William J. Lowery, Junzo Chino, and Laura J. Havrilesky
Primary vaginal cancer is an uncommon gynecologic malignancy and constitutes only 1% to 2% of gynecologic malignancies. Because of its rarity, there are specific guidelines for the diagnosis of primary vaginal cancer. A malignancy located in the vagina and not involving any adjacent pelvic organs is considered to be a primary vaginal cancer. If the malignancy extends to the cervix or vulva, it is considered a primary lesion of the nonvaginal site. Based on the observation that 95% of patients with recurrent cervical cancer will experience relapse within 5 years, all squamous cell carcinomas identified in the vagina within this period are defined as recurrences. Only those squamous cell carcinomas found more than 5 years after the diagnosis of cervical cancer are defined as primary vaginal cancers.1 If there is a history of endometrial cancer, a diagnosis of adenocarcinoma in the vagina is usually considered a recurrence regardless of the time from primary treatment.
Primary vaginal malignancies are most commonly located in the upper third of the vagina and on the posterior wall (Figure 10-1). The most common histo-logic type is squamous cell carcinoma, which accounts for approximately 80% of all primary vaginal malignancies. Less commonly encountered are adenocarcinomas (10%), melanomas (3%), sarcomas (3%), and other rare tumors. Eighty-four percent of malignancies identified in the vagina are secondary, most commonly originating from the cervix (32%) and endometrium (18%); less common primary sites include the vulva, gastrointestinal tract, and ovary, as well as gestational trophoblastic disease.2
FIGURE 10-1. Squamous cell carcinoma of the vagina. (Reprinted with permission of Robboy SJ and Robboy Associates LLC [Chapel Hill, NC], copyright holder of Robboy’s Pathology of the Female Reproductive Tract,Elsevier Pub, London.)
Prior to the mid-20th century, vaginal cancer was generally considered to be an incurable disease. Advances in radiation therapy and surgical techniques have been associated with significant improvement in cure rates, even in women with advanced disease.
1. Risk factors for vaginal cancer include human papillomavirus infection, smoking, in utero diethylstilbestrol exposure, and a prior history of cervical cancer.
2. Vaginal intraepithelial neoplasia (VAIN) is a potential precursor lesion to invasive squamous cell carcinoma of the vagina.
3. A history of pelvic radiation is a risk factor for vaginal sarcoma.
Primary vaginal cancer is a rare entity and constitutes only 1% to 2% of gynecologic malignancies. It has an incidence of approximately 1 in 100,000 women per year. The American Cancer Society estimates that there will be 2300 new vaginal cancers diagnosed in 2010 with approximately 780 deaths.3
The peak incidence of vaginal cancer is in the sixth and seventh decades. Risk factors for the disease closely mirror those for cervical cancer and include an increased number of lifetime sexual partners, younger age at first intercourse, human papillomavirus (HPV) infection, history of smoking, in utero diethylstilbestrol exposure, and a prior history of cervical cancer.4,5 There is also an association between vaginal cancer and chronic vaginal irritation, as with long-term pessary use. In a 10-year review of the National Cancer Data Base, Creasman and colleagues6 observed that survival was related to the stage of disease and the histologic type, with melanoma having the poorest prognosis. In a later review of the Surveillance, Epidemiology, and End Result (SEER) program by Shah and colleagues,7 stage, tumor size, histology, and treatment modality were the most significant prognostic factors.
Although VAIN is recognized as a premalignant condition, its progression rate to invasive cancer is not well understood. Aho and colleagues8 followed 23 patients with untreated VAIN in an attempt to define the natural history of the disease and reported a 9% progression rate from high-grade VAIN to vaginal cancer among women who were followed for at least 3 years. A subsequent retrospective study by Schookaert and colleagues9 examining the incidence of high-grade VAIN after hysterectomy for high-grade cervical intraepithelial neoplasia also suggested progression from VAIN to invasive vaginal cancer. A total of 7.6% of patients developed VAIN 2, VAIN 3, or invasive carcinoma with a mean interval between hysterectomy and the first vaginal biopsy of 45 months, with 3% of these high-grade vaginal lesions subsequently progressing to invasive vaginal cancer. All of the patients were reported to have had a negative vaginal colposcopy before their hysterectomy for cervical dysplasia, suggesting that the subsequent cancers were of vaginal origin.
One recognized risk factor for the development of vaginal cancer is a history of treatment for an anogenital tumor. In a large, population-based, case control study, Daling and colleagues5 reported that 30% of women with vaginal cancer had a history of treatment for an anogenital tumor. This is most likely secondary to the shared pathophysiology of HPV infections. Up to 90% of anal cancers in women harbor HPV; previous treatment for a genital cancer confers a 10-fold increased risk of anal cancer.10 Other risk factors for squamous cell carcinoma of the vagina include pelvic radiation, tobacco abuse, and other factors associated with HPV, such as an increased number of sexual partners and younger age at first intercourse. Finally, 10% to 20% of women with a primary vaginal cancer have a history of pelvic irradiation, most commonly as treatment for cervical cancer. A prior history of pelvic radiotherapy is more frequent in women with vaginal sarcomas than in women with vaginal cancers of other histologic subtypes.
1. Vaginal cancer may present with an abnormal Pap smear or with vaginal bleeding.
2. Biopsy of suspicious vaginal lesions is critical to diagnosis of this disease.
Vaginal cancer is often identified at the time of screening for cervical cancer. Although there is ample literature addressing optimal strategies to screen for cervical cancer, the rarity of vaginal cancer makes it difficult to assess any screening strategy. It is generally accepted that women who have had a hysterectomy for benign disease do not need continued vaginal cytologic screening if there is no evidence of HPV-related cervical lesions on pathology. There is also agreement that it is likely safe for older women to discontinue screening if there is a history of negative cytology and an absence of risk factors. Women who have been treated for cervical cancer should continue to undergo routine surveillance with vaginal cytologic testing. It is also reasonable to continue to screen women who have undergone a hysterectomy and who have a history of cervical dysplasia.11
The most common presenting symptom of vaginal cancer is abnormal vaginal bleeding. Other presenting symptoms include abnormal discharge and pelvic pain or dysuria, although these often present later in the disease course secondary to tumor spread outside of the vagina. A careful vaginal examination is required in these patients, as a small lesion can be difficult to visualize in the folds of the vagina or can be covered by blades of the speculum. The differential diagnosis for vaginal lesions is broad (Table 10-1), and biopsy should never be delayed when a suspicious lesion is encountered.
Table 10-1 Differential Diagnosis for Vaginal Lesions
The most common symptom at diagnosis of a vaginal melanoma is vaginal bleeding,12,13 but up to one-third of these lesions present as a mass at the time of routine pelvic examination.13 The majority of vaginal melanomas are pigmented or ulcerated at diagnosis, but up to one-fourth have been reported as grossly amelanotic.12,13 The most common location for vaginal melanoma is the lower anterior vaginal wall.
Sarcomas are often bulky lesions that appear most commonly in the upper vagina. Sarcoma botryoides is a subtype of rhabdomyosarcoma and primarily affects children, predominantly arising from the anterior wall of the vagina. The name derives from the Greek word for grapes and grossly has a grapelike cluster appearance.
