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INTRODUCTION: Glioblastoma is a uniformly lethal primary central nervous system neoplasm. Despite the increased understanding of its pathophysiology and treatment advancements, median overall survival for patients with glioblastoma, IDH-wild type remains 14 to 21 months from diagnosis. CASE REPORT: We present the case of a 48-year-old female who presented with a focal seizure and was found to have a right frontal lobe mass on the brain magnetic resonance imaging. She underwent gross total resection and received a histological diagnosis of glioblastoma. She received radiotherapy and 6 cycles of carmustine (BCNU). Seventeen months later, she developed left hemiparesis. Imaging was concerning for tumor progression, and she was treated with 1 cycle of mechlorethamine, vincristine (oncovin), procarbazine, and prednisone (MOPP). Subsequent surveillance imaging demonstrated a therapeutic response. Twenty-seven years after her glioblastoma diagnosis, she developed status epilepticus and died from respiratory failure. Neuropathology on autopsy demonstrated extensive treatment-related changes but no evidence of recurrent glioblastoma. Genomic testing performed over 30 years after her original diagnosis revealed a profile diagnostic of glioblastoma, IDH-wild type per 2021 World Health Organization criteria. CONCLUSIONS: This patient is one of the longest-known survivors of glioblastoma, IDH-wild type, with pathologic confirmation of glioblastoma at the time of her resection and no evidence of residual disease 26 years after her last treatment. She presented with multiple factors associated with long-term glioblastoma survivorship, including female sex, young age, high Karnofsky score, and multimodal therapy. This case shows that long-term survival after glioblastoma diagnosis is possible and likely mediated through a combination of individual, tumor, and treatment factors.
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Neoplasias Encefálicas , Glioblastoma , Humanos , Glioblastoma/terapia , Glioblastoma/diagnóstico por imagem , Glioblastoma/patologia , Feminino , Pessoa de Meia-Idade , Neoplasias Encefálicas/patologia , Isocitrato Desidrogenase/genética , Evolução FatalRESUMO
Diffuse midline glioma, H3 K27-altered (DMG-H3 K27) is an aggressive group of diffuse gliomas that predominantly occurs in pediatric patients, involves midline structures, and displays loss of H3 p.K28me3 (K27me3) expression by immunohistochemistry and characteristic genetic/epigenetic profile. Rare examples of a diffuse glioma with an H3 p.K28M (K27M) mutation and without involvement of the midline structures, so-called "diffuse hemispheric glioma with H3 p.K28M (K27M) mutation" (DHG-H3 K27), have been reported. Herein, we describe 2 additional cases of radiologically confirmed DHG-H3 K27 and summarize previously reported cases. We performed histological, immunohistochemical, molecular, and DNA methylation analysis and provided clinical follow-up in both cases. Overall, DHG-H3 K27 is an unusual group of diffuse gliomas that shows similar clinical, histopathological, genomic, and epigenetic features to DMG-H3 K27 as well as enrichment for activating alterations in MAPK pathway genes. These findings suggest that DHG-H3 K27 is closely related to DMG-H3 K27 and may represent an unusual presentation of DMG-H3 K27 without apparent midline involvement and with frequent MAPK pathway activation. Detailed reports of additional cases with clinical follow-up will be important to expand our understanding of this unusual group of diffuse gliomas and to better define the clinical outcome and how to classify DHG-H3 K27.
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Neoplasias Encefálicas , Glioma , Humanos , Criança , Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Histonas/genética , Glioma/genética , Glioma/patologia , Mutação/genética , EpigenômicaRESUMO
BACKGROUND AND AIMS: Comprehensive study of sural nerve biopsy utility based on individual histopathologic preparations is lacking. We aimed to quantify the value of different histologic preparations in diagnosis. METHODS: One hundred consecutive sural nerves were studied by standard histological preparations plus graded teased nerve fibers (GTNF), immunohistochemistry, and epoxy-semithin morphometry. Three examiners scored the individual preparations separately by a questionnaire of neuropathic and interstitial abnormalities, masked to the biopsy number, versus a gold-standard of all preparations. Multivariate modeling was utilized to determine best approach versus the gold-standard. RESULTS: Highest confidence (range 8-9 of 10) and inter-rater reliability (99%) for fiber abnormalities came from GTNF, and interstitial abnormalities from paraffin stains (range 7-8, 99%). Vasculitic neuropathy associated with GTNF axonal degeneration (moderate to severe 79%) with OR 3.8, 95% CI (1.001-14.7), p = .04, but not significantly with the other preparations. Clinicopathologic diagnoses associated with teased fiber abnormalities in chronic inflammatory demyelinating polyradiculoneuropathy, 80% (8/10); amyloidosis, 50% (1/2); adult-onset polyglucosan disease 100% (1/1). GTNF and paraffin stains significantly correlated with fiber density determined by morphometric analysis (GTNF: OR 9.9, p < .0001, paraffin: OR 3.8, p = .03). GTNF combined with paraffin sections had highest accuracy for clinicopathologic diagnoses and fiber density with 0.86 C-stat prediction versus morphometric analysis. Pathological results lead to initiation or changes of immunotherapy in 70% (35/50; initiation n = 22, reduction n = 9, escalation n = 4) with the remaining having alternative intervention or no change. INTERPRETATION: Nerve biopsy paraffin stains combined with GTNF have highest diagnostic utility, confidence, inter-rater reliability, improving accuracy for a pathologic diagnosis aiding treatment recommendations. Immunostains and epoxy preparations are also demonstrated useful supporting consensus guidelines. This study provides class II evidence for individual nerve preparation utility.
