Etiology and Epidemiology

Based upon surgical series, approximately 8000 meningiomas are diagnosed each year in the United States. Radiographic and autopsy studies suggest an even greater number of patients with clinically occult tumors.² A recent epidemiologic study revealed that meningiomas are the most frequently reported primary intracranial neoplasm, constituting approximately 30% of all brain primary tumors.³

The likelihood of developing a meningioma is proportional to age. Pediatric meningiomas are rare but are more likely to exhibit an aggressive clinical course.⁴ Meningiomas are most often diagnosed during the sixth to seventh decades of life. However, the age-specific incidence continues to rise thereafter, even beyond 85 years of age.³

Although there are known associations with certain genetic, environmental, and hormonal risk factors, most meningiomas arise without discernible causation. Genetic factors will be discussed in an ensuing section on Biologic Characteristics and Molecular Biology. Radiation exposure—stemming largely from studies of atomic bomb fallout but also from studies of cranial and scalp irradiation for tinea capitis—is a well-described environmental etiologic factor for meningiomas. Indeed, radiation-induced meningiomas are the most commonly reported secondary neoplasm.²

A role for sex hormones in meningioma induction is supported by several findings. Meningiomas occur more frequently in females, at a ratio of 2 or 3:1.² The incidence appears to increase with hormone replacement therapy or long-acting oral contraceptive use and in obese individuals. Moreover, tumor size or symptoms may worsen during the luteal phase of menses or pregnancy. In spite of these observations, the precise role of hormones is unclear. In both sexes, more than 70% of meningiomas express progesterone receptors, and up to 40% estrogen receptors, but nearly 40% express androgen receptors as well.^2,5

Prevention and Early Detection

At this time, there are no known preventive interventions and there is no evidence in favor of screening. For patients with asymptomatic, incidentally detected meningiomas, surveillance, with the intent of ruling out aggressive clinical behavior, remains a judicious practice.

Biologic Characteristics and Molecular Biology

Meningiomas occur more frequently in certain rare genetic conditions, such as type 2 neurofibromatosis (NF2).⁴ Mutation in the NF2 gene on chromosome 22q12 is the most common cytogenetic alteration. Nearly all NF2 meningiomas have mutations of the NF2 gene, and most susceptible families have alterations of the NF2 locus.⁶ Genetic losses of chromosomes 1p, 10, and 14q have been linked with malignant progression or recurrence but have not yet been validated as independent prognostic markers.^2,6 Markers of tumor aggressiveness have been studied. MIB-1 expression has been correlated with time to recurrence in some series⁷ but not in others.⁸

Pathology and Pathways of Spread

The World Health Organization (WHO) recently published updated grading criteria.⁵ This system describes 3 grades and 13 histologic subtypes of meningioma (Table 26-1). Strong associations between grade, relapse-free survival (RFS), and overall survival (OS) have been confirmed,⁵ but even with improved criteria there remain disparities, particularly regarding the proportion of patients with grade II (atypical) histology. A recent large analysis reported that 5% of meningiomas were atypical.³ However, Perry and associates⁵ found that over 20% of meningiomas were WHO grade II tumors.³ Willis and colleagues⁹ re-graded patients using modern WHO guidelines and reported that 20.4% were atypical. Another recent analysis found that, whereas 4.4% of meningiomas were categorized as atypical from 1994 to 1999, this percentage has steadily increased to 32.7% to 35.5% since 2004.¹⁰

TABLE 26-1 The 2007 World Health Organization (WHO) Criteria for Meningioma Grading

hpf, high-power field.

Modified from Perry A, Louis DN, Scheithauer BW, et al: Meningeal tumours. In Louis DN, Ohgaki H, Wiestler OD, Cavenee WK (eds): WHO Classification of Tumours of the Central Nervous System. Lyon, IARC 2007. Modified with the kind assistance of Arie Perry.

The WHO grade is a dominant prognostic factor. Compared with a grade I meningioma, a grade II tumor carries a sevenfold to eightfold increased recurrence risk at 3 to 5 years. Grade III meningiomas are even more aggressive, with a 5-year OS of 32% to 64%.11,12,13,14

Clinical Manifestations, Patient Evaluation, and Staging

Most data regarding the diagnosis and treatment of meningiomas are based on surgical series. As such, there is an inherent bias toward symptomatic tumors. Symptoms depend largely on the location of the lesion but can be influenced considerably by the presence of edema. Skull base meningiomas can present with cranial nerve palsies or neuropathies. Sphenoid wing meningiomas may present with seizures.¹⁵

With the increasing use of contrast-enhanced CT and MRI scanning for head trauma, headaches, and so on, the number of incidentally discovered meningiomas has risen. Incidentally discovered meningiomas are often smaller and may show little growth over time.¹⁶Although the clinical behavior of incidental meningiomas is not uniformly predictable, younger age and larger size at detection portend increased progression risk.¹⁶

Contrast-enhanced MRI is the imaging modality of choice for meningiomas. Tumors at the skull base may also be imaged with CT to evaluate bony invasion, involvement of skull base foramina, or hyperostosis. Additionally, CT may identify calcifications, a finding predictive of more indolent growth.² MRI is generally superior for visualization of the contrast-enhanced lesion, and MRI T2 signal changes may presage more aggressive behavior.²

Primary Therapy

Tumors with Benign Histologic Findings (WHO Grade I Tumors)

