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 somatostatin receptors (SSTR1-SSTR5) in meningiomas and its clinicopathological significance

Meningiomas are benign brain tumors that are usually to recur. Studies have shown in vitro and in vivo that meningiomas, regardless of histology and classification, express somatostatin receptors (SSTRs). We investigated the immunohistochemical expression of five SSTR subtypes (SSTR1-SSTR5) in tumor tissue sections from 60 patients with diagnosis of meningioma who underwent surgical resection and relating it to patient age and sex, tumor histology, location, regrowth/recurrence and follow-up. Mean (SD) patients age was 53.18 (12.6) years and 44 were women (73.3%). According to the WHO histological grading criteria, 47 (78.3%) meningiomas were grade I, 11 (18.3%) were grade II, and 2 (3.3%) were grade III. All five SSTRs were expressed in our sample, at frequencies ranging from 61.6 to 100%, with a predominance of SSTR2. SSTR5 was more frequently expressed in tumors benign than in tumors malignant (P<0.013). Recurrence-free survival rate at 2 years was 75.2%. There were no significant differences in SSTR expression regarding age, sex, tumor location and regrowth/recurrence. SSTR expression was detected at a significant frequency in this series. SSTR5 showed higher expression in tumors benign supporting the use of these SSTRs in diagnostic of meningiomas and their influence in process of tumorigenesis in meningiomas recurrence.     

An immunohistochemical study of HER2 expression in meningioma and its correlation with tumor grade

Meningiomas account for about 15-30% of all primary intracranial tumors. According to the 2007 WHO classification, meningiomas are divided into three grades (I, II and III). Recurrence is an issue following surgical treatment of meningioma, especially in grades II and III. HER2 (also known as erbB-2) is a 185-kD transmembrane glycoprotein with tyrosine kinase activity. HER2 is expressed in some human malignancies and can be a potential target for therapeutic intervention with selective inhibitors. There are only a few studies on the relationship between meningioma and HER2 expression, and the results are different as well. The aim of this study was to determine this relationship. Seventy-two paraffin blocks of meningioma were selected randomly, and immunohistochemical staining was then performed for each specimen. Thirty-one of the 72 meningiomas were HER2-positive. HER2 expression was observed in 11 (55%) of the 20 grade II/III, and 20 (38.5%) of the 52 grade I meningiomas. Consequently, HER2 expression was detected in 43% of meningiomas. No significant difference was seen between grade I and grade II/III meningiomas, primary and recurrent tumors, and males and females from the point of view of HER2 expression.     

Osteopontin predicts the behaviour of atypical meningioma

Lin C‐K, Tsai W‐C, Lin Y‐C & Hueng D‐Y
(2012) Histopathology  60, 320–325
Osteopontin predicts the behaviour of atypical meningioma Aim: Although the World Health Organization (WHO) histological criteria distinguishing benign from atypical and malignant meningioma are clear, discerning benign from atypical meningioma is still somewhat difficult, leading to interobserver diagnostic variability. Osteopontin (OPN) and cortactin play important roles in tumorigenesis, invasion and metastasis of several human cancers. The aim of this study was to evaluate the usefulness of OPN and cortactin immunohistochemistry for distinguishing between benign, atypical and malignant meningioma and predicting their recurrence. Methods and results: Seventy‐five specimens (48 benign, 17 atypical and 10 malignant meningiomas) were investigated immunohistochemically. The mean immunohistochemical scoreimmunohistochemical score ± SE of the mean of both OPN and cortactin were significantly higher in grade II or grade III meningiomas than in grade I meningioma. Discriminant analysis of immunohistochemical OPN expression showed correct classification of 97.7% of WHO grade I meningiomas and 88.2% of WHO grade II meningiomas (95.4% accuracy). However, the same analysis of cortactin expression showed correct classification of 95.8% of WHO grade I meningiomas and only 23.5% of WHO grade II meningiomas (76.9% accuracy). A cut‐off for predicting grades I and II meningioma recurrence was determined for OPN (3.0) but not for cortactin. Finally, logistic regression identified both this cut‐off (P < 0.05) and WHO grade (P < 0.05) as independent risk factors for recurrence. Conclusions: OPN expression is a valuable marker for diagnosis of atypical meningioma and prediction of grades I and II meningioma recurrence.     

