Primary cancers of the vagina are rare. The estimated number of new cases in the United States in 2002 was 2000, or 2.5%, of all gynecologic malignancies, with 800 estimated deaths (3.1%).¹ Most vaginal cancers are of squamous cell origin (approximately 93%); adenocarcinomas account for less than 5%.^2,3 Vaginal carcinoma comprises a heterogeneous group of tumors: endodermal sinus tumor⁴ and embryonal rhabdomyosarcoma (sarcoma botryoides) present in childhood⁵; clear-cell adenocarcinoma typically presents in adolescence^6,7,8; and squamous cell carcinoma, adenocarcinoma, melanoma, and sarcoma predominate in adult life.^2,9,10 Most malignancies found in the vagina, however, are metastatic. They may be the first manifestation of an occult neoplasm, commonly arising from an endometrial, cervical, or vulvar carcinoma. Up to 14% of endometrial carcinomas metastasize to the vagina, presumably by retrograde spread through submucosal lymphatics. Infrequently, vaginal metastases originate from malignancies of the ovary, rectum, kidney, or choriocarcinoma.^1,2,3

By definition, primary vaginal neoplasms arise in the vagina and do not involve the external os of the cervix superiorly or the vulva inferiorly (the former tumors are classified as cervical and the latter as vulvar cancers).¹⁰ Growth limited to the urethra should be classified as a urethral primary. Vaginal cancers are staged according to criteria set forth by the International Federation of Gynecology and Obstetrics (FIGO)^11,12 (Table 1).

Table 1. FIGO Staging System for Vaginal Carcinoma: 2001

Source: Beller U, Sideri M, Maisonneuve P, et al: Carcinoma of the vagina, J Epidemiol Biostat 6: 141, 2001

The vagina is a fibromuscular tube that forms the distal portion of the female reproductive tract, extending from the uterus to the vulva. The vagina averages 7 cm in length and is located posterior to the base of the bladder and urethra and anterior to the rectum. The lower three-fourths of the posterior wall are in contact with the rectum, whereas the upper one-fourth is separated from the rectosigmoid by the pouch of Douglas. At the superior end of the vagina, the cervix projects through the vaginal wall, creating a circular sulcus that entirely surrounds the cervix, termed the vaginal fornices.¹³

The vaginal wall consists of three layers: mucosa, muscularis, and adventitia. Grossly, the mucosal membrane has numerous infoldings, or rugae, separated by transverse folds. This mucosal surface is lined by stratified, nonkeratinizing squamous epithelium. The vaginal mucosa does not contain glands and is lubricated by transudation across the mucosa and by cervical secretions. Epithelial changes are minimal in response to the reproductive cycle. The muscularis layer is composed of smooth muscle fibers arranged circularly on the inner portion and longitudinally on the thicker outer portion. This muscular layer encircles a highly vascular submucosa that contains a venous plexus and loose connective tissue. A vaginal sphincter is formed by skeletal muscle at the introitus. The adventitia is a thin, outer connective tissue layer abundantly supplied with elastic fibers and further venous and lymphatic plexuses that merges with the outer connective tissue layer of adjacent organs.

The vagina is supported by external fibrous and muscular tissue, the central parts of which coalesce to blend with the pelvic floor musculature. The most important of these vaginal supports are the cardinal ligaments cranially and the perineal body caudally. The paired vaginal arteries arise from the adjacent internal iliac arteries or uterine vessels. The vaginal arteries lie lateral to the vagina and anastomose with the uterine, inferior vesical, and middle rectal arteries. The longitudinal anterior and posterior azygos arteries develop from the lateral and anastomotic branches that join in the midline. Branches of the internal pudendal arteries supply the distal vagina. The vaginal venous plexus communicates with the vesical, hemorrhoidal, and uterine plexuses and eventually drains into the hypogastric vein.¹³

Vaginal lymphatics form a meshed net in the mucosal membrane and anastomose with lymphatic vessels in the muscularis.¹³ The lymphatics of the upper vagina communicate with those of the cervix and drain into the pelvic nodes. The posterior vaginal wall is defined by lymphatics that anastomose with the rectal lymphatic system. Lymph from the posterior vagina is channeled to the deep pelvic nodes, such as the inferior gluteal, sacral, and rectal nodes. The anterior wall is drained by lymphatics that flow to the nodes of the lateral pelvic walls. The lymphatics of the distal third of the vagina drain to inguinal and pelvic nodes.

Vaginal carcinoma spreads primarily by local tissue invasion and lymphatic permeation with embolization, similar to cervical and vulvar malignancies, although hematogenous spread can occur. The vagina has a fine network of capillaries throughout the mucosa and the muscularis that anastomose freely and join laterally into major drainage channels. The lymphatic system of the vagina has many variations, which may account for some treatment failures.¹³ Once the preferred routes of drainage are obstructed by tumor, the very extensive anastomotic connections may account for the often bizarre and widespread nature of metastases. The tumor may locally infiltrate the paracolpium, parametrium, bladder, and rectovaginal septum. The proximity of the cervix and vulva make it inevitable that a significant number of vaginal cancers become classified as cervical or vulvar primaries.

