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Increasing evidence suggests the oncogenic role of missense mutation (AKT1-E17K) of AKT1 gene in meningiomas. Upon investigating the connection between the pro-tumorigenic role of AKT1-E17K and cellular metabolic adaptations, elevated levels of glycolytic enzyme hexokinase 2 (HK2) was observed in meningioma patients with AKT1-E17K compared to patients harboring wild-type AKT1. In vitro experiments also suggested higher HK2 levels and its activity in AKT1-E17K cells. Treatment with the conventional drug of choice AZD5363 (a pan AKT inhibitor) enhanced cell death and diminished HK2 levels in AKT1 mutants. Given the role of AKT phosphorylation in eliciting inflammatory responses, we observed increased levels of inflammatory mediators (IL-1ß, IL6, IL8, and TLR4) in AKT1-E17K cells compared to AKT1-WT cells. Treatment with AKT or HK2 inhibitors dampened the heightened levels of inflammatory markers in AKT1-E17K cells. As AKT and HK2 regulates redox homeostasis, diminished ROS generation concomitant with increased levels of NF-E2- related factor 2 (Nrf2) and superoxide dismutase 1 (SOD1) were observed in AKT1-E17K cells. Increased sensitivity of AKT1-E17K cells to AZD5363 in the presence of HK2 inhibitor Lonidamine was reversed upon treatment with ROS inhibitor NAC. By affecting metabolism, inflammation, and redox homeostasis AKT1-E17K confers a survival advantage in meningioma cells. Our findings suggest that targeting AKT-HK2 cross-talk to induce ROS-dependent cell death could be exploited as novel therapeutic approach in meningiomas.
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Neoplasias Meníngeas , Meningioma , Humanos , Mutación con Ganancia de Función , Hexoquinasa/genética , Hexoquinasa/metabolismo , Neoplasias Meníngeas/genética , Meningioma/genética , Estrés Oxidativo/genética , Proteínas Proto-Oncogénicas c-akt/metabolismo , Especies Reactivas de OxígenoRESUMEN
Adamantinomatous craniopharyngioma is a grade 1 tumor that arises in a sellar/suprasellar location. Despite being a grade 1 tumor, there is high recurrence and endocrinal insufficiency. Malignancy arising in craniopharyngioma is extremely rare, has a dismal prognosis, and is currently not included as a separate entity in the World Health Organization Classification of Central Nervous System 5th edition. Here we describe a case of adamantinomatous craniopharyngioma and its malignant counterpart. The malignant part had unique histomorphology and basaloid cells with pseudoglandular architecture and a myxoid background. It bore a striking resemblance to adenoid cystic carcinoma. Both the benign and malignant counterparts were beta-catenin and SOX-2 positive, providing proof of the malignant part arising from the benign part. Tumors like squamous cell carcinoma and odontogenic ghost cell carcinoma have been described in cranipharyngioma. This case study is the first to describe this unique morphology of adenoid cystic carcinoma-like features. The possibility of adenoid cystic carcinoma was excluded by immunohistochemistry.
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Craneofaringioma , Neoplasias Hipofisarias , Humanos , Craneofaringioma/patología , Neoplasias Hipofisarias/patología , Masculino , Carcinoma Adenoide Quístico/patología , Adulto , FemeninoRESUMEN
BACKGROUND: Pilocytic astrocytoma (PAs) represents a significant portion of childhood primary brain tumors, with distinct histological and radiological features. The prevalence of KIAA1549::BRAF fusion in PAs has been well-established, this study aims to assess the prevalence of KIAA1549::BRAF fusions and explore their associations with tumor characteristics, radiological findings, and patient outcomes in PAs. METHODS: Histologically confirmed cases of PAs from a 5-year period were included in the study. Demographic, histopathological, and radiological data were collected, and immunohistochemistry was performed to characterize tumor markers. FISH and qRT-PCR assays were employed to detect KIAA1549::BRAF fusions. Statistical analyses were conducted to examine associations between fusion status and various other parameters. RESULTS: Histological analysis revealed no significant differences in tumor features based on fusion status. However, younger age groups showed higher fusion prevalence. Radiologically, fusion-positive cases were distributed across different tumor subtypes SE, CWE and NCWE. Survival analysis did not demonstrate a significant impact of fusion status on overall survival, however most cases with recurrence and death harboured KIAA1549::BRAF fusion. Of 200 PAs, KIAA1549::BRAF fusions were detected in 64 % and 74 % of cases via qRT-PCR and FISH, respectively. Concordance between the two platforms was substantial (86 %). CONCLUSION: KIAA1549::BRAF fusions are prevalent in PAs and can be reliably detected using both FISH and qRT-PCR assays. Cost considerations suggest qRT-PCR as a more economical option for fusion detection in routine clinical practice.
