Purpose of review
Brain tumors are the most frequent solid cancer in the pediatric population. Owing to the rarity of environmental clues about their origin, it is tempting to consider these ...neoplasms as developmental processes gone awry. Our review will explore the heuristic power of this hypothesis and the influence of these findings on the clinical management.
Recent finding
A more accurate description of cancer predisposition syndrome has shown their frequent association with developmental abnormalities. Several genes involved in pediatric brain tumor oncogenesis are involved in developmental processes. Modeling of several pediatric brain tumor in cerebral organoids, mimicking embryonal stage of brain development, indicates that early events during brain development create the conditions necessary for their oncogenesis.
Summary
The onset of multiple brain tumor types early in life suggests a functional relationship between brain development and oncogenesis. A growing body of evidence seems to support the hypothesis that some of the main developmental steps in the brain can be highjacked by the tumors during their initiation. Collaborations between neuroscientists and oncologists should provide room for improvement in the knowledge for these neoplasms.
PURPOSE OF REVIEWMalignant germ cell tumors in the central nervous system are rare and not well known because they occur mainly in adolescents, an age in which patients are dispersed in adult and ...pediatric wards. Their biology starts to be unraveled by high-throughput genomics and their treatment is now well defined thanks to international studies, including patients from childhood through adulthood.
RECENT FINDINGSChemotherapy gained definitively a role apart from radiotherapy in order to improve tumor control in secreting neoplasms, but also to decrease the volume or dose of radiation therapy in germinomas. Neurocognitive outcome remains good with some disparities because of tumor location, patients with pineal tumors being less impaired than those with supratentorial malignant germ cell tumors. Alterations in the KIT/RAS as well as in the mTOR/AKT pathways have been frequently reported and could represent interesting opportunities to introduce targeted therapies in these neoplasms.
SUMMARYDiagnosis and treatment of malignant germ cell tumor of the brain are now well established within experienced multidisciplinary teams taking care of adolescents and young adults. The prognosis of secreting tumors has not yet reached the excellent results obtained for germinomas but aggressive chemotherapy including high-dose chemotherapy with stem-cell support may contribute to improve their outcome. The role of targeted therapies has yet to be determined in view of the recently described molecular findings.
The cIMPACT-NOW Update 7 has replaced the WHO nosology of "ependymoma, RELA fusion positive" by "Supratentorial-ependymoma, C11orf95-fusion positive". This modification reinforces the idea that ...supratentorial-ependymomas exhibiting fusion that implicates the C11orf95 (now called ZFTA) gene with or without the RELA gene, represent the same histomolecular entity. A hot off the press molecular study has identified distinct clusters of the DNA methylation class of ZFTA fusion-positive tumors. Interestingly, clusters 2 and 4 comprised tumors of different morphologies, with various ZFTA fusions without involvement of RELA. In this paper, we present a detailed series of thirteen cases of non-RELA ZFTA-fused supratentorial tumors with extensive clinical, radiological, histopathological, immunohistochemical, genetic and epigenetic (DNA methylation profiling) characterization. Contrary to the age of onset and MRI aspects similar to RELA fusion-positive EPN, we noted significant histopathological heterogeneity (pleomorphic xanthoastrocytoma-like, astroblastoma-like, ependymoma-like, and even sarcoma-like patterns) in this cohort. Immunophenotypically, these NFκB immunonegative tumors expressed GFAP variably, but EMA constantly and L1CAM frequently. Different gene partners were fused with ZFTA: NCOA1/2, MAML2 and for the first time MN1. These tumors had epigenetic homologies within the DNA methylation class of ependymomas-RELA and were classified as satellite clusters 2 and 4. Cluster 2 (n = 9) corresponded to tumors with classic ependymal histological features (n = 4) but also had astroblastic features (n = 5). Various types of ZFTA fusions were associated with cluster 2, but as in the original report, ZFTA:MAML2 fusion was frequent. Cluster 4 was enriched with sarcoma-like tumors. Moreover, we reported a novel anatomy of three ZFTA:NCOA1/2 fusions with only 1 ZFTA zinc finger domain in the putative fusion protein, whereas all previously reported non-RELA ZFTA fusions have 4 ZFTA zinc fingers. All three cases presented a sarcoma-like morphology. This genotype/phenotype association requires further studies for confirmation. Our series is the first to extensively characterize this new subset of supratentorial ZFTA-fused ependymomas and highlights the usefulness of ZFTA FISH analysis to confirm the existence of a rearrangement without RELA abnormality.