The developmental origin of the vagina remains controversial. Three origins of the vagina have been proposed:

1. epithelium derived from the müllerian ducts;
   
2. epithelium derived from müllerian and wolffian ducts; and
   
3. urogenital sinus derivation.^6,7,8 Vaginal embryogenesis is a complex process, because three epithelial layers interact over a limited area.
   

The occurrence of lower genital tract anomalies and clear-cell carcinomas in women exposed to diethylstilbestrol (DES) in utero stimulated further interest in determining the developmental origin of the vagina.¹⁴ At 4 weeks of development, the müllerian (paramesonephric) duct system begins as an invagination of the coelomic epithelium in the urogenital fold just lateral to the cranial end of the mesonephric ducts. The paired müllerian ducts extend caudally, fuse in the midline, and reach the urogenital sinus by 7 weeks of gestational age. The septum formed by fusion of the müllerian ducts disappears, forming a single cavity: the uterovaginal canal.

The simple columnar epithelium of the vagina is transformed into a stratified epithelium of polygonal cells. The vaginal plate arises at the urogenital sinus and exhibits progressive cephalad growth into the uterovaginal canal, thereby obliterating the vaginal lumen. The vaginal plate then capitates, leaving behind the stratified squamous epithelium of the vagina. In utero exposure to DES results in hormonally mediated persistence of müllerian glandular epithelium (adenosis) within the vagina.^6,7,8

Most cancers found in the vagina (80%–90%) are metastatic from other primary sites, involving the vagina by direct extension or by lymphatic or hematogenous routes. Primary carcinoma of the vagina is rare; it represents only 1% to 3% of all gynecologic malignancies.^1,2,3,12 There has been a decrease in the incidence of primary vaginal tumors. This decrease suggests either the benefits of early detection by Papanicolaou smears or the application of more rigid diagnostic criteria that have eliminated primary cancers arising from adjacent organs such as the cervix, vulva, and endometrium.^1,8,14 Risk factors associated with vaginal carcinoma include low socioeconomic level, a history of genital warts, vaginal discharge/irritation, previous abnormal results on Pap smear, early hysterectomy, and vaginal trauma.^{12,15,16,17,18,19} Possible etiologic agents, including cervical fluids, cellular debris, and irritants such as chemical douches, feminine hygiene preparations, and retained tampons, have not been found to be causative agents.

Human papillomavirus (HPV) has been implicated in the pathogenesis of vaginal cancer, much like cervical carcinoma.^{15,16,17,18,19} Waggoner and colleagues²⁰ found HPV-31 DNA exclusively in the clear-cell adenocarcinomas that contained HPV sequences. A larger, population-based study of patients with vaginal intraepithelial neoplasia (VAIN) III and invasive vaginal squamous cell cancers²¹ found similar risk factors as those related to cervical cancer. Compared with controls, these patients were more likely to have multiple sexual partners, early age at first intercourse, and to be current smokers. HPV DNA was detected in more than 80% of patients with VAIN III and 60% of patients with invasive cancers. Antibodies to HPV 16 were strongly related to the risk for cancer.²¹

In 1971, Herbst and associates first reported the correlation between clear-cell adenocarcinoma of the vagina and cervix and the use of DES.⁸ The incidence of clear-cell adenocarcinoma in women prenatally exposed to DES is estimated to be between 0.14 and 1.4 cases per 100,000.^6,7,8,14 The median age of these DES-exposed patients at tumor diagnosis was 19 years. An association was found between the risk for vaginal cancer and the time of first exposure to DES. The greatest risk for vaginal cancer from exposure to DES was found to occur during the first 16 weeks of pregnancy. This risk decreased when exposure began at 17 weeks or later.⁷ A question that remains unanswered is whether DES exposure is related to vaginal and cervical squamous cell cancers, which typically present later in life. To address this issue, Hatch and colleagues performed a retrospective cohort study of 3899 DES-exposed women versus 1374 controls.²² They found a relative risk of 2.1 (95% confidence interval: 1.2–3.8) for high-grade dysplasia of the vagina or cervix with DES exposure. The low incidence of invasion precluded statistical analysis regarding cancer.

