A Study Between Aquaporin-4and Peritumoral Brain Edema In Meningiomas

Background and ObjectiveMeningiomas are commonly intracranial tumors outside of the brain parenchyma, the specific mechanism of peritumoral brain edema (PTBE) in meningiomas is still unknown. As so far, there are many researches about the formation mechanism of PTBE in meningiomas. Many domestic and international researches showed that the PTBE in meningiomas was related to the following aspects:(1) Pial blood supply and PTBE in meningiomas. Domestic and international studies found that the formation of PTBE in meningiomas was related to the adhesion of the tumor and surrounding tissue, when the intracranial blood vessels wear through arachnoid or the tumor tissue infiltrated arachnoid and led to vascular permeability enhancement, then the macromolecules, which can caused edema and produced by the tumor tissue, through the split connection point or channel of capillary endothelial cells into the tumor stroma. If the continuity of the pial and arachnoid damaged, this molecular substances into the brain tissue will lead to PTBE in meningiomas.(2) The influence on the change of interface between the brain tissue and tumor. Currently, tumor-brain interface and PTBE are two key factors in the clinical treatment of meningiomas. Most people think that the loose of connect vascular structures in the tumor-brain interface led to the blood-brain barrier damage and resulting in PTBE in meningiomas. There is great significance in existence and integrity of the brain-tumor interface in formation of PTBE in meningiomas.(3) Hydrodynamic processes in formation of PTBE in meningiomas. The theory of hydrodynamic processes flow dynamics think that the increased vascular permeability of meningiomas lead to the leakage of the serum and protein composition from blood vessels to the space of tumor cells, resulting in tumor internal pressure increased, in a tumor-brain transport and the positive pressure gradient between tumor and brain, the liquid from tumor tissue followed into the peritumoral brain tissue caused PTBE in meningiomas.(4) The development of draining veins of meningiomas and its PTBE. Super-selective angiography found that the formation of PTBE in meningiomas was concerned to the development of draining veins of the tumor’s own, pointed out that the tumor drainage vein hypoplasia lead to venous congestion within the tumor and cause the venous pressure increased result in PTBE in meningiomas, the development integrity of the drainage vein can reduce the formation of PTBE in meningiomas.(5) Protein factors in PTBE in meningiomas. Meningiomas can secrete a number of protein factors, many of these protein factors may participate the formation of PTBE in meningioma, such as vascular endothelial growth factor (VEGF)and its receptors, Matrix metalloproteinase, Interleukin-6, Cyclooxygenase-2, the Sex hormone receptors, Nitric Oxide, EphB2, Somatostatin and so on.(6) Other factors and PTBE in meningiomas, such as tumor location, size, tumor morphology, pathological types, but the relationship between these factors and PTBE in meningiomas were different in domestic and abroad reports.Aquaporins (AQPs) is a selective water channel of the inner membrane protein, belonging to the main intrinsic protein family members, and widely distributed in animals, plants and microbes.13types of aquaporins has been discovered in human. There were7types of aquaporins has been discovered in the human brian tissues, AQP1, AQP3,AQP4, AQP5, AQP8and AQP9, AQP4in the brain is the most widely, is the most abundant aquaporin in the brain tissue, mainly distributed in the ependymal cells, choroid plexus epithelium, the pia mater, cortex, corpus callosum, hypothalamus, supraoptic nucleus, room nucleus, the hippocampal dentate gyrus, cerebellum purkinje fiber cells, microvascular endothelial cell surface, which is the most abundant expression in the astrocyte foot processes in direct contact with blood vessels, arachnoid and pia mater, mainly involved in the regulation of plasma osmolality, blood-brain barrier development and maintain its function, and both the function of extracellular osmoreceptors. Mediated by the brain parenchyma and blood, and out of the water molecules between the cerebrospinal fluid, and various types of brain edema formation. The results show:AQP4plays an important role in the cytotoxicity induced by water intoxication, brain ischemia, meningitis, cerebral edema, and vasogenic edema caused by the tumor, frostbite cortex, brain abscess, pathological physiological processes. AQP4may be the molecular basis of formation of brain edema.There are a lot of reports on the study of the formation of the PTBE in meningiomas, but its pathogenesis remains unclear, AQP4is water channel membrane-bound protein, widely expressed in the brain, involved in regulation of the intracranial water balance. People pay more and more attention to the role of AQP4in the pathophysiological process of brain edema. What the relationship between the expression of AQP4and PTBE in meningiomas? Whether the AQP4participate in the formation of PTBE in meningiomas? What is the mechanism? There have no systemic reportes at home and abroad. This research will study the relationship between the expression level of AQP4and PTBE in meningiomas, to explore the role of AQP4in PTBE in meningiomas and its pathogenesis, to further improve the pathogenesis