Abstract
Background: Primary melanoma of the vagina (PMV) is a rare entity. The prognosis of women with PMV is poor and there is no standardized therapy for this type of malignancy. We present the case of a 72-year-old woman with PMV (cT2, pN0, M0). Case Report: Imaging studies showed no evidence of regional or distant metastases. Molecular analysis demonstrated wild-type B-Raf proto-oncogene, serine/threonine kinase (BRAF). Staging laparoscopy with pelvic lymphadenectomy and subsequent radiotherapy with 60 Gy delivered as pelvic teletherapy and vaginal brachytherapy was applied. Systematic literature review: A total of 805 cases of PMV were identified. Most lesions were melanotic (65%) and localized (66%), whereas amelanotic (35%) and primary advanced lesions (34%) were only seen in a minority of patients. BRAF mutation was detected in none out of 33 cases, tumor protein 53 (TP53) mutations and mast/stem cell growth factor receptor CD117 (KIT) amplification were identified in one case each. The most common treatment was surgery, reported in 43% of cases. Surgery combined with adjuvant radiotherapy, adjuvant immunotherapy (mostly with interferon-alpha), or adjuvant chemotherapy were given in 35%, 8%, and 3% of cases, respectively. Radiotherapy or chemotherapy as sole treatments were used in 5% and 1% of patients, respectively. Among patients with recurrence, chemotherapy (mostly dacarbazine) alone or in combination with surgery, radiotherapy or immunotherapy was the most common treatment in 61% of cases. The mean durations of recurrence-free and overall survival were 16.4 and 22.2 months, respectively. Conclusion: PMV is a rare malignancy with a poor prognosis. Surgery, radiotherapy, and immunotherapy with interferon-alpha are the mainstay of treatment for localized disease, while chemotherapy with dacarbazine is mostly used for unresectable and recurrent disease. No data on the clinical value of immune checkpoint inhibitors in PMV have been published.
Melanoma is caused by the malignant transformation of pigment cells. Apart from the skin, pigment cells such as melanocytes are present in various mucosal linings such as those of the gastrointestinal, respiratory, and urogenital tracts (1). Thus, in addition to the common cutaneous locations, melanomas may also arise in mucosal areas of various organs. Cutaneous melanomas are estimated to be the sixth most common cancer entity among females in the US (2). In contrast, mucosal melanomas are rare and account for only 1.4% of all melanomas. Of note, gender plays an important role in the epidemiology of mucosal melanomas. With almost three cases per million women, which is half that for men, mucosal melanomas are significantly more often diagnosed among women (3). This gender gap is caused by the fact that genital tract mucosal melanomas are more common among women than they are among men, whereas extra-genital mucosal melanomas are evenly distributed between the sexes (3).
In the female genital tract, the predominant location of melanoma is the vulva whereas the vagina is rarely affected (3). Specifically, the incidence of primary melanoma of the vagina (PMV) is about three cases per 10,000,000 women per year. Primary melanomas of the vulva are four to nine times more frequent than PMV (4, 5). PMV is typically diagnosed in elderly women at an advanced stage and is characterized by early recurrence and a poor prognosis (2). The 5-year overall survival rate for PMV is below 20% compared to around 45% for those with vulvar melanoma and >80% for those with cutaneous melanoma (2-6). This remarkable difference has been attributed to a variety of factors, among them poorer visibility of PMV compared to cutaneous melanomas, late diagnosis, anatomical proximity to the vulvovaginal venous plexus, and tumor biology. Moreover, the relatively high rate of amelanotic tumors among PMV may also result in a later diagnosis.
