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A novel histomolecular tumor of the central nervous system, the “intracranial mesenchymal tumor (IMT), FET-CREB fusion-positive” has recently been identified in the literature and will be added to the 2021 World Health Organization Classification of Tumors of the Central Nervous System. However, our latest study using DNA-methylation analyses has revealed that intracranial FET-CREB fused tumors do not represent a single molecular tumor entity. Among them, the main subgroup presented classical features of angiomatoid fibrous histiocytoma, having ultrastructural features of arachnoidal cells, for. Another tumor type with clear cell component and histopathological signs of aggressivity clustered in close vicinity with clear cell sarcoma of soft tissue. Herein, we report one case of IMT with a novel SMARCA2-CREM fusion which has until now never been described in soft tissue or the central nervous system. We compare its clinical, histopathological, immunophenotypic, genetic and epigenetic features with those previously described in IMT, FET-CREB fusion-positive. Interestingly, the current case did not cluster with IMT, FET-CREB fusion-positive but rather presented histopathological (clear cell morphology with signs of malignancy), clinical (with a dismal course with several recurrences, metastases and finally the patient’s death), genetic (fusion implicating the CREM gene), and epigenetic (DNA-methylation profiling) similarities with our previously reported clear cell sarcoma-like tumor of the central nervous system. Our results added data suggesting that different clinical and histomolecular tumor subtypes or grades seem to be included within the terminology “IMT, FET-CREB fusion-positive”, and that further series of cases are needed to better characterize them.

Central nervous system (CNS) tumors with the BCOR (BCL6 Corepressor) internal tandem duplication (ITD) were recently isolated by a DNA-methylation profile from a series of primitive neuroectodermal tumors [1]. They are mainly characterized by a recurrent BCOR ITD and express BCOR by immunohistochemistry (IHC) [2]. In rare cases, they present an EP300-BCOR fusion inducing the absence of expression of BCOR by IHC [3]. In soft tissue and kidney tumors with different types of BCOR alterations, SATB2 has been considered a diagnostic hallmark and BCOR IHC is not highly specific in some other contexts (soft tissue and uterine tumors) [4]. In a recent paper, SATB2 immunoexpression has been evidenced in one CNS-tumor with proven BCOR ITD [5]. The aim of our study was to evaluate the sensitivity and specificity of the BCOR and SATB2 immunostainings in a large cohort of pediatric CNS tumors.

NTRK gene fusions have been described in a wide variety of central nervous system (CNS) and soft tissue tumors, including the provisional tumor type "spindle cell neoplasm, NTRK-rearranged" (SCN-NTRK), added to the 2020 World Health Organization Classification of Soft Tissue Tumors. Because of histopathological and molecular overlaps with other soft tissue entities, controversy remains concerning the lineage and terminology of SCN-NTRK.This study included 16 mesenchymal tumors displaying kinase gene fusions (NTRK fusions and one MET fusion) initially diagnosed as infantile fibrosarcomas (IFS), SCN-NTRK, and adult-type fibrosarcomas from the soft tissue, viscera and CNS. We used immunohistochemistry, DNA methylation profiling, whole RNA-sequencing and ultrastructural analysis to characterize them. Unsupervised t-distributed stochastic neighbor embedding analysis showed that 11 cases (2 CNS tumors and 9 extra-CNS) formed a unique and new methylation cluster, while all tumors but one, initially diagnosed as IFS, clustered in a distinct methylation class. All the tumors except one formed a single cluster within the hierarchical clustering of whole RNA-sequencing data. Tumors from the novel methylation class co-expressed CD34 and S100, had variable histopathological grades and frequently displayed a CDKN2A deletion. Ultrastructural analyses evidenced a myofibroblastic differentiation.Our findings confirm that SCN-NTRK share similar features in adults and children and in all locations combine an infiltrative pattern, distinct epigenetic and transcriptomic profiles, and ultrastructural evidence of a myofibroblastic lineage. Further studies may support the use of new terminology to better describe their myofibroblastic nature.

Conventional MRI plays a key role in the management of patients with high grade glioma but multiparametric MRI and PET tracers could provide further information to better characterize the tumor metabolism and heterogeneity, by identifying the regions having a high risk of recurrence. In this study, we focused on the proliferation, hypervascularization and hypoxia, all factors considered as factors of poor prognosis. They were assessed by measuring the uptake of 18F-FLT, the rCBV maps and the uptake of 18F-FMISO, respectively. For each modality, the volumes and high uptake sub-volumes (hotspots) were semi-automatically segmented and compared to contrast enhancement (CE) volume on T1w-Gd images, commonly used in the management of patient with glioblastoma. Methods: DSC MRI (31 patients), 18F-FLT PET (20 patients) and/or 18F-FMISO PET (20 patients), for a total of 31 patients, were performed on pre-operative glioblastoma patients. Volumes and hotspots were segmented on SUV maps for 18F-FLT (using FLAB) and 18F-FMISO (using mean contralateral + 3.3 SD) PET and on rCBV maps (using mean contralateral + 1.96 SD) for DSC MRI and overlaid on T1w-Gd images. For each modality, the percentage of peripheral volumes and the peripheral hotspot outside the CE volume were calculated. Results: All tumors showed high proliferation, hypervascularization and hypoxic regions. Images also showed pronounced heterogeneity of both tracers uptake and rCBV maps, within each individual case. Overlaid volumes on T1w-Gd images showed that some proliferative, hypervascularization and hypoxic regions extended beyond the CE volume but with marked differences between patients. The ranges of peripheral volume outside the CE volume were [1.6% - 155.5 %], [1.5% - 89.5%] and [3.1% - 78.0%] for 18F-FLT, rCBV and 18F-FMISO respectively. All patients had hyperproliferative hotspots outside CE volume, whereas hotspots of hypervasculature and hypoxia were mainly detected within the enhancing region. Conclusion: The spatial analysis of the multiparametric maps with the segmented volumes and hotspots provides valuable information to optimize the management and treatment of the patients with glioblastoma.

