CNS tumors with PLAGL1-fusion: beyond ZFTA and YAP1 in the genetic spectrum of supratentorial ependymomas.

A novel methylation class, "neuroepithelial tumor, with PLAGL1 fusion" (NET-PLAGL1), has recently been described, based on epigenetic features, as a supratentorial pediatric brain tumor with recurrent histopathological features suggesting an ependymal differentiation. Because of the recent identification of this neoplastic entity, few histopathological, radiological and clinical data are available. Herein, we present a detailed series of nine cases of PLAGL1-fused supratentorial tumors, reclassified from a series of supratentorial ependymomas, non-ZFTA/non-YAP1 fusion-positive and subependymomas of the young. This study included extensive clinical, radiological, histopathological, ultrastructural, immunohistochemical, genetic and epigenetic (DNA methylation profiling) data for characterization. An important aim of this work was to evaluate the sensitivity and specificity of a novel fluorescent in situ hybridization (FISH) targeting the PLAGL1 gene. Using histopathology, immunohistochemistry and electron microscopy, we confirmed the ependymal differentiation of this new neoplastic entity. Indeed, the cases histopathologically presented as "mixed subependymomas-ependymomas" with well-circumscribed tumors exhibiting a diffuse immunoreactivity for GFAP, without expression of Olig2 or SOX10. Ultrastructurally, they also harbored features reminiscent of ependymal differentiation, such as cilia. Different gene partners were fused with PLAGL1: FOXO1, EWSR1 and for the first time MAML2. The PLAGL1 FISH presented a 100% sensitivity and specificity according to RNA sequencing and DNA methylation profiling results. This cohort of supratentorial PLAGL1-fused tumors highlights: 1/ the ependymal cell origin of this new neoplastic entity; 2/ benefit of looking for a PLAGL1 fusion in supratentorial cases of non-ZFTA/non-YAP1 ependymomas; and 3/ the usefulness of PLAGL1 FISH.

Pineal anlage tumor: clinical and diagnostic features, and rationales for treatment.

PURPOSE: To provide a treatment-focused review and develop basic treatment guidelines for patients diagnosed with pineal anlage tumor (PAT). METHODS: Prospectively collected data of three patients with pineal anlage tumor from Germany was combined with clinical details and treatment information from 17 published cases. RESULTS: Overall, 20 cases of PAT were identified (3 not previously reported German cases, 17 cases from published reports). Age at diagnosis ranged from 0.3 to 35.0 (median: 3.2 ± 7.8) years. All but three cases were diagnosed before the age of three years. For three cases, metastatic disease at initial staging was described. All patients underwent tumor surgery (gross-total resection: 9, subtotal resection/biopsy: 9, extent of resection unknown: 2). 15/20 patients were alive at last follow-up. Median follow-up for 10/15 surviving patients with available follow-up and treatment data was 2.4 years (0.3-6.5). Relapse was reported for 3 patients within 0.8 years after diagnosis. Five patients died, 3 after relapse and 2 from early postoperative complications. Two-year-progression-free- and -overall survival were 65.2 ± 12.7% and 49.2 ± 18.2%, respectively. All 4 patients who received intensive chemotherapy including high-dose chemotherapy combined with radiotherapy (2 focal, 2 craniospinal [CSI]) had no recurrence. Focal radiotherapy- and CSI-free survival rates in 13 evaluable patients were 46.2% (6/13) and 61.5% (8/13), respectively. CONCLUSION: PAT is an aggressive disease mostly affecting young children. Therefore, adjuvant therapy using intensive chemotherapy and considering radiotherapy appears to comprise an appropriate treatment strategy. Reporting further cases is crucial to evaluate distinct treatment strategies.

Supratentorial extra-ventricular ependymoma as a mass lesion in a child: report and literature review.

Supratentorial extra-ventricular ependymoma (SEE) are extremely rare in pediatric population and have varied presentation based on size, location, epicentre and compression on neurovascular structure. The authors report a 7-year-old girl presenting with seizure, who had a lobar SEE on MRI scan, successfully treated by microsurgical resection and adjuvant therapy.

Paediatric supratentorial tumours do not cause microstructural alterations in contralateral white matter: a preliminary study.

