Multifocal Rosette-forming Glioneuronal Tumor-like Low-Grade Glioneuronal Tumor with Dysembryoplastic Neuroepithelial Tumor Features Associated with Drug-Resistant Epilepsy: A Case Report and Literature Review

Multifocal Rosette-forming Glioneuronal Tumor-like Low-Grade Glioneuronal Tumor with Dysembryoplastic Neuroepithelial Tumor Features Associated with Drug-Resistant Epilepsy: A Case Report and Literature Review | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Multifocal Rosette-forming Glioneuronal Tumor-like Low-Grade Glioneuronal Tumor with Dysembryoplastic Neuroepithelial Tumor Features Associated with Drug-Resistant Epilepsy: A Case Report and Literature Review yuuki ishida, Koki Ise, Kenichi Sato, Taku Asanome, Ryunosuke Yoshihara, and 7 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7597140/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 06 Jan, 2026 Read the published version in Brain Tumor Pathology → Version 1 posted 4 You are reading this latest preprint version Abstract Rosette-forming glioneuronal tumors (RGNTs) are rare, World Health Organization grade 1 tumors that typically arise around the fourth ventricle. However, cerebral hemisphere RGNTs have recently been reported, with some exhibiting clinical features resembling low-grade epilepsy-associated tumor (LEAT). We report a case of multifocal RGNT involving the temporal lobe and thalamus in a patient with drug-refractory epilepsy. During evaluation for head trauma, a 14-year-old woman was incidentally found to have a brain tumor. Magnetic resonance imaging revealed multifocal lesions in the left temporal lobe and bilateral thalamus. The tumor enlarged over time, and epilepsy developed at age 24, becoming drug-resistant and necessitating surgery at age 26. Partial tumor resection and anterior temporal lobectomy were performed. Histopathology revealed a glioneuronal tumor with oligodendroglia-like cells, neurocytic rosette, and perivascular pseudorosette. Genetic analysis revealed Fibroblast Growth Factor Receptor 1 mutation, and the tumor was diagnosed as an RGNT-like low-grade glioneuronal tumor with dysembryoplastic neuroepithelial tumor (DNT) features. Cases presenting with a LEAT-like clinical course and exhibiting histopathological features of RGNT are often difficult to definitively distinguish from DNT based on histological and genetic findings. Epilepsy-associated RGNT may harbor genetic profiles distinct from those of prototypical RGNTs, highlighting the need for further investigation. Rosette-forming glioneuronal tumor Dysembryoplastic neuroepithelial tumor Low-grade epilepsy associated tumor FGFR1 Multifocal Figures Figure 1 Figure 2 Figure 3 Introduction Rosette-forming glioneuronal tumors (RGNTs) are rare World Health Organization (WHO) grade I neoplasms, initially defined as “RGNT of the fourth ventricle” [ 1 ] because of their typical site of origin. However, more recent reports have documented RGNTs arising in atypical locations, including the cerebral hemispheres, often presenting with epilepsy [ 2 – 8 ]. Low-grade epilepsy-associated tumors (LEATs) are a group of brain neoplasms frequently linked with drug-resistant epilepsy (DRE), particularly in younger patients [ 9 ]. Dysembryoplastic neuroepithelial tumor (DNT) is a well-established glioneuronal LEAT subtype and accounts for approximately 20% of such cases [ 10 ]. DNTs typically arise in the temporal cortex and present with early-onset seizures that are frequently resistant to medical therapy. Magnetic resonance imaging (MRI) often reveals well-demarcated, pseudocystic or multicystic lesions with hypointensity on T1-weighted imaging, hyperintensity on T2-weighted imaging, and minimal or no gadolinium enhancement [ 11 ]. Interestingly, similar imaging features have been reported for epilepsy-associated hemispheric RGNTs. Multifocality is rare for both RGNTs[ 2 ] and DNTs [ 12 , 13 ], and poses significant diagnostic challenges. Moreover, RGNT cases with overlapping DNT-like histopathological features have been described [ 2 – 8 ], complicating definitive diagnosis. Here, we report a rare case of a multifocal, epilepsy-associated low-grade glioneuronal tumor exhibiting histological features of both RGNT and DNT. Clinical Summary A 26-year-old woman with no significant medical history was found incidentally to have a left medial temporal lobe lesion at age 14 following a minor head injury. Initial MRI revealed a non-enhancing lesion with T1 hypointensity and T2 hyperintensity (Fig. 1 A). As she remained asymptomatic, a surveillance approach was chosen. Over several years, the lesion slowly enlarged and developed increasing multicystic morphology. At age 21, the patient developed recurrent focal seizures characterized by behavioral arrest, amnesia, and right-sided paresthesia. EEG showed anterior temporal spike-wave discharges, and MRI revealed further enlargement of the known lesion (Fig. 1 B). She was diagnosed with tumor-related epilepsy and was prescribed anti-seizure medications. Despite polytherapy, seizures persisted, indicating DRE. At age 25, MRI revealed further tumor progression involving the amygdala and hippocampus, with small cystic satellite lesions in the temporal neocortex and bilateral thalami(Fig. 1 C, 2 A-E). Although the lesion’s imaging resembled DNT, the multifocal nature and progressive enlargement were atypical. Surgical treatment was pursued at age 26. Chronic intracranial EEG was conducted using subdural and depth electrodes over the lateral and basal temporal lobes, thalamus, and frontal cortex. Ictal EEG showed initial discharges in the thalamus, followed by propagation from the basal to lateral temporal regions. Based on functional mapping and seizure localization, anterior temporal lobectomy with maximal safe resection of the tumor was performed, sparing eloquent cortex. Intraoperatively, the tumor was found to be poorly vascularized, exhibiting an extremely soft, gelatinous consistency. Owing to the difficulty in achieving en bloc resection, a representative portion was submitted for histopathological analysis, while the remaining bulk of the tumor was removed via suction. Partial resection was performed to minimize the risk of brainstem injury, with residual tumor tissue adjacent to the brainstem. Postoperative MRI revealed residual tumor in the medial and posterior temporal lobe (Fig. 2 F). More than two years after surgery, there has been no evidence of tumor regrowth, and the patient has remained seizure-free. Pathological Findings Hematoxylin and eosin staining of the resected specimens revealed predominantly cerebral cortex with extension into the underlying white matter, consistent with an infiltrative growth pattern. Both neuronal and glial components were identified. The neuronal component was primarily located in the cortex and consisted of small round cells within a myxoid background (Fig. 3 A). A single neurocytic rosette was noted (Fig. 3 C), along with perivascular pseudorosettes (Fig. 3 A). Despite the myxoid background, floating neurons were not identified (Fig. 3 A). The glial component was predominantly located in the white matter and was characterized by oligodendroglia-like cells (OLCs) with microcystic architecture and perinuclear halos (Fig. 3 B). No areas resembling pilocytic astrocytoma were identified. Immunohistochemical staining of the small round cells in the neuronal component was negative for glial fibrillary acidic protein (GFAP), and positive for oligodendrocyte transcription factor 2 (Olig2) and microtubule-associated