What are the characteristics of Neurofibromatosis (NF) in Oncology?

From the Guidelines

Neurofibromatosis (NF) is a genetic disorder characterized by the development of tumors throughout the nervous system, with a high risk of developing malignant peripheral nerve sheath tumors (MPNST), particularly in NF1 patients, and requires a multidisciplinary approach with regular monitoring and advanced imaging modalities such as whole-body magnetic resonance imaging (WB-MRI) for early detection and treatment. The characteristics of NF in oncology include the development of MPNST, a type of soft-tissue sarcoma, which frequently arises from a pre-existing plexiform neurofibroma (PN) in NF1 patients 1. Key features of MPNST include:

• Low-grade MPNST accounts for ~ 5% of NF1-associated MPNST and is associated with a 100% ten-year survival, in contrast with high-grade tumors (~20% 5-year survival) 1
• Surgery remains the cornerstone of treatment for high-grade MPNST, with the aim of achieving clear margins 1
• Advanced imaging modalities such as WB-MRI have proven their efficacy in detecting number, volume, and distribution of neurofibromas in NF patients, and may play a role in the early detection of MPNST 1
• The optimal use, timing, and utility of 18F-fluorodeoxyglucose positron emission tomography (18F-FDG PET), PET/CT, and MRI (whole-body and focused studies) to screen for MPNST are not known, but a sensitivity of 0.89 and a specificity of 0.95 have been reported for 18 F-FDG-PET and PET/CT in diagnosing NF1-associated MPNST 1
• Regular follow-up with specialists including neurologists, oncologists, ophthalmologists, and orthopedists is crucial for early intervention of complications, and genetic counseling is important as NF has a 50% inheritance risk 1

From the Research

Characteristics of Neurofibromatosis (NF) in Oncology

• Neurofibromatosis type 1 (NF1) is associated with a high risk of developing malignant peripheral nerve sheath tumors (MPNSTs) 2, 3, 4, 5.
• Almost all individuals with NF1 develop peripheral nerve sheath tumors (PNSTs), mainly benign neurofibromas, but about 10% of PNSTs will undergo transformation to MPNSTs 2.
• NF1 PNTs present some peculiarities, including a large prevalence of neurofibromas, the presence of pathognomonic tumoral forms (plexiform neurofibromas), and a higher incidence and earlier age of onset of MPNSTs 3.
• The lifetime risk of developing MPNSTs in NF1 patients is estimated to be 8-13% 3, 4.
• MPNSTs in NF1 patients tend to have a poor prognosis and do not respond to standard chemotherapy or radiation therapy 4, 5.
• Early diagnosis and surgery are considered the most effective treatment for MPNSTs, but early diagnosis is often hampered by the frequent occurrence of MPNSTs within preexisting large tumors 4, 5.

Treatment Options for NF1-Associated Tumors

• Surgical treatment of PNSTs has traditionally been regarded as a standard approach, but new agents that target specific molecular pathways involved in the pathogenesis of PNST have led to a number of clinical trials 2.
• Inhibitors of the mitogen-activated protein kinase (MEK) have shown promising results in clinical trials for the treatment of symptomatic plexiform neurofibromas in NF1 patients 6.
• However, MEK inhibitors do not work in all patients and have significant side effects, and preliminary evidence suggests that single agent use of MEK inhibitors for MPNST treatment will fail 6.
• New approaches, such as exploiting drug screening and synthetic lethality with NF1 loss of function mutations in human Schwann cells using CRISPR/Cas9 technology, are being explored to find targets other than MEK for treatment of MPNSTs 6.