Introduction
Head and neck cancers represent a significant global health burden, with oropharyngeal cancers (oropharyngeal cancers) accounting for over one-third of all head and neck cancers in most continents. The incidence of human papillomavirus (HPV)-related oropharyngeal squamous cell carcinoma (SCC) has risen sharply in recent years, with the USA and Europe reporting a 20-year incidence change of 20 per cent to over 70 per cent. The USA also reports that the annual number of oropharyngeal cancer cases surpassed that of cervical cancer in 2011 and is projected to exceed three times the number of cases of cervical cancer by 2030.Reference Sun, Yu, An, Liang, Sun and Liu1, Reference Sathish, Wang and Yuan2 In the UK, the annual number of HPV-related oropharyngeal SCC cases has also surpassed that of cervical cancer. The direct treatment cost of oropharyngeal SCC in men alone is estimated to be about £1.6 billion, with the wider societal costs estimated to reach £14.3 billion within the next 15 years.Reference Rehman, Liu, Oakley, O’Mahony, Holsinger and Masterson3
Human papillomavirus-related head and neck cancers arise more frequently in the oropharynx than in any other head and neck subsite. This includes the tonsils, base of tongue, soft palate and posterior pharyngeal wall. Unlike traditional head and neck cancers, which are mainly related to smoking and alcohol use, HPV-positive oropharyngeal cancers now contribute substantially to cancer cases, even where cancers caused by other risk factors are falling in the same populations. In the UK, 51 per cent of oropharyngeal SCC cases have been found to be involved with HPV carcinogenic infection whilst a systematic review of 134 studies showed that 48.1 per cent of all oropharyngeal cancer patients were HPV-positive, with HPV16 as the predominant genotype.Reference Ullah, Mikhailova, Alkhathami, Carbajal, Zuta and Rasulova4, Reference Lechner, Liu, Masterson and Fenton5
The rising incidence of HPV-related oropharyngeal cancers has been attributed to evolving sexual behaviours. A pooled analysis of 5642 head and neck cancer patients across multiple countries concluded that oropharyngeal cancer was associated with having six or more lifetime sexual partners and four or more oral sex partners.Reference Heck, Berthiller, Vaccarella, Winn, Smith and Shan’gina6
Human papillomavirus is a virus that belongs to the Papillomaviridae family. It is the most common sexually transmitted infection among both males and females globally, with over 80 per cent of sexually active people having an infection at some point in their lives.Reference Gardella, Pasquali and Dominoni7 Whilst most people will clear the infection, the virus can remain latent and cause cancer later in life. Human papillomavirus has been classically associated with cervical cancer, but there has been a marked increase in the disease burden of HPV-associated oropharyngeal cancer, with its incidence now exceeding that of cervical cancer in the United States and the United Kingdom. Disease transmission varies across different mucosal sites, spreading through autoinoculation, direct transmission (including perinatal and sexual transmission) and indirect transmission between individuals. Transmission of HPV to the oral cavity has been attributed to oral sexual contact, with the virus entering through tears in the oral cavity.Reference Gardella, Pasquali and Dominoni7
Awareness of HPV’s links to oropharyngeal cancers in the UK has consistently been found to be poor. Following the introduction of a gender-neutral vaccine in the UK, a population survey found that less than half of participants had heard of HPV and less than 20 per cent understood that HPV is a risk factor of oropharyngeal cancers.Reference Rehman, Liu, Oakley, O’Mahony, Holsinger and Masterson3, Reference Heck, Berthiller, Vaccarella, Winn, Smith and Shan’gina6 With the global rising incidence of HPV-related oropharyngeal cancers, rising burden of disease and lack of awareness, it is essential that the clinicians who manage and educate these patients understand the pathogenesis of this disease process and the role of preventive treatment such as vaccination.
Methods
A narrative literature review was conducted using PubMed, Embase and Medline databases for articles published up to December 2025. Search terms included combinations of ‘oropharyngeal’, ‘squamous cell carcinoma’, ‘HPV’, ‘vaccines’, ‘pathogenesis’ and ‘PI3K’. Studies were selected based on relevance to HPV-driven oropharyngeal malignancy. Those focusing primarily on gynaecological HPV-related malignancies were excluded. Reference lists of included articles were hand-searched to identify additional relevant studies.
