RESUMO
The "isomorphic subtype of diffuse astrocytoma" was identified histologically in 2004 as a supratentorial, highly differentiated glioma with low cellularity, low proliferation and focal diffuse brain infiltration. Patients typically had seizures since childhood and all were operated on as adults. To define the position of these lesions among brain tumours, we histologically, molecularly and clinically analysed 26 histologically prototypical isomorphic diffuse gliomas. Immunohistochemically, they were GFAP-positive, MAP2-, OLIG2- and CD34-negative, nuclear ATRX-expression was retained and proliferation was low. All 24 cases sequenced were IDH-wildtype. In cluster analyses of DNA methylation data, isomorphic diffuse gliomas formed a group clearly distinct from other glial/glio-neuronal brain tumours and normal hemispheric tissue, most closely related to paediatric MYB/MYBL1-altered diffuse astrocytomas and angiocentric gliomas. Half of the isomorphic diffuse gliomas had copy number alterations of MYBL1 or MYB (13/25, 52%). Gene fusions of MYBL1 or MYB with various gene partners were identified in 11/22 (50%) and were associated with an increased RNA-expression of the respective MYB-family gene. Integrating copy number alterations and available RNA sequencing data, 20/26 (77%) of isomorphic diffuse gliomas demonstrated MYBL1 (54%) or MYB (23%) alterations. Clinically, 89% of patients were seizure-free after surgery and all had a good outcome. In summary, we here define a distinct benign tumour class belonging to the family of MYB/MYBL1-altered gliomas. Isomorphic diffuse glioma occurs both in children and adults, has a concise morphology, frequent MYBL1 and MYB alterations and a specific DNA methylation profile. As an exclusively histological diagnosis may be very challenging and as paediatric MYB/MYBL1-altered diffuse astrocytomas may have the same gene fusions, we consider DNA methylation profiling very helpful for their identification.
Assuntos
Neoplasias Encefálicas/genética , Glioma/genética , Proteínas Proto-Oncogênicas c-myb/genética , Proteínas Proto-Oncogênicas/genética , Transativadores/genética , Adulto , Neoplasias Encefálicas/patologia , Criança , Pré-Escolar , Variações do Número de Cópias de DNA , Metilação de DNA , Feminino , Glioma/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Fusão Oncogênica , Adulto JovemRESUMO
BACKGROUND: The spatial distribution and colocalization of functionally related metabolites is analysed in order to investigate the spatial (and functional) aspects of molecular networks. We propose to consider community detection for the analysis of m/z-images to group molecules with correlative spatial distribution into communities so they hint at functional networks or pathway activity. To detect communities, we investigate a spectral approach by optimizing the modularity measure. We present an analysis pipeline and an online interactive visualization tool to facilitate explorative analysis of the results. The approach is illustrated with synthetical benchmark data and two real world data sets (barley seed and glioblastoma section). RESULTS: For the barley sample data set, our approach is able to reproduce the findings of a previous work that identified groups of molecules with distributions that correlate with anatomical structures of the barley seed. The analysis of glioblastoma section data revealed that some molecular compositions are locally focused, indicating the existence of a meaningful separation in at least two areas. This result is in line with the prior histological knowledge. In addition to confirming prior findings, the resulting graph structures revealed new subcommunities of m/z-images (i.e. metabolites) with more detailed distribution patterns. Another result of our work is the development of an interactive webtool called GRINE (Analysis of GRaph mapped Image Data NEtworks). CONCLUSIONS: The proposed method was successfully applied to identify molecular communities of laterally co-localized molecules. For both application examples, the detected communities showed inherent substructures that could easily be investigated with the proposed visualization tool. This shows the potential of this approach as a complementary addition to pixel clustering methods.
