Transcriptional features of low-grade neuroepithelial tumors with the BRAF V600E mutation associated with epileptogenicity.

Low-grade neuroepithelial tumors are major causes of drug-resistant focal epilepsy. Clinically, these tumors are defined as low-grade epilepsy-associated neuroepithelial tumors (LEATs). The BRAF V600E mutation is frequently observed in LEAT and linked to poor seizure outcomes. However, its molecular role in epileptogenicity remains elusive. To understand the molecular mechanism underlying the epileptogenicity in LEAT with the BRAF V600E genetic mutation (BRAF V600E-LEAT), we conducted RNA sequencing (RNA-seq) analysis using surgical specimens of BRAF V600E-LEAT obtained and stored at a single institute. We obtained 21 BRAF V600E-LEAT specimens and 4 control specimens, including 24 from Japanese patients and 1 from a patient of Central Asian origin, along with comprehensive clinical data. We submitted the transcriptome dataset of 21 BRAF V600E-LEAT plus 4 controls, as well as detailed clinical information, to a public database. Preliminary bioinformatics analysis using this dataset identified 2134 differentially expressed genes between BRAF V600E-LEAT and control. Additionally, gene set enrichment analysis provided novel insights into the association between estrogen response-related pathways and the epileptogenicity of BRAF V600E-LEAT patients. Our datasets and findings will contribute toward the understanding of the pathology of epilepsy caused by LEAT and the identification of new therapeutic targets.

Revisiting prognostic factors of gliomatosis cerebri in adult-type diffuse gliomas.

PURPOSE: There is lack of comprehensive analysis evaluating the impact of clinical, molecular, imaging, and surgical data on survival of patients with gliomatosis cerebri (GC). This study aimed to investigate prognostic factors of GC in adult-type diffuse glioma patients. METHODS: Retrospective chart and imaging review was performed in 99 GC patients from adult-type diffuse glioma (among 1,211 patients; 6 oligodendroglioma, 16 IDH-mutant astrocytoma, and 77 IDH-wildtype glioblastoma) from a single institution between 2005 and 2021. Predictors of overall survival (OS) of entire patients and IDH-wildtype glioblastoma patients were determined. RESULTS: The median OS was 16.7 months (95% confidence interval [CI] 14.2-22.2) in entire patients and 14.3 months (95% CI 12.2-61.9) in IDH-wildtype glioblastoma patients. In entire patients, KPS (hazard ratio [HR] = 0.98, P = 0.004), no 1p/19q codeletion (HR = 10.75, P = 0.019), MGMTp methylation (HR = 0.54, P = 0.028), and hemorrhage (HR = 3.45, P = 0.001) were independent prognostic factors on multivariable analysis. In IDH-wildtype glioblastoma patients, KPS (HR = 2.24, P = 0.075) was the only independent prognostic factor on multivariable analysis. In subgroup of IDH-wildtype glioblastoma with CE tumors, total resection of CE tumor did not remain as a significant prognostic factor (HR = 1.13, P = 0.685). CONCLUSIONS: The prognosis of GC patients is determined by its underlying molecular type and patient performance status. Compared with diffuse glioma without GC, aggressive surgery of CE tumor in GC patients does not improve survival.

Survivors of infant atypical teratoid/rhabdoid tumors present with severely impaired cognitive functions especially for fluid intelligence and visual processing: data from the German brain tumor studies.

