Decision Making in Meningiomas

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CHAPTER 18 Decision Making in Meningiomas

M. Necmettin Pamir, Peter M. Black, Rudolf Fahlbusch

INTRODUCTION

The goal of management strategy in meningiomas is to keep the patient fully functional and provide long-term relief or prevent intracranial tumor growth associated problems. The clinical picture at presentation is very variable, and very little is known regarding the natural history of these tumors; therefore the management strategy is not universal. The initial dilemma that the surgeon faces starts with the decision to treat or not to treat. Only then is this followed by the decision of how to treat. Both decisions are taken together with the patient and the surgeon plays the role of an advisor, rather than directly deciding for the patient. Treatment choice in patients who present to medical attention for the first time with a symptomatic meningioma or in those with neural compression is mostly straightforward. The goal is well defined and the possible gains most commonly far outweigh the risks. However; decision making is not so easy in non- or marginally symptomatic patients, for whom the risks of treatment should be weighed against the risk of iatrogenic injury. The mortality and morbidity of surgical treatment decreased significantly and continuously in the last century, mainly as a result of the application of microsurgery, bipolar coagulation, and other new technologies. A better appreciation of microsurgical anatomy and increasing use of skull-base surgery have further improved results. The advent and popularization of alternative treatment modalities such as radiation treatment and radiosurgery have also made significant contributions. Finally, with accumulating experience and scientific data much more is known today about the biology of meningiomas. Even with all these advances, today’s neurosurgeon still has very little clinical evidence on which to base his or her clinical decisions. This chapter aims to summarize the controversies, discussing different management paradigms and thus providing a general guideline for treatment (or nontreatment) of meningiomas.

Five factors influence the treatment decision in meningiomas: operative gains, operative risks, tumor biology, mass effect/symptomatology, and the preference of the patient. In short, the balance between the risks and benefits of surgery is evaluated in light of the tumor’s biology, mass effect/symptomatology, and preference of the patient (Fig. 18-1).

FIGURE 18-1 In many situations the physician will guide the meningioma patient during the management of the disease. The decision to treat or not to treat relies on a fine balance between the risks and benefits of surgery, which in turn should be evaluated in the light of the tumor’s biology, presence of mass effect/symptomatology and very importantly, the preference of the patient.

MASS EFFECT AND SYMPTOMATOLOGY

For well circumscribed benign intracranial tumors, such as meningiomas, total surgical excision provides immediate symptom relief and long-term control of tumor growth and tumor-associated problems. Therefore, for a symptomatic meningioma surgery remains the treatment of choice, provided that it can be performed with acceptable morbidity and mortality. The presence of a mass effect in the form of (present or imminent) neural compression and increased intracranial pressure are also direct indications for surgery, independent of whether the patient is symptomatic or asymptomatic. In asymptomatic cases with radiologically documented neural compression, surgery is performed with the intent of altering the natural history. The treatment decision in asymptomatic, incidental meningiomas is much more difficult. With advances in noninvasive diagnostic technologies and an aging population, incidental meningiomas are more commonly diagnosed than ever before. Close radiologic follow-up in such an incidental, asymptomatic meningioma that does not cause neural compression is an acceptable strategy, and a large proportion of these cases remain asymptomatic during follow-up.

