Metabolic alterations in meningioma reflect the clinical course.

BACKGROUND: Meningiomas are common brain tumours that are usually defined by benign clinical course. However, some meningiomas undergo a malignant transformation and recur within a short time period regardless of their World Health Organization (WHO) grade. The current study aimed to identify potential markers that can discriminate between benign and malignant meningioma courses. METHODS: We profiled the metabolites from 43 patients with low- and high-grade meningiomas. Tumour specimens were analyzed by nuclear magnetic resonance analysis; 270 metabolites were identified and clustered with the AutoPipe algorithm. RESULTS: We observed two distinct clusters marked by alterations in glycine/serine and choline/tryptophan metabolism. Glycine/serine cluster showed significantly lower WHO grades and proliferation rates. Also progression-free survival was significantly longer in the glycine/serine cluster. CONCLUSION: Our findings suggest that alterations in glycine/serine metabolism are associated with lower proliferation and more recurrent tumours. Altered choline/tryptophan metabolism was associated with increases proliferation, and recurrence. Our results suggest that tumour malignancy can be reflected by metabolic alterations, which may support histological classifications to predict the clinical outcome of patients with meningiomas.

Novel histopathological classification of meningiomas based on dural invasion.

AIMS: Histological invasion into the adjacent brain parenchyma is frequently investigated in meningioma because it is an important morphological criterion for grade II meningioma according to the 2016 WHO classification. However, few studies have focused on dural invasion of meningiomas. Herein, we propose a novel histopathological classification based on dural invasion of meningiomas. METHODS: Forty-nine cases with WHO grade I meningiomas who underwent Simpson grade I removal were collected. After the meningeal layer (ML) and periosteal layer (PL) of dura mater were visualised by Masson's trichrome stain, we evaluated the depth (to the ML and PL) and the patterns (1, expanding; 2, infiltrating) of dural invasion of meningiomas using serial paraffin sections. Invasion-associated markers, including Ki-67, matrix metalloproteinase (MMP)-1, MMP-9 and MMP-13, aquaporin 1 and Na-K-2Cl cotransporter, were quantitatively analysed by immunohistochemistry. RESULTS: Thirty-five cases (71.4%) showed the dural invasion. In 27 of these 35 cases (77.1%), dural invasion was localised in ML. Type 1 (expanding type) and type 2 (infiltrating type) invasions were observed in 23 and 12 cases, respectively. The recurrence rate in cases with type 2 invasion was significantly higher than that in cases with type 1 invasion. The percentage of MMP-1-positive tumour cells was also significantly higher in cases with dural invasion than those without, suggesting involvement of MMP-1 in dural invasion. CONCLUSIONS: We quantitatively evaluated the depth and patterns of dural invasion in meningiomas. The patterns of dural invasion were associated with meningioma recurrence.

Primary pulmonary meningiomas: report of two cases and review of the literature.

BACKGROUND: Meningiomas rarely occur outside the skull, and primary pulmonary meningiomas (PPMs) are more rare. Only a few cases have been reported in the literature. The clinicopathological characteristics are not clear and it is easy to be misdiagnosed, so it is very important to master its diagnosis and differential diagnosis. METHODS: We report two women with primary pulmonary meningioma. At the time of physical examination, the small solitary pulmonary nodules were detected on chest radiograph, and wedge resection was performed by Video-assisted Thoracoscope Surgery(VATS), and histologic evaluation showed that the lesions were benign PPMs. The clinicopathological features, immunophenotype and differential diagnosis of PPMs were analyzed, with a review of the cases published in the literature. RESULTS: The study group comprised of 40 patients, 14 males and 26 females. The median age was 56.5 years (range 18-108). Thirty patients who underwent routine screening studies were asymptomatic but had a pulmonary nodule detected on chest X-ray. Nine patients had respiratory symptoms. Only 1 patient had non-specific symptoms. Most of the PPMs were benign, only 3 cases were malignant. Benign PPMs ranged from 0.6 cm to 6 cm in diameter (median 2 cm). The 3 malignant PPMs were 5 cm, 6.5 cm and 15 cm in diameter. The prognosis of benign PPM resection is good, with almost no recurrence or metastasis. But the two of three malignant PPMs relapsed. CONCLUSIONS: PPM is very rare. It needs to be diagnosed by combining histology and immunohistochemistry. Diseases that need to be identified include spindle cell mesothelioma, spindle cell thymoma, spindle cell carcinoma, metastatic tumor, etc.

