Effect of Serum Level of Human Epididymis Protein 4 and Interleukin-6 as Biomarkers in Patients with Adnexal Mass

Document Type : Original Articles

Authors

1 Department of Microbiology, College of Medicine, University of Basrah, Basrah, Iraq

2 Department of Gynecology and Obstetrics, College of Medicine, University of Basrah, Basrah, Iraq

Abstract

Ovarian carcinoma is one of the most common types of neoplasms in women and the fifth leading cause of cancer death among women worldwide. Adnexal masses are classified as simple or complicated and can be benign or malignant. No single biomarker has demonstrated high sensitivity and specificity for detecting early ovarian cancer. Therefore, the current study was designed to investigate the influence of using two biomarkers as a tool for diagnosis in patients with an adnexal mass. This prospective case-control study was carried out on female patients diagnosed by ultrasound and magnetic resonance imaging with adnexal masses and scheduled for surgery and healthy women as a control group (n=50 each). The patients were in the age range of 16-80 years old and had attended the surgical rooms of Basrah hospitals, Basrah, Iraq, from January to July 2021. The levels of serum biomarkers were quantitatively assessed using the enzyme-linked immunosorbent assay. The serum concentration of the human epididymis protein 4 (HE4) biomarker exhibited significant differences between females with adnexal mass and healthy women. There was no significant association between neither the patient’s age nor the menopausal state and the serum level of HE4. The serum level of HE4 had a sensitivity of 92% and a specificity of 66% as a serum marker for the presence of adnexal mass with a positive predictive value of 73% and a negative predictive value of 89%. In this study, serum interleukin-6 (IL-6) had a sensitivity of 30% and specificity of 64% in determining patients with adnexal mass pathology. It was found that the level of IL-6 was similar in all patients, compared to that in the control group. The median levels of serum HE4 showed high value in patients in the age groups of 21-40, 41-50, and >50 than in the control group; however, it was not statistically different (P=0.413). Human epididymis protein 4 was the top biomarker representing a higher concentration in adnexal mass; moreover, it demonstrated the highest performance in all samples with Adnexal mass. The results of our study showed that combining more than one marker measurement increased both the sensitivity and specificity of distinguishing patients with adnexal mass pathology.

