What is the evaluation and management approach for peripheral nerve sheath tumors (PNSTs)?

Evaluation and Management of Peripheral Nerve Sheath Tumors (PNSTs)

The optimal management of peripheral nerve sheath tumors requires an integrated diagnostic approach combining histopathologic, immunohistochemical, and molecular features to guide appropriate treatment decisions and improve patient outcomes. 1

Diagnostic Evaluation

Initial Assessment

• Patients with suspected PNSTs should undergo evaluation by a specialized multidisciplinary team, ideally at a dedicated neurofibromatosis clinic, as this approach significantly reduces morbidity and mortality 2
• Concerning clinical features warranting urgent evaluation include:
  • Rapid growth of a preexisting mass
  • Pain (particularly new or worsening)
  • Motor and sensory deficits
  • Mass size >5 cm 3

Imaging Studies

• Ultrasound serves as an excellent initial imaging modality for suspected superficial neurofibromas due to its non-invasive nature 4
• MRI is recommended for:
  • Baseline assessment of known or suspected non-superficial plexiform neurofibromas 2
  • Further characterization of lesions with atypical features on ultrasound 4
  • Note: Standard MRI alone has limited accuracy in distinguishing benign from malignant lesions, with discordant diagnoses between preoperative imaging and postoperative pathology in up to 51% of cases 5
• FDG-PET or diffusion-weighted MRI should be considered for lesions with concerning features to identify areas of increased metabolic activity or decreased apparent diffusion coefficient (ADC) 1

Biopsy Procedure

• For clinically or radiologically suspicious lesions, a standardized biopsy approach is recommended:
  • Use 14-18G biopsy needles
  • Obtain a minimum of 6 core biopsies if safe and feasible
  • Target radiologically concerning but surgically accessible areas
  • Label specimens with specific site of origin 1
• Core biopsies should be divided into multiple blocks with no more than 2 core biopsies per block to minimize tissue depletion 1

Pathological Assessment

• Histologic evaluation should be performed by a subspecialized pathologist 1
• The minimum standardized set of histologic features to assess includes:
  • Cytologic atypia
  • Loss of neurofibromatous architecture
  • Hypercellularity
  • Mitotic count per 10 high-power fields
  • Presence of necrosis 1
• Immunohistochemical stains should be performed when sufficient tissue is available to assess:
  • SOX10 and S100 expression (decreased expression suggests higher-grade lesion)
  • CD34 (loss of lattice-like network suggests malignant transformation)
  • p16 expression (complete loss may correlate with CDKN2A/B deletion)
  • H3K27me3 (loss may indicate alterations to PRC2 proteins)
  • p53 (increased immunoreactivity raises concern)
  • Ki-67 labeling index 1

Molecular Testing

• Molecular profiling is recommended for all clinically or radiologically worrisome noncutaneous lesions in patients with NF1 1
• Key molecular features to assess include:
  • CDKN2A/B homozygous or heterozygous inactivation (diagnostic of ANNUBP)
  • SUZ12, EED, or TP53 inactivating mutations (diagnostic of MPNST)
  • Significant aneuploidy (diagnostic of MPNST) 1
• When tissue is limited, a targeted sequencing panel assessing SUZ12, EED, and TP53 mutations along with array comparative genomic hybridization for copy number analysis is recommended 1

Management Approach

Benign PNSTs (Neurofibromas, Schwannomas)

• Complete surgical resection should be attempted where possible, as subtotal resection is associated with increased recurrence 6
• The extent of resection is influenced by tumor location and histopathology 6
• Patients with genetic predisposition syndromes (NF1, NF3) have higher recurrence rates even with complete resection 6

Atypical Neurofibromatous Neoplasm of Uncertain Biologic Potential (ANNUBP)

• Defined by the presence of at least 2 of the following features:
  • Cytologic atypia
  • Loss of neurofibroma architecture
  • Hypercellularity
  • Mitotic count >1/50 high-power fields but <3/10 high-power fields 1
• Complete surgical resection is recommended when feasible 6
• Close surveillance is warranted due to uncertain biologic potential 1

Malignant Peripheral Nerve Sheath Tumors (MPNSTs)

• Complete surgical resection with negative margins is the only known curative therapy 7
• Adjuvant radiation therapy is recommended for:
  • Larger lesions
  • Tumors with aggressive histology
  • Cases with positive surgical margins 7
• Multimodal approach is necessary for optimal management 6
• Prognosis is poor with 5-year survival rates of 15-50% 3

Surveillance and Follow-up

• Annual general medical evaluation is recommended for patients with NF1, including:
  • Assessment for signs/symptoms of MPNST
  • Evaluation for pheochromocytoma
  • Screening for neuropathy
  • Assessment for depression and chronic pain
  • Blood pressure measurement
  • Clinical evaluation for scoliosis 2
• For women with NF1, annual mammogram starting at age 30 and consideration of breast MRI with contrast between ages 30-50 is recommended 2

Special Considerations

• The risk of NF1-associated MPNST increases with age: 8.5% by age 30,12.3% by age 50, and 15.8% by age 85 2
• Life expectancy in NF1 is reduced by 8-15 years compared to the general population, primarily due to malignant neoplasms and cardiovascular causes 2
• Pregnant women with NF1 should be referred to a high-risk obstetrician and educated about the 50% offspring recurrence risk 2