Analysis of the Prognosis of High-Grade gliomas in the View of New Immunohistochemistry Markers and 2016 WHO Classification.

AIM: To evaluate isocitrate dehydrogenase (IDH) mutation status and Ki67 percentages of tumors that were treated in our institution to determine whether these markers affected the initial diagnosis and survival rates. MATERIAL AND METHODS: High-grade glioma patients, who were operated in our department between 2013 and 2018, were enrolled in the study and retrospectively reviewed. New immunohistochemistry staining studies were conducted and survival analyses were performed. RESULTS: Of 135 patients and 136 tumors, 117 were glioblastoma multiforme (GBM), 8 were grade III-IV glioma, 4 were anaplastic astrocytoma and 7 were anaplastic oligodendroglioma. One patient had two different lesions, which were GBM and anaplastic astrocytoma respectively. Mean age was 55 (7-85) years, and 88 (65%) were male and 47 (35%) were female. The most common complaint was motor deficit (56%). Fourteen patients underwent reoperation due to recurrent disease. Tumors were most commonly found in the frontal lobe (53, 39%). Magnetic resonance imaging (MRI) features showed that existence of necrosis is strongly related to GBM (p < 0.01). Approximately 126 patients were found to be IDH-wildtype, which changed 6 patients? diagnosis to GBM, IDH wildtype from grade III-IV glioma. Five patients, who were diagnosed with anaplastic astrocytoma and anaplastic oligodendroglioma initially were found to be IDH wildtype. IDH mutation status, extend of resection, and age were found to affect survival. CONCLUSION: IDH mutation status is important in classifying high-grade gliomas, as well as its effects on prognosis. This mutation is related to several radiological features of tumors. Extent of resection and patient age are also profoundly affect survival. Detailing the diagnosis with molecular features will help physicians to shape targeted adjuvant therapies, which would better outcomes.

Clinical implications of molecular analysis in diffuse glioma stratification.

The revised 4th edition of the 2016 World Health Organization Classification of Tumors of the Central Nervous System (2016 CNS WHO) has introduced the integrated diagnostic classification that combines molecular and histological diagnoses for diffuse gliomas. In this study, we evaluated the molecular alterations for consecutive 300 diffuse glioma cases (grade 2, 56; grade 3, 62; grade 4, 182) based on this classification. Mutations in the isocitrate dehydrogenase (IDH) genes were common in lower grade glioma (LGG: grade2-3), and when combined with 1p/19q status, LGGs could be stratified into three groups except for four cases (Astrocytoma, IDH-mutant: 44; Oligodendroglioma, IDH-mutant and 1p/19q codeleted: 37; Astrocytoma, IDH-wildtype: 33). 1p/19q-codeleted oligodendrogliomas were clinically the most favorable subgroup even with upfront chemotherapy. In contrast, IDH-wildtype astrocytomas had a relatively worse prognosis; however, this subgroup was more heterogeneous. Of this subgroup, 11 cases had TERT promoter (pTERT) mutation with shorter overall survival than 12 pTERT-wildtype cases. Additionally, a longitudinal analysis indicated pTERT mutation as early molecular event for gliomagenesis. Therefore, pTERT mutation is critical for the diagnosis of molecular glioblastoma (WHO grade 4), regardless of histological findings, and future treatment strategy should be considered based on the precise molecular analysis.

Extent of resection, molecular signature, and survival in 1p19q-codeleted gliomas.

