Dimensions of hepatocellular carcinoma phenotypic diversity

Hepatocellular carcinoma (HCC) is the 3^rd leading cause of cancer-related death worldwide. More than 80% of HCCs arise within chronic liver disease resulting from viral hepatitis, alcohol, hemochromatosis, obesity and metabolic syndrome or genotoxins. Projections based on Western lifestyle and its metabolic consequences anticipate a further increase in incidence, despite recent breakthroughs in the management of viral hepatitis. HCCs display high heterogeneity of molecular phenotypes, which challenges clinical management. However, emerging molecular classifications of HCCs have not yet formed a unified corpus translatable to the clinical practice. Thus, patient management is currently based upon tumor number, size, vascular invasion, performance status and functional liver reserve. Nonetheless, an impressive body of molecular evidence emerged within the last 20 years and is becoming increasingly available to medical practitioners and researchers in the form of repositories. Therefore, the aim this work is to review molecular data underlying HCC classifications and to organize this corpus into the major dimensions explaining HCC phenotypic diversity. Major efforts have been recently made worldwide toward a unifying "clinically-friendly" molecular landscape. As a result, a consensus emerges on three major dimensions explaining the HCC heterogeneity. In the first dimension, tumor cell proliferation and differentiation enabled allocation of HCCs to two major classes presenting profoundly different clinical aggressiveness. In the second dimension, HCC microenvironment and tumor immunity underlie recent therapeutic breakthroughs prolonging patients' survival. In the third dimension, metabolic reprogramming, with the recent emergence of subclass-specific metabolic profiles, may lead to adaptive and combined therapeutic approaches. Therefore, here we review recent molecular evidence, their impact on tumor histopathological features and clinical behavior and highlight the remaining challenges to translate our cognitive corpus into patient diagnosis and allocation to therapeutic options.