BACKGROUND: The contribution of tumor type, multimodal treatment, and other patient-related factors upon long-term cognitive sequelae in infant brain tumor survivors remains undefined. We add our retrospective analysis of neuropsychological and quality of survival (QoS) outcome data of survivors of atypical teratoid/rhabdoid tumors (ATRT) and extracranial malignant rhabdoid tumors of the soft tissues (eMRT) and kidneys (RTK) treated within the same framework. Neuropsychological data from children with ATRT were compared to data from children with non-irradiated low-grade glioma (LGG). PATIENTS AND METHODS: Following surgery, patients (0-36 months at diagnosis) had received radio-chemotherapy (up to 54 Gy; ATRT: n = 13; eMRT/RTK: n = 7), chemotherapy only (LGG: n = 4; eMRT/RTK: n = 1) or had been observed (LGG: n = 11). Neuropsychological evaluation employing comparable tests was performed at median 6.8 years (ATRT), 6.6 years (eMRT/RTK), and 5.2 years (LGG) post diagnosis. RESULTS: We detected sequelae in various domains for all tumor types. Group comparison showed impairments, specifically in fluid intelligence (p = .041; d = 1.11) and visual processing (p = .001; d = 2.09) in ATRT patients when compared to LGG patients. Results for psychomotor speed and attention abilities were significantly below the norm for both groups (p < .001-.019; d = 0.79-1.90). Diagnosis predicted impairments of cognitive outcome, while sex- and age-related variables did not. QoS outcome for all rhabdoid patients displayed impairments mainly in social (p = .008; d = 0.74) and school functioning (p = .048; d = 0.67), as well as lower overall scores in psychosocial functioning (p = .023; d = 0.78) and quality of life (p = .006; d = 0.79) compared to healthy controls. CONCLUSION: Survivors of infant ATRT experience various late effects in cognition and QoS following multimodal treatment, while infant LGG patients without radiotherapy demonstrated comparable impairments in psychomotor and attention abilities. Early onset and multimodal treatment of rhabdoid tumors require close monitoring of neuropsychological and QoS sequelae.

The anatomy of neuroepithelial tumours.

Many neurological conditions conceal specific anatomical patterns. Their study contributes to the understanding of disease biology and to tailored diagnostics and therapy. Neuroepithelial tumours exhibit distinct anatomical phenotypes and spatiotemporal dynamics that differ from those of other brain tumours. Brain metastases display a preference for the cortico-subcortical boundaries of watershed areas and have a predominantly spherical growth. Primary CNS lymphomas localize to the white matter and generally invade along fibre tracts. In neuroepithelial tumours, topographic probability mapping and unsupervised topological clustering have identified an inherent radial anatomy and adherence to ventriculopial configurations of specific hierarchical orders. Spatiotemporal probability and multivariate survival analyses have identified a temporal and prognostic sequence underlying the anatomical phenotypes of neuroepithelial tumours. Gradual neuroepithelial de-differentiation and declining prognosis follow (i) an expansion into higher order radial units; (ii) a subventricular spread; and (iii) the presence of mesenchymal patterns (expansion along white matter tracts, leptomeningeal or perivascular invasion, CSF spread). While different pathophysiological hypotheses have been proposed, the cellular and molecular mechanisms dictating this anatomical behaviour remain largely unknown. Here we adopt an ontogenetic approach towards the understanding of neuroepithelial tumour anatomy. Contemporary perception of histo- and morphogenetic processes during neurodevelopment permit us to conceptualize the architecture of the brain into hierarchically organized radial units. The anatomical phenotypes in neuroepithelial tumours and their temporal and prognostic sequences share remarkable similarities with the ontogenetic organization of the brain and the anatomical specifications that occur during neurodevelopment. This macroscopic coherence is reinforced by cellular and molecular observations that the initiation of various neuroepithelial tumours, their intratumoural hierarchy and tumour progression are associated with the aberrant reactivation of surprisingly normal ontogenetic programs. Generalizable topological phenotypes could provide the basis for an anatomical refinement of the current classification of neuroepithelial tumours. In addition, we have proposed a staging system for adult-type diffuse gliomas that is based on the prognostically critical steps along the sequence of anatomical tumour progression. Considering the parallels in anatomical behaviour between different neuroepithelial tumours, analogous staging systems may be implemented for other neuroepithelial tumour types and subtypes. Both the anatomical stage of a neuroepithelial tumour and the spatial configuration of its hosting radial unit harbour the potential to stratify treatment decisions at diagnosis and during follow-up. More data on specific neuroepithelial tumour types and subtypes are needed to increase the anatomical granularity in their classification and to determine the clinical impact of stage-adapted and anatomically tailored therapy and surveillance.

Astroblastoma With a Novel YAP1::BEND2 Fusion: A Case Report.

