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Page 8 of 11 Puoti. Hepatoma Res 2018;4:57 I http://dx.doi.org/10.20517/2394-5079.2018.67

surgical resection as first option, because if modern MRI is applied in pre-operative staging, the fact that
solitary large tumors remain single and with no macrovascular involvement - which might be common in
[8]
HBV-related HCC - reflects a more benign biological behaviour .
Variables related to liver function are relevant for candidates to resection. Absence of clinically relevant
portal hypertension and normal bilirubin are key predictors of survival in patients with single tumors
undergoing resection [50,51] . Similarly, Child-Pugh class A is the strongest prognostic variable in patients
[50]
undergoing local ablation, along with tumor size and response to treatment . Since liver transplantation
may potentially cure both the tumor and the underlying liver disease, variables mostly related with HCC
have been clearly established as prognostic factors (single tumors < 5 cm or 3 nodules < 3 cm), defining the
so-called Milan criteria.

Stage B - patients in the intermediate stage B show multinodular asymptomatic HCC without an
invasive pattern. Liver function may be preserved (Child A), or early decompensation might be seen
(Child B). Performance Status is = 0. These patients might receive a survival benefit from transarterial
chemoembolization, while other treatments such PEI or RFA should be avoided.

Stage C - these subjects suffer from advanced HCC (N1, M1), that consists of macroscopic vascular invasion
(portal vein invasion), extrahepatic spread (lymph nodes and metastasis) or cancer-related symptoms
(performance status 1-2). They cannot receive treatments other than first line therapy with sorafenib.

Stage D - patients with terminal stage (stage D) have decompensed cirrhosis (Child C) and PST > 2. Only
supportive, symptomatic treatment can be offered.

Prognosis and survival
Due to the high clinical variability among the different stages of the BCLC classification, a significant
difference in terms of survival exist.

Patients presenting with very early (stage 0) and early-stage diseases (stage A) represent 20%-30% of patients
with HCC. This group, suitable for curative treatments such as resection, liver transplantation, or local
ablation with PEI or RFA, have a 5-year survival of 50%-70%.

By contrast, patients in intermediate stage B and more advanced stage C stages, who account for 50%-60%
of patients, have a poorer prognosis, presenting a 3-year overall survival of 10%-40%. Finally, symptomatic
subjects with end-stage disease (stage D; 10%-20%) have a survival < 3 months.

Several new tools will be available to identify cirrhotic patients at higher risk to develop HCC, such as
DNA-fusion genes, genetic mutations and epigenetic changes, messenger RNA (mRNA), non-coding RNA-
including microRNAs (miRNA), long non-coding RNAs (lncRNA) and other species, proteins and post-
translational protein modifications (e.g., phosphorylation), metabolites and antibodies, AFP L3, des-gamma
carboxy prothombin [8,52,53] . In the next future, these tools would be possible biomarkers for prognosis,
diagnosis and as therapeutic targets for hepatocellular carcinoma.

OPEN ISSUES AND CONCLUSIONS
Despite substantial advancements in the knowledge and the management of patients with cirrhosis
and HCC, several controversies and open issues exist, regarding the timing of surveillance, the optimal
[8]
diagnostic tools, the increase of HCC after treatment with new DAAs, etc. .
There is considerable debate regarding this latter issue. Indeed, two years ago, two papers from Spain and