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Sugawara et al. Hepatoma Res 2018;4:33 I http://dx.doi.org/10.20517/2394-5079.2018.69 Page 3 of 5

The principle criteria I have adopted for LDLT for HCC in University of Tokyo is “tumor numbers ≤ 5 cm and
number of the tumors ≤ 5” (5-5 rule). Of the 125 HCC patients, 118 (94%) were within the 5-5 rule and 109
[13]
(87%) were within the Milan criteria. Overall survival was 88%, 82%, and 76% at 1, 3, and 5 years, respectively.
Eleven patients (9%) developed the recurrence of HCC with a rate of 6%, 9%, and 11% at 1, 3, and 5 years,
respectively. Multivariate analysis showed that the tumor status beyond the 5-5 rule, alpha-feto-protein level
> 400 ng/mL, and DCP level > 200 mAU/mL were independent risk factors for recurrence of HCC.

The Kyushu University proposed the extended criteria which is “tumor size ≤ 5 cm (no restrictions on
[14]
the numbers) and DCP level ≤ 300 mAU/mL”. One hundred nine HCC patients underwent LDLT. Of these,
103 patients (94%) were within the criteria while 55 (50%) met the Milan criteria. The 5-year recurrence
free survival of the patients who met the criteria was 71%, while all the 6 patients beyond the criteria
developed recurrence of HCC within 2 years after transplantation. Totally 90 patients within the criteria
were prospectively analyzed . The 5-year recurrence-free survival of the within-Milan and that of beyond
[15]
were 90% and 80%, respectively with no significant difference (P = 0.22).

LDLT FOR HCC IN ASIAN COUNTIES OTHER THAN JAPAN
In Asian countries/regions other than Japan, the majority of liver transplantation for HCC patients are also
LDLT . Apart from the predominance of hepatitis B related HCC [8,16] , therefore, the situation in other Asian
[6]
countries/regions is similar to that in Japan. The Taiwan group adopted the Milan criteria in LDLT . The
[17]
1-, 3-, and 5-year survivals were 98%, 96%, and 90%, respectively. The Asan medical center in South Korea ,
[18]
like Japanese institutions, advocates their own criteria, stressing “the tumor numbers ≤ 6 and the maximum
diameter of the tumor size ≤ 5 cm”. The overall 5-year patient survival rates were 76.3%. The Hong Kong
group has changed the criteria. Before 2002, the radiological Milan criteria were used. From 2002 till
[19]
2005, the selection criteria were expanded to match the radiological University of California, San Francisco
criteria (1 tumor ≤ 6.5 cm, or 2-3 tumors ≤ 4.5 cm and total tumor diameter ≤ 8 cm). From 2006 onwards,
the selected patients with more advanced HCC were enrolled for LDLT according to the following exclusion
criteria: (1) no evidence of gross vascular tumor invasion, (2) no evidence of distant metastases and (3) no
evidence of diffuse HCC.

Notably, most expanded criteria in the Asian countries/regions restrict the tumor ≤ 5 cm as the indication for
LDLT. In contrast there is a large discrepancy regarding the limitation for the numbers. Previous studies
[20]
indicated that tumors > 5 cm have a high recurrence rate after transplantation. There may be an association
between tumor size, vascular invasion and poor differentiation. Microscopic vascular invasion was present
in the 20% of tumors ≤ 2 cm, 30% to 60% of those of 2-5 cm, and up to 60% to 90% for those > 5 cm .
[21]

ANTIVIRAL THERAPY
In Japan, the incidence of hepatitis-associated HCC is high (~90%) and the antiviral therapy for patients
undergoing liver transplantation for hepatocellular carcinoma is mandatory. The combination of long-term
antiviral and low-dose hepatitis B immune globulin can effectively prevent hepatitis B virus recurrence
in more than 90% of transplant recipients . As to hepatitis C, now direct antiviral agents (DAA) have
[22]
enabled us effective treatment for patients who underwent liver transplantation for hepatitis C virus related
cirrhosis . The currently available direct antiviral agents achieve a satisfactory sustained viral response in
[23]
post-liver transplantation patients . Optimal timing of the DAA treatment is not yet established, but it may
[24]
be appropriate to consider DAA treatment after the patients’ condition and graft function become stable.

CONCLUSION
As the number of the deceased donors was scarce in Japan, unique indications and strategies in liver
transplantation have been developed. LDLT will continue to be a mainstay treatment for patients with