To assess feasibility and safety of function-based resection under awake conditions for solitary brain metastasis patients. Retrospective, observational, single-institution case-control study (2014-2019). Inclusion criteria are adult patients, solitary brain metastasis, supratentorial location within eloquent areas, and function-based awake resection. Case matching (1:1) criteria between metastasis group and control group (high-grade gliomas) are sex, tumor location, tumor volume, preoperative Karnofsky Performance Status score, age, and educational level. Twenty patients were included. Intraoperatively, all patients were cooperative; no obstacles precluded the procedure from being performed. A positive functional mapping was achieved at both cortical and subcortical levels, allowing for a function-based resection in all patients. The case-matched analysis showed that intraoperative and postoperative events were similar, except for a shorter duration of the surgery (p

Embryonal tumor with multilayered rosettes, constitutes an aggressive and rare pediatric embryonal tumor of the central nervous system characterized by alterations of the C19MC locus at 19q13.12. Embryonal tumors with multilayered rosettes (ETMRs) span a broad histopathological spectrum with primitive neural features and abundant neuropil. Before the molecular definition of this entity, exceptional cases with heterologous differentiation have been evidenced in the literature. Herein, we report the first case of an ETMR featuring a sarcomatous component with proven C19MC alteration in both components by an in situ hybridization analysis. This data supports the hypothesis of a divergent differentiation of tumoral cells in this case.

BackgroundMeningioangiomatosis is a poorly studied, rare, benign, and epileptogenic brain lesion.ObjectiveTo demonstrate that surgical resection and a short-time interval to surgery improves epileptic seizure control, we performed a systematic review and meta-analysis of meningioangiomatosis cases.MethodsUsing PRISMA-IPD guidelines, the authors performed a systematic review and meta-analysis of histopathologically-proven meningioangiomatosis cases. Literature search in French and English languages (PubMed, Embase, the Cochrane Library, and the Science Citation Index) including all studies (January 1981 to June 2020) dealing with histopathologically-proven meningioangiomatosis, without age restriction. We assessed clinical, imaging, histomolecular, management, and outcome findings of patients with meningioangiomatosis.ResultsTwo-hundred and seven cases of meningioangiomatosis from 78 studies were included. Most meningioangiomatosis was sporadic, preferentially concerned male patients, younger than 20 years old, and allowed a functionally independent status. Epileptic seizure was the main symptom, with 81.4% of patients having uncontrolled seizures at the time of surgery. Meningioangiomatosis mainly had frontal (32.3%) or temporal (30.7%) locations. Imaging presentation was heterogeneous, and the diagnosis was often missed preoperatively. The histopathologic pattern was similar whatever the clinical presentation, and immunohistochemistry had limited diagnostic value. On molecular analysis, allelic loss at 22q12 was more frequent in samples of meningioangiomatosis-associated meningioma (37.5%) than in isolated meningioangiomatosis (23.1%). Time interval from diagnosis to surgery (p = 0.011) and lack of surgical resection of the meningioangiomatosis (p = 0.009) were independent predictors of postoperative seizure control.ConclusionsOwing to low scientific evidence, a multicentric prospective study should help refining the management of meningioangiomatosis.

Medulloblastomas (MBs) are the most frequent childhood malignant brain tumor. Four histopathologic variants and 4 genetic subgroups have been defined in the World Health Organization (WHO) 2016 Classification and constitute major risk stratification items directly affecting the patient management. Although MB subgroups have been molecularly defined, immunohistochemical surrogates are needed. The aim of our retrospective study was to evaluate the concordance between immunohistochemistry, using 4 antibodies (YAP1, GAB1, OTX2, and β-catenin), and DNA-methylation profiling in MB subgrouping. From a series of 155 MBs, the κ coefficient of concordance was almost perfect (0.90), with only 8/152 discrepant cases (no DNA-methylation analysis was available in 3 cases). Interestingly, the discrepancies mostly concerned (7/8 cases) MBs with divergent differentiations (myogenic, melanotic, and others) with all of those classified into group 3 (n=6) and group 4 (n=1) by DNA-methylation profiling. Another discrepant case concerned a WNT-activated MB (showing only 1% of immunopositive tumor cell nuclei), highlighting the difficulties of determining an appropriate β-catenin immunostaining cutoff. The high concordance of the routine immunohistochemical panel (YAP1, GAB1, OTX2, and β-catenin) and DNA-methylation profiling confirm its utility as a reliable predictive marker of molecular subtype in MBs. We analyzed the accuracy of 10 different IHC combinations for the determination of MB subtype and found that a combination of 2 antibodies (YAP1 and OTX2) allows for the successful characterization of 144 cases of 152 cases. Finally, our series extends the molecular data of the rare morphologic variant of MBs with melanotic/myogenic differentiations.

