Schwannoma (Neurilemmoma)

A schwannoma (also called a neurilemmoma or neurinoma) is a benign peripheral nerve sheath tumour arising from Schwann cells. Schwannomas account for approximately 5% of all benign soft-tissue tumours and are the most common tumour of peripheral nerves after the neurofibroma.

Why the diagnosis matters. A schwannoma grows eccentrically and displaces the nerve fascicles, which leaves a natural cleavage plane and allows microsurgical enucleation without dividing the nerve trunk. A neurofibroma infiltrates the fascicles and usually requires nerve sacrifice for complete excision. Telling the two apart before surgery decides the operation and what the patient is told about neurological outcome.

Incidence. The overall incidence is 1-2 per 100,000 population per year, and peripheral nerve schwannomas are 90% solitary and sporadic. Vestibular schwannoma, at 1 per 100,000 per year, is the most common cerebellopontine angle tumour and accounts for 8-10% of intracranial tumours.

Distribution. The limbs carry most peripheral tumours:

• Upper extremity - 40% (median, ulnar and radial nerves common)
• Lower extremity - 30% (sciatic, tibial and peroneal nerves)
• Head and neck - 25% (vestibular, vagus, sympathetic chain)
• Trunk - 5% (intercostal and paraspinal nerves)

Special locations. The vestibular schwannoma, or acoustic neuroma, arises on the 8th cranial nerve. Spinal schwannomas are most commonly intradural extramedullary. Mediastinal and retroperitoneal tumours are rare and often large at presentation.

Origin. Schwannomas arise by neoplastic transformation of Schwann cells, the myelinating cells of peripheral nerves. The genetic lesion is loss of the NF2 gene on chromosome 22q12, which encodes merlin (schwannomin), a tumour suppressor that links the cell membrane to the cytoskeleton and regulates cell growth. Loss of heterozygosity follows the two-hit hypothesis: a germline plus a somatic mutation in NF2.

Growth pattern. The tumour grows eccentrically from the nerve inside a true capsule of compressed epineurium and perineurium. The normal fascicles are displaced to the periphery of the tumour rather than infiltrated, and the natural plane between capsule and fascicles is the one enucleation follows. Growth is slow: 1-2 mm/year is quoted for peripheral tumours and as the mean for vestibular schwannomas.

NF2-related schwannomatosis (formerly neurofibromatosis type 2). Inheritance is autosomal dominant, with 50% penetrance by age 30 and nearly 100% by age 60. Half of cases are sporadic new mutations and half are familial. The disease produces:

• Bilateral vestibular schwannomas - pathognomonic, in nearly 100% of NF2 patients by age 60, with progressive bilateral sensorineural hearing loss
• Multiple schwannomas of peripheral, cranial and spinal nerves; the peripheral ones may be subcutaneous
• Multiple CNS tumours, characteristically meningiomas (45-58%) and spinal ependymomas (33%)
• Juvenile posterior subcapsular or cortical cataracts (60-81%)
• Fewer café-au-lait spots than NF1

NF1 produces neurofibromas rather than schwannomas, with café-au-lait spots, and its plexiform type transforms to MPNST.

Diagnostic criteria. The modified National Institutes of Health criteria make the diagnosis on any of:

1. Bilateral vestibular schwannomas on MRI or histology - diagnostic alone
2. A unilateral vestibular schwannoma plus a first-degree relative with NF2
3. A unilateral vestibular schwannoma plus two of meningioma, schwannoma, glioma or juvenile cataract
4. Two or more peripheral schwannomas plus a first-degree relative with NF2

Schwannomatosis, the third syndrome. The classic exam triad is NF1 versus NF2 versus schwannomatosis, and schwannomatosis is the one that must be separated from NF2. It is defined by multiple (usually non-vestibular) schwannomas in the absence of bilateral vestibular schwannomas, and that absence is what separates it from NF2. The cause is germline loss-of-function in SMARCB1 or LZTR1, both on chromosome 22 near the NF2 locus, and many cases are sporadic.

How it presents. The dominant clinical feature is chronic, often disproportionate pain, rather than a hearing loss or a single mass, with peripheral and spinal schwannomas. Intracranial meningiomas can occur, especially with SMARCB1; the cataracts and other NF2 stigmata are absent. Pain control is central to management, with excision of symptomatic schwannomas, surveillance imaging and genetic counselling.

