Significance of sequential cellular changes inside and outside foci of altered hepatocytes during hepatocarcinogenesis.

A variety of phenotypic cellular changes emerge in the liver of different species prior to the appearance of hepatocellular adenomas and carcinomas induced by carcinogenic agents (chemicals, radiation, hepadna viruses) or develop "spontaneously." Foci of altered hepatocytes have been studied most extensively in rats treated with chemical carcinogens; they are considered preneoplastic lesions and have been used in several laboratories as endpoints in carcinogenicity testing. The principles and problems of the morphological classification of foci of altered hepatocytes are presented. In addition to the 4 types of foci generally accepted (clear, acidophilic, basophilic and mixed cell foci), further subtypes (intermediate cell foci) or other types of foci, namely tigroid cell foci and amphophilic cell foci, have more recently been separated as distinct pathomorphological entities. Whereas the amphophilic foci might result from a modulation of clear and acidophilic cell foci, the tigroid cell foci apparently represent a stage in a separate cell lineage leading to hepatocellular adenomas. It remains open whether the tigroid cell foci may also progress to carcinomas. Extrafocal phenotypic changes of hepatocytes might also be involved in hepatocarcinogenesis. The cellular phenotypes within foci also depend strongly, among many other factors, on the dose and duration of the carcinogenic treatment. Cytomorphological, cytochemical, microbiochemical and stereological studies suggest that the predominant sequence of cellular changes during hepatocarcinogenesis leads from the clear and acidophilic cell foci storing glycogen in excess through mixed cell foci and nodules to basophilic cell populations prevailing in hepatocellular carcinomas. A multitude of metabolic aberrations is associated with the sequential cellular changes. Aberrations in carbohydrate metabolism are particularly prominent and might be causally related to the neoplastic transformation of the hepatocytes.