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Astrocitoma , Biomarcadores de Tumor , Neoplasias Encefálicas , Proteínas de Fusión Oncogénica , Proteínas Proto-Oncogénicas B-raf , Humanos , Femenino , Masculino , Niño , Astrocitoma/genética , Astrocitoma/patología , Preescolar , Proteínas de Fusión Oncogénica/genética , Proteínas Proto-Oncogénicas B-raf/genética , Adolescente , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patología , Lactante , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Inmunohistoquímica/métodos , Hibridación Fluorescente in Situ/métodos , Adulto JovenRESUMEN
Mutation of the isocitrate dehydrogenase 1 (IDH1) gene leads to the production of oncometabolite D-2-hydroxyglutarate (2-HG) from α-ketoglutarate and is associated with better prognosis in glioma. As Yes-associated protein 1 (YAP1) is an important regulator of tumor progression, its role in glioma expressing IDH1 with an R132H mutation was investigated. Diminished nuclear levels of YAP1 in IDH1 mutant glioma tissues and cell lines were accompanied by decreased levels of mitochondrial transcription factor A (TFAM). Luciferase reporter assays and chromatin immunoprecipitation were used to investigate the functionality of the TEAD2-binding site on the TFAM promoter in mediating its YAP1-dependent expression. YAP1-dependent mitochondrial fragmentation and ROS generation were accompanied by decreased telomerase reverse transcriptase (TERT) levels and increased mitochondrial TERT localization in IDH1 R132H cells. Treatment with the Src kinase inhibitor bosutinib, which prevents extranuclear shuttling of TERT, further elevated ROS in IDH1 R132H cells and triggered apoptosis. Importantly, bosutinib treatment also increased ROS levels and induced apoptosis in IDH1 wild-type cells when YAP1 was concurrently depleted. These findings highlight the involvement of YAP1 in coupling mitochondrial dysfunction with mitochondrial shuttling of TERT to constitute an essential non-canonical function of YAP1 in the regulation of redox homeostasis. This article has an associated First Person interview with the first author of the paper.
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Glioma , Dinámicas Mitocondriales , Proteínas Señalizadoras YAP/genética , Glioma/genética , Humanos , Isocitrato Deshidrogenasa/genética , TelomerasaRESUMEN
The atypical cadherin FAT1 function either as a pro or antitumorigenic in tumors of different tissue origins. Our group previously demonstrated the protumorigenic nature of FAT1 signaling in glioblastoma (GBM). In this study, we investigated how FAT1 influences the expression of clustered oncomiRs (miR-221-3p/miR-222-3p) and their downstream effects in GBM. Through several experiments involving the measurement of specific gene/microRNA expression, gene knockdowns, protein and cellular assays, we have demonstrated a novel oncogenic signaling pathway mediated by FAT1 in glioma. These results have been verified using antimiRs and miR-mimic assays. Initially, in glioma-derived cell lines (U87MG and LN229), we observed FAT1 as a novel up-regulator of the transcription factor NFκB-RelA. RelA then promotes the expression of the clustered-oncomiRs, miR-221-3p/miR-222-3p, which in turn suppresses the expression of the tumor suppressor gene (TSG), PDCD10 (Programmed cell death protein10). The suppression of PDCD10, and other known TSG targets (PTEN/PUMA), by miR-221-3p/miR-222-3p, leads to increased clonogenicity, migration, and invasion of glioma cells. Consistent with our in-vitro findings, we observed a positive expression correlation of FAT1 and miR-221-3p, and an inverse correlation of FAT1 and the miR-targets (PDCD10/PTEN/PUMA), in GBM tissue-samples. These findings were also supported by publicly available GBM databases (The Cancer Genome Atlas [TCGA] and The Repository of Molecular Brain Neoplasia Data [Rembrandt]). Patients with tumors displaying high levels of FAT1 and miR-221-3p expression (50% and 65% respectively) experienced shorter overall survival. Similar results were observed in the TCGA-GBM database. Thus, our findings show a novel FAT1/RelA/miR-221/miR-222 oncogenic-effector pathway that downregulates the TSG, PDCD10, in GBM, which could be targeted therapeutically in a specific manner.
