Abstract
Background and Objectives Human papillomavirus (HPV)-driven oropharyngeal squamous cell carcinoma (OPSCC) is increasing globally. In Taiwan, HPV-positive OPSCC is obscured by tobacco, alcohol, and betel quid use. We investigated the role of high-risk HPV (hrHPV) in a large retrospective Taiwan OPSCC cohort.
Methods and Results The cohort of 541 OPSCCs treated at Chang Gung Memorial Hospital from 1998-2016 consisted of 507 men (94%) and 34 women (6%). Most used tobacco (81%), alcohol (51%), and betel quid (65%). Formalin-fixed, paraffin-embedded tissue was used for p16 staining (a surrogate marker for HPV) and testing for HPV DNA presence and type by Multiplex HPV PCR-MassArray. HPV DNA and/or p16 staining (HPV-positive) was found in 28.4% (150/528) tumors. p16 and HPV DNA were strongly correlated (F < 0.0001). HPV16 was present in 82.8%, and HPV58 in 7.5% of HPV-positive tumors. HPV was associated with higher age (55.5 vs. 52.7 years, p = 0.004), lower T-stage (p = 0.008) better overall survival (OS) (hazard ratio [HR] 0.58 [95% CI 0.42-0.81], p = 0.001), and disease-free survival (DFS) (HR 0.54 [95% CI 0.40-0.73], p < 0.0001). Alcohol was strongly associated with recurrence and death (OS: HR 2.06 [95% CI 1.54-2.74], p < 0.0001; DFS: HR 1.72 [95% CI 1.33-2.24], p < 0.0001). OS and DFS in HPV-positive cases decreased for alcohol users (p < 0.0001). Obscured by the strong alcohol effect, predictive associations were not found for tobacco or betel quid.
Conclusions As with HPV-positive OPSCC globally, HPV is an increasingly important etiological factor in Taiwanese OPSCC. HPV-positive OPSCC has considerable survival benefit, but that is reduced by alcohol, tobacco, and betel quid use. hrHPV is a cancer risk factor in males and females. Vaccinating both sexes with a multivalent vaccine including HPV58, combined with alcohol and tobacco cessation policies will be effective cancer-prevention public health strategies in Taiwan.
Competing Interest Statement
The authors have declared no competing interest.
Clinical Trial
NA
Funding Statement
This study was funded by the University of Michigan-Chang Gung Memorial Hospital Pilot Grant (https://www.rogelcancercenter.org and https://www.cgmh.org.tw/en) to K-PC and TEC; the National Cancer Institute at the National Institutes of Health (https://www.cancer.gov), CA194536 to TEC and HMW, and CA194536-S1 to GLH; the Chang Gung Memorial Hospital, CMRPG3H0852, CMRPG3J1251, and CORPG3G0171 to K-PC; the Taiwan Ministry of Science and Technology (https://www.most.gov.tw), MOST 108-2314-B-182A-108-MY3 to K-PC; and, funds from the University of Michigan Undergraduate Research Opportunity Program (https://lsa.umich.edu/urop) to GLH, TEC and HMW. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Author Declarations
I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.
Yes
The details of the IRB/oversight body that provided approval or exemption for the research described are given below:
This retrospective study was approved by the Institutional Review Boards of the University of Michigan Medical School and the Chang Gung Memorial Hospital and conducted in compliance with the ethical guidelines of the World Medical Association's Declaration of Helsinki (1964, amended in 2013) and local regulations. Additional patient consent was not required by the institutional review boards as this OPSCC cohort comprised secondary use of tissue specimens with unidentified chart data. All information stripped of personal identifiers to ensure that the data cannot be linked to individual cases in this cohort, are available in the supplementary S1 Table. The procedures described in this manuscript followed the reporting standards for human subject research of the EQUATOR Network, which are detailed in the STROBE report for this study (S1 Checklist).
All necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived.
Yes
I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).
Yes
I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable.
Yes
Footnotes
This manuscript was sent back to us because during the screening process it came as containing too much identifying information. By error, we attached an S1 Table file that still contained the ages of the individuals in our cohort. This has been solved, leaving all minimal data necessary to replicate the study (notice that age and genre are key to the results). A new S1 Table file has been attached. The cases were unidentified in Taiwan and the sample/patient IDs were not known to anyone outside the Taiwanese research team. No other researcher from the Michigan team or outside the research group had access to patient identification. Thank you for your help!
Data Availability
All relevant data needed to reproduce our findings are included in this manuscript and its Supporting Information, excepting sensitive dates that could allow the identification of the patients in this study.
Abbreviations
- CGMH
- Chang Gung Memorial Hospital
- DFS
- disease-free survival
- EQUATOR
- Enhancing the QUAlity and Transparency Of health Research Network
- FFPE
- formalin-fixed, paraffin-embedded
- HPV
- human papillomavirus
- hrHPV
- high-risk human papillomavirus
- IHC
- immunohistochemical staining
- OS
- overall survival
- OPSCC
- oropharyngeal squamous cell carcinoma
- PCR-MA
- multiplex PCR-MassArray
- STROBE
- Strengthening the Reporting of Observational Studies in Epidemiology