Vaginal carcinoma often presents as either an ulcerative or exophytic lesion, with the exophytic or fungating lesion being more common.²³ The vaginal skin can be undermined by the growing cancer, producing thickening and rigidity of the vagina. This phenomenon is more commonly associated with clear-cell carcinoma. Early infiltration of the submucosa is a frequently observed feature, and local tissue reaction and induration tend to give the impression of significant extension, even in small tumors. More than half of vaginal carcinomas occur in the posterior wall of the upper third of the vagina. The second most common site is the anterior wall of the lower third of the vagina.^24,25

The prognosis is better for patients in whom the tumor occupies the upper third of the vagina, because the pattern of spread is similar to that of cervical carcinoma. Lower vaginal tumors have a tendency to spread by the pelvic and inguinal lymphatics, making management more complicated. The incidence of clinically positive nodes at initial diagnosis ranges from 5.3% to 20%, depending on the anatomic location of the lesion. Involvement of inguinal nodes is more common if the lesion involves the lower third of the vagina. Therefore, the site of the carcinoma and the disease stage must be considered to optimize patient management.

Abnormal vaginal bleeding is a presenting symptom in 50%–75% of patients with primary vaginal tumors. It most commonly occurs as random bleeding or postcoital spotting; however, antepartum bleeding has been described.²⁶ Vaginal discharge is frequent. Less common presenting symptoms are dysuria or pelvic pain.

As for any suspected cancer, a complete history and physical examination should be performed. It is critical to uncover any signs or symptoms that could indicate a primary tumor elsewhere in the patient. Pelvic assessment should include a rectovaginal and a detailed speculum examination. Frick and coworkers²⁷ reported that at least 19% of cases are missed on initial examination. This is particularly true when the lesion is small and situated in the lower two thirds of the vagina, where it may be covered by the blades of the speculum (if not rotated to visualize the anterior and posterior walls). Definitive diagnosis is made by biopsy of a gross lesion, which can usually be performed in the office. Examination under anesthesia (with biopsy and clinical staging ± cystoscopy and proctoscopy) is useful for locally advanced tumors and for certain patients who are debilitated, very elderly, or have vaginal stenosis. Primary cancer of the vagina is a diagnosis of exclusion. If there is evidence of a primary tumor in an adjacent organ, then the vaginal cancer diagnosis cannot be made.

Clear-cell adenocarcinomas often grow into the submucosa and are not detected on cytologic smear. Early squamous cancers, however, can be detected in this manner. Colposcopy, with the use of Lugol's solution and/or acetic acid, is useful for identification and biopsy of a lesion. Multicentric disease can only be fully appreciated with the aid of careful colposcopy.

Radiological evaluation can be useful in determining the extent of local disease and detecting metastases.^28,29,30 Chest x-ray is simple and inexpensive and can be followed by computed tomography (CT) or magnetic resonance imaging (MRI) if clinically indicated. MRI appears to have a superior ability to differentiate tumor from fibrosis,^29,30 which can be difficult clinically. The recent encouraging data on the use of positron-emission tomography (PET) in cervix cancer³¹ would also seem to apply to many patients with vaginal carcinoma. However, these data are limited.²⁸

Cancers are clinically staged according to the FIGO staging system (Table 1).¹¹ In-situ carcinomas (VAIN III) are superficial tumors that have not penetrated the basement membrane of the mucosal layer. They tend to be multicentric. Stage I lesions, although confined to the mucosa, may spread to involve more than one vaginal wall. Many practicing clinicians subdivide stage II disease into IIa (subvaginal) and IIb (parametrial), as proposed by Perez.¹² Although those tumors with parametrial involvement appear to behave more aggressively, this subclassification is not officially part of the FIGO staging system. Enlarged inguinal lymph nodes should be evaluated by fine-needle aspiration to determine the stage and the radiation treatment ports. Most patients initially present with stage I or stage II disease (Table 2).

Table 2. Approximate Stage Distribution of Primary Vaginal Carcinomas

Treatment and prognosis for vaginal squamous cell carcinomas are discussed later, whereas those for all other histologies are discussed in this section.

Squamous Cell Carcinoma

Squamous cell carcinoma is the most common primary vaginal malignancy but constitutes only 1% of all gynecologic cancers (Table 3). The mean age of patients with vaginal squamous cell carcinoma initially diagnosed is 60 years (range: 25–98).^10,12,19 More than 75% of these lesions occur in patients older than age 50 years.¹² The cause of squamous cell carcinoma of the vagina is becoming clearer. Recent interest has focused on the association between HPV infection and multifocal carcinoma of the lower female genital tract.²⁴ Between 20%–60% of cases of vaginal cancer have been associated with HPV DNA, usually type 16.^{15,16,17,20,21,32}

Table 3. Approximate Percentages of Primary Vaginal Malignancies According to Histology

VAIN has been proposed as a precursor of vaginal cancer, although the true malignant potential of VAIN is unknown. The “HPV field-effect” hypothesis also has merit, because patients with VAIN commonly had cancer in other genital organs. Women with primary vaginal carcinoma have a 20% chance for previous invasive cervical cancer and a 70% chance for previous cervical intraepithelial neoplasia (CIN).^17,23 The median interval between the diagnosis of cervical cancer and the diagnosis of vaginal cancer is 14 years, with a range of approximately 6 to 28 years. Sixteen percent of these patients have a history of previous pelvic radiation.^10,18

