OBJECTIVE: No guidelines exist for the clinical target volume (CTV) and radiotherapy dose in sinonasal mucosal melanoma (SNMM). Thus, we aimed to determine the carbon-ion radiotherapy (CIRT) CTV and dose for SNMM.
METHODS: In total, 135 patients with SNMM who received CIRT were reviewed. The relative biological effectiveness-weighted dose was 57.6 or 64 Gy in 16 fractions. CTV was classified into small CTV, which included the gross tumor and visible melanosis with a certain margin, and extended CTV, which included the tumor site and adjacent anatomical structures. Local recurrence (LR) patterns were pattern I, II, and III, defined as recurrence over the gross tumor, visible melanosis and subclinical area, which would be covered if extended CTV was applied, and outside the extended CTV, respectively.
RESULTS: The 5-year LR rate was 35.3 %. The prescribed dose was not a significant risk factor for pattern I LR; however, 57.6 Gy for a large tumor was insufficient for local control. Using an extended CTV was significantly associated with a lower risk of pattern II LR, and these recurrences did not occur in regions that received > 40 Gy. The 5-year pattern III LR rate was 6.4 %.
CONCLUSIONS: Utilizing an extended CTV in CIRT for SNMM is appropriate even for small tumors. Using a smaller CTV after an extended CTV of at least 40 Gy is recommended to reduce adverse events. Although the optimal dose for gross tumors remains unclear, the latest technology with 64 Gy showed good outcomes.

Sinonasal mucosal melanoma originates from melanocytes and it is a rare malignancy in the sinonasal tract. It is an aggressive melanocytic neoplasm with a very poor prognosis. The symptoms are nonspecific and the diagnosis is delayed, usually until the advanced stages of the disease. The current study performs a correlation between the histopathological aspects of sinonasal mucosal melanoma and different types of immune cells present in the microenvironment, with prognostic and therapeutic implications. The endpoint is to quantify the cellular immune microenvironment and correlate it with patient survival. This study presents nine cases of primary sinonasal mucosal melanomas diagnosed at the Emergency City Hospital Timisoara, Romania during a period of 15 years. The histopathological examination was performed in the Department of Pathology of the same hospital, using morphological hematoxylin-eosin staining. Additional immunohistochemical reactions were performed to confirm the diagnosis and evaluate the components of the tumor immune microenvironment. This study identifies eosinophils, macrophages, natural killer cells and plasma cells as favorable prognostic factors. Therefore, a CD8:CD4 ratio of more than 3 is correlated with a good response to PD-1 inhibitor therapy.

Background/Objectives: Building upon the rising value of Confocal Laser Endomicroscopy (CLE) in squamous cell carcinoma of the head and neck, we present the first application of CLE during the resection of sinonasal malignant melanomas. This study aims to evaluate the potential of CLE to assist surgeons in intraoperative decision-making, with a particular focus on resection margin assessment within the constrained nasal cavity. Methods: Two cases of sinonasal malignant melanoma were included in this study. CLE was employed to examine visible tumors and their margins, both pre- and post-endoscopic resection. The findings were compared to histopathological results as well as data on squamous cell carcinoma, for which malignancy criteria had already been established in prior projects. Results: CLE provided the real-time visualization of sinonasal malignant melanomas and their margins, successfully differentiating between healthy and neoplastic tissue compared to histopathological findings. Conclusion: CLE offers the potential for real-time assessment, aiding surgeons in more precise tumor resection and potentially improving patient outcomes. This study demonstrates the feasibility of using CLE in the resection of sinonasal malignant melanoma, highlighting its ability to differentiate between healthy and neoplastic tissue intraoperatively.

Sinonasal mucosal melanoma (SNMM) is a rare malignancy with poor prognosis and high recurrence rate. In those with recurrence, survival is dismal. Immunotherapy is an emerging area of investigation; however, there is a scarcity of data on immunotherapy outcomes in SNMM patients with recurrence. We report outcomes of immunotherapy in recurrent SNMM patients with distant versus nondistant recurrence. Fifty-four patients with recurrent SNMM were identified, and 31 (57.4%) had distant recurrence. One-year overall survival (OS) following recurrence was 47.5% (95% confidence interval [CI]: 34.0%-60.9%), with a median survival of 2.8 years (95% CI: 2.0-5.3). In those with distant recurrence, receipt of immunotherapy was associated with better OS compared to those without immunotherapy (hazard ratio [HR] = 0.29 [95% CI: 0.12-0.68], P = .004). While patients with nondistant recurrence (n = 23), who received immunotherapy (n = 6) had worse OS compared to those who did not receive immunotherapy (HR = 4.76 [95% CI: 1.36, 15.89], P = .02). LEVEL OF EVIDENCE: Level IV.

