Introduction

Primary cancer of the vagina comprises approximately 3% of all malignant neoplasms of the female genital tract. Approximately 3000 cases are diagnosed annually in the United States, with almost 900 deaths . The incidence of in situ or invasive squamous cell cancer of the vagina is one per 100,000 women . Most vaginal cancers occur in postmenopausal or elderly women . When occurring in younger women, the disease seems to be etiologically related to cervical neoplasia, and thus human papillomavirus (HPV) dependent . Vaginal carcinoma is increasingly seen in younger women possibly due to infection with high-risk HPV infections.

Squamous cell carcinoma is the most common histologic type of cancer occurring in the vagina. Squamous cell carcinoma tends to occur more commonly in the proximal third of the vagina , especially the posterior vaginal wall. Adenocarcinoma may also arise in the vagina, the majority of these being clear cell histology, in young women exposed to diethylstilbestrol (DES) in utero. DES-associated tumors are mostly seen in the anterior upper vaginal wall. The peak occurrence is between the ages of 15 and 27 years (median 19 years) . These tumors are rarely seen today as DES is no longer used in pregnancy, and they are associated with a good prognosis. By contrast, non-DES-associated vaginal cancers (NDAV) occur in older women between 37 and 77 years (median 55 years), are more aggressive, and have high recurrence rates .

The main patterns of disease are an ulcerating or fungating mass or an annular constricting lesion. The vagina extends from the vulva upward to the uterine cervix. Cases should be classified as carcinoma of the vagina when the primary site of the growth is in the vagina. Tumors presenting in the vagina as secondary growths, from either genital or extragenital sites, should be excluded. A growth that has extended to the portio and reached the external os should be assigned as carcinoma of the cervix. A growth limited to the urethra should be classified as carcinoma of the urethra. Tumors involving the vulva should be classified as carcinoma of the vulva. Histologic verification of the disease should be carried out . Although primary vaginal cancer is rare, metastatic disease to the vagina is not uncommon. The vagina can be a common site of metastatic gynecological cancer, either by direct extension of cervical or vulvar tumors or through lymphatic or vascular metastases, as seen in endometrial cancer and gestational trophoblastic disease, respectively. Metastatic or direct extension of non-gynecologic tumors to the vagina can also occur from the urinary bladder, urethra, periurethral glands, rectum, and rarely the breast, lung, or other sites .

Most vaginal tumors are squamous cell carcinomas (83.4%), but adenocarcinoma melanoma, sarcoma, and other histologic types such as carcinoid, small cell, lymphomas, and undifferentiated have also been reported . Histologic grade has been classified as follows: Gx, grade cannot be assessed; G1, well differentiated; grade 2, moderately differentiated; and G3, poorly differentiated or undifferentiated .

In general, risk factors for in situ and invasive vaginal neoplasias are associated with the same risk factors as in cervical neoplasia: multiple lifetime sexual partners (five or more), early age at first intercourse (<17 years), smoking, alcohol, abnormal cytology, and prior hysterectomy . In a population-based study from Denmark 89% of women with squamous cell carcinoma of the vagina were high-risk HPV positive . Women treated for a previous anogenital cancer, especially carcinoma of the cervix, also have a high risk of developing vaginal cancer . Most cases of vaginal cancer are likely mediated by HPV infection, as with cervical cancer . An invasive squamous cell carcinoma occurring in the vagina >5 years after treatment for invasive squamous cell carcinoma of the cervix is assumed to be a new primary vaginal cancer . There is evidence that some high-grade vulvar and vaginal intraepithelial neoplasias are monoclonal lesions derived from high-grade or malignant cervical disease .

Some vaginal cancers may be preceded by vaginal intraepithelial neoplasia (VAIN), but their exact incidence is not known. A recent study showed that 89% of women treated experienced normalization, while the disease persisted or recurred in 11%; hence, lifelong surveillance is indicated . Another recent study showed that the risk of progression to cancer occurs in 3% of high-grade VAIN despite treatment . Prior pelvic radiation has also been considered a possible cause of vaginal cancer . A large study of follow-up of women after pelvic radiation showed a 30.5% incidence of secondary cancers, which included colorectal, anal, bladder, vulvar, and skin cancers, but no vaginal cancer was reported. In addition, the women who were followed up received radiation between 1968 and 1974 . How frequently secondary vaginal cancers occur after introduction of modern pelvic radiation techniques is not reported.

