Comparison of Serum Human Epididymis Protein 4 and Carbohydrate Antigen 125 in Diagnosing Endometrial Cancer: A Systematic Review_Chinese Journal of Evidence-Based Medicine

Authors：

 HULing-li ¹ , GUOWan-hua ¹ , CHENDe-zhu ¹ , LIYing ² ,  DUShi-zheng ³

1. Department of Nuclear Medicine, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing 210008, China;
2. Department of Clinical Laboratory, Zhongda Hospital, The Affiliated Hospital of Southeast University, Nanjing 210009, China;
3. School of Nursing, Nanjing University of Chinese Medicine, Nanjing 210023, China;

Corresponding author：

DUShi-zheng, Email: dushizheng007@163.com

Keywords：

Human epididymis protein 4; Carbohydrate antigen 125; Endometrial cancer; Systematic review; Meta analysis; Diagnostic test

DOI：

10.7507/1672-2531.20150175

Video：

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Objective To systematically review the diagnostic value between serum human epididymis protein 4 (HE4) and carbohydrate antigen 125 (CA125) for endometrial cancer (EC). Methods We electronically searched databases including PubMed, The Cochrane Library, Web of Science, ScienceDirect, EBSCO, CNKI and VIP to collect diagnostic accuracy studies of serum HE4 and/or CA125 versus golden standard (pathology) for EC from inception to August 2014. Two reviewers independently screened literature, extracted data and assessed the risk bias of included studies by QUADAS-2 tool. Then, meta-analysis was performed by Meta-Disc 1.4 software. Results A total of 20 studies involving 4 351 participants were included. The results of meta-analysis showed that:the pooled sensitivity (Sen), specificity (Spe), positive likelihood ratio (+LR), and negative likelihood ratio (-LR), and diagnostic odds ratio (DOR) of HE4 in the diagnosis of EC were 0.56 (95%CI 0.54 to 0.58), 0.89 (95%CI 0.88 to 0.90), 6.19 (95%CI 4.31 to 8.88), 0.49 (95%CI 0.44 to 0.56), and 14.27 (95%CI 9.50 to 21.42), respectively. The area under the curve (AUC) of SROC was 0.855 9. The pooled Sen, Spe, +LR,-LR, and DOR of CA125 in the diagnosis of EC were 0.33 (95%CI 0.31 to 0.34), 0.80 (95%CI 0.78 to 0.82), 2.07 (95%CI 1.45 to 2.95), 0.83 (95%CI 0.76 to 0.91), and 2.65 (95%CI 1.63 to 4.32), respectively. The SROC AUC was 0.657 5. Conclusion Compared with CA125, HE4 has higher diagnostic accuracy for EC. Due to limited quality and quantity of the included studies, more high quality studies are needed to verify the above conclusion.

Citation： HULing-li, GUOWan-hua, CHENDe-zhu, LIYing, DUShi-zheng. Comparison of Serum Human Epididymis Protein 4 and Carbohydrate Antigen 125 in Diagnosing Endometrial Cancer: A Systematic Review. Chinese Journal of Evidence-Based Medicine, 2015, 15(9): 1049-1058. doi: 10.7507/1672-2531.20150175 Copy

