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.

Genetic mutation and immune infiltration in embryonal tumor with multilayered rosettes.

PURPOSE: Genetic mutations stand as pivotal factors leading to the occurrence of embryonal tumor with multilayered rosettes (ETMR). This study aims to identify improved treatment approaches by unraveling the genetic drivers and immune infiltration in ETMR. METHODS: Two siblings with ETMR, treated at the General Hospital of Ningxia Medical University, were enrolled. Diagnosis involved MRI, Hematoxylin and Eosin (HE), and immunohistochemical (IHC) staining. Differentially expressed genes (DEGs) in ETMR were identified using GSE122077 and GSE14296 datasets. GO and KEGG analyses were used to determine ETMR-related pathways. Whole exome sequencing (WES) was utilized to annotate genetic variations in ETMR. Core genes, identified by protein-protein interaction (PPI), formed a diagnostic model evaluated by Logistic Regression. Single-sample Gene Set Enrichment Analysis (ssGSEA) assessed immune infiltration in ETMR, examining correlations between immune cells and core genes. RESULTS: Two siblings were diagnosed with ETMR. In ETMR, 135 DEGs were identified, of which 25 genes were annotated with 28 mutation sites. Moreover, ETMR-related pathways included cell cycle, synaptic functions, and neurodegeneration. Three ETMR-related core genes (ALB, PSMD1, and PAK2) were screened by protein-protein interaction (PPI). The diagnostic model constructed using these genes demonstrated an AUC value of 0.901 (95% CI: 0.811-0.991) in the training set, indicating accurate predictions in ETMR. Enhanced ssGSEA scores for 16 immune cells in ETMR tissues suggested a strong immune response. CONCLUSION: This study identifies diagnostic models associated with three core variant genes (ALB, PSMD1, PAK2) and enhanced immune cell activity in ETMR. It reveals crucial genetic features and significant immune responses in ETMR.

Non-C19MC-altered embryonal tumor with multilayered rosettes in a young woman with DICER1 syndrome: case report and review of the literature.

Embryonal tumors with multilayered rosettes (ETMR) are highly aggressive and therapy-resistant pediatric central nervous system (CNS) tumors that have three histological patters: embryonal tumor with abundant neuropil and true rosettes, ependymoblastoma, and medulloepithelioma. We present a case of ETMR in an 18-year-old woman with DICER1 syndrome. This report confirms the important role of DNA-methylation analysis in the classification of CNS embryonal tumors and the importance of investigating somatic and germline DICER1 mutations in all CNS embryonal tumors.

Embryonal tumor with multilayered rosettes arising from the internal auditory canal of an adult: Illustrative case with molecular investigations.

Embryonal tumors with multilayered rosettes (ETMRs) are aggressive central nervous system (CNS) tumors that usually occur in young children. Here, we describe the first incidence of ETMR in an adult patient that also originated in the novel location of the internal auditory canal (IAC). The 36-year-old patient initially presented with unsteadiness, diplopia, and tinnitus. The tumor in the IAC was discovered on brain magnetic resonance imaging, and gross total resection was performed followed by pathological and molecular diagnosis. The patient received whole brain and spinal cord radiotherapy after an intracranial recurrence and adjuvant chemotherapy consisting of four cycles of ifosfamide, cisplatin, and etoposide. Progression was rapid; however, the patient survived for 22 months after diagnosis before succumbing to the disease. Molecular investigation revealed a DICER1 mutation at exon 25, and methylation classification categorized the tumor as ETMR, non-C19MC-altered. This case underscores the diverse possible presentations of ETMR, DICER1-mutated and the importance of molecular techniques to characterize and promptly treat atypical ETMR.

Management and outcome of unusual pediatric brain tumors: challenges experienced at a tertiary care center of a developing country.

