WHO Classification Of Brain Tumors Research Articles

P14.12.A PLASMA CFDNA LIQUID BIOPSY IN THE FOLLOW-UP OF HIGH-GRADE GLIOMAS

Abstract BACKGROUND As highlighted by the 2021 WHO classification of brain tumors, molecular characterization of gliomas is now critical to complement histopathological evaluation. However, intratumor heterogeneity may lead to surgical specimens not being fully representative of the whole tumor. Moreover, given the invasiveness of surgery, tissue analyses are not repeatable over time, thus limiting the possibility to monitor the response to therapies. In this context, we investigated the potential value of plasmatic cell-free DNA (PcfDNA) as a non-invasive ‘liquid biopsy’ marker of disease evolution. MATERIAL AND METHODS Patients’ blood was collected at 4 time points (TP), in parallel to clinical follow-up. A reproducible pipeline was optimized for blood withdrawal, centrifugation, plasma storage, cfDNA extraction from plasma by QIAamp MinElute ccfDNA Midi Kit (Quiagen) and cfDNA fluorometric quantification by Qubit (Thermo Fisher Scientific). MRI volumes were segmented in T1+contrast and T2-FLAIR sequences. RESULTS Fifty-four high-grade glioma patients and 14 healthy controls were enrolled. Blood samples were collected from all 54 patients at radiological diagnosis before surgery (TP0), from 33 patients after surgery (TP1), from 21 patients after radio-chemotherapy(TP2), from 10 patients at the first radiological progression (TP3). At T0, a significantly higher concentration of PcfDNA was detected in patients than in controls. IDH-wild-type gliomas showed a trend toward higher PcfDNA when compared with IDH-mutant gliomas. Digital-droplet PCR, performed at T0on PcfDNA of 4 patients with IDH-mutations in tumor tissues, identified the same IDH1-R132H mutation in all cases. When PcfDNA at TP0 was compared to that at TP1 of the same patient (n=33), there was a significant reduction of plasmatic cfDNA after surgery, mirroring the extensive tumor-resection shown by MRI. Finally, PcfDNA was evaluated in 10 patients until their radiological progression. Interestingly, PcfDNA levels not only followed the same trend of the volumes of T2-FLAIR hyperintensities and T1 contrast-enhancements, but were also mirrored by the evolution of KPS and NANO scores. CONCLUSION Preliminary results suggest that PcfDNA content may be an informative tool to complement MRI during the follow-up of high-grade gliomas.

Ependymoma in WHO Classification of Tumours 5th Edition

Ependymoma is a rare central nervous system tumor that occurs in all age groups and is one of the most common childhood malignant brain tumors. Until the 3rd edition of the WHO Classification of Brain Tumours, ependymoma was classified based solely on histologic findings, but advances in molecular analysis led to the incorporation of molecular information into the diagnosis of ependymoma for the first time in the 2016 WHO Classification, 4th edition. However, the low correlation between tumor grade and survival prognosis remained a problem. Unlike other malignant brain tumors, ependymoma is genetically and epigenetically characterized with few identified point mutations. Methylation profiling was found to classify ependymoma into distinct subgroups, and the 2021 WHO Classification, 5th Edition, adopted new classifications by histologic findings, genetic alterations, methylation patterns, and anatomic location. This new classification includes 10 diagnostic entities: 1)supratentorial subependymoma; 2)supratentorial ependymoma, ZFTA-fusion positive; 3)supratentorial ependymoma, YAP1-fusion positive; 4)posterior fossa subependymoma; 5)posterior fossa group A ependymoma; 6)posterior fossa group B ependymoma; 7)spinal subependymoma; 8)spinal ependymoma; 9)spinal myxopapillary ependymoma; and 10)spinal ependymoma, MYCN-amplified. The previously accepted term "anaplastic ependymoma" was dropped. As with other CNS tumors, a new classification was introduced based on an integrated diagnosis that incorporates histologic and molecular diagnosis. In this article, we summarize the molecular classification of ependymoma in the WHO Classification of Brain Tumours, 5th edition.

