RESUMEN
OBJECTIVES: To elucidate the relationship between DNA methylation profiling (DMP) and pathological diagnosis (PD) in pediatric glial and glioneuronal tumors with B-Raf proto-oncogene, serine/threonine kinase (BRAF) mutations, addressing their diagnostic challenges. METHODS: This retrospective study, conducted in Saudi Arabia, analyzed 47 cases from the Children's Brain Tumor Network online database using scanned images, next-generation sequencing data, and methylation profiles processed using the Heidelberg methylation brain tumor classifiers v12.5 and v12.8. The data was last access on 10 November 2023. RESULTS: The highest prevalence of BRAF mutations was observed in pilocytic astrocytoma and ganglioglioma. The DMP was consistent with PD in 23 cases, but discrepancies emerged in others, including diagnostic changes in diffuse leptomeningeal glioneuronal tumor and polymorphous low-grade neuroepithelial tumor of the young. A key inconsistency appeared between a pilocytic astrocytoma MC and a glioneuronal tumor PD. Two high-grade astrocytomas were misclassified as pleomorphic xanthoastrocytomas. Additionally, low variant allelic frequency in gangliogliomas likely contributed to misclassifications as control in 5 cases. CONCLUSION: This study emphasized the importance of integrating DMP with PD in diagnosing pediatric glial and glioneuronal tumors with BRAF mutations. Although DMP offers significant diagnostic insights, its limitations, particularly in cases with low tumor content, necessitate cautious interpretation, as well as its use as a complementary diagnostic tool, rather than a definitive method.
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Neoplasias Encefálicas , Metilación de ADN , Mutación , Proto-Oncogenes Mas , Proteínas Proto-Oncogénicas B-raf , Humanos , Proteínas Proto-Oncogénicas B-raf/genética , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patología , Neoplasias Encefálicas/diagnóstico , Neoplasias Encefálicas/diagnóstico por imagen , Niño , Masculino , Femenino , Metilación de ADN/genética , Estudios Retrospectivos , Preescolar , Ganglioglioma/genética , Ganglioglioma/patología , Ganglioglioma/diagnóstico por imagen , Adolescente , Glioma/genética , Glioma/patología , Glioma/diagnóstico , Astrocitoma/genética , Astrocitoma/patología , Astrocitoma/diagnóstico por imagen , Astrocitoma/diagnóstico , Lactante , Arabia SauditaRESUMEN
Objective: To investigate the clinical, radiological, and pathological features of anaplastic gangliogliomas (AGGs) and to determine whether these tumors represent a distinct entity. Methods: Consecutive 667 cases of ganglioglioma (GG) diagnosed at the Xuanwu Hospital, Capital Medical University, Beijing, China between January 2015 and July 2023 were screened. Among these cases, 9 pathologically confirmed AGG cases were identified. Their clinical, radiological, treatment, and outcome data were analyzed retrospectively. Most of the tumor samples were subject to next-generation sequencing, while a subset of them were subject to DNA methylation profiling. Results: Among the 9 patients, there were five males and four females, with a median age of 8 years. Epileptic seizures (5/9) were the most frequently presented symptom. Radiological examinations showed three types of radiological manifestations: four cases showed abnormal MRI signals with no significant mass effects and mild enhancement; two cases demonstrated a mixed solid-cystic density lesion with peritumoral edema, which showed significant heterogeneous enhancement and obvious mass effects, and one case displayed cystic cavity formation with nodules on MRI, which showed evident enhancements. All cases exhibited mutations that were predicted to activate the MAP kinase signaling pathway, including seven with BRAF p.V600E mutation and two with NF1 mutation. Five AGGs with mutations involving the MAP kinase signaling pathway also had concurrent mutations, including three with CDKN2A homozygous deletion, one with a TERT promoter mutation, one with a H3F3A mutation, and one with a PTEN mutation. Conclusions: AGG exhibits a distinct spectrum of pathology, genetic mutations and clinical behaviors, differing from GG. Given these characteristics suggest that AGG may be a distinct tumor type, further expansion of the case series is needed. Therefore, a comprehensive integration of clinical, histological, and molecular analyses is required to correctly diagnose AGG. It will also help guide treatments and prognostication.
