Neurofibroma
Definition
- A benign tumor consisting of a mixture of cell types, including Schwann cells, perineurial-like cells, fibroblastic cells and entrapped axons that may be well-demarcated if intraneural or cutaneous but are diffusely infiltrative if located in extraneural soft tissue
General Diagnostic Criteria
- Randomly oriented thin spindled cells with wavy, hyperchromatic nuclei
- Cellularity and organization are generally insufficient to produce palisading
- Thin processes with indistinct cytoplasm
- Most nuclei are small and bland
- Generally hypocellular
- Thin and thick collagen strands (“shredded carrot collagen”)
- Variable myxoid material surrounding cells and collagen
- Occasional mast cells and lymphocytes, rare foam cells
- Diffusely S100 immunoreactive
- Entrapped axons of overrun nerve frequently scattered within lesion
- Nerve frequently not grossly identifiable
- May show localized hyperchromatic atypical cells (“ancient change”)
- Localized cells with large, pleomorphic nuclei, cytoplasmic intranuclear inclusions, smudgy chromatin, and inconspicuous nucleoli
- Often large, long standing lesions
- Low mitotic index
Subtypes
- Localized (Sporadic) Cutaneous Neurofibroma
- Most common type
- Circumscribed but not encapsulated
- Permeative growth in nerve quickly proceeds to diffuse infiltration of surrounding soft tissue
- Often in dermis and subcutis and ≤2 cm
- Arise from small cutaneous nerves
- Overrun axons may be identified within
- May contain fat
- Usually sporadic lesions in patients without NF1
- Malignant transformation very rare
- Localized Intraneural Neurofibroma
- Second-most common type
- Segmental, fusiform nerve enlargement
- Residual axons traverse through lesion
- Neurofilament immunohistochemistry and Bielshowsky stain show axons within center of lesion
- Often contains coarse, refractile collagen
- Malignant change infrequent
- Diffuse Neurofibroma
- Most common in head and neck region
- Ill-defined, diffuse, infiltrative spread through subcutaneous tissues
- Nondestructive, envelops normal structures (e.g., fat cells and adnexal structures)
- Uniform matrix of fine, fibrillary collagen
- Shorter, rounder Schwann cells
- Clusters of pseudomeissnerian body-like structures may be seen
- A subset of patients have NF1
- Rare malignant change
- Plexiform Neurofibroma
- Almost exclusive to patients with NF1 (see clinical section below)
- Macroscopically distorts nerve to resemble a “bag of worms”
- Tumors that are only microscopically plexiform should not be interpreted as plexiform for the purposes of diagnosing NF1
- May include a diffuse component extending into adjacent soft tissue
- Up to 5% risk of malignant transformation
- Pigmented Neurofibroma
- Neurofibroma with melanin-bearing pigmented cells, usually only appreciated microscopically
- Not considered a true subtype
- No increased risk of malignant transformation
Clinical
- WHO grade 1
- Neurofibromas are rarely painful
- The presence of multiple neurofibromas is a hallmark of neurofibromatosis type 1 (NF1), also known as von Recklinghausen disease
- NF1 diagnostic criteria require two or more of the following:
- ≥6 Cafe au lait macules
- ≥2 neurofibromas or one plexiform neurofibroma
- Axillary/inguinal freckling
- Optic glioma
- ≥2 Lisch nodules
- Distinctive osseous lesions (e.g., sphenoid dysplasia)
- First-degree relative with NF1
- Most common type of neurofibroma in NF1 is the localized neurofibroma, but these are nonspecific
- Plexiform lesions are almost unique to NF1
- Diffuse neurofibromas are usually associated with NF1
- Increased risk for CNS tumors including astrocytomas and heterotopias
Differential Diagnosis
- Schwannoma
- Solitary circumscribed neuroma (palisaded encapsulated neuroma)
- Traumatic neuroma
- Neurotized nevus
- Superficial angiomyxoma
- Nerve sheath myxoma
- Malignant peripheral nerve sheath tumor (MPNST)
- Dermatofibrosarcoma protuberans (DFSP)
- Spindle cell lipoma
Immunohistochemical |
||
S-100 and Sox10 |
Moderate positivity |
Strong, diffuse positivity |
CD34 |
Moderate |
Scattered cells in Antoni B areas |
Neurofilament (and Bielshowsky) |
