Vascular endothelial growth factor (VEGF) operates as a highly selective heparin-binding molecule that targets vascular endothelial cells, where it orchestrates both angiogenic processes and modulation of vascular permeability through receptor-mediated mechanisms (38). The family of VEGF genes includes several ligands, such as VEGF-A, VEGF-B, VEGF-C, VEGF-D, and placental growth factor. Among these, VEGF-A serves as the principal mediator of angiogenic processes (39). These ligands exert their biological effects by interacting with three different receptor tyrosine kinases, namely VEGFR-1, VEGFR-2, and VEGFR-3 (40–42). VEGFR-1 and VEGFR-2 are expressed on the surface of the vascular endothelium (40, 43), and VEGFR-3 has a preferential expression in the lymphatic endothelial network (44). VEGF binding to VEGFR-2 activates subsequently implemented downstream signaling pathways, especially through the PI3K/AKT pathway, which is strongly linked to tumor-associated angiogenesis and related alterations in vascular permeability (14). The mechanism by which VEGF binds to VEGFR-1 is unclear, but it appears to play a role in pathological angiogenesis of adult tumors and inflammation, and the regulation of vascular morphogenesis (14). Tumor development is often accompanied by dysregulation of VEGF expression, which affects the formation of PTBE. Schmid et al. (15) found that VEGF plays the main role in the neovascularization of meningiomas and that VEGF expression in soft meningeal blood supply is closely related to PTBE. Similarly, Nassehi et al. (16), in a study of 101 meningioma cases, found that 43 patients had PTBE, which correlated positively with VEGF expression. Another study (45) observed that varying degrees of VEGF expression in meningioma tissue exhibit a significant association with tumor grade and are detectable throughout all phases of peritumoral brain edema. Collectively, VEGF stimulates the growth of tumor-associated blood vessels and increases vascular permeability. This results in the leakage of fluid and proteins from blood vessels, thereby playing a part in the generation of brain edema around tumors.

Matrix metalloproteinases (MMPs) are zinc-dependent enzymes mainly produced by tumor cells that degrade extracellular matrix and basement membrane components, aiding tissue remodeling. MMP-9 is the largest enzyme by molecular weight in the MMP family and specifically promotes angiogenesis and tumor metastasis by degrading type IV and V collagen and gelatin in the extracellular matrix (45, 46). In addition to structural effects, evidence indicates that MMP-9 contributes to PTBE by influencing the MAP kinase signaling pathway and activating glial cells, which increase local inflammation (21, 22). In a comprehensive analysis by Reszec et al. (45), MMP-9 was found in 65 of 93 meningioma samples, with higher levels in atypical, malignant tumors, and in patients with grade II or III PTBE. Consistent with these findings, Jung et al. (47) also confirmed that MMP-9 levels correlate with PTBE severity. The evidence indicates that MMPs are closely linked to PTBE and can be used as a predictive factor for the severity of PTBE.

Multiple different angiogenic factors exist in meningiomas, such as platelet-derived growth factor and VEGF (48–50). The interactions of these factors within the tumor’s extracellular matrix cannot be separated from other crucial factors. Tenascin C is a glycoprotein family widely present in the human extracellular matrix, which, although rarely expressed in normal adult tissues, participates in embryonic development, injury, inflammation, wound repair, and tumor angiogenesis (51, 52). Multiple studies have established that tenascin C expression is strongly associated with tumor angiogenesis (53, 54). Research has found that Tenascin C enhances the motility of vascular endothelial cells and stimulates endothelial cell proliferation by binding integrin receptors and activating the MAPK signaling pathway (53, 55). In a retrospective examination of 20 typical, 20 atypical, and 5 malignant meningioma cases, Kilic et al. (56) observed that Tenascin C expression within meningiomas correlated with both VEGF levels and the presence of PTBE. They speculated that Tenascin C participates in tumor invasion and tumor angiogenesis, promoting the occurrence of PTBE. However, the specific mechanism of Tenascin C in meningioma-related PTBE lacks subsequent research for confirmation.

