Value of HE4 combined with cancer Antigen 125 in the diagnosis of Endometrial Cancer.
Objective: To investigate the clinical significance of human epididymal secretory protein E4 (HE4) in combination with cancer antigen 125 (CA125) in the diagnosis of endometrial cancer.
Methods: One hundred and fifty patients with endometrial cancer who were admitted to Binzhou People's Hospital, Shandong, China, between June 2013 and July 2014, were enrolled and set as an endometrial cancer group; another one hundred patients with benign uterine diseases and one hundred healthy females were also enrolled. The serum was collected from the subjects for the detection of HE4 level. The level of CA125 was detected using electrochemiluminescence assay (ELISA). Receiver Operating Characteristic (ROC) curve was drawn to analyze the cutoff points of HE4 and CA125 levels for the diagnosis of endometrial cancer. The diagnostic efficacy based on the detection of the two indexes separately and jointly was evaluated.
Results: The area under curve (AUC) for diagnosis of endometrial cancer based on HE4 was superior to that based on CA125 (0.819 vs 0.757). The optimal diagnosis cutoff point of HE4 and CA125 on the ROC curves was 92.21 pmol/L and 31.32KU/L, respectively. The sensitivity, Youden index, coincidence rate and negative predicted value of diagnosing endometrial cancer with HE4 in combination with CA125 (73.2%, 0.641, 83.5% and 83.4%) were significantly higher than those of diagnosing endometrial cancer with the two indexes separately. The ROC-AUC value of serum HE4 and CA125 was 0.749 and 0.528 respectively, much lower than that of HE4 in combination with CA125 (0.794; P0.05). The enrolled patients signed informed consent, and this study has been approved by the ethics committee.
Inclusion and exclusion criteria: Patients who were confirmed by histopathology, did not undergo uterus surgery three months before admission, and did not receive any systemic treatment were included. Those who had primary or malignant tumors in other organs or had severe liver and kidney function deficiency or females at lactation period were excluded.
Blood specimens were collected from the patients in the endometrial cancer group and the benign uterine diseases group prior to treatment. 5 ml of fasting blood was extracted from each subject in the morning. Serum was separated from the blood specimens for the detection of HE4 and CA125.
The level of serum CA125 was detected with a USA NAXSY biochemical analyzer and the matched reagents using electrochemiluminescence assay. The level of serum HE4 was detected with a kit (Wuhan Boster Biological Engineering Co., Ltd., Hubei, China) and CODA microplate reader (BIO-RAD, US) using enzyme-linked immune-sorbent assay (ELISA).
Pathological diagnosis was regarded as the gold standard. The malignant group was determined as true positive. Receiver Operating Characteristic (ROC) curves were drawn to analyze the cutoff points of HE4 and CA125 levels for the diagnosis of endometrial cancer. Moreover, the diagnostic efficacy based on the detection of two indexes separately and jointly was evaluated.
The reference scope of the serum HE4 and CA125 was less than 86 pmol/L and less than 35 U/mL, respectively. The level higher than the critical value was defined as positive. Duplicable test was performed in the detection of HE4 in combination with CA125. The result of the combination detection was determined as positive if the level of any of them was positive.
Data was analyzed using SPSS 20.0. Enumeration data (percentage) were compared between groups using Chi-square test. Difference was considered as statistically significant if P<0.05.
Analysis of ROC curves of diagnosis of endometrial cancer based on HE4 and CA125: The subjects in the benign uterine diseases group and healthy control group were determined as negative, while the patients in the malignant group were determined as positive. ROC curves were drawn for the diagnostic sensitivity and specificity of endometrial cancer based on different cutoff points of HE4 and CA125 (Fig.1).
Comparison of the parameters of curves for diagnosis based on HE4 and CA125: AUC of diagnosis based on HE4 was superior to that based on CA125 (0.819 vs 0.757). The cutoff points corresponding to the largest Youden index of the ROC curves, i.e., 0.518 for HE4 and 0.455 for CA125, were determined as optimal (Table-I).
Table-I: Comparison of parameters of HE4 and CA125 ROC curves.
###Item###AUC###Standard deviation###P###95% confidence interval###Optimal cutoff points
Comparison of negative and positive conditions of HE4 and CA125 under the optimal cutoff points: When the optimal cutoff points confirmed before were applied, there were differences in the number of negative and positive cases of HE4 and CA125 between the three groups (P<0.05). In the comparison of the endometrial cancer group with the benign uterine diseases group and the healthy control group, the difference was statistically significant (P0.05) (Table-II).
Table-II: Comparison of the negative and positive conditions of CA125 and HE4 under the optimal cutoff points.