OBJECTIVE: Genomic analysis in neurooncology has underscored the importance of understanding the patterns of survival in different molecular subtypes within gliomas and their responses to treatment. In particular, diffuse gliomas are now principally characterized by their mutation status (IDH1 and 1p/19q codeletion), yet there remains a paucity of information regarding the prognostic value of molecular markers and extent of resection (EOR) on survival. Furthermore, given the modern emphasis on molecular rather than histological diagnosis, it is important to examine the effect of maximal resection on survival in all gliomas with 1p/q19 codeletions, as these will now be classified as oligodendrogliomas under the new WHO guidelines. The objectives of the present study were twofold: 1) to assess the association between EOR and survival for patients with oligodendrogliomas in the National Cancer Database (NCDB), which includes information on mutation status, and 2) to demonstrate the same effect for all patients with 1p/19q codeleted gliomas in the NCDB. METHODS: The NCDB was queried for all cases of oligodendroglioma between 2004 and 2014, with follow-up dates through 2016. The authors found 2514 cases of histologically confirmed oligodendrogliomas for the final analysis of the effect of EOR on survival. Upon further query, 1067 1p/19q-codeleted tumors were identified in the NCDB. Patients who received subtotal resection (STR) or gross-total resection (GTR) were compared to those who received no tumor debulking surgery. Univariable and multivariable analyses of both overall survival and cause-specific survival were performed. RESULTS: EOR was associated with increased overall survival for both histologically confirmed oligodendrogliomas and all 1p/19q-codeleted-defined tumors (p < 0.001 and p = 0.002, respectively). Tumor grade, location, and size covaried predictably with EOR. When evaluating tumors by each classification system for predictors of overall survival, facility setting, age, comorbidity index, grade, location, chemotherapy, and radiation therapy were all shown to be significantly associated with overall survival. STR and GTR were independent predictors of improved survival in historically classified oligodendrogliomas (HR 0.83, p = 0.18; HR 0.69, p = 0.01, respectively) and in 1p/19q-codeleted tumors (HR 0.49, p < 0.01; HR 0.43, p < 0.01, respectively). CONCLUSIONS: By using the NCDB, the authors have demonstrated a side-by-side comparison of the survival benefits of greater EOR in 1p/19q-codeleted gliomas.

[Analysis of the clinical impact of the diagnostic reclassification of brain gliomas according to the World Health Organization classification (2016)]. / Análisis del impacto clínico de la reclasificación diagnóstica de gliomas cerebrales según la clasificación de la Organización Mundial de la Salud (2016).

INTRODUCTION: Since the introduction of genetic and molecular criteria in the 2016 World Health Organization (WHO) classification of brain tumours, there has been a diagnostic reclassification between certain astrocytomas and oligodendro-gliomas with histological and genetic discordances, the prognosis of which is unknown. AIM: To analyse the implications of the diagnostic reclassification of brain gliomas according to the 2016 WHO criteria, especially depending on isocitrate dehydrogenase (IDH) mutation and 1p19q codeletion. PATIENTS AND METHODS: We conducted a retrospective study of gliomas treated from 1 January 2012 to 31 December 2016, with analyses of clinicoradiological aspects and prognoses, and with available and complete follow-up until 31 March 2019. RESULTS: From a total of 147 brain gliomas, a molecular diagnosis and a diagnostic re-evaluation were carried out in 69 cases (grade II-IV astrocytomas or oligodendrogliomas). Twenty-four reclassified gliomas were detected, usually oligodendro-gliomas that became astrocytomas, and which showed greater survival, derived from their not being classified as grade IV. The reclassified gliomas, all grades II/III, mostly began with seizures, without focus, with single lesions, < 17 cm3 and with oedema, although with similar survival rates. The prognostic factors were: young age, focus, grade II and no contrast enhancement or necrosis, or multiplicity. No variations were detected according to the molecular pattern with IDH mutation or codeletion. CONCLUSION: The changes in diagnosis after the WHO classification of 2016 present specific clinical-radiological characteristics in this series, but no greater survival, although, due to the habitual survival in these cases, they would require a longer follow-up time.

