{"paper_id":"68c73dcf-f085-409c-a993-bae85973bc1b","body_text":"Clin. Exp. Obstet. Gynecol. 2024; 51(2): 45\nhttps://doi.org/10.31083/j.ceog5102045\nCopyright: © 2024 The Author(s). Published by IMR Press.\nThis is an open access article under the CC BY 4.0 license .\nPublisher’s Note: IMR Press stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.\nOriginal Research\nThe Value of CA125 and CA19-9 in the Diagnosis of Stage Ⅲ and Ⅳ\nEndometriosis\nWenwen Zhang1,†, Huimin Tang2,†, Qiucheng Jia 2, Jiming Chen 2,*, Genhai Zhu 3,*\n1Department of Gynecology, Hainan Medical College, 571199 Haikou, Hainan, China\n2Department of Gynecology, The Affiliated Changzhou Second People’s Hospital of Nanjing Medical University, 213000 Changzhou, Jiangsu, China\n3Department of Gynecology, Hainan Hospital Affiliated to Hainan Medical College, 570311 Haikou, Hainan, China\n*Correspondence: cjming@126.com (Jiming Chen); genhaizhu@163.com (Genhai Zhu)\n†These authors contributed equally.\nAcademic Editor: V alerio Gaetano V ellone\nSubmitted: 28 August 2023 Revised: 19 November 2023 Accepted: 28 November 2023 Published: 21 February 2024\nAbstract\nBackground: To evaluate the effect of carbohydrate antigen 125 (CA125) and CA19-9 in distinguishing stage Ⅲ and Ⅳ endometriosis\nfrom benign and malignant tumors, and to explore whether it is related to the clinical features of the disease. Methods: In a retrospective\ncohort study based on clinical data from hospitals, a total of 183 patients with pathologically confirmed diagnosis of ovarian endometriotic\ncysts (OEC) in Hainan Provincial People’s Hospital for surgical treatment from January 2019 to August 2022 were selected as the case\ngroup, and a total of 276 cases of benign diseases, including 184 cases of benign ovarian tumors, 94 cases of gynecological common\ndiseases, and 102 cases of malignant ovarian tumors were selected as the control group, with a total of 276 cases of benign diseases,\nincluding 184 cases of benign ovarian tumors, 94 cases of gynecological common diseases, and 102 cases of malignant ovarian tumors.\nThere were also 23 cases of ruptured ectopic cysts. We compared the clinical characteristics (age of onset, fertility, dysmenorrhea,\npreoperative CA125 and CA19-9 values) of the patients in the OEC group with those of the other control groups; analyzed the serum\nCA125 and CA19-9 values in relation to the pathological characteristics of OEC (recurrence, unilateral and bilaterality, multilocularity\nand unilocularity, rupture, dysmenorrhea, fertility, and staging); and analyzed the CA125 and CA19-9 values by unordered logistic\nregression, CA19-9 to predict OEC; sensitivity, specificity and cut-off values of CA125, CA19-9 and their combined indexes to diagnose\nOEC. Results: The symptoms of dysmenorrhea and infertility in OEC group were significantly higher than those in the other three\ngroups. The preoperative CA125 value in OEC group was higher than that in benign tumor and other gynecological diseases group, and\nsignificantly lower than that in malignant tumor group. There was no significant difference in the value of CA19-9 and CA125 in the\ndegree of dysmenorrhea, recurrence and infertility. The values of CA19-9 and CA125 of multilocular cysts were higher than those of\nunicameral cysts, bilateral cysts were higher than unilateral cysts, and ruptured cysts were significantly higher than unruptured cysts. The\nvalue of CA125 in the dysmenorrhea group was higher than that in the non-dysmenorrhea