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Since the World Health Organization (WHO) 2016 revision, the number of molecular markers required for diffuse gliomas has increased, placing a burden on clinical practice. We have established an in-house, molecular diagnostic platform using Senshin-Iryo, a feature of Japan's unique healthcare system, and partially modified the analysis method in accordance with the WHO 2021 revision. Herein, we review over a total 5 years of achievements using this platform. Analyses of IDH, BRAF, and H3 point mutations, loss of heterozygosity (LOH) on 1p/19q and chromosomes 10 and 17, and MGMT methylation were combined into a set that was submitted to Senshin-Iryo as "Drug resistance gene testing for anticancer chemotherapy" and was approved in August 2018. Subsequently, in October 2021, Sanger sequencing for the TERT promoter mutation was added to the set, and LOH analysis was replaced with multiplex ligation-dependent probe amplification (MLPA) to analyze 1p/19q codeletion and newly required genetic markers, such as EGFR, PTEN, and CDKN2A from WHO 2021. Among the over 200 cases included, 54 were analyzed after the WHO 2021 revision. The laboratory has maintained a diagnostic platform where molecular diagnoses are confirmed within 2 weeks. Initial expenditures exceeded the income from patient copayments; however, it has gradually been reduced to running costs alone and is approaching profitability. After the WHO 2021 revision, diagnoses were confirmed using molecular markers obtained from Senshin-Iryo in 38 of 54 cases (70.1%). Among the remaining 16 patients, only four (7.4%) were diagnosed with diffuse glioma, not elsewhere classified, which was excluded in 12 cases where glioblastoma was confirmed by histopathological diagnosis. Our Senshin-Iryo trial functioned as a salvage system to overcome the transition period between continued revisions of WHO classification that has caused a clinical dilemma in the Japanese healthcare system.
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The mutation p.K27M in H3F3A (H3 K27M mutation) is mainly detected in diffuse midline glioma. However, recent studies have demonstrated that H3 K27M mutation could also be observed in a subset of gangliogliomas. Importantly, most H3 K27-mutated ganglioglioma cases also harbor BRAF V600E mutation. Herein, we report a rare case of H3 K27M-mutated ganglioglioma grade 3 without BRAF mutation arising in the medial temporal lobe in an elderly man. A small biopsy specimen was sampled. The pathological diagnosis was diffuse astrocytoma. The tumor progressed gradually during an 18-month follow-up period. Gadolinium enhancement on magnetic resonance imaging was noted 36 months after the biopsy. The patient was referred to a hospital for tumor resection. Histological analysis of resected specimens led to a diagnosis of ganglioglioma grade 3 with H3 K27M mutation. The patient underwent concurrent temozolomide chemotherapy with radiotherapy. Although the patient's condition deteriorated after chemotherapy due to disease progression, he survived for more than 23 months after tumor resection. We present this rare case and discuss the involvement of H3 K27M mutation in ganglioglioma grade 3.
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Neoplasias Encefálicas , Ganglioglioma , Glioma , Idoso , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Meios de Contraste , Gadolínio , Ganglioglioma/genética , Glioma/genética , Histonas/genética , Humanos , Masculino , Mutação , Proteínas Proto-Oncogênicas B-raf/genética , Lobo Temporal/patologiaRESUMO
PURPOSE: Conventional genetic analyzers require surgically obtained tumor tissues to confirm the molecular diagnosis of diffuse glioma. Recent technical breakthroughs have enabled increased utilization of cell-free tumor DNA (ctDNA) in body fluids as a reliable resource for molecular diagnosis in various cancers. Here, we tested the application of a chip-based digital PCR system for the less invasive diagnosis (i.e., liquid biopsy) of diffuse glioma using the cerebrospinal fluid (CSF). METHODS: CSF samples from 34 patients with diffuse glioma were collected from the surgical field during craniotomy. Preoperative lumbar CSF collection was also performed in 11 patients. Extracted ctDNA was used to analyze diagnostic point mutations in IDH1 R132H, TERT promoter (C228T and C250T), and H3F3A (K27M) on the QuantStudio® 3D Digital PCR System. These results were compared with their corresponding tumor DNA samples. RESULTS: We detected either of the diagnostic mutations in tumor DNA samples from 28 of 34 patients. Among them, we achieved precise molecular diagnoses using intracranial CSF in 20 (71%). Univariate analyses revealed that the World Health Organization (WHO) grade (p = 0.0034), radiographic enhancement (p = 0.0006), and Mib1 index (p = 0.01) were significant predictors of precise CSF-based molecular diagnosis. We precisely diagnosed WHO grade III or IV diffuse gliomas using lumbar CSF obtained from 6 (87%) of 7 patients with tumors harboring any mutation. CONCLUSION: We established a novel, non-invasive molecular diagnostic method using a chip-based digital PCR system targeting ctDNA derived from CSF with high sensitivity and specificity, especially for high-grade gliomas.