Spectrochemical differentiation of meningioma tumours based on attenuated total reflection Fourier-transform infrared (ATR-FTIR) spectroscopy.

Meningiomas are the commonest types of tumours in the central nervous system (CNS). It is a benign type of tumour divided into three WHO grades (I, II and III) associated with tumour growth rate and likelihood of recurrence, where surgical outcomes and patient treatments are dependent on the meningioma grade and histological subtype. The development of alternative approaches based on attenuated total reflection Fourier-transform infrared (ATR-FTIR) spectroscopy could aid meningioma grade determination and its biospectrochemical profiling in an automated fashion. Herein, ATR-FTIR in combination with chemometric techniques is employed to distinguish grade I, grade II and grade I meningiomas that re-occurred. Ninety-nine patients were investigated in this study where their formalin-fixed paraffin-embedded (FFPE) brain tissue samples were analysed by ATR-FTIR spectroscopy. Subsequent classification was performed via principal component analysis plus linear discriminant analysis (PCA-LDA) and partial least squares plus discriminant analysis (PLS-DA). PLS-DA gave the best results where grade I and grade II meningiomas were discriminated with 79% accuracy, 80% sensitivity and 73% specificity, while grade I versus grade I recurrence and grade II versus grade I recurrence were discriminated with 94% accuracy (94% sensitivity and specificity) and 97% accuracy (97% sensitivity and 100% specificity), respectively. Several wavenumbers were identified as possible biomarkers towards tumour differentiation. The majority of these were associated with lipids, protein, DNA/RNA and carbohydrate alterations. These findings demonstrate the potential of ATR-FTIR spectroscopy towards meningioma grade discrimination as a fast, low-cost, non-destructive and sensitive tool for clinical settings. Graphical abstract Attenuated total reflection Fourier-transform infrared (ATR-FTIR) spectroscopy was used to discriminate meningioma WHO grade I, grade II and grade I recurrence tumours.

Constant expression of somatostatin receptor 2a in minute pulmonary meningothelial-like nodules.

AIMS: Although ultrastructural studies showed that minute pulmonary meningothelial-like nodules (MPMNs) cells closely resembled meningothelial cells, their immunophenotype has not been well characterised, partly due to their rarity. METHODS: Somatostatin receptor 2a (SSTR2a) and other markers of meningioma, including epithelial membrane antigen (EMA), progesterone receptor (PR) and S100, were analysed retrospectively in 19 MPMN cases from two institutions in China. RESULTS: The median age of patients with MPMNs was 62.5 years (32-73 years), with a male-to-female ratio of 1:8.5. Most (15/19) patients with MPMNs had coexisting diseases, including adenocarcinomas (12 cases), bronchiectasis (1 case) and tuberculosis (2 cases). Just over half of the cases (10/19) were multifocal lesions (2-5 lesions). An additional 53 cases with 123 lesions from the literature were reviewed with reported immunophenotype information. In total, 162 lesions were included in the analysis. The size of nodules was 1-4 mm. All MPMN lesions (39/39) in the 19 cases showed strong and diffuse cytoplasmic expression of SSTR2a. The expression rate of SSTR2a was higher than that of conventional markers of meningioma, including EMA (86/138), PR (32/68) and S100 (1/125). CONCLUSIONS: Our observations expand the spectrum of recognised SSTR2a-positive lesions and once again demonstrated that MPMNs show immunohistochemical characteristics similar to meningothelial cells.

Transient receptor potential vanilloid (TRPV) channel expression in meningiomas: prognostic and predictive significance.