Meningiomas develop within a complex immune microenvironment that includes mast cells, macrophages, T and B lymphocytes (57). Studies have found that mast cells can store and secrete mediators such as VEGF, prostaglandins, and substance P (57–59), and the release of these mediators can disrupt the BBB and cause inflammatory responses (57, 59). Polyzoidis et al. (57) and colleagues reported mast cell infiltration in nearly 90% of high-grade meningiomas. Building on this, Reszec et al. (60) proposed a simplified classification dividing tumors into low-grade (WHO grade I) and high-grade (WHO grade II and III). The results showed that mast cells appeared in 31.8% of the low-grade group, with all cases also displaying significant PTBE. In contrast, 86% of the high-grade group contained mast cells, and all of these cases also showed PTBE. Moreover, there is a possible connection between mast cell activation and the regulation of HIF-1 overexpression in hypoxic conditions (60).

HIF-1 is a heterodimeric transcription factor composed of HIF-1α and HIF-1β. Under normoxia, HIF-1α is hydroxylated and degraded, but in hypoxia, it stabilizes, moves to the nucleus, and binds HIF-1β to activate genes (like VEGF, MMPs), promoting angiogenesis, glycolysis, and cell survival (61). In a hypoxic microenvironment, HIF-1 attaches to sites in the VEGF enhancer, leading to increased VEGF transcription via the PI3K/Akt pathway (62). It also stabilizes VEGF and its receptors, which promotes angiogenesis (63). Related studies indicate that HIF-1 is detected in 55.7% of low-grade and 84% of high-grade meningiomas (64). MMP is another important target gene of HIF-1α, and HIF-1 can directly or indirectly induce the expression or activation of MMPs, leading to basement membrane degradation and impaired function of tight junction proteins (45). Therefore, hypoxia can promote mast cell activation and HIF-1 overexpression, resulting in the destruction of the BBB, thereby triggering PTBE.

Interleukin-6 (IL-6) is a pro-inflammatory factor produced by macrophages during tissue injury or inflammation (65). It is playing a pivotal role in helping mediate inflammation, cell differentiation, and immune responses in many cell types, including tumor cells, endothelial cells, and astrocytes (66). The role of IL-6 in the CNS continues to be debated. Trans-signaling involves the classic membrane-bound IL-6 receptor or the soluble IL-6 receptor (sIL-6R). It activates downstream pathways (like JAK/STAT, Ras/MAPK, and PI3K/AKT), which regulate cell survival, proliferation, the inflammation process, and stimulate angiogenesis (23). However, in a study by Todo et al. (24), exogenous low-dose IL-6 was shown to inhibit thymidine incorporation in meningioma cells, suggesting that IL-6 secreted by meningiomas might act as a local growth inhibitory signal, rather than a growth promoter. In a case series reported by Park et al. (25), on investigating the PTBE volume in 36 patients with benign meningioma, it was noted that 12 out of 16 patients with PTBE were positive for IL-6, whereas only 6 out of 20 patients without edema were positive. Notably, the IL-6 level in the edema group was 7.72 times higher than in controls, and PTBE severity was significantly linked to IL-6 expression. Recent research can provide a mechanistic explanation for the above findings: IL-6 leads to decreased expression or rearrangement of tight junction proteins through cellular signaling pathways, thereby disrupting the selectivity and permeability of the BBB and promoting the formation of PTBE (26).

Cadherins are a family of glycoprotein receptors that are either transmembrane or attached to the membrane. They enable calcium-dependent cell adhesion and are crucial for the synchronized development of different tissues and organs (67). Among the molecules closely associated with cadherin-mediated adhesion, β-catenin functions as a multifunctional signaling protein. In epithelial tissues, E-cadherins interact with β-catenin molecules to form adhesive structures that are involved in the maintenance of junction stability, as well as in the regulation of signaling pathways (67). It is through this regulatory function that it indirectly influences the proliferation of tumor cells and the transmission of cellular signals (67–69). Accumulating research suggests that cadherins are probably a pivotal and determinative segment in the invasive behavior of meningiomas and the degree of associated PTBE. As one illustration, Zhou et al. (70) noted that higher tumor grade in meningiomas is associated with reduced E-catenin and β-catenin, which is almost absent in malignant types. This describes a decrease in cell adhesion with tumor progression. Another investigation by Rutkowski et al. (71) revealed that in 154 intracranial meningioma instances, N-cadherin was remarkably upregulated in high-grade tumors, with the accumulation of β-catenin happening in the cell nuclei. Importantly, both the molecular alterations correlated strongly with postoperatively evaluated levels of PTBE, and this correlation was particularly pronounced in tumors of more aggressive grades. Collectively, these findings indicate a consistent association between disruptions in cadherin and β-catenin signaling pathways and the progression of PTBE severity. It has therefore been proposed that dysregulation of cadherins and β-catenin contributes to the disruption of intercellular junctions, weakening BBB integrity, and promoting the formation of PTBE.