OBJECTIVE: The aim of this work is to comprehensively review and synthesize the literature related to sinonasal mucosal melanoma (SNMM) treatment with immunotherapy, including potentially targetable genetic mutations, survival outcomes, and adverse events.
METHODS: Embase, Cochrane, Scopus, and Web of Science.
METHODS: The study protocol was designed according to Preferred Reporting Items for Systematic Reviews and Meta-analysis statement. Databases were searched from inception through May 23, 2023.
RESULTS: A total of 42 studies met inclusion criteria. Twenty-four of the included studies reported genetic mutations for a combined 787 patients with SNMM. 8.1% (95% confidence interval, CI: 7.6-8.6), 18.9% (95% CI: 18.1-19.8), and 8.5% (95% CI: 8.1-9.0) of reported patients were positive for BRAF, NRAS, and KIT mutations, respectively. The presence of brisk tumor-infiltrating lymphocytes was associated with improved recurrence-free survival and overall survival (OS). Six studies reported a combined 5-year OS after adjuvant immunotherapy treatment of 42.6% (95% CI: 39.4-45.8). Thirteen studies encompassing 117 patients reported adjuvant or salvage immune checkpoint inhibitor (ICI) immunotherapy response rates: 40.2% (95% CI: 36.8-43.6) had a positive response (tumor volume reduction or resolution). Eleven studies reported direct comparisons between SNMM patients treated with or without immunotherapy; the majority (7/11) reported survival benefit for their entire cohort or select subgroups of SNMM patients. With the transition to modern ICIs, there is a stronger trend toward survival improvement with adjuvant ICI. Tumors with Ki67 <40% may respond better to ICI\'s.
CONCLUSIONS: ICI therapy can be an effective in select SNMM patients, especially those with advanced/metastatic disease.

BACKGROUND: Sinonasal mucosal melanoma (SNMM) is a relatively rare malignant tumour with a poor prognosis. This study was designed to identify prognostic factors and establish a nomogram model to predict the overall survival (OS) of patients with SNMM.
METHODS: A total of 459 patients with SNMM were selected from the Surveillance, Epidemiology, and End Results (SEER) database as the training cohort. Univariate and multivariate Cox regression analyses were used to screen for independent factors associated with patient prognosis and develop the nomogram model. In addition, external validation was performed to evaluate the effectiveness of the nomogram with a cohort of 34 patients with SNMM from Peking Union Medical College Hospital.
RESULTS: The median OS in the cohort from the SEER database was 28 months. The 1-year, 3-year and 5-year OS rates were 69.8%, 40.4%, and 30.0%, respectively. Multivariate Cox regression analysis indicated that age, T stage, N stage, surgery and radiotherapy were independent variables associated with OS. The areas under the receiver operating characteristic curves (AUCs) of the nomograms for predicting 1-, 3- and 5-year OS were 0.78, 0.71 and 0.71, respectively, in the training cohort. In the validation cohort, the area under the curve (AUC) of the nomogram for predicting 1-, 3- and 5-year OS were 0.90, 0.75 and 0.78, respectively. Patients were classified into low- and high-risk groups based on the total score of the nomogram. Patients in the low-risk group had a significantly better survival prognosis than patients in the high-risk group in both the training cohort (P < 0.0001) and the validation cohort (P = 0.0016).
CONCLUSIONS: We established and validated a novel nomogram model to predict the OS of SNMM patients stratified by age, T stage, N stage, surgery and radiotherapy. This predictive tool is of potential importance in the realms of patient counselling and clinical decision-making.

OBJECTIVE: Mucosal melanoma is a rare malignancy; however, the reported incidence rate of mucosal melanoma is higher in Asians than in Caucasians. Sinonasal mucosal melanoma (SNMM) is an aggressive malignancy with a poor prognosis due to distant metastasis. Systemic therapy with BRAF inhibitor and MEK inhibitor is one of the standards of care for cutaneous melanoma patients with BRAF V600 mutations. However, no molecular targeted therapy for patients with mucosal melanoma has been established. Relatively few studies have described the genetic mutations associated with mucosal melanoma because of its low frequency. Furthermore, to the best of our knowledge, the genetic mutations among Japanese patients have not been reported. Therefore, in the current study, we evaluated the genetic and clinicopathological characteristics of patients with SNMM.
METHODS: A total of 18 tissue samples obtained from patients with SNMM were analyzed for genetic mutations based on targeted next-generation sequencing to investigate the driver of tumorigenesis and/or candidate genes for predicting clinical outcomes in SNMM. We also performed immunohistochemistry for patients identified with CTNNB1 mutations.
RESULTS: Eight of the 18 (44 %) patients had genetic mutations. The most frequent mutation was NRAS (6/18, 33 %), followed by CTNNB1 (2/18, 11 %) and BRAF (1/18, 5.6 %). One patient had both NRAS and CTNNB1 mutations. Clinical outcomes did not differ significantly between those with and without genetic mutations. NRAS mutations were associated with relatively higher T classification and worse survival rates, although the differences were not significant. The nuclear translocation of β-catenin was detected in both tumors with CTNNB1 mutations. The amino acid change in the BRAF mutation was K601R in exon 15. In the current study, no BRAF V600 mutations were detected.
CONCLUSIONS: Genetic mutations were not significantly associated with clinical outcomes. However, NRAS mutations may be a prognostic predictor and CTNNB1 mutation may be a treatment effector for immune check inhibitors. A larger prospective study is required to clarify the clinical importance of genetic mutations in patients with SNMM.