Significance of COX‐2 and VEGF expression in histopathologic grading and invasiveness of meningiomas

Meningiomas are slow‐growing neoplasms that recur locally. Their morphologic grading does not always correlate with patient outcome. We evaluated the status of several immunohistochemical markers with histopathologic parameters in various grades of meningioma.Eighty‐eight meningioma specimens were examined immunohistochemically to determine the status of Ki‐67, cyclin D1, epidermal growth factor receptor (EGFR), cyclooxygenase‐2 (COX‐2), vascular endothelial growth factor (VEGF), and bcl‐2. Several clinical and pathological parameters were investigated.Forty‐nine Grade I, 33 Grade II, and 6 Grade III meningiomas were observed. VEGF and Ki‐67 expression was correlated with higher tumor grade. The association between grade and other immunohistochemical markers expression was not significant. A correlation was observed between COX‐2 expression and invasiveness to the brain or adjacent soft tissue. Tumor recurrence was correlated with brain or adjacent soft tissue invasion. We also observed a relationship between VEGF level and COX‐2 expression, and they were both correlated with necrosis.Immunohistochemical evaluation of VEGF, COX‐2, and Ki‐67 expression can provide information regarding the behavior of meningiomas, particularly for cases in which histological grading is not straightforward.     

Multiple meningioma with different grades of malignancy: case report with genetic analysis applying single-nucleotide polymorphism array and classical cytogenetics

Multiple meningiomas with synchronous tumor lesions represent only 1-9% of all meningiomas and usually show a uniform histology. The simultaneous occurrence of different grades of malignancy in these nodules is observed in only one third of multiple meningiomas. We report a case of a sporadic multiple meningioma presenting with different histopathological grades (WHO I and II). The tumor genome of both nodules was analyzed by GTG-banding, spectral karyotyping (SKY), locus-specific FISH, and single nucleotide polymorphism array (SNP-A) karyotyping. GTG-banding and SKY revealed 25 structural and 33 numerical aberrations with a slightly increased aberration frequency in the WHO grade II nodule. We could confirm terminal deletions on chromosomes 1p [ish del(1)(p36)(p58-,pter-) 16.5% WHO grade I and 20.9% WHO grade II], partial deletions on 22q, and/or monosomy 22 (monosomy 22 14% WHO grade I and 34% WHO grade II) as the most frequent aberrations in both meningioma nodules. In the meningioma WHO grade II, in addition, a de novo paracentric inversion within chromosomal band 1p36 was detectable. Furthermore, for meningiomas de novo, dicentric chromosomes 4 could be identified in both tumor nodules. We also detected previously published segmental uniparental disomy regions 1p31.1, 6q14.1, 10q21.1, and 14q23.3 in normal control DNA of the patient and in both tumor nodules. Taken together, we describe a very rare case of multiple meningioma with overlapping but also distinct genetic aberration patterns in two nodules of different WHO grades of malignancy.     

Hypermethylation and Transcriptional Downregulation of the TIMP3 Gene is Associated with Allelic Loss on 22q12.3 and Malignancy in Meningiomas

