Intradural nerve sheath tumors

INTRODUCTION — Spinal tumors are classified as extradural, intradural and extramedullary, or intradural intramedullary based upon their anatomic location. Intramedullary tumors involve the spinal cord, while extramedullary tumors arise outside of the spinal cord. Nerve sheath tumors (NSTs) constitute approximately 25 percent of tumors arising in the intradural extramedullary space [1,2].

Although the majority of NSTs are confined to the intradural extramedullary space, some of these tumors extend into either the extradural compartment or the spinal cord. In addition, occasional spinal NSTs are confined to either the extradural or intramedullary spaces [3].

NSTs are derived from the Schwann cells and perineurial cells of the peripheral nervous system. Approximately 65 percent of intradural NSTs are schwannomas, and most of the remainder are neurofibromas [4]. Malignant NSTs (MNSTs) are rare, constituting approximately 5 percent of such tumors.

The clinical presentation, diagnosis, and treatment of NSTs will be reviewed here. Peripheral extradural NSTs, intramedullary spinal tumors, and meningiomas of the spinal cord are discussed separately. (See "Spinal cord tumors", section on 'Intramedullary tumors' and "Spinal cord tumors", section on 'Meningioma' and "Clinical presentation, histopathology, diagnostic evaluation, and staging of soft tissue sarcoma", section on 'Introduction'.)

EPIDEMIOLOGY AND ETIOLOGY — Intradural, extramedullary NSTs may be either sporadic or associated with one of three inherited disorders: neurofibromatosis type 1 (NF1), NF2-related schwannomatosis (NF2), and schwannomatosis.

Sporadic tumors — Sporadic NSTs are most common in the fifth to seventh decades and have a similar incidence in males and females [3].

NF1 — Neurofibromas are a characteristic component of NF1. Although the majority of these lesions are located in the periphery, they also occur within the spinal canal [5]. Most of the spinal neurofibromas are asymptomatic, but 2 percent of patients with NF1 have neurologic symptoms from a spinal lesion [6]. Plexiform neurofibromas arise in 30 to 50 percent of patients with NF1; these tumors can invade and erode surrounding tissues and may undergo malignant transformation [7]. (See "Neurofibromatosis type 1 (NF1): Pathogenesis, clinical features, and diagnosis", section on 'Tumors'.)

NF2 — Spinal tumors are found in up to 90 percent of patients with NF2. The tumors are often multiple, consisting primarily of schwannomas, but including some meningiomas [8]. Approximately 2 percent of all spinal schwannomas are seen in patients with NF2, while the vast majority are sporadic [9]. (See "NF2-related schwannomatosis (formerly neurofibromatosis type 2)", section on 'Spinal tumors'.)

Schwannomatosis — Spinal schwannomas are found in up to 75 percent of patients with schwannomatosis, a neurocutaneous syndrome that is distinguished from NF2 primarily by the absence of bilateral vestibular schwannomas. Schwannomatosis patients account for less than 10 percent of all patients undergoing spinal schwannoma resection [10].

The majority of cases of schwannomatosis are caused by pathogenic variants in SMARCB1 or LZTR1, tumor suppressor genes on chromosome 22. (See "Schwannomatoses related to genetic variants other than NF2".)

PATHOLOGY — Schwannomas are thought to be predominantly a proliferation of Schwann cells, while neurofibromas are derived from a mixture of Schwann, perineurial, and fibroblastic cells [11]. This observation is based upon histopathologic and immunochemical analyses of these tumors.

Schwannomas — Schwannomas arise from macroscopically recognizable nerves and generally occur as growths that are closely associated with, but relatively circumscribed from, the nerve. Immunochemical staining for the S-100 protein shows that the neoplastic proliferation consists almost exclusively of Schwann cells. Neurofilament stains demonstrate few or no axons within the neoplastic proliferation.

Microscopically, spindle cells are arranged in short, intersecting fascicles. Nuclear palisading is a typical feature; when pronounced, this results in the formation of Verocay bodies [11]. Two different histologic patterns have been described that coexist within schwannomas (picture 1A-C). The Antoni A regions consist of compact areas of spindle cells with pink cytoplasm. These alternate with looser Antoni B tissue, which is comprised of cells showing clear, vacuolated cytoplasm due to lipid accumulation. Myxoid change is not prominent, except in myxoid variants [12].

Neurofibromas — Neurofibromas grow as fusiform expansions of the involved nerve with tumor cells intermingling with axons. Histologically, there are several features that help to distinguish neurofibromas from schwannomas:

●Neurofibromas are less compact and less cellular.

