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Accurate pathological diagnosis is crucial for optimal management of patients with cancer. For the approximately 100 known tumour types of the central nervous system, standardization of the diagnostic process has been shown to be particularly challenging-with substantial inter-observer variability in the histopathological diagnosis of many tumour types. Here we present a comprehensive approach for the DNA methylation-based classification of central nervous system tumours across all entities and age groups, and demonstrate its application in a routine diagnostic setting. We show that the availability of this method may have a substantial impact on diagnostic precision compared to standard methods, resulting in a change of diagnosis in up to 12% of prospective cases. For broader accessibility, we have designed a free online classifier tool, the use of which does not require any additional onsite data processing. Our results provide a blueprint for the generation of machine-learning-based tumour classifiers across other cancer entities, with the potential to fundamentally transform tumour pathology.
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Neoplasias do Sistema Nervoso Central/diagnóstico , Neoplasias do Sistema Nervoso Central/genética , Metilação de DNA , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias do Sistema Nervoso Central/classificação , Neoplasias do Sistema Nervoso Central/patologia , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Reprodutibilidade dos Testes , Aprendizado de Máquina não Supervisionado , Adulto JovemRESUMO
Ependymomas encompass a heterogeneous group of central nervous system (CNS) neoplasms that occur along the entire neuroaxis. In recent years, extensive (epi-)genomic profiling efforts have identified several molecular groups of ependymoma that are characterized by distinct molecular alterations and/or patterns. Based on unsupervised visualization of a large cohort of genome-wide DNA methylation data, we identified a highly distinct group of pediatric-type tumors (n = 40) forming a cluster separate from all established CNS tumor types, of which a high proportion were histopathologically diagnosed as ependymoma. RNA sequencing revealed recurrent fusions involving the pleomorphic adenoma gene-like 1 (PLAGL1) gene in 19 of 20 of the samples analyzed, with the most common fusion being EWSR1:PLAGL1 (n = 13). Five tumors showed a PLAGL1:FOXO1 fusion and one a PLAGL1:EP300 fusion. High transcript levels of PLAGL1 were noted in these tumors, with concurrent overexpression of the imprinted genes H19 and IGF2, which are regulated by PLAGL1. Histopathological review of cases with sufficient material (n = 16) demonstrated a broad morphological spectrum of tumors with predominant ependymoma-like features. Immunohistochemically, tumors were GFAP positive and OLIG2- and SOX10 negative. In 3/16 of the cases, a dot-like positivity for EMA was detected. All tumors in our series were located in the supratentorial compartment. Median age of the patients at the time of diagnosis was 6.2 years. Median progression-free survival was 35 months (for 11 patients with data available). In summary, our findings suggest the existence of a novel group of supratentorial neuroepithelial tumors that are characterized by recurrent PLAGL1 fusions and enriched for pediatric patients.
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Proteínas de Ciclo Celular/genética , Ependimoma/genética , Neoplasias Supratentoriais/genética , Fatores de Transcrição/genética , Proteínas Supressoras de Tumor/genética , Criança , Feminino , Humanos , Masculino , Fusão OncogênicaRESUMO
BACKGROUND: The diagnostic gold standard of Hirschsprung's disease (HD) is based on the histopathological assessment of colorectal biopsies. Although data on cholinergic innervation and ganglion cell (GC) distribution exist, only few studies have examined these two key features together. We assessed the pattern of cholinergic innervation and the amount of GCs in colorectal specimens of 14 HD patients. METHODS: We established a semi-quantitative score for cholinergic innervation using acetylcholinesterase (AChE) enzyme histochemistry and quantitatively analyzed the number of GCs via NADH tetrazolium reductase (NADH) enzyme histochemistry. We examined both the entire length of the resected specimens as well as defined areas of the transition zone of both pathological and healthy appearing segment. RESULTS: High AChE score values were associated with absence of GCs, and AChE scores were inversely correlated with the number of GCs. Nevertheless, we observed several cases in which one of the two features revealed a normal distribution pattern, whereas the other still displayed pathological features. CONCLUSIONS: Our data support the need for transmural colon biopsies, to enable the best evaluation of both cholinergic innervation and GCs for a reliable assessment of HD.