BACKGROUND AND PURPOSE: Intracranial tumours in children can exhibit different characteristics compared to those in adults. Understanding the microstructural changes in the contralateral normal-appearing white matter (NAWM) in children with primary intracranial masses is essential for optimizing treatment strategies. This study aimed to investigate the apparent diffusion coefficient (ADC) changes in contralateral NAWM using fully automated methods and deep learning algorithms. METHODS: We included 22 paediatric patients with primary supratentorial intracranial masses (23% high-grade) in the study. ADC values of the contralateral NAWM in the patient group were compared to those of a control group. Deep learning algorithms were utilized to analyse diffusion changes in NAWM. RESULTS: The mean ADC values of contralateral NAWM in the patient group were 0.80 ± 0.03 × 10-3 mm2/s, while the control group had a mean ADC value of 0.81 ± 0.03 × 10-3 mm2/s. There was no statistically significant difference between the groups (p = 0.39). Our findings indicate that there are no significant diffusion changes in the contralateral white matter of children with supratentorial intracranial masses. CONCLUSION: Primary supratentorial intracranial masses in children do not cause microstructural changes in contralateral normal-appearing white matter. This could be attributed to the less infiltrative nature and different biochemical profile of these tumour groups in the paediatric population. Further studies using advanced imaging techniques could provide additional insights into the distinct characteristics of paediatric intracranial tumours and improve patient management.

[Pediatric supratentorial brain tumors]. / Supratentorielle Hirntumoren im Kindesalter.

BACKGROUND: Pediatric brain tumors differ regarding location and histopathological features compared to those in adults. In children, 30% of pediatric brain tumors are supratentorial lesions. Low-grade astrocytomas, e.g. pilocystic astrocytoma or craniopharyngioma, are the most common tumors. IMAGING MODALITIES: Magnetic resonance imaging (MRI) is the default imaging technique that is used to evaluate the findings. Ultrasound and cranial computed tomography (CCT) accompany the imaging, although CCT is mainly used in emergency situations. TOPICS COVERED: The following article describes the most common pediatric supratentorial brain tumors with reference to imaging criteria as well as changes in the World Health Organization (WHO) classification.

Imaging in a new pediatric brain tumor-a supratentorial neuroepithelial tumor with PLAGL1 fusion.

Molecular diagnostics have dramatically influenced the classification of tumor groups in the 2021 WHO CNS tumor classification. Studies focusing on molecular diagnostics continue to identify new tumors. Soon after the summary of the new classification was published, "Supratentorial Neuroepithelial Tumor with PLAGL1 Fusion" was described as a distinct entity. Although this new entity is defined pathologically, its imaging features are undefined. This case report discusses the imaging findings and possible differential diagnosis of the new tumor.

Activation of Hedgehog signaling by the oncogenic RELA fusion reveals a primary cilia-dependent vulnerability in supratentorial ependymoma.

BACKGROUND: Supratentorial RELA fusion (ST-RELA) ependymomas (EPNs) are resistant tumors without an approved chemotherapeutic treatment. Unfortunately, the molecular mechanisms that lead to chemoresistance traits of ST-RELA remain elusive. The aim of this study was to assess RELA fusion-dependent signaling modules, specifically the role of the Hedgehog (Hh) pathway as a novel targetable vulnerability in ST-RELA. METHODS: Gene expression was analyzed in EPN from patient cohorts, by microarray, RNA-seq, qRT-PCR, and scRNA-seq. Inhibitors against Smoothened (SMO) (Sonidegib) and Aurora kinase A (AURKA) (Alisertib) were evaluated. Protein expression, primary cilia formation, and drug effects were assessed by immunoblot, immunofluorescence, and immunohistochemistry. RESULTS: Hh components were selectively overexpressed in EPNs induced by the RELA fusion. Single-cell analysis showed that the Hh signature was primarily confined to undifferentiated, stem-like cell subpopulations. Sonidegib exhibited potent growth-inhibitory effects on ST-RELA cells, suggesting a key role in active Hh signaling; importantly, the effect of Sonidegib was reversed by primary cilia loss. We, thus, tested the effect of AURKA inhibition by Alisertib, to induce cilia stabilization/reassembly. Strikingly, Alisertib rescued ciliogenesis and synergized with Sonidegib in killing ST-RELA cells. Using a xenograft model, we show that cilia loss is a mechanism for acquiring resistance to the inhibitory effect of Sonidegib. However, Alisertib fails to rescue cilia and highlights the need for other strategies to promote cilia reassembly, for treating ST-RELA tumors. CONCLUSION: Our study reveals a crucial role for the Hh pathway in ST-RELA tumor growth, and suggests that rescue of primary cilia represents a vulnerability of the ST-RELA EPNs.