In general, computed tomography (CT) and, more recently, positron emission tomography (PET) or single-photon emission computed tomography (SPECT) have been shown to be a valuable adjunct in the identification of lymph node metastasis. Although not part of the standard staging criteria, these imaging techniques may have a role in surgical and/or radiation therapy planning.
1. Squamous cell carcinomas comprise the majority of vaginal cancers, and up to 70% are associated with infection with high-risk HPV subtypes.
2. Adenocarcinomas of the vagina are commonly of clear cell histology and are attributed to in utero exposure to diethylstilbestrol.
3. Vaginal cancers are clinically staged using International Federation of Gynecology and Obstetrics (FIGO) criteria; this system is limited by the accuracy of determining extension into subvaginal tissues.
Squamous cell carcinomas (Figure 10-2) comprise approximately 80% of primary vaginal malignancies and histologically resemble squamous cell carcinomas of the cervix. There is no established or consistent precursor lesion to vaginal cancer. HPV infection appears to be associated with the development of vaginal cancer, similar to cervical cancer. Daling and colleagues5 detected HPV in the tissue of more than 80% of patients with carcinoma in situ and more than 60% of patients with invasive squamous cell cancer. More recent studies have suggested that approximately 70% of squamous cell vaginal cancers and greater than 90% of VAIN 2 and VAIN 3 can be attributed to high-risk HPV subtypes.14,15
FIGURE 10-2. Squamous cell carcinoma. Hematoxylin and eosin stain of squamous cell carcinoma of the vagina showing malignant invasion of the dermal layer with associated inflammatory reaction. (Image contributed by Dr. Rex Bentley.)
Adenocarcinomas of the vagina (Figure 10-3) account for approximately 10% of primary vaginal carcinomas. The origin of these lesions may include embryonic elements and normal glandular tissue residing in the vagina. The majority of reported cases are clear cell adenocarcinomas in individuals exposed in utero to diethylstilbestrol (DES). These DES-associated adenocarcinomas are histologically identical to the clear cell adenocarcinomas of the ovary and endometrium. DES is a synthetic nonsteroidal estrogen that was used from the 1930s until 1971 primarily to prevent spontaneous miscarriage in patients considered as high risk. Herbst and Scully16 described 7 women aged 15 to 22 years with clear cell adenocarcinoma of the vagina and noted that 6 of these patients had been exposed to DES in utero. DES was subsequently removed from the market in the United States. Herbst and Scully16 subsequently established a registry to track cases of clear cell adenocarcinoma. As of December 2007, the registry has accessioned approximately 760 cases of clear cell adenocarcinoma of the vagina and cervix, two-thirds of which were associated with DES exposure. Hatch and colleagues17 examined the cancer risk in daughters exposed to DES and found that the standardized incidence ratio for clear cell adenocarcinoma was 40 times that expected in the general population. The age-incidence curve peaks between the ages of 15 and 25 years, with an estimated risk of development of 1 per 1000 of these individuals exposed, but cases up to the age of 55 have been accessioned to the registry.
FIGURE 10-3. Clear cell adenocarcinoma. Hematoxylin and eosin stain of clear cell carcinoma of the vagina showing clear cells secondary to a large quantity of glycogen in the cytoplasm. (Image contributed by Dr. Rex Bentley.)
The number of DES-associated adenocarcinomas has sharply declined over the last several decades after the removal of DES from the market. Frank and colleagues18 described a series of patients with primary non–DES-associated adenocarcinoma of the vagina. The patients presented at an older age and, stage for stage, carried a worse prognosis than DES-associated adenocarcinoma. Local and distant recurrence rates were also higher in non–DES-associated malignancies.18 The role of HPV in the pathogenesis of non–clear cell adenocarcinomas of the vagina is unclear.
There are several vaginal cancers of less common histology; these include melanomas, sarcomas, verrucous carcinomas, and endodermal sinus tumors. Vaginal melanoma (Figure 10-4) constitutes 3% to 5% of all vaginal malignancies19,20 and less than 1% of all melanomas19,21 and occurs at a mean age of 60 to 65 years. Unlike many cutaneous melanomas, exposure to ultraviolet radiation is not a risk factor for mucosal melanomas. Melanoma is thought to arise from melanocytes, which are present as a normal variant in the vaginal epithelium in approximately 3% of women.22
FIGURE 10-4. Melanoma. Hematoxylin and eosin stain of melanoma demonstrating melanocytes proliferating along the dermal/epidermal juction in a continuous band with scattered single melanocytes extending into the upper layers of the dermis. (Image contributed by Dr. Angelica Selim.)
Sarcomas account for approximately 3% to 4% of all primary malignancies of the vagina.6,23 Prior radiotherapy is a risk factor, with 35% of cases having a history of pelvic radiotherapy, usually for cervical cancer, 8 to 26 years prior.24 Grade is an important prognostic factor; a series of 24 vulvar and vaginal sarcomas demonstrated no deaths in patients with low-grade tumors, whereas the 5-year overall survival rate was approximately 50% for high-grade lesions.25 There was no survival difference between leiomyosarcomas and other histologic types in this series, although numbers were limited.
Embryonal rhabdomyosarcoma is the most common malignant neoplasm of the vagina in infants and children and accounts for 75% of the vaginal rhabdomyosarcomas. Although a majority of these cases are diagnosed before age 5 years, these malignancies can be found elsewhere in the female genital tract later in life.
Verrucous carcinoma is a rare malignancy of the female genital tract, with only a few cases reported in the vagina. It is primarily found in postmenopausal women. HPV is likely a causative agent or factor in its development, but the pathogenesis is not completely understood. It is a slowly growing tumor that generally “pushes” into adjacent tissue rather than invades it, and accompanying inflammatory enlargement of the regional lymph nodes is encountered as opposed to metastasis.26
Endodermal sinus tumors, or yolk sac tumors, are germ cell tumors that are rarely found in the vagina. They are primarily diagnosed before the age of 3 years. The most common presenting symptom is vaginal bleeding. In children, the majority of germ cell tumors are extragonadal, with thoracic and central nervous system being most common. Only a small proportion of these are primary vaginal tumors.27The most common presenting symptom is vaginal bleeding. α-Fetoprotein is generally elevated in these patients and can be used as a marker of response to treatment.
Metastatic Spread Patterns
The vagina is bordered laterally by the levator ani muscles, pelvic fascia, and ureters. Deep invasion anteriorly or posteriorly can result in bladder or rectal involvement, which may lead to fistula formation during or after radiotherapy. Disease extending to the sidewall may result in ureteral obstruction and renal failure. The lymphatic drainage of vaginal cancers is complex and depends on the anatomic level of the lesion. Much like cervical cancer, the lymphatic drainage can follow multiple pathways.28 The upper two-thirds of the vagina drain into the internal and external iliac lymph nodes, whereas the lower one-third drains into the sacral, common iliac, and superficial inguinal lymph nodes.
