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Page 2 of 5 Feier. Hepatoma Res 2020;6:75 I http://dx.doi.org/10.20517/2394-5079.2020.68

living donor liver transplantation (LDLT) has progressively expanded as the best alternative for such
[2]
patients. In Asian countries, it is the most prevalent form of LT - 95% of LT in Japan as opposed to 4.4% in
[3,4]
[1]
the USA , with excellent outcomes in both recipients and donors . Certainly, donor safety is an ongoing
concern, as a healthy individual will undergo a major surgical procedure. However, current morbidity and
[5]
mortality rates following living liver donation have been reported to be 15%-25% and 0.5%, respectively .
Driven by these results, the indications for LDLT in HCC patients were gradually expanded. The premise
was that the survival benefit potentially achieved for those patients, within these expanded criteria, would
not compromise the liver transplant allocation policy.

The inclusion criteria for HCC patients has dominated the scientific debate in the last years. Decades ago,
the results from Mazzafero’s group helped establish criteria to indicate LT for patients with HCC. The
so-called Milan Criteria (MC) (single tumor ≤ 5 cm, or less than 3 tumors ≤ 3 cm without major vessel
[6]
involvement) reported a post-LT 4-year survival of 75% for patients meeting these criteria . This expected
survival was comparable to that of patients transplanted for other indications, justifying organ allocation
for patients with HCC.

However, several centers around the world considered the MC to be too strict, possibly excluding patients
that still could benefit from LT. The University of California San Francisco expanded the criteria to a single
nodule with a maximum diameter of 65 mm, or two or three tumors, each with a maximum diameter of
[7]
45 mm, and a sum tumor diameter ≤ 80 mm, with a 5-year survival rate of 75% . Also achieving a similar
survival (71.2%), came the up-to-seven criteria [the total of the size of the largest tumor (in cm) and the
[8]
[9]
number of tumors no larger than 7] , among others .
According to cultural and religious particularities, deceased donor liver transplantation (DDLT) is
precluded, or rarely performed in some Eastern countries. In that scenario, centers developed criteria to
indicate LDLT for HCC patients. Tokyo has implemented the 5-5 rule (up to five nodules with a maximum
[10]
diameter of 5 cm), with an overall 5-years survival rate of 75% . The South Korea criteria expanded the
[3]
Tokyo criteria to 6 nodules, with a 5-year survival rate of 76.3% . Choi et al. expanded the criteria for
[11]
LDLT even more (up to seven tumors with the greatest diameter ≤ 70 mm) reporting a 5-year survival rate
of 72%.

Going further, it did not seem logical to restrict the indications only to size and number of nodules without
considering the biological behavior of the tumor. Alpha-fetoprotein (AFP) level was included in a couple
of studies, with different cutoff values - less than 400 ng/mL, or less than 1000 ng/mL - and were associated
[12]
[10]
with tumor number or diameter . Shimamura et al. included AFP levels to select patients for LDLT,
calling the 5-5-500 criteria (tumor size ≤ 5 cm diameter, ≤ 5 nodules, AFP ≤ 500 ng/mL), and achieved a
5-year recurrence-free survival of 90%.

Other markers are recently being included, such as des-gamma-carboxy prothrombin (DCP), also called
protein induced by vitamin K absence or antagonist II. This marker was also associated with the presence
[3]
of microvascular invasion . DCP measurement was included in the Kyoto group LDLT criteria (the
number of HCC nodules up to ten in addition to the largest diameter ≤ 5 cm and serum DCP level ≤
[13]
400 mAU/mL). The 5-year disease-free and overall survival rates were 93 and 82%, respectively . In the
[14]
same direction, Taketomi et al. included all HCCs with a diameter of ≤ 5 cm and DCP < 300 mAU/mL,
achieving a 5-year recurrence-free survival rate of 80%. Both Hangzhou and Toronto groups included the
HCC biopsy result in their selection criteria .
[12]

The MoRAL score was developed in Korea to predict HCC recurrence after LDLT, and includes serum
tumor markers, AFP and DCP. The MoRAL score has a high predictive power for tumor recurrence in