Malignant diseases of the vagina are either primary vaginal cancers or metastatic cancers from adjacent or distant organs. Primary vaginal cancers are defined as arising solely from the vagina, with no involvement of the external cervical os proximally or the vulva distally. The importance of this definition lies in the different clinical approaches to the treatment of upper and lower vaginal cancer.
According to the International Federation of Gynecology and Obstetrics (FIGO), a vaginal lesion involving the external os of the cervix should be considered cervical cancer and treated as such; a tumor involving both the vulva and the vagina should be considered vulvar cancer.
About 80% of vaginal cancers are metastatic, primarily from the cervix or endometrium. Metastatic cancer from the vulva, ovaries, choriocarcinoma, rectosigmoid, and bladder are less common. These cancers usually invade the vagina directly. Cancers from distant sites that metastasize to the vagina through the blood or lymphatic system also occur, including colon cancer, renal cell carcinoma, melanoma, and breast cancer.
Although primary vaginal carcinoma is a rare gynecologic malignancy, its impact on women's health should not be underestimated, especially when considering the demographic increase in elderly women. As more women survive past age 60 years, physicians need to consider the likelihood that more women will present with vaginal cancer.
Because the 5-year survival rate of treated early stage vaginal cancer is significantly higher than that of vaginal cancer in the advanced stages, early detection is key to improving treatment outcomes. To improve outcomes of primary vaginal carcinoma, select referral oncology centers should see additional cases per month in order to plan appropriate randomized, prospective studies. This would increase the experience of any of these centers in treating primary vaginal carcinoma.
History of pelvic exenteration
In 1946, Alexander Brunschwig published the first cases of pelvic exenteration. In his first series, 5 of 22 surgical patients died from the operation itself. The original procedure consisted of connecting the ureters to the colostomy. In 1950, Bricker modified the procedure by isolating a loop of ileum, closing one end, anastomosing the ureters to it, and bringing the patent end out as a stoma.  Since then, several other modifications have improved the outcome of this procedure. Today, with vaginal reconstruction and continent vesicostomy, the procedure is accepted as a surgical treatment in selected cases.
Occurrence of vaginal cancer
Primary vaginal carcinoma is rare, constituting only 1-2% of all malignant gynecologic tumors. It ranks fifth in frequency behind cancer of the uterus, cervix, ovary, and vulva. The age-adjusted incidence in the United States is 0.6 per 100,000 population. The strict criteria used in defining vaginal carcinoma contribute to this low incidence.
In June 2006, the Advisory Committee on Immunization Practices (ACIP) voted to recommend the first vaccine developed to prevent cervical cancer and other diseases caused by HPV type 6, 11, 16, and 18. The vaccine is almost 100% effective in preventing precancerous lesions of the cervix, vulva and vagina, and genital warts caused by the HPV 6, 11, 16, and 18. The FDA has approved Gardasil for girls and women ages 9-26. In 2014, Gardasil 9 was approved to prevent disease from HPV type 6, 11, 16, 18, 31, 33, 45, 52 and 58.
The vagina is located in the true pelvis, which also contains the rest of the internal genital tract, the rectosigmoid, the bladder, the proximal urethra, and the pelvic portions of the ureters. The pelvic organs are partially covered by the peritoneum. The endopelvic fascia covers these organs and forms their supporting ligaments in conjunction with the pelvic vasculature and musculature.
The pelvic cavity is divided into anterior and posterior compartments by the transversely positioned broad ligament. The uterus is centered within the broad ligament and is attached to the round ligaments, which run anterolaterally within the broad ligament from the uterus to the pelvic wall.
Anterior and posterior cul-de-sacs
The anterior cul-de-sac, also known as the vesicouterine pouch, is located between the uterus and the bladder. It has small, lateral recesses known as the paravesical fossae. This pouch ends where the cervix and the bladder connect and does not extend down to the vagina.
The posterior cul-de-sac, known as the rectouterine pouch of Douglas, is located between the uterus (posteriorly) and the rectum (anteriorly). It is continuous with the pararectal fossae and contrary to the anterior pouch. It extends about 1-2cm down to the vagina, separating the cervix from the rectum.
The vagina itself is a muscular tube that extends from the cervix to the hymenal ring, penetrating the levator ani and the urogenital diaphragm. These latter structures provide vaginal support inferiorly. From the outermost to the innermost layers, the vagina is composed of an endopelvic fascia—which contains an abundant plexus of vessels, lymphatics, and nerves—as well as outer longitudinal and inner circular smooth muscle layers, submucosa, and mucosa.
Rectal and bladder pillars
The vagina is attached to the rectum posteriorly by the rectal pillars, while the bladder pillars provide anterior vaginal attachment to the bladder. During vaginal inspection with a speculum, the anterior and posterior sulci provide the anatomic landmark of the site of attachment of these pillars. These are most easily observed in nulliparous women.
The rectal and bladder pillars are paired, parallel, longitudinal, fibrovascular bundles containing extensive vascular and lymphatic networks between the vagina and the rectum and bladder, respectively. They both run the entire length of the vagina. The bladder pillars also contain the paravaginal tissues (paracolpium).
As it joins the lower end of the cervix, the upper end of the bladder pillar forms the vesicouterine ligament. This ligament forms a tunnel through which the ureters run inferomedially to reach the inferolateral portion of the bladder. The tunnel divides the vesicouterine ligament into anterior and posterior leaves. This anatomic structure is important during radical hysterectomy when careful dissection of the ligament is needed to mobilize the ureters. The rectal pillars receive the middle rectal arteries from the cardinal ligament.
The cardinal ligaments are wedge-shaped fibrovascular bundles containing the uterine, vaginal, inferior vesical, and middle rectal arteries and veins, as well as the lymphatic system. On each side, they run from the lateral aspect of the cervix to the lateral pelvic sidewall, traversing the pelvic plane at a 30° angle from the transverse pelvic diameter and dividing the paravesical and paravaginal spaces from the pararectal spaces.
On the pelvic wall, they insert on the endopelvic fascia and the hypogastric vasculature. The anterior part of the cardinal ligament is more vascular, while the posterior part is more fibrous and contains the autonomic system of the bladder and rectum.
An important landmark is the uterine artery that crosses the anterior-most portion of the cardinal ligament. The ureter enters the upper portion of the ligament beneath this artery (water under the bridge) and 1-2cm lateral to the isthmus of the uterus. The uterine veins cross below the ureters.
The uterosacral ligaments run from the posterolateral aspect of the cervix to the anterolateral part of the rectum. They are in close contact to the rectal pillars and straddle the posterior cul-de-sac.
Paravesical, pararectal, rectovaginal, and vesicovaginal spaces
Several avascular tissue planes are developed during pelvic surgery. The paravesical space is bordered by the symphysis pubis anteriorly, the cardinal ligaments posteriorly, the obliterated umbilical artery along the bladder medially, and the obturator internus laterally.
The pararectal space is bordered by the cardinal ligament anteriorly, the sacrum posteriorly, the rectum medially, and the hypogastric artery laterally. The rectovaginal space is bounded by the vagina anteriorly and the rectum posteriorly, while the rectal pillars form its lateral walls.
The vesicovaginal space is limited laterally by the bladder pillars, anteriorly by the bladder, and posteriorly by the vagina. To develop this space, the peritoneal reflection of the anterior cul-de-sac is entered.
The levator ani forms the major support of the pelvic structures and is the major component of the pelvic diaphragm. It is penetrated anteriorly by the rectum, vagina, and urethra. It forms the floor of all the planes discussed above.
Vaginal blood supply
The upper part of the vagina receives its blood supply from the uterine and the internal pudendal arteries, from which the vaginal artery arises. The inferior rectal artery and other branches arising from the internal pudendal artery supply the lower vagina. The vaginal venous plexus mainly drains into the pelvic wall through the parametrial veins, and to a lesser degree to the vesical and rectal plexuses.
Vaginal lymphatic system
Crossover of the vaginal lymphatic system is extensive. The middle to upper vagina communicates superiorly with the cervical lymphatics and drains into the pelvic obturator node, the internal and external iliac chains, and then the para-aortic nodes. The distal third of the vagina drains to the inguinal and then the pelvic nodes. The posterior wall lymphatics communicate with the rectal lymphatics and drain to the inferior gluteal, sacral, and rectal nodes.
The vagina stays in close proximity to the bladder and urethra anteriorly, which increases the risk of accidental injury to these structures during surgery. The sigmoid, on the other hand, reflects away from the posterior vaginal wall at its midpoint, facilitating an approach to the vagina posteriorly through the posterior cul-de-sac and a developed rectovaginal plane.
The etiology of vaginal cancer has not been identified. Note that vaginal cancer is not histologically homogeneous; several types of lesions exist, each with its own characteristics, age predilection, aggressiveness, and prognosis (see Table 1, below). This suggests that a single etiologic factor is unlikely. Although some histologic types of vaginal cancer have been associated with exposure to certain agents, so far no clear cause-and-effect relationship has been found between any of those agents and vaginal carcinoma.
