AccScience Publishing / EJMO / Online First / DOI: 10.36922/EJMO026340435
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ORIGINAL RESEARCH ARTICLE

Diagnostic performance of human epididymis protein 4 in predicting occult endometrial carcinoma among women with endometrial intraepithelial neoplasia

Aysel Mammadova1* ,  Gulnara Jafarova1
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1 Department of Oncology, Oncology Clinic, Azerbaijan Medical University, Baku , Azerbaijan
EJMO, 026340435 https://doi.org/10.36922/EJMO026340435
Received: 18 August 2026 | Revised: 12 September 2026 | Accepted: 23 September 2026 | Published online: 22 October 2026
© 2026 by the Author(s). This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution -Noncommercial 4.0 International License (CC-by the license) ( https://creativecommons.org/licenses/by-nc/4.0/ )
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Abstract

Introduction: Endometrial intraepithelial neoplasia (EIN) carries a substantial risk of concurrent occult endometrial carcinoma. Accurate preoperative risk assessment is important for appropriate surgical planning

Objective: To assess the diagnostic accuracy of serum human epididymis protein 4 (HE4) in identifying occult endometrial carcinoma in women with EIN, compare its performance with cancer antigen 125 (CA-125) and the Risk of Ovarian Malignancy Algorithm (ROMA) index, and assess the value of integrating clinical, ultrasonographic, histopathological, and biomarker variables into a preoperative prediction model.

Methods: This retrospective study included 113 women with histologically confirmed EIN who underwent hysterectomy between 2019 and 2025. Clinical, ultrasonographic, histopathological, and biomarker data, including serum CA-125, HE4, and ROMA, were evaluated. Diagnostic performance was assessed using receiver operating characteristic analysis, and independent predictors were identified by multivariable logistic regression.

Results: Occult endometrial carcinoma was identified in 46/113 women (40.7%). Malignant postoperative findings were associated with age > 50 years, obesity, postmenopausal status, endometrial thickness >10 mm, and high-risk preoperative histopathology. HE4 showed the highest diagnostic performance (area under the curve [AUC] = 0.912; 95% confidence interval [CI]: 0.832–0.961; p < 0.001), compared with ROMA (AUC = 0.846) and CA-125 (AUC = 0.563). High-risk preoperative histopathology (odds ratio = 31.85; 95% CI: 8.71–116.42; p < 0.001) and HE4 (OR = 4.53 per 50 pmol/L increase; 95% CI: 1.86–11.02; p = 0.001) were independent predictors. The final model demonstrated excellent discrimination (AUC = 0.951), with 84.8% sensitivity, 97.0% specificity, and 92.0% accuracy.

Conclusion: HE4 outperformed CA-125 and ROMA and remained an independent predictor of occult carcinoma. Integrating HE4 with clinicopathological variables may improve preoperative risk stratification and surgical decision-making in women with EIN.

