Liver transplantation for hepatocellular carcinoma: the current status and perspective
Shu-Sen Zheng
Division of Hepatobiliary-Pancreatic Surgery and Liver Transplantation, Department of Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Road, Hangzhou, 310003, P.R.China

Hepatocellular carcinoma (HCC) is the most common primary form of malignant liver tumor. Relative to other tumors, it ranks fifth in overall frequency (fifth in men and eighth in women) and fourth in annual mortality rate. China is one of the highest prevalent areas of HCC and Liver transplantation (LT) is the ideal treatment for patients with HCC in the setting of cirrhosis with liver failure, since it treats both the tumor and the underlying liver disease, and the prognosis has also been greatly improved．
However，the shortage of donor resources is the limiting factor that curtail the development of LT for HCC. Therefore, to choose the most suitable HCC patients and to explore the most scientific criteria are the present mainstream point of view. In recent years, several selection criterion for HCC patients have been established by some transplant centers. Such as Milan criteria, Pittsburgh modified TNM criteria, University of California San Francisco (UCSF) criteria, Turkey criteria, Kyoto criteria, Tokyo 5-5 rule, Asan criteria and so on. A scientific and effective criteria is considered to meet the following condition. First, The criterion should be not too restrictive. There are many patients with HCC who also have a significant chance for cure. Second, the criteria should be able to select patients eliminating the risk of post transplant HCC recurrence. Macro morphological characteristics of HCC, in fact, give an imprecise estimate of the tumor’s aggressiveness since a significant number of small HCC already have aggressive features such as a poorly differentiated grade or microscopic vascular invasion. Moreover, in China, nearly 40% donor livers are offered to HCC patients, who have hepatitis B related backgrounds and more advanced or aggressive tumor characteristics. Based on more than 10 years’ work, Hangzhou criteria was established by our center from Zhejiang University, Hangzhou, China. Apart from the presence of macrovascular invasion, HCC patients meeting Hangzhou criteria must fulfill one of the two following items: (a) Total tumor diameter less than or equal to 8 cm; (b) total tumor diameter more than 8 cm, with histopathologic grade I or II and preoperative AFP level less than or equal to 400ng/mL, simultaneously. The difference between survival curves of patients fulfilling Milan criteria and patients fulfilling Hangzhou criteria did not achieve statistical significance.There are two advantages of Hangzhou criteria. First, a new cut-off point of total tumor size at 8 cm was set. Second, the new criteria does not only rely on tumor size, but also increase reliance on the histopathologic grading and serum AFP level. Hangzhou criteria expands the Milan criteria without significantly increasing the probability of post transplant HCC recurrence, and have achieved the similar long-term survival of Milan criteria through several transplant centers’ practical proof, so that more patients with HCC can be candidates for LT. This result is widely recognized and highly evaluated by many international transplant experts. Hangzhou criteria can lay a good foundation for not only the establishment of China criteria, but also the long-term development of LT in China.
Liver transplantation (LT) offers a potential curative option for patients with HCC, but post-operative tumor recurrence remains one of the most prevalent causes of unsatisfactory long-term survival. Therefore, identification of reliable prognostic factors for tumor recurrence and death could have significant clinical importance. Detection of tumor-associated biomarkers, especially the serum ones have a more extensive clinical application. Over the past few years, many groups have focused on searching for reliable molecular biomarkers to better distinguish subtypes. Our group have indicated that the expression of CpG island methylator phenotype (CIMP), Multidrug resistance 1 (MDR1) gene, HOTAIR and the protein level of X-linked inhibitor of apoptosis protein-associated factor 1 (XAF1) could be candidate biomarkers for predicting tumor recurrence in HCC patients who have undergone liver transplant. With the development of Molecular Biology and Genetic Engineering, more and more doctors transfer their viewpoint onto the gene which can be predicted the risk of tumor recurrence in HCC after transplantation.
Despite the striking success of LT, its application is limited by organ availability. The demand for deceased donors exceeds the supply of deceased donor organs. The scarcity of donor organs has leaded to develop living donor liver transplantation (LDLT) to increase the donor pool for LT, taking advantage of the liver’s regenerative capacity. Concerning LT for HCC, some researches showed that LDLT and DDLT have the similar HCC recurrence rate and overall survival, defeating the some reports of higher rates of HCC recurrence and inferior patient survival after LDLT for HCC versus DDLT.
Future studies will be focused on searching for molecular biomarkers to reflect the phenotype and Pathological features and to combine the biomarkers with criteria of HCC for LT, and proposing a more reasonable and optimized model for patient selection and prognosis prediction, which will benefit more HCC patients for LT.