Liver transplantation for hepatocellular carcinoma: how far can the selection criteria be expanded?

Abstract

Hepatocellular carcinoma (HCC) is the fifth most common malignancy in the world and is associated with the third highest number of cancer-related deaths [1]. Surgical curative treatments for HCC include complete tumor resection and liver transplantation (LT). The LT offers the potential advantage of removing both the tumor and the organ at risk for developing future malignancies [2]. However, although LT is a widely accepted treatment for HCC, the basis for transplant selection can still be controversial. The famous Milan criteria described in the landmark paper by Mazzaferro et al. [3] demonstrated that in patients with cirrhosis and a single tumor up to 5 cm, or up to 3 lesions none larger than 3 cm, and with no evidence of extrahepatic spread or macrovascular invasion, the 4-year actuarial and recurrence-free survival rates were 75 and 83%, respectively. Milan criteria were rapidly established as the standard for transplantation and were introduced to clinical practice. Despite being validated by many studies, some believed that the Milan criteria were too restrictive and excluded a subset of patients with HCC who could have excellent outcomes if they were transplanted [4]. Yao et al. [5] further expanded the selection criteria and proposed the University of California at San Francisco (UCSF) criteria (a single tumor nodule with a diameter of up to 6.5 cm or 3 or fewer tumors, the largest of which has a diameter of 4.5 cm with the sum of the tumor diameters not more than 8 cm, and without extrahepatic metastasis) on the basis of preoperative imaging findings with survival rates of 90% at 1 year and 75.2% at 5 years. Currently, however, there is no international consensus regarding these approaches in clinical practice. Following the thought-provoking findings of UCSF’s study, other groups have also ventured into pushing the limits set by the Milan criteria without compromising overall patient survival and HCC recurrence rate. Mazzaferro et al. [6] suggested the replacement of their strict Milan criteria with the use of the ‘‘up-to-seven’’ criteria, where the seven refers to the sum of the largest tumor in centimeters and the number of tumor nodules. In their retrospective survey of over 1,000 patients, the authors showed that a group of patients who had survival rates similar to those transplanted within the Milan criteria could be identified by the use of this ‘‘upto-seven’’ rule. It is unlikely that the size and number of tumors reflect more than a marker for tumor biology and it is widely accepted that they are poor surrogates for the likelihood of the transplant ‘‘curing’’ the patient, but serological, molecular, or histological biomarkers are not yet sufficiently established to form a robust basis for treatment decisions [7]. Hence the challenge is to decide which histopathologic features, other than size and number, may better assess the biological behavior of HCC in these transplant recipients and add to the prognostic value. Microvascular invasion, defined as microscopic tumor invasion in smaller intrahepatic vessels, was stressed as a poor prognostic factor of liver resection (LR) and LT in several studies [8–10]; however, this was not clear in other reports [5, 11]. It would be useful to clarify the significance of microvascular invasion for lesions within the ‘‘up-to-7 criteria.’’ The study by Chan et al., reported in this issue of Hepatology International, investigated how significant microvascular invasion is compromising the long-term survival of LT recipients, regardless of whether a deceased donor graft or a living donor graft was used and also N. Allam (&) Department of Hepatology and Liver Transplantation, National Liver Institute, Shebin El kom, Egypt e-mail: naglaaallam@yahoo.com