Surgery

Surgery remains the standard of care, and the extent of surgical resection has been correlated with rates of tumor recurrence. In 1957 Simpson reported a series of 265 patients treated surgically, giving rise to the standard system used to describe the extent of resection.¹ The Simpson grade of resection and the associated crude recurrence rates are depicted in Table 26-2. Modern series employing current surgical and imaging techniques have validated this association.¹⁷

TABLE 26-2 Simpson’s Definitions of “Five Distinct Grades of Operation,” with Respective Recurrence Risk*

Grade	Definition of Resection Extent	Recurrence
I	Macroscopically complete removal of tumor, with excision of its dural attachments and any abnormal bone	9%
II	Macroscopically complete removal of tumor, with coagulation of its dural attachments	19%
III	Macroscopically complete removal of tumor, without resection or coagulation of dural attachments or of extradural extensions (e.g., invaded sinus or hyperostotic bone)	29%
IV	Partial removal, leaving tumor in situ	44%
V	Simple decompression or biopsy	N/A

N/A, not applicable.

* Recurrences were identified “in a purely clinical sense to imply the reappearance of symptoms.” Dr. Simpson calculated recurrence risk in a crude fashion, often excluding patients who had had surgery within the prior 5 years.

Modified from Simpson D: J Neurol Neurosurg Psychiatry 20:22-39, 1957.

Surgery remains an appropriate therapy for many meningiomas. Convexity meningiomas are often managed with resection because they can typically be completely resected without significant morbidity. However, even with convexity tumors, those surrounding or invading major draining veins or venous sinuses can pose considerable difficulty. Tumors involving the skull base are more challenging but may also be managed surgically. As is the case with meningiomas of the cavernous sinus and other select skull base sites, close proximity to critical neurovascular structures renders radical resection potentially morbid. Optic nerve sheath meningiomas intricately involve the nerve’s vasculature. Resection, which commonly leads to vision loss, is rarely advised, and primary radiation therapy has a favorable track record.

Postoperative Radiotherapy

Adjuvant radiotherapy is not recommended following gross total resection of a newly diagnosed grade I meningioma. Radiotherapy has often been used after subtotal resection, although considering the absence of randomized trials, differences in clinical practice are to be expected. Many patients are observed after subtotal resection. However, a multitude of retrospective series have reported that radiotherapy improves local control after subtotal resection. Figure 26-1 illustrates progression-free survival (PFS) outcomes from 27 series with long-term results following gross total resection alone, subtotal resection alone, and subtotal resection with external beam irradiation (EBRT).^2,18 Some of the series, including many of the recent reports, include patients treated with primary radiotherapy.

Figure 26-1 Scatterplot comparing 5-year progression-free survival following gross total resection alone (GTR), subtotal resection alone (STR), and subtotal resection plus external beam irradiation (STR+EBRT) for patients with meningioma. The x axis is the year of publication. Some patients plotted as STR+EBRT were treated with primary EBRT without surgery or histologic confirmation.

Goldsmith and colleagues¹¹ reported a series of 140 patients who received radiotherapy following subtotal resection and identified a dose response. Benign subtotally resected tumors had significantly improved rates of PFS (93% vs. 65% at 10 years) when a dose greater than 52 Gy was delivered. Moreover, the researchers found significantly improved outcome with CT- or MRI-based treatment planning¹¹ (Fig. 26-2). Other studies evaluating radiotherapy after subtotal resection have exhibited superior cause-specific and possibly even OS.^19,20

Figure 26-2 Progression-free survival rates of meningioma patients treated with external beam radiotherapy based on treatment era. Treatment planning techniques changed after 1980 with the advent of CT and MRI. Local control has likely improved secondary to better targeting of the tumor.⁵

Recurrent meningiomas, whether benign or atypical, display a considerably higher rate of recurrence after surgery alone than newly diagnosed tumors.19,20,21 In this setting, postoperative radiotherapy decreases the rate of tumor progression.^20,21 In a series by Taylor and associates,²⁰ the local control benefit of postoperative radiotherapy at the time of first recurrence (88% vs. 30% at 5 years) translated into an OS benefit (90% vs. 45% at 5 years).²⁰

Definitive External Beam Radiation Therapy

Early reports of primary radiotherapy revealed inferior results, with local control rates on the order of 47%.²² However, these reports included patients treated in the 1960s and 1970s, before the advent of current imaging and treatment planning paradigms. Many recent series using conformal techniques have corroborated excellent results from definitive radiotherapy with local control in excess of 90% at 5 to 10 years.^2,18,23,24 Total doses have ranged from 45 Gy¹⁸ to 57.6 Gy,²⁵ typically in 1.8- to 2-Gy fractions. The higher cumulative doses were predominately for higher-grade, large, or recurrent meningiomas. For most patients, modern imaging-based planning and treatment with doses in the range of 50 to 54 Gy with standard fractionation have produced excellent results. Figure 26-3 depicts two examples of tumors appropriate for definitive EBRT.

Figure 26-3 Examples of meningioma cases for which fractionated external beam irradiation (EBRT) would be indicated. A, An axial slice of a T1-weighted MRI of a patient with an optic nerve sheath meningioma encasing the optic chiasm. This patient was treated with fractionated EBRT and exhibited stable, useful vision at last follow-up 3 years after therapy. B, An axial slice of a spoiled gradient recall (SPGT) MRI sequence of a patient with type 2 neurofibromatosis. The patient developed multiple meningiomas, including a parietal meningioma that was resected, two right sphenoid wing meningiomas that were treated with radiosurgery, and a left sphenoid wing meningioma that required fractionated radiotherapy at time of progression. C and D, The EBRT isodoses for these cases. The optic nerve sheath meningioma was prescribed a dose of 52.2 Gy in 1.8-Gy fractions. The sphenoid wing meningioma, which exhibited more rapid progression on serial imaging, was treated to 54 Gy in 1.8-Gy fractions. The lesions remained controlled at 3 and 2 years, respectively.