Table 1. Most Common Forms of Primary Carcinoma of the Vagina (Open Table in a new window)
|Histologic Type||Cases of Vaginal Carcinoma||Peak Age||Spread||Characteristics|
|Squamous cell carcinoma||85-87%||60y||Local, blood, lymphatic||Most common in upper third of vagina|
|Verrucous carcinoma||Rare||60y||Local||Variant of squamous cell, cauliflowerlike, aggressive, radiotherapy contraindicated|
|Clear cell adenocarcinoma||9%||19y||Local, blood, lymphatic||Associated with in utero exposure to diethylstilbestrol (DES), tubulocystic pattern most favorable prognosis, late recurrence common|
|Melanoma||0.5-2%||60y||Local, blood, lymphatic||White women, lower anterior vaginal wall, size more prognostically significant than invasion, poor prognosis|
|Sarcoma botryoides (embryonal rhabdomyosarcoma)||Rare||3y||Local, blood, lymphatic||Most common vaginal cancer among children, grapelike mass, strap cells|
|Endodermal sinus tumor (yolk sac tumor)||Very rare||10mo||Local||Aggressive, alpha-fetoprotein (AFP) as marker|
|Leiomyosarcoma||< 2%||Wide range||Local, blood, lymphatic||Grade is most important prognostic factor, can be secondary to pelvic irradiation|
HPV and other infectious agents
The identification of HPV deoxyribonucleic acid (DNA) in squamous cell cancer cells by in situ hybridization (21%) and southern blot hybridization (56%) strongly suggests a possible role for HPV in the pathogenesis of squamous cell vaginal carcinoma. [2, 3]
HPV subtypes 16 and 18 have the highest oncogenic potential and are most commonly linked to dysplastic changes in the female genital tract. Because HPV is sexually transmitted, this association raises the question as to whether women who engage in high-risk sexual behaviors, such as sex with multiple partners, are at risk for developing vaginal cancer.
Another association that strengthens the link between HPV infection and vaginal cancer is the presence of a premalignant lesion in the vagina, known as vaginal intraepithelial neoplasia (VAIN). Aho and coworkers reported that 5-9% of patients treated for VAIN progressed to invasive carcinoma.  This suggested that VAIN may be a precursor to vaginal cancer even though the incidence of VAIN in the United States is 0.2-0.3 per 100,000 women  , which is less than the incidence of diagnosed vaginal cancer. This is because of the fact that women with VAIN are usually asymptomatic and that screening for VAIN is not recommended for the general population. Still, the true malignant potential of VAIN needs to be clarified.
Other infectious agents that appear to be associated with vaginal cancer are herpes simplex virus (HSV) and Trichomonas vaginalis. In 2000, Lee and colleagues reported a case of rapidly progressive vaginal squamous cell carcinoma in a young woman with a 2-year history of human immunodeficiency virus (HIV) infection.  They suggested that young women infected with both HIV and HPV are at increased risk for a more aggressive and less responsive vaginal cancer.
History of carcinoma
A history of cervical intraepithelial neoplasia (CIN), invasive cervical carcinoma, or invasive vulvar carcinoma has also been associated with vaginal carcinoma. Several studies indicate that up to 30% of patients with primary vaginal carcinoma have a history of in situ or invasive carcinoma that was treated at least 5 years before diagnosis.
Diethylstilbestrol (DES), a drug previously used in the first trimester to prevent pregnancy loss, has a strong association with clear cell adenocarcinoma of the vagina. Herbst and colleagues first observed this association in 1971,  which led to the discontinuation of DES that same year.
By 1987, the Registry for Hormonal Transplacental Carcinogenesis, established by Herbst and Scully, identified 524 women with clear cell adenocarcinoma, but only 60% had a history of DES exposure. Disease in the other 40% of patients with no history of DES exposure could be explained by recall bias or exposure to other unidentified factors. Women with in utero exposure to DES are at higher risk of developing adenocarcinoma than the general population. The estimated risk in these women is 1 in 1000.
Although 59% of women with vaginal cancer had a prior hysterectomy, in a 1986 report, Herman and colleagues demonstrated that when age and prior cervical cancer are controlled for, risk of vaginal cancer is not increased following hysterectomy for benign disease.  Note that hysterectomy by itself is not a risk factor; rather, women who underwent hysterectomy were poorly monitored.
In a 2004 publication, Hellman et al reviewed 341 cases of primary carcinoma of the vagina from 1956-1996 and suggested that the etiology of vaginal cancer may be age related.  In younger women, the disease occurred in the upper part of the vagina and seemed to be related to cervical dysplasia and HPV infection, while in older patients, the tumors were exophytic. There was significant correlation with late menarche, suggesting hormonal factors and trauma to the vagina as probable etiologies.
Long-term pessary use and chronic irritation of vaginal mucosa in women with procidentia have been associated with vaginal cancer. Other predisposing factors include cigarette smoking, immunosuppressive therapy, chemotherapy, and radiation therapy. Approximately 10% of women diagnosed with primary vaginal carcinoma have a previous history of irradiation to the pelvis.
Pukkala and colleagues reported an association between low socioeconomic class in Finland and an increased incidence of cervical, endometrial, and vaginal cancer. 
The presence of different stages of histologic differentiation in vaginal cancer—VAIN, carcinoma in situ, possible microinvasive carcinoma, and invasive cancer—suggests a continuum of transformation from less malignant to more invasive; this is similar to the continuum described for cervical cancer.
HPV and history of carcinoma
On the other hand, the significant association of vaginal cancer with a history of cervical or vulvar cancer suggests that the entire genital tract is at risk for squamous cell carcinoma once malignancy has occurred anywhere along the tract; this is a phenomenon known as the "field effect." 
HPV infection, which evidence indicates is associated with the pathogenesis of squamous cell vaginal carcinoma, could explain this phenomenon, because HPV is associated with cervical, vaginal, and vulvar disease.
Koyamatsu et al suggested that in cervical cancer, HPV 16 and 18 plays a common causal role, that in vulvar cancer, p53 gene mutations are the main carcinogenic cause, and that vaginal cancer has transitional characteristics between cervical and vulvar cancer. The investigators did a comparative analysis of the presence of HPV types 16 and 18 by polymerase chain reaction (PCR) assay and expression of p53 gene and Ki-67 antigen using immunohistochemistry in cervical, vaginal, and vulvar cancer.  There was no significant difference in overexpression of Ki-67 antigen among the 3 cancers.
Another explanation for the association between vaginal cancer and cervical and vulvar carcinoma is that an occult residual disease such as VAIN is trapped within the vaginal cuff posthysterectomy and goes unnoticed until it develops into invasive carcinoma. This possibility illustrates the theory of the field effect and HPV infection, because HPV has also been linked to VAIN. It also partially explains why vaginal cancer in women who have undergone a hysterectomy goes unnoticed until the patients present with advanced-stage vaginal carcinoma.
A third possibility for the association between vaginal cancer and carcinoma of the cervix or vulva is radiation carcinogenesis.
The pathogenesis by which DES may play a role in inducing clear cell adenocarcinoma is unclear. In 1972, Forsberg and colleagues  proposed the possibility of estrogen-induced maturation arrest of the müllerian ducts, and in 1984, Robboy and colleagues  suggested that atypical vaginal adenosis and atypical cervical ectropion of the tuboendometrial type might act as the precursors of clear cell adenocarcinoma of the vagina and cervix.
Most vaginal cancers occur in the upper third of the vagina. Reports are contradictory as to whether the anterolateral wall or the posterior wall is the more frequent site. Reports suggesting that the upper posterior wall is the most common site favor the hypothesis that irritating substances, such as vaginal secretions and semen, pool in the posterior fornix and cause chronic irritation, which could lead to induction of a carcinogenic process.
The proximity of the bladder anteriorly and the rectum posteriorly to the vagina predisposes these organs to direct invasion by the tumor. Lymphatic dissemination follows the lymphatic drainage of the vagina. The middle-to-upper vagina communicates superiorly with the lymphatics of the cervix and drains into the pelvic obturator node, the internal and external iliac chains, and then to the para-aortic nodes.
The distal third of vagina drains to the inguinal node and then the pelvic node. Posterior wall lymphatics communicate with rectal lymphatics and drain to the inferior gluteal, sacral, and rectal nodes. Hematogenous dissemination to distant sites includes the lungs, liver, bone, and skin. A submucosal lesion suggests that the malignancy is metastatic via the vaginal lymphatics.
The duration of symptoms in vaginal cancer averages 6-12 months before diagnosis, with a range of 0-11 years. Delay in the diagnosis of vaginal carcinoma is not uncommon; this is partially due to the rarity of the disease, as well as with delays in relating patient symptoms to a vaginal origin. As expected, the longer the delay, the more advanced the cancer once the diagnosis is made, resulting in a poorer outcome.
Painless vaginal bleeding is the most common symptom, accounting for 65-80% of all presentations. Bleeding is postmenopausal in about 70% of patients, which is consistent with the peak age of 60 years for squamous cell carcinoma, the most common type. Menorrhagia, intermenstrual bleeding, and postcoital bleeding have also been reported.
