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Page 14 of 21 Toniutto et al. Hepatoma Res 2020;6:50 I http://dx.doi.org/10.20517/2394-5079.2020.40

Recipient characteristics
Overweight or obese recipients transplanted for HCC seem to be more exposed to HCC recurrence
compared to lean recipients [148] . The mechanisms proposed to support this observation are very similar to
those discussed for steatotic grafts. The altered production of adipokines could occur in obese patients, and
are known to be responsible for increased cell proliferation and the reduction of apoptosis in neoplastic cell
lines. In certain cases, adipokines can also be responsible for the increased expression of VEGF and other
mediators capable of increasing angiogenesis and tumor recurrence [149,150] .

2
Clinical studies have identified a body mass index cutoff value of > 30 kg/m or the presence of obesity as
independent predictors of more frequent HCC recurrence [148,151] . Regarding recipient age, several studies
have reported that elderly patients who underwent LT experienced lower survival and higher rates of HCC
recurrence [126] ; however, the mechanisms involved in explaining these observations are not entirely clear.
The most probable hypothesis is that advanced age represents a factor associated with reduced efficiency of
the immune system in reducing the development of neoplastic cell clones, which would be more evident
during prolonged immunosuppressive therapy [152] .

Impact of immunosuppression schemes adopted after LT
The impact of immunosuppressive therapy after LT has been extensively studied with regard to the
development of metabolic complications such as diabetes, arterial hypertension, hyperlipidemia, and renal
failure. This was motivated by the observation that the main cause of mortality in the medium to long term
after LT is not linked to allograft dysfunction, but rather to the development of metabolic complications
and de novo tumors [153] .

Much less studied has been the impact of immunosuppressive therapy in modifying the risk of HCC
recurrence after LT. The role of immunosuppression in promoting oncologic cell transformations has been
extensively proven in both in vitro and in vivo studies [154] . Furthermore, research conducted in cell lines
and observational clinical studies indicate that not only the type and the schemes of immunosuppressive
treatments, but also the total immunosuppressive load, are likely determinants in promoting cancer
recurrence [154] .

Among the very few studies designed to evaluate the impact of immunosuppressive treatment on HCC
recurrence after LT, a high level of heterogeneity among patients and HCC selection criteria are present.
Furthermore, many immunosuppressive schemes have adopted the simultaneous use of different classes of
drugs, with potential pro- or anti-oncogenic effects that may not always be synergistic. Thus, the inherent
limitations in the design of these studies make it very difficult to draw solid conclusions.

A recent literature review [154] identified 21 studies, of which only one was prospective and randomized,
[155]
while two were meta-analyses and evaluated the potential anticancer effect of sirolimus . Other studies
evaluated the impact of the type and load of calcineurin inhibitors (CNIs), as well as the impact of
corticosteroids or anti-thymoglobulin antibodies. By summarizing the results of these studies, which
highlighted HCC recurrence rates ranging from 12% to 54%, two key messages may be reported: (1) an
increased rate of HCC recurrence risk was associated with higher exposure to both CNIs (cyclosporine or
tacrolimus); and (2) the use of a mammalian target of rapamycin (mTOR) inhibitors was associated with a
lower risk of HCC recurrence [156] . To confirm the potential beneficial role of the mTOR inhibitor sirolimus
in decreasing the risk of HCC recurrence after LT, a prospective multicenter and randomized study was
performed [157] . The results of this study were disappointing since they only showed a lower recurrence rate
3 years after LT in patients with early HCC, though this advantage was lost at 5 years. Moreover, in patients
with HCC within the Milan criteria, the rate of recurrence was not statistically different from that obtained
by adopting immunosuppressive schemes without mTOR inhibitors [154] . The main limitations of this study