Integration of histopathology and molecular features for the classification of benign and malignant hepatocellular neoplasms

The diagnostic of hepatocellular adenoma (HCA) and hepatocellular carcinoma (HCC) has shifted from a classical morphological evaluation to a complex and precise morpho-molecular analysis that represents a core focus of the updated 6th edition of the WHO classification of digestive system tumours. Four molecular pathways across five distinct subtypes have been identified for HCA, with clinical implications. When specific immunohistochemical and molecular techniques are applied, less than 5% of HCAs remain unclassified. At least 39% of progressed HCCs display unique morpho-molecular characteristics spanning nine distinct subtypes, while the remainder is classified as conventional HCC (cHCC). These subtypes encompass categories with a poor prognosis (macrotrabecular-massive, neutrophil-rich, and sarcomatoid), a favorable prognosis (lymphocyte-rich and clear cell), a variable prognosis (scirrhous), and a prognosis similar to cHCC (steatohepatitic, chromophobe, and fibrolamellar). Recently, two novel histological patterns have been introduced: the vessels encapsulating tumour clusters pattern and the CTNNB1-mutated pattern. Moreover, keratin 19 remains a well-established immunohistochemical marker strongly associated with a poor prognosis. Together, these advancements underscore the critical need to integrate molecular and histological data to optimize patient stratification and therapeutic outcomes.