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Marasco et al. Hepatoma Res 2020;6:33 I http://dx.doi.org/10.20517/2394-5079.2020.01 Page 11 of 19

analysis), lower homogeneity, and smaller tumor size are all significant predictors of complete response after
TACE [158] .

Recently, in patients with very early and early HCC, the presence of hypovascular hepatic nodules represents
a significant risk factor for recurrence and a bad prognosis after treatment; this is a contraindication to the
procedure in these patients [159] . Moreover, a CT image analysis method known as the parametric response
map approach is more sensitive for finding changes in the response to treatment than the conventional
approach based on the recap of statistics assessed on a region of interest. Briefly, parametric response map
aligns spatially the longitudinal images before and after treatment and classifies the patient’s images into
three categories: reduced, unchanged, and increased intensity [160] .

MRI has a central role in the identification of focal liver lesions. With technical progress, liver MRI
has improved with many imaging modalities now for the diagnosis of HCC [161] . Indeed, gadoxetic acid
(Primovist, Bayer Schering Pharma) provides dynamic perfusion imaging and also, evaluation of delayed
hepatocyte uptake and biliary excretion which concurs with the precise detection and characterisation of
HCC [206] . Gadoxetic acid-enhanced liver MRI is now widely used and plays a crucial role, not just in the
initial diagnosis of HCC, but also in the evaluation of therapeutic efficacy and early diagnosis of residual
or recurrent tumor after TACE [207] . Indeed, HCCs showing high uptake of gadoxetic acid appear to be
[162]
susceptible to TACE with increasing HCC free-survival in these patients . Combined diffusion-weighted
imaging and choline levels measured at hydrogen-1 magnetic resonance spectroscopy can be used as an early
imaging biomarker of treatment response in HCC patients after DEB-TACE [163] . Moreover, in unresectable
2
-3
HCC, baseline early apparent diffusion coefficients < 0.83 × 10 mm /s is a predictor of treatment response
at 1 and 3 months after DEB-TACE and OS with high specificity and sensitivity [155] . Finally, a sophisticated
3D MRI and CT method based on quantitative tumor response (volumetric Response Evaluation Criteria in
Solid Tumors and the European Association for Study of the Liver guidelines) were early response markers
that can be used to predict survival after initial TACE and allow univocal identification of responders and
non-responders in terms of median OS [208] .

CONCLUSION
HCC characteristics and the severity of the underlying liver disease are the main considerations in the
decision-making process for the best therapeutic strategy for each patient, in order to improve survival and
reduce recurrence rates. HCC early recurrence remains related to the aggressiveness of the treated HCC and
the technique used. HCC late recurrence, being a “de novo” tumor, is mainly predicted by markers of severity
of liver fibrosis and the degree of portal hypertension.

Beyond liver disease etiology and the continuous presence of pro-carcinogenetic factors that are etiology-
related, the most reliable markers for predicting HCC recurrence after LR are the presence of macro- and
micro-vascular invasion, tumor size and the assessment of liver disease severity through the use of LSM.
For the same purpose, no definitive data are available in the setting of RFA, even if most studies seem to
support a role for LSM. On the other hand, one of the most reliable predictive factors for HCC recurrence
after TACE is tumor hypervascularity. The novel circulating, genetic and imaging related markers still need
additional validation. Thus, further prospective and well-designed studies are needed to discover new and
reliable predictive markers for HCC recurrence after treatments with curative intent.

DECLARATIONS
Authors’ contributions
Conceptualized and designed the review: Marasco G, Colecchia A
Wrote, reviewed and edited the manuscript: Marasco G, Ravaioli F, Vestito A, Rossini B, Dajti E, Renzulli M
Provided the tables: Rossini B, Colecchia L, Gjini K