PURPOSE: Primary brain tumors are the most frequent solid pediatric tumors, accounting for 40-50% of all cancers in children. Eighty to ninety percent of the 250,000 new cases of pediatric cancer each year are discovered in low and middle-income nations, where nearly 88 percent of the world's children reside. This article aims to emphasize the unusual presentation, management, and surgical outcome of complex pediatric brain tumors. METHODS: We performed a retrospective study of patients who were admitted to the neurosurgery department with unusual pediatric brain tumors between March 1, 2019, and March 1, 2022. The study included pediatric patients up to age 18 years. We included those pediatric brain tumors whose (i) location was uncommon, or (ii) presented with unusual clinical presentation, or (iii) histopathology suggested to be a rare tumor, or (iv) radiological features were atypical. RESULTS: We included 9 cases of rare unusual pediatric brain tumors. Three out of 9 cases required preoperative embolization due to its hypervascular nature on digital subtraction angiography (DSA). All patients underwent surgical excision within 24-48 h of tumor devascularization. One out of 9 cases died in follow-up period due to pleural effusion and distant metastasis to lungs. CONCLUSION: Treatment considerations for unusual pediatric brain tumors include a comprehensive multidisciplinary approach, including community-based screening and proper referral system for early treatment, a variety of treatment modalities, and sophisticated follow-up strategy. Government shall work in coherence with tertiary centers to spread social awareness and provide various financial scheme to prevent treatment dropouts.

Intraocular neuroectodermal embryonal tumor in two rabbits.

Spontaneous intraocular tumors are rarely reported in rabbits, despite their widespread use as laboratory animals. We describe two cases of intraocular neuroectodermal embryonal tumors, formerly primitive neuroectodermal tumors, in young rabbits. Histologically, both tumors exhibited prominent rosette or pseudorosettes, consistent with the histomorphology seen in human tumors. The neuroectodermal subtype is supported by immunoreactivity for the neuronal markers, SRY-box transcription factor 2, microtubule-associated protein 2, neuronal nuclear protein, and neuron-specific enolase. In one of the rabbits, there was metastasis to the contralateral conjunctiva. Intraocular neoplasms can occur in young rabbits and eyes with refractory disease should be enucleated for clinical management.

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.

Clinicopathological characteristics and outcomes in embryonal tumor with multilayered rosettes: A decade long experience from a tertiary care centre in North India.

BACKGROUND: Embryonal tumor with multilayered rosettes (ETMR) are a heterogenous group clinically, pathologically and topographically. Due to limited cases, data regarding its molecular genetics, pathology and prognostic factors is evolving. We retrospectively analysed our cohort of ETMR over last decade in order to study their clinicopathological characteristics and outcome. METHODS: Our cohort consisted of patients diagnosed with Embryonal tumor with abundant neuropil and true rosettes (ETANTR)/Ependymoblastoma (EBL)/ Medulloepithelioma (MEPL) over the past decade. Clinical details, including outcome and imaging data was retrieved. Histological analysis including immunohistochemical work-up was performed. RESULTS: Cohort included 15 patients with age range between 1 and 28 years and M:F ratio of 1.5:1. Supratentorial location predominated in comparison to tumors arising in posterior fossa. ETANTR and EBL patterns were equally distributed (40% each), followed by one case each of mixed pattern (EBL + ETANTR), MEPL and embryonal tumor, unclassified. All tumors readily expressed LIN 28A and INI-1 was retained. Recurrence with evidence of glial and rhabdoid differentiation was noted in a single patient 9 months following resection. Follow-up period ranged from 1 to 31 months, with overall median survival of 6.4 months. Eight patients were planned for adjuvant treatment following surgery, of which only four could complete it. All patients, except for one, succumbed to the disease. CONCLUSIONS: ETMR have a heterogenous morphology and gathers ETANTR, EBL, MEPL within its spectrum. Following treatment, the recurrent tumor may feature glial/rhabdoid differentiation. LIN28A is expressed in all cases, however should be interpreted in context of histology. Prognosis of ETMR remains dismal despite multimodal therapy.

BCOR Internal Tandem Duplication Expression in Neural Stem Cells Promotes Growth, Invasion, and Expression of PRC2 Targets.