Neuroendoscopy in the management of pineal region tumours in children.

INTRODUCTION: Pineal region tumours (PRTs) are more common in children and represent a wide variety of lesions. The practise of a radiation test dose is obsolete and a biochemical/histological diagnosis is recommended before further therapy. Many patients present with hydrocephalus. Advances in neuroendoscopic techniques have allowed safe and effective management of this obstructive hydrocephalus with an opportunity to sample cerebrospinal fluid (CSF) and obtain tissue for histopathology. Definitive surgery is required in less than a third. Endoscopic visualisation and assistance is increasingly used for radical resection, where indicated. METHODOLOGY: Our experience of endoscopic surgery for paediatric PRTs from 2002 to 2021 is presented. All patients underwent MRI with contrast. Serum tumour markers were checked. If negative, endoscopic biopsy and endoscopic third ventriculostomy (ETV) were performed; and CSF collected for tumour markers and abnormal cells. For radical surgery, endoscope-assisted microsurgery procedures were performed to minimise retraction, visualise the extent of resection and confirm haemostasis. RESULTS: M:F ratio was 2:1. The median age of presentation was 11 years. Raised ICP (88.88%) was the commonest mode of presentation. Nineteen patients had pineal tumours, one had a suprasellar and pineal tumour, one had disseminated disease, while six had tectal tumours. The ETB diagnosis rate was 95.45%, accuracy rate was 83.3% and ETV success rate was 86.96%. CONCLUSION: Neuroendoscopy has revolutionised the management of paediatric PRTs. It is a safe and effective procedure with good diagnostic yield and allows successful concurrent CSF diversion, thereby avoiding major surgeries and shunt implantation. It is also helpful in radical resection of lesions, where indicated.

Temporal profile of serum melatonin levels in paediatric pineal tumours subjected to surgery: newer insights.

INTRODUCTION: Pineal tumours (PTs) are rare and histologically variable. Serum melatonin is a well-known product of this gland, albeit with uncertain clinical implications vis-à-vis its utility as a potential tumour marker. In particular, the temporal profile of serum melatonin during the disease course remains unclear and infrequently studied. METHODS: Ten children with pineal tumours were prospectively studied over 2 years. Midnight serum melatonin levels were estimated before and after surgery (6-week postoperatively) and at the time of clinical-radiological progression. Different clinical, radiological, histological and treatment variables were correlated with the mean change in the pre- and postoperative serum melatonin levels using statistical methods. RESULTS: Histopathologically, 5 of these cases (50%) were pineal cell tumours, while the rest were tumours of non-pineal cell origin. The mean preoperative serum melatonin level was 94.9 pg/ml (range 20-397 pg/ml), while the mean postoperative level was 69.6 pg/ml (range 45-156 pg/ml; in one case, the levels became non-detectable). Tumour histology (p = 0.04) and gender (p = 0.03) correlated with high preoperative serum levels. While the change in overall mean value did not have any statistical significance (effect size 0.29, p value 0.340), postoperative serum melatonin elevation was significant in tumours of non-pineal cell origin (large effect size 0.93, p value 0.004). CONCLUSION: The serum melatonin may be affected by age, gender and symptom duration. However, the dynamic of serum melatonin in the perioperative period is largely dependent on the cell of origin of the PT.

Pineal anlage tumor: a case report and the literature review.

