{"paper_id":"3062f8a9-8e82-4797-aa59-bb058368293b","body_text":"Diagnostic value of tumor biomarkers CA125 and CA72-4 in differentiation\nof epithelial ovarian cancer and endometrioma.\nJafari Shobeiri Mehri1, Sepasi Farnaz1*, Dastranj Tabrizi Ali1, Mostafa Gharabaghi Parvin1,\nOuladsahebmadarek Elaheh1, Parizad Marziyeh1, Hakimi Parvin1, Sarbakhsh Parvin2, Ziaee\nMojtaba3,4\n1Women’s Reproductive Health Research Center, Tabriz University of Medical Sciences, Tabriz, Iran\n2Department of Statistics and Epidemiology, Tabriz University of Medical Sciences, Tabriz, Iran\n3Phytopharmacology Research Center, Maragheh University of Medical Sciences, Maragheh, IR Iran\n4Cardiovascular Research Center, Tabriz University of Medical Sciences, Tabriz, Iran\nAbstract\nOvarian cancer is the leading cause of gynecological malignancy-related mortality. CA125 level in\npatients with Epithelial Ovarian Cancer (EOC) and endometrioma can frequently be high. CA72-4 level\nwas also elevated in several carcinomas including ovarian cancer. Due to its lack of specificity, however,\nthis marker has a limited role in the differential diagnosis between EOC and endometrioma. In this\nresearch, we studied the levels of biomarkers CA125 and CA72-4 to determine their potential role in the\ndifferential diagnosis of endometrioma and EOC. For this goal, biomarkers CA125 and CA72-4 were\nidentified in 75 patients with ovarian cancer and 75 patients with endometrioma. Cut-off levels for\nCA125 and CA72-4 were considered 35 U/ml and 3.8 U/ml, respectively. The data have been analyzed by\nSPSS, with a p-value<0.05 considered significant. Both markers CA125 and CA72-4 were remarkably\nelevated in EOC (p=0.001). Areas under the ROC curve for CA125 and CA72-4, with sensitivity of 0.48\nand specificity of 0.52, were 0.633 and 0.624, respectively. The differences were not significant. It has\nbeen shown that CA125 and CA72-4 serum levels are elevated in patients with EOC; however, this did\nnot lead to detection of malignancy. This means that CA72-4 level does not demonstrate a significant\ndifference in malignancy diagnoses when compared to the use of CA125 alone.\nKeywords: CA125, CA72-4, Epithelial ovarian cancer, Endometrioma.\nAccepted on March 01, 2018\nIntroduction\nOvarian cancer is the seventh-most prevalent cancer worldwide\nand comprises about 35% of reproductive system malignancies\nin women [1]. Today, it represents the fifth-most common\nreason of deaths caused by malignancies among women. The\nmajority of women who suffer from ovarian cancer have\nunspecific and enigmatic signs which lead to late diagnosis at\nprogressed stages of the cancer. The chance of survival for this\ntype of cancer is less than 20% after the 5 th y. Practically, less\nthan 25% of ovarian tumors are diagnosed in the early stages\nof the disease, while most patients have metastatic symptoms\n[2]. To ameliorate the prognosis and diagnose ovarian cancer in\nthe early stages, new and effective techniques are needed to be\ndeveloped.\nA large number of women with ovarian cysts and pelvic\nmasses undergo surgery. A recent study has shown that patients\ndiagnosed with ovarian tumors have a high chance of survival\nupon surgical operation and tumor removal [3]. It is very\nimportant to evaluate the risk of ovarian cancer by pelvic mass\nassessment and by referring patients to the suitable health care\ncentres [4]. Today, pre-symptomatically, the CA125 tumor\nmarker is used to diagnose ovarian cancer [5]. This marker\nappears in 80% of progressed ovarian cancers (>35 U/ml)\ncomparing with 50% of stage I epithelial cancers [6,7]. This\nmeans that the serum level of CA125 rises abnormally in non-\novarian cancers such as endometrial, pancreas, lung, breast and\ncolorectal cancers. Therefore, this marker has diminished\nspecificity and cannot be used in diagnosis of endometrial\ncancer [5]. Moreover, CA125 levels are generally higher under\nthe condition of benign non-gynecological diseases; such as\ntuberculosis, liver cirrhosis, pregnancy or different phases of\nmenstruation [8]. Several studies have shown that\nendometrioma increases CA125 levels, but due to its low\nspecificity in differentiation, clinically it has a low value [9].