Skip to main content

Advertisement

Log in

HE-4 A Novel Tumour Marker for Ovarian Mass and Its Comparison with CA 125

  • Original Article
  • Published:
Indian Journal of Gynecologic Oncology Aims and scope Submit manuscript

Abstract

Introduction

IARC released on 14th December the updated Globocan 2020 with new estimates on the global cancer burden, indicating that it has risen to 19.3 million cases and 10 million cancer deaths in 2020. Ovarian cancer is the 8th most commonly occurring cancer in women and the 18th most common cancer overall. There were more than 313,000 new cases of ovarian cancer in 2020 as per the Globocan 2020. Despite advances in the diagnosis and treatment, there has been little change in the mortality rate of ovarian cancer as most of patients were diagnosed at advanced stage. Tumour markers are the biochemical substances which are detected in the presence of tumours.Usually they are either the products of tumour tissues or secreted from the normal cells which are in the close with tumour tissue (2). Serum CA125 assay has low sensitivity in the early stages and also can be increased in certain conditions such as menstruation or endometriosis. Many studies reported that HE4 is absent in normal ovarian surface epithelium but is expressed specifically in 100% of endometroid and serous epithelial ovarian cancers (2). Furthermore, this combined measure can correct the variations in HE4 and CA125 which are due to other pathology.

Aims and Objective

1. To evaluate HE4 and CA125 in ovarian tumour patients preoperatively. 2. To compare the utility of HE4 and CA 125 for diagnosing and distinguishing malignant ovarian tumour.

Materials and Methods

In this prospective study, 149 patients of ovarian tumour were evaluated for serum CA125 and HE4. Out of which, 18 patients were lost to follow-up. Their levels were determined by the electrochemiluminescence (ECLIA) technique. Positive cut-off of CA 125 was taken > 35 U/mL. The HE4 positive cut-off values for premenopausal and postmenopausal women were > 70 pmol/l and > 140 pmol/l, respectively. Sensitivity, specificity and predictive value were calculated for each tumour marker.

Result

In patients with benign diseases, abnormal serum levels of HE4 and CA125 were found in 0.86% and 9.4% of patients, respectively. Specificity of HE4 and CA125 of diagnosing benign tumour were 99.03% and 81.55%, respectively. Tumour marker sensitivity in ovarian cancer was 100% for HE4 and 85.71% for CA 125. Among patients with ovarian epithelial cancer, HE4 (in contrast to CA 125) had significantly higher concentrations than in other malignancies (p < 0.001). In differentiating benign gynaecological diseases from malignant ovarian cancer, HE4 was found to be more positive predictive than CA125 (96.55% and 55.81%, respectively).

Conclusion

In this study, HE4 was found to be more sensitivity and specificity (p < 0.001) for ovarian malignancyas compare to CA 125. HE4 is better in diagnosing and distinguishing ovarian cancer from benign ovarian tumour as compare to CA125 preoperatively. It may be considered as novel ovarian tumour marker.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Similar content being viewed by others

References

  1. Sung H, Ferlay J, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021;71:209–49. https://doi.org/10.3322/caac.21660. (American Cancer Society).

    Article  CAS  PubMed  Google Scholar 

  2. Henderson JT, Webber EM, et al. Screening for ovarian cancer updated evidence report and systematic review for the US Preventive Services Task Force. JAMA. 2018;319(6):595–606. https://doi.org/10.1001/jama.2017.21421.

    Article  PubMed  Google Scholar 

  3. Heintz AP, Odicino F, Maisonneuve P, Quinn MA, Benedet JL, Creasman WT, Ngan HY, Pecorelli S, Beller U. Carcinoma of the fallopian tube. FIGO 26th annual report on the results of treatment in gynecological Cancer. Int J Gynaecol Obstet. 2006;95(Suppl 1):S145–60. https://doi.org/10.1016/S0020-7292(6)60033-7.

