Obstetrics & Gynecology:
Vulvar Melanoma: A Multivariable Analysis of 644 Patients
Sugiyama, Valerie E. MD2; Chan, John K. MD1; Shin, Jacob Y.2; Berek, Jonathan S. MD, MMS2; Osann, Kathryn PhD4; Kapp, Daniel S. MD, PhD3
From the 1Division of Gynecologic Oncology, Department of Obstetrics, Gynecology, and Reproductive Sciences, University of California, San Francisco School of Medicine, University of California, San Francisco Comprehensive Cancer Center, San Francisco, California; 2Division of Gynecologic Oncology, Department of Obstetrics and Gynecology and 3Department of Radiation Oncology, Stanford University School of Medicine, Stanford Cancer Center, Stanford, California; and 4Division of Hematology/Oncology, Department of Medicine, Chao Family Comprehensive Cancer Center, University of California, Irvine Medical Center, Orange, California.
Corresponding author: John K. Chan, MD, Division of Gynecologic Oncology, Department of Obstetrics, Gynecology, and Reproductive Sciences, University of California, San Francisco School of Medicine, University of California, San Francisco Comprehensive Cancer Center, 1600 Divisadero Street, Box 1702, San Francisco, CA; e-mail: firstname.lastname@example.org.
Financial Disclosure The authors have no potential conflicts of interest to disclose.
OBJECTIVES: To determine the prognostic factors associated with the survival of vulvar melanoma patients.
METHODS: Data were obtained from the Surveillance Epidemiology and End Results database from 1973 to 2003. Kaplan-Meier survival curves and Cox regression models were used for analysis.
RESULTS: Of the 644 vulvar melanoma patients, the median age was 68 years. Of these 572 women were white, 28 were Hispanic, 18 were African-American, and 14 were Asian. A total of 302 had localized disease, 168 had regional disease, and 28 had distant disease. Of the participants who underwent surgical resection, 171 (26.6%) had conservative surgery, 164 (25.5%) had radical excision, and 241 (37.5%) had unspecified surgical resections. One hundred seventy-nine (27.8%) had lymph node resections, and 33 patients had concurrent radiation therapy. Nodal metastases were identified in 58 (9%) of the participants. The 5-year disease-specific survival rates for those with localized, regional, and distant disease were 75.5%, 38.7%, and 22.1%, respectively (P<.001). Women aged 68 years or younger had a better survival rate than older patients (72.0% compared with 47.7%; P<.001). Those with 0, 1, and 2 or more positive lymph nodes had survival rates of 68.3%, 29%, and 19.5%, respectively (P<.001). In a multivariable analysis, younger age, localized disease, and negative lymph nodes were independent prognostic factors for improved survival.
CONCLUSION: Age, stage, and lymph node involvement were significant factors for survival in vulvar melanoma.
LEVEL OF EVIDENCE: III
Vulvar cancer accounts for approximately 4% of all gynecologic malignancies.1,2 In 2006, in the United States there were 3,740 new cases of vulvar cancer diagnosed and 880 deaths.3 The majority (90%) were squamous cell carcinoma, with vulvar melanoma as the second (3.4–10%) most common histologic type.
Because vulvar melanomas are rare, there are few large studies that have defined demographic-pathologic features for this tumor. A comprehensive review of studies before 1994 identified 322 cases of vulvar melanoma. In univariable analysis, International Federation of Obstetrics and Gynecology (FIGO) stage and presence of groin metastases were important prognostic factors.4 More recently, a population-based study of 219 women found that for stage I patients, macroscopic amelanosis and tumor ulceration were predictors of poor survival on multivariable analysis.5 There have also been smaller case series and literature reviews showing that vulvar melanoma had prognostic factors and biologic behavior similar to cutaneous melanomas.6 In this current population-based analysis, we determined the significant demographic, clinicopathologic, and treatment factors associated with the disease-specific survival of vulvar melanoma patients.
MATERIALS AND METHODS
Using the Surveillance Epidemiology and End Results (SEER) database from the National Cancer Institute between 1973 to 2003, 644 cases of vulvar melanoma were identified (ICD-9 histology codes included 8720, 8721, 8730, 8740, 8742, 8743, 8744, 8746, 8770, 8771, and 8772). All participants with in situ disease were excluded from our study group. Surveillance Epidemiology and End Results is a national cancer surveillance program that collects information from all incident cancer cases diagnosed in residents from 17 standard geographic areas in the United States. This database represents approximately 26% of the United States population.7 Information, including age at diagnosis, race, stage of disease, extent of nodal disease, surgery, and adjuvant therapy, were extracted and analyzed. This analysis of the SEER database was exempt from institutional review board approval.
