Correlation Between Molecular Genetic Analysis and Nuclear Pleomorphism in Long-Term Recurrent and Metastatic Chordoma

Background/Objectives: Recurrences and metastases occur frequently in chordoma and are the main influence on overall survival. However, prognostic biomarkers for recurrence remain limited. This study examines whether quantitative nuclear morphometry captures recurrence evolution and whether it aligns with immunophenotype and genomic profiling. Methods: 26 specimens from 12 adults (eight non-recurrent tumors and four patients with multiple long-term recurrences and metastases over seven to sixteen years) were analyzed using whole-exome-sequencing, immunohistochemistry and nuclear morphometry. Results: Imaging studies and routine histology showed no consistent differences between groups. Morphometry revealed substantial intertumoral variability among non-recurrent tumors and significant longitudinal nuclear remodeling throughout recurrences, dominated by increased nuclear size and asymmetry as well as altered shape. Primary tumors from patients who later recurred had smaller, more asymmetric and denser nuclei than non-recurrent tumors. Recurrent samples showed higher proliferation and decreased lamin A/C expression with focal disruption and detachment from the nuclear envelope in pleomorphic nuclei. The tumor mutational burden was overall low, varied between patients and timepoints and tended to be higher in recurrent cases. Conclusions: Quantitative nuclear morphometry, integrated with immunophenotyping and genomic profiling captures recurrence-associated phenotypic remodeling in chordoma and may support/train future AI-models for risk stratification.