Evaluation of cerebrospinal fluid human epididymis protein 4 for leptomeningeal metastasis in non-small cell lung cancer: a prospective cohort study

Diagnosing and monitoring leptomeningeal metastasis (LM) presents a significant clinical challenge. This study evaluated cerebrospinal fluid (CSF) Human Epididymis Protein 4 (HE4) as a novel diagnostic and monitoring biomarker for LM in non-small cell lung cancer (NSCLC). A prospective cohort study enrolled 117 participants (including 61 NSCLC patients with LM and 56 controls without central nervous system malignancies) from March 2023 to December 2024. Paired CSF and serum levels of HE4, carcinoembryonic antigen (CEA), and Cytokeratin 19 Fragment (CYFRA21-1) were measured using electrochemiluminescence immunoassay. Multivariable binary logistic regression, adjusting for clinical covariates (KPS, ICP, and symptom-to-diagnosis interval), was employed to identify independent diagnostic predictors. Diagnostic performance was quantified using receiver operating characteristic (ROC) curve analysis and compared via the DeLong test. Serial CSF HE4 monitoring was performed in a subset of patients to assess treatment response. CSF HE4 levels were markedly elevated in LM patients compared to controls (median 807.00 vs. 99.35 pmol/L, P < 0.001). Multivariable logistic regression revealed that CSF HE4 was a robust, independent diagnostic factor for LM (Adjusted OR = 1.027; 95% CIs : 1.010–1.044; P = 0.001), along with the CSF-to-serum HE4 ratio (Q HE4 ; P = 0.046). The multivariable model demonstrated excellent calibration (Hosmer-Lemeshow test, P = 0.366). In ROC analysis, CSF HE4 (AUC = 0.895) significantly outperformed Q HE4 (AUC = 0.769), CSF CEA (AUC = 0.701), and CSF CYFRA21-1 (AUC = 0.664) (all P < 0.05). At an optimal cutoff of 173.00 pmol/L, CSF HE4 yielded a sensitivity of 83.21% and specificity of 92.86%. Subgroup analysis indicated higher CSF HE4 in cytology-positive and progressive disease patients. Longitudinal monitoring showed that dynamic fluctuations in CSF HE4 closely mirrored clinical treatment response and disease progression. CSF HE4 is a promising biomarker for the diagnosis of NSCLC related LM. For CSF HE4, its robust diagnostic performance and correlation with disease activity support its use for both initial diagnosis and therapeutic monitoring.