ABSTRACT
Meningiomas are the most common primary intracranial tumour in adults1. Patients with symptoms are generally treated with surgery as there are no effective medical therapies. The World Health Organization histopathological grade of the tumour and the extent of resection at surgery (Simpson grade) are associated with the recurrence of disease; however, they do not accurately reflect the clinical behaviour of all meningiomas2. Molecular classifications of meningioma that reliably reflect tumour behaviour and inform on therapies are required. Here we introduce four consensus molecular groups of meningioma by combining DNA somatic copy-number aberrations, DNA somatic point mutations, DNA methylation and messenger RNA abundance in a unified analysis. These molecular groups more accurately predicted clinical outcomes compared with existing classification schemes. Each molecular group showed distinctive and prototypical biology (immunogenic, benign NF2 wild-type, hypermetabolic and proliferative) that informed therapeutic options. Proteogenomic characterization reinforced the robustness of the newly defined molecular groups and uncovered highly abundant and group-specific protein targets that we validated using immunohistochemistry. Single-cell RNA sequencing revealed inter-individual variations in meningioma as well as variations in intrinsic expression programs in neoplastic cells that mirrored the biology of the molecular groups identified.
Subject(s)
Biomarkers, Tumor/metabolism , Meningioma/classification , Meningioma/metabolism , Proteogenomics , DNA Methylation , Data Analysis , Drug Discovery , Female , Gene Expression Regulation, Neoplastic , Humans , Immunohistochemistry , Male , Meningioma/drug therapy , Meningioma/genetics , Mutation , RNA-Seq , Reproducibility of Results , Single-Cell AnalysisABSTRACT
PURPOSE: Accurate classification of cancer subgroups is essential for precision medicine, tailoring treatments to individual patients based on their cancer subtypes. In recent years, advances in high-throughput sequencing technologies have enabled the generation of large-scale transcriptomic data from cancer samples. These data have provided opportunities for developing computational methods that can improve cancer subtyping and enable better personalized treatment strategies. METHODS: Here in this study, we evaluated different feature selection schemes in the context of meningioma classification. To integrate interpretable features from the bulk (n = 77 samples) and single-cell profiling (â¼ 10 K cells), we developed an algorithm named CLIPPR which combines the top-performing single-cell models, RNA-inferred copy number variation (CNV) signals, and the initial bulk model to create a meta-model. RESULTS: While the scheme relying solely on bulk transcriptomic data showed good classification accuracy, it exhibited confusion between malignant and benign molecular classes in approximately â¼ 8% of meningioma samples. In contrast, models trained on features learned from meningioma single-cell data accurately resolved the sub-groups confused by bulk-transcriptomic data but showed limited overall accuracy. CLIPPR showed superior overall accuracy and resolved benign-malignant confusion as validated on n = 789 bulk meningioma samples gathered from multiple institutions. Finally, we showed the generalizability of our algorithm using our in-house single-cell (â¼ 200 K cells) and bulk TCGA glioma data (n = 711 samples). CONCLUSION: Overall, our algorithm CLIPPR synergizes the resolution of single-cell data with the depth of bulk sequencing and enables improved cancer sub-group diagnoses and insights into their biology.
Subject(s)
Algorithms , Meningeal Neoplasms , Meningioma , Sequence Analysis, RNA , Single-Cell Analysis , Humans , Single-Cell Analysis/methods , Meningeal Neoplasms/genetics , Meningeal Neoplasms/pathology , Meningeal Neoplasms/classification , Meningioma/genetics , Meningioma/pathology , Meningioma/classification , Sequence Analysis, RNA/methods , DNA Copy Number Variations , Biomarkers, Tumor/genetics , High-Throughput Nucleotide Sequencing/methods , Transcriptome , Gene Expression Profiling/methodsABSTRACT
PURPOSE OF REVIEW: Our understanding of the genetic and epigenetic alterations in meningioma and the underlying tumor biology of meningioma has significantly changed over the past decade and resulted in revision of prognostically relevant meningioma subclasses within and beyond the WHO classification of CNS tumors. RECENT FINDINGS: The 2016 WHO classification of CNS tumors recognizes WHO grade I, II, and III based on histopathological features. Recent work has identified genetic alterations with prognostic implications, including mutations of the TERT promoter, loss of function of the DMD gene, and inactivation of the tumor suppressor BAP-1. Studies of DNA methylation patterns in meningiomas have resulted in a novel and prognostically relevant meningioma subclassification schema. There have been major advances in our understanding of prognostically relevant genetic and epigenetic changes in meningioma which will hopefully allow for improvement in clinical trial design and the development of more effective therapies for meningioma.
