RESUMO
Pilocytic astrocytomas (PA) typically exhibit distinct clinical, radiological, histopathological, and genetic features. DNA-methylation profiling distinguishes PA according to their location (infratentorial, midline, hemispheric, or spinal). In the hemispheric location, distinguishing PA from glioneuronal tumors remains a common diagnostic challenge for neuropathologists. Furthermore, the current version of the DKFZ classifier seems to have difficulty separating them from gangliogliomas. In this study, after central radiological review, we identified a histopathologically defined set of PA (histPA, n = 11) and a cohort of DNA-methylation defined PA (mcPA, n = 11). Nine out of the 11 histPA matched the methylation class of hemispheric PA, whereas 2 cases were classified at the end of the study as dysembryoplastic neuroepithelial tumors. Similarly, the mcPA cohort contained tumors mainly classified as PA (7/11), but 4 cases were classified as glioneuronal. The analysis of the 16 tumors with an integrated diagnosis of PA revealed that they affect mainly children with a wide spectrum of radiological, histopathological (i.e. a predominantly diffuse growth pattern), and genetic characteristics (large range of mitogen-activated protein kinase alterations). Based on these results, we consider hemispheric PA to be different from their counterparts in other locations and to overlap with other glioneuronal tumors, reinforcing the necessity of interpreting all data to obtain an accurate diagnosis.
Assuntos
Ácido 2-Metil-4-clorofenoxiacético , Astrocitoma , Neoplasias Encefálicas , Neoplasias do Sistema Nervoso Central , Glioma , Neoplasias Neuroepiteliomatosas , Criança , Humanos , Astrocitoma/patologia , Glioma/genética , Neoplasias Neuroepiteliomatosas/genética , Neoplasias Neuroepiteliomatosas/patologia , Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/genética , DNARESUMO
Diffuse midline glioma with two components: classical glial and ependymal.
Assuntos
Neoplasias Encefálicas , Glioma , Humanos , Glioma/genética , Neoplasias Encefálicas/genética , Histonas , Neuroglia , Receptores ErbB/genéticaAssuntos
Neoplasias Encefálicas , Glioma , Oligodendroglioma , Humanos , Oligodendroglioma/diagnóstico , Oligodendroglioma/genética , Neoplasias Encefálicas/diagnóstico , Neoplasias Encefálicas/genética , Isocitrato Desidrogenase/genética , Cromossomos Humanos Par 1/genética , Mutação/genética , Cromossomos Humanos Par 19/genéticaRESUMO
Recent epigenomic analyses have revealed the existence of a new DNA methylation class (MC) of infant-type hemispheric glioma (IHG). Like desmoplastic infantile ganglioglioma/astrocytoma (DIG/DIA), these tumors mainly affect infants and are supratentorial. While DIG/DIA is characterized by BRAF or RAF1 alterations, IHG has been shown to have receptor tyrosine kinase (RTK) gene fusions (ALK, ROS1, NTRK1/2/3, and MET). However, in this rapidly evolving field, a more comprehensive analysis of infantile glial/glioneuronal tumors including clinical, radiological, histopathological, and molecular data is needed. Here, we retrospectively investigated data from 30 infantile glial/glioneuronal tumors, consecutively compiled from our center. They were analyzed by two experienced pediatric neuroradiologists in consensus, without former knowledge of the molecular data. We also performed a comprehensive clinical, and histopathological examination (including molecular evaluation by next-generation sequencing, RNA sequencing, and fluorescence in situ hybridization [FISH] analyses), as well as DNA methylation profiling for the samples having sufficient material available. The integrative histopathological, genetic, and epigenetic analyses, including t-distributed stochastic neighbor embedding (t-SNE) analyses segregated tumors into 10 DIG/DIA (33.3%), six IHG (20.0%), three gangliogliomas (10.0%), two pleomorphic xanthoastrocytomas (6.7%), two pilocytic astrocytomas (6.7%), two supratentorial ependymomas, ZFTA fusion-positive (6.7%), two supratentorial ependymomas, YAP1 fusion-positive (6.7%), two embryonal tumors with PLAGL2-family amplification (6.7%), and one diffuse low-grade glioma, MAPK-pathway altered. This study highlights the significant differential features, in terms of histopathology (leptomeningeal infiltration, intense desmoplasia and ganglion cells in DIG/DIA and necrosis, microvascular proliferation, and siderophages in IHG), and radiology between DIG/DIA and IHG. Moreover, these results are consistent with the literature data concerning the molecular dichotomy (BRAF/RAF1 alterations vs. RTK genes' fusions) between DIG/DIA and IHG. This study characterized histopathologically and radiologically two additional cases of the novel embryonal tumor characterized by PLAGL2 gene amplification.
