RESUMEN
Epithelioid glioblastoma (eGB) is a rare GB subtype exhibiting characteristic morphology and genetic alterations. The efficacy of BRAF and MEK-1/2 inhibitors is demonstrated in eGB treatment, and therefore, considering eGB is important to enhance patient care and prognosis.
RESUMEN
PURPOSE: Measuring serum and cerebrospinal fluid human chorionic gonadotropin (hCG) is essential for the diagnosis of intracranial germ cell tumors. There are three types of hCG-related markers in clinical use: hCGß, intact hCG, and total hCG. The best marker for the diagnosis of intracranial germ cell tumors, especially germinoma, is currently unknown. This study aimed to evaluate the usefulness of these hCG-related markers. METHODS: We investigated 19 serum samples obtained from 6 patients with histologically diagnosed germinoma treated in our institute. Serum hCGß, intact hCG, and total hCG values were measured before, during, and after treatment. Samples with hCG values above the lower limits were considered positive. RESULTS: The positivity rates of serum hCGß, intact hCG, and total hCG were 6% (1/17), 47% (7/15), and 42% (8/19), respectively, with the latter two having significantly higher positivity rates than hCGß (p = 0.041). Both intact and total hCGs showed similar values. The median values of hCGß, intact hCG, and total hCG before treatment were 0.1 ng/mL, 4.6 mIU/mL, and 4.5 mIU/mL, respectively. CONCLUSION: Serum intact and total hCGs have higher detection rates than hCGß in patients with germinoma using available commercial measurement tools.
Asunto(s)
Neoplasias Encefálicas , Germinoma , Humanos , Biomarcadores de Tumor , Relevancia Clínica , Gonadotropina Coriónica/líquido cefalorraquídeo , Gonadotropina Coriónica Humana de Subunidad beta/líquido cefalorraquídeo , Germinoma/diagnóstico , Neoplasias Encefálicas/diagnósticoRESUMEN
BACKGROUND: Pediatric intra-cranial germ cell tumors (iGCTs) occur at an incidence of 0.6-1.2 cases/million/year in Western countries. The incidence is reported up to 5 times higher in Japan. It is unknown whether this increased incidence is due to genetic predisposition or environment. METHODS: The incidence of iGCTs in children ages 0-19 years was evaluated from December 1st, 1996-December 1st, 2016 in stable Japanese immigrant populations living abroad and compared to current native Japanese registry data. The incidence of medullobblastoma was used as a control to account for assumptions in the data. Sites were identified based on historical and population data of known large scale emigration from Japan during a period of industrialization from 1868-1912 which resulted in large, stable Japanese immigrant populations abroad. These three representative sites included Lima, Peru, San Paolo, Brazil, and Vancouver, Canada. Data was collected from registry and hospital-based resources within each region. RESULTS: A review of the Brain Tumor Registry of Japan from 1984-2004 revealed an incidence of 2.5 cases/million/year, lower than previously reported, and a lower incidence of medulloblastoma at 1.2 cases/million/year. Data from Vancouver, Canada, Lima, Peru, and San Paolo, Brazil included a total population of 731,174 Japanese persons. The ratio of all medulloblastoma to iGCT cases in Japan was identified as 1:2 while the ratio was 2:1, 6.5:1, and 5:1, respectively, in the other three locations. The data suggests increased incidence in native Japan may not translate to higher incidence in immigrant Japanese populations abroad and a clear genetic component was not found in our data set. CONCLUSIONS: A more precise and comprehensive study is needed to determine the cause of this difference in incidence. This study also emphasizes the importance of national and state registries and is a call to collaborate on state and country level epidemiology studies.