\nCA72-4 is another biomarker that rises in response to ovarian\nadenocarcinoma, stomach cancer, colon cancer and breast\ncancer [10]. This marker can be simultaneously evaluated\nISSN 0970-938X\nwww.biomedres.info\nBiomed Res 2018 Volume 29 Issue 8 1697\nBiomedical Research 2018; 29 (8): 1697-1701\n\nalong other biomarkers; such as CA125. Notably, CA72-4\nlevels do not increase in response to pregnancy and\nmenstruation phases, thus it is worthwhile to trace these tumor\nmarkers in patients suffering from ovarian epithelial tumors\n[6,11]. Recent studies have shown that CA125 and CA72-4\nmarkers, when used together, demonstrate high specificity in\ndiagnosis of ovarian cancers and high levels of these factors\nsynchronically, or CA72-4 singularly, provide the highest\naccuracy rate in diagnosis of the disease [12,13].\nIn patients with ovarian endometrioma, surgical treatment\nresults in adverse effects in the form of destruction of the\novarian tissue and loss of egg resources. Unfortunately, this\ntype of surgery is unavoidable in patients who are under\novarian stimulatory treatments for infertility or those that are\nsuspected for ovarian epithelial malignancies. In women with\nhigh serum level of CA72-4, this marker can discriminate\novarian epithelial cancer (13). Specificity of CA72-4 (90%) in\novarian cancer was significantly higher than CA125 (67%).\nHowever, in endometerioma, the specificity of CA125 (56.1%)\nwas higher than that of CA72-4 (7%) [11]. Regarding the\nimportance of differentiation between endometrioma and\novarian cancer, this study evaluated the diagnostic values of\ntwo tumor markers CA125 and CA72-4.\nMaterials and Methods\nStudy population\nThis prospective study was conducted from June 2014 to May\n2016 in the oncology and surgery section of the Alzahra\nEducational Hospital of Tabriz, with permission from the\nEthics Committee of Tabriz University of Medical Sciences\ncode no 935 in accordance with the principles outlined in the\nDeclaration of Helsinki. 150 women diagnosed with an ovarian\ncyst or pelvic mass through sonography (scheduled to undergo\nsurgery for mass removal) were eligible for enrolment in the\nstudy. Exclusion criteria included chronic disease, history of\nany cancer and previous chemotherapy, current hormonal\ntherapy and pregnancy. Seventy five patients signed with\novarian cancer through clinical and laboratory data were placed\nin the malignant group, while the other half, who was\ndiagnosed with benign tumors, was selected for the benign\ngroup. Patients diagnosed with ovarian cancer were\ndifferentiated based on the Federation of Obstetrics and\nGynecology Guidelines (FIGO); however the type, stage and\ngrade of tumor were determined later. All patients signed the\nconsent declaration form [14].\nLaboratory analysis\n5 ml of peripheral blood samples were drawn from all and\nwithin an hour were centrifuged at 3000 rpm for 10 min at 4°C.\nThereafter, blood samples were dispensed into 5 cm3 cryotubes\nand were kept at -80°C.\nCA125 level was analyzed using commercial\nchemiluminescent enzyme immunoassay (MyBioSource Co,\nSan Diego, USA).