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Neurologic complications of symptomatic COVID-19 are common. Brain tissues from 13 autopsies of people who died of COVID-19 were examined. Cultured endothelial and neuronal cells were incubated with and wild type mice were injected IV with different spike subunits. In situ analyses were used to detect SARS-CoV-2 proteins and the host response. In 13/13 brains from fatal COVID-19, pseudovirions (spike, envelope, and membrane proteins without viral RNA) were present in the endothelia of microvessels ranging from 0 to 14 positive cells/200× field (mean 4.3). The pseudovirions strongly co-localized with caspase-3, ACE2, IL6, TNFα, and C5b-9. The surrounding neurons demonstrated increased NMDAR2 and neuronal NOS plus decreased MFSD2a and SHIP1 proteins. Tail vein injection of the full length S1 spike subunit in mice led to neurologic signs (increased thirst, stressed behavior) not evident in those injected with the S2 subunit. The S1 subunit localized to the endothelia of microvessels in the mice brain and showed co-localization with caspase-3, ACE2, IL6, TNFα, and C5b-9. The surrounding neurons showed increased neuronal NOS and decreased MFSD2a. It is concluded that ACE2+ endothelial damage is a central part of SARS-CoV2 pathology and may be induced by the spike protein alone. Thus, the diagnostic pathologist can use either hematoxylin and eosin stain or immunohistochemistry for caspase 3 and ACE2 to document the endothelial cell damage of COVID-19.
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COVID-19/virologia , Células Endoteliais/virologia , SARS-CoV-2/metabolismo , Glicoproteína da Espícula de Coronavírus/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Autopsia/métodos , Modelos Animais de Doenças , Células Endoteliais/metabolismo , Feminino , Humanos , Masculino , Camundongos , Microvasos/metabolismo , Microvasos/virologia , Pessoa de Meia-Idade , Subunidades Proteicas/metabolismo , RNA Viral/genética , SARS-CoV-2/genética , Glicoproteína da Espícula de Coronavírus/genéticaRESUMO
In this case report, we present a rare and previously unreported case of spontaneous regression of a histologically consistent clival chordoma. At the time of diagnosis, imaging demonstrated a T2 hyperintense and T1 isointense midline skull base mass, centered in the nasopharynx, with scalloping of the ventral clivus consistent with a chordoma measuring 3.1 × 1.9 × 3.0 cm (8.84 cm3). On pre-operative imaging 2 months later, with no intervening therapy, the mass had regressed by 61.7% to a size of 2.3 × 2.1 × 1.4 cm (3.38 cm3). The patient self-administered several herbal supplements and animal oils which may have contributed to tumor regression. The purpose of this report is to document this rare occurrence and provide a comprehensive description of the case details and list of the various medications, herbs, and supplements used prior to this rare event.
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Cordoma/patologia , Regressão Neoplásica Espontânea , Neoplasias da Base do Crânio/patologia , Idoso , Cordoma/diagnóstico por imagem , Cordoma/tratamento farmacológico , Fossa Craniana Posterior/patologia , Feminino , Humanos , Imageamento por Ressonância Magnética , Extratos Vegetais/administração & dosagem , Extratos Vegetais/uso terapêutico , Autoadministração , Neoplasias da Base do Crânio/diagnóstico por imagem , Neoplasias da Base do Crânio/tratamento farmacológicoRESUMO
Mutations in the gene SCAPER (S-phase CyclinA Associated Protein residing in the Endoplasmic Reticulum) have recently been identified as causing syndromic autosomal recessive retinitis pigmentosa with the extraocular manifestations of intellectual disability and attention-deficit/hyperactivity disorder. We present the case of an 11-year-old boy that presented to our clinic with the complaint of decreased night vision. Clinical presentation, family history, and diagnostic imaging were congruent with the diagnosis of autosomal recessive retinitis pigmentosa. Genetic testing of the patient and both parents via whole-exome sequencing revealed the homozygous mutation c.2023-2A>G in SCAPER. Unique to our patient's presentation is the absence of intellectual disability and attention-deficit/hyperactivity disorder, suggesting that SCAPER-associated retinitis pigmentosa can also present without systemic manifestations.
