Is human epididymis protein 4 an effective tool for the differential diagnosis of benign and malignant endometrial tumours?

Purpose of investigation: This study was designed to evaluate the use of human epididymis protein 4 (HE4) as a biomarker in the differential diagnosis of malignant and benign endometrial tumours. Materials and Methods: The study, conducted between July 2009 and June 2014, included a total of 150 patients with endometrioid adenocarcinoma and a control group of 150 patients with benign endometrial lesions. The serum of all patients was analyzed with respect to HE4 and CA125 levels. The median and ranges of serum levels were determined in relation to histological results. The statistical analysis procedure employed in this study utilized logarithmic-transformed values of biomarkers and logistic regression. Results: An analysis of two groups of patients with different histologies yielded a statistically significant difference (p-value < 0.05) only in the case of HE4, in which case a cut-off value of 48.5 pmol/l resulted in an achieved sensitivity of 87.8%, a specificity of 56.6%, and a negative predictive value of 81.1%. Conclusion: In combination with clinical and ultrasound findings, HE4 could help with the differentiation of prognostically varied patient groups as well as with the decision-making process associated with the development of individual treatment plans. However, the optimal cut-off for HE4 has not been established yet and further studies are needed.

Benign endometrial tumours; Endometrial cancer; Human epididymis protein 4.

[1] Ferlay J., Shin H.R., Bray F., Norman D., Mathers C., Parkin D.M.: “Globocan 2012 v1.1, cancer incidence and mortality worldwide: IARC cancerbase no. 10”. Lyon: International Agency for Research on Cancer, 2012. Available at: http://globocan-iarc.fr.

[2] DiSaia P.J., Creasman W.T.: (eds). Clinical gynaecologic oncology. 7thed. Philadelphia: Mosby, 2007, 812.

[3] Dundr P.: “Histhological classification of endometrial cancer”. In: Cibula D., Petruzelka L. (eds). Oncogynecology. Prague: Grada Publishing, 2009, 459.

[4] Bouchard D., Morriset D., Bourbonnais Y., Tremblay G.M.: “Proteins with whey-acidic-protein motifs and cancer”. Lancet Oncol., 2006, 7, 167.

[5] Bingle L., Singleton V., Bingle C.D.: “The putative ovarian tumor marker gene HE4 (WFCD2), is expressed in normal tissues and undergoes complex alternative splicing to yield multiple protein isoforms”. Oncogene, 2002, 21, 2768.

[6] Kirchhoff C., Habben I., Ivell R., Krull N.: “A major human epididymis- specific cDNA encodes a protein with sequence homology to extracellular proteinase inhibitors”. Biol. Reprod., 1991, 45, 350.

[7] Kirchhoff C.: “Molecular characterisation of epididymal proteins”. Rev. Reprod., 1998, 3, 86.

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

[9] Drapkin R., von Horsten H.H., Lin Y., Mok S.C., Crum Ch.P., Welch W.R., et al.: “Human epididymis protein 4 (HE4) is a secreted glycoprotein that is overexpressed by serous and endometrioid ovarian carcinomas”. Cancer Res., 2005, 65, 2162.

[10] Hellström I., Raycraft J., Hayden-Ledbetter M., Ledbetter J.A., Schummer M., McIntosh M., et al.: “The HE4 (WFCD2) protein is a biomarker for ovarian carcinoma”. Cancer Res., 2003, 63, 3695.

[11] Chung H.H., Kim J.W., Park N.H., Song Y.S., Kang S.O., Lee H.P.,et al.: “Use of preoperative serum CA125 levels for pred iction of lymph node metastasis and prognosis in endometrial cancer”. Acta Obstet. Gynecol. Scand., 2006, 85, 1501.

[12] Ebina Y., Sakuragi N., Hareyama H., Todo Y., Nomura E., TakedaM., et al.: “Para- aortic lymph node metastasis in relation to serum CA125 levels and nuclear grade in endometrial carcinoma”. Acta Obstet. Gynecol. Scand., 2002, 81, 458.

[13] Cherchi P.L., Dessole S., Ruiu G.A., Ambrosini G., Farina M., Capobianco G., et al.: “The value of serum CA124 and association CA125/CA19-9 in endometrial carcinoma”. Eur. J. Gynecol. Oncol., 1999, 20, 315.

[14] Farias-Eisner G., Su F., Robbins T., Kotlerman J., Reddy S., Farias-Eisner R.: “Validation of serum biomarkers for detection of earlyand late-stage endometrial cancer”. Am. J. Obstet. Gynecol., 2010, 202, 73.e1.

[15] Yurkovetsky Z., Ta’asan S., Skates S., Rand A., Lomakin A., Linkov F., et al.: “Development of multimarker panel for early d etection of endometrial cancer. High prognostic power of prolactin”. Gynecol. Oncol., 2007, 107, 58.

[16] Omer B., Genc S., Takmaz O., Dirican A., Kusku- Kiraz Z., BerkmanS., et al.: “The diagnostic role of human epididymis protein 4 and serum amyloid-A in early-stage endometrial cancer patients”. Tumour Biol., 2013, 34, 2645.

[17] Moore R.G., Brown A.K., Miller M.C., Badgwell D., Lu Z., Allard W.J., et al.: “Utility of a novel serum tumor biomarker HE4 in patients with endometrioid adenocarcinoma of the uterus”. Gynecol. Oncol., 2008, 110, 196.

[18] Moore R.G., Miller M.C., Disilvestro P., Landrum R.M., Gajewski W., Ball J.J., et al.: “Evaluation of the diagnostic accuracy of the risk of ovarian malignancy algorithm in women with a pelvic mass”. Obstet. Gynecol., 2011, 118, 280.

[19] Angioli R., Plotti F., Capriglione S., Montera R., Damiani P., Ricciardi R., et al.: “The role of novel biomarker HE4 in endometrial cancer: a case control prospective study”. Tumour Biol., 2013, 34, 571.

[20] Zanotti L., Bignotti E., Calza S., Bandiera E., Ruggeri G., Galli C., 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, 2189.