Anaplastic astrocytoma with piloid features, a novel molecular class of IDH wildtype glioma with recurrent MAPK pathway, CDKN2A/B and ATRX alterations
Annekathrin ReinhardtDamian StichelDaniel SchrimpfFelix SahmAndrey KorshunovDavid ReußChristian KoelscheKristin HuangAnnika K. WefersVolker HovestadtMartin SillDorothee GramatzkiJoerg FelsbergGuido ReifenbergerArend KochUlrich-W. ThomaleAlbert J. BeckerVolkmar HansMarco PrinzOri StaszewskiTill AckerHildegard DohmenChristian HartmannWolf MuellerMuin S. A. TuffahaWerner PaulusKatharina HeßBenjamin BrokinkelJens SchittenhelmCamelia-Maria MonoranuAlmuth F. KeßlerMario LoehrRolf BusleiMartina DeckertChristian MawrinPatricia KohlhofEkkehard HewerAdriana OlarFausto J. RodríguezCaterina GianniniAmulya NageswaraRaoUri TaboriNuno M. NunesMichael WellerUte PohlZane JaunmuktaneSebastian BrandnerAndreas UnterbergDaniel HänggiMichael PlattenStefan M. PfisterWolfgang WickChristel Herold‐MendeDavid JonesAndreas von DeimlingDavid Capper
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Pilocytic astrocytoma
Anaplastic astrocytoma
Anaplastic large-cell lymphoma
Introduction: Tumors with histological features of pilocytic astrocytoma but with increased mitotic activity and additional high grade features (i.e. microvascular proliferation, necrosis) have been designated anaplastic pilocytic astrocytomas (APA). Patients with such tumors are thought to have an [for full text, please go to the a.m. URL]
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Solitary gliomas have been well described in the literature. Multiple gliomas, however, have not received the same notoriety, and as such further studies may be helpful in elucidating their unique clinicopathologic features and molecular basis. We present two patients, each with multiple high-grade gliomas, and describe their clinicopathologic and molecular characteristics in comparison with those reported in the literature in an attempt to better understand their shared tumorigenic mechanisms. Extensive molecular, FISH and genomic profiling studies detected multiple unique abnormalities in our two cases with shared molecular features of retained ATRX, wild-type IDH, losses of CDKN2A genes and alterations in the PTEN-PI3K Axis.
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To describe the role of immunohistochemistry in the classification of glioblastoma and anaplastic astrocytoma at Kenyatta National Hospital. Laboratory-based retrospective descriptive study conducted at KNH/UON. Study included diagnosed glioblastoma and anaplastic astrocytoma cases (46). Patients’ data and histopathological reports were retrieved from the archives and reanalyzed to identify those with a glioblastoma and anaplastic astrocytoma. Histopathology evaluation was done using formalin-fixed, paraffin-embedded blocks and routine H&E and Ki-67, a cell proliferative marker. Immunohistochemical markers isocitrate dehydrogenase (IDH1) and ATRX were done on tissue microarray blocks. The data were processed in STATA. Descriptive analysis and bivariate analyses were performed to correlate ATRX expression with IDH-1 in the cases. The results were presented in the form of charts, tables, and figures. The lesions were multisited but most commonly in the cerebral cortex. On review of the previous vs current diagnosis: previous WHO grades III and IV (GBM 89.1%, AA 6.5%, AT/RT 2.2%, oligoastrocytoma 2.2%) and current diagnosis after consensus (GBM 95.6%, AA 2.2%, and one case of no tumor). There were 44 GBM cases: classical subtype (77.3%) and one case of oligodencytric (2.3%). Forty-five cases underwent IHC. In the majority of the cases (28/44), Ki-67 had a mitotic score (mean [SD] 27.1% [15.1%]) of the GBM cases. The AA case mitotic rate was 7%. IDH1 mutations were present in 11 of 44 GBM cases and in the AA case. ATRX loss was in 17 of 44 GBM cases and the AA case. The anaplastic astrocytoma displayed both IDH1 mutation and ATRX loss. The glioblastoma IDH wild type were the majority in this study and have been shown to have poor prognosis as compared to the longer survival time of the glioblastoma, IDH-mutant, and I would recommend a correlation study of survival time to be carried out within our study population.
