Dysembryoplastic Neuroepithelial Tumor Research Articles

The T2-FLAIR mismatch sign in oncologic neuroradiology: History, current use, emerging data, and future directions.

The T2-Fluid-Attenuated Inversion Recovery (T2-FLAIR) mismatch sign is a radiogenomic marker that is easily discernible on preoperative conventional MR imaging. Application of strict criteria (adult population, cerebral hemisphere location, and classic imaging morphology) permits the noninvasive preoperative diagnosis of isocitrate dehydrogenase (IDH)-mutant 1p/19q-non-codeleted diffuse astrocytoma with near-perfect specificity, albeit with variably low sensitivity. This leads to improved preoperative planning and patient counseling. More recent research has shown that the application of less strict criteria compromises the near-perfect specificity of the sign but remains adequate for ruling out IDH-wildtype (glioblastoma) phenotype, which bears a far grimmer prognosis compared to IDH-mutant diffuse astrocytic disease. In this review, we elaborate on the various definitions of the T2-FLAIR mismatch sign present in the literature, illustrate these with images obtained at a comprehensive cancer center, discuss the potential of the mismatch sign for application to certain pediatric-type brain tumors, namely dysembryoplastic neuroepithelial tumor and diffuse midline glioma, and elaborate upon the clinical, histologic, and molecular associations of the T2-FLAIR mismatch sign as recognized to date. Finally, the sign's correlates in diffusion- and perfusion-weighted imaging are presented, and opportunities to further maximize the diagnostic and prognostic applications of the sign in the context of the 2021 revision of the WHO Classification of Central Nervous System Tumors are discussed.

A Pediatric Case Report: Dysembryoplastic Neuroepithelial Tumor or Ganglioglioma?

Dysembryoplastic Neuroepithelial Tumor (DNET) is a benign glioneuronal neoplasm that most frequently affects children and young adults. It can cause chronic seizures that are medically refractory. This tumor’s cortical architecture and absence of a bulk effect or perilesional edema on radiographs are its defining features. The most typical manifestation of seizures is focal seizures with impaired awareness. Three DNET histologic subtypes have been identified. For either complicated or simple DNET types, histological detection of a distinct, particular glioneuronal component in brain tumor samples from individuals with medically refractory, chronic epilepsy serves as a diagnostic characteristic. We present one case of a child diagnosed with DNETs, who arrived at the hospital following seizures. The clinical, radiographic, histological, immunohistochemical, and molecular genetic characteristics characteristics of all three forms of DNETs as well as the differences between DNETs and gangliogliomas will be the main topics of this review.

An imaging review of the hippocampus and its common pathologies.

The hippocampus is a complex structure located in the mesial temporal lobe that plays a critical role in cognitive and memory-related processes. The hippocampal formation consists of the dentate gyrus, hippocampus proper, and subiculum, and its importance in the neural circuitry makes it a key anatomic structure to evaluate in neuroimaging studies. Advancements in imaging techniques now allow detailed assessment of hippocampus internal architecture and signal features that has improved identification and characterization of hippocampal abnormalities. This review aims to summarize the neuroimaging features of the hippocampus and its common pathologies. It provides an overview of the hippocampal anatomy on magnetic resonance imaging and discusses how various imaging techniques can be used to assess the hippocampus. The review explores neuroimaging findings related to hippocampal variants (incomplete hippocampal inversion, sulcal remnant and choroidal fissure cysts), and pathologies of neoplastic (astrocytoma and glioma, ganglioglioma, dysembryoplastic neuroepithelial tumor, multinodular and vacuolating neuronal tumor, and metastasis), epileptic (mesial temporal sclerosis and focal cortical dysplasia), neurodegenerative (Alzheimer's disease, progressive primary aphasia, and frontotemporal dementia), infectious (Herpes simplex virus and limbic encephalitis), vascular (ischemic stroke, arteriovenous malformation, and cerebral cavernous malformations), and toxic-metabolic (transient global amnesia and opioid-associated amnestic syndrome) etiologies.

RADIOLOGICAL SURVEILLANCE AFTER RESECTION OF LOW GRADE DYSEMBRYOPLASTIC NEUROEPITHELIAL TUMOUR AND GANGLIOGLIOMA: HOW OFTEN AND FOR HOW LONG?

