Malignant peripheral nerve sheath tumors arising in SMARCB1-associated schwannomatosis: illustrative cases

BACKGROUND Schwannomatosis is a rare tumor predisposition syndrome characterized by benign peripheral nerve sheath tumors in the absence of bilateral vestibular schwannomas. In rare cases, malignant peripheral nerve sheath tumors (MPNSTs) may arise with schwannomatosis, particularly with SMARCB1 mutations. These malignancies pose significant diagnostic and therapeutic challenges and a poor prognosis. OBSERVATIONS The authors present 2 cases of high-grade MPNST with SMARCB1 -associated schwannomatosis. Both presented with rapidly enlarging and concerning imaging features, including heterogeneous enhancement, central necrosis, and low apparent diffusion coefficient values. Histopathological analysis confirmed high-grade MPNST with elevated mitotic activity and loss of H3K27me3. Both patients underwent en bloc resection with negative margins. One patient remains disease free at 5 years; the other patient developed metastatic recurrence and died. A systematic review identified 20 cases in the literature. LESSONS These cases emphasize clinical vigilance for malignant transformation in schwannomatosis, particularly with rapidly enlarging lesions or new neurological symptoms. MRI and FDG-PET can aid in identifying concerning features. Despite margin-negative resection, recurrence and metastasis may occur, reflecting the tumor’s aggressive biology. Genetic counseling may be considered in SMARCB1 -associated cases. While malignant transformation is much more common in NF1 lesions, rare cases do arise in schwannomatosis, requiring close surveillance and multidisciplinary management. https://thejns.org/doi/10.3171/CASE25610