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approximately 15 months following standard of care therapy.However, 10 % survival at 5 years was observed in a randomized phase III study.At GBM recurrence, the addition of bevacizumab (BEV), a humanized monoclonal antibody against circulating vascular endothelial growth factor (VEGF), resulted in a 3-4 month prolongation of progression-free survival (PFS) without improving overall survival (OS).A 45-year-old female who underwent surgery for left fronto-temporal WHO grade II astrocytoma associated with epilepsy in 2005, 125I seed implantation at disease progression in 2009 and seed explantation 9 months later, was diagnosed with MGMT methylated GBM on the occasion of partial tumor resection in 2010 followed by radiotherapy plus concomitant and adjuvant temozolomide (TMZ) chemotherapy, which was stopped after 4 months due to resection of a left temporal tumor cyst and recurrent cyst within 1 month.TMZ treatment causing prolonged thrombocytopenia was discontinued after 1 additional cycle.Immediately after this cycle, the patient experienced left median cerebral artery stroke resulting in right hemianopia, Broca's aphasia and severe hemiparesis of the right side.Three months later, BEV 10 mg/kg i.v.q14d was initiated, shortly interrupted for abdominal herniotomy in 2012, and continued for 3 years.Since 2014, concurrent low molecular weight heparin was given because of right lower limb deep venous thrombosis suspicion.Whereas GBM progression had not been detected for 2 years during anti-VEGF therapy, methionine PET MRI 6 months after BEV discontinuation revealed left temporal tumor recurrence.Rechallenge with BEV was initiated and the patient remained in stable clinical and radiographical condition for 10 months until now.This case highlights the utility of sequential BEV treatment in a patient being at high risk to develop chemotherapy-induced myelotoxicity.Long-term survival (> 3 years after diagnosis) in GBM has been attributed to patient-derived rather than tumor-derived factors.To our knowledge, this is the first description of effective long-term monotherapy with BEV for GBM and ongoing therapeutic response to single-agent BEV rechallenge in a patient with recurrent secondary GBM.
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Abstract All cancer cells need to maintain functional telomeres to sustain continuous cell division and proliferation. In human diffuse gliomas, functional telomeres are maintained due either to reactivation of telomerase expression, the main pathway in most cancer types, or to activation of a mechanism called the alternative lengthening of telomeres (ALT). The presence of IDH1/2 mutations (IDH-mutant) together with loss of ATRX expression (ATRX-lost) are frequently associated with ALT in diffuse gliomas. However, detection of ALT, and a fortiori its quantification, are rarely, if ever, measured in neuropathology laboratories. We measured the level of ALT activity using the previously described quantitative “C-circle” assay and analyzed it in a well characterized cohort of 104 IDH-mutant and ATRX-lost adult diffuse gliomas. We report that in IDH-mutant ATRX-lost anaplastic astrocytomas, the intensity of ALT was inversely correlated with age ( p < 0.001), the younger the patient, the higher the intensity of ALT. Strikingly, glioblastomas having progressed from anaplastic astrocytomas did not exhibit this correlation. ALT activity level in the tumor did not depend on telomere length in healthy tissue cells from the same patient. In summary, we have uncovered the existence, in anaplastic astrocytomas but not in glioblastomas with the same IDH and ATRX mutations, of a correlation between patient age and the level of activity of ALT, a telomerase-independent pathway of telomere maintenance.
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Lower-grade (World Health Organization Grades II and III) gliomas vary widely in clinical behavior and are classified as astrocytic, oligodendroglial, or mixed. Anaplasia depends greatly on mitotic activity, with CDKN2A loss considered as the most common mechanism for cell cycle dysregulation. We investigated whether loss of the CDKN2A gene is associated with overall survival across pathologically and genetically defined glioma subtypes. After adjustment for IDH mutation, sex, and age, CDKN2A deletion was strongly associated with poorer overall survival in astrocytomas but not in oligodendrogliomas or oligoastrocytomas. Molecular classification of astrocytomas by IDH mutation, TP53 mutation, and /or ATRX loss of expression revealed that CDKN2A loss in IDH/TP53 mutated tumors was strongly associated with worse overall survival. CDKN2A loss in IDH mutated tumors with ATRX loss was only weakly associated with worse overall survival. These findings suggest that CDKN2A testing may provide further clinical aid in lower-grade glioma substratification beyond IDH mutation and 1p19q codeletion status, particularly in IDH/TP53 mutated astrocytomas.
