Peritumoral edema in meningiomas: pathophysiology, predictors, and principles for treatment.

Meningiomas is a tumor of the meninges and is among the most common intracranial neoplasms in adults, accounting for over a third of all primary brain tumors in the United States. Meningiomas can be associated with peritumoral brain edema (PTBE) which if not managed appropriately can lead to poor clinical outcomes. In this review, we summarize the relevant pathophysiology, predictors, and principles for treatment of PTBE. The results of various case-reports and case-series have found that meningioma-associated PTBE have patterns in age, tumor size, and hormone receptor positivity. Our study describes how increased age, increased tumor size, tumor location in the middle fossa, and positive expression of hormone receptors, VEGF, and MMP-9 can all be predictors for worse clinical outcomes. We also characterize treatment options for PTBE such as glucocorticoids and VEGF inhibitors along with the ongoing clinical trials attempting to alleviate PTBE in meningioma cases. The trends summarized in this review can be used to better predict the behavior of meningioma-associated PTBE and establish prognosis models to identify at risk patients.

DNA repair and cell synthesis proteins: immunohistochemical expression and correlation with recurrence-regrowth in meningiomas.

Meningiomas are considered the second most common neoplasm of the central nervous system in adults. Most of them are benign with slow growth, frequent in women and with a high recurrence rate. In tumors, DNA error repair processes lose efficacy, providing mutagenesis and genomic instability. This work evaluated the expression of proteins involved in cell synthesis (cyclin D1) and DNA errors repair (MUTYH, XPF, XPG) in meningiomas, relating them to clinical, tumor and survival variables. The study included 85 patients, with a mean age of 52 ± 13.3 years and most of them women (2:1 ratio). Sixty-seven cases were grade I (79%). Grade II tumors were independent predictors of recurrence-regrowth (HR: 2.8; p = 0.038). The high expression of cyclin D1 was associated with grade II (p = 0.001) and low MUTYH expression with grade I (p = 0.04). Strong expression of XPF and XPG was associated with grade II (p = 0.002; p < 0.001) and with recurrence-regrowth (p = 0.04; p = 0.003). Strong XPF expression was significantly related to large tumors (p = 0.03). An association of cyclin D1, MUTYH and XPF were found. Survival was not associated with the expression of any of the proteins studied. To know the role of DNA repair proteins and cell synthesis is important for understanding the processes of origin and tumor development. Grade II meningiomas and strong expression of XPF and XPG were predictors of recurrence or regrowth and may assist in clinical management, considering the high recurrence of meningiomas and the absence of consensus regarding treatment.

Ganoderic acid A/DM-induced NDRG2 over-expression suppresses high-grade meningioma growth.

PURPOSE: N-myc downstream-regulated gene 2 (NDRG2) is down-regulated in grade-III meningioma [anaplastic meningioma (AM)] and associated with clinically aggressive behavior. Current therapies in the treatment of high-grade meningioma are lacking with limited success. This study aims to validate the effect of NDRG2-targeted therapy using structurally related bioactive triterpene compounds derived from the edible mushroom Ganoderma lucidum (ganoderic acid A:GA-A/ganoderic acid DM:GA-DM) in human AM in relevant pre-clinical models. METHODS: Tissue samples from the AM tumor regions of three human patients and control non-tumor samples were used to analyze the expression pattern of NDRG2. In vitro cell culture and in vivo cell-line-derived orthotopic xenograft animal models of AM were utilized to assess efficacy of treatment with GA-A/DM. RESULTS: Downregulation of NDRG2 expression was observed in surgically resected high-grade meningiomas compared to normal brain. These results prompt us to use NDRG2-targeting agents GA-A/DM. In vitro results showed that 72-h treatments of 25 µM GA-A/DM induced AM cell death, upregulate NDRG2 protein expression, downregulate NDRG2 promoter methylation in meningioma cells as compared to azacitidine and decitabine, the most commonly used demethylating agents. Our results also demonstrated that GA-A/DM does not have any detrimental effect on normal human neurons and arachnoid cells. GA-A/DM promoted apoptotic factors (Bax) while suppressing MMP-9, p-P13K, p-AKT, p-mTOR, and Wnt-2 protein expression. RNAi-mediated knockdown of NDRG2 protein expression increased tumor proliferation, while forced expression of wt-NDRG2 decreased proliferation in an in vitro model. Magnetic resonance (MR) imaging and Hematoxylin (H&E) staining demonstrated gross reduction of tumor volume in GA-A/DM treated mice at 5 weeks when compared with saline-treated orthotopic AM xenografted controls. There was an overall decrease in tumor cell proliferation with increased survival in GA-A/DM-treated animals. Enzyme assays showed that GA-A/DM did not negatively impact hepatic function. CONCLUSION: GA-A/DM may be a promising natural therapeutic reagent in the treatment of AM by suppressing growth via NDRG2 modulation and altering of intracellular signal pathways. We have shown it could potentially be an effective treatment for AM with decreased cellular proliferation in vitro, decreased tumor volume and increased survival in vivo.

