Are You Confident of the Diagnosis?
Neurofibromas are benign tumors of the peripheral nerve sheath. Neurofibromas present as slow-growing tumors. They typically appear after puberty. They are generally asymptomatic, but may become painful, irritated, or pruritic.
Characteristic findings on physical examination
Neurofibromas may be solitary (Figure 1, most common) or multiple (Figure 2). Multiple tumors are should raise the possibility of neurofibromatosis type 1 (NF1). Two or more neurofibromas fulfills one of the seven National Institutes of Health (NIH) diagnostic criteria for NF1. These tumors can occur anywhere, but are most common on the trunk, followed by the head and neck. When multiple they can be seen in a segmental or widespread distribution. Cutaneous neurofibromas may be dermal or subcutaneous (Figure 3, Figure 4).
Dermal neurofibromas appear as soft, flesh-colored to pink or brown, exophytic papules or nodules. They may become pedunculated. Dermal neurofibromas may also present as more subtle blue or violaceous macules or slightly raised papulonodules. The tumors are easily invaginated (“buttonhole sign”). Subcutaneous neurofibromas present as firm, spherical subcutaneous nodules that are frequently painful.
Plexiform neurofibromas (Figure 5) are a distinctive type of neurofibroma. This type of neurofibroma grows along the length of the nerve and often involves multiple fascicles. Most plexiform neurofibromas are congenital or appear early in life. The significance of a plexiform neurofibroma is that it is most often seen in the setting of NF1. Having a single plexiform neurofibroma fulfills one of the seven NIH diagnostic criteria for NF1. It is estimated that 25% to 30% of patients with NF1 have either a superficial or deep plexiform neurofibroma. Superficial plexiform neurofibromas present as infiltrated plaques. Overlying hyperpigmentation, hypertrichosis and vascular staining are common. Plexiform neurofibromas can be associated with overgrowth of soft tissue or bone. They can become quite large and disfiguring.
Expected results of diagnostic studies
The diagnosis of a neurofibroma can usually be suspected clinically, but a skin biopsy is confirmatory. If a skin biopsy from a cutaneous neurofibroma is done, one sees a non-encapsulated tumor composed of fascicles of slender, spindle-shaped cells (Figure 6). The surrounding matrix is pale staining with delicate, wavy collagen. These tumors also show increased numbers of mast cells and stain positive for S100 protein. Subcutaneous and plexiform meurofibromas are often encapsulated, surrounded by perineurium or epineurium. They contain numerous large nerve fasicles embedded in a cellular matrix containing mucin, collagen, fibroblasts and Schwann cells. Magnetic resonance imaging (MRI) may be necessary with plexiform neurofibromas to define the extent of involvement. Genetic testing for NF1 is available if clinical suspicion exists, but clinical criteria are not met.
The differential diagnosis for a cutaneous neurofibroma includes: (1) dermal melanocytic nevus; (2) neuroma; (3) lipoma; (4) fibroma and (5) acrochordon. Biopsy can usually differentiate these conditions from neurofibromas. Completely neurotized melanocytic nevi can look identical to neurofibromas, but the latter should stain with antibodies directed against factor XIIIa, glial fibrillary acidic protein, and myelin basic protein. The differential diagnosis for a plexiform neurofibroma is: (1) congenital melanocytic nevus (hyperpigmentation and hypertrichosis common in both, a plexiform neurofibroma would have a more rope-like feel on palpation); (2) Klippel-Trenaunay syndrome (overgrowth and vascular staining can cause confusion, Klippel-Trenaunay is also associated with venous and lymphatic malformations); and (3) Proteus syndrome (overgrowth can cause confusion, Proteus has connective tissue nevi and lipomas, but not neurofibromas).
Who is at Risk for Developing this Disease?
Neurofibromas are typically seen in adults. There is no racial or sex predilection. Solitary neurofibromas are common. Multiple neurofibromas are most frequently seen in NF1. Neurofibromas may increase in number and size during puberty and pregnancy. Plexiform neurofibromas are often congenital and almost always associated with NF1. A recent study found that 116 out of 124 plexiform neurofibromas were seen in patients with NF1. The remaining 8 lesions were seen in patients with no evidence of NF1.
What is the Cause of the Disease?
Neurofibromas are complex proliferations of Schwann cells, perineural cells, fibroblasts and mast cells. NF1-associated neurofibromas are caused by a germline mutation in the NF1 gene followed by loss of the wild-type allele.
NF1 is located on chromosome 17q11.2 and encodes a tumor suppressor protein, neurofibromin. Loss of neurofibromin leads to activation of the RAS-MAPK pathway and tumor formation. The etiology of sporadic neurofibromas is unknown.
Systemic Implications and Complications
Solitary neurofibromas are benign and not associated with any systemic complications. The risk of transformation of solitary dermal neurofibromas into malignant peripheral nerve sheath tumors is exceedingly rare. Multiple neurofibromas are a marker for NF1. Plexiform neurofibromas are most commonly seen in NF1. Plexiform neurofibromas can infiltrate surrounding tissues and impinge on vital structures. Neurological or functional impairment may occur. They also carry a risk for malignant transformation into a malignant peripheral nerve sheath tumor (MPNST). The exact incidence of malignancy is unknown, but is estimated to be between 7 and 13%. Rapid growth or unrelenting pain in an otherwise stable plexiform neurofibroma are signs of malignant transformation. MPNSTs frequently metastasize and outcome is poor.
