Molecular characterization of sessile serrated adenoma/polyps with dysplasia/carcinoma based on immunohistochemistry, next-generation sequencing, and microsatellite instability testing: a case series study

Diagn Pathol. 2018 Nov 20;13(1):88. doi: 10.1186/s13000-018-0771-3.

Abstract

Background: Colorectal sessile serrated adenoma/polyps (SSA/Ps) are considered early precursor lesions in the serrated neoplasia pathway. Recent studies have shown associations of SSA/Ps with lost MLH1 expression, a CpG island methylator phenotype, and BRAF mutations. However, the molecular biological features of SSA/Ps with early neoplastic progression have not yet been fully elucidated, owing to the rarity of cases of SSA/P with advanced histology such as cytologic dysplasia or invasive carcinoma. In this study, we aimed to elucidate the molecular biological features of SSA/Ps with dysplasia/carcinoma, representing relatively early stages of the serrated neoplasia pathway.

Methods: We performed immunostaining for β-catenin, MLH1, and mucins (e.g., MUC2, MUC5AC, MUC6, and CD10); targeted next-generation sequencing; and microsatellite instability (MSI) testing in 8 SSA/P lesions comprised of 4 SSA/Ps with high-grade dysplasia and 4 SSA/Ps with submucosal carcinoma.

Results: Lost MLH1 expression was found in 5 cases. All lesions studied were positive for nuclear β-catenin expression. Regarding phenotypic mucin expression, all lesions were positive for MUC2, but negative for CD10. MUC5AC and MUC6 positivity was observed in 7 cases. Genetically, the most frequently mutated gene was BRAF (7 cases), and other mutations were detected in FBXW7 (3 cases); TP53 (2 cases), and KIT, PTEN, SMAD4, and SMARCB1 (1 case each). Furthermore, 4 of 8 lesions were MSI-high and the remaining 4 lesions were microsatellite-stable (MSS). Interestingly, all 4 MSI-high lesions displayed MLH1 loss, 3 of which harbored a FBXW7 mutation, but not a TP53 mutation. However, 2 MSS lesions harbored a TP53 mutation, although none harbored a FBXW7 mutation.

Conclusions: SSA/Ps with dysplasia/carcinoma frequently harbored BRAF mutations. Activation of the WNT/β-catenin signaling pathway may facilitate the development of dysplasia in SSA/Ps and progression to carcinoma. Furthermore, our results suggested that these lesions might be associated with both MSI-high and MSS colorectal cancer, which might be distinguished by distinct molecular biological features such as lost MLH1 expression, FBXW7 mutations, and TP53 mutations.

Keywords: Colorectal carcinoma; FBXW7; MLH1; Microsatellite instability; Sessile serrated adenoma/polyp; TP53.

MeSH terms

  • Adenocarcinoma* / chemistry
  • Adenocarcinoma* / genetics
  • Adenocarcinoma* / pathology
  • Adenocarcinoma* / surgery
  • Adenomatous Polyps* / chemistry
  • Adenomatous Polyps* / genetics
  • Adenomatous Polyps* / pathology
  • Adenomatous Polyps* / surgery
  • Aged
  • Biomarkers, Tumor* / analysis
  • Biomarkers, Tumor* / genetics
  • Colonic Polyps* / chemistry
  • Colonic Polyps* / genetics
  • Colonic Polyps* / pathology
  • Colonic Polyps* / surgery
  • Colorectal Neoplasms* / chemistry
  • Colorectal Neoplasms* / genetics
  • Colorectal Neoplasms* / pathology
  • Colorectal Neoplasms* / surgery
  • DNA Mutational Analysis / methods*
  • Female
  • Genetic Predisposition to Disease
  • High-Throughput Nucleotide Sequencing*
  • Humans
  • Immunohistochemistry*
  • Male
  • Microsatellite Instability*
  • Middle Aged
  • Mutation*
  • Neoplasm Staging
  • Phenotype
  • Predictive Value of Tests

Substances

  • Biomarkers, Tumor