Whole-Exome Sequencing Analysis of Inflammatory Bowel Disease-Associated Serrated Dysplasia

Abstract

The clinicopathologic and molecular features of serrated lesions with dysplasia in inflammatory bowel disease (IBD) remain poorly understood. We examined a total of 2396 patients treated for IBD at the University of Szeged between 2011 and 2023. Among them, 177 (7%) patients were diagnosed with colorectal neoplasia, of which only 11 (6%) had serrated dysplasia (n = 13). Of the 13 lesions, 5 (38%) showed features of sessile serrated lesion (SSL)-like dysplasia; 1 (8%) exhibited characteristics of traditional serrated adenoma (TSA)-like dysplasia; 6 (46%) were classified as serrated dysplasia, not otherwise specified (NOS); and 1 (8%) displayed mixed features of SSL-like and TSA-like dysplasias. At the time of the serrated dysplasia diagnosis, the mean age of the patients was 56 years. Ten (91%) patients had ulcerative colitis, and one (9%) had Crohn's disease. Pancolitis was observed in seven (64%) patients. The mean duration of IBD at the time of the serrated dysplasia diagnosis was 26 years. Most lesions (n = 9; 69%) were found in the left colon, including SSL-like dysplasia (3/5; 60%) and serrated dysplasia NOS (5/6, 83%). Eleven (85%) lesions had a polypoid endoscopic appearance. The mean size of the serrated dysplasia was 0.8 cm. Most lesions (n = 8; 62%) showed low-grade dysplasia. Serrated dysplasia was often associated with conventional (n = 3; 27%) or nonconventional dysplasia (n = 3; 27%). During the follow-up, 5 (45%) of the 11 patients developed colorectal cancer, including 3 patients with serrated dysplasia NOS, 1 with SSL-like dysplasia, and 1 with TSA-like dysplasia. Whole-exome sequencing revealed that the SSL-like dysplasia harbored mutations in BRAF (p.V600E), MLH1, KRAS, PTEN, POLE, KMT2C, and/or EXT1, whereas the serrated dysplasia NOS showed mutations in TP53, POLG, BRAF (p.G469A), KMT2C, and/or EXT1. One patient with both SSL-like dysplasia and mixed SSL-like/TSA-like dysplasia carried a pathogenic MUTYH (p.R217H) mutation, along with mutations in MADD. Serrated dysplasia was rare in IBD, with a prevalence rate of 6%. The SSL-like dysplasia exhibited distinct clinicopathologic and molecular characteristics compared with its sporadic counterpart. Similarly, serrated dysplasia NOS displayed unique molecular features compared with SSL-like dysplasia and could carry a higher risk of malignancy.

Keywords: dysplasia; inflammatory bowel disease; nonconventional; serrated dysplasia; sessile serrated lesion; traditional serrated adenoma.

Figure 1

Serrated dysplastic subtypes. (A) SSL-like dysplasia shows dilated crypts at the interface with the muscularis mucosae, accompanied by a dysplastic epithelium (HE, 5×). (B) Serrated dysplasia NOS demonstrates a complex serrated architecture with dysplasia. There is no definite evidence of SSL-like dysplasia or TSA-like dysplasia (HE, 5×). (C,D) In mixed SSL-like/TSA-like dysplasia, one area shows SSL-like dysplasia characterized by dilated L-shaped or inverted T-shaped crypts at the interface with the muscularis mucosae (C) (HE, 5×), while another area shows TSA-like dysplasia featuring a tubulovillous growth pattern, eosinophilic cytoplasm, and slit-like serrations (D) (HE, 5×). Abbreviations: HE, Hematoxyilin and eosin; NOS, not otherwise specified; SSL, sessile serrated lesion; TSA, traditional serrated adenoma.

Figure 2

Immunohistochemical analysis of SSL-like dysplasia and serrated dysplasia NOS. (A) MLH1 immunohistochemistry showed a loss of staining in SSL-like dysplasia (5×). (B) p53 immunohistochemistry demonstrated overexpression in serrated dysplasia NOS (5×).