Histological and Immunohistochemical Characterization of the Similarity and Difference Between Ovarian Endometriomas and Deep Infiltrating Endometriosis
Restricted accessResearch articleFirst published online March, 2018
Histological and Immunohistochemical Characterization of the Similarity and Difference Between Ovarian Endometriomas and Deep Infiltrating Endometriosis
Ovarian endometrioma (OMA) and deep infiltrating endometriosis (DIE) have long been recognized to have different histology and, as such, postulated to be 2 separate disease entities. Few studies, however, have attempted to elucidate the causes for their differences. Making use of ectopic endometrial tissue samples from 25 and 20 women with OMA and DIE, respectively, and control endometrial tissue samples from 25 women without endometriosis, we conducted an immunohistochemical analysis to evaluate the expression of a group of carefully chosen markers for epithelial–mesenchymal transition (EMT), fibroblast-to-myofibroblast transdifferentiation (FMT), smooth muscle metaplasia (SMM), fibrosis, vascularity, hormonal receptors, and proteins involved in epigenetic modifications. We found that both OMA and DIE lesions exhibited the same cellular changes consistent with EMT, FMT, SMM, and fibrosis as already shown in animal models. Compared to OMA, DIE lesions underwent more thorough and extensive EMT, FMT, and SMM and, consequently, displayed significantly higher fibrotic content but less vascularity. The 2 conditions also showed different expression levels of hormonal receptors. Both OMA and DIE lesions, especially the latter, showed significantly higher staining of enhancer of zeste homolog 2, H3K9me3, and H3K27me3 than that of control endometrium, suggesting progressive epigenetic changes concomitant with cellular ones. Finally, proteins that are known to be involved in fibrogenesis, such as thymocyte differentiation antigen 1 and peroxisome proliferator-activated receptor γ , were also aberrantly expressed under both conditions. The many similarities shared by both OMA and DIE indicate that the 2 conditions may actually share the same pathogenesis/pathophysiology. Their differences, however, suggest that the source of these differences may result from the different lesional microenvironments.
Von RokitanskyC. Ueber uterusdrusen-neubildung in uterus and ovarilsarcomen. Z Gesellschaft Aerzte Wein. 1860;186:445–473.
3.
RedwineDB. Age-related evolution in color appearance of endometriosis. Fertil Steril. 1987;48(6):1062–1063.
4.
NisolleMCasanas-RouxFAnafVMineJMDonnezJ. Morphometric study of the stromal vascularization in peritoneal endometriosis. Fertil Steril. 1993;59(3):681–684.
5.
BrosensIA. Is mild endometriosis a progressive disease?Hum Reprod. 1994;9(12):2209–2211.
6.
HarirchianPGashawILipskindST. Lesion kinetics in a non-human primate model of endometriosis. Hum Reprod. 2012;27(8):2341–2351.
7.
JenkinsSOliveDLHaneyAF. Endometriosis: pathogenetic implications of the anatomic distribution. Obstet Gynecol. 1986;67(3):335–338.
8.
GylfasonJTKristjanssonKASverrisdottirGJonsdottirKRafnssonVGeirssonRT. Pelvic endometriosis diagnosed in an entire nation over 20 years. Am J Epidemiol. 2010;172(3):237–243.
9.
KoninckxPRMartinDC. Deep endometriosis: a consequence of infiltration or retraction or possibly adenomyosis externa?. Fertil Steril. 1992;58(5):924–928.
10.
KoninckxPRUssiaAAdamyanLWattiezADonnezJ. Deep endometriosis: definition, diagnosis, and treatment. Fertil Steril. 2012;98(3):564–571.
11.
AnafVSimonPFaytINoelJ. Smooth muscles are frequent components of endometriotic lesions. Hum Reprod. 2000;15(4):767–771.
12.
KoninckxPR.Biases in the endometriosis literature. Illustrated by 20 years of endometriosis research in Leuven. Eur J Obstet Gynecol Reprod Biol. 1998;81(2):259–271.
13.
TostiCPinzautiSSantulliPChapronCPetragliaF. Pathogenetic mechanisms of deep infiltrating endometriosis. Reprod Sci. 2015;22(9):1053–1059
14.
NisolleMDonnezJ. Peritoneal endometriosis, ovarian endometriosis, and adenomyotic nodules of the rectovaginal septum are three different entities. Fertil Steril. 1997;68(4):585–596.
15.
WuYKajdacsy-BallaAStrawnE. Transcriptional characterizations of differences between eutopic and ectopic endometrium. Endocrinology. 2006;147(1):232–246.
16.
GarryR. Is insulin resistance an essential component of PCOS?: the endometriosis syndromes: a clinical classification in the presence of aetiological confusion and therapeutic anarchy. Hum Reprod. 2004;19(4):760–768.
17.