Objectives  Sinonasal mucosal melanoma (SNMM) is an extremely rare and challenging sinonasal malignancy with a poor prognosis. Standard treatment involves complete surgical resection, but the role of adjuvant therapy remains unclear. Crucially, our understanding of its clinical presentation, course, and optimal treatment remains limited, and few advancements in improving its management have been made in the recent past. Methods  We conducted an international multicenter retrospective analysis of 505 SNMM cases from 11 institutions across the United States, United Kingdom, Ireland, and continental Europe. Data on clinical presentation, diagnosis, treatment, and clinical outcomes were assessed. Results  One-, three-, and five-year recurrence-free and overall survival were 61.4, 30.6, and 22.0%, and 77.6, 49.2, and 38.3%, respectively. Compared with disease confined to the nasal cavity, sinus involvement confers significantly worse survival; based on this, further stratifying the T3 stage was highly prognostic ( p  < 0.001) with implications for a potential modification to the current TNM staging system. There was a statistically significant survival benefit for patients who received adjuvant radiotherapy, compared with those who underwent surgery alone (hazard ratio [HR] = 0.74, 95% confidence interval [CI]: 0.57-0.96, p  = 0.021). Immune checkpoint blockade for the management of recurrent or persistent disease, with or without distant metastasis, conferred longer survival (HR = 0.50, 95% CI: 0.25-1.00, p  = 0.036). Conclusions  We present findings from the largest cohort of SNMM reported to date. We demonstrate the potential utility of further stratifying the T3 stage by sinus involvement and present promising data on the benefit of immune checkpoint inhibitors for recurrent, persistent, or metastatic disease with implications for future clinical trials in this field.

BACKGROUND: The standard of care for sinonasal mucosal melanoma is surgery and postoperative radiotherapy (PORT). Our treatment strategy comprises endoscopic resection and PORT. We performed combined endoscopic and open resection or applied an external approach alone when sufficient resection was difficult to achieve endoscopically. The objective of this study was to evaluate the validity of our treatment strategy.
METHODS: We assessed 30 patients with sinonasal mucosal melanoma who underwent definitive therapy between January 2002 and April 2021, and conducted a retrospective analysis. The median follow-up period was 2.2 years. The primary endpoint was overall survival. The Kaplan-Meier method was used for the calculation of survival rates, the cumulative incidence of distant metastasis, and local recurrence.
RESULTS: Twenty-eight patients underwent surgery. The other two patients were treated by definitive proton beam therapy. Twenty-one of 28 (75%) patients underwent resection by endoscopic approach alone. Postoperative radiotherapy was performed for all 28 patients who underwent surgery. Twenty-one patients (70%) experienced recurrence during the observation period. Overall, distant metastasis was observed in 19 patients. Twelve patients died during the observation period, with 10 of the 12 patients (83%) dying of distant metastasis. The overall survival rate at 2 and 5 years was 70% and 46%, respectively. The cumulative incidence rate of distant metastasis at 2 years was 63%, while the 2-year cumulative incidence rate of local recurrence was 6.7%.
CONCLUSIONS: The local disease was controlled by our treatment strategy. To improve treatment outcomes, control of the distant metastasis is needed.

Sinonasal mucosal melanoma (SNMM) is a rare malignant neoplasm. The regional failure pattern and effectiveness of elective neck irradiation (ENI) were not well defined. Here, we would assess the value of ENI for clinical node negative (cN0) SNMM patients.
A total of 107 SNMM patients treated at our institution over a period of 30 years was retrospectively analyzed.
Five patients had lymph node metastases at diagnosis. Among the 102 cN0 patients analyzed, 37 patients had received ENI, and 65 patients had not. ENI significantly reduced the regional recurrence rate from 23.1% (15/65) to 2.7% (1/37). Ipsilateral levels Ib and II were the most common locations of regional relapse. Multivariate analysis also showed that ENI was the only independent favorable predictor for the achievement of regional control (HR: 9.120; 95% CI: 1.204-69.109; P = 0.032).
This is the largest cohort of SNMM patients from a single institution analyzed for the assessment of the value of ENI on regional control and survival. ENI significantly reduced the regional relapse rate in our study. Ipsilateral levels Ib and II might be considerable when deliver elective neck irradiation, more evidence is needed in the future.