B-cell lymphoma 6; HSCORE; computer-assisted analysis; diagnosis; endometriosis; infertility; Medicine (all); General Medicine
Abstract :
[en] BCL6 (B-cell lymphoma 6) is a proto-oncogene and transcriptional repressor initially described as being involved in B-cell lymphoma. Recently, this factor has been identified as a promising tissue biomarker which could be used to diagnose women affected by endometriosis. Previous studies used HSCORE for BCL6 staining quantification in the endometrium. However, this semi-quantitative technique of analysis has some limitations, including a lack of objectivity, robustness, and reproducibility that may lead to intra- and inter-observer variability. Our main goal was to develop an original computer-assisted method to quantify BCL6 staining from whole-slide images reliably. In order to test the efficiency of our new digital method of quantification, we compared endometrial BCL6 expression between fertile and infertile women without or with different stages of endometriosis by using the widely used HSCORE analysis and our new automatic digital image analysis. We find a higher expression of BCL6 in the endometrium of infertile women with endometriosis and women with stage IV endometriosis. Furthermore, we demonstrate a significant correlation between the two types of independent measurements, indicating the robustness of results and also the reliability of our computer-assisted method for BCL6 quantification. In conclusion, our work, by using this original computer-assisted method, enables BCL6 quantification more objectively, reliably, robustly, and promptly compared to HSCORE analysis.
Disciplines :
Reproductive medicine (gynecology, andrology, obstetrics)
This research was supported by grants from the Fonds de la Recherche Scientifique—FNRS (F.R.S.-FNRS, Belgium, grant number T.0171.21 attributed to M.N. and grant J.0143.22 attributed to C.M.), the Foundation against Cancer (foundation of public interest, Belgium), the Fonds spéciaux de la Recherche (University of Liège), the Centre Anticancéreux près l’Université de Liège, and the Fondation Hospitalo Universitaire Léon Fredericq (FHULF, University of Liège).
Evans-Hoeker E. Lessey B.A. Jeong J.W. Savaris R.F. Palomino W.A. Yuan L. Schammel D.P. Young S.L. Endometrial BCL6 Overexpression in Eutopic Endometrium of Women with Endometriosis Reprod. Sci. 2016 23 1234 1241 10.1177/1933719116649711 27222232
Sansone A.M. Hisrich B.V. Young R.B. Abel W.F. Bowens Z. Blair B.B. Funkhouser A.T. Schammel D.P. Green L.J. Lessey B.A. et al. Evaluation of BCL6 and SIRT1 as Non-Invasive Diagnostic Markers of Endometriosis Curr. Issues Mol. Biol. 2021 43 96 10.3390/cimb43030096 34698105
Nezhat C. Rambhatla A. Miranda-Silva C. Asiaii A. Nguyen K. Eyvazzadeh A. Tazuke S. Agarwal S. Jun S. Nezhat A. et al. BCL-6 Overexpression as a Predictor for Endometriosis in Patients Undergoing In Vitro Fertilization J. Soc. Laparosc. Robot. Surg. 2020 24 e2020.00064 10.4293/JSLS.2020.00064 33414614
Nezhat C. Agarwal S. Lee D.A. Tavallaee M. Can we accurately diagnose endometriosis without a diagnostic laparoscopy? J. Turk. Ger. Gynecol. Assoc. 2022 23 117 119 10.4274/jtgga.galenos.2022.2022-2-2
Bunting K.L. Melnick A.M. New effector functions and regulatory mechanisms of BCL6 in normal and malignant lymphocytes Curr. Opin. Immunol. 2013 25 339 346 10.1016/j.coi.2013.05.003
