Risk factors for recurrence of ovarian endometriomas after surgical treatment: retrospective cohort study

Aim. To identify risk factors for recurrence of ovarian endometriomas after surgical treatment.

Materials and methods. The retrospective cohort study included 82 patients operated on for the first time for ovarian endometriomas, the follow-up period was 30 months. The recurrence developed in 19 patients (group 1), in 63 the recurrence was not diagnosed (group 2). Data prior to surgery (clinical characteristics, level CA-125), during surgery (cytokine concentration in peritoneal fluid, immunohistochemical analysis in capsule of ovarian endometriomas), postoperative therapy were evaluated as risk factors for recurrence. The Mann-Whitney U-test, the Fisher exact test was used to compare the groups. Specificity, sensitivity, accuracy, AUC ROC and threshold values were calculated.

Results. The recurrence rate of ovarian endometriomas was 23%. There were no differences between groups according to age, proportion of smokers, body mass index, gynecological anamnesis, obstetric status and postoperative hormone therapy. Preoperative concentrations of CA-125 in group 1 were higher than in group 2: 62.5 U/ml [40.7; 112.3] vs 40.3 U/ml [20.3; 68.8], р < 0.05. The concentration of IL-6, IL-8, TNFα, IL-1β, IL-17, VEGF, MCP 1 in peritoneal fluid taken during surgery was statistically significantly higher in group 1. The highest AUC ROC was received for VEGF 0.875 (0.778–0.973) and IL-8 0.953 (0.896–1.009). For VEGF the threshold value was 125.6 pg/ml, sensitivity 100%, specificity 71%, accuracy 79.8%. For IL-8 the threshold value was 128.78 pg/ml, sensitivity 93%, specificity 87.1%, accuracy 88.9%. In group 1, higher expression values of VEGF and CD34 angiogenesis markers in ovarian endometriomas were recorded. The highest AUC ROC was noted for CD34 — 0.844 (0.683–1.000), threshold value was 2.5%, sensitivity 90%, specificity 75%, accuracy 80.8%.

Conclusion. Risk factors for recurrence of ovarian endometriomas after operative treatment include VEGF and IL-8 levels in peritoneal fluid and expression of CD34 in the capsule.

1. Protasova A.EH., Vandeeva E.N., Kuz’mina N.S. Ehndometrioz — dobrokachestvennoe zabolevanie? Sovremennye diskussionnye aspekty ehndometrioz-assotsiirovannykh opukholei yaichnika. [Endometriosis — a benign disease? Modern debatable aspects of endometriosis-associated ovarian tumors]. Russian Journal of Human Reproduction = Problemy reproduktsii. 2016; 22 (5): 98– 109 (In Russian). https://doi.org/10.17116/repro201622598-109

2. Popova O. S. Kletki immunnoi sistemy kak biomarkery v diagnostike ehndometrioza. [Cells of the immune system as biomarkers in the diagnosis of endometriosis]. Russian Journal of Human Reproduction = Problemy reproduktsii. 2019; 25(2): 8–15 (In Russian). https://doi.org/10.17116/repro2019250218

3. Fassbender A., Overbergh L., Verdrengh E., et al. How can macroscopically normal peritoneum contribute to the pathogenesis of endometriosis? Fertility and sterility. 2011; 96 (3): 697–9. https://doi.org/10.1016/j.fertnstert.2011.06.034 PMID: 21762896

4. Mita S., Aznaurova Y.B., Zhumataev M.B., et al. Molecular aspects of development and regulation of endometriosis. Reproductive Biology and Endocrinology. 2014; 12: 50–68. https://doi.org/10.1186/1477-7827-12-50 PMID: 24927773

5. Adamyan L. V., Andreeva E.N. Rol’ sovremennoi gormonmoduliruyushchei terapii v kompleksnom lechenii, genital’nogo ehndometrioza. [Role of modern hormone-modulating therapy in the complex treatment of genital endometriosis]. Russian Journal of Human Reproduction = Problemy reproduktsii. 2011; 17(6): 66–67 (In Russian).

