[Neuroepithelial tumor with PATZ1 fusion - case report and focus on an ill-defined entity]. / Tumeur neuroépithéliale avec fusion PATZ1 ­ à propos d'un cas et mise au point sur une entité mal définie.

The neuroepithelial tumor with PATZ1 fusion is a recently described tumor type, at the border between central nervous system and mesenchymal tumors. The histopathological diagnosis of this neoplasm, not recognized by the 2021 WHO classification, is challenging due to its varied and non-specific morphologic features. Most cases are densely cellular with monomorphous nuclei. Perivascular pseudo-rosettes of the ependymal type and astroblastic features are frequent. Blood vessels may be hyalinized. The tumor may display low- or high-grade features. OLIG2 and GFAP are variably expressed. Guided by DNA methylation profiling, a pathologist aware of this tumor type will search for a fusion involving PATZ1 and EWSR1 or MN1. The physiopathology of neuroepithelial tumor with PATZ1 fusion is not fully understood. The prognosis appears to align with that of intermediate-grade tumors but follow-up data are scarce. The therapeutic management is often similar to that of high-grade neoplasms. Nonetheless, PATZ1 fusion is a potential therapeutic avenue that may lead to personalized and less aggressive treatments.

Natural history of spinal cord metastasis from brain glioblastomas.

BACKGROUND AND OBJECTIVES: Spinal cord metastasis arising from an intracranial glioblastoma is a rare and late event during the natural course of the disease. These pathological entities remain poorly characterized. This study aimed to identify and investigate the timeline, clinical and imaging findings, and prognostic factors of spinal cord metastasis from a glioblastoma. METHODS: Consecutive histopathological cases of spinal cord metastasis from glioblastomas in adults entered in the French nationwide database between January 2004 and 2016 were screened. RESULTS: Overall, 14 adult patients with a brain glioblastoma (median age 55.2 years) and harboring a spinal cord metastasis were included. The median overall survival as 16.0 months (range, 9.8-22.2). The median spinal cord Metastasis Free Survival (time interval between the glioblastoma diagnosis and the spinal cord metastasis diagnosis) was 13.6 months (range, 0.0-27.9). The occurrence of a spinal cord metastasis diagnosis greatly impacted neurological status: 57.2% of patients were not ambulatory, which contributed to dramatically decreased Karnofsky Performance Status (KPS) scores (12/14, 85.7% with a KPS score ≤ 70). The median overall survival following spinal cord metastasis was 3.3 months (range, 1.3-5.3). Patients with a cerebral ventricle effraction during the initial brain surgery had a shorter spinal cord Metastasis Free Survival (6.6 vs 18.3 months, p = 0.023). Out of the 14 patients, eleven (78.6%) had a brain IDH-wildtype glioblastoma. CONCLUSIONS: Spinal cord metastasis from a brain IDH-wildtype glioblastoma has a poor prognosis. Spinal MRI can be proposed during the follow-up of glioblastoma patients especially those who have benefited from cerebral surgical resection with opening of the cerebral ventricles.

[Tyrosine kinase receptor gene fusion: A series of four cases of infantile-type hemispheric glioma]. / Gènes de fusion à activité tyrosine kinase : une série de quatre cas de gliome hémisphérique infantile.

INTRODUCTION: Infant-type hemispheric gliomas belong to pediatric-type diffuse high-grade gliomas according to the 2021 WHO classification of central nervous system tumors. They are characterized by tyrosine kinase gene rearrangements (NTRK1/2/3, ALK, ROS1, MET). The aim of the study was to describe the clinical, histopathologic, and molecular characteristics of such tumors, and to provide a review of the literature. PATIENTS AND METHODS: This retrospective series comprises four cases of infant-type hemispheric glioma diagnosed at Angers University Hospital between 2020 and 2022. The diagnosis was suspected based on morphology and immunohistochemistry and was confirmed by molecular biology techniques. RESULTS: The most common clinical sign was raised intracranial pressure. Imaging showed a large cerebral hemispheric tumor with contrast enhancement. Microscopic examination revealed diffuse astrocytoma with high-grade features, sometimes with neuronal or pseudo-ependymal differentiation. Identification of a gene fusion involving a tyrosine kinase gene allowed to make a definitive diagnosis of infant-type hemispheric glioma. DISCUSSION AND CONCLUSION: Infant-type hemispheric gliomas are rare and present as large cerebral hemispheric tumors in very young children. Searching for a tyrosine kinase gene fusion should be systematic when dealing with a high-grade glioma in an infant. Importantly, these gene fusions are therapeutic targets. The impact of targeted therapies on patient survival should be evaluated in future prospective studies.