TITLE: Análisis del impacto clínico de la reclasificación diagnóstica de gliomas cerebrales según la clasificación de la Organización Mundial de la Salud (2016).Introducción. Desde la introducción de los criterios genéticos y moleculares en la clasificación de la Organización Mundial de la Salud (OMS) de tumores cerebrales de 2016, se ha producido una reclasificación diagnóstica entre determinados astrocitomas y oligodendrogliomas con discordancias histológicas y genéticas, cuyo pronóstico se desconoce. Objetivo. Analizar las implicaciones de la reclasificación diagnóstica de los gliomas cerebrales según los criterios de la OMS de 2016, especialmente según la mutación de la isocitrato deshidrogenasa (IDH) y la codeleción 1p19q. Pacientes y métodos. Estudio retrospectivo de los gliomas tratados desde el 1 de enero de 2012 hasta el 31 de diciembre de 2016, con análisis de los aspectos clinicorradiológicos y pronósticos, y con seguimiento disponible y completo hasta el 31 de marzo de 2019. Resultados. De 147 gliomas cerebrales, en 69 (astrocitomas u oligodendrogliomas de grados II-IV) se realizaron un diagnóstico molecular y una reevaluación diagnóstica. Se detectaron 24 gliomas reclasificados, habitualmente oligodendrogliomas que pasaron a astrocitomas, y que mostraron mayores supervivencias, derivadas de la no reclasificación en grado IV. Los gliomas reclasificados, todos de grados II/III, comenzaron mayoritariamente con crisis, sin focalidad, con lesiones únicas, < 17 cm3 y con edema, aunque con similar supervivencia. Los factores pronósticos fueron: edad joven, focalidad, grado II y no captación de contraste o necrosis, o multiplicidad. No se detectaron variaciones según el patrón molecular con mutación en la IDH o codeleción. Conclusión. Los cambios diagnósticos tras la clasificación de la OMS de 2016 presentan características clinicorradiológicas específicas en esta serie, aunque no mayores supervivencias, si bien, por la supervivencia habitual en estos casos, precisarían un mayor tiempo de seguimiento.

Análisis del impacto clínico de la reclasificación diagnóstica de gliomas cerebrales según la clasificación de la Organización Mundial de la Salud (2016) / Analysis of the clinical impact of the diagnostic reclassification of brain gliomas according to the World Health Organization classification (2016)

Introducción: Desde la introducción de los criterios genéticos y moleculares en la clasificación de la Organización Mundial de la Salud (OMS) de tumores cerebrales de 2016, se ha producido una reclasificación diagnóstica entre determinados astrocitomas y oligodendrogliomas con discordancias histológicas y genéticas, cuyo pronóstico se desconoce. Objetivo: Analizar las implicaciones de la reclasificación diagnóstica de los gliomas cerebrales según los criterios de la OMS de 2016, especialmente según la mutación de la isocitrato deshidrogenasa (IDH) y la codeleción 1p19q. Pacientes y métodos. Estudio retrospectivo de los gliomas tratados desde el 1 de enero de 2012 hasta el 31 de diciembre de 2016, con análisis de los aspectos clinicorradiológicos y pronósticos, y con seguimiento disponible y completo hasta el 31 de marzo de 2019. Resultados: De 147 gliomas cerebrales, en 69 (astrocitomas u oligodendrogliomas de grados II-IV) se realizaron un diagnóstico molecular y una reevaluación diagnóstica. Se detectaron 24 gliomas reclasificados, habitualmente oligodendrogliomas que pasaron a astrocitomas, y que mostraron mayores supervivencias, derivadas de la no reclasificación en grado IV. Los gliomas reclasificados, todos de grados II/III, comenzaron mayoritariamente con crisis, sin focalidad, con lesiones únicas, <17 cm3 y con edema, aunque con similar supervivencia. Los factores pronósticos fueron: edad joven, focalidad, grado II y no captación de contraste o necrosis, o multiplicidad. No se detectaron variaciones según el patrón molecular con mutación en la IDH o codeleción. Conclusión: Los cambios diagnósticos tras la clasificación de la OMS de 2016 presentan características clinicorradiológicas específicas en esta serie, aunque no mayores supervivencias, si bien, por la supervivencia habitual en estos casos, precisarían un mayor tiempo de seguimiento

Introduction: Since the introduction of genetic and molecular criteria in the 2016 World Health Organization (WHO) classification of brain tumours, there has been a diagnostic reclassification between certain astrocytomas and oligodendrogliomas with histological and genetic discordances, the prognosis of which is unknown. Aim: To analyse the implications of the diagnostic reclassification of brain gliomas according to the 2016 WHO criteria, especially depending on isocitrate dehydrogenase (IDH) mutation and 1p19q codeletion. Patients and methods: We conducted a retrospective study of gliomas treated from 1 January 2012 to 31 December 2016, with analyses of clinicoradiological aspects and prognoses, and with available and complete follow-up until 31 March 2019. Results: From a total of 147 brain gliomas, a molecular diagnosis and a diagnostic re-evaluation were carried out in 69 cases (grade II-IV astrocytomas or oligodendrogliomas). Twenty-four reclassified gliomas were detected, usually oligodendrogliomas that became astrocytomas, and which showed greater survival, derived from their not being classified as grade IV. The reclassified gliomas, all grades II/III, mostly began with seizures, without focus, with single lesions, <17 cm3 and with oedema, although with similar survival rates. The prognostic factors were: young age, focus, grade II and no contrast enhancement or necrosis, or multiplicity. No variations were detected according to the molecular pattern with IDH mutation or codeletion. Conclusion: The changes in diagnosis after the WHO classification of 2016 present specific clinical-radiological characteristics in this series, but no greater survival, although, due to the habitual survival in these cases, they would require a longer follow-up time

Practical procedures for the integrated diagnosis of astrocytic and oligodendroglial tumors.