Vaginal discharge occurs in 30% of patients, while 20% of patients report urinary symptoms, which are caused by an anterior lesion compressing or invading the bladder, the urethra, or both. This causes bladder pain, dysuria, urgency, and hematuria.
About 15-30% of patients present with pelvic pain. Posterior lesions compress or invade the rectosigmoid, which causes tenesmus or constipation.
Only 10% of patients report a vaginal mass or vaginal prolapse. In 2000, Eltabbakh and coworkers reported a single patient who presented with a cystic pelvic mass arising from the posterior vaginal wall that mimicked an ovarian neoplasm. 
About 10-27% of patients are asymptomatic; diagnosis is made during routine pelvic examination. These patients tend to be caught at a much earlier stage than those presenting with symptoms, and their prognosis is much better.
Routine screening for vaginal carcinoma is not justified for all patients, because it is not cost effective. Women at risk, however, particularly those with a history of cervical neoplasia and risky sexual behavior, should receive a Papanicolaou test on a regular basis.
Screening after hysterectomy
Screening women with previous hysterectomy is controversial. In 1990, Manetta and colleagues suggested that women with previous hysterectomy should be counseled to continue their gynecologic cancer surveillance program.  They reported that 63% of patients who were diagnosed after the onset of their symptoms and who tended to have an unfavorable prognosis had undergone a prior hysterectomy.
In a 1996 report, however, Pearce et al reviewed 9,610 vaginal smears from 5,682 women who underwent hysterectomy for benign gynecologic diseases and found that the probability of an abnormal Papanicolaou smear in these women was 1.1%, with a 0% positive predictive value for detecting vaginal cancer.  Similarly, in 2000, Videlefsky et al  and Fetters et al concluded that routine vaginal cuff testing for most patients who underwent hysterectomy for benign conditions is not indicated.
The American College of Obstetricians and Gynecologists recommends discontinuing screening in women who have undergone hysterectomy for benign diseases who have no prior history of high-grade cervical dysplasia. Women with a history of CIN 2 or CIN 3 are at increased risk of developing recurrent dysplasia or carcinoma of the vaginal cuff; therefore, in these women and in those in whom a negative history of high-grade dysplasia could not be verified, screening after hysterectomy should continue. 
Screening in women exposed to DES
Young girls who were exposed to DES in utero should be routinely examined starting at puberty or at the age of 14 years. Examination includes cytologic screening of the cervix and vagina, followed by careful inspection and palpation of the genital tract. Staining with half-strength Lugol iodine helps to mark areas of adenosis. As long as cytologic findings are negative, colposcopy is unnecessary.
Visual Examination, Palpation, and Biopsy
During routine vaginal examination, the speculum blades should be rotated laterally in order to visualize the anterior and posterior vaginal walls. Inspect all vaginal mucosa while withdrawing the speculum. Vaginal cancer is multifocal and, although it is typically located in the vaginal apex, the disease may involve any part of the vagina. Visual inspection alone is not enough, and careful circumferential palpation of the entire vagina is required in order to feel any raised or hardened areas.
Vaginal lesions, particularly when small and located in the lower third of the vagina, are often missed during the first vaginal inspection because the blades of the speculum normally cover the anterior and posterior vaginal walls. This can lead to diagnostic delays. Frick and colleagues reported that about 19% of cases of vaginal cancer were missed on initial examination.
Other reasons for delay are the rarity of vaginal carcinoma (1-2%) and the attribution of patient symptoms to more common diseases, such as postmenopausal bleeding and endometrial cancer.
All visible lesions should be biopsied using either Eppendorf or Kevorkian punch biopsy forceps or similar instruments. Although the procedure is uncomfortable, local anesthesia is not recommended, because it is as uncomfortable as the biopsy itself. In elderly patients, particularly those with some degree of vaginal stenosis, the examination should be performed under general anesthesia to allow adequate biopsy.
Patients with carcinoma in situ or very early invasive carcinoma are usually asymptomatic. Diagnosis is made when a routine Papanicolaou smear identifies abnormal cells. If the cervix is present, then the physician must rule out cervical neoplasia, because cervical cancer is much more common than vaginal cancer.
After a cervical origin has been ruled out through colposcopy, then the physician should perform a vaginal colposcopy. Because this is a time-consuming and difficult procedure, especially in elderly patients, it should be done under general anesthesia. Lugol iodine solution can help to identify regions to obtain biopsies from; malignant cells lack glycogen and so, unlike healthy vaginal mucosa, do not stain dark brown.
Because healthy vaginal epithelium needs to be estrogenized in order to have sufficient glycogen, use of local estrogen cream for 1-2 weeks before examination may be helpful for postmenopausal patients. Estrogen cream should be discontinued 2 days prior to colposcopy.
Patients with previous hysterectomy and abnormal cytologic findings should also undergo vaginal colposcopy. If no lesion is observed and the abnormal cytology persists, then resecting the vaginal cuff may be considered because the lesion may be buried in the closed vaginal cuff at the time of hysterectomy.
As mentioned before, primary vaginal carcinoma is not homogeneous. It is classified into several histologic types, each with its own characteristics (see Table 1). The following are brief descriptions of the most common types.
Squamous cell carcinoma
Squamous cell carcinoma is by far the most common type, accounting for 85-87% of all cases of primary vaginal carcinoma. It generally occurs in women older than 50 years and peak incidence is in people aged 60 years; however, several cases have been reported in women as young as 18 years.
Grossly, it appears as an ulcerating lesion (50%), a fungating mass (30%), or an annular, constricting mass (20%). Secondary infections in an ulcerating tumor are common. Histologically, it resembles squamous cell carcinoma arising from the cervix, confusing the physician as to whether the lesion is cervical or vaginal in origin. This illustrates the need for a strict definition of primary vaginal carcinoma.
The most common site of occurrence is the upper third of the vagina. Because of the thin vaginal wall, squamous cell carcinoma tends to spread early by directly invading the bladder and rectal walls. It also metastasizes through the blood or lymphatics. In 1981, Al-Kurdi and coworkers reported that about 28.6% of patients had pelvic lymph node involvement upon diagnosis.  Squamous cell carcinoma can metastasize to virtually any organ; cutaneous metastasis was reported by Plataniotis and colleagues. 
Verrucous carcinoma is rare in the vagina and is more commonly observed in the vulva. It is observed in women older than 50 years and is considered a variant of squamous cell carcinoma. Its clinical and pathologic characteristics are similar to their vulvar counterparts.
On visual examination, verrucous carcinoma has a large, warty, cauliflowerlike appearance similar to that of condylomata acuminata, but the papillary fronds lack a central core of connective tissue.
Verrucous carcinoma is slow growing, locally aggressive, and rarely metastatic. Radiation is contraindicated because it has been implicated in potentiating this tumor to a more malignant phenotype.
Clear cell adenocarcinoma
This is the second most common type of primary vaginal carcinoma, accounting for about 9% of all cases. Unlike squamous cell carcinoma, clear cell adenocarcinoma manifests in patients at a very early age, usually after age 14 years, with peak incidence in people aged 19 years. As discussed previously, an association with intrauterine exposure to DES has been established. The estimated risk in the exposed population is about 1 in 1000.
Clear cell adenocarcinoma is thought to arise mainly from areas of vaginal adenosis but may also arise in wolffian rest elements, periurethral glands, and foci of endometriosis. In patients who have not been exposed to DES, ectopic cervical glands are a possible origin.
Grossly, vaginal adenosis appears as multiple cysts 0.5-4cm in diameter or as a diffuse, erythematous, granular mucosal lesion. The cancerous lesion appears polypoid, papillary, flat, or ulcerated.
Microscopically, 3 histologic patterns are predominant: tubulocystic, solid, and papillary. The tubulocystic pattern has the most favorable outcome.
The tumor can spread by local invasion or by hematogenous or lymphatic dissemination. Upon presentation, 70% of cases are stage I disease, but recurrence is frequent and can occur as late as 20 years after initial therapy. Secondary tumors from the colon, endometrium, cervix, breast, or ovary should be considered.
Vaginal melanoma is rare, accounting for 0.5-2% of all primary vaginal cancers. Fewer than 150 cases have been reported. Vaginal melanoma tends to occur in white women; it usually manifests in women older than 50 years, with peak incidence in women aged 60 years.
Melanoma is most commonly found in the lower anterior vaginal wall. Grossly, it appears as blue or black, soft, mucosal or submucosal nodules, but it may also be nonpigmented and is frequently ulcerated, mimicking squamous cell carcinoma. Histologically, it is similar to cutaneous melanoma, except that it is more invasive.
Melanoma is thought to arise from melanocytes, which are present in 3% of healthy vaginas. The source probably is an aberrant melanocyte migration or melanocyte metaplasia.
The Breslow and Clark systems are used as part of staging; however, because deep invasion is invariably present upon presentation, tumor size, rather than depth, is a more significant prognostic factor. Tumors tend to recur locally, and metastasis to the lungs is common.
