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. 2021 Apr 23;16(4):e0250530.
doi: 10.1371/journal.pone.0250530. eCollection 2021.

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

Guadalupe Lorenzatti Hiles  1   2 , Kai-Ping Chang  3   4 , Emily L Bellile  5 , Chun-I Wang  6 , Wei-Chen Yen  3 , Christine M Goudsmit  1   2 , Hannah L Briggs  1   2 , Trey B Thomas  1   2 , Lila Peters  1   2 , Macy A Afsari  1   2 , Lisa M Pinatti  1   2   7 , Anna C Morris  1   2 , Nadine Jawad  1   2 , Thomas E Carey  1   2 , Heather M Walline  1   2
Affiliations

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

Guadalupe Lorenzatti Hiles et al. PLoS One. .

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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Conflict of interest statement

The authors have declared that no competing interests exist.

Figures

Fig 1
Fig 1. Flow diagram of cases included in the Taiwan retrospective cohort and study design.
1Results missing due to absent slide or tissue core, or major artifacts that prevented evaluation. 2Results missing due to absent DNA or invalid test. OPSCC, oropharyngeal squamous cell carcinoma; HPV, human papillomavirus; FFPE, formalin-fixed, paraffin-embedded; IHC, immunohistochemical staining; PCR-MA, multiplex PCR-MassArray.
Fig 2
Fig 2. Yearly HPV occurrence among OPSCC cases by HPV DNA and/or p16 (A) or p16 alone (B).
The graphs show the correlation between the total frequency of HPV-positive (HPV+) and HPV-negative (HPV-) OPSCC cases, and the study years (see S3 Table). HPV status was assessed by (A) HPV DNA and p16 testing (N = 528) or (B) p16 scoring (N = 458). The association was evaluated in the Taiwan cohort from March 1998 to February 2016 by Spearman’s coefficient (ρ) and linear regression (R2). (A) HPV-: ρ = 0.6953, p = 0.0014; R2 = 0.5201, p = 0.0007. HPV+ ρ = 0.4093, p = 0.0917; R2 = 0.1952, p = 0.0664. (B) p16-: ρ = 0.6991, p = 0.0012; R2 = 0.5555, p = 0.0004. p16+ ρ = 0.4741, p = 0.0469; R2 = 0.2455, p = 0.0365.
Fig 3
Fig 3. HPV-positive OPSCC is associated with increased survival time.
(A-B) Up to 5-year overall survival (OS) and disease-free survival (DFS) prognostic outcomes of the HPV variable in the whole OPSCC Taiwan cohort. HPV positivity is defined as HPV DNA-positive and/or p16-positive. (A) Table includes the multivariable hazard probabilities analyzed using Cox survival models and hazard ratio (HR) estimations, visualized by forest plots. The complete analysis is found in S6 Table, where estimates were reported for the full model with all covariates (HPV status, alcohol, smoking, betel quid, age, N- and T-stage) included as fixed effects. (B) Kaplan-Meier survival analysis. Plots represent the results for up to 5-year OS (left) and DFS (right) comparison between HPV-negative (HPV-) and HPV-positive (HPV+) groups. Log-rank analysis was used to compare the survival distributions (log-rank p-values are in the plots). HPV-, HPV-negative; HPV+, HPV-positive.
Fig 4
Fig 4. Alcohol is associated with reduced OPSCC survival time.
(A-D) Prognostic outcomes of the alcohol, smoking, and betel quid variables within the whole cohort. We analyzed up to 5-year overall survival (OS) and disease-free survival (DFS) outcomes for high-risk habits. (A) Table includes the multivariable hazard probabilities analyzed using Cox survival models and hazard ratio (HR) estimations, visualized by forest plots, where estimates were reported for full model with all covariates (HPV status, alcohol, smoking, betel quid, age, N- and T-stage) included as fixed effects. The complete analysis is found in S6 Table. (B-D) Kaplan-Meier survival analysis. Plots represent the results for up to 5-year OS (left) and DFS (right) comparison between alcohol (B), smoke (C), and betel quid (D) groups. Log-rank analysis was used to compare the survival distributions (log-rank p-values are in the plots).
Fig 5
Fig 5. In alcohol users, HPV is associated with improved OPSCC survival time.
(A-C) Prognostic outcomes of the alcohol, smoking, and betel quid variables within HPV risk groups. HPV positivity is defined as HPV DNA-positive and/or p16-positive. We analyzed up to 5-year overall survival (OS) and disease-free survival (DFS) outcomes. (A) Table includes the multivariable hazard probabilities analyzed using Cox survival models and hazard ratio (HR) estimations, adjusted for age, T- and N-stage, and visualized by forest plots. (B-C) Kaplan-Meier survival analysis. Plots represent the results for up to 5-year OS (B) and DFS (C) comparison between HPV groups stratified by alcohol groups. Log-rank analysis was used to compare the survival distributions (log-rank p-values are in the plots). The complete analysis is found in S7 Table and S3 Fig. HPV-, HPV-negative; HPV+, HPV-positive.
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