Abstract 2115: Zero-waste molecular diagnostics from biopsy needle wash water

Abstract Background: Over the past decade, the WHO classification of brain tumors has increasingly integrated molecular diagnostics into official classification criteria. However, biopsy tissue is precious due to high morbidity associated with repeat biopsies, and usually earmarked for histology, leaving little or no tissue for clinical molecular diagnostics. We have identified that the fluid used to wash biopsy needles after cores contains excess tumor DNA and cells that can be diagnostically useful. Additional research of tumor DNA and tumor tissue recovered from biopsy needle washes provides an opportunity for improvement in the diagnosis and treatment for brain tumor patients, while utilizing material that is otherwise thrown away. Methods: In two cases, surgeons were instructed to save 5-15ml of fluid used to wash biopsy needles. Isothermal targeted amplification of H3.3 and H3.1 histone genes was performed on raw wash fluid. Resulting amplicons were sequenced using an Oxford Nanopore MinION. DNA extracted from wash fluid was subjected to NGS sequencing via the Illumina TruSight Oncology 500 panel and compared to a CLIA certified NGS sequencing results from clinically indicated biopsy tissue. Results: For case 1, 5ul of raw wash fluid was subjected to rapid Loop-mediated Isothermal Amplification (LAMP) targeting the H3.1 and H3.3 K27M histone mutations and immediately sequenced using a MinION sequencer via rapid library preparation. Sequencing revealed a H3.3 K27M histone mutation present in wash fluid at 12% variant allele fraction (VAF). The variant call (99.99% CI) was available 1hr5mins after acquisition of material. For case 2, 5ml of wash fluid was processed using a cell-free DNA extraction kit resulting in ~250ng of recovered DNA. A LAMP assay targeting the H3.3 K27M mutation was performed on extracted DNA from wash fluid. Sequencing revealed an H3.3 K27M histone mutation present at 55% VAF, which was later corroborated using digital droplet PCR. Clinically indicated tissue from both biopsies was submitted for cancer panel sequencing in a CLIA certified setting. DNA extracted from wash fluid from both cases was subjected to Illumina TruSight Oncology 500 panel sequencing. In both cases, the panel was able to corroborate all SNV mutations reported by clinical sequencing that were also covered by the panel. Accrual of needle wash specimens is ongoing, with multiple monthly procedures. Conclusions: Large amounts of diagnostically useful material is present in biopsy needle wash fluid, which is usually discarded. Isothermal assays coupled with MinION sequencing can rapidly identify clinically relevant point mutations directly from wash fluid (e.g. IDH1), and enough DNA was recovered from wash fluid from both case-studies to submit for targeted cancer panel sequencing. These results suggest biopsy needle wash fluid should be considered a first-class diagnostic resource in any cancer. Citation Format: Jack Wadden, Vishal John, Seongbae Kong, Kait Verbal, Amy K. Bruzek, Wajd Al-Holou, Jason A. Heth, Hugh Garton, Carl Koschmann. Zero-waste molecular diagnostics from biopsy needle wash water [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2115.

An enduring debate on gliomatosis cerebri

Gliomatosis cerebri (GC) is a unique glial tumor that extensively invades the cerebral white matter and has been recognized as an entity of neuroepithelial tumors since the first edition of the WHO classification of brain tumors in 1979. Thereafter, in the fourth edition of the WHO classification in 2007, it was clearly defined as a specific type of astrocytic tumor. However, in the WHO 2016 classification, which was based on the concept of integrated diagnosis using molecular genetics, GC was deleted as it was considered to be only one growth pattern of diffuse glioma and not a specific pathological entity. Since then, there has been criticism by many neuro-oncologists and the establishment of the GC working group at the NIH, and many activities in the world arguing that GC should not be deleted from the clinical discussion of brain tumors. In Japan, positive activities toward multicenter research on GC pathology should be performed, and molecular pathological evidence that can contribute to the WHO classification in the future should be developed. In this article, the author outlined the pathological characteristics of GC, which has been repeated changing since its conception, and also describes his opinion on GC as a neuro-oncologist.

