{"paper_id":"72ab04e5-187d-43a3-b7cd-181c36bd2272","body_text":"Abohashim et al. \nMiddle East Fertility Society Journal           (2024) 29:15  \nhttps://doi.org/10.1186/s43043-024-00174-w\nRESEARCH Open Access\n© The Author(s) 2024. Open Access  This article is licensed under a Creative Commons Attribution 4.0 International License, which \npermits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the \noriginal author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or \nother third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line \nto the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory \nregulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this \nlicence, visit http:// creat iveco mmons. org/ licen ses/ by/4. 0/.\nMiddle East Fertility\nSociety Journal\nPreoperative predictive parameters \nfor accurate detection of stage IV endometriosis\nMohmed Fathy Abohashim1, Waleed M. Etman1, Mohamed A. Wasfy1, Amany M. Abdallah2, \nEnas Mahmoud Hamed3, Mona Mahmoud Eladl3, Sherif Yehia Mohammed4, Ola A. Harb5*, Fawaz E. Edris6,7, \nAhmed Baker A. Alshaikh8 and Mohamed Elbakry Lashin1 \nAbstract \nBackground Surgery is the main line of treatment of endometriosis. Patients with stage IV endometriosis have more \nextensive adhesions, which make the surgery difficult. There are no accurate non-invasive predictive preoperative \nparameters of stage IV endometriosis and no consensus has been reached.\nTherefore, the aim of the present study was to evaluate and detect preoperative non-invasive parameters \nfor the detection of stage IV endometriosis.\nPatients and methods In the present study, we included 150 females admitted for surgical removal of endome-\ntriosis. We scored and classified endometriosis into four stages according to the revised ASRM classification. We \ncompared between baseline characteristics of patients with different stages of endometriosis, and then we selected \nthe best combination of diagnostic and predictive parameters of stage IV endometriosis.\nResults Predictors of stage IV endometriosis and indicators for safety surgery were as follows: VAS ≥ 4 (p < 0.001), fixed \nuterus (p = 0.005), fixed ovarian cysts (p < 0.001), tender uterosacral ligament nodule (p < 0.001), tender rectovaginal \nseptum nodule (p = 0.003), bilateral endometriosis (p < 0.001), and sum of sizes of endometriotic nodules (p < 0.001).\nConclusion Fixed uterus, fixed ovarian cysts, tender uterosacral ligament nodule, tender rectovaginal septum nod-\nule, bilateral endometriosis, and indications for surgery were significantly considered adequate predictive markers \nfor stage IV endometriosis.\nKeywords Stage IV endometriosis, Predictive models, Surgery\n*Correspondence:\nOla A. Harb\nolaharb2015@gmail.com\n1 Department of Gynecology and Obstetrics, Faculty of Medicine, Zagazig \nUniversity, Zagazig, Egypt\n2 Department of Family Medicine, Faculty of Medicine, Zagazig University, \nZagazig, Egypt\n3 Department of Clinical Radiology, Faculty of Medicine, Zagazig \nUniversity, Zagazig, Egypt\n4 Department of Clinical Pathology, Zagazig University Faculty \nof Medicine, Zagazig University, Zagazig, Egypt\n5 Department of Pathology, Zagazig University Faculty of Medicine, \nZagazig University, Zagazig 44519, Egypt\n6 Department of Obstetrics and Gynecology, Faculty of Medicine, Umm \nAl-Qura University, Makkah, Saudi Arabia\n7 Assisted Conception Unit at the International Medical Centre, Jeddah, \nSaudi Arabia\n8 Department of Obstetrics and Gynecology, College of Medicine, Jouf \nUniversity, Sakaka, Saudi Arabia\n\nPage 2 of 6Abohashim et al. Middle East Fertility Society Journal           (2024) 29:15 \nIntroduction\nEndometriosis, which is a chronic disease that is char -\nacterized by the presence of endometrial-like tissue \noutside the uterine cavity has a prevalence rate of 10%, \nleads to pain and infertility and inversely affects the life \nquality of patients [1 ]. \nThe revised American Fertility Society (r-AFS) clas -\nsification system was applied for staging endometriosis \nand classified it into four stages: I (minimal), II (mild), \nIII (moderate), and IV (severe) (revised- ASRM classifi -\ncation of endometriosis 1996).