Pediatric Chordoma: A Tale of Two Genomes.

Little is known regarding the genomic alterations in chordoma, with the exception of loss of SMARCB1, a core member of the SWI/SNF complex, in poorly differentiated chordomas. A TBXT duplication and rs2305089 polymorphism, located at 6q27, are known genetic susceptibility loci. A comprehensive genomic analysis of the nuclear and mitochondrial genomes in pediatric chordoma has not yet been reported. In this study, we performed whole exome and mitochondrial DNA (mtDNA) genome sequencing on 29 chordomas from 23 pediatric patients. Findings were compared with that from whole genome sequencing datasets of 80 adult skull base chordoma patients. In the pediatric chordoma cohort, 81% percent of the somatic mtDNA mutations were observed in NADH complex genes, which is significantly enriched compared to the rest of the mtDNA genes (p=0.001). In adult chordomas, mtDNA mutations were also enriched in the NADH complex genes (p<0.0001). Furthermore, a progressive increase in heteroplasmy of non-synonymous mtDNA mutations was noted in patients with multiple tumors (p=0.0007). In the nuclear genome, rare likely germline in-frame indels in ARID1B, a member of the SWI/SNF complex located at 6q25.3, were observed in five pediatric patients (22%) and four patients in the adult cohort (5%). The frequency of rare ARID1B indels in the pediatric cohort is significantly higher than that of the adult cohort (p=0.0236, Fisher's exact test), but they were both significantly higher than that in the ethnicity-matched populations (p<5.9e-07 and p<0.0001174, respectively). Implications: germline ARID1B indels and mtDNA aberrations appear important for chordoma genesis, especially in pediatric chordoma.

Postmortem Protocols of Implantable Neurosurgical Devices: A Cross-Sectional Survey.

BACKGROUND: Implantable devices are increasingly more common for management of movement disorders, pain, and epilepsy. These devices are often complex and constructed of nonbiodegradable or hazardous materials. Therefore, proper postmortem handling of these devices is exceedingly important. Unfortunately, there is no consolidated resource available for postmortem neuromodulation device protocols. Thus, we surveyed and catalogued the protocols for implantable devices to summarize proper postmortem device protocols for implantable neurosurgical devices currently on the market. METHODS: We performed a cross-sectional study of companies producing commonly implanted neurosurgical devices. Using information from company websites, user manuals, and catalogs we categorized devices into 3 groups: A (formal recommendation for explantation), B (recommendation for explantation without formal company protocol), and C (explantation is not necessary). We then compiled the data into a stoplight diagram, providing a clear postmortem disposal algorithm for each device category. RESULTS: Twelve companies were queried regarding 46 devices. Postmortem protocols were available for 50% (23/46) of devices; the remaining devices did not have formal recommendations. Overall, 50% of devices were classified as category A "red light" on the stoplight diagram based on recommendations, 10.9% as category B "yellow light," and the remaining 39.1% were classified as category C "green light" indicating they are safe to bury or cremate. CONCLUSIONS: Evolution in therapies and growth in functional neurosurgery has expanded the range of implantable neurosurgical devices. We provide an educational document summarizing their postmortem protocols. This resource aims to aid health-care providers and encourage proper disposal practices during burial or cremation.

Clinical utility of whole-genome DNA methylation profiling as a primary molecular diagnostic assay for central nervous system tumors-A prospective study and guidelines for clinical testing.