Discussion
Pathogenesis of human papillomavirus-driven oropharyngeal squamous cell carcinoma
Human papillomavirus E6 and E7 oncoproteins
Human papillomavirus is a highly potent human carcinogen; acting on epithelial cells, it exerts its oncogenic potential through the expression of E6 and E7 oncogenes. There are over 200 different genotypes of the Papillomaviridae virus, which can be classified into high risk and low risk based on their ability to trigger malignant changes in host cells.Reference Galloway and Laimins8 Human papillomavirus 16 and 18 are of particular interest because they are examples of high-risk HPV genotypes, linked to high-grade squamous intra-epithelial lesions and invasive cancer, and recognised by the World Health Organization.Reference Ullah, Mikhailova, Alkhathami, Carbajal, Zuta and Rasulova4 This contrasts with low-risk HPV types such as 6 and 11, usually associated with benign lesions.
The viral genome of HPV encompasses three distinct segments: early (E), late (L) and upstream. The E segment contains six proteins, E1, E2, E4, E5, E6 and E7, which aid in viral DNA replication and synthesis of new virus particles within infected host cells.Reference Hussain, Abullais, Bottu, Thirumani, Misbah and Madar9, Reference Hamid, Brown and Gaston10 The following discussion focuses on the oncogenic role of the early viral segments.
Human papillomavirus infects the stratified squamous epithelial layer of the oropharynx through mucosal micro-abrasions, accessing basal keratinocytes, where it maintains its genome during early infection.Reference Mlynarczyk-Bonikowska and Rudnicka11 The virus persists particularly well in the lingual and palatine tonsils because of their thin, discontinuous basement membranes, deep tonsillar crypt invaginations and local immunotolerance. The shape and discontinuity allow for easy viral access, reduced immune clearance and chance for recurrent infection in repeated tonsilitis.Reference Roberts, Szymula, Huang, Jiang, Harris and Bhatt12 These features are part of what explains the predilection of HPV-related oropharyngeal cancers in the subsite of the oropharynx.
High-risk HPV frequently integrates into the host genome. This integration disrupts the viral E2 gene and reduces its expression. Because E2 normally represses transcription of E6 and E7, it’s loss results in unregulated expression of these oncogenes.Reference Hamid, Brown and Gaston10 The continuous expression of these oncoproteins alters the molecular pathways of the infected cells and promotes malignant transformation.Reference Ullah, Mikhailova, Alkhathami, Carbajal, Zuta and Rasulova4, Reference Hussain, Abullais, Bottu, Thirumani, Misbah and Madar9
E6 promotes degradation of the tumour suppressor protein p53, a process in which E6 binds to E6AP (ubiquitin protein ligase) and tags p53 for proteasomal degradation.Reference Martinez-Zapien, Ruiz, Poirson, Mitschler, Ramirez and Forster13 p53 is essential for maintaining genomic stability by detecting cellular stress and inducing cell cycle arrest, DNA repair and apoptosis.Reference Kastenhuber and Lowe14 In contrast, E7 binds to retinoblastoma protein and releases the E2 promoter-binding factor (E2F) family of transcription factors. This disrupts the cell cycle checkpoint between the first gap phase (G1), during which the cell grows, and the synthesis phase (S), during which DNA is replicated. Cells are therefore forced into the synthesis phase, resulting in uncontrolled proliferation.Reference Hamid, Brown and Gaston10, Reference Niklander15 The combined actions of these oncogenes promote genomic instability by removing cellular safeguards, leading to immortalisation and malignant transformation of the infected epithelial cells.Reference Hussain, Abullais, Bottu, Thirumani, Misbah and Madar9 Immortalisation occurs when cells become capable of continuous proliferation and proliferate indefinitely.Reference Hamid, Brown and Gaston10 This process is summarised in Figure 1.
