Histopathologic Features of Chimeric Antigen Receptor (CAR) T-cell Therapy-associated Gastrointestinal Mucosal Injury

Chimeric antigen receptor (CAR) T-cell therapy is an effective treatment for refractory hematologic malignancies; however, gastrointestinal adverse events (GI-AEs) are increasingly recognized as its use expands. We identified 6 patients with GI-AEs following CAR-T therapy over a 5-year period at our institution and conducted a comprehensive PubMed literature review to characterize histopathologic patterns and highlight differential diagnostic considerations. In the institutional cohort, the colon was most frequently involved (83%), followed by the small bowel (67%) and stomach (33%). Most patients developed watery diarrhea (83%) with negative infectious studies. Symptom onset occurred at a median of 107 days after infusion (range, 19 to 236 d). Twenty-one gastrointestinal biopsies were evaluated; 15 (71%) showed histologic abnormalities. Four histologic patterns were identified: active inflammation (33%), chronic active inflammation (27%), apoptosis-predominant injury (27%), and chronic inflammation (13%). Crypt epithelial apoptosis or intraepithelial apoptotic bodies were present in 67% of biopsies. Site-specific patterns included active colitis in the colon, chronic or chronic active duodenitis in the duodenum, apoptosis-predominant ileal injury, and active gastritis in the stomach. The literature review identified 22 additional patients, with histopathologic data available in 21 cases. Findings overlapped substantially with the institutional cohort and most commonly involved the colon and small intestine, with heterogeneous clinical outcomes. Overall, CAR-T-associated GI-AEs demonstrate reproducible yet nonspecific clinicopathologic features that overlap with immune-mediated, drug-related, infectious, and inflammatory conditions, necessitating careful clinicopathologic correlation and exclusion of alternative etiologies.