group, and that in the fourth stage was higher\nthan that in the third stage, and the difference was statistically significant ( p < 0.05). Unordered multicategorical logistic regression\nanalysis determined that CA125, could be a predictor in the comparison of OEC with benign disease; in the benign control group the\ncut-off value for CA125 was >23.1 IU/mL with an area under the curve (AUC) value of 0.90 (0.869–0.926), a sensitivity of 89.62% and\na specificity of 81.52%. In the malignant control group the cut-off value for CA125 was ≤209.2 with an AUC value of 0.859 (0.813–\n0.897), sensitivity 95.08% and specificity 71.57%. Conclusions: The effect of serum CA19-9 in the diagnosis of Endometriosis (EMT)\nis not ideal. CA125 has a certain value in the diagnosis of endometriosis, but it is necessary to explore the range of cut-off value.\nKeywords: endometriosis; CA125; CA19-9\n1. Introduction\nEndometriosis (EMT), is an estrogen-dependent dis-\nease in which functional endometrial tissue exists and\ngrows outside the uterine cavity. Common symptoms in-\nclude infertility, dysmenorrhea, chronic pelvic pain, sex-\nual discomfort and defecation pain, affecting 10%–15% of\nwomen of childbearing age. EMT is a risk factor for ovar-\nian cancer and some reports suggest that ovarian endometri-\noid adenocarcinoma and ovarian clear cell adenocarcinoma\noriginate from ovarian endometriosis [ 1,2]. There are three\nmain types of EMT: ovarian endometriotic cyst (OEC), su-\nperficial peritoneal endometriosis and deep invasive en-\ndometriosis (DIE) [3–5]. OEC is the most common clinical\ntype, accounting for 17%–44% of all endometriosis [6]. La-\nparoscopy is the gold standard for the diagnosis of EMT [7].\nIt is an invasive examination with high cost, surgical risk\nand the possibility of postoperative adhesion. Transvaginal\nultrasound and magnetic resonance imaging can diagnose\nectopic disease. The sensitivity and specificity of transvagi-\nnal ultrasound and magnetic resonance imaging are simi-\nlar to those of surgery, and the accuracy of examination is\nhighly related to the personal skills of doctors [ 8,9]. Car-\nbohydrate antigen 125 (CA125) and CA19-9 are commonly\nused tumor markers in clinic. The purpose of this study was\nto review the expression of CA125 and CA19-9 in stage Ⅲ\n\nTable 1. Comparison of clinical features.\nAge Dysmenorrhea Infertility CA19-9 CA125\nOEC n = 183 32 (28–38) 69 (37.7%) 19 (10.4%) 30.67 (9.54–68.35) 54 (31–108.3)\nχ2/p value 253.676/0.000 22.602/0.000\nBenign tumor n = 182 31 (26–40) 12 (6.6%) 2 (1.1%) 11.96 (4.47–31.69) 16.55 (12.82–21.43)\nOEC vs. p value 1.0 0.000 0.000\nOvarian teratoma: a report of 97 cases 22.63 (6.81–47.75) 15.9 (13.3–21.0)\n10 cases of sex cord stromal tumor 9.64 (4.19–13.63) 19.8 (14.97–28.02)\nSerous mucinous cystadenoma: a report of 12 cases 7.63 (2.0–19.07) 16.1 (11.15–24.27)\nSerous cystadenoma: a report of 25 cases 7.76 (4.34–14.94) 15.0 (10.45–23.75)\nMucinous cystadenoma: a report of 38 cases 8.46 (2.42–18.9) 16.6 (11.9–23.57)\nMalignant tumor n = 102 51 (43–59) 6 (5.9%) 2 (2.0%) 10.47 (3.32–32.09) 540.1 (144.5–1000)\nOEC vs. p value 0.000 0.000 0.000\n70 cases of serous carcinoma of ovary 7.27 (3.12–19.71) 980.0 (374.5–1000)\nMucinous ovarian carcinoma: a report of 5 cases 16.15 (2.13–22.56) 113.2 (14.85–333.2)\n12 cases of endometrioid carcinoma of ovary 111.7 (13.22–788.7) 229.8 (141.0–691.6)\nBorderline ovarian tumors: a report of 15 cases 24.2 (3.99–52.44) 64.7 (26.4–265.9)\nOther gynaecology n = 94 36 (30.75–40) 5 (5.4%) 2 (2.1%) 6.69 (2.71–14.46) 13.88 (10.6–19.67)\nOEC vs. p value 0.84 0.000 0.000\n57 cases of uterine leiomyoma 7.34 (2.69–14.55) 13.96 (11.85–19.95)\n14 cases of endometrial polyps 3.91 (2.0–10.96) 12.3 (9.77–15.42)\n23 cases of pelvic inflammatory diseases 6.9 (3.67–13.15) 16.0 (9.7–23.1)\nOEC, ovarian endometriotic cysts; CA125, carbohydrate antigen 125.