It is often difficult to accurately determine the spread into subvaginal tissues, particularly the spread of anterior and posterior lesions. Therefore, differences in clinical observations are common. This is reflected in the wide range of reported stage distributions and survival rates per stage. The best data estimate that approximately 25% of patients present with stage I, 33% with stage II, 25% with stage III, and 15% with stage IV disease (Table 2).^{10,12,33,34,35}

The most common site for squamous cell carcinoma is the upper third of the vagina. Fifty-one percent of these lesions are found to arise from the upper third, 19% from the middle third, and 30% from the distal third. Fifty-seven percent of tumors originate from the posterior wall, 27% from the anterior wall, and 16% from the lateral wall.^23,33,34,35

Tumor size can range from an occult lesion to a large mass measuring more than 10 cm in diameter. ³⁵ Grossly, these tumors may be polypoid fungating masses or indurated, ulcerative plaques. On microscopic examination, the carcinoma consists of malignant squamous cells infiltrating from the vaginal epithelium and extending between the submucosa (Fig. 1). Cords of malignant cells advance into the submucosa and are usually surrounded by a large inflammatory reaction. Initially, local extension is into the submucosa, with later spread into the paracolpium and parametrium.^36,37 Squamous cell carcinomas are usually moderately differentiated and nonkeratinizing. The degree of histologic differentiation, based on the amount of keratinization and number of squamous pearls, does not constitute a sound basis for assessing prognosis.²⁴ The major prognostic factors are the stage of the tumor at the time of diagnosis and the size.¹⁶

Verrucous carcinoma is a distinctive variant of well-differentiated squamous cell carcinoma that rarely occurs in the vagina.^38,39 This tumor typically presents as a relatively large, well-circumscribed, soft, cauliflower-like mass. Microscopically, it exhibits a papillary growth pattern with marked hyperkeratosis and broad, bulbous pegs of acanthotic epithelium that push into the underlying stroma. Cytologic features of malignancy are lacking. Because of its well-differentiated character, the microscopic diagnosis of invasive carcinoma may be difficult, especially if the biopsy specimens are superficial. Verrucous carcinoma can recur locally after surgery, but it rarely metastasizes. This behavior difference justifies treating this carcinoma as a distinct tumor entity.

Adenocarcinoma

Approximately 5% of primary vaginal malignancies are adenocarcinomas (Table 3). Whenever this diagnosis is considered, it is necessary to rule out metastatic lesions from the bowel, uterus, or ovary. The most common variant is the clear-cell adenocarcinoma, which can occur spontaneously and in women with in utero exposure to DES.^6,7,8,14,40 Primary non-DES-related adenocarcinoma of the vagina is rare and occurs predominately in postmenopausal women.

DES was used extensively in the late 1940s and early 1950s to maintain high-risk pregnancies, such as those in women with a past history of abortion, diabetes, or multiple gestation.^41,42,43 Approximately 5% of all pregnant women in the United States during the late 1940s and early 1950s used DES. In 1953, Dieckmann and colleagues⁴¹ reported that DES offered no improvement in fetal outcome, and its use gradually decreased until it was discontinued by the Food and Drug Administration in 1971. In the same year, Herbst and associates⁷ reported seven young women (ages 15–22 years) who presented to Vincent Memorial Hospital (Boston, MA, USA) between 1966 and 1969 with a diagnosis of clear-cell carcinoma or endometrioid-type adenocarcinoma with intrauterine exposure to DES. The Registry for Hormonal Transplacental Carcinogenesis and the Registry for Research on Hormonal Transplacental Carcinogenesis were established to correlate clinical and pathologic data on these unusual cancers.⁴⁴

Many DES-exposed women have unusual vaginal epithelial changes such as adenosis.^40,45 Vaginal adenosis is a condition in which müllerian-type glandular epithelium is present after vaginal development is complete. It most commonly involves the anterior wall and upper third of the vagina, and the classical gross appearance is that of red, velvety, grape-like clusters.^7,8,14 The process may involve the surface epithelium or glands in the superficial stroma. Microscopically, the glandular epithelium can be composed of any of the müllerian epithelial cell types, but cervical-type mucus cells are most common. The glands within the lamina propria may be lined by tuboendometrial-type epithelium, which exists in approximately 25% of cases and is more common in the lower vagina. Robboy and associates⁴⁵ suggested that atypical vaginal adenosis and atypical cervical ectropion of the tuboendometrial type are precursors of adenocarcinoma.

