Systemic Therapy for High-Grade Olfactory Neuroblastoma: From Molecular Lineages to Targeted and Immune Strategies

Advanced olfactory neuroblastoma (ONB) remains a therapeutic challenge because evidence for systemic treatment is derived largely from small retrospective series and extrapolation from related neuroendocrine malignancies. This narrative review brings together diagnostic pathology, multi-omics classification, contemporary guideline-based management, and emerging systemic approaches for high-grade, recurrent, or metastatic ONB. Neural and Basal molecular programs provide a useful biological framework, but they are not validated tools for treatment selection. Delta-like ligand 3 (DLL3)-directed therapy and epigenetic-immune combinations are supported mainly by lineage-based or preclinical evidence, whereas somatostatin receptor (SSTR)-directed strategies and immune checkpoint blockade have generated only limited ONB-specific clinical data. All remain investigational. The first prospective immunotherapy trial in recurrent or metastatic ONB did not meet its objective-response endpoint, although prolonged disease stabilization was observed in a subset of patients. We therefore outline a practical approach that preserves established multidisciplinary care while using molecular and immune profiling to clarify diagnosis and guide clinical-trial referral. Routine biomarker-directed systemic therapy will require prospective multicenter validation using standardized assays and predefined biomarkers.