Oral Neurofibroma 

Updated: Jun 19, 2018
Author: Indraneel Bhattacharyya, DDS, MSD; Chief Editor: Jeff Burgess, DDS, MSD 

Overview

Background

Neurofibroma is an uncommon benign tumor of the oral cavity derived from the cells that constitute the nerve sheath.[1] See the images below.

Multiple neurofibromas on the tongue. Multiple neurofibromas on the tongue.
An 11-year-old girl with an asymptomatic raised le An 11-year-old girl with an asymptomatic raised lesion on the anterior mandibular gingiva.
Solitary neurofibroma on the hard palate. Solitary neurofibroma on the hard palate.

Neurofibroma is seen either as a solitary lesion or as part of the generalized syndrome of neurofibromatosis (usually neurofibromatosis type 1 [NF-1], also called von Recklinghausen disease of the skin). The solitary form does not differ from the disseminated form or the multiple form of the disease, except that systemic and hereditary factors present in the disseminated form are absent in the solitary type. Multiple neurofibromas have also been strongly associated with the polyglandular syndrome multiple endocrine neoplasia type 3 (MEN-3).[2]

Oral cavity involvement by a solitary and peripheral plexiform neurofibroma in patients with no other signs of neurofibromatosis is uncommon. Sporadic cases have been reported in the submandibular gland, tongue, and on the periosteum at the mental foramen. This sporadic syndromic occurrence has also been seen in the cutaneous region, and several authors have suggested that these isolated neurofibromas may represent a hamartomatous growth.

The World Health Organization (WHO) has subdivided neurofibromas into 2 broad categories: dermal and plexiform. Dermal neurofibromas arise from a single peripheral nerve, while plexiform neurofibromas are associated with multiple nerve bundles.[3] Other clinicopathologic subtypes include localized neurofibroma (sporadic neurofibroma), diffuse neurofibroma, plexiform neurofibroma, and epithelioid neurofibroma.

Localized or solitary neurofibroma is the most frequent manifestation and develops along a peripheral nerve as a focal mass with well-defined margins but not encapsulated. Localized or solitary neurofibroma is rare in infancy and typically appears in late childhood or during teenage years. The majority of isolated or solitary neurofibromas are sporadic, and a small minority may be associated with the NF-1 syndrome. Most of these arise in the third to fourth decades of life. Neurofibroma involving a major nerve, especially those encased in bone, such as the inferior alveolar nerve in the mandible, results in a fusiform expansion of the nerve canal—the so-called blunderbuss canal formation. Soft tissue growths are noted when smaller peripheral nerves are involved.[4, 5]

Plexiform neurofibroma arises along peripheral nerves and tends to involve the smaller branches of the nerves, producing a poorly circumscribed and locally invasive tumor. Approximately 21% of patients with NF-I present with plexiform neurofibromas.[6] These lesions can result in substantial morbidity, mainly due to their size and ability to cause disfigurement. Plexiform neurofibromas are considered to be pathognomonic of for NF-1. These lesions produce the classic "bag-of-worms" appearance. Occasionally, malignant transformation of plexiform neurofibroma is reported (< 5%). This tumor is better designated as a malignant peripheral nerve sheath tumor (MPNST), which tends to exhibit a poor prognosis compared with nonsyndromic MPNSTs.

An uncommon variant of neurofibroma is the diffuse neurofibroma, which typically involves the skin and subcutaneous tissues, resulting in enlargement of affected tissues. Diffuse neurofibromas are most often seen in the head and neck region and may involve the oral cavity.[7, 8] These lesions are more common in adolescents or young adults. Malignant transformation of diffuse neurofibromas is rare, and rapid growth and careful microscopic examination of the biopsy sample is essential to rule out such a change. A minority of diffuse neurofibromas (< 10%) are seen in the setting of NF-1.

Intrabony presentation of neurofibroma. Note the e Intrabony presentation of neurofibroma. Note the extensive bone destruction caused by the lesion.

Pathophysiology

The cell of origin for neurofibroma has not been definitively identified. Some believe it arises from the Schwann cell. Perineural fibroblasts are neuroectodermal tissue cells that synthesize collagen and create a network that envelops the individual axis cylinders of the nerves with their associated Schwann cells. Some investigators believe that perineural fibroblasts give rise to the neurofibroma.

The cause of solitary neurofibroma is unknown. However, neurofibromatosis is inherited as an autosomal dominant trait with a high degree of penetrance but variable expressivity. As many as 50% of cases are reported to be the result of spontaneous mutation. Two subsets have been defined: one is associated with the NF-1 (NF1) gene, and the other is associated with the neurofibromatosis type 2 (NF2) gene.[9]

Etiology

The cause of these lesions is unknown; however, neurofibromatosis syndrome or the disseminated form is inherited as an autosomal dominant trait and may present with a variety of lesions, including a highly variable number of neurofibromas.

