Background The prognosis of HCC depends in large measure on maximum tumor diameter (MTD). Aims To examine characteristics of tumor aggressiveness over an MTD range of< 2 to 8 cm. Methods A large HCC database was examined retrospectively for trends in serum alpha-fetoprotein (AFP), and percent of patients with macroscopic portal vein thrombosis (PVT) or tumor multifocality. Results There was a significant trend to increased serum AFP levels and percent of patients with PVT, for each,p < 0.001. Within those trends, there were clearly identifiable sub-trends for variations of AFP or percent PVT patients, associated with specific MTD ranges. Calculation of the fold increase for either AFP or percent PVT patients over distinct MTD ranges showed a greater increase of AFP or percent PVT patients compared with the related MTD increase. Interestingly, the increase in percent PVT was mainly independent of AFP. Conclusions Patterns of AFP and PVT increase can be discerned with increasing MTD, which are nonlinear. The greater fold increase in tumor aggressiveness factors compared with MTD suggests that HCCs may change with increasing size to a more aggressive phenotype. Baseline HCC biopsies might therefore be insufficient in future rational HCC management, and repeated liquid biopsies have potential in following HCC evolution and thus choices of therapies.