\nSerum biomarker level was measured for CA72-4 using ELISA\nkit (IBL, Hamburg, Germany). All assays were carried out by\npersonnel who had no knowledge on t clinical history of the\npatients. Additionally, all surgical samples were processed for\npathological examination by a gynecologic pathologist, and\neach diagnosis was reviewed and classified as either benign or\nmalignant.\nStatistical analysis\nStatistical analysis was performed using SPSS, version 21.0\n(SPSS Inc., Chicago, IL). Normal distribution of variables was\ndefined by the Kolmogorov-Smirnov test. The results of\ncontinuous normally distributed variables were shown as the\nmean ± standard deviation (SD). Nonparametric statistical\ntests, such as the Mann-Whitney U test or Pearson’s chi-square\ntest, were utilized to evaluate the statistical significance of\ndifferences between groups when appropriate. Normally\ndistributed continuous variables were compared using\nStudent’s t test and non-normally distributed variables,\nanalyzed by the Mann-Whitney U test. ANOV A was applied\nfor other clinical parameters. p values of less than 0.05 were\nconsidered statistically significant.\nResults\nThe mean age of patients was 40.5 ± 13.7 y. 75 women\ndiagnosed with ovarian endometrioma (mean age: 33.6 ± 8.1 y,\nrange: 16-58) were classified as the benign ovarian tumor\ngroup, and the remaining 75 patients with ovarian carcinoma\nwere parted as the malignant group (mean age: 47.3 ± 14.6 y\nold, range: 24-79). Histology confirmed the diagnosis, and\nstaging was conducted according to FIGO [14]. Serous\nadenocarcinoma was found the most common malignant tumor\ntype of the ovary (53%), whereas patients diagnosed with stage\n3 (65.3%) and grade 3 (69.3%) were more frequent.\nCA125 and CA72-4 serum biomarker levels were assessed in\nboth groups. In patients from the benign group, the average\nCA125 level was 131.0 ± 242.0 U/mL, while in other group,\nthe average level was 255.3 ± 349.4 U/mL. The mean\ndifference in CA125 levels between both benign and malignant\ngroups was statistically significant (p=0.005).\nFor the benign group, the average CA72-4 level was 2.6 ± 6.5\nU/mL, while in the malignant group; the average level for this\nbiomarker was 3.5 ± 5.5 U/mL. The difference in CA72-4\nlevels between both groups was statistically significant\n(p=0.003).\nTable 1. Frequency distribution of patients with malignant ovarian\ntumor; histopathology, tumor grade and stage (n=75).\nHistology Frequency Percentage\nSerous cyst adenocarcinoma 40 0.53\nMucinous cystadenoma 17 0.23\nEndometrioid adenocarcinoma 12 0.16\nClear cell adenocarcinoma 6 0.08\nMehri/Farnaz/Ali/Parvin/Elaheh/Marziyeh/Parvin/Parvin/Mojtaba\n1698 Biomed Res 2018 Volume 29 Issue 8\n\nStage FIGO\nI 3 0.04\nII 18 0.24\nIII 49 0.654\nIV 5 0.0666\nTumor grade\n1 9 0.12\n2 14 0.186\n3 52 0.693\nTable 1 demonstrates the values of CA125 and CA72-4 in\npatients with malignant tumors based on their different stages\nand grades. The difference between the average level of\nCA125 in patients in stages I-II (early stages) of ovarian cancer\nin comparison to the average level of CA125 in patients in\nstage III-IVs (advanced stages) was not statistically significant\n(p=0.763). The average CA72-4 level in patients in stage I-II\nof ovarian cancer was not statistically significant (p=0.176).\nThe mean serum levels of CA125 and CA72-4 in the malignant\ngroup with grades of 1and 2 were not statistically significant in\ncomparison to patients with grade 3 ovarian cancer (Table 2).\nTable 2.  Serum level of CA72-4 and CA125 of malignant ovarian\ntumor in various stages and grades (n=75).