Central nervous system (CNS)-type tumors may occur in the ovary, often associated with a mature teratomatous component. Because of their rarity, little is known about the tumor types historically designated within the primitive neuroectodermal tumors (PNET) terminology and whether they share histopathological and molecular features akin to those of their CNS counterparts. Herein, we retrospectively investigated data from 13 ovarian tumors, initially diagnosed as either “PNETs” or CNS-type neoplasms. For each tumor we performed comprehensive histopathologic, genetic and epigenetic analyses and retrieved clinical data when available. Integrated diagnoses were established after a central review of histopathological and molecular data, the following entities were identified: four embryonal tumors with multilayered rosettes (non C19MC-altered), three medulloblastomas, SHH-activated, three ependymomas not elsewhere classified, one Ewing sarcoma, one sarcoma, DICER1-mutant, and one peripheral neuroblastoma. Interestingly, none of the ETMRs harbored a C19MC amplification or DICER1 mutation. The three medulloblastomas, SHH-activated were histopathologically and molecularly similar to their CNS counterparts. Ependymomas did not show any classifying molecular alteration and presented a distinct epigenetic profile when compared with CNS ependymomas. These results indicate that ovarian “PNETs” comprise a heterogeneous spectrum of CNS and extra-CNS embryonal or non-embryonal tumor types, and that brain tumor methylation classifiers may be used to classify these tumors. Moreover, these components are characterized by distinct molecular alterations from primary CNS tumors, without C19MC alterations for ETMRs, with an overrepresented SHH-subgroup for medulloblastomas, and with an epigenetic profile distinct from CNS counterparts in ovarian ependymomas. These data need to be confirmed before they can be incorporated into future patient personalized treatment.

Two new cases of low-grade diffusely infiltrative tumour (LGDIT), SMARCB1 mutant, are described in an 18-year-old and a 50-year-old male, both with supratentorial lesions, characteristic rhabdoid histology on a myxoid-collagenous background, and complete INI1 loss. Both tumours showed homozygous SMARCB1 deletion and clustered with previously reported LGDIT on t-SNE analysis, in proximity to ATRT-MYC. These observations reinforce the distinct clinicopathological profile of LGDIT and support its consideration as a provisional CNS tumour type.

BackgroundAngioleiomyomas are ubiquitous perivascular tumors, and harbor recurrent GJA4 mutations identified in the orbitary and dural locations. Herein, we reported for the first time a sinonasal angioleiomyoma presenting this typical genetic alteration.Case PresentationA 76-year-old man with an unremarkable medical history presented with a chronic nasal obstruction for more than 6 months. Computerized tomodensitometry and magnetic resonance imaging showed a lesion measuring 4 cm, arising from the right middle turbinate with partial enhancement following gadolinium administration. Total endoscopic resection was performed. Histopathologically, the lesion consisted of aggregates of abnormally enlarged vascular cavities, separated by thick uneven fibrous septa and lined by a single layer of endothelial cells stained by the CD34 antibody. The endothelial cells did not present atypia, mitotic activity, or plump epithelioid cytology. There were some myxoid changes and adipocytic metaplasia. Immunostainings for smooth muscular actin and h-caldesmon showed muscular layers of varying thickness surrounding the vascular cavities. Genetic analyses revealed the presence of the variant p.Gly41Cys in the GJA4 gene. A diagnosis of angioleiomyoma (cavernous subtype) was made. One month after the surgery, the patient was well, without any residual symptoms.ConclusionsThe current case represents, to our knowledge, the first angioleiomyoma with a GJA4 mutation in the sinonasal tract. Main vascular and perivascular tumors of the sinonasal tract are represented by the hemangioma, the glomangiopericytoma, and the angiosarcoma, to which can be added the angiofibroma, belonging to the fibroblastic neoplasms. Consequently, in this location, the angioleiomyoma is probably misdiagnosed. Further reports and studies are needed to determine the frequency of this mutation in the sinonasal tract and its correlation with histopathological subtype.

