Role of Human Epididymis Protein 4 for Detection of Ovarian Carcinoma in Adnexal Masses

Abstract Objectives To document the maternal and fetal cord blood levels of human epididymis protein 4 (HE-4) in term and preterm newborns in order to investigate the possible physiological role of HE-4 in fetal lung development. Methods This cross-sectional study was conducted in a university-affiliated hospital between April 2018 and September 2018. The study population consisted of cesarean section (C-section) deliveries after 24 weeks of pregnancy. Both maternal and umbilical cord HE-4 levels (mHE-4 and uHE-4, respectively) were measured using chemiluminescent microparticle immunoassay. Amniotic fluid was sampled from each case to determine the lamellar body count (LBC) as the gold standard test for lung maturation. All the parameters, including the uHE-4 levels, were compared between the term delivery (≥37 weeks) (n=52) and preterm delivery (24–37th weeks) (n=30) groups. The best cut-off value of uHE-4 was calculated for fetal lung maturity. Results There were no statistically significant differences between the groups regarding the demographic data. The mHE-4 levels did not statistically significantly differ between the groups (p>0.05) whereas the uHE-4 level of the preterm newborns was significantly higher than that of the term newborns (p<0.05). There was a significant negative association between the uHE-4 level and LBC (r=−0.389; p<0.001). The uHE-4 level was the only statistically significant fetal parameter indicating fetal lung maturity confirmed by LBC. At a cut-off value of 281 pmol/L, uHE-4 had 96.8% sensitivity, 45% specificity, 84.5% positive predictive value, and 81.8% negative predictive value for fetal lung maturity. Conclusions Although the exact physiological role of HE-4 has not yet been elucidated, this preliminary study supports the idea that HE-4 plays a role in fetal lung maturation to some extent.

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1315 Clinical role of human epididymis protein 4 (HE4) in epithelial ovarian cancer

European Journal of Cancer Supplements ◽

10.1016/s1359-6349(09)70488-4 ◽

2009 ◽

Vol 7 (2) ◽

pp. 143

Author(s):

E. Bandiera ◽

M. Ragnoli ◽

L. Zanotti ◽

E. Bignotti ◽

C. Romani ◽

...

Keyword(s):

Ovarian Cancer ◽

Epithelial Ovarian Cancer ◽

Clinical Role ◽

Human Epididymis Protein 4 ◽

Human Epididymis

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The role of human epididymis protein 4 as a biomarker in gynecologic malignancies

Minerva Ginecologica ◽

10.23736/s0026-4784.18.04328-9 ◽

2019 ◽

Vol 71 (1) ◽

Cited By ~ 3

Author(s):

Francesco Plotti ◽

Giuseppe Scaletta ◽

Corrado Terranova ◽

Roberto Montera ◽

Carlo De Cicco Nardone ◽

...

Keyword(s):

Gynecologic Malignancies ◽

Human Epididymis Protein 4 ◽

Human Epididymis

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The diagnostic accuracy of two human epididymis protein 4 (HE4) testing systems in combination with CA125 in the differential diagnosis of ovarian masses

Clinical Chemistry and Laboratory Medicine (CCLM) ◽

10.1515/cclm.2011.709 ◽

2011 ◽

Vol 49 (12) ◽

Cited By ~ 31

Author(s):

Miriam Lenhard ◽

Petra Stieber ◽

Linda Hertlein ◽

Angela Kirschenhofer ◽

Sophie Fürst ◽

...

Keyword(s):

