MAPK pathway alterations in polymorphous low-grade neuroepithelial tumor of the young: diagnostic considerations.

Polymorphous low-grade neuroepithelial tumor of the young (PLNTY) is a recently recognised tumor type with indolent behaviour with characteristic imaging and histomolecular features. We describe the clinical, imaging, histo-molecular features of 15 cases diagnosed as low-grade glioma suggestive of PLNTY, over a period of 3 years. Immunohistochemistry (IHC) and fluorescence in situ hybridisation were used to assess molecular alterations. The tumors were seen predominantly in children (range 5-65 years). Most of the patients presented with history of seizures. Imaging revealed cortical-subcortical well demarcated solid-cystic tumor with intratumoral calcification. Histopathology revealed a low-grade tumor with oligodendroglia-Iike cells admixed with astrocytic cells immunopositive for CD34. BRAF p.V600E mutations and FGFR2 breakapart were observed in six cases each, while three showed FGFR3 breakapart. FGFR2 breakapart positive PLNTY were seen in children exclusively. The majority of cases were seizure free post-surgery, except two patients who succumbed to the illness. PLNTY, needs to be considered as a prime differential diagnosis in a solid-cystic tumor in a young patient with history of seizures. Characteristic clinical features, radiology, histomorphology with an IHC panel of OLIG2, GFAP and CD34 correlates with one of the MAPK alterations in PLNTY (BRAF p.V600E, FGFR2/3 gene rearrangement). In a resource limited setting, this limited panel may be sufficient for a correlative diagnosis.

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.

Glioneuronal and neuronal tumors: A review with special reference to the new types in the WHO CNS5 classification.

Glioneuronal and neuronal tumors (GNTs) are slow-growing lower-grade neuroepithelial tumors with mature neuronal and, less consistently, glial differentiation. Their identification has relied solely on histological proof of neuronal differentiation, which was considered to represent the well-differentiated nature of GNTs. However, after discovering the genetic alterations in GNTs, particularly those in the MAP-kinase pathway, it became evident that histological diagnoses are not always concurrent with genetic alterations and vice versa. Furthermore, since several inhibitors mediating the MAP-kinase pathway are available, at least for clinical trials, molecular-based classification is now warranted. Thus, the upcoming WHO Classification of Central Nervous System Tumors, 5th edition (WHO5CNS) applied DNA methylation profiling to segregate low-grade neuroepithelial tumors. This review gives an overview of the pathological features of GNTs with particular reference to the newly listed tumor types in WHO5CNS. The knowledge and awareness of each tumor type are essential to make a correct diagnosis and avoid unnecessary radical resection and chemoradiotherapy, as GNTs are relatively indolent and have a prolonged clinical course. In addition, being distinctive in location, age group, and histology, the integration of clinicopathological information will help identify relevant tumor types of GNTs without genetic testing, even in resource-limited settings.

Surgical resection of dysembryoplatic neuroepithelioma tumor associated with epilepsy based on imaging classification.

OBJECTIVE: Dysembryoplastic neuroepithelioma tumors (DNETs) are rare glioneuronal tumors usually present with partial epilepsy. We analyzed the surgical curative effect of DNETs based on imaging classification. METHODS: The clinical, neuroimaging, seizure history, neuropathological data, and other medical records of 21 cases of cerebral hemisphere DNETs were collected and analyzed retrospectively. According to the magnetic resonance imaging (MRI) classification of Chassoux, these cases were divided into 8 cases of type I (thylakoid type), 6 cases of type II (nodular type), and 7 cases of type III (dysplasia). All patients received detailed preoperative evaluation and underwent surgical treatment. We statistically compared the postoperative seizure outcome of different DNET MRI types by Engel classification. RESULTS: All tumors were surgically removed and pathologically diagnosed as DNETs. The follow-up period was 5-68 months Engel class I outcome was achieved in all type I cases, 3 (50%) type II cases, and 3 (42.9%) type III cases. The postoperative seizure outcome of MRI type I was better than that of type II and III. CONCLUSION: Based on the MRI classification of DNET by Chassoux, the postoperative epilepsy control of type I is better than that of type II and type III, which may be related to the residual FCD around the tumor of type II and type III. Thus, the MRI classification of DNET can contribute to the preoperative design of the resection plan. Total resection of type I and extended resection of type II, as well as type III, will help to improve the postoperative seizure-free rate in DNET.

