findings? Have all the studies defining risk factors for HCC recurrence been missing the boat? Recurrence of HCC occurs after hepatic resection, where immunosuppression is not employed, as well as after transplantation. In transplant cases destined to recur, metastasis has already occurred prior to initiating immunosuppression; if indeed there is a negative effect of the drugs, it would more likely be to accelerate the appearance of metastasis rather than to be the determining factor in its appearance. By what mechanism might recurrence be promoted? All patients were immunosuppressed sufficiently to allow continued graft function, and in fact rejection was more common in patients with high CsA exposure, suggesting that they were less effectively immunosuppressed. The small number of patients in this study is reason to consider the findings tentative at best, especially since one patient recurred at 2 months, hardly long enough to implicate CsA. Further, the use of the parameter “CsA exposure” may be flawed, in that measurements of CsA levels in patients who recurred were not considered after the appearance of recurrence (which in 4 of 7 cases was under 1 year), whereas late posttransplantation levels were considered in calculating CsA exposure for patients without recurrence. As CsA levels are maintained at a higher level early after transplantation and are run lower with the passing of time, exposure as defined by the authors is naturally going to be high in patients with early recurrence. Nevertheless, the findings are not to be rejected out of hand. Calcineurin inhibitors do more than prevent rejection. Promotion of tumor growth (adenocarcinoma) by both cyclosporine and tacrolimus through a nonimmunologically-mediated mechanism related to augmented transforming growth factor-beta production has been demonstrated in vitro and in mice11, 12; additionally, cyclosporine has been shown to enhance colonic tumor angiogenesis in mice via elevated expression of vascular endothelial growth factor (VEGF).13 On the other hand, sirolimus has been shown to inhibit a wide variety of cancer types. Interference with angiogenesis in metastatic tumors by reduction of VEGF has been shown in a mouse model.13 The apoptotic regulator Akt, a serine-threonine kinase, is activated in many cancers,14-16 and its downregulation by sirolimus has been demonstrated to interfere with tumor growth in prostate,17 breast,18 renal,19 and hematologic20 models, as well as in HCC.21 A randomized phase II trial of the sirolimus analog CCI-779 in advanced renal carcinoma showed antitumor activity and encouraging survival.22 Based on studies such as these, a number of centers are now using sirolimus with or without calcineurin inhibitors as primary immunosuppression in patients with HCC who undergo transplantation.23 Does immunosuppressive therapy affect the course of tumors in patients with HCC who undergo transplantation? We are not sure, and the current paper by Vivarelli et al. does not convince us, but lacking data from a randomized trial, it seems rational to use a sirolimus-based regimen for patients in whom pathological examination of the liver reveals a tumor with high risk for recurrence, and that is what we do.