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Doença de Hirschsprung , Biópsia , Colinérgicos , Doença de Hirschsprung/diagnóstico , Histocitoquímica , Humanos , Intestinos , RetoRESUMO
BACKGROUND: It is still controversial whether an increased proliferation index is correlated with the tumor invasiveness of pituitary adenomas. A homogeneous large monocentric series of pituitary adenomas was retrospectively analyzed. The correlation between the proliferation indices (Ki-67 and p53 expression levels) and invasiveness and size of pituitary adenomas was investigated in primary operated and recurrent adenomas. METHOD: Four hundred thirty-nine patients after resection of pituitary adenomas were retrospectively included (43 recurrent tumors, 196 null cell adenomas, 86 somatotroph adenomas, 55 corticotroph adenomas, 55 prolactinomas, 4 thyreotroph adenomas). The maximum tumor diameter and tumor invasiveness in Knosp grading were assessed and Ki-67 and p53 immunostaining was performed. The role of invasiveness was evaluated using a cumulative odds ordinal logistic regression. For calculating the effect of tumor size, a one-way analysis of variance (ANOVA) was conducted. RESULTS: Overall and in the subgroups, no significant correlation between proliferation indices and mean tumor diameter was found. No significant predictive expression value of Ki-67 and p53 on tumor invasiveness and in recurrent tumors could be demonstrated. There was a tendency that Ki-67 LI and p53 LI are higher in recurrent corticotroph adenomas and lactotroph adenomas but values did not reach the significant level. CONCLUSION: Invasive character of pituitary adenomas is neither correlated with increased Ki-67 LI nor with increased p53 expression. Proliferation parameters are independent from adenoma size at initial presentation. The partly elevated expression of Ki-67 in recurrent tumors underlines the clinical importance of the marker.
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Adenoma/patologia , Biomarcadores Tumorais/metabolismo , Antígeno Ki-67/metabolismo , Neoplasias Hipofisárias/patologia , Proteína Supressora de Tumor p53/metabolismo , Adenoma/metabolismo , Adulto , Biomarcadores Tumorais/genética , Feminino , Humanos , Antígeno Ki-67/genética , Masculino , Pessoa de Meia-Idade , Índice Mitótico , Invasividade Neoplásica , Neoplasias Hipofisárias/metabolismo , Proteína Supressora de Tumor p53/genéticaRESUMO
Extraventricular neurocytoma (EVN) is a rare primary brain tumor occurring in brain parenchyma outside the ventricular system. Histopathological characteristics resemble those of central neurocytoma but exhibit a wider morphologic spectrum. Accurate diagnosis of these histologically heterogeneous tumors is often challenging because of the overlapping morphological features and the lack of defining molecular markers. Here, we explored the molecular landscape of 40 tumors diagnosed histologically as EVN by investigating copy number profiles and DNA methylation array data. DNA methylation profiles were compared with those of relevant differential diagnoses of EVN and with a broader spectrum of diverse brain tumor entities. Based on this, our tumor cohort segregated into different groups. While a large fraction (n = 22) formed a separate epigenetic group clearly distinct from established DNA methylation profiles of other entities, a subset (n = 14) of histologically diagnosed EVN grouped with clusters of other defined entities. Three cases formed a small group close to but separated from the epigenetically distinct EVN cases, and one sample clustered with non-neoplastic brain tissue. Four additional samples originally diagnosed otherwise were found to molecularly resemble EVN. Thus, our results highlight a distinct DNA methylation pattern for the majority of tumors diagnosed as EVN, but also indicate that approximately one third of morphological diagnoses of EVN epigenetically correspond to other brain tumor entities. Copy number analysis and confirmation through RNA sequencing revealed FGFR1-TACC1 fusion as a distinctive, recurrent feature within the EVN methylation group (60%), in addition to a small number of other FGFR rearrangements (13%). In conclusion, our data demonstrate a specific epigenetic signature of EVN suitable for characterization of these tumors as a molecularly distinct entity, and reveal a high frequency of potentially druggable FGFR pathway activation in this tumor group.