Assuntos
Visualização de Dados , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz/métodos , Neoplasias Encefálicas/patologia , Análise por Conglomerados , Glioblastoma/patologia , Hordeum , Humanos , Análise de Componente Principal , Sementes/anatomia & histologia , Sementes/químicaRESUMO
Tumors with histological features of pilocytic astrocytoma (PA), but with increased mitotic activity and additional high-grade features (particularly microvascular proliferation and palisading necrosis) have often been designated anaplastic pilocytic astrocytomas. The status of these tumors as a separate entity has not yet been conclusively demonstrated and molecular features have only been partially characterized. We performed DNA methylation profiling of 102 histologically defined anaplastic pilocytic astrocytomas. T-distributed stochastic neighbor-embedding (t-SNE) and hierarchical clustering analysis of these 102 cases against 158 reference cases from 12 glioma reference classes revealed that a subset of 83 of these tumors share a common DNA methylation profile that is distinct from the reference classes. These 83 tumors were thus denominated DNA methylation class anaplastic astrocytoma with piloid features (MC AAP). The 19 remaining tumors were distributed amongst the reference classes, with additional testing confirming the molecular diagnosis in most cases. Median age of patients with MC AAP was 41.5 years. The most frequent localization was the posterior fossa (74%). Deletions of CDKN2A/B (66/83, 80%), MAPK pathway gene alterations (49/65, 75%, most frequently affecting NF1, followed by BRAF and FGFR1) and mutations of ATRX or loss of ATRX expression (33/74, 45%) were the most common molecular alterations. All tumors were IDH1/2 wildtype. The MGMT promoter was methylated in 38/83 tumors (45%). Outcome analysis confirmed an unfavorable clinical course in comparison to PA, but better than IDH wildtype glioblastoma. In conclusion, we show that a subset of histologically defined anaplastic pilocytic astrocytomas forms a separate DNA methylation cluster, harbors recurrent alterations in MAPK pathway genes in combination with alterations of CDKN2A/B and ATRX, affects patients who are on average older than those diagnosed with PA and has an intermediate clinical outcome.
Assuntos
Astrocitoma/genética , Neoplasias Encefálicas/genética , Isocitrato Desidrogenase/genética , Transdução de Sinais/genética , Adolescente , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Inibidor p16 de Quinase Dependente de Ciclina/genética , Metilação de DNA/genética , Metilases de Modificação do DNA/metabolismo , Enzimas Reparadoras do DNA/metabolismo , Feminino , Histonas/genética , Histonas/metabolismo , Humanos , Lactente , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Quinases de Proteína Quinase Ativadas por Mitógeno/genética , Mutação/genética , Estudos Retrospectivos , Proteínas Supressoras de Tumor/metabolismo , Proteína Nuclear Ligada ao X/genética , Adulto JovemRESUMO
The definition of minimal standards remains pivotal as a basis for a high standard of care and as a basis for staff allocation or reimbursement. Only limited publications are available regarding the required staffing or methodologic expertise in epilepsy centers. The executive board of the working group (WG) on presurgical epilepsy diagnosis and operative epilepsy treatment published the first guidelines in 2000 for Austria, Germany, and Switzerland. In 2014, revised guidelines were published and the WG decided to publish an unaltered English translation in this report. Because epilepsy surgery is an elective procedure, quality standards are particularly high. As detailed in the first edition of these guidelines, quality control relates to seven different domains: (1) establishing centers with a sufficient number of sufficiently and specifically trained personnel, (2) minimum technical standards and equipment, (3) continuous medical education of employees, (4) surveillance by trained personnel during video electroencephalography (EEG) monitoring (VEM), (5) systematic acquisition of clinical and outcome data, (6) the minimum number of preoperative evaluations and epilepsy surgery procedures, and (7) the cooperation of epilepsy centers. These standards required the certification of the different professions involved and minimum numbers of procedures. In the subsequent decade, quite a number of colleagues were certified by the trinational WG; therefore, the executive board of the WG decided in 2013 to make these standards obligatory. This revised version is particularly relevant given that the German procedure classification explicitly refers to the guidelines of the WG with regard to noninvasive/invasive preoperative video-EEG monitoring and invasive intraoperative diagnostics in epilepsy.
Assuntos
Epilepsia/diagnóstico , Epilepsia/cirurgia , Procedimentos Neurocirúrgicos/normas , Guias de Prática Clínica como Assunto , Cuidados Pré-Operatórios/normas , Áustria , Eletroencefalografia , Alemanha , Humanos , Monitorização Intraoperatória/normas , SuíçaRESUMO
In a strategy to identify novel genes involved in glioma pathogenesis by molecular characterization of chromosomal translocation breakpoints, we identified the KIAA1797 gene, encoding a protein with an as yet undefined function, to be disrupted by a 7;9 translocation in a primary glioblastoma culture. Array-based comparative genomic hybridization detected deletions involving KIAA1797 in around half of glioblastoma cell lines and glioblastomas investigated. Quantification of messenger RNA levels in human tissues demonstrated highest KIAA1797 expression in brain, reduced levels in all glioblastoma cell lines and most glioblastomas and similar levels in glial and neuronal cells by analysis of different hippocampal regions from murine brain. Antibodies against KIAA1797 were generated and showed similar protein levels in cortex and subcortical white matter of human brain, while levels were significantly reduced in glioblastomas with KIAA1797 deletion. By immunofluorescence of astrocytoma cells, KIAA1797 co-localized with vinculin in focal adhesions. Physical interaction between KIAA1797 and vinculin was demonstrated via co-immunoprecipitation. Functional in vitro assays demonstrated a significant decrease in colony formation, migration and invasion capacity of LN18 and U87MG glioma cells carrying a homozygous KIAA1797 deletion ectopically expressing KIAA1797 compared with mock-transduced cells. In an in vivo orthotopic xenograft mouse model, U87MG tumour lesions expressing KIAA1797 had a significantly reduced volume compared to tumours not expressing KIAA1797. In summary, the frequently deleted KIAA1797 gene encodes a novel focal adhesion complex protein with tumour suppressor function in gliomas, which we name 'focadhesin'. Since KIAA1797 genetic variation has been implicated in Alzheimer's disease, our data are also relevant for neurodegeneration.