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Neoplasias Encefálicas , Metilación de ADN , Ganglioglioma , Imagen por Resonancia Magnética , Mutación , Fosfohidrolasa PTEN , Proteínas Proto-Oncogénicas B-raf , Humanos , Ganglioglioma/patología , Ganglioglioma/genética , Masculino , Femenino , Niño , Estudios Retrospectivos , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patología , Neoplasias Encefálicas/diagnóstico por imagen , Proteínas Proto-Oncogénicas B-raf/genética , Fosfohidrolasa PTEN/genética , Fosfohidrolasa PTEN/metabolismo , Telomerasa/genética , Histonas/genética , Histonas/metabolismo , Inhibidor p16 de la Quinasa Dependiente de Ciclina/genética , Inhibidor p16 de la Quinasa Dependiente de Ciclina/metabolismo , Epilepsia/patología , Epilepsia/genéticaRESUMEN
Ganglioglioma (GG) with anaplasia (anaplastic ganglioglioma) is a rare and controversial diagnosis. When present, anaplasia involves the glial component of the tumor, either at presentation or at recurrence. To date, most published cases lack molecular characterization. We describe the histologic and molecular features of 3 patients presenting with BRAF p. V600E-mutant GG (CNS WHO grade 1) with high-grade glial transformation at recurrence. The tumors occurred in pediatric patients (age 9-16 years) with time to recurrence from 20 months to 7 years. At presentation, each tumor was low-grade, with a BRAFV600E-positive ganglion cell component and a glial component resembling pleomorphic xanthoastrocytoma (PXA) or fibrillary astrocytoma. At recurrence, tumors resembled anaplastic PXA or high-grade astrocytomas without neuronal differentiation. CDKN2A homozygous deletion (HD) was absent in all primary tumors. At recurrence, 2 cases acquired CDKN2A HD; the third case showed loss of p16 and MTAP immunoexpression, but no CDKN2A/B HD or mutation was identified. By DNA methylation profiling, all primary and recurrent tumors either grouped or definitely matched to different methylation classes. Our findings indicate that malignant progression of the glial component can occur in GG and suggest that CDKN2A/B inactivation plays a significant role in this process.
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Neoplasias Encefálicas , Ganglioglioma , Humanos , Ganglioglioma/genética , Ganglioglioma/patología , Adolescente , Niño , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patología , Masculino , Femenino , Proteínas Proto-Oncogénicas B-raf/genética , Epigénesis Genética , Recurrencia Local de Neoplasia/genética , Recurrencia Local de Neoplasia/patología , Transformación Celular Neoplásica/genética , Transformación Celular Neoplásica/patologíaRESUMEN
RATIONALE AND OBJECTIVES: This study was designed to investigate the value of nomograms based on MRI radiomics and clinical semantic features in identifying pleomorphic xanthoastrocytoma (PXA) and ganglioglioma (GG) as well as predicting BRAFV600E expression. MATERIALS AND METHODS: This study included 265 patients histologically diagnosed with PXA (n = 113) and GG (n = 152). T1WI, T2WI, and CET1 sequences were utilized to extract radiomics features. Univariate analysis, Spearman correlation analysis, and the least absolute shrinkage and selection operator were used for dimensionality reduction and feature selection. Following this, logistic regression was utilized to establish the radiomics model. Univariate and multivariate analyses of clinical semantic features were applied, and clinical models were constructed. The nomograms were established by merging radiomics and clinical features. Furthermore, ROC curve analysis was used for examining the model performance, whereas the decision curve analysis (DCA) examined the clinical utility of the nomograms. RESULTS: Nomograms achieved the best predictive efficacy compared to clinical and radiomics models alone. Concerning the differentiation between PXA and GG, the area under the curve (AUC) values of the nomogram were 0.879 (0.828-0.930) and 0.887 (0.805-0.969) for the training and testing cohorts, respectively. For predicting BRAFV600E expression, the AUC values of the nomogram were 0.873 (0.811-0.936) and 0.851 (0.740-0.963) for the training and testing cohorts, respectively. DCA confirmed the clinical utility of the nomograms. CONCLUSION: Nomograms based on radiomics and clinical semantic features were noninvasive tools for differential diagnosis of PXA and GG and predicting BRAFV600E expression, which may be helpful for assessing patient prognosis and developing individualized treatment strategies.
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Astrocitoma , Neoplasias Encefálicas , Ganglioglioma , Humanos , Diagnóstico Diferencial , Nomogramas , Ganglioglioma/diagnóstico por imagen , Ganglioglioma/genética , Radiómica , Astrocitoma/diagnóstico por imagen , Astrocitoma/genética , Imagen por Resonancia Magnética , Neoplasias Encefálicas/diagnóstico por imagen , Neoplasias Encefálicas/genética , Estudios RetrospectivosRESUMEN
BACKGROUND: BRAF V600E mutation is a common genomic alteration in gangliogliomas (GGs) and pleomorphic xanthoastrocytomas (PXAs) with prognostic and therapeutic implications. PURPOSE: To investigate the ability of magnetic resonance imaging (MRI) features to predict BRAF V600E status in GGs and PXAs and their prognostic values. MATERIAL AND METHODS: A cohort of 44 patients with histologically confirmed GGs and PXAs was reviewed retrospectively. BRAF V600E status was determined by immunohistochemistry (IHC) staining and fluorescence quantitative polymerase chain reaction (PCR). Demographics and MRI characteristics of the two groups were evaluated and compared. Univariate and multivariate Cox regression analyses were performed to identify MRI features that were prognostic for progression-free survival (PFS). RESULTS: T1/FLAIR ratio, enhancing margin, and mean relative apparent diffusion coefficient (rADCmea) value showed significant differences between the BRAF V600E-mutant and BRAF V600E-wild groups (all P < 0.05). Binary logistic regression analysis revealed only rADCmea value was the independent predictive factor for BRAF V600E status (P = 0.027). Univariate Cox regression analysis showed age at diagnosis (P = 0.032), WHO grade (P = 0.020), enhancing margin (P = 0.029), and rADCmea value (P = 0.005) were significant prognostic factors for PFS. In multivariate Cox regression analysis, increasing age (P = 0.040, hazard ratio [HR] = 1.04, 95% confidence interval [CI] = 1.002-1.079) and lower rADCmea values (P = 0.021, HR = 0.036, 95% CI = 0.002-0.602) were associated with poor PFS in GGs and PXAs. CONCLUSION: Imaging features are potentially predictive of BRAF V600E status in GGs and PXAs. Furthermore, rADCmea value is a valuable prognostic factor for patients with GGs or PXAs.
