Serum human epididymis protein 4 can be a useful tumor marker in the differential diagnosis of adnexal masses during pregnancy: a pilot study

Purpose: The purpose of this study was to evaluate serum concentrations of human epididymis protein 4 (HE4) and cancer antigen 125 (CA 125) in healthy women and their pregnant counterparts to determine the influence of pregnancy on these biomarkers. Materials and Methods: Serum concentrations of CA 125 and HE4 were measured in 27 healthy non-pregnant women and 26 healthy pregnant women in the first and second trimesters. Results: Higher concentration of CA 125 was found in pregnants than in non-pregnant women (p = 0.002). There was no difference in CA 125 concentrations between first and second trimesters (p = 0.13). Serum HE4 concentration was not different in pregnant group compared to non-pregnant women (p = 0.510). Likewise, no difference was found in HE4 levels between the trimesters (p = 0.485). There was a positive correlation between increasing parity and CA 125 (p = 0.023), but not HE4 (p = 1.0). Conclusion: HE4 serum biomarker is unaffected by pregnancy status and may be useful for evaluation of doubtful pelvic masses in pregnancy. Contrarily, increased serum levels of CA 125 could yield increased number of false-positive results.

Cancer antigen 125; Human epididymis protein 4; Tumor markers in pregnancy.

[1] Hoover K., Jenkins T.R.: “Evaluation and management of adnexal mass in pregnancy”. Am. J. Obstet. Gynecol., 2011, 205, 97.

[2] Moore R.D., Smith W.G.: “Laparoscopic management of adnexal masses in pregnant women”. J. Reprod. Med., 1999, 44, 97.

[3] Schmeler K.M., Mayo-Smith W.W., Peipert J.F., Weitzen S., Manuel M.D., Gordinier M.E.: “Adnexal masses in pregnancy: surgery compared with observation”. Obstet. Gynecol., 2005, 105, 1098.

[4] Ko M.L., Lai T.H., Chen S.C.: “Laparoscopic management of complicated adnexal masses in the first trimester of pregnancy”. Fertil. Steril., 2009, 92, 283.

[5] Whitecar M.P., Turner S., Higby M.K.: “Adnexal masses in pregnancy: a review of 130 cases undergoing surgical management”. Am. J. Obstet. Gynecol., 1999, 181, 19.

[6] Leiserowitz G.S.: “Managing ovarian masses during pregnancy.” Obstet. Gynecol. Surv., 2006, 61, 463.

[7] Leiserowitz G.S., Xing G., Cress R., Brahmbhatt B., Dalrymple J.L., Smith L.H.: “Adnexal masses in pregnancy: how often are they malignant?” Gynecol. Oncol., 2006, 101, 315.

[8] Bast R.C. Jr., Badgwell D., Lu Z., Marquez R., Rosen D., Liu J., et al.: “New tumor markers: CA125 and beyond”. Int. J. Gynecol. Cancer, 2005, 15, 274.

[9] Moore R.G., McMeekin D.S., Brown A.K., Disilvestro P., Miller M.C., Allard W.J., et al.: “A novel multiple marker bioassay utilizing HE4 and CA125 for the prediction of ovarian cancer in patients with a pelvic mass”. Gynecol. Oncol., 2009, 112, 40.

[10] Bon G.G., Kenemans P., Dekker J.J., Hompes P.G., Verstraeten R.A., van Kamp G.J., Schoemaker J.: “Fluctuations in CA 125 and Ca 15- 3 serum concentrations during spontaneous ovulatory cycles”. Hum. Reprod. 1999, 14, 566.

[11] Schlageter M.H., Larghero J., Cassinat B., Toubert M.E., Borschneck C., Rain J.D.: “Serum carcinoembryonic antigen, cancer antigen 125, cancer antigen 15-3, squamous cell carcinoma, and tumor-associated trypsin inhibitor concentrations during healthy pregnancy”. Clin. Chem., 1998, 44, 1995.

[12] “CA-125. Test interpretation”. Available at: http://www.clinlabnavigator. com/ca-125.html

[13] Jacobs I.J., Menon U.: “Progress and challenges in screening for early detection of ovarian cancer”. Mol. Cell. Proteomics, 2004, 3, 355.

[14] Duffy M.J., Bonfrer J.M., Kulpa J., Rustin G.J., Soletormos G., Torre G.C., et al.: “CA125 in ovarian cancer: European Group on Tumor Markers guidelines for clinical use”. Int. J. Gynecol. Cancer, 2005, 15, 679.

