Evaluation of cerebrospinal fluid Human Epididymis Protein 4 for leptomeningeal metastasis in Non-Small Cell Lung Cancer: A retrospective cohort study

Background : Diagnosing and monitoring leptomeningeal metastasis presents a significant clinical challenge. This study evaluated cerebrospinal fluid (CSF) Human Epididymis Protein 4 (HE4) as a novel diagnostic and monitoring biomarker for leptomeningeal metastasis in non-small cell lung cancer. Methods : A prospective cohort study enrolled 117 participants (including 61 non-small cell lung cancer patients with leptomeningeal metastasis and 56 controls without central nervous systemmalignancies) from March 2023 to December 2024. Paired CSF and serum levels of HE4, carcinoembryonic antigen (CEA), and CYFRA21-1 were measured using electrochemiluminescence immunoassay. Diagnostic performance was assessed using receiver operating characteristic (ROC) curve analysis. Serial monitoring was also performed in a subset of patients. Results : CSF HE4 levels were significantly higher in leptomeningeal metastasis patients compared to controls (median 807.00 vs. 99.35 pmol/L, P < 0.001) and markedly exceeded paired serum levels, indicating a distinct CSF-serum gradient. For leptomeningeal metastasis diagnosis, CSF HE4 (AUC = 0.895) demonstrated superior performance to CSF CEA and CYFRA21-1. At an optimal cutoff of 173.00 pmol/L, the sensitivity and specificity were 83.21% and 92.86%, respectively. Subgroup analysis revealed significantly higher CSF HE4 levels in patients with positive CSF cytology, particularly those with progressive disease. Serial monitoring demonstrated that dynamic changes in CSF HE4 levels correlated with treatment response during intrathecal chemotherapy. Conclusion : CSF HE4 is a promising biomarker for the diagnosis of non-small cell lung cancer related leptomeningeal metastasis. For CSF HE4, its robust diagnostic performance and correlation with disease activity support its use for both initial diagnosis and therapeutic monitoring.