Adding HE4 to the IOTA ADNEX model for differentiating adnexal masses: A Danish prospective, multicenter study

Objective: To assess the incremental value of incorporating human epididymis protein 4 (HE4) as an additional predictor in the International Ovarian Tumor Analysis (IOTA) Assessment of Different NEoplasias in the adneXa (ADNEX) model for differentiating benign from malignant adnexal masses. Methods: Prospective enrollment of 782 patients with adnexal masses was performed across 14 Danish gynecology units, including one tertiary center (2020−2023). ADNEX malignancy risk estimates with and without CA125 were calculated, and serum HE4 was incorporated. Patients were split into training and test subsets for internal validation. Model performance was evaluated using the area under the receiver operating characteristic curve (AUC), prediction error (Brier score), and predictive values at thresholds of 5–20%, stratified by center type. Malignancy was defined by histopathology or at least 12 months of follow-up. Results: In the tertiary center, ADNEX models incorporating HE4 performed slightly better than the original models with and without CA125 (AUC 86.2–86.3% vs. 83.8% and 85.4%; Brier scores 14.7–14.8 vs. 15.5–16.4). A modest incremental effect of HE4 was observed at 10–15% thresholds (positive predictive values 46–55% vs. 43–47% and 43–53%), while negative predictive values remained comparable across models. In non-tertiary centers, model performance was similar across all models, with no improvement from incorporating HE4. Conclusion: Incorporating HE4 into the ADNEX model provided limited incremental value, with threshold-dependent performance changes, no improvement in non-tertiary centers, and only modest gains in the tertiary center. These findings do not support inclusion of HE4 in the ADNEX model.