Assuntos
Neoplasias Encefálicas/genética , Adesões Focais/genética , Regulação Neoplásica da Expressão Gênica/fisiologia , Genes Supressores de Tumor/fisiologia , Glioblastoma/genética , Animais , Animais Recém-Nascidos , Encéfalo/metabolismo , Linhagem Celular Tumoral , Movimento Celular/genética , Hibridização Genômica Comparativa , Inibidor de Quinase Dependente de Ciclina p15/metabolismo , Inibidor p16 de Quinase Dependente de Ciclina/metabolismo , Modelos Animais de Doenças , Feminino , Adesões Focais/imunologia , Adesões Focais/metabolismo , Gadolínio , Regulação Neoplásica da Expressão Gênica/genética , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Humanos , Imunoprecipitação , Técnicas In Vitro , Imageamento por Ressonância Magnética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Nus , Neuroglia/metabolismo , Neurônios/metabolismo , RNA Mensageiro/metabolismo , Transfecção , Ensaio Tumoral de Célula-Tronco/métodos , Proteínas Supressoras de Tumor/genética , Proteínas Supressoras de Tumor/metabolismo , Vinculina/metabolismo , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Cerebral 3α-hydroxysteroid dehydrogenase (3α-HSD) activity was suggested to be responsible for the local directed formation of neuroactive 5α,3α-tetrahydrosteroids (5α,3α-THSs) from 5α-dihydrosteroids. We show for the first time that within human brain tissue 5α-dihydroprogesterone and 5α-dihydrotestosterone are converted via non-stereo-selective 3-ketosteroid reductase activity to produce the respective 5α,3α-THSs and 5α,3ß-THSs. Apart from this, we prove that within the human temporal lobe and limbic system cytochrome P450c17 and 3ß-HSD/Δ(5-4) ketosteroid isomerase are not expressed. Thus, it appears that these brain regions are unable to conduct de novo biosynthesis of Δ(4)-3-ketosteroids from Δ(5)-3ß-hydroxysteroids. Consequently, the local formation of THSs will depend on the uptake of circulating Δ(4)-3-ketosteroids such as progesterone and testosterone. 3α- and 3ß-HSD activity were (i) equally enriched in the cytosol, (ii) showed equal distribution between cerebral neocortex and subcortical white matter without sex- or age-dependency, (iii) demonstrated a strong and significant positive correlation when comparing 46 different specimens and (iv) exhibited similar sensitivities to different inhibitors of enzyme activity. These findings led to the assumption that cerebral 3-ketosteroid reductase activity might be catalyzed by a single enzyme and is possibly attributed to the expression of a soluble AKR1C aldo-keto reductase. AKR1Cs are known to act as non-stereo-selective 3-ketosteroid reductases; low AKR1C mRNA expression was detected. However, the cerebral 3-ketosteroid reductase was clearly refractory to inhibition by AKR1C inhibitors indicating the expression of a currently unidentified enzyme. Its lack of stereo-selectivity is of physiological significance, since only 5α,3α-THSs enhance the effect of GABA on the GABA(A) receptor, whereas 5α,3ß-THSs are antagonists.
Assuntos
20-Hidroxiesteroide Desidrogenases/genética , Encéfalo/metabolismo , Regulação Enzimológica da Expressão Gênica , 20-Hidroxiesteroide Desidrogenases/antagonistas & inibidores , 3-Hidroxiesteroide Desidrogenases/metabolismo , Adulto , Idoso , Encéfalo/patologia , Linhagem Celular Tumoral , Cromatografia em Camada Fina/métodos , Feminino , Cromatografia Gasosa-Espectrometria de Massas/métodos , Humanos , Lactente , Pessoa de Meia-Idade , Esteroide 17-alfa-Hidroxilase/genética , Esteroides/química , Lobo Temporal/patologiaAssuntos
Encéfalo/fisiologia , alfa Carioferinas/metabolismo , Animais , Encéfalo/crescimento & desenvolvimento , Diferenciação Celular , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Células de Purkinje/citologia , Células de Purkinje/metabolismo , Células Piramidais/citologia , Células Piramidais/metabolismo , Medula Espinal/crescimento & desenvolvimento , Medula Espinal/fisiologia , alfa Carioferinas/genéticaRESUMO
We report the clinical presentation, neuroradiologic characteristics, and detailed histopathologic findings in a unique case of drug-resistant focal epilepsy due to sublobar dysplasia (SLD), treated successfully by resection of the malformed cortex. Histopathology with leptomeningeal and subcortical heterotopia, disturbance of cortical lamination and marked cortical and subcortical astrocytosis, but absence of balloon cells, points to a disorder of neuronal migration and organization rather than proliferation in SLD. The additional presence of a lateral proboscis and meningocele in our case as well as further associated callosal and cerebellar anomalies may suggest an etiologic unknown damage of pathways controlling the embryogenesis of craniofacial field processes.
