Morphological basis of multistep process in experimental colonic carcinogenesis.

Carcinogenesis has been shown to be a multistep process. However, the morphological basis of the multistep process in colonic carcinogenesis has not been adequately investigated. In the distal colon of adult female CF-1 mice given weekly injections of DMH, we are able to demonstrate that colonic adenocarcinomas develop and evolve in four distinct but continuous steps on morphological grounds. (1) A colonic neoplasm develops in a single crypt. A given crypt is first repopulated by atypical epithelial cells which have either originated at the cryptal base or occurred as an outpocketing pouch in the proliferative zone of the crypt. (2) In the atypical crypt thus repopulated by atypical cells, the epithelial lining becomes invaginated and/or evaginated in the upper half to form an earliest identifiable neoplastic glandular lesion there. (3) The neoplastic lesion thus formed keeps invaginating, evaginating and expanding in various directions by unceasing proliferation of neoplastic cells, giving rise to a polypoid or a discoid lesion. (4) As the neoplasm grows, its leading downward edge would eventually penetrate the muscularis mucosae, and the malignant behavior of the neoplasm becomes apparent with further invasion into the submucosa, muscularis externa and serosa. In the due process, we have also explored the mode of villous formation in some neoplasms and analyzed the possible regulatory mechanisms in the various steps of colonic carcinogenesis.