Xenomorphic hepatocellular precursors and neoplastic progression of tigroid cell foci induced in rats with low doses of N-nitrosomorpholine

Tigroid cell foci (TCF) are a well-defined entity induced in rat liver by c hemical carcinogens, their significance for hepatocarcinogenesis being cont roversial. Using cytomorphological, cytochemical and morphometric approache s, we studied the evolution and fate of TCF sequentially from 7 to 110 week s in groups of 50 male Sprague-Dawley rats, which remained untreated or rec eived N-nitrosomorpholine (NNM) orally at concentrations of 3 and 1 mg/kg b ody wt/day for 7 and up to 75 weeks, respectively. An increased incidence o f hepatocellular neoplasms developed in exposed animals compared with contr ols, which was significant for adenomas at both dose levels, and for carcin omas (HCC) after the longer exposure to the lower dose level (P < 0.0001). TCF appeared frequently in addition to other types of proliferative foci of altered hepatocytes (FAH) including clear/acidophilic and mixed cell foci (MCF) in NNM-treated and rarely in untreated rats. Striking similarities in the cellular phenotypes of TCF and many hepatocellular neoplasms indicated the potential of TCF for progression to both adenomas and carcinomas. TCF emerged from xenomorphic cell foci (XCF), which consisted of hypertrophied hepatocytes typically presenting an enlarged nucleus, abundant glycogen, sm ooth and rough endoplasmic reticulum, altered activities of several enzymes of carbohydrate metabolism and an increased cell proliferation (P < 0.001) compared with the extrafocal parenchyma. TCF shared many features with XCF , but their basophilia and proliferative activity was higher. The number of FAH appearing at the two dose levels of NNM was similar but the average si ze of TCF and MCF was frequently higher at late time points in the group de veloping a significantly higher incidence of HCC, which suggests a pronounc ed acceleration of neoplastic conversion in established preneoplastic cell populations rather than the induction of additional FAH by sustained effect s of low doses of carcinogens.