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Neurofibroma

Plexiform neurofibroma


Valeriya Skorobogatko, B.A.
Brandon Umphress, M.D.

Last author update: 16 May 2023
Last staff update: 16 May 2023

Copyright: 2002-2023, PathologyOutlines.com, Inc.

PubMed Search: Plexiform neurofibroma

Valeriya Skorobogatko, B.A.
Brandon Umphress, M.D.
Page views in 2022: 14,228
Page views in 2023 to date: 7,650
Table of Contents
Definition / general | Essential features | Terminology | ICD coding | Epidemiology | Sites | Pathophysiology | Etiology | Clinical features | Diagnosis | Laboratory | Radiology description | Radiology images | Prognostic factors | Case reports | Treatment | Clinical images | Gross description | Gross images | Microscopic (histologic) description | Microscopic (histologic) images | Virtual slides | Positive stains | Negative stains | Electron microscopy description | Molecular / cytogenetics description | Videos | Sample pathology report | Differential diagnosis | Board review style question #1 | Board review style answer #1 | Board review style question #2 | Board review style answer #2
Cite this page: Skorobogatko V, Umphress B. Plexiform neurofibroma. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/softtissueneurofibromaplexiform.html. Accessed June 10th, 2023.
Definition / general
  • Benign, peripheral nerve sheath tumor that arises from Schwann cells; generally surrounds multiple nerve fascicles
  • Demonstrates irregularly thickened and distorted, tortuous configurations
  • Plexiform: complex; in the form of a plexus or network
Essential features
  • Benign tumor arising from nerve sheath cells
  • Most likely congenital and strongly associated with neurofibromatosis 1 (NF1)
  • May be locally aggressive and infiltrate into surrounding tissue causing symptoms
  • Immunohistochemistry shows scattered S100 reactivity and EMA can highlight perineurial cells
  • Carries risk of developing into malignant peripheral nerve sheath tumor (MPNST)
  • Surgical excision can be curative; however, recurrence rate is high
    • Medications such as MEK inhibitors have also shown promising results in NF1 patients
Terminology
  • Plexiform neurofibroma (PN, PNF)
ICD coding
  • ICD-10: D36.10 - benign neoplasm of peripheral nerves and autonomic nervous system, unspecified
Epidemiology
Sites
Pathophysiology
  • Neural crest stem cell (variable NF1) → neuro / glial lineage or Schwann cell lineage (variable NF1) → plexiform neurofibroma (negative NF1)
  • Cell of origin: Schwann cell precursors (Neurooncol Adv 2019;2:i13)
  • Normally, activated Ras (GTP) is dephosphorylated by neurofibromin to inactivated Ras (GDP)
  • Loss of heterozygosity → inactive neurofibromin
  • Inactive neurofibromin → activated Ras stays constitutively on to activate signaling pathways downstream → tumor development (Nat Rev Cancer 2015;15:290)
  • PN formation involves tumor cells and immune cells, such as mast cells and macrophages, to participate in growth through inflammation (Neurooncol Adv 2019;2:i23, J Clin Invest 2018;128:2848)
  • Mast cells are recruited by chemoattractant stem cell factors within tumors (Stem Cell Res 2020;49:102068)
  • Inhibition of JAK / STAT3 pathway was shown to reduce inflammatory cytokine expression and number of macrophages within tumor → reduced tumor growth (Oncogene 2019;38:2876)
Etiology
Clinical features
Diagnosis
  • Typically a clinical diagnosis with biopsy demonstrating classic histologic characteristics
  • MRI or PET / CT may be utilized based on the size and location of the lesion
  • F-FDG PET / CT may be used to discriminate between benign and malignant PN and monitor tumor progression (Medicine (Baltimore) 2018;97:e10648)
Laboratory
Radiology description
Radiology images

Images hosted on other servers:

Neck mass (ultrasound)

Face and neck tumor (CT)

Face and neck tumor (MRI)

Wrist mass (MRI)

Prognostic factors
  • Increased mortality risk in pediatric NF1 populations (J Pediatr 2012;160:461)
  • Recurrence following surgery is common (Neurol Sci 2022;43:1281)
    • Partial resection (< 50% excision): 55 - 68% recurrence
    • Subtotal resection (50 - 90% excision): 29 - 45% recurrence
    • Near total resection (> 90% excision): 40% recurrence
  • Greatest risk of recurrence postsurgery is in children < 10 years old with head and neck PN (Arch Otolaryngol Head Neck Surg 2005;131:712)
  • PNs are 20x more likely to have malignant transformation into MPNST compared to cutaneous neurofibromas (Neurology 2005;65:205)
Case reports
Treatment
Clinical images

Images hosted on other servers:

Periorbital swelling with hypertrichosis

Facial mass

Thigh mass

Hyperpigmentation overlying tumor

Palmar mass

Gastric mass

Gross description
Gross images

Images hosted on other servers:

Soft irregular mass

Multiple tubular structures

Myxoid-like white tan tissue

Irregular, encapsulated, nodular mass

Microscopic (histologic) description
  • Multinodular, plexiform or tortuous bundles of bland spindle cells consistent with expanded nerve branches
  • On high power, cytologic characteristics are often analogous to those of conventional neurofibromas
  • Can be relatively hypocellular with myxoid type changes, comprised of Schwann cells, fibroblasts and mast cells
  • Outer area of the proliferation is lined by perineurium
  • Rarely is pigmented due to melanocytes (J Am Acad Dermatol 2007;56:862)
  • Can display nuclear atypia; care should be exercised when viewing lesions with increased cellularity and increased atypia as these lesions can undergo malignant transformation
  • Small cutaneous lesions showing a microscopic plexiform pattern may not necessarily be associated with NF1
Microscopic (histologic) images

Contributed by Brandon Umphress, M.D.

