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Toniutto et al. Hepatoma Res 2020;6:50 I http://dx.doi.org/10.20517/2394-5079.2020.40 Page 13 of 21

HCC recurrence [127-129] . A further mechanism could be linked to the short waiting time on LDLT
waiting lists [130,131] . This short waiting time may not be able to highlight tumors with greater biological
aggressiveness, expressed as having rapid growth over time. Finally, the LDLT technique associated with
sparing of the inferior vena cava and with more extensive manipulation of the liver during transplant
operations may contribute towards increasing the risk of HCC recurrence [132] . The same considerations
may be applied to LT performed by the piggyback technique with cadaveric donors since it theoretically
carries a higher risk of positive vena cava margins and requires greater manipulation of the diseased liver,
thus leading to an increased risk of HCC spread [133] . Nevertheless, it remains important to highlight that
the piggyback technique is the preferred approach in many liver transplant centers since it provides several
advantages compared to conventional techniques, such as shorter operation times, anhepatic phases, warm
ischemia times, and stays in intensive care units [132,134] .

Graft and donor-related factors
Besides the use of partial grafts for LT, several reports have indicated that prolonged cold and warm
ischemia times could be associated with an increased risk of HCC recurrence [135] . Multiple biological
mechanisms have been proffered to explain how ischemia-reperfusion injury can affect the risk of HCC
recurrence, based on in vivo and in vitro experiments [136-138] One of these mechanisms hypothesizes that
the exposure of micrometastases to prolonged hypoxia could lead to the abnormal expression of genes and
cytokines that increase angiogenesis, cell proliferation, and growth [136] . Notably, it has been hypothesized
that female grafts may be more susceptible to ischemia-reperfusion injury and may have increased
sensitivity to reoxygenation damage following prolonged cold storage [139,140] . Furthermore, hypoxia stabilizes
and activates the transcription factor for hypoxia - inducible factor, which represents a key oxygen
response regulator able to activate the transcription of genes stimulating angiogenesis such VEGF-A [141,142] .
However, the relationship between prolonged graft ischemia time and the risk of HCC recurrence was most
convincing in recipients who presented additional risk factors for recurrence at baseline, such as HCC
beyond the Milan criteria, the presence of MVI, or high AFP serum levels [126] .

The increased susceptibility to ischemia-reperfusion injury of older grafts support some observations, thus
indicating that recipients transplanted with older donors experienced HCC recurrence more frequently
than those transplanted with younger donors [143] . Although these observations are of interest, previous
studies have not confirmed them in subsequent studies [144,145] .

Given the growing number of donors with metabolic syndrome, one aspect that appears to be of particular
interest is the potential impact of graft steatosis on the risk of HCC recurrence. It has been accepted that
grafts with moderate to severe steatosis present low tolerability to ischemia-reperfusion injury [146] . This
injury may be able to promote a release of lipid peroxides and downregulate the secretion of adipokines
that can protect the steatotic grafts [147] . Thus, the induced inflammatory cascade within the graft could
be responsible for the increase in angiogenesis, which is considered the key factor in promoting tumor
recurrence. All of these observations have not been validated in prospective studies and a large number of
patients; thus, no current evidence exists to modify the allocation criteria for steatotic grafts based on the
presence of HCC in recipients.

There is emerging evidence that persistent HBV infection contributes to cancer development within the
liver, increasing genetic instability of and promoting hepatocyte destruction and regeneration. Several
reports indicate that in patients transplanted for HCC related to chronic HBV infection, the reappearance
of active HBV replication in the graft was associated with an increased risk of HCC recurrence and with
shorter overall survival [126] . These reports were more frequent in the past when prophylaxis against HBV
recurrence was given only with immunoglobulins against HBV or with Lamivudine.