WHO Classification Of Brain Tumors Research Articles

Role of adjuvant radiotherapy in atypical (WHO grade II) and anaplastic (WHO grade III) meningiomas: a systematic review.

The systematic adoption of the histopathologic criteria provided by the 2016 update of the WHO classification of brain tumors has markedly increased the relative proportion of atypical and anaplastic meningiomas. These tumors exhibit a much greater recurrence rate compared to benign meningiomas, which negatively impacts survival. In recent years, the publication of numerous retrospective case series, yet no randomized controlled trials, on the impact of radiation therapy in non-benign meningioma, has yielded conflicting evidence. At present, maximum safe resection, including the dural attachment, is the preferred primary treatment modality for all types of meningiomas. Adjuvant radiotherapy is currently recommended for subtotally resected grade II and for all grade III meningiomas. However, in grade II meningiomas achieving complete resection, close radiologic and clinical observation is a feasible option. Despite the great amount of non-benign meningiomas available and eligible for trials, there is a striking lack of prospective studies testing adjuvant therapies against observation for this subset of patients. An updated and systematic literature review is provided on the effectiveness and indications of radiotherapy on grade II and III meningiomas.

Machine learning applications in R for the differentiation of primary CNS tumors.

Primary Central Nervous System (CNS) malignancies consist of various groups of tumors. Each sub‐class results in distinct clinical decision and related outcomes. According to current WHO classification of brain tumors, the integration of both histomorphology and molecular features is critical for diagnosis including tumor grade, and directly impacts treatment approaches and prognosis. However, in the United States and worldwide, scarce resources are available to perform all the required tests.The aim of this work is to improve and standardize neuropathological diagnoses for brain cancer patients throughout the world, with a particular emphasis on resource‐poor diagnostic scenarios. To achieve this goal, we have developed a population model based on articles from the open resources of MEDLINE database and the latest version of WHO classification of CNS tumors. Our data frame is comprised of 50 primary brain tumor diagnoses. Data on clinical, histomorphology and molecular features were carefully sorted according to particularities of each individual CNS tumor type. To distinguish features with the highest value for accurate diagnosis prediction we used Boruta function (Figure 1) and Model Weights Extraction (Table 1). Both methods could not detect tentative features and showed that common clinical data (age and specific tumor location) have a high impact on diagnosis prediction. In our work we implemented modern machine learning (ML) classification algorithms, such as randomForest (RF), Support Vector Machine (SVM) and Naive Bayes (NB) after splitting the data into training and validation set. We discovered that models trained to predict diagnosis on the basis of top 6 Boruta and Weight selected features showed the highest diagnostic accuracy on the validation set even in the absence of molecular data. The accuracy for all 3 algorithms with the mentioned features was as follows: RF (92%); SVM (79%); NB (52%). We also observed that ki67 plays a key role in differentiating CNS tumors as its presence significantly increased the accuracy for each trained model independently of ML algorithm. Importantly, despite the obvious value in further clinical decisions, the inclusion of all molecular data (BRAFV600E, FISH codeletion 1p19q, EGFR amplification, MGMT status and etc.) did little to contribute to distinguishing between different primary CNS malignancies in our study. In fact, the molecular data managed to slightly improve the accuracy of our prediction models (only ~ 5–6 %) compared to data on ki67 alone (~37%), suggesting that the proliferation markers should be considered as a more reliable tool for accurate staging and morphological evaluation of CNS tumors.In conclusion, our results confirm that the implementation of open sources and computing platforms by pathologists in low resource environments in the US and abroad would allow to develop a reliable cost‐effective panel of markers and significantly improve the quality of neuropathological diagnoses.The value of features according to BorutaFigure 1 The value of features according to Weight Extraction Model ## names attribute_importance ## 32 site 1.790710364 ## 18 ki67 1.123777357 ## 1 Age 0.887462753 ## 34 solid.with.infiltration 0.553816679 ## 13 GFAP 0.454128477 ## 29 perivascular.pseudorosettes 0.442591199 ## 17 infiltrative.diffuse 0.436200109 ## 14 high.cellularity 0.398945890 ## 25 Necrosis 0.330965699 ## 26 nodular 0.318905215 ## 10 Endothelial.Proliferation 0.295229054 ## 19 low.cellularity 0.279927747 ## 5 chicken.wire 0.278482297 ## 7 desmoplasia 0.260748678 ## 8 dysplastic.neurons 0.246787762 ## 28 perivascular.lymphocytes 0.244935349 ## 11 eosinophil.granular.bodies 0.239584778 ## 30 pseudopapiliar.papillary 0.228171358 ## 33 Solid.discohesive 0.217511802 ## 20 medium.cellularity 0.216013780 ## 6 columns.cords 0.212469602 ## 15 idh1.2.mutation 0.201122902 ## 22 microcystic 0.199572761 ## 35 storiform 0.189573543 ## 24 myxoid.areas 0.186702316 ## 16 idh1.R132H 0.170479121 ## 4 calcifications 0.163422951 ## 36 FISH_codeletion_1p19q 0.158014816 ## 37 LOH_codeletion_1p19q 0.150564459 ## 27 p53 0.149535733 ## 21 MGMT 0.128631095 ## 3 BRAF.V600E.mutation 0.103997736 ## 2 ATRX.loss 0.100807078 ## 31 rosenthal.fibers 0.089142945 ## 9 EGFR.amplification 0.058714262 ## 12 Gender 0.022632343 ## 23 multilayered.rosettes 0.008671977

