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Page 2 of 19 Marasco et al. Hepatoma Res 2020;6:33 I http://dx.doi.org/10.20517/2394-5079.2020.01

[3]
patients . HCC remains a widespread tumor due to the persistence of a high prevalence of hepatitis B virus
(HBV) infection in African and Asian countries, and from the increasing incidence of non-alcoholic fatty
liver disease, alcoholic and non-alcoholic steatohepatitis (ASH/NASH) patients in Western countries.

There are different therapeutic strategies to manage HCC according to both the underlying extent of liver
disease and tumor-related factors, as stated by the different guidelines available [2,4-6] . The recommended
[2,7]
treatment of choice in these guidelines is mainly an adaptation from the BCLC classification . Patients
with HCC are classified into five stages by tumor related factors (size, number, vascular invasion, N1, M1),
[2]
liver function (bilirubin, portal hypertension, liver function preservation) and health status (ECOG) .
These guidelines were developed to provide the best treatment to maximize overall survival (OS) according
to tumor characteristics listed above. Liver resection (LR) is recommended mainly for single HCCs of any
size and in particular, for size > 2 cm, with preserved hepatic function and sufficient residual liver volume.
In patients with BCLC 0 and A, or in single tumors 2 to 3 cm in size not suitable for surgery, the treatment
of choice is thermal ablation with radiofrequency (RFA) as an alternative to surgical resection. In patients
[2]
with BCLC B, trans-arterial chemoembolization (TACE) is recommended . Even though treatment choice
is tailored for individual patients, HCC recurrence remains the most important concern and can occur
[8]
irregardless of treatment .
In fact, in curative treatments such as liver resection, HCC recurrence developes in up to 70% of patients
at 5 years after hepatic resection, both within (early recurrence) or after 24 months (late recurrence) [1,2,9] .
Several authors [10-13] have explored the differences between early and late recurrence and investigated the risk
[14]
factors for each. Predictive factors for early recurrence are well-known . On the other hand, the prediction
of late recurrences is limited by poor data; it can also be considered a ‘de novo’ tumour and thus, has been
associated mainly with the degree of fibrosis and extent of portal hypertension (PH) [15-17] .

The aim of this review is to summarize the most recent advances in the role of predictive factors for HCC
recurrence in patients undergoing curative HCC treatment beyond liver transplantation such as LR, RFA and
TACE. Furthermore, when possible, biomarkers and imaging predictors are also differentiated.

LIVER RESECTION
[4,5]
LR is the standard of care of patients with solitary tumors and preserved liver function . The major
[14]
complication after LR is HCC recurrence which reaches an incidence of more than 70% at 5 years .
As stated, HCC recurrence can be classified as early or late [11,18] . Early recurrences have well-established
predictive factors which are mainly related to tumor biology (i.e., tumor size, tumor number, presence of
[14]
microsatellites and vascular invasion) and the treatment modality used . In particular, vascular invasion
(both macroscopic and microscopic) is one of the most reliable predictors of recurrence and survival and
[14]
strictly associated with histological differentiation and tumor size . On the other hand, the development of
late recurrences is widely considered a de novo HCC affected by the underlying liver status [19,20] . Thus, the
presence and degree of PH could play an important role in predicting late recurrences. Indeed, the extent of
[25]
PH is directly correlated with the risk of developing complications [21-24] , including HCC . Recently, several
studies have highlighted the role of non-invasive tests such as liver (LSM) and spleen stiffness measurements
(SSM) as predictors of late recurrence of HCC [16,17,26] . The predictive factors for early and late HCC recurrence
after LR are summarized in Table 1.

Early HCC recurrence
Tumor-related factors
[27]
A clear correlation has already been highlighted between tumor size, number and HCC recurrence .
These factors remain the best pre-operative prognostic factors such that both the American and European
[2,4]
Association for the Study of the Liver endorsed these criteria in their staging systems . Indeed, HCC