Most DES-associated tumors have occurred in women between ages 17–21 years (median age: 19 years).^6,7 Clear-cell carcinoma develops in 0.1% of exposed women. The DES-associated clear-cell cervical adenocarcinomas have a predilection for the ectocervix. Most vaginal carcinomas arise on the anterior wall, usually in the upper third, corresponding to the most common site of adenosis. The tumors vary greatly in size (range: 1–30 cm). Most of the tumors are exophytic and superficially invasive.⁴⁶ The larger tumors are polypoid and nodular, and the smaller tumors appear flat or ulcerated with a granular or indurated surface. Small tumors can be easily missed on colposcopic examination if confined to the lamina propria and if covered by intact, normal epithelium. These small tumors are usually asymptomatic and are detected only by palpation and directed biopsies as part of a thorough examination for a DES-exposed patient. Microscopically, they exhibit three basic histologic patterns: tubulocystic (most common); papillary; and solid.⁴⁰ The tumor cells are cuboidal or columnar with clear cytoplasm and a distinct cell membrane, or they are the hobnail-type with large, atypical, protruding nuclei rimmed by a small amount of cytoplasm (Fig. 2). Glycogen is also found to be abundant.

Treatment can involve surgical intervention and radiation therapy.^{7,46,47,48,49,50,51} For stage I clear-cell adenocarcinoma in the typical young patient, surgery may be considered to preserve ovarian function.^{6,7,8,10,13,14} Surgery for vaginal clear-cell adenocarcinoma requires a radical hysterectomy and vaginectomy with reconstruction. The vaginectomy is performed only to the level required to obtain an adequate margin. Local excision appears inferior to radical surgery. The role of chemotherapy has not been determined.

The overall recurrence rate for clear-cell carcinoma approaches 21%, with the lungs, supraclavicular lymph nodes, and pelvis being the most common areas.⁷ Such cancers appear to have recurrence patterns different from those of squamous cell carcinomas, with a greater tendency to develop metastases in these distant sites.^{47,48,49,50,51} Although most recur within 3 years, late relapse of more than 19 years has been reported.^{7,46,47,48,49,50,51} Recurrent disease can be treated with radiation, surgery, or chemotherapy if widely metastatic. For central recurrences after surgery, pelvic radiation with external and interstitial therapy has been used. Pelvic exenteration appears to be more successful for patients with clear-cell carcinoma than for those with squamous cell carcinoma.⁴⁷

Small-Cell Carcinoma

Small-cell carcinoma can occur in the vagina in pure form or associated with squamous or glandular elements. A high proportion of small-cell carcinoma cases show ultrastructural or immunocytochemical evidence of neuroendocrine differentiation. Scully and associates⁵² first reported a vaginal small-cell carcinoma confirmed by immunohistochemical staining for neuroendocrine features in 1984. Histologically, these tumors are small and round, with a rim of sparse cytoplasm around the nuclei. Growth patterns include sheets, ribbons, rosettes, and palisades. The tumors are reactive for neuron-specific enolase and cytokeratin. Peters and coworkers⁵³ reported that patients with small-cell tumors (5 patients) were a mean age of 61 years.

Optimal therapy for small-cell carcinoma has yet to be determined. Therapeutic decisions are based on the examination results of patients with cervical or lung cancer. Because small-cell carcinoma is associated with early metastases, aggressive treatment with radiation for local control combined with systemic multi-agent chemotherapy is recommended.^54,55,56

Melanoma

Primary malignant melanoma is the second most common cancer of the vagina (5% of all primary vaginal tumors) and has the worst prognosis of all vaginal malignancies.^10,33 The incidence is estimated to be 0.03 per 100,000 women per year. Symptoms have usually been present for 3–6 months before a biopsy is performed. A recent review of 26 patients treated more than 30 years confirmed the previously cited clinicopathologic features.⁵⁷ Most patients are white, with a mean age of 60 years (range: 38–90 years). The most common presenting symptom is vaginal bleeding, followed by a palpable vaginal mass.

The lesions are polypoid–nodular in most cases with ulceration and a thickness greater than 3 mm.^10,33 They are typically located in the distal third of the anterior vagina and appear pigmented black or dark blue. The disease is usually locally advanced on initial examination. Microscopically, these tumors are similar to those in other sites (Fig. 3).{FIG3} Poorly differentiated lesions that are difficult to distinguish from sarcomas or squamous cell carcinomas can be identified by their distinctive ultrastructural features or by immunohistochemical staining patterns. S-100 remains the most sensitive immunohistochemical marker for these tumors.⁵⁷ MART-1 and tyrosinase can be helpful when S-100 is negative. Tumor depth according to the method of Breslow⁵⁸ should be assessed, because depth of tumor invasion is the best predictor of survival.