Central nervous system tumor with BCL6-corepressor internal tandem duplication (CNS-BCOR ITD) is a malignant entity characterized by recurrent alterations in exon 15 encoding the essential binding domain for the polycomb repressive complex (PRC). In contrast to deletion or truncating mutations seen in other tumors, BCOR expression is upregulated in CNS-BCOR ITD, and a distinct oncogenic mechanism has been suggested. However, the effects of this change on the biology of neuroepithelial cells is poorly understood. In this study, we introduced either wildtype BCOR or BCOR-ITD into human and murine neural stem cells and analyzed them with quantitative RT-PCR and RNA-sequencing, as well as growth, clonogenicity, and invasion assays. In human cells, BCOR-ITD promoted derepression of PRC2-target genes compared to wildtype BCOR. A similar effect was found in clinical specimens from previous studies. However, no growth advantage was seen in the human neural stem cells expressing BCOR-ITD, and long-term models could not be established. In the murine cells, both wildtype BCOR and BCOR-ITD overexpression affected cellular differentiation and histone methylation, but only BCOR-ITD increased cellular growth, invasion, and migration. BCOR-ITD overexpression drives transcriptional changes, possibly due to altered PRC function, and contributes to the oncogenic transformation of neural precursors.

Reflection of neuroblastoma intratumor heterogeneity in the new OHC-NB1 disease model.

Accurate modeling of intratumor heterogeneity presents a bottleneck against drug testing. Flexibility in a preclinical platform is also desirable to support assessment of different endpoints. We established the model system, OHC-NB1, from a bone marrow metastasis from a patient diagnosed with MYCN-amplified neuroblastoma and performed whole-exome sequencing on the source metastasis and the different models and passages during model development (monolayer cell line, 3D spheroid culture and subcutaneous xenograft tumors propagated in mice). OHC-NB1 harbors a MYCN amplification in double minutes, 1p deletion, 17q gain and diploid karyotype, which persisted in all models. A total of 80-540 single-nucleotide variants (SNVs) was detected in each sample, and comparisons between the source metastasis and models identified 34 of 80 somatic SNVs to be propagated in the models. Clonal reconstruction using the combined copy number and SNV data revealed marked clonal heterogeneity in the originating metastasis, with four clones being reflected in the model systems. The set of OHC-NB1 models represents 43% of somatic SNVs and 23% of the cellularity in the originating metastasis with varying clonal compositions, indicating that heterogeneity is partially preserved in our model system.

Minimally invasive surgery to treat embryonal tumors of childhood.

Minimally invasive surgery (MIS) to resect primary and metastatic pediatric embryonal tumors offers the potential for reduced postoperative morbidity with smaller wounds, less pain, fewer surgical site infections, decreased blood loss, shorter hospital stays, and less disruption to treatment regimens. However, significant controversy surrounds the question of whether a high-fidelity oncologic resection of childhood embryonal tumors with gross total resection, negative margins, and appropriate lymph node sampling can be achieved through MIS. This review outlines the diverse applications of MIS to treat definitively pediatric embryonal malignancies, including this approach to metastatic deposits. It outlines specific patient populations and presentations that may be particularly amenable to the minimally invasive approach. This work further summarizes the current evidence supporting the efficacy of MIS to accomplish a definitive, oncologic resection without compromising relapse-free or overall survival. Finally, the review offers technical considerations to consider in order to achieve a safe and complete resection.

Pontine Embryonal Tumor With Multilayered Rosettes: An Autopsy Case Exhibiting Extensive Posttreatment Glial and Neuronal Maturation.

Embryonal tumor with multilayered rosettes (ETMR) is a rare and highly aggressive embryonal central nervous system tumor that primarily affects young children. It is characterized by (1) amplification of the C19MC miRNA cluster at 19q13.42 and (2) immunohistochemical tumor cell positivity for LIN28A. We describe the case of a 3-year-old girl who presented with a 2-week history of multiple neurological deficits. Based primarily on imaging findings that revealed a large pontine tumor, biopsy was not performed and the patient was clinically diagnosed with a "diffuse intrinsic pontine glioma." She was subsequently treated with radiation and concurrent adjuvant temozolomide, but unfortunately there was minimal response and the patient died 6 months after diagnosis. Autopsy revealed an ETMR that was confirmed via C19MC fluorescence in situ hybridization and LIN28 immunohistochemistry. Although widespread central nervous system dissemination was observed, large portions of the main pontine mass exhibited evidence of extensive glial and neuronal maturation (ie, differentiation). We consider this tissue "maturation" to have been induced by chemotherapy and radiation. Herein, we discuss the importance of antemortem biopsy of intrinsic pontine tumors and the clinical significance of glial and neuronal maturation post therapy in the context of ETMR.

