Vaginal Cancer - Perez & Brady's Principles and Practice of Radiation Oncology (Perez and Bradys Principles and Practice of Radiation Oncology), 6 Ed.

Perez & Brady's Principles and Practice of Radiation Oncology (Perez and Bradys Principles and Practice of Radiation Oncology), 6 Ed.

Chapter 72. Vaginal Cancer

Josephine Kang and Akila N. Viswanathan

Primary vaginal cancer is a rare malignancy, constituting 1% to 2% of all gynecologic malignancies. According to the American Cancer Society estimates for 2010, there were approximately 2,300 new cases and 780 deaths from this disease.¹ The majority of malignant lesions in the vagina are metastatic from other gynecologic malignancies or involve direct extension from adjacent sites, which excludes diagnosis as a primary vaginal malignancy. According to the staging system set by the International Federation of Obstetrics and Gynecology (FIGO), a diagnosis of primary vaginal cancer excludes any tumors involving the cervix or vulva.² According to one study of 141 vaginal carcinoma cases, only 26% met the criteria of being a primary vaginal cancer,³ defined as a lesion that arises in the vagina without involving the cervix or vulva.

The majority of primary vaginal malignancies are squamous cell carcinomas (SCC). According to a National Cancer Data Base (NCDB) report⁴ based on 4,885 patients with primary vaginal cancer registered from 1985 to 1994, approximately 92% of patients were diagnosed with in situ or invasive SCC or adenocarcinomas, 4% with melanomas, 3% with sarcomas, and 1% with other or unspecified types of cancer. Sixty-six percent of all vaginal cancers were invasive, with SCC representing 79% of all invasive cases.

The peak incidence of primary vaginal cancer is in the sixth and seventh decades of life. According to data from the Surveillance, Epidemiology, and End Results (SEER) program,¹ 2,149 women in the United States were diagnosed with primary vaginal cancer from 1990 to 2004. The mean age at diagnosis was 65.7 ± 14.3 years and incidence rates increased with age. Vaginal cancer incidence is increasing in younger women, possibly due to an increase in human papilloma virus (HPV) infection or other sexually transmitted diseases. However, there has been an overall decrease in the incidence of primary vaginal tumors, possibly attributable to earlier detection and to implementation of strict exclusion criteria in the FIGO staging system. At the same time, there has been a steady increase in the diagnosis of vaginal intraepithelial neoplasia (VAIN) over the past several decades, due to expanded cytologic screening and increased awareness.⁵ Due to infrequent presentation, treatment recommendations are based on results from relatively small retrospective series, the majority of which are based on heterogeneous patient populations and treatments.

ANATOMY

The vagina is a fibromuscular tube that extends from the cervix down to the vestibule, or cleft, between the labia minora (Fig. 72.1). It lies dorsal to the urethra and bladder base and ventral to the rectum. Superiorly, it joins the uterine cervix at an angle and, as a result, the posterior vaginal wall is longer than the anterior wall, with an overall average length of 7.5 cm. The upper aspect of the posterior vaginal wall is separated from the rectum by a reflection of peritoneum, the pouch of Douglas. The cervix projects into the upper lumen of the vagina, creating invaginations between the vaginal mucosa and the cervix, which are termed the anterior, posterior, and lateral fornices. Inferiorly, the vagina extends through the urogenital diaphragm and lies directly adjacent to the rectum up to where the fibromuscular perineal body tissue separates the vagina from the anal canal. Laterally, the vagina is adjacent to the pelvic fascia and levator ani muscles. At the introitus, the vagina has a perforated fold of thin connective tissue and mucous membrane known as the hymen.

The vaginal wall is composed of three layers: the mucosa, muscularis, and adventitia. The inner lining of the vagina is formed by a nonkeratinizing stratified squamous epithelium overlying a basement membrane with many papillae. The epithelium lacks glandular structures and instead receives lubrication from mucous secretions originating in the cervix. Underneath the mucosa is connective tissue composed of elastin and a thick muscularis layer composed of two layers of smooth muscle. The inner layer is arranged circularly, whereas the outer layer is arranged longitudinally. This muscular layer is covered by a thin adventitia that merges with neighboring organs. At the vaginal introitus, skeletal muscle forms a sphincter.

Proximally, the vagina is supplied by the vaginal artery, which arises from the cervical branch of the uterine artery and runs lateral to the vagina until it anastomoses with the inferior vesical and middle rectal arteries. The venous plexus runs parallel to the arteries, draining into the internal iliac vein. The vaginal vault is innervated by the lumbar plexus and pudendal nerve, with branches from sacral roots 2 to 4.⁶

The vagina has a complex, extensive network of lymphatic drainage, with vessels that course through the submucosal and muscularis layer. The uppermost portion drains primarily via cervical lymphatics. The superior anterior vagina drains along cervical channels to the interiliac and parametrial nodes, and the posterior upper vagina drains into the inferior gluteal, presacral, and anorectal nodes (Fig. 72.2). The inferior aspect of the vagina drains into the inguinal and femoral nodes and ultimately to the pelvic nodes, following drainage patterns of the vulva. Lesions in the midvagina have been shown to drain either way.⁷ Lesions infiltrating the rectovaginal septum may spread to the pararectal and presacral nodes. There are multiple interconnections between lymphatic channels, and pattern of drainage cannot be reliably predicted based on location of the primary tumor. Embryologically, the vagina is believed to be of dual origin, with the upper third derived from the uterine canal, while the lower two-thirds are derived from the urogenital sinus.⁸

EPIDEMIOLOGY, PRESENTATION, AND GENERAL MANAGEMENT

Vaginal Intraepithelial Neoplasia

Epidemiology

Incidence of VAIN is estimated to be 0.2 to 0.3 cases per 100,000, with peak incidence between 40 and 60 years of age.⁵^,⁹^,¹⁰ Most studies do not report differences in mean age between women with low-grade and those with high-grade VAIN,¹¹^–¹⁵ although a few series have reported that patients with VAIN-1 or -2 were younger than patients with VAIN-3.¹⁶^–¹⁹ Incidence of in situ vaginal cancer is estimated to be 0.1 per 100,000 women, with peak incidence between ages 70 to 79, according to data from the U.S. Centers for Disease Control and Prevention’s National Program of Cancer Registries, and the National Cancer Institute’s SEER program.²⁰ Risk factors for VAIN include low sociocultural level, history of genital warts, hysterectomy at an early age, history of cervical intraepithelial neoplasia, immunosuppression, prior pelvic radiation, smoking, exposure to diethylstilbestrol (DES), and history of sexually transmissible diseases (STDs) or HPV infection.¹⁵^,¹⁷^,²¹^,²²

The diagnosis of VAIN is associated with prior or concurrent neoplasia elsewhere in the lower genital tract. Multiple series suggest approximately 50% to 90% of patients with VAIN have concurrent or prior history of intraepithelial neoplasia or carcinoma of the cervix or vulva.⁹^,¹⁶^,¹⁷ Immunosuppression from human immunodeficiency virus (HIV) is also a risk factor for both VAIN and HPV, although a higher incidence of invasive vaginal cancer in infected women has not been demonstrated.²³^–²⁵ The role of pelvic radiation in the development of secondary vaginal neoplasia is unclear, with conflicting data suggesting a history of ionizing radiation may predispose to VAIN or vaginal cancer after a latency period of many years.¹²^,²⁶^,²⁷ In utero exposure to DES may double the risk of VAIN, thought to be due to transformation zone enlargement, increasing the risk of HPV infection.²⁸

FIGURE 72.1. Median section of the female pelvis. The vagina is a fibromuscular tube situated posterior to the bladder and urethra and anterior to the rectum. The anterior and posterior fornices are formed by protrusion of the cervix into the vaginal canal. (From Moore KL. Clinical oriented anatomy, 4th ed. Baltimore: Lippincott Williams & Wilkins, 1999, with permission.)

Natural History

Although the likelihood of VAIN progressing to invasive disease is not fully understood, several clinical series have demonstrated a significant increase in risk of invasive vaginal cancer after a diagnosis of VAIN.¹²^,¹⁶^,²⁹^,³⁰ Similar risk factors for VAIN and invasive vaginal cancer, as well as the younger average age at presentation of VAIN compared with invasive disease, add support to the theory that VAIN may be a precursor lesion to invasive SCC. In one series, 23 patients with VAIN, with a mean age of 41 years, were followed for at least 3 years without treatment;¹⁶ this included multifocal lesions as well as lesions associated with cervical intraepithelial neoplasia (CIN) or vulvar dysplasia. Two cases (9%) progressed to invasive cancer; one patient had VAIN-1 and progressed to stage I vaginal carcinoma in 5 years, and the second patient had VAIN-3 and progressed to stage I vaginal carcinoma in 4 years. The overall spontaneous regression rate was 78%, with the majority (78%) occurring in patients with VAIN-1 or -2. Similarly, several additional studies have demonstrated a range of 2% to 20% of patients with VAIN progressing to invasive vaginal cancer.¹²^,¹⁶^,²⁹^,³¹^–³³

The rate of occult invasive disease in patients with VAIN-3 has been reported to be as high as 28%.³⁴ The risk of malignant transformation in VAIN-1 and -2 is less clearly elucidated; there have been reports of patients with low-grade VAIN subsequently developing invasive vaginal carcinoma.¹⁴^,¹⁵

FIGURE 72.2. Lymphatic drainage of the vagina to the inguinal and pelvic lymph nodes. (Asset provided by the Anatomical Chart Company.)

Pathology

VAIN is defined as the presence of squamous cell atypia without evidence of invasion (Fig. 72.3). VAIN is further classified according to depth of epithelial involvement, with involvement of the lower one-third, two-thirds, and greater than two-thirds of the epithelium classified as VAIN-1, -2 and -3, respectively. Carcinoma in situ encompasses the full epithelial thickness and is included under VAIN-3. Excluded from diagnosis of VAIN is the presence of glandular intraepithelial dysplasia or atypical vaginal adenosis; these entities are associated with in utero DES exposure and are deemed to be precursors of DES-associated clear cell adenocarcinoma.³⁵ VAIN is frequently multifocal and most commonly involves the upper portion of the vagina.

Histopathologically, most lesions are epidermoid and exhibit full-thickness alterations with atypical mitoses and hyperchromatism (Fig. 72.3).³⁶ Punctation and mosaic patterns are often noted with high-grade VAIN.¹⁴ Most lesions are multifocal and can involve all surfaces of the vagina, although the superior one-third of the vagina is most common.¹²^,¹⁶

VAIN is associated with HPV infection.³⁷ A review of 232 published VAIN cases documented a high prevalence of HPV using polymerase chain reaction or hybrid capture assays for detection, with 98.5% and 92.6% of VAIN-1 and VAIN-2 or -3 cases positive for HPV.³⁸ A series by Sugase and Matsukura³⁹ examining 71 biopsy specimens of VAIN found HPV in 100% of samples. Fifteen different known subtypes were identified (HPV-16, -18, -30, -31, -35, -40, -42, -43, -51, -52, -53, -54, -56, -58, -66). Types HPV-16 or -18 comprised 9%, 7%, and 67% of VAIN-1, -2, and -3 cases, respectively.

FIGURE 72.3. Normal vaginal epithelium (A), vaginal intraepithelial neoplasia (VAIN)-2 (B) and VAIN-3 (C). Compared with normal vaginal mucosa, VAIN lesions display architectural and cytologic abnormalities, such as nuclear hyperchromasia, pleomorphism, undifferentiated cells scattered within the epithelium, and cellular crowding. In VAIN-3, dysplastic cells involve the full epithelial thickness without stromal invasion. (Courtesy of Marisa R. Nucci and Carlos Parra-Herran.)

Clinical Presentation

VAIN is usually asymptomatic¹² and most commonly detected after cytologic evaluation as part of surveillance in patients with a history of CIN or invasive cervical carcinoma. According to the American Cancer Society guidelines from 2002, surveillance cytology for VAIN in posthysterectomy patients is recommended if there is a history of cervical pathology.⁴⁰ However, evidence does not support routine surveillance in patients without a history of CIN or invasive cervical cancer.

Prognostic Factors

A study by So et al.⁴¹ on 48 women with VAIN reports a significant association between higher viral load of HPV and the likelihood of persistent disease after treatment. There is also an association between a history of pelvic radiation and development of VAIN,³³^,⁴²^,⁴³ with up to 20% of patients with prior radiation developing vaginal dysplasia. A retrospective review of 33 patients with VAIN treated at the University of Pennsylvania found patients with a history of radiation therapy to be more refractory to treatment, with a significantly higher likelihood of recurrence after surgical and ablative therapy.³¹ Patients with a history of radiation had an odds ratio of 3.6 for recurrent disease (95% confidence interval, 1.5 to 9.0) compared with patients without a history of radiation.

Treatment Options

The management of VAIN is heterogeneous, with a wide variety of treatments available. There is currently no consensus on optimal treatment modality, as reported data are generally retrospective and based on decades of experience with varied treatments and patient characteristics; thus it is difficult to compare different treatment modalities (Table 72.1). Treatment approaches include local excision, partial or total vaginectomy, laser vaporization, electrocoagulation, topical 5% fluorouracil (5-FU) administration, and radiation.¹⁴^,¹⁵^,¹⁷^–¹⁹^,⁴⁷^,⁵⁴^,⁶⁴^,⁶⁶^,⁶⁷ Reported success rates for different approaches range from 48% to 100% for laser vaporization,⁵⁰^,⁶⁸^,⁶⁹ 52% to 100% for colpectomy,³⁴^,⁴⁷^,⁵¹ 75% to 100% for topical 5-FU,⁵³^,⁵⁴^,⁵⁵^,⁵⁶^,⁷⁰^,⁷¹^,⁷²^,⁷³ and 83% to 100% for radiation.⁶¹^,⁶²^,⁶⁵^,⁶⁷^,⁷⁴ Given the breadth of available therapies, an individualized approach to patient management is advised, with consideration given to the patient’s overall health, desire to preserve sexual function, candidacy for surgery, disease multifocality, and prior treatment failures.

Most patients with VAIN-1 are offered close surveillance. Lesions often regress spontaneously; in one study by Aho et al.,¹⁶ 78% of patients with VAIN-1 or -2 had spontaneous regression of disease without treatment. Appropriate treatment for VAIN-2 should be determined on an individual basis, based on disease extent and associated patient factors. Therapy for VAIN-3 should be more aggressive, as there is a higher likelihood of progression to invasive disease, including occult invasive disease.³⁴^,⁴⁷

TABLE 72.1 LOCAL CONTROL OF VAGINAL INTRAEPITHELIAL NEOPLASIA BY TREATMENT MODALITY

Surgical and Ablative Therapies

Surgical approaches include local excision, partial vaginectomy, and, in rare cases, total vaginectomy for highly extensive disease, which provides the advantage of obtaining a complete pathologic diagnosis. Most resections can be performed through a transvaginal approach. Location of VAIN in the vaginal vault or posthysterectomy suture recesses may require partial vaginectomy for complete resection.

Local therapy is achieved through a cold-knife approach, electrosurgical loop excision, laser, or via ultrasonic surgical aspiration.⁷⁵^–⁷⁷ The carbon dioxide laser has been used for ablation of local tissue, with multiple treatments required in approximately one-third of patients.⁴⁹^,⁵⁰^,⁵²^,⁵⁶^,⁶⁹^,⁷⁸^,⁷⁹ Complications include postoperative pain, scarring, and bleeding; however, the treatment is overall fairly well tolerated, with minimum impact on sexual function.⁸⁰Diakomanolis et al.⁵¹ reported on 52 patients who underwent laser treatment or partial vaginectomy and found results to favor laser ablation for multifocal disease and partial vaginectomy for unifocal disease. Ultrasonic surgical aspiration is another technique that has shown efficacy similar that of to laser ablation; in one series of 110 patients, 1-year recurrence-free survival rates were 24% and 26%, respectively.⁴⁷

Series on surgical treatment of VAIN report recurrence rates in the range of 0% to 50%, with follow-up times ranging from 3 months to 18 years.⁹^,¹²^,¹⁷^,³⁴^,⁴⁴ Overall, series looking specifically at upper vaginectomy report control rates of 68% to 88%.¹⁹^,²⁹^,³⁴^,⁴⁷^,⁵¹ For example, Hoffman et al.³⁴ reported that 83% of patients with VAIN-3 remained free of disease with a mean follow-up time of 38 months. Of note, 28% of all patients were found to have occult invasive disease upon upper vaginectomy. A subsequent study by Indermaur et al.,⁴⁷ which retrospectively reviewed 36 patients treated with upper vaginectomy for VAIN, reported 88% to be free of recurrence with a mean follow-up time of 25 months. Thirteen patients (12%) were found to have invasive cancer; 8 of 13 had frank invasive disease, while 5 patients had microinvasive carcinoma. Complication rates of upper vaginectomy have been variably reported; in the series by Indermaur et al.,⁴⁷ there was a 9% complication rate. Potential complications from surgery depend on the extent and method of surgical resection, and they range from vaginal shortening and stenosis to standard postoperative morbidity associated with abdominal procedures. It should be noted that patients with a history of radiation treatment are at higher risk of postoperative complications, with a higher rate of fistula formation reported in one study.⁹

Topical Treatments

Topical therapies have been utilized in patients with early-stage lesions, multifocal disease, or multiple comorbidities, rendering them nonideal surgical candidates. Topical applications have also been utilized prior to surgery to reduce lesion size and improve stripping of neoplastic epithelial cells from underlying stroma.¹⁷ Treatments include topical 5-FU and 5% imiquimod cream, with response rates in 71% to 78% of patients for imiquimod and 41% to 88% for 5-FU.⁵³^,⁵⁵^,⁵⁶^,⁵⁷^,⁵⁸^,⁶⁷^,⁷¹^,⁷²^,⁸¹^,⁸² Imiquimod increases levels of interferon-alfa, interleukin-12, and tumor necrosis factor,⁵⁸ resulting in immunomodulation of the vaginal mucosa. Side effects of topical treatments include local irritation, with burning and ulceration being the most commonly reported adverse events.⁵³^,⁷¹

Radiation Therapy

Radiation therapy is an alternate treatment with a long history of efficacy, with several small series over the past 20 to 30 years reporting control rates ranging from 80% to 100%.¹²^,¹⁸^,⁴⁹^,⁶²^,⁶⁴^, ⁶⁵^,⁶⁷^,⁷⁴^,⁸³^,⁸⁴ High-dose-rate (HDR), medium-dose-rate (MDR), and low-dose-rate (LDR) techniques have been reported with acceptable results, although it is difficult to compare regimens due to small patient numbers, generally short follow-up times, and overall nonuniformity among series. Generally, radiation is reserved for patients who relapse after more conservative treatments. Drawbacks to radiation include potential undertreatment of occult invasive disease, the risk of secondary malignancy, and long-term morbidity, although there are no prospective data available regarding the impact of treatment on sexual function and quality of life.