Multifocal lesions are observed in 30% of patients, and nodal or distant spread is found in 20%. Sixty-six percent of patients (6/9) in one study⁵⁹ had more that one focus of melanoma, either at initial diagnosis or at follow-up. The melanocytes probably come from aberrant melanocyte migration or melanocyte metaplasia. These tumors have poorer prognoses then cutaneous melanomas, with 5-year survival rates of 5% to 21% compared with 48%.^{60,61,62,63,64} The most frequent site of recurrence is local; the most common distant site is the lung.⁶²

The only potentially curative treatment for vaginal melanoma is surgery. Most investigators have found no long-term survival difference between treatment with radical surgery and treatment with conservative therapy. Van Nostrand and colleagues in 1994⁶⁵ reported that radical surgery gave patients a significant improvement in the 2-year survival rate if the initial lesion was smaller than 1 cm² (48% vs. 20%). However, the overall 5-year survival was similar. The resection must include all obvious disease, and conservative to ultraradical operations have been used.^65,66,67 Regardless of the type of operation, positive histologic margins for melanoma or melanoma in situ result in a higher incidence of local failure and decreased survival rates. Irradiation alone, or in combination with surgery, has been successful in treating some patients.⁶⁸

Local recurrences (usually within 2 years of initial treatment) can develop regardless of the type of surgical procedure. Recurrences can be treated with reoperation or radiation therapy. The exact role of chemotherapy in the adjuvant setting and for metastatic disease has not been determined.^57,69

Endodermal Sinus Tumor

Extraovarian endodermal sinus tumors (EST) are extremely rare and generally originate in the vagina or cervix of young girls. EST of the vagina was first recognized in 1965. Because of the tumor's resemblance to the endodermal sinus structures of the rat placenta, which derive from the yolk sac endoderm, the names EST and yolk sac tumor were proposed.⁷⁰ Most cases have been reported in patients younger than age 3 years.^70,71,72,73 A bloody vaginal discharge is the typical clinical presentation. The disease appears to be locally aggressive and capable of metastasizing by hematogenous and lymphatic pathways. Grossly, the tumor appears as a polypoid mass that distends the vaginal lumen and may protrude through the introitus. The tumor may also appear as a sessile thickening of the vaginal wall with mucosal ulceration. Schiller-Duval bodies can be diagnosed on microscopic examination but are found in only a minority of cases. Alpha-fetoprotein can be demonstrated by immunoperoxidase staining, and serum levels can usually be used as a marker of disease.

Previously, untreated patients died within 2–4 months of presentation; however, with more effective chemotherapy, the prognosis has improved significantly. Copeland and coworkers⁷⁴ reported on six patients with EST of the vagina and cervix who received excisional surgery with adjuvant vincristine, actinomycin-D, and cyclophosphamide (VAC) chemotherapy. They found that four of the six patients had been disease-free for 2 to 23 years. The Maligne Keimzelltumoren Study Group from Germany reviewed 14 patients with vaginal EST.⁷⁵ The protocol consisted of neoadjuvant cisplatin-based chemotherapy followed by surgical removal of tumor (if necessary) and further cisplatin-based chemotherapy. In 10 children, the residual mass was completely resected, whereas in the remaining four only vaginoscopy was necessary, because no visible tumor remained. All children were free of disease after a median follow-up of 76 months (range: 9–150). Primary chemotherapy was also successful in the treatment of three children, as reported by Handel and collegues.⁷⁶

Embryonal Rhabdomyosarcoma

Embryonal rhabdomyosarcoma is a malignant tumor of the rhabdomyoblasts characterized by two structural variances:

1. a solid form and
   
2. a multicystic grape-like form referred to as sarcoma botryoides.⁵ Sarcoma botryoides is a highly malignant tumor and is the most common malignant tumor of the vagina in infants and children.^77,78,79
   

Ninety percent occur in children younger than age 5 years. Although variable in size and location, rhabdomyosarcomas have a characteristic gross appearance consisting of multiple gray-red, translucent, edematous, grape-like masses that fill and protrude from the vagina. The tumors are typically found in the vagina during infancy and early childhood, in the cervix during the reproductive years, and in the uterine corpus during the rare postmenopausal patient. Microscopically, there is a continuous zone of dense round or spindle cells (they can be layered) immediately beneath the intact vaginal epithelium. The neoplastic cells are immature rhabdomyoblasts that surround blood vessels. Elsewhere, the tumor is composed of small, dark cells that are sparsely distributed in the myxoid stroma. Some cells may show cytologic evidence of differentiation by intensely staining eosinophilic cytoplasm with cross-striation(Fig. 4).