Assuntos
Epilepsia/patologia , Epilepsia/cirurgia , Malformações do Desenvolvimento Cortical/patologia , Malformações do Desenvolvimento Cortical/cirurgia , Córtex Cerebral/anormalidades , Córtex Cerebral/cirurgia , Epilepsias Parciais/patologia , Epilepsias Parciais/cirurgia , Humanos , Procedimentos NeurocirúrgicosRESUMO
Ependymoma with YAP1-MAMLD1 fusion is a rare, recently described supratentorial neoplasm of childhood, with few cases published so far. We report on 15 pediatric patients with ependymomas carrying YAP1-MAMLD1 fusions, with their characteristic histopathology, immunophenotype and molecular/cytogenetic, radiological and clinical features. The YAP1-MAMLD1 fusion was documented by RT-PCR/Sanger sequencing, and tumor genomes were studied by molecular inversion probe (MIP) analysis. Significant copy number alterations were identified by GISTIC (Genomic Identification of Significant Targets in Cancer) analysis. All cases showed similar histopathological features including areas of high cellularity, presence of perivascular pseudo-rosettes, small to medium-sized nuclei with characteristic granular chromatin and strikingly abundant cells with dot-like cytoplasmic expression of epithelial membrane antigen. Eleven cases presented features of anaplasia, corresponding to WHO grade III. MRI showed large supratentorial multinodular tumors with cystic components, heterogeneous contrast enhancement, located in the ventricular or periventricular region. One of two variants of YAP1-MAMLD1 fusions was detected in all cases. The MIP genome profiles showed balanced profiles, with focal alterations of the YAP1 locus at 11q22.1-11q21.2 (7/14), MAMLD1 locus (Xp28) (10/14) and losses of chromosome arm 22q (5/14). Most patients were female (13/15) and younger than 3 years at diagnosis (12/15; median age, 8.2 months). Apart from one patient who died during surgery, all patients are alive without evidence of disease progression after receiving different treatment protocols, three without postoperative further treatment (median follow-up, 4.84 years). In this to date, largest series of ependymomas with YAP1-MAMLD1 fusions we show that they harbor characteristic histopathological, cytogenetic and imaging features, occur mostly in young girls under 3 years and are associated with good outcome. Therefore, this genetically defined neoplasm should be considered a distinct disease entity. The diagnosis should be confirmed by demonstration of the specific fusion. Further studies on large collaborative series are warranted to confirm our findings.
Assuntos
Ependimoma/genética , Ependimoma/patologia , Neoplasias Supratentoriais/patologia , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Criança , Pré-Escolar , Variações do Número de Cópias de DNA/genética , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Feminino , Humanos , Lactente , Masculino , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Fosfoproteínas/genética , Fosfoproteínas/metabolismo , Estudos Retrospectivos , Neoplasias Supratentoriais/genética , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Proteínas de Sinalização YAPRESUMO
In this multi-institutional study we compiled a retrospective cohort of 86 posterior fossa tumors having received the diagnosis of cerebellar glioblastoma (cGBM). All tumors were reviewed histologically and subjected to array-based methylation analysis followed by algorithm-based classification into distinct methylation classes (MCs). The single MC containing the largest proportion of 25 tumors diagnosed as cGBM was MC anaplastic astrocytoma with piloid features representing a recently-described molecular tumor entity not yet included in the WHO Classification of Tumours of the Central Nervous System (WHO classification). Twenty-nine tumors molecularly corresponded to either of 6 methylation subclasses subsumed in the MC family GBM IDH wildtype. Further we identified 6 tumors belonging to the MC diffuse midline glioma H3 K27 M mutant and 6 tumors allotted to the MC IDH mutant glioma subclass astrocytoma. Two tumors were classified as MC pilocytic astrocytoma of the posterior fossa, one as MC CNS high grade neuroepithelial tumor with BCOR alteration and one as MC control tissue, inflammatory tumor microenvironment. The methylation profiles of 16 tumors could not clearly be assigned to one distinct MC. In comparison to supratentorial localization, the MC GBM IDH wildtype subclass midline was overrepresented, whereas the MCs GBM IDH wildtype subclass mesenchymal and subclass RTK II were underrepresented in the cerebellum. Based on the integration of molecular and histological findings all tumors received an integrated diagnosis in line with the WHO classification 2016. In conclusion, cGBM does not represent a molecularly uniform tumor entity, but rather comprises different brain tumor entities with diverse prognosis and therapeutic options. Distinction of these molecular tumor classes requires molecular analysis. More than 30% of tumors diagnosed as cGBM belong to the recently described molecular entity of anaplastic astrocytoma with piloid features.