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Astrocitoma , Neoplasias Encefálicas , Ganglioglioma , Humanos , Ganglioglioma/diagnóstico por imagen , Ganglioglioma/genética , Proteínas Proto-Oncogénicas B-raf/genética , Neoplasias Encefálicas/diagnóstico por imagen , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patología , Estudios Retrospectivos , Mutación , Astrocitoma/patología , Imagen por Resonancia MagnéticaRESUMEN
BACKGROUND: The postoperative epilepsy outcome and clinicopathological features in children with ganglioglioma (GG) are not well understood. METHODS: Data from 51 consecutive pediatric patients diagnosed with GGs who underwent surgery were collected. The correlations between the expression of CD34 and BRAF V600E mutations and clinical features were analyzed. The related factors affecting the outcome of epilepsy were analyzed. RESULTS: The average follow-up was 44.2 months, and 48 patients were seizure-free. A high proportion of BRAF V600E mutation (78.8%) and CD34 expression (77.8%) was detected in GG. The onset age of epilepsy with the BRAF V600E mutation was earlier than that without. The expression of CD34 increased with the age of onset, the duration of epilepsy, and the age of operation. Focal cortical dysplasia (FCD) I was found in 62.7% of patients, and FCD II was found in 11.8% of patients approximately in the cortex surrounding GG. There was no significant correlation between the outcome of epilepsy and BRAF V600E mutation, CD34 expression, and combination with FCD. CONCLUSIONS: The overall outcome of GG and epilepsy in children is optimistic, and the outcome is not closely related to the presence of BRAF V600E mutation and CD34 (+). The FCD surrounding GG could be type I or type II. Incomplete resection of the surrounding FCD has the risk of unsatisfactory control of epilepsy. Children with the BRAF V600E mutation may be prone to early-onset epilepsy. The expression of CD34 is more likely to be detected in children with older age and a long duration of epilepsy.
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Neoplasias Encefálicas , Epilepsia , Displasia Cortical Focal , Ganglioglioma , Humanos , Niño , Ganglioglioma/complicaciones , Ganglioglioma/genética , Ganglioglioma/cirugía , Proteínas Proto-Oncogénicas B-raf/genética , Corteza Cerebral , Epilepsia/genética , Epilepsia/cirugía , Neoplasias Encefálicas/complicaciones , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/cirugíaRESUMEN
Recent epigenomic analyses have revealed the existence of a new DNA methylation class (MC) of infant-type hemispheric glioma (IHG). Like desmoplastic infantile ganglioglioma/astrocytoma (DIG/DIA), these tumors mainly affect infants and are supratentorial. While DIG/DIA is characterized by BRAF or RAF1 alterations, IHG has been shown to have receptor tyrosine kinase (RTK) gene fusions (ALK, ROS1, NTRK1/2/3, and MET). However, in this rapidly evolving field, a more comprehensive analysis of infantile glial/glioneuronal tumors including clinical, radiological, histopathological, and molecular data is needed. Here, we retrospectively investigated data from 30 infantile glial/glioneuronal tumors, consecutively compiled from our center. They were analyzed by two experienced pediatric neuroradiologists in consensus, without former knowledge of the molecular data. We also performed a comprehensive clinical, and histopathological examination (including molecular evaluation by next-generation sequencing, RNA sequencing, and fluorescence in situ hybridization [FISH] analyses), as well as DNA methylation profiling for the samples having sufficient material available. The integrative histopathological, genetic, and epigenetic analyses, including t-distributed stochastic neighbor embedding (t-SNE) analyses segregated tumors into 10 DIG/DIA (33.3%), six IHG (20.0%), three gangliogliomas (10.0%), two pleomorphic xanthoastrocytomas (6.7%), two pilocytic astrocytomas (6.7%), two supratentorial ependymomas, ZFTA fusion-positive (6.7%), two supratentorial ependymomas, YAP1 fusion-positive (6.7%), two embryonal tumors with PLAGL2-family amplification (6.7%), and one diffuse low-grade glioma, MAPK-pathway altered. This study highlights the significant differential features, in terms of histopathology (leptomeningeal infiltration, intense desmoplasia and ganglion cells in DIG/DIA and necrosis, microvascular proliferation, and siderophages in IHG), and radiology between DIG/DIA and IHG. Moreover, these results are consistent with the literature data concerning the molecular dichotomy (BRAF/RAF1 alterations vs. RTK genes' fusions) between DIG/DIA and IHG. This study characterized histopathologically and radiologically two additional cases of the novel embryonal tumor characterized by PLAGL2 gene amplification.