[15] Dgani R., Shoham Z., Atar E., Zosmer A., Lancet M.: “Ovarian carcinoma during pregnancy: a study of 23 cases in Israel between the years 1960 and 1984”. Gynecol. Oncol., 1989, 33, 326.

[16] Schummer M., Ng W.V., Bumgarner R.E., Nelson P.S., Schummer B., Bednarski D.W., et al.: “Comparative hybridization of an array of 21,500 ovarian cDNAs for the discovery of genes overexpressed in ovarian carcinomas”. Gene, 1999, 238, 375.

[17] Lu K.H., Patterson A.P., Wang L., Marquez R.T., Atkinson E.N., Baggerly K.A., et al.: “Selection of potential markers for epithelial ovarian cancer with gene expression arrays and recursive descent partition analysis”. Clin. Cancer. Res., 2004, 10, 3291.

[18] Welsh J.B., Zarrinkar P.P., Sapinoso L.M., Kern S.G., Behling C.A., Monk B.J., et al.: “Analysis of gene expression profiles in normal and neoplastic ovarian tissue samples identifies candidate molecular markers of epithelial ovarian cancer”. Proc. Natl. Acad. Sci. U S A, 2001, 98, 1176.

[19] Schaner M.E., Ross D.T., Ciaravino G., Sorlie T., Troyanskaya O., Diehn M., et al.: “Gene expression patterns in ovarian carcinomas”. Mol. Biol. Cell., 2003, 14, 4376.

[20] Schwartz D.R., Kardia S.L., Shedden K.A., Kuick R., Michailidis G., Taylor J.M., et al.: “Gene expression in ovarian cancer reflects both morphology and biological behavior, distinguishing clear cell from other poor-prognosis ovarian carcinomas”. Cancer Res., 2002, 62, 4722.

[21] Galgano M.T., Hampton G.M., Frierson H.F. Jr.: “Comprehensive analysis of HE4 expression in normal and malignant human tissues”. Mod. Pathol., 2006, 19, 847.

[22] Hellström I., Raycraft J., Hayden-Ledbetter M., Ledbetter J.A., Schummer M., McIntosh M.: “The HE4 (WFDC2) protein is a biomarker for ovarian carcinoma”. Cancer Res., 2003, 63, 3695.

[23] Havrilesky L.J., Whitehead C.M., Rubatt J.M., Cheek R.L., Groelke J., He Q., et al.: “Evaluation of biomarker panels for early stage ovarian cancer detection and monitoring for disease recurrence”. Gynecol. Oncol., 2008, 110, 374.

[24] Hellstrom I., Hellstrom K.E.: “SMRP and HE4 as biomarkers for ovarian carcinoma when used alone and in combination with CA125 and/or each other”. Adv. Exp. Med. Biol., 2008, 622, 15.

[25] Moore R.G., Miller M.C., Eklund E.E., Lu K.H., Bast R.C. Jr., Lambert- Messerlian G.: “Serum levels of the ovarian cancer biomarker HE4 are decreased in pregnancy and increase with age”. Am. J. Obstet. Gynecol., 2012, 206, 349.

[26] Seki K., Kikuchi Y., Uesato T., Kato K.: “Increased serum CA 125 levels during the first trimester of pregnancy”. Acta Obstet. Gynecol. Scand., 1986, 65, 583.

[27] Fendrick J.L., Staley K.A., Gee M.K., McDougald S.R., Quirk J.G. Jr., O’Brien T.J.: “Characterization of CA 125 synthesized by the human epithelial amnion WISH cell line”. Tumour Biol., 1993, 14, 310.

[28] Bon G.G., Kenemans P., Verstraeten A.A., Go S., Philipi P.A., van Kamp G.J., et al.: “Maternal serum Ca125 and Ca15-3 antigen levels in normal and pathological pregnancy”. Fetal. Diagn. Ther., 2001, 16, 166.

[29] Lowe K.A., Shah C., Wallace E., Anderson G., Paley P., McIntosh M., et al.: “Effects of personal characteristics on serum CA125, mesothelin, and HE4 levels in healthy postmenopausal women at high-risk for ovarian cancer”. Cancer Epidemiol. Biomarkers Prev., 2008, 17, 2480.

[30] Cramer D.W., Vitonis A.F., Welch W.R., Terry K.L., Goodman A., Rueda B.R., Berkowitz R.S.: “Correlates of the preoperative level.of CA125 at presentation of ovarian cancer”. Gynecol. Oncol., 2010, 119, 462.