protein 2 (MAP2) (Fig. 3 D). In the glial component, the OLCs were negative for GFAP and MAP2, but positive for Olig2 (Fig. 3 E). Additionally, the core of the neurocytic rosette was positive for synaptophysin (Fig. 3 F). Sanger sequencing identified a Fibroblast Growth Factor Receptor 1 (FGFR1)-K656E mutation. No mutations were detected in Isocitrate Dehydrogenase (IDH)1/2, Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA), or Phosphoinositide-3-kinase regulatory subunit 1 (PIK3R1). Multiplex ligation-dependent probe amplification revealed neither 1p/19q codeletion nor Cyclin-Dependent Kinase Inhibitor 2A/B (CDKN2A/B) homozygous deletion. Neurofibromin 1(NF1) mutation examination was not performed. Methylation profiling analysis using the DKFZ classifier (version 12.8) identified a match with the “low-grade glioneuronal tumor” methylation class (calibrated score: 0.95); however, no subclass category yielded a significant match. Based on histopathological and immunohistochemical findings, the lesion was provisionally diagnosed as a low-grade glioneuronal tumor. Although the presence of OLCs was suggestive of DNT, the identification of a neurocytic rosette and perivascular pseudorosettes was more indicative of RGNT. The detected FGFR1 mutation is commonly observed in both DNT and RGNT, and thus lacks diagnostic specificity. While the observed neurocytic rosette was not entirely typical of RGNT, diagnostic weight was given to its presence, leading to a final diagnosis of RGNT-like glioneuronal tumor with DNT features. Discussion This report describes a rare case of DRE associated with a multifocal glioneuronal tumor that exhibited histological features of both RGNT and DNT. While RGNT is typically a midline lesion, the present case involved the temporal lobe and was multifocal; combined with overlapping histopathological and molecular features, this posed a considerable diagnostic challenge. We discuss three major aspects of this case: the diagnostic justification for RGNT, the differential diagnosis between RGNT and DNT, and implications for prognosis and treatment in epilepsy-associated RGNT. 1. Clinical and Pathological Basis for RGNT Diagnosis RGNTs were initially characterized in 2002 by Komori et al. as arising preferentially in the fourth ventricle. The initial 2007 WHO classification was “RGNT of the fourth ventricle,” but was renamed to “RGNT” in the 2021 edition to reflect its broader anatomical distribution. Reported locations include the pineal gland [ 14 ], optic chiasm [ 15 , 16 ], spinal cord [ 17 , 18 ], and cerebral hemispheres [ 2 – 8 ]. Histologically, RGNT is defined by biphasic architecture: a neurocytic component with rosettes and/or perivascular pseudorosettes that express synaptophysin, and a glial component resembling pilocytic astrocytoma [ 19 ]. In the present case, the tumor exhibited a glioneuronal biphasic pattern with Olig2-positive neurocytic rosettes and OLCs. While floating neurons and specific glioneuronal elements typical of DNT were not observed, sampling error cannot be entirely excluded. Given the presence of neurocytic rosette and synaptophysin positivity, the histological features aligned more closely with RGNT than DNT. Immunohistochemistry further supported a glioneuronal classification. Molecular profiling revealed an FGFR1 mutation without additional alterations in PIK3CA, PIK3R1. According to a large molecular study by Appay et al., most midline RGNTs with FGFR1 mutations also carry co-mutations in PIK3CA, PIK3CA, or NF1. In contrast, supratentorial cases tend to lack these additional mutations. Based on these findings, the authors propose that the presence of an FGFR1 mutation and a midline intracranial location should be considered essential diagnostic criteria for RGNT [ 20 ]. According to this proposal, the anatomical location and genetic profile of the present case do not represent typical RGNT. However, given that the histopathological and immunohistochemical findings closely correspond to the WHO diagnostic criteria for RGNT, the tumor was ultimately diagnosed as an RGNT-like glioneuronal tumor with DNT features. 2. Diagnostic Overlap Between RGNT and DNT in LEAT-like Tumors Differentiating RGNT from DNT can be particularly difficult in hemispheric tumors presenting with epilepsy alone. DNTs are WHO grade 1 cortical tumors, typically found in the temporal lobe of young patients with early-onset epilepsy [ 21 ]. Radiologically, they often present as a multicystic lesion with a characteristic “bubbly” appearance on T2-weighted MRI, with minimal gadolinium enhancement. Histologically, DNT is defined by the presence of a specific glioneuronal element, including floating neurons in a mucinous matrix, and OLCs [ 11 ]. FGFR1 mutations are common in both DNT and RGNT, limiting their diagnostic specificity. In recent WHO classifications, DNT diagnosis also considers DNA methylation profiling [ 21 ]. The present tumor exhibited some features commonly observed in DNT, particularly OLCs and cortical location, but lacked the defining glioneuronal element and floating neurons. Moreover, the neurocytic rosettes and perivascular pseudorosettes are atypical for DNT but characteristic of RGNT, favoring a RGNT diagnosis. Owusu et al. recently reviewed 129 RGNT cases and found that 49 (37.8%) were located in the cerebral hemispheres [ 22 ]. Of these, 15 patients (44%) presented with epilepsy, and seven exhibited early-onset DRE without signs of elevated intracranial pressure—clinical features mimicking LEATs (Table 1). Interestingly, all seven of these DRE cases demonstrated histological features reminiscent of DNT, particularly the presence of OLCs, and all harbored FGFR1 mutations. However, none exhibited PIK3CA or NF1 mutations, again distinguishing them from midline RGNTs. These observations support the hypothesis that some hemispheric RGNTs may exist on a spectrum of glioneuronal tumors with DNT-like features. Similarly, Daumas-Duport et al. previously categorized DNT into simple, complex, and non-specific forms [ 24 – 26 ]. Before RGNT was defined in 2002, some unrecognized cases—particularly those with rosette formation—may have been diagnosed as non-specific DNTs. The multifocal appearance of the present tumor further complicated the differential diagnosis. Although rare, multifocal lesions have been reported in cases of both DNT and RGNT [ 2 , 12 , 13 ]; multifocality cannot therefore be considered a distinguishing feature. Many epilepsy-associated glioneuronal tumors with RGNT features demonstrate overlapping DNT-like properties. While morphological and immunohistochemical evaluations are important for the accurate diagnosis of glioneuronal tumors, genetic analyses are also stipulated by WHO criteria [ 19 , 21 ]. However, it should be noted that the PIK3CA and NF1 mutations described in the WHO classification are based on cases arising in the third and fourth ventricles; no such mutations have been reported in RGNTs presenting with a LEAT-like clinical course, such as the present case. While FGFR1 mutations are common in these tumors, this feature is shared with DNT, limiting their utility in differential diagnosis. The discovery of genetic markers that distinguish DNT and RGNT in epilepsy-associated tumors in the cerebral hemisphere remains an important target for future research. 