HE4 Integration in the IOTA ADNEX Model: A Clinical Review

Differentiating between benign and malignant adnexal masses remains a critical challenge in gynecology. Recently, a Danish prospective study evaluated the IOTA ADNEX model and the potential benefit of adding human epididymis protein 4 (HE4) to its framework. While ultrasound-based models provide strong diagnostic power, many clinicians investigate whether additional biomarkers can further refine risk estimates.

Study Methodology and Key Findings

Researchers enrolled 782 patients across 14 Danish centers to compare model performance with and without HE4. Specifically, the study analyzed diagnostic accuracy using the Area Under the Curve (AUC) and Brier scores. In tertiary centers, adding HE4 to the IOTA ADNEX model showed minor AUC improvements. However, this gain was extremely modest and depended heavily on the chosen risk thresholds. Consequently, the researchers noted that negative predictive values remained almost identical across all tested models.

Practical Performance of the IOTA ADNEX Model

Notably, the results shifted when analyzing non-tertiary centers. In these settings, the inclusion of HE4 failed to provide any statistical improvement in diagnostic performance. Furthermore, the existing parameters within the IOTA ADNEX model already offer high sensitivity and specificity. Therefore, adding HE4 does not seem to justify the additional cost in routine clinical scenarios outside of specialized oncology units. Similarly, other studies suggest that ultrasound-based assessments often outperform independent tumor marker analysis.

Clinical Implications for Gynecologists

The findings emphasize that the current IOTA ADNEX model remains a robust tool for preoperative evaluation. Since HE4 provided limited incremental value, its routine integration into this specific model is not currently supported. Physicians should continue prioritizing high-quality ultrasound imaging and established clinical risk factors. Moreover, the study highlights that diagnostic tools may perform differently based on the clinical environment and center expertise. As a result, maintaining standardized IOTA protocols remains the most effective strategy for managing adnexal masses.

Frequently Asked Questions

What is the IOTA ADNEX model?

The ADNEX model is a multiclass risk assessment tool developed by the International Ovarian Tumor Analysis group. It uses clinical data and ultrasound features to predict the probability of different types of adnexal tumors.

Does HE4 significantly improve the accuracy of the ADNEX model?

Current research indicates that HE4 provides only marginal benefit in tertiary oncology centers and no significant improvement in non-tertiary settings. Therefore, its routine addition is not recommended.

Which biomarkers are currently used in the ADNEX model?

The primary biomarker used optionally in the ADNEX model is CA125, which helps differentiate between various malignant subtypes, though the model can also function without it using ultrasound predictors alone.

Disclaimer: This content is for informational and educational purposes only and does not constitute medical advice or a professional relationship. Always seek the advice of a qualified healthcare provider for any medical condition. Refer to the latest local and national guidelines for clinical practice.

References

1. Karlsen NS et al. Adding HE4 to the IOTA ADNEX model for differentiating adnexal masses: A Danish prospective, multicenter study. Gynecol Oncol. 2026 May 14. doi: undefined. PMID: 42134000.


2. Timmerman D et al. Predicting the risk of malignancy in adnexal masses: external validation of the ADNEX model. BMJ. 2014;349:g5919.


3. Van Calster B et al. Evaluating the risk of ovarian cancer before surgery using the ADNEX model: a multicentre external validation study. Lancet Oncol. 2014;15(11):1256-1264.