The TRPV1-4 members of TRPV cation channel subfamily are mainly regarded as polymodal receptors that may be activated by diverse changes in cellular microenvironment and endogenous and exogenous agents. Abnormal expression of these channels has been reported in various tumors but not in meningiomas. Meningioma cells are thought to originate from arachnoid cap cells due to cytological and functional similarities between the two types of cells. To investigate the expression profile of TRPV1-4 channels in meningiomas and compare with TRPV1-4 channel expression in leptomeninges, we used immunohistochemistry in formalin-fixed, paraffin-embedded semi-serial tissue sections from 175 meningiomas with different grades and histological subtypes, and normal brain or meningioma specimens that contained leptomeninges. The labeling index (LI), defined as the percentage of positive (labeled) cells out of the total number of tumor cells counted, was determined. Leptomeninges were TRPV1-4 immunonegative. A significant percentage of tumors exhibited TRPV1-4 channel expression which was independent of the proliferation index of the tumors but was significantly associated with histopathological subtypes. The TRPV1 and TRPV3 immunoexpression was decreased whereas TRPV4 immunoexpression was significantly greater in high-grade (WHO, grade II and III) as compared with low-grade (WHO, grade I) meningiomas. Additionally, TRPV4 emerged as an independent predictor for the degree of malignancy using the binary logistic regression model [dependent variable: grade I versus higher grades (II and III)]. Kaplan-Meier analysis for 102 patients showed no significant association of TRPV1-4 expression with overall survival. The above data support that TRPV1-4 channels are implicated in meningioma pathogenesis, and TRPV4 has predictive significance in the disease.

[Use of the PELICAN software for the creation and export of standardized pathology reports in central nervous system tumors: Example of meningiomas]. / Utilisation du logiciel PELICAN pour la saisie et l'export de comptes rendus standardisés dans les tumeurs du système nerveux central : application aux méningiomes.

INTRODUCTION: PELICAN ("Partager Efficacement en Laboratoire les Informations des Comptes rendus ANatomopathologiques") is a software, which generates standardized reports, and allows to automatically create a database. It has been used in central nervous system tumor pathology at the University Hospital of Nancy since 2014. The purpose of this article was to illustrate the use of this application for meningiomas, with a first statistical evaluation. MATERIALS AND METHODS: The export of data included all cases of meningiomas recorded in the PELICAN application until July 2018. The PELICAN application is a Microsoft Excel file containing a software, written in Visual Basic for Applications, and used by the pathologist to create the report. The main clinical data were collected from the Hérault Register census form. Follow-up was systematically reported for atypical meningiomas. RESULTS: Two hundred and ninety-five meningiomas were analyzed, including 250 grade I meningiomas, 42 grade II meningiomas, and 3 grade III meningiomas. Grade II meningiomas were characterized by a significantly higher proportion of men (P=0.002) and dural infiltration (P<0.001), a significant increase in the Ki-67 index (P<0.0001), and a significant decrease in progesterone receptor expression (P<0.001). In atypical meningiomas, a Ki-67 index of more than 20 % was significantly correlated with a shorter progression-free survival (P=0.032). CONCLUSION: The PELICAN software is an easy-to-use tool that allows to generate standardized reports and feed a database, opening very interesting perspectives from an epidemiological and scientific point of view.

Preoperative grading of intracranial meningioma by magnetic resonance spectroscopy (1H-MRS).

Although proton magnetic resonance spectroscopy (1H-MRS) is a common method for the evaluation of intracranial meningiomas, controversy exists regarding which parameter of 1H-MRS best predicts the histopathological grade of an intracranial meningioma. In this study, we evaluated the results of pre-operative 1H-MRS to identify predictive factors for high-grade intracranial meningioma. Thirteen patients with World Health Organization (WHO) grade II-III meningioma (confirmed by pathology) were defined as high-grade; twenty-two patients with WHO grade I meningioma were defined as low-grade. All patients were evaluated by 1H-MRS before surgery. The relationships between the ratios of metabolites (N-acetylaspartate [NAA], creatine [Cr], and choline [Cho]) and the diagnosis of high-grade meningioma were analyzed. According to Mann-Whitney U test analysis, the Cho/NAA ratio in cases of high-grade meningioma was significantly higher than in cases of low-grade meningioma (6.34 ± 7.90 vs. 1.58 ± 0.77, p<0.05); however, there were no differences in age, Cho/Cr, or NAA/Cr. According to conditional inference tree analysis, the optimal cut-off point for the Cho/NAA ration between high-grade and low-grade meningioma was 2.409 (sensitivity = 61.54%; specificity = 86.36%). This analysis of pre-operative 1H-MRS metabolite ratio demonstrated that the Cho/NAA ratio may provide a simple and practical predictive value for high-grade intracranial meningiomas, and may aid neurosurgeons in efforts to design an appropriate surgical plan and treatment strategy before surgery.