The gene for the tissue inhibitor of metalloproteinase 3 (TIMP3) on 22q12.3 had been reported to be inactivated by promoter methylation in various types of cancers, with controversial findings in meningiomas. We performed direct sodium bisulfite sequencing in a series of 50 meningiomas, including 27 benign meningiomas [World Health Organization (WHO) grade I], 11 atypical meningiomas (WHO grade II) and 12 anaplastic meningiomas (WHO grade III), and found hypermethylation of TIMP3 in 67% of anaplastic meningiomas, but only 22% of atypical and 17% of benign meningiomas. Moreover, TIMP3 methylation scores were significantly inversely correlated with TIMP3 mRNA expression levels (P = 0.0123), and treatment of the meningioma cell line Ben‐Men‐1 with demethylating agents induced an increased TIMP3 mRNA expression. TIMP3 is located in the chromosomal band 22q12, the allelic loss of which occurs early in meningioma tumorigenesis and preferentially targets the NF2 tumor suppressor gene. In our tumor panel, all meningiomas with TIMP3 hypermethylation—except for a single case—exhibited allelic losses on 22q12.3. Thus, TIMP3 inactivation by methylation seems fairly exclusive to meningiomas with allelic losses on 22q12 but—in contrast to NF2 mutation—appears to be involved in meningioma progression as it is associated with a more aggressive, high‐grade meningioma phenotype.     

Expression of E-cadherin and catenins in meningioma: ubiquitous expression and its irrelevance to malignancy

The expression of cell adhesion molecules in 107 meningiomas was analyzed with immunohistochemical methods using antibodies to epithelial (E)-cadherin and catenins (alpha, beta and gamma). According to the provided World Health Organization (WHO) grading, 84, 18 and five cases were classified as grade I, II and III, respectively. In addition, hemangioblastoma (15 cases) and hemangiopericytoma (four cases) were also evaluated. In most meningiomas, E-cadherin, alpha- and beta-catenins were expressed along the cell membrane or inside the cytoplasm. The tumor cells constituting whorls and glandular structures of secretory type showed a strong immunoreactivity. gamma-Catenin expression tended to be weak and infrequent in fibrous meningiomas, while other types exhibited diffuse stainings. Even in meningiomas of more than grade II, the expressions of cell adhesion molecules were detected in all cases. Hemangiopericytoma was positive for alpha- and beta-catenins, and hemangioblastomas were positive for beta-catenin alone, which was distinct from the expression pattern in meningiomas. Quantitatively, there were no correlations between the histological variants, Ki-67 indexes, or grades of meningiomas and the immunoreactive scores except for gamma-catenin scores of fibrous meningiomas. The present study demonstrates that cell adhesion molecules are ubiquitously expressed in all variants of meningioma and may be involved in the tumor morphogenesis. This result suggests that the expression of cell adhesion molecules is not a reliable indicator of malignancy in meningiomas. The present study also suggests that these markers may be useful for the differential diagnosis of meningioma.     

Correlation between histological grade, MIB-1, p53, and recurrence in 69 completely resected primary intracranial meningiomas with a 6 year mean follow-up

Sixty-nine intracranial, totally excised meningiomas were immunostained for MIB-1 and p53 protein expression. According to the 1993 WHO criteria, revised by Perry et al., the 69 meningiomas were classified into: grade I = 54 benign meningiomas, grade II = 10 atypical meningiomas, grade III = 5 malignant meningiomas. The patients were followed until death or for an average of 6.7 years. The 69 meningiomas were divided into two groups, according to the absence (n = 42) or presence (n = 27) of recurrences. In the last group we included 3 patients who died of meningioma recurrence. According to the percentage of MIB-1 positively stained cells, meningiomas were divided into three groups: <1% (n = 36), 1-10% (n = 28), >10% (n = 5). We found the MIB-1 labeling index (LI) <1% in 33 grade I (61%) and in 3 grade II (30%) meningiomas. On the other hand, 7 grade II (70%) and all grade III (100%) meningiomas presented a MIB-1 LI >1%. Correlation between histological grade and MIB-1 LI was statistically significant (p = 0.0006). The correlation between MIB-1 LI and follow-up was also highly significant (p < 0.001): the majority of meningiomas which did not recur (32/42 equal to 76%) were characterized by a low (<1%) MIB-1 LI. In the recurrence group MIB-1 LI was significantly higher than in the disease-free patients' group. Moreover, MIB-1 appeared to be a prognostic parameter not strongly related to the histological grade. In fact, it was significantly higher in recurrent histologically benign meningiomas, as compared with benign meningiomas without recurrence (p = 0.0006). Positive p53 protein expression (>1%) was shown in 26/45 meningiomas (57%), with an LI of 1-10% in 18 (40%) and an LI of >10% in 8 (17%) meningiomas. Although the p53 LI tended to be higher in atypical and malignant meningiomas, no significant correlation was found between the p53 expression and the recurrence (p = 0.05). The authors conclude that quantitative MIB-1 labeling is a useful technique in the routine diagnostic assessment of meningiomas, and helpful in obtaining more information about prognosis and thereby in planning the most suitable treatment.     

