Ongoing advances in liver disease management and basic research in recent years have changed our knowledge of the natural history of hepatocellular carcinoma (HCC). Indeed, the natural history of this tumor is fairly long and covers a preclinical and a clinical phase. Some of the biological steps involved in cell transformation and different carcinogenic pathways have been identified, disclosing potential novel markers for HCC. Following the progress in surveillance and early diagnosis, much more is now known about precancerous lesions and the process leading to overt HCC, including growth patterns, dedifferentiation and neoangiogenenesis. In particular, research has focused on clinical and biological factors predicting tumor aggressiveness and patients’ prognosis. Lastly, clinical studies have described tumor presentation, evolution and causes of patients’ death and how the new knowledge has influenced clinical management and patients’ survival in recent years. By addressing 10 key questions, this review will summarize well-established and novel features of the natural history of HCC.

The Barcelona Clinic Liver Cancer (BCLC) advanced stage (BCLC C) of hepatocellular carcinoma (HCC) includes a heterogeneous population, where sorafenib alone is the recommended treatment. In this study, our aim was to assess treatment and overall survival (OS) of BCLC C patients subclassified according to clinical features (performance status [PS], macrovascular invasion [MVI], extrahepatic spread [EHS] or MVI + EHS) determining their allocation to this stage. From the Italian Liver Cancer database, we analyzed 835 consecutive BCLC C patients diagnosed between 2008 and 2014. Patients were subclassified as: PS1 alone (n = 385; 46.1%), PS2 alone (n = 146; 17.5%), MVI (n = 224; 26.8%), EHS (n = 51; 6.1%), and MVI + EHS (n = 29; 3.5%). MVI, EHS, and MVI + EHS patients had larger and multifocal/massive HCCs and higher alpha‐fetoprotein (AFP) levels than PS1 and PS2 patients. Median OS significantly declined from PS1 (38.6 months) to PS2 (22.3 months), EHS (11.2 months), MVI (8.2 months), and MVI + EHS (3.1 months; P < 0.001). Among MVI patients, OS was longer in those with peripheral than with central (portal trunk) MVI (11.2 vs. 7.1 months; P = 0.005). The most frequent treatments were: curative approaches in PS1 (39.7%), supportive therapy in PS2 (41.8%), sorafenib in MVI (39.3%) and EHS (37.3%), and best supportive care in MVI + EHS patients (51.7%). Independent prognostic factors were: Model for End‐stage Liver Disease score, Child‐Pugh class, ascites, platelet count, albumin, tumor size, MVI, EHS, AFP levels, and treatment type. Conclusion: BCLC C stage does not identify patients homogeneous enough to be allocated to a single stage. PS1 alone is not sufficient to include a patient into this stage. The remaining patients should be subclassified according to PS and tumor features, and new patient‐tailored therapeutic indications are needed. (Hepatology 2018;67:1784‐1796).