CERVOXY; International audience; IDH (isocitrate dehydrogenase) mutation, hypoxia, and neo-angiogenesis, three hallmarks of diffuse gliomas, modulate the expression of small non-coding RNAs (miRNA). In this paper, we tested whether pro-angiogenic and/or pro-hypoxic miRNAs could be used to monitor patients with glioma. The miRNAs were extracted from tumoral surgical specimens embedded in the paraffin of 97 patients with diffuse gliomas and, for 7 patients, from a blood sample too. The expression of 10 pro-angiogenic and/or pro-hypoxic miRNAs was assayed by qRT-PCR and normalized to the miRNA expression of non-tumoral brain tissues. We confirmed in vitro that IDH in hypoxia (1% O2, 24 h) alters pro-angiogenic and/or pro-hypoxic miRNA expression in HBT-14 (U-87 MG) cells. Then, we reported that the expression of these miRNAs is (i) strongly affected in patients with glioma compared to that in a non-tumoral brain; (ii) correlated with the histology/grade of glioma according to the 2016 WHO classification; and (iii) predicts the overall and/or progression-free survival of patients with glioma in univariate but not in a multivariate analysis after adjusting for sex, age at diagnosis, and WHO classification. Finally, the expression of miRNAs was found to be the same between the plasma and glial tumor of the same patient. This study highlights a panel of seven pro-angiogenic and/or pro-hypoxic miRNAs as a potential tool for monitoring patients with glioma.

The International Society for the Study of Vascular Anomalies (ISSVA) has defined four vascular lesions in the central nervous system (CNS): arteriovenous malformations, cavernous angiomas (also known as cerebral cavernous malformations), venous malformations, and telangiectasias. From a retrospective central radiological and histopathological review of 202 CNS vascular lesions, we identified three cases of unclassified vascular lesions. Interestingly, they shared the same radiological and histopathological features evoking the cavernous subtype of angioleiomyomas described in the soft tissue. We grouped them together with four additional similar cases from our clinicopathological network and performed combined molecular analyses. In addition, cases were compared with a cohort of 5 soft tissue angioleiomyomas. Three out 6 CNS lesions presented the same p.Gly41Cys GJA4 mutation recently reported in hepatic hemangiomas and cutaneous venous malformations and found in 4/5 soft tissue angioleiomyomas of our cohort with available data. Most DNA methylation profiles were not classifiable using the CNS brain tumor (version 12.5), and sarcoma (version 12.2) classifiers. However, using unsupervised t-SNE analysis and hierarchical clustering analysis, 5 of the 6 lesions grouped together and formed a distinct epigenetic group, separated from the clusters of soft tissue angioleiomyomas, other vascular tumors, inflammatory myofibroblastic tumors and meningiomas. Our extensive literature review identified several cases similar to these lesions, with a wide variety of denominations. Based on radiological and histomolecular findings, we suggest the new terminology of “dural angioleiomyomas” (DALM) to designate these lesions characterized by a distinct DNA methylation pattern and frequent GJA4 mutations.

A previously healthy 12-year-old boy began experiencing intracranial hypertension symptoms. Cerebral magnetic resonance imaging (MRI) showed a pineal mass. Cerebrospinal fluid and blood tested negative for β-human chorionic gonadotrophin, α-foetoprotein, carcinoembryonic antigen, and placental alkaline phosphatase.

Aims Meningeal chondromas constitute a small fraction of central nervous system tumors, with only 61 cases reported in the literature. Somatic mutations of IDH1/2 genes have been described in enchondromas, and, in soft-tissue chondromas, rearrangements of the HMGA2 gene have been reported. The aim of our study was to perform molecular analyses of 3 additional cases and to do a complete review of the literature to better characterize this rare entity. Materials and methods Here, we report 3 cases of primitive meningeal chondromas in children and young adults. Immunohistochemical analyses for HMGA2 and IDH1R132H, molecular analyses of IDH1/2 mutations, and FISH analysis of the HMGA2 locus were performed. Results Immunohistochemical analyses of all cases were negative for IDH1R132H and HMGA2 proteins. Molecular analyses failed to reveal IDH1/2 mutations, and FISH analyses did not evidence any HMGA2 rearrangements. Similarly to what is reported in the literature, the 3 meningeal chondromas in this study were benign tumors with no recurrence after complete resection with a follow-up of 85, 46, and 89 months. Conclusion Meningeal chondroma is rare. It affects predominantly young adults and has a good outcome. No molecular alterations have currently been described in this entity.