New developments in the pathology of skull base tumors

As an anatomical interface between various tissues, the skull base harbors an exceptionally broad variety of neoplasms, some of which pose a major challenge for surgical pathology. The characterization of distinct immunohistochemical expression profiles and the identification of molecular genetic alterations associated with different tumor entities have significantly advanced this field. The new World Health Organization (WHO) classification of tumors of the nervous system lists 15 histopathological variants of meningioma. Of clinical importance are those entities that carry an increased risk of recurrence and a poor prognosis, i.e., the atypical meningioma (WHO grade II), clear-cell meningioma (WHO grade II), chordoid meningioma (WHO grade II), rhabdoid meningioma (WHO grade III), papillary meningioma (WHO grade III), and anaplastic meningioma (WHO grade III). Diagnostic criteria for atypical and anaplastic meningioma variants have now been stringently defined. The differential diagnosis of meningiomas includes hemangiopericytoma, hemangioblastoma, solitary fibrous tumor, sarcomas, and chordoid neoplasms. Recent data highlight the importance of distinguishing chordoma and chondrosarcoma of the skull base since chondrosarcomas show a significantly better clinical outcome. Among the less common, aggressive tumor entities in this anatomical region, infiltrating pituitary adenoma/pituitary carcinoma, superficial malignant gliomas, rhabdomyosarcoma, olfactory neuroblastoma, various sarcomas, and malignant lymphoma must be considered. Profiles of molecular genetic alterations have been established for several of these neoplasms and may facilitate the differential diagnosis. This review summarizes recent developments in the histopathological characterization, classification, and molecular pathology of neoplasms arising at the skull base.     

Expression of extracellular matrix-degrading proteins in classic, atypical, and anaplastic meningiomas

Although the majority of meningiomas, commonly benign tumors (WHO I), are amenable to surgical resection, a percentage of up to 3% will recur as higher-grade meningiomas with potential brain invasion. Our study aims at the in situ identification of proteolytic, extracellular matrix-degrading enzymes in a broad spectrum of meningiomas. We examined 80 meningiomas (50 classic meningiomas WHO I, 19 meningiomas WHO II, including atypical, chordoid, and clear cell types, as well as 11 anaplastic meningiomas WHO III) for the immunohistochemical expression patterns of cathepsin D and metalloproteinases MMP-2 and MMP-9. Meningiomas of all types and grades revealed a distinct expression of MMP-9 and cathepsin D, while MMP-2 was found predominantly in WHO II and III meningiomas. There was a significant increase in positive tumor cells from WHO grade I to II and III for MMP-2 (p<0.001), but not for cathepsin D (p=0.099). MMP-9 displayed an increased number of positive tumor cells from WHO grade I to II, but a decrease in WHO III meningiomas (p<0.002). Routine screening for the expression of metalloproteinases and cathepsin D will not reveal any new diagnostically or prognostically relevant information. However, these factors may represent a potential target for pharmacological blocking as an anti-invasive therapy.     

