Encyclopedia
Please note this is a comparison between Version 1 by Maria Caffo and Version 2 by Camila Xu.
Meningiomas are extra-axial, slow-growing, and (usually) benign tumors. These tumors arise from meningothelial cells of the arachnoid layer, so they can be encountered anywhere this type of cell is localized.
- biomarkers
- genetics
- meningioma
- molecular therapy
1. Introduction
Meningiomas are the most frequent histotype of tumors of the central nervous system (CNS). Their incidence is approximately 35% of all primary brain tumors and approximately 50% of all benign cerebral tumors [1]. These neoplasms are classified into three grades according to the World Health Organization (WHO) [2]. Commonly, patients with meningioma may present with headache, onset of critical episodes, altered mental status, speech impairment, strength impairment, and cranial nerve deficits. The neurological signs are clearly related to the site of the lesion. Initial treatment involves observation and surgical treatment, while radiotherapy and radiosurgery should be considered in cases of atypical and anaplastic meningioma. The site of the lesion as well as close proximity to vital structures can cause complications during surgical procedures. The treatment of recurrent tumors includes radiotherapy and repeated surgery. Some histotypes, despite surgical removal, show an aggressive trend with an early tendency toward recurrence.
2. Meningiomas
Meningiomas are extra-axial, slow-growing, and (usually) benign tumors. These tumors arise from meningothelial cells of the arachnoid layer, so they can be encountered anywhere this type of cell is localized. The most common locations (which make up about 50% of cases) are para-sagittal (28.8%), convexity (15.2%) and tuberculum sellae (12.8%). According to the statistical USA report by Ostrom et al. [1], meningiomas represent 36.6% of all primary CNS tumors and 53.2% of non-malignant primary CNS tumors. Although they have the reputation of benign lesions, meningiomas are often associated with a decreased quality of life (QoL) due to focal neurological deficits that may be related, and in 20% of cases, they display an aggressive behavior, even when the best standard of care is provided [3]. Meningiomas are most common in the elderly population (the median age at diagnosis is 66 years [1], and the occurrence risk increases with age) and have a female preponderance (1.8:1) [4]; however, grades II and III occur more often in males [5]. Only 1.5% of meningiomas occur in childhood or adolescence, and about 30% of these have an intra-ventricular localization [4]. Overall 5-year survival varies with age between 97% and 87.3% for non-malignant cases and between 85 and 50.2% for the malignant meningiomas [6]. Meningioma is considered a single type in the WHO CNS, and its broad morphological spectrum is reflected in 15 subtypes [2]. It is now emphasized that the criteria defining atypical or anaplastic (i.e., grade 2 and 3) meningioma should be applied regardless of the underlying subtype. As in prior classifications, chordoid and clear cell meningioma are noted to have a higher likelihood of recurrence than the average CNS WHO grade 1 meningioma and have hence been assigned to CNS WHO grade 2; however, larger and prospective studies would be helpful to validate these suggested CNS WHO grade 2 assignments and to suggest additional prognostic biomarkers. While papillary and rhabdoid features are often seen in combination with other aggressive features, more recent studies suggest that the grading of these tumors should not be carried out on the basis of rhabdoid cytology or papillary architecture alone. Several molecular biomarkers are associated with classification and grading of meningiomas, including SMARCE1 (clear cell subtype), BAP1 (rhabdoid and papillary subtypes), KLF4/TRAF (secretory subtype), TERT promoter mutation and/or homozygous deletion of CDKN2A/B (WHO grade 3), H3K27me3 loss of nuclear expression (potentially worse prognosis), and methylome profiling (prognostic subtyping) [7][8][9][10][11][7,8,9,10,11]. In meningiomas with a high risk of recurrence, meningiomas with a high proliferation index may be included, characterized by frequent mitotic figures and recurrence even after an apparently total removal, as well as particular subtypes of meningiomas such as atypical or rhabdoid meningiomas [4].
2.1. Risk Factors
The onset of meningiomas can be linked to environmental factors such as ionizing radiation. Ionizing radiation is the only established environmental risk factor, with higher risk in patients who have undergone radiation therapy [4]. It seems there is a genetic susceptibility to the development of radiation-induced meningiomas [12]. Numerous studies searching for the correlation between meningiomas and environmental factors (e.g., hormonal influence, diet, allergies, or phone use) have been conducted, but none with statistically significant results. Meningiomas occur with greater frequency in patients with germline mutations of genes such as type-2 neurofibromatosis (NF2) [13], type-1 neurofibromatosis (NF1, 19–24% of adolescent meningiomas) [4], type-1 multiple endocrine neoplasia (MEN1) [14], SMARCB1, LZTR1, or SMARCE1 genes [5].
