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Page 2 of 21 Toniutto et al. Hepatoma Res 2020;6:50 I http://dx.doi.org/10.20517/2394-5079.2020.40

INTRODUCTION
Hepatocellular carcinoma (HCC) is the most frequent primary liver cancer and is ranked as the sixth most
[1]
common neoplasm and the third leading cause of cancer death . In Western countries, the vast majority of
HCCs develop in the presence of liver cirrhosis caused by chronic viral hepatitis, alcohol abuse, and - more
[2,3]
recently - following the complications of non-alcoholic steatohepatitis .
In 1963, liver transplantation (LT) was originally introduced in clinical practice with the concept of treating
[4]
unresectable liver tumors . Early LT experiences were unsatisfactory since it became clear that post-
[5]
transplant survival was reduced due to high rates of primary tumor recurrence . The major revolution in
improving the survival of HCC transplanted patients has been the introduction of more stringent selection
criteria. The Milan criteria, published in 1996, highlighted that the selection of patients to be transplanted
[6]
should be based on both the number (up to three) and diameter (up to 5 cm) of HCC nodules . In the
absence of macrovascular invasion and extrahepatic spread, LT allowed patients a 4-year survival rate of
[6]
[6]
75% . Despite these excellent results, HCC recurred in 8% of patients and was the main cause of death .
In subsequent studies focused on LT patients fulfilling the Milan criteria, HCC recurrence were found
[7-9]
in 10%-16% of cases . These data demonstrated that HCC recurrence occurs despite the application of
stringent selection criteria for LT, and is likely due to HCC dissemination from circulating cancer cells and
[10]
micrometastases before or during total hepatectomy . A recent debate on the need to expand the Milan
criteria for LT poses the question of whether the price to pay for adopting this policy is increased HCC
[11]
recurrence .

The purpose of this paper is to present a review of the scientific data available on the risk factors for
HCC recurrence after LT. Risk factors related mainly to cancer and the host, as well as the impact of
immunosuppressive therapy regimens adopted after transplantation, have been considered. Since many of
the risk factors have been incorporated into predictive HCC recurrence risk models, this review focuses
only on models that have been validated in different cohorts of LT patients.

FACTORS ASSOCIATED WITH HCC RECURRENCE AFTER LIVER TRANSPLANTATION
The development of post-LT HCC recurrence appears to be multifactorial [Table 1]. Risk factors involved
in HCC recurrence may be divided into factors related to the tumor and those unrelated to the tumor.
Risk factors related to the tumor are those pertaining to the morphological, histological, and serological
characteristics of HCC, as well as those from the response of HCC to anticancer treatments. Risk factors
unrelated to the tumor are those referring to the demographic and clinical characteristics of the recipient
(age, gender, severity of underlying liver disease), of the liver graft (percentage of steatosis, cold ischemia
time, living versus cadaveric donor), and the impact of immunosuppression after LT. All of these have been
studied extensively to develop risk prediction models of HCC recurrence after LT.

Risk prediction models can be classified into three categories: preoperative, postoperative, and general
models. Preoperative models consider the morphological, serological, and histological characteristics of
HCC [Table 2]. Thus, these models may be adopted to select a candidate for LT by estimating the future
risk of developing HCC recurrence. Postoperative models [Table 3] are developed from histological risk
factors based on the evaluation of HCC characteristics in the explanted liver, such as tumor grade and
the presence of microvascular invasion (MVI). General risk models are derived from a combination of
pre- and postoperative risk factors; for this reason, they cannot be used to select candidates with HCC
for LT. Conversely, general risk models can be adopted to determine optimal screening intervals for HCC
recurrence in high-risk patients or to design clinical trials on neo-adjuvant therapies .
[12]