Central Nervous System Embryonal Tumors Research Articles

Central nervous system embryonal tumor with PLAGL1 amplification: a case report of a novel entity focusing on imaging findings.

The embryonal central nervous system (CNS) tumor with PLAGL1 (pleomorphic adenoma gene-like) amplification is a novel type of pediatric neoplasm with a distinct methylation profile, described for the first time in 2022. It may be located anywhere in the neuroaxis and, as its name implies, it is driven by the amplification and overexpression of one of the PLAG family genes. Although the associated clinical, immunohistopathological, and molecular characteristics are well characterized in the seminal report of this entity, data on the radiological features is still lacking. Here, we present a case report of a 4-year-old girl with a biopsy-proven PLAGL1-amplified brainstem tumor and provide a detailed description of the corresponding conventional neuroimaging characteristics, aiming to better delineate this entity and to increase the awareness of this pathology in the radiological community.

Central nervous system embryonal tumors with EWSR1-PLAGL1 rearrangements reclassified as INI-1 deficient tumors at relapse.

Central nervous system (CNS) embryonal tumors are a diverse group of malignant tumors typically affecting pediatric patients that recently have been better defined, and this paper describes evolution of a unique type of embryonal tumor at relapse. Two pediatric patients with CNS embryonal tumors with EWSR1-PLAGL1 rearrangements treated at Arkansas Children's Hospital with histopathologic and molecular data are described. These two patients at diagnosis were classified as CNS embryonal tumors with EWSR1-PLAGL1 rearrangements based on histologic appearance and molecular data. At relapse both patient's disease was reclassified as atypical teratoid rhabdoid tumor (ATRT) based on loss of INI-1, presence of SMARCB1 alterations, and methylation profiling results. CNS embryonal tumors with EWSR1-PLAGL1 rearrangements acquire or include a population of cells with SMARCB1 alterations that are the component that predominate at relapse, suggesting treatment aimed at this disease component at diagnosis should be considered.

Molecular and clinicopathologic characteristics of CNS embryonal tumors with BRD4::LEUTX fusion.

Central nervous system (CNS) embryonal tumors are a heterogeneous group of high-grade malignancies, and the increasing clinical use of methylation profiling and next-generation sequencing has led to the identification of molecularly distinct subtypes. One proposed tumor type, CNS tumor with BRD4::LEUTX fusion, has been described. As only a few CNS tumors with BRD4::LEUTX fusions have been described, we herein characterize a cohort of 9 such cases (4 new, 5 previously published) to further describe their clinicopathologic and molecular features. We demonstrate that CNS embryonal tumor with BRD4::LEUTX fusion comprises a well-defined methylation class/cluster. We find that patients are young (4years or younger), with large tumors at variable locations, and frequently with evidence of leptomeningeal/cerebrospinal fluid (CSF) dissemination. Histologically, tumors were highly cellular with high-grade embryonal features. Immunohistochemically, 5/5 cases showed synaptophysin and 4/5 showed OLIG2 expression, thus overlapping with CNS neuroblastoma, FOXR2-activated. DNA copy number profiles were generally flat; however, two tumors had chromosome 1q gains. No recurring genomic changes, besides the presence of the fusion, were found. The LEUTX portion of the fusion transcript was constant in all cases assessed, while the BRD4 portion varied but included a domain with proto-oncogenic activity in all cases. Two patients with clinical follow up available had tumors with excellent response to chemotherapy. Two of our patients were alive without evidence of recurrence or progression after gross total resection and chemotherapy at 16 and 33months. One patient relapsed, and the last of our four patients died of disease one month after diagnosis. Overall, this case series provides additional evidence for this as a distinct tumor type defined by the presence of a specific fusion as well as a distinct DNA methylation signature. Studies on larger series are required to further characterize these tumors.

Preoperative 11 C-Methionine PET-MRI in Pediatric Infratentorial Tumors.