Sarcoma botryoides (embryonal rhabdomyosarcoma)
Although this tumor is rare, it is the most common vaginal cancer in children. It manifests in girls younger than 8 years, with peak incidence in girls aged 3 years. Sarcoma botryoides is highly malignant and very aggressive. Initially, it tends to invade locally; it then metastasizes to the inguinal, pelvic, retroperitoneal, and mediastinal lymph nodes, as well as to the lungs, pericardium, liver, kidney, and bones.
Grossly, sarcoma botryoides occurs in 2 structural forms: solid and multicystic grapelike. (The term botryoides comes from the Greek word botrys, which means grapes.) It originates in the subepithelial layers and expands outward to fill the vaginal cavity. Histologically, it is characterized by a loose, myxomatous stroma with malignant pleomorphic cells and characteristic cross-striated rhabdomyoblasts (strap cells), staining positively for muscle markers. Patients most commonly present with abnormal vaginal bleeding; they occasionally present with a polypoid mass protruding from the introitus.
Endodermal sinus tumor (yolk sac tumor)
This type of adenocarcinoma is very rare. It is classified as a germ cell tumor and most commonly occurs in the ovary. It manifests in patients at a very young age, usually girls younger than 2 years, and peak incidence is in babies aged 10 months. To date, about 20 vaginal cases have been documented. Characteristically, it secretes alpha-fetoprotein (AFP), which is frequently used as a marker of recurrence.
This tumor of smooth muscle origin is rare and accounts for fewer than 2% of all primary vaginal cancers. It occurs over a wide patient age range, from 25 to 86 years, and may follow radiation therapy to the genital tract.
Grossly, vaginal leiomyosarcoma manifests as a bulky submucosal lesion, mainly in the upper vagina. Histologically, it is similar to leiomyosarcoma of the uterus. Tavassoli and Norris established the following microscopic criteria to diagnose leiomyosarcoma of the vagina: moderate to marked atypia with 5 or more mitotic figures per 10 high-power fields (HPF). Histologic grade is the most important predictor of outcome. 
Treatment Determination and Staging
Once the diagnosis of cancer is established, staging should proceed to determine the best treatment. As with the other gynecologic cancers, staging is done according to FIGO classification. For vaginal cancer, staging is clinical and based on findings during general examination, pelvic examination, cystoscopy (for anterior wall tumors), proctoscopy (for posterior wall tumors), and chest radiography. If the patient reports bone pain, then skeletal radiography should be performed to rule out bone involvement.
Computed tomography (CT) scanning or magnetic resonance imaging (MRI) of the upper abdomen and pelvis are not FIGO recommendations, although they are frequently performed because they help in establishing the presence of enlarged lymph nodes, ureteral compression, hydronephrosis, and liver metastasis. Oudouxa et al suggested that F-18 fluorodeoxyglucose positron emission tomography (FDG-PET) scanning provides a more accurate assessment of the extent of disease in a patient with malignant melanoma as compared with conventional methods. 
Baseline levels of carcinoembryonic antigen (CEA), cancer antigen–125 (CA-125), and squamous cell carcinoma antigen are recommended because they are elevated in patients with some carcinoma types.
Evaluation for origin and metastasis of adenocarcinoma
Patients in whom adenocarcinoma is diagnosed should undergo thorough exploration for possible metastasis, mainly in the uterus, cervix, ovary, and colon. In these patients, a fractional dilatation and curettage is indicated to rule out endometrial origin. A barium enema with either sigmoidoscopy or colonoscopy is also indicated to rule out colonic origin. In addition, mammography, chest radiography, and CT scanning of the abdomen or pelvis should follow. CA-125 should be taken as baseline for post-treatment follow-up.
Surgical staging is not usually required, but it is performed in selected premenopausal patients prior to radiotherapy. In these patients, pretreatment laparotomy allows the transposition of at least 1 ovary away from the field of radiation. It also allows for better assessment of the extent of the disease through dissection of the pelvic lymph nodes. In addition, for patients scheduled for exenterative surgery, an exploratory laparotomy is required to rule out metastasis or lateral spread to the pelvic sidewall before proceeding with exenteration.
FIGO staging classification of vaginal carcinoma is as follows:
Stage 0 - Carcinoma is carcinoma in situ (VAIN)
Stage I - Carcinoma is limited to the vaginal wall
Stage II - Carcinoma involves subvaginal tissue but has not extended to the pelvic wall
Stage III - Carcinoma extends to the pelvic wall
Stage IV - Carcinoma extends beyond the true pelvis or involves mucosa of bladder or rectum; bullous edema as such precludes inclusion in the stage IV classification
Stage Iva - Carcinoma invades bladder or rectal mucosa or directly extends beyond the true pelvis
Stage IVb - Carcinoma spreads to distant organs
Radiation Treatment and Chemotherapy
Primary vaginal cancer is so rare that large, randomized, controlled treatment trials are nearly impossible and, therefore, most treatment novelties are adopted from those for more common cancers, such as cervical and anal cancers. 
In 1999, the National Cancer Institute issued a clinical alert as to the importance of adding cisplatin-based chemotherapy concurrently with radiation in the treatment of locally advanced cervical cancer. This chemoradiation regimen led to significant improvement in progression-free and overall survival.  Since then, chemoradiation therapy has largely replaced radiation alone in the treatment of primary vaginal cancer.
By analyzing data from 17 population-based cancer registries participating in the Surveillance, Epidemiology, and End Results (SEERS) program, Shirag et al noted a survival advantage in women treated for primary vaginal cancer that was temporally related to the advent of chemoradiation. 
A retrospective study by Greenwalt et al indicated that radiotherapy is a very effective definitive treatment for primary vaginal carcinoma. In the study, 71 individuals with primary vaginal adenocarcinoma or squamous cell carcinoma underwent either external-beam radiotherapy plus brachytherapy (93% of patients) or brachytherapy alone (7% of patients); median follow-up was 6.24 years. For patients with stage I disease, the cause-specific survival rate at both 5 and 10 years was 96%, while for stage II patients, the 5- and 10-year survival rates were 75% and 68%, respectively, and for stage III patients, 69% and 64%, respectively. The survival rate for stage IVA patients at both 5 and 10 years was 53%. 
As evaluated for all patients in the study, distant metastasis-free survival rates at 5 and 10 years were 87% and 85%, respectively. Despite the efficacy of radiotherapy for primary vaginal carcinoma, however, the investigators warned that the treatment carries a high risk of severe complications. 
Indications and Contraindications for Surgery
Consensus as to the proper treatment for vaginal carcinoma is lacking, mainly because of the rarity of the disease. The most commonly used treatment modality is radiotherapy. Surgery, with or without concomitant radiation therapy, is indicated in the following conditions:
Squamous cell carcinoma - Stage I disease in the upper posterior vagina; stage IVa disease, particularly in the presence of a rectovaginal or vesicovaginal fistula; central recurrence after radiotherapy; ovary transposition in young patients prior to radiotherapy
Clear cell adenocarcinoma - Although the etiology is different, the presentation may be similar to that of squamous cell carcinoma.
Verrucous carcinoma - Radiation therapy is contraindicated because it has been implicated in potentiating this tumor to a more malignant phenotype; therefore, surgery is the only treatment
Other cases - Melanoma, sarcoma, embryonal rhabdomyosarcoma, endodermal sinus tumor
Metastasis and extension to pelvic sidewalls are contraindications for exenteration. Microscopic pelvic node involvement is more of a controversy than a contraindication, and patients with positive pelvic nodes and no other poor prognostic factors can be considered candidates for exenteration. Involvement of both the pelvic and para-aortic nodes should warrant aborting the surgery.
Squamous Cell Carcinoma Surgery
Stage I disease
Stage I disease involving the upper posterior vagina is treated by radical hysterectomy, partial vaginectomy, and bilateral pelvic lymphadenectomy. Lymphadenectomy is required to ensure that metastatic disease is not present.
If the patient had a previous hysterectomy, then a radical upper vaginectomy with pelvic lymphadenectomy is performed after the paravesicular and pararectal spaces are developed to avoid injury to the bladder and rectum, respectively. Each ureter is also dissected out to its point of entry into the bladder.
If the lesion is multifocal or if it extends to the lower third of the vagina, inguinal lymphadenectomy should also be performed, and a total vaginectomy is required. If the depth of the invasion is questioned during the operation, then a frozen section from the margins should be taken to ensure that tumor resection was adequate.
In general, tumors of the upper posterior wall are more operable because the sigmoid reflects away from the posterior vaginal wall while the entire length of the anterior vaginal wall stays in close proximity to the bladder. A lower vaginal lesion can be treated with radical hemivulvectomy and lower vaginectomy with bilateral inguinal node dissection. Radiation therapy is commonly used as an alternative to surgery.
Stage II, III, and IV disease
Stages II and III are treated with radiation therapy. In premenopausal patients, a pretreatment laparotomy is performed in order to transpose the ovaries away from the field of radiation and to resect any enlarged lymph nodes. If the patient has a central recurrence with no signs of metastasis after radiotherapy, then pelvic exenteration is the only option.
