Sporadic Spinal Schwannomas and Neurofibromas – a Review

Tumours arising from the spinal nerve roots are more common in men between the third and fourth decades of life, located mainly in the intradural space of the lumbar region. The clinical symptoms of spinal schwannomas and neurofibromas are similar and depend on the location of the tumour and its relationship to the spinal cord and nerve roots. The pain (radiculalgia and/or vertebralgia) is the earliest symptom, followed by sensory deficit, while motor deficits and sphincter disorders are late symptoms. Magnetic resonance imaging is the diagnostic tool of choice and should be performed when the disease is suspected, as early and accurate diagnosis is essential for treatment outcome. The treatment of these lesions is surgical aiming at total tumour resection that promotes neurological recovery and prevents from recurrences. Subtotal removal also provides favourable outcome but at higher recurrence rates. The aim of this literature review was to study some important characteristics of sporadic spinal schwannomas (SSS) and neurofibromas (SSN), i.e. those not associated with neurofibromatosis type I and II.


INTRODUCTION
About 40% of spinal tumours are intradural extramedullary, 55% are extradural, and 5% are intradural intramedullary. 1 Some of the most common intradural extramedullary neoplasms are the tumours originating from the Schwann cells of the spinal nerve roots, precisely schwannomas and neurofibromas. 2 These tumours are described together under either the name of schwannomas (neurinomas) or neurofibromas. 3 Most of them are benign and show significant cellular maturity, but multiple forms are observed in cases with neurofibromatosis. 4 Neurofibromatosis type 1 (NF1) has been found to be associated with a defect in the neurofibrin gene in chromosome 17, and neurofibromatosis type 2 -with a defect in the merlin/schwannomin gene in chromosome 22. 3 Neurofibromas are associated primarily with NF1, while schwannomas are associated with NF2. 4 The aim of this literature review was to study some important characteristics of sporadic spinal schwannomas (SSS) and neurofibromas (SSN), i.e. those not associated with neurofibromatosis type I and type II.

EPIDEMIOLOGY
Primary spinal tumours are relatively rare and account for about 4-6% of all central nervous system (CNS) neoplasms. 5 Due to differences in the size of the studied population and the classification of neoplasms, the frequency of different spinal cord tumours varies in the different publications. Although there are many reports on the epidemiology of all CNS tumours, there are significantly fewer reports focused only on the epidemiology of spinal cord tumours. 6 Sporadic spinal schwannomas account for about 25% of spinal intradural tumours, while neurofibromas account for only 3%. 2 Solitary SSSs are the most common tumours arising from the nerve sheaths of the spinal nerve roots. 7 In a large retrospective study involving 678 primary spinal tumours, Hirano et al. found 388 (57.3%) SSS and 23 neurofibromas (3.4%), while the meningiomas were only 79 (11.6%). 5 Various publications show that in Asian countries, the incidence of tumours originating from the sheaths of the spinal nerve roots (TOSSNR) is higher than that of meningiomas. 5 This trend is particularly pronounced in East Asian countries, while the incidence of meningiomas in the United States, Europe, and Australia is equal to or greater than that of TOSSNR tumours. 5