Abstract AIMS Prolonged follow-up with imaging has costs both financial and psychological. We sought to review clinical and radiological follow-up for operated dysembryoplastic neuroepithelial tumour (DNET) and ganglioglioma in our unit. METHOD Retrospective review of patients diagnosed with WHO grade 1 DNET or ganglioglioma identified from our histopathology database over the last 20 years. RESULTS 44 patients were identified (DNET n=23, ganglioglioma n=21). Mean age at first surgery was 27.2 and 22.3 respectively. The median length of follow-up was 3.45 (0.84-13.9) years for DNET, and 5.03 (0.4-12.6) years for ganglioglioma. The majority of the patients had epilepsy (39/44, 88.6%) prior to surgery. Patients with DNET had 0.58 postoperative scans per year, whilst those with ganglioglioma had 1.17 scans per year. 11 (47.8%) DNET and 9 (42.9%) ganglioglioma patients had residual tumour after first surgery. None of the DNET patients had radiological change during follow-up. 9 (43%) patients with ganglioglioma had radiological change noted at least once during follow-up. 3 (13%) patients with DNET and 4 (19%) with ganglioglioma had further surgery for ongoing seizures due to residual tumour, but not for radiological progression. CONCLUSIONS Radiological change following tumour resection did not occur for DNET whereas it was more common for gangliogliomas. A reduction in postoperative imaging in our practice could be considered for operated low grade DNET and ganglioglioma, given that for all patients the indication for reoperation was seizures rather than tumour progression.

OS04.4.A LONG- AND SHORT-TERM SURVIVORS AMONG ADULT PATIENTS WITH DIFFUSE WHO GRADE 2-3 GLIOMA: CLINICAL FEATURES, MOLECULAR RECLASSIFICATION AND DNA METHYLATION PATTERNS

Abstract BACKGROUND Diffuse gliomas show considerable heterogeneity in terms of survival. The WHO classifications of 2016 and 2021 improved prognostic stratification due to the definition of biologically and clinically homogeneous tumor entities. However, further prognostic models considering clinical and molecular factors are needed to balance survival benefit with adverse treatment-related long-term effects in therapeutic decisions. MATERIALS AND METHODS Patients with diffuse gliomas of WHO grades 2 and 3 diagnosed in 2000 - 2019 have been included. Long term survivors (LTS) were defined as patients with an overall survival (OS) of >10 years after radiological diagnosis, whereas short-term survivors (STS) had an OS of <1 year. Histological diagnosis was performed by a board-certified neuropathologist. DNA methylation analysis of formalin-fixed, paraffin-embedded tumor tissue was conducted using the Illumina EPIC 850k platform. The Heidelberg Methylation Classifier was applied to obtain methylation-based diagnoses. RESULTS Of 697 patients with WHO grade 2 and 3 glioma, 182 (26.1%) were LTS, and 42 (6.0%) were STS. LTS were younger than STS (median age: 36 vs. 59.5; p<0.001) and had a higher Karnofsky Performance Score at diagnosis (median: 90% vs. 80%; p<0.001). LTS more frequently presented with epileptic seizures (p<0.001), while more STS had motoric (p<0.001), sensory (p=0.021), and visual deficits (p=0.027) as well as aphasia (p<0.001) and behavioral changes (p=0.009). Histological diagnoses (including pre-2016) showed astrocytic histology in 117 (70.9% LTS, 29.1% STS), oligodendroglial in 61 (93.4% LTS, 6.6% STS), oligo-astroglial in 43 (97.7% LTS, 2.3% STS) and not otherwise specified in 3 (all STS; p<0.001). Molecular reclassification of pre-2016 diagnoses (n = 143) yielded divergent entities in 46 (32.2%) cases. Overall, integrated molecular diagnoses included astrocytoma (isocitrate dehydrogenase [IDH]-mutant] in 65 patients (95.4% LTS and 4.6% STS), oligodendroglioma (IDH-mutant, 1p/19q-codeleted) in 64 patients (98.4% LTS and 1.6% STS), IDH-wildtype gliomas in 24 patients (100% STS), anaplastic pilocytic astrocytoma in 2 STS, diffuse midline glioma (H3K27-altered) in 1 STS, and dysembryoplastic neuroepithelial tumor in 1 LTS, while not otherwise specified diagnoses were found in 4 patients (75% LTS, 25% STS; p<0.001). Unsupervised clustering based on DNA methylation profiling revealed two major clusters consisting of IDH-wildtype STS (cluster A) and IDH-mutant patients (cluster B; 94.6% LTS, 5.4% STS). In cluster B, one subcluster (n = 8) contained 3/4 IDH-mt STS. Further analyses of these cases including validation with publicly available DNA methylation data are ongoing. CONCLUSION LTS and STS show distinct clinical and molecular features. Further profiling of cases with divergent survival could provide more refined prognostic stratification.

