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Chronic inflammation, both endoscopic and histologic, in a contiguous and symmetric distribution is said to be important in distinguishing ulcerative colitis (UC) from Crohn's disease. Little is known whether this rule holds during the course of the disease and whether endoscopic/histologic correlation persists. In this study, we analyzed histologic patterns of UC in sequential sets of biopsy specimens to assess whether endoscopic and histologic findings correlate with time and treatment and to see whether distribution changes. Two hundred seventeen sets of colorectal biopsy specimens from 797 sites from 41 patients with clinical UC were studied and correlated with endoscopic findings. Each biopsy specimen was classified as definite or suspicious for chronic colitis or normal. Two histologic patterns of disease were identified: (1) diffuse, when all areas in all pieces from a biopsy segment had clear-cut colitis and (2) nondiffuse, when not all pieces were involved or single pieces had disease and normal mucosa both. Of 41 patients, the maximal extent of histologic disease was pancolitis in 30; 25 had less extensive disease at some point in the course. The maximal extent was left-sided in eight patients, seven of whom had less extent at some point. Of the three patients in whom the maximal extent was proctosigmoiditis, in one the inflammation disappeared. Seventy percent of the biopsy sites had diffuse patterns and 30% had nondiffuse. Histologic and endoscopic disease reverted to normal in 22 and 24 of 41 patients, respectively. Endoscopic and histologic findings were similar in 65% of the biopsy sites. Our results indicate that in long-standing UC (1) histologic disease may revert to normal mucosa, (2) because endoscopy alone may be insufficient to identify the mucosa as normal, biopsies should also be performed on the endoscopically normal mucosa, (3) the full extent of UC often is not established by a single set of biopsies, and (4) nondiffuse chronic inflammation and rectal sparing occurs in UC and are not necessarily markers of Crohn's disease.