Clinicopathologic features of minute pulmonary meningothelial-like nodules.

Purpose Minute pulmonary meningothelial-like nodules are incidentally discovered in lung specimens. We analyzed the clinicopathologic features of 14 cases identified in surgically resected lungs. Methods Among patients who underwent lung resection in our hospital from October 2007 to March 2016, 14 were found to have minute pulmonary meningothelial-like nodules. The clinical parameters, radiologic findings, and pathologic features of these patients were retrospectively reviewed using the medical records. Results The patients included 4 men and 10 women, with a mean age of 69 years (range 53-82 years). The coexisting main disease was adenocarcinoma in 8 patients, squamous cell carcinoma in 1, atypical adenomatous hyperplasia in 1, and metastatic pulmonary tumor in 3. In one patient, the minute pulmonary meningothelial-like nodules presented as multiple lung nodules on chest computed tomography. The median size of the nodules was 1.4 mm (range 0.3-6.0 mm). Similar to meningioma, one case had immunoreactivity to progesterone receptor and epithelial membrane antigen, although the minute pulmonary meningothelial-like nodules were not associated with a meningioma. Conclusions The relationship between minute pulmonary meningothelial-like nodules and meningioma should be investigated. If minute pulmonary meningothelial-like nodules are found on preoperative computed tomography, thoracoscopic lung biopsy is helpful for differential diagnosis.

Intranodal meningothelial proliferation in a patient with Cowden syndrome: a case report.

Ectopic meningothelial proliferations are rare and can occur in a multitude of extracranial/spinal anatomic locations. Perineurioma is another uncommon entity that shares similar histological characteristics to those found in meningothelial proliferations. These include bland spindle cells with thin, bipolar nuclei; eosinophilic cytoplasm; and indistinct cell borders, arranged in short fascicles with whorl formation. Given their uncommon occurrence and shared histological and immunohistochemical features, their distinction can present a diagnostic challenge. Immunohistochemical studies can provide guidance when attempting to distinguish between these 2 lesions. Here, we present an unusual case of a patient with Cowden syndrome who was discovered to have a meningothelial proliferation within an axillary lymph node. To the best of our knowledge, this is the first case in which a meningothelial proliferation has been identified in a lymph node. Furthermore, the occurrence in a patient with Cowden syndrome is intriguing and raises the possibility of a pathogenetic link.

Prognostic value of Ki67: comparison of the proliferation index between meningiomas with and without infiltration of glial tissue.

BACKGROUND: Although generally considered benign, meningiomas can cause significant morbidity and mortality.  Histologic grade is the most useful morphologic predictor of recurrence. OBJECTIVES: To compare Ki67 labeling index between meningioma grade I and meningioma grade II with brain invasion. METHODS: We analyzed 20 primary meningioma, 10 of which were grade I and 10 of which were grade II. Ki67 proliferative indices were determined in all cases. RESULTS: The patient population consisted of 9 males and 11 females with mean age of 60 years. For meningioma grade I, the Ki67 labeling index varied between 1 and 15% with an average of 3.1%. A diagnosis of gradeII meningiomas was made solely on the basis of brain invasion. The immunohistochemical study noted that the Ki67 index varied between 1 and 20% with an average of 6,8%. CONCLUSION: The Ki67 labeling index shows a significant increase from grade I to grade II.  It may provide useful prognostic information.