High-grade glioma, IDH- and H3-wildtype in young adults is a rare and poorly known entity. We compared newly diagnosed cases in young adults (18–39 years) to those in adult patients (> 39 years). We performed an observational, retrospective, single-centre cohort study at a tertiary neurosurgical oncology centre between January 2006 and December 2023. We included 1.139 adult patients with a newly diagnosed high-grade glioma, IDH- and H3-wildtype. Young adults: (1) represent a small proportion of patients with high-grade glioma (n = 33, 2.9

Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease, projected to affect 55% globally by 2040. Up to one-third of NAFLD patients develop non-alcoholic steatohepatitis (NASH), with 40% progressing to fibrosis. However, there are currently few reliable tools to predict disease progression. Impaired mitochondrial dynamics, characterized by dysregulated fission, fusion, and mitophagy, have emerged as key events in NAFLD pathophysiology, contributing to hepatocyte death and inflammation. This study explored the transition from steatosis to NASH through transcriptomic analyses, including data from patients with steatosis and those with NASH at different fibrosis stages. By identifying a transcriptomic signature associated with disease progression, the study revealed increased expression of genes involved in mitochondrial dynamics in NASH compared to steatosis and during NASH-related fibrosis. Histological analyses highlighted the central role of Dynamin-related protein 1 (Drp1), a dynamin GTPase essential for mitochondrial fission and mitophagy. In human liver biopsies, Drp1 expression progressively increased from NAFLD to NASH and NASH-related fibrosis and cirrhosis, predominantly in Kupffer cells. These finding suggest Drp1 is a potential driver of the transition to more severe liver damage, making it a promising biomarker for NASH development and progression and a potential therapeutic target in metabolic disorders.

ATRX immunostaining constitutes a routinely used biomarker for the practice of neuropathology. The loss of ATRX expression correlating with ATRX gene alterations is implicated in a wide variety of pediatric and adult gliomas, and has been indexed as a desirable or essential diagnostic criterion for four tumor types featured in the latest world health organization classification of central nervous system Tumors. In adult-type diffuse glioma, the loss of ATRX expression is a hallmark of astrocytoma, IDH-mutant. Recently, novel tumor types and alterations have been referenced in the literature. These include the high-grade astrocytoma with piloid features (HGAP), for which no consistent clinicopathological features have been defined, and the presence of other alterations in the Krebs cycle genes (variants of the Fumarate hydratase -FH- gene) found in gliomas resembling astrocytomas, IDH-mutant. Because of this rapidly evolving classification and histomolecular landscape, we retrospectively analyzed adult gliomas diagnosed over a four consecutive year period to identify supratentorial gliomas, lacking H3 alterations or IDH mutations and harboring a loss of ATRX expression, in order to update their diagnoses in terms of histopathology, genetics and epigenetics. Four specimens (from 620 adult gliomas, 0.7%) were reclassified at the end of the molecular workup, as: 1/ one HGAP, 2/ one malignant transformation with a primitive neuronal component of an astrocytoma, IDH-mutant which lost the IDH2 mutation at recurrence, 3/ a glioma, FH-mutant for which the histopathological and epigenetic features were similar to an astrocytoma, IDH-mutant, and 4/ a glioblastoma, IDH-wildtype. To conclude, these exceptional cases extend the spectrum of ATRX loss in gliomas, beyond the astrocytoma, IDH-mutant and the diffuse hemispheric glioma, H3 G34-mutant.

