Neurofibroma differential diagnosis

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sara Mohsin, M.D.[2] Shanshan Cen, M.D. [3]

Overview

Neurofibroma must be differentiated from schwannoma, dermatofibrosarcoma protuberans (DFSP), ganglioneuroma, dermal neurotized melanocytic nevus, myxoid liposarcoma, solitary circumscribed neuroma, traumatic neuroma, superficial angiomyxoma, nerve sheath myxoma, malignant peripheral nerve sheath tumor, spindle cell lipoma, Leiomyoma, inflammatory myofibroblastic tumor, and fibroepithelial polyp.

Differential Diagnosis

Neurofibroma must be differentiated from:[1][2][3]

Differentiating neurofibroma from other diseases
Disease entity Etiology (Genetic or others) Histopathological findings Immunohistochemical staining Risk factors Common site of involvement Clinical manifestations Other associated features
Neurofibroma[4][5][6][7][8][9][10][7][11][12][13]

Can be sporadic or as a part of Neurofibromatosis 1 and 2

  • Uniphasic, low to moderate cellularity
  • No peripheral perineural capsule
  • Random pattern, only rare palisading
  • No well formed verocy bodies
  • Hypocellular with abundant mucinous/myxoid matrix without hypercellular areas
  • Frequent mast cells
  • Contains neural fibroblasts and fibrillary or shredded carrot collagen
  • Random proliferation of Schwann cells and scattered admixed axons
  • No nevoid cells
  • No epithelial component
  • Diffuse growth pattern
  • Scant cytoplasm
  • Wavy spindle cells with buckled nuclei
  • Pseudomeissnerian bodies representing specific differentiation may be present
  • Lacks storiform pattern

Neurofibroma with degenerative atypia ("ancient change") has following microscopic features:

  • Localized cells with large pleomorphic nuclei, cytoplasmic nuclear inclusions, smudgy chromatin, and inconspicuous nuclei
  • Absent or very low mitotic activity
  • Low to moderate cellularity
Positive for:
  • Nerve often not identified, incorporates nerve, axons often present in lesion
  • Seldom cystic
  • Frequently multiple
  • Widespread soft tissue infiltration
  • Tends to displace adnexa
  • <2cm in diameter
  • Lacks distinct lobulation
  • Lacks fat
  • Affects individuals between 20-40 years of age
  • Men and women are equally affected
  • Plexiform neurofibroma are thought to be congenital and occur earlier in life
Schwannoma[14][15][16][17][18]
  • Loss of function of the tumor suppressor gene merlin (schwannomin)
  • Direct genetic change involving the NF2 gene on chromosome 22
  • Can occur spontaneously
  • Mutations and biallelic inactivation of SMARCB1 (spinal schwannomas)
  • Encapsulated
  • Aggregates of spindled cells with indistinct cytoplasm and elongated nuclei with blunt pointed ends
  • Ancient changes may show nuclear pleomorphism and occasionally nuclear inclusions as well
  • Infrequent extracellular collagen
  • Biphasic: majority entirely, and compactly hypercellular Antoni A & myxoid hypocellular Antoni B areas (may be absent in small tumors)
  • Nuclear palisading evident around fibrillary process (Verocay bodies) in cellular areas
  • Large, irregularly spaced vessels prominent in Antoni B areas
  • Narrow, elongated and wavy cells with tapered ends, interspersed with collagen fibers
  • Tumor cells with ill defined cytoplasm, dense chromatin
  • Often displays degenerative nuclear atypia (ancient change)
  • Rare mitotic figures
  • Blood vessels may show gaping tortuous lumina having thickened hyalinized walls; may have thrombi
  • Dilated vessels surrounded/invested by hemorrhage
  • Foamy macrophages
  • Lymphoid aggregates
  • Amianthoid fibers or collagenous spherules: large nodular masses of collagen with radiating edges
  • No axons except where nerve is attached
  • Malignant transformation may have malignant epithelioid cells and rarely shows divergent differentiation as angiosarcoma-like areas
Positive for:
  • S-100
  • SOX10
  • CD56
  • Podoplanin
  • CD34 (weak)
  • Neurofilament (and Bielshowsky)
  • Factor XIIIa (focal)
  • Calretinin
  • GFAP
  • EMA (capsule) highlights the perineural fibroblasts
  • Laminin
  • Type IV collagen
  • Vimentin
  • CD68

