Vestibular Schwannoma

Etiology

Approximately 90% of the schwannomas are sporadic. Schwannomas occurring in specific syndromes (neurofibromatosis type 2, schwannomatosis, and Carney complex) may have a possible genetic etiology, not only in the syndromic schwannoma but in sporadic cases. Neurofibromatosis type 2 accounts for 3% of the syndromic schwannomas, while schwannomatosis for 2%, and meningiomatosis with or without neurofibromatosis type 2 in 5%.

Genetic studies show that the NF2 gene on chromosome 22 plays an essential role in sporadic and syndromic schwannoma development. The NF2 gene encodes for the merlin protein (schwannomin). Specific gene mutations in the NF2 gene cause the inactivation of the gene, thus preventing the formation of the merlin protein. Inactivation of both alleles of the NF2 gene is observed in most schwannomas. Carney complex may have a loss of PRKAR1A expression.

Spinal schwannomas can have SMARCB1 mutations and inactivation.[7]

Epidemiology

Schwannoma is the most common of all nerve sheath tumors in approximately 89% of cases. About 60% of benign schwannomas are vestibular schwannomas.[8] Schwannomas usually affect persons between the ages of 50 to 60. No sex or racial predilection is recognized. Tumors are generally located in the upper limbs, followed by the head, trunk, and flexor surfaces of the lower extremities. Other locations include the posterior mediastinum, retroperitoneum, spinal roots, bone, gastrointestinal tract, pancreas, liver, thyroid, adrenal glands, and lymph nodes.

The Central Brain Tumor Registry of the United States shows that non−malignant nerve sheath tumors account for 8.6% of all central nervous system tumors reported, with no gender predominance, but a higher incidence in whites.[9] The median age at diagnosis is 56 years. The incidence is 4.4 to 5.23 cases per 100,000 adults/year; in children and adolescents, it is 0.44 cases per 100,000/year.[9] The incidence of malignant nerve sheath tumors is 0.03 cases per 100,000/year.

The incidence of vestibular schwannomas in the USA is 1.2 cases per 100,000/year. The median age of patients is 55 years.[8][10] Similar rates occur among males and females, but higher in Whites than non-Whites. In Denmark, vestibular schwannomas have an incidence of 3.4 cases per 100,000/year, with a mean age at diagnosis of 60 years.[11] Other reported incidences of vestibular schwannomas varied between 1.8 to 2.6 cases per 100,000/year.[12][13]

Spinal schwannoma incidence is 0.24 cases per 100,000/year. Spinal schwannomas are more common in white males, usually affecting persons between the ages of 65 and 74.[14]

Histopathology

Although rare, it is important to acknowledge the existence of primary malignant tumors of this cell type as their histology is distinct from schwannomas. Malignant transformation may show malignant epithelioid cells, which occur even without neurofibromatosis.[15]

Classic Schwannoma: This is an encapsulated tumor with two distinct histological regions. Antoni A tissue shows hypercellular spindle cells, sometimes palisade around eosinophilic areas (Verocay bodies). Immunostain is positive for S100 protein staining.[16] Antoni B tissue shows a hypocellular myxomatous pattern with a background of loose connective tissue. Cysts, hemorrhage, and fatty degeneration may be present. Calcifications and mitotic figures are rare.

Cellular schwannoma: It is a relatively uncommon but significant variant of schwannoma. It is located principally in the paravertebral region. It shows compact hypercellular areas composed entirely of Antoni A areas and devoid of Verocay bodies. Cellular schwannoma prompts consideration of malignancy due to its high cellularity, increased mitotic activity, fascicular growth pattern, and occasional locally destructive character. Clues that aid in the diagnosis include the presence of histiocyte aggregates and high expression of pericellular collagen IV. The diffuse expression of the S100 protein is uncommon in spindled malignant peripheral nerve sheath tumors (MPNST), which should point toward cellular schwannoma if present. Cytokeratin immunoreactivity may manifest in some cellular schwannomas and may indicate cross-reactivity with glial fibrillary acid protein. It is important to note that cellular schwannoma is characterized by weak expression of desmin, smooth muscle actin, CD117, and DOG1.

