Non-cirrhotic hepatocellular carcinoma in chronic viral hepatitis: Current insights and advancements

Abstract

Primary liver cancers carry significant morbidity and mortality. Hepatocellular carcinoma (HCC) develops within the hepatic parenchyma and is the most common malignancy originating from the liver. Although 80% of HCCs develop within background cirrhosis, 20% may arise in a non-cirrhotic milieu and are referred to non-cirrhotic-HCC (NCHCC). NCHCC is often diagnosed late due to lack of surveillance. In addition, the rising prevalence of non-alcoholic fatty liver disease and diabetes mellitus have increased the risk of developing HCC on non-cirrhotic patients. Viral infections such as chronic Hepatitis B and less often chronic hepatitis C with advance fibrosis are associated with NCHCC. NCHCC individuals may have Hepatitis B core antibodies and occult HBV infection, signifying the role of Hepatitis B infection in NCHCC. Given the effectiveness of current antiviral therapies, surgical techniques and locoregional treatment options, nowadays such patients have more options and potential for cure. However, these lesions need early identification with diagnostic models and multiple surveillance strategies to improve overall outcomes. Better understanding of the NCHCC risk factors, tumorigenesis, diagnostic tools and treatment options are critical to improving prognosis and overall outcomes on these patients. In this review, we aim to discuss NCHCC epidemiology, risk factors, and pathogenesis, and elaborate on NCHCC diagnosis and treatment strategies.

Keywords: Cirrhosis; Hepatic fibrosis; Hepatitis B virus; Hepatitis C virus; Hepatocellular carcinoma; Hepatoma; Liver cancer; Liver resection; Liver transplantation; Non-alcoholic liver disease; Primary liver cancer.

Figure 1

Mechanisms of oncogenesis in hepatitis B virus induced non-cirrhotic hepatocellular carcinoma. Entry of hepatitis B virus (HBV) virion into hepatocytes results incorporation of DNA into the host genome resulting in covalently closed circular DNA. Integration of HBV DNA leads to expression of multiple stem cell markers. These markers differ based on the region of the HBV genome (preS1, S, core, X). Three mechanisms of oncogenesis with insertional mutagenesis, chromosomal instability and mutant protein formation shown. HBV: Hepatitis B virus; NTCP: Na+-taurocholate co-transporting polypeptide; cccDNA: Covalently closed circular DNA; EpCAM: Epithelial cell adhesion molecule; OCT4: Octamer-binding transcription factor 4; Nanog: Homeobox protein; CK19: Cytokeratin 19; CD: Cluster of differentiation; TERT: Telomerase reverse transcriptase; MLL4: Myeloid lymphoid leukemia 4; CKD15: Cyclin dependent kinase 15; NCHCC: Noncirrhotic hepatocellular carcinoma.

Figure 2

Mechanisms of oncogenesis in hepatitis C virus induced non-cirrhotic hepatocellular carcinoma. Entry of single stranded hepatitis C virus (HBV) RNA into hepatocytes leads to expression of multiple oncogenic proteins. The core section and NS5A sections of the HCV genome produces c-Kit and Nanog-CD133 proteins respectively. HCV infected hepatocytes can lead to sphere formation, sub-genomic replication formation and multiple other mechanism are noted in the schema. Ss: Single stranded; NS: Non-structural; c-Kit: Proto-oncogene, Cam Kinase-like-1; Lgr5: Leucine rich G-protein receptor; CD: Cluster of differentiation; Lin28: RNA binding protein; CK19: Cytokeratin 19; AFP: Alfa fetoprotein; TLR4: Toll-like receptor 4; TGFβ-1: Transforming growth factor-1; NCHCC: Noncirrhotic hepatocellular carcinoma.