Peripheral nerve tumors are uncommon lesions. The involvement of multiple specialties in the treatment of disorders of the peripheral nerves may cause these rare lesions to be encountered infrequently by any given specialist. Peripheral nerve tumors generally are categorized into nerve sheath, primary neuronal, and non-neuronal neoplasms. Nerve sheath tumors are the most common. Peripheral nerve tumors may be malignant or benign, with the benign tumors more common. The spectrum of peripheral nerve tumors is presented in Table 1.

Benign Nerve Sheath Tumors

Nomenclature has been a source of confusion with regard to descriptions of nerve sheath tumors. Benign nerve sheath tumors include the neurofibroma and the schwannoma. The latter is occasionally referred to as a neurilemmoma or neurinoma. Electron microscopic analysis has made it evident that both of these tumors arise from a double basement membrane cell believed to be unique to the Schwann cell, yet the perineural fibroblast, a nonmyelin-producing cell, has a basement membrane indistinguishable from that of the Schwann cell. The neurofibroma is a more invasive form of the neoplasm arising from the perineural fibroblast, whereas the less invasive schwannoma arises from the Schwann cell. Pathologists tend to agree that there are distinguishing features and even subtypes of each. For example, the cellular schwannoma or plexiform schwannoma must be distinguished from its more malignant counterparts. For the purpose of this discussion, the simple terminology for benign nerve sheath tumors of schwannoma and neurofibroma will be used.

Schwannoma

Schwannomas arise from the nerve sheath and generally involve one or two fascicles of the nerve. The remaining fascicles are displaced eccentrically by this well-encapsulated tumor. Schwannomas may arise from any nerve, including the peripheral portion of the cranial nerves, and are almost always solitary lesions, No known etiologic factor exists and no racial or sexual predilection is apparent. The eighth cranial nerve is the most common cranial nerve involved. Schwannomas account for 10% of all primary intracranial tumors. Bilateral eighth cranial nerve schwannomas may be a forme fruste of von Recklinghausen's disease or of neurofibromatosis type 2. Peripherally, schwannomas are most often found in nerves of the head and neck, or the flexor surfaces of the extremities. They rarely occur in the foot.

Grossly, a schwannoma is oval and well circumscribed and appears to be encapsulated. The cut surface may reveal areas of cystic degeneration but generally has a yellow fleshy appearance. Microscopically, two distinct cell populations are usually present: densely packed palisading cells (Antoni A) and loosely meshed, areolar areas (Antoni B). Although both types are common, a single type may predominate. An area of densely palisading Antoni A cells is known as a Verocay body. Benign variants of the classic schwannoma include the cellular schwannoma, which may mimic a sarcoma microscopically, and the plexiform schwannoma, which should be differentiated from the plexiform neurofibroma, because the latter has a greater tendency toward malignant degeneration.

Neurofibroma

Neurofibromas, although arising from the nerve sheath, involve the majority of the fascicles of the nerve either by encasement or invasion, An occasional solitary neurofibroma may be encountered, but these tumors are usually multiple and frequently occur in the patient with neurofibromatosis type 1 (von Recklinghausen's disease). Neurofibromatosis is a genetic disorder transmitted through an autosomal dominant mutant gene with full penetrance but variable expression. Features of the disease include six or more cafe au lait spots greater than 1.5 cm in size, in addition to few or numerous subcutaneous nodules or neurofibromas. Neurofibromas may be found in the central nervous system and autonomic nerves, as well as in the peripheral nerves. There is a marked tendency toward malignant degeneration in multiple tissues.

Grossly, the neurofibroma appears as an enlargement of the nerve, either cylindric or plexiform. Cross-section shows a fleshy, granular tumor that microscopically has fewer Schwann cells, more abundant collagen and reticulin fibers, and invariable axon cylinders. Occasional islands of what appear to be typical schwannoma cells may be identified in the background of disordered collagen and axons.

Clinical Considerations

Solitary, benign nerve sheath tumors generally are asymptomatic when small but cause pain or neurologic dysfunction as they enlarge and compress the adjacent neural elements. In the extremity, there is often the history of a well-circumscribed mass being present for months or years. The mass may be moved from side to side but is fixed in a longitudinal direction. Tinel's sign may be elicited with vigorous manipulation of the mass. Pain is seldom a presenting symptom of a benign tumor. A suspected tumor may be visualized preoperatively with ultrasound. Increased experience with and technical improvements in this technique make it a reliable modality for preoperative visualization. In tumors of the brachial or lumbosacral plexus, the mass may become sizable before presenting clinically, but even the benign tumor in these sites may present with pain and sudden neurologic dysfunction after hemorrhage in the tumor.