3. Prognosis and Management in Epilepsy-Associated RGNT At two years post-surgery, the patient remains seizure-free, suggesting that the epileptogenic focus was successfully resected. However, residual tumor remains, and future recurrence cannot be excluded. In prior reports, seizure recurrence has been associated with tumor progression or incomplete resection in cases of DNT [ 27 ]. Gross total resection is generally considered optimal for seizure control. Incomplete resection and the presence of satellite lesions are associated with poorer outcomes in DNT studies [ 28 ]. Although temporary seizure freedom may be achieved after partial resection, the likelihood of recurrence increases over time. In the present case, the residual lesion lies near eloquent cortex, limiting the feasibility of reoperation. For such cases, alternative treatment strategies must be considered. Neuromodulation, including vagus nerve stimulation (VNS), has shown efficacy in select cases of tumor-related epilepsy [ 29 ]. Although data are limited, VNS may be a viable adjunct in managing recurrent seizures when further resection is not possible. Another emerging approach is targeted molecular therapy. FGFR1 inhibitors, such as erdafitinib, have been approved for use in other malignancies, including bladder cancer and cholangiocarcinoma [ 30 ]. Owusu et al. reported radiological improvement in a progressive RGNT case treated off-label with erdafitinib [ 22 ]. Although not yet approved for central nervous system tumors, these agents hold promise, particularly for surgically unresectable FGFR1-mutant tumors. A “watchful waiting” strategy with the potential for targeted therapy may be appropriate in selected cases. Malignant transformation[ 31 ] and leptomeningeal dissemination [ 32 ] have been reported in RGNTs, highlighting the need for long-term monitoring. Despite shared features, the prognosis and optimal follow-up strategies for RGNT and DNT may differ, and accurate diagnosis is essential for guiding management. Conclusion This case underscores the diagnostic and therapeutic challenges posed by glioneuronal tumors exhibiting overlapping features of RGNT and DNT. In the current case, a multifocal presentation, combined with histological evidence of neurocytic rosettes and OLCs and a solitary FGFR1 mutation, supports classification as an RGNT-like tumor with DNT features. However, the possibility of a rare DNT variant remains, particularly noting the absence of RGNT-specific co-mutations. Accumulation of additional well-characterized cases will be vital to clarify the pathological spectrum of epilepsy-associated glioneuronal tumors and refine diagnostic criteria. For similar multifocal lesions in eloquent areas where gross total resection is not feasible, the risk of seizure recurrence is high. In such cases, multimodal management, including neuromodulation and future molecular targeting therapy, should be considered, alongside vigilant long-term follow-up. Declarations Acknowledgment We thank Wilf Gardner, PhD, from Edanz (https://jp.edanz.com/ac) for editing a draft of this manuscript. Ethics declarations Conflict of interest The authors declare that they have no conflict of interest. Ethical approval and consent to patient The patient provided written informed consent for the case to be published. Author information Author and Affiliations Department of Neurosurgery, Nakamura Memorial Hospital, South1, West14, Chuo-ku, Sapporo, 060-8570, Japan. Yuuki Ishida, Kenichi Sato ,Taku Asanome ＆ Ryunosuke Yoshihara Department of Cancer Pathology, Faculty of Medicine, Hokkaido University, Sapporo, Japan. Koki Ise ,Yoshitaka Oda, Hirokazu Sugino,Masumi Tsuda ＆ Shinya Tanaka Department of Neurology, Nakamura Memorial Hospital, Sapporo, Japan. Yoko Aburakawa Center of Epilepsy and Functional neurology, Seirei Hamamatsu General hospital, Hamamatsu, Japan. Yuuki Ishida＆ Masaki Izumi Department of Surgical Pathology, Hokkaido University Hospital, Sapporo, Japan. Zen-ichi Tanei ＆ Shinya Tanaka WPI-ICReDD, Hokkaido University, Sapporo, Japan. Masumi Tsuda ＆ Shinya Tanaka . Contributions Conception,design and drafting of the manuscript: YI. Clinical deta acquisition: YI, KS, TA, RY and YA. Pathological diagnosis: KI, YO, HS, ZT and ST. Genetic analysis: MT. Revision of the manuscript: KS, MI and ST. All authors read and approved the final manuscript Corresponding author Correspondance to Yuuki Ishida. References T. Komori, B. W. Scheithauer and T. Hirose . A rosette-forming glioneuronal tumor of the fourth ventricle: infratentorial form of dysembryoplastic neuroepithelial tumor?. 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Dissemination Patterns and Short-Term Management of Multifocal Rosette-Forming Glioneuronal Tumors. World Neurosurg 2021 Vol. 149 Pages 86-93 Table 1 Table 1 is available in the Supplementary Files section. Supplementary Files renamed5a2954.png Table1 : Summary of LEAT-like epilepsy associated tumor with pathological features of RGNT. Cite Share Download PDF Status: Published Journal Publication published 06 Jan, 2026 Read the published version in Brain Tumor Pathology → Version 1 posted Reviewers agreed at journal 10 Oct, 2025 Reviewers invited by journal 10 Oct, 2025 Editor assigned by journal 13 Sep, 2025 First submitted to journal 11 Sep, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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Nakamura Kinen Byoin Fuzoku Kango Gakko","correspondingAuthor":false,"prefix":"","firstName":"Ryunosuke","middleName":"","lastName":"Yoshihara","suffix":""},{"id":527676789,"identity":"21d534af-35a0-428d-bd45-7627ca4c27d0","order_by":5,"name":"Yoko Aburakawa","email":"","orcid":"","institution":"Nakamura Memorial Hospital Affiliated School Nursing: Nakamura Kinen Byoin Fuzoku Kango Gakko","correspondingAuthor":false,"prefix":"","firstName":"Yoko","middleName":"","lastName":"Aburakawa","suffix":""},{"id":527676790,"identity":"24b5e2fd-f487-4391-a8f6-a841c8685da8","order_by":6,"name":"Masaki Izumi","email":"","orcid":"","institution":"Seirei Hamamatsu Hospital: Seirei Hamamatsu Byoin","correspondingAuthor":false,"prefix":"","firstName":"Masaki","middleName":"","lastName":"Izumi","suffix":""},{"id":527676791,"identity":"cd86a8bb-9be2-481f-b293-aad16abe4fa6","order_by":7,"name":"Yoshitaka Oda","email":"","orcid":"","institution":"Hokkaido University: Hokkaido Daigaku","correspondingAuthor":false,"prefix":"","firstName":"Yoshitaka","middleName":"","lastName":"Oda","suffix":""},{"id":527676792,"identity":"c23f7bfc-4f9f-4f66-8a81-b8473b0b2090","order_by":8,"name":"Hirokazu Sugino","email":"","orcid":"","institution":"Hokkaido University: Hokkaido Daigaku","correspondingAuthor":false,"prefix":"","firstName":"Hirokazu","middleName":"","lastName":"Sugino","suffix":""},{"id":527676793,"identity":"8a0bb98b-0aba-4dfd-bba5-621eab492c4a","order_by":9,"name":"Zen-ichi Tanei","email":"","orcid":"","institution":"Hokkaido University: Hokkaido Daigaku","correspondingAuthor":false,"prefix":"","firstName":"Zen-ichi","middleName":"","lastName":"Tanei","suffix":""},{"id":527676794,"identity":"b1001adf-10b0-41ca-bdbf-25f6408855ba","order_by":10,"name":"Masumi Tsuda","email":"","orcid":"","institution":"Hokkaido University: Hokkaido Daigaku","correspondingAuthor":false,"prefix":"","firstName":"Masumi","middleName":"","lastName":"Tsuda","suffix":""},{"id":527676795,"identity":"c485eeca-ed09-4e4f-a877-b4aafe2f1421","order_by":11,"name":"Shinya Tanaka","email":"","orcid":"","institution":"Hokkaido University: Hokkaido Daigaku","correspondingAuthor":false,"prefix":"","firstName":"Shinya","middleName":"","lastName":"Tanaka","suffix":""}],"badges":[],"createdAt":"2025-09-12 