P14.96 Gliomatosis cerebri imaging pattern: a treatment-independent marker for worse overall survival in WHO grade II and III gliomas

Abstract BACKGROUND The term gliomatosis cerebri (GC) refers to glial brain tumors with widespread tumor expansion affecting three or more cerebral lobes. Formerly considered a distinct tumor entity, recent studies found no difference in the mutational profile of glial tumors with GC growth pattern compared to non-GC gliomas. Thus, in the new WHO classification of brain tumors, GC is no longer included as a separate diagnosis. While the presence of gliomas with GC growth pattern is associated with worse overall survival (OS), the underlying factors remain to be identified. Here, we asked whether differing therapeutic strategies in first line treatment could account for the worse outcome of patients with GC growth pattern and grade II and III histology. MATERIAL AND METHODS From the patient data bank of the University Cancer Center (UCT) Frankfurt, 47 patients with histological diagnosis of WHO grade II or III glioma, and with record of GC imaging pattern were identified. GC tumor expansion was confirmed by review of MRI scans prior to treatment initiation. Patients with WHO grade II or III glioma without GC growth pattern served as control cohort (n=379). IDH mutational status was available for 75% of GC tumors (IDH R132H mutated 32%; non-mutated 43%) and 69% of non-GC tumors (IDH R132H mutated 57%; non-mutated 12%). RESULTS Within the GC patient cohort, patients with tumors without contrast enhancement, lower WHO grade and mutated IDH status showed better OS. Compared to the control cohort, patients with GC had significantly shorter OS. This was independent of histological diagnosis or IDH mutation status. Patients with GC more frequently underwent radiochemotherapy (17% vs. 9% in the non-GC cohort), and drastically more often received chemotherapy alone (51% vs. 5%). We then analyzed OS in GC and non-GC patients that had received the same first line treatments. For radiochemotherapy in GC versus non-GC patients, OS was 1.1 years vs. 12.7 years (p =0.0075, log-rank test). For upfront chemotherapy alone, OS was significantly shorter in the GC cohort than in the non-GC cohort (3,6 years vs. undefined, p =0.0016, log-rank test). CONCLUSION Differences in first-line treatment cannot account for the worse prognosis of patients with GC imaging pattern. Further studies are needed to pinpoint biological or clinical factors that might influence responsiveness to therapy and prognosis of GC tumors.

Integrating a Large Next-Generation Sequencing Panel into the Clinical Diagnosis of Gliomas Provides a Comprehensive Platform for Classification from FFPE Tissue or Smear Preparations.

