ABSTRACT: Melanomas of the vulva and vagina comprise less than 2% of melanomas in women. Although their biologic behavior appears to be similar to that of cutaneous melanoma, vulvar and vaginal melanomas appear to have a different etiology. Women presenting with pigmented vulvar lesions should undergo expedited examination and full-thickness biopsy. Vulvar and vaginal melanomas should be staged surgically using the AJCC system, which incorporates Breslow and Clark microstaging. Adverse prognostic factors include advanced age at diagnosis, central location of tumor, capillary lymphatic space involvement, ulceration, high mitotic rate, and aneuploidy. Primary surgery should include radical local excision with 1-cm skin margins for melanomas less than 1 mm thick and 2-cm margins for melanomas 1 to 4 mm thick. Deep margins should be at least 1 to 2 cm. Femoral inguinal lymphadenectomy should be performed in patients at increased risk of lymph node metastases on the basis of primary tumor characteristics. Adjuvant interferon-alfa appears to confer survival benefits in patients with regional nodal disease. Effective salvage therapy has not yet been identified. [ONCOLOGY 10(7):1017-1023, 1996]
Melanomas of the vulva and vagina are rare, accounting for no more that 2% of melanomas among women. Population-based studies of vulvar and vaginal melanomas have recently been reported from the United States and Sweden [1,2]. In the United States, information was derived from the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) program, which collects data from cancer registries covering about 10% of the US population. Over a 15-year period from 1973 to 1987, 30,295 melanomas were diagnosed among men and women. Among these were 203 vulvar melanomas and 51 vaginal melanomas, which comprised 1.3% and 0.3%, respectively, of all melanomas among women. The annual incidence rates were .108 per 100,000 women for vulvar melanoma and .026 per 100,000 women for vaginal melanoma.
The Swedish study looked at melanomas of the vulva and vagina diagnosed over a 25-year period between 1960 and 1984, using the Swedish National Cancer Registry. Since 1958, Swedish law has required that all neoplasms be reported to their national cancer registry linked to a national death registry. The study identified 219 patients with vulvar melanoma and 26 patients with vaginal melanoma. A decline in the incidence of vulvar melanoma was noted, from .27 per 100,000 women per year between 1960 and 1964 to .14 per 100,000 women per year between 1980 and 1984. In contrast, the incidence of cutaneous melanoma rose in Sweden by 6% per year between 1960 and 1982, suggesting that vulvar melanoma may have a different etiology than cutaneous melanoma.
In both the United States and Sweden, vulvar and vaginal melanomas tended to occur among older women, as opposed to cutaneous melanomas, which were more common among younger women. The median age at diagnosis among US women was 66 years for vulvar melanoma and 70 years for vaginal melanoma. Among Swedish women, the mean age at diagnosis was 67.7 years for vulvar melanoma and 66.3 years for vaginal melanoma.
In the United States, vulvar melanoma appeared to be more common among white women than among black women (relative risk, 2.6; 95% confidence interval [CI], 1.2 to 6.0). No such racial difference was noted for vaginal melanoma.
In the United States, women with vulvar melanoma had a median survival of 61 months, with a 60% adjusted (for expected mortality) survival rate at 5 years and a 50% rate at 10 years. Survival for US women with vaginal melanoma was markedly worse than for those with vulvar melanoma. Women with vaginal melanoma experienced a median survival of 19 months and had a 5-year relative survival rate of 25%.
Similar survival rates were noted in Sweden. Swedish women with vulvar melanoma had a 47% relative survival rate at 5 years and a 44% rate at 10 years. Among Swedish women with vaginal melanoma, the 5-year relative survival rate was 18%.
Among US patients with vulvar melanoma, age and race were significant independent predictors of survival. The hazard ratio for black race, adjusted for age, was 5.1 (95% CI, 2.0 to 13.1). The hazard ratio for age was 1.4 per 10 years of age (95% CI, 1.3 to 1.6).
In the one prospective trial evaluating outcome in patients with vulvar melanoma, conducted by the Gynecologic Oncology Group (GOG), older patients were at significantly increased risk for recurrence, with a 26% increase for each decade (P = .02) ; this is consistent with SEER findings. Retrospective studies conducted by Podratz et al, Rose et al, Bradgate et al, Trimble et al, and Scheistroen et al also found a worse prognosis conferred by advanced age at diagnosis [4-8].
Women should be instructed in routine surveillance of all skin, including that of the vulva. A hand-held mirror may facilitate examination of the vulva. Any pigmented lesions, particularly those which appear to be growing rapidly or seem irregularly irregular--with varying colors, thickness, and borders--should be reported immediately.
