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 spindleshaped 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 deepseated 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

Differential Diagnoses
Astrocytoma
Ependymoma
Fibrous meningioma
Leiomyoma
Neurofibromatosis
Subependymoma

Other Problems to Be Considered

Neurofibroma
Palisaded encapsulated neuroma
Cutaneous leiomyoma

Workup
Laboratory Studies

Microscopic examination of the tumor biopsy tissue and clinicopathologic correlation establishes

the correct diagnosis. The diagnostic microscopic features are described in Histologic Findings.
Masson trichrome stain can be used to demonstrate the presence of longitudinal striations
observed in smooth muscle tumors to differentiate a cutaneous leiomyoma from an NL, which
lacks striations.

Immunostaining using anti S-100 protein antibody confirms the presence of Schwann cells.

Imaging Studies

With routine radiographic examination, NLs generally appear as sharply circumscribed tumor

masses.
CT scan images show circumscribed, low-attenuation masses with uniform or heterogeneous
contrast enhancement.

MRI reveals a high T2 signal and heterogeneous contrast enhancement.

Both CT scan images and MRI show that large tumors often have areas of cystic changes. Benign
NLs do not show active irregular invasion of bone, as is observed in malignant peripheral nerve
sheath tumors.

Histologic Findings
The correct diagnosis of NL is established by microscopic examination of tumor biopsy tissue.
Gross appearance
In general, NLs are firm, smooth-surfaced tumors smaller than 10 cm. Most NLs affect small nerves. The
smaller examples are rounded, somewhat elastic in consistency, and milky-white or semitranslucent. The
larger tumors are lobulated irregularly and, by virtue of secondary degenerative changes, become partly or
mainly cystic with calcification (ie, ancient change). Areas of hemorrhage and opaque creamy-yellow
tumorous tissue are observed on the cut surface (see Media File 3). Some tumors manifest as a firm
rubbery nodule with a whorled appearance on the cut surface, resembling smooth muscle tumors of the
uterus. The plexiform or multinodular variant, which accounts for approximately 5% of NLs, may be
discernible upon gross examination (see Media Files 4-5).
Microscopic appearance
Most tumors are unilocular masses surrounded by a fibrous capsule composed of epineurium and residual
nerve fibers. While this capsule is evident in most tumors, those arising in mucosa (eg, nose,
nasopharynx), the central nervous system, and viscera often lack a capsule. Intradermal NLs and the
plexiform or multinodular growth pattern similar to a plexiform neurofibroma are rare. Histologically, the
characteristic feature of an NL is the pattern of alternating Antoni type A and B areas.
Antoni type A areas (see Media File 6) consist of compact, spindle-shaped cells with twisted nuclei,
indistinct cytoplasmic borders, and, occasionally, clear intranuclear vacuoles. The cells are arranged in
short bundles or interlacing fascicles with nuclear palisading, whorling of the cells, and Verocay bodies.
Verocay bodies are formed by 2 compact rows of well-aligned nuclei and cell processes that are arranged
in a roughly oval shape (see Media File 7). Verocay bodies are more distinctive of schwannomas than the
Antoni A and Antoni B patterns, but they are not seen in all schwannomas.
Mitotic figures are rare. S-100 protein, an acidic protein commonly found in the supporting cells of the
central and peripheral nervous system, is demonstrated in NLs, particularly in the Antoni type A areas.
Antoni B areas are less cellular and are often disorderly. The spindle or oval cells are arranged haphazardly
in the loose matrix with microcystic changes, inflammatory cells, and delicate collagen fibers. Prominent,
irregularly spaced blood vessels are present in the stroma. The psammomatous melanotic NL
(schwannoma) shows, in addition to the above features, melanin deposition and concentric calcified bodies
(psammoma bodies).
Schwannomas have been variably observed to be glial fibrillary acid protein (GFAP) and occasionally
keratin positive, with antibodies reacting with multiple keratins (pankeratins, keratin cocktail (CK)
(AE1/AE3). Both markers highlighted the cellular Antoni A areas, particularly adjacent to the capsule,
myxoid or degenerative areas, and perivascularly. In recent studies of a large series of retroperitoneal
schwannomas, 84% of the tumors stained positive for both AE1/AE3 and GFAP. However, the tumor cells
were negative for specific keratin polypeptides (K). The findings can be attributed to cross reactivity of
AE1/AE3 with other intermediate filament proteins, such as GFAP.3 Schwannomas contain Leu7 and S-100
protein.
Ultrastructural examination of the tumor reveals almost exclusively a single cell type (ie, Schwann cells).
They have characteristic thin cell processes that arrange in undulating layers and are continuous from the
cell body. The Schwann cell surface is coated with basal lamina composed of electron-dense material

