{"paper_id":"f0edb6c9-fb2b-4a02-b8a5-42613abb7a79","body_text":"225\n© 2016 The Korean Society of Pathologists/The Korean Society for Cytopathology\nThis is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/ \nby-nc/3.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.\npISSN 2383-7837\neISSN 2383-7845\nInvestigation of the Roles of Cyclooxygenase-2 and Galectin-3 Expression \nin the Pathogenesis of Premenopausal Endometrial Polyps\nEsin Kasap · Serap Karaarslan1 \nEsra Bahar Gur · Mine Genc \nNur Sahin · Serkan Güclü\nDepartments of Obstetrics and Gynecology and \n1Pathology, Sifa University School of Medicine, \nIzmir, Turkey\nBackground: The pathogenesis and etiology of endometrial polyps has not been elucidated. In \nthis study, we aimed to examine the pathogenic mechanisms of endometrial polyp development \nusing immunohistochemistry. We evaluated the expression of galectin-3 and cyclooxgenase-2 \n(COX-2) during the menstrual cycle in premenopausal women with endometrial polyps or normal \nendometrium. Methods: Thirty-one patients with endometrial polyps and 50 healthy control pa-\ntients were included in this study. The levels of expression of COX-2 and galectin-3 were studied \nby immunohistochemistry. Results: The percentage of COX-2–positive cells and the intensity of \nCOX-2 staining in the endometrium did not vary during the menstrual cycle either in the control \ngroup or in patients with endometrial polyps. However, expression of galectin-3 was significantly \nlower in endometrial polyps and during the proliferative phase of the endometrium compared \nwith the secretory phase. Conclusions: Our data suggests that the pathogenesis of endometrial \npolyps does not involve expression of COX-2 or galectin-3.\nKey Words: Endometrial polyps; Cyclooxgenase-2; Galectin-3; Immunohistochemistry\nReceived: January 13, 2016\nRevised: March 6, 2016\nAccepted: March 8, 2016\nCorresponding Author\nEsin Kasap, MD\nDepartment of Obstetrics and Gynecology,  \nSifa University School of Medicine,  \nFevzipasa Boulvard, No. 172/2, 35240,  \nBasmane/I˙zmir, Türkiye \nTel: +90-232-4460880\nFax: +90-232-4460770\nE-mail: dresincelik@windowslive.com\nJournal of Pathology and Translational Medicine 2016; 50: 225-230\nhttp://dx.doi.org/10.4132/jptm.2016.03.08\n▒ ORIGINAL ARTICLE ▒\nFocal endometrial projections containing endometrial glands \nand stroma are termed endometrial polyps.1 The reported prev-\nalence of endometrial polyps in premenopausal women with ab-\nnormal uterine bleeding is 33%, but only 10% in asymptom-\natic women.2 While endometrial polyps can occur in women of \nall ages, they are more common in women between the ages of \n40 and 49.3 Because endometrial polyps have not been reported \nto occur before the onset of menstruation, estrogenic stimulation \nis thought to be associated with endometrial polyp growth.4 \nHowever, the pathogenesis and etiology of endometrial polyps \nhas not been clearly determined. Endometrial polyps are be-\nlieved to form due to hormonal factors, e.g., estrogen and pro-\ngesterone, which mediate endometrial proliferation and differen-\ntiation via steroid receptors;5 however, the mechanisms involved \nin the development of endometrial polyps are still unclear. \nCyclooxygenase (COX) is a key enzyme involved in the con-\nversion of arachidonic acid to prostaglandins and other eico-\nsanoids. Two isoforms of COX have been identified: COX-1 and \nCOX-2. COX-1 is constitutively expressed in many tissues, \nwhereas COX-2 is induced by a variety of factors including cy-\ntokines, growth factors, and tumor promoters. COX-2, which \nis involved in inflammatory responses and production of prosta-\nglandins mediating uterine contractions, has been shown to in-\nduce excessive formation of some pro-angiogenic factors when \noverexpressed in colon cancer cell lines in vitro.6 Furthermore, \nrecent studies have shown the influence of COX-2 in neoplastic \ndevelopment.5 However, the relationship between COX-2 and \nendometrial polyps has not been well established.