Background: Central nervous system (CNS) cancer is the 10th leading cause of cancer-associated deaths for adults, but the leading cause in pediatric patients and young adults. The variety and complexity of histologic subtypes can lead to diagnostic errors. DNA methylation is an epigenetic modification that provides a tumor type-specific signature that can be used for diagnosis. Methods: We performed a prospective study using DNA methylation analysis as a primary diagnostic method for 1921 brain tumors. All tumors received a pathology diagnosis and profiling by whole genome DNA methylation, followed by next-generation DNA and RNA sequencing. Results were stratified by concordance between DNA methylation and histopathology, establishing diagnostic utility. Results: Of the 1602 cases with a World Health Organization histologic diagnosis, DNA methylation identified a diagnostic mismatch in 225 cases (14%), 78 cases (5%) did not classify with any class, and in an additional 110 (7%) cases DNA methylation confirmed the diagnosis and provided prognostic information. Of 319 cases carrying 195 different descriptive histologic diagnoses, DNA methylation provided a definitive diagnosis in 273 (86%) cases, separated them into 55 methylation classes, and changed the grading in 58 (18%) cases. Conclusions: DNA methylation analysis is a robust method to diagnose primary CNS tumors, improving diagnostic accuracy, decreasing diagnostic errors and inconclusive diagnoses, and providing prognostic subclassification. This study provides a framework for inclusion of DNA methylation profiling as a primary molecular diagnostic test into professional guidelines for CNS tumors. The benefits include increased diagnostic accuracy, improved patient management, and refinements in clinical trial design.

An adolescent case of sellar osteochondromyxoma in the setting of spondyloepiphyseal dysplasia.

PURPOSE: Osteochondromyxomas (OMX) are rare congenital bone tumors that have only been described in the context of Carney complex syndrome (CNC). Data on OMX as a separate entity and in association with other disorders remain limited, making both diagnosis and treatment difficult. METHODS: A case report of a 17-year-old female diagnosed with sellar OMX is presented in the setting of spondyloepiphyseal dysplasia (SED). We discuss the radiographic and histopathological interpretations in addition to reviewing the current literature on OMX. RESULTS: A successful gross total resection of the tumor was achieved via an endonasal endoscopic transsphenoidal approach. A diagnosis was established radiographically and pathologically. CONCLUSION: The diagnosis and treatment of OMX are best achieved via tissue biopsy. Following confirmed osteochondromyxoma cases long term for recurrence and outcomes will be essential in understanding its natural tumor history and in establishing standard treatments.

Neuroblastoma Arising in an Immature Teratoma of the Ovary in a 13-Year-Old.

Somatic malignancies arising in mature teratomas are exceedingly rare entities and even more so are those arising in immature teratomas. Here, we present a unique case of a 13-year-old who initially underwent ovarian sparing cystectomy for a 7.7 cm left ovarian mass with a pre-operative diagnosis of mature cystic teratoma. Histologically, all 3 germ cell layers were present and immature neuroepithelial tubules were also identified. Subsequent sections revealed a nodular lesion composed of neuropil, neuroblasts with a spectrum of maturation, and Schwannian-type stroma. The neuroblasts were diffusely positive for PHOX2B. Neuroblastoma arising in an immature teratoma has only been described in the literature once previously in an adult patient.

Pediatric benign triton tumor of trigeminal nerve: a case report and literature review.

PURPOSE: Benign triton tumors (BTTs) in the pediatric population are extremely rare occurrences. Paucity of data on BTTs poses both diagnostic and therapeutic challenges, particularly when found intracranially. METHODS: A case report of a 10-year-old male diagnosed with incidental maxillary trigeminal (V2) BTT is presented. We discuss radiographic and histopathological interpretations. Furthermore, we provide a brief review of current literature and historical background on pediatric trigeminal BTT diagnosis, histopathology, and management. RESULTS: Successful gross total resection of the tumor was achieved via Dolenc approach to the cavernous sinus. Management options with consideration of outcomes from the few prior cases reported in the literature are presented. CONCLUSION: Treatment of trigeminal nerve tumors requires a broad differential diagnosis and understanding rare tumors is essential in the diagnosis and treatment algorithm.

Pediatric spinal intramedullary anaplastic myxopapillary ependymoma: a case report.

