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HPV status fully mediates sex-related survival differences in oropharyngeal cancer: a population-based analysis with formal interaction testing

Published online by Cambridge University Press:  01 June 2026

Adrian Hoenle Open the ORCID record for Adrian Hoenle [Opens in a new window] ,
Dorothee Rickert ,
Helmut Steinhart  and
Stephan Lorenz
Adrian Hoenle*
Affiliation:
Division of ENT, Head and Neck Surgery, Marienhospital Stuttgart, Germany
Dorothee Rickert
Affiliation:
Division of ENT, Head and Neck Surgery, Marienhospital Stuttgart, Germany
Helmut Steinhart
Affiliation:
Division of ENT, Head and Neck Surgery, Marienhospital Stuttgart, Germany
Stephan Lorenz
Affiliation:
Division of Emergency Medicine, Klinikum Stuttgart, Germany
*
Corresponding author: Adrian Hoenle; Email: adrian.hoenle@gmx.net
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Abstract

Objectives

To determine whether sex independently predicts survival in oropharyngeal squamous cell carcinoma and whether human papillomavirus status mediates apparent sex-related survival differences at the population level.

Methods

Population-based cohort study using the Surveillance, Epidemiology, and End Results (SEER) database (17 Registries, 2018–2021). Multivariable Cox regression and a formal sex–human papillomavirus interaction test (likelihood ratio test) were performed in 19,716 patients with known p16/HPV status.

Results

p16-positive disease was more prevalent in males (73.6 per cent vs. 56.2 per cent; p < 0.001). Within human papillomavirus subgroups, survival did not differ significantly between sexes (all p > 0.30). After full adjustment, female sex was not independently associated with overall survival (hazard ratio 0.98; 95 per cent confidence interval 0.91–1.05; p = 0.52) or disease-specific survival (hazard ratio 1.01; p = 0.80). The sex–human papillomavirus interaction was non-significant (hazard ratio 1.057; p = 0.459), confirming human papillomavirus status fully mediates the apparent female survival disadvantage.

Conclusion

Sex is not an independent prognostic variable in oropharyngeal squamous cell carcinoma. HPV/p16-based stratification remains the primary prognostic framework.

Keywords

oropharyngeal neoplasmspapillomavirus infectionssex factorssurvival analysisprognosis

Information

Type
Main Article
Information
The Journal of Laryngology & Otology , Volume 140 , Issue 7 , July 2026 , pp. 775 - 782
Copyright
© The Author(s), 2026. Published by Cambridge University Press on behalf of J.L.O. (1984) LIMITED.

Introduction

Oropharyngeal squamous cell carcinoma (OPSCC) exhibits one of the most pronounced sex disparities of any solid malignancy, with males accounting for approximately 80–85 per cent of all cases in Western populations.Reference Gillison, Chaturvedi, Anderson and Fakhry1, Reference Chaturvedi, Engels, Pfeiffer, Hernandez, Xiao and Kim2 This imbalance is driven primarily by the higher prevalence of human papillomavirus (HPV)-associated disease in men, reflecting differences in sexual behaviour, oral HPV acquisition rates and immune clearance.Reference Gillison, Koch, Capone, Spafford, Westra and Wu3, Reference D’Souza, Kreimer, Viscidi, Pawlita, Fakhry and Koch4 As a consequence, males disproportionately benefit from the favourable prognosis conferred by p16-positive, HPV-driven tumours, while females more frequently present with p16-negative disease and its substantially inferior survival outcomes.Reference Ang, Harris, Wheeler, Weber, Rosenthal and Nguyen-Tân5, Reference O’Sullivan, Huang, Su, Garden, Sturgis and Dahlstrom6

The central question is whether sex itself — independent of HPV status, stage, age and treatment — constitutes a meaningful prognostic variable, or whether it acts purely as a surrogate for differential HPV prevalence. Prior systematic reviews and meta-analyses, including analyses of over 100,000 patients, have reported that sex loses prognostic significance after HPV adjustment.Reference Gordis, Cagle, Nguyen and Newman7, Reference Chun, Chernov, Chen, Nguyen, Marrero-Gonzalez and Stevens8 However, these analyses were predominantly based on institutional series predating the American Joint Committee on Cancer (AJCC) 8th Edition, and critically, none performed a formal statistical test of the sex–HPV interaction at population level.

