Neurofibromas are uncommon benign skin tumors that can be solitary but are more commonly found in multiples in patients with neurofibromatosis. Neurofibromatosis is one of the more common genodermatoses, afflicting 1 in every 3000 to 4000 individuals. It is caused by a defective tumor suppressor gene.
Clinical Findings: Neurofibromas are small (up to 1 cm on average) papules or nodules that have a soft, rubbery feel. They are flesh colored to slightly hyperpigmented. When pressed, they show a characteristic “buttonholing” phenomenon, in which the neurofibroma invaginates into the underlying dermis and subcutaneous fat. The neurofibroma returns to its natural location once it is unconfined. Most solitary neurofibromas are asymptomatic. The clinical differential diagnosis is between a neurofibroma and a common acquired melanocytic nevus (compound or intradermal nevus). When multiple neurofibromas are seen in an individual patient, the clinician should look for other signs of neurofibromatosis.
Neurofibromatosis type 1 (previously known as von Recklinghausen disease) is a common genetic systemic disease with cutaneous findings. It is inherited in an autosomal dominant pattern but can also result from a spontaneous mutation. The gene that has been impli- cated, known as NF1, is located on the long arm of chromosome 17 and encodes the tumor suppressor protein, neurofibromin. This guanosine triphosphatase (GTPase) protein is critical in the regulation of the Ras cell signaling pathway. Other forms of neurofibromatosis have been described and show variations of the clinical phenotype. Neurofibromatosis type 2 is caused by a defect in NF2, a gene on the long arm of chromosome 22.
Patients with neurofibromatosis type 1 begin developing neurofibromas at puberty, and the lesions increase in number dramatically over their life span. They are often larger than solitary neurofibromas and can range from a handful to thousands. The sheer number of neurofibromas can cause significant disfigurement and can affect social and psychological well-being. In this genetic disease, neurofibromas can occur not only in the skin but along any nerve in the body. Neurofibromas that occur in areas where there is minimal room for expansion (e.g., in the intervertebral foramen) can cause significant morbidity and need for surgical intervention.
Patients with neurofibromatosis type 1 have many other skin findings, including multiple café-au-lait macules, axillary freckling, and plexiform neurofibromas. Plexiform neurofibromas are a unique variant of the neurofibroma and are considered pathognomonic for this disease. They are composed of multiple indi- vidual neurofibromas grouped into a large plaque. Systemic findings seen in neurofibromatosis include optic gliomas, Lisch nodules on the iris, multiple bony findings, various impairments of the central nervous system, and a number of endocrine disorders. The varying phenotypes of this disease may result from different mutations in the involved gene. These patients are also at much higher risk for malignancy than non-afflicted controls.
Pathogenesis: Solitary neurofibromas have not been found to contain defects in the neurofibromin protein. They arise as a result of unknown factors that cause proliferation within the dermis of all the components of a nerve filament. The neurofibromas found in neurofibromatosis are believed to be caused by the genetic defect in the tumor suppressor gene. How this defect ultimately regulates the formation of neurofibromas is not fully understood.
Histology: Individual neurofibromas have a well- circumscribed, spindle-shaped proliferation within the dermis. No capsule is present. Schwann cell proliferation and proliferation of the axonal components of the nerve are seen. Many mast cells are present in these tumors. The epidermis is uninvolved, and a small grenz zone is often appreciated.
Treatment: Definitive treatment of a solitary neurofibroma is complete excision. This is curative and results in a very low recurrence rate. No treatment is necessary, because the transformation into malignancy is extremely low.
Any neurofibroma that starts growing or becomes hard or tender should be removed to look for degeneration into neurofibrosarcoma.
Patients with neurofibromatosis require a multidisciplinary approach and need to see a good internist to coordinate all the potential systemic complications. The neurofibromas may be removed surgically. This approach is not ideal, because the number of lesions typically precludes removal of only the bothersome ones. Plexiform neurofibromas should be removed by a plastic surgeon, because they can have large subcutaneous extensions that are not visible clinically. There is no cure for this genetic disease; lifelong screening and follow-up are required, and the patient should be referred for genetic counseling before reaching child-bearing age.