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Integrated Proteogenomic Characterization across Major Histological Types of Pediatric Brain Cancer.Cell Dec 2020We report a comprehensive proteogenomics analysis, including whole-genome sequencing, RNA sequencing, and proteomics and phosphoproteomics profiling, of 218 tumors...
We report a comprehensive proteogenomics analysis, including whole-genome sequencing, RNA sequencing, and proteomics and phosphoproteomics profiling, of 218 tumors across 7 histological types of childhood brain cancer: low-grade glioma (n = 93), ependymoma (32), high-grade glioma (25), medulloblastoma (22), ganglioglioma (18), craniopharyngioma (16), and atypical teratoid rhabdoid tumor (12). Proteomics data identify common biological themes that span histological boundaries, suggesting that treatments used for one histological type may be applied effectively to other tumors sharing similar proteomics features. Immune landscape characterization reveals diverse tumor microenvironments across and within diagnoses. Proteomics data further reveal functional effects of somatic mutations and copy number variations (CNVs) not evident in transcriptomics data. Kinase-substrate association and co-expression network analysis identify important biological mechanisms of tumorigenesis. This is the first large-scale proteogenomics analysis across traditional histological boundaries to uncover foundational pediatric brain tumor biology and inform rational treatment selection.
Topics: Brain Neoplasms; Child; DNA Copy Number Variations; Gene Expression Regulation, Neoplastic; Gene Regulatory Networks; Genome, Human; Glioma; Humans; Lymphocytes, Tumor-Infiltrating; Mutation; Neoplasm Grading; Neoplasm Recurrence, Local; Phosphoproteins; Phosphorylation; Proteogenomics; RNA, Messenger; Transcriptome
PubMed: 33242424
DOI: 10.1016/j.cell.2020.10.044 -
Seizure Jan 2020To investigate the expression of somatostatin receptors (SSTRs) and markers of mTOR pathway in paediatric glioneuronal tumours and correlate these findings with tumour...
PURPOSE
To investigate the expression of somatostatin receptors (SSTRs) and markers of mTOR pathway in paediatric glioneuronal tumours and correlate these findings with tumour type, BRAFV600E mutational status and clinical characteristics such as tumour location, seizure frequency and duration, and age.
METHOD
37 children and adolescents with a neuropathological diagnosis of glioneuronal tumour were identified over a 22-year period. Immunohistochemical analyses for SSTRs type 1, 2A, 3, 5 and ezrin-radixin-moesin (ERM) and phosphorylated S6 (pS6), which are indicators of mTOR pathway activation, were performed in tumour specimens from 33 patients and evaluated using the immunoreactive score (IRS). The IRS were compared to tumour type, BRAFV600E status and clinical characteristics.
RESULTS
Ganglioglioma (GG) was the most frequently encountered subgroup (n = 27), followed by dysembryoplastic neuroepithelial tumour (DNET; n = 4). GGs expressed SSTR2A and SSTR3 to a high extent, 56 % and 44 % respectively. Expression of SSTR2A was also found in DNETs. Signs of mTOR pathway activation were abundant in GGs, but only present in one DNET. No correlations with BRAFV600E presence or clinical characteristics were found.
CONCLUSIONS
Expression of SSTRs and activation of mTOR pathway in paediatric glioneuronal tumour suggest that somatostatin analogues and mTOR inhibitors may have potential therapeutic implications in a subset of inoperable childhood glioneuronal tumours causing medically refractory epilepsy and/or tumour growth. Further clinical studies are warranted to validate these findings.
PubMed: 32062323
DOI: 10.1016/j.seizure.2020.01.011 -
Journal of Korean Neurosurgical Society May 2019Brain tumors are the second most common type of structural brain lesion that causes chronic epilepsy. Patients with low-grade brain tumors often experience chronic...