Treatment options are summarized in Table I.
|None||Shave biopsyExcisionCO2 laser vaporizationElectrosugical excision||None|
Optimal Therapeutic Approach for this Disease
Treatment of cutaneous neurofibromas may be necessary for symptom relief (eg, pain, pruritus, bleeding), functional impairment (eg, irritated by clothing), or to improve cosmesis. Simple excision via shave biopsy is the treatment of choice for solitary neurofibromas. Multiple lesions can also be removed by simple excision. CO2 laser vaporization and electrosurgical excision have been reported to be effective methods for removing large numbers of lesions in patients with NF1. Hypertrophic scarring and recurrence is a risk with all of these methods.
Plexiform neurofibromas, because of their infiltrative nature, are more difficult to completely excise and recurrence is common. An MRI prior to surgical excision is necessary to define the extent of the lesion and the likelihood for successful excision. Hemorrhage and nerve damage are major risks. Medical treatment of plexiform neurofibromas is empiric. Drugs reported include methotrexate, interferon-alpha, vincristine, and thalidomide. There are multiple ongoing clinical trials evaluating the use of sirolimus (mTOR inhibitor), imatinib (c-kit inhibitor), ranibizumab (VEGF inhibitor), photodynamic therapy, pirfenadone (antifibrotic agent), and sorafenib (tyrosine kinase receptor inhibitor) for progressive or problematic plexiform neurofibromas.
Patients with a solitary neurofibroma can be reassured that this is a benign lesion without risk of malignant transformation. Simple excision or shave removal can be offered if it is symptomatic or cosmetically undesirable. Patients with two or more neurofibromas need to undergo a thorough skin examination looking for other cutaneous stigmata of NF1 (cafe-au-lait macules, skin fold freckling). They should also have an ophthalmologic evaluation with slit lamp examination looking for Lisch nodules. If they meet criteria, see the Patient Management section in the Neurofibromatosis chapter.
Patients with a plexiform neurofibroma should have a careful evaluation for NF1 as above. As plexiform neurofibromas can infiltrate or compress underlying structures, MRI should be considered in patients who are having pain or functional deficits. Plexiform neurofibromas have a risk for maligant transformation and the patient should be monitored for rapid growth or unrelenting pain. PET scanning using 18-fluorodeoxyglucose has been shown to be helpful in distinguishing benign from maligant areas. A targeted biopsy using the results of the PET scan should be done if there is concern for malignant transformation. These patients should be managed by a multidisciplinary team that includes a medical and surgical oncologist, neurosurgeon, radiologist, geneticist, and dermatologist.
Unusual Clinical Scenarios to Consider in Patient Management
Multiple neurofibromas localized to a body region suggests segmental NF1. Cafe-au-lait macules and freckling may or may not be present. More serious complications of NF1 are generally absent. Segmental NF1 is caused due to a somatic or post zygotic mutation in the NF1 gene. The risk of transmitting full-blown NF1 to offspring is low, but has been reported. An NF1 mutation will not be identified in the blood, but can be detected from a skin biopsy of a neurofibroma. Genetic counseling prior to childbearing in patients with segmental NF1 is helpful for explaining potential risks to offspring.
Neurofibromas, both isolated and in the setting of NF1, have been reported in a number of noncutaneous sites. These include the oral cavity (tongue, lip, gingival mucosa, hard palate), layrnx, parotid gland, abdominal wall, and bone (particularly the facial bones).
What is the Evidence?
Woodruff, Jm. “Pathology of tumors of the peripheral nerve sheath in type 1 neurofibromatosis”. Am J Med Genet. vol. 89. 1999. pp. 23-30. (A review detailing the histopathological findings of neurofibromas, plexiform neurofibromas, and malignant peripheral nerve sheath tumors in NF1.)
Boyd, KP, Korf, BR, Theos, A. “Neurofibromatosis type 1”. J Am Acad Dermatol. vol. 61. 2009. pp. 1-14. (An updated review article of NF1. The review includes clinical features, molecular genetics, and pathophysiology of NF1.)
Theos, A, Korf, BR. “American College of Physicians, American Physiological Society”. Ann Intern Med. vol. 144. 2006. pp. 842-49. (A detailed review of what is known about the pathophysiology of various clinical features in NF1, including neurofibromas.)
Packer, RJ, Gutmann, DH, Rubenstein, A, Viskochil, D, Zimmerman, RA. “Plexiform neurofibromas in NF1: toward biologic-based therapy”. Neurology. vol. 58. 2002. pp. 1461-70. (Reviews the pathophysiology of plexiform neurofibromas, summarizes past clinical trials, and details ongoing clinical trials that are using drugs that target the molecular genetic factors and cytokines that are involved in neurofibroma formation.)
Ruggieri, M, Huson, S. “The clinical and diagnostic implications of mosaicism in the neurofibromatosis”. Neurology. vol. 56. 2001. pp. 1433-43. (Reviews the different presentations of mosaicism in NF1. Reports on eight plexiform neurofibromas out of 124 tumors that did not appear to be associated with NF1. Somatic mosaicism is a possible explanation for this.)
Moreno, JC, Mathoret, C, Lantieri, L, Zeller, J, revuz, J, Wolkenstein, P. “Carbon dioxide laser for removal of multiple cutaneous neurofibromas”. Br J Dermatol. vol. 144. 2001. pp. 1096-98. (Describes 11 patients with NF1 who had numerous (> 100) neurofibromas removed by CO2 laser vaporization. In most instances, the cosmetic improvement and scarring were satisfactory.)
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