MRI is the main imaging modality for pediatric brain tumors, but amino acid PET can provide additional information. Simultaneous PET-MRI acquisition allows to fully assess the tumor and lower the radiation exposure. Although symptomatic posterior fossa tumors are typically resected, the patient management is evolving and will benefit from an improved preoperative tumor characterization. We aimed to explore, in children with newly diagnosed posterior fossa tumor, the complementarity of the information provided by amino acid PET and MRI parameters and the correlation to histopathological results. Children with a newly diagnosed posterior fossa tumor prospectively underwent a preoperative 11 C-methionine (MET) PET-MRI. Images were assessed visually and semiquantitatively. Using correlation, minimum apparent diffusion coefficient (ADC min ) and contrast enhancement were compared with MET SUV max . The diameter of the enhancing lesions was compared with metabolic tumoral volume. Lesions were classified according to the 2021 World Health Organization (WHO) classification. Ten children were included 4 pilocytic astrocytomas, 2 medulloblastomas, 1 ganglioglioma, 1 central nervous system embryonal tumor, and 1 schwannoma. All lesions showed visually increased MET uptake. A negative moderate correlation was found between ADC min and SUV max values ( r = -0.39). Mean SUV max was 3.8 (range, 3.3-4.2) in WHO grade 4 versus 2.5 (range, 1.7-3.0) in WHO grade 1 lesions. A positive moderate correlation was found between metabolic tumoral volume and diameter values ( r = 0.34). There was no correlation between SUV max and contrast enhancement intensity ( r = -0.15). Preoperative 11 C-MET PET and MRI could provide complementary information to characterize pediatric infratentorial tumors.

Genome-Wide DNA Methylation Profiling as Frontline Diagnostics for Central Nervous System Embryonal Tumors in Hong Kong.

This paper examines the link between CNS tumor biology and heterogeneity and the use of genome-wide DNA methylation profiling as a clinical diagnostic platform. CNS tumors are the most common solid tumors in children, and their prognosis remains poor. This study retrospectively analyzed pediatric patients with CNS embryonal tumors in Hong Kong between 1999 and 2017, using data from the territory-wide registry and available formalin-fixed paraffin-embedded tumor tissue. After processing archival tumor tissue via DNA extraction, quantification, and methylation profiling, the data were analyzed by using the web-based DKFZ classifier (Molecular Neuropathology (MNP) 2.0 v11b4) and t-SNE analysis. Methylation profiles were deemed informative in 85 samples. Epigenetic data allowed molecular subgrouping and confirmed diagnosis in 65 samples, verified histologic diagnosis in 8, and suggested an alternative diagnosis in 12. This study demonstrates the potential of DNA methylation profiling in characterizing pediatric CNS embryonal tumors in a large cohort from Hong Kong, which should enable regional and international collaboration in future pediatric neuro-oncology research.

