Purpose: Idiopathic spinal cord herniation (iSCH) is a rare cause of myelopathy characterized by protrusion of the spinal cord through a focal defect in the dura mater. Its pathogenesis remains poorly understood. In this study, we present evidence supporting an acquired mechanism involving dural dissection. Methods: We conducted a single-center case series of patients diagnosed with iSCH, with a focus on clinical and radiological features that provide insight into the condition’s etiology and natural history. Results: We identified 18 patients with iSCH, including 15 who underwent surgical treatment. In 14 patients (78

Introduction Les neuropathies vascularitiques entraînent des lésions axonales ischémiques. Les caractéristiques démyélinisantes aux ENMG peuvent retarder le diagnostic en imitant une polyradiculoneuropathie démyélinisante inflammatoire chronique. Objectifs Déterminer la fréquence et les caractéristiques des anomalies démyélinisantes aux études de conduction nerveuse chez des patients présentant une neuropathie vascularitique confirmée histologiquement. Méthodes Nous avons analysé rétrospectivement les données cliniques et électroneuromyographiques de patients ayant une neuropathie vascularitique confirmée par biopsie. Nous avons caractérisé les anomalies évoquant une démyélinisation répondant aux critères EAN/PNS de polyradiculoneuropathie démyélinisante inflammatoire chronique. Les paramètres moteurs et sensitifs, incluant vitesses de conduction, latences des ondes F et blocs de conduction, ont été systématiquement évalués. Résultats Soixante-trois patients atteints de neuropathie vascularitique ont été inclus. Les formes observées comprenaient une neuropathie vascularitique non systémique, une périartérite noueuse et une vascularite associée aux ANCA. Les ENMG montraient une polyneuropathie distale symétrique, une polyneuropathie asymétrique ou des multinévrites. Des critères démyélinisants EAN/PNS étaient présents chez près de la moitié des patients, incluant blocs de conduction, ralentissement des vitesses et anomalies des ondes F. Discussion Les profils électrophysiologiques démyélinisants observés dans la neuropathie vascularitique peuvent créer une confusion diagnostique avec la polyradiculoneuropathie démyélinisante inflammatoire chronique. Cette similitude souligne la nécessité d’intégrer les données cliniques, histopathologiques et électrophysiologiques pour éviter les erreurs diagnostiques et adapter rapidement la prise en charge. Conclusion Les caractéristiques électrophysiologiques évoquant des anomalies démyélinisantes sont fréquentes dans la neuropathie vascularitique. Une interprétation intégrée est essentielle pour éviter les retards diagnostiques.

BACKGROUND:Parvovirus B19 (B19V) infection has been associated with neurological complications. Rarely, patients present with multiple mononeuropathy (MM). The present study aimed to better characterize the clinical, electrophysiological, and prognostic features of patients with B19V-related MM. METHODS:This retrospective, observational, multicenter study included patients with B19V-related MM diagnosed between January 2015 and January 2025 in seven university hospitals in France and Switzerland. RESULTS:Twenty-one patients were included. Twelve were female (57%). All were immunocompetent. The median age at symptom onset was 40 years [IQR: 31-44]. All patients experienced sensory symptoms, 19 (90%) reported neuropathic pain, nine (43%) developed motor weakness, and seven (33%) had cranial nerve involvement. The most frequently involved nerves were the median (14 patients, 67%), fibular (n = 13; 62%), and ulnar (n = 10; 48%) nerves. B19V IgM antibodies were present in 12/20 patients (60%), and all 21 patients were positive for IgG. B19V DNA was detected in blood by PCR in 20 patients (95%). Nerve biopsy showed necrotizing small-vessel vasculitis in one patient (17%), perivascular lymphocytic and macrophagic infiltrates in five (83%), and B19V DNA was detected by PCR in all four tested nerves. Most patients received immunomodulatory treatment (n = 19; 90%). MM relapse occurred in four patients (19%). A partial recovery was observed in 17/20 patients (85%), two remained stable (10%), and one achieved complete recovery (5%). CONCLUSIONS:B19V infection should be systematically investigated in patients presenting with MM, especially in young individuals (including children) with predominantly sensory symptoms, predominant upper limb nerve involvement, and/or cranial nerve involvement.

