Endometriosis (EMT), is an estrogen-dependent disease in which functional endometrial tissue exists and grows outside the uterine cavity. Common symptoms include infertility, dysmenorrhea, chronic pelvic pain, sexual discomfort and defecation pain, affecting 10%–15% of women of childbearing age. EMT is a risk factor for ovarian cancer and some reports suggest that ovarian endometrioid adenocarcinoma and ovarian clear cell adenocarcinoma originate from ovarian endometriosis [1, 2]. There are three main types of EMT: ovarian endometriotic cyst (OEC), superficial peritoneal endometriosis and deep invasive endometriosis (DIE) [3, 4, 5]. OEC is the most common clinical type, accounting for 17%–44% of all endometriosis [6]. Laparoscopy is the gold standard for the diagnosis of EMT [7]. It is an invasive examination with high cost, surgical risk and the possibility of postoperative adhesion. Transvaginal ultrasound and magnetic resonance imaging can diagnose ectopic disease. The sensitivity and specificity of transvaginal ultrasound and magnetic resonance imaging are similar to those of surgery, and the accuracy of examination is highly related to the personal skills of doctors [8, 9]. Carbohydrate antigen 125 (CA125) and CA19-9 are commonly used tumor markers in clinic. The purpose of this study was to review the expression of CA125 and CA19-9 in stage Ⅲ and Ⅳ endometriosis, and to evaluate the effect of these two tumor markers in differentiating stage Ⅲ and Ⅳ endometriosis from benign and malignant tumors.

EMT is a recognized chronic inflammatory disease, the common symptoms are dysmenorrhea, infertility, chronic pelvic pain, sexual discomfort, etc., the infertility rate is as high as 50% [5]. Dysmenorrhea and infertility in OEC group are higher than those in the other three groups, which may be due to ovarian dysfunction caused by chronic abdominal inflammation, changes in fertilization process and pelvic adhesion in EMT patients [11]. Chronic inflammation leads to prostaglandin overdose, peripheral and central sensitization, and abnormal stress response leading to secondary dysmenorrhea and severe symptoms [11, 12].

We determined that all five predictors, age, dysmenorrhea, infertility, CA125, and CA19-9, differed among the three groups of diseases, and then determined, by unordered multiclassified logistic regression analysis, that CA125 was a predictor of CA19-9 in the comparison of OEC with benign and malignant diseases; CA19-9 was not statistically significant as a predictor.

CA19-9 is synthesized in pancreas and bile duct cells, stomach, colon, endometrium and saliva epithelial cells, and can be overexpressed in some benign and malignant gastrointestinal diseases. Serum levels can also be significantly increased [13]. An increase was also found in the serum of patients with EMT, and some previous studies suggested that CA19-9 could be used as a diagnostic marker for EMT [14, 15]. In our study, the value of CA19-9 in OEC group was significantly higher than that in benign diseases, but the CA19-9 value in malignant diseases varied greatly with the nature of tumors. Some studies have pointed out that the increase of serum CA19-9 is related to tumor pathology and tumor size, mainly in mucinous tumors, which is often used as a tumor marker of gastrointestinal tract [16], and also reported a significant increase in ovarian mucinous tumors (borderline and malignant) [17]. In our study, the expression of CA19-9 is low in serous ovarian carcinoma and high in ovarian endometrioid carcinoma. These results are consistent with the previous experimental results [18]. Because borderline and malignant mucinous tumors are less included in our cases, it is impossible to further compare the expression of OEC with borderline and malignant mucinous tumors, which limits our study. We analyzed that CA19-9 was not statistically significant as a predictor of OEC by logistic regression [19].

CA125 is a mature tumor marker, which is produced in the epithelial cells of the body cavity during embryonic development. The role of ovarian cancer in the diagnosis of ovarian cancer has been widely recognized, and the serum levels of patients with EMT are also increased in varying degrees [20]. A large number of studies have recommended the use of CA125 to assist in the diagnosis of patients suspected of having EMT [21, 22, 23]. However, the conclusions of the study on the sensitivity of biomarkers are not consistent, and the key is to select the appropriate cut-off value [24]. At present, $\ge$35 IU/mL is the recommended reference value for epithelial ovarian cancer. Therefore, this study included both benign and malignant diseases as a control to explore a more accurate range of cut-off values. ROC analysis showed a CA125 cut-off value of $>$23.1 U/mL when controlled with benign disease, with a sensitivity and specificity of 89.62%, 81.52%, and an AUC of 0.90, respectively (p 0.0001). The sensitivity and specificity were 95.08%, 7%, 71.57 AUC 0.859 (p 0.0001) for CA125 cut-off value of $\le$209.2 U/mL against malignant disease. CA125 as a predictor of OEC was best predicted within the range of 23.1 U/mL CA125 209.2 U/mL. The sensitivity and specificity were 89.62%, 81.52%, and AUC 0.90 (p 0.0001) for the cut-off value of $>$23.1 U/mL against malignant disease.