2.2. Diagnosis
The gold standard for diagnosis and surveillance of meningiomas is magnetic resonance imaging (MRI). In MRI sequences, meningiomas appear as well-circumscribed and dural-based lesions, isointense to gray matter on non-contrast sequences, and homogeneously enhanced with gadolinium. Meningiomas may or not be associated with brain edema. A common but non-pathognomonic finding, especially in benign lesions, is the so-called dural tail: an enhancement of the dura due to a thickening of the dural layer adjacent to the mass. Moreover, MRI is very accurate in predicting venous sinus involvement (accuracy of about 90%) [15]. Meningiomas are usually single lesions. However, sometimes multiple lesions may suggest a genetic syndrome (e.g., NF2) or the presence of metastases. Other possible diseases to keep in consideration in differential diagnosis are [4][16][4,16]: pleomorphic xanthoastrocytoma which tend to be peripherally located and may have dural tail, dural metastases, gliosarcoma, Rosai-Dorfman disease, a connective tissue disorder with sinus histiocytosis, massive painless lymphadenopathy and dural based enhancing masses with characteristics similar to meningioma.
3. Treatment
3.1. Surgery
While radiological surveillance may be an acceptable strategy for many patients who present with asymptomatic incidental meningiomas [17], for growing and symptomatic tumors the standard of care remains maximal safe surgical resection. Surgical treatment allows for the removal of the lesion and, consequently, of the bulking effect; clinically, the improvement of neurological functions and the resolution of seizures can be seen [18][19][18,19]. In meningioma surgery, the optimal goal is, whenever safely possible, the complete removal of the lesion and affected tissue. This minimizes neurological morbidity and allows for greater long-term control. Surgical treatment also makes it possible to obtain the correct histological diagnosis. Minimally invasive neurosurgery refers to the technological advances made in improving surgical access, thereby enabling neurosurgeons to reduce morbidity and greatly improve the precision of neurosurgical procedures. The introduction of the operating microscope and advances in neuroendoscopy have allowed for the refinement of lighting and the magnification of deep structures [20]. The use of micro-tools allows for the fine dissection of the neoplastic lesion from the nerves and vascular structures. Furthermore, advances in surgical neuronavigation and neuromonitoring allow, during the surgical approach, for minimum brain retraction, as well as the ability to highlight ischemic alterations and pressure variations in eloquent areas. In any case, surgical removal is limited by various factors, such as the location of the tumor and the incorporation within the lesion of nerves, venous sinuses, veins, and arteries. Simpson’s grading scale (Table 1) correlates to the extent of tumor resection, associated dural attachments, and any hyperostotic bone to local recurrence risk and five defined grades of resection, which are associated with distinct rates of recurrence [21].Table 1.
The Simpson Grade.
| Simpson Grade | Description |
|---|---|
| Grade 1 | Macroscopically complete tumor resection including removal of affected dura and underlying bone |
| Grade 2 | Macroscopically complete tumor resection with coagulation of affected dura |
| Grade 3 | Macroscopically complete tumor resection without removal of affected dura and underlying bone |
| Grade 4 | Incomplete excision, subtotal tumor resection |
| Grade 5 | Decompression with or without biopsy |
3.2. Radiation Therapy
Radiation therapy (RT) has commonly been utilized following subtotal resection surgery as an adjuvant therapy for recurrence of previously resected WHO grade II or grade III meningiomas [23]. Radiation therapy is individualized and must be chosen depending on meningioma size, proximity to critical structures, and any prior radiation to the same site. The goal of RT is to reduce meningioma’s proliferation and control its progress. Stereotactic radiotherapy (SRT) is defined as a method of external beam radiotherapy, in which a defined target volume is treated with a high radiation dose in up to 12 fractions, delivered on separate days of treatment. By means of SRT technology, it is possible to irradiate a specific target with a high dose in a single time; the dose of radiation absorbed outside the target area is inversely proportional to the distance from it, and the peripheral tissues around the focus are not damaged. Stereotactic radiosurgery (SRS) is the precise, single-session delivery of a therapeutically effective radiation dose to a certain target. SRS utilizes a single fraction of high-dose radiation but is associated with peculiar toxicities such as radiation-induced brain necrosis or intralesional hemorrhage [24]. Gamma knife radiosurgery (also known as stereotactic radiosurgery) focuses many tiny beams of radiation with