The tumor invades adjacent structures and metastasizes to local lymph nodes and distant sites by lymphatic and hematogenous dissemination. Lymph node metastasis exceeds 25% at initial presentation. Previously, the overall 5-year survival rate was approximately 35%. Local excision combined with multiagent chemotherapy for early-stage disease has significantly improved survival.^{78,79,80,81,82} Neoadjuvant chemotherapy along with postoperative radiation therapy have also improved outcomes, even in older patients.^81,83

Other Sarcomas and Rare Vaginal Primaries

Leiomyosarcomas,⁸⁴ spindle cell sarcomas, angiosarcomas,⁸⁵ alveolar soft-part sarcomas,^86,87,88 fibrosarcomas, neurofibrosarcomas, and mixed mesodermal tumors of the vagina occur predominately in older patients but are rare (2% of all malignant vaginal tumors).⁸⁴ Leiomyosarcomas are the most common of the adult vaginal sarcomas. These tumors usually develop along the vaginal sidewall and present as a lump that may cause problems with micturition, defecation, or intercourse. Because they are usually subdermal in location, bleeding and discharge are late symptoms.

Alveolar soft-part sarcoma of the genital tract is extremely rare, constituting 0.5% to 1% of all soft-tissue sarcomas.^86,87 Patients are treated with radiation therapy after local excision and, occasionally, chemotherapy. Christopherson in 1952⁸⁸ described alveolar soft-part sarcoma microscopically as dense, fibrous trabeculae of varying thickness dividing the tumor into compact compartments of irregular size. Current periodic acid-Schiff (PAS) staining reveals various amounts of intracellular glycogen and characteristically PAS-positive, diastase-resistant crystalline material. These crystals are diagnostic features of this tumor.

Hemangiopericytoma has been reported to develop as an ulcerative mass on the vaginal epithelium, with bleeding occurring both spontaneously and after trauma.⁸⁹ This tumor is characterized by proliferation of capillaries surrounded by a cell population derived from the myoepithelial pericyte. It can be mistakenly diagnosed as leiomyosarcoma.

The genital tract, especially the vagina, is an infrequent site for metastatic lymphomas, and it is rare for the vagina to be a primary site. These tumors can occur in premenopausal and postmenopausal patients.⁹⁰ Bleeding is the most common presenting symptom, with pain and dyspareunia also occurring. Masses may be noted on routine pelvic examination.

General Concepts

Radiation therapy and surgical intervention have been used as primary treatment for carcinoma of the vagina.^91–105 Treatment choices have been determined by extent of disease and by individual and institutional preferences. Radiation therapy is considered the treatment of choice because of excellent tumor control and good functional results. Surgical procedures may be reserved for the treatment of radiation failures, nonepithelial tumors, and early-stage disease in young, sexually active women. Limited surgery alone has quality-of-life advantages, including ovarian preservation and a lower risk for vaginal stenosis.

Principles of radiation treatment include the application of adequate tumoricidal doses to the cancer and the primary routes of dissemination (if at risk). For tumors of the middle and upper vagina, the pelvic lymph nodes must be included in any treatment field. The inguinal nodes must also be included for tumors of the lower vagina. In an effort to deliver substantial dose to the primary site while minimizing dosage applied to nearby organs, brachytherapy is commonly used.^93,94,100 This can be delivered via interstitial implants or with a simple vaginal cylinder.¹⁰⁶ Low-dose-rate and high-dose-rate systems are available.¹⁰⁷ The final decision on treatment apparatus and dose-rate is determined by many factors, including tumor volume, location, availability of technology, and physician preference.

Definitive conservative surgical treatment is a rarely used option. It is often difficult to obtain adequate tumor-free margins because of proximity of the bladder and rectum. Sacrifice of the whole vagina, or at least a significant part of the vagina, must be accepted. Replacement with skin grafts or other plastic surgical procedures can never be regarded as a return to normalcy. Distal vaginal tumors treated surgically may require inguinal lymph node dissection. Sentinel node evaluation has been demonstrated in cases of vaginal melanoma,^108,109 but not extensively in squamous cell vaginal cancer. Surgical intervention is also useful as an adjunct to radiation therapy for more advanced lesions and to treat tumors that do not respond to radiation. Davis and colleagues⁹⁵ reported that the Mayo Clinic surgical experience yielded a 5-year survival rate of 82%. Patients with central recurrences or persistence of tumor after radiotherapy are candidates for exenterative surgery.

Stage I

Stage I carcinoma of the vagina is primarily treated with radiation therapy.^{91,103,104,105} Lesions of the vagina that involve the upper vaginal fornices, particularly the posterior and lateral fornices, allow the option of surgical treatment involving a radical hysterectomy, pelvic lymphadenectomy, and partial or total vaginectomy.