Epileptic versus neuro-oncological focus of management in pediatric patients with concurrent primary brain lesion and seizures: a systematic review.

Seizures can be a debilitating manifestation of underlying neoplastic intracranial pathology. Existing literature offers a paucity of scientific consensus regarding risk factors, seizure semiology, operative techniques, and tumor characteristics in pediatric patients with a concurrent diagnosis of primary intracranial neoplasm and seizures. To address the limited evidence in current literature, the authors systematically reviewed published literature on current clinical characteristics and management strategies for patients presenting concurrently with seizures and a newly diagnosed brain lesion, while aiming to synthesize a potential management protocol or set of recommendations for these patients. An initial search revealed 792 papers, of which 196 studies were excluded, leaving 596 studies available for abstract review. After further stratification, 546 studies were eliminated, leaving 50 studies for eligibility assessment. Of the 50 studies, 12 met the criteria for outcome extraction. The results indicate that patients with a mean age of 9 years with a newly diagnosed brain tumor and presenting symptoms of seizure are likely to present with daily seizures of the complex partial subtype, with the most likely primary epileptogenic and neoplastic foci occurring in the temporal lobe. The most common tumor subtypes were low-grade gliomas, ganglioglioma, dysembryoplastic neuroepithelial tumor, or astrocytoma. With the aim of gross-total resection, 77.54% of patients are likely to achieve seizure freedom. This study highlights the demographic, clinical, seizure, tumor, and postoperative outcomes for pediatric patients presenting with a primary brain tumor and concurrent seizures. Further prospective multicenter studies are necessary to understand and compare varying treatment approaches and to develop standardized guidelines for these patients, with the goal of optimizing neuro-oncological and seizure-related outcomes.

Clinicopathological features of dysembryoplastic neuroepithelial tumor: a case series

BackgroundDysembryoplastic neuroepithelial tumors are rare benign supratentotrial epilepsy-associated glioneuronal tumors of children and young adults. Patients have a long history of seizures. Proper surgical resection achieves long term seizure control. We describe the clinicopathological features of dysembryoplastic neuroepithelial tumor cases reported in our practice and review the published literature.MethodsAll cases of Pakistani ethnicity were diagnosed between 2015 and 2021 were included. Slides were reviewed and clinicopathological features were recorded. Follow-up was obtained. Extensive literature review was conducted.ResultsFourteen cases were reported. There were 12 males and 2 females. Age range was 9–45 years (mean 19 years). Majority were located in the temporal and frontal lobes. Duration of seizures prior to resection ranged from 2 months to 9 years with mean and median duration of 3.2 and 3 years, respectively. Histologically, all cases demonstrated a multinodular pattern, specific glioneuronal component, and floating neurons. Simple and complex forms comprised seven cases each. No significant nuclear atypia, mitotic activity, or necrosis was seen. Ki-67 proliferative index was very low. Cortical dysplasia was noted in adjacent glial tissue in four cases. Follow-up ranged from 20 to 94 months. Seizures continued following resection in all but one case but were reduced in frequency and intensity. In one case, seizures stopped completely following surgery.ConclusionClinicopathological features were similar to those in published literature. However, a marked male predominance was noted in our series. Seizures continued following resection in all but one case but were reduced in frequency and intensity. This series will help raise awareness among clinicians and pathologists in our part of the world about this seizure-associated tumor of children and young adults.

T2-FLAIR Mismatch Sign in Pediatric Low-Grade Glioma.