associated PTBE in meningiomas.Methods1.96patients with meningiomass were selected during November2010to December2011in Neurosurgery of Guangdong General Hospital. All patients were routine check by cranial Magnetic Resonance Imaging (MRI) at preoperative, and record age, sex, three-dimensional diameter of tumor and edema, tumor location and pathology results data. After operative, conventional sent tumor sample for pathological examination. Exclude intracranial presence of other underlying diseases.2. The patients were divided into two groups according to age:the≤50-year-old group and the>50-year-old group, were divided into the male group and the female group according to sex, were divided into three groups according to the volume of tumor:the VT≤20cm3group,the20<VT≤60cm3group and the VT>60cm3group, were divided into the supratentorial group and the infratentorial group according to the tumor location, were divided into the WHOⅠ level group, the WHOⅡ level group and the WHOⅢ level group according to pathological results, and were divided into four groups, namely:non-edema group (EI=0), mild edema group(0<EI≤1), moderate edema group(1<EI≤2) and severe edema group(EI>2) according to edema index (EI).3. Immunohistochemistry was used to detect of the expression levels of AQP4and VEGF in meningiomas specimens. The experiment results were divided into the negative group (-), the weak positive group (+), the moderate positive group (++) and the strongly positive group (+++).4. Select the age, gender, tumor size, tumor location, pathological findings, the level of AQP4and VEGF as variables to analyze the relationship with PTBE in meningiomas. 5. Statistical methods:Firstly, we have used the Chi-Square test of univariate analysis to screening the influencing factors. Secondly, selected variable factors(P <0.1) make logistic regression analysis after univariate analysis. Spearman rank correlation analysis were used to analysis the relationship between the two level variable, choose0.05as the inspection level, multiple analysis were used to analysis the mutual relations between the factors.Results1. Degree of edema:39cases showed no edema,21cases showed mild edema,21cases had moderate edema, and15cases had severe edema, the incidence of edema was59.4%(57/96).2. Univariate analysis2.1The expression of AQP4and PTBE:AQP4was mainly expressed in the membrane of tumor cell. There was a positive relationship between the level of AQP4and degree of PTBE (r=0.543, P<0.05). The incidence rate of PTBE [71.6%(53/74)]in the AQP4positive group was higher than that in the AQP4negative group [18.2%(4/22)], χ2=20.078, P<0.05.2.2The expression of VEGF and PTBE:VEGF was mainly expressed in the cytoplasm of tumor cells. There was a positive relationship between the level of AQP4and degree of PTBE (r=0.508, P<0.05). The incidence rate of PTBE in the VEGF positive group [69.3%(48/69)] was higher than that in the VEGF negative group[33.3%(9/27)],χ2=10.562,P=0.001.2.3The relationship between AQP4and VEGF:there was positive relationship between the expression level of AQP4and VEGF (r=0.661, P<0.01).2.4Pathological nature of tumor and PTBE:There was a positive relationship between the pathological level and the degree of PTBE (r=0.386, P=0.029). The incidence rate of PTBE was higher in the non-benign group[82.4%(28/34))]than in the non-benign group [46.8%(29/62)], χ2=11.523, P=0.001.2.5AQP4and pathological grade:The positive rate of AQP4in the WHO grade I group was71%(44/62),91.3%(21/23) in the WHOⅡlevel group and81.8%(9/11) in the WHO Ⅲ level group, there was no statistically significant in three groups (x2=4.085p=0.130). There was no correlation between the expression level of AQP4and pathological grade (r=0.187, P=0.068).2.6Tumor size and PTBE:The incidence rate of edema in the small tumor group was48.8%(20/41),68.4%(26/38) in the middle-size tumor group and64.7%(11/17) in the large tumor group, there was no statistically significant in three groups(x2=3.397, P=0.183).2.7Tumor position and PTBE:The incidence rate of edema in the supratentorial group was65.1%(54/83) and23.1%(3/13) in the infratentorial group, there was a statistically significant between two groups (x2=8.213, P<0.05). The edema incidence of the supratentorial group was higher than the infratentorial group’s.2.8Age and PTBE:The incidence rate of edema in the<50-year-old group was59.0%(23/39), and59.6%(34/57) in the>5050-year-old group, there was not statistically significant between in two groups(x2=0.004, P=0.947).2.9Sex and PTBE:The incidence rate of edema in the male group was70.6%(24/34) and53.2%(33/62) in the female group, there was not statistically significant between in the two groups (x2=2.744,P=0.098>0.05).3Multivariate logistic regression analysisLogistic regression analysis showed that the expression of AQP4, tumor nature and tumor location were the risk factors in formation of PTBE, which AQP4-positive expression and non-benign tumor were the risk factors (OR=7.540and4.956respectively.) in the formation of PTBE in meningiomas, infratentorial tumors is a protection factor (OR=0.093) in the formation of PTBE in meningiomas.Conclusion The expression of AQP4paticipated in the formation of PTBE in meningiomas, and the higher expression level of AQP4, the more severity PTBE in meningiomas In addition, the tumor position and pathological nature of the meningioma also participated in the formation of a meningioma PTBE.