Malignant peripheral nerve sheath tumors

Abstract

Malignant peripheral nerve sheath tumors (MPNST) are uncommon, biologically aggressive soft tissue sarcomas of neural origin that pose tremendous challenges to effective therapy. In 50% of cases, they occur in the context of neurofibromatosis type I, characterized by loss of function mutations to the tumor suppressor neurofibromin; the remainder arise sporadically or following radiation therapy. Prognosis is generally poor, with high rates of relapse following multimodality therapy in early disease, low response rates to cytotoxic chemotherapy in advanced disease, and propensity for rapid disease progression and high mortality. The last few years have seen an explosion in data surrounding the potential molecular drivers and targets for therapy above and beyond neurofibromin loss. These data span multiple nodes at various levels of cellular control, including major signal transduction pathways, angiogenesis, apoptosis, mitosis, and epigenetics. These include classical cancer-driving genetic aberrations such as TP53 and phosphatase and tensin homolog (PTEN) loss of function, and upregulation of mitogen-activated protein kinase (MAPK) and (mechanistic) target of rapamycin (TOR) pathways, as well as less ubiquitous molecular abnormalities involving inhibitors of apoptosis proteins, aurora kinases, and the Wingless/int (Wnt) signaling pathway. We review the current understanding of MPNST biology, current best practices of management, and recent research developments in this disease, with a view to informing future advancements in patient care.

Keywords: Clinical trials; Malignant peripheral nerve sheath tumor; Molecular targeted therapy; Neurofibromatosis type 1; Sarcoma.

Figure 1.

Radiological findings in malignant peripheral nerve sheath tumors (MPNST). (A): 24-year-old male with neurofibromatosis type 1 presenting with large thigh mass. Contrast MRI revealed dominant mass within the left vastus medialis muscle with heterogeneous signal intensity and enhancement with areas of central necrosis. Biopsy confirmed MPNST, for which he underwent local resection and adjuvant RT. (B): 45-year-old male presenting with thoracic cord compression. Magnetic resonance imaging revealed a homogeneously enhancing mass within the right posterior mediastinum extending through the right T3-T4 neural foramen into the spinal canal with associated compression of the spinal cord. Biopsy confirmed MPNST; he underwent extensive resection and adjuvant radiotherapy.

Figure 2.

Histopathologic features of (A): Low power view (×20) of MPNST demonstrating variable hypo- and hypercellular areas. (B): Low power view (×40) showing more cellular MPNST with scattered pleomorphic cells. (C): Moderate power view (×100) showing hypercellular area with intersecting fascicles of monotonous spindle cells.

Figure 3.

Pathways and potential targets in malignant peripheral nerve sheath tumors (MPNST). Depicted in this cartoon are the multiple nodes implicated in the pathogenesis of MPNST, involving intracellular signaling pathways, epigenetic regulation, mitosis, angiogenesis and interactions with the tumor environment. Alongside these nodes are indicated the currently available classes of pharmacological agents that can act upon them, thence potentially retarding tumor growth and bringing therapeutic benefit. Abbreviations: EGFR, epidermal growth factor receptor; VEGF, vascular endothelial growth factor; VEGF R1/R2, vascular endothelial growth factor receptor 1/2; RAF, rapidly accelerated fibrosarcoma; MAPK, mitogen-activated protein kinase; MEK, mitogen-activated protein kinase/extracellular signal-regulated kinase kinase; IAP, inhibitor of apoptotic proteins; HDAC, Histone deacetylase; ERK, extracellular-signal-regulated kinase; PI3K, phosphatidyl inositol 3-kinase; AKT, mouse strain AK thymoma; TOR, (mechanistic) target of rapamycin; PTEN, phosphatase and tensin homolog.