BrosensIA. Endometriosis—a disease because it is characterized by bleeding. Am J Obstet Gynecol. 1997;176(2):263–267.
18.
GuoSWDingDShenMLiuX. Dating endometriotic ovarian cysts based on the content of cyst fluid and its potential clinical implications. Reprod Sci. 2015;22(7):873–883.
19.
ZhangQDuanJOlsonMFazleabasAGuoSW. Cellular changes consistent with epithelial-mesenchymal transition and fibroblast-to-myofibroblast transdifferentiation in the progression of experimental endometriosis in baboons. Reprod Sci. 2016;23(10):1409–1421.
20.
ZhangQDuanJLiuXGuoSW. Platelets drive smooth muscle metaplasia and fibrogenesis in endometriosis through epithelial-mesenchymal transition and fibroblast-to-myofibroblast transdifferentiation. Mol Cell Endocrinol. 2016;428:1–16.
21.
ItogaTMatsumotoTTakeuchiH. Fibrosis and smooth muscle metaplasia in rectovaginal endometriosis. Pathol Int. 2003;53(6):371–375.
22.
KhareVKMartinDCEltorkyM. A comparative study of ovarian and pelvic wall-infiltrating endometriosis. J Am Assoc Gynecol Laparosc. 1996;3(2):235–239.
23.
MatsuzakiSDarchaC. Involvement of the Wnt/beta-catenin signaling pathway in the cellular and molecular mechanisms of fibrosis in endometriosis. PLoS One. 2013;8(10):e76808.
24.
MechsnerSBartleyJLoddenkemperCSalomonDSStarzinski-PowitzAEbertAD. Oxytocin receptor expression in smooth muscle cells of peritoneal endometriotic lesions and ovarian endometriotic cysts. Fertil Steril. 2005;83(suppl 1):1220–1231.
25.
LiuXShenSQiQZhangHGuoSW. Corroborating evidence for platelet-induced epithelial-mesenchymal transition and fibroblast-to-myofibroblast transdifferentiation in the development of adenomyosis. Hum Reprod. 2016;31(4):734–749.
26.
ShenMLiuXZhangHGuoSW. Transforming growth factor β1 signaling coincides with mediated epithelial-mesenchymal transition and fibroblast-to-myofibroblast transdifferentiation in drive the development of adenomyosis in mice. Hum Reprod. 2016. In press.
27.
ZhangQLiuXGuoSW. Progressive development of endometriosis and its hindrance by anti-platelet treatment in mice with induced endometriosis. Reprod Biomed Online. 2017;34(2):124–136.
28.
KamergorodskyGRibeiroPAGalvaoMA. Histologic classification of specimens from women affected by superficial endometriosis, deeply infiltrating endometriosis, and ovarian endometriomas. Fertil Steril. 2009;92(6):2074–2077.
29.
SchweppeKWDmowskiWPWynnRM. Ultrastructural changes in endometriotic tissue during danazol treatment. Fertil Steril. 1981;36(1):20–26.
30.
SchweppeKWWynnRM. Endocrine dependency of endometriosis: an ultrastructural study. Eur J Obstet Gynecol Reprod Biol. 1984;17(2-3):193–208.
31.
AbraoMSNemeRMCarvalhoFMAldrighiJMPinottiJA. Histological classification of endometriosis as a predictor of response to treatment. Int J Gynaecol Obstet. 2003;82(1):31–40.
32.
ZhangQDongPLiuXSakuragiNGuoSW. Enhancer of Zeste homolog 2 (EZH2) induces epithelial-mesenchymal transition in endometriosis. Sci Rep, in press.
33.
BulunSEMonsavaisDPavoneME. Role of estrogen receptor-beta in endometriosis. Semin Reprod Med. 2012;30(1):39–45.
34.
NoyesRWHamanJO. Accuracy of endometrial dating; correlation of endometrial dating with basal body temperature and menses. Fertil Steril. 1953;4(6):504–517.
35.
HagoodJSPrabhakaranPKumblaP. Loss of fibroblast Thy-1 expression correlates with lung fibrogenesis. Am J Pathol. 2005;167(2):365–379.
36.
MannJChuDCMaxwellA. MeCP2 controls an epigenetic pathway that promotes myofibroblast transdifferentiation and fibrosis. Gastroenterology. 2010;138(2):705–714, 14 e1–e4.
37.
LongQLiuXQiQGuoSW. Chronic stress accelerates the development of endometriosis in mouse through adrenergic receptor beta2. Hum Reprod. 2016;31(11):2506–2519.
38.
DingDLiuXDuanJGuoSW. Platelets are an unindicted culprit in the development of endometriosis: clinical and experimental evidence. Hum Reprod. 2015;30(4):812–832.
39.
