Peripheral nerve tumors

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Peripheral nerve tumors

Authors: James M Gilchrist, MD, John E Donahue, MD
Section Editors: Jeremy M Shefner, MD, PhD, Robert Maki, MD, PhD, Glenn A Tung, MD, FACR
Deputy Editor: April F Eichler, MD, MPH

Contributor Disclosures

All topics are updated as new evidence becomes available and our peer review process is complete.

Literature review current through: Jan 2024. | This topic last updated: Oct 27, 2023.

INTRODUCTION

Peripheral nerve tumors are a heterogeneous group of mostly benign tumors that are rare
in the general population. Certain types, including neurofibromas and schwannomas, may
occur sporadically or in association with neurofibromatosis (NF).

This topic review will focus on various benign and malignant neoplasms and benign non-
neoplastic tumors of the peripheral nerve. NF type 1 (NF1), NF2-related schwannomatosis
(NF2) and schwannomatosis are discussed separately. (See "Neurofibromatosis type 1
(NF1): Pathogenesis, clinical features, and diagnosis" and "NF2-related schwannomatosis
(formerly neurofibromatosis type 2)" and "Schwannomatoses related to genetic variants
other than NF2".)

Nerve sheath tumors affecting the spinal cord are reviewed elsewhere. (See "Intradural
nerve sheath tumors".)

CLINICAL PRESENTATION

Symptoms and signs of peripheral nerve tumors are caused by direct nerve invasion,
involvement of surrounding tissues, or mass effect [1]. There are no specific clinical
presentations unique or even especially suggestive of a particular nerve tumor, with the
exception of neurofibromatosis type 1 (NF1), NF2-related schwannomatosis (NF2) and
schwannomatosis. (See "Neurofibromatosis type 1 (NF1): Pathogenesis, clinical features,
and diagnosis" and "NF2-related schwannomatosis (formerly neurofibromatosis type 2)"
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and "Schwannomatoses related to genetic variants other than NF2".)

● Symptoms and signs – Patients present for evaluation of peripheral nerve tumors
because of a soft tissue mass, pain, or focal neurologic findings, approximately in that
order of frequency [2]. The duration and progression of symptoms or signs are
important, as most benign tumors have a longer duration and a slow rate of
progression, while malignant tumors tend to progress rapidly in size, amount of pain,
and neurologic deficit [2-4].

Any mass changing its clinical character should be taken seriously, as that is one of
the few clinical clues to its potentially malignant nature. In particular, rapidly
expanding soft tissue masses in patients with NF are very suspicious for the presence
of a malignant peripheral nerve sheath tumor (MPNST) and should be evaluated
promptly [3].
● Family history – A careful family history is important in the assessment of an
underlying neurogenetic disorder, such as NF. A significant minority of peripheral
nerve tumors are associated with NF1, NF2, or schwannomatosis.
● Examination – On examination, peripheral nerve tumors tend to be mobile
perpendicular to the axis of the peripheral nerve but fixed along the axis [4].
Ganglion cysts, lipomas, and lipofibromatous hamartomas are usually easily
compressible, while neoplastic tumors are often firm in texture. Pain will occur in the
region of the tumor and any nerve the tumor involves, but pain may not be specific
enough to discern the particular involved nerve. Neurologic deficits of sensory and
motor function correspond to the nerve in which the tumor originates or which it is
compressing, and as such will often be most useful in localizing the tumor.

Obtaining a Tinel sign (radiating paresthesia elicited by tapping with a finger or

hammer) over a nerve or tumor may also assist in localization to a particular nerve
[5,6].

EVALUATION

The goal of laboratory evaluation of the patient with a peripheral nerve tumor is to
determine the type and location. Imaging is the most useful modality. Electrodiagnostic
testing can help to localize involvement of specific nerves or portions of a plexus but is
nonspecific for differentiating peripheral nerve tumors. Surgical biopsy is important for
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tumors that are deep or potentially malignant [3,4].

Genetic testing for neurofibromatosis type 1 (NF1) or NF2-related schwannomatosis (NF2)

is available but is not helpful in the evaluation of peripheral nerve tumors per se, as the
diagnostic criteria for both diseases are clinical and most solitary neurofibromas and
schwannomas occur in patients without NF.

Imaging — Imaging is the most valuable tool for evaluation of peripheral nerve tumors
[4,6]. Many tumors are first identified by imaging done for symptoms of pain, sensory loss,
or weakness.
● Magnetic resonance imaging (MRI) is the most helpful imaging modality, especially in
denoting the presence of a mass, determining whether the mass is intrinsic or
extrinsic to the nerve, and delineating involvement of adjacent structures (
image 1) [7]. MRI is less helpful in determining the specific type of the tumor, as
there are no pathognomonic signal characteristics for any type of tumor. However,
there are signs on neuroimaging that may suggest whether a peripheral nerve
sheath tumor is a schwannoma or a neurofibroma based on its relationship to the
parent nerve. (See 'Neurofibroma' below.)

Although not definitive, MRI can sometimes be helpful in determining the malignant
nature of a tumor. Rapid growth of a known tumor, inhomogeneous enhancement,
hemorrhage, necrosis, and heterogeneous signal intensity suggest, but are not
specific for, malignant peripheral nerve sheath tumor (MPNST). Large tumors
exceeding 5 cm, ill-defined margins, invasion of fat planes, and edema around the
tumor all raise the possibility of malignancy ( image 2) [7]. (See 'Malignant
peripheral nerve sheath tumors' below.)
● Peripheral nerve ultrasonography, particularly in patients without diagnosis, can be a
reasonable initial test in a patient with a suspected peripheral nerve tumor [8].
Ultrasound is inexpensive, widely accessible, can delineate location of lesion and its
relationship to a peripheral nerve, and provides information as to probable diagnosis
[9]. (See "Musculoskeletal ultrasonography: Clinical applications", section on
'Peripheral nerves'.)
● Computed tomography (CT) scan is not the best imaging method, as many tumors
have signal densities similar to muscle and so are not well defined. However, CT can
be useful in demonstrating bony remodeling adjacent to the tumor, such as spinal
neural foramina [6].
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● 18-F fluorodeoxyglucose positron emission tomography (FDG-PET) may be useful in
distinguishing MPNSTs from benign tumors [4].

Metastatic cancer to peripheral nerve is not common, but in that scenario, CT, MRI, and
PET scanning take on the additional importance of determining the primary tumor and
staging the cancer.

Electrodiagnostic testing — Electrodiagnostic studies with electromyography and nerve

conduction testing are not particularly helpful in the evaluation of peripheral nerve
tumors, beyond indicating which nerve, nerves, or portions of a plexus may be involved [6].
There are no specific electrodiagnostic findings for any peripheral nerve tumors and no
distinction can be made between benign or malignant tumors. However, electrodiagnostic
testing may provide some indication of the function of a particular nerve, and as such, may
propel the patient and surgeon towards or against surgery.

More value may arise from intraoperative electrophysiologic monitoring to assist the
surgeon in determining what is or is not functional neural tissue. A nonfunctional nerve
found preoperatively needs to be verified intraoperatively but might allow the surgeon
freer access to removal of the tumor [6].

