Teaching NeuroImages: Histopathologically Confirmed Intracranial Enchondroma/Low-Grade Chondrosarcoma and IDH1-Mutated Diffuse Glioma in Ollier Disease

In 2016, the WHO incorporated molecular markers, in addition to histology, into the diagnostic classification of central nervous system (CNS) tumours. This improves diagnostic accuracy and prognostication: oligo-astrocytoma no longer exists as a clinical entity; isocitrate dehydrogenase (IDH) mutant and 1p/19q co-deleted oligodendroglioma is a smaller category with better prognosis; IDH wild-type ‘low-grade’ glioma has a much poorer prognosis; and glioblastoma is divided into IDH mutant (with an better prognosis than pre-2016 glioblastoma) and IDH wild type (with a poorer prognosis). Previous advice based on phenotype alone will change with respect to median survival, best management plan and response to treatment. There are implications for routine neuropathology reporting and future trial design. Cases that are difficult to classify may need more advanced molecular genetic classification through DNA methylation-based classification of CNS tumours (Heidelberg Classifier). We discuss the practical implications.

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Multifocal supratentorial diffuse glioma in a young patient with Ollier disease

Journal of Clinical Neuroscience ◽

10.1016/j.jocn.2011.06.019 ◽

2012 ◽

Vol 19 (3) ◽

pp. 477-478 ◽

Cited By ~ 9

Author(s):

P. Pearce ◽

T. Robertson ◽

J.D. Ortiz-Gomez ◽

T. Rajah ◽

G. Tollesson

Keyword(s):

Young Patient ◽

Diffuse Glioma ◽

Ollier Disease

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WP1-18 Risk factors and patterns of recurrence of low grade glioma: a systematic review

Journal of Neurology Neurosurgery & Psychiatry ◽

10.1136/jnnp-2019-abn.19 ◽

2019 ◽

Vol 90 (3) ◽

pp. e6.3-e6

Author(s):

V Narbad ◽

JP Lavrador ◽

A Elhag ◽

S Acharya ◽

J Hanrahan ◽

...

Keyword(s):

Risk Factors ◽

Systematic Review ◽

Tp53 Mutation ◽

Methylation Status ◽

Low Grade Glioma ◽

Low Grade ◽

Diffuse Glioma ◽

Idh Mutation ◽

Mgmt Methylation ◽

Inclusion Criteria

ObjectivesTo review the risk factors and patterns of progression/recurrence of low grade glioma (LGG).DesignSystematic review of the published literature.SubjectsInclusion criteria were peer reviewed publications of cohort studies of recurrent/progressive LGG. Studies of wider populations were included if relevant LGG data could be analysed separately.MethodsMedline and Cochrane databases were searched using MeSH and non-MeSH terms, including ‘glioma’, ‘astrocytoma’, ‘oligoastrocytoma’, ‘diffuse glioma’, ‘oligodendroglioma’, ‘low grade’ and ‘disease recurrence’ by two independent reviewers.ResultsOverall, 917 studies were screened, of which 57 studies met the inclusion criteria. The most frequently described risk factor for recurrent LGG was suboptimal extent of resection (EOR) of the initial tumour (in 20 studies); recurrence was also associated with the patient’s age (2), tumour location (4), neurological status (3), tumour volume (6), bihemispherical tumour (3) and astrocytic histology (6). IDH mutation was associated with recurrence in 1 out of 3 studies, but TP53 mutation (2 of 4) and MGMT methylation status (4) were not. Malignant transformation was associated with TP53 mutations (3), IDH mutation (1) and EOR (1). Favourable progression free survival (PFS) and/or overall survival (OS) were associated with greater EOR (16), oligodendroglioma histology (2 of 4), initial KPS (3) and the use of adjuvant therapies (9 of 14). IDH mutation was associated with improved PFS and OS (3 of 4). TP53 mutation improved PFS in 1 of 3 studies. MGMT methylation and 1 p/19q codeletion may predict treatment response but their effects on survival are unclear.ConclusionsAstrocytoma histology, IDH and TP53 mutation statuses and surgical treatment (EOR) are essential in determining the time to recurrence or progression in LGG.