\nGalectin-3 is a β-galactoside–binding animal lectin that con-\ntains carbohydrate-recognition domains and is involved in a mul-\ntitude of biological tasks,7 including embryogenesis, growth, \ncell adhesion, proliferation, differentiation, cell-cycle progression, \napoptosis, mRNA splicing, and immune system regulation. Ga-\nlectin-3 is also involved in tumorigenesis, angiogenesis, and tu-\nmor metastasis, and is expressed in various cells and tissues in-\ncluding activated macrophages, eosinophils, neutrophils, mast \ncells, gastrointestinal and respiratory tract epithelial cells, kid-\nneys cells, and some sensory neurons.7,8 Interestingly, extracel-\nlular galectin-3 plays a role in inflammation, while intracellular \ngalectin-3 participates in cell growth and anti-apoptotic processes \n\n\nhttp://jpatholtm.org/ http://dx.doi.org/10.4132/jptm.2016.03.08\n226     •  Kasap E, et al.\nand modulates cell adhesion and migration.7\nPolyps tend to occur when apoptosis is inhibited and there is \nunopposed growth.9 However, the mechanisms mediating these \nendometrial alterations are unknown. Previous studies have sug-\ngested that endometrial polyps are a result of endometrial inflam-\nmation, i.e., endometritis, since the vessel axis of polyps has been \nshown to develop during endometritis.10 This finding suggests \nthat identification of markers of inflammation and tissue growth \nmay help to elucidate the pathogenic mechanisms of endometri-\nal polyps. Indeed, recent studies have shown that the levels of \nexpression of COX-2 and galectin-3 are increased during the \nprogression from hyperplasia to cancer in the endometrial tis-\nsue, suggesting that these proteins may play a role in tumor cell \nfunction. However, the association of COX-2 and galectin-3 \nexpression with polyps has not yet been established.\nTherefore, in this study, we analyzed the levels of expression of \nCOX-2 and galectin-3 in endometrial polyps and normal endo-\nmetrium using immunohistochemistry.\nMATERIALS AND METHODS\nPatients\nWe examined a total of 81 cases of endometrial tissues in pa-\ntients who were treated in the Department of Obstetrics and \nGynecology of our hospital. Tissues were sampled between 2012 \nand 2014. All procedures were approved by the I˙zmir Sifa Uni-\nversity Human Ethics Committee and followed the principles \nof the Declaration of Helsinki.\nAll patients were premenopausal (mean age, 37 years; range, \n27 to 52 years) and had a recent history of regular menstruation \n(cycle of 25–35 days). None of the women included in the study \nused nonsteroidal anti-inflammatory drugs, hormone replace-\nment therapy, or any other estrogen-containing pills. Thirty-one \nof the 81 patients had endometrial polyps, including 10 who had \nundergone hysterectomy and 21 who had undergone polypecto-\nmy and endometrial curettage. None of the patients had identi-\nfiable leiomyoma or adenomyosis by ultrasonography and/or \nmagnetic resonance imaging. The control group consisted of \nsamples from a total of 50 additional patients with normal en-\ndometrium, and included 23 samples collected during the pro-\nliferative phase and 27 samples collected during the secretory \nphase. Control patients were recruited from patients with benign \novarian cysts or a uterine prolapse but no other pathology, and \nthe endometrial samples in this group were collected during hys-\nterectomy procedures. Endometrial samples were grouped ac-\ncording to menstrual cycle phases: proliferative (days 1–14 of \nthe cycle) and secretory (days 15–28 of the cycle). The day of the \nmenstrual cycle was established from the women’s menstrual his-\ntory and confirmed by endometrial dating using the criteria de-\nscribed by Noyes et al.11\nImmunohistochemistry\nAll tissue samples were fixed in 10% formalin and sent to \npathology for analysis. Routine hematoxylin and eosin staining \nwas carried out in all samples either to confirm the diagnosis of \npolyps or to date the endometrium. Samples were embedded in \nparaffin blocks, cut into 4-μm-thick sections, and deparaffinized. \nThe sections were then stained with primary monoclonal anti-\nbodies against COX-2 (1:100, clone CX-294, Dako, Glostrup, \nDenmark) and galectin-3 (1:100, NCL-GAL3, clone 9C4, No-\nvaCastra, Hamburg, Germany) using a Dako Cytomation Au-\ntostainer (Dako). After staining, each sample was evaluated under \na light microscope (200×, Olympus BX53, Olympus, Tokyo, \nJapan) to determine the percentage of COX-2–positive cells, \nthe intensity of COX-2 staining, and the percentage of galec-\ntin-3–positive cells. For positive controls, staining of breast car-\ncinoma tissue for COX-2 and papillary thyroid carcinoma tis-\nsue for galectin-3 were used. Primary monoclonal antibodies \nwere omitted in negative controls.