Is a malignant peripheral nerve sheath tumour (MPNST) a malignancy, particularly in individuals with neurofibromatosis type 1 (NF1)?

Is Malignant Peripheral Nerve Sheath Tumour a Malignancy?

Yes, malignant peripheral nerve sheath tumor (MPNST) is definitively a malignancy—it is an aggressive sarcoma that arises from or differentiates along peripheral nerves, accounting for approximately 5% of all soft tissue malignancies. 1, 2

Classification and Definition

MPNST is classified as a high-grade malignant tumor when it demonstrates:

• Brisk mitotic activity (≥10 mitoses per 10 high-power fields) 1
• Areas of tissue necrosis 1
• Specific molecular alterations including SUZ12, EED, or TP53 inactivating mutations, or significant aneuploidy 1, 3

The 2021 WHO Classification of Tumors of the Central Nervous System and 2022 WHO Classification of Tumors of Soft Tissue and Bone have codified MPNST as a malignant entity. 1

Critical Distinction: High-Grade vs. Low-Grade

A crucial recent consensus recommendation proposes eliminating the term "low-grade MPNST" entirely, renaming it "ANNUBP with increased proliferation" to avoid using the "malignant" designation for tumors with uncertain biologic potential. 1 This reflects:

• High-grade MPNSTs carry a dismal prognosis with approximately 20% 5-year survival 3
• "Low-grade MPNSTs" (now recommended to be called ANNUBP with increased proliferation) have 100% 10-year survival, representing only 5% of NF1-associated cases 3

Association with Neurofibromatosis Type 1

Approximately 50% of MPNSTs arise in patients with NF1, who present with distinct characteristics: 2, 4

• Younger age at presentation 4
• Larger tumor size 4
• Commonly associated with extensive plexiform neurofibromas 4
• 10% lifetime risk of malignant transformation from plexiform neurofibromas 5
• Increased mortality compared to sporadic cases 3

The cumulative risk in NF1 patients increases with age: 8.5% by age 30,12.3% by age 50, and 15.8% by age 85. 6

Clinical Behavior Confirming Malignancy

MPNST demonstrates aggressive malignant behavior through:

• High recurrence rates even after complete resection 7
• Metastatic potential requiring systemic treatment 8
• Resistance to conventional therapies except surgical resection 9
• Infiltrative growth along peripheral nerves 2

Treatment Approach Reflects Malignant Nature

The American College of Medical Genetics and Genomics recommends oncologic management: 3

• Complete surgical resection with wide negative margins as primary treatment 3, 4
• Adjuvant radiation therapy to doses ≥60 Gy for local control, particularly with positive/uncertain margins 3
• Chemotherapy consideration for advanced/metastatic disease (doxorubicin plus ifosfamide achieves ~21% response rates) 3

Gross-total resection significantly prolongs overall survival (p=0.01), with surgical margin status being a critical prognostic factor (p=0.034). 4

Molecular Features Defining Malignancy

The malignant nature is confirmed by specific molecular alterations: 1, 3, 6

• PRC2 component mutations (SUZ12, EED) resulting in loss of H3K27me3 9
• TP53 inactivating mutations 1, 3
• Significant aneuploidy distinguishing MPNST from benign neurofibromas 1, 3
• CDKN2A/B homozygous deletion (though this alone indicates ANNUBP, not frank MPNST) 3, 5

Common Pitfall to Avoid

Do not confuse ANNUBP (atypical neurofibromatous neoplasm of uncertain biologic potential) with MPNST. ANNUBP has at least 2 of these features: cytologic atypia, loss of neurofibroma architecture, hypercellularity, or mitotic count >1/50 but <3/10 HPF—but lacks the high mitotic activity and necrosis defining true MPNST. 1, 6 The biologic potential of ANNUBP remains uncertain, hence the recent recommendation to avoid calling lower-grade lesions "malignant." 1