Central nervous system high-grade neuroepithelial tumor with BCOR alteration: a short report

Central nervous system high-grade neuroepithelial tumors with BCOR alteration are rare. Currently, there are only 24 cases reported in the literature. These tumors are characterized by a change involving the BCOR gene and have a poor prognosis. Studies are needed to improve the current therapy and outcomes of these neoplasms. This case report describes the clinical history of a patient with this disease and aims to contribute to the current knowledge about this new entity.

Cerebral astroblastoma with oligodendroglial-like cells: A case report.

RATIONALE: Astroblastoma is a rare tumor of the central nervous system with uncertain biological behavior and origin. Its histopathological features have been well established, while, to our knowledge, astroblastoma with oligodendroglial-like cells have not been reported. PATIENT CONCERNS: A 15-year-old girl presented with nausea, vomiting, headache, and visual disturbance. DIAGNOSIS: Magnetic resonance imaging revealed a large neoplasm in the left temporal. Histologically, the tumor showed solid and pseudopapillary structure. Immunohistochemical staining showed that the tumor cells were positive for glial fibrillary acidic protein and vimentin. The oligodendroglial-like cells were positive for glial fibrillary acidic protein, vimentin, and oligodendrocyte transcription factor 2. The antigen KI67 labeling index was about 4%. Sequencing for isocitrate dehydrogenase (IDH) 1 codon 132 and IDH2 codon 172 gene mutations showed negative results. Furthermore, fluorescent analysis revealed neither 1p nor 19q deletion in the lesion. Based on these findings, the girl was finally diagnosed as astroblastoma. INTERVENTIONS: A craniotomy with total excision of the tumor was performed. OUTCOMES: The follow-up time was 1 year, no evidence of disease recurrence was found in magnetic resonance imaging. LESSONS: Cerebral astroblastoma with oligodendroglial-like cells is a clinically rare tumor of central nervous system. Clear distinction and diagnosis are critical.

A rare case of paediatric astroblastoma with concomitant MN1-GTSE1 and EWSR1-PATZ1 gene fusions altering management.

In a case of astroblastoma, methylation analysis was uninformative, with no clustering with known CNS-HGNET-MN1 cases. Whole genome sequencing however identified a novel MN1-GTSE1 gene fusion (image), confirming the diagnosis of astroblastoma, as well as an EWSR1-PATZ1 gene fusion. Whole genome sequencing, alongside methylation profiling and conventional neuropathology, will continue to lead to improved diagnostics and prognostication for children with brain tumours.

SURGICAL AND SEIZURE TREATMENT OUTCOMES IN ADULT DYSEMBRYOPLASTIC NEUROEPITHELIAL TUMORS: A CASE SERIES.

Dysembryoplastic neuroepithelial tumors (DNETs) are benign neoplasms classified in the category of glioneuronal tumors. The estimated incidence of DNETs is 0.03 per 100,000 person per year with the age peak in a range between 10 and 14 years, and decreasing dramatically with increasing age. They are seldom diagnosed in persons above 20 years of age, being a cause of tumor-related intractable epilepsy that begins in childhood or adolescence. They have been proven to be the second most common type of epileptogenic tumors in pediatric population. These rare tumors cause chronic drug-resistant partial complex seizures with or without secondary generalization. Herein, we provide institutional case series of six adult patients with temporal lobe DNET presenting with complex partial seizures. Lesionectomy was performed with tumor resection in toto in three patients. In another three, partial resection was performed, whereas tumor remnant was left intact to avoid possible basal ganglia damage. All patients were seizure free postoperatively. Lesionectomy alone in temporal lobe epilepsy was associated with less favorable outcome than anterior temporal lobectomy. Total tumor removal is considered a major prognostic factor in most studies.

Canine Gliomatosis Cerebri: Morphologic and Immunohistochemical Characterization Is Supportive of Glial Histogenesis.