Differential Diagnosis ◽

Diagnostic Accuracy ◽

Area Under The Curve ◽

Stage I ◽

Cancer Antigen 125 ◽

Human Epididymis Protein 4 ◽

Adnexal Masses ◽

Human Epididymis ◽

Single Marker ◽

Ovarian Masses

AbstractCancer antigen 125 (CA125) is the best known single tumor marker for ovarian cancer (OC). We investigated whether the additional information of the human epididymis protein 4 (HE4) improves diagnostic accuracy.We retrospectively analyzed preoperative sera of 109 healthy women, 285 patients with benign ovarian masses (cystadenoma: n=78, leimyoma: n=66, endometriosis: n=52, functional ovarian cysts: n=79, other: n=10), 16 low malignant potential (LMP) ovarian tumors and 125 OC (stage I: 22, II: 15, III: 78, IV: 10). CA125 was analyzed using the ARCHITECT system, HE4 using the ARCHITECT(a) system and EIA(e) technology additionally.The lowest concentrations of CA125 and HE4 were observed in healthy individuals, followed by patients with benign adnexal masses and patients with LMP tumors and OC. The area under the curve (AUC) for the differential diagnosis of adnexal masses of CA125 alone was not significantly different to HE4 alone in premenopausal (CA125: 86.7, HE4(a): 82.6, HE4(e): 81.6% p>0.05) but significantly different in postmenopausal [CA125: 93.4 vs. HE4(a): 88.3 p=0.023 and vs. HE4(e): 87.8% p=0.012] patients. For stage I OC, HE4 as a single marker was superior to CA125, which was the best single marker in stage II-IV. The combination of CA125 and HE4 using risk of malignancy algorithm (ROMA) gained the highest sensitivity at 95% specificity for the differential diagnosis of adnexal masses [CA125: 70.9, HE4(a): 67.4, HE4(e): 66.0, ROMA(a): 76.6 and ROMA(e): 74.5%], especially in stage I OC [CA125: 27.3, HE4(a): 40.9, HE4(e): 40.9, ROMA(a): 45.5 and ROMA(e): 45.5%].CA125 is still the best single marker in the diagnosis of OC. HE4 alone and even more the combined analysis of CA125 and HE4 using ROMA improve the diagnostic accuracy of adnexal masses, especially in early OC.

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Human epididymis protein 4 offers superior specificity in the differentiation of benign and malignant adnexal masses in premenopausal women

American Journal of Obstetrics and Gynecology ◽

10.1016/j.ajog.2011.05.017 ◽

2011 ◽

Vol 205 (4) ◽

pp. 358.e1-358.e6 ◽

Cited By ~ 54

Author(s):

Kevin Holcomb ◽

Zivjena Vucetic ◽

M. Craig Miller ◽

Robert C. Knapp

Keyword(s):

Premenopausal Women ◽

Human Epididymis Protein 4 ◽

Adnexal Masses ◽

Human Epididymis

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Role of Human Epididymis Protein 4 (HE4) in Determining Survival of Patients With Endometrial Cancer: A Meta-Analysis

Technology in Cancer Research & Treatment ◽

10.1177/1533033820971660 ◽

2020 ◽

Vol 19 ◽

pp. 153303382097166

Author(s):

Ying He ◽

Jing Wang ◽

Chun-Xing Ma ◽

Yan-Hua Kang

Keyword(s):

Endometrial Cancer ◽

Cancer Patients ◽

Science Studies ◽

Meta Analysis ◽

High Serum ◽

Baseline Serum ◽

Human Epididymis Protein 4 ◽

Human Epididymis ◽

Low Serum

Background: Human epididymis protein 4 (HE4) is a novel cancer biomarker. This study evaluates the prognostic role of HE4 in determining the survival of endometrial cancer patients. Methods: Literature search was conducted in electronic databases (Embase, Ovid, PubMed, Scopus, and Web of Science). Studies were selected if they reported the relationship between HE4 and the survival of endometrial cancer patients. Random-effects meta-analyses were performed to achieve estimates of baseline serum HE4 levels, the 5-year survival with high and low serum HE4 levels/expression, and the hazard ratios (HRs) of the survival between patients with high and low serum HE4 levels. Results: 9 studies (1404 patients; age 63.1 years [95% confidence interval (CI): 61.2, 64.9]; follow-up 35.9 months [95% CI: 32.2, 39.6]) were included. In these patients, serum HE4 levels were 83.36 picomole/liter (pM) [95% CI: 70.15, 96.56] overall but these were higher in patients with recurrence (108.13 pM [95% CI: 63.09, 153.18] and lower in patients with no recurrence (67.88 pM [95% CI: 65.09, 70.67]). The 5-year overall survival rate was higher in patients with low HE4 levels/expression (86% [95% CI: 79, 92] but lower in patients with high HE4 levels/expression (63% [95% CI: 58, 68]. A pooled HR of survival between patients with high and low serum HE4 levels of 2.25 [95% CI: 1.56, 2.94] indicated shorter survival in patients with high serum HE4 levels. Conclusion: High HE4 concentrations in patients with endometrial cancer are found to be associated with shorter survival.

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Diagnostic Value of Serum Human Epididymis Protein 4 (HE4) in Ovarian Carcinoma: A Systematic Review and Meta-Analysis

International Journal of Gynecological Cancer ◽

10.1097/igc.0b013e318263efa2 ◽

2012 ◽

Vol 22 (7) ◽

pp. 1106-1112 ◽

Cited By ~ 48

Author(s):

Li Wu ◽

Zhi-Yuan Dai ◽

Yong-Hong Qian ◽

Yan Shi ◽

Feng-Ju Liu ◽

...

