Chronic liver disease (CLD) is associated with inflammation, fibrosis, and cirrhosis. The ongoing inflammation, injury, repair, and regeneration are responsible for the activation of genetic and epigenetic mechanisms of neoplasia resulting in the formation of dysplastic nodules which are precancerous lesions with high susceptibility to develop into HCC. HCC develops at a rate ∼3.5% per year and an average 10 years median time is needed for the development of HCC in cirrhosis (7). Various somatic genetic and epigenetic mutations telomerase reverse transcriptase (TERT), catenin beta-1 (CTNNB1), axis inhibition protein 1 (AXIN1), tumor protein 53 (TP53), AT-rich interaction domain 1A (ARID1A), and ARID1B occur in CLD patients leading to activation of hepatocarcinogenic pathways like wingless-related integration site (WNT)–β-catenin signaling, receptor tyrosine kinase (RTK)–RAS–phosphatidylinositol 3-kinase (PI3K) cascades, oxidative stress, telomere shortening, and chromatin modification (8–12). Unlike in other solid tumors, no single gene mutation is responsible for HCC. This is why targeted molecular therapy for HCC has not been developed to date. HCC can also occur in the non-cirrhotic liver like in HBV infections, NASH, and uncommonly in benign lesions like hepatocellular adenomas (HCAs). TERT and CTNNB1 mutations have been documented to be associated with malignant transformation in <10% of HCAs (13). Almost 80% of HCC develop from mature hepatocytes; however, ∼20% may develop from hepatic progenitor cells or dedifferentiated hepatocytes (14).

Researchers all over the world have done extensive genomic, epigenomic, and transcriptomic profiling of resected tumors to understand the tumor biology. Based on these findings, a molecular classification of HCC has been proposed which has clinical and prognostic implications as well as it may guide in the selection of therapeutic modality. Two classes proliferative and non-proliferative have been suggested. The proliferative class has chromosomal instability with more prevalence of TP53 inactivation, cyclin D1 (CCND1), and fibroblast growth factor 19 (FGF19) amplifications leading to activation of RAS–MAPK (mitogen activated protein kinase), phosphatidylinositol-3-kinase (PI3K)/Akt and the mammalian target of rapamycin (mTOR) and tyrosine-protein kinase Met signaing pathways affecting cell proliferation and survival. Two subclasses S1 and S2 based on their pathways and gene activation have been proposed. HBV-related HCC belongs to the proliferative class with poor outcomes (Figure 1).

The non-proliferative class has three subclasses with more heterogeneity. It is associated with HCV and alcoholic liver diseases. The canonical pathway of WNT-signaling and β-catenin mutation is characteristically involved in non-proliferative tumors.

As a part of “The Cancer Gene Atlas” (TCGA) research network, Wheelar et al. (15) performed a comprehensive integrated analysis of resected specimens of HCC among 363 patients which included six data platforms DNA exome sequencing, DNA methylation, mRNA expressions, miRNA expressions, copy number data, and proteomics to understand the molecular landscape of HCC. The aim was to understand the clinical correlation with mutations and molecular markers, prognostication of various molecular classes, and for identification of therapeutic targets based upon immunogenetics.

Chronic liver disease is associated with chronic inflammation with immune cell infiltration which over a long period increases the risk of HCC. Sia et al. (16) have suggested a novel immune-based classification of HCC. It comprises “Immune HCC” in ∼30% HCC with increased immune cell infiltration like cytotoxic T cells, macrophages, etc. associated with increased expression of programmed cell death receptor 1 ligand 1 (PD-L1), PD-1, and IFN-γ signal and “Immune excluded” in ∼25% HCC with less chromosomal aberrations and decreased immune cell infiltration with CTNNB1 mutation (16). Immune HCC class is further subdivided into “active immune” and “immune exhausted” classes. The immune HCC and immune excluded HCC classes overlap with proliferative and non-proliferative classes, respectively. However, 45% of HCC lie in the immune intermediate class at present due to their indeterminate genetic signatures. The immune-based classification may guide us for the development of immune checkpoint inhibitors (CPIs) for HCC in future.

