Nerve Sheath Anatomy and Origin of the Nerve Sheath Tumors

Nerve sheath tumors (NSTs) tend to arise from the transition zone of the central nervous system (CNS) to the peripheral nervous system (PNS), where the myelin-forming cells change from oligodentrocytes to Schwann cells. This is also known as Obersteiner-Redlich zone. The peripheral nerves themselves are arranged in several bundles, the smallest constituent of which is a fascicle. Several nerve fibers are surrounded closely by myelin-forming Schwann cells and a loose connective tissue called endoneurium. The fascicles themselves are surrounded by another thicker layer called the perineurium. The nerve itself is surrounded by an even thicker connective tissue layer called the epineurium. The SNSTs arise most commonly from the dorsal rootlets exiting from the spinal cord. Depending on their size and growth pattern, they can remain completely intradural or can exit the dura along with the epineurium of the exiting nerve.

Classification and Pathology

The current classification divides benign NSTs into schwannomas and neurofibromas and combines all malignant variants of this entity into a single group called malignant nerve sheaths tumors (MNSTs).

Schwannomas are well-encapsulated tumors that arise from a single nerve fascicle that displace other uninvolved fascicles by progressive tumor growth. Although the tumor can occur anywhere along the peripheral nerves, favored locations are vestibular part of 8th cranial nerve and dorsal spinal rootlets. Schwannomas are characterized by compact and cellular Antoni A areas with palisading arrangements, called Verocay bodies, and less cellular Antoni B areas that have microcystic changes but no palisading. The neoplastic cells in schwannomas are Schwann cells that stain for S-100, vimentin, and Leu-7.^3,⁴ The tumor rarely contains any functional neural tissue. Secondary changes such as hyalinization, cysts, microhemorrhages, and even mineralization are observed. Variants include ancient schwannomas, cellular schwannomas, and melanotic schwannomas. Schwannomas occur in a sporadic manner as well as well as with certain conditions such as NF-2, schwannomatosis, and Carny’s complex. NF-1 and NF-2 are discussed in more detail below. Schwannomatosis refers to occurrence of multiple schwannomas without other defining features of NF-1 or NF-2.^5,⁶ Patients with Carny’s complex have facial pigmentation, cardiac myxomas, endocrine abnormalities, and melanotic schwannomas, of which 10% may be malignant.^7,⁸

Neurofibromas occur primarily in patients with NF-1 but can also occur sporadically in cutaneous and deep peripheral nerves. They are less well encapsulated than schwannomas and present with more diffuse expansions of the nerve rather than a discrete, dissectable mass. They may have single or multiple fascicles that enter and leave the nerve, making surgical removal almost impossible without sacrificing the peripheral nerve. Often the nerve of origin is nonfunctional on presentation. Plexiform neurofibromas have a predominant intrafascicular histologic growth pattern with redundant loops of expanded nerve fascicles. The presence of axons within the tumor helps distinguish a neurofibroma from a schwannoma. The spindle cells may also stain with S-100 and Leu-7, but less frequently than schwannomas. They lack the densely packed structure like that of Antoni A areas. The presence of mucopolysaccharides in the loose connective tissue also distinguishes these from the schwannomas.

Malignant peripheral nerve sheath tumors (MPNSTs) represent 5% to 10% of soft tissue sarcomas. They are malignant neoplasms that usually arise in the presence of a neurofibroma and very rarely a schwannoma. The term currently includes tumors from multiple different classification schemes used in the past such as neurosarcoma, neurofibrosarcoma, and malignant neuroma. The histologic diagnosis is often difficult given their heterogeneity and dedifferentiation. As many as 67% of MNSTs stain for S-100 and they are thought to be composed, at least partially, of cells that differentiate toward Schwann cells. However, the staining patterns of these tumors are somewhat erratic. Around half of these tumors occur in patients with NF-1. Conversely, around 5% of all patients with NF-1 will develop MNSTs.^1,⁹^–¹¹ The principal differential diagnosis includes cellular schwannoma, fibrosarcoma, malignant fibrous histiocytoma, synovial sarcoma, and leiomyosarcoma.¹²

Neurofibromatosis

The neurofibromatoses (NFs) are two distinct and well-described, autosomal dominant genetic syndromes caused by mutations in genes coding for neurofibromin on chromosome 17 (NF-1) and merlin for chromosome 22 (NF-2). Both are transmitted in an autosomal dominant pattern but can occur as a result of spontaneous mutation as well. These deficits predispose patients to the development of both benign and malignant NSTs. NF-1 (Von Recklinghausen’s disease) is the more common condition (1 in 2500) and has a strong association with MNSTs.

