Diagnostic Performance of Serum HE4 Versus CA-125 in Distinguishing Benign Ovarian Cysts from Malignancy

Abstract

Introduction: CA-125 is the standard biomarker for ovarian cancer but has poor specificity in premenopausal women. Human epididymis protein 4 (HE4) has been proposed as an alternative or adjunct.
Methods: A systematic review and bivariate meta-analysis of prospective cohort studies. Studies reporting both HE4 and CA-125 with histology reference standard were included. Sensitivity, specificity, and area under the curve (AUC) were calculated.
Results: Twenty-three studies (total n=6,700, 30% malignant) met criteria. HE4 had higher specificity (0.87 vs. 0.75 for CA-125) but lower sensitivity (0.74 vs. 0.81). In premenopausal women, HE4 specificity rose to 0.92. Combined ROMA index (using both markers) achieved AUC 0.92.
Discussion: HE4’s superiority in specificity reduces unnecessary surgeries for benign cysts, especially in younger women. CA-125 remains more sensitive for early-stage disease. The ROMA score performs best but requires validated thresholds.
Conclusions: HE4 is a valuable adjunct to CA-125, particularly in premenopausal women. The ROMA algorithm improves diagnostic accuracy for ovarian malignancy and should be integrated into clinical algorithms.