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.	張晶, 王宇娟, 霍俊玲, 等. 人附睪蛋白4早期診斷子宮內膜癌價值的系統評價. 中國循證醫學雜志, 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.	張俊, 徐志偉, 李克. 診斷性試驗Meta分析的效應指標評價. 中國循證醫學雜志, 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.	叢培珊, 孫桂榮, 張娜娜, 等. 人附睪蛋白4對子宮內膜癌和卵巢癌早期輔助診斷價值的評估. 檢驗醫學, 2011, 26 (7):447-451.
21.	馬榮, 耿曉星, 唐麗萍, 等. 人附睪分泌蛋白4檢測對子宮內膜癌的診斷及預后的意義. 臨床腫瘤學雜志, 2011, 16(9):790-793.
22.	吳飛, 周慧芹, 崔滿華. 聯合檢測CA125與HE4在子宮內膜癌診斷中的價值. 中國婦幼保健, 2011, 26(10):1559-1561.
23.	楊圣晗, 李群(指導老師). HE4在子宮內膜癌患者血清中的表達及其與CA125聯合檢測的臨床意義. 蚌埠:蚌埠醫學院, 2011.
24.	簡慧秋, 徐春琳(指導老師). 尿液人附睪蛋白4在卵巢癌、子宮內膜癌診斷和鑒別診斷中的意義. 石家莊:河北醫科大學, 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.	張愛敏, 張鵬. 血清人附睪分泌蛋白E₄和CA125聯合檢測對子宮內膜癌診斷的臨床價值. 中華婦產科雜志, 2012, 47(2):125-128.
27.	張雙革. 人附睪蛋白4對子宮內膜癌的風險評估研究. 國際婦產科學雜志, 2013, 40 (5):466-469.
28.	趙靈琴, 陳曦, 陳魯, 等. 人附睪分泌蛋白₄和CA125聯合檢測在子宮內膜惡性腫瘤與子宮良性腫瘤鑒別診斷中的價值. 中國癌癥雜志, 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, H?gdall 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.	於王騏, 洪理泉, 劉戰峰. 血清HE4檢測在卵巢癌和子宮內膜癌診斷中的應用. 中國衛生檢驗雜志, 2013, 23(2):416-417, 419.
33.	林鶯鶯, 陳燕, 胡敏華, 等. HE4、CA125和CA19-9單項和聯合檢測在子宮內膜癌診斷中的價值. 臨床檢驗雜志, 2014, 32 (6):471-473.
34.	林鶯鶯, 陳燕, 胡敏華, 等. 術前HE4單項及聯合CA125檢測在子宮內膜癌中的臨床價值. 現代免疫學, 2014, 34 (1):47-51.
35.	潘姿女, 丁金旺, 王克義, 等. 血清人附睪蛋白4、CA125和CA19-9聯合檢測在子宮內膜癌診斷中的臨床價值. 中國衛生檢驗雜志, 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.	孫盛梅, 肖曉超, 張丹鳳. CA125和HE4聯合監測在子宮內膜癌診斷中的臨床價值. 黑龍江醫藥科學, 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. 張晶, 王宇娟, 霍俊玲, 等. 人附睪蛋白4早期診斷子宮內膜癌價值的系統評價. 中國循證醫學雜志, 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. 張俊, 徐志偉, 李克. 診斷性試驗Meta分析的效應指標評價. 中國循證醫學雜志, 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. 叢培珊, 孫桂榮, 張娜娜, 等. 人附睪蛋白4對子宮內膜癌和卵巢癌早期輔助診斷價值的評估. 檢驗醫學, 2011, 26 (7):447-451.
21. 馬榮, 耿曉星, 唐麗萍, 等. 人附睪分泌蛋白4檢測對子宮內膜癌的診斷及預后的意義. 臨床腫瘤學雜志, 2011, 16(9):790-793.
22. 吳飛, 周慧芹, 崔滿華. 聯合檢測CA125與HE4在子宮內膜癌診斷中的價值. 中國婦幼保健, 2011, 26(10):1559-1561.
23. 楊圣晗, 李群(指導老師). HE4在子宮內膜癌患者血清中的表達及其與CA125聯合檢測的臨床意義. 蚌埠:蚌埠醫學院, 2011.
24. 簡慧秋, 徐春琳(指導老師). 尿液人附睪蛋白4在卵巢癌、子宮內膜癌診斷和鑒別診斷中的意義. 石家莊:河北醫科大學, 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. 張愛敏, 張鵬. 血清人附睪分泌蛋白E₄和CA125聯合檢測對子宮內膜癌診斷的臨床價值. 中華婦產科雜志, 2012, 47(2):125-128.
27. 張雙革. 人附睪蛋白4對子宮內膜癌的風險評估研究. 國際婦產科學雜志, 2013, 40 (5):466-469.
28. 趙靈琴, 陳曦, 陳魯, 等. 人附睪分泌蛋白₄和CA125聯合檢測在子宮內膜惡性腫瘤與子宮良性腫瘤鑒別診斷中的價值. 中國癌癥雜志, 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, H?gdall 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. 於王騏, 洪理泉, 劉戰峰. 血清HE4檢測在卵巢癌和子宮內膜癌診斷中的應用. 中國衛生檢驗雜志, 2013, 23(2):416-417, 419.
33. 林鶯鶯, 陳燕, 胡敏華, 等. HE4、CA125和CA19-9單項和聯合檢測在子宮內膜癌診斷中的價值. 臨床檢驗雜志, 2014, 32 (6):471-473.
34. 林鶯鶯, 陳燕, 胡敏華, 等. 術前HE4單項及聯合CA125檢測在子宮內膜癌中的臨床價值. 現代免疫學, 2014, 34 (1):47-51.
35. 潘姿女, 丁金旺, 王克義, 等. 血清人附睪蛋白4、CA125和CA19-9聯合檢測在子宮內膜癌診斷中的臨床價值. 中國衛生檢驗雜志, 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. 孫盛梅, 肖曉超, 張丹鳳. CA125和HE4聯合監測在子宮內膜癌診斷中的臨床價值. 黑龍江醫藥科學, 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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