Characterization of sessile serrated adenomas with dysplasia including intramucosal adenocarcinoma and colorectal carcinoma with a microsatellite instability phenotype

Hum Pathol. 2024 Mar:145:9-15. doi: 10.1016/j.humpath.2023.12.007. Epub 2024 Jan 11.


Recent studies have shown that sessile serrated lesions (SSLs) lead to the development of colorectal cancer (CRC) with a microsatellite instability (MSI) phenotype via a dysplasia-carcinoma sequence. However, the pathological and molecular mechanisms of SSL with dysplasia (SSLD) are unclear. Here, we aimed to examine the clinicopathological and molecular alterations in SSLD and to evaluate the significance of such alterations with regard to lesion progression. Fifty-four SSLDs (20 serrated dysplasia cases and 17 intestinal dysplasia cases, including 30 low-grade dysplasia [LGD] cases, 7 high-grade dysplasia [HGD] cases, and 17 intramucosal adenocarcinomas [IMAs]) were evaluated. Molecular alterations, including immunohistochemical expression of various markers, DNA methylation status, and multiple genetic mutations (using next-generation sequencing), were assessed. Additionally, such alterations were also investigated in 41 CRCs with an MSI phenotype (invasion beyond submucosa). The frequency of mismatch repair (MMR) deficiency in SSLD was 12 of 39 cases (32.4 %), whereas the MMR proficient type was observed in 17 of 39 SSLD cases. SSLD with serrated dysplasia showed a significantly higher frequency of loss of MMR protein expression and methylation status. Moreover, loss of MMR protein expression differed significantly between LGD and IMA. Furthermore, the frequency of TP53 mutation was significantly higher in IMA than in LGD. The current findings demonstrated that SSL with serrated dysplasia may be associated with an increased risk of malignant transformation compared with intestinal dysplasia. Loss of MMR proteins and mutation of TP53 may play important roles in tumor progression from dysplasia to carcinomatous lesions.

MeSH terms

  • Adenocarcinoma* / genetics
  • Adenocarcinoma* / pathology
  • Adenoma* / genetics
  • Adenoma* / pathology
  • Brain Neoplasms*
  • Colonic Polyps* / genetics
  • Colonic Polyps* / pathology
  • Colorectal Neoplasms* / pathology
  • Humans
  • Hyperplasia
  • Microsatellite Instability
  • Mutation
  • Neoplastic Syndromes, Hereditary*
  • Phenotype
  • Proto-Oncogene Proteins B-raf / genetics


  • Proto-Oncogene Proteins B-raf

Supplementary concepts

  • Turcot syndrome