In retrospective series, women with vulvar melanomas present with signs and symptoms similar to those of other vulvar malignancies. They note a lump or mass on the vulva; bleeding or itching also are frequent complaints. Such reports should prompt immediate inspection of the vulva with excisional biopsy of suspicious lesions. Colposcopy with acetic acid may be helpful. Excisions should not be "shave" biopsies. Rather, small lesions should be circumferentially resected with the underlying subcutaneous tissue so that the thickness of the lesion may be measured. For larger lesions, full-thickness biopsies should be performed, such as those obtained with a Keyes punch.
Benign pigmented lesions of the vulva include lentigo simplex; vulvar melanosis; junctional, compound, and intradermal nevi; dysplastic nevi; acanthosis nigricans; and seborrheic keratosis. Pigmented vulvar neoplasia may include vulvar intraepithelial neoplasia, squamous carcinoma, and Paget's disease, in addition to melanoma. Immunohistochemical studies and electron microscopy may be helpful in making the differential diagnosis. Melanomas are usually immunoreactive for S-100 protein and HMB-45. On electron microscopy, melanoma cells contain melanosomes and other ultrastructural features not present in Paget's cells.
In the past, cutaneous melanomas were staged using a clinical staging system, as well as microstaging systems based on tumor thickness or depth of invasion . In 1983, the American Joint Committee on Cancer (AJCC) recommended the use of a new staging system that incorporates surgical staging, as well as tumor thickness or depth of invasion .
Vulvar melanomas have been staged using two macrostaging systems--the AJCC staging system for cutaneous melanomas and the International Federation of Obstetrics and Gynecology (FIGO) system for squamous vulvar carcinoma (Table 1) . Both of these staging systems now correlate with the TNM system . In addition, a variety of microstaging systems have been used, including the Clark and Breslow systems for cutaneous melanomas and the Chung modification of the Clark system for vulvar melanoma (Table 2) [13-15]. The Clark system of levels is based on the depth of invasion relative to papillary dermis, reticular dermis, and subcutaneous fat. The Breslow system of levels is based on melanoma thickness as a multiple of 0.75 mm.
Both the Clark and Breslow systems have been shown to correlate with prognosis in patients with cutaneous melanoma. Chung and colleagues argued that Clark microstaging was inappropriate for the vulva and labia, which lack a well-defined papillary dermis, and substituted measurement of tumor thickness as a multiple of 1 mm for the middle three Clark levels.
In the predominantly retrospective literature on women with vulvar and vaginal melanoma, there has been little consistency in the use of macrostaging or microstaging systems. In addition, older series of patients with vulvar melanoma often used the older FIGO staging, in which regional lymph nodes were assessed clinically, not surgically. Several patterns emerge from this literature, however: Breslow and Chung microstaging systems appear to be more accurate than the Clark system. Also, AJCC staging appears to be more predictive of outcome than FIGO staging.
In the only prospective study of patients with vulvar melanoma, conducted by the GOG,  AJCC staging for cutaneous melanoma had the most significant correlation with recurrence-free interval. At 5 years, for example, the GOG noted an 85% survival rate for those with AJCC stage I disease, 40% for those with stage II disease, and 25% for those with stage III disease. FIGO staging was not found to be an important discriminant of recurrence-free interval. The GOG concluded that AJCC staging should be used for patients with vulvar melanomas "for the determination of prognosis and selection of therapies." In the absence of AJCC stage, Breslow levels were the next most prognostic.
Podratz et al identified 48 patients with vulvar melanoma treated at the Mayo Clinic between 1950 and 1980 . They found FIGO stage to be of little value in predicting outcome, whereas both Clark and Breslow microstaging had prognostic significance. Patients with level 5 disease, whether Breslow or Clark, had significantly worse survival than patients with more superficial disease.
Trimble et al  analyzed outcome in 80 patients with vulvar melanoma treated at Memorial Sloan-Kettering Cancer Center, including 44 previously reported by Chung et al. Chung microstaging was a more accurate predictor of survival and risk of nodal disease than was Breslow tumor thickness.
Scheistroen et al identified 43 patients with vulvar melanoma treated at the Norwegian Radium Hospital between 1956 and 1987 . Prognosis was related to Breslow tumor thickness, with significantly worse survival observed in patients with tumor thickness more than 5.0 mm (P = .002).
No prospective studies have addressed staging in patients with vaginal melanoma. Reid et al compiled data on 115 patients reported retrospectively from a variety of institutions . FIGO stage, reported for only 42 patients, was not found to affect survival or time to recurrence. Tumor size was important; patients with lesions less than 3 cm experienced significantly better survival than those with lesions equal to or more than 3 cm (P = .024). Tumor thickness, reported in only 31 patients, was a significant prognostic variable for disease-free interval but not survival.
In light of the prospective data from the GOG study in vulvar melanoma, it would seem reasonable to use AJCC staging in vaginal melanoma.