In patients with stage I lesions, it is important to individualize radiation therapy techniques to obtain optimal subsequent vaginal function. Superficial tumors can be treated with cylinder brachytherapy alone to the entire vagina (6000–7000 cGy mucosal dose and an additional 2000–3000 cGy mucosal dose to the tumor area).^{91,102,103,104,105}

Larger lesions may require an interstitial implant to selectively increase the tumor dose and limit excessive radiation to the entire vaginal mucosa.^{92,101,102,103,104,105,106} A dose of 6000 to 6500 cGy is delivered to the entire vaginal mucosa, and an additional 1500 to 2000 cGy is calculated 0.5 cm beyond the plane of the implant to the gross tumor, with the involved vaginal mucosa receiving an estimated 8000–10,000 cGy.^{91,92,101,102,103,104,105}

Use of external beam radiation in stage I disease should be considered to supplement intracavitary and interstitial therapy for bulky lesions, marked infiltration, or poor differentiation. The whole pelvis is treated with 1000 to 2000 cGy. Additional split pelvic radiation to a total dose of 4500–5000 cGy to the parametria should be delivered.^{91,92,93,94,101,102,103,104,105}

Stage II

Patients with stage IIa¹² disease have significantly improved survival compared with patients with more advanced disease. Perez and associates⁹⁶ suggest that these patients should be treated with a greater external radiation dose: 2000 cGy to the whole pelvis and an additional parametrial dose with a midline block, for a total dose of 4500 to 5000 cGy (in comparison with stage I patients). A combination of interstitial and intracavitary therapy can also be used to deliver 5000–6000 cGy 0.5 cm beyond the deep margin of the tumor in addition to the whole-pelvis dose for gross disease.

Advanced Disease: Stages III and IV

For advanced disease (including IIb¹²), a 4000-cGy dose to the whole pelvis and a 5500-cGy to 6000-cGy total parametrial dose (with midline shielding) have been given in combination with interstitial and intracavitary insertions to deliver a total vaginal mucosal dose of 7500 to 10,000 cGy; the total dose to a depth of 0.5 cm from the vaginal mucosa is 6000 to 8000 cGy.^{91,92,93,96,97,98,99,100,101,102,103,104,105,106}

Treatment of Vaginal Recurrence

Tabata and collegues¹¹⁰ noted that all relapses in their patients with stage 0-II tumors were local. Poor outcome in patients with advanced-stage disease stemmed from either local persistence or new distant spread. The authors highlight the importance of aggressive local control. Isolated recurrences can be effectively treated with surgery after postradiation local failure. The surgical procedure can range from a wide local excision or partial vaginectomy to a pelvic exenteration.^47,105

Radiation is the treatment of choice after primary surgical therapy has failed. The Syed-Nesbitt template used for interstitial brachytherapy in a patient treated for recurrent vaginal clear-cell adenocarcinoma is shown in Figure 5A. An orthogonal radiograph obtained for treatment planning is shown in Figure 5B. Figure 5C demonstrates the isodose plan. This patient received interstitial iridium (Ir) 192 after external beam radiation therapy.

With adequate therapy, the survival rates of patients with squamous cell carcinoma of the vagina are comparable with those reported for cervical cancer. The most important predictor of survival is stage^10,33 (Table 4). The overall 5-year survival rate is 80%. The 5-year survival rates for the International Federation of Gynecology and Obstetrics (FIGO) stage I tumors range from 66% to 90%.

Table 4. 5-Year Overall Survival Rates for Primary Vaginal Carcinoma

Regarding stage II disease, Kirkbride and coworkers⁹¹ reported a 5-year survival rate of 82% for patients treated with radiation therapy. Stock and colleagues¹⁰⁵ reported a significant improvement in disease-free survival (DFS) in patients treated with surgery (53%) compared with that of those treated with radiation therapy (31%). The variation in survival ranged from 31% to 82% and was dependent on many factors, such as tumor stage (IIA vs. IIB), lesion size, histologic type and grade, tumor location, patient age, treatment modality, and radiation dose. Older patients with large, poorly differentiated tumors have a significantly worse prognosis when compared with other patients within the same disease stage.

The 5-year survival rate for patients with more advanced disease (stage III and stage IV) ranges from 0% to 62%. Lee and associates¹⁰⁴ found that the single most important predictor of pelvic control was overall treatment time. They found that if the entire course of radiotherapy was completed within 9 weeks (63 days), the pelvic control rate was 67% for stage IVA and 97% for all stages. However, the pelvic control rate was only 54% if treatment time extended beyond 9 weeks (p = .0003).

Malignant tumors of the vagina are rare and commonly present with abnormal vaginal bleeding. It is a diagnosis of exclusion. If there is evidence of a primary tumor in an adjacent organ, then the vaginal cancer diagnosis cannot be made. Major histologic subtypes include squamous cell carcinoma, adenocarcinoma (typically clear cell), small-cell carcinoma, melanoma, endodermal sinus tumor, and sarcoma (particularly embryonal rhabdomyosarcoma). Radiation therapy is generally considered the treatment of choice because of excellent tumor control and good functional results. Surgical procedures may be reserved for the treatment of radiation failures, nonepithelial tumors, and early-stage disease in young, sexually active women. FIGO stage, patient age, lymph node status, histologic grade, and radiation treatment time are predictors of survival^10,104.

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