No qualitative imaging feature currently predicts molecular alterations of pediatric low-grade gliomas with high sensitivity or specificity. The T2-FLAIR mismatch sign predicts IDH-mutated 1p19q noncodeleted adult gliomas with high specificity. We aimed to assess the significance of the T2-FLAIR mismatch sign in pediatric low-grade gliomas. Pretreatment MR images acquired between January 2001 and August 2018 in pediatric patients with pediatric low-grade gliomas were retrospectively identified. Inclusion criteria were the following: 1) 0-18 years of age, 2) availability of molecular information in histopathologically confirmed cases, and 3) availability of preoperative brain MR imaging with non-motion-degraded T2-weighted and FLAIR sequences. Spinal cord tumors were excluded. Three hundred forty-nine patients were included (187 boys; mean age, 8.7 [SD, 4.8] years; range, 0.5-17.7 years). KIAA1549-B-Raf proto-oncogene (BRAF) fusion and BRAF p.V600E mutation were the most common molecular markers (n = 148, 42%, and n = 73, 20.7%, respectively). The T2-FLAIR mismatch sign was present in 25 patients (7.2%). Of these, 9 were dysembryoplastic neuroepithelial tumors; 8, low-grade astrocytomas; 5, diffuse astrocytomas; 1, a pilocytic astrocytoma; 1, a glioneuronal tumor; and 1, an angiocentric glioma. None of the 25 T2-FLAIR mismatch pediatric low-grade gliomas were BRAF p.V600E-mutated. Fourteen of 25 pediatric low-grade gliomas with the T2-FLAIR mismatch sign had rare molecular alterations, while the molecular subtype was unknown for 11 tumors. The T2-FLAIR mismatch sign was not observed in the common molecular alterations, BRAF p.V600E-mutated and KIAA1549-BRAF fused pediatric low-grade gliomas, while it was encountered in pediatric low-grade gliomas with rare pediatric molecular alterations.

Surgical treatment of epilepsy - Initial experience from a comprehensive epilepsy program in coastal South India.

The objectives of this study were to share our initial experience with epilepsy surgery and provide an overview on the surgical treatments of epilepsies. This was a retrospective analysis of the demographics and clinical and investigative features of patients who underwent epilepsy surgery between January 2016 and August 2021. Postoperative seizure outcome was categorized according to modified Engel's classification, and the minimum period of follow-up was 1 year. The study group included 30 patients with an age ranging from 6 years to 45 years (mean: 22.28 years, median: 20 years) and a male: female ratio of 20:10. The epilepsy duration before surgery ranged from 3 years to 32 years (median: 7 years). Majority of our patients underwent resective surgeries (28/30 = 93.3%), and disconnection procedures were done in two patients. This included one functional hemispherotomy and one posterior quadrantic disconnection. Temporal lobe resective surgery was the most common procedure (16/30 = 53.3%), followed by eight frontal lobe and two parietal lobe surgeries. Among resective surgeries, majority were lesional surgeries and the pathologies included mesial temporal sclerosis (4), dysembryoplastic neuroepithelial tumor (8), ganglioglioma (6), cavernoma (4), focal cortical dysplasia (2), gliosis (1), and one case of hypothalamic hamartoma. Intraoperative electrocorticography was used in all cases for optimizing surgical resection/disconnection. Nearly two-thirds of our patients (66.6%) had an Engel's Class I outcome, five patients had Engel's Class II outcome, three patients had Class III outcome, and one patient did not have any worthwhile improvement. Temporal lobe surgery patients had a better seizure outcome compared to extratemporal surgeries (84% vs. 74%). Overall, complications were minimal and short lasting, and comprised meningitis in three patients (5.6%) and transient worsening of hemiparesis following hemispherotomy in two patients. There was no mortality or long-lasting major morbidity in our patients. In carefully selected patients with drug-resistant epilepsy, surgery offers an excellent chance of becoming seizure-free with significant improvement in overall quality of life. Majority of the common epilepsy surgery procedures can be performed through a multidisciplinary approach even in centers with limited resources.

Dysembryoplastic Neuroepithelial Tumor (Dnet) in a Young Female: A Rare Case Presentation

Dysembryoplastic neuroepithelial tumor (DNET) is a recently described, morphologically unique, and surgically curable low grade brain tumor which is included in the WHO CNS classification as neuronal and mixed neuronal glial tumor. It is usually seen in children and young adults. This entity first described by Damas-Duport in 1998 is usually non-recurring with an excellent prognosis. We present a case of 30 year old female experiencing seizures with well defined space occupying lesion in the frontal region of brain. Contrast enhanced Magnetic Resonance Imaging was done which revealed well defined multilobulated solid cystic mass lesion in cortical/ subcortical region of left frontal lobe. Histological features suggested dysembryoplastic neuroepithelial tumor which was subsequently confirmed on immunohistochemistry by GFAP and S-100 positivity. The principal differential diagnosis is oligodendrogliomas and gangliogliomas. Patient did not receive any adjuvant therapy post operatively and showed no signs of residual disease or recurrence on magnetic resonance imaging during follow up. Patient is on phenytoin for prophylaxis of seizures.