P21.05.B CAPTURING EVOLVING DEFINITIONS OF 12 SELECT RARE CNS TUMORS: A TIMELY REPORT FROM CBTRUS AND NCI-CONNECT

Abstract BACKGROUND Histopathology-specific incidence, prevalence, and survival are essential population-based cancer statistics that describe cancer burden. The National Cancer Institute’s Comprehensive Oncology Network Evaluating Rare CNS Tumors (NCI-CONNECT) aims to improve understanding of tumor biology and patient outcomes for 12 selected rare brain and other central nervous system (CNS) tumor types to improve approaches to care and treatment. These types included atypical teratoid/rhabdoid tumor, brainstem and midline gliomas, choroid plexus tumors, ependymomas, high grade meningiomas, gliomatosis cerebri, medulloblastoma, oligodendrogliomas, pineal region tumors, pleomorphic xanthoastrocytomas, CNS embryonal tumors, NEC/NOS and primary CNS sarcoma. The analysis aimed to estimate the incidence (new cases per year), prevalence (currently living cases), and survival rates for these selected rare brain and other CNS tumor types. MATERIAL AND METHODS The Central Brain Tumor Registry of the United States (CBTRUS) data, which contains data from the Centers for Disease Control and Preventions National Program of Cancer Registries (NPCR) and National Cancer Institute’s Surveillance, Epidemiology and End Results (SEER) data, from 2008-2019 were used to calculate average annual age-adjusted incidence rates (AAAIR) per 100,000 population overall and by sex, race/ethnicity, and age. Incidence time trends were calculated for diagnosis years 2004-2019. NPCR survival data from 2001-2018 were used to calculate relative survival (RS) estimates. Estimated prevalence counts as of December 31, 2019 were estimated using incidence from CBTRUS and overall survival rates from SEER. RESULTS Overall AAAIR for all 12 subtypes combined was 1.51 per 100,000 population, with the highest subtype-specific incidence in ependymomas (AAAIR=0.41/100,000). Overall, most subtypes were more common in males and people who are non-Hispanic White. Incidence of all subtypes varied by age. Ependymomas were most prevalent with 19,339 cases; followed by oligodendrogliomas with 15,070 cases. Time trends in incidence varied by subtype, with significant decreases in incidence of gliomatosis cerebri, CNS embryonal tumor, and primary CNS sarcoma. RS for all subtypes combined at 1, 5, and 10 years was 86.6%, 71.9%, and 65.3%, respectively. Ependymomas had the highest RS (1-year=96.1%, 5-years=90.6%, 10-years=86.6%) and primary CNS sarcomas had the lowest RS (1-year=48.2%, 5-years=7.7%, 10-years=5.2%). CONCLUSION Incidence, prevalence, and survival patterns for these 12 selected rare cancer subtypes varied significantly by type. Population based data are critical to guiding effective design of and accrual expectations for clinical trials in rare cancers.

Medulloblastomas, CNS embryonal tumors, and cerebellar mutism syndrome: advances in care and future directions.

Central nervous system (CNS) embryonal tumors, commonly found in pediatric patients, represent a heterogeneous mix of lesions with an overall poor (though improving) prognosis. Medulloblastomas are by far the most frequently encountered and most widely studied subtype, though others include atypical teratoid/rhabdoid tumors (AT/RTs), embryonal tumor with multilayered rosettes (ETMRs), and CNS neuroblastomas, FOX-R2 activated. The classification, diagnosis, and treatment of these lesions have evolved drastically over the years as their molecular underpinnings have been elucidated. We describe the most recent 2021 WHO Classification system, discuss current understanding of the genetic basis, and demonstrate current thinking in treatment for these highly complex tumors. Since surgical resection continues to remain a mainstay of treatment, preventing and managing surgical complications, especially cerebellar mutism syndrome (CMS), is paramount. We describe the current theories for the etiology of CMS and two centers' experience in mitigating its risks. As our surgical toolbox continues to evolve along with our understanding of these tumors, we hope future patients can benefit from both improved overall survival and quality of life.

OUTC-06. BEST PRACTICES FOR THE SUCCESSFUL ADMINISTRATION OF COMBINATION METRONOMIC ANTI-ANGIOGENIC AND INTRAVENTRICULAR THERAPY

Abstract BACKGROUND Combination metronomic anti-angiogenic and intraventricular therapy incorporates a customized administration of a five-drug oral antiangiogenic regimen with intravenous bevacizumab and intraventricular chemotherapy and is an effective treatment regimen for children with recurrent central nervous system embryonal tumors. This treatment can be administered while maintaining quality of life and avoiding severe side effects through personalized therapy schedules; however, dosing modifications, available dosage formulations, and complexity of medication administration creates challenges for families and clinical staff. METHODS A retrospective chart review was completed on 11 patients who received this treatment with various combinations of oral medications (thalidomide, etoposide, cyclophosphamide, celecoxib, and fenofibrate), intravenous (IV) medication (bevacizumab), and intraventricular chemotherapy (cytarabine, etoposide, and topotecan). We implemented successful nursing interventions, family education, variable scheduling options, dosage formulation selections, and innovative oral and intraventricular administration techniques. RESULTS Patients were able to successfully receive therapy for an average of 14 months and no patient came off for toxicity. Treatment was generally well-tolerated, with most toxicities being hematologic or gastrointestinal in nature. CONCLUSION Education, innovative dosing schedules, recognition of potential side effects, and medication administration allow for successful administration of this complex therapy.

