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2 points were classified as having a low risk of HCC recurrence; on the contrary, patients with a final score
≥ 3 were classified as high risk. Interestingly, patients with AFP serum levels > 1000 ng/mL reached 3 points
irrespective of the number or size of nodules; therefore, they could immediately be classified as patients
at high risk of HCC recurrence. The validation of the AFP model in several countries [44,56-58] and LDLT
confirms that this model better discriminated the risk of HCC recurrence compared to the Milan criteria. It
is evident that patients within the Milan criteria but with AFP serum levels > 1000 ng/mL experienced HCC
recurrence in 37.7% of cases, compared to patients exceeding the Milan criteria but with AFP < 100 ng/mL,
[41]
with HCC recurrence in 14.4% of cases . Due to the aforementioned characteristics, the AFP model was
adopted for the liver allocation policy of France in 2013.

[59]
More recently, Mazzaferro et al. developed a new predictive model of HCC recurrence based on AFP
serum levels and the morphological characteristics of HCC in Italy, and validated this model in Asian
patient cohorts. This model, known as the Metroticket 2.0 model, identified the sum of tumor number and
size, and the log of AFP level as being significantly associated with HCC-specific death. For patients with
10
HCC to have a 70% chance of HCC-specific survival 5 years after transplantation, their AFP level should be
< 200 ng/mL and the sum of the number and size of tumors (in centimeters) should not exceed 7 cm; if the
AFP level was 200-400 ng/mL, the sum of the number and size of tumors should be ≤ 5 cm; if their AFP
level was 400-1000 ng/mL, the sum of the number and size of tumors should be ≤ 4 cm. This model, based
on serum AFP level and HCC number and size, outperformed the Milan, UCSF, and AFP French model to
predict which patients will survive for 5 years after LT.

The availability of recent models that combine the morphological and biological elements of the tumor
has made it possible for patients with HCC, who would have been excluded by applying selection models
based exclusively on morphological characteristics of the tumor, to undergo LT. More importantly, this has
been achieved by keeping post-transplant survival unchanged. The relative simplicity of calculating the
size and number of nodules in addition to AFP serum levels as surrogate biological markers of the tumor,
make these models suitable for extensive and standardized use. An important innovation of these models
is their possibility of being used “dynamically”, to evaluate the evolution of the tumor in the patient before
the transplant. This implies that these models could be used in addition with the response to neo-adjuvant
treatments as the reference criteria for defining transplant feasibility in patients with HCC.

DCP
[60]
Increased serum DCP levels have been detected in patients with HCC and they correlate with the degree
of HCC malignancy, including the presence of intrahepatic metastases, capsule infiltration, and portal
vein invasion [61,62] . Moreover, HCC expressing normal levels of AFP and increased levels of DCP showed a
lower grade of differentiation and more frequent MVI [63,64] . For these reasons, DCP has been proposed as
a stronger predictor of HCC recurrence after LT than AFP [61,65] . Two Japanese groups have developed and
validated the selection criteria for LDLT by considering the size and number of nodules as well as DCP
serum levels. The Kyoto criteria [66-68] were considered for LT patients with up to 10 HCC ≤ 5 cm in diameter
and DCP serum levels ≤ 400 mAU/mL. Patients that exceeded the Milan criteria but met the Kyoto criteria
[66]
had similar HCC recurrence rates to patients within the Milan criteria . Similar results were obtained by
adopting the Kyushu criteria , which selects for LT patients with any number of HCC < 5 cm in diameter
[69]
and DCP serum levels < 300 mAU/ml. These criteria were more sensitive than the UCSF and Kyoto criteria
in predicting HCC recurrence [61,70] .

A further attractive strategy to construct a model to predict HCC recurrence involves combining AFP and
[71]
DCP levels. The MoRAL model was developed from this hypothesis in patients exceeding the Milan
criteria who underwent LDLT. The authors included a total of 566 consecutive patients who underwent
LDLT in Korea, 410 of which exceeded the Milan criteria. Serum levels of AFP and DCP provided good