Outcomes of malignant melanotic nerve sheath tumors (MMNST): A retrospective cohort study.

e23556 Background: MMNST is a rare and aggressive peripheral nerve sheath tumor characterized by melanocytic differentiation and frequently misdiagnosed as melanoma due to overlapping histologic and immunophenotypic features. MMNST is commonly associated with PRKAR1A loss-of-function mutations and Carney complex, though it can also occur sporadically. Due to its rarity, optimal management and prognostic factors remain poorly defined. We performed a retrospective cohort study to characterize clinicopathologic features, genomic alterations, treatment patterns, and outcomes in patients with MMNST. Methods: We retrospectively identified patients with pathologically confirmed MMNST treated at MD Anderson Cancer Center between 2016-2025. Clinical data including demographics, tumor location, stage, treatments received, recurrence patterns, and survival outcomes were abstracted from medical records. Survival outcomes were estimated using the Kaplan-Meier method. Results: A total of 13 patients with MMNST were identified. Median age at diagnosis was 39 years (range 29-72), and 61.5% were male. Primary tumors most commonly arose in the paraspinal (46.2%, n = 6), head/neck (30.8%, n = 4), thoracic (15.4%, n = 2), and abdominopelvic (7.7%, n = 1) locations. Next generation sequencing testing was completed in 84.6% (11/13) of cases, and 72.7% (8/11) had PRKAR1A loss-of-function mutation. 7.7% (n = 1) of patients had metastatic disease at presentation. Surgical resection was performed in 83.3% (10/12) with localized disease, with radiation and/or systemic chemotherapy administered in 66.7% (8/12). At a median follow-up of 29.3 months, 66.7% (8/12) of patients with localized disease at presentation developed local recurrence (2/12) or distant metastases (6/12), with median recurrence-free survival of 25.9 months (95% CI 15.1-29.7 months). 88.9% (8/9) of patients with metastatic disease received systemic therapy, and the most common regimen was ipilimumab plus nivolumab (7/9); responses to different regimens will be detailed at the meeting. Median overall survival from the time of distant metastasis development was 50.6 months. Median overall survival in the whole cohort was 81.4 months. Conclusions: MMNST is a rare malignancy most commonly arising in paraspinal and head/neck locations. Despite aggressive local management, most patients with initially localized disease experienced recurrence or metastasis by about two years. These findings highlight the need for improved local and systemic treatment strategies and prospective, collaborative studies for this rare malignancy.