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Neoplasias Encefálicas , Neoplasias Cerebelosas , Emigrantes e Inmigrantes , Meduloblastoma , Neoplasias de Células Germinales y Embrionarias , Adolescente , Adulto , Neoplasias Encefálicas/epidemiología , Neoplasias Encefálicas/patología , Niño , Preescolar , Humanos , Incidencia , Lactante , Recién Nacido , Japón/epidemiología , Neoplasias de Células Germinales y Embrionarias/epidemiología , Sistema de Registros , Adulto JovenRESUMEN
BACKGROUND: Sick sinus syndrome (SSS) is known to occur due to lesions in the medulla oblongata. Although medullary lesions have occurred in patients with neuromyelitis optica spectrum disorder (NMOSD), there are few reports of SSS associated with NMOSD. We report a patient with NMOSD who developed refractory nausea, vomiting and SSS as the initial manifestation. CASE PRESENTATION: A 77-year-old female developed refractory nausea and frequent episodes of syncope. The patient was diagnosed with SSS because sinus pauses lasting five to six seconds were observed, and pacemaker implantation was performed. Two months later, she was referred to our hospital because of limb weakness and sensory impairment that progressed over a month. The patient was confirmed to have muscle weakness; manual muscle testing revealed grade 4 in the upper extremities and grade 3 in the lower extremities. Tendon reflexes were diminished, while no pathological reflexes were present. Thermal and pain sensations were impaired in the upper and lower extremities, and vibration sensation was impaired in both lower extremities. Bladder and rectal disturbances were also noted. Optic neuritis was not detected. T2-weighted magnetic resonance imaging (MRI) showed high-intensity lesions in the dorsal part of the medulla oblongata and C3-6 cervical cord. Her serum was positive for antibodies against aquaporin 4, and a diagnosis of NMOSD was made. She was treated with two courses of an intravenous methylprednisolone pulse and one course of plasma exchange. Then, she was transferred to another hospital for rehabilitation. CONCLUSIONS: Because SSS is a life-threatening complication, clinicians should be aware of the possibility that medullary lesions in NMOSD can cause SSS as the initial manifestation.
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Neuromielitis Óptica , Neuritis Óptica , Anciano , Acuaporina 4 , Autoanticuerpos , Femenino , Humanos , Imagen por Resonancia Magnética , Neuromielitis Óptica/complicaciones , Neuromielitis Óptica/diagnóstico por imagen , Síndrome del Seno Enfermo/complicaciones , Síndrome del Seno Enfermo/diagnóstico , Síndrome del Seno Enfermo/terapiaRESUMEN
Intraventricular tumors often cause hydrocephalus because their location in the ventricles affect cerebrospinal fluid circulation. Even small tumors can lead to acute hydrocephalus when they block the cerebrospinal fluid flow. They may also be found as large tumors occurring in large spaces, such as in lateral ventricles. Since various histological tumors occur in ventricles, it is important to consider the treatment strategy according to the expected histological type before treating hydrocephalus in the early stage. In addition, it is beneficial to predict and evaluate the site and size of the tumor, the cause of hydrocephalus, and the effect of postoperative chemotherapy and radiation therapy. Some tumors are sensitive to chemotherapy and radiation therapy, so there is an advantage in performing a biopsy at the same time as hydrocephalus treatment. Ventricular drainage and ventricular peritoneal shunts for patients with high intracranial pressure are at risk of developing ascending hernias, so we should be careful with the procedure.
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Neoplasias del Ventrículo Cerebral , Hidrocefalia , Neoplasias del Ventrículo Cerebral/complicaciones , Neoplasias del Ventrículo Cerebral/cirugía , Ventrículos Cerebrales/patología , Derivaciones del Líquido Cefalorraquídeo/efectos adversos , Humanos , Hidrocefalia/etiología , Hidrocefalia/cirugía , Presión IntracranealRESUMEN
Intracranial germ cell tumours (IGCTs) are a group of rare heterogeneous brain tumours that are clinically and histologically similar to the more common gonadal GCTs. IGCTs show great variation in their geographical and gender distribution, histological composition and treatment outcomes. The incidence of IGCTs is historically five- to eightfold greater in Japan and other East Asian countries than in Western countries, with peak incidence near the time of puberty. About half of the tumours are located in the pineal region. The male-to-female incidence ratio is approximately 3-4:1 overall, but is even higher for tumours located in the pineal region. Owing to the scarcity of tumour specimens available for research, little is currently known about this rare disease. Here we report the analysis of 62 cases by next-generation sequencing, single nucleotide polymorphism array and expression array. We find the KIT/RAS signalling pathway frequently mutated in more than 50% of IGCTs, including novel recurrent somatic mutations in KIT, its downstream mediators KRAS and NRAS, and its negative regulator CBL. Novel somatic alterations in the AKT/mTOR pathway included copy number gains of the AKT1 locus at 14q32.33 in 19% of patients, with corresponding upregulation of AKT1 expression. We identified loss-of-function mutations in BCORL1, a transcriptional co-repressor and tumour suppressor. We report significant enrichment of novel and rare germline variants in JMJD1C, which codes for a histone demethylase and is a coactivator of the androgen receptor, among Japanese IGCT patients. This study establishes a molecular foundation for understanding the biology of IGCTs and suggests potentially promising therapeutic strategies focusing on the inhibition of KIT/RAS activation and the AKT1/mTOR pathway.
