Vaginal cancer

INTRODUCTION — 

Primary cancer of the vagina is less common than uterine corpus, ovarian, and cervical cancer; in the United States, vaginal cancer is more common than vulvar cancer [1]. Most vaginal tumors are squamous cell carcinomas, but melanoma, sarcoma, adenocarcinoma, and other histologic types also occur (table 1). Although primary vaginal cancer is rare, metastatic disease to the vagina or local extension from adjacent gynecologic structures is not uncommon. As a result, the majority of vaginal malignancies are metastatic, often arising from the endometrium, cervix, vulva, ovary, breast, rectum, and kidney [2-5]. Vaginal metastases may occur by direct extension (eg, cervix, vulva, endometrium) or by lymphatic or hematogenous spread (eg, breast, ovary, kidney).

The clinical manifestations, evaluation, and therapy of invasive vaginal cancer are reviewed here. Vaginal intraepithelial neoplasia is discussed elsewhere. (See "Vaginal intraepithelial neoplasia".)

EPIDEMIOLOGY AND RISK FACTORS — 

Approximately 1 in 100,000 women will be diagnosed with in situ or invasive vaginal cancer (typically of squamous cell histology) [6,7]. The mean age at diagnosis of squamous cell carcinoma, the most common histologic type of vaginal cancer, is approximately 60 years, although the disease is seen occasionally in women in their 20s and 30s. Squamous carcinoma is more common as the age of the patient increases [6].

Most cases of vaginal cancer are likely mediated by human papillomavirus (HPV) infection, as with cervical cancer [8]. In a case-control study of 156 women with in situ or invasive vaginal cancer, over 50 percent were positive for antibodies to HPV subtypes 16 or 18 [9]. Thus, vaginal cancer has the same risk factors as cervical neoplasia: multiple lifetime sexual partners, early age at first intercourse, and being a current smoker [9,10].

There is evidence that some high-grade vulvar and vaginal intraepithelial neoplasia are monoclonal lesions derived from high-grade or malignant cervical disease [11]. This was supported by a retrospective cohort study of over 130,000 women in which women with cervical intraepithelial neoplasia 3 (CIN 3) had a significantly increased rate of developing vaginal cancer compared with all women within the same population and time period (standardized incidence ratio 6.8, 95% CI 5.6-8.2) [12]. A fourfold or greater increased risk was found until 25 years following CIN 3 diagnosis. Similarly, in a case series, 30 percent of all women with in situ or invasive vaginal disease had been treated for a prior anogenital tumor (primarily cervical), and 17 of 25 (70 percent) of invasive cancer biopsy specimens contained HPV 16/18 DNA. Similarly, in a series of 153 women with vaginal cancer treated at the Princess Margaret Hospital, 51 patients had a prior gynecologic malignancy; of these, 34 had cervical cancer [13]. (See "Vaginal intraepithelial neoplasia", section on 'Epidemiology' and "Vaginal intraepithelial neoplasia", section on 'Risk factors, pathogenesis, and prevention'.)

CLINICAL MANIFESTATIONS — 

Vaginal bleeding is the most common clinical presentation of vaginal cancer. Many women are asymptomatic.

Vaginal bleeding associated with vaginal cancer is typically postcoital or postmenopausal. Any unscheduled vaginal bleeding should be investigated to determine if the source is vaginal. A watery, blood-tinged, or malodorous vaginal discharge may also be present [14-16].

A vaginal mass may also be noted by the patient. Other potential symptoms are related to local extension of disease, urinary symptoms (eg, frequency, dysuria, hematuria), or gastrointestinal complaints (eg, tenesmus, constipation, melena) [14-16]. Pelvic pain from extension of disease beyond the vagina is present in 5 percent of patients.

As many as 20 percent of women are asymptomatic at time of diagnosis [17-19]. These vaginal cancers may be detected as a result of cytologic screening for cervical cancer or may be an incidental finding of a vaginal mass on pelvic examination.

DIAGNOSTIC EVALUATION — 

The key elements of the diagnostic evaluation are the pelvic examination, vaginal cytology, and vaginal biopsy.

History — The history should include questions about symptoms associated with vaginal cancer. (See 'Clinical manifestations' above.)

A gynecologic history should be taken, including a history of cervical or vulvar neoplasia, because history of other gynecologic malignancy could exclude the diagnosis of vaginal cancer. A medical, surgical, and medication history should be taken. This should include assessment of medical comorbidities that may impact treatment decisions.

Physical examination — A complete pelvic examination is performed. During the speculum examination, the vagina should be inspected thoroughly, including visualization of the entire circumference and the fornices by moving the position of the speculum. Any abnormal areas or masses should be biopsied. The bimanual examination should include palpation of the vaginal walls for masses and evaluation for other pelvic masses. The groins should be palpated to assess for enlarged lymph nodes.

