What is the management approach for Neurofibromatosis (NF)?

Management of Neurofibromatosis Type 1

All patients with NF1 should be managed through a specialized multidisciplinary NF clinic with annual comprehensive evaluations, as this approach significantly reduces morbidity and mortality from this complex tumor predisposition syndrome. 1, 2, 3

Core Surveillance Strategy

Annual Clinical Monitoring

Every patient requires yearly assessment for:

• Progressive severe pain, rapid tumor growth, or new neurologic symptoms (warning signs of malignant peripheral nerve sheath tumor transformation) 1, 3, 4
• Blood pressure measurement (screening for pheochromocytoma and essential hypertension) 1, 3
• Scoliosis evaluation using Adam's forward bend test with orthopedic referral if abnormal 1, 3
• Depression screening and chronic pain assessment 1, 3
• Peripheral neuropathy evaluation 3

Imaging Surveillance

• Baseline MRI of all known or suspected non-superficial plexiform neurofibromas 3
• For orbital/periorbital plexiform neurofibromas: high-resolution brain and orbit MRI with and without contrast, avoiding CT radiation exposure 1
• Growing tumors or those near critical structures (e.g., cavernous sinus) require MRI every 3-6 months until stability confirmed 1
• 18F-FDG PET/CT for suspected malignant transformation (sensitivity 0.89, specificity 0.95) 4

Cancer Screening

• Women: annual mammogram starting at age 30, with consideration of breast MRI between ages 30-50 1, 3, 4
• Standard age-appropriate cancer screening for general population 1

Treatment Approach by Clinical Scenario

Newly Diagnosed Plexiform Neurofibromas

Initial management is close observation with serial ophthalmologic and MRI evaluations, as many will not progress. 1

Indications to initiate treatment:

• Visual decline or imminent vision threat 1, 2
• Progressive tumor growth threatening critical structures (cavernous sinus invasion) 1, 2
• New or worsening functional deficits (strabismus, proptosis, ptosis, amblyopia, glaucoma) 1, 2
• Progressive disfigurement 1, 2

Medical Therapy for Plexiform Neurofibromas

Selumetinib (KOSELUGO) is FDA-approved for children ≥2 years with symptomatic, inoperable plexiform neurofibromas at 25 mg/m² twice daily. 2, 5

• Produces tumor volume decreases ≥20% with clinically meaningful functional improvement 2
• Early intervention may prevent progression and facial disfigurement in children with small orbital-periorbital lesions 2
• Alternative: Trametinib when selumetinib unavailable 2
• For patients ≥16 years: Cabozantinib (receptor tyrosine kinase inhibitor) shows activity 2

Critical caveat: Unknown whether MEK inhibitors modify transformation risk to atypical neurofibromatous neoplasm of uncertain biologic potential (ANNUBP) or MPNST—close monitoring mandatory throughout treatment 2

Surgical Management

For children with growing tumors:

• Debulking surgery considered for visual decline, progressive tumor threatening critical structures, or likely new functional deficits 1
• Conservative approach favors later surgery after growth phase attenuates and disease stabilizes 1

For adults:

• More aggressive/definitive surgical approach before medical therapy, as tumors less likely to continue growing 1
• Always balance present function against risk to future function from surgical intervention 1

Malignant Peripheral Nerve Sheath Tumor (MPNST)

Surgery with clear margins is the cornerstone of treatment, demonstrating benefit even for large abdominal tumors. 2, 4

• Adjuvant chemotherapy and radiation may have a role in non-metastatic disease (though randomized studies lacking) 2, 4
• Advanced/metastatic disease: Doxorubicin plus ifosfamide produces ~21% response rates 2, 4
• High-grade MPNSTs are usually fatal and contribute significantly to NF1 mortality 3
• Lifetime MPNST risk: 8.5% by age 30,12.3% by age 50,15.8% by age 85 3, 4

Atypical Neurofibromatous Neoplasm of Uncertain Biologic Potential (ANNUBP)

Complete surgical resection when feasible, with close surveillance due to uncertain biologic potential. 4

Molecular profiling recommended for all clinically/radiologically worrisome noncutaneous lesions:

• CDKN2A/B inactivation identifies ANNUBP 1
• SUZ12, EED, or TP53 mutations or significant aneuploidy identifies MPNST 1
• Comprehensive next-generation sequencing panel with copy number assessment recommended 1

Cutaneous Neurofibromas

Treatment options for symptomatic lesions include surgical excision, CO2 laser ablation, or electrodesiccation. 1

• CO2 laser: >90% patient satisfaction, minimal pain, good healing, few complications 1
• Electrodesiccation: mean 450 lesions removed per session, minimal scarring, high satisfaction 1
• Cutaneous neurofibromas very rarely, if ever, undergo malignant transformation 1
• Increase during puberty and pregnancy 1

Symptomatic Management

• Pain: routine screening with pain-interference scales, referral to pain clinics for pharmacologic and non-pharmacologic approaches 2
• Migraine, seizures, sleep disorders: standard medications used in general population 2
• Pruritus: often localized to neurofibromas, limited response to emollients or antihistamines 1

Ophthalmologic Complications

For strabismic amblyopia: focus on non-surgical treatment including refractive error correction, occlusion therapy with patching or atropine penalization, and prisms for smaller angle misalignment 1

• Surgical strabismus correction considered if severity precludes effective amblyopia treatment 1
• Conservative approach advocates later surgery once OPPN growth attenuates 1

Bone Health

Vitamin D supplementation recommended to achieve sufficient serum 25-hydroxyvitamin D concentrations. 1

• Osteoporosis occurs earlier and progresses over time in NF1 1
• Treatment follows general population recommendations 1

Pregnancy and Reproductive Counseling

Pregnant women with NF1 require referral to high-risk obstetrician. 1, 2, 3

• Educate about 50% offspring recurrence risk (autosomal dominant inheritance) 1, 2, 3
• Preimplantation genetic diagnosis and prenatal diagnosis available 1, 2, 3
• Preanesthesia neuraxial imaging for spinal/paraspinal neurofibromas probably not needed; consider spinal anesthesia if concerns 1

Contraception considerations:

• Oral estrogen-progestogen or pure progestogen preparations appear safe (89% report no neurofibroma growth) 2
• Avoid high-dose depot contraceptives with synthetic progesterone (3% report significant tumor growth) 2

Multidisciplinary Team Composition

Core team should include: medical genetics, neurology, oncology, ophthalmology, orthopedics, and dermatology 2, 3

Additional specialists as needed: neuro-ophthalmology, oculofacial plastics, craniofacial surgery, pain medicine, high-risk obstetrics 1, 2

Prognostic Considerations

Life expectancy reduced by 8-15 years compared to general population, primarily from malignant neoplasms and cardiovascular causes. 3, 4

• Malignant transformation most commonly occurs in adults, infrequently in head/neck region 1
• Radiation therapy to orbital region is a known risk factor for malignant transformation 1