Ganglioglioma Research Articles

Mixed pleomorphic xanthoastrocytoma and ganglioglioma with existence of BRAF V600E mutation

Objective To investigate the clinicopathological and molecular genetic features of one case of mixed pleomorphic xanthoastrocytoma (PXA) and ganglioglioma (GG) with BRAF V600E mutation. Methods and Results A 14-year-old boy mainly presented paroxymal loss of consciousness and tic of limbs for 6 years. Head MRI displayed circular abnormal signal on the hippocampus of left temporal lobe, considering space-occupying lesion. The patient underwent operation, and the lesion was totally removed. Pink gyri in deep temporal lobe could be seen during the operation. The tumor tissue was red grey, tough, nonencapsulated, with calcification, cystic degeneration, rich blood supply and clear boundary. Morphology showed the tumor grew diffusely and was heterogeneous: some areas showed the structure of GG and others showed the structure of PXA. Immunohistochemical staining and special staining showed in the region of GG, the tumor was scatteredly positive for glial fibrillary acidic protein (GFAP) and neurofilament protein (NF), gangliocyte-like cells were positive for microtubule associated protein-2 (MAP-2) and neuronal nuclei (NeuN), Ki-67 labeling index was 2%; in the region of PXA, spindle tumor cells were scatteredly positive for GFAP and NF, xanthomatoid cells were positive for CD163 and CD68, Ki-67 labeling index was 3%-5%, reticular fibers were abundant. Molecular detection showed that BRAF V600E mutation existed in both parts of the tumor. The patient was not treated by postoperative radiotherapy or chemotherapy. He took antiepileptic drugs (AEDs) orally [sodium valproate 1.20 g (twice a day) and levetiracetam 0.50 g (twice a day)] for one year, and the symptoms were greatly improved. He had no evidence of tumor recurrence in the 18-month follow-up period. Conclusions Combined PXA and GG is a rare tumor of the central nervous system (CNS). The tumor showed different morphological features of PXA and GG, but with the same BRAF V600E mutation molecular characteristics. This case may support the study on morphology, histological origin and molecular genetics for PXA and GG. DOI: 10.3969/j.issn.1672-6731.2017.03.008

Co-occurrence of histone H3 K27M and BRAF V600E mutations in paediatric midline grade I ganglioglioma.

Ganglioglioma (GG) is a grade I tumor characterized by alterations in the MAPK pathway, including BRAF V600E mutation. Recently, diffuse midline glioma with an H3 K27M mutation was added to the WHO 2016 classification as a new grade IV entity. As co-occurrence of H3 K27M and BRAF V600E mutations has been reported in midline tumors and anaplastic GG, we searched for BRAF V600E and H3 K27M mutations in a series of 54 paediatric midline grade I GG (midline GG) to determine the frequency of double mutations and its relevance for prognosis. Twenty-seven patients (50%) possessed the BRAF V600E mutation. The frequency of the co-occurrence of H3F3A/BRAF mutations at diagnosis was 9.3%. No H3 K27M mutation was detected in the absence of the BRAF V600E mutation. Double-immunostaining revealed that BRAF V600E and H3 K27M mutant proteins were present in both the glial and neuronal components. Immunopositivity for the BRAF V600E mutant protein correlated with BRAF mutation status as detected by massARRAY or digital droplet PCR. The median follow-up of patients with double mutation was 4 years. One patient died of progressive disease 8 years after diagnosis, whereas the four other patients were all alive with stable disease at the last clinical follow-up (at 9 months, 1 year and 7 years) without adjuvant therapy. We demonstrate in this first series of midline GGs that the H3 K27M mutation can occur in association with the BRAF V600E mutation in grade I glioneuronal tumors. Despite the presence of H3 K27M mutations, these cases should not be graded and treated as grade IV tumors because they have a better spontaneous outcome than classic diffuse midline H3 K27M-mutant glioma. These data suggest that H3 K27M cannot be considered a specific hallmark of grade IV diffuse gliomas and highlight the importance of integrated histomolecular diagnosis in paediatric brain tumors.

BRAF gene alterations and enhanced mammalian target of rapamycin signaling in gangliogliomas.