In the most recent fifth edition of the World Health Organization Classification of Tumors of the Central Nervous System, astroblastoma has been defined by molecular rearrangements involving the MN1 gene, with common partners being BEND2 or CXXC5 . Accordingly, this tumor entity is now known as "astroblastoma, MN1 -altered." However, gliomas with EWSR1::BEND2 fusions, devoid of MN1 fusion alterations, have recently been shown to exhibit astroblastoma-like histomorphologic features and reside in a distinct epigenetic subgroup based on DNA methylation studies similar to high-grade neuroepithelial tumor with MN1 alteration, which includes astroblastoma, MN1 altered tumors. This new epigenetically distinct subtype of astroblastoma containing EWSR1::BEND2 fusions lacks the required MN1 alteration and, thus, does not satisfy the current molecular classification of these lesions. Here, we describe a case of glioma with histologic features and DNA methylation profiling consistent with astroblastoma with a novel YAP1: : BEND2 fusion. This case and others further expand the molecular findings observable in astroblastoma-like tumors outside the constraints of MN1 alteration. Such cases of astroblastoma with EWSR1::BEND2 and YAP1::BEND2 fusions challenge the current molecular classification of astroblastoma based solely on an MN1 alteration.

Polymorphous low-grade neuroepithelial tumor of the young (PLNTY): A case report with surgical and neuropathological differential diagnosis.

BACKGROUND: Polymorphous low-grade neuroepithelial tumor of the young (PLNTY) is a rare entity of low-grade neuroepithelial tumors that primarily affects children and young adults. This distinct type of tumor presents unique challenges in diagnosis and management. With its relatively recent identification, researchers and clinicians are striving to understand the characteristics, behavior, and optimal treatment strategies. The symptoms are primarily related to seizures. However, PLNTY can be asymptomatic in some cases. MATERIALS AND METHODS: This is a single-center case report study and a literature review paper. We reviewed a case treated and diagnosed at the Ankara University Faculty of Medicine, Department of Neurosurgery. The demographic data, clinical follow-ups, laboratory, and radiological data of the patients were assessed. RESULTS: We present a 32-year-old male patient who has undergone gross total surgical excision with strict clinical follow-up. Clinical course as well as surgical data of the patient were observed and analyzed. CONCLUSION: On imaging, morphologic resembling and indistinctive clinical course can be nonspecific, contributing to diagnostic uncertainties. This case report was written with the notion that rare diagnoses present an opportunity to understand the progression and patho-oncological factors that can pave the way for better treatment.

SWI/SNF-deficient tumors of the central nervous system: An update.

Atypical teratoid/rhabdoid tumor (AT/RT) is a highly malignant tumor of the central nervous system characterized by biallelic inactivation of SWI/SNF chromatin remodeling complex members SMARCB1/INI1 or (rarely) SMARCA4/BRG1. Most high-grade central nervous system lesions showing loss of nuclear SMARCB1 or SMARCA4 protein expression can indeed be categorized as AT/RT. However, some high-grade lesions have been identified, whose clinical and/or molecular features justify separation from AT/RT. Furthermore, other recently described tumor types such as desmoplastic myxoid tumor, SMARCB1-mutant, and low-grade diffusely infiltrative tumor, SMARCB1-mutant, may even manifest as low-grade lesions. Here, we review recent developments in the definition of the molecular landscape of AT/RT and give an update on other rare high- and low-grade SWI/SNF-deficient central nervous system tumors.

A case of disseminated spinal astroblastoma harboring a MAMLD1::BEND2 fusion.

Astroblastoma, MN1-altered, is a rare neoplasm of the central nervous system (CNS). This malignancy shares similar histopathological features with other CNS tumors, including ependymomas, making it challenging to diagnose. DNA methylation profiling is a new and robust technique that may be used to overcome this diagnostic hurdle. We report the case of a now 25-year-old female diagnosed with what was initially called an ependymoma located in the cervical spine at the age of 2 years old. After initial resection, the tumor recurred multiple times and within 2 years of diagnosis had disseminated disease throughout the brain and spinal cord. She has now undergone over two decades of treatment, including multiple surgical resections, radiation therapy, and administration of numerous chemotherapeutic agents. In 2021, the patient presented to our institution with lumbosacral radicular symptoms due to enlarging lesions within the lumbosacral spine. Reexamination of formalin-fixed, paraffin-embedded material from the patient's tumor using genomic DNA methylation profiling resulted in a diagnostic change from grade III anaplastic ependymoma to astroblastoma, MN1-altered. This work describes another confirmed case of astroblastoma, MN1-altered, to the growing body of literature.