LDR treatment is most commonly delivered with an intracavitary vaginal cylinder using cesium-137. Typically, a dose of 60 Gy is prescribed to the vaginal mucosa, but a wide range of doses, depending on depth of dose prescription, as well as a variety of techniques, have been reported.⁶³^,⁶⁵^,⁶⁷^,⁷⁴^,⁸⁴ Chyle et al.⁶⁰ prescribed 70 to 80 Gy to the vaginal surface and reported a 17% recurrence rate at 10 years in their series of 37 patients. Perez et al.⁶³treated patients to the vaginal surface with a dose of 60 to 70 Gy, and reported 1 recurrence in 20 patients. The recurrence occurred in the distal vagina and was noted to be a marginal recurrence. Blanchard et al.⁶⁵ reported on a series of 28 patients with VAIN-3 treated at Institut Gustave Roussy from 1985 to 2008. Patients were treated with LDR brachytherapy, using a vaginal mold technique, to a dose of 60 Gy prescribed 5 mm below the vaginal surface; 18 patients received treatment to the upper half of the vagina, 6 were treated to the upper two-thirds, and 4 were treated to the whole vaginal length. With a median follow-up time of 41 months, the authors report only one in-field recurrence, with a 10-year local control rate of 93%. Treatment with LDR brachytherapy is overall well tolerated; in the Blanchard et al.⁶⁵ series, there were no grade 3 or 4 late toxicities and only one grade 2 gastrointestinal toxicity noted. This is consistent with the Perez et al.⁶³ series, in which there was only one grade 3 urinary complication among 40 patients with VAIN-3 or stage I vaginal cancer treated with LDR. Overall, excellent local control and low toxicity have been reported for LDR brachytherapy.

Graham et al.⁶⁴ reviewed their experience using MDR intracavitary brachytherapy for VAIN-3 at the Beatson Oncology Centre in Glasgow, UK. Using a MDR Selectron (Nucletron, Holland), 48 Gy was prescribed 0.5 cm lateral to the ovoid surface (point Z) over two insertions, spaced 1 week apart. Ovoids were chosen over vaginal cylinder placement in order to adequately cover epithelium sutured into the superolateral vagina at hysterectomy. With a median follow-up duration of 77 months, recurrent or residual VAIN-3 was documented in three patients, and two of these patients subsequently developed invasive or microinvasive vaginal carcinoma. One other patient developed late progression 14 years after treatment. There were minimal acute effects during treatment; however, with longer follow-up, all patients were noted to have grade 1–2 mucosal atrophy, dryness and telangiectasia. Four patients developed grade 3 toxicity with severe vaginal stenosis, and one patient developed grade 4 toxicity, with a vaginal ulcer that presented 2 years after treatment. An additional patient developed grade 3 urinary toxicity with urethral stricture requiring intermittent self-catheterization.

HDR brachytherapy has been used for patients with VAIN-3. Ogino et al.⁶² reported their experience treating six patients with VAIN-3 at Kanagawa Cancer Center from 1983 to 1993, with a mean dose of 23.3 Gy (range, 15 to 30 Gy); most treatments were delivered in 5 fractions using two ovoids, with dose calculated to a point 1 cm superior to the vaginal apex. Lesions distal to the vaginal vault had doses calculated 1 cm beyond the plane of the vaginal cylinder in order to deliver adequate dose to the entire vagina. Median follow-up was 90.5 months, and there was no evidence of disease recurrence in the treated patients. Two patients developed moderate to severe vaginal stenosis, and three patients developed rectal bleeding, which resolved. MacLeod et al.⁶¹ reviewed their experience treating 14 patients with VAIN-3 from 1985 to 1995. Total dose was 34 to 45 Gy to the vaginal surface, in 8.5-Gy fractions delivered twice a week or 4.5-Gy fractions delivered 4 times a week. One patient developed invasive cancer, and one patient had persistent VAIN-3. There were no major acute toxicities, and two patients developed late grade 3 vaginal atrophy and stenosis. Mock et al.⁸³ reported treatment of six patients with HDR intracavitary brachytherapy, with 100% 5-year disease-specific survival.

Malignant Tumors of the Vagina: Squamous Cell Carcinoma

Epidemiology

A review of five series, including a total of 1,375 cases of vaginal cancer, reported a FIGO stage distribution as follows: 26% stage I, 37% stage II, 24% stage III, and 13% stage IV.⁸⁵ Consistent with these data, the NCDB review by Creasman et al.,⁴ for the period of 1985 to 1994, revealed 3,244 cases of invasive primary vaginal carcinoma, with 24% of patients presenting with American Joint Committee on Cancer (AJCC) stage I disease, 20% AJCC stage II, 24% AJCC stages III an IV, and 32% unknown. Most tumors were moderately (28%) or poorly (28%) differentiated at presentation.

According to the SEER study by Shah et al.,¹ most women diagnosed with primary vaginal cancer are non-Hispanic whites (66%), followed by African Americans (14%), Hispanic whites (12%), Asian/Pacific Islanders (7%), and others (1%). Incidence rates were highest for African American women (1.24/100,000 person-years) and lowest for Asian/Pacific Islanders (0.64/100,000 person-years). The greatest proportion of women (36%) presented with stage I disease, and 65% had squamous histology, consistent with other reports.

Risk Factors

Primary vaginal SCC shares similar risk factors with VAIN and, in general, with cervical neoplasia. Potential risk factors for SCC include HPV infection, history of CIN, vulvar intraepithelial neoplasia, immunosuppression, and possibly history of pelvic radiation, although this is controversial. In a population-based case-control study of 156 women with VAIN or invasive cancer, risk factors included early onset of intercourse, increased number of lifetime sexual partners, and current smoking. HPV DNA was detectable in 80% of patients with in situ disease and 60% of those with invasive disease, and 30% of patients reported a history of treatment for invasive malignancy, most commonly cervix or in situ anogenital neoplasia.³⁰ A case-control study of 41 women with in situ disease or invasive carcinoma identified low socioeconomic status, history of genital warts, vaginal discharge or irritation, history of abnormal cytology, prior hysterectomy, and vaginal trauma as potential risk factors.⁸⁶ A larger case-control study of 36,856 women found an increased risk of vaginal cancer in alcoholic women, likely associated with a higher incidence of lifestyle factors, such as promiscuity and smoking, which are also associated with a higher incidence of HPV infection. Early hysterectomy appears to be a risk factor in some studies, if performed for malignant or premalignant disease.³⁰^,⁸⁷

Patients with a history of cervical cancer have a significantly higher risk of developing in situ as well as invasive carcinoma. Studies suggest that 10% to 50% of patients with a history of VAIN or invasive carcinoma of the vagina have undergone treatment for in situ or invasive cervical carcinoma,¹²^,⁶⁰^,⁸⁸^–⁹⁴ with the interval from treatment of cervical disease to development of vaginal carcinoma averaging approximately 14 years.⁹⁰^,⁹⁵ HIV-infected women are also at higher risk of developing vaginal carcinoma, which tends to behave more aggressively in this setting than in HIV-negative patients.⁹⁶

The role of ionizing radiation to the pelvis in the development of vaginal carcinoma is unclear, with conflicting reports. According to one study that analyzed 1,200 patients treated over a 20-year period for carcinoma of the cervix, prior radiation therapy was not shown to result in increased secondary pelvic neoplasms.²⁷ A second study by Boice et al.,²⁶ however, reported a 14-fold increased risk of vaginal cancer in women with a history of pelvic irradiation before the age of 45, with a significant dose–response relationship.

Other proposed causes include chronic irritation of the vaginal mucosa, resulting in chronic inflammation, hyperkeratosis, thickening, and acanthosis,⁹⁶ with subsequent metaplastic and dysplastic changes. Although older studies showed that more vaginal cancers arise from the posterior vaginal wall, other studies report approximately equal distribution of invasive carcinomas on the anterior and posterior walls,²⁹^,⁹⁰^,⁹⁷^–⁹⁸^,⁹⁹ arguing against the theory that pooling of irritating substances in the posterior fornix contributes to development of vaginal cancers, particularly on the posterior wall. Chronic irritation from use of vaginal pessaries has also been implicated as a contributor in vaginal cancer development.¹⁰⁰^,¹⁰¹

Clinical Presentation

Vaginal tumors can spread along the vaginal walls to involve the cervix or vulva, but involvement of the cervix or vulva at the time of diagnosis excludes classification as a primary vaginal cancer. Lesions can extend radially, either into the lumen to form exophytic masses or through the vaginal wall to invade surrounding musculature and organs. Anterior wall lesions can infiltrate the vesicovaginal septum or urethra. Posterior wall lesions can infiltrate the rectovaginal septum and involve the rectal mucosa. Advanced disease can extend laterally toward the parametrium and paracolpal tissues or into the urogenital diaphragm, levator ani muscles, or pelvic fascia, and eventually to the pelvic side wall.

Grossly, SCC of the vagina can present as nodular, ulcerated, indurated, exophytic, or endophytic lesions, and it is difficult to histologically distinguish a primary vaginal SCC from recurrent cervical or vulvar carcinoma. Histologically, tumors are graded as well, moderate, or poorly differentiated and have been described as keratinizing, nonkeratinizing, basaloid, warty, or verrucous. The majority of these lesions are nonkeratinizing and moderately differentiated (Fig. 72.4).¹⁰²

Vaginal carcinoma most frequently involves the superior one-third of the vaginal canal, with series reporting 50% to 83% of cases occurring in this region.²⁹^,⁹⁸^,⁹⁹^,¹⁰³^–¹⁰⁶ A high proportion of patients have a history of prior hysterectomy. There is approximately equal involvement of the middle and inferior thirds,²⁹ although some studies suggest that involvement of the lower third is more common than involvement of the middle third.⁹⁰^,⁹⁹ Older series report involvement of the posterior vaginal wall to be more common, although other series suggest involvement of the anterior and posterior walls occurs at equal frequencies.⁹⁰^,⁹⁸^,⁹⁹ The lateral walls are less frequently involved. Tumors may exhibit an exophytic or ulcerative, infiltrating growth pattern.

HPV has been implicated in the pathogenesis of vaginal SCC. Fuste et al.¹⁰⁷ examined histopathologic patterns of HPV infection and vaginal SCC. They did not find any association between the type of HPV and histology (keratinizing, basaloid, warty). Overall, 75% of specimens were positive for HPV. HPV-16 was identified in 72% of positive samples. Ferreira et al.¹⁰⁸ also noted a high percentage of HPV-positive tumors, with 81% of SCC specimens positive for HPV and HPV16 found in the majority of tumors.

FIGURE 72.4. Invasive squamous cell carcinoma of the vagina at 10X (A) and 40X (B) magnification. (Courtesy of Marisa R. Nucci and Carlos Parra-Herran.)

Verrucous carcinoma is a distinct histologic variant of vaginal SCC that commonly presents as a well-circumscribed, soft, cauliflower-like mass that is microscopically well differentiated, with a papillary growth pattern and acanthotic epithelium.¹⁰⁹ There is surface maturation with parakeratosis or hyperkeratosis without koilocytosis. This variant of SCC exhibits less aggressive behavior and rarely metastasizes.¹⁰⁹^–¹¹² Therefore, it should be considered a distinct entity from other vaginal SCC.

Up to 65% of patients present with irregular vaginal bleeding as their primary symptom.⁹⁰^,¹¹³^,¹¹⁴ Vaginal discharge is the second most common symptom, occurring in 10% to 15% of patients. Less frequent symptoms, associated with locally advanced disease, include the presence of a mass; pain; urinary symptoms, including frequency, dysuria, or hematuria; or gastrointestinal complaints such as tenesmus, constipation, or melena. Due to the proximity of anterior wall lesions to the urethra and bladder, urinary symptoms can be seen more commonly in vaginal cancer than in cervical cancer. Up to 20% of women are asymptomatic at the time of diagnosis,⁹⁰^,¹¹⁵ with lesions detected via cytologic screening or by speculum examination.

Patterns of Lymphatic Drainage

The lymphatic system of the vagina is complex, with many interconnections. Lymphatic channels in the mucosa run parallel to networks of channels in the submucosa and muscular layer, ultimately converging to form trunks at the vaginal wall periphery, which subsequently drain to major pelvic nodal groups. The upper vagina drains to the obturator and hypogastric nodes, similar to the cervix. The lower vagina drains to the inguinal, femoral, and external iliac nodes, and posteriorly situated lesions can drain to the inferior gluteal, presacral, or perirectal nodes. Due to considerable crossover drainage, the location of the primary tumor is not a reliable indicator of drainage site.

Frumovitz et al.¹¹⁶ utilized lymphoscintigraphy to determine patterns of lymphatic drainage in 14 women diagnosed with primary vaginal cancers and found a substantial degree of anomalous drainage, resulting in a change in radiation treatment for 33% of patients. For example, among four women with lesions located in the upper third of the vagina, which is predicted to drain along the cervical lymphatic chains to the pelvis, two (50%) were found to have a sentinel node in the inguinal region. Among five women with lesions located at the vaginal introitus, a location predicted to drain along the vulvar lymphatic chains to the inguinal triangle, three (60%) were found to have a sentinel node in the pelvis.

The risk of nodal metastasis appears to increase significantly with stage, although the true incidence of positive lymph nodes is difficult to determine because most patients receive treatment with radiation therapy and do not undergo surgical lymphadenectomy. Sparse data on nodal metastases are derived from series in which exploratory laparotomies and lymphadenectomies were performed.⁹⁵ The incidence of lymph node involvement has been reported to be 0% to 14% in stage I and 21% to 32% in stage II disease.⁹⁵^,¹¹⁷^,¹¹⁸ The incidence of nodal involvement in stages III and IV has been reported to be as high as 78% and 83%, respectively.⁹⁹ At diagnosis, up to 20% of patients have clinically positive inguinal nodes, with reported ranges of 5.3% to 20%.⁶³^,⁹³ The risk of nodal failure increases significantly with local recurrence. Chyle et al.⁶⁰ reported 10-year inguinal and pelvic failure rates of 16% and 28%, respectively, in patients with local recurrence, in contrast to 2% and 4%, respectively, in patients without local recurrence.

Distant metastases can occur with advanced disease at presentation or upon recurrence after primary therapy. The most frequent site of hematogenous metastasis is the lung, with less commonly noted sites being liver and bone.⁶⁰In a series by Perez et al.,⁹³ the incidence of distant metastasis was 16% for stage I, 31% for stage II, 46% for stage IIB, 62% for stage III, and 50% for stage IV. Some histologies may have a higher likelihood of distant metastases than others. Chyle et al.⁶⁰ noted a higher incidence of distant metastases in patients with adenocarcinoma (48%) than in those with SCC (10%), with correspondingly lower 10-year survival rates (20% vs. 50%). Leiomyosarcomas are also aggressive; they undergo early hematogenous dissemination, frequently occur locally,⁴^,¹¹⁹ and demonstrate frequent pulmonary metastases.¹²⁰ Vaginal melanoma and neuroendocrine small cell tumors are highly malignant, and both have a propensity for early hematogenous spread.¹²¹^,¹²²

Diagnostic Workup

The diagnostic workup should start with a thorough history and physical examination, with careful attention given to the pelvis. Examination under anesthesia is recommended for complete assessment of tumor extent and assessment of vaginal walls. During speculum examination, the speculum blades can obscure the anterior and posterior walls, so it is essential to rotate the speculum for visualization of all four walls from the introitus to the apex. Bimanual examination, with careful digital palpation, should be performed.

A definitive diagnosis is achieved with biopsy of suspected lesions, which can present as an exophytic mass, plaque, or ulcer. Up to 20% of vaginal malignancies are detected incidentally as a result of cytologic surveillance.⁹⁰ If a lesion is not visible in the setting of abnormal cytology, colposcopy with acetic acid, followed by Lugol’s iodine stain, is conducted. Biopsies of white epithelium or atypical vascularity should be obtained after application of acetic acid. Iodine will identify Schiller-positive regions, which are nonstaining and should correspond with areas identified following application of acetic acid. Adequate biopsies should include the cervix, if present, to rule out a cervical primary. Patients can present with multiple regions of abnormality. Inguinal nodes should be palpated for disease involvement, particularly if the primary lesion is situated in the lower portion of the vagina, as 5% to 20% of patients have been reported to have involved inguinal nodes at presentation.⁶³^,⁹³ Suspicious nodes warrant a biopsy. Laboratory tests include a complete blood count with differential and assessment of renal and hepatic function.

FIGO staging of vaginal cancer is clinical and allows chest x-ray, intravenous pyelography (IVP), barium enema, cystoscopy, and proctosigmoidoscopy. Cystoscopy or proctosigmoidoscopy may be necessary in patients with symptoms suggestive of bladder or rectal infiltration. Computed tomographic (CT) imaging and magnetic resonance imaging (MRI) do not affect FIGO stage assignment and are commonly used. CT of the pelvis is obtained in place of IVP to assess the renal parenchyma and also to obtain information on the extent of local disease and lymph node status. MRI can provide salient treatment planning information by characterizing extent of invasion and differentiating malignant tumor, which is isointense to muscle on T1 and hyperintense on T2, from normal structures or fibrosis.¹²³ Advantages of MRI over other imaging modalities include superior soft tissue contrast resolution, allowing accurate assessment of tumor volume and extent of local invasion, and accurate assessment of pelvic-nodal involvement. In general, MRI is regarded as superior to CT for staging of gynecologic malignancies and should be obtained when available.