extreme accuracy on a target. Each beam has very little effect on the brain tissue it passes through. Fractional stereotactic radiation therapy (FSRT) is administered over the course of several days, rather than in a single dose, reducing the dose exposure to normal brain tissue. SRS was developed by combining radiotherapy and stereotaxis. SRS is a widely accepted technique for small grade I or II lesions, while EBRT is recommended for grade III meningiomas, which require larger doses (50–60 Gy) to achieve local control [25][26][25,26]. Single-fraction SRS is typically used in meningiomas with a maximum diameter of <3 cm, located more than 3 mm from radiosensitive structures [27]. Although surgery remains the primary option, radiotherapy has become a first-line option for some meningiomas, particularly lesions of the cranial base that enclose vascular-nerve structures such as the optic nerve sheath or the cavernous sinus. Radiation therapy and fractional and hypofractionated stereotaxic radiosurgery, in single or multiple doses, have been shown to be beneficial for patients with a high rate of tumor control ranging from 85 to 100% at 5 years [28]. Side effects of stereotaxic radiotherapy for small tumors are mild [29][30][29,30], but cases of radionecrosis have been reported, and pituitary function should also be monitored after skull-base irradiation [31]. A long-term study of 290 consecutive patients showed progression-free control rates of 88.7 and 87.2% at 10 years and 20 years at follow-up, respectively, with adverse radiation effects in 3.1% of patients [32]. With the advent of SRS, surgical goals may be modified with plans for less-aggressive surgical resections, with the knowledge that radiosurgery offers an excellent option for long-term management of incompletely resected meningiomas. This aspect is particularly recommended for large meningiomas in surgically inaccessible locations. Such lesions may require pre-surgical planning for subtotal surgical resections, with planned adjuvant gamma knife radiosurgery to treat residual tumor due to its capacity to provide excellent long-term control of tumor growth while minimizing injury associated with tumor removal.3.3. Chemotherapy
At long-term follow-up, up to 60% of meningiomas can recur after 15 years and exhibit aggressive behavior. RTOG 0539, a phase II trial that stratified meningioma risk based on pathologic grade and extent of resection, outlines options for postoperative management [33]. In RTOG 0539, meningiomas were stratified as follows: low risk—grade I and gross total resection (GTR) or subtotal resection (STR); intermediate risk—recurrent grade I or grade II after GTR; and high risk—STR or recurrent grade II and any grade III. Low-risk tumors demonstrated a progression-free survival (PFS) at 3 years of 92%, intermediate risk PFS of 94%, and high-risk PFS of 59% [34]. Due to their limited effectiveness, systemic therapies should be considered once all surgical and radiotherapy possibilities have been excluded and should be planned on an individual basis. There is little evidence in the literature to support systemic therapeutic treatment, and numerous clinical trials and case series have shown that chemotherapy has a minimal role and does not improve patients’ outcomes [35][36][35,36]. A major problem in interpreting the published literature on medical therapies for recurrent meningioma is the inclusion of different histology in reports of patients at various stages of their disease, ranging from newly diagnosed tumors to tumors that have relapsed after multiple surgeries and radiotherapy treatments and, in some cases, multiple chemotherapy regimens. Classic chemotherapeutic agents, including temozolomide, irinotecan, doxorubicin, ifosfamide, adriamycin, and vincristine, have not been shown to be effective against meningiomas [37][38][37,38]. Hydroxyurea, a ribonucleotide reductase inhibitor, can induce apoptosis and cell cycle arrest in the S-phase. An Italian randomized study showed the association between hydroxyurea, with or without imatinib, and recurrent or progressive meningiomas without, however, reaching conclusive data due to the small number of patients enrolled [39]. Hydroxyurea has shown stabilizing activity in only a few cases, but this has not been fully confirmed. It can be considered another adjuvant tool for atypical meningiomas if postoperative adjuvant radiotherapy cannot be applied. A recent study suggested that adjuvant treatment after STR of atypical meningiomas correlates with a longer PFS than conservative treatment and that there are no significant differences in PFS between hydroxyurea chemotherapy and radiotherapy after surgery [40]. In addition, hydroxyurea chemotherapy was shown to be effective in a retrospective study that analyzed 19 patients with atypical meningiomas. These were treated with hydroxyurea after GKR. The results of the present study suggest the safety and efficacy of HU after GKR with stabilization or shrinkage of atypical (grade II) meningiomas [41]. The possibility of systemic treatment as adjuvant therapy after surgery was also evaluated in a prospective study that enrolled 14 patients with malignant meningioma. After surgery and 2–4 weeks of radiotherapy (median dose 60 Gy), all patients were treated with cyclophosphamide, Adriamycin, and vincristine. This approach demonstrated moderate efficacy with partial response and disease stability in 3 and 11 patients, respectively, resulting in a median overall survival of 5.3 years and progression-free survival of 4.6 years [42].4. Genetic and Biomarkers for Meningiomas