The diagnosis of NF-1 is made from presence of two or more of the following seven criteria ^13,¹⁴:

NF-2 is much less common than NF-1 (1 in 50,000 people). It was first recognized in 1970 as a distinct entity. Cutaneous manifestations are less common than in NF-1, and indeed in older literature, this was referred to as the “central form” of neurofibromatosis compared to the peripheral form, now called NF-1.¹⁵ The criteria for diagnosis of NF-2 are met by an individual who satisfies condition 1 or 2 of the following^13,¹⁴:

Spinal NSTs occur much more frequently in patients with neurofibromatosis. Multiple spinal neurofibromas are seen almost exclusively in patients with NF-1.¹⁶ However multiple spinal schwannomas can occur (albeit uncommonly) without neurofibromatosis. NF-1 patients commonly have multiple SNSTs, usually neurofibromas. Occurrence of multiple SNSTs in NF-2 patients is uncommon, but when they occur, they are usually schwannomas.^16,¹⁷

Tumor Location

Spinal NSTs are almost equally distributed at all levels of the spinal column, but cervical or lumbar predilections have also been described.^2,¹⁸ In a recent series from Japan, of 149 SNSTs treated between 1980 and 2001, 28 arose from first two cervical roots, 54 from C3–C8 roots, 38 from the thoracic spine, 13 from the conus region, and 43 from the rest of the lumbosacral spinal roots.¹⁹ In Seppala’s series, 26% of all schwannomas were cervical, 30% were thoracic, 18% were in the region of conus medullaris, and 21% were lumbosacral.² In contrast, of 179 SNSTs analyzed by Conti et al., almost half were in the lumbosacral region, one-third in the thoracic region and the rest in the cervical spine.²⁰

Two thirds or more of all SNSTs are purely intradural. The rest are variably divided between pure extradural and dumbbell tumors. In extremely rare cases, purely intramedullary schwannomas have been described. They presumably arise from aberrant Schwann cells or small nerves entering the spinal cord around penetrating spinal arteries.²¹

In the series by Seppala et al. of 187 spinal schwannomas, 66% were intradural, 13% were extradural, and 19% were both intra- and extra-dural. Analyzing the series further, they found that the cervical tumors had a higher likelihood of being purely extradural. They attributed this to relatively short intradural cervical nerve roots, compared to the thoracic and lumbar roots. This has also been our experience at the University of Miami. In their series, 76% of cervical tumors had an extradural component, while this was the case only in 28% of thoracic tumors and 11% of lumbar tumors.² Neurofibromas, on the other hand are more commonly extradural or dumbbell shaped. Jinnai and Koyama¹⁹ analyzed 149 cases of SNSTs and found that strictly intradural tumors comprise only 8% of tumors of the first two cervical roots. The percentage of these tumors increased gradually from the high cervical region to the thoracolumbar region, where it was more than 80%. In contrast, the percentage of strictly extradural tumors gradually decreased from the cervical to lumbar region. They also attributed these changes in the growth pattern to anatomic features of the spinal nerve roots, which have a longer intradural component at the more caudal portion of the spinal axis.¹⁹

Clinical Presentation

Spinal NSTs occur equally in males and females. They usually peak in the fourth to fifth decades and are uncommon in children and the elderly.² About half of all IDEMs in adults are nerve sheath tumors compared to less than 5% in children. Most of the spinal tumors in children tend to be intramedullary.²²

The signs and symptoms are not specific to the tumors but are related to the radiculopathy and myelopathy caused by these tumors at various spinal levels. Radicular pain is a common initial complaint and can be attributed initially to a prolapsed disc in the cervical or lumbar region. Local pain related to stretching of the dura is also not uncommon. Subjective sensory complaints are very common but can sometimes be difficult to define objectively. A sensory level may exist in advanced cases. Sensory deficit could either be related to the radiculopathy at the level of the tumor or due to spinal cord compression of dorsal columns and/or spinothalamic tracts. This is in contrast with the early loss of pain and temperature and relative sparing of touch and proprioception in case of intramedullary tumors. Focal lower motor neuron weakness could be seen in upper or lower extremities in cases of cervical or lumbar SNSTs, again due to nerve root involvement, but is uncommon compared to sensory findings. Spastic weakness due to compression of corticospinal tracts can occur with cervical or thoracic tumors due to cord compression. Bladder and bowel involvement is usually late and is more common in lesions affecting the conus.

