J Clin Pathol 66:273-281 doi:10.1136/jclinpath-2012-201031
  • Review

Serum human epididymis protein 4 vs carbohydrate antigen 125 for ovarian cancer diagnosis: a systematic review

Editor's Choice
  1. Mauro Panteghini1
  1. 1Laboratorio Analisi Chimico-Cliniche, Azienda Ospedaliera ‘Luigi Sacco’, and Cattedra di Biochimica Clinica e Biologia Molecolare Clinica, Università degli Studi, Milano, Italy
  2. 2Sezione di Statistica Medica e Biometria, Università degli Studi, Milano, Italy
  3. 3Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy
  1. Correspondence to Dr Simona Ferraro, Laboratorio Analisi Chimico-Cliniche, Ospedale ‘Luigi Sacco’, Via G.B. Grassi 74, Milano 20157, Italy; ferraro.simona{at}
  • Received 27 June 2012
  • Revised 7 December 2012
  • Accepted 13 December 2012
  • Published Online First 20 February 2013


Background Human epididymis protein 4 (HE4) measurements in serum have been proposed for improving the specificity of laboratory identification of ovarian cancer (OC).

Objective To critically revise the available literature on the comparison between the diagnostic accuracy of HE4 and carbohydrate antigen 125 (CA-125) to confirm the additional clinical value of HE4.

Methods A literature search was undertaken on electronic databases and references from retrieved articles; articles were analysed according to predefined criteria. Meta-analyses for HE4 and CA-125 biomarkers with OR, diagnostic sensitivity, specificity, positive (LR+) and negative (LR–) likelihood ratios as effect sizes were performed.

Results 16 articles were originally included in meta-analyses, but two for HE4 and one for CA-125 were eliminated as outliers. Furthermore, for HE4 a publication bias was detected. ORs for both HE4 (37.2, 95% CI 19.0 to 72.7, adjusted for publication bias) and CA-125 (15.4, 95% CI 10.4 to 22.8) were significant, although in a heterogeneous set of studies (p<0.0001). By combining sensitivity and specificity, the overall LR+ and LR– were 13.0 (95% CI 8.2 to 20.7) and 0.23 (95% CI 0.19 to 0.28) for HE4 and 4.2 (95% CI 3.1 to 5.6) and 0.27 (95% CI 0.23 to 0.31) for CA-125, respectively.

Conclusions HE4 measurement seems to be superior to CA-125 in terms of diagnostic performance for identification of OC in women with suspected gynaecological disease. Due to the high prevalence of OC in post-menopausal women and the need for data focused on early tumour stages, more studies tailored on these specific subsets are needed.