LGG-14. TREATMENT OF TWO PEDIATRIC FGFR-ALTERED LOW-GRADE GLIONEURONAL TUMORS WITH MEK INHIBITION

Abstract Somatic alterations in the fibroblast growth factor receptor (FGFR) gene family (FGFR1/2/3) have been implicated in tumorigenesis across pediatric low-grade glioneuronal neoplasms and represent a potential therapeutic target. FGFR rearrangements and internal tandem duplication (ITD) cause constitutive receptor tyrosine kinase activation, thereby promoting tumor cell growth, differentiation, and survival through complex downstream signaling, including via the mitogen activated protein kinase (MAPK) pathway. With increasing safety and efficacy data in pediatric neuro-oncology, MEK inhibitors may be considered to target MAPK pathway activation in FGFR-altered low-grade glioneuronal tumors, although clinical evidence within this specific molecular subgroup is lacking. Herein, we describe two cases of pediatric low-grade glioneuronal tumors harboring FGFR aberrations with encouraging clinical and radiographic response to MEK inhibition. The first patient has a multiply recurrent left parietal dysembryoplastic neuroepithelial tumor (DNET) with an FGFR1 ITD, diagnosed at eight years of age after presenting with seizures. Despite two surgical resections (with identical pathology), his disease slowly progressed. Oral MEK inhibitor therapy with trametinib was initiated, which he has remained on for the past 9+ months, with stable residual tumor without continued radiographic progression. The second patient was diagnosed at three years of age with focal epilepsy, prompting imaging demonstrating an infiltrative T2/FLAIR-hyperintense right temporal mass. Subtotal resection was performed, with pathology consistent with pediatric-type diffuse low-grade glioma. Molecular profiling identified an FGFR3-TACC3 fusion, with suspected enrichment for MAPK-pathway activation by preliminary RNA-sequencing analyses. Adjuvant therapy with trametinib was started, with small reduction in residual disease burden observed radiographically three months into treatment. Both patients continue on MEK inhibitor therapy with minimal toxicity and adequate control of underlying seizures. Though further research in larger, prospective cohorts with comprehensive biology data is necessary, oral MEK inhibitors represent a feasible and rational treatment consideration for pediatric FGFR-altered low-grade glioneuronal tumors.

Abstract 2730: Antisense-oligonucleotide therapy targeting BRAF alleviates pediatric brain tumors with intractable epilepsy

Abstract Rationale: BRAF mutations leading to aberrant MAPK/ERK signaling are one of the major driver mutations in low-grade pediatric brain tumors (e.g., pilocytic astrocytoma, ganglioglioma, dysembryoplastic neuroepithelial tumor, and diffuse astrocytoma). These variants are highly associated with poor prognosis and intractable epilepsy. We previously identified that BRAF mutations originate from neural stem cells during embryonic brain development and lead to epilepsy-associated pediatric brain tumors (Koh et al, Nat Med 2018). Existing BRAF inhibitors such as Vemurafenib and Dabrafenib are specific to BRAF V600E protein and have limited penetrance into the blood-brain barrier (BBB). Antisense oligonucleotide (ASO) therapy via intrathecal injection bypasses BBB and degrades the transcript of the target gene in the brain. Thus, it is a promising and effective therapeutic tool in neurological disorders with genetically and molecularly identified targets. Methods: We developed the genetically engineered mouse model of Braf-derived pediatric brain tumors with intractable epilepsy by introducing Braf p.V600E mutation into neural stem cells during embryonic brain development. These mice show a gradual increase in tumor size and epileptic seizures and a decrease in survival rate over time, thereby recapitulating BRAF-derived pediatric brain tumors with intractable epilepsy. We administrated the most effective ASO inhibiting mouse Braf RNA selected by in silico and in vitro screening. ASO was delivered by single bolus intracerebroventricular (i.c.v.) injection at 10 weeks after pre-monitoring of behavior seizure and tumor size. Results: Oral administration of existing BRAF inhibitors could not significantly reduce seizures and tumor size in BRAF pediatric tumor models. Single ICV injection of Braf ASO successfully reduced the transcript and encoded protein in a dose-dependent manner and its knock-down effect lasted at least 3 months. Injected ASOs are well distributed to CD34-positive regions and tumor cells in Braf-derived neuro-glial tumors. The behavioral and electrographic seizure frequency is remarkably reduced after treatment of the ASO. The size of tumors and enlarged dysmorphic neurons are significantly reduced. The survival rate was significantly increased. Also, the bodyweight is rescued in Braf ASO treated group, compared to the vehicle-treated control group. No behavioral and molecular toxicity was found at two months after i.c.v. administration of ASO. Conclusions: In our study, ASO therapy targeting BRAF shows strong therapeutic effects on various aspects of BRAF-derived pediatric brain tumors, including the epileptic seizures, tumor size, survival rate as well as dysmorphic neurons. Therefore, ASO therapy targeting BRAF will be a promising and effect therapy in BRAF-derived pediatric brain tumors with intractable epilepsy. Citation Format: Jeong Ho Lee, Seyeon Kim. Antisense-oligonucleotide therapy targeting BRAF alleviates pediatric brain tumors with intractable epilepsy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2730.

