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]. 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].

In cases of partial occlusion of a venous sinus, the tumor component is not removed due to the high risk of hemorrhage, thrombosis, and gas embolism. Removal of meningiomas at the base of the skull, due to their relationship to bony anatomy (sphenoid wing, olfactory sulcus, saddle tubercle, ponto-cerebellar angle, or petroclival region) or those involving blood vessels and cranial nerves are at higher risk and require more advanced surgical techniques in order to minimize brain retraction and protect neurovascular structures [22]. Several midline anterior skull-base tumors are resected via an endoscopic endonasal approach. The advantages of this approach are the visualization of the ventral side of the deep skull-base tumor and safer resection which avoids traction of the brain tissue during the operation.

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]. 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], 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.

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]. 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]. 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].

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]. 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]. 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]. 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]. 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]. The CDKN2A and BAP1 mutation seem to be associated with aggressive forms of meningioma [8,56], while the SMASRCE1 mutation is attributable to the onset of spinal meningiomas [52].

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]. 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].

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]. In clear cell meningioma, (WHO grade II) mutations of SMARCE1 occur frequently [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]. 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.

Currently, the most widely used pharmacological compounds in the treatment of high-grade and recurrent meningiomas or in cases in which surgical and/or radiotherapy treatment are found to be ineffective are anti-VEGF molecules and mTOR inhibitors. The expression of VEGF has been frequently associated with the grade of meningiomas and with their different histological types, but, to date, the information gathered to support this hypothesis appears to be conflicting. VEGF acts as a major vascular permeability factor and as a mitogen/survival promoter for endothelial cells and plays a key role in the formation of peritumoral edema [64]. Yamasaki et al. demonstrated that high levels of VEGF expression were significantly associated with tumor recurrence, suggesting that this factor is one of the main predictors of recurrence [65]. Sakuma et al. found evidence that VEGF expression was linked to development of peritumoral edema and to histological grade [66]. On the other hand, Barresi showed the absence of correlation between VEGF expression and WHO tumor grade [67]. Baxter et al. did not report any significant relationship, in 175 patients, between VEGF expression and histological meningioma grade [68]. In other studies, similarly, no significant correlation was found between VEGF expression and histological grade [69,70]. A recent study demonstrated that VEGF should not be used as a marker of severity or histological grade [71]. It is likely that expression of VEGF could be linked to the biomolecular and histologic characteristics of the various tumor subtypes. Since meningiomas are highly vascularized and express growth factors such as VEGF and PDGF, reduced angiogenesis may be useful for treatment.

It has been shown in in vitro meningioma extracts that these induce endothelial chemotaxis and the formation of small capillaries. In addition, VEGF plays an important role in the development of peritumor edema, which contributes to morbidity associated with high-grade meningiomas [72,73]. A phase II clinical trial in 2016 suggests that patients with refractory meningioma could benefit from a combined therapy with bevacizumab (a monoclonal antibody that inhibits binding between VEGF-A and VEGFR) and everolimus [74]. Antibodies to VEGF have been shown to be effective in controlling peritumoral edema and slowing lesion growth compared to other systemic therapies such as cytotoxic chemotherapy, somatostatin analogs, and tyrosine kinase inhibitors [75]. Unfortunately, studies using these targeted therapies alone or in combination in the treatment of meningioma have shown disappointing results [74,76,77]. In some studies using bevacizumab, a slight improvement in PFS was reported in patients with recurrent meningiomas [78,79]. Notably, a systematic review of bevacizumab in recurrent meningioma reports a median PFS of 15.3 months in recurrent atypical meningiomas and 3.7 months in anaplastic meningiomas. Franke et al. [80] suggested the use of bevacizumab only in specific circumstances such as treatment-refractory, high-grade cases, or cases with elevated vascularity; although surgery and radiosurgery represent the first therapeutic strategy for relapsing meningiomas, bevacizumab can delay relapse and thus can also serve as a potential neoadjuvant option to radiotherapy/surgery; patients with symptomatic multiple meningiomas are often difficult to treat due to the complexity of the surgery, the distance between lesions, and the predisposition to relapse. In these cases, resection is typically reserved for the largest symptomatic and surgically accessible lesions; therefore, adjuvant treatment such as radiotherapy/radiosurgery or chemotherapy (bevacizumab) may be potential options for patients with multiple meningiomas and radiation-induced meningiomas.