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Neoplasias Encefálicas/genética , Mutación de Línea Germinal/genética , Mutación/genética , Neoplasias de Células Germinales y Embrionarias/genética , Adulto , Neoplasias Encefálicas/patología , Niño , Femenino , Humanos , Japón , Masculino , Neoplasias de Células Germinales y Embrionarias/patología , Proteína Oncogénica v-akt/genética , Proteínas Proto-Oncogénicas c-kit/genética , Reproducibilidad de los Resultados , Transducción de Señal/genética , Serina-Treonina Quinasas TOR/genética , Adulto Joven , Proteínas ras/genéticaRESUMEN
Among variations of the anterior cerebral artery (ACA), anastomosis of its A1-A2 junction with the ophthalmic segment of the internal carotid artery is rare and described as carotid-ACA anastomosis or infraoptic course of the ACA. One common variant, an azygos ACA, demonstrates no pairing of the A2 segment. To our knowledge, association of a carotid-ACA anastomosis with an azygos ACA is not reported in the English-language literature. We report a case diagnosed by magnetic resonance angiography in which right carotid-ACA anastomosis was associated with an azygos ACA and the right ophthalmic artery originated from the middle meningeal artery.
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Variación Anatómica , Arteria Cerebral Anterior/anomalías , Arteria Carótida Interna/anomalías , Arterias Meníngeas/anomalías , Arteria Oftálmica/anomalías , Adolescente , Arteria Cerebral Anterior/diagnóstico por imagen , Arteria Carótida Interna/diagnóstico por imagen , Angiografía Cerebral , Humanos , Angiografía por Resonancia Magnética , Masculino , Arterias Meníngeas/diagnóstico por imagen , Arteria Oftálmica/diagnóstico por imagenRESUMEN
PURPOSE: Alterations in the promoter of the telomerase reverse transcriptase (TERT) gene are a major mechanism of upregulating telomerase, which plays a crucial role in tumor development. Mutations in the TERT promoter have been observed in a subset of brain tumors, including adult gliomas and high-grade meningiomas. In pituitary adenomas (PAs), however, abnormalities in TERT are not fully understood. The present study aimed to investigate not only mutational but also methylation changes in the TERT promoter in PAs and to analyze their correlations with clinical variables. METHODS: We retrospectively studied 70 PAs consisting of 53 primary and 17 recurrent samples. Clinical data, including age at surgery, sex, largest tumor dimension, tumor subtype, resection rate, and progression-free survival (PFS), were obtained from medical records. We investigated TERT promoter hotspot mutations via Sanger sequencing and quantified the methylation status of the TERT promoter using methylation-sensitive high-resolution melting analysis (MS-HRM). Additionally, we investigated TERT mRNA expression using real-time quantitative PCR. RESULTS: TERT promoter hotspot mutations were not observed in any PA sample, while 16% of PAs exhibited TERT promoter methylation. PAs with methylated TERT promoters were significantly more likely to show disease progression, shorter PFS, and higher TERT expression levels compared to those with unmethylated promoters. CONCLUSIONS: This is the first study showing that TERT promoter methylation is associated with disease progression and shorter PFS as well as upregulated TERT expression in PAs. Our results suggest that TERT promoter methylation may be a potential biomarker for predicting tumor recurrence in PAs.