The lesion may be missed on initial examination if it is small and situated in the lower two-thirds of the vagina. During visual examination of the vagina, the anterior and posterior blades of the speculum obscure this area, so the tumor may be missed unless the vagina is inspected as the speculum is removed or the lesion is palpated on bimanual examination.

Rectovaginal exam should also be performed to assess for parametrial and pelvic sidewall involvement and possible rectal involvement.

The posterior wall of the upper one-third of the vagina is the most common site of primary vaginal carcinoma. In one review, tumors occurred in the upper-, middle-, and lower-third of the vagina in 50, 20, and 30 percent of cases, respectively, with more than one-half of the tumors arising from the posterior vaginal wall [7,20].

The lesion may appear as a mass, a plaque, or an ulcer.

A focused physical examination is performed to assess for metastatic disease. In particular, the inguinal area should be examined for enlarged lymph nodes.

Vaginal cytology — A vaginal cytology specimen should be obtained during the pelvic examination. Twenty percent of vaginal cancers are detected incidentally as a result of cytologic screening for cervical cancer [21]. (See "Cervical cancer screening: The cytology and human papillomavirus report", section on 'Vaginal cytology'.)

Vaginal colposcopy — If a lesion is not visualized and there are abnormal cytology results, colposcopy of the cervix and vagina should be performed with acetic acid followed by Lugol iodine stain. In addition, if a gross lesion is visualized, some experts advise performing vaginal colposcopy to examine the rest of the vagina. (See "Colposcopy", section on 'Vaginal colposcopy'.)

Vaginal biopsy — An office biopsy of abnormal areas of the vagina can be done with either punch (Baker or Keyes) or cervical (Tischler or Burke) biopsy forceps. An examination under anesthesia may be necessary for examination and biopsy for women with significant vaginal stenosis that precludes an adequate office examination, in older adult women, or if cystoscopy and proctoscopy are necessary for clinical staging. (See 'Staging' below.)

Imaging studies — The only imaging studies that are part of the International Federation of Gynecology and Obstetrics (FIGO) staging for vaginal cancer are chest and skeletal radiography (see 'Staging' below). However, advanced imaging, such as computed tomography (CT), magnetic resonance imaging (MRI), and 18-fluoro-2-deoxyglucose-positron emission tomography and CT (FDG-PET/CT) can be helpful for treatment planning. MRI can assist in determining the primary vaginal tumor size and local extent [22,23]. Vaginal tumors generally are best seen on T2 imaging, and instilling gel into the vaginal canal, which distends the vaginal walls, often aids in visualizing and assessing the thickness of the vaginal tumor. FDG-PET can also be helpful for evaluating the primary vaginal tumor and abnormal lymph nodes [24].

DIAGNOSIS — 

Vaginal cancer is a histologic diagnosis based upon a vaginal biopsy and no history of a previous gynecologic malignancy that could better define the vaginal disease as a recurrent cancer as opposed to a new primary.

DIFFERENTIAL DIAGNOSIS — 

The differential diagnosis of vaginal bleeding requires first that bleeding from other genital tract sites is excluded. This can typically be accomplished with pelvic examination.

Vaginal bleeding may be caused by vaginal atrophy in menopausal women. In addition, vaginal infection, inflammation, or trauma may result in bleeding. Rarely, vaginal bleeding is due to a dermatologic condition (eg, toxic epidermal necrolysis). Bleeding from these etiologies may result in focal bleeding from a fissure or laceration, which is not generally found in vaginal cancer. Or, it may result in an ulcer or diffuse bleeding, which may also be found in vaginal cancer.

A vaginal mass may also be benign, including Gartner duct cysts, vaginal polyps, vaginal adenosis, endometriosis, or a dermoid cyst (rare) [25].

The differential diagnosis of female genital tract bleeding is discussed in detail separately. (See "Causes of female genital tract bleeding".)

HISTOPATHOLOGY — 

Primary vaginal tumors comprise a heterogeneous group of malignancies (table 1) that can be multicentric, thus, the entire vaginal mucosa is at risk.

Squamous cell carcinoma — Squamous cell carcinoma accounts for the majority of vaginal cancers. The mean age at diagnosis of squamous cell carcinomas is approximately 60 years, as noted above [26]. Grossly, these tumors may be nodular, ulcerative, indurated, endophytic, or exophytic. Histologically, they are similar to squamous cell tumors from other sites. Vaginal cancer is also associated with the human papillomavirus (HPV). However, vaginal epithelium is more stable than cervical epithelium, which undergoes constant metaplasia, and is thus less susceptible to oncogenic viruses [27]. (See 'Epidemiology and risk factors' above.)

Verrucous carcinoma is an uncommon variant of vaginal squamous cell carcinoma that is well-differentiated and has low malignant potential [28]. It usually presents as a large, warty, fungating mass that is locally aggressive but rarely metastasizes. Histologically, it is composed of large papillary fronds covered by dense keratin. Its deep margin creates a pushing border of well-oriented rete ridges in contrast to the well-demarcated margins of benign condyloma acuminata.