The publication of the 2016 World Health Organization Classification of Tumors of the Central Nervous System (2016 WHO CNS) represented a major change in the classification of brain tumors. However, many pathologists in Japan cannot diagnose astrocytic or oligodendroglial tumors according to the 2016 WHO CNS due to financial or technical problems. Therefore, the Japan Society of Brain Tumor Pathology established a committee for molecular diagnosis to facilitate the integrated diagnosis of astrocytic and oligodendroglial tumors in Japan. We created three levels of diagnoses: Level 1 was defined as simple histopathological diagnosis using hematoxylin and eosin staining and routine cell lineage-based immunostaining. Level 2 was defined as immunohistochemical diagnosis using immunohistochemical examinations using R132H mutation-specific IDH1, ATRX, and/or p53 antibodies. Level 3 was defined as molecular diagnosis, such as diagnosis based on 1p/19q status or the mutation status of the IDH1 and IDH2 genes. In principle, astrocytic and oligodendroglial tumors should be diagnosed based on the 2016 WHO CNS and/or cIMPACT-NOW criteria; however, the findings obtained through our diagnostic flowchart can be added to the histological diagnosis in parentheses. This classification system would be helpful for pathologists with limited resources.

Detection of chromosome structural variation by targeted next-generation sequencing and a deep learning application.

Molecular testing is increasingly important in cancer diagnosis. Targeted next generation sequencing (NGS) is widely accepted method but structural variation (SV) detection by targeted NGS remains challenging. In the brain tumor, identification of molecular alterations, including 1p/19q co-deletion, is essential for accurate glial tumor classification. Hence, we used targeted NGS to detect 1p/19q co-deletion using a newly developed deep learning (DL) model in 61 tumors, including 19 oligodendroglial tumors. An ensemble 1-dimentional convolution neural network was developed and used to detect the 1p/19q co-deletion. External validation was performed using 427 low-grade glial tumors from The Cancer Genome Atlas (TCGA). Manual review of the copy number plot from the targeted NGS identified the 1p/19q co-deletion in all 19 oligodendroglial tumors. Our DL model also perfectly detected the 1p/19q co-deletion (area under the curve, AUC = 1) in the testing set, and yielded reproducible results (AUC = 0.9652) in the validation set (n = 427), although the validation data were generated on a completely different platform (SNP Array 6.0 platform). In conclusion, targeted NGS using a cancer gene panel is a promising approach for classifying glial tumors, and DL can be successfully integrated for the SV detection in NGS data.

Neuroimaging-Based Classification Algorithm for Predicting 1p/19q-Codeletion Status in IDH-Mutant Lower Grade Gliomas.

BACKGROUND AND PURPOSE: Isocitrate dehydrogenase (IDH)-mutant lower grade gliomas are classified as oligodendrogliomas or diffuse astrocytomas based on 1p/19q-codeletion status. We aimed to test and validate neuroradiologists' performances in predicting the codeletion status of IDH-mutant lower grade gliomas based on simple neuroimaging metrics. MATERIALS AND METHODS: One hundred two IDH-mutant lower grade gliomas with preoperative MR imaging and known 1p/19q status from The Cancer Genome Atlas composed a training dataset. Two neuroradiologists in consensus analyzed the training dataset for various imaging features: tumor texture, margins, cortical infiltration, T2-FLAIR mismatch, tumor cyst, T2* susceptibility, hydrocephalus, midline shift, maximum dimension, primary lobe, necrosis, enhancement, edema, and gliomatosis. Statistical analysis of the training data produced a multivariate classification model for codeletion prediction based on a subset of MR imaging features and patient age. To validate the classification model, 2 different independent neuroradiologists analyzed a separate cohort of 106 institutional IDH-mutant lower grade gliomas. RESULTS: Training dataset analysis produced a 2-step classification algorithm with 86.3% codeletion prediction accuracy, based on the following: 1) the presence of the T2-FLAIR mismatch sign, which was 100% predictive of noncodeleted lower grade gliomas, (n = 21); and 2) a logistic regression model based on texture, patient age, T2* susceptibility, primary lobe, and hydrocephalus. Independent validation of the classification algorithm rendered codeletion prediction accuracies of 81.1% and 79.2% in 2 independent readers. The metrics used in the algorithm were associated with moderate-substantial interreader agreement (κ = 0.56-0.79). CONCLUSIONS: We have validated a classification algorithm based on simple, reproducible neuroimaging metrics and patient age that demonstrates a moderate prediction accuracy of 1p/19q-codeletion status among IDH-mutant lower grade gliomas.