The majority of women with vaginal carcinoma present with vaginal bleeding, either postmenopausal or postcoital. Other symptoms include a watery, blood-tinged, or malodorous vaginal discharge, vaginal mass, urinary symptoms (frequency, dysuria, and hematuria), or gastrointestinal complaints (tenesmus, constipation, and melena). Bladder pain and frequency of micturition occur early in women with anterior vaginal cancers as the bladder neck is close to the vagina . Likewise, posterior tumors present with painful defecation. Pelvic pain from extension of disease beyond the vagina may occur. Many vaginal cancers are asymptomatic at the time of diagnosis but detected as a result of cytological screening for cervical cancer.

Routine screening for vaginal cancer following hysterectomy for benign disease is not recommended because these women are at an extremely low risk of developing vaginal cancer. However, women who have had a hysterectomy for invasive carcinoma cervix or treated for cervical intraepithelial neoplasia (CIN) may need a lifelong follow-up as vaginal cancers can occur as a result of persistent HPV infections, and also women treated with pelvic radiation are at a higher risk of developing secondary vaginal cancers .

Staging for vaginal cancers

Vaginal cancers are staged clinically, and the International Federation of Gynecology and Obstetrics (FIGO) staging system (2009) is the current system used for clinical staging . A few aspects need to be taken into account while staging vaginal cancer, some of which have been described in an earlier section. The anatomic limits of the vagina are from the vulva to the cervix. Only those cancers primarily confined to the vagina without extension to the cervix or vulva are considered primary vaginal cancers. Care should be taken to exclude metastatic growths to the vagina from extragenital sites and from genital structures such as cervix, uterus, vulva, etc. Histopathological confirmation with grade is an absolute necessity before staging.

Staging for vaginal cancers

Vaginal cancers are staged clinically, and the International Federation of Gynecology and Obstetrics (FIGO) staging system (2009) is the current system used for clinical staging . A few aspects need to be taken into account while staging vaginal cancer, some of which have been described in an earlier section. The anatomic limits of the vagina are from the vulva to the cervix. Only those cancers primarily confined to the vagina without extension to the cervix or vulva are considered primary vaginal cancers. Care should be taken to exclude metastatic growths to the vagina from extragenital sites and from genital structures such as cervix, uterus, vulva, etc. Histopathological confirmation with grade is an absolute necessity before staging.

Patterns of spread

To comprehend staging systems, a thorough understanding of the spread of vaginal cancers must be known. The most significant factor is anatomic spread, which reflects the extent of invasion into the surrounding tissues and metastatic spread to distant sites. Vaginal tumors may invade locally and disseminate by several routes. Direct extension occurs to pelvic soft-tissue structures: paravaginal tissues, parametrium, bladder, urethra, and rectum. Most tumors occur in the upper third of the vagina in the posterior wall. Tumors of the anterior vaginal wall may involve the vesicovaginal septum and urethra, while that of the posterior wall involves the rectovaginal septum and rectum.

Lymphatic drainage of the vagina is complex with an extensive communicating network in the submucosa and muscularis, ultimately uniting laterally and following the course of uterine vessels in the upper vagina and vaginal vessels in the lower vagina. Lymphatic spread occurs to the pelvic nodes first and rarely to para-aortic lymph nodes for tumors situated in the upper vagina. The upper vagina is drained by lymphatics to the pelvic nodes, including the obturator, internal iliac (hypogastric), and external iliac nodes. Lymphatics follow the course of the uterine vessels from the upper vagina. The lower third of the vagina drains to the groin nodes, both femoral and inguinal and lymphatics, and follows the vaginal vessels. Cancer in the mid-vagina may follow both lymphatic routes. External iliac lymph nodes may also be involved as in vulvar cancer. Because of the complexity of lymphatics in the vagina, bilateral involvement of the pelvic and inguinal nodes should be considered in upper and lower vaginal cancers, respectively . Hematogenous dissemination to other organs, including the lungs, liver, and bone, are late manifestations. The most common sites of distant spread include aortic lymph nodes, lungs, and skeleton.

