Inflammatory response in serrated precursor lesions of the colon classified according to WHO entities, clinical parameters and phenotype–genotype correlation

Abstract

Studies on traditional serrated adenoma (TSA) and sessile serrated adenoma with dysplasia (SSA‐D) are rare due to the low frequency of these lesions, which are well defined by the latest WHO classification. However, introducing new morphological criteria such as intra‐epithelial lymphocytes (IELs) might facilitate colorectal polyp diagnoses. Additionally, the phenotype–genotype correlation needs to be updated as the terminology has repeatedly changed. This study analysed 516 polyps, consisting of 118 classical adenomas (CAD), 116 hyperplastic polyps (HPP), 179 SSAs, 41 SSA‐Ds, and 62 TSAs. The lesions were analysed in relation to the patients’ clinical parameters including gender, age, localisation, and size. The inflammatory background of the polyps was quantified and BRAF and KRAS mutations as well as MLH1 and CDKN2A promoter methylation were assessed. In multivariate analyses, an increase in IELs was an independent and robust new criterion for the diagnosis of SSA‐D (p < 0.001). Superficial erosions and acute neutrophil granulocytes led to reactive changes potentially resembling dysplasia. KRAS and BRAF mutations were associated with CAD/TSA and HPP/SSA, respectively. However, almost half of TSAs had a BRAF mutation and were KRAS wild type. CDKN2A seems to precede MLH1 hyper‐methylation within the serrated carcinogenesis model. The genotyping of WHO‐based entities – and especially SSA – has sharpened in comparison to previously published data. TSAs can be sub‐grouped according to their mutation status. Of note, the higher number of IELs in SSA‐D reflects their close relationship to colorectal cancers with micro‐satellite instability. Therefore, IELs might represent a new diagnostic tool for SSA‐D.

Distinctive crypt shape in a sessile serrated adenoma/polyp: Distribution of Ki67-, p16INK4a-, WNT5A-positive cells and intraepithelial lymphocytes

“…In the mouse intestine, Wnt5a is secreted by stromal pericrypt myofibroblasts and is necessary for proliferation and branching of crypt epithelium and maintaining of homeostasis ( 21 , 22 ). Additionally, dysplasia branching from SSA/Ps has been reported to be closely associated with a high rate of intraepithelial lymphocytes (IELs) ( 23 ). However, the localization and role of WNT5A and IELs in the HP-SSA/P sequence are unknown.…”

Clinicopathological factors associated with BRAF‐V600E mutation in colorectal serrated adenomas

“…Forty studies assessing 3511 serrated adenomas were included . The whole process of study selection is reported schematically in Figure .…”

Traditional serrated adenoma: an overview of pathology and emphasis on molecular pathogenesis

“…TSAs have been shown to have a relatively increased number of intraepithelial lymphocytes (figure 1E), as compared with classical adenomas, but much less than that of SSAs harbouring conventional adenomatous dysplasia 27. Furthermore, the mucin-rich TSAs have been shown to have more intraepithelial lymphocytes than classic TSAs 31…”

“…The authors have appreciated that the lesional cells in TSAs more or less resemble the normal mucosa of the duodenum, having a brush-border, indented, flat-topped luminal slit-like serrations, pencillate nuclei and eosinophilic cytoplasm 27…”

“…Many TSAs contain adjacent areas of HP (characterised by glands with saw-toothed, serrated luminal profiles and straight or V-shaped basal or lower one-third gland profiles) or SSA (glands which are also saw-toothed but with very characteristic basal architecture: instead of being straight the basal aspects of glands are dilated, fan out horizontally and give rise to boot-shaped or L-shaped glandular profiles), thought to be a precursor polyp in this setting12 17 27 33 (figure 1F). In a study exploring the association of precursor polyps with TSA, 28 were HPs (36%) and 18 were SSAs (23%) 33.…”