Page 371 - Read Online

Page 6 of 19 Marasco et al. Hepatoma Res 2020;6:33 I http://dx.doi.org/10.20517/2394-5079.2020.01

On the other hand, the extent of resection is another key factor to take into account when predicting
tumor recurrence. If anatomical resection (whole hepatic segment) allows reduction of risk for intrahepatic
metastasis due to microsatellite nodules and segmental neoplastic thrombi, most surgeons would prefer non-
[40]
anatomical resections instead in order to reduce the risk of post-hepatectomy liver failure . Most studies on
this topic are affected by much heterogeneity amongst the patients enrolled, since non-anatomical resections
are performed mainly in patients with small HCC nodules and with a higher degree of liver dysfunction. A
large series has demonstrated that non-anatomical resection is equally safe in terms of recurrence for HCC
nodules less than 2 cm [105] . On the other hand, for larger tumors, anatomical resection is equally able to
[8]
guarantee a lower rate of early HCC recurrence .

Late HCC recurrence
Late HCC recurrence is currently not considered a true recurrence of the primary HCC since it seems to
be a “de novo” tumor and thus, dependent on the degree of underlying liver cirrhosis [106] . Most studies on
this topic highlight predictive factors for late recurrence including the severity of liver cirrhosis, presence
of active hepatitis and the degree of PH [11,16,17,26,57,61,77,107] . Indeed, the sole presence of liver cirrhosis itself
[11]
leads to a doubling of risk for late recurrences . In the specific setting of HBV, Ishak activity > 6, an
indocyanine green clearance (ICG-15) > 10% and HBsAg > 250 IU/mL were found to be predictors of late
[58]
HCC recurrence [15,61] . With regard to HCV etiology, a recent study demonstrated that HCV-eradication
was able to reduce the recurrence of HCC, independent of HCC treatment and the HCV-treatment regimen
administered. Further confirmation of the importance of viral eradication came from a recent North
[59]
American study on new direct antiviral agents and regimens, which demonstrated that the risk of HCC
[60]
recurrence was not increased by this treatment, as previously postulated . Even continuous alcohol intake
in patients with Alcohol-related Liver Disease seems to be a HCC risk factor for both the occurrence of
primary HCC and late recurrences, since the development of HCC depends both on direct (genotoxic) and
[63]
indirect factors (cirrhosis development) [62,108] . Indeed, a recent study by Kudo et al. found that preoperative
excessive alcohol intake was related to decreased disease-free survival rate of HCC recurrence after surgery.
Similarly, the presence of obesity at the time of LR has been reported as a risk factor for HCC recurrence [109] .

Going back to liver cirrhosis, also in this setting there is an increasing need for non-invasive tests to stratify
[83]
late HCC recurrences. One of the most frequently used and non-invasive test is the ALBI grade , which is
an objective and discriminatory method for assessing liver function in HCC, and is gradually replacing the
Child-Pugh score. The ALBI has also been found to be a predictor of late HCC recurrence after resection
[84]
ALBI grades 2 and 3 (P < 0.001) . Recently, a composite score [110] for predicting both early and late HCC
recurrences in HBV has been developed and validated; this DFT score includes liver function through
the use of FIB-4, which is a surrogate marker of liver fibrosis, tumor burden and grade of differentiation.
A combination of ALBI and FIB-4 has also been proposed with good accuracy in predicting HCC
[78]
recurrence .
[26]
In line with these efforts, Jung et al. found that patients with LSM values > 13.4 kilopascal (kPa) were at
increased risk for late HCC recurrence with a HR of 1.9. Another research group followed up patients with
[77]
HCC after treatment and found that a decrease in LSM < 8 kPa suggested a reduced risk of late recurrence .
[16]
In a subsequent study by Jung et al. , the LSM value, together with activity grade II-III, the presence of
multiple tumours, and ICG R15 achieved good accuracy in predicting late HCC recurrence. Another non-
invasive test capable of mirroring the degree of PH is the evaluation of SSM [23,24,111,112] , which has been
[17]
demonstrated to be associated with post-hepatectomy liver failure too [113] . We recently demonstrated in
a cohort of compensated advanced chronic liver disease patients undergoing LR for primary HCC, that
univariate analyses of late HCC recurrences were associated with esophageal varices, spleen length, platelet/
spleen length ratio, LSM and SSM. Multivariate analyses however, showed that SSM was the only predictor
of late recurrence (HR = 1.046). Thus, it is possible to conclude that NITs focused on the evaluation of the