Comparison of ovarian cancer markers in endometriosis favours HE4 over CA125

Mckinnon,Brett; Mueller,Michael   D.; Nirgianakis,Konstantinos; Bersinger,Nick  A.

doi:10.3892/mmr.2015.4062

Comparison of ovarian cancer markers in endometriosis favours HE4 over CA125

Authors:
- Brett Mckinnon
- Michael D. Mueller
- Konstantinos Nirgianakis
- Nick A. Bersinger
View Affiliations

Affiliations: Department of Clinical Research, University of Berne, Berne CH-3010, Switzerland, Department of Obstetrics and Gynaecology, University of Berne, Berne CH-3010, Switzerland
Published online on: July 8, 2015 https://doi.org/10.3892/mmr.2015.4062
Pages: 5179-5184

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Endometriosis is a gynaecological condition with an associated chronic inflammatory response. The ectopic growth of ‘lesions’, consisting of endometrial cells outside the uterine cavity, stimulates an inflammatory response initiating the activation of macrophages, and resulting in increased cytokine and growth factor concentrations in the peritoneal fluid (PF). Endometriosis‑associated inflammation is chronic and long lasting. In patients with endometriosis, the risk of developing ovarian cancer within 10 years, particularly of the endometrioid or clear cell subtype, is increased 2.5‑4 times. Endometriosis creates a peritoneal environment that exposes the affected endometriotic and the normal ovarian surface epithelial cells to agents that have been suggested to be involved in the pathogenesis of cancer. Concentrations of several cytokines and growth factors were increased in the PF of patients with endometriosis. The ovarian cancer marker, CA125, was one such growth factor; however, this remains to be confirmed. Human epididymis protein 4 (HE4) was detected at high concentrations in patients with ovarian cancer and was identified as the best biomarker for the detection of ovarian cancer. The present study determined the levels of HE4 and CA125 in the peritoneal fluid of 258 patients with and 100 control individuals without endometriosis attending the Department of Obstetrics and Gynaecology, University of Berne (Berne, Switzerland) between 2007 and 2014. The cases were subdivided into groups without hormonal treatment (n=107), or treated with combined oral contraceptives (n=45), continuous gestagens (n=56) or GnRH agonists (n=50). Both of these markers were significantly increased in the non‑treated endometriosis samples compared with the control group. Hormone treatment with either of the three agents mentioned resulted in the concentration of CA125 returning to the control levels and the concentration of HE4 decreasing to below the control levels. CA125, however not HE4, significantly differed between the proliferative and secretory cycle phases. Since HE4 is sensitive to hormonal treatment and robust towards menstrual cycle variation, HE4 is potentially superior to CA125 as an endometriosis marker and therefore has greater potential as a marker for the identification of women at risk of developing ovarian cancer.

