Research Article: Identification of Malignancy-Associated Changes in Histologically Normal Tumor-Adjacent Epithelium of Patients with HPV-Positive Oropharyngeal Cancer

Date Published: March 11, 2018

Publisher: Hindawi

Author(s): James Jabalee, Anita Carraro, Tony Ng, Eitan Prisman, Cathie Garnis, Martial Guillaud.


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

Partial Text

Oropharyngeal cancers (OPCs), which include malignancies of the tonsils, posterior pharyngeal wall, soft palate, and tongue base, have undergone a dramatic epidemiological shift. While the rate of tobacco and alcohol-related head and neck cancers is declining in North America, the incidence of HPV-positive OPC (HPV+ OPC) has been steadily rising since the early 1980s and is especially prevalent among young individuals (<60 years of age) [1]. These observations highlight the need for improved means of detecting and managing the disease. A total of 4830 tumor and 3352 contralateral normal nuclei were used to train the random forest classifier. When applied to the test set, the model showed an area under the ROC curve of 0.90. A total of 84.7% of the 1207 tumor and 80.8% of the 837 contralateral normal test set nuclei were correctly classified (Table 2). The rising incidence of HPV+ OPC presents new challenges for the detection and management of oropharyngeal malignancies. Given the relatively young age and good health of this cohort, much attention is being given to methods that deescalate the intensity of therapy without sacrificing its effectiveness, thus reducing morbidity and improving long-term patient quality of life [27]. TORS is a promising means for achieving this goal as it provides an alternative to standard CRT for individuals with early-stage tumors. TORS has similar disease outcomes when compared to CRT [28–30] but with improved functional outcomes [28–35]. Importantly, TORS has been found to result in significantly lower rates of dysphagia requiring either a gastrostomy tube or tracheotomy [28, 34], which are among the most common and challenging complications associated with CRT [2, 3, 34]. Strikingly, Moore et al. report preservation of swallowing function in >90% of TORS patients [28], whereas the rate of dysphagia requiring a gastrostomy tube following CRT approaches 45% [3, 36]. Patients treated with TORS also tend to score higher on factors related to quality of life, including eating, speech, and social, than did those treated with adjuvant radiation therapy or chemoradiation therapy [31, 32, 35]. Unfortunately, the use of TORS is limited to patients with early-stage tumors exhibiting limited nodal involvement [6]. A method of screening high-risk individuals would increase the number of TORS-eligible patients, thus avoiding the need for CRT and improving patient quality of life.

Malignancy-associated changes are reliably detected in histologically normal (normal-appearing) oropharyngeal epithelial cells located adjacent to a tumor and could be used as a noninvasive means of detecting early-stage oropharyngeal tumors.




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