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BRAFv600e mutated gliomas: From biology to radiology and treatments.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.e13552 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. e13552-e13552

Author(s):

Benoit Lhermitte ◽

Eric Guerin ◽

Agathe Chammas ◽

Izzie Jacques Namer ◽

Guillaume Gauchotte ◽

...

Keyword(s):

Surgical Resection ◽

De Novo ◽

Mapk Signaling ◽

Braf V600e ◽

Glioneuronal Tumor ◽

Low Grade ◽

Diffuse Glioma ◽

Metabolomic Profile ◽

Cdkn2a Deletion ◽

The Impact

e13552 Background: BRAF V600E mutation is encountered in brain tumor, mostly low grade pediatric diffuse glioma (LGG) and epileptogenic glioneuronal tumor such as gangliogliomas (GG) or pleomorphic xanthoastrocytomas (PXA). Less frequently this mutation is present in high grade glial or glioneuronal tumors such as pleomorphic xanthoastrocytomas with anaplasia, anaplastic ganglioglioma, anaplastic diffuse astrocytomas or glioblastomas. Recently, few publications were highlighting differently the impact of BRAF mutation and CDKN2A deletion, as independent prognostic factors linked to a worst outcome in low grade forms. Methods: We studied retrospectively a monocentric cohort of 12 LGGs and 9 HGG with BRAFv600e positivity. The patients were aged from 1 to 47 years. Most of the LGG were under 25 years and only 3 patients with HGGs had less than 18 years old. We focused on extended biology assessment by Next generation sequencing of the tumors and their relapses, tumor metabolomics analyses, radiology comprising MRI, PET-scanning and spectroscopy and correlate them to tumor’s evolution and its treatment. Results: Among the LGGs, we had 9 GG and 3 pilocytic astrocytomas and only one had a CDKN2A deletion and one a gain on chromosome 5. 6 had a complete surgical resection, 2 had a minimal residue and 4 had chemotherapeutic treatment after partial surgery and underwent relapses. All HGGs had a surgical resection followed by chemotherapy (mainly Stupp protocol) and radiotherapy. 5 relapsed rapidly, benefit from targeted therapy with vemurafenib and are still in long term remission. In this HGG group, we had two subgroups: 4 patients with “de novo” tumors and 5 patients with a past history of LGG tumors in the same brain region. Both were responding well to targeted treatments and all had an additional CDKN2A deletion. Specific radiological and spectroscopic signs were linked to those two groups and seem to be associated to a specific metabolomic profile in each group. Currently, we are going further in the correlation between MAPK signaling pathway and metabolomic profile to be able to predict in LGG their potential evolution. Conclusions: BRAF mutated gliomas seem to have specific radiological and metabolomic correlations associated to their biology

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Return to work following diagnosis of low-grade glioma

Neurology ◽

10.1212/wnl.0000000000009982 ◽

2020 ◽

Vol 95 (7) ◽

pp. e856-e866 ◽

Cited By ~ 1

Author(s):

Isabelle Rydén ◽

Louise Carstam ◽

Sasha Gulati ◽

Anja Smits ◽

Katharina S. Sunnerhagen ◽

...

Keyword(s):

Sick Leave ◽

Return To Work ◽

Adjuvant Treatment ◽

Older Age ◽

First Year ◽

Low Grade ◽

Diffuse Glioma ◽

Who Grade ◽

Female Sex ◽

One Year

ObjectiveReturn-to-work (RTW) following diagnosis of infiltrative low-grade gliomas is unknown.MethodsSwedish patients with histopathologic verified WHO grade II diffuse glioma diagnosed between 2005 and 2015 were included. Data were acquired from several Swedish registries. A total of 381 patients aged 18–60 were eligible. A matched control population (n = 1,900) was acquired. Individual data on sick leave, compensations, comorbidity, and treatments assigned were assessed. Predictors were explored using multivariable logistic regression.ResultsOne year before surgery/index date, 88% of cases were working, compared to 91% of controls. The proportion of controls working remained constant, while patients had a rapid increase in sick leave approximately 6 months prior to surgery. After 1 and 2 years, respectively, 52% and 63% of the patients were working. Predictors for no RTW after 1 year were previous sick leave (odds ratio [OR] 0.92, 95% confidence interval [CI] 0.88–0.96, p < 0.001), older age (OR 0.96, 95% CI 0.94–0.99, p = 0.005), and lower functional level (OR 0.64 95% CI, 0.45–0.91 p = 0.01). Patients receiving adjuvant treatment were less likely to RTW within the first year. At 2 years, biopsy (as opposed to resection), female sex, and comorbidity were also unfavorable, while age and adjuvant treatment were no longer significant.ConclusionsApproximately half of patients RTW within the first year. Lower functional status, previous sick leave, older age, and adjuvant treatment were risk factors for no RTW at 1 year after surgery. Female sex, comorbidity, and biopsy only were also unfavorable for RTW at 2 years.