Background Despite the development of anterior skull base surgery, the anatomy of the nasal bone and anterior cribriform plate remains unclear. A recent study confirmed 2 distinct foramina in the anterior part of cribriform plate: the ethmoidal slit (ES) and the cribroethmoidal foramen (CF). The aim of this study was to specify their content, their anatomic relationship to the frontal sinus and skull base, and their potential value in skull base surgery. Methods Dissections were performed on 36 cadaver heads. Macro- and microscopic examinations were carried out. Microcomputed tomography scans contrasted with osmium were performed to identify vessels and nerves. Histology with neural, meningeal, or luteinizing hormone-releasing hormone immunomarkers was performed on the content of the foramina. Finally, endonasal surgical dissections were carried out. Results The ES and the CF were observed in all cases. They measured a mean of 4.2 and 1.6 mm, respectively. The ES contained dura mater, arachnoid tissues, lymphatics, and the terminal nerve. The CF contained the anterior ethmoidal nerve and artery. This foramen continued forward with the cribroethmoidal groove, which measured a mean of 2.5 mm. This groove was under the frontal sinus and in front of the skull base. We also described a "cribroethmoidal canal" and a "nasal bone foramen." Conclusion The clinical applications of this new anatomic description concern both cribriform plate and frontal sinus surgeries. Identifying the terminal nerve passing through the ES is a step forward in understanding pheromone recognition in humans.

Diagnostic updates, an increased precision of tumor sub-type classification and the development of new diagnostic biomarkers (immunohistochemistry (IHC), Fluorescence in situ hybridization (FISH) and other molecular pathology techniques), have a significant impact on pathologists' management of tissue samples. The objective of this work was to test and validate the FISH technique on detached IHC slides. An IHC technique was first performed on 30 tissue samples. After detachment of the lamella, a FISH technique was then performed according to the usual protocol with a centromeric probe. A validation cohort (n=10) with duplicate testing using a traditional FISH technique and an IHC slide with a detached lamella was then carried out. Finally, a cohort of 20 "old" cases (IHC carried out over 2years ago) was also tested. Different types of probes (specific locus, break apart) have been used. All the slides were interpreted by a technician and a pathologist. Evaluation criteria were: the general interpretability of the slide ; the percentage of labeled nuclei; intensity of the signal and the presence or absence of autofluorescence. FISH was interpretable in 100% of recently treated cases and 90% of "old" cases with a satisfactory intensity and a high percentage of labeled nuclei, without autofluorescence. The results of our study show that the reuse of IHC slides for performing FISH is a powerful means of economizing tissue samples, especially for small samples and in the absence of archived representative material.

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.

CERVOXY-LDM TEP; International audience; Introduction L'IRM conventionnelle joue un rôle clé dans la prise en charge des patients atteints de glioblastomes, cependant, l’IRM multiparamétrique et la TEP pourraient fournir des informations supplémentaires en identifiant les régions à haut risque de récidive. Dans cette étude, nous nous sommes intéressés à la prolifération, l'hypervascularisation et l'hypoxie, considérées comme des facteurs de mauvais pronostic. Elles ont été évaluées en mesurant respectivement la captation du 18F-FLT, le rCBV et la captation du 18F-FMISO et comparées à la prise de contraste (PC) sur la séquence T1w-Gd.Méthodes Une IRM de perfusion (31 patients), une TEP au 18F-FLT (20 patients) et/ou une TEP 18F-FMISO (20 patients, dont 9 ayant eu les deux radiotraceurs), ont été réalisées en préopératoire. Les volumes et les hotspots (5% max de chaque volume) ont été segmentés semi-automatiquement sur les SUV des TEP 18F-FLT et 18F-FMISO, ainsi que sur les rCBV. Le pourcentage des volumes et des hotspots en dehors de la PC, a été calculé.Résultats Toutes les tumeurs ont montré une prolifération, une hypervascularisation et des régions hypoxiques élevées. Les volumes superposés sur les images T1w-Gd ont montré que certaines régions prolifératives, d'hypervascularisation et d'hypoxie s'étendaient au-delà de la PC, mais avec des différences marquées entre les patients. Les plages de volume périphérique en dehors de la PC étaient [1,6% - 155,5%], [1,5% - 89,5%] et [3,1% - 78,0%] pour 18F-FLT, rCBV et 18F-FMISO respectivement. Tous les patients avaient des hotspots hyperprolifératifs en dehors de la PC, tandis que les hotspots d'hypervascularisation et d'hypoxie étaient principalement détectés dans la PC.Conclusion L'analyse spatiale des cartographies multimodales avec les volumes segmentés et les hotspots fournit des informations précieuses pour optimiser la prise en charge et le traitement des glioblastomes.

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.

Introduction: Although frequent in NSCLC, patients with brain metastases (BMs) are often excluded from immune checkpoint inhibitor (ICI) trials. We evaluated BM outcome in a less-selected NSCLC cohort.Methods: Data from consecutive patients with advanced ICI-treated NSCLC were collected. Active BMs were defined as new and/or growing lesions without any subsequent local treatment before the start of ICI treatment. Objective response rate (ORR), progression-free survival, and overall survival (OS) were evaluated. Multivariate analyses were performed by using a Cox proportional hazards model and logistic regression.Results: A total of 1025 patients were included; the median follow-up time from start of ICI treatment was 15.8 months. Of these patients, 255 (24.9%) had BMs (39.2% active, 14.3% symptomatic, and 27.4% being treated with steroids). Disease-specific Graded Prognostic Assessment (ds-GPA) score was known for 94.5% of patients (35.7% with a score of 0-1, 58.5% with a score of 1.5-2.5, and 5.8% with a score of 3). The ORRs with BM versus without BM were similar: 20.6% (with BM) versus 22.7% (without BM) (p = 0.484). The intracranial ORR (active BM with follow-up brain imaging [n = 73]) was 27.3%. The median progression-free survival times were 1.7 (95% confidence interval [CI]: 1.5-2.1) and 2.1 (95% CI: 1.9-2.5) months, respectively (p = 0.009). Of the patients with BMs, 12.7% had a dissociated cranial-extracranial response and two (0.8%) had brain pseudoprogression. Brain progression occurred more in active BM than in stable BM (54.2% versus 30% [p Conclusion: In multivariate analysis BMs are not associated with a poorer survival in patients with ICI-treated NSCLC. Stable patients with BM without baseline corticosteroids and a good ds-GPA classification have the best prognosis. (C) 2019 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.