Outcomes of SARS-CoV-2 infection in 126 children and adolescents with central nervous system tumors.

The Global Registry of COVID-19 in Childhood Cancer (GRCCC) seeks to describe the natural history of SARS-CoV-2 in children with cancer across the world. Here, we report the disease course and management of coronavirus disease 2019 (COVID-19) infection in the subset of children and adolescents with central nervous system (CNS) tumors who were included in the GRCCC until February 2021, the first data freeze. The GRCCC is a deidentified web-based registry of patients less than 19years of age with cancer or recipients of a hematopoietic stem cell transplant and laboratory-confirmed SARS-CoV-2 infection. Demographic data, cancer diagnosis, cancer-directed therapy, and clinical characteristics of SARS-CoV-2 infection were collected. Outcomes were collected at 30 and 60days post infection. The GRCCC included 1500 cases from 45 countries, including 126 children with CNS tumors (8.4%). Sixty percent of the cases were from middle-income countries, while no cases were reported from low-income countries. Low-grade gliomas, high-grade gliomas, and CNS embryonal tumors were the most common CNS cancer diagnoses (67%, 84/126). Follow-up at 30days was available for 107 (85%) patients. Based on the composite measure of severity, 53.3% (57/107) of reported SARS-CoV-2 infections were asymptomatic, 39.3% (42/107) were mild/moderate, and 6.5% (7/107) were severe or critical. One patient died from SARS-CoV-2 infection. There was a significant association between infection severity and absolute neutrophil count less than 500 (p=.04). Of 107 patients with follow-up available, 40 patients (37.4%) were not receiving cancer-directed therapy. Thirty-four patients (50.7%) had a modification to their treatment due to withholding of chemotherapy or delays in radiotherapy or surgery. In this cohort of patients with CNS tumors and COVID-19, the frequency of severe infection appears to be low, although severe disease and death do occur. We found that greater severity was seen in patients with severe neutropenia, although treatment modifications were not associated with infection severity or cytopenias. Additional analyses are needed to further describe this unique group of patients.

Clinical and histopathological spectrum of cranial small round cell tumors: An experience from a tertiary care center.

Small round cell tumors (SRCTs) are a group of malignant neoplasms with minimal or no differentiation, characterized by the presence of round cells with high nuclear-cytoplasmic ratio. Although SRCTs can occur in any part of the body, involvement of central nervous system (CNS) is uncommon. We aimed to study the clinicopathological spectrum of cranial SRCT diagnosed in our institute over a period of four years (2016-2019). A retrospective review of medical records (2016-2019) with a morphological diagnosis of cranial SRCT was made. Both intra-axial and extra-axial tumors were included. A total of 60 cases were retrieved, and the clinical and histopathological features were studied. Special cytochemical staining and immunohistochemistry were performed, where needed. The mean age at presentation was 18.4 years (range, 1-60 years), with a male-to-female ratio of 2.5:1. The most common site was posterior fossa of brain (n = 28, 47%), followed by dorso-lumbar spine (n = 9, 15%). The most common type of tumor was medulloblastoma (n = 29, 48.3%), followed by Ewing sarcoma (ES)/peripheral primitive neuroectodermal tumor (pPNET) (n = 11, 18.3%), non-Hodgkin lymphoma (NHL) (n = 9, 15%), neuroblastoma (n = 3, 5%), and CNS embryonal tumor, NOS (n = 2, 3.3%). One case each of atypical teratoid rhabdoid tumor (ATRT), rhabdomyosarcoma, pineoblastoma, melanoma, rhabdomyosarcoma, and undifferentiated pleomorphic sarcoma was also documented. SRCTs have a variable age of presentation. Their incidence in CNS is low as compared to other organ systems. On light microscopy, the histopathology of these lesions is overlapping, posing a great diagnostic dilemma for the pathologist. The use of ancillary techniques like immunohistochemistry helps in arriving at the correct diagnosis. Treatment strategy and tumor prognosis also vary along the entire spectrum of SRCT, thus making exact characterization essential for proper management.

