Preneoplastic lesions in the liver: Molecular insights and relevance for clinical practice

Hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA) are the most frequent primary liver cancers, accounting for approximately 80% and 15%, respectively. HCC carcinogenesis occurs mostly in cirrhosis and is a complex multi-step process, from precancerous lesions (low-grade and high-grade dysplastic nodules) to progressed HCC. During the different stages of liver carcinogenesis, there is an accumulation of pathological, genetic and epigenetic changes leading to initiation, malignant transformation and finally tumour progression. In contrast, a small subset of HCC occurs in normal liver from the transformation of hepatocellular adenoma (HCA), a benign hepatocellular tumour. The recent molecular classification enables to stratify HCAs according to their risk of complication, in particular malignant transformation, associated with mutations in exon 3 of the catenin beta 1 (CTNNB1) gene. Cholangiocarcinoma (CCA) derives from the multistep malignant transformation of preneoplastic lesions, like biliary intraepithelial neoplasia (BilIN) and intraductal papillary neoplasm of the bile duct (IPNB), for which a pre-operative diagnosis remains difficult. Different genetic alterations are involved in BilIN and IPNB progression, leading to the development of tubular or intestinal adenocarcinoma. The aims of this review are to describe the main clinical and molecular features of preneoplastic lesions leading to the development of HCC and CCA, their implications in clinical practice and the perspectives for future research.