Patients with stage IVa disease have the option of radiation therapy or pelvic exenteration. The latter is highly recommended if a rectovaginal or vesicovaginal fistula is present. Stage IVb is a contraindication for surgery.
Clear Cell Adenocarcinoma Surgery
Therapeutic considerations are very similar to those for patients with squamous cell carcinoma, although most patients are young, and every effort should be made to preserve functional ovaries and a functional vagina. Surgery is the primary treatment modality.
In stage I and early stage II disease, radical hysterectomy, pelvic lymphadenectomy, and vaginectomy with split-thickness skin graft have been successful.
Alternatively, in 1987, Senekjian and colleagues reported a 5-year survival rate of 92% for patients with very early, small lesions treated by wide local excision, laparotomy for retroperitoneal lymphadenectomy, and local irradiation to the immediate adjacent tissues.  The best candidates are patients with tumors of less than 2cm in diameter, a predominant tubulocystic pattern, and a depth of invasion of less than 3cm.
If radiation is used as the sole treatment, then transposition of at least 1 ovary up into the paracolic gutter beyond the radiation field should be done with pelvic lymph node dissection.
Local excision without radiation is not recommended, since Herbst and colleagues reported that 16% of patients with stage I disease have positive pelvic nodes. Pelvic exenteration is done for central recurrences after primary irradiation.
Matthews et al presented a case report on a fertility-sparing procedure, a radical abdominal trachelectomy and upper vaginectomy performed on a 22-year-old woman with clinical stage I vaginal clear cell adenocarcinoma in the left fornix. The authors found 28 months after the initial surgery that the woman had no evidence of recurrence and was having regular menstrual cycles. The authors concluded that this procedure can be considered to conserve fertility in young women. 
The best treatment for vaginal melanoma remains controversial. Radical surgery has been the main treatment modality, although a more conservative approach has been advocated by some authors. For example, Reid et al, in 1989,  and Buchanan et al, in 1998,  , showed no significant difference in 5-year survival rates or disease-free intervals for radical versus conservative surgery.
On the other hand, in 1994, Van Nostrand and colleagues demonstrated that radical surgery had a significant 2-year survival advantage over conservative surgery (48% vs 20%, respectively); they recommended a radical approach to patients with lesions smaller than 10cm2. 
Detection of lymph node involvement
Recently, detection of nodal involvement prior to radical procedures has been suggested because positive lymph nodes indicate poor prognosis and radical surgery might be unjustified. Siu et al used laparoscopic ultrasonography to successfully detect enlarged pelvic lymph nodes. 
Rodier et al used technetium-99m (99m Tc)-sulfur colloid injected around the lesion and detected the sentinel lymph node with hot spot by lymphoscintigraphy.  Nakagawa et al succeeded in evaluating the sentinel lymph node to decide the extent of surgery using a dye injection method  ; 1mL of methylene blue was injected into the subcutaneous layer at the boundary between the lesion and the vaginal mucosa, followed by incision in the ipsilateral groin to detect the stained lymph node.
Radical surgery varies depending on tumor size and location. Small lesions in the upper vagina are treated by radical hysterectomy, subtotal vaginectomy, and pelvic lymphadenectomy. Lesions in the lower vagina are managed by partial vaginectomy, total or partial vulvectomy, and bilateral inguinal lymphadenectomy. Larger and more invasive lesions (>3 mm) are treated with exenterative surgery.
Note that whenever vaginal mucosa is left in situ after partial or subtotal vaginectomy, frozen sections should be obtained to exclude lateral superficial spread, because the most common site of initial recurrence is the vagina.
Conservative management includes wide local excision and simple hysterectomy combined with radiotherapy and/or chemotherapy. Radiation therapy with high-dose fractions (>400cGy/fx) has been effective in selected patients. This type of response is consistent with the higher response rate seen with cutaneous melanoma when large, individual fractions are compared with conventional fractionation.
Irvin et al reported in their case series higher locoregional control using wide local excision followed by high-dose fractionation teletherapy, compared with more radical surgical resection. 
Tumor Excision and Vaginal Resection in Other Cancers
As mentioned previously, radiation therapy is contraindicated in verrucous carcinoma because it tends to induce aggressive cancer types. The only treatment option is surgical resection. If the lesion is small, a wide surgical excision is performed. With larger lesions, vaginectomy or exenteration is recommended. Because this tumor rarely metastasizes, dissecting the lymph nodes is unnecessary unless they appear enlarged.
Because the typical patient is prepubertal, preserve ovarian function and reproductive organs. Currently, a conservative approach is used instead of exenterative surgery. Preoperative and/or postoperative chemotherapy and radiotherapy improve the outcome.
For small, easily resectable tumors, the lesion is excised. Chemotherapy VAC (vincristine, actinomycin D, and cyclophosphamide) and radiotherapy follow. If the tumor is bulky, preoperative chemotherapy or radiotherapy is administered before the lesion is excised.
Endodermal sinus tumor
This very rare tumor is treated with chemotherapy VAC to reduce the tumor size. Chemotherapy is followed by partial colpectomy, radiotherapy, or both.
These tumors vary in their malignancy depending on how well they are differentiated. Well-differentiated tumors are less likely to metastasize and are managed by surgical excision. Frozen sections are taken to ensure that the tumor is well contained within the surgical margins. Poorly differentiated tumors should receive adjuvant radiotherapy.
Preoperative Evaluation for Exenterative Surgery
The first and most important requirement for exenterative surgery is that the patient have no underlying medical illnesses. The patient must be fit for a prolonged operation with potential blood loss and major fluid shifts. A psychological evaluation is also necessary; owing to postoperative physical and physiologic changes, the patient must have a stable personality and a supportive social environment.
Signs of systemic spread should be absent. Evaluation starts with a physical examination, which includes palpation of all peripheral lymph nodes, especially the inguinal and supraclavicular nodes. The clinical triad of unilateral leg edema, sciatic pain, and ureteral obstruction suggest involvement of the posterolateral pelvic sidewall, which is a sign of lack of resectability. (Thus, extension of the tumor into the pelvic sidewall is a contraindication to the procedure.) Each sign by itself is not a contraindication for exploratory laparotomy, although each is associated with decreased probability of resection and decreased probability of long-term survival, even if the cancer is resected with clear margins.
Realize that age by itself is not a contraindication; the patient's health is the first prerequisite for considering pelvic exenteration.
Chest radiography or CT scanning of the chest, upper abdomen, and pelvis are mandatory to rule out lung, liver, and para-aortic metastasis, respectively. Any suspicious lymph node should undergo fine-needle aspiration cytology to rule out metastasis. In a 1989 report, Manetta and colleagues dismissed the need to biopsy nonsuspicious supraclavicular lymph nodes in a random fashion.
Unfortunately, neither CT scanning nor MRI is sensitive and specific enough to rule out pelvic sidewall involvement. This is because radiation fibrosis and chronic inflammation cannot be differentiated from cancer with these techniques.
Laparotomy and biopsy
If resectability is questionable, then an exploratory laparotomy with parametrial biopsies should be performed to rule out pelvic wall involvement. Alternatively, laparoscopy could be performed to obtain a biopsy from the pelvic wall and any suspicious lymph nodes. Miller and colleagues reported that nearly 30% of patients undergoing exploratory laparotomy had unresectable cancer because of peritoneal disease (44%), lymph node metastasis (40%), parametrial fixation (13%), and hepatic or bowel involvement (4.5%). 
Nutritional assessment and laboratory studies
Nutritional assessment is an important preoperative consideration because malnourished patients are at higher intraoperative and postoperative risk. Anthropometrics, serum electrolytes, total serum protein, albumin, transferrin, and immunologic function need to be evaluated. The latter is assessed by calculating the absolute lymphocyte count (reference range is >2000/mm3) and by examining delayed cutaneous hypersensitivity responses to skin test antigens.
Kidney function must be evaluated because the patient is at risk for massive fluid shifts and major blood loss and because urinary diversion is likely to be performed. A complete urine analysis with serum creatinine provides a good evaluation.
A complete blood count (CBC) is required, and hemostatic function is evaluated through patient history of bleeding and family history of coagulopathy. Also, prothrombin time (PT) and activated partial thromboplastin time (aPTT) are required because cancer is associated with coagulation abnormalities.
Consult an electrocardiography (ECG) specialist and cardiologist. Clear the patient from cardiac risks before surgery because most patients are older than 50 years and may have underlying coronary heart disease. Also, the surgery is radical in nature, with unavoidable blood and fluid losses.
Patient Counseling in Exenterative Surgery
Once the patient is medically cleared for surgery, she should undergo extensive preoperative counseling. During counseling, the patient should be informed that preoperative evaluation of tumor resectability is not as accurate as intraoperative assessment; therefore, the possibility of aborting the procedure still exists.
The patient should also be informed of the radical nature of the surgery and of all possible intraoperative and postoperative complications, including intraoperative mortality. She should be informed that intraoperative and postoperative blood product administration is inevitable and that a postoperative stay in the intensive care unit (ICU) and prolonged hospitalization are common.