Distinction of paraganglioma (PGL) from epithelial neuroendocrine tumors (NETs) can be difficult as they can mimic each other by nested architecture and expression of neuroendocrine markers. In this study we examined differential diagnostic markers in 262 PGLs (142 adrenal pheochromocytomas and 120 extra-adrenal PGLs), 9 duodenal gangliocytic PGLs and 3 cauda equina PGLs, and 286 NETs (81 GI, 78 pancreatic, 42 thoracic, 37 medullary thyroid carcinomas, and 48 high-grade NETs including 32 small cell carcinomas of lung). While keratin expression was nearly uniform in NETs with the exception of few tumors, extensive keratin expression was seen in only one PGL (90% of PGLs but only in 2% of NETs, usually focally. Tyrosine hydroxylase (TH) was expressed in >90% of adrenal, abdominal, and thoracic PGLs but only in 37% of head and neck PGLs reflecting their variable catecholamine synthesis. Focal or occasional extensive TH-expression was detected in 10% of NETs. CDX2 was a helpful discriminator seen in 28% of pancreatic and most GI NETs but in no PGLs. SOX10 detected sustentacular cells in 85% of PGLs and 7% of NETs, while GFAP detected sustentacular cells mainly in PGLs of neck and was absent in NETs. Duodenal gangliocytic PGLs (n = 9) and all cauda equina PGLs (n = 3) expressed keratins, lacked GATA3, showed no or minimal TH expression as some NETs, and contained SOX10 and S100 protein-positive spindle cells negative for GFAP. Ganglion-like epithelioid cells were keratin-positive and negative for TH and SOX10 differing from true ganglion cells. We conclude that duodenal gangliocytic and cauda equina PGLs have a NET-like immunoprofile and differ from ordinary PGLs. NETs can be distinguished from PGLs by their expression of keratins and general lack of GATA3, TH, and GFAP-positive sustentacular cells, and sometimes by expression of CDX2 or TTF1.

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., The 2016 WHO classification and the cIMPACT‐NOW update 3 improve diagnostic and prognostic accuracy of diffus gliomas in adults. We identified three subgroups of molecular glioblastomas with a particular prognosis using integrated MRI data analysis. Concomitant analysis of neoangiogenesis on histopathology and contrast enhancement on imaging improves diagnosis and prognosis accuracy.

Background Postoperative intracerebral haematomas represent a serious complication following stereotactic biopsy. We investigated the possible underlying causes - poor planning or poor execution - of postoperative intracerebral haematomas following stereotactic biopsies. Methods We performed a technical investigation using a retrospective single-centre consecutive series of robot-assisted stereotactic biopsies for a supratentorial diffuse glioma in adults. Each actual biopsy trajectory was reviewed to search for a conflict with an anatomical structure at risk. Results From 379 patients, 12 (3.2%) presented with a postoperative intracerebral haematoma ≥20 mm on postoperative CT-scan (3 requiring surgical evacuation); 11 of them had available intraoperative imaging (bi-planar stereoscopic teleangiography x-rays at each biopsy site). The actual biopsy trajectory was similar to the planned biopsy trajectory in these 11 cases. In 72.7% (8/11) of these cases, the actual biopsy trajectory was found to contact a structure at risk (blood vessel and cerebral sulcus) and identified as the intracerebral haematoma origin. Conclusions Robot-assisted stereotactic biopsy is an accurate procedure. Postoperative intracerebral haematomas mainly derive from human-related errors during trajectory planning.

Additional file 1: Table S1. Immunohistochemical findings of our cases of HGNET-BCOR with EP300:BCOR fusion.

Embryonal tumor with multilayered rosettes, constitutes an aggressive and rare pediatric embryonal tumor of the central nervous system characterized by alterations of the

Object Adult brainstem gliomas are a rare group of heterogeneous brain tumors. Classical clinical presentation includes progressive impairment of cranial nerves associated with long tract signs. The prognosis and response to treatment are poor; nevertheless, some patients do have a long survival. The objective of this study was to describe a series of patients with an isolated persistent hemifacial spasm and/or facial nerve palsy as the presenting symptom of a brainstem glioma. Methods Fourteen patients from 3 French hospitals (Paris, Caen, Lille) were included. Clinical and radiological features and overall survival were retrospectively analyzed. A review of the literature of similar cases was performed. Results Mean age at diagnosis was 35 years (range 19–57 years). Mean duration of facial nerve involvement before diagnosis was 17 months (range 1–48 months). Tumors were characterized on MRI by a lateralized location in the pons, a T1-weighted hyposignal, a T2-weighted hypersignal and no contrast enhancement after Gadolinium injection except for 2 cases. Biopsies were performed in 10 cases and showed 8 low-grade and 2 high-grade gliomas. All the patients were initially treated with radiotherapy and 6 patients with chemotherapy after progression. Eleven patients died from tumor progression. Median survival time was 90 months. Conclusions Adult brainstem gliomas revealed by a progressive isolated involvement of the facial nerve seem to have particular clinico-radiological features of slow progressive tumors and may be associated with long patient survival.