The 2016 WHO classification of brain tumors represents a major step towards the integration of molecular data into pathologic diagnoses. Our institution has included massively parallel sequencing technology in the diagnostic work-up of all gliomas since January 2016. The utilized platform successfully identifies copy number variations, individual gene mutations, small insertions and deletions, and selected gene fusions. Herein, we retrospectively review the first 51 glial tumor samples run for clinical purposes using the UCM-OncoPlus platform, a 1213 gene targeted hybrid-capture next generation sequencing (NGS) panel. NGS paired with histomorphology and clinical data allowed for reliable, comprehensive, and cost-effective classification of all the analyzed gliomas (51/51) with minimal tissue required and without the need for additional testing. In addition to detecting all diagnostically relevant mutations according to the 2016 WHO system, our data suggest a large NGS-based platform may improve the accuracy of classifying gliomas beyond the 2016 WHO system, to provide truly personalized diagnostics. Furthermore, this methodology assists in classifying histologically challenging or clinically unusual cases. And, finally, the versatile nature of this testing methodology allows for near effortless expansion as new therapeutic targets and prognostic markers are discovered.

Supratentorial high-grade astrocytoma with leptomeningeal spread to the fourth ventricle: a lethal dissemination with dismal prognosis.

Leptomeningeal spread to the fourth ventricle (LSFV) from supratentorial high-grade astrocytoma (HGA) is rarely investigated. The incidence and prognostic merit of LSFV were analyzed in this study. A consecutive cohort of 175 patients with pathologically diagnosed HGA according to the 2016 WHO classification of brain tumors was enrolled. LSFV was defined as radiological occupation in the fourth ventricle at the moment of initial progression. Clinical, radiological, and pathological data were analyzed to explore the difference between HGA patients with and without LSFV. There were 18 of 175 (10.3%) HGAs confirmed with LSFV. The difference of survival rate between patients with LSFV or not was significant in both overall survival (OS) (14.5 vs. 24months, P = 0.0007) and post progression survival (PPS) (6.0 vs. 11.5months, P = 0.0004), while no significant difference was observed in time to progression (TTP) (8.5 months vs. 9.5months P = 0.6795). In the Cox multivariate analysis, LSFV was confirmed as an independent prognostic risk factor for OS (HR 2.06, P = 0.010). LSFV was correlated with younger age (P = 0.044), ventricle infringement of primary tumor (P < 0.001) and higher Ki-67 index (P = 0.013) in further analysis, and the latter two have been validated in the Logistic regression analysis (OR 18.16, P = 0.006; OR 4.04, P = 0.012, respectively). LSFV was indicative of end-stage for supratentorial HGA patients, which shortened patients' PPS and OS instead of TTP. It's never too cautious to alert this lethal event when tumor harbored ventricle infringement and higher Ki-67 index in routine clinical course.

Assessment of the impact of glioma diagnostic reclassification following the new 2016 WHO classification on a series of cases.

The aim of this project is to assess diagnostic reclassification based on molecular data over morphology in a series of glial tumours since the introduction of the 2016 WHO classification of brain tumours. Retrospective review of glial tumours (oligodendrogliomas and astrocytomas) treated in our centre between January 2012 and June 2016 in which a review of diagnosis was performed when molecular studies were added. Statistical analysis included evaluation of variables of epidemiology, morphology and molecular data (mainly IDH mutation and 1p19q codeletion), diagnostic changes after new classification was considered, and clinical impact in cases of diagnostic reclassification. From a total of 147 glial tumours reviewed in our centre, molecular diagnosis was obtained in 74 cases (50.3%). Initial diagnosis changed in 23 cases (31%), and 20 (87%) of them had a prior histological diagnosis of oligodendroglioma (69.6% grade ii and 17.4% grade iii). Only 3 of these 23 cases diagnosis changed from astrocytoma to oligodendroglioma. Among reclassified tumours, there was a common molecular pattern, as findings showed mutant IDH in 16 cases (69.6%) and no codeletion in 20 cases (87%). According to the cell of origin, of the whole group of 27 oligodendrogliomas in our series (reclassified and non-reclassifed), 20 cases (74%) became astrocytomas, despite typical oligodendroglial morphology, due to absence of 1p19q codeletion. There was a trend for diagnosis reclassification in younger patients (<40 years), P=.065, mainly in those with a prior diagnosis of oligodendroglioma, with no statistical differences based on gender or clinical data. Besides, reclassification was more common among tumours with mutant IDH (69.6%), P=.003, than those with wild type IDH. In terms of survival, despite receiving different treatments, no significant changes were detected between reclassified and non-reclassified tumours after a mean follow-up of 16 months, partly related to lower grade of these lesions. Within the spectrum of the glial tumours treated in our institution, this new classification including molecular genetics over morphological data has provided marked diagnostic changes. These changes appear mainly in tumours previously diagnosed as oligodendrogliomas and in younger patients, with molecular patterns of mutant IDH and 1p19q codeletion. Although diagnosis reclassification may affect clinic, prognosis or therapeutic management of these tumours, deeper and prospective studies on these specific aspects are needed.