Gangliogliomas (GGs) are slow-growing glioneuronal tumors seen in children and young adults. They are associated with intractable epilepsy, and have recently been found to harbor BRAF (B- rapidly accelerated fibrosarcoma) gene mutations. However, the mammalian target of rapamycin (mTOR) signaling pathway, downstream of BRAF, has not been evaluated extensively in GGs. GG cases were retrieved, clinical data obtained, and histopathological features reviewed. Sequencing for BRAF V600E mutation, analysis of BRAF copy number by quantitative real-time polymerase chain reaction, and immunohistochemistry for mTOR pathway markers p-S6 and p-4EBP1 were performed. Sixty-four cases of GG were identified (0.9% of central nervous system tumors). Of these, 28 had sufficient tumor tissue for further evaluation. Mixed glial and neuronal morphology was the commonest (64%) type. Focal cortical dysplasia was identified in the adjacent cortex (6 cases). BRAF V600E mutation was identified in 30% of GGs; BRAF copy number gain was observed in 50% of them. p-S6 and p-4EBP1 immunopositivity was seen in 57% cases each. Thus, mTOR pathway activation was seen in 81% cases, and was independent of BRAF alterations. 87% patients had Engel grade I outcome, while 13% had Engel grade II outcome. Both the Engel grade II cases analyzed showed BRAF V600E mutation. BRAF V600E mutation is frequent in GGs, as is BRAF gain; the former may serve as a target for personalized therapy in patients with residual tumors, necessitating its assessment in routine pathology reporting of these tumors. Evidence of mTOR pathway activation highlights similarities in the pathogenetic mechanisms underlying GG and focal cortical dysplasia, and suggests that mTOR inhibitors may be of utility in GG patients with persistent seizures after surgery.

A Phase II Study of Antineoplastons A10 and AS2-1 in Children with Brain Tumors. Final Report (Protocol BT-10)

Despite dramatic progress over the last 50 years in the treatment of many childhood cancers, primary brain tumors remain the leading cause of death in pediatric oncology. This phase II study evaluated the efficacy and safety of Antineoplastons A10 and AS2-1 given in combination (ANP). Thirty-four patients, with a median age of 10.4 years, were enrolled in the study. Thirty-two patients (94.1%), were Caucasians while 21 (61.8%) were female and 13 were male (38.2%). Twenty-four patients (70.6%) suffered from a brainstem glioma (BSG) or high-grade tumor. Ten patients (29.4%) suffered from a low-grade tumor. A distinct sub-group of three patients with low grade tumors had a ganglioglioma (GG). Eighty-two percent of patients had failed standard treatment. Daily ANP was administered by IV infusion, every four hours, until an objective response (OR) was documented, and then for an additional eight months. The median doses of A10 and AS2-1 were 11.64 g/kg/d and 0.45 g/kg/d, respectively. A complete response (CR) was documented in two patients (5.9%), a partial response (PR) in four patients (11.8%), and stable disease (SD) in six patients (17.6%). Objective responses were observed in diffuse intrinsic pontine glioma (DIPG), thalamic pilocytic astrocytoma with brainstem involvement, ganglioglioma and pilocytic astrocytoma. Six-month progression-free survival (PFS) was 35.3%. Overall survival (OS) at two and five years was 37.6% and 34.5%, respectively. Two patients experienced grade 4 hypernatremia while three experienced grade 3 hypokalemia. In this group of patients, ANP showed good efficacy and an acceptable toxicity profile.

A comprehensive analysis identifies BRAF hotspot mutations associated with gliomas with peculiar epithelial morphology.

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 G596A 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.