Vaginal cancer is clinically staged using the criteria established by the International Federation of Gynecology and Obstetrics (FIGO) (Table 10-2), which uses history and physical examination, routine laboratory evaluation, bimanual rectovaginal examination, cystos-copy, proctoscopy, intravenous pyelogram, and plain film radiographs if there is a concern for bony metastasis. One of the limitations of this staging system is the inability to accurately determine spread into subvaginal tissues. This is reflected in a wide range of survival data within a given stage. Perez and colleagues1 have suggested that stage II disease be subdivided into 2 groups: (1) lesions that involve the submucosa but do not extend into the parametria, and (2) lesions that involve the parametria without reaching the pelvic sidewall, but this has not consistently been demonstrated to have prognostic significance.7,29
Table 10-2 Staging of Vaginal Cancer Adapted From the International Federation of Gynecology and Obstetrics
Because it does not account for tumor size or regional lymph node status, the FIGO staging system is not generally used for melanomas. Likewise, the Clark and Chung methods are not applicable because of the difference in histologic landmarks between cutaneous structures and the vagina. Vaginal melanomas may best be classified using the Breslow thickness,30 which describes the tumor thickness, or the American Joint Committee on Cancer (AJCC) staging system (AJCC 2001), which takes into account thickness, presence or absence of ulceration, lymph node metastasis, and other metastatic sites of disease.19 The size of the lesion is an important prognostic factor as well, with a size of greater than 3 cm generally indicating worse outcomes.31-33 Similarly, the staging of sarcoma botryoides follows that of pediatric rhabdomyosarcoma.
1. Stage I squamous cell carcinomas of the vagina may be treated primarily with surgical excision or primary radiotherapy. Advanced-stage lesions likely requiring postsurgical radiation are typically managed with primary radiotherapy alone.
2. Lymph node dissection is recommended with surgical excision of early-stage vaginal cancers.
3. Radiotherapy is the treatment of choice for a majority of vaginal cancers because of its effectiveness in achieving long-term survival and preservation of adjacent organs; chemosensitization with platinum regimens may improve disease control.
Stage I squamous cell carcinoma of the vagina may be treated either surgically or with primary radiotherapy, and this decision should be tailored not only to the size of the lesion, but also to the patient’s desire to maintain optimal sexual function (Figure 10-5). Minimally invasive lesions discovered incidentally at the time of surgical excision of presumed VAIN have been managed with surveillance with acceptable outcomes.34,35 Women who have small, known invasive lesions and who have previously undergone a hysterectomy are usually treated by partial or total vaginectomy, parametrectomy, and lymph node dissection. For women who have an intact uterus, radical hysterectomy is also indicated.36-38 A significant portion of patients who undergo primary surgical therapy also receive adjuvant radiotherapy, with lymph node metastasis or surgical margin involvement being the most common indications.36-39Those at high risk for requiring postoperative radiation, as when lymph node metastasis is suspected, are generally not also subjected to primary surgical excision, as this combination is associated with higher rates of adverse events.
FIGURE 10-5. Treatment of vaginal cancer by stage algorithm. Vaginal cancer treatment decision tree.
Adenocarcinoma of the vagina is treated similarly to squamous cell carcinoma. In the past, consideration was given to conservation of ovarian and sexual function, as patients with early-stage DES-associated adenocarcinoma were usually younger, but DES-associated malignancies are now a rare entity. Simple excision is not recommended for adenocarcinomas regardless of size because of their more aggressive nature and propensity for lymphatic spread, and as with squamous cell carcinomas, options include radical surgery or primary radiotherapy with or without chemotherapy.18
Although the role of lymph node metastasis is not well defined in the FIGO staging system, it is a poor prognostic indicator. As outlined earlier, the lymphatic drainage of the vagina is somewhat complicated and depends on the level of the lesion. In patients undergoing surgical management of early-stage vaginal cancer, a lymph node dissection is routinely performed.36,38 Because the majority of patients diagnosed with vaginal cancer undergo radiation therapy, the true incidence of lymph node metastasis is unknown. Identification of sentinel nodes has the potential to aid in radiation treatment planning. Frumovitz and colleagues40 were able to identify a sentinel node in 79% of the patients with vaginal cancer evaluated with pretreatment lymphoscintigraphy, and van Dam and colleagues41 were able to detect a sentinel lymph node in 2 of 3 patients with vaginal cancer laparoscopically.
Radiotherapy (RT) is an effective, curative treatment modality for vaginal cancer and is often the treatment of choice for many reasons. First, radical surgery to remove large, invasive primary vaginal lesions with negative margins often carries risks of significant morbidity because of the close proximity of the vagina to critical structures; RT affords preservation of adjacent organs. Second, the vagina is an ideal site for brachy-therapy (BT) for conformal treatment to curative doses. Finally, given the broad lymph drainage patterns of vaginal cancer, prophylactic nodal treatment is often more appropriately accomplished with whole-pelvic RT than with multiple large dissections.
Combined Chemotherapy and Radiotherapy for Vaginal Cancer
Interest in combining chemotherapy and RT for treatment of vaginal cancer has increased in the last decade as a result of the tremendous success with concurrent cisplatin-based regimens in cervical cancer.42-45 Because of the small numbers and stage heterogeneity, direct comparison of combined chemotherapy plus RT and RT alone is difficult. Most series include a majority of advanced-stage disease, and in this unfavorable cohort, disease control is achievable using combined chemotherapy and RT in approximately 50% to 60% of patients. Concurrent chemotherapy is generally well tolerated in appropriately selected patients, and there is no evidence of significantly worse late toxicity as compared with RT alone. As such, it has been our approach to include concurrent platinum-based chemotherapy in the treatment of appropriate patients with advanced-stage disease.
RT for vaginal cancer is highly individualized and depends on the site and extent of disease, as well as the tolerance of neighboring critical organs. Before initiation of treatment, it is optimal for the radiation oncologist to perform a thorough physical examination to delineate the location of the primary disease and its extent. Often fiducial markers (radio-opaque seeds) are placed during the initial examination so that appropriate boost planning can be performed. If this is not done, in the event of a response to initial external-beam RT, boost planning can only be based on estimates of the initial extent of disease.
The use of brachytherapy alone should be limited to the smallest and most favorable vaginal lesions (low grade, ≤ 5-mm thick, ≤2 cm in greatest diameter). In these selected cases, the entire vaginal mucosa is treated to between 50 and 60 Gy, with a boost at the primary site to a total dose of 65 to 85 Gy to 5-mm depth. The technique is best established with low-dose rate applicators, although experience with high-dose rate applicators is comparable.46 Whole vaginal treatment can be accomplished with a single line of intracavitary sources; boost doses can be achieved by loading only the most superior positions in the case of apical lesions, whereas for distal or lateral lesions, using asymmetrically leaded cylinders or differential loading of multicatheter applicators can result in more optimal dose distributions (Figure 10-6). Doses to the normal vaginal mucosa at the apex should be limited to 140 Gy, with the distal mucosa limited to 100 Gy.
FIGURE 10-6. Intracavitary brachytherapy. A. Single-channel intracavitary brachytherapy for a thin apical lesion. The prescription isodose line is green and is symmetric. B. Multichannel intracavitary brachytherapy for a thin lateral wall lesion. The green prescription isodose line is well lateralized.