Assessment of the impact of glioma diagnostic reclassification following the new 2016 WHO classification on a series of cases

Background and objectivesThe aim of this project is to assess diagnostic reclassification based on molecular data over morphology in a series of glial tumours since the introduction of the 2016 WHO classification of brain tumours. Materials and methodsRetrospective review of glial tumours (oligodendrogliomas and astrocytomas) treated in our centre between January 2012 and June 2016 in which a review of diagnosis was performed when molecular studies were added. Statistical analysis included evaluation of variables of epidemiology, morphology and molecular data (mainly IDH mutation and 1p19q codeletion), diagnostic changes after new classification was considered, and clinical impact in cases of diagnostic reclassification. ResultsFrom a total of 147 glial tumours reviewed in our centre, molecular diagnosis was obtained in 74 cases (50.3%). Initial diagnosis changed in 23 cases (31%), and 20 (87%) of them had a prior histological diagnosis of oligodendroglioma (69.6% grade ii and 17.4% grade iii). Only 3 of these 23 cases diagnosis changed from astrocytoma to oligodendroglioma. Among reclassified tumours, there was a common molecular pattern, as findings showed mutant IDH in 16 cases (69.6%) and no codeletion in 20 cases (87%). According to the cell of origin, of the whole group of 27 oligodendrogliomas in our series (reclassified and non-reclassified), 20 cases (74%) became astrocytomas, despite typical oligodendroglial morphology, due to absence of 1p19q codeletion. There was a trend for diagnosis reclassification in younger patients (<40 years), p=0.065, mainly in those with a prior diagnosis of oligodendroglioma, with no statistical differences based on gender or clinical data. Besides, reclassification was more common among tumours with mutant IDH (69.6%), p=0.003, than those with wild type IDH. In terms of survival, despite receiving different treatments, no significant changes were detected between reclassified and non-reclassified tumours after a mean follow-up of 16 months, partly related to lower grade of these lesions. ConclusionsWithin the spectrum of the glial tumours treated in our institution, this new classification including molecular genetics over morphological data has provided marked diagnostic changes. These changes appear mainly in tumours previously diagnosed as oligodendrogliomas and in younger patients, with molecular patterns of mutant IDH and 1p19q codeletion. Although diagnosis reclassification may affect clinic, prognosis or therapeutic management of these tumours, deeper and prospective studies on these specific aspects are needed.

Cerebellar liponeurocytoma - molecular signature of a rare entity and the importance of an accurate diagnosis