Spinal astroblastoma, MN1 altered in 3-year-old child: An uncommon tumor at an unusual site.

Astroblastoma is an uncommon circumscribed glial tumor mostly involving the cerebral hemisphere. The characteristic molecular alteration is meningioma (disrupted in balanced translocation) 1 (MN1) rearrangement. No definite World Health Organization grade has been assigned as both low- and high-grade tumors are known to occur. Tumors in the spine are extremely rare; to date only three cases have been reported in the literature. A vigilant microscopy and ancillary testing aid in diagnosis when the tumors present in unusual locations, as in our case. The prompt differentiation of this tumor from its mimickers is a mandate as modalities of management are different and not clearly established.

Polymorphous low-grade neuroepithelial tumour of young (PLNTY): the new kid on the block.

INTRODUCTION: Polymorphous low grade neuroepithelial tumor of the young (PLNTY) is a newly described epileptogenic tumor first reported by Jason. T. Huse et al. in 2016. Only a very few cases have been reported so far and has been recently incorporated in the World Health Organization (WHO) Central Nervous System Classification of tumours, 5th edition, 2021. Here we report a rare case of PLNTY which closely resembles DNET (Dysembryoplastic neuroepithelial tumor) with plenty of interesting findings which would otherwise go unnoticed resulting in a nonspecific or misclassified diagnosis. CASE REPORT: A 12 year old boy presented to the Neurosurgery OPD with seizures for the past five years and was given multiple antiepileptics for the same. Magnetic resonance imaging (MRI) showed a well-defined lobulated cortical mass with T1 hypo intensity and T2 hyperintensity in the left temporal lobe measuring 2.1 × 2 × 1.3 cm suggesting a DNET. Left temporal craniotomy and excision of the lesion was done. Frozen section showed features of a low grade glial neoplasm. Routine sections demonstrated polymorphous findings including oligodendroglia like features, neuronal nuclear pleomorphism, spindled astroglial elements, perivascular rosettes, calcification, and vascular mineralization. By immunohistochemistry (IHC), the tumor cells were diffusely positive for GFAP and CD34.Ki67 labelling index was low. A final diagnosis of PLNTY was made based on the above findings. The child has been epilepsy free since the past one-month post-surgery and is on follow up. DISCUSSION/CONCLUSION: PLNTY is a newly discovered distinct pediatric low grade glial neoplasm which was earlier grouped into nonspecific forms of DNET. It is characterized morphologically and molecularly by the presence of oligodendroglial component, CD34 expression, BRAFV600E mutation and alterations in the MAP kinase pathway. They are known to behave in a low-grade fashion amenable to control by excision with occasional cases of recurrence reported. It is important to recognize and report similar tumors to determine the long-term risk of recurrence and create a more complete understanding on their radiology and molecular genetics.

Systematic review and cumulative analysis of clinical properties of BRAF V600E mutations in PLNTY histological samples.