Whole-pelvic RT is generally included in unfavorable stage I patients and in all those with stage II or greater disease. For those with disease limited to the proximal third of the vagina, standard pelvic fields are appropriate either via anterior-posterior (AP)/posterior-anterior (PA) field arrangement or a 4-field technique. Care should be taken to extend the field inferiorly to obtain a minimum of a 4-cm margin on the vaginal disease. Doses of 45 to 50 Gy in 1.8- to 2-Gy daily fractions are used. Some investigators advocate the addition of a midline block after 10 to 20 Gy, relying on brachytherapy for treatment of the central disease and thus sparing the bladder and rectum.
In situations in which the inguinal nodal basins are at risk (ie, involvement of the distal two-thirds of the vagina), the inguinofemoral nodes must be covered. Opposed AP/PA fields appropriately cover the targets, but lead to a significant dose to the femoral heads. A wide AP (covering the inguinofemoral basins) and narrow PA field (blocking the majority of the femoral heads) may be used, with supplemental anterior electrons or low-energy photons to portions of the AP field blocked in the PA, which can significantly reduce femoral head dose (Figure 10-7).47 Intensity-modulated radiotherapy (IMRT) has shown promise in reducing dose to the femoral heads, the intergluteal cleft, and nontarget pelvic organs, although special care must be taken to account for both inter- and intra-fractional organ motion due to the highly conformal nature of the treatment (Figure 10-8).48-50
FIGURE 10-7. Wide AP and narrow PA technique for treating inguinofemoral nodes. Wide AP (A) and narrow PA (B) fields may be used to spare femoral heads; however, the portion of the AP field that is blocked in the PA must be supplemented with additional electrons or low-energy photons to bring dose to prescription.
FIGURE 10-8. Opposed AP-PA treatment versus IMRT for treatment of inguinofemoral nodes. A. Opposed AP-PA fields cover targets appropriately but treat the femoral heads to full dose. B. IMRT may be used to spare the femoral heads and other neighboring critical structures.
Gross disease should be treated to a total dose 65 to 85 Gy as normal tissue tolerance allows. Generally brachytherapy is the preferred modality for boosting after whole-pelvic RT, as it offers extremely conformal isodose distributions and eliminates the need for organ motion margins. Both intracavitary and interstitial techniques are often used to boost gross disease, as dictated by the extension of the primary and normal tissue tolerance. For thin lesions (≤ 5 mm) of the vaginal vault, intracavitary techniques previously described are quite sufficient for treatment. For thicker lesions, an interstitial implant is required.
Several techniques exist for interstitial implants, including the Syed-Neblett template, the Martinez Universal Perineal Interstitial Template, and other freehand and custom template techniques (Figure 10-9).51,52 These techniques all involve the introduction of needles or catheters through the volume, requiring treatment with approximately 1-cm spacing and ideally with a 1- to 2-cm margin around the target. If there is close approximation of the target volume and the peritoneum (such as in a post-hysterectomy apical tumor), laparoscopy is used to ensure that the peritoneal cavity is not entered. Treatment planning can be performed with orthogonal films or with CT and/or magnetic resonance imaging (MRI). Iridium-192 (Ir-192) wires or stranded seeds are then after loaded into the catheters/needles after treatment planning. Interstitial boosts are ideal for thick apical and lateral wall lesions. Discrete distal anterior and posterior lesions can also be treated with interstitial boosts, or combined with an external-beam RT boost.
FIGURE 10-9. Customized interstitial template for a deeply invasive lateral lesion. A. A perineal template is fashioned based on clinical examination and imaging, with holes drilled to guide interstitial catheters. B. After completing external-beam radiotherapy, the patient is brought to the OR for catheter placement. C. CT or MRI 3-dimensional treatment planning is performed, and catheters are loaded with Ir-192 strands in a shielded inpatient room. (Images courtesy of Gustavo Montana, MD.)
For large and extensive lesions or for disease extension into areas in which an implant will not cover adequately, 3-dimensional (3D) conformal or IMRT boosts are often required to cover the targets appropriately. Often the dose to the target must be limited to ≤ 75 Gy due to normal tissue limits. Special care must be taken to ensure that tightly conformal plans are indeed treating the correct volumes, and regular use of real-time confirmation (cone-beam CT and on-board imaging) is extremely useful. Even with the best imaging, however, intra fractional motion must still be accounted for.
An additional application for 3D conformal/IMRT boosts is for node-positive disease. With careful treatment planning and image guidance, boosts to involved lymph nodes can be designed to take these regions of gross disease to 55 to 65 Gy, although this is often limited by approximation to small bowel, particularly in the upper pelvis and para-aortic region. Significant volumes of small bowel should not be taken beyond 50 to 52 Gy due to the risk of obstruction, fistula, and perforation.
Treatment of Melanoma
The primary treatment of vaginal melanoma remains surgical. Although several case series have suggested that radical procedures such as exenteration should be the preferred approach,33,53 other studies have failed to demonstrate either superior local control or a survival advantage for radical surgery.32 Given the increased morbidity of radical procedures and the poor 5-year survival of vaginal melanoma regardless of treatment approach, conservative resection procedures are most commonly used. RT has been used for the primary, neoadjuvant, adjuvant, and palliative setting for vaginal melanoma.19,31,54 Although primary surgical intervention has generally been associated with better outcomes than primary radiotherapy in limited case series of vaginal melanoma, selection of healthier and better-prognosis patients for surgery undoubtedly biases these studies in favor of the surgical approach. In general, primary RT has been reserved for women who refuse surgery or are poor operative candidates.
Primary surgery for vaginal melanoma should consist, at a minimum, of the wide excision of all visible disease.13 RT has been added after conservative surgery, with several small series suggesting improved locoregional control when radiotherapy is incorporated.31,55 There are several case reports suggesting satisfactory palliative outcomes with salvage radiotherapy using brachytherapy or external-beam treatment.56
Routine inguinal or pelvic lymphadenectomy have no known therapeutic value in the management of vaginal melanoma. Assessment for distant sites of disease is usually made using CT or PET/CT. For patients with vaginal melanoma in whom no distant disease is detected on imaging, consideration may be given to sentinel lymph node assessment; approximately 10 such cases have been reported in the literature.13,19,57,58 For women with lower vaginal lesions, identification and removal of groin sentinel lymph nodes may be reasonable for prognostic purposes.
Treatment of Sarcoma
Primary surgery is the preferred treatment, with RT reserved for selected postoperative cases, or for definitive management of those who are not appropriate for surgery. There are scant data on chemotherapy for vaginal leiomyosarcoma or carcinosarcoma, and it has not been routinely incorporated into initial treatment for localized disease. Agents chosen to treat recurrent or metastatic vaginal sarcomas are derived from the uterine experience; the preferred agents in leiomyosarcoma are doxorubicin, gemcitabine, and docetaxel, whereas carcinosarcomas are commonly treated with ifosfamide, platinum, and paclitaxel.59-63
In children, rhabdomyosarcoma is the dominant histologic type. The prognosis is good in most patients with initial chemotherapy, followed by tailored surgery or RT in those with residual disease. In the National Cancer Data Base study, 30 pediatric patient were identified, the majority with rhabdomyosarcoma.6 More than 75% of the pediatric cases were treated with chemotherapy, and 80% had surgery.