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Neoplasias Encefálicas , Glioblastoma , Glioma , MicroARNs , Humanos , Glioblastoma/metabolismo , Cadherinas/genética , Cadherinas/metabolismo , Proteínas Reguladoras de la Apoptosis/genética , Proteínas Reguladoras de la Apoptosis/metabolismo , Glioma/genética , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , MicroARNs/genética , MicroARNs/metabolismo , Línea Celular Tumoral , Regulación Neoplásica de la Expresión Génica , Proliferación Celular/genética , Movimiento Celular/genética , Proteínas de la Membrana/genética , Proteínas Proto-Oncogénicas/genéticaRESUMEN
BACKGROUND: Introduction of the classification of brain tumours based on DNA methylation profile has significantly changed the diagnostic approach. Due to the paucity of data on the molecular profiling of meningiomas and their clinical implications, no effective therapies and new treatments have been implemented. METHODS: DNA methylation profiling, copy number analysis, targeted sequencing and H3K27me3 expression was performed on 35 meningiomas and 5 controls. RESULTS: Unsupervised hierarchical clustering (UHC) analysis revealed four distinct molecular subgroups: Malignant; Intermediate; Benign A, and Benign B. Molecular heterogeneity was observed within the same grade as the Intermediate, Benign A, and Benign B subgroups were composed of WHO grade 1 as well as grade 2 cases. There was association of mutations with distinct methylation subgroups (NF2, AKT1, SMO, TRAF7 and pTERT). Loss of chromosome 22q was observed across all subgroups. 1p/14q co-deletion was seen in 50% of malignant and intermediate while CDKN2A loss was predominantly observed in malignant subgroup (50%). Majority of malignant (75%) and a small proportion of other subgroups (Intermediate: 25%, Benign A: 38.5%, and Benign B: 20%) harboured H3K27me3 loss. 38,734 genes were dysregulated amongst the four subgroups. DKFZ classified 71% cases with acceptable score. On survival analysis, methylation profiling had significant impact on progression-free-survival in WHO grade1 and 2 meningiomas (p = 0.0051). CONCLUSION: Genome-wide DNA methylation profiling highlights clinically distinct molecular subgroups and heterogeneity within the same grade of meningiomas. Molecular profiling can usher in a paradigm shift in meningioma classification, prognostic prediction, and treatment strategy.
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Neoplasias Meníngeas , Meningioma , Humanos , Meningioma/genética , Meningioma/patología , Neoplasias Meníngeas/genética , Neoplasias Meníngeas/patología , Histonas/genética , Metilación de ADN , Mutación , Aberraciones CromosómicasRESUMEN
Glioblastoma is the most life-threatening tumor of the central nervous system. Despite recent therapeutic advancements, maximum survival of glioblastoma patients remains dismal. The mediator complex is a set of proteins, essential for eukaryotic gene expression. Abnormal expression/mutations of specific mediator genes have been associated with progression of various cancers, however, its role and status in glioblastoma remains largely unknown. Our work shows overexpression of a subunit of kinase assembly of mediator complex, MED12, in various glioblastoma patient cohorts including Indian glioblastoma patients and cell lines. Functional characterization of MED12 using both overexpression and knockdown approach revealed that it promotes glioblastoma cell proliferation, migration and inhibits apoptosis. Transcriptome analysis post MED12 knockdown revealed Vitamin D receptor (VDR) pathway to be one of the key pathways affected by MED12 in glioblastoma. We studied direct interaction of MED12 with VDR protein using docking studies and co-immunoprecipitation assay. We identify BCL6, a secondary regulator of VDR signaling, to be directly regulated by MED12 through a combination of chromatin immunoprecipitation, qRT-PCR and western analyses. We further show that MED12 brings about the inhibition of p53 levels and apoptosis partly through induction of BCL6 in glioblastoma. Overall, this stands as the first report of MED12 over-expression and involvement in glioblastoma pathogenesis and identifies MED12 as an important mediator of VDR signaling and an attractive molecule for development of new therapeutic interventions.
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Neoplasias Encefálicas/genética , Glioblastoma/genética , Complejo Mediador/genética , Oncogenes/genética , Proteínas Proto-Oncogénicas c-bcl-6/genética , Receptores de Calcitriol/genética , Proteína p53 Supresora de Tumor/genética , Apoptosis/genética , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patología , Línea Celular Tumoral , Perfilación de la Expresión Génica/métodos , Regulación Neoplásica de la Expresión Génica , Glioblastoma/metabolismo , Glioblastoma/patología , Humanos , Estimación de Kaplan-Meier , Complejo Mediador/metabolismo , Pronóstico , Unión Proteica , Proteínas Proto-Oncogénicas c-bcl-6/metabolismo , Interferencia de ARN , Receptores de Calcitriol/metabolismo , Proteína p53 Supresora de Tumor/metabolismoRESUMEN
OBJECTIVE: Amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) is an ionotropic transmembrane receptor for glutamate. AMPA receptor blockers have been reported to prevent neurological damage and enhance the post stroke recovery in rats. Decanoic acid, a medium-chain fatty acid, has been reported to exhibit non-competitive AMPA receptor antagonism. This study evaluated the effect of decanoic acid administered before and after ischemia reperfusion injury on neurological damage and post stroke recovery in rats. METHODS: Middle cerebral artery occlusion (MCAo) was performed by using the intraluminal method to induce focal cerebral ischemia. Decanoic acid (120 mg/kg) was administered orally for 1 day (5-10 min post reperfusion) in one group and for 2 days (24 h pre and 5-10 min post reperfusion) in the other group. Effect on neurological damage and post stroke recovery was assessed by neurobehavioral parameters, MRI and TTC staining along with inflammatory, oxidative, apoptotic, and neuroprotective biomarkers. RESULTS: Decanoic acid significantly reduced the MCAo induced neurological damage and infarct size. Decanoic acid treatment increased the motor coordination and grip strength. Furthermore, levels of inflammatory (TNFα, IL-1ß and IL-6), oxidative stress (MDA), apoptotic (TUNEL positive cells) and neurological injury (GFAP) biomarkers were reduced after decanoic acid treatment. Anti-inflammatory cytokine (IL-10) and neuroprotective markers (NT-3, BDNF and TrkB) were found to be significantly increased with decanoic acid treatment. CONCLUSION: This study showed protective effects of decanoic acid against ischemia reperfusion injury in rats. Anti-inflammatory, antioxidant, neuroprotective, and anti-apoptotic properties may be responsible for the beneficial effects of decanoic acid observed in the study.