The introduction of the AJCC 8th Edition staging system in 2018, with systematic p16/HPV documentation in Surveillance, Epidemiology, and End Results (SEER), provides for the first time the population-level data needed to address this question with adequate statistical power.Reference O’Sullivan, Huang, Su, Garden, Sturgis and Dahlstrom6, Reference Amin, Greene, Edge, Compton, Gershenwald and Brookland9, 10 We formally test the sex–HPV interaction at a population level — the first such test performed at this scale. We addressed four specific questions: (1) Does sex independently predict overall survival (OS) or disease-specific survival (DSS) after full adjustment? (2) Is the HPV survival benefit equivalent in males and females? (3) Does stage distribution differ between sexes within HPV subgroups? (4) Do treatment utilisation rates differ by sex and to what clinical magnitude?

Materials and methods

Study design and data source

This retrospective population-based cohort study used data from the SEER Research Data, 17 Registries, November 2024 Submission (2000–2022), accessed via SEER*Stat version 8.4.2.10 Institutional review board approval was not required as de-identified publicly available registry data were used. Reporting follows Strengthening the Reporting of OBservational Studies in Epidemiology (STROBE) guidelines.Reference von Elm, Altman, Egger, Pocock, Gøtzsche and Vandenbroucke11

Study population

Patients with histologically confirmed OPSCC diagnosed between 2018 and 2021 with explicitly documented p16/HPV status were eligible. Eligible ICD-O-3 sites: base of tongue (C01.9), tonsil (C09.0–C09.9) and oropharynx (C10.2, C10.3, C10.8, C10.9). Exclusion criteria: age less than 15 years, unknown vital status and survival of zero months with concurrent alive status.

Variables and outcomes

p16/HPV status was classified via the SEER Schema ID (2018+) variable as p16-positive or p16-negative, reflecting p16 immunohistochemistry as a validated surrogate for high-risk HPV.Reference JS, Beadle, Bishop, Chernock, Colasacco and Lacchetti12, Reference Fakhry, Lacchetti, Rooper, Jordan, Rischin and Sturgis13 Primary endpoint was OS; secondary endpoint was DSS. Covariates included age group, race, AJCC 8th Edition stage, chemotherapy, radiation therapy, surgical treatment and diagnosis year.

Statistical analysis

Analyses were performed in R (version 4.5.2).Reference Core14 Survival was estimated by the Kaplan–Meier method.Reference Kaplan and Meier15 The primary analytical innovation was the formal sex–HPV interaction test: a sex–HPV interaction term was incorporated into a multivariable Cox proportional hazards model and tested by likelihood ratio test (LRT).Reference Cox16 The proportional hazards assumption was assessed using Schoenfeld residuals.Reference Schoenfeld17 Treatment differences were assessed by Pearson chi-squared with Cramér’s V effect sizes.Reference Cramér18 All tests two-sided; α = 0.05.

Results and analysis

Cohort characteristics

The cohort comprised 19,716 patients: 16,519 males (83.8 per cent) and 3,197 females (16.2 per cent). p16-positive disease was present in 70.8 per cent overall: 73.6 per cent of males versus 56.2 per cent of females (p < 0.001). Females presented more often with Stage IV disease (19.0 per cent vs. 14.9 per cent) and less often with Stage II (10.4 per cent vs. 16.1 per cent; both p < 0.001). Males received chemotherapy (65.4 per cent vs. 54.7 per cent) and radiation therapy (79.9 per cent vs. 72.1 per cent) more frequently; females underwent surgery more often (31.8 per cent vs. 28.0 per cent; all p < 0.001). Baseline characteristics are presented in Table 1.

Table 1.

Baseline characteristics stratified by sex and p16/HPV status

Across both sexes, p16-positive cases are far more often early-stage and more likely to receive chemo and radiation than p16-negative cases. See long description.
Table 1 Long description

The table compares baseline characteristics for males and females, each split into p16-positive and p16-negative groups, reporting counts and percentages plus within-sex p-values. Age differs by p16 status in both sexes: p16-negative groups skew older, with the 80+ category higher in p16-negative than p16-positive for males (8.5% vs 4.2%) and females (13% vs 7.2%). Race distributions also differ: White patients are more common in p16-positive than p16-negative for both males (91% vs 82%) and females (89% vs 80%), while Black patients are more common in p16-negative than p16-positive (males 12% vs 5.4%; females 13% vs 5.2%). AJCC stage shows the largest contrast: p16-positive is mostly stage I (males 51%, females 57%), whereas p16-negative has much higher stage IV (males 48%, females 40%) and more unknown stage (males 37%, females 42%). Treatment patterns differ similarly: chemotherapy is more frequent in p16-positive than p16-negative (males 68% vs 57%; females 61% vs 47%), and radiation is also more frequent (males 85% vs 67%; females 81% vs 60%). Surgery is less common in p16-negative than p16-positive for both sexes (males 21% vs 30%; females 29% vs 34%). All listed comparisons show statistically significant differences within each sex group, but p-values do not indicate effect size or clinical importance.