A 6-year-old girl presented with a 1-week history of progressive upper and lower extremity weakness and bilateral upper extremity dysesthesia. Imaging demonstrated a 4.7 × 1.2-cm enhancing intramedullary lesion in the cervical spine from level C2 to C5 with associated cystic components and syringomyelia. The patient underwent a C2-C5 laminoplasty, with gross total resection of the intramedullary lesion. Histological analysis showed small to medium-sized epithelioid cells, with predominantly a solid architecture focally infiltrating into the adjacent spinal cord tissue. Focal papillary differentiation was present along with peri-vascular pseudorosettes, mucin microcysts, and globules of dense collagen. Focal anaplasia was noted with mitosis (5/10 HPF), focal necrosis, and elevated Ki67 10-15%. These findings were consistent with a myxopapillary ependymoma with anaplastic features. CSF cytology was negative for tumor cells. MYCN amplification was not present. She was treated with targeted proton-beam radiation therapy. This is the fourth case of an intramedullary anaplastic myxopapillary ependymoma to date, and the first case in the cervical spine reported in the literature.

Primary Biphasic Hepatic Sarcoma in DICER1 Syndrome.

DICER1 tumor predisposition syndrome is a rare genetic disorder that predisposes individuals to multiple benign and malignant neoplasms. The phenotype is vast and includes pleuropulmonary blastoma (PPB), thyroid nodules, cystic nephroma, Wilms tumor, ovarian Sertoli-Leydig cell tumor, and medulloepithelioma, among others. Herein, we describe a patient with a DICER1 germline pathogenic variant presenting with two neoplasms that are not commonly encountered in the context of DICER1 syndrome. The first tumor is a multiloculated cystic hepatic lesion with a biphasic pattern, composed of cysts lined by bland biliary type (CK19-positive) epithelium surrounded by a condensation of sarcomatous spindled cell proliferation in a myxoid stroma. This neoplasm resembled PPB or cystic nephroma with malignant transformation. The second tumor is a chest nodule consistent with low-grade hidradenocarcinoma. Although it is difficult to speculate with just a single case, these unusual neoplasms occurring in particular at a young age raises the possibility that they can be inherent to, and thus, be part of the DICER1 tumor predisposition syndrome phenotype.

Platelet-derived growth factor beta is a potent inflammatory driver in paediatric high-grade glioma.

Paediatric high-grade gliomas (HGGs) account for the most brain tumour-related deaths in children and have a median survival of 12-15 months. One promising avenue of research is the development of novel therapies targeting the properties of non-neoplastic cell-types within the tumour such as tumour associated macrophages (TAMs). TAMs are immunosuppressive and promote tumour malignancy in adult HGG; however, in paediatric medulloblastoma, TAMs exhibit anti-tumour properties. Much is known about TAMs in adult HGG, yet little is known about them in the paediatric setting. This raises the question of whether paediatric HGGs possess a distinct constituency of TAMs because of their unique genetic landscapes. Using human paediatric HGG tissue samples and murine models of paediatric HGG, we demonstrate diffuse midline gliomas possess a greater inflammatory gene expression profile compared to hemispheric paediatric HGGs. We also show despite possessing sparse T-cell infiltration, human paediatric HGGs possess high infiltration of IBA1+ TAMs. CD31, PDGFRß, and PDGFB all strongly correlate with IBA1+ TAM infiltration. To investigate the TAM population, we used the RCAS/tv-a system to recapitulate paediatric HGG in newborn immunocompetent mice. Tumours are induced in Nestin-positive brain cells by PDGFA or PDGFB overexpression with Cdkn2a or Tp53 co-mutations. Tumours driven by PDGFB have a significantly lower median survival compared to PDGFA-driven tumours and have increased TAM infiltration. NanoString and quantitative PCR analysis indicates PDGFB-driven tumours have a highly inflammatory microenvironment characterized by high chemokine expression. In vitro bone marrow-derived monocyte and microglial cultures demonstrate bone marrow-derived monocytes are most responsible for the production of inflammatory signals in the tumour microenvironment in response to PDGFB stimulation. Lastly, using knockout mice deficient for individual chemokines, we demonstrate the feasibility of reducing TAM infiltration and prolonging survival in both PDGFA and PDGFB-driven tumours. We identify CCL3 as a potential key chemokine in these processes in both humans and mice. Together, these studies provide evidence for the potent inflammatory effects PDGFB has in paediatric HGGs.