\nTable 2. CA125 and CA19-9 after OEC rupture.\nBreak time * CA19-9 CA125\n<3 Days (n = 7) 512.44 (310.88–1200) 963.7 (542.2–1000)\n<7 Days (n = 5) 437.08 (79.25–857.2) 210.6 (147.15–900)\n<30 Days (n = 11) 72.91 (26.61–191.67) 217.7 (104.1–366.4)\n*Break time: the time from the onset of acute abdominal pain to\nadmission for surgery. All of the 23 patients had occasional acute\nsevere abdominal pain and were found to have a tear in the cyst\nor a large amount of cyst fluid in the abdominal peritoneum.\nand Ⅳ endometriosis, and to evaluate the effect of these\ntwo tumor markers in differentiating stage Ⅲ and Ⅳ en-\ndometriosis from benign and malignant tumors.\n2. Materials and Methods\n2.1 Materials\nThis was a retrospective cohort study conducted in\nHainan Provincial People’s Hospital, and a total of 183 pa-\ntients with pathologically confirmed diagnosis of OEC in\nsurgical treatment at Hainan Provincial People’s Hospital,\nChina, from January 2019 to August 2022 were selected as\nthe case group; a total of 276 cases of benign diseases, in-\ncluding 184 benign ovarian tumors, 94 cases of gynecolog-\nical general diseases (57 cases of uterine fibroids, 14 cases\nof endometrial polyps, and 23 cases of inflammatory dis-\neases of the pelvis) and 102 cases of malignant ovarian tu-\nmors were selected as the control group. There were also\n23 cases of OEC rupture. The staging method proposed by\nthe American Fertility Society (r-AFS) was used as a crite-\nrion for staging the group of cases. Stage Ⅰ (Minimal) 1–5,\nstage II (Mild) 6–15, stage III (Moderate) 16–40, stage IV\n(Severe) >40 [10]. See Tables 1, 2.\nInclusion criteria: ¬ operated in our hospital and con-\nfirmed by postoperative pathology; ­ the case group was\nmainly diagnosed as OEC; ® the medical history is com-\nplete; ¯ the patients in the case group did not use corticos-\nteroids within 6 months before operation; ° both the case\nand control groups were operated on electively, and the pa-\ntients were in the proliferative stage of endometrium.\nExclusion criteria: ¬ the case and the control group\nwere complicated with severe chronic diseases, accompa-\nnied by severe systemic diseases such as heart, brain, lung,\nkidney, liver insufficiency and thyroid dysfunction;­ those\nwith incomplete medical history; ® the disease occurred in\nthe same case in the case group and the control group. This\nstudy was approved by the Ethics Committee of Hainan\nProvincial people’s Hospital (approval number: Med-Eth-\nRe [2023] 145).\n2.2 Method\n2.2.1 Collection and Processing of Specimens\nWhole blood was collected from surgical patients 1\nday before surgery and sent to the Laboratory Department,\nthen CA125 and CA19-9 were detected by enzyme-linked\nimmunosorbent assay (ELISA) luminescence. Comparison\nof clinical characteristics (age of onset, fertility, dysmen-\norrhea, preoperative CA125 and CA19-9 values) between\npatients in the OEC group and other control patients; anal-\nysis of serum CA125 and CA19-9 values and patholog-\n2\n\n\nTable 3. CA19-9 and CA125 are more effective after age correction in malignant tumor group and OEC group.