Positron emission tomography (PET) has shown efficacy in detecting the extent of primary tumor and abnormal lymph nodes in vaginal cancer with higher sensitivity than CT,¹²⁴ as is the case with cervical carcinoma. Primary vaginal carcinoma and metastatic lesions demonstrate avid uptake of 2-[fluorine-18]fluoro-2-deoxy-D-glucose (FDG). In one study, 23 patients with primary vaginal carcinoma received both PET and CT during staging. CT identified the primary tumor in only 43% of patients, whereas PET identified the tumor in 100%. PET identified suspicious uptake in groin and pelvic nodes in 8 of 23 patients, compared with 4 of 23 with CT. Treatment planning was modified in 14% of patients due to findings from PET, and the authors concluded that PET detects primary tumor and abnormal lymph nodes more often than CT.¹²⁴ It is important that the patient have an empty bladder prior to imaging, as physiologic FDG activity in a filled bladder can potentially interfere with accurate estimation of vaginal involvement. In practice, most patients undergoing planning for radiation treatment are assessed with CT as well as MRI or PET, based on extrapolation from studies of other gynecologic malignances as well as these studies.

TABLE 72.2 AMERICAN JOINT COMMITTEE ON CANCER’S STAGING OF VAGINAL CANCER

TABLE 72.3 INTERNATIONAL FEDERATION OF GYNECOLOGY AND OBSTETRICS STAGING SYSTEM FOR CARCINOMA OF THE VAGINA

Staging

The AJCC¹²⁵ and FIGO² systems are used to stage vaginal cancer (Tables 72.2 and 72.3). FIGO is a clinical staging system that allows chest x-ray, IVP, barium enema, cystoscopy, and rectosigmoidoscopy for staging purposes. Vaginal cancer is a diagnosis of exclusion, with involvement of the cervix or vulva classified as primary cervical or vulvar cancers, respectively. Primary vaginal melanomas and lymphomas are staged according to the AJCC staging systems for melanomas and lymphomas, respectively.¹²⁵

For patients with a prior gynecologic malignancy, a 5-year period free of disease is generally considered adequate to allow for distinction between recurrent disease and a new primary vaginal cancer. FIGO no longer recognizes carcinoma in situ as stage 0.

Stage I disease is defined as limited to the vaginal wall, and stage II disease involves subvaginal tissue without extension to the pelvic wall. Discriminating between stages I and II can be subjective; thin tumors <0.5 cm are generally classified as stage I, with thicker infiltrating tumors or those with paravaginal nodularity classified as stage II. Perez et al.⁶³ proposed a modification to the FIGO system in 1973, distinguishing tumors with paravaginal submucosal extension only (stage IIA) from tumors with parametrial infiltration (stage IIB). The study reported a 20% 5-year survival difference (55% vs. 35%) between stages IIA and IIB. This modification has not been adopted into FIGO staging; however, some investigators consider the distinction to be prognostically relevant.⁵⁹^,⁹³

Prognostic Factors

The most significant prognostic factor is stage at time of presentation;¹^,⁶³^,⁹¹^,¹²⁶^–¹²⁹ the NCDB, the largest population-based series on vaginal cancer thus far, reports 5-year survival rates of 96% for stage 0, 73% for stage I, 58% for stage II, and 36% for stages III and IV disease.⁴ The series by Shah et al.,¹ based on SEER data for women diagnosed between 1990 and 2004, also reveals the correlation between stage and outcome, with 5-year disease-specific survival rates of 84% for stage I, 75% for stage II, and 57% for stages III and IV; the adjusted hazard ratio for mortality, on multivariate analysis, was 4.67. In the Perez et al.⁹³ series, 165 patients with primary vaginal cancer were treated with definitive radiation therapy and had 10-year actuarial disease-free survival rates of 94% for stage 0, 75% for stage I, 55% for stage IIA, 43% for stage IIB, 32% for stage III, and 0% for stage IV. Lymph node involvement also carries an unfavorable prognosis.¹³⁰

Size of the initial lesion is a prognostic factor that has shown significance in several series. The SEER database study,¹ which included 2,149 women with primary vaginal cancer, noted a significantly lower 5-year survival rate in women with tumors ≥4 cm than in women with tumors <4 cm (65% vs. 84%); however, size information was missing for 52% of women. After multivariate analysis, the women with the larger tumors had an adjusted hazard ratio of 1.71 for mortality. Chyle et al.,⁶⁰ in their review of 301 patients treated at the MD Anderson Cancer Center (MDACC) from 1953 to 1991, found that women with lesions >5 cm in maximum diameter had a significantly higher 10-year local recurrence rate than those with smaller lesions (40% vs. 20%). The series by Hellman et al.,¹²⁸ with 314 patients treated at the Karolinska University Hospital from 1956 to 1996, found only three factors to independently predict for poor survival on multivariate analysis: advanced age, tumor size ≥4 cm, and advanced stage. Tumors comprising two-thirds or more of the vagina and tumors growing circumferentially were associated with an extremely poor prognosis. The series by Tran et al.,¹³¹ which reviewed records of 78 patients with SCC treated at Stanford University Medical Center from 1959 to 2005, also found size to be a prognostic factor for disease-free survival on multivariate analysis, along with stage, prior hysterectomy, and pretreatment hemoglobin level. Smaller series by Tjalma et al.¹³² and Kirkbride et al.⁹¹ also describe adverse outcomes with larger tumor size. Other series have failed to show significance, but they likely were hindered by small numbers, difficulties in accurate assessment of size, and treatment heterogeneity. Frank et al.¹¹⁴ reviewed data on 193 patients treated at MDACC between 1970 and 2000 for vaginal SCC and found a nonsignificant difference in disease-specific survival rates between patients with tumors ≤4 cm in diameter and those with tumors >4 cm (82% vs. 60%, respectively). Extent of vaginal canal involvement has also been examined, as a surrogate for tumor size, in the assessment of tumor burden. In a series by Stock et al.,⁹⁸ which examined 100 cases of primary vaginal carcinoma treated at Magee Women’s Hospital from 1962 to 1992, patients with involvement of one-third of the vaginal canal or less had a significantly higher 5-year disease-free survival rate (61%) than patients with more extensive involvement (25%).

There is conflicting evidence on the impact of lesion location on prognosis; it has been noted in some⁶⁰^,¹⁰³^,¹³³^–¹³⁵ but not all⁹³^,¹⁰⁶^,¹³⁶ reports. In an analysis of 110 patients by Kucera et al.,¹³⁷ 5-year survival rates were 60% for lesions of the upper third of the vagina, 37.5% for lesions of the middle third, and 37% for the lower third. Chyle et al.⁶⁰ noted a 17% rate of pelvic relapse in patients with tumors in the upper third of the vagina, 36% for patients with tumors in the middle or lower third, and 42% for patients with whole vaginal involvement. Lesions in the posterior wall were also noted to be associated with a worse prognosis than lesions involving the anterior vaginal wall,⁶⁰with 10-year recurrence rates of 32% versus 19% on univariate analysis (<.007). The Hellman et al.¹²⁸series found no difference in prognosis between anterior and posterior tumors.

Histologic grade has been found to be an independent significant predictor of survival in several series⁹¹^,¹⁰³^,¹³⁵ but not others. Hellman et al.¹²⁸ evaluated the impact of tumor grade and other histopathologic variables (mitotic activity, koilocytosis, growth in vessels, lymphocytic reactions) and found no correlation with survival.

Age at diagnosis correlated significantly with poor survival in both univariate and multivariate analysis in the Hellman et al.¹²⁸ series. Age was also noted to be a significant prognostic factor in the Urbanski et al.¹³⁵ series, with 5-year survival rates of 83% for patients younger than 60 compared with 25% for those 60 years of age or older (P <.0001); other series have failed to demonstrate the statistical significance of age.⁶³^,¹³⁸

Tran et al.¹³¹ reviewed records of 78 patients with primary SCC of the vagina treated at Stanford University Hospital and found a hemoglobin level <12.5 g/dL prior to definitive treatment to be prognostic for worse pelvic control and disease-specific survival;¹¹⁷ 5-year disease-specific survival rates were 55% for women with hemoglobin levels <12.5 g/dL and 76% for those with levels ≥12.5 g/dL. This remained significant after multivariate analysis, along with prior hysterectomy, stage, and tumor size.

Up to 62% of patients with primary vaginal cancer have had a prior hysterectomy.¹³⁹ This high rate reflects the proportion of patients with a history of cervical pathology as well as the increased hysterectomy rate in the general female population.¹⁴⁰ The study by Tran et al.¹³¹ is the first to identify prior hysterectomy as a favorable prognostic factor on multivariate analysis. This may reflect more rigorous surveillance in posthysterectomy patients, resulting in tumors discovered at an earlier stage, or may be a reflection of less overall vaginal tissue as a substrate for tumorigenesis. Two studies have identified hysterectomy as a significant prognostic factor in univariate analysis.⁶⁰^,¹²⁸

The prognostic role of HPV was examined by Brunner et al.¹⁴¹ in their series of 35 patients with primary invasive SCC of the vagina. Using in situ hybridization, HPV was detected in 51.4% of cases. There was no significant influence on clinical stage, grade, or tumor size nor did prognosis differ between HPV-positive and HPV-negative tumors. However, in a subset of patients with FIGO stage III or higher disease, HPV positivity was found to correlate with improved disease-free and overall survival (P .004 and .023, respectively). In contrast, Fuste et al.¹⁰⁷ found a trend toward longer survival in women with HPV-positive tumors in their series of 32 patients, with median survival times of 113.9 months versus 19.7 months for women with HPV-positive and HPV-negative tumors, respectively (P = .15).

For patients treated with radiation, treatment time may be a significant factor impacting tumor control.¹⁴²^,¹⁴³ Lee et al.¹⁴³ found overall treatment time of ≤9 weeks to be associated with a pelvic tumor control rate of 97% as compared with 57% for treatment time >9 weeks (P <.01). Pingley et al.¹⁴² also noted a correlation between treatment time and outcome; patients receiving brachytherapy within 4 weeks of external-beam radiation therapy (EBRT) had a 5-year disease-free survival rate of 60%, compared with a 30% rate in patients who had an interval >4 weeks.

Treatment: Surgery

For most patients with invasive vaginal cancer, radiation is the treatment of choice. Surgery is considered for highly selected patients who have early-stage lesions, when a potentially curative resection can be achieved without extensive functional morbidity. Surgery is also used for previously irradiated patients who cannot receive further radiation. A wide local excision is reserved only for carcinoma in situ or small, superficially invasive lesions that are well demarcated. More extensive lesions in the proximal aspect of the vaginal canal require radical hysterectomy, upper vaginectomy, and bilateral pelvic lymphadenectomy, and patients with positive margins require adjuvant radiation. Lesions that extend to the inferior vagina require a total vaginectomy with radical hysterectomy, pelvic lymphadenectomy, and possibly vulvovaginectomy and inguinofemoral lymphadenectomy.⁸⁹^,⁹⁰^,⁹⁸^,⁹⁹ It is not uncommon for relatively small lesions to invade the rectum or urethra early in the disease course, given the close proximity of the vagina to these structures. Older surgical series often required pelvic exenteration in 40% to 50% of cases to obtain negative margins.⁹⁵^,⁹⁹ Anterior exenteration removes the vagina, urethra, and bladder and is often necessary to achieve negative margins for invasive anterior wall lesions. Posterior exenteration requires resection of the vagina and rectum. Deeply invasive, circumferential lesions may require a total exenteration in order to achieve clear margins. Given the potentially devastating functional results associated with radical surgery, definitive radiation is the treatment of choice for most patients with invasive vaginal cancer and has largely replaced surgery as the primary therapeutic modality.

In select stage I patients, surgery can offer excellent results, with series reporting 5-year survival rates ranging from 56% to 100% for women with stage I disease.⁴^,⁸⁹^,⁹⁵^,⁹⁸^,¹³²^,¹⁴⁴ The NCDB review for cancers of the vagina noted superior survival rates in patients treated with surgery,⁴ although this likely reflects selection of healthier patients with good performance status for radical surgery. A more recent analysis utilizing the SEER database¹ found that women with stage I disease who underwent surgery only, had a lower risk of mortality than those treated with radiation only, combined modalities, or no treatment; however, this difference did not reach statistical significance. For stage II vaginal cancer patients, there was a similar trend toward increased mortality in women who did not have surgery alone as their primary treatment modality, but values once again did not reach statistical significance in their multivariate adjusted model.

In a review of 100 cases by Stock et al.⁹⁸ surgical treatment was noted to be a significantly favorable prognostic factor for disease-free survival, versus treatment with radiation alone, in stage II patients but not stage I patients. For stage I patients, survival rates were 56% and 80% for patients treated with surgery versus radiation, respectively. For stage II patients, survival rates were 68% and 31% after surgery and radiation, respectively, although this likely reflects selection bias, with patients with more extensive involvement offered radiation. Overall 5-year survival was 47%. Stock et al.⁹⁸ concluded that surgery that consists of radical hysterectomy, pelvic lymphadenectomy, and upper vaginectomy could be reasonable for stage I lesions and select stage II lesions, with radiation being the preferred primary modality for patients with stage IIB disease. It should be noted, however, that 23 of 33 stage II patients (70%) treated with surgery required a total vaginectomy or exenterative procedure, which carries significant morbidity and functional impairment.

Other series also report excellent results with primary surgical therapy, although authors acknowledge bias resulting from selection of healthier patients with less extensive disease for primary surgery over radiation. Tjalma et al.¹³²reported on 55 cases of primary vaginal SCC. Of 27 patients with stage I disease, 26 received surgery, with 4 subsequently receiving some form of adjuvant radiation. With a median follow-up time of 45 month, 5-year survival was reported to be 91%. Otton et al.,¹⁴⁴ in their retrospective review of 70 patients with stage I or II vaginal carcinoma treated at Queensland Centre for Gynaecological Cancer between 1982 and 1998, report that patients treated with surgery alone, or a combination of surgery and radiation, had significantly longer survival times than patients treated with radiation alone. The authors suggest that surgery may be effective in a select subset of patients with small, localized tumors that permit clear surgical margins. Peters et al.¹⁰⁶ reviewed records of 86 patients with vaginal carcinoma, including 68 SCC cases, treated at University of Michigan Medical Center. Twelve selected patients had surgery as primary therapy, with a 75% survival rate. Similarly, Rubin et al.⁹⁹ reported on eight patients with stage I or II disease who received surgery as primary treatment; 5-year survival was 75%, and the overall local control rate for the stage I patients was 80%, suggesting that highly selected patients can achieve excellent outcomes with surgery. Davis et al.⁹⁵ reported on 89 patients with vaginal carcinoma treated primarily at the Mayo Clinic from 1960 to 1987. A total of 52 patients were treated with surgery as primary therapy, with 5-year survival of 85% compared with 65% for patients who received radiation alone. In the stage II patients, the 5-year survival rates were 49%, 50%, and 69% for surgery, radiation, and combined treatment with surgery and radiation, respectively. However, treatment modalities cannot be effectively compared using retrospective series, which reflect strong selection biases.

Ling et al.,¹⁴⁵ in a small series with 4 patients who had stage I disease, report their experience using laparoscopic radical hysterectomy with vaginectomy and reconstruction of the vagina. With follow-up times ranging from 40 to 54 months, they reported all patients to be free of disease, with satisfactory sexual function. The authors suggest that laparoscopic surgery can be an option for select patients with early-stage disease, with good outcomes.

Several series report their experience using surgery for advanced stage III or IV patients, with most cases requiring pelvic exenteration.⁸⁹^,⁹⁰^,⁹⁸^,⁹⁹ Control rates at best were 50% in highly selected patients. In practice, given the overall poor prognosis and morbidity associated with surgery, advanced-stage patients should receive treatment with definitive radiation, typically in combination with chemotherapy.

Neoadjuvant chemotherapy followed by radical surgery has been proposed for selected patients with vaginal cancer.¹⁴⁶^,¹⁴⁷ Benedetti et al.¹⁴⁷ reported results on 11 patients with stage II SCC of the vagina, using 3 cycles of neoadjuvant paclitaxel and cisplatin. Ninety-one percent of patients obtained a partial or complete response to neoadjuvant chemotherapy; 27% achieved a complete response. All patients had disease-free resection margins after surgery, and only one patient had positive lymph nodes. At a median follow-up time of 75 months, 10 of 11 patients (91%) were alive, and of those, 8 (73%) were free of disease. Postoperative complications were mild. A case report documented the use of neoadjuvant chemotherapy, consisting of bleomycin and cisplatin, followed by radical surgery in one patient with stage II SCC of the vagina.¹⁴⁶ The patient was free of disease, with satisfactory sexual function, at 30 months. However, larger series of patients treated with this approach, with longer follow-up, are necessary to further evaluate the feasibility of this treatment.

Treatment: Radiation

Stage I

It is difficult to compare results for stage I and stage II disease from different series, as the distinction between them is made clinically, based on physical examination, and can be subject to variability. In general, stage I lesions are 0.5 to 1 cm in thickness. It is important to individualize radiation therapy techniques based on size, depth, and location of the lesion.

Selected patients with small, superficial tumors may be adequately treated with brachytherapy alone, with reported local control rates of 67% to 100%.⁹²^,⁹³^,⁹⁷^,¹⁰³^,¹¹⁴^,¹³⁵^,¹⁴⁸^,¹⁴⁹ Perez et al.⁶³ reported pelvic tumor control of 88% in patients with stage I disease who received brachytherapy alone, using a dose of 60 to 70 Gy, prescribed 5 mm beyond the plane of the implant or vaginal mucosa, with a vaginal surface dose of 80 to 120 Gy. Frank et al.¹¹⁴ reported on 21 patients with stage I disease who were treated with local radiation only, without regional node coverage. Nine received brachytherapy alone, 11 received EBRT with or without brachytherapy, and 1 received local EBRT using a transvaginal orthovoltage cone. Three of 9 patients treated with brachytherapy alone developed recurrent disease in the pelvis, resulting in a 10-year pelvic disease control rate of 67%. Patients who had received EBRT with or without brachytherapy did not have pelvic recurrences. In the series by Dancuart et al.,¹⁴⁸ patients treated with brachytherapy or transvaginal cone irradiation alone had a local failure rate of 18%. A pelvic relapse rate of 18% at 10 years was noted by Frank et al.,¹¹⁴ with all pelvic failures occurring in patients treated with brachytherapy alone.