The Essentials of Molecular Testing in CNS Tumors: What to Order and How to Integrate Results.

PURPOSE OF REVIEW: Molecular testing has become essential for the optimal workup of central nervous system (CNS) tumors. There is a vast array of testing from which to choose, and it can sometimes be challenging to appropriately incorporate findings into an integrated report. This article reviews various molecular tests and provides a concise overview of the most important molecular findings in the most commonly encountered CNS tumors. RECENT FINDINGS: Many molecular alterations in CNS tumors have been identified over recent years, some of which are incorporated into the 2016 World Health Organization (WHO) classification and the Consortium to Inform Molecular and Practical Approaches to CNS Tumor Taxonomy-Not Official WHO (cIMPACT-NOW) updates. Array-based methylation profiling has emerged over the past couple of years and will likely replace much of currently used ancillary testing for diagnostic purposes. A combination of next-generation sequencing (NGS) panel and copy number array is ideal for diffuse gliomas and embryonal tumors, with a low threshold to employ in other tumor types. With the recent advances in molecular diagnostics, it will be ever more important for the pathologist to recognize the molecular testing available, which tests to perform, and to appropriately integrate results in light of clinical, radiologic, and histologic findings.

Double Pathology in Rasmussen Encephalitis.

Investigators from Children's Hospital Colorado and University of Colorado conducted a retrospective review of electronic medical records to identify all Rasmussen Encephalitis (RE) cases that had undergone surgery with subsequent pathologic evaluation at Children's Hospital Colorado during 2005-2019 to determine the frequency of double pathology.

Clinical Utility of GlioSeq Next-Generation Sequencing Test in Pediatric and Young Adult Patients With Brain Tumors.

Brain tumors are the leading cause of death in children. Establishing an accurate diagnosis and therapy is critical for patient management. This study evaluated the clinical utility of GlioSeq, a next-generation sequencing (NGS) assay, for the diagnosis and management of pediatric and young adult patients with brain tumors. Between May 2015 and March 2017, 142 consecutive brain tumors were tested using GlioSeq v1 and subset using GlioSeq v2. Out of 142 samples, 63% were resection specimens and 37% were small stereotactic biopsies. GlioSeq sequencing was successful in 100% and 98.6% of the cases for the detection of mutations and copy number changes, and gene fusions, respectively. Average turnaround time was 8.7 days. Clinically significant genetic alterations were detected in 95%, 66.6%, and 66.1% of high-grade gliomas, medulloblastomas, and low-grade gliomas, respectively. GlioSeq enabled molecular-based stratification in 92 (65%) cases by specific molecular subtype assignment (70, 76.1%), substantiating a neuropathologic diagnosis (18, 19.6%), and diagnostic recategorization (4, 4.3%). Fifty-seven percent of the cases harbored therapeutically actionable findings. GlioSeq NGS analysis offers rapid detection of a wide range of genetic alterations across a spectrum of pediatric brain tumors using formalin-fixed, paraffin-embedded specimens and facilitates integrated molecular-morphologic classification and personalized management of pediatric brain tumors.

Pediatric primary spinal atypical teratoid rhabdoid tumor: a case series and review of the literature.