Rosette-forming glioneuronal tumours are midline, FGFR1-mutated tumours.

AIM: Rosette-forming glioneuronal tumour (RGNT) is a rare central nervous system (CNS) World Health Organization (WHO) grade 1 brain neoplasm. According to the WHO 2021, essential diagnostic criteria are a 'biphasic histomorphology with neurocytic and a glial component, and uniform neurocytes forming rosettes and/or perivascular pseudorosettes associated with synaptophysin expression' and/or DNA methylation profile of RGNT whereas 'FGFR1 mutation with co-occurring PIK3CA and/or NF1 mutation' are desirable criteria. MATERIAL AND METHODS: We report a series of 46 cases fulfilling the essential pathological diagnostic criteria for RGNT. FGFR1 and PIK3CA hotspot mutations were searched for by multiplexed digital PCR in all cases, whereas DNA methylation profiling and/or PIK3R1 and NF1 alterations were analysed in a subset of cases. RESULTS: Three groups were observed. The first one included 21 intracranial midline tumours demonstrating FGFR1 mutation associated with PIK3CA or PIK3R1 (n = 19) or NF1 (n = 1) or PIK3CA and NF1 (n = 1) mutation. By DNA methylation profiling, eight cases were classified as RGNT (they demonstrated FGFR1 and PIK3CA or PIK3R1 mutations). Group 2 comprised 11 cases associated with one single FGFR1 mutation. Group 3 included six cases classified as low-grade glioma (LGG) other than RGNT (one-sixth showed FGFR1 mutation and one a FGFR1 and NF1 mutation) and eight cases without FGFR1 mutation. Groups 2 and 3 were enriched in lateral and spinal cases. CONCLUSIONS: We suggest adding FGFR1 mutation and intracranial midline location as essential diagnostic criteria. When DNA methylation profiling is not available, a RGNT diagnosis remains certain in cases demonstrating characteristic pathological features and FGFR1 mutation associated with either PIK3CA or PIK3R1 mutation.

[The 2021 WHO classification of tumours of the central nervous system]. / La classification de l'OMS 2021 des tumeurs du système nerveux central.

Rapid technical advances in molecular biology allowed for the identification of key genetic alterations in central nervous system (CNS) tumors. Our ever-expanding knowledge of brain tumor genetics and the development of new technologies, such as DNA-methylation profiling, required an update of the 2016 fourth edition of the WHO classification of CNS tumors. Updates were regularly published by the Consortium to Inform Molecular Practical Approaches to CNS Tumor Taxonomy-Not Official WHO (c-IMPACT-NOW) until the publication of the fifth edition of the WHO classification of CNS tumors in 2021. In that edition, new types and subtypes are introduced and criteria for histo-molecular diagnostic and grading are refined, especially for diffuse gliomas. The definition of a broad category "diffuse glioma, pediatric subtype" (low or high grade) is a major improvement of the classification. Moreover, the nomenclature was simplified and aligned with that of other blue books. The 2021 edition truly advances the role of molecular diagnostics in CNS tumor classification. Methyloma profiling may become a cornerstone of CNS tumor diagnostic. The new WHO classification will lead to better management of brain tumor patients.

LentiRILES, a miRNA-ON sensor system for monitoring the functionality of miRNA in cancer biology and therapy.

A major unresolved challenge in miRNA biology is the capacity to monitor the spatiotemporal activity of miRNAs expressed in animal disease models. We recently reported that the miRNA-ON monitoring system called RILES (RNAi-inducible expression Luciferase system) implanted in lentivirus expression system (LentiRILES) offers unique opportunity to decipher the kinetics of miRNA activity in vitro, in relation with their intracellular trafficking in glioblastoma cells. In this study, we describe in detail the method for the production of LentiRILES stable cell lines and employed it in several applications in the field of miRNA biology and therapy. We show that LentiRILES is a robust, highly specific and sensitive miRNA sensor system that can be used in vitro as a single-cell miRNA monitoring method, cell-based screening platform for miRNA therapeutics and as a tool to analyse the structure-function relationship of the miRNA duplex. Furthermore, we report the kinetics of miRNA activity upon the intracranial delivery of miRNA mimics in an orthotopic animal model of glioblastoma. This information is exploited to evaluate the tumour suppressive function of miRNA-200c as locoregional therapeutic modality to treat glioblastoma. Our data provide evidence that LentiRILES is a robust system, well suited to resolve the activity of endogenous and exogenously expressed miRNAs from basic research to gene and cell therapy.

Cerebral epidural empyema due to Bartonella henselae: a case report.

