Introduction
Background
A neurilemoma (NL) is a benign, usually encapsulated neoplasm derived from Schwann cells and, along with neurofibroma, constitutes one of the 2 most common benign peripheral nerve sheath tumors. The peripheral nervous system can be defined as nervous tissue outside the brain and spinal cord. It extends from the glial-schwannian junction in the cranial nerves and spinal roots to the termination of the nerve fibers in their end organ receptors and includes the posterior root ganglia and those of the autonomic nervous system. NLs may affect any location in the course of the peripheral nervous system (ie, cranial and spinal nerve roots, cranial and peripheral nerves, end organ receptors, small nerve twigs). They are common in paravertebral locations and the flexor regions of the extremities (especially near the elbow, wrist, and knee) and occasionally involve the skin. The presence of a noninvasive tumor next to a peripheral nerve suggests the diagnosis of neurilemmoma.
Four major forms of NL are recognized. These include conventional (common, solitary), cellular, plexiform, and ancient forms. Specific variants have been associated with an increased risk of local recurrence following incomplete excision (plexiform and giant sacral NL). Other variants are associated with genetic syndromes such as Carney complex (ie, psammomatous melanotic schwannoma), neurofibromatosis type 2 (NF2, ie, cranial or spinal root NL), and neurilemmomatosis (schwannomatosis), which is a variant of NF2 characterized by multiple NLs.
Of note, the benign nerve sheath tumors are classified as World Health Organization grade I on the basis of their benign cytologic features, in contrast to the malignant counterparts, which are World Health Organization grade III or IV.
The synonym schwannoma is often used interchangeably with NL. Other synonyms include neurolemmoma and peripheral fibroblastoma.
Pathophysiology
An understanding of the relationship of the Schwann cell to other neuronal elements in the peripheral nervous system is helpful in conceptualizing the pathophysiology of an NL.
The peripheral nervous system differs from the central nervous system in the nature of its supporting cell; the Schwann cell supports the former and the neuroglial cells support the latter. It is generally accepted that in embryogenesis, the Schwann cells are derived from the neural crest and are of neuroectodermal origin. As the peripheral nerves form, the Schwann cells migrate peripherally from the spinal ganglia, parallel to the axons, and encase them with their cytoplasm. In myelinated fibers, only one axon segment is encased by one Schwann cell.
The myelin sheath is created by a synthesis and wrapping of Schwann cell plasma membrane around the axon. Schwann cells sheath the axons from the point at which the latter penetrate the pia mater to their terminations. Upon penetrating the pia, the neuroglia is lost; the individual nerve fibers pass through a sievelike structure composed of reticulin (young collagen fibers), and, thereafter, each is contained within its ensheathing tube of reticulin and Schwann cell elements.
At this site, perineurial cells (perineural epithelium) also make their appearance. In nonmyelinated nerves, several axon segments are ensheathed by a common Schwann cell. In a fully developed nerve, a layer of connective tissue, or epineurium, surrounds the entire nerve trunk. Several nerve fascicles lie within the confines of the epineurium, and each is surrounded by a well-defined perineurium. The smallest connective tissue unit of the nerve is the endoneurium, which is a network of fibroblasts, blood vessels, and collagen encircling individual nerve fibers).
NLs arise within a nerve consisting of a single fascicle. The tumors are composed entirely of the supporting Schwann cells and peripherally displaced nerve fibers, resulting in a globoid eccentric tumor mass. In the early intrafascicular growth phase, small NLs displace nerve fibers without forming a capsule. The larger tumors increase the size of the parent nerve and become separated from surrounding fascicles by a capsule derived from perineurium and epineurium (see Media File 1).
Most NLs are of the conventional (common) type, arise as solitary tumors smaller than 10 cm, and are not associated with a genetic syndrome. They display the classic gross and microscopic features described in Histologic Findings. The cellular variant is rare in the skin, developing more commonly as a tumor of the mediastinum, retroperitoneum, and deep soft tissue. It is composed of a hypercellular mass of spindle-shaped cells forming intertwining fascicles and cords. Mild-to-moderate cytologic atypia and a low mitotic rate (5 mitoses per 20 high-powered fields) are characteristic.
The plexiform variant demonstrates a multinodular growth pattern of predominantly Antoni type A tissue (see Histologic Findings) in the dermis and subcutis. In contrast to plexiform neurofibroma, plexiform NL is not pathognomonic of neurofibromatosis and malignant transformation is exceedingly rare. Ancient NLs are characterized by degenerative changes and cytologic atypia typical of Antoni type B tissue, of which they are almost entirely composed. Despite sometimes striking cytologic atypia, mitotic figures are rare.
Frequency
United States
The exact prevalence of NLs (benign schwannomas) of all anatomic sites is unknown. In 1971, Ingles and colleagues reviewed 3364 cases of neurogenic neoplasms of the intercostal nerves and posterior mediastinum reported in the literature and found that 141 cases (4.2%) were NLs. This rate placed third, after neurofibromas and ganglioneuromas. In 1935, a review by Stout showed a rate of NLs associated with NF2 of approximately 18%. Numerous subsequent reports have confirmed that this association is more than coincidental.
Mortality/Morbidity
NLs behave in a benign fashion. Incompletely excised examples are capable of slow recurrence. Higher recurrent rates are noted with intraspinal, sacral, and intracranial NLs and with the plexiform variety. Locally aggressive behavior is observed in tumors with increased cellularity, higher mitotic rates (mean, 4 per 10 high-power fields), and underlying bone extension (observed in occasional cases of orbital NL). One newborn with an orbital tumor died of a locally invasive tumor within a year.