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Biomarcadores Tumorais/líquido cefalorraquidiano , Biomarcadores Tumorais/genética , Neoplasias Encefálicas/diagnóstico , Glioma/diagnóstico , Reação em Cadeia da Polimerase/métodos , Adolescente , Adulto , Idoso , Neoplasias Encefálicas/líquido cefalorraquidiano , Neoplasias Encefálicas/genética , DNA Tumoral Circulante/líquido cefalorraquidiano , Análise Mutacional de DNA/métodos , Feminino , Glioma/líquido cefalorraquidiano , Glioma/genética , Histonas/genética , Humanos , Isocitrato Desidrogenase/genética , Biópsia Líquida/métodos , Masculino , Pessoa de Meia-Idade , Mutação , Patologia Molecular/métodos , Telomerase/genética , Adulto JovemRESUMO
PURPOSE: Although we have shown the clinical benefit of bevacizumab (BEV) in the treatment of unresectable newly diagnosed glioblastomas (nd-GBM), the relationship between early radiographic response and survival outcome remains unclear. We performed a volumetric study of early radiographic responses in nd-GBM treated with BEV. METHODS: Twenty-two patients with unresectable nd-GBM treated with BEV during concurrent temozolomide radiotherapy were analyzed. An experienced neuroradiologist interpreted early responses on fluid-attenuated inversion recovery (FLAIR) and gadolinium-enhanced T1-weighted images (GdT1WI). Volumetric changes were evaluated using diffusion-weighted imaging (DWI) and GdT1WI according to the Response Assessment in Neuro-Oncology (RANO) criteria. The results were categorized into improved (complete response [CR] or partial response [PR]) or non-improved (stable disease [SD] or progressive disease [PD]) groups; outcomes were compared using Kaplan-Meier analysis. RESULTS: The volumetric GdT1WI improvement was a significant predictive factor for overall survival (OS) prolongation (p = 0.0093, median OS: 24.7 vs. 13.6 months); however, FLAIR and DWI images were not predictive. The threshold for the neuroradiologist's interpretation of improvement in GdT1WI was nearly 20% of volume reduction, which was lesser than 50%, the definition of PR applied in the RANO criteria. However, even less stringent neuroradiologist interpretation could successfully predict OS prolongation (improved vs. non-improved: p = 0.0067, median OS: 17.6 vs. 8.3 months). Significant impact of OS on the early response in volumetric GdT1WI was observed within the cut-off range of 20-50% (20%, p = 0.0315; 30%, p = 0.087; 40%, p = 0.0456). CONCLUSIONS: Early response during BEV-containing chemoradiation can be a predictive indicator of patient outcome in unresectable nd-GBM.
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Neoplasias Encefálicas , Glioblastoma , Bevacizumab/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/terapia , Quimiorradioterapia , Gadolínio , Glioblastoma/tratamento farmacológico , Glioblastoma/terapia , Humanos , Temozolomida/uso terapêutico , Resultado do TratamentoRESUMO
High vascularization is a biological characteristic of glioblastoma (GBM); however, an in-vitro experimental model to verify the mechanism and physiological role of vasculogenesis in GBM is not well-established. Recently, we established a self-organizing vasculogenic model using human umbilical vein endothelial cells (HUVECs) co-cultivated with human lung fibroblasts (hLFs). Here, we exploited this system to establish a realistic model of vasculogenesis in GBM. We developed two polydimethylsiloxane (PDMS) devices, a doughnut-hole dish and a 5-lane microfluidic device to observe the contact-independent effects of glioblastoma cells on HUVECs. We tested five patient-derived and five widely used GBM cell lines. Confocal fluorescence microscopy was used to observe the morphological changes in Red Fluorescent Protein (RFP)-HUVECs and fluorescein isothiocyanate (FITC)-dextran perfusion. The genetic and expression properties of GBM cell lines were analyzed. The doughnut-hole dish assay revealed KNS1451 as the only cells to induce HUVEC transformation to vessel-like structures, similar to hLFs. The 5-lane device assay demonstrated that KNS1451 promoted the formation of a vascular network that was fully perfused, revealing the functioning luminal construction. Microarray analysis revealed that KNS1451 is a mesenchymal subtype of GBM. Using a patient-derived mesenchymal GBM cell line, mature de-novo vessel formation could be induced in HUVECs by contact-independent co-culture with GBM in a microfluidic device. These results support the development of a novel in vitro research model and provide novel insights in the neovasculogenic mechanism of GBM and may potentially facilitate the future detection of unknown molecular targets.