1.	World Health Organization. GLOBOCAN 2012:Estimated Cancer incidence, Mortality, and Prevalence Worldwide in 2012.[2015-05-17] Available at:http://globocan.iarc.fr/Default.aspx.
2.	Ali AT. Reproductive factors and the risk of endometrial cancer. Int J Gynecol Cancer, 2014, 24(3):384-393.
3.	Lajer H, Elnegaard S, Christensen RD, et al. Survival after stage IA endometrial cancer; can follow-up be altered? A prospective nationwide Danish survey. Acta Obstet Gynecol Scand, 2012, 91(8):976-982.
4.	Aggarwal P, Kehoe S. Serum tumour markers in gynaecological cancers. Maturitas, 2010, 67(1):46-53.
5.	Kirchhoff C, Habben I, Ivell R, et al. A major human epididymis-specific cDNA encodes a protein with sequence homology to extracellular proteinase inhibitors. Biol Reprod, 1991, 45(2):350-357.
6.	Zhen S, Bian LH, Chang LL, et al. Comparison of serum human epididymis protein 4 and carbohydrate antigen 125 as markers in ovarian cancer:A meta-analysis. Mol Clin Oncol, 2014, 2(4):559-566.
7.	Lin J, Qin J, Sangvatanakul V. Human epididymis protein 4 for differential diagnosis between benign gynecologic disease and ovarian cancer:a systematic review and meta-analysis. Eur J Obstet Gynecol Reprod Biol, 2013, 167(1):81-85.
8.	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(4):273-281.
9.	Lin JY, Qin JB, Li XY, Dong P, et al. Diagnostic value of human epididymis protein 4 compared with mesothelin for ovarian cancer:a systematic review and meta-analysis. Asian Pac J Cancer Prev, 2012, 13(11):5427-5432.
10.	Cheng D, Sun Y, He H. The diagnostic accuracy of HE4 in lung cancer:a meta-analysis. Dis Markers, 2015:352670.
11.	Bie Y, Zhang Z. Diagnostic value of serum HE4 in endometrial cancer:a meta-analysis. World J Surg Oncol, 2014, 12(3):169.
12.	张晶, 王宇娟, 霍俊玲, 等. 人附睾蛋白4早期诊断子宫内膜癌价值的系统评价. 中国循证医学杂志, 2014, 14(1):72-78.
13.	Whiting PF, Rutjes AW, Westwood ME, et al. QUADAS-2 Group. QUADAS-2:a revised tool for the quality assessment of diagnostic accuracy studies. Ann Intern Med, 2011, 155(8):529-536.
14.	张俊, 徐志伟, 李克. 诊断性试验Meta分析的效应指标评价. 中国循证医学杂志, 2013, 13(7):890-895.
15.	Devillé WL, Buntinx F, Bouter LM, et al. Conducting systematic reviews of diagnostic studies:didactic guidelines. BMC Med Res Methodol, 2002, 2:9.
16.	Zhen S, Bian LH, Chang LL, et al. Comparison of serum human epididymis protein 4 and carbohydrate antigen 125 as markers in ovarian cancer:A meta-analysis. Mol Clin Oncol, 2014, 2(4):559-566.
17.	Pepe MS, Feng Z, Janes H, et al. Pivotal evaluation of the accuracy of a biomarker used for classification or prediction:standards for study design. J Natl Cancer Inst, 2008, 100(20):1432-1438.