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Astrocitoma , Neoplasias Encefálicas , Neoplasias del Sistema Nervioso Central , Ependimoma , Ganglioglioma , Neoplasias Neuroepiteliales , Humanos , Ganglioglioma/genética , Ganglioglioma/patología , Neoplasias Encefálicas/patología , Proteínas Proto-Oncogénicas B-raf/genética , Estudios Retrospectivos , Hibridación Fluorescente in Situ , Proteínas Tirosina Quinasas , Proteínas Proto-Oncogénicas/genética , Astrocitoma/genética , Astrocitoma/patología , Proteínas de Unión al ADN/genética , Factores de Transcripción/genética , Proteínas de Unión al ARNRESUMEN
Exome-wide sequencing studies recently described PTPN11 as a novel brain somatic epilepsy gene. In contrast, germline mutations of PTPN11 are known to cause Noonan syndrome, a multisystem disorder characterized by abnormal facial features, developmental delay, and sporadically, also brain tumors. Herein, we performed a deep phenotype-genotype analysis of a comprehensive series of ganglioglioma (GG) with brain somatic alterations of the PTPN11/KRAS/NF1 genes compared to GG with common MAP-Kinase signaling pathway alterations, i.e., BRAFV600E. Seventy-two GG were submitted to whole exome sequencing and genotyping and 84 low grade epilepsy associated tumors (LEAT) to DNA-methylation analysis. In 28 tumours, both analyses were available from the same sample. Clinical data were retrieved from hospital files including disease onset, age at surgery, brain localization, and seizure outcome. A comprehensive histopathology staining panel was available in all cases. We identified eight GG with PTPN11 alterations, copy number variant (CNV) gains of chromosome 12, and the commonality of additional CNV gains in NF1, KRAS, FGFR4 and RHEB, as well as BRAFV600E alterations. Histopathology revealed an atypical glio-neuronal phenotype with subarachnoidal tumor spread and large, pleomorphic, and multinuclear cellular features. Only three out of eight patients with GG and PTPN11/KRAS/NF1 alterations were free of disabling-seizures 2 years after surgery (38% had Engel I). This was remarkably different from our series of GG with only BRAFV600E mutations (85% had Engel I). Unsupervised cluster analysis of DNA methylation arrays separated these tumours from well-established LEAT categories. Our data point to a subgroup of GG with cellular atypia in glial and neuronal cell components, adverse postsurgical outcome, and genetically characterized by complex alterations in PTPN11 and other RAS-/MAP-Kinase and/or mTOR signaling pathways. These findings need prospective validation in clinical practice as they argue for an adaptation of the WHO grading system in developmental, glio-neuronal tumors associated with early onset focal epilepsy.
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Epilepsia , Ganglioglioma , Humanos , Epilepsia/patología , Ganglioglioma/genética , Ganglioglioma/patología , Mutación/genética , Fenotipo , Proteína Tirosina Fosfatasa no Receptora Tipo 11/genética , Proteínas Proto-Oncogénicas p21(ras)/genética , Genes ras , Sistema de Señalización de MAP QuinasasRESUMEN
INTRODUCTION: The recently updated World Health Organization classification of central nervous system (CNS) tumors, 5th edition, (CNS5) reclassifies pediatric tumors according to their distinct molecular drivers, recognizing a new entity-infant-type hemispheric glioma (IHG). Defined by its unique epigenetic signature, and/or genomic fusions in ALK, ROS1, NTRK, or MET gene, IHG subsumes many cases previously classified as congenital glioblastoma (cGBM). Histologic features of IHG are still poorly defined with known overlap with a clinic radiologically similar entity-desmoplastic infantile ganglioglioma/astrocytoma (DIG). METHODS: We revisited our cohort of cGBMs and DIGs, now reclassifying them according to CNS5 and compared the clinical, radiologic, molecular and histologic features between the two. RESULTS: 3/6 cases of cGBM that underwent targeted NGS fusion mutation panel were positive for ALK fusions (involving MAP4, MZT2Bex2, and EML4 genes as fusion partners), and 1/6 showed GOPC:ROS1 fusion. Interestingly, GOPC:ROS1 fusion was also shared by 1/5 cases of histologically defined DIG. DNA methylation profiling using the Heidelberg classifier (v12.3) recategorized 2/5 DIG cases as IHG (including the case with ROS1 alteration). CONCLUSION: In conclusion, histology alone is insufficient to distinguish IHG from DIG, necessitating epigenomic and genomic testing for the diagnosis of early-life gliomas.