Given the very poor prognosis for children with recurrent medulloblastoma, we aimed to identify prognostic factors for survival post-relapse in children with childhood medulloblastoma. We ...retrospectively collected clinico-biological data at diagnosis and main clinical characteristics at relapse of children newly diagnosed with a medulloblastoma between 2007 and 2017 at Gustave Roussy and Necker Hospital. At a median follow-up of 6.6 years (range, 0.4-12.3 years), relapse occurred in 48 out 155 patients (31%). The median time from diagnosis to relapse was 14.3 months (range, 1.2-87.2 months). Relapse was local in 9, metastatic in 22 and combined (local and metastatic) in 17 patients. Second-line treatment consisted of chemotherapy in 31 cases, radiotherapy in 9, SHH-inhibitor in four and no treatment in the remaining four. The 1-year overall survival rate post-relapse was 44.8% (CI 95%, 31.5% to 59.0%). While molecular subgrouping at diagnosis was significantly associated with survival post-relapse, the use of radiotherapy at relapse and time to first relapse (>12 months) might also have a potential impact on post-relapse survival.
Some previous epidemiological studies have suggested that pesticide exposure during pregnancy may have a possible role in the development of childhood brain tumors (CBT). We pooled data from two ...French national population‐based, case–control studies to investigate the association between maternal residential use of pesticides during pregnancy and the risk of CBT. The mothers of 437 CBT cases and 3,102 controls aged under 15 years who resided in France at diagnosis/interview, frequency‐matched by age and gender, answered a structured telephone interview conducted by trained interviewers. Unconditional logistic regression was used to estimate pooled odds ratio (OR) and 95% confidence intervals (95% CI). CBT was significantly associated with the maternal home use of pesticides during pregnancy (OR 1.4, 95% CI 1.2–1.8) and, more specifically, with insecticide (OR 1.4, 1.2–1.8). We could not draw any conclusions about herbicides and/or fungicides because few women used them during pregnancy and most of these mothers also used insecticides. Although potential recall bias cannot be excluded, our findings of this pooled analysis support the hypothesis that residential maternal use of pesticides during pregnancy and particularly insecticides may increase the risk of CBT. Future investigations to verify these findings and to explore for CBT subtypes and dose–response are necessary to have a better understanding of the possible role of pesticides in etiology of CBT.
What's new?
The etiology of childhood brain tumor (CBT) remains unknown. Several perinatal factors are suspected to increase CBT risk, including maternal exposure to pesticides. In our study of malignant CBT, the authors found a positive association between maternal residential pesticide use (particularly of insecticides) during pregnancy, and malignant CBT. These results further implicate pesticides in the development of these cancers in children.
Abstract Pediatric spinal low-grade glioma (LGG) and glioneuronal tumours are rare, accounting for less 2.8–5.2% of pediatric LGG. New tumour types frequently found in spinal location such as diffuse ...leptomeningeal glioneuronal tumours (DLGNT) have been added to the World Health Organization (WHO) classification of tumours of the central nervous system since 2016, but their distinction from others gliomas and particularly from pilocytic astrocytoma (PA) are poorly defined. Most large studies on this subject were published before the era of the molecular diagnosis and did not address the differential diagnosis between PAs and DLGNTs in this peculiar location. Our study retrospectively examined a cohort of 28 children with LGGs and glioneuronal intramedullary tumours using detailed radiological, clinico-pathological and molecular analysis. 25% of spinal PAs were reclassified as DLGNTs. PA and DLGNT are nearly indistinguishable in histopathology or neuroradiology. 83% of spinal DLGNTs presented first without leptomeningeal contrast enhancement. Unsupervised t-distributed stochastic neighbor embedding (t-SNE) analysis of DNA methylation profiles showed that spinal PAs formed a unique methylation cluster distinct from reference midline and posterior fossa PAs, whereas spinal DLGNTs clustered with reference DLGNT cohort. FGFR1 alterations were found in 36% of spinal tumours and were restricted to PAs. Spinal PAs affected significantly younger patients (median age 2 years old) than DLGNTs (median age 8.2 years old). Progression-free survival was similar among the two groups. In this location, histopathology and radiology are of limited interest, but molecular data (methyloma, 1p and FGFR1 status) represent important tools differentiating these two mitogen-activated protein kinase (MAPK) altered tumour types, PA and DLGNT. Thus, these molecular alterations should systematically be explored in this type of tumour in a spinal location.