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GENE-47. A 3D ATLAS TO EVALUATE THE SPATIAL PATTERNING OF GENETIC ALTERATIONS AND TUMOR CELL STATES IN GLIOMA

Neuro-Oncology ◽

10.1093/neuonc/noz175.449 ◽

2019 ◽

Vol 21 (Supplement_6) ◽

pp. vi107-vi108

Author(s):

Stephanie Hilz ◽

Chibo Hong ◽

Llewellyn Jalbert ◽

Tali Mazor ◽

Michael Martin ◽

...

Keyword(s):

Gene Expression ◽

Expression Profiles ◽

Expression Patterns ◽

Gene Expression Profiles ◽

Genetic Alterations ◽

Cell Populations ◽

Low Grade ◽

Lower Grade ◽

Diffuse Glioma ◽

Spatial Patterning

Abstract BACKGROUND Previous studies of solid tumors have been restricted in their ability to map how heterogeneous cell populations evolved within the tumor in three-dimensional (3D) space due to insufficient sampling, typically one sample per tumor, and a lack of knowledge of where within the tumor the sample was obtained. Knowledge of the extensivity of heterogeneity and how it is spatially distributed is crucial for assessing whether a therapeutic target is truly tumor-wide, and for exploring how mutations relate to heterogeneity in the local microenvironment. METHODS We developed a novel platform to integrate and visualize in 3D multi-omics data generated from each of 8–10 spatially mapped samples per tumor. Together, the 171 samples collected using this approach from 16 adult diffuse glioma at diagnosis and recurrence form a novel resource – the 3D Glioma Atlas. RESULTS By maximally sampling the tumor geography without excluding samples based on low cancer cell fraction (CCF), we identify a subpopulation of glioblastoma with pervasively lower CCF likely excluded by other atlases, such as the TCGA, that used stringent CCF cutoffs. Exome sequencing of 3D-mapped samples from lower-grade tumors revealed that clonal expansions are typically spatially segregated, implying minimal tumor-wide intermixing of genetically heterogenous cells. Heterogeneity is less spatially segregated for faster-growing high-grade tumors, suggesting that cell populations expand in these tumors differently. Recurrent low-grade tumors have greater intratumoral mutational heterogeneity than newly diagnosed tumors, though this did not translate into greater dissimilarity in gene expression profiles for recurrent tumors, suggesting minimal functional impact of this additional mutational diversity on gene expression. CONCLUSIONS The delineation of spatial patterns of heterogeneity that our work provides enables more informed interpretation of biopsies and greater insight into the factors shaping intratumoral variation of gene expression patterns. Ongoing work is exploring the spatial patterning of amplification events and the tumor microenvironment.

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Gene of the month: IDH1

Journal of Clinical Pathology ◽

10.1136/jclinpath-2020-206813 ◽

2020 ◽

Vol 73 (10) ◽

pp. 611-615

Author(s):

Cassandra Bruce-Brand ◽

Dhirendra Govender

Keyword(s):

Somatic Mutations ◽

Oxidative Decarboxylation ◽

Low Grade ◽

Isocitrate Dehydrogenase 1 ◽

Maffucci Syndrome ◽

Downstream Effects ◽

Diffuse Gliomas ◽

Ollier Disease ◽

Mutant Idh1 ◽

Acute Myeloid

Isocitrate dehydrogenase 1 (IDH1) encodes a protein which catalyses the oxidative decarboxylation of isocitrate to α-ketoglutarate. Mutant IDH1 favours the production of 2-hydroxyglutarate, an oncometabolite with multiple downstream effects which promote tumourigenesis. IDH1 mutations have been described in a number of neoplasms most notably low-grade diffuse gliomas, conventional central and periosteal cartilaginous tumours and cytogenetically normal acute myeloid leukaemia. Post zygotic somatic mutations of IDH1 characterise the majority of cases of Ollier disease and Maffucci syndrome. IDH1 mutations are uncommon in epithelial neoplasia but have been described in cholangiocarcinoma.