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Astrocitoma , Neoplasias Encefálicas , Ganglioglioma , Glioblastoma , Lactante , Niño , Humanos , Glioblastoma/diagnóstico por imagen , Glioblastoma/genética , Ganglioglioma/diagnóstico por imagen , Ganglioglioma/genética , Ganglioglioma/patología , Proteínas Tirosina Quinasas/genética , Epigenómica , Neoplasias Encefálicas/diagnóstico por imagen , Neoplasias Encefálicas/genética , Proteínas Proto-Oncogénicas/genética , Astrocitoma/genética , Genómica , Proteínas Tirosina Quinasas ReceptorasRESUMEN
BACKGROUND: Gliomas with FGFR3::TACC3 fusion mainly occur in adults, display pathological features of glioblastomas (GB) and are usually classified as glioblastoma, IDH-wildtype. However, cases demonstrating pathological features of low-grade glioma (LGG) lead to difficulties in classification and clinical management. We report a series of 8 GB and 14 LGG with FGFR3:TACC3 fusion in order to better characterize them. METHODS: Centralized pathological examination, search for TERT promoter mutation and DNA-methylation profiling were performed in all cases. Search for prognostic factors was done by the Kaplan-Meir method. RESULTS: TERT promoter mutation was recorded in all GB and 6/14 LGG. Among the 7 cases with a methylation score > 0.9 in the classifier (v12.5), 2 were classified as glioblastoma, 4 as ganglioglioma (GG) and 1 as dysembryoplastic neuroepithelial tumor (DNET). t-SNE analysis showed that the 22 cases clustered into three groups: one included 12 cases close to glioblastoma, IDH-wildtype methylation class (MC), 5 cases each clustered with GG or DNET MC but none with PLNTY MC. Unsupervised clustering analysis revealed four groups, two of them being clearly distinct: 5 cases shared age (< 40), pathological features of LGG, lack of TERT promoter mutation, FGFR3(Exon 17)::TACC3(Exon 10) fusion type and LGG MC. In contrast, 4 cases shared age (> 40), pathological features of glioblastoma, and were TERT-mutated. Relevant factors associated with a better prognosis were age < 40 and lack of TERT promoter mutation. CONCLUSION: Among gliomas with FGFR3::TACC3 fusion, age, TERT promoter mutation, pathological features, DNA-methylation profiling and fusion subtype are of interest to determine patients' risk.
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Neoplasias Encefálicas , Ganglioglioma , Glioblastoma , Glioma , Adulto , Humanos , Niño , Glioblastoma/genética , Mutación/genética , Glioma/genética , Glioma/patología , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patología , Pronóstico , Ganglioglioma/genética , Epigénesis Genética , ADN , Isocitrato Deshidrogenasa/genética , Receptor Tipo 3 de Factor de Crecimiento de Fibroblastos/genética , Proteínas Asociadas a Microtúbulos/genéticaRESUMEN
BACKGROUND: Down's syndrome is the most common chromosomal abnormality in humans. It has been associated with central nervous system tumors such as primary acute lymphoblastic leukemia and germinomas, but desmoplastic infantile astrocytoma has not yet been reported with Down's syndrome. Desmoplastic infantile astrocytoma is a rare intracranial tumor that mostly occurs in the first 2 years of life. It usually presents as a large, aggressive tumor with both solid and cystic components. Genetically, it has been linked to the BRAF V600E mutation. Despite the rapid growth pattern, it usually has a favorable prognosis after neurosurgical excision. The presence of this extremely rare, genetically linked tumor, and its combination with Down's syndrome, the most common human genetic defect, makes this a very novel clinical presentation. It also raises a very research-worthy question of an undiscovered link between these two genetic disorders. CASE PRESENTATION: In this case, we report a 1-year-old Pakistani origin male child with Down's syndrome, who presented with progressive macrocephaly and developmental regression over the last 2 months. He was unable to sit by himself, and had lost his handgrip bilaterally. Down's Syndrome was diagnosed soon after birth, based on typical facial features and presence of palmar crease, and later confirmed karyotypically for Trisomy 21. Upon presentation, initial blood tests did not show any abnormality. Magnetic resonance imaging of the brain was done, and showed a mixed intensity cystic mass with solid dural component posteriorly in the right parieto temporo occipital region. Craniotomy was performed, and about 85% of the tumor mass was excised. Histological examination and immunochemistry confirmed the suspected radiological diagnosis of desmoplastic infantile astrocytoma. After surgical excision, our patient gradually reacquired his previously regressed developmental milestones. Unfortunately, the remaining mass, which could not be excised due to its attachment to the highly vascular dura mater, showed regrowth on repeat brain magnetic resonance imaging. As his parents did not consent to further surgery, chemotherapy was offered as the next treatment option to prevent tumor regrowth. CONCLUSIONS: This case report highlights the need for more case data and research to understand desmoplastic infantile astrocytoma, and their genetic correlation with Down's syndrome. From a clinical standpoint, since desmoplastic infantile astrocytoma has a good postresection prognosis in a majority of early-diagnosed clinical cases, pediatricians, radiologists, and pathologists should consider desmoplastic infantile astrocytoma in their initial differential diagnosis in Down's syndrome patients with macrocephaly and developmental regression during the first 2 years of life.
