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Page 2 of 11 Ichida et al. Hepatoma Res 2020;6:54 I http://dx.doi.org/10.20517/2394-5079.2020.59

Conclusion: The results suggest that the 5-5-500 criteria and the Japanese DEC are the appropriate selection
criteria for patients with HCC in LDLT. Among five biomarkers investigated, AFP was most reliable to predict HCC
recurrence, which justified the utilization of AFP in the 5-5-500 criteria and the Japanese DEC.

Keywords: Indication criteria of liver transplantation for hepatocellular carcinoma, the 5-5-500 criteria, the
Japanese double eligibility criteria, alfa-fetoprotein, the lens culinaris agglutinin-reactive fraction of alfa-
fetoprotein, the des-gamma-carboxy prothrombin, the neutrophil-lymphocyte ratio, the platelet-lymphocyte ratio

INTRODUCTION
[1]
Expansion of the conventional Milan criteria has been debated over the last two decades [2-11] . Though
recurrence of hepatocellular carcinoma (HCC) after liver transplantation (LT) has decreased since the
[11]
proposal of the Milan criteria in 1996, it has been criticized as being too restrictive . Initially, several
extended criteria focused on expanding the upper limit of tumor size and number were reported [2-5] .
In recent years, however, many authors have reported that an extended criteria should include the
parameters reflecting the biologic behavior of the tumor [6-10] . With regard to the biomarkers incorporated
into the expanded criteria, tumor markers such as alfa-fetoprotein (AFP) [7,10,12-15] and des-gamma-carboxy
prothrombin (DCP) [6,8,15] have been investigated by many researchers and recently, other markers such
[17]
as the neutrophil-lymphocyte ratio (NLR) [16,17] , the platelet-lymphocyte ratio (PLR) , and fluorine-18-
fluorodeoxyglucose positron emission tomography (FDG-PET) [18,19] were reported to be useful for selection
of the high risk group and prediction for recurrence. Another biomarker, the lens culinaris agglutinin-
reactive fraction of AFP (AFP-L3), is widely used for the prediction of malignant biological behavior and
poor prognosis of HCC patients in Japan, and may be a possible biomarker for recurrent HCC after LT [20-23] .

In Japan, living-donor liver transplantation (LDLT) has been the mainstay for end-stage liver disease
patients with HCC due to the severe scarcity of deceased donors. While the gold standard has long been the
Milan criteria, several center-oriented expanded criteria have been reported [3,6,8] . We proposed the Tokyo
criteria in 2007, the detail of which was as follows; the number of tumors should be five or less, and the
[3]
maximum diameter should be 5 cm or less, without distant metastasis nor vascular invasion . Similarly,
[6,8]
Kyoto and Kyushu advocated their own expanded criteria and included DCP as a biological marker .
These expanded criteria, however, had not been approved by the government, and those beyond the Milan
criteria but still within each expanded criterion had to undergo LDLT as private practice, which led us to
establish the government-approved expanded criterion. Most recently, the 5-5-500 criteria (nodule size ≤
5 cm in diameter, nodule number ≤ 5, and AFP value ≤ 500 ng/mL) was established based on retrospective
data analysis of the Japanese Liver Transplant Registry by our colleagues . This expanded criteria was
[24]
approved as the new national selection criteria for liver transplant candidates with HCC and started in
August 2019. Now, the double eligibility criteria (DEC), Milan + 5-5-500, has been adopted as the new
indication criteria for Japanese patients with HCC.

The aim of the present study was to validate the Japanese DEC and the 5-5-500 criteria in our single-center
cohort. In addition, the usefulness of biological markers (AFP, AFP-L3, DCP, NLR, and PLR) in predicting
the recurrence of HCC after LT was also verified.

METHODS
Patients
From January 1996 until the end of 2019, a total of 563 adult patients underwent LDLT at the University
of Tokyo Hospital. Among them, 153 patients were treated for HCC and were the subjects of the present
study. Preoperative diagnosis of HCC was based on dynamic multi-detector computed tomography (MDCT)