Large tumors (eg, giant sacral schwannomas) are prone to local recurrence. A recent clinicopathologic study has found that patients with asymptomatic NLs occurring in association with NF2 not only have more severe neurologic deficits but also have little postoperative improvement and a higher rate of tumor recurrence. Malignant changes in NLs are exceedingly rare. Malignant NLs are not regarded as malignant counterparts of NLs.
Race
No racial predilection is noted for this neoplasm.
Sex
The tumor affects the sexes in roughly equal numbers. However, intracranial NLs are encountered more commonly in female patients; the rate for female patients with NL is reported as 76%.
Age
NLs occur in persons of any age but are most common in patients aged 20-50 years. The cellular form of NL has a peak incidence in the fourth decade of life, and approximately 5% of NLs occur in childhood and adolescence. Three congenital cases have been reported. In the nearly 50 reported cases of plexiform NL, the age ranged from 50 days to 80 years, with a mean of 34 years. In melanotic NL, the age range was reported at 10-84 years, with a mean age of 37 years. Overall, approximately 75% of NLs occur in the first 4 decades of life.
Clinical
History
While NLs almost always occur as solitary lesions with no associated genetic syndrome, in some instances they are multiple or occur in association with neurofibromatosis, particularly NF2. Rare examples are associated with NF1 (ie, von Recklinghausen disease).
- Patients generally report a slow-growing tumor, which has been present for several years.
- Pain and neurologic symptoms are uncommon unless the tumor is large or, by virtue of a deep-seated location, is impinging on neighboring structures.
- Waxing and waning of the tumor size may be noted and is attributed to fluctuations in the amount of cystic change within the neoplasm.
Physical
NLs have a predilection for the head, neck, and flexor surfaces of the upper and lower extremities. One rare case report described subungual (under the nailbed) schwannoma.1 The feet are usually spared. The spinal roots and the cervical, sympathetic, vagus, peroneal, and ulnar nerves are affected most commonly. Superficial NLs in the skin may display a prominent plexiform (nodular) growth pattern. Deep-seated tumors are found most commonly in the posterior mediastinum and the retroperitoneum. Intracranial NLs comprise approximately 8% of all primary tumors of this region.
- Sensory nerves tend to be affected selectively. The auditory nerve is overwhelmingly the most frequently involved. Acoustic NLs, also known as vestibular schwannoma, acoustic neuroma, or acoustic neurinoma, arise from the vestibular nerve, and they are observed in the setting of NF2. Patients with NF2 and acoustic NLs may present with bilateral hearing loss. If the tumor becomes large, it may eventually press against nearby brain structures (eg, brain stem, cerebellum), becoming life threatening.
- Neurilemmomatosis or schwannomatosis, a variant of NF2, is an autosomal dominant disorder with full penetrance. Although very few familial cases of neurilemmomatosis have been reported, most (90%) NLs in this setting have been multiple, encapsulated, and located in the subcutaneous tissue, while 10% have been plexiform, involving the neck, trunk, and extremities.
- When the tumor involves small nerves (see Media File 2), it is freely movable. When the tumor involves large nerves (see Media File 3), it is movable but moves along the long axis of the nerve where the attachment restricts mobility.
- Most NLs are asymptomatic, nontender, and not associated with neurologic signs or symptoms.
- A special form of inherited NL (ie, psammomatous melanotic variant) occurs in the setting of Carney complex, which is an autosomal dominant disorder characterized by the combination of spotty pigmentation (ie, lentigines), cardiac myxomas, and endocrine overactivity. More than 50% of patients with a psammomatous melanotic NL (ie, schwannoma) have Carney complex. In contrast to the conventional NL, the melanotic variant is not associated with NF2; thus, conventional NLs are not observed in association with Carney complex. Another difference between the 2 variants is that approximately 10% of melanotic tumors are malignant, whereas conventional NLs almost never undergo malignant change.
Causes
The etiology of NLs is uncertain. Most tumors have shown aberrations of chromosome 22.
- The NF2 gene has been localized to band 22q12. Alteration or loss of the NF2 gene product (also designated as Merlin), a presumed tumor suppressor gene, is postulated to be involved in NL formation. Partial or complete monosomy of the chromosome occurs (ie, loss or mutation of both NF2 alleles and mutation of the NF2 gene protein).
- The negative staining of NL cells by immunohistochemical stain for NF2 protein suggests that loss of NF2 protein function is a prerequisite for NL formation.
- More than 150 cases of radiation-induced intracranial and peripheral NLs have been reported. The mean latency period is approximately 20 years, and most of these are solitary tumors.
- Bilateral eighth cranial nerve schwannomas indicate neurofibromatosis of NF2 type. Unusual locations and associations with meningeal proliferation are also seen with NF2.2
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Further Reading
Keywords
NL, neurilemmoma, benign schwannoma, neurinoma, neurolemmoma, peripheral fibroblastoma, perineural fibroblastoma, peripheral nerve sheath tumor, nerve sheath tumor, conventional neurilemoma, common neurilemoma, solitary neurilemoma, cellular neurilemoma, plexiform neurilemoma, ancient neurilemoma, giant sacral neurilemoma, Carney complex, psammomatous melanotic schwannoma, type 2 neurofibromatosis, cranial neurilemoma, spinal root neurilemoma, neurilemmomatosis, schwannomatosis
