Targeted next-generation sequencing supports serrated epithelial change as an early precursor to inflammatory bowel disease-associated colorectal neoplasia

Abstract

Serrated epithelial change (SEC) manifests in patients with long-standing inflammatory bowel disease (IBD) and is characterized by disorganized crypt architecture, irregular serrations, and goblet cell-rich epithelium. The serrated nature of SEC is reminiscent of serrated colorectal polyps, which frequently harbor KRAS/BRAF mutations. SEC is, however, not only histologically distinct from sporadic serrated polyps but also associated with colorectal neoplasia. Whether SEC is a precursor to IBD-associated neoplasia remains unclear. To further define the relationship of SEC with serrated colorectal polyps and IBD-associated neoplasia, we performed targeted next-generation sequencing on colorectal specimens to include the following: SEC without dysplasia/neoplasia (n = 10), SEC with separate foci of associated dysplasia/adenocarcinoma from the same patients (n = 17), and uninvolved mucosa (n = 10) from 14 patients. In addition, we molecularly profiled sessile serrated lesion (SSL)-like or serrated lesion, not otherwise specified (SL-NOS), specimens, from 11 patients who also had IBD. This control cohort included SSL-like/SL-NOS without dysplasia/neoplasia (n = 11), SSL-like/SL-NOS with associated low-grade dysplasia (n = 2), and uninvolved mucosa (n = 8). By next-generation sequencing, the most frequently mutated gene in SEC without neoplasia and associated dysplasia/adenocarcinoma from separate foci in the same patients was TP53. Recurrent TP53 mutations were present in 50% of SEC specimens without dysplasia/neoplasia. In addition, alterations in TP53 were detected at a prevalence of 71% in low-grade dysplasia, 83% in high-grade dysplasia, and 100% in adenocarcinoma. Paired sequencing of SEC and associated neoplasia revealed identical TP53 missense mutations for 3 patients. In contrast, 91% of SSL-like/SL-NOS specimens without dysplasia/neoplasia harbored KRAS/BRAF mutations, which were conserved in associated low-grade dysplasia. No genomic alterations were found in uninvolved mucosa from either patients with SEC or patients with SSL-like/SL-NOS. Based on our findings, we conclude SEC is distinct from SSL-like serrated colorectal lesions in patients with IBD and an early precursor to IBD-associated neoplasia that warrants colonoscopic surveillance.

Keywords: Colon cancer; Crohn disease; Hyperplastic polyp; Serrated dysplasia; Sessile serrated adenoma/lesion; Ulcerative colitis.

Fig. 1

Serrated epithelial change (SEC) is microscopically characterized by a strikingly distorted architecture with crypts exhibiting loss of orientation and loss of their perpendicular arrangement to the muscularis mucosae (A). For a subset of cases, the crypts of SEC do not touch the muscularis mucosae and are separated by a layer of chronic inflammation (B). In addition, the serrated epithelium is present throughout the lesion, but irregular, unlike sessile serrated adenomas/lesions and hyperplastic polyps, and is rich in goblet cells. In this particular example, a boot-shaped crypt akin to sessile serrated adenomas/lesions is present but differs by exhibiting subtle serrated and other cytologic differences (C). Additional pathologic findings seen in association with SEC include low-grade dysplasia (D), high-grade dysplasia (E), and invasive adenocarcinoma (F).

Fig. 2

Sessile serrated lesion (SSL)–like and serrated lesion, not otherwise specified (SL-NOS), lesions can mimic an SEC owing to their serrated histologic findings. However, SSL-like/SL-NOS lesions show notable differences and do not exhibit all SEC-associated microscopic features. In contrast to SEC, SSL-like/SL-NOS can be villous or bullous in architecture (A) and exhibit serrations that are more prominent at either the mucosal surface (B) or base than throughout the lesion. In addition, a goblet cell–rich epithelium is typically absent in SSL-like/SL-NOS (C), but adjacent low-grade dysplasia can be seen in association (D). SEC, serrated epithelial change.

Fig. 3

Summary of detected genomic alterations in SEC, SSL-like/SL-NOS, and associated dysplasia. The most prevalent genomic alterations in SEC and associated dysplasia occurred in TP53, whereas SSL-like/SL-NOS and associated dysplasia predominantly harbored KRAS missense mutations. SEC, serrated epithelial change; SSL, sessile serrated lesion; SL-NOS, serrated lesion, not otherwise specified.