Benign Brain Tumors: Meningiomas and Vestibular Schwannomas

Etiology and Epidemiology

Based on 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. A recent epidemiologic study revealed that meningiomas are the most frequently reported primary intracranial neoplasm, constituting approximately 35% of all brain primaries.

The likelihood of developing a meningioma is proportional to age. Pediatric meningiomas are rare, but are more likely to exhibit an aggressive clinical course. 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.

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 “Biologic Characteristics/Molecular Biology” section. Radiation exposure—stemming largely from studies of atomic bomb fallout, but also from studies of cranial and scalp irradiation (tinea capitis)—is a well-described etiologic factor for meningiomas. Recent data suggest lower dose exposure, such as seen in dental x-rays, may also increase the risk of meningioma development. Indeed, radiation-induced meningiomas are the most commonly reported secondary neoplasm.

A role for sex hormones in meningioma induction is supported by several findings. Meningiomas occur more frequently in females, at a ratio of 2 : 1 or 3 : 1. The incidence appears to increase with hormone replacement therapy, with long-acting oral contraceptives, and with obesity. Moreover, tumor size or symptoms may worsen during the luteal phase of menses or pregnancy. Despite these observations, the precise role of hormones is unclear. In both sexes, more than 70% of meningiomas express progesterone receptors, up to 40% estrogen receptors, but nearly 40% androgen receptors as well. Although clinical responses to mifepristone, an antiprogestational agent have been described, this approach proved negative in a randomized trial.

Prevention and Early Detection

At this time, there are no known preventative interventions and no evidence in favor of screening. For patients with asymptomatic, incidentally detected meningiomas, surveillance with magnetic resonance imaging (MRI) (annually, for example), with the intent of ruling out aggressive clinical behavior, remains a judicious practice.

Biologic Characteristics/Molecular Biology

Meningiomas occur more frequently in certain rare genetic conditions, such as type 2 neurofibromatosis (NF2). 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. 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. Markers of tumor aggressiveness have been studied. MIB-1 expression has been correlated with time to recurrence in some series, but not in others. Tumors with NF2, AKT1, SMO, PIK3CA, and TRAF7 mutations have been found in approximately 80% of sporadic meningiomas, but none has been reliably correlated to more aggressive biologic behavior. The loss of CDKN2A (generally through locus loss on 9p) has been identified as a marker associated with progression from grade I to grade II tumors. Telomerase reverse transcriptase promoter (TERTp) mutations have been aligned with shorter overall survival with progressive and higher grade meningioma, with median overall survival 2.7 years with a TERTp mutation versus 10.8 years without it ( p = 0.003).

Recently, six distinct DNA methylation-based tumor classes have been identified and validated as having an increased likelihood of recurrence. A study by Sahm et al. suggested that these methylation classes more accurately identified patients with grade I tumors that were at higher risk of progression, and grade II tumor associated with a lower recurrence risk, in comparison to the traditional World Health Organization (WHO) grading system.

Pathology and Pathways of Spread

The WHO published updated grading criteria in 2016. This system describes 3 grades and 13 histologic subtypes of meningioma ( Table 33.1 ). Strong associations between grade, recurrence-free survival, and overall survival have been confirmed, but even with improved criteria disparities remain, particularly regarding the proportion of patients with grade II (atypical) histology. A recent, large analysis reported that 5% of meningiomas were atypical. However, Perry et al. found that over 20% were WHO grade II. Willis et al. re-graded patients using WHO 2007 guidelines, and reported that 20.4% were atypical. Another analysis found that, whereas 4.4% of meningiomas were categorized as atypical from 1994 to 1999, this steadily increased to 32.7% to 35.5% since 2004 ( Fig. 33.1 ).

The WHO grade is a dominant prognostic factor. Compared with a grade I meningioma, a grade II tumor carries a 7- to 8-fold increased recurrence risk at 3 to 5 years. Grade III meningiomas are even more aggressive, with a 5-year overall survival of 32% to 64%.

In addition to grade considerable differences in meningioma outcomes are seen by site of origin. Tumors at the base of skull tend to be more favorable with respect to outcomes despite being less readily resectable owing to location. These differences are also reflected in molecular profile, progression risk, tumor grade, and even the likelihood of transformation to a higher grade.

Meningiomas tend to spread along the dura and, when located at the skull base, may spread through skull foramina. Peritumoral vasogenic edema can develop as a result of invasive tumor growth into surrounding brain, but more commonly is not a manifestation of brain invasion, rather of vascular compromise or a result of vasoactive substrates.

Clinical Manifestations/Patient Evaluation/Staging

Most data regarding the diagnosis and treatment of meningiomas are based on surgical series. As such, an inherent bias exists 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.