Preoperative workup

The diagnosis of vaginal carcinoma may not be straightforward. Vaginal tumors may be detected incidentally as a result of cytologic screening for cervical cancer. Careful vaginal examination inspecting all vaginal walls to avoid missing high or lateral lesions must be carried out. Definitive diagnosis is accomplished by biopsy of the suspected lesion, which may appear as a mass, a plaque, or an ulcer. If a lesion is not visualized in the presence of abnormal cytologic results, colposcopy of the cervix and vagina must be performed with acetic acid followed by Lugol’s iodine staining. An office biopsy of abnormal areas of the vagina can be performed with either a punch (Baker’s or Keyes) or cervical (Tischler or Kervokian) biopsy forceps. It may be necessary to take multiple biopsies from various sites and vaginal levels. Local primary disease assessment requires a very careful gynecological examination, if possible by more than one physician, and it may need general anesthesia if the woman is in pain or discomfort. The site of the tumor within the vagina, the macroscopic characteristics (exophytic and/or ulcerative growth), and any regional spread outside the vagina must be carefully assessed and documented. The results of biopsy or fine-needle aspiration of inguinal/femoral or other nodes may be included in the clinical staging. The rules of staging are similar to those for carcinoma of the cervix.

Staging for vaginal cancer is based on clinical evaluation according to the FIGO system. This system allows the use of chest radiographs, examination under anesthesia with bimanual and rectovaginal examination, cystoscopy and/or proctoscopy (in patients with urinary or rectal symptoms), and intravenous pyelogram to evaluate for hydronephrosis.

Role of imaging modalities

Clinical appropriateness criteria for the management of vaginal cancer were developed after extensively reviewing the literature and applying well-established consensus methodology by the American College of Radiology . This consensus meeting was carried out as vaginal cancer is a rare disease and management is usually extrapolated from institutional reports. An approach to pretreatment evaluation and management is discussed in this report.

As in cervical cancer staging, FIGO encourages the use of advanced imaging modalities, such as computed tomography (CT), magnetic resonance imaging (MRI), and positron emission tomography (PET), to guide therapy, but the imaging findings may not be used to change or reassign the stage.

Magnetic resonance imaging

Given its superior soft-tissue resolution, MRI is particularly useful in delineating tumor size and extent, and it is more sensitive than physical examination in assessing paravaginal or parametrial involvement in women with cervical cancer . Primary vaginal tumors are best visualized on T2-weighted images and appear hyperintense . Visualization of the vaginal tumor is enhanced with the instillation of vaginal gel or a dry vaginal tampon, which distends the vaginal walls and allows for assessment of the tumor thickness . In stage I cancer, the carcinoma is limited to the vagina, and the paravaginal fat remains of high signal intensity on T1-weighted images. In stage II cancers, the normal low-signal-intensity vaginal wall cannot be identified, and the paravaginal fat is of abnormal low signal intensity on T1, best seen on axial images. In stage III cancers, the carcinoma extends to the pelvic sidewall with disruption of the normal low signal intensity of pelvic sidewall muscles on T2-weighted images. In stage IV cancers, the carcinoma extends beyond the true pelvis or invades the rectum or bladder with resulting loss of the normal low-signal-intensity rectal or bladder wall on T2-weighted images . The overall MR accuracy for all metastatic tumors involving the vagina has been reported to be as high as 92% . Both primary and metastatic tumors demonstrate similar imaging characteristics, usually of low to intermediate signal intensity on T1-weighted imaging and of intermediate to high signal intensity on T2-weighted imaging. A mucin-producing adenocarcinoma may demonstrate more high-signal components on T2 than squamous cell carcinoma . MR imaging is also useful in recurrent cancers. Vaginal cancer often recurs within 2 years of treatment of the primary tumor with surgery or radiotherapy .

PET/CT/Ultrasound

Data on the role of 2-fluoro-2-deoxy-D-glucose PET imaging in the management of vulvar and vaginal cancer are relatively sparse, but the modality appears to be of value in staging disease and is more effective than conventional diagnostic modalities with respect to detecting nodal metastasis in both malignancies . Both PET and PET–CT are useful for the diagnosis of recurrent cervical cancer . PET imaging has also been used as a diagnostic tool in the initial staging of cervical cancer . PET has shown a similar applicability for vaginal cancer, as its sensitivity for detecting primary vaginal tumors and involved inguinal or pelvic lymph nodes is greater than that of CT alone .

CT may be used to delineate the disease extent and evaluate for nodal and distant metastatic spread, although its sensitivity is modest compared to MRI and PET. CT is primarily used for three-dimensional (3-D) conformal treatment planning for radiotherapy delivery .

Transvaginal and/or transrectal sonography helps to delineate the precise morphology, location, and topography of the tumor in the vagina. It may be used in the initial workup of patient. However, evaluating the extent of spread, nodal metastases, and invasion of the bladder/rectum may not be optimal. Sectional imaging methods, in particular CT and MRI, are better suited for assessing the topography of the bladder, rectum, sigmoid, and intestine.