●Tumor cells are spindle shaped with a wavier or buckled nuclear profile, compared with cells in schwannomas.

●Neurofibromas often contain crisscrossing bundles of collagen, a moderate amount of myxoid matrix, and readily identifiable mast cells, features that are uncommon in schwannomas.

Malignant nerve sheath tumors — Malignant NSTs (MNSTs) arise sporadically as sarcomas or from dedifferentiation of neurofibromas in patients with neurofibromatosis type 1 (NF1). Although MNSTs more commonly arise from peripheral nerves, they comprise up to 6 percent of intradural NSTs [4,13,14].

Microscopically, MNSTs are highly cellular and show a fascicular pattern, spindle-shaped nuclei, and scant cytoplasm. Necrosis and a high mitotic index are also frequently observed. (See "Clinical presentation, histopathology, diagnostic evaluation, and staging of soft tissue sarcoma", section on 'Introduction'.)

CLINICAL PRESENTATION — Schwannomas and neurofibromas typically are slow growing and often fill a significant volume of the spinal canal before causing symptoms. By contrast, malignant NSTs (MNSTs) are relatively fast growing, producing rapidly progressive symptoms, and carry a worse prognosis.

The specific symptoms of NSTs depend upon the spinal level involved. NSTs commonly present with pain, which is typically worse at night or in the morning and resolves during the day. Schwannomas and neurofibromas usually arise from the dorsal sensory roots and may present with radicular sensory changes. Radiculopathy with motor manifestations is not common, even with involvement of functional roots in the cervical or lumbar spine [15].

Once a tumor reaches a critical mass and causes spinal cord compression, signs and symptoms of myelopathy can progress rapidly. The myelopathy has no distinctive features, and the differential diagnosis includes herniated disc, amyotrophic lateral sclerosis, multiple sclerosis, transverse myelitis, and other epidural and intradural spinal cord tumors. (See "Clinical features and diagnosis of neoplastic epidural spinal cord compression".)

DIAGNOSIS — Contrast-enhanced magnetic resonance imaging (MRI) is the most sensitive and specific imaging modality to evaluate possible spinal column lesions. The majority of NSTs enhance diffusely with contrast, but heterogeneous enhancement can be seen when intratumoral cysts, hemorrhage, or necrosis are present (image 1A-B) [16].

MRI can define the anatomic interface between the tumor and spinal cord, but cannot reliably establish a histopathologic diagnosis [17]. In addition to NSTs, the differential diagnosis of intradural extramedullary tumors includes meningioma, myxopapillary ependymoma, paraganglioma, ganglioneuroma, hemangioma, and cavernous angioma.

Once a tumor is identified, MRIs of the head and the remainder of the spine are routinely obtained to determine whether other lesions are present. Additional lesions may be found in patients with neurofibromatosis, when another brain tumor has spread to lower levels of the spinal cord (so-called "drop metastasis"), or with leptomeningeal tumor. If there is a suspicion of leptomeningeal tumor, a lumbar puncture and cerebrospinal fluid (CSF) cytology are indicated prior to open biopsy and/or attempted surgical resection. (See "Clinical features and diagnosis of leptomeningeal disease from solid tumors".)

Determining whether an intradural tumor is extramedullary or intramedullary can be difficult, although the following distinctions may be helpful:

●The common intramedullary tumors (astrocytomas, ependymomas) expand the spinal cord and often have an associated polar cyst, which makes them readily distinguishable from extramedullary tumors. By contrast, exophytic intramedullary tumors may not be easily differentiated from extramedullary tumors.

●Extramedullary NSTs can penetrate the pial membrane and infiltrate or become adherent to the spinal cord.

●Spinal cord edema out of proportion to the degree of spinal cord compression, as evidenced by hyperintensity on T2-weighted MRI sequences, may indicate spinal cord invasion.

We have not found myelography to be useful in predicting intramedullary extension. Careful intraoperative exploration may be the only conclusive means of determining whether or not tumor involves the spinal cord.

Approximately 15 percent of intradural NSTs extend through the nerve root sleeve into the epidural space. Although typical, these "dumbbell-shaped" tumors are not pathognomonic for schwannomas and neurofibromas. The differential diagnosis also includes exophytic meningiomas, lipomas, chordoma, and chondrosarcoma. (See "Spinal cord tumors" and "Chordoma and chondrosarcoma of the skull base".)

A "dumbbell-shaped" configuration may also be caused by an epidural tumor extending inward through the neural foramen. This distinction from extradural extension of an intradural tumor is important because epidural tumors extending inward can be completely resected with an epidural approach without intradural exploration.