OBJECTIVES:Several studies reported an association between Sjögren's disease (SjD) and inclusion body myositis (IBM). However, the potential specificities of IBM when associated with SjD have been poorly investigated. Here, we compared the muscular inflammatory infiltrates between IBM patients with or without associated SjD. METHODS:Formalin-fixed and paraffin-embedded muscle biopsies of patients with IBM, associated with SjD (IBM-SjD) and sporadic (sIBM) forms, from six French expert centres, were collected. Imaging mass cytometry (IMC) multiplex immunostaining (34 markers) was used to quantify and analyse inflammatory infiltrate composition. Supervised and unsupervised descriptive and comparative analyses were performed. RESULTS:Fourteen IBM-SjD and seven sIBM muscle samples were analysed. No statistically significant difference was encountered but some trends were pointed. IBM-SjD samples had a broader inflammatory infiltrate surface (median 4.8%, IQR: 1.4-8.6) than sIBM samples (median 1.6% IQR: 1.2-2.4). In both groups, the main inflammatory cells in muscle infiltrate were primarily macrophages and T cells. However, the proportion of plasma cells (14.7% IQR: 5.4-24.6 vs 8.5% IQR: 4.6-9.8) and B cells (3.1% IQR: 0.4-5.6 vs 0.5% IQR: 0.0-3.2) were higher in IBM-SjD patients. CONCLUSION:Using IMC on muscle biopsies, IBM-SjD and sIBM patients share common histological features, but there are notable distinctions (more extensive infiltrate, high numbers of B cells and plasma cells in IBM-SjD). These observations were exploratory and based on a small number of patients but may suggest IBM-SjD has distinct SjD-related pathophysiology compared with sIBM, and open to further research with potential diagnostic and therapeutic implications.

Abstract Background Clinical scores incompletely capture outcomes in primary central nervous system lymphoma (PCNSL). We quantified morphologic heterogeneity in pretreatment hematoxylin and eosin (H&E) whole slides. Patients and methods Three independent cohorts of immunocompetent, HIV- and EBV-negative patients treated recently were analyzed: LOC 2023 (122 slides), phase III BLOCAGE-01 (245 slides; NCT02313389 ), and external Barcelona (BCN; 41 slides). UNI embeddings, prototype learning, spatial metrics, and elastic-net Cox regression defined ITH-C. Results Models achieved bootstrap-corrected concordance of 0.797–0.834. Age-, sex-, and KPS-adjusted ITH-C HRs were 1.29 (95% CI 1.01–1.64), 1.27 (1.07–1.51), and 2.13 (1.35–3.37), respectively. Adding ITH-C increased MSKCC C-index from 0.671 to 0.717, 0.560 to 0.593, and 0.588 to 0.706. Spatial transcriptomics linked ITH-C to immune programs. Conclusions Routine H&E encodes prognostic spatial heterogeneity in PCNSL. ITH-C complements clinical scores, supporting prospective risk stratification.

BACKGROUND AND OBJECTIVES:Peripheral neuropathies (PNs) associated with T-cell lymphoproliferative disorders (T-Ly) are exceptionally rare and poorly characterized. Whether their mechanisms, clinical features, and outcome differ from PN associated with B-cell lymphoproliferative disorders (B-Ly) remains unclear. We aimed to characterize the clinical, electrophysiologic, and pathologic spectrum of T-Ly-associated PN, evaluate treatment responses, and compare these findings with B-Ly-associated PN. METHODS:We conducted a retrospective multicentric cohort study across 17 PN reference centers in France and Switzerland. Adult patients with confirmed PN and T-Ly were included after exclusion of alternative PN etiologies and isolated CNS involvement. Clinical, electrophysiologic, imaging, and histopathologic data were collected. PN were classified as neurolymphomatosis or dysimmune neuropathy based on multidisciplinary consensus. Functional outcomes were assessed using the modified Rankin Scale (mRS) and Overall Neuropathy Limitations Scale. The results were compared with a reference cohort of B-Ly-associated PN. RESULTS:Nineteen patients were included (mean age 67.0 ± 11.4 years, 52.6% female) with a median follow-up of 22 months (interquartile range 11.5-30.5). Neurolymphomatosis accounted for 11 cases (58%) and typically presented with multifocal, predominantly axonal neuropathy, including meningoradiculitis and multiple mononeuropathies. Eight patients (42%) had dysimmune neuropathy, most often demyelinating and strongly associated with angio-immunoblastic T-cell lymphoma. Neurologic improvement occurred in 72% of treated patients; however, most patients with neurolymphomatosis showed only partial recovery and persistent disability. IV immunoglobulins were uniformly ineffective, whereas corticosteroids yielded the greatest PN-specific benefit. Compared with B-Ly-associated PN (n = 33), T-Ly-associated PN were associated with more severe disability (median mRS 3 vs 2, p = 0.014), more frequent motor involvement, pain, cranial nerve involvement, and a higher prevalence of neurolymphomatosis. DISCUSSION:T-Ly-associated PN are predominantly driven by neurolymphomatosis and exhibit more severe clinical profiles and poorer neurologic outcomes than B-Ly-associated PN. Dysimmune neuropathies represent a substantial subset, particularly in angioimmunoblastic T-cell lymphoma. Limitations include the retrospective design and heterogeneity of diagnostic investigations. These findings underscore the need for early recognition and mechanism-specific therapeutic strategies.