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Proteínas de Transporte/genética , Sequenciamento do Exoma , Retinose Pigmentar/genética , Criança , Exoma/genética , Proteínas do Olho/genética , Heterozigoto , Humanos , Masculino , Mutação , LinhagemRESUMO
OBJECTIVEThere is a need for advanced imaging biomarkers to improve radiation treatment planning and response assessment. T1-weighted dynamic contrast-enhanced perfusion MRI (DCE MRI) allows quantitative assessment of tissue perfusion and blood-brain barrier dysfunction and has entered clinical practice in the management of primary and secondary brain neoplasms. The authors sought to retrospectively investigate DCE MRI parameters in meningiomas treated with resection and adjuvant radiation therapy using volumetric segmentation.METHODSA retrospective review of more than 300 patients with meningiomas resected between January 2015 and December 2018 identified 14 eligible patients with 18 meningiomas who underwent resection and adjuvant radiotherapy. Patients were excluded if they did not undergo adjuvant radiation therapy or DCE MRI. Demographic and clinical characteristics were obtained and compared to DCE perfusion metrics, including mean plasma volume (vp), extracellular volume (ve), volume transfer constant (Ktrans), rate constant (kep), and wash-in rate of contrast into the tissue, which were derived from volumetric analysis of the enhancing volumes of interest.RESULTSThe mean patient age was 64 years (range 49-86 years), and 50% of patients (7/14) were female. The average tumor volume was 8.07 cm3 (range 0.21-27.89 cm3). The median Ki-67 in the cohort was 15%. When stratified by median Ki-67, patients with Ki-67 greater than 15% had lower median vp (0.02 vs 0.10, p = 0.002), and lower median wash-in rate (1.27 vs 4.08 sec-1, p = 0.04) than patients with Ki-67 of 15% or below. Logistic regression analysis demonstrated a statistically significant, moderate positive correlation between ve and time to progression (r = 0.49, p < 0.05). Furthermore, there was a moderate positive correlation between Ktrans and time to progression, which approached, but did not reach, statistical significance (r = 0.48, p = 0.05).CONCLUSIONSThis study demonstrates a potential role for DCE MRI in the preoperative characterization and stratification of meningiomas, laying the foundation for future prospective studies incorporating DCE as a biomarker in meningioma diagnosis and treatment planning.
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Meios de Contraste/farmacocinética , Irradiação Craniana , Gadolínio DTPA/farmacocinética , Imageamento por Ressonância Magnética/métodos , Neoplasias Meníngeas/diagnóstico por imagem , Meningioma/diagnóstico por imagem , Neuroimagem/métodos , Radiocirurgia , Radioterapia Adjuvante , Idoso , Idoso de 80 Anos ou mais , Volume Sanguíneo , Feminino , Humanos , Antígeno Ki-67/análise , Masculino , Neoplasias Meníngeas/radioterapia , Neoplasias Meníngeas/cirurgia , Meningioma/radioterapia , Meningioma/cirurgia , Pessoa de Meia-Idade , Estudos Retrospectivos , Neoplasias da Base do Crânio/diagnóstico por imagem , Neoplasias da Base do Crânio/radioterapia , Neoplasias da Base do Crânio/cirurgiaRESUMO
Malignant transformation of intracranial epidermoid cysts is a rare occurrence. We present the second case of such an event occurring in the pineal region and the first case sent for detailed genomic profiling. MRI demonstrated two lesions: a cyst in a quadrigeminal cistern with restricted diffusion on DWI-weighted images and an adjacent, peripherally enhancing tumor with cerebellar infiltration. Both the lesions were completely resected with a small residual of the epidermoid cyst. The final pathology of both lesions was consistent with epidermoid cyst and squamous cell carcinoma (SCC), respectively. The tumor specimen was sent for comprehensive genomic profiling which revealed stable microsatellite status and loss of CDKN2A/B, MTAP (exons 2-8), and PTEN (exons 6-9). Although reports of primary SCC originating from the epidermoid cyst have been previously described, this is the first description of the genomic profile of such a tumor.
