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Gliomas arising in the setting of neurofibromatosis type 1 (NF1) are heterogeneous, occurring from childhood through adulthood, can be histologically low-grade or high-grade, and follow an indolent or aggressive clinical course. Comprehensive profiling of genetic alterations beyond NF1 inactivation and epigenetic classification of these tumors remain limited. Through next-generation sequencing, copy number analysis, and DNA methylation profiling of gliomas from 47 NF1 patients, we identified 2 molecular subgroups of NF1-associated gliomas. The first harbored biallelic NF1 inactivation only, occurred primarily during childhood, followed a more indolent clinical course, and had a unique epigenetic signature for which we propose the terminology "pilocytic astrocytoma, arising in the setting of NF1". The second subgroup harbored additional oncogenic alterations including CDKN2A homozygous deletion and ATRX mutation, occurred primarily during adulthood, followed a more aggressive clinical course, and was epigenetically diverse, with most tumors aligning with either high-grade astrocytoma with piloid features or various subclasses of IDH-wildtype glioblastoma. Several patients were treated with small molecule MEK inhibitors that resulted in stable disease or tumor regression when used as a single agent, but only in the context of those tumors with NF1 inactivation lacking additional oncogenic alterations. Together, these findings highlight recurrently altered pathways in NF1-associated gliomas and help inform targeted therapeutic strategies for this patient population.
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Astrocitoma , Neoplasias Encefálicas , Glioma , Neurofibromatose 1 , Adulto , Astrocitoma/genética , Neoplasias Encefálicas/genética , Glioma/genética , Glioma/patologia , Homozigoto , Humanos , Neurofibromatose 1/complicações , Neurofibromatose 1/genética , Deleção de SequênciaRESUMO
Meningiomas are the most common primary central nervous system neoplasm. Despite promising recent progress in elucidating the genomic landscape and underlying biology of these histologically, molecularly, and clinically diverse tumors, the mainstays of meningioma treatment remain maximal safe resection and radiation therapy. The aim of this review of meningioma radiotherapy is to provide a concise summary of the history, current evidence, and future for application of radiotherapy in meningioma treatment.
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Neoplasias Meníngeas , Meningioma , Humanos , Meningioma/patologia , Neoplasias Meníngeas/patologia , Radioterapia AdjuvanteRESUMO
BACKGROUND: Disseminated diffuse midline glioma (DMG) is a devastating diagnosis. Molecular subtyping has increased our understanding of this tumor. CASE: Here, we report the case of an 8-year-old girl who presented with symptoms of brainstem dysfunction and was found to have disseminated DMG with lesions in the pons, thalamus and bilateral temporal lobes. Molecular subtyping of the temporal lobe tumor tissue was consistent with H3 K27me3 loss and EZHIP overexpression, falling under the newly designated "H3 K27-altered" AQ5WHO subtype of DMG. Pathology from biopsy of the orbital lesion showed poorly differentiated rhabdoid-like disseminated tumor cells. The patient went on to develop lesions in the peritoneum, infratemporal fossa, and along the lumbosacral nerve roots. CONCLUSION: This unique case illustrates the aggressive behavior of H3 K27-altered tumors and their potential to metastasize.
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Neoplasias Encefálicas , Glioma , Neoplasias Encefálicas/cirurgia , Criança , Feminino , Glioma/complicações , Glioma/diagnóstico por imagem , Glioma/patologia , Histonas/genética , Humanos , Mutação , Ponte/patologia , Tálamo/patologiaRESUMO
Sudden death due to leukostasis and lymphocyte thrombi in patients with chronic hematologic malignancies is rare. Leukostasis is characterized by highly elevated leukemic cell count and decreased tissue perfusion symptoms, leading to severe complications and even death. Chronic lymphocytic leukemia (CLL) is a chronic lymphoproliferative disorder that shows a highly heterogeneous clinical course, ranging from indolent form to very aggressive disease. Due to its low metabolic and mitotic rate, there is a lower incidence of clinically significant leukostasis in patients with CLL. Two main theories have been proposed in the development of leukostasis: (1) increased blood viscosity due to large leukemic cell populations; (2) high metabolic activity and cytokine production by leukemic cells. Both mechanisms lead to local hypoxic damage.We present a case of a 70-year-old man who died suddenly in the absence of symptoms. Autopsy and histology examinations revealed findings consistent with CLL and diffuse leukostasis involving the major organs' vessels.In the presence of gross and/or microscopic findings suggesting a potential hematologic malignancy, undiagnosed or relapsing hematologic malignancies should be considered in the differential diagnosis of sudden deaths.