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Daño por Reperfusión , Accidente Cerebrovascular , Animales , Ratas , Infarto de la Arteria Cerebral Media/tratamiento farmacológico , Receptores AMPA , Accidente Cerebrovascular/tratamiento farmacológico , Daño por Reperfusión/tratamiento farmacológico , Daño por Reperfusión/prevención & control , Estrés Oxidativo , ÉsteresRESUMEN
Pleomorphic xanthoastrocytomas (PXAs) are rare tumors accounting for less than 1% of astrocytomas. They commonly occur in young patients and have relatively favorable prognosis. However, they are well known to have heterogenous morphology and biological behavior with the potential to recur and disseminate throughout the central nervous system, especially their anaplastic counterparts. Recent advances in the molecular characterization have discovered BRAFp.V600E mutations in conjunction with CDKN2A/B deletions and TERTp mutations to be the most frequent alterations in PXAs. These tumors can present a diagnostic challenge as they share overlapping histopathological, genomic as well as methylation profile with various other tumor types, particularly epithelioid glioblastomas (eGBs). This review provides the spectrum of evolution of PXAs from their genesis to recent molecular insights and attempts to review pathogenesis and relationship to other tumors that they mimic especially eGB. It is postulated based on evidence from literature that PXA and eGB are possibly related and not distinct entities, being two ends of a continuous spectrum of malignant progression (grade 2-grade 4) with anaplastic PXA (grade 3) lying in between. Future WHO classifications will have to possibly redefine these tumors using more confirmatory data from larger studies.
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Astrocitoma , Neoplasias Encefálicas , Glioblastoma , Astrocitoma/genética , Astrocitoma/patología , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patología , Humanos , Mutación , Pronóstico , Proteínas Proto-Oncogénicas B-raf/genéticaRESUMEN
OBJECTIVE: The authors aimed to assess the frequency of homozygous CDKN2A deletion in isocitrate dehydrogenase (IDH)-mutant diffuse astrocytomas (grade 2/3) and to narrow down the clinicopathological indications in which the CDKN2A fluorescence in situ hybridization (FISH) assay is cost-effective in resource-constrained settings. METHODS: IDH-mutant astrocytomas were analyzed for ATRX, p53, MIB1-LI, and p16 expression using immunohistochemistry. The FISH assay was used to evaluate CDKN2A deletion and 1p/19q codeletion. Survival outcomes were assessed according to the different molecular markers. RESULTS: A total of 150 adult patients with IDH-mutant grade 2 (n = 95) and grade 3 (n = 55) astrocytomas (145 primary and 5 recurrent) were analyzed. Using a cutoff value of 30% for defining significant homozygous CDKN2A deletion, none of the grade 2 and 10.9% (6/55) of grade 3 astrocytomas showed this deletion (4 primary and 2 recurrent grade 3 tumors) and were reclassified as grade 4. This mutation was more frequent in recurrent (40%, 2/5) than primary (2.76%, 4/145) gliomas. Half (3/6, 50%) of the CDKN2A-deleted cases demonstrated poor outcomes; 2 of these cases experienced recurrence at 12 and 36 months after surgery, and 1 died at 5 months. The majority of CDKN2A-deleted cases showed marked cellularity (100%), pleomorphism (100%), brisk mitosis (83.3%), and tumor giant cell formation (83.4%). None of the cases with retained p16 expression harbored this deletion. Both overall survival (p = 0.039) and progression-free survival (p = 0.0045) were found to be worse in cases with p16 loss. Selectively performing CDKN2A FISH only in high-risk cases with histomorphological features of anaplasia, p16 loss, or recurrent tumors achieved a sensitivity and negative predictive value of 100%. This approach would have resulted in saving 41.1% of the original expenditure ($6900 US per 150 samples) and 27.6 person-minutes per sample without compromising the identification of deleted cases. CONCLUSIONS: Homozygous CDKN2A deletion is conspicuously absent in grade 2 and rare in primary grade 3 IDH-mutant astrocytomas. The authors propose that restricting use of the FISH assay to cases showing histomorphological features of anaplasia, p16 loss, or recurrent tumors will help this platform to be utilized in the most cost-effective manner in resource-constrained settings.
