Malignant Peripheral Nerve Sheath Tumour

Malignant peripheral nerve sheath tumour (MPNST) is an aggressive spindle cell sarcoma that arises from a peripheral nerve, from a pre-existing neurofibroma, or de novo, with nerve sheath differentiation. About half are associated with neurofibromatosis type 1 (NF1).

It makes up 5% to 10% of soft tissue sarcomas. Lifetime risk in NF1 is about 8% to 13%, with onset at 20 to 40 years. Sporadic tumours present at 40 to 60 years. About 10% follow radiotherapy after a latency of years.

Common sites are the trunk, limbs (sciatic nerve, brachial plexus) and head and neck. A plexiform neurofibroma or an atypical neurofibromatous neoplasm of uncertain biological potential is the usual precursor in NF1.

Pathophysiology. Biallelic NF1 loss activates RAS signalling. Progression needs CDKN2A and CDKN2B loss and inactivation of the PRC2 complex (EED or SUZ12), which leads to loss of H3K27me3 staining in a majority of tumours. TP53 alterations are frequent.

Grade. Most tumours are high grade, with hypercellular fascicles, nuclear atypia, mitoses and necrosis (the marbled pattern is typical).

Behaviour. Local recurrence occurs in 30% to 50% and distant metastasis in 40% to 60% (lung first, then liver, bone and brain). Five year survival is about 40% to 50%, and lower in NF1-associated tumours (about 20% to 40%). Size over 5 cm and incomplete resection worsen outcome.

• Enlarging mass along a nerve, or growth of a known neurofibroma, with pain and tenderness.
• Neurological deficit, paraesthesia or radiating pain along the nerve distribution.
• Large, deep tumours of the trunk or retroperitoneum may be silent until late.

Red flags (in NF1).

• New persistent pain, especially nocturnal pain or pain unrelated to activity.
• Rapid growth, a change from soft to hard consistency, or growth over a few weeks to months.
• New or progressive neurological deficit.
• A neurofibroma over 5 cm with loss of the target sign on imaging.

• MRI of the lesion and the nerve: heterogeneous mass with necrosis, loss of the target sign, perilesional oedema and irregular borders. Whole body MRI in NF1 identifies the lesions that need follow up.
• FDG-PET: SUVmax over about 3.5 favours malignancy in an NF1 neurofibroma, and the area of highest uptake is the target for biopsy.
• Image targeted core biopsy. Immunohistochemistry: S100 is focal or absent in many tumours, SOX10 variable, H3K27me3 loss supports the diagnosis in sporadic and NF1 tumours, and CD34 may be positive.
• Staging with CT chest, and imaging of the abdomen and pelvis for deep lesions. MRI brain only for symptoms.
• Genetic assessment: NF1 diagnosis by clinical criteria and NF1 variant testing when uncertain.

Differential diagnosis.

• Neurofibroma, plexiform neurofibroma and atypical neurofibromatous neoplasm of uncertain biological potential
• Cellular schwannoma
• Synovial sarcoma and fibrosarcoma
• Undifferentiated pleomorphic sarcoma
• Spindle cell melanoma
• Leiomyosarcoma and dedifferentiated liposarcoma
• Dermatofibrosarcoma protuberans and desmoid type fibromatosis

Localised disease. Wide excision with negative margins is the only curative treatment, with sacrifice of the involved nerve and amputation for extensive limb disease.

• Radiotherapy: preoperative 50 Gy in 25 fractions, or postoperative 60 Gy in 30 fractions (66 Gy for positive margins). In NF1 the second malignancy risk is higher, so the benefit is weighed against it.
• Adjuvant chemotherapy is considered for large (over 5 cm) high grade tumours in fit patients, with limited evidence of benefit.

Advanced disease.

• Doxorubicin:
  • 75 mg/m2 IV every 3 weeks for up to 6 cycles.
  • Maximum cumulative working ceiling 450 mg/m2.
  • Monitoring: echocardiography at baseline and every 2 cycles, FBC before each cycle.
  • Adjustment: bilirubin 20 to 51 micromol/L reduce by 50%, 53 to 85 micromol/L reduce by 75%, over 85 micromol/L avoid.
  • Consider reduction when eGFR is under 30 mL/min/1.73 m2.
• Doxorubicin with ifosfamide (fit patients needing a response):
  • Doxorubicin 75 mg/m2 total each cycle (25 mg/m2 daily on days 1 to 3) with ifosfamide 10 g/m2 total (2.5 g/m2 daily on days 1 to 4) IV.
  • Mesna at a total of 60% to 100% of the ifosfamide dose.
  • Pegfilgrastim 6 mg subcutaneously 24 to 72 hours after chemotherapy.
  • Repeat every 3 weeks for up to 6 cycles.
  • Maximum doxorubicin cumulative working ceiling 450 mg/m2 and ifosfamide 10 g/m2 each cycle.
  • Monitoring: FBC, creatinine, urinalysis for haematuria, neurological status (ifosfamide encephalopathy), echocardiography.
  • Adjustment: avoid ifosfamide when eGFR is under 30 mL/min/1.73 m2 and reduce by about 25% to 50% when it is 30 to 59.
  • Stop for grade 2 neurotoxicity.
  • Reduce doxorubicin for hepatic impairment (bilirubin 20 to 51 micromol/L by 50%, 53 to 85 micromol/L by 75%, over 85 micromol/L avoid).
• Response rates are modest (about 20% to 30% with combination therapy), and MEK inhibitors used for plexiform neurofibroma have not been established in MPNST.
• Resection or stereotactic radiotherapy of limited metastases.

Monitoring. After resection, MRI of the site every 3 to 4 months for 2 years, then 6 monthly to year 5. CT chest at the same intervals. In NF1, annual clinical review with imaging of lesions that change.

Referral and escalation.

• Urgent sarcoma centre referral of any NF1 patient with a red flag, before any biopsy or excision.
• Genetic counselling for NF1 families.

Special groups.

• NF1: radiotherapy and DNA-damaging chemotherapy raise second tumour risk, and surveillance is lifelong.
• Children and adolescents: manage in a paediatric sarcoma centre.
• Pregnancy: neurofibromas can grow rapidly. Biopsy any lesion that changes quickly.