Diagnosis and management of malignant peripheral nerve sheath tumors: Current practice and future perspectives

Abstract

One of the most common malignancies affecting adults with the neurofibromatosis type 1 (NF1) cancer predisposition syndrome is the malignant peripheral nerve sheath tumor (MPNST), a highly aggressive sarcoma that typically develops from benign plexiform neurofibromas. Approximately 8-13% of individuals with NF1 will develop MPNST during young adulthood. There are few therapeutic options, and the vast majority of people with these cancers will die within 5 years of diagnosis. Despite efforts to understand the pathogenesis of these aggressive tumors, the overall prognosis remains dismal. This manuscript will review the current understanding of the cellular and molecular progression of MPNST, diagnostic workup of patients with these tumors, current treatment paradigms, and investigational treatment options. Additionally, we highlight novel areas of preclinical research, which may lead to future clinical trials. In summary, MPNST remains a diagnostic and therapeutic challenge, and future work is needed to develop novel and rational combinational therapy for these tumors.

Keywords: MPNST; diagnosis; neurofibromatosis; treatment.

Figure 1.

Neurofibromin is a negative RAS regulator. Growth factor binding to cognate receptor tyrosine kinases (EGFR, RTK) or chemokine binding to G-protein coupled receptors (GPCR) lead to activation of RAS and subsequent phosphorylation of downstream RAS effectors, including AKT (mTOR) and RAF (MEK/ERK). Neurofibromin functions in part as a RAS-GTPase activating-related protein that stimulates inherent GTPase activity of RAS, increasing the conversion of active GTP-RAS to inactive GDP-RAS. Loss of neurofibromin leads to increased RAS/RAF effector activity, and greater cell growth. Signals from the microenvironment, HIPPO pathway, Janus kinases, epigenetic regulators, and protein stability pathways also contribute to malignant cell growth. Drugs that have been tested in clinical trials for MPNST are depicted in red alongside their respective targets. Potential drug targets to include in novel combinations for MPNST are depicted in blue alongside the respective targets.

Figure 2.

Genomic Evolution of NF1-MPNST. (A) Patients with NF1 start life with one mutant and one normal copy of the NF1 gene in the cells within their body. (B) Preneoplastic Schwann cell precursors undergo somatic NF1 loss, resulting in bi-allelic NF1 inactivation and benign neurofibroma formation. Factors in the NF1 heterozygous microenvironment also influence tumor formation through the secretion of growth factors, chemokines, and inflammatory mediators. (C) Loss of CDKN2A leads to atypical neurofibroma (AN) formation, and (D) mutations in other genes, including TP53, EGFR, and SUZ12, lead to MPNST formation.