Despite their high cellularity, cellular schwannomas do not have malignant potential and do not metastasize. Local recurrence varies and may be higher compared to classic schwannomas. This recurrence relates partially to the location considering the propensity for deep anatomic regions not always amenable to gross total resection. However, recurrent lesions have slow growth. Most of the time, mitotic activity does not exceed 5 per 10 high-power fields. Mitotic activity above 10 per 10 high power fields may occur in rare instances. If other diagnostic features of cellular schwannoma are present, the proliferative action is still compatible with a benign diagnosis.

Plexiform schwannoma: This variant occurs in subcutaneous or cutaneous superficial locations and is defined by a pattern of growth that may be considered plexiform. Plexiform schwannoma is associated with schwannomatosis, NF2, and other schwannoma-predisposing syndromes. These tumors may not be as circumscribed as a classic schwannoma, and a capsule might even be absent. They involve multiple fascicles. The tumors have an Antoni A pattern. Neurofilament protein immunoreactive axons are present within the lesion.

Plexiform schwannomas that originate in deep anatomic lesions are more problematic. The anatomic locations may be within soft tissues or principal peripheral nerves. They may demonstrate high mitotic activity and cellularity and may not be easily distinguishable from MPNST. Although their potential for malignancy is negligible, these tumors may have a relatively high local recurrence, occurring in approximately 50% of the cases.

Melanotic schwannoma: This subtype of schwannoma may be described as a distinctive, rare, potentially malignant neoplasm that presents with epithelioid cells and melanin accumulated in neoplastic cells and melanophages. Usually arises around the spinal nerve roots. It is positive for MelanA and sometimes for glial fibrillary acidic protein and neurofilament protein.

History and Physical

Schwannomas grow slowly and may exist for years without any symptom manifestation. Schwannomas can present in various locations, which explains the variations in clinical presentations. Tenderness is felt when palpating the mass. Neurologic symptoms may show if the tumor is large. Approximately there is a 5-year delay between symptoms and diagnosis.

Schwannomas in the extremities may present as an asymptomatic mass, mild pain in the area, or paresthesia due to pressure on the parent nerve. Sciatic nerve schwannomas can mimic disk herniation with low back pain with radiation down the leg. Schwannoma, which involves the C7 nerve root, can produce thoracic outlet syndrome. A schwannoma in the ankle or wrist can present as tarsal tunnel syndrome or carpal tunnel syndrome. The presentation of distal symptoms can be due to a lesion in a proximal nerve. Schwannoma may trigger a physiological deficit due to local pressure on the originating nerve.

Vestibular schwannomas usually present with decreased hearing, tinnitus, and imbalance. Rarely will a patient show facial nerve palsy. Trigeminal schwannoma causes numbness or pain in the trigeminal nerve distribution. If the tumor is located at a specific root (V1, V2, or V3), pain and numbness are at the corresponding anatomical area of the face.

Evaluation

Plain radiography is usually not specific. Intraosseous schwannoma typically has a benign appearance. Bone foramina in the spine can be expanded. Chordomas, giant cell tumors, and chondroblastomas are part of the differential diagnoses for schwannomas. Bone destruction is usually present with these lesions, especially when the sacrum is involved.

Magnetic resonance imaging (MRI) and computed tomography (CT) scans are among special studies to consider, but MRI is preferred. The MRI usually shows an oval or round mass with an isointense or hypointense signal on T1-weighted images and a hyperintense, heterogeneous signal on T2-weighted images. The lesion enhances uniformly with gadolinium contrast. A target sign (central area of hypointensity with a peripheral T2 signal hyperintensity) is the most specific sign of a peripheral nerve sheath tumor but is not specific for a schwannoma.

Ultrasound can be used to detect schwannomas under the skin and can be useful during surgery.[17]

Treatment / Management

There are several means of managing vestibular schwannomas. Small asymptomatic schwannomas may be observed. Surgical resection and radiotherapy may be used for progressive and/or symptomatic lesions. However, the ability to preserve hearing varies by treatment technique as well as the size of the tumor. Baseline audiometry and an MRI of the brain should be obtained regardless of the management strategy.

