Definition
- Essential:
- Infiltrative, low-cellularity spindle cell neoplasm associated with a variably myxoid to collagenous stroma and a mixed cell population
- Consisting of neoplastic, well-differentiated Schwann cells intermixed with non-neoplastic elements including perineurial-like cells, fibroblasts, mast cells, a variably myxoid to collagenous matrix, and residual axons or ganglion cells.
- Desirable:
- S100 positivity in the Schwann cell population, with a lattice-like CD34 pattern, highlighting the stromal component
- Intraneural localization
- Patient has NF type 1
- Atypical histological features (nuclear enlargement, hypercellularity, architectural loss, mitoses) for atypical neurofibroma / atypical neurofibromatous neoplasm of uncertain biological potential in the setting of neurofibromatosis type 1, often with loss of p16 expression
Numbers
- Patients of any race, age, or sex can be affected.
CNS WHO grading
- Grade I
Origin
Intraneural neurofibromas
- Arise from NF1-deficient Schwann cells and are composed of a mixture of Schwann cells, fibroblasts, perineural cells, and mast cells
- Arise in a process similar to wound healing in peripheral nerve
- NF1 haplo-insufficient (one wildtype allele and one variant allele that is insufficient to produce the appropriate phenotype) mast cells has the ability to hone to NF 1-deficient Schwann cells → these haplo-insufficient mast cell release cytokines into the Schwann cell microenvironment → NF-1 deficient Schwann cell grow and form neurofibromas
- NF1 loss can lead to activation of the RAS/MAPK and AKT/mTOR pathways.
Cutaneous neurofibromas:
- Different cell of origin than (e.g. dermal skin derived precursors)
Localisation
- Skin
- Nerve
- Peripheral
- Spinal roots
Genetic
- Multiple and plexiform neurofibromas are typically associated with neurofibromatosis type 1 (NF1),
- Sporadic neurofibromas
- Less common when compared to schwannoma
- Mostly cutaneous tumours that can affect patients of any age and any area of the body.
- Neurofibromas are common and occur either as sporadic solitary nodules unrelated to any apparent syndrome or (far less frequently) as solitary, multiple, or numerous lesions in individuals with NF1
Histopathology
Macroscopic
- Tumour involves the cross section of the nerve fascicle
- Hence it lacks a surgical cleavage plane between the normal nerve fibres and the tumour.
- Neurofibromas confined to nerves are fusiform and (in all but their proximal and distal margins) well circumscribed
- Plexiform neurofibromas
- Consist either of multinodular tangles (resembling a bag of worms), when involving multiple trunks of a neural plexus, or of rope-like lesions, when multiple fascicles of a large, non-branching nerve such as the sciatic nerve are affected
- Cut surface, they are firm, glistening, and greyish tan
Microscopy
- Spindled Schwann cells with wire like collagen fibrils mixing with axons, stromal mucosubstances, mast cells, Wagner-Meissner corpuscles and fibroblasts
- A crucial histologic feature is that, unlike schwannomas, the tumor involves the cross section of the nerve fascicle, resulting in a lack of surgical cleavage plane between normal nerve fibers and tumor
- Proliferating cells spread along the nerve fibers and expand the fascicle
Features | Schwannoma | Neurofibroma |
Vessel hyalinization | Yes | No |
Antoni | A & B | B |
Verocay bodies | Yes | No |
Clinical features
- Rarely painful
- Presents as a mass
- Intraneural neurofibromas
- Deeper tumours, including paraspinal forms, present with motor and sensory deficits attributable to the nerve of origin.
- Growth pattern
- Well demarcated intraneural type
- Cutaneous neurofibromas
- Are nodular to polypoid and circumscribed, or are diffuse,
- Involve skin and subcutaneous tissue
- Relatively common
- Growth pattern
- Diffuse infiltration of soft tissue
Radiological
CT
- Well-defined hypodense mass
- Minimal or no contrast enhancement
MRI
- T1: hypointense
- T2
- Hyperintense
- Target sign
- A hyperintense rim and central area of a low signal may be seen
- This is thought to be due to a dense central area of collagenous stroma
- Although this sign is highly suggestive of neurofibroma, it is occasionally also seen in schwannomas and malignant peripheral nerve sheath tumours
- Fascicular sign
- A finding on T2-weighted MRI images that suggests a lesion of neurogenic origin.