Objectives
Posterior fossa ependymoma group A (EPN_PFA) and group B (EPN_PFB) can be distinguished by their DNA methylation and give rise to different prognoses. We compared the MRI characteristics ...of EPN_PFA and EPN_PFB at presentation.
Methods
Preoperative imaging of 68 patients with posterior fossa ependymoma from two centers was reviewed by three independent readers, blinded for histomolecular grouping. Location, tumor extension, tumor volume, hydrocephalus, calcifications, tissue component, enhancement or diffusion signal, and histopathological data (cellular density, calcifications, necrosis, mitoses, vascularization, and microvascular proliferation) were compared between the groups. Categorical data were compared between groups using Fisher’s exact tests, and quantitative data using Mann–Whitney tests. We performed a Benjamini–Hochberg correction of the
p
values to account for multiple tests.
Results
Fifty-six patients were categorized as EPN_PFA and 12 as EPN_PFB, with median ages of 2 and 20 years, respectively (
p
= 0.0008). The median EPN_PFA tumoral volume was larger (57 vs 29 cm
3
,
p
= 0.003), with more pronounced hydrocephalus (
p
= 0.002). EPN_PFA showed an exclusive central position within the 4th ventricle in 61% of patients vs 92% for EPN_PFB (
p
= 0.01). Intratumor calcifications were found in 93% of EPN_PFA vs 40% of EPN_PFB (
p
= 0.001). Invasion of the posterior fossa foramina was mostly found for EPN_PFA, particularly the foramina of Luschka (
p
= 0.0008). EPN_PFA showed whole and homogeneous tumor enhancement in 5% vs 75% of EPN_PFB (
p
= 0.0008). All mainly cystic tumors were EPN_PFB (
p
= 0.002). The minimal and maximal relative ADC was slightly lower in EPN_PFA (
p
= 0.02 and
p
= 0.01, respectively).
Conclusion
Morphological characteristics from imaging differ between posterior fossa ependymoma subtypes and may help to distinguish them preoperatively.
Clinical relevance statement
This study provides a tool to differentiate between group A and group B ependymomas, which will ultimately allow the therapeutic strategy to be adapted in the early stages of patient management.
Key Points
•
Posterior fossa ependymoma subtypes often have different imaging characteristics
.
•
Posterior fossa ependymomas group A are commonly median or lateral tissular calcified masses, with incomplete enhancement, affecting young children and responsible for pronounced hydrocephalus and invasion of the posterior fossa foramina
.
•
Posterior fossa ependymomas group B are commonly median non-calcified masses of adolescents and adults, predominantly cystic, and minimally invasive, with total and homogeneous enhancement.
Differential diagnosis between
and
) is crucial as treatment and surveillance differ. We report the case of a girl with a clinical diagnosis of sporadic NF1 who developed a glioblastoma. ...Immunohistochemistry for MMR proteins identified PMS2 loss in tumour and normal cells and WES showed the tumour had an ultra-hypermutated phenotype, supporting the diagnosis of CMMRD. Germline analyses identified two variants (one pathogenic variant and one classified as variant(s) of unknown significance) in the
gene and subsequent functional assays on blood lymphocytes confirmed the diagnosis of CMMRD. The large plexiform neurofibroma of the thigh and the freckling were however more compatible with NF1. Indeed, a
PV (variant allele frequencies of 20%, 3% and 9% and in blood, skin and saliva samples, respectively) was identified confirming a mosaicism for NF1. Retrospective analysis of a French cohort identified NF1 mosaicism in blood DNA in 2 out of 22 patients with CMMRD, underlining the existence of early postzygotic PV of
gene in patients with CMMRD whose tumours have been frequently reported to exhibit somatic
mutations. It highlights the potential role of this pathway in the pathogenesis of CMMRD-associated gliomas and argues in favour of testing MEK inhibitors in this context.
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