In addition to the clinical behavior, the molecular characteristics of PMV are also markedly different from those of cutaneous melanomas and vulvar melanomas. For example, cutaneous melanomas have mutations in B-Raf proto-oncogene, serine/threonine kinase (BRAF) in up to 66% of cases, whereas they are virtually absent in PMV (7, 8). In addition, vulvar and vaginal melanomas significantly differ in their molecular characteristics regarding mast/stem cell growth factor receptor CD117 (KIT) mutations. Aulmann et al. investigated 65 cases of PMV and vulvar melanomas for mutations in BRAF, N-rat sarcoma virus proto-oncogene (NRAS), and KIT genes, and KIT gene amplification (8) They found that none of the PMV cases had BRAF mutations, whereas NRAS mutations and KIT amplifications were detected in 12% of both vulvar and vaginal tumors. In contrast, KIT mutations were present in 18% of vulvar melanomas but in none of the cases of PMV. Moderate or strong KIT protein expression was detected in all tumors with KIT mutations and most of the tumors with KIT amplification. In accordance with these results, Rouzbahman et al. found BRAF mutations in 8%, KIT mutations in 28%, NRAS mutations in 28%, and TP53 mutations in 8% of vulvar melanomas, whereas they detected only one TP53 mutation in the investigated PMV (9). Taken together, these findings suggest that in spite of their close anatomic proximity, the ontogenetic developments of vulvar and vaginal melanomas follow different molecular pathways.
To date, there is no consensus regarding the optimal management of women with PMV (1, 3, 10). Specifically, it is unclear if treatment strategies should follow current practice regarding female genital tract cancer or should be extrapolated from established strategies used for cutaneous melanomas (11, 12). In addition, the clinical rationale of molecular tumor characterization of PMV regarding BRAF, KIT, or NRAS as well as the therapeutic value of immunotherapies and targeted therapies such as the monoclonal antibodies to the programmed cell death protein-1 (PD-1) nivolumab and pembrolizumab and the antibody to the cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) ipilimumab has not been established for patients with PMV (13).
To highlight the clinical characteristics, management, and prognosis of women with PMV, we report the case of a woman with histologically verified PMV and present a systematic review of the literature with cohort studies, case series, and case reports published about women with PMV. We discuss the most common therapies and respective outcomes.
Case Report
A 72-year-old woman was admitted to our outpatient dysplasia clinic in July 2017 with a vaginal mass of unclear nature for further evaluation. She reported no local pain or vaginal bleeding. She had a history of synchronous bilateral breast cancer diagnosed in 2015, treated with bilateral breast-conserving surgery, breast irradiation, and endocrine therapy with an aromatase inhibitor for 5 years. Vaginal examination revealed a solid, black and grey solid mass of 66 cm in the lower third of the anterior vaginal wall extending to the right and left vaginal wall. The upper two-thirds of the vagina and the vaginal fornices were free of disease. Both parametria and the rectum were free on palpation. There was no inguinal lymphadenopathy. The external genitalia, uterus, and ovaries also appeared normal. A biopsy of the mass was performed and demonstrated PMV with polymorphic tumor cells, brown cytoplasm, tumor necrosis, and a high mitotic figure rate (8 mitoses per 10 high-power fields). Figure 1 shows hematoxylin-eosin and immunohistochemical stains of the PMV demonstrating expression of S100 and melan-A, as well as a low expression of pan-cytokeratin MNF116. Molecular analysis showed negativity for p.G469A (c.1406T>A), p.D594G (c.1781A>G), and p.V600E (c.1799T>A) mutations of the BRAF gene. Thus, the tumor was classified as wild-type BRAF.
Staging procedures, including computed tomography of the chest, mammography, and magnetic resonance tomography of the pelvis and abdomen, showed no signs of regional or distant metastases. Liver cirrhosis consistent with a history of alcohol abuse was diagnosed. Total body skin examination showed no evidence of cutaneous melanoma. The patient was treated with laparoscopic pelvic lymph node staging and subsequent vaginal brachytherapy with 50 Gy. Adjuvant immunotherapy with interferon-alpha was refused by the patient. At the time of this report, the patient was alive and with no evidence of disease.