Gross appearance. An ovoid or fusiform mass along the nerve, typically 2-5 cm at presentation though it can be larger, with a well-defined, smooth, glistening capsule. The nerve fascicles are visible at the poles of the tumour, displaced rather than infiltrated. The cut surface is tan-yellow to grey-white, and central cystic degeneration is common in large tumours.

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The biphasic pattern. Two kinds of tissue lie side by side. Their proportion varies, some tumours mostly Antoni A and others mostly Antoni B, and has no prognostic significance.

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Antoni A (cellular). Highly cellular spindle cells in compact fascicles with little stroma. The nuclei are elongated, wavy and buckled with pointed, tapered ends, the cytoplasm is minimal, and there is no significant atypia unless the tumour is ancient. Antoni A areas dominate most schwannomas.

Verocay bodies. Rows of palisaded nuclei around an intervening anuclear eosinophilic zone, found in Antoni A tissue. They are pathognomonic: highly specific for schwannoma and not seen in neurofibroma, though they may be sparse or absent in some schwannomas.

Antoni B (hypocellular). Loosely arranged spindle cells in abundant myxoid to collagenous, oedematous stroma, with common microcystic change and thick-walled hyalinised vessels. Lipidised cells and haemosiderin-laden macrophages from old haemorrhage may be present. Antoni B areas reflect degenerative change and long-standing lesions.

Immunohistochemistry is essential for the diagnosis and for separating schwannoma from other spindle-cell tumours.

The negative markers exclude the mimics:

• EMA (epithelial membrane antigen) - negative; positive in perineurioma
• Neurofilament - negative within the tumour, highlighting entrapped axons at the periphery
• Desmin and SMA - negative, excluding smooth-muscle tumours

Variants that mimic malignancy. Beyond the ancient and plexiform forms, two histological variants are high-yield. The cellular schwannoma is benign but is repeatedly over-called as malignant; the melanotic schwannoma is the one variant with real malignant potential.

Cellular schwannoma. A highly cellular tumour composed almost entirely of Antoni A tissue with few or no Verocay bodies, sometimes with brisk mitoses, so it is frequently misdiagnosed as MPNST or a spindle-cell sarcoma. It favours deep, axial sites: retroperitoneum, pelvis, mediastinum and paravertebral region. Do not over-call malignancy on cellularity or mitoses alone; these features confirm it is benign:

• Diffuse strong S100 (MPNST loses S100)
• An intact pericellular basement membrane (collagen IV, laminin)
• A peripheral lymphocytic cuff and a capsule, with subcapsular foamy macrophages
• Absence of true geographic necrosis and of infiltrative growth

Melanotic schwannoma. A pigmented, melanin-containing variant. The psammomatous melanotic form is associated with the Carney complex and, unlike other schwannomas, has genuine malignant potential, roughly 10 percent behaving malignantly, so it warrants closer follow-up. A benign microcystic/reticular variant, often in the GI tract, also exists.

History. The most common presentation is a painless mass (60-70%), usually present for years. Paraesthesiae or numbness in the nerve's distribution occur in 30-40%. Motor weakness is uncommon unless the tumour is large or on a critical nerve.

Presentations by site.

• Vestibular schwannoma - unilateral hearing loss, tinnitus, imbalance
• Spinal schwannoma - radicular pain, myelopathy
• Sympathetic chain - Horner syndrome
• Vagus nerve - hoarseness, dysphagia

Inspection. A fusiform swelling along the course of the nerve, with normal overlying skin, unlike the skin changes over a plexiform neurofibroma. Multiple masses suggest NF2 or schwannomatosis, so look for café-au-lait spots.

Palpation. The mass is firm and rubbery, firmer than a neurofibroma, with smooth, well-defined margins from its capsule, and is non-tender unless compressed or malignant. It moves perpendicular to the nerve axis but is fixed parallel to it, because it is attached to the nerve.

Tinel sign. Tap directly over the mass with a reflex hammer; a positive test is an electric-shock sensation radiating in the nerve's distribution. It is highly suggestive of a nerve sheath tumour, schwannoma or neurofibroma, with a sensitivity of 60-70% and a specificity of 85-90%.