Observation

Vestibular schwannomas have an average growth rate of 1.4mm/year.[18] There is a lack of prospective data regarding the best approach. Large retrospective analysis suggests that tumor control with observation alone is 65%, and serviceable hearing is 71% at two years. It should be emphasized that neither surgical resection nor radiation restore lost hearing and carries the risk of further neurological dysfunction. Observation may be considered in patients with small tumors <1.5 cm, patients with multiple medical comorbidities, no growth, and stable symptoms.[19] However, patients should be counseled that they should undergo regular surveillance with MRIs of the brain every six months and audiological assessments at the same time.[19] If there is no growth, imaging and audiological assessments will occur annually. Patients should be made aware that hearing loss can occur during observation regardless of tumor growth due to neurovascular compression. Retrospective series have demonstrated that patients who underwent observation for schwannomas declined from 70% at diagnosis to 31% at ten years.[19] 

Differential Diagnosis

• Meningioma
• Neurofibroma
• Malignant peripheral nerve sheath tumor
• Carcinomatous meningitis
• Plexiform neurofibroma
• Metastatic melanoma
• Malignant melanoma
• Pigmented neurofibroma
• Leiomyoma/leiomyosarcoma
• Chordomas
• Chondroblastomas
• Giant cell tumors 
• Traumatic neuroma
• Pleomorphic hyalinizing angiectatic tumor
• Palisaded encapsulated neuroma

Surgical Oncology

Surgery

Surgery for vestibular schwannomas results in low rates of recurrence and a high probability of resection.[20][21][20] Careful selection of patients and an experienced surgeon are important for optimal outcomes.[22] A large review of 1000 vestibular schwannoma resections noted a 98% complete resection rate with a 68% hearing preservation rate and 1.1% mortality.[20] The local recurrence rate is 0-2% with complete resection.[19] If only a subtotal resection is possible, there is approximately a 30% rate of regrowth.[19] 

Various approaches may be employed in the resection. The retromastoid approach makes an incision behind the area and mastoid bone with the advantage of preserving hearing but with the risk of incomplete resection. The middle cranial fossa approach has the incision made anterior to the ear and may preserve hearing depending on the extent of the tumor. The translabyrinthine approach goes through the inner ear and invariably results in hearing loss. This approach may be suited for patients without any serviceable hearing. Overall, surgical resection is indicated in patients with large tumors >4cm, recurrent tumors after radiotherapy, brain stem compression, cranial neuropathy, and hydrocephalus.[19]

Complications include post-operative CSF leak (9 to 13%), headache, CN V and VII neuropathies, hearing deficits,  hematoma, hydrocephalus, aseptic meningitis (2 to 4%), and hemiparesis.[20] 

Radiation Oncology

Radiation

The use of radiation in the treatment of vestibular schwannomas is well established. It is a noninvasive means of controlling tumor growth with excellent functional and oncological outcomes. Several treatment delivery approaches have been utilized. All have a different side effect profile, but all produce high rates of local control.

Treatment Delivery

Single-fraction stereotactic radiosurgery (SRS) can be delivered using several platforms, including GammaKnife®, Cyberknife ®, or Linac-based systems. The advantage, in this case, is patient convenience; however, there are size limitations and a higher risk of side effects. Stereotactic radiotherapy (FSRT) is another option and can be employed on both linac-based and cyber knife treatment platforms. It is typically delivered over five fractions. Conventionally fractionated radiation can also be employed and may be used if the dose constraints cannot be met; there are concerns regarding long-term hearing viability or large tumor size.

Doses

For single fraction treatments with SRS, the dose typically ranges from 12 to 13Gy. SBRT dosing ranges from 20 to 25Gy in 5 fractions. Conventionally fractionated doses range from 46.8Gy to 50.4Gy in 26-28 fractions.

Dose Constraints

Constraints used vary based on the dose fractionation scheme used. The critical organs at risk include the brainstem, spinal cord, and cochlea. For SRS, The brainstem dose max should be kept below 12.5Gy, which has a <5% risk of radio necrosis.[23] The brain V12< 5 to 10 cc carries a risk of radionecrosis, which varies by tissue volume and brain location.[24] The cochlear max dose is <14Gy with <25% risk of sensorineural hearing loss.[25] The mean radiation dose to the central cochlea should be less than 4.2 Gy.[26] The spinal cord max <13Gy yields a <1% risk of spinal cord myelopathy for SRS.[27] Typically the dose is prescribed to the 50% isodose line when using GammaKnife ® systems and an 80 to 85% isodose line with linac-based SRS. 

For SBRT/hypofractionated radiotherapy, the brain stem dose with a 5-fraction regimen should have a dose max of 28Gy with <0.5cc getting less than 23Gy. The V24Gy for the brain should be kept under 20cc for a <10% risk of radionecrosis. Cochlear doses should be kept at <27.5Gy max dose. The spinal cord maximum dose is kept below <30Gy.

