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The American Journal of Pathology Jun 2023Because of their ability to infiltrate normal brain tissue, gliomas frequently evade microscopic surgical excision. The histologic infiltrative property of human glioma... (Review)
Review
Because of their ability to infiltrate normal brain tissue, gliomas frequently evade microscopic surgical excision. The histologic infiltrative property of human glioma has been previously characterized as Scherer secondary structures, of which the perivascular satellitosis is a prospective target for anti-angiogenic treatment in high-grade gliomas. However, the mechanisms underlying perineuronal satellitosis remain unclear, and therapy remains lacking. Our knowledge of the mechanism underlying Scherer secondary structures has improved over time. New techniques, such as laser capture microdissection and optogenetic stimulation, have advanced our understanding of glioma invasion mechanisms. Although laser capture microdissection is a useful tool for studying gliomas that infiltrate the normal brain microenvironment, optogenetics and mouse xenograft glioma models have been extensively used in studies demonstrating the unique role of synaptogenesis in glioma proliferation and identification of potential therapeutic targets. Moreover, a rare glioma cell line is established that, when transplanted in the mouse brain, can replicate and recapitulate the human diffuse invasion phenotype. This review discusses the primary molecular causes of glioma, its histopathology-based invasive mechanisms, and the importance of neuronal activity and interactions between glioma cells and neurons in the brain microenvironment. It also explores current methods and models of gliomas.
Topics: Humans; Mice; Animals; Brain Neoplasms; Glioma; Brain; Neurons; Cell Line; Disease Models, Animal; Neoplasm Invasiveness; Tumor Microenvironment
PubMed: 37286277
DOI: 10.1016/j.ajpath.2023.02.018 -
Brain Sciences Jan 2023The extent of resection beyond the enhancing core (EC) in glioblastoma IDH-wild type (GBM, IDHwt) is one of the most debated topics in neuro-oncology. Indeed, it has...
The extent of resection beyond the enhancing core (EC) in glioblastoma IDH-wild type (GBM, IDHwt) is one of the most debated topics in neuro-oncology. Indeed, it has been demonstrated that local disease recurrence often arises in peritumoral areas and that radiologically-defined FLAIR hyperintensity areas of GBM IDHwt are often visible beyond the conventional EC. Therefore, the need to extend the surgical resection also to the FLAIR hyperintensity areas is a matter of debate. Since little is known about the histological composition of FLAIR hyperintensity regions, in this study we aimed to provide a comprehensive description of the histological features of EC and FLAIR hyperintensity regions sampled intraoperatively using neuronavigation and 5-aminolevulinic acid (5-ALA) fluorescence, in 33 patients with GBM, IDHwt. Assessing a total 109 histological samples, we found that FLAIR areas consisted in: (i) fragments of white matter focally to diffusely infiltrated by tumor cells in 76% of cases; (ii) a mixture of white matter with reactive astrogliosis and grey matter with perineuronal satellitosis in 15% and (iii) tumor tissue in 9%. A deeper knowledge of the histology of FLAIR hyperintensity areas in GBM, IDH-wt may serve to better guide neurosurgeons on the choice of the most appropriate surgical approach in patients with this neoplasm.
PubMed: 36831791
DOI: 10.3390/brainsci13020248 -
Avian Pathology : Journal of the W.V.P.A Aug 2022Perineuronal or neuronal satellitosis is the term describing the presence of glial cells in the satellite space surrounding the neuronal perikaryon. Confusingly, this...
Perineuronal or neuronal satellitosis is the term describing the presence of glial cells in the satellite space surrounding the neuronal perikaryon. Confusingly, this finding has been described both as a physiologic and pathologic condition in humans and animals. In animals, neuronal satellitosis has been described in mammals, as well as in avian species. For the latter, the authors wondered whether neuronal satellitosis is expressed in the normal telencephalon of different avian orders and families and whether this pattern in different species shows a specific brain-region association. For these aims, this study explored the presence of neuronal satellitosis in the major areas of the healthy telencephalon in wild and domestic avian species of different orders and families, evaluating its grade in different brain regions. Neuronal satellitosis was seen in the hyperpallium and mesopallium as areas with the highest grade. Passeriformes showed the highest grade of neuronal satellitosis compared to diurnal or nocturnal raptors, and Charadriiformes. To clarify the exact role of neuronal satellitosis in animals without neurological disease, further studies are needed.RESEARCH HIGHLIGHTSNeuronal satellitosis is a common finding in the healthy avian telencephalon.Neuronal satellitosis is a species- and brain-region-associated finding in birds.Passeriformes have the highest grade of neuronal satellitosis.