PURPOSE: Pineal anlage tumor is an extremely rare tumor which was considered as a subtype of pineovlatoma with an overall poor prognosis. This case-based review further summarize the clinical profile. METHODS: A patient with pineal anlage tumor was reported, her clinical data and gene analysis results were recorded. RESULTS: An 8-month-old girl, with an obvious enhancing pineal occupancy and obstructive hydrocephalus. Her histological and immunohistochemical findings contained rhabdomyoblastic, melanin pigment and cartilage island. The wholeexpme sequencing and genome-wide copy number variation sequencing were performed, no mutations associated with pineoblatoma as well as copy number variants were identified. In terms of treatment, our patient underwent subtotal resection without radiotherapy or chemotherapy, and the residual tumor enlarged 4 months after surgery. We have followed her up for 10 months, and the child is still alive. CONCLUSION: Surgery combined radiotherapy and chemotherapy is still the best treatment currently,and genetic testing for patients is necessary.

Preoperative assessment of optic nerve sheath diameter and heart rate variability to predict intraoperative brain condition in patients with supratentorial tumors: a prospective observational study.

Brain relaxation is an important requirement in intracranial neurosurgical procedures and optimal brain relaxation improves the operating conditions. Optic nerve sheath diameter (ONSD) is a non-invasive bedside surrogate marker of intracranial pressure (ICP) status. Elevated ICP is often associated with marked autonomic dysfunction. There is no standard measure to predict intraoperative brain condition non-invasively, considering both anatomical displacement and physiological effects due to raised ICP and brain oedema. This study was aimed to determine the usefulness of heart rate variability (HRV) parameters and ONSD preoperatively in predicting intraoperative brain relaxation in patients with supratentorial tumors undergoing surgery.This prospective observational study was conducted in a tertiary care centre. 58 patients with supratentorial brain tumors undergoing elective surgery were studied. Preoperative clinical presentation, computed tomography (CT) findings, ONSD and HRV parameters were assessed in determining intraoperative brain condition. Intraoperative hemodynamic parameters and brain relaxation score after craniotomy were studied. There was significant difference in CT grade, ONSD and HRV parameters in patients between lax and tight brain. A receiver operating curve was constructed to determine the cut off to predict intraoperative brain bulge. A CT grade more than 2, ONSD of greater than 0.63 cms and ratio of low frequency to high ratio (LF/HF) of more than 1.8 were good predictors of brain bulge. The changes in ONSD and HRV parameters, with the CT findings can be used as surrogate markers of increased ICP to help predict intraoperative brain condition.

Supratentorial meningeal melanocytoma mimicking meningioma: case report and literature review.

Introduction: Primary melanocytic tumors originating from CNS melanocytes are rare, with a low incidence of 0.7 cases per 10 million annually. This study focuses on primary leptomeningeal melanocytomas, emphasizing their epidemiology, clinical characteristics, and diagnostic challenges. Despite their infrequency, these tumors warrant attention due to their unique features and potential for local recurrence. Case Report: A 32-year-old female presented with syncope and seizures, leading to the discovery of two left-sided supratentorial lesions initially misidentified as convexity meningiomas. Detailed imaging suggested meningioma-like features, but intraoperative findings revealed unexpected hyperpigmented lesions. Histopathological examination, supported by immunohistochemistry, confirmed primary leptomeningeal melanocytoma. The surgical approach and subsequent management are discussed. Discussion: The discussion emphasizes challenges in diagnosing primary leptomeningeal melanocytomas. Treatment debates, especially regarding adjuvant radiotherapy, are explored. Recurrence risks stress the importance of vigilant follow-up, advocating for complete surgical resection as the primary approach. The rarity of supratentorial cases adds complexity to diagnosis, necessitating a multidisciplinary approach. Insights from this case contribute to understanding and managing primary leptomeningeal melanocytomas, addressing challenges in differentiation from more common tumors and prompting ongoing research for refined diagnostics and optimized treatments. Conclusion: This study contributes insights into primary leptomeningeal melanocytomas, highlighting their rarity in supratentorial regions. The case underscores the importance of a multidisciplinary approach, incorporating clinical, radiological, and histopathological expertise for accurate diagnosis and tailored management. Ongoing research is crucial to refine treatment strategies, enhance prognostic precision, and improve outcomes for individuals with this uncommon CNS neoplasm.

Supratentorial extra-axial RELA fusion-positive ependymoma misdiagnosed as meningioma by intraoperative histological and cytological examinations: a case report.