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Astrocitoma , Neoplasias Encefálicas , Síndrome de Down , Ganglioglioma , Megalencefalia , Humanos , Lactante , Masculino , Astrocitoma/complicaciones , Astrocitoma/diagnóstico , Astrocitoma/genética , Neoplasias Encefálicas/genética , Síndrome de Down/complicaciones , Ganglioglioma/genética , Ganglioglioma/patología , Fuerza de la Mano , Hiperplasia , Imagen por Resonancia MagnéticaRESUMEN
In the new WHO 2021 Classification of CNS Tumors the chapter "Circumscribed astrocytic gliomas, glioneuronal and neuronal tumors" encompasses several different rare tumor entities, which occur more frequently in children, adolescents, and young adults. The Task Force has reviewed the evidence of diagnostic and therapeutic interventions, which is low particularly for adult patients, and draw recommendations accordingly. Tumor diagnosis, based on WHO 2021, is primarily performed using conventional histological techniques; however, a molecular workup is important for differential diagnosis, in particular, DNA methylation profiling for the definitive classification of histologically unresolved cases. Molecular factors are increasing of prognostic and predictive importance. MRI finding are non-specific, but for some tumors are characteristic and suggestive. Gross total resection, when feasible, is the most important treatment in terms of prolonging survival and achieving long-term seizure control. Conformal radiotherapy should be considered in grade 3 and incompletely resected grade 2 tumors. In recurrent tumors reoperation and radiotherapy, including stereotactic radiotherapy, can be useful. Targeted therapies may be used in selected patients: BRAF and MEK inhibitors in pilocytic astrocytomas, pleomorphic xanthoastrocytomas, and gangliogliomas when BRAF altered, and mTOR inhibitor everolimus in subependymal giant cells astrocytomas. Sequencing to identify molecular targets is advocated for diagnostic clarification and to direct potential targeted therapies.
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Astrocitoma , Neoplasias Encefálicas , Ganglioglioma , Glioma , Niño , Adolescente , Adulto Joven , Humanos , Glioma/diagnóstico , Glioma/genética , Glioma/terapia , Neoplasias Encefálicas/diagnóstico , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/terapia , Proteínas Proto-Oncogénicas B-raf/genética , Astrocitoma/diagnóstico , Astrocitoma/genética , Astrocitoma/terapia , Ganglioglioma/diagnóstico , Ganglioglioma/genética , Ganglioglioma/terapiaRESUMEN
Desmoplastic infantile astrocytoma (DIA) is rare, cystic and solid tumor of infants usually found in superficial cerebral hemispheres. Although DIA is usually benign, uncommon cases bearing malignant histological and aggressive clinical features have been described in the literature. We report a newborn patient who was diagnosed with a DIA and died postresection. Pathologic examination revealed that the main part of the tumor had benign features, but the internal region showed areas with a more aggressive appearance, with higher-proliferative cells, anaplastic GFAP positive cells with cellular polymorphism, necrosis foci, vascular hyperplasia with endothelial proliferation and microtrombosis. Genetic study, performed in both regions of the tumor, showed a BRAF V600E mutation and a homozygous deletion in PTEN, without changes in other relevant genes like EGFR, CDKN2A, TP53, NFKBIA, CDK4, MDM2 and PDGFRA. Although PTEN homozygous deletions are described in gliomas, the present case constitutes the first report of a PTEN mutation in a DIA, and this genetic feature may be related to the malignant behavior of a usually benign tumor. These genetic findings may point at the need of further and deeper genetic characterization of DIAs, in order to better understand the biology of this tumor and to obtain new prognostic approaches, a better clinical management and targeted therapies, especially in malignant cases of DIA.
