Neurofibroma

Neurofibroma is a benign peripheral nerve sheath tumor composed of Schwann cells, perineural cells, and endoneural fibroblasts.[1][2] It arises from the endoneurium and represents the most common type of peripheral nerve neoplasm, accounting for approximately 29% of neural lesions in the oral and maxillofacial complex.[1] Neurofibromas occur as solitary (sporadic) lesions or as multiple tumors in the setting of neurofibromatosis type 1 (NF1), an autosomal dominant tumor predisposition syndrome caused by pathogenic variants in the NF1 tumor suppressor gene on chromosome 17q11.2.[3][4] The NF1 gene encodes neurofibromin, a GTPase-activating protein that negatively regulates the RAS signaling pathway; loss of neurofibromin function leads to uncontrolled RAS/MAPK activation, driving tumorigenesis.[3][5] In the jaws, neurofibromas most commonly present as soft tissue masses of the oral mucosa; intraosseous (central) involvement is rare.[1][6] On dental radiographs, intraosseous lesions typically appear as radiolucent areas with variable border definition, while NF1-associated disease may produce characteristic mandibular skeletal deformities and enlargement of the mandibular canal.[7][8] Treatment is surgical excision, and the prognosis is favorable with low recurrence rates for solitary lesions.[1][2]

The 2020 WHO Classification of Tumours of Soft Tissue and Bone lists neurofibroma as a distinct entity within the peripheral nerve sheath tumor category.[9] Recognized growth-pattern subtypes include:

• Localized (circumscribed) neurofibroma — the most common form, comprising approximately 90% of cases[10]
• Diffuse neurofibroma — an infiltrative, poorly circumscribed variant that extends through dermis and subcutis[11][12]
• Plexiform neurofibroma — grows along the length of a nerve involving multiple fascicles in a multinodular or vermiform pattern; pathognomonic for NF1[12][13]

The eponym "von Recklinghausen disease" refers to NF1 itself, not to the individual tumor, and its use is declining.[14] The term "neurofibrosarcoma" is obsolete; the current designation for the malignant counterpart is malignant peripheral nerve sheath tumor (MPNST).[9] An intermediate category, atypical neurofibromatous neoplasm of uncertain biologic potential (ANNUBP), is recognized as a premalignant stage between plexiform neurofibroma and MPNST.[5][15]

• Age: Solitary oral neurofibromas present across a wide age range, with a mean age of approximately 39 years. NF1-associated oral neurofibromas tend to present in younger patients.[1][16]
• Sex: A female predominance is reported, with a female-to-male ratio of approximately 3:1 in oral and maxillofacial series.[1]
• Frequency: Oral neurofibromas are uncommon, representing 0.15% of all oral and maxillofacial lesions in one large pathology service. Among intraosseous benign peripheral nerve sheath tumors of the jaws, schwannomas are more common than neurofibromas. Approximately 161 total cases of intraosseous benign peripheral nerve sheath tumors (neurofibromas and schwannomas combined) have been reported in the jaws.[1][6]
• Syndromic context: NF1 has a birth incidence of approximately 1:2,000–1:3,000. Oral neurofibromas are present in up to 72% of NF1 patients, though the majority of oral neurofibromas encountered in pathology services are sporadic.[1][14][17][18]
• Anatomic distribution: Oral soft tissue neurofibromas favor the tongue, buccal mucosa, lips, gingiva/alveolar ridge, and palate. Intraosseous neurofibromas occur predominantly in the posterior mandible.[1][14][16]

Presentation and symptoms

• Oral neurofibromas typically present as slow-growing, painless, submucosal nodules or polypoid masses with normal-colored overlying mucosa.[1][2]
• Lesions are usually soft to firm, well circumscribed on palpation, and range from a few millimeters to several centimeters.[12]
• Most are asymptomatic and discovered incidentally; symptoms, when present, may include discomfort from trauma to the mass depending on location (tongue, palate).[14]

Examination findings

• Solitary lesions are indistinguishable clinically from fibromas, other reactive processes, and other benign neoplasms; biopsy is mandatory for definitive diagnosis.[1]
• Gingival neurofibromas may mimic or exacerbate periodontal disease by creating pseudo-pockets and limiting oral hygiene.[14][19]
• Intraosseous lesions are usually clinically silent and detected on routine radiographic examination.[20]

NF1-associated findings

• Multiple oral neurofibromas, café-au-lait macules, axillary/inguinal freckling, iris Lisch nodules, and enlargement of the fungiform papillae of the tongue are characteristic.[14][21]
• Impacted teeth, supernumerary teeth, dental spacing, and enlarged alveolar processes may be present.[22]
• Plexiform neurofibromas of the face may produce a characteristic "bag of worms" feel on palpation and cause facial asymmetry, disfigurement, and bony hypertrophy.[4][13]

Red flags

• Persistent or new-onset pain, rapid increase in size, change in texture, or new neurological deficit in a known neurofibroma should raise concern for malignant transformation to MPNST.[4][13]

Most oral neurofibromas are soft tissue masses without radiographic jaw findings. When intraosseous involvement or NF1-associated skeletal changes are present, the following features may be observed.