Assuntos
Astrocitoma , Neoplasias Encefálicas , Neoplasias do Sistema Nervoso Central , Ependimoma , Ganglioglioma , Neoplasias Neuroepiteliomatosas , Humanos , Ganglioglioma/genética , Ganglioglioma/patologia , Neoplasias Encefálicas/patologia , Proteínas Proto-Oncogênicas B-raf/genética , Estudos Retrospectivos , Hibridização in Situ Fluorescente , Proteínas Tirosina Quinases , Proteínas Proto-Oncogênicas/genética , Astrocitoma/genética , Astrocitoma/patologia , Proteínas de Ligação a DNA/genética , Fatores de Transcrição/genética , Proteínas de Ligação a RNARESUMO
The Central Nervous System (CNS) tumor with BCOR internal tandem duplication (ITD) has recently been added as a novel embryonal histomolecular tumor type to the 2021 World Health Organization (WHO) Classification of CNS Tumors. In addition, other CNS tumors harboring a BCOR/BCORL1 fusion, which are defined by a distinct DNA-methylation profile, have been recently identified in the literature but clinical, radiological and histopathological data remain scarce. Herein, we present two adult cases of CNS tumors with EP300::BCOR fusion. These two cases presented radiological, histopathological, and immunohistochemical homologies with CNS tumors having BCOR ITD in children. To compare these tumors with different BCOR alterations, we performed a literature review with a meta-analysis. CNS tumors with EP300::BCOR fusion seem to be distinct from their BCOR ITD counterparts in terms of age, location, progression-free survival, tumor growth pattern, and immunopositivity for the BCOR protein. CNS tumors from the EP300::BCOR fusion methylation class in adults may be added to the future WHO classification.
Assuntos
Neoplasias do Sistema Nervoso Central , Criança , Adulto , Humanos , Prevalência , Neoplasias do Sistema Nervoso Central/genética , Biomarcadores Tumorais/análise , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas/metabolismo , Proteínas Repressoras/genética , Proteína p300 Associada a E1A/genéticaAssuntos
Glioma , Síndrome de Li-Fraumeni , Criança , Humanos , Síndrome de Li-Fraumeni/complicações , Síndrome de Li-Fraumeni/genética , Proteína Proto-Oncogênica N-Myc/genética , Proteína Supressora de Tumor p53/genética , Predisposição Genética para Doença , Glioma/complicações , Glioma/genética , Mutação em Linhagem GerminativaRESUMO
BACKGROUND: Gliomas with FGFR3::TACC3 fusion mainly occur in adults, display pathological features of glioblastomas (GB) and are usually classified as glioblastoma, IDH-wildtype. However, cases demonstrating pathological features of low-grade glioma (LGG) lead to difficulties in classification and clinical management. We report a series of 8 GB and 14 LGG with FGFR3:TACC3 fusion in order to better characterize them. METHODS: Centralized pathological examination, search for TERT promoter mutation and DNA-methylation profiling were performed in all cases. Search for prognostic factors was done by the Kaplan-Meir method. RESULTS: TERT promoter mutation was recorded in all GB and 6/14 LGG. Among the 7 cases with a methylation score > 0.9 in the classifier (v12.5), 2 were classified as glioblastoma, 4 as ganglioglioma (GG) and 1 as dysembryoplastic neuroepithelial tumor (DNET). t-SNE analysis showed that the 22 cases clustered into three groups: one included 12 cases close to glioblastoma, IDH-wildtype methylation class (MC), 5 cases each clustered with GG or DNET MC but none with PLNTY MC. Unsupervised clustering analysis revealed four groups, two of them being clearly distinct: 5 cases shared age (< 40), pathological features of LGG, lack of TERT promoter mutation, FGFR3(Exon 17)::TACC3(Exon 10) fusion type and LGG MC. In contrast, 4 cases shared age (> 40), pathological features of glioblastoma, and were TERT-mutated. Relevant factors associated with a better prognosis were age < 40 and lack of TERT promoter mutation. CONCLUSION: Among gliomas with FGFR3::TACC3 fusion, age, TERT promoter mutation, pathological features, DNA-methylation profiling and fusion subtype are of interest to determine patients' risk.