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

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

Biologic imaging has been evaluated as an imaging modality for meningioma and, although still considered experimental, may ultimately prove useful in determination of grade, in tumor delineation for radiation treatment planning, and for differentiation of recurrence from treatment-related imaging findings. Current limitations of biologic imaging include lack of specificity of compounds (specifically, octreotide-labelled compounds when tumors are located around the sella) and lack of prospective data. Despite these limitations, based on recent data, especially for skull-base locations, Gallium tetraxentan octreotate (Ga-DOTATATE) positron emission tomography (PET) imaging has been accepted as a standard in Europe, especially to aid radiotherapy treatment planning.

Primary Therapy

Benign Histology (WHO Grade I)

Surgery.

Surgery is a mainstay in the management of meningioma. It provides tissue for histologic typing and grading; in the majority of series the extent of resection correlates with rates of tumor recurrence. In 1957 Simpson reported a series of 265 patients treated surgically, giving rise to the standard system used to grade the extent of resection. The Simpson grade of resection, and the associated crude recurrence rates are summarized in Table 33.2 . Modern series employing current surgical and imaging techniques have validated this association.

TABLE 33.2

Simpson's Definitions of “Five Distinct Grades of Operation,” With Respective Recurrence Risk ^a

Modified from Simpson D. The recurrence of intracranial meningiomas after surgical treatment. J Neurol Neurosurg Psychiat. 1957;20:22–39.

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.

a 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 surgery within the prior 5 years.

Surgery remains an appropriate therapy for many patients with meningioma. Convexity meningiomas are often managed with resection because these 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, and resection, which commonly leads to vision loss, is rarely advised. However, primary radiation therapy has a favorable track record.

The major risk factors for postsurgical recurrence include tumor grade, extent of resection, prior recurrence, and presence of per-tumoral edema.

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. A multitude of retrospective series have reported that radiotherapy improves local control after subtotal resection. Fig. 33.2 illustrates progression-free survival (PFS) outcomes from 70 series with long-term results following gross total resection alone, subtotal resection alone, subtotal resection with EBRT, primary radiotherapy, and SRS.

Goldsmith et al. reported a series of 140 patients who received radiotherapy following subtotal resection, and identified a dose - response. Benign, subtotally resected tumors had significantly improved PFS (93% vs. 65% at 10 years) when a dose greater than 52 Gy was delivered. Moreover, they found significantly improved outcome with CT or MRI-based treatment planning ( Fig. 33.3 ). Other studies have exhibited superior cause-specific and possibly even overall survival with radiotherapy after subtotal resection.

Recurrent Meningioma

Recurrent meningiomas of any WHO grade display a considerably higher rate of recurrence than newly diagnosed tumors. In this setting, postoperative radiotherapy decreases the rate of tumor progression. In a series by Taylor et al. , the local control benefit of postoperative radiotherapy at first recurrence (88% vs. 30% at 5 years) translated into an overall survival benefit (90% vs. 45% at 5 years). Miralbel et al. reported 78% PFS at 8 years for recurrent tumors treated with surgery and postoperative radiotherapy after first recurrence versus 11% for patients treated with surgery alone. In the Radiation Therapy Oncology Group (RTOG) 0539 protocol, recurrent meningiomas were classified into the intermediate risk cohort. Of note, there was no statistical difference in outcomes between grade II and recurrent grade I tumors at the first report of RTOG 0539, underscoring the worse prognosis of even grade I recurrent tumors.

Ultimately multiply recurrent meningiomas of any grade behave very aggressively, and progression rates become similar, irrespective of grade. In a Response Assessment in Neuro-Oncology (RANO) review of 555 patients who in large measure were surgery and radiation refractory, the results of medical therapies for meningioma were reported. The weighted average 6-month progression-free survival rate (PFS6) was 29% for the WHO grade I group, similar to a PFS6 of 26% for the WHO grades II and III, further underscoring the biologic aggressiveness of recurrent tumors.

Definitive external beam radiation therapy.

Early reports of primary radiotherapy revealed inferior local control rates on the order of 47%, compared with resection. However, these reports included patients treated in the 1960s and 1970s, prior to the advent of modern imaging and treatment planning paradigms, possibly resulting in significant geographic miss. 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. Total doses have ranged from 45 Gy to 57.6 Gy, typically in 1.8 to 2.0 Gy per fraction. The higher cumulative doses were predominately for higher - grade, large, or recurrent meningiomas. For most patients, doses in the range of 50 Gy to 54 Gy with standard fractionation have produced excellent results with current imaging-based planning and treatment. Fig. 33.4 depicts two examples of tumors appropriate for definitive external beam radiotherapy. Recently, fractionated stereotactic (FSRT) series have been reported with excellent local control and superior functional outcomes in such regions as the cavernous sinus; however, these results are not directly comparable, because the largest tumors are typically not treated with FSRT ( Fig. 33.5 ).

