Vulvovaginal and Vaginal Cancer

Vulvar and vaginal cancers are uncommon malignancies of the lower female genital tract. Most are squamous cell carcinomas, and they arise through two broad pathways: one driven by high-risk human papillomavirus (HPV) and one independent of HPV, the latter often associated with chronic inflammatory skin conditions such as lichen sclerosus.

Definition

Vulvovaginal cancer refers to malignant neoplasms of the vulva and vagina, most commonly squamous cell carcinoma, arising either from HPV-associated intraepithelial precursors or, in the HPV-independent pathway, from differentiated precursor lesions linked to chronic dermatoses.

Scope

This entry covers the anatomy and main histology of vulvar and vaginal cancers, the dual HPV-dependent and HPV-independent carcinogenic pathways, their precursor intraepithelial lesions, and the epidemiologic pattern of these relatively rare tumors. It is reference material and does not provide individualized clinical management advice.

Core questions

• What are the two main carcinogenic pathways for vulvar and vaginal squamous cell carcinoma?
• What fraction of these cancers is attributable to HPV?
• How do precursor intraepithelial lesions differ between the HPV-associated and HPV-independent pathways?
• Why are vulvar and vaginal cancers comparatively rare, and who is most affected?

Key concepts

• Vulvar and vaginal squamous cell carcinoma
• HPV-associated pathway
• HPV-independent pathway
• Vulvar intraepithelial neoplasia (precursor lesions)
• Lichen sclerosus and differentiated precursors
• HPV genotype attribution
• Lower genital tract field effect

Mechanisms

Vulvar and vaginal squamous cell carcinomas arise by two distinct routes. The HPV-associated pathway parallels cervical carcinogenesis: persistent high-risk HPV infection produces high-grade intraepithelial lesions that can progress to invasive cancer (Schiffman, 2007). The HPV-independent pathway typically arises in older women against a background of chronic vulvar dermatoses such as lichen sclerosus, with differentiated precursor lesions and frequent TP53 alterations. Worldwide genotype-attribution data show that a substantial but not universal proportion of vulvar lesions are HPV-positive, with the proportion higher in intraepithelial than in invasive lesions and dominated by HPV-16 (de Sanjose, 2013). The same global program quantified HPV genotype attribution across the lower genital tract (de Sanjose, 2010).

Clinical relevance

Recognizing the dual pathways explains why some vulvovaginal cancers are HPV-preventable while others relate to chronic skin conditions, and why precursor lesions and dermatoses are relevant to understanding risk. This entry is educational reference material and is not a basis for individual diagnosis or treatment.

Epidemiology

Vulvar and vaginal cancers are among the less common gynecologic malignancies (Bray, 2024). HPV-associated tumors tend to occur in somewhat younger women and share risk factors with cervical disease, whereas HPV-independent vulvar cancers predominate in older women with chronic vulvar dermatoses. The proportion attributable to HPV varies by site and lesion grade (de Sanjose, 2013).

History

Vulvar and vaginal cancers were long understood mainly through surgical pathology. The recognition of HPV as a cause of much lower-genital-tract neoplasia, and subsequent large international genotype-attribution studies (de Sanjose, 2010; de Sanjose, 2013), clarified the dual HPV-dependent and HPV-independent pathways and connected a share of these cancers to the same preventable viral cause as cervical cancer.

Debates

Classification and terminology of vulvar precursor lesions

Distinguishing HPV-associated high-grade squamous intraepithelial lesions from HPV-independent differentiated precursors is important because the two carry different cancer risks and biology, and the terminology used to classify them has been revised over time.

Key figures

• Silvia de Sanjose
• Laia Alemany
• Xavier Bosch

Seminal works

• desanjose-2013-vulva
• desanjose-2010

Frequently asked questions

Are vulvar and vaginal cancers caused by HPV?

A meaningful fraction are HPV-associated, particularly intraepithelial precursor lesions, but many invasive vulvar cancers arise through an HPV-independent pathway linked to chronic skin conditions such as lichen sclerosus.

Are these cancers common?

No — vulvar and vaginal cancers are among the rarer gynecologic malignancies, far less frequent than cervical, endometrial, or ovarian cancer.