Abstract
BACKGROUND:
Lifetime risk of developing endometrial cancer is 2.17%. There is controversy regarding the predictive value of Cancer Antigen 125 (CA125) in endometrial cancer as well as the significance of its relationship with prognostic factors and appropriate cut-off value.
OBJECTIVE:
The aim of the present study was to investigate the prognostic role of CA125 in advanced endometrial carcinoma and determination of the appropriate cut-off value.
METHODS:
A sample of 91 patients was retrospectively selected from a population of 501 patients suffering from endometrial cancer during 1995 to 2015 in accordance with the inclusion criteria. The relation between clinicopathological variables and CA125 were analyzed. In order to determine sensitivity and specificity of various cut-off levels, receiver operating characteristic (ROC) curve analysis was performed for associated factors confirmed by logistic regression analysis.
RESULTS:
In 35% of patients, CA125 values were 35 u/ml, and in 52%, the values were equal to or greater than 20 u/ml. High preoperative CA125 was significantly related with advanced stage, ovarian involvement, omental metastasis, and myometrial invasion equal to or greater than 50%. According to the ROC curve, the suitable cut-off value for CA125 in advanced stage (sensitivity
CONCLUSIONS:
In endometrial carcinoma, due to the relationship of CA125 with numerous prognostic factors, it is recommended that CA125 measurement be included in preoperative evaluation. In case of high CA125 levels, complete surgical staging including lymphadenectomy and omentectomy should be considered.
Introduction
Endometrial cancer is the most common form of gynaecologic malignancy and the fourth most common cancer among women in Western countries, afflicting over 28,000 women worldwide per annum [1, 2]. The lifetime risk of developing endometrial cancer in the UK is 1 in every 46 women (2.17%) [3]. The annual expected incidence of endometrial cancer is on the rise [4, 5]. The increase in the incidence rate of endometrial cancer in recent years is due to factors such as obesity, aging populations, and use of unopposed oestrogen (i.e. without progesterone) [6, 7]. Based on clinical, pathological, molecular, and biological criteria, endometrial cancer is divided into two categories [8]. Subtype 1 (endometrioid): With a frequency of 80%, this subtype consists of the most prevalent type of endometrial cancer. It is usually diagnosed in the early stages and associated with a better overall prognosis. Subtype 2 (none-endometrioid): This type includes papillary serous carcinoma and clear-cell carcinoma comprising 15–20% of cases of endometrial cancer. It behaves aggressively, involves high-grade tumours, and has a poor prognosis [9, 10]. Advanced stage, poor differentiation, lymph node metastasis, positive peritoneal cytology, myometrial invasion equal to or greater than 50%, cervical involvement, and adnexal metastasis are considered among the factors for poor prognosis [11, 12]. Many of these prognostic factors are postoperatively evaluable, and it seems necessary to determine relevant preoperatively evaluable factors.
The CA125 as tumour marker was first discovered in 1981 in ovarian epithelial cancer patients by Niloff et al. [13]. Since 1984, many researchers have carried out studies on the role of CA125 in endometrial cancer and its relationship with deep myometrial invasion, extra-uterine and lymph node involvement, metastasis, advanced stage, recurrence, and positive peritoneal cytology [11, 12, 14, 15, 16, 17, 18]. The role of CA125 as a tumour marker useful in preoperative evaluation as well as in the treatment plan and extent of surgery is still in dispute. In addition, there is no consensus regarding suitable CA125 cut-off levels in endometrial cancer for its role as a predictor or its relationship with prognostic factors with numerous studies indicating varying levels. Therefore, the aim of the present study is an investigation of the relationship of preoperative CA125 with important clinicopathological and prognostic factors as well as appropriate cut-off levels in the patients under study.
Methods and materials
In a retrospective study, the medical records of 501 patients suffering from endometrial carcinoma as per pathologic diagnosis in the period from 1995 to 2015 in the Gynaecologic Oncology Clinic of Vali-e-Asr Hospital affiliated with Tehran University of Medical Sciences was examined. Review board approval was obtained from the relevant department. Since the study was retrospective, informed consent was not obtained from the patients.
Inclusion criteria included histopathological confirmation of endometrial carcinoma including endometrioid, adenosquamous, mucinous, papillary serous and clear-cell, patients who received CA125 testing at most 10 days prior to operation and patients diagnosed with endometrial carcinoma who were operated on in Vali-e-Asr Hospital.
Exclusion criteria included reception of other methods of treatment for endometrial carcinoma including radiotherapy (as primary treatment) and neoadjuvant chemotherapy, patients who did not undergo CA125 testing, patients whose records were incomplete and incomplete surgery.
Among 501 records, 91 cases adhered to the required criteria and were entered into the study.
After receiving endometrial biopsy as outpatients (pipelle biopsy) or fractional dilation and curettage (D&C) and subsequent histopathologic diagnosis of endometrial carcinoma, the study patients underwent preoperative evaluations including CA125 testing (using radioimmunoassay (RIA)) and imaging (ultrasonography, CT scan, or MRI). Next, the patients underwent total hysterectomy, bilateral salpingo- oophorectomy, peritoneal washing, lymphadenectomy (pelvic
In this study, useful information such as age, menopause status, histological tumour type, stage, and grade was gathered. Correlations of preoperative CA125 with stage, grade, recurrence, involvement of ovary, lymph node, cervix, parametrium, and omentum, LVSI, deep myometrial invasion, and peritoneal cytology were investigated and an appropriate cut-off was determined.