\nAge p value CA19-9 p value CA125 p value\nOEC n = 35 46 (42–48) 43.71 (10.9–126.9) 46.8 (24.7–109.9)\nSerous carcinoma, n = 43 48 (43–51) 0.196 9.89 (2.41–22.2) 0.001 913.3 (300–1000) 0.000\nOEC n = 18 48 (46.7–50) 40.29 (9.42–89.8) 44.5 (24.7–120.9)\nEndometrioid carcinoma, n = 12 50.5 (46.2–58.7) 0.305 111.7 (13.2–788.7) 0.15 229.8 (141.05–691.6) 0.001\nOEC n = 10 43 (26.25–50.25) 44.72 (18.58–89.69) 77.7 (35.25–112.27)\nMucinous ovarian carcinoma, n = 5 43 (25–54) 0.951 16.15 (2.13–22.56) 0.075 113.2 (14.85–333.2) 0.540\nOEC n = 73 32 (28–38.5) 36.87 (9.45–71.29) 54.7 (29.35–105.05)\nBorderline tumor, n = 15 33 (25–51) 0.356 24.27 (3.99–52.44) 0.328 64.7 (26.4–265.9) 0.495\nTable 4. The results were compared among groups with different pathological features in OEC group.\nCA19-9 p CA125 p\nDysmenorrhea\nY es (n = 69) 25.4 (6.64–74.58) 74.5 (35.1–126.9)\nNone (n = 111) 35.14 (10.78–67.64) 0.647 50.5 (31–87.3) 0.016*\nDegree of dysmenorrhea\nBearable (n = 42) 23.60 (5.6–75.74) 67.75 (30.15–134.72)\nIntolerable (n = 27) 40.16 (11.03–74.24) 0.423 75.8 (44.5–119.2) 0.740\nRelapseH\nY es (n = 11) 22.63 (7.45–48.1) 59.7 (35.2–94.7)\nNo (n = 172) 31.41 (9.55–69.52) 0.499 53.5 (30.85–109.5) 0.587\nPackage block\nSingle room (n = 158) 26.03 (9.15–65.17) 49.05 (29. 42–88.52)\nmulti room (n = 25) 55.29 (22.63–140.75) 0.030* 90.5 (65.15–127.25) 0.000*\nUnilateral (n = 121) 25.19 (8.93–51.5) 44 (27.55–82.4)\nBoth sides (n = 62) 49.25 (15.05–116.16) 0.032* 80.05 (48.37–152.2) 0.000*\nRupture (n = 23) 191.67 (59.71–514.47) 347.9 (143.1–800)\nUnbroken (n = 183) 30.67 (9.54–68.35) 0.000* 54 (31–108.3) 0.000*\nInfertility\nY es (n = 19) 26.7 (6.89–43.65) 60.0 (31.8–108.3)\nNo (n = 163) 30.67 (9.54–69.92) 0.421 53.1 (30.8–109.9) 0.64\nStaging\nⅢ (n = 88) 25.29 (9.41–44.73) 44.2 (28.22–83.37)\nⅣ (n = 95) 41.53 (9.58–84.77) 0.105 65.6 (35.7–119.2) 0.005*\n*p value < 0.05; H11 patients with recurrent OEC were recorded as the recurrence, with the remaining 172\nas the initial onset.\nical characteristics of OEC (recurrent, unilateral, bilater-\nally, multilocular unilocular, rupture, dysmenorrhea, fertil-\nity, and staging); analysis of age, dysmenorrhea, infertility,\nCA125, and CA19-9 to predict OEC by unordered logistic\nregression; and sensitivity, specificity, and cut-off value of\nCA125 to diagnose OEC.\n2.2.2 Statistical Analysis\nStatistical processing SPSS 25.0 software (IBM Corp.,\nArmonk, NY , USA) for data analysis. The measurement\ndata did not conform to the normal distribution in terms of\nmedian and quartile spacing. Mann-Whitney U rank sum\ntest was used for comparison between the two groups, and\nKruskal-Wallis test was used for comparison between mul-\ntiple groups. The counting data were expressed by the num-\nber of cases, and the comparison between groups was made\nby χ2 test. Sensitivity, specificity, area under the curve\n(AUC) and comparison were analyzed by MedCalc v20.100\nsoftware (MedCalc Software Ltd., Mariakerke, East Flan-\nders, Belgium). The difference was statistically significant\n(p < 0.05).\n3. Results\n3.1 Comparison of Different Clinical Characteristics of\nPatients in Four Groups\nThe CA19-9 levels in the OEC group were 30.67\n(9.54–68.35) U/mL, and CA125 levels were 54 (31–108.3)\nU/mL. The CA19-9 levels in other benign tumors, malig-\nnant tumors, and other gynecological groups were 11.96\n(4.47–31.69) U/mL, 10.47 (3.32–32.09) U/mL, and 6.69\n(2.71–14.46) U/mL, respectively; CA125 is 16.55 (12.82–\n3\n\nTable 5. Significance of disordered multiple classification logical regression analysis of CA19-9 and CA125 in the diagnosis of\nOEC.