Serrated polyposis: an enigmatic model of colorectal cancer predisposition

Abstract

Serrated polyposis has only recently been accepted as a condition which carries an increased personal and familial risk of colorectal cancer. Described over four decades ago, it remains one of the most underrecognized and poorly understood of all the intestinal polyposes. With a variety of phenotypic presentations, it is likely that serrated polyposis represents a group of diseases rather than a single entity. Further, neoplastic progression in serrated polyposis may be associated with premature aging in the normal mucosa, typified by widespread gene promoter hypermethylation. From this epigenetically altered field, arise diverse polyps and cancers which show a range of molecular features. Despite a high serrated polyp count, only one-third of colorectal cancers demonstrate a BRAF V600E mutation, the molecular hallmark of the canonical serrated pathway, suggesting that though multiple serrated polyps act as a marker of an abnormal mucosa, the majority of CRC in these patients arise within lesions other than BRAF-mutated serrated polyps.

Figure 1

Colectomy specimen from a patient with serrated polyposis showing multiple flat polyps on mucosal folds, measuring less than 10 mm, distributed throughout the colon (courtesy of Dr. Andrew Clouston, Envoi Pathologists, Brisbane).

Figure 2

Showing 4 serrated polyp subtypes. (a) Microvesicular hyperplastic polyp with crypt serration and proliferative crypt bases. (b) Sessile serrated adenoma/polyp, showing asymmetrical serrated crypts and dilated crypts. (c) Traditional serrated adenoma, with prominent complex serration and hypereosinophilic cells. (d) Sessile serrated adenoma/polyp with high-grade dysplasia (right).

Figure 3

The canonical serrated pathway showing progression through MVHP (microvessicular hyperplastic polyp) to SSA/P (sessile serrated adenoma/sessile serrated polyp) and SSA/P-D (SSA/P with dysplasia) to CRC with CIMP and high levels of BRAF mutation frequently arising in the proximal colon. CRC with CIMP can evolve into MSI-H and non-MSI-H subtypes. Though KRAS mutation can be observed in CIMP CRC, these are relatively rare [103, 104].