Comparative study of diffuse midline glioma and glioblastoma: Magnetic Resonance Imaging (MRI) in the characteristics and demography

Introduction: Diffuse midline glioma and glioblastoma are classified as grade IV CNS tumors (WHO). The entity ‘diffuse midline glioma, H3 K27 mutant’ was introduced in the 4th revised edition of the 2016 WHO classification of brain tumors; however, there are only a few reports on Magnetic Resonance Imaging of these tumors. Thus, we conducted a retrospective study focused on Magnetic Resonance Imaging features of diffuse midline glioma compared to glioblastoma. This study aims to evaluate and compare the demographic characteristics, anatomic location of lesions, and MRI characteristics of diffuse midline glioma and glioblastoma. Methods: We histologically confirmed 30 patients with diffuse midline glioma and 70 patients with glioblastoma were enrolled in this retrospective study. Pretreatment MRI of each patient was reviewed by a neuroradiology issuing physician and neuroradiology reporting physician for MRI characteristics of tumors. Comparative analysis was performed of the imaging pattern to show differences between diffuse midline glioma and glioblastoma with the p-value. Results: The age of patients with diffuse midline glioma (mean age =24.7 ±10.4) was significantly lower than in those with glioblastoma (mean age =48.2 ±1). The majority of patients with diffuse midline glioma (56.7%) and glioblastoma (51.4%) were ≤ 25 and ≥ 50 years age group respectively. The most common location of diffuse midline glioma and glioblastoma were the thalamus (73.3%) and frontal lobe (37.1%) respectively. The presence of hydrocephalus, edema, and invasion were statistically significantly differences in patients with diffuse midline glioma (hydrocephalus = 46.7%, edema = 53.3%, and invasion =30%) than in those with glioblastoma (hydrocephalus = 12.9%, edema = 88.6%, and invasion =5.7%) (P < 0.05 each). Conclusions: Despite having similar imaging features, diffuse midline glioma exhibited marked differences in age, edema, invasion, and hydrocephalus in MRI compared to Glioblastoma.

INSP-14. Novel approaches to molecular diagnostics

The 2021 WHO classification of brain tumors introduces a variety of novel tumor types and subtypes, especially in pediatric neuro-oncology. Most of these tumor types are characterized by specific molecular profiles and alterations. In turn, diagnostic molecular evaluation of brain tumor specimen becomes substantially more complex. The talk will review the basic concepts of the new WHO classification and present novel methodology developments with the respective implications in diagnostic routine. This covers, first, RNA sequencing for fusion detection and expression profiling, highlighting examples of novel tumor types identified by pathognomonic rearrangements. Second, long-read sequencing approaches selecting DNA fragments of interest during sequencing will be discussed. Third, an outlook on the use of artificial intelligence to classify and detect molecular alterations based on H&E staning alone will be provided.

Validation Study for Non-Invasive Prediction of IDH Mutation Status in Patients with Glioma Using In Vivo 1H-Magnetic Resonance Spectroscopy and Machine Learning.

