Association of HPV with Oral and Oropharyngeal Cancer: Current Evidence

Abstract

Oral cancer is a significant worldwide health issue which has an annual incidence of over 377,000 new cases. It was historically associated with tobacco and alcohol use, but recent research has also emphasized the role of human papilloma virus (HPV), specifically types 16 and 18, to the development of oropharyngeal malignancies. Human papilloma virus, a common sexually transmitted infection, impacts approximately 9-13% of the worldwide population. Currently, there have been 202 recognized virus types associated with HPV. HPV-positive oral cancers have different clinical and molecular features compared to HPV-negative ones. The HPV-positive tumors tend to better respond to radiation and chemotherapy treatments. This review compiles findings from an extensive literature search in PubMed and Google Scholar. It highlights the growing occurrence of HPV-positive oropharyngeal malignancies, especially among younger age groups, in different regions of the world. There has been a noticeable increase in the occurrence of these tumors, particularly in Europe and the Middle East. The rates of HPV infection are influenced by factors such as inadequate oral hygiene, sexual habits and gender differences. The research emphasizes the necessity for enhanced diagnostic methods, such as PCR-based assays, and shows the potential advantages of HPV vaccination and public health education in reducing the increasing cancer burden. Conducting additional research is crucial in order to create efficient methods for preventing and treating these conditions.

Keywords:: oral cancer, oropharyngeal cancer, human papilloma virus (HPV), HPV vaccination, oral squamous cell carcinoma (OSCC).

INTRODUCTION

Oral cancer is a substantial worldwide health problem, with an estimated 389,000 new cases identified every year. Tobacco use and alcohol consumption remain significant risk factors. However, recent evidence highlights that certain strains of human papilloma virus (HPV) also play a critical role in the development of oral cancer (1). Human papilloma virus infection is thought to be the most widespread sexually transmitted infection (STI). According to Candotto et al, the condition is already present in 9.0-13% of the global population, with approximately six million new cases detected yearly (2). The virus belongs to a long-established group of pathogens that have been observed to infect mammals, birds, reptiles and amphibians' epithelial tissues. Together with polyomaviruses and Papillomaviridae, this group of DNA viruses makes up the distinct Papovaviridae family. Using phylogenetic analysis, HPV can be categorized into genera, species and types (3). So far, a total of 202 distinct variants of the virus have been identified. According to sequence research carried out by Soung Min Kim in 2016, L1 gene is the most conserved gene among all known papillomaviruses, which represents the primary basis for this classification (4). HPV 6 and HPV 11 are categorized as low-risk strains primarily linked to non-cancerous conditions such as benign warts. In contrast, certain high-risk types of HPV, such as HPV16 and HPV18, have been associated with the appearance of several malignancies, including oropharyngeal tumors (5).

Recently, there has been an increasing awareness of the connection between HPV infection and oropharyngeal cancer. This includes the study of epidemiological trends, molecular causes, diagnostic methods and treatment implications (6). The epidemiology of HPV-associated oropharyngeal cancer is intricate, with substantial geographic and demographic variations in incidence, risk factors and outcomes. High-income regions, such as North America, Europe and Oceania, report higher incidences of HPV-related oropharyngeal cancers, which are often attributed to behavioral factors like increased oral HPV exposure. In contrast, the burden of oral and oropharyngeal cancers in lowand middle-income countries remains significant, largely due to limited healthcare access, late diagnoses and restricted treatment options. Furthermore, observed disparities in survival rates across demographic groups are influenced by factors such as age, gender, socioeconomic status and regional healthcare infrastructure. For example, males exhibit a higher incidence of HPV-related oropharyngeal cancers compared to females. Addressing these disparities requires targeted interventions, including improving access to preventive measures like HPV vaccination and enhancing early detection programs globally (7). Determining the fundamental causes of these differences is crucial to create focused treatments that will lower the incidence of oral cancer and enhance patient outcomes (7). This review aims to provide a comprehensive overview of the current understanding of the association between HPV and oral cancer.

MATERIALS AND METHODS

This research project involved conducting a review of articles from popular online databases, namely PubMed, Google Scholar, AACR Journals, MDPI, BMC (part of Springer Nature) and Frontiers. The focus was on exploring the connection between HPV and oral cancer. By using keywords such as “human papilloma virus”, “oral cancer” and “HPV” in combinations, we refined our search criteria. Our selection criteria included reviews, systematic reviews, meta-analyses and original research papers written in English and published within a timetable of mainly ten years. The selection of articles for this study was conducted over a period of five months, ensuring the inclusion of the most recent and relevant publications. To ensure rigor and minimize bias, all authors contributed to the article selection process. Initial screenings based on titles and abstracts were conducted and followed by a detailed review of full texts (Figure 1). Each author's contribution ensured that the final pool of studies reflected a balanced and inclusive representation of the available evidence.