Sex hormones, particularly estrogen and progesterone, together with their corresponding receptors, have long been implicated in the initiation and progression of meningiomas, as well as in shaping the tumor microenvironment. Evidence shows progesterone receptors are common in meningiomas, while estrogen receptors are rare, usually below 10% or absent (72). Some studies have indicated that progesterone receptor expression levels are higher in benign meningiomas than in atypical or anaplastic meningiomas. They speculate that progesterone receptor expression levels are closely related to the type and prognosis of meningiomas, with higher progesterone receptor expression indicating better prognosis, while meningiomas with lower progesterone receptor expression or the presence of estrogen receptor expression may suggest poor prognosis (73). In early studies on brain edema and sex hormone positivity, Maiuri et al. (74) found that progesterone may induce the secretion of pro-inflammatory markers, thereby causing brain edema. A recent study found that among 22 meningioma cases, 19 cases showed progesterone positivity and all exhibited significant PTBE (75). Although the precise mechanisms linking sex hormones and their receptors to PTBE in meningioma remain unclear, current evidence suggests that sex hormones may represent a potential therapeutic target. Further investigation into their mechanistic roles is therefore warranted.

Aquaporins (AQPs) are a group of transmembrane channels found on the plasma membranes of major human organs and tissues (76). AQP-4 is currently the most water-permeable aquaporin known and serves as the main water channel protein in the mammalian CNS (77). Its localization is very polarized, and there is dense expression at astrocytic end-feet covering cerebral microvessels, placing AQP-4 at the crucial boundary between the brain tissue and blood vessels (77, 78). Through this distribution, AQP-4 is important in maintaining BBB function and water balance within the CNS (78). The specific mechanisms by which AQP-4 is involved in PTBE development in meningiomas are still incompletely understood. Accumulating evidence suggests there is a strong correlative association between high AQP-4 and the presence and severity of PTBE. Elevated AQP-4 in meningioma tissues is also linked to VEGF, suggesting involvement in the formation of edema in a pro-angiogenic and permeability-enhancing environment (17–19). Experimental studies further indicate that the role of AQP-4 may differ based on the type of cerebral edema. In mouse models of cytotoxic edema, using inhibitors to block AQP-4 activity has been demonstrated to reduce both the formation and severity of brain swelling (79, 80). In contrast, loss of AQP-4 activity in vasogenic edema appears to exacerbate tissue swelling, a phenomenon attributed to impaired clearance of excess interstitial fluid from the brain tissue (76, 81, 82). Furthermore, other aquaporin subtypes may also participate in PTBE pathogenesis. Lambertz et al. (20) found that AQP-5 is expressed in meningiomas and is correlated with the occurrence and severity of PTBE, providing data to support its involvement in the maintenance of brain water balance.

Brain natriuretic peptide (BNP) is primarily produced by the myocardial cells of the dilated ventricles. After binding to its receptors, BNP exerts regulatory effects on water–electrolyte homeostasis by suppressing sympathetic nervous system activity and modulating the renin–angiotensin–aldosterone axis. In clinical practice, BNP is commonly regarded as a biomarker for heart failure and also as an indicator of hypoxia. In the CNS, BNP receptors are widely distributed. Clinical studies have reported a strong link between circulating BNP levels and the mass effect induced by PTBE (83, 84). Ruggieri et al. (84) demonstrated that serum BNP levels in patients with brain tumors are positively correlated with PTBE volume. Nevertheless, the precise mechanism underlying this correlation remains unknown, and it is uncertain whether BNP is merely a byproduct of PTBE or if it actively contributes to its pathogenesis. Still, serum BNP levels in brain tumors can indicate the effectiveness of anti-edema drug therapy (84).