Topics: Animals; Birds; Neurons; Telencephalon
PubMed: 35503252
DOI: 10.1080/03079457.2022.2073193 -
Neuro-oncology Advances 2021Gliomas typically escape surgical resection and recur due to their "diffuse invasion" phenotype, enabling them to infiltrate diffusely into the normal brain parenchyma....
BACKGROUND
Gliomas typically escape surgical resection and recur due to their "diffuse invasion" phenotype, enabling them to infiltrate diffusely into the normal brain parenchyma. Over the past 80 years, studies have revealed 2 key features of the "diffuse invasion" phenotype, designated the Scherer's secondary structure, and include perineuronal satellitosis (PS) and perivascular satellitosis (PVS). However, the mechanisms are still unknown.
METHODS
We established a mouse glioma cell line (IG27) by manipulating the histone H3K27M mutation, frequently harboring in diffuse intrinsic pontine gliomas, that reproduced the diffuse invasion phenotype, PS and PVS, following intracranial transplantation in the mouse brain. Further, to broadly apply the results in this mouse model to human gliomas, we analyzed data from 66 glioma patients.
RESULTS
Increased H3K27 acetylation in IG27 cells activated glucose transporter 1 (Glut1) expression and induced aerobic glycolysis and TCA cycle activation, leading to lactate, acetyl-CoA, and oncometabolite production irrespective of oxygen and glucose levels. Gain- and loss-of-function in vivo experiments demonstrated that Glut1 controls the PS of glioma cells, that is, attachment to and contact with neurons. GLUT1 is also associated with early progression in glioma patients.
CONCLUSIONS
Targeting the transporter Glut1 suppresses the unique phenotype, "diffuse invasion" in the diffuse glioma mouse model. This work leads to promising therapeutic and potential useful imaging targets for anti-invasion in human gliomas widely.
PubMed: 33506198
DOI: 10.1093/noajnl/vdaa150 -
Pediatric Neurology Mar 2021The ratio between excitatory (glutamatergic) and inhibitory (GABAergic) inputs into maturing individual cortical neurons influences their epileptic potential. Structural... (Review)
Review
BACKGROUND
The ratio between excitatory (glutamatergic) and inhibitory (GABAergic) inputs into maturing individual cortical neurons influences their epileptic potential. Structural factors during development that alter synaptic inputs can be demonstrated neuropathologically. Increased mitochondrial activity identifies neurons with excessive discharge rates.
METHODS
This study focuses on the neuropathological examinaion of surgical resections for epilepsy and at autopsy, in fetuses, infants, and children, using immunocytochemical markers, and electron microscopy in selected cases. Polymicrogyria and Down syndrome are highlighted.
RESULTS
Factors influencing afferent synaptic ratios include the following: (1) synaptic short-circuitry in fused molecular zones of adjacent gyri (polymicrogyria); (2) impaired development of dendritic spines decreasing excitation (Down syndrome); (3) extracellular keratan sulfate proteoglycan binding to somatic membranes but not dendritic spines may be focally diminished (cerebral atrophy, schizencephaly, lissencephaly, polymicrogyria) or augmented, ensheathing individual axons (holoprosencephaly), or acting as a barrier to axonal passage in the U-fiber layer. If keratan is diminished, glutamate receptors on the neuronal soma enable ectopic axosomatic excitatory synapses to form; (4) dysplastic, megalocytic neurons and balloon cells in mammalian target of rapamycin disorders; (5) satellitosis of glial cells displacing axosomatic synapses; (6) peri-neuronal inflammation (tuberous sclerosis) and heat-shock proteins.