Optic Nerve Sheath Meningioma

Optic nerve sheath meningiomas represent only 1% to 2% of meningiomas² but pose considerable clinical challenges owing to their intimate association with the optic nerve and its vasculature. Historically, treatments included resection or observation, both leaving patients with poor functional outcomes. On this account, fractionated radiation therapy is being increasingly used.

Turbin and colleagues²⁶ reported 64 patients managed with surgery alone, surgery plus radiotherapy, radiotherapy alone, or observation. They found that radiotherapy alone resulted in excellent tumor control and was the only modality not leading to worsening of visual acuity. Other series have confirmed excellent outcomes, with stabilization or improvement in visual acuity in up to 90% of patients, with local control exceeding 90%.^2,21 Doses of 40 to 54 Gy with fractions of 1.6 to 1.8 Gy have been standard and have produced results more favorable than observation, surgery alone, or surgery plus irradiation.^2,26,27

Stereotactic Radiosurgery

Over the past two decades, radiosurgery has become an acceptable and frequently used modality and is generally considered suitable for meningiomas of less than 3 to 4 cm in maximum diameter, with distinct margins, with little or no surrounding edema, and situated at a sufficient distance from critical normal tissues to permit appropriate dose restrictions.17,28 Long-term local control has exceeded 85% in the majority of studies.²

Table 26-3 compares the outcomes for radiosurgery with those of definitive EBRT; this is not a direct comparison but is a compilation of retrospective series reported in the literature and is therefore inherently biased in terms of patient selection. The University of Pittsburgh’s initial publication of long-term outcomes used a median marginal dose of 16 Gy.²⁸ The rate of new neurologic toxicity was 5%. Since this report, it has become evident that lower single doses may be sufficient. In the University of Pittsburgh’s recent update²⁹ of 972 patients, the median marginal dose was 14 Gy. Other reports have shown good local control with doses of 12 Gy. Figure 26-4 illustrates the potential dosimetric advantages of lower marginal doses.

TABLE 26-3 Comparative Analysis of Results with SRS and EBRT by Grade of Meningioma in Multiple Retrospective Series*

Figure 26-4 Comparison of dose profiles of cavernous sinus meningioma using a standard marginal dose of 14 Gy (left) versus 12 Gy (right). Note the proximity of the 8-Gy isodose line (green) to the optic structures (red contours) with each prescription dose, given otherwise identical plans.

Tumor volume has also been shown to be a predictor for success with radiosurgery. DiBiase and colleagues³⁰ reported 5-year disease-free intervals of 91.9% for patients with tumors of 10 cc or smaller versus 68% for larger tumors. Kondziolka and associates²⁸ similarly cited a decreased control rate with larger tumors.

Irradiation Techniques and Tolerance

Several methods of target delineation have been described, and there is controversy concerning the optimal method to account for microscopic spread along dura and bone and into the brain. With EBRT, margins as large as 2 cm beyond the gross tumor volume (GTV) have been described using modern imaging.¹⁹ However, margins as small as 1 to 2 mm in fractionated stereotactic radiotherapy series have produced good long-term outcome (although the follow-up in such series is shorter, and the patients selected may be inherently different).^23,24 Such tight margins may not be safe for meningiomas beyond grade I. Recent reports of radiosurgery for atypical meningiomas have found that increased conformality predicted for a higher rate of local failure.³¹

Targeting of the dural tail within the clinical target volume (CTV) is also controversial. Surgical series have found that the dural tail is composed almost entirely of hypervascular dura, and is typically an imaging finding, not routinely visualized at surgery.² The dural tail is not included in the Simpson resection grading scale, and the results of surgery alone have largely been obtained without specific attention to it. Furthermore, radiosurgical series have generally not targeted the dural tail.^2,28,42

Inclusion of hyperostotic bone within the CTV is also worthy of discussion. A Simpson grade 1 resection includes gross total resection of tumor, its dural attachments, and any abnormal bone.¹ Biopsy series have demonstrated a significant rate of bone involvement by meningioma in cases of hyperostosis,⁴³ and this is associated with a higher rate of recurrence.⁴⁴ This question needs to be addressed more thoroughly, but it is clearly justifiable to target hyperostotic bone within the treatment volume when this can be accomplished safely.

Treatment Algorithm, Controversies, and Clinical Trials

A treatment algorithm is presented in Figure 26-5. Corresponding dose and treatment volume guidelines are contained in Table 26-4. These depict a literature-based approach defined by risk strata. However, many controversies persist. There is substantial debate concerning which patients to observe, which to treat with primary fractionated radiotherapy or radiosurgery rather than surgery, and which to select for postoperative radiotherapy. Gross total resection of a benign (WHO grade I) meningioma is considered definitive therapy, but there is less agreement about this following subtotal resection of a WHO grade I tumor or after gross total resection of a grade II meningioma. Subtotally resected grade II meningiomas are frequently managed with irradiation, and all grade III meningiomas demand aggressive treatment, irrespective of resection extent. Despite aggressive management, however, current approaches are insufficient for many high-risk patients. New systemic and biologic treatments are needed.