Treatment of Verrucous Carcinoma
Given the indolent nature of verrucous carcinoma and the fact that spontaneous metastasis is rare, local excision of the tumor is generally accepted as the therapy of choice. The use of RT in the treatment of verrucous carcinoma is controversial. There is concern for ana-plastic transformation of verrucous carcinomas of both head and neck sites and the female genital tract,64,65 but other investigators have used RT with success.66
Treatment of Endodermal Sinus Tumor
In the past, the treatment of vaginal endodermal sinus tumors has consisted of chemotherapy in combination with surgery as well as RT. Although effective, this treatment regimen leaves little hope for future fertility. More recently, there have been multiple reports of successful treatment with chemotherapy only, using a regimen of cisplatin, etoposide, and bleomycin.67,68
SURVIVAL AND PROGNOSIS
1. Stage remains the most important prognostic factor in vaginal cancers.
2. Surgical management may afford improved survival in early-stage vaginal cancers, but data may be biased as a result of patient selection factors.
3. Rhabdomyosarcomas have an excellent prognosis, with 5-year survival rates of 90%.
According to the SEER database, the overall 5-year survival rate after a diagnosis of vaginal cancer is 51.4%. Clinical stage is recognized as the most important prognostic factor. Although vaginal cancer appears to have a shared pathophysiology with cervical and vulvar cancer, it has a worse prognosis at each stage. The 5-year survival rate for each stage is as follows: stage I, 77.6%; stage II, 52.2%; stage III, 42.5%; stage IVA, 20.5%; stage IVB, 12.9%69(Figures 10-10 and 10-11).
FIGURE 10-10. Vaginal cancer: overall survival by stage. Overall survival by stage for vaginal cancer, adapted from SEER data.
FIGURE 10-11. Vaginal cancer: cause-specific survival by stage. Cause-specific survival by stage for vaginal cancer, adapted from SEER data.
Selected early-stage disease may be treated with surgery, surgery followed by tailored adjuvant RT, or RT alone (Table 10-3). In retrospective series, women with stage I disease treated with surgery alone, the majority having squamous lesions, have a 5-year survival rate of 85% to 92%.6,37,38 Those with stage II disease managed surgically have a 49% to 70% 5-year survival rate.6,38 In these same series, the 5-year survival rates for women with stage I and stage II disease undergoing primary RT are 44% to 63% and 50% to 57%, respectively. Women treated with a combination of surgery and adjuvant RT have comparable outcomes: Tjalma and colleagues37 reported a 71% 5-year survival rate for women with stage I disease, whereas Davis and colleagues38 reported a 100% and 69% survival rate for women with stage I and II disease, respectively. Although survival in these series appears to favor the surgical management of early-stage disease, selection bias likely accounts for some of the observed difference in outcomes.
Table 10-3 Results for Definitive Radiotherapy With and Without Chemotherapy for Vaginal Cancer by FIGO Stage
Advanced-stage vaginal lesions are usually treated with concurrent chemotherapy and RT. Historically, prognostic data are based on RT alone, with a 5-year survival rate of approximately 35%,6 but more recent analyses include patients who received concurrent chemotherapy. The Mallinckrodt Institute1 reported 212 patients managed with primary RT from 1953 through 1991. The majority of patients with advanced-stage disease received both external-beam RT and brachytherapy; 10-year disease-specific survival was 38% for stage III disease. The MD Anderson Cancer Center reported a series of 301 women, of whom 66% with stage III or IVA disease were treated with external-beam RT alone, whereas 17% of the advanced-stage disease cohort received chemotherapy as well. The 5-year disease-specific survival rate was 58% women with stage III/IVA disease, and 5-year pelvic control was 71%.70 A series of 153 women from Princess Margaret Hospital (PMH) reported that patients with advanced-stage disease who underwent RT or RT with concurrent chemotherapy had a cause-specific survival of 60% for stage III and 42% for stage IV disease.71 Vaginal stenosis is commonly encountered after RT, with Kirkbride and colleagues71 reporting an incidence of 38%. Severe adverse events occur in 10% to 13% of patients undergoing primary RT, most commonly proctitis, vaginal necrosis, intestinal obstruction, or fistula formation.2,70,71
For the most part, clinical series include adenocarcinomas. In patients who have clear cell adenocarcinoma as a result of DES exposure in utero, the 5-year survival rate is improved for early-stage disease but worse for late-stage disease. Herbst72 reported that the 5-year survival rate for women with stage I clear cell adenocarcinoma exceeded 90% but reported no 5-year survivors with stage IV disease.
In the National Cancer Data Base study, of 105 adults with vaginal sarcomas, leiomyosarcoma was the dominant histology (46 of 105), with 25 cases of complex, mixed, or stromal tumors.6 Sixty-seven of 105 were treated surgically, with 29 receiving adjuvant RT and 10 receiving adjuvant chemotherapy. Five-year overall survival rates were 84% in women aged 20 to 49 years and 48% in women aged 50 to 69 years, and 2-year survival was 30% in women ≥ 70 years. In the largest single series of 17 patients, the 3 long-term survivors had stage I or II disease and had exenteration as primary treatment.24 The 5-year survival rate for patients with leiomyosarcoma was 36%. It was noted that most recurrences were pelvic; therefore, judicious postoperative RT may be considered when optimal resection is not possible.
Rhabdomyosarcomas typically have a better prognosis. The 5-year survival rate reported in 12 children less than 5 years of ages was 90% in the National Cancer Data Base study. In one series, 38 children with vaginal, vulvar, or uterine rhabdomyosarcoma were enrolled on sequential International Society of Pediatric Oncology trials; the majority were treated with chemotherapy initially, with the most common regimen consisting of ifosfamide, vincristine, and actinomycin D.73 Seventeen of 38 required additional local treatment, with 10 undergoing RT, 3 undergoing surgery, and 4 undergoing both RT and surgery. The 5-year survival rate was 91%, with a disease-free survival rate of 78%. Additional series from the Intergroup Rhabdomyosarcoma Study support the use of chemotherapy followed by conservative surgery and/or RT for residual disease.74
The prognosis of vaginal melanomas is generally poor, with 5-year survival rates ranging from 5% to 25% in various case series.21,31,55,75
MANAGEMENT OF RECURRENT DISEASE
1. Local recurrences of vaginal cancer may be curable with radiotherapy or pelvic exenteration.
2. Distant recurrences are typically managed with chemotherapy, although prognosis is poor.
Management of recurrent vaginal cancer provides a significant challenge. Factors to consider before determining therapy include previous treatment modalities, extent of recurrent disease, site of recurrence, and the patient’s health and performance status. Consideration must also be given to whether the goal of treatment is curative or palliative. Distant metastasis is generally associated with a poor prognosis, but patients with small local recurrences are potentially curable.