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Astrocitoma , Neoplasias Encefálicas , Ganglioglioma , Astrocitoma/patología , Neoplasias Encefálicas/patología , Ganglioglioma/genética , Homocigoto , Humanos , Mutación/genética , Fosfohidrolasa PTEN/genética , Fenotipo , Proteínas Proto-Oncogénicas B-raf/genética , Eliminación de SecuenciaAsunto(s)
Neoplasias Encefálicas , Ganglioglioma , Neoplasias Neuroepiteliales , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patología , Metilación de ADN , Ganglioglioma/genética , Humanos , Neoplasias Neuroepiteliales/genética , Neoplasias Neuroepiteliales/patología , Lóbulo Temporal/patologíaRESUMEN
The mutation p.K27M in H3F3A (H3 K27M mutation) is mainly detected in diffuse midline glioma. However, recent studies have demonstrated that H3 K27M mutation could also be observed in a subset of gangliogliomas. Importantly, most H3 K27-mutated ganglioglioma cases also harbor BRAF V600E mutation. Herein, we report a rare case of H3 K27M-mutated ganglioglioma grade 3 without BRAF mutation arising in the medial temporal lobe in an elderly man. A small biopsy specimen was sampled. The pathological diagnosis was diffuse astrocytoma. The tumor progressed gradually during an 18-month follow-up period. Gadolinium enhancement on magnetic resonance imaging was noted 36 months after the biopsy. The patient was referred to a hospital for tumor resection. Histological analysis of resected specimens led to a diagnosis of ganglioglioma grade 3 with H3 K27M mutation. The patient underwent concurrent temozolomide chemotherapy with radiotherapy. Although the patient's condition deteriorated after chemotherapy due to disease progression, he survived for more than 23 months after tumor resection. We present this rare case and discuss the involvement of H3 K27M mutation in ganglioglioma grade 3.
Asunto(s)
Neoplasias Encefálicas , Ganglioglioma , Glioma , Anciano , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patología , Medios de Contraste , Gadolinio , Ganglioglioma/genética , Glioma/genética , Histonas/genética , Humanos , Masculino , Mutación , Proteínas Proto-Oncogénicas B-raf/genética , Lóbulo Temporal/patologíaRESUMEN
AIMS: Desmoplastic infantile astrocytomas and gangliogliomas (DIA/DIGs) are rare brain tumours of infancy. A distinctive feature of their histopathology is a combination of low-grade and high-grade features. Most DIA/DIGs can be surgically resected and have a good prognosis. However, high-grade features often dominate recurrent tumours, some of which have a poor outcome. In this study, we test the hypothesis that low-grade and high-grade areas in DIA/DIGs have distinct molecular characteristics. METHODS: Tissue samples from microdissected low-grade and high-grade areas in 12 DIA/DIGs were analysed by DNA methylation profiling, whole exome sequencing, RNA sequencing and immunohistochemistry to search for potential differences at multiple molecular levels. RESULTS: Copy number variants among tumours and between the two morphologically distinct areas were infrequent. No recurrent genetic alterations were identified across the tumour series, and high-grade areas did not have additional genetic alterations to explain their distinct morphology or biological behaviour. However, high-grade areas showed relative hypomethylation in genes downstream of the transcription factors SOX9 and LEF1 and evidence of a core SOX9 transcription network alongside activation of the BMP, WNT and MAPK signalling pathways. CONCLUSIONS: This study contributes to our knowledge of molecular genetic alterations in DIA/DIGs, uncovers molecular differences between the two distinct cell populations in these tumours and suggests potential therapeutic targets among the more proliferative cell population in DIA/DIGs.
Asunto(s)
Astrocitoma , Neoplasias Encefálicas , Ganglioglioma , Astrocitoma/genética , Astrocitoma/patología , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patología , Ganglioglioma/genética , Ganglioglioma/patología , Humanos , Lactante , Imagen por Resonancia Magnética , Mutación , Secuenciación del ExomaRESUMEN
BACKGROUND: Developmental brain tumors harboring BRAFV600E somatic mutation are diverse. Here, we describe molecular factors that determine BRAFV600E-induced tumor biology and function. METHODS: Intraventricular in utero electroporation in combination with the piggyBac transposon system was utilized to generate developmental brain neoplasms, which were comprehensively analyzed with regard to growth using near-infrared in-vivo imaging, transcript signatures by RNA sequencing, and neuronal activity by multielectrode arrays. RESULTS: BRAF V600E expression in murine neural progenitors elicits benign neoplasms composed of enlarged dysmorphic neurons and neoplastic astroglia recapitulating ganglioglioma (GG) only in concert with active Akt/mTOR-signaling. Purely glial tumors resembling aspects of polymorphous low-grade neuroepithelial tumors of the young (PLNTYs) emerge from BRAFV600E alone. Additional somatic Trp53-loss is sufficient to generate anaplastic GGs (aGGs) with glioneuronal clonality. Functionally, only BRAFV600E/pAkt tumors intrinsically generate substantial neuronal activity and show enhanced relay to adjacent tissue conferring high epilepsy propensity. In contrast, PLNTY- and aGG models lack significant spike activity, which appears in line with the glial differentiation of the former and a dysfunctional tissue structure combined with reduced neuronal transcript signatures in the latter. CONCLUSION: mTOR-signaling and Trp53-loss critically determine the biological diversity and electrical activity of BRAFV600E-induced tumors.