Biopsy — Surgical biopsy is important in the evaluation of tumors, especially those that
are deep or thought to be malignant, as pathology will determine further surgical options.
According to an international consensus statement on MPNSTs in NF, all patients with pain,
enlargement of a soft tissue mass, change in texture, or advancement of neurologic deficit
should have biopsy to assess for malignancy [10].

A pathologist with expertise in peripheral nerve tumors is obviously important, as the

differentiation between schwannoma and neurofibroma is key (eg, schwannomas are seen
in NF2 and other schwannomatoses, neurofibromas are seen in NF1; neurofibromas can
undergo malignant transformation, schwannomas do not) and the determination of
malignancy can be difficult [4].

APPROACH TO TREATMENT

Treatment for peripheral nerve tumors is largely based on surgical removal. Not all
patients with a peripheral nerve tumor will need surgery [11]. Some may be best treated
conservatively with observation, such as the following [6]:

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● Asymptomatic schwannomas or other tumors with no characteristics suspicious for
malignancy
● Subcutaneous neurofibromas, dermal neurofibromas, plexiform neurofibromas with
low suspicion for malignancy
● Non-neoplastic tumors
● Tumors causing minimal symptoms in older adults, the medically impaired, or the
debilitated patient

For patients with tumors that require treatment, surgery is the primary tool [8].
Disfigurement, bleeding, pain, neurologic deficit, and suspicion for malignancy are the
prime indications for surgical removal [12,13]. For benign tumors, removal of the tumor
with minimization of residual neurologic deficit is the goal [11], though that can be
impossible given the location of the tumor and intertwining with nerve fascicles, especially
if the tumor is nonencapsulated [1,6].

Treatment of malignant peripheral nerve sheath tumors (MPNSTs) is discussed below. (See
'Treatment of MPNSTs' below.)

NOMENCLATURE

The nomenclature of peripheral nerve tumors is confusing, as tumors often have more
than one name, different tumors are called the same name, and some tumor cell types are
not yet definitively characterized.

It is no surprise then that there is currently no widely accepted, overarching classification

scheme for peripheral nerve tumors. Most authors utilize a system based on the presence
or absence of neoplasia, whether the neoplasia is benign or malignant, and the presumed
cellular origin of the underlying neoplasia, ie, nerve sheath origin or not ( table 1).

BENIGN NON-NEOPLASTIC NERVE TUMORS

The category of benign non-neoplastic nerve tumors includes neuroma, ganglion cyst,
intraneural heterotopic ossification, sarcoid granuloma, inflammatory pseudotumor of
nerve, leprosy, hypertrophic neuropathy, lipofibromatous hamartoma, and neuromuscular
choristoma.
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Neuroma — Neuromas belong to a class of tumors best called reactive [11]. Traumatic
neuromas occur after nerve injury causing interrupted axons (neurotmesis). Regenerating
axons lack an endoneurial tube to follow, which results in a mass of disorganized axons
that is often quite painful and tender ( picture 1). Neuromas tend to be small and firm in
texture, and require excision for cure and diagnosis.
● Morton neuroma is a subject of controversy regarding its nomenclature, pathology,
and appropriate treatment. Abnormalities ascribed to Morton neuroma are typically
located between the metatarsals of the third and fourth toes or at the bifurcation of
the fourth plantar digital nerve ( image 3 and image 4). The lesions look like a
traumatic neuroma grossly, and are comprised of degenerated and/or demyelinated
axons, vascular hyalinization, and fibrosis [14,15]. Clinical manifestations can include
pain and tenderness, but similar lesions are common in patients who are
asymptomatic. Management of Morton neuroma is discussed separately. (See
"Evaluation, diagnosis, and select management of common causes of forefoot pain in
adults", section on 'Interdigital (Morton) neuroma'.)
● Solitary circumscribed neuromas (also known as palisaded encapsulated neuromas)
are small, firm, nonpigmented, painless nodules found in proximity to
mucocutaneous junctions, usually in the face. They are benign but may be mistaken
for a basal cell carcinoma. Surgical removal is curative.
● Mucosal neuromas are associated with multiple endocrine neoplasia type 2b, which is
inherited as an autosomal dominant trait due to a single mutation in the ret proto-
oncogene (RET) [11,16]. Mucosal neuromas present as diffusely enlarged lips, tongue
nodules, and thickened eyelids, either diffusely or focally, usually in the first or
second decade. Pathologically, mucosal neuromas are comprised by markedly
enlarged nerve fibers. There is no specific treatment. (See "Clinical manifestations
and diagnosis of multiple endocrine neoplasia type 2", section on 'MEN2B'.)

Ganglion cyst — Ganglion cysts are non-neural benign cystic tumors that usually occur in
proximity to joints or tendons. They develop from chronic local mechanical irritation in
perineural tissue or extend from joints to enter the epineurium [11]. The common
peroneal nerve is frequently affected, as are the hands and wrists. A mucous cyst is a
ganglion occurring at the distal interphalangeal joint, usually in patients between 40 and
70 years old [11].

Ganglion cysts are more common in women than men. Pain and neurologic deficits of
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sensation and strength in the territory of the affected nerve are typical presenting
manifestations, arising from either intra- or extraneural compression. Asymptomatic cysts
found on magnetic resonance imaging (MRI) are frequent ( image 5). Surgical removal or
aspiration is indicated if symptoms and signs warrant, but intrafascicular dissection and
neurolysis in cysts with intraneural involvement may be required [17].

Intraneural heterotopic ossification — Heterotopic ossification of peripheral nerve has

been reported rarely and resembles myositis ossificans pathologically with a central
fibroblastic core, an intermediate zone of osteoid production, and a peripheral zone of
ossification. Like myositis ossificans, it is thought to occur secondary to local trauma. Pain,
paresthesias, and weakness in the distribution of the affected nerve are the presenting
complaints [11,18].

Sarcoid granuloma — Sarcoid granulomas can involve cranial and peripheral nerves,
which appear firm and thickened. This can be a focal or multifocal process, causing pain,
sensory loss, paresthesias, and weakness. The diagnosis may require nerve biopsy. The
mainstay of treatment is glucocorticoids, as with systemic sarcoidosis. (See "Neurologic
sarcoidosis" and "Treatment of pulmonary sarcoidosis refractory to initial therapy".)

Inflammatory pseudotumor of nerve — Inflammatory pseudotumor of nerve is another

rare disorder [11,19]. The swelling is composed of chronic inflammatory (mostly T
lymphocytes) and reactive mesenchymal cells, resulting in segmental fusiform or nodular
enlargement. The infiltrate is usually limited to the epineurium. Sensorimotor deficits in
the territory of the affected nerve lead to evaluation, and surgery is usually done because
of the deficits and the presumed diagnosis of nerve sheath tumor.

Leprosy — Leprous neuropathy results from infection with Mycobacterium leprae and is a
common cause of neuropathy in underdeveloped countries. (See "Leprosy: Epidemiology,
microbiology, clinical manifestations, and diagnosis", section on 'Neuropathy'.)

Leprosy has a tuberculoid and lepromatous form, dependent on each patient's immune
response. Tuberculoid leprosy involves cutaneous and subcutaneous nerves, with
extensive destruction of nerve fibers secondary to the inflammatory response engendered
by the infection [11]. Nerves are often enlarged due to the inflammation and from cold
abscesses and fibrosis within the nerve. This is less likely in lepromatous leprosy, which
results from hematogenous dissemination.

