Low-grade Glioneuronal Tumors Research Articles

Dysembryoplastic Neuroepithelial Tumor of the Septum Pellucidum and the Supratentorial Midline: Histopathologic, Neuroradiologic, and Molecular Features of 7 Cases.

Dysembryoplastic neuroepithelial tumors (DNTs) are one of the most common epilepsy-associated low-grade glioneuronal tumors of the central nervous system. Although most DNTs occur in the cerebral cortex, DNT-like tumors with unusual intraventricular or periventricular localizations have been reported. Most of them involve the septum pellucidum and the foramen of Monro. In this study, we have described the neuroradiologic, histopathologic, and molecular features of 7 cases (4 female and 3 male; patient age range, 3 to 34 y; mean age, 16.7 y). The tumors, all localized near the supratentorial midline structures in proximity to the foramen of Monro and septum pellucidum, appeared in magnetic resonance imaging as well-delimited cystic lesions with cerebrospinal fluid-like signal on T1-weighted and T2-weighted images, some of them with typical fluid-attenuated inversion recovery ring sign. Histologically, they shared features with classic cortical DNTs but did not display aspects of multinodularity. From a molecular point of view the cases investigated did not show KIAA1549-BRAF fusions or FGFR1 mutations, alterations otherwise observed in pilocytic astrocytomas, or MYB and MYBL1 alterations that have been identified in a large group of pediatric low-grade gliomas. Moreover, BRAF mutations, which so far represent the most common molecular alteration found in cortical DNTs, were absent in this group of rare periventricular tumors.

GE-01 * MOLECULAR AND PATHOLOGIC SUBSETS OF LOW GRADE GLIOMAS AND GLIONEURONAL TUMORS IDENTIFIED BY microRNA PROFILING

Low-grade (WHO I-II) gliomas represent the most frequent primary tumors of the central nervous system in children. They often have a good prognosis following total resection, however they can create many neurological complications due to mass effect, and may be difficult to resect depending on anatomic location. MicroRNAs have been identified as molecular regulators of protein expression that can repress multiple mRNAs concurrently through base pairing. Specific microRNAs are often suppressed during early cell differentiation to promote the expression of mitogenic proteins that are associated with the maintenance of specific stem cell types, a mechanism for growth and survival that is frequently exploited in cancer cells. Identification of these microRNA signatures present in low grade glioma and glioneuronal tumor sub-types could therefore lead to a wealth of candidate biomarkers. We used NanoString technology to analyze the expression levels of 800 microRNAs in nine low-grade glial and glioneuronal tumor subtypes (n = 45) using formalin-fixed paraffin-embedded tissue. We then generated hierarchical clusters following evaluation via significant analysis of microarrays (SAMs). Hierarchical clustering separated tumors from non-neoplastic brain. When looking at individual tumors, subependymal giant cell astrocytomas (SEGA) clustered sharply together, consistent with a unique microRNA expression signature in this tuberous sclerosis associated tumor subtype, compared to other low grade glial and glioneuronal tumors. Candidate microRNAs were validated using qRT-PCR. In SEGAs, microRNAs miR-219-5p, miR-129-2-3p, miR-338-3p, miR-487b, miR-885-5p, and miR-323-3p were significantly down-regulated by more than 15 fold as compared to normal brain and were also significantly down-regulated as compared to other low grade gliomas. In summary, altered microRNA expression is a feature of low grade glial and glioneuronal tumors. MicroRNA profiling may therefore be useful in subtyping these tumors and to provide important insights into their biology.