Gliomatosis cerebri (GC) is a glioma subtype with diffuse neuroparenchymal infiltration without architectural distortion. GC was first used in human neuropathology and remained controversial until its elimination from the diagnostic lexicon in 2016. GC is currently defined as a diffuse growth pattern of glioma rather than a distinct entity. In this article, we characterize 24 cases of canine GC and classify these neoplasms as diffuse gliomas. Selected cases of canine GC were reviewed and immunolabeled for oligodendrocyte lineage transcription factor 2 (Olig2), glial fibrillary acidic protein (GFAP), and 2',3'-cyclic-nucleotide 3'-phosphodiesterase (CNPase). The mean age of affected dogs was 7 years, and 9 were brachycephalic. Gross lesions (8 cases) consisted mainly of parenchymal swelling. Histologically, of the 24 cases, there was widespread infiltration of neoplastic cells with astrocytic (12 cases), oligodendroglial (8 cases), or mixed morphology (4 cases) in the brain (18 cases), spinal cord (4 cases), or both (2 cases). Secondary structures occurred across different tumor grades and were not restricted to high-grade neoplasms. Astrocytic neoplasms had moderate nuclear immunolabeling for Olig2 and robust cytoplasmic immunolabeling for GFAP. Oligodendroglial neoplasms had robust nuclear immunolabeling for Olig2, moderate or absent cytoplasmic immunolabeling for GFAP, and moderate cytoplasmic immunolabeling for CNPase. Tumors with mixed morphology had robust nuclear immunolabeling for Olig2 and variable cytoplasmic immunolabeling for GFAP and CNPase. Morphologic and immunohistochemical features confirmed a glial histogenesis for all tumors and allowed for their classification as diffuse, low- or high-grade astrocytoma; oligodendroglioma; or undefined glioma. Further research is needed to confirm or refute the hypothesis that canine GC represents an infiltrative growth pattern of canine glioma.

Predictive factors for overall survival in surgical cases of gliomatosis cerebri from the National Cancer Database.

Gliomatosis Cerebri (GC) is a rare, aggressive, diffusely infiltrating cerebral tumor. Prognostic indicators and management strategies are currently poorly characterized. The National Cancer Database was queried for patients with histologically confirmed GC between 2004 and 2016. Demographic, tumor, and treatment characteristics were collected, including the Charlson/Deyo score, a comorbidity index adapted from the Charleston Comorbidity Index. Allowable values for the Charlson/Deyo score are 0 (no recorded comorbidities), 1, 2, and 3+ (most severe). Factors associated with overall survival were identified via bivariate log-rank tests and multivariate stepwise Cox proportional hazards models. The query returned 108 GC patients. The median age was 60.0 years, males were predominantly affected (63%), and most patients were white (86%). While 12% of cases achieved near/gross total resection and 27% of cases achieved partial resection, most surgeries were for biopsy (61%). Treatments included radiation therapy in 64% and chemotherapy in 63% of patients. The median overall survival was 15.1 (95% confidence interval [CI] = 11.1-24.8) months. On bivariate analysis, chemotherapy improved overall survival (p = 0.01) while radiation therapy (p = 0.07) and extent of resection (p = 0.48) did not. On multivariate analysis, older patients (hazard ratio [HR] = 1.07, CI = 1.03-1.11, p < 0.01) and Charlson/Deyo scores of ≥1 versus 0 (HR = 3.47, CI = 1.40-8.60, p < 0.01) had significantly increased mortality risk following surgery. In particular, the Charlson/Deyo score is a novel prognostic factor for GC that may guide clinical and surgical decision-making for this rare, rapidly fatal tumor. Further prospective studies are warranted to clarify the effects of chemotherapy versus radiation as treatment modalities for GC.

ILAE Neuroimaging Task Force highlight: Review MRI scans with semiology in mind.

The ILAE Neuroimaging Task Force aims to publish educational case reports highlighting basic aspects related to neuroimaging in epilepsy consistent with the educational mission of the ILAE. It is important to obtain MRI scans early in the clinical course of epilepsy, using an optimized protocol. Furthermore, it is critical that MRI scans are reviewed by experts who have been provided with all the clinical information and results from other investigations. We report a patient with a 21-year history of drug-resistant seizures who was admitted from another centre for presurgical evaluation. She had four previous MRI scans from this centre which were reported as unremarkable. However, a review of the MRI scan obtained on the day of admission, with the patient's ictal semiology in mind, resulted in identification of an epileptogenic lesion which was later confirmed by video-EEG monitoring and interictal PET. This lesion was present on all previous MRI scans and showed no change. The patient underwent lesionectomy, and histopathology of the resected specimen was consistent with a dysembryoplastic neuroepithelial tumour. The patient remains seizure-free, 2.5 years after surgery. This case highlights the importance of obtaining detailed descriptions of seizure semiology and considering them when reviewing MR images.

