Table 1.

Result of systematic review and summary of main data from selected articles.

	Location
Cornelius et al., 2013 [12]	Location not at the skull base and age ≥65 years are significant risk factors for higher WHO grade
Garzon-Muvdi et al., 2020 [5]	Falcine and parasagittal meningiomas associated to chromosomal mutations/structural alteration
Yuzawa et al., 2016 [13] Jungwirth et al., 2019 [14]	Higher frequency of NF2, TRAF7, AKT1, KLF4, SMO, and PI1K3CA mutations Loss of chromosomes 22q (89%) and 1p (44%) and NF2 mutation (44%) in IVMs
Yeung et al., 2021 [15] Terabe et al., 2021 [16]	Immunological microenvironment defines and modulates tumor behavior with prognostic and therapeutic implications
Zador et al., 2020 [17] Kosugi et al., 2019 [18]	Gamma-delta T cells, monocytes, and plasma cells dominant in SBMs Mast cells and neutrophils overexpressed in convexity meningiomas TILs, Treg, HIF-1α, VEGF-A, VEGFRs-1 & 2, TAMs significantly lower in CS
Savardekar et al., 2018 [19]	No differences in PFS, tumor grading and Ki-67 index between SBMs and nSBMs
	Immunogenetics
Al-Rashed, et al., 2020 [20]	Increasing meningioma grade associated with increased VEGF, Ki67, TOP2, PD-1, and PDGFRB Cytostatic mTOR inhibitors promising in controlling tumor growth Inhibition of EZH2 potentially improve outcomes
Goutagny et al., 2010 [21]	NF2 loss associated with chromosome instability Most grade I meningiomas do not progress to a higher grade and are characterized by very few chromosome alterations, mainly isolated 22q loss
Brastianos et al., 2013 [22]	A subset of meningiomas lacking NF2 alterations harbored oncogenic mutations in AKT1 (E17K) and SMO (W535L) These mutations were present in therapeutically challenging SBMs and higher-grade tumors
Strickland et al., 2016 [23]	Mutation rates at high frequency for SMO (11%) and AKT1 (19%) in both WHO Grade I and Grade II anterior skull base meningiomas Genotyping of SMO and AKT1 is likely to be high yield in anterior skull base meningiomas with available surgical tissue
Bi et al., 2016 [24]	Recurrent somatic mutations in NF2, TRAF7, KLF4, AKT1, SMO, and PIK3CA are collectively present in ~80% of sporadic meningiomas The recent identification of AKT1, SMO, and PIK3CA mutations opens the door for targeted pharmacotherapeutics in ~20% of grade I meningiomas.
Hao et al., 2019 [25]	KLF4- and TRAF7-mutated tumors were predominantly secretory skull base meningiomas SMO-mutated tumors exhibited higher calcification, and half of these tumors were observed in the brain midline TRAF7 mutations could play a key role in skull base meningiomas by regulating the expression of inhibitory immune checkpoints and suppressing immune responses
Karimi et al., 2020 [26]	A significantly positive relationship between higher PD-L1 expression and grading is shown PD-L1 expression levels represent an independent prognostic factor to predict tumor recurrence Hypoxia is one of the potential regulatory mechanisms for PD-L1 expression in meningioma
Williams et al., 2019 [27]	A large subset of posterior fossa meningiomas (foramen magnum) harbor AKT1 E17K mutations and are therefore potentially amenable to targeted medical therapy In contrast to AKT1 mutations, SMO or PIK3CA mutations were absent in the posterior fossa
Mei et al., 2017 [28]	OGN contribute to meningioma cell growth through interaction with NF2, AKT, and mTOR OGN downregulate NF2, the canonical tumor suppressor altered in approximately half of meningiomas AKT inhibition reduces OGN protein levels in meningioma cells, with a concomitant increase in cell death
Kerr et al., 2018 [29]	Combining histology, genetics, epigenetics, and clinical findings will provide the best system for classification Increased risk of meningioma: NF2, nevoid basal cell carcinoma syndrome, multiple endocrine neoplasia 1 (MEN1), Cowden syndrome, Werner syndrome, BAP1 tumor predisposition syndrome, Rubinstein-Taybi syndrome, and familial meningiomatosis caused by germline mutations in the SMARCB1 and SMARCE1 genes
	Immunotherapy
Garzon-Muvdi et al., 2020 [5]	Role of VEGF in meningioma pathogenesis, and its expression correlates with tumor grade, peritumoral edema, and necrosis Receptor tyrosine kinase inhibitors that target PDGF and EFG in clinical trial Grade III meningiomas showed increased MDSCs that overexpress PD-L1, corroborating the hypothesis of the systemic immunosuppression Utilization of monoclonal antibodies targeting PD1/PDL1 CAR-T cells show potential effects on immunosuppression in tumor microenvironment Promising clinical trials testing CAR-T therapy, especially for refractory meningiomas
Wen et al., 2010 [30]	Specific chemotherapeutic agents (doxorubicin, irinotecan, vincristine, and temozolomide) not effective in improving PSF for HGMs
Scerrati et al., 2020 [31]	High expression of VEGF is a predictor factor for higher risk recurrence Antiangiogenic agents evaluated with suboptimal results
Garzon-Muvdi et al., 2020 [5] Domingues et al., 2012 [32] Pinton et al., 2018 [33]	Treatment targets on mutations in AK1, PIK3CA, SMO, and NF2 in clinical trials