BACKGROUND: Cat scratch disease frequently involves a benign, self-limited disease. Neurological forms associated with Bartonella henselae are uncommon, consisting mostly in neuroretinitis, encephalitis and meningitis. Cerebral epidural empyema has never described. CASE PRESENTATION: An adult patient was hospitalized for isolated headaches. Magnetic Resonance Imaging (MRI) identified typical features of cerebral epidural empyema. The diagnosis of B. henselae was performed incidentally by 16S rDNA gene sequencing on the abscess fluid, and confirmed by specific qPCR. We report here the first case, to our knowledge, of cerebral epidural empyema associated with B. henselae. Further follow-up visits allowed identifying frequent cat scratches on the scalp as the presumptive source of infection. CONCLUSIONS: This case report alerts about such atypical clinical presentation, which requires an extensive clinical investigation. It also emphasizes on the usefulness of additional molecular diagnosis techniques in such CNS infection cases.

[Histomolecular diagnosis of glial and glioneuronal tumours]. / Le diagnostic histo-moléculaire des tumeurs gliales et glioneuronales.

While rare compared to extra-cranial neoplasms, glial and glioneuronal tumors are responsible of high morbidity and mortality. In 2016, the World Health Organization introduced histo-molecular ("integrated") diagnostics for central nervous system tumors based on morphology, immunohistochemistry and the presence of key genetic alterations. This combined phenotypic-genotypic classification allows for a more objective diagnostic of brain tumors. The implementation of such a classification in daily practice requires immunohistochemical surrogates to detect common genetic alterations and sometimes expensive and not widely available molecular biology techniques. The first step in brain tumor diagnostics is to inquire about the clinical picture and the imaging findings. When dealing with a glial tumor, the pathologist needs to assess its nature, infiltrative or circumscribed. If the tumor is infiltrative, IDH1/2 genes (prognostic marker) and chromosomes 1p/19q (diagnosis of oligodendroglioma) need to be assessed. If the tumor appears circumscribed, the pathologist should look for a neuronal component associated with the glial component (glioneuronal tumor). A limited immunohistochemistry panel will help distinguish between diffuse glioma (IDH1-R132H, ATRX, p53) and circumscribed glial/glioneuronal tumor (CD34, neuronal markers, BRAF-V600E), and some antibodies may reliably detect genetic alterations (IDH1-R132H, BRAF-V600E and H3-K27M mutations). Chromosomal imbalances (1p/19q codeletion in oligodendroglioma; chromosome 7 gain/chromosome 10 loss and EGFR amplification in glioblastoma) and gene rearrangements (BRAF fusion, FGFR1 fusion) will be identified by molecular biology techniques. The up-coming edition of the WHO classification of the central nervous system tumors will rely more heavily on molecular alterations to accurately diagnose and treat brain tumors.

Pineoblastoma segregates into molecular sub-groups with distinct clinico-pathologic features: a Rare Brain Tumor Consortium registry study.

Pineoblastomas (PBs) are rare, aggressive pediatric brain tumors of the pineal gland with modest overall survival despite intensive therapy. We sought to define the clinical and molecular spectra of PB to inform new treatment approaches for this orphan cancer. Tumor, blood, and clinical data from 91 patients with PB or supratentorial primitive neuroectodermal tumor (sPNETs/CNS-PNETs), and 2 pineal parenchymal tumors of intermediate differentiation (PPTIDs) were collected from 29 centres in the Rare Brain Tumor Consortium. We used global DNA methylation profiling to define a core group of PB from 72/93 cases, which were delineated into five molecular sub-groups. Copy number, whole exome and targeted sequencing, and miRNA expression analyses were used to evaluate the clinico-pathologic significance of each sub-group. Tumors designated as group 1 and 2 almost exclusively exhibited deleterious homozygous loss-of-function alterations in miRNA biogenesis genes (DICER1, DROSHA, and DGCR8) in 62 and 100% of group 1 and 2 tumors, respectively. Recurrent alterations of the oncogenic MYC-miR-17/92-RB1 pathway were observed in the RB and MYC sub-group, respectively, characterized by RB1 loss with gain of miR-17/92, and recurrent gain or amplification of MYC. PB sub-groups exhibited distinct clinical features: group 1-3 arose in older children (median ages 5.2-14.0 years) and had intermediate to excellent survival (5-year OS of 68.0-100%), while Group RB and MYC PB patients were much younger (median age 1.3-1.4 years) with dismal survival (5-year OS 37.5% and 28.6%, respectively). We identified age < 3 years at diagnosis, metastatic disease, omission of upfront radiation, and chr 16q loss as significant negative prognostic factors across all PBs. Our findings demonstrate that PB exhibits substantial molecular heterogeneity with sub-group-associated clinical phenotypes and survival. In addition to revealing novel biology and therapeutics, molecular sub-grouping of PB can be exploited to reduce treatment intensity for patients with favorable biology tumors.

