CNS neuroblastoma, FOXR2-activated and its mimics: a relevant panel approach for work-up and accurate diagnosis of this rare neoplasm

Tauziède‐Espariat, Arnault; Figarella‐Branger, Dominique; Métais, Alice; Uro‐Coste, Emmanuelle; Maurage, Claude‐Alain; Lhermitte, Benoît; Aline-Fardin, Aude; Hasty, Lauren; Vasiljevic, Alexandre; Chiforeanu, Dan Cristian; Chotard, Guillaume; Adle‐Biassette, Homa; Meurgey, Alexandra; Saffroy, Raphaël; Guillemot, Delphine; Sievers, Philipp; Varlet, Pascale

doi:10.1186/s40478-023-01536-7

Cited by 7 publications

(8 citation statements)

References 4 publications

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“…We confirm previous reports that demonstrated the use of SOX10 as a diagnostic marker to discriminate CNS NB from other embryonal tumours. 3,4 We also confirm that no ependymal tumour expressed SOX10, regardless of their location or molecular subtype, as was previously reported in supratentorial, ependymomas ZFTA-fusion positive and in cohorts of ependymomas from different locations (but without genetic or epigenetic characterization). 3 all DNA-methylation proven diffuse leptomeningeal glioneuronal tumours from our cohort were immunopositive for SOX10 (Figure S1).…”

supporting

confidence: 88%

“…1,2 Currently, SOX10 is used as an immunohistochemical (IHC) marker for peripheral nerves and melanocytic tumours, but very little information exists about its expression and potential use in CNS tumour diagnoses. [3][4][5] The aim of our study was to characterize the expression of SOX10 in a large cohort of adult and paediatric CNS tumours and to evaluate its potential use as a biomarker.…”

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confidence: 99%

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Utility of combining OLIG2 and SOX10 IHC expression in CNS tumours: promising biomarkers for subtyping paediatric‐ and adult‐type gliomas

Aboubakr,

Métais,

Maillard

et al. 2024

Histopathology

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AimsThe SOX10 transcription factor is important for the maturation of oligodendrocytes involved in central nervous system (CNS) myelination. Currently, very little information exists about its expression and potential use in CNS tumour diagnoses. The aim of our study was to characterize the expression of SOX10 in a large cohort of CNS tumours and to evaluate its potential use as a biomarker.MethodsWe performed immunohistochemistry (IHC) for SOX10 and OLIG2 in a series of 683 cases of adult‐ and paediatric‐type CNS tumours from different subtypes. The nuclear immunostaining results for SOX10 and OLIG2 were scored as positive (≥10% positive tumour cells) or negative.ResultsOLIG2 and SOX10 were positive in diffuse midline gliomas (DMG), H3‐mutant, and EZHIP‐overexpressed. However, in all DMG, EGFR‐mutant, SOX10 was constantly negative. In diffuse paediatric‐type high‐grade gliomas (HGG), all RTK1 cases were positive for both OLIG2 and SOX10. RTK2 cases were all negative for both OLIG2 and SOX10. MYCN cases variably expressed OLIG2 and were all immunonegative for SOX10. In glioblastoma, IDH‐wildtype, OLIG2 was mostly positive, but SOX10 was variably expressed, depending on the epigenetic subtype. All circumscribed astrocytic gliomas were positive for both OLIG2 and SOX10 except pleomorphic xanthoastrocytomas, astroblastomas, MN1‐altered, and subependymal giant cell astrocytomas. SOX10 was negative in ependymomas, meningiomas, pinealoblastomas, choroid plexus tumours, intracranial Ewing sarcomas, and embryonal tumours except neuroblastoma, FOXR2‐activated.ConclusionTo conclude, SOX10 can be incorporated into the IHC panel routinely used by neuropathologists in the diagnostic algorithm of embryonal tumours and for the subtyping of paediatric and adult‐type HGG.

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confidence: 88%

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confidence: 99%

Utility of combining OLIG2 and SOX10 IHC expression in CNS tumours: promising biomarkers for subtyping paediatric‐ and adult‐type gliomas

Aboubakr,

Métais,

Maillard

et al. 2024

Histopathology

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“…Five previously published cases [ 4 – 8 ] were identified in the following manner. One case presented a dedicated case report for a tumor matching to the methylation class “CNS embryonal tumor with BRD4::LEUTX fusion”, with demonstration of the fusion [ 4 ].…”

Section: Resultsmentioning

confidence: 99%

“…One of these reports characterized the fusion in a large series of pediatric cancers [ 5 ], while the other incorporated detailed clinical and pathological data, including methylome analysis matching to the novel Heidelberg version 12 classifier class “CNS embryonal tumor with BRD4::LEUTX fusion” [ 4 ]. Three additional cases also exist in the literature, which while not specifically described as such, were initially presented before the version 12 of the Heidelberg classifier was available to interrogate this provisional tumor type [ 6 – 8 ]. In addition to these 5 cases, we describe 4 additional unpublished new cases of CNS tumors with BRD4::LEUTX fusions, thereby expanding the limited characterization available for this tumor type to date.…”