Type I Cutaneous Meningioma (Rudimentary Meningocele) With Intradural Attachment to the Phylum Terminale.

Cutaneous meningiomas (CM) are a small subset of meningiomas, further classified into three subtypes. The authors present a 15-year-old male with a symptomatic congenital type I CM and describe the histopathological and immunohistochemical findings. To the authors' knowledge, this is the first report of an extraspinal lumbar type I CM with intradural attachment to the phylum terminale.

Content-based analysis of Ki-67 stained meningioma specimens for automatic hot-spot selection.

BACKGROUND: Hot-spot based examination of immunohistochemically stained histological specimens is one of the most important procedures in pathomorphological practice. The development of image acquisition equipment and computational units allows for the automation of this process. Moreover, a lot of possible technical problems occur in everyday histological material, which increases the complexity of the problem. Thus, a full context-based analysis of histological specimens is also needed in the quantification of immunohistochemically stained specimens. One of the most important reactions is the Ki-67 proliferation marker in meningiomas, the most frequent intracranial tumour. The aim of our study is to propose a context-based analysis of Ki-67 stained specimens of meningiomas for automatic selection of hot-spots. METHODS: The proposed solution is based on textural analysis, mathematical morphology, feature ranking and classification, as well as on the proposed hot-spot gradual extinction algorithm to allow for the proper detection of a set of hot-spot fields. The designed whole slide image processing scheme eliminates such artifacts as hemorrhages, folds or stained vessels from the region of interest. To validate automatic results, a set of 104 meningioma specimens were selected and twenty hot-spots inside them were identified independently by two experts. The Spearman rho correlation coefficient was used to compare the results which were also analyzed with the help of a Bland-Altman plot. RESULTS: The results show that most of the cases (84) were automatically examined properly with two fields of view with a technical problem at the very most. Next, 13 had three such fields, and only seven specimens did not meet the requirement for the automatic examination. Generally, the Automatic System identifies hot-spot areas, especially their maximum points, better. Analysis of the results confirms the very high concordance between an automatic Ki-67 examination and the expert's results, with a Spearman rho higher than 0.95. CONCLUSION: The proposed hot-spot selection algorithm with an extended context-based analysis of whole slide images and hot-spot gradual extinction algorithm provides an efficient tool for simulation of a manual examination. The presented results have confirmed that the automatic examination of Ki-67 in meningiomas could be introduced in the near future.

[Diagnostic value of STAT6 immunohistochemistry in solitary fibrous tumor/meningeal hemangiopericytoma].

OBJECTIVE: To investigate the diagnostic role of STAT6 immunohistochemistry in solitary fibrous tumors (SFT)/meningeal hemangiopericytomas (HPC). METHOD: Evaluated the expression of STAT6, vimentin, CD34, EMA, PR, S-100, CD56, GFAP and Ki-67 in a cohort of 37 SFT/meningeal HPC, 30 meningiomas and 30 schwannomas by immunohistochemistry staining. RESULTS: All SFT/meningeal HPC demonstrated nuclear positivity for STAT6, and the proportion of positive tumor cells ranged from 60% to 95%, with no significant difference cases.Vimentin was strongly positive in all cases. CD34, EMA and PR positivity was found in 32 cases, 1 case and 4 cases, respectively.S-100 protein, CD56 and GFAP were negative; Ki-67 labeling index was 1%-8%. However, the meningiomas and schwannomas were negative for STAT6. CONCLUSIONS: STAT6 is a relatively specific biomarker for SFT/meningeal HPC, and may be used in the diagnosis and differential diagnosis of SFT/meningeal HPC, especially for the atypical cases, and allows the precise pathologic diagnosis of SFT/meningeal HPC.

Differential Diagnosis of Meningeal SFT-HPC and Meningioma: Which Immunohistochemical Markers Should Be Used?

