Most vaginal cancers are caused by persistent infection with human papillomavirus (HPV), the same virus responsible for cervical cancer. Beyond HPV, a handful of other factors can trigger the disease, including exposure to a synthetic hormone called DES, previous pelvic radiation, and rare genetic mutations. Vaginal cancer is uncommon overall, accounting for about 1 to 2 percent of gynecological cancers, but understanding its causes helps clarify who is most at risk and how to reduce that risk.
HPV: The Leading Cause
The majority of vaginal cancers are squamous cell carcinomas, meaning they develop in the thin, flat cells lining the vaginal wall. These cancers are driven by high-risk strains of HPV, particularly types 16 and 18. Other high-risk strains include types 31, 33, 35, and 39. HPV is extremely common, and most infections clear on their own within a year or two. In a small number of cases, the virus persists and causes cells to grow abnormally over many years, eventually leading to cancer.
The virus works by producing proteins that disable two of the body’s key tumor-suppressing mechanisms. Without those brakes, infected cells can accumulate DNA damage and multiply unchecked. This process is slow, typically unfolding over a decade or more, which is why screening can catch precancerous changes well before they become dangerous.
Precancerous Changes in the Vagina
Before squamous cell vaginal cancer develops, cells typically pass through a precancerous stage called vaginal intraepithelial neoplasia, or VAIN. The World Health Organization classifies these changes into two categories: low-grade lesions (VAIN 1), where cell abnormalities are mild, and high-grade lesions (VAIN 2 and VAIN 3), where abnormalities are more serious and closer to cancerous.
Low-grade lesions often resolve without treatment as the immune system clears the HPV infection. High-grade lesions carry a meaningfully higher risk. Studies estimate that 2 to 12 percent of high-grade VAIN cases progress to invasive vaginal cancer. That range depends on factors like immune health, whether the person smokes, and whether they receive treatment. When high-grade VAIN is detected, doctors typically treat it to prevent progression.
DES Exposure Before Birth
Between 1940 and 1971, a synthetic estrogen called diethylstilbestrol (DES) was prescribed to pregnant women to prevent miscarriage. It was later discovered that daughters born to women who took DES had about 40 times the normal risk of developing a specific type of vaginal cancer called clear cell adenocarcinoma. This cancer arises from glandular cells rather than the flat squamous cells involved in HPV-related cancers.
Despite the dramatic increase in relative risk, the absolute risk remained low: roughly 1 in 1,000 DES daughters developed clear cell adenocarcinoma. Early cases appeared in very young women, some in their teens. Later research showed the risk remained elevated into the 40s and 50s. DES is now classified as an endocrine-disrupting chemical. Animal studies suggest it causes heritable DNA changes during early development, alterations in chemical patterns on genes that can potentially affect subsequent generations. The youngest DES daughters were born in 1972, so this population is now over 50.
Previous Pelvic Radiation
Women who received radiation therapy for cervical cancer or other pelvic cancers face a higher risk of developing a secondary cancer in the vagina or surrounding pelvic area. A large population-based analysis found that cervical cancer patients treated with radiation had roughly 1.7 times the rate of secondary pelvic cancers compared to those who were not treated with radiation (4.51 cases per 1,000 person-years versus 2.62). Among patients with localized cervical cancer, radiation also shortened the time to a secondary pelvic cancer: a median of about 81 months in radiation patients compared to 131 months in those who didn’t receive radiation.
This doesn’t mean radiation therapy is the wrong choice. For many cervical cancers, radiation is lifesaving. But it does mean that women who’ve had pelvic radiation benefit from long-term monitoring of the vaginal area.
Rare Types With Different Causes
A small percentage of vaginal cancers are melanomas or sarcomas, which arise from entirely different cell types and have little to do with HPV.
Vaginal melanoma develops from pigment-producing cells. Unlike skin melanoma, it isn’t caused by UV radiation, since the vagina has no sun exposure. Instead, these cancers appear to be driven by specific genetic mutations. Research has identified mutations in a gene called SF3B1 in roughly 26 to 44 percent of vulvovaginal melanomas. Mutations in NRAS also appear at higher rates in vaginal melanomas compared to other genital melanomas. The well-known BRAF mutation common in skin melanoma is less frequent in genital melanomas. The primary risk factors for vaginal melanoma are advanced age (average diagnosis is over 60) and being white.
Vaginal sarcomas, which develop from muscle or connective tissue in the vaginal wall, are even rarer, and their causes are poorly understood.
Other Risk Factors
Several factors increase the likelihood of vaginal cancer without directly causing it. Smoking is one of the most significant. Tobacco byproducts concentrate in vaginal and cervical tissue, where they’re thought to damage cell DNA and weaken the local immune response against HPV. Women who smoke and have an HPV infection face a compounded risk.
A weakened immune system, whether from HIV, organ transplant medications, or other causes, makes it harder for the body to clear HPV infections. This extends the window during which the virus can cause precancerous changes. A personal history of cervical cancer or cervical precancerous lesions also increases vaginal cancer risk, since both conditions share HPV as a root cause. Age plays a role too: most vaginal cancers are diagnosed in women over 60, reflecting the long timeline from initial HPV infection to cancer development.
How HPV Vaccination Reduces Risk
Because HPV drives the majority of vaginal cancers, vaccination offers strong protection. In clinical trials, the HPV vaccine showed 100 percent efficacy against high-grade vaginal and vulvar precancerous lesions caused by the HPV types the vaccine targets, in women who completed the full vaccine series before exposure to the virus. Even in broader populations that included women who may have already been exposed, efficacy against high-grade vaginal or vulvar lesions associated with HPV 16 or 18 was 71 percent.
Real-world data from the United States backs this up. After HPV vaccination programs were introduced, vaginal cancer rates dropped among young women. Women aged 25 to 34 saw a 35 percent reduction in vaginal cancer incidence when comparing the period before vaccination (2002 to 2006) with the years after widespread uptake (2015 to 2019). The effects were even more dramatic for vulvar cancers in younger age groups, with reductions as high as 82 percent among women aged 15 to 24.
The vaccine is most effective when given before any HPV exposure, which is why it’s routinely recommended starting at age 11 or 12. It can be given up to age 26 for most people, and in some cases up to age 45 after a discussion with a healthcare provider about potential benefit.