Adenocarcinoma — Adenocarcinomas represent nearly all of the primary vaginal cancers in women younger than 20 years old [26]. Adenocarcinomas may arise in areas of vaginal adenosis, Wolffian rest elements, periurethral glands, and foci of endometriosis. Clear cell variants are the best known type of adenocarcinoma, primarily because of their occurrence in young women who have been exposed in utero to diethylstilbestrol (DES) [15,29]. Grossly, clear cell carcinomas of the vagina usually present as polypoid masses, most often on the anterior wall of the vagina. Approximately 70 percent of patients are stage I at the time of diagnosis.

DES exposure can result in both cervical and vaginal clear cell adenocarcinomas. As an example, in one report of genital clear cell carcinomas in the Netherlands, vaginal tumors were detected in 33 percent of cases and cervical tumors were detected in 80 percent [30]. In addition, the incidence of invasive or in situ squamous cell cancer of the cervix is increased in women exposed to DES in utero. In one report from the Netherlands DES Information Center, the prevalence of cervical cancer was 5.4-fold higher than expected, based on age and period-specific prevalence rates from the Netherlands cancer registry [31].

In females exposed in utero to DES, the actual risk of developing clear cell adenocarcinoma through age 34 is only 1 in 1000, with the highest risk in those who were exposed before 12 weeks of gestation [32,33]. The median age at diagnosis of DES-related clear cell adenocarcinoma of the vagina is 19 years, with a range of 7 to 33 years [32]. Nonmalignant abnormalities can also occur; areas of vaginal adenosis and structural abnormalities of the uterus, cervix, or vagina are present in 45 and 25 percent of these women, respectively. Thus, it is recommended that women exposed to DES in utero have their first gynecologic examination at menarche with a careful assessment of the cervix and vagina, in addition to cervical and vaginal cytological examination. An examination of DES-exposed women should consist of colposcopic inspection of the cervix and vagina, yearly cytologic examination of the cervix and vagina, and careful palpation of the cervix and entire vaginal wall. (See "Outcome and follow-up of diethylstilbestrol (DES) exposed individuals".)

Most women with DES-associated clear cell vaginal cancer have good outcomes with primary radiation, surgery, or both [34,35]. On the other hand, adenocarcinomas that occur in non-DES-exposed women tend to have a poorer outcome [36].

Sarcoma — Leiomyosarcomas, endometrial stromal sarcomas, malignant mixed Müllerian tumors, and rhabdomyosarcomas are the major types of primary vaginal sarcomas. The most common of these is the embryonal rhabdomyosarcoma (sarcoma botryoides), a highly malignant tumor that occurs in the vagina during infancy and early childhood (mean age, three years) [37]. This sarcoma generally presents as soft nodules that fill and sometimes protrude from the vagina, resembling a bunch of grapes (botryoides comes from the Greek word botrys, which means "grapes") (picture 1). The prognosis for patients with this malignancy has improved with the use of multimodality therapy, including surgery, chemotherapy (vincristine, cyclophosphamide, and actinomycin D), and radiation [38]. (See "Rhabdomyosarcoma in childhood and adolescence: Epidemiology, pathology, and molecular pathogenesis".)

Melanoma — Melanomas arising on the vaginal mucosa are rare and are thought to originate from mucosal melanocytes in areas of melanosis or from atypical melanocytic hyperplasia [39]. The majority all of the reported cases have been in White women [39,40]. These malignancies occur at a mean age of approximately 60 years (range, 22 to 84 years). The presenting symptom is most commonly vaginal bleeding. They appear as a blue-black or black-brown mass, plaque, or ulceration, most frequently on the distal one-third of the anterior vaginal wall. Importantly, they are often nonpigmented. Primary malignant melanomas of the urogenital mucous membranes may have aggressive biologic behavior with a high rate of local failure and metastases. The five-year survival rate for vaginal melanomas is usually less than 20 percent [26,40-42]. (See "Locoregional mucosal melanoma: Epidemiology, clinical diagnosis, and treatment", section on 'Vulvovaginal melanoma' and "Radiation therapy in the management of melanoma", section on 'Mucosal melanoma'.)

STAGING

Staging system — The International Federation of Gynecology and Obstetrics (FIGO) and Tumor, Node, Metastasis (TNM) staging use a clinical staging system for vaginal cancer (table 2) [43,44].

Clinical staging is based upon findings from physical examination, cystoscopy, proctoscopy, and chest and skeletal radiography. The results of biopsy or fine-needle aspiration of the inguinal/femoral or other nodes may be included in the clinical staging. In addition to data used for clinical staging, information available from examination of the resected specimen, including pelvic and peritoneal lymph nodes, is to be used, as noted using the TNM system.

