Vulvar cancer develops through two distinct pathways: one driven by certain strains of human papillomavirus (HPV), and another linked to chronic inflammatory skin conditions. About a third of vulvar cancers are HPV-related, while the majority arise independently of HPV, typically in older women with longstanding vulvar skin disease. Understanding which pathway is involved matters because the risk factors, age of onset, and precancerous changes look different for each.
HPV-Related Vulvar Cancer
HPV is responsible for roughly 34% of vulvar cancers based on pooled data from multiple studies. The strains most commonly found in vulvar cancer tissue are HPV 16 and HPV 18, the same high-risk types linked to cervical cancer. Other strains detected include HPV 6, 11, 31, and 33. HPV causes cancer by inserting its genetic material into healthy cells and producing proteins that disable the cell’s natural tumor-suppression mechanisms. Over years or decades, this can lead to uncontrolled cell growth.
Before becoming invasive cancer, HPV-related vulvar disease typically passes through a precancerous stage called usual-type vulvar intraepithelial neoplasia (uVIN). These lesions tend to appear as raised, multifocal spots around the vaginal opening and outer labia. Because HPV-driven disease requires sustained infection, anything that weakens the immune system makes it harder for the body to clear the virus and increases the chance that precancerous changes will progress.
Chronic Skin Conditions and HPV-Independent Cancer
The majority of vulvar cancers, roughly two-thirds, develop without any HPV involvement. Instead, they arise from chronic inflammatory conditions of the vulvar skin, most notably lichen sclerosus. In women with lichen sclerosus, the lifetime risk of developing vulvar cancer is about 2.2%, compared to less than 0.5% in the general population. That means the condition roughly quadruples baseline risk. Lichen planus, a related inflammatory condition, carries a smaller increase at about 0.3%.
These conditions cause persistent inflammation and oxidative damage to the skin’s DNA over time. The repeated cycle of tissue breakdown and repair eventually produces genetic errors that accumulate. This pathway leads to a different precancerous stage called differentiated vulvar intraepithelial neoplasia (dVIN), which appears as poorly defined pink or white plaques on the vulvar skin. Unlike HPV-related precancerous changes, dVIN lesions are often difficult to spot and tend not to respond well to medical treatment, which is one reason HPV-independent cancers can be harder to catch early.
The Role of Genetic Mutations
At the molecular level, the two pathways leave different fingerprints. In HPV-negative vulvar cancers, mutations in the TP53 gene are the most common finding, appearing in the majority of tumors. TP53 normally acts as a brake on cell division, triggering repair or cell death when DNA is damaged. When it’s mutated, damaged cells are free to keep multiplying. Additional mutations in genes involved in cell growth regulation are also frequently seen in HPV-negative cases.
In HPV-positive cancers, the virus itself disables many of these same protective mechanisms through its own proteins rather than through direct DNA mutation. The end result is similar (uncontrolled cell growth) but the underlying biology is different, which is why researchers classify these as two fundamentally separate diseases sharing the same anatomical location.
Smoking and Vulvar Cancer Risk
Current smokers face more than three times the risk of vulvar squamous cell carcinoma compared to nonsmokers. One large study found an odds ratio of nearly 4.0 for current smokers, making tobacco one of the strongest modifiable risk factors. The exact biological mechanism isn’t fully established, but the leading theory involves local immune suppression. Nicotine and other cigarette smoke byproducts have been detected in cervical and genital mucus, where they reduce populations of immune cells that would normally patrol for abnormal or virus-infected cells. By weakening this local immune surveillance, smoking likely gives both HPV infections and precancerous changes a better foothold.
Weakened Immune System
People living with HIV have a higher risk of vulvar cancer, primarily because a weakened immune system is less able to clear HPV infections. The connection is straightforward: HIV and HPV share some common routes of transmission, so co-infection is more likely, and once HPV is present, the suppressed immune system struggles to eliminate it. The same principle applies to organ transplant recipients taking immunosuppressive medications. In both cases, the cancer may also be diagnosed at a more advanced stage and carry a worse prognosis, partly due to the ongoing immune impairment.
Age and Demographic Patterns
Vulvar cancer incidence has risen significantly among women aged 55 and older between 2000 and 2020, with both HPV-positive and HPV-negative cases contributing to the increase. The sharpest jump in HPV-positive cases occurred in the 55 to 64 age group, where incidence rose by 53%. HPV-negative cases in the same age group increased by 23%. Women over 65 also saw increases in both subtypes, though less dramatically.
In contrast, women under 55 actually saw a slight decline in both HPV-positive and HPV-negative cases over the same period. This shift toward older populations may partly reflect the aging of generations that acquired HPV before widespread vaccination, combined with longer life expectancy giving chronic inflammatory conditions more time to progress toward cancer.
Less Common Types
About 5% of vulvar cancers are melanomas rather than squamous cell carcinomas, and they have a distinct set of risk factors. Vulvar melanoma is considered multifactorial, with risk increasing with age, a family history of skin melanoma, and white ethnicity (white women develop vulvar melanoma at roughly three times the rate of other racial groups). Chronic inflammatory conditions like lichen sclerosus may play a role here as well. UV radiation has been suggested as an indirect contributor, though the vulvar skin receives minimal direct sun exposure. Vulvar melanoma is unrelated to HPV.
Paget disease of the vulva is another rare type that presents as red, scaly patches and is associated with underlying adenocarcinoma in some cases. Its causes are poorly understood compared to squamous cell types.