Atypical teratoid rhabdoid tumors (ATRTs) are rare malignant central nervous system tumors, commonly occurring before 3 years of age. Median overall survival (OS) of patients with these tumors is about 1 year, despite aggressive multimodal therapy. Pediatric primary spinal ATRTs are even more rare, with fewer than 50 cases reported. The authors present a series of four patients who were treated at Ann and Robert H. Lurie Children's Hospital of Chicago in the period from 1996 to 2017.These patients, with ages 2-11 years, presented with pain and a decline in motor functions. They were found to have lesions in the lumbar, thoracic, and/or cervical spine. One patient's tumor was intramedullary with exophytic components, while another patient's tumor had both intra- and extradural components. All patients underwent resection followed by chemotherapy (systemic and intrathecal). Two patients had fractionated radiation therapy and one had an autologous stem cell transplant. Three patients are known to be deceased (OS 8.5-45 months). The fourth patient was in remission 19 years after her initial diagnosis. To the authors' knowledge, this is the largest series of pediatric primary spinal ATRTs documented at a single institution. These cases illustrate a variety of presentations of spinal ATRT and add to the body of literature on this aggressive pathology.A systematic MEDLINE search was also conducted using the keywords "atypical teratoid rhabdoid tumor," "pediatric spinal rhabdoid tumor," and "malignant rhabdoid tumor spine." Reports were included for patients younger than 21 years, without evidence of intracranial or systemic disease at the time of diagnosis. Clinical characteristics and outcomes of the four institutional cases were compared to those in the literature. This review yielded an additional 48 cases of primary pediatric spinal ATRTs reported in the English-language literature. Patients (ages 2 months to 19 years) presented with symptoms of pain, regression of motor function, and spinal cord compression. The majority of tumors were intradural (14 extramedullary, 8 intramedullary, 1 both). Eleven cases in the literature described tumors limited to extradural structures, while 10 tumors involved the intra- and extradural spine. Four reports did not specify tumor location. Although rare, spinal ATRT should be considered in the differential diagnosis of pediatric patients presenting with a new spinal mass.

Radiosensitization by Histone H3 Demethylase Inhibition in Diffuse Intrinsic Pontine Glioma.

PURPOSE: Radiotherapy (RT) has long been and remains the only treatment option for diffuse intrinsic pontine glioma (DIPG). However, all patients show evidence of disease progression within months of completing RT. No further clinical benefit has been achieved using alternative radiation strategies. Here, we tested the hypothesis that histone demethylase inhibition by GSK-J4 enhances radiation-induced DNA damage, making it a potential radiosensitizer in the treatment of DIPG.Experimental Design: We evaluated the effects of GSK-J4 on genes associated with DNA double-strand break (DSB) repair in DIPG cells by RNA sequence, ATAC sequence, and quantitative real-time PCR. Radiation-induced DNA DSB repair was analyzed by immunocytochemistry of DSB markers γH2AX and 53BP1, DNA-repair assay, and cell-cycle distribution. Clonogenic survival assay was used to determine the effect of GSK-J4 on radiation response of DIPG cells. In vivo response to radiation monotherapy and combination therapy of RT and GSK-J4 was evaluated in patient-derived DIPG xenografts. RESULTS: GSK-J4 significantly reduced the expression of DNA DSB repair genes and DNA accessibility in DIPG cells. GSK-J4 sustained high levels of γH2AX and 53BP1 in irradiated DIPG cells, thereby inhibiting DNA DSB repair through homologous recombination pathway. GSK-J4 reduced clonogenic survival and enhanced radiation effect in DIPG cells. In vivo studies revealed increased survival of animals treated with combination therapy of RT and GSK-J4 compared with either monotherapy. CONCLUSIONS: Together, these results highlight GSK-J4 as a potential radiosensitizer and provide a rationale for developing combination therapy with radiation in the treatment of DIPG.

Global Reduction of H3K4me3 Improves Chemotherapeutic Efficacy for Pediatric Ependymomas.