Typically, the entire length of the vagina is treated to a mucosal dose of 60 to 65 Gy, with an additional mucosal dose of 20 to 30 Gy delivered to the area of tumor involvement.¹⁵⁰ With LDR, treatment can be delivered in two applications, with the first designed to treat the entire vaginal wall and a second application to cover the tumor volume. This can be delivered with a shielded vaginal cylinder to treat the tumor with a 2-cm margin and block uninvolved mucosal surfaces. HDR can also be used to treat superficial lesions. In general, the vaginal mucosa is treated to a dose of 21 to 25 Gy, prescribed to a depth of 5 mm, in weekly fractions of 5 to 7 Gy each. An additional 21 to 25 Gy, prescribed to a depth of 5 mm, is delivered to the tumor via shielded vaginal cylinder, with weekly fractions of 5 to 7 Gy, to bring the total dose to 42 to 50 Gy. For lesions thicker than 5 mm, a combination of intracavitary and interstitial brachytherapy can be utilized. For such lesions, a vaginal cylinder typically delivers 45 Gy (LDR) or 21 to 25 Gy (HDR) to a depth of 5 mm into the vaginal mucosa. Subsequent therapy is delivered via interstitial implant, to deliver an additional dose of 25 to 35 Gy (LDR) to the tumor volume.

A combination of EBRT and brachytherapy is suggested for more extensive stage I lesions that exhibit greater infiltration or poor differentiation. Perez et al.⁶³ noted that tumor control in stage I vaginal carcinoma was approximately the same with brachytherapy alone as when given in combination with EBRT, consistent with observations made by some groups¹³⁷^,¹⁵¹ but not others.¹¹⁴ Given possible underestimation of submucosal disease or nodal disease, resulting in a potentially high likelihood of recurrence with brachytherapy alone, some groups recommend incorporating EBRT into treatment of all stage I patients, except for those with very small, superficial lesions.¹¹⁴Frank et al.,¹¹⁴ in their series of patients with vaginal cancer treated at MDACC between 1970 and 2000, noted an increased trend toward increasing use of EBRT for stage I vaginal SCC over time.

Actuarial 5-year survival rates for stage I disease range from 60% to 85%.¹^,⁹³^,¹¹⁴^,¹³¹ Disease-specific survival rates for stage I disease, treated with definitive radiation, range from 75% to 95%.⁶³^,⁶⁰^,⁹⁴ The 10-year pelvic-relapse rate, comprising local, pelvic nodal, and inguinal nodal failures, was noted to be 16% by Frank et al.¹¹⁴ for stage I patients. Distant metastases are uncommon and occur in about 5% of patients.⁶³^,⁹⁵^,¹⁴⁸

Stage II

Radiation is the primary treatment for stage II disease and involves a combination of EBRT and brachytherapy. Perez et al.⁶³ noted a 36% pelvic tumor control rate in stage II patients treated with brachytherapy alone, compared with 67% in patients treated with a combination of EBRT and brachytherapy. The benefit of combining EBRT and brachytherapy, as opposed to using either alone, has been shown in other series as well.⁶⁰^,⁹⁸

Generally, patients with stage II disease are treated with EBRT followed by interstitial or intracavitary brachytherapy. The pelvis receives 45 to 50.4 Gy in 1.8 Gy fractions, with consideration of a parametrial boost if there is extensive primary infiltration or high suspicion of nodal disease. Inguinal lymph nodes are included in a modified whole pelvic field for lesions involving the distal vaginal canal.

Chyle et al.⁶⁰ reported an 89% local-control rate in the vagina for patients treated with brachytherapy alone, although the rate of pelvic wall relapse was not reported in this cohort. Of 28 patients treated with EBRT alone, with carefully designed shrinking fields, three (11%) developed vaginal recurrences. In comparison, there were 12 recurrences (21%) in 58 patients treated with combined EBRT and brachytherapy. The authors concluded that coverage of the entire tumor volume is critical for optimal outcome.

Brachytherapy should be carefully delivered to ensure adequate coverage of tumor volume. An interstitial technique, ideally with three-dimensional (3D) imaging for treatment planning, is required for tumors >5 mm in depth.⁹²^,¹⁵² Extensive tumors, or deeply infiltrating tumors with nondistinct margins, may be poor candidates for brachytherapy. In such cases, boosting tumors with conformal techniques or intensity-modulated radiation therapy (IMRT) may be preferred and may yield better outcomes than suboptimal brachytherapy.¹¹⁴ The tumor volume should receive a minimum of 75 to 80 Gy using combined EBRT and brachytherapy. Fleming et al.¹⁵³ and Puthawala et al.¹⁵⁴ both report improved outcomes with higher doses of 80 to 100 Gy.

The 5-year survival rate for patients with stage II disease treated with radiation therapy alone ranges from 35% to 70% for stage IIA to 35% to 60% for stage IIB.²⁹^,¹⁵³ Pelvic relapse at 10 years has been reported to be 25% by Frank et al.,¹¹⁴ consistent with recent series reporting 5-year pelvic-control rates ranging from 76% to 84%.¹³¹ The likelihood of distant metastasis is higher for stage IIB lesions compared with stage IIA,⁹³^,¹⁵¹ with overall reported rates ranging from 22% to 46%.⁹³^,⁹⁵

Stages III and IVA

Patients with more advanced disease generally also receive EBRT to the pelvis, followed in certain cases by additional dose to the parametrium. If adequate tumor coverage can be achieved without undue toxicity, interstitial brachytherapy is employed to deliver a minimum tumor dose of 75 to 80 Gy. If brachytherapy is not feasible, due to extensive tumor infiltration of the rectovaginal septum or bladder, a shrinking-field technique or IMRT has been used to deliver additional dose to the primary lesion.¹⁵⁵^,¹⁵⁶ The overall cure rate for patients with stage III disease ranges from 30% to 50%. Stage IVA carries a worse prognosis. In highly selected patients with small volume stage IV disease, pelvic exenteration can yield good long-term control; however, in practice, EBRT remains the primary treatment.¹^,⁴^,⁶³^,⁹⁸^,⁹⁹^,¹¹⁴^,¹³⁵^,¹⁵⁷^,¹⁵⁸ Five-year actuarial survival rates for women with stage III disease range from 25% to 58%,¹^,⁴^,¹⁵⁹ with local failure rates of 30% to 75%.⁹³^,¹¹⁴^,¹³¹ Outcomes for stage IV disease are worse, with survival rates of 0% to 40%.⁶⁰^,⁹⁸^,¹⁶⁰ Despite treatment with EBRT and brachytherapy, only 20% to 30% of patients with stages III and IV disease achieve local control. Pelvic recurrences occur more often than distant recurrences.¹¹⁴

Role of Chemotherapy and Radiation

There are no randomized trials that compare radiation alone with radiation plus chemotherapy in vaginal cancer, and many studies of chemoradiation for primary vaginal cancer are limited by small numbers or inclusion of other cancers, such as cervical and vulvar carcinomas. However, many clinicians incorporate the use of cisplatin for treatment of vaginal cancers, extrapolating from data demonstrating improved progression-free and overall survival in cervical cancer when cisplatin is added to radiation.⁶³^,¹⁶¹^–¹⁶⁴

Holleboom et al.¹⁶⁵ published a case report documenting the use of cisplatin with EBRT and brachytherapy in a patient with advanced stage SCC of the vagina. The patient was free of disease at 16 months. Evans et al.¹⁶⁶ reported the use of radiation with 5-FU and mitomycin-C (MMC) in seven patients with vaginal cancer. Four of seven patients were free of disease with follow-up times ranging from 19 to 39 months. Roberts et al.¹⁶⁷ reported results for seven patients with vaginal cancer treated with concurrent 5-FU, cisplatin, and radiation. Three patients received interstitial brachytherapy after EBRT, and two patients received intracavitary brachytherapy after EBRT. Eighty-five percent of patients achieved a complete response initially. Ultimately, 61% recurred, with a median time to recurrence of 6 months. There were three local recurrences and one distant metastasis and the 5-year overall survival rate was 22%. Kirkbride et al.⁹¹ reported on the use of concurrent 5-FU, with or without MMC, in 26 of 153 patients with vaginal carcinoma treated at Princess Margaret Hospital. Seventy-seven percent of the patients had stage III or IV disease. Radiation was EBRT followed by interstitial or intracavitary brachytherapy to a total dose of 62 to 74 Gy. The 5-year survival rate was 50%. Dalrymple et al.¹⁶⁸ reported results using 5-FU-based chemotherapy in combination with radiation for treatment of primary SCC of the vagina. Thirteen of 14 patients (93%) had stage I or II disease. The median dose of radiation was 63 Gy, achieved using EBRT alone or EBRT with intracavitary brachytherapy. The 5-year survival rate was 86% for all patients, and nine patients were free of disease with a median follow-up time of 100 months, suggesting that good local control can be achieved despite the use of lower radiation doses. There was a 31% rate of severe bowel complications reported, with two deaths as a result of bowel obstruction.

A retrospective series from MDACC by Frank et al.¹¹⁴ included nine patients with stage II or IVA SCC of the vagina treated with radiation therapy and concurrent cisplatin-based chemoradiation. With a mean follow-up time of 129 months, improved local control with the use of chemotherapy was noted, with 44% of patients treated with concurrent chemoradiation remaining free of disease. Samant et al.¹⁶⁹ published a review of 12 vaginal cancer patients, stage II to IVA, treated with concurrent weekly cisplatin at a dose of 40 mg/m² for 5 weeks. Patients received concurrent EBRT to a median dose of 45 Gy, with LDR interstitial or an HDR intracavitary brachytherapy boost of median dose 30 Gy. Six patients had stage II disease, four had stage III disease, and two had stage IVA. Ten of 12 (83%) patients had SCC; the other 2 had adenocarcinoma. Overall, treatment was well tolerated, with 92% of patients completing therapy as prescribed. Two of 10 patients who received interstitial brachytherapy required surgery for fistula repair. The 5-year overall survival, progression-free survival, and locoregional progression-free survival rates were 66%, 75%, and 92%, respectively, supporting use of concurrent weekly cisplatin therapy. A small series of six patients treated with chemoradiation at the University of the Ryukyus was reported by Nashiro et al.¹⁷⁰ All patients received EBRT to 50 Gy, followed by either a boost with shrinking fields (n = 4) or intracavitary brachytherapy (n = 2). Radiation was delivered with two to three cycles of cisplatin. Two patients had stage II, one had stage III, and three had stage IVA disease. All six achieved a complete response, and four of six patients remained free of disease at follow-up times of 18 to 55 months.

In a retrospective analysis of 71 patients with primary vaginal cancer treated at Dana-Farber Cancer Institute/Brigham and Women’s Hospital from 1972 to 2009, 51 patients were treated with radiation alone and 20 were treated with chemotherapy and radiation.¹⁷⁰ Of patients treated with chemosensitization during radiation, 85% of patients received weekly cisplatin chemotherapy, while the remainder received either carboplatin or 5-FU. Three-year actuarial overall survival and disease-free survival was 56% for the radiation alone group, compared with 79% for the chemoradiation group (P = .01). Three-year disease-free survival was 43% for the radiation alone group, compared with 73% for the chemoradiation group (P = .01). At a median follow-up of 3 years, tumor relapse was seen in 15% of patients treated with chemoradiation compared with 45% of patients treated with radiation alone (P = .03).

Ghia et al.¹⁷² published a retrospective patterns-of-care analysis using the SEER database, analyzing data from women with primary vaginal cancer treated with EBRT or brachytherapy between 1991 and 2005. Of the 326 women in the study cohort, 80.4% had SCC. It was noted that chemoradiation was used in 7.5% of patients treated before 1999 compared with 36.1% of those treated afterward (P <.001). Cisplatin was the most frequently utilized agent, accounting for 59% of chemoradiation treatments. Chemotherapy was significantly less likely to be used in conjunction with radiation for women over 80 years of age; otherwise, there was no difference for race, stage, grade, histologic diagnosis, comorbidities, or brachytherapy use. On multivariate analysis, chemoradiation was not found to correlate with improved cause-specific or overall survival.

TABLE 72.4 OUTCOMES FOR VAGINAL CANCER BY TREATMENT MODALITY

Outcomes

Overall survival rates by stage, based on reports from smaller series, are shown in Table 72.4. The NCDB report by Creasman et al.,⁴ which focused on 4,885 women diagnosed with vaginal cancer between 1985 and 1994, found 5-year survival rates of 96% for stage 0, 73% for stage I, 58% for stage II, and 36% for stages III and IV, with 85% of invasive cases being SCC. The more recent study by Shah et al.¹ analyzed records from the SEER database of 2,149 women diagnosed with primary vaginal cancer between 1990 and 2004. The risk of mortality is noted to have decreased over time, with a 17% decrease in the risk of death for women diagnosed after 2000 relative to those diagnosed between 1990 and 1994. The authors reported 5-year disease-specific survival rates of 84% for stage I, 75% for stage II, and 57% for stage III or IV.

Overall rates of locoregional recurrence, by stage, are shown in Table 72.4. In general, the rate of locoregional recurrence ranges from 10% to 20% for stage I and 30% to 40% for stage II. Patients with advanced disease often have persistent disease despite treatment. In a series by Dixit et al.,¹³⁸ 68% of failures in stage III patients were due to persistent disease. Most treatment failures occur within 5 years, with a median time to recurrence of 6 to 12 months,¹¹⁴^,¹⁷⁸ and local recurrence is the most common pattern of treatment failure in the majority of published series. Extravaginal recurrences in the pelvic lymph nodes are less common. The reported rates of distant metastasis vary, ranging from 7% to 33%, and usually occur later in the course of disease, with approximately half of all distant metastases presenting at the time of local recurrence.⁹²^,⁹³^,¹⁰⁴^,¹³⁸

Clear Cell Adenocarcinoma

Epidemiology

Clear cell adenocarcinoma of the vagina was first reported in 1971 by Herbst et al.¹⁷⁹ who documented six cases of primary vaginal clear cell carcinoma in patients 15 to 22 years of age: five of the six had been exposed to the synthetic estrogen DES in uteroduring the first trimester. This was the first report suggesting in utero exposure to DES, prescribed during the mid-1940s to 1960s for high-risk pregnancies, could result in an increased risk of clear cell adenocarcinoma. DES-related clear cell adenocarcinoma presents at a young age, with studies documenting median age at presentation to be within the second or third decade of life.¹⁷⁹^,¹⁸⁰ Studies suggest that there is a bimodal distribution for clear cell adenocarcinoma of the vagina, with the first peak among young women with a mean age of 26, most of whom were exposed to DES in utero, and a second peak among women with a mean age of 71 years, born prior to 1950 and thus not exposed to DES.¹⁷⁹^,¹⁸¹

The majority of patients present with stage I or II disease.¹⁷⁹^,¹⁸² In 45% to 95% of cases, clear cell adenocarcinoma of the vagina is associated with vaginal adenosis, most commonly tuboendometrial in morphology, although three patterns of adenosis have been described: endocervical, tuboendometrial, and embryonic.³⁵^,¹⁸³^,¹⁸⁴ Grossly, clear cell adenocarcinoma has polypoid morphology and presents most commonly on the anterior vaginal wall.

Risk Factors

The risk of developing clear cell adenocarcinoma in DES-exposed women is estimated to be 1 in 1,000,¹⁸² suggesting that there are multiple factors contributing to pathogenesis. Additional factors associated with increased risk include DES exposure prior to the 12th week of pregnancy, a maternal history of prior miscarriage, birth in autumn, and prematurity.¹⁸⁵

Vaginal adenosis, defined as the abnormal presence of glandular epithelium in the vagina, is believed to be a precursor lesion to clear cell adenocarcinoma of the vagina and, therefore, is a common histologic abnormality in women who have been exposed to DES in utero, presenting in up to 95% of such women.¹⁸³^,¹⁸⁶ However, it is not strictly confined to this population.¹⁸⁷ Grossly, vaginal adenosis appears as red, velvety, grape-like clusters in the vagina. Glandular columnar epithelium of müllerian type either appears beneath the squamous epithelium or replaces it, undergoing progressive squamous metaplasia.¹⁸⁸

Histology

Clear cell adenocarcinoma of the vagina is most often located in the upper third of the anterior vagina and can vary greatly in size. These cancers can also arise in the cervix. Grossly, they exhibit exophytic growth and are superficially invasive.¹⁸⁹ Microscopically, they are composed of vacuolated, glycogen-rich cells, hence the term clear cell carcinoma. The most common histologic pattern is tubulocystic, although solid, papillary, and mixed cell patterns have also been described.¹¹⁴^,¹⁹⁰ Cells are cuboidal or columnar in shape, with large, atypical protruding nuclei, rimmed by a small amount of vacuolated cytoplasm.

Clinical Presentation

Patients with clear cell adenocarcinoma most often present with abnormal vaginal bleeding,¹⁷⁹ which is found in 50% to 75% of cases. Cytology is not reliable, revealing abnormality in only 33% of cases; therefore, careful assessment of the entire vaginal vault to assess for submucosal irregularity is recommended, in addition to four-quadrant cytologic assessment.¹⁹¹ Abnormal discharge, urinary symptoms, and lower gastrointestinal complaints can also be noted, particularly in advanced cases. The differential diagnosis of vaginal adenocarcinoma is often challenging, because it must be distinguished from metastases from distant sites.

Prognostic Factors

For clear cell adenocarcinoma, prognostic variables associated with worse survival include advanced stage, nontubulocystic pattern of histology, size >3 cm, and depth of invasion >3 mm.¹⁸⁹ A study of 21 women with clear cell carcinoma of the vagina and cervix reported overexpression of wild-type p53 to be associated with a more favorable prognosis.¹⁹² Primary adenocarcinoma of the vagina not associated with DES exposure is extremely rare. In a review of 26 such cases by Frank et al.,¹⁹³ 5-year overall survival was 34%, significantly worse than for patients with SCC.

