Angiocentric Glioma Research Articles

Angiocentric glioma: A case report and review of the literature

BackgroundAngiocentric glioma (AG) is a rare, low-grade glioma with slow growth. In 2007, AG was first classified as a solid tumor according to the WHO classification of the central nervous system (WHO class I). The outcome and prognosis of most of the cases are very good, but a few cases with tumor metastasis and disease progression, even death, have been reported. We report a case and systematically analyze previous literature to increase our understanding of the disease and determine the factors that may affect disease progression to make prognostic judgments. Case presentationA young male patient complained of a 3-year history of epilepsy. Anti-epileptic drug treatment was ineffective. An imaging examination revealed a lesion in the left parietal cortex area. Thus, the lesion was completely resected. The pathological diagnosis was angiocentric glioma. During a follow-up of two years, the patient had epilepsy relief controlled by sodium valproate and a disease-free period. ConclusionAG is an epilepsy-related low-grade glioma that heals after complete resection in most reported cases. However, few reported cases have had disease progression and death. This result may be due to the pathological complexity of the diseased tissue. In addition, AG is usually found to have an MYB–QKI rearrangement on genetic analysis. Due to the small number of reported cases and studies, our understanding and knowledge of this disease are still lacking. The potential malignant changes and prognostic factors need to be verified in more than clinical cases and basic research in the future.

Clinical Characteristics of BRAF V600E Gene Mutation in Patients of Epilepsy-Associated Brain Tumor: a Meta-analysis.

Epilepsy-associated brain tumors (EATs) are usually slow-growing, with seizures as the primary and most dominant symptom. BRAF (v-raf murine sarcoma viral oncogene homolog B1) gene mutations have been found in several subsets of EATs; the V600E mutation is currently believed to contribute to the intrinsic epileptogenicity and tumor growth. However, the relationship between BRAF V600E gene mutation and clinical characteristics in EAT patients is not clear. In this study, we aimed to systematically review the frequency of BRAF V600E gene mutation, as well as the relationship between BRAF V600E gene mutation and clinical characteristics, which may help with the diagnosis and treatment of EATs. Cochrane Library, PubMed, Embase, CNKI, WanFang Data, CQVIP, and SinoMed databases were searched up to October 2020 to identify peer-reviewed human studies on assessing the relationship between BRAF V600E gene mutations and clinical characteristics in EATs. The following data were calculated: the frequency of BRAF V600E mutation and clinical feature comparison between BRAF V600E mutations and wild type in EATs, such as gender, age of seizure onset, duration of epilepsy, location of tumors, and Engel outcome. A total of 12 articles were included in the analysis. Five hundred and nine patients with epilepsy-associated brain tumors were screened for the BRAF V600E gene mutation. Among them, 193 patients had the BRAF V600E mutation (34.06%, 95% CI=0.25 to 0.43). The subgroup analyses of BRAF V600E mutation showed positive frequency of 44.76% (95% CI=0.36 to 0.54) in ganglioglioma, 24.75% (95% CI=0.14 to 0.37) in gysembryoplastic neuroepithelial tumor, 2.15% (95% CI=0 to 0.19) in angiocentric glioma, and 50.16% (95% CI=0.33 to 0.68) in pleomorphic xanthoastrocytoma. Compared with the overall frequency, the BRAF V600E positive frequency in ganglioglioma was significantly higher (P=0.0283). We also found that BRAF V600E gene mutation was significantly associated with age at seizure onset (MD=-2.37; 95% CI=-4.33 to -0.41; P=0.02). There was no statistical difference between BRAF V600E mutations and wild type in gender, duration of epilepsy, tumor site, and Engel outcome comparison. In conclusion, our updated and comprehensive meta-analysis based on a large number of clinical data demonstrated that BRAF V600E mutation is a specific biomarker and could be a pharmacological target for ganglioglioma patients and an exclusion diagnostic criterion for angiocentric glioma. This meta-analysis suggested the critical role of BRAF V600E mutation in the occurrence and development of EATs. Our findings help to elucidate the progression mechanisms in EATs and develop future therapeutic strategies for EATs.