Assuntos
Neoplasias Encefálicas/genética , Proteínas Fetais/genética , Proteínas Associadas aos Microtúbulos/genética , Neurocitoma/genética , Proteínas Nucleares/genética , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/genética , Metilação de DNA/genética , Feminino , Proteínas Fetais/metabolismo , Histonas/genética , Humanos , Isocitrato Desidrogenase/genética , Isocitrato Desidrogenase/metabolismo , Estimativa de Kaplan-Meier , Antígeno Ki-67/metabolismo , Masculino , Proteínas Associadas aos Microtúbulos/metabolismo , Proteínas Nucleares/metabolismo , Proteínas de Fusão Oncogênica/genética , Proteínas de Fusão Oncogênica/metabolismo , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/metabolismo , Estudos Retrospectivos , TranscriptomaAssuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Neoplasias Encefálicas/genética , Glioma/genética , Proteínas da Matriz do Complexo de Golgi/genética , Proteínas Tirosina Quinases/genética , Proteínas Proto-Oncogênicas/genética , Humanos , Terapia de Alvo Molecular , Fusão Oncogênica/genética , Proteínas de Fusão Oncogênica/genéticaRESUMO
AIMS: The paired box gene 8 (PAX8) plays crucial roles in organ patterning and cellular differentiation during development and tumorigenesis. Although its function is partly understood in vertebrate development, there is poor data concerning human central nervous system (CNS) development and brain tumours. METHODS: We investigated developing human (n = 19) and mouse (n = 3) brains as well as medulloblastomas (MBs) (n = 113) for PAX8 expression by immunohistochemistry. Human MB cell lines were assessed for PAX8 expression using polymerase chain reaction and immunoblotting and analysed for growth and migration following PAX8 knock-down by small interfering ribonucleic acid (siRNA). RESULTS: PAX8 protein expression was associated with germinal layers in human and murine forebrain and hindbrain development. PAX8 expression significantly decreased over time in the external granule cell layer but increased in the internal granule cell layer. In MB subtypes, we observed an association of PAX8 expression with sonic hedgehog (SHH) and wingless int subtypes but not with group 3 and 4 MBs. Beyond that, we detected high PAX8 levels in desmoplastic MB subtypes. Univariate analyses revealed high PAX8 levels as a prognostic factor associated with a significantly better patient prognosis in human MB (overall survival: Log-Rank P = 0.0404, Wilcoxon P = 0.0280; progression-free survival: Log-Rank P = 0.0225; Wilcoxon P = 0.0136). In vitro assays revealed increased proliferation and migration of MB cell lines after PAX8 siRNA knock-down. CONCLUSION: In summary, high PAX8 expression is linked to better prognosis in MBs potentially by suppressing both proliferative and migratory properties of MB cells. The distinct spatio-temporal expression pattern of PAX8 during brain development might contribute to the understanding of distinct MB subtype histogenesis.