Treatment Options

The optimal management of clear cell adenocarcinoma is unclear. There are several published series on DES-related clear cell adenocarcinomas¹¹⁴^,¹⁸⁹^,¹⁹⁴^–¹⁹⁷ using conventional treatments similar to those used for squamous cell carcinoma of the vagina for stage I or II disease, including surgery with radical hysterectomy, vaginectomy, and lymphadenectomy with construction of a neovagina, or definitive radiation with consideration of radiosensitizing concurrent chemotherapy.¹⁷⁰^,¹⁹⁸ There has been an emphasis on preservation of ovarian and vaginal function, likely due to the earlier age at diagnosis in DES-exposed patients. According to data from the U.S. Registry for Research on Hormonal Transplacental Carcinogenesis, approximately half of all vaginal clear cell adenocarcinoma cases were treated with radical surgery alone as primary therapy.¹⁹⁹

Wharton et al.²⁰⁰ reported on the use of intracavitary or transvaginal irradiation for early-stage disease, with excellent tumor control and preservation of ovarian function. Herbst et al.²⁰¹ reported on 142 cases of stage I clear cell adenocarcinoma. For the 117 patients treated with radical surgery, there was an 8% risk of recurrence and 87% overall survival. For patients treated with radiation, there was a 36% risk of recurrence. The authors acknowledge that it is difficult to compare surgery to radiation, as radiation was most likely used in patients with larger lesions less amenable to resection.

A series by Senekjian et al.¹⁹⁵ reported on 219 cases of stage I clear cell vaginal adenocarcinoma. Forty-three patients received local therapy alone, consisting of vaginectomy, local excision, or local irradiation with or without excision, and the rest had conventional radical surgery. At 10 years, the actuarial survival rates were equivalent (88% vs. 90%) for patients who had received local therapy only and those treated conventionally, respectively. However, the actuarial recurrence rate was significantly higher (40% vs. 13%) with local excision alone. Patients who received local irradiation, with or without local excision, had decreased local recurrence compared with those treated with excision alone (P <.03).

A subsequent series by Senekjian et al.¹¹⁸ reviewed 76 cases of stage II clear cell adenocarcinoma. The 10-year overall survival rate was 65%. The 5-year survival rates were 80% for patients treated with surgery, 87% for patients treated with radiation, and 85% for patients treated with both. The authors advocate treatment with combination EBRT and brachytherapy for stage II disease, with surgery reserved for smaller, more easily resectable lesions in the upper vagina. The use of pelvic exenteration for primary and recurrent lesions has been reported by Senekjian et al.¹⁹⁶ Survival outcomes were comparable to those of patients treated with other modalities. Thus, to minimize morbidity and preserve quality of life, exenterative approaches are advocated only for patients with disease recurrence after radiation. The 5-year survival rate after pelvic relapse is reported to be 40% by Herbst et al.¹⁹⁴

Most recurrences occur within 3 years of therapy, although recurrences occurring 10 to 20 years after treatment have been reported.²⁰² Most recurrences are local or locoregional, with approximately one-third detected at distant sites, most commonly in the lungs or extrapelvic lymph nodes, although there have been rare cases of central nervous system metastases manifesting years after treatment.²⁰³ The 10-year actuarial survival rate for clear cell adenocarcinoma of the vagina is 79%. For stages I and II disease, survival rates are 90% and 80%, respectively.

Other Adenocarcinomas

Most adenocarcinomas found in the vagina represent metastatic deposits from other sites. Vaginal metastases from adenocarcinoma of the breast, or other gynecological primary sites, and from renal cell carcinomas have been described.²⁰⁴^–²⁰⁶ Primary non–clear cell adenocarcinoma of the vagina is extremely rare and occurs predominantly in postmenopausal women. Histologic variants include endometrioid, mucinous, mesonephric, and papillary serous adenocarcinoma. Vaginal endometrioid adenocarcinoma is the most common non–clear cell subtype and presents most often in women with a history of endometriosis. Only a few case reports or series have been published in detail about endometrioid adenocarcinoma of the vagina.²⁰⁷^–²¹⁷ In one series of 18 cases of primary vaginal endometrioid adenocarcinoma, 10 cases arose from the apex.²⁰⁷ Fourteen of 18 cases had vaginal endometriosis, important in indicating a primary vaginal tumor rather than secondary spread from the endothelium. Median age at presentation was 57, with a range from 45 to 81 years. There have been case reports of mucinous adenocarcinoma of the vagina,²¹⁸^–²²⁰ with at least one arising from a focus of endocervicosis.²²¹

On gross examination, endometrioid adenocarcinomas can be polypoid, papillary, rough, granular, fungating, exophytic, or flat, and most arise from the superior aspect of the vagina. Microscopically, tumors display a predominant component of typical endometrioid carcinoma, with tubular glands lined by columnar cells that have moderate amounts of eosinophilic cytoplasm and large elongated nuclei. Only a few cases of mucinous adenocarcinoma have been described,²⁰⁵^,²¹⁸^–²²⁰ including rare cases arising in neovaginas²²² or arising from endocervicosis.²²¹ Mesonephric adenocarcinoma arises from the mesonephric duct remnants situated in the lateral vaginal wall.²²³^,²²⁴ Primary papillary serous adenocarcinoma of the vagina has rarely been reported.²²⁵

Melanoma

Melanomas arising from the vaginal mucosa are rare, accounting for 2.8% to 5% of all vaginal neoplasms,²²⁶^–²²⁸ with just over 100 new cases of vaginal melanoma reported each year in the United States. According to the NCDB report by Creasman et al.,⁴ vaginal melanomas comprise 4% of all primary vaginal cancers. The incidence of vaginal melanoma has remained stable and is reported to be approximately 0.26 per million.²²⁹ Most reported cases are in white women; one study of 37 women with primary melanoma of the vagina reported 84% of patients to be white and only 3% African American.²²⁶ According to a report by Hu et al.²³⁰ analyzing SEER data from 1992 to 2005 on 125 cases of vaginal melanoma with known race or ethnicity, there is no significant difference in the incidence rate of vaginal melanoma between whites and African American women, with a white to black ratio of 1.02 after age adjustment. In the report by Creasman et al.,⁴ most patients were of advanced age at presentation, with only 23% of patients diagnosed before the age of 60; 28% were diagnosed between the ages of 60 and 69, 28% were diagnosed between the ages of 70 and 79, and 22% were diagnosed at age 80 or older.

Melanomas arising from the vaginal mucosa are thought to originate from mucosal melanocytes in regions of melanosis or from atypical melanocytic hyperplasia. Grossly, melanoma of the vagina tends to be pigmented and may present as a dark mass, plaque, or ulceration; multifocal presentation is also common. The most common appearance is polypoid-nodular.²³¹ The most common location at presentation is the anterior vaginal wall and lower one-third of the vagina.²²⁶^,²²⁷^,²³²

In a case series of 37 women with primary vaginal melanoma reported by Frumovitz et al.,²²⁶ median tumor size at presentation was 3 cm (range, 0.4 to 5 cm), with median depth of invasion of 7 mm (range, 1 to 21 mm). Twenty-one percent of patients presented with multifocal disease; 24 patients (65%) presented with lesions in the distal third of the vagina or introitus.

Microscopically, tumors may be composed of epithelioid, spindle, or nevus-like cells and stain frequently positive for S-100 protein, HMB-45, and melan-A. When S-100 is negative or only focally positive, tyrosinase and MART-1 are useful markers. Poorly differentiated tumors may be difficult to distinguish from carcinomas or sarcomas. Tumor thickness correlates with prognosis and may be measured by the methods described by Breslow.²³³

Vaginal melanoma is a highly malignant disease with a propensity for early hematogenous spread. The most common presenting symptoms reported have been slight vaginal bleeding and vaginal discharge, which is usually blood-tinged, foul smelling, or purulent.¹²¹ Reid et al.²³⁴ reviewed 115 patients with primary melanoma of the vagina and found depth of invasion and lesion size >3 cm to be negative prognostic factors. Stage was not found to be prognostic for outcome, but only 42 of the 115 patients had this information available. Compared with women who have SCC, patients with vaginal melanoma have a significant 1.5-fold increased risk of mortality.¹

Treatment Options

Primary vaginal melanoma is uncommon and, as a result, treatment outcomes for only a small number of patients have been reported¹²¹^,²²⁶^,²³⁵^–²³⁸ and it is difficult to make definitive treatment recommendations. Treatments used in published series include wide local excision, radical surgery, radiation and chemotherapy, or a combination of modalities. Overall prognosis is poor, with historic 5-year survival rates ranging from 5% to 30% regardless of treatment modality or extent of surgical resection.²³⁴^,²³⁵^,²³⁸ There is a high rate of distant metastases, ranging from 66% to 100%.²³⁵^,²³⁹^,²⁴⁰

Regardless of primary treatment, outcomes have been disappointing. Some authors advocate radical surgical resection.²⁴¹^–²⁴³ Geisler et al.²⁴¹ recommend primary pelvic exenteration for vaginal melanomas with >3-mm invasion, reporting a 5-year survival rate of 50% if pelvic nodes are free of disease. Morrow and DiSaia,²⁴³ in their review of gynecologic melanoma, recommend radical surgery based on a review of the literature revealing 3 of 19 long-term survivors after exenteration with wide local excision. Chung et al.²³⁵ reviewed 19 cases of primary vaginal melanoma treated between 1934 and 1976. All patients who received wide local excision developed recurrence. Five-year survival was only 21%. Miner et al.²⁴⁴ reported on 35 patients treated at Memorial Sloan-Kettering Cancer Center from 1977 to 2001. Sixty-nine percent underwent surgery, which was either en bloc removal of the involved pelvic organs, wide excision, or total vaginectomy, with elective pelvic lymph node dissection in 74% of cases. Thirty-one percent of patients received definitive radiation. Primary surgical therapy was significantly associated with a longer overall survival time (25 vs. 13 months). Recurrence-free survival was not found to correlate with surgical extent.

Several series comparing radical surgery and local excision find equivalent outcomes.¹²¹^,²³⁶^,²⁴⁵^,²⁴⁶ In general, treatment modality does not appear to significantly affect survival. Bonner et al.²⁴⁷ reported on nine cases of vaginal melanoma. Three patients were treated with wide local excision and six underwent radical surgery. All nine patients developed locoregional recurrence. As a result, these authors suggest adding pelvic radiation therapy to improve local control. The use of wide local excision followed by postoperative EBRT and brachytherapy has been proposed. A recently published review by Frumovitz et al.²²⁶ reported that radiation after wide local excision can reduce local recurrences. However, most patients develop distant metastases, most commonly in the lungs and liver.

Given the high rates of distant metastases, chemotherapy has been used, either alone or in conjunction with radiation.²²⁶^,²⁴⁸ The use of systemic chemotherapy or immunotherapy has not been shown to improve patient outcomes thus far.²⁴⁸ Frumovitz et al.,²²⁶ in their review of 37 women with stage I melanoma of the vagina treated at MDACC between 1980 and 2009, report very poor prognosis even in this group of patients with localized disease, with a 5-year overall survival rate of 20%. In that study, 10% of patients received nonsurgical treatment with radiation, chemotherapy, or both. Patients treated surgically had significantly longer survival times compared with those treated nonsurgically. Radiation delivered after wide local excision reduced local recurrence and demonstrated a trend toward longer survival times, from 16.1 to 29.4 months.

Retrospective data suggest that radiation may improve local control for vaginal melanoma.¹²¹^,²⁴⁹ Among the few long-term survivors reported in the literature are a handful of patients who were treated with radiation. Harwood and Cummings²⁵⁰ described a complete response in four patients with vaginal melanoma treated with radiation, although two subsequently relapsed. Rogo et al.,²⁵¹ in their series of 22 cases of vulvovaginal melanoma, reported comparable results for surgery and radiation, with eight patients (36%) alive 5 years after treatment. Petru et al.,²⁴⁹ in their series documenting 14 patients treated for primary malignant melanoma of the vagina, noted that three of nine patients treated with radiation, either as primary treatment (n = 2) or in the postoperative setting (n = 1), survived longer than 5 years. Median overall survival for all patients was 10 months, with a 5-year disease-free survival rate of 14% and an overall survival rate of 21%. Typically, vaginal melanoma is treated similarly to vaginal carcinoma, with volumes and doses ranging from 50 Gy for subclinical disease to 75 Gy for gross tumor. Radiation is offered in the adjuvant setting based on limited data suggesting an improvement in local control.

Sarcoma

Sarcomas represent 3% of all primary vaginal cancers.⁴ In a report based on data from the NCDB between 1985 and 1994,⁴ there were 135 cases of primary vaginal sarcoma, with heterogeneous histologies and varying age. Twenty-two percent of patients were under 14 years of age, with a median age at presentation of approximately 50 years. In the pediatric population, embryonal rhabdomyosarcoma or sarcoma botryoides is the most common histology,²⁵²with 90% of cases occurring in children younger than 5 years of age.²⁵³ Vaginal sarcoma most frequently presents as an asymptomatic vaginal mass.¹¹⁹ In one series, this was the most frequent symptom, found in 35% of patients, followed by vaginal, rectal, or bladder pain (26%), bleeding or serosanguineous discharge from the vagina or rectum (18%), leucorrhea (9%), dyspareunia (7%), or difficulty in micturition (7%).

Leiomyosarcoma is the most common histology in adults, representing up to 65% of all vaginal sarcoma cases; however, overall numbers are very small, with <150 published reports in the literature.¹¹⁹ Other less common histologies include malignant mixed müllerian tumor (MMT), endometrial stromal sarcoma, and angiosarcoma.²⁵⁴^,²⁵⁵ Vaginal leiomyosarcomas originate from the smooth muscle of the vaginal wall, but may also develop from smooth muscle cells in tissues adjacent to the vagina. Grossly, patients present with a palpable submucosal nodule, although advanced tumors may demonstrate palpable necrosis or exophytic polypoid tissue.²⁵⁶ Criteria to distinguish between benign leiomyoma and leiomyosarcoma include more than five mitoses per 10 high-power fields, moderate or marked cytologic atypia, and infiltrating margins.²⁵⁷ Due to considerable variation in smooth muscle tumors from area to area, adequate sampling is recommended to achieve an accurate diagnosis. Microscopically, leiomyosarcomas demonstrate interlacing bundles of spindle-shaped cells, with blunt-ended nuclei and fibrillar cytoplasm.¹²¹^,²⁵⁷ Leiomyosarcomas have a predilection for the posterior vaginal wall, with published reports suggesting approximately 43% to 45% in the posterior vagina, 17% to 21% anteriorly, and 34% to 39% laterally.¹¹⁹^,²⁵⁸

MMT, also called carcinosarcomas, are highly aggressive, biphasic neoplasms composed of an epithelial component as well as a sarcomatous component. The epithelial component in vaginal MMT is most often SCC.²⁵⁴ The sarcomatous component can be composed of fibroblasts and smooth muscle or include cartilage, striated muscle, bone, and other heterologous tissues. The metaplastic carcinoma theory suggests that there is a common cell of origin for MMT, with carcinoma giving rise to the sarcomatous component via metaplasia.²⁵⁹ The most common differential diagnosis is sarcomatoid carcinoma. The spindle and carcinomatous components are positive for cytokeratin in sarcomatous carcinoma, whereas MMT demonstrates a sarcomatous component that is positive for vimentin, with the carcinomatous component positive for cytokeratin.²⁵⁴

The first case of vaginal MMT was described in 1975 by Davis and Franklin²⁶⁰; since then, only 11 cases have been reported in the literature, with age ranging from 57 to 74 years.²⁵⁴^,²⁶¹^–²⁶⁵ At least one case report of MMT of the vagina detected high-risk HPV in both the carcinomatous and sarcomatous components, suggesting that some vaginal MMTs may be related to HPV.²⁶¹ Fewer than 10 cases of angiosarcoma of the vagina have been reported in the literature.²⁶⁶^,²⁶⁷ A history of pelvic radiation is a risk factor for pelvic sarcomas, particularly angiosarcoma.²⁵⁵

Prognostic Factors

Review of the literature indicates that vaginal sarcomas undergo early hematogenous dissemination as well as frequent local recurrence. Pulmonary metastases are common.¹¹⁹^,²⁵⁸ Adverse prognostic factors for vaginal sarcoma include high histologic grade, stage, size >3 cm, infiltrative pushing borders, and cytologic atypia.¹²⁰

Treatment Options

Unfortunately, most sarcomas are diagnosed at an advanced stage. Despite surgery and the use of adjuvant radiation therapy in select cases, sarcoma patients sustain poor outcomes due to a high incidence of local recurrence and distant metastasis. Locoregional control is especially important for vaginal leiomyosarcoma. A series by Peters et al.²⁶⁸ reported on 17 cases comprising 10 patients with leiomyosarcoma, 4 with MMT, and 3 with other types of sarcomas. There were only three patients alive and free of disease with follow-up times of 84 to 161 months. All three of these patients had undergone pelvic exenteration. Patients who received other forms of primary therapy all died of recurrence, with the pelvis as the first site of recurrence in all cases. In 50% of cases, the pelvis was the only site of failure, stressing the importance of local treatment. Overall survival of 8 and 10 years following wide local excision have been reported.²⁵⁸

Postoperative radiation therapy has been used to manage soft tissue sarcomas in other sites to reduce locoregional recurrence rates.²⁶⁹ Results from adjuvant radiation for high-grade sarcoma in other regions of the body have been extrapolated to vaginal cancer. In patients with involved margins, high doses above 62.5 Gy are generally required to achieve local control.²⁷⁰ Systemic treatment with doxorubicin is standard for leiomyosarcoma.²⁷¹

Outcomes

Five-year survival was 36% for patients with leiomyosarcoma in the Peters et al.²⁶⁸ series. The survival rate for patients with MMT was even lower, at 17%. There are only a few case reports and small series detailing treatment of primary vaginal MMT. Neesham et al.²⁶³ published a case report of a 74-year-old patient treated with wide local excision and radiation for a 5.5-cm stage I MMT. She developed distant metastases within 6 months of local therapy. Analysis of patterns of failure suggests that local therapy does not have a significant impact on survival due to early distant spread. For that reason, chemotherapy is typically administered after surgery for MMT in other sites and should be considered for primary vaginal lesions, along with adjuvant radiation as warranted. Platinum-based chemotherapy has been used for MMT occurring elsewhere in the pelvis. It has not yet been determined whether platinum agents are best administered alone or in combination with other agents. Combination regimens include a platinum agent or paclitaxel or ifosfamide.²⁷²^–²⁷⁵

Lymphoma

Primary malignant lymphomas of the female genital tract account for only 1% of all primary extranodal lymphomas.²⁷⁶ Of this group, lymphomas of the vagina are rare, with fewer than 30 cases reported in the literature.²⁷⁷^–²⁹⁶ In one review from the Armed Forces Institute of Pathology, only 4 of 9,500 cases of lymphoma were determined to originate from the vagina.²⁹⁷ Most primary lymphomas of the vagina are of diffuse large B-cell type, although there have been reports of lymphoplasmacytic, Burkitt’s, and mucosa-associated lymphoid tissue lymphomas.²⁸⁴ Tumor is usually palpable on examination, with infiltrative thickening of the vaginal wall; at least one case report has described ulceration of the vaginal wall.²⁹² Immunohistochemical analyses are valuable techniques for confirming diagnosis, with tumors typically expressing CD20.²⁸⁵^,²⁹⁵ The most common symptom at presentation is vaginal bleeding. Leukemic infiltrates may be difficult to distinguish from lymphoma; therefore chloroacetate esterase or myeloperoxidase staining may be useful.