Subject(s)
Meningeal Neoplasms/genetics , Meningioma/genetics , DNA Copy Number Variations , DNA Methylation , Humans , Meningeal Neoplasms/classification , Meningeal Neoplasms/immunology , Meningeal Neoplasms/therapy , Meningioma/classification , Meningioma/immunology , Meningioma/therapy , Mutation , Neurofibromin 2/genetics , Phosphatidylinositol 3-Kinases/physiology , Signal Transduction/physiology , Tumor MicroenvironmentABSTRACT
World Health Organization (WHO) grade I meningiomas are intracranial extracerebral tumors, in which microsurgery as a stand-alone therapy provides high rates of disease control and low recurrence rates. Our aim was to identify prognostic factors of overall survival and time-to-retreat (OS; TTR) in a cohort of patients with surgically managed WHO grade I meningioma. Patients with WHO grade I meningiomas from a retrospectively (1990 to 2002) and prospectively managed (2003 to 2010) databank of Oslo University Hospital, Norway, were included. The mean follow-up was 9.2 ± 5.7 years, with a total of 11,414 patient-years. One thousand three hundred fifty-five patients were included. The mean age was 58 ± 13.2, mean Karnofsky Performance Status (KPS) 92.6 ± 26.1 and female-to-male ratio 2.5:1. The 1-year, 5-year, 10-year, 15-year, and 20-year probabilities were 0.98, 0.91, 0.87, 0.84, and 0.8 for TTR. Patient age (OR 0.92 [0.91, 0.94]), male sex (OR 0.59 [0.45, 0.76]), preoperative KPS ≥ 70 (OR 2.22 [1.59, 3.13]), skull base location (OR 0.77 [0.60, 1]), and the occurrence of a postoperative hematoma (OR 0.44 [0.26, 0.76]) were identified as independent prognostic factors of OS. Patient age (OR 1.02 [1.01, 1.03]) and skull base location (OR 0.30 [0.21, 0.45]) were independent predictors of decreased PFS. Using a recursive partitioning analysis, we suggest a classification tree for the prediction of 5-year PFS based on patient and tumor characteristics. The findings from this cohort of meningioma WHO I patients helps to identify patients at risk of recurrence and tailor the therapeutic management.
Subject(s)
Meningeal Neoplasms/classification , Meningeal Neoplasms/mortality , Meningioma/classification , Meningioma/mortality , Adult , Aged , Aged, 80 and over , Cohort Studies , Disease Progression , Female , Humans , Male , Meningeal Neoplasms/surgery , Meningioma/surgery , Middle Aged , Norway , Prognosis , Retrospective Studies , World Health Organization , Young AdultABSTRACT
Introduction: In order for brain tumours to be successfully treated, maximal resection is beneficial. A method to detect infiltrative tumour edges intraoperatively, improving on current methods would be clinically useful. Vibrational spectroscopy offers the potential to provide a handheld, reagent-free method for tumour detection.Purpose: This study was designed to determine the ability of both Raman and Fourier-transform infrared (FTIR) spectroscopy towards differentiating between normal brain tissue, glioma or meningioma.Method: Unfixed brain tissue, which had previously only been frozen, comprising normal, glioma or meningioma tissue was placed onto calcium fluoride slides for analysis using Raman and attenuated total reflection (ATR)-FTIR spectroscopy. Matched haematoxylin and eosin slides were used to confirm tumour areas. Analyses were then conducted to generate a classification model.Results: This study demonstrates the ability of both Raman and ATR-FTIR spectroscopy to discriminate tumour from non-tumour fresh frozen brain tissue with 94% and 97.2% of cases correctly classified, with sensitivities of 98.8% and 100%, respectively. This decreases when spectroscopy is used to determine tumour type.Conclusion: The study demonstrates the ability of both Raman and ATR-FTIR spectroscopy to detect tumour tissue from non-tumour brain tissue with a high degree of accuracy. This demonstrates the ability of spectroscopy when targeted for a cancer diagnosis. However, further improvement would be required for a classification model to determine tumour type using this technology, in order to make this tool clinically viable.
Subject(s)
Brain Neoplasms/diagnosis , Brain Neoplasms/surgery , Neurosurgical Procedures/methods , Brain Neoplasms/classification , Diagnosis, Differential , Glioma/classification , Glioma/diagnosis , Humans , Meningioma/classification , Meningioma/diagnosis , Spectroscopy, Fourier Transform Infrared , Spectrum Analysis, Raman , Tissue PreservationABSTRACT
The majority of meningiomas are grade I, but some grade I tumours are clinically more aggressive. Recent advances in the genetic study of meningiomas has allowed investigation into the influence of genetics on the tumour microenvironment, which is important for tumorigenesis. We have established that the endpoint genotyping method Kompetitive Allele Specific PCR (KASP™) is a fast, reliable method for the screening of meningioma samples into different non-NF2 mutational groups using a standard real-time PCR instrument. This genotyping method and four-colour flow cytometry has enabled us to assess the variability in the largest immune cell infiltrate population, M2 macrophages (CD45+HLA-DR+CD14+CD163+) in 42 meningioma samples, and to suggest that underlying genetics is relevant. Further immunohistochemistry analysis comparing AKT1 E17K mutants to WHO grade I NF2-negative samples showed significantly lower levels of CD163-positive activated M2 macrophages in meningiomas with mutated AKT1 E17K, signifying a more immunosuppressive tumour microenvironment in NF2 meningiomas. Our data suggested that underlying tumour genetics play a part in the development of the immune composition of the tumour microenvironment. Stratifying meningiomas by mutational status and correlating this with their cellular composition will aid in the development of new immunotherapies for patients.