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Neoplasias Cerebelares/patologia , Proteínas Hedgehog/metabolismo , Meduloblastoma/patologia , Fatores de Transcrição Box Pareados/biossíntese , Proteínas Wnt/metabolismo , Adolescente , Animais , Western Blotting , Encéfalo/embriologia , Encéfalo/metabolismo , Neoplasias Cerebelares/metabolismo , Neoplasias Cerebelares/mortalidade , Criança , Pré-Escolar , Intervalo Livre de Doença , Feminino , Imunofluorescência , Técnicas de Silenciamento de Genes , Humanos , Imuno-Histoquímica , Lactente , Masculino , Meduloblastoma/metabolismo , Meduloblastoma/mortalidade , Camundongos , Fator de Transcrição PAX8 , Prognóstico , RNA Interferente Pequeno , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Análise Serial de Tecidos , TransfecçãoRESUMO
A 61-year-old patient was diagnosed with a left-sided falx meningioma. Histopathological analysis following extirpation showed a meningothelial meningioma ZNS WHO grade 1 with sparse mitoses. Over the course of 12 years, the patient received irradiation (54.0 Gy), peptide radio-receptor therapy (177Lu-DOMITATE) and targeted therapy (mTOR inhibitor). Follow-up imaging revealed an increased size of the residual tumor. Due to increased liver function parameters, imaging of the liver was performed, showing widespread space-occupying lesions with atypical appearance. Biopsy revealed metastasis of the meningioma, now with 2.7 mitoses/mm2, necrosis and homozygous CDKN2A/B deletion, corresponding to an anaplastic CNS meningioma WHO grade 3. A second small meningioma on the left petroclival side has been consistent in size over 12 years. Metastatic meningiomas pose a pertinent clinical challenge due to poor prognosis. The lung, bone, liver and cervical lymph nodes are the most common sites of extracranial metastasis. According to the World Health Organization criteria, the most important predictive factor for recurrence and metastasis is the tumor grade.
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Gonadotroph adenomas comprise 15-40% of all pituitary tumors, are usually non-functioning and are often large and invasive at presentation. Surgery is the first-choice treatment, but complete resection is not always achieved, leading to high recurrence rates. As gonadotroph adenomas poorly respond to conventional pharmacological therapies, novel treatment strategies are needed. Their identification has been hampered by our incomplete understanding of the molecular pathogenesis of these tumors. Recently, we demonstrated that MENX-affected rats develop gonadotroph adenomas closely resembling their human counterparts. To discover new genes/pathways involved in gonadotroph cells tumorigenesis, we performed transcriptome profiling of rat tumors versus normal pituitary. Adenomas showed overrepresentation of genes involved in cell cycle, development, cell differentiation/proliferation, and lipid metabolism. Bioinformatic analysis identified downstream targets of the transcription factor SF-1 as being up-regulated in rat (and human) adenomas. Meta-analyses demonstrated remarkable similarities between gonadotroph adenomas in rats and humans, and highlighted common dysregulated genes, several of which were not previously implicated in pituitary tumorigenesis. Two such genes, CYP11A1 and NUSAP1, were analyzed in 39 human gonadotroph adenomas by qRT-PCR and found to be up-regulated in 77 and 95% of cases, respectively. Immunohistochemistry detected high P450scc (encoded by CYP11A1) and NuSAP expression in 18 human gonadotroph tumors. In vitro studies demonstrated for the first time that Cyp11a1 is a target of SF-1 in gonadotroph cells and promotes proliferation/survival of rat pituitary adenoma primary cells and cell lines. Our studies reveal clues about the molecular mechanisms driving rat and human gonadotroph adenomas development, and may help identify previously unexplored biomarkers for clinical use.
Assuntos
Adenoma/genética , Adenoma/patologia , Gonadotropinas Hipofisárias/metabolismo , Neoplasias Hipofisárias/genética , Neoplasias Hipofisárias/patologia , Fatores de Transcrição/genética , Animais , Bioestatística , Linhagem Celular Tumoral , Transformação Celular Neoplásica/genética , Enzima de Clivagem da Cadeia Lateral do Colesterol/genética , Enzima de Clivagem da Cadeia Lateral do Colesterol/metabolismo , Biologia Computacional , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica/genética , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Humanos , Análise em Microsséries , Proteínas Associadas aos Microtúbulos/genética , Proteínas Associadas aos Microtúbulos/metabolismo , Interferência de RNA/fisiologia , Ratos , Fatores de Transcrição/metabolismo , TransfecçãoRESUMO
The migration of polymorphonuclear granulocytes (PMN) into the brain parenchyma and release of their abundant proteases are considered the main causes of neuronal cell death and reperfusion injury following ischemia. Yet, therapies targeting PMN egress have been largely ineffective. To address this discrepancy we investigated the temporo-spatial localization of PMNs early after transient ischemia in a murine transient middle cerebral artery occlusion (tMCAO) model and human stroke specimens. Using specific markers that distinguish PMN (Ly6G) from monocytes/macrophages (Ly6C) and that define the cellular and basement membrane boundaries of the neurovascular unit (NVU), histology and confocal microscopy revealed that virtually no PMNs entered the infarcted CNS parenchyma. Regardless of tMCAO duration, PMNs were mainly restricted to luminal surfaces or perivascular spaces of cerebral vessels. Vascular PMN accumulation showed no spatial correlation with increased vessel permeability, enhanced expression of endothelial cell adhesion molecules, platelet aggregation or release of neutrophil extracellular traps. Live cell imaging studies confirmed that oxygen and glucose deprivation followed by reoxygenation fail to induce PMN migration across a brain endothelial monolayer under flow conditions in vitro. The absence of PMN infiltration in infarcted brain tissues was corroborated in 25 human stroke specimens collected at early time points after infarction. Our observations identify the NVU rather than the brain parenchyma as the site of PMN action after CNS ischemia and suggest reappraisal of targets for therapies to reduce reperfusion injury after stroke.
