Soft tissue
Peripheral nerve
Neurofibroma - general


Topic Completed: 4 June 2019

Revised: 11 June 2019

Copyright: 2002-2019, PathologyOutlines.com, Inc.

PubMed Search: Neurofibroma [title] soft tissue

Engy Abdellatif, M.D., Ph.D.
Dia Kamel, M.D., Ph.D.
Page views in 2018: 42,845
Page views in 2019 to date: 34,481
Cite this page: Abdellatif E, Kamel D. Neurofibroma - general. PathologyOutlines.com website. http://www.pathologyoutlines.com/topic/softtissueneurofibroma.html. Accessed August 26th, 2019.
Definition / general
  • Benign peripheral nerve sheath tumor with classic identifiable features including the presence of a neuronal component comprising transformed Schwann cells and a nonneoplastic fibrous component that includes fibroblasts
Essential features
  • Well circumscribed, unencapsulated
  • Interlacing bundles of elongated cells with wavy darkly stained nuclei
  • Wire-like (shredded carrot) collagen
  • Dotted stroma with mast cells and lymphocytes
  • Small to moderate amount of mucoid material separating the cells and the collagen
  • CD34 positivity in cells of unclear histogenesis
  • S100 positivity in neural cells
Epidemiology
Sites
  • Localized neurofibromas are superficial and evenly disturbed over the body surface
  • Diffuse neurofibromas are usually in the head and neck region (Int J Trichology 2010;2:60)
  • Plexiform neurofibromas are localized to a major nerve trunk
Etiology
  • Neurofibromas are caused by a biallelic inactivation of the tumor suppressor gene neurofibromatosis type 1 which is located on 17q11.2
  • Non myelinating p75+ Schwann cell progenitors are the candidate cell for neurofibromatosis type 1 loss in plexiform neurofibroma (Cancer Cell 2008;13:117)
  • Dermal neurofibromas may have a non Schwannian precursor of a neural stem cell / progenitor
Diagrams / tables
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Common sites

Clinical features
  • Sporadic (localized variant)
    • Occurs in individuals who do not have neurofibromatosis type 1
    • Painless, slowly growing, solitary, skin colored, soft, flaccid, rubbery to firm papule or nodule with a smooth surface measuring up to 2 cm
    • Lesion invaginates with pressure
  • Cutaneous and subcutaneous
  • Inherited (diffuse and plexiform variants)
    • Close associations with neurofibromatosis type 1
  • Symptoms in patients with neurofibromatosis type 1 include chronic pain, disfigurement, stigma and anxiety (Am J Med Genet A 2017;173:79)
  • Rarely, neurofibromatous neuropathy can occur due to endoneurial fibrosis due to an altered relationship between Schwann cells and collagen fibrils (Ultrastruct Pathol 2018;42:312)
  • Diagnostic criteria of neurofibromatosis type 1 are met if 2 or more of the following are present:
    • ≥ 6 café au lait patches > 0.5 cm in prepubertal individuals or > 1.5 cm in postpubertal individuals
    • ≥ 2 neurofibromas of any type or 1 plexiform neurofibroma
    • Axillary or inguinal freckling
    • ≥ 2 Lisch nodules
    • Optic glioma
    • Sphenoid dysplasia or thinning of long bone cortex with or without pseudoarthrosis
    • First degree relative diagnosed with neurofibromatosis type 1
Radiology description
  • On CT, appears as a well defined hypodense mass with minimal or no contrast enhancement
  • On MRI, appears as a T1 hypointense and T2 hyperintense lesion with heterogeneous contrast enhancement
  • On MRI of a superficial neurofibroma, the signal characteristics are usually homogeneous or heterogeneous without targets (AJR Am J Roentgenol 2005;184:962)
  • Hybrid PET / MRI for the whole body of neurofibromatosis type 1 patients may be used for the detection of malignant transformation to malignant peripheral nerve sheath tumors (World J Nucl Med 2018;17:241)
  • Does not reliably differentiate between neurofibroma and schwannoma (Semin Musculoskelet Radiol 2019;23:76)
Radiology images

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CT mouth tumor

MRI mouth tumor

Ultrasound intrascrotal mass

Prognostic factors
  • Malignant transformation to malignant peripheral nerve sheath tumor in deeply seated neurofibromas in a subset of neurofibromatosis type 1 patients
  • Nuclear atypia (focal or diffuse) are accepted in neurofibromas
  • Low grade malignant peripheral nerve sheath tumor may be diagnosed if there is diffuse nuclear atypia, high cellularity and low level of mitotic activity
  • Nuclear atypia includes nuclear enlargement (nuclear size ≥ 3 times normal Schwann cells) and hyperchromasia
  • p16 can help to differentiate neurofibroma with atypical features from low grade malignant peripheral nerve sheath tumor (Am J Pathol 1999;155:1879)
Case reports
Treatment
  • Sporadic lesions not associated with neurofibromatosis type 1
    • Superficial neurofibromas respond well to marginal excision and deep-seated neurofibromas are treated conservatively
    • Sometimes it is difficult to be separated from the parent nerve, which may require sacrificing of the parent nerve to ensure complete excision
  • Inherited lesions associated with neurofibromatosis type 1
Clinical images