Brain tumors are the second most common type of structural brain lesion that causes chronic epilepsy. Patients with low-grade brain tumors often experience chronic drug-resistant epilepsy starting in childhood, which led to the concept of long-term epilepsy-associated tumors (LEATs). Dysembryoplastic neuroepithelial tumor and ganglioglioma are representative LEATs and are characterized by young age of onset, frequent temporal lobe location, benign tumor biology, and chronic epilepsy. Although highly relevant in clinical epileptology, the concept of LEATs has been criticized in the neuro-oncology field. Recent genomic and molecular studies have challenged traditional views on LEATs and low-grade gliomas. Molecular studies have revealed that lowgrade gliomas can largely be divided into three groups : LEATs, pediatric-type diffuse low-grade glioma (DLGG; astrocytoma and oligodendroglioma), and adult-type DLGG. There is substantial overlap between conventional LEATs and pediatric-type DLGG in regard to clinical features, histology, and molecular characteristics. LEATs and pediatric-type DLGG are characterized by mutations in BRAF, FGFR1, and MYB/MYBL1, which converge on the RAS-RAF-MAPK pathway. Gene (mutation)-centered classification of epilepsyassociated tumors could provide new insight into these heterogeneous and diverse neoplasms and may lead to novel molecular targeted therapies for epilepsy in the near future.
PubMed: 31085957
DOI: 10.3340/jkns.2019.0033 -
Yonago Acta Medica Dec 2017We report the case of a 19-year-old female with cerebellar ganglioglioma that was diagnosed at 4 years of age. Despite treatment with partial resection, radiation, and...
We report the case of a 19-year-old female with cerebellar ganglioglioma that was diagnosed at 4 years of age. Despite treatment with partial resection, radiation, and chemotherapy, residual tumor slowly expanded into the brainstem and upper cervical cord, resulting in nocturnal hypopnea, progressive tetraparesis, and feeding difficulty during 8-10 years of age. Initiation of temozolomide and bevacizumab was effective in preventing further expansion of the tumor, and the patient has been treated at home and in school with noninvasive positive pressure ventilation and gastrostomy. Histopathologic examination of the resected tumor tissue revealed phospho-S6-positive tumor cells of either neuronal or astroglial appearance. This suggests that a higher proportion of cells of glial lineage could be linked to the progression of cerebellar ganglioglioma in childhood. Possible treatment options with mammalian target of rapamycin inhibitors are discussed.
PubMed: 29434497
DOI: 10.24563/yam.2017.12.008 -
Child's Nervous System : ChNS :... Oct 2015Cerebellopontine angle (CPA) and cerebellomedullary fissure (CMF) tumors are rare in children and information is scarce in the literature. This retrospective study...
OBJECTIVE
Cerebellopontine angle (CPA) and cerebellomedullary fissure (CMF) tumors are rare in children and information is scarce in the literature. This retrospective study reports their histological distribution and tumor origin, and describes surgical resections and post-operative outcome based upon the authors' consecutive personal series.
METHODS
Clinical data of infants and children 16 years old or younger of age treated from 2001 to 2012 by a single surgeon was retrospectively reviewed. All had histologically verified CPA/CMF tumors and underwent radical tumor resection through craniotomy except for two children who had a stereotactic biopsy for malignant tumors (glioblastoma and primitive neuroectodermal tumor (PNET)). Tumors' pathological distributions, tumors' origin, surgical approaches, and patients' outcome were reviewed.