Assuntos
Neoplasias Cerebelares/diagnóstico , Neoplasias Cerebelares/metabolismo , Glioblastoma/diagnóstico , Glioblastoma/metabolismo , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias Cerebelares/patologia , Criança , Pré-Escolar , Inibidor p16 de Quinase Dependente de Ciclina/metabolismo , Receptores ErbB/metabolismo , Feminino , Glioblastoma/patologia , Humanos , Lactente , Recém-Nascido , Neoplasias Infratentoriais/diagnóstico , Neoplasias Infratentoriais/metabolismo , Neoplasias Infratentoriais/patologia , Masculino , Metilação , Pessoa de Meia-Idade , Estudos Retrospectivos , Telomerase/metabolismo , Adulto JovemRESUMO
Coenzyme Q10 (CoQ10) deficiency is an autosomal recessive disorder with heterogenous phenotypic manifestations and genetic background. We describe seven patients from five independent families with an isolated myopathic phenotype of CoQ10 deficiency. The clinical, histological and biochemical presentation of our patients was very homogenous. All patients presented with exercise intolerance, fatigue, proximal myopathy and high serum CK. Muscle histology showed lipid accumulation and subtle signs of mitochondrial myopathy. Biochemical measurement of muscle homogenates showed severely decreased activities of respiratory chain complexes I and II + III, while complex IV (COX) was moderately decreased. CoQ10 was significantly decreased in the skeletal muscle of all patients. Tandem mass spectrometry detected multiple acyl-CoA deficiency, leading to the analysis of the electron-transferring-flavoprotein dehydrogenase (ETFDH) gene, previously shown to result in another metabolic disorder, glutaric aciduria type II (GAII). All of our patients carried autosomal recessive mutations in ETFDH, suggesting that ETFDH deficiency leads to a secondary CoQ10 deficiency. Our results indicate that the late-onset form of GAII and the myopathic form of CoQ10 deficiency are allelic diseases. Since this condition is treatable, correct diagnosis is of the utmost importance and should be considered both in children and in adults. We suggest to give patients both CoQ10 and riboflavin supplementation, especially for long-term treatment.
Assuntos
Flavoproteínas Transferidoras de Elétrons/genética , Proteínas Ferro-Enxofre/genética , Doenças Musculares/genética , Mutação , Oxirredutases atuantes sobre Doadores de Grupo CH-NH/genética , Ubiquinona/análogos & derivados , Adolescente , Adulto , Biópsia , Criança , Coenzimas/deficiência , Coenzimas/uso terapêutico , Feminino , Seguimentos , Humanos , Masculino , Músculo Esquelético/enzimologia , Músculo Esquelético/patologia , Doenças Musculares/tratamento farmacológico , Doenças Musculares/enzimologia , Riboflavina/uso terapêutico , Ubiquinona/deficiência , Ubiquinona/uso terapêuticoRESUMO
Background: The novel entity of "diffuse midline glioma, H3 K27M-mutant" has been defined in the 2016 revision of the World Health Organization (WHO) classification of tumors of the central nervous system (CNS). Tumors of this entity arise in CNS midline structures of predominantly pediatric patients and are associated with an overall dismal prognosis. They are defined by K27M mutations in H3F3A or HIST1H3B/C, encoding for histone 3 variants H3.3 and H3.1, respectively, which are considered hallmark events driving gliomagenesis. Methods: Here, we characterized 85 centrally reviewed diffuse gliomas on midline locations enrolled in the nationwide pediatric German HIT-HGG registry regarding tumor site, histone 3 mutational status, WHO grade, age, sex, and extent of tumor resection. Results: We found 56 H3.3 K27M-mutant tumors (66%), 6 H3.1 K27M-mutant tumors (7%), and 23 H3-wildtype tumors (27%). H3 K27M-mutant gliomas shared an aggressive clinical course independent of their anatomic location. Multivariate regression analysis confirmed the significant impact of the H3 K27M mutation as the only independent parameter predictive of overall survival (P = 0.009). In H3 K27M-mutant tumors, neither anatomic midline location nor histopathological grading nor extent of tumor resection had an influence on survival. Conclusion: These results substantiate the clinical significance of considering diffuse midline glioma, H3 K27M-mutant, as a distinct entity corresponding to WHO grade IV, carrying a universally fatal prognosis.
