Schwannoma

Schwannomas (also known as neurilemmomas) are benign nerve sheath tumors in the peripheral nervous system (PNS), arising from Schwann cells that encase the peripheral nerves. Schwannomas are the most common tumors in the PNS. Although schwannomas are typically sporadic, they can be associated with neurofibromatosis type II and schwannomatosis. The clinical presentation of schwannomas depends on their specific location, but general signs and symptoms include a palpable mass on the skin, pain, and/or paresthesias due to nerve compression. The diagnosis is established primarily based on imaging studies (MRI or CT), and the treatment is usually surgical resection.

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Overview

Definition

Schwannomas are benign, encapsulated nerve sheath tumors in the peripheral nervous system (PNS), arising from Schwann cells.

  • Schwann cells are a type of glial cell found in the PNS:
    • Envelop nerve fibers 
    • Produce the myelin sheath for peripheral nerves
    • Assist in the regeneration of damaged nerve fibers
  • Schwannomas are encapsulated with their cells of origin.
  • Malignant transformation is rare but possible.

Classification of nervous system tumors

Table: Classification of nervous system tumors
Categories Specific tumors
Neuroepithelial tumors in the CNS
  • Astrocytomas, including glioblastoma multiforme
  • Oligodendroglioma
  • Ependymoma and choroid-plexus tumors
  • Medulloblastomas (embryonal tumors)
Meningeal tumors
  • Meningiomas
  • Hemangioblastomas
Sellar region tumors
  • Craniopharyngioma
  • Pituitary adenoma
  • Pinealoma/pinealoblastoma
Primary CNS lymphoma Primary CNS lymphoma
Metastasis to the brain (5x more common than primary brain tumors) Most commonly arising from:
  • Lung, breast, and renal cell carcinomas
  • Melanoma
Peripheral tumors
  • Schwannomas, including acoustic neuroma
  • Neuroblastoma

Epidemiology

  • Most common tumor of the PNS
  • 60% are vestibular schwannomas (also known as acoustic neuromas).
  • Incidence: approximately 5 per 100,000 adults per year
  • Age of peak incidence: 20 to 60 years
  • No racial/ethnic or sex predilections

Etiology

  • Cause is unknown.
  • 90% of cases are sporadic.
  • Some cases are associated with:
    • Neurofibromatosis type II
    • Schwannomatosis
    • Carney complex (disorder characterized by multiple tumors)

Pathophysiology

  • NF2 gene on chromosome 22:
    • Appears to play an essential role in sporadic and syndromic schwannoma development
    • Encodes for the merlin protein (also known as schwannomin)
    • Merlin protein: a tumor suppressor protein involved in cytoskeletal organization
    • NF2 gene mutations → ↓ merlin formation 
    • Inactivation of both alleles of NF2 is observed in most schwannoma cases.
  • In Carney complex: loss of expression of PRKAR1A (which codes for a regulatory subunit of protein kinase A)
  • Most cases arise sporadically and with only a single lesion: Multiple lesions are more common with an associated genetic condition.

Classification

Schwannomas can be classified into 1 of 4 primary types based on histology.

Table: Classification of schwannomas
Type of schwannoma Key points
Classic schwannoma
  • Most common type
  • Encapsulated, benign tumors
Cellular schwannoma
  • ↑ Cellularity and mitotic activity
  • No malignant potential
  • Recurrence is higher than in classic schwannoma.
  • Primarily found in the paravertebral region
Plexiform schwannoma
  • Aggregation of multiple schwannomas
  • Forms along a nerve plexus (e.g., brachial plexus, lumbosacral plexus)
  • Can be associated with neurofibromatosis type II and schwannomatosis
  • High local recurrence rate
  • No malignant potential
Melanotic schwannoma
  • Malignant potential
  • Rare, arising around spinal nerve roots
  • Can produce melanin A pigmentation

Clinical Presentation

Locations

Aside from acoustic neuromas (which arise from the 8th cranial nerve), schwannomas may form in a variety of locations throughout the body:

  • Most commonly in the upper limbs
  • Other common locations:
    • Head
    • Trunk
    • Flexor surfaces of the lower extremities
  • Less common/rare locations:
    • Spinal roots
    • Posterior mediastinum
    • Retroperitoneum
    • Bone
    • GI tract
    • Liver and pancreas
    • Thyroid and adrenal glands

Symptom development

  • Signs and symptoms of schwannoma depend on the specific location of the tumor. 
  • Symptoms develop due to local compression of the adjacent nerve.
  • Schwannomas typically grow slowly and may exist for years without symptoms; most are asymptomatic.
  • Average time from onset of symptoms to diagnosis is 5.5 years.

