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Toniutto et al. Hepatoma Res 2020;6:50 I http://dx.doi.org/10.20517/2394-5079.2020.40 Page 11 of 21

Despite these important limitations, it has recently been accepted that patients with HCC listed for LT
and receiving loco-regional treatments associated with objective response, improved waitlist and post-
transplant outcomes. More importantly, the degree of tumor response to loco-regional treatments may help
in defining LT priority in candidates with HCC [108] .

POST-LIVER TRANSPLANTATION TUMOR-RELATED RISK FACTORS ASSOCIATED WITH

HCC RECURRENCE
In all prognostic risk models, the number and size of tumors, as well as the presence of MVI, were found
to be statistically associated with the risk of HCC recurrence after LT. As previously mentioned, it is known
that pre-transplant staging methods based on radiologic imaging fail to predict the exact number and size
of HCC at pathology in approximately 25%-35% of patients due to over- or understaging [28,111,112] . These
observations justified the development of HCC recurrence risk models based on the accurate assessment of
[113]
tumor burden in the explanted liver. In a large US database of HCC liver transplanted patients, Onaca et al.
evaluated the number and size of HCC in all explanted livers and correlated them with HCC-free survival
after LT. The authors demonstrated that patients with 2-4 tumors < 5 cm or with a single lesion < 6 cm had
recurrence-free survival equivalent to patients with a single tumor of 3.1-5.0 cm or 2-3 lesions all < 3 cm in
diameter, which represents the Milan criteria.

[29]
As previously reported, the assessment of MVI before LT is difficult and often inaccurate ; on the
contrary, evaluation of the presence of MVI appears very accurate on histological examination obtained in
[11]
the explanted liver. On this basis, Mazzaferro et al. developed a predictive model of the risk of mortality
and recurrence of HCC after LT based on histopathological analysis performed on the explanted liver. The
histological characteristics evaluated include the number and size of the nodules, the presence of MVI,
and the grading of the tumor. The authors collected a sample of 1,556 patients transplanted for HCC from
several US, European, and Asian centers, of which only 444 had tumor characteristics under the Milan
criteria at explant. The combination of HCC characteristics exceeding the Milan criteria but resulting in
an estimated 5-year overall survival of at least 70% generated a subgroup of patients that, in the absence of
MVI, fulfilled the so-called “up-to-seven criteria”, which involves seven being the result of the sum of the
size (in cm) and the number of tumors, for any given HCC. The overall survival reported in this subgroup
of patients was 71.2%, which was similar (73.3%) to that obtained in the subgroup of patients fulfilling
the Milan criteria, irrespective of the presence of MVI. On the contrary, patients exceeding the up-to-
seven criteria, plus patients with MVI who were beyond the Milan criteria and within the up-to-seven
criteria, had a 5-year survival rate after LT of 48.1%. The presence of MVI at any size and number category
of tumors was paralleled by a significant worsening of survival and the cumulative incidence of HCC
recurrence.

A similar model was developed and validated in France [114] , which considered the pathological
characteristics of HCC assessed in the explanted liver, including the number, size, and grading of tumors.
To obtain a final numeric risk score, the authors attributed point values for any of the following tumor
characteristics: the number of nodules, the diameter of the largest nodule, and tumor differentiation (well,
moderate and poor). For Cox regression analysis, the number of nodules, maximal diameter of the largest
nodule, and tumor differentiation were independent predictors of HCC-free survival. Interestingly, in
patients with a score < 4, there was no significant difference in 5-year tumor-free survival between those
within and exceeding the Milan criteria. A very similar approach was followed in one of the largest single
institution dataset of HCC patients undergoing LT in the US [115] , to update the original MoRAL score.
The evaluation of histology in the explanted liver showed that grade IV HCC, the presence of more than
3 lesions, the largest tumor size > 3 cm, and MVI were independently associated with HCC recurrence.
This model, called the post-MoRAL score, was therefore combined with the original pre-MoRAL score to