Molecular identification of CNS NB-FOXR2, CNS EFT-CIC, CNS HGNET-MN1 and CNS HGNET-BCOR pediatric brain tumors using tumor-specific signature genes.

Four molecular types of rare central nervous system (CNS) tumors have been recently identified by gene methylation profiling: CNS Neuroblastoma with FOXR2 activation (CNS NB-FOXR2), CNS Ewing Sarcoma Family Tumor with CIC alteration (CNS EFT-CIC), CNS high grade neuroepithelial tumor with MN1 alteration (CNS HGNET-MN1) and CNS high grade neuroepithelial tumor with BCOR alteration (CNS HGNET-BCOR). Although they are not represented in 2016 updated WHO classification of CNS tumors, their diagnostic recognition is important because of clinical consequences. We have introduced a diagnostic method based on transcription profiling of tumor specific signature genes from formalin-fixed, paraffin-embedded tumor blocks using NanoString nCounter Technology. Altogether, 14 out of 187 (7.4%) high grade pediatric brain tumors were diagnosed with either of four new CNS categories. Histopathological examination of the tumors confirmed, that they demonstrate a spectrum of morphology mimicking other CNS high grade tumors. However, they also exhibit some suggestive histopathological and immunohistochemical features that allow for a presumptive diagnosis prior to molecular assessment. Clinical characteristics of patients corroborated with the previous findings for CNS EFT-CIC, CNS NB-FOXR2 and CNS HGNET-MN1 patients, with a favorable survival rate for the latter two groups. Among six CNS HGNET-BCOR patients, three patients are long term survivors, suggesting possible heterogeneity within this molecular category of tumors. In summary, we confirmed the effectiveness of NanoString method using a single, multi-gene tumor specific signature and recommend this novel approach for identification of either one of the four newly described CNS tumor entities.

Pediatric low-grade glioma in the era of molecular diagnostics.

Low grade gliomas are the most frequent brain tumors in children and encompass a spectrum of histologic entities which are currently assigned World Health Organisation grades I and II. They differ substantially from their adult counterparts in both their underlying genetic alterations and in the infrequency with which they transform to higher grade tumors. Nonetheless, children with low grade glioma are a therapeutic challenge due to the heterogeneity in their clinical behavior - in particular, those with incomplete surgical resection often suffer repeat progressions with resultant morbidity and, in some cases, mortality. The identification of up-regulation of the RAS-mitogen-activated protein kinase (RAS/MAPK) pathway as a near universal feature of these tumors has led to the development of targeted therapeutics aimed at improving responses while mitigating patient morbidity. Here, we review how molecular information can help to further define the entities which fall under the umbrella of pediatric-type low-grade glioma. In doing so we discuss the specific molecular drivers of pediatric low grade glioma and how to effectively test for them, review the newest therapeutic agents and their utility in treating this disease, and propose a risk-based stratification system that considers both clinical and molecular parameters to aid clinicians in making treatment decisions.

A Cerebellar High-Grade Neuroepithelial Tumour with BCOR Alteration in a five-year-old Child: A case report.

New groups of high-grade neuroepithelial tumours (HGNET) have emerged from the reclassification of central nervous system (CNS) embryonal tumours that have recognised CNS HGNET with BCOR alteration (CNS HGNET-BCOR). We report a two-year, nine-month-old Omani boy who presented to the Royal Hospital, Muscat, Oman, in 2015 with subacute head tilting and neck pain. A well-defined cerebellar lesion was found and he was treated with standard chemoradiotherapy. After a relapse at the age of five years, molecular testing revealed a BCOR alteration. He was treated with further surgery and high-dose chemotherapy; unfortunately, he relapsed and died three years after he was diagnosed.

MN1 rearrangement in astroblastoma: study of eight cases and review of literature.