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Metilación de ADN , Progresión de la Enfermedad , Neoplasias Hipofisarias/genética , Telomerasa/genética , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Mutación , Neoplasias Hipofisarias/metabolismo , Supervivencia sin Progresión , Regiones Promotoras Genéticas , Estudios Retrospectivos , Telomerasa/metabolismo , Regulación hacia Arriba , Adulto JovenRESUMEN
According to the 2016 World Health Organization Classification of Tumors of the Central Nervous System (2016 CNS WHO), IDH-mutant astrocytic gliomas comprised WHO grade II diffuse astrocytoma, IDH-mutant (AIIIDHmut), WHO grade III anaplastic astrocytoma, IDH-mutant (AAIIIIDHmut), and WHO grade IV glioblastoma, IDH-mutant (GBMIDHmut). Notably, IDH gene status has been made the major criterion for classification while the manner of grading has remained unchanged: it is based on histological criteria that arose from studies which antedated knowledge of the importance of IDH status in diffuse astrocytic tumor prognostic assessment. Several studies have now demonstrated that the anticipated differences in survival between the newly defined AIIIDHmut and AAIIIIDHmut have lost their significance. In contrast, GBMIDHmut still exhibits a significantly worse outcome than its lower grade IDH-mutant counterparts. To address the problem of establishing prognostically significant grading for IDH-mutant astrocytic gliomas in the IDH era, we undertook a comprehensive study that included assessment of histological and genetic approaches to prognosis in these tumors. A discovery cohort of 211 IDH-mutant astrocytic gliomas with an extended observation was subjected to histological review, image analysis, and DNA methylation studies. Tumor group-specific methylation profiles and copy number variation (CNV) profiles were established for all gliomas. Algorithms for automated CNV analysis were developed. All tumors exhibiting 1p/19q codeletion were excluded from the series. We developed algorithms for grading, based on molecular, morphological and clinical data. Performance of these algorithms was compared with that of WHO grading. Three independent cohorts of 108, 154 and 224 IDH-mutant astrocytic gliomas were used to validate this approach. In the discovery cohort several molecular and clinical parameters were of prognostic relevance. Most relevant for overall survival (OS) was CDKN2A/B homozygous deletion. Other parameters with major influence were necrosis and the total number of CNV. Proliferation as assessed by mitotic count, which is a key parameter in 2016 CNS WHO grading, was of only minor influence. Employing the parameters most relevant for OS in our discovery set, we developed two models for grading these tumors. These models performed significantly better than WHO grading in both the discovery and the validation sets. Our novel algorithms for grading IDH-mutant astrocytic gliomas overcome the challenges caused by introduction of IDH status into the WHO classification of diffuse astrocytic tumors. We propose that these revised approaches be used for grading of these tumors and incorporated into future WHO criteria.
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Astrocitoma/genética , Astrocitoma/patología , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patología , Isocitrato Deshidrogenasa/genética , Mutación/genética , Adolescente , Adulto , Anciano , Algoritmos , Astrocitoma/mortalidad , Neoplasias Encefálicas/mortalidad , Inhibidor p16 de la Quinasa Dependiente de Ciclina/genética , Inhibidor p16 de la Quinasa Dependiente de Ciclina/metabolismo , Femenino , Regulación Neoplásica de la Expresión Génica/genética , Humanos , Antígeno Ki-67/metabolismo , Masculino , Persona de Mediana Edad , Modelos Biológicos , Clasificación del Tumor , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Organización Mundial de la Salud , Adulto JovenRESUMEN
Recent studies have demonstrated that tumor-driving alterations are often different among gliomas that originated from different brain regions and have underscored the importance of analyzing molecular characteristics of gliomas stratified by brain region. Therefore, to elucidate molecular characteristics of diffuse cerebellar gliomas (DCGs), 27 adult, mostly glioblastoma cases were analyzed. Comprehensive analysis using whole-exome sequencing, RNA sequencing, and Infinium methylation array (n = 17) demonstrated their distinct molecular profile compared to gliomas in other brain regions. Frequent mutations in chromatin-modifier genes were identified including, noticeably, a truncating mutation in SETD2 (n = 4), which resulted in loss of H3K36 trimethylation and was mutually exclusive with H3F3A K27M mutation (n = 3), suggesting that epigenetic dysregulation may lead to DCG tumorigenesis. Alterations that cause loss of p53 function including TP53 mutation (n = 9), PPM1D mutation (n = 2), and a novel type of PPM1D fusion (n = 1), were also frequent. On the other hand, mutations and copy number changes commonly observed in cerebral gliomas were infrequent. DNA methylation profile analysis demonstrated that all DCGs except for those with H3F3A mutations were categorized in the "RTK I (PDGFRA)" group, and those DCGs had a gene expression signature that was highly associated with PDGFRA. Furthermore, compared with the data of 315 gliomas derived from different brain regions, promoter methylation of transcription factors genes associated with glial development showed a characteristic pattern presumably reflecting their tumor origin. Notably, SOX10, a key transcription factor associated with oligodendroglial differentiation and PDGFRA regulation, was up-regulated in both DCG and H3 K27M-mutant diffuse midline glioma, suggesting their developmental and biological commonality. In contrast, SOX10 was silenced by promoter methylation in most cerebral gliomas. These findings may suggest potential tailored targeted therapy for gliomas according to their brain region, in addition to providing molecular clues to identify the region-related cellular origin of DCGs.