Note: p-Values: Pearson’s chi-squared test within each sex group.

AJCC = American Joint Committee on Cancer; HPV = human papillomavirus.

Stage distribution

Stage distribution, as shown in Figure 1, differed significantly between sexes within both HPV subgroups (both p < 0.001). Among p16-positive patients, early-stage (I–II) disease was comparable at 71.2 per cent in males and 71.9 per cent in females, indicating no clinically meaningful difference in stage at presentation within the HPV-positive group.

Figure 1.

AJCC 8th Edition stage distribution (EOD 2018) by sex and p16/HPV status. Left panel: p16-positive; right panel: p16-negative. Both comparisons p < 0.001. Percentages are calculated from the total group including patients with unknown stage; bars therefore do not sum to 100 per cent. AJCC = American Joint Committee on Cancer; EOD = Extent of Disease; HPV = human papillomavirus.

A grouped bar graph showing A J C C stage distribution by sex for p 16 positive and p 16 negative groups.

Survival outcomes

Kaplan–Meier curves are shown in Figures 2 and 3. Within males, five-year OS was 74.2 per cent (95 per cent confidence interval [CI] 73.0–75.4 per cent) for p16-positive versus 42.6 per cent (95 per cent CI 40.5–44.9 per cent) for p16-negative patients (p < 0.001). Within females, five-year OS was 76.0 per cent (95 per cent CI 72.7–79.5 per cent) for p16-positive versus 42.6 per cent (95 per cent CI 38.8–46.7 per cent) for p16-negative disease (p < 0.001). Within each HPV subgroup, survival did not differ significantly between sexes (all p > 0.30). The formal sex–HPV interaction test was non-significant (interaction hazard ratio [HR] 1.057; 95 per cent CI 0.93–1.20; p = 0.459). The proportional hazards assumption was assessed using Schoenfeld residuals; a violation was detected for HPV status and AJCC stage, consistent with the time-varying nature of the HPV survival benefit, but does not affect the primary conclusions regarding sex.

Figure 2.

OS stratified by sex and p16/HPV status (male/p16-positive, female/p16-positive, male/p16-negative, female/p16-negative), SEER 2018–2021 (n = 19,716). Black lines = p16-positive; grey lines = p16-negative; solid = male; dashed = female. Y-axis range 0.25–1.0. Global log-rank p < 0.0001. HPV = human papillomavirus; OS = overall survival; SEER = Surveillance, Epidemiology, and End Results.

A multi-line graph showing overall survival probability over time for male and female groups with p16-positive and p16-negative status.
Figure 3.

DSS stratified by sex and p16/HPV status. Line styles as per Figure 2. Global log-rank p < 0.0001. DSS = disease-specific survival; HPV = human papillomavirus.

A multi-line graph showing disease-specific survival probability over time for male and female groups with p16-positive and p16-negative status.

Multivariable Cox regression

Sex-stratified Cox regression results are presented in Table 2. After full adjustment, female sex was not independently associated with OS (HR 0.98; 95 per cent CI 0.91–1.05; p = 0.52) or DSS (HR 1.01; 95 per cent CI 0.93–1.10; p = 0.80). p16-negative status was an independent adverse prognostic factor in both sexes (all p < 0.001).

Table 2.

Sex-stratified multivariable Cox proportional hazards regression for OS and DSS

Higher AJCC stage and older age strongly increase death risk for both sexes; p16-negative status also raises risk for overall and disease-specific survival. See long description.
Table 2 Long description

Sex-stratified multivariable Cox regression results report hazard ratios and p-values for overall survival and disease-specific survival in males (16,519) and females (3,197). Across both outcomes and sexes, higher AJCC stage shows the largest risk increases versus stage I, rising from about two and a half to three times higher at stage II to about five to seven times higher at stage IV, with strong statistical support. Older age groups show a clear dose-response pattern, reaching roughly five times higher overall-survival risk for males and females age 80 and older compared with under 45, and similarly large increases for disease-specific survival. p16-negative status is consistently associated with higher risk in both sexes for both outcomes, around one and one third to one and two fifths higher than p16-positive, with statistically significant p-values. Black race is associated with about one and a half times higher risk than White for both outcomes in both sexes, while Other or Unknown race is not clearly different from White. Not receiving chemotherapy is linked to a modestly higher risk in males but is not statistically clear in females; not receiving radiation is associated with roughly two and a half to three times higher risk in both sexes and outcomes. Diagnosis year effects are small and inconsistent, with some modest increases in males in 2019 and 2021 and mostly non-significant findings in females. Estimates are relative to the stated reference categories and reflect associations after adjustment, not proof of causation.