Kumagai T. Miki T. Kikuchi M. Fukuda T. Miyasaka N. Kamiyama R. Hirosawa S. The proto-oncogene Bc16 inhibits apoptotic cell death in differentiation-induced mouse myogenic cells Oncogene 1999 18 467 475 10.1038/sj.onc.1202306
Hatzi K. Nance J.P. Kroenke M.A. Bothwell M. Haddad E.K. Melnick A. Crotty S. BCL6 orchestrates Tfh cell differentiation via multiple distinct mechanisms J. Exp. Med. 2015 212 539 553 10.1084/jem.20141380
Valls E. Lobry C. Geng H. Wang L. Cardenas M. Rivas M. Cerchietti L. Oh P. Yang S.N. Oswald E. et al. BCL6 Antagonizes NOTCH2 to Maintain Survival of Human Follicular Lymphoma Cells Cancer Discov. 2017 7 506 521 10.1158/2159-8290.CD-16-1189
Zondervan K.T. Becker C.M. Missmer S.A. Endometriosis N. Engl. J. Med. 2020 382 1244 1256 10.1056/NEJMra1810764
Vallve-Juanico J. Houshdaran S. Giudice L.C. The endometrial immune environment of women with endometriosis Hum. Reprod. Update 2019 25 564 591 10.1093/humupd/dmz018
Giacomini E. Minetto S. Li Piani L. Pagliardini L. Somigliana E. Vigano P. Genetics and Inflammation in Endometriosis: Improving Knowledge for Development of New Pharmacological Strategies Int. J. Mol. Sci. 2021 22 9033 10.3390/ijms22169033 34445738
Nisolle M. Alvarez M.L. Colombo M. Foidart J.M. Pathogenesis of endometriosis Gynecol. Obstet. Fertil. 2007 35 898 903 10.1016/j.gyobfe.2007.07.021 17714973
Zondervan K.T. Becker C.M. Koga K. Missmer S.A. Taylor R.N. Vigano P. Endometriosis Nat. Rev. Dis. Primers 2018 4 9 10.1038/s41572-018-0008-5 30026507
Vercellini P. Fedele L. Aimi G. Pietropaolo G. Consonni D. Crosignani P.G. Association between endometriosis stage, lesion type, patient characteristics and severity of pelvic pain symptoms: A multivariate analysis of over 1000 patients Hum. Reprod. 2007 22 266 271 10.1093/humrep/del339
Agarwal S.K. Chapron C. Giudice L.C. Laufer M.R. Leyland N. Missmer S.A. Singh S.S. Taylor H.S. Clinical diagnosis of endometriosis: A call to action Am. J. Obstet. Gynecol. 2019 220 354.e1 354.e12 10.1016/j.ajog.2018.12.039
Kiesel L. Sourouni M. Diagnosis of endometriosis in the 21st century Climacteric 2019 22 296 302 10.1080/13697137.2019.1578743
Hudson N. The missed disease? Endometriosis as an example of ‘undone science’ Reprod. Biomed. Soc. Online 2022 14 20 27 10.1016/j.rbms.2021.07.003
Koninckx P.R. Ussia A. Adamyan L. Tahlak M. Keckstein J. Wattiez A. Martin D.C. The epidemiology of endometriosis is poorly known as the pathophysiology and diagnosis are unclear Best Pract. Res. Clin. Obstet. Gynaecol. 2021 71 14 26 10.1016/j.bpobgyn.2020.08.005
Henry L. Vervier J. Boucher A. Brichant G. Gaspard O. Labied S. Munaut C. Ravet S. Nisolle M. Oocyte Cryopreservation in Patients with Endometriosis: Current Knowledge and Number Needed to Treat J. Clin. Med. 2022 11 4559 10.3390/jcm11154559
Simoens S. Dunselman G. Dirksen C. Hummelshoj L. Bokor A. Brandes I. Brodszky V. Canis M. Colombo G.L. DeLeire T. et al. The burden of endometriosis: Costs and quality of life of women with endometriosis and treated in referral centres Hum. Reprod. 2012 27 1292 1299 10.1093/humrep/des073
Eisenberg V.H. Decter D.H. Chodick G. Shalev V. Weil C. Burden of Endometriosis: Infertility, Comorbidities, and Healthcare Resource Utilization J. Clin. Med. 2022 11 1133 10.3390/jcm11041133
Hudelist G. English J. Thomas A.E. Tinelli A. Singer C.F. Keckstein J. Diagnostic accuracy of transvaginal ultrasound for non-invasive diagnosis of bowel endometriosis: Systematic review and meta-analysis Ultrasound Obstet. Gynecol. 2011 37 257 263 10.1002/uog.8858