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Leucemia Linfocítica Crônica de Células B , Leucostasia , Idoso , Morte Súbita/etiologia , Humanos , MasculinoRESUMO
Myxedema Ascites is a rare finding of primary hypothyroidism, thereby leading to delayed diagnosis. However, prompt treatment with levothyroxine leads to complete resolution of the condition. We present a rare case of myxedema ascites in an elderly female and highlight the importance of early diagnosis and management. We also present ischemic colitis in the same patient, which has not been reported thus far in literature as a complication of myxedema ascites.
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Ascite/complicações , Colite Isquêmica/complicações , Mixedema/complicações , Idoso , Ascite/diagnóstico , Ascite/diagnóstico por imagem , Colite Isquêmica/diagnóstico , Colite Isquêmica/patologia , Colonoscopia , Feminino , Humanos , Hipotireoidismo/complicações , Mixedema/diagnóstico , Mixedema/diagnóstico por imagem , UltrassonografiaRESUMO
The use of postmortem computed tomography (PMCT) to support autopsy pathology has increased in recent decades. To some extent, PMCT has also been contemplated as a potential alternative to conventional postmortem examination. The purpose of this study was to investigate the ability of PMCT to detect specific pathologic findings in the head and brain in natural hospital deaths.We examined postmortem CT images and autopsy data from 31 subjects who died at SUNY (State University of New York) Upstate University Hospital between 2013 and 2018. Each subject underwent a noncontrast PMCT and a traditional autopsy. A neuroradiologist analyzed PMCT images for head and brain abnormalities. The autopsies were performed by pathologists who were aware of the radiology results.In our series, PMCT was able to detect the majority of the significant space-occupying lesions, although it was not always reliable in ascertaining their nature. Postmortem computed tomography revealed findings usually challenging to detect at autopsy. Unfortunately, there were also situations in which PMCT was misleading, showing changes that were difficult to interpret, or that could be related to postmortem events. Therefore, we conclude PMCT should be used as an adjunct rather than a substitute to autopsy.
Assuntos
Autopsia/métodos , Encéfalo/diagnóstico por imagem , Crânio/diagnóstico por imagem , Tomografia Computadorizada por Raios X , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Encefalopatias/diagnóstico por imagem , Encefalopatias/patologia , Criança , Pré-Escolar , Feminino , Hematoma/diagnóstico por imagem , Hematoma/patologia , Hematoma Subdural/diagnóstico por imagem , Hematoma Subdural/patologia , Humanos , Masculino , Pessoa de Meia-Idade , New York , Fraturas Cranianas/diagnóstico por imagem , Fraturas Cranianas/patologia , Hemorragia Subaracnóidea/diagnóstico por imagem , Hemorragia Subaracnóidea/patologia , Adulto JovemAssuntos
Proteína Forkhead Box M1 , Neoplasias Meníngeas , Meningioma , RNA Mensageiro , Proteínas de Ligação a RNA , Humanos , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/metabolismo , RNA Mensageiro/metabolismo , RNA Mensageiro/genética , Proteína Forkhead Box M1/genética , Proteína Forkhead Box M1/metabolismo , Neoplasias Meníngeas/genética , Neoplasias Meníngeas/patologia , Neoplasias Meníngeas/metabolismo , Meningioma/genética , Meningioma/metabolismo , Meningioma/patologia , Estabilidade de RNA/genética , Regulação Neoplásica da Expressão GênicaRESUMO