KoumasLKingAECritchleyHOKellyRWPhippsRP. Fibroblast heterogeneity: existence of functionally distinct Thy 1(+) and Thy 1(−) human female reproductive tract fibroblasts. Am J Pathol. 2001;159(3):925–935.
40.
PeetersLLVigneJLTeeMKZhaoDWaiteLLTaylorRN. PPAR gamma represses VEGF expression in human endometrial cells: implications for uterine angiogenesis. Angiogenesis. 2005;8(4):373–379.
41.
HasegawaTHasegawaFHiroseTSanoTMatsunoY. Expression of smooth muscle markers in so called malignant fibrous histiocytomas. J Clin Pathol. 2003;(56):666–671.
RegeTAHagoodJS. Thy-1 as a regulator of cell-cell and cell-matrix interactions in axon regeneration, apoptosis, adhesion, migration, cancer, and fibrosis. FASEB J. 2006;20(8):1045–1054.
44.
BulunSEChengYHPavoneME. Estrogen receptor-beta, estrogen receptor-alpha, and progesterone resistance in endometriosis. Semin Reprod Med. 2010;28(1):36–43.
45.
HornungDWaiteLLRickeEABentzienFWallwienerDTaylorRN. Nuclear peroxisome proliferator-activated receptors alpha and gamma have opposing effects on monocyte chemotaxis in endometriosis. J Clin Endocrinol Metab. 2001;86(7):3108–3114.
46.
McKinnonBBersingerNAHuberAWKuhnAMuellerMD. PPAR-gamma expression in peritoneal endometriotic lesions correlates with pain experienced by patients. Fertil Steril. 2010;93(1):293–296.
47.
XueQLinZChengYH. Promoter methylation regulates estrogen receptor 2 in human endometrium and endometriosis. Biol Reprod. 2007;77(4):681–687.
SignorilePGCampioniMVincenziBD’AvinoABaldiA. Rectovaginal septum endometriosis: an immunohistochemical analysis of 62 cases. In Vivo. 2009;23(3):459–464.
50.
MeyerJLZimbardiDPodgaecSAmorimRLAbraoMSRainhoCA. DNA methylation patterns of steroid receptor genes ESR1, ESR2, and PGR in deep endometriosis compromising the rectum. Int J Mol Med. 2014;33(4):897–904.
51.
VinciGArkwrightSAudebourgA. Correlation between the clinical parameters and tissue phenotype in patients affected by deep-infiltrating endometriosis. Reprod Sci. 2016;23(9):1258–1268.
52.
NoelJCChapronCBucellaD. Estrogen and progesterone receptors in smooth muscle component of deep infiltrating endometriosis. Fertil Steril2010;93(6):1774–1777.
53.
Barcena de ArellanoMLGerickeJReicheltU. Immunohistochemical characterization of endometriosis-associated smooth muscle cells in human peritoneal endometriotic lesions. Hum Reprod. 2011;26(10):2721–2730.
54.
BoyleDPMcCluggageWG. Peritoneal stromal endometriosis: a detailed morphological analysis of a large series of cases of a common and under-recognised form of endometriosis. J Clin Pathol. 2009;62(6):530–533.
55.
ClementPB. The pathology of endometriosis: a survey of the many faces of a common disease emphasizing diagnostic pitfalls and unusual and newly appreciated aspects. Adv Anat Pathol. 2007;14(4):241–260.
56.
MaiKTYazdiHMPerkinsDGParksW. Pathogenetic role of the stromal cells in endometriosis and adenomyosis. Histopathology. 1997;30(5):430–442.
57.
DossBJWanekSMJacquesSMQureshiFRamirezNCLawrenceWD. Ovarian smooth muscle metaplasia: an uncommon and possibly underrecognized entity. Int J Gynecol Pathol. 1999;18(1):58–62.
58.
FukunagaM. Smooth muscle metaplasia in ovarian endometriosis. Histopathology. 2000;36(4):348–352.
59.
BonteHChapronCVieiraM. Histologic appearance of endometriosis infiltrating uterosacral ligaments in women with painful symptoms. J Am Assoc Gynecol Laparosc. 2002;9(4):519–524.
60.
van KaamKJSchoutenJPNapAWDunselmanGAGroothuisPG. Fibromuscular differentiation in deeply infiltrating endometriosis is a reaction of resident fibroblasts to the presence of ectopic endometrium. Hum Reprod. 2008;23(12):2692–2700.
61.
LeyendeckerGHerbertzMKunzGMallG. Endometriosis results from the dislocation of basal endometrium. Hum Reprod. 2002;17(10):2725–2736.
StovallDWAnnersJAHalmeJ. Immunohistochemical detection of type I, III, and IV collagen in endometriosis implants. Fertil Steril. 1992;57(5):984–989.
64.
MatsuzakiSCanisMDarchaCDechelottePPoulyJLBruhatMA. Fibrogenesis in peritoneal endometriosis. A semi-quantitative analysis of type-I collagen. Gynecol Obstet Invest. 1999;47(3):197–199.