Location and distribution

• Intraosseous neurofibromas have a strong predilection for the posterior mandible, particularly the body and ramus, often in proximity to the inferior alveolar nerve canal.[16][20]
• Maxillary intraosseous involvement is less common.[1]
• In NF1, skeletal deformities are characteristically unilateral, ipsilateral to a plexiform neurofibroma of the trigeminal nerve.[7][23]

Periphery and shape

• Solitary intraosseous neurofibromas commonly present as a unilocular radiolucency.[6][24]
• Borders may be well defined with a corticated margin, or poorly defined with irregular, diffuse margins; both patterns are reported.[6][8]
• Occasional cases present as multilocular or ill-defined radiolucencies that can mimic odontogenic lesions.[6]

Internal architecture

• The internal structure is characteristically radiolucent without calcification or internal septa in most cases.[8][24]
• Rare cases may show a faintly trabeculated or multilocular internal pattern.[6]

Effects on teeth and adjacent structures

• Displacement of adjacent teeth is common when the lesion is in a tooth-bearing area.[22]
• Root resorption may occur but is not a consistent feature.[19]
• Gingival or alveolar neurofibromas can produce alveolar bone destruction mimicking periodontal disease.[19]

Relationship to the inferior alveolar canal

• Enlargement (widening) of the mandibular canal is the most common radiographic finding in NF1 patients and is considered characteristic of the syndrome.[7][25]
• Enlargement of the mandibular foramen and mental foramen may also be observed.[22]
• A fusiform lesion continuous with the inferior alveolar nerve canal, when present, is a helpful diagnostic clue for a neurogenic origin.[26]

Mandibular skeletal deformities (NF1-associated)

These findings are seen in NF1 patients with craniofacial plexiform neurofibromas and are not features of solitary neurofibroma:

• Deepening of the sigmoid notch, elongation and thinning of the coronoid process, shortening of the ramus, and notching of the posterior mandibular border.[22][23]
• Deformities typically manifest distal to the premolar region and are thought to reflect postnatal interaction between the growing tumor and developing bone.[23][27]
• Profound, often bizarre unilateral mandibular and maxillary deformities may be present in patients with large plexiform neurofibromas.[7]

Cortical involvement and expansion

• Cortical expansion with thinning is common in intraosseous lesions.[16]
• Cortical perforation may occur in larger or more aggressive-appearing lesions.
• CBCT provides superior assessment of cortical thinning, expansion, and destruction compared with panoramic radiography.[28][29]

CBCT contributions to feature assessment

• CBCT improves evaluation of border cortication and its continuity, three-dimensional extent, and relationship to the inferior alveolar canal compared with panoramic radiography.[28][29]
• The three-dimensional relationship of the lesion to adjacent teeth, cortical plates, and neurovascular structures is better delineated on CBCT, aiding surgical planning.

MRI

MRI is the modality of choice for characterizing the soft tissue extent of neurofibromas, particularly plexiform neurofibromas, and for monitoring growth over time.[13][30]

• On T1-weighted images, neurofibromas are typically isointense or slightly hyperintense relative to muscle.[31]
• On T2-weighted images, a characteristic target sign may be seen — a biphasic pattern of peripheral hyperintensity (corresponding to myxomatous tissue) and central hypointensity (corresponding to fibrocollagenous tissue). This sign is present in approximately half of benign nerve sheath tumors and is absent in MPNST, making it a useful discriminator.[31][32][33][34]
• The split fat sign (a rim of fat surrounding the lesion on T1-weighted images) and the tail sign (tissue continuous with the parent nerve) suggest neurogenic origin.[35][36][37]
• Plexiform neurofibromas demonstrate a characteristic multilobulated, vermiform morphology along nerve trunks.[38]
• Absence of a target sign, large size (>5 cm), perilesional edema, infiltrative margins, and low ADC values on diffusion-weighted imaging raise concern for malignant transformation.[34][36][37]

Medical CT

• On contrast-enhanced CT, neurofibromas appear hypodense prior to contrast and show moderate to intense enhancement.[38]
• CT is complementary to MRI for evaluating osseous involvement and surgical planning.[13][39]

FDG-PET/CT

• FDG-PET/CT assists in distinguishing benign from malignant peripheral nerve sheath tumors and can guide biopsy of suspicious lesions, though definitive differentiation requires histologic examination.[13][15]

Intraosseous neurofibroma of the jaw produces a nonspecific radiolucency that overlaps with several odontogenic and non-odontogenic entities. The clinical context — particularly the presence or absence of NF1 stigmata, relationship to the inferior alveolar canal, and soft tissue component — guides the differential.