06:35:49","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-7597140/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-7597140/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1007/s10014-025-00526-y","type":"published","date":"2026-01-06T15:58:35+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":94398483,"identity":"f2f5fdc9-62f9-469c-84db-02ca7bc2e39d","added_by":"auto","created_at":"2025-10-27 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13:57:12","extension":"pptx","order_by":6,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":11924259,"visible":true,"origin":"","legend":"","description":"","filename":"renamed5a295.pptx","url":"https://assets-eu.researchsquare.com/files/rs-7597140/v1/c62b96318734766c1e0dcbef.pptx"},{"id":94396423,"identity":"dc0cc9ba-bf04-4b42-bff1-d7ab25446fe1","added_by":"auto","created_at":"2025-10-27 13:55:59","extension":"xml","order_by":7,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":65888,"visible":true,"origin":"","legend":"","description":"","filename":"BTPAD25002070structuring.xml","url":"https://assets-eu.researchsquare.com/files/rs-7597140/v1/b2e3c9814797c4afced08ad7.xml"},{"id":94398607,"identity":"e5b6b74d-9d35-4b92-a73a-69df1b5dc924","added_by":"auto","created_at":"2025-10-27 13:57:09","extension":"html","order_by":8,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":72024,"visible":true,"origin":"","legend":"","description":"","filename":"earlyproof.html","url":"https://assets-eu.researchsquare.com/files/rs-7597140/v1/ceb7e8b988eab1ade6c2c05f.html"},{"id":94396573,"identity":"9a0e8543-a053-4ee0-b581-f685086af07b","added_by":"auto","created_at":"2025-10-27 13:56:04","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":253006,"visible":true,"origin":"","legend":"\u003cp\u003eT2-weighted MRI performed in year X-12 (A) revealed a hyperintense tumor located in the medial temporal lobe.\u003c/p\u003e\n\u003cp\u003eT2-weighted MRI performed in year X-5 (B) and X (C) demonstrated progression of multi-cystic changes and gradual enlargement.\u003c/p\u003e","description":"","filename":"renamed5a2951.png","url":"https://assets-eu.researchsquare.com/files/rs-7597140/v1/b88600577571723636fc6504.png"},{"id":94398663,"identity":"e50bb1f7-da87-475c-9569-6e2734e109b0","added_by":"auto","created_at":"2025-10-27 13:57:10","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":588437,"visible":true,"origin":"","legend":"\u003cp\u003eT1-weighted MRI revealed the tumor as hypointense (A), and contrast-enhanced T1-weighted MRI demonstrated no enhancement (B).\u003c/p\u003e\n\u003cp\u003eT2-weighted MRI revealed satellite lesions in the bilateral thalami (dotted circle) (C).\u003c/p\u003e\n\u003cp\u003eCoronal T2-weighted MRI showed tumor involvement of the hippocampus and amygdala (D) and small satellite lesions in the temporal lobe cortex (arrow)(E).\u003c/p\u003e\n\u003cp\u003ePostoperative coronal T2-weighted MRI demonstrated resection of the cortex in the anterolateral temporal lobe, with residual tumor identified in the medial components (F).\u003c/p\u003e","description":"","filename":"renamed5a2952.png","url":"https://assets-eu.researchsquare.com/files/rs-7597140/v1/08398f9c2e807f4b0af0e45b.png"},{"id":94399188,"identity":"4a2cfb6b-ca60-46e8-96e5-31b250325a44","added_by":"auto","created_at":"2025-10-27 13:57:23","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":1076832,"visible":true,"origin":"","legend":"\u003cp\u003eHistopathological findings with hematoxylin and eosin staining\u003c/p\u003e\n\u003cp\u003e(A) The cortical specimen comprised a predominantly neuronal component composed of small round cells and perivascular pseudorosettes. Although a myxoid background was observed, floating neurons were not detected.\u003c/p\u003e\n\u003cp\u003e(B) The white matter specimen was predominantly composed of glial elements, mainly consisting of OLCs.\u003c/p\u003e\n\u003cp\u003e(C) Neurocytic rosettes (arrow) were identified within the neuronal component.\u003c/p\u003e\n\u003cp\u003eImmunohistochemical findings\u003c/p\u003e\n\u003cp\u003e(D) The small round cells were negative for GFAP and positive for Olig2.\u003c/p\u003e\n\u003cp\u003e(E) OLCs were GFAP-negative and Olig2-positive.\u003c/p\u003e\n\u003cp\u003e(F) The core of the neurocytic rosettes was positive for synaptophysin (arrow).\u003c/p\u003e","description":"","filename":"renamed5a2953.png","url":"https://assets-eu.researchsquare.com/files/rs-7597140/v1/f5d3ac3f820933c978dab8dd.png"},{"id":100070011,"identity":"aa334549-486d-42e8-bbcf-db2d87bb1196","added_by":"auto","created_at":"2026-01-12 16:15:54","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2493301,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7597140/v1/5a0e02a4-4c90-4575-8650-c4f462a6fbc7.pdf"},{"id":94398725,"identity":"71db16d0-b97d-4bd0-b232-b8bc170b0e34","added_by":"auto","created_at":"2025-10-27 13:57:12","extension":"png","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":26629,"visible":true,"origin":"","legend":"\u003cp\u003eTable1 : Summary of LEAT-like epilepsy associated tumor with pathological features of RGNT.\u003c/p\u003e","description":"","filename":"renamed5a2954.png","url":"https://assets-eu.researchsquare.com/files/rs-7597140/v1/7f52394e2bffef61e893227c.png"}],"financialInterests":"","formattedTitle":"\u003cp\u003eMultifocal Rosette-forming Glioneuronal Tumor-like Low-Grade Glioneuronal Tumor with Dysembryoplastic Neuroepithelial Tumor Features Associated with Drug-Resistant Epilepsy: A Case Report and Literature Review\u003c/p\u003e","fulltext":[{"header":"Introduction","content":"\u003cp\u003eRosette-forming glioneuronal tumors (RGNTs) are rare World Health Organization (WHO) grade I neoplasms, initially defined as \u0026ldquo;RGNT of the fourth ventricle\u0026rdquo; [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e] because of their typical site of origin. However, more recent reports have documented RGNTs arising in atypical locations, including the cerebral hemispheres, often presenting with epilepsy [\u003cspan additionalcitationids=\"CR3 CR4 CR5 CR6 CR7\" citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eLow-grade epilepsy-associated tumors (LEATs) are a group of brain neoplasms frequently linked with drug-resistant epilepsy (DRE), particularly in younger patients [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. Dysembryoplastic neuroepithelial tumor (DNT) is a well-established glioneuronal LEAT subtype and accounts for approximately 20% of such cases [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. DNTs typically arise in the temporal cortex and present with early-onset seizures that are frequently resistant to medical therapy. Magnetic resonance imaging (MRI) often reveals well-demarcated, pseudocystic or multicystic lesions with hypointensity on T1-weighted imaging, hyperintensity on T2-weighted imaging, and minimal or no gadolinium enhancement [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. Interestingly, similar imaging features have been reported for epilepsy-associated hemispheric RGNTs.\u003c/p\u003e\u003cp\u003eMultifocality is rare for both RGNTs[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e] and DNTs [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e], and poses significant diagnostic challenges. Moreover, RGNT cases with overlapping DNT-like histopathological features have been described [\u003cspan additionalcitationids=\"CR3 CR4 CR5 CR6 CR7\" citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e], complicating definitive diagnosis. Here, we report a rare case of a multifocal, epilepsy-associated low-grade glioneuronal tumor exhibiting histological features of both RGNT and DNT.