In the patient with an apparently solitary peripheral lesion and no evidence of neurofibromatosis, no further work-up may be necessary. Surgical excision, or biopsy if appropriate, of the symptomatic lesion is curative or becomes the basis for further diagnostic testing.

For tumors involving the brachial or lumbo­sacral plexus, a computed tomographic (CT) scan or magnetic resonance imaging (MRI) preoperatively provides valuable information regarding the extent of the tumor. It therefore aids in planning the appropriate surgical approach. The potential for extension into or from the spinal canal along a spinal root must be considered for the paramidline or proximally located tumor. Imaging of the spinal contents preoperatively is mandatory, and if the so-called "dumbbell tumor" is present, the intraspinal component should be removed first. This prevents inadvertent traction upon and possible loss of function in the spinal cord during resection of the extraspinal component.

In the patient with known or clinically apparent neurofibromatosis, more extensive diagnostic testing may be warranted. The extent of the disease and the involvement of other systems may be determined with a CT scan of the chest and abdomen and an MRI of the central nervous system. Radioisotope bone scanning also may be of value if malignant degeneration is suspected. Meticulous examination of the skin also may reveal nevi with the potential to degenerate into malignant melanoma. From a practical perspective though, only the symptomatic lesion should be approached surgically for diagnostic, palliative, or cosmetic purposes.

Surgical Considerations

Schwannomas in general may be completely resected with little or no loss of neurologic function. Principles to be adhered to include (1) adequate exposure of the involved nerve, both proximally and distally, (2) loupe or microscope magnification, (3) meticulous hemostasis, and (4) microsurgical dissection technique. If possible, anesthesia should be planned so that neuromuscular blockade is not present, and a nerve stimulator can be used to identify and preserve intact fascicles. Use of a stimulation/recording system that provides intraoperative identification of nerve action potentials in functional nerve fascicles is mandatory. We have found that a disposable stimulator with variable voltage settings or a bipolar generator-based stimulator works well in the absence of neuromuscular blockade. Visualization of the extremity distal to the lesion is also mandatory to confirm responses to the stimulator. Sweeping over the surface of the tumor with the stimulator often identifies intact fascicles that may not be readily apparent visually, but whose preservation is important.

The vascular pedicle of the tumor is usually at the proximal pole of the tumor. Dissecting and transecting this pedicle with involved fascicles allow subsequent gentle avulsion of the tumor away from the nerve. In large tumors of the brachial or lumbosacral plexus or in the pelvis, debulking the tumor with an ultrasonic aspirator (CUSA) may allow a more gentle avulsion of the tumor remnant from the surrounding neural elements. Preoperative classification schemes have been developed to assist in the identification of tumors of large nerves or plexi that may not appear to be resectable.

Solitary nonplexiform neurofibromas may be approached surgically in a manner similar to the approach to a schwannoma. The need for more meticulous identification of functional fascicles should be anticipated.

Neurofibromas associated with neurofibromatosis or plexiform neurofibromas cannot be resected without sacrifice of the majority of the nerve fibers and the consequent loss of function. Resection of a neurofibroma on a major nerve trunk must be weighted against the deficit incurred by loss of the nerve, The major role of a surgical approach is initially to confirm the diagnosis with a biopsy. Malignant degeneration is known to occur in 10% to 13 % of patients. The role of biopsy in the newly symptomatic lesion is to determine whether malignant change has occurred and to plan further therapy A benign tumor that has caused significant neurologic dysfunction in a major nerve may be considered for resection and nerve repair. This may require a cable graft, and appropriate preparation of the calf for sural nerve harvest should be made. The location of the tumor on a major nerve, the degree of dysfunction, the overall condition of the patient, and the availability of a tumor-free cable graft should all be considered seriously before this radical resection therapy is considered. Other indications for surgical intervention in patients with extensive neurofibromatosis include rapid enlargement, cosmetic disfigurement, and hemorrhage into or infection of a large pachydermatocele.