RESULTS
There were 44 infants and children with the age at diagnosis ranging from 11 weeks to 16 years; 32 were predominantly in the CPA and/or CMF whereas 12 showed an extension to the fourth ventricle. Pathology showed 14 ependymomas, 12 benign gliomas (11 pilocytic astrocytomas, 1 ganglioglioma), 4 atypical teratoid rhabdoid tumors (ATRTs), 4 epidermoids, 3 primitive neuroectodermal tumors (PNETs), 3 meningiomas, 3 nerve sheath tumors, and 1 glioblastoma. The anatomical site of tumor origin was the lateral recess of the fourth ventricle in 13 patients, the ventral cerebellar hemisphere in 8, the cerebellar peduncle in 7, and the brain stem in 6. Others were from embryonal nest, cranial nerve, or meninges. For 42 tumor resections, 38 were approached through a posterior fossa craniotomy and 4 through a temporal craniotomy and transtentorial approach. At tumor resection, 26 had a gross total or near total resection, 12 subtotal resection, and 4 partial resection. There were no mortalities. The most significant morbidity was ninth and tenth nerve palsy; 15 patients had unilateral vocal cord palsy or dysphagia. Of these, nine were treated with nasogastric (NG) feeding tube, five with a combination of gastrostomy (G-tube) and tracheotomy, and one with G-tube. All had successful removal of NG feeding from 1 month to 2 years (average 6 months). The tracheostomy and G-tube were removed between 4 months and 2 years (average 14 months) in all.
CONCLUSION
A plethora of tumor types occur in childhood at the CPA/CMF and our review indicated 50 % were benign in histology. High rates of lower cranial nerve morbidity were experienced but their dysfunctions were often recovered or compensated in 2 years. However, one should be cognizant of these complications and conduct resection with appropriate surgical approach, intraoperative monitoring, and surgical microscope.
Topics: Adolescent; Cerebellar Neoplasms; Cerebellopontine Angle; Child; Child, Preschool; Female; Humans; Infant; Male; Neuroma, Acoustic; Retrospective Studies
PubMed: 26351227
DOI: 10.1007/s00381-015-2747-x -
Journal of Cancer Research and... 2021Dysembryoplastic neuroepithelial tumor (DNT) is a rare benign brain tumor predominantly involving children and young adults. Histologically, it corresponds to WHO Grade...
INTRODUCTION
Dysembryoplastic neuroepithelial tumor (DNT) is a rare benign brain tumor predominantly involving children and young adults. Histologically, it corresponds to WHO Grade I tumors; however, it may masquerade aggressive neural tumors such as oligodendroglioma, oligoastrocytoma, pilocytic astrocytoma, and ganglioglioma. The literature on clinical, radiological, and pathological spectrum of DNT is described mostly in the form of case reports, with only a few case series reported till date.
METHODS
A retrospective review of files with diagnosis of DNT (2016 to 2018) was made in the Department of Pathology, National Institute of Pathology, New Delhi. A total of ten cases were retrieved, and their clinical, radiological, and histopathological features were reviewed and studied. Special stains and immunohistochemistry were done, wherever required.
RESULTS
The mean age was 14.8 (±7.9) years, with a male-to-female ratio of 1.5:1. The most common mode of presentation was recurrent, intractable seizures. The most common site of lesion was parietal lobe followed by temporal and frontal lobes of the brain. On histology, mucoid matrix admixed with floating neurons and oligodendrocyte-like cells was a consistent feature; however, the presence of specific glioneuronal elements was observed in only a few cases.
CONCLUSIONS
DNT is a benign, low-grade, nonrecurrent neuroepithelial neoplasm. It is important to differentiate this rare entity from other mimickers, as it is surgically curable and carries an excellent prognosis without the need for adjuvant chemotherapy and radiotherapy. The study helps to enrich the clinicopathological aspects of this rare but important entity.
Topics: Adolescent; Adult; Brain Neoplasms; Child; Female; Follow-Up Studies; Humans; Male; Middle Aged; Neoplasm Recurrence, Local; Neoplasms, Neuroepithelial; Prognosis; Retrospective Studies; Tertiary Care Centers; Young Adult
PubMed: 34528541
DOI: 10.4103/jcrt.JCRT_632_19 -
Neuro-ophthalmology (Aeolus Press) 2014Primary optic nerve gliomas are most commonly benign pilocytic astrocytomas (World Health Organization [WHO] Grade I) occurring in childhood and following an indolent...