BACKGROUND: Dura-attached supratentorial extra-axial ependymoma is a very rare type of tumor, with only nine reported cases. Preoperative diagnosis of dura-attached supratentorial extra-axial ependymoma is difficult and often radiologically misdiagnosed as a meningioma. We report a case of dura-attached supratentorial extra-axial ependymoma that was misdiagnosed using intraoperative histological and cytological examinations. CASE PRESENTATION: A 26-year-old Japanese man with headache and nausea was referred to our medical facility. Magnetic resonance imaging revealed a cystic mass of 70 × 53 × 57 mm in the left temporoparietal lobe. A peritumoral band with hyperintensity on T2-weighted imaging was observed at the periphery of the lesion, suggesting an extra-axial lesion with no apparent connection to the ventricle. A dural tail sign was also noted on the gadolinium-enhanced T1-weighted image. Preoperative clinical diagnosis was meningioma. Proliferated tumor cells in sheets with intermingled branching vessels were observed in the frozen tissue. Perivascular rosettes were inconspicuous, and the tumor cells had rhabdoid cytoplasm. The tumor was intraoperatively diagnosed as a meningioma, suspected to be a rhabdoid meningioma. Perivascular rosettes were evident in the formalin-fixed paraffin-embedded tissues, suggesting ependymoma. The tumor cells had eosinophilic cytoplasm without a rhabdoid appearance. Anaplastic features, such as high tumor cellularity, increased mitotic activity, microvascular proliferation, and necrosis, were observed. Ependymal differentiation was confirmed on the basis of ultrastructural analysis. Molecular analysis detected C11orf95-RELA fusion gene. The final diagnosis was RELA fusion-positive ependymoma, World Health Organization grade III. CONCLUSION: Owing to its unusual location, dura-attached supratentorial extra-axial ependymomas are frequently misdiagnosed as meningiomas. Neuropathologists should take great precaution in intraoperatively diagnosing this rare subtype of ependymoma to avoid misdiagnosis of the lesion as other common dura-attached tumors.

Imaging finding and analysis of brain lymphoma in contrast-enhanced fluid attenuated inversion recovery sequence.

OBJECTIVE: The purpose of this retrospective study was to report and analyze the image findings of contrast-enhanced fluid-attenuated inversion recovery (CE-FLAIR) sequence of lymphoma in the brain. MATERIAL AND METHODS: Thirty-two immunocompetent patients with biopsy-proven diffuse large B-cell type lymphoma in the brain were evaluated with pre-treatment MRI examinations from August 2014 to April 2020. As stereotactic studies on the day of biopsy, FLAIR and T1-weighted axial images were acquired in 2 mm thickness, before and after administrating gadolinium-based contrast agents, with 3.0 Tesla MR machines. Respective subtraction images were also obtained for both CE-FLAIR and contrast-enhanced T1-wieghted image (CE-T1WI) sequences. The imaging findings, especially the enhancement pattern on CE-FLAIR sequence, were analyzed qualitatively and quantitatively, using semi-automatic segmentation. RESULTS: On CE-FLAIR images, brain lymphomas were poorly enhanced, while showing peripheral rim enhancement (54 of 58 lesions, 93.1 %) and central enhancing foci (40 of 58 lesions, 69.0 %). Seventy percent of central enhancing foci were correlated to areas with low signal intensity on CE-T1WI. In quantitative analysis, the mean signal intensity of CE-T1WI subtraction was 490.44 and that of FLAIR subtraction was 206.13. The standard deviation of all signal intensity values in CE-T1WI subtraction sequence was 143.45, while that of CE-FLAIR subtraction sequence was 118.41. CONCLUSION: On CE-FLAIR, brain lymphomas showed relatively poor and homogeneous enhancement, when compared to CE-T1WI. Most brain lymphomas displayed peripheral rim enhancement and central enhancing foci.

Extra-Axial supratentorial anaplastic ependymoma: Unusual location of an aggressive tumor, A case report.