Giant cell tumors (GCTs) of the bone are typically benign but locally aggressive tumors usually affecting the long bones of young adults. Rarely, these tumors may arise in the skull, most often involving the sphenoid or temporal bones. Here, we performed a systematic literature review and identified 79 previously reported cases of GCTs of the sphenoid bone, and we added two illustrative cases of patients affected by this condition. The first patient, a 22-year-old woman, was treated with surgery and radiotherapy and has been followed up for 17 years without evidence of tumor recurrence. The second patient has been seen recently and was treated with two successive surgeries. These tumors usually occur between the second and the third decade of life and are more prevalent in women. Symptoms leading to diagnosis are related to local mass effect and include headache, third and sixth cranial nerve palsy, impaired facial sensitivity, diplopia, and decreased vision, and clinical manifestations of endocrine dysfunction may also be present. Imaging techniques usually depict an osteolytic lesion of the sphenoid bone extending to adjacent anatomical structures. Differential diagnoses include invasive pituitary adenomas, chordomas, chondrosarcomas, brown tumors, and giant cell reparative granulomas. The diagnosis is confirmed histologically, characterized by numerous osteoclast-like multinucleated giant cells, mononuclear cells, and stromal cells, the latter showing histone H3 G34W/R/V mutations on immunohistochemistry. Transsphenoidal surgery remains the first-line treatment, while radiotherapy or denosumab may be considered in cases of residual, progressive, or recurrent disease.

OBJECTIVE:To assess the effectiveness of labial minor salivary gland biopsy (LSGB) alone or in combination with punch skin biopsy (SB) for the detection of amyloid deposits in hereditary transthyretin amyloidosis with polyneuropathy (ATTRv-PN). METHODS:In this single-center retrospective study, Congo red staining of minimal invasive LSGB (4 mm) and SB (3 mm) was assessed in ATTRv-PN patients consecutively evaluated between 2012 and 2023. RESULTS:Histopathological data of 171 ATTRv-PN, including 49 early-onset p.Val50Met, 58 late-onset p.Val50Met, and 64 non-p.Val50Met, were reviewed. LSGB and SB identified amyloid deposits in 123/171 (72%) and 131/171 (77%) patients respectively (p = 0.2). Combining LSGB and SB increased the amyloid detection rate to 150/171 (88%), especially in late-onset p.Val50Met (48/58 [83%]) and non-p.Val50Met patients (55/64 [86%]). LSGB and SB have a similar rate of detection of amyloid depositions in early onset p.Val50Met patients (94%). Also, the LSGB/SB combination identified amyloidosis in 89% (55/62) of early-stage ATTRv-PN patients. CONCLUSIONS:In our study, combining LSGB and SB allowed the detection of amyloid deposits in 88% of ATTRv-PN patients. LSGB/SB analysis may be of major interest to confirm entry in the disease at very early-stage ATTRv-PN, with implications in disease-modifying treatment initiation.

Neurolymphomatoses (NL) are defined as the direct infiltration of the peripheral nervous system (PNS) by lymphomatous or leukaemic cells. The diagnosis of this rare disease is complex, typically relying on peripheral nerve histology, an invasive examination with a risk of sequelae. This diagnostic entity should be considered in the presence of a painful neuropathy, sometimes severe, whether or not associated with immunohaematological abnormalities, and in cases of resistance to first-line immunomodulatory treatments. NLs are classified into primary, which are limited to or originate from the peripheral nerve, and secondary NLs resulting from systemic involvement. The epineurium, the perineurium and the endoneurium might be affected. Diffuse large B-cell lymphomas are the most frequent histological entity, followed by marginal zone and lymphoplasmacytic lymphomas. The genesis of these infiltrations and their links with primary central nervous system lymphomas are not clearly established. In the future, the contribution of multimodal imaging techniques (whole-body PET, plexus MRI, nerve ultrasound) and sensitive technologies for detecting lymphoid clones (molecular biology, immunophenotyping) as well as therapeutic sequences will need to be clarified by dedicated multicentre studies.