\u003c/p\u003e"},{"header":"Clinical Summary","content":"\u003cp\u003eA 26-year-old woman with no significant medical history was found incidentally to have a left medial temporal lobe lesion at age 14 following a minor head injury. Initial MRI revealed a non-enhancing lesion with T1 hypointensity and T2 hyperintensity (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eA). As she remained asymptomatic, a surveillance approach was chosen. Over several years, the lesion slowly enlarged and developed increasing multicystic morphology.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eAt age 21, the patient developed recurrent focal seizures characterized by behavioral arrest, amnesia, and right-sided paresthesia. EEG showed anterior temporal spike-wave discharges, and MRI revealed further enlargement of the known lesion (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eB). She was diagnosed with tumor-related epilepsy and was prescribed anti-seizure medications. Despite polytherapy, seizures persisted, indicating DRE.\u003c/p\u003e\u003cp\u003eAt age 25, MRI revealed further tumor progression involving the amygdala and hippocampus, with small cystic satellite lesions in the temporal neocortex and bilateral thalami(Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eC,\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eA-E). Although the lesion’s imaging resembled DNT, the multifocal nature and progressive enlargement were atypical.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eSurgical treatment was pursued at age 26. Chronic intracranial EEG was conducted using subdural and depth electrodes over the lateral and basal temporal lobes, thalamus, and frontal cortex. Ictal EEG showed initial discharges in the thalamus, followed by propagation from the basal to lateral temporal regions. Based on functional mapping and seizure localization, anterior temporal lobectomy with maximal safe resection of the tumor was performed, sparing eloquent cortex. Intraoperatively, the tumor was found to be poorly vascularized, exhibiting an extremely soft, gelatinous consistency. Owing to the difficulty in achieving en bloc resection, a representative portion was submitted for histopathological analysis, while the remaining bulk of the tumor was removed via suction. Partial resection was performed to minimize the risk of brainstem injury, with residual tumor tissue adjacent to the brainstem. Postoperative MRI revealed residual tumor in the medial and posterior temporal lobe (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eF). More than two years after surgery, there has been no evidence of tumor regrowth, and the patient has remained seizure-free.\u003c/p\u003e"},{"header":"Pathological Findings","content":"\u003cp\u003eHematoxylin and eosin staining of the resected specimens revealed predominantly cerebral cortex with extension into the underlying white matter, consistent with an infiltrative growth pattern. Both neuronal and glial components were identified. The neuronal component was primarily located in the cortex and consisted of small round cells within a myxoid background (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eA). A single neurocytic rosette was noted (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eC), along with perivascular pseudorosettes (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eA). Despite the myxoid background, floating neurons were not identified (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eA). The glial component was predominantly located in the white matter and was characterized by oligodendroglia-like cells (OLCs) with microcystic architecture and perinuclear halos (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eB). No areas resembling pilocytic astrocytoma were identified. Immunohistochemical staining of the small round cells in the neuronal component was negative for glial fibrillary acidic protein (GFAP), and positive for oligodendrocyte transcription factor 2 (Olig2) and microtubule-associated protein 2 (MAP2) (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eD). In the glial component, the OLCs were negative for GFAP and MAP2, but positive for Olig2 (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eE). Additionally, the core of the neurocytic rosette was positive for synaptophysin (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eF).\u003c/p\u003e\u003cp\u003eSanger sequencing identified a Fibroblast Growth Factor Receptor 1 (FGFR1)-K656E mutation. No mutations were detected in Isocitrate Dehydrogenase (IDH)1/2, Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA), or Phosphoinositide-3-kinase regulatory subunit 1 (PIK3R1). Multiplex ligation-dependent probe amplification revealed neither 1p/19q codeletion nor Cyclin-Dependent Kinase Inhibitor 2A/B (CDKN2A/B) homozygous deletion. Neurofibromin 1(NF1) mutation examination was not performed.\u003c/p\u003e\u003cp\u003eMethylation profiling analysis using the DKFZ classifier (version 12.8) identified a match with the “low-grade glioneuronal tumor” methylation class (calibrated score: 0.95); however, no subclass category yielded a significant match.\u003c/p\u003e\u003cp\u003eBased on histopathological and immunohistochemical findings, the lesion was provisionally diagnosed as a low-grade glioneuronal tumor. Although the presence of OLCs was suggestive of DNT, the identification of a neurocytic rosette and perivascular pseudorosettes was more indicative of RGNT. The detected FGFR1 mutation is commonly observed in both DNT and RGNT, and thus lacks diagnostic specificity. While the observed neurocytic rosette was not entirely typical of RGNT, diagnostic weight was given to its presence, leading to a final diagnosis of RGNT-like glioneuronal tumor with DNT features.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis report describes a rare case of DRE associated with a multifocal glioneuronal tumor that exhibited histological features of both RGNT and DNT. While RGNT is typically a midline lesion, the present case involved the temporal lobe and was multifocal; combined with overlapping histopathological and molecular features, this posed a considerable diagnostic challenge. We discuss three major aspects of this case: the diagnostic justification for RGNT, the differential diagnosis between RGNT and DNT, and implications for prognosis and treatment in epilepsy-associated RGNT.\u003c/p\u003e\u003cp\u003e\u003cb\u003e1. Clinical and Pathological Basis for RGNT Diagnosis\u003c/b\u003e\u003c/p\u003e\u003cp\u003eRGNTs were initially characterized in 2002 by Komori et al. as arising preferentially in the fourth ventricle. The initial 2007 WHO classification was \u0026ldquo;RGNT of the fourth ventricle,\u0026rdquo; but was renamed to \u0026ldquo;RGNT\u0026rdquo; in the 2021 edition to reflect its broader anatomical distribution. Reported locations include the pineal gland [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e], optic chiasm [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e], spinal cord [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e], and cerebral hemispheres [\u003cspan additionalcitationids=\"CR3 CR4 CR5 CR6 CR7\" citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. Histologically, RGNT is defined by biphasic architecture: a neurocytic component with rosettes and/or perivascular pseudorosettes that express synaptophysin, and a glial component resembling pilocytic astrocytoma [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eIn the present case, the tumor exhibited a glioneuronal biphasic pattern with Olig2-positive neurocytic rosettes and OLCs. While floating neurons and specific glioneuronal elements typical of DNT were not observed, sampling error cannot be entirely excluded. Given the presence of neurocytic rosette and synaptophysin positivity, the histological features aligned more closely with RGNT than DNT. Immunohistochemistry further supported a glioneuronal classification.