\nSurgery is the main line of treatment of endometrio -\nsis. Patients presented with stage IV endometriosis have \nmore extensive pelvic adhesions which make surgery to \nbe more difficult. Additionally, surgical management \nof ovarian endometriosis might lead to a reduction in \novarian reserve [2 ]. Detection of predictive non-inva -\nsive preoperative parameters for patients with stage IV \nendometriosis lead to adequate preparation for surgery \nin addition to allow using gonadotropin-releasing hor -\nmone (GnRH) agonists preoperatively for reducing pel -\nvic congestion, decreasing the size of lesions, reducing \nsurgery difficulty, and increasing its safety.\nThere are no accurate non-invasive predictive pre -\noperative parameters of stage IV endometriosis, and \nno consensus was reached [3 ]. Conroy showed that the \nonly predictor for stage IV endometriosis is increas -\ning age [4 ]. Guo et al. advised using imaging for better \nprediction of stage IV endometriosis [5 ]. Therefore, the \naim of the present study was to evaluate and detect pre -\noperative non-invasive parameters for the detection of \nstage IV endometriosis.\nPatients and methods\nIn the present study, we included all females admitted \nfor surgical removal of endometriosis in the Depart -\nment of Obstetrics and Gynecology, Faculty of Medi -\ncine, Zagazig University from March 2017 to May 2023.\n• The inclusion criteria: patients with accurate post-\noperative diagnosis of endometriosis who need \nsurgical management. Indications for surgery in \nincluded patients were primary infertility, ovar -\nian cysts with high suspicion of endometriosis by \ntrans-vaginal ultrasonography, and pain and ovar -\nian cysts by trans-vaginal ultrasonography.\n• The exclusion criteria: patients with adenomyo -\nsis, myoma, malignant gynecological tumor, ovar -\nian benign tumor, presence of pelvic inflammatory \ndisease, and patients presented with endometriosis \naccidentally detected at the time of surgery.\nNo patients received preoperative GnRH or any other \nmedications.\nDiagnosis of endometriosis was done according to \nlaparoscopic visual evidence followed by histo-patho -\nlogical confirmation.\nWe scored and classified endometriosis into four \nstages according to the revised ASRM classification.\nWe recorded all clinical data, such as chief complaint, \nage at the first visit, previous pregnancies, and chief \ncomplaint. Different types of pain were recorded as fol -\nlows: dysmenorrhea, dyspareunia, dyschezia, and non-\ncyclic abdominal or pelvic pain.\nWe performed a visual analogue scale (VAS) for \nmeasuring the intensity of the pain (from 0, no pain to \n10, unbearable pain).\nVAS was routinely recorded in the patient history, \nand patients with missed data were excluded.\nWe performed a complete pelvic examination; we \nrecorded the presence of fixed uterine, fixed ovarian \ncysts, and the presence of a tended nodule in the utero -\nsacral ligament, or rectovaginal septum.\nWe detected and recorded accurate size, bilaterality \nand multiplicity of lesions by transvaginal ultrasound.\nWe compared between baseline characteristics of \npatients with different stages of endometriosis, and \nthen we selected the best combination of diagnostic \nand predictive parameters of stage IV endometriosis.\nThis study was approved by the local ethical commit -\ntee of the Faculty of Medicine, Zagazig University.