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PURPOSE: Pediatric secondary high grade glioma (sHGG), which result from malignant transformation of low grade glioma (PLGG), are a poorly understood group of tumors with devastating outcomes. PATIENTS AND METHODS: We performed a population-based study combined with long-term follow-up of PLGG that transformed to sHGG. Exonic-sequencing and copy number alterations were investigated on a discovery cohort, followed by detailed genetic analysis of all tumors. Clinical and outcome data analysis of a genetically distinct subgroup was performed. RESULTS: sHGG were observed in 28/888 (3.2%) patients treated in Southern Ontario for PLGG with a median latency of 2.74 years (range, 0.18-20.3 years). sHGG were characterized by a high somatic mutation load (23 per genome). Alterations in chromatin modifying genes and major telomere maintenance pathways were observed in 57% and 54% of sHGG respectively. However, specific mutations in IDH1, H3F3A G34 and ATRX were extremely rare. The most recurrent somatic alterations were the oncogenic BRAF V600E mutation and deletion of the tumor suppressor gene CDKN2A, observed in 39% and 57% of sHGG respectively. Importantly, all BRAF V600E and 80% of CDKN2A alterations could be traced to the patient-matched PLGG counterparts. These early alterations were rarely observed in non-transformed PLGG (p < 0.0001) and primary childhood high grade glioma (p = 0.0023). The BRAF mutant sHGG subgroup was characterized by longer latency periods to transformation than non-BRAF mutant sHGG (median 6.59 versus 1.62 years; p < 0.0001). Furthermore, 5-year overall survival of children with BRAF mutant and wild-type PLGG that transformed were 75% ± 15% and 29% ± 12% respectively (p = 0.024). CONCLUSION: BRAF V600E mutations and CDKN2A deletions constitute a clinically distinct subtype of sHGG. The prolonged course to transformation provides a window of opportunity for aggressive surgical interventions, targeted therapy against oncogenic BRAF, and extended surveillance to potentially mitigate the devastating transformation event.
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Background: According to the current World Health Organization (WHO) classification of central nervous system (CNS) tumors ( 2016), histological diagnosis of gliomas should be supplemented by molecular information.This study was carried out to determine the frequency of isocitrate dehydrogenase 1 (IDH1), ATRX, and BRAF V600E mutations in different grade astrocytomas and their prognostic value.Methods: Eighty cases of astrocytoma (15 pilocytic astrocytoma, 25 diffuse astrocytoma, 15 anaplastic astrocytoma, and 25 glioblastoma) with follow-up information were analyzed using immunohistochemistry for IDH1 mutant protein, ATRX, p53, and BRAF.Sanger sequencing was carried out for IDH1 exon 4 and BRAF exon 15.Results: All pilocytic astrocytoma and primary glioblastoma cases were negative for IDH1 mutation.IDH1 mutation was detected in 80% (20/25) DA and 87% (13/15) AA cases.IDH1 R132H was the commonest IDH1 mutation (94.1%) and immunohistochemistry showed 100% sensitivity and specificity to detect this mutation.Loss of nuclear ATRX expression was found in 87% (20/23) and 100% (14/14) DA and AA cases, respectively.IDH1 mutant DA patients had longer overall survival than IDH1 wild cases, although this difference was not significant (79.5 months vs. 42.5 months, P value 0.417).BRAF V600E mutation was not detected in any astrocytic tumor.Conclusions: IDH1 and ATRX mutations are very common in diffuse astrocytoma and anaplastic astrocytoma, while they are rare in pilocytic astrocytoma and glioblastoma.Immunohistochemistry for IDH1 and ATRX can successfully characterize the diffuse gliomas into molecularly defined groups in majority of the cases.BRAF V600E mutation is rare in astrocytic tumors in Indian population.
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Low-grade gliomas (LGG) constitute grades I and II tumors of astrocytic and grade II tumors of oligodendroglial lineage. Although these tumors are typically slow growing, they may be associated with significant morbidity and mortality because of recurrence and malignant progression, even in the setting of optimal resection. LGG in pediatric and adult age groups are currently classified by morphologic criteria. Recent years have heralded a molecular revolution in understanding brain tumors, including LGG. Next-generation sequencing has definitively demonstrated that pediatric and adult LGG fundamentally differ in their underlying molecular characteristics, despite being histologically similar. Pediatric LGG show alterations in FGFR1 and BRAF in pilocytic astrocytomas and FGFR1 alterations in diffuse astrocytomas, each converging on the mitogen-activated protein kinase signaling pathway. Adult LGG are characterized by IDH1/2 mutations and ATRX mutations in astrocytic tumors and IDH1/2 mutations and 1p/19q codeletions in oligodendroglial tumors. TERT promoter mutations are also noted in LGG and are mainly associated with oligodendrogliomas. These findings have considerably refined approaches to classifying these tumors. Moreover, many of the molecular alterations identified in LGG directly impact on prognosis, tumor biology, and the development of novel therapies.
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