Expression of merlin, NDRG2, ERBB2, and c-MYC in meningiomas: relationship with tumor grade and recurrence.

Meningiomas are common, usually benign tumors of the central nervous system that have a high rate of post-surgical recurrence or regrowth. We determined expression of the proteins merlin, NDRG2, ERBB2, and c-MYC in meningiomas using immunohistochemistry and assessed relationships between protein expression and gender, age, tumor grade, and recurrence or regrowth. The study sample comprised 60 patients, (44 women and 16 men) with a mean age of 53.2 ± 12.7 years. Tumors were classified as grade I (n=48) or grades II and III (n=12). Expression of merlin, NDRG2, ERBB2, and c-MYC was not significantly different statistically with relation to gender, age, or meningioma recurrence or regrowth. Merlin was expressed in 100% of the cases. No statistically significant difference between tumor grade and recurrence or regrowth was identified. Statistically significant differences were identified between the mean age of patients with grade I (54.83 ± 11.60) and grades II and III (46.58 ± 15.08) meningiomas (P=0.043), between strong c-MYC expression and grades II and III (P<0.001), and between partial surgical resection and tumor recurrence or regrowth (P<0.001). These findings reveal the lower mean age among grades II and III meningioma patients than grade I patients, the influence of the protein merlin on tumorigenesis, the association of c-MYC with aggressive meningiomas, and that partial surgical resection is associated with tumor recurrence or regrowth.

Expression of merlin, NDRG2, ERBB2, and c-MYC in meningiomas: relationship with tumor grade and recurrence

Meningiomas are common, usually benign tumors of the central nervous system that have a high rate of post-surgical recurrence or regrowth. We determined expression of the proteins merlin, NDRG2, ERBB2, and c-MYC in meningiomas using immunohistochemistry and assessed relationships between protein expression and gender, age, tumor grade, and recurrence or regrowth. The study sample comprised 60 patients, (44 women and 16 men) with a mean age of 53.2±12.7 years. Tumors were classified as grade I (n=48) or grades II and III (n=12). Expression of merlin, NDRG2, ERBB2, and c-MYC was not significantly different statistically with relation to gender, age, or meningioma recurrence or regrowth. Merlin was expressed in 100% of the cases. No statistically significant difference between tumor grade and recurrence or regrowth was identified. Statistically significant differences were identified between the mean age of patients with grade I (54.83±11.60) and grades II and III (46.58±15.08) meningiomas (P=0.043), between strong c-MYC expression and grades II and III (P<0.001), and between partial surgical resection and tumor recurrence or regrowth (P<0.001). These findings reveal the lower mean age among grades II and III meningioma patients than grade I patients, the influence of the protein merlin on tumorigenesis, the association of c-MYC with aggressive meningiomas, and that partial surgical resection is associated with tumor recurrence or regrowth.