\nStatistical analysis\nData analysis was performed using the software SPSS \n(Statistical Package for the Social Sciences) version 26. \nCategorical variables were described using their abso -\nlute frequencies and were compared using chi square \ntest and Fisher exact when appropriate. Shapiro–Wilk \ntest was used to verify assumptions for use in para -\nmetric tests. Quantitative variables were described \nusing their means and standard deviations or median \nand interquartile range according to the type of data. \nTo compare quantitative data between two groups, \nthe independents sample t  test (for normally distrib -\nuted data) and Mann–Whitney test (for not normally \ndistributed data) were used. Binary logistic regression \nwas used to identify independent risk factors associ -\nated with certain health problems and to identify fac -\ntors included in the predictive model. The ROC curve \nwas used to determine the best cutoff of the predictive \nmodel in the diagnosis of certain health problems. The \nlevel of statistical significance was set at p  < 0.05. Highly \nsignificant difference was present if p  ≤ 0.001.\n\nPage 3 of 6\nAbohashim et al. Middle East Fertility Society Journal           (2024) 29:15 \n \nResults\nBaseline characteristics of selected patients include 19 \ncases of stage I endometriosis (12.7%), 9 cases of stage II \nendometriosis (6%), 53 cases of stage III endometriosis \n(35.3%), and 69 cases of stage IV endometriosis (46%). \nThe mean age was 33.23 years (Table 1 ).\nPredictors of stage IV endometriosis: Tables 2, 3 \nand 4\nThe following variables were different between patients \nwith stages I–III endometriosis (n = 81) and those \nwith IV endometriosis (n = 69): VAS ≥ 4 (p < 0.001), \nfixed uterus (p = 0.005), fixed ovarian cysts (p < 0.001), \ntender uterosacral ligament nodule (p < 0.001), \ntender rectovaginal septum nodule (p = 0.003), \nbilateral endometriosis (p < 0.001), sum of sizes of \nendometriotic nodules (p < 0.001), and indications for \nsurgery (p = 0.005). However, there is a non-significant \ndifference between them regarding age, sterility, previous \npregnancy, and CA-125 or hs-CRP .\nAll these parameters were significantly associated with \nstage IV endometriosis.\nAOR adjusted odds ratio CI confidence interval \n**p ≤ 0.001 is statistically highly significant.\nOn doing multivariate regression analysis, VAS \nscore ≥ 4, bilateral endometriosis, and the presence of \npainful nodules on the uterosacral ligament can increase \nthe risk of grade IV by 5.341, 12.678, and 14.433 folds, \nrespectively (Table 4, Fig. 1).\nA predictive score ≥ 13.5 can predict endometriosis \ngrade IV with the area under curve 0.844, sensitivity of \n55.1%, specificity of 96.3%, positive predictive value of \n71.6%, negative predictive value of 92.7%, and overall \naccuracy of 77.3%.\nTable 1 Baseline data of studied patients\nn = 150\nAge (year) [mean ± SD] 33.23 ± 5.7\nSterility; n (%) 4 (2.7%)\nPrevious pregnancy; n (%) 124 (82.7%)\nStage of endometriosis\n I 19 (12.7%)\n II 9 (6%)\n III 53 (35.31%)\n IV 69 (46%)\nVAS score ≥ 4; n (%) 56 (37.3%)\nBilateral EMS; n (%) 28 (18.7%)\nSum of size of EMS [mean ± SD] 5.96 ± 2.26\nPositive signs: n (%)\n Fixed uterine 40 (26.7%)\n Fixed ovarian cyst 103 (68.7%)\n Painful uterosacral ligament nodule 32 (21.3%)\n Painful rectovaginal septum nodule 13 (8.7%)\nCA-125 (U/ml) [median (IQR)] 45.9 (30.4–88.08)\nHs-CRP (mg/L) [median (IQR)] 5 (3–8)\nIndication of surgery: n (%)\n Pain 64 (42.7%)\n Others 86 (57.3%)\nTable 2 Relation between grade of endometriosis and studied parameters\n* p < 0.05 is statistically significant, **p ≤ 0.001 is statistically highly significant, χ2 chi square test\nEndometriosis grades I–III (n = 81) Endometriosis grade IV (n = 69) p\nAge (year) [mean ± SD] 33.5 ± 5.26 32.91 ± 6.2 0.526\nSterility; n (%) 1 (1.2%) 3 (4.3%) 0.334\nPrevious pregnancy; n (%) 67 (82.7%) 57 (82.6%) 0.986\nVAS score ≥ 4; n (%) 17 (21%) 39 (56.5%)  < 0.001**\nBilateral EMS; n (%) 3 (3.7%) 25 (36.2%)  < 0.001**\nSum of size of EMS [mean ± SD] 5.04 ± 1.37 7.03 ± 2.61  < 0.001**\nPositive signs: n (%)\n Fixed uterine 14 (17.3%) 26 (37.7%) 0.005*\n Fixed ovarian cyst 46 (56.8%) 57 (82.6%)  < 0.001**\n Painful uterosacral ligament nodule 3 (3.7%) 29 (42%)  < 0.001**\n Painful rectovaginal septum nodule 2 (2.5%) 11 (15.9%) 0.003*\nCA-125 (U/ml) [median (IQR)] 43.1(27.1–64) 49.8(40.15–108.45) 0.064\nHs-CRP (mg/L) [median (IQR)] 4(3–7.5) 5(3–8) 0.19\nIndication of surgery: n (%)\n Pain 26 (32.1%) 38 (55.1%)\n Others 55 (67.9%) 31 (44.9%) 0.005*\n\nPage 4 of 6Abohashim et al. Middle East Fertility Society Journal           (2024) 29:15 \nThis score was collectively reached from a detailed sta -\ntistical analysis of all parameters.\nSo, the predictive score had a good negative value \nhelped in the exclusion of endometriosis grade IV rather \nthan being a good positive test (Table 4, Fig. 2).\nDiscussion\nIn cases of endometriosis, it was found that laparoscopy \nis risky and costly, and additionally, open surgery may \nlead to damage and loss of advanced intervention oppor -\ntunities. Patient’s past medical history, symptoms such \nas different types of pain, signs detected during pelvic \nexaminations, data result from laboratory examinations, \nand radiological examinations might be beneficial in the \npreoperative diagnosis of endometriosis [3], but roles of \nthese parameters and other parameters in performing a \npredictive model for diagnosis and staging endometriosis \nwere not sufficiently studied.\nWe detected that fixed uterus, fixed ovarian cysts, ten -\nder uterosacral ligament nodule, tender rectovaginal sep -\ntum nodule, bilateral endometriosis, the sum of sizes of \nendometriotic nodules, and indications for surgery were \nsignificantly considered adequate predictive markers for \nstage IV endometriosis, and our results were in line with \nresults of Zhao et  al. [6], who found that for predicting \nstage IV endometriosis, there are 3 main clinical markers: \nVAS score, presence of painful nodules in uterosacral lig-\naments during pelvic examination, and presence of bilat -\neral lesions during transvaginal ultrasound examination.\nNnoaham et  al. [7] demonstrated that menstrual dis -\nturbances and a history of previous benign ovarian cysts \nwere strong predictors of stages III and IV endometriosis.\nIdentification of such non-invasive parameters leads \nto detection of females with priority of surgical manage -\nment, which is in line with our findings in such study.\nOur study is more representative and comprehensive \nin comparison to other studies because we added pelvic \nexamination, laboratory findings, and transvaginal ultra -\nsound similar to the results of previous reports [5, 8, 9]. \nSo, preoperative diagnosis could be done appropriately \nby the clinician for optimal therapeutic management and \nto decide whether or not to perform surgery and choose \nthe appropriate surgical approach.\nIn the present study, we showed that the VAS score was \ndifferent between patients with stages I–III endometrio -\nsis and patients with stage IV endometriosis; thus, stage \nTable 3 Multivariate regression analysis of factors associated \nwith endometriosis grade IV\n** p ≤ 0.001 is statistically highly significant\nβ p AOR 95% C.I\nLower Upper\nVAS score (≥ 4) 1.675  < 0.001** 5.341 2.262 12.607\nBilateral EMS 2.540  < 0.001** 12.678 3.232 49.734\nPainful nodules \non uterosacral liga-\nment\n2.670  < 0.001** 14.433 3.789 54.982\nTable 4 Performance of predictive score in diagnosis of endometriosis grade IV among studied patients\nAUC  area under curve, PPV positive predictive value, NPV negative predictive value\n** p 0.001 is statistically highly significant\nCutoff AUC Sensitivity Specificity PPV NPV Accuracy p\n ≥ 13.5 0.844 55.1% 96.3% 71.6% 92.7% 77.3%  < 0.001**\nFig. 1 Boxplot showing predictive score among patients with endometriosis grades I–III and IV\n\nPage 5 of 6\nAbohashim et al. Middle East Fertility Society Journal           (2024) 29:15 \n \nIV endometriosis increases with