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Page 4 of 19 Marasco et al. Hepatoma Res 2020;6:33 I http://dx.doi.org/10.20517/2394-5079.2020.01

6 clinico-pathological characteristics (clinical stage, differentiation level, capsular invasion, tumor number,
tumor diameter, and AFP level) and 8 immunomarkers (CD34, CDKN1A, E-cadherin, HRas, PCNA, p53,
[86]
TGF-β and VEGF). Other authors evaluated the Epstein-Barr virus-induced gene 3 (EBI3) which encodes
a secretory glycoprotein which was previously found to be upregulated in different tumors; they found that
EBI3 was a predictor for tumor recurrence. Among the myriad of other tumoral-tissue related markers, a
[87]
prognostic role was also reported for the Peroxiredoxin 1 (PRDX1) ; the divalent metal-ion transporter-1
[89]
[88]
(DMT1) ; the cell cycle factor NIMA-related kinase 2 (NEK2) ; among the non-coding tumoral RNAs,
[65]
[64]
the miR-210 and miR-550a-1 were associated with a high risk of recurrence , similar to miR-483-3p ; low
[90]
[91]
c-Myc protein expression ; low MHC class I chain-related gene A (MICA) ; the long noncoding RNA
[92]
[93]
(lncRNA) expression signature ; and the NUF2 . However, all these tumoral-tissue related markers have
not found clinical application yet.
Circulating biomarkers
Several circulating markers have been identified to be able to predict early HCC recurrence. Certainly, AFP
is used not only for diagnosing HCC but also plays a key role in predicting recurrence [44-46] with a cut-off
[46]
that has recently been lowered from 200 ng/mL to 100 ng/mL . Since the liver is the organ that synthesizes
lipoprotein (a) [Lp (a)], reduced levels of this lipoprotein could be a sign of liver dysfunction. Thus, as
[94]
Lp (a) mirrors hepatic function and the degree of underlying disease, it has recently been found in a cohort
of HCC patients that low Lp (a) levels (≤ 20 mg/dL) significantly correlated with low time to recurrence
(P = 0.009) and low OS (P = 0.007). Among other circulating markers or composite scores, the albumin-
[79]
bilirubin (ALBI) score has been validated as a predictor of survival in HCC . Recently, an Asiatic
[80]
study evaluated the role of ALBI in predicting early recurrence. It was found that an ALBI grade ≥ 2
(P = 0.003) in addition to HBV surface antigen (HBsAg)-positive status (P < 0.001), tumor size ≥ 3.5 cm
(P ≤ 0.001), lympho-vascular invasion (P = 0.001), and the presence of satellite lesions (P = 0.009) were the
only predictors of early HCC recurrence on multivariate analysis. The same results on ALBI were recently
[55]
reported by other authors [55,81,82] , among whom Chan et al. developed the ERASL-pre score, which
included male gender, large tumor size, multinodular tumors, high ALBI grade and high serum AFP. More
[95]
recently, an elevated fibrinogen/albumin ratio was found to be significantly correlated with shorter survival
and an increase risk of HCC recurrence. On the same line, the ratio between high-sensitivity C-reactive
[96]
protein (hsCRP) and albumin was associated with a 1.19-fold increase in the risk of HCC recurrence . In
an additional study on hsCRP, it was found to be associated with lymphocyte ratio (HCLR) and positively
[48]
correlated with large tumor size, TNM stage, MVI, and HCC recurrence . A further composite score is
[56]
represented by REACH which includes NxS factor, MVI, differentiation, serum albumin, platelet count
and indocyanine green retention rate at 15 min and was able to predict the risk of HCC recurrence.

Other simple factors that are able to predict early recurrence of HCC that should be taken into account are
[49]
the lymphocyte and neutrophil levels computed into the NLR , which mirrors a pro-tumor inflammatory
environment and the activity of host immunity. In fact, these authors found that patients with pre-operative
NLR < 2.5 were at lower risk of recurrence. Thus, others have tried to refine the predictive value of these
[97]
scores by building a composite score with ALBI and platelet to-lymphocyte ratio , which was able to
predict the outcome after liver resection, including HCC recurrence. Platelet to-lymphocyte ratio was further
[50]
associated with NLR with good results . Finally, other immune-biomarkers that have promising results
[52]
[51]
are the lymphocyte-to-monocyte ratio , gamma-glutamyl transpeptidase to lymphocyte count ratio
[54]
[53]
and systemic inflammation score . A Chinese group recently demonstrated that IgG4/IgG ratio is an
independent indicator of tumor recurrence and a high ratio is associated with a shorter time to recurrence.
Circulating microparticles are novel biomarkers with a potential prognostic role in patients with cancer.
[98]
Their role in HCC has been investigated by Abbate et al. and it was found that the number of circulating
HepPar1+ microparticles before resection was higher in patients with early recurrence compared to those