RESULTS

Epidemiological studies presented convincing evidence of a correlation between HPV infection and occurrence of specific forms of oral malignancies, specifically in the oropharyngeal area. Prevalence rates for HPV in oral cancers vary widely, often due to differing methodologies in detecting HPV DNA (8). In 2005, Kreimer et al conducted a comprehensive analysis of the global literature, which revealed that HPV DNA was found in 35.6% of oropharyngeal malignancies, with HPV 16 being the most common subtype (87%) (2). According to existing research, approximately 6.9% of the population has an active oral or oropharyngeal HPV infection at any given time. Most HPV infections are cleared by the immune system within one year to two years, but only about half of those with confirmed infections develop detectable antibodies (9). The exact rate of lifetime oral exposure to HPV is uncertain, although it is estimated that between 80% and 90% of sexually active individuals have been exposed to HPV at any area in the body, including the oral, genital or anal regions (10). Over a period of 20 years, the rate of HPV-positive oral squamous cell carcinoma (OSCC) has increased from less than 20% to more than 70% in the United States and certain European nations (11). Until recently, it was believed that around 20% of oral cancers and 60% to 80% of oropharyngeal cancers were caused by HPV infection (4). Poor oral hygiene and oral health, as indicated by infrequent teeth brushing or tooth loss, are recognized as risk factors for oral and oropharyngeal cancers. These variables can contribute to the development of these cancers both individually and in combination with tobacco and alcohol use (12). No prior research has been conducted to investigate the correlation between oral HPV infection and oral health. The relationship between poor oral health and the risk of oral HPV infection as well as the potential compensatory effect of good oral health remains uncertain (13). Research has also indicated that males had an increased risk than females of acquiring an oral HPV infection (14). The reason for this could be that the female genital mucosa tends to have a higher concentration of HPV virus compared to the male genital mucosa/skin. As a result, males who perform oral sex on women are more likely to be exposed to a higher dose of the virus compared to the opposite way. Over the past few decades, there has been a decline in the age at which people first have sex and an increase in the number of sexual partners. These trends may have led to a higher incidence of oral or oropharyngeal HPV exposures (15) as the risk of oral HPV infection rises with the number of oral sexual partners (16). According to Mork et al (17), it is highly likely that oropharyngeal HPV infection is a crucial factor in the development of HPV-related OPSCC. Age plays a significant role in mouth infections caused by HPV. Studies have demonstrated a bimodal distribution of oral HPV infections, with a first peak being observed among individuals aged 30–34 years, likely due to increased sexual activity, and a second peak among those aged 60–64 years (18). Similarly, a study conducted in China found that the highest occurrence of HPVs was observed in individuals below the age of 35, with a noticeable decline in older individuals (19).

In 2013, Chaturvedi AK et al conducted a study (20) based on registries from 23 countries and found that the incidence of oropharyngeal cancer increased among men under the age of 50 in industrialized countries such as the United States, Australia, Denmark, United Kingdom, Slovakia and Canada. Furthermore, the prevalence of HPV-related OSCC increased over time from 40.5%, in studies published before 2000 to 64.3% in studies published between 2000 and 2004, to 72.2% in studies published between 2005 and 2009, according to a recent metaanalysis that included 269 studies and 19,638 patients, the majority of whom were Americans or Europeans (21). Additionally, the HPV-positivity ranged from 0% in India (22) to 85% in Lebanon (23) in a global epidemiological study conducted by Carlander AF et al in 2021 (24). Every region showed evidence of both high and low HPV prevalence. Based on the above-mentioned research, we can confidently state that the Middle East and Europe have the highest rates of oropharyngeal cancer linked to HPV. Furthermore, In Thailand, the percentage of increase went up from 16% in 2012 to 26% in 2017 (25). In the USA, the percentage of increase in women rose from 54% in 2010 to 60% in 2015, while in men it increased from 65% in 2010 to 75% in 2015 (26). Germany experienced a twofold increase from 20% in 2005 to 40% in 2014 (27). In Denmark there was an increase from 50% between 2000-2010 to 56% between 2015-2017 (28). Italy witnessed an increase from 40% between 2010-2014 to 54% between 2015-2019, as reported by Dona et al (29). Additionally, according to Del Mistro et al (30), the percentage increased from 16% between 2000-2006 to 46% between 2013-2018 (31).