\u003c/p\u003e\u003cp\u003eMolecular profiling revealed an FGFR1 mutation without additional alterations in PIK3CA, PIK3R1. According to a large molecular study by Appay et al., most midline RGNTs with FGFR1 mutations also carry co-mutations in PIK3CA, PIK3CA, or NF1. In contrast, supratentorial cases tend to lack these additional mutations. Based on these findings, the authors propose that the presence of an FGFR1 mutation and a midline intracranial location should be considered essential diagnostic criteria for RGNT [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. According to this proposal, the anatomical location and genetic profile of the present case do not represent typical RGNT. However, given that the histopathological and immunohistochemical findings closely correspond to the WHO diagnostic criteria for RGNT, the tumor was ultimately diagnosed as an RGNT-like glioneuronal tumor with DNT features.\u003c/p\u003e\u003cp\u003e\u003cb\u003e2. Diagnostic Overlap Between RGNT and DNT in LEAT-like Tumors\u003c/b\u003e\u003c/p\u003e\u003cp\u003eDifferentiating RGNT from DNT can be particularly difficult in hemispheric tumors presenting with epilepsy alone. DNTs are WHO grade 1 cortical tumors, typically found in the temporal lobe of young patients with early-onset epilepsy [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. Radiologically, they often present as a multicystic lesion with a characteristic \u0026ldquo;bubbly\u0026rdquo; appearance on T2-weighted MRI, with minimal gadolinium enhancement. Histologically, DNT is defined by the presence of a specific glioneuronal element, including floating neurons in a mucinous matrix, and OLCs [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. FGFR1 mutations are common in both DNT and RGNT, limiting their diagnostic specificity. In recent WHO classifications, DNT diagnosis also considers DNA methylation profiling [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eThe present tumor exhibited some features commonly observed in DNT, particularly OLCs and cortical location, but lacked the defining glioneuronal element and floating neurons. Moreover, the neurocytic rosettes and perivascular pseudorosettes are atypical for DNT but characteristic of RGNT, favoring a RGNT diagnosis.\u003c/p\u003e\u003cp\u003eOwusu et al. recently reviewed 129 RGNT cases and found that 49 (37.8%) were located in the cerebral hemispheres [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. Of these, 15 patients (44%) presented with epilepsy, and seven exhibited early-onset DRE without signs of elevated intracranial pressure\u0026mdash;clinical features mimicking LEATs (Table\u0026nbsp;1). Interestingly, all seven of these DRE cases demonstrated histological features reminiscent of DNT, particularly the presence of OLCs, and all harbored FGFR1 mutations. However, none exhibited PIK3CA or NF1 mutations, again distinguishing them from midline RGNTs. These observations support the hypothesis that some hemispheric RGNTs may exist on a spectrum of glioneuronal tumors with DNT-like features. Similarly, Daumas-Duport et al. previously categorized DNT into simple, complex, and non-specific forms [\u003cspan additionalcitationids=\"CR25\" citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. Before RGNT was defined in 2002, some unrecognized cases\u0026mdash;particularly those with rosette formation\u0026mdash;may have been diagnosed as non-specific DNTs.\u003c/p\u003e\u003cp\u003eThe multifocal appearance of the present tumor further complicated the differential diagnosis. Although rare, multifocal lesions have been reported in cases of both DNT and RGNT [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]; multifocality cannot therefore be considered a distinguishing feature. Many epilepsy-associated glioneuronal tumors with RGNT features demonstrate overlapping DNT-like properties.\u003c/p\u003e\u003cp\u003eWhile morphological and immunohistochemical evaluations are important for the accurate diagnosis of glioneuronal tumors, genetic analyses are also stipulated by WHO criteria [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. However, it should be noted that the PIK3CA and NF1 mutations described in the WHO classification are based on cases arising in the third and fourth ventricles; no such mutations have been reported in RGNTs presenting with a LEAT-like clinical course, such as the present case. While FGFR1 mutations are common in these tumors, this feature is shared with DNT, limiting their utility in differential diagnosis. The discovery of genetic markers that distinguish DNT and RGNT in epilepsy-associated tumors in the cerebral hemisphere remains an important target for future research.\u003c/p\u003e\u003cp\u003e\u003cb\u003e3. Prognosis and Management in Epilepsy-Associated RGNT\u003c/b\u003e\u003c/p\u003e\u003cp\u003eAt two years post-surgery, the patient remains seizure-free, suggesting that the epileptogenic focus was successfully resected. However, residual tumor remains, and future recurrence cannot be excluded. In prior reports, seizure recurrence has been associated with tumor progression or incomplete resection in cases of DNT [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]. Gross total resection is generally considered optimal for seizure control. Incomplete resection and the presence of satellite lesions are associated with poorer outcomes in DNT studies [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]. Although temporary seizure freedom may be achieved after partial resection, the likelihood of recurrence increases over time.\u003c/p\u003e\u003cp\u003eIn the present case, the residual lesion lies near eloquent cortex, limiting the feasibility of reoperation. For such cases, alternative treatment strategies must be considered. Neuromodulation, including vagus nerve stimulation (VNS), has shown efficacy in select cases of tumor-related epilepsy [\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]. Although data are limited, VNS may be a viable adjunct in managing recurrent seizures when further resection is not possible.\u003c/p\u003e\u003cp\u003eAnother emerging approach is targeted molecular therapy. FGFR1 inhibitors, such as erdafitinib, have been approved for use in other malignancies, including bladder cancer and cholangiocarcinoma [\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]. Owusu et al. reported radiological improvement in a progressive RGNT case treated off-label with erdafitinib [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. Although not yet approved for central nervous system tumors, these agents hold promise, particularly for surgically unresectable FGFR1-mutant tumors. A \u0026ldquo;watchful waiting\u0026rdquo; strategy with the potential for targeted therapy may be appropriate in selected cases.