increasing VAS scores. \nMoreover, we showed a positive association between the \nstage of endometriosis and dysmenorrhoea and non-\nmenstrual pain severity which was similar to the results \nof [10]. Results were explained by that endometriosis-\nassociated chronic inflammation plays a role in pain \nsymptoms pathogenesis [11], and additionally, new nerve \nfiber growth increases stress and the presence of psy -\nchological factors [12]. It was previously found that the \npresence of pelvic adhesions is more important than the \ndiameter of the cyst as a cause of occurrence of pain [13], \nso, marked adhesions are accompanied by severe inflam -\nmatory response, difficult surgical procedures, and stage \nIV endometriosis.\nPrevious studies showed that the presence of symptoms \nis related to advanced endometriosis, but the association \nbetween intensity of pelvic pain and endometriosis sever-\nity was not proven [5, 14].\nWe showed that the presence of tender nodule in the \nuterosacral ligament during pelvic examination is an \nindicator of stage IV endometriosis similarly [15].\nPrevious studies showed that pelvic examination might \nlead to a preoperative prediction of severe endometrio -\nsis [16], which is more aggressive, multi-focal, and invade \nthe peritoneal surfaces [17].\nPatients with severe endometriosis are more liable to \nfixed uterine, uterosacral ligament nodule with tender -\nness, and rectovaginal septum nodule with tenderness \nwhich could be detected by preoperative pelvic exami -\nnation [18]. So, priority must be given to patients with \ntender uterosacral ligament nodules as an indicator for \nstage IV endometriosis [19].\nLimitations of our study\nFirst, the retrospective nature of the study leads to \nsome subjective bias, and as we aimed at detecting \nfixed predictive parameters, we need to make it based \non prospective analysis.\nSecond, we could not cover additional factors for pre -\noperative prediction of endometriosis severity, as direct \nnative IgG levels analysis in patients’ serum might be \nbeneficial diagnostic parameters for patients with \nmarked endometriosis [20]. Additionally, we did not \nuse MRI in the predictive models, but it is considered \na highly accurate diagnostic tool for preoperative sus -\npected endometriosis or Pascoal et al. [18].\nThird, we depend on patients with typical symptoms, \nbut it was previously demonstrated that not all patients \nwith stage IV endometriosis had typical symptoms that \nled to their accurate preoperative diagnosis.\nFig. 2 ROC curve showing performance of predictive score in the diagnosis of endometriosis grade IV among studied patients\n\nPage 6 of 6Abohashim et al. Middle East Fertility Society Journal           (2024) 29:15 \nIn conclusion\nIn the present study, we put an easily applicable predic -\ntive model for stage IV endometriosis depending on \nnon-invasive parameters such as preoperative patient \nsymptoms such as pain, dysmenorrhea, and VAS scores; \ncomplete pelvic examination; and imaging techniques \nsuch as transvaginal ultrasound. These findings could \nbe applied for preoperative detection of advanced \nendometriosis.\nAcknowledgements\nNot applicable\nAuthors’ contributions\nAll authors shared in designing and writing the manuscript, in data collection, \nand in statistical analysis.\nAuthors’ information\nNot applicable.\nFunding\nNo funds were received.\nAvailability of data and materials\nNot applicable.\nDeclarations\nEthics approval and consent to participate\nEthics approval and consent to participate are obtained from the local insti-\ntutional review board of the Faculty of Medicine, Zagazig University, Zagazig, \nEgypt.\nConsent for publication\n(NA) we have no individual person’s data.\nCompeting interests\nThe authors declare that they have no competing interests.