Surgical Pathological Features of Epileptogenic Brain Lesions: Cortical Dysplasia and Tumors

Cortical dysplasia and tumors are representative brain lesions associated with intractable epilepsy. Focal cortical dysplasia type II is characterized by cortical cytoarchitectural abnormalities, dysmorphic neurons, and balloon cells, and is associated with somatic mutations of mTOR pathway molecules. Glioneuronal and neuronal tumors, including dysembryoplastic neuroepithelial tumor and ganglioglioma, are the major tumor types for the clinical phenotype. Recently, various subtypes and characterizing molecular profiles have been recognized.

Stereo-electroencephalography (SEEG)-Guided Surgery in Epilepsy With Cingulate Gyrus Involvement: Electrode Implantation Strategies and Postoperative Seizure Outcome.

Surgical treatment of cingulate gyrus epilepsy is associated with good results on seizures despite its rarity and challenging aspects. Invasive EEG monitoring is often mandatory to assess the epileptogenic zone in these patients. To date, only small surgical series have been published, and a consensus about management of these complex cases did not emerge. The authors retrospectively analyzed a large surgical series of patients in whom at least part of the cingulate gyrus was confirmed as included in the epileptogenic zone by means of stereo-electroencephalography and was thus resected. One hundred twenty-seven patients were selected. Stereo-electroencephalography-guided implantation of intracerebral electrodes was performed in the right hemisphere in 62 patients (48.8%) and in the left hemisphere in 44 patients (34.7%), whereas 21 patients (16.5%) underwent bilateral implantations. The median number of implanted electrodes per patient was 13 (interquartile range 12-15). The median number of electrodes targeting the cingulate gyrus was 4 (interquartile range 3-5). The cingulate gyrus was explored bilaterally in 19 patients (15%). Complication rate was 0.8%. A favorable outcome (Engel class I) was obtained in 54.3% of patients, with a median follow-up of 60 months. The chance to obtain seizure freedom increased in cases in whom histologic diagnosis was type-IIb focal cortical dysplasia or tumor (mostly ganglioglioma or dysembryoplastic neuroepithelial tumor) and with male gender. Higher seizure frequency predicted better outcome with a trend toward significance. Our findings suggest that stereo-electroencephalography is a safe and effective methodology in achieving seizure freedom in complex cases of epilepsy with cingulate gyrus involvement.

Enhancing the Reliability of Intraoperative Ultrasound in Pediatric Space-Occupying Brain Lesions

Intraoperative ultrasound (IOUS) may aid the resection of space-occupying brain lesions, though technical limits may hinder its reliability. IOUS (MyLabTwice®, Esaote, Italy) with a microconvex probe was utilized in 45 consecutive cases of children with supratentorial space-occupying lesions aiming to localize the lesion (pre-IOUS) and evaluate the extent of resection (EOR, post-IOUS). Technical limits were carefully assessed, and strategies to enhance the reliability of real-time imaging were accordingly proposed. Pre-IOUS allowed us to localize the lesion accurately in all of the cases (16 low-grade gliomas, 12 high-grade gliomas, eight gangliogliomas, seven dysembryoplastic neuroepithelial tumors, five cavernomas, and five other lesions, namely two focal cortical dysplasias, one meningioma, one subependymal giant cell astrocytoma, and one histiocytosis). In 10 deeply located lesions, IOUS with hyperechoic marker, eventually coupled with neuronavigation, was useful to plan the surgical route. In seven cases, the administration of contrast ensured a better definition of the vascular pattern of the tumor. Post-IOUS allowed the evaluation of EOR reliably in small lesions (<2 cm). In large lesions (>2 cm) assessing EOR is hindered by the collapsed surgical cavity, especially when the ventricular system is opened, and by artifacts that may simulate or hide residual tumors. The main strategies to overcome the former limit are inflation of the surgical cavity through pressure irrigation while insonating, and closure of the ventricular opening with Gelfoam before insonating. The strategies to overcome the latter are avoiding the use of hemostatic agents before IOUS and insonating through normal adjacent brain instead of corticotomy. These technical nuances enhanced the reliability of post-IOUS, with a total concordance to postoperative MRI. Indeed, the surgical plan was changed in about 30% of cases, as IOUS showed a residual tumor that was left behind. IOUS ensures reliable real-time imaging in the surgery of space-occupying brain lesions. Limits may be overcome with technical nuances and proper training.