Assuntos
Barreira Hematoencefálica/fisiopatologia , Encéfalo/patologia , Granulócitos/patologia , Infarto da Artéria Cerebral Média/imunologia , Infarto da Artéria Cerebral Média/patologia , Animais , Antígenos CD/metabolismo , Antígenos Ly/metabolismo , Vasos Sanguíneos/patologia , Vasos Sanguíneos/fisiopatologia , Barreira Hematoencefálica/patologia , Moléculas de Adesão Celular/metabolismo , Células Cultivadas , Modelos Animais de Doenças , Endotélio/patologia , Lateralidade Funcional , Regulação da Expressão Gênica/fisiologia , Glucose/deficiência , Humanos , Hipóxia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Modelos Biológicos , Oxigênio/administração & dosagemRESUMO
The prevalence of pathogenic and likely pathogenic (P/LP) variants in genes associated with cancer predisposition syndromes (CPS) is estimated to be 8-18% for paediatric cancer patients. In more than half of the carriers, the family history is unsuspicious for CPS. Therefore, broad genetic testing could identify germline predisposition in additional children with cancer resulting in important implications for themselves and their families. We thus evaluated clinical trio genome sequencing (TGS) in a cohort of 72 paediatric patients with solid cancers other than retinoblastoma or CNS-tumours. The most prevalent cancer types were sarcoma (n = 26), neuroblastoma (n = 15), and nephroblastoma (n = 10). Overall, P/LP variants in CPS genes were identified in 18.1% of patients (13/72) and P/LP variants in autosomal-dominant CPS genes in 9.7% (7/72). Genetic evaluation would have been recommended for the majority of patients with P/LP variants according to the Jongmans criteria. Four patients (5.6%, 4/72) carried P/LP variants in autosomal-dominant genes known to be associated with their tumour type. With the immediate information on variant inheritance, TGS facilitated the identification of a de novo P/LP in NF1, a gonadosomatic mosaic in WT1 and two pathogenic variants in one patient (DICER1 and PALB2). TGS allows a more detailed characterization of structural variants with base-pair resolution of breakpoints which can be relevant for the interpretation of copy number variants. Altogether, TGS allows comprehensive identification of children with a CPS and supports the individualised clinical management of index patients and high-risk relatives.