Unusual mixed gangliocytoma-pituitary adenoma in sellar region

Background The presence of ganglion cells within an endocrine pituitary adenoma in sellar region is rare, and is usually diagnosed as "mixed gangliocytoma-pituitary adenoma". Due to lack of radiological characteristics, it is very difficult to make an accurate diagnosis preoperatively. Herein we describe one case of unusual mixed gangliocytoma - growth hormone (GH) secreting pituitary adenoma in sellar region and review related literatures, so as to summarize the clinicopathological characteristics and improve the diagnosis and differential diagnosis of this tumor. Methods and Results A 28 - year - old female presented with headache and blurred vision for 8 months. She also complained of acromegaly and amenorrhea. Head CT and MRI examinations showed a sellar and suprasellar mass with clear boundary compressing the optic chiasm and buttom of the third ventricle. The mass exhibited isointense signal or mild hypointensity on T 1 WI and mild hyperintensity on T 2 WI with heterogeneous enhancement on the contrast MRI. The tumor was removed totally. The histological sections demonstrated two parts of intermixed areas. One part of areas was marked by a proliferation of scattered gangliocyte - like cells arranged in a fibrillary background. Other areas were marked by a sheet - like or locally papillary proliferation of round and oval cells. Immunohistochemically, cytoplasm of gangliocyte-cells were diffusely positive for synaptophysin (Syn), and negative for adenohypophysial hormones; cytoplasm of round and oval cells were diffusely positive for Syn, and almost 30% cells were positive for GH, and negative for other neurohypophysial hormones. A final diagnosis of mixed gangliocytoma-GH secreting pituitary adenoma in sellar region (WHO grade Ⅰ) was made. The patient did not receive postoperatively adjuvant therapy and was followed-up for one year, without any neurological deficit or signs of recurrence. Conclusions Mixed gangliocytoma - pituitary adenoma is extremely rare and a definite diagnosis should be made under microscopy examination. Since the histogenesis of this tumor suggests that the uncommitted stem/progenitor cells consist of both adenohypophysial and neuronal characteristics and are capable of giving rise to pituitary adenoma with neuronal component, a diagnostic term of "pituitary adenoma with ganglionic differentiation" is suggested for this independent entity rather than collision tumor combined by two separate tumors. DOI: 10.3969/j.issn.1672-6731.2016.10.011

Droplet digital PCR is a powerful technique to demonstrate frequent FGFR1 duplication in dysembryoplastic neuroepithelial tumors.

Dysembryoplastic neuroepithelial tumors (DNT) share V600E mutation in the BRAF gene with other low grade neuroepithelial tumors (LGNTs). FGFR1 internal tandem duplication of the tyrosine-kinase domain (FGFR1-ITD), another genetic alteration that also leads to MAP kinase pathway alteration, has been previously reported in LGNTs by whole-genome sequencing. In the present study we searched for FGFR1-ITD by droplet digital PCR (DDPCR™) and for FGFR1 point mutations by HRM-sequencing in a series of formalin-fixed paraffin-embedded (FFPE) LGNTs including 12 DNT, 2 oligodendrogliomas lacking IDH mutation and 1p/19q co- deletion (pediatric-type oligodendrogliomas; PTOs), 3 pediatric diffuse astrocytomas (PDAs), 14 gangliogliomas (GGs) and 5 pilocytic astrocytomas (PAs). We showed by DDPCR™ that 5/12 DNT, but none of the other LGNTs, demonstrated FGFR1-ITD. In addition, these cases also accumulated phosphorylated-FGFR1 protein as shown by immunohistochemistry. FGFR1G539R point mutation was only recorded in one DNT that also showed FGFR1-ITD. Interestingly, these FGFR1 alterations were mutually exclusive from BRAFV600E mutation that was recorded in 13 LGNTs (3 DNTs, 1 PTO, 2 PDAs, 5 GGs and 2 PAs). Therefore, FGFR1 alteration mainly represented by FGFR1-ITD is a frequent event in DNT. DDPCR™ is an easy and alternative method than whole-genome sequencing to detect FGFR1-ITD in FFPE brain tumors, in routine practice.

Longitudinal mutational analysis of a cerebellar pilocytic astrocytoma recurring as a ganglioglioma

A cerebellar pilocytic astrocytoma (PA) in a child recurred first with a PA histology and then with features of a ganglioglioma (GG). Molecular genetic analyses of the tumors confirmed a BRAF V600E mutation in all. They also all harbored a T202M mutation in ERK1, a kinase downstream of BRAF that is implicated in glial versus neuronal differentiation. The GG sample contained several variants that were not present in the PA samples; in particular, it had a truncating mutation in MAP2. These findings not only underscore the role of BRAF as oncogenic driver but also suggest that other genes may influence tumor morphology.

PS1 - 218 Characterization of Ganglioglioma as a Neurodevelopmental Disorder: A Cast of Arrested Development?