The incidence of asymptomatic meningiomas in the general population ranges from 1% to 1.4% both in noninvasive imaging studies in the general population ^1,² and in autopsy series.³^–⁵ The prevalence of meningiomas steadily increases with age;^1,^2,⁶^–⁹ in patients older than 60 years of age it is 3%.⁴ Similarly, the incidence of patients with meningiomas who come to clinical attention is reported to be 3.5 times higher over the age of 70.¹⁰ This observation is in line with the hypothesis that oncogenesis in meningiomas is a slow process, which occurs over decades. Most meningiomas remain asymptomatic throughout life, and in fact; half of all meningiomas are discovered only at autopsy.⁵ Studies that have analyzed the clinical behavior in asymptomatic meningiomas have reported growth rates ranging from 0 to 37.3%,¹¹^–¹⁷ which indicates that in the short term at least 2/3 of meningiomas do not grow. There are, however, no long-term studies that have evaluated the incidence of growth in asymptomatic meningiomas. Yano and colleagues¹⁶ reported their experience with 351 conservatively treated incidental meningiomas. Over a period of 5 years tumor growth was detected in 37.3%, and 16.4% had tumor growth and became symptomatic. Several authors have analyzed factors that may indicate growth potential in meningiomas. A summary of these studies is provided in Table 18-1. As can be seen in the table, there is no general consensus on this issue. The presence of calcifications and a low T2 signal was associated with nongrowth in all studies. In four of six studies age correlated significantly with nongrowth. Many other studies also indicate that, disproportionally with their increasing incidence, the likelihood of a meningioma becoming symptomatic decreases with age. Most meningiomas in the elderly, detected at autopsy, are less than 1 cm in diameter.⁴ However, the incidence of growth in incidental meningiomas in the elderly is comparable to that in the younger population. Niiro and colleagues¹⁴ have reported on the natural history of 40 incidental meningiomas in patients older than the age of 70. During a mean follow-up of 38.4 months, 35% of the tumors showed radiologically documented growth and 12.5% became symptomatic. In contrast, meningiomas in the pediatric population have greater risk of aggressive behavior.¹⁰ Several authors have looked for an association between the initial tumor size and the annual growth rate. A higher growth rate was reported in larger tumors by some authors.^14,¹⁸ Still others have reported very high tumor growth rates in very small tumors.¹¹ A summary of reported growth rates is also presented in Table 18-1.

TABLE 18-1 Studies on growth of incidental meningiomas

TUMOR BIOLOGY

The natural history of the tumor and its behavior after treatment depend on its intrinsic biology. Many biologic and clinical parameters were found to provide clues on the biology of a meningioma. None of these is exclusively predictive of the clinical behavior, but when considered together these parameters strongly influence treatment strategy.

Histology

Most meningiomas are slow growing benign tumors that histologically correspond to World Health Organization (WHO) grade I. Rare histologic variants such as clear cell, chordoid, papillary, and rhabdoid meningiomas, as well as atypical (WHO grade II) and anaplastic (WHO grade III) meningiomas can present with more aggressive behavior and relentless growth despite multimodal treatment, and have a high incidence of recurrences and a less favorable prognosis.¹⁰

Molecular Biology and Genetics

Molecular genetic analysis of meningiomas has revealed that they carry a wide variety of chromosomal aberrations. In general the complexity of these aberrations correlates with increasing histologic grade.¹⁹ Partial loss or monosomy of chromosomes 1, 10, and 14 is associated with aggressive behavior and higher histologic grades.²⁰^–²³

Angiogenesis

Meningiomas are highly vascular tumors and their angiogenic potential plays an important role in their growth. Studies have shown that an increased expression of vascular endothelial growth factor (VEGF) was correlated with an increased risk of recurrence and higher incidence of peritumoral edema.²⁴^–²⁶ Extracellular matrix associated structural proteins and growth factors such as tenascin and matrix metalloprotease MMP-9 were also shown to have a correlation with tumor recurrence.^27,²⁸

Hormonal Influences

Hormonal dependence of meningiomas has been suggested by clinical observations such as predominance of female patients, growth during pregnancy, and the luteal phase of pregnancy. Further, the presence of progesterone receptors was associated with benign histology and lower likelihood of recurrences.²⁹^–³¹

Growth Rate of Meningiomas

As is the case for most other parameters on meningiomas, very little is known concerning the growth kinetics of meningiomas. Most meningiomas are slow growing tumors. But there is significant variation between the growth rates of individual meningiomas. Current classification schemes, such as histologic grading, fall short of predicting this growth rate. Jaaskelainen and colleagues ³² have shown that the histologic appearance correlated only grossly with the growth rate but did not exactly predict the tumor doubling time. When typical, atypical, and malignant meningiomas were considered there was significant variation within and significant overlap between histologic subgroups.³²

In addition to the variability in growth rate between individual tumors, it is also likely that there are temporal changes in the growth rate of individual meningiomas. The assumption that a meningioma will grow at a constant rate is most likely an oversimplification, and most meningiomas do not exhibit a constant growth rate but change in their growth characteristics during their clinical course. Clinical analyses have indicated that they do have variations in the growth characteristics of meningiomas during their growth.³³ This is certainly not unexpected. Current evidence indicates that meningiomas, like most other malignancies, develop and progress as a result of accumulating genetic and epigenetic changes; therefore one can easily conclude that the growth rate will change with increasing malignancy.¹⁰ As expected, studies have concluded that the growth rate increased with successive recurrences.^32,³⁴ This finding was also supported by the demonstration of a decreasing time interval between recurrences.^35,³⁶

It is also not known whether tumor growth rate changes during pregnancy or in women receiving postmenopausal hormone treatment.

