Abstract
BACKGROUND: Rare embryonal and sarcomatous CNS tumours represent a diagnostic and therapeutic challenge. In the latest WHO 2021 several new tumour types, defined by molecular alterations, have been introduced. Some of these tumours have molecular counterparts outside the CNS e.g. CNS tumour with BCOR alteration or CIC-altered sarcoma.We report a CNS tumour with unusual histological and molecular features. METHODS/RESULTS: A 3-year-old boy presented with a 5x3 cm sized tumour in the left lateral ventricle, which was removed at an external institution. After treatment with 1 cycle carboplatin/etoposide the patient presented at our clinic with leptomeningeal dissemination across all CNS compartments. Therapy was switched to HIT-MED Guidance augmented by intraventricular therapy. Histology showed a highly cellular tumour composed of small uniform cells with round nuclei, distinct nucleoli and a scant cytoplasm. The cells were arranged sheet-like without discernible background. Mitotic figures were conspicuous. Immunohistochemically, expression of Olig2, Chromogranin A, NCAM, BCOR and EGFR was present; synaptophysin and SOX10 were positive in a fraction of cells. DNA methylation profiling using the DKFZ and the Bethesda CNS tumour classifier did not match with any methylation class. Archer FUSIONPlex panel revealed a ZNF532::NUTM1 fusion, which was confirmed by RNA sequencing, leading to the diagnosis of a CNS embryonal tumour NEC with ZNF532::NUTM1 fusion. CONCLUSIONS: NUTM1 fusion oncogenes, including among other fusion partners ZNF532, are drivers of aggressive NUT carcinomas. Furthermore, NUTM1 can be a fusion partner in CIC-rearranged sarcoma. The present case neither qualified as carcinoma nor sarcoma. As no clear response was evident after 3 cycles of HIT-MED Guidance therapy was switched to the Scandinavian Sarcoma Protocol. A similar case showing embryonal morphology has been recently reported (PMID 37203791). In conclusion, the spectrum of NUTM1-rearranged tumours is expanding and rare unclassifiable CNS embryonal tumours should be checked for NUTM1 immunopositivity/rearrangement.