Although there is no established treatment protocol for primary lymphoma of the vagina, it seems reasonable to extrapolate from results for extranodal lymphomas elsewhere in the body and to use similar chemotherapeutic and response-based radiation regimens. For patients wishing to retain fertility, chemotherapy alone may be an option in select cases.

The prognosis for women with vaginal lymphoma can be excellent, particularly if diagnosed at an early stage, with 5-year survival rates ranging up to 90%. Of 10 cases reported in the literature between 1994 and 2007, all patients except one were cured of disease after treatment with chemotherapy or a combination of radiation and chemotherapy.²⁸³^,²⁸⁵^,²⁸⁹^,²⁹¹^,²⁹⁸^–³⁰¹ Follow-up periods for these 10 case reports ranged from 6 to 120 months, and one patient died from other causes. Eight patients had Ann Arbor stage IEA disease, one had IIEA, and one did not have a stage reported. The most common chemotherapy regimen was cyclophosphamide, doxorubicin, vincristine, and prednisone. Complete remission was also achieved using methotrexate, doxorubicin, cyclophosphamide, vincristine, prednisone, and bleomycin in one patient. Half of the patients did not receive radiation due to an excellent response with chemotherapy alone.

Small Cell Carcinoma and Other Histologies

Primary small cell carcinoma of the vagina is exceedingly rare, with fewer than 25 cases reported in the literature.³⁰² Mean age at diagnosis is 59 years, with poor outcome due to early widespread dissemination. Eighty-five percent of patients die within 1 year of diagnosis.¹²²^,³⁰³ Microscopically, it is indistinguishable from that of the lung. Neuroendocrine differentiation is often manifested by secretory granules, argyrophilia, and expression of neuroendocrine markers,³⁰⁴^,³⁰⁵ staining positive for cytokeratin, neuron-specific enolase, chromogranin-A, and serotonin. Thyroid transcription factor-1 can also be positive and should not be used to differentiate primary from metastatic disease.³⁰⁶These tumors can occur in pure form or be associated with squamous or glandular elements.³⁰³^,³⁰⁴ Ectopic Cushing’s syndrome has been documented to occur in primary small cell carcinoma of the vagina.³⁰⁵ Treatment typically follows general principles for small cell carcinomas of the cervix, with aggressive therapy, including combination cisplatin-based chemotherapy, radiation therapy, brachytherapy, and surgery, if feasible, indicated.

Adenosquamous carcinoma of the vagina is also extremely rare. Microscopically, tumor cells are composed of glandular and squamous elements. One case report described adenosquamous carcinoma associated with small cell carcinoma of the endometrium in a 64-year-old female.³⁰⁷ Treatment similarly follows general approaches for squamous cell carcinoma of the vagina, including combined consideration of combination chemoradiation for patients with gross disease.

RADIOTHERAPY TECHNIQUES

Definitive treatment of primary vaginal cancer with radiation involves EBRT, brachytherapy, or more typically a combination of the two. With advances in conformal radiation therapy, tumor dose can be escalated while the dose to surrounding normal structures, such as small bowel, rectum, bladder, urethra, and the femoral heads, can be minimized. Brachytherapy can be delivered via intracavitary or interstitial approaches, using LDR or HDR techniques. The use of 3D-based imaging to guide brachytherapy treatment planning is evolving, and recent results published for vaginal cancer show excellent short-term outcomes.³⁰⁸

External-Beam Radiotherapy

In general, when radiation is delivered as primary therapy, EBRT is prescribed prior to or, in some cases, without brachytherapy for a subset of patients with stage I and all patients with stages II to IVA disease. The treatment technique, dose prescription, and selection of the appropriate energy level must be individualized for each patient. The distal tumor margin can be identified using a radio-opaque marker at the time of simulation. CT simulation allows contouring of vessels as a surrogate for lymph node localization, allowing more precise and individualized field delineation relative to pelvic bony anatomy.³⁰⁹^,³¹⁰ If inguinal nodes are to be treated, a “frog leg” position can be considered. Unless contraindicated, the use of oral and intravenous contrast can be helpful, allowing delineation of vascular structures and facilitating the contouring of bladder, small bowel, and rectum. When available, fusion of diagnostic pelvic MRI or PET-CT to the treatment planning CT can assist in defining the tumor (Fig. 72.5).

FIGURE 72.5. Computed tomography positron emission tomography fusion images of vaginal carcinoma. This localized invasive vaginal carcinoma extends into the paravaginal tissue on the left side.

Two-Dimensional Treatment Planning

Traditionally, EBRT is delivered most commonly with opposed anterior and posterior (AP/PA) fields, although patients with extensive loops of small bowel in the treatment field may benefit from a four-field plan, with placement of small bowel blocks on lateral fields. If lateral fields are used, care must be taken to avoid shielding any potential regions of nodal involvement, including the presacral, perirectal, and anterior external iliac nodes. Selection of higher photon energy is preferred for superior dose distribution.

The target volume for EBRT is influenced by diagnostic imaging results and stage of disease. Treatment fields are designed to ensure coverage of the vagina and common iliac, external iliac, hypogastric, and obturator lymph nodes. A standard field has the L5-S1 interspace as the superior border, which ensures coverage of retroperitoneal nodes that lie caudal to the common iliac bifurcation.³¹¹^,³¹² However, because many initial failures occur predominantly in the vagina, paracolpos, and parametria, some authors suggest setting the superior border 1 to 2 cm superior to the inferior margin of the sacroiliac joints in patients with negative imaging of regional nodes in order to minimize treatment toxicity.³¹³ If there are positive pelvic lymph nodes, the superior border should be raised to the L4-5 interspace or higher in order to cover the common iliac nodes. The inferior border lies at the introitus to ensure coverage of the entire vagina, or 4 cm distal to the most caudal aspect of the vaginal tumor. Lateral borders are 1.5 to 2.0 cm lateral to the pelvic brim. Lateral fields, when utilized, should extend anteriorly to the pubic symphysis and posteriorly to the junction of the S2-3 interspace. The border should be extended accordingly to include the inguinal nodes, if warranted. The dose to the inguinal nodes should be calculated during treatment planning to ensure appropriate coverage. When designing treatment fields, the interconnectivity of vaginal lymph node drainage should be kept in mind. Unexpected nodal drainage is possible and should be considered. In a study of 14 women with vaginal cancer who received pretreatment lymphatic mapping with sentinel lymph node identification, two of four women with a lesion in the upper one-third of the vagina were found to have a sentinel lymph node in the inguinal region.¹¹⁶

Several techniques can be considered when treating the inguinal region to minimize dose to the femoral heads. An electron boost can be used to raise the inguinal dose to appropriate levels. Alternately, unequally weighted beams (2:1, AP:PA) or a combination of low- and high-energy photons (4 to 6 MV AP; 15 to 18 MV PA) can be used. Another method uses a wide AP and a narrow PA field, with a daily photon boost to the inguinal nodes delivered with asymmetric collimator jaws.³¹⁴

Three-Dimensional Conformal Treatment

The use of 3D imaging has increased dramatically over the past decade. CT scanning is currently used in most centers for simulation; this allows treatment fields to be tailored to a patient’s specific anatomy. The gross tumor volume (GTV) is defined as the extent of gross disease found on clinical examination, as well as palpable lymph nodes and suspicious lymph nodes and regions seen on CT, MRI, or PET. The GTV is expanded by 1 to 2 cm to form the clinical target volume (CTV), which also includes the entire length of the vagina, paravaginal tissue up to the pelvic sidewall, and bilateral pelvic lymph nodes. Visualization of vessels allows approximation of lymph node locations. The pelvic–nodal CTV can be defined as a 1- to 2-cm margin around blood vessels and should include the common iliac, external iliac, internal iliac, obturator, perirectal, and presacral lymph node regions. For distal vaginal involvement, inguinal lymph nodes are commonly included, with the inferior border set at the lowest aspect of the ischial tuberosity or lesser trochanter. The CTV is expanded by 1 cm to form the planning target volume (PTV). The small bowel, bladder, and rectum are contoured.

Standard dose to the pelvis is 45 to 50.4 Gy in 1.8-Gy fractions, followed in select cases by a parametrial boost ranging from 50 to 65 Gy. Elective nodal irradiation of the inguinal nodes may be delivered to 45 to 50 Gy. Gross nodal disease should receive 60 to 65 Gy, if feasible, using conformal therapy. For clinically palpable inguinal nodes, this can be achieved with reduced portals, using low-energy photons or electrons.

Radiation therapy should be tailored based on tumor location and size. After external-beam radiation to the pelvis, tumors of the vaginal apex >0.5 cm in depth can receive interstitial brachytherapy or external-beam boost; tumors <0.5 cm should receive intracavitary brachytherapy. Tumors of the midvagina, depending on location, can be treated with freehand interstitial brachytherapy or external-beam boost. In general, anterior or lateral tumors of the midvagina are better suited for interstitial brachytherapy. Tumors of the distal vagina can also either be treated with interstitial brachytherapy, especially if they are relatively confined, or external-beam boost for larger tumors. Brachytherapy follows external beam and allows dose escalation to the vaginal tumor to 70 to 80 Gy.

Intensity-Modulated Radiation Therapy

The use of IMRT must be considered with caution for any gynecologic malignancy given significant shifts in tumor position due to constant normal tissue changes and rapid tumor regression during treatment. The large degree of normal tissue and vaginal tumor movement in the pelvis results in the need to contour an integrated vaginal volume, encompassing the position of the vagina with both bladder full and bladder empty, paying close attention to rectal filling.³¹⁵ IMRT may allow dose escalation to gross disease in areas such as inguinal or pelvic lymph nodes, diffusely infiltrative disease, or sidewall tumors inaccessible to brachytherapy. Shrinking field techniques or IMRT can be used for dose escalation if brachytherapy is not feasible.³¹⁶^,³¹⁷ In such circumstances, a total dose of 70 to 75 Gy minimum should be delivered to gross disease. Higher doses are difficult to achieve without substantially increasing the risk of toxicity to adjacent normal tissues such as urethra, bladder, and rectum. Typical IMRT input parameters based on those used for postoperative endometrial cancer for the Radiation Therapy Oncology Group (RTOG) trial 0921 include no more than 30% of entire small and large bowel volume receiving more than 40 Gy, with a dose of 2 cc of the small bowel (D2cc) maximum of 55 Gy; at least 35% of the bladder volume must receive ≤45 Gy with a D2cc maximum of 90 Gy; at least 60% of the recto-sigmoid volume must receive ≤40 Gy, with a D2cc maximum of 70 to 75 Gy; and at least 15% of the femoral head volume must receive ≤35 Gy. The IMRT plans are optimized to minimize the volume of PTV that receives more than 110% of the prescribed dose.³¹⁸

Brachytherapy

Patients are re-examined after EBRT to determine their suitability for intracavitary or interstitial brachytherapy. In general, patients with superficial disease that is ≤5 mm in thickness can receive intracavitary treatment, whereas thicker lesions require interstitial brachytherapy. Intracavitary brachytherapy as monotherapy is typically reserved for patients with VAIN and highly selected stage I patients with minimally invasive disease. In most cases, vaginal brachytherapy is used after EBRT to boost the cumulative dose to 70 to 80 Gy in patients with small lesions <5 mm thick.

Low-Dose-Rate Intracavitary Brachytherapy

Low-dose-rate intracavitary brachytherapy (LDR-ICB) is most commonly performed using a vaginal cylinder loaded with cesium-137 radioactive sources. A variety of vaginal applicators are available, such as those described by Declos et al, Perez et al. or Slessinger et al.³¹⁹^–³²¹ Some cylinders have lead shielding to protect regions of the vagina, bladder, and rectum. Most applicators come in different diameters, and the largest diameter cylinder that can be comfortably accommodated by the patient should be used to improve the ratio of mucosa to tumor dose. Usually, two to three cesium sources are placed along the central tandem of the cylinder. Due to the rapid decrease in dose with distance from intravaginal sources, ICB is most appropriate for lesions that are ≤5 mm thick. For LDR-ICB, the labia are typically sutured closed to secure the implant.

In cases where disease is localized to the upper vagina or vaginal fornices, an intrauterine tandem can be used to anchor the vaginal cylinder or used with vaginal colpostats. Vaginal colpostats can be used alone as well to treat the upper vagina. Some institutions report good results using custom vaginal molds.³²² It is important to avoid placing a source over the vulva, as this may increase skin toxicity. With appropriate selection of dose specification points, a uniform dose distribution can be achieved over the entire length of the vagina. Use of LDR remote control afterloading can also minimize radiation exposure to hospital personnel.

A retrospective series by Pingley et al.¹⁴² reported their experience treating 134 women with primary vaginal cancer. Only the 75 patients who completed treatment were analyzed. Most patients received EBRT to 50 Gy, and 59 patients received subsequent brachytherapy (30 with LDR-ICB, 29 interstitial). The 5-year disease-free survival rate in patients treated with LDR-ICB was 53%; it was 30% for patients who did not receive brachytherapy. Patients who received brachytherapy within 4 weeks of EBRT had a disease-free survival rate of 60%, compared with 30% in those who did not, suggesting that a shorter interval between EBRT and brachytherapy is preferable.

High-Dose-Rate Intracavitary Brachytherapy

In order to sufficiently reduce the dose to normal tissues, 3D-treatment planning, using CT or MRI, should be performed with HDR cases. HDR-ICB delivers treatment over a span of several minutes and has the potential advantages of limiting exposure to caregivers, as well as the ability to optimize dose distribution through varying dwell times.³²³^,³²⁴ Compared with LDR radiation, there is less potential sublethal damage repair and thus a theoretically increased likelihood of toxicity in normal tissue. This has been best examined in cervical cancer, where several prospective and retrospective studies have failed to demonstrate any difference in local control, survival, or toxicity outcomes between HDR and LDR brachytherapy.³²⁵

HDR-ICB is typically performed using iridium-192, with applicators that are similar to those described for LDR. A variety of treatment regimens have been published, ranging from one to six insertions, with doses of 3 to 8 Gy per fraction.⁹⁷^,³⁰⁸^,³²⁶ There is no consensus on the optimal fractionation schedule. Single-institution studies with small numbers of patients have shown HDR to be a feasible and safe technique.¹⁷⁵^,³²⁷

Stock et al.⁹⁷ reported results for 49 patients treated with primary carcinoma of the vagina. Of this group, 15 patients were treated with EBRT and HDR brachytherapy for vaginal carcinoma, with dose per treatment ranging from 3 to 8 Gy. The total median dose delivered via HDR was 21 Gy, and the total median tumor dose overall was 63 Gy. No significant difference in outcome was noted between patients treated with LDR versus HDR. Five-year actuarial survival was reported to be 50% in the HDR brachytherapy group. In comparison, the 5-year survival rate for patients who received EBRT alone (n = 11) was 9% (P <.001), with a higher rate of stage IV disease in the EBRT-alone group (36%) compared with the brachytherapy group (5%).

The largest series of HDR brachytherapy for vaginal cancer is from Vienna by Mock et al.,⁸³ which reported on 86 patients. Patients with stage 0 to stage II disease received treatment with intracavitary HDR brachytherapy alone (n = 26). Prescribed dose per fraction ranged from 5 to 8 Gy, with a mean dose of 7 Gy, and the number of insertions ranged from two to six, with a median of five. In that series, the 5-year recurrence-free survival rates were 100%, 77%, and 50% for stages 0, I, and II, respectively. These authors noted similar local failure rates for HDR brachytherapy administered with or without EBRT, for both stages I and II disease. Treatment was well tolerated.

Nanavati et al.³²⁶ published their experience treating 13 patients with primary vaginal cancer with EBRT to 45 Gy followed by HDR-ICB of 20 to 28 Gy, delivered in 3 to 4 fractions and calculated 0.5 cm from the surface of the applicator. All 13 patients achieved a complete response; with a median follow-up time of 2.6 years, the local control rate was 92%. No grade 3 or 4 acute or chronic intestinal or bladder toxicity was noted during this short follow-up period, but 46% of patients developed moderate to severe vaginal stenosis. All patients had stage I or II disease, and these authors concluded that EBRT plus HDR-ICB is an acceptable treatment with a high response rate, good local control and survival, and minimal toxicity.

Kucera et al.³²⁸ described their experience with 80 patients who received treatment with HDR-ICB, with or without EBRT. Compared with a historical group of patients treated with LDR-ICB, with or without EBRT, no significant differences were noted for local and distant recurrences or rate of complications. Three-year actuarial overall and disease-specific survival rates were 51% and 61%, respectively. Three-year disease-specific survival rates for stages I and II patients were 83% and 66%, respectively.

Beriwal et al.¹⁷⁵ described their experience using intracavitary HDR brachytherapy in five patients with either primary or recurrent vaginal cancer treated between 2000 and 2006. The median dose for intracavitary brachytherapy was 20 Gy in 3 to 5 fractions, prescribed 0.5 cm from the surface of the applicator. One patient received intracavitary brachytherapy only, due to prior radiation therapy with EBRT and HDR brachytherapy. Interpretation is limited due to short follow-up, and the results are combined with interstitial brachytherapy patients but suggest that EBRT followed by HDR brachytherapy is efficacious in the short term as a treatment for vaginal cancer.

Interstitial Brachytherapy

Any paravaginal extension at the time of diagnosis, regardless of treatment response, merits consideration of interstitial brachytherapy, as a vaginal cylinder is unable to deliver sufficient coverage to this region. Other candidates for interstitial brachytherapy include patients with lesions thicker than 5 mm, distal vaginal extension, or those with a vagina that is unable to accommodate standard intracavitary applicators. In general, interstitial brachytherapy is delivered after completion of all EBRT.