Primary optic nerve gliomas are most commonly benign pilocytic astrocytomas (World Health Organization [WHO] Grade I) occurring in childhood and following an indolent course. Malignant optic gliomas occur in adulthood and follow an extremely aggressive course, with rapid infiltration of the chiasm, blindness, and death typically within months. A third category of optic glioma, occurring in adulthood, histopathologically benign (WHO Grade I-II) but following an aggressive course, has been rarely reported. The authors describe clinical and histopathologic features of clinically aggressive but histopathologically benign optic nerve gliomas of adulthood. Retrospective review of cases of biopsy-proven optic nerve glioma in the neuro-ophthalmology division of the Jules Stein Eye Institute from 1990 to 2011 was carried out. Cases following an aggressive course were selected for review of clinical, neuroradiologic, and histopathologic features. Three cases were selected for detailed study. Ages ranged from 31 to 45 years. All were initially diagnosed with optic nerve inflammation or benign neoplasm based on clinical and neuroradiologic features, but all suffered neuroradiologic extension and rapid deterioration of vision in the affected eye to no light perception over 3-8 weeks. Optic nerve biopsies were undertaken for the suspicion of malignancy. Features ranged from WHO Grade I (pilocytic astrocytoma, ganglioglioma) in two cases, to WHO Grade II in one case (diffuse astrocytoma, histopathologically benign, but associated with aggressive features such as high p53 [13-21%] and Ki-67 [40%]). The diffuse astrocytoma case subsequently developed extensive intracranial extension suspicious for malignant transformation. These findings indicate that benign optic nerve glioma in adults may be initially misdiagnosed as inflammation, be clinically aggressive, and require excision to prevent further intracranial involvement.
PubMed: 27928317
DOI: 10.3109/01658107.2014.966851 -
Acta Neuropathologica Jan 2019Radiotherapy improves survival for common childhood cancers such as medulloblastoma, leukemia, and germ cell tumors. Unfortunately, long-term survivors suffer sequelae...
Radiotherapy improves survival for common childhood cancers such as medulloblastoma, leukemia, and germ cell tumors. Unfortunately, long-term survivors suffer sequelae that can include secondary neoplasia. Gliomas are common secondary neoplasms after cranial or craniospinal radiation, most often manifesting as high-grade astrocytomas with poor clinical outcomes. Here, we performed genetic profiling on a cohort of 12 gliomas arising after therapeutic radiation to determine their molecular pathogenesis and assess for differences in genomic signature compared to their spontaneous counterparts. We identified a high frequency of TP53 mutations, CDK4 amplification or CDKN2A homozygous deletion, and amplifications or rearrangements involving receptor tyrosine kinase and Ras-Raf-MAP kinase pathway genes including PDGFRA, MET, BRAF, and RRAS2. Notably, all tumors lacked alterations in IDH1, IDH2, H3F3A, HIST1H3B, HIST1H3C, TERT (including promoter region), and PTEN, which genetically define the major subtypes of diffuse gliomas in children and adults. All gliomas in this cohort had very low somatic mutation burden (less than three somatic single nucleotide variants or small indels per Mb). The ten high-grade gliomas demonstrated markedly aneuploid genomes, with significantly increased quantity of intrachromosomal copy number breakpoints and focal amplifications/homozygous deletions compared to spontaneous high-grade gliomas, likely as a result of DNA double-strand breaks induced by gamma radiation. Together, these findings demonstrate a distinct molecular pathogenesis of secondary gliomas arising after radiation therapy and identify a genomic signature that may aid in differentiating these tumors from their spontaneous counterparts.
Topics: Adolescent; Adult; Astrocytoma; Biomarkers, Tumor; Brain Neoplasms; Child; Child, Preschool; Female; Genomics; Glioma; Homozygote; Humans; Male; Mutation; Sequence Deletion; Telomerase; Young Adult
PubMed: 30196423
DOI: 10.1007/s00401-018-1906-z -
Journal of Medical Case Reports Nov 2022Down's syndrome is the most common chromosomal abnormality in humans. It has been associated with central nervous system tumors such as primary acute lymphoblastic...
