Relationship among histochemically distinguishable early lesions in multistep-multistage hepatocarcinogenesis.

The evolution of liver cancer is discussed on the basis of the multistep-multistage hypothesis. In rat liver the sequential generation of the tumor cell via intermediate precancerous cell populations is strongly supported by histopathological evidence (focus-in-focus lesions) indicating precursor-product relationships, inducibility of progression in an initiation-promotion-initiation type of experiment, and by the kinetics of focus and tumor induction. The formation of mouse liver tumors, either spontaneously in susceptible strains, or induced by a short initiating dose of carcinogen, may follow the same general pathway. The frequent observation of focus-in-focus patterns in mouse and the kinetic characteristics of that process favour the sequential development of cancer cell formation. The kinetic analysis suggested that (large) basophilic foci in mouse liver may be the result of spontaneous progression from an initiated cell population which is represented by either the small basophilic foci or by a cell population generally not recognized due to the lack of a suitable marker reaction. Furthermore, the basophilic foci may represent the precursor cell population leading by another step of spontaneous progression to hepatocellular carcinoma.