The tumor doubling time in recurrent benign meningiomas was estimated to be 317 days using computed tomography (CT) volumetrics and bromodeoxyuridine labeling and 415 days using CT planimetry.^32,³⁷ Much variation is reported in the tumor doubling times, but it ranged from 138 to 1045 days (mean 415 days) in WHO grade I, 34 to 551 days (mean 178 days) in WHO grade II and 30 to 472 (mean 205 days) in grade III meningiomas.³² The clinical implication of this is that recurrences should be expected late in the course in most meningiomas. Ninety-five percent of meningiomas are either adherent or invasive to the surrounding neurovascular structures, which will preclude a “true” oncologic resection of meningiomas and residual tumor cells will be the source of a recurrence. Jaaskelainen and colleagues have calculated the estimated time to a recurrence detectable by CT, after a seemingly gross total surgical resection to be approximately 8.5 years. This hypothesis is supported by Simpson’s elegant demonstration that up to 10% of meningiomas recurred 10 years after a seemingly complete resection.³⁸ The incidence of detected recurrences increased over time, reaching 20% at the end of the second decade after surgery.^36,^38,³⁹ This and other studies have shown that up to 50% of all recurrences occurred after 5 years.^36,^38,³⁹

Quantification of the proliferative potential is important for predicting future recurrences and planning an optimal management strategy. Several studies have looked for histopathologic findings to evaluate the growth potential of meningiomas. Tumor growth is a function of cell proliferation and death. Cell death has not been systematically studied in meningiomas. Proliferative indices, however, are commonly used. Demonstration of proliferating cell nuclear antigen (PCNA), silver staining for nucleolar organizer regions (AgNOR), immunohistochemistry for MIB-1 (Ki-67), and bromodeoxyuridine (BrdU) labeling are the most common methods for demonstrating the proportion of proliferating cell fraction.^10,^40,⁴¹ There is a well demonstrated correlation between high proliferative indices and recurrences. However, this correlation is not exclusive. Low MIB-1 indices were demonstrated in many recurrent tumors and very high proliferative indices are sometimes demonstrated in typical meningiomas.⁴²

Anatomic Localization

Natural history, symptomatology, and the surgical outcome vary significantly among meningiomas in different intracranial localizations.⁴³ To present a striking example, a small meningioma in the optic canal will come to clinical attention much earlier than a large convexity meningioma. Therefore, clinical correlates of localization should be taken into consideration when planning surgery for meningiomas. Eighty to ninety-six percent of tuberculum sella meningiomas present to clinical attention with progressive visual impairment. Despite wide availability of magnetic resonance imaging (MRI), most anterior fossa meningiomas are quite large at presentation. Seventy-three percent of anterior fossa meningiomas present when larger than 4 cm.⁴⁴ The same holds true for olfactory groove meningiomas, 65% of which have a diameter larger than 3 cm at presentation.⁴⁵ Optic nerve sheath meningiomas are associated also with a progressive decrease in vision. Kennerdell and colleagues⁴⁶ observed 18 patients without treatment, and none of the patients who had normal visual acuity retained it for more than 5 years. Similarly, Keane and colleagues⁴⁷ and Sarkies⁴⁸ reported progressive decrease in vision in 20 of 22 patients. Petroclival meningiomas have variable and unpredictable growth patterns. Radiologic growth was reported in 76% of patients at a median follow-up of 85 months, and in 63% this growth was associated with functional deterioration.⁴⁹