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NCOG-25. REVISITING THE PIGNATTI RISK SCORE IN LOW-GRADE GLIOMA PATIENTS IN THE MOLECULAR ERA

Neuro-Oncology ◽

10.1093/neuonc/noab196.616 ◽

2021 ◽

Vol 23 (Supplement_6) ◽

pp. vi157-vi157

Author(s):

Christine Jungk ◽

Mara Gluszak ◽

Philip Dao Trong ◽

Andreas von Deimling ◽

Christel Herold-Mende ◽

...

Keyword(s):

Prognostic Factors ◽

Risk Score ◽

Low Grade ◽

Tumor Diameter ◽

Diffuse Glioma ◽

Who Grade ◽

Cox Regression Analysis ◽

Diffuse Gliomas ◽

The Individual

Abstract Until now, the Pignatti risk score has been used to guide treatment decisions after histological diagnosis of diffuse glioma WHO grade 2. However, its prognostic value was derived from a historic cohort that has been diagnosed by morphologic rather than molecular criteria. We re-challenged the Pignatti score in a contemporary, molecularly characterized cohort. From our institutional cohort of 422 diffuse gliomas WHO grade 2, 202 patients were identified for whom IDH mutation status was known and 1p/19q co-deletion or loss of ATRX expression unambiguously classified tumors into astrocytoma or oligodendroglioma. Patients with IDH wildtype astrocytoma (n=9), multifocal lesions or brainstem involvement were excluded. Potential prognostic factors including the individual items of the Pignatti score (astrocytoma; age ≥40 years; neurologic deficit; maximum tumor diameter ≥6cm; tumor crossing midline) were correlated with progression-free survival (PFS) by univariate log-rank und multivariate Cox regression analysis. 165 patients with astrocytoma or oligodendroglioma were analysed of whom 109 (66%) did not receive adjuvant radio- or chemotherapy. 94 untreated patients with a minimum follow-up of 24 months entered survival analysis. These patients were classified as “high-risk” (Pignatti 3-5) and “low-risk” (Pignatti 0-2) in 15% and 85% and did not differ with regard to potential prognostic factors (gender; resection vs. biopsy; tumor recurrence) other than the individual Pignatti score items. Diameter ≥6 cm (p=0.006; HR=2.18) and midline crossing (p=0.003; HR=3.54) were identified as independent prognostic factors of PFS. Noteworthy, prognostic factors coincided when all patients (n=144) with a minimum follow-up of 24 months, regardless of adjuvant treatment, were analysed. In IDH mutant, molecularly characterized diffuse gliomas WHO grade 2, the Pignatti risk score as a whole no longer seems to be of prognostic relevance. Instead, outcome seems to be determined by tumor burden.

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Molecular Classification of Diffuse Gliomas

Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques ◽

10.1017/cjn.2020.10 ◽

2020 ◽

Vol 47 (4) ◽

pp. 464-473

Author(s):

Navya Kalidindi ◽

Rosemarylin Or ◽

Sam Babak ◽

Warren Mason

Keyword(s):

Dna Methylation ◽

Molecular Markers ◽

World Health ◽

Low Grade ◽

Diffuse Glioma ◽

Isocitrate Dehydrogenase 1 ◽

Anaplastic Gliomas ◽

Diffuse Gliomas ◽

The Impact

ABSTRACT:Technological advances in the field of molecular genetics have improved the ability to classify brain tumors into subgroups with distinct clinical features and important therapeutic implications. The World Health Organization’s newest update on classification of gliomas (2016) incorporated isocitrate dehydrogenase 1 and 2 mutations, ATRX loss, 1p/19q codeletion status, and TP53 mutations to allow for improved classification of glioblastomas, low-grade and anaplastic gliomas. This paper reviews current advances in the understanding of diffuse glioma classification and the impact of molecular markers and DNA methylation studies on survival of patients with these tumors. We also discuss whether the classification and grading of diffuse gliomas should be based on histological findings, molecular markers, or DNA methylation subgroups in future iterations of the classification system.

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