Medulloblastoma and ABO-Rh Blood Group: Evidence of an Association between the Distribution of Blood Group Antigens and Medulloblastoma

Abstract Objective Medulloblastoma is the most common central nervous system embryonal tumor and the most common malignant brain tumor of childhood. This study aims to find out the incidence of the ABO-Rh blood group in medulloblastoma patients of northern India to assess the utility of the blood group as a preclinical non-modifiable risk factor. Materials and Methods The study cohort consisted of 87 pediatric patients (age up to 18 years) who were diagnosed after histopathological examination with medulloblastoma at a university hospital in Lucknow between 2014 and 2019. Hundred random pediatric individuals from the same population who were admitted to the same hospital between 2014 and 2019 for non-tumor cases were selected as the control group. Data concerning characteristics including age, sex, ABO blood group, and Rh factor were collected from hospital records. The distribution of ABO-Rh blood groups in the study population was compared with the general population using the χ2 test. Statistical analysis of the ABO-Rh blood groups in the study population was done using the IBM SPSS statistics version 24.0. Results Data analysis revealed that blood group A was significantly associated with medulloblastoma cases (odds ratio [OR] = 2.93; 95% confidence interval [CI]: 1.35–6.34). We find that the classical subtype was prevalent with the blood group A (43.8%), while the desmoplastic subtype was associated with the blood group O (38.5%). Conclusions Blood group A has a higher risk for the development of medulloblastoma while blood group O has the least risk. These findings suggest that blood group antigen should be considered as a non-modifiable preclinical risk factor for developing medulloblastoma.

Clinicopathological and molecular characterization of a case classified by DNA‑methylation profiling as “CNS embryonal tumor with BRD4–LEUTX fusion”

Central Nervous System (CNS) embryonal tumors represent a heterogeneous group of highly aggressive tumors occurring preferentially in children but also described in adolescents and adults. In 2021, the CNS World Health Organization (WHO) classification drastically changed the diagnosis of the other CNS embryonal tumors including new histo-molecular tumor types. Here, we report a pediatric case of a novel tumor type among the other CNS embryonal tumors classified within the methylation class “CNS Embryonal Tumor with BRD4–LEUTX Fusion”. The patient was a 4-year girl with no previous history of disease. For a few weeks, she suffered from headaches, vomiting and mild fever associated with increasing asthenia and loss of weight leading to a global deterioration of health. MRI brain examination revealed a large, grossly well-circumscribed tumoral mass lesion located in the left parietal lobe, contralateral hydrocephalus and midline shift. Microscopic examination showed a highly cellular tumor with a polymorphic aspect. The majority of the tumor harbored neuroectodermal features composed of small cells with scant cytoplasm and hyperchromatic nuclei associated with small “medulloblastoma-like” cells characterized by syncytial arrangement and focally a streaming pattern. Tumor cells were diffusely positive for Synaptophysin, CD56, INI1 and SMARCA4 associated with negativity for GFAP, OLIG-2, EMA, BCOR, LIN28A and MIC-2. Additional IHC features included p53 protein expression in more than 10% of the tumor’s cells and very interestingly, loss of H3K27me3 expression. The Heidelberg DNA-methylation classifier classified this case as “CNS Embryonal Tumor with BRD4:LEUTX Fusion”. RNA-sequencing analyses confirmed the BRD4 (exon 13)–LEUTX (exon 2) fusion with no other molecular alterations found by DNA sequencing. Our case report confirmed that a new subgroup of CNS embryonal tumor with high aggressive potential, loss of H3K27me3 protein expression, BRDA4–LEUTX fusion, named “Embryonal CNS tumor with BRD4–LEUTX fusion”, has to be considered into the new CNS WHO classification.