The patient should also expect an alteration in her physical appearance and physiologic function, such as the presence of stomas, and should understand the possible psychological impact such alteration will have on her.
The patient should be offered vaginal reconstruction and be given the option, if it exists, to choose the donor sites for skin grafts and musculocutaneous flaps. 
Most importantly, the patient should know that despite the radical nature of the surgery, cure is not guaranteed.
Preoperative Preparation for Pelvic Exenteration
Mechanical bowel preparation
Mechanical bowel preparation was the standard practice and typically began 2 days prior to the operation to reduce the incidence of postoperative infectious complications. In a 1977 report, Clarke and colleagues demonstrated that preoperative oral antibiotics reduce septic complications of colon surgery from 43% in unprepared patients to 9% in prepared patients. 
However, a meta-analysis of several randomized clinical trials involving patients who had colorectal surgery, comparing outcomes in those who underwent mechanical bowel preparation with those in patients who did not have such preparation, failed to show any benefit from bowel preparation. The report also found a significant increase in anastomotic leakages in patients who underwent bowel preparation (specifically, those who underwent preparation with polyethylene glycol) compared with those who did not (5.6% vs 3.2%, respectively). [40, 41]
No similar clinical trials have been conducted on major gynecologic surgery; the practice of mechanical bowel preparation depends on the surgeon's preference and should be individualized to the patient.
Prophylactic antibiotics are administered intravenously or intramuscularly within 1 hour before incision. Cefazolin 1g (2g if the patient’s body mass index [BMI] >35kg/m2) is most commonly used, due to its longer half-life of 1.8 hours and low cost. Bacterial vaginosis should be treated prior to the surgery. 
Because of the high risk of thromboembolic diseases in this category of patients, vascular thromboembolic prophylaxis is recommended using either low-dose unfractionated heparin (LDUH, 5000 units 2 hours prior to surgery and every 8 hours postoperatively), low-molecular weight heparin (LMWH, 12 hours prior to surgery and daily postoperatively), or intermittent pneumatic compressors (IPC, starting immediately before surgery and used continuously until the patient ambulates).
Although no randomized clinical trials have been performed, using a combination of LMWH or LDUH with IPC has also been recommended for these high-risk patients. 
Arterial evaluation for reconstruction
If vaginal reconstruction is desired and a transpelvic rectus abdominis myocutaneous pedicle (TRAM) flap is considered, then the left epigastric artery should be evaluated in patients with prior pelvic surgery, prior transverse abdominal incision, or abdominoplasty. Preoperative evaluation of epigastric patency can be performed with preoperative arteriography or intraoperative Doppler ultrasonography.
Preoperative bowel preparation
The protocol for preoperative bowel preparation is as follows:
Preoperative day 2 - Clear-liquid diet; tap water or Fleet enema at night (optional)
Preoperative day 1 - Clear-liquid diet; 1 bottle of mineral oil or 2L polyethylene glycol at 8 am; oral neomycin base, 1g every 4 hours for 3 doses; oral erythromycin base, 1g every 4 hours for 3 doses; tap water or Fleet enema repeated until no solid stool at night
Operative day 0 - Fleet enema repeated until clear
Intraoperative Details of Pelvic Exenteration
Pelvic exenteration is classified as follows:
Total exenteration for apical lesions involving the bladder and rectum
Anterior exenteration for anterior lesions involving the bladder
Posterior exenteration for posterior lesions involving the rectum
The patient is placed in the low lithotomy position with stirrups supporting the hips, thighs, and knees. This allows surgeons to work on the abdominal and perineal areas at the same time. Intermittent pneumatic compression of the calves should be continued and deep vein thrombosis (DVT) prophylaxis given preoperatively. An epidural catheter for postoperative pain control is inserted before general anesthesia. A number 16 Foley catheter is placed in the bladder and connected to straight drainage. A nasogastric (NG) tube is inserted. The stoma sites are marked.
A midline abdominal incision is made from the symphysis pubis to a point approximately 3cm above and to the left of the umbilicus. This allows adequate exploration of the upper abdomen (eg, liver and omentum) and good exposure for pelvic surgery. The liver, omentum, abdominal peritoneum, and para-aortic nodes should be carefully palpated and the rest of the abdomen explored. Obtain biopsies from suspicious areas and send them for frozen section.
If pelvic nodes are involved, then bilateral frozen sections of the para-aortic nodes should be taken before continuing the operation. These should be sent for frozen section. The operation should be aborted if the frozen sections are positive for malignancy, if both pelvic and para-aortic nodes are positive, if peritoneal breakthrough of the tumor has occurred, or if tumor implants are present in the abdomen or pelvis.
The round ligaments are then cut at the pelvic sidewall, and the anterior and posterior leaves of the broad ligament are opened. The prevesical, paravesical, pararectal, and presacral spaces are all developed. Any enlarged lymph node is removed and sent for frozen section. If the lateral pelvic walls and ligaments are not invaded by the tumor, the operation is continued.
The anterior division of the internal iliac arteries is ligated bilaterally just after they cross the internal iliac veins. This cuts the blood supply of the uterine, vesical, and obliterated umbilical arteries. The hypogastric artery is left untouched, as it carries the blood supply to the internal pudendal and inferior hemorrhoidal arteries, which constitute the main circulation to the anal canal and lower rectum. The latter are needed to perform a low rectal anastomosis. Another artery of importance is the obturator artery, which supplies the gracilis muscle used for vaginal reconstruction (neovagina).
The cardinal ligaments are divided at the sidewall; the rectal attachment to the sacrum and the vaginal attachment to the tendinous arch are divided. At this point, the rectum and the vagina are completely mobilized, allowing free access to the pubococcygeus muscle. The site of excision of the pubococcygeus muscle depends on whether an anterior or total exenteration will be performed.
The aim is to remove the uterus, cervix, bladder, urethra, and anterior vagina while preserving the rectum and posterior vagina. This procedure is divided into a perineal phase and an abdominal phase. Intraoperative, bimanual palpation ensures that the mass is completely resected.
In the perineal phase, the urethra and anterior vagina are removed. A long, curved clamp is placed beneath the pubis and directed caudad and anterior to the urethra. Another clamp is placed lateral to the pubourethral ligaments and directed out under the symphysis pubis at the 2-o'clock position and then at the 10-o'clock position. This isolates the right and left pubourethral ligaments for division. The anterior vaginal wall is incised with at least 4cm of margin under direct vision from the vaginal side. The levator ani is divided anterior to rectum, allowing removal of the specimen that includes the urethra and anterior vagina.
In the abdominal phase, the ureters are transected below the level of the common iliac arteries. The bladder is separated from the retropubic space, and the lateral vesicle attachments are sharply incised. The uterosacral ligaments are cut, and the uterus is removed with the bladder, fallopian tubes, and ovaries.
An omental J-flap is made by incising the omental attachment to the colon from the hepatic flexure medially to the midportion of the stomach. The left gastroepiploic artery provides the blood supply to this pedicle.
The flap is mobilized and brought down to the left pelvic gutter and into the pelvis, where it is sewn to the posterior vaginal mucosal over the rectum and to the pelvic sidewalls. It will be used to cover the denuded area of the rectum and provide a receptacle for neovaginal construction by a split-thickness skin graft. In 1984, Hatch described the use of the bulbocavernosus flap if there is not enough omentum. A continent vesicostomy is constructed, and Hemovac drains are placed in the pelvis.
Supralevator total exenteration
This procedure is similar to anterior exenteration, except that the rectum involved by the tumor is removed en bloc with the whole vagina, cervix, uterus, and bladder. It differs from the classic total exenteration by the performance of a low rectal anastomosis, as opposed to a permanent colostomy. This procedure became possible with the advent of circular stapling. In order to perform this anastomosis, the anal canal and the levator ani should be free of any tumor involvement and preserved during surgery.
The sigmoid is usually divided to allow for better exposure and development of the presacral space. The superior rectal and middle rectal arteries are ligated and severed, which allows the rectum to be cut from its blood supply.
The vaginal mucosa is incised about 1-2cm inside the hymenal ring. The bladder, vagina, and urethra are detached from the pelvic walls above the levator ani, so they are loose and attached only by the rectum.
Using a thoracoabdominal stapling device, the rectum is resected at its lower end, which leaves a 4cm margin, and the whole specimen is removed en bloc. Before applying the stapling device, continuous cephalad traction is applied to the rectum while its base is held above the levator ani. This provides adequate exposure of the rectum and easy access for the stapling device.
Preservation of the lower rectum
Preserving enough of the lower rectum to allow the patient good continence and stool storage after the low rectal anastomosis is advisable. This step is performed by first severing the sigmoidal arteries in order to mobilize the left colon. The inferior mesenteric arteries are preserved because they will supply the sigmoid. A colonic J-pouch is formed from the sigmoid, and the low anastomosis to the stump of the lower rectum is performed using the stapling device. As with the anterior exenteration, the omentum is mobilized and used to cover the denuded pelvic area and reinforce the stapled anastomosis.
