Mucosal melanomas primarily occur in the head and neck region (e.g. nasal and oral cavities), followed by the gastrointestinal tract (anorectum) and the female genital tract (vulva and vagina). Melanoma of the female genital tract is an uncommon malignancy that is associated with a high-risk of recurrence and distant metastases. Prognosis is generally poor, with a 5-year overall survival (OS) of about 8%–60% across different series [123], due to lacking well-established protocols for staging and treatment, late diagnosis at disease presentation and anatomic location, often precluding complete surgical resection [4]. Survival of women affected by genital melanoma has not significantly changed during the last decades, especially for patients with advanced stage and recurrent/metastatic disease. In fact, despite recent therapeutic developments, patients' outcomes remain poor and difficult to predict.

Traditional cytotoxic agents (such as platinum compounds, dacarbazine and temozolomide, either alone or in combination) have shown limited or no benefit in the treatment of metastatic disease, like those observed in cutaneous melanoma [5]. Oncologic outcomes of patients with cutaneous melanoma have dramatically improved over the last 5 years with the introduction of 2 distinct class of drugs, the monoclonal antibodies targeting the cytotoxic T lymphocyte-associated antigen 4 (CTLA4), and the programmed cell death 1 (PD-1), and the small molecule inhibitors of MAPK signaling pathway (serine/threonine-protein kinase B-Raf [BRAF] and mitogen-activated protein kinase kinase) [678910]. However, mucosal melanoma only in less than 10% of the cases shows activating BRAF mutations, thus making these latter drugs not effective usable for treatment. Mucosal melanoma shows different molecular features compared to its cutaneous counterpart [1112]: aberrations in KIT, a receptor tyrosine kinase, are found in nearly 30%–40% of patients but phase II study investigating the efficacy of KIT inhibitors have shown only suboptimal results [131415].

Therefore, immunotherapy remains the only promising therapeutic option for advanced genital melanoma. A limited evidence on the safety and efficacy of immunotherapy in advanced/recurrent female genital melanoma is currently available, with data coming from few case reports [1617] and subpopulation analysis in the context of large clinical trials [1819]. In the present series we aimed to describe our preliminary experience of advanced/recurrent genital melanoma treated with immunotherapeutic agents.

This is a retrospective study on patients with advanced/recurrent female lower genital tract melanoma who received immunotherapy at IRCCS National Cancer Institute—Milan (Italy) between January 2011 and December 2016. Institutional Review Board (IRB) was obtained from the Ethical Committee of the IRCCS National Cancer Institute of Milan (Italy) (IRB06812). All patients gave written consent for data collection for health research and data publication.

Inclusion criteria were: 1) histological diagnosis of genital melanoma; 2) advanced or recurrent disease; and 3) treatment with immunotherapeutic agents (anti-CTLA4, and/or anti-PD-1). Exclusion criteria were: 1) age less than 18 years; 2) autoimmune diseases; 3) poor performance status (PS) not allowing systemic treatments; and 4) necessity of chronic corticosteroid treatment.

The IRB-approved database contained data of consecutive women undergoing systemic treatment for genital melanoma. Data regarding baseline demographical characteristics, therapeutic schedules, and treatment-related toxicity were recorded. Moreover, data concerning details of follow-up visits were recorded prospectively in our computerized database, with a research-quality database maintained by trained residents or fellows and up-dated on regular basis. Rigorous efforts were made to collect details of patients experiencing disease progression.

Primary treatment of women affected by genital melanoma included radical surgery. Details on surgical treatments have been presented elsewhere [20]. Over the study period, adjuvant treatments were not considered for patients who had complete resection of the disease. Patients with metastatic disease were treated with chemotherapy or immunotherapy, in some cases in association with local radiotherapy, if clinically indicated.

Demographic and baseline patients' characteristics were collected for the present study, together with data regarding previous systemic treatment. Genital melanoma was staged according to the 2017 classification of the American Joint Committee on Cancer (AJCC) 8th edition [21]. BRAF mutation status was determined on tumor tissue with polymerase chain reaction amplification and direct sequencing (3500 DX Genetic Analyzer; Thermo Fisher Scientific, Life Technologies, Carlsbad, CA, USA). PS at the beginning of treatment was assessed according to the Eastern Cooperative Oncology Group scale.

