Vulvar and Vaginal Cancers and NIH Women's Health Research

Signs, Symptoms, and Risk Factors

Vulvar and vaginal cancers are rare forms of female reproductive tract cancers. Vulvar cancer accounts for about 4% to 8% of cases of gynecologic malignancies in the United States,^{1 - 4} with about 2.6 new cases diagnosed per 100,000 women per year.⁵ Most cases arise in the labia majora or labia minora, but in extremely rare cases, this cancer may occur in the clitoris or vestibular glands.^{1 , 4} Primary vaginal cancer only accounts for about 1% to 2% of cancers of the female genital system (with about 0.6 new cases diagnosed per 100,000 women per year) because most instances of vaginal cancer metastasize from other locations in the reproductive tract (e.g., cervix, endometrium) or other sites in the body (e.g., breast, pancreas).^{6 - 9}

Squamous cell carcinoma is by far the most common histologic subtype of vulvar and vaginal cancers, representing approximately 90% of cases for both. Less-common subtypes include vulvar melanoma; vulvar basal cell carcinoma; and adenocarcinoma, melanoma, sarcoma, and lymphoma of the vagina.^{6 , 10} Women with vulvar cancer often present with vulvar pruritus or pain, ulceration, or unusual vaginal bleeding or discharge.^{4 , 10 , 11} Likewise, abnormal vaginal bleeding or discharge are common signs of vaginal cancer, along with pelvic pain.^{6 , 7 , 12} However, the signs and symptoms of these cancers can vary depending on the subtype and the stage, and patients may be asymptomatic, especially during the early stages.^{4 , 6 , 7 , 10}

Two of the major risk factors for both vulvar and vaginal cancers are older age and long-term infection with high-risk human papillomavirus (HPV), especially HPV types 16 and 18.^{6 , 10 - 12} These HPV infections are also associated with an increased risk of cervical cancer; accordingly, a history of cervical cancer can increase the risk of vulvar and vaginal cancers. Other risk factors for vulvar and vaginal cancers include smoking and immunocompromising conditions (e.g., HIV infection).^{6 , 10 , 13 , 14}

Diagnosis and Treatment

Diagnosis for these cancers typically includes a medical history, a physical examination, HPV testing, a colposcopy, and a biopsy of any suspicious lesions. There are currently no routine screening guidelines for vulvar or vaginal cancers, and these types of cancer are often only discovered through abnormal cervical cytology or external genitalia examinations.^{4 , 6 , 15} The primary prevention strategy is the HPV vaccine, which protects against infections from a number of HPV types. Importantly, the HPV vaccine is most effective when administered at an early age, before exposure to the virus. The Centers for Disease Control and Prevention recommend routine HPV vaccination for preteens aged 11 or 12 years, although the series can be started as early as age 9. Vaccination is also recommended for those up to age 26 years who were not adequately vaccinated at a younger age.^{16 , 17} The HPV vaccine provides less of a benefit for older individuals,¹⁶ and it was not available for some of the generations of women who are currently at risk of HPV-related cancers.

The treatment for vulvar cancer generally involves surgical resection. A combination of surgery and adjuvant radiation and chemotherapy may be necessary for more advanced cases.^{2 , 18} Similarly, radiation therapy, either alone or with concurrent chemotherapy; surgery; or a combination of approaches are the standard therapies for early stage vaginal cancer. External-beam radiation therapy and brachytherapy may be employed in the later stages of the disease.⁷ Because vulvar and vaginal cancers are so uncommon, some of the recommendations for treating them are extrapolated from strategies that are used to treat other cancers (e.g., cervical cancer).^{2 , 7}

Ongoing Research

Major gaps remain in the scientific understanding of these cancers, and effective screening and diagnosis protocols and optimal treatment strategies are still being developed.

There is currently no protocol for performing routine screening for vulvar or vaginal cancers in women who do not have a history of gynecological cancers.⁹ More research is needed to develop this type of preventive care for high-risk women, especially immunocompromised women. To improve the current treatments for these cancers, some researchers are investigating new systemic treatment options for patients who present with metastatic disease, including the use of immunotherapies (e.g., pembrolizumab, nivolumab). Image-guided brachytherapy also remains an important area of research in vaginal cancer treatment.

The Center for Cancer Research (CCR) is an intramural research program at the National Cancer Institute (NCI) that is dedicated to improving the care for patients with cancer through translational and clinical research. As part of a Phase 2 clinical trial, CCR researchers are evaluating the use of autologous gene-engineered T cells called E7 TCR-T cells for the treatment of cancers that are associated with the HPV 16 type, including vulvar and vaginal cancers. E7 TCR-T cells target the HPV oncoprotein E7, which plays a key role in carcinogenesis. This trial will assess tumor response rates in patients with metastatic, recurrent, or refractory HPV-associated cancers who receive an infusion of E7 TCR-T cells. Administering E7 TCR-T cells could offer an alternative therapeutic approach to HPV-associated cancers that do not respond to surgery or radiation.¹⁹

NCI also provided support for the Dual Anti-CTLA-4 and Anti-PD-1 Blockade in Rare Tumors (DART) trial, a prospective, open-label Phase 2 clinical trial that is evaluating the use of the immune checkpoint inhibitors ipilimumab and nivolumab in people with rare tumors. In a subcohort of seven patients from this trial who had metastatic vaginal cancer, the combination of ipilimumab plus nivolumab showed durable clinical activity across multiple histologies. One patient achieved a complete response for nearly 15 months; another achieved a partial response that lasted for around 45 months.²⁰ Although this study was small, it provides evidence to support the use of immunotherapy as a potential treatment strategy in patients with vaginal cancer.