Angiocentric glioma-associated seizures: The possible role of EATT2, pyruvate carboxylase and glutamine synthetase

PurposeOur purpose was to better understand the pathogenesis of seizures associated with angiocentric glioma. Angiocentric glioma is an indolent and rare low-grade glioma. Its typical clinical presentation is with epileptic seizures. The pathogenesis of tumor-associated seizures is poorly understood. Among the possible pathomechanisms, the increased neurotoxic concentrations of the glutamate has been proposed. Glutamate transporters, pyruvate carboxylase and glutamine synthetase are involved in maintaining the physiological concentration of glutamate in the inter synaptic spaces. MethodsWe evaluated the immunohistochemical expression of EAAT2 (the most important glutamate transporter), pyruvate carboxylase and glutamine synthetase in 17 angiocentric gliomas. ResultsEAAT2 was never expressed (0%) in the neoplastic cells in none of the cases studied. Pyruvate carboxylase was expressed in the cytoplasm of the neoplastic cells in 16/17 cases (94 %). Glutamine synthetase was expressed in the cytoplasm of the neoplastic cells in 15/17 cases (88 %). ConclusionThe net result of this enzymatic expression, in particular considering the loss of EAAT2, could be an increased glutamate concentration in the synaptic clef, which might increase local network excitability initially involving intratumoral neurons. The observation that the angiocentric glioma-associated epilepsy might be at least in part related to EAAT2 deficiency opens up interesting therapeutic perspectives.

Molecular Immunohistochemical Profile of Angiocentric Glioma.

Background and PurposeAngiocentric glioma is a rare, World Health Organization grade I tumor that is seen predominantly in children and young adults and typically presents with seizures. Histologically, it shows features of both infiltrating glioma and ependymoma.MethodsWe examined molecular immunohistochemical markers which could help in distinguishing this entity from its differential diagnostic considerations.ResultsWe retrospectively reviewed the clinicopathologic features of angiocentric gliomas and performed immunohistochemical staining for isocitrate dehydrogenase 1 (IDH-1) (R132H), p53, ATRX, BRAF V600E, Ki-67, and H3 K27M on formalin-fixed, paraffin-embedded tissue. Seven cases in total were found and included six excisional specimens and one biopsy. ATRX staining was retained in all cases. There was no evidence of staining with antibodies to IDH-1 (R132H), H3 K27M, or BRAF V600E. Five tumors showed no staining with antibody to p53 and two tumors showed less than 5% positivity. Ki-67 indices were less than 1% in five tumors, 4–5% in one tumor, and 9–10% in one tumor.ConclusionsIn conclusion, the immunohistochemical markers for ATRX, p53, IDH-1 (R132H), BRAF V600E, H3 K27M show wild-type staining, potentially aiding in avoiding misdiagnoses in cases morphologically similar to other low-grade gliomas. Ki-67 labeling indices are low in most tumors.

LGG-33. ISOMORPHIC DIFFUSE GLIOMA HAS RECURRENT GENE FUSIONS OF MYBL1 OR MYB AND CAN BE DISTINGUISHED FROM OTHER MYB/MYBL1 ALTERED GLIOMAS BASED ON A DISTINCT MORPHOLOGY AND DNA METHYLATION PROFILE