Literature Review
In a systematic literature search of the PubMed and Cochrane Central Register of Controlled Trials databases (search date 15-06-2017; time restriction to the last 20 years 1997-2017) using the search terms (“melanoma”[MeSH Terms] OR “melanoma”[All Fields]) AND (“vagina”[MeSH Terms] OR “vagina”[All Fields]), we identified 67 citations reporting on women with PMV, defined for the purpose of this review as primary melanocytic or amelanocytic melanoma of the vagina with or without regional/distant metastases, but without concurrent cutaneous manifestation of melanoma (6, 8, 9, 11, 14-76). Studies not reporting on women with PMV, double publications, and studies reporting on women with vulvar melanomas or melanomas metastatic to the vagina were excluded. The 67 identified studies were retrieved in full and were analyzed for this review. Figure 2 shows a flow diagram of the literature search algorithm.
Hematoxylin-eosin (H&E) (A) and immunohistochemical (B to C) stains for S100 (B) and melan-A (C) of a primary melanoma of the vagina. The specimens demonstrate positive expression of S100 and melan-A. Bars, 50 μm and 20 μm.
Among the 67 studies, we found three retrospective cohort studies, two studies with data from national cancer registries, 20 retrospective cases series, and 42 case reports. No prospectively collected data were identified. Sixteen studies reported on >10 patients with PMV describing 11 (22), 13 (44), 14 (27, 72), 15 (8, 35), 22 (24, 76), 23 (50), 25 (68), 26 (61), 31 (30), 37 (38), and 44 (28) cases, respectively. The two studies with data from national cancer registries described 192 (71) and 201 (31) cases of PMV. Table I shows the study characteristics and outcomes of patients with PMV described in all 67 studies. In summary, 805 cases of PMV have been reported in the literature during the past 20 years. At the time of first presentation, singular and multiple lesions were described in 102 (96%) and four (4%) cases, respectively. Most lesions were melanotic (65%) and localized (66%), whereas amelanotic (35%) and primary advanced lesions (34%) were only seen in a minority of patients. Only four studies with a total of 33 cases assessed the molecular characteristics of PMV. In these studies, BRAF mutation was not identified in any of the investigated PMVs (0/33). TP53 mutations and KIT amplification were identified in one case each.
Treatment modalities and outcomes are shown in Table II. In a pooled analysis, the treatment most commonly used for PMV was surgery without any further treatment modality, which was reported in 43% of cases. Surgery combined with adjuvant radiotherapy, adjuvant immunotherapy (mostly interferon-alpha), or adjuvant chemotherapy (mostly dacarbazine) were given in 35%, 8%, and 3% of cases, respectively. Radiotherapy or chemotherapy as exclusive primary treatment were used in 5% and 1% of patients, respectively.
Among patients with recurrence of PMV, in contrast, chemotherapy alone or in combination with surgery, radiotherapy or immunotherapy was the most commonly used treatment, with 61% of cases. There is no standard chemotherapy regimen for PMV, but dacarbazine was the most commonly used substance; it was administered alone or in combination with vincristine, cisplatin/carboplatin, or nimustine. Overall, the prognosis of women with PMV was poor. The mean duration of recurrence-free survival was short at 16.4 months and the mean overall survival of women with PMV was only 22.2 months.
Flow diagram of the literature search algorithm. PMV, Primary melanoma of the vagina.
Immunotherapy was reported in a minority of patients both in primary and recurrent settings. Specifically, interferon-alpha was reported in 43/613 (7%) cases and in 2/18 (11%) cases with detailed information on which therapeutic compound was used.
Clinical studies describing women with primary melanoma of the vagina.
Data on targeted therapies or immune checkpoint inhibitors such as ipilimumab, nivolumab, or pembrolizumab were only reported in 2/805 cases of PMV. In these two cases, nivolumab was used alone and in combination with surgery and dacarbazine, both in the recurrent setting (6).
The largest cohort of women with PMV was published by two US cancer registries, the Surveillance, Epidemiology, and End Result (SEER) database (31) and the National Cancer Data Base (NCDB) (71). The study using SEER data comprised of 201 cases of PMV. In this study, the median age of affected women was 68 years. Sixty-four percent of the patient had early-stage PMV. Patients were operated upon in 70% of cases and had regional lymph node dissection in half of these patients and adjuvant radiotherapy in 40% of patients. Overall survival at 2 and 5 years were 24% and 15%, respectively. The presence of metastases in regional lymph nodes was associated with a significantly worsened overall survival. Adjuvant radiation did not result in a statistically significant overall survival advantage compared to surgery alone (31).
