Pathology and molecular mechanisms of multistage human hepatocarcinogenesis

Recent fundamental research has disclosed the presence of multiple genetic alterations including activation of oncogenes and inactivation of tumor suppressor genes in various human cancers. These multiple genetic alterations are thought to be correlated with multiple stages of carcinogenesis and further progression. Hepatocellular carcinoma (HCC) is a typical example. The majority of HCCs are associated with infection by hepatitis virus B or C. In the damaged liver, small nodular lesions develop due to clonal expansion of hepatocytes. Some of these nodules are diagnosed as early HCC of the well differentiated type and correspond to in situ or microinvasive carcinoma. Within these nodules, moderately or poorly differentiated HCCs often emerge as nodule-in-nodule lesions when the diameter of the nodules exceeds 1.5 cm. Ordinary HCCs formed by progression show highly increased cell proliferation, neovascularization, production of high-molecular-mass forms of basic fibroblast growth factor and aneuploidy in some tumors. Corresponding to this stage of malignant progression, HCCs show loss of heterozygosity for multiple chromosomes including chromosomes 4, 16q and 17p. Tumor suppressor gene p53, located on 17p, is frequently mutated in high-grade, but not in early, HCCs. Thus, it is strongly suggested that inactivation of multiple tumor suppressor genes plays an important role in progression, and probably directly or indirectly causes chromosome instability, enhanced cell proliferation and neovascularization.