Hepatocellular adenomas are benign tumors that can be difficult to diagnose. To refine their classification, we performed a comprehensive analysis of their genetic, pathological, and clinical features. A multicentric series of 96 liver tumors with a firm or possible diagnosis of hepatocellular adenoma was reviewed by liver pathologists. In all cases, the genes coding for hepatocyte nuclear factor 1␣ (HNF1␣) and ␤-catenin were sequenced. No tumors were mutated in both HNF1␣ and ␤-catenin enabling tumors to be classified into 3 groups, according to genotype. Tumors with HNF1␣ mutations formed the most important group of adenomas (44 cases). They were phenotypically characterized by marked steatosis (P < 10 ؊4 ), lack of cytological abnormalities (P < 10 ؊6 ), and no inflammatory infiltrates (P < 10 ؊4 ). In contrast, the group of tumors defined by ␤-catenin activation included 13 lesions with frequent cytological abnormalities and pseudo-glandular formation (P < 10 ؊5 ). The third group of tumors without mutation was divided into two subgroups based on the presence of inflammatory infiltrates. The subgroup of tumors consisting of 17 inflammatory lesions, resembled telangiectatic focal nodular hyperplasias, with frequent cytological abnormalities (P ‫؍‬ 10 ؊3 ), ductular reaction (P < 10 ؊2 ), and dystrophic vessels (P ‫؍‬ .02). In this classification, hepatocellular carcinoma associated with adenoma or borderline lesions between carcinoma and adenoma is found in 46% of the ␤-catenin-mutated tumors whereas they are never observed in inflammatory lesions and are rarely found in HNF1␣ mutated tumors (P ‫؍‬ .004). In conclusion, the molecular and pathological classification of hepatocellular adenomas permits the identification of strong genotype-phenotype correlations and suggests that adenomas with ␤-catenin activation have a higher risk of malignant transformation. (

Using sequencing and gene expression analyses, we identified a subgroup of HCA characterized by fusion of the INHBE and GLI1 genes and activation of sonic hedgehog pathway. Molecular subtypes of HCAs associated with different patients' risk factors for HCA, disease progression, and pathology features of tumors. This classification system might be used to select treatment strategies for patients with HCA.