Sinonasal mucosal melanoma: treatment strategies and survival rates for a rare disease entity

Malignant mucosal melanoma of the nasal cavity and paranasal sinuses, is a rare disease entity with an incidence of 0.02–0.2 cases per 100,000 per year [1‐6] and a 5-year survival outcome of approximately 30% [7, 8]. Despite technological advances and growing possibilities of treatment options for oncological patients in the last two decades, such as enhanced visibility for endoscopic surgery, 3‑dimensional radiotherapy or novel systemic therapies, local control and distant metastasis in patients with SNMM remain hard to handle and prognosis is poor [7, 9].

Macroscopically SNMM typically appear as a polypoid mass with or without pigmentation and the tumors are frequently ulcerated and may present in an unspecific variety of appearances, such as brownish, black, reddish, crimson, grey-white or even amelanotic imitating other tumors [10‐12].

An SNMM typically has a delayed clinical presentation with unspecific and misleading symptoms, such as unilateral nasal obstruction and epistaxis, either occurring alone or combined [11, 14]. Given the unspecific clinical presentation and the variable macroscopic and microscopic appearances of SNMM, immunohistochemical investigations are often essential for diagnosis. A panel of markers including protein S‑100, HMB-45 and tyrosinase is recommended to accurately diagnose SNMM [12, 13].

Only about 5% of patients with SNMM have lymph node metastasis at the time of initial presentation. While only 10–15% of patients with SNMM initially present with distant metastasis, it has been shown that 40–70% of these patients develop distant metastases during the course of the disease, thus being the main treatment failure in SNMM [7, 15‐17]. Most common sites of distant metastases are the lungs, liver, bone and brain [11, 15, 18].

The primary treatment of SNMM is surgical resection of the tumor. A wide resection to achieve clear margins should be the goal of every operation. In cases where free margins are obtained, patient outcome tends to be significantly better [19, 20].

In low grade tumor masses en bloc resection is possible, for larger tumors piecemeal resections were found to have similar oncological efficacy compared to en bloc resections by external surgical techniques [21‐23].

Adjuvant treatment, such as radiotherapy and systemic therapy are frequently used; however, there are no standardized treatment regimens and recommendations mostly emphasize treatment on a patient to patient basis [24]. Conventional fractionation schedules consist of around 50 Gy delivered in 20 fractions of 2.5 Gy [25] and conventional chemotherapeutic agents, such as dacarbazine, carboplatin, cisplatin, vincristine, temozolomide and trofosfamide do not seem to have a satisfactory impact on regional and distant metastases [14, 25‐27]. Novel targeted systemic therapies with monoclonal antibodies have already proven their effectiveness in cutaneous melanomas and have recently shown positive effects in mucosal melanomas [7, 28, 29]. For SNMM specifically, Zebrary et al. summarized reported frequencies of mutations in SNMM of five studies and found high variability between these studies: KIT 0–60%, NRAS 22–60% and BRAF 0–6% [30].

In this paper, we present our clinical experience with SNMM over a 19-year period at an academic center. The aim of our study was to expand the body of literature on this rare disease entity. In addition, we performed a literature review on SNMM to compare and discuss our results.

Sinonasal mucosal melanoma is a rare tumour entity with an average 5‑year OS rate not exceeding 35%. Given the rarity of this tumor, its anatomically difficult location und its histopathological and immunohistochemical peculiarities, survival rates remain poor compared to cutaneous melanomas. Although some prognostic findings were made by several single center and multicentric studies, nationwide database reviews and meta-analyses, there is still no consensus for a standard of treatment regarding adjuvant therapy. The reasons for this might be the retrospective character of existing studies and their diversity in terms of patient selection, staging and treatment-specific survival outcome, which makes bias-free comparison and analysis difficult.

While smaller, single center case series have a limited number of cases and therefore have no specific inclusion criteria, multicentric and nationwide studies can afford more detailed inclusion criteria in terms of patient history, initial staging, curative and palliative treatment intent. Given these differences, statistical comparison and analysis would increase the probability of selection bias and decrease its scientific value.