6. Ouchi N., Akira S., Mine K., et al. Recurrence of ovarian endometrioma after laparoscopic excision: risk factors and prevention. Journal of obstetrics and gynaecology research (Tokyo, Japan). 2014; 40(1): 230–6. https://doi.org/10.1111/jog.12164 PMID: 24102958

7. Davydov A.I., Strizhakova M.A., Orlov O. N. Klinicheskaya otsenka ehkspressii leptina i interleikina-6 pri ehndometrioze yaichnikov. [A clinical evaluation of the expression of leptin and interleukin-6 in ovarian endometriosis]. Vopr. ginekol. akus. perinatol. (Gynecology, Obstetrics and Perinatology) 2005; 2(4): 44–9 (In Russian).

8. Dubrovina S.O., Berlim YU.D., Krasil’nikova L.V., et al. Prognozirovanie retsidiva ehndometrioidnykh kist yaichnika vo vremya pervichnogo operativnogo vmeshatel’stva. [Prediction for recurrence of ovarian endometriomas during primary surgical interventions]. Tavricheskiy Mediko-Biologicheskiy Vestnik. 2018; 21(2): 26–30 (In Russian).

9. Pshenichnyuk E.YU., Asaturova A.V., Adamyan L.V., Zaitsev N.V. Prognozirovanie rannego retsidivirovaniya ehndometrioidnykh kist yaichnikov posle operativnogo lecheniya: faktory riska i profilaktiki. [Predictive factors of ovarian endometrioma of recurrence after laparoscopic excision: risk factors and prevention]. Russian Journal of Human Reproduction = Problemy reproduktsii. 2018; 24(2): 97–107 (In Russian). https://doi.org/10.17116/repro201824297-107

10. Wickiewicz D., Chrobak A., Gmyrek G.B., et al. Diagnostic accuracy of interleukin-6 levels in peritoneal fluid for detection of endometriosis. Archives of Gynecology and Obstetrics. 2013; 288 (4): 805–14. https://doi.org/10.1007/s00404-013-2828-6 PMID: 23553197

11. Funamizu А., Fukui А., Kamoi М., et al. Expression of natural cytotoxicity receptors on peritoneal fluid natural killer cell and cytokine production by peritoneal fluid natural killer cell in women with endometriosis. American journal of reproductive immunology. 2014; 71(4): 359–67. https://doi.org/10.1111/aji.12206 PMID: 24495049

12. Tobiume Т., Kotani Y., Takaya H., et. al. Determinant factors of postoperative recurrence of endometriosis: difference between endometrioma and pain. European journal of obstetrics, gynecology and reproductive biology. 2016; 205: 54–9. https://doi.org/10.1016/j.ejogrb.2016.07.516

13. Guzel A.I., Topcu H.O., Ekilinc S., et al. Recurrence factors in women underwent laparoscopic surgery for endometrioma. Minerva Chir. 2014; 69(5): 277–82. PMID: 25267018

14. Li X.Y., Chao X.P., Leng J.N., et al. Risk factors for postoperative recurrence of ovarian endometriosis: long-term follow-up of 358 women. Journal of Ovarian Research. 2019; 12(1): 79. https://doi.org/10.1186/s13048-019-0552-y PMID: 31470880

15. Adamyan L.V., Sonova M.M., Arslanyan K.N., et al. Osobennosti khronicheskoi tazovoi boli u patsientok s naruzhnym genital’nym ehndometriozom. [Features of chronic pelvic pain in patients with external genital endometriosis]. Lechaschi Vrach. 2019; 9: 3–87 (In Russian). https://www.lvrach.ru/2019/09/15437391