Subject(s)
Macrophages/metabolism , Meningioma/genetics , Proto-Oncogene Proteins c-akt/genetics , Tumor Microenvironment/genetics , Alleles , Antigens, CD/genetics , Antigens, Differentiation, Myelomonocytic/genetics , Cell Lineage/genetics , Female , Genotype , HLA-DR Antigens/genetics , Humans , Leukocyte Common Antigens/genetics , Lipopolysaccharide Receptors/genetics , Macrophages/classification , Macrophages/pathology , Male , Meningioma/classification , Meningioma/pathology , Middle Aged , Mutation/genetics , Neurofibromin 2/genetics , Receptors, Cell Surface/geneticsABSTRACT
DNA methylation patterns delineate clinically relevant subgroups of meningioma. We previously established the six meningioma methylation classes (MC) benign 1-3, intermediate A and B, and malignant. Here, we set out to identify subgroup-specific mutational patterns and gene regulation. Whole genome sequencing was performed on 62 samples across all MCs and WHO grades from 62 patients with matched blood control, including 40 sporadic meningiomas and 22 meningiomas arising after radiation (Mrad). RNA sequencing was added for 18 of these cases and chromatin-immunoprecipitation for histone H3 lysine 27 acetylation (H3K27ac) followed by sequencing (ChIP-seq) for 16 samples. Besides the known mutations in meningioma, structural variants were found as the mechanism of NF2 inactivation in a small subset (5%) of sporadic meningiomas, similar to previous reports for Mrad. Aberrations of DMD were found to be enriched in MCs with NF2 mutations, and DMD was among the most differentially upregulated genes in NF2 mutant compared to NF2 wild-type cases. The mutational signature AC3, which has been associated with defects in homologous recombination repair (HRR), was detected in both sporadic meningioma and Mrad, but widely distributed across the genome in sporadic cases and enriched near genomic breakpoints in Mrad. Compared to the other MCs, the number of single nucleotide variants matching the AC3 pattern was significantly higher in the malignant MC, which also exhibited higher genomic instability, determined by the numbers of both large segments affected by copy number alterations and breakpoints between large segments. ChIP-seq analysis for H3K27ac revealed a specific activation of genes regulated by the transcription factor FOXM1 in the malignant MC. This analysis also revealed a super enhancer near the HOXD gene cluster in this MC, which, together with general upregulation of HOX genes in the malignant MC, indicates a role of HOX genes in meningioma aggressiveness. This data elucidates the biological mechanisms rendering different epigenetic subgroups of meningiomas, and suggests leveraging HRR as a novel therapeutic target.
Subject(s)
DNA Methylation , DNA, Neoplasm/genetics , Gene Expression Regulation, Neoplastic/genetics , Meningeal Neoplasms/classification , Meningioma/classification , Mutation , Chromatin Immunoprecipitation , Gene Dosage , Genomic Instability , Humans , Meningeal Neoplasms/etiology , Meningeal Neoplasms/genetics , Meningeal Neoplasms/pathology , Meningioma/etiology , Meningioma/genetics , Meningioma/pathology , Neoplasm Proteins/genetics , Neoplasms, Radiation-Induced/genetics , Neoplasms, Radiation-Induced/pathology , Polymorphism, Single Nucleotide , RNA, Messenger/genetics , RNA, Neoplasm/genetics , Recombinational DNA Repair , Sequence Alignment , Transcription Factors/physiology , Transcriptome , Whole Genome SequencingABSTRACT
Raman spectroscopy is a powerful technique used to analyse biological materials, where spectral markers such as proteins (1500-1700 cm-1), carbohydrates (470-1200 cm-1) and phosphate groups of DNA (980, 1080-1240 cm-1) can be detected in a complex biological medium. Herein, Raman microspectroscopy imaging was used to investigate 90 brain tissue samples in order to differentiate meningioma Grade I and Grade II samples, which are the commonest types of brain tumour. Several classification algorithms using feature extraction and selection methods were tested, in which the best classification performances were achieved by principal component analysis-quadratic discriminant analysis (PCA-QDA) and successive projections algorithm-quadratic discriminant analysis (SPA-QDA), resulting in accuracies of 96.2%, sensitivities of 85.7% and specificities of 100% using both methods. A biochemical profiling in terms of spectral markers was investigated using the difference-between-mean (DBM) spectrum, PCA loadings, SPA-QDA selected wavenumbers, and the recovered imaging profiles after multivariate curve resolution alternating least squares (MCR-ALS), where the following wavenumbers were found to be associated with class differentiation: 850 cm-1 (amino acids or polysaccharides), 1130 cm-1 (phospholipid structural changes), the region between 1230-1360 cm-1 (Amide III and CH2 deformation), 1450 cm-1 (CH2 bending), and 1858 cm-1 (C[double bond, length as m-dash]O stretching). These findings highlight the potential of Raman microspectroscopy imaging for determination of meningioma tumour grades.