Continent vesicostomy and neovaginal construction
Continent vesicostomy and neovaginal construction are performed. Unlike the neovagina constructed in anterior exenteration, in which the posterior vaginal wall is preserved, the omentum in this case may be insufficient for a split-thickness skin graft. For this reason, the rectus abdominis muscle or the gracilis muscles in the medial thigh are good alternatives as a source of a myocutaneous graft.
Classic total exenteration
This procedure is indicated when the levator ani are involved and need to be resected with the rest of the anus. The procedure is similar to the supralevator total exenteration; however, after mobilizing the whole specimen, a perineal incision is made around the anus, leaving a generous margin from the center of the tumor. The anococcygeal and pubococcygeal muscles are divided along the margin.
This procedure results in a large defect in the perineum, and reconstruction is done using the bilateral gracilis or the rectus abdominis muscles as a myocutaneous flap to fill in the defect. The omentum flap is used as a protective barrier against potential intestinal adhesions, and it provides additional blood supply to the reconstructed pelvis and perineum. A permanent colostomy and continent vesicostomy are performed.
The procedure is similar to total exenteration, but the bladder and urethra are preserved.
A neovagina can be constructed in several ways. The procedure depends on how much vaginal tissue is preserved after the exenteration as well as the size of the pelvic or perineal defect.
A split-thickness graft is usually used when an anterior or a supralevator exenteration has been performed, because these procedures leave a smaller defect. The mobilized omentum is used to create a pocket to receive the neovagina. A split-thickness skin graft is obtained from either the buttock (cosmetic advantage) or the anterior or medial thigh (more accessible and more comfortable postoperatively). The skin graft is sewn over a vaginal stent, preferably a Heyer-Schulte stent because it is inflatable and has its own drainage. The stent is inserted through the introitus into the omental pocket, which provides a blood supply to the graft.
Myocutaneous flaps are preferred whenever the defect is larger, such as after a total exenteration. The 2 most common flaps are the TRAM flap and the gracilis myocutaneous flap.
For a TRAM flap, the rectus abdominis on the side of the abdominal incision is used. The full thickness of the muscle, fascia, and skin are sutured from side to side, with one end left open and the skin facing the inside, which forms a tubular musculocutaneous mass. The tubular neovagina is mobilized into the pelvis, and the open end is sutured to the intact vaginal introitus.
Gracilis myocutaneous flap
For a gracilis myocutaneous flap, 2 flaps are needed. They are obtained from both medial thighs after incising the overlying skin and transecting the gracilis muscles distally. On each side, the flap is mobilized beneath a skin bridge of the vulva, which separates the vaginal introitus from the proximal pedicle. The flap should be about 5 X 10cm to be adequate.
The 2 flaps are sutured end to end into a cylindrical shape, with the skin facing the inside. The neovagina is inserted into the pelvis, and the open end is sutured to the introitus. The apex is sutured to the symphysis pubis and to the anterior sacrum. Finally, the omentum is mobilized to cover the neovagina and the rest of the pelvic floor.
The disadvantage of the gracilis myocutaneous flap is the presence of incisions on both inner thighs; the TRAM flap requires no additional incisions. A disadvantage of the TRAM flap, however, is that a limited amount of tissue can be mobilized from the anterior abdomen without causing much tension during closure of the abdominal incision and creating an abdominal wall distortion.
A third myocutaneous flap, the vulvobulbocavernosus pedicle, was described in 1984 by Hatch in the construction of a neovagina after exenteration.  Originally, this pedicle was used in repairing radiation-induced rectovaginal fistulae (Martius procedure). An incision is made over each labia majora, and the bulbocavernosus muscles are mobilized on their posterior pedicles by transecting them anteriorly. Each flap is tunneled under the skin just lateral to the posterior introitus, and once inside the perineal defect, they are sutured together, forming a neovagina.
The objective of a radical hysterectomy is resection of the tissue adjacent to the cervix and vaginal fornices, along with removal of the uterus and cervix and the part of the vagina involved by the lesion, while preserving a functional urinary apparatus and rectum.
The procedure starts with a midline incision as previously described for exenteration. Alternatively, a low transverse Maylard or Cherney incision provides adequate exposure to the pelvis but not enough to explore the entire abdomen. For this reason, a midline incision is preferable. Abdominal exploration is performed as previously described.
Steady upward traction is applied to the uterus, and the retroperitoneum is entered through the round ligaments on both sides. Once the ureter is identified as it crosses the pelvic rim, the pelvic spaces are developed as before. The vesicouterine fold of the peritoneum is opened, and the bladder is dissected away from the cervix and upper vagina. If the bladder is involved, then an anterior exenteration is performed. The uterine artery is ligated at its origin from the superior vesicle or internal iliac artery and then mobilized over the ureter. The uterine veins are clipped to avoid excessive bleeding.
The anterior vesicouterine ligament, which forms the roof of the uteric tunnel, is carefully dissected. This allows mobilization of the ureters off their peritoneal attachments and away from the uterus. Care must be taken to avoid severing the blood supply to the ureters. Once this is done, the posterior vesicouterine ligament could be divided. This frees the uterus from its anterior attachments in the pelvis.
Posteriorly, the peritoneum over the Douglas pouch is incised and the rectovaginal space developed by applying smooth traction on the rectum. This allows dissection and division of the uterosacral ligaments midway from the sacrum, which frees the uterus from its posterior attachment in the pelvis. To release the uterus from its lateral pelvic attachment, the cardinal ligaments are clamped and divided at the level of the pelvic sidewall, all the way across the paravaginal tissues down to the vagina.
If the ovaries are to be preserved, then the ovarian ligaments and fallopian tubes are transected. Otherwise, the infundibulopelvic ligaments are divided and the ovaries are freed from the pelvic attachments and removed with the uterus.
A vaginectomy is performed by continuing the dissection of the vesicovaginal and rectovaginal spaces and dividing the bladder and rectal pillars down to the pelvic floor. The vagina is entered anteriorly and transected at the desired level using a knife or scissors. The vault is closed, and the vaginal angles are sutured to the paravaginal tissues. The pelvic peritoneum is not closed, and drains are used only if doubt exists regarding the adequacy of hemostasis. In 1993, Jensen and colleagues reported that drains may increase febrile morbidity, pelvic cellulitis, and postoperative ileus.  A suprapubic catheter is placed in the bladder.
Radical vaginectomy is employed for invasive vaginal carcinoma, while simple vaginectomy is performed in cases of VAIN.
Vaginectomy may be partial, subtotal, or total, depending on the extent of the disease, how well-circumscribed the lesion is, and whether it is multifocal. The excision should include 2cm of normal vagina distal to the lesion and the entire vagina proximal to the lesion. If more than a third of the upper vagina is removed, then vaginal reconstruction using a split-thickness skin graft is required in order to have normal sexual function.
Simple vaginectomy is indicated when invasion is suspected in a patient with VAIN. The approach usually is vaginal. In postmenopausal women with poorly estrogenized vaginal mucosa, estrogen cream can be used 2-4 weeks prior to the operation. Lugol solution is used to delineate the abnormal mucosa. Injecting saline solution into the submucosa elevates the lesion from the underlying tissue layer and helps in the excision. Usually, a 3-5mm margin of healthy mucosa is adequate. For lesions located in the upper vagina, sutures are placed in the apex to place traction and the upper vagina is excised. The bladder and rectal pillars (lymph vascular pillars) are transected from their vaginal attachments. Blunt dissection is used to further remove the specimen. The surgeon must keep in mind the proximity of the ureters to the corners of the apex. The vagina is closed with interrupted biodegradable sutures.
When the uterus is in situ, radical vaginectomy can be approached vaginally or abdominally. If two thirds of the vagina needs to be removed, however, a combined approach is required to mobilize the distant vagina. In patients with previous hysterectomy, the abdominal approach or a combined approach is required because of a higher risk of injury to the ureters during resection of the cardinal ligaments and the proximal bladder pillars.
The vesicovaginal (anterior), rectovaginal (posterior), and 2 lateral paravaginal spaces are developed, and the bladder and rectal pillars are transected at their attachments to the bladder and rectum, respectively (as opposed to their vaginal attachments in simple vaginectomy). The ureters should be dissected away before resection of the vagina with the cardinal and vesicouterine ligaments. The specimen is resected in a manner similar to that used in simple vaginectomy.
The NG tube is removed in the recovery room or at the end of the surgery. Upon admission to the recovery room, chest radiography is performed to rule out pneumothorax and to check the tip of the central line. When stabilized, the patient is transferred to the ICU.
Fluid status is accurately measured by Swan-Ganz catheter because urine output may not be reliable (because of the diversion) and large loss of fluid is expected because of third spacing and oozing of serum from the large abdominal and pelvic defects. The urostomy is placed on continuous gravity drainage. Hemovac drainage should be measured and used as an indication for proper replacement of protein and electrolyte losses because drainage content is an approximation of serum content. The volume of the pelvic drainage can reach up to 1000mL over 24 hours.