18.	Moore RG, Brown AK, Miller MC, 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.
19.	Bignotti E, Ragnoli M, Zanotti L, et al. Diagnostic and prognostic impact of serum HE4 detection in endometrial carcinoma patients. Br J Cancer, 2011, 104(9):1418-1425.
20.	丛培珊, 孙桂荣, 张娜娜, 等. 人附睾蛋白4对子宫内膜癌和卵巢癌早期辅助诊断价值的评估. 检验医学, 2011, 26 (7):447-451.
21.	马荣, 耿晓星, 唐丽萍, 等. 人附睾分泌蛋白4检测对子宫内膜癌的诊断及预后的意义. 临床肿瘤学杂志, 2011, 16(9):790-793.
22.	吴飞, 周慧芹, 崔满华. 联合检测CA125与HE4在子宫内膜癌诊断中的价值. 中国妇幼保健, 2011, 26(10):1559-1561.
23.	杨圣晗, 李群(指导老师). HE4在子宫内膜癌患者血清中的表达及其与CA125联合检测的临床意义. 蚌埠:蚌埠医学院, 2011.
24.	简慧秋, 徐春琳(指导老师). 尿液人附睾蛋白4在卵巢癌、子宫内膜癌诊断和鉴别诊断中的意义. 石家庄:河北医科大学, 2012.
25.	Zanotti L, Bignotti E, Calza S, et al. Human epididymis protein 4 as a serum marker for diagnosis of endometrial carcinoma and prediction of clinical outcome. Clin Chem Lab Med, 2012, 50(12):2189-2198.
26.	张爱敏, 张鹏. 血清人附睾分泌蛋白E₄和CA125联合检测对子宫内膜癌诊断的临床价值. 中华妇产科杂志, 2012, 47(2):125-128.
27.	张双革. 人附睾蛋白4对子宫内膜癌的风险评估研究. 国际妇产科学杂志, 2013, 40 (5):466-469.
28.	赵灵琴, 陈曦, 陈鲁, 等. 人附睾分泌蛋白₄和CA125联合检测在子宫内膜恶性肿瘤与子宫良性肿瘤鉴别诊断中的价值. 中国癌症杂志, 2012, 22(11):820-824.
29.	Angioli R, Plotti F, Capriglione S, et al. The role of novel biomarker HE4 in endometrial cancer:a case control prospective study. Tumour Biol, 2013, 34(1):571-576.
30.	Antonsen SL, Høgdall E, Christensen IJ, et al. HE4 and CA125 levels in the preoperative assessment of endometrial cancer patients:a prospective multicenterstudy (ENDOMET). Acta Obstet Gynecol Scand, 2013, 92(11):1313-1322.
31.	Omer B, Genc S, Takmaz O, et al. The diagnostic role of human epididymis protein 4 and serum amyloid-A in early-stage endometrial cancer patients. Tumour Biol, 2013, 34(5):2645-2650.
32.	於王骐, 洪理泉, 刘战峰. 血清HE4检测在卵巢癌和子宫内膜癌诊断中的应用. 中国卫生检验杂志, 2013, 23(2):416-417, 419.
33.	林莺莺, 陈燕, 胡敏华, 等. HE4、CA125和CA19-9单项和联合检测在子宫内膜癌诊断中的价值. 临床检验杂志, 2014, 32 (6):471-473.
34.	林莺莺, 陈燕, 胡敏华, 等. 术前HE4单项及联合CA125检测在子宫内膜癌中的临床价值. 现代免疫学, 2014, 34 (1):47-51.
35.	潘姿女, 丁金旺, 王克义, 等. 血清人附睾蛋白4、CA125和CA19-9联合检测在子宫内膜癌诊断中的临床价值. 中国卫生检验杂志, 2014, 24 (11):1600-1603.
36.	Presl J, Novotny Z, Topolcan O, et al. CA125 and HE4 levels in a Czech female population diagnosed with endometrial cancer in preoperative management. Anticancer Res, 2014, 34(1):327-331.
37.	孙盛梅, 肖晓超, 张丹凤. CA125和HE4联合监测在子宫内膜癌诊断中的临床价值. 黑龙江医药科学, 2014, 37 (3):2-3.
38.	Moore RG, Bast RC Jr. How do you distinguish a malignant pelvic mass from a benign pelvic mass? Imaging, biomarkers, or none of the above. J Clin Oncol, 2007, 25(27):4159-4161.
39.	Nagy B Jr, Krasznai ZT, Balla H, et al. Elevated human epididymis protein 4 concentrations in chronic kidney disease. Ann Clin Biochem, 2012, 49(Pt 4):377-380.

