Malignant peripheral nerve sheath tumor pathophysiology

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Marjan Khan M.B.B.S.[2]

Overview

On gross pathology, a large firm mass with necrosis and hemorrhage is the characteristic finding of malignant peripheral nerve sheath tumor. On microscopic histopathological analysis, spindle cells, nuclear atypia, mitoses, and a herring bone pattern are characteristic findings of malignant peripheral nerve sheath tumor. The neurofibromatosis type I (NF1) gene is involved in the pathogenesis of malignant peripheral nerve sheath tumor.

Pathogenesis

• Malignant peripheral nerve sheath tumors are a rare type of cancer that arise from the soft tissue that surrounds nerves. They are a type of sarcoma. Most malignant peripheral nerve sheath tumors arise from the nerve plexuses that distribute nerves into the limbs—the brachial and lumbar plexuses—or from nerves as they arise from the trunk.

Genetics

• The genotypic hallmark of NF1 involves mutations to or other loss of the 350 kilobase gene NF1 on the long arm of chromosome 17, which encodes the tumor suppressor protein neurofibromin.
• NF1 inactivation leads to ras hyperactivity and consequent activation of multiple downstream survival and proliferative pathways, including the mitogen-activated protein kinase (MAPK), mammalian target of rapamycin (mTOR), and AKT (Mouse breed AK thymoma, also termed protein kinase B, or PKB) pathways.
• Molecular pathways from neurofibroma to MPNST in NF1 syndrome remains uncertain, although NF1 deficiency in and of itself is clearly insufficient, given that only approximately 10% of all NF1 patients eventually develop MPNST.

• About half of the cases of malignant peripheral nerve sheath tumor (MPNST) occur along with NF1. The lifetime risk of having both of these conditions is at 8–13% while those with only MPNST have a 0.001% in the general population.

• A recent study in a genetically engineered mouse model showed that EGFR overexpression was sufficient to transform neurofibroma into MPNST via Janus kinase 2/signal transducer and activator of transcription 3 (STAT3) activation.

• Recent studies have demonstrated that there is an overall downregulation of genes in MPNST as compared with neurofibromas

• The NF1 gene locus is on chromosome 17q11.2 and the gene product is neurofibromin, acts as a tumour suppressor; inactivation of the gene thus predisposes to tumour development.
• Necrosis
• Hemorrhage

Microscopic Pathology

• Histologic features of MPNST are rather nonspecific.
• tumors are composed of monotonous spindle cells arranged in intersecting fascicles.
• Hypercellular and hypocellular areas may be present often with hypercellular areas localized in close proximity to blood vessels.
• Malignant peripheral nerve sheath tumors demonstrate a marked increase in tumor cellularity, pleomorphism, and mitotic activity and show a more organized cellular growth pattern, with less extracellular matrix material when compared with benign neurofibromas.
• Malignant peripheral nerve sheath tumors demonstrating skeletal muscle differentiation are particularly aggressive and associated with poor prognosis.
• There is no pathognomonic molecular or immunohistochemical study for malignant peripheral nerve sheath tumors.

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  Malignant peripheral nerve sheath tumor