Subject(s)
Brain Neoplasms/classification , Meningeal Neoplasms/classification , Meningioma/classification , Algorithms , Discriminant Analysis , Humans , Least-Squares Analysis , Principal Component Analysis , ROC Curve , Spectrum Analysis, Raman/methodsABSTRACT
Microcystic meningioma (MM) is a rare subtype of intracranial meningiomas, with clinical and radiologic features not well characterized in the literature. Based on our experience, we propose a classification system of intracranial MMs. We reviewed the medical records, radiographic studies, and operative notes of a group of consecutive patients with intracranial MM. The mean age of the 69 patients was 46.8 ± 10.6 years (range, 21-75 years). Three types of intracranial MMs could be identified. Type 1 MMs presented as a solid lesion, hypointense or isointense on T1WI, hyperintense on T2WI, and homogeneous or heterogeneous enhancement, and were found in 43 patients (67.2%). Type 2 MMs represented signals similar to CSF both on T1WI and T2WI, and faint reticular enhancement with marginal enhancement, and these were found in 7 patients (10.9%). Type 3 MMs consisted of cystic-solid or cystic lesion and were found in 14 patients (21.9%). Significant differences were observed among the different types of MMs for the following variables: sex, presence of severe peritumoral brain edema (PTBE), and extent of tumor resection. Females were found in all of patients with type 2 MMs, but were only 35.7% of those with type 3 MMs (P = 0.018). Severe PTBEs were more common among patients with type 1 MMs (55.8%) than among those with type 2 (14.3%) and type 3 MMs (14.3%) (P = 0.007). Type 1 MMs (97.7%) were associated with a significantly higher rate of gross total resection compared with the other two types (71.4 and 78.6%) (P = 0.019). Total length of hospital stay after craniotomy ranged from 4 to 30 days (median, 8 days). There were no significant differences in progression-free survival among the three types of MMs (P = 0.788). The current classification identifies three distinct types of intracranial MM based on their radiological findings and growth patterns. The type 1 MMs are more commonly associated with severe PTBE. Type 2 and Type 3 MMs have a higher predilection towards parasaggital location with venous involvement and therefore have a lower rate of gross total resection.
Subject(s)
Meningeal Neoplasms/classification , Meningeal Neoplasms/diagnosis , Meningioma/classification , Meningioma/diagnosis , Adult , Aged , Brain Edema/etiology , Craniotomy , Female , Humans , Male , Meningeal Neoplasms/surgery , Meningioma/surgery , Middle Aged , Neoplasm Grading , Progression-Free Survival , Retrospective Studies , Treatment Outcome , Young AdultABSTRACT
Foramen magnum meningiomas (FMMs) are challenging lesions and controversy still exists regarding their optimal management. In the present paper, we propose some principles of surgical treatment of FMMs. We analyzed our series of 39 patients: the average maximum diameter was 31.1 mm (sd, 10.7). In two cases, there was extradural extension. We operated all anterior lesions through dorsolateral approach to craniovertebral junction and all posterior lesions through midline suboccipital approach and C1 laminectomy, following the prevalence of side of the tumor. There were no complications except for one case of post-operative hypoglossus paresis. We translated our experience with surgery of foramen magnum meningiomas into a classification system and a complexity score, in order to assign a score to each individual case and plan the surgical strategy. When the complexity score is 5 or more, we propose subtotal removal, in consideration of the benign nature.
