Human papillomavirus (HPV) is the primary cause of vaginal cancer, detected in roughly 75% of cases. The remaining cases arise from a mix of factors including prenatal drug exposure, weakened immunity, and prior gynecological conditions. Vaginal cancer itself is rare, accounting for less than 1% of all cancers, but understanding its causes helps clarify who faces higher risk.
HPV Is the Leading Cause
HPV drives the majority of vaginal cancers, particularly the squamous cell type, which is the most common form. In a registry-based study of 60 invasive vaginal cancer cases, HPV DNA was found in 75% of them. HPV 16 was by far the dominant strain, present in 55% of all cases. The second most common strain was HPV 33, found in 18% of cases. HPV 18, which plays a major role in cervical cancer, appeared in only about 2% of vaginal cancer cases. About 15% of HPV-positive cases involved multiple strains at once.
HPV is sexually transmitted and extremely common. Most infections clear on their own within a year or two. The problem arises when an infection persists for years, allowing the virus to gradually alter the DNA of vaginal lining cells. This slow process is why vaginal cancer typically develops in older women, with the highest rates appearing in those aged 85 to 89.
Precancerous Changes in Vaginal Tissue
Before vaginal cancer develops, the tissue often passes through a precancerous stage called vaginal intraepithelial neoplasia, or VAIN. These abnormal cells are graded by severity: low-grade changes (VAIN 1) are mild and frequently resolve without treatment, while high-grade changes (VAIN 2 and VAIN 3) carry a real risk of progressing to invasive cancer. Studies estimate that 2% to 12% of high-grade cases eventually become cancerous.
VAIN is most often caused by the same HPV strains responsible for vaginal cancer. It’s typically caught during routine screening, which is one reason continued Pap tests or HPV tests matter even after a hysterectomy, particularly if the hysterectomy was performed for cervical precancer or cancer.
DES Exposure During Pregnancy
Between 1940 and 1971, millions of pregnant women were prescribed diethylstilbestrol (DES), a synthetic estrogen intended to prevent miscarriage and premature labor. Decades later, researchers discovered that daughters born to these women faced a sharply elevated risk of a specific and unusual form of vaginal cancer called clear cell adenocarcinoma.
DES daughters carry about 40 times the risk of developing this cancer compared to unexposed women. Despite that dramatic increase, the absolute risk remains small: roughly 1 in 1,000 DES daughters developed it. DES was pulled from the market in 1971, so this risk factor applies to women born before the early 1970s. As this group ages, DES-related cases are becoming increasingly uncommon.
Weakened Immune System
A healthy immune system can usually suppress or clear HPV before it causes lasting damage. When immunity is compromised, particularly by HIV, the body loses that protective ability. Research on HIV-positive women shows a clear dose-response relationship: the lower a person’s immune cell count, the higher their risk of HPV-related cancers. Women with the most severe immune suppression faced a 7.7-fold increase in HPV-related cancer incidence compared to HIV-negative women, while those with moderate suppression had a 3-fold increase.
This pattern applies to other forms of immune suppression as well. Organ transplant recipients on long-term anti-rejection medications and people with autoimmune conditions requiring immunosuppressive therapy also face elevated risk, because their bodies are less equipped to fight persistent HPV infections.
Prior Hysterectomy for Cervical Disease
Women who have had a hysterectomy for cervical precancer or cervical cancer carry a slightly higher risk of developing vaginal cancer later. The logic is straightforward: the same HPV infection that caused cervical disease can also affect the vaginal tissue that remains after surgery. Research confirms that precancerous vaginal changes are more common in this group, though the actual cancer rate stays very low, around 0.01%. This is why some doctors recommend continued vaginal screening even after the cervix has been removed.
Smoking and Other Contributing Factors
Smoking is consistently listed as a risk factor for vaginal cancer, likely through the same mechanisms that link it to cervical cancer. Tobacco byproducts concentrate in cervical and vaginal mucus, where they can damage cell DNA and weaken the local immune response. This makes it harder for your body to clear HPV infections and easier for abnormal cells to take hold.
Age itself is a significant factor. Vaginal cancer becomes more common with each decade of life, and about 9% of all new cases are diagnosed in women between 85 and 89. A personal history of cervical cancer also raises risk, since the same HPV types target both areas.
Survival Rates by Stage
When vaginal cancer is caught while still confined to the vaginal wall, the five-year relative survival rate is 76%. If it has spread to nearby tissues or lymph nodes, that drops to 59%. For cancer that has reached distant organs, the rate falls to 24%. Across all stages combined, the five-year survival rate is 55%. These figures are based on women diagnosed between 2015 and 2021, so they reflect relatively current treatment approaches but not the very latest advances.
Because vaginal cancer is so rare and often develops slowly from precancerous stages, routine screening and HPV vaccination remain the most effective ways to reduce risk. The HPV vaccine targets the strains responsible for the vast majority of cases, making it one of the few cancers with a direct preventive tool available.