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Page 10 of 17 Calinescu et al. Hepatoma Res 2021;7:59 https://dx.doi.org/10.20517/2394-5079.2021.26

followed: while HCC are selected for LT in adults with smaller tumors, in term of mass and/or number (the
[82]
[82]
Milan criteria) , there are no well-defined pediatric criteria to contraindicate the HCC candidate for LT
as follows:
[12]
(1) Unlike adults, HCC occurs in children mainly in the absence of concomitant cirrhosis , and this is one
reason for a different selection strategy. The Milan criteria, developed for adults with cirrhotic liver disease,
have been adopted by some centers (one tumor of 5 cm or less or no more than three nodules of 3 cm or
less) in an effort to improve survival rates . The more liberal criteria of the University of California San
[3]
Francisco (UCSF) are partially adopted by some other centers . More extensive criteria, “up to seven”
[72]
(number of lesions and diameter), show a minimal decrease in survival rate, from 71% to 65% .
[83]
(2) The practice guidelines of the American Association for Transplantation and the North American
Society for Pediatric Gastroenterology, Hepatology and Nutrition recommend an individualized indication
[84]
for LT for each patient . Basically, LT is recommended for HCC patients in the case of no extrahepatic
tumor or gross vascular invasion on radiological imaging, irrespective of the number or size of the lesions .
[84]
(3) In Japan, the Japanese Organ Transplantation Act proposed the rule of 5-5-500: tumor size ≤ 5 cm
[85]
diameter, tumor number ≤ 5, and AFP level ≤ 500 ng/mL for living donor LT for HCC in adults .
Modifications of this rule were adopted (Kyoto criteria, Tokyo 5-5 rule, and Kyushu University) with larger
[85]
inclusion of patients but lower survival and higher recurrence rates .
Of note, none of these are validated in pediatric HCC . A general consensus is to offer LT for unresectable
[86]
HCC patients and no extrahepatic disease , while LT should be considered even for patients with HCC
[87]
[88]
PRETEXT I or II in selected cases .
Contraindications
Because HCC in children is different to that in adults and the Milan criteria do not strictly apply, proposing
LT in pediatric HCC remains a delicate choice and strategy: patients should be evaluated individually within
multidisciplinary teams including oncologists, hepatologists, pediatric surgeons, and pediatric liver
transplant surgeons . As evidenced for HBL, tumor behavior during chemotherapy and downsizing may
[89]
be important elements to consider for indicating LT as a curative option.

Major vascular venous invasion (especially the extrahepatic invasion of vena cava and portal vein trunk) is a
contraindication for transplantation in HCC due to poor long-term prognosis - unless neoadjuvant
[90]
chemotherapy achieves an evident down staging . As for HBL, the presence of extrahepatic tumor is a
contraindication for transplantion . Fibrolamellar variant of HCC constitutes the third contraindication .
[91]
[14]
Survival after liver transplantation for hepatocellular carcinoma
HCC seems to behave differently in children than in adults as LT for lesions outside the Milan and UCSF
criteria still lead to excellent long-term survival . A Surveillance, Epidemiology and End Results database
[4]
review identified an 89% 4-year overall survival with 27.6% of the patient most likely outside and 34.5%
[92]
definitely outside the Milan criteria . A retrospective UNOS database analysis identified an overall patient
and graft survival of 63% with 3-year overall patient and graft survival of 84% starting with 2009 [Table 3].
[8]
Poor prognostic factors for HCC are as follows: metastasis, large tumor size, lymph node extension, and
[1,3]
macroscopic vascular invasion [Table 4].