INTRODUCTION

According to the Central Brain Tumor Registry of the United States, meningiomas account for more than 30% of all primary brain tumors.¹ It is well recognized that there is a significant difference in the incidence of meningiomas between females and males. Among females, meningiomas represent about 38% of all intracranial tumors compared to 20% of all tumors in males, a difference that is much higher for spinal extramedullary tumors.² Age represents another relevant factor in their epidemiology, with the incidence of meningiomas increasing from 0.3/100,000 in childhood to more than 8.4/100,000 in the elderly population.³

Despite their prevalence, the vast majority of meningiomas are extra-axial, benign slow-growing tumors arising from arachnoid cap cells. Hence, many meningiomas, including those that are relatively large, are asymptomatic and do not require active intervention, especially in the elderly or in those with medical comorbidities. However, meningiomas can cause neurologic symptoms due to local growth and compression of adjacent brain structures and cranial nerves; irritation of the adjacent cortex leading to seizures; and pain syndromes due to involvement of cranial nerves, adjacent dura, and skull base structures. The majority of these symptoms evolve slowly and are related to the insidious growth of the benign meningioma. Elective surgery, supplemented with adjuvant radiation when indicated, usually provides long-term cure or tumor control with minimal morbidity, as discussed elsewhere. However, certain locations and biological subtypes of meningiomas still pose significant management challenges requiring a multidisciplinary approach and ongoing research into the molecular biology of these tumors.²

In a minority of cases, meningiomas may cause symptoms on a more acute basis, a result of several potential etiologies:

MENINGIOMA AND PERITUMORAL BRAIN EDEMA

The presence of peritumoral brain edema (PTBE) associated with meningiomas is relatively common and has been quoted in different series to be present between 40% and 92% of the time.^4–6 The incidence of PTBE resulting in significant neurologic deficit, thereby reducing the patient’s performance status and negatively affecting the surgical outcome, is unknown. Although this number is likely much lower, PTBE still represents a significant pre- and postoperative clinical issue in a sizable number of patients.^7,8 As discussed in the text that follows, several structural, pathologic, and molecular correlates of meningiomas and associated PTBE have been proposed, with likely no one single etiology that adequately explains all cases. For example, although the incidence of significant PTBE is more with malignant meningiomas, the vast majority occur in the much more common totally benign meningioma (Figs. 9-1 and 9-2). Location around major venous sinuses or draining veins has been implicated as another association, but meningiomas with significant PTBE are found in the convexity, skull base, as well as those in the parasagittal region (see Fig. 9-2). Size of the meningioma has also been linked to PTBE, but large series have not clearly documented this to be true, as demonstrated by the significant PTBE in the smaller of two meningiomas in the same patient in (Fig. 9-2D).

FIGURE 9-1 PTBE is more prevalent in malignant meningiomas (WHO grade III) compared to benign, but due to their rarity the majority of meningiomas with significant PTBE are benign meningiomas of varying histopathologic subtypes. Three examples of malignant meningiomas associated with extensive edema are depicted. A, MRI FLAIR axial image of a right convexity malignant meningioma (WHO grade III) in a patient who underwent multiple resections. B, MRI T2-weighted axial image of a falx malignant meningioma; note the involvement of the entire falx and of part of the right frontal convexity. C, MRI T2 weighted axial image of another malignant meningioma of the falx, with extensive bilateral edema.

FIGURE 9-2 Cases demonstrating that size and location are not sole determinants of PTBE associated with meningiomas. A, Large-convexity meningioma with minimal edema (T2 axial MRI). B, Large petroclival meningioma with significant brain stem compression but no PTBE (T2 axial MRI). C, Falx meningioma of moderate size inducing PTBE only on the right frontal lobe despite a larger extension on the left side (FLAIR axial MRI). D, Small anterior skull base meningioma determining significant left frontal lobe edema (CT axial + coronal reconstruction). Interestingly, in this patient a larger meningioma on the right convexity did not show any PTBE. E, Olfactory groove meningioma with bifrontal edema (CT axial). A second smaller meningioma of the right convexity is noted. F, Large left sphenoid wing meningioma with significant PTBE (T2 axial MRI). G, Small falcine meningioma with disproportionate brain edema (T1 coronal with gadolinium + T2 axial MRI). H, Large-convexity cystic meningioma surrounded by hemispheric edema (FLAIR axial MRI).

There is agreement that at a histologic level, ablation of the usually present intact arachnoid plane separating the tumor from adjacent brain (Fig. 9-3A) or subpial extension of the tumor, such as in malignant meningioma, is associated with increased incidence and severity of PTBE. The presence of T2 signal change in the parenchyma at the tumor–brain interface correlates well to the loss of a patent arachnoid plane (Fig. 9-3B, C). These subtle but important preoperative radiologic features should be recognized to properly plan the extent of resection with minimal exacerbation of neurologic deficits, especially in meningiomas that grow against eloquent regions of the brain, such as the brain stem (Fig. 9-3C).

FIGURE 9-3 The importance of the preserved pia–arachnoid plane in PTBE associated with meningiomas: A, Demonstration of the patent arachnoid plane (arrow) separating the tumor–brain interface in a gross coronal pathologic specimen of a falcine meningioma. B, T2-weighted axial MRI of a large left petroclival meningioma with significant brain stem displacement but no PTBE, likely representing a preserved arachnoid plane. C, T2-weighted axial MRI of a left petroclival meningioma with minor brain stem displacement. However, PTBE is appreciable in the pons and in the mesencephalon (arrow), indicating a disruption of the pia–arachnoid plane. This pre-operative observation is important as likely the tumor–brain interface has been breached in these regions and one may elect to leave a tumor carpet rather than risk injury to the brain stem.

MECHANISM(S) AND QUANTIFICATION OF BRAIN EDEMA

Brain edema can be broadly classified as cytotoxic, vasogenic, and transependymal, based on its underlying etiology. Transependymal ependyma occurs in the context of obstructive hydrocephalus due to physiologic lack of a brain–CSF barrier. On rare occasions, as mentioned earlier, obstructive hydrocephalus with transependymal edema can be a presentation of a meningioma located strategically along CSF pathways. Cytotoxic edema is characterized by swelling of cellular elements of the central nervous system (CNS), a consequence of lack of energy supply to maintain the normal intra- versus extracellular ionic and osmotic gradients of the cells. Cerebral ischemia resulting in swelling of neurons, glia, and endothelial cells occurs within minutes due to failure of ATP-dependent ion transport channels, which are pivotal in maintenance of osmotic gradients. Rapid accumulation of intracellular sodium occurs with failure of these ion pumps, resulting in in-flow of extracellular free water and resultant cellular swelling in order to maintain osmotic equilibrium. In addition, intracellular accumulation of other ions, such as calcium, activates phospholipases and release of arachidonic acid, leading to the release of oxygen-derived free radicals and ultimately cell death.

Vasogenic edema is the most relevant type of edema associated with intra- or extra-axial tumor-associated PTBE, including meningiomas.⁹ Vasogenic edema is characterized by an increase in extracellular fluid volume due to breakdown of the blood–brain barrier (BBB), with increased permeability of brain capillary endothelial cells to macromolecular serum proteins such as albumin. The main ultrastructural basis of the intact BBB is the presence of endothelial cell tight junctions or zona occludens, a key differentiating factor of CNS versus systemic vasculature. In addition to tight junctions, the fully mature BBB is also dependent on the glial foot processes that wrap around the vessels and lack of pinocytic transcellular vesicular transport in the CNS endothelial cells. The onset of vasogenic edema is more subacute to chronic compared to cytotoxic edema, as it requires disruption of the substrates of the BBB described in the preceding text. However, acute cytotoxic edema is usually followed within the next few hours to days by the development of vasogenic edema, as endothelial and glial cell death leads to disruption of the BBB. Breakdown of the ultrastructural substrates of the BBB mentioned earlier in the peritumoral brain is usually not secondary to a primary cytotoxic injury. It likely is a result of combination of potentially reversible mechanical, physiologic, and molecular alterations triggered by the tumor, as discussed in detail later. To better understand and potentially treat PTBE it is essential to be able to quantify it both in preclinical and clinical settings. Accordingly, the simple edema index defined by magnetic resonance imaging (MRI) volumetric measurements as:

has proven to be reliable measurement of communication between investigators.^10–13 Accordingly, an edema index of 1 by definition implies lack of any PTBE.

POTENTIAL ETIOLOGIES OF MENINGIOMA-ASSOCIATED PTBE

Many studies have investigated epidemiologic factors that may be related to the occurrence of PTBE in meningiomas. These include age, sex, tumor size, tumor location, presence/absence of tumor lobulation, histologic subtype and grade as per the WHO classification, type of arterial blood supply (meningeal ± pial), type of venous drainage (superficial, deep, parasagittal, sinus involvement), and presence of peritumoral brain ischemia. In summary, none of these epidemiological factors has consistently been able to predict and thereby provide a unifying explanation of PTBE in meningiomas.

MOLECULAR BIOLOGY OF MENINGIOMA-RELATED PTBE

As per the preceding discussion, there does not seem to be one unifying epidemiologic, pathologic, clinical, or structural cause for all meningioma-associated PTBE. However, general agreement exists that disruption of the BBB is mandatory for PTBE, and this requires a breach of the arachnoid plane at the tumor–brain interface.^29,35 However, breach of the arachnoid plain likely does not suffice to induce PTBE by itself, but facilitates transgress of various edemogenic cytokines being released by the tumor to disrupt the integrity of the BBB in the adjacent parenchymal vessels.³⁶ Loss of the arachnoid plane prevents removal and dilution of these cytokines by the CSF to facilitate penetration of these cytokines into the brain by disruption of the pial border. In addition, cytokines such as VEGF are not only edemogenic but also often angiogenic, thereby promoting neo-angiogenesis and establishment of cerebral–pial tumor vessels. As discussed, these cerebral–pial vessels usually lack a mature BBB and thereby further exacerbate PTBE.

What are some of these edemogenic and angiogenic cytokines released by meningiomas that may underlie PTBE? One of the most important and best studied growth factors in cancers, including meningiomas, is VEGF. VEGF was originally described as a potent edemogenic factor and coined to be vascular permeability factor (VPF).³⁷ The subsequent independent isolation and sequencing of VPF and VEGF demonstrated absolute homology and realization they were the same protein. VEGF is a 34- to 45-kDa highly soluble dimeric glycosylated protein, with structural homology to platelet-derived growth factor (PDGF). Several VEGF family members have been identified (VEGF-A, VEGF-B, VEGF-C, VEGF-D, PIGF), with different but overlying function in regulating not only the vascular but also related lymphatic system (Fig. 9-4A). VEGF-A is synonymous to VEGF and plays a pivotal role in normal developmental and physiological angiogenesis, as well as pathological neoangiogenesis such as in cancer. There are several isoforms of VEGF in humans, with the most abundant, diffusible, and active being the smallest two isoforms, VEGF₁₂₁ and VEGF₁₆₅ (Fig. 9-4B). VEGF is a potent mitogen and chemotactic factor for endothelial cells, as well as inducing the production of proteases (plasminogen activators, collagenases, etc.), to degrade the extracellular matrix.^38–40 The important tumor angiogenic role of VEGF is not detailed in this chapter, but its importance is demonstrated by promising clinical trials in neurooncology utilizing a variety of strategies to inhibit VEGF with the potential of inhibiting brain tumor angiogenesis and thereby growth.

FIGURE 9-4 Vascular endothelial growth factor (VEGF): A, VEGF receptors and their specific high-affinity ligands are shown. VEGF-A is what is commonly referred to as VEGF in the context of tumor angiogenesis and edema. The main ultrastructural characteristics are depicted and explained in the legend. All three receptors are tyrosine kinases that upon ligand binding are able to activate important intracellular pathways, which control angiogenesis, cell proliferation, and chemotaxis (see text for details). B, The six isoforms of VEGF resulting from alternative mRNA splicing are schematically shown. The most abundant and highly soluble isoform is VEGF₁₆₅.

VEGF is able to increase vascular permeability of normal blood vessels to plasma proteins, without inducing inflammation or endothelial cell injury.⁴¹ It is approximately 1000 times more potent as histamine in inducing vascular edema, by acting directly on endothelial cells of venules and arterioles, but not on smooth muscle cells or fibroblasts. The specificity toward endothelial cells is a result of the two cognate VEGF receptors, VEGFR-1 (or Flt-1) and VEGFR-2 (or Flk-1/KDR), being specifically expressed on endothelial cells (see Fig. 9-4A). VEGF, especially the most abundant VEGF₁₆₅ isoform, has the highest affinity to bind VEGFR-2 and plays a more dominant role in tumor angiogenesis and growth.^42–44 VEGF expression at the mRNA level and PTBE in meningiomas has been linked.⁴⁵ We extended these observations to VEGF proteins expression by immunohistochemical analysis and found it to correlate to meningioma vascularization.³⁶ We then correlated the degree of meningioma vascularization to degree of PTBE, as measured by the previously described edema index. Although all meningiomas with a significant edema index (>2, where the amount of maximal PTBE was twice the maximal size of the meningioma) had a high degree of tumor angiogenesis and VEGF expression, not all highly vascular meningiomas had significant PTBE. We postulate that for PTBE to occur, both breach of the arachnoid plane and high levels of VEGF secretion by the tumor cells were required. In support of this postulate another group demonstrated that expression of both VEGFR-1 and VEGFR-2 in meningioma endothelium cells is related to degree of VEGF expression and associated PTBE in these tumors.⁴⁶

Although implicating VEGF, the sequence of events how VEGF induces PTBE development in meningiomas is still matter of debate. From the literature two potential mechanisms, which are not mutually exclusive but could act independently or in synergism, have been proposed, as schematically depicted in Figure 9-5. One mechanism suggests that VEGF acted as a potent edemogenic factor only when growth of the meningioma physically leads to disruption of the arachnoid (see Figs. 9-2 and 9-3).⁴⁷ After breakdown of the arachnoid plane, VEGF, which is highly soluble, can induce vascular permeability as well as proliferation of subpial microvessels leading to cerebral-pial vascular supply to the tumor. Another potential but not exclusive mechanism takes into account the noted observation that meningiomas with significant PTBE express high levels of VEGF.³⁶ VEGF regulates expression of several proteases, which in addition to the physical growth of the tumor can facilitate breakdown of the arachnoid plane and extracellular matrix (see Figs. 9-2 and 9-3).⁴⁸ In support, PTBE in meningiomas correlated significantly with expression of matrix metalloproteinase-9 (MMP-9) by the tumor cells, one of the most common and potent proteolytic enzymes capable of breaking down the basal membrane (collagen IV) and the connective tissue.⁴⁸ In addition, integrins such as αvβ3 and αvβ5 play a fundamental role in angiogenesis and invasion and are expressed in meningiomas, particularly at the brain–tumor interface where cerebral–pial vascularization and PTBE occur.⁴⁹ In contrast to normal brain, the peritumoral brain around meningiomas express high levels of these integrins, especially α v β 5, thereby representing a state of activated, immature and edemogenic vasculature.⁴⁹ In support of the role of integrins, tenascin, which is an ECM glycoprotein and a ligand of α v β5, correlates to the extent of PTBE and VEGF expression in meningiomas.⁵⁰

FIGURE 9-5 The two principal hypothesis of PTBE development are schematically summarized. Of note, these hypothesis are not mutually exclusive but can be present independently or even simultaneously in the same patient: A, (1) A physical breach in the pia–arachnoidal plane between meningioma and surrounding brain is the initiating event. (2) The brain and meningioma vasculature are activated and expresses αvβ3 integrins. (3) Once the pia–arachnoidal plane is interrupted, meningioma released growth factors such as VEGF can diffuse freely into the brain and induce edema and also induce and recruit the immature pial vasculature to the tumor, to further add to PTBE. B, (1) Overexpression of VEGF by the meningioma is the initiating event. VEGF production by certain meningiomas are increased, for reasons that are not entirely clear and include environmental factors such as hypoxia and primary genetic alterations such as growth factor-signaling pathways. Increased VEGF contributes to meningioma growth by promoting angiogenesis and is significantly further increased in malignant meningiomas, which are highly associated with PTBE. (2) In addition, the increased VEGF released by the meningioma promotes breakdown of the pial–arachnoid plane by release of various proteases and expression of αvβ3 integrins. (3) Subsequent extravasation of meningioma growth factors in the brain parenchyma leads to vasogenic edema by disruption of the blood–brain barrier and tumor neovascularization by the immature pial vasculature.

Why some meningiomas express high levels of VEGF and thereby potentially lead to significant PTBE, while others do not, is not known. Primary mutations, amplifications, and translocations leading to increased VEGF expression have not been identified in meningiomas, or in fact other human cancers. Differences in intratumoral hypoxia are suspect, as hypoxia is the most potent physiologic inducer of VEGF.⁵¹ In meningiomas, different degrees of ischemia have been demonstrated at the meningioma–brain interface, suggesting that this hypoxic environment might be able to induce VEGF and thus PTBE development.⁵² Hypoxia leads to VEGF induction by increasing its transcription by stabilizing the transcription factor hypoxia-inducible factor-1α (HIF-1α), which acts on the hypoxia-responsive element (HRE) promoter region of VEGF. Furthermore, hypoxia stabilizes VEGF at the mRNA level^53–55 and induces the expression of growth factors such as PDGF and epidermal growth factor (EGF), which in turn induces VEGF expression.

However, a variation in tumor hypoxia likely is not the main underlying etiology for noted differences in the VEGF expression profile among meningiomas. If it was, one would predict that larger meningiomas with greater hypoxic regions may have higher levels of VEGF and thereby demonstrate more PTBE, a correlation that has not been verified, as previously discussed. This brings forth the thesis that primary growth-promoting molecular aberrations in certain meningiomas may also increase VEGF expression by these tumors and make them more susceptible to PTBE if there is breakdown of the arachnoid–pial plane. These include cytokines such as transforming growth factor (TGF-β) fibroblast growth factor (FGF), interleukin-6 (IL-6), platelet-activating factor (PAF), and prostaglandins.^11,56 Further, downstream signaling pathways to these cytokine receptors, such as p21-Ras and PI3 kinase, also can induce VEGF.³⁶ In summary, meningiomas and other cancers lack a primary genetic basis for increased VEGF expression. However, VEGF can be secondarily induced by tumor hypoxia and primary genetic alterations in the tumors, such as aberrant growth factor-receptor–signaling pathways, that may underlie the molecular mechanisms of PTBE in meningiomas.

PRINCIPLES OF TREATMENT OF PTBE IN MENINGIOMAS

The long-term permanent therapy of PTBE associated with meningiomas is microneurosurgical removal of the tumor, with preservation of the tumor–arachnoid plane. In some instances, the surgical volume of the symptomatic meningioma that requires removal is actually small, with most of the clinical symptoms due to PTBE (see Fig. 9-2). Preservation of the arachnoid plane at the tumor–brain interface, avoiding damage to cortical veins and not attempting tumor removal from the posterior two thirds of the sagittal sinus, are important to minimize parenchymal dysfunction and postoperative neurologic worsening due to increased PTBE or venous engorgement and subsequent venous infarction. The presence of preoperative edema as detected on MRI would indicate those regions of the tumor–brain interface to have a breached arachnoid plane (see Fig. 9-3). Attempted total removal of the tumor in these interfaces has a high probability of increasing PTBE, leading to significant mortality, especially in highly eloquent regions such as the brain stem. In these cases, it is more prudent to leave a “carpet” of tumor over these interfaces. In less eloquent regions, total tumor removal can be achieved without added postoperative deficits, with meticulous dissection of the tumor–brain interface.

The main medical therapy for PTBE in patients who cannot undergo surgery for medical reasons or in the perioperative or postoperative period is corticosteroids.^57,58 Steroids reduce VEGF expression by the tumor cell and inhibit the edemogenic response of the brain microvascular bed to VEGF and other cytokines, by stabilization of endothelial cell permeability and inhibiting vasogenic edema.⁵⁹ In support, VEGF applied to cultured endothelial cells increases intracellular influx of calcium associated with cytoskeletal rearrangement, a response antagonized by steroids.⁶⁰ The effect of dexamethasone on PTBE and associated clinical sequelae can be quite abrupt and gratifying to the patient and family. However, the long-term use of steroids is significant, including weight gain, diabetes, immunosuppression, osteoporosis, gastrointestinal problems, myopathy, increased risk of deep vein thrombosis, or pulmonary embolism. These side effects need close monitoring and preclude using steroids on a prolonged basis for the management of PTBE in meningiomas.

Therapeutic strategies that decrease PTBE other than steroids include agents that selectively target VEGF or VEGF receptors. VEGF antagonists currently under preclinical and clinical study include neutralizing or blocking antibodies to VEGF and small-molecule VEGF-receptor inhibitors.⁶¹ In addition to PTBE, VEGF antagonists may also inhibit overall tumorigenic growth by their antiangiogenic effects. Another group of compounds that also deserve attention in the management of PTBE are the cycloxygenase-2 (COX-2) inhibitors, as ubiquitous expression of COX-2 in meningiomas has been demonstrated.⁶² COX-2 is an enzyme responsible for the production of relevant mediators of inflammation and is the rate-limiting enzyme for the synthesis of prostaglandins from arachidonic acid. Prostaglandins possess tumorigenic properties via their angiogenic, antiapoptotic, and cell proliferative effects. Nonsteroidal anti-inflammatory drugs (NSAIDs) and selective COX-2 inhibitors are effective antagonists of prostaglandin synthesis and potentially also possess antitumorigenic effects. In addition, COX-2 inhibitors also reduce expression of the transcription factor Sp1, which inhibits generation of VEGF transcripts and thereby expression.⁶³ In support, the COX-2 inhibitor SC-236 demonstrated promising results in a preclinical gliosarcoma model.⁶⁴ Rofecoxib, another specific COX-2 inhibitor, was as effective in reducing PTBE as dexamethasone also in animal models of PTBE. Celecoxib, a specific COX-2 inhibitor, was found to be effective in management of PTBE, although the effect was not immediate and varied with duration of use.⁶² Although promising, none of these nonsteroidal agents has been conclusively demonstrated to be equivalent or superior to conventional steroids, which remains the prime medical therapy of PTBE when indicated.

CONCLUSIONS

The pathogenic understanding of PTBE associated with meningiomas remains uncertain and likely is multifactorial. At a minimum, it involves obliteration of the arachnoid plane at the tumor–brain interface with extravasation of edemogenic cytokines, notably VEGF, into the parenchyma resulting in vasogenic edema and neoangiogenesis. In a minority, but not insignificant number of patients, PTBE accounts for the main clinical presenting or postoperative symptomology. Medical management of PTBE currently involves steroids, with all of their accompanying side effects. Hence, whenever possible, surgical removal of the culprit meningioma is desirable for long-term cure. Further understanding of meningioma biology should provide additional biological and hopefully therapeutic insights in PTBE associated with these tumors.