Histogenesis of pseudo-ductular changes induced in the pancreas of guinea pigs treated with N-methyl-N-nitrosourea.

Tumors of the exocrine pancreas of the inbred strain 13 guinea pigs, induced by N-methyl-N-nitrosourea, reveal duct-like glandular differentiation and marked desmoplastic reaction of the stroma, characteristic of adenocarcinoma of human pancreas. During the course of induction of these tumors in the guinea pigs by N-methyl-N-nitrosourea, atypical pseudo-ductular proliferations were encountered in the pancreas which appeared to be precursor lesions for pancreatic carcinoma. The histogenesis of these pseudo-ductular lesions was studied by light and electron microscopy. The earliest changes consisted of dilatation of acinar lumina with decrease of apical cytoplasm and increased mitotic activity of the acinar cells. The actively proliferating, well-formed pseudo-ductules were lined by cuboidal or flattened epithelium containing a prominent nucleus and scant cytoplasm with few or no discernible zymogen granules by light microscopy. By electron microscopy, the cells lining the pseudo-ductules displayed features of immature or embryonic pancreatic acinar cells characterized by prominent nucleoli, marked decrease in rough endoplasmic reticulum with increase of free ribosomes, atypical zymogen granules and abundant microfilaments and microtubules. In two guinea pigs, transition from pseudo-ductular changes to adenocarcinoma was clearly evident. On the basis of these findings, it is proposed that the pseudo-ductular lesions of the guinea pig pancreas, and possibly those occuring in other species, are derived from acinar cells as a consequence of carcinogen induced cell proliferation leading to immature or dedifferentiated phenotypes. This hypothesis can, in part, be confirmed by immunocytochemical localization of pancreatic acinar cell specific secretory proteins and lectins in these pseudo-ductules.