Variability in morphology and immunohistochemistry of Crohn's disease-associated small bowel neoplasms: implications of Claudin 18 and Cadherin 17 expression for tumor-targeted immunotherapies

Abstract

Aims: Inflammatory bowel disease-associated colorectal carcinomas are known to have different morphology, immunoprofile, and genetic findings from sporadic colorectal carcinomas; however, little is known for Crohn's disease-associated small bowel neoplasms (CD-SBNs). Cadherin 17 is a useful biomarker of adenocarcinomas with intestinal phenotype and recently reported as an ideal target for chimeric antigen receptor T-cells (CAR-T) therapy for gastrointestinal carcinoma. Claudin 18 is a cell adhesion protein, and Claudin18 isoform 2 (CLDN18.2) is frequently expressed at high levels in gastric-type adenocarcinoma. Zolbetuximab, a targeted monoclonal antibody, has been developed for CLDN18.2-positive gastroesophageal adenocarcinoma. We examined a series of CD-SBNs for both Cadherin 17 and Claudin 18, and also hypothesized that expression of Claudin 18 was associated with gastric phenotype.

Methods and results: We performed histological and immunohistochemical examinations on 25 CD-SBNs. Most of adenocarcinomas showed tubular morphology as seen in gastric carcinomas, whereas a subset of dysplasia was morphologically similar to that of the large bowel. Cadherin17 and Claudin 18 expression was identified in 93% and 57% CD-associated adenocarcinomas respectively. In Cadherin 17-positive CD-SBNs, frequent MUC5AC, MUC6, and Claudin18 expression was identified (61%, 57%, and 57%, respectively). Claudin 18-positive CD-SBNs showed significantly more MUC5AC and MUC6 expression than Claudin 18-negative CD-SBNs (P = 0.005, < 0.001 respectively).

Conclusion: In CD-associated small bowel adenocarcinomas, Cadherin 17 expression was frequently retained and Claudin 18 was frequently co-expressed. Claudin 18 had a positive correlation with the expression of gastric mucins. These results suggest that CD-associated small bowel adenocarcinomas may be candidates for Cadherin 17- and Claudin 18-targeted immunotherapies.

Keywords: Claudin 18 and Cadherin 17; Crohn’s disease, small bowel; Inflammatory bowel disease-associated carcinoma, dysplasia.

Fig. 1

Histology of Crohn’s disease-associated small bowel adenocarcinomas. Low-power view of infiltrating pattern (a) and high-power view of tubular morphology (b). Tubular and mucinous morphology (c) with focal signet ring cell differentiation (d)

Fig. 2

Histology of Crohn’s disease-associated small bowel dysplasias. Thickened villous appearance with irregular small glands (a), these glands are diffusely immunoreactive for p53 (mutant pattern) (b). Dystrophic goblet cells are seen in the small glands (high-power view of a) (c); (a–c; terminally differentiated (non-conventional type) dysplasia). Terminally differentiated dysplasia with mucin depletion (d). Serrated dysplasia (e). Adenomatous (conventional type) dysplasia (f)

Fig. 3

Low-power view of Crohn’s disease-associated small bowel adenocarcinoma (mixed (tubular and poorly cohesive) adenocarcinoma histology). a With diffuse cadherin 17 expression (b) and claudin 18 expression (c). High-power view H&E (d) with diffuse strong cadherin 17 expression (e), claudin 18 expression (f), MUC5AC expression (g), and MUC6 expression (h)