Negative for:

  • Cytokeratin
  • Desmin
  • SMA
  • NF-2 associated
  • Schwannomatosis
  • Carney complex
  • Upper limbs
  • Head and neck area (oral cavity, orbit and salivary glands)
  • Deeply seated tumors are mainly in:
    • Posterior mediastinum
    • Retroperitoneum
  • Posterior spinal roots
  • Bone
  • Gastrointestinal tract
  • Pancreas
  • Liver
  • Thyroid
  • Adrenal glands
  • Lymph nodes
  • Penis (rarely)
  • Vulva (rarely)

Symptoms of schwannoma depend on the location of the tumor:

  • Nerve often identifiable
  • Eccentric to nerve, axons generally absent within lesion
  • Occasionally cystic
  • Can cause other neoplasms including:
    • Meningioma
    • Mesothelioma
    • Glioma multiforme
    • Breast CA
    • Colorectal CA
    • Kidney (clear cell type) CA
    • Hepatocellular CA
    • Prostatic CA
    • Dermal CA
  • Affects individuals between 20-50 years of age
  • Men and women are equally affected
Palisaded encapsulated neuroma (PEN) /solitary circumscribed neuroma
  • Spontaneous development
  • RET proto-oncogene genetic mutations (inherited PEN)
  • Solitary dermal or subcutaneous tumor
  • Encapsulated by perineurium
  • Club-like extension in the subcutaneous tissue
  • Moderately cellular lesion with proliferation of schwann cells and axons
  • Nuclear palisading may be present
  • Rare mast cells
  • Silver stains show the axons traversing the Schwann cells
Positive for:
  • EMA
  • S100 (schwann cells)
  • Neurofilament (axons)
  • Collagen type IV
  • EMA (perineurium)
  • Neuron-specific Enolase
  • CD57 (Leu-7)
  • Myelin basic proteins

Negative for:

  • Positive family history of tumor occurrence
  • Multiple mucosal neuroma syndrome
  • Multiple endocrine neoplasia syndrome (MEN 2B)
90% lesions affect the face involving:
  • Eyelid
  • Nose
  • Oral mucosa

Remaining 10% can occur anywhere in body involving:

  • Shoulder
  • Arm
  • Hand
  • Foot
  • Glans of penis
  • Small, solitary, raised, dome-shaped, firm, flesh-colored painless nodule on skin
  • Cosmetic issues due to facial involvement
  • Scar after surgery
  • Benign tumor of the nerve fibers
  • Affects middle aged people (40-60 years)
  • No known familial association
  • Affects females more frequently than males
Traumatic neuroma
  • Numerous well formed small nerve twigs
  • Limited soft tissue infiltration
  • Contains axons in haphazardly arranged nerves
  • History of trauma or surgery
Neurotized Melanocytic Nevus
  • Biphasic consisting of malignant melanoma and mature appearing neural component
  • Superficial classic nevoid melanocytes
  • Congenital and nested growth patterns
  • More abundant cytoplasm
  • Tends to surround adnexa
Positive for:

Negative for:

  • Factor XIIIa
  • Head and neck area
Cutaneous Myxoma (Superficial angiomyxoma)
  • Spindle to stellate cells with oval nuclei
  • 1-5cm in diameter
Positive for:
  • Associated with Carney complex
Nerve sheath myxoma Positive for:
Malignant peripheral nerve sheath tumor (MPNST)/malignant schwannoma[19][20][21][22][23][24]
  • 50% arise denovo
  • 50% associated with neurofibromatosis (loss of heterozygosity of p53 on 17p chromosome)
  • Generalized atypia
  • Increased mitotic activity
  • Diffuse hypercellularity
  • Infiltrative growth
  • Pleomorphic nuclei
  • Areas of geographic necrosis may show divergent differentiation, with tumor palisading at edges, resembling glioblastoma multiforme
  • Monomorphic serpentine cells, large gaping vascular spaces, perivascular plump tumor cells
  • May have bizarre cells
  • 15% have metaplastic cartilage, bone, muscle
  • May have glandular differentiation, if so, presume malignant
  • May have melanin in tumor cells, particularly if arise from spinal nerve roots (overlaps with primary melanoma of nerves)
  • Some have no discernable Schwannian features at any level