A review of five series, which included 1375 cases of vaginal cancer, reported the following distribution of patients by FIGO stage: stage I (26 percent), stage II (37 percent), stage III (24 percent), and stage IV (13 percent) (table 3) [45].

Routes of spread — Vaginal tumors may invade locally and disseminate by several routes:

●Direct extension to pelvic soft tissue structures: parametria, bladder, urethra, and rectum. Eventually, the bony pelvis may become involved.

●Lymphatic spread to the pelvic and paraaortic lymph nodes. The lymphatic drainage of the upper vagina communicates with that of the cervix, draining initially into the pelvic nodes and then the paraaortic nodes. By comparison, the lymphatics of the distal one-third of the vagina drain first into the inguinal and femoral nodes, and secondarily into the pelvic nodes.

●Hematogenous dissemination to other organs, including the lungs, liver, and bone; usually is a late manifestation.

TREATMENT — 

There are no randomized trials defining treatment for vaginal cancer, given its rarity. Instead, treatment approach is extrapolated from cervical and anal cancers. Additionally, treatment plans should be individualized depending on the location, size, and clinical stage of the tumor. This was illustrated by a single-institution review that showed tumor stage, site, and size are all important prognostic factors in patients with vaginal cancer [46]. In addition, treatment should take into account:

●Local anatomic constraints, which may not permit wide negative surgical margins without an exenterative procedure (eg, removal of the internal genitalia, supporting structures, rectosigmoid, lymphatic pathways, and bladder).

●Psychosexual issues, including the patient's desire to maintain a functional vagina.

Stage I tumors — For most patients with stage I tumors, we suggest surgical excision. However, radiation therapy (RT) may be appropriate for some patients, especially those with tumor >2 cm or lesions that involve the mid to lower vagina, including patients with:

●Tumors located in the mid to lower vagina – This is due to anatomic considerations, because surgical resection of tumors at this location frequently requires vulvovaginectomy in addition to inguinal node dissection to achieve negative margins and acceptable oncologic outcomes [47]. By contrast, surgical resection with preservation of anatomy is more feasible for patients with a lesion in the upper posterior vagina.

●Tumor >2 to 3 cm in diameter – We typically prefer RT to surgery, as it is difficult to achieve negative margins [48]. In addition, if surgical resection is attempted, it is difficult to get an adequate margin if the lesion is too close to the bladder or rectum.

Inguinal lymph nodes will also have to be assessed if the tumor is in the distal portion of the vagina.

Surgery — The surgical approach for vaginal cancer requires a radical hysterectomy, upper vaginectomy, and bilateral pelvic lymphadenectomy. If a hysterectomy has been performed previously, then radical vaginectomy and bilateral lymphadenectomies should be done to complete the surgical therapy. Patients with stage I vaginal cancer appear to have the best outcomes when treated surgically. In a literature review of patients with early-stage vaginal cancer, mean five-year survival rate of 77 percent, which was far better than those with later-stage disease, regardless of whether or not adjuvant RT was administered [6,49].

Surgical technique — Positioning of the patient is dependent on the surgical approach (ie, abdominal only, perineal only, combined abdominoperineal). For the abdominal (including laparoscopic) approach, the modified lithotomy position has the advantage of allowing access to the vagina from below during the procedure.

●Concurrent hysterectomy – A total abdominal or vaginal hysterectomy is usually performed concurrently in patients with an intact uterus who require total vaginectomy or upper partial vaginectomy. If two surgeons are available, a combined abdominoperineal approach facilitates the surgery.

To determine whether a total or partial vaginectomy is to be performed, the vagina is initially inspected and the margins of resection identified. Placing one or more sutures to mark the extent of planned resection may facilitate subsequent dissection, particularly if the procedure is being performed by the abdominal route. When small lesions are excised, the mucosa of the vagina can be closed using 3-0 polyglactin sutures.

In a combined abdominovaginal procedure, the vaginal part of the procedure is usually quicker than the abdominal, so the vaginal operator may delay this dissection until the uterus has been mobilized. An adjustable, self-retaining retractor system (eg, Lone Star) is often helpful for visualization of the vagina. The lower incision is made circumferentially around the vagina. Forceps are applied to the upper edge; applying gentle traction allows the operator to dissect the vaginal skin off underlying structures with scissors. Care must be taken anteriorly over the urethra because the tough underlying connective tissue makes dissection difficult. "Buttonholes" and tears of the vagina should be avoided. Dissection is continued as far up the vagina as can be reached easily. Bleeding may be reduced by the prophylactic injection of a vasoconstricting agent (eg, epinephrine diluted to 1 to 100,000 in saline) but, even then, bleeding from venous sinuses may require hemostatic suture.