Simple SummaryThe enzyme isocitrate dehydrogenase (IDH) affects glioma cell metabolism in multiple ways. Mutation of IDH is not only indicative of the presence of astrocytoma or oligodendroglioma but it also comes with a better prognosis and constitutes a promising therapeutic target. Therefore, determination of IDH mutation status is essential in clinical practice. In most patients, tissue can be obtained by resection or biopsy to determine IDH status histologically. However, in some cases, this is not possible for technical reasons. We recently showed in a small cohort of patients that non-invasive determination of IDH mutation status using proton magnetic resonance spectroscopy (1H-MRS) at 3.0 Tesla (T) together with machine learning techniques is feasible in a standard clinical setting and with acceptable effort. Here, we demonstrate that our approach showed comparably good results in sensitivity (82.6%) and specificity (72.7%) in a larger validation cohort employing 1H-MRS at 1.5 T in a retrospective, distinct setting. We concluded that our method works well regardless of the magnetic field strength and scanner used, and thus, may improve patient care.The isocitrate dehydrogenase (IDH) mutation status is an indispensable prerequisite for diagnosis of glioma (astrocytoma and oligodendroglioma) according to the WHO classification of brain tumors 2021 and is a potential therapeutic target. Usually, immunohistochemistry followed by sequencing of tumor tissue is performed for this purpose. In clinical routine, however, non-invasive determination of IDH mutation status is desirable in cases where tumor biopsy is not possible and for monitoring neuro-oncological therapies. In a previous publication, we presented reliable prediction of IDH mutation status employing proton magnetic resonance spectroscopy (1H-MRS) on a 3.0 Tesla (T) scanner and machine learning in a prospective cohort of 34 glioma patients. Here, we validated this approach in an independent cohort of 67 patients, for which 1H-MR spectra were acquired at 1.5 T between 2002 and 2007, using the same data analysis approach. Despite different technical conditions, a sensitivity of 82.6% (95% CI, 61.2–95.1%) and a specificity of 72.7% (95% CI, 57.2–85.0%) could be achieved. We concluded that our 1H-MRS based approach can be established in a routine clinical setting with affordable effort and time, independent of technical conditions employed. Therefore, the method provides a non-invasive tool for determining IDH status that is well-applicable in an everyday clinical setting.

GP.6 The Impact of Brain Invasion on Intracranial Meningioma Grading

Background: In 2016, the WHO Classification of Brain Tumors included brain invasion as a standalone diagnostic criterion for grade 2 meningioma diagnosis. In this study we explored the impact of this change on the incidence and distribution of meningioma grades. Methods: All cases of meningiomas diagnosed from 2007-2020 at a tertiary care hospital were identified. The distribution of meningioma grades before (WHO 2007) and after (WHO 2016) the introduction of the 2016 WHO criteria were compared. Each case in the 2007 cohort was re-graded according to the 2016 criteria to determine the intra-class correlation (ICC) between grading criteria. Results: Of 814 cases, 532 (65.4%) were in the 2007 WHO cohort and 282 (34.6%) were in the 2016 WHO cohort. There were no differences in the distribution of meningioma grades between cohorts (p=0.11). Upon re-grading, 21 cases (3.9%) were changed. ICC between original and revised grade was 0.92 (95% CIs: 0.91-0.93). Amongst Grade 2 meningiomas with brain invasion, 75.8% had three or more atypical histologic features or an elevated mitotic index. Conclusions: Brain invasion alone has minimal impact on the incidence or distribution of specific meningioma grade tumors, likely due to cosegregation of grade elevating features.

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 KLF4K409Q/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.

The impact of brain invasion criteria on the incidence and distribution of WHO grade 1, 2, and 3 meningiomas.

In 2016 brain invasion was added as a standalone diagnostic criterion for Grade 2 meningiomas in the WHO Classification of Brain Tumors. The aim of this study was to compare the incidence and distribution of meningiomas, and agreement, between the 2007 and 2016 WHO criteria. All cases of intracranial meningiomas diagnosed between 2007 and 2020 at a tertiary care academic hospital were identified. The incidence of each meningioma grade in the WHO 2007 and WHO 2016 cohorts were compared. Additionally, each case in the 2007 cohort was re-graded according to the WHO 2016 criteria to determine the intra-class correlation (ICC) between criteria. Of 814 cases, 532 (65.4%) were in the 2007 WHO cohort and 282 (34.6%) were in the 2016 WHO cohort. There were no differences in the distribution of meningioma grades between cohorts (P = .11). Incidence rates were: 75.0% vs. 75.2% for Grade 1, 22.7% vs. 24.5% for Grade 2, and 2.3% vs. 0.4% for Grade 3, for the 2007 and 2016 cohorts, respectively. Upon re-grading, 21 cases (3.9%) were changed. ICC between original and revised grade was 0.92 (95% CI: 0.91-0.93). Amongst Grade 2 meningiomas with brain invasion, 75.8% had three or more atypical histologic features or an elevated mitotic index. Including brain invasion as a standalone diagnostic criterion for Grade 2 meningiomas had minimal impact on the incidence of specific meningioma grade tumors. There is strong agreement between the 2007 and 2016 WHO criteria, likely due to cosegregation of grade elevating features.