Isomorphic diffuse glioma (IDG) was first described in 2004 as an epilepsy-associated supratentorial diffuse glioma with low cellularity, low proliferation and very monomorphic tumour cells. Most patients had seizures since childhood but were operated on as adults. To study the position of these lesions among brain tumours we histologically, molecularly and clinically analysed 26 histologically typical IDGs. Tumour cells were GFAP-positive, MAP2-, OLIG2- and CD34-negative and the nuclear ATRX-expression was retained. Proliferation was very low. Sequencing of 24 cases revealed an IDH-wildtype status. Cluster analyses of DNA methylation data showed that IDG has a DNA methylation profile distinct from those of different glial/glio-neuronal brain tumours and normal hemispheric tissue. About half of IDGs had copy number alterations of MYBL1 or MYB (13/25) and half of the cases analysed by RNA-sequencing had gene fusions of MYBL1 or MYB with various gene partners (11/22), often associated with an increased RNA-expression of the respective MYB-family gene. Integrating all data available, 77% of IDGs had either MYBL1 (54%) or MYB (23%) alterations. All patients had a good outcome and most were seizure-free after surgery. In summary, we show that isomorphic diffuse glioma is a distinct benign tumour in the family of MYB/MYBL1-altered gliomas. DNA methylation analysis is very helpful for their identification. More recent analyses of a large cohort of MYB/MYBL1-altered brain tumours suggest the presence of a third methylation group that primarily contains paediatric cases and seems to be distinct from IDG and angiocentric gliomas. Further histological, molecular and clinical analyses are ongoing.

LGG-46. MOLECULAR CHARACTERIZATION OF HEMISPHERIC LOW-GRADE GLIOMAS IN CHILDREN

BACKGROUNDHeterogeneous pathology in hemispheric low-grade gliomas (hemLGG) stress the importance of molecular testing in terms of prognosis prediction and targeted therapy options.METHODSDemographic data was collected and targeted genomic approach was employed in the single institutional study. RT-PCR was used to screen for KIAA1549-BRAF fusion and FGFR1 tyrosine-kinase domain duplication (FGFR1-ITD). Direct sequencing evaluated point mutations (BRAF ex15 and ex11, FGFR1 ex12 and ex14). Samples with no detected alteration were subjected to panel RNA-sequencing (FusionPlex Archer Diagnostics).RESULTSWithin 2000–2019 were diagnosed 76 patients with hemLGG (median age 11.1y, range 0.0y–18.5y) comprising predominantly of ganglioglioma, dysembryoplastic neuroepithelial tumors, and diffuse astrocytoma. 40 % of hemLGG were characterized by BRAF alterations with over 2/3 of those cases harboring BRAF point mutations (two BRAFex11, 12 BRAFV600E). Notably, BRAF fusions were uncommon and detected only in six patients (two KIAA-BRAF fusion, two minor oncogenic BRAF variants, two non-KIAA BRAF fusion). 25 % of alterations were found in genes for receptor tyrosine kinases, consisting of seven patients with FGFR1-ITD, three FGFR2/3 fusions, two FGFR1 mutations, two ALK fusions, and one ROS fusion. Out of MAP kinase pathway, the most frequent alteration was IDH1 mutations (n=9). Two angiocentric gliomas were characterized by MYB-QKI fusion.CONCLUSIONTargeted sequencing combined with RNA-sequencing is feasible to establish molecular diagnosis in majority of cases and reveal new and rare alterations. Significant prevalence of non-BRAF alterations explains heterogeneity among hemLGG.

LGG-35. FUNCTIONAL GENOMIC APPROACHES TO IDENTIFY THERAPEUTIC TARGETS IN MYB AND MYBL1 EXPRESSING PEDIATRIC LOW-GRADE GLIOMAS

