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Mycophenolate mofetil (MMF) is a commonly used immunosuppressive drug used in the management of transplant recipients. Although gastrointestinal (GI) toxicity is a known complication of MMF, the literature characterizing the pathologic features of MMF in the GI tract is sparse. This study characterizes the pathologic features of MMF toxicity in both the upper and lower GI tract, correlating it with clinical and endoscopic findings. Seventy-five GI biopsies (9 esophageal, 15 gastric, 16 duodenal, 5 ileal, 30 colonic) from 46 transplant recipients from 2002 to 2006 were obtained and assessed for multiple histologic features. Clinical features were recorded for all cases and endoscopic findings. Only MMF patients showed ulcerative esophagitis (5/7 cases) and reactive gastropathy (4/10 cases). Only MMF patients showed graft-versus-host disease (GVHD)-like features in duodenal (4/12 cases) and ileal (1/5 cases) biopsies. GVHD-like changes were seen more frequently among patients on MMF compared with those not on MMF [9 (56%) vs. 2 (14%); P=0.017]. Crypt architectural disarray [12 (75%) vs. 2 (14%); P=0.001], lamina propria edema [9 (56%) vs. 2 (14%); P=0.017], increased lamina propria inflammation [13 (81%) vs. 3 (21%); P=0.001], dilated damaged crypts [7 (44%) vs. 1 (7%); P=0.024], and increased crypt epithelial apoptosis [9 (56%) vs. 2 (14%); P=0.017] were more common with MMF patients compared with non-MMF patients. In conclusion, pathologists should be aware of the potential manifestations of MMF toxicity throughout the GI tract, including ulcerative esophagitis, reactive gastropathy, and GVHD-like features in intestinal biopsies.