Background We quantified the spontaneous imaging growth rate of oligodendrogliomas. We assessed whether (i) it discriminates between World Health Organization (WHO) grade II and grade III oligodendrogliomas, and (ii) grade III oligodendrogliomas with neo-angiogenesis are associated with more fast growth rates (≥8 mm/y). Methods This work employed a retrospective bicentric cohort study (2010–2016) of adult patients harboring a newly diagnosed supratentorial oligodendroglioma, isocitrate dehydrogenase (IDH) mutant and 1p/19q codeleted (WHO 2016 classification), with a minimum of 2 available MRIs before any treatment (minimum 6-week interval) to measure the spontaneous tumor growth rate. Results We included 108 patients (age 44.7 ± 14.1 y, 60 males). The tumor growth rate was higher in grade III oligodendrogliomas with neo-angiogenesis (n = 37, median 10.4 mm/y, mean 10.0 ± 6.9) than in grade III oligodendrogliomas with increased mitosis count only (cutoff ≥6 mitoses, n = 18, median 3.9 mm/y, mean 4.5 ± 3.2; P = 0.004), and higher than in grade II oligodendrogliomas (n = 53, median 2.3 mm/y, mean 2.8 ± 2.2; P < 0.001). There was increased prevalence of fast tumor growth rates in grade III oligodendrogliomas with neo-angiogenesis (54.1%) compared with grade III oligodendrogliomas with increased mitosis count only (11.1%; P < 0.001), and in grade II oligodendrogliomas (0.0%; P < 0.001). The tumor growth rate trends did not differ between centers (P = 0.121). Neo-angiogenesis (P < 0.001) and mitosis count at ≥9 (P = 0.013) were independently associated with tumor growth rates ≥8 mm/year. A tumor growth rate ≥8 mm/year was the only predictor independently associated with shorter progression-free survival (P = 0.041). Conclusions The spontaneous tumor growth rate recapitulates oligodendroglioma aggressiveness, permits identification of grade III oligodendrogliomas preoperatively when ≥8 mm/year, and questions the grading by mitosis count.

Visual Abstract, Conventional MRI plays a key role in the management of patients with high-grade glioma, but multiparametric MRI and PET tracers could provide further information to better characterize tumor metabolism and heterogeneity by identifying regions having a high risk of recurrence. In this study, we focused on proliferation, hypervascularization, and hypoxia, all factors considered indicative of poor prognosis. They were assessed by measuring uptake of 18F-3'-deoxy-3'-18F-fluorothymidine (18F-FLT), relative cerebral blood volume (rCBV) maps, and uptake of 18F-fluoromisonidazole (18F-FMISO), respectively. For each modality, the volumes and high-uptake subvolumes (hot spots) were semiautomatically segmented and compared with the contrast enhancement (CE) volume on T1-weighted gadolinium-enhanced (T1w-Gd) images, commonly used in the management of patients with glioblastoma. Methods: Dynamic susceptibility contrast-enhanced MRI (31 patients), 18F-FLT PET (20 patients), or 18F-FMISO PET (20 patients), for a total of 31 patients, was performed on preoperative glioblastoma patients. Volumes and hot spots were segmented on SUV maps for 18F-FLT PET (using the fuzzy locally adaptive bayesian algorithm) and 18F-FMISO PET (using a mean contralateral image + 3.3 SDs) and on rCBV maps (using a mean contralateral image + 1.96 SDs) for dynamic susceptibility contrast-enhanced MRI and overlaid on T1w-Gd images. For each modality, the percentages of the peripheral volumes and the peripheral hot spots outside the CE volume were calculated. Results: All tumors showed highly proliferated, hypervascularized, and hypoxic regions. The images also showed pronounced heterogeneity of both tracers regarding their uptake and rCBV maps, within each individual patient. Overlaid volumes on T1w-Gd images showed that some proliferative, hypervascularized, and hypoxic regions extended beyond the CE volume but with marked differences between patients. The ranges of peripheral volume outside the CE volume were 1.6%–155.5%, 1.5%–89.5%, and 3.1%–78.0% for 18F-FLT, rCBV, and 18F-FMISO, respectively. All patients had hyperproliferative hot spots outside the CE volume, whereas hypervascularized and hypoxic hot spots were detected mainly within the enhancing region. Conclusion: Spatial analysis of multiparametric maps with segmented volumes and hot spots provides valuable information to optimize the management and treatment of patients with glioblastoma.