Clinical examination provides a rough estimate of tumor thickness. MRI is superior to other imaging modalities for determination of tumor thickness, although contrast such as ultrasound gel placed to distend the vagina aids in visualization of the tumor. T1- with gadolinium and T2-weighted MRI may be obtained if possible after EBRT to assess residual disease. Use of a radio-opaque marker in the vagina placed at the time of diagnosis and after external beam will facilitate assessment of the lesion on CT imaging.

Applicator Selection

Template systems are available to secure the position of the needles in the target volumes, and include the Syed-Neblett template, the modified Syed-Neblett, and the Martinez Universal Perineal Interstitial Template.³²⁹ These systems consist of a perineal template, a vaginal cylindrical obturator, and hollow guides for loading radionuclide sources. The vaginal obturator allows for placement of a tandem, making it possible to combine interstitial with intracavitary treatment if desired. The perineal template requires suturing to perineal skin. A freehand technique is best reserved for lower vaginal tumors, where the mass can be readily palpated and visualized.

Preoperative Assessment

Routine preoperative assessment with an anesthesiologist may occur prior to the procedure in anticipation of general, epidural, or spinal anesthesia. Patients with a history of laminectomy, significant degenerative disease, or labile blood pressure are suboptimal candidates for epidural anesthesia. Epidural anesthesia allows the patient to control the degree of pelvic anesthesia, while avoiding the systemic effects, somnolence, and potential mental-status changes that may occur with a peripheral patient-controlled anesthesia device. When feasible, a combination of general anesthesia during the insertion followed by an epidural patient-controlled anesthesia approach that continues during the entire inpatient hospitalization maximizes pain relief.

Patients on anticoagulation with medications such as warfarin should switch to low-molecular-weight (LMR) heparin approximately 1 week prior to the procedure, and LMR heparin may be discontinued 24 hours prior to insertion time and be withheld during the duration of the implant, although subcutaneous heparin for thrombosis prophylaxis may be initiated after the procedure is completed. Patients may have a gentle bowel preparation orally or an enema before the procedure.

Procedure

The patient is placed into a dorsal lithotomy position; the physician should be aware that the needles may slightly displace when the legs are lowered back to the supine position. A digital and speculum examination allows assessment of vaginal width, tumor size and location, amount and thickness of residual parametrial or paravaginal disease, and presence of a fistula. A sterile setup is used at the time of insertion. A Foley catheter is placed for bladder drainage. Radio-opaque markers can be placed to define tumor borders. For patients with an intact uterus, a central tandem may be inserted to anchor the applicator. A vaginal central plastic cylindrical is placed over the tandem and secured. The template, which contains multiple openings through which needles can be inserted, is placed onto the perineum. The tumor volume is implanted by inserting the needles through the holes of the template, with the goal of covering the GTV with a 1- to 2-cm margin, ideally using 3D imaging to confirm proper needle location. A uniform dose distribution around the tumor volume is desired.

If possible, performing implants with image guidance or under direct visualization is optimal, particularly in patients with a prior hysterectomy. To improve target localization and needle placement, there are several modalities available, including laparoscopic guidance, ultrasound, CT, and MRI. Stock et al.³³⁰ reported the use of real-time transrectal ultrasound as guidance, allowing visualization of pelvic structures during implant placement. The ultrasound probe can be brought into close proximity to the vagina, parametria, and cervix, and the longitudinal mode of the ultrasound probe is useful in determining the optimum depth of needle insertion. Transverse imaging is also utilized during the procedure to ensure coverage of the target area and avoid entry into bladder, rectum, or small bowel. Using this technique, invasive laparotomy or laparoscopy can often be avoided.

Several investigators have used laparoscopic guidance or laparotomy to improve the accuracy and safety of interstitial implant placement.³²⁹^–³³⁴ With open laparotomy, the bladder and urethra can be visualized during needle placement. The bladder and rectum can be protected either by using slings or tissue expanders or by lysis of adhesions. Disaia and Creasman³³⁵ described the creation of an “omental carpet,” where a section of omentum is placed along the descending colon into the pelvis in order to separate the bladder and rectum from the implant and prevent small bowel adhesions. If laparotomy is performed in a two-application course of treatment, it is typically done for the first application only. There can be a significant degree of associated morbidity with the use of laparotomy, including increased operative time, longer postoperative recovery, risk of bleeding, and ileus. As an alternative to open laparotomy, laparoscopic visualization has been used. Although laparoscopy is less invasive, both laparoscopic approaches and open laparotomy are limited by an inability to visualize extraperitoneal structures, such as parts of the bladder, uterus, and cervix, as well as the vagina and paravaginal tissues. However, these techniques can be helpful, particularly in posthysterectomy patients, when CT or MRI is not available during brachytherapy, to avoid needle insertion through the small bowel and sigmoid.

The use of 3D imaging during brachytherapy has increased with the rise of CT and MR availability.³³⁶^,³³⁷ The integration of 3D treatment planning during brachytherapy allows a high dose to be delivered to the tumor volume, while sparing critical adjacent organs. Three-dimensional imaging allows determination of depth and location of insertion and enables repositioning if perforation into the bladder or rectum is detected. In cervical cancer, 3D image-based HDR brachytherapy has been shown to improve local control and decrease treatment-related toxicities.³³⁸^,³³⁹ There are fewer published reports on 3D HDR brachytherapy for primary vaginal cancer. MRI provides superior tumor delineation, whereas CT images can cause overestimation of tumor extension.³⁴⁰ The use of MRI at the time of implant can be limited by lack of access, as well as the requirement for specific applicators and increased scanning time. It is not feasible at many institutions to obtain an MRI at the time of brachytherapy. A diagnostic MRI obtained after EBRT prior to brachytherapy can be used instead to assist with treatment planning. Only a few institutions have access to real-time image guidance during brachytherapy³⁴¹; most scan patients after insertion is complete, with readjustment of inappropriately placed needles after CT and MRI.

FIGURE 72.6. Interstitial implantation of a vaginal tumor extending above the vaginal obturator at the inguinal apex. The vaginal length is treated with the prescription dose in this case. Axial, sagittal, and coronal isodose distributions are depicted with a dose–volume histogram.

Although LDR or HDR can be used, HDR interstitial brachytherapy has the advantage of limiting exposure to caregivers and visitors and offers the ability to optimize dose distribution using 3D image-based treatment planning.³⁰⁸^,³²⁴^,³⁴² Permanent implants using gold-198 or iodine-125 have also been reported,³⁴³ and they can provide long-lasting control in elderly or previously irradiated patients and are typically utilized for smaller volume disease. In general, temporary implants are preferred over permanent implants due to their relative safety or simplicity, cost-effectiveness, easy applicability, readily controlled distribution of sources, and easier modification of dose distribution. Given close proximity of the rectum and bladder, it is important to minimize treatment toxicity by avoiding overdose of critical normal structures. However, underdosing the target volume is also a serious risk, thus optimizing target localization and needle placement is critical.³⁴⁴

Vaginal cancer with gross residual disease at the time of brachytherapy is prescribed a dose of 70 to 90 Gy, with 60 Gy prescribed to the entire vaginal surface. Special care should be taken to minimize the dose to the bowel, which often lies in close proximity to gross disease. Image-based planning software, when available, allows the dose to conform to the target areas while avoiding organs at risk. As a result, optimal dose distribution can be achieved. The primary mass is contoured based on information from 3D imaging.

For HDR-ICB, different fractionation regimens are used and depend on the institution. Given the difficulty of insertion, physicians may insert the applicator once and treat patients over a several day inpatient hospitalization, with ranges of 9 to 10 fractions of 2 to 3 Gy per fraction, twice a day, or 3 to 5 fractions, ranging from 4.5 to 6.5 Gy, twice a day, with at least 6 hours between fractions. It is also feasible to perform two separate insertions with two hospitalizations required. A representative isodose distribution is depicted in Figure 72.6.³¹⁸

For HDR patients who have 3D CT or MRI based treatment planning, the D90, D100, V100, V150, and V200 are parameters used to describe tumor volumes and the doses to those volumes. D90 and D100 are defined as the minimum dose delivered to 90% and 100% of the volume, respectively. V100, V150, and V200 are defined as the volumes receiving 100%, 150%, and 200% of the prescribed physical dose, respectively.³⁴⁵ The bladder, rectum, sigmoid, urethra, and, when necessary, small bowel are contoured as volumes at risk, and the D2cc and D0.1cc calculated.³⁴⁶ The high-risk CTV (HRCTV) is defined as clinically palpable disease, plus any residual disease seen on MRI, and the entire circumference of the adjacent vagina at the level of the residual tumor. The intermediate-risk CTV (IRCTV) includes the region of initial tumor extension and the remaining vagina, in order to encompass potential submucosal tumor spread. The low-risk CTV (LRCTV) is the remaining vagina. The use of MRI-guided adaptive brachytherapy in locally advanced vaginal cancer was recently reported by Dimopoulos et al.³⁴⁷ with excellent outcomes. Thirteen patients with stage II to IV disease were treated, with 3-year local control and overall survival rates of 92% and 85%, respectively, with a mean D90 to the HRCTV of 86 (±13) Gy. Mean D2cc doses to the bladder, urethra, rectum, and sigmoid colon were 80, 76, 70 and 60 Gy, respectively. Two patients developed fistulas and one patient had periurethral necrosis. This study supports the use of the following parameters for image-guided adaptive brachytherapy: for HRCTV, D90 of ≥85 Gy; for IRCTV, D90 ~60 Gy; and for LRCTV, D90 of ~50 Gy.

The recommended maximum equivalent dose in 2-Gy fractions (EQD2) D2cc to the rectum and sigmoid is 70 to 75 Gy and should be <70 Gy when feasible. Maximum EQD2 D2cc for the bladder should be 90 Gy. There are no dose–volume histogram parameters specific to the female urethra, but in general the D2cc should be comparable to parameters for bladder and rectum. A study from Brigham and Women’s Hospital reported the grade 3 or higher complication rates in 51 women undergoing HDR 3D planned interstitial brachytherapy.³⁴⁸ Median D2cc for bladder, rectum, and sigmoid were 64.6, 61.0, and 51.9 Gy, respectively. The actuarial rates of grade 3 or 4 complications at 2 years were 20% gastrointestinal, 9% vaginal, 6% skin, 3% musculoskeletal, and 2% lymphatic. The D2cc for the rectum was significantly higher in patients with grade 2 or more gastrointestinal toxicity. On univariate analysis, D2cc and D0.1cc for rectum and sigmoid, tumor size, and tumor volume at the time of brachytherapy were associated with gastrointestinal complications. This analysis validated the recommended D0.1 cc and D2cc for the rectum and sigmoid.

Precautions for Interstitial Patients

All hospitalized patients should receive subcutaneous heparin as prophylaxis against deep vein thrombosis. Patients should be checked to ensure that a decubitus ulcer has not developed prior to discharge and should be seen in follow-up 2 to 4 weeks after implant removal for a skin check, then at 3-month intervals up to a year, then every 6 months. Dilute hydrogen peroxide douching is advised for patients with tissue-necrosis development. Antibiotics with anaerobic coverage are recommended if a malodorous discharge accompanies the necrosis.

Outcomes with Interstitial Technique

Kushner et al.³⁴⁹ reported outcomes of HDR brachytherapy in 19 patients with primary vaginal cancer. Two-dimensional treatment planning was performed, with interstitial brachytherapy delivered to 8 patients at a median dose of 23 Gy in 4 fractions. The 2-year overall survival rate for patients for all patients was 66.1%. Three patients (15.8%) had serious late effects, including ureteral stenosis, vaginal necrosis, and small bowel obstruction; two of these patients were treated with interstitial brachytherapy.

A series by Tewari et al.³⁵⁰ reviewed long-term results using interstitial brachytherapy, with or without EBRT, in 71 patients with primary vaginal cancer. A Syed-Neblett template was used with an interstitial iridium-192 afterloading technique. Patients received a minimum of 20 Gy via implant, with a total tumor dose of approximately 80 Gy. With a median follow-up time of 66 months, 5-year disease-free survival rates were reported to be 100%, 60%, 61%, 30%, and 0% for stages I, IIA, IIB, III, and IV patients, respectively. Significant complications were noted in 13% of patients, including necrosis, fistula, and small bowel obstruction. Overall, 75% of patients achieved local control.

Beriwal et al.³⁰⁸ describe results using 3D image-based HDR interstitial brachytherapy at the University of Pittsburgh Cancer Institute. A total of 30 patients with primary vaginal cancer (n = 17) or recurrent gynecologic cancer to the vagina (n = 13) were treated using the Syed-Neblett template, with CT scan done after placement of needles for confirmation and treatment planning. Of the subset of 17 patients with primary vaginal cancer, the numbers of patients with stage I, II, III, and IVA disease were 2, 9, 5, and 1, respectively. Fifty-three percent of patients received concurrent chemotherapy with weekly cisplatin at 40 mg/m², and apical lesions had laparoscopic guidance during needle placement. The CTV and organs at risk were contoured on CT scan for treatment planning after placement of needles. Most patients (93.3%) received EBRT to a median dose of 45 Gy, followed by HDR-ICB at 3.75 to 5 Gy per fraction in 5 fractions to a median dose of 21.3 Gy. Overall median D90 to the high-risk CTV was 74.3 Gy, and median D2cc to the bladder, rectum, and sigmoid were 58.5, 57.2, and 50 Gy, respectively, showing excellent sparing of critical organs. At a median follow-up time of 16.7 months, the 2-year locoregional control and overall survival rates were 78.8% and 70.2%, respectively, suggesting good local control. Overall, the treatment was fairly well tolerated. There were no grade 3 or higher gastrointestinal complications. One patient developed late grade 3 vaginal ulceration and another had grade 4 vaginal necrosis.

Brachytherapy Versus External-Beam Boost

Brachytherapy provides an ideal method to provide requisite radiation dose to the central regions of the tumor. Nevertheless, in special circumstances when patients are not appropriate candidates for brachytherapy, IMRT is a useful tool that can be used to boost residual gross disease. A retrospective dosimetric analysis from Princess Margaret Hospital reported data comparing IMRT boost treatment plans with conventional and four-field radiation boost plans for 12 patients with cervical (n = 8), endometrial (n = 2), or vaginal (n = 2) cancer.³⁵¹ IMRT conferred a significant improvement in dose conformity, with overall improvement in rectal and bladder dose–volume distributions, relative to conformal radiation, although inferior to brachytherapy. Overall, the use of IMRT, compared with four-field treatment, reduced the volume of rectum that received a dose >66% of prescription by 22% (P <.001) and reduced the corresponding volume of bladder by 19% (P <.001). However, when comparing an ideal photon or proton external-beam boost to brachytherapy, brachytherapy provided the best coverage and normal tissue sparing.³⁵²

Barraclough et al.³⁵³ used an EBRT boost in 21 patients with cervical cancer who could not undergo intracavitary brachytherapy. A 3D-conformal boost was used to deliver a total dose of 54 to 70 Gy. With a median follow-up time of 2.3 years, 48% of patients had recurrent disease, with central recurrence in 16 of 21 patients, significantly higher than the 3% to 4% local recurrence rates reported with MRI-planned brachytherapy. These results are dramatically inferior to those reported with traditional EBRT followed by brachytherapy, suggesting that external-beam boosts should only be considered as an alternative if brachytherapy is not feasible.

Similarly, there is limited literature on the use of stereotactic body radiotherapy (SBRT) in vaginal cancer, showing inferior outcomes to standard management. A review by Higginson et al.³⁵⁴ reported on two vaginal cancer patients treated with an SBRT boost instead of brachytherapy. Fiducials were placed into the paravaginal, parametrial, or cervical tissues during outpatient clinical examination. The two patients with vaginal cancer received 40 to 45 Gy EBRT followed by 25 Gy in 5 fractions of SBRT; one patient had a local recurrence at 5 months, and another developed distant disease 17 months’ posttreatment. Toxicity included one acute grade 2 cystitis and one late grade 3 rectal bleeding. Therefore, SBRT is not recommended instead of brachytherapy for vaginal cancer.

PATTERNS OF FAILURE

FIGURE 72.7. Displacement of the vagina with bladder filling. Axial, coronal, and sagittal images are shown for the same patient. The left panel shows a relatively empty bladder, with the vaginal cuff contoured in yellow. The middle panel shows a full bladder, with the vaginal cuff contoured in blue. The right panel shows a full bladder with the two vaginal contours superimposed, demonstrating the posterior deviation of the vaginal cuff that occurs with bladder filling.

GENERAL MANAGEMENT, TREATMENT OPTIONS, AND OUTCOMES: SPECIAL SCENARIOS

The Posthysterectomy Patient

According to retrospective series, approximately 60% of patients with primary vaginal cancer have had a prior hysterectomy, which likely reflects the high proportion of patients with a history of cervical neoplasia and carcinoma, as well as overall increased rates of hysterectomy in the general female population.¹³⁹^,¹⁴⁰ After hysterectomy, the small bowel tends to fall lower into the pelvis, increasing the likelihood of it being irradiated during treatment. There is also daily variation in vaginal vault position (Fig. 72.7). Finding methods to improve target positioning during EBRT becomes especially important as treatment delivery becomes increasingly more conformal, and techniques such as IMRT and image-guided brachytherapy are useful.

A study by Jhingran et al.³¹⁵ evaluated the variations in vaginal vault position and bladder and rectal volumes in posthysterectomy patients undergoing IMRT and found significant variations in the position of the vaginal vault depending on bladder and rectal filling. Patients were instructed to have a full bladder prior to radiation treatment; however, the study showed a median difference of 247 cc during IMRT treatment. It is likely that bladder movement impacts vaginal position. For patients with fiducial markers placed in the vagina, the median movement during treatment was 0.59 cm in the right-left direction, 1.46 cm in the anterior-posterior direction, and 1.2 cm in the superior-inferior direction. Thus, it is important to be mindful of target movement when delineating clinical target volumes.

