Cancer of the Peripheral Nerve in Neurofibromatosis Type 1

Abstract

The RASopathy neurofibromatosis 1 is an autosomal dominant hereditary cancer syndrome that represents a major risk for the development of malignancies, particularly malignant peripheral nerve sheath tumors (MPNSTs). MPNSTs are unique sarcomas that originate from the peripheral nerve and represent the only primary cancer of the peripheral nervous system. To date, surgery is the only treatment modality proven to have survival benefit for MPNSTs and even when maximal surgery is feasible, these tumors are rarely curable, despite the use of chemotherapy and radiation. In this review, we discuss the current state-of-the-art treatments for MPNSTs, latest therapeutic developments, and critical aspects of the underlying molecular and pathophysiology that appear promising for therapeutic developments in the future. In particular, we discuss the specific elements of cancer in the peripheral nerve and how that may impel development of unique therapies for this form of sarcoma.

Keywords: Chemoprevention; Malignant peripheral nerve sheath tumor; Malignant transformation; Neurofibromatosis; Sarcoma; Treatment.

Fig. 1

Plexiform neurofibroma involving the right brachial plexus. Multiple nerve sheath tumors (neurofibromas) at each level of the cervical spine and extending through the brachial plexus

Fig. 2

Imaging features of various peripheral nerve sheath tumors in the left leg of a person with neurofibromatosis 1 (NF1). (A) T2-weighted image with fat saturation sequence showing increased signal, the anterior lesion with poorly defined boundaries (white arrowhead), and the posterior with well-demarcated boundaries (green arrowhead). (B) Apparent diffusion coefficient (ADC) imaging shows low signal and a quantified minimum ADC of only 0.2 × 10^–3/mm²/s in the anterior lesion (white arrowhead) compared with the posterior lesion with a normal minimum ADC value of 2.1 × 10^–3/mm²/s (green arrowhead). (C) Fluorodeoxyglucose (FDG) positron emission tomography of the anterior lesion demonstrates an increased SUV_max of 6.4 (white arrowhead), while the posterior lesion shows no significant FDG uptake (green arrowhead)

Fig. 3

Schematic overview of underlying pathophysiology and targeted therapies in neurofibromatosis 1 (NF1)-associated malignant peripheral nerve sheath tumors (MPNSTs). MPNSTs arise from plexiform neurofibromas (pNFs) via a stepwise malignant transformation process that includes the loss of NF1 (gray box), deletion of CDKN2A, and loss of TP53 and PRC2. The hyperactivation of the Ras pathway and acquired epigenetic alterations provide therapeutic targets for various molecule inhibitors (yellow boxes) GPCR = G-protein coupled receptor; RTK = receptor tyrosine kinase; HSP = heat shock protein; MEK = mitogen-activated protein kinase; ERK = extracelluar regulated kinase; PI3K = phosphatidylinositol 3-kinase; AKT = protein kinase B; mTOR = mammalian target of rapamycin; AURKA = Aurora kinase A; BET = bromodomain and extraterminal; PRC2 = polycomb repressive complex 2; aNF = atypical neurofibroma; pNF = plexiform neurofibroma