Peritumoral Edema

A significant proportion of meningiomas present with varying degrees of edema in the surrounding brain parenchyma. Different studies have reported incidences ranging from 46% to 92%.^31,⁵⁰ The presence and extent of edema are highly variable and the underlying pathogenesis is not entirely clear. Tumor compression, parasitization of pial vasculature, convexity/middle fossa/anterior fossa localization, irregular tumor–brain interface, hyperintensity on T2-weighted images, brain invasion, high grade, secretory, microcystic and/or angiomatous variants, and high VEGF expression have all been suggested as the cause of edema but none has been proven to date.³¹ A minor amount of edema may be negligible but significant peritumoral edema may interfere with normal brain function and may be the patient’s presenting symptom.⁵⁰ Peritumoral edema is also reported to complicate surgery and to be a source of perioperative morbidity.⁵⁰ Therefore surgical resection is favored in cases with peritumoral edema.⁵⁰

Invasion of Surrounding Structures

Meningiomas are mesenchymal tumors and have a tendency to invade the surrounding structures including dura, bone, muscle, and brain parenchyma.³¹ Bone invasion is common in meningiomas, particularly those at the skull base, and presents as hyperostosis and less commonly as bone destruction.⁵¹ Hyperostosis is almost invariably associated with tumor invasion. Invaded bone is a source of recurrence and should be removed along with the tumor. The need for bone removal creates a significant challenge in the skull base. Neurovascular invasion is also a significant problem in meningiomas. Such invasion of neighboring brain parenchyma, cranial nerves, and blood vessels is observed in only a minority of meningiomas but in those cases it precludes a gross total resection and is a source of relapse.¹⁰ Yasargil⁵² has reported that 5% of meningiomas were nonadherent, 85% were adherent, and 10% were adhesive so that dissection is impossible without damaging vital structures. Neurovascular invasion may be observed in benign, atypical, and anaplastic meningiomas; however, it signifies a more aggressive biologic behavior so that benign meningiomas with brain invasion have a prognosis similar to that of atypical meningiomas.¹⁰ Borovich and colleagues^53,⁵⁴ have demonstrated isolated tumor cell nests detectable at a distance from the main tumor bulk. Preoperative radiologic diagnosis of neural or vascular invasion is not reliable.⁵²

Multiplicity

Multiplicity is observed in 0.9% to 8.9% of meningiomas in clinical series. In 50% of these cases, multiple meningiomas are diagnosed at the initial presentation, excluding the possibility of recurrence, seeding, or metastasis. Autopsy series report a higher incidence of multiplicity.⁴ Most of these cases are associated with neurofibromatosis type II. Sixty to ninety percent of multiple meningiomas are observed in women. No difference in clinical tumor behavior or outcome has been reported for multiple meningiomas, and the treatment decision does not differ from that for solitary meningioma cases.

Special Conditions

Meningiomas are the second most commonly encountered intracranial tumor in neurofibromatosis type 2 (NF-2) and are seen in approximately 50% of the cases.¹⁰ The incidence of this association is clearer in pediatric meningiomas, 25% to 40% of which are seen in association with NF-2. The clinical behavior (their anatomic localization, growth rate, and recurrence rates) of meningiomas associated with NF-2 is not significantly different from sporadic cases. Multiplicity is more commonly observed in meningiomas associated with NF-2.

Meningiomas in children are rare, comprising 1% to 7.7% of all pediatric brain tumors and 2% of all meningiomas.^10,^55,⁵⁶ Very little is known regarding the characteristics of meningiomas in children, and the number of reports add up to only a few hundred cases. Studies to date have concluded that pediatric meningioma patients have a poorer prognosis that their adult counterparts due to higher incidence of malignant or aggressive forms of meningioma, increased relative size of the tumors, and their unusual and complicated anatomic localizations.^10,⁵⁵^–⁵⁷ Cases occurring in association with NF-2 (25%–40% of cases) or secondary to radiation are more common than in the adult population and the predominance of female cases documented in adults is not observed.^55,⁵⁶ The incidence of unusual anatomic localizations such as the orbit and the ventricular system, the incidence of cases in the posterior fossa, and the incidence of meningiomas without a dural attachment are higher in the pediatric population.^55,⁵⁶ Pediatric cases almost invariably are symptomatic and present with increased head size in infants, focal neurologic deficits, seizures, and increased intracranial pressure and this justifies a surgical intervention. Drake and Hoffman⁵⁵ analyzed 207 patients from 11 available series published between 1972 and 1987 and calculated the overall 5-year survival to be 76%. When meningeal sarcomas were excluded, the overall survival increased to 84%. Malignant meningiomas and meningeal sarcomas made up 15% of all childhood meningiomas. A 5-year survival rate of 94% was reported in cases without recurrence and 64% in cases with recurrences.⁵⁵ The mean operative mortality was 3%.⁵⁵ In summary, children with typical meningiomas and a gross total surgical resection benefited from surgery. However, those with a papillary histologic subtype, meningeal sarcomas, or subtotally resected tumors and those with recurrences had a poorer prognosis.