Summary pathogenesis of E6/E7-mediated human papillomavirus (HPV)-driven oropharyngeal squamous cell carcinoma (OPSCC).
Figure 1 Long description
A vertical flowchart, read from top to bottom, titled “Pathogenesis of HPV-driven OPSCC”. Boxes are colour-coded by stage, with a key at the foot of the figure giving five categories: HPV entry (grey), integration (purple), E6 pathway (coral), E7 pathway (teal) and oncogenic outcome (red). Arrows connect each box to the next. The sequence begins with three boxes in a single column. The first, “HPV entry into oropharynx”, notes entry via mucosal micro-abrasions into basal keratinocytes. An arrow leads to “Viral genome integration”, where high-risk HPV types 16 and 18 disrupt the E2 gene. A further arrow leads to “E2 loss leads to unregulated E6/E7 expression”. From this box the flowchart divides into two parallel columns, labelled E6 on the left and E7 on the right. The left column contains “E6 oncoprotein”, which binds E6AP and targets p53 for degradation, followed by “p53 degradation”, annotated as no apoptosis or DNA repair. The right column contains “E7 oncoprotein”, which binds and inactivates pRb, followed by “pRb inactivation”, annotated as E2F release and G1/S checkpoint bypass. The two columns then converge into a single column of three further boxes: “Genomic instability”, then “Cell immortalisation”, and finally “Malignant transformation”, annotated as HPV-positive OPSCC.
Although the expression of high-risk HPV, particularly HPV16 and HPV18, leads to uncontrolled proliferation, this alone does not explain the phenotypic changes in HPV-positive oropharyngeal SCC.Reference Lechner, Liu, Masterson and Fenton5 Several studies have investigated the molecular mechanisms involved in HPV-driven carcinogenesis, beyond cell cycle disruption. E6 and E7 simultaneously reprogram multiple oncogenic pathways in HPV-positive oropharyngeal SCC, affecting genes involved in telomere elongation, epithelial–mesenchymal transition and stress response proteins (SIRT1, HSP90AA1).Reference Hussain, Abullais, Bottu, Thirumani, Misbah and Madar9 Epithelial–mesenchymal transition enables epithelial cells to lose adhesion and become invasive, contributing to metastasis. The inflammation-rich tumour microenvironment further promotes invasion and metastasis through tumour necrosis factor-α-mediated angiogenesis and neutrophil recruitment.Reference Hussain, Abullais, Bottu, Thirumani, Misbah and Madar9, Reference Niklander15 Notably, the immune landscape of oropharyngeal SCC differs markedly by HPV status. Human papillomavirus-negative tumours harbour significantly greater tumour-associated neutrophil infiltration than the HPV-positive counterparts, consistent with the comparatively poorer prognosis of HPV-negative disease.Reference Al-Sahaf, Hendawi, Ollington, Bolt, Ottewell and Hunter16
Phosphoinositide 3 kinase/AKT/mTOR pathway
The phosphoinositide 3 kinase signalling pathway promotes cell survival, growth and differentiation. It also plays a key pro-carcinogenic role in the development of many tumours and is the most commonly mutated pathway in head and neck squamous cell carcinoma.Reference Cai, Dodhia and Su17 Human papillomavirus-positive tumours show an increased frequency of mutations in this pathway compared with HPV-negative tumours.Reference Cai, Dodhia and Su17 Tight regulation of the phosphoinositide 3 kinase pathway is crucial for oral epithelial homeostasis and to prevent aberrant cell proliferation and invasion. Phosphoinositide 3 kinases are grouped into classes IA, IB, II and III, depending on their upstream activating receptor, such as receptor tyrosine kinases or G-protein-coupled receptors.Reference Ghafouri-Fard, Noie Alamdari, Noee Alamdari, Abak, Hussen and Taheri18 Of these classes, IA phosphoinositide 3 kinases have been studied the most extensively.