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Neoplasias Encefálicas/genética , Diferenciação Celular/genética , Glioblastoma/genética , Neovascularização Patológica/genética , Vasos Sanguíneos/crescimento & desenvolvimento , Vasos Sanguíneos/patologia , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Proliferação de Células/genética , Técnicas de Cocultura , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Glioblastoma/metabolismo , Glioblastoma/patologia , Células Endoteliais da Veia Umbilical Humana , Humanos , Dispositivos Lab-On-A-Chip , Proteínas Luminescentes/metabolismo , Células-Tronco Mesenquimais/metabolismo , Mesoderma/crescimento & desenvolvimento , Mesoderma/patologia , Neovascularização Patológica/metabolismo , Neovascularização Patológica/patologia , Proteína Vermelha FluorescenteRESUMO
BACKGROUND: In the treatment for glioblastoma (GBM), treatment modalities, such as bevacizumab (BEV) and carmustine wafers implants have been approved in Japan since 2013. However, it is unclear whether such a trend in treatment complexity can accelerate treatment centralization. The aim of this study was to reveal the current trend in the treatment of GBM in Japan. METHODS: We used diagnostic procedure combination (DPC) database to analyze the data of 1,774 patients from 305 institutions between April 2016 and March 2019. To analyze the situations associated with first-line BEV use during concurrent TMZ (temozolomide)-radiotherapy, we compared TMZ alone and TMZ-BEV groups. RESULTS: Of the 1,774 patients with GBM, tumor removal by craniotomy was performed in 1,572 (88.6%) patients, and stereotactic biopsy was performed in 156 (8.8%) patients. A total of 1,229 (69.3%) patients underwent radiotherapy, and 1,287 (72.5%) patients underwent chemotherapy. TMZ alone was administered to 878 (68.2%) and TMZ combined with BEV in 381 (29.6%) patients. In the TMZ-BEV group, as compared to the TMZ-alone group, the rate of discharge to home was significantly lower (P = 0.0044), and the rate of stereotactic biopsy was significantly higher (P < 0.0001). No significant difference was observed in the distribution of patients between the TMZ alone and TMZ-BEV groups depending on the scale of institution (P = 0.1240). CONCLUSION: First-line BEV administration seems to be selected properly regardless of the institutional scale. This Japan-wide study of GBM treatment revealed that high level and newly introduced treatments have been steadily generalized in Japanese institutions.
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Glioblastoma (GBM) most commonly appears to be intraparenchymal tumor, and intraventricular GBMs are rarely reported. In previous reports, the sites of origin were not identified. Here, we report a rare case of intraventricular mucin-producing GBM in a 73-year-old woman who had a strongly enhancing tumor in the right anterior horn of the lateral ventricle. The tumor had previously been identified one and a half years ago as a small asymptomatic lesion attached to the septum pellucidum. It had been documented to gradually enlarge during subsequent follow-up examinations. The patient underwent a gross total resection of the tumor, and a soft and gelatinous mass was observed. The pathological diagnosis was compatible with GBM, and numerous tumor cells having cytoplasmic mucin vacuoles were observed. Genetic analysis revealed TP53 and NFKBIA deletions. The patient received postoperative concurrent chemotherapy with temozolomide and radiotherapy, followed by maintenance administration of temozolomide. A follow-up examination seven months later detected an asymptomatic local recurrent lesion, which was treated with gamma-knife therapy, followed by bevacizumab administration for six months. The patient has remained clinically well for five years following surgery. The origin of a rare tumor entity, intraventricular GBM, and the specific spatial and pathological findings in our case are discussed in this report.
