Meningioma is the most frequently diagnosed primary brain tumor, and it accounts for approximately one-third of all primary brain and spinal tumors (9). Despite its generally benign and slow-growing nature, the biological behavior of meningioma varies considerably, and it cannot be predicted using histomorphological classification alone. Benign meningioma has a recurrence rate of 7–25% (5). According to previous studies, specific MMPs have been demonstrated to enhance angiogenesis (18), and they are predictive of the recurrence of meningioma (22). MMP-2 expression is reportedly higher in high-grade meningioma (22) (23). In this study, clinicopathological data, MMP-2 expression, and CD34 expression (MVD) were determined and analyzed in all cases.
HUSM is a referral center for brain tumors in the East Coast region, which explains the high number of brain tumors treated at this institution. In this study, the vast majority of patients had WHO grade I tumors, corresponding with previous findings that benign meningioma is more common atypical and anaplastic meningioma (24)(25)(26). The sex predilection of meningioma was established in several studies, and it is most likely explained by presence of higher levels of sex hormones in women (9)(27)(28). Meanwhile, the finding that most patients were of Malay ethnicity is explained by the fact that the Kelantan population predominantly consists of Malay people (29).
According to the WHO Classification of Tumours of the Central Nervous System (5), meningioma arises in intracranial, intraspinal, and epidural regions. The frequent locations within the intracranial region are the cerebral convexities, olfactory grooves, sphenoid ridges, para-suprasellar region, optic nerve sheath, petrous ridges, tentorium, and posterior fossa.
The role of MMPs, including MMP-2 in various neoplasms is well studied, and their involvement in tumor invasion and progression has been established (18). MMP-2 is more highly expressed in higher-grade brain neoplasms such as glioblastoma and is associated with poor survival (30) (31). Our findings that most high-grade meningiomas in this study exhibited high MMP-2 expression are consistent with previous studies illustrating a significant increase in MMP-2 expression from lower-grade to higher-grade meningioma (22) (23).
We also observed that that most low-grade meningiomas also displayed high MMP-2 expression. Although this finding does not support our hypothesis, a few studies assessed MMP expression among different low-grade histological subtypes. Das et al. (32) noted a moderate or high level of MMP-2 in patients with transitional and meningothelial meningioma. Rooprai et al. (16) found that the fibroblastic subtype meningioma exhibited the highest MMP-2 expression, followed by the transitional and meningothelial subtypes.
In addition to incomplete surgical removal of low-grade meningioma, high expression of MMP-2 also is a prognostic factor for tumor recurrence (33). However, one study found no MMP-2 expression in patients with meningothelial meningioma, and its expression was only in patients with transitional, fibromatous, psammomatous, and angiomatous subtypes (23). An evaluation of 12 patients with grade I meningioma conducted by Kirches et al. (34) using zymography and reverse transcription PCR detected no MMP activity in any samples. These contradictory findings relative to our results may be attributable to the use of different laboratory methods and scoring systems for MMP-2 expression.
MMP-2 is known to be involved in tumor angiogenesis, and it has been proven to play a critical role in the ‘angiogenic switch’ during the early development of vascularization (18). MMP-2 is also one of the most studied MMPs concerning its role in tumor angiogenesis (15) (35) (36) (37). To the best of our knowledge, no prior study examined the association between MMP-2 expression and angiogenesis in meningioma, prompting this study.
The lack of an association between MMP-2 expression and grade of meningioma in this study may be related to the small number of patients with high-grade lesions. We can conclude that meningioma of all grades expresses MMP-2 at varying intensity. Strong MMP-2 expression is associated with a high risk of recurrence and poor survival rates. However, more samples from patients with higher-grade meningioma are required to ensure the findings are not biased.
MVD is a measure of the vessel count per high-power field that is used as an independent prognostic indicator (38). Most patients in the present study exhibited a low level of angiogenesis, but the majority of patients with low-level angiogenesis exhibited high MMP-2 expression, contradicting our hypothesis. MMP-2 degrades the basement membrane and ECM components, thereby releasing proangiogenic factors, and it also directly binds to αvβ3, an integrin receptor on the endothelial surface, to induce integrin signaling, thereby contributing to endothelial survival and proliferation (15).
Angiogenesis is well studied in meningioma, and it has been reported to be associated with peritumoral edema, recurrence, and higher tumor grades (39) (14) (40). However, the antibodies used in IHC to evaluate angiogenesis differed among prior studies, including VEGF, CD31, and CD105, but MMP-2 was not included.
In this study, we also analyzed the MVD score according to the grade of meningioma. According to Barresi et al., extensive neoangiogenesis is significantly associated with a high proliferation index in meningioma and thus a higher tumor grade, which we could not verify in this study.
Many other studies supported the findings of Barresi et al. despite the use of different immunohistochemical markers for angiogenesis, including (38) (40) (41), CD105 (42), and CD34 (43). However, a few studies reported similar results as our study (44) (45). The possible explanation for these contradictory results is most likely the use of different methods for quantifying angiogenesis and the use of IHC for CD34. CD34 is a pan-endothelial marker that is stained in both newly formed vessels and the endothelial cells of pre-existing vessels. In the future, it would be better and more accurate to use more specific IHC markers that only stain newly formed blood vessels, such as CD105 (endoglin), as suggested by Barresi et al.