Note: Reference categories: p16-positive, age less than 45 years, White race, Stage I, chemotherapy yes, radiation yes, diagnosis year 2018. Sex × HPV interaction test (OS): HR 1.057, p = 0.459.

AJCC = American Joint Committee on Cancer; DSS = disease-specific survival; HPV = human papillomavirus HR = hazard ratio; OS = overall survival.

Treatment utilisation

Treatment differences by sex and HPV subgroup are shown in Figure 4. All Cramér’s V values were less than or equal to 0.083, indicating negligible clinical effect size for all treatment differences despite statistical significance.

Figure 4.

Treatment utilisation (chemotherapy, radiation therapy, surgery) by sex and p16/HPV status. Dark bars = male; light bars = female. Left: p16-positive; right: p16-negative. All Cramér’s V less than or equal to 0.083. HPV = human papillomavirus.

A grouped bar graph showing treatment modality by sex for p16-positive and p16-negative groups.

Discussion

This population-based analysis of 19,716 OPSCC patients demonstrates that sex does not independently predict OS or DSS after adjustment for HPV status, stage, age, race and treatment. The key advance over prior work, including existing systematic reviews and meta-analyses of over 100,000 patients, is the formal statistical testing of the sex–HPV interaction at population level.Reference Gordis, Cagle, Nguyen and Newman7, Reference Chun, Chernov, Chen, Nguyen, Marrero-Gonzalez and Stevens8 The non-significant interaction HR of 1.057 (p = 0.459) provides unambiguous evidence that the HPV survival benefit is of equivalent magnitude in males and females and that HPV status fully and mechanistically accounts for the apparent female survival disadvantage.

The mechanistic basis of this finding is well established. The prognostic benefit of HPV-associated OPSCC is mediated through tumour-intrinsic biological mechanisms — enhanced radiosensitivity, functional p53 preservation and robust anti-tumour CD8+ T-cell responses — that are independent of host biological sex.Reference Ang, Harris, Wheeler, Weber, Rosenthal and Nguyen-Tân5, Reference Fakhry, Westra, Li, Cmelak, Ridge and Pinto19, Reference Faraji, Zaidi, Fakhry and Gaykalova20 Our data confirm that once these tumour-biological variables are controlled for through HPV stratification, sex carries no additional prognostic information. Prior meta-analyses concluded that sex is not an independent prognostic factor in HPV-adjusted OPSCC analyses.Reference Gordis, Cagle, Nguyen and Newman7, Reference Chun, Chernov, Chen, Nguyen, Marrero-Gonzalez and Stevens8 The present study extends and strengthens this evidence through the first formal population-level sex–HPV interaction test in a systematically HPV-documented cohort under AJCC 8th Edition criteria (2018–2021).Reference O’Sullivan, Huang, Su, Garden, Sturgis and Dahlstrom6, Reference Huang, Xu, Waldron, Siu, Shen and Tong21

The non-significant interaction result has a direct implication for treatment de-escalation trials. Trials such as ORATOR, De-ESCALaTE HPV and PATHOS have enrolled predominantly male populations.Reference Nichols, Theurer, Prisman, Read, Berthelet and Tran22–Reference Owadally, Hurt, Timmins, Parsons, Townsend and Patterson24 Our data confirm that survival benefits demonstrated in these trials are directly applicable to female patients. The statistically significant but clinically negligible treatment differences by sex (Cramér’s V ≤0.083) are consistent with prior population-based observations and confirm that treatment allocation does not substantially confound the sex–survival relationship.Reference Klasen, Wuerdemann, Rothbart, Prinz, Eckel and Suchan25 The independent prognostic significance of Black race (HR ∼1.50; p < 0.001) underscores racial disparities in OPSCC as a distinct research priority.Reference Settle, Posner, Schumaker, Tan, Suntharalingam and Goloubeva26, Reference Ragin and Taioli27

The study period (2018–2021) predates AJCC Version 9 (effective January 2026); these findings provide a definitive AJCC 8th Edition era benchmark for future comparisons. Limitations include the absence of smoking history, performance status and comorbidity data in SEER.Reference Rettig, Fakhry, Khararjian and Westra28, Reference Pytynia, Dahlstrom and Sturgis29 p16 IHC is a surrogate for HPV status; misclassification is possible.Reference JS, Beadle, Bishop, Chernock, Colasacco and Lacchetti12, Reference Fakhry, Lacchetti, Rooper, Jordan, Rischin and Sturgis13 SEER Extent of Disease (EOD) 2018 reflects clinical staging; pathological staging was unavailable for most non-surgically treated patients.