Plexiform, tortuous architecture

Detached fragments of plexiform growth

Cytologic and background features

Adjacent peripheral nerve


Cytologic characteristics

 

Plexiform growth

Virtual slides

Images hosted on other servers:
 

Vague plexiform growth

Deep subcutaneous lesion

Dermal and subcutaneous involvement

Positive stains
Electron microscopy description
  • Tumor contains neuronal axons, Schwann cells, fibroblasts
  • Peripheral nerves with mucinous degeneration (Eur J Med Res 2010;15:84)
Molecular / cytogenetics description
  • NF1 loss appears to frequently be the driver of plexiform neurofibroma tumorigenesis in NF1 patients (Oncogene 2017;36:3168)
  • Epidermal growth factor receptor erb-b2 receptor tyrosine kinase 2 (ERBB2) and ERBB3 were significantly upregulated in PN (Anticancer Res 2022;42:2327)
  • MicroRNA-155 has demonstrated a role in PN growth and Schwann cell proliferation; microRNA-155 deletion in vivo significantly decreased tumor number and volume in mouse models (Oncogene 2021;40:951)
  • Deletion of chemokine Cxcl10 receptor Cxcr3 prevents PN formation in mouse models, demonstrating T cell and dendritic cell role; Cxcr3 expression in both of those cells is required to maintain elevated macrophages and the inflammatory microenvironment (JCI Insight 2019;4:e98601)
  • CXCR4 gene expression is increased 3 - 120 fold and CXCL12 gene expression is increased 33 - 512 fold (Childs Nerv Syst 2018;34:877)
  • IL8, GRO1 / CXCL1, IL1B, IL6, TNF and leukemia inhibitory factor are overexpressed (Clin Cancer Res 2004;10:3763)
  • Upregulation of AP1 transcription factor family including FOS, FOSB, JUN and JUNB are implicated in cell transformation, invasive growth, angiogenesis and metastasis (Clin Cancer Res 2004;10:3763)
  • Upregulation of apoptotic genes including TNFRSF10A / TRAILR1 and TNFRSF10B / TRAILR2 (Clin Cancer Res 2004;10:3763)
  • KIS gene is overexpressed in PN and MPNSTs compared to dermal neurofibromas (Brain Res Mol Brain Res 2003;114:55)
Videos

Plexiform neurofibroma

Sample pathology report
  • Left thigh, subcutaneous tissue, excision:
    • Plexiform neurofibroma (see comment)
    • Comment: The findings are those of an expansile proliferation within the subcutaneous fat, which demonstrates tortuous bundles of bland cells with wavy and elongated nuclei. Subtle background features of myxoid change are appreciated. Furthermore, overt evidence of malignancy (atypia, necrosis and mitoses) is not appreciated. In the context of the patient's reported history of neurofibromatosis type 1 (NF1), the histologic findings would be most consistent with those of a plexiform neurofibroma. In this regard, clinicopathologic correlation is recommended.
Differential diagnosis
  • Plexiform schwannoma:
    • S100+ (strong and diffuse)
    • Histologically demonstrates multiple nodules of varying sizes with a very thin capsule and otherwise typical features of schwannoma (hypercellular and hypocellular areas, Verocay bodies)
  • MPNST:
    • Histologically demonstrates hypercellularity, significant atypia, increased mitotic figures and a marbled appearance
      • Loss of nuclear H3K27me3 in high grade and radiation associated tumors
      • Loss of INI1 can be seen in epithelioid MPNSTs
  • Perineurioma:
    • S100-, EMA+, claudin1+, GLUT1+
    • Nonencapsulated, well demarcated spindle cell tumor composed of cells with a slender, fibroblast-like appearance with long, delicate cytoplasmic processes
    • Histologically demonstrates fibrotic stroma, frequent myxoid generation, variable celluarity
  • Dermatofibroma:
    • Exhibits collagen trapping
    • Typically FXIIIa+ and CD34-
  • Plexiform fibrohistiocytic tumor:
    • Can exhibit plexiform growth, however, demonstrates nodular fibrous tissue with associated histiocytes and possibly osteoclast-like giant cells
    • S100-
Board review style question #1


A 16 year old boy presents with a mass on his neck. Physical exam reveals multiple café au lait macules on the trunk and axillary freckling. Biopsy of the mass demonstrates multiple torturous nodules with cylindrical enlargement of nerves, scattered mast cells and variable S100 reactivity. When did the patient likely develop the mass?

  1. Birth
  2. 1 - 5 years of age
  3. 6 - 10 years of age
  4. 11 - 16 years of age
Board review style answer #1
A. Birth. A is the correct answer because the diagnosis is plexiform neurofibroma. Diagnosis is supported with clinical features of NF1 and histological findings. PNs are congenital tumors that may take several years to manifest clinically due to slow growth. B, C and D are not the correct answers because the tumor was more than likely present at birth.

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Reference: Plexiform neurofibroma
Board review style question #2
Which of the following stains is positive in plexiform neurofibroma?

  1. Cytokeratin AE1 / AE3
  2. Mucicarmine
  3. SMA
  4. S100
Board review style answer #2
D. S100. Plexiform neurofibromas stain with S100 in scattered cells. Answers A - C are incorrect because PN does not demonstrate cytokeratin AE1 / AE3, mucicarmine or SMA positivity.

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Reference: Plexiform neurofibroma
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