Molecular pathology of tumors of the central nervous system.

Since the update of the 4th edition of the WHO Classification of Central Nervous System (CNS) Tumors published in 2016, particular molecular characteristics are part of the definition of a subset of these neoplasms. This combined 'histo-molecular' approach allows for a much more precise diagnosis of especially diffuse gliomas and embryonal CNS tumors. This review provides an update of the most important diagnostic and prognostic markers for state-of-the-art diagnosis of primary CNS tumors. Defining molecular markers for diffuse gliomas are IDH1/IDH2 mutations, 1p/19q codeletion and mutations in histone H3 genes. Medulloblastomas, the most frequent embryonal CNS tumors, are divided into four molecularly defined groups according to the WHO 2016 Classification: wingless/integrated (WNT) signaling pathway activated, sonic hedgehog (SHH) signaling pathway activated and tumor protein p53 gene (TP53)-mutant, SHH-activated and TP53-wildtype, and non-WNT/non-SHH-activated. Molecular characteristics are also important for the diagnosis of several other CNS tumors, such as RELA fusion-positive subtype of ependymoma, atypical teratoid rhabdoid tumor (AT/RT), embryonal tumor with multilayered rosettes, and solitary fibrous tumor/hemangiopericytoma. Immunohistochemistry is a helpful alternative for further molecular characterization of several of these tumors. Additionally, genome-wide methylation profiling is a very promising new tool in CNS tumor diagnostics. Much progress has thus been made by translating the most relevant molecular knowledge into a more precise clinical diagnosis of CNS tumors. Hopefully, this will enable more specific and more effective therapeutic approaches for the patients suffering from these tumors.

Targeted radioimmunotherapy for embryonal tumor with multilayered rosettes.

PURPOSE: We explored the use of intraventricular 131I-Omburtamab targeting B7-H3 in patients with ETMR. METHODS: Patients were enrolled in an IRB approved, phase 1, 3 + 3 dose escalation trial. Patients with CNS disease expressing the antibody target antigen B7-H3 were eligible. We report on a cohort of three patients with ETMR who were enrolled on the study. Three symptomatic children (ages 14 months, 3 and 3.5 years) had large parietal masses confirmed to be B7-H3-reactive ETMR. Patients received 2 mCi 131I-Omburtamab as a tracer followed by one or two therapeutic 131I-Omburtamab injections. Dosimetry was based on serial CSF, blood samplings and region of interest (ROI) on nuclear scans. Brain and spine MRIs and CSF cytology were done at baseline, 5 weeks after 131I-Omburtamab, and approximately every 3 months thereafter. Acute toxicities and survival were noted. RESULTS: Patients received surgery, focal radiation, and high dose chemotherapy. Patients 1 and 2 received 131I-Omburtamab (80 and 53 mCi, respectively). Patient 3 had a local recurrence prior to 131I-Omburtamab treated with surgery, external beam radiation, chemotherapy, then 131I-Omburtamab (36 mCi). 131I-Omburtamab was well-tolerated. Mean dose delivered by 131I-Omburtamab was 68.4 cGy/mCi to CSF and 1.95 cGy/mCi to blood. Mean ROI doses were 230.4 (ventricular) and 58.2 (spinal) cGy/mCi. Patients 1 and 2 remain in remission 6.8 years and 2.3 years after diagnosis, respectively; patient 3 died of progressive disease 7 months after therapy (2 years after diagnosis). CONCLUSIONS: 131I-Omburtamab appears safe with favorable dosimetry therapeutic index. When used as consolidation following surgery and chemoradiation therapy, 131I-Omburtamab may have therapeutic benefit for patients with ETMR.

Intracranial Ewing sarcoma with whole genome study.