What is already known on this subject

  • • Oropharyngeal squamous cell carcinoma (OPSCC) affects males approximately five times more frequently than females, largely due to higher human papillomavirus (HPV) prevalence in men.

  • • p16/HPV-positive OPSCC carries substantially superior prognosis compared with p16-negative disease.

  • • Prior meta-analyses suggest sex loses prognostic significance after HPV adjustment, but no formal interaction test had been performed at population level.

What this paper adds to our understanding

  • • The first formal population-level sex–HPV interaction test (hazard ratio [HR] 1.057; p = 0.459) confirms HPV status fully mediates apparent sex-related survival differences

  • • After full adjustment, sex is not an independent prognostic factor for overall survival (OS) (HR 0.98; p = 0.52) or disease-specific survival (DSS; HR 1.01; p = 0.80)

  • • Treatment differences between sexes are statistically significant but clinically negligible (Cramér’s V less than or equal to 0.083)

  • • De-escalation trial results from predominantly male cohorts are directly applicable to female patients

Conclusion

HPV status fully and mechanistically explains the apparent survival disadvantage of female OPSCC patients. Sex is not an independent prognostic factor for OS or DSS. The first formal population-level sex–HPV interaction test (HR 1.057; p = 0.459) confirms that the HPV survival benefit is of equivalent magnitude in males and females. These findings support HPV/p16 status as the dominant prognostic stratifier in OPSCC and provide justification for sex-disaggregated reporting in future de-escalation trials.

Acknowledgments

The authors used artificial intelligence (AI) -assisted writing tools for language editing during manuscript preparation.

Financial support

This research received no specific grant from any funding agency, commercial or not-for-profit sectors.

Author contributions (CRediT)

Adrian Hoenle: Conceptualisation, Data curation, Formal analysis, Methodology, Writing – original draft, Writing – review & editing. Dorothee Rickert: Writing – review & editing, Validation. Helmut Steinhart: Supervision, Writing – review & editing. Stephan Lorenz: Supervision, Project administration, Writing – review & editing.

Data availability

Data are available from NCI SEER (https://seer.cancer.gov) upon data use agreement.

Competing interests

The author(s) declare none.

Ethics statement

De-identified publicly available registry data; no institutional review board approval required.

Ethical standards

The authors assert that all procedures contributing to this work comply with the ethical standards of the relevant national and institutional guidelines on human experimentation and with the Helsinki Declaration of 1975, as revised in 2008. De-identified publicly available registry data were used; no institutional review board approval was required.

Footnotes

Adrian Hoenle takes responsibility for the integrity of the content of the paper

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Figure 0

Table 1. Baseline characteristics stratified by sex and p16/HPV statusTable 1 long description.

Figure 1

Figure 1. AJCC 8th Edition stage distribution (EOD 2018) by sex and p16/HPV status. Left panel: p16-positive; right panel: p16-negative. Both comparisons p < 0.001. Percentages are calculated from the total group including patients with unknown stage; bars therefore do not sum to 100 per cent. AJCC = American Joint Committee on Cancer; EOD = Extent of Disease; HPV = human papillomavirus.

Figure 2

Figure 2. OS stratified by sex and p16/HPV status (male/p16-positive, female/p16-positive, male/p16-negative, female/p16-negative), SEER 2018–2021 (n = 19,716). Black lines = p16-positive; grey lines = p16-negative; solid = male; dashed = female. Y-axis range 0.25–1.0. Global log-rank p < 0.0001. HPV = human papillomavirus; OS = overall survival; SEER = Surveillance, Epidemiology, and End Results.

Figure 3

Figure 3. DSS stratified by sex and p16/HPV status. Line styles as per Figure 2. Global log-rank p < 0.0001. DSS = disease-specific survival; HPV = human papillomavirus.

Figure 4

Table 2. Sex-stratified multivariable Cox proportional hazards regression for OS and DSSTable 2 long description.

Figure 5

Figure 4. Treatment utilisation (chemotherapy, radiation therapy, surgery) by sex and p16/HPV status. Dark bars = male; light bars = female. Left: p16-positive; right: p16-negative. All Cramér’s V less than or equal to 0.083. HPV = human papillomavirus.