Discussion

NF type 1 is an autosomal dominant condition caused by germline mutation in the NF-1 tumour suppressor gene with a high rate (50%) of new mutations.2 Mutations generally result in deceased levels of neurofibromin protein, which leads to increased cascade signalling of the RAS/MAPK pathway. This results in prolonged activation of the RAS/MAPK signalling pathway and ultimately a loss of growth control and increased cellular proliferation.3 The Pi3K/AKT/mTOR pathway is also stimulated which protects cells from apoptosis. Hence, the NF population has a higher incidence of malignancy. A Swedish cancer registry study reported a fourfold increase in malignant conditions in the NF-1 population.4 The most commonly associated malignancies are peripheral nerve sheath tumours, gliomas, breast cancer, GIST, malignant fibrous histiocytomas, phaeochromocytomas and rhabdomyosarcomas.5 Though melanoma can be associated with mutation in the NF-1 gene, the risk of melanoma in patients with NF-1 is only minimally increased compared with the general population.2

Approximately 7% of patients with NF develop GIST in their lifetime.4 NF-1-associated  GISTs demonstrate a higher prevalence in the small intestine as in our case.6 NF-1-associated GISTs are phenotypically and genotypically distinct from sporadic GISTs. They tend to have a low mitotic rate, stain positive for CD117 and are not associated with KIT and PDGRA mutations.6 7 In addition, 17% of patients with GIST develop additional cancers.8 There have been two previous case reports of synchronous melanoma and GIST, one of which was a mucosal melanoma.9 10 To the authors knowledge, there have been no previous case reports of vulvar melanoma and GIST in a patient with NF.

Vulvar melanoma is rare and accounts for 7%–10% of vulvar malignancies. In the USA, it is estimated to have an annual incidence rate of 1 per 1 000 000 women.11 Mucosal melanomas present one decade later on average than cutaneous melanoma and usually at a more advanced stage; consequently, they are associated with a higher mortality rate than cutaneous melanoma. Vulvar melanoma can be associated with late metastases and 5-year survival rates are in the order of 25%–50%.11 The mean time of survival from first metastasis is 9.1 months.12 There are no established protocols for staging and treatment of mucosal melanomas due to their scarcity.11 Tumour thickness is the strongest prognostic factor, and therefore, used most frequently for staging.13 Lymph node status and ulceration are also important prognostic factors. In most cases, standard staging and resection principles for cutaneous melanoma are applied to the mucosal melanoma patient population.

Mucosal melanomas also have distinct molecular features which distinguish them from cutaneous melanomas. BRAF mutation, common in cutaneous melanoma, is rare in mucosal melanoma and gain of function mutations in c-KIT may be present up to 39% according to Curtin et al.14 There have been several reports of c-KIT directed therapies in the treatment of mucosal melanoma which show some promise15–17; although the specific KIT mutation present may be critical for appropriate patient selection. c-KIT mutations are also commonly found in GISTs with 80%–90% found to stain immunohistochemically for c-KIT (CD117). Of these, over half contain activating mutations in the c-KIT receptor tyrosine kinase.18 The GIST tumour in our case was found to be diffusely positive for CD117 but there was no mutation detected in KIT as would be expected with an NF-associated tumour. Somatic NF-1 mutations may be critical drivers in multiple cancers and are associated with 12%–30% of sporadic melanoma.12 Recent studies have begun to better characterise the mutational profile of mucosal melanoma using next generation sequencing with the intention of identifying therapeutically targetable mutations. Cosgarea et al analysed samples from 75 patients with mucosal melanoma at a number of anatomical sites; 25 of these originated in the genital area.19 NF-1 was the most common driver mutation identified in 18.3% of those tested; in two in three of these patients, a clearly inactivating mutation was present resulting in a nonsense or frameshift mutation which would be important for constitutive MAPK activation. RAS alterations were identified in 16.9% of samples but, BRAF and KIT mutations were identified in <10% of samples. Similarly, in a population of anorectal melanomas, Yang et al found that 3/15 samples harboured NF-1 mutations.20 In most cases, this was a single driver mutation and NF-1 mutation was mutually exclusive with KIT, RAS, BRAF mutations. As in Cosgarea’s study, the majority were loss of function mutations and were associated with RAS activation as well as mitogen activated protein kinase kinase (MEK) dependence in the melanoma cell lines. This raises the possibility of MEK inhibition as a potential treatment strategy. NF-1 mutations are also important in the acquisition of drug resistance, for example, BRAF and EGFR inhibitors.12 NF-1 mutations have been found in melanomas that lack both BRAF and NRAS mutations, with 25%–30% of such melanomas found to harbour deleterious NF-1 gene mutations. Melanomas with NF-1 mutations typically occur on chronically sun-exposed skin however, which is not the case with mucosal melanoma.2 In fact, there are some data to suggest that sunshine may be a protective factor in the development of vulvar melanoma.21

Lymphatic drainage of the vulva is usually first to the superficial inguinal nodes followed by the cribriform fascia to the deep inguinal or femoral nodes. There are three distinct patterns of metastatic dissemination of melanoma—to regional lymph nodes, direct distant metastatic spread and by satellite or in-transit metastases. In vulvar melanomas, the most common sites of metastases are the inguinal lymphatic nodes. Other reported sites of metastases are the lungs, vagina, liver and brain.1 The pattern of spread to an isolated omental site in the absence of disease elsewhere is unusual.