Myxoid glioneuronal tumor: Histopathologic, neuroradiologic, and molecular features in a single center series

BackgroundMyxoid glioneuronal tumor (MGT) is a benign glioneuronal neoplasm recently introduced in the World Health Organization (WHO) classification of the central nervous system (CNS) tumors. MGTs are typically located in the septum pellucidum, foramen of Monro or periventricular white matter of the lateral ventricle. They were previously diagnosed as dysembryoplastic neuroepithelial tumors (DNT), showing histological features almost indistinguishable from classical cortical DNT. Despite that, MGTs have been associated with a specific dinucleotide substitution at codon 385 in the platelet-derived growth factor receptor alpha (PDGFRA) gene, replacing a lysine residue with either leucine or isoleucine (p. LysK385Leu/Iso). This genetic variation has never been described in any other CNS tumor. Materials and methodsThirty-one consecutive tumors, previously diagnosed as DNTs at the Meyer Children's Hospital IRCCS between January 2010 and June 2021 were collected for a comprehensive study of their clinical, imaging, pathological features, and molecular profile. ResultsIn six out of the thirty-one tumors we had previously diagnosed as DNTs, we identified the recurrent dinucleotide mutation in the PDGFRA. All six tumors were typically located within the periventricular white matter of the lateral ventricle and in the septum pellucidum. We then renamed these lesions as MGT, according to the latest WHO CNS classification. In all patients we observed an indolent clinical course, without recurrence. ConclusionMGT represent a rare but distinct group of neoplasm with a typical molecular profiling, a characteristic localization, and a relative indolent clinical course.

Association between features of intraoperative ultrasound and magnetic resonance imaging in the diagnosis of dysembryoplastic neuroepithelial tumor.

To analyze the characteristics of images from intraoperative ultrasound (IoUS) and preoperative magnetic resonance imaging (MRI) and their relationship with pathological components of dysembryoplastic neuroepithelial tumor (DNT) and to discuss the role of IoUS in detecting tumor residues. The clinical and image data of 24 patients with postoperative pathology-confirmed DNT were analyzed retrospectively. Baseline characteristics, imaging features, and intraoperative residues were recorded for further analysis. Cohen's kappa consistency evaluation was performed on the echo and signal characteristics of the lesions. Cohen's kappa coefficient between the echo and signal of the lesion was 0.832. The characteristics of IoUS were gyrus or mass hyperechoic solid nodules located under the cortex, insufficient blood flow signals, and clear boundaries, in addition to mixed cystic and solid echo nodules. The solid part of the lesion consisted of pathologically nodular specific glioneuronal element (SGE) or was combined with glial nodules and focal cortical dysplasia (FCD), which was characterized by a high echo or long T1 long T2 signal and uniform or uneven distribution. The cystic part consisted of a mucinous matrix, showing echoless or long T1 long T2 on fluid attenuated inversion recovery (FLAIR), which was higher than that in cerebrospinal fluid but lower than that in the cerebral cortex. The residual lesion discovered using IoUS was confirmed with postoperative MRI. The IoUS characteristics of DNT are strongly consistent with MRI, and its imaging features are related to pathological components. IoUS can assist the operator to judge the mode and scope of tumor resection, detect residual tumor, and improve the rate of total tumor resection.

Value of quantitative apparent diffusion coefficients in differentiating low-grade gliomas from mixed neuronal-glial tumors