Brown-Séquard syndrome is not uncommonly seen in these patients due to the frequent lateral/dorsolateral location of these tumors with respect to the spinal cord. Indeed, SNSTs are among the most common causes of partial or complete Brown-Séquard syndrome in clinical practice. The classic progression from radicular symptoms and segmental motor-sensory symptoms to Brown-Séquard syndrome to complete cord impairment is rarely seen in modern times due to early diagnosis and intervention.

Presence of multiple tumors or tumors at younger age should raise suspicion of neurofibromatosis, and appropriate workup should be done including imaging of the entire neuraxis.

Imaging Features

Magnetic resonance imaging (MRI) is the imaging modality of choice. Schwannomas are usually isointense (75%) or hypointense (25%) on T1- and hyperintense on T2-weighted images with intense contrast enhancement.²³ Cystic changes may sometimes be seen in 20% to 40% of cases. MRI defines the anatomy in all three planes and reveals the tumor relationship to the spinal cord, nerve roots, and the surrounding structures. These tumors usually remodel the surrounding structures, expanding in whatever space available to them. Dumbbell lesions are more common in the lower spine than in the cervical spine.²⁴ Because of space constraints, the dumbbell tumors are smaller within the canal but can expand to large sizes in the relatively open spaces of the retroperitonium or the chest. Infiltration and invasion of surrounding structures are not seen unless there is a malignant change.

Magnetic resonance angiography (MRA) is obtained to identify the relationship of the tumor to the vertebral artery, especially in dumbbell tumor and extradural tumors. This is particularly important for surgical planning. If both MRI and MRA are inconclusive, regular angiography may be considered to define adjacent vascular anatomy. On rare occasions, preoperative embolization may be helpful if the tumor is large, has many flow voids on MRI, and the feeders are embolizable. Preoperative vertebral balloon occlusion test and planned vertebral artery sacrifice are other reasons when regular angiography is obtained during the preoperative workup.

Computed tomography (CT) scanning may demonstrate tumor calcification and help in defining bony anatomy. The tumor itself is usually isodense to the cord on CT scans and enhances on contrast. CT scan is usually not needed unless the spinal stability is in question before or after surgery and the patient is being considered for bony fusion. This scenario is relatively uncommon.

Regular myelogram is mostly of historical interest and has largely been replaced by CT-myelogram. It is a useful modality in patients in whom MRI cannot be obtained and defines both the bony anatomy and the level of the block in the cerebrospinal fluid (CSF).

Plain x-rays are no longer universally obtained in patients suspected of having SNSTs. They may demonstrate enlarged neural foramen, increased interpedicular distance, scalloping of posterior vertebral bodies, and thinning of pedicles. These nonspecific changes are due to the slow growth of the tumors over time causing bony remodeling. Some of these changes can be seen in NF-1 even without neurofibromas.²⁵

Differential Diagnosis

Spinal meningioma is the main differential diagnosis in patients with SNSTs. In contrast to schwannomas, they are much more common in women, favor the thoracic spine, may show calcification on CT, rarely extend extradurally, are more commonly hypointense on the T2-weighted sequence, and may have an enhancing tail on MRI. Other rare tumors of the nerve sheaths to be included in the differential diagnosis are neuroblastomas, ganglioneuromas, ganglioneuroblastomas, and paragangliomas. Local malignancies like carcinomas and sarcomas may extend into the spinal canal from outside. Ependymomas, spinal hemangioblastomas, lipomas, and metastasis can also be intradural, as well as drop metastasis from CNS cancers. Extruded or herniated intervertebral discs and synovial cysts can also sometimes present in a similar fashion.

