The adenoma carcinoma sequence: an indoctrinated model for tumorigenesis, but is it always a clinical reality?

Abstract

Objective: Evidence exists to support alternative pathways to the adenoma carcinoma sequence. Some mutations in key onco-suppressor genes relate to the anatomical site of the tumour. This link is typified by microsatellite instability and proximal neoplasia. However, rectal tumours are rarely considered separately. We hypothesized that tumour behaviour in the rectum may differ in terms of pathogenesis and malignant propensity. Therefore, we aimed to look for an association between the histopathological features of adenomas and their anatomical location as compared with the distribution of cancers.

Methods: A single centre prospective study was undertaken over a four-year period. Patients referred to a colorectal assessment clinic with bowel symptoms underwent a minimum investigation of flexible sigmiodoscopy. Neoplastic lesions were either biopsied or removed after noting distance from the anal margin. Adenomas, differentiated by size, villous architecture and degree of dysplasia were compared to both early and advanced carcinomas.

Results: Of 4089 patients, polyps were identified in 8.0% and cancer in 4.2%. There was a clear difference between the distribution of cancer and adenomas > 1 cm, P < 0.001. All degrees of dysplasia in large adenomas were more prevalent in the sigmoid colon as compared to cancer, P < 0.001. Seventy-five percent of high risk diminutive adenomas were rectal in origin.

Conclusion: Our data provides indirect evidence to support the concept that a significant proportion of rectal cancers may arise via an alternative pathway to the Vogelstein model. Polyp behaviour along with malignant propensity may actually be site dependent, with rectal polyps harbouring a more aggressive phenotype.