Hong LiFollow

Date of Award

January 2019

Document Type


Degree Name

Medical Doctor (MD)



First Advisor

Benjamin L. Judson


Head and neck cancers are the 6th most common solid cancer in the world. Human papillomavirus (HPV) infections are now accepted to be a previously unrecognized causative agent for head and neck squamous cell carcinomas (HNSCCs). However, research surrounding HPV’s effect at non-oropharynx sub-site is limited. There is also mixed literature over the prognostic effect of patient sex and age on overall survival in HNSCCs. We sought to utilize the National Cancer Database from 2004-2013 to evaluate the outcomes of the aforementioned objectives. Univariate and multivariate survival analyses were conducted with chi-square tests, Kaplan-Meier estimates, log-rank tests, and Cox proportional hazards multivariable modeling.

The main findings of the study were:

1. HPV-positive status was associated with survival at 4 tumor subsites: oral cavity (hazard ratio [HR], 0.76; 95% CI, 0.66-0.87), oropharynx (HR, 0.44; 95% CI, 0.41-0.47), hypopharynx (HR, 0.59; 95% CI, 0.45-0.77), and larynx (HR, 0.71; 95% CI, 0.59-0.85). The HPV status was the greatest factor in survival outcome between the HPV-positive and -negative cohorts at the oropharynx subsite (77.6% vs 50.7%; survival difference, 26.9%; 95% CI, 25.6%-28.2%) and hypopharynx subsites (52.2% vs 28.8%; survival difference, 23.4%; 95% CI, 17.5%-29.3%). For the nasopharynx (HR, 1.03; 95% CI, 0.75-1.42) and sinonasal tract (HR, 0.63; 95% CI, 0.39-1.01) subsites, HPV-positive status was not an independent prognostic factor.

2. Though there were no significant differences in OS between the sexes in OP HPV-associated cancers, female sex was associated with worse OS in OP HPV- cancers (HR: 1.15; 95% CI 1.04–1.28, p = 0.004), whereas it was associated with improved OS in OC HPV-associated and HPV- cancers (HPV-associated: HR: 0.71; 95% CI 0.50–0.99, p = 0.048; HPV-: HR: 0.87; 95% CI 0.78–0.95, p = 0.004).

3. A younger age was independently associated with an improved OS in both OC and OPSCCs (OC- HR: 0.580; p<0.001; OP- HR: 0.556; p<0.001). Within the OPSCC group, age, however, still plays a secondary role to the effect of HPV (HPV-high risk serotype and young age significantly diminishes the chance of death by approximately 60% and 44% when compared to HPV-negative and old age respectively).

In conclusion, HPV positivity was associated with improved survival in 4 subsites (oropharynx, hypopharynx, oral cavity, and larynx), and the largest survival difference was noted in the oropharynx and hypopharynx subsites. In the nasopharynx and sinonasal tract subsites, HPV positivity had no association with OS. The effect of sex on OS in OC and OP SCC appears to vary based on tumor location and HPV status. Patients <40 years old have an improved OS compared to matched older controls.

As clinicians, when treating individual head and neck patients, it is important to consider all aspects of the patient and their disease (its cancer sub-site, HPV-positivity status, sex and age) to optimize overall survival for our head and neck cancer patients.


This thesis is restricted to Yale network users only. It will be made publicly available on 07/15/2021