Cerebellar liponeurocytoma is an extremely rare tumour entity of the central nervous system. It is histologically characterised by prominent neuronal/neurocytic differentiation with focal lipidisation and corresponding histologically to WHO grade II. It typically develops in adults, and usually shows a low proliferative potential. Recurrences have been reported in almost 50% of cases, and in some cases the recurrent tumour may display increased mitotic activity and proliferation index, vascular proliferations and necrosis. Thus pathological diagnosis of liponeurocytoma is challenging. This case presentation highlights the main clinical, radiographic and pathological features of a cerebellar liponeurocytoma. A 59-year-old, right-handed woman presented at our department with a short history of persistent headache, vertigo and gait disturbances. Examination at presentation revealed that the patient was awake, alert and fully oriented. The cranial nerve status was normal. Uncertainties were noted in the bilateral finger-to-nose testing with bradydiadochokinesis on both sides. Strength was full and no pronator drift was observed. Sensation was intact. No signs of pyramidal tract dysfunction were detected. Her gait appeared insecure. The patient underwent surgical resection. Afterward no further disturbances could be detected. To date >40 cases of liponeurocytoma have been reported, including cases with supratentorial location. A review of the 5 published cases of recurrent cerebellar. Liponeurocytoma revealed that the median interval between the first and second relapse was rather short, indicating uncertain malignant potential. The most recent WHO classification of brain tumours (2016) classifies the cerebellar liponeurocytoma as a separate entity and assigns the tumour to WHO grade II. Medulloblastoma is the most important differential diagnosis commonly seen in children and young adults. In contrast, cerebellar liponeurocytoma is typically diagnosed in adults. The importance of accurate diagnosis should not be underestimated especially in the view of possible further therapeutic interventions and for the determination of the patient's prognosis.

Anaplastic Glioma: Treatment Approaches in the Era of Molecular Diagnostics.

The treatment paradigm for anaplastic glioma has shifted, owing to new diagnostic criteria and new phase III clinical trial evidence. In 2016, the WHO classification of brain tumors including diffuse gliomas was redefined to include molecular criteria, often supplanting the morphological appearance of the tumor cells. This was necessary as prognosis is more closely associated with molecular diagnosis than with morphology and grade. Recently, the benefit of adjuvant chemotherapy in addition to radiotherapy has been demonstrated in both anaplastic oligodendroglioma and anaplastic astrocytoma, as well as lower grade gliomas with the most marked benefit evident in IDH-mutated (astrocytoma) and 1p/19q co-deleted (oligodendroglial) tumors. The defining principle of recent breakthroughs has been the benefit of combinatorial therapy (chemo-radiation) as opposed to treatment in series or treatment of either modality after a period of observation upon evidence of progression.

How is stereotactic brain biopsy evolving? A multicentric analysis of a series of 421 cases treated in Rome over the last sixteen years

ObjectiveIn recent decades, frame-based (FBB) and frame-less stereotactic brain biopsy (FLB) have played a crucial role in defining the diagnosis and management of expanding intracranial lesions in critical areas. During the same period, there have been significant advances in diagnostic imaging, a shift in surgical strategies towards extensive resection in gliomas and new molecular classification of brain tumors. Taking these advances into account, we have evaluated whether significant changes have occurred over the last sixteen years of our clinical practice in terms of frequency, indications, target selection, and the histologic results of stereotactic brain biopsy (SBB) procedures. Patients and MethodsWe analyzed a series of 421 SBB cases treated between January 2002 and June 2017 in three major neurosurgical institutes in Rome, serving a total of 1.5 million people. Within this series, 94.8% of patients underwent FBB, while, more recently, FLB was performed in 5.2% of cases. The entire period under consideration, running from 2002 to 2017, has been further stratified into four-year time-frames (2002–2005, 2006–2009, 2010–2013, 2014–2017) for the purpose of analysis. ResultsThe diagnostic yield was 97%. Final diagnoses revealed tumors in 90% of cases and non-neoplastic masses in 7%, while 3% of cases were not conclusive.The morbidity rate was 3% (12 cases) and mortality was 0.7% (3 cases). Intra-operative frozen sections were made in 78% of biopsies.In our three institutes, the number of SBBs decreased steadily throughout the time-frames under consideration. We have also observed a statistically significant reduction in biopsy procedures in lobar lesions, while those performed on the basal ganglia increased and the number of SBBs of multiple masses and lesions of the corpus callosum remained stable. Primary central nervous system diagnosis of lymphomas (PCNSL) was the sole diagnosis whose incidence increased significantly. ConclusionsOver the last sixteen years, we have witnessed a significant decrease in SBB procedures and a modification in target selection and histologic results. Despite the significant evolution of neuroimaging, an accurate non-invasive diagnosis of intracranial expanding lesions has not yet been achieved. Furthermore, the most recent WHO classification of brain tumors (2016), which incorporates molecular and morphological features, has boosted the need for molecular processing of tissue samples in all expanding brain lesions. For these reasons, it is likely that SBBs will continue to be performed in specific cases, playing a significant role in diagnostic confirmation by providing tissue samples, so as to better assess the biology and the prognosis of cerebral lesions, as well as their sensitivity to standard radio-chemotherapy or to new molecular target therapies.