Increased Co-Expression of Macrophage Migration Inhibitory Factor and Matrix Metalloproteinase 9 Is Associated with Tumor Recurrence of Meningioma

Background and Objective: We detected the expression of MIF and matrix metalloproteinase 9 (MMP9) in meningiomas to determine whether they are valuable recurrence predictor for meningioma.Methods: 67 cases of meningiomas, including 57 benign tumors (WHO grade I) and 10 non-benign tumors (WHO grade II and III), were collected, and expression of MIF and MMP9 in tissue microarray was evaluated immunohistochemically. The correlations between immunostainings and clinicopathological parameters, as well as the follow-up data of patients, were analyzed statistically.Results: Increased expressions of both MIF (58.2%, 39/67) and MMP9 (55.2%, 37/67) were significantly associated with microvessel density (MVD) of tumor, but only dual high-expression of MIF and MMP9 was in relation to tumor invasion (P=0.016) and tumor recurrence (P=0.001). Based on univariate analysis, histological grade, tumor invasion and co-expression of MIF and MMP9 were significant predictors for recurrence. However, only histological grade and co-expression of MIF and MMP9 in tumor were independent recurrence factors with a hazard ratio of 49.033 (P=0.002) and 37.766 (P=0.002) in multivariate analysis.Conclusions: Together with histological grade, increased co-expression of MIF and MMP9 in tumor might be a valuable predictor for recurrence, especially for benign meningiomas.     

Molecular neuropathology of brain‐invasive meningiomas

Invasion of brain tissue by meningiomas has been identified as one key factor for meningioma recurrence. The identification of meningioma tumor tissue surrounded by brain tissue in neurosurgical samples has been touted as a criterion for atypical meningioma (CNS WHO grade 2), but is only rarely seen in the absence of other high‐grade features, with brain‐invasive otherwise benign (BIOB) meningiomas remaining controversial. While post‐surgery irradiation therapy might be initiated in brain‐invasive meningiomas to prevent recurrences, specific treatment approaches targeting key molecules involved in the invasive process are not established. Here we have compiled the current knowledge about mechanisms supporting brain tissue invasion by meningiomas and summarize preclinical models studying targeted therapies with potential inhibitory effects.     

Cyclooxygenase-2 (COX-2) overexpression in meningiomas: real time PCR and immunohistochemistry.

Cyclooxygenase-2 (COX-2) is the inducible form of the enzyme involved in the first steps of the prostaglandins and thromboxane synthesis. COX-2 up-regulation is demonstrated in tumors where it can modulate tumoral progression, metastasis, multidrug resistance, and angiogenesis. Experimental data suggest a possible therapeutic use of the COX-inhibitors nonsteroidal antiinflammatory drugs (NSAIDs). NSAIDs can block tumor growth through many mechanisms, especially through antiangiogenic and proapoptotic effects. Moreover, NSAIDs can also improve the efficacy of radiotherapy, chemotherapy, and hormonal therapy. This study reviews the COX-2 expression as evaluated through immunohistochemistry and real time polymerase chain reaction (RT-PCR) in 23 meningiomas [14 World Health Organization (WHO) grade I; 5 WHO grade II; 3 WHO grade III; 1 oncocytic meningioma]. At immunohistochemistry all the lesions but 4 (83%) were COX-2 positive. At RT-PCR 9 meningiomas, 8 WHO grade I and 1 WHO grade II, showed a COX-2 expression greater than the reference value (average expression of all meningiomas that we studied). The association between tumor grade and immunohistochemical or RT-PCR COX-2 expression was not significant (P=0.427 and P=0.251, respectively). In conclusion, even if further studies on larger series are necessary, the common COX-2 overexpression in meningiomas may suggest considering the COX-2 inhibitors, alone or in combination with radiotherapy, a potential area of therapeutic intervention in some selected meningiomas.     