On activation, phosphoinositide 3 kinase phosphorylates molecule phosphatidylinositol 4,5-bisphosphate (PIP2), converting it to phosphatidylinositol 3,4,5-trisphosphate (PIP3). The key downstream effector of phosphoinositide 3 kinase, protein kinase B, is then recruited and binds to phosphatidylinositol 3,4,5-trisphosphate via its pleckstrin homology domains.Reference Cai, Dodhia and Su17, Reference Ghafouri-Fard, Noie Alamdari, Noee Alamdari, Abak, Hussen and Taheri18 The protein kinase B family (protein kinase B isoforms 1, 2 and 3) are serine and/or threonine protein kinases which regulate several downstream effectors, such as the protein kinase mechanistic target of rapamycin (mTor). This process integrates signals from multiple pathways, including nutrients (e.g. amino acids and glucose), growth factors (e.g. insulin and insulin-like growth factor 1), hormones (e.g. leptin) and stresses (e.g. starvation, hypoxia and DNA damage), regulating cell functions such as cell growth, differentiation, cell survival, metabolism, energy balance and stress response.Reference Cai, Dodhia and Su17
In head and neck squamous cell carcinoma, protein kinase B and mechanistic target of rapamycin have been found to display mutations, leading to overexpression, which enables cell growth and proliferation even in unfavourable conditions such as when there is nutrient absence or cell damage.Reference Cai, Dodhia and Su17 Dysregulation of the phosphoinositide 3 kinase, protein kinase B and mechanistic target of rapamycin pathway is associated with treatment resistance and the aggressiveness of oropharyngeal SCC tumours. The pathway has been implicated in tumorigenic processes such as cell proliferation, invasion, angiogenesis and metastasis.Reference Cai, Dodhia and Su17, Reference Ghafouri-Fard, Noie Alamdari, Noee Alamdari, Abak, Hussen and Taheri18
Compared with tobacco-associated oropharyngeal SCC, HPV-positive tumours exhibit a higher frequency of mutations within the phosphoinositide 3 kinase pathway, particularly affecting the PIK3CA and phosphatase and tensin homolog genes.Reference Chiosea, Grandis, Lui, Diergaarde, Maxwell and Ferris19 Phosphatase and tensin homolog, deleted from chromosome 10, is a key negative regulator of the phosphoinositide 3 kinase pathway, dephosphorylating phosphatidylinositol 3,4,5-trisphosphate back to phosphatidylinositol 4,5-bisphosphate. Its deletion in HPV-positive head and neck cancers removes this inhibitory constraint, sustaining aberrant pathway activation.Reference Cai, Dodhia and Su17, Reference Chiosea, Grandis, Lui, Diergaarde, Maxwell and Ferris19 PIK3CA is the most commonly mutated gene in HPV-associated oropharyngeal SCC, detected in approximately 20–30 per cent of cases, with overexpression of mutant PIK3CA driving enhanced phosphoinositide 3 kinase activity and oncogenic transformation.Reference Beaty, Moon, Shen, Amdur, Weiss and Grilley-Olson20, Reference Lee, Kim and Waldman21 Human papillomavirus infections are responsible for causing high-frequency mutations within the PIK3CA gene, driving PIK3CA mutagenesis and HPV-induced cellular transformation via the actions of the apolipoprotein B messenger RNA-editing enzyme, catalytic polypeptide-like family.Reference Henderson, Chakravarthy, Su, Boshoff and Fenton22
Oncoproteins E6 and E7 also exert direct effects on the phosphoinositide 3 kinase pathway, as well as enhancing signalling through p53 and/or retinoblastoma protein loss. Previous studies have highlighted a positive feedback loop between p53 and phosphatase and tensin homolog, which regulates tumour-suppressive signalling.Reference Lee, Kim and Waldman21 Tumour suppressor p53 upregulates phosphatase and tensin homolog expression, while phosphatase and tensin homolog prevents p53 degradation. Loss of either disrupts this regulatory signalling loop, resulting in increased protein kinase B activation and promotion of tumour initiation and progression.Reference Lee, Kim and Waldman21 Uncovering the virus’s effect on this signalling pathway allows prognostic molecular biomarkers to be identified for use in diagnosis and therapeutic opportunities for treating HPV-induced cancers through the development of pathway inhibitors such as alpelisib, a class IA phosphoinositide 3 kinase inhibitor, or dactolisib, a dual phosphoinositide 3 kinase/mTOR inhibitor.Reference Mishra, Patel, Alanazi, Kilroy and Garrett23 This is summarised in Figure 2.