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Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/patologia , Transformação Celular Neoplásica/genética , Cisto Epidérmico/genética , Cisto Epidérmico/patologia , Pinealoma/genética , Pinealoma/patologia , Idoso , Neoplasias Encefálicas/diagnóstico por imagem , Carcinoma de Células Escamosas/diagnóstico por imagem , Ângulo Cerebelopontino , Cisto Epidérmico/diagnóstico por imagem , Feminino , Perfilação da Expressão Gênica , Humanos , Imageamento por Ressonância Magnética , Pinealoma/diagnóstico por imagem , Tomografia por Emissão de Pósitrons , Cuidados Pós-Operatórios , Tomografia Computadorizada por Raios X , Resultado do TratamentoRESUMO
Epigenetic patterns on the level of DNA methylation have already been shown to separate clinically relevant subgroups of meningiomas. We here set out to identify potential prognostic implications of epigenetic modification on the level of histones with focus on H3K27 trimethylation (H3K27me3). H3K27me3 was assessed by immunohistochemistry on 232 meningiomas from 232 patients. In 194 cases, trimethylation was detected in tumor cells. In 25 cases, staining was limited to vessels while all tumor cells were negative. Finally, 13 cases yielded equivocal staining patterns. Reduced abundance of H3K27me3 in cases with staining limited to vessels was confirmed by mass spectrometry on a subset of cases. Lack of staining for H3K27me3 in all tumor cells was significantly associated with more rapid progression (p = 0.009). In line, H3K27me3-negative cases were associated with a DNA methylation pattern of the more aggressive types among the recently introduced DNA methylation groups. Also, NF2 and SUFU mutations were enriched among cases with complete lack of H3K27me3 staining in tumor cells (p < 0.0001 and p = 0.029, respectively). H3K27me3 staining pattern added significant prognostic insight into WHO grade II cases and in the compound subset of WHO grade I and II cases (p = 0.04 and p = 0.007, respectively). However, it did not further stratify within WHO grade III cases. Collectively, these data indicate that epigenetic modifications beyond DNA methylation are involved in the aggressiveness of meningioma. It also suggests that H3K27me3 immunohistochemistry might be a useful adjunct in meningioma diagnostics, particularly for cases with WHO grade II histology or at the borderline between WHO grade I and II.
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Metilação de DNA , Histonas/metabolismo , Neoplasias Meníngeas/metabolismo , Meningioma/metabolismo , Recidiva Local de Neoplasia/metabolismo , Idoso , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Estudos de Coortes , Epigênese Genética , Feminino , Genes da Neurofibromatose 2 , Histonas/genética , Humanos , Masculino , Neoplasias Meníngeas/genética , Neoplasias Meníngeas/patologia , Meningioma/genética , Meningioma/patologia , Pessoa de Meia-Idade , Mutação , Gradação de Tumores , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/patologia , Prognóstico , Intervalo Livre de Progressão , Proteínas Repressoras/genéticaRESUMO
Immune checkpoint inhibitors targeting programmed cell death 1 (PD-1) or its ligand (PD-L1) have been shown to be effective in treating patients with a variety of cancers. Biomarker studies have found positive associations between clinical response rates and PD-L1 expression on tumor cells, as well as the presence of tumor infiltrating lymphocytes (TILs). It is currently unknown whether tumors associated with neurofibromatosis types 1 and 2 (NF1 and NF2) express PD-L1. We performed immunohistochemistry for PD-L1 (clones SP142 and E1L3N), CD3, CD20, CD8, and CD68 in NF1-related tumors (ten dermal and six plexiform neurofibromas) and NF2-related tumors (ten meningiomas and ten schwannomas) using archival formalin-fixed paraffin-embedded tissues. Expression of PD-L1 was considered positive in cases with > 5% membranous staining of tumor cells, in accordance with previously published biomarker studies. PD-L1 expression in tumor cells (using the SP142 and E1L3N clones, respectively) was assessed as positive in plexiform neurofibromas (6/6 and 5/6) dermal neurofibromas (8/10 and 6/10), schwannomas (7/10 and 10/10), and meningiomas (4/10 and 2/10). Sparse to moderate presence of CD68, CD3, or CD8 positive TILs was found in 36 (100%) of tumor specimens. Our findings indicate that adaptive resistance to cell-mediated immunity may play a major role in the tumor immune microenvironment of NF1 and NF2-associated tumors. Expression of PD-L1 on tumor cells and the presence of TILs suggest that these tumors might be responsive to immunotherapy with immune checkpoint inhibitors, which should be explored in clinical trials for NF patients.