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Predisposição Genética para Doença , Neoplasias , Humanos , Criança , Mutação em Linhagem Germinativa , Neoplasias/genética , Testes Genéticos/métodos , Genótipo , Ribonuclease III/genética , RNA Helicases DEAD-box/genéticaRESUMO
Background: The clinical utility of molecular profiling and targeted therapies for neuro-oncology patients outside of clinical trials is not established. We aimed at investigating feasibility and clinical utility of molecular profiling and targeted therapy in adult patients with advanced tumors in the nervous system within a prospective observational study. Methods: molecular tumor board (MTB)@ZPM (NCT03503149) is a prospective observational precision medicine study for patients with advanced tumors. After inclusion of patients, we performed comprehensive molecular profiling, formulated ranked biomarker-guided therapy recommendations based on consensus by the MTB, and collected prospective clinical outcome data. Results: Here, we present initial data of 661 adult patients with tumors of the nervous system enrolled by December 31, 2021. Of these, 408 patients were presented at the MTB. Molecular-instructed therapy recommendations could be made in 380/408 (93.1%) cases and were prioritized by evidence levels. Therapies were initiated in 86/380 (22.6%) cases until data cutoff. We observed a progression-free survival ratio >1.3 in 31.3% of patients. Conclusions: Our study supports the clinical utility of biomarker-guided therapies for neuro-oncology patients and indicates clinical benefit in a subset of patients. Our data might inform future clinical trials, translational studies, and even clinical care.
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Immune checkpoint blockade therapy is beneficial and even curative for some cancer patients. However, the majority don't respond to immune therapy. Across different tumor types, pre-existing T cell infiltrates predict response to checkpoint-based immunotherapy. Based on in vitro pharmacological studies, mouse models and analyses of human melanoma patients, we show that the cytokine GDF-15 impairs LFA-1/ß2-integrin-mediated adhesion of T cells to activated endothelial cells, which is a pre-requisite of T cell extravasation. In melanoma patients, GDF-15 serum levels strongly correlate with failure of PD-1-based immune checkpoint blockade therapy. Neutralization of GDF-15 improves both T cell trafficking and therapy efficiency in murine tumor models. Thus GDF-15, beside its known role in cancer-related anorexia and cachexia, emerges as a regulator of T cell extravasation into the tumor microenvironment, which provides an even stronger rationale for therapeutic anti-GDF-15 antibody development.
Assuntos
Melanoma , Linfócitos T , Humanos , Camundongos , Animais , Linfócitos T/patologia , Antígeno-1 Associado à Função Linfocitária , Células Endoteliais/patologia , Inibidores de Checkpoint Imunológico/farmacologia , Inibidores de Checkpoint Imunológico/uso terapêutico , Melanoma/patologia , Imunoterapia , Microambiente TumoralRESUMO
In human glioblastoma, the blood-brain barrier (BBB) is disturbed. According to our concept, the glio-vascular relationships and thus the control of the BBB are essentially dependent on the polarity of astroglial cells. This polarity is characterized by the uneven distribution of the water channel protein aquaporin-4 (AQP4), dystroglycan and other molecules. Recently, we were able to show that the extracellular matrix component agrin is important for the construction and localization of the so-called orthogonal arrays of particles (OAPs), which consist in AQP4. Here, combining freeze-fracture electron microscopy, immunohistochemistry and Western blotting, we describe alterations of expression and distribution of AQP4, dystroglycan, agrin and the matrix metalloproteinases (MMP) 2, 3 and 9 in human primary glioblastomas (eight primary tumours, six recurrent tumours). Increase of MMP3- and MMP2/9 immunoreactivities went along with loss of agrin and dystroglycan respectively. On the protein level, AQP4 expression was increased in glioblastoma compared to control tissue. This was not accompanied by an increase of OAPs, suggesting that AQP4 can also occur without forming OAPs. The results underline our concept of the loss of glioma cell polarity as one of the factors responsible for the disturbance of the neurovascular unit and as an explanation for the formation of edemas in the glioblastoma.