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Neoplasias Encefálicas , Glioblastoma , Idoso , Feminino , Humanos , Ventrículos Laterais , Mucinas , Recidiva Local de Neoplasia , Septo PelúcidoRESUMO
INTRODUCTION: First-line bevacizumab (BEV) is now available as a treatment option for glioblastoma patients with severe clinical conditions in Japan. However, the survival benefits remain controversial. To elucidate these potential survival benefits, we retrospectively analyzed survival in glioblastoma patients receiving BEV. METHODS: We analyzed survival in 120 patients with IDH-wild type glioblastoma treated from 2002 to 2018. Overall survival (OS) was assessed in three treatment era subgroups [pre-temozolomide (TMZ), TMZ, and TMZ-BEV], and the correlations of prognostic factors with survival were evaluated. RESULTS: An improvement in survival was observed after BEV approval (median OS in the pre-TMZ, TMZ, and TMZ-BEV eras: 14.6, 14.9, and 22.1 months, respectively). A Cox proportional hazards model identified extent of resection and MGMT methylation status as significant prognostic factors in the TMZ era; however, these factors were not significant in the TMZ-BEV era. In subgroup analyses, patients with MGMT methylation had improved OS after TMZ introduction (pre-TMZ vs. TMZ, 18.5 vs. 28.1 months; P = 0.13), and those without MGMT methylation had significantly increased OS after BEV approval (TMZ vs. TMZ-BEV, 12.2 vs. 16.7 months; P = 0.04). CONCLUSIONS: Our findings imply that optional first-line administration of BEV can overcome the impact of conventional risk factors and prolong survival complementary to TMZ. The patient subgroups benefitting from TMZ and BEV did not seem to overlap, and stratification based on risk factors, including MGMT methylation status, might be effective for selecting patients in whom BEV should be preferentially used as a first-line therapy.
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Antineoplásicos Alquilantes/uso terapêutico , Antineoplásicos Imunológicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Bevacizumab/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico , Glioblastoma/tratamento farmacológico , Temozolomida/uso terapêutico , Idoso , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Resultado do TratamentoRESUMO
PURPOSE: Diffusion-weighted imaging (DWI) plays an important role in the preoperative assessment of gliomas; however, the diagnostic performance of histogram-derived parameters from mono-, bi-, and stretched-exponential DWI models in the grading of gliomas has not been fully investigated. Therefore, we compared these models' ability to differentiate between high-grade and low-grade gliomas. METHODS: This retrospective study included 22 patients with diffuse gliomas (age, 23-74 years; 12 males; 11 high-grade and 11 low-grade gliomas) who underwent preoperative 3 T-magnetic resonance imaging from October 2014 to August 2019. The apparent diffusion coefficient was calculated from the mono-exponential model. Using 13 b-values, the true-diffusion coefficient, pseudo-diffusion coefficient, and perfusion fraction were obtained from the bi-exponential model, and the distributed-diffusion coefficient and heterogeneity index were obtained from the stretched-exponential model. Region-of-interests were drawn on each imaging parameter map for subsequent histogram analyses. RESULTS: The skewness of the apparent diffusion, true-diffusion, and distributed-diffusion coefficients was significantly higher in high-grade than in low-grade gliomas (0.67 ± 0.67 vs. - 0.18 ± 0.63, 0.68 ± 0.74 vs. - 0.08 ± 0.66, 0.63 ± 0.72 vs. - 0.15 ± 0.73; P = 0.0066, 0.0192, and 0.0128, respectively). The 10th percentile of the heterogeneity index was significantly lower (0.77 ± 0.08 vs. 0.88 ± 0.04; P = 0.0004), and the 90th percentile of the perfusion fraction was significantly higher (12.64 ± 3.44 vs. 7.14 ± 1.70%: P < 0.0001), in high-grade than in low-grade gliomas. The combination of the 10th percentile of the true-diffusion coefficient and 90th percentile of the perfusion fraction showed the best area under the receiver operating characteristic curve (0.96). CONCLUSION: The bi-exponential model exhibited the best diagnostic performance for differentiating high-grade from low-grade gliomas.
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Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/patologia , Imagem de Difusão por Ressonância Magnética/métodos , Glioma/diagnóstico por imagem , Glioma/patologia , Adulto , Idoso , Diagnóstico Diferencial , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Estudos RetrospectivosRESUMO
Diffuse midline glioma, H3 K27M mutant arises from midline structures of the central nervous system and predominately affects pediatric patients. However, this disease entity was only recently established, and the clinical phenotypic spectrum remains largely unclear. We herein report a rare case of diffuse midline glioma, H3 K27M mutant with an unusual distribution in an elderly woman who presented with a diffuse glioma that invaded both sides of the thalami, and left hippocampus and frontoparietal lobes, thus mimicking a hemispheric malignant glioma. A biopsy of the lobular lesion led to a molecular diagnostic confirmation of diffuse midline glioma, H3 K27M mutant. The patient received concurrent bevacizumab and temozolomide therapy with radiation therapy and survived for 30 months. This case highlights the possibility that a glioma with cerebral hemispheric spread in an elderly patient may harbor the H3 K27M mutation.