Figure 26-5 Treatment algorithm for meningiomas based upon grade and operative status.

Etiology and Epidemiology

The incidence of vestibular schwannoma has been estimated at 0.6 to 0.8 per 100,000 person-years, and is increasing, at least in part because of the more widespread use of intracranial imaging with CT and MRI and a controversially claimed association with cellular telephone usage, although there is no convincing evidence for this.⁵⁰ Roughly 85% to 90% of cerebellopontine angle tumors are vestibular schwannomas. Vestibular schwannomas are identified on MRI in 0.2% of asymptomatic patients.⁵¹ Some cases can be attributed to genetic syndromes such as NF2, which pathognomonically presents with bilateral vestibular schwannomas. Over 90% of cases, however, are sporadic and unilateral. Case-control series suggest a potential correlation between vestibular schwannoma and cell phone usage—although these data remain highly controversial⁵²—or occupational exposure to loud noise,⁵³ also an association mired in controversy. The median age of patients at diagnosis is 50 years; however, patients with NF2 typically manifest symptoms by age 20 to 30 years.

Biologic Characteristics

Biallelic inactivating mutations of the tumor suppressor gene NF2, located on chromosome 22q12, are commonly found in both sporadic and NF2-associated vestibular schwannomas.⁵⁴ NF2 encodes the cytoskeletal protein merlin, which functions in embryonic development, cell adherence, and cell proliferation. Merlin as a growth suppressor is activated when it is dephosphorylated by MYPT-1, which in turn can be inactivated by CPI-17, an up-regulated gene in humans. Multiple pathways, including Ras, Raf, MEK, and ERK, can be blocked via merlin as opposed to normally being activated by growth factors such as insulin-like growth factor (IGF), platelet-derived growth factor (PDGF), and vascular endothelial growth factor (VEGF). Merlin is also able to inhibit ErbB2 by binding to CD44, a known promoter of tumorigenesis. As a result, merlin may become a novel target for therapy.⁵⁵

Pathology and Pathways of Spread

Vestibular schwannomas are histologically similar to schwannomas arising from other cranial and peripheral nerves. Their histologic appearance is characterized by alternating zones of dense and sparse cellularity, known as Antoni A and B areas (Fig. 26-6).

Figure 26-6 Histopathology of vestibular schwannoma. Tumors are well-circumscribed with areas of hypercellularity and hypocellularity (Antoni A and B areas) and contain thick-walled vessels. A, Hypercellularity (Antoni A area). B, Hypocellularity (Antoni B area) adjacent to a hypertrophic blood vessel.

Courtesy Michael Castro, MD.

Most vestibular schwannomas arise from the superior and inferior branches of the vestibular portion of the eighth cranial nerve, within the internal auditory canal. It is rare for these tumors to originate along the cochlear nerve. Over time, progressive tumor growth may fill the internal auditory canal and extend into the cerebellopontine angle, causing compression of the brainstem and other nearby cranial nerves, most commonly the trigeminal and facial nerves.

The natural history of vestibular schwannoma is typically characterized by gradually progressive growth with gradual sensorineural hearing loss and potentially other cranial nerve deficits. A subset of patients can present with sudden hearing loss. Less than 5% of tumors may regress slightly with surveillance.⁵⁶ The average growth rate has been estimated at 1 to 2 mm per year for sporadic lesions^56,57 and 3 mm per year for patients with NF2-associated lesions.⁵⁸ Tumor size and growth rate do not consistently correlate with hearing loss, however. Cystic schwannoma is a well-recognized tumor subtype that tends to behave more aggressively, invading and splaying adjacent cranial nerves. It is rare for malignant degeneration to occur.

Clinical Manifestations, Patient Evaluation, and Staging

Vestibular schwannoma is increasingly detected as an incidental finding on MRI or CT performed for other reasons. MRI is the imaging method of choice for visualizing vestibular schwannomas, which typically appear as contrast-enhancing lesions originating within the internal auditory canal on T1-weighted MRI images (Fig. 26-7A and B). The extent of tumor may be described using the Koos grading system (Table 26-5).

Figure 26-7 T1-weighted, contrast-enhanced MRI images from a 39-year-old woman with a right-sided vestibular schwannoma. She was treated with FSRT to 50.4 Gy at 1.8 Gy per fraction. Shown are representative pretreatment axial (A) and coronal (B) images, and posttreatment axial (C) and coronal (D) images obtained 19 months after completing FSRT. Increased central necrosis is demonstrated in the posttreatment images.

TABLE 26-5 Koos Staging System for Vestibular Schwannoma

Adapted from Koos WT, Day JD, Matula C, Levy DI: Neurotopographic considerations in the microsurgical treatment of small acoustic neuromas, J Neurosurg 88(3):506-512, 1998.