AIMRecurrent structural variants involving MYB and MYBL1 transcription factors were recently identified in pediatric low-grade gliomas (pLGGs), such as the MYB-QKI rearrangement in Angiocentric Gliomas and truncations of MYBL1 (MYBL1tr) in Diffuse Astrocytomas. However, therapeutic dependencies induced by these alterations remain unexplored.METHODOLOGYWe have generated in vitro pLGG mouse neural stem cell (NSCs) models engineered to harbor distinct MYB/MYBL1 genomic alterations. We used single cell RNA sequencing approaches to determine the transcriptional profile and dissect the central regulatory networks of our in vitro pLGG models over time. To identify specific genetic dependencies associated with MYB/MYBL1 mutations, we employed the Brie genome-wide mouse CRISPR lentiviral knockout pooled library, consisting of 78,637 single guide RNAs (sgRNAs) targeting 19,674 mouse genes.RESULTS MYB/MYBL1 expression in neural stem cells induced activation of cell-cycle related, glioma-related and senescence-related pathways that are involved in normal development, including activation of MAPK and mTOR signaling which are also activated in human pLGG samples. Genome-scale CRISPR-cas9 screens in isogenic NSCs expressing MYB-QKI or MYBL1tr identified differential genetic dependencies relative to GFP controls. These included regulators of cell-cycle progression and several modulators of the ubiquitin-proteasome degradation pathway. Analysis of RNA-sequencing data from human tumors revealed several of these dependencies identified in the cell line model to be differentially expressed in MYB-altered pLGG tumors relative to normal brain.CONCLUSIONExpression of MYB family alterations induces expression of key developmental and oncogenic pathways and genetic dependencies that represent potential therapeutic targets for MYB or MYBL1 rearranged pLGGs.

EPID-05. EVALUATION OF THE INCIDENCE OF CENTRAL NERVOUS SYSTEM TUMORS IN A CHILDHOOD CANCER TREATMENT CENTER AND THE CREATION OF A SPECIFIC GROUP

Central Nervous System Tumors (CNST) are the main solid neoplasm of childhood, representing 20% diagnosis. Based on this information, a search was carried out at a reference treatment center for childhood cancer in the state of Sao Paulo, belonging to University of Sao Paulo- ITACI/HCFMUSP, and at between 2017 and 2019, 352 new patients, 116 of which were neoplasm of CNS (32.9%). Aiming at an incidence of new cases, in 2019, an institutional group was created, with a team composed of Pediatric Oncologists, Neurosurgeons, Radiologists, Radiotherapists and Pathologists. In this first year, 31,8% of the 132 new patients were diagnosed with CNS tumor. According to WHO 2016, 15 patients were classified as a group that includes Diffuse Astrocytomas, Oligodendrioglial Tumors and Other Astrocytic Tumors. Among the other patients, 14.2% were Medulloblastomas, 4.7% Embryonic Tumors and 2.3% ART / RT. Patients diagnosed with diffuse brainstem glioma accounted for 11.9% of the total. The institution had a diagnosis of Angiocentric Glioma, Craniopharyngioma, Plexiform Neurofibroma and Anaplastic Ependymoma. Neuronal-glial tumors accounted for 9.5% of cases. Choroid plexus tumors represents 5%. Among them, 4.72% had metastatic tumors: Neuroblastoma and Ewing’s Sarcoma. Of the total of 42 patients, there were 5 deaths, 4 due to disease progression and one due to clinical complications. With the group, the discussions were carried out, allowing us to analyze that the presence of the Radiotherapy, Neurosurgery and Pathology team from the first moment, optimized the beginning of treatment and increased the patients’ survival.

MYB-QKI rearrangement in angiocentric glioma.

To evaluate the occurrence and diagnostic value of MYB-QKI rearrangement status in angiocentric glioma (AG) in Chinese patients. 27 cases were collected from six hospitals, followed by a retrospective analysis of clinical, radiological, and morphological data. MYB protein expression was assessed by immunohistochemical staining (IHC), and the MYB-QKI rearrangement was detected by fluorescence in situ hybridization (FISH). Among the 27 cases (16 males), the median age at surgery was 17 years (range 3 - 43 years); 24 (88.9%) cases had a history of refractory epilepsy, and the mean history of pre-surgical epilepsy was 13 years (range 1.5 - 27 years); 26 (96.3%) cases had lesions located in the superficial cerebrocortical regions, and 1 (3.7%) case had a lesion in the brainstem. Except for the classic histological features, the involvement of superficial cortex extending to the leptomeninges, microcalcification, and cystic pattern with microcystic formations was observed in 11 (40.7%), 3 (11.1%), and 4 (14.8%) cases, respectively. IHC showed that all 27 cases were positive for glial fibrillary acidic protein (GFAP) and vimentin, and negative for neuronal nuclear antigen (NeuN). The positive rates of epithelial membrane antigen (EMA) and D2-40 were 81.5% (22/27) and 74.1% (20/27), respectively. A total of 14 (51.9%) cases were positive for MYB. The rate of Ki-67 proliferation was 1 - 5% in 25 cases, and in 2 cases with anaplastic features it was 10 and 20%. MYB-QKI rearrangement was revealed by FISH examination in 95.8% (23/24) of the AGs, including 3 cases with atypical histological appearance. Compared to IHC, FISH was more appropriate for detecting MYB-QKI rearrangement. MYB-QKI rearrangement was detected in the majority of Chinese AG cases, and therefore represents a potential diagnostic biomarker for AG.