Supplemental imaging studies are often useful to determine whether there is bony destruction or involvement of paraspinal structures such as the vertebral artery or the brachial plexus. MR angiography (MRA) can be obtained to evaluate the caliber and patency of the vertebral arteries, and specific protocols can be requested to image the brachial plexus fully, for example.

TREATMENT — Surgery is the primary treatment modality for large or symptomatic intradural NSTs, as the results have improved with advances such as the operating microscope and intraoperative spinal cord monitoring. There is no established role for chemotherapy in patients with benign NSTs. Radiation therapy is used in selected patients, primarily in the setting of malignant or recurrent tumors.

Small, asymptomatic tumors — Small, asymptomatic tumors, which may be detected incidentally on magnetic resonance imaging (MRI) of the spine performed for evaluation of chronic low back pain or other symptoms, are best observed with serial imaging in most patients before committing to definitive therapy. We typically perform a repeat MRI three to six months after the initial study to ensure short-term stability and then obtain annual imaging to monitor for growth over time.

Large or symptomatic tumors — Surgery is the treatment of choice for large or symptomatic intradural NSTs. Gross total resection of benign tumors is often curative, and the majority of tumors can be safely resected. Since the majority of NSTs are benign and slow growing, function-sparing operations are important, even if this results in subtotal resection. (See 'Surgical technique' below.)

For patients who are not candidates for surgical resection or in whom only a partial resection is possible, fractionated radiation therapy or stereotactic radiosurgery may be used to treat symptomatic tumors [18-20]. Favorable results have been reported after radiosurgical treatment of benign spinal tumors [18,19]. (See "Radiation therapy techniques in cancer treatment", section on 'Stereotactic radiation therapy techniques'.)

Surgical technique — Complete surgical resection requires sacrifice of a nerve root or nerve root fascicles. Although these are typically sensory and their loss is well tolerated, sensory deficits should be anticipated and discussed with the patient preoperatively. Motor deficits are less common even with neuroforaminal extension of these tumors. Myelopathy from spinal cord compression typically resolves quickly following tumor resection.

Neural monitoring is often used during tumor resection. Somatosensory evoked potentials and motor evoked potentials can be used to monitor function with tumors causing spinal cord compression in the cervical and thoracic spine [21]. Electromyography is used to aid in resection of tumors from functional nerve roots in the cervical, lumbar, and sacral spine. Anal sphincter electrodes are helpful in identifying sacral motor roots.

Resection of intradural NSTs generally uses a posterior or posterolateral approach [22]. Rarely, an anterior approach may be required for midline ventrally located tumors [23]. Minimally invasive approaches that utilize tubular or expandable retractors for transmuscular access have also been described [24]. Intraoperative radiographs are taken to identify the appropriate levels. Following laminectomy, ultrasound may be used over the dura to confirm the location of the tumor. For tumors with epidural extension into the neural foramen, the facet joint may need to be resected followed by instrumented fusion. Carbon fiber instrumentation may provide a favorable stabilization option since it decreases the MRI artifact, which may be particularly helpful in patients who require close imaging follow-up, such as in cases of subtotal tumor resection [25].

A biopsy is sent for intraoperative analysis to determine the histopathology of the lesion. If the tumor is large, debulking may be undertaken. As the tumor is mobilized, the nerve stimulator is used to identify motor roots, which are dissected from the capsule. Once the root or rootlet of origin has been identified, it is sectioned both proximally and distally, and the tumor is removed.

If the tumor extends into the extradural space, motor stimulation is essential to determine whether there is motor root involvement. If there is no motor root stimulation, the entire root can be sacrificed. However, a functional motor root involved by tumor should be spared to avoid a significant postoperative neurologic deficit, even though this produces a subtotal resection [26].

Spinal fluid leak is a rare complication. Although this may result from a residual pinhole opening in the dura, it is thought that some patients develop chemical meningitis secondary to blood or tumor debris in the cerebrospinal fluid (CSF), causing an increase in CSF pressure. Spinal leaks often occur postoperatively while doses of steroids are being tapered. Slowing the tapering of steroids or temporarily increasing the steroid dose may help eliminate a leak or pseudomeningocele. Persistent leaks may be managed with a lumbar drain or implantation of a shunt.