BACKGROUND: Viral encephalitis is a dangerous compromise between the need to robustly clear pathogen from the brain and the need to protect neurons from bystander injury. Theiler's murine encephalomyelitis virus (TMEV) infection of C57Bl/6 mice is a model of viral encephalitis in which the compromise results in hippocampal damage and permanent neurological sequelae. We previously identified brain-infiltrating inflammatory monocytes as the primary driver of this hippocampal pathology, but the mechanisms involved in recruiting these cells to the brain were unclear. METHODS: Chemokine expression levels in the hippocampus were assessed by microarray, ELISA, RT-PCR, and immunofluorescence. Monocyte infiltration during acute TMEV infection was measured by flow cytometry. CCL2 levels were manipulated by immunodepletion and by specific removal from neurons in mice generated by crossing a line expressing the Cre recombinase behind the synapsin promoter to animals with floxed CCL2. RESULTS: Inoculation of the brain with TMEV induced hippocampal production of the proinflammatory chemokine CCL2 that peaked at 6 h postinfection, whereas inoculation with UV-inactivated TMEV did not elicit this response. Immunofluorescence revealed that hippocampal neurons expressed high levels of CCL2 at this timepoint. Genetic deletion of CCR2 and systemic immunodepletion of CCL2 abrogated or blunted the infiltration of inflammatory monocytes into the brain during acute infection. Specific genetic deletion of CCL2 from neurons reduced serum and hippocampal CCL2 levels and inhibited inflammatory monocyte infiltration into the brain. CONCLUSIONS: We conclude that intracranial inoculation with infectious TMEV rapidly induces the expression of CCL2 in neurons, and this cellular source is necessary for CCR2-dependent infiltration of inflammatory monocytes into the brain during the most acute stage of encephalitis. These findings highlight a unique role for neuronal production of chemokines in the initiation of leukocytic infiltration into the infected central nervous system.
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Quimiocina CCL2/biossíntese , Encefalite Viral/mortalidade , Hipocampo/patologia , Monócitos/imunologia , Neurônios/metabolismo , Animais , Infecções por Cardiovirus/imunologia , Infecções por Cardiovirus/metabolismo , Infecções por Cardiovirus/patologia , Quimiotaxia de Leucócito/imunologia , Encefalite Viral/imunologia , Encefalite Viral/metabolismo , Encefalite Viral/patologia , Hipocampo/imunologia , Hipocampo/virologia , Camundongos , Camundongos Endogâmicos C57BL , TheilovirusAssuntos
Quinase do Linfoma Anaplásico/genética , Astrocitoma/genética , Neoplasias Encefálicas/genética , Glicoproteínas de Membrana/genética , Receptor trkB/genética , Astrocitoma/patologia , Neoplasias Encefálicas/patologia , Pré-Escolar , Feminino , Humanos , Masculino , Proteínas de Fusão OncogênicaAssuntos
Adenocarcinoma Mucinoso , Neoplasias Pulmonares , Humanos , Pulmão/patologia , Piperidinas/uso terapêutico , Carbazóis/uso terapêutico , Adenocarcinoma Mucinoso/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Inibidores de Proteínas QuinasesRESUMO
Chromosome instability leading to accumulation of copy number gains or losses is a hallmark of cancer. Copy number variant (CNV) signatures are increasingly used for clinical risk-stratification, but size thresholds for defining CNVs are variable and the biological or clinical implications of CNV size heterogeneity or co-occurrence patterns are incompletely understood. Here we analyze CNV and clinical data from 565 meningiomas and 9,885 tumors from The Cancer Genome Atlas (TCGA) to develop tumor-and chromosome-specific CNV size-dependent and co-occurrence models for clinical outcomes. Our results reveal prognostic CNVs with optimized size thresholds and co-occurrence patterns that refine risk-stratification across a diversity of human cancers.