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Polirradiculoneuropatia Desmielinizante Inflamatória Crônica , Nervo Sural , Adulto , Humanos , Nervo Sural/patologia , Parafina , Reprodutibilidade dos Testes , Polirradiculoneuropatia Desmielinizante Inflamatória Crônica/diagnóstico , Biópsia/métodosAssuntos
Neoplasias Encefálicas , Glioma , Adulto , Humanos , Glioma/genética , Neoplasias Encefálicas/genética , MutaçãoRESUMO
PURPOSE: Frequent activating mutations in the mitogen-activated protein kinase (MAPK) pathway genes have been identified in histiocytoses. MAPK signaling consistently upregulates cyclin D1. The goal of this study was to determine whether cyclin D1 expression by immunohistochemistry is a useful diagnostic marker for periocular histiocytoses and to further characterize their genetic basis. DESIGN: Retrospective observational case series. METHODS: Pathology records were searched for all patients with histiocytoses diagnosed between 1995 and 2020. Eleven histiocyte-rich inflammatory lesions and 10 xanthelasma served as controls. Cyclin D1 immunohistochemistry was performed on all tissues. A subset of histiocytoses was evaluated by next-generation sequencing (NGS) and droplet digital PCR (ddPCR). RESULTS: There were 36 patients, 15 males (42%) and 21 females (58%), with histiocytoses: 9 juvenile xanthogranuloma (25%), 8 adult-onset asthma and periocular xanthogranuloma (22%), 7 Langerhans cell histiocytosis (19%), 5 Rosai-Dorfman disease (14%), 5 xanthogranuloma-not otherwise specified (14%), 1 Erdheim-Chester disease (3%), and 1 histiocytic sarcoma (3%). Moderate to strong nuclear cyclin D1 expression was present in ≥50% of lesional cells in histiocytoses (23/36, 64%), significantly more when compared to histiocyte-rich inflammatory lesions (0/11, 0%, P<.001) and xanthelasma (0/10, 0%, P<.001). Cyclin D1 was expressed in <10% of lesional cells in all 11 histiocyte-rich inflammatory lesions (P<.001) and all 10 xanthelasma lesions (P<.001). MAPK pathway gene mutations were detected in 12 of 14 (86%) histiocytoses successfully assayed by NGS and/or ddPCR. CONCLUSIONS: Our study confirms that the cyclin D1 immunohistochemical stain is a useful diagnostic marker for periocular histiocytoses, correlating with underlying mutations in MAPK pathway genes.