Clinical characteristics, treatment and prognosis of angiocentric glioma.

Angiocentric glioma (AG) is a rare subtype of neuroepithelial tumor in children and young adults that commonly presents with seizures. To study the clinical characteristics, treatment and prognosis of patients with AG, the features of two cases of AG were described and 108 cases reported in the literature were assessed. The cases of the present study were two males aged 8 and 16 years, who mainly presented with seizures. MRI revealed superficial, non-enhanced lesions in the left temporal and right frontal lobe, respectively. The two patients underwent gross total resection (GTR) and remained seizure-free without neurological deficits after 3.5 and 2.5 years, respectively. Histopathological examination revealed that the tumors consisted of monomorphous cells that surrounded the blood vessels and neurons in the cerebral cortex, and formed concentric sleeves or pseudorosettes. Furthermore, immunostaining indicated that the diffuse infiltrative neoplastic cells were positive for glial fibrillary acidic protein and a dot-like pattern of epithelial membrane antigen was observed. AG mostly appeared similar to low-grade gliomas on MRI. GTR of the lesions was curative and radiation or chemotherapy were not required. AG typically has a favorable prognosis, with low mortality and incidence of disability.

Unusual imaging appearance of a rare cortical ependymoma mimicking angiocentric glioma.

Cortical ependymomas are uncommon lesions. We report a cortical ependymoma displaying an unusual imaging pattern. The lesion demonstrated a T1 hyperintense rim and limited perilesional edema but lacked contrast enhancement. T1 hyperintense rim and stalk-like ventricular extension of FLAIR hyperintensity have previously been considered pathognomonic of angiocentric glioma. Hence, we conclude that the radiologists should be aware of this uncommon imaging pattern of cortical ependymoma. The condition warrants prompt surgical management in view of the increased potential for higher grade transformation, unlike grade I roman numeral may be given angiocentric gliomas.

Squash smear cytology and histopathology findings of angiocentric glioma

ENWEndNote BIBJabRef, Mendeley RISPapers, Reference Manager, RefWorks, Zotero AMA Tabakow P, Kubicki K, Jeleń M, Gajdzis P. Squash smear cytology and histopathology findings of angiocentric glioma. Polish Journal of Pathology. 2020;71(4):363-367. doi:10.5114/pjp.2020.103718. APA Tabakow, P., Kubicki, K., Jeleń, M., & Gajdzis, P. (2020). Squash smear cytology and histopathology findings of angiocentric glioma. Polish Journal of Pathology, 71(4), 363-367. https://doi.org/10.5114/pjp.2020.103718 Chicago Tabakow, Paweł, Konrad Kubicki, Michał Jeleń, and Paweł Gajdzis. 2020. "Squash smear cytology and histopathology findings of angiocentric glioma". Polish Journal of Pathology 71 (4): 363-367. doi:10.5114/pjp.2020.103718. Harvard Tabakow, P., Kubicki, K., Jeleń, M., and Gajdzis, P. (2020). Squash smear cytology and histopathology findings of angiocentric glioma. Polish Journal of Pathology, 71(4), pp.363-367. https://doi.org/10.5114/pjp.2020.103718 MLA Tabakow, Paweł et al. "Squash smear cytology and histopathology findings of angiocentric glioma." Polish Journal of Pathology, vol. 71, no. 4, 2020, pp. 363-367. doi:10.5114/pjp.2020.103718. Vancouver Tabakow P, Kubicki K, Jeleń M, Gajdzis P. Squash smear cytology and histopathology findings of angiocentric glioma. Polish Journal of Pathology. 2020;71(4):363-367. doi:10.5114/pjp.2020.103718.

