Yasuhiko Sugawara

Department of Transplantation/Pediatric Surgery, Postgraduate School of Life Science, Kumamoto University, 1-1-1 Honjo, Chuo-ku, Kumamoto 8603-8556, Japan

Liver transplantation has now been a standard therapy for pa- tients with hepatocellular carcinoma (HCC) in the early stage [1] . Liver transplantation is an ideal treatment for HCC which can treat both the tumors and the underlying damaged liver and thus, has higher chance of cure than the other treatments for HCC.

Early outcome [2] following liver transplantation is, however, associated with high incidence of HCC recurrence. After that, Mazzaferro et al. [3] proposed the criteria on tumor stage: a single tumor ≤5 cm or two or three tumors ≤3 cm without major vessel invasion or extrahepatic tumor spread based on the imaging studies. Of patients meeting this criteria, the 4-year patient survival was 75% and the recurrence-free survival was 83% after liver transplantation. The criteria has now been adopted for deceased donor liver transplantation and also living donor liver transplantation (LDLT) in many centers in the world. At the same time, however, the criteria have been estimated too strict for many patients to be listed for transplantation.

In Asian countries [4] including Japan, different from the Western countries, LDLT has remained the majority of transplanta- tions [5] . LDLT is a private issue among the patients and their fam- ilies and the indications from the view point of tumor status can be considered on case-by-case. Accordingly, the criteria beyond the Milan criteria [6] have been adopted by many transplantation cen- ters for LDLT to include patients with slightly larger and/or more tumors as candidates without a significantly higher rate of HCC re- currence after LDLT.

In Japan, the Japanese Organ Transplantation Act was approved in 1997 and it was revised in 2006. However, deceased donor liv- ers are still not enough. By the end of 2016, 378 liver transplanta- tions have been performed using deceased donor grafts while 8825 LDLTs have been performed during the same period. Of these, 1598 were indicated for HCC. The 1-, 3-, 5-, 10-, 15-, and 20-year sur- vival rates of LDLT for HCC were 85%, 75%, 70%, 62%, 55%, and 54%, respectively.

Recently, a survey [7] was done using a database consisting of the 965 patients who underwent LDLT for HCC between 1990 and 2005. Of these patients, 301 patients were beyond the Milan crite- ria. The new criteria were proposed, which consists of tumor num- ber, serum alpha-fetoprotein levels and maintaining the maximal tumor diameter at 5 cm, which enables the maximal enrollment of candidates securing a 5-year recurrence rate less than 10%. Ac- cording to the analysis, the new expanded criteria for LDLT, tumor size ≤5 cm in diameter, tumor number ≤5, and alfa-fetoprotein level ≤500 ng/mL (the 5-5-500 rule), candidates with HCC, were established.

In response to this study, the insuring system of the Japanese Ministry of Health, Labor, and Welfare has now covered the pa- tients who underwent transplantation satisfying the 5-5-500 rule for LDLT and also deceased donor liver transplantation for listing. The tumors should be diagnosed as HCC by computed tomography or magnetic resonance imagines obtained within one month before transplantation. The tumors should be diagnosed on the dynamic computed tomography to be low density in plain, high in arterial phase, and low in portal phase. Local treatment for HCC must be done at least 3 months before transplantation.

The Kyoto group [8] proposed the criteria to “tumor size ≤5 cm and tumor number ≤10, and des-gamma carboxy prothrom- bin (DCP) levels ＜ 400 mAU/mL”. Totally 198 patients underwent LDLT, and 147 (74.2%) patients met the Milan criteria. The 5-year survival rate of those within and beyond the Kyoto criteria was 82% and 42%, respectively ( P ＜ 0.001). The 5-year recurrence rate for those within and beyond the Kyoto criteria were 4% and 51%, respectively, with significant difference ( P ＜ 0.001). A study [9] of 62 patients who underwent LDLT after implementation of the Ky- oto criteria showed that the 5-year overall survival rate and the recurrence rate were 82% and 7%, respectively.

The principle criteria [10] which have been adopted for LDLT for HCC in the University of Tokyo is “tumor size ≤5 cm and tu- mor number ≤5” (‘5-5 rule’). Of the 125 HCC patients, 118 (94.4%) were within the 5-5 rule and 109 (87.2%) within the Milan criteria. Overall survival was 88%, 82%, and 76% at 1, 3, and 5 years, respec- tively. Eleven patients (8.8%) was complicated with HCC recurrence and the recurrence rate was 6%, 9%, and 11% at 1, 3, and 5 years, respectively. Multivariate analysis disclosed that the tumor status beyond the 5-5 rule, alpha-fetoprotein level ＞ 400 ng/mL, and DCP level ＞ 200 mAU/mL to be risk factors for HCC recurrence.

The criteria, “tumor size ≤ 5 cm (no restrictions on the numbers) and DCP level ≤300 mAU/mL” was proposed by the Kyushu University [11] . Totally 109 patients underwent LDLT for HCC. Of these, 103 (94.5%) patients were within the criteria and 55 (50.5%) met the Milan criteria. The 5-year recurrence- free survival of the patients who met the Kyushu Univer- sity criteria was 71%, while all the 6 patients beyond the Kyushu University criteria was complicated with HCC recur- rence. Thereafter - 90 patients within the criteria were prospec- tively analyzed, and the 5-year recurrence-free survival of pa- tients within the Milan criteria and beyond the Milan criteria were 90% and 80%, respectively, without a significant difference ( P = 0.22) [12] .

In 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 treat- ment for patients with HCC and cirrhosis.

CRediT authorship contribution statement

Yasuhiko Sugawara:Conceptualization, Supervision, Writing - original draft, Writing - review & editing.

Funding

None.

Ethical approval

Not needed.

Competing interest

No benefits in any form have been received or will be received from a commercial party related directly or indirectly to the sub- ject of this article.