The highest-risk diagnostic pitfall is failure to recognize an intraosseous neurofibroma in a patient with undiagnosed NF1, as this may delay identification of the syndrome and its associated risk of MPNST. Any patient with an oral neurofibroma — particularly if multiple, plexiform, or associated with mandibular canal enlargement — should be evaluated for NF1.[1][24]

Microscopic features

• Neurofibromas are characteristically non-encapsulated tumors composed of interlacing bundles of elongated spindle cells with wavy, comma-shaped nuclei set in a myxoid to collagenous stroma.[1][42]
• The cellular composition is heterogeneous: neoplastic Schwann cells are admixed with non-neoplastic fibroblasts, perineurial cells, mast cells, lymphocytes, and residual axons.[4][42]
• Mast cell infiltration is a histologic hallmark.[1][43]
• Small neurites (intralesional nerve fibers) can be identified coursing through the tumor, a feature that helps distinguish neurofibroma from schwannoma.[2][44]
• Wire-like collagen strands intimately associated with the spindle cells are characteristic.[1]

Variants

• Plexiform neurofibroma: extends along nerve sheaths in a multinodular pattern rather than forming a central mass; pathognomonic for NF1.[11][12]
• Diffuse neurofibroma: infiltrates dermis and subcutis with poorly defined margins, enveloping but not destroying local structures.[11][12]
• Pacinian neurofibroma: an extraordinarily rare variant containing structures resembling Pacinian corpuscles; reported in the oral cavity.[1]

Immunohistochemistry

• S-100 protein: positive in the Schwann cell component (mixed/partial staining pattern), unlike the diffuse strong positivity seen in schwannoma.[2][41]
• EMA: highlights perineurial cells; negative in Schwann cells.
• CD34: positive in the fibroblastic component.[42]

Radiologic-pathologic correlation

The target sign observed on MRI corresponds histologically to a zonal architecture: a peripheral zone of myxomatous tissue (T2-hyperintense) surrounding a central core of dense fibrocollagenous tissue (T2-hypointense).[31][33] The non-encapsulated, infiltrative nature of neurofibroma explains the difficulty of separating the tumor from the parent nerve at surgery, in contrast to the encapsulated schwannoma.[45]

Molecular considerations

• Sporadic neurofibromas harbor somatic biallelic NF1 inactivation in the Schwann cell component.[3][4]
• In NF1, progression from benign neurofibroma to MPNST follows a multistep molecular cascade: biallelic NF1 loss → CDKN2A loss → disruption of Polycomb Repressive Complex 2 (PRC2), with resultant epigenetic dysregulation.[5]

Workup and referral

• All patients diagnosed with an oral neurofibroma should be clinically evaluated for NF1, including skin examination for café-au-lait macules, freckling, and additional neurofibromas.[1][14]
• Patients meeting NF1 diagnostic criteria require multidisciplinary referral for genetic counseling, ophthalmologic evaluation (Lisch nodules, optic pathway glioma screening), and tumor surveillance.[15][18]
• For intraosseous lesions, cross-sectional imaging (CBCT for osseous detail; MRI for soft tissue extent) is recommended prior to surgical planning.[13][28]

Definitive treatment

• Surgical excision is the standard treatment for solitary oral neurofibromas. Complete excision is curative in most cases.[1][2]
• Because neurofibromas are non-encapsulated and intimately associated with nerve fascicles, separation from the parent nerve may be difficult; preservation of functionally important nerves (e.g., inferior alveolar nerve) should be attempted when feasible.[45]
• For NF1-associated plexiform neurofibromas that are symptomatic and inoperable, MEK inhibitors (selumetinib, mirdametinib) are FDA-approved options.[46][47]

Recurrence

• Solitary neurofibromas have low recurrence rates after complete excision.[1]
• Neurofibromas overall exhibit a higher recurrence rate than schwannomas (approximately 16% vs. 5%), with NF1 status, younger age, and postoperative motor deficits identified as risk factors for recurrence.[48]

Malignant transformation

• Malignant transformation of solitary sporadic neurofibromas is very rare.[1][2]
• In NF1, the lifetime risk of MPNST is approximately 8–13%, with most arising from preexisting plexiform neurofibromas. Involvement of cranial nerve ganglia is an independent risk factor for malignant transformation of head and neck plexiform neurofibromas.[5][21][49]
• Surveillance for malignant transformation in NF1 includes clinical monitoring for pain, rapid growth, or texture change, with MRI and FDG-PET/CT for suspicious lesions.[13][15]

Prognosis

• Prognosis for solitary oral neurofibroma is excellent after complete excision.[1]
• NF1-associated disease carries a guarded long-term prognosis due to the cumulative morbidity of multiple neurofibromas, risk of MPNST, and associated systemic manifestations.[15][18]

NF1 diagnostic criteria and screening

The revised diagnostic criteria for NF1 require two or more of the following: ≥6 café-au-lait macules, axillary/inguinal freckling, ≥2 neurofibromas or one plexiform neurofibroma, optic pathway glioma, ≥2 Lisch nodules or ≥2 choroidal abnormalities, a distinctive osseous lesion, or a pathogenic NF1 variant.[17][18] A plexiform neurofibroma alone is sufficient