The treatment of leprosy is discussed separately. (See "Leprosy: Treatment and

prevention", section on 'Antimicrobial therapy' and "Leprosy: Treatment and prevention".)
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Hypertrophic neuropathy — There are two forms of hypertrophic neuropathy:

● Localized hypertrophic neuropathy is a rare condition resulting in onion bulb-like
Schwann cell hypertrophy from repeated demyelination and remyelination [11,20].
The fusiform enlargement of the nerve is focal and separable from the hypertrophic
neuropathies (Charcot-Marie-Tooth disease, Dejerine-Sottas disease, hereditary
neuropathy with liability to pressure palsy, and chronic inflammatory demyelinating
polyneuropathy) only by the lack of a diffuse polyneuropathy.
● Hypertrophic inflammatory neuropathy, another rare condition, often involves the
brachial plexus with focal fusiform swelling of a nerve [11,21]. Like hypertrophic
neuropathy, it is endoneurial in origin with onion bulb-like hyperplasia around axons,
but differs in having extensive edema, localized inflammatory infiltrates, and fibrosis.
The diagnosis requires tissue, so biopsy and/or excision are often required to
differentiate this entity from a neoplastic lesion.

Miscellaneous — Lipofibromatous hamartoma is another unusual condition, most

commonly involving the median nerve in children or young adults, and at times associated
with macrodactyly [11]. These tumors involve the epineurium with fibrosis and fat, and
sometimes other tissues such as muscle. Lipomas of the nerve may be hard to differentiate
but are often encapsulated and contain only adipose tissue. Patients present with either a
mass, enlarged fingers, or neurologic symptoms due to compression of the nerve.
Neurologic symptoms are most likely if the distal median nerve is involved in the carpal
tunnel. Treatment is by surgical excision, which may be limited to debulking or carpal
tunnel release [17]. (See "Surgery for carpal tunnel syndrome".)

Benign triton tumor, also known as neuromuscular choristoma or neuromuscular

hamartoma, is a peripheral nerve tumor made of well-differentiated muscle. It usually
affects large nerves in children and is solitary. In a study that reviewed 19 cases, nearly
one-third involved the sciatic nerve [22]. Most presented with pain and foot deformities
such as talipes or atrophy, but minimal neurologic deficits. The brachial plexus is also
commonly involved.

BENIGN NEOPLASMS OF NON-NEURAL SHEATH ORIGIN

Desmoid tumor — Desmoid tumors, also known as aggressive fibromatosis, uncommonly

can affect the nerve, usually by secondary involvement [17,23]. These are neoplastic
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tumors often comprised of well-differentiated, firm masses of fibrous tissue. They are
infiltrative and frequently recurrent ( image 6). Muscle and muscle fascia is the usual site
of origin. Up to 10 to 15 percent of patients with familial adenomatous polyposis will have
desmoid tumors. They often present as painful masses most commonly affecting proximal
and truncal areas. (See "Desmoid tumors: Epidemiology, molecular pathogenesis, clinical
presentation, diagnosis, and local therapy".)

Focal sensorimotor deficits are common when desmoid tumors involve nerves. Total
resection is difficult and may require sacrifice of the nerve [23], but as the brachial plexus is
a common site of involvement, total resection may not be appropriate [17].

Neurothekeoma — Neurothekeomas are superficial tumors of variable pathology, which

may encompass a spectrum of disease.

The terminology is evolving, and the name "neurothekeoma" may over time disappear
from usage [24]. Neurothekeomas were originally called "nerve sheath myxoma" [25], but
in a later series, 53 tumors with similar pathology were termed "neurothekeoma" [26].
Neurothekeomas had been classified as myxoid, cellular, or mixed type ( picture 2).
However, those classified as myxoid most likely represent nerve sheath myxomas, and
nerve sheath myxomas are no longer considered a type of neurothekeoma [24]. (See
'Dermal nerve sheath myxoma' below.)

Thus, the term "neurothekeoma" should probably be reserved for use in the cellular or
mixed-type tumors [27].

Neurothekeomas presumably arise from small cutaneous nerves [28,29]. In contrast to

nerve sheath myxomas, neurothekeomas have a predilection to occur in the head, neck,
and shoulders, but also in limbs [30]. They tend to affect females more than males, usually
in the second and early third decades of life, with a mean age at presentation of 15 to 21
years [28-30].

Neurothekeomas occur in the dermis and are composed of spindle and epithelial cells
arranged in a fascicular or concentric whorl pattern. There is no well-defined
encapsulation. Unlike nerve sheath myxomas, the cellular neurothekeomas have negative
S100 staining, indicating they are not of Schwann cell origin. They are also negative for
epithelial membrane antigen (EMA), indicating they are not of perineural cell origin either
[29], which raises the issue of whether cellular or mixed-type neurothekeomas are of nerve
sheath origin. Indeed, cellular neurothekeomas are now thought to be of fibrohistiocytic
origin [27].
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Treatment is by surgical excision, usually because the tumor is believed to be something

else, such as a schwannoma. Recurrence is rare [31].

BENIGN NERVE SHEATH NEOPLASMS

The category of benign nerve sheath neoplasms includes neurofibroma, schwannoma,

perineurioma, hybrid nerve sheath tumors, cellular and mixed-type neurothekeoma,
dermal nerve sheath myxoma, ganglioneuroma, and hemangioblastoma.

Nerve sheath tumors affecting the spinal cord are reviewed elsewhere. (See "Intradural
nerve sheath tumors".)

Neurofibroma — Neurofibromas are tumors composed of a mix of Schwann cells,

perineurial-like cells, and fibroblasts, interspersed with nerve fibers, wire-like strands of
collagen, and myxoid matrix ( picture 3) [7,32]. The majority are solitary (up to 90
percent) and not associated with neurofibromatosis type 1 (NF1). The patient is often
young, between 20 and 30 years of age [7]. Neurofibromas are pathologically and
genetically different from schwannomas, but there is no pathologic difference between
neurofibromas from patients without and with NF1 [31]. The neoplastic cell of origin is the
Schwann cell, and the presence of intratumor nerve fibers is a cardinal feature that helps
distinguish neurofibromas from schwannomas [31,32].

Neurofibromas are usually classified by location and appearance [32].

● Cutaneous, or dermal, neurofibromas are small, nodular tumors of the skin and
subcutaneous tissue, arising from small cutaneous nerves, which may cause local
pain or bleeding but do not cause neurologic deficits. In NF1, they are by far the most
common form of tumor.
● Intraneural neurofibromas are deeper, focal, well-circumscribed, fusiform lesions
involving nerve roots, nerve trunks, nerve plexuses, or peripheral nerves. The nerve
enters the mass at one end, exits at the other, and is intermixed with tumor
components through the length of the mass. These tumors usually present as a
mass, with local or radicular pain, or with sensorimotor neurologic symptoms and
signs [12]. Tumors within the epineurium will be encapsulated, but most extend
beyond the epineurium, and though circumscribed, they are not encapsulated.