Gangliogliomas (GG) are low grade neuroepithelial tumours of the central nervous system (CNS) comprised of neoplastic glial and neuronal cells. There are no animal models or cell lines to study. Microarray data of a panel of low grade gliomas including GG revealed overexpression of the DLX2 homeobox gene required for tangential interneuronal migration and differentiation in the embryonic forebrain. We hypothesized that DLX2 regulates neural versus glial cell fate decisions in CNS progenitors and that GG are arrested in development. METHODS: DLX2 expression was examined along with glial fibrillary acidic protein (GFAP; glial marker) and synaptophysin and/or NeuN (neuronal markers) expression in a cohort of GG tumours using immunohistochemistry and dual immunofluorescence labelling of formalin fixed paraffin embedded (FFPE) tissue sections. BRAF mutational status was also assessed. RESULTS: In our discovery cohort (Genoa), 10/30 samples (33%) expressed DLX2. In our validation cohort (Edmonton), 22/36 (61%) expressed nuclear DLX2 and 12/22 DLX2+cases had BRAF mutations (55%; 11 V600E, 1 V600G). 12/18 cases with BRAF mutations were DLX2+(67%). One heavily pre-treated child with progressive cervicomedullary GG has had a very good partial response to BRAF inhibitor therapy. All 22 DLX2+tumours co-expressed GFAP (100%) and 21/22 (95%) also expressed synaptophysin or NeuN. CONCLUSIONS: Our results support GG as neurodevelopmental tumours arising from bipotential CNS progenitors that are arrested at the neural-glial cell fate "decision" point. Biological or differentiation-based treatments could be considered+/- BRAF inhibitors for those GG with/without the V600E mutation, respectively.

Glioneuronal tumors of cerebral hemisphere in children: correlation of surgical resection with seizure outcomes and tumor recurrences

Glioneuronal tumors are common neoplasms among the cerebral hemisphere during childhood. They consist of several histological types, of which gangliogliomas (GGs) and dysembryoplastic neuroepithelial tumors (DNTs) are most common and often present with seizures. A great majority of glioneuronal tumors are benign. However, there are conflict reports regarding postoperative tumor recurrence rates and seizure control. The authors analyzed and compared these tumors for their locations and histology and the tumor and seizure control following resection. The authors conducted a retrospective analysis of patients with pediatric glioneuronal tumors in the cerebral hemisphere. All histology reports and neuroimaging are reviewed. Seizure group and non-seizure group were compared with their tumor types and locations. The extent of tumor resections were divided into gross total resection (GTR) and subtotal resection (STR). Postoperative tumor recurrence-free survival (RFS) and seizure-free survival for patients who had the initial surgery done at our institution were calculated using Kaplan-Meier method. There were 90 glioneuronal tumors including 58 GGs, 22 DNTs, 3 papillary glioneuronal tumor, 3 desmoplastic infantile gangliogliomas, 3 anaplastic GGs, and 1 central neurocytoma. Seventy-one patients (seizure group) presented with seizures. The temporal lobe is the most common location, 50% in this series. GTR was attained in 79 patients and STR in 11. All of the patients with GTR had lesionectomy, and only six of them had extended corticectomy or partial lobectomy. Postoperative seizure outcome showed that 64 (90%) of seizure group had Engel's class I, but five patients subsequently developed recurrent seizures. Patients with DNTs had a higher seizure recurrence rate. Tumor RFS was 87% at 5years and 75.5% at 10years. There are no significant difference in tumor recurrences between GGs and DNTs (p = 0.876). Comparison between GRT (67) and STR (9) showed that in spite of the better 5-year tumor RFSs among GRT group (94%) than STR group (66%), the 10-year RFSs showed no significant difference between GRT and STR groups (p = 0.719). Recurrent seizures are often related to recurrent tumor. Lesionectomy alone often provides a high-rate seizure freedom. GGs and DNTs are benign tumor, but recurrences of GGs and DNTs are not uncommon. They may show late recurrences in spite of GTR. These patients need longer follow-up for 10years. Recurrent seizures are often related to a tumor recurrence.

Clinical, Imaging, Histopathological and Molecular Characterization of Anaplastic Ganglioglioma.