Details on tumor microstaging (Clark's level and Breslow depth) were not recorded in the database. Stage of disease was used according to the SEER description of localized, regional, and distant disease. Localized disease was defined as a neoplasm confined entirely to the organ of origin, regional disease extended beyond the limits of the organ of origin, invading directly into surrounding organs or tissues or regional lymph node involvement, and distant disease spread to parts of the body remote from the primary tumor either by direct extension or by metastasis to distant organs or distant lymph nodes.7 Surgery for the primary site was grouped as none (including biopsy), conservative (local ablative or wide local excision) or radical excision. Based on the SEER Program Code Manual, 3rd Edition,8 the definitions of conservative surgery include simple or partial surgical removal of the primary site, whereas radical excision is defined as partial or total removal of the primary side with an en bloc resection (partial or total removal) of other organs. Information on regional lymph node involvement was characterized as zero, one, or two or more positive nodes. Radiotherapy was categorized as either receiving or not receiving radiation therapy.
Statistical analysis was performed using the Intercooled Stata 8.0 program (StataCorp LP, College Station, TX). Survival analysis was performed using the Kaplan-Meier estimates of survival probability, and the Cox proportional hazards model was used to identify independent predictors of disease-specific survival. A two-tailed P<.05 was considered statistically significant.
A total of 644 women were identified with vulvar melanoma. The demographics of the study population are presented in Table 1. The median age at diagnosis in our series was 68 years old (range 10–99). There were 572 (88.8%) white (non-Hispanic) women, 28 (4.3%) Hispanic, 18 (2.8%) African-American, 14 (2.2%) Asian, and 12 (1.8%) were not racially categorized. Of the overall study group, 302 had localized disease, 168 had regional, 28 had distant, and in 146 disease stage was undetermined. Of the 58 (9%) participants who had positive lymph nodes, 4.3% had one positive lymph node and 4.7% had two or more positive nodes. Fifty-three (8.2%) of the participants who had regional disease had lymph node metastasis, and five (0.8%) with distant disease had lymph node metastasis. Thirty-three (5.1%) of the participants received radiation therapy.
The overall 5-year disease-specific survival rate was 61.0%. The survival rates based on demographic, clinicopathologic, and treatment factors are summarized in Table 2. Using the median age of the participants, we found that younger participants (aged 68 years or younger) had a 5-year disease-specific survival rate of 72% compared with 47.7% in older women (P<.001, Fig. 1). There were no statistically significant survival differences between the racial groups of white, Hispanic, African American, and Asian (P=.139). The 5-year disease-specific survival rate was 75.5% for localized disease, 38.7% for regional disease, and 22.1% for distant disease (P<.001, Fig. 2). The 5-year disease-specific survival rate for women with positive lymph nodes was 24.0% compared with 68.3% (P<.001) for women with negative lymph nodes. The survival rate for women with no positive lymph nodes, one positive lymph node, and two or more lymph nodes was 68.3%, 29%, and 19.5%, respectively (Fig. 3). Of the participants with localized disease, there was no statistically significant difference between those who underwent a radical compared with conservative surgery (79.4% compared with 75.2%, P=.851). The year of diagnosis was divided into three groups and survival was not found to be significantly different as a function of year (Tables 1 and 2).
In a multivariable analysis factors of older age, advanced stage, and positive lymph nodes were significant factors for worsened disease-specific survival (Table 3). On the other hand, race, types of surgery, and radiation were not significant prognosticators.
Vulvar melanoma is an uncommon gynecologic malignancy. Due to the small numbers of cases per year, most of the information is derived from retrospective analyses or literature reviews with less than 350 patients.4–6,9–19 Our current study is a large population-based analysis of vulvar melanoma.