BACKGROUND
Down's syndrome is the most common chromosomal abnormality in humans. It has been associated with central nervous system tumors such as primary acute lymphoblastic leukemia and germinomas, but desmoplastic infantile astrocytoma has not yet been reported with Down's syndrome. Desmoplastic infantile astrocytoma is a rare intracranial tumor that mostly occurs in the first 2 years of life. It usually presents as a large, aggressive tumor with both solid and cystic components. Genetically, it has been linked to the BRAF V600E mutation. Despite the rapid growth pattern, it usually has a favorable prognosis after neurosurgical excision. The presence of this extremely rare, genetically linked tumor, and its combination with Down's syndrome, the most common human genetic defect, makes this a very novel clinical presentation. It also raises a very research-worthy question of an undiscovered link between these two genetic disorders.
CASE PRESENTATION
In this case, we report a 1-year-old Pakistani origin male child with Down's syndrome, who presented with progressive macrocephaly and developmental regression over the last 2 months. He was unable to sit by himself, and had lost his handgrip bilaterally. Down's Syndrome was diagnosed soon after birth, based on typical facial features and presence of palmar crease, and later confirmed karyotypically for Trisomy 21. Upon presentation, initial blood tests did not show any abnormality. Magnetic resonance imaging of the brain was done, and showed a mixed intensity cystic mass with solid dural component posteriorly in the right parieto temporo occipital region. Craniotomy was performed, and about 85% of the tumor mass was excised. Histological examination and immunochemistry confirmed the suspected radiological diagnosis of desmoplastic infantile astrocytoma. After surgical excision, our patient gradually reacquired his previously regressed developmental milestones. Unfortunately, the remaining mass, which could not be excised due to its attachment to the highly vascular dura mater, showed regrowth on repeat brain magnetic resonance imaging. As his parents did not consent to further surgery, chemotherapy was offered as the next treatment option to prevent tumor regrowth.
CONCLUSIONS
This case report highlights the need for more case data and research to understand desmoplastic infantile astrocytoma, and their genetic correlation with Down's syndrome. From a clinical standpoint, since desmoplastic infantile astrocytoma has a good postresection prognosis in a majority of early-diagnosed clinical cases, pediatricians, radiologists, and pathologists should consider desmoplastic infantile astrocytoma in their initial differential diagnosis in Down's syndrome patients with macrocephaly and developmental regression during the first 2 years of life.
Topics: Humans; Infant; Male; Astrocytoma; Brain Neoplasms; Down Syndrome; Ganglioglioma; Hand Strength; Hyperplasia; Magnetic Resonance Imaging; Megalencephaly
PubMed: 36333774
DOI: 10.1186/s13256-022-03615-0 -
Neurology Apr 2023Drug-resistant epilepsy, defined as the failure of 2 or more antiseizure medications to achieve seizure freedom, is responsible for 2/3 of epilepsy cases. Tumors are...
Drug-resistant epilepsy, defined as the failure of 2 or more antiseizure medications to achieve seizure freedom, is responsible for 2/3 of epilepsy cases. Tumors are responsible for up to 15% of all adult onset and up to 6% of childhood onset epilepsies. Among these tumors, commonly known subtypes DNET, ganglioglioma, and low-grade astrocytoma are often suspected. New advances in tumor classification have been made, with genetics playing a key role in tumor classification. Polymorphic low-grade neuroepithelial tumor of the young (PLNTY) is a highly epileptogenic subtype of tumors that may mimic low-grade gliomas but offer pathologic and genetic clues: oligodendroglioma-like cellular components and infiltration patterns and strong CD34-immunopositive stain. In addition, a key finding is radiologic: a unifocal abnormality best seen on MRI brain in FLAIR sequence as the "salt and pepper sign" and calcifications appreciated on CT head.
Topics: Humans; Brain Neoplasms; Neoplasms, Neuroepithelial; Glioma; Epilepsy; Oligodendroglioma; Drug Resistant Epilepsy
PubMed: 36564206
DOI: 10.1212/WNL.0000000000206782