Keywords

Main Subjects


  1. Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, et al. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer. 2015;136(5):359-86.
  2. Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68(6):394-424.
  3. Cohen JG, White M, Cruz A, Farias-Eisner R. In 2014, can we do better than CA125 in the early detection of ovarian cancer? World J Biol Chem. 2014;5(3):286-300.
  4. Abood R, Abdahmed K, Mazyed S. Epidemiology of Different Types of Cancers Reported in Basra, Iraq. Sultan Qaboos Univ Med J. 2020;20:295.
  5. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2018. CA Cancer J Clin. 2018;68(1):7-30.
  6. Lee SW, Lee HY, Bang HJ, Song HJ, Kong SW, Kim YM. An Improved Prediction Model for Ovarian Cancer Using Urinary Biomarkers and a Novel Validation Strategy. Int J Mol Sci. 2019;20(19).
  7. Tarver T. Cancer Facts & Figures 2012. American Cancer Society (ACS). J Consum Health Internet. 2012;16(3):366-7.
  8. Collaborative Group on Epidemiological Studies of Ovarian C. Menopausal hormone use and ovarian cancer risk: individual participant meta-analysis of 52 epidemiological studies. Lancet. 2015;385(9980):1835-42.
  9. Moore RG, Brown AK, Miller MC, Skates S, Allard WJ, Verch T, et al. The use of multiple novel tumor biomarkers for the detection of ovarian carcinoma in patients with a pelvic mass. Gynecol Oncol. 2008;108(2):402-8.
  10. Conway C, Zalud I, Dilena M, Maulik D, Schulman H, Haley J, et al. Simple cyst in the postmenopausal patient: detection and management. J Ultrasound Med. 1998;17(6):369-72; quiz 73-4.
  11. Dorum A, Blom GP, Ekerhovd E, Granberg S. Prevalence and histologic diagnosis of adnexal cysts in postmenopausal women: an autopsy study. Am J Obstet Gynecol. 2005;192(1):48-54.
  12. Sevinc A, Adli M, Kalender ME, Camci C. Benign causes of increased serum CA-125 concentration. Lancet Oncol. 2007;8(12):1054-5.
  13. Fotopoulou C, Gabra H, Blagden SP. Surgical and Medical Management of Epithelial Ovarian Cancer. Dewhurst's Textbook of Obstetrics & Gynaecology2018. p. 884-904.
  14. Kumari S. Serum Biomarker Based Algorithms in Diagnosis of Ovarian Cancer: A Review. Indian J Clin Biochem. 2018;33(4):382-6.
  15. Hellstrom I, Hellstrom KE. 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;622:15-21.
  16. Moore RG, McMeekin DS, Brown AK, DiSilvestro P, Miller MC, Allard WJ, 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(1):40-6.
  17. Nilsson MB, Langley RR, Fidler IJ. Interleukin-6, secreted by human ovarian carcinoma cells, is a potent proangiogenic cytokine. Cancer Res. 2005;65(23):10794-800.
  18. Alhumrani SA-R, Jamalludeen NM, Abdulhameed AA. Study of Interleukin 6 as marker of inflammation and a predictor of in-hospital complications in patients with acute coronary syndrome. Med J Basrah Univ. 2020;38(2):115-9.
  19. Maccio A, Madeddu C. Inflammation and ovarian cancer. Cytokine. 2012;58(2):133-47.
  20. Bast RC, Jr., Skates S, Lokshin A, Moore RG. Differential diagnosis of a pelvic mass: improved algorithms and novel biomarkers. Int J Gynecol Cancer. 2012;22 Suppl 1:5-8.
  21. Granato T, Midulla C, Longo F, Colaprisca B, Frati L, Anastasi E. Role of HE4, CA72.4, and CA125 in monitoring ovarian cancer. Tumour Biol. 2012;33(5):1335-9.
  22. Moore RG, Miller MC, Steinhoff MM, Skates SJ, Lu KH, Lambert-Messerlian G, et al. Serum HE4 levels are less frequently elevated than CA125 in women with benign gynecologic disorders. Am J Obstet Gynecol. 2012;206(4):351 e1-8.
  23. Rosen DG, Wang L, Atkinson JN, Yu Y, Lu KH, Diamandis EP, et al. Potential markers that complement expression of CA125 in epithelial ovarian cancer. Gynecol Oncol. 2005;99(2):267-77.
  24. Hellström 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(13):3695-700.
  25. Havrilesky LJ, Whitehead CM, Rubatt JM, Cheek RL, 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(3):374-82.