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Neoplasias Cerebelosas/genética , Neoplasias Cerebelosas/metabolismo , Glioma/genética , Glioma/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias Cerebelosas/patología , Neoplasias Cerebelosas/cirugía , Cerebelo/diagnóstico por imagen , Cerebelo/metabolismo , Cerebelo/patología , Cerebelo/cirugía , Epigénesis Genética , Regulación Neoplásica de la Expresión Génica , Predisposición Genética a la Enfermedad , Glioma/patología , Glioma/cirugía , Humanos , Persona de Mediana EdadRESUMEN
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.
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Neoplasias Encefálicas/genética , Germinoma/genética , Transducción de Señal/genética , Adolescente , Adulto , Anciano , Niño , Preescolar , Inestabilidad Cromosómica/genética , Metilación de ADN , Análisis Mutacional de ADN , Femenino , Células Germinativas , Humanos , Lactante , Japón , Elementos de Nucleótido Esparcido Largo/genética , Masculino , Persona de Mediana Edad , Quinasas de Proteína Quinasa Activadas por Mitógenos/genética , Mutación , Fosfatidilinositol 3-Quinasas/genética , ARN Mensajero/metabolismo , Estadísticas no Paramétricas , Adulto JovenRESUMEN
Germ cell tumors constitute a heterogeneous group that displays a broad spectrum of morphology. They often arise in testes; however, extragonadal occurrence, in particular brain, is not uncommon, and whether they share a common pathogenesis is unknown. We performed whole exome sequencing in 41 pairs of central nervous system germ cell tumors (CNS GCTs) of various histology and their matched normal tissues. We then performed targeted sequencing of 41 selected genes in a total of 124 CNS GCTs, 65 testicular germ cell tumors (tGCTs) and 8 metastatic GCTs to the CNS. The results showed that mutually exclusive mutations of genes involved in the MAPK pathway were most common (48.4 %), typically in KIT (27.4 %), followed by those in the PI3K pathway (12.9 %), particularly in MTOR (6.5 %), among the 124 CNS GCTs. Pure germinomas and non-germinomatous germ cell tumors (NGGCTs), as well as CNS and testicular GCTs, showed similar mutational profiles, suggesting that GCTs share a common molecular pathogenesis. Mutated MTOR identified in CNS GCTs upregulated phosphorylation of the AKT pathway proteins including AKT and 4EBP1 in nutrient-deprived conditions and enhanced soft-agar colony formation; both events were suppressed in a dose-dependent manner by addition of the MTOR inhibitor pp242. Our findings indicate that the dominant genetic drivers of GCTs regardless of the site of origin are activation of the MAPK and/or PI3K pathways by somatic point mutations. Mutated MTOR represents a potential target for novel targeted therapies for refractory GCTs.