Practical Implications of the Updated WHO Classification of Brain Tumors.

The updated 2016 WHO classification of Central Nervous System tumors introduced a novel concept of neuropathology diagnostics. Molecular parameters are now included into the definition of several entities. This evolution from a previously purely histology-based classification to an integrated approach of histology and genetic characteristics has implications in daily diagnostic and clinical practice. Both the spectrum of diagnostic workup demanded from the neuropathologist and the range of relevant markers to be considered by clinicians and clinical investigators have increased. This article reviews the major changes in the classification of diffuse gliomas, ependymoma, and medulloblastoma, the practical consequences for diagnostics and clinical trials, and points toward recent developments that potentially will influence the next update of the classification.

Advances in meningioma genetics: novel therapeutic opportunities.

Meningiomas currently are among the most frequent intracranial tumours. Although the majority of meningiomas can be cured by surgical resection, ∼20% of patients have an aggressive clinical course with tumour recurrence or progressive disease, resulting in substantial morbidity and increased mortality of affected patients. During the past 3 years, exciting new data have been published that provide insights into the molecular background of meningiomas and link sites of tumour development with characteristic histopathological and molecular features, opening a new road to novel and promising treatment options for aggressive meningiomas. A growing number of the newly discovered recurrent mutations have been linked to a particular clinicopathological phenotype. Moreover, the updated WHO classification of brain tumours published in 2016 has incorporated some of these molecular findings, setting the stage for the improvement of future therapeutic efforts through the integration of essential molecular findings. Finally, an additional potential classification of meningiomas based on methylation profiling has been launched, which provides clues in the assessment of individual risk of meningioma recurrence. All of these developments are creating new prospects for effective molecularly driven diagnosis and therapy of meningiomas.

The role of treatments in IDH mutant molecular astrocytomas

Background: Low grade glioma (LGG) is a heterogeneous disease. Recently, the 2016 WHO classification of brain tumors has underlined the role of genetic and molecular features. Molecular astrocytomas have been defined as grade II tumors with IDH mutation and without 1p19q codeletion. Methods: We evaluated 213 consecutive patients with LGG who received surgery or biopsy and had adequate tissue to assess molecular characterization. IDH mutations were assessed by immunohistochemistry (IHC) and next generation sequencing (NGS) in IHC negative cases, MGMT methylation status was assessed by polymerase chain reaction (PCR) and 1p19q deletion was assessed by fluorescence in situ hybridation (FISH). Results: 198 patients (93.0%) showed IDH-mutation. Ninety patients (49.2%) were 1p19q non codeleted (molecular astrocytomas). The median follow up was 98.3 months. Median age was 36 (range: 18-69), 11 patients (12.2%) underwent biopsy, 48 (53.3%) patients subtotal resection and 31 (34.4%) patients total resection. According to RTOG criteria, 68 patients (75.6%) were considered high risk (> 40 years and/or incomplete resection), and 22 patients (24.4%) were considered low risk (< 40 years and/or complete resection). 59 patients (65.5%) did not receive any post-surgical treatment, but only follow-up, 31 patients (34.4%) received post-surgical treatments: 20 (22.2%) received radiotherapy (RT), 7 (7.8%) received chemotherapy (CT), 4 (4.4%) received CT+RT. Median progression-free survival (PFS) was 44.3 months. Significant differences in PFS were observed between treated and untreated patients (64.8 vs 35.7 months p = 0.004) and treated with RT versus follow-up (60.0 vs 35.7 months p = 0.004). Multivariate analysis confirmed the treatment after surgery as an independent prognostic factor (HR 0.456, p = 0.005). Median overall survival (OS) was 164.0 months. At time of analysis no significant differences in OS were available. Conclusions: Post-surgical treatment after resection of IDH mutant molecular astrocytomas is an independent prognostic factor. A longer follow-up is needed for worthy results in terms of OS.

