Evaluation of Serum HE4 in Ovarian Tumors, Its Comparison with Serum CA125 and Correlation with Histological Subtypes

  • Shikha Khati
  • Riddhi JaiswalEmail author
  • Nisha Singh
Original Article



Ovarian cancer is the seventh most common cancer in women and second most common female genital cancer in India. The high mortality is due to the fact that ovarian cancer is detected in later stages because of its non-specific symptoms like bloating, pain and increased size, gastrointestinal symptoms like indigestion, constipation or nausea with pelvic symptoms like bleeding. Cancer antigen 125 (CA125) has been useful for detection of ovarian cancer and also for follow-up. Recently, another tumor marker for ovarian cancer has been proposed, the Human Epididymis 4 protein (HE4), frequently over-expressed in ovarian cancers, especially in serous and endometrioid histology.

Materials and Methods

Descriptive study on 64 patients was done over a period of 1 year using pre- and postoperative serum samples for CA125 and HE4 and comparing them with histological diagnosis. ELISA for HE4 (Quantikine® Human HE4/WFDC2 Immunoassay) and chemiluminescence (ARCHITECT CA125 II assay) were used to assess CA125 levels and in serum. Results were compared between the two tumor markers, and statistical analysis (SPSS package Windows version 15.0) was done to compare the results.

Results and Conclusion

CA125 and HE4 levels were increased in malignant cases more than in benign cases. HE4 was seen as more specific than CA125, but, however, it did not prove superior in sensitivity. Hence, we conclude that CA125 along with HE4 will prove both as sensitive and as specific markers and hence prevent benign lesions being over-diagnosed and operated unnecessarily.