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BACKGROUND: Meningeal solitary fibrous tumors (SFTs) are rare mesenchymal neoplasms that are associated with local recurrence and hematogenous metastasis. The cell states and spatial transcriptomic architecture underlying the unique clinical behavior of meningeal SFTs are unknown. METHODS: Single-cell (n=4), spatial (n=8), and bulk RNA sequencing (n=22) was used to define the cell states and spatial transcriptomic architecture of meningeal SFTs across histological grades and in patient-matched pairs of primary/recurrent or intracranial/metastatic samples. Immunofluorescence, immunohistochemistry, and comparison of single-cell types to meningiomas, or to cerebral vascular development or homeostasis, were used for validation. RESULTS: Here we show meningeal SFTs are comprised of regionally distinct gene expression programs that resemble cerebral vascular development or homeostasis. Single-cell trajectory analysis and pseudotemporal ordering of single-cells suggest that meningeal SFT cell fate decisions are dynamic and interchangeable. Cell-cell communication analyses demonstrate receptor-ligand interactions throughout the meningeal SFT microenvironment, particularly between SFT cells, endothelia, and immature neurons. Direct comparison of single-cell transcriptomes from meningeal SFTs versus meningiomas shows that SFT cells are enriched in expression of endothelial markers while meningiomas cells are enriched in expression of mural cells markers. Meningeal SFT spatial transcriptomes show regionally distinct intratumor heterogeneity in cell states, gene expression programs, and cell-cell interactions across WHO histological grades and in patient-matched pairs of primary/recurrent or intracranial/metastatic samples. CONCLUSIONS: These results shed light on pathways underlying meningeal SFT biology in comparison to other central nervous system tumors and provide a framework for integrating single-cell, spatial, and bulk RNA sequencing data across human cancers and normal tissues.
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Intratumor heterogeneity underlies cancer evolution and treatment resistance, but targetable mechanisms driving intratumor heterogeneity are poorly understood. Meningiomas are the most common primary intracranial tumors and are resistant to all medical therapies, and high-grade meningiomas have significant intratumor heterogeneity. Here we use spatial approaches to identify genomic, biochemical and cellular mechanisms linking intratumor heterogeneity to the molecular, temporal and spatial evolution of high-grade meningiomas. We show that divergent intratumor gene and protein expression programs distinguish high-grade meningiomas that are otherwise grouped together by current classification systems. Analyses of matched pairs of primary and recurrent meningiomas reveal spatial expansion of subclonal copy number variants associated with treatment resistance. Multiplexed sequential immunofluorescence and deconvolution of meningioma spatial transcriptomes using cell types from single-cell RNA sequencing show decreased immune infiltration, decreased MAPK signaling, increased PI3K-AKT signaling and increased cell proliferation, which are associated with meningioma recurrence. To translate these findings to preclinical models, we use CRISPR interference and lineage tracing approaches to identify combination therapies that target intratumor heterogeneity in meningioma cell co-cultures.
Assuntos
Heterogeneidade Genética , Neoplasias Meníngeas , Meningioma , Meningioma/genética , Meningioma/patologia , Humanos , Neoplasias Meníngeas/genética , Neoplasias Meníngeas/patologia , Variações do Número de Cópias de DNA , Regulação Neoplásica da Expressão Gênica , Genômica/métodos , Análise de Célula Única , Proliferação de Células/genética , Recidiva Local de Neoplasia/genética , Transdução de Sinais/genética , Linhagem Celular Tumoral , TranscriptomaRESUMO
Schwann cell tumors are the most common cancers of the peripheral nervous system and can arise in patients with neurofibromatosis type-1 (NF-1) or neurofibromatosis type-2 (NF-2). Functional interactions between NF1 and NF2 and broader mechanisms underlying malignant transformation of the Schwann lineage are unclear. Here we integrate bulk and single-cell genomics, biochemistry, and pharmacology across human samples, cell lines, and mouse allografts to identify cellular de-differentiation mechanisms driving malignant transformation and treatment resistance. We find DNA methylation groups of Schwann cell tumors can be distinguished by differentiation programs that correlate with response to the MEK inhibitor selumetinib. Functional genomic screening in NF1-mutant tumor cells reveals NF2 loss and PAK activation underlie selumetinib resistance, and we find that concurrent MEK and PAK inhibition is effective in vivo. These data support a de-differentiation paradigm underlying malignant transformation and treatment resistance of Schwann cell tumors and elucidate a functional link between NF1 and NF2.