Flowchart of the role of human papillomavirus (HPV) in the P13K/AKT/mTOR pathway. RTK = receptor tyrosine kinase; GPCR = G protein-coupled receptor; PI3K = phosphoinositide 3-kinase; IA = class IA; PIK3CA = phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha; PTEN = phosphatase and tensin homolog; PIP2 = phosphatidylinositol 4,5-bisphosphate; PIP3 = phosphatidylinositol 3,4,5-trisphosphate; AKT = protein kinase B; PH = Pleckstrin homology; mTOR = mechanistic target of rapamycin; PI3Ki = phosphoinositide 3-kinase inhibi.
Figure 2 Long description
A flowchart titled “PI3K/AKT/mTOR pathway dysregulation in HPV-driven OPSCC”, with a central column of connected boxes and two columns of annotation boxes surrounding it. The left-hand side is headed “Negative regulation” and the right-hand side “HPV dysregulation”. A key at the base of the figure gives six colour categories: signals, PI3K cascade, AKT/mTOR, PTEN, HPV dysregulation, outcomes and therapeutics. The central column runs from top to bottom as follows. “RTK/GPCR activation”, annotated as growth factors, nutrients and stress signals. “PI3K class IA activation”. “PIP2 to PIP3 conversion”, annotated as occurring via PI3K phosphorylation. “AKT activation”, annotated as binding PIP3 via the PH domain. “mTOR activation”. “Oncogenic outcomes”, annotated as invasion, metastasis and treatment resistance. Finally “Therapeutic targeting”, listing alpelisib as a PI3K inhibitor and dactolisib as a dual PI3K/mTOR inhibitor. On the left, a single box labelled PTEN, annotated as converting PIP3 back to PIP2, connects to the PIP2 to PIP3 conversion step with a blunt-ended inhibitory line rather than an arrow. On the right, three boxes feed into the centre. “PIK3CA mutation” connects to PI3K class IA activation. “PTEN deletion”, annotated as increased PIP3 signalling, connects to the PIP2 to PIP3 conversion step. “E6/E7 effects”, annotated as loss of the p53/PTEN loop, connects to AKT activation.
p16 protein as a biomarker of human papillomavirus infection
The tumour suppressor protein p16 (Cyclin-Dependent Kinase Inhibitor 2A) is an established surrogate biomarker for HPV infection in oropharyngeal SCC.Reference Ullah, Mikhailova, Alkhathami, Carbajal, Zuta and Rasulova4, Reference Mehanna, Taberna, Von Buchwald, Tous, Brooks and Mena24 Protein p16 acts to arrest the cell cycle by inhibition of retinoblastoma protein, therefore the HPV E7-mediated degradation of retinoblastoma protein is thought to trigger compensatory p16 overexpression.Reference Hamid, Brown and Gaston10 Recent studies have suggested that other E7-mediated processes are also responsible for p16 overexpressionReference Lechner, Liu, Masterson and Fenton5; regardless, this rise is detectable by immunohistochemistry. p16 immunohistochemistry is the most widely implemented technique used within clinical setting. However, its use as a standalone marker has been questioned, with a subset of HPV-DNA and messenger RNA-negative head and neck SCCs showing positive p16 staining, suggesting results may not be specific to HPV-driven overexpression.Reference Mehanna, Taberna, Von Buchwald, Tous, Brooks and Mena24, Reference Taberna, Mena, Pavon, Alemany, Gillison and Mesia25 Its prognostic value is also poorer in oral cavity and laryngeal subsites than in the oropharynx.Reference Taberna, Mena, Pavon, Alemany, Gillison and Mesia25, Reference Lewis, Thorstad, Chernock, Haughey, Yip and Zhang26 Whilst p16 overexpression reflects the oncogenic cellular disruption caused by HPV infection and remains beneficial as a surrogate biomarker, it does not reflect direct HPV detection. This prompts the need for continued combined detection methods for other HPV detection techniques such as detection of HPV-DNA by in situ hybridisation or polymerase chain reaction.Reference Taberna, Mena, Pavon, Alemany, Gillison and Mesia25
Key features of human papillomavirus (HPV)-associated oropharyngeal squamous cell carcinoma (OPSCC). OPC = oropharyngeal cancers; HNC = head and neck cancers; PI3K = phosphoinositide 3 kinase; AKT = protein kinase B; mTOR = mechanistic target of rapamycin; IHC = immunohistochemistry; ISH/PCR = in situ hybridisation/polymerase chain reaction; VLP = virus-like particle; IgG = immunoglobulin G.