Abundant immunohistochemical expression of dopamine D2 receptor and p53 protein in meningiomas: follow-up, relation to gender, age, tumor grade, and recurrence.

Meningiomas are common, usually benign tumors, with a high postoperative recurrence rate. However, the genesis and development of these tumors remain controversial. We aimed to investigate the presence and implications of a mutated p53 protein and dopamine D2 receptor in a representative series of meningiomas and to correlate these findings with age, gender, tumor grade, and recurrence. Tumor tissue samples of 157 patients diagnosed with meningioma (37 males and 120 females, mean age 53.6 ± 14.3 years) who underwent surgical resection between 2003 and 2012 at our institution were immunohistochemically evaluated for the presence of p53 protein and dopamine D2 receptor and were followed-up to analyze tumor recurrence or regrowth. Tumors were classified as grades I (n=141, 89.8%), II (n=13, 8.3%), or grade III (n=3, 1.9%). Dopamine D2 receptor and p53 protein expression were positive in 93.6% and 49.7% of the cases, respectively. Neither of the markers showed significant expression differences among different tumor grades or recurrence or regrowth statuses. Our findings highlight the potential role of p53 protein in meningioma development and/or progression. The high positivity of dopamine D2 receptor observed in this study warrants further investigation of the therapeutic potential of dopamine agonists in the evolution of meningiomas.

Expression of aquaporin-4 in human supratentorial meningiomas with peritumoral brain edema and correlation of VEGF with edema formation.

Peritumoral brain edema is a common complication of meningiomas. It is believed that vascular endothelial growth factor (VEGF), as an angiogenic factor, plays a vital role in edema formation. Aquaporin-4 (AQP4) is a small integral membrane protein that regulates water in the normal brain. However, the expression of AQP4 and its relationship to VEGF in edematous meningiomas are not well known. We studied tumor specimens of 59 human supratentorial meningiomas. Western blot analysis was used to detect the expression of AQP4, and double-labeling immunofluorescence histochemical staining was performed to determine the relationship between AQP4 and VEGF. The AQP4 expression was significantly higher in the edema group, in which the protein level was correlated with the extent of edema. Greater VEGF expression was also observed in the edema group, and a relationship between AQP4 and VEGF was found. We conclude that AQP4 is involved in peritumoral brain edema formation in meningiomas and is also closely related to the expression of VEGF.

Chordoid meningioma: a report of ten cases.

Chordoid meningioma is a rare variant of meningioma with histological features resembling those of chordoma. This tumor has a great risk of recurrence and aggressive growth (WHO grade II). This study was done to document the clinical and pathological features of ten patients with chordoid meningioma who submitted to surgery at the National Institute of Neurology and Neurosurgery in Mexico City. Clinical, histological and immunohistochemical features were examined. The age range was from 30 to 67 years old (mean, 34.2 years). Seven patients were female and three male. The duration of symptoms varied from 3.5 months to 5 years (mean, 14.1 months). No systemic symptoms were noted. The tumor was localized in eight cases in the supratentorial compartments. Histologically, the tumors were characterized by strands and cords of meningothelial cells arranged in a mucinous stroma. Two of the ten tumors showed metaplasic changes, and seven showed brain invasion. Tumor cells demonstrated CK7, EMA and focal S-100 protein and Ep-CAM. Cytokeratin AE1/AE3, GFAP and synaptophysin were negative. The MIB-1 proliferative index was from 6 to 9% (mean 7.8). PCNA Li was 6 to 20% (mean, 14), and microvascular density was 6-16 (mean, 14.5). The mean rate of the MIB-1 labeling index in recurrences was 7.1% versus 6.33% for no tumor recurrence. Chordoid meningioma, World Health Organization grade II, is an uncommon variant of meningioma with a propensity for aggressive behavior and increased likelihood of recurrence. Chordoid meningiomas are predominantly tumors of young adults with a predilection for the supratentorial location. Intraventricular location and absence of systemic manifestations, despite the presence of abundant B-lymphocytes, mast cells and low MIB-1 LI, are some of the interesting findings in the present series that need further study. Hence, a larger number of cases with adequate follow-up data need to be studied further to establish the clinical relevance of this variant.