The abdominal surgeon performs the first stages of a total abdominal or radical hysterectomy (see "Hysterectomy: Abdominal (open) route" and "Radical hysterectomy"). The broad ligaments are clamped and cut, the uterovesical fold of peritoneum is divided, and the bladder dissected off the adjacent upper vagina. The uterine arteries are divided and ligated. Further bladder dissection is aided by traction on the uterus, which stretches the vagina, together with gentle retraction of the previously dissected bladder (figure 1). Sharp dissection should be used to reduce bleeding and preserve tissue planes. The dissection should be continued laterally posterior to the distal ureter on each side. The peritoneum of the cul-de-sac (pouch of Douglas) is incised in the midline close to its attachment to the cervix and vagina, and the rectum is dissected gently away. This dissection can be completed readily with the assistance of the perineal surgeon.

Straight Zeppelin clamps are placed on the paravaginal tissues along the line of the vagina medial to the uterine artery pedicles. A scalpel is used to divide the tissues on the vaginal side, and the pedicles are transfixed and ligated. It is important to ensure that the ureters are not caught in the forceps or resulting pedicle. If the ureters cannot be clearly identified, they should be dissected off the parametrium after deroofing the ureteric tunnel, employing a technique similar to that used for radical hysterectomy (see "Radical hysterectomy"). Additional pedicles are clamped and cut until the lower limit of resection is reached. The vagina is opened anteriorly from above, with the perineal surgeon guiding the appropriate point of entry.

Following removal of the specimen, hemostasis is secured using electrocauterization and suture ligatures. The procedure now depends upon the extent of the vaginectomy and the need for vaginal reconstruction.

●Previous hysterectomy – If the patient has had a previous hysterectomy, total or partial vaginectomy can be performed separately, from above or below. There are proponents of both routes, but the abdominal approach has the advantage of allowing better visualization and dissection of the ureters, and facilitating a more complete excision of the vault and corners of the vaginal vault where intraepithelial neoplasia can remain hidden. Bowel adherent to the vault can also be more easily dissected free. A technique of vaginal resection performed from below for locally recurrent carcinoma of the cervix in patients who have previously undergone hysterectomy has been described [50], but care must be taken to include all vaginal skin in the angles and vault of the vagina.

In the abdominal approach, the vault of the vagina is identified with the aid of an instrument (eg, end-to-end anastomosis [EEA] sizer, gauze roll on a sponge holder) placed in the vagina to stretch up the vault. After incising the peritoneum over the vault, the bladder is dissected off the vagina. The posterior cul-de-sac peritoneum is incised, and the rectum is separated from the vagina and uterosacral ligaments. The course of the ureters may have been distorted as a result of previous surgery, and care must be taken to identify them. They may have to be dissected off, and away from, the upper vagina, as with a radical hysterectomy. Once the bladder, ureters, and rectum are clear, the dissection continues as described above. When vaginectomy is performed from above, use of a laparoscopic approach may be feasible and has the advantage of avoiding a larger incision [51].

●Closure – If no vaginal reconstruction is to be performed, the edges of the residual vagina may be run from above or below with continuous suture for hemostasis and left open, or closed with interrupted sutures. If there is only residual vaginal skin at the lower end no special closure is necessary, although it is sometimes possible to mobilize the residual skin and sew the anterior and posterior edges together to prevent sequestration of vaginal epithelium in which intraepithelial neoplasia may develop.

Following the extensive dissection, bladder integrity can be tested by distending it with saline, with or without dilute methylene blue.

●Radical vaginectomy – When performed concurrently with radical hysterectomy or parametrectomy, but not as part of an exenteration procedure, the distal ureters and bladder are dissected from the upper vagina, paracolpium, and parametrium. The rectum is separated from the vagina and uterosacral ligaments, and the uterosacral ligaments are divided as part of the radical hysterectomy. (See "Radical hysterectomy".)

A nerve-sparing technique to preserve the autonomic nerves to the bladder should be used whenever possible at the time of upper vaginectomy performed with radical hysterectomy [52].

The parametrial tissues are clamped and ligated. The bladder and ureters are then gently elevated by retractors and, while the uterus and vagina are stretched cephalad, the surgeon dissects the bladder distally off the vagina. The excisional part of the procedure is completed when the vagina is transected at the required level. If the whole vagina is to be removed, it is best for two surgeons to work together. While the abdominal surgeon dissects the ureters, bladder, and rectum away from the vagina, parametrium, and paracolpium, the perineal surgeon pushes the vagina medially and guides placement of the straight Zeppelin forceps onto these tissues by the abdominal surgeon (figure 2). The upper lateral tissues of the paracolpium are clamped, divided, and ligated until the vagina is freed on both sides. Hemostasis is then secured and vaginal reconstruction is performed, if planned.

A laparoscopic approach can be used for radical vaginectomy performed both at the time of radical hysterectomy [53] and at the time of total pelvic exenteration [54]. A robotic-assisted upper vaginectomy at the time of radical parametrectomy has been described [55] as has a laparoscopic approach to total vaginectomy for patients with primary vaginal carcinoma [56]. Although it is usually necessary to remove the upper 2 to 3 cm of the vagina at the time of radical hysterectomy for cervix cancer clinically confined to the cervix, preservation of bladder function can be facilitated by avoidance of injury to the autonomic nerves running in the dorsal and posterior part of the parametrium. Care should be taken to restrict resection to only the medial paracolpium tissues in the upper third of the vagina [57].