For conventionally fractionated dose constraints, the brainstem max dose should be kept under 54% with the risk of necrosis <5%.[23] The cochlear max dose should be kept under 45Gy. The risk of sensorineural hearing loss is approximately 30% at 45Gy.[25] Spinal cord max of 50Gy should be attainable and carries a risk of 0.2% for myelitis.[27] 

Simulation and Treatment Planning

Patients undergoing radiation treatment will require immobilization of the head. Although a CT simulation is needed for planning and calculating isocurve curves using the attenuation data, target visualization is quite poor. Therefore a thin-cut MRI of the brain is typically required T1 with contrast, or T2 weighted imaging is needed to better identify the target.  

Outcomes

A retrospective comparison of microsurgery versus SRS suggests that local control rates are comparable (91% vs. 100% at one year).[21] However, facial and trigeminal neuropathy rates were significantly higher, with microsurgery at 35.3% vs. 6.1% and 22% vs. 12.2%.[21] Hearing preservation was significantly higher with radiosurgery at 57.5% vs. 14.4%.[21] Other reviews have confirmed the stark differences in hearing preservation rates, with preservation rates approaching 70% in patients undergoing SRS compared to 37.5% with surgery.[28] In addition, perioperative complications and length of hospital stay were significantly longer with microsurgery.[21] Overall, radiosurgery is well tolerated and may offer better functional outcomes than microsurgery

Fractionation schemes ranging from SRS to conventional treatment have also been compared in retrospective or prospective trials. One prospective trial randomized schwannoma patients based on whether or not they had teeth. They were randomized to either a 5-fraction regimen (Dentate) or single fraction SRS (Edentate). The results demonstrated comparable tumor control, hearing preservation, facial neuropathy, and trigeminal neuropathy.[29] Other comparative studies of 50Gy in 25 fractions to 12Gy in a single fraction did demonstrate comparable tumor control rates of 97% vs. 98% but a significant difference in hearing preservation, 33% vs. 81%, in favor of the fractionated regimen.[30] Dose De-escalation has also been investigated with 46.8Gy in 26 fractions vs. 50.4Gy in 28 fractions and demonstrated a significant difference in 3-year hearing preservation, 79% vs. 68%, and 100% tumor control in both groups.[31]

Proton therapy has also been used for the treatment of schwannomas. The dosimetric properties of protons make proton therapy ideal when the dose constraints cannot be met using other techniques. Proton therapy can be used to deliver SRS (10-18CGE) or fractionated radiation (54-60CGE). Serviceable hearing in this group is approximately 30%, with local control rates exceeding 90% at four years.[32][33]

Medical Oncology

Systemic Therapy

Systemic therapy is limited to a select group of patients but is still of great interest given the increasingly sophisticated understanding of aberrant cell signaling pathways. There are case reports using various targeted agents to help improve and address growth. Vascular endothelial growth factor receptor (VEGF) and its receptor VEGF-R are critical to angiogenesis and have been detected in schwannomas. As a result, Bevacizumab, a monoclonal antibody VEGF inhibitor, has been utilized in patients with NF-2 that have progressive vestibular schwannomas and are not candidates for standard therapies. It was reported that 9 of the 10 patients treated had tumor shrinkage, with 4 having a hearing response.[34] Complications were limited to Grade 1 and 2 events.[34] Erlotinib, an oral tyrosine kinase inhibitor, was also attempted for us in NF-2 patients. Unfortunately, there was no radiographic evidence of regression or hearing response.[35]

Staging

While the AJCC does not offer a formal TNM staging system for acoustic schwannomas, the Koos grading system has been utilized. It is based largely on the extracanilicular extension and degree of brainstem compression. An alternative system is the Hanover Grading system which uses a T stage with a similar classification to Koos. Both the Koos and Hanover systems have been validated in reliability studies.[36][37] The table below outlines both grading schemes.

Prognosis

The prognosis is excellent—recurrence after total resection is uncommon. Malignant changes may occur in long-standing schwannomas, although this is rarely reported. The malignant changes mostly occur in patients that have an underlying neurofibromatosis. The prognosis also depends on the size, location of the tumor, and underlying conditions.[26]