SPSS software version 20 (SPSS Chicago, IL, USA) was utilised for analysis of data. In order to determine sensitivity and specificity of various cut-off levels, receiver operating characteristic (ROC) curve analysis was performed for associated factors confirmed by logistic regression analysis.
Area under curve (AUC) of sensitivity and specificity was determined. In this study, confidence limits of 95% (P value
Results
Clinical characteristics of the patient (
91)
Clinical characteristics of the patient (
Different values of preoperative CA125 in clinicopathological aspects in endometrial carcinoma
Diagnostic values of preoperative CA125 for predicting clinicopathological factors in endometrial carcinoma
ROC curve for advanced stage in relation with preoperative CA125 levels in endometrial carcinoma.
Out of 501 patients, 91 were suitable for the present study. The mean age in the sample was 55.17
ROC curve for omental involvement in relation with preoperative CA125 levels in endometrial carcinoma.
According to the ROC curve, the suitable cut-off value for CA125 in advanced stage (sensitivity
The results of the present study demonstrate that preoperative CA125 levels had significant relationships with advanced stage endometrial carcinoma, myometrial invasion equal to or greater than 50%, and omental and ovarian metastasis. The suitable CA125 cut-off value was 20 u/ml in advanced stage and deep myometrial invasion and 35 u/ml in extrauterine metastasis (involvement of the omentum and ovaries).
Considering that CA125 levels greater than 35 u/ml were observed in 35% of study patients and CA125 levels greater than 20 u/ml were observed in 51.6% of study patients, this tumour marker does not seem to be suitable as a diagnostic marker.
This result bears similarity with previous studies which reported CA125 levels greater than 35 u/ml in 11–34.9% of patients afflicted with endometrial cancer [19, 20, 21, 22].
In the study of Jiang et al., based on pathologic reports, 10.05% showed lymph node metastasis and the best cut-off value for detection of this type of metastasis was 25 u/ml [22].
In their study, high CA125 values had a relationship with adnexal involvement and extrauterine metastasis including lymph node metastasis and positive peritoneal cytology. In our study, lymph node metastasis was similar to the Jiang et al.’s study (11%) [22]; however, we did not discover a significant relationship between high CA125 and lymph node metastasis (
The Nikolaou et al. study supported a cut-off value of 20 u/ml in endometrial carcinoma [6]. Furthermore, high preoperative CA125 levels were related with advanced stage in both the present study and Nikolaou et al. Deep myometrial invasion in endometrial carcinoma was strongly related with lymph node metastasis, risk of recurrence, and disease prognosis [23].
In Nikolaou et al. [6], high CA125 levels were related with deep myometrial invasion and extrauterine involvement although this relationship was not significant. In our study, high preoperative CA125 was significantly related with both (
Supporting our study, a relationship between high preoperative CA125 and advanced stage had been shown in many preceding studies [12, 14, 26, 27].
In other studies, a relationship between high preoperative CA125 levels and metastatic disease as well as endometrial cancer recurrence was revealed [18, 28, 29, 30]. In the present study, high preoperative CA125 levels were significantly related with metastatic disease but not with recurrence. It should be noted that further study is required to discover whether CA125 levels increase with recurrence of cancer.
For the first time, in 1994, a lower cut-off level for CA125 was suggested for endometrial cancer [31]. Subsequent studies utilized cut-off levels of 20 and 35 u/ml for extrauterine metastasis [18, 24, 27, 32]. In our study, the suitable cut-off value for extrauterine metastasis (metastasis to the omentum and ovaries) was 35 u/ml and for advanced stage and deep myometrial invasion, it was 20 u/ml.
One additional matter not found in previous studies was the significant relationship between high preoperative CA125 levels and omental metastasis with a cut-off of 35 u/ml (
The limitations of the present study included the following. First, the study was retrospective and did not have the means for intervention. Second, the study was single-centre. A multicentre study would involve a greater sample size and perhaps more reliable results. Third, due to failure to perform or record preoperative CA125 testing, incomplete surgical staging, and lack of follow-up, many records were excluded from the study resulting in a smaller sample size. Fourth, high preoperative CA125 levels had no involvement in patient treatment plans.
Conclusion
CA125 is a useful tumour marker that was first discovered in relation with epithelial ovarian cancer. Its use was next posited in relation with endometrial cancer but with a different cut-off value. Much research has been performed in this regard. The results of the present study indicate that CA125 is a suitable, inexpensive, and widely available tumour marker as a prognostic factor in preoperative measurement. Due to its relationship with advanced stage and extrauterine metastasis with cut-off values of 20 and 35 u/ml respectively, it is recommended for inclusion in preoperative evaluation of patients suffering from endometrial cancer. In the case of high levels, complete staging including total hysterectomy, bilateral salpingo-oophorectomy, lymphadenectomy, omentectomy, and peritoneal washing may be highly recommended.
Conflict of interest
All authors declare that they have no conflict of interest.
Footnotes
Acknowledgments
We, authors of the present paper, sincerely express our gratitude to all professors of the Department of Gynaecologic Oncology and members of the Multidisciplinary Tumour Board of Tehran Vali-e-Asr Hospital who had a part in examination, surgery, and treatment of the patients as well as the staff of the Gynaecologic Oncology Clinic who aided us in this study.
