Liver carcinogenesis: diagnostic and clinical aspects of preneoplastic nodules

In multistep hepatocarcinogenesis, sizable lesions can precede the development of hepatocellular carcinoma (HCC). These lesions are currently classified as low grade (LG)- and high grade (HG)-dysplastic nodules. Following international guidelines recommending the surveillance of cirrhotic patients, a growing number of 1-2 cm hepatocellular nodules are recognized including early hepatocellular carcinoma (eHCC) and DN the latter accounting for as many as 70％ of nodules < 1 cm. HG-DN are currently considered the most advanced HCC precursors. The histological diagnosis of low-grade dysplastic nodule (LG-DN), high- grade dysplastic nodule (HG-DN) and eHCC in small liver biopsies requires a comprehensive stepwise morphological and immunocytochemical approach. By imaging the differential diagnosis among these lesions is a challenge. According to vascular enhancement at dynamic computed tomography (CT) or magnetic resonance imaging (MRI) these precursors are classified as hypo-vascular/indeterminate nodules even though distinction between LG-DN and HG-DN is almost impossible. The introduction of gadoexetic acid-enhanced MRI has represented an extremely important advance in this field allowing a better differentiation of dysplastic lesions from eHCC and progressed HCC. Additional MRI features as diffusion-weighted imaging further improved diagnostic accuracy of imaging. According to Liver Imaging Reporting and Data System (LI-RADS), either CT/MRI or Contrast-Enhanced Ultrasound LI-RADS, the dysplastic lesions should be categorized as LR-3 or LR-4. Natural history of these lesions confirmed that HCC can develop from HG-DN but which nodule and when it will undergo malignant transformation is not predictable. The search and validation of radiological and tissue markers able to select lesions more prone to HCC development, is currently underway. Whether and how HG-DN should be ablated or closely followed up is currently debated.