Curative therapies like transplant and resection are recommended only for early-stage HCC with 5-year survival rates of 70% whereas only palliative treatment is possible for intermediate and advanced stage HCC with a median survival of 1–3 years. Chronic liver diseases pose a risk for HCC by chronic inflammation, fibrosis, and cirrhosis. CHB has a higher risk among males, African <40 years, with advanced fibrosis or cirrhosis (3–8% per year) and with a positive family history of HCC. Cirrhosis due to HCV (3–5% per year), NASH, alcohol, primary biliary cholangitis with stage 4 fibrosis, Wilson’s disease, hemochromatosis, and α1-antitrypsin deficiency are other risk factors. Singal et al. (17) in a meta-analysis for HCC surveillance in patients with cirrhosis showed improvement in the detection rate of early-stage HCC (Odds ratio [OR] 2.08, 95% confidence interval [CI] 1.80–2.37), higher treatment rate (OR 2.24, 95% CI 1.99–2.52), and better survival (OR 1.90, 95% CI 1.67–2.17). HCC surveillance has uncertain benefits in HCV with stage 3 fibrosis, young HBV carriers’ Asian males <40 years and females <50 years, and NAFLD without fibrosis. American Association for the study of Liver Disease (AASLD) and European Association for Study of the Liver (EASL) guidelines jointly recommend HCC surveillance with ultrasonography (USG) and alpha-fetoprotein (AFP) levels 20 ng/mL at regular intervals preferably every 6 months in cirrhosis of the liver to be cost-effective. Computed tomography (CT) or magnetic resonance imaging (MRI) scan at present is not recommended for HCC surveillance as they are not cost-effective and it is impractical to repeat them periodically except when ultrasound is inadequate (18). Park et al. (19) have shown limited non-enhanced MRI (Diffusion weighted imaging with T2; diffusion restriction with T2 hyperintensity) to be better than USG for HCC surveillance with higher sensitivity (79% vs 28%), comparable specificity (98% vs 94%), higher positive predictive value (62% vs 17%), and comparable negative predictive value (99% vs 97%). They showed limited MRI imaging having a study time duration of 6 min with room occupancy time of 15–25 min as compared to 10–15 min for USG. On the other hand, Labgaa et al. (20) have recently demonstrated the presence of cell-free DNA (cfDNA) in plasma samples of patients with HCC for detecting somatic mutations in tumor tissues as a new minimally invasive method for determination of HCC genetics. The new technique called “Liquid biopsy” holds great promise in future for diagnosing HCC especially in lesions <2 cm in size, predicting the prognosis of the lesion based upon certain genetic mutations and better selection of therapeutic modality based upon immunogenetics (21, 22).

Hepatocellular carcinoma classically arises from dysplasia of cirrhotic nodules (Figure 2). During the dysplasia, the vascular supply dominantly becomes arterial and with malignant transformation, there is the formation of arterioportal fistulas. The liver imaging by CT/MRI scan shows hyperenhancement of HCC during the arterial phase due to rapid fill-in of intravenous contrast and rapid washout of contrast during the portal venous phase when the rest of the liver shows enhancement which becomes more pronounced during delayed venous phases. A recent meta-analysis by Roberts et al. (23) has demonstrated higher sensitivity (0.82 vs 0.66), comparable specificity (0.91 vs 0.92) with lower negative likelihood ratio (0.20 vs 0.37), and comparable positive likelihood ratio (8.8 vs 8.1) for triphasic contrast MRI and CT scan, respectively. However, MRI for <1 cm size nodule had higher sensitivity (0.69 vs 0.49) and lower specificity (0.46 vs 0.69) than a CT scan. On the other hand, MRI should not be the first choice for patients with ascites (artefacts), poor breath-hold (artefacts), and decompensated liver disease (poor gadoxetate sodium uptake by liver parenchyma).

Contrast-enhanced ultrasound is a better modality for HCC diagnosis in patients with contrast allergy or renal dysfunction. The liver imaging reporting and data system (LI-RADS) version 2018 has provided the algorithm for surveillance, diagnosis, and assessment of treatment response for HCC to achieve a universal approach for standardization and consistency in image reporting (24). Features suggesting HCC include enhancing capsule, non-rim arterial phase hyperenhancement, non-peripheral washout, size of tumor, and threshold growth of tumor over a duration on multiphase contrast-enhanced CT or MRI. On the USG size of the lesion, architectural distortion of the liver, venous thrombus in the liver, and refractive edge shadows around the lesion are features suggestive of HCC.

Hepatocellular carcinoma is a carcinoma that most frequently arises in the background of cirrhosis. In any staging system in addition to tumor nodule numbers and size, the severity of liver dysfunction is taken into consideration. Decompensated cirrhosis has a large impact on the outcome of any therapy for HCC. The Barcelona clinic liver cancer (BCLC) staging system (25) is most accepted in various guidelines and practiced (Figure 3). The staging in BCLC is linked to most appropriate therapy for HCC according to the stage of tumor which includes nodule size and number along with intrahepatic or extrahepatic vascular invasion, extrahepatic metastases, Child–Pugh class for the severity of liver decompensation, and performance status of the patient as assessed by Eastern Cooperative Oncology Group (ECOG) criteria. This is imperative to understand that selection of therapy and its best outcome is always dependent on the extent of liver disease in a given patient. There are other staging systems like the Cancer of the Liver Italian Program (26) and the Hong Kong Liver Cancer staging system (27); however, they are more geographically restricted. Over the years, experts have found that the BCLC staging system has a rigid approach with a selection of patients best for stage associated therapy rather than the best treatment modality for a given patient. Various studies have also shown superior results for aggressive surgical approach than locoregional therapy in HCC. Therefore, the concept of “treatment stage migration” is emerging with either “left to right” or even “right to left” shift for selection of therapy in the BCLC algorithm (28). This means considering liver resection in patients with either vascular invasion or consideration of liver transplantation in patients with downstaging of tumor with locoregional therapy or outside Milan’s criteria (29–31).