    Article  PubMed  Google Scholar 

  4. Enakpene CA, Omigbodun AO, Goecke TW, Odukogbe AT, Beckmann MW. Preoperative evaluation and triage of women with suspicious adnexal masses using risk of malignancy index. J Obstet Gynaecol Res. 2009;35:131–8. https://doi.org/10.1111/j.1447-0756.2008.00869.x.

    Article  PubMed  Google Scholar 

  5. Karlsen MA, Sandhu N, Høgdall C, Christensen IJ, Nedergaard L, Lundvall L, Engelholm SA, Pedersen AT, Hartwell D, Lydolph M, et al. Evaluation of HE4, CA125, risk of ovarian malignancy algorithm (ROMA) and risk of malignancy index (RMI) as diagnostic tools of epithelial ovarian cancer in patients with a pelvic mass. Gynecol Oncol. 2012;127:379–83. https://doi.org/10.1016/jgyno.2012.07.106.

    Article  PubMed  Google Scholar 

  6. Sun ML, Yang ZY, et al. The role of human epididymis protein 4 in the diagnosis and prognosis of diseases: an umbrella review of systematic reviews and meta-analyses of observational studies. Front Med (Lausanne). 2022;24(9): 842002. https://doi.org/10.3389/fmed.2022.842002. (PMID: 35402435).

    Article  Google Scholar 

  7. Stiekema A, Lok C, Korse CM, et al. Serum HE4 is correlated to prognostic factors and survival in patients with endometrial cancer. Virchows Arch. 2017;470(6):655–64. https://doi.org/10.1007/s00428-017-2115-1. (Epub 2017 Apr 11).

    Article  CAS  PubMed  Google Scholar 

  8. El-Nadeim MZ, Ahmed YKB, Mowad HH, et al. Does CA 125 have a Role in Early Diagnosis of Ovarian Malignancy in non-menopausal women? J Biomed Res Environ Sci. 2022;3(4):393–6. https://doi.org/10.37871/jbres1454. (Article ID: jbres 1454).

    Article  Google Scholar 

  9. Su Wei, Hui Li, Bei Zhang. The diagnostic value of serum HE4 and CA125 and ROMA index in ovarian cancer. Biomed Rep. Spandidos publication 2016;5:41–6. https://doi.org/10.3892/br.2016.682

  10. Levanon K, Crum C, Drapkin R. New Insight into the pathogenesis of serous Ovarian Cancer and its clinical impact. J Clin Oncol. 2008;26(32):5284–93. https://doi.org/10.1200/JCO.2008.18.1107.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Anton C, Carvalho FM. Comparison of CA125, HE4, risk ovarian malignancy algorithm (ROMA), and risk malignancy index (RMI) for the classification of ovarian masses. Clinical Sciences. Clinics. 2012;67(5). https://doi.org/10.6061/clinics/2012(05)06

  12. Zeng Q, Liu M, Zhou N, Liu L, Song X. Serum human epididymis protein 4 (HE4) may be a better tumor marker in early lung cancer. Clin Chim Acta. 2016;455:102–6. https://doi.org/10.1016/j.cca.2016.02.002.

    Article  CAS  PubMed  Google Scholar 

  13. Bingle L, Cross SS, High AS, Wallace WA, Rassl D, Yuan G, et al. WFDC2 (HE4): a potential role in the innate immunity of the oral cavity and respiratory tract and the development of adenocarcinomas of the lung. Respir Res. 2006;7:61. https://doi.org/10.1186/1465-9921-7-61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Bouchard D, Morisset D, Bourbonnais Y, Tremblay GM. Proteins with whey-acidic-protein motifs and cancer. Lancet Oncol. 2006;7:167–74. https://doi.org/10.1016/S1470-2045(06)70579-4.

    Article  CAS  PubMed  Google Scholar 

  15. Granato T, Porpora MG, Longo F, Angeloni A, Manganaro L, Anastasi E. HE4 in the differential diagnosis of ovarian cancer. Clin Chim Acta. 2015;15(446):147–55. https://doi.org/10.1016/j.cca.2015.03.047. (Epub 2015 Apr 16).