Figure 3 Long description
A summary diagram titled “Key Features of HPV-Associated Oropharyngeal Squamous Cell Carcinoma (OPSCC)”. At the centre is a pink circle labelled HPV, Oropharynx, listing the tonsils, base of tongue, soft palate and posterior pharyngeal wall. Eight rectangular boxes are arranged around the circle and joined to it by dashed lines. Each box carries a heading and a short list of bulleted facts. At the top, “Disease Burden” records that oropharyngeal cancer accounts for more than one third of all head and neck cancers globally, that HPV-positive OPSCC has surpassed cervical cancer incidence in the UK and US, and that the wider UK societal cost is £14.3 billion over 15 years. On the upper left, “Risk Factors” lists tobacco and alcohol as traditional factors, sexual contact as the HPV-driven route, six or more lifetime sexual partners and four or more oral sex partners, and a male to female ratio of approximately four to one. On the upper right, “Epidemiology” records that 48.1 per cent of oropharyngeal cancer patients are HPV-positive, that HPV16 is the predominant genotype, that incidence has risen from 20 per cent to more than 70 per cent over 20 years, and that rates are rising sharply in high-income countries. On the middle left, “Pathogenesis” lists E6 degradation of p53 causing loss of apoptosis, E7 inactivation of pRb causing uncontrolled proliferation, PI3K/AKT/mTOR pathway dysregulation, and genomic instability with cell immortalisation. On the middle right, “Prognosis and Biomarkers” records the significantly better prognosis of HPV-positive OPSCC, with five-year survival of 80 per cent against 40 per cent, and notes p16 immunohistochemistry as a widely used surrogate biomarker for which combined detection by in situ hybridisation or polymerase chain reaction is recommended. On the lower left, “Vaccination” lists L1 virus-like particle vaccines in bivalent, quadrivalent and 9-valent forms, an 83.9 per cent reduction in oral HPV infection, seroconversion approaching 100 per cent, IgG detectable in oral fluids, and a 19-fold higher risk in the unvaccinated. On the lower right, “Public Health” records the UK gender-neutral vaccine from 2019, male uptake of 68.7 per cent against 74.4 per cent in females, fewer than half the UK public being aware of HPV, and the frequent exclusion of oral HPV from sex education. At the bottom, “Transmission” states that oral HPV is transmitted by sexual contact, with the virus entering through mucosal microabrasions, and that it persists in the tonsillar crypts because of local immunotolerance.