DJ-1和mTOR表达在良性脑膜瘤复发中的意义

目的：探讨DJ-1和哺乳动物雷帕霉素靶蛋白（mammalian target of rapamycin,mTOR）在各类型脑膜瘤中的表达及其与良性脑膜瘤复发和演进的关系。方法：收集广东同江医院和中山大学附属第一医院行手术切除并随访的脑膜瘤病例72例,其中术后无复发的良性（WHO I级）脑膜瘤50例,术后复发良性脑膜瘤12例,高级别脑膜瘤（WHO II~III级）10例。采用免疫组织化学方法检测DJ-1和mTOR在脑膜瘤组织中的表达。结果：DJ-1和mTOR在术后无复发和术后复发的良性脑膜瘤及高级别的脑膜瘤中表达不同,DJ-1在3种脑膜瘤组织中的高表达分别为3,5和6例,mTOR的高表达分别为3,4和5例,DJ-1和mTOR在高级别和复发性良性脑膜瘤中均呈高表达状态（P〈0.05）。mTOR与DJ-1的表达有关（P〈0.05）,DJ-1,mTOR的表达强度与良性脑膜瘤的复发有关（P=0.001）。结论：DJ-1和mTOR的高表达可能促进了良性脑膜瘤的复发,结合组织学分级,二者的高表达可能是预测良性肿瘤复发的有临床价值的生物学指标。     

Mitotic Index is an Independent Predictor of Recurrence‐Free Survival in Meningioma

While World Health Organization (WHO) grading of meningioma stratifies patients according to recurrence risk overall, there is substantial within‐grade heterogeneity with respect to recurrence‐free survival (RFS). Most meningiomas are graded according to mitotic counts per unit area on hematoxylin and eosin sections, a method potentially confounded by tumor cellularity, as well as potential limitations of accurate mitotic figure detection on routine histology. To refine mitotic figure assessment, we evaluated 363 meningiomas with phospho‐histone H3 (Ser10) and determined the mitotic index (number of mitoses per 1000 tumor cells). The median mitotic indices among WHO grade I (n = 268), grade II (n = 84) and grade III (n = 11) tumors were 1, 4 and 12. Classification and regression tree analysis to categorize cut‐offs identified three subgroups defined by mitotic indices of 0–2, 3–4 and ≥5, which on univariate analysis were associated with RFS (P < 0.01). In multivariate analysis, mitotic index subgrouped in this manner was significantly associated with RFS (P < 0.01) after adjustment for Simpson grade, WHO grade and MIB‐1 index. Mitotic index was then examined within individual WHO grade, showing that for grade I and grade II meningiomas, mitotic index can add additional information to RFS risk. The results suggest that the use of a robust mitotic marker in meningioma could refine risk stratification.     

Merlin expression in secretory meningiomas: evidence of an NF2-independent pathogenesis? Immunohistochemical study.

One of the most common chromosomal regions implicated in the meningiomas tumorigenesis is 22q12 where the neurofibromatosis 2 (NF2) gene resides. The NF2 tumor-suppressor gene encodes for the merlin/schwannomin protein, which is responsible for the inherited disease neurofibromatosis 2. NF2 gene mutations predominantly occur in transitional and fibroblastic meningiomas, whereas the meningothelial variant is less affected. Secretory meningioma is an infrequent meningioma subtype. Its most typical morphologic feature is the presence of intracytoplasmic or extracytoplasmic round hyaline, eosinophilic, and periodic acid Shiff-positive bodies in a lesion frequently otherwise classifiable as meningothelial meningioma. This study reviews the immunohistochemical merlin expression in 14 consecutive secretory meningiomas. Our purpose was to investigate if secretory meningiomas, analogous to meningothelial meningiomas, follow a molecular route of pathogenesis independent of the neurorofibromatosis 2 gene-associated pathway. All meningiomas showed positive immunocoloration involving the majority of the hyaline inclusions and secretory cells; in 12 (86%) meningiomas, a positive immunoreaction was also documented in nonsecretory tumoral cells. Our results may indicate a molecular, besides morphologic, similarity between secretory and meningothelial meningiomas: the almost constant merlin immunohistochemical expression in our series gives evidence for a possible NF2 gene-independent pathogenesis in secretory meningiomas.     

