Serrated pathway: alternative route to colorectal cancer

Abstract

Serrated polyps have been an area of intense focus for gastroenterologists over the past several years. Contrary to what was thought before, a growing body of literature indicates that these polyps can be precursors of colorectal cancer (CRC). Most of these lesions, particularly those in the proximal colon, have so far been under-recognized and missed during colonoscopy, qualifying these lesions to be the main cause of interval cancers. It is estimated that 10%-20% of CRCs evolve through this alternative, serrated pathway, with a distinct genetic and epigenetic profile. Aberrant DNA methylation plays a central role in the development of this CRC subtype. This characteristic molecular background is reflected in a unique pathological and clinical manifestation different from cancers arising via the traditional pathway. In this review we would like to highlight morphological, molecular and clinical features of this emerging pathway that are essential for gastroenterologists and may influence their everyday practice.

Keywords: Colorectal cancer; DNA methylation; Endoscopic surveillance; Hyperplastic polyps; Serrated adenomas; Serrated pathway.

Figure 1

Microscopic features of serrated polyps. A: On cross section serrated crypt shows a stellate or starlike appearance; B: In longitudinal section a characteristic serrated or saw-toothed appearance can be seen.

Figure 2

Schematic representation of the sessile and traditional serrated pathways. N: Normal mucosa; ACF-Hs: Serrated hyperplastic-type aberrant crypt focus; ACF-Hns: Non-serrated hyperplastic-type aberrant crypt focus; MVHP: Microvesicular hyperplastic polyp; OIS: Oncogene-induced senescence; GCHP: Goblet cell-rich hyperplastic polyp; SSA: Sessile serrated adenoma; TSA: Traditional serrated adenoma; SSA-HGD: Sessile serrated adenoma with high grade dysplasia; TSA-HGD: Traditional serrated adenoma with high grade dysplasia; SAC: Serrated adenocarcinoma; IGFBP7: Insulin-like growth factor-binding protein 7; MAPK: Mitogen activated protein kinase-ERK pathway; MLH1: MutL homolog 1; MGMT: O-6-methylguanine-DNA methyltransferase; CIMP-H: CpG island methylator phenotype-high; CIMP-L: CpG island methylator phenotype-low; MSI-H: High-level microsatellite instability; MSI-L: Low-level microsatellite instability; MSS: Microsatellite stable.