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Quantitative Grading of Rat Esophageal Carcinogenesis Using Computer-assisted Image Tile Analysis

Chemopreventive Agent Development Research Group, Division of Cancer Prevention, National Cancer Institute, Bethesda, Maryland 20892-7322 [C. W. B., G. J. K.]; Division of Environmental Health Sciences, The Ohio State University School of Public Health, CHRI 1148, 300 West Tenth Avenue, Columbus, Ohio 43210-1240 [G. D. S., M. A. M.]; and Bacus Laboratories, Lombard, Illinois 60148 [J. V. B., V. K., J. W. B.]

Our objective was to grade, by computer-assisted quantitative image tile analysis, the intraepithelial neoplasia (also called dysplasia) that develops in esophagi of rats given N-nitrosomethybenzylamine (NMBA) for 5 weeks. To perform image tile analysis, the computer divides the video image of the neoplastic epithelium into a row of contiguous small rectangular images, or "tiles," 84 x 292 µm in size, and quantitatively measures four selected tissue features within each image tile. The computer then calculates a tile grade for each image tile as the weighted sum of the four feature measurements, transformed into statistical Z-scores, the weights being determined by Fisher linear discriminant analysis of 300 tile grades of the neoplastic epithelium referenced to the mean tile grade (MTG) of 300 image tiles of normal epithelium. The two grading parameters, MTG and the percentage of tile grades exceeding the MTG of normal epithelium by >4 SD units (%TG>4SD), were validated as endpoints for screening chemopreventive agents in the rat NMBA-induced esophageal carcinogenesis model in two ways: (a) after NMBA treatment, %TG>4SD developed in parallel with tumor incidence and tumor multiplicity (number of papillomas/tumor-bearing rat); and (b) placing the chemopreventive phenethylisothiocyanate in the food of NMBA-treated rats produced parallel reductions in MTG, tumor incidence, and tumor multiplicity. Both MTG and %TG>4SD, measured by quantitative image tile analysis, are sensitive and objective continuous parametric response variables expressed to three significant figures, with wide dynamic range, that may be evaluated by t tests to compare tissue neoplastic changes before and after treatment with a chemopreventive agent.

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