In our study, we also found that CA125 is elevated in borderline tumors, which makes the accuracy of CA125 as a diagnostic criterion for distinguishing benign or potential malignant diseases very challenging [25].

In the analysis of the relationship between clinical characteristics, there was no significant difference in the recurrence and initial onset of CA125 between the two groups, which was different from the results of previous studies [26, 27]. It may be because fewer patients in the relapse group in our study do not really reflect the differences between the two groups. In staging comparison, stage Ⅳ was significantly higher than stage III, which was the same as the previous study [23]. CA125 was more sensitive in severe patients [28, 29]. Previously, most of them used CA125 to distinguish between mild (Ⅰ, Ⅱ) and severe (Ⅲ, Ⅳ). But our study only compared between stage Ⅲ and Ⅳ, lack of stage Ⅰ and Ⅱ, which is another limitation of our results. In our results, the CA125 value of bilateral cysts was higher than that of unilateral cysts, and that of multilocular cysts was higher than that of single cysts. It is suggested that the larger the cystoma is, the higher the CA125 is. The size of ectopic cystoma is also related to the stage [16, 30]. The CA125 value of patients with dysmenorrhea is significantly higher than that of patients without dysmenorrhea, which is consistent with the results of Liu et al. [31]. Dysmenorrhea symptoms combined with increased CA125 can provide some evidence for the diagnosis of dysmenorrhea related to ectopic menstruation. CA125 and CA19-9 increased significantly when OEC ruptured, and the combination of them has obvious significance in the diagnosis of OEC rupture [32]. One of the advantages of our study is that all the selected cases are surgical cases, which can completely exclude the patients with endometriosis in the control group. One of the strengths of our study is that all the cases selected were post-surgical cases with pathologic findings, which made the diagnosis more convincing and allowed complete exclusion of patients with endometriosis from the control group. The controls I chose were all our common and frequent diseases and our study used benign controls as well as malignant controls in order to explore the critical values of CA125 and CA19-9 used in OEC. See Fig. 3. and Fig. 4.

Fig. 3.

The ROC curve of the combined indicators of CA19-9 and CA125 in the diagnosis of malignant diseases and OEC.

Fig. 4.

Comparison of ROC curves between CA19-9, CA125, and combined indicators in the diagnosis of malignant diseases and OEC.

We concluded that the effect of serum CA19-9 in the diagnosis of EMT is not ideal. CA125 has a certain value in the diagnosis of endometriosis, but it is necessary to explore the range of cut-off value. When serum 23.1 U/mL CA125 209.2 U/mL has obvious clinical symptoms and ultrasonic signs, endometriosis is highly suspected.

The effect of serum CA19-9 in the diagnosis of EMT is not ideal. CA125 has a certain value in the diagnosis of endometriosis, but it is necessary to explore the range of cut-off value.

All data points generated or analyzed during this study are included in this article and there are no further underlying data necessary to reproduce the results.

GZ and JC designed the research study. WZ performed the research. HT provided help and advice on the ELISA experiments. QJ analyzed the data. All authors contributed to editorial changes in the manuscript. All authors read and approved the final manuscript. All authors have participated sufficiently in the work and agreed to be accountable for all aspects of the work.

All subjects gave their informed consent for inclusion before they participated in the study. The study was conducted in accordance with the Declaration of Helsinki, and the protocol was approved by the Ethics Committee of Hainan Provincial People’s Hospital (approval number: Med-Eth-Re [2023] 145).

We would like to express our gratitude to all those who helped us during the writing of this manuscript. Thanks to all the peer reviewers for their opinions and suggestions.

This research received no external funding.

The authors declare no conflict of interest. Jiming Chen is serving as one of the Guest editors of this journal. We declare that Jiming Chen had no involvement in the peer review of this article and has no access to information regarding its peer review. Full responsibility for the editorial process for this article was delegated to Valerio Gaetano Vellone.