What types of cancer, besides cervical cancer, are associated with Human Papillomavirus (HPV)?

HPV-Associated Cancers Beyond Cervical Cancer

Human papillomavirus (HPV) causes multiple cancers beyond cervical cancer, including vaginal, vulvar, anal, penile, and oropharyngeal cancers, with HPV types 16 and 18 responsible for the majority of these HPV-attributable malignancies. 1

HPV-Associated Cancers by Anatomical Site

Vaginal Cancer

• HPV is associated with the majority of vaginal cancers and vaginal intraepithelial neoplasia III (VaIN III), with HPV 16 being the most common type 1
• Vaginal cancer is relatively rare, with approximately 1,070 cases annually in the United States (incidence rate: 0.7 per 100,000 females) 1
• The median age for diagnosis of vaginal cancer is 69 years, significantly higher than for cervical cancer 1

Vulvar Cancer

• HPV is associated with approximately half of vulvar squamous cell cancers, the most common type of vulvar cancer 1
• HPV-associated vulvar cancer tends to occur in younger women and may be preceded by vulvar intraepithelial neoplasia (VIN) 1
• HPV types 16 or 18 are detected in 76% of VIN 2/3 and 42% of vulvar carcinoma samples 1
• In the United States, approximately 3,507 cases of vulvar cancer occur annually (incidence rate: 2.2 per 100,000 females) 1

Anal Cancer

• HPV is associated with approximately 90% of anal squamous cell cancers 1, 2
• Anal intraepithelial neoplasia (AIN) is recognized as a precursor of anal cancer 1
• Anal cancer is more common in women (1.6 per 100,000) than in men (1.3 per 100,000) 1
• High-risk populations include women with high-grade cervical lesions, men who have sex with men, and persons with HIV infection 1

Penile Cancer

• Up to 50% of penile cancer cases are linked to HPV infection, with HPV type 16 being the most frequent 3, 4
• Penile cancers are now classified as HPV-associated or HPV-independent based on the 2022 WHO classification 3
• The incidence of penile cancer is approximately 36-40% attributable to HPV infection 4

Oropharyngeal Cancer

• HPV is responsible for a significant proportion (63-72%) of oropharyngeal cancers 1, 4
• Oropharyngeal cancers are more common in males (72%) than females (63%) 1
• The incidence of HPV-related oropharyngeal cancers has been increasing in recent years, especially among men 4

Epidemiology and Disease Burden

• An estimated 34,800 HPV-attributable cancers occur annually in the United States, with 92% (32,100) attributable to the HPV types targeted by the 9-valent HPV vaccine 2
• Of these HPV-attributable cancers, 19,000 occur among females and 13,100 among males 2
• The most common HPV-attributable cancers are cervical (9,700) and oropharyngeal cancers (12,600) 2
• While incidence rates for cervical cancer have declined significantly with screening, incidence rates for anal, oropharyngeal, and vulvar cancers have increased substantially in recent years 4

HPV Types and Cancer Risk

• HPV types 16 and 18 account for 70-76% of cervical cancers and 63-95% of non-cervical HPV-related cancers 4
• HPV 16 is the most likely to both persist and progress to cancer across all anatomical sites 5
• The 9-valent HPV vaccine protects against oncogenic HPV types 16,18,31,33,45,52, and 58, which collectively cause approximately 73% of all HPV-associated cancers 2, 5

Risk Factors and Pathogenesis

• Persistent infection with high-risk HPV types is necessary for progression to cancer 6
• Common risk factors for HPV-related cancers include multiple sexual partners, current tobacco use, immune deficiency, and co-infection with other sexually transmitted diseases 1
• Immunosuppression significantly increases the risk of HPV-related cancers, with solid organ transplant recipients showing higher standardized incidence ratios for these malignancies 1
• The HPV E6 and E7 oncoproteins disrupt host cell regulatory machinery, allowing infected cells to replicate with compromised DNA repair mechanisms 6

Prevention and Clinical Implications

• HPV vaccination can prevent up to 90% of cervical cancers and significantly reduce the risk of other HPV-related cancers 6, 2
• Most HPV infections (approximately 90%) are transient and clear within 1-2 years 6, 2
• The presence of HPV alone is insufficient for cancer development; cofactors including immune status, smoking, and genetic factors play important roles 6
• Unlike cervical cancer, there are no standardized screening recommendations for most other HPV-related cancers, making prevention through vaccination particularly important 1