The department of neuropathology of Sainte-Anne Hospital uses zinc-formalin as the fixative agent for its samples. No publication referenced in Pubmed has proven the validity of this fixative agent. In the context of the accreditation of our standard staining (HPS for Hemalun-Phloxin-Saffron), we started a file for the validation of this method in which the fixative agent constitutes an « interfering » substance which can modify the quality of the technique. The aim of this study was to prove that the use of zinc-formalin as a fixative agent is as suitable as the fixation with 4 % buffered formalin.A cohort of samples fixed by zinc-formalin and by 4 % buffered formalin was performed on fresh samples, then cut and stained by HPS. The slides were interpreted by three pathologists (one of them was outside our centre) ``blind '' to the fixative agent and they evaluated four criteria (general quality of the staining, components of the extracellular matrix, cytoplasmic details, and nuclear details) and scored them (from 0 to 3) according to the Association française en assurance qualité (AFAQAP) recommendations.The cohort included 43 samples. The results of the analysis showed that for samples fixed by zinc-formalin, three of the four criteria obtained significantly a better score than the samples fixed by classical formalin.Our results show that the zinc-formalin fixative does not constitute an ``interfering '' agent for the quality of the HPS staining for neuropathological samples.

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Additional file 5: Table S1. Immunoprofile of HGNET-MN1 of our series

Solute transport through the brain is of major importance for the clearance of toxic molecules and metabolites, and it plays key roles in the pathophysiology of the central nervous system. This solute transport notably depends on the cerebrospinal fluid (CSF) flow, which circulates in the subarachnoid spaces, the ventricles and the perivascular spaces. We hypothesized that the CSF flow may be different in the perinatal period compared to the adult period. Using in vivo magnetic resonance imaging (MRI) and near-infrared fluorescence imaging (NIRF), we assessed the dynamic of the CSF flow in rodents at different ages. By injecting a contrast agent into the CSF, we first used MRI to demonstrate that CSF flow gradually increases with age, with the adult pattern observed at P90. This observation was confirmed by NIRF, which revealed an increased CSF flow in P90 rats when compared with P4 rats not only at the surface of the brain but also deep in the brain structures. Lastly, we evaluated the exit routes of the CSF from the brain. We demonstrated that indocyanine green injected directly into the striatum spread throughout the parenchyma in adult rats, whereas it stayed at the injection point in P4 rats. Moreover, the ability of CSF to exit through the nasal mucosa was increased in the adult rodents. Our results provide evidence that the perinatal brain has nonoptimal CSF flow and exit and, thus, may have impaired clean-up capacity. © 2018 Wiley Periodicals, Inc. Develop Neurobiol, 2018.

Background: Although awake resection using intraoperative cortico-subcortical functional brain mapping is the benchmark technique for diffuse gliomas within eloquent brain areas, it is still rarely proposed for IDH-wildtype glioblastomas. We have assessed the feasibility, safety, and efficacy of awake resection for IDH-wildtype glioblastomas. Methods: Observational single-institution cohort (2012–2018) of 453 adult patients harboring supratentorial IDH-wildtype glioblastomas who benefited from awake resection, from asleep resection, or from a biopsy. Case matching (1:1) criteria between the awake group and asleep group: gender, age, RTOG-RPA class, tumor side, location and volume and neurosurgeon experience. Results: In patients in the awake resection subgroup (n = 42), supratotal resections were more frequent (21.4% vs. 3.1%, p &lt, 0.0001) while partial resections were less frequent (21.4% vs. 40.1%, p &lt, 0.0001) compared to the asleep (n = 222) resection subgroup. In multivariable analyses, postoperative standard radiochemistry (aHR = 0.04, p &lt, 0.0001), supratotal resection (aHR = 0.27, p = 0.0021), total resection (aHR = 0.43, p &lt, 0.0001), KPS score &gt, 70 (HR = 0.66, p = 0.0013), MGMT promoter methylation (HR = 0.55, p = 0.0031), and awake surgery (HR = 0.54, p = 0.0156) were independent predictors of overall survival. After case matching, a longer overall survival was found for awake resection (HR = 0.47, p = 0.0103). Conclusions: Awake resection is safe, allows larger resections than asleep surgery, and positively impacts overall survival of IDH-wildtype glioblastoma in selected adult patients.

L’International Society for the Study of Vascular Anomalies (ISSVA) a defini quatre lesions vasculaires du systeme nerveux central (SNC) : malformations arterio-veineuses, cavernomes, malformations veineuses et telangiectasies. A partir de la base de donnees du centre hospitalier Sainte-Anne, nous avons effectue une relecture histopathologique des lesions vasculaires du SNC sur une periode de 21 ans. Parmi 223 cas relus histologiquement, nous avons identifie cinq lesions (concernant 2 enfants et 3 adultes) avec des aspects histopathologiques (cavites vasculaires contigues aux parois musculaires epaisses, Fig. 1 ) et radiologiques (lesion extra-durale spontanement dense, en hyposignal T1, hypersignal T2 Flair homogene, prenant le contraste de facon heterogene, sans remaniements hemorragiques et sans depots d’hemosiderine, Fig. 2 ) similaires, correspondant a des angioleiomyomes duraux (DALM). L’« angioleiomyome » est une tumeur classiquement developpee dans les tissus mous et dans la peau. La classification de l’OMS des tissus mous en distingue trois sous-types : solide, veineux et caverneux. Le sous-type caverneux est frequemment confondu avec un authentique cavernome. Afin de clarifier la nosologie de cette lesion, nous avons realise une revue de la litterature etendue des lesions vasculaires durales. Les criteres diagnostiques decrits ci-dessus nous ont permis de trouver 73 cas analogues de DALM. Cette revue exhaustive de la litterature nous a permis de definir les caracteristiques radiologiques et histopathologiques de cette entite meconnue des neuropathologistes et des neuroradiologues. Les DALM montrent des aspects differents des cavernomes intraparenchymateux et constituent un diagnostic differentiel des lesions durales et en particulier des meningiomes. Elles sont toutes d’excellent pronostic avec un seul cas de recidive locale dans la litterature. En conclusion, les DALM sont des tumeurs vasculaires intracrâniennes rares et benignes correspondant a une entite meconnue dont nous definissons les criteres diagnostiques cliniques, radiologiques et histopathologiques au travers de la presentation de 5 cas et d’une revue de la litterature.