BACKGROUND: Ependymomas (EPNs) are the third most common brain tumor in children. These tumors are resistant to available chemotherapeutic treatments, therefore new effective targeted therapeutics must be identified. Increasing evidence shows epigenetic alterations including histone posttranslational modifications (PTMs), are associated with malignancy, chemotherapeutic resistance and prognosis for pediatric EPNs. In this study we examined histone PTMs in EPNs and identified potential targets to improve chemotherapeutic efficacy. METHODS: Global histone H3 lysine 4 trimethylation (H3K4me3) levels were detected in pediatric EPN tumor samples with immunohistochemistry and immunoblots. Candidate genes conferring therapeutic resistance were profiled in pediatric EPN tumor samples with micro-array. Promoter H3K4me3 was examined for two candidate genes, CCND1 and ERBB2, with chromatin-immunoprecipitation coupled with real-time PCR (ChIP-PCR). These methods and MTS assay were used to verify a relationship between H3K4me3 levels and CCND1 and ERBB2, and to investigate cell viability in response to chemotherapeutic drugs in primary cultured pediatric EPN cells. RESULTS: H3K4me3 levels positively correlate with WHO grade malignancy in pediatric EPNs and are associated with progression free survival in patients with posterior fossa group A EPNs (PF-EPN-A). Reduction of H3K4me3 by silencing its methyltransferase SETD1A, in primary cultured EPN cells increased cell response to chemotherapy. CONCLUSIONS: Our results support the development of a novel treatment that targets H3K4me3 to increase chemotherapeutic efficacy in pediatric PF-EPN-A tumors.

Primary Central Nervous System Malignant Melanoma in Children: A Case Series and Review of the Literature.

We describe 2 cases of rapidly progressive primary central nervous system malignant melanoma, and summarize 18 previously reported cases of this extremely rare tumor in children. Both patients presented with focal neurologic symptoms, with no evidence of skin or other organ system involvement. One patient was treated with temozolomide and etoposide, whereas the other was treated with multiple surgical resections, radiation therapy, and a trial of ipilimumab. New molecularly targeted and immune-based therapies used in metastatic melanoma in adults are potential new treatment options, but their efficacy and safety in pediatric patients needs to be established.

Extended diffusion weighted magnetic resonance imaging with two-compartment and anomalous diffusion models for differentiation of low-grade and high-grade brain tumors in pediatric patients.

PURPOSE: The purpose of this study was to examine advanced diffusion-weighted magnetic resonance imaging (DW-MRI) models for differentiation of low- and high-grade tumors in the diagnosis of pediatric brain neoplasms. METHODS: Sixty-two pediatric patients with various types and grades of brain tumors were evaluated in a retrospective study. Tumor type and grade were classified using the World Health Organization classification (WHO I-IV) and confirmed by pathological analysis. Patients underwent DW-MRI before treatment. Diffusion-weighted images with 16 b-values (0-3500 s/mm2) were acquired. Averaged signal intensity decay within solid tumor regions was fitted using two-compartment and anomalous diffusion models. Intracellular and extracellular diffusion coefficients (Dslow and Dfast), fractional volumes (Vslow and Vfast), generalized diffusion coefficient (D), spatial constant (µ), heterogeneity index (ß), and a diffusion index (index_diff = µ × Vslow/ß) were calculated. Multivariate logistic regression models with stepwise model selection algorithm and receiver operating characteristic (ROC) analyses were performed to evaluate the ability of each diffusion parameter to distinguish tumor grade. RESULTS: Among all parameter combinations, D and index_diff jointly provided the best predictor for tumor grades, where lower D (p = 0.03) and higher index_diff (p = 0.009) were significantly associated with higher tumor grades. In ROC analyses of differentiating low-grade (I-II) and high-grade (III-IV) tumors, index_diff provided the highest specificity of 0.97 and D provided the highest sensitivity of 0.96. CONCLUSIONS: Multi-parametric diffusion measurements using two-compartment and anomalous diffusion models were found to be significant discriminants of tumor grading in pediatric brain neoplasms.

Medulloblastoma with extensive nodularity (SHH medulloblastoma).

Medulloblastoma is the most common CNS embryonal tumor and the most common malignant tumor of childhood. Its overall incidence is 1.8 cases per 1 million people, with a childhood incidence of 6 cases per 1 million. 77 percent of patients are less than 19 years old. Medulloblastoma occurs in the 4th ventricle and usually presents with symptoms of increased intracranial pressure (headaches, nausea, vomiting) and signs of obstructive hydrocephalus. Medulloblastoma is both histologically and genetically defined with prognosis that depends on classification.