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Marasco et al. Hepatoma Res 2020;6:33 I http://dx.doi.org/10.20517/2394-5079.2020.01 Page 5 of 19

without (P = 0.02). With regard to other cancer biomarkers, platelet derived growth factor-BB has been
[99]
claimed to be one of the key cytokines in malignant transformation of different cells and recently ,
diminished perioperative platelet derived growth factor-BB has been linked to HCC recurrence. Another
potential biomarker concerns serum proteome alterations [100] : PGK1, which is directly involved with
carcinogenesis and the intracellular inflammation cascade, was found to be increased in patients with early
tumor recurrence. Recently, a glycan-based immunoassay targeting Wisteria floribunda agglutinin-positive
+
human Mac-2 binding protein (WFA -M2BP) was evaluated as a noninvasive biomarker of liver fibrosis and
predictor of HCC and HCC recurrence, as it was associated with pro-carcinogenic activity in patients with
chronic liver disease [101] . In a further study, it was associated with both early (HR = 1.667) and late recurrence
(HR = 1.416) with multivariate analysis [102] .

In conclusion, some circulating biomarkers have gradually been endorsed in clinical practice in several
centers for their simplicity and real-time application based on standard liver tests, and are able to give reliable
prognostic information on these patients.

Imaging predictive factors
Pre-operative imaging signatures have been proposed in the last decade for predicting HCC recurrence
before resection. With regard to computed-tomography (CT) scan prediction, beyond the classic HCC
features associated with HCC recurrence, a HCC texture based study found good correlation with
[66]
histological grade and thus, the risk of disease recurrence .

As for magnetic resonance imaging (MRI), correlation between the preoperative diffusion-weighted imaging
[67]
and early recurrence has been found [67,68] , specifically with minimal apparent diffusion coefficient values.
Several studies reported that imaging findings based on peri-tumoral tissue enhancement and hypointensity
in the hepatobiliary phase were useful for predicting MVI and early recurrence in HCC [68-70] .

[70]
A Korean study carried out in 2017 , which is one of the largest among those stated above, included 197
patients and using gadoxetic acid-enhanced MRI for predicting MVI, highlighted that the combination of at
least two of the following - arterial peri-tumoral enhancement, non-smooth tumor margin, and peri-tumoral
hypointensity on hepatobiliary phase - was able to predict MVI with > 90% specificity and associated with
early recurrence after a single HCC nodule resection. These results have been further confirmed by other
[71]
groups worldwide [68,69] . To enhance the predictive accuracy of these findings, a recent study used Radiomics
[72]
on CT-scans for this purpose. Radiomics is a new method for medical image analysis , defined as the high-
throughput extraction of quantitative metric features that result in the conversion of images into mineable
[71]
data. These authors found that peri-tumoral radiomics was better in predicting HCC early recurrence than
[73]
tumoral radiomics . Other authors using radiomics on pre-operative CT-scans found a good correlation with
[74]
MVI (AUC 0.80) . Beyond texture, using 3D MRI was also possible to evaluate tissue stiffness; a multicenter
[75]
study recently found that HCCs with subsequent recurrence had higher tumor stiffness.
Finally, an additional prognostic role has also been investigated for fluoro-deoxyglucose (FDG)-positron
emission tomoscintigraphy (PET). Indeed, a recent study [103] with FDG-PET before surgery concluded
that a larger tumor size and serum AFP were correlated with higher SUV max (≥ 4.9), which was able to
distinguish between patients with or without HCC recurrence after resection.

Beyond the standard evaluation of HCC (tumor number, size, location, vascular invasion) however, the
above evaluation methods remain as research and are only applied in highly specialized centers.

Resection-related factors
Strong evidence is available on the role of tumor-free margins in HCC [104] . Most previous studies have stated
that tumor margins should be at least 1 cm [42,43] . A randomized controlled trial showed however, that in order
to improve survival margins should be at least 2 cm [104] .