Subject(s)
Foramen Magnum , Meningeal Neoplasms/surgery , Meningioma/surgery , Postoperative Complications/epidemiology , Adolescent , Adult , Aged , Cohort Studies , Female , Humans , Male , Meningeal Neoplasms/classification , Meningeal Neoplasms/pathology , Meningioma/classification , Meningioma/pathology , Middle Aged , Paresis/etiology , Treatment Outcome , Young AdultABSTRACT
PURPOSE: To evaluate the clinical behavior of spheno-orbital meningiomas with regard to World Health Organization (WHO) tumor grade and Ki-67, a cellular marker of proliferation. METHODS: A retrospective review over a 16-year period of the demographic, clinical, radiographic, and surgical data of all patients with spheno-orbital meningioma who underwent surgical resection. Tumor specimens were examined histologically using the current WHO 2016 classification and immunohistochemically using Ki-67/MIB-1 monoclonal antibody. RESULTS: Thirty-eight patients met all inclusion criteria: 78.9% of tumors were WHO grade I with a mean Ki-67 of 3.76, and 93% of patients were clinically stable at last follow up; 10.5% of lesions were WHO grade II (atypical) with a mean Ki-67 of 14.93, and 10.5% of lesions were WHO grade III (anaplastic) with a mean Ki-67 of 58.3. All grade II and III meningiomas exhibited an aggressive clinical course. There were statistically significant correlations between disease clinical progression and WHO tumor grade (p < 0.001), between disease clinical progression and Ki-67 (p < 0.001), and between increasing Ki-67 index and higher WHO grade (p < 0.001). For WHO grade I lesions, a Ki-67 of ≥3.3 correlated with recurrence (p = 0.0256). Overall, disease-specific mortality occurred in 5 (13%) patients. CONCLUSIONS: Ki-67 index is a valuable marker to use in conjunction with WHO grade to predict meningioma behavior, particularly in histologically borderline lesions, and possibly to identify a subset of WHO grade I tumors at risk of recurrence. This combination of methods can aid in tailoring treatment and surveillance strategies.
Subject(s)
Biomarkers, Tumor/metabolism , Ki-67 Antigen/metabolism , Meningioma , Orbital Neoplasms , Sphenoid Bone , Adult , Aged , Aged, 80 and over , Antibodies, Antinuclear/metabolism , Antibodies, Monoclonal/metabolism , Female , Humans , Immunohistochemistry , Male , Meningioma/classification , Meningioma/metabolism , Meningioma/pathology , Middle Aged , Orbital Neoplasms/classification , Orbital Neoplasms/metabolism , Orbital Neoplasms/pathology , Retrospective Studies , World Health OrganizationABSTRACT
BACKGROUND: The WHO classification of brain tumours describes 15 subtypes of meningioma. Nine of these subtypes are allotted to WHO grade I, and three each to grade II and grade III. Grading is based solely on histology, with an absence of molecular markers. Although the existing classification and grading approach is of prognostic value, it harbours shortcomings such as ill-defined parameters for subtypes and grading criteria prone to arbitrary judgment. In this study, we aimed for a comprehensive characterisation of the entire molecular genetic landscape of meningioma to identify biologically and clinically relevant subgroups. METHODS: In this multicentre, retrospective analysis, we investigated genome-wide DNA methylation patterns of meningiomas from ten European academic neuro-oncology centres to identify distinct methylation classes of meningiomas. The methylation classes were further characterised by DNA copy number analysis, mutational profiling, and RNA sequencing. Methylation classes were analysed for progression-free survival outcomes by the Kaplan-Meier method. The DNA methylation-based and WHO classification schema were compared using the Brier prediction score, analysed in an independent cohort with WHO grading, progression-free survival, and disease-specific survival data available, collected at the Medical University Vienna (Vienna, Austria), assessing methylation patterns with an alternative methylation chip. FINDINGS: We retrospectively collected 497 meningiomas along with 309 samples of other extra-axial skull tumours that might histologically mimic meningioma variants. Unsupervised clustering of DNA methylation data clearly segregated all meningiomas from other skull tumours. We generated genome-wide DNA methylation profiles from all 497 meningioma samples. DNA methylation profiling distinguished six distinct clinically relevant methylation classes associated with typical mutational, cytogenetic, and gene expression patterns. Compared with WHO grading, classification by individual and combined methylation classes more accurately identifies patients at high risk of disease progression in tumours with WHO grade I histology, and patients at lower risk of recurrence among WHO grade II tumours (p=0·0096) from the Brier prediction test). We validated this finding in our independent cohort of 140 patients with meningioma. INTERPRETATION: DNA methylation-based meningioma classification captures clinically more homogenous groups and has a higher power for predicting tumour recurrence and prognosis than the WHO classification. The approach presented here is potentially very useful for stratifying meningioma patients to observation-only or adjuvant treatment groups. We consider methylation-based tumour classification highly relevant for the future diagnosis and treatment of meningioma. FUNDING: German Cancer Aid, Else Kröner-Fresenius Foundation, and DKFZ/Heidelberg Institute of Personalized Oncology/Precision Oncology Program.