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Histiocitose de Células de Langerhans , Neoplasias , Adulto , Ciclina D1/genética , Células Dendríticas/metabolismo , Células Dendríticas/patologia , Feminino , Histiocitose de Células de Langerhans/genética , Histiocitose de Células de Langerhans/metabolismo , Histiocitose de Células de Langerhans/patologia , Humanos , Macrófagos/metabolismo , Macrófagos/patologia , Masculino , Proteínas Quinases Ativadas por Mitógeno , Biologia Molecular , Estudos RetrospectivosRESUMO
Introduction: Loss of BAP1 protein expression emerged as a negative prognostic marker in uveal melanoma (UM) and has primarily been studied in enucleations. Intraocular biopsy is frequently performed prior to UM globe-conserving therapy. Methods: We retrospectively evaluated BAP1 immunostaining of UM in 16 biopsies and 8 subsequent enucleations, and results were correlated with the UM-specific gene expression profile (GEP; n = 11), chromosome 3 status by FISH and/or chromosomal microarray (n = 12; 9 also had GEP), and clinical outcomes. Results: UM involved the choroid in 15 (of 16) cases. Biopsy was performed for prognostication (n = 12) or diagnosis (n = 4). Treatment included brachytherapy (n = 13; 5 followed by enucleation) or enucleation only (n = 3). BAP1 nuclear immunostaining was positive in 9, negative in 4, and equivocal in 3 biopsies. For the 3 equivocal biopsies, BAP1 immunostaining was positive in 2 (of 3) subsequent enucleations. BAP1 immunostaining was concordant between all 5 remaining biopsies and enucleations. BAP1-positive biopsies had disomy 3 (n = 6) or 3p loss (n = 1) and class 1 GEP (n = 6). BAP1-negative biopsies had monosomy 3 (n = 3) and class 2 GEP (n = 2). Median follow-up was 62.5 months (range, 17-150). For BAP1-positive UM patients, 8 were alive (7 without metastatic disease) and 3 had died (1 melanoma-related death). Among BAP1-negative UM patients, 2 were alive (1 with metastatic disease) and 3 had melanoma-related deaths. Conclusion: BAP1 immunostaining in biopsies highly correlates with results in subsequent enucleations and with well-established UM prognostic markers, representing a potential additional prognostic tool for UM biopsies.
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PURPOSE: Several professional societies have published guidelines for the clinical interpretation of somatic variants, which specifically address diagnostic, prognostic, and therapeutic implications. Although these guidelines for the clinical interpretation of variants include data types that may be used to determine the oncogenicity of a variant (eg, population frequency, functional, and in silico data or somatic frequency), they do not provide a direct, systematic, and comprehensive set of standards and rules to classify the oncogenicity of a somatic variant. This insufficient guidance leads to inconsistent classification of rare somatic variants in cancer, generates variability in their clinical interpretation, and, importantly, affects patient care. Therefore, it is essential to address this unmet need. METHODS: Clinical Genome Resource (ClinGen) Somatic Cancer Clinical Domain Working Group and ClinGen Germline/Somatic Variant Subcommittee, the Cancer Genomics Consortium, and the Variant Interpretation for Cancer Consortium used a consensus approach to develop a standard operating procedure (SOP) for the classification of oncogenicity of somatic variants. RESULTS: This comprehensive SOP has been developed to improve consistency in somatic variant classification and has been validated on 94 somatic variants in 10 common cancer-related genes. CONCLUSION: The comprehensive SOP is now available for classification of oncogenicity of somatic variants.
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Genoma Humano , Neoplasias , Testes Genéticos/métodos , Variação Genética/genética , Genoma Humano/genética , Genômica/métodos , Humanos , Neoplasias/genética , VirulênciaRESUMO
PURPOSE: The aim of this study was to demonstrate the role of carbon fiducial markers (fiducials) for guiding radiotherapy in the management of uveal melanoma (UM). METHODS: This is a retrospective interventional case series at a single-center ocular oncology practice. The medical records were reviewed retrospectively for all patients with UM treated with stereotactic radiosurgery using episcleral fiducials. We report our short-term experience with surgical placement of fiducials, UM localization, treatment outcomes, and optimization approaches. RESULTS: We evaluated 11 cases of UM (mean age: 65 years; 64% female). The placed fiducials were numbered from 2 to 4, each secured to the sclera with a surgical microscope or surgical loupes and either 5-0 or 8-0 nylon sutures at 50% scleral depth and 3 mm beyond the tumor margin. Over a median follow-up of 11 months (range: 4.2-43.2 months), no recurrences of intraocular UM were observed. One case of enucleation after stereotactic radiosurgery developed because of radiation-related surface irritation, ocular dryness, and secondary keratopathy. Two patients (18%) with 5-0 nylon sutures required fiducial removal because of suture exposure, successfully accomplished in an outpatient setting. CONCLUSIONS: Fiducials represent a viable alternative to tantalum rings for guiding stereotactic radiotherapy to manage UM and provide additional definition of the tumor border with linear orientation that helps optimize targeted radiation delivery. Fiducial placement with a 3-mm margin from the visible tumor border should not result in clinically important radiation dose attenuation at the tumor margins. Anteriorly placed fiducials may cause discomfort, yet they are easily removed in the outpatient setting.