\nDisease type V ariable β Standard error Wald p OR 95% CI\nBenign disease CA19-9 0.000 0.001 0.100 0.751 1.000 0.998 1.001\nCA125 –0.034 0.004 63.616 0.000* 0.966 0.958 0.974\nMalignant tumor CA19-9 0.001 0.001 0.522 0.470 1.001 0.999 1.002\nCA125 0.007 0.001 39.329 0.000* 1.007 1.005 1.010\n*p value < 0.05. OR, odds ratio; 95% CI, 95% confidence interval.\nTable 6. Sensitivity and specificity of CA125, CA19-9, and their combined indicators in diagnosing OEC.\nAUC (95% CI) Sensitivity % Specificity % Truncation value Y oden index p\nBenign diseases\nCA125 0.90 (0.869–0.926) 89.62 81.52 >23.10 0.7114 <0.0001\nCA19-9 0.678 (0.633–0.721) 63.39 69.20 >18.87 0.3259 <0.0001\nBenign OEC 0.899 (0.868–0.925) 89.62 81.16 >0.287 0.7078 <0.0001\nMalignancy\nCA125 0.859 (0.813–0.897) 95.08 71.57 ≤209.20 0.6665 <0.0001\nCA19-9 0.635 (0.576–0.691) 65.03 64.71 >17.32 0.2973 0.0001\nMalignant OEC 0.859 (0.814–0.898) 95.08 72.55 >0.591 0.6763 <0.0001\nBenign OEC is a combined indicator of CA125 and CA19-9 in the benign control group. Malignant OEC is a combined indicator\nof CA125 and CA19-9 in the malignant control group. AUC, area under the curve.\n21.43) U/mL, 540.1 (144.5–1000) U/mL, and 13.88 (10.6–\n19.67) U/mL, respectively. The symptoms of dysmenor-\nrhea and infertility in OEC group were significantly higher\nthan those in the other three groups ( p = 0.000), and the\npreoperative CA19-9 value in OEC group was significantly\nhigher than that in the other three groups ( p = 0.000). The\npreoperative CA125 value in OEC group was higher than\nthat in benign tumor group and other gynecological disease\ngroup, but significantly lower than that in malignant tumor\ngroup (p = 0.000). See Table 1.\nThe age of onset in the malignant tumor group was\nsignificantly higher than that in the other three groups, and\nthe difference was statistically significant ( p = 0.000). Af-\nter adjusting the age of patients in malignant tumor group\nand OEC group, malignant tumors were divided into three\nsubgroups and compared with OEC group. In serous ovar-\nian cancer, CA19-9 was lower than OEC group, CA125 was\nhigher than OEC group, the difference was statistically sig-\nnificant. CA19-9 and CA125 in ovarian endometrioid car-\ncinoma were higher than those in OEC group, and the dif-\nference was statistically significant. There was no signifi-\ncant difference in CA19-9 and CA125 between borderline\ntumors and OEC group. See Table 3.\n3.2 Grouping and Comparison of Different Pathological\nFeatures in OEC Group\nThere was no significant difference in the value of\nCA19-9 and CA125 in the degree of dysmenorrhea, re-\ncurrence and infertility ( p > 0.05).The values of CA19-9\nand CA125 of multilocular cysts were higher than those\nof unicameral cysts, bilateral cysts were higher than unilat-\neral cysts, and ruptured cysts were significantly higher than\nFig. 1. The receiver operating characteristic (ROC) curve of\nthe combined indicators of CA19-9 and CA125 in the diagnosis\nof benign diseases and OEC.\nunruptured cysts ( p < 0.05).The value of CA125 in dys-\nmenorrhea group was higher than that in non-dysmenorrhea\ngroup, and that in stage Ⅳ was higher than that in stage III,\nand the difference was statistically significant ( p < 0.05),\nbut there was no significant difference in CA19-9 value be-\ntween dysmenorrhea and staging ( p > 0.05). See Table 4.