Sunitinib, unlike the previous single-target therapies, is a small-molecule kinase that inhibits different targets, such as VEGFR, PDGFR, FMS-like tyrosine kinase, KIT, CSF1R (macrophage colony-stimulating factor-1 receptor) and RET (a proto-oncogene), and most of them are highly represented in meningiomas. In 2015, a prospective and multicentric phase II trial [76] for recurrent and progressive atypical/anaplastic meningiomas was conducted. The authors concluded that sunitinib is active in recurrent atypical/malignant meningioma patients and suggested performing a randomized trial for a better evaluation of this molecule. In particular, an improvement in PFS of 42% at 6 months was observed compared to PFS of 5–30% at 6 months reported in the natural history. The limit is toxicity, with 60% of patients experiencing grade 3 toxicities, 32% of patients requiring dose reduction, and 22% of patients being removed from the study. Toxicities included CNS hemorrhage, GI symptoms, and anorexia [76].

mTOR is a protein kinase that forms the core of two proteins, mTORC1 and mTORC2. Both proteins possess regulatory activity on cell metabolism, growth and survival, and autophagic mechanisms [81]. The mTOR protein complex is an integral part of the PI3K complex, a pathway linked to the development of meningiomas. In an experimental study, the effects of the mTOR inhibitors sirolimus and tensirolimus were evaluated. Both inhibited the activity of mTORC1 and managed to decrease the viability and proliferation of neoplastic cells [82]. A recent clinical trial (CEVOREM) tested a combination of mTOR inhibitor everolimus and the somatostatin agonist octreotide on aggressive meningiomas. The results demonstrated an increase in PFS6 and a reduction in growth rate [83]. Interestingly, a reduction in the tumor growth rate (78% of patients) and an improvement in PFS at six months were observed. Other ongoing clinical trials (NCT03071874, NCT02831257) are evaluating the inhibitory activity of vistusertib against mTORC1 and MTORC2 [50]. Given their promising results, larger prospective phase III randomized clinical studies should be performed to draw conclusions about the role of this treatment in the context of meningiomas of different grades.

The expression of EGFR seems to be higher in low-grade meningiomas, but it is still unclear what the relation is between its expression and clinical prognosis [84]. The role of EGFR inhibitors in meningiomas is unclear. Some studies, however, have tried to evaluate the effects of EGFR inhibitor (e.g., gefitinib, erlotinib, or lapatinib [36,85]), but further randomized controlled trials should be carried out [63]. Erlotinib and gefitinib are small-molecule EGFR kinase inhibitors that have been investigated in phase II studies for recurrent meningioma. Although these treatments were well tolerated, neither gefitinib nor erlotinib appear to have significant activity in improving the PFS or overall survival of the patients analyzed [36]. Similarly, in a phase II study of imatinib, a small-molecule kinase inhibitor of the PDGF receptor, the imatinib was well tolerated but had no significant activity in recurrent meningiomas [86].

Evaluation of multi-targeted inhibitors and EGFR inhibitors in combination with other targeted molecular agents may be warranted. A phase II clinical trial of vatalanib (PTK787), a VEGFR and PDGFR inhibitor, was conducted by enrolling 25 patients with grade I, II, and III meningioma [77]. Each treatment cycle was 4 weeks with an MRI conducted every 8 weeks. On average, four cycles of PTK787 were administered to each patient. Vatalanib was safe, and minor toxicities including fatigue, hypertension and elevated transaminases were reported. Patients with atypical meningioma had progression-free survival (PFS) of 64.3%, median PFS of 6.5 months, and overall survival (OS) of 26 months; patients with malignant meningioma had PFS of 37.5%, median PFS of 3.6 months, and OS of 23 months [78]. It has been shown that NF2 mutant tumor cells interact with FAK inhibition. For this reason, a recent experimental study (NCT02523014) using GSK2256098 [87], a FAK inhibitor, in patients with NF2 mutant meningiomas, is now under evaluation [88].

5. Other Medical Treatments

5.1. Estrogen and Progesterone Receptor Antagonists

5.2. Interferon-Alpha

5.3. Somatostatin Receptors

5.4. Immunotherapy

5.5. MicroRNAs