\nAssessment of COX-2 and galectin-3 staining\nSemi-quantitative analysis of immunostaining for COX-2 and \ngalectin-3 was performed as follows based on the percentage of \ncells with positive cytoplasmic staining: 0%, 0; < 10%, 1; 10%–\n50%, 2; 51%–80%, 3; and ≥ 80%, 4. In addition, staining in-\ntensity was evaluated as either negative (0), weak (1+), moderate \n(2+), or strong (3+). Semi-quantitative and intensity scores were \nanalyzed separately. Additionally, the positivity of cells was \nevaluated as positive or negative.12 COX-2 and galectin-3 ex-\npression was evaluated in glandular epithelial cells and stromal \ncells. Assessment of staining results was performed by one ob-\nserver in a blinded fashion.\nStatistical analysis\nStatistical analysis was performed using software (Rstudio \nsoftware ver. 0.98.501 via R language, R Studio Inc., Boston, \nMA, USA). Data describing continuous variables are presented \nas the mean ± standard deviation. The Kruskal-Wallis and Pear-\nson chi-square exact tests were used to compare continuous and \ncategorical variables, respectively. Differences with p-values less \nthan .05 were accepted as significant.\n\nhttp://jpatholtm.org/http://dx.doi.org/10.4132/jptm.2016.03.08\nCox-2 and Galectin-3 in Endometrial Polyps  •     227\nRESULTS\nPatient demographics \nThere was no statistically significant difference between the \nages of healthy control individuals and patients with endome-\ntrial polyps.\nCOX-2 expression\nImmunoreactivity for COX-2 was observed in glandular epi-\nthelial cells and stromal cells. COX-2–positive cells were pre-\ndominantly observed in the endometrial glandular epithelium, \nwhere expression peaked during the secretory phase. COX-\n2-positive cells were also observed in stromal cells, albeit to a \nlesser extent (Table 1, Fig. 1A). The percentage of COX-2–pos-\nitive cells and the intensity of COX-2 staining in stromal cells \nand glandular epithelial cells did not vary during different peri-\nods of the menstrual cycle in the control group or in patients \nwith endometrial polyps (Fig. 1B). Mean COX-2 scores in \nglandular epithelial cells and stromal cells were not significantly \ndifferent between endometrial polyp specimens and normal en-\ndometrium specimens (Table 1).\nGalectin-3 expression\nGalectin-3 immunoreactivity was present in the endometrial \nglandular epithelial cells and stromal cells. Immunostaining was \ntypically cytoplasmic. Galectin-3–positive cells were predomi-\nnantly observed in the endometrial glandular epithelium, where \nexpression levels peaked during the secretory phase. Galectin-3 \nexpression was also observed to a lesser extent in stromal cells \n(Table 2). The mean percentage score of galectin-3 expression \nwere lower both in endometrial polyps and the proliferative \nphase in normal endometrium than in the secretory phase in \nnormal endometrium (Table 2, Fig. 1C). In glandular epithelial \ncells, no statistically significant differences in galectin-3 expres-\nsion were found between endometrial polyps and normal endo-\nmetrium during the proliferative phase. However, in patients \nwith normal endometrium, galectin-3 expression was higher \nduring the secretory phase (p = .349) (Fig. 1C). Finally, there \nTable 1. Percentages of COX-2–positive cells and intensity of COX-2 staining\nProliferative phase Secretory phase Endometrial polyps p-value\nGlandular epithelial tissues COX-2 intensity 2.04 ± 1.02 2.07 ± 0.83 1.77 ± 1.11 .489\na\n0–1 7 6 12 .398b\n2–3 16 21 19\nCOX-2 percentage score 2.35 ± 1.12 2.67 ± 1.04 2.35 ± 1.38 .614\na\n0–1 4 3 8 .351\nb\n2–4 19 24 23\nEndometrial stroma COX-2 intensity 0.65 ± 0.71 0.70 ± 0.67 0.53 ± 0.68 .564\na\n0–1 20 24 27 .941\nb\n2–3 3 3 3\nCOX-2 percentage score 0.61 ± 0.65 0.81 ± 0.78 0.61 ± 0.76 .525\na\n0–1 21 21 26 .430\nb\n2–4 2 6 5\nValues are presented as mean ± standard deviation. \nCOX, cyclooxgenase.