Primary treatment of vulvar melanoma is surgical excision with adequate tumour-free margins. Historically, the surgery consisted of a radical vulvectomy with bilateral inguinal lymphadenectomy. Most authors conclude that radical surgery however does not improve survival.22 Prophylactic lymph node dissection is no longer recommended based on several retrospective studies that failed to show any benefit in clinical outcome.4 Expert consensus now recommends wide local excision with macroscopic tumour-free margins of 2 cm. Sentinel lymph node sampling is routinely done in vulvar melanomas that are greater than 1 mm thick or ulcerated.23 In de Hullu et al’s study, sentinel lymph node procedures increased the risk of locoregional recurrence, especially in thick tumours, therefore, the authors recommended sentinel lymph node biopsy only in tumours of depth 1–4 mm.13 National Comprehensive Cancer Network (NCCN) guidelines recommend discussion of sentinel lymph node biopsy in stage 2 disease, however, there is a lack of proven survival advantage. Therefore, the authors recommend that during discussion, consideration be given to what will be done differently if the sentinel node status is known. In our case, as adjuvant therapy was planned regardless of sentinel node status given the Breslow depth of 4.8 mm, and both groin ultrasound and PET imaging were negative for nodal disease, it was decided to proceed without sentinel lymph node biopsy. The role of completion lymph node dissection (CLND) in the event of a positive sentinel node is also controversial. It has been found to improve recurrence-free survival but has shown no benefit in overall survival (OS) or melanoma-specific survival. There are two trials currently ongoing to investigate the therapeutic value of CLND.

Our patient received high-dose IFN 2A in the adjuvant setting following initial resection. For patients with completely resected high-risk disease, recommendations thus far for mucosal melanoma are as for cutaneous melanoma. High-risk IFN 2A has been shown in a number of trials to increase relapse-free survival in cutaneous melanoma and though individual trials have had varying results, meta-analysis showed improved OS.24 Pegylated IFN improved recurrence-free survival compared with observation but with no increase in OS.25 Biochemotherapy as adjuvant therapy for fully resected stage III cutaneous melanoma was investigated in the Southwest Oncology Group (SWOG) S0008 phase 3 randomised trial which compared cisplatin, vinblastine, dacarbazine, interleukin-2 (IL-2) and IFN with high-dose IFN alfa-2b monotherapy.26 At 7.2 years, recurrence-free survival was 4.0 vs 1.9 months favouring the biochemotherapy arm, with no significant difference in OS, however, mucosal melanomas were excluded from this trial. There has been one randomised phase II trial specifically looking at adjuvant treatment of resected mucosal melanoma.27 Lian et al randomised 189 patients with resected stage II/III mucosal melanoma to observation, high-dose IFN or high-dose temozolomide/cisplatin. Estimated median OS was 21.2, 40.4 and 48.7, respectively, indicating that in the mucosal melanoma subgroup, temozolomide/cisplatin might be a preferential regimen to high-dose IFN.

Immunotherapy has revolutionised the management of cutaneous melanoma, with durable effects both in the adjuvant setting for high-risk disease28–30 and in the metastatic setting.31–33 However, there are limited data on the use of immunotherapy in the setting of mucosal melanoma as this cohort has often been excluded from larger phase III trials. A 2013 study in Memorial Sloan Kettering reviewed 33 cases of advanced mucosal melanoma treated with the CTLA-4 inhibitor ipilimumab and found overall response rates to be low, with a median OS from first dose of ipilimumab of 6.4 months.34 An evaluation of 71 patients with metastatic mucosal melanoma treated with ipilimumab via the expanded access programme in Italy found a similar overall response rate of 6.4 months.35 Anti-PD-1 agents look more promising. A cross-centre analysis of using nivolumab alone and in combination with ipilimumab demonstrated greater efficacy for the combination than with either drug alone, but the progression-free survival was still markedly inferior in the mucosal melanoma group versus the cutaneous melanoma group (5.9 months vs 11.7 months).36 This may be due to reduced mutational burden in the mucosal group. A similar multi-institutional study assessing the efficacy of PD-1 inhibition in acral and mucosal melanomas, most of whom had been pretreated, found an overall response rate of 23% in the mucosal melanoma group with median OS of 12.4 months supporting further exploration of the use of anti-PD-1 agents in clinical practice.37 A recent case series from Memorial Sloan Kettering indicated a positive response to combination radiation therapy and ipilimumab to mucosal melanoma of the lower genital tract, however, this included just four patients.38

In terms of follow-up, the NCCN guidelines for melanoma recommend routine imaging be considered every 3–12 months for stage IIb to stage IV disease. Routine imaging for asymptomatic recurrence or metastatic disease is not recommended after 3–5 years. Given that our patient was 5 years from original diagnosis at the time of recurrence, and in light of the fact that mucosal melanomas tend to recur later, it may be justified to extend the period of routine imaging in this subgroup of patients.