Treatment with immune-checkpoint inhibitors included: ipilimumab 3 mg/kg once every 21 days (4 total courses); pembrolizumab 2 mg/kg once every 21 days; nivolumab 3 mg/kg once every 14 days. Immunotherapy was administered until disease progression, a report of unacceptable toxicity, or patients' decision. Clinical assessments were performed according to the standard of care criteria at the treating Institution. Radiological disease assessment was made with whole body computed tomography scans performed at baseline every 3 months. Radiological response was evaluated using the response evaluation criteria in solid tumors guideline version 1.1 [22].

Safety profile of immunotherapy was assessed recording the onset of immune-related adverse events (irAEs). Adverse events were graded according to the Common Terminology Criteria for Adverse Events version 4.0 (National Cancer Institute 2009). Progression-free survival (PFS) was defined as the time from treatment start until the date of the first recurrence (local, regional, or distant metastasis) or new primary melanoma. OS was defined as the time from treatment start until the date of death from any cause.

The present paper reports 7 cases of metastatic melanoma of the female genital tract treated with immune-checkpoint inhibitors, thus reporting a number of noteworthy findings. The response rate to immunotherapy of patients in our series is nearly 28% and mean (SD) survival is about 6.1 (± 2.2) months. Therefore, we observed that even when using innovative therapeutic strategies, the prognosis of this subset of patients remains poor. Furthermore, although the limitations of the small sample size and the short-term follow-up do not allow us to draw any definitive conclusion, we observed that anti-PD-1 treatment is related to improved outcomes in comparison to our and literature data referring to anti-CTLA4 therapy. Finally, we found that treatment was well tolerated, with a relatively low reported incidence of irAEs and an overall manageable toxicity profile.

Evidence regarding outcomes of patients with melanoma of the female genital tract is limited. Only a few papers reported outcomes of early stage disease with discordant results [2023]. Surgery represents the mainstay of treatment for early stage genital melanoma [2024]. In fact, there is still no consensus on the use of adjuvant therapy and only a single case series and few case reports on this topic are available [161725]. Schiavone et al., [16] reviewed data of 4 patients receiving combined radiation therapy and immunotherapy (ipilimumab) in the adjuvant setting of melanoma of the lower genital tract (vagina [n=3] and cervix [n=1]). The reported OS rates were good (2 patients recurred and 1 died of disease), considering that this population did not include metastatic patients.

Chanal et al., [17] reported a case report of a woman with locally advanced/unresectable melanoma arising into the vagina. The patient was treated with the combination of the TKI imatinib and ipilimumab, with no objective response. After disease progression, the patient received a second line treatment with pembrolizumab, experiencing partial response with an important reduction in target lesions.

Accumulating evidence supports the role of immunotherapy in improving survival of patients with metastatic melanoma [78919202627]. Due to the rarity of mucosal melanoma, there are no randomized clinical trials evaluating the role of systemic therapies in this subset of patients. Thus, data on the efficacy of innovative treatments are mostly based on anecdotal evidence and small retrospective analyses [19282930]. The recent paper by D'angelo et al. [18] provides a pooled analysis of 6 clinical studies reporting a clinically meaningful improvement in PFS and response-rate for nivolumab combined with ipilimumab compared with either agent alone, with evidence of durable tumor responses. Safety profiles were consistent with those observed in cutaneous melanoma. However, to date there are no studies specifically evaluating the role of immunotherapy in metastatic melanoma of the female genital tract. Thus, our study is the first investigating the safety and effectiveness of immunotherapy in metastatic female genital tract melanoma. In agreement with the literature background, we reported that the response rate is quite poor, as observed in other primary sites mucosal melanoma. The inherent biases of the single center study design represent the weakness of the present investigation. Moreover, the relatively small sample size of our report and the length of follow-up might influence the interpretation of our results. Notwithstanding, this is the largest case series to date describing outcomes of metastatic melanoma of the female lower genital tract.

In conclusion, metastatic melanoma of the lower genital tract represents an aggressive disease. Owing to its rarity, an international register should be created in order to evaluate the real efficacy of different treatment modalities. Moreover, further studies are warranted to test safety and long-term efficacy of immunotherapy in this cluster of patients. A better knowledge of molecular, genetic and epigenetic factors influencing tumor progression is needed to better understand factors improving outcomes of these patients.