\n4\n\n\nFig. 2. Comparison of ROC curves between CA19-9, CA125,\nand combined indicators in the diagnosis of benign diseases\nand OEC.\n3.3 Unordered Logistic Regression Analysis of CA125 and\nCA19-9 for Prediction of OEC\nIn the comparison of OEC with benign diseases:\nCA19-9 was not statistically significant; higher CA125\nhad a statistically significant higher risk of developing en-\ndometriosis [odds ratio (OR) = 0.966; 95% confidence in-\nterval (95% CI): 0.958–0.974].\nIn the comparison of OEC with malignancy: CA19-9\nwas not statistically significant; higher CA125 had a statis-\ntically significant higher risk of malignancy [OR = 1.007;\n95% CI: 1.005–1.010], see Table 5.\n3.4 Sensitivity and Specificity of CA125 for Diagnosing\nOEC\nSensitivity, specificity and cut-off values were cal-\nculated by using receiver operating characteristic (ROC)\ncurves, see Table 6. In the benign disease control group\nthe cut-off value of CA125 was 23.1 IU/mL with an AUC\nvalue of 0.90 (0.869–0.926), a sensitivity of 89.62% and a\nspecificity of 81.52%; the ROC curve is shown in Fig. 1.\nIn the malignant control group the cut-off value of\nCA125 was ≤209.2 with an AUC value of 0.859 (0.813–\n0.897), sensitivity of 95.08% and specificity of 71.57%; the\nROC curve is shown in Fig. 2.\n4. Discussion\nEMT is a recognized chronic inflammatory dis-\nease, the common symptoms are dysmenorrhea, infertility,\nchronic pelvic pain, sexual discomfort, etc., the infertility\nrate is as high as 50% [ 5]. Dysmenorrhea and infertility in\nOEC group are higher than those in the other three groups,\nwhich may be due to ovarian dysfunction caused by chronic\nabdominal inflammation, changes in fertilization process\nand pelvic adhesion in EMT patients [ 11]. Chronic inflam-\nmation leads to prostaglandin overdose, peripheral and cen-\ntral sensitization, and abnormal stress response leading to\nsecondary dysmenorrhea and severe symptoms [ 11,12].\nWe determined that all five predictors, age, dysmen-\norrhea, infertility, CA125, and CA19-9, differed among the\nthree groups of diseases, and then determined, by unordered\nmulticlassified logistic regression analysis, that CA125 was\na predictor of CA19-9 in the comparison of OEC with be-\nnign and malignant diseases; CA19-9 was not statistically\nsignificant as a predictor.\nCA19-9 is synthesized in pancreas and bile duct cells,\nstomach, colon, endometrium and saliva epithelial cells,\nand can be overexpressed in some benign and malignant\ngastrointestinal diseases. Serum levels can also be sig-\nnificantly increased [ 13]. An increase was also found in\nthe serum of patients with EMT, and some previous stud-\nies suggested that CA19-9 could be used as a diagnostic\nmarker for EMT [14,15]. In our study, the value of CA19-9\nin OEC group was significantly higher than that in benign\ndiseases, but the CA19-9 value in malignant diseases var-\nied greatly with the nature of tumors. Some studies have\npointed out that the increase of serum CA19-9 is related to\ntumor pathology and tumor size, mainly in mucinous tu-\nmors, which is often used as a tumor marker of gastroin-\ntestinal tract [16], and also reported a significant increase in\novarian mucinous tumors (borderline and malignant) [ 17].