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Neoplasias Encefálicas/genética , Glioma/genética , Histona Desmetilases com o Domínio Jumonji/genética , Mutação/genética , Idoso , Neoplasias Encefálicas/diagnóstico por imagem , Feminino , Glioma/diagnóstico por imagem , HumanosRESUMO
Here, we report a juvenile (18-year-old male) case of epilepsy-associated, isocitrate dehydrogenase wild-type/histone 3 wild-type diffuse glioma with a rare BRAF mutation and a focal atypical feature resembling diffuse astrocytoma. The patient presented with refractory temporal lobe epilepsy. Subsequently, magnetic resonance imaging revealed a hyperintense lesion in the right temporal lobe on fluid attenuated inversion recovery images. The patient underwent right lateral temporal lobectomy and amygdalohippocampectomy. Histopathologically, the tumor showed isomorphic, diffuse, infiltrative proliferation of glial tumor cells and intense CD34 immunoreactivity. The tumor cells were immunonegative for isocitrate dehydrogenase 1 (IDH1) R132H and BRAF V600E. Notably, the tumor cells showed the lack of nuclear staining for α-thalassemia/mental retardation syndrome, X-linked (ATRX). In addition, the Ki-67 labeling index, using a monoclonal antibody MIB-1, was elevated focally at tumor cells with p53 immunoreactivity. Molecular analyses identified a BRAFA598T mutation, the first case reported in a glioma. BRAFA598T is predicted to result in loss of kinase action; however, inactive mutants can stimulate mitogen-activated protein kinase kinase (MEK)-extracellular signal-regulated kinase (ERK) signaling through CRAF activation. Thus, according to the recent update of the consortium to inform molecular and practical approaches to central nervous system tumor taxonomy (cIMPACT-NOW update 4), our case is also compatible with diffuse glioma with the mitogen-activated protein kinase (MAPK) pathway alteration. Thorough immunohistochemical and molecular studies are necessary for diagnosis of epilepsy-associated, diffuse gliomas. Partial resemblance in histopathological and molecular genetic features to diffuse astrocytoma also calls for attention.
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Neoplasias Encefálicas/genética , Epilepsia do Lobo Temporal/complicações , Glioma/genética , Proteínas Proto-Oncogênicas B-raf/genética , Adolescente , Neoplasias Encefálicas/complicações , Neoplasias Encefálicas/patologia , Glioma/complicações , Glioma/patologia , Histonas , Humanos , Isocitrato Desidrogenase , Masculino , MutaçãoRESUMO
BACKGROUND: Intracranial interdural cyst is a rare lesion. The exact pathophysiology of these cysts remains unknown. CLINICAL PRESENTATION: We report an infant with interdural cyst of the tentorium cerebelli. Although the cyst mimicked an arachnoid cyst on pre- and postnatal magnetic resonance images, lateral suboccipital craniotomy revealed the cyst within the tentorium. Fenestration on the infratentorial side was performed with successful results. Histologically, the inner surface of the cyst was lined with arachnoid cells. CONCLUSION: We report detailed neuroradiological, intraoperative, and histological findings, and discuss the pathophysiology of the cyst in this case.
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Cistos Aracnóideos , Cistos Aracnóideos/diagnóstico por imagem , Cistos Aracnóideos/cirurgia , Craniotomia , Dura-Máter/diagnóstico por imagem , Dura-Máter/cirurgia , Humanos , Lactente , Imageamento por Ressonância MagnéticaRESUMO
INTRODUCTION: Endodermal cysts are congenital benign cystic lesions in the central nervous system and cause various symptoms. Although some have been reported in the posterior fossa, endodermal cysts located dorsal to the brainstem are extremely rare. CASE PRESENTATION: The case was of a 10-year-old girl who presented with bilateral upper limb weakness and tremor. Magnetic resonance imaging demonstrated a 4.5-cm cystic lesion with T1-weighted hypointense and T2-weighted hyperintense content in the midline of the cisterna magna dorsal to the medulla oblongata. The cyst was cerebrospinal fluid-like, causing us to suspect a symptomatic arachnoid cyst. The lucent cyst wall had no apparent attachment, and complete recovery ensued following total excision of the cyst wall. Pathology confirmed a diagnosis of endodermal cyst. DISCUSSION/CONCLUSION: Herein, we review the past literature on this rare entity. An endodermal cyst in the cisterna magna tends to be less strongly attached and to show a cerebrospinal fluid-like component on magnetic resonance images that mimics an arachnoid cyst. The characteristics of dorsally located endodermal cysts may differ from those in other locations.
