Squamous cell cancer of the vagina arises within its stratified nonkeratinized epithelium (Fig. 32-1). As with other cancers of the lower reproductive tract, human papillomavirus (HPV) has been closely linked with squamous cell vaginal cancer (Chap. 30). A systematic review found an HPV prevalence of 65 percent in samples from invasive vaginal cancer, and a 93-percent prevalence in high-grade vaginal dysplasia lesions. HPV 16 was the most common type and was present in 55 percent of vaginal cancer samplings (Smith, 2009). A retrospective cross-sectional study involving 31 countries found similar results (Alemany, 2014).
Sections showing invasive squamous cell carcinoma of the vagina. A. Invasive, well-differentiated squamous cell carcinoma of the vagina (bracket) invading the subepithelial stroma (×4). B. Invasive, well-differentiated squamous cell carcinoma of the vagina (×10). Invasive tumor is composed of irregular nests of malignant squamous cells with keratin pearls (arrow) and intercellular bridges. (Used with permission from Dr. Kelley Carrick.)
Because of this association with HPV infection, vaginal in situ and invasive squamous cell carcinomas share risk factors similar to those for cervical cancer. Some of these include multiple lifetime sexual partners, early age at first intercourse, and current cigarette smoking. Women with a vulvar or cervical cancer history are also at increased risk. This last association may stem from the field effect of HPV affecting multiple lower genital tract epithelia or may result from direct tumor spread.
Vaginal intraepithelial neoplasia (VaIN) is a precursor to invasive vaginal cancer, and approximately 2 to 3 percent of patients with VaIN will progress to invasive cancer (Dodge, 2001; Ratnavelu, 2013). The quadrivalent HPV vaccine is effective in preventing VaIN 2 and 3 associated with HPV 16 or 18 (Joura, 2007). It is possible that use of this vaccine will decrease invasive vaginal cancer rates in the future.
Vaginal bleeding is the most common complaint associated with vaginal cancer, although pelvic pain and vaginal discharge also may be noted. Less frequently, lesions involving the anterior vaginal wall may lead to dysuria, hematuria, or urgency. Alternatively, constipation may result from posterior wall masses. Most vaginal cancers develop in the upper third of the vagina. Moreover, of those with cancers, women who have had a prior hysterectomy are significantly more likely to have lesions in the upper vagina (70 percent) than those without prior hysterectomy (36 percent) (Chyle, 1996).
During pelvic evaluation in all women, the vagina is inspected as the speculum is inserted or removed. If a gross lesion is found, vaginal cancer usually can be diagnosed by punch biopsy in the office. Biopsy may be obtained with Tischler biopsy forceps (Fig. 29-16). An Emmett hook, one type of skin hook, may be useful to elevate and stabilize vaginal tissue during biopsy. Monsel paste is applied as needed for hemostasis. If a gross lesion is not detectable, vaginoscopy can guide directed biopsy. Bimanual examination assists in determining the tumor size, and rectovaginal examination is especially important for posterior wall lesions.
Once cancer is diagnosed, no specific laboratory testing other than that used generally for preoperative preparation such as complete blood count and serum chemistry panel is required.
Staging and Classification
Vaginal cancer staging is similar to that for cervical cancer and is completed clinically by physical examination and with the assistance of cystourethroscopy and/or proctosigmoidoscopy depending on tumor location. Chest radiography aids the search for metastatic disease (Table 32-1 and Table 32-2). If needed, general anesthesia can permit a more detailed pelvic examination for accurate staging. Proctosigmoidoscopy to a depth of at least 15 cm can detect local bowel invasion, whereas cystourethroscopy assists identification of bladder or urethral involvement.
TABLE 32-1Vaginal Cancer Evaluation ||Download (.pdf) TABLE 32-1 Vaginal Cancer Evaluation
|Vaginal biopsy |
|Physical examination |
|Endocervical curettage |
|Endometrial biopsy |
|Chest radiograph |
|Abdominopelvic CT scan, MR imaging, or PET CT a |
TABLE 32-2FIGO Staging Classification of Vaginal Cancer ||Download (.pdf) TABLE 32-2 FIGO Staging Classification of Vaginal Cancer
|Stage ||Characteristics |
|I ||The carcinoma is limited to the vaginal wall |
|II ||The carcinoma has involved the subvaginal tissue but has not extended to the pelvic wall |
|III ||The carcinoma has extended to the pelvic wall |
|IV ||The carcinoma has extended beyond the true pelvis or has involved the mucosa of the bladder or rectum; bullous edema as such does not permit a case to be allotted to stage IV |
|IVA ||Tumor invades bladder and/or rectal mucosa and/or direct extension beyond the true pelvis |
|IVB ||Spread to distant organs |
Computed tomography (CT) scanning, magnetic resonance (MR) imaging, and fluorodeoxyglucose-positron emission tomography (FDG-PET) may also be useful in treatment planning but are not classically used to determine disease stage. CT scanning can delineate the size and extent of many tumors (Fig. 32-2). However, if the extent of cancer expansion is unclear, MR imaging is the most useful radiologic tool available to visualize the vagina due to its superior soft tissue resolution. FDG-PET can also be selected to evaluate lymph node involvement and distant metastases. In one study, FDG-PET was more sensitive than CT for detection of abnormal lymph nodes (Lamoreaux, 2005).