PurposeTo retrospectively assess if diffusion-weighted MR imaging (DWI) and quantitative apparent–diffusion coefficient (ADC) maps could be used to differentiate between low-grade gliomas (LGGs) and mixed neuronal–glial tumors (MNGTs including Dysembryoplastic Neuroepithelial Tumor and Ganglioglioma). Materials and methodsWe retrospectively searched the clinical, pathological, and radiological databases for a span of 9 years and identified 24 patients with biopsy proven LGG. This included WHO (fourth edition) grade I and II tumors including astrocytoma, oligoastrocytoma and oligodendrogliomas. We also identified 22 patients with MNGTs (WHO grade I) including 13 patients with DNET and 9 patients with Ganglioglioma. All patients with pathologically confirmed tumors who had MRI including DWI sequence were included in the study. Regions of interest (ROIs) of 0.1–0.15 cm2 were manually positioned on the ADC maps and multiple values (10−6 mm2/s) were obtained including the ADCmean. Optimal thresholds of ADC values and ADC ratios for distinguishing low-grade gliomas from mixed neuronal–glial tumors were determined by receiver operating characteristic (ROC) curve analysis. ResultsAll the four ADC measurement variables, including the minimum (ADC min), the (ADC max) maximum, the mean of ADC values (ADC mean) and the ADC ratios (ADC mean/ADCnormal) showed significant difference between the MNGTs and LGGs. The most significant difference was seen with the maximum ADC value (ADC max) of the tumor where the values for LGGs were 1317 ± 314 whereas the values for MNGTs were 2134 ± 438. In both subsets of patients with MNGTs (DNET and Ganglioglioma), this difference was statistically significant (P = .015 and P = .0066, respectively). However, there was no significant difference between the ADC values of these subtypes of MNGTs. ConclusionThe ADC values of MNGTs are significantly higher compared to LGGs and can be helpful in radiological demarcation of these two conditions. The high ADC of MNGTs may be attributable to the presence of large extracellular spaces and their cellularity, which is much lower than that of pure glial neoplasms.

Clinico-pathological and epigenetic heterogeneity of diffuse gliomas with FGFR3::TACC3 fusion

BackgroundGliomas with FGFR3::TACC3 fusion mainly occur in adults, display pathological features of glioblastomas (GB) and are usually classified as glioblastoma, IDH-wildtype. However, cases demonstrating pathological features of low-grade glioma (LGG) lead to difficulties in classification and clinical management. We report a series of 8 GB and 14 LGG with FGFR3:TACC3 fusion in order to better characterize them.MethodsCentralized pathological examination, search for TERT promoter mutation and DNA-methylation profiling were performed in all cases. Search for prognostic factors was done by the Kaplan–Meir method.ResultsTERT promoter mutation was recorded in all GB and 6/14 LGG. Among the 7 cases with a methylation score > 0.9 in the classifier (v12.5), 2 were classified as glioblastoma, 4 as ganglioglioma (GG) and 1 as dysembryoplastic neuroepithelial tumor (DNET). t-SNE analysis showed that the 22 cases clustered into three groups: one included 12 cases close to glioblastoma, IDH-wildtype methylation class (MC), 5 cases each clustered with GG or DNET MC but none with PLNTY MC. Unsupervised clustering analysis revealed four groups, two of them being clearly distinct: 5 cases shared age (< 40), pathological features of LGG, lack of TERT promoter mutation, FGFR3(Exon 17)::TACC3(Exon 10) fusion type and LGG MC. In contrast, 4 cases shared age (> 40), pathological features of glioblastoma, and were TERT-mutated. Relevant factors associated with a better prognosis were age < 40 and lack of TERT promoter mutation.ConclusionAmong gliomas with FGFR3::TACC3 fusion, age, TERT promoter mutation, pathological features, DNA-methylation profiling and fusion subtype are of interest to determine patients’ risk.

Genomic analysis as a tool to infer disparate phylogenetic origins of dysembryoplastic neuroepithelial tumors and their satellite lesions

Dysembryoplastic neuroepithelial tumor (DNET) is a low-grade brain tumor commonly associated with drug-resistant epilepsy. About half of DNETs are accompanied by tiny nodular lesions separated from the main mass. The existence of these satellite lesions (SLs) has shown a strong association with tumor recurrence, suggesting that they are true tumors. However, it is not known whether SLs represent multiple foci of progenitor tumor cell extension and migration or a multifocal development of the main DNET. This study was designed to elucidate the histopathology and pathogenesis of SLs in DNETs. Separate biopsies from the main masses and SLs with DNET were analyzed. We performed comparative lesion sequencing and phylogenetic analysis. FGFR1 K656E and K655I mutations or duplication of the tyrosine kinase domain was found in all 3 DNET patients and the main masses and their SLs shared the same FGFR1 alterations. The phylogenic analysis revealed that the SLs developed independently from their main masses. It is possible that the main mass and its SLs were separated at an early stage in oncogenesis with shared FGFR1 alterations, and then they further expanded in different places. SLs of DNET are true tumors sharing pathogenic mutations with the main masses. It is plausible that multifocal tumor development takes place in the dysplastic cortex containing cells with a pathogenic genetic alteration.