The majority of recurrences are pelvic, with a historical 5-year survival rate of 12% after salvage therapy.70 Improvements in RT and advances in chemotherapy have the potential to increase the survival of this population of women. In patients with central recurrences who underwent surgical management as their primary treatment, the treatment of choice is RT. In patients who have previously received RT with local recurrence, treatment is usually limited to pelvic exenteration. Berek et al76 noted an approximately 50% 5-year survival rate in patients who underwent pelvic exenterations for recurrent or persistent gynecologic malignancies, including vaginal cancer.
Herbst4 noted a 23% recurrence rate in patients with a history of clear cell adenocarcinoma of the vagina. Sixty percent of patients had recurrence in the pelvis, 36% in the lungs, and 20% in the supraclavicular lymph nodes. Various treatment strategies were evaluated, including chemotherapy, RT, and radical surgery, with a 3-year survival rate of only 20%. Patients with small central recurrences had an overall better prognosis when treated with surgical management.
SPECIAL MANAGEMENT PROBLEMS
The majority of malignancies identified in the vagina are metastatic in origin. Most cases are secondary to direct invasion or lymphatic spread from the primary tumor, and the diagnosis is easily made. In rare cases, the metastasis is from a distant organ and the diagnosis can prove challenging. Although case reports of metastasis to the vagina are reported from a wide variety of sites, treatment is generally guided by the origin of the primary tumor.
Gestational trophoblastic disease (GTD) often metastasizes to the vagina, which is second only to the lung as the most common site of distant spread. Berry and colleagues77 reported vaginal metastases from GTD in 4.5% of patients. The World Health Organization does not consider vaginal metastasis as a high-risk prognostic factor, and according to FIGO, GTD with metastasis confined to genital structures is considered stage II disease and is usually treated with single-agent chemotherapy, most commonly methotrexate.77,78 Although metastatic disease to the vagina has a good prognosis, vaginal tumors are often highly vascular and can cause significant hemorrhage when biopsied.
Given the low number of patients diagnosed with primary vaginal cancer, it is unlikely that there will ever be randomized control trials evaluating different treatment regimens. With the shared pathophysiology between squamous cells carcinoma of the vagina and cervix, the results of randomized trials involving cervical cancer may be cautiously applied to the treatment of vaginal cancer. It is likely that widespread acceptance and utilization of the HPV vaccine will further reduce the number of cases of vaginal carcinoma, although the degree of this reduction is a matter of debate.
1. Perez CA, Grigsby PW, Garipagaoglu M, Mutch DG, Lockett MA. Factors affecting long-term outcome of irradiation in carcinoma of the vagina. Int J Radiat Oncol Biol Phys. 1999;44(1):37-45.
2. Fu Y. Pathology of the Uterine Cervix, Vagina, and Vulva. 2nd ed. Philadelphia, PA: Saunders; 2002.
3. American Cancer Society. Vaginal Cancer. 2010. http://www.cancer.org/Cancer/VaginalCancer/DetailedGuide/vaginal-cancer-key-statistics. Accessed January 10, 2012.
4. Herbst AL, Norusis MJ, Rosenow PJ, Welch WR, Scully RE. An analysis of 346 cases of clear cell adenocarcinoma of the vagina and cervix with emphasis on recurrence and survival. Gynecol Oncol.1979;7(2):111-122.
5. Daling JR, et al. A population-based study of squamous cell vaginal cancer: HPV and cofactors. Gynecol Oncol. 2002;84(2):263-270.
6. Creasman WT, Phillips JL, Menck HR. The National Cancer Data Base report on cancer of the vagina. Cancer. 1998;83(5): 1033-1040.
7. Shah CA, Goff BA, Lowe K, Peters WA. Factors affecting risk of mortality in women with vaginal cancer. Obstet Gynecol. 2009;113(5):1038-1045.
8. Aho M, Vesterinen E, Meyer B, Purola E, Paavonen J. Natural history of vaginal intraepithelial neoplasia. Cancer. 1991;68(1): 195-197.
9. Schockaert S, Poppe W, Arbyn M, Verguts T, Verguts J. Incidence of vaginal intraepithelial neoplasia after hysterectomy for cervical intraepithelial neoplasia: a retrospective study. Am J Obstet Gynecol.2008;199(2):113e1-113e5.
10. Jimenez W, Paszat L, Kupets R, Wilton A, Tinmouth J. Presumed previous human papillomavirus (HPV) related gynecological cancer in women diagnosed with anal cancer in the province of Ontario. Gynecol Oncol.2009;114(3):395-398.
11. ACOG Practice Bulletin no. 109. Cervical cytology screening. Obstet Gynecol. 2009;114(6):1409-1420.
12. Gupta D, Malpica A, Deavers MT, Silva EG. Vaginal melanoma: a clinicopathologic and immunohistochemical study of 26 cases. Am J Surg Pathol. 2002;26(11):1450-1457.
13. Miner TJ, Delgado R, Zeisler J, et al. Primary vaginal melanoma: a critical analysis of therapy. Ann Surg Oncol. 2004;11(1):34-39.
14. Insinga RP, Liaw KL, Johnson LG, Madeleine MM. A systematic review of the prevalence and attribution of human papillomavirus types among cervical, vaginal, and vulvar precancers and cancers in the United States. Cancer Epidemiol Biomarkers Prev. 2008;17(7):1611-1622.
15. Smith JS, Backes DM, Hoots BE, Kurman RJ, Pimenta JM. Human papillomavirus type-distribution in vulvar and vaginal cancers and their associated precursors. Obstet Gynecol. 2009;113(4):917-924.
16. Herbst AL, Scully RE. Adenocarcinoma of the vagina in adolescence. A report of 7 cases including 6 clear-cell carcinomas (so-called mesonephromas). Cancer. 1970;25(4):745-757.
17. Hatch EE, Palmer JR, Titus-Ernstoff L, et al. Cancer risk in women exposed to diethylstilbestrol in utero. JAMA. 1998;280(7):630-634.
18. Frank SJ, Deavers MT, Jhingran A, Bodurka DC, Eifel PJ. Primary adenocarcinoma of the vagina not associated with diethylstilbestrol (DES) exposure. Gynecol Oncol. 2007;105(2): 470-474.
19. Piura B. Management of primary melanoma of the female urogenital tract. Lancet Oncol. 2008;9(10):973-981.
20. Sugiyama VE, Chan JK, Kapp DS. Management of melanomas of the female genital tract. Curr Opin Oncol. 2008;20(5):565-569.
21. Weinstock MA. Malignant melanoma of the vulva and vagina in the United States: patterns of incidence and population-based estimates of survival. Am J Obstet Gynecol. 1994;171(5): 1225-1230.
22. Nigogosyan G, Delapava S, Pickren JW. Melanoblasts in vaginal mucosa. Origin for primary malignant melanoma. Cancer. 1964; 17:912-913.
23. Herbst AL, Green TR Jr, Ulfelder H. Primary carcinoma of the vagina. An analysis of 68 cases. Am J Obstet Gynecol. 1970;106(2): 210-218.
24. Peters WA 3rd, Kumar NB, Andersen WA, Morley GW. Primary sarcoma of the adult vagina: a clinicopathologic study. Obstet Gynecol. 1985;65(5):699-704.