PURPOSE: Polymorphous low-grade neuroepithelial tumors of the young (PLNTY) represent a rare pediatric-type tumor that most commonly presents as medically refractory epilepsy. PLNTY has only recently been recognized as a distinct clinical entity, having been first described in 2016 and added to the World Health Organization classification of CNS tumors in 2021. Molecular studies have determined that PLNTY is uniformly driven by aberrant MAPK pathway activation, with most tumors carrying either a BRAF V600E mutation or activating FGFR2 or FGFR3 fusion protein. Although it is known that these driver mutations are mutually exclusive, little is known about differences in clinical presentation or treatment outcomes between PLNTY cases driven by these distinct mutations. METHODS: We performed a systematic review and cumulative analysis of PLNTY cases to assess whether or not PLNTY tumors carrying the BRAF V600E mutation exhibit different clinical behaviors. By searching the literature for all cases of PLNTY wherein BRAF V600E status was characterized, we compiled a dataset of 62 unique patient instances. Using a logistic regression-based approach, we assessed a primary outcome of what factors of a clinical presentation were associated with BRAF V600E mutations and a secondary outcome of what factors predicted total seizure freedom post-surgical resection. RESULTS: PLNTY cases carrying BRAF V600E mutations in the literature were strongly positively associated with adult patients (p = 0.0055, OR = 6.556; 95% Conf. Int. = 1.737-24.742). BRAF V600E status was also positively associated with tumor involvement of the temporal lobe (p = 0.0046, OR = 11.036; 95% Conf. Int. = 2.100-58.006). Male sex was also positively associated with BRAF V600E status, but the result did not quite achieve statistical significance (p = 0.0731). BRAF V600E status was not found to be associated with post-operative seizure freedom. CONCLUSIONS: These findings indicate that BRAF V600E-positive PLNTY exhibit characteristic clinical presentations but are not necessarily different in treatment responsiveness. Non-BRAF V600E tumors are more commonly associated with young patients.

Bright diffusion sign: A sensitive and specific radiologic biomarker for multinodular and vacuolating neuronal tumor.

BACKGROUND AND PURPOSE: Accurate differentiation between multinodular and vacuolating neuronal tumor (MVNT) and dysembryoplastic neuroepithelial tumor (DNET) is important for treatment decision-making. We aimed to develop an accurate radiologic diagnostic model for differentiating MVNT from DNET using T2WI and diffusion-weighted imaging (DWI). MATERIALS AND METHODS: A total of 56 patients (mean age, 47.48±17.78 years; 31 women) diagnosed with MVNT (n = 37) or DNET (n = 19) who underwent brain MRI, including T2WI and DWI, were included. Two board-certified neuroradiologists performed qualitative (bubble appearance, cortical involvement, bright diffusion sign, and bright apparent diffusion coefficient [ADC] sign) and quantitative (nDWI and nADC) assessments. A diagnostic tree model was developed with significant and reliable imaging findings using an exhaustive chi-squared Automatic Interaction Detector (CHAID) algorithm. RESULTS: In visual assessment, the imaging features that showed high diagnostic accuracy and interobserver reliability were the bright diffusion sign and absence of cortical involvement (bright diffusion sign: accuracy, 94.64 %; sensitivity, 91.89 %; specificity, 100.00 %; interobserver agreement, 1.00; absence of cortical involvement: accuracy, 92.86 %; sensitivity, 89.19 %; specificity, 100.00 %; interobserver agreement, 1.00). In quantitative analysis, nDWI was significantly higher in MVNT than in DENT (1.52 ± 0.34 vs. 0.91 ± 0.27, p < 0.001), but the interobserver agreement was fair (intraclass correlation coefficient = 0.321). The overall diagnostic accuracy of the tree model with visual assessment parameters was 98.21 % (55/56). CONCLUSION: The bright diffusion sign and absence of cortical involvement are accurate and reliable imaging findings for differentiating MVNT from DNET. By using simple, intuitive, and reliable imaging findings, such as the bright diffusion sign, MVNT can be accurately differentiated from DNET.

[Disseminated ependymal dysembryoplastic neuroepithelial tumor: a case report and literature review]. / Disseminirovannaya vnutrizheludochkovaya dizembrioplasticheskaya neiroepitelial'naya opukhol': klinicheskii sluchai i obzor literatury.

Dysembryoplastic neuroepithelial tumor (DNET) is a benign mixed neuronal-glial neoplasm (WHO grade 1). DNET is most often localized in temporal lobes and found in children and young people with epilepsy. There a few cases of DNET in ventricular system with dissemination along the ependyma in the world literature. MATERIAL AND METHODS: We present a rare case of T1- and T2-negative ventricular system tumor. Only FIESTA imaging revealed dissemination with multiple focal lesions of the third ventricle, its bottom and lateral walls, anterior horns of lateral ventricles, cerebellar vermis, cervical and lumbar spinal cord. RESULTS: The patient underwent transcortical endoscopic biopsy of the third ventricle tumor with simultaneous ventriculoperitoneal shunting. DNET was diagnosed, and radiotherapy was subsequently performed. Literature data on this issue were analyzed. CONCLUSION: To date, disseminated forms of DNET are extremely rare. X-ray features and morphological results allow us to establish the correct diagnosis and determine further treatment strategy.