To minimize underdosing the target, the authors suggest fusing planning CT scans taken with full and empty bladder in order to estimate the potential range of target volume positions during treatment. Another approach, although less practical, is to fill the bladder with a fixed volume of saline using a Foley catheter immediately prior to treatment or to use fiducial markers to adjust daily treatments. These approaches may be more useful for short treatment courses or when boosting a limited target. Alternatively, ultrasound can be used to assess bladder volume prior to treatment.

History of Prior Gynecologic Malignancy

Up to 10% to 50% of patients with VAIN or invasive carcinoma of the vagina have undergone treatment for in situ or invasive cervical carcinoma,¹²^,⁶⁰^,⁸⁸^–⁹⁴ with the interval from treatment of cervical disease to development of vaginal carcinoma averaging approximately 14 years.⁹⁰^,⁹⁵ Ninety-five percent of recurrences after treatment of a primary carcinoma of the cervix or endometrium occur within 5 years of treatment; thus, vaginal lesions arising after 5 years are considered to be second primary lesions. Reports by Perez et al.⁹³ and Perez and Camel³⁵⁵ on patients with primary vaginal cancer in the setting of prior gynecologic malignancy more than 5 years earlier showed survival and tumor control rates were equivalent to patients with de novo primary vaginal carcinoma.

For patients with a history of radiation to the pelvis, reirradiation can be considered, but it carries an increased risk of toxicity. Xiang et al.³⁵⁶ published a series on 73 patients with a history of radiation treatment for cervical carcinoma who received a second diagnosis of vaginal malignancy 5 to 30 years later. All patients received EBRT and brachytherapy for treatment of their initial cancer. Reirradiation for the vaginal malignancy was planned according to site and volume of the vaginal tumor and location and dose of the prior radiation. Patients received brachytherapy, using either radium delivered to the tumor base (30 to 40 Gy in 3 to 5 fractions) or HDR with cobalt-60 to the tumor base (20 to 35 Gy in 3 to 5 fractions), followed by a dose to 0.5 cm below the vaginal mucosa at 20 to 30 Gy in 4 to 6 fractions delivered using a vaginal mold. For involvement of the vulva or groin, patients additionally received EBRT to a dose of 30 to 40 Gy. Most patients received radiation alone; 11 also received chemotherapy, most typically cisplatin based. The 5-year survival rate was 40.3% and three patients survived more than 15 years. There were significant side effects with reirradiation: 18 of 73 patients developed radionecrosis. Other side effects included one (1.4%) vesicovaginal fistula and eight (11%) rectovaginal fistulas, hematuria (12.3%), and moderate to severe rectal sequelae (13.6%).

Beriwal et al.¹⁷⁵ reported on the use of HDR interstitial and intracavitary brachytherapy for five patients with recurrent vaginal cancer with a history of pelvic irradiation. Median time from prior radiation to recurrence was 4 years (range, 6 months to 18 years). The recurrence was within 2 cm of the prior field in two patients and within the previous field for four patients. All patients received EBRT to a median dose of 45 Gy, followed by brachytherapy. For the four patients with prior overlapping fields, the cumulative EQD2 to the vaginal mucosa ranged from 120.7 Gy to 154.54 Gy. Of these patients, one developed a rectovaginal fistula 2 years after treatment and another developed chronic vaginal ulceration with vaginal shortening to 2 cm; the EQD2 values were 142.98 and 154 Gy, respectively. There were no significant grade 3 or higher toxicities noted in the other patients.

Carcinoma of the Neovagina

In the past several decades, various methods have been described for vaginal reconstruction or neovaginal construction, including split-skin grafts, myocutaneous flaps, and formation of an artificial canal between the rectum and vagina. Such techniques have been used to construct a vaginal canal for patients with congenitally deformed or absent genitalia or to reconstruct a functional vagina after surgery for gynecologic malignancy.³⁵⁷ There are very few reports of in situ or invasive carcinoma arising in the neovagina. A review of published literature reveals six published reports of carcinoma in situ.³⁵⁸^–³⁶³ The period of development of carcinoma in situ ranged from 6 months to 20 years after constructive surgery. Five patients were treated with surgical therapy. Although topical approaches such as 5-FU or laser ablation can be used, surgery offers a full pathologic evaluation. The extent of disease, patient characteristics, and treatment goals should be used to guide the choice of treatment.

Invasive carcinoma of the neovagina tends to be poorly differentiated. All reported patients have presented with large tumor masses and evidence of rapid progression.²²²^,³⁶⁴^–³⁶⁷ Treatment options include radiation, with or without an attempt at radical resection, and, in select cases, lymph node dissection. Of 16 reported cases from a review by Steiner et al.,³⁵⁷ nine received primary radiation alone, one received radiation followed by exenteration and intraoperative radiation, and four underwent exenteration. Although most cases were SCC (n = 11), there were also five cases of adenocarcinoma. Recurrence status was not documented for all patients. Three were found to have rapid disease recurrence within several months. Two patients were free of disease at 10 and 18 months, respectively. One patient had a recurrence-free interval of 3 years but died a year later from disease.

Recommendations for patients with vaginal reconstruction include regular cytologic surveillance, biopsy of suspicious granulation tissue, and avoidance of chronic irritation, which may contribute to the risk of malignancy. Although there is no optimal treatment, resection followed by consideration of adjuvant radiation is preferable to definitive radiation alone, as definitive radiation may be associated with higher recurrence rates.

Carcinoma in an Episiotomy Scar

There have been case reports documenting implantation of cervical or vulvar carcinoma in an episiotomy scar.³⁶⁸^–³⁷¹ At presentation, the lesions have been described as nodular, or granular, ranging in size from subcentimeter to over 4 cm. Patients treated with excision and radiation do well, with no evidence of disease recurrence,³⁶⁹ favoring a diagnosis of implantation over metastatic deposit. In general, patients with a history of premalignant or malignant gynecologic lesions should receive careful inspection and biopsy of any suspicious lesions in episiotomy scars during routine follow-up. Overall outcomes appear to be favorable and should be tailored to each patient given the rarity of this entity.

Salvage Therapy

For patients with recurrent or persistent disease, it is important to determine whether there is a reasonable chance of cure with salvage treatment or whether the primary goal is palliation. Thus, multiple factors, including extent of disease, site and extent of recurrence, disease-free interval, status of systemic disease, patient age, comorbidities, and overall performance status, must be considered.

Theoretically, stages I and II lesions that recur after radiation therapy can be salvaged with surgical procedures, ranging from total vaginectomy to total pelvic exenteration. A retrospective review of pelvic exenteration for recurrent gynecologic malignancies at University of California–Los Angeles Medical Center from 1956 to 2001 reported survival rates for patients with recurrent cervical and vaginal cancer to be 73% at 1 year and 54% at 5 years.³⁷²

Early-stage lesions that recur after limited surgical procedures can be salvaged using more extensive surgery or radiation. If radiation is used, concurrent chemotherapy with a cisplatin-based regimen may be reasonable. Recurrent disease in advanced-stage patients is more challenging to treat. Most patients have received prior EBRT and thus have options limited to radical surgery or, in patients with localized disease, reirradiation. For patients with small pelvic recurrences, reirradiation with intracavitary or interstitial brachytherapy has been reported, with control rates between 50% and 75%, and grade 3 or higher complication rates between 7% and 15%.¹⁷⁵^,³⁵⁶^,³⁷³^–³⁷⁶ A recent series by Beriwal et al.¹⁷⁵ evaluated HDR brachytherapy for primary and recurrent vaginal malignancy. In the subset of patients with a previous malignancy, crude local control rates were 100% for patients without prior radiation and 67% for patients with a history of radiation.

Palliative Therapy

Patients with stage IVB disease have no curative options, but they can receive substantial symptomatic benefit from local radiation treatment. Advanced disease can result in vaginal bleeding, pelvic pain, lymphedema, and visceral obstruction. Although most series on palliation of gynecologic malignancies involve EBRT, brachytherapy can also be considered for effective symptom management, particularly in the case of vaginal disease. Various regimens have been used. Treatment intensity and duration must be balanced with the extent of expected palliation, potential toxicity, and life expectancy.

Vaginal bleeding is a common symptom for which radiation is prescribed. Bleeding can be minimal, due to tumor friability, or may become brisk when tumor erodes into a larger vessel. Large fractions of radiation delivered initially during the treatment course may be useful in achieving hemostasis for such cases. Other options include embolization, infusion of vasopressin, and balloon catheterization for severe hemodynamic losses. Commonly prescribed palliative regimens, based on clinical experience from other tumor sites, are doses of 30 to 40 Gy in 10 to 20 Gy fractions, resulting in protracted treatment times. As this may not be the most appropriate regimen for patients with a limited life expectancy, shorter courses of radiation have been explored. Larger doses per fraction may increase the risk of late toxicity, but many patients may not live long enough for it to manifest these side effects.

The phase II RTOG-7905 trial explored the use of hypofractionation delivered concurrently with misonidazole, a hypoxic cell sensitizer, in patients with advanced pelvic malignancies.³⁷⁷ Radiation was 10 Gy delivered every 4 weeks for a total of 3 treatments. Although the overall response rate was 41% for patients who completed all three courses, the protocol was closed early due to an unacceptably high risk of late gastrointestinal complications (45% grade 3 and 4). A follow-up study, RTOG-8502, sought to decrease toxicity with an alternative fractionation regimen of 3.7 Gy delivered twice daily, for a total of 14.8 Gy, to be repeated at 4-week intervals up to 3 times.³⁷⁸ The overall tumor response rate was 32% for evaluated patients and 45% for patients who completed all 3 courses of radiation, with a substantially lower late complication rate of 7%. The phase III portion of RTOG-8502 was initiated with patients randomized to a 2- or 4-week treatment break between radiation cycles in the hope of limiting tumor repopulation by decreasing the treatment interval. However, no differences in tumor response or palliation were found. Overall, bleeding and obstruction were substantially or completely palliated in 90% of patients and 68% reported relief of pain.³⁷⁹ Although there was a trend toward increased toxicity in patients with shorter rest periods, there was no significant difference in late toxicity between the two regimens.

There have been smaller series documenting use of hypofractionated regimens for palliation of gynecologic malignancies. Yan et al.³⁸⁰ published a series on 51 patients with advanced gynecologic malignancies, including 10 with vaginal cancer, treated over a 10-year period at Princess Margaret Hospital. A regimen of 24 Gy delivered in 3 fractions with 7 and 14 days between subsequent fractions was used. Ninety-four percent of patients received at least 2 fractions. Overall, 92% of patients had complete or partial resolution of vaginal bleeding, and 76% reported decreased pain, comparable to other reported regimens for pelvic malignancies.

FIGURE 72.8. Proposed treatment algorithm for invasive squamous cell cancer of the vagina.

TREATMENT COMPLICATIONS AND MANAGEMENT

Radiation Toxicity

Pathologic changes in the vaginal mucosa after radiation treatment include marked mucosal atrophy with epithelial thinning and loss of the overlying stratified squamous layer. There can be hyalinization and collagenization of submucosal connective tissues, with fibrosis of the muscular layer and vasculature. Such changes result in compromised oxygenation of injured tissues, promoting ulceration and fistula formation. It is common to find cytologic abnormalities within the first 6 months after radiation, and it is important to distinguish postradiation atypia from new or recurrent malignancy during posttreatment follow-up.³⁸¹

Clinically, vaginal stenosis and shortening can manifest several months after radiation, although presentation as late as 15 years posttreatment has been documented.³⁸² The reported incidence varies between series. Most of the available data are based on experience treating cervical cancer. In a retrospective review by Eifel et al.³⁸² of records for 1,784 patients treated with radiation for cervical cancer, the risk of severe vaginal shortening, defined as >50% of the length, was significantly higher for older patients; the 10-year incidence was 5% for those treated after the age of 50 and was 1% for younger patients. Rectovaginal and vesicovaginal fistulas form typically within 2 years of radiation therapy completion, often with preceding pelvic pain and nonhealing ulceration.³⁸³ Symptoms include passage of vaginal stool or watery discharge. Diagnosis is made on vaginoscopy or cystoscopy, although CT or MRI with contrast can yield characteristic findings.

There are limited long-term data on late toxicity following radiation treatment of vaginal cancer. Perez et al.,⁹³ in their series on 205 patients treated with radiation for VAIN or vaginal carcinoma, reported a 12% crude rate of late complications in 25 patients, which included rectovaginal fistulas (n = 6), vesicovaginal fistulas (n = 3), bladder-neck contractures or urethral strictures (n = 2), rectal strictures (n = 2), and proctitis (n = 2). Other complications included rectal ulceration, vaginal necrosis, small bowel obstruction, cystitis, leg edema, neuritis, severe vaginal stenosis, and diverticulitis.

Chyle et al.,⁶⁰ in a review of 301 patients treated with radiation, reported a 19% incidence of severe complications at 20 years, including fistulas (n = 10), rectal ulceration, proctitis or stricture (n = 10), urethral stricture (n = 6), vaginal ulceration or necrosis (n = 8), and small bowel obstruction (n = 7). A subsequent series from MDACC described 193 patients with vaginal SCC treated between 1970 and 2000 with a variety of techniques.¹¹⁴ The majority of patients with advanced-stage disease (66%) received radiation to a mean dose of 64 Gy. The cumulative rate of grade 3 or 4 complications was 17% at 10 years (n = 20). Nineteen of 25 total complications were gastrointestinal, with proctitis (n = 7), fistulas (n = 5), and small bowel obstruction (n = 4) being the three most frequent. Of the 11 patients with severe rectal complications, eight had tumors involving the posterior aspect of the vaginal wall. Likewise, all major genitourinary complications occurred in patients with tumor involving the anterior wall. On univariate analysis, FIGO stage and smoking status correlated significantly with the risk of late complications.

The vagina is considered to be a relatively radioresistant organ. Although the tolerance dose is not clearly defined, several studies have shown significantly increased toxicity with increased dose. Lian et al.¹⁷⁴ reviewed records of 68 patients treated with radiation for primary vaginal cancer at the Cross Cancer Institute in Edmonton, Canada, from 1986 to 2006. Patients were treated with EBRT, brachytherapy, or a combination of the two and total doses for the three treatment groups were 60.5 Gy, 34.5 to 60 Gy and 70.5 to 72.6 Gy, respectively. There were no reported grade 3 or 4 bowel or bladder toxicities. Six patients (10%) developed grade 3 to 4 vaginal injury, with five rectovaginal fistulas; dose >70 Gy was significantly associated with the incidence of vaginal toxicity. Beriwal et al.,¹⁷⁵ in a series of 18 patients treated with HDR brachytherapy, found two patients (treated to total doses of 142.98 and 154 Gy) who developed late grade 3 or 4 toxicity; one patient had a rectovaginal fistula 2 years after treatment, and the other developed a chronic vaginal ulcer with significant narrowing and shortening of the vagina.

Patient-related factors contributing to radiation injury include age at treatment, location of the primary tumor, and smoking status. Age over 50 has been shown to correlate with incidence of vaginal stenosis.³⁸⁴ Several studies demonstrate an increased rate of fistula formation after treatment of vaginal cancers that invade into the bladder or rectum.³⁸³ A retrospective review from MDACC demonstrated that current smokers had a 5-year complication risk of 25% compared with 5% for those who had never smoked.³⁸² There are numerous treatment-related factors that may potentially impact radiation toxicity, including fractionation pattern, size of intracavitary cylinder and resultant vaginal surface dose, use of concurrent chemotherapy, and surgery. There is no clear association between the use of chemotherapy and increased radiation sequelae; however, data are limited. Several series have shown an increased risk of fistula formation in patients who undergo surgery prior to radiation compared with patients who receive either surgery or radiation alone³⁸²^,³⁸⁵^,³⁸⁶; although these reviews were conducted on cervical cancer patients, it stands to reason that a similar association may exist in patients treated for vaginal cancer.

Symptom Management and Prevention

Acute injury to the vaginal mucosa should be managed symptomatically through hygiene, recognition and treatment of infection, and pain control. There should be a low threshold for starting antifungal medications, as candida can exacerbate vaginitis. Sitz baths and topical ointments may be useful for radiation dermatitis, and both topical and oral analgesics can be prescribed for mucositis and general discomfort during radiation.

The bladder and rectum are located in close proximity to the vagina, and it is common for patients to develop acute toxicity during treatment.³⁸⁷ Increased urinary frequency, urgency, and dysuria can be managed with phenazopyridine, a urinary tract analgesic, as well as oral anticholinergic and antispasmodic medications. Antidiarrheal medications such as loperamide, and in more severe cases tincture of opium, should be prescribed for management early in the development of symptoms. Irritation of the anal mucosa can cause exacerbation of hemorrhoids and occasional hemorrhagic spotting and discomfort with defecation; topical hemorrhoidal ointments or suppositories can be used.

Regular use of a vaginal dilator to decrease stenosis and shortening should be recommended shortly after completion of radiation, as it is difficult to reverse stenosis and shortening once fibrosis has ensued. Topical estrogen, applied 3 times a week for 6 to 9 months after radiation, was shown in a randomized controlled trial published in 1975 to reduce the incidence of stenosis, dyspareunia, and cytologic changes in vaginal epithelium.³⁸⁸ However, due to a small potential for systemic absorption with untoward effects on endometrial proliferation, the use of topical estrogens is not favored for all patients.

Radiation necrosis can be conservatively managed with local debridement, peroxide douches, antimicrobials, and estrogen. There is some evidence that hyperbaric oxygen can facilitate healing, with a >50% reduction in vaginal ulceration noted in one series.³⁸⁹ Fistulas present more of a treatment challenge. Despite the use of interventions such as urinary or fecal diversions, additional surgical correction is often required for effective management, particularly in the case of rectovaginal fistulas.³⁹⁰

TREATMENT ALGORITHM AND CONCLUSIONS

A treatment algorithm for invasive SCC of the vagina is shown in Figure 72.8. Vaginal cancer is a rare disease with a poor prognosis. It is hoped that improvements in local control will yield superior patient outcomes. Optimizing delivery of radiation to tumor volumes while minimizing treatment toxicity remains critical for progress. The increasing use of 3D imaging, conformal external-beam treatments, and image-guided brachytherapy in gynecologic malignancies should optimize the efficacy and precision of radiation dose delivery. Given the low incidence of vaginal cancer, it is unlikely that randomized clinical trials will be undertaken; thus single-institution series will be important in guiding our understanding and management of this disease.

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