Efficacy and safety of bevacizumab, irinotecan, and temozolomide combination for relapsed or refractory pediatric central nervous system embryonal tumor: a single-institution study.

This study aimed to evaluate the efficacy and safety of combination therapy with bevacizumab (Bev), irinotecan (CPT-11), and temozolomide (TMZ) in children with central nervous system (CNS) embryonal tumor relapse. The authors retrospectively examined 13 consecutive pediatric patients with relapsed or refractory CNS embryonal tumors who received combination therapy comprising Bev, CPT-11, and TMZ. Specifically, 9 patients had medulloblastoma, 3 had atypical teratoid/rhabdoid tumor (AT/RT), and 1 had CNS embryonal tumor with rhabdoid features. Of the 9 medulloblastoma cases, 2 were categorized in the Sonic hedgehog subgroup and 6 in molecular subgroup 3 for medulloblastoma. The complete and partial objective response rates were 66.6% in patients with medulloblastoma and 75.0% in patients with AT/RT or CNS embryonal tumors with rhabdoid features. Furthermore, the 12- and 24-month progression-free survival rates were 69.2% and 51.9% for all patients with recurrent or refractory CNS embryonal tumors, respectively. In contrast, the 12- and 24-month overall survival rates were 67.1% and 58.7%, respectively, for all patients with relapsed or refractory CNS embryonal tumors. The authors observed grade 3 neutropenia, thrombocytopenia, proteinuria, hypertension, diarrhea, and constipation in 23.1%, 7.7%, 23.1%, 7.7%, 7.7%, and 7.7% of patients, respectively. Furthermore, grade 4 neutropenia was observed in 7.1% of patients. Nonhematological adverse effects, such as nausea and constipation, were mild and controlled with standard antiemetics. This study demonstrated favorable survival outcomes in patients with relapsed or refractory pediatric CNS embryonal tumors and thus helped to investigate the efficacy of combination therapy comprising Bev, CPT-11, and TMZ. Moreover, combination chemotherapy had high objective response rates, and all adverse events were tolerable. To date, data supporting the efficacy and safety of this regimen in the relapsed or refractory AT/RT population are limited. These findings suggest the potential efficacy and safety of combination chemotherapy in patients with relapsed or refractory pediatric CNS embryonal tumors.

Unusual manifestation of cerebellopontine angle medulloblastoma with tinnitus and sensorineural hearing loss

Abstract BACKGROUND. Medulloblastoma is the most common central nervous system embryonal tumor in children. In adults, this tumor is extremely rare, accounting for nearly 1% of primary brain tumors. Raised intracranial pressure signs are common manifestations of posterior fossa tumors, but tinnitus and/or sensorineural hearing loss are very uncommon presenting symptoms. MATERIAL AND METHODS. Starting from a very rare case of a 39-year-old male with left tinnitus and progressive left sensorineural hearing loss as isolated symptoms of a medulloblastoma, we performed a literature survey using the PubMed, ProQuest, Web of Science, Science Direct, Wiley Online search engines for patients with medulloblastoma and tinnitus and/or sensorineural hearing loss. RESULTS. All patients found in the relevant literature with auditory dysfunctions presented sensorineural hearing loss. Other frequent manifestations were: ataxia, facial numbness, vertigo, headache, nystagmus. Two patients were found with tinnitus and sensorineural hearing loss as isolated symptoms of medulloblastoma, as in our case, and in two other cases the sensorineural hearing loss was the unique symptom. With refers to the onset of medulloblastoma, just 3 patients had the first symptoms sensorineural hearing loss and tinnitus. Concerning the tumor location, in patients manifested with isolated tinnitus and sensorineural hearing loss, like our patient, the tumor arised from the internal auditory meatus, extended to the cerebellopontine angle or involved the vestibulocochlear nerve. With regards to treatment, surgery in association with radiotherapy and chemotherapy was elected in most cases (38%). CONCLUSION. It is important to pay attention at patients with isolated auditory dysfunction that may mimic significant posterior fossa tumors, such as a medulloblastoma.