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Neoplasias del Sistema Nervioso Central/genética , Mutación/genética , Neoplasias de Células Germinales y Embrionarias/genética , Serina-Treonina Quinasas TOR/genética , Neoplasias Testiculares/genética , Neoplasias del Sistema Nervioso Central/patología , Femenino , Humanos , Masculino , Neoplasias de Células Germinales y Embrionarias/terapia , Fosfatidilinositol 3-Quinasas/genética , Recurrencia , Serina-Treonina Quinasas TOR/metabolismo , Neoplasias Testiculares/terapiaRESUMEN
Human chorionic gonadotropin (hCG) production has been utilized as a diagnostic marker for germinoma with syncytiotrophoblastic giant cells (STGC) and choriocarcinoma. Elevated hCG in germinoma is considered to predict less favorable prognosis, and an intensive treatment strategy may accordingly be applied. However, there is some evidence that any germinoma may produce hCG to varying extent. We investigated mRNA expression of the hCG ß subunit (hCGß) using real time quantitative polymerase chain reaction in 94 germ cell tumors (GCTs). Most (93.3 %) GCTs showed higher expression levels compared with that of normal brain tissue (1.09 × 10(0)-1.40 × 10(5) fold). The expression was the highest in GCTs which harbor choriocarcinoma or STGC components. The expression level of hCGß in germinoma was highly variable (1.09 × 10(0)-5.88 × 10(4) fold) in linear but not bimodal distribution. hCG concentrations in serum and CSF correlated with gene expression, especially when GCTs with single histological component were analyzed separately. The expression was not significantly associated with recurrence in pure germinoma. These results suggest that the serum/CSF hCG levels may need to be interpreted with caution as most GCTs appear to have the capacity of producing hCG irrespective of their histology. The clinical significance of ubiquitous hCG expression in GCTs needs further investigation.
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Neoplasias Encefálicas/metabolismo , Gonadotropina Coriónica Humana de Subunidad beta/metabolismo , Neoplasias de Células Germinales y Embrionarias/metabolismo , Adolescente , Adulto , Neoplasias Encefálicas/diagnóstico , Niño , Preescolar , Gonadotropina Coriónica/sangre , Femenino , Humanos , Lactante , Masculino , Persona de Mediana Edad , Neoplasias de Células Germinales y Embrionarias/diagnóstico , ARN Mensajero/metabolismo , Adulto JovenRESUMEN
PURPOSE: There is little information on pediatric oligodendroglial tumor located in the brainstem because of its rarity. METHODS: Here, we present two pediatric cases of pontine oligodendroglial tumors with radiological findings atypical for diffuse intrinsic pontine glioma. RESULTS: The first patient was an 8-year-old boy. Brain magnetic resonance imaging (MRI) demonstrated diffuse high-intensity changes in the pons, left middle cerebellar peduncle, and part of the left cerebellar hemisphere on T2-weighted and fluid-attenuated inversion recovery images, with an enhanced spot lesion in the left cerebellar hemisphere. The pathological diagnosis was anaplastic oligodendroglioma, and we identified a mutation in histone H3.3 in the tumor specimen. He succumbed to massive disseminated relapse 7 months from diagnosis despite local radiation therapy. The second patient, a 2-year-old girl, was diagnosed with oligoastrocytoma. Brain MRI revealed a large mass in her rostral pons extended to the fourth ventricle with obstructive hydrocephalus. The tumor recurred with intracranial dissemination 56 months post-surgery. CONCLUSIONS: Pediatric brainstem oligodendroglial tumors can include histone H3.3-mutated tumors and have a tendency to disseminate throughout the neuroaxis at the time of relapse.
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Neoplasias del Tronco Encefálico/genética , Histonas/genética , Mutación/genética , Oligodendroglioma/genética , Neoplasias del Tronco Encefálico/patología , Niño , Preescolar , Análisis Mutacional de ADN , Femenino , Humanos , Imagen por Resonancia Magnética , Masculino , Oligodendroglioma/patologíaRESUMEN
We report the case of a 19-year-old woman with a highly malignant intracranial germ cell tumor (GCT) that developed 14 years after treatment for neurohypophyseal germinoma. Magnetic resonance imaging (MRI) showed a large neurohypophyseal mass and a synchronous lesion in the pineal region. Plasma α-fetoprotein was elevated to 3038 ng/mL. Although the tumor shrank and tumor marker levels normalized after chemotherapy and craniospinal irradiation, treatment was switched to oral etoposide for the residual tumor because of adverse events. MRI after oral etoposide introduction showed additional tumor shrinkage for 27 months after the onset of the second tumor. To the best of our knowledge, this is the longest interval between germinoma onset and the development of highly malignant recurrent GCT to be reported in the English-language literature. Oral etoposide prevented regrowth of the GCT, which has a poor prognosis, and decreased the size of the residual tumor.