Computed tomography (CT) scan reveals size and extent of vaginal mass (arrow).
The prognosis of vaginal squamous cell carcinoma has improved since the 1950s, when the 5-year survival rate was only 18 percent. Advances in radiation technology and earlier diagnosis are largely responsible for the improved 5-year survival rate, which now ranges from 45 to 68 percent for all stages (Ghia, 2011; Hellman, 2006).
The prognosis of vaginal squamous cell carcinoma depends primarily on FIGO stage (Fig. 32-3 and Table 32-2) (Frank, 2005; Peters, 1985). Other factors associated with poor prognosis include larger tumor size, adenocarcinoma cell type, and older age (Hellman, 2006; Tjalma, 2001; Tran, 2007). The 5-year disease-specific survival rate is 85 to 92 percent for women with stage I disease, 68 to 78 percent for those with stage II, and 13 to 58 percent for those with stage III or IV (Fig. 32-4) (Frank, 2005; Tran, 2007).
FIGO (International Federation of Gynecology and Obstetrics) staging of vaginal cancer.
Disease-specific survival stratified by International Federation of Gynecology and Obstetrics (FIGO) stage. (Reproduced with permission from Tran PT, Su Z, Lee P, et al: Prognostic factors for outcomes and complications for primary squamous cell carcinoma of the vagina treated with radiation. Gynecol Oncol 2007 Jun;105(3):641–649.)
Because of vaginal cancer’s rarity, data are limited to guide evidence-based treatment. Therefore, therapy is individualized and based on factors such as tumor type, stage, location, and size.
For stage I disease, both surgery and radiotherapy are options. However, surgery is preferred for most if negative surgical margins can be achieved. Surgery includes radical vaginectomy, radical hysterectomy (for women with an intact uterus), and pelvic lymphadenectomy for most tumors located in the upper third of the vaginal vault. A review of the National Cancer Data Base showed that women with stage I disease treated with surgery alone had a significantly improved 5-year survival rate compared with those treated with radiation (90 percent versus 63 percent) (Creasman, 1998). However, other reports have found no significant difference in disease-free survival rates in women with stage I disease treated with surgery compared with radiation alone (Stock, 1995). Radiotherapy may be delivered by external beam, with or without brachytherapy. Further, brachytherapy alone has been used successfully to treat selected small stage I lesions (Nori, 1983; Perez, 1999; Reddy, 1991).
Depending on circumstances and the treating clinician, primary surgery or radiation may be selected for stage II cancers. Stock and colleagues (1995) found a significant survival advantage at 5 years in those with stage II disease treated with surgery compared with those treated with radiation (62 percent versus 53 percent). Review of the National Cancer Data Base showed that the 5-year survival rate for women with stage II disease treated with surgery alone was 70 percent; with radiotherapy alone, 57 percent; and with a combination of surgery and radiotherapy, 58 percent (Creasman, 1998). However, other researchers have found no survival advantage from surgery compared with radiotherapy in stage II disease (Davis, 1991; Rubin, 1985).
Radiation is generally recommended if negative margins cannot be achieved surgically due to tumor location or size or to patient comorbidities that preclude surgery. If primary radiation is administered for stage II disease, a combination of external beam radiation and brachytherapy is the most common regimen. External beam radiation generally is given first, and depending on tumor response, brachytherapy is tailored to remaining disease. As discussed subsequently, adjuvant chemotherapy is often administered during radiation therapy.
For advanced disease, external beam radiation alone or in combination with brachytherapy is usually administered (Frank, 2005). Concurrent chemotherapy with cisplatin as a radiation sensitizer is generally also recommended.
