New Frontiers in Therapy of Peripheral Nerve Sheath Tumors in Patients With Neurofibromatosis Type 1: Latest Evidence and Clinical Implications

Abstract

Almost all individuals with neurofibromatosis type 1 (NF1) develop peripheral nerve sheath tumors (PNSTs), mainly benign neurofibromas, however about 10% of PNSTs will undergo transformation to malignant peripheral nerve sheath tumors (MPNSTs). Surgical treatment of PNSTs has traditionally been regarded as a standard approach. The availability of new agents that target specific molecular pathways involved in the pathogenesis of PNST has led to a number of clinical trials, which resulted in increased chances for better survival and quality of life. This review presents the latest evidence and clinical implications for new therapies of PNSTs in patients with NF1 emphasizing the potential benefit from the use of Ras/MAPK pathway inhibitors, immunotherapy, chemotherapy or radiation therapy. We present evaluation of current knowledge on available treatment modalities. Neurofibromatosis type 1 (NF1) is an autosomal dominant neurocutaneous disease affecting about 1 in 3500 people worldwide (1). The hallmark clinical features of NF1 include multiple café-au-lait macules, neurofibromas, intertriginous freckling, osseous lesions, Lisch nodules and optic pathway gliomas. The disorder is typified by the presence of multisystem tumors, which carries a high risk of malignant transformation (2, 3). Nearly 100% of individuals with NF1 develop benign peripheral nerve sheath tumors (BPNSTs) and in approximately 30-50% of them atypical and plexiform neurofibromas (PNFs) are found. In about 10% of NF1 patients, neurofibromas may undergo transformation to malignant peripheral nerve sheath tumors (MPNSTs), which are highly aggressive. The differentiation between atypical neurofibroma and low grade MPNST is probably the most challenging issue in the pathology of peripheral nerve sheath tumors (PNSTs), particularly in NF1 patients. Clinically, atypical tumors often develop as extensive, slowly growing neoplasms, and pain can be a characteristic feature (4, 5). The poor response to currently available therapies underlines the need for more effective, targeted treatment methods for NF1-associated PNSTs (6, 7). In this review, we analyzed the latest evidence and clinical implications of new therapies of PNSTs in patients with NF1 emphasizing the importance of patient risk stratification to identify those who are likely to benefit from the use of Ras/MAPK pathway inhibitors, immunotherapy, chemotherapy or radiotherapy. We also analyzed the limitations of administering these therapies to all individuals with NF1-associated PNSTs together with future perspectives. Methodology PubMed searches were performed to identify potentially clinically relevant English-language studies published in the last 15 years. The searches were based on a combination of indexed terms and free text terms ("peripheral nerve sheath tumors"

Understanding the Biological Activities of Vitamin D in Type 1 Neurofibromatosis: New Insights into Disease Pathogenesis and Therapeutic Design

“…Optic gliomas usually require chemotherapeutic treatment agents, such as vincristine or carboplatin [ 377 ]. MPNSTs are best treated by surgery and/or radiation therapy [ 319 , 323 , 378 ].…”

Increased nuclear translation of YAP might act as a potential therapeutic target for NF1-related plexiform neurofibroma

“…Among diverse inhibitors applied in clinical trials related to pNF, the selective inhibitor for MEK1/2 selumetinib (AZD6244, ARRY-142886) is the only treatment available for children with symptomatic pNF approved by the FDA [6]. Compelled by the efficiency of selumetinib, selumetinib and other MEK inhibitors have also been gradually included in clinical trials for adolescents or adults with inoperable pNF [24]. With application in additional clinical trials, the deficiencies and side reactions of selumetinib have also received additional attention.…”

Impact of Multimodality Imaging to Improve Radiation Therapy (RT) Target Volume Definition for Malignant Peripheral Nerve Sheath Tumor (MPNST)

“…An enlarging mass may be present with weakness, paresthesia, and pain symptoms. Surgery, RT, and systemic agents are among the therapeutic options with ongoing extensive research for optimal management of MPNST [7][8][9][10][11]. RT has been utilized for management of selected patients with MPNST [9][10][11].…”