Assuntos
Neoplasias Encefálicas , Ganglioglioma , Glioblastoma , Glioma , Adulto , Humanos , Criança , Glioblastoma/genética , Mutação/genética , Glioma/genética , Glioma/patologia , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Prognóstico , Ganglioglioma/genética , Epigênese Genética , DNA , Isocitrato Desidrogenase/genética , Receptor Tipo 3 de Fator de Crescimento de Fibroblastos/genética , Proteínas Associadas aos Microtúbulos/genéticaRESUMO
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.
Assuntos
Astrocitoma , Neoplasias Encefálicas , Neoplasias do Sistema Nervoso Central , Glioma , Humanos , Criança , Pré-Escolar , Estudos Retrospectivos , Astrocitoma/patologia , Neoplasias do Sistema Nervoso Central/genética , Glioma/genética , Epigênese Genética , Neoplasias Encefálicas/genéticaRESUMO
Posterior fossa group A ependymomas (EPN_PFA) are characterized by a loss of H3 K27 trimethylation due to either EZHIP overexpression or H3 p.K27M mutation, similar to H3 K27-altered diffuse midline gliomas (DMG), but in reverse proportions. Very little data is available in the literature concerning H3 K27M-mutant EPN_PFA. Here, we retrospectively studied a series of nine pediatric tumors initially diagnosed as H3 K27M-mutant EPN_PFA to compare them to EZHIP-overexpressing EPN_PFA in terms of radiology, follow-up, histopathology, and molecular biology (including DNA-methylation profiling). Seven tumors clustered within EPN_PFA by DNA-methylation analysis and t-distributed stochastic neighbor embedding. Among the two remaining cases, one was reclassified as a DMG and the last was unclassified. H3 K27M-mutant EPN_PFA cases were significantly older than their counterparts with an EZHIP overexpression. Radiological and histopathological central review of our seven H3 K27M-mutant EPN_PFA cases found them to be similar to their counterparts with an EZHIP overexpression. Sequencing analyses revealed HIST1H3B (n = 2), HIST1H3C (n = 2), H3F3A (n = 1), and HIST1H3D (n = 1) K27M mutations (no sequencing analysis available for the last case which was immunopositive for H3K27M). Consequently, HIST1H3C/D mutations are more frequently observed in EPN_PFA than in classic pontine DMG, H3K27-mutant. Overall survival and event-free survival of EZHIP-overexpressing and H3 K27M-mutant EPN_PFA were similar. After surgery and radiation therapy, 5/7 patients were alive at the end of the follow-up. In summary, the diagnosis of EPN_PFA must include tumor location, growth pattern, Olig2 expression, and DNA-methylation profiling before it can be differentiated from DMG, H3 K27-altered.
Assuntos
Neoplasias Encefálicas , Ependimoma , Glioma , Radiologia , Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Criança , DNA , Ependimoma/diagnóstico por imagem , Ependimoma/genética , Ependimoma/patologia , Glioma/genética , Histonas/genética , Humanos , Estudos RetrospectivosRESUMO
AIMS: Dysembryoplastic neuroepithelial tumour (DNT) is a glioneuronal tumour that is challenging to diagnose, with a wide spectrum of histological features. Three histopathological patterns have been described: specific DNTs (both the simple form and the complex form) comprising the specific glioneuronal element, and also the non-specific/diffuse form which lacks it, and has unclear phenotype-genotype correlations with numerous differential diagnoses. METHODS: We used targeted methods (immunohistochemistry, fluorescence in situ hybridisation and targeted sequencing) and large-scale genomic methodologies including DNA methylation profiling to perform an integrative analysis to better characterise a large retrospective cohort of 82 DNTs, enriched for tumours that showed progression on imaging. RESULTS: We confirmed that specific DNTs are characterised by a single driver event with a high frequency of FGFR1 variants. However, a subset of DNA methylation-confirmed DNTs harbour alternative genomic alterations to FGFR1 duplication/mutation. We also demonstrated that a subset of DNTs sharing the same FGFR1 alterations can show in situ progression. In contrast to the specific forms, "non-specific/diffuse DNTs" corresponded to a heterogeneous molecular group encompassing diverse, newly-described, molecularly distinct entities. CONCLUSIONS: Specific DNT is a homogeneous group of tumours sharing characteristics of paediatric low-grade gliomas: a quiet genome with a recurrent genomic alteration in the RAS-MAPK signalling pathway, a distinct DNA methylation profile and a good prognosis but showing progression in some cases. The "non-specific/diffuse DNTs" subgroup encompasses various recently described histomolecular entities, such as PLNTY and diffuse astrocytoma, MYB or MYBL1 altered.
