Case Report: Unclassifiable cerebellar high-grade neuroepithelial tumor with a CCDC6::RET fusion manifesting...

A 20-year-old woman presented with a 1-month history of positional vertigo, occipital headaches, and progressive gait ataxia. Neuroimaging demonstrated a 3.7 × 4.2 × 3.3 cm heterogeneously enhancing mass in the left cerebellar hemisphere with fourth-ventricle compression, approximately 8 mm tonsillar herniation, and obstructive hydrocephalus. Urgent resection was performed through a midline suboccipital approach with neuronavigation and fluorescein guidance, achieving gross total removal. Histopathology showed an undifferentiated high-grade neuroepithelial malignancy with brisk mitotic activity and necrosis. The Ki-67 labeling index exceeded 80% in hotspot regions. Immunophenotyping showed partial glial marker expression and neuroendocrine marker expression; INI1 was retained and other markers did not support more common defined entities. Hybrid-capture DNA and RNA next-generation sequencing identified TP53 c.524G > A (p.R175H), amplification of CDK4 and AURKA, and an in-frame CCDC6 (exon 1)::RET (exon 12) fusion. Based on the integrated histologic, immunophenotypic, and molecular findings available, the tumor could not be assigned to a specific WHO-defined CNS tumor entity. Despite gross total resection and postoperative oncologic management, the tumor recurred rapidly with leptomeningeal dissemination and progressed to multifocal posterior fossa and brainstem disease. The patient died five months after diagnosis. This case illustrates the diagnostic and therapeutic challenges posed by rare, highly aggressive CNS neoplasms that do not map to a WHO-defined entity on available testing and highlights the potential clinical relevance of identifying actionable RET fusions in high-grade neuroepithelial tumors.