Meningeal solitary fibrous tumors-hemangiopericytomas (SFT-HPC) and meningiomas can be difficult to distinguish on histologic examination. STAT6 immunohistochemistry (IHC) is a reliable diagnostic marker of SFT-HPCs. Recently, GRIA2 has also been reported to be a diagnostic marker of SFT-HPC, although no extensive data are available for meningeal SFT-HPCs yet. The aim of this study was to test their diagnostic performance in a large cohort of SFT-HPCs and meningiomas. IHC analyses for GRIA2 and STAT6 were performed on tissue microarrays containing 76 SFT-HPCs and 181 meningiomas. Results were compared with previous data with ALDH1 and CD34. Two different anti-STAT6 antibodies were tested: SC-20 polyclonal and YE361 monoclonal antibody. Ninety-six percent of meningeal SFT-HPCs but no meningioma displayed nuclear STAT6 positivity. With SC-20 antibody, concomitant cytoplasmic staining for STAT6 was observed in >50% of all cases, including meningiomas. However, using YE361 antibody, cytoplasmic staining was absent, and nuclear signal intensity was stronger leading to better interpretation of STAT6 IHC. GRIA2 was positive in 84% of SFT-HPCs and in 16% of meningiomas. STAT6 had excellent sensitivity (96%) and specificity (100%), ALDH1 and GRIA2 had same sensitivity (84%), but ALDH1 and CD34 had better specificity than GRIA2 (97% and 96% vs. 84%, respectively). For the differential diagnosis of SFT-HPCs versus meningiomas, the best diagnostic approach is to perform STAT6, followed by ALDH1 and CD34 in the case of uncommon STAT6-negative cases. Because of meningioma positivity, GRIA2 seems less useful in this indication.

Meningeal Hemangiopericytomas and Meningomas: a Comparative Immunohistochemical and Genetic Study.

BACKGROUND: The meningeal hemangiopericytoma (MHPC) is a vascular tumor arising from pericytes. Most intracranial MHPCs resemble meningiomas (MNGs) in their clinical presentation and histological features and may therefore be misdiagnosed, despite important differences in prognosis. MATERIALS AND METHODS: We report 8 cases of MHPC and 5 cases of MNG collected from 2007 to 2011 from the Neuro-Surgery and Histopathology departments. All 13 samples were re reviewed by two independent pathologists and investigated by immunohistochemistry (IHC) using mesenchymal, epithelial and neuro-glial markers. Additionally, we screened all tumors for a large panel of chromosomal alterations using multiplex ligation probe amplification (MLPA). Presence of the NAB2-STAT6 fusion gene was inferred by immunohistochemical staining for STAT6. RESULTS: Compared with MNG, MHPCs showed strong VIM (100% of cases), CD99 (62%), bcl-2 (87%), and p16 (75%) staining but only focal positivity with EMA (33%) and NSE (37%). The p21 antibody was positive in 62% of MHPC and less than 1% in all MNGs. MLPA data did not distinguish HPC from MNG, with PTEN loss and ERBB2 gain found in both. By contrast, STAT6 nuclear staining was observed in 3 MHPC cases and was absent from MNG. CONCLUSIONS: MNG and MHPC comprise a spectrum of tumors that cannot be easily differentiated based on histopathology. The presence of STAT6 nuclear positivity may however be a useful diagnostic marker.

The application of flow cytometry for evaluating biological aggressiveness of intracranial meningiomas.

BACKGROUND: Meningiomas have classically been considered to include benign and atypical/anaplastic tumors. Despite the availability of clinical and pathologic parameters for prognostic prediction prognosis, the behavior of each meningioma may be difficult to predict. Here, we used DNA flow-cytometric studies to predict biological tumor behaviors of intracranial meningiomas. METHODS: The specimens were obtained from fresh tumoral tissues of 43 microsurgically resected meningiomas as approved by the institutional review board. The presence of G2/M-phase and S+G2/M-phase fractions were analyzed and correlated with the proliferation index of Ki-67 and the World Health Organization grading. The check point of G2/M-phase fraction, cyclin B, and pCdk1 (Y15), were analyzed by Western blotting. RESULTS: Our results showed that there were significant differences in Ki-67, G2/M-phase, S+G2/M-phase fractions, and cyclin B between benign and atypical/anaplastic meningiomas. The optimal cutoff point of G2/M-phase and S+G2/M-phase fractions were 5.12 and 7.52%, respectively, and this can be used to discriminate those cases with benign or atypical/anaplastic meningiomas. Besides, both the G2/M-phase and S+G2/M-phase fractions were correlated well with Ki-67 and the histopathological features such as focal necrosis, infiltration of dura mater and mitotic activity. In addition, the occurrence of tumor recurrence and patient age were correlated to the G2/M-phase and S+G2/M-phase fractions, respectively. The G2/M-phase and S+G2/M-phase fractions, however, did not correlate well with histologic invasion to adjacent bone, sinus, or brain tissues. CONCLUSIONS: The use of flow cytometry facilitates additional information for G2/M-phase and S+G2/M-phase fractions represent tumoral grading and risk of recurrence in patients with meningiomas.

