Short-term induction of neoplastic nodules in the rat liver. II. Study of their development and the effects of withdrawal of 2-acetylaminofluorene.

Neoplastic liver nodules were induced by a single administration of N-nitrosodiethylamine (NDEA) and selectively stimulated to growth by 2-acetylaminofluorene (2-AAF) and partial hepatectomy to provide morphological data on very early and late stages of preneoplastic development. Presumptive preneoplastic liver cells were recognizable by light and electron microscopy by 2 days after partial hepatectomy, and they developed within 2 weeks into large, solid nodules consisting of plates of 2 or 3 cell layers thick, that compressed the surrounding non-nodular tissue. The cells showed nuclei with an enlarged nucleolus, tortuously dispersed rough endoplasmic reticulum (RER) and an electron lucent cytoplasm. These features remained present throughout the first 2 weeks of growth. During this period the initially small, distinct smooth endoplasmic reticulum areas proliferated gradually. They were associated with an increasing incidence of cytoplasmic membranes whorl formation and incidentally with annulate lamellae. After withdrawal of 2-AAF the majority of the nodules regressed resulting in slowly disappearing foci of glycogen rich cells. A relatively small number of solid nodules persisted. They were characterized by large cells with a homogeneous eosinophilic cytoplasm, enlarged cells with a homogeneous eosinophilic cytoplasm, enlarged nucleoli and dispersed RER. Because these characteristics were absent in nodular cells that had reverted to normal liver cells, it is not appropriate to consider these characteristics to represent neoplastic transformation per se.