Work in progress: Changes to who brain tumor classification

The WHO classification of central nervous system (CNS) tumors had been revised in 2016 to include for the first time molecular biomarkers that are important for tumor classification and clinical decision making. Thereafter, the cIMPACT-NOW (Consortium to Inform Molecular and Practical Approaches to CNS Tumor Taxonomy – not officially WHO) formed to further refine CNS tumor classification through specific recommendations that addressed issues of classification still controversial in 2016. Several cIMPACT-NOW proposals have shaped the new 2021 WHO classification of brain tumors. Mutations in the isocitrate dehydrogenase (IDH) 1 or 2 genes continue to play a major role in glioma classification beyond 2021. Among IDH-mutant gliomas, loss of ATRX expression identifies IDH-mutant astrocytomas without necessity for 1p/19q codeletion testing. Conversely, etection of a 1p/19q codeletion in an IDH-mutant glioma defines an oligodendroglial tumor. The nomenclature for IDH-mutant glioblastoma has been changed to astrocytoma, IDH-mutant, WHO grade 4, with CDKN2A homozygous deletion representing a molecular marker for these tumors. IDH-wildtype astrocytomas that lack microvascular proliferation or necrosis but exhibit telomerase reverse transcriptase promoter mutation, epidermal growth factor receptor amplification and/or a + 7/−10 genotype are now classified as IDH-wildtype glioblastoma. H3.3 G34-mutant diffuse hemispheric gliomas have been proposed as a new entity separate from IDH-wildtype glioblastoma. The new WHO classification increases the diagnostic accuracy and refines clinical care by changing treatment recommendations, e.g. for patients with IDH-wildtype astrocytomas showing molecular features of glioblastoma. It also has major implications for clinical trial design, notable inclusion and exclusion criteria for ongoing and upcoming clinical trials.

IDH mutated gliomas

IDH mutated gliomas are a group of diffuse glioma characterized by a mutation in either the IDH1 or IDH2 gene. These mutations are present in 70% of all grade 2 and grade 3 glioma. IDH mutations (mt) are now key for the WHO classification of Brain Tumors, tumros are diagnosed as as astrocytoma, IDHmt or an oligodendroglioma if accompanied by 1p/19q co-deletion. IDH mutated tumors produce an oncometabolite, 2-hydroxyglutarate which accumulation is the cause of many characteristics of IDH mutated tumors, including the sensitivity to radiotherapy and chemotherapy.

P14.82 Glioneuronal tumors - a rare tumor entity with diagnostic and therapeutic challenges: report of two cases and review of literature

Abstract BACKGROUND The 2007 WHO classification of brain tumors first encompassed two new entities of glioneuronal tumors, including papillary glioneuronal tumors (PGNT) and rosette-forming glioneuronal tumours. The reviewed version of the 2016 WHO classification additionally included diffuse leptomeningeal glioneuronal tumours. The histopathological, genetic, and clinical understanding of glioneuronal tumors is currently evolving, however there are no guidelines for diagnostic and clinical management yet. MATERIAL AND METHODS We report two male patients with glioneuronal tumors and performed a review of literature. RESULTS The first patient was diagnosed with a PGNT (MIB-1 proliferation index = 5%) located in the right parietal lobe at the age of 33 years and received surgical resection. Two years later, the tumor recurred in the same location. A second tumor resection was performed followed by concomitant radiochemotherapy with temozolomide (60/2 Gray). A next-generation sequencing gene panel (Oncomine) confirmed the initial diagnosis of a PGNT. The patient has remained in remission for the past 10 years. The second patient developed complex partial seizures which were first misdiagnosed as anxiety disorder at the age of 26 years. An MRI scan revealed a contrast-enhancing bifrontal cystic lesions 5 years later and he received a gross total tumor resection. The diagnosis of a glioneuronal tumor was made, however molecular pathology and methylation analysis were not able to classify the tumor entity further. There was no evidence of tumor recurrence one year after surgery and he remained seizure-free with antiepileptic treatment. CONCLUSION Glioneuronal tumors encompass rare and heterogenous tumor entities which primarily present in young patients and often show a favorable clinical course. Although the increasing number of reports in the literature have improved our understanding of these tumors, uncertainty remains in diagnostic challenging cases and patients with progressive disease after surgery. The value of next-generation sequencing and the choice of adjuvant treatment modalities have not been systematically evaluated in this patient group.