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Astrocitoma , Glioma , Humanos , Anaplasia , Hibridación Fluorescente in Situ , Astrocitoma/genética , Supervivencia sin Progresión , Inhibidor p16 de la Quinasa Dependiente de Ciclina/genéticaRESUMEN
PURPOSE: H3K27M mutant diffuse midline gliomas (DMGs) are considered grade IV irrespective of histological features and have dismal prognosis. We evaluated clinico-pathologic, radiological, and molecular characteristics of DMGs across all ages. METHODS: One twenty-six DMGs were identified over 10 years. Immunohistochemistry was done for H3K27M, ATRX, IDH1, and p53, and Sanger sequencing performed for IDH1 and H3K27M mutation. Patient demographics and clinico-radiologic characteristics were reviewed and survival analysis performed. RESULTS: DMGs comprised 5.3% of all gliomas with 49.2% H3K27M mutant and 50.8% wild types. Majority (75.68%) of pediatric and 38.20% of adults were H3K27M mutant (p = 0.0001). Amongst H3K27M mutants, brainstem (46.43%) was the commonest location in pediatric and thalamus (61.76%) in adults. H3K27M mutation was mutually exclusive with IDH mutation in 93.55%, while p53, ATRX mutation were seen in 56.4% and 30.6% cases respectively. Software-based immunohistochemistry evaluation (H-scoring) showed 99.2% concordance with sequencing for H3K27M mutation. Radiologically, no significant difference in contrast enhancement was seen between mutant and wild types (p = 0.05). The difference in overall survival (OS) was not significant in mutant versus wild types, with age or location. Tumor resection independently and on correlation with H3K27M did not influence OS (p = 0.51 and p = 0.47). Adjuvant therapy impacted survival significantly in adults (p = 0.0009), however, not in pediatric cases (p = 0.06). CONCLUSIONS: The study highlights the differences in frequency and location of pediatric and adult DMGs. IHC (H-scoring) for H3K27M mutation is an excellent surrogate for sequencing. Prognosis remains dismal irrespective of age, location, and H3K27M status. Potential therapeutic targets need to be explored.
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Neoplasias Encefálicas , Glioma , Adulto , Neoplasias Encefálicas/genética , Niño , Glioma/genética , Histonas/genética , Humanos , Isocitrato Deshidrogenasa/genética , Mutación , PronósticoRESUMEN
Ependymoma is a relatively rare glial tumor of the central nervous system that arise from the cells lining the ventricles and central canal of the spinal cord. Ependymosarcoma (ES) is a newly introduced tumor entity of uncertain prognosis characterized by a rare phenomenon of a malignant mesenchymal transition arising within an ependymoma. ESs are surgically challenging tumors for diagnosis and therapy with a high incidence of morbidity and mortality. Here, we report two diagnostically challenging cases of primary ES in a 25-year-old female and a 17-year-old male. Both the cases presented with progressive and sequential neurological deficits over a period of five to eight months, and histological examination revealed a biphasic gliomesenchymal architecture comprised of anaplastic ependymomatous and sarcomatous components. Molecular genetic analysis revealed the presence of type 1 C11orf95:RELA fusion transcript. To date, 22 cases of ES have been reported in the literature, and only one case harbored type 1 C11orf95:RELA fusion transcript.
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Ependimoma , Glioma , Adolescente , Adulto , Femenino , Humanos , Masculino , Pronóstico , Proteínas , Factor de Transcripción ReIARESUMEN
INTRODUCTION: CNS embryonal tumors (CET) other than medulloblastomas (MB) and atypical teratoid/rhabdoid tumors (AT/RTs), previously designated as 'central nervous system primitive neuroectodermal tumors' ('CNS PNETs'), are a heterogenous subset of tumors with poorly defined diagnostic criteria. Other than the subset of embryonal tumor with multilayered rosettes (ETMR) defined by C19MC amplification, most CETs are diagnosed by exclusion of other molecularly defined entities and histological mimics including MB, AT/RTs, and high-grade gliomas, and termed as CET, not otherwise specified (NOS) in the 2016 WHO classification. AIM: To reclassify 'CNS PNETs' as per WHO 2016, and estimate the true proportion of CET, NOS in a tertiary healthcare setting, and to evaluate the diagnostic utility of C19MC amplification, Lin28A and Olig2 expression in the subclassification of CETs. METHODS: Previously diagnosed cases of 'CNS PNETs' (2002-2016) were first evaluated by immunohistochemistry (IHC) for MIC2, RelaA, L1CAM, IDH1R132H, H3K27M, H3G34R, H3G34V, INI1, and BRG1 proteins and by fluorescence in-situ hybridization (FISH) for EWSR1 translocation to exclude histological mimics. The selected CETs (case cohort) and 79 histological mimics (comparison cohort) comprising of MB, AT/RT, pineal parenchymal tumors, Ewing sarcoma, esthesioneuroblastoma, intraocular medulloepithelioma, and H3G34R mutant high-grade glioma were subject to IHC for Olig2 and Lin28A, and FISH for C19MC amplification. RESULTS: Twenty-two cases of 'CNS PNETs' were retrieved, all of which were negative for the first panel of markers and showed retained INI-1/BRG1 expression. Three of them (3/22, 13.6%) showed C19MC amplification (ETMR, C19MC-altered) with ETMR histology, Lin28A positivity, and Olig2 negativity. Among the remaining 19 CETs, one showed medulloepithelioma histology (Medulloepithelioma, NOS) and remaining were non-descript small round cell tumors (CET, NOS), all negative for Lin28A. Olig2 was positive in only 3 CETs (13.6%), all being CET, NOS. All tumors in the comparison cohort were negative for C19MC amplification, Lin28A and Olig2 except for 27% of ATRTs that were Lin28A positive. CONCLUSION: ETMR, C19MC-altered constitute less than 14% of CETs, with majority remaining uncharacterized as CET, NOS. Lin28A is 100% sensitive for the detection of C19MC amplification; however, its specificity is limited by its expression in ATRTs. Olig2 expression is seen only in a small subset of CET, NOS and is of limited diagnostic utility.