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Mouth

Skin

Gross description
  • Skin colored with glistening tan-white cut section
  • Localized neurofibroma can appear as a fusiform growth with myxoid and cystic areas (J Neurosci Rural Pract 2016;7:346)
  • Those arising from major nerves show fusiform expansion of the affected nerves and may appear encapsulated
  • Those arising from small nerves are well circumscribed but not encapsulated
  • Deeper tumors may cause tortuous enlargement of peripheral nerves (plexiform neurofibromas) (Acta Neuropathol 2012;123:295, Am J Med Genet 1999;89:23)
Gross images

Contributed by Engy Abdellatif MBBCh, M.D., Ph.D.
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Neurofibromatosis type I



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Large inguinal mass

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Esophageal mass

Microscopic (histologic) description
  • Proliferation of all elements of peripheral nerves
  • Schwann cells with wire-like collagen fibrils (wavy serpentine nuclei and pointed ends), stromal mucosubstances, mast cells, Wagner-Meissner corpuscles, Pacinian corpuscles, axons (highlight with silver or acetylcholinesterase stain, NSE, neurofilament), fibroblasts and collagen
  • Perineurial cells in plexiform types, mitotic figures are rare
  • May be infiltrative, have myxoid areas, contain melanin pigment, have epithelioid morphology
  • Rarely has skeletal differentiation
  • No Verocay bodies, no nuclear palisading, no hyalinized thickening of vessel walls (Acta Neuropathol 2012;123:295, Am J Med Genet 1999;89:23)
  • Subtypes
    • Plexiform: irregularly expanded nerve bundles with nodular appearance, prominent myxoid matrix; associated with neurofibromatosis type 1
    • Diffuse cutaneous: traps adnexa, infiltrates into fat
    • Focal cutaneous
    • Intraneural
Microscopic (histologic) images

Contributed by Engy Abdellatif MBBCh, M.D., Ph.D.

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Hypocellular spindle cells

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Mast cells

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Spindle cells and shredded carrot collagen

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Neurofibromatosis type I skin nodule

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S100 IHC

Virtual slides

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Abdominal skin lesion

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Polypoid skin lesion in arm

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Nodular skin lesion in shoulder

Cytology description
  • Loosely arranged small groups of spindle cells
  • Cells have scant cytoplasm and oval elongated and regular nuclei
  • Nucleoli are not seen
Cytology images

Contributed by Engy Abdellatif MBBCh, M.D., Ph.D.
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Bland spindle cells

Positive stains
Negative stains
Electron microscopy description
Videos

Different types of neurofibroma

Differential diagnosis
Schwannoma  Neurofibroma   
Epidemiology Age 20 - 50 Age 20 - 40
May occur in younger age 
Etiology Sporadic but may occur
in neurofibromatosis type 2 >
neurofibromatosis type 1
Sporadic, some in neurofibromatosis type 1
Macroscopic Encapsulated Softer, usually lacks capsule
Microscopic Antoni A and Antoni B
Alternating hypercellular
and hypocellular areas
Spindle cells, shredded
carrot collagen, mast cells,
hypocellular, myxoid areas
without hypercellular areas
Plexiform variant Less common More common
Immunohistochemistry S100: almost diffuse
Calretinin: stronger
CD34: scattered
(Korean J Pathol 2011;45:30)
Factor XIIIa: negative / focal 
S100: weaker
Calretinin: focal
CD34: stronger
(Korean J Pathol 2011;45:30)
Factor XIIIa: stronger 
Malignant transformation  Extremely rare Rare but can occur in
2 - 3% of neurofibromatosis type 1 patients


Neurofibroma  Malignant peripheral nerve
sheath tumor 
Microscopic features Smaller nuclear size, minimal hyperchromasia,
wavy nuclei, abundant shredded carrot type
collagen, rare fascicular growth pattern, no
necrosis and rare mitosis 
Larger nuclear size, marked hyperchromasia,
less evident wavy nuclei, rare shredded carrot
type collagen, obvious fascicular growth pattern, 
shows necrosis and conspicuous mitosis
S100 ++/+++ +/++
Collagen type IV ++/+++ +/++
EMA + -
CD34 +++ ++
Neurofilament protein  ++ +/+++
Podoplanin + +
SOX10 +++ +/++
Hyaluronan Lower levels Higher levels (Clin Exp Metastasi 2014;31:715)

This table was modified from (Acta Neuropathol 2012;123:295)

Board review question #1
    How can you differentiate between desmoplastic melanoma and neurofibroma using IHC?

  1. CD34
  2. EMA
  3. HMB45
  4. MelanA
  5. S100
Board review answer #1
A. CD34 is rarely positive in desmoplastic melanoma and is often patchy when it is.

Comment Here
Board review question #2
    Which one of the following immunohistochemical stains is positive in neurofibroma?

  1. CD34
  2. CK5 / 6
  3. EMA
  4. HMB45
  5. MelanA
Board review answer #2
A. CD34

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