Anaplastic ganglioglioma (AGG) is a rare and malignant variant of ganglioglioma. According to the World Health Organization classification version 2016, their histopathological grading criteria are still ill-defined. The aim of the present study was to assess the clinical, imaging, histopathological, and molecular characteristics and outcomes of AGGs in a large consecutive and retrospective adult and pediatric case series. Eighteen patients with AGGs (13 adults and 5 children) were identified (14 de novo and 4 secondary) from a cohort of 222 gangliogliomas (GG) (8%) treated at our institution between 2000 and 2015. AGGs represented a very aggressive disease with poor outcome (median progression-free survival, 10 months; median overall survival, 27 months). They were located in the temporal lobe only in 22% and presented with seizures (44%) or increased intracranial pressure (44%) at diagnosis. Concerning histopathological and molecular data, they shared morphological characteristics and BRAF V600E mutation (39%) with their benign counterparts but also showed hTERT promoter mutation (61%), p53 accumulation (39%), ATRX loss (17%), or p.K27M H3F3A mutation (17%). AGGs are malignant neoplasms requiring aggressive oncological treatment. In the perspective of targeted therapies, AGGs should be screened for BRAF V600E, hTERT, ATRX, and mutations of histone genes.

Application of diffusion-weighted imaging and dynamic susceptibility contrast perfusion-weighted imaging for ganglioglioma in adults: Comparison study with oligodendroglioma

To evaluate diffusion-weighted imaging (DWI) and dynamic susceptibility contrast perfusion-weighted imaging (DSC-PWI) of ganglioglioma (GG) compared with oligodendroglioma (ODG). We enrolled 36 patients with histopathologically confirmed GG (12 patients) or ODG (24 patients). The volumetric analyses of normalized ADC (nADC) and normalized CBV (nCBV) maps, tumor volume, and ratio of enhancing portion compared to the tumor volume were performed. The microvessel area (MVA) was analyzed by staining with the CD34 monoclonal antibody. GGs occurred more frequently in the temporal lobe than in the frontal lobe. GGs showed a smaller tumor volume, and higher ratio of enhancing portion per tumor volume than ODGs (P=.002, and P=.010, respectively). GGs also showed lower nADC values (1.055±0.063 vs 1.204±0.030, P=.021) and higher nCBV values (0.777±0.032 vs 0.514±0.025, P<.001) than ODGs. Among the parameters in the multivariate model, nCBV was the most significant factor for differentiating GGs and ODGs (P<.0001). GGs showed significantly higher MVAs than ODGs (0.48±0.09 vs 0.24±0.04, P=.025). Our results suggest that GGs tend to have relatively smaller tumor volume with higher ratio of enhancing portions, lower nADC values, and higher nCBV values than ODGs. Among these parameters, measurement of nCBV, which is correlated with a higher MVA measurement in GGs, can be the most useful tool for differentiating GGs from ODGs.

LG-44OCCURRENCE OF BRAF V600E MUTATION IN A PEDIATRIC BRAINSTEM GANGLIOGLIOMA WITH NEAR EXCLUSIVE GLIAL COMPONENT IN THE ORIGINAL BIOPSY

LG-44. OCCURRENCE OF BRAF V600E MUTATION IN A PEDIATRIC BRAINSTEM GANGLIOGLIOMA WITH NEAR EXCLUSIVE GLIAL COMPONENT IN THE ORIGINAL BIOPSY Alex Feldman, David Kelly, Alyssa Reddy, Jeffrey Blount, and Rong Li; University of Alabama at Birmingham, Birmingham, AL, USA A five-year-old male who initially presented with apneic episodes and morbid obesity underwent imaging studies, which revealed a dorsally exophytic medullary tumor in 2014. A biopsy showed a classic pilocytic astrocytoma (PA) with no apparent neoplastic neuronal component. Following completion of chemotherapy, the patient presented again in January of 2016 with worsening symptoms; the tumor was found to have grown in size with brainstem compression. Debulking was performed. Unexpectedly, the histology of this tumor showed a ganglioglioma (GG) with many clusters of enlarged, misshapen, dysmorphic-appearing and occasionally binucleated neurons. Furthermore, BRAF V600E mutations were identified in both prior and recurrent tumors. Recent publications have found that the BRAF V600E mutation is seen in 20-58% of all GGs. In particular, pediatric brainstem GGs appear to harbor this mutation at a rate greater than 50%. Few studies have investigated the distribution of BRAF aberrations among neuronal and glial components in GGs. Pilocytic astrocytomas often possess BRAF abnormalities, though fusion genes (i.e BRAF-KIAA1549) are considerably more common (60-80%) than the BRAF V600E missense mutations (only seen in 10-12% of pediatric brainstem PAs). This case highlights the presence of the BRAF point mutation in both glial and neuronal component of a pediatric brainstem GG, supporting the hypothesis that a glioneuronal lineage precursor is initially affected by the mutation. Additionally, the presence of the BRAF point mutation in a brainstem pilocytic astrocytoma should raise the possibility of a GG in which sampling artifact highlights a near exclusive glial component. Neuro-Oncology 18:iii78–iii96, 2016. doi:10.1093/neuonc/now075.44 #The Author(s) 2016. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Abundance of LRP12 C-rs9694676 allelic promoter variant in epilepsy-associated gangliogliomas