1. World Health Organization. GLOBOCAN 2012:Estimated Cancer incidence, Mortality, and Prevalence Worldwide in 2012.[2015-05-17] Available at:http://globocan.iarc.fr/Default.aspx.
2. Ali AT. Reproductive factors and the risk of endometrial cancer. Int J Gynecol Cancer, 2014, 24(3):384-393.
3. Lajer H, Elnegaard S, Christensen RD, et al. Survival after stage IA endometrial cancer; can follow-up be altered? A prospective nationwide Danish survey. Acta Obstet Gynecol Scand, 2012, 91(8):976-982.
4. Aggarwal P, Kehoe S. Serum tumour markers in gynaecological cancers. Maturitas, 2010, 67(1):46-53.
5. Kirchhoff C, Habben I, Ivell R, et al. A major human epididymis-specific cDNA encodes a protein with sequence homology to extracellular proteinase inhibitors. Biol Reprod, 1991, 45(2):350-357.
6. Zhen S, Bian LH, Chang LL, et al. Comparison of serum human epididymis protein 4 and carbohydrate antigen 125 as markers in ovarian cancer:A meta-analysis. Mol Clin Oncol, 2014, 2(4):559-566.
7. Lin J, Qin J, Sangvatanakul V. Human epididymis protein 4 for differential diagnosis between benign gynecologic disease and ovarian cancer:a systematic review and meta-analysis. Eur J Obstet Gynecol Reprod Biol, 2013, 167(1):81-85.
8. 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(4):273-281.
9. Lin JY, Qin JB, Li XY, Dong P, et al. Diagnostic value of human epididymis protein 4 compared with mesothelin for ovarian cancer:a systematic review and meta-analysis. Asian Pac J Cancer Prev, 2012, 13(11):5427-5432.
10. Cheng D, Sun Y, He H. The diagnostic accuracy of HE4 in lung cancer:a meta-analysis. Dis Markers, 2015:352670.
11. Bie Y, Zhang Z. Diagnostic value of serum HE4 in endometrial cancer:a meta-analysis. World J Surg Oncol, 2014, 12(3):169.
12. 张晶, 王宇娟, 霍俊玲, 等. 人附睾蛋白4早期诊断子宫内膜癌价值的系统评价. 中国循证医学杂志, 2014, 14(1):72-78.
13. Whiting PF, Rutjes AW, Westwood ME, et al. QUADAS-2 Group. QUADAS-2:a revised tool for the quality assessment of diagnostic accuracy studies. Ann Intern Med, 2011, 155(8):529-536.
14. 张俊, 徐志伟, 李克. 诊断性试验Meta分析的效应指标评价. 中国循证医学杂志, 2013, 13(7):890-895.
15. Devillé WL, Buntinx F, Bouter LM, et al. Conducting systematic reviews of diagnostic studies:didactic guidelines. BMC Med Res Methodol, 2002, 2:9.
16. Zhen S, Bian LH, Chang LL, et al. Comparison of serum human epididymis protein 4 and carbohydrate antigen 125 as markers in ovarian cancer:A meta-analysis. Mol Clin Oncol, 2014, 2(4):559-566.
17. Pepe MS, Feng Z, Janes H, et al. Pivotal evaluation of the accuracy of a biomarker used for classification or prediction:standards for study design. J Natl Cancer Inst, 2008, 100(20):1432-1438.
18. Moore RG, Brown AK, Miller MC, 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.