Angiogenesis and expression of estrogen and progesterone receptors as predictive factors for recurrence of meningioma.

Meningiomas are benign tumors, with low rate of recurrence after surgery. The most important factor predicting recurrence is the extent of surgical resection; other factors have been studied with conflicting results. Angiogenesis, an important substratum for growth and spread of neoplasic cells, and the expression of estrogen and progesterone receptors (ER, PR), could play a role in the recurrence of meningioma. We evaluated 42 patients with meningioma diagnosis (confirmed by histopathology) treated exclusively by surgery between January 1995 and December 1999, and compared the recurring and non-recurring groups after a ten-year follow-up period. Recurrence was associated with several factors including vascular density (VD), cell proliferation index (CPI), ER, PR, and cyclin E (CE) tissue expression, as evaluated by immunohistochemistry. Complete surgical resection was achieved in 41% of patients. Recurrence of meningioma was found in 17 patients (40%). Median + or - standard deviation (SD) of recurrence time was 32 + or - 5 months. When recurrence versus no recurrence was compared, mean + or - SD of VD and CPI were 9 + or - 3.6 and 607.6 + or - 233 (40x/10 fields) respectively. Tissue expression was positive for ER, PR, and CE in 28, 62 and 91% of patients, respectively. The sole significant recurrence-associated factors were extent of resection (P = 0.003) and VD (P = 0.004). ER, PR, and CE-tissue expression were not statistically significant. The most important factor associated with meningioma relapse was vascular density, independently of hormonal status and extent of surgical resection. Patients with a high risk of recurrence could benefit from additional treatment.

Expression of cell adhesion proteins and proteins related to angiogenesis and fatty acid metabolism in benign, atypical, and anaplastic meningiomas.

Most meningiomas are benign tumours of arachnoidal origin, although a small number have high proliferative rates and invasive properties which complicate complete surgical resection and are associated with increased recurrence rates. Few prognostic indicators exist for meningiomas and further research is necessary to identify factors that influence tumour invasion, oedema and recurrence. Paraffin sections from 25 intracranial meningiomas were analysed for expression of the proteins vascular endothelial growth factor (VEGF), VEGF receptors Flt1 and Flk1, E-cadherin, metalloproteinases 2 and 9 (MMP2, MMP9), CD44, receptor for hyaluronic acid-mediated motility (RHAMM), hyaluronic acid (HA), CD45, cyclooxygenase 2 (COX2), brain fatty acid binding protein (BFABP), Ki67, and proliferating cell nuclear antigen (PCNA). Correlations among protein expression were found for several markers of proliferation (Ki67, PCNA, MI) and microvessel density (MVD). COX2 expression increased with increasing with tumour grade and correlated with Ki67, PCNA, MI, MVD, and BFABP. BFABP expression also correlated with Ki67 and PCNA expression. Relationships were also identified among angiogenic factors (VEGF, Flt1, Flk1) and proliferation markers. Oedema was found to correlate with MMP9 expression and MMP9 also correlated with proliferation markers. No correlations were found for MMP2, E-cadherin, or CD44 in meningiomas. In conclusion Ki67, PCNA, MI, MVD, BFABP, and COX2 were significantly correlated with meningioma tumour grade and with each other. These findings, by correlating both intracellular fatty acid transport and eicosanoid metabolism with tumour proliferation, as determined by Ki67 labelling and mitotic index, suggest fatty acids are involved in the progression of meningiomas.

Frontotemporal clear cell meningioma. Report of 3 cases.

