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Management of Benign and Aggressive Intracranial Meningiomas

Management of Benign and Aggressive Intracranial Meningiomas

ABSTRACT: Usually considered benign tumors, meningiomas can display aggressive behavior characterized by multiple recurrences and invasion of the brain, dura, and adjacent bone. The aggressive or malignant phenotype is difficult to characterize due to the broad spectrum of behaviors exhibited by meningiomas. Recent classification schemes based on features of anaplasia rather than histopathology have been used successfully to identify meningiomas that exhibit features of the aggressive phenotype. Some such tumors can be identified preoperatively by radiographic characteristics. Surgery is the cornerstone of treatment for all types of meningiomas. Conventional radiation therapy is beneficial for patients with recurrent (or incompletely resected) benign meningiomas and is recommended for those with aggressive and malignant meningiomas. Stereotactic radiation and interstitial brachytherapy are useful in some refractory or recurrent meningiomas. Traditional chemotherapeutic agents are not very effective against meningiomas, but hormonal manipulation is under study for patients with inoperable tumors or those who are medically unsuitable for surgery. [ONCOLOGY 10(5):747-759, 1996]

Introduction

Meningiomas are histologically benign tumors of the intracranial
and intraspinal compartments arising from meningothelial cells
of the arachnoid layer ("arachnoidal cap cells") surrounding
the central nervous system. Their behavior is sometimes far from
benign, however, as they can be the source of significant morbidity
and even mortality. Although slow-growing, meningiomas cannot
be completely resected in many instances, and are characterized
by a high rate of recurrence, propensity for disturbing vital
and anatomically complex structures within the nervous system,
and poor response to traditional medical treatment regimens. Recurrence
is often accompanied by a more aggressive profile of histopathology
and biologic activity. The more aggressive varieties, the so-called
atypical and malignant meningiomas, present their own specific
problems for treatment. Meningiomas, therefore, pose definite
therapeutic challenges to practicing neurosurgeons and oncologists.

Pathology

Recent advances in the neuropathology of meningiomas have produced
more specific histopathologic and cytologic criteria for classifying
these tumors, more sophisticated markers of aggressive behavior,
and further clarification and characterization of the malignant
phenotype. This information is essential for the practitioner
treating patients harboring these tumors, as it helps identify
those requiring more aggressive medical and surgical treatment
regimens.

Classification

Traditionally, meningiomas have been classified based on their
histologic appearance, and predictions of aggressive behavior
are derived from such classifications. Cushing and Eisenhardt
proposed a scheme containing nine types of meningioma with 22
subtypes [1]. The most widely used classification system, that
of Russell and Rubenstein, described three classic types of meningiomas
(syncytial, fibroblastic, and transitional), with a number of
histologic variants or subtypes [2].

With the exception of the papillary, hemangiopericytic, and angioblastic
varieties of meningiomas, classification by histologic appearance
alone has no bearing on prognosis or behavior [2]. However, such
features as hypervascularity, hemosiderin deposition, indistinct
architectural pattern, increased numbers of mitotic figures, necrosis,
prominent nucleoli, and moderate nuclear pleomorphism have been
associated with recurrence in meningiomas [3]. It remains controversial
as to whether the hemangiopericytoma truly belongs among the meningiomas
by virtue of a common precursor cell, or whether it represents
a separate tumor type with a distinct oncogenesis [2].

The system of classification proposed by the World Health Organization
(WHO) in 1979 [4] and revised in 1993 [5] is based on cytologic
features of anaplasia rather than purely histopathologic descriptions.
This system classifies meningiomas as benign, atypical, or malignant
based on six individual features of anaplasia: loss of architecture,
hypercellularity, nuclear pleomorphism, mitotic figures, focal
necrosis, and brain invasion.

Jääskeläinen et al [6] and Rohringer et al [7]
have refined the WHO system by applying scores from 0 to 3 to
each of the parameters based on the degree of severity of that
feature, with the exception of brain invasion, which is scored
as absent (0) or present (3). Based on the sum of the scores,
meningiomas are designated as benign (grade I; 0 to 2 points),
atypical (grade II; 3 to 6 points), anaplastic (grade III; 7 to
11 points), or sarcomatous (grade IV; 12 or more points). Mahmood
et al [8] have further revised this scheme by providing defined,
objective criteria for the scores of 1, 2, or 3 for each of the
classification parameters.

Cell Kinetics

In an attempt to determine more precisely the correlates of aggressiveness
and future growth of these tumors, researchers have developed
quantitative methods of measuring the proliferative activity of
meningioma cells. Analyses of the DNA content of meningioma cells
using flow cytometry have been performed [9-11]. Tumor aneuploidy
has been associated with poor clinical outcome [9]. The proliferation
index, ie, the percentage of cells in the S + G2/M phases of the
cell cycle, correlates with clinically aggressive behavior in
meningiomas [10] and with meningioma recurrence [11].

The mitotic, or labeling, index of many meningiomas has been determined
using bromodeoxyuridine labeling. The labeling index is obtained
by briefly exposing the tumor to a thymidine analog and calculating
the percentage of total tumor cells incorporating the analog into
DNA. By combining the in vivo exposure of the tumor to bromodeoxyuridine
with in vitro exposure to iododeoxyuridine, the time required
for DNA synthesis can be calculated [12,13].

Bromodeoxyuridine labeling correlates well with recurrence rates
of meningiomas. Shibuya et al [12] demonstrated that tumors with
a bromodeoxyuridine labeling index > 5% have a 100% recurrence
rate, as compared with a 56% recurrence rate for tumors with a
labeling index of 3% to 5%, and a 31% rate for those with a labeling
index of 1% to 3%. Labeling indexes of 9% and 13.6% were reported
by Fukui et al for two recurrent meningiomas with highly malignant
behavior, as compared to labeling indexes of 0.1% to 0.9% for
benign meningiomas [13].

Malignant Meningioma Phenotype

A concise definition of the malignant meningioma remains elusive
and controversial. The situation is complicated by the fact that
a histologic and biologic continuum probably exists between atypical
or aggressive meningiomas and malignant meningiomas. Nevertheless,
the modified WHO system of classification has proved useful in
identifying meningiomas with potential for either aggressive future
behavior or for recurrence. Using these criteria, recurrence at
5 years after complete removal is 3% for grade I tumors, 38% for
grade II, and 78% for grade III, with median times to recurrence
of 7.5, 2.4, and 3.5 years, respectively [14]. Mahmood et al found
5-year recurrence rates after total surgical excision of 50% for
atypical tumors (grade II) and 33% for malignant meningiomas (grades
III and IV), but these differences were not statistically significant
[8].

In many recent studies of meningiomas, the term "malignant"
is usually applied to both grade III and IV tumors, ie, those
expected to display evidence of more aggressive biologic behavior.
However, in practical use, the diagnosis of malignant meningioma
is reserved for those tumors displaying histologic evidence of
brain invasion or evidence of distant metastasis, features that
are not always easily assessed. Traditionally, pathologists have
been reluctant to classify a meningiomas as "malignant"
unless definite brain invasion is present. Those few meningiomas
that metastasize (1% or less of all histologic types, and one-third
of those designated as malignant) would by definition need vascular
invasion, occult or overt, to accomplish distant spread. Evaluating
brain invasion remains subjective, in that postsurgical changes
seen in patients with recurrent meningiomas can make delineation
of the boundaries between tumor and brain difficult. Sampling
bias may cause underdiagnosis of brain invasion, and some atypical
tumors may actually be malignant by that criterion.

Comprehensive Classification Scheme--The most comprehensive
classification of meningiomas would combine histopathologic, cytologic,
and kinetic information to reveal the precise position of a given
tumor within the broad and complex spectrum of these tumors. One
such scheme is that proposed by Wilson [15], who suggested meningioma
designations such as grade I, which consists of meningotheliomatous
tumors and those with a labeling index of 1% ("classic"
or "benign"); and grade III, which includes tumors with
a papillary pattern or a labeling index of 3.5% (anaplastic).
Thus, the malignant designation would be applied to tumors with
one or more indices of aggressive behavior, such as a high grade
(III or IV), a histologic appearance associated with aggressive
behavior, a labeling index > 3%, and/or evidence of brain invasion.
The presence of distant metastasis provides additional evidence
of highly aggressive behavior, and thus, a poorer expected outcome.

The clinical predictive value of such an ecumenical scheme remains
to be shown in systematic studies. For now, it provides useful
criteria with which to stratify those meningiomas expected to
display more aggressive biologic behavior, and thus, to require
more aggressive surgical and medical treatment.

Clinicopathologic Correlation

Certain features have been identified that distinguish the aggressive
meningiomas from the more common benign types. The reported incidence
of meningiomas with histologic anaplasia varies based on the specific
criteria used, and is obviously dependent on referral patterns,
but it ranges from 0.9% to 11% [16-19]. Salcman combined the incidence
of malignant meningiomas in several large recent studies that
use a variety of classification criteria and found that an average
of 2.8% of meningiomas qualify for the malignant designation [20].
Using the WHO classification and its modifications mentioned above,
benign meningiomas represent 93% (grade I) and atypical tumors,
5% (grade II); about 2% are anaplastic or sarcomatous (grades
III and IV) [5,6,8,14].

Although the most common presenting symptoms, seizures and headaches,
are equally frequent in benign and malignant meningiomas [7],
the incidence of hemiparesis or focal neurologic deficits is higher
in patients with malignant meningiomas [8,14,20]. While benign
meningiomas are known to show nearly a 2:1 female-male predilection,
malignant meningiomas demonstrate either a male predominance [14]
or are evenly split between the genders [8]. In two series combined,
10 of 12 malignant meningiomas occurred in males [21,22]. Most
malignant meningiomas are located over the convexity or in parasagittal
locations [7,8].

Distinguishing Radiographic Features--Certain radiographic
features may be used to distinguish malignant meningiomas from
benign tumors. Malignant meningiomas are approximately half as
likely as benign tumors to show homogeneous enhancement on CT
scans and are more frequently associated with moderate to severe
peritumoral edema [7,14]. Unlike their benign counterparts, few,
if any, malignant meningiomas are calcified [7,14].

Other features seen on CT that correlate with an aggressive histology
or behavior are "mushrooming," or irregular projections
of the tumor along or into the brain surface; indistinct tumor
margins; fringes of tumor extending into the brain substance;
marked bone destruction; and large areas of low-density, central
necrosis [7,8,14]. Some malignant meningiomas display a CT appearance
consistent with dural-based glioma or metastasis [14]. In one
retrospective series, 12 of 17 atypical mengiomas and 13 of 16
anaplastic tumors could have been distinguished from benign meningiomas
preoperatively based on radiographic characteristics alone [14].

Malignant meningiomas commonly display increased signal on both
T1- and T2-weighted MRI studies (see Figure 1) [20]. As with other
intracranial tumors, however, correlation of radiologic with histologic
features is imperfect. Although tumors that appear aggressive
on radiologic images are generally confirmed to be atypical or
malignant, those with a benign appearance may grow and recur quickly
and show anaplastic features, despite the absence of radiologic
predictors.

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