What is the management approach for lung masses associated with neurofibromatosis (NF)?

Management of Lung Masses Associated with Neurofibromatosis

For lung masses in NF1 patients, prioritize integrated diagnostic evaluation combining imaging characteristics with tissue-based molecular profiling to distinguish benign neurofibromas from atypical lesions (ANNUBP) or malignant peripheral nerve sheath tumors (MPNST), as molecular features now supersede morphology alone in guiding treatment decisions. 1

Initial Diagnostic Approach

Imaging Evaluation

• Obtain high-resolution CT chest to characterize the mass and assess for typical NF1-associated diffuse lung disease patterns (upper-lobe cysts/bullae and basilar interstitial changes) versus discrete mass lesions 2, 3
• FDG-PET or diffusion-weighted MRI should be performed for any suspicious lesion to identify areas of increased metabolic activity or decreased apparent diffusion coefficient (ADC), which suggest malignant transformation 1, 4
• Rapidly growing masses, heterogeneous appearance, irregular margins, or increased vascularity are concerning features warranting urgent evaluation 5

Critical Clinical Context

• Assess for malignant transformation risk factors: new-onset or worsening pain (most important red flag), rapid growth exceeding typical age-related progression, or growth rate faster than expected for patient age 1, 6
• Malignant transformation occurs in 8-13% of NF1 patients cumulatively, with risk increasing to 8.5% by age 30,12.3% by age 50, and 15.8% by age 85 4
• Tracheobronchial neurofibromas can present with airway obstruction symptoms (cough, wheezing, dyspnea) and require bronchoscopy for anatomic definition 7

Tissue Acquisition Strategy

Biopsy Technique (for suspicious lesions)

• Use 14-18G core biopsy needles with image guidance 1, 4
• Obtain minimum of 6 core biopsies if safe and feasible to account for intratumoral heterogeneity 1
• Target multiple radiologically-concerning areas (FDG-PET avid regions, areas with decreased ADC), clearly labeling each biopsy site container separately 1
• Process with no more than 2 cores per formalin-fixed paraffin-embedded block to minimize tissue depletion 1

Pathologic Evaluation

All noncutaneous neurofibromas undergoing biopsy should be screened for molecular features given that referral for biopsy indicates worrisome clinical/radiologic features 1

Histologic Assessment (standardized features to report):

• Cytologic atypia 1
• Loss of neurofibromatous architecture 1
• Hypercellularity 1
• Mitotic count per 10 high-power fields 1
• Presence of necrosis 1

Immunohistochemistry (when tissue sufficient):

• Reduced SOX10 and/or S100 expression (worrisome for higher-grade lesion) 1, 4
• Loss of CD34-positive lattice-like network 1, 4
• Complete loss of p16 expression (suggests CDKN2A/B deletion) 1, 4
• Complete H3K27me3 loss (suggests PRC2 alterations) 1, 4
• Increased p53 immunoreactivity 1, 4

Integrated Molecular Diagnosis

Molecular profiling is mandatory for all clinically or radiologically worrisome noncutaneous lesions to identify diagnostically-relevant features 1, 4

Molecular Classification Framework:

Benign Neurofibroma:

• Lacks worrisome histologic features AND lacks molecular alterations 1

ANNUBP (Atypical Neurofibromatous Neoplasm of Uncertain Biologic Potential):

• Histologic criteria: ≥2 of 4 features (cytologic atypia, loss of architecture, hypercellularity, mitotic index >1/50 HPF but <3/10 HPF) 1, 4
• OR molecular criteria: CDKN2A/B homozygous inactivation (even without worrisome histology) 1
• CDKN2A/B heterozygous inactivation combined with ≥1 histologic feature also qualifies 1

ANNUBP with Increased Proliferation (formerly "low-grade MPNST"):

• ANNUBP features with mitotic index 3-9/10 HPF WITHOUT necrosis 1
• Lacks molecular features sufficient for MPNST diagnosis 1

MPNST (Malignant Peripheral Nerve Sheath Tumor):

• Histologic criteria: ≥10 mitotic figures/10 HPF OR 3-9 mitotic figures/10 HPF combined with necrosis 1
• OR molecular criteria (sufficient even without high-grade histology): SUZ12/EED inactivating mutation, TP53 inactivating mutation, OR significant aneuploidy (segmental gain/loss of ≥8 chromosome arms) 1

Molecular Testing Approach:

• Comprehensive next-generation sequencing panel with copy number and zygosity assessment is recommended 1
• Assess for: CDKN2A/B status, SUZ12, EED, TP53 mutations (ideally biallelic), and aneuploidy 1, 4
• Alternative for limited tissue: targeted panel for SUZ12/EED/TP53 plus array comparative genomic hybridization for copy number analysis 1

Treatment Algorithm

For Benign Neurofibromas:

• Observation if asymptomatic 6
• Surgical excision if causing functional impairment, pain, or significant cosmetic burden 6
• Selumetinib (MEK inhibitor) for symptomatic, inoperable plexiform neurofibromas in patients ≥2 years old (FDA-approved) 6

For ANNUBP:

• Complete surgical resection when feasible with close surveillance due to uncertain biologic potential 4
• Multidisciplinary team evaluation including neuro-oncology, thoracic surgery, and genetics 1, 4

For MPNST:

• Oncologic surgical resection with consideration of neoadjuvant therapy based on molecular features 1
• Extent of resection and treatment intensity guided by molecular profile 1
• Radiation therapy to orbital/thoracic region is a known risk factor for malignant transformation and should be used judiciously 1

Surveillance Strategy

• Annual comprehensive evaluation for all NF1 patients including assessment for signs/symptoms of MPNST, blood pressure measurement, and clinical evaluation 4
• Regular imaging surveillance for known lung masses with interval comparison to detect growth patterns 8
• Immediate evaluation for new-onset severe pain, rapid growth, or new neurologic symptoms 6

Critical Pitfalls to Avoid

• Do not assume lung changes are solely smoking-related in NF1 patients; NF-associated diffuse lung disease (NF-DLD) can develop independent of smoking history 3
• Do not rely on histology alone for diagnosis; molecular features supersede morphologic features in current classification 1
• Do not perform inadequate sampling; heterogeneity within these tumors means single biopsies may miss higher-grade areas 1
• Evaluation by subspecialized pathologist is essential given diagnostic complexity 1
• Subclonal molecular alterations at low frequency still count for integrated MPNST diagnosis 1