NON-CASEATING GRANULOMAS ARE ASSOCIATED WITH STRICTURING CROHN’S DISEASE AND THEIR NUMBER AND SIZE ARE INCREASED IN THE MUSCULARIS PROPRIA OF STRICTURED COMPARED TO NON-STRICTURED INTESTINGAL SEGMENTS

Abstract

Abstract BACKGROUND Crohn’s disease (CD) is a chronic inflammatory disorder of the gastrointestinal tract that progressively leads to fibrosis-induced narrowing of the intestinal lumen, bowel obstruction, and need for surgery. CD exhibits transmural inflammation manifested by immune cell infiltrates composed of multiple immune cell types spanning the entire gut wall. Non-caseating granulomas are a typical hallmark of up to 60% of CD patients. Scarce evidence indicates an association of granulomas with post-operative recurrence suggesting a role of granulomas in disease pathogenesis. Strikingly, while evidence exists from other granulomatous diseases, granulomas have not been linked with stricturing CD. METHODS A total of 348 H&E stained sections from segments of small bowel CD surgical resection specimens were evaluated for non-caseating granulomas. Granulomas were defined by a trained inflammatory bowel disease pathologist as a cluster of ≥ 5 epithelioid histiocytes with or without the presence of multinucleated giant cells. CD segments were classified as non-involved (CDni), inflamed non-strictured (CDi), and strictured (CDs) to confirm whether histopathological presence of granulomas correlates with stricturing CD. Paired sets were available in 150 segments of 50 CD patients and analyzed further to determine whether granuloma number, location within the intestinal wall, or size of granulomas correlates with stricturing CD. RESULTS Granulomas were present in 20% of all CD tissue segments. 28% of CDs, 9% of CDi, and 5% of CDni segments were found to have granulomas and the fraction of segments containing granulomas was significantly higher in CDs compared to CDni and CDi (P<0.0001). The paired patient sections resembled the larger dataset with 16% of patients having granulomas in at least one of the three segments (16% of CDs, 8% of CDi, and 0% CDni). Further comparing the CDi and CDs sections in this subset of patients, we found that neither the total number nor the average size of granulomas were significantly different between CDs versus CDi tissue sections. Analysis of the layers of the intestinal wall revealed that the number (P<0.05) and average size (P<0.01) of granulomas were significantly increased in the muscularis propria of CDs versus CDi sections. There were no significant changes in number or average size in the mucosal or submucosal layers of the intestinal wall. CONCLUSION Together these data indicate that non-caseating granulomas are associated with stricturing CD and these granulomas are increased in number and size in the muscularis propria of strictured versus inflamed tissues from the same patient, but not other intestinal layers. This suggests a potential link between granulomas and the pathogenesis of stricturing CD.