Ovarian lesions Tumor markers Serum HE4 


Compliance with Ethical Standards

Conflict of interest



  1. 1.
    WHO. Cancer country profile of India. Geneva: WHO; 2014.Google Scholar
  2. 2.
    Dikshit RA (2012) Cancer Statistics in Indian women. Times of India, October 21, 2012 Google Scholar
  3. 3.
    Goff BA, Mandel L, Muntz HG, Melancon CH. Ovarian carcinoma diagnosis. Cancer. 2000;89:2068–75.CrossRefPubMedGoogle Scholar
  4. 4.
    Brain KE, Smits S, Simon AE, Forbes LJ, Roberts C, Robbé IJ, Steward J, White C, Neal RD, Hanson J. Ovarian cancer symptom awareness and anticipated delayed presentation in a population sample. BMC Cancer. 2014;14:171.CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Smith LH, Morris CR, Yasmeen S, Parikh-Patel A. Ovarian cancer: can we make the clinical diagnosis earlier? Cancer. 2005;104(7):1398–407.CrossRefPubMedGoogle Scholar
  6. 6.
    Gajjar K, Ogden G, Mujahid MI, Razvi K. Symptoms and risk factors of ovarian cancer: a survey in primary care. ISRN Obstet Gynecol 2012; Article ID 754197, 6 pages.Google Scholar
  7. 7.
    Murthy NS, Shlini S, Suman G, Pruthvish S, Mathew A. Changing trends in incidence of ovarian cancer the Indian Scenario. Asian Pac J Cancer Prev. 2009;10:1025–30.PubMedGoogle Scholar
  8. 8.
    Valentin L. Use of morphology to characterize and manage common adnexal masses. Best Pract Res Clin Obstet Gyn. 2004;18(1):71–89.CrossRefGoogle Scholar
  9. 9.
    van Nagell JR. Ovarian cancer screening with annual transvaginal sonography: findings of 25,000 women screened. Int J Womens Health. 2014;6:25–33.Google Scholar
  10. 10.
    European Group on Tumour Markers. Tumour markers in gynaecological cancers—EGTM recommendations. Anticancer Res. 1999;19:2807–10.Google Scholar
  11. 11.
    Duffy MJ, Bonfrer JM, Kulpa J, Rustin GJ, Soletormos G, Torre GC, et al. CA 125 in ovarian cancer: European Group on Tumour Markers guidelines for clinical use. Int J Gynecol Cancer. 2005;15:679–91.CrossRefPubMedGoogle Scholar
  12. 12.
    Rosen DG, Wang L, Atkinson JN, Yu Y, Lu KH, Diamandis EP, et al. Potential markers that complement expression of CA 125 in epithelial ovarian cancer. Gynecol Oncol. 2005;99:267–77.CrossRefPubMedGoogle Scholar
  13. 13.
    Rosenthal AN, Menon U, Jacobs IJ. Screening for ovarian cancer. Clin Obstet Gynecol. 2006;49:433–47.CrossRefPubMedGoogle Scholar
  14. 14.
    Buys SS, Partridge E, Greene MH, Prorok PC, Reding D, Riley TL, et al. Ovarian cancer screening in the Prostate, Lung, Colorectal and Ovarian (PLCO) cancer screening trial: findings from the initial screen of a randomized trial. Am J Obstet Gynecol. 2005;193:1630–9.CrossRefPubMedGoogle Scholar
  15. 15.
    Sturgeon CM, Duffy MJ, Stenman UH, Lilja H, Brunner N, Chan DW, et al. National Academy of Clinical Biochemistry laboratory medicine practice guidelines for use of tumour markers in testicular, prostate, colorectal, breast, and ovarian cancers. Clin Chem. 2008;54:e11–79.CrossRefPubMedGoogle Scholar
  16. 16.
    Van Dalen A, Favier J, Hallensleben E, Burges A, Stieber P, de Bruijn HW, et al. Significance of serum CA 125 and TPS antigen levels for determination of overall survival after three chemotherapy courses in ovarian cancer patients during long-term follow-up. Eur J Gynaecol Oncol. 2009;30:609–15.PubMedGoogle Scholar
  17. 17.
    Bast RC Jr, Knapp RC. Use of the CA 125 antigen in diagnosis and monitoring of ovarian carcinoma. Eur J Obstet Gynecol Reprod Biol. 1985;19:354–6.CrossRefPubMedGoogle Scholar
  18. 18.
    Molina R, Filella X, Bruix J, Mengual P, Bosch J, Calvet X, et al. Cancer antigen 125 in serum and ascitic fluid of patients with liver diseases. Clin Chem. 1991;37:1379–83.PubMedGoogle Scholar
  19. 19.
    Bingle L, Singleton V, Bingle CD. The putative ovarian tumour marker gene HE4 (WFDC2), is expressed in normal tissues and undergoes complex alternative splicing to yield multiple protein isoforms. Oncogene. 2002;21:2768–73.CrossRefPubMedGoogle Scholar
  20. 20.
    Hellstrom I, Raycraft J, Hayden-Ledbetter M, Ledbetter JA, Schummer M, McIntosh M, et al. The HE4 (WFDC2) protein is a biomarker for ovarian carcinoma. Cancer Res. 2003;63:3695–700.PubMedGoogle Scholar
  21. 21.
    Galgano MT, Hampton GM, Frierson HF Jr. Comprehensive analysis of HE4 expression in normal and malignant human tissues. Mod Pathol. 2006;19:847–53.CrossRefPubMedGoogle Scholar
  22. 22.
    Anastasi E, Marchei GG, Viggiani V, Gennarini G, Frati L, Reale MG. HE4: a new potential early biomarker for the recurrence of ovarian cancer. Tumour Biol. 2010;31:113–9.CrossRefPubMedGoogle Scholar
  23. 23.
    Moore RG, Jabre-Raughley M, Brown AK, Robison KM, Miller MC, Allard WJ, et al. Comparison of a novel multiple marker assay vs the Risk of Malignancy Index for the prediction of epithelial ovarian cancer in patients with a pelvic mass. Am J Obstet Gynecol. 2010;203:226–8.CrossRefGoogle Scholar
  24. 24.
    Kristjansdottir B, Levan K, Partheen K, et al. Diagnostic performance of the biomarkers HE4 and CA125 in type I and type II epithelial ovarian cancer. Gynecol Oncol. 2013;131:52–8.CrossRefPubMedGoogle Scholar
  25. 25.
    Anastasi E, Granato T, Falzarano R, et al. The use of HE4, CA125 and CA72-4 biomarkers for differential diagnosis between ovarian endometrioma and epithelial ovarian cancer. J Ovarian Res. 2013;6:44.CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Kim YM, Whang DH, et al. Evaluation of the accuracy of serum human epididymis protein 4 in combination with CA125 for detecting ovarian cancer: a prospective case–control study in a Korean population. Clin Chem Lab Med. 2011;49(3):527–34.CrossRefPubMedGoogle Scholar
  27. 27.
    Park Y, Kim Y, Lee EY, Lee J-H, Kim H-S. Reference ranges for HE4 and CA125 in a large Asian population by automated assays and diagnostic performances for ovarian cancer. Int J Cancer. 2012;130:1136–44.CrossRefPubMedGoogle Scholar
  28. 28.
    Abdel-Azeez HA, Labib HA, et al. HE4 and mesothelin: novel biomarkers of ovarian carcinoma in patients with pelvic masses. Asian Pac J Cancer Prev. 2010;11:111–6.PubMedGoogle Scholar

Copyright information

© Association of Gynecologic Oncologists of India 2018

Authors and Affiliations

  1. 1.Department of PathologyKGMULucknowIndia
  2. 2.Department of Obstetrics and GynecologyKGMULucknowIndia

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