Medulloblastoma: experimental models and reality.

Medulloblastoma is the most frequent malignant brain tumor in childhood, but it may also affect infants, adolescents, and young adults. Recent advances in the understanding of the disease have shed light on molecular and clinical heterogeneity, which is now reflected in the updated WHO classification of brain tumors. At the same time, it is well accepted that preclinical research and clinical trials have to be subgroup-specific. Hence, valid models have to be generated specifically for every medulloblastoma subgroup to properly mimic molecular fingerprints, clinical features, and responsiveness to targeted therapies. This review summarizes the availability of experimental medulloblastoma models with a particular focus on how well these models reflect the actual disease subgroup. We further describe technical advantages and disadvantages of the models and finally point out how some models have successfully been used to introduce new drugs and why some medulloblastoma subgroups are extraordinary difficult to model.

DNA methylation-based classification and grading system for meningioma: a multicentre, retrospective analysis

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. 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. 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. 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. German Cancer Aid, Else Kröner-Fresenius Foundation, and DKFZ/Heidelberg Institute of Personalized Oncology/Precision Oncology Program.

MPTH-22INTEGRATING MOLECULAR MARKERS INTO THE WORLD HEALTH ORGANIZATION (WHO) CLASSIFICATION OF GLIOMAS: SURVEY RESULTS FROM THE SNO MEMBERSHIP

INTRODUCTION: Gliomas are currently classified based on the 2007 WHO Classification of Tumours of the Central Nervous System, which uses histological features to classify and grade these heterogeneous tumors. With recent advances in the development of clinically relevant molecular signatures, there is an interest to incorporate appropriate molecular markers in to the classification. The views of the neuro-oncology community on such changes would be informative for advising this process. METHODS: A survey with 8 questions regarding molecular markers in tumor classification was sent to an email list of SNO members and attendees of prior meetings (n = 5065). There were 403 respondents. Analysis was performed using whole group response and based on self-reported subspecialty. RESULTS: Survey results among all respondents show support for incorporating our molecular knowledge of brain tumors into the WHO classification. Across all seven subspecialty groups, 370% of respondents agreed to this integration. Interestingly, despite support in the majority of questions, neuropathologists were more inclined to disagree that molecular markers should be included in the WHO classification (25% for neuropathologists versus 13% overall). This is in contrast to radiation oncologists who were less inclined (3%) to disagree with this statement. Additionally, neuropathologists were more inclined to state there was no need to change the structure of diagnosis into a “layered” format (17% versus 6% overall) or to agree that pediatric diffuse gliomas should be classified differently from adult tumors despite different molecular features (23% versus 5% overall). CONCLUSION: Based on a survey provided to SNO membership, we report strong support for the integration of molecular markers into the WHO classification of brain tumors, as well as for using an integrated “layered” diagnostic format. While membership from each specialty showed support, there was variation by specialty in enthusiasm regarding proposed changes.

Integrated Diagnostic Approach for Adult Oligodendroglioma and Oligoastrocytoma

Diffuse gliomas with clear cell morphology are represented in the 2007 WHO classification of brain tumors as oligoastrocytomas and oligodendrogliomas of grades II and III. Although preoperative neuroimaging of these brain tumors are often successful, histopathologic evaluation of neurosurgically removed tumor specimens is still required for a definite diagnosis and subsequent molecular analysis. Such CNS tumors show an extensive variety of histological and cytological appearance making diagnosis in clear cell gliomas somewhat difficult, especially as oligoastrocytomas are often less clearly defined. There is an ongoing debate whether these tumors indeed constitute an entity or whether they represent a mixed bag containing both astrocytomas and oligodendroglioma. Recent advances with molecular data on these tumors have a major impact on neuopathological typing, prognosis and therapy of the patients. This neuro-oncologic review focuses on neuropathological and molecular features of the different types of diffusely infiltrating gliomas. Core features and distinct patterns and variants are also introduced and illustrated. Recent advances in immunohistochemistry and molecular biology have contributed to an improved classification and are discussed. Different methodologies for molecular analysis of 1p/19q codeletion, ATRX loss, MGMT promoter methylation and isocitrate dehydrogenase mutations are presented in detail and their prognostic and predictive implications for therapy are discussed.

