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Carcinogenic (high-risk) HPV infection refers to persistent infection with oncogenic human papillomavirus genotypes (primarily HPV 16 and 18, but also 31, 33, 45, 52, 58), which can progress from low-grade intraepithelial lesions (CIN I) to high-grade lesions (CIN II/III) and eventually to invasive carcinoma of the cervix and other anogenital/oropharyngeal sites.

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Virology & Types

• High-risk HPV (HR-HPV): 16, 18 (≈70% of cervical cancers), 31, 33, 45, 52, 58.
• Low-risk HPV (non-oncogenic): 6, 11 (cause warts, not cancer).

Carcinogenesis

1. HPV entry: Virus infects basal epithelial cells via microabrasions.
2. Viral persistence: Most infections clear within 1–2 years; persistence of HR-HPV is the key step in carcinogenesis.
3. Viral oncogenes:
   • E6 protein → binds and degrades p53 (inhibits apoptosis, promotes DNA damage tolerance).
   • E7 protein → inactivates Rb protein (loss of cell cycle control, unchecked proliferation).
4. Integration into host genome: HR-HPV DNA integrates into host chromosomes, disrupting normal regulation.
5. Progression: CIN I (low-grade) → CIN II/III (high-grade) → invasive squamous cell carcinoma or adenocarcinoma.

![Conceptual model of HPV infection leading to cervical cancer: Cervical cancer arises via a series of necessary steps (infection; persistence, rather than clearance; associated with precancer; and invasive cancer), with each stage mainly occurring at characteristic ages. The peak prevalence of human papillomavirus (HPV) infection is highly associated with sexual transmission in youth. The secondary peak of precancer occurs a number of years later depending on the intensity of screening, whereas the peak or plateau of invasive cancer occurs many years later. Thus, the slow growth of a precancer before invasion dictates the time taken between causative infection and a cancer diagnosis.

Schiffman, M. & Wentzensen, N. Human papillomavirus infection and the multistage carcinogenesis of cervical cancer. Cancer Epidemiol. Biomarkers Prev. 22, 553–560 (2013). Schiffman, M., Doorbar, J., Wentzensen, N. et al. Carcinogenic human papillomavirus infection. Nat Rev Dis Primers 2, 16086 (2016). https://doi.org/10.1038/nrdp.2016.86](attachment:7adf1982-2ab9-4e3b-974b-78f143d1fee9:image.png)

Conceptual model of HPV infection leading to cervical cancer: Cervical cancer arises via a series of necessary steps (infection; persistence, rather than clearance; associated with precancer; and invasive cancer), with each stage mainly occurring at characteristic ages. The peak prevalence of human papillomavirus (HPV) infection is highly associated with sexual transmission in youth. The secondary peak of precancer occurs a number of years later depending on the intensity of screening, whereas the peak or plateau of invasive cancer occurs many years later. Thus, the slow growth of a precancer before invasion dictates the time taken between causative infection and a cancer diagnosis.

Schiffman, M. & Wentzensen, N. Human papillomavirus infection and the multistage carcinogenesis of cervical cancer. Cancer Epidemiol. Biomarkers Prev. 22, 553–560 (2013). Schiffman, M., Doorbar, J., Wentzensen, N. et al. Carcinogenic human papillomavirus infection. Nat Rev Dis Primers 2, 16086 (2016). https://doi.org/10.1038/nrdp.2016.86

Clinical Relevance

Cancers associated with carcinogenic HPV:

• Cervical cancer (squamous cell carcinoma, adenocarcinoma).