Assuntos
Neoplasias Encefálicas , Glioma , Neoplasias Neuroepiteliomatosas , Neoplasias Encefálicas/patologia , Genômica , Humanos , Neoplasias Neuroepiteliomatosas/genética , Neoplasias Neuroepiteliomatosas/patologia , Estudos RetrospectivosRESUMO
Pediatric bithalamic gliomas encompass several histomolecular tumoral types from benign to malignant and underlines the central role of a comprehensive neuropathological review, including immunohistochemistry, genetic, and epigenetic analyses, to achieve an accurate diagnosis.
Assuntos
Neoplasias Encefálicas , Glioma , Neoplasias Encefálicas/patologia , Criança , Epigênese Genética , Epigenômica , Glioma/genética , Glioma/patologia , HumanosRESUMO
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.
Assuntos
Ependimoma/genética , Proteínas/genética , Neoplasias Supratentoriais/genética , Adolescente , Adulto , Criança , Pré-Escolar , Metilação de DNA/genética , Ependimoma/classificação , Ependimoma/metabolismo , Ependimoma/patologia , Feminino , Fusão Gênica/genética , Genótipo , Proteína Glial Fibrilar Ácida/metabolismo , Humanos , Lactente , Masculino , NF-kappa B/metabolismo , Molécula L1 de Adesão de Célula Nervosa/metabolismo , Coativador 1 de Receptor Nuclear/genética , Coativador 2 de Receptor Nuclear/genética , Fenótipo , Neoplasias Supratentoriais/classificação , Neoplasias Supratentoriais/metabolismo , Neoplasias Supratentoriais/patologia , Transativadores/genética , Fator de Transcrição RelA/genética , Proteínas Supressoras de Tumor/genética , Adulto JovemRESUMO
We report the case of a 32-year-old man, who was admitted for a recurrent pneumopathy. The thoracic computed tomography revealed a small well-circumscribed lesion of the lower right lobe of the lung. Microscopic examination from the biopsy material of the endoscopy concluded a mucoepidermoid carcinoma. A lobectomy was realized. Microscopic examination revealed the presence of a well-delineated lesion composed of glands and cysts containing mucous and limited by mucous and cylindric and ciliated cells without atypia. The proliferation index was very low. A diagnosis of mucous gland adenoma was made. It is an exceptional tumor and is very difficult to diagnose on biopsy material but should be known by pathologists. It is associated with a good prognosis. The aims of our observation are to present the macroscopic and microscopic features of this tumor and data from recent literature review to better diagnose it. This is also the second observation with molecular details for this entity.
Assuntos
Adenoma , Neoplasias Brônquicas , Carcinoma Mucoepidermoide , Adenoma/diagnóstico , Adulto , Biópsia , Neoplasias Brônquicas/diagnóstico , Neoplasias Brônquicas/cirurgia , Carcinoma Mucoepidermoide/cirurgia , Humanos , Masculino , Tomografia Computadorizada por Raios XRESUMO
Assess the contribution of preoperative MRI data in improving grading of adult astrocytomas reclassified according to the WHO 2016 and cIMPACT-NOW update 3. Retrospective unicentric cohort study of 679 adult patients treated for newly diagnosed diffuse astrocytic and oligodendroglial tumors (January 2006-December 2016). We first systematically compared radiological (contrast enhancement present [CE+] vs. absent [CE-]) and histopathological findings (microvascular proliferation present [MPV+] vs. absent [MPV-]) to validate whether this comparing step of neoangiogenesis represents an efficient method to appreciate the representativity of the tumoral sampling. We focused on 629 cases of astrocytomas for radio-histological integrated analyses. In 598 cases (95.1%), neoangiogenesis evaluated by MRI or histology (CE+/MPV+ or CE-/MPV-) was identical. For the CE+/MPV- and CE-/MPV+ groups (23 cases), the radio-histological face-to-face evaluation allowed us to assess that for 13 cases (56.5%) the reason for this discrepancy was an undersampled tumor. We analyzed the group of CE+/MPV- (n = 8) and CE-/MPV+ (n = 2) in verified image-guided tumoral samples. Finally, we identified three new prognostic subgroups for molecular glioblastomas: (1) "non-representative sampling" (n = 9), (2) "Non neoangiogenic glioblastoma at the time of diagnosis, without contrast enhancement and microvascular proliferation" (n = 8), and (3) "contrast enhancing glioblastoma but without microvascular proliferation in a representative sample" (n = 4). Neoangiogenesis processes should be assessed to improve the prognosis accuracy of the current integrated diagnosis. We suggest adding imaging analyses during the neuropathological analysis of astrocytomas in adults.