Posterior fossa and spinal gangliogliomas form two distinct clinicopathologic and molecular subgroups

BackgroundGangliogliomas are low-grade glioneuronal tumors of the central nervous system and the commonest cause of chronic intractable epilepsy. Most gangliogliomas (>70%) arise in the temporal lobe, and infratentorial tumors account for less than 10%. Posterior fossa gangliogliomas can have the features of a classic supratentorial tumor or a pilocytic astrocytoma with focal gangliocytic differentiation, and this observation led to the hypothesis tested in this study - gangliogliomas of the posterior fossa and spinal cord consist of two morphologic types that can be distinguished by specific genetic alterations.ResultsHistological review of 27 pediatric gangliogliomas from the posterior fossa and spinal cord indicated that they could be readily placed into two groups: classic gangliogliomas (group I; n = 16) and tumors that appeared largely as a pilocytic astrocytoma, but with foci of gangliocytic differentiation (group II; n = 11). Detailed radiological review, which was blind to morphologic assignment, identified a triad of features, hemorrhage, midline location, and the presence of cysts or necrosis, that distinguished the two morphological groups with a sensitivity of 91% and specificity of 100%. Molecular genetic analysis revealed BRAF duplication and a KIAA1549-BRAF fusion gene in 82% of group II tumors, but in none of the group I tumors, and a BRAF:p.V600E mutation in 43% of group I tumors, but in none of the group II tumors.ConclusionsOur study provides support for a classification that would divide infratentorial gangliogliomas into two categories, (classic) gangliogliomas and pilocytic astrocytomas with gangliocytic differentiation, which have distinct morphological, radiological, and molecular characteristics.

Limbic Tumors of the Temporal Lobe: Radiologic–Pathologic Correlation

The purpose of this study was to assess imaging and pathologic characteristics of limbic tumors. Our hypothesis was that temporal lobe limbic tumors have distinctive features from extralimbic tumors. This retrospective radiologic-pathologic correlation study of primary temporal lobe tumors (excluding glioblastoma) distinguished limbic from extralimbic tumors based on preoperative magnetic resonance imaging. Limbic tumors were categorized according to Yaşargil's classification into (1) mediobasal temporal (mbT), (2) insular-temporo-opercular (I-TO), and (3) fronto-orbital-insular-temporopolar (FO-I-TP). A total of 50 cases with a mean age at diagnosis of 38 ± 19.9 years (14 women, 36 men) were included. Pathologic diagnoses were as follows: 20 anaplastic astrocytomas, 11 gangliogliomas, 8 astrocytomas (World Health Organization grade II), 3 pilocytic astrocytomas, 2 dysembryoplastic neuroepithelial tumors, 2 oligodendrogliomas (grade II), 2 anaplastic oligodendrogliomas, 1 low-grade glioneuronal tumor, and 1 atypical extraventricular neurocytoma. In all, 36 tumors were limbic and displayed consistent growth patterns (16 mbT, 11 I-TO, 8 FO-I-TP, and 1 pantemporal) and 14 were extralimbic. There were no differences between limbic and extralimbic tumors with regard to age, sex, pathologic diagnosis, and presentation with seizures. mbT tumors had more frequent neuronal differentiation (50 %) than I-TO (0 %) and FO-I-TP (25 %) tumors (chi-square = 7.8, df = 2, p = 0.02). Neuronal differentiation correlated with lower grade (r = 0.52, p < 0.01) and younger age (r = 0.52, p < 0.01). Limbic tumors displayed consistent growth routes. mbT limbic tumors had more frequent neuronal differentiation, which may result from proximity to the neurogenic subgranular zone of the hippocampus. Neuronal differentiation was maximal in mbT and lowest in I-TO and FO-I-TP tumors and correlated with lower tumor grade and younger age at diagnosis.

Whole-genome sequencing identifies genetic alterations in pediatric low-grade gliomas

The commonest pediatric brain tumors are low-grade gliomas (LGGs). We utilized whole genome sequencing to discover multiple novel genetic alterations involving BRAF, RAF1, FGFR1, MYB, MYBL1 and genes with histone-related functions, including H3F3A and ATRX, in 39 LGGs and low-grade glioneuronal tumors (LGGNTs). Only a single non-silent somatic alteration was detected in 24/39 (62%) tumors. Intragenic duplications of the FGFR1 tyrosine kinase domain (TKD) and rearrangements of MYB were recurrent and mutually exclusive in 53% of grade II diffuse LGGs. Transplantation of Trp53-null neonatal astrocytes containing TKD-duplicated FGFR1 into brains of nude mice generated high-grade astrocytomas with short latency and 100% penetrance. TKD-duplicated FGFR1 induced FGFR1 autophosphorylation and upregulation of the MAPK/ERK and PI3K pathways, which could be blocked by specific inhibitors. Focusing on the therapeutically challenging diffuse LGGs, our study of 151 tumors has discovered genetic alterations and potential therapeutic targets across the entire range of pediatric LGGs/LGGNTs.

