Neurofibromatosis is a group of genetic conditions that cause tumors to grow on nerves throughout the body. While the tumors are generally non-cancerous, they can cause significant health issues due to their size, location, and potential to press on nerves or organs. The tumors can often be surgically excised or medically reduced, but because the underlying cause is genetic, the condition itself is a lifelong disorder. Treatment aims to manage symptoms, preserve function, and reduce the overall tumor burden.
Understanding Neurofibromatosis: The Underlying Cause
Neurofibromatosis (NF) arises from a fault in specific genes that normally function to control cell growth and division. Neurofibromatosis Type 1 (NF1) is the most common type, affecting about one in every 3,000 people worldwide. NF1 is caused by a mutation in the NF1 gene on chromosome 17, which provides instructions for the tumor suppressor protein neurofibromin. When this protein is not properly produced, cells multiply uncontrollably along the nerves, leading to the formation of neurofibromas.
Neurofibromatosis Type 2 (NF2) is rarer, affecting about one in 25,000 people, and involves the NF2 gene on chromosome 22, which codes for the tumor suppressor protein merlin. Both NF1 and NF2 result in the growth of tumors along the peripheral nervous system.
The tumors associated with NF1 are primarily neurofibromas, which can be small, discrete lumps on or under the skin (cutaneous neurofibromas) or large, diffuse masses known as plexiform neurofibromas. Plexiform neurofibromas are challenging because they involve multiple nerve branches and can infiltrate surrounding tissues, making complete removal difficult. Because the genetic mutation is present in every cell, the potential for new tumor growth or recurrence remains constant throughout life, even after successful removal.
Surgical Removal of Neurofibromas and Plexiform Tumors
Surgery remains the traditional method for managing specific neurofibromas and plexiform tumors. Excision is generally considered when a tumor causes significant symptoms, such as severe pain, functional impairment (like loss of movement or vision), or disfigurement. Surgery may also be necessary if there is suspicion that a tumor has undergone malignant transformation into a malignant peripheral nerve sheath tumor (MPNST), a rare but serious complication.
For discrete neurofibromas located just under the skin, surgical removal is often straightforward, though there is still a risk of scarring and recurrence. The process is significantly more complex for plexiform neurofibromas due to their diffuse nature. These tumors often wrap around major nerves and blood vessels, meaning that attempting a complete excision carries a high risk of causing permanent neurological deficit or severe disability.
Surgeons frequently aim for a partial or debulking removal rather than a complete cure, especially for large plexiform tumors. This palliative approach is designed to relieve pressure on organs or nerves, reduce pain, or improve cosmetic appearance without sacrificing nerve function. Recurrence is a recognized complication, even when the tumor appears to have been fully removed.
Emerging Medical Therapies for Tumor Reduction
The limitations of surgery, particularly for large or inoperable plexiform neurofibromas, have driven the development of systemic treatments to shrink tumors without a physical incision. These targeted drug therapies focus on the specific molecular pathway overactive in NF1-related tumors. The lack of functional neurofibromin leads to continuous activation of the Ras-MAPK signaling pathway, which drives cell proliferation.
Targeting this pathway, MEK inhibitors have shown significant promise in reducing tumor volume. Selumetinib, an oral MEK inhibitor, was the first drug approved specifically for this purpose in pediatric patients aged two years and older with symptomatic, inoperable plexiform neurofibromas. Clinical trials demonstrated that a substantial percentage of children treated experienced a reduction in tumor volume of 20% or more. This often translates into clinical benefits, including decreased pain, improved motor function, and better quality of life.
Selumetinib works by blocking the activity of the MEK protein, thereby slowing the tumor cells’ uncontrolled growth signals. The drug has also shown efficacy in reducing the burden of spinal neurofibromas, potentially preventing the need for complex spinal surgery in some patients. While not a cure, these systemic therapies offer a major non-surgical option to manage the growth of large, difficult-to-remove tumors.
Monitoring and Managing Recurrence
Because neurofibromatosis is a chronic, progressive genetic condition, management shifts from acute treatment to long-term surveillance once tumors are removed or reduced. The lifelong potential for tumors to regrow or for new ones to emerge requires consistent monitoring. Regular clinical assessments are essential to detect changes in existing tumors or the development of new manifestations.
Surveillance protocols typically involve annual neurological examinations and comprehensive eye exams, especially in children. Magnetic resonance imaging (MRI) is often used to monitor internal tumor burden, particularly for plexiform neurofibromas, and to identify rapid growth that may signal a malignant transformation. Patients are also educated on the signs of a potential malignant change, such as sudden, severe pain or rapid tumor enlargement, which requires immediate evaluation. This proactive management strategy is fundamental to addressing the progressive nature of the condition and ensuring the best possible long-term outcomes.