Assuntos
Neurilemoma , Neurofibromatoses , Neurofibromatose 1 , Neurofibromatose 2 , Animais , Humanos , Camundongos , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , Neurilemoma/genética , Neurilemoma/patologia , Neurofibromatoses/metabolismo , Neurofibromatoses/patologia , Neurofibromatose 1/genética , Neurofibromatose 1/metabolismo , Neurofibromatose 2/genética , Neurofibromatose 2/patologia , Células de Schwann/metabolismo , Resistencia a Medicamentos Antineoplásicos/genéticaRESUMO
Gliosarcoma (GS) is an extraordinarily rare variant of glioblastoma, which is differentiated by its distinct biphasic histopathological morphology consisting of both glial and mesenchymal elements. Although GS has a predilection for the cortical hemispheres, rare occurrences of intraventricular gliosarcoma (IVGS) have been documented in the literature. In this report, we present a 68-year-old female patient with a primary IVGS arising from the frontal horn of the left ventricle with corresponding left ventricular entrapment. The clinical course as well as associated tumor features as observed on computed tomography (CT), magnetic resonance imaging (MRI), and immunohistochemical studies are presented along with a relevant review of the current literature.
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The tumor formerly known as "cauda equina paraganglioma" was recently renamed as cauda equina neuroendocrine tumor (CENET) based on distinct biological and genetic properties. Nevertheless, it remains insufficiently understood. For this study, we retrieved CENETs (some previously reported), from the pathology files of 3 institutions; we examined their immunohistochemical profile, including common neuroendocrine tumor-associated hormones and transcription factors. We identified 24 CENETs from 7 female and 17 male adult patients, with a median age of 47 years. Six included neurofilament-positive ganglion cells. All tumors tested were positive for INSM1, synaptophysin, chromogranin A, SSTR2, and CD56 as well as at least 1 keratin (AE1/AE3, CAM5.2); CK7 and CK20 were negative. Glial fibrillary acidic protein was negative, except for peripheral nontumoral elements. S100 protein was variable but mainly expressed in scattered sustentacular cells. All but 1 tumor tested were positive for HOXB13; several stained for SATB2, and all tumors were consistently negative for GATA3. All tumors tested were negative for transcription factors found in various other epithelial neuroendocrine neoplasms including TTF1, CDX2, PIT1, TPIT, SF1, and PAX8; staining for T-brachyury was negative. Four of 5 CENETs tested had at least focal tyrosine hydroxylase reactivity. Serotonin expression was detected in all 21 tumors tested; it was diffusely positive in 5 and had variable positivity in the remainder. A few tumors had scattered cells expressing gastrin, calcitonin, pancreatic polypeptide, and peptide YY, while glucagon, adrenocorticotropic hormone, and monoclonal carcinoembryonic antigen were negative. PSAP expression was found focally in 4 of 5 tumors examined. SDHB was consistently intact; ATRX was intact in 14 tumors and showed only focal loss in 3. The median Ki-67 labeling index was 4.5% (range: 1% to 15%). We conclude that CENET represents a distinct neuroendocrine neoplasm; the subset with ganglion cells qualifies for designation as composite gangliocytoma/neuroma-neuroendocrine tumor (CoGNET) as defined in the 2022 WHO classification of neuroendocrine neoplasms. In addition to INSM1, chromogranin, synaptophysin, and keratins, the most characteristic finding is nuclear HOXB13 expression; a subset also express SATB2. Serotonin is the most common hormone expressed. The cytogenesis and pathogenesis of these lesions remains unclear.