Targeted fusion analysis can aid in the classification and treatment of pediatric glioma, ependymoma, and glioneuronal tumors.

The use of next-generation sequencing for fusion identification is being increasingly applied and aids our understanding of tumor biology. Some fusions are responsive to approved targeted agents, while others have future potential for therapeutic targeting. Although some pediatric central nervous system tumors may be cured with surgery alone, many require adjuvant therapy associated with acute and long-term toxicities. Identification of targetable fusions can shift the treatment paradigm toward earlier integration of molecularly targeted agents. Patients diagnosed with glial, glioneuronal, and ependymal tumors between 2002 and 2019 were retrospectively reviewed for fusion testing. Testing was done primarily using the ArcherDx FusionPlex Solid Tumor panel, which assesses fusions in 53 genes. In contrast to many previously published series chronicling fusions in pediatric patients, we compared histological features and the tumor classification subtype with the specific fusion identified. We report 24 cases of glial, glioneuronal, or ependymal tumors from pediatric patients with identified fusions. With the exception of BRAF:KIAA1549 and pilocytic/pilomyxoid astrocytoma morphology, and possibly QKI-MYB and angiocentric glioma, there was not a strong correlation between histological features/tumor subtype and the specific fusion. We report the unusual fusions of PPP1CB-ALK, CIC-LEUTX, FGFR2-KIAA159, and MN1-CXXC5 and detail their morphological features. Fusion testing proved to be informative in a high percentage of cases. A large majority of fusion events in pediatric glial, glioneuronal, and ependymal tumors can be identified by relatively small gene panels.

Isomorphic diffuse glioma is a morphologically and molecularly distinct tumour entity with recurrent gene fusions of MYBL1 or MYB and a benign disease course.

The "isomorphic subtype of diffuse astrocytoma" was identified histologically in 2004 as a supratentorial, highly differentiated glioma with low cellularity, low proliferation and focal diffuse brain infiltration. Patients typically had seizures since childhood and all were operated on as adults. To define the position of these lesions among brain tumours, we histologically, molecularly and clinically analysed 26 histologically prototypical isomorphic diffuse gliomas. Immunohistochemically, they were GFAP-positive, MAP2-, OLIG2- and CD34-negative, nuclear ATRX-expression was retained and proliferation was low. All 24 cases sequenced were IDH-wildtype. In cluster analyses of DNA methylation data, isomorphic diffuse gliomas formed a group clearly distinct from other glial/glio-neuronal brain tumours and normal hemispheric tissue, most closely related to paediatric MYB/MYBL1-altered diffuse astrocytomas and angiocentric gliomas. Half of the isomorphic diffuse gliomas had copy number alterations of MYBL1 or MYB (13/25, 52%). Gene fusions of MYBL1 or MYB with various gene partners were identified in 11/22 (50%) and were associated with an increased RNA-expression of the respective MYB-family gene. Integrating copy number alterations and available RNA sequencing data, 20/26 (77%) of isomorphic diffuse gliomas demonstrated MYBL1 (54%) or MYB (23%) alterations. Clinically, 89% of patients were seizure-free after surgery and all had a good outcome. In summary, we here define a distinct benign tumour class belonging to the family of MYB/MYBL1-altered gliomas. Isomorphic diffuse glioma occurs both in children and adults, has a concise morphology, frequent MYBL1 and MYB alterations and a specific DNA methylation profile. As an exclusively histological diagnosis may be very challenging and as paediatric MYB/MYBL1-altered diffuse astrocytomas may have the same gene fusions, we consider DNA methylation profiling very helpful for their identification.

