Defining Prognostic Markers and Clinical Outcomes in Epithelioid Malignant Peripheral Nerve Sheath Tumor.

Epithelioid malignant peripheral nerve sheath tumor (EMPNST) is recognized as a distinct entity in the 2026 World Health Organization classification, defined by characteristic morphology and frequent SMARCB1 (INI1) loss, which differentiates it from conventional MPNST. Limited data suggest EMPNST may have a more favorable prognosis, but prognostic markers remain undefined. We studied 78 primary EMPNSTs and compared them with 60 conventional MPNSTs. Patients with EMPNST included 41 females and 37 males, with a median age of 45 (range, 6-84) years. Necrosis was observed in 20% of cases, cytologic atypia was mild (25%), moderate (57%), or severe (18%), and mitoses ranged from 0 to 42/10 (median 7/10) high-power fields. SMARCB1 loss was observed in 81% of EMPNSTs and correlated with prominent nucleoli (64%, P < .001). EMPNSTs predominantly arose in the lower extremities, with 32% superficial, whereas conventional MPNSTs were mostly truncal. Targeted sequencing in 34 EMPNSTs identified SMARCB1 inactivation in 77% of cases, which was associated with SMARCB1 loss (P < .001), and recurrent alterations targeting 2q35/XRCC5 in 59% of cases. Among 34 patients with follow-up (median, 43 months; range, 0-225), 9 developed local recurrence, 15 metastases, and 10 died of disease. Compared with conventional MPNST, EMPNST demonstrated longer median progression-free survival (34 vs 19 months, P value for global difference of survival curves = .35); overall survival was not reached in EMPNST (vs 85 months in conventional MPNST, P value for global difference of survival curves = .16). In multivariable analysis, tumor size and mitotic rate were independently associated with poor prognosis (hazard ratio [HR], 5.2; 95% CI, 1.5-17.7; HR, 1.1; 95% CI, 1.01-1.2, respectively). A risk score integrating tumor size > 5 cm, mitoses > 7 of 10 high-power fields, and necrosis predicted poor outcomes (HR, 4.1; 95% CI, 1.4-12). In conclusion, EMPNST tumor size and mitotic activity are key prognostic factors, supporting a simple risk stratification model. SMARCB1 inactivation is the most frequent genomic event, followed by gains at 2q35 potentially targeting XRCC5, highlighting molecular underpinnings for this distinct sarcoma subtype.