Due to the anatomical location of the tumors, the lack of symptoms in lower stages might contribute to delayed diagnosis in advanced stages and the generally poor outcome rates.

The vast majority of patients throughout the literature had either nasal obstruction or epistaxis or both as principle symptoms [5, 9, 14, 18, 19, 33‐36, 40, 41], which is in accordance with our patient series.

Documentation of involved structures varied widely in reviewed studies, subdivisions ranging from nasal cavity and paranasal sinuses to structures of the nasal cavity. Some authors divided roughly into nasal cavity and paranasal sinuses for primary origin while others divided particularly into specific anatomic structures of the nasal cavity such as the lateral nasal wall or the nasal septum, or each one of the sinuses. Also, as bigger tumors involved more than one site, some authors list more than one location for one tumor.

Numerous prognostic factors for SNMM were found in the literature. Patients with primary tumors arising from the nasal cavity had better survival outcome than those originating from any of the paranasal sinuses [3, 9, 14, 24, 36, 37, 39]. A possible cause for this divergence could be that paranasal sinus lesions might be diagnosed at a more advanced tumor stage than lesions in the nasal cavity due to their hidden anatomic location [2, 3, 6, 42]. Furthermore, negative margins after resection [3, 19, 32, 43], advanced stage [6, 18, 19, 33, 37] and, interestingly, the level of pigmentation [14, 41] turned out to be significant prognostic factors.

There are still several different methods at use to stage SNMM which makes comparison of different series more difficult. Although some authors argued that the former TNM system of 2002 (AJCC 6th) [44] had adequate prognostic value and was better known internationally [18], several studies have shown that the accuracy of the newer AJCC 7th edition staging system is equal or superior to others, especially in the staging of advanced tumors [4, 6, 45]. No significant changes regarding mucosal melanomas were made in the AJCC 8th edition staging system.

Complete tumor excision is commonly accepted as standard treatment for patients with SNMM. Several studies have shown that survival is significantly better in patients with free surgical margins [3, 19, 43]. Due to the complex anatomy of the sinonasal cavities near vital structures, and the tumor patterns of locally invasive and destructive growth, surgical resection with free margins is challenging and may not be possible in many cases [14, 34, 37, 40]. Moreover, radical surgical procedures which often come with significant cosmetic and functional deficiencies do not seem to be justified when over 40% of the patients develop distant metastasis after achieving local control with surgery [14, 22, 24, 46]. Because of the lack of prospective, randomized trials concerning SNMM it is not possible to collect data about the quality of life of patients who underwent different surgical approaches [47]. Most studies show similar outcomes in comparing open to endoscopic surgery. Amit et al. showed that the oncological efficacy of endoscopic surgery was similar to open surgery but with a potentially lower risk of morbidity [24].

Won et al. and Moreno et al. demonstrated significantly higher survival rates in patients who underwent an endoscopic resection; however, since an external approach tends to be used in higher staged tumors, the possibility of a selection bias cannot be excluded in these studies [9, 14]. Nevertheless, external or combined (endoscopic and external) approaches are still recommended as effective surgical options in SNMM massively infiltrating surrounding and bony structures [19, 23].

There is broad consistency in pointing out that adjuvant radiotherapy improves local control in reducing local tumor recurrence rate but has no significant effect on survival outcome [3, 9, 14, 16, 33, 36, 37, 40, 41, 48, 49]. Information about radiation dose, fractionation and techniques is inconsistent and different radiation regimens have been presented. Moreno et al. found improvement of locoregional control when a total dose of more than 54 Gy was used in a standard fractionation schedule [14], which was confirmed by Yu et al. and Wada et al. [41, 49]. Meng et al. and Caspers et al. found improvement of local control giving mean total dosages of 63.4 Gy and 64 Gy, respectively [34, 50]. An even higher dosage above 70 Gy was suggested by Greenwalt et al. to increase locoregional control [51].