SEX AND AGE
According to McCormick et al., SSSs are distributed equally between the two sexes, and according to Conti et al., they are more common in men. 8,9 In a study of 367 patients with SSS, Lenzi et al. 10 found a male-to-female ratio of 51.5:49.5%. Hirano et al. 5 found that out of 388 patients with schwannomas and 23 with neurofibromas, males were 241 (58.7%) while females -170 (41.3%). Generally, SSSs are observed in middle age, most often in the 4th and 5th decades of life, while SSNs occur at a younger age between 30 and 40 years. 2,9 LOCALIZATION SSS are commonly found in the lumbar region in 25.6% to 60% of the cases. 1,5,10,11 According to Jinnai et al., the higher incidence of lumbar SSS is due to the anatomical features of the spinal nerves which run a longer distance in the composition of cauda equina. 12 The second most common localization is the thoracic and thoracolumbar regions while Emel et al. report that this is the cervical region. 1,10,13 Sporadic spinal neurofibromas are more often localized in the cervical region and this frequency varies from 30 to 66%. 3,14 About 80% of SSS arise from the intradural part of the sensory radices of the nerve roots and present as a globular, well-defined, encapsulated mass, separated from adjacent spinal cord roots. 15,16 Rarely do SSS arise from the anterior (motor) roots. 17 In about 15% of cases, the SSS cross the dura mater, due to growth of the tumour along the nerve root, forming an intra-and extradural part, or the so-called dumbbell-type tumour 12 (Fig. 1). In contrast to SSS, neurofibromas more often pass through the dura mater into the extradural space, with a frequency ranging from 25% to 66%. 3,18

HISTOLOGY
Neurinomas and neurofibromas are difficult to distinguish clinically and histologically, so they are often described together as tumours of the nerve sheaths. 16 Sporadic spinal schwannomas and SSN belong to a large category of tumours originating from the Schwann's sheath of peripheral nerves, but differ in their etiology, location and histology. 19 The majority of SSSs are benign tumours with cell maturity with rounded solid shape, and contain Antoni A and Antoni B type cells 1 (Fig. 2). They contain benign neoplastic Schwann cells, while neurofibromas are composed of a mixture of Schwann cells, perineural cells, and fibroblasts, interconnected with nerve fibers and myxoid matrices 20 (Fig. 3). Sporadic spinal neurofibromas can be nodular and well-demarcated or diffuse, with intraneural neurofibromas usually growing along the length of the nerve. 21 At certain sites, SSNs may contain Antoni B cell types, but unlike SSS, Antoni A cell types and hyalinized blood vessels are absent,  with the cellular component of Schwann cells expressing the S100 and SOX10 proteins. 21 The highly cellular, monomorphic neurofibromas with nuclear atypism and random mitotic figures are atypical. Microscopic examinations of the nerve roots from which SSS originate show that they, as well as the feeding artery, are usually unaffected by the pathological process, although its axons are abundant in both the tumour capsule and tumour tissue. 22 It is suspected that the affected spinal nerve root conduction is gradually deactivated, and its functions are slowly compensated by the surrounding roots. 22,23 This statement explains why the postoperative neurological deficit is limited or absent, when the spinal nerve root from which the tumour originates is cut. A study by Celli et al. indicates that a significant number of patients with postoperative deficits show a partial or complete recovery after several months or years. 11

CLINICAL PRESENTATION
The duration of complaints before diagnosis varies from 3-4 weeks to 2 or more years, while in the series of Celli et al. the longest period is 6 years. 11,16 The clinical symptoms of SSS and SSN are similar and depend on the location of the tumour and its relationship to the spinal cord and nerve roots. The pain (radiculalgia and/or vertebralgia) is reported as the earliest symptom, followed by sensory deficit, while the motor deficits and sphincter disorders are late symptoms. 9,12 Initially, the local pain is due to impaired nerve conduction as a result of a direct or indirect irritation of the nerve root or its compression by the tumour. 11,24 In SSS and SSN, radicular pain is the first symptom in 49 to 75% of cases, the most common symptom in 72 to 85%, and the only symptom in 30%. 11 Lenzi

