What is the treatment for malignant peripheral nerve sheath tumors (MPNSTs)?

Treatment of Malignant Peripheral Nerve Sheath Tumor (MPNST)

Surgery with complete resection and negative margins is the cornerstone of treatment for MPNST and remains the only potentially curative approach, with adjuvant radiation therapy to doses ≥60 Gy recommended to improve local control, particularly when margins are positive or uncertain. 1

Surgical Management

Complete surgical resection with wide negative margins is the primary treatment goal for all localized MPNSTs. 1 This approach has demonstrated benefit even for large, non-extremity tumors (e.g., abdominal MPNSTs). 1

• Surgical margin status is the most critical prognostic factor for both survival and local control on multivariate analysis. 2, 3
• For retroperitoneal MPNSTs, resection should include the tumor with negative margins and typically requires sacrifice of the nerve of origin. 1
• Positive or uncertain surgical margins are associated with a 5-fold increased risk of local recurrence (28% vs. 5% for negative margins at 5 years). 3

Radiation Therapy

Adjuvant radiation therapy should be administered to doses ≥60 Gy to optimize local control, particularly when surgical margins are positive or uncertain. 2

• Radiation doses ≥60 Gy are significantly associated with improved local control on multivariate analysis. 2
• The inclusion of intraoperative electron radiation therapy (IOERT) or brachytherapy is associated with superior local control compared to external beam radiation alone. 2
• Preoperative radiation (median 50 Gy) or postoperative radiation (median 64 Gy) can be used as part of multimodality treatment. 3
• The 5-year local control rate with combined surgery and radiation therapy is approximately 84%. 3
• Postoperative radiotherapy following complete resection of retroperitoneal sarcomas has limited value and significant toxicities, and should only be considered in selected cases with well-defined areas at risk for local recurrence. 1

Chemotherapy

The role of chemotherapy remains uncertain, with no randomized studies demonstrating clear benefit, though it may be considered in select patients with non-metastatic disease or advanced/metastatic disease. 1

• For advanced and metastatic MPNST, doxorubicin plus ifosfamide achieves response rates of approximately 21% in multi-institutional retrospective studies. 1
• Meta-analysis and recent studies suggest there may be a role for adjuvant chemotherapy in some MPNST patients with non-metastatic disease, though evidence is not definitive. 1
• Preoperative chemotherapy can be considered for borderline resectable tumors, though this is currently under investigation. 1

Prognosis and Tumor Grade Considerations

High-grade MPNSTs have a dismal prognosis with approximately 20% 5-year survival, while low-grade MPNSTs (now termed "ANNUBP with increased proliferation") have 100% 10-year survival. 1

• Low-grade MPNST accounts for approximately 5% of NF1-associated MPNSTs. 1
• NF1-associated MPNSTs have increased mortality compared to sporadic cases, though outcomes have improved in the past decade. 1
• The 5-year disease-specific survival rate with combined surgery and radiation is approximately 66%. 3
• Distant metastases occur in approximately 49% of patients and remain the primary cause of treatment failure, with limited salvage success at the time of relapse. 3

Diagnostic Workup Prior to Treatment

Molecular profiling is recommended for all clinically or radiologically worrisome noncutaneous lesions to identify diagnostically-relevant features including CDKN2A/B inactivation, SUZ12, EED, or TP53 inactivating mutations, and significant aneuploidy. 1, 4

• FDG-PET or diffusion-weighted MRI should be performed for lesions with concerning features, with SUVmax of 3.5 commonly used as a threshold for biopsy. 1
• Core needle biopsy using 14-18G needles with a minimum of 6 cores is recommended when safe and feasible. 4
• Histologic evaluation should assess cytologic atypia, loss of neurofibromatous architecture, hypercellularity, mitotic count, and presence of necrosis. 1, 4

Common Pitfalls

• Avoid inadequate surgical margins: Positive margins dramatically increase local recurrence risk and worsen survival. 2, 3
• Do not underutilize radiation therapy: Doses <60 Gy are associated with inferior local control. 2
• Recognize that distant recurrences are common: Approximately 49% of patients develop distant metastases despite optimal local therapy, with limited salvage options. 3
• Be aware of NF1-associated risk factors: Germline microdeletion of the NF1 locus and previous radiation exposure increase MPNST risk. 1

Emerging and Investigational Approaches

No targeted therapies have demonstrated objective responses in clinical trials to date, with cumulative disease control rates of only 22.9-34.8%. 5

• Combinatorial approaches targeting multiple signal transduction mechanisms (including Ras/AKT/mTOR/MAPK, EGFR, p53, PTEN, and PRC2 pathways) are hallmarks of ongoing clinical trials. 5, 6
• Small-molecule inhibitors of MEK, CDK4/6, and SHP2 are promising therapeutics, especially when combined, but have yet to gain approval. 6
• Immunotherapeutic approaches have limited utility as single agents due to the immunosuppressive tumor microenvironment of MPNSTs. 6