Stains entrapped axons within lesion |
Stains peripherally located axons of parent nerve |
Factor XIIIa |
Moderate |
Negative to focal |
Calretinin |
Negative to focal |
Moderate |
GFAP |
Variable, weak |
Variable, moderate |
- Only the neurofilament and Bielshowsky stains are very helpful
- S100 and SOX10 stain classic lesions with different intensities because of their differing cellularities
- They are not very helpful for distinguishing problematic examples of these two lesions
Neurofibroma |
|
Uniphasic, Low to moderate cellularity |
Biphasic (cellular Antoni A & hypocellular Antoni B), some hypercellularity |
Non-encapsulated |
Encapsulated |
Random pattern, only rare palisading, no well formed Verocay bodies |
Palisading and Verocay bodies |
Nerve often not identified |
Nerve often identifiable |
If nerve identified: incorporates nerve, axons often present in lesion |
Eccentric to nerve, axons generally absent within lesion |
Seldom cystic |
Occasionally cystic |
NF1-associated; Not NF2 |
Not NF1-associated; Occasionally NF2 |
Plexiform Neurofibroma |
|
Cells separated by collagen bundles |
Infrequent extracellular collagen |
Hypocellular with abundant mucinous matrix |
Infrequent hypocellular Antoni B areas (majority entirely hypercellular Antoni A) |
Associated with NF1 |
Associated with NF2 |
Neurofibroma |
|
Can occur anywhere |
90% of lesions affect the face |
Frequently multiple |
Usually solitary |
Hypocellular lesion |
Moderately cellular lesion |
No peripheral perineurial capsule |
Delicate EMA peripheral positivity |
Can be GFAP positive |
GFAP negative |
Frequent mast cells |
Rare mast cells |
Contain neural fibroblasts and fibrillary collagen |
Predominantly composed of Schwann cells |
May be associated with neurofibromatosis |
No known familial association |
Neurofibroma |
|
No history of prior trauma or surgery |
History of trauma or surgery |
Random proliferation of Schwann cells and axons |
Numerous well formed small nerve twigs |
Widespread soft tissue infiltration |
Limited soft tissue infiltration |
Contains scattered admixed axons |
Contains axons in abundant haphazardly arranged nerves |
Cutaneous Neurofibroma |
Neurotized Melanocytic Nevus |
Lacks nevoid cells |
Superficial classic nevoid melanocytes |
More diffuse growth pattern |
Congenital and nested growth patterns |
Scant cytoplasm |
More abundant cytoplasm |
Tends to displace adnexa |
Tends to surround adnexa |
Neurofibroma |
|
Wavy cells with buckled nuclei |
Spindled to stellate cells with oval nuclei |
Usually smaller (<2cm) |
Generally larger (between 1 and 5 cm) |
S100 positive |
Rarely express S100 |
Associated with NF-1 |
Associated with Carney Complex |
| No epitheliaal component | Frequent entrapped epithelium |
Neurofibroma |
Nerve Sheath Myxoma |
Usually has at least areas of typical neurofibroma |
Markedly hypocellular with abundant mucopolysaccharides |
Lacks distinct lobulation |
Lobulated architecture |
Features of specific differentiation (e.g., pseudomeissnerian bodies) occasionally may be present |
Absent |
Localized cells with large, pleomorphic nuclei, cytoplasmic nuclear inclusions, smudgy chromatin, and inconspicuous nucleoli |
Generalized atypia |
Absent or very low mitotic activity |
Increased mitotic activity |
Low to moderate cellularity |
Diffuse hypercellularity |
S100 positive 100% |
S100 variably positive, about 30% |
Diffuse Neurofibroma |
|
Less cellular |
More cellular |
Lack uniform storiform pattern |
Distinct storiform pattern |
S100 immunoreactive, CD34 stains only a subset of spindled cells |
Strong CD34 immunoreactivity, |
Diffuse process |
Usually forms a mass |
Neurofibroma |
|
Variable location |
Deep soft tissue posterior neck |
Unencapsulated |
Delicate encapsulation |
Generally lack fat |
Most cases contain fat |
May show degenerative atypia |
Lacks degenerative atypia, may see floret cell formation |
S100 immunoreactive, CD34 stains only a subset of spindled cells |
Strong CD34 immunoreactivity, |
Bibliography
Kurt Schaberg MD
Donald Born MD
Robert V Rouse MD
Department of Pathology
Stanford University School of Medicine
Stanford CA 94305-5342
Original posting : 9/2/15