Malignant Nerve Sheath Tumors

Nomenclature of malignant nerve sheath tumors also has been plagued by the use of a variety of terms that, in reality, all identify a similar or the same disease process. Malignant neurilemmoma, malignant schwannoma, malignant nerve sheath tumor, neurogenic sarcoma, and neurofibrosarcoma are all terms used to describe these malignant tumors. Some pathologists claim that at least two basic types exist: a malignant schwannoma, and a nerve sheath fibrosarcoma, the cell of origin being the Schwann cell in the first and a perineural fibroblast in the second. For this discussion, malignant nerve sheath tumor (MNST) as an all-inclusive term will be used. The MNST rarely, if ever, develops from the benign schwannoma, but rather from the plexiform neurofibroma. Although MNSTs may occur sporadically, their association with neurofibromatosis type 1 (von Recklinghausen's disease) is well recognized.

Grossly, the tumor may appear to be densely attached to or invading the involved nerve or plexus. Yet, because the malignant tumor is so similar in gross appearance to the plexiform neurofibroma, unequivocal microscopic pathologic diagnosis is mandated before proceeding with any radical surgical extirpation. Histologically, a reasonably reproducible and distinctive pattern exists, characterized by alternating cellular fascicular areas and more myxoid foci, striking perivascular whorling by tumor cells that often seem to extend into the vessel wall, very pale cytoplasm, and characteristically elongated and tapering nuclei. The immunohistochemical demonstration of S-100 protein positivity is the best marker of neural differentiation in the context of a spindle-cell soft-tissue neoplasm, although the presence of the Leu-7 antigen is helpful as well. If there is apparent transformation into a rhabdomyosarcoma, the term triton tumor is used.

Clinical Considerations

Initially, there may be little clinical evidence that distinguishes MNST from its benign counterpart. The mass may have been present for several months or years and only recently may have become painful or associated with a neurologic deficit. These tumors may occur more frequently in male patients (56%) if not associated with neurofibromatosis type 1. In the presence of that condition, however, an 80% male predominance has been reported. MNSTs are also reported to occur in women at a younger age (mid-30s) as opposed to men (mid-40s). This difference, however, merely may be a manifestation of an earlier diagnosis in women because of symptomatic changes during pregnancy. The tumors tend to be located more proximally on major nerve trunks or intercostal nerves.

If an MNST is suspected preoperatively or if the diagnosis has been established by biopsy, a determination of the extent of the disease should be undertaken. CT scanning of the chest and abdomen should identify metastatic lesions. The lung is the most common site of metastasis. As with neurofibromatosis type 1, central nervous system imaging also should be part of the initial staging of MNST.

Surgical Considerations

Although radical local resection or amputation is the hallmark of the treatment of MNST, the clinical and histologic ambiguities mandate a careful and positive pathologic diagnosis before a radical surgical procedure is undertaken. If the tumor is peripherally situated and there is no evidence of invasion of the surrounding tissue, a block dissection, including 5-10 cm of the nerve proximal to the lesion, may suffice. The nerve is then anatomically reconstructed with a sural nerve cable graft. Frozen-section analysis by an experienced pathologist at the time of the resection is necessary to ensure that the surrounding soft tissue and nerve are free of tumor invasion. If tumor-free margins cannot be obtained without compromise of a major muscle or limb vasculature, or if there are adjacent multiple "benign" plexiform neurofibromas in the patient with neurofibromatosis type 1, a proximal amputation should be performed. If the tumor is proximally located on a major nerve without significant plexus involvement, disarticulation of the extremity (scapulohumeral or iliofemoral) appears to be appropriate. If the distal plexus is involved, interscapulothoracic (forequarter) amputation or hemipelvectomy (hindquarter amputation) probably offers the greatest potential for prolonged survival.

Patients with proximal plexus involvement or invasion of the major vessels will not benefit from amputation. In this setting, the role of surgical exploration includes the confirmation of the diagnosis and debulking of the tumor for relief or control of symptoms. As with its benign counterpart, when a proximally placed malignant tumor is noted or suspected, preoperative evaluation of the intraspinal structures with CT myelography or MRI should be considered to evaluate the possibility of intraspinal extension along a spinal root. If such an extension is present, the intraspinal component of the tumor should be approached first and the involved root amputated to prevent traction on the spinal cord if further dissection of the extraspinal component is anticipated.