Assuntos
Neoplasias Encefálicas/genética , Glioma/genética , Histonas/genética , Mutação/genética , Adolescente , Neoplasias Encefálicas/diagnóstico , Neoplasias Encefálicas/patologia , Criança , Feminino , Glioma/diagnóstico , Glioma/patologia , Humanos , Masculino , Gradação de Tumores , PrognósticoRESUMO
Angiocentric glioma has recently been described as a novel epilepsy associated tumor with distinct clinico-pathologic features. We report the clinical and pathologic findings in 8 additional cases of this rare tumor type and extend its characterization by genomic profiling. Almost all patients had a history of long-standing drug-resistant epilepsy. Cortico-subcortical tumors were located in the temporal and parietal lobes. Seizures began at 3 to 14 years of age and surgery was performed at 6 to 70 years. Histologically, the tumors were characterized by diffuse growth and prominent perivascular tumor cell arrangements with features of astrocytic/ependymal differentiation, but lacking neoplastic neuronal features. Necrosis and vascular proliferation were not observed and mitoses were sparse or absent. MIB-1 proliferation indices ranged from <1% to 5%. Immunohistochemically, all cases stained positively for glial fibrillary acidic protein, vimentin, protein S100B, variably for podoplanin, and showed epithelial membrane antigen-positive cytoplasmic dots. Electron microscopy showed ependymal characteristics in 2 of 3 cases investigated. An analysis of genomic imbalances by chromosomal comparative genomic hybridization revealed loss of chromosomal bands 6q24 to q25 as the only alteration in 1 of 8 cases. In 1 of 3 cases, a high-resolution screen by array-comparative genomic hybridization identified a copy number gain of 2 adjacent clones from chromosomal band 11p11.2 containing the protein-tyrosine phosphatase receptor type J (PTPRJ) gene. All patients are seizure free and without evidence of tumor recurrence at follow-up times ranging from 1/2 to 6.9 years. Our findings support 2 previous reports proposing that angiocentric glioma is a novel glial tumor entity of low-grade malignancy.
Assuntos
Neoplasias Encefálicas/genética , Neoplasias Encefálicas/ultraestrutura , Epilepsia/genética , Regulação Neoplásica da Expressão Gênica , Glioma/genética , Glioma/ultraestrutura , Adolescente , Adulto , Idoso , Astrócitos/patologia , Neoplasias Encefálicas/química , Neoplasias Encefálicas/complicações , Neoplasias Encefálicas/cirurgia , Diferenciação Celular , Proliferação de Células , Criança , Pré-Escolar , Deleção Cromossômica , Cromossomos Humanos Par 11 , Cromossomos Humanos Par 6 , Epêndima/patologia , Epilepsia/patologia , Epilepsia/prevenção & controle , Europa (Continente) , Feminino , Seguimentos , Dosagem de Genes , Perfilação da Expressão Gênica/métodos , Proteína Glial Fibrilar Ácida/análise , Glioma/química , Glioma/complicações , Glioma/cirurgia , Humanos , Imageamento por Ressonância Magnética , Masculino , Glicoproteínas de Membrana/análise , Pessoa de Meia-Idade , Mucina-1/análise , Fatores de Crescimento Neural/análise , Hibridização de Ácido Nucleico , Análise de Sequência com Séries de Oligonucleotídeos , Proteínas Tirosina Fosfatases Classe 3 Semelhantes a Receptores/genética , Subunidade beta da Proteína Ligante de Cálcio S100 , Proteínas S100/análise , Fatores de Tempo , Resultado do Tratamento , Vimentina/análiseRESUMO
OBJECTIVE: Thunderclap headache and visual disturbances are typical clinical features of pituitary apoplexy (PA). Because of the acute symptomatology, many patients are referred to a neurosurgical department without prior endocrinological assessment. It is the aim of the present study to analyze initial presenting symptoms, outcome and associated endocrine disturbances in a cohort of patients with pituitary apoplexy primarily seen by neurosurgeons. PATIENTS AND METHODS: Retrospective single-center study in a neurosurgical department. Patients' records were reviewed for clinical, neuropathological and endocrinological findings. The diagnosis of PA was based on clinical, imaging and histological findings. RESULTS: A total of 60 patients were studied. They were referred most often by neurologists (n=16), and family physicians (n=12). Only 2 patients received an endocrinological work-up prior to admission. The most frequently documented presenting symptoms were headache (n=54), visual field defects (n=13), reduction of visual acuity (n=17) and/or diplopia (n=19). An endocrinological history had rarely been taken and hormone blood tests were oftentimes incomplete or not ordered. At 3-month follow-up 18/44 patients had complete anterior hypopituitarism. At 12 months, 21/60 patients were lost to endocrinological follow-up. CONCLUSIONS: The classic neurological symptoms of PA were well documented in our patient cohort, whereas endocrinological symptoms, especially those indicative of pituitary dysfunction were underreported. Neurologists and neurosurgeons need to be aware of the endocrinological sequelae of pituitary apoplexy in order to avoid potentially lethal complications. Patients should be counselled to adhere to long-term endocrinological and neurosurgical follow-up.