These two types (cutaneous and intraneural) could be considered discrete tumors [12], and

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they comprise 90 percent of neurofibromas.

● Plexiform neurofibroma, a third type, is nondiscrete ( picture 4 and image 7).
These are multinodular elongated masses affecting large nerves that may appear as
a tangle of thick strands or as a ropy mass, like a "bag of worms" [32]. These are
nearly pathognomonic for NF1 but rarely can be seen as solitary lesions [7].
● Massive soft tissue neurofibromas are large, diffuse masses causing regional or
single-limb enlargement (formerly known as elephantiasis) seen in NF1 patients [32].

Solitary intraneural neurofibromas account for approximately two-thirds of neurofibromas

removed at surgery [33], with the others being associated with NF1.

Multiple neurofibromas are nearly diagnostic of NF1 ( table 2). They can be found
affecting virtually any nerve or plexus; they affect a young patient population (20 to 30
years of age); and for an unknown reason, they occur more frequently on the right side
than the left [31]. Solitary neurofibromas rarely degrade to malignancy, but discrete
neurofibromas in NF1 can and do become malignant, and plexiform neurofibromas carry a
substantial risk of becoming malignant. (See 'Malignant peripheral nerve sheath tumors'
below.)

Imaging can be helpful in localizing the mass, as well as determining its extent and any
involvement of extraneural tissues. On computed tomography (CT), intraneural
neurofibromas are well-demarcated masses that are hypodense to muscle [7]. Contrast
enhancement is minimal, if any. Since the neurofibroma is intermixed with tumor
components throughout its length, it appears as a fusiform enlargement of the nerve that
is inseparable from the parent nerve ( image 8). This is in contrast to schwannoma,
which is more often eccentric and not centered along the course of the nerve. On magnetic
resonance imaging (MRI), neurofibromas show a low signal intensity on T1-weighted
images and high signal intensity on T2-weighted images [7]. They enhance frequently, and
usually heterogeneously. On T2 images, the tumors will often show a characteristic central
hypodense region, called the target sign, which is presumed due to dense collagen and
fibrous tissue in the center ( image 9 and image 8). This pattern is very suggestive of
neurofibroma but has been reported in schwannoma and in malignant peripheral nerve
sheath tumors (MPNSTs) [7]. CT and MRI of plexiform neurofibromas show large
multilobulated and conglomerated masses, comprised of numerous neurofibromas,
extending along nerves and nerve branches [7].

Treatment of solitary intraneural neurofibromas is dependent on symptoms and signs.

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Cutaneous neurofibromas should not be removed, whether the patient has NF1 or not,
unless there is a reason such as pain, bleeding, interference with function, or
disfigurement [6].

Solitary intraneural neurofibromas can be managed by observation if the patient is

asymptomatic. For patients with pain, with progressive neurologic deficits, or in whom the
diagnosis is uncertain, surgical resection becomes necessary [31,34]. Solitary intraneural
neurofibromas suspicious for malignancy should either be resected or first biopsied and
then resected if malignant.

For patients with solitary or multiple intraneural neurofibromas or plexiform

neurofibromas requiring treatment, surgical resection with preservation of neurologic
function is the goal [13]. However, this is more likely to be accomplished in patients with
solitary neurofibromas than patients with NF1. The greater likelihood of pain and
neurologic deficits in patients with NF1 is due in part to the occurrence of plexiform
neurofibromas in NF1 and to the need to attempt total resection in NF1 tumors because of
the risk of malignant deterioration. In a series reporting surgical excision of 123
neurofibromas in 121 patients without NF1, stable or improved motor function and good
pain resolution were observed in 90 and 88 percent of patients, respectively [5]. The same
series reported 59 patients with NF1 who had 80 tumors removed; stable or improved
motor function and improved pain were observed in 83 and 74 percent, respectively, but
new or worse pain occurred in 16 percent.

The location of the tumor also has great bearing on the operative outcome. Tumors in the
brachial plexus are associated with a relatively high proportion of postoperative morbidity.
In one study, removal of neurofibromas involving the brachial plexus in patients without
NF1 who had no neurologic deficits resulted in some degree of postoperative weakness in
8 of 31 patients (26 percent) [33]. Similarly, 28 percent of patients with NF1 who had no
preoperative weakness experienced significant postoperative weakness.

A number of plexiform neurofibromas will degenerate into a more aggressive nodular

lesion with increased avidity on 18-F fluorodeoxyglucose positron emission tomography
(FDG-PET) [35]. These nodular lesions grow more aggressively than the plexiform
neurofibromas themselves and degenerate into MPNSTs. Special attention, and
occasionally surgery, must be considered for these rapidly changing lesions. (See
'Malignant peripheral nerve sheath tumors' below.)

An additional type of nodular neurofibroma in patients with NF1 is "atypical

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neurofibromatous neoplasm with uncertain biologic potential" (ANNUBP). These are

tumors with concerning histologic features but that are not definitively malignant.
Histologic criteria for ANNUBP include histologic nuclear atypia, hypercellularity, increased
mitotic activity (at least one mitosis in 50 high-power fields [HPF] but less than 3 mitoses
per 10 HPF), and focal loss of neurofibroma architecture (eg, herringbone and/or fascicular
storiform growth patterns) [36,37]. Caution must be exercised in making a pathologic
diagnosis of ANNUBP in small biopsies because they may not be representative of the
entire tumor. Close clinical and radiologic follow-up are indicated with additional biopsy
sampling if necessary. (See "Neurofibromatosis type 1 (NF1): Pathogenesis, clinical
features, and diagnosis", section on 'Nodular neurofibromas'.)

Schwannoma — Schwannomas (also called neurilemomas) are encapsulated tumors

made entirely of benign neoplastic Schwann cells [7,32]. They are the most common tumor
of peripheral nerves. They do not transform to malignancy, with the exception of atypical
types mentioned below [6,13].

Schwannomas grow from peripheral nerves or nerve roots in an eccentric fashion with the
nerve itself usually incorporated into the capsule. This appearance should be contrasted
with that of neurofibroma. However, in large schwannomas, nerve fibers can be difficult to
find [7].

Vestibular schwannomas (also called acoustic neuromas) account for 80 to 90 percent of

cerebellopontine angle tumors in adults and are discussed separately. (See "Vestibular
schwannoma (acoustic neuroma)".)

Schwannomas show a biphasic architecture of Antoni A (dense) and B (loose) patterns, as

well as nuclear palisading (Verocay bodies) and a fibrous capsule containing the parent
nerve [32]. Neoplastic Schwann cells typically show spindle-shaped nuclei ( picture 5).
Pathologic variants include the following [32]:
● Cellular schwannomas are predominantly Antoni A tissue without Verocay bodies.
● Melanotic schwannomas show dense melanin pigmentation but are otherwise typical
( image 10). Psammomatous melanotic schwannomas are a subtype of melanotic
schwannoma with psammoma bodies, which are round, laminated bodies of calcium.
Melanotic schwannomas, unlike other schwannomas, can become malignant.
● Plexiform schwannomas are rare, usually occurring along nerve plexuses as
conglomerations of multiple schwannomas, and can be sporadic or associated with

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NF2-related schwannomatosis (NF2) or other schwannomatoses. Unlike plexiform

neurofibromas, they do not become malignant.