Symptoms associated with vestibular schwannoma are related to the tumor’s size and location with respect to nearby critical structures. When tumors are symptomatic, patients may complain of hearing loss (95% objective, 66% subjective), tinnitus (63%), imbalance or vertigo (61%), facial numbness or pain (17%), facial paresis or taste disturbance (6%), other cranial nerve deficits, or cerebellar dysfunction.⁵⁹

Sensorineural hearing loss classically affects high frequencies preferentially and may therefore be mistaken for noise- or age-related hearing loss. An example of a typical patient’s audiogram is shown in Figure 26-8, along with the two mainstream classification systems for audiogram findings specific to patients with vestibular schwannoma, namely the Gardner-Robertson⁶⁰ and American Academy of Otolaryngology–Head and Neck Surgery (AAO-HNS)⁶¹ methods. As a rule of thumb, patients whose speech discrimination score is 50% or less at 50 dB or more may not benefit from an approach focused on the preservation of hearing.⁶² Each case must be considered individually, however, particularly in patients with bilateral vestibular schwannomas or other causes of contralateral hearing compromise.

Figure 26-8 Pretreatment audiogram of vestibular schwannoma patient showing typical high-frequency sensorineural hearing loss (A). Findings are used to classify hearing into varying grades of serviceable or nonserviceable hearing. The Gardner-Robertson system assigned a grade of I to V, with grades I to II representing serviceable hearing (B). The American Academy of Otolaryngology—Head and Neck Surgery (AAO-HNS) system assigns a class of A to D, with A to B representing serviceable hearing (C).

Facial nerve function is characterized clinically by the House-Brackmann grading scale (Table 26-6). When clinically indicated, additional studies may be performed, such as facial nerve electromyography, caloric testing, or electronystagmography (Table 26-7).

TABLE 26-6 House-Brackmann Facial Nerve Grading Scale

From House JW, Brackmann DE, Facial nerve grading system. Otolaryngol Head Neck Surg 93(2):146-147, 1985.

TABLE 26-7 Approach to Diagnosis and Surveillance of Vestibular Schwannoma

Primary Therapy

Because vestibular schwannoma is rarely a life-threatening diagnosis, the primary goals of therapy are local control and preservation of function. Options include surveillance, surgical resection, stereotactic radiosurgery (SRS), and fractionated stereotactic radiotherapy (FSRT).

There have been no true randomized, controlled trials published about patients with vestibular schwannoma, and interpretation of single-institution series is limited by differences in factors such as patient selection, treatment techniques, and methods of assessing and reporting tumor control and treatment or tumor-related neurologic deficits. For example, local control may be determined radiographically as a lack of tumor growth, a sign of progressive tumor growth, or a sign of need for further intervention. The natural history of vestibular schwannoma following radiation therapy may be characterized by a transient increase in size,⁶³ often with a necrotic-appearing center (Fig. 26-7C and D), followed by stability or regression. This type of MRI finding may confound the results of some published SRS series, particularly in early years before this phenomenon was recognized. Hearing deficits are also analyzed in multiple different fashions, including subjectively (typically by querying patients about their ability to use the telephone with the affected ear) or using objective audiometric data. Facial function is typically scored using the House-Brackmann system (see Table 26-6), but investigators differ in their method of defining “significant” facial and other cranial nerve toxicity. Outcomes may also be reported as crude or actuarial rates, adding to the heterogeneity of published case series.

Currently, the choice of treatment modality is based on physician familiarity, bias and choice, patient characteristics (age, symptoms, location and size of lesions), and the availability of different technologies.

* The three major approaches are listed along with their general indications, advantages, and disadvantages.

With suboccipital and middle fossa approaches, published hearing preservation rates for vestibular schwannoma range from 20% to 71%.⁶⁴ Factors associated with increased preservation of functional hearing include better preoperative hearing, shorter intra-aural and absolute wave V latency on preoperative auditory brainstem response testing, and superior vestibular nerve origin.⁶⁴ Better preoperative hearing measured by audiogram and smaller tumor size predict for hearing preservation in some studies but not in others.^64,65,66

Other potential side effects of surgery include craniospinal fluid leakage, facial nerve injury, headache, and meningitis.⁶² Preservation of facial nerve function may be more likely for smaller tumors (i.e., <2 to 3 cm) and with increasing surgical experience.⁶⁷

Stereotactic Radiosurgery

The first report of SRS for vestibular schwannoma was published by Leksell in 1971. Modern radiosurgery can be performed with the Gamma Knife, linear accelerator, or proton beam techniques. Because of the minimally invasive nature and excellent clinical outcomes achieved with SRS, practice patterns at some institutions are shifting to favor SRS over resection. The ideal candidates have tumors less than 3 to 4 cm in size.

Several large, single-institution experiences with SRS for vestibular schwannoma have been reported (Table 26-9). Using modern techniques and doses, as detailed below, local control rates with SRS are generally greater than 90% and significant cranial nerve toxicity rates are less than 10%.

Published hearing preservation rates are variable; 57% overall in a recent systemic review of patients treated with an average dose of 16 Gy.⁷⁹ Proposed mechanisms of hearing loss following SRS (in the absence of progressive tumor growth) include transient conductive hearing loss resulting from serous otitis media and delayed sensorineural hearing loss because of direct radiation injury to the vestibulocochlear nerve or cochlea, compression of the vestibulocochlear nerve or internal auditory artery from tumor edema, or thrombosis of the internal auditory artery. Patient-related factors that may correlate with increased likelihood of hearing preservation after SRS include age younger than 60 years, tumor volume less than 0.75 cm³, intracanalicular tumor location, and better pretreatment hearing (class I Gardner-Robertson, speech discrimination score ≥80%, pure tone average <20 dB).⁸⁰