\nap-value for Kruskal-Wallis tests, bp-value for Pearson chi-square test.\nA B C\nFig. 1. Expression of cyclooxgenase 2 (COX-2) and galectin-3 in endometrium samples. (A) COX-2 expression in both the glandular epitheli-\num and stroma during the secretory phase. (B) COX-2 expression in both the glandular epithelium and stroma of an endometrial polyp. (C) \nGalectin-3 expression in both the glandular epithelium and stroma during the secretory phase.\n\nhttp://jpatholtm.org/ http://dx.doi.org/10.4132/jptm.2016.03.08\n228     •  Kasap E, et al.\nwere no differences in galectin-3 expression in stromal cells of en-\ndometrial polyps and those of the endometrium at any phase of \nthe menstrual cycle (Table 2).\nDISCUSSION\nIn this study, we compared galectin-3 and COX-2 expression \nand staining patterns using immunohistochemistry in endome-\ntrial polyps and normal endometrium during the secretory and \nproliferative phases. Our data indicated that both galectin-3 and \nCOX-2 were not associated with the formation of endometrial \npolyps.\nEstrogen is known to play a pivotal role in the pathogenesis of \nendometrial malignant and benign cancers. However, the role \nof estrogen biosynthesis from stromal cells of the endometrium \nand its impact on malignancies has not been fully elucidated. \nInterestingly, estrogens are known to activate COX-2 in endo-\nmetriosis, which increases levels of estradiol and prostaglandin \nabove normal in women.13 Therefore, the pathogenesis of peri-\ntoneal endometriosis may be a consequence of enhanced prosta-\nglandins in the eutopic endometrium that stimulate COX-2 ex-\npression and activity.14,15 This mechanism may also affect other \nendometrial pathologies, although no specific roles have been \ndescribed. \nCOX-2 is expressed at higher levels in the glandular epithelial \ncells of the endometrium during the secretory phase of the men-\nstrual cycle compared with the proliferative phase; however, its \nexpression is similar during the secretory and proliferative phases \nin endometrial stromal cells.16 In the present study, we observed \nthat COX-2 expression tended to be higher during the secreto-\nry phase than in either the proliferative phase or endometrial \npolyps in glandular epithelial cells. \nSome studies have suggested that endometrial polyps may \noriginate from endometrial inflammation.17 After demonstrating \nthat COX-2 is expressed in the epithelial lining of postmeno-\npausal polyps, Maia et al.18 concluded that COX-2 may be in-\nvolved in the regulation of polyp growth. Nevertheless, COX-2 \nexpression has not been shown to differ significantly between \nnormal endometrial tissue and endometrial polyps.19 \nIn 2006, Maia and colleagues compared COX-2 expression \nbetween endometrial polyps and normal endometrium in wom-\nen with a regular menstrual cycle and found no significant dif-\nference in COX-2 expression between polyps and the normal \nendometrium.19 In addition, Pinheiro et al.20 observed higher \nCOX-2 expression in the glandular epithelium of obese women \nthan in women of normal weight. This finding indicates that ex-\npression of COX-2 expression may be influenced by metabolic \nchanges and growth factors associated with obesity.20 Here, we \nalso demonstrated that COX-2 expression in the glandular epi-\nthelium and stromal cells in endometrial polyps did not differ \nsignificantly from that of normal endometrium. Thus, our data \nsuggest that COX-2 expression may not be associated with the \nformation of endometrial polyps.\nWe previously reported that expression of galectin-3 is aug-\nmented during the formation of the receptive endometrium and \nthe mid-secretory phase of the menstrual cycle.21 In addition, \nthere is mounting evidence for a strong relationship between \nembryo implantation and tumor invasion and metastasis. Inter-\nestingly, galectin-3 has been reported to have anti-apoptotic po-\ntential in tumor cells, although there is no evidence for the role \nof galectin-3 in endometrial cell apoptosis. Thus, we hypothe-\nsize that galectin-3 functions as an anti-apoptotic factor in the \nendometrium and may facilitate the development of endome-\ntrial polyps.