Oral cancer and human papillomavirus
Näytönastekatsaukset
26.5.2026
Level of evidence: B
Human papilloma virus (HPV) is probably found in only a small proportion of oral squamous cell carcinomas, and HPV positivity does probably not affect the prognosis of oral cancer.
HPV is found in less than 10% of oral squamous cell carcinomas. HPV does not appear to be a necessary or strong risk factor for the development of oral cancer. Risk factors for HPV-positive oral cancer include older age, male gender, frequent sexual intercourse, smoking, drug use, poor oral health, and concurrent genital HPV infection.
Evidence comes from meta-analysis of mainly observational studies. Studies have many limitations: variable sample collection that may not be oral cavity specific, variable HPV detection methods such as p16, DNA and mRNA. Studies also vary on how many genotypes they have detected. Over 200 HPV genotypes have been found but only small subset is well-characterized. Only DNA analysis with PCR gives the result on genotype level and active infection is detected only by mRNA. Furthermore, all prevalence studies do not have control group. HPV is present in almost 80% of people. However, this does not mean active infection, HPV DNA may be a sign of a passenger infection and p16 over-expression is not HPV specific.
RCT=randomized controlled trial; SR=systematic review; MA=meta-analysis, OSCC=oral squamous cell carcinoma
| Reference | Comments |
|---|---|
| «Katirachi SK, Grønlund MP, Jakobsen KK, ym. The Prevalence of HPV in Oral Cavity Squamous Cell Carcinoma. Viruses 2023;15(2): »1 | The studies were published 2017-2022.Study periods were between 1986-2019. The inconsistency of HPV detection methods among the studies was remarkable and a limitation to this review. |
| «Fonsêca TC, Jural LA, Marañón-Vásquez GA, ym. Global prevalence of human papillomavirus-related oral and oropharyngeal squamous cell carcinomas: a systematic review and meta-analysis. Clin Oral Invest»2 | The studies were published before 10/2022-Regarding the way the participants were sampled, none of the 65 articles met the initial inclusion criteria. This occurred because all the papers used a non-probabilistic sample, once they were all a convenience sample. |
| «Kaur G, Yap T, Ramani R, ym. Assessing bias in the causal role of HPV in oral cancer: A systematic review and meta-analysis. Oral Dis 2024;30(8):5379-5387 »3 | The studies were published during 2001-2021 All included studies were case control studies and had moderate- to- severe risk of bias. Study limitations such as inconsistent measurements, no mRNA E6/E/ analysis, high confounding, and lack of gold standard testing. |
| «Melo BAC, Vilar LG, Oliveira NR, ym. Human papillomavirus infection and oral squamous cell carcinoma - a systematic review. Braz J Otorhinolaryngol 2021;87(3):346-352 »4 | The studies were until 2/2018 The quality score average of included articles was five points (on a scale 0-14). It was not possible to assess if HPV infection was associated with oral squamous cell carcinomas because none of the studies included was longitudinal and cross-sectional investigations do not have control group. |
| «Sahovaler A, Kim MH, Mendez A, ym. Survival Outcomes in Human Papillomavirus-Associated Nonoropharyngeal Squamous Cell Carcinomas: A Systematic Review and Meta-analysis. JAMA Otolaryngol Head Neck Sur»5 | The studies were from years 1946-2019. Significant heterogeneity among studies in some models. In the oral cavity, heterogeneity was still present after subgroup analysis by diagnostic method. |
| «Christianto S, Li KY, Huang TH, ym. The Prognostic Value of Human Papilloma Virus Infection in Oral Cavity Squamous Cell Carcinoma: A Meta-Analysis. Laryngoscope 2022;132(9):1760-1770 »6 | The studies were from years 1996-2020. The included studies were heterogenous according to cancer stage, age, treatment modalities, and history of tobacco or alcohol consumption that may affect the prognosis. Another limitation was the use of different HPV detection methods in these included articles. In meta-analysis for disease free survival one study (of eight studies) by Chiba et al. was excluded due to 100% DFS proportion in patient with HPV-positive along the follow-up period. And further, meta-analysis for disease specific survival excluded two studies (of nine) Lee et al. and Minami et al. due to the 100% DSS proportion from HPV-positive group. |
