Hepatocellular Carcinoma Precursor Lesions: From Pathological Basis to Risk Stratification and Precision Intervention

Hepatocellular carcinoma (HCC) predominantly arises against a background of chronic liver disease and cirrhosis, with its development typically following the three-step pattern of "hepatitis-cirrhosis-liver cancer." Hepatocellular carcinoma precursor lesions represent a critical stage in this process and constitute a vital window for early diagnosis and targeted intervention. This review aims to systematically summarize the pathological basis, malignant potential, diagnostic approaches, risk stratification strategies, and precision intervention perspectives of HCC precursor lesions. Specifically, we review the pathological characteristics and malignant potential of HCC precursor lesions such as hepatocellular large/small cell transformation, dysplastic foci (DF), low/high-grade dysplastic nodules (LGDN/HGDN), and β-catenin-activated hepatocellular adenoma. We further summarize the application value and limitations of ultrasound/contrast-enhanced ultrasound (US), computed tomography (CT), and Gd-EOB-DTPA-enhanced magnetic resonance imaging (MRI) in screening and differential diagnosis. In addition, we discuss the progress in serum markers such as AFP, AFP-L3, DCP, and GP73, as well as liquid biopsy markers including CTC, ctDNA methylation, cfRNA, and tumor metabolites. We also outline the application of multivariable risk models like age-Male-ALBI-Platelet (aMAP), Gender-Age-AFP-L3-AFP-DCP (GALAD), and THRI in risk stratification and dynamic monitoring of high-risk populations. Finally, we review current treatment and follow-up strategies for HCC precursor lesions and explore the potential of radiomics, artificial intelligence, and multi-omics integration to improve risk assessment and diagnostic support, while also discussing their current limitations and the gap between research findings and routine clinical implementation. Overall, HCC precursor lesions represent an important target for early surveillance and precise intervention, and the integrated application of pathology, imaging, biomarkers, risk models, and emerging technologies may improve early identification, individualized management, and future translational research in HCC.