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Antígeno B7-H1/metabolismo , Neoplasias do Sistema Nervoso Central , Linfócitos do Interstício Tumoral/patologia , Meningioma , Neurilemoma , Neurofibromatose 1/complicações , Neurofibromatose 2/complicações , Adolescente , Adulto , Antígenos CD/metabolismo , Neoplasias do Sistema Nervoso Central/complicações , Neoplasias do Sistema Nervoso Central/metabolismo , Neoplasias do Sistema Nervoso Central/patologia , Criança , Feminino , Humanos , Masculino , Meningioma/complicações , Meningioma/metabolismo , Meningioma/patologia , Pessoa de Meia-Idade , Neurilemoma/complicações , Neurilemoma/metabolismo , Neurilemoma/patologia , Adulto JovemRESUMO
INTRODUCTION: Tuberous sclerosis is associated with three central nervous system pathologies: cortical/subcortical tubers, subependymal nodules (SENs), and subependymal giant cell astrocytomas (SEGAs). Tubers are associated with epilepsy, which is often medication-resistant and often leads to resective surgery. Recently, mammalian target of rapamycin inhibitors (mTORi) have been shown to be effective reducing seizure burden in some patients with tuberous sclerosis complex (TSC)-related refractory epilepsy. mTORi have also been shown to be an alternative for surgery treating SEGAs. We describe several cases of resected tubers that contained SEGA tissue without an intraventricular SEGA. METHODS: After institutional review board (IRB) protocol approval, we retrospectively reviewed the surgical-pathological data for all TSC patients who underwent cortical resections for treatment of refractory epilepsy at NYU Langone Medical Center and Tel Aviv Medical Center between 2003 and 2013. Data included demographics, epilepsy type, MRI characteristics, epilepsy outcome, and histopathological staining. RESULTS: We reviewed cortical resections from 75 patients with complete pathological studies. In three patients, cortical lesions demonstrated histopathological findings consistent with a SEGA within the resected tuber tissue, with no intraventricular SEGA. All lesions were cortically based and none had any intraventricular extension. No patient had been treated before surgery with an mTORi. Two of the three patients remain Engel grade I-II. All lesions stained positive for glial fibrillary acidic protein (GFAP), synaptophysin, and neuronal nuclear antigen (NeuN). CONCLUSION: This is the first description of cortical tubers harboring SEGA tissue. This observation though preliminary may suggest a subgroup of patients with intractable epilepsy in whom mTORi may be considered before surgical intervention.
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Astrocitoma/etiologia , Neoplasias Encefálicas/etiologia , Córtex Cerebral/diagnóstico por imagem , Esclerose Tuberosa/complicações , Astrocitoma/diagnóstico por imagem , Astrocitoma/terapia , Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/terapia , Córtex Cerebral/metabolismo , Pré-Escolar , Citocinas/metabolismo , Epilepsia/diagnóstico por imagem , Epilepsia/etiologia , Feminino , Proteína Glial Fibrilar Ácida/metabolismo , Humanos , Lactente , Antígeno Ki-67/metabolismo , Imageamento por Ressonância Magnética , Masculino , Procedimentos Neurocirúrgicos , Fosfopiruvato Hidratase/metabolismo , Estudos Retrospectivos , Tomógrafos Computadorizados , Esclerose Tuberosa/diagnóstico por imagem , Esclerose Tuberosa/terapiaRESUMO
While cerebral amyloid angiopathy is a common cause of lobar hemorrhage, rarely it may be associated with an inflammatory response, thought to be incited by amyloid deposits. We report a 73-year-old woman with an extensive cancer history who presented with tumor-like lesions and symptoms of homonymous hemianopia and prosopagnosia. Found to have cerebral amyloid angiopathy-related inflammation proven by brain biopsy, she was treated successfully with immunosuppression.