measuring approximately 50 nm (see Media File 8). The basal lamina lies in stacks between the cells along
with typical and long-spacing collagen fibrils with a 130-nm periodicity. These collagen fibrils are often
referred to as a Luse body (see Media File 9). The cytoplasm contains a flattened and sometimes
invaginated nucleus, microfibrils, rare lysosomes, and scattered mitochondria. In Antoni B areas, the
Schwann cells have increased numbers of lysosomes and myelin figures and fragmented basal lamina.
Immunohistochemical staining using antiS-100 protein antibody demonstrates uniformly and intensely
positive staining of Schwann cells in the tumor (see Media File 10). This technique serves as an important
diagnostic tool, and, in severely degenerated NLs, S-100 protein stain is most valuable for confirming the
diagnosis.
The results of immunostaining for myelin proteins used to identify benign and malignant Schwann cell
tumors have been variable.
Histologic differential diagnosis

Neurofibroma: The loose, myxomatous Antoni type B tissue of a NL may mimic a neurofibroma.

However, neurofibromas lack the thick collagenous capsule of NLs and instead are surrounded by
a variably thickened perineurium and epineurium. Neurofibromas also lack the Antoni type A and B
patterns and Verocay bodies typical of NLs. Neurofibromas are composed of a mucinous matrix
containing scattered, myelinated, and nonmyelinated axons along with a heterogeneous cell
population including Schwann cells, fibroblasts, and perineural cells. Consequently,
immunoreactivity for S-100 protein is observed in only a portion of the cells comprising a
neurofibroma, as opposed to uniform reactivity throughout an NL.
Palisaded encapsulated neuroma: This is an uncommon, generally solitary, asymptomatic
intraneural neuroma that may arise in early childhood or adulthood. It appears as a firm, rubbery,
skin-colored or pink papule commonly affecting the "butterfly area" of the face. Palisaded
encapsulated neuromas are bulbous expansions of a peripheral nerve. They appear as a wellcircumscribed, ovoid, or rounded nodules in the dermis, which, in contrast to NLs, contain a
greater number of axons and Schwann cells in interlacing fascicles along with characteristic
cleftlike spaces.

Schwannoma: These are distinguished from astrocytoma and ependymoma by their abundant
parenchymal reticulin, which is positive for type IV collagen. Schwannomas have characteristic
contiguous basement membranes along the exterior surfaces of their cells. Although occasionally
focal positive staining for GFAP may be present, negative GFAP staining supports the diagnosis of
schwannoma. Astrocytomas are generally GFAP positive.

Fibrous meningiomas: These lack typical meningeal whorls and psammoma bodies, and they can
be difficult to differentiate from schwannomas. EMA is a useful immunomarker for distinguishing
the 2 tumors. Meningiomas are reactive with EMA, while schwannomas are not. GFAP can
sometimes be used, because some schwannomas are positive but meningiomas are negative.

Cutaneous leiomyoma

Leiomyomas are benign smooth muscle tumors. They are not derived from neural tissue
and generally lack the thick, hyalinized capsule and vasculature of an NL. Palisading
resembling Verocay bodies may be observed. The blunt-ended nuclei and densely
eosinophilic cytoplasm of smooth muscle cells showing distinct cell borders and
perinuclear halos help distinguish them from Schwann cells (with their more tapered,
spindle-shaped nuclei).

Immunohistochemical stains readily distinguish leiomyomas from NLs, the former staining
with myogenic cell markers, such as smooth muscle actin and desmin, and the latter
showing positive staining with S-100. Masson trichrome stain may be used to demonstrate
the longitudinal striations characteristic of smooth muscle tumors. The ultrastructural
features of smooth muscle cells are also highly characteristic, being bounded by a
basement membrane and often containing parallel arrays of abundant cytoplasmic
microfilaments (actin) with interspersed fusiform dense bodies and pinocytotic vesicles.

Palisaded myofibroblastoma: These contain palisaded cells and Verocay bodies that may mimic
NLs. However, palisaded myofibroblastomas involve lymph nodes, contain fibroblastic and
myofibroblastic elements, and are negative for S-100 protein staining.

Treatment

Surgical Care
Given the benign nature of NLs, therapy is conservative and directed toward sparing the parent
nerve when one is identified. The treatment of choice is gross total resection of the tumor. Although
NLs are benign, incomplete excision may result in slow local recurrence. Patients with
symptomatic NLs occurring in association with NF2 frequently present with more severe neurologic
deficits. These patients have a high rate of recurrence and less postoperative improvement.
Malignant transformation of NLs is exceedingly rare.