Peripheral nerve tumors

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)" 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 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].

●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]:

●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.

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 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".)

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 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].

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 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. 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 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 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 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 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 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 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 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. 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 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% 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, 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 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 5^th to 6^th 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 10^th to 12^th grade reading level and are best for patients who want in-depth information and are 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. 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.)