Purpose: This was an exploratory study to test two hypotheses related to potential epithelial precursors to ovarian cancer: (a) histologically normal ovarian surface epithelium exhibited changes in the nuclear chromatin pattern, which indicate an ovarian abnormality, and (b) such changes were detectable in the ovarian surface epithelium of cancer-free subjects who were at high risk for ovarian cancer. Experimental Design: Ovaries were carefully collected to avoid damage to the surface epithelium. Five-micron-thick histologic sections were cut and stained with H&E. High-resolution images were recorded from the ovarian surface epithelium and from the underlying stroma of ovaries from normal women (10 cases), women at high risk of developing ovarian cancer (7 cases), and histologically normal areas adjacent to ovarian cancer (3 cases). Karyometric features and measurements of nuclear abnormality were computed for 3,390 epithelial nuclei. Discriminant function analyses and unsupervised learning algorithms were employed to define deviations from normal and to identify the subpopulations of nuclei exhibiting these changes. Results: Epithelium from ovaries harboring a malignant lesion had changes in the nuclear chromatin pattern consistent with a second phenotype, which were not visually detected with histopathologic surveillance. This phenotype was also present in the ovaries obtained from women at increased risk of ovarian cancer, suggesting that it may represent a premalignant abnormality. These changes were statistically significant. Conclusion: The observed changes in karyometric features were sufficiently distinct to warrant further study as both diagnostic and prognostic biomarkers for early detection and prevention of ovarian cancer.
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