Metastatic vaginal cancer is not curable, and treatment may include systemic chemotherapy or supportive hospice care. The most common sites of distant spread include liver, lung, and bone. The choice of chemotherapeutic agents is commonly extrapolated from cervical cancer data. For example, bevacizumab (Avastin) was approved by the Food and Drug Administration (FDA) in 2014 as a treatment for metastatic cervical cancer, in combination with paclitaxel and either cisplatin or topotecan. The addition of bevacizumab to these chemotherapy combinations improved overall survival length by approximately 4 months in women with metastatic cervical cancer (Tewari, 2014).
The numbers of women with vaginal cancer have been too small to make a prospective, randomized trial feasible. However, concurrent chemotherapy with cisplatin can be considered to benefit those with locally advanced vaginal cancer because of its proven efficacy in cervical cancer treatment. The characteristics of this agent are described in Chapter 27 and Figure 30-13. In a small series of vaginal cancer cases, adjuvant chemotherapy provided a 10- to 33-percent decline in the total radiation dose delivered (Dalrymple, 2004). Although not intending to show an improved survival rate with chemoradiation, the authors found that local control of tumor growth and survival rates were comparable with those who had received higher radiation doses alone. Smaller total radiation doses may lead to lower rates of vaginal stenosis and fistula formation.
In a Surveillance Epidemiology and End Result (SEER) database analysis of 326 patients with vaginal cancer treated with external beam radiation and/or brachytherapy between 1991 and 2005, a notable increase in sensitizing chemotherapy use was observed after the 1999 National Cancer Institute announcement confirmed the efficacy of chemoradiation in cervical cancer. Despite this increased use, the authors did not observe any survival advantage among those vaginal cancer patients who received chemoradiation compared with radiation alone (Ghia, 2011).
A recent phase II trial, which included 22 cervical cancer patients and three with stage II–IV vaginal cancer, demonstrated a 96-percent response rate for women given weekly cisplatin, radiation, and triapine, a ribonucleotide reductase inhibitor (Kunos, 2013). Larger studies are planned in cervical cancer patients.
In general, chemotherapy alone is ineffective to treat vaginal cancer, although data are limited. The Gynecologic Oncology Group (GOG) performed a Phase II trial evaluating 50 mg/m2 doses of cisplatin given every 3 weeks for advanced or recurrent vaginal cancer in 26 patients. Only one woman with squamous cell carcinoma achieved a complete response. Five of 16 patients with squamous cell carcinoma had stable disease, and 10 had cancer progression. Based on this trial, single-agent cisplatin is considered to have insignificant activity at that dose and schedule (Thigpen, 1986). To date, this has been the only prospective GOG trial evaluating chemotherapy alone for vaginal cancer.
Radiation to the primary tumor usually involves pelvic external beam with or without brachytherapy, and often concurrent platinum-based sensitizing chemotherapy depending on the stage and other factors described above. Additionally, groin radiation is effective in patients with palpable nodal metastases. Moreover, elective irradiation may be delivered to clinically negative inguinal lymph nodes if the distal third of the vagina is involved. In a retrospective review, Perez and colleagues (1999) found that of 100 women who did not receive groin radiation, if disease was confined to the upper two thirds of the vagina, then none developed groin metastases. However, 10 percent of patients with lower-third primary tumors and 5 percent with tumors involving the entire length of the vagina developed inguinal node metastases.
Treatment failures usually develop within 2 years of primary therapy completion. Thus, patients are typically examined every 3 months for the first 2 years and then every 6 months until 5 years of surveillance is completed (Pingley, 2000; Rubin, 1985). After 5 years following treatment, women can be seen annually. A Pap smear and pelvic examination with careful attention to the inguinal and scalene nodes are performed. Surveillance with CT or MR imaging is at the clinician’s discretion.
Disease recurrence should be confirmed by biopsy if further treatment is planned. Therapeutic options in women with central pelvic recurrence who have had prior pelvic radiation are limited. Pelvic exenteration can be considered if a patient is psychologically and medically fit to undergo radical surgery associated with high morbidity (Chap. 46). It is attempted only in those whose disease is limited to the central pelvis. Therefore, clinicians are alert to the triad of sciatic pain, leg edema, and hydronephrosis, which suggests pelvic sidewall disease. These women are not surgical candidates but can be managed with chemoradiation or with chemotherapy alone for women previously irradiated.
Survival after relapse is poor. In a review of 301 patients, 5-year survival was 20 percent for local recurrence and 4 percent for metastatic disease recurrence (Chyle, 1996).