Tumors of the central nervous system in children and adolescents

Brain tumors are the most common solid tumors in childhood and the most frequent cancer after leukemia. The incidence is continuously increasing. The WHO classification of brain tumors, valid since 2016, is now based on the combination of histological and molecular genetic diagnostics. Diagnostics are mainly performed with magnetic resonance imaging (MRI); only in emergencies with computed tomography (CT). Diffusion and susceptibility weighted and dynamic contrast-enhanced imaging and spectroscopy are used. Improved diagnosis regarding dignity, size determination, adjacency assessment, and morphological description of tumor composition. Modern MRI with functional techniques is now the gold standard for differential diagnosis and staging of central nervous system (CNS) tumors in pediatrics.

Neuroimaging in the Era of the Evolving WHO Classification of Brain Tumors, From the AJR Special Series on Cancer Staging.

The inclusion of molecular and genetic information with histopathologic information defines the framework for brain tumor classification and grading. This framework is reflected in the major restructuring of the WHO brain tumor classification system in 2016 and in numerous subsequent proposed updates reflecting ongoing developments in understanding the impact of tumor genotype on classification and grading. This incorporation of molecular and genetic features improves tumor diagnosis and prediction of tumor behavior and response to treatment. Neuroimaging is essential for the noninvasive assessment of pretreatment tumor grading and for identification and determination of therapeutic efficacy. Use of conventional neuroimaging and physiologic imaging techniques, such as diffusion- and perfusion-weighted MRI, can increase diagnostic confidence before and after treatment. Although the use of neuroimaging to consistently determine tumor genetics is not yet robust, promising developments are on the horizon. Given the complexity of the brain tumor microenvironment, the development and implementation of a standardized reporting system can aid in conveying to radiologists, referring providers, and patients important information about brain tumor response to treatment. The purpose of this article is to review the current state and role of neuroimaging in this continuously evolving field.

The prognostic significance of clinicopathological features in meningiomas: Microscopic brain invasion can predict patient outcome in otherwise benign meningiomas.

Brain invasion (BI) was firstly defined as a single criterion of atypia in otherwise benign meningiomas in the revised fourth edition of 2016 WHO classification of brain tumours after being previously inconsistently addressed. However, recent studies have raised doubts about the prognostic significance of BI in otherwise benign meningiomas. In our study, we investigate the reproducibility of such a prognostic effect. We identified two cohorts one consisting of 483 patients with meningioma WHO grade I (M°I) or atypical meningioma WHO grade II (M°II) from Hannover Medical School and the other including atypical meningiomas defined according to the classical WHO criteria (M°IIb) from the University Hospital Heidelberg. Follow-up data with a median observation time of 38.2months were available from 308 cases. These included 243 M°I and 65 M°II patients with the latter group consisting of 25 patients with otherwise benign meningiomas with BI (M°IIa) and 40 with M°IIb. A significant difference of progression-free interval (PFI) was found between patients with M°I and M°II, M°I and M°IIa and those with M°I and M°IIb of both cohorts and each separately. However, PFI of M°IIa and M°IIb patients showed no significant difference. In the multivariate regression analysis adjusted for M°I/M°IIa versus M°IIb, sex, age, extent of resection and tumour location, BI exhibited the strongest risk of relapse (Hazard ratio: 4.95) serving as an independent predictor of PFI (p=0.002). Our results clearly support the definition of BI as a single criterion of atypia in WHO classification of 2016.

Clinicopathological characteristics and treatment outcomes of epithelioid glioblastoma.