Surgical Indications

Spinal NST is a surgical disease, and surgical excision is recommended in a majority of patients. Conservative management is usually reserved for patients who are very poor surgical candidates, are asymptomatic, or have minimally symptomatic lesions with neurofibromatosis and multiple tumors. In all sporadic cases, surgery is indicated for symptomatic lesions or large/growing asymptomatic lesions. This is because in most cases, the surgery is fairly straightforward for neurosurgeons adept in microsurgical techniques and there is no guarantee of improvement in neurologic symptoms after they occur.

Radiation therapy or chemotherapy traditionally has no role in the management of benign SNSTs. More recently, fractionated stereotactic radiation with Cyberknife (Accuray, Sunnyvale, CA) has been shown to be helpful in these cases. In 2006, Dodd et al. published their results on treatment of 51 patients with Cyberknife. Of the 28 patients with more than 2 years follow-up, all had either stable (61%) or smaller (39%) tumors. One patient had radiation-induced myelopathy and three patients out of 51 needed surgery within 1 year of treatment due to worsening disease.²⁶ The intermediate term follow-up had similar results.²⁷ Cyberknife treatment is an alternative to surgery in patients who are poor surgical candidates, have multiple tumors with neurofibromatosis, or have recurrent progressive disease that is not amenable to safe resection. Surgery still remains the first line of treatment in these tumors. In cases of malignant spinal NSTs (MSNSTs), postoperative radiation is employed for local disease control. Chemotherapy is not very helpful in most of these cases.²⁸ Outcome in malignant cases is very poor despite aggressive therapy.

Surgical Approaches

Intradural Tumors

Most SNSTs are intradural. Almost all of these tumors can be removed by a posterior approach, including those with a significant ventral component or small part going into the neural foramen. For large midline ventral tumors, anterior corpectomy and reconstruction comprise an option but this approach is challenging and very rarely needed.²⁹ Standard techniques of laminectomy and microsurgery are employed for removal of the vast majority of these tumors. For cervical tumors with spinal cord compression, awake fiberoptic intubation is preferred. We monitor somatosensory evoked potentials (SSEPs) in both upper and lower extremities along with motor-evoked potentials (MEPs) during the surgery to recognize early threats to the spinal cord. Electrodes are placed by the neuromonitoring team after intubation, and baseline recordings are obtained. All our cases are implemented in prone position. A radiolucent table top is used in cases where instrumentation is being planned. We prefer Mayfield three-point skull fixation during the prone position to avoid any kind of pressure on the face or eyes. The patient is turned into prone position carefully with “spine precautions.” Adequate padding is confirmed at all bony prominences and genitals. The table is positioned in a way that the eyes are above the heart to avoid ovular venous congestion. It also enhances venous drainage in cervical operations. Care is also taken to free the lower chest and abdomen from any pressure to promote good respiratory excursions and prevent engorgement of epidural venous plexus.

Perioperative antibiotics are given according to the hospital protocol so that peak levels are present in the blood at the time of incision. We prefer cefazolin 2 g at induction followed by 1 g every 8 hours for 24 hours for most of our cases. Patients who are at high risk for methicillin-resistant Staphylococcus aureus (MRSA) infections (chronic wound care, previous MRSA infection, or present colonization) are given vancomycin, which is started when the patient enters the room.

The importance of correct localization cannot be overemphasized. The incision site is marked before scrubbing the patient using fluoroscopy and again confirmed before laminectomy. In children, we prefer laminoplasty over laminectomy. Yasuoka et al.³⁰ found 46% incidence of spinal column deformity if laminectomies were done in children less than 15 years of age, compared to 6% in patients aged 15 to 25 years and 0% in those older than 25 years. A midline vertical incision is then made over the appropriate site, and paraspinal muscles are dissected off the spinous processes and lamina in a subperiosteal manner. In cervical or thoracic spine, the laminectomy is done very carefully to prevent any pressure on the cord, particularly if there is pre-existing spinal cord compression. We prefer a combination of high-speed drill, Leksell rongeurs, and/or Kerrison (2 or 3 mm) punches for removing the lamina, taking care not to put the instruments under the lamina. The laminectomy should extend both above and below the tumor to expose the tumor entirely. Meticulous extradural hemostasis is important at this stage as a decrease in epidural pressure on opening the dura and egress of CSF will increase epidural bleeding, making the operation messy.