19. Bignotti E, Ragnoli M, Zanotti L, et al. Diagnostic and prognostic impact of serum HE4 detection in endometrial carcinoma patients. Br J Cancer, 2011, 104(9):1418-1425.
20. 丛培珊, 孙桂荣, 张娜娜, 等. 人附睾蛋白4对子宫内膜癌和卵巢癌早期辅助诊断价值的评估. 检验医学, 2011, 26 (7):447-451.
21. 马荣, 耿晓星, 唐丽萍, 等. 人附睾分泌蛋白4检测对子宫内膜癌的诊断及预后的意义. 临床肿瘤学杂志, 2011, 16(9):790-793.
22. 吴飞, 周慧芹, 崔满华. 联合检测CA125与HE4在子宫内膜癌诊断中的价值. 中国妇幼保健, 2011, 26(10):1559-1561.
23. 杨圣晗, 李群(指导老师). HE4在子宫内膜癌患者血清中的表达及其与CA125联合检测的临床意义. 蚌埠:蚌埠医学院, 2011.
24. 简慧秋, 徐春琳(指导老师). 尿液人附睾蛋白4在卵巢癌、子宫内膜癌诊断和鉴别诊断中的意义. 石家庄:河北医科大学, 2012.
25. Zanotti L, Bignotti E, Calza S, et al. Human epididymis protein 4 as a serum marker for diagnosis of endometrial carcinoma and prediction of clinical outcome. Clin Chem Lab Med, 2012, 50(12):2189-2198.
26. 张爱敏, 张鹏. 血清人附睾分泌蛋白E₄和CA125联合检测对子宫内膜癌诊断的临床价值. 中华妇产科杂志, 2012, 47(2):125-128.
27. 张双革. 人附睾蛋白4对子宫内膜癌的风险评估研究. 国际妇产科学杂志, 2013, 40 (5):466-469.
28. 赵灵琴, 陈曦, 陈鲁, 等. 人附睾分泌蛋白₄和CA125联合检测在子宫内膜恶性肿瘤与子宫良性肿瘤鉴别诊断中的价值. 中国癌症杂志, 2012, 22(11):820-824.
29. Angioli R, Plotti F, Capriglione S, et al. The role of novel biomarker HE4 in endometrial cancer:a case control prospective study. Tumour Biol, 2013, 34(1):571-576.
30. Antonsen SL, Høgdall E, Christensen IJ, et al. HE4 and CA125 levels in the preoperative assessment of endometrial cancer patients:a prospective multicenterstudy (ENDOMET). Acta Obstet Gynecol Scand, 2013, 92(11):1313-1322.
31. Omer B, Genc S, Takmaz O, et al. The diagnostic role of human epididymis protein 4 and serum amyloid-A in early-stage endometrial cancer patients. Tumour Biol, 2013, 34(5):2645-2650.
32. 於王骐, 洪理泉, 刘战峰. 血清HE4检测在卵巢癌和子宫内膜癌诊断中的应用. 中国卫生检验杂志, 2013, 23(2):416-417, 419.
33. 林莺莺, 陈燕, 胡敏华, 等. HE4、CA125和CA19-9单项和联合检测在子宫内膜癌诊断中的价值. 临床检验杂志, 2014, 32 (6):471-473.
34. 林莺莺, 陈燕, 胡敏华, 等. 术前HE4单项及联合CA125检测在子宫内膜癌中的临床价值. 现代免疫学, 2014, 34 (1):47-51.
35. 潘姿女, 丁金旺, 王克义, 等. 血清人附睾蛋白4、CA125和CA19-9联合检测在子宫内膜癌诊断中的临床价值. 中国卫生检验杂志, 2014, 24 (11):1600-1603.
36. Presl J, Novotny Z, Topolcan O, et al. CA125 and HE4 levels in a Czech female population diagnosed with endometrial cancer in preoperative management. Anticancer Res, 2014, 34(1):327-331.
37. 孙盛梅, 肖晓超, 张丹凤. CA125和HE4联合监测在子宫内膜癌诊断中的临床价值. 黑龙江医药科学, 2014, 37 (3):2-3.
38. Moore RG, Bast RC Jr. How do you distinguish a malignant pelvic mass from a benign pelvic mass? Imaging, biomarkers, or none of the above. J Clin Oncol, 2007, 25(27):4159-4161.
39. Nagy B Jr, Krasznai ZT, Balla H, et al. Elevated human epididymis protein 4 concentrations in chronic kidney disease. Ann Clin Biochem, 2012, 49(Pt 4):377-380.

Chinese Journal of Evidence-Based Medicine

Comparison of Serum Human Epididymis Protein 4 and Carbohydrate Antigen 125 in Diagnosing Endometrial Cancer: A Systematic Review

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