Vaginal reconstruction — The goals of vaginal reconstruction are to promote rapid wound healing, decrease pelvic dead space, restore the pelvic floor, and re-establish good sexual function and body image [58].

Vaginal reconstruction may be indicated in patients who have vaginal defects from treatment of benign disease, gynecologic cancer, or nongynecologic cancer invading, or in close proximity to, the vagina.

Vaginal reconstruction is best performed at primary surgery because the cavity is "ready" and does not require further dissection. Delayed procedures are more difficult because of scarring and soft tissue contracture. In older patients with severe uterovaginal prolapse, the vagina may be resected and the cavity obliterated [59].

If only vaginectomy has been performed, without removal of the bladder or rectum, a number of techniques are available. A split-thickness skin graft may be applied to the residual tissues, if sufficient, or to an omental tube. A full-thickness skin graft, a transposition skin flap (eg, pudendal thigh flap [60]), or a sigmoid colon or cecal neovagina are alternatives. Myocutaneous flaps are too bulky after nonradical surgery (see "Congenital anomalies of the hymen and vagina", section on 'Vaginal agenesis (Mayer-Rokitansky-Kuster-Hauser syndrome)'). The use of an acellular dermal graft has been reported [61].

Following vaginectomy in combination with exenteration, reconstruction of a neovagina with skin flaps is inadequate due to poor vascularity, dead space, and lack of pelvic support. Myocutaneous flaps bring bulky vascularized tissue into the pelvis, which reduces the chance of the empty pelvis syndrome developing. Possibilities include gracilis [62] and rectus abdominis flaps [63], with the latter being more reliable [64].

Radiation therapy — For some patients, radiation alone is adequate treatment. As an example, the outcomes with contemporary RT alone for early-stage vaginal cancer were shown in one series of 91 women treated at a single institution; for patients with stage I disease (n = 38), the two-year rates of overall survival, locoregional control rate, and distant metastasis-free survival were 96.2, 80.6, and 87.5 percent, respectively [20]. The use of brachytherapy is particularly important, as a Surveillance, Epidemiology, and End Results (SEER) study including over 2500 vaginal cancer patients found an improved median survival with treatment including brachytherapy compared with external radiation alone, 6.1 versus 3.6 years [65].

Technique — A total radiation dose of at least 70 to 75 Gy is generally recommend, with 45 to 50 Gy being delivered with external beam radiation and the additional radiation being delivered with intracavitary or interstitial brachytherapy radiation, depending on the thickness of the primary tumor. The external radiation should include the pelvic lymph nodes, vaginal tumor with a margin, vagina, and paravaginal tissues and inguinal lymph nodes if the vaginal tumor is in the lower half of the vaginal canal. Brachytherapy radiation should immediately follow the completion of external radiation. Residual vaginal tumors less than 5 mm thick can be treated with vaginal cylinder or similar applicator, while tumors thicker than 5 mm require an interstitial treatment for adequate dose and normal tissue sparing [66].

Stage II to IV tumors — Patients with more advanced disease are often not candidates for surgery. Given the relatively poor outcomes with treatment using RT alone, we often administer chemoradiation rather than RT. However, given the lack of high-quality data to inform the benefits of chemoradiation, RT is a reasonable alternative, particularly for patients who are not candidates for cisplatin-based chemotherapy for whatever reason.

Chemoradiation — In light of frequent problems with control of central tumor, the concurrent use of RT with chemotherapy (fluorouracil [FU] and/or cisplatin) is our preferred choice for patients with advanced vaginal cancer. Because of the poor prognosis with radiation alone (predominantly local failures) [67], we often proceed with the combined use of radiation and concurrent chemotherapy in women with high-risk disease (eg, stage III or IV, or tumor size larger than 4 cm) [68-70]. This is largely based on an extrapolation of the improved outcomes with chemoradiation for the treatment of locally advanced cervical cancer. (See "Management of locally advanced cervical cancer".)

There are low-quality data to support this approach specifically for vaginal cancer, largely limited to small retrospective series [68,70-72], which consistently show that locoregional control rates are high after chemoradiotherapy, and radiation-related long-term side effects do not seem worse compared with RT alone. However, whether chemoradiation provides a benefit to these patients is not entirely clear due to the limitation of the data, including that:

●Many of these studies enrolled women with stage I or II disease, which limits their applicability to these patients.

●No randomized, clinical trials have been performed due to the rarity of this disease.