The Applicability of Haarlem Integrated Diagnostic System in Diffuse Glial Tumors and Molecular Methods Affecting Prognosis

Background: With the help of genetic studies, it is possible to obtain information about diagnosis and prognosis of glial tumors. Aims: To categorize the cases according to the new World Health Organization Central Nervous System classification by reconsidering the histologic features of oligodendrogliomas, astrocytomas and oligoastrocytomas. We also evaluated whether these genetic features have prognostic significance. Study Design: Diagnostic accuracy study. Methods: Between the years 2011 and 2016, 60 gliomas were examined. Archival material from the Department of Pathology was used for histopathological, immunohistochemical, and molecular analyses. All the cases were classified and graded according to the new 2016 World Health Organization criteria. IDH1 (R132H), alpha thalassemia/mental retardation syndrome, and p53 antibodies were applied immunohistochemically. The 1p/19q status and platelet-derived growth factor receptor-α/CEP4 amplification were evaluated by fluorescence in situ hybridization. After molecular tests, if the diagnosis of oligodendroglioma or astrocytoma is not diagnosed, case should be diagnosed as oligoastrocytoma. Sensitivity, specificity, positive predictive level, negative predictive level, and accuracy rate were evaluated in accordance with the specified threshold levels. Results: Except for 1 case (3.7%), all cases of grade 2 and grade 3 oligoastrocytoma were diagnosed with astrocytoma or oligodendroglioma without any change of grade. Except for 2 case (6.8%), all cases of grade 2 and grade 3 oligodendroglioma were diagnosed oligodendroglioma. All astrocytomas (100%) were given same diagnosis. There is no specific or sensitive test for the diagnosis of oligoastrocytoma. However, 1p/19q codeletion was spesific (100%) and sensitive (100%) for oligodendroglioma. ATRX and p53 mutation showed high spesificity (100% and 95.1% respectively) for diagnosing astrocytoma. Platelet-derived growth factor receptor-α/ CEP4 was not detected in any of the cases. There was association between isocitrate dehydrogenase mutation and 1p/19q loss with longer survival (respectively p=0.147 and p=0.178). Conclusion: In grade 2 and grade 3 glial tumors, pathological diagnosis is not possible only by histological examination. Overall, there was a diagnosis change in 28 cases (46.6%). Especially in cases of oligoastrocytoma, the diagnosis is changed by molecular tests.

Assessment of the impact of glioma diagnostic reclassification following the new 2016 WHO classification on a series of cases. / Evaluación del impacto del cambio diagnóstico de los gliomas aplicando la nueva clasificación de la OMS de 2016 sobre una serie de casos.

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

Grade II and III Oligodendroglioma and Astrocytoma.

In the 2016 WHO classification of diffuse glioma, the diagnosis of an (anaplastic) oligodendroglioma requires the presence of both an IDH mutation (mt) and 1p/19q codeletion, whereas (anaplastic) astrocytoma are divided in IDH wild-type and IDHmt tumors. Standard of care for grade II and III glioma consists of resection. For patients with tumors that require postoperative treatment, radiotherapy and chemotherapy are recommended. Trials in newly diagnosed grade II and III glioma have shown survival benefit of the addition of chemotherapy to radiotherapy compared with initial treatment with radiotherapy alone; both temozolomide and PCV have been shown to improve survival.

Molecularly defined diffuse leptomeningeal glioneuronal tumor (DLGNT) comprises two subgroups with distinct clinical and genetic features.