Signs and symptoms

When symptoms do occur, they may include:

  • Circular mass palpable on the skin
  • Tenderness to palpation
  • Paresthesias due to nerve compression
  • Weakness and/or sensory loss along the distribution of the affected peripheral nerve: 
    • Radicular pain from spinal nerve or plexus impingement
    • Sciatic nerve schwannomas: can present similarly to disc herniation with low back and lower extremity radicular symptoms
    • C7 nerve root involvement: may produce thoracic outlet syndrome
    • Ankle: tarsal tunnel symptoms
    • Wrist: carpal tunnel symptoms
    • Trigeminal involvement: causes numbness or pain in the trigeminal nerve distribution
  • Acoustic neuromas present with:
    • Decreased hearing
    • Tinnitus
    • Imbalance

Diagnosis

Following a suggestive history and exam, the diagnosis is primarily established via imaging and can be confirmed on biopsy.

Imaging

  • MRI scan:
    • Imaging modality of choice
    • Oval or round mass that enhances uniformly with gadolinium contrast
    • T1-weighted MRI: isodense (or hypodense) to muscle
    • T2-weighted MRI: hyperdense to muscle
    • Target sign may be present:
      • Central area of hypodensity with a peripheral T2 signal hyperintensity
      • Most specific sign of a peripheral nerve sheath tumor
      • Not specific for schwannoma
  • CT scan:
    • Hypodense to muscle
    • Enhances with contrast
  • Ultrasound:
    • Can detect schwannomas under the skin
    • Useful during surgery
Mri showing schwannoma

MRI showing schwannoma involving dorsal cutaneous branch of ulnar nerve

Image: “Schwannoma in the upper limbs” by Tang CY, Fung B, Fok M, Zhu J. License: CC BY 3.0

Biopsy and histopathology

Classic schwannomas:

  • Surrounded by a well-defined fibrous capsule
  • Contains 2 distinct histologic regions:
    • Antoni A tissue: 
      • Dense hypercellular area
      • Predominantly benign spindle cells in intersecting bundles
      • May palisade around eosinophilic areas (Verocay bodies)
      • Positive for S100 protein staining
    • Antoni B tissue:
      • Loose, hypocellular, myxoid area
      • Background of loose connective tissue (myxomatous in appearance)
  • Degenerative changes in longstanding (sometimes referred to as “ancient”) schwannomas:
    • Marked nuclear pleomorphism
    • Degenerative cysts
    • Signs of remote hemorrhage and calcifications
    • Blood vessel hyalinization

Distinctive features of other types:

  • Cellular schwannomas: 
    • Predominantly Antoni A tissue without Verocay bodies
    • ↑ Cellularity and mitotic activity
    • May be locally destructive
    • Will stain positive for S100 protein
  • Plexiform schwannomas: 
    • Aggregations of multiple schwannomas: plexiform pattern of growth involving multiple fascicles
    • Less well circumscribed and may even lack a capsule
    • Predominantly Antoni A tissue
    • ↑ Cellularity and mitotic activity
  • Melanotic schwannomas: 
    • Show dense melanin pigmentation
    • May stain positive for:
      • MelanA
      • Glial fibrillary acidic protein (GFAP, more commonly seen in astrocytomas)
      • Neurofilament protein

Grading

Schwannomas are commonly classified according to the Enneking system of benign lesions. There are 3 grades, and most schwannomas are grade II or III lesions.

  • Grade I: inactive lesions
  • Grade II: not destructive or locally aggressive but may cause deformation of surrounding tissues
  • Grade III: locally aggressive and may invade local tissues but are not metastatic

Management

Asymptomatic cases

  • Observation and follow-up
  • Consider a biopsy.

