Since the widespread adoption of new direct-acting antiviral agents (DAAs), the approach to hepatitis C virus (HCV) infection has changed profoundly as almost all patients can be cured regardless of the stage of their liver disease. On the other hand, there are a few conflicting reports on the risk of hepatocellular carcinoma (HCC) occurring and recurring in patients given DAA-based therapy. The present review focuses on the latest and most relevant literature providing evidence on the occurrence and recurrence of HCC after HCV antiviral treatment with the new DAAs. Retaining the distinction between HCC occurrence and recurrence, we also discuss its patterns of presentation and speculate on the possible pathogenic mechanisms. We offer our personal viewpoints on this important issue, which has kept clinicians second-guessing in real-world clinical practice, when dealing with HCV eradication in the setting of advanced liver disease in this interferon-free era.

Heterogeneity is a cardinal hallmark of cancer, including primary liver cancer (PLC), and occurs at different layers including putative cell-of-origin. Current evidence suggests that within cellular subpopulations in PLC there are stem-like cells, the cancer stem cells (CSCs). The CSC concept has been recently proposed as an explanation of such intra-tumor heterogeneity. According to this model, CSCs are responsible for tumor initiation, recurrence, metastasis as well as drug-resistance. However, although the CSC hypothesis is intriguing and supported by a large number of experimental studies, there are still open questions regarding the origin of putative CSCs. Since chemo-resistance and recurrence represent major issues in PLC treatment, the development of new therapeutic strategies is needed, for which a good understanding of tumor behavior and in particular of CSCs biology is an imperative prerequisite. In this review we summarize the regulatory pathways that support CSC features in PLC. Moreover, we highlight the key features of hepatic CSC, in terms of enhanced drug-resistance, increased metastatic potential and metabolic rearrangement. Knowledge of the molecular mechanisms underlying CSC biology may provide novel options for PLC combination therapies.

The development of second generation ultrasound (US) contrast-medium and specific imaging techniques with dedicated softwares, allows to observe the liver perfusion in real time, becoming an useful and less invasive method to describe precisely the vascularization of hepatic lesions. This significantly increased the ability of US to detect and characterize focal liver lesions. The aim of this review article is to evaluate the role of contrast enhancement US in the diagnosis of hepatocellular carcinoma in cirrhotic liver, with reference to the guidelines of American Association for the Study of Liver Diseases, European Association for the Study of the Liver and European Federation of Societies for Ultrasound in Medicine and Biology.

Primary liver cancer represents the 4th most common tumor in males (4% of all cancers) and the 7th most common tumor in females (2.3% of all cancers), with a prevalence of 53/100,000 in males and 22/100,000 in females (male-to-female ratio = 2:1). In the majority of the cases, hepatocellular carcinoma (HCC) develops in patients with cirrhosis and thus the risk factors for HCC and chronic liver disease are overlapping. Viral infections (hepatitis B virus, hepatitis C virus), alcohol and fat (nonalcoholic fatty liver disease/non-alcoholic steatohepatitis) represent the main risk factors for development of HCC on cirrhotic liver. Several prospective studies reported that at present HCC does represent the first cause of death of cirrhotic patients, while in the past morbidity and mortality in cirrhosis were mainly determined by other non-neoplastic complications of the disease. From a clinical point of view, staging systems in HCC should define outcome prediction and treatment assignment. Due to the nature of HCC, the main prognostic variables are the tumor stage, liver function and performance status. The most accepted clinical classification of HCC has been proposed by the Barcelona Clinic Liver Cancer. The BCLC staging system has come to be widely accepted in clinical practice and is also being used for many clinical trials of new drugs to treat HCC. Therefore, it has become the de facto staging system that is used.

Obesity and diabetes are associated with the onset of hepatocellular carcinoma (HCC). These two illnesses correlate also with the development of non-alcoholic fatty liver disease (NAFLD). Currently, NAFL is considered the leading form of chronic liver disease in the Western industrialized countries. Insulin resistance is the common pathogenic factor among these three pathologies. NAFL is characterized by fat accumulation in the liver that involves greater than 5% of the liver parenchyma with no evidence of hepatocyte injury. However, NAFL may progress toward non-alcoholic steatohepatitis that in turn may lead to advanced fibrosis, cirrhosis and HCC. It is alarming that NAFLD related HCC has been, at present, considered as a growing burden worldwide, and its prevalence is tending to further increase together with the increasing incidence of obesity and diabetes. Worthy of note is that in the presence of chronic accumulation of fat in the liver it has been reported the emergence of HCC during chronic liver disease in absence of liver cirrhosis, usually the major risk factor for the development of HCC. Thus, in the future NAFLD related HCCs will place a growing strain on health-care systems from the need for their management. Unfortunately, most of the NAFLD related HCC patients are diagnosed at advanced stages and are characterized by a poor prognosis, because they are ineligible to radical treatments. Thus, it is urgent to boost up new screening policies to make early diagnoses, as well as to develop preventive-therapeutic strategies.