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Neoplasias Encefálicas/tratamiento farmacológico , Transformación Celular Neoplásica , Etopósido/administración & dosificación , Predicción , Germinoma/tratamiento farmacológico , Neurohipófisis/patología , Administración Oral , Antineoplásicos Fitogénicos/administración & dosificación , Neoplasias Encefálicas/diagnóstico , Progresión de la Enfermedad , Relación Dosis-Respuesta a Droga , Femenino , Germinoma/diagnóstico , Humanos , Imagen por Resonancia Magnética , Factores de Tiempo , Adulto JovenRESUMEN
Intracranial germ cell tumors (iGCTs) are the second most common brain tumors among children under 15 in Japan. The pathogenesis of iGCTs is largely unexplored. Although a subset of iGCTs is known to have KIT mutation, its impact on the biology and patients' survival has not been established. In this study, we investigated genes involved in the KIT signaling pathway. 65 iGCTs (30 pure germinomas, 14 teratomas, 18 mixed GCTs, 2 yolk sac tumors, 1 choriocarcinoma) were screened for mutation of KIT, KRAS, NRAS, HRAS, BRAF, PDGFRA, and IDH1 by direct sequencing. KIT expression was examined by immunohistochemistry and quantitative PCR. Chromosomal status was analyzed by array-comparative genomic hybridization (aCGH). Somatic mutations were detected only in KIT and RAS, which were frequently observed in pure germinomas (60.0 %), but rare in non-germinomatous GCTs (NGGCTs) (8.6 %). All KIT/RAS mutations were mutually exclusive. Regardless of the mutation status or mRNA expression, the KIT protein was expressed in all germinomas, while only in 54.3 % of NGGCTs. Amplification of KIT was found in one pure germinoma by aCGH. In pure germinomas, high expression of KIT mRNA was associated with the presence of KIT/RAS alterations and severe chromosomal instability. Our results indicate that alterations of the KIT signaling pathway play an important role in the development of germinomas. Pure germinomas may develop through two distinct pathogeneses: one with KIT/RAS alterations, elevated KIT mRNA expression and severe chromosomal instability, and the other through yet an unidentified mechanism without any of the above abnormalities.
Asunto(s)
Neoplasias Encefálicas/genética , Inestabilidad Cromosómica , Germinoma/genética , Mutación , Proteínas Proto-Oncogénicas c-kit/genética , Proteínas ras/genética , Adolescente , Adulto , Neoplasias Encefálicas/metabolismo , Niño , Preescolar , Femenino , Germinoma/metabolismo , Humanos , Lactante , Masculino , Persona de Mediana Edad , Proteínas Proto-Oncogénicas c-kit/metabolismo , ARN Mensajero/metabolismo , Adulto JovenRESUMEN
BACKGROUNDS: Intracranial germ cell tumors (GCTs) are rare and heterogeneous with very little is known about their pathogenesis and underlying genetic abnormalities. PROCEDURES: In order to identify candidate genes and pathways which are involved in the pathogenesis of these tumors, we have profiled 62 intracranial GCTs for DNA copy number alterations (CNAs) and loss of heterozygosity (LOH) by using single nucleotide polymorphism (SNP) array and quantitative real time PCR (qPCR). RESULTS: Initially 27 cases of tumor tissues with matched blood samples were fully analyzed by SNP microarray and qPCR. Statistical analysis using the genomic identification of significant targets in cancer (GISTIC) tool identified 10 regions of significant copy number gain and 11 regions of significant copy number loss. While overall pattern of genomic aberration was similar between germinoma and nongerminomatous germ cell tumors (NGGCTs), a few subtype-specific peak regions were identified. Analysis by SNP array and qPCR was replicated using an independent cohort of 35 cases. CONCLUSIONS: Frequent aberrations of CCND2 (12p13) and RB1 (13q14) suggest that Cyclin/CDK-RB-E2F pathway might play a critical role in the pathogenesis of intracranial GCTs. Frequent gain of PRDM14 (8q13) implies that transcriptional regulation of primordial germ cell specification might be an important factor in the development of this tumor.