OPERATIVE GAINS

The two goals of meningioma surgery are symptom palliation and alteration of the tumor’s natural history. Resection of the tumor results in decompression of the nearby neural structures and also of their vascular supply.

Surgical Outcome in Different Anatomic Localizations

As is the case for their natural history, anatomic localization of the meningioma also strongly influences the surgical outcome. A summary of the surgical outcome in meningiomas at different anatomic localizations is provided in Table 18-2.

TABLE 18-2 Surgical results in selected meningiomas in relation to localization

Anterior fossa meningiomas are notorious for remaining asymptomatic for long periods, presenting with large sizes and having a high incidence of recurrence.¹⁰⁵ Mathiesen and colleagues¹⁰⁶ showed that 10% of these cases recur at 10 years and that 20% of the patients die as a result of these recurrences. Surgical resection of olfactory groove meningiomas is complicated by the fact that they may invade the anterior skull base and the paranasal sinuses.¹⁰⁷ Radical resection of the tumor, involved dura, and bone in the anterior fossa or the paranasal sinuses is technically difficult and is associated with a high risk of complications. More conservative resections, in contrast, may result in recurrences as high as 41% at 10 years.³⁶ Bakay¹⁰⁸ reported subtotal resection in 17% of his patients, which was associated with blindness in half of these patients due to recurrence. The likelihood of preserving smell after resection of olfactory groove meningiomas is possible in tumors smaller than 3 cm in diameter, whereas ipsilateral smell is lost in all cases.¹⁰⁹ In tuberculum sella meningiomas, surgery provides objective, quantifiable, and significant improvement in vision.^62,⁶⁶ The reported likelihood of visual improvement after surgery ranges from 42.4% to 80% in a recent series.⁶²^–⁶⁷ In contrast, some studies reported 10% to 20% incidence of iatrogenic worsening in vision.⁶²^–⁶⁷ The visual outcome in young patients after surgical resection is significantly better than in the elderly^62,^66,⁶⁷ Severity and duration of visual symptoms were also shown as predictors of a poor visual outcome.^62,^65–67,^110,¹¹¹ Size of the tumor,^66,¹¹² shape of the tumor,⁶⁶ extent of tumor removal,^62,⁶⁶ absence of an arachnoid plane,⁶⁶ binocular involvement,⁶² optic disc pallor,¹¹⁰ and presence of significant peritumoral edema⁶⁶ were associated with a worse outcome as reported by some authors and contradicted or not supported by others. Large tumors may involve distal branches of the anterior cerebral artery which will preclude total resection and increase recurrences. Another source of recurrences is small tumor extensions in the optic canals, which can easily be missed when not inspected during surgery. Several authors also have shown that a simple pterional craniotomy is sufficient to achieve high total resection rates with very little morbidity.^62,⁶⁶ Low morbidity rates and good chance of benefit to the patient favor a surgical treatment in tuberculum sella meningiomas. Sphenoid wing meningiomas are classified into pterional, alar, clinoidal, and en plaque subtypes according to their epicenter along the sphenoid ridge.¹¹³ The elegant report by Al-Mefty and colleagues⁶⁸ established clinoidal meningiomas as a new meningioma subtype, distinct from sphenoid wing meningiomas. Clinoidal meningiomas can be differentiated from sphenoid wing meningiomas radiologically, unless the tumor has reached a giant size.⁷¹ Visual symptomatology is reported in 45.5% to 91.6% of patients with clinoidal meningiomas.⁶⁸^–⁷³ The most important factor that determines the surgical outcome in clinoidal meningiomas is the anatomic relationship of the tumor to the internal carotid artery and surrounding arachnoid cisterns.⁶⁸ Large tumor size⁷¹ and cavernous sinus invasion⁶⁸^–⁷³ are other factors that have a negative impact on surgical outcome.