- Characterised by multiple small ring-like structures with peripheral hyperintensity representing the fascicular bundles within the nerves.
- It is found in various neurogenic tumours, including:
- Neurofibroma
- Schwannoma / neurilemoma
- Malignant peripheral nerve sheath tumour (PNST): a spindle cell carcinoma arising from a nerve or a neurofibroma
- T1 C+ (Gd): heterogeneous enhancement
Images
Classification
Localised cutaneous neurofibromas
- Most common form
- Grow as hyperpigmented nodular lesions of the skin
- Occurs sporadically in most cases
Diffuse cutaneous neurofibromas
- A plaque- like enlargement and usually occur in the head and neck region.
- Involve skin and subcutaneous tissue
- More extensive than localised cutaneous neurofibromas
- Approximately 10% of cases are ultimately proven to be associated with NF1
Intraneural neurofibromas
- Localised intraneural neurofibromas grow within peripheral nerves, envelope nerve fascicles, and cause focal fusiform dilation
- Spinal nerves
- In sporadic cases: Rarely
- In NF1 cases
- Common
- Multiple bilateral tumours
- Associated with scoliosis
- Risks of malignant transformation
- Cranial nerves
- Almost never involved
- Plexiform neurofibromas
- Multinodular tumors that arise in peripheral nerves or at the level of nerve plexuses
- Cause longitudinal sausage like enlargement of the parent nerve(s).
- All NF1
- A recognized precursor for MPNST in NF1 patients
- Involvement of multiple fascicles, which are expanded by tumour cells and collagen, but commonly demonstrate residual, bundled nerve fibres at their centres.
- Found in
- Extremities
- Head and neck
- High rate of malignancy
Mixed neurofibromas
- Massive soft tissue neurofibromas infiltrate the soft tissue of an extremity and can cause elephantiasis neuromatosa, gigantism, or disfiguring soft tissue masses, and can have underlying intraneural or plexiform neurofibromas
Ancient neurofibromas
- Defined by degenerative nuclear atypia alone (marked nuclear hyperchromasia and pleomorphism without inc in mitosis ) and should be distinguished from atypical neurofibroma, given the lack of any associated clinical relevance
- This is similar to ancient schwannoma, which has degenerative atypia but lacks any other features of malignancy.
Atypical neurofibromas
- A variant defined by worrisome features such as
- High cellularity,
- Scattered mitotic figures,
- Monomorphic cytology, and/or
- Fascicular growth in addition to cytological atypia,
- May show premalignant features
- Notoriously difficult to distinguish from low-grade malignant peripheral nerve sheath tumour (MPNST)
- CDKN2A/CDKN2B losses are generally considered a sign of malignant transformation, and these losses are also commonly found in tumours diagnosed as atypical neurofibromas in patients with NF1, suggesting that such tumors may be premalignant lesions
Immunophenotype
- Positive stains
- S100 shows strong positivity
- CD34 shows fingerprints-like positivity
- SOX10 shows strong positivity
- Factor XIIIa is useful to differentiate neurofibroma from neurotized neavi
- Calretinin shows focal positivity
- EMA shows weak positivity
- Podoplanin shows weak positivity
- Neurofilaments stains entrapped axons
- Collagen type IV shows strong positivity
- Negative stains
- EMA (except in plexiform neurofibromas)
- Cytokeratin, SMA and desmin
- Low Ki67
Prognosis
- Plexiform neurofibromas and neurofibromas of major nerves are considered potential precursors of MPNST
- Malignant transformation occurs in 5-10% of large plexiform tumours, but is a rare event in diffuse cutaneous and massive soft tissue neurofibromas.
- A patient with a sizable plexiform neurofibroma is highly likely to have NF1 and should be investigated for other evidence of the disorder.
- Similar to low-grade MPNST, an atypical neurofibroma that extends to a surgical margin has a low risk of subsequent recurrence, but essentially no associated mortality
- The absence of functional neurofibromin increases cell proliferation and survival.
Differential diagnosis
- Schwannoma
- A crucial histological feature that distinguishes them from schwannomas is that the neurofibromas involves the cross section of the nerve fascicle:
- Hence it lacks a surgical cleavage plane between the normal nerve fibres and the tumour.
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