Subject(s)
DNA Methylation , Meningeal Neoplasms/classification , Meningeal Neoplasms/genetics , Meningioma/classification , Meningioma/genetics , Neoplasm Recurrence, Local/genetics , DNA Copy Number Variations , DNA Mutational Analysis , DNA-Binding Proteins/genetics , Disease Progression , Disease-Free Survival , Female , Genome , Humans , Kruppel-Like Factor 4 , Kruppel-Like Transcription Factors/genetics , Male , Meningeal Neoplasms/pathology , Meningioma/pathology , Neoplasm Grading , Neoplasm Recurrence, Local/pathology , Neurofibromin 2/genetics , Nuclear Proteins/genetics , Proto-Oncogene Proteins c-akt/genetics , Retrospective Studies , Sequence Analysis, RNA , Smoothened Receptor/genetics , Survival Rate , Transcription Factors/genetics , Transcriptome , Tumor Necrosis Factor Receptor-Associated Peptides and Proteins/geneticsABSTRACT
AIMS: Clear cell meningioma (CCM) is a rare subtype of meningioma and shows not only unusual histology, but also unique clinical features. Recently, SMARCE1 mutations have been shown to cause spinal and cranial CCMs. We present 12 cases which were diagnosed with CCM in a single institution between 1997 and 2014, and investigate their SMARCE1 mutation status. METHODS AND RESULTS: To investigate the SMARCE1 mutation status of these tumours, we used a combination of Sanger sequencing and multiplex ligation-dependent probe amplification analysis and also performed SMARCE1 immunohistochemical staining. We found both SMARCE1 mutational hits, including novel SMARCE1 mutations, in six of eight tested patients. Immunohistochemical analysis showed loss of SMARCE1 protein staining in all but two cases. Two individuals who were diagnosed originally with CCM were negative for SMARCE1 mutations, but tested positive for NF2 mutations. As a result, these two tumours were re-analysed and eventually reclassified, as a microcystic and a mixed pattern of meningothelial meningioma with focal clear cell areas, respectively. CONCLUSIONS: These results expand the spectrum of pathogenic variants in SMARCE1 and show that mutation screening can help to facilitate meningioma classification. This may have implications for prognosis and future clinical management of patients, as CCMs are classed as grade II tumours, while microcystic and meningothelial meningiomas are classed as grade I.
Subject(s)
Chromosomal Proteins, Non-Histone/genetics , DNA-Binding Proteins/genetics , Meningeal Neoplasms/classification , Meningeal Neoplasms/genetics , Meningioma/classification , Meningioma/genetics , Adolescent , Adult , Child , DNA Mutational Analysis , Female , Humans , Immunohistochemistry , Male , Meningeal Neoplasms/pathology , Meningioma/pathology , Middle Aged , Multiplex Polymerase Chain Reaction , Young AdultABSTRACT
Meningiomas represent the most common primary tumors of the central nervous system (CNS) in adulthood. They are currently classified into several histotypes and into three grades of malignancy according to the criteria of the World Health Organization (WHO) classification of tumors of the CNS. WHO histological grade is currently the most significant morphological predictor of recurrence risk of meningiomas. For this reason, it is fully taken into consideration in postsurgical therapeutic decision making in patients with meningioma. However, the main drawback of the WHO grading system system is that criteria for its assessment are rather subjective and poorly standardized. Hence, additional factors are warranted to predict recurrence risk of meningiomas, so that patients may actually receive the most appropriate therapy. In recent years, biomolecular pathogenesis of meningiomas has been partially clarified, and many efforts have been made in the identification of molecular factors associated with recurrence risk of meningioma. Here we review WHO criteria currently used for classification of meningiomas and discuss on pitfalls and limits of grading assessment. In addition we present the latest advancement in the knowledge of biomolecular alterations involved in the pathogenesis and progression of meningiomas. Similarly to what has already happened for gliomas, a novel classification integrating histology and molecular information might overcome the limits of histological classification in terms of reproducibility as well as of prognostic and predictive relevance. © 2016 Wiley Periodicals, Inc.
Subject(s)
Central Nervous System Neoplasms/classification , Meningioma/classification , Central Nervous System Neoplasms/pathology , Humans , Meningioma/pathology , Neoplasm Grading , Prognosis , Reproducibility of ResultsABSTRACT
The 2016 World Health Organization Classification of Tumors of the Central Nervous System is both a conceptual and practical advance over its 2007 predecessor. For the first time, the WHO classification of CNS tumors uses molecular parameters in addition to histology to define many tumor entities, thus formulating a concept for how CNS tumor diagnoses should be structured in the molecular era. As such, the 2016 CNS WHO presents major restructuring of the diffuse gliomas, medulloblastomas and other embryonal tumors, and incorporates new entities that are defined by both histology and molecular features, including glioblastoma, IDH-wildtype and glioblastoma, IDH-mutant; diffuse midline glioma, H3 K27M-mutant; RELA fusion-positive ependymoma; medulloblastoma, WNT-activated and medulloblastoma, SHH-activated; and embryonal tumour with multilayered rosettes, C19MC-altered. The 2016 edition has added newly recognized neoplasms, and has deleted some entities, variants and patterns that no longer have diagnostic and/or biological relevance. Other notable changes include the addition of brain invasion as a criterion for atypical meningioma and the introduction of a soft tissue-type grading system for the now combined entity of solitary fibrous tumor / hemangiopericytoma-a departure from the manner by which other CNS tumors are graded. Overall, it is hoped that the 2016 CNS WHO will facilitate clinical, experimental and epidemiological studies that will lead to improvements in the lives of patients with brain tumors.