Epidemiology

US frequency

Little information is available regarding the relative frequency of solitary oral neurofibromas and oral manifestations of neurofibromatosis. A survey of series on oral neurofibromas has reported that approximately 20-60% of cases are associated with neurofibromatosis. Intraoral neurofibromas may be seen in as many as 25% of patients with neurofibromatosis. Another review of head and neck neurofibromas reported that approximately 25% of all neurofibromas are seen in the head and neck region and 6.5% occur in the oral cavity as solitary or multiple lesions associated with NF-1.

Although these lesions may be seen anywhere in the oral cavity, the most common location of this tumor is the tongue. They have also been described on the gingiva, palate, major salivary glands, and maxillary bones.

Race

No racial predilection is recognized for oral neurofibromas.

Sex

No sexual predilection has been described for oral neurofibromas.

Age

The average age of patients presenting with solitary neurofibromas ranges from 10 months to 70 years, with an average of approximately 45 years; however, for intraoral neurofibromas associated with neurofibromatosis, the lesions may present at any age, with no specific bias.[10]

Prognosis

Solitary neurofibromas have a good prognosis, with only rare instances of local recurrence after excision. However, in neurofibromatosis, a larger proportion of patients develop recurrence after excision, and multiple recurrences are associated with malignant transformation. Spontaneous malignant transformation of 1 or more lesions is also reported. The rate of transformation is estimated to be 5-15%. This neurofibrosarcomatous change has an extremely poor prognosis, and distant metastasis is common. The average 5-year survival rate is dismal and ranges around 10-15%. A study involving 66 cases of head and neck neurofibromas reported that no recurrence of the neurofibromas was detected after surgical removal in approximately 33% of the patients during follow-up ranging from 3-230 months.

 

Presentation

History

Patients usually present with an uninflamed, slowly enlarging, asymptomatic lesion that varies greatly in size from tiny nodules to large pendulous masses. The lesion is rarely painful; however, patients may experience pain if the lesion is secondarily traumatized due to its location, eg, on the tongue or on the hard palate.

Physical Examination

Oral neurofibromas usually present as submucosal, nontender, discrete masses that range in size from a few millimeters to several centimeters (see images below). The lesions are typically pedunculated or sessile, usually painless, but occasionally pain or paresthesia is reported due to nerve compression. Typically, lesions are less than 2 cm in greatest diameter. Larger lesions of up to 8 centimeters are usually seen in syndromic cases.

Multiple neurofibromas on the tongue. Multiple neurofibromas on the tongue.
Solitary neurofibroma on the hard palate. Solitary neurofibroma on the hard palate.
An 11-year-old girl with an asymptomatic raised le An 11-year-old girl with an asymptomatic raised lesion on the anterior mandibular gingiva.
Isolated palatal lesion in a 27-year-old African A Isolated palatal lesion in a 27-year-old African American woman.

The tumors tend to grow slowly, and patients are usually asymptomatic.

Manifestations of neurofibromatosis specific to the oral cavity include enlarged fungiform papillae on the dorsum of the tongue and diffuse enlargement of the gingiva.

In patients with mandibular involvement, enlargement of the inferior alveolar canal in the mandible and a flaring of the inferior alveolar foramen (the so-called blunderbuss foramen) have been reported.

Oral manifestations may be seen in as many as 70% of patients with neurofibromatosis. Involvement of the trigeminal nerve may cause facial pain or paresthesia. Neurofibromatosis of the skin may present as multiple nodules or as a single pendulous mass.

In patients with neurofibromatosis, extensive destruction of alveolar bone, mimicking periodontal bone loss, has been reported. This may be confused with routine periodontitis or other systemic disease. Owing to the potential systemic and genetic implications, the diagnosis of oral neurofibroma requires referral to the appropriate medical specialist to rule out the association with neurofibromatosis.

The tongue, the buccal mucosa, and the vestibular areas are the most common sites of presentation.

Rare cases of diffuse unilateral enlargement of gingiva have been reported in association with neurofibromatosis. In a recent case report, an 8-year-old child presented with gingival enlargement around all teeth of the right side of both jaws. This may resemble drug-induced gingival enlargement or gingival fibromatosis.

Occasional cases of neurofibroma located centrally within the jaw have been reported. These intraosseous lesions may exhibit large sizes with a considerable expansion potential (see image below).

Multiple neurofibromas on the tongue. Multiple neurofibromas on the tongue.
 

DDx

Diagnostic Considerations

Also consider the following:

  • Granular cell tumor
  • Fibroma
  • Scar tissue
  • Neurilemmoma (schwannoma)
  • Leiomyoma
  • Rhabdomyoma
  • Other benign mesenchymal entities

Diffuse neurofibroma (as sometimes seen with neurofibromatosis) may involve the tongue, resulting in macroglossia that may require differentiation from amyloidosis and lymphangioma.

A solitary neurofibroma may be a precursor to neurofibromatosis (also see Neurofibromatosis, Type 1), and the patient should be evaluated with this in mind. Close clinical follow up and/or genetic testing may be required, especially if a lesion recurs multiple times or more than one lesion is seen.