Assuntos
Agrina/metabolismo , Aquaporina 4/metabolismo , Neoplasias Encefálicas/metabolismo , Encéfalo/metabolismo , Distroglicanas/metabolismo , Glioblastoma/metabolismo , Metaloproteinases da Matriz/metabolismo , Barreira Hematoencefálica/metabolismo , Polaridade Celular , Matriz Extracelular/metabolismo , Técnica de Fratura por Congelamento , Humanos , Imuno-Histoquímica , Microscopia EletrônicaRESUMO
PURPOSE: Low-grade gliomas (LGG) and mixed neuronal-glial tumors (MNGT) show frequent MAPK pathway alterations. Oncogenic fibroblast growth factor receptor 1 (FGFR1) tyrosinase kinase domain has been reported in brain tumors of various histologies. We sought to determine the frequency of FGFR1 hotspot mutations N546 and K656 in driver-unknown LGG/MNGT and examined FGFR1 immunohistochemistry as a potential tool to detect those alterations. METHODS: We analyzed 476 LGG/MNGT tumors for KIAA-1549-BRAF fusion, IDH1/2, TERT promotor, NF1, H3F3A and the remaining cases for FGFR1 mutation frequency and correlated FGFR1 immunohistochemistry in 106 cases. RESULTS: 368 of 476 LGG/MNGT tumors contained non-FGFR1 alterations. We identified 9 FGFR1 p.N546K and 4 FGFR1 p.K656E mutations among the 108 remaining driver-unknown samples. Five tumors were classified as dysembryoplastic neuroepithelial tumor (DNT), 4 as pilocytic astrocytoma (PA) and 3 as rosette-forming glioneuronal tumor (RGNT). FGFR1 mutations were associated with oligodendroglia-like cells, but not with age or tumor location. FGFR1 immunohistochemical expression was observed in 92 cases. FGFR1 immunoreactivity score was higher in PA and DNT compared to diffuse astrocytoma, but no correlation between FGFR1 mutation in tumors and FGFR1 expression level was observed. CONCLUSION: FGFR1 hotspot mutations are the fifth most prevailing alteration in LGG/MNGT. Performing FGFR1 sequencing analysis in driver-unknown low-grade brain tumors could yield up to 12% FGFR1 N546/K656 mutant cases.
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Astrocitoma , Neoplasias Encefálicas , Glioma , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos , Astrocitoma/patologia , Neoplasias Encefálicas/patologia , Criança , Glioma/genética , Glioma/patologia , Humanos , Mutação , Oncogenes , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/genéticaRESUMO
Optic pathway gliomas in children carry significant morbidity and therapeutic challenges. For the subgroup of pre-chiasmatic gliomas, intraorbital and intradural resection is a curative option after blindness. We present a two-center cohort using different surgical approaches. A retrospective analysis was performed, including 10 children. Mean age at surgery was 6.8 years. Interval between diagnosis and surgery was 1-74 (mean 24 ± 5.5, median 10) months. Indications for surgery were exophthalmos, pain, tumor progression, or a combination. Eight patients underwent an extradural trans-orbital-roof approach to resect the intra-orbital tumor, including the optic canal part plus intradural pre-chiasmatic resection. Gross total resection was achieved in 7/8, and none had a recurrence. One residual behind the bulbus showed progression, treated by chemotherapy. In two patients, a combined supra-orbital mini-craniotomy plus orbital frame osteotomy was used for intraorbital tumor resection + intradural pre-chiasmatic dissection. In these two patients, remnants of the optic nerve within the optic canal remained stable. No patient had a chiasmatic functional affection nor permanent oculomotor deficits. In selected patients, a surgical resection from bulb to chiasm ± removal of optic canal tumor was safe without long-term sequela and with an excellent cosmetic result. Surgery normalizes exophthalmos and provides an effective tumor control.
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Atypical teratoid/rhabdoid tumors (AT/RT) are aggressive embryonal tumors having a poor prognosis and are associated with mutations in the tumor suppressor gene hSNF5/SMARCB1/INI1. Differential diagnosis includes choroid plexus carcinoma which has occasionally been attributed as showing an inactivation of INI1/SMARCB1 nuclear staining in immunohistochemistry. However, these findings have been challenged by others. We therefore examined eight AT/RTs from six patients by immunohistochemistry for membranous expression of the inward rectifier potassium channel Kir7.1, which was in the central nervous system so far considered specific for choroid plexus tumors and normal choroid plexus epithelium. Two AT/RT cases exhibited membranous staining of Kir7.1, indicating a plexus epithelial differentiation of these tumors. The implications of these results on tumor diagnosis are discussed.