\nIn our study, the expression of CA19-9 is low in serous\novarian carcinoma and high in ovarian endometrioid car-\ncinoma. These results are consistent with the previous ex-\nperimental results [ 18]. Because borderline and malignant\nmucinous tumors are less included in our cases, it is impos-\nsible to further compare the expression of OEC with bor-\nderline and malignant mucinous tumors, which limits our\nstudy. We analyzed that CA19-9 was not statistically sig-\nnificant as a predictor of OEC by logistic regression [ 19].\nCA125 is a mature tumor marker, which is produced\nin the epithelial cells of the body cavity during embryonic\ndevelopment. The role of ovarian cancer in the diagnosis of\novarian cancer has been widely recognized, and the serum\nlevels of patients with EMT are also increased in varying\ndegrees [20]. A large number of studies have recommended\nthe use of CA125 to assist in the diagnosis of patients sus-\npected of having EMT [ 21–23]. However, the conclusions\nof the study on the sensitivity of biomarkers are not con-\nsistent, and the key is to select the appropriate cut-off value\n[24]. At present, ≥35 IU/mL is the recommended reference\nvalue for epithelial ovarian cancer. Therefore, this study in-\ncluded both benign and malignant diseases as a control to\nexplore a more accurate range of cut-off values. ROC anal-\nysis showed a CA125 cut-off value of >23.1 U/mL when\ncontrolled with benign disease, with a sensitivity and speci-\nficity of 89.62%, 81.52%, and an AUC of 0.90, respec-\ntively ( p < 0.0001). The sensitivity and specificity were\n5\n\n95.08%, 7%, 71.57 AUC 0.859 ( p < 0.0001) for CA125\ncut-off value of ≤209.2 U/mL against malignant disease.\nCA125 as a predictor of OEC was best predicted within the\nrange of 23.1 U/mL < CA125 < 209.2 U/mL. The sensi-\ntivity and specificity were 89.62%, 81.52%, and AUC 0.90\n(p < 0.0001) for the cut-off value of >23.1 U/mL against\nmalignant disease.\nIn our study, we also found that CA125 is elevated in\nborderline tumors, which makes the accuracy of CA125 as\na diagnostic criterion for distinguishing benign or potential\nmalignant diseases very challenging [ 25].\nIn the analysis of the relationship between clinical\ncharacteristics, there was no significant difference in the\nrecurrence and initial onset of CA125 between the two\ngroups, which was different from the results of previous\nstudies [ 26,27]. It may be because fewer patients in the\nrelapse group in our study do not really reflect the differ-\nences between the two groups. In staging comparison, stage\nⅣ was significantly higher than stage III, which was the\nsame as the previous study [ 23]. CA125 was more sensi-\ntive in severe patients [ 28,29]. Previously, most of them\nused CA125 to distinguish between mild (Ⅰ, Ⅱ) and severe\n(Ⅲ, Ⅳ). But our study only compared between stage Ⅲ\nand Ⅳ, lack of stage Ⅰ and Ⅱ, which is another limitation of\nour results. In our results, the CA125 value of bilateral cysts\nwas higher than that of unilateral cysts, and that of multi-\nlocular cysts was higher than that of single cysts. It is sug-\ngested that the larger the cystoma is, the higher the CA125\nis. The size of ectopic cystoma is also related to the stage\n[16,30]. The CA125 value of patients with dysmenorrhea is\nsignificantly higher than that of patients without dysmenor-\nrhea, which is consistent with the results of Liu et al. [ 31].