Pleural fluid human epididymis secretory protein 4 in differentiating between malignant and benign pleural effusions: a systematic review and meta-analysis.

BACKGROUND

Soluble biomarkers in pleural fluid are a promising diagnostic tool for malignant pleural effusion (MPE) due to their advantages of low cost, short turnaround time, and less invasiveness. Several studies have investigated the value of pleural fluid human epididymis secretory protein 4 (HE4) in detecting MPE, but the results varied. This systematic review and meta-analysis aimed to assess the value of pleural fluid HE4 in differentiating between MPE and benign pleural effusion (BPE).

METHODS

The PubMed and Web of Science databases were used to identify eligible studies regarding the diagnostic value of pleural fluid HE4 for MPE and published before May 1, 2025. We extracted the following information from all eligible studies: first author, country, sample sizes of MPE and BPE, publication year, study design (e.g., prospective, retrospective), HE4 assay, the definition for MPE, the area under the curve (AUC) of HE4, sensitivity, specificity, and corresponding threshold. We used the revised Quality Assessment for Diagnostic Accuracy Studies tool (QUADAS-2) to assess the risk of bias in eligible studies. The bivariate model was used to calculate the pooled sensitivity and specificity. The summary receiver operating characteristic (sROC) curve was constructed to estimate the value of HE4 for differentiating between MPE and BPE. Deeks's test was employed to assess the risk of publication bias.

RESULTS

Seven studies with 1,216 patients (592 MPEs and 624 BPEs) were included in this meta-analysis. The meta-analysis revealed HE4 had a pooled sensitivity of 0.59 [95% confidence interval (CI): 0.43-0.74] and specificity of 0.94 (95% CI: 0.82-0.98). HE4 had an AUC of 0.83 (95% CI: 0.80-0.86). No significant publication bias across the included studies was observed. The primary risk of bias was the representativeness of the cohort, data-driven threshold selection, and particle verification bias.

CONCLUSIONS

Pleural fluid HE4 has a moderate value for differentiating between MPE and BPE. However, it cannot be used to confirm or rule out MPE when used alone.