###Endometrial cancer group###150###73###77###65###85
###Benign uterine diseases group###100###94*###6*###93*###7*
###Healthy control group###100###92*####8*####97*####3*#
Methodological evaluation on the application of HE4, CA125 and HE4 in combination with CA125 in diagnosing endometrial cancer: The results demonstrated that, the sensitivity, Youden index and coincidence rate of diagnosing endometrial cancer with HE4 were superior to those with CA125. The sensitivity, Youden index, coincidence rate and negative predicted value of diagnosing endometrial cancer with HE4 in combination with CA125 were higher (Table-III).
Table-III: Comparison of performance of serum HE4 and CA125 in the diagnosis of endometrial cancer.
Item###Sensitivity (%)###Specificity (%)###Youden index###Coincidence rate (%)###NPV (%)###PPV (%)
Endometrial cancer refers to epitheliogenic malignant tumor initially occurring in endometrium, and adenocarcinoma derived from endometrial glands is the most common. Currently the pathogenesis and pathogenesis of endometrial cancer have not been clearly known. Most experts thought that endometrial cancer generates under the combined effect of inheritance, internal secretion and external environment.11 Though endometrial cancer manifests as increased menstrual volume, menostaxis and irregular vaginal bleeding, about 30% of patients who show no clinical symptoms have been at the advanced state when being diagnosed. Previously diagnostic curettage was regarded as the most common method for diagnosing endometrial cancer; however, it is a kind of invasive examination which is easy to cause physical and mental damages and moreover it is of small significance to clinical staging and has no values for treatment guidance and prediction of prognosis.
Serum tumor markers which has advantages of small trauma and simple operation have gradually been the research hotspot.
CA125 is the major marker in the diagnosis and monitoring of endometrial cancer. But compared to ovarian cancer, the sensitivity and specificity of CA125 in diagnosing endometrial cancer are lower; hence it is only suitable for patients with advanced endometrial cancer or recurrent endometrial cancer. Therefore, finding out other tumor markets is of great significance. HE4 is considered as a novel marker for gynecolgical tumor. In malignant tumors especially malignant ovarian epithelial tumors, the expression level of HE4 increases, inducing the changes of serum HE4 level.
Moore et al.12 found that the serum HE4 level of patients with endometrial cancer was significantly higher than that of healthy people and that the strong positive expression of HE4 in endometrial cancer tissues accounted for more than 90%, suggesting HE4 might be assistant to the diagnosis of endometrial cancer. Zhang Zhi et al.13 found that the level of HE4 in patients with endometrial cancer was obviously higher than that of patients with benign uterine diseases. The results of this study also suggested that the level of HE4 in the endometrial cancer group was much higher than that in the other two groups. HE4 is superior to other tumor markers in the diagnosis of early endometrial cancer. HE4 is more valuable than CA125 in the identification of benign endometrial cancer.14,15 The results of this study suggested that the area under ROC of diagnosis based on single detection of HE4 was larger than that based on single detection of CA125, which were similar to the studies mentioned above.
Therefore, patients with higher HE4 level should be paid more attention. If diagnostic curettage does not indicate endometrial lesions, hysteroscopy can be carried out to reduce miss diagnosis and avoid delayed treatment.
The methodology evaluation on HE4 and CA125 demonstrated that, the sensitivity, Youden index and coincidence rate of diagnosis based on HE4 were superior to those of CA125. Some scholars proposed that, the sensitivity of CA125 in the diagnosis of endometrial cancer is unable to satisfy the diagnostic requirement in clinics, which requires further study. Angioli found that, the sensitivity of HE4 in the diagnosis of endometrial cancer was 59.4%, but that of CA125 was only 19.8%.16 Omer improved the sensitivity of diagnosing endometrial cancer to 84% by using detection of multiple serum markers such as HE4, CA125, CA15-3, carcino embryonie antigen and CA19-9,17 suggesting combined detection of HE4 and CA125 were expected to provide more information for the diagnosis of endometrial cancer to make up the deficiency of single detection.
The research results suggested that, the sensitivity of diagnosing endometrial cancer with HE4 was much higher than that with CA125 was (51.7% vs 57.2%); the sensitivity of diagnosing endometrial cancer based on HE4 in combination with CA125 was 73.2%, much superior to the separate detection, which was consistent with previous research results. Therefore, it was considered that, CA125 in combination with HE4 had an important clinical value in the early diagnosis of endometrial cancer.
In addition, the analysis of ROC curve suggested that, the ROC-AUC value of the serum HE4 was higher than that of the CA125 and the ROC-AUC value of the combined detection was much higher than that of the detection of single index, which also suggested the superiority of the combined detection.
The detection of serum markers is an important approach for the diagnosis of endometrial cancer. Serum HE4 level of patients with endometrial cancer is higher than that of healthy controls and patients with uterine benign lesions. The detection HE4 in combination with CA125 can more effectively identify benign and malignant endometrial cancer; hence it is worth promotion in clinical practice.
Declaration of interest: All authors declared there was no conflict interests involved.
Grant Support and Financial Disclosures: None.
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|Publication:||Pakistan Journal of Medical Sciences|
|Date:||Aug 31, 2017|
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