Diffuse leptomeningeal glioneuronal tumors (DLGNT) represent rare CNS neoplasms which have been included in the 2016 update of the WHO classification. The wide spectrum of histopathological and radiological features can make this enigmatic tumor entity difficult to diagnose. In recent years, large-scale genomic and epigenomic analyses have afforded insight into key genetic alterations occurring in multiple types of brain tumors and provide unbiased, complementary tools to improve diagnostic accuracy. Through genome-wide DNA methylation screening of > 25,000 tumors, we discovered a molecularly distinct class comprising 30 tumors, mostly diagnosed histologically as DLGNTs. Copy-number profiles derived from the methylation arrays revealed unifying characteristics, including loss of chromosomal arm 1p in all cases. Furthermore, this molecular DLGNT class can be subdivided into two subgroups [DLGNT methylation class (MC)-1 and DLGNT methylation class (MC)-2], with all DLGNT-MC-2 additionally displaying a gain of chromosomal arm 1q. Co-deletion of 1p/19q, commonly seen in IDH-mutant oligodendroglioma, was frequently observed in DLGNT, especially in DLGNT-MC-1 cases. Both subgroups also had recurrent genetic alterations leading to an aberrant MAPK/ERK pathway, with KIAA1549:BRAF fusion being the most frequent event. Other alterations included fusions of NTRK1/2/3 and TRIM33:RAF1, adding up to an MAPK/ERK pathway activation identified in 80% of cases. In the DLGNT-MC-1 group, age at diagnosis was significantly lower (median 5 vs 14 years, p < 0.01) and clinical course less aggressive (5-year OS 100, vs 43% in DLGNT-MC-2). Our study proposes an additional molecular layer to the current histopathological classification of DLGNT, of particular use for cases without typical morphological or radiological characteristics, such as diffuse growth and radiologic leptomeningeal dissemination. Recurrent 1p deletion and MAPK/ERK pathway activation represent diagnostic biomarkers and therapeutic targets, respectively-laying the foundation for future clinical trials with, e.g., MEK inhibitors that may improve the clinical outcome of patients with DLGNT.

Recent advances in subtyping tumors of the central nervous system using molecular data.

INTRODUCTION: Primary brain tumors account for substantial morbidity and mortality. They often infiltrate the brain diffusely, continue growing, and cause adverse events, such as headaches, seizures, and neurological deficits. The classification of primary brain tumors, based for decades on histology, has been fundamentally changed by the World Health Organization in 2016 by incorporation of molecular data. Areas covered: Literature from glioblastomas, high- and low-grade astrocytic, oligodendroglial, glioneuronal and ependymal tumors from the last five years were reviewed. Results from comprehensive molecular profiling of neoplasms and impact of recent molecular subtyping on neuropathological diagnosis are presented. Expert commentary: The identification of frequent acquired mutations shows that adult and pediatric glioblastomas have divergent biology with differing prognoses. Astrocytoma and oligodendroglioma are more closely related than previously thought. Molecular profiling now enables the precise classification of most diffuse gliomas into three clinically and therapeutically different subtypes according to the presence or absence of IDH mutation and 1p/19q codeletion. New subgroups with different clinical outcomes and anatomic locations have emerged in ependymomas and pediatric embryonal tumors.

Moving the needle: Optimizing classification for glioma.

Genomic markers provide unbiased information that is increasingly being used to enhance traditional histopathology approaches for classification of cancer samples.

PREDICTING SIGNIFICANCE OF UNKNOWN VARIANTS IN GLIAL TUMORS THROUGH SUB-CLASS ENRICHMENT.

Glial tumors have been heavily studied and sequenced, leading to scores of findings about altered genes. This explosion in knowledge has not been matched with clinical success, but efforts to understand the synergies between drivers of glial tumors may alleviate the situation. We present a novel molecular classification system that captures the combinatorial nature of relationships between alterations in these diseases. We use this classification to mine for enrichment of variants of unknown significance, and demonstrate a method for segregating unknown variants with functional importance from passengers and SNPs.

Combined ATRX/IDH1 immunohistochemistry predicts genotype of oligoastrocytomas.