Purpose.Glioblastomas, IDH- and H3-wildtype in young adults is a rare and poorly known entity. We compared newly diagnosed glioblastomas, IDH- and H3-wildtype in young adults (18–39 years) to those in adult patients (> 39 years).Methods.We performed an observational, retrospective, single-centre cohort study at a tertiary neurosurgical oncology centre between January 2006 and December 2022.Results.We included 1.139 adult patients with a newly diagnosed glioblastoma, IDH- and H3-wildtype. Young adults: 1) represent a small proportion of patients with glioblastoma, IDH- and H3-wildtype (n = 33, 2.9%); 2) have a high rate of unclassified cases according to WHO criteria and epigenetics (n = 10, 30.3%); 3) have a longer progression-free survival (p = 0.003) and overall survival (p = 0.001) and; 4) do not have higher surgically-related adverse event rates (p = 0.198). Concerning young adults, surgical resection was associated with improved progression-free and overall survival (p < 0.001 and p < 0.001, respectively). The DNA-methylation class significantly impacts the overall survival (p = 0.028), however, the MGMT methylation status is not significantly associated with either progression-free or overall survival (p = 0.320 and p = 0.639, respectively).Conclusion.Glioblastomas, IDH- and H3-wildtype is a rare histo-molecular subtype in young adults with a better prognosis than older adults. In young adults, DNA-methylation subtypes are different from their adult counterpart and had a significant impact on survival unlike MGMT status. Given the rarity of glioblastoma IDH- and H3-wildtype in young adults, a dedicated management in specialized neurosurgical oncology centres is preferred. Further histo-molecular and epigenetic analyses are required to understand the differences in prognosis compared to adult patients.

The presence of a CDKN2A homozygous deletion (HD) plays an important role in the diagnostic approach for neuropathologists and the clinical prognostic stratification of several CNS tumors. CDKN2A is located on chromosome 9p21 next to CDKN2B and MTAP and encodes for the protein p16. Various molecular diagnostics are routinely used for assessing the deletion. In this context, we studied a cohort of 40 adult-type gliomas to analyze the concordance of three different molecular techniques, ie, FISH, NGS, and SNP array, for determining CDKN2A status and compared the results to p16 and MTAP immunostainings. The results showed that SNP array is the most reliable technique for the detection of CDKN2A HD and that p16 IHC constitutes a surrogate for the detection of biallelic inactivation of CDKN2A. p16 IHC was more accurate than MTAP IHC in detecting CDKN2A HD because a subset of CDKN2A HD gliomas did not present a deletion of the MTAP gene. IHC also allowed the detection of tumors with a hemizygous deletion of CDKN2A harboring a concomitant second molecular event on the remaining allele, ie, hypermethylation of CDKN2A promoter. We conclude that p16 immunostaining is an accurate biomarker for detecting CDKN2A HD.

INTRODUCTION:The 2021 World Health Organisation (WHO) classification of tumours of the central nervous system introduced molecular biomarkers (homozygous deletion of CDKN2A/B and TERT promoter mutation) in the grading of meningiomas. Since, the cIMPACT-NOW consortium has proposed a new prognostic algorithm (published in the update 8), integrating epigenetic and genetic data. The aim of the study was to report on the experience of the neuropathology department of Sainte-Anne Hospital in integrating this algorithm into the gradingof meningiomas. MATERIALS AND METHODS:This study included meningiomas diagnosed between 01/09/2024 and 30/04/2025, for which molecular analyses were mandatory according to the recommendations of the cIMPACT-NOW update 8. Next-generation sequencing (pTERT and CDKN2A/B status) and DNA-methylation analyses (methylation class and chromosomal copy number variations) were performed for each case. RESULTS:Seventy-one meningiomas were included. In 62% of cases, the grading was revised after integration of genetic and epigenetic data. In 35 cases, the final grade was lower than the initial grade, and in nine cases, the final grade was higher. DISCUSSION AND CONCLUSIONS:Invasion of the cerebral parenchyma alone no longer constitutes a criterion for grade 2. In our study, 47% of meningiomas graded as grade 2 solely on the basis of their invasive nature were downgraded to grade 1. The presence of a pTERT mutation and/or homozygous deletion of CDKN2A/B allowed two meningiomas initially graded as WHO grade 2 to be reclassified as grade 3. The presence of a combined loss of chromosomes 1p and 22q, associated with a grade 2 according to cIMPACT-NOW recommendations, led to the reclassification of four meningiomas initially considered to be grade 1. The cIMPACT-NOW update 8 has revolutionised pathologists' practice in grading meningiomas, with the need to integrate genetic and epigenetic data to morphological results.