Asunto(s)
Biomarcadores de Tumor/genética , Neoplasias Encefálicas/genética , Variaciones en el Número de Copia de ADN/genética , Genoma Humano , Pérdida de Heterocigocidad , Neoplasias de Células Germinales y Embrionarias/genética , Polimorfismo de Nucleótido Simple/genética , Adolescente , Adulto , Estudios de Casos y Controles , Niño , Preescolar , Hibridación Genómica Comparativa , Femenino , Estudios de Seguimiento , Humanos , Lactante , Recién Nacido , Masculino , Mutación/genética , Análisis de Secuencia por Matrices de Oligonucleótidos , Pronóstico , Adulto JovenRESUMEN
BACKGROUND: The initial presentation of central nervous system (CNS) tumors in children frequently mimics other more common and less serious conditions, resulting in diagnostic difficulty and a prolonged time to diagnosis. Yet whether early diagnosis contributes to better life prognosis and functional outcome has not been elucidated. Only a few such reports have originated from Japan, where neuroimaging techniques are the best in the world. We examined the time to diagnosis, the so-called prediagnostic symptomatic interval (PSI), and its impact on prognosis and functional outcome in children with CNS tumors. METHODS: We reviewed the records of 127 patients aged <15 years with CNS tumors, who were treated at our two institutions between November 1993 and October 2011. RESULTS: The median age at diagnosis was 7.2 years (range, 3 weeks-14.9 years). The male-to-female ratio was 63:64. Median PSI was 1.5 months (0-36 months). Overall survival and progression-free survival did not differ significantly between the groups, regardless of whether the PSI was longer than the median PSI. The PSI was significantly longer in patients with long-lasting clinical signs after the initial treatment than in patients with temporary symptoms only at onset. Both univariate and multivariate analysis showed that high histological grading was statistically correlated with short PSI. CONCLUSIONS: A short PSI was significantly associated with high-grade tumors. Earlier diagnosis did not lead to better life prognosis, but possibly to better functional outcome in children with CNS tumors.
Asunto(s)
Neoplasias del Sistema Nervioso Central/diagnóstico , Neoplasias del Sistema Nervioso Central/mortalidad , Adolescente , Neoplasias del Sistema Nervioso Central/terapia , Niño , Preescolar , Diagnóstico Tardío , Detección Precoz del Cáncer , Femenino , Humanos , Lactante , Recién Nacido , Japón , Masculino , Pronóstico , Recuperación de la Función , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
Intramedullary spinal cord abscess is a rare and severe infectious disease characterized by devastating neurological deficits. We report a case of cervical intramedullary spinal cord abscess in a 74-year-old diabetic male with a 3-day history of neck pain and weakness in the right lower extremity. Magnetic resonance imaging revealed a ring-shaped contrast lesion in C3-C6 of the cervical spinal cord with extensive edema. Further, 1 day after admission, he became comatose (Glasgow Coma Scale E1VtM1), and a computed tomography head scan revealed hydrocephalus. Despite emergency ventricular drainage, the patient's level of consciousness remained unchanged. Magnetic resonance imaging performed 1 day after surgery revealed bilateral intracranial extension of the abscess into the thalamus and caudate nucleus. The patient died 19 days after admission. Our report is the first case of extensive brain abscess development over a short period. Based on our experience, prompt administration of antibiotics and emergency abscess drainage of the cervical cord (and ventricular drainage, if necessary) are recommended in cases of neurological deterioration in patients with cervical intramedullary spinal cord abscess.
RESUMEN
We herein report a case of acute subdural hematoma caused by hemorrhagic falx meningioma. The patient was a 64-year-old woman with no significant medical history or prior history of trauma. She experienced a sudden onset of headache and weakness in her extremities. Computed tomography (CT) scan and magnetic resonance imaging (MRI) showed a mass lesion with intratumoral hemorrhage or faint calcification along the left side of the fronto-parietal cerebral falx. There was also a linear lesion at the left side of the falx, suggesting acute subdural hematoma. MRI was performed again on the eleventh day. On precontrast T1-weighted images, intratumoral hemorrhage and widespread left subdural hematoma were shown as high intensity. On postcontrast T1-weighted images, the tumor showed heterogeneous enhancement with a dural tail sign on the falx, indicative of a falx meningioma. She underwent surgical resection, and the histological subtype was transitional meningioma. Nine cases of hemorrhagic falx meningioma associated with acute subdural hematoma have been reported. If not limited to the site of occurrence, there have been 59 reported cases overall. In our investigation, the incidence of hemorrhage is higher in the convexity and lower in the skull base. It is higher for fibrous, angiomatous, and metaplastic subtypes and lower for meningothelial subtype. The location and histological subtype might be risk factors for meningioma associated with subdural hematoma. Further accumulation of cases will be necessary to establish the cause of bleeding.