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Adenocarcinoma/complicações , Angiopatia Amiloide Cerebral/complicações , Hemianopsia/etiologia , Neoplasias Pulmonares/complicações , Prosopagnosia/etiologia , Adenocarcinoma/diagnóstico , Adenocarcinoma de Pulmão , Idoso , Biópsia , Angiopatia Amiloide Cerebral/diagnóstico , Feminino , Hemianopsia/diagnóstico , Humanos , Neoplasias Pulmonares/diagnóstico , Imageamento por Ressonância Magnética , Tomografia por Emissão de Pósitrons , Prosopagnosia/diagnóstico , Tomografia Computadorizada por Raios XAssuntos
Neoplasias Encefálicas/patologia , Neoplasias Neuroepiteliomatosas/patologia , Adolescente , Antineoplásicos Alquilantes/uso terapêutico , Edema Encefálico/etiologia , Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/cirurgia , Quimiorradioterapia , Feminino , Fusão Gênica , Humanos , Imageamento por Ressonância Magnética , Proteínas Associadas aos Microtúbulos/genética , Neoplasias Neuroepiteliomatosas/diagnóstico por imagem , Neoplasias Neuroepiteliomatosas/cirurgia , Receptor Tipo 3 de Fator de Crescimento de Fibroblastos/genética , Temozolomida/uso terapêuticoRESUMO
IDH1 and IDH2 mutational status is a critical biomarker with diagnostic, prognostic, and treatment implications in glioma. Although IDH1 p.R132H-specific immunohistochemistry is available, it is unable to identify other mutations in IDH1/2. Next-generation sequencing can accurately determine IDH1/2 mutational status but suffers from long turnaround time when urgent treatment planning and initiation is medically necessary. The Idylla assay can detect IDH1/2 mutational status from unstained formalin-fixed paraffin-embedded (FFPE) slides in as little as a few hours. In a clinical validation, we demonstrate clinical accuracy of 97% compared to next-generation sequencing. Sensitivity studies demonstrated a limit of detection of 2.5-5% variant allele frequency, even at DNA inputs below the manufacturer's recommended threshold. Overall, the assay is an effective and accurate method for rapid determination of IDH1/2 mutational status.
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Neoplasias Encefálicas , Glioma , Isocitrato Desidrogenase , Mutação , Humanos , Isocitrato Desidrogenase/genética , Glioma/genética , Glioma/patologia , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/enzimologia , Análise Mutacional de DNA/métodos , Inclusão em Parafina , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/análise , Sequenciamento de Nucleotídeos em Larga Escala , Formaldeído , Fixação de Tecidos/métodos , Reprodutibilidade dos TestesRESUMO
BACKGROUND AND PURPOSE: WHO grade 3 meningiomas are rare and poorly understood and have a higher propensity for recurrence, metastasis, and worsened clinical outcomes compared with lower-grade meningiomas. The purpose of our study was to prospectively evaluate the molecular profile, PET characteristics, and outcomes of patients with World Health Organization grade 3 meningiomas who were imaged with gallium 68 (68Ga) DOTATATE PET/MR imaging. MATERIALS AND METHODS: Patients with World Health Organization grade 3 meningiomas enrolled in our prospective observational cohort evaluating the utility of (68Ga) DOTATATE PET/MR imaging in somatostatin receptor positive brain tumors were included. We stratified patients by de novo-versus-secondary-progressive status and evaluated the differences in the PET standard uptake value, molecular profiles, and clinical outcomes. RESULTS: Patients met the inclusion criteria (secondary-progressive: 7/14; de novo: 7/14). The secondary-progressive cohort had a significantly higher per-patient number of surgeries (4.1 versus 1.6; P = .011) and trended toward a higher number of radiation therapy courses (2.4 versus 1.6; P = .23) and cumulative radiation therapy doses (106Gy versus 68.3Gy; P = .31). The secondary-progressive cohort had a significantly lower progression-free survival compared with the de novo cohort (4.8 versus 37.7 months; P = .004). Secondary-progressive tumors had distinct molecular pathology profiles with higher numbers of mutations (3.5 versus 1.2; P = .024). Secondary-progressive tumors demonstrated higher PET standard uptake values (17.1 versus 12.4; P = .0021). CONCLUSIONS: Our study confirms prior work illustrating distinct clinical outcomes in secondary-progressive and de novo World Health Organization grade 3 meningiomas. Furthermore, our findings support (68Ga) DOTATATE PET/MR imaging as a useful management strategy in World Health Organization grade 3 meningiomas and provide insight into meningioma biology, as well as clinical management implications.