Longstanding schwannomas can show degenerative changes, such as marked nuclear

pleomorphism, widespread blood vessel hyalinization, signs of remote hemorrhage, focal
necrosis, and calcifications. At one time, these were called "ancient schwannomas," and
some still refer to them as such [7]. These tumors are not clinically distinctive, and many
pathologists do not consider them a specific variant of schwannoma.

Sporadic schwannomas affect patients of all ages, reaching a peak between 20 and 50,
with no predilection to sex or race [7]. Many schwannomas are discovered incidentally as
solitary tumors on flexor surfaces in middle-aged people [6]. The vast majority of
schwannomas occur sporadically and singly, but they also are seen, usually as multiple
schwannomas, as part of NF2, other schwannomatoses, Carney complex, and as part of a
syndrome with nevi and vaginal leiomyomas [38]. Schwannomas do not occur in NF1. (See
"Schwannomatoses related to genetic variants other than NF2" and "NF2-related
schwannomatosis (formerly neurofibromatosis type 2)".)

Most patients are asymptomatic, but dysesthesia (often elicited by palpation), radicular-
type pain, sensory loss, and weakness can occur, usually from impingement on adjacent
neural structures such as the brachial plexus [39].

The imaging of schwannomas is similar to neurofibromas, and often the two tumors
cannot be distinguished ( image 1). On CT, schwannomas are hypodense to muscle, and
they enhance with contrast [7]. On MRI with T1-weighted imaging, schwannomas have an
intermediate signal intensity similar to muscle, and on T2-weighted images, they are
hyperintense [7,40]. They enhance intensely, and most (70 percent) show a low-intensity
rim consistent with a capsule. Fusiform shape and a target sign on both T2-weighted and
postcontrast images can be seen in both schwannomas and neurofibromas. When it can
be identified, a mass relative to a nerve on ultrasound, CT, or MRI suggests schwannoma,
and a heterogeneous appearance with cystic degeneration is more common with
schwannoma [7].

Though schwannomas are the most common peripheral nerve tumor, the proportion with
symptoms and signs necessitating surgical removal is approximately one-half of that seen
in neurofibromas. One series of 351 benign nerve sheath tumors included 124
schwannomas of the upper or lower limbs, of which 44 percent of the schwannomas
removed involved the brachial plexus [33]. Prognosis after surgery is somewhat better
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than for neurofibromas: In patients with full strength before surgical removal of a
schwannoma of the brachial plexus, 88 percent maintained normal strength, while 90
percent of those with weakness were either unchanged or improved after surgery [33]. In
another series of 291 sporadic schwannomas, 80 percent were resected, 52 percent of
patients had resolution of symptoms and signs, and 18 percent were improved. There were
no recurrences in patients who underwent complete resection [41].

Perineurioma — Perineuriomas are tumors comprised of perineurial cells. They are

classified as two forms: intraneural, which are rare, or the more common extraneural soft
tissue perineurioma [42].

At one time, intraneural perineuriomas were thought to be the same as localized

hypertrophic neuropathy, but the presence of pseudo-onion bulbing (intraneural form
only) and clonal monosomy of chromosome 22 (both intraneural and extraneural forms)
has indicated a true neoplastic origin [43,44]. Mutations in TNF receptor-associated factor
7 (TRAF7) are present in up to 60 percent of perineuriomas and may be an important
pathogenic mechanism [45].

Clinically, intraneural perineuriomas mimic schwannomas, appearing as fusiform masses

along the course of large nerves, usually affecting individuals in the second and third
decades. Weakness, sensory loss, and a mass are the presenting complaints and findings.
On the other hand, soft tissue extraneural perineuriomas typically affect middle-aged
adults, with a slight female preponderance and no neurologic symptoms [42].

Magnetic resonance neurography can help localize the lesion but is unlikely to effectively
differentiate perineurioma from schwannoma [46].

Intraneural perineuriomas can be distinguished pathologically from schwannomas by

pseudo-onion bulbing and by immunohistochemistry [32,42]. Pseudo-onion bulbs consist
of concentrically arranged perineurial cells surrounding an axon, in contrast to true onion
bulbs seen in hypertrophic neuropathies, which are composed of Schwann cells. Using
immunohistochemistry, perineurial cells (and perineuriomas) are positive for epithelial
membrane antigen (EMA) and claudin-1, a membrane protein of the tight junction. They
are negative for S100 (a family of calcium-binding proteins), and neurofilaments. Schwann
cells (and schwannomas) are negative for EMA and positive for S100 and neurofilaments
[6,42].

Treatment of perineuriomas consists of surgical excision if the tumor is causing neurologic

compromise or pain. Since axons course through the tumor, residual nerve dysfunction
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Peripheral nerve tumors

may occur. Recurrence is unlikely. However, perineuriomas can be the source of an MPNST.
In one study, perineurial origin of MPNST was found for 5 of 23 (13 percent) tumors, only
one of which was associated with a nerve [34]. There has been no association with NF.
MPNSTs of perineurial cell origin may have a better prognosis than those from Schwann
cell origin.

Hybrid nerve sheath tumors — Hybrid nerve sheath tumors bear features of more than
one type of conventional nerve sheath tumor [47]. The most common type is a hybrid
schwannoma/perineurioma, which typically occurs on the distal extremities of adults,
although there is a wide anatomic distribution. Other hybrid tumors, such as hybrid
neurofibroma/schwannomas, are most common in patients with NF1 and
schwannomatosis [48].

Dermal nerve sheath myxoma — Prior descriptions of neurothekeomas have included

myxomas, largely due to ill-defined pathologic criteria and unclear determination of the
specific cell of origin. This has been better clarified in recent years, and dermal nerve
sheath myxoma has been established as a benign neoplasia separate from
neurothekeoma [24,47]. Regardless, the two tumor types unfortunately remain conflated
in many contexts [1,49]. (See 'Neurothekeoma' above.)

Nerve sheath myxomas are uncommon, being significantly rarer than neurothekeomas.
They are superficial, multinodular, and solitary tumors, usually growing slowly over several
years. The most common locations are finger, knee, lower leg and ankle, and forearm and
hand, in that order. They affect males and females equally, with a mean age of
presentation in the fourth decade. They usually present as a mass and are painful in less
than 25 percent of cases. No apparent nerve is associated with the tumor, and neurologic
deficits are not described [24].

The tumor involves the dermis or subdermis, with abundant myxoid matrix and a
peripheral fibrous border. Schwann cells are the predominant cell by appearance and by
immunohistochemical staining: These tumors are universally positive for S100 and glial
fibrillary acidic protein (GFAP), consistent with a Schwann cell origin, and only slightly
positive for EMA, an indicator of perineurial cells [24]. Only scattered axons are seen. All
these features raise the possibility that nerve sheath myxomas are related to
schwannomas [24].

Treatment is by surgical resection, to include the capsule and a margin of normal tissue.
The tumors can be up to 4.5 cm in diameter. Surprisingly, the rate of recurrence is nearly
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Peripheral nerve tumors

50 percent, sometimes with multiple tumors. Neither the first, nor recurrent, tumors show
evidence for malignancy [24].