In a recently published retrospective study of 152 patients treated at the MD Anderson Cancer Center, Houston, Texas, Amit el al. described a standard scheme for radiation therapy using intensity modulated radiation therapy with a total dose of 60–70 Gy at 1.8–2 Gy per fraction over 6–7 weeks [24]. Because of the heterogeneity of various studies, it is not always clear which was the prevailing argument for the use of higher dose fractions and since hypofractionation is commonly used in palliative cases, a selection bias cannot be excluded [25]. In a recent nationwide study by Ajmani et al. the addition of standard adjuvant therapy (RT and CRT) does not seem to offer a survival benefit except for advanced tumors staged IVB. They conclude, the same as other authors that due to the lack of survival benefit and the added morbidity of radiation, radiotherapy should be prescribed individually and with caution [7, 32].

Systemic therapy in SNMM does not seem to have the desired effects on survival outcome in advanced stages of the disease [14, 16, 25, 48]. While regional lymph metastases are uncommon, distant metastases are one of the main treatment failures of SNMM. Classical chemotherapeutic agents like dacarbazine, or cisplatin derivatives do not seem to significantly impact SNMM, while other treatment approaches like novel immunotherapeutic agents indicate better response rates and disease control rates for mucosal melanomas [14, 25, 52]. Due to the rarity of SNMM, most studies regarding novel systemic therapies cover subgroups of melanoma including cutaneous and mucosal melanomas.

Studies regarding the effectiveness of adjuvant biochemotherapy indicate that the addition of interleukin 2 and interferon alpha‑2 to chemotherapeutic agents like dacarbazine or carboplatin may not improve durable responses or survival outcome [3, 53, 54]. Gene expressions in mucosal melanomas like c‑KIT, NRAS or BRAF might be of potential use for selective inhibitors. Although mutations of these gene expressions were found by other authors, only wild-type sequences were found in tumors assessed in the present series. In a study by Hodi et al. patients with c‑KIT mutations in advanced disease, were treated with the tyrosine kinase inhibitor imatinib and had a tumor response rate of 54% and an overall disease control rate of 77% [55]. Nivolumab and ipilimumab are immune checkpoint inhibitors. Nivolumab showed improved overall survival and better response rate versus dacarbazine in patients with BRAF wild-type melanoma in a phase III study by Robert et al. [56]. The combination of nivolumab and ipilimumab in patients with mucosal melanoma showed higher efficacy than either agent alone [28].

Surgery with confirmed free margins remains the standard treatment for SNMM. With technological advances in terms of visualization and instruments, endoscopic resections do not seem to be inferior to external approaches; however, the surgical approach ought to be chosen based on the probability to gain free margins. Adjuvant radiotherapy with a total radiation dose of 54 Gy or higher with standard fractionation schemes might be considered if margin status cannot be assessed with certainty or complex anatomic circumstances of the primary tumor make a definite assertion difficult. Local recurrence and distant metastasis remain the main treatment failures in SNMM, even after achieving local control and R0 resections. Although standard chemotherapy does not seem to have a satisfactory impact on SNMM, newer biological systemic agents like imatinib or the combination of ipilimumab plus nivolumab might improve overall survival of this fatal tumor. For further evaluation of effectiveness of these novel therapies it is important to consider the possibility of different genetic alterations between the tumor cells of cutaneous melanoma, mucosal melanoma, and particularly sinonasal mucosal melanoma. Therefore, it is necessary to investigate treatment modalities and outcomes distinctly for SNMM.

The number of different heterogeneic single-centered or multi-centered case series and nationwide studies, all with a retrospective character, make reasonable comparison with useful statements regarding treatment options, including systemic therapy and survival outcome in SNMM difficult. Many authors in literature conclude similarly that prospective multicentric studies are needed to reach higher patient numbers and improve scientific conclusions. Beswick et al. designed a web-based multi-institutional registry for patients with sinonasal malignancies, a web-based, secure database to prospectively collect data in cases diagnosed with sinonasal malignancies [57]. This could be an incitement for further research of similar portals, especially in Europe.

In conclusion, early diagnosis, free surgical margins and effective systemic therapy are needed to improve survival outcome in SNMM.