Clear cell meningioma (CCM) is an uncommon meningioma. Some cases have been reported, and the localization of most of them is the spinal region. We present 3 cases of CCMs in the frontotemporal lobes. All cases were postmenopausal women with a history of arterial hypertension and uterine leiomyomatosis. The radiologic appearance in 2 cases was similar to that of dural hematomas, and in 1 case, the imaging study was consistent with the diagnosis of meningioma. On histologic examination, there were sheets of glycogenated polygonal cells with abundant clear cytoplasm and round, uniform, bland appearing nuclei. Numerous hyalinized blood vessels and collagenous stroma with fibrillary appearance were present in 2 cases. They were immunoreactive to epithelial membrane antigen, epithelial cell adhesion molecule, and progesterone receptors. However, 2 cases showed weak and focal reaction to Her-2/neu. In our knowledge, some cases of CCMs have been reported and no immunoexpression has been noted with those markers used. These cases illustrate a rare variant of meningioma in the frontotemporal lobes and their immunohistochemical profiles. Differential diagnosis is discussed.

Infiltrative chordoid meningioma of the pineal region: a study of 2 cases.

OBJECTIVE: Meningiomas involving the pineal region are rare. Herein we describe two cases of chordoid meningioma with histologic evidence of pineal gland infiltration. MATERIALS AND METHODS: Clinical histories were abstracted from chart review and consultation letters. HE-stained slides were reviewed in both cases. Selected immunohistochemical stains were performed. RESULTS: the patients included a 44-year-old male and a 37-year-old female who presented with symptoms of intracranial tumor referable to the pineal region. On magnetic resonance imaging (MRI), both lesions demonstrated heterogeneous contrast enhancement. Histologically, the tumors were characterized by strands and cords ofmeningothelial cells arranged in a mucinous stroma. In addition, obvious meningothelial cytology as well as focal osseous metaplasia (Case 1), and transitional histology (Case 2) were also noted. Tumor cells demonstrated EMA and focal S100 protein immunoreactivity, but lacked cytokeratin AE1/AE3 and glial fibrillary acidic protein (GFAP) staining. Synaptophysin and neurofilament protein highlighted the overrun pineal gland parenchyma. MIB1-proliferative index was 8.4 and 20.1%, respectively. CONCLUSIONS: Chordoid meningioma, although rare, may occur in the pineal region. The differential diagnosis of this meningioma subtype in this location is discussed.

Parkia pendula lectin as histochemistry marker for meningothelial tumour.

Lectins have been intensively used in histochemical techniques for cell surface characterization. These proteins are involved in several biological processes and their use as histochemical markers have been evaluated since they can indicate differences in cell surfaces. Parkia pendula lectin (PpeL) was evaluated as histochemical marker for meningothelial meningioma biopsies. Tissue slices were incubated with PpeL conjugated to horseradish peroxidase (PpeL-HRP) and Concanavalin A-HRP (ConA-HPR) and the binding visualized with diaminobenzidine and hydrogen peroxide. The lectin-tissue binding was inhibited with D-glucose. PpeL showed to be a useful tool for the characterization of meningothelial tumour and clinico-pathological diagnosis.

Meningioma with extensive noncalcifying collagenous whorls and glial fibrillary acidic protein expression: new variant of meningioma diagnosed by smear preparation.

The purpose of this report is to describe the unique cytological findings of a new recently characterized type of meningioma that has extensive noncalcifying collagenous whorls and glial fibrillary acid protein (GFAP) expression. This new entity, described by Haberler and colleagues, was named whorling sclerosing variant of meningioma. The patient was a 34-yr-old white man with a large tumor in the brainstem. Intraoperative smear preparations showed a tumor with a large number of solid hyaline masses in a loose background and in focal areas tumor cells formed cohesive nests with a somewhat whorling appearance. The histological sections showed a neoplasia composed of innumerable eosinophilic, collagenous, noncalcified round deposits, cuffed by scattered meningothelial tumor cells. The neoplastic cells showed diffuse cytoplasmic reactivity for EMA and vimentin, as well as positivity to GFAP. This is the first cytological description of this new entity in the literature.

p53 Protein expression in meningiomas - a clinicopathologic study of 55 patients.