Optic Nerve Sheath Meningioma

Optic nerve sheath meningiomas represent only 1% to 2% of total tumors, 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 visual outcomes. On this account, fractionated EBRT is increasingly utilized.

Turbin et al. reported 64 patients treated with either 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%, with local control exceeding 90%. Doses of 40 Gy to 54 Gy with fractions of 1.6 Gy to 1.8 Gy have been standard, and have produced results more favorable than observation, surgery alone, or surgery plus irradiation.

Stereotactic radiosurgery.

Over the past two decades, SRS has become an acceptable and frequently utilized modality and it is generally considered suitable for meningiomas less than 3 cm in maximum diameter, with well-defined margins (a crucial selection factor, because SRS, unlike EBRT or FSRT, utilizes no clinical target volume/planning target volume [CTV/PTV] margins), with little or no surrounding edema, and at sufficient distance from critical normal tissues to permit appropriate dose restrictions. Long-term local control has exceeded 85% in the majority of studies. Table 33.3 compares the outcomes for SRS to those of definitive EBRT; this is not a direct comparison, but a compilation of retrospective series reported in the literature and therefore inherently biased in terms of patient selection. Radiosurgery also appears to have equivalent local control outcomes to surgery for smaller meningiomas. Pollock et al. found that PFS after radiosurgery was equivalent to Simpson grade 1 resection, and superior to Simpson grade 2 or 3 to 4 resection. A recent series by Kano et al. demonstrates no benefit of prior microsurgery for patients with cavernous sinus meningiomas.

TABLE 33.3

Comparative Analysis of Results With SRS and EBRT by Grade of Meningioma in Multiple Retrospective Series ^a

Grade/Treatment	Number ( n )	Mean or Median Follow-Up (mo)	5-Year PFS (%)	5-Year OS (%)
Gr I—SRS	2281	19–103	75–100	82–100
—EBRT	3588	21–108	79–100	74–97
Gr II—SRS	119	27–48	26–72	40–83
—EBRT	345	32–66	20–68	28–91
Gr III—SRS	39	32–48	0–72	0–59
—EBRT	123	34–59	9–52	28–47

EBRT, External beam radiotherapy; mo , months; SRS, stereotactic radiosurgery.

a Five-year progression-free survival (PFS) and overall survival (OS) are compared for all series combined.

The University of Pittsburgh's initial publication of the long-term outcomes following SRS described the utilization of a median marginal dose of 16 Gy. The rate of new neurologic toxicity was 5%. Since this report it has become evident that lower single doses may be a sufficient. In the University of Pittsburgh's recent update of 972 patients, the median marginal dose was 14 Gy. Other reports have shown good local control with doses of 12 Gy. Fig. 33.6 illustrates the potential dosimetric advantages of lower marginal doses.

Tumor volume is also associated with the success or failure of SRS. DiBiase et al. reported 5-year disease-free survival of 91.9% for patients with tumors 10 cc or smaller versus 68% for larger tumors. Kondziolka et al . similarly cited a decreased control rate with larger tumors.

Hypofractionated stereotactic radiotherapy.

The use of hypofractionated stereotactic radiotherapy (FSRT) for meningiomas has increased with the increased availability of technology to deliver stereotactic radiotherapy. Recent data suggest that for larger volume tumors (>4.9 cc), the use of hypofractionation may decrease the likelihood of posttreatment edema as compared with single fraction radiosurgery. As such, larger tumors may be more safely treated with hypofractionated radiotherapy. In contrast, Conti et al. reported outcomes of 229 patients with 245 meningiomas treated with single or multifraction radiosurgery; they identified that tumor volume, tumor grade, brain/tumor interface, and lesion location influenced posttreatment edema (PTE), whereas hypofractionation did not provide sufficient prevention of PTE. Moreover, no patient with a skull-base meningioma developed symptomatic PTE.

Additional potential indications for hypofractionation include tumors with greater proximity to the optic apparatus, as well as reirradiation. Several series have now been reported for FSRT showing equivalent local control to SRS and conventionally fractionated EBRT. The most commonly reported fractionation scheme for treatment of benign meningioma has been 25 Gy in five fractions.

In practice, certain patterns are emerging. SRS is employed for small volume (generally ≤ 3 cm or < 4 cc) well-defined tumors, either definitively or postoperatively, FSRT is used for slightly larger tumors (generally 3 cm to 5 cm, or smaller than 12 to 15 cc), whereas EBRT is used for larger tumors, tumors with poorly defined margins, tumors with parenchymal invasion, multifocal relapses, high-grade tumors, and tumors with significant edema.