INTRODUCTION: Ewing sarcoma (ES) as a primary intracranial tumor is very rare. Recently, CNS embryonal tumors with ES-like genomic change have been reported. Patients and methods We report a case of intracranial Ewing sarcoma in a 13-year-old girl who complained of headache and migraine. The tumor had developed in the right middle cranial fossa with a mass effect on the brain with impending transuncal herniation. RESULTS: Undifferentiated small round cell morphology with completely negative results for friend leukemia integration 1 transcription factor (Fli-1) and a nonspecific cytoplasmic CD99-positive staining pattern mislead the diagnosis as central nervous system (CNS) embryonal tumor, NOS. However, whole genome sequencing (WGS) revealed Ewing sarcoma (EWS)-Fli-1 gene fusion, which was confirmed by fluorescence in situ hybridization study and the diagnosis was revised to ES. CONCLUSIONS: This case is a true intracranial but extra-axial ES confirmed by WGS. We report this case of intracranial ES to demonstrate the importance of marker gene studies using FISH or NGS.

Medulloepithelioma with heterologous osteoid component: a case report and review of literature.

PURPOSE: Medulloepithelioma is a rare brain tumor that has been classified as embryonal tumor with multilayered rosettes (ETMR) if it harbors C19MC amplification. In rare instances, it shows evidence of heterologous differentiation. METHODS: We report a case of a 10-year-old female who presented with headache, squint, and minimal left sided weakness of 1 week duration. RESULTS: Microscopy revealed a small round blue cell tumor with focal glandular and tubular differentiation. In one focus, well-developed osteoid was identified. The tumor labeled with LIN28A immunostain. CONCLUSIONS: Unusual features can be encountered in medulloepithelioma which should be in the differential diagnosis of CNS embryonal tumors. Full description of the case with review of the literature and comparison between cases with and without heterologous elements is presented.

Embryonal tumor with multilayered rosettes: Diagnosis on intra-operative squash smear.

We describe a rare example of infratentorial primitive neuroectodermal tumor categorized as embryonal tumor with multilayered rosettes diagnosed on intra-operative squash smear and frozen section and discuss its key diagnostic features, pitfalls and differentials. Correct interpretation at the time of frozen section is crucial as it helps in deciding the further course of surgery. To the best of our knowledge, this is the first such report in the literature.

Raman spectroscopy for medulloblastoma.

PURPOSE: The aim of the study is to use Raman spectroscopy to analyze the biochemical composition of medulloblastoma and normal tissues from the safety margin of the CNS and to find specific Raman biomarkers capable of differentiating between tumorous and normal tissues. METHODS: The tissue samples consisted of medulloblastoma (grade IV) (n = 11). The tissues from the negative margins were used as normal controls. Raman images were generated by a confocal Raman microscope-WITec alpha 300 RSA. RESULTS: Raman vibrational signatures can predict which tissue has tumorous biochemistry and can identify medulloblastoma. The Raman technique makes use of the fact that tumors contain large amounts of protein and far less lipids (fatty compounds), while healthy tissue is rich in both. CONCLUSION: The ability of Raman spectroscopy and imaging to detect medulloblastoma tumors fills the niche in diagnostics. These powerful analytical techniques are capable of monitoring tissue morphology and biochemistry. Our results demonstrate that RS can be used to discriminate between normal and medulloblastoma tissues.

The incidence of brainstem primitive neuroectodermal tumors of childhood based on SEER data.

PURPOSE: Incidence of BS primitive neuroectodermal tumors (BS-PNET) in children is not reported to date. Our main objectives were to estimate the incidence and report the outcome of BS-PNET in children. METHODS: Data were collected using the Surveillance Epidemiology and End Results cancer registry. RESULTS: From 1973 to 2013, we identified 83 pediatric patients (aged 0-21 years). Patients were divided into two age groups (0-3 years and 4-21 years). Median overall survival was 53 months. Patients in the older age group had a significant survival advantage (P < 0.001), as did those who received three modalities of therapy (surgery, chemotherapy, and radiation therapy) (P < 0.001) and patients with gross or subtotal tumor resection (P < 0.001). CONCLUSIONS: This study presents the first estimate of incidence and the largest cohort of pediatric BS-PNETs to date. A high index of suspicion of BS-PNET in similar cases is crucial for diagnosis, treatment, and outcome.