According to the current World Health Organization classification of central nervous system tumors, the angiocentric glioma (AG) assigned a grade 1, characterized by recurrent MYB fusions. However, it also mentions that increased proliferative activity and other anaplastic features have been reported, but the clinical significance of such findings is unclear as an increased proliferative activity alone does not necessarily alter the benign behavior of AGs. Most cases with “anaplasia” were mainly described before the molecular era. Herein, we report the case of a 3-year-old female with epilepsy symptomatic of a left temporo-parietal tumor. Histopathologically, the initial tumor displayed atypical AG morphology and a proliferation index of 1

Introduction La classification de l’Organisation mondiale de la santé (OMS) des tumeurs du système nerveux central de 2021 a introduit des biomarqueurs moléculaires (délétion homozygote de CDKN2A/B et mutation du promoteur de TERT) dans le grading des méningiomes. Depuis, le groupe d’experts du cIMPACT-NOW a proposé un nouvel algorithme pronostique (publié dans l’update 8), intégrant des données épigénétiques et génétiques. Le but de ce travail était de rapporter l’expérience du service de neuropathologie de l’Hôpital Sainte-Anne dans l’intégration de cet algorithme dans le grading des méningiomes. Matériels et méthodes Ce travail a inclus des méningiomes, diagnostiqués entre le 01/09/2024 et le 30/04/2025, pour lesquels des analyses moléculaires étaient obligatoires selon les recommandations du cIMPACT-NOW update 8. Un séquençage à haut débit (statut pTERT et CDKN2A/B) et un méthylome (classe de méthylation et anomalies de nombre des chromosomes) ont été réalisés pour chaque cas. Résultats Soixante-et-onze méningiomes ont été inclus. Dans 62 % des cas, le grading a été modifié après intégration des données génétiques et épigénétiques. Dans 35 cas, le grade final était plus bas que le grade initial et dans neuf cas, le grade final était plus élevé. Discussion et conclusions L’invasion du parenchyme cérébral ne représente plus à elle seule un critère de grade 2. Dans notre étude, 47 % des méningiomes classés en grade 2 sur leur caractère uniquement invasif ont été down-gradés en 1. La présence d’une mutation de pTERT et/ou d’une délétion homozygote de CDKN2A/B a permis ici de reclasser deux méningiomes classés initialement en grade 2 de l'OMS en grade 3. La présence d’une perte combinée des chromosomes 1p et 22q, associée à un grade 2 selon les recommandations du cIMPACT-NOW, a permis de reclasser quatre méningiomes initialement considérés de grade 1. L’update 8 du cIMPACT-NOW révolutionne la pratique des pathologistes dans le grading des méningiomes, devant alors intégrer les données génétiques et épigénétiques aux données morphologiques.

In the Central Nervous System (CNS), MYB/MYBL1 alterations are found in two tumor types: angiocentric glioma (AG), and diffuse astrocytoma (DA). These tumors share clinical features (mainly epileptic pediatric tumors located in the supratentorial area), a histopathological pattern (AG can look like DA) and seem to be associated with comparably favorable prognoses. However, aggressive cases of AG have been reported in the literature, one of them harboring a MYB::QKI fusion. This study aims to compare and contrast aggressive cases of low-grade gliomas (LGGs), MYB/MYBL1-altered to typically indolent cases in order to identify factors (clinical, radiological or histomolecular) associated with aggressive forms of AG and DA. We retrospectively reviewed and fully characterized 28 LGGs (14 AGs and 14 DAs) with MYB/MYBL1 alterations in terms of clinical course, radiology, histopathology and molecular biology (including DNA-methylation profiling). While most AGs and DAs in our cohort had a favorable oncological outcome, we describe three cases of AG and one case of DA with tumor progression and one terminal case of AG. Initial signs of histopathological anaplasia were exclusively found in aggressive AGs (2/3) but their significance in DA is unclear as they were encountered in the aggressive case but also in two indolent cases, and because DA seem to respond well to chemotherapy. Two aggressive AGs also were found to have a chromosome 6 chromothripsis and harbored additional molecular alterations in their initial tumor sample (KRAS, hTERT, and TP53 mutations). No radiological pattern, fusion partner or methylation cluster was associated with progression in LGG, MYB/MYBL1-altered. These cases with an aggressive clinical course raise the question of potential higher grades of LGG, MYB/MYBL1-altered, which need to be confirmed by additional reports.