View Figures

View References

1	Eskenazi B and Warner ML: Epidemiology of endometriosis. Obstet Gynecol Clin North Am. 24:235–258. 1997. View Article : Google Scholar : PubMed/NCBI
2	Evans S, Moalem-Taylor G and Tracey DJ: Pain and endometriosis. Pain. 132(Suppl 1): S22–S25. 2007. View Article : Google Scholar : PubMed/NCBI
3	D'Hooghe TM, Debrock S, Hill JA and Meuleman C: Endometriosis and subfertility: Is the relationship resolved. Semin Reprod Med. 21:243–254. 2003. View Article : Google Scholar : PubMed/NCBI
4	Chung SY, Kim SJ, Kim TH, et al: Computed tomography findings of pathologically confirmed pulmonary parenchymal endometriosis. J Comput Assist Tomogr. 29:815–818. 2005. View Article : Google Scholar : PubMed/NCBI
5	Fraser IS: Recognising, understanding and managing endometriosis. J Reprod Sci. 1:56–64. 2008. View Article : Google Scholar
6	Sampson J: Peritoneal endometriosis due to the menstrual dissemination of endometrial tissue into the peritoneal cavity. Am J Obstet Gynecol. 14:422–469. 1927.
7	Halme J, Hammond M, Hulka J, Raj S and Talbert L: Retrograde menstruation in healthy women and in patients with endometriosis. Obstet Gynecol. 64:151–154. 1984.PubMed/NCBI
8	Brinton LA, Gridley G, Persson I, Baron J and Bergqvist A: Cancer risk after a hospital discharge diagnosis of endometriosis. Am J Obstet Gynecol. 176:572–579. 1997. View Article : Google Scholar : PubMed/NCBI
9	Swiersz L: Role of endometriosis in cancer and tumour development. Ann NY Acad Sci. 955:281–292. 2002. View Article : Google Scholar
10	Martin DC: Cancer and endometriosis: Do we need to be concerned? Semin Reprod Endocrinol. 15:319–324. 1997. View Article : Google Scholar : PubMed/NCBI
11	Gwinn ML, Lee NC, Rhodes PH, Layde PM and Rubin GL: Pregnancy, breast feeding, and oral contraceptives and the risk of epithelial ovarian cancer. J Clin Epidemiol. 43:559–568. 1991. View Article : Google Scholar
12	Fraser IS and Kovacs GT: The efficacy of non-contraceptive uses for hormonal contraceptives. Med J Aust. 178:621–623. 2003.PubMed/NCBI
13	Fathalla MF: Incessant ovulation - a factor in ovarian neoplasia? Lancet. 2:1631971. View Article : Google Scholar
14	Ness RB, Cramer DW, Goodman MT, et al: Infertility, fertility drugs, and ovarian cancer: A pooled analysis of case-control studies. Am J Epidemiol. 155:217–224. 2002. View Article : Google Scholar : PubMed/NCBI
15	Booth M, Beral V and Smith P: Risk factors for ovarian cancer: A case-control study. Br J Cancer. 60:592–598. 1989. View Article : Google Scholar : PubMed/NCBI
16	Risch HA, Marrett LD and Howe GR: Parity, contraception, infertility, and the risk of epithelial ovarian cancer. Am J Epidemiol. 140:585–597. 1994.PubMed/NCBI
17	Ryan IP, Tseng JF, Schriock ED, Khorram O, Landers DV and Taylor RN: Interleukin-8 concentrations are elevated in peritoneal fluid of women with endometriosis. Fertil Steril. 63:929–932. 1995.PubMed/NCBI
18	Lebovic DI, Mueller MD and Taylor RN: Immunobiology of endometriosis. Fertil Steril. 75:1–10. 2001. View Article : Google Scholar : PubMed/NCBI
19	Bersinger NA, von Roten S, Wunder DM, Raio L, Dreher E and Mueller MD: PAPP-A and osteoprotegerin, together with interleukin-8 and RANTES, are elevated in the peritoneal fluid of women with endometriosis. Am J Obstet Gynecol. 195:103–108. 2006. View Article : Google Scholar : PubMed/NCBI
20	Siristatidis C, Nissotakis C, Chrelias C, Iacovidou H and Salamalekis E: Immunological factors and their role in the genesis and the development of endometriosis. J Obstet Gynaecol Res. 32:162–170. 2006. View Article : Google Scholar : PubMed/NCBI
21	Bersinger NA, Dechaud H, Mckinnon B and Mueller MD: Analysis of cytokines in the peritoneal fluid of endometriosis patients as a function of the menstrual cycle stage using the Bio-Plex platform. Arch Physiol Biochem. 118:210–218. 2012. View Article : Google Scholar : PubMed/NCBI
22	Moen MH, Hagen B and Onsrud M: CA-125 in peritoneal fluid from patients with endometriosis. Hum Reprod. 6:1400–1403. 1991.PubMed/NCBI
23	Koninckx PR, Riitinen L, Seppala M and Cornillie FJ: CA-125 and placental protein 14 concentrations in plasma and peritoneal fluid of women with deeply infiltrating pelvic endometriosis. Fertil Steril. 57:523–530. 1992.PubMed/NCBI