Symptomatic cases

For patients with functional deficits and/or pain due to nerve compression, treatment is recommended.

  • Surgical excision (mainstay of treatment):
    • The vast majority of patients tolerate surgery well and have rapid symptom relief.
    • Complications: neuropraxia (rare but can be permanent)
  • Radiation therapy:
    • May be considered, especially in patients with acoustic neuromas or tumors near vital blood vessels or nerves
    • Typically not needed due to low risk of metastasis and recurrence

Differential Diagnosis

  • Neurofibroma: another benign tumor of the peripheral nervous system, arising from a mix of Schwann cells, perineural-like cells, nerve fibers, myxoid stroma, and fibroblasts. Neurofibromas can arise sporadically or in association with neurofibromatosis type I. Neurofibromas present as a palpable circular mass on the skin accompanied by pain, paresthesia, and bleeding. Diagnosis is made by imaging studies and biopsy, and treatment is either observation or, in symptomatic patients, surgical resection. 
  • Malignant peripheral nerve sheath tumor (MPNST): also referred to as malignant schwannomas, these are highly malignant, locally invasive sarcomas. These tumors do not arise from benign schwannomas; rather, they arise from de novo mutations or degeneration of plexiform neurofibromas. Malignant peripheral nerve sheath tumors are strongly associated with neurofibromatosis type I and mutations in the NF1 gene. These tumors may appear similar to cellular or plexiform schwannomas in particular, but MPNSTs generally do not express S100 protein.
  • Perineurioma: benign PNS tumors arising from the perineural cells. Perineuriomas are most commonly sporadic and present with palpable skin masses along the large nerves, pain, and paresthesias. As with schwannomas, diagnosis is made via imaging and biopsy, and the treatment is surgical resection in symptomatic patients. 
  • Ganglioneuroma: slow-growing, large, encapsulated tumors arising from the sympathetic ganglion cells. Ganglioneuromas can occur anywhere along the sympathetic chain. Clinical presentation depends on their specific location, with common locations including the mediastinum, retroperitoneum, and adrenal glands, and the symptoms are due to mass effect (e.g., constipation, radicular pain). Diagnosis is made by imaging studies and biopsy, and treatment is surgical resection. 
  • Ganglion cyst: benign cystic tumors filled with a mucinous, gelatinous fluid that arise from a herniation of connective tissue associated with nearby joints or tendons. Ganglion cysts form primarily on the dorsal wrist, and presentation is related to pressure on surrounding nerves with resultant pain, numbness, and weakness. Diagnosis is made by history and physical exam findings, as well as plain X-rays, MRI, or ultrasound. Symptomatic management is with aspiration or surgery (open or arthroscopic).
  • Lipoma: benign tumors of the subcutaneous fat that can occur on any part of the body. Lipomas are typically soft, painless nodules. Diagnosis is typically clinical, though ultrasound can help distinguish a lipoma from cystic structures. Treatment is observation or surgical excision.

References

  1. Gilchrist, JM, Donahue, JE. (2021). Peripheral nerve tumors. UpToDate. Retrieved May 16, 2021, from https://www.uptodate.com/contents/peripheral-nerve-tumors 
  2. Laufer, I, Bilsky, M. (2021). Intradural nerve sheath tumors. UpToDate. Retrieved May 16, 2021, from https://www.uptodate.com/contents/intradural-nerve-sheath-tumors 
  3. Dickey, ID. (2020). Neurilemmoma (Schwannoma): Practice essentials, etiology, epidemiology. Medscape. Retrieved May 17, 2021, from https://emedicine.medscape.com/article/1256405-overview
  4. Davis, DD, Kane, SM. (2020). Neurilemmoma. StatPearls. Retrieved May 15, 2021, from https://pubmed.ncbi.nlm.nih.gov/32809662/
  5. Sheikh, MM, De Jesus, O. (2021). Schwannoma. StatPearls. Retrieved May 16, 2021, from https://www.statpearls.com/articlelibrary/viewarticle/28766/ 

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