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Page 12 of 21 Toniutto et al. Hepatoma Res 2020;6:50 I http://dx.doi.org/10.20517/2394-5079.2020.40

develop a new model, called the combo-MoRAL score. In this new model, patients were stratified according
to an increased HCC recurrence risk score ranging from 0 to 26. Those patients presenting a combo-
MoRAL score of up to 6 were identified as low-intermediate risk, while those exceeding 6 points were
considered to have a high-very high risk of HCC recurrence. Patients outside the Milan criteria who had a
combo-MoRAL score of up to 6 experienced a risk of recurrence similar to those within the Milan criteria.
A recent and particularly relevant Risk Estimation of Tumor Recurrence After Transplant (RETREAT)
score [116] was developed and validated for patients with HCC that met the Milan criteria based on imaging.
A total of 1061 patients were enrolled in the study, which was developed in the US and validated in
Canada. In the development cohort, 9.4% of patients had MVI and 22.1% exceeded the Milan criteria on
explant. Cumulative probabilities of HCC recurrence at 1 and 5 years were 5.7% and 12.8%, respectively.
For multivariable Cox proportional hazards regression, three variables were independently associated with
HCC recurrence: MVI, AFP value at time of LT, and the sum of the largest viable tumor diameter and the
number of viable tumors on explant. The RETREAT score was created using these three variables, with
scores ranging from 0 to 5 or higher being highly predictive of HCC recurrence. The RETREAT model was
able to stratify 5-year post-LT recurrence risk ranging from less than 3% with a score of 0 to greater than
75% with a score of 5 or higher.

A critical point that can be applied to the majority of models that aim to predict HCC recurrence is that the
time of recurrence after transplant is rarely mentioned. Although this time is variable, several studies have
identified a peak of HCC recurrence within 2-3 years after transplant while after 5 years, recurrence is very
infrequent [117] . Since HCC recurrence after LT impacts negatively on overall survival, the time to recurrence
represents an important prognostic factor. Early (within 12 months after LT) HCC recurrence is associated
with a more severe prognosis [117] . The reasons why it occurs may be related to the presence of non-detected
extra-hepatic HCC metastases at the time of transplant, or as a consequence of circulating neoplastic clones
of HCC able to engraft and growing in the transplanted liver or in other organs. Recurrences occurring
more than 12 months following LT, particularly if associated with AFP serum levels < 100 ng/mL at the time
of recurrence, are associated with a better prognosis and with 5-year survival nearing 50% [118,119] . These data
strongly suggest maintaining a very stringent surveillance of the recurrence of HCC in the first 3 years after
LT, prolonging up to the fifth year, since very late recurrence of the tumor is also associated, if promptly
[10]
discovered and treated, with a better prognosis . Regarding the best way to perform surveillance, in the
absence of specific evidence-based risk stratification criteria, the majority of LT centers suggest to perform
a total body contrast CT or MRI scan every 6 months for at least 3 years, that can then be extended to
5 years after LT, in addition to AFP serum measurements [117] .

Taking into account the aforementioned considerations HCC recurrence risk models based on the
evaluation of tumor characteristics on the explanted liver should improve post-LT HCC surveillance
strategies and to help identify patients who may benefit from future adjuvant therapies. On the contrary, all
of these models have the major limitation in that they cannot be used to select patients with HCC for LT.

TUMOR UNRELATED RISK FACTORS ASSOCIATED WITH HCC RECURRENCE
Transplant type
Conflicting results exist regarding the potential impact of influencing HCC recurrence following LT
performed using cadaveric donors versus LDLT [120-126] . In addition to more advanced clinical characteristics
of the tumor that are often recognized in LDLT [120] , there are other potential explanations to support
the hypothesis that HCC recurrence may be more frequent in LDLT when compared to using cadaveric
donors. A potential mechanism to promote tumor progression and recurrence may be related to the
release of growth factors in the course of liver regeneration involving a partial graft. Moreover, it has
been demonstrated that small-sized grafts are more likely to cause acute phase graft injury, promoting
cell adhesion, increased angiogenesis, and cell migration. All of these factors may contribute to increased