25. Curtin JP, Saigo P, Slucher B, Venkatraman ES, Mychalczak B, Hoskins WJ. Soft-tissue sarcoma of the vagina and vulva: a clinicopathologic study. Obstet Gynecol. 1995;86(2):269-272.
26. Powell JL, Franklin EW, 3rd, Nickerson JF, Burrell MO. Verrucous carcinoma of the female genital tract. Gynecol Oncol. 1978;6(6):565-573.
27. Handel LN, Scott SM, Giller RH, Greffe BS, Lovell MA, Koyle MA. New perspectives on therapy for vaginal endodermal sinus tumors. J Urol. 2002;168(2):687-690.
28. Plentl AA, Friedman EA. Lymphatic system of the female genitalia. The morphologic basis of oncologic diagnosis and therapy. Major Probl Obstet Gynecol. 1971;2:1-223.
29. Lian J, Dundas G, Carlone M, Ghosh S, Pearcey R. Twenty-year review of radiotherapy for vaginal cancer: an institutional experience. Gynecol Oncol. 2008;111(2):298-306.
30. Breslow A. Thickness, cross-sectional areas and depth of invasion in the prognosis of cutaneous melanoma. Ann Surg. 1970;172(5):902-908.
31. Petru E, Nagele F, Czerwenka K, et al. Primary malignant melanoma of the vagina: long-term remission following radiation therapy. Gynecol Oncol. 1998;70(1):23-26.
32. Reid GC, Schmidt RW, Roberts JA, Hopkins MP, Barrett RJ, Morley GW. Primary melanoma of the vagina: a clinicopatho-logic analysis. Obstet Gynecol. 1989;74(2):190-199.
33. Van Nostrand KM, Lucci JA, 3rd, Schell M, Berman ML, Manetta A, DiSaia PJ. Primary vaginal melanoma: improved survival with radical pelvic surgery. Gynecol Oncol. 1994;55(2): 234-237.
34. Hoffman MS, DeCesare SL, Roberts WS, Fiorica JV, Finan MA, Cavanagh D. Upper vaginectomy for in situ and occult, superficially invasive carcinoma of the vagina. Am J Obstet Gynecol. 1992;166(1 pt 1):30-33.
35. Peters WA 3rd, Kumar NB, Morley GW. Microinvasive carcinoma of the vagina: a distinct clinical entity? Am J Obstet Gynecol. 1985;153(5):505-507.
36. Stock RG, Chen AS, Seski J. A 30-year experience in the management of primary carcinoma of the vagina: analysis of prognostic factors and treatment modalities. Gynecol Oncol. 1995;56(1):45-52.
37. Tjalma WA, Monaghan JM, de Barros Lopes A, Naik R, Nordin AJ, Weyler JJ. The role of surgery in invasive squamous carcinoma of the vagina. Gynecol Oncol. 2001;81(3):360-365.
38. Davis KP, Stanhope CR, Garton GR, Atkinson EJ, O’Brien PC. Invasive vaginal carcinoma: analysis of early-stage disease. Gynecol Oncol. 1991;42(2):131-136.
39. Cutillo G, Cignini P, Pizzi G, et al. Conservative treatment of reproductive and sexual function in young woman with squamous carcinoma of the vagina. Gynecol Oncol. 2006;103(1): 234-237.
40. Frumovitz M, Gayed IW, Jhingran A, et al. Lymphatic mapping and sentinel lymph node detection in women with vaginal cancer. Gynecol Oncol. 2008;108(3):478-481.
41. van Dam P, Sonnemans H, van Dam PJ, Verkinderen L, Dirix LY. Sentinel node detection in patients with vaginal carcinoma. Gynecol Oncol. 2004;92(1):89-92.
42. Eifel PJ, Winter K, Morris M, et al. Pelvic irradiation with concurrent chemotherapy versus pelvic and para-aortic irradiation for high-risk cervical cancer: an update of radiation therapy oncology group trial (RTOG) 90-01. J Clin Oncol. 2004;22(5):872-880.
43. Rose PG, Ali S, Watkins E, et al. Long-term follow-up of a randomized trial comparing concurrent single agent cisplatin, cisplatin-based combination chemotherapy, or hydroxyurea during pelvic irradiation for locally advanced cervical cancer: a Gynecologic Oncology Group Study. J Clin Oncol. 2007;25(19): 2804-2810.
44. Whitney CW, Sause W, Bundy BN, et al. Randomized comparison of fluorouracil plus cisplatin versus hydroxyurea as an adjunct to radiation therapy in stage IIB-IVA carcinoma of the cervix with negative para-aortic lymph nodes: a Gynecologic Oncology Group and Southwest Oncology Group study. J Clin Oncol. 1999;17(5):1339-1348.
45. Peters WA 3rd, Liu PY, Barrett RJ, 2nd, et al. Concurrent chemotherapy and pelvic radiation therapy compared with pelvic radiation therapy alone as adjuvant therapy after radical surgery in high-risk early-stage cancer of the cervix. J Clin Oncol. 2000;18(8):1606-1613.
46. Mock U, Kucera H, Fellner C, Knocke TH, Potter R. High-dose-rate (HDR) brachytherapy with or without external beam radiotherapy in the treatment of primary vaginal carcinoma: long-term results and side effects. Int J Radiat Oncol Biol Phys. 2003;56(4):950-957.
47. Gilroy JS, Amdur RJ, Louis DA, Li JG, Mendenhall WM. Irradiating the groin nodes without breaking a leg: a comparison of techniques for groin node irradiation. Med Dosim. 2004;29(4):258-264.
48. Taylor A, Powell ME. An assessment of interfractional uterine and cervical motion: implications for radiotherapy target volume definition in gynaecological cancer. Radiother Oncol. 2008;88(2):250-257.
49. Beadle BM, Jhingran A, Salehpour M, Sam M, Iyer RB, Eifel PJ. Cervix regression and motion during the course of external beam chemoradiation for cervical cancer. Int J Radiat Oncol Biol Phys.2009;73(1):235-241.
50. Chen YJ, Liu A, Tsai PT, et al. Organ sparing by conformal avoidance intensity-modulated radiation therapy for anal cancer: dosimetric evaluation of coverage of pelvis and inguinal/femoral nodes. Int J Radiat Oncol Biol Phys.2005;63(1):274-281.
51. Fleming P, Nisar Syed AM, Neblett D, Puthawala A, George FW, 3rd, Townsend D. Description of an afterloading 192Ir interstitial-intracavitary technique in the treatment of carcinoma of the vagina. Obstet Gynecol.1980;55(4):525-530.
52. Martinez A, Cox RS, Edmundson GK. A multiple-site peri-neal applicator (MUPIT) for treatment of prostatic, anorectal, and gynecologic malignancies. Int J Radiat Oncol Biol Phys. 1984;10(2):297-305.
53. Geisler JP, Look KY, Moore DA, Sutton GP. Pelvic exenteration for malignant melanomas of the vagina or urethra with over 3 mm of invasion. Gynecol Oncol. 1995;59(3):338-341.
54. Bonner JA, Perez-Tamayo C, Reid GC, Roberts JA, Morley GW. The management of vaginal melanoma. Cancer. 1988;62(9):2066-2072.
