The incidence of HPV-positive oropharyngeal cancer (HPV+ OPC) is increasing, thus presenting new challenges for disease\ndetection and management. Noninvasive methods involving brush biopsies of diseased tissues were recently reported as\ninsufficient for tumor detection in HPV+ OPC patients, likely due to differences between the site of tumor initiation at the base\nof involuted crypts and the site of brush biopsy at the crypt surface. We hypothesized that histologically normal surface\nepithelial cells in the oropharynx contain changes in nuclear morphology that arise due to tumor proximity. We analyzed the\nnuclear phenotype of matched tumor, tumor-adjacent normal, and contralateral normal tissues from biopsies of nine HPV+\nOPC patients. Measurements of 89 nuclear features were used to train a random forest-based classifier to discriminate between\nnormal and tumor nuclei. We then extracted voting scores from the trained classifier, which classify nuclei on a continuous\nscale from zero (ââ?¬Å?normal-likeââ?¬Â) to one (ââ?¬Å?tumor-likeââ?¬Â). In each case, the average score of the adjacent normal nuclei was\nintermediate between the tumor and contralateral normal nuclei. These results provide evidence for the existence of phenotypic\nchanges in histologically normal, tumor-adjacent surface epithelial cells, which could be used as brush biopsy-based biomarkers\nfor HPV+OPC detection.
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