  26. Moore RG, Brown AK, Miller MC, Badgwell D, Lu Z, Allard WJ, et al. Utility of a novel serum tumor biomarker HE4 in patients with endometrioid adenocarcinoma of the uterus. Gynecol Oncol. 2008;110(2):196-201.
  27. Huhtinen K, Suvitie P, Hiissa J, Junnila J, Huvila J, Kujari H, et al. Serum HE4 concentration differentiates malignant ovarian tumours from ovarian endometriotic cysts. Br J Cancer. 2009;100(8):1315-9.
  28. Zhang Y, Qiao C, Li L, Zhao X, Li Y. Serum HE4 is more suitable as a biomarker than CA125 in Chinese women with benign gynecologic disorders. Afr Health Sci. 2014;14(4):913-8.
  29. Moore RG, Miller MC, Disilvestro P, Landrum LM, Gajewski W, Ball JJ, et al. Evaluation of the diagnostic accuracy of the risk of ovarian malignancy algorithm in women with a pelvic mass. Obstet Gynecol. 2011;118(2 Pt 1):280-8.
  30. Ruggeri G, Bandiera E, Zanotti L, Belloli S, Ravaggi A, Romani C, et al. HE4 and epithelial ovarian cancer: comparison and clinical evaluation of two immunoassays and a combination algorithm. Clin Chim Acta. 2011;412(15-16):1447-53.
  31. Moore RG, Miller MC, Eklund EE, Lu KH, Bast RC, 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(4):349 e1-7.
  32. Lowe KA, 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(9):2480-7.
  33. Mokhtar N, Thevarajah M, Ma N, M I. Human epididymis protein 4 reference intervals in a multiethnic asian women population. Asian Pac J Cancer Prev. 2012;13(12):6391-5.
  34. Dehaghani AS, Ghiam AF, Hosseini M, Mansouri S, Ghaderi A. Factors influencing serum concentration of CA125 and CA15-3 in Iranian healthy postmenopausal women. Pathol Oncol Res. 2007;13(4):360-4.
  35. Dubé L-R. Approach to Gynecological Adnexal Masses. Mcgill J Med. 2022;20(1).
  36. Dubé L-RJMJoM. Approach to Gynecological Adnexal Masses. 2022;20(1).
  37. Van Gorp T, Cadron I, Despierre E, Daemen A, Leunen K, Amant F, et al. HE4 and CA125 as a diagnostic test in ovarian cancer: prospective validation of the Risk of Ovarian Malignancy Algorithm. Br J Cancer. 2011;104(5):863-70.
  38. Kampan NC, Madondo MT, Reynolds J, Hallo J, McNally OM, Jobling TW, et al. Pre-operative sera interleukin-6 in the diagnosis of high-grade serous ovarian cancer. Sci Rep. 2020;10(1):2213.
  39. Mikula-Pietrasik J, Uruski P, Matuszkiewicz K, Szubert S, Moszynski R, Szpurek D, et al. Ovarian cancer-derived ascitic fluids induce a senescence-dependent pro-cancerogenic phenotype in normal peritoneal mesothelial cells. Cell Oncol (Dordr). 2016;39(5):473-81.
  40. Sanguinete MMM, Oliveira PH, Martins-Filho A, Micheli DC, Tavares-Murta BM, Murta EFC, et al. Serum IL-6 and IL-8 Correlate with Prognostic Factors in Ovarian Cancer. Immunol Invest. 2017;46(7):677-88.
  1. Darai E, Detchev R, Hugol D, Quang NT. Serum and cyst fluid levels of interleukin (IL) -6, IL-8 and tumour necrosis factor-alpha in women with endometriomas and benign and malignant cystic ovarian tumours. Hum Reprod. 2003;18(8):1681-5.
  2. Block MS, Maurer MJ, Goergen K, Kalli KR, Erskine CL, Behrens MD, et al. Plasma immune analytes in patients with epithelial ovarian cancer. Cytokine. 2015;73(1):108-13.
  3. Chudecka-Glaz AM, Cymbaluk-Ploska AA, Menkiszak JL, Pius-Sadowska E, Machalinski BB, Sompolska-Rzechula A, et al. Assessment of selected cytokines, proteins, and growth factors in the peritoneal fluid of patients with ovarian cancer and benign gynecological conditions. Onco Targets Ther. 2015;8:471-85.
  4. Lane D, Matte I, Garde-Granger P, Laplante C, Carignan A, Rancourt C, et al. Inflammation-regulating factors in ascites as predictive biomarkers of drug resistance and progression-free survival in serous epithelial ovarian cancers. BMC Cancer. 2015;15:492.
  5. Maggio M, Guralnik JM, Longo DL, Ferrucci L. Interleukin-6 in aging and chronic disease: a magnificent pathway. J Gerontol A Biol Sci Med Sci. 2006;61(6):575-84.
  6. Terry KL, Sluss PM, Skates SJ, Mok SC, Ye B, Vitonis AF, et al. Blood and urine markers for ovarian cancer: a comprehensive review. Dis Markers. 2004;20(2):53-70.