Neurofibromatosis type 1 (NF-1) is an autosomal-dominant disorder that occurs in approximately 1 in 3,000 births and affects males and females equally.1
Patients with NF-1 can have café-au-lait spots, Lisch nodules, cognitive impairment, axillary and/or inguinal freckling, bony deformities, and cutaneous neurofibromas. Aside from these clinical findings, patients with NF-1 are also at higher risk for both benign and malignant neoplasms, especially in the nervous system, muscles, skin, and gastrointestinal tract.
The exact incidence varies between studies, however, as many as 15% of patients with NF-1 will be diagnosed with a malignancy, which is as high as four-times the risk of a person without NF-1.1,2
Patients with NF-1 have a mutation in the NF1 gene, which is located on chromosome 17 (17q11.2). This mutation leads to lower expression of neurofibromin, which normally functions as a tumor suppressor and negative regulator of the RAS pathway.3
Deregulation of the RAS pathway by neurofibromin leads to activation of the AKT/mTOR and mitogen-activated protein kinase pathways resulting in amplified cell proliferation.3 Although the exact effect of neurofibromin on these pathways is not entirely understood, it represents a potential pharmacologic target for future clinical trials that are currently under development.
The most striking clinical feature in patients with NF-1 is typically diffuse peripheral neurofibromas, which are typically benign. The benign neurofibromas can undergo malignant transformation into malignant peripheral nerve sheath tumors (MPNSTs), which are considered relatively aggressive tumors.
These lesions typically increase in size out of proportion to other neurofibromas and can be painful, which is not typical of benign neurofibromas. Depending on the location of the MPNSTs, patients can also present with new neurologic findings.
Patients with NF-1 who develop MPNSTs are more likely to present at a younger age compared with patients without NF-1.2 MPNSTs are extremely difficult to treat and often metastasize to the lung, bone, peritoneum, brain, kidneys, and liver early in their course.
The most common central nervous system tumors seen in patients with NF-1 are optic gliomas, which are typically diagnosed in childhood. Both diagnosis and treatment is challenging based on their slow-growing nature.2 Patients with NF-1 are also at higher risk to develop leukemia including non-Hodgkin lymphoma, acute lymphoblastic leukemia, and chronic myelomonocytic leukemia.2
Patients with NF-1 and gastrointestinal tumors are most likely to have gastrointestinal stromal tumors, carcinoid tumors, and hyperplasia of the intestinal submucosal plexuses.1
Patients with NF-1 have many challenging medical issues, of which the risk of malignancy represents one of the most important. The medical management of these patients requires a multidisciplinary approach and should include an emphasis of the early detection of malignancies based on their history, physical exam, and diagnostic tests.
- Relles D, Baek J, Witkiewicz A, Yeo CJ. Periampullary and duodenal neoplasms in neurofibromatosis type 1: two cases and an updated 20-year review of the literature yielding 76 cases. J Gastrointest Surg. 2010;14(6):1052-1061.
- Korf BR. Malignancy in neurofibromatosis type 1. Oncologist. 2000;5(6):477-485.
- Le LQ, Parada LF. Tumor microenvironment and neurofibromatosis type I: connecting the GAPs. Oncogene. 2007;26(32):4609-4616.