Electron micropscopy shows:

  • Cell membrane infoldings with lamellar configuration, discontinuous basal lamina, conspicuous intercellular junctions, and occasional dense-core granules
Positive for:
  • CD99/O13 (86%)
  • S-100 (patchy in 62% cases)
  • CD57 (55%)
  • Collagen IV
  • p53
  • Leu7/CD57 (in neurofibroma-like areas)
  • Protein gene product 9.5 (more sensitive than S100 but not specific)

In case of glandular differentiation (malignant), positive for:

  • Keratin
  • EMA
  • CEA
  • Chromogranin

Negative for:

  • CD19
Associated with:
  • NF1

May be associated with:

  • Radiations
  • Ganglioneuroma (rarely)
Bulky deep-seated tumor usually arising from major nerves in:
  • Neck
  • Forearm
  • Lower leg
  • Buttock
  • Painless swelling in extremities (arms or legs, aka peripheral edema)
  • Difficulty moving the extremity with tumor (limping)
  • Localized soreness in tumor area
  • Neurological symptoms
  • Pain or discomfort: numbness, burning, or tingling (pins and needles)
  • Dizziness
  • Loss of balance
  • Most common frequent soft tissue sarcoma in the pediatrics population
Dermatofibrosarcoma protuberans (DFSP)
  • t(17,22)(q21;q13) (collagen type 1 alpha 1(COL1A1) gene and platelet derived growth factor (PDGF) beta chain gene), resulting fusion protein is processed into mature platelet-derived growth factor which is a potent growth factor
  • Supernumerary ring chromosomes derived from t(17;22)
  • Usually forms a mass
  • Non circumscribed, highly cellular, tight storiform pattern (cells radiating in spokes at right angles around a central point that often contains a vessel) deeply infiltrating into subcutaneous tissue and entraping fat cells leading to characteristic honeycomb pattern
  • Areas of fascicular growth (some tumors)
  • Distinct storiform pattern may be absent in early plaque stage
  • Monomorphic, thin and spindly cells with scant eosinophilic cytoplasm and hyperchromatic nuclei (resembling neurofibroma)
  • Numerous mitotic figures (not atypical ones)
  • Non-polarizable and thin collagen
  • Only mild pleomorphism and focal atypia
  • May coexist with giant cell fibroblastoma
  • Usually no significant pleomorphism, no / rare histiocytes, no histiocyte-like cells, no foam cells, no giant cells or other inflammatory cells
  • Variants: Atrophic (depressed lesion), collagenous (with central thick collagen bundles), granular cell, myxoid, palisading, pigmented, and sclerosing
Positive for:
  • CD34 (strong in 95%)
  • Vimentin
  • Actin (focal)
  • ApoD
  • Bcl2
  • NKI-C3
  • CD99

Negative for:

  • S-100
  • Factor XIIIa (usually)
  • Keratin
  • EMA
  • S100
  • HMB45
  • Desmin
  • CD117
_
  • Head
  • Deep soft tissue of (posterior) neck
  • Trunk
  • Arms
  • Legs
  • Doesn't involve hands and feet
  • Begins as a minor firm area of skin
  • 1 to 5 cm in diameter
  • Resembles a bruise, birthmark, or pimple
  • Can become a raised nodule after growth
  • May cause redness, open up or bleed
  • Also called intermediate (borderline) fibrous histiocytoma
  • More common in blacks in US
  • Involves adults of 20 - 40 years of age
Spindle cell lipoma
  • 16q abnormalities (usually)
  • Delicate encapsulation
  • Floret cell formation
  • No degenerative atypia
  • Mixture of mature adipocytes and mildly pleomorphic bland spindle cells (pale eosinophilic cytoplasm with uniform wavy nuclei similar to neurofibroma) in mucinous / myxoid or fibrous background with thick collagen bundles
  • Spindle cells arranged in short fascicles with occasional nuclear palisading
  • Hemangiopericytic or angiomatous vascular pattern may be seen
  • Minimal or no fat
  • Variable mast cells and lymphocytes
  • No storiform pattern, no lipoblasts, no/rare mitotic activity
Positive for:
  • CD34 (strongly, spindle cells)
  • Androgen receptors in men and usually women (spindle cells)
  • S-100(stains only adipocytes)

Spindle cells are negative for:

  • S100
  • Desmin
_
  • Neck
  • Posterior upper back
  • Shoulder
  • Multiple well-circumscribed painless nodules involving several body parts
_
Ganglioneuroma[25][26] Genes involved in the pathogenesis of ganglioneuroma include:
  • MYCN oncogene
  • Chromosome 1p36
  • Activating RET protooncogene mutation (adrenal ganglioneuromas)
  • Derived from the primordial neural crest cells (undifferentiated cells of the sympathetic nervous system)
  • Admixture of ganglion cells, schwann cells, and fibrous tissue
  • Doesn't contain neuroblasts, intermediate cells, or mitotic figures
  • Characterized by spindle-shaped cells with cell borders in a fibrillar matrix containing ganglion cells with large round nuclei, prominent nucleoli, and abundant eosinophilic cytoplasm
  • No significant atypia, necrosis or mitotic activity is present
  • Well differentiated neuronal tumors that do not contain immature elements
  • Ganglion cells are mature to mildly dysmorphic:
    • Mature: compact, eosinophilic cytoplasm with distinct cell borders, single eccentric nucleus, prominent nucleolus
    • Dysmorphic: single or multiple pyknotic nuclei
    • Vary in distribution and number, may be quite sparse
    • May contain finely granular, gold to brown pigment (lipofuscin or neuromelanin)
  • Schwann cells:
    • Ensheath neuritic processes
    • Arranged in small intersecting fascicles, separated by loose myxoid stroma

Two histologic subtypes:

  • Mature = every ganglion cell is mature
  • Maturing = minor component of scattered collections of differentiating neuroblasts or maturing ganglion cells (Unlike intermixed subtype of ganglioneuroblastoma, these immature foci do not form distinct microscopic nests)
  • Background may include lobules of mature adipose tissue (especially at periphery of lesion), mast cells, chronic inflammation, dense collagenized stroma
  • Mild variation in cellularity may be present
  • Masculinizing ganglioneuroma is an admixture of ganglioneuroma and Leydig cells with crystalloids of Reinke or strands/clusters of cells resembling adrenal cortical cells
  • Electron microscopy:
    • Mixture of neural bundles and normal appearing ganglion cells with eccentric nuclei and large numbers of cytoplasmic organelles
Positive for:
  • Schwann cells/stroma:
    • S100
    • Synaptophysin
    • Neurofilament (NF) protein
  • Ganglion cells:
    • S100
    • Synaptophysin
    • Chromogranin A
    • NF protein
    • Glial fibrillary acidic protein (GFAP)
    • PGP 9.5
    • Type IV collagen
    • Vasoactive intestinal peptide (VIP)

Negative for:

  • EMA
  • Cytokeratin
  • HMB45
  • WT1
  • CD99
  • CD45
  • Desmin
  • Myogenic markers (myogenin, MyoD1)

Ganglioneuromas may be associated with:

Located along distribution of sympathetic nervous system:

  • Posterior paraspinal mediastinum (most common)
  • Adrenal gland (~20-30% of cases)
  • Paraspinal retroperitoneum (especially presacral space)
  • Cervical and parapharyngeal area in neck
  • Urinary bladder
  • Prostate
  • Bone
  • Pancreas
  • Skin
  • Orbit
  • Paratesticular area
  • Appendix
  • Gastrointestinal tract
Symptoms of ganglioneuroma vary depending on the location of tumor, and include the following:
  • Mediastinum:
    • Dyspnea
    • Chest pain
    • Trachea compression
  • Retroperitoneum:
    • Abdominal pain
    • Bloating
  • Spinal cord:
    • Paresis
    • Pain and numbness/loss of sensation in limbs

Patients with ganglioneuroma may also have paraneoplastic syndrome, which may manifest with:

Ganglioneuromas are included in the neuroblastic tumors group, which includes:

  • Ganglioneuroma (benign)
  • Ganglioneuroblastoma (intermediate).
  • Neuroblastoma (aggressive)
Myxoid liposarcoma[27][28][29][30][31][32][33][34][35][36]

Atypical lipomatous tumor/well differentiated liposarcoma and dedifferentiated liposarcoma are associated with:

Myxoid liposarcoma is associated with:

Pleomorphicliposarcoma is associated with:

Well-differentiated liposarcoma:

De-differentiated liposarcoma:

Atypical lipomatous tumor/well differentiated liposarcoma is positive for:

_
Leiomyoma[37][38][39][40][41][42][43][44][38][41][45]

Positive for:

Negative for:

_
Inflammatory myofibroblastic tumor(IMT)[37][38][39][40][41][42][43][44][38][41][45]

Unknown underlying etiology, may be due to inflammatory reaction to:

Mutations such as:

Positive for:

Negative for:

Also known as:

Fibroepithelial polyp/Acrochordon[46][47][48][49][50][51][52][53][54][55][56][57][58][59][60][61][62][63][64][65] Associated with:
  • HPV 6 (low risk)
  • HPV 11
  • Fibrovascular cores covered by squamous epithelium
  • Larger lesions may have a flattened epidermis
  • Smaller lesions can have epidermal hyperplasia or seborrheic keratosis-like changes
  • Central core composed of loose collagen with increased blood vessels
  • In larger lesion, may have a central core of adipose tissue
  • Pagetoid dyskeratosis is sometimes present as an incidental finding
  • May have ischemic necrosis due to torsion
Positive for:
  • Desmin
  • Vimentin
  • ER
  • PR

Negative for:

  • Actin
Associated with:
  • Diabetes (elevated blood sugar and insulin)
  • Abnormal lipid profile
  • Other components of metabolic syndrome
  • Birt-Hogg-Dube syndrome
  • Acromegaly
  • Polycystic ovary syndrome
  • May increase in number during pregnancy
  • Occurs usually in intertriginous areas (i.e. axilla, groin)
  • Face
  • Neck
  • Eyelids
  • Vulva
  • Tonsils
  • Ureter
  • Bowel
  • Urinary bladder
  • Bronchi
  • Soft papilloma, flesh colored to dark brown, sessile to pedunculated
  • A few millimeters to multiple centimeters in size
  • Larger lesions often attach to skin by slender stalks
  • Benign skin lesions in adults, excised for cosmetic reasons

Also known as:

  • Skin tag
  • Soft fibroma
  • Cutaneous papilloma
  • Cutaneous tag
  • Fibroma pendulum
  • Fibroma molluscum

References

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  3. http://surgpathcriteria.stanford.edu/peripheral-nerve/neurofibroma/
  4. Rodriguez, Fausto J.; Folpe, Andrew L.; Giannini, Caterina; Perry, Arie (2012). "Pathology of peripheral nerve sheath tumors: diagnostic overview and update on selected diagnostic problems". Acta Neuropathologica. 123 (3): 295–319. doi:10.1007/s00401-012-0954-z. ISSN 0001-6322.
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  15. Vestibular Schwannoma. Wikipedia(2015) https://en.wikipedia.org/wiki/Vestibular_schwannoma Accessed on October 2 2015
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  26. https://radiopaedia.org/articles/ganglioneuroma
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