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Neoplasias Encefálicas , Neoplasias del Sistema Nervioso Central , Neoplasias de Células Germinales y Embrionarias , Tumores Neuroectodérmicos Primitivos , Glándula Pineal , Neoplasias Encefálicas/genética , Humanos , Neoplasias de Células Germinales y Embrionarias/genética , Tumores Neuroectodérmicos Primitivos/genética , Factor de Transcripción 2 de los Oligodendrocitos , Estudios Retrospectivos , Centros de Atención TerciariaRESUMEN
Extrarenal extracranial malignant rhabdoid tumour (MRT) is a rare and highly aggressive tumour representing <1% of paediatric soft tissue malignancies. Only a few cases of MRT of the thigh arising from the sciatic nerve have been reported in medical literature to date. A 5-year-old girl presented with progressively increasing painless lump in the posterior aspect of the left thigh. A contrast-enhanced magnetic resonance imaging (MRI) of the left thigh showed a 4.7 × 5 × 10.5 cm well-marginated, lobulated, homogeneously enhancing lesion in the posterior compartment of the left thigh along the course of the sciatic nerve. She underwent en bloc excision of the left sciatic nerve tumour and end-to-end anastomosis of the left sciatic nerve with a right sural nerve graft. Histopathological and immunohistochemical examination of the surgical specimen revealed a malignant rhabdoid tumour. INI-1 immunoexpression was lost in the tumour cells. The metastatic workup was essentially normal. Subsequently, she received post-operative radiotherapy to the tumour bed (50.4 Gray in 28 fractions over 5.5 weeks) followed by six cycles of multiagent chemotherapy with ICE (Ifosfamide, Carboplatin, and Etoposide) regimen. On the last follow-up visit, 20 months after surgery, she was in complete clinical and radiological response. Aggressive multimodality management comprising radical resection of tumour, post-operative radiotherapy to the tumour bed, and multiagent chemotherapy with ICE regimen can lead to favourable outcomes in patients with this rare tumour.
RESUMEN
Atrial myxomas are the most common primary benign cardiac tumors. The embolization of tumor particles is not infrequent, and in nearly half of them, the cerebral arteries are affected, usually leading to embolic ischemic stroke. Formation of intracranial aneurysms, development of parenchymal brain metastasis, and intracerebral hemorrhage due to ruptured aneurysms are rarer. Diagnosis of such lesions in a previously undiagnosed case of myxoma may be challenging for a pathologist. Herein, we present two patients of cardiac myxoma with varied neurological manifestations and their pathological findings.
