Malignant peripheral nerve sheath tumors in schwannomatosis: a case series

OBJECTIVE Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive sarcomas predominantly associated with neurofibromatosis type 1 (NF1). However, their occurrence within NF type 2 (NF2)–related and SMARCB1-related schwannomatosis remains rare and poorly characterized. Accurate and timely diagnosis is challenging due to clinical and radiological similarities with benign schwannomas, potentially delaying appropriate management and impacting outcomes. This study presents an institutional case series aiming to better characterize the clinical presentations specifically for MPNSTs arising in patients with NF2- and SMARCB1-related schwannomatosis. METHODS This retrospective case series included patients diagnosed with schwannomatosis who subsequently developed histopathologically confirmed MPNSTs. Conducted at Mayo Clinic (Rochester, Minnesota) and University Health Network (Toronto, Canada), the study spanned January 1, 2003, to November 1, 2024. Patients were selected based on clinical or genetic diagnoses of schwannomatosis using International Consensus Group on Neurofibromatosis Diagnostic Criteria. Comprehensive clinical, radiological, and pathological data, including demographics, presenting symptoms, tumor features (size, location, immunohistochemistry, genetics), treatments (resection, chemotherapy, radiotherapy), and follow-up outcomes were extracted from electronic medical records. RESULTS The authors identified 8 patients with a mean age of 36 years, half of whom had NF2-related schwannomatosis. The most common presenting symptom was pain (71%). The mean tumor size was 8.2 ± 7.0 cm, with gross-total resection being the most common surgical treatment (67%), typically supplemented with radiation therapy (78%). More than half of the patients (56%) exhibited metastatic disease, and all tumors with reported grading were Fédération Nationale des Centres de Lutte Contre le Cancer grade 3. No tumors were associated with LZTR1 mutations. One notable case involved a 39-year-old male with SMARCB1-related schwannomatosis who had a femoral MPNST resected 13 years prior and subsequently developed a sciatic nerve MPNST that was managed successfully with neoadjuvant chemotherapy, radiation therapy, and negative margin resection. Of note, the second lesion arose from a hybrid neurofibroma/schwannoma. Another case, a 33-year-old male with SMARCB1-related schwannomatosis, had an incidental finding of epithelioid MPNST in a minimally symptomatic small palmar lesion. CONCLUSIONS This case series highlights that MPNSTs, although uncommon, can arise in NF2- and SMARCB1-related schwannomatosis without prior radiation exposure, presenting significant diagnostic challenges due to their similarity to benign schwannomas. The findings underscore the importance of maintaining clinical vigilance and employing individualized management strategies, balancing thorough resection with the preservation of function and patient quality of life.