AIMS: To assess whether in oligoastrocytomas ATRX deficiency, as a surrogate of the alternative lengthening of telomeres (ALT) pathway, has a role in predicting the presence or absence of loss of heterozygosity (LOH) of 1p and 19q, the genetic signature of oligodendroglial differentiation and a favourable prognostic marker. METHODS AND RESULTS: A series of 54 oligoastrocytomas were investigated by immunohistochemistry as well as microsatellite analysis for LOH 1p19q. Genetic findings were correlated with morphological assessment. CONCLUSIONS: ATRX deficiency was mutually exclusive with LOH. Conversely, ATRX-proficient tumours immunoreactive for R132H-mutant isocitrate dehydrogenase 1 (IDH1) showed a high rate (85%) of LOH. A more oligodendroglioma-like morphology was associated with a higher rate of LOH even in the morphologically ambiguous group of oligoastrocytomas. Our findings support the concept that oligoastrocytomas represent a morphological grey zone, rather than a group of truly 'mixed' or 'intermediate' tumours. More precise classification of diffuse gliomas may also improve grading of borderline cases. We propose an immunohistochemical algorithm for classification of morphologically ambiguous diffuse gliomas.

Prognostic significance of relative 1p/19q codeletion in oligodendroglial tumors.

1p/19q codeletion is a favorable prognostic marker for oligodendroglial tumors (OT). Compare outcome in OT with simple deletions of 1p or 19q to those with relative deletions defined as the presence of both increased copy number (polysomy) and 1p/19q codeletion. 525 cases were examined by fluorescence in situ hybridization (FISH) using dual color probes to determine the deletion status of chromosome arms 1p and 19q. Categories included simple deletions defined as a proportion of either 1p32 or 19q13 FISH signals compared to 1q42 or 19p13 signals less than 0.80 and relative deletions (1p or 19q) defined as the combination of a <0.80 proportion with >30 % of nuclei showing increased chromosome number (based on enumeration of 1q25 or 19p13). 464 (80 %) were WHO Grade II or III OT of which 209 (48 %) had both 1p and 19q deleted (codeletion). 72 (16 %) had relative deletions for either one or both 1p and 19q of which 28 (6 %) had relative deletions of 1p and 19q (relative codeletion). Overall survival in WHO Grade II OT was 13 + years when 1p/19q codeleted (n = 156); 5 + years in uni- or nondeleted (n = 86); 6 + years in relative deletion for either 1p or 19q (n = 41); and 6 + years in relative 1p/19q codeletion (n = 15). Similarly in WHO Grade III OT (n = 168) overall survival was 11 + years in 1p/19q codeleted (n = 54) OT; 2.5 years in uni- or nondeleted (n = 70); 3 years in relative deletion for one or both 1p or 19q (n = 31); and 4 + years in relative 1p/19q codeletion (n = 13). Survival for OT regardless of grade with relative codeletion of 1p/19q was approximately one half that of 1p/19q codeleted tumors. The presence of relative 1p/19q codeletion is of prognostic significance.

Coexpression of cyclin D1 and alpha-internexin in oligodendroglial tumors.

Oligodendroglial tumors with neuronal differentiation cases have been reported in recent studies. Oligodendrocyte precursor cells (OPCs) give rise to both oligodendrocytes and neurons; however, little is known about the association between OPCs and oligodendroglial tumors with neuronal differentiation. Previously, we observed the coexpression of cyclin D1, one of the OPC markers, and alpha-internexin (INA) in oligodendroglial tumor cells. INA is a neuronal marker, and has been indicated as an immunohistochemical surrogate of chromosome 1p/19q co-deletion in oligodendroglial tumors. In this study, we investigated the expression status in 83 gliomas immunohistochemically, and found that cyclin D1-positive cells were commonly detected in gliomas. There was no correlation between the cyclin D1 and Ki-67 labeling indices, suggesting an unrecognized role of cyclin D1 other than a cell cycle regulator in gliomas. Cyclin D1/INA double-positive cells were consistently observed in oligodendroglial tumors regardless of histological grade. In 2 cases of oligodendroglioma with neuronal differentiation, the tumor cells of neuronal morphology showed higher expression of INA, suggesting INA expression may be associated with a bona fide neuronal phenotype. The prevalence of cyclin D1/INA double-positive cells is a distinct feature of oligodendroglial tumors. This new characteristic finding may have practical utility in glioma classification.