Patients with syndromic tumors — Patients with spinal NSTs in the context of neurofibromatosis type 1 (NF1), NF2-related schwannomatosis (NF2), or schwannomatosis may have multiple spinal tumors, in addition to other brain and peripheral tumors. Treatment decisions are often complex, and the balance of risks and benefits of active intervention on any given tumor may differ compared with sporadic, single spinal NSTs. Radiation is used sparingly, as there are concerns that patients may have an increased risk of second malignancies based on their underlying genetic syndrome. Whenever possible, patients should be cared for by a multidisciplinary team with expertise in the care of patients with neurofibromatosis. (See "Neurofibromatosis type 1 (NF1): Management and prognosis" and "NF2-related schwannomatosis (formerly neurofibromatosis type 2)" and "Schwannomatoses related to genetic variants other than NF2".)

Patients with malignant NSTs — For patients with malignant NSTs (MNSTs), a multimodality approach involving surgery along with systemic and radiation therapy has been advocated. (See "Peripheral nerve tumors", section on 'Malignant peripheral nerve sheath tumors'.)

Recurrent tumors — Approximately 5 percent of spinal schwannomas recur after definitive surgical resection [14,27-29]. Risk factors for recurrence may include large tumor size, younger age, subtotal resection, and malignant histology. (See 'Prognosis' below.)

The treatment of recurrent tumors is individualized based on multiple factors including rate of growth over time, presence or absence of symptoms, and prior treatment. Fractionated radiation therapy or stereotactic radiosurgery may be used to treat symptomatic tumors [18-20].

PROGNOSIS — The goal of treatment is to prevent recurrence or progression and preserve spinal nerve root function. The prognosis is dependent upon the histopathology of the tumor.

Schwannoma — Patients with sporadic schwannomas generally remain disease free and can maintain their level of neurologic functioning, even if preoperative deficits are not reversed. In a series of 187 patients with benign schwannoma, one-fifth were symptom free at follow-up, and the remainder had varying neurologic symptoms [27]. There did not appear to be any impairment of life expectancy compared with the general population. Considerable improvement in quality of life has been reported after excision of intradural extramedullary benign tumors [30].

Tumors that have undergone subtotal resection have the capacity for regrowth over time; in a small retrospective series that included 27 patients with residual spinal schwannomas after surgery, 30 percent showed evidence of regrowth (>2 mm increase in tumor diameter) over a mean follow-up of five years, but only two patients required reoperation [31]. The only significant predictor of tumor regrowth in this study was an elevated Ki-67 labeling index. The recurrence rate after complete resection of spinal schwannomas is approximately 5 percent [28].

The neurologic prognosis is not as good for patients with schwannoma secondary to NF2-related schwannomatosis (NF2), since there is a high incidence of new tumors with additional morbidity [3]. (See "NF2-related schwannomatosis (formerly neurofibromatosis type 2)".)

Neurofibroma — Patients with sporadic neurofibromas do well, similar to those with sporadic schwannomas. By contrast, patients with neurofibromas associated with neurofibromatosis type 1 (NF1) are often younger at the time of diagnosis, and the lesions are often multiple and can undergo malignant degeneration [5].

Malignant NSTs — Spinal MNSTs have a poor prognosis. The tumor cannot often be completely resected, and obtaining a wide margin is not possible. Intradural resection is complicated and can lead to leptomeningeal spread. As in all sarcomas, the grade of the tumor is closely associated with the prognosis [32]. Even with maximal resection and adjuvant therapy, many tumors recur; five-year survival is approximately 40 to 50 percent [33,34]. Recurrent or progressive disease may benefit from radiation and systemic therapy. (See "Peripheral nerve tumors", section on 'Treatment of MPNSTs'.)

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".)

SUMMARY

●Intradural, extramedullary nerve sheath tumors (NSTs) may be either sporadic or associated with neurofibromatosis type 1 (NF1), NF2-related schwannomatosis (NF2), or schwannomatosis. Pathologically these tumors include schwannomas, neurofibromas, and malignant NSTs (MNSTs). (See 'Epidemiology and etiology' above and 'Pathology' above.)

●Schwannomas and neurofibromas typically are slow-growing tumors, whose clinical manifestations depend upon the level of the spinal cord involved, while MNSTs are faster growing. Symptoms can progress rapidly if spinal cord compression occurs. Contrast-enhanced magnetic resonance imaging (MRI) of the head and spine is indicated to define the presence and extent of tumor involvement. (See 'Clinical presentation' above and 'Diagnosis' above.)

●Surgical resection is the treatment of choice for most individuals with a schwannoma or neurofibroma. For sporadic tumors, the prognosis is generally good; for those with neurofibromatosis, there is a significant risk of multiple tumors. (See 'Treatment' above and 'Prognosis' above.)