Ganglioneuroma — Ganglioneuromas are rare, slow-growing, large tumors that arise

from sympathetic ganglion cells. They can be grouped among the peripheral neuroblastic
tumors but consist of mature ganglion cells, and as such are benign. The cell of origin is
derived from embryonic neural crest cells, and ganglioneuromas are thought to represent
the final stage of maturation from neuroblastomas [50]. They are large tumors, with an
average size of 7 cm, and they are encapsulated [50].

Ganglioneuromas tend to occur more frequently in females, with 60 percent occurring

before age 20. They occur anywhere along the sympathetic chain, with common locations
being the mediastinum, retroperitoneum, and adrenal glands ( image 11). They are
asymptomatic except for local mass effect, such as causing constipation when located in
the pelvis, or radicular pain if presacral.

Histopathology reveals large, mature ganglion cells (neurons), axons, satellite cells,
Schwann cells, and fibrous stroma ( picture 6) [32]. The Schwann cells are not neoplastic
but associate with the neurons, though they do not elaborate any myelin. This separates
them from schwannomas and neurofibromas in which the Schwann cells are neoplastic.
Immunohistochemistry shows strong staining of the ganglion cells for neurofilaments, and
strong staining of Schwann cells by S100 [32].

Treatment is surgical excision, though given the large size, care must be taken for
adjoining structures and nerves. The capsule may itself be adherent to important
structures, and total excision, though desirable, may not be possible [50]. Postoperative
autonomic dysfunction otherwise seems uncommon [50].

Hemangioblastoma — Hemangioblastomas most commonly occur in the brain or spinal

cord and only rarely are seen outside the central nervous system (CNS) involving proximal
nerve roots, and even rarer, peripheral nerves. Hemangioblastoma within the CNS is
discussed in greater detail elsewhere. (See "Hemangioblastoma".)

Hemangioblastomas in the CNS are commonly associated with von Hippel-Lindau disease,
but less than half of peripheral nervous system hemangioblastomas are associated with
von Hippel-Lindau. (See "Clinical features, diagnosis, and management of von Hippel-
Lindau disease".)

The literature on peripheral nerve hemangioblastomas consists of only a few cases, one of

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Peripheral nerve tumors

which was in a patient with von Hippel-Lindau [51]. Patients present with progressive
neurologic deficits. Imaging with magnetic resonance reveals diffuse enhancement, except
for frequent cystic components, and large associated blood vessels. Angiography will also
show large associated blood vessels, confirming the vascular nature of the tumor.

The pathology of peripheral hemangioblastomas is similar to that of central

hemangioblastomas with neoplastic large vacuolated stromal cells within a rich non-
neoplastic capillary network and interspersed large-caliber blood vessels [51]. Cysts are
common. The tumors arise from the epineurium and appear exophytic from the nerve.
They have well-defined margins.

Treatment is surgical removal. If the vascular nature of the tumor is not suspected
beforehand, the tumor may bleed extensively.

MALIGNANT PERIPHERAL NERVE SHEATH TUMORS

Malignant peripheral nerve sheath tumors (MPNSTs) are an uncommon but devastating
tumor of peripheral nerve, representing only approximately 10 percent of tumors
encountered by a peripheral nerve surgeon [52]. The incidence of MPNSTs in the general
population is 0.001 percent.

MPNSTs, which are classified as malignant soft tissue sarcomas, can arise from pre-existing
plexiform neurofibromas or perineuriomas, or normal nerves. They do not arise from
schwannomas. MPNSTs also occur as secondary neoplasms 10 to 20 years after radiation
therapy (RT), accounting for up to 10 percent of MPNSTs [4]. The incidence of MPNST in
childhood cancer survivors is 40-fold higher than the expected rate in the general
population [53]. Twenty-two to 50 percent of MPNSTs occur in patients with
neurofibromatosis type 1 (NF1), the rest being sporadic [2,52,54].

The risk of developing an MPNST in a patient with NF1 is between 8 and 13 percent [55],
with most, if not all, arising from pre-existing plexiform neurofibromas [56]. In patients
with NF1, the presence of an internal plexiform neurofibroma is associated with a 20-fold
increased risk of developing an MPNST compared with the risk in those lacking an internal
plexiform neurofibroma [56]. MPNSTs tend to present at an earlier age in patients with NF1
(third or fourth decade of life, versus seventh decade in patients who do not have NF1)
[55].

MPNSTs are most commonly found on the extremities and trunk, and less often on the
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Peripheral nerve tumors

head and neck [57,58]. The clinical picture is characterized by rapid change, whether in
pain, size of tumor mass, or progression of neurologic deficit, especially when occurring in
a pre-existing peripheral nerve tumor [2]. In particular, change in tumor size is most
predictive of malignancy [3]. Major nerve trunks (eg, the brachial plexus) are frequent sites
of involvement [52], but a nerve of origin is often not evident [2].

The diagnosis of malignant versus benign tumor requires biopsy, which should be open
and involve multiple sections of the tumor [6,52]. Conventional radiographic imaging may
help but cannot reliably differentiate between malignant and benign. Ultrasonography of
the affected nerve can begin to delineate tumor type, location, and relationship to the
underlying nerve [9]. On magnetic resonance imaging (MRI), signs that are more
consistent with MPNST than neurofibroma include large tumor size (>5 cm), heterogeneity
on precontrast T1-weighted imaging, intratumoral cystic change, ill-defined margins, lack
of a "target" sign, and a perilesional edema-like zone ( image 2 and image 12)
[7,59,60].

Emerging data suggest that MRI diffusion-weighted imaging (DWI) is at least as accurate
as 18-F fluorodeoxyglucose positron emission tomography (FDG-PET)/computed
tomography (CT) in differentiating benign from malignant tumors [61]. PET/CT-guided
percutaneous biopsy resulted in conclusive pathologic diagnosis in 26 of 26 patients with
NF1, 17 of whom were diagnosed with MPNST, and may provide a less invasive method for
diagnosis [62]. (See "Clinical presentation, histopathology, diagnostic evaluation, and
staging of soft tissue sarcoma", section on 'PET and PET/CT'.)

Radiographic imaging (typically chest imaging to evaluate for pulmonary metastases) is

also important as part of a metastatic evaluation. MPNSTs are staged according to the
American Joint Committee on Cancer (AJCC) tumor, node, metastasis (TNM) system along
with other soft tissue sarcomas arising in the trunk and extremities ( table 3). (See
"Clinical presentation, histopathology, diagnostic evaluation, and staging of soft tissue
sarcoma", section on 'Evaluation for metastatic disease' and "Clinical presentation,
histopathology, diagnostic evaluation, and staging of soft tissue sarcoma", section on
'Staging'.)

By gross inspection, MPNSTs tend to be large, firm tumors, containing areas of necrosis
and hemorrhage [32]. Microscopically, most MPNSTs are highly cellular, comprised of
spindle cells reminiscent of Schwann cells. The cells are mitotically active ( picture 7). The
cells are weakly S100 positive, consistent with dedifferentiation from Schwann cells.

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Peripheral nerve tumors

Variations include malignant triton tumor (MPNST with rhabdomyosarcomatous

differentiation), a highly malignant tumor containing embryonic striated muscle
components [63,64].