Human papillomavirus vaccination: mechanism and efficiency
Prophylactic HPV vaccines are based on non-pathogenic virus-like particles composed of the L1 major capsid protein, which resemble the viral capsid without containing viral DNA.Reference Frazer27 This gives them a superior safety profile when compared with live-attenuated, subunit, killed or particulate vaccines because the virus-like particle is unable to replicate and is non-infectious.Reference Donaldson, Lateef, Walker, Young and Ward28 Currently available formulations include the bivalent vaccine Cervarix (HPV16/18), the quadrivalent vaccine Gardasil (HPV6/11/16/18) and the nine-valent vaccine Gardasil 9 (nine genotypes). The latter nine-valent vaccine protects against 90 per cent of HPV-related carcinomas.Reference Lehtinen, Van Damme, Beddows, Pinto, Mariz and Gray29
Virus-like particle vaccines induce robust host immunity. Following internalisation by antigen-presenting cells, virus-like particle-derived peptides are presented on major histocompatibility complex II to CD4+(cluster of differentiation 4-positive) T-helper cells, which drive B-cell activation and differentiation into antibody-producing plasma cells and long-lived memory B cells.Reference Donaldson, Lateef, Walker, Young and Ward28 Seroconversion following vaccination has been shown to approach close to 100 per cent in all individuals, with antibody levels exceeding those required for protection and persisting for at least a decade, even after a single dose.Reference Lehtinen, Van Damme, Beddows, Pinto, Mariz and Gray29, Reference Schiller and Lowy30
Vaccination induces immunoglobulin G in both blood and oral fluids, suggesting that that there may be protection against specific HPV-positive oropharyngeal diseases.Reference Handisurya, Schellenbacher, Haitel, Senger and Kirnbauer31 Crucially, one hospital-based cross-sectional study found that unvaccinated patients were 19 times more likely to develop oropharyngeal carcinomas than vaccinated individuals.Reference Katz32
Clinical impacts and public health implications
Oropharyngeal SCC is expected to cost the UK approximately £14.3 billion over the coming 15 years, with treatment for men alone projected at £1.6 billion.Reference Sun, Yu, An, Liang, Sun and Liu1, Reference Rehman, Liu, Oakley, O’Mahony, Holsinger and Masterson3 Treatment regimens are rigorous, typically combining high-dose chemoradiotherapy with surgery such as resection and associated neck dissection. Survivors frequently experience long-term difficulties with swallowing, speech and facial disfigurement, profoundly affecting quality of life.Reference Fabiny Garb, Mohebbi, Lawas, Xia, Maag and Ahn33 The burden of overall head and neck cancers is linked with socioeconomic status, with a 50 per cent higher risk of death seen in populations from areas of deprivation compared with wealthy areas.Reference Watt, Heilmann and Conway34 Human papillomavirus-positive oropharyngeal SCC is associated with significantly higher overall survival rates compared with HPV-negative oropharyngeal SCC, despite HPV-positive cancers being diagnosed at more advanced stages of disease. Human papillomavirus-positive oropharyngeal SCC has a reported 5-year survival rate of 70–80 per cent, whilst HPV-negative disease is reported at 25–40 per cent.Reference Sharkey Ochoa, O’Regan, Toner, Kay, Faul and O’Keane35
The UK introduced HPV vaccination for 12–13-year-old females in 2008, extending it to males as well in 2019. The initial 2008 vaccination schedule was 3 doses of Bivalent (Cervarix; GlaxoSmithKline Biologicals SA, Rixensart, Belgium; HPV16 and 18), but this was changed to quadrivalent (Gardasil; Merck Sharp & Dohme LLC, Rahway, New Jersey, USA; HPV6, 11, 16 and 18) and as of 2023 9-valent (Gardasil 9; Merck Sharp & Dohme LLC, Rahway, New Jersey, USA; nine genotypes) vaccination has been used for all genders.36, 37 The delayed inclusion of boys meant that in Scotland in 2024–2025 only 69.7 per cent of first-year high school males received a first dose compared with 75.7 per cent of females, and uptake dropped to 62.0 per cent in the most deprived areas versus 83.4 per cent in the least deprived.38 Post-coronavirus disease 2019, data from the UK Health Security Agency also show that HPV vaccine uptake rates have not returned to pre-pandemic levels.Reference Watt, Heilmann and Conway34 In the National Health Service, for those who have missed the vaccination schedule, it is available to be administered until the age of 25 years and it is offered for any men who have male sexual partners until the age of 45.39 Oropharyngeal SCC incidence is projected to continue rising in unvaccinated cohorts until at least 2045, although modelling suggests that with high compliance incidence may begin falling by 2040.Reference Rehman, Liu, Oakley, O’Mahony, Holsinger and Masterson3, Reference Lechner, Breeze, O’Mahony and Masterson40
Expanding gender-neutral vaccination programmes and improving uptake in deprived communities are essential strategies. Sexual health education should also address oral HPV transmission because oral sex is often excluded from prevention messaging despite being the primary route of oropharyngeal infection.Reference Dhingra41 Routine dental visits also provide an important opportunity for early detection and patient education, with dentists playing a vital role in screening and referral.Reference Watt, Heilmann and Conway34 This is summarised in Figure 3.
