The Histogenesis of the Third Pathway of Colonic Carcinogenesis in Rats

Background/ Aim: Conventional (tubular or villous) adenomas, and the more recently described serrated adenomas, are non-invasive neoplasias that precede colon carcinomas in carcinogen-treated rats. In contrast, the histological steps antedating carcinomas in gut-associated lymphoid tissue (GALT) in rats, i. e. the third pathway of colonic carcinogenesis, remain unidentified. Aim of the study was to investigate the histological changes preceding colonic GALT carcinomas in Sprague-Dawley (SD) rats. Materials and Methods: Archived sections from previous experiments showing GALT mucosal domains in 292 rats were re-evaluated: 276 were injected with 1,2-dimethylhydrazine (DMH) suspended in ethylenedia-minetetra acetic acid (EDTA), and 16 were controls (8 EDTA-treated, and 8 untreated). Results: A total of 402 colonic GALT mucosal domains were found in the 292 rats: 382 in 276 DMH-treated, 10 in eight EDTA-treated, and 10 in eight-untreated rats. In DMH-treated rats, corrupted crypts (CCS; i. e. with asymmetric fission or abnormal crypt-alignment) were recorded in 50% of the GALT domains (15% had no dysplasia and 35% had epithelial dysplasia). Adenomas on top of GALT domains were found in 7%, and GALT carcinomas in 53%. Histology of the 146 colonic GALT carcinomas revealed highly differentiated carcinomas or signet-ring cell carcinomas. EDTA-treated and untreated animals showed no dysplastic CCS, or other neoplasia. Conclusion: This study demonstrated that GALT mucosal domains in carcinogen-treated rats often develop dysplastic CCS. Non-dysplastic CCS appear to act as scaffolds for the top-down replacement/ transformation by dysplastic cells. Importantly, highly differentiated carcinomas were seen to evolve from dysplastic CCS and from adenomas, and signet-ring cell carcinomas from dysplastic goblet cells present at the base of crypts. This is the first study showing that non-invasive neoplastic lesions ( dysplastic CCS and adenomas) antedate colonic GALT carcinomas in DMH-treated SD rats. The DMH-SD paradigm permits detailed study of the histological events preceding GALT carcinoma under standard laboratory conditions.