Colorectal serrated pathway cancers and precursors

Histopathology. 2015 Jan;66(1):49-65. doi: 10.1111/his.12564. Epub 2014 Dec 1.


The serrated pathway (SP) can be viewed as two parallel, but partially overlapping, arrays of colorectal precursor lesions, and their respective endpoint carcinomas, that are distinct from those of the conventional adenoma-carcinoma sequence (APC-pathway). In this review we focus at the outset on the clinical impact, pathological features, molecular genetics and biological behaviours of the various SP cancers. Then we summarize the clinicopathological features, classification and molecular profiles of the two main precursor lesions that anchor the respective pathways: (i) sessile serrated adenoma/polyp (SSA/P), also called sessile serrated lesion (SSL), and (ii) traditional serrated adenoma (TSA). Activating mutations of the RAS-RAF-MAPK pathway initiate and sustain the lesions of the SP, and CpG island methylation of the promoter regions of tumour suppressor and DNA repair genes play the major role in their neoplastic progression. The SP includes microsatellite stable (MSS) carcinomas that are among the most biologically aggressive colorectal carcinomas (CRC), and also accounts for the great preponderance of sporadic hypermutated, mismatch repair (MMR)-deficient or microsatellite instable (MSI) CRC. The identification, removal and appropriate classification of at-risk SP precursors and surveillance of individuals who harbour these lesions present a challenge and opportunity for CRC prevention and mortality reduction.

Keywords: BRAF; CIMP; KRAS; colorectal carcinoma; hyperplastic polyp; microsatellite instability; molecular pathology; serrated carcinoma; sessile serrated adenoma; sessile serrated lesion; traditional serrated adenoma.

Publication types

  • Review

MeSH terms

  • Adenoma / genetics
  • Adenoma / pathology
  • Colorectal Neoplasms / genetics
  • Colorectal Neoplasms / pathology*
  • Humans
  • Precancerous Conditions / pathology*