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Cistos Aracnóideos , Cistos do Sistema Nervoso Central , Cistos Aracnóideos/diagnóstico por imagem , Cistos Aracnóideos/cirurgia , Criança , Feminino , Forame Magno , Humanos , Imageamento por Ressonância MagnéticaRESUMO
BACKGROUND: Patients with hereditary hemorrhagic telangiectasia(HHT)are known to have high rates of cerebral arteriovenous malformations(AVMs). Compared to patients with sporadic AVMs, patients with HHT are less likely to present with ruptured AVMs. CASE REPORT: A 14-year-old male patient presented with headache that had lasted for 2 days. CT revealed an intracerebral hemorrhage in the right parietal lobe, and enhanced CT revealed an AVM in the upper part of the hematoma. The size of the nidus was 20 mm, and its feeders were the right superior internal parietal artery and a branch of the anterior cerebral artery. In addition, the AVM had no deep drainer. We also found another AVM in the right temporal lobe and identified telangiectasia of the nose using digital subtraction angiography. We suspected HHT and performed whole body CT, which revealed an arteriovenous fistula in the right lung and a hematoma-like lesion in the spleen. Thus, we diagnosed the patient with HHT. His ruptured AVM was removed electively. CONCLUSION: We report a case of HHT that presented as an intracerebral hemorrhage in a patient. Based on our case study findings, it is necessary to perform long-term follow-up not only for brain AVMs but also for visceral vascular malformations in such patients, as well as perform HHT screening for families. Although such cases are rare, some features of HHT must be considered to accurately diagnose suspected HHT.
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Fístula Arteriovenosa , Hemorragia Cerebral/cirurgia , Malformações Arteriovenosas Intracranianas , Telangiectasia Hemorrágica Hereditária , Adolescente , Angiografia Digital , Fístula Arteriovenosa/complicações , Fístula Arteriovenosa/cirurgia , Hemorragia Cerebral/etiologia , Humanos , Malformações Arteriovenosas Intracranianas/complicações , Malformações Arteriovenosas Intracranianas/cirurgia , Masculino , Telangiectasia Hemorrágica Hereditária/etiologia , Telangiectasia Hemorrágica Hereditária/cirurgiaRESUMO
Craniopharyngioma consists of adamantinomatous and papillary subtypes. Recent genetic analysis has demonstrated that the two subtypes are different, not only in clinicopathological features, but also in molecular oncogenesis. Papillary craniopharyngioma (pCP) is characterized by a BRAF mutation, the V600E (Val 600 Glu) mutation. Adamantinomatous craniopharyngioma (aCP) can be distinguished by frequent ß-catenin gene (CTNNB1) mutations. Although these genetic alterations can be a diagnostic molecular marker, the precise frequency of these mutations in clinical specimens remains unknown. In this study, we first evaluated BRAF V600E and CTNNB1 mutations in four and 14 cases of pCP and aCP, respectively, using high-resolution melting analysis followed by Sanger sequencing. The results showed that 100% (4/4) of pCP cases had BRAF V600E mutations, while 78% (11/14) of the aCP cases had CTNNB1 mutations, with these genetic alterations being subtype-specific and mutually exclusive. Second, we evaluated BRAF V600E and CTNNB1 mutations by immunohistochemical analysis (IHC). All pCP cases showed positive cytoplasmic staining with the BRAF V600E-mutant antibody (VE-1), whereas 86% (12/14) of aCP cases showed positive cytoplasmic and nuclear staining for CTNNB1, suggesting a CTNNB1 mutation. Only one case of wild-type CTNNB1 on the DNA analysis showed immunopositivity on IHC. We did not detect a coexistence of BRAF V600E and CTNNB1 mutations in any single tumor, which indicated that these genetic alterations were mutually exclusive. We also report our modified IHC protocol for VE-1 staining, and present the possibility that BRAF V600E mutations can be used as a diagnostic marker of pCP in the differentiation of Rathke cleft cyst with squamous metaplasia.