Formalin-fixed, paraffin-embedded surgical specimens from 55 meningiomas were immunostained with monoclonal antibody against p53 (Immunotech, Marseilles, France). There were 38 women and 17 men ranging between 9 and 82 years of age. The patients were divided into two groups: group I (47 patients) - mildly symptomatic and group II (eight patients) - severe initial symptoms. There were 43 WHO grade I, 11 WHO grade II, and one WHO grade III meningiomas according to the 1999 WHO classification of brain tumors. In group A (n=49), the tumors were attached to the dura mater of the skull base, and in group B (n=6) they were not. Tumor volume ranged from 1.23 cm(3) to 303.37 cm(3). Peritumoral edema was classified into three grades: grade 0 (n=28) no or minimum edema, grade I (n=19) edema reaches at least half of one cerebral hemisphere, and grade II (n=8) holohemispheric edema. Immunostaining for p53 was found in the neuronal nuclei of 18 meningiomas. It was not correlated with gender, age, anatomical location, tumor volume, degree of peritumoral edema, or Simpson's resection grade. Labeling for p53 was observed in 9/12 meningiomas of WHO grades II or III and was correlated with severity of symptoms (P=0.033) and histological grade (P=0.0009). Immunolocalization of p53 was not correlated with the degree of malignancy.

The biology and pathology of selected skull base tumors.

This paper describes the pathobiology of some of the more common skull base tumors. In addition to clinicopathologic features, emphasis is placed upon methods of diagnosis utilizing immunoperoxidase stains and molecular markers that may or may not impact upon prognosis.

Steroid receptors in meningiomas.

Cytosolic estrogen (ER), progesterone (PR), androgen (AR) and glucocorticoid receptors (GR) were evaluated in 10 meningiomas using a dextran charcoal coated method. We consider as positive specific receptor values greater than or equal to 10 fMol/mg protein. In this study 20% of the meningiomas contained very low titers of specific ER. PR was detectable in 90% of the tumors, at high levels. The mean PR content of PR+ tumors was 60 +/- 38 fMol/mg prot. GR and AR were present in moderate levels, in 70% of the tumors. Competition studies demonstrated steroid specificity for these hormone-binding proteins. Female patients have a higher receptor incidence and titer. In conclusion, it can be hypothesized that the meningioma are a target tissue for steroids and that endocrine therapy may be relevant to unoperable and/or recurrent tumors.

Steroid receptors in meningiomas

Dados epidemiológicos sugerem uma associaçäo entre meningiomas e hormônios sexuais. Há preponderância da incidência da incidência destes tumores em mulheres, sendo diagnosticados mais frequentemente entre 35 e 55 anos. Progressäo tumoral pode ocorrer durante a gravidez e a associaçäo entre meningiomas e câncer de mama é estatisticamente significativa. O efeito benéfico positivo dos glicocorticóides no tratamento clínico de tumores intracranianos está bem documentado, embora este efeito seja relacionado com o edema cerebral e näo com proliferaçäo tumoral. A presença de receptores intracelulares específicos parece ser condiçäo necessaria embora näo suficiente para a expressäo dos efeitos celulares destes esteróides. O objetivo do nosso trabalho foi a determinaçäo de receptores de estrógeno (ER), progesterona (PR), andrógeno (AR) e glicocorticóide (GR) em 10 meningiomas através da metodologia do carväo-dextrana. Neste estudo verificamos que somente 20% dos meningiomas contém receptores de estrógeno e as concentraçöes determinadas säo baixas. Receptores de progesterona estäo presentes em 90% dos tumores, em alta concentraçäo (média + ou - dp = 60 + ou - 38 fMol/mg prot). Cerca de 70% dos meningiomas contém níveis intermediários de AR e GR. Testes de competiçäo demonstram que todos os receptores säo específicos. Incidência e concentraçäo de todos os receptores säo maiores em pacientes do sexo feminino. A ocorrência de receptores de progesterona, andrógeno e glicocorticóide pode indicar a possível utilidade de manipulaçäo endócrinas em meningiomas näo operáveis