In all NF1-associated MPNSTs and most sporadic MPNSTs, both NF1 alleles are lost.
However, homozygous loss of NF1 is not sufficient to generate an MPNST, and additional
genetic hits are necessary, such as mutations in p53 and deletions in cyclin-dependent
kinase inhibitor 2A (CDKN2A) [65]. Positive p53 staining is very common in MPNSTs, and
intense immunoreactivity to p53 may be an indicator of malignancy [32,66]. In addition,
somatic loss-of-function mutations in SUZ12, polycomb repressive complex 2 subunit
(SUZ12) and embryonic ectoderm development (EED), two genes that encode for subunits
of the polycomb repressive complex 2 (PRC2), have been identified in approximately half of
MPNSTs [67,68]. Loss of histone H3K27 dimethylation staining in MPNST is highly specific
for PRC2 loss and a diagnostic indicator of malignancy [69]. PRC2 mutations appear to
cooperate in MPNST tumorigenesis by amplifying Ras pathway activation, an alteration
that may have therapeutic potential [67,68,70].

BRAF V600E mutations are found in a subset of MPNSTs (1 of 13 sporadic MPNSTs in one
series, 5 of 25 sporadic and 1 of 37 NF1-associated MPNSTs in another series) [71,72], but
this finding does not presently have therapeutic implications. It is not clear if such genetic
alterations are driver or passenger mutations.

Treatment of MPNSTs — MPNSTs are staged and treated as malignant soft tissue
sarcomas. Because of their rarity and the frequent need for multimodal treatment, the
evaluation and management of MPNSTs ideally should be carried out in a center with
expertise in the treatment of sarcomas, including surgical, orthopedic, medical, and
radiation oncology. (See "Overview of multimodality treatment for primary soft tissue
sarcoma of the extremities and superficial trunk", section on 'Importance of
multidisciplinary evaluation and management'.)

For limb primaries, surgical resection alone with a sufficient wide margin to achieve a
potentially curative operation may require amputation of the limb proximal to the tumor,
or disarticulation of a shoulder or hip, with sacrifice of nerves, nerve trunks, and adjacent
soft tissue structures [6,52,73]. Nerve grafting is not appropriate due to the proximal
nature of the remaining nerve, the use of adjuvant RT, and the natural history of MPNSTs.
At other sites (eg, the head and neck), wide excision may be impossible due to the
constraints of the local anatomy. (See "Head and neck sarcomas", section on 'Other adult

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Peripheral nerve tumors

soft tissue sarcomas' and "Head and neck sarcomas", section on 'Surgical principles' and
"Surgical resection of primary soft tissue sarcoma of the extremities", section on 'Sarcoma
resection and reconstruction'.)

Although the rarity of these tumors has precluded any definitive efficacy trials [4], as with
other adult-type soft tissue sarcomas, adjunctive RT can provide an opportunity for limb
salvage and also improve local control where the attainment of wide excision margins by
surgery alone is difficult. Adjunctive RT may be administered preoperatively or
postoperatively. (See "Overview of multimodality treatment for primary soft tissue sarcoma
of the extremities and superficial trunk", section on 'Radiation therapy' and "Overview of
multimodality treatment for primary soft tissue sarcoma of the extremities and superficial
trunk", section on 'Choosing between preoperative and postoperative RT'.)

Management of locally advanced or locally recurrent tumors is challenging. Initial RT or

chemoradiotherapy may permit some initially unresectable tumors to undergo later limb-
sparing surgery. Where available, isolated limb perfusion, isolated limb infusion, or
regional hyperthermia with systemic chemotherapy represent potentially limb-preserving
options, but expertise is limited, and these procedures are not in widespread use in the
United States. (See "Treatment of locally recurrent and unresectable, locally advanced soft
tissue sarcoma of the extremities", section on 'Regional chemotherapy' and "Treatment of
locally recurrent and unresectable, locally advanced soft tissue sarcoma of the
extremities", section on 'Systemic chemotherapy with and without regional hyperthermia'.)

Chemotherapy treatment for advanced disease is discussed elsewhere. (See "Overview of

the initial treatment of metastatic soft tissue sarcoma".)

Prognosis — Even with aggressive surgical and radiation treatment, the prognosis is not
good. Poor prognostic signs include tumors exceeding 5 cm in size, higher tumor grade,
association with NF1, older age, distant metastases at the time of diagnosis, and inability
to achieve tumor-free margins [2,6,57,74-76]. In various studies, five-year survival ranged
from 34 to 64 percent [2,6,52,57,74,75]. The variable outcomes among these reports may
be due in part to differences in treatment protocols and to the proportion of NF1-
associated MPNSTs, which often present at a later stage with larger tumors than sporadic
MPNSTs [77]. A survival meta-analysis of 28 studies published from 1963 through 2011
demonstrated worse survival for NF1-associated tumors compared with sporadic tumors
(hazard ratio [HR] 1.39, 95% CI 1.10-1.72); however, in an analysis limited to series
published since 2001, the pooled HR was smaller and no longer significant (HR 1.19, 95%

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Peripheral nerve tumors

CI 0.85-1.66), suggesting that observed differences in outcome between NF1 and sporadic
tumors may be lessening over time [75].

One of the largest studies evaluating MPNSTs was a single-center retrospective review of
175 cases seen over a 25-year period [57]. The median age was 44, and one-third of
MPNSTs arose in the setting of NF1. The extremities were the most common site (45
percent), followed by the trunk (34 percent) and head and neck (19 percent). At
presentation, 84 percent had locoregional disease, while 16 percent had distant
metastases. A complete (R0) resection was accomplished in 69 percent of cases, and the
majority had adjuvant treatment with RT, chemotherapy, or both. At a median follow-up of
74 months, the local recurrence rate was 22 percent, and the 5- and 10-year disease-
specific survival rates were 60 and 45 percent, respectively. On multivariate analysis, higher
tumor grade, size ≥5 cm, truncal location, and local recurrence were associated with a
significantly worse prognosis. Patients with NF1 presented with larger tumors (median 9.9
versus 6.6 cm for sporadic tumors), and there was a statistically nonsignificant trend
toward worse five-year disease-specific survival (54 versus 75 percent for sporadic cases).

MALIGNANT NON-NEURAL SHEATH TUMORS

The peripheral nervous system is often involved in patients with cancer, most commonly as
a result of chemotherapy or radiation therapy (RT). However, peripheral nerves can also be
involved by compression or infiltration from solid tumors (by extension or metastases) and
lymphomas.