\u003c/p\u003e\u003cp\u003eMalignant transformation[\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e] and leptomeningeal dissemination [\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e] have been reported in RGNTs, highlighting the need for long-term monitoring. Despite shared features, the prognosis and optimal follow-up strategies for RGNT and DNT may differ, and accurate diagnosis is essential for guiding management.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eThis case underscores the diagnostic and therapeutic challenges posed by glioneuronal tumors exhibiting overlapping features of RGNT and DNT. In the current case, a multifocal presentation, combined with histological evidence of neurocytic rosettes and OLCs and a solitary FGFR1 mutation, supports classification as an RGNT-like tumor with DNT features. However, the possibility of a rare DNT variant remains, particularly noting the absence of RGNT-specific co-mutations. Accumulation of additional well-characterized cases will be vital to clarify the pathological spectrum of epilepsy-associated glioneuronal tumors and refine diagnostic criteria. For similar multifocal lesions in eloquent areas where gross total resection is not feasible, the risk of seizure recurrence is high. In such cases, multimodal management, including neuromodulation and future molecular targeting therapy, should be considered, alongside vigilant long-term follow-up.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgment\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe thank Wilf Gardner, PhD, from Edanz (https://jp.edanz.com/ac) for editing a draft of this manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics declarations\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eConflict of interest\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no conflict of interest.\u003c/p\u003e\n\u003cp\u003eEthical approval and consent to patient\u003c/p\u003e\n\u003cp\u003eThe patient provided written informed consent for the case to be published.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eAuthor information\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor and Affiliations\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDepartment of Neurosurgery, Nakamura Memorial Hospital, South1, West14, Chuo-ku, Sapporo, 060-8570, Japan.\u003c/p\u003e\n\u003cp\u003eYuuki Ishida, Kenichi Sato ,Taku Asanome ＆ Ryunosuke Yoshihara\u003c/p\u003e\n\u003cp\u003eDepartment of Cancer Pathology, Faculty of Medicine, Hokkaido University, Sapporo, Japan.\u003c/p\u003e\n\u003cp\u003eKoki Ise ,Yoshitaka Oda, Hirokazu Sugino,Masumi Tsuda ＆ Shinya Tanaka\u003c/p\u003e\n\u003cp\u003eDepartment of Neurology, Nakamura Memorial Hospital, Sapporo, Japan.\u003c/p\u003e\n\u003cp\u003eYoko Aburakawa\u003c/p\u003e\n\u003cp\u003eCenter of Epilepsy and Functional neurology, Seirei Hamamatsu General hospital, Hamamatsu, Japan.\u003c/p\u003e\n\u003cp\u003eYuuki Ishida＆ Masaki Izumi\u003c/p\u003e\n\u003cp\u003eDepartment of Surgical Pathology, Hokkaido University Hospital, Sapporo, Japan.\u003c/p\u003e\n\u003cp\u003eZen-ichi Tanei ＆ Shinya Tanaka\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eWPI-ICReDD, Hokkaido University, Sapporo, Japan.\u003c/p\u003e\n\u003cp\u003eMasumi Tsuda ＆ Shinya Tanaka .\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eContributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eConception,design and drafting of the manuscript: YI. Clinical deta acquisition: YI, KS, TA, RY and YA. Pathological diagnosis: KI, YO, HS, ZT and ST. Genetic analysis: MT. Revision of the manuscript: KS, MI and ST.\u003c/p\u003e\n\u003cp\u003eAll authors read and approved the final manuscript \u0026nbsp;\u003c/p\u003e\n\u003cp\u003eCorresponding author\u003c/p\u003e\n\u003cp\u003eCorrespondance to Yuuki Ishida.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eT. Komori, B. W. Scheithauer and T. Hirose . A rosette-forming glioneuronal tumor of the fourth ventricle: infratentorial form of dysembryoplastic neuroepithelial tumor?. Am J Surg Pathol 2002 Vol. 26 Issue 5 Pages 582-91\u003c/li\u003e\n\u003cli\u003eT. Uchiyama, A. Gomi, S. Nobusawa, et al. A case of a rosette-forming glioneuronal tumor with clinicopathological features of a dysembryoplastic neuroepithelial tumor and fibroblast growth factor receptor 1 internal tandem duplication. Brain Tumor Pathol 2021 Vol. 38 Issue 3 Pages 250-256\u003c/li\u003e\n\u003cli\u003eA. Halfpenny, S. P. Ferris, M. Grafe et al. A case of recurrent epilepsy-associated rosette-forming glioneuronal tumor with anaplastic transformation in the absence of therapy. Neuropathology 2019 Vol. 39 Issue 5 Pages 389-393\u003c/li\u003e\n\u003cli\u003eS. Yamada, S. Nobusawa, T. Yamazaki, T et al. An epilepsy-associated glioneuronal tumor with mixed morphology harboring FGFR1 mutation. Pathol Int 2019 Vol. 69 Issue 6 Pages 372-377\u003c/li\u003e\n\u003cli\u003eN. Sumitomo, A. Ishiyama, M. Shibuya et al. Intractable epilepsy due to a rosette-forming glioneuronal tumor with a dysembryoplastic neuroepithelial background. Neuropathology 2018 Vol. 38 Issue 3 Pages 300-304\u003c/li\u003e\n\u003cli\u003eE. Matyja, W. Grajkowska, P. Kunert at al. A peculiar histopathological form of dysembryoplastic neuroepithelial tumor with separated pilocytic astrocytoma and rosette-forming glioneuronal tumor components. Neuropathology 2014 Vol. 34 Issue 5 Pages 491-8\u003c/li\u003e\n\u003cli\u003eJ. Xiong, L. Ding, H. Chen et al. Mixed glioneuronal tumor: a dysembryoplastic neuroepithelial tumor with rosette-forming glioneuronal tumor component. Neuropathology 2013 Vol. 33 Issue 4 Pages 431-5\u003c/li\u003e\n\u003cli\u003eS. Y. Chen, W. Wang, L. M. Wang et al. Glioneuronal tumours with features of rosette-forming glioneuronal tumours of the fourth ventricle and dysembryoplastic neuroepithelial tumours: a report of three cases. Histopathology 2016 Vol. 68 Issue 3 Pages 378-87\u003c/li\u003e\n\u003cli\u003eS. Rosemberg. Long-term epilepsy associated-tumors (LEATs): what is new? Arq Neuropsiquiatr 2023 Vol. 81 Issue 12 Pages 1146-1151\u003c/li\u003e\n\u003cli\u003eC. Mann, N. Melzer D. M\u0026uuml;nch. Epilepsy in LEAT and other brain tumors: A focused review. Epilepsy Behav 2024 Vol. 160 Pages 110092\u003c/li\u003e\n\u003cli\u003eJ. H. Phi, S. H. Kim. Dysembryoplastic Neuroepithelial Tumor: A Benign but Complex Tumor of the Cerebral Cortex. Brain Tumor Res Treat 2022 Vol. 10 Issue 3 Pages 144-150\u003c/li\u003e\n\u003cli\u003eJ. Schittenhelm, M. Mittelbronn, M. Wolff et al. Multifocal dysembryoplastic neuroepithelial tumor with signs of atypia after regrowth. Neuropathology 2007 Vol. 27 Issue 4 Pages 383-9\u003c/li\u003e\n\u003cli\u003eA. I. Yang, A. M. Khawaja, L. Ballester-Fuentes et al. Multifocal dysembryoplastic neuroepithelial tumours associated with refractory epilepsy. Epileptic Disord 2014 Vol. 16 Issue 3 Pages 328-32\u003c/li\u003e\n\u003cli\u003eA. Michel, T. F. Dinger, R. Jabbarli et al. Treatment of Pineal Region Rosette-Forming Glioneuronal Tumors (RGNT).Cancers (Basel) 2022 Vol. 14 Issue 19. \u003c/li\u003e\n\u003cli\u003eR. Bharadwaj, Y. T. Chickabasaviah, S. Rao et al. Rosette-forming Glioneuronal Tumor in the Optic Pathway of a Child. J Pediatr Hematol Oncol 2020 Vol. 42 Issue 7 Pages e655-e658\u003c/li\u003e\n\u003cli\u003eA. Sekar, S. Rudrappa, S. Gopal, N et al. Rosette-Forming Glioneuronal Tumor in Opticochiasmatic Region-Novel Entity in New Location. World Neurosurg 2019 Vol. 125 Pages 253-256\u003c/li\u003e\n\u003cli\u003eA. Collin, H. Adle-Biassette and A. Lecler. Rosette-Forming Glioneuronal Tumor of Spinal Cord. World Neurosurg 2018 Vol. 119 Pages 242-243\u003c/li\u003e\n\u003cli\u003eS. A. Sreenivasan, K. Garg, A. Nambirajan et al. Rosette-forming glioneuronal tumour of dorsolumbar spinal cord. Childs Nerv Syst 2019 Vol. 35 Issue 8 Pages 1277-1279\u003c/li\u003e\n\u003cli\u003eJ.A Hainfellner, T.S Jacques, D.T.W Jones et al, Rosette-forming glioneuronal tumour World Health Organization Classification of Tumours of the Central Nervous System.5th Edition Pages 133-135.