[Supratentorial neuroepithelial tumor with PLAGL1 gene fusion - a new type of morphologically variable pediatric brain neoplasm defined by a distinct DNA methylation class. A case report and literature review]. / Supratentorial'naya neiroepitelial'naya opukhol' so sliyaniem gena PLAGL1 u detei ­ novyi tip opukholi mozga s raznoobraznoi morfologicheskoi kartinoi i otlichitel'nym metilyatsionnym profilem(sluchai iz praktiki i obzor literatury).

BACKGROUND: Methylation analysis has become a powerful diagnostic tool in modern neurooncology. This technique is valuable to diagnose new brain tumor types. OBJECTIVE: To describe the MRI and histological pattern of neuroepithelial tumor with PLAGL1 gene fusion. MATERIAL AND METHODS: We present a 6-year-old patient with small right frontal intraaxial tumor causing drug resistant epilepsy. Despite indolent preoperative clinical course and MRI features suggesting glioneuronal tumor, histological evaluation revealed characteristics of high-grade glioma, ependymoma and neuroblastoma. RESULTS: Methylation analysis of tumor DNA confirmed a new type of a recently discovered neoplasm - neuroepithelial tumor with PLAGL1 fusion (NET PLAGL1). PCR confirmed fusion of PLAGL1 and EWSR1 genes. No seizures were observed throughout the follow-up period. There was no tumor relapse a year after surgery. CONCLUSION: Methylation analysis in neurooncology is essential for unclear tumor morphology or divergence between histological and clinical data. In our case, this technique confirmed benign nature of tumor, and we preferred follow-up without unnecessary adjuvant treatment.

DNA methylation-based classification of glioneuronal tumours synergises with histology and radiology to refine accurate molecular stratification.

AIMS: Glioneuronal tumours (GNTs) are poorly distinguished by their histology and lack robust diagnostic indicators. Previously, we showed that common GNTs comprise two molecularly distinct groups, correlating poorly with histology. To refine diagnosis, we constructed a methylation-based model for GNT classification, subsequently evaluating standards for molecular stratification by methylation, histology and radiology. METHODS: We comprehensively analysed methylation, radiology and histology for 83 GNT samples: a training cohort of 49, previously classified into molecularly defined groups by genomic profiles, plus a validation cohort of 34. We identified histological and radiological correlates to molecular classification and constructed a methylation-based support vector machine (SVM) model for prediction. Subsequently, we contrasted methylation, radiological and histological classifications in validation GNTs. RESULTS: By methylation clustering, all training and 23/34 validation GNTs segregated into two groups, the remaining 11 clustering alongside control cortex. Histological review identified prominent astrocytic/oligodendrocyte-like components, dysplastic neurons and a specific glioneuronal element as discriminators between groups. However, these were present in only a subset of tumours. Radiological review identified location, margin definition, enhancement and T2 FLAIR-rim sign as discriminators. When validation GNTs were classified by SVM, 22/23 classified correctly, comparing favourably against histology and radiology that resolved 17/22 and 15/21, respectively, where data were available for comparison. CONCLUSIONS: Diagnostic criteria inadequately reflect glioneuronal tumour biology, leaving a proportion unresolvable. In the largest cohort of molecularly defined glioneuronal tumours, we develop molecular, histological and radiological approaches for biologically meaningful classification and demonstrate almost all cases are resolvable, emphasising the importance of an integrated diagnostic approach.

Glioneuronal tumor with ATRX alteration, kinase fusion and anaplastic features (GTAKA): a molecularly distinct brain tumor type with recurrent NTRK gene fusions.