A hemilamincetomy may be sufficient for laterally situated small tumors. For tumors with small extensions into the neural foramen, medial facetectomy may be needed. In either case, the bony exposure should not be compromised. We prefer using intraoperative ultrasound again at this stage to confirm tumor location and the adequacy of bony exposure.

The dura is then opened in the midline with the option to curve the dural opening to the side of the tumor at the upper and lower end of durotomy. As an alternative, a paramedian durotomy toward the side of the tumor can be made as well and the dura hitched up to the paraspinal muscles using 5-0 prolene or silk sutures. A small “T” can be made in the dural incision for tumor with extensions into the neural foramina. We prefer to open the dura in two layers, holding up the superficial layer with jeweler’s forceps while incising the deeper layer and preserving the arachnoid to prevent cord herniation or epidural bleeding from the sudden release of CSF. Durotomy is taken above and below the tumor level, and the arachnoid is then opened and stitched to dura if needed. Care is taken to minimize the blood running into the canal by placing Cottonoid Patties at the top and bottom of the dural opening. The tumor should be clearly visible at this time.

We use an operating microscope at this time, although the dural opening could be done under microscope as well, depending on the surgeon’s preference. The technique of tumor removal depends on the size, consistency, vascularity, and adhesions of the tumor to the surrounding rootlets. There is usually a very good plane between the tumor and the spinal cord, but larger tumors may be stuck to the anterior rootlets. Schwannomas usually arise from one or more nerve fascicles in the dorsal rootlets. Effort should be made to separate these fascicles from the tumor by developing a plane between the tumor and the rootlets using a combination of Rhoton microdissecting instruments and a No. 6 Penfield dissector. Smaller tumors can usually be excised en toto, whereas larger tumors need internal decompression and piecemeal removal. Every effort should be made to prevent retraction or pressure on the cord itself beyond that already exerted by the growing tumor.³¹

Dorsal rootlets are often sacrificed in removing these tumors, but anterior rootlets should be preserved, especially in the cervical and lumbar regions. This is usually possible in small- to moderate-sized schwannomas with careful microdissection. There are usually no major neurologic deficits resulting from sacrifice of the dorsal roots. In the cervical spine, spinal rootlets of the spinal accessory nerve usually course superiorly anterior to the plane of the tumor and should be preserved. Intraoperative assessment of nerve root function is also very helpful in deciding whether a root can be sacrificed. If the nerve shows preserved motor function on stimulation (0.5 to 1 mA), we make every effort to preserve it in the cervical and lumbar regions. If there is no function, it usually means other roots have taken over the function, and neurologic deficit, if any, from the sacrifice of the nerve root will be minor. In either case, we warn the patient before surgery of the potential risk of a small neurologic deficit in trying to remove the tumor completely to minimize the risk of recurrence.

Larger tumors should be debulked first using the Cavitron ultrasonic aspirator (CUSA-Valleylab, Boulder, CO), laser, or suction-bipolar techniques depending on tumor consistency and vascularity, and the capsule can then be carefully peeled off. For more ventral tumors, partial facetectomy and drilling of the pedicles may be necessary. Dentate ligaments can be cut for use as a handle for very gentle retraction of the cord. Neurofibromas usually involve the entire nerve root, with no good plane between the tumor and the nerve, and in cervical and lumbar regions, partial debulking only and preserving the anterior motor rootlets is probably a better approach to preserve motor function.

After tumor removal, hemostasis is carefully checked. The dura is closed in a watertight manner with 5-0 prolene sutures. In the event that the dura has shrunk or a “T” incision in the dura laterally prevents a watertight closing, a duraplasty with cadaveric dura or other synthetic dural substitutes is done. For small defects, muscle or fat graft with fibrin glue could also be used. If the dural closure is inadequate, a lumbar drain can be inserted at the end of the procedure to minimize CSF pressure and allow the tissues to heal. We take consent for placement of lumbar drain before surgery when such an event is anticipated. Muscles are approximated and fascia is closed tightly with vicryl sutures. We typically use 4-0 monocryl subcuticular sutures for skin closure.

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