Graphical abstract
Keywords
Endometrial intraepithelial neoplasia
Occult endometrial carcinoma
Human epididymis protein 4
Cancer antigen 125
Risk of Ovarian Malignancy Algorithm index
Logistic regression
Risk prediction
Funding
None.
Conflict of interest
The authors declare that they have no competing interests.
References
  1. Wu M, Kaur H, Sosa S. A 60-year-old woman with endometrial intraepithelial neoplasia: a case of persistent postmenopausal bleeding. Cureus. 2026;18(2):e103797. doi: 10.7759/cureus.103797
  2. Barbosa L, Nunes L, Napoleao B, Ribeiro M, Pagani M, Silveira V. Endometrioid intraepithelial neoplasia: analysis of postoperative outcome. Int J Gynecol Cancer. 2025;35(11):102458. doi: 10.1016/j.ijgc.2025.102458
  3. Nees LK, Heublein S, Steinmacher S, et al. Endometrial hyperplasia as a risk factor of endometrial cancer. Arch Gynecol Obstet. 2022;306(2):407-421. doi: 10.1007/s00404-021-06380-5
  4. Lundeberg KR, Gregg RW, Hope ER, Winkler SS, Riggs M. Management of endometrial intraepithelial neoplasia: a retrospective review of practice patterns at a single military treatment facility and civilian partner hospital. Womens Health Rep. 2025;6(1):919-924. doi: 10.1177/26884844251379404
  5. Höhn AK, Brambs CE, Hiller GGR, May D, Schmoeckel E, Horn LC. 2020 WHO classification of female genital tumors. Geburtshilfe Frauenheilkd. 2021;81(10):1145-1153. doi: 10.1055/a-1545-4279
  6. Giannella L, Grelloni C, Bernardi M, et al. Atypical endometrial hyperplasia and concurrent cancer: a comprehensive overview on a challenging clinical condition. Cancers (Basel). 2024;16(5):914. doi: 10.3390/cancers16050914
  7. Vetter MH, Smith B, Benedict J, et al. Preoperative predictors of endometrial cancer at time of hysterectomy for endometrial intraepithelial neoplasia or complex atypical hyperplasia. Am J Obstet Gynecol. 2020;222(1):60.e1-60.e7. doi: 10.1016/j.ajog.2019.08.002
  8. Chen H, Strickland AL, Castrillon DH. Histopathologic diagnosis of endometrial precancers: updates and future directions. Semin Diagn Pathol. 2022;39(3):137-147. doi: 10.1053/j.semdp.2021.12.001
  9. McCoy CA, Coleman HG, McShane CM, et al. Factors associated with interobserver variation amongst pathologists in the diagnosis of endometrial hyperplasia: a systematic review. PLoS One. 2024;19(4):e0302252. doi: 10.1371/journal.pone.0302252
  10. Thongsang W, Kuljarusnont S, Hanamornroongruang S, Ruengkhachorn I. Prevalence of occult endometrial carcinoma in patients with endometrial intraepithelial neoplasia who underwent hysterectomy. World J Surg Oncol. 2025;23(1):24. doi: 10.1186/s12957-025-03677-6
  11. Wolff K, Gumin D, Shqara RA, et al. Risk factors and predictive modeling for occult endometrial cancer in women with atypical hyperplasia: a retrospective study. Arch Gynecol Obstet. 2026;313(1):67. doi: 10.1007/s00404-026-08329-y
  12. Behrouzi R, Barr CE, Crosbie EJ. HE4 as a biomarker for endometrial cancer. Cancers (Basel). 2021;13(19):4764. doi: 10.3390/cancers13194764
  13. Lou Y, Jiang F, Du Y, Guan J. Nomogram using human epididymis protein 4 predicted concurrent endometrial cancer from endometrial atypical hyperplasia before surgery. Front Oncol. 2024;14:1442127. doi: 10.3389/fonc.2024.1442127
  14. Barr CE, Njoku K, Jones ER, et al. Serum CA125 and HE4 as biomarkers for the detection of endometrial cancer and associated high-risk features. Diagnostics (Basel). 2022;12(11):2834. doi: 10.3390/diagnostics12112834
  15. Crha T, Ovesná P, Weinberger V, et al. Serum levels of CA125 and HE4 as a tool for predicting regional lymph node metastatic involvement in endometrial carcinoma. Cancers (Basel). 2025;17(17):2740. doi: 10.3390/cancers17172740
  16. Lombaers MS, Cornel KMC, Visser NCM, et al. Preoperative CA125 significantly improves risk stratification in high-grade endometrial cancer. Cancers (Basel). 2023;15(9):2605. doi: 10.3390/cancers15092605
  17. Wang Y, Han C, Teng F, Bai Z, Tian W, Xue F. Predictive value of serum HE4 and CA125 concentrations for lymphatic metastasis of endometrial cancer. Int J Gynaecol Obstet. 2017;136(1):58-63. doi: 10.1002/ijgo.12010
  18. Koleva V, Shefket S, Stoencheva S. Clinical significance of human epididymis protein 4 (HE4), cancer antigen 125 (CA125), the risk of ovarian malignancy algorithm (ROMA), and Copenhagen index for the diagnosis of endometrial carcinoma. Folia Med (Plovdiv). 2025;67(1). doi: 10.3897/folmed.67.e143849
  19. Liu J, Han L, Sun Q, Li Y, Niyazi M. Meta-analysis of the diagnostic accuracy of HE4 for endometrial carcinoma. Eur J Obstet Gynecol Reprod Biol. 2020;252:404-411. doi: 10.1016/j.ejogrb.2020.07.015
  20. Levin G, Matanes E, Brezinov Y, et al. Machine learning for prediction of concurrent endometrial carcinoma in patients diagnosed with endometrial intraepithelial neoplasia. Eur J Surg Oncol. 2024;50(3):108006. doi: 10.1016/j.ejso.2024.108006
  21. Gumin D, Sharon A, Mustafa Mikhail S, et al. Diagnostic accuracy of endometrial sampling methods for determining histologic type and grade in endometrial cancer: a retrospective cohort study. Cureus. 2025;17:e95428. doi: 10.7759/cureus.95428