Garzon-Muvdi et al., 2020 [5] Arasanz et al., 2017 [34]	The use of immunotherapy could become an alternative for HGMs over the limits of the conventional therapy The target is the immunosuppressive microenvironment PD-L1 is expressed on the surface of tumor cells, and it inhibits T-cell activation by binding to the PD-1 receptor on T- and B-cells. It is one of the major mechanisms used by meningiomas to evade the host immune system
Proctor et al., 2019 [8] Flem-Karlsen et al., 2018 [35] Han et al., 2016 [36]	PD-L2 (receptor for PD-1), B7-H3, CTLA-4, and NY-ESO-1 were highly in meningiomas, and in patients who carry genetic mutations in PI3K/AKT/mTOR pathway PD-L2 is overexpressed throughout all meningioma grades, and it has been presumed to play a role as a predictor for immunotherapy response CTLA-4 were highly in patients with carry genetic mutations in PIK3CA or SMO Clinical trials for the use of PD-1 blockade immunotherapy (Nivolumab, Avelumab, Pembrolizumab), comparing with anti-CTLA4 antibody (Ipilimumab)
Thomas et al., 2018 [37]	NY-ESO-1 contributes in both humoral and cellular immune responses apart from tumor grade Promising clinical trials testing NY-ESO-1 base immunotherapies
Giles et al., 2019 [38]	Allogenic NK lymphocytes considered a reasonable alternative for meningiomas
	Immune cells infiltrate
Giles et al., 2019 [38]	NK lymphocyte subtype with antitumoral effect by ADCC killing Their effect is blocked by PD-1/PD-L1 system
Garzon-Muvdi et al., 2020 [5] Proctor et al., 2019 [8] Pinton et al., 2018 [33] Proctor et al., 2019 [8] Han et al., 2016 [36] Rossi et al., 1988 [39]	Higher B7- H3, and PD-L2 l in patients with PI3K/AKT/mTOR pathway mutations Higher CTLA-4 in PIK3CA or SMO mutations. Higher expression of PD-L2 compared to PD-L1 throughout all meningioma grades NY-ESO-1 provokes humoral and cellular immune responses. TAMs represent the largest part of immune infiltrate of meningiomas They are able to polarize into M1 phenotype (anti-tumor, stimulator of immune system, better prognosis) or M2 (pro-tumor, immunosuppressive effect by stimulating PD-L1 expression, promoting meningioma growth and recurrence) Decreased M1:M2 ratio in higher meningiomas with higher recurrence rate, and higher M1:M2 ratio associated with improved PFS
Garzon-Muvdi et al., 2020 [5] Pinton et al., 2018 [33] Proctor et al., 2019 [8] Domingues et al., 2016 [6]	MDSCs, a heterogeneous group of immature myeloid cells, with immunosuppressive activity and most represented in grade 2 or 3 meningiomas Role in promoting vascularization, enhancing PD-L1 and NF2 expression, and tumorigenesis and tumor escaping Newly discovered role in reducing immune activity by blocking CD8+ T cell and NK activation, M1 polarization, tumor antigen presentation to DCs, and inducing M2 switch
Polyzoidis et al., 2015 [9] Reszec et al., 2012 [40] Domingues et al., 2012 [32] Theoharides et al., 2012 [41] Tirakotai et al., 2006 [42] Schober et al., 1988 [43]	MCs important role in cancer promoting Role in producing metalloproteinases and secreting CRH, NT, substance P, tryptase, VEGF, TNF, prostaglandins, leukotrienes, and thus contributing to tumor diffusion and to disruption the integrity of the BBB and stimulating PTBE formation MCs association to recurrence rate and bad prognosis of meningiomas is still debated, and microenvironment of both low and high grade meningiomas contains MCs
Zador et al., 2020 [17] Garzon-Muvdi et al., 2020 [5] Li et al., 2019 [44] Domingues et al., 2016 [6]	Treg are inhinitory T cells Their percentage is higher in higher grade meningiomas supporting their immunosuppressive potentiality Their negative impact on survival has been demonstrated in different tumor types Their effective role in meningiomas is still debated, and Treg infiltration has not been yet demonstrated as independent prognostic factor
	PTBE
Berhouma et al., 2019 [45]	Incidence ranges from 38% to 67% and is associated with higher mortality and morbidity
Gilbert et al., 1983 [46]	PTBE is related to ischemic-compressive phenomena related to tumor size
Regelsberger et al., 2009 [47]	Some meningioma histotypes correlate with a more extensive PTBE Secretory hystotype is associated with higher CK and CEA expression
Bitzer et al., 1997 [48]	Increased intratumoral venous pressure leads to tumor congestion and expansion of the PTBE
Tanaka et al., 2006 [49]	Hydrodynamic mechanism results in altered intratumoral rheology, venous congestion and release of vasogenic substances
Nassehi et al., 2013 [50] Reszec et al., 2013 [51]	Alterations to the VEGF pathway appear to be implicated in the pathogenesis of PTBE Increase in MMP-9 and HIF-1 correlates with a higher PTBE
Kilic et al., 2002 [52] Gawlitza et al., 2017 [53] Polyzoidis et al., 2015 [9]	Other molecular alterations underlying PTBE appear to involve ECM protein or membrane ion channel protein Mast cells promote BBB destruction by increasing PTBE

IVMs: intraventricular meningiomas; TILs: tumor-infiltrating lymphocytes; Treg: regulatory T cells; TAMs: tumor-associated macrophages; PFS: progression free survival; SMBs: skull base meningiomas; nSMBs: non-skull base meningiomas; PTBE: peritumoral brain edema; MDSCs: myeloid derived suppressor cells.