Differential Diagnoses

 

Workup

Laboratory Studies

A definitive diagnosis of oral neurofibroma can only be rendered after an incisional biopsy or an excisional biopsy followed by histopathologic examination.

Imaging Studies

Magnetic resonance patterns for neurofibromas are characteristic. Patterns include the following:

  • Low-to-intermediate signal intensity on T1-weighted images

  • Enhancement of the solid component of the tumor after administration of contrast medium

  • Heterogeneity on T2-weighted images

  • Multiple target signs due to a central collagen area (some patients)

Other Tests

Cytogenetic testing for neurofibromatosis is discussed in detail in other articles (eg, Neurofibromatosis, Type 1, Neurofibromatosis, Neurofibromatosis). In short, unbalanced t(2;19) and unbalanced t(2;16) translocations have been identified.

The NF1 or neurofibromin 1 gene product has been identified and is located on the band 17q11.2. This gene product acts a negative regulator of the ras signal transduction pathway. More information on the gene and its products can be found on the public domain at Entrez Gene.

Histologic Findings

Macroscopically or grossly, neurofibromas appear to display a doughy consistency with a shiny, whitish surface.

Histopathologies of solitary and multiple neurofibromas are essentially identical. Neurofibromas contain spindle-shaped cells, with fusiform or wavy comma-shaped nuclei distributed on a background of delicate connective tissue matrix. This matrix is rich in mucopolysaccharides and is usually myxomatous. The lesion may be well circumscribed, or it may be diffuse with no apparent margins. Mast cells are usually scattered within the specimen.

In neurofibromatosis, a plexiform pattern may be predominant in which distorted masses of myxomatous peripheral nerve tissue still within the perineural sheath are scattered within a collagen-rich matrix. This histologic picture is considered to be virtually diagnostic of neurofibromatosis, even in the absence of other manifestations.

The histologic spectrum of neurofibromas includes interlacing bundles of cells with ovoid-to-spindle, often curved nuclei within a myxocollagenous background containing ropey collagen bundles. Plexiform neurofibroma, which is considered pathognomonic for neurofibromatosis type 1 (NF-1) exhibits multifocal, well-circumscribed, tortuous aggregates of neural tissue distributed in a myxoid matrix. Foci of possible nuclear atypia may be seen and should be carefully examined to rule out malignant transformation.

Diffuse neurofibroma presents with an ill-defined infiltration of neoplastic neural tissue into underlying connective tissue and consists of a matrix of fine fibrillary collagen with spindle-shaped or fusiform or rounded Schwann cells. Occasionally, clusters of Meissner body–like structures may be seen, which are helpful in the diagnosis. Diffuse neurofibromas occur more frequently than the plexiform type.

Immunohistochemistry is often used to aid in confirming the diagnosis made by using histologic findings. The lesional cells are uniformly positive for S-100 protein, signifying that they originate from neural crest–derived tissue. Immunopositivity for S-100 protein is seen in 85-100% of the cases. Antibodies to epithelial membrane antigen, CD57, and collagen IV are of secondary value and are used only when histologic differentiation with other neural tumors is difficult.

A rare variant of solitary neurofibroma with a large adipose tissue content has been reported. This lipomatous neurofibroma manifested as a solitary mucosal mass on the palatal gingiva. Based on limited biopsy material, it was initially diagnosed as a spindle cell lipoma; however, a subsequent review of the resected lesion revealed characteristic neurofibromatous areas, intricately admixed with mature adipose tissue. Immunohistochemically, many of the spindle cells were positive for common neural markers, with patchy staining for CD34 and epithelial membrane antigen. S-100 protein was also positive in adipocytes. Ultrastructural examination confirmed the diagnosis of neurofibroma.

 

Treatment

Surgical Care

Solitary oral neurofibromas are usually treated by surgical excision, depending on the extent and the site. Excision with preservation of the nerve is preferred. However, for neurofibromas associated with neurofibromatosis, surgical removal is attempted only for functional or cosmetic reasons. Surgical removal may result in recurrence, and multiple recurrences have been associated with malignant transformation. Genetic evaluation and counseling is suggested if a syndromic effect is suspected.

Consultations

Many authorities believe that any individual presenting with neurofibroma at an early age (< 20 y) should be referred for genetic studies to rule out the possibility of neurofibromatosis. Consultation with a geneticist and a family physician may be critical in establishing a diagnosis of neurofibromatosis.

Complications

A possible, although extremely rare, complication may be recurrence of the lesion. Other potential complications that may be seen are purely associated with surgical treatment and may include scarring and numbness.

Prevention

No special precaution is recommended for prevention of recurrence. Surgical excision is usually curative.

Long-Term Monitoring

Solitary neurofibromas are treated by surgical excision and exhibit very low recurrence. The patient should be instructed to report any new growth seen in the area or any abnormal sensations, such as tingling. These signs may signify a recurrence, and lesions may require repeat excision.