24	Matalliotakis IM, Goumenou AG, Mulayim N, Karkavitsas N and Koumantakis EE: High concentrations of the CA-125, CA 19-9 and CA 15-3 in the peritoneal fluid between patients with and without endometriosis. Arch Gynecol Obstet. 271:40–45. 2005. View Article : Google Scholar
25	Amaral VF, Ferriani RA, Sá MF, Nogueira AA, Rosa e Silva JC, Rosa e Silva AC and Moura MD: Positive correlation between serum and peritoneal fluid CA-125 levels in women with pelvic endometriosis. Sao Paulo Med J. 124:223–227. 2006. View Article : Google Scholar : PubMed/NCBI
26	Bersinger NA, Sinosich MJ, Baber R, Torode H and Saunders DM: Development of an endometrial explant model for the investigation of uterine readiness for implantation in the human. Implantation in Mammals. Serono Symposia; 91. pp. 301–308. 1993
27	Duffy MJ: Role of tumour markers in patients with solid cancers. A critical review. Eur J Intern Med. 18:175–184. 2007. View Article : Google Scholar : PubMed/NCBI
28	Anderson MR, Goff BA, Lowe KA, et al: Combining a symptoms index with CA125 to improve detection of ovarian cancer. Cancer. 113:484–489. 2008. View Article : Google Scholar
29	Ataseven H, Oztürk ZA, Arhan M, et al: Cancer antigen 125 levels in inflammatory bowel diseases. J Clin Lab Anal. 23:244–248. 2009. View Article : Google Scholar : PubMed/NCBI
30	Drapkin R, Von Horsten HH, Lin Y, et al: Human epididymis protein 4 (HE4) is a secreted glycoprotein that is overexpressed by serous and endometrioid ovarian carcinomas. Cancer Res. 65:2162–2169. 2005. View Article : Google Scholar : PubMed/NCBI
31	Hellstrom I, Raycraft J, Hayden M, et al: The HE4 (WFDC2) protein is a biomarker for ovarian carcinoma. Cancer Res. 63:3695–3700. 2003.PubMed/NCBI
32	Moore RG, Brown AK, Miller MC, et al: The use of multiple novel tumor biomarkers for the detection of ovarian carcinoma in patients with a pelvic mass. Gynecol Oncol. 108:402–408. 2008. View Article : Google Scholar
33	Chang X, Ye X, Dong L, et al: Human epididymis protein 4 (HE4) as a serum tumor biomarker in patients with ovarian carcinoma. Int J Gynecol Cancer. 21:852–858. 2011. View Article : Google Scholar : PubMed/NCBI
34	Escudero JM, Auge JM, Filella X, Torne A, Pahisa J and Molina R: Comparison of serum human epididymis protein 4 with cancer antigen 125 as a tumor marker in patients with malignant and nonmalignant diseases. Clin Chem. 57:1534–1544. 2011. View Article : Google Scholar : PubMed/NCBI
35	Moore RG, Miller MC and Steinhoff MM: Serum HE4 levels are less frequently elevated than CA125 in women with benign gynecologic disorders. Am J Obstet Gynecol. 206:351.e1–e8. 2012. View Article : Google Scholar
36	Huhtinen K, Suvitie P, Hiissa J, et al: Serum HE4 concentration differentiates malignant ovarian tumours from ovarian endometriotic cysts. Br J Cancer. 100:1315–1319. 2009. View Article : Google Scholar : PubMed/NCBI
37	Anastasi E, Granato T, Coppa A, et al: HE4 in the differential diagnosis of a pelvic mass: a case report. Int J Mol Sci. 12:627–632. 2011. View Article : Google Scholar : PubMed/NCBI
38	Hallamaa M, Suvitie P, Huhtinen K, Matomäki J, Poutanen M and Perheentupa A: Serum HE4 concentration is not dependent on menstrual cycle or hormonal treatment among endometriosis patients and healthy premenopausal women. Gynecol Oncol. 125:667–672. 2012. View Article : Google Scholar : PubMed/NCBI
39	McKinnon BD, Bertschi D, Wanner J, Bersinger NA and Mueller MD: Hormonal contraceptive use and the prevalence of endometriotic lesions at different regions within the peritoneal cavity. Biomed Res Int. 2014:5909502014. View Article : Google Scholar : PubMed/NCBI
40	Kupker W, Schultze-Mosgau A and Diedrich K: Paracrine changes in the peritoneal environment of women with endometriosis. Hum Reprod Update. 4:719–723. 1998. View Article : Google Scholar
41	Brown J, Pan A and Hart RJ: Gonadotrophin-releasing hormone analogues for pain associated with endometriosis. Cochrane Database Syst Rev. CD0084752010.PubMed/NCBI
42	Nirgianakis K, Bersinger NA, McKinnon B, Kostov P, Imboden S and Mueller MD: Regression of the inflammatory microenvironment of the peritoneal cavity in women with endometriosis by GnRHa treatment. Eur J Obstet Gynecol Reprod Biol. 170:550–554. 2013. View Article : Google Scholar : PubMed/NCBI