Understanding the impact of high-risk human papillomavirus on oropharyngeal squamous cell carcinomas in Taiwan: A retrospective cohort study

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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 this 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.

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Most cited references 96

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Global Cancer Statistics 2018: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries

Ahmedin Jemal, Lindsey A Torre, Rebecca Siegel … (2018)

This article provides a status report on the global burden of cancer worldwide using the GLOBOCAN 2018 estimates of cancer incidence and mortality produced by the International Agency for Research on Cancer, with a focus on geographic variability across 20 world regions. There will be an estimated 18.1 million new cancer cases (17.0 million excluding nonmelanoma skin cancer) and 9.6 million cancer deaths (9.5 million excluding nonmelanoma skin cancer) in 2018. In both sexes combined, lung cancer is the most commonly diagnosed cancer (11.6% of the total cases) and the leading cause of cancer death (18.4% of the total cancer deaths), closely followed by female breast cancer (11.6%), prostate cancer (7.1%), and colorectal cancer (6.1%) for incidence and colorectal cancer (9.2%), stomach cancer (8.2%), and liver cancer (8.2%) for mortality. Lung cancer is the most frequent cancer and the leading cause of cancer death among males, followed by prostate and colorectal cancer (for incidence) and liver and stomach cancer (for mortality). Among females, breast cancer is the most commonly diagnosed cancer and the leading cause of cancer death, followed by colorectal and lung cancer (for incidence), and vice versa (for mortality); cervical cancer ranks fourth for both incidence and mortality. The most frequently diagnosed cancer and the leading cause of cancer death, however, substantially vary across countries and within each country depending on the degree of economic development and associated social and life style factors. It is noteworthy that high-quality cancer registry data, the basis for planning and implementing evidence-based cancer control programs, are not available in most low- and middle-income countries. The Global Initiative for Cancer Registry Development is an international partnership that supports better estimation, as well as the collection and use of local data, to prioritize and evaluate national cancer control efforts. CA: A Cancer Journal for Clinicians 2018;0:1-31. © 2018 American Cancer Society.

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Cancer statistics, 2019

Rebecca Siegel, Kimberly D Miller, Ahmedin Jemal (2019)

Each year, the American Cancer Society estimates the numbers of new cancer cases and deaths that will occur in the United States and compiles the most recent data on cancer incidence, mortality, and survival. Incidence data, available through 2015, were collected by the Surveillance, Epidemiology, and End Results Program; the National Program of Cancer Registries; and the North American Association of Central Cancer Registries. Mortality data, available through 2016, were collected by the National Center for Health Statistics. In 2019, 1,762,450 new cancer cases and 606,880 cancer deaths are projected to occur in the United States. Over the past decade of data, the cancer incidence rate (2006-2015) was stable in women and declined by approximately 2% per year in men, whereas the cancer death rate (2007-2016) declined annually by 1.4% and 1.8%, respectively. The overall cancer death rate dropped continuously from 1991 to 2016 by a total of 27%, translating into approximately 2,629,200 fewer cancer deaths than would have been expected if death rates had remained at their peak. Although the racial gap in cancer mortality is slowly narrowing, socioeconomic inequalities are widening, with the most notable gaps for the most preventable cancers. For example, compared with the most affluent counties, mortality rates in the poorest counties were 2-fold higher for cervical cancer and 40% higher for male lung and liver cancers during 2012-2016. Some states are home to both the wealthiest and the poorest counties, suggesting the opportunity for more equitable dissemination of effective cancer prevention, early detection, and treatment strategies. A broader application of existing cancer control knowledge with an emphasis on disadvantaged groups would undoubtedly accelerate progress against cancer.

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Human papillomavirus and survival of patients with oropharyngeal cancer.

K Ang, Jonathan Harris, Richard Wheeler … (2010)

Oropharyngeal squamous-cell carcinomas caused by human papillomavirus (HPV) are associated with favorable survival, but the independent prognostic significance of tumor HPV status remains unknown. We performed a retrospective analysis of the association between tumor HPV status and survival among patients with stage III or IV oropharyngeal squamous-cell carcinoma who were enrolled in a randomized trial comparing accelerated-fractionation radiotherapy (with acceleration by means of concomitant boost radiotherapy) with standard-fractionation radiotherapy, each combined with cisplatin therapy, in patients with squamous-cell carcinoma of the head and neck. Proportional-hazards models were used to compare the risk of death among patients with HPV-positive cancer and those with HPV-negative cancer. The median follow-up period was 4.8 years. The 3-year rate of overall survival was similar in the group receiving accelerated-fractionation radiotherapy and the group receiving standard-fractionation radiotherapy (70.3% vs. 64.3%; P=0.18; hazard ratio for death with accelerated-fractionation radiotherapy, 0.90; 95% confidence interval [CI], 0.72 to 1.13), as were the rates of high-grade acute and late toxic events. A total of 63.8% of patients with oropharyngeal cancer (206 of 323) had HPV-positive tumors; these patients had better 3-year rates of overall survival (82.4%, vs. 57.1% among patients with HPV-negative tumors; P<0.001 by the log-rank test) and, after adjustment for age, race, tumor and nodal stage, tobacco exposure, and treatment assignment, had a 58% reduction in the risk of death (hazard ratio, 0.42; 95% CI, 0.27 to 0.66). The risk of death significantly increased with each additional pack-year of tobacco smoking. Using recursive-partitioning analysis, we classified our patients as having a low, intermediate, or high risk of death on the basis of four factors: HPV status, pack-years of tobacco smoking, tumor stage, and nodal stage. Tumor HPV status is a strong and independent prognostic factor for survival among patients with oropharyngeal cancer. (ClinicalTrials.gov number, NCT00047008.) 2010 Massachusetts Medical Society

