Colorectal Carcinogenesis from Gut-associated Lymphoid Tissue Clinical and Experimental Documentation

Abstract

Aims: The conventional (tubular or villous) adenoma-carcinoma pathway and the serrated adenoma-carcinoma pathway evolve in the vast colorectal mucosa built with crypts lined with mucus producing goblet cells and columnar cells. In contrast, few carcinomas developing in the tiny, spotty gut-associated-lymphoid-tissue (GALT) mucosal domain have been reported. Place and Duration of Study: Department of Pathology, Karolinska Institute and University Hospital, Stockholm, Sweden. The experiments in rats were carried out during four years.  Methodology: All publications on human colorectal GALT-carcinomas were reviewed. Archival sections from previous experiments in carcinogen-treated rats exhibiting colonic GALT follicles, were re-evaluated. Results: Only 21 GALT-carcinomas found in 18 patients are in record. Four had ulcerative colitis, two were members of a Lynch syndrome family, two of a CRC family, one of a FAP family, two abdominal pain, two rectal bleedings, one diverticular disease, one a submucosal rectal tumor, one protracted constipation, and two had no symptoms or ground diseases. Conversely, 53% of 276 carcinogen-treated rats had developed GALT-carcinomas. Conclusions: It is generally recognized that the vast majority of the CRCs in humans evolve via the conventional adenoma-carcinoma pathway or the serrated adenoma-carcinoma pathway in the GALT-free colorectal mucosal domain. Less frequently CRCs in humans develop in the tiny, spotty GALT mucosal domain. Whereas natural exposures to dietary/environmental factors, genome differences, obesity, type 2 diabetes, and the colonic microbiome are important for the development of CRC in the GALT-free colorectal mucosa in humans, no factors have been advanced to explain the development of carcinomas in colorectal GALT domains in humans. On the other hand, more than 50% of the SD rats injected with DMH developed colonic GALT-carcinomas. Although the cause(s) for the difference in frequency of GALT carcinomas in the two species remains mute, the results strongly suggest that the carcinogen DMH was the most important single factor for the induction of colonic GALT carcinoma in SD male rats. More research is necessary to unveil the factor(s) responsible for the development of GALT carcinomas in the human colorectal mucosa.