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Toniutto et al. Hepatoma Res 2020;6:50 I http://dx.doi.org/10.20517/2394-5079.2020.40 Page 3 of 21

Table 1. Classification of risk factors implicated in hepatocellular carcinoma recurrence after liver transplantation
Risk factors
Tumor-related
Morphology
Number and size of the nodules
Macrovascular invasion
Extrahepatic spread
Histology
Grading
Microvascular invasion
Genetic signature
Expression of serum markers
AFP
DCP
CRP
NLR
PLR
Molecular markers
TP53 mutations
Gene expression signatures
FAI
HDACs and MMPs
miRNAs
CTC
Response to anticancer treatments
Bridge treatments
Downstaging treatments
Tumor unrelated
Recipient characteristics
Age, gender
Severity of underlying liver disease
Immunological status
Donor characteristics
Age, gender
LDLT vs. DCD
Percentage of graft steatosis
Cold and warm ischemia times
Immunosuppressive regimen after liver transplantation
CNI
mTOR inhibitors
AFP: alpha-fetoprotein; DCP: des-gamma-carboxyprothrombin; CRP: C-reactive protein; NLR: neutrophil/lymphocyte ratio; PLR:
platelet/lymphocyte ratio; TP53: tumor protein p53; FAI: fractional allelic imbalance; HDACs: histone deacetylases; MMPs: matrix
metalloproteinases; miRNAs: micro-RNAs; CTC: circulating tumor cells; LDLT: living donor liver transplantation; DCD: deceased donor,
CNI: calcineurin inhibitors; mTOR: mammalian target of rapamycin

PRE-LIVER TRANSPLANTATION TUMOR-RELATED RISK FACTORS ASSOCIATED WITH HCC

RECURRENCE
Morphological factors
The simplest morphological characteristics of HCC, such as the number of nodules and their size, were
[6]
adopted to develop the Milan criteria . The reason why these criteria, based exclusively on morphological
features, made it possible to obtain an accurate selection of patients with HCC for LT, is linked to the size
and number of HCC nodules which are considered as a surrogate marker for the presence of MVI and/
or poor differentiation of the tumor [13,14] . It has been demonstrated that the presence of MVI and/or poor
[15]
HCC differentiation are independent predictors for HCC recurrence . Since the Milan criteria were
published, several studies conducted in Western countries have reported similar survival rates of HCC
liver transplanted patients using less stringent morphologic selection criteria. These results suggest that the
Milan criteria might exclude some patients with HCC who may benefit from LT . Thus, several studies
[16]
have since explored the possibility of expanding the Milan criteria by considering only the morphologic
characteristics of the tumor(s), which are assessed in the pre-LT period using radiologic techniques [17-20] .
Among these studies, two were validated in different patient cohorts. The first was conducted in China