A 63-year-old woman was referred to our PET/MRI platform to evaluate the possible relapse of a meningeal metastasis, complicating an invasive ductal carcinoma of the left breast. This metastasis was diagnosed on a left hemiparesis and treated by surgery and radiation therapy. One year later, the same symptoms led to another brain MRI examination that found a contrast-enhanced lesion in the operating site. We decided to perform a F-DOPA PET/MRI to document this lesion, which confirmed the diagnosis of a probable relapse and revealed a focal uptake on the bone flap.

Background Tumor location is a main prognostic parameter in patients with glioblastoma. Probabilistic MRI-based brain atlases specifying the probability of tumor location associated with important demographic, clinical, histomolecular, and management data are lacking for isocitrate dehydrogenase (IDH) wild-type glioblastomas. Purpose To correlate glioblastoma location with clinical phenotype, surgical management, and outcomes by using a probabilistic analysis in a three-dimensional (3D) MRI-based atlas. Materials and Methods This retrospective study included all adults surgically treated for newly diagnosed IDH wild-type supratentorial glioblastoma in a tertiary adult surgical neuro-oncology center (2006-2016). Semiautomated tumor segmentation and spatial normalization procedures to build a 3D MRI-based atlas were validated. The authors performed probabilistic analyses by using voxel-based lesion symptom mapping technology. The Liebermeister test was used for binary data, and the generalized linear model was used for continuous data. Results A total of 392 patients (mean age, 61 years ± 13; 233 men) were evaluated. The authors identified the preferential location of glioblastomas according to subventricular zone, age, sex, clinical presentation, revised Radiation Therapy Oncology Group-Recursive Partitioning Analysis class, Karnofsky performance status, O6-methylguanine DNA methyltransferase promoter methylation status, surgical management, and survival. The superficial location distant from the eloquent area was more likely associated with a preserved functional status at diagnosis (348 of 392 patients [89%], P < .05), a large surgical resection (173 of 392 patients [44%], P < .05), and prolonged overall survival (163 of 334 patients [49%], P < .05). In contrast, deep location and location within eloquent brain areas were more likely associated with an impaired functional status at diagnosis (44 of 392 patients [11%], P < .05), a neurologic deficit (282 of 392 patients [72%], P < .05), treatment with biopsy only (183 of 392 patients [47%], P < .05), and shortened overall survival (171 of 334 patients [51%], P < .05). Conclusion The authors identified the preferential location of isocitrate dehydrogenase wild-type glioblastomas according to parameters of interest and provided an image-based integration of multimodal information impacting survival results. This suggests the role of glioblastoma location as a surrogate and multimodal parameter integrating several known prognostic factors. © RSNA, 2019 Online supplemental material is available for this article. See also the editorial by Huang in this issue.

Ras association domain family (RASSF)/Hippo pathway alterations are poorly characterized in diffuse gliomas. We assayed promoter methylation of LATS1/2, MST1(STK4)/MST2(STK3), RASSF1, RASSF2, Nore1A/RASSF5, RASSF6, and RASSF10 genes in 133 diffuse gliomas. The RASSF/Hippo pathway was highly silenced in gliomas, particularly RASSF1A (79.4%) and LATS2 (35.9%). The most frequent combination of promoter hypermethylation of one RASSF gene and one Hippo pathway member's gene was RASSF1/LATS2-coupled hypermethylation [n = 44 (33.08%)]. Hypermethylated profiles were related to IDH mutation, yet not randomly in IDH-mutated gliomas, because LATS2 promoter hypermethylation was more frequent in oligodendroglioma than in astrocytoma. RASSF1 and LATS2 promoter hypermethylation predicted a longer overall survival (OS). Considering hypermethylation of these two promoters, Cox proportional hazard regression analysis categorized the patients into three prognostic groups: i) high risk of death (n = 24; both RASSF1 and LATS2 unmethylated promoters; median OS, 13 months); ii) intermediate risk of death (n = 65; RASSF1 or LATS2 hypermethylated promoter; median OS, 50.5 months; HR = 3.3; 95% CI, 1.6–6.4; P = 0.001); and iii) low risk of death (n = 44; both RASSF1 and LATS2 hypermethylated promoters; median OS, 119 months; HR = 75.1; 95% CI, 3.3–15.1; P = 0.001). We have thus highlighted a simple two-gene (RASSF1/LATS2) methylation signature as a tool to stratify different prognostic groups of patients with diffuse glioma, adding further prognostic information within the IDH-mutated group.