The diagnostic accuracy of human epididymis protein 4 (HE4) for discriminating between benign and malignant pelvic masses: a systematic review and meta‐analysis

Abstract

Introduction: Many women with benign pelvic masses, suspected of ovarian cancer, are unnecessarily referred for treatment at specialized centers. There is an unmet clinical need to improve diagnostic assessment in these patients. Our objective was to obtain summary estimates of the accuracy of human epididymis protein (HE4) for diagnosing ovarian cancer and to compare the performance of HE4 with that of cancer antigen 125 (CA125). Material and methods:We searched PubMed, Ovid and Scopus using search terms for "pelvic masses" and "HE4", to identify studies that evaluated HE4 for diagnosing malignant ovarian masses, in adult women presenting with a pelvic mass, suspected of ovarian cancer, and with diagnosis confirmed by histopathology. Screening, data extraction and Risk of Bias assessment with the QUADAS-2 tool were done independently by two authors. We performed a meta-analysis of the accuracy of HE4 and CA125 using a random-effects bivariate logit-normal model. A study protocol was registered at PROSPERO (CRD42020158073).Results: In the 17 eligible studies, which included 3404 patients, ovarian cancer prevalence ranged from 15% to 71%. Overall, the studies were heterogeneous. All studies seemed to have recruited patients in specialized settings. A meta-analysis of seven HE4 studies resulted in a mean sensitivity of 79.4% (95% confidence interval [CI] 74.1%-83.8%) and a mean specificity of 84.1% (95% CI 79.6%-87.8%), for cut-off values of 67-72 pmol/L. Based on eight studies, the mean sensitivity of CA125 was 81.4% (95% CI 74.6%-86.2%) and the mean specificity was 56.8% (95% CI 47.9%-65.4%), at a cut-off of 35 U/ml. Given a 40% ovarian cancer prevalence, the positive predictive value (PPV) for HE4 would be 76.9% (71.9%-81.2%) vs 55.6% (50.2%-60.9%) for CA125. The negative predictive value (NPV) would be 85.9 (82.8%-88.6%) and 81.9% (76.2%-86.4%), respectively. At a 15% prevalence, the NPV would be 95.8%The search string consisted of a variety of search terms for "pelvic cysts or tumors" and "human epididymis protein 4" (Appendix S1).The search was performed in MEDLINE (PubMed), Embase (Ovid) (95% CI 94.4%-96.7%) for HE4 and 94.4% (95% CI 92.3%-96.0%) for CA125. The PPV would be 46.9% (40.4%-53.4%) and 24.9% (21.1%-29.2%), respectively.Conclusions: HE4 had higher specificity and similar sensitivity compared with CA125.At high prevalence, PPV was also higher for HE4, but at low prevalence, it had a similar NPV to CA125. The field would benefit from studies conducted in general settings.

The Role of Human Epididymis Protein 4 in the Diagnosis and Prognosis of Diseases: An Umbrella Review of Systematic Reviews and Meta-Analyses of Observational Studies

“…Previous epidemiological studies have investigated the diagnostic role of HE4 in some diseases, such as OC ( 13 , 14 ), lung cancer (LC) ( 15 ), renal fibrosis ( 16 ), breast cancer ( 17 ), and endometrial carcinoma (EC) ( 18 ). For example, the results of a meta-analysis showed that HE4 had higher specificity (0.84 vs. 0.57) and similar sensitivity (0.79 vs. 0.81) than CA125 for differentiating malignant from benign pelvic mass disease ( 19 ), similar findings could be observed in those meta-analyses ( 7 , 20 , 21 ). However, a meta-analysis demonstrated that HE4 was no better than CA125 for OC prediction ( 22 ).…”

“…Subsequently, a further 34 articles were excluded for the following reasons: 13 presented insufficient data, 6 did not conduct meta-analysis, 4 explored outcomes that we were not interested in, 4 published not in English, the full text of 3 articles were not available, 2 published duplicated reports, 1 explored exposure that we were not interested in, and 1 conducted less than three original studies. Ultimately, 20 studies ( 7 , 8 , 15 , 19 – 22 , 42 – 54 ) were eligible to be included in the main analysis.…”

“…As reported in Table 1 , 250 primary studies of 17 meta-analyses were included in the 16 articles for diagnosis ( 7 , 15 , 19 – 22 , 42 , 43 , 45 – 50 , 52 , 53 ). These sixteen articles were published between 2012 and 2021.…”

New Analytical Approach for the Alignment of Different HE4 Automated Immunometric Systems: An Italian Multicentric Study

“…Ca125, a mucin, is considered by the FDA to be the gold standard for the management of the OC, although it showed low sensitivity in the early stages of the disease. Increasing levels of this biomarker have been also found in other physiological or pathological conditions, such as menstruation, pregnancy, endometriosis and inflammatory diseases of the peritoneum [ 23 ].…”

Biomarker-Based Models for Preoperative Assessment of Adnexal Mass: A Multicenter Validation Study

“…Circulating CA125 levels increase with tumor burden, but—conversely—they do not exceed the usual cutoff of 35 U/mL at 50% of early OC [ 15 ]. The sensitivity of CA125 has been reported at 0.78–0.86, the specificity at 0.57–0.82, the positive predictive value (PPV) at 0.50–0.68 and the negative predictive value (NPV) at 0.9–0.95 [ 11 , 12 , 16 , 17 , 18 , 19 ]. Amongst a further 200 investigated biomarkers, the cancer antigens CA 72.4, CA 15.3, CA 19.9 and HE4 have been considered the most informative for the evaluation of adnexal mass [ 4 , 13 , 20 ].…”