Synonyms

• Neurofibroma with atypia
• premalignant neurofibroma

Category

Soft tissue

Behaviour

Intermediate

Gender

Both equally

Tissue of Origin

Neural

Epidemiology

• Rare; occurs predominantly in NF1 patients
• Risk of malignant transformation to MPNST
• May arise in plexiform neurofibromas
• Poorly defined entity in current literature

Clinical Features

• Pain or rapid growth in previously stable neurofibroma (red flag)
• Associated with NF1 stigmata (café-au-lait spots, axillary freckling)
• Neurological deficits if large nerve involvement
• Often impossible to distinguish from MPNST clinically

Location

• Deep soft tissue along major nerve trunks
• Any location typical for neurofibroma
• Paravertebral and retroperitoneal in NF1

Imaging

• Fusiform nerve sheath mass on MRI
• Loss of target sign (seen in Benign neurofibroma) may indicate atypia
• High SUV on FDG-PET suggests Malignant transformation
• MRI cannot reliably distinguish atypical from Malignant PNST

Pathology

• Neurofibroma with focal or diffuse nuclear enlargement and hyperchromasia
• Increased cellularity
• Rare mitotic figures
• No necrosis (distinguishes from MPNST)

Genetics

• CDKN2A deletion in 50% - marker of malignant potential
• Loss of H3K27me3 expression in 50%
• Retains S100 positivity unlike High-grade MPNST
• NF1 mutation (germline or somatic) as background

Treatment

• Wide local excision recommended
• Close surveillance given Malignant potential
• No established chemotherapy role for atypical neurofibroma alone

Prognosis

• Intermediate - risk of progression to MPNST
• Estimated 10-year risk of transformation 10–30% in NF1
• Complete excision with negative margins is primary goal

Key Points

• Represents a spectrum between Benign neurofibroma and MPNST
• CDKN2A loss and H3K27me3 loss are molecular markers of progression
• FDG-PET useful to identify lesions at Highest risk of Malignant transformation in NF1
• Diagnosis requires careful pathological assessment

Workup - Blood Tests

• FBC, U&E, LFTs - baseline
• No specific tumour markers

Workup - Local Imaging

MRI primary site

Workup - Biopsy

• Core needle biopsy - multiple cores to capture most cellular/atypical region
• Immunohistochemistry: S100+, SOX10+, H3K27me3 (loss suggests progression toward MPNST)
• CDKN2A FISH - deletion present in 50%; marker of Malignant potential
• Molecular profiling if clinical behaviour suggests High-grade transformation

Workup - Staging

• FDG-PET-CT - for NF1 patients to survey all plexiform neurofibromas simultaneously
• CT chest if MPNST transformation suspected

Workup - Other

• Genetics/NF1 specialist referral if not already under NF1 service
• MDT review at soft tissue sarcoma centre

Follow-up Summary

• ntermediate soft tissue/nerve sheath tumour with Malignant potential - Follow-up required
• Post-op visit at 6 weeks
• Year 1–2: 6-monthly clinical review; MRI primary site if incompletely excised or NF1 context
• FDG-PET surveillance for NF1 patients with residual plexiform neurofibromas - monitor for MPNST transformation
• If NF1: annual clinical review; FDG-PET if new symptoms or rapid growth of neurofibroma
• Advise patient on red flags for MPNST transformation: rapid growth, new neurological deficit, pain
• Genetics referral for NF1 patients if not already under specialist NF1 service