CONCLUSIONS
Synaptic ratio of excitatory/inhibitory afferents is a major fundamental basis of epileptogenesis at the neuronal level. Neuropathology can demonstrate subcellular changes that help explain either epilepsy or lack of seizures in immature brains. Synaptic ratios in malformations influence postnatal epileptogenesis. Single neurons can be hypermetabolic and potentially epileptogenic.
Topics: Down Syndrome; Epilepsy; Fetus; Humans; Infant, Newborn; Malformations of Cortical Development; Neurons, Afferent; Polymicrogyria; Synapses
PubMed: 33450624
DOI: 10.1016/j.pediatrneurol.2020.11.001 -
Cancers Dec 2020The secondary structures of Scherer commonly known as perineuronal and perivascular satellitosis have been identified as a histopathological hallmark of diffuse,... (Review)
Review
The secondary structures of Scherer commonly known as perineuronal and perivascular satellitosis have been identified as a histopathological hallmark of diffuse, invasive, high-grade gliomas. They are recognised as perineuronal satellitosis when clusters of neoplastic glial cells surround neurons cell bodies and perivascular satellitosis when such tumour cells surround blood vessels infiltrating Virchow-Robin spaces. In this review, we provide an overview of emerging knowledge regarding how interactions between neurons and glioma cells can modulate tumour evolution and how neurons play a key role in glioma growth and progression, as well as the role of perivascular satellitosis into mechanisms of glioma cells spread. At the same time, we review the current knowledge about the role of perineuronal satellitosis and perivascular satellitosis within the tumour microenvironment (TME), in order to highlight critical knowledge gaps in research space.
PubMed: 33322379
DOI: 10.3390/cancers12123720 -
World Neurosurgery Dec 2019Polymorphous low-grade neuroepithelial tumor of the young (PLNTY) is a recently recognized epileptogenic neuroepithelial tumor. Despite its distinctiveness, its...
BACKGROUND
Polymorphous low-grade neuroepithelial tumor of the young (PLNTY) is a recently recognized epileptogenic neuroepithelial tumor. Despite its distinctiveness, its polymorphous histology and the nature of its oligodendrocyte-like cells remain unclear.
CASE DESCRIPTION
A 30-year-old, right-handed man was diagnosed with intractable epilepsy since 22 years of age. Magnetic resonance imaging revealed T2 signal hyperintensity and corresponding T1 signal hypointensity within the subcortical white matter of the right middle temporal gyrus. Positron emission tomography scan demonstrated hypometabolism in the right anterior temporal region. Electroencephalography and stereo-electroencephalography monitoring localized seizures to the right temporal lobe, allowing the patient to undergo right temporal lobectomy. Histologic sections demonstrated cortical dysplasia, white matter heterotopia, and hippocampal reactive gliosis without neuronal loss. Interestingly, an approximately 6-mm subcortical neoplasm was identified in the temporal lobectomy. It was composed of well-differentiated oligodendroglial-like cells but exhibited mild-to-moderate nuclear variability and pleomorphism, and mild infiltration into the overlying cortex without perineuronal satellitosis. No mitotic activity, microvascular proliferation, or necrosis was identified, and Ki-67 labeling index was less than 1%. The tumor was diffusely CD34 positive with moderate glial fibrillary acidic protein and retained ATRX staining, and demonstrated the presence of the BRAF V600E mutation. The tumor was negative for reticulin condensation, synaptophysin, SMI31, neuronal nuclei immunostains, and both the IDH1 mutation and 1p19q codeletion. Overall histologic findings were most consistent with PLNTY.
CONCLUSIONS
The correct diagnosis of PLNTY and its distinction from closely resembling low-grade neuroepithelial tumors is important. We hope our proposed diagnostic features will aid in its proper diagnosis and management.