In the past years, thanks to new technologies in genomics, knowledge of genetic factors underlying the development of meningiomas has been significantly improved. With the identification of neurofibromin 2 (NF2) located on 22q12.2 (NF2 codes for the Merlin protein, which shows tumor suppressor properties) and the high percentage of patients (about 50–75%) with NF2 who develop one or more meningiomas, meningiomas represent one of the first types of tumors linked to a genomic driver [14]. Recently, thanks to the advent of next-generation sequencing (NGS), numerous additional somatic mutations have been identified (Table 2), and this has promising implications for new frontiers in target therapy. For this reason, to date, the mutational landscape can be divided into NF2-mutated (approximately 40–60% of cases) and non-NF2-mutated meningioma [43]. Among the non-NF2-mutated group, the most common oncogene in WHO grade I meningiomas is TNF receptor-activated factor 7 (TRAF7), located on chromosome 16p13 (mutated in nearly 25% of all meningiomas), followed by the mutation in codon K409Q of KLF4 (encountered in about 15% of benign meningiomas) [44][45][44,45]. The mutation of TRAF 7 is frequently associated with mutations of AKT1 (which encodes for a kinase that regulates cell proliferation) or KLF4, and this combination is often linked to grade 1 meningiomas [44][45][44,45]. AKT1 mutation occurs at the E17 location, triggering activation of the mTOR and ERK1/2 pathways. The AKT1 p.Glu 17 Lys mutation triggers the abnormal activation of the PI3K pathway, indicating a key role in meningiomas proliferation [46]. POLR2A mutant tumors show dysregulation of key meningeal identity genes, including WNT6 and ZIC1/ZIC4 [47]. Still, smoothened mutations (SMOs) trigger the Sonic Hedgehog signaling pathway promoting angiogenesis and tumor progression [48]. Mutations in Krüppel-like factor 4 (KLF4), a transcription factor in oncogenic activation, have been detected in about 50% of NF2-nonmutated meningiomas [45][49][45,49]. As shown in Table 1, in 20% of cases, the oncogenic mutations remain unclear. Notably, mutations of these genes in meningiomas occur to a large degree without concurrent alteration of NF2 or loss of chromosome 22 [50]. Other rarer mutations include SWI/SNF-related matrix-associated actin-dependent regulator of chromatin, subfamily B member 1 (SMARCB1), SMARCE1, and SUFU genes [51][52][53][51,52,53]. SMARCB1 mutation has also been shown to co-occur in NF2-mutated meningiomas [47]. In higher grade meningiomas, other genomic alterations with independent prognostic value have been reported, namely mutation of TERT promoter and deletions of CDKN2A/B [54][55][54,55]. The CDKN2A and BAP1 mutation seem to be associated with aggressive forms of meningioma [8][56][8,56], while the SMASRCE1 mutation is attributable to the onset of spinal meningiomas [52].Table 2.
Most common mutations in WHO grade I meningiomas.
| Mutation | Co-Occurring Mutations |
|---|---|
| NF2 | SMARCB1 |
| TRAF 7 | AKT1 or KLF4 or PIK3CA |
| AKT1 | / |
| POLR2A | / |
| SMARCB1 | / |
| KLF4 | / |
| SMO | / |
| PIK3CA | / |
| Unknown (20% of cases) | / |
Mutations of TRAF 7 can overlap with AKT1, KLF4, and PIK3CA, but these last cannot overlap with each other; NF2: neurofibromin 2; TRAF 7: TNF receptor-associated factor 7 (a pro-apoptotic E3 ubiquitin ligase TNF receptor-associated factor 7); KLF4: Kruppel-like factor 4 (a pluripotency transcription factor); AKT1: v-Akt murine thymoma viral oncogene homolog 1 (a proto-oncogene); SMO: smoothened (a Hedgehog pathway signaling member); PIK3CA: oncogene.
It has recently been hypothesized that the mutations and the direct molecular pathways activated in the processes of tumorigenesis could be related to their embryological cells of origin and, therefore, to the tumor site (Table 3) [44][47][57][44,47,57]. Okano et al. demonstrated that NF-2 mutant tumors originate from neural crest-derived arachnoid cells, while non-NF-2 tumors stem from the dorsal and paraxial mesoderm [58]. AKT1 mutations are demonstrable in anterior skull-base and convexity meningiomas, while SMO mutations are found in anterior skull-base meningiomas [44]. NF2 mutations are frequent in intraventricular meningiomas [59]. A large genetic analysis found high rates of NF-2 and POLR2A alterations in posterior fossa meningiomas [60].