MR imaging findings of extraventricular neurocytoma: a series of ten patients confirmed by immunohistochemistry of IDH1 gene mutation

Extraventricular neurocytomas (EVNs) are rare neuronal tumors included as neoplasms in the 2007 World Health Organization (WHO) classification of tumors of the CNS. Although a few case reports describing EVNs have been published, a systematic analysis of MR imaging findings of EVN has not been reported. Furthermore, imaging findings of IDH1 mutation-negative EVNs have not yet been reported. The aim of our study is to describe the MR imaging findings of IDH1 mutation-negative EVNs. MR images of ten patients with pathologically confirmed IDH1 mutation-negative EVNs were retrospectively reviewed. Conventional MR imaging of ten EVNs were reviewed with emphasis on the location, signal intensities, patterns, and grades of enhancement as well as the presence/grade of peritumoral edema, intratumoral cyst, hemorrhage, and calcification. The study also reviewed the results of DWI (b = 1,000s/mm(2), n = 7). Seven EVN cases were located in the cerebral hemisphere, and the remaining cases were in the cerebellum and thalamus. Of those in the cerebral hemisphere, five were cortically based tumors. The tumors showed no or mild peritumoral edema. Eight tumors were enhanced on the postcontrast T1WIs. An intratumoral cyst, hemorrhage, and calcification were detected in four, one, and two cases, respectively. On DWI, only one case showed a lower ADC value than the brain parenchyma. EVNs are usually cortically based infiltrative hemispheric tumors with contrast enhancement, higher ADC value, and sometimes small cystic component, but hardly show peritumoral edema or intratumoral hemorrhage. The differential diagnosis of these findings includes low-grade glioneuronal tumors and low-grade gliomas.

Focal Cortical Dysplasias: clinical implication of neuropathological classification systems

Focal Cortical Dysplasias (FCDs) are highly epileptogenic brain lesions and are a frequent cause for drug-resistant focal epilepsies in humans. FCDs present with variable histopathological patterns, including architectural, cytoarchitectural or white matter abnormalities. Pathomechanisms compromising neuroblast proliferation, migration, or differentiation are likely to play a role in the etiology of FCD variants. FCDs were subsumed, therefore, into the broad spectrum of malformations of cortical development. The most frequent subtype comprises FCD Type II, which in general occurs as isolated lesion in extratemporal location and is histopathologically characterized by dysmorphic neurons (Type IIA) and balloon cells (Type IIB). Neuroimaging hallmarks include hyperintense T2-signaling and a "transmantle sign". Electrophysiological recordings show peculiar interictal spike patterns and complete surgical resection results in favorable seizure control. In contrast, FCD Type I can be identified in young children with severe epilepsy and psychomotor retardation. Parietal, temporal, and occipital lobes may be involved in seizure generation, although neuroimaging often reveals normal contrast intensities. Surgical resection strategies ameliorate seizure frequencies in many children, whereas complete seizure relief can be achieved only in rare cases. According to the currently used FCD classification system, the same histopathological FCD Type I variant can be diagnosed as associated lesion in the large cohort of epilepsy patients with hippocampal sclerosis, low-grade glio-neuronal tumors, vascular malformations, or glial scarring. MRI is often not helpful to detect the dysplastic cortical areas. In addition, there is no specific electrophysiological pattern for an associated dysplastic lesion. Surgical resection of the epileptogenic area results, however, in favorable seizure control. These findings argue for a revised neuropathological classification system that distinguishes isolated versus associated FCD variants to obtain a better correlation with electro-clinical findings and prediction of postsurgical seizure control.