Epithelioid glioblastoma is a new variant of glioblastoma that has been recently recognized in the 2016 WHO classification of brain tumors. Given the rarity of epithelioid glioblastoma, the clinical characteristics, pathological features, radiological findings, and treatment outcomes are still not well characterized. Therefore, we identified eighty-four epithelioid glioblastoma cases to investigate these characteristics and identify the possible prognostic factors of survival. There were 55 male and 29 female patients with a mean age of 33.6 years. Headache (77.3%) was the most common clinical symptom, and other common symptoms included nausea or vomiting (34%), dizziness (20.5%), seizures (13.6%), and limb weakness (13.6%). Most lesions (88.1%) were located in cerebral lobes, especially in the frontal lobe and temporal lobe. One hundred percent of the patients were IDH1 wild-type (75/75) and INI-1 positive (58/58), and 57.3% (47/82) of patients harbored BRAFV600E mutation. The median overall survival (OS) of all patients was 10.5 months. Patients who received chemotherapy (p = 0.006) or radiotherapy (p = 0.022) had a longer survival than patients who did not. In addition, the K-M curve showed that the BRAFV600E mutation status was not associated with survival (p = 0.724). These findings may assist clinicians with better understanding and management of epithelioid glioblastoma.

Detailed Clinical and Histopathological Description of 8 Cases of Molecularly Defined CNS Neuroblastomas.

Central nervous system neuroblastoma with FOXR2 activation (CNS NB FOXR2) has recently been described as a class of brain tumors sharing common genetic events and a highly similar DNA methylation profile. Most of these tumors have previously been diagnosed as primitive neuroectodermal tumor (PNET). Whereas the entity of PNET has been removed from the WHO classification of brain tumors in its current edition, CNS neuroblastoma was kept as an entity, but still lacks any molecular detail. Here, we describe 8 cases of CNS NB FOXR2 focusing on histomorphological and immunohistochemical features and include magnetic resonance imaging (MRI) for 2 of these cases. MRI revealed large supratentorial masses in superficial location with prominent cysts and necrosis, but little edema. Diffusion and enhancement characteristics were variable. Histological analyses showed that most of the cases displayed neuronal differentiation with necrosis, endothelial proliferation, and high vascularity. Immunohistochemistry revealed strong expression of synaptophysin, MAP2, and OLIG2 as well as moderate proliferation. These findings suggest that tumors with the molecular diagnosis of CNS NB FOXR2 may fit well into the WHO entity of CNS neuroblastoma. Our findings may be helpful when establishing an integrated diagnosis and may be indispensable if molecular data are unavailable.

Predicting survival in anaplastic astrocytoma patients in a single-center cohort of 108 patients

BackgroundCurrent guidelines for the treatment of anaplastic astrocytoma (AA) recommend maximal safe resection followed by radiotherapy and chemotherapy. Despite this multimodal treatment approach, patients have a limited life expectancy. In the present study, we identified variables associated with overall survival (OS) and constructed a model score to predict the OS of patients with AA at the time of their primary diagnosis.MethodsWe retrospectively evaluated 108 patients with newly diagnosed AA. The patient and tumor characteristics were analyzed for their impact on OS. Variables significantly associated with OS on multivariable analysis were included in our score. The final algorithm was based on the 36-month survival rates corresponding to each characteristic.ResultsOn univariate analysis, age, Karnofsky performance status, isocitrate dehydrogenase status, and extent of resection were significantly associated with OS. On multivariable analysis all four variables remained significant and were consequently incorporated in the score. The total score ranges from 20 to 33 points. We designated three prognostic groups: A (20–25), B (26–29), and C (30–33 points) with 36-month OS rates of 23%, 71%, and 100%, respectively. The OS rate at 5 years was 8% in group A, 61% in group B and 88% in group C.ConclusionsOur model score predicts the OS of patients newly diagnosed with AA and distinguishes patients with a poor survival prognosis from those with a greater life expectancy. Independent and prospective validation is needed. The upcoming changes of the WHO classification of brain tumors as well as the practice changing results from the CATNON trial will most likely require adaption of the score.

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.