Table 3.
Biomarkers of meningiomas, tumor location, WHO grades, and targeted therapies.
| Tumor Location | WHO Grade | Associated Mutations | Target Therapies |
|---|---|---|---|
| Convexity | I–III | 22q, NF2, H3K27me3, SSTR2, BAP1, TERTp, CDKN2A/B, VEGFR | Sunitinib (22q), Everolimus-octreotide (SSTR2), Bevacizumab (VEGFR) |
| Anterior Skull Base | I–III | AKT1, PIK3CA, SMO, TRAF7 | Everolimus-octreotide (SSTR2, AKT1, PI3K), Bevacizumab (VEGFR) |
| Central Skull Base | I | AKT1, PIK3CA, SMO, SUFU, TRAF7, H3K27me3, SSTR2, BAP1, TERTp, CDKN2A/B | Everolimus-octreotide (SSTR2, AKT1, PI3K), Bevacizumab (VEGFR) |
| Other Localizations | I–III | KLF-4, H3K27me3, SSTR2, TERTp, CDKN2A/B, BAP1, POLR2A | Everolimus-octreotide (SSTR2), Bevacizumab (VEGFR) |
| Spinal Meningiomas | I–III | 22q, NF2, SMARCE1, H3K27me3, SSTR2, BAP1, TERTp, CDKN2A/B, VEGFR | Sunitinib (22q), Everolimus-octreotide (SSTR2), Bevacizumab (VEGFR) |
NF2: Neurofibromin 2; H3K27me3: Trimethylation of lysine 27 on histone 3; SSTR2: Somatostatin receptor 2; BAP1: BRCA1-associated protein 1; TERTp: Telomerase reverse transcriptase promoter; CDKN2A/B: cyclin-dependent kinase inhibitor 2A/B; VEGFR: Vascular endothelial growth factor receptor; AKT1: Protein kinase B; PIK3CA: Phosphatidylinositol4,5-bisphosphate 3-kinase catalytic subunit alpha isoform; SMO: Smoothened; TRAF7: Tumor necrosis factor receptor associated factor 7; SUFU: Suppressor of fused homolog; KLF4: Krüppel-like factor 4; POLR2A: RNA polymerase II; TERT: Telomerase reverse transcriptase; SMARCE1: SWI/SNF Related, matrix associated, actin dependent regulator of chromatin, subfamily E, member 1.
In the few last decades, the genetic characteristics of meningiomas have become the target of investigation, and a large number of studies have focused on finding genes and biomarkers useful for predicting recurrence risk, malignant potential, and responsiveness to therapies. Tumor genomics has become a hot point in recent years because of the possibility of providing personalized and targeted therapies to patients. In 2016, the fourth edition of the WHO classification of CNS tumors [2] first used the molecular characteristics as parameters to diagnose this type of tumors, but only in 2021, with the fifth edition, did the WHO classification also introduce this parameter for meningiomas [2]. For example, secretory meningiomas (WHO grade 1) can be diagnosed not only for histological features, but also for the detection of the mutation of KLF4/TRAF 7 [2][23][2,23]. In clear cell meningioma, (WHO grade II) mutations of SMARCE1 occur frequently [7][61][7,61]. Moreover, according to the fifth edition, any meningioma with TERT promoter mutation and/or CDKN2A/B homozygous deletion is considered grade 3 [2][23][2,23]. In 2021, Nassiri et al. [62], by combining molecular characteristics, identified four groups of meningiomas: immunogenic type (MG1), benign NF2 wild-type (MG2), hypermetabolic type (MG3), proliferative type (MG4). The important aspect is that these four molecular groups seem to be able to predict clinical outcomes in a more accurate way (compared with already-existing classification schemes). Some key molecular alterations that could impact clinical management of patients with meningioma are [63] copy number alterations (CNAs), which determine alterations to the relations between oncogene and tumor suppressor activity, including: loss of chromosomes 22q, 1p, 14q, and 18q; mutations of genes NF2, TERTp, AKT1, PIK3CA, SMO, SUFU, TRAF7, KLF4, SMARCE1, BRCA1-associated protein 1 (BAP 1), Duchenne muscular dystrophy gene (DMD), PBRM1, POLR2A, and CDKN2A/B; homozygous deletions; epigenomic alterations; H3K27me3 alterations; TIMP3 methylation; and TP73 promoter (TP73p) methylation.