Astroblastomas are unique tumours with unresolved issues in terms of their origin, molecular biology, clinical behaviour, and response to treatment. To decipher the characteristics of this tumour, we reviewed cases histologically diagnosed as astroblastoma in our institute over the past 8 years, with immunohistochemistry, and performed fluorescence in situ hybridisation (FISH), for the newly emerged MN1 rearrangement which was reported in central nervous system high-grade neuroepithelial tumours. The mean age at diagnosis was 18.6 years with all cases seen in females and with supratentorial localisation. The tumours showed typical circumscription and bubbly appearance on imaging. The cohort included eight cases diagnosed as astroblastoma (two low grades; six anaplastic) based on histology and proliferative index. The tumours displayed characteristic astroblastic pseudorosettes with hyalinised vascular core and variable immunopositivity for glial fibrillary acidic protein, pan cytokeratin, and epithelial membrane antigen. MN1 break-apart by FISH was found in 5/8 of our cases (62.5%), which included 2 low-grade and 3 anaplastic tumours. Tumour recurrence was noted in three cases, with MN1 alteration in two. We account for one of the few series to study the MN1 rearrangement in astroblastoma and conclude that MN1 alteration is seen in a subset of these tumours.

Corticosteroid-induced immunodeficiency in a patient with gliomatosis cerebri: Are corticosteroids indicated in all brain tumors?

An elderly male was admitted to the Department of Neurology for slowly progressive dysarthria and right-sided atactic hemiparesis. Magnetic resonance imaging (MRI) revealed a small contrast-enhanced focus of malignant glioma in the left parietal lobe - with the growth pattern of cerebral gliomatosis - involving the whole left cerebral hemisphere, the corpus callosum, and spreading into the right frontal hemisphere. Diagnostic biopsy was deferred until the exclusion of other possible causes of the brain lesion. A follow-up brain MRI was planned in 6 weeks. In the interim, the patient was treated with dexamethasone, with mild improvement of the neurological symptoms. He was discharged home with a date for a follow-up brain MRI. One week later, the patient was readmitted due to a deterioration of speech and severe respiratory distress. The repeat brain MRI showed regression of contrast enhancement and no progression of the diffuse growth. Laboratory tests demonstrated tracheal candidiasis, invasive aspergillosis, and disseminated strongyloidiasis, including the brain. The patient rapidly deteriorated and died 11 days after the 2nd admission. The autopsy confirmed a small focus of glioblastoma in the left parietal lobe with the diffuse growth pattern of cerebral gliomatosis, laryngeal candidiasis, diffuse alveolar damage, with angioinvasive aspergillosis in the lungs and heart, and disseminated strongyloidiasis.

Dysembryoplastic Neuroepithelial Tumors: What You Need to Know.

OBJECTIVE: An updated and comprehensive review on dysembryoplastic neuroepithelial tumor (DNET) focusing on differential diagnosis, atypical presentation, seizure outcome, and risk of malignant transformation. METHODS: A PubMed/MEDLINE-based literature search has been performed using "dysembryoplastic neuroepithelial tumor" as a keyword. Two treated cases characterized by an atypical presentation have been reviewed. RESULTS: Of 1162 articles, 200 relevant studies have been selected. DNET is a benign mixed neuronal-glial tumor causing drug-resistant epilepsy primarily in children and young adults. The typical radiological pattern is a magnetic resonance imaging (MRI) T1-hypointense, T2-, and fluid-attenuated inversion-recovery hyperintense multicystic lesion involving the cerebral cortex with no edema. Contrast enhancement may be present and a focal cortical dysplasia is commonly associated with it. MRI diffusion, perfusion, and spectroscopy have a paramount role in the differential diagnosis. The "specific glioneuronal elements" are pathognomonic. They are positive for S100 protein, synaptofisin, neuronal nuclei, oligodendrocyte transcription factor, neurite outgrowth inhibitor, and microtubule-associated protein 2, but negative for glial fibrillary acidic protein. As opposed to v-myb avian myeloblastosis viral oncogene homolog, isocitrate dehydrogenase-1/isocitrate dehydrogenase-2 mutation and codeletion 1p-19q, fibroblast growth factor receptor 1 and BRAF V600E mutations are present. The effectiveness of surgery on seizure outcome has been established. Rare malignant transformations have been reported, especially in extra-temporal and complex forms. CONCLUSIONS: Advanced MRI techniques are fundamental in the differential diagnosis for DNET versus other low-grade gliomas. Immuno-phenotype assessment and search for fibroblast growth factor receptor 1 and BRAF V600E mutations limit the risk of misdiagnoses. A gross total tumor removal is generally associated with a seizure-free outcome. Recurrences and malignant transformations may rarely follow, legitimizing MRI surveillance in cases of subtotal tumor resection.