65.
QiuJJLiuMHZhangZXChenLPYangQCLiuHB. Transvaginal color Doppler sonography predicts ovarian interstitial fibrosis and microvascular injury in women with ovarian endometriotic cysts. Acta Obstet Gynecol Scand. 2012;91(5):605–612.
66.
Fernandez-ShawSShorterSCNaishCEBarlowDHStarkeyPM. Isolation and purification of human endometrial stromal and glandular cells using immunomagnetic microspheres. Hum Reprod. 1992;7(2):156–161.
67.
ZhouYHagoodJSMurphy-UllrichJE. Thy-1 expression regulates the ability of rat lung fibroblasts to activate transforming growth factor-beta in response to fibrogenic stimuli. Am J Pathol. 2004;165(2):659–669.
68.
VariscoBMAmbalavananNWhitsettJAHagoodJS. Thy-1 signals through PPARgamma to promote lipofibroblast differentiation in the developing lung. Am J Respir Cell Mol Biol. 2012;46(6):765–772.
69.
SandersYYKumblaPHagoodJS. Enhanced myofibroblastic differentiation and survival in Thy-1(−) lung fibroblasts. Am J Respir Cell Mol Biol. 2007;36(2):226–235.
70.
SandersYYTollefsbolTOVariscoBMHagoodJS. Epigenetic regulation of thy-1 by histone deacetylase inhibitor in rat lung fibroblasts. Am J Respir Cell Mol Biol. 2011;45(1):16–23.
71.
NeveuWAMillsSTStaitiehBSSueblinvongV. TGF-beta1 epigenetically modifies Thy-1 expression in primary lung fibroblasts. Am J Physiol Cell Physiol. 2015;309(9):C616–C626.
72.
OvertonCEFernandez-ShawSHicksBBarlowDHStarkeyP. In vitro culture of endometrial stromal and gland cells as a model for endometriosis: the effect of peritoneal fluid on proliferation. Fertil Steril. 1997;67(1):51–56.
73.
LiTHeHLiuRWangSXPuDM. Isolation and identification of epithelial and stromal stem cells from eutopic endometrium of women with endometriosis. Eur J Obstet Gynecol Reprod Biol. 2014;178:89–94.
74.
HornungDKlingelKDohrnKKandolfRWallwienerDTaylorRN. Regulated on activation, normal T-cell-expressed and -secreted mRNA expression in normal endometrium and endometriotic implants: assessment of autocrine/paracrine regulation by in situ hybridization. Am J Pathol. 2001;158(6):1949–1954.
75.
LebovicDIKavoussiSKLeeJBanuSKAroshJA. PPARgamma activation inhibits growth and survival of human endometriotic cells by suppressing estrogen biosynthesis and PGE2 signaling. Endocrinology. 2013;154(12):4803–4813.
76.
KonKIkejimaKHiroseM. Pioglitazone prevents early-phase hepatic fibrogenesis caused by carbon tetrachloride. Biochem Biophys Res Commun. 2002;291(1):55–61.
77.
DantasATPereiraMCde Melo RegoMJ. The role of PPAR Gamma in systemic sclerosis. PPAR Res. 2015;2015:124624.
78.
HinzBPhanSHThannickalVJ. Recent developments in myofibroblast biology: paradigms for connective tissue remodeling. Am J Pathol. 2012;180(4):1340–1355.
79.
GuoSW. Epigenetics of endometriosis. Mol Hum Reprod. 2009;15(10):587–607.
80.
LiXLiuXGuoSW. Histone deacetylase inhibitors as therapeutics for endometriosis. Exp Rev Obstet Gynecol. 2014;7:451–466.
GuoSWYanDLiuX. Sensory nerve-derived substance P (SP) and calcitonin gene-related peptide (CGRP) promote fibrogenesis in endometriosis. In: The 13th World Congress on Endometriosis. Vancouver, British Columbia; 2017.
83.
DonnezOSoaresMDefrereS. Nerve fiber density in deep nodular endometriotic lesions induced in a baboon experimental model. Fertil Steril. 2013;100(4):1144–1150.
84.
AnafVEl NakadiIDe MoorVChapronCPistofidisGNoelJC. Increased nerve density in deep infiltrating endometriotic nodules. Gynecol Obstet Invest2011;71(2):112–117.
85.
BrosensIGordtsSBenagianoG. Endometriosis in adolescents is a hidden, progressive and severe disease that deserves attention, not just compassion. Hum Reprod. 2013;28(8):2026–2031.
86.
RedwineDB. Ovarian endometriosis: a marker for more extensive pelvic and intestinal disease. Fertil Steril. 1999;72(2):310–315.
Supplementary Material
Please find the following supplemental material available below.
For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.
For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.