Asunto(s)
Neoplasias Encefálicas , Ganglioglioma , Animales , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Ganglioglioma/genética , Humanos , Ratones , Mutación , Proteínas Proto-Oncogénicas B-raf/genética , Proteínas Proto-Oncogénicas B-raf/metabolismo , Proteínas Proto-Oncogénicas c-akt/genética , Proteínas Proto-Oncogénicas c-akt/metabolismo , Transducción de Señal/fisiología , Serina-Treonina Quinasas TOR/genética , Serina-Treonina Quinasas TOR/metabolismoRESUMEN
AIMS: Glioneuronal tumours, although rare, are an important cause of treatment-resistant epilepsy. Differential diagnosis of glioneuronal tumour subtypes is complicated by their variable histological appearance and the lack of pathognomonic histological or molecular biomarkers. In this study we have applied techniques available in a diagnostic laboratory setting to characterise molecular and cytogenetic abnormalities in a single institution cohort of glioneuronal tumours. METHODS: A cohort of 29 glioneuronal tumours that included 21 gangliogliomas and 5 dysembryoplastic neuroepithelial tumours (DNETs) was analysed using low pass whole genome sequencing (WGS) and 2 multiplex ligation-dependent probe amplification (MLPA) central nervous system (CNS) tumour probesets. RESULTS: Low pass WGS identified chromosomal or subchromosomal alterations in 15 specimens. The most common chromosomal alterations were gains of chromosome 7 (n = 8) and chromosome 16 (n = 3). The BRAFV600E mutation was detected by MLPA in 9/21 (42.9%) gangliogliomas and 2/2 pleomorphic xanthoastrocytomas (PXAs). Chromosome 7 gains detected by WGS were reflected in MLPAs by overall gains of chromosome 7 gene probes, including those for BRAF, KIAA1549 and EGFR, while an internal BRAF/MKRN1 duplication was detected in a single ganglioglioma. Homozygous CDKN2A/B loss was detected by MLPA in 3 gangliogliomas, with p16 immunohistochemistry supporting these results. CONCLUSIONS: The combination of low pass WGS and MLPA identifies multiple, diverse genetic and chromosomal alterations in glioneuronal tumours, irrespective of histological tumour grade.
Asunto(s)
Neoplasias Encefálicas/genética , Ganglioglioma/genética , Glioma/genética , Reacción en Cadena de la Polimerasa Multiplex , Adolescente , Adulto , Anciano , Neoplasias Encefálicas/clasificación , Neoplasias Encefálicas/patología , Niño , Preescolar , Femenino , Ganglioglioma/clasificación , Ganglioglioma/patología , Glioma/clasificación , Glioma/patología , Humanos , Lactante , Masculino , Persona de Mediana Edad , Clasificación del Tumor , Secuenciación Completa del Genoma , Adulto JovenRESUMEN
The BRAF p.V600E mutation is the most common genetic alteration in ganglioglioma (GG). Herein, we collected a consecutive series of 30 GG specimens from Xuanwu Hospital in order to corroborate the genetic landscape and genotype-phenotype correlation of this enigmatic and often difficult-to-classify epilepsy-associated brain tumor entity. All specimens with histopathologically confirmed lesions were submitted to targeted next-generation sequencing using a panel of 131 genes. Genetic alterations in three cases with histologically distinct tumor components, that is, GG plus pleomorphic xanthoastrocytoma (PXA), dysembryoplastic neuroepithelial tumor (DNT), or an oligodendroglioma (ODG)-like tumor component, were separately studied. A mean post-surgical follow-up time-period of 23 months was available in 24 patients. Seventy seven percent of GG in our series can be explained by genetic alterations, with BRAF p.V600E mutations being most prevalent (n = 20). Three additional cases showed KRAS p.Q22R and KRAS p.G13R, IRS2 copy number gain (CNG) and a KIAA1549-BRAF fusion. When genetically studying different histopathology patterns from the same tumor we identified composite features with BRAF p.V600E plus CDKN2A/B homozygous deletion in a GG with PXA features, IRS2 CNG in a GG with DNT features, and a BRAF p.V600E plus CNG of chromosome 7 in a GG with ODG-like features. Follow-up revealed no malignant tumor progression but nine patients had seizure recurrence. Eight of these nine GG were immunoreactive for CD34, six patients were male, five were BRAF wildtype, and atypical histopathology features were encountered in four patients, that is, ki-67 proliferation index above 5% or with PXA component. Our results strongly point to activation of the MAP kinase pathway in the vast majority of GG and their molecular-genetic differentiation from the cohort of low-grade pediatric type diffuse glioma remains, however, to be further clarified. In addition, histopathologically distinct tumor components accumulated different genetic alterations suggesting collision or composite glio-neuronal GG variants.