Recent progress and novel approaches to treating atypical teratoid rhabdoid tumor

Atypical teratoid rhabdoid tumors (AT/RT) are malignant central nervous system (CNS) tumors that occur mostly in young children and have historically carried a very poor prognosis. While recent clinical trial results show that this tumor is curable, outcomes are still poor compared to other central nervous system embryonal tumors. We here review prior AT/RT clinical trials and highlight promising pre-clinical results that may inform novel clinical approaches to this aggressive cancer.

Amplification of the PLAG-family genes—PLAGL1 and PLAGL2—is a key feature of the novel tumor type CNS embryonal tumor with PLAGL amplification

Pediatric central nervous system (CNS) tumors represent the most common cause of cancer-related death in children aged 0–14 years. They differ from their adult counterparts, showing extensive clinical and molecular heterogeneity as well as a challenging histopathological spectrum that often impairs accurate diagnosis. Here, we use DNA methylation-based CNS tumor classification in combination with copy number, RNA-seq, and ChIP-seq analysis to characterize a newly identified CNS tumor type. In addition, we report histology, patient characteristics, and survival data in this tumor type. We describe a biologically distinct pediatric CNS tumor type (n = 31 cases) that is characterized by focal high-level amplification and resultant overexpression of either PLAGL1 or PLAGL2, and an absence of recurrent genetic alterations characteristic of other pediatric CNS tumor types. Both genes act as transcription factors for a regulatory subset of imprinted genes (IGs), components of the Wnt/β-Catenin pathway, and the potential drug targets RET and CYP2W1, which are also specifically overexpressed in this tumor type. A derived PLAGL-specific gene expression signature indicates dysregulation of imprinting control and differentiation/development. These tumors occurred throughout the neuroaxis including the cerebral hemispheres, cerebellum, and brainstem, and were predominantly composed of primitive embryonal-like cells lacking robust expression of markers of glial or neuronal differentiation (e.g., GFAP, OLIG2, and synaptophysin). Tumors with PLAGL1 amplification were typically diagnosed during adolescence (median age 10.5 years), whereas those with PLAGL2 amplification were diagnosed during early childhood (median age 2 years). The 10-year overall survival was 66% for PLAGL1-amplified tumors, 25% for PLAGL2-amplified tumors, 18% for male patients, and 82% for female patients. In summary, we describe a new type of biologically distinct CNS tumor characterized by PLAGL1/2 amplification that occurs predominantly in infants and toddlers (PLAGL2) or adolescents (PLAGL1) which we consider best classified as a CNS embryonal tumor and which is associated with intermediate survival. The cell of origin and optimal treatment strategies remain to be defined.