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Craniofaringioma/genética , Análise Mutacional de DNA/métodos , Neoplasias Hipofisárias/genética , Proteínas Proto-Oncogênicas B-raf/genética , beta Catenina/genética , Adolescente , Adulto , Idoso , Biomarcadores Tumorais/análise , Biomarcadores Tumorais/genética , Criança , Pré-Escolar , Feminino , Humanos , Imuno-Histoquímica/métodos , Masculino , Pessoa de Meia-Idade , Proteínas Proto-Oncogênicas B-raf/análise , Estudos Retrospectivos , beta Catenina/análiseRESUMO
BACKGROUND: Limited dorsal myeloschisis (LDM) is characterized by a fibroneural stalk linking the skin lesion to the underlying spinal cord. CASE PRESENTATION : A 7-month-old girl with a lumbosacral "cigarette-burn" flat skin lesion underwent untethering surgery. The intradural tethering stalk appeared to originate at the dural wall and join the cord with no extradural stalk linking to the skin lesion. Histological examination of the intradural stalk revealed glial fibrillary acidic protein-immunopositive neuroglial tissues in the fibrocollagenous band, which is the central histopathological feature of an LDM stalk. CONCLUSION: It is conceivable that the LDM stalk in our patient was originally linked to the skin lesion and subsequently regressed and was replaced by mature adipose tissue. We should be mindful of possible variations in the morphological features of LDM.
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Defeitos do Tubo Neural/patologia , Pele/patologia , Pré-Escolar , Feminino , HumanosRESUMO
Intracranial germ cell tumors (iGCTs) are the second most common brain tumors among children under 14 in Japan. The World Health Organization classification recognizes several subtypes of iGCTs, which are conventionally subclassified into pure germinoma or non-germinomatous GCTs. Recent exhaustive genomic studies showed that mutations of the genes involved in the MAPK and/or PI3K pathways are common in iGCTs; however, the mechanisms of how different subtypes develop, often as a mixed-GCT, are unknown. To elucidate the pathogenesis of iGCTs, we investigated 61 GCTs of various subtypes by genome-wide DNA methylation profiling. We showed that pure germinomas are characterized by global low DNA methylation, a unique epigenetic feature making them distinct from all other iGCTs subtypes. The patterns of methylation strongly resemble that of primordial germ cells (PGC) at the migration phase, possibly indicating the cell of origin for these tumors. Unlike PGC, however, hypomethylation extends to long interspersed nuclear element retrotransposons. Histologically and epigenetically distinct microdissected components of mixed-GCTs shared identical somatic mutations in the MAPK or PI3K pathways, indicating that they developed from a common ancestral cell.
Assuntos
Neoplasias Encefálicas/genética , Germinoma/genética , Transdução de Sinais/genética , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Instabilidade Cromossômica/genética , Metilação de DNA , Análise Mutacional de DNA , Feminino , Células Germinativas , Humanos , Lactente , Japão , Elementos Nucleotídeos Longos e Dispersos/genética , Masculino , Pessoa de Meia-Idade , Quinases de Proteína Quinase Ativadas por Mitógeno/genética , Mutação , Fosfatidilinositol 3-Quinases/genética , RNA Mensageiro/metabolismo , Estatísticas não Paramétricas , Adulto JovemRESUMO
Traditional MRI methods for estimation of blood flow in brain tumors require high-flow injection of contrast agents through large-bore intravenous access, which limits their pediatric utility. In contrast, arterial spin-labeling (ASL) can be used without contrast media. This study aimed to evaluate the relationship between tumor blood flow (TBF) measured by ASL and histopathological vascular density in pediatric brain tumors. Nineteen consecutive children were evaluated (10 boys, 9 girls; median age: 6 years; 8 high-grade and 11 low-grade tumors). ASL was performed with a pseudocontinuous labeling time of 1650 ms and post-labeling delay of 1525 ms. The maximal absolute (aTBF) and relative (rTBF) tumor blood flows were measured. To evaluate the relative vascular area (%Vessel), the total stained vascular area was divided by the whole tissue area. Spearman's rank-order correlation, the Mann-Whitney U test, and receiver operating characteristic analysis were used for statistical analysis. The absolute and relative TBF rates were 4.9-92.9 mL/100 g/min and 0.17-3.59 mL/100 g/min, respectively. The %Vessel was 0.6-30.2%. The %Vessel showed a significant positive correlation with TBF (aTBF: r = 0.87, P < 0.0001; rTBF: r = 0.89, P < 0.0001). The TBF rate of high-grade tumors was significantly higher than that of low-grade tumors (aTBF: P = 0.0050, rTBF: P = 0.0036). The rTBF had the best diagnostic performance (area under the curve: 0.89). ASL perfusion imaging without contrast material can be used for accurate evaluation of histopathological vascular density and may be helpful for tumor grading in children.
