Morphogenesis of colonic carcinoma. Ultrastructural studies of azoxymethane-induced early lesions in colon epithelium of Fischer 344 rats.

Marked dilation and distortion of the crypts have been observed in the colonic epithelium of Fischer-344 rats after four to six weekly doses of azoxymethane (8 mg/kg). These changes precede malignant transformation in this model and, therefore, may be considered premalignant. Ultrastructural morphologic aspects of these crypts can arbitrarily be divided into three stages: an early stage of increased mucus secretion and "exhausted" appearance of mucous cells; an intermediate stage of severe crypt dilation, with extreme thinning of crypt epithelium and neutrophilic emigration to the mucous pool of the crypt lumen; and a late stage characterized by repopulation of the crypts, with epithelial cells showing an increased nuclear-cytoplasmic ratio and bizarre nuclei and nucleoli. The surface epithelium between the crypts shows increased cell loss and alterations of cell membrane. Similar structure of crypts has been described in the mucosa remote from carcinomas in rats and humans, and in various precancerous changes in humans (ie, ulcerative colitis and Crohn's disease). Therefore, I propose that these lesions are significant in human colon carcinogenesis as well.