Some emerging general principles in the pathogenesis of hepatocellular carcinoma.

A rational concept of the key steps in the multistep process of cancer development in liver is emerging. This concept proposes that the strategy of cancer development consists of two major sequences: (a) the genesis of persistent benign focal proliferations (clonal nodules) and (b) the development of hepatocellular cancer from one or more such nodules. Sequence (a) comprises the classical 'initiation and promotion' of chemical carcinogenesis. Sequence (b) is dominated by persistent cell proliferation. In the precancerous steps, cell proliferation is almost balanced by cell loss, leading to only a slow increase in the size of the nodules. With cancer, this balance is lost, leading to a much more rapid enlargement of the focal lesion. The carcinogenic process in the liver is viewed initially as a form of physiological adaptation to certain types of xenobiotic agents generating new focal cell populations. The animals with such new focal lesions are much better able to resist the toxic or lethal effects of many environmental hazards. According to this view, liver cancer development is a consequence of a derivative of the basic adaptation process.