Neurological assessment. Record light touch, pinprick and two-point discrimination in the nerve's distribution, the strength of the muscles it supplies, and the deep tendon reflexes. This baseline is essential before surgery.

MRI is the gold standard for diagnosis and surgical planning. The schwannoma protocol:

• T1-weighted pre-contrast
• T2-weighted with fat saturation
• T1-weighted post-gadolinium contrast
• STIR (short tau inversion recovery)

Signal. On T1 the tumour is isointense to muscle, a fusiform mass along the nerve with fat around it (the split-fat sign). It is hyperintense on T2 and on fat-suppressed T2, where the entering and exiting nerve can be seen. After gadolinium, Antoni A tissue enhances more than Antoni B.

The target sign. Peripheral T2 hyperintensity with central T2 hypointensity. It is a classic feature of neurofibroma, not of schwannoma, though schwannomas can show it. Its established diagnostic value is benign versus malignant: in the series that defined it, the sign was present in all 12 neurofibromas and only 1 of 11 MPNSTs, so loss of a previously present target sign is a warning sign, not a reassuring one.

The fascicular sign, multiple small ring-like fascicles, is the feature that leans towards schwannoma.

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Ultrasound. Useful for superficial palpable nerve tumours, to guide biopsy, to separate a nerve tumour from other soft-tissue masses, and as a lower-cost alternative to MRI, although MRI is superior for surgical planning. The findings:

• Hypoechoic fusiform mass with the entering and exiting nerve visible
• Posterior acoustic enhancement (characteristic)
• Internal vascularity on Doppler (target pattern)
• Split-fat sign - a hyperechoic fat rim around the tumour, indicating nerve origin

Electrodiagnostics. Nerve conduction studies and EMG document baseline nerve function and the extent of nerve involvement before surgery, and help separate a tumour from other causes of neuropathy; they are useful for baseline documentation but not diagnostic. Conduction studies may show focal slowing across the tumour, reduced amplitude when fascicles are significantly compressed, and conduction block in large tumours. EMG shows denervation if motor fascicles are compressed, helps localise the level of the lesion and gives a baseline for postoperative comparison.

The incidental peripheral schwannoma. An asymptomatic tumour can be observed with annual MRI, given its slow growth and low malignant potential.

The symptomatic peripheral schwannoma. Pain, paraesthesiae or mass effect are the indications for microsurgical enucleation. The nerve trunk is spared in over 90% and recurrence is under 5%, but warn that a new deficit is usual early and persists in about 30% (Complications, below).

Vestibular schwannoma. A tumour under 1.5 cm is observed with serial MRI or treated with radiosurgery: growth is slow, and observation preserves hearing. A tumour over 2.5 cm, or a symptomatic one, is excised microsurgically to prevent brainstem compression and decompress the facial nerve. Pollock's prospective comparison (below), in tumours under 3 cm, found equivalent tumour control with normal facial movement and serviceable hearing preserved more often after radiosurgery, and concluded that radiosurgery should be considered first-line for most small-to-medium vestibular schwannomas.

NF2 with bilateral vestibular schwannomas. Surgery is selective, using hearing-preservation techniques, because bilateral deafness is devastating; consider a cochlear implant.

The deficit figures to consent with. A new neurological deficit after enucleation is the rule, not the exception, but series disagree on how often, most likely because they count it differently. Park examined specifically for deficit in 56 upper-limb schwannomas; Abe counted new symptoms reported in 131 tumours. Most of Park's new deficits were minor sensory disturbance that recovered, so the figure that matters to a patient is the major deficit, 10 of 56.

Global Epidemiology

Schwannomas are encountered worldwide and are among the most common benign peripheral nerve tumours. Vestibular schwannoma incidence has risen across high-income health systems over recent decades, largely because of widespread MRI use detecting small intrameatal tumours; reported incidence ranges from roughly 1 to 2 per 100,000 person-years, with most contemporary tumours being small at diagnosis. The Copenhagen national cohort cited incidence approaching 20 per million per year and showed that the majority of observed vestibular schwannomas never grow (DOI). NF2 is rare and broadly consistent across populations at approximately 1 in 33,000 births (DOI).

Side-by-Side Guideline and Society Guidance

Practice Variation and Registry Evidence

Referral and Medicolegal Considerations