Advances in Diagnostic Immunohistochemistry for Primary Tumors of the Central Nervous System.

As genomic characterization becomes increasingly necessary for accurate diagnosis of tumors of the central nervous system, identification of rapidly assessible biomarkers is equally important to avoid excessive cost and delay in initiation of therapy. This article reviews novel immunohistochemical markers that may be used to determine mutation status, activation of signaling pathways, druggable targets, and cell lineage in many diverse tumor types. In particular, recently added entities to the 2016 WHO classification of central nervous system tumors will be addressed, including IDH-mutant gliomas, diffuse midline glioma, epithelioid glioblastoma, angiocentric glioma, RELA-rearranged ependymoma, embryonal tumors (medulloblastoma, atypical teratoid/rhabdoid tumor, pineoblastoma, embryonal tumor with multilayered rosettes, and other genetically defined high-grade neuroepithelial tumors), and meningiomas associated with germline alterations.

Angiocentric glioma: Report of a rare case presenting with psychosis

Angiocentric glioma (AG), first described in 2005, was included as a distinct entity in the 2007 World Health Organization Classification of Tumors of the Central Nervous System. It is a very rare cerebrocortical tumor mainly affecting children and young adults with a history of intractable partial seizures. The histopathological features of this entity are perivascular arrangement of monomorphic, bipolar spindled cells with subpial aggregation of tumor cells and variable neuroparenchymal colonization. Of uncertain histogenesis, this is a stable/slowly growing tumor. Prognosis following total surgical resection is favorable. We describe an AG in a 16-year-old, intellectually disabled, male patient, with psychosis. This is a rare presentation with only one such case in literature. Patient's symptoms ameliorated following surgery.

Angiocentric Glioma: A Review of Clinicopathologic Features

Along with focal cortical dysplasia, hippocampal sclerosis and remote infarcts, tumors are a well known cause of medically intractable or pharmacoresistent epilepsy [1-3]. Most of the tumors encountered in this setting represent low grade glioneuronal neoplasms, particularly gangliogliomas and dysembryoplastic neuroepithelial tumors. In 2005, Wang and colleagues reported on 8 tumors which they designated as so-called “monomorphous angiocentric gliomas” [4]. The title of their paper suggested that these tumors were epileptogenic (all eight patients had epilepsy) and displayed features of infiltrating astrocytoma and ependymoma. During the same month, Lellouch-Tubiana and coworkers reported on a series of 10 children with refractory epilepsy who had similar appearing neoplasms which they referred to as “angiocentric neuroepithelial tumors” [5]. The term “angiocentric glioma” was used in reference to these tumors in a series of eight tumors reported by Preusser et al in 2007 [6] and the entity was included under this designation in the 2007 World Health Organization (WHO) Classification of Tumours of the Central Nervous System [7]. The purpose of this article is to briefly review the salient clinical and pathologic features of this relatively new entity

BRAF V600E mutation and clinicopathologic characteristics in 250 cases of brain tumors associated with epilepsy