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Polymorphous low-grade neuroepithelial tumor of the young (PLNTY) is a recently described epileptogenic tumor characterized by oligodendroglioma-like components, aberrant CD34 expression, and frequent mitogen-activated protein kinase (MAPK) pathway activation. We molecularly profiled 13 cases with diagnostic histopathological features of PLNTY (10 female; median age, 16 years; range, 5-52). Patients frequently presented with seizures (9 of 12 with available history) and temporal lobe tumors (9 of 13). MAPK pathway activating alterations were identified in all 13 cases. Fusions were present in the 7 youngest patients: FGFR2-CTNNA3 (n = 2), FGFR2-KIAA1598 (FGFR2-SHTN1) (n = 1), FGFR2-INA (n = 1), FGFR2-MPRIP (n = 1), QKI-NTRK2 (n = 1), and KIAA1549-BRAF (n = 1). BRAF V600E mutation was present in 6 patients (17 years or older). Two fusion-positive cases additionally harbored TP53/RB1 abnormalities suggesting biallelic inactivation. Copy number changes predominantly involving whole chromosomes were observed in all 10 evaluated cases, with losses of chromosome 10q occurring with FGFR2-KIAA1598 (SHTN1)/CTNNA3 fusions. The KIAA1549-BRAF and QKI-NTRK2 fusions were associated respectively with a 7q34 deletion and 9q21 duplication. This study shows that despite its name, PLNTY also occurs in older adults, who frequently show BRAF V600E mutation. It also expands the spectrum of the MAPK pathway activating alterations associated with PLNTY and demonstrates recurrent chromosomal copy number changes consistent with chromosomal instability.
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Glicoproteínas de Membrana/metabolismo , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , Neoplasias Neuroepiteliomatosas/metabolismo , Receptor trkB/metabolismo , Convulsões/metabolismo , Adulto , Aneuploidia , Cromossomos Humanos Par 9/metabolismo , Feminino , Fusão Gênica/fisiologia , Humanos , Recidiva , Convulsões/genética , Fatores de Transcrição/metabolismoRESUMO
Molecular testing has become part of the routine diagnostic workup of brain tumors after the implementation of integrated histomolecular diagnoses in the 2016 WHO classification update. It is important for every neuropathologist to be aware of practical preanalytical, analytical, and postanalytical factors that impact the performance and interpretation of molecular tests. Prior to testing, optimizing tumor purity and tumor amount increases the ability of the molecular test to detect the genetic alteration of interest. Recognizing basic molecular testing platform analytical characteristics allows selection of the optimal platform for each clinicopathological scenario. Finally, postanalytical considerations to properly interpret molecular test results include understanding the clinical significance of the detected genetic alteration, recognizing that detected clinically significant genetic alterations are occasionally germline constitutional rather than somatic tumor-specific, and being cognizant that recommended and commonly used genetic nomenclature may differ. Potential pitfalls in brain tumor molecular diagnosis are also discussed.
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Neoplasias Encefálicas/diagnóstico , Neoplasias Encefálicas/patologia , Técnicas de Diagnóstico Molecular , Neuropatologia , Patologia Molecular , Pesquisa Biomédica/métodos , Humanos , Mutação/genética , Neuropatologia/métodosRESUMO
Posterior fossa (PF) diffuse gliomas in pediatric patients frequently harbor the H3 K27M mutation. Among adults, PF diffuse gliomas are rare, with limited data regarding molecular features and clinical outcomes. We identified 28 adult PF diffuse glioma patients (17 males; median: 50 y, range: 19 to 78 y), with surgery performed at our institution (13 brainstem; 15 cerebellum). Histologic subtypes included anaplastic astrocytoma (n=21), glioblastoma (n=6), and diffuse astrocytoma (n=1). Immunohistochemistry was performed for H3 K27M (n=26), IDH1-R132H (n=28), and ATRX (n=28). A 150-gene neuro-oncology-targeted next-generation sequencing panel was attempted in 24/28, with sufficient informative material in 15 (51.7%). Tumors comprised 4 distinct groups: driver mutations in H3F3A (brainstem=4; cerebellum=2), IDH1 (brainstem=4; cerebellum=4), TERT promotor mutation (brainstem=0; cerebellum=3), and none of these (n=5), with the latter harboring mutations of TP53, PDGFRA, ATRX, NF1, and RB1. All TERT promoter-mutant cases were IDH-wild-type and arose within the cerebellum. To date, 20 patients have died of disease, with a median survival of 16.3 months, 1-year survival of 67.5%. Median survival within the subgroups included: H3F3A=16.4 months, IDH mutant=113.4 months, and TERT promoter mutant=12.9 months. These findings suggest that PF diffuse gliomas affecting adults show molecular heterogeneity, which may be associated with patient outcomes and possible response to therapy, and supports the utility of molecular testing in these tumors.