Subject(s)
Brain/pathology , Central Nervous System Neoplasms/classification , Central Nervous System/pathology , Glioma/classification , Meningioma/classification , World Health Organization , Animals , Central Nervous System Neoplasms/diagnosis , Central Nervous System Neoplasms/pathology , Glioma/pathology , Humans , Meningioma/diagnosis , Meningioma/pathologyABSTRACT
BACKGROUND: We analyzed WHO grade II meningioma cases to identify factors influencing survival. MATERIALS AND METHODS: Between January 2000 and August 2015, 206 cases of World Health Organization (WHO) grade II meningioma were operated at our institution. This population underwent a total of 298 surgical resections and 55 patients received a radiotherapy. A Cox multivariate regression was conducted on clinical and histological criteria. RESULTS: Sixty-four patients were deceased (31.1 %), of which 38 died following the disease progression (18.4 %). Overall survival probability at 1, 5, and 10 years were 95.4 %, 95 % CI [92.5, 98.4]; 84 %, 95 % CI [78.3, 90.2], and 72.9 %, 95 % CI [64.5, 82.4], respectively (Fig. 1a). At the end of the study, only 87 patients (42.2 %) were alive with no tumor residual or recurrence on the last scan. Age at diagnosis (hazard ratio (HR) = 0.31, 95 % CI [0.15, 0.63], p < 0.001), extent of resection (HR = 0.25, 95 % CI [0.12, 0.49], p < 0.001), and tumoral brain invasion (HR = 0.49, 95 % CI [0.25, 0.98], p = 0.040) were independent factors associated with the overall survival. The patients who received radiotherapy did not demonstrate a longer overall survival (p = 0.540). CONCLUSIONS: WHO grade II meningioma significantly impaired the survival of the patients. In the adjusted Cox regression, a macroscopic gross total resection (Simpson grades 1, 2, and 3), an age below 62 years at diagnosis and the absence of brain invasion were independent factors associated with a longer survival. Radiotherapy may not increase the overall survival after complete or incomplete resection.
Subject(s)
Meningeal Neoplasms/pathology , Meningioma/pathology , Adult , Aged , Female , Humans , Male , Meningeal Neoplasms/classification , Meningeal Neoplasms/radiotherapy , Meningeal Neoplasms/surgery , Meningioma/classification , Meningioma/radiotherapy , Meningioma/surgery , Middle Aged , Neoplasm Grading , Neurosurgical Procedures/adverse effects , Neurosurgical Procedures/statistics & numerical data , Survival Analysis , World Health OrganizationABSTRACT
Objective: To evaluate outcomes of postoperative radiotherapy (RT) for residual WHO grade I meningioma based on subtype classification and relevant factors that may influence the outcomes. Material and Method: Medical records from 252 patients, with known histology of intracranial meningioma, who underwent stereotactic RT in Ramathibodi Hospital between 1998 and 2008, were reviewed. One hundred and two out of 252 patients were included. The data were categorized into 2 groups: common subtype (meningothelial and transitional subtypes) and uncommon subtype (fibroblastic, psammomatous, angiomatous, microcystic, secretory, lymphoplasmacyte-rich and metaplastic subtypes). Analysis of tumor control rate, tumor shrinkage rate and risk factors of treatment failure were conducted. Results: The median of follow-up period was 46 months (interquartile range (IQR): 53). The five-year tumor-control rates of overall, common and uncommon subtypes were 89.9%, 92.9% and 81.5%, respectively, which showed no significant difference between the two groups, p = 0.108. The five years tumor shrinkage rates of overall, common, and uncommon subtypes were 42.5%, 42.3% and 42.7%, respectively, there was no significant difference, p = 0.934. In univariate analysis, gender (male), total minimal dose and fraction demonstrated statistically significant impact on treatment failure. However, only a total minimal dose had any significant effect in multivariate analysis. Conclusion: Radiotherapy is highly effective in controlling postoperative residual meningioma. This study may be useful to evaluate patients' prognosis and possibility of recurrence based on histology subtypes. In addition, total minimal dosage was the sole risk factor of treatment failure found in the present study.
Subject(s)
Meningeal Neoplasms/radiotherapy , Meningioma/radiotherapy , Radiosurgery/statistics & numerical data , Adult , Aged , Female , Follow-Up Studies , Humans , Male , Meningeal Neoplasms/classification , Meningeal Neoplasms/pathology , Meningeal Neoplasms/surgery , Meningioma/classification , Meningioma/pathology , Meningioma/surgery , Middle Aged , Neoplasm Grading , Neoplasm Recurrence, Local/surgery , Prognosis , Retrospective StudiesABSTRACT
Chordoid meningioma (CM) is a rare subtype of meningioma, classified as grade II, which exhibits a high rate of recurrence following subtotal resection. We retrospectively examined nine cases of chordoid meningioma over a case series of 1743 meningiomas (0.52%) operated upon at our institution from 1995 to 2013. All the reported clinicopathological findings were analyzed. Two hundred and twenty-one CM cases have been published to date worldwide and few single-center large case series have been issued. Seventy-five percent of the cases that underwent subtotal resection at our institution had recurrence within 1 year. Total resection of the tumor should be the major objective of surgery to reduce the possibility of tumor recurrence. The percentage of chordoid features within the tumor specimen could assist in predicting the pathogenesis of the lesion. The correlation of the index of proliferation to recurrence rate is still controversial. Much debate exists with regard to the role of adjuvant radiotherapy in CM cases. Immunohistochemical, cytological and ultrastructural studies should be used in combination to assure a correct diagnosis of CM. Owing to the rare occurrence of this meningioma subtype, larger case series are required to assist in providing a reference for diagnosis and to improve the therapeutic management of CM.
