How does Human Papillomavirus (HPV) cause oropharyngeal cancer?

How HPV Causes Throat Cancer

Human papillomavirus (HPV) causes oropharyngeal cancer primarily through the expression of viral oncoproteins E6 and E7, which inactivate crucial tumor suppressor genes p53 and pRb, leading to loss of cell-cycle control, impaired cell differentiation, and p16 protein overexpression. 1

Mechanism of HPV-Induced Carcinogenesis

• HPV DNA integrates into the host cell chromosome during carcinogenic progression, resulting in consistent expression of viral oncoproteins E6 and E7 in HPV-positive carcinomas 1
• The viral oncogenes E6 and E7 inactivate crucial human tumor suppressor genes, specifically:
  • E6 inactivates p53 tumor suppressor protein
  • E7 inactivates retinoblastoma protein (pRb) 1, 2
• This inactivation leads to loss of cell-cycle control and impaired cell differentiation 1
• The disruption of normal cell regulation results in p16 protein overexpression, which serves as a reliable surrogate marker for HPV-driven tumorigenesis in oropharyngeal cancers 1, 2

HPV Types and Oropharyngeal Cancer Risk

• HPV type 16 (HPV16) is the predominant subtype responsible for the vast majority of HPV-related oropharyngeal cancers 1, 3
• HPV16 infection specifically carries a 22.4-fold increased risk for oropharyngeal squamous cell carcinoma 2
• HPV types 18,31, and 33 account for most of the remaining HPV-positive oropharyngeal cancers 1
• Oral HPV16 infection increases the risk of oropharyngeal cancer, with a strong causal relationship established 1, 2

Progression from Infection to Cancer

• The progression to HPV-related oropharyngeal cancer includes:
  • Persistent infection with evasion of immune response in the microenvironment 4
  • Activation of viral early genes (E6, E7) in basal epithelial cells 4
  • Deregulation of cell cycle and accumulation of chromosomal instability 4
• Despite the presence of multiple integrated HPV DNA copies in cancer cells, virus-host fusion transcripts typically originate from only a single integrated HPV DNA copy 5
• Host genomic elements neighboring the integrated HPV DNA are critical for efficient expression of viral oncogenes that leads to clonal cell expansion 5

Clinical and Epidemiological Significance

• HPV is now recognized as the principal cause of increasing incidence rates of oropharyngeal squamous cell carcinoma in many parts of the world 4, 6
• Approximately 60-70% of newly diagnosed oropharyngeal cancers in the United States and parts of the European Union are attributable to HPV 1
• HPV-related oropharyngeal cancers have distinct characteristics compared to traditional tobacco and alcohol-related head and neck cancers:
  • Patients tend to be younger 1, 2
  • Patients are often non-smokers and non-drinkers 4
  • These cancers have a better prognosis 3

Prevention Implications

• HPV vaccination has shown efficacy in preventing oral HPV infections, with vaccinated individuals 46% less likely to develop oral vaccine-type HPV infection 7
• Specifically for HPV16, vaccination results in 80% less likelihood of oral infection 7
• This suggests that HPV vaccination could potentially prevent HPV-related oropharyngeal cancers 1, 7

Diagnostic Considerations

• p16 immunohistochemistry (IHC) serves as a reliable surrogate marker for HPV positivity specifically in oropharyngeal tumors 1, 2
• It's important to note that p16 and HPV are not equivalent outside the oropharynx, as transcriptionally active HPV is uncommon in non-oropharyngeal sites 1
• For definitive HPV testing, additional methods include PCR and in situ hybridization (ISH) 1