\u003c/li\u003e\n\u003cli\u003eR. Appay, F. Bielle, P. Sievers, D. Barets, F. Fina, J. Boutonnat, et al. Rosette-forming glioneuronal tumours are midline, FGFR1-mutated tumours. Neuropathol Appl Neurobiol 2022 Vol. 48 Issue 5 Pages e12813\u003c/li\u003e\n\u003cli\u003eT.Pietsch, D.W.Ellison, T.Hirose et al.Dysembryoplastic neuroepithelial tumour. World Health Organization Classification of Tumours of the Central Nervous System.5th Edition Pages 123-126.\u003c/li\u003e\n\u003cli\u003eB. Owusu-Adjei, C. J. Mietus, J. C. Lim, et al. Diffusely invasive supratentorial rosette-forming glioneuronal tumor: illustrative case. J Neurosurg Case Lessons 2023 Vol. 6 Issue 16.\u003c/li\u003e\n\u003cli\u003eH. Takita, T. Shimono, T. Uda et al. Malignant transformation of a dysembryoplastic neuroepithelial tumor presenting with intraventricular hemorrhage. Radiol Case Rep 2022 Vol. 17 Issue 3 Pages 939-943 Pages 123-126.\u003c/li\u003e\n\u003cli\u003eC. Daumas-Duport, B. W. Scheithauer, J. P. Chodkiewicz et al.Dysembryoplastic neuroepithelial tumor: a surgically curable tumor of young patients with intractable partial seizures. Report of thirty-nine cases. Neurosurgery 1988 Vol. 23 Issue 5 Pages 545-56\u003c/li\u003e\n\u003cli\u003eC. Daumas-Duport. Dysembryoplastic neuroepithelial tumours. Brain Pathol 1993 Vol. 3 Issue 3 Pages 283-95\u003c/li\u003e\n\u003cli\u003eC. Daumas-Duport, P. Varlet, S. Bacha et al. Dysembryoplastic neuroepithelial tumors: nonspecific histological forms -- a study of 40 cases. J Neurooncol 1999 Vol. 41 Issue 3 Pages 267-80\u003c/li\u003e\n\u003cli\u003eJ. Yang, S. K. Kim, K. J. Kim et al. Satellite lesions of DNET: implications for seizure and tumor control after resection. J Neurooncol 2019 Vol. 143 Issue 3 Pages 437-445\u003c/li\u003e\n\u003cli\u003eP. A. Bonney, L. B. Boettcher, A. K. Conner et al. Review of seizure outcomes after surgical resection of dysembryoplastic neuroepithelial tumors. J Neurooncol 2016 Vol. 126 Issue 1 Pages 1-10\u003c/li\u003e\n\u003cli\u003eK. S. Patel, D. R. Labar, C. M. Gordon et al. Efficacy of vagus nerve stimulation as a treatment for medically intractable epilepsy in brain tumor patients. A case-controlled study using the VNS therapy Patient Outcome Registry. Seizure 2013 Vol. 22 Issue 8 Pages 627-33\u003c/li\u003e\n\u003cli\u003eV. Subbiah and S. Verstovsek. Clinical development and management of adverse events associated with FGFR inhibitors. Cell Rep Med 2023 Vol. 4 Issue 10 Pages 101204\u003c/li\u003e\n\u003cli\u003eS. M. Kwon, J. H. Kim, J. Byun et al. Malignant Transformation of a Rosette-Forming Glioneuronal Tumor to Glioblastoma. World Neurosurg 2019 Vol. 130 Pages 271-275\u003c/li\u003e\n\u003cli\u003eJ. T. Hockman, N. E. El Tecle, J. F. Urquiaga et al. Dissemination Patterns and Short-Term Management of Multifocal Rosette-Forming Glioneuronal Tumors. World Neurosurg 2021 Vol. 149 Pages 86-93\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Table 1","content":"\u003cp\u003eTable 1 is available in the Supplementary Files section.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":true,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"brain-tumor-pathology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"btpa","sideBox":"Learn more about [Brain Tumor Pathology](http://link.springer.com/journal/10014)","snPcode":"10014","submissionUrl":"https://www.editorialmanager.com/btpa/default2.aspx","title":"Brain Tumor Pathology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"Rosette-forming glioneuronal tumor, Dysembryoplastic neuroepithelial tumor, Low-grade epilepsy associated tumor, FGFR1, Multifocal","lastPublishedDoi":"10.21203/rs.3.rs-7597140/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7597140/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eRosette-forming glioneuronal tumors (RGNTs) are rare, World Health Organization grade 1 tumors that typically arise around the fourth ventricle. However, cerebral hemisphere RGNTs have recently been reported, with some exhibiting clinical features resembling low-grade epilepsy-associated tumor (LEAT). We report a case of multifocal RGNT involving the temporal lobe and thalamus in a patient with drug-refractory epilepsy. During evaluation for head trauma, a 14-year-old woman was incidentally found to have a brain tumor. Magnetic resonance imaging revealed multifocal lesions in the left temporal lobe and bilateral thalamus. The tumor enlarged over time, and epilepsy developed at age 24, becoming drug-resistant and necessitating surgery at age 26. Partial tumor resection and anterior temporal lobectomy were performed. Histopathology revealed a glioneuronal tumor with oligodendroglia-like cells, neurocytic rosette, and perivascular pseudorosette. Genetic analysis revealed Fibroblast Growth Factor Receptor 1 mutation, and the tumor was diagnosed as an RGNT-like low-grade glioneuronal tumor with dysembryoplastic neuroepithelial tumor (DNT) features. Cases presenting with a LEAT-like clinical course and exhibiting histopathological features of RGNT are often difficult to definitively distinguish from DNT based on histological and genetic findings. Epilepsy-associated RGNT may harbor genetic profiles distinct from those of prototypical RGNTs, highlighting the need for further investigation.\u003c/p\u003e","manuscriptTitle":"Multifocal Rosette-forming Glioneuronal Tumor-like Low-Grade Glioneuronal Tumor with Dysembryoplastic Neuroepithelial Tumor Features Associated with Drug-Resistant Epilepsy: A Case Report and Literature Review","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-10-26 00:36:52","doi":"10.21203/rs.3.rs-7597140/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"reviewerAgreed","content":"","date":"2025-10-10T12:51:49+00:00","index":0,"fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-10-10T12:48:56+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-09-13T07:26:08+00:00","index":"","fulltext":""},{"type":"submitted","content":"Brain Tumor Pathology","date":"2025-09-12T02:35:08+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"brain-tumor-pathology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"btpa","sideBox":"Learn more about [Brain Tumor Pathology](http://link.springer.com/journal/10014)","snPcode":"10014","submissionUrl":"https://www.editorialmanager.com/btpa/default2.aspx","title":"Brain Tumor Pathology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"4f651341-7630-432e-834a-63cf56abe465","owner":[],"postedDate":"October 26th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2026-01-12T16:09:00+00:00","versionOfRecord":{"articleIdentity":"rs-7597140","link":"https://doi.org/10.1007/s10014-025-00526-y","journal":{"identity":"brain-tumor-pathology","isVorOnly":false,"title":"Brain Tumor Pathology"},"publishedOn":"2026-01-06 15:58:35","publishedOnDateReadable":"January 6th, 2026"},"versionCreatedAt":"2025-10-26 00:36:52","video":"","vorDoi":"10.1007/s10014-025-00526-y","vorDoiUrl":"https://doi.org/10.1007/s10014-025-00526-y","workflowStages":[]},"version":"v1","identity":"rs-7597140","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7597140","identity":"rs-7597140","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}