Human papillomavirus (HPV) has long been recognized as a significant factor in the development of cervical and other anogenital cancers, but its role in oropharyngeal cancers (OPC) has received increasing attention in recent years. A comprehensive new systematic review published in BMC Cancer elucidates critical aspects of HPV infection within the oral cavity and tonsils, shedding light on detection methods, prevalence patterns, risk factors, and the potential impact of prophylactic vaccination. This extensive review presents a thorough synthesis of current evidence, underscoring the rising clinical and epidemiological importance of oral HPV infections, especially those caused by high-risk strains like HPV16.
The incidence of HPV-associated oropharyngeal cancers has been on a notable rise globally, an alarming trend linked closely with persistent oral HPV infections. Unlike transient infections, persistence of certain HPV types, particularly HPV16, drives oncogenic transformation of oropharyngeal epithelial cells. This review aggregates data from over 50 studies and meta-analyses, providing an authoritative perspective on oral HPV epidemiology in the general population alongside vulnerable groups such as people living with HIV (PLWH). The synthesis extends from prevalence studies to clinical outcomes, emphasizing both the challenges and progress in detecting these viral infections.
Oral HPV prevalence varies widely across populations but generally remains below 12%, with an average around 5% in healthy individuals. Men show a consistently higher prevalence than women, potentially due to differences in sexual behavior, immune response, or local mucosal environment. Prevalence of high-risk HPV types within oral samples ranges from 0.5% to nearly 5%, with HPV16 overwhelmingly the most detected genotype. This genotype’s predominance parallels its well-established causative role in HPV-driven OPC, confirming it as the principal target for ongoing public health interventions.
Risk factors for acquiring oral HPV infections extend beyond gender and age, encompassing behavioral and health factors that modulate exposure and susceptibility. Notably, increasing age and a greater number of lifetime oral sex partners amplify infection risk, highlighting sexual transmission as a central route for oral HPV acquisition. Additionally, tobacco and drug use are implicated as co-factors that may facilitate viral persistence or impair local immune defenses. Concurrent genital HPV infections also correlate, suggesting repeated exposure or systemic susceptibility to HPV across mucosal sites.
Among special populations, people living with HIV represent a group with disproportionately elevated rates of oral HPV infections. This review identifies oral HPV prevalence in PLWH ranging broadly, from 2% up to 40%, with an average near 20%. Importantly, HIV infection itself acts as an independent risk factor; diminished immune surveillance and increased viral replication dynamics favor not only higher prevalence but potentially prolonged persistence and higher viral loads. This relationship is consistent irrespective of gender or sexual orientation, highlighting the immunocompromised state as a universal facilitator of HPV infection.
Detecting HPV in the oral cavity presents unique challenges, given the anatomical complexity and the often transient nature of oral viral colonization. This review emphasizes the diversity of sampling methods employed in different studies, including oral rinses, swabs, and tonsillar brushings, each with variable sensitivity and practicality. Although oral rinse sampling is widely used due to its noninvasiveness and broad coverage, the authors call for standardizing optimal specimen collection protocols to enhance detection accuracy, especially for screening and monitoring purposes in research and clinical practice.
Beyond detection, understanding the natural history of oral HPV infections—how frequently they clear versus persist—remains a crucial knowledge gap. Persistent infections with high-risk HPV types constitute the main oncogenic threat, yet comprehensive longitudinal data on clearance rates and viral dynamics in the oropharynx are still sparse. The review highlights the essential need for longitudinal cohorts that can unravel these complex host-virus interactions over time, which would inform more precise risk stratification and targeted surveillance.
Perhaps one of the most hopeful aspects brought forward in this review relates to prophylactic HPV vaccination. Initially designed to reduce cervical HPV infection, vaccines covering HPV16 and other oncogenic types show promising evidence for preventing oral HPV infection as well. Clinical and epidemiological data demonstrate vaccine-induced reductions in oral HPV prevalence among vaccinated adolescents and young adults, strongly supporting vaccination campaigns as a critical barrier against the future burden of HPV-driven oropharyngeal cancers.
The implications of these findings stretch beyond individual health outcomes, hinting at broader public health strategies. Attaining high vaccination coverage in children and adolescents could serve as a pivotal intervention to counteract the growing incidence of HPV-associated OPCs expected in coming decades. However, this necessitates addressing vaccine hesitancy and ensuring equitable global access to immunization programs to maximize protective benefits.
While the review provides a compelling snapshot of current knowledge, it also underscores significant research needs. The interplay between host immunity, behavioral factors, and viral biology in oral HPV persistence is still poorly understood. Moreover, the heterogeneity in study design and sampling complicates direct comparisons and meta-analytic interpretations. Establishing unified methodological frameworks and consolidating global data repositories would catalyze more accurate prevalence estimates and risk assessments.
The exploration of oral HPV in special populations beyond PLWH, such as transplant recipients or individuals with other immunocompromising conditions, also remains largely unexplored. These groups may harbor different risk profiles and viral dynamics, warranting focused investigations to tailor screening and preventive measures effectively.
Furthermore, insights into the microenvironment of the oral and tonsillar mucosa—including the role of local microbiota, co-infections, and mucosal immunity—could illuminate mechanisms underpinning viral persistence and carcinogenesis. Such mechanistic studies could catalyze new therapeutic or preventive strategies beyond vaccination alone.
In the context of detection technologies, advances in molecular diagnostics hold promise for more sensitive and specific identification of oral HPV infections. Techniques such as PCR-based assays, digital droplet PCR, and next-generation sequencing are increasingly applied, yet practical deployment in clinical settings requires balancing cost, complexity, and throughput. Continued innovation and validation of these assays are paramount.
The authors’ synthesis makes a crucial contribution to the growing recognition that HPV is not solely a genital virus but a multifaceted pathogen affecting the entire mucosal landscape, including the oral cavity and oropharynx. This broadened understanding demands integrated surveillance frameworks transcending organ-specific siloes and encompassing the full spectrum of HPV-related diseases.
In summary, this systematic literature review provides an authoritative foundation for comprehending the epidemiology and natural history of oral HPV infections. It reinforces the imperative for comprehensive vaccination efforts, standardized detection methodologies, and expanded research into persistent infection mechanisms. As HPV-associated oropharyngeal cancers continue to climb in incidence, such integrative knowledge will be indispensable in shaping effective prevention, early detection, and intervention strategies worldwide.
Subject of Research: Oral Human Papillomavirus (HPV) infection prevalence, detection methods, risk factors, natural history, and impact of prophylactic vaccination on oral and tonsillar HPV infections.
Article Title: Detection and natural history of HPV infection of oral cavity and tonsils – a systematic literature review
Article References: Maltseva, M., Klasen, C., Wuerdemann, N. et al. Detection and natural history of HPV infection of oral cavity and tonsils – a systematic literature review. BMC Cancer 25, 1405 (2025). https://doi.org/10.1186/s12885-025-14547-5
Image Credits: Scienmag.com
DOI: https://doi.org/10.1186/s12885-025-14547-5
Keywords: HPV, oral HPV, oropharyngeal cancer, persistent infection, HPV16, prophylactic vaccination, HIV, detection methods, epidemiology, natural history