\nChiu et al.22 found that immunohistochemical analysis of ga-\nlectin-3 protein expression is a sensitive, specific, and accurate \nmarker for the diagnosis of thyroid cancer and certain other can-\ncers.23 In endometriosis, Noel et al.24 found that galectin-3 pro-\ntein expression, as measured using immunohistochemistry, is \nhigher in endometriosis samples compared to eutopic endome-\ntrium, and also higher in the eutopic endometrium of women \nwith endometriosis compared to those without endometriosis. \nTogether, these data suggest that galectin-3 may have a poten-\ntial role in the development of endometriosis.24 In a study by \nBrustmann et al.,25 galectin-3 expression was assessed by immu-\nnohistochemistry in patients with normal endometrium, simple \nhyperplasia, complex hyperplasia without atypia, atypical hy-\nperplasia, endometrioid carcinoma, serous papillary carcinoma, \nand clear cell carcinoma. They showed that in normal endometri-\num, simple hyperplasia, and complex hyperplasia without atyp-\nTable 2. Percentages of galectin-3–positive cells\nProliferative phase Secretory phase Endometrial polyp p-value\nGalectin-3 glandular epithelial tissues (% score) 1.35 ± 1.19 2.19 ± 1.00 1.71 ± 1.16 .039\na\nGalectin-3 endometrial stroma (% score) 1.43 ± 1.12 1.63 ± 1.15 1.19 ± 0.87 .349\na\nValues are presented as mean ± standard deviation. \nap-value for Kruskal-Wallis tests.\n\nhttp://jpatholtm.org/http://dx.doi.org/10.4132/jptm.2016.03.08\nCox-2 and Galectin-3 in Endometrial Polyps  •     229\nia, the galectin-3 expression did not differ significantly among \nthese groups. Immunohistochemical expression of galectin-3 \nfor atypical hyperplasia and endometrioid carcinoma were signifi-\ncantly higher than those in the aforementioned groups. Serous \npapillary carcinoma and clear cell carcinoma, which are known \nto have a poorer prognosis than endometrioid carcinoma,26 also \ndemonstrated significantly elevated galectin-3 expression levels \nin this study. On the basis of these findings, we assumed that ga-\nlectin-3 expression may be related to the different biological be-\nhaviors of endometrialcarcinomas.25 Importantly, while there \nwas no difference in galectin-3 expression in glandular epitheli-\num and stromal cells of endometrial polyps and normal endo-\nmetrium, our data demonstrated that galectin-3 expression was \nsignificantly lower in both endometrial polyps and the prolifer-\native phase of the endometrium than in the secretory phase of \nthe endometrium. This finding suggests that larger-scale stud-\nies are needed to measure galectin-3 levels in secretory adeno-\ncarcinomas, a subgroup of endometrioid adenocarcinomas, and \nin other endometrial cancers.\nIn analyzing our results, we wondered whether galectin-3 ex-\npression may be regulated by estrogen and progesterone. Al-\nthough previous reports have shown that estrogen and/or pro-\ngesterone increases galectin-3 expression in endometrial cells at \nall concentrations,27 we did not observe any direct effect of these \nhormones on galectin-3 expression, suggesting that the rela-\ntionship may be indirect. Thus, further studies are needed to de-\ntermine the exact nature of the relationship of estrogen and pro-\ngesterone on galectin-3 expression.\nThe small sample size was a limitation of the present study. \nTherefore, the results of this study must be confirmed in larger \nlongitudinal population studies.\nIn summary, our data suggested that endometrial polyps may \nform through certain common pathways that do not involve \nCOX-2 and galectin-3. While COX-2 and galectin-3, in addi-\ntion to angiogenesis, are known to be involved in different steps \nof carcinogenesis,28 these two target proteins may not be involved \nin the formation of endometrial polyps. Further large scale stud-\nies comparing adjacent endometrial tissue and healthy women \nat specific phases of the menstrual cycle should be performed. \nConflicts of Interest\nNo potential conflict of interest relevant to this article was \nreported.\nREFERENCES\n1. 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