Les neurolymphomatoses (NL) sont définies comme l’infiltration directe du système nerveux périphérique (SNP) par des cellules lymphomateuses ou leucémiques. Le diagnostic de cette maladie rare est complexe, reposant généralement sur l’histologie du nerf périphérique, examen invasif et à risque de séquelles. Cette entité diagnostique doit être discutée devant une neuropathie douloureuse, parfois sévère, associée ou non à des anomalies immunohématologiques, et en cas de résistance aux traitements immunomodulateur de première ligne. On distingue les NL primaires, limitées ou à point de départ du nerf périphérique, et les NL secondaires à des atteintes systémiques. L’épinèvre, la périnèvre et l’endonèvre peuvent être atteintes. Les lymphomes B diffus à grandes cellules sont l’entité histologique la plus fréquente, suivie par les lymphomes B de la zone marginale et les lymphomes lymphoplasmocytaires. La genèse de ces infiltrations et les liens avec les lymphomes primitifs du système nerveux central ne sont pas clairement établis. Dans le futur, l’apport des techniques d’imagerie multimodale (TEP corps entier, IRM plexique, échographie du nerf) et des technologies sensibles de détection des clones lymphoïdes (biologie moléculaire, immunophénotypages) ainsi que les séquences thérapeutiques devront être précisées par des études multicentriques dédiées.

Neurolymphomatoses (NL) are defined as the direct infiltration of the peripheral nervous system (PNS) by lymphomatous or leukaemic cells. The diagnosis of this rare disease is complex, typically relying on peripheral nerve histology, an invasive examination with a risk of sequelae. This diagnostic entity should be considered in the presence of a painful neuropathy, sometimes severe, whether or not associated with immunohaematological abnormalities, and in cases of resistance to first-line immunomodulatory treatments. NLs are classified into primary, which are limited to or originate from the peripheral nerve, and secondary NLs resulting from systemic involvement. The epineurium, the perineurium and the endoneurium might be affected. Diffuse large B-cell lymphomas are the most frequent histological entity, followed by marginal zone and lymphoplasmacytic lymphomas. The genesis of these infiltrations and their links with primary central nervous system lymphomas are not clearly established. In the future, the contribution of multimodal imaging techniques (whole-body PET, plexus MRI, nerve ultrasound) and sensitive technologies for detecting lymphoid clones (molecular biology, immunophenotyping) as well as therapeutic sequences will need to be clarified by dedicated multicentre studies. (c) 2025 Societe Nationale Francaise de Medecine Interne (SNFMI). Published by Elsevier Masson SAS. All rights are reserved, including those for text and data mining, AI training, and similar technologies.

Innovative treatment strategies for pituitary tumors are necessary to limit the disease burden and to improve survival in cases of carcinomas. The paucity and inaccuracy of available preclinical models substantially hamper pituitary research and drug discovery. Hence, we describe a novel method to generate orthotopic pituitary tumors via stereotaxic injection of somatotroph GC cells into the pituitaries of immunocompetent Wistar Furth rats. Tumor growth was monitored by repeated 7 Tesla magnetic resonance imaging. The procedure consistently led to rapidly expanding intra- and suprasellar growth hormone-secreting tumors within their native anatomical environment. The generated tumors faithfully reproduced the microarchitecture of human somatotroph pituitary adenomas, including the immune infiltrates and other typical components of their microenvironment, which is a prerequisite for testing immunomodulating agents. This orthotopic model of proliferative pituitary tumors developed in immunocompetent hosts therefore unlocks new opportunities for preclinical studies.

( BJOG . 2024;131(6):759–767. https://doi.org/10.1111/1471-0528.17624) Myelomeningocele (MMC), also referred to as open spina bifida, is the most severe type of spina bifida and a significant abnormality in the neural tube. It consists of a sac filled with fluid found on the back of infants and is linked to dysfunction with the lower limbs, digestion, and urinary systems, as well as possible cognitive impacts. Research conducted by MOMS revealed the advantages of prenatal repair for MMC compared with surgery after birth, resulting in the widespread acceptance of prenatal surgical methods. Even with these improvements, 71% of patients are still unable to walk without assistance by the time they turn 8, and 75% must use a urinary catheter every day by the age of 10. Therefore, further tactics are needed to improve results. Umbilical cord mesenchymal stem cells (UC-MSCs) may be beneficial in MMC due to their protective and repair mechanisms. Preliminary research showed only slight, insignificant enhancements in motor function from UC-MSCs in a sheep MMC model, leading to the need for more study.