16. McKinnon B., Bersinger N.A., Wotzkow C., Mueller M.D. Endometriosis-associated nerve fibers, peritoneal fluid cytokine concentrations, and pain in endometriotic lesions from different locations. Fertility and sterility. 2012; 97 (2): 373–80. https://doi.org/10.1016/j.fertnstert.2011.11.011 PMID: 22154765

17. Zolbin М.М., Mamillapalli R., Nematian S.E., et al. Adipocyte alterations in endometriosis: reduced numbers of stem cells and microRNA induced alterations in adipocyte metabolic gene expression. Reproductive biology and endocrinology: RB&E. 2019; 17(6): 36. https://doi.org/10.1186/s12958-019-0480-0

18. Holdsworth-Carson S.J., Rogers P.A.W. The complex relationship between body mass index and endometriosis. Journal of endometriosis and pelvic pain disorders. 2018; 10(4): 187–9. https://doi.org/10.1177/2284026518810586

19. Bebneva T. N., Damirovа K.F. Vospalitel’nye zabolevaniya organov malogo taza. [Inflammatory diseases of the pelvic organs]. Gynecology. 2019; 5: 39–44 (In Russian).

20. Lin J., Gu Y. Effect of monocyte chemoattractant protein-1 and estradiol on the secretion of vascular endothelial growth factor in endometrial stromal cells in vitro. Fertility and sterility. 2005; 84(6): 1793–6. https://doi.org/10.1016/j.fertnstert.2005.03.090

21. Smith S. K. Regulation of angiogenesis in the endometrium. Trends Endocrinology and Metabolism. 2001; 12(4): 147–51. https://doi.org/10.1016/s1043-2760(01)00379-4 PMID: 11295569

22. Pittatore G., Moggio A., Benedetto C., et al. Endometrial adult/ progenitor stem cells: pathogenetic theory and new antiangiogenic approach for endometriosis therapy. Reprod Sci. 2014; 21(3): 296–304. https://doi.org/10.1177/1933719113503405 PMID: 24037753

23. Pavlov R. V., Kundokhova M.S. Immunologicheskie kriterii rannego prognozirovaniya retsidivov naruzhnogo genital’nogo ehndometrioza. [Immunological criteria for early prediction of recurrence of external genital endometriosis]. Medical news of the North Caucasus. 2011; 1: 39–43 (In Russian).

24. Markar’yan I.V., Ermolova N.V., Linde V.A., et al. Markery proliferatsii i apoptoza pri naruzhnom genital’nom ehndometrioze. [Markers of proliferation and apoptosis in external genital endometriosis]. Tavricheskiy Mediko-Biologicheskiy Vestnik. 2015; 18(1): 145–9 (In Russian).

25. Pydra A.R., Pavlov R.V., Aksenenko V.A. Kundokhova M.S. Osobennosti immunnoi disfunkii pri retsidivirovanii naruzhnogo genital’nogo ehndometrioza. [Features of immune dysfunction in the recurrence of external genital endometriosis]. Medical news of the North Caucasus. 2011; 4: 55–8 (In Russian).

26. Kondrat’eva P.G., Sokolov D.I., Kolobov A.V. Uchastie faktorov angiogeneza v razvitii naruzhnogo genital’nogo ehndometrioza. [Participation of angiogenesis factors in the development of external genital endometriosis]. Journal of obstetrics and women’s diseases. 2007; 56(3): 70–4 (In Russian).

27. Chanturiya T. Z. Rol’ immunologicheskikh faktorov pri razvitii razlichnykh form ehndometrioza. [the Role of immunological factors in the development of various forms of endometriosis]. Aktual’nye problemy meditsiny i biologii. 2018; 3: 25–30 (In Russian).

28. Sazonova N. G., Salmina A.B., Makarenko T.A. Neoangiogenez v razvitii ehndometrioza (obzor literatury). [Neoangiogenesis in the development of endometriosis (literature review)]. Problems of reproduction = Problemy reproduktsii. 2017; 23 (3): 12–8 (In Russian). https://doi.org/10.17116/repro201723312-18