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Neoplasias Encefálicas/secundario , Accidente Cerebrovascular Embólico/etiología , Neoplasias Cardíacas/complicaciones , Neoplasias Cardíacas/patología , Mixoma/complicaciones , Mixoma/patología , Adolescente , Femenino , Atrios Cardíacos/patología , Humanos , Masculino , Persona de Mediana EdadRESUMEN
BACKGROUND: Focal cortical dysplasia (FCD) is a localized cortical malformation and considerable morphological overlap exists between FCD IIB and neurological lesions associated with Tuberous sclerosis complex (TSC). Abnormal mTOR pathway secondary to somatic mTOR mutation and TSC gene mutation linked to PI3K/AKT/mTOR pathway have supported the hypothesis of common pathogenesis involved. Role of converging pathway, viz. Wnt/ß-Catenin and mTOR is unknown in FCD. We aimed to analyse FCD IIB for TSC1/TSC2 mutations, immunoreactivity of hamartin, tuberin, mTOR and Wnt signalling cascades, and stem cell markers. MATERIALS AND METHODS: Sixteen FCD IIB cases were retrieved along with 16 FCD IIA cases for comparison. Immunohistochemistry was performed for tuberin, hamartin, mTOR pathway markers, markers of stem cell phenotype, and Wnt pathway markers. Mutation analysis for TSC1 and TSC2 was performed by sequencing in 9 FCD cases. RESULTS: All FCD cases showed preserved hamartin and tuberin immunoreactivity. Aberrant immunoreactivity of phospho-P70S6 kinase, S6 ribosomal, phospho-S6 ribosomal and Stat3 was noted in FCD IIB, with variable phospho-4E-BP1 (45%) and absent phospho-Stat3 expression. Immunoreactivity for phospho-P70S6 kinase (100%), S6 ribosomal protein (100%) and Stat3 (100%) was noted in FCD IIA, but not for phospho-S6 ribosomal, phospho-4E-BP1 and phospho-Stat3. c-Myc immunoreactivity was noted in all FCD cases. Nestin (81%) and Sox 2 (88%) stained balloon cells in FCD IIB (44%), while in FCD IIA cases were negative. All FCD cases were immunopositive for Wnt, but were negative for ß-Catenin and cyclin-D1. TSC mutations were detected in two cases of FCD IIB. CONCLUSION: Abnormal mTOR pathway activation exists in FCD IIB and IIA, however, shows differential immunoreactivity profile, indicating varying degrees of dysregulation. Labelling of neuronal stem cell markers in balloon cells suggests they are phenotypically immature. TSC1/2 mutation play role in the pathogenesis of FCD. Deep targeted sequencing is preferred diagnostic technique since conventional sanger sequencing often fails to detect low-allele frequency variants involved in mTOR/TSC pathway genes, commonly found in FCD.
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Epilepsia/metabolismo , Epilepsia/patología , Malformaciones del Desarrollo Cortical de Grupo I/metabolismo , Malformaciones del Desarrollo Cortical de Grupo I/patología , Transducción de Señal/fisiología , Serina-Treonina Quinasas TOR/metabolismo , Adolescente , Adulto , Niño , Preescolar , Femenino , Humanos , Lactante , Masculino , Adulto JovenRESUMEN
INTRODUCTION: Molecular classification of medulloblastomas (MB) is prognostically and therapeutically relevant and helps in better risk-stratification. Translation of this subgrouping to routine practice still remains a challenge. The most pathologist accessible techniques for molecular subgrouping include immunohistochemistry (IHC), fluorescent in-situ hybridization (FISH) and NanoString. OBJECTIVES: (1) Molecular subgrouping of MBs by IHC and FISH, and NanoString assay (2) To compare their efficacy and cost for applicability in resource constrained centers. METHODS: Ninety-five cases of MB with adequate tissue were included. Molecular subgrouping was performed by IHC for ß-catenin, GAB1 and YAP1; FISH for MYC amplification, and sequencing for CTNNB1, and by NanoString Assay on the same set of MBs. A subset of cases was subjected to 850k DNA methylation array. RESULTS: IHC + FISH classified MBs into 15.8% WNT, 16.8% SHH, and 67.4% non-WNT/non-SHH subgroups; with MYC amplification identified in 20.3% cases of non-WNT/non-SHH. NanoString successfully classified 91.6% MBs into 25.3% WNT, 17.2% SHH, 23% Group 3 and 34.5% Group 4. However, NanoString assay failure was seen in eight cases, all of which were > 8-years-old formalin-fixed paraffin-embedded tissue blocks. Concordant subgroup assignment was noted in 88.5% cases, while subgroup switching was seen in 11.5% cases. Both methods showed prognostic correlation. Methylation profiling performed on discordant cases revealed 1 out of 4 extra WNT identified by NanoString to be WNT, others aligned with IHC subgroups; extra SHH by NanoString turned out to be SHH by methylation. CONCLUSIONS: Both IHC supplemented by FISH and NanoString are robust methods for molecular subgrouping, albeit with few disadvantages. IHC cannot differentiate between Groups 3 and 4, while NanoString cannot classify older-archived tumors, and is not available at most centres. Thus, both the methods complement each other and can be used in concert for high confidence allotment of molecular subgroups in clinical practice.
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Neoplasias Cerebelosas/clasificación , Inmunohistoquímica/métodos , Hibridación Fluorescente in Situ/métodos , Meduloblastoma/clasificación , Nanotecnología/métodos , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa/métodos , Adolescente , Adulto , Anciano , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Neoplasias Cerebelosas/genética , Neoplasias Cerebelosas/metabolismo , Neoplasias Cerebelosas/patología , Niño , Preescolar , Estudios de Cohortes , Terapia Combinada , Metilación de ADN , Femenino , Estudios de Seguimiento , Recursos en Salud , Humanos , Lactante , Masculino , Meduloblastoma/genética , Meduloblastoma/metabolismo , Meduloblastoma/patología , Persona de Mediana Edad , Pronóstico , Tasa de Supervivencia , Adulto JovenRESUMEN
Malignant ectomesenchymoma (MEM) is an exceedingly rare rapidly progressing tumor of soft tissues of the central nervous system, believed to be derived from neural crest cells. The majority of cases have been observed in young children or adolescents. So far only 11 patients with intracranial manifestations (with confirmed clinicopathological data) have been documented. We report the first case of adult intracranial MEM in a 54-year-old man who presented with a 4 months history of headache and weakness of right side of the body. Magnetic resonance imaging showed a homogenously enhanced dural-based lesion in the left fronto-temporo-parietal lobe with significant perilesional edema and mass effect. No metastatic disease was identified and the lesion was grossly resected. Histopathological and immunohistochemical examination revealed mature and immature neurons and bizarre astrocytes admixed with a mesenchymal spindle cell (rhabdomyoblastic) component. Specific risk factors that contribute toward the development of MEM are unknown. Due to the scarcity of reported cases the role of adjuvant therapy is unclear.
