What virus is most closely associated with oral squamous cell carcinoma of the oropharynx?

Human Papillomavirus (HPV) is Most Closely Associated with Oral Squamous Cell Carcinoma of the Oropharynx

High-risk human papillomavirus (HPV), particularly HPV type 16, is the virus most closely associated with oral squamous cell carcinoma of the oropharynx.

Epidemiology and Association

• HPV is recognized as the principal cause of increasing incidence rates of oropharyngeal squamous cell carcinoma (OPSCC) in high-income countries 1
• Approximately 72% of newly diagnosed head and neck cancer patients are HPV-positive, with oral HPV infection associated with a 12.3-fold increased risk for head and neck cancer 2
• HPV type 16 infection specifically carries the highest risk, with an odds ratio of 14.6 for head and neck cancer and 22.4 for oropharyngeal squamous cell carcinoma 2
• The prevalence of oropharyngeal cancer attributable to HPV varies globally but is estimated at around 30-35% 2

Diagnostic Evaluation

• HPV evaluation using p16 immunohistochemistry (IHC) should be performed on all patients with newly diagnosed oropharyngeal SCC 2
• p16 IHC is a reliable surrogate marker for HPV positivity in the oropharynx, although 10-15% of false-positive results can occur 2
• For neck metastases of unknown origin, p16 status should be assessed, and if positive, another specific HPV test (e.g., DNA, RNA, or in situ hybridization) should be performed to confirm HPV status 2
• The prognostic value of p16 has only been observed in oropharyngeal SCC, not in laryngeal, hypopharyngeal, or oral cavity tumors 2

Clinical and Prognostic Significance

• HPV-positive OPSCC patients have significantly better outcomes compared to HPV-negative patients 3, 1
• Patients with HPV-positive OPSCC have at least half the risk of death compared to HPV-negative patients 4
• HPV-positive patients tend to be younger, nonsmokers, and nondrinkers compared to those with HPV-negative disease 2, 4
• The improved prognosis of HPV-positive OPSCC has led to its separate classification in the 8th edition of the UICC/AJCC staging system 3

Molecular Biology and Carcinogenesis

• HPV carcinogenesis involves persistent infection with evasion of immune response, activation of viral early genes (E6, E7) in basal epithelial cells, deregulation of cell cycle, and accumulation of chromosomal instability 1
• HPV16 is identified in the overwhelming majority of HPV-positive tumors, which have molecular-genetic alterations indicative of viral oncogene function 4
• Different HPV16 genotypes may have prognostic implications - genotypes divergent from HPV16-A1 reference are associated with improved recurrence-free survival 5

Prevention and Management Implications

• HPV vaccination has been shown to be effective in preventing oropharyngeal infections caused by HPV types 16 and 18 (82.4% efficacy) and against non-vaccine HPV types 31 and 45 (75.3% efficacy) 2
• The risk of developing oropharyngeal cancer in unvaccinated individuals is 19 times higher than in vaccinated groups 2
• Due to better prognosis and greater prevalence in younger individuals, numerous trials are examining treatment de-intensification strategies to improve quality of life while maintaining acceptable survival outcomes 3

Clinical Considerations

• Diagnostic workup for suspected oropharyngeal cancer should include complete physical examination with neck palpation, flexible head and neck fibreoptic endoscopy, pathological confirmation, and imaging studies 2
• Key symptoms prompting evaluation include chronic pain in the throat, persistent hoarseness, painful or difficult swallowing, and neck masses 2
• For patients with HPV-positive OPSCC, treatment selection should consider both oncologic outcomes and functional preservation (voice, swallowing) 6