In a single-institution series of 71 patients treated with definitive RT with (n = 20) or without (n = 51) concurrent chemotherapy, the addition of chemosensitization resulted in improvement in three-year disease-free survival (43 versus 73 percent) and three-year overall survival (56 versus 79 percent), and remaining predictor of disease-free survival on multivariate analysis [73].

Radiation therapy — For patients with stage II to IV disease, RT (with intracavitary or interstitial therapy, depending on tumor thickness) is a reasonable option for patients who are not deemed to be candidates for chemoradiation [67,68,74-77].

However, the outcomes following RT alone for more advanced-stage disease are not as good as they are for patients with stage I disease. In the same single-institution series discussed above, the two-year rates of overall survival, locoregional control rate, and distant metastasis-free survival stratified by stage were [20]:

●Stage II – 92.3, 64.7, and 84.6 percent, respectively

●Stage III – 66.6, 44.4, and 50 percent

●Stage IV – 25, 14.3, and 25 percent

Is there a role for surgery? — Surgery as a primary treatment modality is associated with less favorable outcomes than chemoradiation for patients with advanced disease. As an example, in one literature review, the mean five-year survival for patients with stage II, III, and IV disease was 52, 44, and 14 percent, respectively, following surgery, with or without adjuvant radiotherapy [49].

In addition, it is typically difficult to obtain negative margins in women with large or extensive lesions without compromise of the bladder or rectum.

Neoadjuvant therapy — For these patients, neoadjuvant chemotherapy followed by radical surgery is a promising alternative to RT. However, until more data become available, we consider it largely experimental.

The potential role of neoadjuvant therapy was shown in a small prospective study of 11 patients with stage II disease who were treated with three 21-day cycles of paclitaxel (175 mg/m²) and cisplatin (75 mg/m²) chemotherapy prior to attempted surgery [78]. Of these patients, 91 percent demonstrated a clinical response and all were able to undergo surgical resection. The pathologic complete response rate was 27 percent [78].

TREATMENT-RELATED COMPLICATIONS — 

Ten to 15 percent of patients treated for vaginal cancer will develop treatment-related complications [79]. Early complications include infection, delayed wound healing, loss of the flap due to necrosis, and small bowel herniation [58]. Later complications include rectovaginal or vesicovaginal fistulas, radiation cystitis or proctitis, rectal and vaginal strictures, and rarely, vaginal necrosis. The close proximity of the urethra, bladder, and rectum predisposes these structures to injury from surgery or radiation.

To decrease the degree of vaginal stenosis, women are encouraged to use a vaginal dilator following completion of vaginal reconstruction or radiation. Generally, we recommend that women start using the dilator one week after the completion of radiation and use it daily. Women who are regularly sexually active may use the dilator less frequently.

In women under 40 years of age who receive radiation for vaginal cancer, the risk of radiation-induced premature menopause is substantial (see "Fertility and reproductive hormone preservation: Overview of care prior to gonadotoxic therapy or surgery", section on 'Radiation-sparing approaches'). Attempts to reduce the toxicity of radiation exposure by moving the ovaries either behind the uterus or to the lateral pelvic walls (oophoropexy) have been variably successful [80,81]. We perform oophoropexy in selected cases.

RECURRENT DISEASE — 

Patients with a recurrence may be candidates for surgery. However, for those who are not candidates for surgery for whatever reason, treatment options are more limited due to the lack of prospective trials in this disease.

Surgery — For patients with a central recurrence and no other sites of disease, pelvic exenteration with or without vaginal reconstruction may be curative [82-84]. Exenteration may also be considered in patients with stage IVa disease, especially if a rectovaginal or vesicovaginal fistula is present. (See "Exenteration for gynecologic cancer".)

Chemotherapy — The role of chemotherapy in patients with recurrent or advanced vaginal cancer is unclear. Therefore, we administer chemotherapy to patients with recurrent vaginal cancer if there are no other alternatives (ie, surgery or radiation therapy [RT]) available, or if there is evidence of metastatic disease beyond the pelvis. However, patients and providers should be clear that there is a lack of high-quality data to inform whether there are benefits to treatment that justify the toxicities associated with systemic chemotherapy. In the absence of a clear benefit, these patients should be referred to palliative care as appropriate. (See "Benefits, services, and models of subspecialty palliative care".)

The Gynecologic Oncology Group experience in 26 patients with advanced disease suggested that cisplatin has insignificant activity in these patients, although the dose was subtherapeutic by modern standards (50 mg/m² every three weeks) [85]. Similarly, combination therapy with bleomycin, vincristine, mitomycin, and cisplatin appears to be relatively inactive in patients with advanced or recurrent disease despite significant activity in earlier-stage disease [86]. Anecdotal reports suggest activity for carboplatin; combination vinblastine, bleomycin, and cisplatin; and irinotecan and cisplatin in patients with early-stage squamous vaginal cancer [26,87,88]. However, there are no large series of these regimens to confirm activity in advanced disease.