55. Irvin WP Jr, Bliss SA, Rice LW, Taylor PT, Jr., Andersen WA. Malignant melanoma of the vagina and locoregional control: radical surgery revisited. Gynecol Oncol. 1998;71(3):476-480.
56. McGuire SE, Frank SJ, Eifel PJ. Treatment of recurrent vaginal melanoma with external beam radiation therapy and palladium-103 brachytherapy. Brachytherapy. 2008;7(4):359-363.
57. Abramova L, Parekh J, Irvin WP, Jr., et al. Sentinel node biopsy in vulvar and vaginal melanoma: presentation of six cases and a literature review. Ann Surg Oncol. 2002;9(9):840-846.
58. Kobayashi K, Ramirez PT, Kim EE, et al. Sentinel node mapping in vulvovaginal melanoma using SPECT/CT lymphoscintigraphy. Clin Nucl Med. 2009;34(12):859-861.
59. Muss HB, Bundy B, DiSaia PJ, et al. Treatment of recurrent or advanced uterine sarcoma. A randomized trial of doxorubicin versus doxorubicin and cyclophosphamide (a phase III trial of the Gynecologic Oncology Group). Cancer. 1985;55(8):1648-1653.
60. Sutton G, Blessing JA, Ball H. Phase II trial of paclitaxel in leiomyosarcoma of the uterus: a gynecologic oncology group study. Gynecol Oncol. 1999;74(3):346-349.
61. Thigpen JT, Blessing JA, Beecham J, Homesley H, Yordan E. Phase II trial of cisplatin as first-line chemotherapy in patients with advanced or recurrent uterine sarcmas: a Gynecologic Oncology Group study. J Clin Oncol. 1991;9(11):1962-1966.
62. Homesley HD, Filiaci V, Markman M, et al. Phase III trial of ifosfamide with or without paclitaxel in advanced uterine carcinosarcoma: a Gynecologic Oncology Group Study. J Clin Oncol.2007;25(5):526-531.
63. Sutton G, Brunetto VL, Kilgore L, et al. A phase III trial of ifosfamide with or without cisplatin in carcinosarcoma of the uterus: a Gynecologic Oncology Group Study. Gynecol Oncol. 2000;79(2):147-153.
64. Perez CA, Kraus FT, Evans JC, Powers WE. Anaplastic transformation in verrucous carcinoma of the oral cavity after radiation therapy. Radiology. 1966;86(1):108-115.
65. Crowther ME, Lowe DG, Shepherd JH. Verrucous carcinoma of the female genital tract: a review. Obstet Gynecol Surv. 1988;43(5):263-280.
66. Huang SH, Lockwood G, Irish J, et al. Truths and myths about radiotherapy for verrucous carcinoma of larynx. Int J Radiat Oncol Biol Phys. 2009;73(4):1110-1115.
67. Terenziani M, preafico F, Collini P, Meazza C, Massimino M, Piva L. Endodermal sinus tumor of the vagina. Pediatr Blood Cancer. 2007;48(5):577-578.
68. Lacy J, Capra M, Allen L. Endodermal sinus tumor of the infant vagina treated exclusively with chemotherapy. J Pediatr Hematol Oncol. 2006;28(11):768-771.
69. Beller U, Benedet JL, Creasman WT, et al. Carcinoma of the vagina. FIGO 6th Annual Report on the Results of Treatment in Gynecological Cancer. Int J Gynaecol Obstet. 2006;95(suppl 1):S29-S42.
70. Chyle V, Zagars GK, Wheeler JA, Wharton JT, Delclos L. Definitive radiotherapy for carcinoma of the vagina: outcome and prognostic factors. Int J Radiat Oncol Biol Phys. 1996;35(5):891-905.
71. Kirkbride P, Fyles A, Rawlings GA, et al. Carcinoma of the vagina—experience at the Princess Margaret Hospital (1974-1989). Gynecol Oncol. 1995;56(3):435-443.
72. Herbst AL, Anderson D. Clear cell adenocarcinoma of the vagina and cervix secondary to intrauterine exposure to diethylstilbestrol. Semin Surg Oncol. 1990;6(6):343-346.
73. Martelli H, Oberlin O, Rey A, et al. Conservative treatment for girls with nonmetastatic rhabdomyosarcoma of the genital tract: a report from the Study Committee of the International Society of Pediatric Oncology. J Clin Oncol.1999;17(7):2117-2122.
74. Andrassy RJ, Hays DM, Raney RB, et al. Conservative surgical management of vaginal and vulvar pediatric rhabdomyosarcoma: a report from the Intergroup Rhabdomyosarcoma Study III. J Pediatr Surg. 1995;30(7):1034-1036; discussion 1036-1037.
75. Ragnarsson-Olding B, Johansson H, Rutqvist LE, Ringborg U. Malignant melanoma of the vulva and vagina. Trends in incidence, age distribution, and long-term survival among 245 consecutive cases in Sweden 1960-1984. Cancer. 1993;71(5):1893-1897.
76. Berek JS, Howe C, Lagasse LD, Hacker NF. Pelvic exenteration for recurrent gynecologic malignancy: survival and morbidity analysis of the 45-year experience at UCLA. Gynecol Oncol.2005;99(1):153-159.
77. Berry E, Hagopian GS, Lurain JR. Vaginal metastases in gestational trophoblastic neoplasia. J Reprod Med. 2008;53(7):487-492.
78. El-Helw LM, Hancock BW. Treatment of metastatic gestational trophoblastic neoplasia. Lancet Oncol. 2007;8(8):715-724.
79. Ball HG, Berman ML. Management of primary vaginal carcinoma. Gynecol Oncol. 1982;14(2):154-163.
80. Frank SJ, Jhingran A, Levenback C, Eifel PJ. Definitive radiation therapy for squamous cell carcinoma of the vagina. Int J Radiat Oncol Biol Phys. 2005;62(1):138-147.
81. de Crevoisier R, Sanfilippo N, Gerbaulet A, et al. Exclusive radiotherapy for primary squamous cell carcinoma of the vagina. Radiother Oncol. 2007;85(3):362-370.
82. Tran PT, Su Z, Lee P, et al. Prognostic factors for outcomes and complications for primary squamous cell carcinoma of the vagina treated with radiation. Gynecol Oncol. 2007;105(3): 641-649.
83. Samant R, Lau B, E C, Le T, Tam T. Primary vaginal cancer treated with concurrent chemoradiation using Cis-platinum. Int J Radiat Oncol Biol Phys. 2007;69(3):746-750.
84. Nashiro T, Yagi C, Hirakawa M, et al. Concurrent chemo-radiation for locally advanced squamous cell carcinoma of the vagina: case series and literature review. Int J Clin Oncol. 2008;13(4):335-339.
85. Dalrymple JL, et al. Chemoradiation for primary invasive squamous carcinoma of the vagina. Int J Gynecol Cancer. 2004;14(1): 110-117.
86. Sinha B, Stehman F, Schilder J, Clark L, Cardenes H. Indiana University experience in the management of vaginal cancer. Int J Gynecol Cancer. 2009;19(4):686-693.