Several retrospective reports have compared outcomes of patients treated with surgery versus SRS^81–84 (Table 26-10), demonstrating that both approaches achieve comparable local control rates of 91% to 100%,^82,84 but SRS produces equivalent or superior functional outcomes. A prospective analysis of 82 patients with small tumors (≤3 cm) eligible for either surgery or SRS at the Mayo Clinic found that patients who chose SRS subsequently had better preservation of normal facial movement and serviceable hearing.⁸² A prospective analysis of 91 patients with small vestibular schwannomas (≤2.5 cm) treated with surgery (n = 28) or SRS (n = 28) at Haukeland University Hospital also showed better facial nerve function and hearing preservation in patients who underwent radiosurgery.⁸¹ A comparison of patients treated with surgery (n = 110) or SRS (n = 100) published by Régis and colleagues⁸³ found better preservation of serviceable hearing and facial and trigeminal function with SRS. Finally, a retrospective analysis of 96 patients performed by Karpinos and associates⁸⁴ showed better preservation of measurable (but not serviceable) hearing and lower rates of facial and trigeminal neuropathy in patients treated with SRS. Tumor size was larger in the surgical group, however.

Fractionated Stereotactic Radiation Therapy

Fractionated stereotactic radiation therapy (FSRT) has been a part of the treatment armamentarium for vestibular schwannoma at selected institutions for the past 10 years and longer. Vestibular schwannomas are slowly proliferating tumors with a low estimated α/β ratio of 2.5 to 4. The hypothesized radiobiologic advantage of FSRT, therefore, is based on reducing late toxicity to surrounding normal structures, such as the cranial nerves and brainstem. Stereotactic localization techniques also contribute to reduction of toxicity by allowing reduction of treatment volumes. Typical candidates are those with tumors too large for radiosurgery or rare patients with malignant schwannomas, although FSRT can certainly be performed for patients with smaller tumors.

Published single-institution outcomes of FSRT are comparable with those achieved with current, moderate-dose SRS, with local control rates greater than 90% and cranial nerve toxicity rates less than 10% (Table 26-11). Serviceable hearing preservation rates may be higher than those achieved with SRS. It will be important to monitor local control rates with increasing follow-up to ensure that they remain high.

Four (one prospective and three retrospective) single-institution analyses have compared outcomes of SRS with those of FSRT (see Table 26-10), all of which show equal rates of local control.^85,87,88 Meijer and colleagues⁸⁷ conducted a prospective study of 129 patients with vestibular schwannomas who were allocated to SRS versus hypofractionated FSRT on the basis of dentition, with dentate patients (n = 80) receiving FSRT and edentulous patients (n = 49) receiving SRS. Toxicity rates were low for both groups, but trigeminal nerve preservation was slightly higher in the FSRT group (98% vs. 92% at 5 years, p = .048). A review of 125 patients treated with SRS (n = 69) or conventional FSRT (n = 56) at Thomas Jefferson University also showed comparable outcomes, with the exception of functional hearing preservation, which was better for patients treated with FSRT.⁸⁸ A recent analysis of 202 vestibular schwannomas treated with SRS (n = 30) versus conventional FSRT (n = 172) at the University of Heidelberg found equivalent outcomes between the two groups, with the exception of patients treated with SRS doses of more than 13 Gy, who had lower rates of hearing preservation.⁸⁵ Finally, in a recent analysis from the University of Wisconsin, patients treated with SRS (n = 49), conventional FSRT (n = 32), and hypofractionated FSRT (n = 32) were found to have equivalent 5-year PFS of 92.3% overall, whereas FSRT produced lower actuarial rates of late trigeminal nerve toxicity (0% vs. 10.2%; p = .028) and a trend toward better serviceable hearing preservation (65.4% vs. 33.3%; p = .087).⁸⁶

Surveillance

Surveillance may be the best option for elderly patients or those with significant other medical comorbidities and can be considered for patients with small, asymptomatic tumors. Contraindications include brainstem compression, hydrocephalus, and, arguably, the desire to preserve hearing.

A systematic review of 903 patients observed by MRI and/or CT over a mean period of 3.1 years found that 51% of tumors grew and 20% required intervention after a mean time of 2.1 years, primarily because of tumor growth with progressive symptoms.⁵⁶ Audiologic data from a subset of 60 patients with serviceable hearing at presentation revealed loss of serviceable hearing in 37%. Recently, analysis of nearly 1000 patients managed expectantly demonstrated an overall hearing preservation rate of 54%.⁹⁵ Hearing preservation was more likely in tumors with average annual growth rates of 2.5 mm per year or less (75% vs. 32% for faster-growing tumors). The facial nerve preservation rate was higher than 97%.

Targeted Therapy

Very recent data indicate that antiangiogenic agents such as bevacizumab can induce tumor regression and also, in some patients, restore hearing.⁹⁶ Larger trials with this agent are therefore planned in NF2-associated vestibular schwannoma. Other systemic agents currently under investigation include sorafenib, trastuzumab, lapatinib, protein kinase inhibitors, and p21-activated kinase inhibitors.⁹⁷

Combined-Modality Therapy

Combined-modality therapy is rarely indicated in the initial management of vestibular schwannoma. Patients who fail surgical management commonly go on to receive radiation therapy, however, and the opposite is also true.