Objective: To investigate the clinicopathologic characteristics and BRAF V600E mutation of brain tumors associated with epilepsy. Methods: Totally 250 patients with brain tumors associated with epilepsy were included from March 2008 to August 2017 retrospectively at Sanbo Brain Hospital, Capital Medical University.The clinical manifestations, histological features and BRAF V600E mutation results were collected and analyzed. Results: There were 132 males and 118 females, and the male to female ratio was 1.1∶1.0. The age of patients ranged from 2 to 67 years(mean 22 years). The tumors had obvious local space occupying effect on MRI. The temporal lobe was the most common site (44.4%, 111/250). There were 58.4% (146/250) of ganglioglioma (GG), 24.0% (60/250) of dysembryoplastic neuroepithelial tumor (DNT), 12.8% (32/250) of pleomorphic xanthoastrocytoma(PXA), 4.0% (10/250) of angiocentric glioma (AG) and 0.8% (2/250) of papillary glioneuronal tumor (PGNT). Mixed GG, PXA and DNT morphological structures were found in 9 of patients. Among 250 cases, 35 cases were accompanied by focal cortical dysplasia(FCD). BRAF V600E was seen in 43 of 74 (58.1%) GG and 13 of 28 (46.4%) PXA. The most common pathologic grade of GG, DNT, AG and PGNT was WHO I. Some of the tumor cells from GG (34 cases) showed higher proliferative activity (WHO Ⅱ/Ⅲ). Most cases of PXA were WHOⅡand high proliferative activity was seen in nine cases. Conclusions: The association of low-grade glioneuronal tumors with intractable epilepsy was well-recognized. The most common low-grade glioneuronal tumors were GG.GG may occur in any part of the central nervous system, with a predilection for temporal lobe. Each type of low-grade glioneuronal tumors has its own unique histological morphology, but some may show complex features with 2 or 3 mixed components. The occurrence of BRAF V600E mutations in GG is common, and their detection may be valuable for the diagnosis and treatment in GG.

Paradoxical results obtained with Ki67-labeling and PHH3-mitosis index in glial tumors: a literature analysis.

Precise tiered tumor grading is essential for predicting prognosis, selecting different treatment options and for follow-up of brain tumor patients. Ki67 labeling index (LI) is widely employed in assessing aggressiveness of glial brain tumors. However, Ki67 is subject to interlaboratory variability, and its antigen is expressed on all cell cycle phases except G0, which hinders its usage as a precise criterion for assessing cell proliferation. Indeed, there exist peculiar observations pertinent to increases of Ki67 index in glial tumors following radiotherapy or treatment with tyrosine kinase inhibitors. Moreover, we have witnessed a reduced Ki67 labeling in a gemistocytic glioma during its rapid recurrence under temozolomide treatment. Therefore, we reviewed pitfalls in employing Ki67 indices for predicting glial tumor biology and tried to answer whether the mitotic marker PHH3 (phosphorylated histone H3) could provide additional information in predicting glial tumor biology. PHH3-based assessment of proliferating cell fraction provides novel potentials, but it has also its own weaknesses. It has not yet been determined whether it would be more advantageous to report: a mitotic count (MC) per unit-area (e.g., 10 high power fields (HPF)) or a mitotic index (MI) (per 1,000 tumor cells). Further, there exist peculiarities in terms of unexpectedly low or high PHH3 values in pilocytic astrocytomas and angiocentric gliomas, respectively. Indeed, we encountered almost no staining with PHH3 in our unique gemistocytic astrocytoma case. Hence, at least in some glial malignancies, PHH3 may not be necessary for cell proliferation. Awareness of the weaknesses of proliferation markers in brain tumors may improve patient monitoring and treatment. .

Characterization of gliomas: from morphology to molecules.

This article reviews the histologic and molecular characterization of gliomas, including the new "integrated diagnoses" of the World Health Organization Classification, 2016 edition. The entities reviewed within include diffuse gliomas (astrocytoma, oligodendroglioma, glioblastoma), as well as circumscribed and low-grade gliomas (angiocentric glioma, pilocytic astrocytoma, subependymal giant cell astrocytoma, pleomorphic xanthoastrocytoma, pilomyxoid astrocytoma, ependymoma, myxopapillary ependymoma, and subependymoma). Diagnostic, prognostic, and predictive biomarkers are discussed for each entity. We review how molecular testing for IDH1 and ATRX and detection of chromosome 1p/19q codeletion can be used to categorize glioblastomas as IDH-wildtype or IDH-mutant, and lower grade diffuse gliomas into three molecular groups that correlate better with patient outcomes than histologic subtyping. Pediatric diffuse gliomas are highlighted, including diffuse midline glioma, H3 K27M-mutant, and inherited germline mutations that predispose to pediatric gliomas. The utility of genomic profiling of certain gliomas is discussed, including identifying candidates for experimental therapies. This review is meant to be a concise summary of glioma characterization for the practicing pathologist.