Vulvar melanoma is a disease that usually occurs in advanced age and is associated with a poor 5-year survival, with rates of 27–59%.5,10–12,15–21 In our univariable analysis, we found that patients who were diagnosed with vulvar melanoma at a younger age (68 years or younger) had a better survival rate than those diagnosed at a later age (P<.001) (Fig. 1). This is consistent with several studies that also found that age was an important prognostic factor.9,12,13,15,21 However, another study did not find a significant difference in age and overall survival.11
Over the past four decades, there have been different ways of staging vulvar melanomas, including the current American Joint Committee on Cancer Staging (for cutaneous melanomas),22 the Chung classification,23 Breslow depth,24 Clark,25 and FIGO staging systems. All these systems include some measure of depth of invasion. Due to the lack of data reported, we were unable to assess the tumor's depth of invasion, which has been associated with survival.10,14,16,20,26–28 Based on the available information, we categorized the vulvar melanomas according to the SEER classification of localized, regional, and distant disease. Consistent with what previous studies have shown,11,12,15,29 our data confirmed that patients with localized stage disease had a better 5-year survival rate than those with regional or distant disease (75.5% compared with 38.7% compared with 22.1%, P<.0001) (Fig. 2). Our results are in agreement with those found for cutaneous melanomas at other sites as reported in an analysis of the 1988–2001 SEER database for cutaneous melanomas.30
In the past, vulvar melanomas have been treated with a radical vulvectomy and bilateral inguinal-femoral lymph node dissections. In cutaneous melanomas, clinical trials have been unable to reveal a survival advantage in those who underwent more radical compared with conservative surgeries. Likewise, there is an overall trend toward a more conservative resection in vulvar melanomas.10,14,31,32 Hacker and Berek1 reported that tumor with invasion of less than 1 mm may be treated with radical local excision alone as opposed to the traditional en bloc resection of the primary tumor. Davidson et al33 reported on 32 patients with vulvar melanoma and found similar outcomes in those who underwent local excision (n=14), simple vulvectomy (n=7), or radical resection (n=11). Trimble et al14 reported on 59 patients who underwent radical vulvectomy compared with 19 who underwent more conservative resections and found that survival was not improved by a more radical approach. These authors recommended a radical local excision for the primary tumor with groin dissection for tumors thicker than 1 mm. The results of the Gynecologic Oncology Group prospective clinicopathologic study of primary malignant melanoma of the vulva13 concluded that there did not exist enough evidence to make recommendations as to the optimal extent of local resection or the efficacy of regional node resection. On review of the literature, there was no survival advantage of radical vulvectomy compared with radical local resection with adequate margins, and that adequate, but less radical resection results in less impairment of body image and sexual function.13 Likewise, our data did not find a survival difference in patients with localized disease who received a more conservative surgery compared with a radical approach (75.2% compared with 79.4% respectively, P=.851) (Table 2).
As for cutaneous melanomas at other sites, it is unclear whether regional node dissection of clinically negative draining nodes is of therapeutic value for subsets of patients. Our finding of the significant effect of lymph node involvement in survival supports the previously reported results. A composite of the studies before 1974 revealed a 5-year survival rate of 14.3% for node-positive patients compared with 56.1% for those with negative regional nodes.4 Similarly, Podratz et al16 reported a 31% 10-year survival rate for patients with positive nodes compared with 59% for those with negative nodes. Raber et al12 in a series of 89 patients reported a 5-year survival rate of 9.2% in patients with positive nodes compared with 57% for those with negative nodes. Similarly, Raspagliesi et al11 reported a 5-year survival rate of 26.8% in patients with positive lymph nodes compared with 65.2% for those with negative nodes. Our study also demonstrated a significant decrease in survival based on the number of positive nodes, with 5-year survival rates of 68.3%, 29%, and 19.5% for patients with zero, one, or two or more positive nodes, respectively. (Fig. 3) This is in agreement with results from Raspagliesi et al,11 who reported 5-year survival rates of 65% compared with 20% compared with 0% for patients with zero, one-three positive, and three or more positive nodes, respectively.
The role of adjuvant therapy for treatment of melanomas is unclear. Adjuvant interferon alfa-2b has been demonstrated to be of benefit in select subgroups of patients with cutaneous melanomas.34 Although melanomas were once felt to be radioresistant, altered dose fractionation schedules have been effective in a select group of patients with cutaneous and mucosal melanomas.35 Of the 33 women in our study who received radiation therapy, most were older than 65 years. A larger number of patients will be required to demonstrate any potential benefit of adjuvant radiation after excision of the primary tumor. Radiation may be of benefit for patients who have tumor at the margins of their surgical resection and as adjuvant treatment for patients with lymph nodal metastasis. This has been demonstrated for patients with cutaneous melanoma and squamous cell vulvar cancers.36–38
Although our study was a large population-based series on vulvar melanoma, it has several limitations, including a lack of central pathology review, no detailed information on tumor size, site of disease, depth of invasion, tumor ulceration, resection margin status, surgeon specialty, and specific type and duration of adjuvant therapy and missing data for several of the measures studied. However, our multivariate analysis, used to identify significant prognostic factors, was performed on the entire cohort of 644 patients, including those with missing data.
A major strength of our study includes the large number of patients from the SEER database, which represents the United States population.7 Because many previous studies have been based on single academic institutions, the patient population may be biased toward high-risk patients who may not represent the general population in the United States. The SEER database represents 17 regions of the United States to obtain a broad representation of the general population.
In summary, this current analysis of 644 patients is a large study on vulvar melanoma. We found that age, stage, and number of positive lymph nodes were important prognostic factors for disease-specific survival. Our findings support the view that the biologic behavior of vulvar melanoma is similar to that of cutaneous melanomas of other sites. Patient management should consider the application of the diagnostic and therapeutic approaches used in cutaneous melanomas when appropriate.6 Given the poor prognosis of patients with advanced-stage vulvar melanoma, aggressive novel therapies are warranted. Although prospective trials are needed, this may be difficult to perform because of the rarity of these tumors. Future medical treatments, including immunotherapy with vaccines using whole tumor cells, peptides, and cytokine-mediated dendritic cells, may eventually be effective adjuvant therapies for this rare but aggressive cancer.39,40
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