Evolving pathologic concepts of serrated lesions of the colorectum

Abstract

Here, we provide an up-to-date review of the histopathology and molecular pathology of serrated colorectal lesions. First, we introduce the updated contents of the 2019 World Health Organization classification for serrated lesions. The sessile serrated lesion (SSL) is a new diagnostic terminology that replaces sessile serrated adenoma and sessile serrated polyp. The diagnostic criteria for SSL were revised to require only one unequivocal distorted serrated crypt, which is sufficient for diagnosis. Unclassified serrated adenomas have been included as a new category of serrated lesions. Second, we review ongoing issues concerning the morphology of serrated lesions. Minor morphologic variants with distinct molecular features were recently defined, including serrated tubulovillous adenoma, mucin-rich variant of traditional serrated adenoma (TSA), and superficially serrated adenoma. In addition to intestinal dysplasia and serrated dysplasia, minimal deviation dysplasia and not otherwise specified dysplasia were newly suggested as dysplasia subtypes of SSLs. Third, we summarize the molecular features of serrated lesions. The critical determinant of CpG island methylation development in SSLs is patient age. Interestingly, there may be ethnic differences in BRAF/KRAS mutation frequencies in SSLs. The molecular pathogenesis of TSAs is divided into KRAS and BRAF mutation pathways. SSLs with MLH1 methylation can progress into favorable prognostic microsatellite instability-positive (MSI+)/CpG island methylator phenotype-positive (CIMP+) carcinomas, whereas MLH1-unmethylated SSLs and BRAF-mutated TSAs can be precursors of poor-prognostic MSI-/CIMP+ carcinomas. Finally, based on our recent data, we propose an algorithm for stratifying risk subgroups of non-dysplastic SSLs.

Keywords: Adenoma; Colonic polyps; Colorectal neoplasms; Serrated pathway; Serrated polyp.

Conflict of interest statement

Conflicts of Interest

J.H.K. and G.H.K., contributing editors of the Journal of Pathology and Translational Medicine, were not involved in the editorial evaluation or decision to publish this article.

Figures

Fig. 1.

Summary of changes in terminology and categorization of serrated colorectal lesions from the 4th to the 5th edition of the World Health Organization classification.

Fig. 2.

Histologic features defining sessile serrated lesions (SSLs). Architecturally distorted serrated crypts defining SSLs. Although all five vertically well-sectioned crypts included in this photomicrograph show extended serration into the lower half of the crypt, crypt base serration is subtle in all the crypts. Instead, prominent dilatation or horizontal growth of the crypt base is definite in unequivocally distorted serrated crypts (red square and arrows). Note the equivocally distorted serrated crypts showing crypt branching or mild symmetrical dilatation of the crypt base (green square and arrows). These equivocal crypts must not be counted for the diagnosis of SSL.

Fig. 3.

Histologic features defining traditional serrated adenomas (TSAs). (A) A low power view of a TSA showing typical histologic features. (B) Morphologic features defining TSA. Note the centrally arranged, pencillate nuclei with abundant dense eosinophilic cytoplasm. Slit-like serrations indicate sharp invaginations (arrowheads) along the flat-topped, small intestine-like luminal border (asterisks). (C, D) Ectopic crypt formation (ECF) in a TSA (C) and in a serrated tubulovillous adenoma (D). Note the small, laterally budding crypt-like structures not reaching the muscularis mucosa (arrowheads). Although ECF is one of the morphologic characteristics of TSAs, it is not exclusive to or essential for TSAs.

Fig. 4.

Updated features of CpG island methylation and MLH1 alteration in the sessile serrated neoplasia pathway. (A) A sequence model of CpG island methylation and MLH1 alteration during the multistep sessile serrated lesion (SSL)-to-carcinoma pathway. Note that both MLH1 promoter methylation and CpG island methylator phenotype-positivity (CIMP+) are late-step epigenetic events during the progression of non-dysplastic SSLs, and mainly occur in proximal, large (>5 mm) SSLs in older patients (≥50 years). (B) Complete loss of MLH1 expression in an SSL with dysplasia harboring the MLH1 methylation. (C) Partial loss of MLH1 expression (involving a few non-dysplastic crypts; red ellipse) in a non-dysplastic SSL with MLH1 methylation. Modified from Lee et al. J Pathol Transl Med 2019; 53: 225-35.

Fig. 5.

Serrated lesions as precursors of different molecular subtypes of colorectal carcinoma (CRC). (A) Prognostically implicated molecular subtypes of CRCs and their conceptually matched precursor lesions. SSL, sessile serrated lesion; TSA, traditional serrated adenoma; MrTSA, mucin-rich traditional serrated adenoma; USA, unclassified serrated adenoma; sTVA, serrated tubulovillous adenoma; SuSA, superficially serrated adenoma; TA, tubular adenoma; TVA, tubulovillous adenoma; VA, villous adenoma; MSI, microsatellite instability; MSI+, MSI-positive; MSI−, MSI-negative; CIMP, CpG island methylator phenotype; CIMP+, CIMP-positive; CIMP−, CIMP-negative; mt, mutant-type; wt, wild-type. (B) An example of a two-step screening algorithm to stratify the risk subgroups of non-dysplastic SSLs.