Sessile Serrated Adenoma With Early Neoplastic Progression

Abstract

Sessile serrated adenoma (SSA), also referred to as sessile serrated polyp, has been proposed as a precursor lesion to microsatellite unstable carcinoma. However, the mechanism of stepwise progression from SSA to early invasive carcinoma has been unclear. The purpose of this study was to elucidate the histologic characteristics and possible role of p53, β-catenin, BRAF, KRAS, and PIK3CA in the development and progression of SSA. We analyzed 12 cases of SSA with neoplastic progression (SSAN), including 7 cases of intraepithelial high-grade dysplasia (HGD) and 5 cases of submucosal invasive carcinoma, and compared them with 53 SSAs and 66 hyperplastic polyps (HPs) by immunohistochemistry and gene mutation analysis. Histologically, 75% (9 of 12) of SSANs showed tubular or tubulovillous growth patterns rather than serrated ones in the HGD/intramucosal carcinoma component. All 5 SSANs with invasive carcinoma lost their serrated structure and developed increased extracellular mucin in their submucosal carcinoma component, a consistent feature of mucinous adenocarcinoma. Nuclear accumulations of β-catenin and p53 were observed in 50% (6 of 12) and 41.7% (5 of 12) of SSANs, respectively, and were exclusively present in HGD/carcinoma areas. By contrast, neither nuclear β-catenin nor p53 expressions were seen in HPs or SSAs (P<0.0001). BRAF mutations (V600E) were observed in 45.8% (11 of 24) of HPs, 60.9% (14 of 23) of SSAs, and 63.6% (7 of 11) of SSANs, and were equally found in both SSA and carcinoma/HGD areas of the individual SSANs. KRAS exon 1 mutations were uncommon in all 3 groups (4.2%, 4.4%, and 0%, respectively). No mutations of PIK3CA exon 9 or exon 20 were found in any cases that were examined. These findings suggest that BRAF mutations may be associated with the pathogenesis of SSA, but progression to HGD or early invasive carcinoma may be associated with other factors, such as alterations of p53 and β-catenin. In addition, our histologic observations suggest a possible close association between SSAN and mucinous adenocarcinoma.

Distinct WNT/β-catenin signaling activation in the serrated neoplasia pathway and the adenoma-carcinoma sequence of the colorectum

“…13,14,22,25,26 In previous reports, 18-100% of adenomas and 78% of adenocarcinomas of the colorectum displayed nuclear b-catenin immunoreactivity. 14,22,25 Various investigators have reported that nuclear b-catenin expression was observed in 0-60% of SSA/Ps, 7,9,13,14,22,25,26 43-100% of SSA/Ps with high-grade dysplasia, 9,13,14 and 60% of SSA/Ps with submucosal carcinoma. 13 Nuclear b-catenin labeling indices in our study were significantly lower in the SSA/P series than the adenoma series, suggesting that levels of WNT/b-catenin signaling activation may be different between the serrated neoplasia pathway and the conventional adenoma-carcinoma sequence.…”

“…14,22,25 Various investigators have reported that nuclear b-catenin expression was observed in 0-60% of SSA/Ps, 7,9,13,14,22,25,26 43-100% of SSA/Ps with high-grade dysplasia, 9,13,14 and 60% of SSA/Ps with submucosal carcinoma. 13 Nuclear b-catenin labeling indices in our study were significantly lower in the SSA/P series than the adenoma series, suggesting that levels of WNT/b-catenin signaling activation may be different between the serrated neoplasia pathway and the conventional adenoma-carcinoma sequence. Interestingly, we found that nuclear b-catenin labeling indices were significantly increased with progression from SSA/Ps to those with high-grade dysplasia and with submucosal carcinoma, and that high expressers were more frequent in SSA/Ps with high-grade dysplasia and those with submucosal carcinoma than SSA/Ps.…”

“…These comprised 27 SSA/Ps, 14 SSA/Ps with high-grade dysplasia, 9 SSA/Ps with submucosal carcinoma, 19 conventional tubular adenomas, 26 tubular adenomas with high-grade dysplasia, and 25 tubular adenomas with submucosal carcinoma. The histologic features of the high-grade dysplasia were assessed according to the previous description 2, 13 as follows: a tubular, tubulovillous, or fused glandular pattern, mimicking conventional adenomatous high-grade dysplasia or a serrated glandular pattern, preserving the serrated or sawtoothed structure with infolding of the crypt epithelium, which consisted of cuboidal and eosinophilic dysplastic cells with substantially larger nuclei, irregular thickening of the nuclear membrane (so-called 'serrated type' high-grade dysplasia). All samples were reviewed independently by two experienced gastrointestinal pathologists (HM and TY) applying the criteria for sessile serrated adenomas of Torlakovic et al 1 Interobserver variation was resolved by re-evaluation and discussion to reach consensus.…”

“…shown associations of SSA/P and those with dysplasia or carcinoma with methylation or loss of protein expression for DNA repair genes, ie, MLH1, 1,4,6-9 a CpG island methylator phenotype, 3,4,6,8 BRAF mutations, 3,4,[6][7][8][9][10][11][12][13][14] and a lack of genetic alterations in CTNNB1 (the gene coding for b-catenin protein). 14 This pathway is thought to be distinct from the conventional adenoma-carcinoma pathway, where adenomas progress to invasive colorectal carcinomas through the influence of a series of genetic alterations including adenomatous polyposis coli (APC) and KRAS mutations.…”

“…24 Although the conventional adenoma-carcinoma pathway is associated with activation of the WNT/bcatenin signaling pathway, 15,16,18,25 any contribution to serrated neoplasia remains controversial. 13,14,22,25,26 The aim of this study was thus to elucidate the potential roles of WNT/b-catenin signaling in association with MLH1 methylation or BRAF/KRAS mutations in the serrated neoplasia pathway, in comparison with the conventional adenoma-carcinoma sequence.…”