Biological markers of preneoplastic foci and neoplastic nodules in rodent liver.

Foci of altered hepatocytes are regularly observed early during hepatocarcinogenesis in rodents. The abnormal hepatocytes may show a number of different phenotypes as characterized by various cytomorphological and cytochemical markers. The first appearance and the further development of the abnormal cell populations depend on the dose of the carcinogen given and on the duration of the carcinogenic treatment. According to cytochemical, morphometric and autoradiographic findings in rats receiving low doses (2-10% of the LD 50/kg bw/day) of hepatocarcinogens for limited periods ("stop" experiments), glycogenotic (clear or acidophilic) hepatocytes indicate the first step of the neoplastic cell transformation which can be detected by these methods at present. The glycogenotic cells undergo a characteristic metamorphosis and give rise to basophilic tumor cells poor in glycogen, but rich in ribosomes. Under extreme experimental conditions, such as a single or repeated application of higher doses of one or several chemical carcinogens a puzzling picture emerges which is "reversible" to a large extent after withdrawal of the respective compounds. This observation points to a phenotypic instability of the cellular changes induced in certain experimental systems. Foci of altered hepatocytes persisting after withdrawal of the carcinogenic compounds are considered preneoplastic lesions. They may transform into neoplastic nodules which are also persistent and share a number of cytomorphological and cytochemical markers with the focal lesions. The persistent nodules progress to hepatocarcinomas after lag periods of weeks or months. However, the foci may also progress to hepatocarcinomas without passing a nodular intermediate stage. The development of both neoplastic nodules and carcinomas from the preneoplastic glycogen storage foci can proceed independent of further administration of carcinogen. The sequence of cellular changes during hepatocarcinogenesis derived from the experimental results in rodents is strongly supported by observations in humans, especially by the increasing reports on the appearance of hepatic tumors in patients who suffer from inborn hepatic glycogenosis.