Subject(s)
Meningeal Neoplasms/pathology , Meningioma/pathology , Adult , Aged , Aged, 80 and over , Female , Humans , Incidence , Male , Meningeal Neoplasms/classification , Meningeal Neoplasms/epidemiology , Meningioma/classification , Meningioma/epidemiology , Middle Aged , Retrospective Studies , Young AdultABSTRACT
Glucose transporter-1 (GLUT-1) is one of the major isoforms of the family of glucose transporter proteins that facilitates the import of glucose in human cells to fuel anaerobic metabolism. The present study was meant to determine the extent of the anaerobic/hypoxic state of the intratumoral microenvironment by staining for GLUT-1 in intracranial non-embolized typical (WHO grade I; n = 40), brain invasive and atypical (each WHO grade II; n = 38) and anaplastic meningiomas (WHO grade III, n = 6). In addition, GLUT-1 staining levels were compared with the various histological criteria used for diagnosing WHO grade II and III meningiomas, namely, brain invasion, increased mitotic activity and atypical cytoarchitectural change, defined by the presence of at least three out of hypercellularity, sheet-like growth, prominent nucleoli, small cell change and "spontaneous" necrosis. The level of tumor hypoxia was assessed by converting the extent and intensity of the stainings by multiplication in an immunoreactive score (IRS) and statistically evaluated. The results were as follows. (1) While GLUT-1 expression was found to be mainly weak in WHO grade I meningiomas (IRS = 1-4) and to be consistently strong in WHO grade III meningiomas (IRS = 6-12), in WHO grade II meningiomas GLUT-1 expression was variable (IRS = 1-9). (2) Histologically typical, but brain invasive meningiomas (WHO grade II) showed no or similarly low levels of GLUT-1 expression as observed in WHO grade I meningiomas (IRS = 0-4). (3) GLUT-1 expression was observed in the form of a patchy, multifocal staining reaction in 76% of stained WHO grade I-III meningiomas, while diffuse staining (in 11%) and combined multifocal and areas of diffuse staining (in 13%) were only detected in WHO grades II and III meningiomas, except for uniform staining in angiomatous WHO grade I meningioma. (4) "Spontaneous" necrosis and small cell change typically occurred away from the intratumoral capillary network embedded within the pattern of GLUT-1 staining. Taken together, GLUT-1 staining cannot be applied as a substitute for histologic grading in order to predict tumor behavior. However, assessment of tumor hypoxia in association with "spontaneous" necrosis and foci of small cell change may substantially contribute to the neuropathologic diagnosis of WHO grades II and III meningioma.
Subject(s)
Brain Neoplasms/metabolism , Glucose Transporter Type 1/metabolism , Meningeal Neoplasms/metabolism , Meningioma/metabolism , Tumor Microenvironment , Adult , Aged , Aged, 80 and over , Brain Neoplasms/classification , Brain Neoplasms/pathology , Female , Humans , Immunohistochemistry , Male , Meningeal Neoplasms/classification , Meningeal Neoplasms/pathology , Meningioma/classification , Meningioma/pathology , Middle Aged , Necrosis , Neoplasm GradingABSTRACT
The management of WHO Grade II "atypical" meningiomas (AMs) and Grade III "malignant" meningiomas (MMs) remains controversial and under-investigated in prospective studies. The roles of surgery, radiation therapy, radiosurgery, and chemotherapy have been incompletely delineated. This has left physicians to decipher how they should treat patients on a case-by-case basis. In this study, the authors review the English-language literature on the management and clinical outcomes associated with AMs and MMs diagnosed using the WHO 2000/2007 grading criteria. Twenty-two studies for AMs and 7 studies for MMs were examined in detail. The authors examined clinical decision points using the literature and concepts from evidence-based medicine. Acknowledging the retrospective nature of the studies concerning AM and MM, the authors did find evidence for the following clinical strategies: 1) maximal safe resection of AM and MM; 2) active surveillance after gross-total resection of AM; 3) adjuvant radiation therapy after subtotal resection of AM, especially in the absence of putative radioresistant features; and 4) adjuvant radiation therapy after resection of MM.