Aas-Eng M.K. Montanari E. Lieng M. Keckstein J. Hudelist G. Transvaginal Sonographic Imaging and Associated Techniques for Diagnosis of Ovarian, Deep Endometriosis, and Adenomyosis: A Comprehensive Review Semin. Reprod. Med. 2020 38 216 226 10.1055/s-0040-1718740
Agrawal S. Tapmeier T. Rahmioglu N. Kirtley S. Zondervan K. Becker C. The miRNA Mirage: How Close Are We to Finding a Non-Invasive Diagnostic Biomarker in Endometriosis? A Systematic Review Int. J. Mol. Sci. 2018 19 599 10.3390/ijms19020599
May K.E. Conduit-Hulbert S.A. Villar J. Kirtley S. Kennedy S.H. Becker C.M. Peripheral biomarkers of endometriosis: A systematic review Hum. Reprod. Update 2010 16 651 674 10.1093/humupd/dmq009
Nisenblat V. Hull M.L. Biomarkers in Endometriosis How to Perform Ultrasonography in Endometriosis Guerriero S. Condous G. Alcázar J.L. Springer International Publishing Cham, Switzerland 2018 169 183 10.1007/978-3-319-71138-6_16
Slizewski D. Crowe R. Young S.L. Lessey B.A. Endometriosis is a common denominator in unexplained pregnancy loss and infertility based on BCL6 testing Fertil. Steril. 2015 104 e83 e84 10.1016/j.fertnstert.2015.07.257
Almquist L.D. Likes C.E. Stone B. Brown K.R. Savaris R. Forstein D.A. Miller P.B. Lessey B.A. Endometrial BCL6 testing for the prediction of in vitro fertilization outcomes: A cohort study Fertil. Steril. 2017 108 1063 1069 10.1016/j.fertnstert.2017.09.017
Likes C.E. Cooper L.J. Efird J. Forstein D.A. Miller P.B. Savaris R. Lessey B.A. Medical or surgical treatment before embryo transfer improves outcomes in women with abnormal endometrial BCL6 expression J. Assist. Reprod. Genet. 2019 36 483 490 10.1007/s10815-018-1388-x
Louwen F. Kreis N.N. Ritter A. Friemel A. Solbach C. Yuan J. BCL6, a key oncogene, in the placenta, pre-eclampsia and endometriosis Hum. Reprod. Update 2022 dmac027 10.1093/humupd/dmac027
Canis M. Donnez J.G. Guzick D.S. Halme J.K. Rock J.A. Schenken R.S. Vernon M.W. Revised American Society for Reproductive Medicine classification of endometriosis: 1996 Fertil. Steril. 1997 67 817 821 10.1016/s0015-0282(97)81391-x
Fedchenko N. Reifenrath J. Different approaches for interpretation and reporting of immunohistochemistry analysis results in the bone tissue—A review Diagn. Pathol. 2014 9 221 10.1186/s13000-014-0221-9 25432701
Otsu N. A Threshold Selection Method from Gray-Level Histograms IEEE Trans. Syst. Man Cybern. 1979 9 62 66 10.1109/TSMC.1979.4310076
Soille P. Morphological Image Analysis: Principles and Applications Springer Berlin/Heidelberg, Germany 1999 10.1007/978-3-662-03939-7
Lessey B.A. Implantation defects in infertile women with endometriosis Ann. N. Y. Acad. Sci. 2002 955 265 280 10.1111/j.1749-6632.2002.tb02787.x
Lessey B.A. Kim J.J. Endometrial receptivity in the eutopic endometrium of women with endometriosis: It is affected, and let me show you why Fertil. Steril. 2017 108 19 27 10.1016/j.fertnstert.2017.05.031
Vannuccini S. Clifton V.L. Fraser I.S. Taylor H.S. Critchley H. Giudice L.C. Petraglia F. Infertility and reproductive disorders: Impact of hormonal and inflammatory mechanisms on pregnancy outcome Hum. Reprod. Update 2016 22 104 115 10.1093/humupd/dmv044
Brichant G. Laraki I. Henry L. Munaut C. Nisolle M. New Therapeutics in Endometriosis: A Review of Hormonal, Non-Hormonal, and Non-Coding RNA Treatments Int. J. Mol. Sci. 2021 22 10498 10.3390/ijms221910498