\n \nCA 72-4 (U/mL) CA 125 (U/mL)\nMean ± SD Mean ± SD\nStage FIGO\nI+II 6.6 ± 4.27 397.7 ± 297.3\nIII+IV 5.1 ± 3.25 331 ± 239.05\np value 0.176 0.763\nTumor grade\n1+2 7.6 ± 5.02 212 ± 182.2\n3 4.3 ± 2.9 392 ± 287.7\np value 0.572 0.895\nThe mean level of CA125 in benign ovarian masses was 131.0\n± 242.0 U/mL, whereas the mean level of CA125 in malignant\nepithelial tumors was 255.3 ± 349.4 U/mL, the latter of which\nwas statistically significant (p=0.005). The mean level of\nCA72-4 in benign ovarian masses was 2.69 ± 6.5 U/mL,\nwhereas the mean level of CA72-4 in malignant epithelial\ntumors was 3.5 ± 5.5 U/mL, the latter of which was statistically\nsignificant (p=0.003).\nIn patients with benign ovarian masses, the mean CA125 level\nin menopausal women was 292.6 ± 398.1 U/mL, while in non-\nmenopausal women it was 234.9 ± 322.7 U/mL. Considering\np=0.68, there were no meaningful statistical differences\nbetween the two groups of menopausal and non-menopausal\nwomen.\nThe mean CA72-4 in menopausal women was 4.1 ± 4.9 U/mL,\nand in non-menopausal women it was 3.15 ± 5.9 U/mL.\nConsidering p=0.19, there were no meaningful statistical\ndifferences between the two groups.\nFinally, diagnostic performance of the discriminating\nbiomarkers between malignant and benign ovarian tumors was\nassessed using ROC analysis. The resulting accuracy (ROC\nArea) values for CA125 and CA72-4 and their corresponding\nROC curves are shown in Figure 1. The AUC of these methods\nwas calculated, and no significant differences were observed\n(Figure 1).\nFigure 1.  ROC curve for evaluation of two tumor makers in the\ndiagnosis of ovarian malignancy.\nBased on ROC analysis, if 63.3 is considered as the cut-off\nvalue for CA125, the sensitivity is equal to 48% and the\nspecificity is equal to 52%. Regarding CA72-4, when 62.4 is\nconsidered to be the cut-off value; the sensitivity level is\ncalculated 48% and the specificity level as 50%. The\ncombination of CA125 and CA72-4 had a cut-off value at\n62.5% (Figure 1). Thus, the inclusion of additional markers did\nnot significantly increase the sensitivity. Analysis of the area\nunder the ROC curve showed that there were no statistically\nsignificant differences in sensitivity, when CA125 and CA72-4\nwere combined.\nDiscussion\nEndometriosis is a health and fertility threat that often occurs\nin adolescent females, even before the onset of menstruation.\nSeveral studies reported delay in diagnosis of endomerioma\nand EOC [15]. There are reasons to believe that delay in\ndiagnosis of endomerioma and EOC may cause serious damage\nin young women and endanger their normal life and fertility as\na major global public health problem [16,17]. The differential\ndiagnosis of epithelial ovarian cancer and endometrioma is\ncrucial and non-specific symptoms may result in serious\nproblems for the patient. The current diagnosis of\nendometrioma is based on the clinical and imaging technique\nevaluations which are confirmed by surgery along with\nhistological examination. Although, CA125 is applied in\ndiagnostic and prognostic approaches, but this marker has a\nDiagnostic value of tumor biomarkers CA125 and CA72-4 in differentiation of epithelial ovarian cancer and\nendometrioma\nBiomed Res 2018 Volume 29 Issue 8 1699\n\nlimited specificity to differentiate between endometriosis and\novarian cancer [13]. Recently, many attempts were made to\nfind new tumor markers to develop a simple blood test for\nearly detection of epithelial ovarian malignancies, however\nfailed to conquer the high mortality rate of the disease.\nCombinations of multi- tumor biomarkers have been proven to\namplify the sensitivity of the early stages diagnosis in\ncomparison to that of a single type [18].\nIn this study, we monitored the CA125 and CA72-4 levels in\novarian masses of 75 benign patients versus 75 malignant\nsubjects.\nConfirming previous studies, CA125 level was elevated in\n80% of patients with epithelial ovarian cancers, but in only half\nof them at the early stages of the disease [13,19-22].