Introductory Chapter: Meningioma – The Essentials from Bench to Bedside

Abstract

Meningiomas arising from the meningeal layers are the most prevalent primary central nervous system (CNS) tumors.[1] These lesions comprise more than 35% of CNS tumors and present a complex and enigmatic challenge in the field of neurosurgery. These tumors are characterized by their slow growth, variable clinical manifestations, and intricate histopathological features. First identified by Rudolf Virchow in the 19th century, meningiomas have since been the subject of extensive research and clinical scrutiny, leading to a deeper understanding of their biology, classification, and therapeutic approaches.[2] The incidence of meningiomas is reported to be 1.8 to 13 per 100,000 persons per year, with more than 170,000 affected individuals in the United States.[4, 5] Accurate diagnosis of meningiomas relies on a combination of clinical evaluation, neuroimaging studies, and histopathological examination. Magnetic Resonance Imaging (MRI) is the modality of choice for the assessment of meningiomas. The therapeutic approach to meningiomas is guided by several factors, including tumor size, location, histological grade, patient age, and comorbidities, as well as the presence of symptoms and neurological deficits. Treatment modalities for meningiomas include observation, surgical resection, radiation therapy, and, rarely, systemic therapy.

1. Introduction

Meningiomas arising from the meningeal layers are the most prevalent primary central nervous system (CNS) tumors [1]. These lesions comprise more than 35% of CNS tumors and present a complex and enigmatic challenge in the field of neurosurgery. These tumors are characterized by their slow growth, variable clinical manifestations, and intricate histopathological features. First identified by Rudolf Virchow in the nineteenth century, meningiomas have since been the subject of extensive research and clinical scrutiny, leading to a deeper understanding of their biology, classification, and therapeutic approaches [2].

2. Epidemiology

Meningiomas constitute a substantial portion of primary brain tumors, accounting for approximately 36% of all cases [3]. The incidence of meningiomas is reported to be 1.8 to 13 per 100,000 persons per year, with more than 170,000 affected individuals in the United States [4, 5]. Although they can occur at any age, meningiomas are most frequently diagnosed in older individuals, with a median age of 66 at diagnosis [1, 6, 7]. Meningiomas occurrence has demonstrated a predilection for females as they are affected nearly twice as often as males [1]. It should be noted that this gender predilection observed in meningioma incidence has been shown to be age-dependent, as the rates are more comparable in younger ages. The reasons behind the female predominance remain an area of investigation, with hormonal influences and genetic factors being considered as potential contributors. Despite the predominance of sporadic cases, familial predisposition has been identified in a subset of meningiomas [8].

3. Etiology and risk factors

The etiology of meningiomas, though not fully elucidated, represents a complex interplay of genetic, hormonal, and environmental factors. While the majority of meningiomas are sporadic, emerging evidence points to specific genetic mutations and hereditary syndromes that contribute to their development. Investigating the etiological underpinnings of meningiomas is vital for unraveling the molecular mechanisms driving tumorigenesis and guiding targeted therapeutic interventions.

Regarding genetic predisposition to meningiomas, chromosomal instability emerges as a prominent molecular hallmark influencing tumor recurrence and prognosis in meningiomas [8, 9, 10, 11]. Higher-grade meningiomas, including atypical and anaplastic subtypes, exhibit a more complex cytogenetic profile compared to benign tumors [12, 13, 14]. Sporadic high-grade meningiomas and low-grade tumors progressing to higher grades typically demonstrate a higher number of cytogenetic aberrations, which strongly correlates with the risk of recurrence [12, 13, 14, 15]. Notably, loss of chromosome 22q, housing the NF2 gene (a tumor suppressor gene), is the most common chromosomal abnormality, occurring in a good proportion of meningiomas and increasing with tumor grade [13, 16]. Overall, the evolving malignant biology of meningiomas correlates with increasing chromosomal and genomic abnormalities, underscoring the need for further research into specific mutations to elucidate key tumorigenic events.

Several familial syndromes are associated with an increased risk of meningiomas, shedding light on the genetic underpinnings of these tumors. Neurofibromatosis Type 2 (NF2), as mentioned earlier, has been found to have a strong association with meningioma development. The result of germline mutations of the NF2 gene has been associated with over 50% of patients developing intracranial meningiomas, often earlier in life and more aggressively than sporadic cases [9, 17, 18]. Gorlin Syndrome, associated with mutations in PTCH1, PTCH2, and SUFU genes, increases meningioma risk due to abnormal signaling in the sonic hedgehog pathway [9, 19]. Cowden Syndrome, part of the PTEN (Phosphatase and tensin homolog) hamartoma tumor syndrome (PHTS), results from PTEN mutations and is linked to an 8.25% incidence of meningiomas [19]. Werner Syndrome, an autosomal recessive disorder, significantly elevates meningioma risk due to dysfunctional WRN gene mutations [20]. BAP1 Tumor Predisposition Syndrome, arising from BAP1 mutations, particularly predisposes individuals to aggressive meningiomas [21]. Familial syndromes associated with SMARCB1 and SMARCE1 mutations, impacting the SWI/SNF chromatin remodeling complex, contribute to familial meningiomatosis, with specific mutations correlating with distinct clinical presentations [22]. Additionally, other syndromes such as Gardener, Li-Fraumeni, Turcot, Rubinstein–Taybi syndrome, von Hippel-Lindau, and multiple endocrine neoplasia type I have been related to the development of meningiomas.