Cancer — Cancers can involve the peripheral nervous system by compression from
primary or metastatic tumor, by extension/infiltration of the tumor into the nerve, by
metastatic invasion of the nerve, or by spread along the nerve (perineural extension).
Proximal nerve roots and trunks (plexi) are most commonly involved, but distal, large
nerves can also be compromised.
● In the cervical plexus, lymph node metastases from head and neck cancers,
lymphoma, and adenocarcinomas of the breast and lung are the most common
sources of involvement [78], leading to pain in the throat, neck, or scalp, with effects
on speech, swallowing, and breathing (phrenic nerve), as well as abnormal sensation.
(See "Overview of cancer pain syndromes", section on 'Plexopathies'.)
● The brachial plexus may be involved in up to 1 percent of all patients with cancer,
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Peripheral nerve tumors

with breast and lung cancer most common [78]. The lower trunk is most commonly
involved due to its proximity to axillary lymph nodes and the upper lobe of the lung (
image 13). Pain is the usual presentation, and helps differentiate cancerous from
radiation-induced plexopathy. Sensorimotor deficits of the arm, usually in the C8-T1
myotomes and dermatomes; Horner syndrome; and a supraclavicular or axillary
mass can be present on exam. (See "Brachial plexus syndromes", section on
'Neoplastic and radiation-induced brachial plexopathy'.)
● The lumbosacral plexus is involved approximately as frequently as the brachial plexus
(0.71 percent) [79], usually from direct extension from pelvic and abdominal cancers
such as cervical, colon, and bladder, or metastatic disease from lymphoma, breast,
and prostate ( image 14). Insidious pain is present in over 90 percent of patients
and, like the brachial plexus, can precede neurologic symptoms by several months.
Sensory abnormalities, weakness, edema, and changes in limb temperature ("hot
foot sign") are frequent on examination [78]. Involvement is usually unilateral,
whereas radiation-induced lumbosacral plexopathy is often bilateral. (See
"Lumbosacral plexus syndromes", section on 'Neoplastic invasion'.)

Involvement of individual peripheral nerves is uncommon (especially if cranial nerves are

not included) and arises in most instances from compression. It is distinctly rare for
peripheral nerves to develop intraneural metastases, with only a few descriptions in the
literature [80]. Another rare manner in which peripheral nerves may be involved is
perineural spread, in which neoplastic cells migrate along the endoneurial tubes, with no
extension beyond the perineurium. This is in contrast to intraneural metastases that arrive
hematogenously and infiltrate from the epineurium inward [81]. This has been described
in squamous cell carcinoma of the head and neck, malignant melanoma [81], and prostate
cancer. Symptoms are relevant to the involved nerve, including local mass, pain, and
sensorimotor deficits. The course of perineural spread is unusually long, often years,
before diagnosis.

Magnetic resonance imaging (MRI) is the most useful imaging test, as it can best
differentiate between mass, neural structures, and other soft tissues. (See "Brachial plexus
syndromes", section on 'Neoplastic and radiation-induced brachial plexopathy' and
"Lumbosacral plexus syndromes", section on 'Neoplastic invasion'.)

Neurolymphomatosis — Neurolymphomatosis is the term for systemic lymphoma that

has invaded the peripheral nervous system ( image 15). Neurolymphomatosis is

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Peripheral nerve tumors

uncommon and can represent either a primary presentation or a relapse of systemic or

primary central nervous system (CNS) lymphoma. Although usually of B cell origin,
peripheral nerve invasion has been reported with primary CNS lymphoma of T cell origin
[82] and with Sézary syndrome [83]. (See "Primary central nervous system lymphoma:
Clinical features, diagnosis, and extent of disease evaluation" and "Secondary central
nervous system lymphoma: Clinical features and diagnosis" and "Clinical manifestations,
pathologic features, and diagnosis of mycosis fungoides".)

Neurolymphomatosis often presents with pain, involving either one or more peripheral
nerves, nerve roots, or cranial nerves, though painless involvement is not uncommon. MRI
shows enlarged nerves that enhance, and biopsy shows infiltrative lymphoma. (See
"Primary central nervous system lymphoma: Clinical features, diagnosis, and extent of
disease evaluation".)

The initial evaluation of the patient with suspected non-Hodgkin lymphoma must establish
the extent and sites of disease. The treatment approach and prognosis are strongly
dependent upon this information. (See "Clinical presentation and initial evaluation of non-
Hodgkin lymphoma" and "Pretreatment evaluation and staging of non-Hodgkin
lymphomas".)

SOCIETY GUIDELINE LINKS

Links to society and government-sponsored guidelines from selected countries and

regions around the world are provided separately. (See "Society guideline links: Soft tissue
sarcoma".)

INFORMATION FOR PATIENTS

UpToDate offers two types of patient education materials, "The Basics" and "Beyond the
Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th
grade reading level, and they answer the four or five key questions a patient might have
about a given condition. These articles are best for patients who want a general overview
and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces
are longer, more sophisticated, and more detailed. These articles are written at the 10th to
12th grade reading level and are best for patients who want in-depth information and are

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Peripheral nerve tumors

comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to
print or e-mail these topics to your patients. (You can also locate patient education articles
on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
● Basics topic (see "Patient education: Neurofibromatosis type 1 (The Basics)")

SUMMARY

● Clinical presentation – Symptoms and signs of peripheral nerve tumors are caused
by direct nerve invasion, involvement of surrounding tissues, or mass effect. There
are no specific clinical presentations unique or even especially suggestive of a
particular nerve tumor, with the exception of the clinical signs of neurofibromatosis
type 1 (NF1) or NF2-related schwannomatosis (NF2). (See 'Clinical presentation'
above.)
● Evaluation – The goal of the evaluation of the patient with a suspected peripheral
nerve tumor is to determine the type and location. Imaging, particularly with
magnetic resonance imaging (MRI), is the most useful modality. Electrodiagnostic
testing can help to localize involvement of specific nerves or portions of a plexus, but
the findings are nonspecific for differentiating peripheral nerve tumors. Surgical
biopsy is important for tumors that are deep or potentially malignant. (See
'Evaluation' above.)
● Classification – Peripheral nerve tumors can be classified according to the presence
or absence of neoplasia, whether the neoplasia is benign or malignant, and the
presumed cellular origin of the underlying neoplasia, ie, nerve sheath origin or not (
table 1). (See 'Nomenclature' above.)
● Treatment – Treatment for peripheral nerve tumors is largely based on surgical
removal. However, some patients with asymptomatic, non-neoplastic, and/or benign
tumors can be treated conservatively. (See 'Approach to treatment' above.)
● Specific tumors

• The category of benign non-neoplastic nerve tumors includes neuroma, ganglion

cyst, heterotopic ossification, sarcoid granuloma, inflammatory pseudotumor of
nerve, leprosy, localized hypertrophic neuropathy, and miscellaneous causes.

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Peripheral nerve tumors

Desmoid tumors are benign neoplasms of non-neural sheath origin. (See 'Benign
non-neoplastic nerve tumors' above and 'Benign neoplasms of non-neural sheath
origin' above.)

• Tumor types classified as benign nerve sheath neoplasms include neurofibroma,

schwannoma, perineurioma, cellular and mixed-type neurothekeoma, dermal
nerve sheath myxoma, ganglioneuroma, and hemangioblastoma. (See 'Benign
nerve sheath neoplasms' above.)

• Malignant peripheral nerve sheath tumors (MPNSTs) are an uncommon but

devastating tumor of peripheral nerve. The diagnosis of malignant versus benign
tumor requires biopsy, which should be open and involve multiple sections of the
tumor. Surgical removal may require amputation of the limb proximal to the
tumor. (See 'Malignant peripheral nerve sheath tumors' above.)

• Peripheral nerves can also be involved by compression or infiltration from solid

tumors (by extension or metastases) and lymphomas. (See 'Malignant non-neural
sheath tumors' above.)

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malignancy of peripheral nerve sheath tumours: a retrospective study of 69 patients
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