AimsChronic epilepsy associated gangliogliomas (GGs) represent tumors composed of irregularly distributed, often dysmorphic, neurons and neoplastic astroglia. The pathogenesis of GGs is largely unknown. Low-density lipoprotein receptor-related protein 12 (LRP12) is critical for brain development and involved in tumorigenesis of non-cerebral neoplasms. Main methodsHere, we have examined a potential role of LRP12 in the pathogenesis of GGs by a combination of mRNA quantification and molecular-biological in vitro assays. Key findingsWe observed a significant increase of the single nucleotide polymorphism (SNP) rs9694676 C-allele, located in the LRP12 promoter, in GGs compared to normal control individuals. C-allele expression is correlated with abundant seizure frequency. Expression of LRP12 was lower in GGs than in control brain. In luciferase assays, the C-allele of rs9694676 decreases both, the basal LRP12 core promoter activity and the stimulatory effect of the transcription factor (TF) STAT5a. SignificanceAccumulation of functional promoter-associated allelic variants with impact on the transcriptional regulation of LRP12 provides a new pathomechanism for GGs, i.e. highly differentiated epileptogenic brain tumors.

A national perspective of adult gangliogliomas

Gangliogliomas (GG) are rare tumors of the nervous system. Patient characteristics and clinical outcomes of low and high-grade GG have been difficult to elucidate in the adult population. This study aims to further elaborate on GG treatment and overall survival utilizing a larger cohort than previously published. The USA National Cancer Database was utilized to evaluate adult (age 18years and older) patients diagnosed with GG between 2004 and 2006. Descriptive statistics and Kaplan–Meier overall survival estimates were provided. A total of 198 adult GG patients were diagnosed between 2004 and 2006. Of these, 181 (91.4%) were low-grade and 17 (8.6%) high-grade GG. Overall, the median age was 36years; approximately 50% of patients were female, and 86.5% Caucasian. Most patients (59%) had near/gross total resection. Radiation and chemotherapy were prescribed in 18 (9.1%) and 11 (5.7%) patients, respectively. Radiation (64.7% versus 3.9%, p<.0001) and chemotherapy (47.1% versus 1.7%, p<.0001) were more frequently given to patients with high-grade tumors than low-grade. The median overall survival of high-grade GG was 44.4months (95% confidence interval [CI]: 10.5–92.5) while the corresponding estimate for low-grade tumors was not reached. Older age (hazard ratio [HR] 1.72, 95% CI: 1.26–2.34) and high tumor grade (HR 3.91, 95% CI: 1.43–10.8) were found to be associated with poor survival. Adult GG have a temporal lobe predilection and overall gross total resection rate of 59%. Older patients with high-grade tumors had an increased hazard of mortality. High-grade GG were significantly more likely to be treated with radiation therapy and chemotherapy.

Radiological Evaluation of Infratentorial Gangliogliomas in Various Anatomic Locations of the Cerebellum and Brainstem.