BACKGROUND:The classification of Sjögren's disease partly relies on focus score grading from a minor salivary gland biopsy. Expert regrading of the focus score leads to disease reclassification in half of cases. This study aimed to leverage machine learning to automatically classify the focus score and Sjögren's disease to identify new histological disease subtypes based on minor salivary gland biopsy. METHODS:This retrospective cohort study included minor salivary gland biopsy scanned haematoxylin and eosin slides from six expert centres (three centres in the UK and one each in Greece, Portugal, and France) of the European H2020 NECESSITY consortium. Participants with sicca but without Sjögren's disease and patients with Sjögren's disease and a focus score of either at least 1 or less than 1 where included. All patients with Sjögren's disease fulfilled the American College of Rheumatology-European League Against Rheumatism 2016 criteria. A deep learning model was trained on slides from five centres and validated on slides from the sixth centre. The primary outcome was the area under the receiver operator curve (AUROC) to classify the focus score and Sjögren's disease. Shapley values, an explainable machine learning technology, were computed to identify histological patterns driving the model's classification. People with lived experience of Sjögren's disease were involved in the decision to fund this research and in the dissemination of the findings. FINDINGS:The study was conducted between Oct 13, 2021, and Sept 5, 2024, and included 545 participants with a mean age of 54·2 (SD 13·5); 490 (90%) were female and 55 (10%) were male. After external validation, the model had an AUROC of 0·88 (95% CI 0·82-0·94) for the focus score classification task and an AUROC of 0·89 (0·82-0·94) for Sjögren's disease classification. The performance of Sjögren's disease classification for patients who were negative for anti-Sjögren's syndrome-related antigen A was 0·92 (0·87-1·00). Of histological patterns identified by the model, a new pattern of CD8+ T cells around acinar epithelial cells was associated with Sjögren's disease diagnosis. INTERPRETATION:This study showed that deep learning can reliably classify the focus score and Sjögren's disease using minor salivary gland biopsy exclusively. The study identified that CD8+ T-cell infiltration in acini was associated with Sjögren's disease. Further studies are needed to validate the models. FUNDING:Société Française de Rhumatologie, European Alliance of Associations for Rheumatology.

BACKGROUND:Hereditary transthyretin amyloidosis (ATTRv amyloidosis) is an autosomal dominant systemic disease, with an overall poor prognosis. Markers of disease onset are urgently required to optimize the timing of treatment initiation. Nerve conduction studies (NCS) are an objective, reproducible, and non-invasive tool for following large nerve fiber involvement. Our objective was to determine whether the presence of intracutaneous amyloid deposition (ICAD) was associated with a higher risk of developing the disease, defined as a decline observed on nerve conduction studies, in a population of carriers not meeting the criteria for overt disease. METHODS:We included 98 presumed asymptomatic pathogenic variant TTR carriers with normal baseline NCS results and available follow-up testing results. Baseline evaluation included a neurological examination, short-term heart rate variability (HRV), electrochemical sweat conductance (ESC), intraepidermal nerve fiber density (IENFD), assessment of the presence of intracutaneous amyloid deposits (ICAD), and cardiac parameters. Follow-up neurological and cardiological evaluations were performed. NCS deterioration was defined as a 20% decrease in sensory nerve action potential (SNAP) in the lower limbs. RESULTS:During a median follow-up of 5 years, 11/98 (11%) carriers presented a NCS deterioration. Presence of ICAD at baseline was significantly associated with NCS decline. CONCLUSION:The presence of ICAD at baseline is associated with a subsequent NCS deterioration in presumed asymptomatic pathogenic variant TTR carriers. Skin biopsy for the analysis of amyloidosis deposit and small fiber density should be recommended in the evaluation of carriers and lead to discuss treatment initiation when abnormal, even in asymptomatic carriers.