Assuntos
Cefaleia/cirurgia , Neurocirurgiões , Apoplexia Hipofisária/cirurgia , Neoplasias Hipofisárias/cirurgia , Progressão da Doença , Cefaleia/complicações , Humanos , Apoplexia Hipofisária/diagnóstico , Neoplasias Hipofisárias/diagnóstico , Resultado do TratamentoRESUMO
Onconeural antibodies are associated with cancer and paraneoplastic encephalitis. While their pathogenic role is still largely unknown, their high diagnostic value is undisputed. In this study we describe the discovery of a novel target of autoimmunity in an index case of paraneoplastic encephalitis associated with urogenital cancer.A 75-year-old man with a history of invasive bladder carcinoma 6 years ago with multiple recurrences and a newly discovered renal cell carcinoma presented with seizures and progressive cognitive decline followed by super-refractory status epilepticus. Clinical and ancillary findings including brain biopsy suggested paraneoplastic encephalitis. Immunohistochemistry of the brain biopsy was used to characterize the inflammatory response. Indirect immunofluorescence assay (IFA) was used for autoantibody screening. The autoantigen was identified by histo-immunoprecipitation and mass spectrometry and was validated by expressing the recombinant antigen in HEK293 cells and neutralization tests. Sera from 125 control patients were screened using IFA to test for the novel autoantibodies.IFA analysis of serum revealed a novel autoantibody against brain tissue. An intracellular enzyme, Rho-associated protein kinase 2 (ROCK2), was identified as target-antigen. ROCK2 was expressed in affected brain tissue and archival bladder tumor samples of this patient. Brain histopathology revealed appositions of cytotoxic CD8+ T cells on ROCK2-positive neurons. ROCK2 antibodies were not found in the sera of 20 patients with bladder cancer and 17 with renal cancer, both without neurological symptoms, 49 healthy controls, and 39 patients with other antineuronal autoantibodies. In conclusion, novel onconeural antibodies targeting ROCK2 are associated with paraneoplastic encephalitis and should be screened for when paraneoplastic neurological syndromes, especially in patients with urogenital cancers, occur.
Assuntos
Autoanticorpos/imunologia , Doenças Autoimunes do Sistema Nervoso/enzimologia , Encefalite/enzimologia , Encefalite/imunologia , Síndromes Paraneoplásicas do Sistema Nervoso/enzimologia , Síndromes Paraneoplásicas do Sistema Nervoso/imunologia , Quinases Associadas a rho/imunologia , Idoso , Autoanticorpos/sangue , Doenças Autoimunes do Sistema Nervoso/imunologia , Autoimunidade , Encéfalo/enzimologia , Encéfalo/imunologia , Carcinoma/imunologia , Células HEK293 , Humanos , Neoplasias Renais/imunologia , Masculino , Neoplasias da Bexiga Urinária/imunologiaRESUMO
The prognostic significance of atypical histologic features in choroid plexus tumors remains uncertain. Therefore, a series of 164 choroid plexus tumors was evaluated for the presence of atypical histologic features, including mitotic activity, increased cellularity, nuclear pleomorphism, blurring of papillary growth pattern, and necrosis. The impact of histopathologic and clinical features on the probability of recurrence and survival was investigated. Twenty-four tumors displaying frank signs of malignancy were diagnosed as choroid plexus carcinoma according to World Health Organization criteria. Of 124 choroid plexus papillomas that had not received adjuvant treatment, 46 tumors (37%) displayed at least one atypical feature, including increased cellularity (n = 25 [20%]), mitotic activity (> or =2 mitoses per 10 high-power fields; n = 19 [15%]), nuclear pleomorphism (n = 16 [13%]), solid growth (n = 15 [12%]), and necrosis (n = 5 [4%]). Only one tumor-related death, but 10 recurrences, were observed on a mean observation time of 58 months. On univariate analysis, incomplete surgical resection (p = 0.03) and mitotic activity (p < 0.001) were the only clinicopathologic factors associated with recurrence. Using a multivariate model, an independent effect of mitotic activity on the probability of recurrence could be confirmed (p = 0.001). Because mitotic activity is the sole atypical histologic feature independently associated with recurrence, we propose to define atypical choroid plexus papilloma by mitotic activity (> or =2 mitoses per 10 high-power fields) corresponding to World Health Organization grade II, thus adjoining other intermediate tumor entities associated with increased mitotic activity such as atypical meningioma. Close follow up of patients harboring atypical choroid plexus papillomas may be warranted.