To review the imaging features of infratentorial gangliogliomas (GGs) and compare between Infratentorial GGs located within the cerebellum and brainstem. The cases of 24 patients with histologically-confirmed infratentorial GGs were reviewed retrospectively. These subjects' cases were divided into a cerebellar group (n = 8) and a brainstem group (n = 16) based upon the anatomic location of the tumor. Imaging features (including tumor volume, margins, cystic/solid ratio, enhancement, peritumoral edema, and ipsilateral cerebellar atrophy) were compared between these two groups. On magnetic resonance imaging, infratentorial GGs showed isointensity or hypointensity on T1WI and heterogeneous hyperintensity on T2WI, with ipsilateral cerebellar atrophy observed in seven cases. Computed tomography images available in the cerebellar group showed heterogeneous isodensity with calcifications. Cerebellar GGs (median = 67.25cm3, inter-quartile range = 27.78-83.27cm3) were larger in volume than brainstem GGs (median = 16.89cm3, interquartile range = 6.08-27.26cm3) (p = 0.002). Cystic-solid mass (5 of 8) and solid mass (11 of 16) were more commonly represented in the cerebellar and brainstem group, respectively (p = 0.033). Cerebellar GGs showed varying degrees of enhancement, while most of brainstem GGs showed moderate-to-marked enhancement (p = 0.012). Dorsal-predominant enhancement (n = 3) and posterior-marginal enhancement (n = 5) were observed in the brainstem group. The degrees of peritumoral edema and rate of ipsilateral cerebellar atrophy were not significantly different between the two study groups. Ipsilateral cerebellar atrophy can be found in infratentorial GGs involving the middle and inferior cerebellar peduncles. GGs should therefore be considered in the differential diagnoses when a solid-cystic mass with calcification is encountered in the cerebellum. Brainstem GGs tend to be smaller, solid masses with moderate-to-marked enhancement. Dorsal-predominant and posterior-marginal enhancement may be the specific imaging findings for brainstem GGs.

MRI-characteristics of epileptogenic supratentorial brain tumors in children

To analyze MR-images in patients with symptomatic epilepsy associated with the brain tumor. MRI results of 52 patients with symptomatic epilepsy operated for tumors of supratentorial localization were analyzed. The most epileptogenic tumors with atypical MRI signs and subtle clinical presentation were identified. All patients with tumors were operated using different methods of surgical intervention. Dysembryoplastic neuroepithelial tumors (DNET), diffuse astrocytomas (DA) and gangliogliomas (GG) were the most frequent epileptogenic tumors. In all the cases of DNET and in 4 patients with GG, epileptic seizures were the first, and in 4 of 5 cases of DIO were the only clinical sign of tumor presence. In DNET, DA and GG, there was an iso- or hypointensive signal on T1 WI and a signal varying in intensity from moderate to hyperintense in T2 and FLAIR WI, while in cases with DNET and GG, no mass effect and perifocal edema was practically seen. The so-called «spume-like» (multicystic) structure was most clearly observed in FLAIR WI. No significant changes in the dimensions of the DNET and GG were identified. The combination of DNET with focal cortical dysplasia was noted in one case. In DA, it was difficult to distinguish the perifocal edema from tumorous tissue and normal brain tissues, and the growth potential of malformation was slow. Epileptogenic tumors can imitate the x-ray characteristics of each other, and mimicry to gangliogliomas, oligodendrogliomas and astrocytomas Gr I, II, and others. They are the most frequent causes of symptomatic focal epilepsy. The presence of these malformations is necessary to exclude first of all in all cases of pharmacoresistant epilepsy.

PRE-SURGERY MR-VISUALIZATION OF THE EPILEPTOGENIC SUPRATENTORIAL BRAIN TUMORS IN CHILDREN

Symptomatic focal epilepsies are commonly caused by the supratentorial brain tumors in chtldren. Among the 79 pediatric patients with supratentorial brain tumors 56 patients had symptomatic epilepsy (69,3%). The most epileptogenic tumors were dysembryoplastic neuroepithelial tumors (DNET), diffuse astrocytomas (DA) and gangliogliomas (GG). In all the cases of DNET and in 4 patients with GG epileptic seizures were the first manifestation, and in 4 of 5 cases of DNEO they were the only clinical sign of tumor. On the neuroimaging the MR-features of DNET, DA and GG were represented by iso- or hypointensive signal on T1 weighted image (WI) and varying in intensity from moderate to hyperintensive signal in T2 and FLAIR WI, while in cases with DNET and GG practically no mass effect and perifocal edema were seen, and on FLAIR WI the so-called "spume-like" (multicystic) structure was most clearly observed. During the follow up period no significant changes in the dimensions of identified DNET and GG were observed. In one case the combination of DNET with focal cortical dysplasia was noted. In DA it is difficult to distinguish the perifocal edema from tumorous tissue and normal brain tissue, and the growth potential of tumor is slow. The contrast enhancement of these tumors is ambiguous. Along with DNET (which is epileptogenic in 100% of cases), the most epileptogenic brain tumors are DA (in 91.7% of cases) and GG (in 80% of cases) which should be excluded in drug-resistant cases of focal epilepsy.