    Article  CAS  Google Scholar 

  16. Richards A, Herbst U, Manalang J, Pather S, Saidi S, Tejada-Berges T, Tan K, Williams P, Carter J. HE4, CA125, the Risk of Malignancy Algorithm and the Risk of Malignancy Index and complex pelvic masses – a peospectivecomparision in the pre- operative evaluation of pelvic masses in an Australian population. Aust N Z J ObstetGynaecol. 2015;55(5):493–7. https://doi.org/10.1111/ajo.12363. (Epub 2015 Jul 14).

    Article  Google Scholar 

  17. Ferraro S, Borille S, Caruso S, et al. Body mass index does not influence human epididymis protein 4 concentrations in serum. Clin Chim Acta. 2015;446:163–4. https://doi.org/10.1016/j.cca.2015.04.028.

    Article  CAS  PubMed  Google Scholar 

  18. Ferraro S, Schiumarini D, Panteghini M. Human epididymis protein 4: factors of variation. Clin Chim Acta. 2015;438:171–7. https://doi.org/10.1016/j.cca.2014.08.020.

    Article  CAS  PubMed  Google Scholar 

  19. LeBleu VS, Teng Y, O’Connell JT, Charytan D, Muller GA, Muller CA, et al. Identification of human epididymis protein-4 as a fibroblast-derived mediator of fibrosis. Nat Med. 2013;19:227–31. https://doi.org/10.1038/nm.2989.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Piek A, Meijers WC, Schroten NF, Gansevoort RT, de Boer RA, Sillje HH. HE4 serum levels are associated with heart failure severity in patients with chronic heart failure. J Card Fail. 2017;23:12–9. https://doi.org/10.1016/j.cardfail.2016.05.002.

    Article  CAS  PubMed  Google Scholar 

  21. Kurman RJ, Shih I-M. Molecular pathogenesis and extraovarian origin of epithelial ovarian cancer-shifting the paradigm. Hum Pathol. 2011;42(7):918–31. https://doi.org/10.1016/j.humpath.2011.03.003.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Dikmen ZG, Colak A, Dogan P, Tuncer S, Akbiyik F. Diagnostic performances of CA125, HE4, and ROMA index in ovarian cancer. Eur J Gynaecol Oncol. 2015; XXXVI(4). https://doi.org/10.12892/ejgo2714.2015. ISSN: 0392-2936.

  23. Suri A, Perumal V, Ammalli P, Suryan V, Bansal SK. Diagnostic measures comparison for ovarian malignancy risk in Epithelial ovarian cancer patients: a meta-analysis. Sci Rep. 2021;11(1):17308. https://doi.org/10.1038/s41598-021-96552-9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Ferraro S, Braga F, Lanzoni M, et al. Serum human epididymis protein 4 vs carbohydrate antigen 125 for ovarian cancer diagnosis: a systematic review. J Clin Pathol. 2013;66:273–81.

    Article  CAS  PubMed  Google Scholar 

  25. Chen X, Zhou H, Chen R, et al. Development of a multimarker assay for differential diagnosis of benign and malignant pelvic masses. Clin Chim Acta. 2014;440C:57–63.

    Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Sangeeta Pankaj.

Ethics declarations

Conflict of Interest

We declare that this manuscript is original; it has not been published anywhere before and is not currently being considered for publication elsewhere. We also confirm that the authors do not have any conflict of interest associated with publication of this work and no significant financial support/funding for this work has been received to influenced the outcome. The manuscript is read and approved, and consent is given by all the authors. We give our permission to reproduce any material of the article.

Ethical Approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.

Informed Consent

Informed consent was obtained from all individual participants included in the study. This article does not contain any studies with animals performed by any of the authors.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Kumari, J., Amrita, Pankaj, S. et al. HE-4 A Novel Tumour Marker for Ovarian Mass and Its Comparison with CA 125. Indian J Gynecol Oncolog 22, 72 (2024). https://doi.org/10.1007/s40944-024-00838-5

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s40944-024-00838-5

Keywords

Navigation