Hepatocellular benign tumors-from molecular classification to personalized clinical care

Focal nodular hyperplasia (FNH) and hepatocellular adenoma (HCA) are benign hepatocellular tumors that develop most frequently in women without cirrhosis. Genomic approaches have identified signaling pathways related to these benign hepatocyte proliferations. FNH, a polyclonal lesion, is characterized by local vascular abnormalities and heterogeneous activation of Wnt/β-catenin and transforming growth factor β signaling. Four major subgroups of HCAs have been identified based on mutations in specific oncogenes and tumor suppressor genes. Each molecular subtype of HCA has been associated with specific pathways, providing new information about benign tumorigenesis. Key features include metabolic alterations (induced by defects in HNF1A), oncogene-induced inflammation (activation of JAK-STAT signaling in inflammatory adenomas), and an association between activation of Wnt/β-catenin signaling and progression of HCAs in hepatocellular carcinomas. Benign hepatocellular tumors can be classified using immunohistochemical analyses. Studies of genotypes and phenotypes of FNH and HCAs have led to the identification of risk factors and improved invasive and noninvasive diagnostic techniques, evaluation of prognosis, and treatment. We review the molecular pathways involved in benign hepatocyte proliferation and discuss how this basic knowledge has been progressively translated into personalized clinical care.