Introduction: Ependymomas are more common in the pediatric population, in whom they are commonly infratentorial. Extra axial location of a supratentorial ependymoma is extremely rare. Diagnosis: Radiologically these tumors are often misdiagnosed as meningioma or other extra axial lesions owing to their unusual location and lack of any pathognomonic features. Hence, histopathological examination becomes imperative for proper evaluation and an adequate diagnosis. Case: Herein we report a case of a supratentorial extra axial anaplastic ependymoma misdiagnosed as a metastatic tumor on radiological examination and mimicking meningioma intra operatively, located in the frontal and temporal region in a 20 year old man.

False-positive results in transcranial motor evoked potentials for outcome prognostication during surgery for supratentorial lesions.

During monitoring of motor evoked potentials (MEP) elicited by transcranial electrical stimulation (TES) for prognostication of postoperative motor deficit, significant MEP changes without postoperative deterioration of motor function represent false-positive results. We aimed to investigate this phenomenon in a large series of patients who underwent resection of supratentorial lesions. TES was applied in 264 patients during resection of motor-eloquent supratentorial lesions. MEP were recorded bilaterally from arm, leg, and/ or facial muscles. The threshold criterion was applied assessing percentage increase in threshold level, which was considered significant if being > 20% higher on affected side than on the unaffected side. Subcortical stimulation was additionally applied to estimate the distance to corticospinal tract. Motor function was evaluated at 24 h after surgery and at 3-month follow-up. Patients with false-positive results were analyzed regarding tumor location, tumor volume, and characteristics of the monitoring. MEP were recorded from 399 muscles (264 arm muscles, 75 leg muscles, and 60 facial muscles). Motor function was unchanged postoperatively in 359 muscles in 228 patients. Among these cases, the threshold level did not change significantly in 354 muscles in 224 patients, while it increased significantly in the remaining 5 muscles in 4 patients (abductor pollicis brevis in all four patients and orbicularis oris in one patient), leading to a false-positive rate of 1.1%. Tumor volume, opening the ventricle, and negative subcortical stimulation did not significantly correlate with false-positive results, while the tumor location in the parietal lobe dorsal to the postcentral gyrus correlated significantly (p = 0.012, odds ratio 11.2, 95% CI 1.8 to 69.8). False-negative results took place in 1.1% of cases in a large series of TES-MEP monitoring using the threshold criterion. Tumor location in the parietal lobe dorsal to the postcentral gyrus was the only predictor of false-positive results.

Contralateral Interhemispheric Transfalcine Approach for Supratentorial Extraventricular Ependymoma Resection.

BACKGROUND/AIM: Extraventricular supratentorial ependymomas are rare entities. Most ependymomas are located at the infratentorial and intraventricular level, and only in a small group of cases they do not present continuity with the ventricular system. This is a case report of a patient with an atypical location of a cerebral ependymoma, which required the implementation of a complex and infrequent approach for its complete microsurgical removal. CASE REPORT: A 16-year-old male patient was referred at our department with a diagnosis of a 40 mm × 50 mm × 60 mm solid-cystic space-occupying lesion, sited between the left superior frontal-cingulate gyri. A contralateral transfalcine interhemispheric approach was selected, which achieved total resection of the tumor. The histopathological diagnosis of Grade II ependymoma was obtained according to WHO classification. CONCLUSION: The contralateral transfalcine interhemispheric approach represents a favorable surgical corridor to achieve a total resection of the tumor lesion and is favored by an adequate working angle and reduced brain manipulation.

Overview of recent advances in the classification of ependymomas in WHO CNS5 classification: Simplified approach to their integrated diagnosis.

Ependymomas can arise along the entire neuraxis; however, they possess site-specific unique molecular alterations and a methylome pattern which is directly related with the prognostic outcomes. Since 2016, when the updated fourth edition of World Health Organization (WHO) classification of tumors of the central nervous system was published, it has been emphasized to classify ependymomas by anatomic site and molecular signatures associated genetic alterations so that classification of the disease reflects its underlying biology. In continuation, the fifth edition of the WHO classification of CNS tumors introduces major changes, including site-specific molecular profiles as the basis of classifying ependymomas. Furthermore, an integrated tier system of reporting is recommended for better clinical correlation and predicting outcomes. WHO grading can still be included in a specific tier, along with molecular markers.