What is the recommended treatment for a 30-year-old male with Neurofibromatosis Type 1 (NF1) presenting with symptoms suggestive of malignant transformation of a plexiform neurofibroma into a Malignant Peripheral Nerve Sheath Tumor (MPNST), including rapid growth, pain, neurologic deficits, and constitutional symptoms?

Treatment of MPNST in NF1: Aggressive Surgical Resection with Adjuvant Therapy

Complete surgical resection with wide negative margins is the cornerstone and primary treatment for this patient's MPNST, and should be pursued urgently given the rapid progression, neurologic deficits, and extensive necrosis on pathology. 1, 2

Immediate Surgical Management

Oncologic resection of the pelvic MPNST must be performed as soon as feasible, targeting complete excision with wide negative margins. 1, 2 The presence of extensive necrosis, S100 negativity, rapid growth over 2 months, and neurologic deficits (right leg weakness 4/5) all confirm high-grade MPNST requiring aggressive surgical intervention. 3

Critical Surgical Considerations:

• The goal is R0 resection (microscopically negative margins), as this is the single most important prognostic factor for survival and local control. 1, 2
• The large pelvic location (causing urinary retention and lumbosacral plexus compression) makes this technically challenging, but even large abdominal/pelvic MPNSTs benefit from complete resection. 2
• The forearm mass (20×10 cm, present >5 years) should also be evaluated intraoperatively or with staging imaging, as multifocal MPNST can occur in NF1 patients. 4

Adjuvant Radiation Therapy

Adjuvant radiation therapy to doses ≥60 Gy should be strongly considered if margins are positive, close, or uncertain after resection. 1 This improves local control in high-grade MPNST, though the retroperitoneal/pelvic location presents challenges with toxicity. 1

Radiation Therapy Nuances:

• For retroperitoneal locations, postoperative radiotherapy has limited value and significant toxicities, and should only be used in selected cases with well-defined areas at risk. 1
• If margins are definitively negative (R0 resection), observation may be appropriate, though this patient's high-grade features (extensive necrosis, rapid growth, neurologic symptoms) suggest higher recurrence risk. 1

Role of Chemotherapy

Chemotherapy is NOT recommended for completely excised MPNST in the adjuvant setting, as no randomized studies demonstrate clear benefit, and response rates are poor (21% for doxorubicin plus ifosfamide). 1, 2

When to Consider Chemotherapy:

• Only consider chemotherapy if the tumor is unresectable, metastatic, or recurrent after surgery. 1, 2
• Doxorubicin plus ifosfamide achieves only 21% response rates in advanced disease, making it a poor option for adjuvant therapy. 1, 2

Prognostic Context and Surveillance

This patient has high-grade MPNST (not pT1 low-grade disease), evidenced by extensive necrosis, S100 loss, rapid growth, and neurologic symptoms. 3 High-grade MPNST carries approximately 20% 5-year survival, dramatically worse than the 100% 10-year survival of low-grade lesions. 1

Surveillance Strategy:

• Baseline MRI of the resection site immediately post-surgery to establish characteristics for future comparison. 1, 2
• Serial MRI every 3-6 months for the first 2-3 years, then every 6-12 months depending on stability. 2
• FDG-PET or diffusion-weighted MRI should be performed immediately if concerning features develop (new pain, rapid growth, neurologic symptoms), using SUVmax ≥3.5 as a threshold for malignancy. 1, 2, 5
• Annual comprehensive evaluation assessing for signs/symptoms of recurrence, new masses, and blood pressure (for pheochromocytoma screening). 1, 2

Critical Pitfalls to Avoid

Do not delay surgery for extensive preoperative workup beyond staging imaging. The 2-month progression from asymptomatic to urinary retention and leg weakness indicates aggressive biology requiring urgent intervention. 6

Do not apply low-grade MPNST or ANNUBP treatment protocols to this patient. The pathology (extensive necrosis, S100 negativity, spindle cell morphology) and clinical presentation (rapid growth, neurologic deficits, constitutional symptoms with ESR 128) confirm high-grade MPNST. 3, 1

Do not assume the forearm mass is benign despite 5+ years of stability. Multifocal MPNST transformation can occur in NF1, and this lesion warrants FDG-PET or biopsy evaluation. 4

Ensure subspecialized pathology review of all specimens, as distinguishing ANNUBP from MPNST can be challenging, and accurate diagnosis is crucial for guiding treatment and predicting recurrence risk. 3, 4

Special NF1 Considerations

NF1-associated MPNSTs have increased mortality compared to sporadic cases, and this patient's family history (relative with abdominal mass and malignancy) suggests aggressive disease biology. 1, 2

Life expectancy in NF1 is reduced by 8-15 years primarily due to malignant neoplasms, making aggressive treatment of MPNST essential for improving survival. 1, 2

The risk of MPNST in NF1 increases with age (8.5% by age 30), and this 30-year-old patient is at peak risk for malignant transformation. 1, 2