The NCDB data comprised of 206 cases of PMV (71). Sixty-six percent of these patients were treated surgically and 40% of them received radiotherapy. Surgery as well as radiotherapy was used more frequently for patients with advanced-stage disease. The 5-year overall survival rate in this study was 14%. The authors concluded that due to the limited evidence, the optimal therapy of PMV is unclear. However, it can be stated that younger patients were primarily treated with surgery, whereas primary radiotherapy was generally used in older patients and in those with advanced disease. Survival was poor and was primarily related to the level of tumor invasion. Specifically, the 3-year relative survival rate for patients with Clark levels of invasion II, II, IV, and V were 45%, 36%, 27%, and 14%, respectively.
Besides these two large registry studies, smaller cohort studies and case series describing between 11 (22) and 44 (28) patients with PMV were identified (8, 24, 27, 30, 35, 38, 44, 50, 61, 68, 72, 76). As expected, the heterogeneity among these studies with low numbers of patients with PMV was considerable. However, as shown in Table II, most patients were treated with surgery, whereas radiotherapy and chemotherapy were rarely used as primary therapy. For example, a large and well-documented cohort study, published by Frumovitz et al. (38) identified 37 patients with PMV treated between 1980 and 2009 (38). In this representative cohort of patients from the MD Anderson Cancer Center, vaginal bleeding was the most common presenting symptom. PMV were typically located in the distal third of the vagina (65% of cases). Initial management included wide local or radical excision in 76% of patients, pelvic exenteration in 14%, and radiotherapy, chemotherapy, or radiotherapy combined with chemotherapy in 10% of cases. Disease recurrence was observed in most patients 33/37 89 of cases Distant recurrence was observed in 88% of patients and was mostly located in the lungs and liver. Median progression-free survival was 11.4 months and median overall survival was 19 months. In contrast to other studies, radiotherapy after local wide excision reduced the risk of local recurrence and increased survival from 16.1 to 29.4 months.
The bulk of studies identified in our systematic review of the literature were case reports. The tumor characteristics and treatment modalities of these case reports are shown in Tables I and II. Among these 42 cases, long-term survivors were almost exclusively found in cases of localized disease at initial presentation and complete tumor resection with clear resection margins. For example, Panek et al. described the case of a woman with a small PMV, treated with surgical resection and vaginal brachytherapy, who survived for 10 years (64).
Treatment modalities and outcomes of women with primary melanoma of the vagina.
Discussion
In a case report and systematic review of the literature, we found that PMV is a rare female genital malignancy and carries a poor prognosis. Among 805 cases reported in the literature during the past 20 years, the mean duration of recurrence-free survival was short at 16 months and the mean overall survival time was only 22 months. No standard treatment for PMV has been established in the literature, but surgical excision either by local wide excision or radical surgery with colpectomy with/without exenteration is the mainstay of treatment for women with PMV. Many adjuvant treatment options have been described including radiotherapy, immunotherapy (mostly interferon-alpha), and chemotherapy (mostly dacarbazine). However, adjuvant radiotherapy and immunotherapy were only given in a minority of patients. Adjuvant chemotherapy was only used in 3% of cases. Among patients with recurrent PMV, chemotherapy alone or in combination with surgery, radiotherapy, or immunotherapy, on the other hand, was the most common treatment reported in 61% of cases. There is no standard chemotherapy regimen for PMV, but dacarbazine is the most commonly used substance. As for other types of melanomas, sensitivity to chemotherapy of PMV is low, thus underlining the need for molecularly based treatment strategies.
