Neurofibroma

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).

Figure 1.

Figure 2.

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.

Figure 5.

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.

Figure 6.

Diagnosis confirmation

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?

Etiology

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.

Pathophysiology

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

Treatment options are summarized in Table I.