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Neoplasias do Plexo Corióideo/patologia , Tumor Rabdoide/patologia , Teratoma/patologia , Adolescente , Criança , Pré-Escolar , Neoplasias do Plexo Corióideo/química , Neoplasias do Plexo Corióideo/metabolismo , Feminino , Humanos , Lactente , Masculino , Canais de Potássio Corretores do Fluxo de Internalização/biossíntese , Tumor Rabdoide/química , Tumor Rabdoide/metabolismo , Teratoma/química , Teratoma/metabolismoRESUMO
Scedosporium (S.) apiospermum is a typical mold causing cerebral abscesses, often after near-drowning. Infections are associated with high morbidity and mortality due to diagnostic challenges including the need for prolonged incubation of cultures. In addition, histopathological differentiation from other filamentous fungi, including Aspergillus fumigatus, may not be possible, excluding early specific diagnosis and targeted therapy. Polymerase chain reaction (PCR) on tissue samples can rapidly identify fungi, leading to an earlier adequate treatment. Due to an extensive spectrum of causative fungi, broad-range PCRs with amplicon sequencing have been endorsed as the best DNA amplification strategy. We herein describe a case with brain abscesses due to S. apiospermum in a 66-year-old immunocompromised female patient. While broad-range PCR failed to identify a fungal pathogen from a cerebral biopsy demonstrating hyaline mold hyphae, specific quantitative PCR (qPCR) identified Scedosporium and ruled out Aspergillus, the most prevalent agent of central nervous system mold infection. A panel of specific qPCR assays, guided by the morphology of fungal elements in tissue or as a multiplex assay, may be a successful molecular approach to identify fungal agents of brain abscesses. This also applies in the presence of negative broad-range fungal PCR, therefore providing diagnostic and therapeutic potential for early specific management and improvement of patient clinical outcome.
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Antígenos de Superfície/metabolismo , Fluordesoxiglucose F18/farmacocinética , Glioblastoma/diagnóstico por imagem , Glutamato Carboxipeptidase II/metabolismo , Compostos Radiofarmacêuticos/farmacocinética , Doença de Hodgkin/diagnóstico por imagem , Humanos , Tomografia por Emissão de Pósitrons , Distribuição TecidualRESUMO
PURPOSE: Seeding of craniopharyngioma has been rarely reported. We present three cases that ectopically recurred with seeding along the surgical route and CSF spaces. METHODS: The first patient was a 13-year-old boy who had initially undergone radical excision of a suprasellar and retrosellar craniopharyngioma by a right pterional approach. Postoperative MRI showed no evidence of residual tumor. Two years later, MRI revealed a local recurrence and in addition a separated cystic tumor on the right side adjacent to the middle cerebral artery consistent with seeding along the surgical route. Both tumors were removed by re-operation. On histopathological examination, both, the local recurrent tumor and the distant deposit turned out to be adamantinomatous craniopharyngiomas. The second patient was a 27-year-old woman who was operated on for the first time via a right pterional and 1 year later for a recurrent craniopharyngioma via a transsphenoidal approach. Two years later, MRI revealed a right fronto-lateral intracranial metastasis at the site of the former craniotomy, which was removed by re-craniotomy. This deposit in the operative pathway was found to be an adamantinomatous craniopharyngioma, as was the initial tumor. The third patient was a 42-year-old man who was operated on 10 years ago for the first time via a right fronto-temporal approach. The recent control MRT revealed a right parietal intracranial tumor with peripheral contrast enhancement, which was located distant to the former craniotomy. The tumor was removed and histopathological examination revealed an adamantinomatous craniopharyngioma in accordance with the initial tumor. Postoperatively, the three patients were neurologically intact. CONCLUSION: Although craniopharyngiomas exhibit a benign histopathological pattern, cerebrospinal fluid seeding along the surgical route or along the CSF pathways has been observed. Ectopic recurrence of craniopharyngioma suggests that meticulous protection of the whole surgical field and careful handling of the tumor during the operation are required. It should be emphasized that long-term follow-up is mandatory, even in patients undergoing a total removal.