Despite the fact that targeted therapies such as the anti-PD-1 monoclonal antibodies nivolumab and pembrolizumab and the anti-CTLA-4 antibody ipilimumab have been well established in patients with cutaneous melanomas, we identified such therapies were used in only two out of 805 cases of women with PMV. This is not surprising due to the rare occurrence of the disease and the fact that these therapies have only been available during the last couple of years. In the two cases described above, nivolumab was used alone and in combination with surgery and dacarbazine, both in the recurrent setting (6). In addition, the number of cases with molecular characterization was low. Based on these data, there is no evidence supporting the clinical efficacy of nivolumab, pembrolizumab, and ipilimumab in women with PMV. This is unfortunate because the clinical effectiveness of ipilimumab, nivolumab, and pembrolizumab has been clearly demonstrated in patients with primary advanced or recurrent metastatic cutaneous melanoma. Due to the rarity of PMV, clinical trials assessing the efficacy of these targeted treatments in PMV cannot be reasonably expected. Thus, efficacy assessments should be extrapolated from data on patients with cutaneous or mucosal melanoma, dependent on the molecular profile, or from anecdotal evidence for patients with PMV.
In accordance with the lack of data on the clinical efficacy of targeted therapies, molecular characterization of BRAF, cKIT, and NRAS as well as PD-1 surface expression were described in only four studies with 33 cases. In these studies, a BRAF mutation was not identified in any of the investigated PMV (0/33). TP53 mutations and KIT amplification were only identified in one case each. Based on these data, there is no evidence for the clinical efficacy of nivolumab, pembrolizumab, and ipilimumab in women with PMV. In addition, BRAF, NRAS, KIT, and TP53 mutations were virtually absent among PMV cases. Thus, PMV might not be a suitable tumor entity for these targeted therapies. On the other hand, nivolumab has been demonstrated to be efficacious in cutaneous melanomas without BRAF mutation (77). In a large, randomized phase III trial of 418 patients with previously untreated metastatic melanoma without BRAF mutation, nivolumab was superior to dacarbazine regarding tumor response (40% vs. 14%), progression-free survival (5.1 vs. 2.2 months), and overall survival (1-year survival: 73% vs. 42%). Therefore, it is reasonable to believe that nivolumab may also be efficacious in PMV, which is typically BRAF-negative, as demonstrated above. We consider molecular characterization of PMV as important, firstly in order to identify possible therapeutic options, such as PD-1 inhibitors. Secondly, the BRAF mutation status may also help to distinguish PMV from metastases of a cutaneous melanoma which might have already undergone apoptosis at the time of diagnosis.
Chemotherapy, although only rarely used in the adjuvant setting, was typically used in patients with recurrent disease. In our pooled analysis, chemotherapy was given to 61% of these patients. However, this high number of patients treated with chemotherapy has to be interpreted in light of the fact that targeted therapies were not available at the time these patients were treated. Chemotherapy was either administered as the sole treatment or in combination with surgery, radiotherapy or immunotherapy. The choice of drug regimen, clearly, was empirical and there is no standard chemotherapy regimen for PMV based on the available evidence. Among the many regimens and substances, dacarbazine was the most commonly used compound. In addition, vincristine, cisplatin/carboplatin, or nimustine have been used alone and in combination with dacarbazine. It is difficult to assess the benefit of chemotherapy in women with PMV. However, it can be clearly stated that PMV does not seem to be a very chemo-sensitive disease given that the mean overall survival of patients with PMV was only 22.2 months despite the use of chemotherapy in cases of recurrence.
Immunotherapy with interferon-alpha was used in 7% of patients as adjuvant treatment and in 11% of patients as treatment for recurrence. As with chemotherapy, it is difficult to assess the clinical benefit of interferon-alpha in patients with PMV due to lack of comparative studies.
In conclusion, we found that PMV is a rare form of melanoma with a poor prognosis. Surgery is the mainstay of treatment for localized disease while systemic chemotherapy and radiotherapy are appropriate for women with disseminated or recurrent PMV. Immunotherapy with interferon-alpha has been used in some patients and may be a useful adjunct therapy, but evidence for its efficacy is lacking.
Footnotes
This Article is freely accessible online.
Declarations
Ethics approval and consent to participate. Not applicable Consent for publication. Patient's consent for publication is available.
Conflicts of Interest
The Authors declare that they have no competing interests.
- Received September 10, 2017.
- Revision received October 7, 2017.
- Accepted October 12, 2017.
- Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved
