Multiple Meningiomas

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CHAPTER 49 Multiple Meningiomas

Nejat Akalan, Tunçalp Özgen

INTRODUCTION

Multiple meningiomas are defined as two or more meningiomas detected simultaneously at different intracranial locations in the same patient. While the incidence was initially reported as 1% to 2% of meningioma cases by Cushing and Eisenhardt, the figures increased to 10.5%¹ with the clinical application of computed tomography (CT) and 20% with magnetic resonance imaging (MRI).² As multiplicity in meningiomas is not uncommon, multiple meningiomas not only offer a challenging clinical decision making process but also provide an invaluable opportunity in neuroscience to probe the mechanisms of tumorigenesis.

HISTORICAL BACKGROUND

The “multiple meningiomas” concept can be traced back to 1889; Anfimov and Blumenau are credited for the first report on the presence of more than one meningioma in a patient without phacomatosis.³^–⁵ In 1938, Cushing and Eisenhardt⁶ used the term “multiple meningiomas” to refer to “something more than one meningioma and less than a diffusion in the absence of stigmata of Von Recklinghausen’s disease.” Although this description was clear enough to differentiate “meningiomatosis” and “multiple meningiomas,” both terms have been used interchangeably.⁷ Discussions in the following years aimed mainly to establish a valid terminology to distinguish true multiplicity distinct from those associated with various other tumors in neurofibromatosis type 2 (NF2).⁸^–¹¹ Insofar as the descriptions were based solely on clinical observations without radiologic and genetic support, it remained elusive whether true multiple meningiomas exist as a separate disease entity or represent one end of the spectrum of NF2.⁵ From then, technical advancements influenced the meningioma concept in several ways. The advent of modern neuroimaging has resulted in changing concepts for meningiomas in terms of treatment planning and assessment, natural course, and incidence. Multiple meningiomas, as mentioned earlier, have been detected in much higher proportions, and the same conceptual discussions regarding meningiomas in general began to appear from different centers. On the other hand, evolution of genetic studies extending to intracranial tumor biology led to meningiomas becoming an attractive subject for cytogenetic and molecular genetics analyses. Within this context, multiple meningiomas are expected to provide important insights into the mechanisms of meningioma tumorigenesis.¹²

At present, multiple meningiomas are believed to occur either as a part of NF2 or spontaneously without any inherited genetic background. Confusion still exists in inserting meningiomatosis within this frame, as well as those appearing after an initial meningioma resection, indicating a possibility of dissemination.

PATHOGENESIS

Numerous publications have described alterations in the NF2 gene (both in patients with and without NF2), which predispose individuals to nervous system tumors, including schwannomas, meningiomas, and ependymomas.¹³^–²³ There are two rare familial conditions (NF2 and meningiomatosis), both inherited as autosomal-dominant traits, that predispose patients to developing meningiomas. Rarely, these tumors may occur after either low-dose radiotherapy, as was once administered for tinea capitis, or after high-dose radiotherapy for head and neck malignancies. In both instances, long delays of more than 10 years occur between the administration of radiotherapy and meningioma occurrence and, not infrequently, multifocal tumors develop.²⁴^–²⁸

Apart from various triggering factors from trauma to radiation, there are enough data to accept that meningiomas occur due to gene-related alterations. Meningiomas were one of the first solid tumors in humans to be shown to have consistent chromosomal abnormalities. The first confirmed tumor-associated gene in meningioma is the NF2 gene located on chromosome 22q and 60% of sporadic meningiomas exhibit either mutations in NF2 or deletions in 22q.²⁹ Deletions of the short arm of chromosome 1 are the second most frequent alteration detected on cytogenetic analysis of meningiomas, and abnormalities in other chromosomes and genes have also been implicated.^12,^30,³¹ Sporadic, NF2-associated, pediatric, and radiation-induced meningiomas all potentially having various genetic differences suggest that research on multiple meningiomas apart from those with NF2 can contribute to meningioma tumorigenesis and development.¹² Current data indicate that meningioma initiation is closely linked to the inactivation of one or more members of the highly conserved protein 4.1 superfamily, including the neurofibromatosis type 2 gene product merlin/schwannomin, protein 4.IB (DAL-1) and protein 4.1R.³² Based on the cytogenetic and molecular genetic analyses on meningiomas, two mechanisms can be speculated for the development of multiple meningiomas. Either the tumors arise independently, or originate from a clonal population of common abnormal cells that then spread to other anatomic sites during their development.^12,³³ Polyclonal origin is supported by the findings that reveal different histologic subtypes and karyotypes in the same patient.³⁴^–³⁶ On the other hand, convincing data also exist on monoclonal origin of multiple meningiomas. Stangl and colleagues,² in their study on 12 cases of non-NF2 multiple meningioma cases, have demonstrated a majority of multiple meningiomas with NF2 gene mutations are of somatic and clonal origin; thus spread of tumor cells via cerebrospinal fluid is the most likely mechanism to account for the development of multiple meningiomas. Larson and colleagues,³³ using polymerase chain reaction assays to detect the pattern of X chromosome inactivation, demonstrated 15 tumors resected in 4 patients with multiple meningiomas showed inactivation of the same X chromosome, suggesting that tumors arose from the same clone of cells.

However, it is not yet possible to attribute the occurrence of multiple meningiomas to random inactivation, expression, loss, or mutation of specific genes or spreading after they originate from a clone of common abnormal cells. It is also possible that poli- and monoclonality are both valid for subtypes that are yet elusive to contemporary diagnostic and cytogenetic protocols. Nevertheless, multiple meningiomas present an invaluable opportunity to investigate the complex mechanism of tumor origin and spread in the central nervous system.

PRESENTATION

Before the introduction of modern neuroimaging technology, the incidence of multiple meningiomas was less than 2% in large series (Table 49-1). Most of the cases presented with signs and symptoms of a single intracranial tumor, due to the localization and the size, while the meningioma diagnosis would rely on the impression of the surgeon during surgery and finally on the histopathologic examination. Within these circumstances, multiplicity would be a concern only if associated meningiomas occurred in the vicinity of the primary tumor identified by the neurosurgeon. This scenario before the CT and MR era had several drawbacks. The reported incidence would be less than the actual, as “incidental” cases would be excluded. Those with locations distant from the primary symptomatic meningioma would also be elusive, as well demonstrated by Wood and colleagues³⁷ in their 1957 monograph in which they reported a 16% incidence at autopsy. The lack of appropriate diagnosis from the beginning provoked another debate. Those detected within the vicinity after initial resection raise the question of recurrence, regrowth, or seeding versus unidentified multiplicity at the beginning. These speculations were resolved with modern neuroimaging; consecutive utilization of CT and MR in diagnosis brought the incidence of multiplicity to 20% in a recent series.² Besides detection potential, MR especially enables better differentiation of meningiomatosis and NF2-associated disease from true multiple meningiomas.

TABLE 49-1 Reported incidence of multiple meningiomas in selected series

The clinical presentation of meningiomas, as in all intracranial tumors, is dependent on tumor location. As with all slow-growing tumors, symptoms are usually subtle in nature and assumed to be long standing before a final diagnosis. Traditionally, a number of topographic anatomical tumor syndromes have been defined not necessarily specific to meningiomas.³⁸ Review of the major published series on multiple meningiomas, most of them belonging to the CT era, do not distinguish any specific pathognomic features similar to single meningioma series.^1,^4,^34,³⁹ Most of the symptoms belong to a single meningioma specific to its’ size or localization rather than multiplicity. At present, easy access to highly specific noninvasive neuroimaging makes it possible to detect intracranial slow-growing masses such as meningiomas well before any long-lasting symptoms appear, unless focal symptoms such as seizure, diplopia, or tinnitus are the initial complaint. In this context, future series most probably will have much higher rates of both single or multiple meningiomas incidentally detected, compared to present series. Comparison of published patient data of meningioma series with multiple meningiomas reveals two major discrepancies. Multiple meningiomas are more common in females, and this predominance seems to be greater in multiple meningiomas than in meningiomas in general.⁷ Second, average age at presentation is younger in multiple meningioma cases.^1,^5,³⁹ This might be suggestive for both indication of different genetic background of multiplicity, or simply unrecognized NF2 cases, misinterpreted as spontaneous meningiomas.