An arterial line should be available for blood product, colloid, and crystalloid administration; fluid replacement should be adequate to avoid intravascular compromise with renal hypoperfusion and failure. The hematocrit should be carefully monitored and stabilized above 30% by infusing packed red blood cells (RBCs) or whole blood when needed. PT and aPTT are kept within the reference range with administration of fresh frozen plasma (FFP).
Routinely check the lower extremities for evidence of adequate vascular perfusion, with daily checks for evidence of DVT. Continuously monitor the patient's respiratory and cardiac function for evidence of pulmonary embolus, atelectasis, pleural effusion, and cardiac ischemia. When the patient is stabilized, the Swan-Ganz catheter is J-wired and a central line is placed for total parenteral nutrition (TPN), usually on postoperative day 2 or 3.
Antibiotic prophylaxis is discontinued after 48 hours if no postoperative fever has been reported. Otherwise, the antibiotic is changed according to the fever workup and cultures are obtained. If the cultures are negative for infection, then the antibiotics should be changed to cover anaerobic and gram-negative organisms.
Check stomas daily for evidence of vascular perfusion. If a stoma becomes dusky, then a scope is introduced to check the condition of the underlying bowel. Once bowel sounds are auscultated and the patient passes flatus, then oral feeding is initiated; the TPN is withdrawn when oral intake is adequate.
Intermittent, pneumatic calf compression is continued until the patient is fully ambulatory. Ambulation should begin as soon as the patient's strength is regained and pain is well controlled.
Regarding outcome and prognosis, the main concern of the patient and physician is the possibility of recurrence of the primary disease.
After surgery, monitor the patient for complications and any sign of recurrence. No data exist regarding the frequency and effectiveness of follow-up care for recurrence. In general, patients receive a pelvic examination and Papanicolaou smear every 3-6 months for the first 5 years. Patients treated for clear cell adenocarcinoma need to be monitored for a long time because late recurrences and second primaries in DES-exposed women have been reported to occur 17-20 years after the initial treatment, particularly in the lungs and supraclavicular areas. As many as 36% of recurrences appear in extrapelvic sites.
Follow-up for postoperative complications includes evaluation of the stomas, observation of the incisions for healing, and evaluation for signs of necrosis in split-thickness skin grafts and musculocutaneous flaps. Psychological evaluation includes questions about quality of life, body image, and sexual satisfaction. Patients should be counseled about these issues.
The overall mortality rate for patients undergoing exenteration is less than 5%; however, complications occur in about 50% of patients, because of the nature and length of surgery, the advanced age of the patients, the large amount of blood loss, and the inability to accurately monitor fluid intake and output secondary to urinary diversion. Hemorrhage is the most significant intraoperative complication (1.5-4L).
Hemorrhage should be dealt with promptly with percutaneous embolization because reexploration carries high mortality and morbidity rates. Intravascular fluid loss from wound oozing and third spacing is expected.
Pelvic sepsis (10%) and wound sepsis and dehiscence (12%) are minimized by bowel preparation, but the risk is still present because of the radical nature of the surgery, the length of the operation, and the age of the patient.
Pulmonary embolus occurs in 1.5% of patients despite prophylaxis. This is also due to the length of the operation and prolonged bed rest after surgery.
Lower rectal anastomosis complications
Anastomotic leakage depends on the distance of the anastomosis from the anus, as well as on the vascularity and tension on the anastomotic site. Along with fistulae, it carries a very high mortality rate of approximately 50%.
Rectovaginal fistulae and strictures are more common in patients with previous irradiation. Using the omentum as an additional blood supply could prevent this. The inability to empty the J-pouch is the most significant drawback to this procedure.
Small bowel obstruction occurs in 4-9% of patients. The most common site is the distal ileum if an ileal anastomosis has been performed, with obstruction most frequently occurring if irradiation was previously administered. Avoiding an ileal anastomosis and generously reconstructing the pelvic floor decreases this complication. In case of an obstruction, reoperation should not be considered, because of its high mortality rate (8-10%). Instead, NG decompression should be attempted and TPN feeding continued.
Fistulae (12-32%) are more common with ileoileal anastomosis and previous irradiation. With the use of a transverse colon conduit for urinary diversion, this complication now is uncommon.
With the use of a transverse colon, urinary leaks and intestinal fistulae now are rare. In case they occur, management is conservative because of the high mortality rate associated with reoperation. Percutaneous drainage is required. Ureteral strictures are uncommon with the use of stents. The long-term complication is pyelonephritis, with 2.7% risk of renal failure due to ureteral obstruction. 
Complications from vaginal reconstruction include necrosis of the graft and stenosis of the neovagina.
TPN complications include pneumothorax (1-2%), which is diagnosed on the basis of chest radiographic findings. It usually resolves spontaneously, but a chest tube may be required.
Subclavian venous thrombosis occurs in 5-10% of patients. Flush with heparin solution (300U/mL) for prevention. Once it occurs, remove the catheter, administer a full course of heparin, and continue nutrition through a peripheral vein.
Infection occurs in 2-5% of patients. If the patient is febrile and the source of infection is not identified after 96 hours, remove the catheter and send the catheter tip for culture. If a peripheral source was identified, then removing the catheter is unnecessary; treat the infection accordingly.
Metabolic complications include overfeeding (most common; leads to excess carbon dioxide production), hyperglycemia (treat with insulin), and metabolic acidosis (rare with addition of acetate buffer).
Postoperative Prognosis Following Exenteration
The outcome of exenteration has improved significantly over time in terms of operative mortality and 5-year survival rates. In 1965, Brunschwig reported an operative mortality rate of 16% and a 5-year survival rate of 20%  ; in 1989, Morley et al reported an operative mortality rate of 2% and a 5-year survival rate of 61%  .
In general, the operative mortality rate in exenteration is less than 5%, and the 5-year survival rate is about 40%. Improved hemodynamic monitoring, nutritional support, and advances in surgical techniques and instruments have contributed to the decrease in intraoperative mortality and morbidity. Anterior exenteration has a better survival rate than does total exenteration (30-60% versus 20-46%, respectively).
In a study of outcomes from pelvic exenteration, Maggioni et al found that the 5-year survival rate was highest for patients with cervical cancer (52%) but was only 19% for vaginal cancer. The authors published their 10-year experience with pelvic exenteration between June 1996 and April 2007 for cancers of the cervix (62 patients), vagina (21 patients), vulva (9 patients), endometrium (9 patients), and ovary (4 patients) and for uterine sarcoma (1 patient).
In the study, the survival of patients with cervical and vaginal cancer was significantly affected by the presence of positive lymph node involvement (30% vs 60% at 5 years) and positive margins (25% vs 60% at 5 years). There was no operative or early postoperative mortality (< 30 days after surgery), but the postoperative complication rate was 66.6%, with 87% of early complications being completely resolved. 
Clinical factors that affect survival
These include the following:
Length of time from initial radiation therapy to exenteration - Less than 1 year is a poor prognostic sign.
Size of the central mass (>3 cm)
Preoperative sidewall fixation as determined by clinical examination
Pathologic factors that affect survival
Pathologic factors that impact survival include the following:
Tumor extension - In 1989, Anthopoulos and colleagues reported that the most important risk factor for reduced survival was the extension of the tumor laterally into the surgical margins 
Positive nodes - In 1989, Morley et al reported a 5-year survival rate of 70% for negative nodes versus 0% for positive nodes 
Spread of tumor to adjacent organs
Additional factors in prognosis
Age can affect the operative mortality rate but not the 5-year survival rate. In 1992, Matthews et al reported that patients older than 65 years had the same 5-year survival rate of 45% as patients younger than 65 years.  The operative mortality rate of the older group was 11% versus 8.5% in the younger group.
Anthopoulos et al found that 84% of the patients were rehospitalized for complications that occurred more than 30 days after surgery; complications usually involved the gastrointestinal or urinary tract.  Surgical intervention was required for 58% of patients with complications occurring 1 year after surgery, while 74% required surgery within the first year.
Organ reconstruction, including low rectal anastomosis, continent vesicostomy, and vaginal reconstruction, has significantly improved patients’ quality of life after pelvic exenteration. In 1997, Hawighorst-Knapstein and colleagues reported that patients with no ostomies have a much better quality of life and body image than patients with 2 ostomies.  They also reported that women with vaginal reconstruction reported fewer problems related to quality of life and significantly fewer sexual problems.
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- Risk Factors
- Patient History
- Visual Examination, Palpation, and Biopsy
- Histologic Findings
- Treatment Determination and Staging
- Radiation Treatment and Chemotherapy
- Indications and Contraindications for Surgery
- Squamous Cell Carcinoma Surgery
- Clear Cell Adenocarcinoma Surgery
- Melanoma Surgery
- Tumor Excision and Vaginal Resection in Other Cancers
- Preoperative Evaluation for Exenterative Surgery
- Patient Counseling in Exenterative Surgery
- Preoperative Preparation for Pelvic Exenteration
- Intraoperative Details of Pelvic Exenteration
- Vaginal Reconstruction
- Radical Hysterectomy
- Postoperative Details
- Postoperative Follow-Up
- Postoperative Prognosis Following Exenteration
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