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.

Cancer Research UK and UCL Cancer Trials Centre University College London London United Kingdom

Cancer Sciences Unit Faculty of Medicine University of Southampton United Kingdom

CAS Key Laboratory of Computational Biology Shanghai Institute of Nutrition and Health University of Chinese Academy of Sciences Shanghai People's Republic of China

Center for Cranial Base Surgery University of Pittsburgh Medical Center Pittsburgh Pennsylvania United States

Department of Clinical Oncology The Christie NHS Foundation Trust Manchester United Kingdom

Department of ENT Barts Health NHS Trust London United Kingdom

Department of Head and Neck Oncology Instituto de Investigación Sanitaria del Principado de Asturias Oviedo Spain

Department of Head and Neck Surgery The University of Texas MD Anderson Cancer Center Houston Texas United States

Department of Histopathology University College London Hospitals NHS Trust London United Kingdom

Department of Neurosurgery Johns Hopkins University School of Medicine Baltimore Maryland United States

Department of Oncology Haematology and Bone Marrow Transplantation with Section Pneumology Hubertus Wald Tumorzentrum University Medical Center Hamburg Eppendorf Hamburg Germany

Department of Oncology Johns Hopkins University School of Medicine Baltimore Maryland United States

Department of Otolaryngology Head and Neck Surgery Beaumont Hospital Dublin Ireland

Department of Otolaryngology Head and Neck Surgery Johns Hopkins School of Medicine Baltimore United States

Department of Otolaryngology Head and Neck Surgery Lebanese American University Beirut Lebanon

Department of Otolaryngology University of Pittsburgh Medical Center Pittsburgh United States

Department of Otorhinolaryngology Medical University of Innsbruck Innsbruck Austria

Department of Radiation Oncology Stanford University School of Medicine Palo Alto California United States

Department of Translational Research University of Pisa Pisa Italy

Disease Team Alignment Head and Neck City of Hope Medical Center Duarte California United States

Division of Dentistry University of Manchester Manchester United Kingdom

Head and Neck Centre University College London Hospitals NHS Trust London United Kingdom

Liverpool Head and Neck Centre University of Liverpool Liverpool United Kingdom

Medical Oncology Department of Medical and Surgical Specialities Radiological Sciences and Public Health University of Brescia Brescia Italy

Pathology Unit Department of Molecular and Translational Medicine University of Brescia ASST Spedali Civili Brescia Italy

Rhinology and Endoscopic Skull Base Surgery Department of Otolaryngology Head and Neck Surgery Stanford University School of Medicine Palo Alto California United States

Royal National ENT Hospital and Head and Neck Centre University College London Hospitals NHS Trust London United Kingdom

Section of Otorhinolaryngology Head and Neck Surgery Department of Neurosciences University of Padova Padova Italy

Sinonasal and Skull Base Tumor Program Head and Neck Surgery Branch National Institute on Deafness and Other Communication Disorders National Institutes of Health Bethesda Maryland United States

The Fingerland Department of Pathology Charles University Faculty of Medicine and University Hospital Hradec Kralove Czech Republic

The Royal College of Surgeons in Ireland Dublin Ireland

UCL Cancer Institute University College London London United Kingdom

UCL Division of Surgery and Interventional Science University College London London United Kingdom

Unit of Otorhinolaryngology Head and Neck Surgery Department of Biotechnology and Life Sciences University of Insubria Varese Italy

Unit of Otorhinolaryngology Head and Neck Surgery Department of Medical and Surgical Specialties Radiological Sciences and Public Health University of Brescia Brescia Italy

Unit of Pathology ASST Sette Laghi University of Insubria Varese Italy

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