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Author and article information

Contributors

Guadalupe Lorenzatti Hiles:

ORCID: https://orcid.org/0000-0002-8423-3279

Role: ConceptualizationRole: Data curationRole: Formal analysisRole: Funding acquisitionRole: InvestigationRole: MethodologyRole: Project administrationRole: ValidationRole: VisualizationRole: Writing – original draft

Kai-Ping Chang:

ORCID: https://orcid.org/0000-0003-1777-9578

Role: ConceptualizationRole: Data curationRole: Funding acquisitionRole: InvestigationRole: Project administrationRole: ResourcesRole: SupervisionRole: Writing – review & editing

Emily L. Bellile:

ORCID: https://orcid.org/0000-0003-4350-4658

Role: ConceptualizationRole: Data curationRole: Formal analysisRole: ValidationRole: VisualizationRole: Writing – review & editing

Chun-I Wang: Role: Data curationRole: InvestigationRole: Writing – review & editing

Wei-Chen Yen: Role: Data curationRole: InvestigationRole: Writing – review & editing

Christine M. Goudsmit: Role: InvestigationRole: Project administrationRole: Writing – review & editing

Hannah L. Briggs:

ORCID: https://orcid.org/0000-0003-0686-4523

Role: InvestigationRole: ValidationRole: Writing – review & editing

Trey B. Thomas:

ORCID: https://orcid.org/0000-0002-5730-5417

Role: InvestigationRole: Writing – review & editing

Lila Peters: Role: InvestigationRole: Writing – review & editing

Macy A. Afsari:

ORCID: https://orcid.org/0000-0003-3784-3848

Role: InvestigationRole: ValidationRole: VisualizationRole: Writing – review & editing

Lisa M. Pinatti:

ORCID: https://orcid.org/0000-0002-4864-5698

Role: Data curationRole: Writing – review & editing

Anna C. Morris: Role: InvestigationRole: Writing – review & editing

Nadine Jawad:

ORCID: https://orcid.org/0000-0003-0325-5319

Role: InvestigationRole: Writing – review & editing

Thomas E. Carey:

ORCID: https://orcid.org/0000-0002-5202-7518

Role: ConceptualizationRole: Funding acquisitionRole: Project administrationRole: ResourcesRole: SupervisionRole: Writing – review & editing

Heather M. Walline:

ORCID: https://orcid.org/0000-0003-3790-5738

Role: ConceptualizationRole: Data curationRole: Formal analysisRole: Funding acquisitionRole: InvestigationRole: Project administrationRole: ResourcesRole: SupervisionRole: ValidationRole: Writing – review & editing

Maria Lina Tornesello: Role: Editor

Journal

Journal ID (nlm-ta): PLoS One

Journal ID (iso-abbrev): PLoS One

Journal ID (publisher-id): plos

Journal ID (pmc): plosone

Title: PLoS ONE

Publisher: Public Library of Science (San Francisco, CA USA )

ISSN (Electronic): 1932-6203

Publication date (Electronic): 23 April 2021

Publication date Collection: 2021

Volume: 16

Issue: 4

Electronic Location Identifier: e0250530

Affiliations

[1 ] Division of Head and Neck Surgery, Department of Otolaryngology, University of Michigan Medical School, Ann Arbor, Michigan, United States of America

[2 ] University of Michigan Rogel Cancer Center, Ann Arbor, Michigan, United States of America

[3 ] Department of Otolaryngology-Head & Neck Surgery, Chang Gung Memorial Hospital (Linkou Medical Center), Taoyuan, Taiwan, Republic of China

[4 ] College of Medicine, Chang Gung University, Taoyuan, Taiwan, Republic of China

[5 ] Department of Biostatistics, School of Public Health, University of Michigan, Ann Arbor, Michigan, United States of America

[6 ] Radiation Biology Research Center, Institute for Radiological Research, Chang Gung University and Chang Gung Memorial Hospital, Taoyuan, Taiwan, Republic of China

[7 ] Cancer Biology Program, Rackham Graduate School, University of Michigan, Ann Arbor, Michigan, United States of America

Istituto Nazionale Tumori IRCCS Fondazione Pascale, ITALY

Author notes

Competing Interests: The authors have declared that no competing interests exist.

