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

Treatment of Malignant Peripheral Nerve Sheath Tumors (MPNST)

Complete surgical resection with wide negative margins is the primary curative treatment for MPNST, and adjuvant radiation therapy to doses ≥60 Gy significantly improves local control, particularly when combined with intraoperative electron radiation therapy (IOERT) or brachytherapy. 1

Surgical Management

Surgery with wide excisional margins remains the cornerstone of curative treatment for localized MPNST. 2, 3, 4

• Achieving negative surgical margins is the single most critical prognostic factor for both survival and local control on multivariate analysis 1
• Patients with positive or uncertain surgical margins have a 5-year local relapse rate of 28% versus only 5% for negative margins (hazard ratio 5.92) 5
• Evaluation and surgical planning should be performed by a specialized multidisciplinary team, ideally at a dedicated neurofibromatosis clinic, as this approach significantly reduces morbidity and mortality 6

Radiation Therapy

Adjuvant radiation therapy is strongly recommended for larger lesions, those with aggressive histology, or when surgical margins are compromised. 1, 3

• Radiation doses ≥60 Gy are associated with significantly improved local control compared to lower doses 1
• The addition of IOERT or brachytherapy to external beam radiation provides superior local control (p=0.016 on multivariate analysis) 1
• Preoperative radiation (median 50 Gy) can be used for downstaging, while postoperative radiation (median 64 Gy) is more commonly employed 5
• Combined surgery and radiation therapy achieves 5-year local control rates of 84% 5

Systemic Therapy

Chemotherapy with anthracyclines plus ifosfamide has uncertain but potentially promising roles in local control, downstaging, and palliation for advanced or metastatic disease. 2

• No targeted therapy has demonstrated objective responses in MPNST, with cumulative disease control rates of only 22.9-34.8% across multiple trials 2
• Multiple signal transduction pathways are implicated (Ras/AKT/mTOR/MAPK, EGFR, p53, PTEN, PRC2), but no single druggable target has emerged 2
• Combinatorial approaches targeting multiple pathways are the focus of ongoing clinical trials 2, 3

Diagnostic Workup Prior to Treatment

Accurate integrated diagnosis combining histopathology and molecular profiling is essential before initiating treatment. 6

• FDG-PET or diffusion-weighted MRI should be obtained for lesions with concerning features to identify areas of increased metabolic activity 6
• Core needle biopsy using 14-18G needles with minimum 6 cores (if safe and feasible) should be performed under MRI or ultrasound guidance 6, 2
• Molecular profiling is mandatory for all clinically or radiologically worrisome noncutaneous lesions, assessing for SUZ12, EED, or TP53 inactivating mutations, CDKN2A/B inactivation, and significant aneuploidy (≥8 chromosome arms with segmental gain/loss) 7, 6
• Immunohistochemical staining should assess SOX10, S100, CD34, p16, H3K27me3, and p53 expression 6

Treatment Outcomes and Prognosis

Despite multimodality treatment, MPNST-specific survival has not improved in decades, with 5-year and 10-year survival rates of 52% and 34%, respectively. 1

• Both local and distant failure rates at 5 years are 49%, highlighting the aggressive nature of these tumors 1
• Of patients who experience disease relapse (49%), only 3 were ultimately salvaged, emphasizing the importance of achieving complete initial resection 5
• The 5-year distant metastatic-free survival is only 62%, and disease-specific survival is 66% 5
• History of prior irradiation and positive surgical margins are the only factors that remain significant for survival on multivariate analysis 1

Common Pitfalls

• Inadequate surgical margins are the most common preventable cause of treatment failure—always prioritize wide excision over nerve-sparing approaches when oncologically indicated 1, 5
• Radiation doses <60 Gy are associated with inferior local control—do not underdose these aggressive tumors 1
• Distant metastases remain the primary cause of mortality, occurring in nearly half of patients despite good local control, underscoring the need for systemic therapy development 1, 5
• Salvage after recurrence is rarely successful, making optimal initial treatment critical 5