Future directions
While prophylactic vaccines address primary prevention, therapeutic vaccines targeting E6 and E7 oncoproteins are under active investigation for patients with established disease. Phase 1 clinical trials of therapeutic vaccines have demonstrated long-lasting immune responses, and combining these vaccines with programmed cell death protein 1 (PD-1) or programmed death-ligand 1 (PD-L1) checkpoint inhibitors is predicted to amplify antitumour immunity.Reference Aggarwal, Cohen, Morrow, Kraynyak, Sylvester and Knoblock42 Intranasal therapeutic vaccines also represent a promising non-invasive approach that triggers mucosal immunity at the upper respiratory tract, with potential application to oropharyngeal disease.Reference Nakahashi-Ouchida, Mori, Yuki, Machita, Katakai and Umemoto43
In addition to immunotherapeutic approaches, salivary biomarkers show diagnostic potential for oropharyngeal SCC. Tumour necrosis factor-α has demonstrated 100 per cent specificity as a salivary biomarker in one oropharyngeal SCC cohort study, and S100 calcium-binding protein A8 (S100A8) has been identified as a significantly upregulated protein in patients with HPV-positive oropharyngeal SCC. Increased expression of S100 calcium-binding protein A8 expression has been shown to suppress antitumour immunity, positioning it as a biomarker candidate and prognostic indicator, as well as a potential therapeutic target.Reference Niklander15, Reference Miranda-Galvis, Soares, Carnielli, Buttura, Sales and Kaminagakura44
• Human papillomavirus (HPV), predominantly genotype 16, has overtaken smoking and alcohol as the leading cause of oropharyngeal squamous cell carcinoma (SCC) in high-income countries
• Human papillomavirus-positive oropharyngeal SCC has surpassed cervical cancer in UK incidence, carrying a substantial projected health and economic burden
• This review consolidates the molecular pathogenesis of HPV-driven oropharyngeal SCC – E6/E7 degradation of p53 and retinoblastoma protein, phosphoinositide 3 kinase/AKT/mTOR dysregulation and APOBEC-mediated PIK3CA mutagenesis – alongside public health prevention in a single, clinician-focused paper
• p16 immunohistochemistry is a useful but imperfect surrogate marker, with false-positive staining in HPV-DNA- and messenger RNA-negative tumours and weaker prognostic value outside the oropharynx, where confirmatory HPV testing is warranted
• Current UK and Public Health Scotland (2024/25) data show falling oral HPV prevalence after vaccination but persistent gender and socioeconomic disparities in uptake relevant to UK ENT services
• Therapeutic HPV vaccines and phosphoinositide 3 kinase-targeted agents are emerging strategies of relevance to head and neck oncology practice
Conclusion
Human papillomavirus-associated oropharyngeal SCC represents an evolving public health challenge driven by shifting sexual behaviours and complex viral–host interactions. The molecular understanding of E6/E7-driven carcinogenesis and phosphoinositide 3 kinase pathway dysregulation offers promising avenues for targeted therapeutics and prognostic stratification. Prophylactic vaccination remains the most effective primary prevention strategy, but achieving high uptake, particularly among males and in socioeconomically deprived communities, is essential. A thorough understanding of this disease among clinicians is critical to supporting vaccination policy, facilitating early detection through routine dental care and advancing research into therapeutic approaches, which together represent the most realistic pathway to reducing the morbidity, mortality and socioeconomic impact of this disease.
Competing interests
None declared.
Acknowledgements
All scientific content was written, verified and edited by the authors. Generative artificial intelligence (AI) and AI-assisted technologies were not used in the preparation of this work.
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