Assuntos
Vasos Sanguíneos/diagnóstico por imagem , Vasos Sanguíneos/patologia , Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/patologia , Imageamento por Ressonância Magnética , Encéfalo/irrigação sanguínea , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Neoplasias Encefálicas/irrigação sanguínea , Circulação Cerebrovascular , Criança , Pré-Escolar , Estudos Transversais , Feminino , Humanos , Lactente , Imageamento por Ressonância Magnética/métodos , Masculino , Gradação de Tumores , Curva ROC , Fluxo Sanguíneo Regional , Estudos Retrospectivos , Marcadores de SpinRESUMO
Brain tumors harbor various BRAF alterations, the vast majority of which are the BRAF kinase-activating V600E mutation. BRAF mutations are most frequently detected in certain subtypes of low-grade glioma, such as pilocytic astrocytoma (PA), pleomorphic xanthoastrocytoma (PXA), ganglioglioma (GG) and dysembryoplastic neuroepithelial tumor (DNT). However, it is unclear whether gliomas harboring BRAF mutations can be invariably regarded as these glioma subtypes or their derivatives. To address this question, we analyzed 274 gliomas in our institutional case series. We performed high-resolution melting analyses and subsequent direct Sanger sequencing on DNA isolated from snap-frozen tumor tissues. As expected, BRAF mutations were detected in the aforementioned low-grade gliomas: in 4/27 PAs, 2/3 PXAs, 4/8 GGs, and 1/6 DNTs. In addition to these gliomas, 1/2 astroblastomas (ABs) and 2/122 glioblastomas (GBs) harbored BRAF mutations. Pathological investigation of the two GBs revealed that one was a GB displaying epithelial features that presumably arose from a precedent GG, whereas the other GB, which harbored a rare G596 A mutation, showed marked epithelial features, including astroblastic rosettes. Our results indicate that in addition to being present in established BRAF-associated gliomas, BRAF mutations might be associated with epithelial features in high-grade gliomas, including sheet-like arrangement of polygonal tumor cells with a plump cytoplasm and astroblastic rosettes, and thus could potentially serve as a genetic marker for these features.
Assuntos
Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Glioma/genética , Glioma/patologia , Mutação , Proteínas Proto-Oncogênicas B-raf/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias Encefálicas/diagnóstico por imagem , Criança , Pré-Escolar , Células Epiteliais/patologia , Feminino , Glioma/diagnóstico por imagem , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Adulto JovemRESUMO
Isocitrate dehydrogenase (IDH) mutation is a good prognostic marker for glioblastoma (GBM). Although it is infrequent in primary tumors, it is found in most lower-grade gliomas. Thus, it is unclear whether IDH mutation is a marker for a specific phenotype of apparently primary de novo GBMs (pGBMs), or a marker for secondary tumors (sGBMs). We addressed this issue by analyzing clinical, radiographic and molecular findings in our institutional case series. Our cases included 92 pGBMs, with five cases of IDH1 mutations at R132 and no IDH2 mutations. The median overall survival of these five patients was 29 months (range: 4 to >40 months), which is considered good prognoses. Clinical and radiographic characteristics were distinct from IDH-wildtype (IDH-wt) pGBMs. IDH-mutant (IDH-mut) tumors consistently involved insular lesions and were subdivided into: (i) the two cases of elderly patients with long clinical histories and features implying multistep tumor development; and (ii) the three cases of younger patients with diffusely swelling insular tumors, slight contrast enhancement and no necrosis. Genetic and expression analyses of IDH-mut pGBMs were similar to those of sGBMs, suggesting that they are indeed distinct from their IDH-wt counterparts. TERT promoter mutation, a genetic marker of oligodendroglial derivation, was detected in one long-surviving case, but genetic alterations in the astrocyte-sGBM pathway were generally prevalent in IDH-mut pGBMs. Our results present a unique phenotype of IDH-mut pGBMs arising from insular cortex region, the molecular backgrounds of which are similar to sGBMs.