Keyword(s):

Systematic Review ◽

Ovarian Cancer ◽

Ovarian Carcinoma ◽

Sensitivity And Specificity ◽

Meta Analysis ◽

Diagnostic Value ◽

Control Group ◽

Human Epididymis Protein 4 ◽

Human Epididymis ◽

Pelvic Masses

ObjectiveHuman epididymis protein 4 (HE4), a precursor of human epididymis protein, has been recently identified as a new promising serum biomarker for ovarian carcinoma. We performed a systematic review of studies that investigated the use of HE4 in the diagnosis of ovarian cancer in patients with pelvic or gynecological masses. We also evaluated the diagnostic performance of HE4 for differentiating between patients with benign gynecological disease and those with ovarian cancer.MethodsWe searched PubMed database (1990–2011) to collect articles in English that evaluated the diagnostic value of HE4 in patients with gynecological or pelvic masses. Two reviewers independently assessed the methodological quality of each study using the quality assessment of diagnostic accuracy studies tool. The data were analyzed using Meta-Disc1.4 software. Meta-analysis of the reported sensitivity and specificity of each study and summary receiver operating characteristic (SROC) curve were performed.ResultsA total of 9 studies involving 1807 women were included. When the control group was composed of healthy women, the pooled sensitivity and specificity for HE4 in diagnosing ovarian cancer were 83% (95% confidence interval [CI], 77%–88%) and 90% (95% CI, 87%–92%), respectively. The area under the SROC curve was 0.9271. When the control group was composed of women with benign disease, the pooled sensitivity and specificity for HE4 were 74% (95% CI, 69%–78%) and 90% (95% CI, 87%–92%). The area under the SROC curve was 0.8853.ConclusionThe current analysis indicated that HE4 may be a valuable marker in the diagnosis of ovarian carcinoma. Serum HE4 detection is not only a useful preoperative test for predicting the benign or malignant nature of pelvic masses but has a potential to be used as an initial step in ovarian cancer screening strategy.

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Role of human epididymis protein 4 (HE4) in detecting recurrence in CA125 negative ovarian cancer patients

International Journal of Gynecological Cancer ◽

10.1136/ijgc-2019-000211 ◽

2019 ◽

Vol 29 (4) ◽

pp. 768-771 ◽

Cited By ~ 5

Author(s):

Francesco Plotti ◽

Federica Guzzo ◽

Teresa Schirò ◽

Corrado Terranova ◽

Carlo De Cicco Nardone ◽

...

Keyword(s):

Ovarian Cancer ◽

Gynecologic Oncology ◽

Residual Tumor ◽

Recurrent Ovarian Cancer ◽

Initial Diagnosis ◽

Histologic Subtype ◽

Human Epididymis Protein 4 ◽

Human Epididymis ◽

Gynecology And Obstetrics

ObjectiveThere are no current guidelines regarding evaluation of patients with normal CA125 at initial diagnosis during routine surveillance after completion of treatment. Thus, the purpose of this study was to evaluate the role of human epididymis protein 4 (HE4) in the detection of recurrence in patients with ovarian cancer and a negative CA125 at diagnosis.MethodsAll patients with ovarian cancer with a negative CA125 referred to the Division of Gynecologic Oncology of the University Campus Bio-Medico of Rome were included in the study. Inclusion criteria were: age between 18 and 70 years old, diagnosis of epithelial ovarian cancer, optimal primary surgery (residual tumor <1 cm), and normal CA125 at initial diagnosis. Patients with other malignancies or chronic diseases were excluded from the study. Statistical analysis was based on the calculation of percentages, means, medians, and ranges of the values.ResultsA total of eight patients were included in the study. The median age was 53 years (range 40–75). All patients had a normal CA125 at initial diagnosis while seven (87.5%) patients had abnormal HE4 levels at diagnosis. The International Federation of Gynecology and Obstetrics (FIGO) stages at enrollment varied from IC to IIIC (IB (1), IC (3), IIC (1), IIIC (3)). The most common histologic subtype was serous (62.5%). Seven patients recurred and had abnormal HE4 and normal CA125 values. The median HE4 at recurrence was 107 pmol/L. The median disease-free interval was 55 months (range 5–108) and all the patients underwent optimal cytoreductive surgery.ConclusionsHE4 levels may serve as a marker for recurrence in patients with a normal CA125 at initial diagnosis. Future studies are needed to evaluate the role of HE4 levels in earlier detection of recurrent ovarian cancer.

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