An individual patient data meta-analysis on characteristics and outcome of patients with papillary glioneuronal tumor, rosette glioneuronal tumor with neuropil-like islands and rosette forming glioneuronal tumor of the fourth ventricle.

Background and PurposeIn 2007, the WHO classification of brain tumors was extended by three new entities of glioneuronal tumors: papillary glioneuronal tumor (PGNT), rosette-forming glioneuronal tumor of the fourth ventricle (RGNT) and glioneuronal tumor with neuropil-like islands (GNTNI). Focusing on clinical characteristics and outcome, the authors performed a comprehensive individual patient data (IPD) meta-analysis of the cases reported in literature until December 2012.MethodsPubMed, Embase and Web of Science were searched for peer-reviewed articles reporting on PGNT, RGNT, and GNTNI using predefined keywords.Results95 publications reported on 182 patients (PGNT, 71; GNTNI, 26; RGNT, 85). Median age at diagnosis was 23 years (range 4–75) for PGNT, 27 years (range 6–79) for RGNT, and 40 years (range 2–65) for GNTNI. Ninety-seven percent of PGNT and 69% of GNTNI were located in the supratentorial region, 23% of GNTNI were in the spinal cord, and 80% of RGNT were localized in the posterior fossa. Complete resection was reported in 52 PGNT (73%), 36 RGNT (42%), and 7 GNTNI (27%) patients. Eight PGNT, 3 RGNT, and 12 GNTNI patients were treated with chemo- and/or radiotherapy as the primary postoperative treatment. Follow-up data were available for 132 cases. After a median follow-up time of 1.5 years (range 0.2–25) across all patients, 1.5-year progression-free survival rates were 52±12% for GNTNI, 86±5% for PGNT, and 100% for RGNT. The 1.5-year overall-survival were 95±5%, 98±2%, and 100%, respectively.ConclusionsThe clinical understanding of the three new entities of glioneuronal tumors, PGNT, RGNT and GNTNI, is currently emerging. The present meta-analysis will hopefully contribute to a delineation of their diagnostic, therapeutic, and prognostic profiles. However, the available data do not provide a solid basis to define the optimum treatment approach. Hence, a central register should be established.

Intracranial hemangiopericytoma: Case study with cytogenetics and genome wide SNP-A analysis

The tumor entity of hemangiopericytoma is not universally recognized as a nosological entity by pathologists, and there is a trend toward reassigning it to other categories gradually. However, hemangiopericytomas occurring in the nervous system are included in the new WHO classification of brain tumors, and are distinguished from both meningioma and fibrous tumors. Since there are few genetic studies, we performed a comprehensive cytogenetic analysis of an infratentorial hemangiopericytoma in a 55-year-old female. It was originally classified as a grade II tumor but recurred as a grade III tumor with a proliferation index of 20%. Using trypsin-Giemsa staining (GTG-banding) and multicolor fluorescence in situ hybridization (M-FISH), we could confirm the loss of chromosomal material 10q, which has been previously described in hemangiopericytoma, and we identified de novo chromosomal aberrations on chromosome 8. Applying genome-wide high-density single nucleotide polymorphism array (SNP-A) analysis, we detected segments with loss or gain, as well as clonal deletions or regions suggestive of segmental uniparental disomy. These findings, together with the results of conventional histological and immunohistochemical characterization, provide additional evidence for the nosological separation of hemangiopericytoma in the central nervous system as a biologically different entity.

The Holy Grail and the Quest for the Gold Standard

In this issue of the American Journal of Neuroradiology , Jaremko et al[1][1] report that apparent diffusion coefficient (ADC) values are not always reliable to discriminate medulloblastomas from pilocytic astrocytomas (PAs according to the 2007 WHO classification of brain tumors[2][2], instead of