Management of Vestibular Schwannoma in the Patient with Neurofibromatosis 2

Bilateral vestibular schwannomas, as mentioned above, occur commonly in patients with type 2 neurofibromatosis, a disorder with an estimated prevalence of 1 in 100,000.⁹⁸ NF2 patients also have a predisposition to develop other tumors of the central nervous system (meningiomas, ependymomas, astrocytomas, neurofibromas), peripheral neuropathy, ocular findings (retinal hamartomas, epiretinal membranes, cataracts), and skin lesions (plaques and subcutaneous tumors), as recently reviewed by Asthagiri and colleagues.⁹⁷ Pretreatment evaluation should therefore include MRI studies of the entire craniospinal axis.

In comparison with sporadic tumors, vestibular schwannomas in patients with NF2 tend to grow more quickly and to more aggressively surround or infiltrate the adjacent cochlear and facial nerves. Functional outcomes after treatment tend to be poorer in this population of patients. For example, in the experience of Combs and colleagues,⁹⁰ a diagnosis of NF2 was associated with significantly reduced likelihood of serviceable hearing preservation in patients treated with FSRT (64% for NF2 vs. 98% for sporadic tumors).

Mathieu and associates⁹⁹ recently published the University of Pittsburgh’s experience treating 74 vestibular schwannomas in 62 NF2 patients with SRS, with a mean marginal dose of 14 Gy (range, 11 to 20 Gy). The actuarial local control rate was 81% at 10 to 15 years. The margin dose was significantly related to serviceable hearing preservation on multivariate analysis, and the actuarial serviceable hearing preservation rate was 48% at 5 years in patients treated with a marginal dose of 14 Gy or less. Tumor volume of more than 5 cm³ and maximum dose of more than 28 Gy predict for the development of other complications, such as facial weakness, trigeminal neuropathy or neuralgia, and vestibular dysfunction. The authors recommend offering treatment only for large symptomatic tumors or tumors manifesting with progressive growth or hearing loss in order to maximize preservation of function and quality of life.⁹⁹ One advantage of earlier intervention may be the potential for sparing function of the cochlear nerve, thereby allowing for future cochlear implantation.

Irradiation Techniques and Tolerance

Stereotactic Radiosurgery

Either linac-based or Gamma Knife radiosurgery may be employed to treat intracranial lesions with submillimeter precision. Examples of popular commercial linac radiosurgical systems include Novalis BrainLAB (BrainLAB AG, Feldkirchen, Germany), Radionics XKnife (Integra, Plainsboro, New Jersey), TomoTherapy (TomoTherapy, Inc., Madison, Wisconsin), and CyberKnife (Accuray, Inc., Sunnyvale, California). This list continues to expand as newer technologies emerge. Most clinical radiosurgery systems currently rely upon placement of a stereotactic head frame, such as the Brown-Roberts-Wells coordinate system, for accurate localization. Frameless radiosurgery systems may use anatomic landmarks or fiducials.

In linac radiosurgery, multiple nonopposing arcs are delivered through collimators that are 4 to 18 mm in diameter. Multiple isocenters may be used to achieve a high degree of conformality while simultaneously sparing normal tissues, and the dose is typically prescribed to the 70% to 90% isodose line.

Depending on the model, a Gamma Knife unit houses 192 or 201 cobalt-60 (⁶⁰Co) sources that are channeled through a tungsten collimator helmet to coincide within 0.1 mm of each other at the geometric center of the helmet. Individual channels can be blocked if indicated, and secondary collimators measuring 4 to 18 mm in diameter are used to adjust the beam’s focus size. Treatment is delivered using one or more isocenters or “shots,” and the dose is typically prescribed to the 50% isodose line. In the modern Gamma Knife unit (Perfexion), this process has been streamlined so that manual plugging and manual change of collimator helmets have now been automated.

High-resolution MRI images should be used during treatment planning, either as the primary dataset or through fusion with a treatment planning CT scan. Care should be taken when relying solely on MRI, however, as spatial distortion may result in targeting errors with resulting compromise in local control.¹⁰⁰ The tumor is best visualized with contrast-enhanced T1 images, whereas the cochlea and semicircular canals are best seen with fast spin echo T2 sequences.

The ideal SRS prescription (marginal) dose is typically 12 to 13 Gy; local control appears to be compromised with doses below this range74,77 and cranial nerve toxicity increases with higher doses.^{76,85,101,102} For example, a recent retrospective analysis by Foote and colleagues⁷⁷ found the 2-year incidence of any cranial neuropathy to be 2% with prescription doses of 12.5 Gy or less versus 24% with doses of more than 12.5 Gy (p <.0003).

Facial, trigeminal, and auditory toxicities have also been shown to correlate with the length of nerve irradiated (represented by the transverse tumor diameter).¹⁰¹ For example, in the early experience with higher-dose SRS, trigeminal and facial neuropathy rates were, respectively, higher in patients with an extracanalicular tumor dimension of more than 1 cm and a sum of extracanalicular and intracanalicular diameter of more than 2 cm.¹⁰³

Other factors that correlate with increased facial nerve preservation rates include age of 60 years or less, tumor volume of 1.5 cm³ or less, and marginal dose of 13 Gy or less.¹⁰⁴ Most cranial neuropathies develop within 2 years of SRS, but hearing loss can occur much later.

MRI treatment planning techniques have been found to correlate with reduced facial and trigeminal neuropathy¹⁰¹ and increased hearing preservation,^77,101 although inter-era comparisons may be confounded by a tendency to prescribe lower marginal doses in more recent years. Other SRS parameters correlated with improved hearing preservation rates include prescribing a marginal dose of 13 Gy or less,¹⁰⁵ limiting the cochlear dose to less than 4.2 to 4.75 Gy,¹⁰⁶ and limiting the dose to the cochlear nucleus to less than 10 Gy.¹⁰⁷ Kondziolka and associates¹⁰⁸ recommend prescribing 12 Gy for tumors of more than 2 cm in extracanalicular diameter, 12.5 Gy for smaller tumors, 13 Gy for patients without serviceable hearing, and potentially up to 14 Gy for patients with hearing loss and facial weakness.