Background and Purpose The cavernous sinus (CS) is often invaded by pituitary adenomas, crossing the medial wall (MW), while the lateral wall (LW) is rarely breached. The structural differences between these walls remain poorly understood. This study investigated collagen subtypes distribution in human fetal and adult CS specimen to explore the basis for MW-specific invasion. Methods Twenty-two CS from eleven adult cadaveric human heads and two fetal specimens were dissected via transcranial and endoscopic approaches. Samples from the MW, LW, anterior wall, and diaphragm sellae were analyzed for collagen types I-IV staining by immunohistochemistry. Results All CS walls were identifiable in adult and fetal specimen. The MW and LW were composed of loose collagenous tissue; cranial nerves were present in the LW. In adults, type I collagen was weakly expressed in the MW and absent in the LW and fetal CS. Type II collagen appeared only in fetal cartilage. Type III collagen was present in the MW and partially in the LW of adults, and across both dural layers in fetuses. Type IV collagen was absent in adult dura but weakly present in fetal dura and strongly expressed in pituitary, perineurium, and carotid walls. Conclusion Collagen composition within the cavernous sinus undergoes marked changes with age, characterized by an increase in type I and III and a decline in type IV collagen. The structural differences, particularly between the MW and LW, may underlie the MW’s increased vulnerability to invasion by pituitary adenomas, potentially driven by MMP-dependent degradation pathways.

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BACKGROUND:Hereditary transthyretin amyloidosis is a life-threatening autosomal dominant systemic disease due to pathogenic TTR variants (ATTRv), mostly affecting the peripheral nerves and heart. The disease is characterised by a combination of symptoms, organ involvement and histological amyloid deposition. The available disease-modifying ATTRv treatments (DMTs) are more effective if initiated early. Pathological nerve conduction studies (NCS) results are the cornerstone of large-fibre polyneuropathy diagnosis, but this anomaly occurs late in the disease. We investigated the utility of a multimodal neurological and cardiac evaluation for detecting early disease onset in ATTRv carriers. METHODS:We retrospectively analysed a cohort of ATTRv carriers with normal NCS results regardless of symptoms. Multimodal denervation and infiltration evaluations included a clinical questionnaire (Lauria and New York Heart Association (NYHA)) and examination, intra-epidermal nerve fibre density assessment, autonomic assessment based on heart rate variability, Sudoscan, meta-iodo-benzyl-guanidine scintigraphy, cardiac biomarkers, echocardiography, MRI and searches for amyloidosis on skin biopsy and bone scintigraphy. RESULTS:We included 130 ATTRv carriers (40.8% men, age: 43.6±13.5 years), with 18 amyloidogenic TTR gene mutations, the majority of which was the late-onset Val30Met variant (42.3%). Amyloidosis was detected in 16.9% of mutation carriers, including 9 (6.9%) with overt disease (Lauria>2 or NYHA>1) and 13 asymptomatic carriers (10%) with organ involvement (small-fibre neuropathy or cardiomyopathy). Most of these patients received DMT. Abnormal test results of unknown significance were obtained for 105 carriers (80.8%). Investigations were normal in only three carriers (2.3%). CONCLUSIONS:Multimodal neurological and cardiac investigation of TTRv carriers is crucial for the early detection of ATTRv amyloidosis and initiation of DMT.

A novel methylation class, "neuroepithelial tumor, with PLAGL1 fusion" (NET-PLAGL1), has recently been described, based on epigenetic features, as a supratentorial pediatric brain tumor with recurrent histopathological features suggesting an ependymal differentiation. Because of the recent identification of this neoplastic entity, few histopathological, radiological and clinical data are available. Herein, we present a detailed series of nine cases of PLAGL1-fused supratentorial tumors, reclassified from a series of supratentorial ependymomas, non-ZFTA/non-YAP1 fusion-positive and subependymomas of the young. This study included extensive clinical, radiological, histopathological, ultrastructural, immunohistochemical, genetic and epigenetic (DNA methylation profiling) data for characterization. An important aim of this work was to evaluate the sensitivity and specificity of a novel fluorescent in situ hybridization (FISH) targeting the PLAGL1 gene. Using histopathology, immunohistochemistry and electron microscopy, we confirmed the ependymal differentiation of this new neoplastic entity. Indeed, the cases histopathologically presented as "mixed subependymomas-ependymomas" with well-circumscribed tumors exhibiting a diffuse immunoreactivity for GFAP, without expression of Olig2 or SOX10. Ultrastructurally, they also harbored features reminiscent of ependymal differentiation, such as cilia. Different gene partners were fused with PLAGL1: FOXO1, EWSR1 and for the first time MAML2. The PLAGL1 FISH presented a 100% sensitivity and specificity according to RNA sequencing and DNA methylation profiling results. This cohort of supratentorial PLAGL1-fused tumors highlights: 1/ the ependymal cell origin of this new neoplastic entity; 2/ benefit of looking for a PLAGL1 fusion in supratentorial cases of non-ZFTA/non-YAP1 ependymomas; and 3/ the usefulness of PLAGL1 FISH.