[¤a]

Current address: School of Public Health, University of Michigan, Ann Arbor, Michigan, United States of America

[¤b]

Current address: Department of Molecular Pathology, Yale New Haven Health, New Haven, Connecticut, United States of America

[¤c]

Current address: Department of Health Policy and Management, Milken Institute School of Public Health, George Washington University, Washington DC, United States of America

[¤d]

Current address: Stanford University School of Medicine, Stanford, California, United States of America

‡ These authors are joint senior authors and also contributed equally to this work

* E-mail: dr.kpchang@ 123456gmail.com (K-PC); careyte@ 123456umich.edu (TEC); hwalline@ 123456med.umich.edu (HMW)

Author information

Guadalupe Lorenzatti Hiles https://orcid.org/0000-0002-8423-3279

Kai-Ping Chang https://orcid.org/0000-0003-1777-9578

Emily L. Bellile https://orcid.org/0000-0003-4350-4658

Hannah L. Briggs https://orcid.org/0000-0003-0686-4523

Trey B. Thomas https://orcid.org/0000-0002-5730-5417

Macy A. Afsari https://orcid.org/0000-0003-3784-3848

Lisa M. Pinatti https://orcid.org/0000-0002-4864-5698

Nadine Jawad https://orcid.org/0000-0003-0325-5319

Thomas E. Carey https://orcid.org/0000-0002-5202-7518

Heather M. Walline https://orcid.org/0000-0003-3790-5738

Article

Publisher ID: PONE-D-20-36961

DOI: 10.1371/journal.pone.0250530

PMC ID: 8064583

PubMed ID: 33891627

SO-VID: 17c0d746-a2c2-4042-a639-f7ec02de677d

License:

This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

History

Date received : 24 November 2020

Date accepted : 8 April 2021

Page count

Figures: 5, Tables: 2, Pages: 24

Funding

Funded by: University of Michigan-Chang Gung Memorial Hospital Pilot Grant

Award Recipient :

ORCID: https://orcid.org/0000-0003-1777-9578

Kai-Ping Chang

Funded by: University of Michigan-Chang Gung Memorial Hospital Pilot Grant

Award Recipient :

ORCID: https://orcid.org/0000-0002-5202-7518

Thomas E. Carey

Funded by: National Cancer Institute at the National Institutes of Health (US)

Award ID: CA194536

Award Recipient :

ORCID: https://orcid.org/0000-0002-5202-7518

Thomas E. Carey

Funded by: National Cancer Institute at the National Institutes of Health (US)

Award ID: CA194536

Award Recipient :

ORCID: https://orcid.org/0000-0003-3790-5738

Heather M. Walline

Funded by: National Cancer Institute at the National Institutes of Health (US)

Award ID: CA194536-S1

Award Recipient :

ORCID: https://orcid.org/0000-0002-8423-3279

Guadalupe Lorenzatti Hiles

Funded by: funder-id http://dx.doi.org/10.13039/100012553, Chang Gung Memorial Hospital;

Award ID: CMRPG3H0852

Award Recipient :

ORCID: https://orcid.org/0000-0003-1777-9578

Kai-Ping Chang

Funded by: funder-id http://dx.doi.org/10.13039/100012553, Chang Gung Memorial Hospital;

Award ID: CMRPG3J1251

Award Recipient :

ORCID: https://orcid.org/0000-0003-1777-9578

Kai-Ping Chang

Funded by: funder-id http://dx.doi.org/10.13039/100012553, Chang Gung Memorial Hospital;

Award ID: CORPG3G0171

Award Recipient :

ORCID: https://orcid.org/0000-0003-1777-9578

Kai-Ping Chang

Funded by: funder-id http://dx.doi.org/10.13039/501100004663, Ministry of Science and Technology, Taiwan;

Award ID: MOST 108-2314-B-182A-108-MY3

Award Recipient :

ORCID: https://orcid.org/0000-0003-1777-9578

Kai-Ping Chang

Funded by: University of Michigan Undergraduate Research Opportunity Program (US)

Award Recipient :

ORCID: https://orcid.org/0000-0002-8423-3279

Guadalupe Lorenzatti Hiles

Funded by: University of Michigan Undergraduate Research Opportunity Program (US)

Award Recipient :

ORCID: https://orcid.org/0000-0002-5202-7518

Thomas E. Carey

Funded by: University of Michigan Undergraduate Research Opportunity Program (US)

Award Recipient :

ORCID: https://orcid.org/0000-0003-3790-5738

Heather M. Walline

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.

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Understanding the impact of high-risk human papillomavirus on oropharyngeal squamous cell carcinomas in Taiwan: A retrospective cohort study

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Abstract

Background and objectives

Methods and results

Conclusions

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PLOS Climate

Most cited references 96

Global Cancer Statistics 2018: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries

Cancer statistics, 2019

Human papillomavirus and survival of patients with oropharyngeal cancer.

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Cited by 7

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