Malignant peripheral nerve sheath tumour (MPNST)

Malignant peripheral nerve sheath tumour arises from Schwann cell lineage in a peripheral nerve or a pre-existing neurofibroma, sporadically, after radiotherapy or, in half of cases, in neurofibromatosis type 1, where atypical neurofibromatous neoplasms of uncertain biological potential are the recognised precursor. Its genome shows loss of NF1, then CDKN2A, then the polycomb repressive complex 2 components SUZ12 or EED, producing global loss of H3K27 trimethylation that pathologists now use as a diagnostic marker, alongside TP53 loss in high-grade tumours.

Treatment of localised disease is wide resection with radiotherapy, which controls local disease but does not prevent metastasis; the tumours are large, deep and often involve major nerves and the spine, so margins are frequently compromised. Chemotherapy activity is modest: the SARC006 phase 2 trial of neoadjuvant doxorubicin-ifosfamide followed by ifosfamide-etoposide produced responses in a minority, more often in sporadic than NF1-associated tumours, and adjuvant chemotherapy is offered to fit patients with high-grade disease on the general sarcoma evidence.

Targeted approaches follow the biology: MEK inhibitors such as selumetinib and mirdametinib, approved for the precursor plexiform neurofibromas, are being combined with mTOR inhibitors (SARC031) and other agents in MPNST; PRC2 loss confers sensitivity to some epigenetic and DNA-damaging strategies in models; and surveillance of people with neurofibromatosis by whole-body MRI and PET to catch transformation early is the most practical current advance.