| «Petrelli F, Cin ED, Ghidini A, ym. Human papillomavirus infection and non-oropharyngeal head and neck cancers: an umbrella review of meta-analysis. Eur Arch Otorhinolaryngol 2023;280(9):3921-3930 »7 | The reviews were from years 2006-2022. Different detection methods for HPV testing were used in the included meta-analysis. Moreover, the included studies in the various meta-analyses had different follow-up periods and likely included patients treated with different modalities, which may have influenced the results. In addition, according to the AMSTAR 2 criteria, 40% of the meta-analyses included in this umbrella analysis had "low or critically low" methodological quality. |
| «Syrjänen S, Lodi G, von Bültzingslöwen I, ym. Human papillomaviruses in oral carcinoma and oral potentially malignant disorders: a systematic review. Oral Dis 2011;17 Suppl 1():58-72 »8 | The studies were from years 1980-1998. |
Results
I=intervention; C=comparison; CI=confidence interval
| Reference | Number of studies and number of patients | Follow-up time | Absolute number of events (%) I | Absolute number of events (%) C | Relative effect (95% CI) HR < 1 mean better OS |
|---|---|---|---|---|---|
| Level of evidence:low The quality of negative evidence is up-graded due to plausible residual confounding. | |||||
| «Petrelli F, Cin ED, Ghidini A, ym. Human papillomavirus infection and non-oropharyngeal head and neck cancers: an umbrella review of meta-analysis. Eur Arch Otorhinolaryngol 2023;280(9):3921-3930 »7 | 3 meta-analyses 28 studies 13743 patients | 0-114 | HR 0.89 (0.47-1.68) I2 87% | ||
| Reference | Number of studies and number of patients (I/C) | Follow-up time | Absolute number of events (%) I | Absolute number of events (%) C | Relative effect (95% CI) HR values > 1 favor/mean decreased DSS |
|---|---|---|---|---|---|
| Level of evidence: low The quality of negative evidence is up-graded due to plausible residual confounding. | |||||
| «Christianto S, Li KY, Huang TH, ym. The Prognostic Value of Human Papilloma Virus Infection in Oral Cavity Squamous Cell Carcinoma: A Meta-Analysis. Laryngoscope 2022;132(9):1760-1770 »6 | 8 studies 1323 patients | HR 1.20 (0.63–2.26)* I2 83% | |||
* HR values > 1 favor HPV negative patients
| Reference | Number of studies and number of patients (I/C) | Follow-up time | Absolute number of events (%) I | Absolute number of events (%) C | Relative effect (95% CI) HR values > 1 favor/mean decreased DFS |
|---|---|---|---|---|---|
| Level of evidence: low The quality of negative evidence is up-graded due to plausible residual confounding. | |||||
| «Sahovaler A, Kim MH, Mendez A, ym. Survival Outcomes in Human Papillomavirus-Associated Nonoropharyngeal Squamous Cell Carcinomas: A Systematic Review and Meta-analysis. JAMA Otolaryngol Head Neck Sur»5 | 7 studies 1796 patients | 36-74 months | HR 1.81 (1.12-2.91)* I2 = 47 % | ||
| «Christianto S, Li KY, Huang TH, ym. The Prognostic Value of Human Papilloma Virus Infection in Oral Cavity Squamous Cell Carcinoma: A Meta-Analysis. Laryngoscope 2022;132(9):1760-1770 »6 | 7 studies 1288 patients | NA | HR 1.23 (0.79–1.93) I2 69 % | ||
* HR values > 1 favor HPV negative patients
References
- Katirachi SK, Grønlund MP, Jakobsen KK, ym. The Prevalence of HPV in Oral Cavity Squamous Cell Carcinoma. Viruses 2023;15(2): «PMID: 36851665»PubMed
- Fonsêca TC, Jural LA, Marañón-Vásquez GA, ym. Global prevalence of human papillomavirus-related oral and oropharyngeal squamous cell carcinomas: a systematic review and meta-analysis. Clin Oral Investig 2023;28(1):62 «PMID: 38158517»PubMed
- Kaur G, Yap T, Ramani R, ym. Assessing bias in the causal role of HPV in oral cancer: A systematic review and meta-analysis. Oral Dis 2024;30(8):5379-5387 «PMID: 38956902»PubMed
- Melo BAC, Vilar LG, Oliveira NR, ym. Human papillomavirus infection and oral squamous cell carcinoma - a systematic review. Braz J Otorhinolaryngol 2021;87(3):346-352 «PMID: 33339760»PubMed
- Sahovaler A, Kim MH, Mendez A, ym. Survival Outcomes in Human Papillomavirus-Associated Nonoropharyngeal Squamous Cell Carcinomas: A Systematic Review and Meta-analysis. JAMA Otolaryngol Head Neck Surg 2020;146(12):1158-1166 «PMID: 33057610»PubMed
- Christianto S, Li KY, Huang TH, ym. The Prognostic Value of Human Papilloma Virus Infection in Oral Cavity Squamous Cell Carcinoma: A Meta-Analysis. Laryngoscope 2022;132(9):1760-1770 «PMID: 34953144»PubMed
- Petrelli F, Cin ED, Ghidini A, ym. Human papillomavirus infection and non-oropharyngeal head and neck cancers: an umbrella review of meta-analysis. Eur Arch Otorhinolaryngol 2023;280(9):3921-3930 «PMID: 37212863»PubMed
- Syrjänen S, Lodi G, von Bültzingslöwen I, ym. Human papillomaviruses in oral carcinoma and oral potentially malignant disorders: a systematic review. Oral Dis 2011;17 Suppl 1():58-72 «PMID: 21382139»PubMed