Section: Introductionmentioning

confidence: 99%

Molecular and clinicopathologic characteristics of CNS embryonal tumors with BRD4::LEUTX fusion

Andreiuolo,

Ferrone,

Rajan

et al. 2024

acta neuropathol commun

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Central nervous system (CNS) embryonal tumors are a heterogeneous group of high-grade malignancies, and the increasing clinical use of methylation profiling and next-generation sequencing has led to the identification of molecularly distinct subtypes. One proposed tumor type, CNS tumor with BRD4::LEUTX fusion, has been described. As only a few CNS tumors with BRD4::LEUTX fusions have been described, we herein characterize a cohort of 9 such cases (4 new, 5 previously published) to further describe their clinicopathologic and molecular features. We demonstrate that CNS embryonal tumor with BRD4::LEUTX fusion comprises a well-defined methylation class/cluster. We find that patients are young (4 years or younger), with large tumors at variable locations, and frequently with evidence of leptomeningeal/cerebrospinal fluid (CSF) dissemination. Histologically, tumors were highly cellular with high-grade embryonal features. Immunohistochemically, 5/5 cases showed synaptophysin and 4/5 showed OLIG2 expression, thus overlapping with CNS neuroblastoma, FOXR2-activated. DNA copy number profiles were generally flat; however, two tumors had chromosome 1q gains. No recurring genomic changes, besides the presence of the fusion, were found. The LEUTX portion of the fusion transcript was constant in all cases assessed, while the BRD4 portion varied but included a domain with proto-oncogenic activity in all cases. Two patients with clinical follow up available had tumors with excellent response to chemotherapy. Two of our patients were alive without evidence of recurrence or progression after gross total resection and chemotherapy at 16 and 33 months. One patient relapsed, and the last of our four patients died of disease one month after diagnosis. Overall, this case series provides additional evidence for this as a distinct tumor type defined by the presence of a specific fusion as well as a distinct DNA methylation signature. Studies on larger series are required to further characterize these tumors.

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“…DNA methylation profiling can recognize this tumor type, while RNA NGS can be used to detect the FOXR2 rearrangement [ 69 ]. Recently, an integrated diagnostic algorithm has been proposed for the diagnostic work-up of suspected CNS neuroblastomas, FOXR2 -activated [ 70 ].…”

Section: Applying Molecular Assays To the Diagnostic Workup Of Cns Tu...mentioning

confidence: 99%

Molecular neuropathology: an essential and evolving toolbox for the diagnosis and clinical management of central nervous system tumors

Bertero,

Mangherini,

Ricci

et al. 2023

Virchows Arch

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Molecular profiling has transformed the diagnostic workflow of CNS tumors during the last years. The latest WHO classification of CNS tumors (5th edition), published in 2021, pushed forward the integration between histopathological features and molecular hallmarks to achieve reproducible and clinically relevant diagnoses. To address these demands, pathologists have to appropriately deal with multiple molecular assays mainly including DNA methylation profiling and DNA/RNA next generation sequencing. Tumor classification by DNA methylation profiling is now a critical tool for many diagnostic tasks in neuropathology including the assessment of complex cases, to evaluate novel tumor types and to perform tumor subgrouping in hetereogenous entities like medulloblastoma or ependymoma. DNA/RNA NGS allow the detection of multiple molecular alterations including single nucleotide variations, small insertions/deletions (InDel), and gene fusions. These molecular markers can provide key insights for diagnosis, for example, if a tumor-specific mutation is detected, but also for treatment since targeted therapies are progressively entering the clinical practice. In the present review, a brief, but comprehensive overview of these tools will be provided, discussing their technical specifications, diagnostic value, and potential limitations. Moreover, the importance of molecular profiling will be shown in a representative series of CNS neoplasms including both the most frequent tumor types and other selected entities for which molecular characterization plays a critical role.

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CNS neuroblastoma, FOXR2-activated and its mimics: a relevant panel approach for work-up and accurate diagnosis of this rare neoplasm

Cited by 7 publications

References 4 publications

Utility of combining OLIG2 and SOX10 IHC expression in CNS tumours: promising biomarkers for subtyping paediatric‐ and adult‐type gliomas

Utility of combining OLIG2 and SOX10 IHC expression in CNS tumours: promising biomarkers for subtyping paediatric‐ and adult‐type gliomas

Molecular and clinicopathologic characteristics of CNS embryonal tumors with BRD4::LEUTX fusion

Molecular neuropathology: an essential and evolving toolbox for the diagnosis and clinical management of central nervous system tumors

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