Adjuvant Therapy

Both benign and malignant nerve sheath tumors are notoriously radioresistant and chemo­resistant. The role of radiation therapy is difficult to ascertain. Several have reported its use in managing incompletely resected proximal tumor for palliation of symptoms or local control of tumor growth. An isolated report indicated the possibility of increased survival with postoperative radiation therapy, 52-78 Gy given in 2-Gy fractions, irrespective of how clean the surgical margins are. A survival rate of 56% at 3 years is noted, but survival may not be different from other series at 5 or 10 years. The well-documented phenomenon of the induction of postradiation sarcoma must be considered when planning postoperative therapy. It seems reasonable to administer a judicious dose of radiation therapy to the operative bed in the incompletely resected tumor or in the case of local recurrence. Chemotherapy has been administered according to soft tissue sarcoma protocols, but as with radiation therapy, it does not appear to affect survival.

Results of Therapy

Although the overall outlook with MNST is dismal in most cases, in certain cases, long-term, disease-free survival is possible. This potential for long-term survival appears to be related to the surgical resectability of the tumor and not to the success of adjuvant therapy. A 30% to 40% survival rate has been reported at 5 years and at 10 years in large groups with tumors in all extremities. Death is most often secondary to metastatic spread, which is most often to the lung.

Primary Neuronal Tumors

Primary neuronal tumors include neuroblastoma or malignant peripheral primitive neuroectodermal tumor, ganglioneuroma and its malignant counterparts, ganglioneuroblastoma, chemodectoma, and pheochromocytoma. These tumors tend to arise from the autonomic nerve ganglion cells along the spine or in the viscera. References providing more detailed information for neuroblastoma, ganglioneuroma, ganglioneuroblastoma, chemodectoma, and pheochromocytoma are included here.

Tumors Metastatic to the Peripheral Nerve

Primary malignant tumors are known to metastasize to peripheral nerves, although rarely. Tumors of origin include melanoma, prostate, and malignant thymoma. Major nerves or plexi are more likely to be affected from local invasion from breast or lung carcinoma that often already has undergone primary surgical and radiation therapy to the affected area. Surgical decompression of the nerve or plexus with subtotal removal of the tumor may provide significant symptomatic relief and should be considered unless widespread disease makes the risk of further surgery prohibitive.

Tumors of Non-Neural Origin

A variety of benign neoplastic or hamartomatous conditions are known to affect peripheral nerves.

Lipoma and Lipofibromatosis

A lipoma may arise as a localized fatty mass within the nerve, simulating a schwannoma. This condition is known as an intraneural lipoma, and if symptomatic, its optimal treatment is surgical resection with preservation of neural elements. A more diffuse or infiltrative form may be identified as an intraneural lipofibroma, fibrofatty infiltration, lipomatous hamartoma, or lipofibromatous hamartoma. This form may become symptomatic slowly and usually presents early in life. If this condition involves the median nerve, decompression of the transverse carpal ligament may provide temporary symptomatic relief. Occasionally, more extensive neurolysis or even resection and grafting may be required for pain control and preservation of protective sensation to the hand.

Ganglion Cysts

The ganglion cyst is one of the most common tumors of the hand. It most likely arises from extra-articular synovial remnants, and although most often found in the intertendinous spaces, it may arise totally within the nerve. Symptomatic compression from an extraneural ganglion cyst occurs most often in the upper extremity, but intraneural ganglion cysts have been reported most often in the common peroneal nerve at the knee. Preoperative diagnosis may be assisted with ultrasound. Treatment consists of excision of the extraneural cyst and obliteration of the connection with an adjacent synovial joint if necessary. Intraneural cysts require careful microsurgical evacuation of cyst contents and removal of the cyst wall if possible without destruction of the surrounding nerve.

Vascular Lesions

The gamut of vascular malformations may present as peripheral nerve tumors. These include venous angiomas, arteriovenous malformations, and hemangiomas. The hemangioma appears to be the most common of this group, although its appearance in the peripheral nerve is still rare. Complete resection with preservation of the nerve using microsurgical technique has been associated with long-term recurrence-free intervals.

Miscellaneous

Endometriosis has been reported with increasing frequency as a cause of sciatica. Cyclic sciatic pain or dysfunction associated with menses is the hallmark of the clinical presentation and there is a well-documented CT and MRI appearance. Although total hysterectomy with salpingo-oophorectorny is the traditional treatment, excision of the mass from the sciatic nerve with preservation of reproductive function has been reported.