\nDysmenorrhea symptoms combined with increased CA125\ncan provide some evidence for the diagnosis of dysmenor-\nrhea related to ectopic menstruation. CA125 and CA19-9\nincreased significantly when OEC ruptured, and the com-\nbination of them has obvious significance in the diagnosis\nof OEC rupture [ 32]. One of the advantages of our study\nis that all the selected cases are surgical cases, which can\ncompletely exclude the patients with endometriosis in the\ncontrol group. One of the strengths of our study is that all\nthe cases selected were post-surgical cases with pathologic\nfindings, which made the diagnosis more convincing and\nallowed complete exclusion of patients with endometriosis\nfrom the control group. The controls I chose were all our\ncommon and frequent diseases and our study used benign\ncontrols as well as malignant controls in order to explore\nthe critical values of CA125 and CA19-9 used in OEC. See\nFig. 3. and Fig. 4.\nWe concluded that the effect of serum CA19-9 in the\ndiagnosis of EMT is not ideal. CA125 has a certain value\nin the diagnosis of endometriosis, but it is necessary to ex-\nplore the range of cut-off value. When serum 23.1 U/mL <\nCA125 < 209.2 U/mL has obvious clinical symptoms and\nultrasonic signs, endometriosis is highly suspected.\nFig. 3. The ROC curve of the combined indicators of CA19-9\nand CA125 in the diagnosis of malignant diseases and OEC.\nFig. 4. Comparison of ROC curves between CA19-9, CA125,\nand combined indicators in the diagnosis of malignant diseases\nand OEC.\n5. Conclusions\nThe effect of serum CA19-9 in the diagnosis of EMT\nis not ideal. CA125 has a certain value in the diagnosis of\nendometriosis, but it is necessary to explore the range of\ncut-off value.\n6\n\n\nAvailability of Data and Materials\nAll data points generated or analyzed during this study\nare included in this article and there are no further underly-\ning data necessary to reproduce the results.\nAuthor Contributions\nGZ and JC designed the research study. WZ per-\nformed the research. HT provided help and advice on the\nELISA experiments. QJ analyzed the data. All authors con-\ntributed to editorial changes in the manuscript. All authors\nread and approved the final manuscript. All authors have\nparticipated sufficiently in the work and agreed to be ac-\ncountable for all aspects of the work.\nEthics Approval and Consent to Participate\nAll subjects gave their informed consent for inclu-\nsion before they participated in the study. The study was\nconducted in accordance with the Declaration of Helsinki,\nand the protocol was approved by the Ethics Committee\nof Hainan Provincial People’s Hospital (approval number:\nMed-Eth-Re [2023] 145).\nAcknowledgment\nWe would like to express our gratitude to all those who\nhelped us during the writing of this manuscript. Thanks to\nall the peer reviewers for their opinions and suggestions.\nFunding\nThis research received no external funding.\nConflict of Interest\nThe authors declare no conflict of interest. Jiming\nChen is serving as one of the Guest editors of this jour-\nnal. We declare that Jiming Chen had no involvement in the\npeer review of this article and has no access to information\nregarding its peer review. Full responsibility for the edito-\nrial process for this article was delegated to V alerio Gaetano\nV ellone.\nReferences\n[1] Murakami K, Kotani Y , Nakai H, Matsumura N. Endometriosis-\nAssociated Ovarian Cancer: The Origin and Targeted Therapy.\nCancers. 2020; 12: 1676.\n[2] Cucinella G, Sozzi G, Di Donna MC, Unti E, Mariani A, Chi-\nantera V . Retroperitoneal Squamous Cell Carcinoma Involving\nthe Pelvic Side Wall Arising from Endometriosis: A Case Re-\nport. Gynecologic and Obstetric Investigation. 2022; 87: 159–\n164.\n[3] Bulun SE. Endometriosis. 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