Existing studies have shown that meningioma-related PTBE is strongly associated with the volume and location of meningiomas. Across multiple clinical studies, a consistent positive relationship has been observed between increasing meningioma volume and the likelihood of PTBE development (9, 10). In a study by Shin et al. (9), a retrospective study of 205 patients with convexity or parasagittal meningiomas found that a tumor size of 13.95 cm³ (or a tumor diameter of 2.99 centimeters) as a cutoff value could predict the incidence of PTBE, with a sensitivity of approximately 76.1% and a specificity as high as 92.5%. In an earlier study by Tamiya et al. (85), in addition to observing a correlation between tumor size and PTBE volume, it was found that convex meningiomas and middle fossa meningiomas had the highest average tumor edema index (PTBE volume/tumor volume). Moreover, the most severe PTBE occurred in convex meningiomas infiltrating the middle fossa. Recently, Liyanage et al. (10) further confirmed that both the mass effect and the probability of PTBE increased with the tumor’s maximum diameter. Furthermore, significant PTBE was observed when meningiomas involved the supratentorial and infratentorial spaces. A plausible explanation for these observations lies in the heterogeneity of intracranial anatomy. The ability of surrounding brain tissue to accommodate tumor-related mass effect varies according to local bony confines and dural structures, which differ markedly across cranial regions. When this compensatory capacity is limited, even moderate tumor enlargement may precipitate disproportionate edema formation (4).

Currently, meningiomas are divided into 15 subtypes. Of these, WHO grade I comprises 9 subtypes, WHO grade II consists of 3 subtypes, and WHO grade III includes 3 subtypes (3) (Table 1). In early studies on the correlation between meningioma histological types and PTBE, Osawa et al. (86) classified nine subtypes of WHO grade I meningiomas into common types (meningothelial, transitional, and fibrous meningiomas) and rare types (psammomatous, angiomatous, microcystic, secretory, lymphoplasmacyte-rich, and metaplastic meningiomas). In a retrospective study of 110 patients with meningiomas, they found that rare-type meningiomas were associated with extensive PTBE, with PTBE volumes ranging from 10 to 100 times those of other common-type meningiomas. In subsequent studies, the incidence and severity of PTBE in angiomatous and secretory meningiomas were significantly higher than in other meningioma types (11–13). Although the mechanisms underlying significant PTBE in specific subtypes of meningiomas are not yet fully understood, multiple studies have proposed potential mechanisms.

For example, angiomatous meningioma is a highly vascularized benign meningioma, and high vascularization may be related to VEGF expression in meningiomas (14, 87). Angiomatous meningioma may produce abnormally extensive PTBE due to the combined effects of its high vascularization and VEGF. Secretory meningiomas contain periodic acid-Schiff positive pseudopsammoma bodies, and this subtype has a higher number of mast cells compared with other meningioma subtypes (88). VEGF, prostaglandins, tumor necrosis factor, and substance P, which are stored and secreted by mast cells, aggravate the degree of PTBE by disrupting the BBB (59). The main characteristics of microcystic meningioma include vacuolization, myxoid degeneration, and microcyst formation, with suspected excessive secretory activity of tumor cells (89). Microcystic meningioma also exhibits high vascularity, and VEGF immunoreactivity in tumor endothelial cells is higher than in other common meningiomas (90). The high degree of vascularization and strong expression of VEGF may be the cause of significant PTBE associated with microcystic meningioma. Lymphoplasmacyte-rich meningioma is characterized by extensive infiltration of inflammatory cells and varying proportions of meningioma cells, with the infiltrated lymphoplasmacytes potentially obscuring the meningothelial cell composition (3). A large infiltration of non-neoplastic lymphocytes and plasma cells can trigger an inflammatory response, which may be key in the development of PTBE linked to lymphoplasmacyte-rich meningioma (91).

Meningiomas typically possess a distinct boundary composed of the pia–arachnoid and tumor matrix, known as the meningioma–brain interface. Theoretically, this interface limits the effects of tumor-related factors such as VEGF and MMPs on adjacent peritumoral brain tissue (60). Therefore, identifying factors that can disrupt this interface is crucial for understanding the pathogenesis of PTBE. From a macroscopic perspective, the integrity of the meningioma-brain interface directly affects the formation of PTBE. In a study by Nakasu et al. (92) involving 50 meningioma surgical cases, it was found that the extent of arachnoid rupture correlated with peritumoral edema. At the microscopic level, Huang et al. (93) utilized single-cell RNA sequencing to analyze cell types with distinct functions and molecular characteristics in meningioma-associated tissues. They identified specific tumor cell subpopulations within the meningioma-brain interface microenvironment that promote tumor angiogenesis. Tumor angiogenesis has been closely linked to the development of PTBE (94).