[Hereditary predisposition to tumors of the central and peripheral nervous systems]. / Prédisposition héréditaire aux tumeurs des systèmes nerveux central et périphérique.

Some tumors of the central and peripheral nervous system may be associated with a cancer predisposition syndrome, either hereditary or occurring de novo. Such a syndrome is usually associated with multiple tumors occurring early in life. Patients with neurofibromatosis type 1 present with multiple neurofibromas, especially of the plexiform type (which may transform into malignant peripheral nerve sheath tumor), and pilocytic astrocytomas of the optic pathways. Neurofibromatosis type 2 patients present with multiple schwannomas (typically bilateral vestibular schwannomas), meningiomas, and ependymomas. Li-Fraumeni syndrome (germline TP53 mutation) is associated with choroid plexus tumors (carcinomas), medulloblastomas, and diffuse astrocytomas. Multiple hemangioblastomas are characteristic of von Hippel-Lindau syndrome while subependymal giant cell astrocytomas are pathognomonic of tuberous sclerosis complex. Dysplastic cerebellar gangliocytomas of adult patients occur in Cowden syndrome. Turcot syndrome overlaps with constitutional mismatch repair deficiency syndrome (CMMRD), which is associated with giant cell glioblastomas. Rhabdoid tumor predisposition syndrome (germline mutation of SMARCB1/INI1) is associated with atypical teratoid/rhabdoid tumors. Tumors arising in the setting of a cancer predisposition syndrome develop along specific genetic pathways. Some histopathological and immunohistochemical characteristics of these tumors may point toward such a syndrome. The diagnosis of a cancer predisposition syndrome is of tremendous importance to the patients and their families who require genetic counseling and long-term follow-up.

Molecular Profiling Reclassifies Adult Astroblastoma into Known and Clinically Distinct Tumor Entities with Frequent Mitogen-Activated Protein Kinase Pathway Alterations.

BACKGROUND: Astroblastoma (ABM) is a rare glial brain tumor. Recurrent meningioma 1 (MN1) alterations have been recently identified in most pediatric cases. Adolescent and adult cases, however, remain molecularly poorly defined. MATERIALS AND METHODS: We performed clinical and molecular characterization of a retrospective cohort of 14 adult and 1 adolescent ABM. RESULTS: Strikingly, we found that MN1 fusions are a rare event in this age group (1/15). Using methylation profiling and targeted sequencing, most cases were reclassified as either pleomorphic xanthoastrocytomas (PXA)-like or high-grade glioma (HGG)-like. PXA-like ABM show BRAF mutation (6/7 with V600E mutation and 1/7 with G466E mutation) and CD34 expression. Conversely, HGG-like ABM harbored specific alterations of diffuse midline glioma (2/5) or glioblastoma (GBM; 3/5). These latter patients showed an unfavorable clinical course with significantly shorter overall survival (p = .021). Mitogen-activated protein kinase pathway alterations (including FGFR fusion, BRAF and NF1 mutations) were present in 10 of 15 patients and overrepresented in the HGG-like group (3/5) compared with previously reported prevalence of these alterations in GBM and diffuse midline glioma. CONCLUSION: We suggest that gliomas with astroblastic features include a variety of molecularly sharply defined entities. Adult ABM harboring molecular features of PXA and HGG should be reclassified. Central nervous system high-grade neuroepithelial tumors with MN1 alterations and histology of ABM appear to be uncommon in adults. Astroblastic morphology in adults should thus prompt thorough molecular investigation aiming at a clear histomolecular diagnosis and identifying actionable drug targets, especially in the mitogen-activated protein kinase pathway. IMPLICATIONS FOR PRACTICE: Astroblastoma (ABM) remains a poorly defined and controversial entity. Although meningioma 1 alterations seem to define a large subset of pediatric cases, adult cases remain molecularly poorly defined. This comprehensive molecular characterization of 1 adolescent and 14 adult ABM revealed that adult ABM histology comprises several molecularly defined entities, which explains clinical diversity and identifies actionable targets. Namely, pleomorphic xanthoastrocytoma-like ABM cases show a favorable prognosis whereas high-grade glioma (glioblastoma and diffuse midline gliome)-like ABM show significantly worse clinical courses. These results call for in-depth molecular analysis of adult gliomas with astroblastic features for diagnostic and therapeutic purposes.