From Histology to Multi-Omics: Review of Chordoma Classification and Its Clinical Implications

Chordoma is a rare malignant neoplasm of the axial skeleton, arising from notochordal remnants. No approved systemic therapies exist and a 10-year overall survival is below 60%. Accurate molecular and pathological classification is a prerequisite for improved prognostication and identification of actionable therapeutic targets, yet molecular classification of chordoma remains significantly less advanced than in other neoplasms. This article reviews and synthesizes proposed classification frameworks for chordoma across histological, radiological, surgical, genomic, epigenomic, transcriptomic, and proteomic domains. PubMed and CENTRAL were searched on 1 February 2026 using five queries: ‘chordoma classification’, ‘chordoma DNA sequencing’, ‘chordoma RNA sequencing’, ‘chordoma methylation’, and ‘chordoma copy number’. Original research articles describing more than one patient and reporting a classification or subtyping framework were included; review articles, case reports, and non-English publications were excluded. Sample size and utilization of validation dataset were identified for each dataset to mitigate risk of bias. Results were synthesized qualitatively. 108 studies encompassing 6,349 individuals were included. Across six domains, four cross-cutting themes with prognostic and potential theranostic value emerged: copy number alterations — particularly CDKN2A/B loss; SWI/SNF complex dysfunction; TGF-β signaling; and immune microenvironment heterogeneity.