For decades, the lack of classical lymphatic vessels within the brain parenchyma led to the prevailing view that protein and metabolic waste clearance depended primarily on intracellular and extracellular degradation pathways, including autophagy and ubiquitin-mediated proteolysis (95, 96). Under this framework, Only a few proteins, such as amyloid-β, can cross the BBB and be cleared by specific transporters (97). As research has advanced, some scholars suggest that features of the glymphatic and meningeal lymphatic systems exist in humans, with the glymphatic system potentially serving as a waste removal pathway and maintaining fluid balance in the brain parenchyma (97). In this context, Toh et al. (98) employed the analysis along the perivascular space (ALPS) index as an imaging surrogate of glymphatic function in a cohort of 80 patients with meningiomas. Their analysis showed a negative correlation between PTBE volume and the ALPS index, indicating that reduced glymphatic activity was associated with more extensive peritumoral edema. Such findings are consistent with the clinical observation that impaired fluid clearance often accompanies edema progression in intracranial tumors.

Currently, the specific mechanism of aquaporin formation with PTBE is not understood in full, and further research is needed in order to elucidate its role in PTBE formation (17–19, 77, 78). Among those channels, AQP-4 has gained special interest due to its prominent expression in astrocytic endfeet and its close relation to fluid homeostasis at the blood-brain interface. In this regard, Goreisan, a traditional herbal preparation widely used in Japan and other East Asian countries (known as Wu Ling San in China and Oreongsan in Korea), has been suggested as a possible cerebral edema modulator via its downregulatory effect on AQP-4 expression (128–130). Studies have shown that Goreisan helps to reduce brain edema in stroke (80). Parallel findings in animal models strengthen this view, since several studies have shown measurable improvements in brain edema following Goreisan administration (131, 132). These results hint that Goreisan may be helpful in treating PTBE, but more research would be needed to determine the therapeutic potential of Goreisan to be used as a treatment for PTBE.

COX-2 is expressed in meningiomas and can increase the production of prostaglandin E₂ (133, 134). Prostaglandin E₂ has vasodilatory effects, is associated with tumor angiogenesis, and may promote the formation of cerebral edema (133). COX-2 has garnered attention not only for its role in tumor angiogenesis but also for its association with tumor progression, metastasis, and the development of drug resistance (134). Despite their potential value, COX-2 inhibitors have been rarely studied in the research of meningioma-related peritumoral brain edema in the past period (135–137). Selective COX-2 inhibition has been linked to severe side effects, especially myocardial infarction and other cardiovascular issues, which have greatly limited their use in therapy (138). The underlying mechanisms responsible for these cardiovascular risks remain incompletely understood, which has led to the withdrawal of several COX-2 inhibitors from clinical practice (138, 139). Therefore, conducting safety assessments is essential for developing COX-2 inhibitors as a possible treatment for PTBE.

Boswellic acid, a phytotherapeutic compound from frankincense resin, has gained growing interest mainly because of its key active component, acetyl-11-keto-β-boswellic acid (AKBA) (140). AKBA shows anti-inflammatory effects and suppresses VEGF, helping reduce brain edema (141, 142). AKBA is a powerful inhibitor for HIF-1α, resulting in inhibition of the downstream expression of VEGF and a reduction in the formation of brain edema. In the meantime, AKBA suppresses 5-lipoxygenase, which is important in the synthesis of leukotrienes from arachidonic acid, and greatly influences the permeability of the vascular wall (141). Clinical observations also help to strengthen these experimental insights. In a randomized study performed by Kirste et al. (143), 44 patients with malignant brain tumors received radiotherapy plus boswellic acid or placebo therapy. After checking the brain edema through MRI, it was noticed that 60% of the patients treated with boswellic acid showed a percentage greater than 75% in the reduction of the edema area, compared to 26% in the placebo group, which achieved a reduction in the area of edema of similar magnitude to the group of patients treated with boswellic acid. A recent study on 20 patients with glioblastoma treated with boswellic acid in combination with radiotherapy found that the administration of boswellic acid greatly reduced brain edema due to chemoradiotherapy (144). While the direct evidence in meningioma patients is currently lacking, the overlap in the pathways of the vascular permeability and the inflammatory signaling mediated by the molecule VEGF seems to make a therapeutic role probable. Therefore, it is thought that the boswellic acid may have some potential therapeutic benefits in treating meningioma-related PTBE.