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Imageamento por Ressonância Magnética , Neoplasias Meníngeas , Meningioma , Imagem Multimodal , Compostos Organometálicos , Tomografia por Emissão de Pósitrons , Humanos , Meningioma/diagnóstico por imagem , Meningioma/patologia , Feminino , Masculino , Pessoa de Meia-Idade , Neoplasias Meníngeas/diagnóstico por imagem , Neoplasias Meníngeas/patologia , Tomografia por Emissão de Pósitrons/métodos , Imageamento por Ressonância Magnética/métodos , Idoso , Imagem Multimodal/métodos , Estudos Prospectivos , Progressão da Doença , Gradação de Tumores , Adulto , Organização Mundial da Saúde , Compostos RadiofarmacêuticosRESUMO
DNA methylation is an essential molecular assay for central nervous system (CNS) tumor diagnostics. While some fusions define specific brain tumors, others occur across many different diagnoses. We performed a retrospective analysis of 219 primary CNS tumors with whole genome DNA methylation and RNA next-generation sequencing. DNA methylation profiling results were compared with RNAseq detected gene fusions. We detected 105 rare fusions involving 31 driver genes, including 23 fusions previously not implicated in brain tumors. In addition, we identified 6 multi-fusion tumors. Rare fusions and multi-fusion events can impact the diagnostic accuracy of DNA methylation by decreasing confidence in the result, such as BRAF, RAF, or FGFR1 fusions, or result in a complete mismatch, such as NTRK, EWSR1, FGFR, and ALK fusions. IMPLICATIONS: DNA methylation signatures need to be interpreted in the context of pathology and discordant results warrant testing for novel and rare gene fusions.
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Neoplasias Encefálicas , Metilação de DNA , Humanos , Metilação de DNA/genética , Estudos Retrospectivos , Neoplasias Encefálicas/diagnóstico , Neoplasias Encefálicas/genética , Fusão Gênica , Proteínas de Fusão Oncogênica/genéticaRESUMO
BACKGROUND: Absence of hydrocephalus on neuroimaging may impart a false sense of security for patients with pineal cysts. In this case series, we characterize a subset of patients with pineal cysts having an occult presentation. Unifying features of worsening paroxysmal headaches suggesting intermittent obstructive hydrocephalus and radiographic evidence of third ventricular invagination characterize these patients as high risk. OBJECTIVE: To define features of occult, high-risk pineal cysts and outcomes of endoscopic cyst fenestration. METHODS: Charts were retrospectively reviewed for patients with pineal cysts evaluated at our institution between 2018 and 2021 who underwent endoscopic cyst fenestration. To capture cysts presenting as occult, patients were excluded if hydrocephalus was noted at presentation. Relevant clinical history, imaging, operative data, and clinical outcomes were reviewed. RESULTS: Of 50 pineal cyst patients, 4 satisfied inclusion criteria. All patients presented with worsening paroxysmal headaches. In addition, 75% (3/4) also experienced intermittent syncope. Patients exhibited no hydrocephalus (n = 3) or fluctuating ventricular size on longitudinal imaging (n = 1). In all cases, high-resolution sagittal 3-dimensional T2 magnetic resonance imaging demonstrated invagination of the cyst anteriorly into the posterior third ventricle. All patients underwent endoscopic cyst fenestration with complete symptom resolution (mean follow-up of 20.6 months; range 3.5-37.4 months). CONCLUSION: The clinical history for occult, high-risk pineal cysts is notable for worsening paroxysmal headaches and episodic alterations of consciousness suggesting intermittent obstructive hydrocephalus. Because ventricular size can appear normal on standard imaging protocols, clinical suspicion should trigger workup with high-resolution magnetic resonance imaging designed to detect these cysts. Endoscopic cyst fenestration is a safe and efficacious management strategy.