Assuntos
Papiloma do Plexo Corióideo/classificação , Papiloma do Plexo Corióideo/patologia , Adulto , Criança , Pré-Escolar , Intervalo Livre de Doença , Feminino , História do Século XV , Humanos , Lactente , Masculino , Índice Mitótico , Necrose/patologia , Recidiva Local de Neoplasia/patologia , Papiloma do Plexo Corióideo/cirurgia , Prognóstico , Análise de Sobrevida , Organização Mundial da SaúdeAssuntos
Cromossomos Humanos Par 19/genética , Tumores Neuroectodérmicos Primitivos/genética , Tumor Rabdoide/genética , Teratoma/genética , Neoplasias Encefálicas , Feminino , Humanos , Lactente , Proteínas do Tecido Nervoso/metabolismo , Tumores Neuroectodérmicos Primitivos/complicações , Tumor Rabdoide/complicações , Teratoma/complicaçõesRESUMO
The original version of this article unfortunately contained a mistake in the author list. The name of one co-author is written wrong in the final version of the article; Dr Hans Ulrich Knappe should be Ulrich Johannes Knappe. The updated author list is provided below: Christian P. Miermeister, Stephan Petersenn, Michael Buchfelder, Rudolf Fahlbusch, Dieter K.Lüdecke, Annett Hölsken, Markus Bergmann, Ulrich Johannes Knappe, Volkmar H. Hans, Jörg Flitsch, Wolfgang Saeger and Rolf Buslei.
RESUMO
INTRODUCTION: The term atypical pituitary adenoma (APA) was revised in the 2004 World Health Organization (WHO) classification of pituitary tumors. However, two of the four parameters required for the diagnosis of APAs were formulated rather vaguely (i.e., "extensive" nuclear staining for p53; "elevated" mitotic index). Based on a case-control study using a representative cohort of typical pituitary adenomas and APAs selected from the German Pituitary Tumor Registry, we aimed to obtain reliable cut-off values for both p53 and the mitotic index. In addition, we analyzed the impact of all four individual parameters (invasiveness, Ki67-index, p53, mitotic index) on the selectivity for differentiating both adenoma subtypes. METHODS: Of the 308 patients included in the study, 98 were diagnosed as APAs (incidence 2.9 %) and 10 patients suffered from a pituitary carcinoma (incidence 0.2 %). As a control group, we selected 200 group matched patients with typical pituitary adenomas (TPAs). Cut-off values were attained using ROC analysis. RESULTS: We determined significant threshold values for p53 (≥2 %; AUC: 0.94) and the mitotic index (≥2 mitosis within 10 high power fields; AUC: 0.89). The most reliable individual marker for differentiating TPAs and APAs was a Ki-67-labeling index ≥ 4 % (AUC: 0.98). Using logistic regression analysis (LRA) we were able to show that all four criteria (Ki-67 (p < 0.001); OR 5.2// p53 (p < 0.001); OR 3.1// mitotic index (p < 0.001); OR 2.1// invasiveness (p < 0.001); OR 8.2)) were significant for the group of APAs. Furthermore, we describe the presence of nucleoli as a new favorable parameter for TPAs (p = 0.008; OR: 0.4; CI95 %: 0.18; 0.77). CONCLUSIONS: Here we present a proposed rectification of the current WHO classification of pituitary tumors describing an additional marker for TPA and specific threshold values for p53 and the mitotic index. This will greatly help in the reliable diagnosis of APAs and facilitate further studies to ascertain the prognostic relevance of this categorization.
Assuntos
Adenoma/patologia , Neoplasias Hipofisárias/patologia , Sistema de Registros , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Alemanha , Humanos , Antígeno Ki-67/metabolismo , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Curva ROC , Sistema de Registros/estatística & dados numéricos , Estudos Retrospectivos , Proteína Supressora de Tumor p53/metabolismo , Adulto JovemRESUMO
An intrasellar lesion resembling a hormone-inactive pituitary adenoma was resected in a 59-year-old woman. The well-differentiated benign tumor was composed of ganglion-like cells, clusters of adenohypophyseal tissue as well as a GH-expressing adenoma. In addition, small cells exhibited an intermediate neuronal and epithelial immunoreactivity. Surrounding the tumor was a spindle cell component that histologically resembled Antoni A areas of a schwannoma, but showed a mixed immunohistochemical profile. Final diagnosis was intrasellar glioneuronal hamartoma with GH-cell pituitary adenoma.