THE ROLE OF MAGNETIC RESONANCE IMAGING IN COMPLEX CLINICAL-EEG-IMAGING EXAMINATION OF EPILEPTOGENIC BRAIN TUMORS IN CHILDREN

Symptomatic epilepsy is common for patients with supratentorial brain tumors. Among 75 children with supratentorial brain tumors 52 patients had symptomatic epilepsy (69,3%). The most epileptogenic tumors were dysembryoplastic neuroepithelial tumors (DNET), diffuse astrocytomas (DA) and gangliogliomas (GG). In all the cases of DNET and in 4 patients with GG epileptic seizures were the first symptom, and in 4 of 5 cases of DNET seizures were the only clinical sign of tumor presence. DNET, DA and GG looked as iso- or hypointensive lumps on T1-weighted images and as moderate or hyperintensive lesions on T2-weighted and FLAIR images, without mass effect or perifocal edema in cases of DNET and GG. On FLAIR images DNET and GG have so-called “spume-like” (multicystic) structure. Follow up MRI did not reveal significant change in DNET and GG. In one case DNET was noted to be associated with focal cortical dysplasia. In DA it is difficult to distinguish the perifocal edema from tumorous tissue and normal brain tissue, and the growth potential of tumor was slow. The tumors differently cumulate contrast and interpretation of scans with contrast enhancement is ambiguous. Along with DNET (which is epileptogenic in 100% of cases), DA and GG are also epileptogenic brain tumors (seizures occur in 91.7% of cases of DA and in 80% of cases of GG) which should be excluded during diagnosis of drug-resistant focal epilepsy.

A clinicopathologic study of diencephalic pediatric low-grade gliomas with BRAF V600 mutation.

Among brain tumors, the BRAF (V600E) mutation is frequently associated with pleomorphic xanthoastrocytomas (PXAs) and gangliogliomas (GGs). This oncogenic mutation is also detected in ~5% of other pediatric low-grade gliomas (LGGs) including pilocytic astrocytomas (PAs) and diffuse astrocytomas. In the current multi-institutional study of 56 non-PXA/non-GG diencephalic pediatric LGGs, the BRAF (V600) mutation rate is 36%. V600-mutant tumors demonstrate a predilection for infants and young children (<age 3) and have a higher tendency for multicentricity. On neuroimaging, BRAF (V600)-mutant tumors appear as nodular, yet infiltrative contrast-enhancing masses. Morphologic examination reveals a monophasic, predominantly compact and partially infiltrative architecture. Due to the lack of classic morphologic features associated with PAs, pilomyxoid astrocytomas (PMAs), or diffuse astrocytomas, 75% of the BRAF (V600)-mutant tumors could not be definitively classified on initial histopathologic evaluation. At a median follow-up of 55months, the 5-year progression-free survival (PFS) rate for BRAF (V600)-mutant diencephalic low-grade astrocytomas (LGAs) was 22±12%, shorter than BRAF (V600)-WT PAs (52±13%) but higher than PMAs (10±6%). Of note, long-term PFS was observed in several adolescent patients with BRAF (V600)-mutant tumors. In children aged 0-12years, 5-year PFS rate and median PFS in BRAF (V600)-mutant LGAs are 9±9% and 19months (95% CI 3-37months), respectively. The PFS is comparable to that in BRAF (V600)-WT PMAs (5-year PFS rate: 10±9%; median PFS: 15months, 95% CI 3-32months; p=0.96) and significantly shorter than BRAF (V600)-WT PAs (5-year PFS rate: 46±13%; median PFS: 51months, 95% CI 20-∞ months; p<0.05). In summary, diencephalic BRAF (V600)-mutant pediatric LGAs are associated with unique clinicopathologic features and have a more aggressive clinical course, especially in children under age 13. The low rate of CDKN2A deletion also suggests that these tumors are molecularly distinct from secondary pediatric high-grade gliomas.