HPV-driven oropharyngeal cancer (HPV-OPC) is a rare disease but its incidence rate is increasing in many countries with high human development index. Although HPV vaccination of adolescents and young adults will ultimately avert HPV-OPC, it will not do so for several decades, given the recommended age at vaccination and the age at cancer diagnosis. Thus, screening and early detection has been considered a potential secondary prevention strategy for HPV-OPC, especially in view of the success of cervical cancer screening. Current research efforts in screening for oropharyngeal cancer focus on addressing the fundamental principles of screening and include:

1. who to screen (identification of a high-risk screening population and suitable risk stratification tools);
2. what to screen for (identification of an HPV-induced pre-cancer or early stage cancer in the oropharynx);
3. how to screen (biomarkers and identification of screening modalities);
4. how to manage screen-positive individuals (treatment of individuals without detectable pre-cancer or early stage cancer, and de-intensified treatment modalities).

So, where are we today in these paradigms? Recent studies have made considerable progress in the ‘how to screen’, by identifying biomarkers, such as systemic HPV antibodies or oral HPV DNA. Antibodies against the HPV16 E6 oncoprotein have been reproducibly demonstrated to have high sensitivity (>90%) and specificity (>99%) for the diagnosis of concurrent HPV16-positive OPC (as assessed by clinical or lab gold-standards, i.e. p16 immunohistochemistry, HPV DNA or RNA in-situ hybridization, or E6*I mRNA positivity).¹ In addition, HPV16 E6 antibodies are rare in cancer-free individuals (<1% prevalence), and they are strongly associated with HPV-induced tumors at the time of or prior to cancer diagnosis (>100-fold risk), preceding cancer diagnosis by approximately 5-15 years.² This underscores their potential utility as a screening biomarker. For HPV16 DNA detection in oral rinses, prospective data for incident HPV-OPC are largely missing at this point, but a meta-analysis summarizing five studies showed HPV detection in oral rinse samples had a sensitivity of 55% (95% CI: 25–82%) and specificity of 94% (95% CI: 85–98%) using HPV positivity in the tumor as the gold standard.³

The ‘who to screen’, ‘what to screen for’, and ‘how to manage screen-positives’ is more challenging. Despite favorable biomarker characteristics, their current value for population-wide OPC screening is unfavorable. This is because the positive predictive value (PPV) for OPC risk by either marker is low, and the number needed to screen to identify one HPV-positive OPC likely exceeds several thousands.⁴ That said, refining the ‘who to screen’ has potential to improve the PPV considerably. Additional factors complicate population-wide screening for HPV-OPC. First, an HPV-induced pre-cancer or early stage cancer akin to carcinoma in-situ has yet to be described. Second, currently available imaging modalities, such as ultrasound and MRI, remain unproven for the identification of early stage cancer. Third, there are no proven risk-mitigation strategies for the prevention of cancer through treatment of pre-cancer or early stage cancer.

Collectively, these considerations argue that widely screening healthy individuals for HPV-OPC in clinical settings is unfounded and likely unethical. Yet, in research settings, several of these paradigms, including risk-stratification tools, identification of HPV-induced pre-cancer, improved imaging modalities, and clinical management of biomarker-positive individuals should continue to be investigated in well designed, carefully considered, and adequately powered studies. Small, one-off studies of a few hundred people when investigating rare exposures and very rare outcomes will only confuse the published literature, mislead science, and generate problems for funding and implementation of high-quality research. If guided by experts who understand the balance of risks and benefits in cancer screening, professionally conducted research addressing these challenges must not be rejected a priori, otherwise this vacuum will be filled by ill-designed studies which will undoubtedly do more harm than good. What we urgently need is equally challenging and important – we need strong studies that allow real improvements. If we succeed in generating meaningful answers to the research questions discussed above, this could enable cost-efficient and ethical study designs that could further advance secondary prevention of HPV-OPC.

DISCLOSUREThe authors declare nothing to disclose.

ARTICLES INCLUDED IN THE HPW SPECIAL ISSUE ON HPV IN OROPHARYNGEAL CANCER:

S Huang. Oropharyngeal Carcinomas: the UICC/AJCC TNM Staging System, 8th Edition

M Taberna, R Mesia, RL Ferris. Clinical management of HPV-related recurrent/metastatic (R/M) oropharyngeal cancer patients

MJ Windon, EM Rettig. Counseling patients with a diagnosis of human papillomavirus-positive oropharyngeal cancer

G D’Souza, A Chaturvedi, E Bigelow. Natural history, from oral HPV infection to HPV-related oropharyngeal cancer

References

1. Holzinger D, Wichmann G, Baboci L et al. Sensitivity and specificity of antibodies against HPV16 E6 and other early proteins for the detection of HPV16-driven oropharyngeal squamous cell carcinoma. Int J Cancer 2017;140(12):2748-2757. Available at: https://pubmed.ncbi.nlm.nih.gov/28316084/

2. Kreimer AR, Ferreiro-Iglesias A, Nygard M et al. Timing of HPV16-E6 antibody seroconversion before OPSCC: findings from the HPVC3 consortium. Ann Oncol 2019;30(8):1335-1343. Available at: https://pubmed.ncbi.nlm.nih.gov/31185496/

3. Gipson BJ, Robbins HA, Fakhry C, D'Souza G. Sensitivity and Specificity of Oral HPV Detection for HPV-Positive Head and Neck Cancer. Oral Oncol 2018; 77: 52–56. Available at: https://pubmed.ncbi.nlm.nih.gov/29362127/

4. Kreimer AR, Shiels MS, Fakhry C et al. Screening for human papillomavirus-driven oropharyngeal cancer: Considerations for feasibility and strategies for research. Cancer 2018;124(9):1859-1866. Available at: https://pubmed.ncbi.nlm.nih.gov/29499070/