1 2 3 OLT is limited by a shortage of deceased donor liver grafts, particularly in Asia, where the rate of deceased donors is negligible. To overcome this shortage, living donor liver transplantation (LDLT) has been developed with favorable preliminary results. Other areas of study include expanding the criteria for liver transplantation to include larger tumors, as shown by the group from the University of California, San Francisco (UCSF) and molecular profiling of HCC to improve prognostication and patient selection. MILAN CRITERIA FOR LIVER TRANSPLANTATION IN HCC 3 4 5 1 TABLE 1. Prognostic factors affecting survival of 250 patients transplanted for HCC according to Conventional Milan Criteria at the National Cancer Institute of Milan 10-year survival: multivariate analysis Variable HR CI (95%) P Overall patient survival Conventional Milan criteria (in vs out) 3.1 1.35–6.93 .007 Tumor-free survival Conventional Milan criteria (in vs out) 5.5 1.39–21.27 .01 Microsatellites (yes vs no) 3.6 1.5–8.71 .004 Microvascular invasion (yes vs no) 3.4 1.36–8.76 .009 Tumor grading (G3 vs G1-2) 3.4 1.04–11.14 .04 6 7 http://www.hcc-olt-metroticket.org 5 7 1 FIG. 1. HCC forecast chart showing probability of 5-year survival based on tumor size and number in explanted liver.  MILAN VERSUS EXPANDED CRITERIA FOR LIVER TRANSPLANTATION 4 5 8 9 6 10 12 12 13 10 5 14 5 LIVING DONOR LIVER TRANSPLANTATION FOR HCC: EASTERN EXPERIENCE 15 16 17 18 13 19 20 21 22 19 13 23 18 19 13 23 24 13 17 25 LIVING DONOR LIVER TRANSPLANTATION FOR HCC: WESTERN EXPERIENCE 26 Typically, LDLT results in a liver graft that is smaller than the expected liver volume of the recipient. The outcome of a relatively small donor organ depends not only on graft size but also on the recipient’s preoperative degree of liver failure and portal hypertension. Compared with patients awaiting transplant for end-stage cirrhosis, candidates with HCC generally have better-preserved liver function and less portal hypertension, and are thus better able to tolerate a small graft. 27 8 9 28 5 SELECTION IN HCC: BIOLOGY OR MORPHOLOGY The distinction between biology and morphology in simple terms can be described as behavior versus appearance. Ultimately, the behavior of HCC is the final deciding factor on patient outcome. The ability to predict the biology of HCC is desperately needed for patient selection in OLT. The current staging criteria for HCC takes into account tumor morphology but not tumor biology, with transplantable stages stratified according to tumor size and number. For treatment options other than liver transplantation (i.e., liver resection, chemotherapy, and cytoablative therapies), tumor morphology as described by the pathological TNM staging system is reasonably adequate. For liver transplantation, however, gross and microscopic morphology are inadequate for predicting outcomes because of the scarcity of the donor organs that must be judiciously allocated. The issue would be less significant if resources were unlimited. Ideally, the TNM or morphology-based staging system would be able to stratify patients into homogeneous groups with the same outcomes. However, the current staging systems are not precise enough to segregate patients with HCC and cirrhosis into such homogeneous groups. As almost all patients with gross invasion of the hepatic venous system, positive lymph nodes, or metastatic disease experience recurrence and are therefore not candidates for transplantation, the N and M components of the TNM classification can immediately be eliminated from the organ allocation scheme. This leaves only the T component upon which we can base our biological prediction, namely tumor size and number. 5 29 30 CONCLUSIONS While patients with early resectable HCC and preserved hepatic function should undergo surgical resection, in those with unresectable disease due to underlying liver dysfunction, orthotopic liver transplantation (OLT) offers the best chance for cure. In the past 10 years, results of OLT have steadily improved because of careful patient selection pioneered by the introduction of the Milan criteria in 1996. Supported by studies showing that many patients with tumor stage beyond the Milan criteria can be cured by OLT, a number of expanded criteria have been proposed. While expanding the criteria for OLT allows more patients to be eligible for transplantation, arguments against expanding the criteria include the increased risk of vascular invasion and tumor recurrence at higher stages of HCC. The principal limitation of OLT for HCC is the shortage of deceased donor living grafts, especially in Asia. The development of LDLT has allowed more patients to benefit from OLT with favorable preliminary survival results. Given the shortage of organs available for OLT and lack of predictive power of currently used staging systems, improved prognostic tools are needed to predict outcomes after OLT. Molecular markers of cancer progression may add significant discriminatory power to the current staging systems and may improve organ allocation schemes for patients with HCC.