POST-TREATMENT SURVEILLANCE — 

The optimal surveillance strategy has not been established and clinical practice is variable. We agree with the recommendations of the Society of Gynecologic Oncology (SGO) [89]:

●Review of symptoms and physical examination:

•For low-risk disease (early-stage, treated with surgery alone, no adjuvant therapy) – Every six months for the first two years, and then annually.

•For high-risk disease (advanced-stage, treated with primary chemotherapy/radiation therapy or surgery plus adjuvant therapy) – Every three months for the first two years; for years 3 through 5, every six months, and then annually.

●Cervical cytology (or vaginal cytology if the cervix has been removed) annually. However, the panel concluded that there was insufficient evidence for use of cytology for detection of cancer recurrence, but it may have value in the detection of other lower genital tract neoplasia.

●Routine use of imaging studies was not recommended. Computed tomography (CT) and/or positron emission tomography (PET) should be performed only if recurrence is suspected.

Vaginal colposcopy and biopsy are indicated if abnormalities are noted on physical examination.

Given the potential for other human papillomavirus (HPV)-related diseases, such as cervical, vulvar, and anal neoplasia, as well as multifocal vaginal disease, these patients should also be screened for these conditions.

Sexual dysfunction and alterations in body image are common after treatment and should be addressed during follow-up visits [90,91].

PROGNOSIS — 

The most important variable affecting prognosis is the stage at the time of presentation, reflecting the size and depth of tumor penetration [13,74,77,92-95]. As an example, data from a United States National Cancer Database showed an increased risk of mortality in women with vaginal cancer with stage II or greater disease and/or tumor size >4 cm (five-year survival 65 versus 84 percent in tumors ≤4 cm); mortality was 51 percent higher in women with melanoma compared with squamous vaginal cancer [95]. Rates of survival according to disease stage as noted in the latest International Federation of Gynecology and Obstetrics (FIGO) statistics are shown in the table (table 4).

The lower survival rates among women with vaginal cancer compared with those with cancer of the cervix or vulva may reflect the higher proportion of vaginal tumors initially diagnosed at an advanced stage and the potential for treatment complications that prevents aggressive therapy.

SOCIETY GUIDELINE LINKS — 

Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Vulvar cancer and vaginal cancer".)

INFORMATION FOR PATIENTS — 

UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topic (see "Patient education: Vaginal cancer (The Basics)")

SUMMARY AND RECOMMENDATIONS

●Histopathology – Primary vaginal cancer is usually a squamous cell carcinoma, but melanoma, sarcoma, adenocarcinoma, and other histologic types also occur (table 1). Metastatic disease to the vagina is not uncommon. (See 'Introduction' above and 'Histopathology' above.)

●Clinical manifestations – The majority of patients present with vaginal bleeding. Other symptoms may include a palpable vaginal mass, urinary symptoms (eg, frequency, dysuria, hematuria), gastrointestinal complaints (eg, tenesmus, constipation, melena), or pelvic pain. Many patients are asymptomatic. (See 'Clinical manifestations' above.)

●Diagnosis – Vaginal cancer is a histologic diagnosis based upon a vaginal biopsy. (See 'Diagnosis' above.)

●Staging – Vaginal tumors are staged clinically, based upon findings from physical and pelvic examination, cystoscopy, proctoscopy, and chest and skeletal radiography (table 2). (See 'Staging' above.)

●Treatment – Treatment planning should be individualized depending upon the location, size, and clinical stage of the tumor. (See 'Treatment' above.)

•For most patients with stage I tumors, we suggest surgical excision (Grade 2C). However, radiation therapy (RT) may be appropriate for some patients, especially those with tumor >2 cm or lesions that involve the mid to lower vagina. (See 'Stage I tumors' above.)

•For patients with more advanced disease (stage II to IV), we suggest chemoradiation rather than RT (Grade 2C). However, given the lack of clear benefits of chemoradiation, RT alone is an appropriate alternative. (See 'Stage II to IV tumors' above.)

●Complications – Up to 15 percent of patients will experience complications related to treatment, including sexual dysfunction and vaginal stenosis. Therefore, use of a vaginal dilator following radiation or chemoradiation is highly recommended. (See 'Treatment-related complications' above.)

●Recurrent disease – Patients with a recurrence may be candidates for surgery. For patients who are not candidates for surgery, systemic chemotherapy may be administered. However, patients should be informed that there is a lack of data to determine whether there are benefits to treatment that justify the risks of toxicity associated with chemotherapy. (See 'Recurrent disease' above.)

●Post-treatment surveillance – Following treatment for vaginal cancer, patients should be routinely evaluated by history and physical exam, plus annual cytology. We advise not performing any imaging studies as part of the surveillance of otherwise asymptomatic patients. (See 'Post-treatment surveillance' above.)

ACKNOWLEDGMENT — 

The UpToDate editorial staff acknowledges John C Elkas, MD, JD, who contributed to an earlier version of this topic review.