DISCUSSION

There has been a rise in the prevalence of oral and oropharyngeal malignancies in recent decades, which poses a significant risk to public health worldwide. This is a concerning pattern that is partially attributed to the carcinogenic HPV, specifically types 16 and 18. The above-mentioned viruses have been recognized as primary causes of some types of oral and oropharyngeal malignancies. These cancers exhibit a unique clinical and molecular profile when compared to cases that are not associated with HPV (32). The prevalence of oral and oropharyngeal cancer associated with HPV has significantly risen to 70%-80%, particularly among younger individuals who had a remarkable 113% increase (33). One potential explanation for this could be the common risk factors, namely tobacco and alcohol consumption. This demographic transition highlights the need of understanding the role of HPV in the development of these cancers and the need for implementing appropriate prevention strategies. From a geographical perspective, there is variance in the occurrence of oral and oropharyngeal cancer that is associated to HPV. Certain regions have observed elevated rates, underscoring the need for targeted monitoring and intervention endeavors. The identification of HPV DNA in tumor samples may now be accomplished with great accuracy and precision utilizing polymerase chain reaction (PCR), a highly sophisticated diagnostic method widely used for detecting HPV-related oral and oropharyngeal malignancies.

PCR-based assays allow the identification of high-risk HPV genotypes, enabling doctors to categorize their patients based on their viral status and customize treatment methods accordingly. Incorporating molecular biomarkers into diagnostic algorithms can enhance risk assessment and prognostic evaluation in HPV-positive individuals (34). In terms of treatment, HPV-positive people with oral and oropharyngeal malignancies have demonstrated positive responses to traditional therapies including radiation and chemotherapy. HPV-positive malignancies often exhibit heightened sensitivity to radiation and chemotherapy compared to HPV-negative tumors. This enhanced sensitivity leads to improved control of the tumor in the local area and higher overall survival rates (35). However, further research is necessary to enhance treatment algorithms and minimize treatment-related complications due to ongoing investigations into the optimal management of different types of cancer (36). Overall, oral and oropharyngeal cancers associated with HPV provide a significant health risk and exhibit distinct epidemiological, clinical and molecular characteristics. In order to mitigate the effects of these malignancies on public health, it is necessary to develop specific prevention and treatment approaches that take into account the fundamental processes that drive the development of HPV-related cancers.

The present research offers a robust contribution to understanding the association between HPV and oral/oropharyngeal cancers. Our study is strengthened by its comprehensive review methodology which incorporates recent global epidemiological data. By focusing on high-risk HPV types 16 and 18, the present research provides critical insights into their role in carcinogenesis, highlighting distinct molecular and clinical profiles of HPV-positive cancers. Furthermore, the inclusion of diagnostic advancements, such as PCR-based assays, underscores the relevance of contemporary diagnostic technologies in improving early detection. The geographic focus on diverse populations enhances the scope of our study, emphasizing variations in HPV prevalence and its implications across different regions and demographic groups.

However, the present study has certain limitations. The reliance on previously published data may introduce biases inherent to the original studies, such as variations in diagnostic methods and population sampling. Additionally, the exclusion of grey literature and non-English publications could limit the comprehensiveness of the findings. While the study discusses HPV vaccination and public health measures, it does not delve deeply into policy implementation challenges in low- and middle-income countries, where the burden of oral cancers is higher. Moreover, the lack of primary data collection restricts the ability to provide new empirical evidence or address gaps in existing knowledge. Future research should aim to incorporate multicenter longitudinal studies to better assess causal relationships and evaluate intervention outcomes.

CONCLUSIONS

In conclusion, to date, studies using different methods have explored the possible association between human HPV infection and oropharyngeal carcinogenesis. The infection with HPV poses a substantial public health challenge due to its strong correlation with an increasing number of oral and oropharyngeal malignancies. The increasing incidence of these cancers, especially among younger individuals and those who do not have conventional risk factors, highlights the changing patterns of disease occurrence influenced by HPV. Furthermore, the increasing occurrence of malignancies caused by HPV infection imposes a significant burden on healthcare systems and emphasizes the immediate requirement for efficient measures to prevent, early detect and specifically treat these types of cancers. Public health interventions, such as widespread HPV vaccination and education on safe sexual practices, are essential for minimizing the effects of HPV and decreasing the occurrence of these cancers, thereby enhancing patient outcomes and quality of life. However, it is obvious that further multicenter prospective trials with a larger patient population and additional research are needed in order to reach safe conclusions.

Conflicts of interest: none declared.

Financial support: none declared.

Authors' contributions: conceptualization, methodology, formal analysis and supervision – AL; data curation – AL, EK; writing/original draft preparation – AL, EK; writing/review and editing – AL, EK, NSB, IM, CT.

FIGURE 1.

Flow diagram of literature search