Topics: Adult; Anterior Temporal Lobectomy; Biomarkers, Tumor; Brain Neoplasms; Diagnosis, Differential; Drug Resistant Epilepsy; Electroencephalography; Humans; Immunohistochemistry; Magnetic Resonance Imaging; Male; Neoplasms, Neuroepithelial; Positron-Emission Tomography
PubMed: 31520766
DOI: 10.1016/j.wneu.2019.08.221 -
Journal of Oncology 2019Glioblastoma (GBM) is the most common and the most malignant primary brain tumor and is characterized by rapid proliferation, invasion into surrounding normal brain... (Review)
Review
Glioblastoma (GBM) is the most common and the most malignant primary brain tumor and is characterized by rapid proliferation, invasion into surrounding normal brain tissues, and consequent aberrant vascularization. In these characteristics of GBM, invasive properties are responsible for its recurrence after various therapies. The histomorphological patterns of glioma cell invasion have often been referred to as the "secondary structures of Scherer." The "secondary structures of Scherer" can be classified mainly into four histological types as (i) perineuronal satellitosis, (ii) perivascular satellitosis, (iii) subpial spread, and (iv) invasion along the white matter tracts. In order to develop therapeutic interventions to mitigate glioma cell migration, it is important to understand the biological mechanism underlying the formation of these secondary structures. The main focus of this review is to examine new molecular pathways based on the histopathological evidence of GBM invasion as major prognostic factors for the high recurrence rate for GBMs. The histopathology-based pharmacological and biological targets for treatment strategies may improve the management of invasive and resistant GBMs.
PubMed: 31320900
DOI: 10.1155/2019/2964783 -
Frontiers in Oncology 2019Laser capture microdissection (LCM) coupled with RNA-seq is a powerful tool to identify genes that are differentially expressed in specific histological tumor subtypes....
Laser capture microdissection (LCM) coupled with RNA-seq is a powerful tool to identify genes that are differentially expressed in specific histological tumor subtypes. To better understand the role of single tumor cell populations in the complex heterogeneity of glioblastoma, we paired microdissection and NGS technology to study intra-tumoral differences into specific histological regions and cells of human GBM FFPE tumors. We here isolated astrocytes, neurons and endothelial cells in 6 different histological contexts: tumor core astrocytes, pseudopalisading astrocytes, perineuronal astrocytes in satellitosis, neurons with satellitosis, tumor blood vessels, and normal blood vessels. A customized protocol was developed for RNA amplification, library construction, and whole transcriptome analysis of each single portion. We first validated our protocol comparing the obtained RNA expression pattern with the gene expression levels of RNA-seq raw data experiments from the BioProject NCBI database, using Spearman's correlation coefficients calculation. We found a good concordance for pseudopalisading and tumor core astrocytes compartments (0.5 Spearman correlation) and a high concordance for perineuronal astrocytes, neurons, normal, and tumor endothelial cells compartments (0.7 Spearman correlation). Then, Principal Component Analysis and differential expression analysis were employed to find differences between tumor compartments and control tissue and between same cell types into distinct tumor contexts. Data consistent with the literature emerged, in which multiple therapeutic targets significant for glioblastoma (such as Integrins, Extracellular Matrix, transmembrane transport, and metabolic processes) play a fundamental role in the disease progression. Moreover, specific cellular processes have been associated with certain cellular subtypes within the tumor. Our results are promising and suggest a compelling method for studying glioblastoma heterogeneity in FFPE samples and its application in both prospective and retrospective studies.
PubMed: 31231613
DOI: 10.3389/fonc.2019.00482 -
Neuro-oncology Sep 2018Perineuronal satellitosis, the microanatomical clustering of glioma cells around neurons in the tumor microenvironment, has been recognized as a histopathological... (Review)
Review
Perineuronal satellitosis, the microanatomical clustering of glioma cells around neurons in the tumor microenvironment, has been recognized as a histopathological hallmark of high-grade gliomas since the seminal observations of Scherer in the 1930s. In this review, we explore the emerging understanding that neuron‒glioma cell interactions regulate malignancy and that neuronal activity is a critical determinant of glioma growth and progression. Elucidation of the interplay between normal and malignant neural circuitry is critical to realizing the promise of effective therapies for these seemingly intractable diseases. Here, we review current knowledge regarding the role of neuronal activity in the glioma microenvironment and highlight critical knowledge gaps in this burgeoning research space.
Topics: Animals; Brain Neoplasms; Disease Progression; Glioma; Humans; Neurons; Tumor Microenvironment
PubMed: 29788372
DOI: 10.1093/neuonc/noy083