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Neoplasias Encefálicas , Cistos do Sistema Nervoso Central , Cistos , Hidrocefalia , Humanos , Estudos Retrospectivos , Cistos/complicações , Cistos/diagnóstico por imagem , Cistos/cirurgia , Hidrocefalia/diagnóstico por imagem , Hidrocefalia/etiologia , Hidrocefalia/cirurgia , Neoplasias Encefálicas/cirurgia , Cistos do Sistema Nervoso Central/complicações , Cistos do Sistema Nervoso Central/diagnóstico por imagem , Cistos do Sistema Nervoso Central/cirurgia , Cefaleia/etiologiaRESUMO
Background: Polymorphous low-grade neuroepithelial tumor of the young (PLNTY) is a recently described entity that can mimic high-grade glioma (HGG) in histologic and molecular features; however, factors predicting aggressive behavior in these tumors are unclear. Methods: We present an indolent neuroepithelial neoplasm in a 59-year-old female with imaging initially suggestive of HGG, and a series of adult patients with HGG harboring FGFR3-TACC3 fusions are also presented for comparison. Results: Pathology in the case patient revealed low-grade cytomorphology, microcalcifications, unusual neovascularization, and a low proliferation index. The lesion was diffusely CD34+ and harbored an FGFR3-TACC3 fusion and TERT promoter mutation. A diagnosis of PLNTY was therefore favored and the patient was observed with no progression at 15-month follow-up. In patients with HGG with FGFR3-TACC3 fusions, molecular findings included IDH-wildtype status, absence of 1p19q codeletion, CDKN2A loss, TERT promoter mutations and lack of MGMT promoter methylation. These patients demonstrated a median 15-month overall survival and a 6-month progression-free survival. Conclusion: PLNTY is a rare low-grade entity that can display characteristics of HGG, particularly in adults. Presence of FGFR3-TACC3 fusions and other high-grade features should raise concern for a more malignant precursor lesion when a diagnosis of PLNTY is considered.
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Pilocytic astrocytomas are the most common pediatric brain tumors, typically presenting as low-grade neoplasms. We report two cases of pilocytic astrocytoma with atypical tumor progression. Case 1 involves a 12-yr-old boy with an unresectable suprasellar tumor, negative for BRAF rearrangement but harboring a BRAF p.V600E mutation. He experienced tumor size reduction and stable disease following dabrafenib treatment. Case 2 describes a 6-yr-old boy with a thalamic tumor that underwent multiple resections, with no actionable driver detected using targeted next-generation sequencing. Whole-genome and RNA-seq analysis identified an internal tandem duplication in FGFR1 and RAS pathway activation. Future management options include FGFR1 inhibitors. These cases demonstrate the importance of escalating molecular diagnostics for pediatric brain cancer, advocating for early reflexing to integrative whole-genome sequencing and transcriptomic profiling when targeted panels are uninformative. Identifying molecular drivers can significantly impact treatment decisions and improve patient outcomes.
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Astrocitoma , Neoplasias Encefálicas , Masculino , Criança , Humanos , Proteínas Proto-Oncogênicas B-raf/genética , Patologia Molecular , Astrocitoma/diagnóstico , Astrocitoma/genética , Neoplasias Encefálicas/diagnóstico , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , MutaçãoRESUMO
Background: Central nervous system (CNS) cancer is the 10th leading cause of cancer-associated deaths for adults, but the leading cause in pediatric patients and young adults. The variety and complexity of histologic subtypes can lead to diagnostic errors. DNA methylation is an epigenetic modification that provides a tumor type-specific signature that can be used for diagnosis. Methods: We performed a prospective study using DNA methylation analysis as a primary diagnostic method for 1921 brain tumors. All tumors received a pathology diagnosis and profiling by whole genome DNA methylation, followed by next-generation DNA and RNA sequencing. Results were stratified by concordance between DNA methylation and histopathology, establishing diagnostic utility. Results: Of the 1602 cases with a World Health Organization histologic diagnosis, DNA methylation identified a diagnostic mismatch in 225 cases (14%), 78 cases (5%) did not classify with any class, and in an additional 110 (7%) cases DNA methylation confirmed the diagnosis and provided prognostic information. Of 319 cases carrying 195 different descriptive histologic diagnoses, DNA methylation provided a definitive diagnosis in 273 (86%) cases, separated them into 55 methylation classes, and changed the grading in 58 (18%) cases. Conclusions: DNA methylation analysis is a robust method to diagnose primary CNS tumors, improving diagnostic accuracy, decreasing diagnostic errors and inconclusive diagnoses, and providing prognostic subclassification. This study provides a framework for inclusion of DNA methylation profiling as a primary molecular diagnostic test into professional guidelines for CNS tumors. The benefits include increased diagnostic accuracy, improved patient management, and refinements in clinical trial design.