Hepatocellular carcinoma (HCC) is one of the most relevant sanitary problems for its prevalence and poor prognosis. This tumor is characterized by highly heterogeneous features, both at clinical and molecular level. SerpinB3 (squamous cell carcinoma antigen-1 or SCCA1) is a serine-protease inhibitor that protects cells from oxidative stress conditions, but in chronic liver damage it may lead to HCC through different strategies, including inhibition of apoptosis, induction of epithelial to mesenchymal transition, cell proliferation and invasiveness. Mechanisms of tumor growth promotion induced by SerpinB3 encompass the inhibition of intratumor infiltration of natural killer cells and the up-regulation of Myc oncogene. Recently this serpin has also been identified as a Ras-responsive factor and modulator of metabolic pathways. In the liver SerpinB3 is undetectable in normal hepatocytes, but its expression progressively increases in chronic liver diseases, dysplastic nodules and hepatocellular carcinoma, especially in those with poor prognosis, in which it could also exert immunomodulatory effects. In serum SerpinB3/4 isoforms (or SCCA) circulate bound to IgMs (SCCA-IgM) in patients with HCC, and in patients with cirrhosis their levels have been found correlated to the risk of HCC development. Preliminary findings in patients with HCC revealed that SCCA-IgM levels are predictive of HCC prognosis.

New regimens with direct-acting antivirals (DAAs) agents have changed both efficacy and safety of hepatitis C virus (HCV)-treatment, as almost all patients can be treated and cured at any stage of liver disease. The rates of sustained virological response to currently available combinations exceed 95% in real-life practice. However, conflicting results have been produced on the occurrence/recurrence of hepatocellular carcinoma (HCC) in patients with HCV-associated cirrhosis treated with DAAs. In this review we analyse the data available in the literature in order to elucidate the impact of DAAs on the risk of HCC occurrence in patients without previous history of tumor, and of recurrence after successful treatment of the tumor. Data on “de novo” HCC incidence were quite homogeneous, suggesting that the treatment with DAAs does not modify the risk of HCC developing during the first 6-12 months after HCV eradication. On the contrary, HCC recurrence rates after DAAs were extremely variable across different studies, reflecting a large heterogeneity in this clinical setting. The possibility that treatment with DAAs may favour tumour growth and spread in individual patients with active HCC foci is supported by some observations but remains unproven.

The multiplicity and phenotype of intratumoral immune infiltrate have been shown to influence the clinical outcome of hepatocellular carcinoma (HCC), thus providing a strong rationale to therapeutic interventions aimed at restoring the dysfunctional immune response against the tumor. Improving the knowledge of the complex interactions between transformed hepatocytes, nonparenchymal resident cells, and infiltrating immune cells (characterizing the HCC microenvironment) will be instrumental to increase the success rate of existing immunotherapeutic strategies and to identify new potential targets for intervention or biomarkers to optimize the selection of candidate patients.

Cholangiocarcinoma (CCA) is a heterogeneous group of malignancies that could develop at any level from the biliary tree. CCA is currently classified into intrahepatic (iCCA), perihilar and distal on the basis of its anatomical location. Of note, these three CCA subtypes have common features but also important inter-tumor and intra-tumor differences that can affect the pathogenesis and outcome. A unique feature of iCCA is that it recognizes as origin tissues, the hepatic parenchyma or large intrahepatic and extrahepatic bile ducts, which are furnished by two distinct stem cell niches, the canals of Hering and the peribiliary glands, respectively. The complexity of iCCA pathogenesis highlights the need of a multidisciplinary, translational and systemic approach to this malignancy. This review will focus on the advances of iCCA epidemiology, histo-morphology, risk factors, molecular pathogenesis, revealing the existence of multiple subsets of iCCA.