Microcystic meningioma of the calvarium: a series of 9 cases and review of the literature.

Meningiomas are one of the most common tumors that arise within the central nervous system; they represent up to 30% of all primary intracranial tumors. Extradural meningiomas are rare (<2% of all meningiomas), and most arise within the calvarium. Intraosseous calvarial meningiomas are usually easy to diagnose histologically if they are of the meningothelial type; however, they may cause diagnostic challenges when they manifest as unusual morphologic variants, such as the microcystic type. To address this issue we present a series of 9 cases of calvarial microcystic meningiomas arising in 7 female and 2 male patients; all patients were adults. The tumors had heterogenous findings on imaging studies and ranged in size from 1.1 to 4.3 cm in greatest dimension. The neoplasms were composed predominantly of stellate and spindle cells with long, thin interconnecting cytoplasmic processes arranged in a complex network. The resulting cellular architecture was "sieve-like" in appearance because of the formation of numerous small "cyst-like" spaces interposed between the cytoplasmic processes of the tumor cells. All of the neoplasms expressed the characteristic immunophenotype of meningiomas (EMA, PR positive). Most tumors were resected, and none of these have recurred during a follow-up period of 1 to 83 months (average 17 mo). The morphology of the tumors and their anatomic location generated problems in diagnosis, especially in 6 patients with a history of malignancy and for whom metastatic disease was suspected clinically. Intraosseous microcystic meningioma is uncommon, and this series, the largest reported to date, describes their clinicopathologic findings, biological behavior, and features that facilitate their accurate diagnosis.

Immunohistochemical characterization of brain-invasive meningiomas.

Brain-invasive meningiomas have an adverse prognosis, so it is important to detect and correctly evaluate brain invasion by light microscopy. Furthermore, the underlying biological mechanisms responsible for brain-invasive growth are incompletely understood. The primary aim of this study was to identify immunohistochemical markers that could improve identification and evaluation of brain invasion in meningiomas. A second aim was to investigate the process of brain invasion using immunohistochemical markers of proliferation, extracellular matrix modulation, and cell adhesion. From a series of 196 human meningiomas, 67 cases were selected for analysis because of the presence of brain tissue in tumor specimens. Fourteen of these 67 meningiomas were brain-invasive. Invasiveness was determined primarily by evaluation of hematoxylin-erytrosin-saffron- (HES-) stained specimens, although glial fibrillary acidic protein (GFAP), anti-collagen IV, and cluster of differentiation 44 (CD44) markers provided additional information. It was important to examine microscopic sections from various levels of the paraffin-embedded tissue block to adequately assess invasiveness. Sections stained using antibodies against Ki-67/MIB-1, phospohistone-H3 (PHH3), matrix metalloproteinase-9 (MMP-9), cathepsin D, plasminogen activator inhibitor-1 (PAI-1), and E-cadherin antigens were used to characterize brain-invasive meningiomas and to investigate the process of brain invasion. Only increased expression of the extracellular matrix modulator MMP-9 correlated with brain-invasive growth (p=0.025). Examination of HES-stained sections identified brain invasion. Use of relevant immunohistochemical markers did not contribute substantially to this evaluation. Evaluation of stepwise sections should be considered when brain-invasive growth is suspected. MMP-9 may be an important mediator of brain-invasive growth.