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Neoplasias Encefálicas/diagnóstico por imagen , Neoplasias Encefálicas/cirugía , Mesenquimoma/diagnóstico por imagen , Mesenquimoma/cirugía , Humanos , Masculino , Persona de Mediana EdadRESUMEN
Diffuse midline gliomas (DMGs) are rare and devastating tumors with limited therapeutic options. Programmed death-ligand 1 (PD-L1) expression represents a potential predictive biomarker for immunotherapy. One hundred and twenty-six DMGs (89 adult and 37 pediatric) were assessed for immune profile (PD-L1, cluster of differentiation (CD3, CD8) and genetic markers (mutation in 27th amino acid of histone H3 (H3K27M), alpha thalassemia/mental retardation syndrome X-linked (ATRX), isocitrate dehydrogenase 1 (IDH1), p53) by immunohistochemistry. Sanger sequencing was done for IDH1 and H3K27M. The thalamus was the commonest site. Four molecular subgroups of DMGs were identified. H3K27M mutation was more frequent in children (P = 0.0001). The difference in median overall survival (OS) was not significant in any of the four molecular subgroups (P > 0.05). PD-L1 expression was significantly higher in H3K27M/IDH1 double-negative adult glioblastomas (GBMs) (P = 0.002). Strong PD-L1 expression was more frequent in grade IV tumors and thalamic location, although the difference was not significant (P = 0.14 and P = 0.19 respectively). Positive PD-L1 expression was significantly associated with high tumor-infiltrating lymphocytes count (P < 0.05). There was no significant difference in median OS in PD-L1-positive versus negative cases among four genetic subgroups (P > 0.05). On univariate analysis, there was no direct correlation of PD-L1 with any genetic alteration, except H3K27M mutation (P = 0.01). CD3 infiltration was similar in both adults and pediatric ages (84.3% and 78.4%, respectively) while CD8 expression was significantly greater in adults compared to children (74.1% vs 37.8%, P = 0.0001). This is the first comprehensive analysis highlighting molecular and immune profiles of DMGs. Despite molecular and clinicopathological diversity, overall survival in DMGs remains dismal. Multicentric studies with larger numbers of cases should be undertaken for stratifying DMGs according to their age, immune and molecular profiles, to develop effective immunotherapies.
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Antígeno B7-H1/biosíntesis , Neoplasias Encefálicas/metabolismo , Regulación Neoplásica de la Expresión Génica , Glioma/metabolismo , Neoplasias de la Médula Espinal/metabolismo , Linfocitos T/metabolismo , Adolescente , Adulto , Anciano , Antígeno B7-H1/genética , Antígeno B7-H1/inmunología , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/inmunología , Niño , Preescolar , Femenino , Glioma/genética , Glioma/inmunología , Humanos , Masculino , Persona de Mediana Edad , Neoplasias de la Médula Espinal/genética , Neoplasias de la Médula Espinal/inmunología , Linfocitos T/inmunología , Adulto JovenRESUMEN
INTRODUCTION: Recent advances in the molecular biology of adult diffuse gliomas have brought about a paradigm shift in their diagnostic criteria, as witnessed in the World Health Organization (WHO) 2016 guidelines for central nervous system tumors. It is now mandatory to perform several molecular tests to reach a definitive integrated diagnosis in most of the cases. This comes with additional cost and higher turnaround time, which is not always affordable in developing countries like India. In addition, the non-uniform distribution of advanced research and diagnostic testing centers adds to the difficulty. METHODS: The Indian Society of Neuro-oncology (ISNO) multidisciplinary expert panel consisting of neuropathologists, neurosurgeons, and radiation/medical oncologists convened to prepare the national consensus guidelines for approach to diagnosis of adult diffuse gliomas. RESULTS: Algorithms for arriving at an integrated diagnosis of adult diffuse gliomas predominantly using immunohistochemistry and with minimum possible additional molecular testing were agreed upon, thus addressing the problems of cost, accessibility, and turnaround time. Mandatory and optional tests were proposed for each case scenario. CONCLUSION: This document represents the consensus of the various neuro-oncology disciplines involved in diagnosis and management of patients with adult diffuse gliomas. The article reflects a practical adaptation of the WHO recommendations to suit a resource constrained setup.