\nReceived: 18 October 2023   Accepted: 27 February 2024\nReferences\n 1. Shafrir AL et al (2018) Risk for and consequences of endometriosis: a criti-\ncal epidemiologic review. Best Pract Res Clin Obstet Gynaecol 51:1–15\n 2. Kasaven LS et al (2022) Study protocol for a randomised controlled trial \non the use of intraoperative ultrasound-guided laparoscopic ovarian \ncystectomy (UGLOC) as a method of fertility preservation in the manage-\nment of benign ovarian cysts. BMJ Open 12(7):e060409\n 3. Agarwal SK et al (2019) Clinical diagnosis of endometriosis: a call to \naction. Am J Obstet Gynecol 220(4):354.e1-354.e12\n 4. Conroy I et al (2021) Pelvic pain: what are the symptoms and predictors \nfor surgery, endometriosis and endometriosis severity. Aust N Z J Obstet \nGynaecol 61(5):765–772\n 5. Guo Z et al (2020) Developing preoperative nomograms to predict \nany- stage and stage III-IV endometriosis in infertile women. Front Med \n7:570483\n 6. Zhao H, Zhang J, Bao ZL, Kong J, Wei W, Gu JQ (2023) A preopera-\ntive predictive model for stage IV endometriosis. J Obstet Gynaecol \n43(1):2188072\n 7. Nnoaham KE et al (2012) Developing symptom-based predictive models \nof endometriosis as a clinical screening tool: results from a multicenter \nstudy. Fertil Steril 98(3):692-701.e5\n 8. Rao T, Condous G, Reid S (2022) Ovarian immobility at transvaginal ultra-\nsound: an important sonographic marker for prediction of need for pelvic \nsidewall surgery in women with suspected endometriosis. J Ultrasound \nMed 41(5):1109–1113\n 9. Aas-Eng MK et al (2020) Transvaginal sonographic imaging and associ-\nated techniques for diagnosis of ovarian, deep endometriosis, and aden-\nomyosis: a comprehensive review. Semin Reprod Med 38(2–03):216–226\n 10. Vercellini P et al (2007) Association between endometriosis stage, lesion \ntype, patient characteristics and severity of pelvic pain symptoms: a \nmultivariate analysis of over 1000 patients. Hum Reprod 22:266–271\n 11. Signorile PG et al (2022) Endometriosis: a retrospective analysis of clinical \ndata from a cohort of 4,083 patients, with focus on symptoms. In Vivo \n36(2):874–883\n 12. Coxon L, Horne AW, Vincent K (2018) Pathophysiology of endometriosis-\nassociated pain: a review of pelvic and central nervous system mecha-\nnisms. Best Practice & Research. Clin Obstet Gynaecol 51:53–67\n 13. Kaya H et al (2005) Does the diameter of an endometrioma predict the \nextent of pelvic adhesions associated with endometriosis? J Reprod Med \n50(3):198–202\n 14. Apostolopoulos NV et al (2016) Association between chronic pelvic pain \nsymptoms and the presence of endometriosis. Archives of Gynecology \nand Obstetrics 293(2):439–445. ASRM 1997\n 15 Habib N et al (2022) Impact of lifestyle and diet on endometriosis: a \nfresh look to a busy corner. Prz Menopauzalny¼Menopause Review \n21(2):124–132\n 16. Zheng YM et al (2020) Incidence of deeply infiltrating endometriosis \namong 240 cases of pelvic endometriosis and analysis of its clinical and \npathological characteristics. Zhonghua Fu Chan Ke Za Zhi 55:384–389\n 17 Perelló M et al (2017) Markers of deep infiltrating endometriosis in \npatients with ovarian endometrioma: a predictive model. Eur J Obstet \nGynecol Reprod Biol 209:55–60\n 18. Pascoal E et al (2022) Strengths and limitations of diagnostic tools for \nendometriosis and relevance in diagnostic test accuracy research. Ultra-\nsound Obstet Gynecol 60:309–327\n 19. Kor E et al (2020) Relationship between the severity of endometriosis \nsymptoms (dyspareunia, dysmenorrhea and chronic pelvic pain) and the \nspread of the disease on ultrasound. BMC Res Notes 13(1):546\n 20. Sołkiewicz K et al (2022) The alterations of serum IgG Fucosylation as a \npotential additional new diagnostic marker in advanced endometriosis. J \nInflamm Res 15:251–266\nPublisher’s Note\nSpringer Nature remains neutral with regard to jurisdictional claims in pub-\nlished maps and institutional affiliations.","source_license":"CC0","license_restricted":false}