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While Machine Learning (ML) models have been increasingly applied to a range of histopathology tasks, there has been little emphasis on characterizing these models and contrasting them with human experts. We present a detailed empirical analysis comparing expert neuropathologists and ML models at predicting IDH mutation status in H&E-stained histology slides of infiltrating gliomas, both independently and synergistically. We find that errors made by neuropathologists and ML models trained using the TCGA dataset are distinct, representing modest agreement between predictions (human-vs.-human κ = 0.656; human-vs.-ML model κ = 0.598). While no ML model surpassed human performance on an independent institutional test dataset (human AUC = 0.901, max ML AUC = 0.881), a hybrid model aggregating human and ML predictions demonstrates predictive performance comparable to the consensus of two expert neuropathologists (hybrid classifier AUC = 0.921 vs. two-neuropathologist consensus AUC = 0.920). We also show that models trained at different levels of magnification exhibit different types of errors, supporting the value of aggregation across spatial scales in the ML approach. Finally, we present a detailed interpretation of our multi-scale ML ensemble model which reveals that predictions are driven by human-identifiable features at the patch-level.
Assuntos
Neoplasias Encefálicas , Glioma , Humanos , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Imageamento por Ressonância Magnética , Mutação , Isocitrato Desidrogenase/genética , Glioma/genética , Glioma/patologia , Aprendizado de MáquinaRESUMO
Biallelic inactivation of NF2 represents the primary or sole oncogenic driver event in the vast majority of schwannomas. We report on a four-year-old female who underwent subtotal resection of a right medullary intraparenchymal schwannoma. RNA sequencing revealed an in-frame fusion between exon 5 of YAP1 and exon 2 of MAML2. YAP1-MAML2 fusions have previously been reported in a variety of tumor types, but not schwannomas. Our report expands the spectrum of oncogenic YAP1 gene fusions an alternative to NF2 inactivation to include sporadic schwannoma, analogous to what has recently been described in NF2-wildtype pediatric meningiomas. Appropriate somatic and germline molecular testing should be undertaken in all young patients with solitary schwannoma and meningioma given the high prevalence of an underlying tumor predisposition syndrome. In such patients, the identification of a somatic non-NF2 driver alteration such as this newly described YAP1 fusion, can help ascertain the diagnosis of a sporadic schwannoma.
Assuntos
Neoplasias Meníngeas , Meningioma , Neurilemoma , Neurofibromatose 2 , Tronco Encefálico/patologia , Criança , Pré-Escolar , Feminino , Fusão Gênica , Humanos , Neoplasias Meníngeas/genética , Meningioma/genética , Neurilemoma/genética , Neurilemoma/patologia , Neurilemoma/cirurgia , Neurofibromatose 2/genética , Transativadores/genética , Fatores de Transcrição/genética , Proteínas de Sinalização YAPRESUMO
Since the introduction of integrated histological and molecular diagnoses by the 2016 World Health Organization (WHO) Classification of Tumors of the Nervous System, an increasing number of molecular markers have been found to have prognostic significance in infiltrating gliomas, many of which have now become incorporated as diagnostic criteria in the 2021 WHO Classification. This has increased the applicability of targeted-next generation sequencing in the diagnostic work-up of neuropathology specimens and in addition, raises the question of whether targeted sequencing can, in practice, reliably replace older, more traditional diagnostic methods such as immunohistochemistry and fluorescence in-situ hybridization. Here, we demonstrate that the Oncomine Cancer Gene Mutation Panel v2 assay targeted-next generation sequencing panel for solid tumors is not only superior to IHC in detecting mutation in IDH1/2 and TP53 but can also predict 1p/19q co-deletion with high sensitivity and specificity relative to fluorescence in-situ hybridization by looking at average copy number of genes sequenced on 1p, 1q, 19p, and 19q. Along with detecting the same molecular data obtained from older methods, targeted-next generation sequencing with an RNA sequencing component provides additional information regarding the presence of RNA based alterations that have diagnostic significance and possible therapeutic implications. From this work, we advocate for expanded use of targeted-next generation sequencing over more traditional methods for the detection of important molecular alterations as a part of the standard diagnostic work up for CNS neoplasms.