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

Biological markers
Biological markers can be divided into three categories: (1) serum markers directly related to HCC biology,
such as AFP and des-gamma-carboxyprothrombin (DCP); (2) systemic inflammation markers, such
[41]
as neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) ; and (3) molecular
biomarkers in tumor tissue and in serum, such as DNA alterations/mutations, enzymes, and micro-RNAs
[42]
(miRNAs) .
Serum markers
AFP
AFP is a surrogate marker of HCC differentiation and vascular invasion [43,44] ; thus, the measurement of
AFP serum levels before LT has been proposed as a useful tool to identify patients with a high risk of HCC
[45]
recurrence . Although AFP has proven to be a valid and simple tool to discriminate HCC recurrence risk,
opinions regarding what the discriminating plasma values of the protein should be are not unanimous.
Several authors have suggested that serial measurements of AFP levels might be more accurate than a
[48]
single measurement. Increasing AFP levels to more than 15 ng/mL [46,47] , more than 50 ng/mL/month , or
[49]
0.1 ng/mL/day during the LT waiting period have been proposed as strong predictors for HCC
recurrence.

The most effective method of using AFP serum levels to predict HCC recurrence after LT is to associate it
[50]
with tumor morphological criteria . Four selection criteria for LT in HCC patients, including AFP serum
levels and the morphologic characteristics of the tumor - both evaluated pre-LT - have been extensively
[51]
validated. The “Toronto criteria” were derived from a general assumption that acceptable survival rates
in LT for HCC can be achieved for any size or number of HCC, provided that: imaging studies ruled out
vascular invasion, the HCC was confined to the liver, and the HCC was not poorly differentiated on biopsy.
The authors demonstrated that by applying these criteria, the only pre-transplant variable associated with
5-year disease-free survival was an AFP serum level value > 400 IU/mL at the time of transplant. In the
[52]
validation cohort of the study , it was confirmed that AFP was the only independent predictive variable
associated with post-LT survival and HCC recurrence, albeit with a cutoff value of 500 IU/mL.

The association of morphologic and histologic characteristics of HCC and AFP serum levels has also been
[53]
utilized in China to develop the Hangzhou criteria . These criteria were defined as no portal vein tumor
invasion, HCC diameter ≤ 8 cm, or patients who have HCC larger than 8 cm would still be eligible for LT if
their AFP serum levels were < 400 ng/mL, and their HCC histological grade was I or II. The 1- and 3-year
survival rates of patients transplanted for HCC within the Hangzhou criteria were not significantly different
from those transplanted within the Milan criteria.

[54]
The criteria proposed by Toso et al. were derived from a large study including over 6000 patients. The
authors demonstrated that a total tumor volume (TTV) of ≤ 115 cm and AFP serum levels ≤ 400 ng/mL
3
identified patients at low risk of HCC recurrence after LT more effectively than both the Milan and UCSF
criteria. The TTV-AFP criteria were validated in a prospective study with patients from different European
[55]
countries and Canada .

The Liver Transplantation French Group developed and validated a prognostic model for predicting HCC
[43]
recurrence after LT, known as the AFP model . This model considered the predictive variables of AFP
serum level, and size and the number of nodules, with different cutoffs for each variable. The following points
were assigned for tumor size: 0, 1, or 4 points when the largest tumor size was ≤ 3 cm, 3-6 cm, or > 6 cm,
respectively. Concerning the number of nodules, 0 or 2 points were assigned for the presence of ≤ 3 or
≥ 4 nodules. Moreover, 0, 2, or 3 points were assigned to AFP serum levels ≤ 100, 100-1000, or > 1000 ng/mL,
respectively. The maximum score obtainable from the AFP model was 9. Patients with a final score of up to