DIAGNOSIS
The final diagnosis of SSS and SSN is made on the basis of clinical findings and magnetic resonance imaging (MRI) results, which is the diagnostic method of choice. 2 MRI visualizes the size, location, presence of cystic degeneration and the relationship of the tumour to the surrounding structures. MRI images in spinal schwannomas and neurofibromas are similar, being hypointense in T1 and moderately hyperintense in T2. In some cases, lower-intensity focal areas associated with intralesional hemorrhages or collagen depositions, as well as higher intensity focal regions corresponding to cystic regions, are observed in T2 sequences (Figs 4, 5). After enhancement, a homogene-   ous or non-homogeneous accumulation of contrast in the tumour is visualized. Spinal schwannomas and neurofibromas have an irregular configuration and can accumulate contrast in the periphery of the tumour (Fig. 6B). Asano et al. found that there is a greater amount of fluid in the Antoni B type SSS which makes them prone to cystic degeneration. 25 Computed tomography (CT) is able to visualize enlargement of the intervertebral foramen and erosion of the pedicles and vertebral bodies (Fig. 7). Schwannomas are usually nodular and have a well-defined capsule which is not always typical of neurofibromas. In some neurofibromas, T2 MRI can demonstrate a central stellate part with low signal intensity that remains non-enhanced, which is caused by the presence of nerve fibers within the tumour (Fig. 6). There is a diagnostic test for schwannomas which is based on several parameters: craniocaudal location, presence of hyperintense and/or heterogeneous signal in the T2-weighted MRI, and heterogeneous accumulation of contrast material in the tumour. 26 This test supports the diagnosis of SSS with a sensitivity of 96.4% and a specificity of 83.3%. 26

TREATMENT
The gold standard of treatment for schwannomas and neurofibromas is total resection, which promotes complete neurological recovery of patients and reduces the recurrence rates. 10 The posterior approach is most commonly utilized by performing laminectomy and incision of the dura mater. 27,28 Subsequent development of instability and deformity due to extensive bone removal may require posterior instrumentation. 1 Although laminoplasty reduces spinal instability, it cannot be completely avoided. 1 Therefore, whenever possible, less destructive approaches such as hemilaminectomy should be employed to remove such tumours. Modified posterior accesses are used for large and dumbbell-type tumours. [27][28][29] The main goal of surgery is to remove the tumour without damaging surrounding neural structures while avoiding spinal instability. 28,30 In some dumbbell-type tumours spreading into the paraspinal thoracic space, the approach has to be widened by performing a costotransversectomy. 27,29 The specific surgical approach and the size of the bone window used must take into account the location of the tumour and the size of its extradural component. 9,24,27 Even for the most skilled spinal surgeons, there is a risk of postoperative neurological deterioration after a surgical intervention due to SSS and SSN. In recent years, intraoperative neurophysiological monitoring in spinal surgery has become extremely important. It enables the surgeon to safely perform total tumour removal without damage to important anatomical structures. 10 Tumours in the subaxial cervical spine can be accessed via anterior, anterolateral or in combination with posterior approach. 11 Radiotherapy is the second treatment option for patients in whom surgery is contraindicated, or in the presence of recurrence. 31

PROGNOSIS
The prognosis of spinal schwannomas and neurofibromas depends on early diagnosis and adequate surgical intervention, as well as on their histological characteristics and location. In general, postoperative outcome is favourable. 1,32 In some difficult cases, total resection is not possible. 7,13 Obstacles to total resection are the presence of dense adhesions between the tumour and spinal cord due to hemorrhage, inflammation or subpial invasion as well as the involvement of major vessels by extradural expansion of the tumour. 33 Giant tumours that violate bone structures and facet joints also pose a challenge to the surgeon. Some  studies have shown that the deficit caused by resecting the nerve root invaded by the tumour is usually not definitive and is well tolerated by patients. 3 Recurrences are usually associated with subtotal resection, but such after total resection have also been reported. 13

CONCLUSIONS
Tumours arising from the sheaths of the spinal nerve roots are one of the most common primary spinal tumours, with schwannomas being more frequent than neurofibromas. They are predominantly benign, slow-growing tumours that affect males more often and debut with radiculalgia and/or vertebralgia and sensory disturbances, but over time can cause significant neurological deficits. MRI is the diagnostic tool of choice and should be performed when the disease is suspected because early and accurate diagnosis is essential for the outcome of treatment. The total tumour removal promotes recovery and prevents from recurrence. Subtotal removal also provides favourable outcome but at higher recurrence rates.