Rare embryonal and sarcomatous central nervous system tumours: State-of-the art and future directions

The introduction of molecular methods into the diagnostics of central nervous system (CNS) tumours and the subsequent deciphering of their molecular heterogeneity has resulted in a significant impact on paediatric neurooncology. Particularly in the field of rare embryonal and sarcomatous CNS tumours, novel tumour types have been delineated and introduced in the recent 5th edition of the WHO classification of CNS tumours. The rarity and novelty of these tumour types result in diagnostic and therapeutic challenges. Apart from distinct histopathological and molecular features, these tumour types exhibit characteristic clinical properties and require different therapeutic approaches for optimal patient management. However, based on the limited availability of clinical data, current therapeutic recommendations have to be based on data from small, predominantly retrospective patient cohorts. Within this article, we provide guidance for diagnostic work-up and clinical management of rare CNS embryonal tumours (‘embryonal tumour with multi-layered rosettes’, ETMR; ‘CNS neuroblastoma, FOXR2-activated’, CNS NB-FOXR2; ‘CNS tumour with BCOR-ITD, CNS BCOR-ITD) and rare CNS sarcomatous tumours (‘primary intracranial sarcoma, DICER1-mutant’, CNS DICER1; ‘CIC-rearranged sarcoma’, CNS CIC). By emphasizing the significant consequences on patient management in paediatric CNS tumours, we want to encourage wide implementation of comprehensive molecular diagnostics and stress the importance for joint international efforts to further collect and study these rare tumour types.

CNS Tumor with BCOR Internal Tandem Duplication: The First Case in Southeast Asia

The central nervous system (CNS) tumor with BCOR internal tandem duplication (ITD) or high-grade neuroepithelial tumor with BCOR alterations (HGNET-BCOR) has been proposed as a new entity of CNS embryonal tumor. We report herein the first case of CNS tumor with BCOR ITD in Southeast Asia. The patient was a 2-year-old girl who presented with head tilt and ataxia. CNS showed a posterior fossa mass, 5.7x5.2x4.2 cm, with faint enhancement and internal hemorrhage. The lesion was removed, and the pathological examination revealed a hypercellular tumor comprising neoplastic cells with oval hyperchromatic nuclei. Perivascular pattern was occasionally observed. Pseudopalisading necrosis was seen but microvascular proliferation was absent. Although the clinical features of HGNET-BCOR are not distinctive and may overlap with other high-grade primary CNS tumors, awareness of the pathological features and the positive BCOR immunostain should lead to a final diagnosis with the identification of BCOR ITD using a molecular method.

Development of GPC2-directed chimeric antigen receptors using mRNA for pediatric brain tumors

BackgroundPediatric brain tumors are the leading cause of cancer death in children with an urgent need for innovative therapies. Glypican 2 (GPC2) is a cell surface oncoprotein expressed in neuroblastoma...

Spectrum of paired-like homeobox 2b immunoexpression in pediatric brain tumors with embryonal morphology.

Paired‐like homeobox 2b (PHOX2B) is an established immunomarker for peripheral neuroblastoma and autonomic nervous system cells. We aimed to evaluate the utility of PHOX2B immunostaining in central nervous system (CNS) tumors with embryonal morphology. Fifty‐one tumors were stained with PHOX2B and submitted for whole slide image analysis: 35 CNS tumors with embryonal morphology (31 CNS embryonal tumors and four gliomas); and 16 peripheral neuroblastomas were included for comparison. Diffuse nuclear immunopositivity was observed in all (16/16) neuroblastomas (primary and metastatic). Among CNS embryonal tumors, focal immunoreactivity for PHOX2B was observed in most (5/7) embryonal tumors with multilayered rosettes (ETMR) and a single high‐grade neuroepithelial tumor (HGNET) with PLAGL2 amplification; the remaining 27 CNS tumors were essentially immunonegative (<0.05% positive). Among ETMR, PHOX2B expression was observed in a small overall proportion (0.04%–4.94%) of neoplastic cells but focally reached up to 39% in 1 mm ‘hot spot’ areas. In the PLAGL2‐amplified case, 0.09% of the total neoplastic population was immunoreactive, with 0.53% in the ‘hot spot’ area. Care should be taken in interpreting PHOX2B immunopositivity in a differential diagnosis that includes metastatic neuroblastoma and CNS tumors; focal or patchy expression should not be considered definitively diagnostic of metastatic peripheral neuroblastoma.