Hormonal influences, particularly estrogen and progesterone, have long been implicated in the development and progression of meningiomas. Studies have shown that meningioma cells often express estrogen and progesterone receptors, suggesting a potential role for these hormones in promoting tumor growth [6]. The observed gender disparity in meningioma incidence, with a higher prevalence in females, further supports the hormonal influence hypothesis. Recent scholars have revealed that the fluctuating hormonal levels during pregnancy and menopause may contribute to the growth of meningiomas [23]. The increased prevalence and growth of meningiomas during reproductive years suggest a potential link between hormonal changes and tumor progression. However, the precise mechanisms by which hormones exert their effects on meningioma cells remain an active area of investigation.

While genetic and hormonal factors play prominent roles in meningioma development, the majority of cases are sporadic. Environmental factors, most importantly radiation exposure, have been associated with an increased risk of meningiomas [8, 24]. Individuals exposed to radiation, either through therapeutic interventions or occupational settings, may exhibit a higher incidence of meningiomas. However, the overall contribution of environmental factors to sporadic meningioma cases remains a subject of ongoing research.

4. Clinical features and pathology

Meningiomas exhibit varied distribution, with common locations being the convexity, parasagittal, spinal, skull base, frontobasal, and sphenoid regions. Grade I tumors tend to occur at the skull base, while higher grades are more prevalent at the convexity, parasagittal, falcine, torcular, and intraventricular regions [22, 25, 26, 27].

The clinical presentation of meningiomas is diverse, ranging from asymptomatic incidental findings to severe neurological deficits [17]. The symptoms of meningiomas are primarily determined by their location and size, with tumors in various regions resulting in a distinct manifestation [28]. Accordingly, intracranial meningiomas commonly present with symptoms related to increased intracranial pressure, such as headaches, nausea, and vomiting [28]. Additionally, focal neurological deficits, seizures, and cognitive impairment may occur, depending on the specific brain regions affected by the tumor. Meningiomas arising from the skull base can manifest with symptoms related to cranial nerve involvement, including visual disturbances, facial numbness, and hearing loss [29, 30]. Spinal meningiomas, though less common, can lead to back pain, radiculopathy, and motor or sensory deficits corresponding to the level of spinal cord involvement [30]. Understanding the diverse clinical presentations is crucial for early detection and timely intervention, optimizing the chances of successful treatment.

The World Health Organization (WHO) classification system categorizes meningiomas into three grades based on their histopathological characteristics, providing valuable insights into their clinical behavior and guiding therapeutic decisions [31].

• Grade I: Representing the majority of cases (around 80–90%), Grade I meningiomas are classified as benign tumors. These tumors typically exhibit slow growth and well-defined borders, making them good candidates for resection with a favorable prognosis. This grade consists of various histopathological subtypes, including Meningothelial, Fibrous, Transitional, Psammomatous, and Angiomatous subtypes.

• Grade II Meningiomas (Atypical Meningiomas): Representing a smaller subset of cases (17%), Grade II meningiomas are characterized by more aggressive features, such as increased mitotic activity and a higher likelihood of recurrence. These tumors pose challenges in terms of management and necessitate a more comprehensive treatment approach. This grade consists of various histopathological subtypes, including Chordoid, Clear Cell, and Atypical subtypes.

• Grade III Meningiomas (Anaplastic Meningiomas): Grade III meningiomas, representing the most malignant subtype with poor prognosis (1.7% of all meningiomas), are characterized by marked cellular atypia, high mitotic activity, and increased vascularity. This grade consists of various histopathological subtypes, including Papillary, Rhabdoid, and Anaplastic subtypes.

5. Diagnosis

Accurate diagnosis of meningiomas relies on a combination of clinical evaluation, neuroimaging studies, and histopathological examination. Magnetic resonance imaging (MRI) is the modality of choice for the assessment of meningiomas, providing detailed information about the tumor’s location, size, and relationship to surrounding structures. On MRI, meningiomas typically appear as well-circumscribed, dural-based, enhancing masses with variable signal intensity on different sequences [31, 32]. Dural tails found on post-contrast imaging of 70% of meningiomas may assist in differentiating these lesions from other extra-axial tumors [32, 33]. Contrast-enhanced computed tomography (CT) scans may also be employed to assess bony involvement and calcifications within the tumor. In addition, cerebral angiography can aid in evaluating the vascular supply to the tumor, particularly in cases where preoperative embolization is considered to reduce intraoperative blood loss [34].

Histopathological examination of biopsy or surgically resected specimens is essential for verification of the diagnosis and determining the tumor grade [35, 36]. Moreover, immunohistochemistry plays a crucial role in differentiating meningiomas from other CNS neoplasms and identifying specific histological subtypes.

6. Treatment

The therapeutic approach to meningiomas is guided by several factors, including tumor size, location, histological grade, patient age, and comorbidities, as well as the presence of symptoms and neurological deficits. Treatment modalities for meningiomas include observation, surgical resection, radiation therapy, and, rarely, systemic therapy.

Observation with serial neuroimaging may be appropriate for asymptomatic, small (<3 cm), and indolent meningiomas, particularly in elderly patients or those with significant comorbidities [37, 38]. Meanwhile, surgical resection remains the treatment of choice for symptomatic, enlarging, or high-grade meningiomas, aiming for maximal safe resection while preserving neurological function and minimizing morbidity [29, 38]. Achieving gross total resection has been associated with a cure in 70–80% of patients [39].

Radiation therapy, including stereotactic radiosurgery (SRS) and fractionated radiotherapy, has been utilized as the primary treatment option for unresectable lesions [35, 38]. Moreover, radiation-based treatments have a mainstay role in the management of residual or recurrent meningiomas. Adjuvant and salvage radiation therapy is reserved for atypical or malignant meningiomas, high-risk histological subtypes, and incompletely resected tumors to improve local control and delay tumor progression [35, 38].

Salvage systemic therapies, including chemotherapy and targeted molecular agents, are used in the treatment of refractory meningiomas [35, 38]. Regardless, limited evidence is available on their efficacy, and no recommendation is given on their use.