Glioneuronal tumors are a heterogenous group of CNS neoplasms that can be challenging to accurately diagnose. Molecular methods are highly useful in classifying these tumors-distinguishing precise classes from their histological mimics and identifying previously unrecognized types of tumors. Using an unsupervised visualization approach of DNA methylation data, we identified a novel group of tumors (n = 20) that formed a cluster separate from all established CNS tumor types. Molecular analyses revealed ATRX alterations (in 16/16 cases by DNA sequencing and/or immunohistochemistry) as well as potentially targetable gene fusions involving receptor tyrosine-kinases (RTK; mostly NTRK1-3) in all of these tumors (16/16; 100%). In addition, copy number profiling showed homozygous deletions of CDKN2A/B in 55% of cases. Histological and immunohistochemical investigations revealed glioneuronal tumors with isomorphic, round and often condensed nuclei, perinuclear clearing, high mitotic activity and microvascular proliferation. Tumors were mainly located supratentorially (84%) and occurred in patients with a median age of 19 years. Survival data were limited (n = 18) but point towards a more aggressive biology as compared to other glioneuronal tumors (median progression-free survival 12.5 months). Given their molecular characteristics in addition to anaplastic features, we suggest the term glioneuronal tumor with ATRX alteration, kinase fusion and anaplastic features (GTAKA) to describe these tumors. In summary, our findings highlight a novel type of glioneuronal tumor driven by different RTK fusions accompanied by recurrent alterations in ATRX and homozygous deletions of CDKN2A/B. Targeted approaches such as NTRK inhibition might represent a therapeutic option for patients suffering from these tumors.

Early ependymal tumor with MN1-BEND2 fusion: a mostly cerebral tumor of female children with a good prognosis that is distinct from classical astroblastoma.

PURPOSE: Review of the clinicopathologic and genetic features of early ependymal tumor with MN1-BEND2 fusion (EET MN1-BEND2), classical astroblastomas, and recently described related pediatric CNS tumors. I also briefly review general mechanisms of gene expression silencing by DNA methylation and chromatin remodeling, and genomic DNA methylation profiling as a powerful new tool for CNS tumor classification. METHODS: Literature review and illustration of tumor histopathologic features and prenatal gene expression timelines. RESULTS: Astroblastoma, originally descried by Bailey and Cushing in 1926, has been an enigmatic tumor. Whether they are of ependymal or astrocytic derivation was argued for decades. Recent genetic evidence supports existence of both ependymal and astrocytic astroblastoma-like tumors. Studies have shown that tumors exhibiting astroblastoma-like histology can be classified into discrete entities based on their genomic DNA methylation profiles, gene expression, and in some cases, the presence of unique gene fusions. One such tumor, EET MN1-BEND2 occurs mostly in female children, and has an overall very good prognosis with surgical management. It contains a gene fusion comprised of portions of the MN1 gene at chromosomal location 22q12.1 and the BEND2 gene at Xp22.13. Other emerging pediatric CNS tumor entities demonstrating ependymal or astroblastoma-like histological features also harbor gene fusions involving chromosome X, 11q22 and 22q12 breakpoint regions. CONCLUSIONS: Genomic DNA profiling has facilitated discovery of several new CNS tumor entities, however, traditional methods, such as immunohistochemistry, DNA or RNA sequencing, and cytogenetic studies, including fluorescence in situ hybridization, remain necessary for their accurate biological classification and diagnosis.

Anatomical phenotyping and staging of brain tumours.