The radiation dose to the brainstem must also be carefully monitored. In 1994, Kihlstrom and colleagues⁴⁶ recommended limiting the brainstem dose to 14 Gy or less with SRS, based on the development of adverse radiation imaging effects (ARIE) in 6 of 7 patients who received 14 to 35 Gy for low-grade gliomas of the tectal midbrain.¹⁰⁹ In 2008, Sharma and colleagues¹¹⁰ demonstrated that ARIE and new neurologic deficits could develop after exposing 0.1 cm or more of brainstem to doses of more than 12 Gy. An example of an SRS treatment plan is shown in Figure 26-9.

Figure 26-9 Linac SRS treatment plan delivering 12.5 Gy to a small left-sided vestibular schwannoma using four isocenters.

Fractionated Stereotactic Radiation Therapy

The objective of FSRT is to combine the radiobiologic advantages of conventional EBRT with the reduced normal tissue exposure of radiosurgery. Multiple localization systems have been developed, most of which achieve patient localization through infrared light-emitting diodes and are accurate to within 1 to 3 mm.

At the University of Wisconsin, FSRT is typically delivered by a linear accelerator with the patient immobilized in an aquaplast head mask (Fig. 26-10). To ensure treatment delivery accuracy, pretreatment and intratreatment continuous, real-time patient localization is carried out using optical guidance. For this purpose, a patient-specific maxillary bite block is manufactured before CT simulation, to which a fiducial array with passive optical markers is attached. Before the planning CT scan and before each treatment fraction, the fiducial array bite block complex is inserted, and setup is continuously monitored with optical guidance. If the patient moves out of the predetermined error tolerance band of 0.3 mm and/or 0.3 degrees of rotation, treatment is interrupted until realignment is achieved.¹¹¹

Figure 26-10 Patient immobilization and localization system for FSRT at the University of Wisconsin.

Common regimens prescribed are on the order of 45 to 50 Gy at 1.8 to 2 Gy per fraction, or 20 to 25 Gy at 4 to 5 Gy per fraction. A recent retrospective analysis of 89 patients treated with FSRT to 46.8 Gy versus 50.4 Gy at 1.8 Gy per fraction found that patients treated to 46.8 Gy were more likely to have preservation of serviceable hearing; however, there was no statistically significant relationship between cochlear dose and serviceable hearing preservation.¹¹² In contrast, a prospective analysis of 34 patients treated with FSRT to 45 Gy at 1.8 Gy per fraction prescribed to the 90% isodose line found that the dose to the cochlea was the only significant prognostic factor for hearing deterioration.¹¹³ In their experience, the median hearing loss was 10 dB for patients with less than 73.3% of the cochlea exposed to 90% or more of the prescription dose (45 Gy), as opposed to 25 dB for patients with a volume getting 90% of the prescription dose (V₉₀) of 73.3% or more. An example of an FSRT plan is shown in Figure 26-11.

Figure 26-11 FSRT treatment plan delivering 20 Gy at 4 Gy per fraction weekly to a left-sided vestibular schwannoma. Representative axial (A), sagittal (B), and coronal (C) isodose lines are shown, along with the dose-volume histogram (DVH) (D) demonstrating good coverage of the gross tumor volume (GTV) and planning target volume (PTV) with minimal dose to adjacent normal structures.

Treatment Algorithms, Challenges, and Future Directions

Patients with newly diagnosed vestibular schwannomas should be evaluated by a multidisciplinary team with expertise in neurosurgery, SRS, and FSRT for discussion of the risks and benefits of treatment, as well as observation (see the treatment algorithm in Fig. 26-12). Resection may be performed for virtually any tumor and especially for large tumors causing brainstem compression or hydrocephalus that cannot effectively be managed nonsurgically. Hearing preservation rates may be lower with surgery than with radiation therapy; however, this has never been tested in a prospective randomized fashion. The ideal candidate for SRS is a patient with a small intracanalicular tumor not approaching the brainstem, with marginal doses of 12 to 13 Gy. Conventional or hypofractionated FSRT may be a safer choice for tumors measuring 3 to 4 cm or larger and may result in higher hearing preservation rates. Randomized, controlled trials comparing various treatment options would be very valuable.

Figure 26-12 Suggested treatment algorithm for vestibular schwannoma. Multidisciplinary evaluation is crucial to ensure that patient-specific factors and institutional strengths that may influence outcomes are taken into consideration. *Controversial and subject to institutional experience.

The cost-effectiveness of various forms of treatment is another important issue to consider. Banerjee and colleagues¹¹⁴ recently performed a comparative analysis of the costs incurred through microsurgery versus SRS for vestibular schwannoma. They determined that the mean cost of microsurgery is higher than the mean cost of SRS ($23,788 vs. $16,143), but the follow-up costs after SRS tend to be higher because of factors such as increased use of MRI and audiograms, although this reflects practice patterns more than clinical necessity. The authors conclude that SRS is likely to be less expensive than microsurgery from a societal perspective, provided that recurrence rates remain low over prolonged follow-up times.¹¹⁴