Steatohepatitic hepatocellular carcinoma

Subtypes of hepatocellular carcinoma are important for 2 primary reasons: they help improve diagnostic accuracy, as different subtypes have their own diagnostic pitfalls; they are an important building block to the personalization of patient care, as subtypes are enriched for shared genetic changes and biological associations. The most common subtype of hepatocellular carcinoma is steatohepatitic hepatocellular carcinoma (SH-HCC), a subtype that is strongly linked to tumorigenesis in the setting of the metabolic syndrome and metabolic-associated liver disease (MAFLD) and/or alcoholic hepatitis. SH-HCC shows macrovesicular steatosis, balloon cells, Mallory hyaline, intratumoral inflammation, and intratumoral fibrosis. This review examines the historical development of this subtype and explores in detail the histological features that are used to define SH-HCC. The strongest molecular correlates to-date include a low frequency of CTNNB1 mutations and possible activation of the IL6/JAK/STAT pathway. In addition, critical unresolved questions are discussed in detail to refine the histological definition of SH-HCC, including the minimal histological thresholds needed to make the diagnosis, as well as whether or not SH-HCC currently is a mixed category of tumors, containing some tumors where the distinctive morphology is driven by tumor-specific genetic changes, and other tumors where the findings are an epiphenomenon, a reflection of metabolic or alcohol-associated fatty liver disease, and not necessarily of genetic/epigenetic changes.