A new amplicon‐based gene panel for next generation sequencing characterization of meningiomas

Meningiomas are the most frequent primary intracranial tumors. The considerable variety of histological subtypes has been expanded by the definition of molecular alterations, which can improve both diagnostic accuracy and determination of individual patient''s outcome. According to the upcoming WHO classification of brain tumors, the in‐time analysis of frequent molecular events in meningiomas may become mandatory to define meningioma subtypes. We have compiled a custom‐made amplicon‐based next generation sequencing (NGS) meningioma panel covering the most frequent known recurrent mutations in 15 different genes. In an unselected consecutive meningioma cohort (109 patients) analyzed over a period of 12 months, we detected mutations in 11 different genes, with most frequent alterations in NF2 (43%), AKT1 ^E17K (15%), and TRAF7 (13%). In 39 tumors (36%), two different mutations were detected, with NF2 and SUFU (n = 5) and KLF4 and TRAF7 (n = 5) being the most frequent combinations. No alterations were found in POLR2A, CDKN2A, CDKN2B, and BAP1, and no homozygous CDKN2A/B deletion was detected. NF2 mutations were found in tumors of all WHO grades, whereas mutations in KLF4, TRAF7, and SMO were restricted to WHO grade I meningiomas. In contrast, SMARCE1 and TERT mutations were associated with WHO grade II meningiomas (according to the WHO classification 2016). The distribution of mutations across histological subtypes or tumor localization was in line with the existing literature, with typical combinations like KLF4K^409Q/TRAF7 for secretory meningiomas and preferential skull base localization of meningiomas harboring SMO and AKT1 ^E17K mutations. Thus, we present a custom‐made NGS meningioma panel providing a time and cost‐efficient reliable detection of relevant somatic molecular alterations in meningiomas suitable for daily routine.     

DNA topoisomerase II-alpha and cyclin A immunoexpression in meningiomas and its prognostic significance: an analysis of 263 cases

CONTEXT: Routine pathologic examination cannot distinctively predict the clinical course of meningiomas because even histologically benign tumors may recur after gross total resection. Therefore, numerous efforts have been made to evaluate the meningioma growth fraction and its prognostic value. However, a universally applicable proliferative marker for meningioma outcome is not yet a reality. OBJECTIVE: To investigate the prognostic utility of 3 proliferative markers, namely, Ki-67, DNA topoisomerase II-alpha (topoII), and cyclin A in a representative series of intracranial meningiomas. DESIGN: Two hundred sixty-three adult patients with intracranial meningiomas (208 benign, 42 atypical, and 13 anaplastic) were studied retrospectively. Tumor specimens were immunohistochemically examined with antibodies to Ki-67 (MM-1), topoII, and cyclin A. A computerized color image analyzer was used to count immunostained nuclei. RESULTS: The topoII and cyclin A scores exhibited a close correlation with Ki-67 immunostaining. Significant differences between the indices for all 3 markers were noted among the 3 grades of meningiomas. The scores for all 3 markers were significantly different between recurrent and nonrecurrent meningiomas, including benign tumors that were treated with gross total resection. Recurrence-free survival was significantly reduced for cases with a Ki-67 labeling index (LI) of 4.4% or greater, a topoII LI of 3.2% or greater, and a cyclin A LI of 3.1% or greater. Multivariate analysis revealed that the risk of recurrence for the entire meningioma cohort was significantly associated with tumor grade (hazard ratio = 2.7; P =.004), topoII LI of 3.2% or greater (hazard ratio = 5.5; P <.001), and a cyclin A LI of 3.1% or greater (hazard ratio = 2.4; P =.01). CONCLUSIONS: There is a close correlation in the expression of these 3 proliferative markers in meningiomas, and all of the markers showed a significant association with tumor grade, recurrence rate, and recurrence-free survival. Consequently, in addition to Ki-67, immunoexpression of topoII and cyclin A is available for predicting meningioma recurrence. Moreover, the topoII and cyclin A staining scores were found to be more sensitive predictors for meningioma progression than Ki-67 and, therefore, either of these 2 markers may prove to be clinically informative and useful.