  22. Boardman L, Novetsky AP, Valea F, et al. Management of endometrial intraepithelial neoplasia or atypical endometrial hyperplasia: ACOG Clinical Consensus No. 5. Obstet Gynecol. 2023;142(3):735-744. doi: 10.1097/AOG.0000000000005297
  23. Concin N, Matias-Guiu X, Vergote I, et al. ESGO/ESTRO/ESP guidelines for the management of patients with endometrial carcinoma. Int J Gynecol Cancer. 2021;31(1):12-39. doi: 10.1136/ijgc-2020-002230
  24. Abu-Rustum NR, Campos SM, Amarnath S, et al. NCCN Guidelines® Insights: uterine neoplasms, version 3.2025. J Natl Compr Canc Netw. 2025;23(8):284-291. doi: 10.6004/jnccn.2025.0038
  25. Zhao J, Hu Y, Zhao Y, Chen D, Fang T, Ding M. Risk factors of endometrial cancer in patients with endometrial hyperplasia: implication for clinical treatments. BMC Womens Health. 2021;21(1):312. doi: 10.1186/s12905-021-01452-9
  26. Raglan O, Kalliala I, Markozannes G, et al. Risk factors for endometrial cancer: an umbrella review of the literature. Int J Cancer. 2019;145(7):1719-1730. doi: 10.1002/ijc.31961
  27. Ordeanu IM, Busuioc CJ, Văduva CC, et al. Obesity as a catalyst for endometrial hyperplasia and cancer progression: a narrative review of epidemiology, molecular pathways, and prevention. Biomedicines. 2025;13(11):2612. doi: 10.3390/biomedicines13112612
  28. Tîrnovanu MC, Cojocaru E, Tîrnovanu VG, et al. The role of ultrasound in diagnosing endometrial pathologies: adherence to IETA Group consensus and preoperative assessment of myometrial invasion in endometrial cancer. Diagnostics (Basel). 2025;15(7):891. doi: 10.3390/diagnostics15070891
  29. Clarke MA, Long BJ, Sherman ME, et al. Risk assessment of endometrial cancer and endometrial intraepithelial neoplasia in women with abnormal bleeding and implications for clinical management algorithms. Am J Obstet Gynecol. 2020;223(4):549.e1-549.e13. doi: 10.1016/j.ajog.2020.03.032
  30. Sabyeying P, Samutchaikij T, Rattanalappaiboon D, Detwongya C. Age-associated with endometrial intraepithelial neoplasia and endometrial carcinoma in patients with abnormal uterine bleeding. Thai J Obstet Gynaecol. 2025;33:95-103. doi: 10.14456/TJOG.2025.11
  31. Shawn LyBarger K, Miller HA, Frieboes HB. CA125 as a predictor of endometrial cancer lymphovascular space invasion and lymph node metastasis for risk stratification in the preoperative setting. Sci Rep. 2022;12(1):19783. doi: 10.1038/s41598-022-22026-1
  32. Ünsal M, Kimyon Comert G, Karalok A, et al. The preoperative serum CA125 can predict the lymph node metastasis in endometrioid-type endometrial cancer. Ginekol Pol. 2018;89(11):599-606. doi: 10.5603/GP.a2018.0103
  33. O'Toole SA, Huang Y, Norris L, et al. HE4 and CA125 as preoperative risk stratifiers for lymph node metastasis in endometrioid carcinoma of the endometrium: a retrospective study in a cohort with histological proof of lymph node status. Gynecol Oncol. 2021;160(2):514-519. doi: 10.1016/j.ygyno.2020.11.004
  34. Abdalla N, Piórkowski R, Stanirowski P, Słomka A, Cendrowski K, Sawicki W. Assessment of levels of the tumor markers HE4 and CA125 considering staging, grading and histological types of endometrial cancer. Prz Menopauzalny. 2016;15(3):133-137. doi: 10.5114/pm.2016.63059
  35. Abbink K, Zusterzeel PL, Geurts-Moespot AJ, et al. HE4 is superior to CA125 in the detection of recurrent disease in high-risk endometrial cancer patients. Tumour Biol. 2018;40(2):1010428318757103. doi: 10.1177/1010428318757103
  36. Bignotti E, Ragnoli M, Zanotti L, et al. Diagnostic and prognostic impact of serum HE4 detection in endometrial carcinoma patients. Br J Cancer. 2011;104(9):1418-1425. doi: 10.1038/bjc.2011.109
  37. Yuan J, Xu C, Liu C, et al. Diagnostic value of serum human epididymal secretory protein 4 for endometrial cancer: a systematic review and meta analysis. Discov Oncol. 2024;15(1):498. doi: 10.1007/s12672-024-01234-3-18
  38. Giordano WG, Pepe L, Martinelli C, et al. Liquid biopsy biomarkers in endometrial cancer: current landscape and future perspectives. Biomolecules. 2026;16(6):911. doi: 10.3390/biom16060911
  39. Zeevi G, Dahan C, Bercovich O, et al. Preoperative risk factors and predictive model for endometrial carcinoma in women with endometrial intraepithelial neoplasia. Int J Gynecol Cancer. 2026;36(2):103393. doi: 10.1016/j.ijgc.2025.103393
  40. Aytekin O, Karagöz Ç, Göktaş E, et al. Preoperative predictors of concurrent endometrial carcinoma in patients with endometrial intraepithelial neoplasia: the role of HALP score and other inflammatory markers. Turk J Obstet Gynecol. 2025;26(1):34-40. doi: 10.4274/jtgga.galenos.2025.2024-12-5
  41. Peters PN, March L, Smith GD, et al. A prospective algorithm for pre-operative risk stratification and individualized lymph node assessment in patients with endometrial intraepithelial neoplasia (EIN). Gynecol Oncol Rep. 2026;66:102177. doi: 10.1016/j.gore.2026.102177
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Eurasian Journal of Medicine and Oncology, Electronic ISSN: 2587-196X Print ISSN: 2587-2400, Published by AccScience Publishing
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