Unlike other tumours, the anatomical extent of brain tumours is not objectified and quantified through staging. Staging systems are based on understanding the anatomical sequence of tumour progression and its relationship to histopathological dedifferentiation and survival. The aim of this study was to describe the spatiotemporal phenotype of the most frequent brain tumour entities, to assess the association of anatomical tumour features with survival probability and to develop a staging system for WHO grade 2 and 3 gliomas and glioblastoma. Anatomical phenotyping was performed on a consecutive cohort of 1000 patients with first diagnosis of a primary or secondary brain tumour. Tumour probability in different topographic, phylogenetic and ontogenetic parcellation units was assessed on preoperative MRI through normalization of the relative tumour prevalence to the relative volume of the respective structure. We analysed the spatiotemporal tumour dynamics by cross-referencing preoperative against preceding and subsequent MRIs of the respective patient. The association between anatomical phenotype and outcome defined prognostically critical anatomical tumour features at diagnosis. Based on a hypothesized sequence of anatomical tumour progression, we developed a three-level staging system for WHO grade 2 and 3 gliomas and glioblastoma. This staging system was validated internally in the original cohort and externally in an independent cohort of 300 consecutive patients. While primary CNS lymphoma showed highest probability along white matter tracts, metastases enriched along terminal arterial flow areas. Neuroepithelial tumours mapped along all sectors of the ventriculocortical axis, while adjacent units were spared, consistent with a transpallial behaviour within phylo-ontogenetic radial units. Their topographic pattern correlated with morphogenetic processes of convergence and divergence of radial units during phylo- and ontogenesis. While a ventriculofugal growth dominated in neuroepithelial tumours, a gradual deviation from this neuroepithelial spatiotemporal behaviour was found with progressive histopathological dedifferentiation. The proposed three-level staging system for WHO grade 2 and 3 gliomas and glioblastoma correlated with the degree of histological dedifferentiation and proved accurate in terms of survival upon both internal and external validation. In conclusion, this study identified specific spatiotemporal phenotypes in brain tumours through topographic probability and growth pattern assessment. The association of anatomical tumour features with survival defined critical steps in the anatomical sequence of neuroepithelial tumour progression, based on which a staging system for WHO grade 2 and 3 gliomas and glioblastoma was developed and validated.

Recurrent high-grade astroblastoma with MN1-BEND2 fusion in spinal cord and literature review.

Astroblastoma is an uncommon tumor of the central nervous system. It is variable in morphology, but the astroblastic pseudorosettes and vascular hyalinization are the most important features. Most astroblastomas occur in the cerebral hemisphere. We report a recurrent high-grade astroblastoma with MN1-BEND2 fusion in the spinal cord. Two lesions were found in the T5-7 level and T12-L1 level, and they were well defined in images. Rhabdoid and signet-ring-like cells were observed. It may be classified as a high-grade tumor due to cellularity, high mitotic count, and pleomorphism. The tumor cells were diffusely positive for GFAP, Olig-2, and S-100 protein. We found the MN1 arrangement and the loss of chromosome 1p by FISH, and further validated the BEN domain containing 2 genes (BEND2), which is the fusion partner of meningioma 1 gene (MN1), by next-generation sequencing (NGS) and Sanger sequencing. The MN1 mutation is crucial in the diagnosis and prognosis of rare astroblastoma. The spinal cord astroblastoma may have a high recurrence rate because of the residual lesion at the unique location and higher grade; the connection with the gene mutation is unclear. Regular follow-up is necessary. Further study and more cases are needed to establish evidence for diagnosis, prognosis, and treatment of astroblastoma with molecular characteristics.

Pediatric and elderly polymorphous low-grade neuroepithelial tumor of the young: Typical and unusual case reports and literature review.

Polymorphous low-grade neuroepithelial tumor of the young (PLNTY), one of the pediatric-type diffuse low-grade gliomas, is characterized by a diffuse infiltrating pattern of oligodendroglioma-like tumor cells showing CD34 positivity and harbors mitogen-activated protein kinase (MAPK) alteration, such as vRAF murine sarcoma viral oncogene homolog B1 (BRAF) p.V600E or fibroblast growth factor fusion genetically. It occurs mainly in pediatric and adolescents with seizures due to the dominant location of the temporal lobe. However, there have been a few cases of PLNTY in adult patients, suggesting the wide range of this tumor spectrum. Here, we describe two cases of PLNTY, one in a 14-year-old female and the other in a 66-year-old female. The pediatric tumor showed typical clinical course and histopathology with BRAF p.V600E mutation, whereas the elderly tumor was unusual because of non-epileptic onset clinically and ependymal differentiation histopathologically harboring KIAA1549-BRAF fusion. There might be unusual but possible PLNTY, as in our elderly case. We also compared typical pediatric and unusual elderly tumors by reviewing the literature.