\nUnfortunately, the sensitivity and specificity of CA125 in\ndetection of the early stages of cancer were too low to have\nclinical value [23-25].\nCA125 has also been examined to predict the presence of an\novarian malignancy in women diagnosed with a pelvic mass.\nFor example, O’Connell et al. showed that a CA125 level\nabove 65 U/ml in postmenopausal women with a pelvic mass\nhad a sensitivity level of 98% in predicting the presence of an\novarian malignancy [26]. Likewise, other studies have shown\nthat premenopausal patients with serum CA125 levels between\n35 U/ml and 65 U/ml have a 50% to 60% risk of ovarian\ncancer [27,28]. The sensitivity and specificity levels of any\nsingle or multiple serum biomarkers would need to be\nsignificantly higher than that achieved with serum CA125\nalone in order to be useful as a triage test before surgery. Thus,\nour results are in concordance with previous studies which\nreported that CA 125 is not a trustworthy marker in the\ndifferential diagnosis between endometrioma and epithelial\novarian cancer [5,13].\nIn addition, we demonstrated that CA125 and CA72-4, alone\nor in combination, do not have sufficient ability to discriminate\nmalignant ovarian tumors in the early or advanced stages.\nAlso, we found that both markers have been elevated\nconsiderably in the epithelial ovarian cancers in comparison\nwith endometrioma, and both markers showed a similar statue\nof sensitivity. These findings contrast the study of Anastasi et\nal., who found that CA72-4 is an effective factor in\ndistinguishing between a malignancy and endometriosis\n[11,13].\nIn 2008, Moore and colleagues calculated AUC for several\nbiomarkers and their combinations. They demonstrated that the\nprognostic value for CA125=82.5% and for CA72-4=77.5%,\nwith a 95% confidence level [5]. They suggested that the\ncombination of HE4+CA125+CA72-4 could distinguish\nbenign cysts from malignancies, with a 95% confidence level\n[5]. The prognostic value of CA125+CA72-4 was mascaraed\n62.7%, with 90% specificity. We found a prognostic value of\n62.5% for the CA125+CA72-4, which is consistent with\nMoore’s study [5].\nConclusion\nOur findings confirm that CA125 and CA72-4 are not\nsufficient to differentiate between epithelial ovarian cancer and\nendometrioma, and additional markers such as HE4 may\nimprove the level of sensitivity. Moreover, pelvic imaging\nsimilar to that of the risk assessment of malignancy indexes\nwould be useful for the triage of patients with benign pelvic\nmass or ovarian cancer.\nAcknowledgments\nThe authors gratefully acknowledge all the health personnel\nand patients who participated in the study, in addition to the\ndata collectors, supervisors and administrative staff of Alzahra\nHospital, Tabriz, Iran. Special thanks to Research Vice\nChancellor Tabriz University of Medical Sciences for all the\nmaterial and financial support.\nFinancial Disclosure\nThere is no financial disclosure.\nFunding Support\nThis article was supported by Research Vice Chancellor of\nTabriz University of Medical Sciences, Tabriz, Iran.\nReferences\n1. Weiderpass  E, Labrèche F. Malignant tumors of the female\nreproductive system. Safety and Health at Work 2012; 3:\n166-180.\n2. Prat J. Staging classification for cancer of the ovary,\nfallopian tube, and peritoneum. Int J Gynecol Obstetr 2014;\n124: 1-5.\n3. 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Obstetr Gynecol\n1988; 72: 23-27.\n*Correspondence to\nSepasi Farnaz\nWomen’s Reproductive Health Research Center\nTabriz University of Medical Sciences\nTabriz\nIran\n \nDiagnostic value of tumor biomarkers CA125 and CA72-4 in differentiation of epithelial ovarian cancer and\nendometrioma\nBiomed Res 2018 Volume 29 Issue 8 1701","source_license":"CC0","license_restricted":false}